US 6,462,032 B1Grant
Cyclic regimens utilizing indoline derivatives
Issue Date:2002-10-08
•16 Claims
Abstract
This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure:
wherein R1and R2may be single substituents or fused to form spirocyclic rings, in combination with progestins, estrogens, or both. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.
Metadata
Assignees
- Wyeth
- Ligand Pharmaceuticals, Inc.
Inventors
- Gary S. Grubb
- Andrew Fensome
- Lori L. Miller
- John W. Ullrich
- Reinhold H. W. Bender
- Puwen Zhang
- Jay E. Wrobel
- James P. Edwards
- Todd K. Jones
- Christopher M. Tegley
- Lin Zhi
Application Information
Application Number:US 09/552,358
Filing Date:2000-04-19
Priority Date:1999-05-04
Art Unit:7
Classifications
IPC:
A61K 3156A61K 31535A61K 3140
Field of Search:
5141715142315514315514409514418
Patent Drawings
This patent does not have any drawings.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0003] This application claims the benefit of the priority of U.S. Provisional Patent Application No. 60/183,052, filed May 4, 1999.
FIELD OF THE INVENTION
[0004] This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
BACKGROUND OF THE INVENTION
[0005] Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
[0006] The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
[0007] A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
[0008] PR antagonists may used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. NY. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
[0009] PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
[0010] PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
[0011] PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N. Y. Acad. Sci., 761, 224, 1995).
[0012] Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A.
[0013] Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand.
[0014] Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand.
[0015] Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998).
[0016] Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998).
[0017] Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995).
[0018] Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994).
[0019] Hamann, et al, described the PR antagonist J (Ann. NY Acad. Sci., 761, 383, 1995)
[0020] Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16thInt. Cong. Het. Chem., Montana, 1997).
[0021] Kurihari, et al., described the PR ligand L (J. Antibiotics, 50, 360, 1997).
[0022] Kuhla, et al, disclosed the oxindole M as having cardiotoric activity (WO 86/03749).
[0023] Weber, teaches the oxidole N for cardiovascular indications (WO 91/06545).
[0024] Fischer, et al, describe a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516).
[0025] Singh, et al, described the PDE III inhibitor P (J. Med. Chem., 37, 248, 1994).
[0026] Andreani, et al, described the cytotoxic agent Q (Acta. Pharn. Nord., 2, 407, 1990).
[0027] Binder, et al, described structure R which is an intermediate for preparing COX II inhbitors (WO 97/13767).
[0028] Walsh described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566).
[0029] R1=F, Cl, Br, alkyl, NH2
[0030] R2=alkyl, alkoxy, F, Cl, NH2, CF3
[0031] Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545).
[0032] Bohm, et al, include the generic structure U (WO 91/04974).
[0033] JP 63112584 A contains the generic structure V:
[0034] Boar, et al, described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).
[0035] Kende, et al, described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982).
[0036] U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding.
DESCRIPTION OF THE INVENTION
[0037] This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
[0038] These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding.
[0039] The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
[0040] The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 μg to about 150 μg levonorgestrel per day, preferably equal in activity to from about 35 μg to about 100 μg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 μg to about 50 μg per day and the estrogen may be administered at a dose of from about 10 μg to about 35 μg per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
[0041] In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
[0042] The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
[0043] Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
[0044] Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 μg of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28. It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28-day cycle.
[0045] In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 μg. This may be followed as described above with an antiprogestin administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28.
[0046] Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in progestational activity to from about 35 to about 100 μg levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 μg. This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 μg. From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo.
[0047] This invention also kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated.
[0048] According to the regimens described above, one 28-day kit may comprise:
[0049] a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 μg levonorgestrel;
[0050] b) a second phase of from 1 to 11 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
[0051] c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.
[0052] A preferred embodiment of this kit may comprise:
[0053] a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 μg levonorgestrel;
[0054] b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
[0055] c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
[0056] Another 28-day cycle packaging regimen or kit of this invention comprises:
[0057] a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 μg; and
[0058] b) a second phase of from 1 to 7 daily dosage units of an antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and
[0059] c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
[0060] A preferred embodiment of the kit described above may comprise:
[0061] a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 μg; and
[0062] b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin administered at a daily dose of from about 2 to 50 mg; and
[0063] c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
[0064] A further 28-day packaged regimen or kit of this invention comprises:
[0065] a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 μg;
[0066] b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 μg; and
[0067] c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
[0068] A preferred embodiment of the package or kit just described comprises:
[0069] a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably from about 35 to about 100 μg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 μg;
[0070] b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 μg; and
[0071] c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
[0072] In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be adrninistered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art.
[0073] In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.
[0074] These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation. In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated.
[0075] Compounds of this invention which may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula 1:
[0076] wherein:
[0077] R1and R2are chosen independently from H, alkyl, substituted alkyl; OH, O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1 -propynyl; or 3-propynyl;
[0078] or R1and R2are joined to form a ring comprising one of the following: —CH2(CH2)nCH2—; —CH2CH2CMe2CH2CH2—; —O(CH2)mCH2—; O(CH2)pO; —CH2CH2OCH2CH2—; or —CH2CH2N(H or alkyl)CH2CH2—;
[0079] or R1and R2comprise a double bond to CMe2, C(cycloalkyl), O, or C(cyloether);
[0080] n is an integer from 0 to 5;
[0081] m is an integer from 1 to 4;
[0082] p is an integer from 1 to 4;
[0083] R3is selected from H, OH, NH2, C1to C6alkyl, substituted C1to C6alkyl, C3to C6alkenyl, alkynyl or substituted alkynyl, or CORA;
[0084] RAis selected from H, C1to C3alkyl, substituted C1to C3alkyl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl;
[0085] R4is selected from H, halogen, CN, NH2, C1to C6alkyl, substituted C1to C6alky, C1to C6alkoxy, substituted C1to C6alkoxy, C1to C6aminoalkyl, or substituted C1to C6aminoalkyl;
[0086] R5is selected from the groups a), b) or c):
[0087] a) R5is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
[0088] wherein:
[0089] X is selected from the group of halogen, OH, CN, C1to C3alkyl, substituted C1to C3alkyl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3thioalkyl, substituted C1to C3thioalkyl, S(O)alkyl, S(O)2alkyl, C1to C3aminoalkyl, substituted C1to C3aminoalkyl, NO2, C1to C3perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatomns, CORB, OCORB, or NRCCORB;
[0090] RBis H, C1to C3alkyl, substituted C1to C3alky, aryl, substituted aryl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl;
[0091] RCis H, C1to C3alkyl, or substituted C1to C3alkyl;
[0092] Y and Z are independently selected from H, halogen, CN, NO2, C1to C3alkoxy, C1to C3alkyl, or C1to C3thioalkyl; or
[0093] b) R5is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatomns selected from O, S, SO, SO2or NR6and containing one or two independent substituents from the group of H, halogen, CN, NO2and C1to C3alkyl, C1to C3alkoxy, C1to C3aminoalkyl, CORD, or NRECORD;
[0094] RDis H, C1to C3alkyl, substituted C1to C3alkyl, aryl, substituted aryl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl;
[0095] REis H, C1to C3alkyl, or substituted C1to C3alkyl;
[0096] R6is H, or C1to C3alkyl; or
[0097] c) R5is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO2, lower alkoxy, or CF3;
[0098] or a pharmaceutically acceptable salt thereof
[0099] A preferred set of compounds of this invention is depicted by structure 2, 2a:
[0100] wherein:
[0101] R5is a disubstituted benzene ring containing the substituents X and Y as shown below:
[0102] X is taken from the group of halogen, CN, C1to C3alkoxy, C1to C3alkyl, NO2, C1to C3perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms or C1to C3thioalkoxy;
[0103] Y is a substituent on the 4′ or 5′ position of the disubstituted benzene ring selected from the group of H, halogen, CN, NO2, C1to C3alkoxy, C1to C4alkyl, or C1to C3thioalkyl;
[0104] or a pharmaceutically acceptable salt thereof
[0105] Another preferred group of this invention comprises compounds of formulas 2 and 2a wherein R5is a five membered nrng with the structure shown below:
[0106] U is O, S, or NR6,
[0107] R6is H, or C1to C3alkyl, C1to C4CO2alkyl,
[0108] X′ is selected from the group of halogen, CN, NO2, C1to C3alkyl or C1to C3alkoxy; with a proviso that, when X′ is CN, U is not NR6;
[0109] Y′ is selected from H, F, CN, NO2or C1to C4alkyl;
[0110] or a pharmaceutically acceptable salt thereof
[0111] Another preferred group of formulas 2 and 2a are those in which R5is a six membered ring with the structure shown
[0112] wherein:
[0113] X1is N or CX2,
[0114] X2is halogen, CN or NO2;
[0115] or pharmaceutically acceptable salt thereof
[0116] The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula 1 and 2 the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
[0117] The term “alkyl” is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms; “alkenyl” is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms; “alkynyl” group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms.
[0118] The terms “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
[0119] The term “aryl” is used herein to refers to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic systerm The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl.
[0120] The term “substituted aryl” refers to aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
[0121] The term “heterocyclic” is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, but are not limited to, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
[0122] The term “substituted heterocyclic” is used herein to describe the heterocyclic just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
[0123] The term “thioalkyl” is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term “alkoxy” is used herein to refer to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term “aryloxy” is used herein to refer to the OR group, where R is aryl or substituted aryl, as defined above. The term “alkylcarbonyl” is used herein to refer to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term “alkylcarboxy” is used herein to refer to the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term “aminoalkyl” refers to both secondary and tertiary amnines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atomn The term “halogen” refers to Cl, Br, F, or I.
[0124] The anti-progestational compounds of this invention may be prepared according to the methods described below.
[0125] According to scheme 1, commercially available oxindole 5 is treated with mixture a strong organo-metallic base (e.g. butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide) in an inert solvent (e.g. THF, diethyl ether) under nitrogen at reduce temperature (ca. −20° C.) (Kende, et al, Synth. Commun., 12, 1, 1982). The resulting di-anion is then treated with excess electrophile such as an alkyl halide, preferably the iodide. If R1and R2are to be joined such as the product 6 contains a spirocycle at position 3, then the electrophile should be biftinctional, i.e. a diiodide. Subsequent bromination of 6 proceeds smoothly with bromine in acetic acid (an organic co-solvent such as dichloromethane may be added as required) in the presence of sodium acetate, to afford the aryl bromide 7. The bromide 7 is reacted with a palladium salt (e.g. tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g. THF, dimethoxyethane, ethanol, toluene) at room temperature under an inert atmosphere (argon, nitrogen). The mixture is then treated with an arylboronic acid or boronic acid ester and a base (sodium carbonate, triethylamine, potassium phosphate) in water or fluoride source (cesium fluoride) under anhydrous conditions. The required product 8 is then isolated and purified by standard means.
[0126] If R1and R2are different, then the intermediate 6 is prepared by reacting the dianion of 5 with one equivalent of the electrophile R1—X (X=leaving group e.g. I). The resultant mono-alkylated compound may be then isolated and re-subjected to the reaction conditions using R2—X, or alternatively used in-situ for the second alkylation with R2—X. Alternatively if the desired product 8 is to contain R2=H, then the isolated mono-alkylated intermediate is taken though the subsequent steps.
[0127] Other methodologies are also available for coupling the pendant aryl group, Ar, to the oxindole platform, for example reaction of compound 7 with an aryl stannane, aryl zinc, or aryl magnesium halide in the presence of a palladium or nickel catalyst (scheme 2). The required aryl-metallic species described above are formed through standard techniques.
[0128] Other ftinctionalities can easily be installed into the 3-position of the indoline platform according to scheme 3. Oxidation of the unsubstituted indoline 9, preferably under neutral or acidic conditions (e.g. selenium dioxide in dry dioxane at reflux) affords the isatin 10. Compound 10 may be further functionalized to provide a ketal 11 by treatment with an alcohol and acid catalyst under dehydrating conditions. Alternatively reaction of 10 with a second ketone under suitable conditions (piperidine in toluene at reflux; or TiCl4/Zn in THF at reflux) affords alkylidene derivatives 12. Reaction of the isatin 10 with a grignard reagent or organolithium affords tertiary alcohols 13 (R=H). These alcohols may then be further ftmctionalized by alkylation or acylation procedures.
[0129] Treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (−50 to −20° C.) with n-butyllithium and N,N,N,N′-tetramethylethylenediamine followed after a suitable period of time by a trialkylborate (trimethyl or triisopropylborate) gives after acidic work-up the boronic acid 14 (scheme 4). Compound 14 may then be reacted under palladium catalyzed conditions (tetrakis(triphenylphosphine)palladium(0), base (NaHCO3, Na2CO3, K2CO3, triethylamine, CsF) solvent (toluene/EtOH/water, THF/water, dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl bromide, aryl iodide, aryltrifluoromethane sulfonate of aryl fluorosulfonate, to provide the desired compounds 8.
[0130] An alternative strategy would be to prepare an organo zinc or magnesium reagent from compound 7 and react it in-situ with an aryl bromide, aryl iodide, aryltrifluoromethane sulfonate of arylfluorosulfonate, under palladium catalyzed conditions to afford compound 8. Such an organo zinc or magnesium species could be prepared by treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et2O) with a strong base (sodium hydride preferred, sodium hexamethyldisilazide, potassium hydride) followed by reaction at reduced temperature (−50 to −20° C.) with n-butyllithium and N,N,N′,N′-tetramethylethylenediamine followed after a suitable period of time by reaction with anhydrous zinc chloride or magnesium bromide.
[0131] The anti-progestational compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional “pro-drug” forms, which, when administered in such form, convert to the active moiety in vivo.
[0132] When the compounds and combinations herein are employed for the utilities described above, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
[0133] These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
[0134] The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
[0135] These combinations may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
[0136] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
[0137] The present invention may be further understood by the following non-limiting examples of anti-progestational compounds.
EXAMPLE 1
5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one
[0138] 5-(Bromo)-1,3-dihydro-indol-2-one.
[0139] A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g, 25.5 mmol) in CHCl3(20 cm3) was treated with bromine (2.4 g, 15.0 mmol) in CHCl3(10 cm3). After 30 min. the mixture was allowed to warm to room temperature (RT) and stirred for 1 hour. The reaction mixture was diluted with EtOAc (500 cm3) and poured into water. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solid which was used without further purification: mp. 221-223° C.; 1H NMR (DMSO-d6) δ 3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33(dd, 1H, J=8.1, 1.7 Hz), 7.37 (s, 1H), 10.49 (br s, 1H); 13C NMR (DMSO-d6) δ 36.10 (t), 111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s), 176.24 (s); MS (EI) m/z 211, 213 (M)+.
[0140] 5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenyl phosphine Pd (0) (0.273 g) were stirred under an atmosphere of nitrogen in ethylene glycol dimethyl ether (35 mL). After 15 minutes, 3-nitrophenyl boronic acid (1.70 g, 10.2 mmol) was added, followed by potassium carbonate (4.24 g, 30.7 mmol) in water (15 mL). The reaction was heated to reflux overnight, cooled to room temperature and then filtered. Saturated ammonium chloride was added. The water layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried MgSO4, filtered, and solvent removed in vacuo. Product purified by flash silica gel chromatography; eluted: 3:2 hexane; ethyl acetate, to give 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one (0.084 g, 65%), Mp=269° C.; 1H NMR (DMSO) δ 10.5 (s, 1H), 8.38-8.36 (m, 1H) 8.17-8.14 (m, 1H), 8.10-8.07 (m, 1H), 7.75-7.60 (m, 3H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s, 2H); IR (KBr) 3420, 3190, 1700 cm−1; MS (EI) m/z 253 (M−H)−; CHN calculated for C14H10N2O: C, 66.14; H, 3.96; N, 11.02; Found: C, 64.59; H, 4.16; N, 9.43.
EXAMPLE 2
3-Methyl-5-(3-nitrophenyl)-1,3-dihydroindol-2-one
[0141] 5-bromo-3-methyl-indol-2-one
[0142] Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) in acetic acid (5 cm3). was added drop wise to a solution of 3-methyl-2-indolinone (0.8749 g, 6.0 mmol) (Kende, et al, Synth. Commun., 12, 1, 1982) and sodium acetate (0.50 g, 6.0 mmol) in acetic acid (10 cm3). The reaction was stirred at room temperature for 3.5 h. Saturated sodium carbonate was added to quench the reaction. The water layer was extracted EtOAc (×3), dried (MgSO4), filtered, and evaporated to give the title compound (1.26 g, 93%), Mp=119-120° C.; 1H NMR (DMSO) δ 1.32 (d, 3H, J=7.66 Hz), 3.45 (q, 1H, J=7.62 Hz), 6.77 (d, 1H, J=8.23 Hz), 7.46 (s, 1H), 7.36-7.33 (m, 1H), 10.4 (s, 1H); IR (KBr) 3200, 1725 cm−1; MS (EI) m/z 224/226 (M−H)−; CHN calculated for C9H8BrNO: C, 47.82; H, 3.57; N, 6.20; Found: C, 47.44; H, 3.42; N, 6.04.
[0143] 5-Bromo-3-methyl-1,3-dihydro-indol-2-one (0.50 g, 2.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (18 cm3). After 15 min., 3-nitrophenyl boronic acid (0.74 g, 4.45 mmol) was added, followed by potassium carbonate (1.86 g, 13.5 mmol) in water (7 cm3). The reaction was heated to reflux for 8 h and then stirred at room temperature overnight. Saturated ammonium chloride was added; and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:2), eluted: 2:1 hexane; ethyl acetate, to give the title compound (0.30 g, 47%), mp 200-203° C.; 1H NMR (DMSO-d6) δ 1.41 (d, 3 H, J=7.61 Hz), 3.50 (q, 1H, J=7.60 Hz), 6.96 (d, 1H, J=8.08 Hz), 7.62 (d, 1H, J=8.06 Hz), 7.75-7.70 (m, 2H), 8.18-8.10 (m, 2H), 8.41-8.39 (m, 1H), 10.5 (s, 1H); IR (KBr) 3450, 1700 cm−1; MS (EI) m/z 267 (M−H); CHN calculated for C15H12N2O3+0.2C4H8O2: C, 66.61; H, 4.46; N, 9.83; Found: C, 66.26; H, 4.59; N, 10.06.
EXAMPLE 3
5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one
[0144] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one
[0145] 3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmnol) and sodium acetate (0.33 g, 4.07 mmol) were stirred in acetic acid (5 cm3) then bromine (0.66 g, 4.13 mmol) in acetic acid (5 cm3) was added drop-wise to the reaction mnixture. The reaction was stirred for 50 min., and then poured into water. The mixture was basified with sodium carbonate and then extracted with ethyl acetate (×3), dried (MgSO4), filtered, and evaporated to the title compound (0.89 g, 92%) 1H NMR (DMSO-d6) δ 1.21 (s, 6H), 6.76 (d, 1H, J=8.22 Hz), 7.29 (dd, 1H, J=2.12 Hz, 8.23 Hz), 7.49 (d, 1H, J=2.03 Hz), 10.4 (s, 1H).
[0146] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.094 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (12 cm3). After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) was added, followed by potassium carbonate (1.15 g, 8.34 mmol) in water (5 cm3). The reaction was heated to reflux for 5 hours, and then cooled to room temperature. Saturated aqueous ammonium chloride and EtOAc were added and the mixture was filtered. The aqueous layer was extracted with EtOAc (×2), and the combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:3) to afford the title compound (0.1 g, 31%), mp=157-158° C.; 1H NMR (DMSO-d6) δ 3.34 (s, 6H), 3.82 (s, 3H), 6.87-6.93 (m, 2H), 7.20-7.15 (m, 2H), 7.37-7.32 (m, 1H), 7.49-7.46 (m, 1H), 7.63 (d, 1H, J=1.14 Hz), 10.4 (s, 1H); MS (EI) m/z 266 (M−H)−; CHN calculated for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C, 76.02; H, 6.49; N, 5.02.
EXAMPLE 4
5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one
[0147] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07 mol) and tetrakis(triphenylphosphine)palladium(0) (0.239 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (35 cm3). After 15 min., 3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added, followed by potassium carbonate (3.40 g, 45 mmol) in water (15 cm3). The reaction was heated to reflux for 2 hours and then stirred at room temperature overnight. The mixture was diluted with sat. ammonium chloride and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane, 1:3) to afford the title compound (0.284 g, 25%): mp 188-189° C.; 1H NMR (DMSO-d6) δ 3.34 (s, 6H), 6.93 (d, 1H, J=8.04 Hz), 7.38-7.35 (m, 1H), 7.53-7.43 (m, 2H), 7.61 (d, 1H, J=7.68 Hz), 7.70 (s, 2H), 10.40 (s, 1H); IR (KBr) 3420, 3150, 3050, 1700 cm−1; MS (EI) m/z 270 (M−H)−; CHN calculated for C16H14ClNO+0.1C4H8O2: C, 70.21; H, 5.32; N, 4.99; Found: C, 70.3; H, 5.44; N, 4.93.
EXAMPLE 5
3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one
[0148] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (1.02 g, 4.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.244 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (35 cm3). After 15 minutes, 3-nitrophenylboronic acid (1.43 g, 2.56 mmol) was added, followed by potassium carbonate (3.54 g, 2.56 mmol) in water (15 cm3). The reaction was heated to reflux for 2 hours and then stirred at room temperature overnight. Saturated ammonium chloride and EtOAc were added and the nixture was filtered. The aqueous layer was extracted with ethyl acetate (×2), and then the combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford the title compound (0.86 g, 67%) mp 234-235° C.; 1H NMR (DMSO-d6) δ 3.33 (s, 6H), 6.98 (d, 1H, J=8.06 Hz), 7.61 (dd, 1H, J=1.85, 8.03 Hz), 7.73 (t, 1H, J=7.98 Hz), 7.81 (d, 1H, J=1.63 Hz), 8.11-8.18 (m, 2H), 8.42-8.43 (m, 1H), 10.5 (s, 1H); MS (EI) m/z 281; CHN calculated for C16H14N2O3.0.2H2O: C, 67.51; H, 4.92; N, 9.37; Found: C, 67.48; H, 5.17; N, 9.48.
EXAMPLE 6
5-(3Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one
[0149] 3-Ethyl-indol-2-one
[0150] A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) under N2was cooled to −25° C. and treated drop wise with n-butyl lithium (2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min. iodoethane (48 ml, 0.6 mol) was added and the reaction mixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into aqueous NH4Cl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the crude product (24.5 g, 51%). A sample (3 g) was recrystallized from EtOAc/hexane to obtain the title compound (1.4 g), m.p. 100-101° C.; 1H-NMR (DMSO-d6) δ 0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69,0.45 Hz), 6.93 (dt, 1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1H), 10.3 (s, 1H); MS (ESI) m/z 270 [M+H].
[0151] 5-Bromo-3-ethyloxindole
[0152] A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, and brine, dried (MgSO4) and evaporated to afford the crude product (9.2 g, 96%). A sample was recrystallized from EtOAc/hexane to obtain the title compound, m.p. 130-132° C.; 1H-NMR (DMSO-d6) δ 0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43 (s, 1H); MS (−ESI) m/z 238/240 (M−H).
[0153] A solution of 5-bromo-3-ethyl-oxindole (3.5 g, 14.6 mmol), 3-chlorophenylboronic acid (2.4 g, 15 mmol), potassium carbonate (4.5 g, 33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.87 g, 0.75 mmol) in dimethoxyethane (160 ml), ethanol (40 ml), and water (40 ml) was heated to reflux to 6 hours. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:3) to afford the title compound (0.46 g, 12%), imp. 118-120° C., 1H-NMR (DMSO-d6) δ 0.78 (t, 3H, J=7.25 Hz) 1.8-2.02 (m, 2H), 3.47 (t, 1H, J=5.71 Hz), 6.89 (d, 3H, J=8.1 Hz), 7.35 (m, 1H), 7.44 (t, 1H, J=7.91 Hz), 7.51 (m, 1H), 7.58 (m, 2H), 7.67 (t, 1H, J=1.76 Hz), 10.5 (s, 1H); MS (−ESI) m/z 270 (M−H).
EXAMPLE 7
5-(3-Chloro-phenyl)-3,3diethyl-1,3-dihydro-indol-2-one
[0154] A solution of 3-ethylindol-2-one (16 g, 0.1 mol) in dry THF (200 ml) under N2was cooled to −25° C. and treated drop wise with n-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resulting solution was added N,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2 mol). After 30 min. iodoethane (8 ml, 0.1 mol) was added and the reaction rnixture was allowed to warm to RT and stirred over night. The reaction mixture was poured into an aqueous HCl solution, extracted with EtOAc (2×) and the combined organic layers were washed with dil. HCl, water, brine, dried (MgSO4) and concentrated. The residual oil was triturated with hexane to afford the title product (9 g, 45%), mp. 156-159° C. 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 7.70-7.69 (t, 1H), 7.62-7.59 (m, 1H), 7.58 (d, 1H J=1.7 Hz), 7.53-7.50 (m, 1H), 7.45-7.41 (t, 1H), 7.36-7.35 (m, 1H), 7.34-7.33 (m, 1H), 6.91-6.89 (d, 1H J=8.2 Hz), 1.87-1.80 (m, 2H), 1.77-1.70 (m, 2H), 0.54-0.50 (t, 6H); MS (+ESI) m/z 190 (M+H).
[0155] 5-Bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one
[0156] A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in aceticacid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, then brine, dried (MgSO4) and evaporated to afford the crude product (7.6 g, 75%). A sample was recrystallized from EtOAc/hexane to obtain the title compound, m.p. 164-165° C.; 1H-NMR (DMSO-d6) δ 10.45 (s, 1H), 7.41-7.40(d, 1H, J=2.2 Hz), 7.34-7.31 (m, 1H), 6.78-6.76 (d, 1H J=8.2 Hz), 1.78-1.65 (t, 4H), 0.50-0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).
[0157] A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one (2.7 g, 10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:3) to afford the title compound (0.8 g, 27%), m.p. 195-197° C.; 1H-NMR (DMSO-d6) δ 7.70 (t, 1H, J=2 Hz), 7.62-7.60 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.52, (dd, 1H, J=8.1, 2 Hz), 7.43 (t, 1H, 7.9 Hz), 7.36-7.33 (m, 1H), 6.90 (d, 1H, J=8.1 Hz), 1.87-1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+APCI) m/z 300/302 (M−H).
EXAMPLE 8
5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one
[0158] A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm3) under N2was cooled to 0° C. and treated drop-wise with methyl magnesium bromide (3M in diethylether, 14.7 cm3, 44 mmol) and the mixture was allowed to warm up-to room temperature. The reaction was poured into sat. ammoniurn chloride solution, then extracted into EtOAc (×3). The combined organic layers were then washed with water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol, 29%): 1H NMR (DMSO-d6) δ 1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7 Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)−.
[0159] 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.0 g, 4.1 mmol) was dissolved in dry DMF (15 cm3) cooled to 0° C. and treated with potassium tert-butoxide (1M in THF, 4.5 cm3, 4.5 mmol). After 15 min. methyl-p-toluenesulfonate (0.93 g, 5 mmol) was added and the mixture was allowed to warm up-to room temperature. After 2 h the mixture was poured into saturated ammonium chloride solution and extracted with EtOAc (×2), then the combined organic layers were washed with water, sodium hydroxide (1N, ×2), water (×3), dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.56 g, 2.2 mmol, 53%): 1H NMR (CDCl3) δ 1.59 (s, 3H), 3.18 (s, 3H), 6.73 (d, 1H, J=8.2 Hz), 7.45 (dd, 1H, J=8.2, 2 Hz), 7.52 (d, 1H, J=2 Hz); MS (EI) m/z 225 (M)+.
[0160] A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) was dissolved in dimmethoxyethane (22 cm3). After 15 min., 3-chlorophenylbororic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0 g) in water (10 cm3) was added and the reaction was heated under reflux. After 2 h the mixture was cooled, poured into water and extracted with EtOAc (×2), the combined organic extracts were washed with sodium hydroxide solution (1N, ×2) water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc: hexane, 5:1) to afford 5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g, 0.58 mmol, 29%): 1H NMR (CDCl3) δ 1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s, 3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H), 7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)+.
EXAMPLE 9
5-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one
[0161] To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100 cm3) at −10° C. under a nitrogen atmosphere was added 1-propynylmagnesium bromide (0.5 M in THF, 47 cm3, 23.5 mmol). After 1 h, the mixture was poured into saturated ammonium chloride and extracted with EtOAc (×3), washed with brine, dried (MgSO4) and evaporated to afford 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g, 10.6 mmol, 97%) which was used without further purification: (CDCl3) δ 1.83 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H), 10.59 (s, 1H); MS ((−) ESI) m/z 264 (M−H)−.
[0162] To a solution of 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (1.0 g, 3.75 mmol) in dry DMF (15 cm3) at 0° C., was added potassium tert-butoxide (1M in THF, 4.1 cm3, 4.1 mmol). After 15 min. methyl p-toluenesulfonate (0.85 g, 4.6 mmol) was added and the mixture was allowed to warm up to room temperature. After 16 h the mixture was poured into saturated ammonium chloride, extracted with EtOAc (×3), washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:3) to afford 5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.62 g, 2.21 mmol, 59%): (CDCl3) δ inter alia 1.87 (s, 3H), 3.19 (s, 3H), 3.35 (s, 1H), 6.72 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=8.3, 2 Hz), 7.63 (d, 1H, J=2 Hz): MS (EI) m/z 279 (M)+.
[0163] 5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) were stirred at room temperature in dimethoxyethane (22 cm3). After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate (1.06 g, 10 mrrol) in water (11 cm3) were added and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were washed with sodium hydroxide (1N, ×2), brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc: hexane, gradient elution) and the product triturated with hexane to afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid: mp. >190° C. (decomp.); (CDCl3) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d, 1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54-7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).
EXAMPLE 10
5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one
[0164] A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) and tetrakis(triphenylphosphine) palladium (0.14 g, 0.12 mnmol) in dimethoxyethane (10 cm3) was stirred under N2for 20 mm. To this mixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol) and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm3). The solution was brought to refiux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate: hexane 1:3) to afford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p. 169-171° C. 1H NMR (THF-d8) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25 (d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5 (br s, 1H); 13C NMR (THF-d8) δ 36.39 (t), 109.80, 123.97, 125.55, 127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s); MS (EI) m/z 243, 245 (M)+; Anal. (C14H10ClNO) C, H, N.
EXAMPLE 11
5′-(3-Chlorophenyl)spiro[1,3-dioxolane-2,3′-3H indol]-2′(1′H)-one
[0165] 5-[3-Chloro-phenyl]-1H-indole-2,3-dione
[0166] A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0 g, 41 mmol) in dioxane (200 cm3) and SeO2(22.8 g, 205 mmol) was brought to reflux for 2 h then cooled to RT and concentrated onto Florisil. The Florisil was washed (acetone:CHCl31:9) and the combined organic extracts were evaporated. The residue was purified by column chromatography (SiO2, acetone:CHCl31:8) to afford the title compound (8 g, 31 mmol, 76%) as a tan solid: mnp. 256-258° C. 1H NMR (THF-d8) δ 6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd, J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz, 1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); 13C NMR (DMSO-d6) δ 113.30 (d), 119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47 (s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256 (M−H)+; Anal. (C14H8ClNO2-0.1 H2O) C, H, N.
[0167] A solution of the 5-[3-chloro-phenyl]-1H-indole-2,3-dione (0.5 g, 1.9 mmol) in toluene (30 cm3) and ethylene glycol (1.1 cm3, 19.4 mmol) and pTsOH (0.04 g, 0.2 mmol) was brought to reflux with azeotropic removal of water for 12 h then cooled to RT. The reaction mixture was diluted with EtOAc (100 cm3) and washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give an oily residue. The residue was purified by colurn chromatography (SiO2, CH2Cl2) to afford the title compound (0.47 g, 1.6 mmol, 80%) as a tan solid: m.p. 159-161° C.; 1H NMR (DMSO-d6) δ 4.29-4.39 (M, 4H), 6.93 (d, J=8.6 Hz, 1H), 7.4 (d, J=8.1 Hz, 1H), 7.46 (dd, J=7.9, 7.9 Hz, 1H), 7.7 (d, J=7.7 Hz, 1H), 7.68-7.71 (m, 3H), 10.55 (s, 1H); 13C NMR (DMSO-d6) δ 65.53 (t), 110.89, 123.25, 124.81 (d), 125.65 (s), 125.83, 126.79, 130.09, 130.61 (d), 132.96, 133.64, 141.53, 14267, 174.36 (s); MS (EI) m/z 301/303 (M)+; Anal. (C16H12ClNO3) C, H, N.
EXAMPLE 12
5′-(3-Chlorophenyl)spiro[1,3-dioxane-2,3′-[3H]indol]-2′(1′H)-one
[0168] The title compound was prepared according to the procedure for example 11: m.p. 242-244° C.; 1H NMR (DMSO-d6) δ 1.7 (m, 1H), 2.2 (m, 1H), 3.95 (m, 2H), 4.78 (t, 2H), 6.9 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.46 (dd, J=7.9, 7.9 Hz, 1H), 7.59-7.68 (m, 3H), 10.59 (br s, H); 13C NMR (DMSO-d6) δ 25.19, 60.68 (t), 93.58(s), 110.94, 122.93, 125.29, 126.29, 127.19(d), 128.65(s), 129.92, 131.07 (d), 133.16, 134.08, 141.61, 142.15, 173.29 (s); MS (EI) m/z 315/317 (M)+; Anal. (C17H14ClNO3) C, H, N.
EXAMPLE 13
5′-(3-Nitrophenyl)spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0169] Spirol[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0170] To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N′,N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), then the combined organic layers were washed with dil. HCl (pH 1), water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:4) to afford the title compound (1.4 g, 7.5 nmnol, 50%) as a tan solid: 1H NMR (CDCl3) δ 1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J7.5, 1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).
[0171] 5-Bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0172] A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm3) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the title compound (0.37 g, 1.47 mmol, 96%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).
[0173] A solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.3 g, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) in dimethoxyethane (8 cm3) was stirred under N2for 20 mn. To this mixture was then added 3-nitrophenylboronic acid (0.23 g, 1.4 mmol) and sodium carbonate (0.36 g, 3.4 mmol) in water (3 cm3). The solution was brought to reflux for 3 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate: hexane 1:3) to afford the title compound (0.21 g, 0.68 mmol, 62%) as a yellow solid: m.p. 238-240° C.; 1H NMR (DMSO-d6) δ 1.89-1.99 (m, 8H), 6.96 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.0, 8.0 Hz, 1H), 8.13 (dd, J=7.0, 1.0 Hz, 2H), 8.4 (d, J=1.8 Hz, 1H), 10.42 (br s, 1H); 13C NMR (dioxane-d8) δ 26.31, 38.13 (t), 53.85 (s), 108.9, 121.15, 121.33, 126.23, 129.38, 132.11 (d), 132.6, 138.32, 141.84, 142.74, 149.14, 182.68 (s); MS (EI) m/z 308 (M)+.
EXAMPLE 14
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde
[0174] Spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one
[0175] A solution of oxindole (25 g, 0.19 mol) in anhydrous tetrahydrofuran (800 cm3) was cooled to −20° C., then n-butyllithium (2.5M in hexanes, 152 cm3, 0.38 mol) was added slowly followed by N,N,N′,N′-tetramethylethylenediamine (51 cm3, 0.38 mol,). After 15 min. 1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 h. saturated aqueous ammonium chloride solution (1L) and EtOAc (1L) were added. After 15 min. the layers were separated and the aqueous phase was extracted EtOAc (×2). The combined organic layers were extracted with hydrochloric acid (1N), then washed with brine (500 cm3), dried (MgSO4), and concentrated to obtain an oil. The oil was triturated with hexane (200 cm3) and benzene (20 cm3). The precipitate was collected and dried in vacuo to obtain the title compound (26.3 g, 69.6%) as colorless crystals: mp 110-114° C.; 1H NMR (DMSO-d6) δ 1.67 (m, 10H), 6.84 (d, 1H, J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8 Hz), 10.3 (S, 1H).
[0176] 5′-Bromospiro[cyclohexane-13′-[3H]indol]-2′(1′H)-one
[0177] To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′ (1H)-one (17.6 g, 0.09 mol) in acetic acid (300 cm3) was added sodium acetate (8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30 min. at room temperature, the reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with water, dried (MgSO4) and evaporated and the residue was triturated with hexane. The precipitate was collected, and dried in vacuo to obtain the title compound (16.5 g, 67%) as off-white crystals: mp 196-199° C.; 1H NMR (DMSO-d6) δ 1.62 (mn, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd, 1H, J=8.2, 1.8 Hz), 10.44 (S, 1H).
[0178] To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.00 g, 3.57 mmol) in dimethoxyethane (20 cm3) was added tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) under nitrogen. After 15 min. 3-formylphenylboronic acid (1.00 g, 6.93 g) was added followed by potassium carbonate (2.90 g, 21 mmol) in water (10 cm3). After 20 h at reflux, the mixture was cooled poured into water and extracted with EtOAc (×3). The combined organic extract was washed with sat. brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, 1H NMR (CDCl3) δ 1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz), 7.48 (dd, 1Hz), J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz), 7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI) m/z 306 (M+H)+.
EXAMPLE 15
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde
[0179] To a solution of 3-(1′,2′-dihydro-2′-oxospirocyclohexane-1,3′-[3H]indol-5′-yl) benzaldehyde (0.59 g, 1.95 mmol) in EtOH: H2O (10 cm3, 8:2) was added hydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20 g, 2.5 mmol). After 20 min. the mixture was concentrated water was added and extracted with EtOAc (×2). The combined organic layers were washed with sat. sodium hydrogen carbonate solution, water, sat. brine, dried (MgSO4) and evaporated to afford the title oxime (0.63 g, 1.95 mmol, 100%) which was used without further purification, 1H NMR (CDCl3) δ 1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J=8 Hz), 7.36 (dd, 1H, J=8, 2 Hz), 7.43-7.50 (m, 1H), 7.57-7.67 (m, 2H), 7.85 (s, 1H, br), 8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((−)ESI) m/z 319 (M−H).
EXAMPLE 16
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde
[0180] To a solution of 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol-5′-yl) benzaldehyde(0.24 g, 0.79 mmol), and sodium acetate (0.083 g, 1.00 mmol) in EtOH: water (5 cm3, 8:2) was added methoxylamiine hydrochloride (0.083 g, 1.00 water (8:2, ×2), to afford the title compound (0.027 g, 0.08 mmol, 10%) as a white solid: mp) 198-200 (decomp.): 1.58-2.07 (m, 10H), 4.00 (s, 3H), 6.98 (d, 1H, J=8 Hz), 7.42-7.49 (m, 2H), 7.53-7.58 (m, 2H), 7.64 (d, 1H, J=2 Hz), 7.75 (s, 1H), 8.07 (s, 1H, br), 8.15 (s, 1H); MS ((+)-ESI) m/z 335 (M+H)+.
EXAMPLE 17
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)pyridine
[0181] A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26 mmol), hexamethylditin (5.00 g, 15.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) in anhydrous dimethoxyethane (30 cm3) under N2was heated under reflux. After 16 h the mixture was concentrated and purified by column chromatography (SiO2, EtOAc: hexane 5:95) to afford 3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%): 1H NMR (CDCl3) δ 0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z 269 (M+H)+.
[0182] A solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.97 g, 7.05 mmol), 3-cyanopyridine-5-trimethylstannane (2.26 g, 8.46 mmol), bis(triphenylphosphine)palladium(II)chloride (0.33 g, 0.47 mmol) and lithium chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm3) was heated under reflux. After 16 h the mixture was cooled, partitioned between EtOAc and water, the aqueous layer was re-extracted with EtOAc (×2), the combined organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc: hexane, 1:2) and then further purified by preparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN: H2O 1:1, 100 cm3/min., RT 7.92 min.) to afford the title compound as white crystals (0.56 g, 1.84 mmol, 26%): mp. 232-234° C. 1H NMR (CDCl3) δ 1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8 Hz), 7.49 (dd, 1H, J=8, 2 Hz), 7.66 (d, 1H, 2 Hz), 8.15 (t, 1H, J=2 Hz), 8.39 (s, 1H, br), 8.89 (d, 1H, J=2 Hz), 9.06 (d, 1H, J=2 Hz); MS ((+)-ESI) m/z 304 (M+H)+; Anal. C19H17N3O CHN.
EXAMPLE 18
5′-(Pyrimidin-5-yl)-spiro[cyclohexane]-1,3′-3H]indol-2′(1H)-one
[0183] To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)-one (11 g, 0.04 mol) in dry tetrahydrofuran (200 cm3) was added sodium hydride (60% dispersion in mineral oil, 1.6 g, 0.04 mol). After 30 min. stirring at room temperature, the mixture was cooled to −78° C. and butyl lithium (1.7M in hexanes, 23.2 cm3, 0.04 mol) was added slowly. After 30 min. di-iso-propylborate (25 cm3, 0.11 mol) was added and the mixture was allowed to warm to room temperature. After 2 hrs. hydrochloric acid (1N, 500 cm3) and ethy,lacetate (500 cm3) was added. The aqueous phase was extracted with ethylacetate, then the combined organic layers were washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with hexane and the precipitate dried in vacuo to obtain (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid (8.3 g, 86%) as an off-white solid that was used without further purification. A sample that was further triturated with ethyl acetate had the following properties: m.p. 255-260° C. dec.; 1H NMR (DMSO-d6) δ 1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72 Hz) 7.66 (d, 1H. J=7.72 Hz) 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((−)ESI) m/z 244 [M−H].
[0184] A stirred mixture of 5-bromopyrimidine (3.2 g, 20 mmol) in toluene (20 cm3), 2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5-′-yl) boronic acid (0.49 g, 2.2 mmol) in ethanol (10 cm3), potassium carbonate (0.28 g, 2.0 mmol) in water (10 cm3) and tetrakis (triphenylphosphine)palladium (0) (0.15 g, 0.13 mol) was heated overnight under reflux and in an atmosphere of nitrogen. The reaction mixture was treated with 20 mL of sodium bicarbonate solution and was then extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with saturated brine, dried (MgSO4). Recrystallization from ethanol gave 0.13 g of pure product, mp 227-228 ° C. IR (KBr) 1700 cm−1 1H-NMR (DMSO-d6) δ 10.48 (s, 1H), 9.13 (s, 1H), 9.11 (s, 2H), 7.86 (s, 1H) 7.63 (dd, 1H; J=1.5Hz and 8.1 Hz), 6.98 (d, 1H J=8.1 Hz), 6.98 (d, 1H, J=8.1) 1.75 (m, 10). MS (ESI) m/z 278 (M−H). CHN Calcd for C17H17N3O, 0.25.H2O
EXAMPLE 19
5-(3-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0185] Prepared according to the procedure for example 14: mp. 164-165° C., 1H NMR (CDCl3) δ 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1 Hz, 1H), 7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H); 13C-NMR (CDCl3) δ 20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94, 124.06, 125.50, 125.79, 125.97, 126.38, 128.96 (d), 132.88, 133.59, 135.60, 139.14, 142.17, 182.89 (s); MS (EI) m/z 310, 312 (M−H)+; Anal. (C19H18ClNO) C, H, N.
EXAMPLE 20
5′-(3-Chloro4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0186] Prepared according to the procedure for example 18: mp 188-189° C.; 1H-NMR (CDCl3) δ 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.41-7.34 (m, 2H), 7.20 (t, 1H, J=8.7 Hz), 9.96 (d, 1H, J=8.1 Hz), 2.04-1.65 (m, 10H); MS ((+)APCI) m/z 330 [M+H]+.
EXAMPLE 21
5′-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0187] Prepared according to the procedure for example 18: mp 171-172° C.; 1H-NMR:(CDCl3) δ 8.43 (s, 1H), 7.62 (d, 1H, J=1.8 Hz), 7.42 (dt, 1H, J=6.2, 2.0 Hz), 7.39-7.37 (m, 1H), 7.33 (dt, 1H, J=5.1, 1.3 Hz), 7.26 (dq, 1H, J=5.9, 2.1 Hz), 7.05-6.99 (m, 2H), 2.03-1.64 (m, 10H); MS ((+)APCI) m/z 296 [M+H]+.
EXAMPLE 22
5′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one 3H]indol]-2′(1′H)-one
[0188] Prepared according to the procedure for example 18: mp 180-183° C.; 1H-NMR (CDCl3) δ 8.35 (s, 1H), 7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H, J=6.2, 2.0 Hz), 7.10-7.03 (m, 2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H, J=4.3, 2.3 Hz), 2.05-1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H]+.
EXAMPLE 23
5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0189] Prepared according to the procedure for example 14: m.p. 187-189° C.; 1H-NMR (DMSO-d6) δ 1.5-2.0 (m, 10H), 6.9 (d, J=8.13 Hz, 1H), 7.40-7.51 (m, 3H), 7.66-7.76 (m, 2H), 10.4 (s, 1H); MS (−ESI) m/z 312 (M−H)−.
EXAMPLE 24
5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]indol]-2(1H)-one
[0190] Prepared according to the procedure for example 18: 1H NMR (CDCl3) δ 1.62-2.06 (m, 10H), 2.54 (s, 3H), 6.96 (d, J=8.0 Hz, 1H), 7.2-7.5 (m, 5H), 7.62 (s, 1H), 7.75 (s, 1H); 13C NMR (DMSO-d6) δ 16.37 (q), 21.62, 25.58, 33.37 (t), 48.67 (s), 110.55, 123.56, 124.36, 125.68, 126.94, 129.64 (d), 135.31, 136.91, 139.33, 140.27, 142.49, 184.29 (s); MS (EI) m/z 324 (M+H)+; Anal. (C20H21NOS-(0.1 H2O)) C, H, N.
EXAMPLE 25
5′-[3-(Methylsulfonylphenyl]spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0191] A solution of 5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]indol]-2(1H)-one (0.15 g, 0.46 mmol) in methanol (6 cm3) was treated with NaIO4(0.11 g, 0.51 mmol). The reaction was allowed to stir at RT overnight. The methanol was evaporated and the residue taken up in EtOAc (50 cm3) and H2O. The EtOAc layer was washed with brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2:methanol, 8:2) to afford the title compound (0.11 g, 0.32 mmol, 70%) as a white solid: m.p. 190-191° C. 1H NMR (CDCl3) δ 1.65-2.05 (m, 10H), 2.80 (s, 3H), 7.02 (dd, J=8.0, 3.1 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.52-7.75 (m, 4H), 7.0 (s, 1H), 8.7 (s, 1H); 13C NMR (DMSO-d6) δ 21.59, 25.54, 33.44 (t), 44.38 (q), 48.46 (s), 110.53, 12.05, 123.31, 127.08, 129.94, 130.15 (d), 134.17, 137.2, 140.73, 143.27, 146.61, 183.71 (s); MS (EI) m/z 339 (M)+; Anal. (C20H21NO2S-(0.2H2O)) C, H, N.
EXAMPLE 26
5-[3-(Methylsulfonyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]
[0192] A solution of the 5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]-indol]-2(1H)-one (0.15 g, 0.46 mmol) in CH2Cl2(2 cm3) was added to a solution of mCPBA (0.4 g, 2.3 mmol) in CH2Cl2(5 cm3) at RT. The reaction was allowed to stir overnight. The mixture was diluted with CH2Cl2(5 cm3) and washed with saturated bicarbonate solution, water, brine, dried (MgSO4), and evaporated. The residue was crystallized (Hexane-EtOAc) to afford the title compound (0.132 g, 0.8 mmol, 80%) as an off white solid: m.p. 240° C.; 1H NMR (CDCl3) δ 1.55-2.1 (m, 10H), 3.15 (s, 3H), 7.01 (d, J=8.1 Hz, 1H), 7.47 (dd, J=8.1, 1.5 Hz, 1H), 7.6-7.7 (m, 2H), 7.82-7.97 (m, 3H), 8.12 (s, 1H); 13C NMR (DMSO-d6) δ 21.54, 25.50, 33.45 (t), 44.97 (q), 48.44 (s), 110.60, 123.28, 125.92, 127.20, 128.52, 130.31 (d), 132.46, 133.65, 137.34, 140.70, 141.53, 143.25, 183.63 (s); MS (EI) m/z 356 (M+H)+; Anal. (C20H21NO3S-(0.2 H2O)) C, H, N.
EXAMPLE 27
5′-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0193] Prepared according to the procedure for example 18: mp 178-180° C.; 1H-NMR (CDCl3) δ 8.50 (s, 1H), 7.57 (d, 1H, J=1.8 Hz), 7.39 (dd, 1H, J=6.2, 1.9 Hz), 7.33-7.32 (m, 1H), 7.15 (dq, 1H, J=5.7, 1.7, 0.7 Hz), 7.06 (dq, 1H, J=4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 2.05-1.64 (m, 10H); MS ((−)ESI) [M−H]− @ m/z 328.
EXAMPLE 28
5-(3-Bromo-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1′H)-one
[0194] Prepared according to the procedure for example 18: mp. 194-196° C.; 1H NMR (CDCl3) δ 1.66-2.04 (m, 10H), 7.00 (d, 1H, J=8.0 Hz), 7.17-7.28 (m, 2H), 7.41 (dd, 1H, J=8, 1.8 Hz), 7.49 (t, 1H, J=1.4 Hz), 7.58 (d, 1H, J=1.5 Hz) and 8.24 (s, 1H, br); MS ((+)-EI) m/z 373/375 [M+].
EXAMPLE 29
5′-(3-Fluoro-5-methylphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0195] 5′-(3-Fluoro-5-methylphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H-one
[0196] A solution of 3-fluoro-5-methoxybenzene trifluoromethanesulfonate (1.6 g, 5.8 mmol) and tetrakis-(triphenylphosphene)-palladium(0) (0.33 g, 286 mmol) in dimethoxyethane (50 mL) was stirred under N2for 20 minutes. To this mixture was then added lithium bromide (1.5 g, 172 mmol). This solution was stirred under N2for 10 minutes. To this mixture was then added (2′-oxo-2, 3-dihydrospiro[cyclohexan-1,3′-[3H]-indol]-5′-yl) boronic acid (1.3 g, 5.7 mmol) and sodium carbonate (1.2 g, 11.5 mmol) in distilled water (5 mL). The solution was brought to reflux for 6 hours, cooled to room temperature, poured into distilled water and extracted with EtOAc (×3). The combined organic extracts were washed with 2N NaOH, water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:Hexane 2:5) to afford the title compound (0.6 g, 32%) as an off-white solid: mp 180-182° C.; 1H-NMR (CDCl3) δ 8.21 (s, 1H), 7.60 (d, 1H, J=1.8 Hz), 7.41 (dd, 1H, J=6.2, 1.9 Hz), 6.97 (d, 1H, J=7.9 Hz), 6.88-6.86 (m, 1H), 6.84 (t, 1H, J=1.8 Hz), 6.59 (dt, 1H, J=6.2, 2.2 Hz), 3.86 (s, 3H), 2.00-1.62 (m, 10H); MS ((−ESI) [M−H]− @ (m/z 324.
EXAMPLE 30
5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol-2′(1′H)-one
[0197] Prepared according to the procedure for example 14: mp. 196-198° C. 1H NMR (CDCl3) δ 1.67-1.81 (m, 6H), 1.82-2.05 (m, 4H), 7.04 (d, 1H, J=8 Hz), 7.48 (dd, 1H, J=8 and 1 Hz), 7.59 (d, 1H, J=8 Hz), 7.63-7.65 (m, 1H), 7.87-7.90 (m, 1H), 8.16-8.20 (m, 1H), 8.38 (s, br, 1H), 8.41 (t, 1H, J=2 Hz); MS ((−)ESI) m/z 321 (M−H)−. Anal. (C19H18N2O3) CHN.
EXAMPLE 31
3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)aniline
[0198] A solution of 5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1H)-one (3.6 g, 11 mmol) in methanol (150 ml) was shaken with 10% palladium on charcoal (1 g) under a hydrogen atmosphere at 40 psi. The catalyst was filtered off and the solution was concentrated to obtain a residue. The residue was dissolved in ether and ethanolic hydrochloric acid was added. The solid thus obtained was recrystallized from methanol/ether to obtain the title compound (1.7 g, 47%): mp. 275-278° C; 1H-NMR (DMSO-d6) δ 1.5-2.0 (m, 10H), 6.98 (d, J=8.05 Hz, 1H), 7.26 (d, J=7.90 Hz, 1H), 7.45-7.62 (m, 4H), 7.67 (d, J=8.3 Hz, 1H), 9.0-11.0 (s, 2H, br), 10.5 (s, 1H), MS ((+)APC1) m/z 293 (M+H).
EXAMPLE 32
5-(3-Fluoro-5-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)one
[0199] Prepared according to the procedure for example 18: mp. 191-193° C.; 1H NMR (CDCl3) δ 1.66-2.07 (m, 10H), 7.07 (d, 1H, J=8 Hz), 7.49 (dd, 1H, J=8, 1.8 Hz), 7.59-7.64 (m, 2H), 7.89 (dt, 1H, J=8.1, 2.1 Hz), 8.25 (s, 1H) and 8.54 (s, 1H); MS ((+)-APCI) m/z 341 [M+H]+.
EXAMPLE 33
5′-(3-Hydroxyphenyl)spiro[cyclohexane-1,3′-3H]indol]-2′(1′H)-one
[0200] Prepared according to the procedure for exarnple 18: mp. 213-216° C.; 1H NMR (CDCl3) δ 1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H, J=8 Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8 Hz), 7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)-APCI) m/z 294 [M+H]+.
EXAMPLE 34
4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitirile
[0201] 3-(Trimethylstannyl)-2-thiophenecarbonitrile
[0202] A solution of the 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.53 g, 1.9 mmol), dichlorobis(triphenylphosphine) palladium(II) (0.1 g, 0.14 mmol) and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm3) was stirred under N2for 20 min. To this mixture was then added 3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol). The solution was brought to reflux for 32 h. After cooling to room temperature the reaction mixture was absorbed onto florisil and purified by column chromatography (SiO2, ethyl acetate:hexane 2:3) to afford the title compound (0.43 g, 1.39 mmol, 74%) as an off white solid: 1H NMR (CDCl3) δ 1.56-2.1 (m, 10H), 6.97 (d,.J=8.0 Hz, 1H), 7.39 (dd, J=8.03, 1.45 Hz, 1H), 7.57 (d, J=1.45 Hz, 1H), 7.59(d,J=1.4 Hz, 1H), 7.84 (d,J=1.4 Hz, 1H), 8.32 (brs, 1H); 13C-NMR (CDCl3) δ 22.07, 26.56, 34.4 (t), 48.13 (s), 110.18 (d), 111.3, 114.75 (s), 122.92, 126.76 (d), 128.44 (s), 137.55 (d), 138.11, 142.71, 144.49, 182.13 (s), MS (EI) m/z 307 (M−H)+; Anal. (C18H16N2OS) C, H, N.
EXAMPLE 35
5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-3H]indol]-5′yl-2-thiophenecarbonitrile
[0203] 5-Bromo-2-thiophenecarbonitrile
[0204] A mixture of 5-bromo-2-thiophenecarboxaldehyde (96.0 g, 500 mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500 mL), and ethanol (500 mL) was heated under nitrogen at reflux for two hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give an oil. The crude product was triturated twice with ice water and the solid obtained was collected on a filter. A mixture of a portion of the above solid (44.31 g, 215 mmol), copper (II) acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heated at reflux for three hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sulfuric acid (2×30 mL), water (2×30 mL), brine (20 mL), and dried (MgSO4). The solvent was removed in vacuo and the residue was dissolved in a minimum amount of chloroform (1L) and allowed to crystallize. The crystal obtained was collected on a filter and the filtrate was concentrated and purified by a chromatography (silica gel, chloroform) to give the title compound as an off-white solid (31.5g combined, 58%).: IR (film) cm−12200; 1H-NMR (CDCl3) δ 7.39-7.38 (d, 1H, J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 100%).
[0205] The title compound was prepared according to the procedure for example 18 using 5-bromo-2-thiophenecarbonitrile and (2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid: mp. 225-228° C.; 1H NMR (DMSO-d6) δ 1.63 (m, 8H), 1.90 (m, 2H) 6.91 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H, J=4.17 Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s, 1H); MS ((+)APC1) m/z 309 [M+H]+.
EXAMPLE 36
4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol-5′-yl-2-thiophene carbonitrile
[0206] Prepared according to the procedure for example 18: m.p. 200-203° C; 1H NMR (DMSO-d6) δ 1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d, 1H, J=8.13 Hz), 7.34 (dd, 1H, J=8.13, 1.98 Hz) 7.54 (d, 1H, J=1.98 Hz), 7.82 (S, 1H) 10.50 (S, 1H); MS ((+)APC1) m/z 323 [M+H]+.
EXAMPLE 37
4-Ethyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile
[0207] Prepared according to the procedure for example 18: mp 214-217° C. 1H NMR (DMSO-d6) δ 10.55 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H), 7.33-7.30 (m, 1H), 6.98-6.96 (d, 2H J=8.0 Hz), 2.67-2.62 (m, 2H), 1.89-1.86 (m, 2H), 1.69-1.55 (m, 8H), 1.20-1.15 (t, 3H); MS ((+)APCI) m/z 337 [M+H]+. Anal.Calc. For C20H20N2OS.1/2 H2O: C, 69.54H, 6.13; N, 8.11. Found: C, 69.51;H, 6.06;
EXAMPLE 38
5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-3H]indol]-5′-yl)thiophene-3-carbonitrile
[0208] Prepared according to the procedure for examnple 18: m.p. 188-190° C.; 1H-NMR (DMSO-d6) δ 1.5-2.0 (m, 10H), 6.89 (d, J=7.91 Hz, 1H), 7.49 (dd, J=7.91, 1.98 Hz, 1H), 7.75 (d, J=1.76 Hz, 1H), 7.86 (d, J=1.32 Hz, 1H), 8.44 (d, J=1.32 Hz, 1H); MS (−ESI) m/z 307 (M−H).
EXAMPLE 39
2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-3H]indol]-5′-yl)-thiophene-2-carbonitrile
[0209] Prepared according to the procedure for example 18: m.p. 207-9° C.; 1H-NMR (DMSO-d6) δ 1.4-2.0 (m, 10H), 7.0 (d, J=8.13 Hz, 1H), 7.48 (d, J=5.27 Hz, 1H), 7.54 (dd, J=8.13 Hz, 1.98 Hz, 1H), 7.71 (d, J=5.49 Hz, 1H), 7.85 (d, J=1.76 Hz, 1H), 10.6 (s, 1H); MS (−ESI) m/z 307 (M−H).
EXAMPLE 40
5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-3H]indol]-5′-yl)-3-furancarbonitrile
[0210] Prepared according to the procedure for example 18: m.p. 243-245° C. 1H-NMR (DMSO-d6) δ 10.48 (s, 1H), 8.62 (d, 1H J=0.7 Hz), 7.76 (d, 1H J=1.5 Hz), 7.58-7.55 (dd, 1H), 7.33 (d, 1H J=0.7 Hz), 6.92-6.90 (d, 1H J=8.1 Hz), 1.87-1.83 (m, 2H), 1.73-1.53 (m, 8H). MS ((+)EI) m/z 292 (M+).
EXAMPLE 41
5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0211] Prepared according to the procedure for example 18: m.p. 191-192° C.; 1H NMR (CDCl3) δ 1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J=4.0 Hz, 1H), 7.36 (dd,J=7.5, 1.6 Hz, 1H), 7.53 (d,J=0.9 Hz, 1H), 7.80 (brs, 1H); 13C-NMR (THF-d8) δ 21.35, 25.33, 33.12 (t), 48.32 (s), 110.40, 121.66, 121.96, 125.44, 127.25 (d), 128.17, 128.43, 136.92, 140.20, 143.43, 183.72 (s), MS (EI) m/z 318 (M+H)+.
EXAMPLE 42
5-(5-Acetyl-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0212] Prepared according to the procedure for example 18: m.p. 195-196° C. 1H NMR (CDCl3) δ 1.6-2.1 (m, 10H), 2.58 (s, 3H), 6.95 (d, J=8.1 Hz, 1H), 7.25 (d, J=4.0 Hz, 1H), 7.54 (dd, J=8.1, 1.7 Hz, 1H), 7.66 (d, J=4.0 Hz, 1H), 7.7 (d, J=1.7 Hz, 1H), 7.9 (br s, 1H); 13C NMR (CDCl3) δ 22.24, 26.19 (t), 27.59 (q), 33.99 (t), 49.02(s), 111.39, 123.45, 124.12, 127.02(d), 128.59(s), 134.79(d), 137.92,142.23, 143.41, 154.47, 184.51, 191.76 (s). MS (EI) m/z 326 (M+H)+.
EXAMPLE 43
5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-nitro-thiophene
[0213] Prepared according to the procedure for example 11: mp. 242° C. (decomp.); 1H NMR (DMSO-d6) δ 1.62-1.67 (m, 6H), 1.90-1.99 (m, 2H), 6.94 (d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=4.5 Hz), 7.67 (dd, 1H, J=8.2, 1.8 Hz), 7.86 (d, 1H, J=1.5 Hz), 8.15 (d, 1H, J=4.5 Hz), 10.62 (s, 1H); MS (EI) m/z 328 (M)−.
EXAMPLE 44
5′-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1H)-one
[0214] 2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol-5′-yl)-1H-pyrrole-1-carboxylic Acid, tert-Butyl Ester
[0215] To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3(2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR(CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10H), 6.18 (m, 1H), 6.23 (‘t’, 1H 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
[0216] 2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylic Acid, tert-Butyl Carbamate.
[0217] To a solution of 2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (72 mg, 0.2 mmol) in MeCN (5 mL) at room temperature was added silver nitrate (1.05 eq, 35 mg, 0.2 nmol). After 5 min, acetyl chloride (1.0 eq, 15 mg, 0.2 mmol) in MeCN (5 mL) was added and the solution was allowed to stir for 16 h. Dichloromethane (10 mL) was added, and the solution was filtered through celite and washed sequentially with water, sat. NaHCO3, water and brine (10 mL of each). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the subtitled compound (56 mg, 70%) as a yellow oil which crystallized from acetone/hexane, mp 163° C. (dec).
[0218] 2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylic acid, tert-butyl ester (0.31 g, 0.85 mmol) was placed in a 5 nL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 200° C. After 5 min at this temperature, the flask was removed from the oil bath and allowed to cool. The black residue was washed into a larger flask with acetone and adsorbed onto a small amount of silica gel. Purification by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) gave the title carbamate (0.20 g, 85%) as a yellow oil which crystallized from acetone/hexane, mp 278° C. (dec). 1H NMR (DMSO-d6; 300 MHz) δ 1.55-1.87 (m, 10H), 6.80 (d, 1H, J=4 Hz), 6.91 (d, 1H, J=8 Hz), 7.27 (d, 1H, J=4 Hz), 7.77 (dd, 1H, J=8, 1 Hz), 8.04 (d, 1H, J=1 Hz), 10.51 (s, 1H), 13.21 (br s, 1H). MS ((+)-APCI) m/z 312 [(M+H)+]. Anal. Calcd for C17H17N3O3: C, 65.58; H, 5.5; N, 13.5. Found: C, 65.57; H, 5.54; N, 13.44.
EXAMPLE 45
5′-(5-Nitro-1-methyl-pyrrol-2-yl)spiro[cyclohexane-1′,3′-3H]indol]-2′(1′H)-one
[0219] 5′-(1-Methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0220] A mixture of 5′-(1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.46 g, 1.7 mmol) and potassium carbonate (5 eq, 1.18 g, 8.6 mmol) in DMF (2 mL) at room temperature was treated with a solution of iodomethane (3 eq, 0.32 g, 5.1 mnmol) in DMF (1 mL). The solution was stirred 16 h at room temperature, then poured into water (10 mL). EtOAC (15 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the subtitled compound (0.44 g, 76%) as a white powder, mp 148-9° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.62 (m, 3H), 1.62-1.82 (m, 5H), 1.83-1.94 (m, 2H), 3.11 (s, 3H), 6.08 (m, 1H), 6.42 (m, 1H), 6.79 (m, 1H), 6.97 (d, 1H, J=8.1 Hz), 7.51 (dd, 1H, J=8.1, 1.8 Hz), 7.70 (d. 1H, J=1.7 Hz), 11.20 (br s, 1H). Anal. Calcd for C18H20N2O,: C, 77.11; H, 7.19; N, 9.98. Found: C, 76.44; H, 7.21; N, 9.96.
[0221] A mixture of 5′-(1-methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.36 g, 1.3 mmol) and silver nitrate (1.1 eq, 0.24 g, 1.4 mmol) in acetonitrile (10 mL) at room temperature was treated with acetyl chloride (1.1 eq, 0.1 mL, 1.4 mmol). The mixture was stirred 1 h at this temperature and then dichloromethane (30 mL) was added and the mixture was filtered through celite. The organic phase was washed sequentially with water (20 mL), sat. aq. NaHCO3(20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (21 mg, 5%) as a yellow powder, mp 210° C. 1H NMR (DMSO6; 300 MHz) δ 1.55-1.97 (m, 10H), 3.15 (s, 3H), 6.77 (dd, 1H, J=4.2, 2.3 Hz), 7.05 (d, 1H, J=8.2 Hz), 7.21 (dd, 1H, J=4.2, 2.3 Hz), 7.83 dd, 1H, J=1.8, 8.2 Hz), 8.0 (d, 1H, J=1.8 Hz), 13.0 (br s, 1H). MS ((+)-APCI) m/z 326 [(M+H)+]. Anal. Calcd for C18H19N3O3: C, 65.45; H, 5.89; N, 12.91. Found: C, 64.66; H, 5.76; N, 12.52.
EXAMPLE 46
5′-(1H-Indol-4-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one
[0222] Prepared according to the procedure for example 18: mp 211-213° C.; 1H-NMR (CDCl3) δ 8.32 (s, 1H), 7.84 (s, 1H), 7.81 (d, 1H, J=1.8 Hz), 7.55 (dd, 1H, J=6.2, 1.8 Hz), 7.40 (dt, 1H, J=6.2, 1.0 Hz), 7.29-7.28 (m, 1H), 7.27 (t, 1H, J=3.1 Hz), 7.18 (dd, 1H, J=6.4, 0.9 Hz), 7.00 (dd, 1H, J=7.5, 0.4 Hz), 6.72-6.71 (m, 1H), 2.00-1.59 (m, 10H); MS ((+)APCI) [M+H]+ @ m/z 317.
EXAMPLE 47
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile
[0223] A solution of 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime (0.48 g, 1.49 mmol) in chloroform (10 cm3) was treated with selenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16 h, the mixture was concentrated and the residue purified by column chromatography (SiO2, EtOAc: hexane 1:4) and the product re-crystallized from EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%) as a white solid: m.p. 190-191° C.; 1H NMR (CDCl3) δ 1.59-1.87 (m, 6H), 1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54 (t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7.2 Hz), 7.83 (m, 1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)+.
EXAMPLE 48
3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile
[0224] To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm3) at −78° C. was added n-butyl lithium (2.5 M, 8 cm3, 20 mmol) dropwise. After 30 min. the mixture was treated with DMF (20 cm3) in diethyl ether (10 cm3) and stirring was continued at −78° C. After 30 mnin. the mixture was quenched with dilute HCl aq., separated and the aqueous layer was extracted with EtOAc. The combined organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: 1H NMR (CDCl3) δ inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m/z 202, 204 [M+].
[0225] To a solution of the last cited compound (4.0 g, 19.7 mmol) in ethanol:water (8:2, 50 cm3), was added sodium acetate (1.72 g, 21 mmol) and hydroxylamine hydrochloride (1.45 g, 21 mmol), and the mixture was heated under reflux. After 30 min., the mixture was cooled, evaporated and the residue partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc and the combined organic layers were washed with water, saturated sodium hydrogen carbonate solution, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76 g, 17.24 mmol, 87%) which was used without ftrther purification: 1H NMR (CDCl3) δ 7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s, 1H); MS (EI) m/z 217 [M+].
[0226] The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370 mg) were dissolved in acetonitrile (100 cm3) under nitrogen and heated under reflux. After 5 h, the mixture was evaporated, the residue taken into EtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol, 89%) which was used without further purification.
[0227] The above bromide (3.0 g, 15 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.86 g, 0.75 mmol) were dissolved in dimethoxyethane (130 cm3) under nitrogen. After 15 min. (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid (2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved in water (40 cm3) were added, and the rmixture heated under reflux. After 8 h the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were then washed with water, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (EtOAc: hexane, gradient elution), and the product recrystallized from methanol to give 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile (1.78 g, 5.55 mmol, 48%): mp 199-205° C. 1H NMR (CDCl3) δ 1.64-2.03 (m, 10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41 (dd, 1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2 Hz), 7.64 (s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M+].
EXAMPLE 49
3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitile
[0228] Prepared according to the procedure for example 18: mp. 205-206° C. 1H NMR (DMSO-d6) δ 10.47 (s, 1H), 8.08-8.06 (dd, 1H), 7.89-7.85 (m, 1H), 7.65 (s, 1H), 7.54-7.49 (m, 1H), 7.43-7.40 (tt, 1H), 6.95-6.93 (d, 1H J=7.9 Hz), 1.97-1.83 (m, 2H), 1.69-1.55 (m, 8H); MS (EI) m/z 320 (M+)
EXAMPLE 50
3-(1′-Diethoxymethyl-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile
[0229] A solution of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) was heated to 150° C. for 1 h. The reaction mixture was allowed to cool, the excess triethylorthoformate was removed in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder, mp 146° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.13 (t, 6H, J=7 Hz), 1.60-1.96 (m, 10H), 3.48 (m, 2H), 3.66 (m, 2H), 6.17 (s, 1H), 7.35 (d, 1H, J=8.3 Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1H, J=1.3, 2.4 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.92 (dt, 1H, J=2.4, 10.5 Hz)8.08 (dd, 1H, J=1.3, 2.9 Hz). MS ((+)-EI) m/z 422 [M+]. Anal. Calcd for C25H27FN2O3: C, 71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.
EXAMPLE 51
3-(7′-Bromo-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile
[0230] A mixture of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (0.40 g, 1.23 mmol) and potassium acetate (0.13 g, 1.3 mmol) in glacial acetic acid (3 mL) at room temperature was treated with a solution of bromine (1.05 eq, 0.21 g, 1.3 mmol) in a glacial acetic acid (3 mL). Aflter stirring for 1 h the mixture was poured onto ice (20 g). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined, washed sequentially with 10% aqueous sodium thiosulfate (20 mL), water (2×10 mL), saturated sodium bicarbonate (10 mL) and brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give the title compound (0.21 g, 43%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 217° C. 1H NMR (CDCl3; 300 MHz) δ 1.56-2.04 (m, 10H), 7.33 (dddd, 1H, J=1.25, 2.3, 3.6 and 9.0 Hz), 7.45 (m, 1H), 7.47 (m, 2H), 7.54 (m, 1H), 7.60 (m, 1H). MS ((−)-ESI) m/z 399 [M−]. Anal. Calcd for C20H16BrFN2O1: C, 60.17; H, 4.04; N, 7.02. Found: C, 60.03; H, 4.08; N, 6.83.
EXAMPLE 52
3-(7′-Nitro-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile
[0231] A mixture of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (0.19 g, 0.6 mmol) and silver nitrate 0.11 g, 0.6 mmol) in trifluoroacetic acid (5 mL) was stirred 1 h at room temperature and then poured onto ice (20 g). Ether (15 mL) was added, the layers were separated, and the aqueous layer was extracted with ether (3×10 mL). The organic layers were combined and washed sequentially with water (2×20 mL), saturated aqueous NaHCO3(20 mL) and brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 20% EtOAc/hexane) to give the title compound (0.2 g, 94%) as a white powder, mp 196° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.46-1.58 (m, 1H), 1.62-1.77 (m, 5H), 1.83 (m, 2H), 1.92-2.20 (m, 2H), 7.85 (dddd, 1H, J=1.3, 2.4, 3.7 and 8.6 Hz), 8.12 (dddd, 1H, J=1.8, 2.4, 4.2 and 10.5 Hz), 8.23 (m, 2H), 8.36 (d, 1H, J=2.0 Hz), 11.17 (bs, 1H). MS ((−)-APCI) m/z 365 [M−]. Anal. Calcd for C20H16FN3O3: C, 65.75; H, 4.41; N, 11.5. Found: C, 65.4; H, 4.54; N, 11.3.
EXAMPLE 53
3-(7′-Amino-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile
[0232] To a solution of 3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at room temperature was added a solution of tin II chloride dihydrate (0.25 g, 1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for 30 min at which point the yellow color disappeared. After cooling to room temperature, 1 N HCl (10 mL) and ether (20 mL) were added. The layers were separated and the aqueous phase was extracted with ether (2×20 mL). The organic layers were combined, washed sequentially with water (2×20 mL), saturated aqueous NaHCO3(20 mL), and brine (20 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 241-3° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.75 (m, 8H), 1.82-1.95(m, 2H), 4.98 (s, 2H), 6.90 (d, 1H, J=Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75 (m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)-APCI) m/z 336 [(M+H)+]. Anal. Calcd for C20H18FN3O: C, 71.63; H, 5.41; N, 12.18. Found: C, 71.16; H, 5.58; N, 12.18.
EXAMPLE 54
5-(3-Cyano-4-fluorothenyl)spiro[cyclohexane-[1,3H]indol]-2(1H)-one
[0233] Prepared according to the procedure for example 18: mp. 239-242° C.; 1H NMR (CDCl3) δ 1.64-1.82 (m, 6H), 1.88-2.04 (m, 2H), 7.00 (d, 1H, J=8 Hz), 7.29-7.31 (m, 1H), 7.36 (dd, 1H, J=8.8, 2 Hz), 7.54 (d, 1H, J=1.5 Hz), 7.73-7.78 (m, 2H) and 8.19 (s, 1H, br); MS ((+)-APCI) m/z 321 [M+H]+.
EXAMPLE 55
5′-(3-Chlorophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one
[0234] A solution of 3,3-dimethylglutaric anhydride in dry THF (60 cm3) was added over 30 min. to lithium aluminum hydride in dry THF (300 cm3) under nitrogen at 0° C. The mixture was then brought gradually up-to reflux. After 3 h, the mixure was cooled, treated with water (3.3 cm3), sodium hydroxide solution (15%, 3.3 cm3) and water (9.9 cm3). The mixture was then filtered, the precipitate extracted with EtOAc (×3), and the combined organics evaporated to afford 3,3-dimethyl-1,5-pentanediol (quantitative yield); 1H NMR (CDCl3) δ 0.95 (s, 6H), 1.57 (t, 4H, J=6.3 Hz), 3.75 (t, 4H, J=6.3 Hz).
[0235] A solution of 3,3-dimethyl-1,5-pentanediol (8.4 g, 63.5 mmol) in dry pyridine (180 cm3) was cooled to 0° C. under nitrogen and treated over 5 h with a solution of toluenesulfonyl chloride (26.7 g, 140 mmol) in dry pyridine (100 cm3). The mixture was then allowed to warm up to room temperature. After 16 h, the mixture was poured into ice/water and extracted with EtOAc (×3). The combined organics were washed with dilute HCl(30%), saturated sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated to afford 1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate (19.8 g, 45 mmol) which was used without further purification: 1H NMR (CDCl3) δ inter alia 0.85 (s, 6H), 1.56. (t, 4H, J=7.0 Hz), 2.45 (s, 6H), 4.02 (t, 4H, J=7.0 Hz), 7.35 (d, 4H, J=8.0 Hz), 7.77 (d, 4H, J=8.0 Hz); MS ((+) APCI) m/z 441 (M +H)+.
[0236] A solution of 1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate (53.0 g, 120 mmol) and sodium iodide (72.0 g, 480 mmol) was dissolved with stirring in dry acetone (500 cm3). After 16 h at reflux the mixture was cooled, poured into water and extracted with diethylether (×3). The combined organic extracts were washed with water, dried (MgSO4), and evaporated to afford 3,3-dimethyl-1,5-diiodopentane (41.3 g, 117 mmol) as a yellow oil that was used without further purification: 1H NMR (CDCl3) δ inter alia 0.90 (s, 6H), 1.87-1.91 (m, 4H), 3.09-3.15 (m, 4H).
[0237] A solution of oxindole (2.0 g, 15 mmol) dissolved in dry THF (50 cm3) under nitrogen was cooled to −60° C. and treated with n-butyllithium (2.5 M in hexanes, 15 cm3, 37.5 mmol) followed by N,N,N′N′-tetramethylethylenediamine (5.66 g, 37.5 mmol). After 20 min. 3,3-dimethyl-1,5-diiodopentane (15.8 g, 45 mmol) in dry THF (10 cm3) was added and the mixture was allowed to warm up to room temperature. After 16 h, the mixture was poured into water, extracted with EtOAc (×3), washed with water, dilute HCl(10%), water, brine, dried (MgSO4) and evaporated. The residue was then subjected to column chromatography (SiO2, EtOAc:hexane, 1:6) to afford spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one (0.37 g, 1.62 mmol, 11%): 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.10 (s, 3H), 1.23-1.30 (m, 2H), 1.54-1.68 (m, 4H), 1.94-2.04 (m, 2H), 6.94 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.7 Hz), 7.42 (d, 1H, J=7.4 Hz), 8.76 (s, 1H, br); MS (EI) m/z 229 (M)+.
[0238] To a solution of the last cited compound (0.37 g, 1.62 mmol) and sodium acetate (0.14 g, 1.7 mmol) in acetic acid (5 cm3) was added bromine (0.27 g, 1.7 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sodium hydroxide solution (2N) and extracted with dichloromethane (×2). The organic extracts were washed with water, dried (MgSO4) and evaporated to afford 5′-bromospiro[4,4-dimethylcyclohexane-1′,3 ′-[3H]indol]-2′(1′)-one (0.435 g, 1.41 mmol, 87%) which was used without further purification: 1H NMR (CDCl3) δ 1.08 (s, 3H), 1.49-1.64 (m, 4H), 1.69-1.74 (m, 2H), 1.89-1.98 (m, 2H), 6.77 (d, 1H,J=8.2 Hz), 7.33 (dd, 1H, J=8.2, 1.8 Hz), 7.48 (d, 1H, J=1.7 Hz), 7.71 (s, 1H, br); MS ((+)APCI) m/z 308 (M+H)+.
[0239] The last cited compound (0.56 g, 1.81 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.1 g, 0.08 mmmol) were dissolved in dimethoxyethane (20 cm3) under nitrogen. After 20 min. 3-chlorophenylboronic acid (0.57 g, 3.64 mmol) and sodium carbonate (0.97 g, 9.15 mmol) were added and the mixture heated under reflux. After 16 h the mixture was cooled, poured into water and extracted with EtOAc (×2). The combined organic layers were washed with sodium hydroxide (2N), water, brine, dried (MgSO4) and evaporated. The residue was then subjected to column chromatography (SiO2, EtOAc:hexanes, 1:5) to afford the title compound which was triturated with hexane to give a solid (0.26 g, 0.77 mmol, 43%): m.p. 184-185° C.; 1H NMR (CDCl3) δ 1.11 (s, 6H), 1.57-1.80 (m, 6H), 1.45-2.03 (m, 2H), 6.98 (d, 1H, J=8.0 Hz), 7.29-7.44 (m, 4H), 5.52-7.55 (m, 2H), 8.12 (s, 1H, br), MS ((+)APCI) m/z 340 (M+H)+.
EXAMPLE 56
5′-(3-Nitrophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one
[0240] To a solution of 5′-bromospiro[4,4-dimethylcyclohexane1′,3′-[3H]indol]-2′(1′H)-one (0.29 g, 0.95 mmol) in dimethoxyethane (15 cm3) was added tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.046 mmol). After 20 min. 3-nitrophenylboronic acid (0.32 g, 1.9 mmol) and sodium carbonate (0.5 g, 4.75 mmol) in water (7.5 cm3) and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×2). The combined organic layers were washed with sodium hydroxide solution (2N), water, brine, dried (MgSO4) and evaporated. The residue was then subjected to column chromatography (SiO2, EtOAc:hexanes, gradient elution), then the product was triturated with hexane to afford the title compound (0.12 g, 0.35 mmol, 37%) as a yellow solid: m.p. 230-231° C.; 1H NMR (CDCl3) δ 1.18-1.24 (m, 6H), 1.57-1.86 (m, 6H), 1.94-2.03 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 7.59-7.64(m, 2H), 7.87 (d, 1H, J=7.7 Hz), 8.06 (s, 1H, br), 8.19 (d, 1H, J=7.7 Hz), 8.40 (s, 1H); MS ((+)APCI) m/z 351 (M+H)+.
EXAMPLE 57
2,3,5,6Tetrahydro-5-(3-nitrophenyl)spiro[3H-indole-3,4-[4H]pyran]-2(1H)-one
[0241] To a solution of sodium iodide (64 g, 0.43 mol) in acetone under N2was added 2-bromoethyl ether (20 g, 0.086 mol), causing a white solid to precipitate. After 16 h the mixture was filtered and the filtrate concentrated. Dichloromethane was added to the residue which was filtered, the cake further washed with dichloromethane, the combined organic layers were dried (MgSO4) and evaporated to give 2-iodoethyl ether (26.61 g, 0.0816 mol, 95%) as a colorless oil: 1H NMR (CDCl3) δ 3.26 (t, 2H, J=7 Hz), 3.78 (t, 2H, J=7 Hz).
[0242] A solution of oxindole (5.00 g, 37.5 mmol) in anhydrous THF under N2was cooled to −20° C. n-butyllithium (2.5 M in hexanes, 30 cm3, 75.1 mmol) was added drop-wise followed by N,N,N′N′-tetramethylethylenediamine (11.4 cm3). After 20 min. a solution of 2-iodoethyl ether (36 g, 112 mmol) in anhydrous THF (20 cm3) was added slowly. The mixture was allowed to warm to room temperature, then after 16 h was brought to reflux. After 5 h the mixture was cooled then poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dil. HCl (pH 1), water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, acetone:hexane 1:5) to afford the title compound (0.78 g, 3.82 mmol, 10%) as a white solid: 1H NMR (CDCl3) δ 1.84-1.95 (m, 4H), 3.91-3.96 (m, 2H), 4.21-4.27 (m, 2H), 6.89-6.92 (m, 1H), 7.06 (t, 1H, J=7, 1 Hz), 7.22 (t, 1H, J=7, 1 Hz), 7.35-7.38 (m,1H)
[0243] A solution of the above product (0.78 g, 3.82 mmol) and sodium acetate (0.32 g, 4.02 mmol) in acetic acid (10 cm3) was treated with bromine (0.64 g, 4.02mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2) washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the title compound (0.59 g, 2 mmol, 54%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.83-2.00 (m, 4H), 3.91-4.03 (m, 2H), 4.22-4.32 (m, 2H), 6.86 (d, 1H, J=7 Hz), 7.38-7.45 (m, 1H), 7.52 (d, 1H, J=1 Hz), 8.36 (s, 1H, br); MS ((+)ESI) m/z 282 (M +H)+.
[0244] A solution of the above product (0.58 g, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol) in dimethoxyethane (16 cm3was stirred under N2for 20 min. To this mixture was then added 3-nitrophenylboronic acid (0.63 g, 4.06 mmol) and potassium carbonate (1.68 g) in water (7 cm3). After 3 h at reflux the mixture was cooled, poured into water and extracted EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4) and evaporated. The residue was then subjected to column chromatography (SiO2, EtOAc:hexane, 1:2) to provide the title compound (0.19 g, 0.58 mmol, 28%). A sample which was further purified by preparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN:H2O 46:54, 100 cm3/min., RT 7.57 min.) had the following properties: mp>250° C. 1H NMR (acetone-d6) δ 1.78-1.88 (m, 2H), 1.92-2.01 (m, 2H), 3.85-3.94 (m, 2H), 4.12-4.23 (2H), 7.08-7.13 (m, 1H), 7.62-7.69 (m, 14H), 7.70-7.79 (m, 1H), 7.92-7.97 (m, 1H), 8.13-8.23 (m, 1H), 8.45-8.51 (m, 1H), 9.55 (s, 1H, br); MS (EI) m/z 341 (M)+.
[0245] A solution of the above product (0.58 g, 2.04 mmol) and tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol) in dimethoxyethane (16 cm3was stirred under N2for 20 min. To this mixture was then added 3-nitrophenylboronic acid (0.63 g, 4.06 mmol) and potassium carbonate (1.68 g) in water (7 cm3). After 3 h at reflux the mixture was cooled, poured into water and extracted EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4) and evaporated. The residue was then subjected to column chromatography (SiO2, EtOAc:hexane, 1:2) to provide the title compound (0.19 g, 0.58 mmol, 28%). A sample which was further purified by preparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN: H2O 46:54, 100 cm3/min., RT 7.57 min.) had the following properties: mp >250° C. 1H NMR (acetone-d6) δ 1.78-1.88 (m, 2H), 1.92-2.01 (m, 2H), 3.85-3.94 (m, 2H), 4.12-4.23 (2H), 7.08-7.13 (m, 1H), 7.62-7.69 (m, 14H), 7.70-7.79 (m, 1H), 7.92-7.97 (m, 1H), 8.13-8.23 (m, 2), 8.45-8.51 (m, 1H), 9.55 (s, 1H, br); MS (EI) m/z 341 (M)+.
EXAMPLE 58
5′-(5Chloro-3-methylbenzo[b]thien-2-yl)spiro[cyclo-hexane-1,3′-[3H]indol]-2′(1′H)-one
[0246] A solution of the 2-bromo-5-chloro-3-methylbenzo[b]-thiophene (0.28 g, 1.1 mmol) and tetrakis-(triphenylphosphine)palladium (0.13 g, 0.1 mmol) in dimethoxyethane (8 cm3) was stirred under N2for 20 min. To this mixture was then added (2′-oxo-2, 3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid (0.32 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in water (4 cm3). The solution was brought to reflux for 12 h then cooled to RT, poured into water and extracted with EtOAc (3×50 cm3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, CH2Cl2) to afford the title compound (0.18 g, 0.47 mmol, 45 %) as a white solid: mp. 256-258° C., 1H NMR (DMSO-d6) δ 1.47-1.97 (m, 10H), 2.42 (s, 3H), 6.99 (d, J=8.0 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.42 (d, J=1.2 Hz, 1H), 7.6 (s, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 10.53 (s, 1H); 13C NMR (DMSO-d6) δ 12.84 (q), 20.96, 25.08, 32.88 (t), 47.23 (s), 109.98, 121.99, 124.25, 124.71, 125.01 (d), 126.47, 126.59, 129.17, 130.01, 136.51, 140.42, 141.79, 142.76, 181.74 (s); MS (EI) m/z 380 (M−H)+.
EXAMPLE 59
5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0247] The title compound was prepared from (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid (3.2 g, 12.5 mmol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) as described for example 18 (0.7 g, 16%) as a yellow solid: mp. 213-215° C., 1H NMR (DMSO-d6) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H, J=8.13 Hz), 7.68 (dd, 1H, J=8.13, 1.76 Hz), 7.74 (dd, 1H, J=8.68, 1.76 Hz), 7.86 (d, 1H, J=1.98 Hz), 7.92 (dd, 1H, J=13.4, 1.76 Hz), 8.18 (t, 1H, J=8.46 Hz) and 10.52 (s, 1H); MS (EI) m/z=340 (M+).
EXAMPLE 60
4-(1,2-Dihydro-2oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile
[0248] A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.4 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.6 g, 6.5 mmol) and sodiun acetate (1.4 g, 13.1 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.45 g, 36%) as an off-white solid. mp: 240-242° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.5 (s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, 1H, J=1.5 6.5 Hz), 6.9 (d, 1H, J=8.0 Hz), 2.0-1.6 (m, 10H); MS (EI) M+ @m/z 292.
EXAMPLE 61
5-[4-Fluoro-3(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0249] The title compound was prepared from (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid (2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8 mmol) as described for example 18, to afford the title compound (0.87 g, 30%) as a solid: m.p. 222° C.; 1H NMR (DMSO-d6) δ 1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.92 (d, 1H, J=8.13 Hz), 7.51 (dd, 1H, J=8.13, 1.76 Hz), 7.55 (dd, 1H, J=10.54, 9.01 Hz) 7.72 (d, 1H, J=1.76 Hz), 7.90 (dd, 1H, J=7.03, 2.20 Hz), 7.98 (m, 1H) and 10.39 (s, 1H); MS (EI) m/z 363 (M+).
EXAMPLE 62
5-[4Fluoro-3nitrophenyl]spiro[cylohexane-1,3-[3H]indol]-2(1H)-one
[0250] The title compound was prepared from (2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid (2.8 g, 11 mmol) and 5-bromo-2-fluoro-nitrobenzene (2.7 g, 12.2 mmol) as described for example 18, to afford the title compound (2.5 g, 66%) as a solid: m.p. 243-245° C.; 1H NMR (DMSO-d6) δ 1.8-2.0 (m, 2H), 1.5-1.8 (m, 8H), 6.94 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.01, 1.87 Hz), 7.63 (dd, J=10.98, 8.79 Hz), 8.07 (m, 1H), 8.30 (dd, 1H, J=7.14, 2.53 Hz) and 10.43 (s, 1H); MS (ESI (neg)) m/z 339 (M−H)−.
EXAMPLE 63
5′-(4-Cyano3-fluorophenyl)-spiro[cylohexane-1,3′-[3H]indol]-2′(1′)-one
[0251] A solution of 4-cyano-3-fluoro-bromobenzene (0.76 g, 3.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.3 g) in ethylene glycol dimethyl ether (15 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclohexane1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.4 g, 5.7 mmol) and sodium acetate (1.2 g, 11.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.45 g, 37%) as an off-white solid. mp: 258-260° C.; 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 7.7-7.6 (m, 2H), 7.5 (td, 2H, J=0.9. 1.5, 5.7 Hz), 7.4 (dd, 1H, J=1.5, 8.8 Hz), 7.0 (d, 1H, J=8.1 Hz), 2.0-1.6 (m, 10H), MS (−)APCI [M−H]− @m/z 319.
EXAMPLE 64
2-fluoro-4-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) benzaldhyde oxime
[0252] A solution of 3-fluoro-4-bromobenzaldehyde oxime (0.5 g, 2.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (10 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.8 g, 3.3 mmol) and sodium acetate (0.7 g, 6.5 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.25 g, 34%) as an off-white solid. mp: 240-242° C.; 1H NMR (DMSO-d6) δ 11.6 (s, 1H), 10.4 (s, 1H), 8.2 (s, 1H), 7.8-7.7 (m, 2H), 7.6-7.5 (m, 3H), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.6 (m, 10H); MS (EI) M+ @m/z 338.
EXAMPLE 65
5-(2′-oxo-2′,3′-Dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′yl-2-nitrothiophene
[0253] A solution of 2-bromo-5-nitrothiophene (0.6 g, 2.9 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.3 mmol) and sodium acetate (1.0 g, 10.0 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.87 g, 96%) as a yellow solid. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.6 (s, 1H), 8.1 (d, 1H, J=4.5 Hz), 7.7 (d, 1H, J=1.8 Hz) 7.6 (m, 2H), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+ @m/z 314.
EXAMPLE 66
5-(3Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one
EXAMPLE 67
3-(3,3-Dimethyl-2-oxo2,3-dihydro-1H-indol-5yl)-benzonitrile
[0254] (2′-oxo-[2,3-Dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic Acid
[0255] A solution of 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (0.35 g, 1.46 dimethoxyethane (10 cm3) was stirred under N2for 20 min. To this mixture was then added 3-chloro-4-fluorobenzene boronic acid (0.26 g, 1.49 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in water (5 cm3). The solution was brought to reflux for 16 h then cooled to RT, poured into saturated ammonium chloride and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the title compound (0.124 g, 0.43 mmol, 30%) as a white solid: m.p. 206.5-207.8° C. 1H NMR (DMSO-d6) δ 1.3 (s, 6H), 6.93 (d, J=8.1 Hz, 1H), 7.45 (dd, J=8.9, 8.9 Hz, 1H), 7.5 (dd, J=8.1, 1.8 Hz, 1H), 7.6 (ddd, J=8.9, 7.1, 2.2 Hz, 1H), 7.7 (d, J=1.8 Hz, 1H), 7.8 (dd, J=7.1, 2.2 Hz, 1H), 10.5 (s, 1H); MS (EI) m/l 289/291 (M)+.
[0256] To a solution of 5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one (3.5 g, 14.6 mmol) in dry tetrahydrofuran (60 cm3) was added of sodium hydride (60% dispersion in mineral oil, 0.59 g, 14.6 mmol). After 30 min. stirring at room temperature, the mixture was cooled to −78° C. and n-butyl lithium (2.5 M in hexanes, 5.9 cm3, 14.6 mmol) was added slowly. After 30 min, tri-isopropyl borate (9 cm3, 38.9 mmol) was added and the mixture was allowed to warm to room temperature. After 8 hrs. hydrochloric acid (1N, 200 cm3) and ethylacetate (200 cm3)was added and the mixture stirred for 20 min. The aqueous phase was extracted with ethylacetate, then the combined organic layers were washed with water, brine, dried (Na2SO4) and evaporated. The residue was triturated with hexane and the precipitate dried in vacuo to obtain (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (1.8 g, 8.8 mmol, 60%) as a yellow-white solid that was used without further purification. 1H NMR (DMSO-d6) δ 1.23 (s, 6H), 6.81 (d, J=7.8 Hz, 1H) 7.63 (d, J=7.8 Hz, 1H) 7.66 (s, 1H), 7.84 (s, 2H) 8.69 (s, 1H).
[0257] A solution of 3-bromobenzonitrile (0.30 g, 1.65 mmol) and tetrakis(triphenylphosphine) palladium (0.13 g, 0.1 mmol) in dimethoxyethane (10 cm3) was stirred under N2for 20 min. To this mixture was then added the (2′-oxo-[2,3-dihydro-3,3-dimethyl-1, 3′-[3H]indol]-5′-yl) boronic acid, (0.41 g, 2.0 mmol) and potassium carbonate (0.86 g, 6.2 mmol) in water (5 cm3). The solution was brought to reflux for 16 h then cooled to RT, poured into saturated ammonium chloride and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:2.5) to afford the title compound (0.22 g, 0.68 mmol, 51%) as a white solid: m.p. 200.2-202.0° C. 1H NMR (DMSO-d6) δ 1.32 (s, 6H), 6.96 (d,J=8.1 Hz, 1H), 7.58 (dd,J=8.1, 1.8, 1H), 7.63 (dd,J=7.8,7.8 Hz, 1H), 7.75-7.78 (m, 2H), 7.98 (d, J=8.0 Hz, 1H), 8.15 (s, 1H), 10.49 (s, 1H); MS (EI) m/z 263 (M)+.
EXAMPLE 68
2-Fluoro-3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5-yl)
[0258] A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol 5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): 1H NMR (CDCl3) δ 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).
[0259] A solution of the last cited compound (3.077 g, 13.2 mmol) in dry toluene (80 ml) at −78° C. under nitrogen was treated with di-iso-butylaluminum hydride in toluene (1M, 15.7 ml, 15.7 mmol). After 1 h at −78° C. the mixture was quenched with aqueous HCl(3M, 16 ml). The mixture was warmed to RT, partitioned between EtOAc/H2O, the aqueous layer was re-extracted with EtOAc, and the combined organic layers were washed with water, dried (MgSO4) and evaporated to afford 3-bromo-2-fluorobenzaldehyde (2.63 g, 12.9 mmol, 98%), which was used without further purification: 1H NMR (CDCl3) δ 10.35 (s, 1H), 7.82 (m, 2H), 7.18 (t, 7.8 Hz).
[0260] A mixture of the last cited compound (2.63 g, 12.9 mmol), hydroxylamine hydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37 g, 14 mmol) was placed in ethanol/H2O (60 ml, 8:2) and the mixture was heated under reflux. After 30 min. the mixture was cooled, evaporated and partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give afford 3-bromo-2-fluorobenzaldoxime which was used without further characterization.
[0261] The title compound was prepared from 3-bromo-2-fluorobenzaldoxime (0.40 g, 1.83 mmol) and (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid as described in example 18, to afford the product (0.094 g, 0.27 mmol, 15% yield) as a white solid: m.p. 213-217° C.; 1H NMR (CDCl3) δ 10.95 (s, 1H), 9.65 (s, 1H), 8.41 (s, 1H), 7.76 (t, 1H, J=7.1 Hz), 7.59 (s, 1H), 7.43-7.33 (m, 3H), 7.19 (t, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8 Hz) and 1.91-1.60 (m, 10H); MS ((+) ESI) m/z=339 [M+H)+.
EXAMPLE 69
5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4methylthiophene-2-carbonitrile
[0262] 5-Bromo-4-methyl-2-thiophene Carboxaldehyde.
[0263] To a solution of diethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added at −40° C. under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol) in hexane. After addition, the solution was stirred at −40° C. under nitrogen for 30 minutes, cooled to −78° C. and treated dropwise with a solution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF (450 mL). The reaction solution was stirred at −78° C. for 30 minutes and treated with anhydrous DMF (100 mL). The mixture was allowed to warm to ambient temperature and was quenched with 1N aqueous hydrochloride solution (1L). The solution was extracted with ethyl acetate(3×450 mL). The extracts were washed with water, brine and dried (MgSO4). After removal of solvent in vacuo, the subtitled compound was obtained as a white solid (46 g, 88.3%). A sample of the product was crystallized from hexane: mp 63-65° C.; IR (KBr) 1654 cm−1. 1H-NMR (CDCl3) δ 9.75 (s, 1H), 7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206 (M30). Anal. Calc. For C6H5BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.
[0264] 5-Bromo-4-methyl-2-thiophenecarbonitrile.
[0265] Prepared from 5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure of Example 35. White solid: mp 40-42° C.; IR (KBr) 2200 cm−1; 1H-NMR (CDCl3) δ 7.29 (s, 1H), 2.21 (s, 3H). MS (EI) m/z 201/203 (M+, 98%/100%), Anal. Calc. For C6H4BrNS: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00; H, 2.14; N, 6.76.
[0266] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (357 mg, 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg, 1.5 mmol) to afford the title compound (227 mg, 0.8 mmol, 55%) as a white solid: m.p. 192.3-193° C., 1H NMR (DMSO-d6) δ 1.29 (s, 6H), 2.29 (s, 3H), 6.97 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0,1.8 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (m)+.
EXAMPLE 70
5-(3-Chloro-5-fluoro-phenyl)-3,3dimethyl-1,3-dihydro-indol-2-one
[0267] Prepared according to the procedure for example 18 for using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (345 mg, 1.7 mmol) and 1-bromo-3-chloro-5-fluorobenzene (295 mg, 1.4 mmol) to afford the title compound (245 mg, 0.85 mmol, 60%) as a white solid: m.p. 205.9-206.8 ° C. 1H NMR (DMSO-d6) δ 1.31 (s, 6H), 6.93 (d, J=8.1 Hz), 7.35 (d, J=8.6 Hz, 1H), 7.5-7.6 (m, 2H), 7.6 (s, 1H), 7.78 (d, J=1.4 Hz, 1H), 10.49 (s, 1H); MS (EI) m/z 290 (M+H)+.
EXAMPLE 71
5-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one
[0268] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (272 mg, 1.3 mmol) and 1-fluoro-3-iodo-5-nitrobenzene (299 mg, 1.1 mmol) to afford the title compound (192 mg, 0.64 mmol, 57%) as a yellow solid: m.p. 231.2-232.7° C., 1H NMR (DMSO-d6) δ 1.33 (s, 6H), 6.97 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.88 (d, J=1.6Hz, 1H), 8.0-8.1 (m, 2H), 8.32 (s, 1H), 10.55 (s, 1H); MS (ESI) m/z 301 (M+H)+.
EXAMPLE 72
4(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)furan-2-carbonitrile
[0269] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol) to afford the title compound (76 mg, 0.3 mmol, 26%) as a white solid: m.p. 199.6-201.4° C., 1H NMR (DMSO-d6) δ 1.28 (s, 6H), 6.89 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 8.1 (s, 1H), 8.5 (s, 1H), 10.46 (s, 1H), MS (ESI) m/z 251 (M−H)−.
EXAMPLE 73
4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile
[0270] (Spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic Acid
[0271] To a solution of 5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (13.1 g, 53 mmol) in anhydrous THF (300 cm3) under N2, was added sodium hydride (60% in mineral oil, 2.1 g, 53 mmol). After 30 minutes, the reaction mixture was cooled to −78° C. and butyl lithium (2.5 M in hexanes, 22 cm3, 53 mmol) was added slowly. After 30 minutes, tris-iso-propylborate (34 cm3, 146 mmol) was added, and the reaction mixture was slowly brought to room temperature, and stirred for 14 hours. The reaction mixture was poured into 1N HCl and extracted with EtOAc (×3). The organic layers were collected and washed with 1N HCl, water, dried (MgSO4) and evaporated to give the subtitled compound (7.8 g, 64%) as a tan solid which was used without further purification. 1H NMR (DMSO-d6) δ 10.3 (s, 1H), 7.9 (s, 1H), 7.7-7.6 (m, 2H), 6.8 (d, 1H, J=7.7 Hz), 3.4 (s, 1H), 2.0-1.7 (m, 8H); MS (FI-POS) m/z @231.
[0272] A solution of 2-bromo-5-cyano-3-methylthiophene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.6 g, 62%) as a pale-yellow solid. mp: 135-136° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 7.8 (s, 1H), 7.4-7.3 (m, 2H), 7.0 (d, 1H, J=8.0 Hz), 2.3 (s, 3H), 2.0-1.8 (m, 8H); MS [M−H]−=307.
EXAMPLE 74
5′-(4Cyano-3-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0273] A solution of 4-cyano-3-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 36%) as a yellow solid. mp: dec. @235° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 7.9 (t, 1H, J=7.6 Hz), 7.9 (dd, 1H, J=1.4, 10.2 Hz), 7.3 (td, 2H, J=1.6, 6.5 Hz), 7.6 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
EXAMPLE 75
5′-(3-cyano-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0274] A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)paladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.10 g, 10%) as white crystals. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.3 (dd, 1H, J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
EXAMPLE 76
5′-(3-Chloro-4fluorophenyl)-spiro [cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0275] A solution of 3-chloro-4-fluoro-bromobenzene (0.4 cm3, 0.66 g, 3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.65 g, 66%) as a pale-yellow solid. mp: 202-204° C., 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 7.9 (dd, 1H, J=2.3, 4.9 Hz), 7.7-7.6 (m, 1H), 7.6 (d, 1H, J=1.5 Hz), 7.5 (s, 1H), 7.4 (d, 1H, J=1.8 Hz), 6.9 (d, 1H, J=8.0 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=314.
EXAMPLE 77
5′-(3Cyanophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0276] A solution of 3-bromobenzonitrile (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.30 g, 40%) as an off-white solid. mp: 217-219° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.2 (s, 1H), 8.0 (d, 1H, J=8.1 Hz), 7.8 (d, 1H, J=7.7 Hz), 7.6 (m, 2H), 7.5 (dd, 1H, J=1.8,6.3Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=287.
EXAMPLE 78
5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-yl)-2-thiophenecarbonitrile
[0277] A solution of 2-bromo-5-cyanothiophene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.3 g, 40%) as a yellow solid. mp: 248° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.5 (d, 1H, J=1.4 Hz), 8.3 (d, 1H, J=1.4 Hz), 7.6 (s, 1H), 7.5 (dd, 1H, J=1.7, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M−H]−=293.
EXAMPLE 79
5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)furan-2-carbonitrile
[0278] A solution of 5-cyano-2-bromofuran (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 49%) as an off-white solid. mp: 193-194° C.; 1H NMR (DMSO-d6) δ 10.6 (s, 1H), 7.7 (d, 2H, J=3.3 Hz), 7.6 (dd, 1H, J=1.6, 6.6 Hz), 7.1 (d, 1H, J=3.8 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.8 (m, 8H); MS [M−H]−=277.
EXAMPLE 80
5′-(3Cyano-5-fluorophenyl)-spiro [cyclopentane-1,3′-[3H]indol]-2′(1′H)-one
[0279] A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.35 g, 44%) as white needles. mp: 235-237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M− @m/z 306.
EXAMPLE 81
3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)phenylacetonitrile
[0280] Prepared from 3-bromophenylacetonitrile and 2′-oxo-2′,3,-dihydrospiro[[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid according to the procedure for example 18 to afford the title compound as a white powder; mp. 190-193° C.; 1H-NMR (DMSO-d6) δ 10.42 (s, 1H), 7.67 (d, 1H, J=1.39 Hz), 7.58 (d, 2H J=6.87 Hz), 7.46 (m, 2H), 7.31 (d, 1H J=7.6 Hz), 6.94 (d, 1H, J=8.05 ) 4.10 (s, 2H) 2.04-1.50 (m, 19H); MS m/z 316 (M+). Anal. Calc. For C21H20N2O2.0.2H2O: C, 78.82, H, 6.42, N, 8.75. Found: C, 78.73, H, 6.44, N, 8.52.
EXAMPLE 82
3-(3,3-Dimethyl-2oxo-2,3-dihydro-1H-indol-5-yl)5-fluoro-benzonitrile
[0281] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (640 mg, 3.1 mmol) and 5-bromo-3-cyano-fluorobenzene (423 mg, 21.2 mmol) to afford the title compound (261 mg, 0.93 mmol, 44%) as a yellow solid: m.p. 231.2-232.3° C., 1H NMR (DMSO-d6) δ 1.32 (s, 6H), 6.95 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.1, 1.8Hz, 1H), 7.76(d, J=8.4 Hz, 1H), 7.85 (d. J=1.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.07 (s, 1H), 10.52 (s, 1H); MS (EI) m/z 280 (M)+.
EXAMPLE 83
3,3-Dimethyl-5-(5nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one
[0282] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (384 mg, 1.9 mmol) and 2-bromo-5-nitrothiophene (300 mg, 1.4 mmol) to afford the title compound (270 mg, 0.9 mmol, 65%) as a yellow brown solid: m.p. 223-225° C., 1H NMR (CDCl3) δ 1.5 (s, 6H), 6.99 (d, J=8.1 Hz, 1H), 7.18 (d, J=4.3 Hz, 1H), 7.44 d, J=1.7 Hz, 1H), 7.51 (dd, J=8.1, 1.9 Hz, 1H), 7.91 (d, J=4.3 Hz, 1H), 8.07 (br s, 1H); MS (EI) m/z 288 (M)+.
EXAMPLE 84
2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic Acid tert-Butyl Ester
[0283] Prepared according to the procedure for example 18 using 5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one (1.24 g, 5.2 mmol) and N-BOC-pyrrole-2-boronic acid (1.5 g, 5.93 mmol) to afford the title compound (506 mg, 1.5 mmol, 30%) as off-white solid: m.p. 168.4-170.2° C., 1H NMR (DMSO-d6) δ 1.26 (s, 6H), 1.28 (s, 9H), 6.1 (dd, J=3.2, 1.8 Hz, 1H), 6.2 (dd, J=3.2, 3.2 Hz, 1H), 6.8 (d, J=7.9Hz, 1H), 7.1 (dd, J=7.9, 1.6 Hz, 1H), 7.2 (d, J=1.6 Hz, 1H), 7.3 (dd, J=3.2, 1.8 Hz, 1H), 10.4 (s, 1H); MS (APCI) m/z 327 (M+H)+.
EXAMPLE 85
2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5yl)-2-nitro-pyrrole
[0284] To a solution of 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester (0.90 g, 2.8 mmol) in acetonitrile (anhydrous, 40 mL) at −15° C. was added silver nitrate (0.49 g, 2.9 mmol) followed by acetyl chloride (0.21 mL, 2.95 mmol). The reaction was allowed to warm to room temperature and stirred 16 h. Dichloromethane (250 mL) was added to the reaction mixture; filtered through celite and washed with water, saturated sodium bicarbonate, water then brine dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (2:3 ethyl acetate/hexane) gave 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylic acid tert-butyl ester as a yellow solid: 1H NMR (CDCl3) δ 1.43 (s, 6H), 1.48 (s, 9H), 6.3 (d, J=4.1 Hz, 1H), 7.0 (d, J=8.0 Hz, 1H), 7.2 (d, J=4.1 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.4 (dd, J=8.0, 1.7 Hz, 1H), 8.2 (s, 1H).
[0285] 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylic acid tert-butyl ester, was placed in a 50 mL round bottomed flask under nitrogen. A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 160° C. After 10 min at this temperature, the flask was removed from the oil bath and allowed to cool. The black residue was washed into a larger flask with acetone and adsorbed onto a small amount of florisil. Purification by flash column chromatography on silica gel (1:2 EtOAc:hexane) to afford the title compound (76 mg, 15%) which was triturated from ether/hexane to provide a greenish-yellow solid, mp 293.9-294.2° C. (dec). 1H NMR (DMSO-d6) δ 1.3 (s, 6H), 6.77 (d, J=4.3 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.26 (d, J=4.3 Hz, 1H), 7.78 (dd, J=8.1, 1.8 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 10.55 (s, 1H), 13.12 (s, 1H); MS (ESI) m/z 270 (M−H)−.
EXAMPLE 86
5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile
[0286] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (570 mg, 2.8 mmol) and 5-bromo-thiophene-2-carbonitrile (350 mg, 1.9 mmol) to afford the title compound (299 mg, 1.1 mmol, 60%) as an off-white solid: m.p. 255-256° C., 1H NMR (CDCl3) δ 1H NMR (CDCl3) δ 1.46 (s, 6H), 6.97 (d, J=8.1 Hz, 1H), 7.21 (d, J=3.9Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.47 (dd, J=8.1, 1.8Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 8.14 (s, 1H); MS (EI) m/z 268 (M)+.
EXAMPLE 87
3-(3,3-Dimethyl-2-oxo-2,3dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile
[0287] Prepared according to the procedure for example 18 using (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl)boronic acid (300 mg, 1.5 mmol) and 4-bromo-2-fluoro-benzonitrile (240 mg, 1.2 mmol) to afford the title compound (185 mg, 0.66 mmol, 55%) as an off white solid: m.p. 270-272° C., 1H NMR (DMSO-d6) δ 1.31 (s, 6H), 6.96 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 1.5 Hz, 1H), 7.85 (s, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.96 (dd, J=7.5, 7.5, 1H), 10.56 (s, 1H); MS (ESI) m/z 279 (M−H)−.
EXAMPLE 88
Pharmacology
[0288] The biological activity for the compounds of the current invention was evaluated in the in-vitro and in-vivo assays described below. In-vitro potencies lie in the range 0.01 nM-10,000 nM, and in-vivo potencies in the range 1 μg/kg to 100 mg/kg.
[0289] A. In-vitro Biology
[0290] The in-vitro biology is determined by (1) competitive Radioligand Binding: using the A-form of the human progesterone receptor with progesterone as the radioligand; (2) co-transfection assay, which provides functional activity expressed as agonist EC50 and Antagonist IC50 values; (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagonist data; and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagonist data.
[0291] 1. hPR Binding Assay
[0292] This assay is carried out in accordance with: Pathirana, C., Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.; Torres, A., Glodman, M. E., Nonsteroidal human progesterone receptor modulators from the marine alga cymnoplia barbata, J. Steroid Biochem Mol. Biol., 1992, 41, 733-738.
[0293] 2. PRE-luciferase Assay in CV-1 Cells
[0294] The object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity in CV-1 cells co-transfected with human PR and PRE-luciferase plasmids. The materials methods used in the assay are as follows.
[0295] a. Medium:
[0296] The growth medium was as follows: DMEM (Bio Whittaker) containing 10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows: DMEM (Bio Whittaker), phenol red-free, containing 10% (v/v) charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
[0297] b. Cell Culture, Transfection, Treatment, and Luciferase Assay
[0298] Stock CV-1 cells are maintained in growth medium. Co-transfection is done using 1.2×107cells, 5 mg pLEM plasmid with hPR-B inserted at SphI and BamHI sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml. Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II. After electroporation, cells are resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 μl. Following overnight incubation, the medium is changed to experimental medium. Cells are then treated with reference or test compounds in experimental medium Compounds are tested for antiprogestational activity in the presence of 3 nM progesterone. Twenty-four hr. after treatment, the medium is discarded, cells are washed three times with D-PBS (GIBCO, BRL). Fifty μl of cell lysis buffer (Promega, Madison, Wis.) is added to each well and the plates are shaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using luciferase reagents from Promega.
[0299] c. Analysis of Results:
[0300] Each treatment consists of at least 4 replicates. Log transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC50or IC50values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear response analyses.
[0301] d. Reference Compounds:
[0302] Progesterone and trimegestone are reference progestins and antiprogestin. All reference compounds are run in full dose-response curves and the EC50or IC50values are calculated.
| TABLE 1 |
|---|
| Estimated EC |
| (CI) for reference progestins from three individual studies |
| TABLE 2 |
|---|
| Estimated IC |
| for the antiprogestin, RU486 from three individual studies |
[0303] Progestational activity: Compounds that increase PRE-luciferase activity significantly (p<0.05) compared to vehicle control are considered active.
[0304] Antiprogestational activity: Compounds that decrease 3 nM progesterone induced PRE-luciferace activity significantly (p<0.05)
[0305] EC50: Concentration of a compound that gives half-maximal increase PRE-luciferase activity (default-nM) with SE.
[0306] IC50: Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced PRE-luciferase activity (default-nM) with SE.
[0307] 3. T47D Cell Proliferation Assay
[0308] The objective of this assay is the determination of progestational and antiprogestational potency by using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. The materials and methods used in this assay are as follows.
[0309] a. Growth Medium:
[0310] DMEM:F12(1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
[0311] b. Treatment Medium
[0312] Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 0.5% charcoal stripped fetal bovine serum, 100 U/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).
[0313] c. Cell Culture
[0314] Stock T47 D cells are maintained in growth medium For BrdU incorporation assay, cells are plated in 96-well plates (Falcon, Becton Dickinson Labware) at 10,000 cells/well in growth medium. After overnight incubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment. Stock compounds are dissolved in appropriate vehicle (100% ethanol or 50% ethanol/50% DMSO), subsequently diluted in treatment medium and added to the cells. Progestin and antiprogestin reference compounds are run in full dose-response curves. The final concentration of vehicle is 0.1%. In control wells, cells receive vehicle only. Antiprogestins are tested in the presence of 0.03 nM trimegestone, the reference progestin agonist. Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, Ill.) in treatment medium for 4 hr.
[0315] d. Cell Proliferation Assay
[0316] At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to manufacturer's instructions. Briefly, cells are fixed in an ethanol containing fixative for 30 min, followed by incubation in a blocking buffer for 30 min to reduce background. Peroxidase-labeled anti-BrdU antibody is added to the wells and incubated for 60 min. The cells are rinsed three times with PBS and incubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20 min depending upon the potency of tested compounds. Then 25 μl of 1 M sulfuric acid is added to each well to stop color reaction and optical density is read in a plate reader at 450 nm within 5 min.
[0317] e. Analysis of Results:
[0318] Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC50or IC50values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analyses in both single dose and dose response studies.
[0319] f. Reference Compounds:
[0320] Trimegestone and medroxyprogesterone acetate (MPA) are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in fill dose-response curves and the EC50or IC50values are calculated.
| TABLE 3 |
|---|
| Estimated EC |
| (CI) for individual studies |
| TABLE 4 |
|---|
| Estimated IC |
| andprogestin, RU486 |
[0321] EC50: Concentration of a compound that gives half-maximal increase in BrdU incorporation with SE; IC50: Concentration of a compound that gives half-maximal decrease in 0.1 trimegestone induced BrdU incorporation with SE
[0322] 4. T47D Cell Alkaline Phosphatase Assay
[0323] The purpose of this assay is to identify progestins or antiprogestins by determining a compound's effect on alkaline phosphatase activity in T47D cells. The materials and methods used in this assay are as follows.
[0324] a. Culture Medium:
[0325] DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (v/v) charcoal stripped fetal bovine serum (not heat-inactivated), 100 U/ml penicillin, 100 μg/ml streptorycin, and 2 mM GlutaMax (GIBCO, BRL).
[0326] b. Alkaline Phosphatase Assay Buffer:
[0327] I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100
[0328] II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate (Sigma).
[0329] c. Cell Culture and Treatment:
[0330] Frozen T47D cells were thawed in a 37° C., water bath and diluted to 280,000 cells/ml in culture medium. To each well in a 96-well plate (Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspension was added. Twenty μl of reference or test compounds diluted in the culture medium was then added to each well. When testing for progestin antagonist activity, reference antiprogestins or test compounds were added in the presence of 1 nM progesterone. The cells were incubated at 37° C. in a 5% CO2/humidified atmosphere for 24 hr.
[0331] d. Alkaline Phosphatase Enzyme Assay:
[0332] At the end of treatment, the medium was removed from the plate and fifty μl of assay buffer I was added to each well. The plates were shaken in a titer plate shaker for 15 min. Then 150 μl of assay buffer II was added to each well. Optical density measurements were taken at 5 min intervals for 30 min at a test wavelength of 405 nM.
[0333] e. Analysis of Results: Analysis of Dose-response Data
[0334] For reference and test compounds, a dose response curve is generated for dose (X-axis) vs. the rate of enzyme reaction (slope) (Y-axis). Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC50or IC50values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear dose response analyses in both single dose and dose response studies.
[0335] f. Reference Compounds:
[0336] Progesterone and trimegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose response curves and the EC50or IC50values are calculated.
| TABLE 5 |
|---|
| Estimated EC |
| (CI) for reference progestins from three independent experiments |
| TABLE 6 |
|---|
| Estimated IC |
| reference antiprogestin RU486 from three independent experiments |
[0337] B. In-vivo Biology
[0338] The primary in-vivo assay is the rat decidualization model which may be used to determine progestational effects of both agonists and antagonists. The secondary in-vivo assay is the rat ovulation inhibition model which is under development and hence the protocol is un-available.
[0339] 1. Rat Decidualization Assay
[0340] The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterine decidualization and compare the relative potencies of various test compounds. The materials and methods used in this assay are as follows.
[0341] a. Methods:
[0342] Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle). Stock solutions of the test compounds in oil (Mazola™) are then prepared by heating (˜80° C.) the mixture to evaporate ethanol. Test compounds are subsequently diluted with 100% corn oil or 10% ethanol in corn oil prior to the treatment of animals. No difference in decidual response was found when these two vehicles were compared.
[0343] b. Animals (RACUC Protocol #5002)
[0344] Ovariectomized mature female Sprague-Dawley rats (˜60-day old and 230 g) are obtained from Taconic (Taconic Farms, NY) following surgery. Ovariectomy is performed at least 10 days prior to treatment to reduce circulating sex steroids. Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum.
[0345] c. Treatment
[0346] Rats are weighed and randomly assigned to groups of 4 or 5 before treatment. Test compounds in 0.2 ml vehicle are administered by subcutaneous injection in the nape of the neck or by gavage using 0.5 ml. The animals are treated once daily for seven days. For testing antiprogestins, animals are given the test compounds and a EC50dose of progesterone (5.6 mg/kg) during the first three days of treatment. Following decidual stimulation, animals continue to receive progesterone until necropsy four days later.
[0347] d. Dosing
[0348] Doses are prepared based upon mg/kg mean group body weight. In all studies, a control group receiving vehicle is included. Determination of dose-response curves is carried out using doses with half log increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg . . . ).
[0349] e. Decidual Induction
[0350] Approximately 24 hr after the third injection, decidualization is induced in one of the uterine horns by scratching the antimesometrial luminal epithelium with a blunt 21 G needle. The contralateral horn is not scratched and serves as an unstimulated control. Approximately 24 hr following the final treatment, rats are sacrificed by CO2asphyxiation and body weight measured. Uteri are removed and trimmed of fat. Decidualized (D-horn) and control (C-horn) uterine horns are weighed separately.
[0351] f. Analysis of Results:
[0352] The increase in weight of the decidualized uterine horn is calculated by D-horn/C-horn and logarithmic transformation is used to maximize normality and homogeneity of variance. The Huber M-estimator is used to down weight the outlying transformed observations for both dose-response curve fitting and one-way analysis of variance. JMP software (SAS Institute, Inc.) is used for both one-way ANOVA and non-linear dose-response analyses.
[0353] g. Reference Compounds:
[0354] All progestin reference compounds were run in full dose-response curves and the EC50for uterine wet weight were calculated.
| TABLE 7 |
|---|
| Estimated EC |
| individual studies |
| TABLE 8 |
|---|
| Estimated average EC |
| intervals for dose-response curves of 3 reference compounds |
| TABLE 9 |
|---|
| Estimated IC |
| antiprogestin, RU 486 |
[0355] Route of administration: Route the compound is administered to the animals
[0356] Body weight: Mean total animal body weight (default-kg)
[0357] D-horn: Wet weight of decidualized uterine horn (default-mg)
[0358] C-horn: Wet weight of control uterine horn (default-mg)
[0359] Decidual response: [(D−C)/C]×100%
[0360] Progestational activity: Compounds that induce decidualization significantly (p<0.05) compared to vehicle control are considered active
[0361] Antiprogestational activity: Compounds that decrease EC50progesterone induced decidualization significantly (p<0.05)
[0362] EC50for uterine weight: Concentration of compound that gives half-maximal increase in decidual response (default-mg/kg)
[0363] IC50for uterine weight: Concentration of compound that gives half-maximal increase in EC50progesterone induced decidual response (default-mg/kg)
| Data for Representative Compounds |
EXAMPLE 89
4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl-2-fluorobenzeneacetonitrile
[0364] Prepared from 4-bromo-2-fluorophenylacetonitrile and (2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid according to the procedure for example 18 to afford the title compound as a white solid; mp. 180-183° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.7 (s, 1H), 7.6-7.7 (m, 4H) 6.9 (d, 1H, J=8.1 Hz), 4.1 (s, 2H),1.9 (m, 2H), 1.7-1.6 (m, 8H). MS (APCI (−)) m/z 333 [M−H]− Anal. calc. for C21H19FN2O. 0.5H2O: C, 73.49, H, 5.87, N, 8.20. Found: C, 73.55, H, 5.50, N, 7.36.
EXAMPLE 90
5-(3-Fluoro4-methoxyphenyl)spiro[cyclohexane1,3-[3H]indol]-2(1H)-one
[0365] Prepared from 4-bromo-2-fluoroanisole and (2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid according to the procedure for example 18 to afford the title compound as a white solid, mp. 178-180° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.65 (d, 1H, J=1.1 Hz), 7.5-7.4 (m, 3H), 7.2(t, 1H, J=8.9 Hz), 6.9 (d, 1H, J=8 Hz), 3.9(s, 3H), 1.9 (m, 2H) 1.7-1.6 (m, 8H); MS (APCI (−)) m/z 324 [M−H]−; Anal. Calc. For C20H20FNO2.: C, 73.83, H, 6.20, N, 4.30. Found: C, 73.55, H, 6.23, N, 4.40.
EXAMPLE 91
5-(3Chlorophenyl)spiro[cyclobutane-1,3-[3H]indole]-2(1H)-one
[0366] 5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one.
[0367] To a stirred solution of spiro[cyclobutane-1,3′-[3H]indol]-2′(1H)-one (J. Med. Chem. 1987, 824-9) (1.0 g, 6 mmol) in glacial acetic acid (10 mL) was added dropwise at room temperature a solution of bromine (0.30 mL, 6 mmol) in glacial acetic acid (6 mL). After stirring for 10 min, anhydrous sodium acetate (0.47 g, 6 mmol) was added and the solution was concentrated in vacuo. The residue was dissolved in ethyl ether (50 mL) and washed sequentially with water (50 mL), aqueous saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethyl ether yielded the product as a white fluffy solid (1.1 g, 73%), mp 235-7° C.; 1H NMR (DMSO-d6, 300 MHz) δ 2.15-2.41 (m, 6H), 6.74 (d, 1H, J=8.2 Hz), 7.33 (dd, 1H, J=2, 8.2 Hz), 7.75 (d, 1H, J=2 Hz), 10.36 (bs, 1H); MS (EI) m/z 251 [M+]; Anal. Calcd for C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 51.98; H, 4.24; N, 5.42.
[0368] To a solution of 5-bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6 g, 2 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). To the solution was added sequentially 3-chlorophenyl boronic acid (0.48 g, 3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water (5 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by HPLC (Zorbax PRO, C 18, 10 u, 15A, 50×250 mm; 35% Water/65% AcCN; 254NM; AMB. temp.) to give the title compound (200 mg, 35%) as a white powder, mp 199.5-201 ° C. 1H NMR (DMSO-d6, 300 MHz) δ 2.21-2.28 (m, 2H), 2.40-2.45 (m, 4H), 6.87 (d, 1H, J=8.1 Hz), 7.37 (‘d’, 1H), 7.44-7.52 (m, 2H), 7.65 (bd, 1H, J=7.8 Hz), 7.76 (bs, 1H), 7.92 (bs, 1H), 10.35 (s, 1H). MS (EI) m/z 283 [M+]. Anal. Calcd for C17H14ClNO: C, 71.96; H, 4.97; N, 4.94. Found: C, 70.75; H, 5.07; N, 4.68.
EXAMPLE 92
5-(3Chlorophenyl)spiro[cyclopropane-1,3-[3H]indole]-2(1H)-one
[0369] To 5-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.2 g, 5 mmol) in tetrahydrofuran (25 mL, anhydrous) at −20° C. was added slowly n-butyllithium (2.5 M solution in hexanes, 3.93 mL, 9.8 mmol), followed by N,N,N′,N′-tramethylethylenediamine (1.48 mL, 9.8 mmol). After 15 min 1,2-dibromoethane (1.27 mL, 15 mmol) was added slowly and the mixture was allowed to reach room temperature. After 5 days, saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL) were added. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with 1 N HCl(25 mL) and brine (25 mL), and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (40% ethyl acetate/hexane) on a pad of silica gel to give the product (40 mg) as white crystals, mp 212-214° C.; 1H NMR (CDCl3, 300 MHz) δ 1.59-1.63 (m 2H), 1.80-1.84 (m, 2H), 7.00-7.03 (m, 2H), 7.28-7.42 (m, 4H), 7.51 (‘t’, 1H), 7.85 (bs, 1H). MS (EI) m/z 269 [M+]. Anal. Calcd for C16H12ClNO: C, 71.25; H, 4.48; N, 5.19. Found: C, 70.78; H, 4.88; N, 5.10.
EXAMPLE 93
2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic Acid, tert-Butyl Ester
[0370] 1-t-Butoxycarbonylpyrrole-2-boronic Acid.
[0371] To 1-tert-butyl pyrrolecarboxylate (Aldrich, 25 g, 0.15 mol, 1.0 eq) in THF at −78° C. (anhydrous, 250 mL) was added LDA (2 M solution in heptane/THF/ethylbenzene, 82 mL, 1.1 eq). After stirring for 30 min at −78° C., trimethylborate (85 mL, 0.750 mol, 5.0 eq) was added. After stirring at −78° C. for 1 h, the dry ice bath was removed and the reaction was allowed to come to room temperature overnight. HCl (0.25 N, 200 mL) was added to the reaction and the THF was removed in vacuo. The aqueous layer was extracted with ethyl ether (3×300 mL). The combined ether layers were washed with water (2×200 mL), then with brine (200 mL), and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. When the product began to crystallize on the rotary, the flask was removed and allowed to stand. The crystals were filtered and washed with ice-cold ethyl ether to give the product (14 g, 44%) as a white solid. Several crystallizations of filtrate from cold ether gave more product (4.5 g, 14%).
[0372] 5-(1,2-Dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic Acid tert-Butyl Ester.
[0373] To a solution of 5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (WAY-163202) (0.6 g, 2.4 mmol) in ethylene glycol dimethyl ether (50 mL) under a nitrogen atmosphere was added tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (0.65 g, 3.1 mmol) and potassium carbonate (0.75 g, 5.4 mmol) in water (5 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography to give the product (0.7 g, 86%) as a tan powder, mp 163-165° C. 1H NMR (DMSO-d6, 400 MHz) δ 1.3 (s, 9H), 2.16-2.49 (m, 6H), 6.19 (dd, 1H, J=1.8, 3.2 Hz), 6.24 (t, 1H, J=3.3 Hz), 6.76 (d, 1H, J=8.1 Hz), 7.09 (dd, 1 H, J=1.8, 8.0 Hz), 7.30 (dd, 1HJ. =1.8, 3.3), 7.48 (d, 1H, J=1.8 Hz), 10.24 (s, 1 H). MS (APCI) m/z 339 [M+H]+. Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C, 69.51; H, 6.38; N, 7.699.
[0374] To a solution of 5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (0.97 g, 2.9 mmol) in acetonitrile (50 mL) and dichloromethane (5 mL) at −20° C. was added silver nitrate (0.51 g, 3.0 mmol). After 20 min, acetyl chloride (0.20 mL, 2.9 mmol) in acetonitrile (3 mL) was added and the solution was allowed to come to room temperature. After 24 h, the reaction mixture was diluted with dichoromethane (100 mL) and filtered through celite. The filtrate was poured into water (100 mL) and the layers were separated. The organic layer was washed with brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (40% ethyl acetate/hexane) to give the title compound (415 mg, 37%) as a yellow powder, mp 265° C. (dec.). 1H NMR (DMSO-d6; 400 MHz) δ 1.45 (s, 9H), 2.17-2.48 (m, 6H), 6.60 (d, 1H, J=4.2 Hz), 6.90 (d, 1H, J=8.1 Hz), 7.35 (dd, 1H, J=2.0, 8.1 Hz), 7.46 (d, 1H, J=4.2 Hz), 7.70 (‘d’, 5 1H, J=1.8 Hz), 10.50 (s, 1H). MS (ESI) m/z 382 [M−H]−. Anal. Calcd for C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C, 62.58; H, 5.60; N, 10.91.
EXAMPLE 94
Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic Acid, tert-Butyl Ester
[0375] To a solution of 5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (1.5 g, 4.0 mmol) in acetonitrile (50 mL) and dichloromethane (5 mL) at −20° C. Was added silver nitrate (0.76 g, 4.5 mmol). After 20 min, acetyl chloride (0.30 mL, 4.0 mmol) in acetonitrile (3 mL) was added and the solution was allowed to come to room temperature. After 24 h, the reaction mixture was diluted with dichloromethane (100 mL) and filtered through celite. The filtrate was poured into water (100 mL) and the layers were separated. The organic layer was washed with brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (40% ethyl acetate/hexane) to give the title compound (650 mg, 41%) as a yellow powder, mp 150-153° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.42 (s, 9H), 1.77-2.00 (m, 8H), 6.55 (d, 1H, J=4.2 Hz), 6.93 (d, 1H, J=8.0 Hz), 7.33 (dd, 1H, J=1.7, 8.0 Hz), 7.37 (‘d’, 1H, J=1.7 Hz), 7.43 (d, 1H, J=4.2 Hz), 10.53 (s, 1H). MS ((−) APCI) m/z 396 [M−H]−. Anal. Calcd for C21H23N3O5: C, 63.47; H, 5.83; N, 10.57. Found: C, 62.95; H, 5.52; N, 10.32.
EXAMPLE 95
5-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclobutane-1,3-[3H]indol]-2(1H)-one
[0376] 2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (350 mg, 0.91 mmol) was placed in a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 150° C. After 20 min at this temperature, the flask was removed from the oil bath and allowed to cool. The residue was dissolved in acetone and was purified by flash column chromatography (40% ethyl acetate/hexane) on a pad of silica gel. Further purification by HPLC gave the title compound (100 mg, 39%) as a bright yellow powder, mp 250° C. (dec.); 1H NMR (DMSO-d6, 400 MHz) δ 2.18-2.48 (m, 6H), 6.77 (dd, 1H, J=2.4, 4.4 Hz), 6.83 (d, 1H, J=8.1 Hz), 7.25 (dd, 1H, J=2.4, 4.3 Hz), 7.73 (dd, 1H, J=2.0, 8.1 Hz), 8.23 (‘d’, 1H, J=1.8 Hz), 10.41 (bs, 1H), 13.13 (s, 1H); MS (ESI) m/z 282 [M−H]. Anal. Calcd. For C15H13N3O3: C, 63.60; H, 4.63; N, 14.83. Found: C, 62.59; H, 4.58; N, 14.28.
EXAMPLE 96
5-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclopentane-1,3-[3H]indol]-2(1H)-one
[0377] 2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (580 mg, 1.5 mmol) was placed in a 25 mL round bottomed flask stoppered with a rubber septum and equipped with nitrogen inlet and a needle to allow gaseous outflow. A vigorous flow of nitrogen was maintained as the flask was placed in an oil bath and heated to 150° C. After 20 min at this temperature, the flask was removed from the oil bath and allowed to cool. The residue was dissolved in acetone and was purified by flash column chromatography (40% ethyl acetate/hexane) on a pad of silica gel. Further purification by HPLC gave the title compound (300 mg, 67%) as a yellow powder, mp 275° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) δ 1.78-2.07 (m, 8H), 6.77 (dd, 1H, J=2.4, 4.2 Hz), 6.86 (d, 1H, J=8.2 Hz), 7.24 (dd, 1H, J=2.4, 4.2 Hz), 7.71 (dd, 1H, J=1.8, 8.2 Hz), 7.87 (‘d’, 1H, J=1.8 Hz), 10.47 (bs, 1H), 13.12 (s, 1H). MS (ESI) m/z 296 [M−H]−. Anal. Calcd. For C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C, 63.82; H, 5.20; N, 13.73.
EXAMPLE 97
5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic Acid, tert-Butyl Ester
[0378] A solution of 5′-Bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1H)-one (2.0 g, 7.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) in ethylene glycol dimethyl ether (50 mL) was stirred under a flow of nitrogen for 15 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassium carbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (30 mL) and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo. Crystallization from 20% ethyl acetate/hexane gave the product (2.2 g, 83%) as a white powder, mp 179-180.5° C. 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (s, 9H), 1.75-1.98 (m 8H), 6.16 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1H, J=7.9 Hz), 7.08 (dd, 1H, J=1.8, 7.9 Hz), 7.14 (‘d’, 1H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz), 10.30 (s, 1H); MS (EI) m/z 352 [M+]; Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.
[0379] To a solution of 5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester (WAY-163755) (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) was added at −78° C. chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). After 90 min, dimethylformamide (11 mL, 140 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash column chromatography on silica gel (30% ethyl acetate/hexane) gave the title compound (1.7 g, 75%) as white crystals, mp 167-9° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.34 (s, 9H), 1.75-1.98 (m, 8H), 6.39 (d, 1H, J=3.7 Hz), 6.84 (d, 1H, J=7.9 Hz), 7.17 (dd, 1H, J=1.8, 7.9 Hz), 7.28 (‘t’, 2H), 10.41 (s, 1H); MS (ESI) m/z 376 [M−H]−. Anal. Calcd. for C22H23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N, 11.04.
EXAMPLE 98
5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile
[0380] The title compound was prepared in a manner similar to example 69 from 5-bromo-4-n-propyl thiophene-2-carbonitrile (1.17 g, 5 mmol), (1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-boronic acid (1.24 g, 5 mmol), tetrakis(triphenylphosphine) palladium, potassium carbonate (2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL) heated at reflux over night, to afford the title compound (0.7 g, 40%): rmp. 168-171° C.; 1H NMR (DMSO-d6) δ 10.56 (s, 1H), 7.93 (s, 1H) 7.52-7.51 (d, 1H, J=1.5 Hz), 7.33-7.29 (dd, 1H, J=1.6 Hz), 7.00-6.96 (d, 1H, J=8.0 Hz), 2.62-2.57 (t, 2H), 1.86 (m, 2H), 1.70-1.56 (m, 11H), 0.88-0.84 (t, H); MS m/z (APCI (+)) 351 [M+H]+. IR (KBr) 1620, 1700, 2200 cm−1; Anal. Calc. For C21H22N2OS1/2H2O: C, 70.2; H, 6.39; N, 7.79. Found. C, 70.67; H, 6.34; N, 7.62.
EXAMPLE 99
5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-n-butyl-2-thiophenecarbonitile.
[0381] The title compound was prepared in a manner similar to example 69 from 5-bromo-4-n-butyl thiophenecarbonitrile1(1.24 g, 5.1 mmol), (1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-boronic acid (1.24 g, 5.05 mmol), tetrakis(triphenylphosphine) palladium (0.25 g), potassium carbonate (2.75 g, 21 mmol), water (10 mL),and dimethoxyethane (50 mL) heated at reflux for 5 hours to afford the title compound (1 g, 54%), m.p. 130-132° C. 1H NMR (DMSO-d6) δ 10.56 (s, 1H), 7.92 (s, 1H), 7.52-7.51 (d, 1H, J=1.2 Hz), 7.32-7.29 (dd, 1H, J=1.5 Hz), 6.98-6.96 (d, 1H, J=8.0 Hz), 2.64-2.59 (t, 2H), 1.99-1.86 (m, 2H), 1.70-1.50 (m, 11H), 1.32-1.22 (m, 2H), 0.86-0.82 (t, 3H ); MS (APCI (+)) m/z 365 [M+H]+; IR (KBr) 1620, 1700; 2200 cm−1; Anal. Caic. For C22H24N2OS 1/4H2O. C, 71.61; H, 6.69; N, 7.59. Found: C, 71.13; H, 6.61 N, 6.91.
EXAMPLE 100
5-(3-Chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0382] To a −25° C. solution of 4-methyl-2-oxindole (3.0 g, 20.2 mmol) (Tett, 1966, 22, 10, 3337-43) in anhydrous THF (100 mL) under N2is added N,N,N′,N′-tetramethylethylenediamine (8.0 mL, 51.0 mmol) followed by dropwise addition of n-butyl lithium (10.0 M in hexanes, 5.1 mL, 51.0 mmol). After 30 min. a solution of 1,5-diuopentane (9.2 mL, 61.0 mmol) in 3 (mL) of THF was added and the reaction mixture was allowed to warm to RT and stir for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dil. HCl (pH 1), water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:4) to afford the product (3.2 g, 15 mmol, 74%) as a tan solid: 1H NMR (CDCl3) δ 1.2-1.45 (m, 1H), 1.55-1.75 (m, 4H), 1.85-1.95 (d,J=13 Hz, 1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H), 6.72 (dd,.J=8.1, 1.0 Hz, 1H), 6.95 (dd,.J=8.1, 8.0 Hz, 1H), 7.32 (dd,J=8.0, 1.0 Hz, 1H), 8.6 (br s, 1H).
[0383] 5-Bromo-4-methylspiro[cyclohexane-1,3-[3H]indol]2(1H)-one.
[0384] A solution of the above oxindole (0.44 g, 2.0 mmol) in CHCl3(10 mL) with sodium acetate (0.28 g, 3.4 mmol) is cooled to 0° C. and treated with bromine (0.11 mL, 2.0 mmol) in CHCl3(4 mL). After 30 min. the mixture is warmed to RT and stirred an additional hour. The reaction mixture is poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give an off-white solid which was purified by column chromatography (SiO2, ethyl acetate: hexane 2:4) to afford (0.2 g, 0.7 mmol, 35%) of the product: 1H NMR (CDCl3) δ 1.2-1.45 (m, 1H), 1.55-1.75 (m 4H), 1.85-1.95 (d, J=13 Hz, 1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H), 6.62 (d, J=8.0 Hz, 1H), 7.4 (d, J=8.0 Hz, 1H), 8.47 (br s, 1H).
[0385] 5-(3-Chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one.
[0386] A solution of the above 5-bromo-4-methyl-oxindole (0.1 g, 0.34 mmol) and tetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol) in dimethoxyethane (10 mL) was stirred under N2for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.065 g, 0.41 mmol) and sodium carbonate (0.1 g, 1.0 mmol) in water (3 mL). The solution was brought to reflux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate:hexane 1:3) to afford the subtitled compound (0.077 g, 0.2 mmol, 70%) as a yellow solid: m.p. 164-165° C.; 1H NMR (CDCl3) δ 1.25-1.4 (m, 1H), 1.6-1.7 (m, 3H), 1.78 (d, J=12.0 Hz, 2H), ), 1.9 (d, J=13.0 Hz, 1H), 2.1-2.35 (m, 3H), 2.49 (s, 3H), 6.75 (d, J=7.9 Hz, 1H), 7.1 (d, J=7.9, Hz, 1H), 7.15-7.18 (m, 1H), 7.26-7.35 (m, 3H), 7.88 (br S, 1H); 13C-NMR (CDCl3) δ 16.71 (q), 20.7, 25.5, 29.9 (t), 48.5 (s), 107.1, 127.0,128.0, 129.4, 129.5, 130 (d), 132.2, 133.0, 134.0, 136.6, 140.1, 144,182.6 (s); MS (EI) m/z 326, (M+H)+ w/1 Cl.
EXAMPLE 101
5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile
[0387] To a solution of tert-bulyl 2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate (0.11 g, 2.6 mmol) in TFA (5 mL) at 0° C. was added silver nitrate (1.1 eq, 49 mg, 2.86 mmol). After 5 min the reaction was poured onto ice, DCM (5 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic layer was washed with brine, dried over MgSO4and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate/hexane to 5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile (20 mg, 21%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 1.4-1.9 (10H, m), 6.94 (d, 1H, J=8.1 Hz), 7.47 (dd, 1H, J=8.1, 1.75 Hz), 7.73 (s, 1H), 7.75 (d, 1H, J=1.75 Hz), 10.6 (s, 1H), 13.4 (s, 1H). M/z (ES) 335 (M−H)−. Anal. calcd for C18H16N4O3, C, 64.3, H, 4.79, N. 16.7. Found, C, 62.2, H, 5.20, N, 15.1.
EXAMPLE 102
5-(2-Nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one.
[0388] According to a procedure described in J. Med. Chem. 1983, 26, p.800, succinic anhydride (2.0 g, 20 mmol) and spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (4.03 g, 20 mmol) gave 4-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoic acid (100%). 1H NMR (d6-DMSO, 300 MHz) δ 1.5-2.0 (m, 10H), 2.56 (t, 1H, J=6 Hz), 3.20 (t, 1H, J=6 Hz), 6.95 (d, 1H, J=8.1 Hz), 7.91 (d, 1H, J=8.1 Hz), 8.0 (s, 1H), 10.7 (s, 1H), 12.1 (s, 1H). MS (EI) m/z 300 (M−H)−.
[0389] According to a procedure described in J. Org. Chem. 1984, p.3840 4-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoic acid (5.64 g, 18 mmol) and thallium nitrate gave dimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate (7.95 g, 18 mmol) as a white powder (71%). 1H NMR (d6-MSO, 300 MHz) δ 1.44-1.84 (m, 1H), 2.68 (dd, 1H, J=4.97, 16.9 Hz), 3.06 (dd, 1H, J=16.9, 10.5 Hz), 3.5 (s, 6H), 4.03 (dd, 1H, J=4.9, 10.5 Hz), 6.78 (d, 1H, J=7.9 Hz), 7.07 (d, 1H, J=7.9 Hz), 7.39 (s, 1H), 10.31 (s, 1H). MS (EI) m/z 346 (M+H)+.
[0390] To a solution of dimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate (2.0 g, 6.0 mmol) in THF (30 mL) was added LiBH4 (2.5 eq, 0.33 g, 15 mmol). The solution was refluxed for 1.5 h, cooled and quenched by the careful addition of 1N HCl. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4and purified by flash column chromatography on silica gel eluting with 5% MeOH/ethyl acetate to give 2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol (78 g, 47%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.53-1.60 (m, 1H), 1.72 (m, 2H), 1.93 (m, 7H), 2.69 (m, 1H), 3.26 (m, 2H), 3.46 (t, 2H, J=5.8 Hz), 4.35 (t, 1H, J=5.2 Hz), 4.55 (t, 1H, J=5.2 Hz), 6.70 (d, 1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 7.03 (s, 1H), 10.2 (s, 1H). M/z (ES) 276 (M+H)+. Anal. calcd for C16H21NO3, C, 96.79, H, 7.69, N, 5.09. Found, C, 70.02, H, 7.64, N, 5.02.
[0391] Oxalyl chloride (4 eq, 1.0 mL, 11 mmol) in DCM (40 mL) at −78° C. was treated with DMSO (8 eq, 1.62 mL, 22 mmol). After 2 min a solution of 2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol (1 eq, 0.78 g, 2.9 mmol) in DMSO:DCM (1:3, 5 mL) was added followed 15 min later by addition of triethylamine (18 eq, 7.2 mL, 52 mmol). The solution was removed from the cooling bath and allowed to reach room temperature. The solution was filtered through celite, concentrated in vacuo and redissolved in MeOH (10 mL). A large excess of ammonium acetate was added and the solution was heated to 60° C. for 1 h then stored in a refrigerator for 16 h. The solution was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4and purified by flash column chromatography on silica gel eluting with 60% ethyl acetate/hexane to give 5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (0.12 g, 19%) as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 1.79-1.83 (m, 2H), 1.95 (m 6H), 6.37 (s, 1H), 6.73 (m, 2H), 7.13 (s, 1H), 7.29 (d, 1H, J=8 Hz), 10.17 (s, 1H), 10.83 (s, 1H). M/z (ES) 253 (M+H)+.
[0392] To a solution of give 5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (45 mg, 0.17 mmol) in DCM:MeCN (1:1, 5 mL) at −40° C. sequentially was added silver nitrate (1.1 eq, 32 mg, 0.19 mmol) and a solution of acetyl chloride (1.1 eq, 0.01 mL, 0.19 mmol) in MeCN (0.5 mL). After 1 h the cooling bath was removed and the reaction was allowed to stir for 16 h. DCM (20 mL) was added and the suspension was filtered through celite, washed sequentially with sat. aq. NaHCO3and brine, dried over MgSO4and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate/hexane to give 5-(2-nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (20 mg, 40%) as a yellow powder. 1H NMR (300 MHz. d6-DMSO) δ 1.63-1.95 (m, 1J), 6.44 (t, 1H, J=2.69 Hz), 6.97 (d, 1H, J=8.1 Hz), 7.22 (t, 1H, J=2.9 Hz), 7.44 (dd, 1H, J=8.1, 1.7 Hz), 7.79 (d, 1H, J=1.4 Hz), 9.39 (s, 1H), 11.85 (s, 1H). M/z 310 (M−H)−.
EXAMPLE 103
5-(4-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0393] The title compound was prepared from CAT-817819 (11.9 g, 7.8 mmol) and 4-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method for Example 18 to afford the product (0.68 g, 42%) as an off white solid: m.p. 226-229° C. 1H NMR (DMSO-d6) δ 10.41 (br s, 1H), 7.68-7.63 (m, 3H), 7.49-7.46 (m, 3H), 6.93 (d, 1H, J=8.0 Hz), 1.99-1.82 (m, 2H), 1.76-1.51 (m, 8H); MS (EI) m/z 311/313 [M]+; C19H18ClON requires C, 73.19; H, 5.82; N, 4.49; Found C, 73.13; H, 5.68; N, 4.40.
EXAMPLE 104
5-(2-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one
[0394] The title compound was prepared from CAT-817819 (1.9 g, 7.8 mmol ) and 2-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method for Example 18 to afford the title compound (0.68 g, 42%) as an off white solid: m.p. 174-175° C.; 1H NMR (DMSO-d6) δ 10.43 (br s, 1H), 7.56-7.52 (m, 2H), 7.43-7.33 (m, 3H), 7.25 (dd, 1H, J=8.0 and 1.7 Hz), 6.93 (d, 1H, J=8.0 Hz), 1.92-1.79 (m, 2H) and 1.77-1.43 (M, 8H); MS (EI) m/z 311/313 [M]+; Anal. Calc. For C19H18ClON: C, 73.19; H, 5.82; N, 4.49; Found C, 73.10; H, 5.86; N, 4.30.
EXAMPLE 105
5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile
[0395] The title compound was prepared from CAT-830083 (0.9 g, 3.9 mmol ) and 5-cyano-furancarbonitrile (0.5 g, 2.6 mmol) according to the method for Example 18 to afford the title compound (0.35, 49%) as an off white solid: m.p. 193-194° C.; 1H NMR (DMSO-d6) δ 10.55 (br s, 1H), 7.69-7.63 (m, 3H), 7.15 (d, 1H, J=3.8 Hz), 6.92 (d, 1H, J=8.1 Hz), 2.00-1.83 (m, 8H); MS (ESI (−)) m/z 277 [M−H]−. Anal. Calc. For C17H14N2O2: C, 73.73; H, 5.07, N, 10.07; Found C, 73.01; H, 4.98; N, 9.6.
[0396] All publications cited in this specification are incorporated herein by reference herein. While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.
Claims
Certificate of Correction present
The claims shown below may not include correction changes. Use the corrected PDF for authoritative text.
What is claimed:
1. A method of contraception, which comprises administering to a female of child bearing age for 28 consecutive days:
a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of Formula 1:
wherein:
R1and R2are selected independently from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), (Oacetyl), aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;
or R1and R2are joined to form a ring comprising —CH2(CH2)nCH2—, —CH2CH2C(CH3)2CH2CH2—,—O(CH2)mCH2—, —O(CH2)pO—, —CH2CH2OCH2—, —CH2CH2N(H)CH2CH2—, or —CH2CH2N(alkyl)CH2CH2—;
or R1and R2comprise a double bond to CMe2, C(cycloalkyl), O, or C(cycloether);
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
R3is selected from the group consisting of H, OH, NH2, C1to C6alkyl, substituted C1to C6alkyl, C3to C6alkenyl, alkynyl, substituted alkynyl, and CORA;
RAis selected from the group consisting of H, C1to C3alkyl, substituted C1to C3alkyl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, and substituted C1to C3aminoalkyl;
R4is selected from the group consisting of H, halogen, CN, NH2, C1to C6alkyl, substituted C1to C6alkyl, C1to C6alkoxy, substituted C1to C6alkoxy, C1to C6aminoalkyl, and substituted C1to C6aminoalkyl;
R5is selected from the group consisting of i), ii), iii); (iv), and (v):
i) a substituted benzene ring with substituents X, Y and Z as shown below:
wherein:
X is selected from the group consisting of halogen, OH, CN, C1to C3alkyl, substituted C1to C3alkyl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3thioalkyl, substituted C1to C3thioalkyl, S(O)alkyl, S(O)2alkyl, C1to C3aminoalkyl, substituted C1to C3aminoalkyl, NO2, C1to C3perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, CORB, OCORB, and NRCCORB;
RBis H, C1to C3alkyl, substituted C1to C3alkyl, aryl, substituted aryl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl;
RCis H, C1to C3alkyl, or substituted C1to C3alkyl;
Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1to C3alkoxy, C1to C3alkyl, and C1to C3thioalkyl;
ii) a five membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, and SO2or 2 or 3 NR6heteroatoms and having one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1to C3alkyl, C1to C3alkoxy, C1to C3aminoalkyl, CORD, and NRECORD;
iii) a five membered heterocyclic ring having in its backbone 1 NR6heteroatom and with one or two independent substituents selected from the group consisting of H, halogen, NO2, C1to C3alkyl, C1to C3alkoxy, C1to C3aminoalkyl, CORD, and NRECORD;
iv) a six membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2and NR6and with one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1to C3alkyl, C1to C3alkoxy, C1to C3aminoalkyl, CORD, and NRECORD;
RDis H, C1to C3alkyl, substituted C1to C3alkyl, aryl, substituted aryl, C1to C3alkoxy, substituted C1to C3alkoxy, C1to C3aminoalkyl, or substituted C1to C3aminoalkyl;
REis H, C1to C3alkyl, or substituted C1to C3alkyl;
R6is H or C1to C3alkyl; and
v) an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, CN, NO2, lower alkoxy, and CF3; or a pharmaceutically acceptable salt thereof; and
c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.
2. The method according to claim 1, wherein the progestational agent is levonorgestrel and the anti-progestin compound has the structure:
wherein:
R5is the substituted benzene ring, wherein Z is H and substituents X and Y are as shown below:
X is selected from the group consisting of halogen, CN, C1to C3alkoxy, C1to C3alkyl, NO2, C1to C3perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms and C1to C3thioalkoxy; and
Y is on the 4′ or 5′ position of the substituted benzene ring and is selected from the group consisting of H, halogen, CN, NO2, C1to C3alkoxy, C1to C3alkyl, and C1to C3thioalkyl.
3. The method according to claim 1, wherein the progestational agent is levonorgestrel and the anti-progestin compound has the structure:
wherein R5is the five membered ring, said ring having the structure:
wherein U is O, S, or NR6;
R6is selected from the group consisting of H and C1to C3alkyl;
X′ is selected from the group consisting of halogen, CN, NO2, C1to C3alkyl and C1to C3alkoxy; zenith the proviso that when X′ is CN, U is not NR6;
Y′ is selected from the group consisting of H, F, CN, NO2and C1to C3alkyl.
4. The method according to claim 1, wherein the progestational agent is levonorgestrel and the anti-progestin is a compound having the structure:
wherein:
R5is the six membered ring, said ring having the structure shown
wherein:
X1is N or CX2;
X2is halogen, CN or NO2.
5. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one;
ii) 3-methyl-5-(3-nitrophenyl)-1,3-dihydroindol-2-one;
iii) 5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;
iv) 5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;
v) 3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one;
vi) 5-(3-Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one;
vii) 5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-3,3-Diethyl-indol-2-one;
vii) 5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one;
viii) 5-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one; and
ix) 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one;
6. The method according to claim 1 wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde;
ii) 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)pyridine carbonitrile;
iii) 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)aniline;
iv) 4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile;
v) 5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-3-carbonitrile;
vi) 2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indo]-5′-yl)-thophiene-2-carbonitrile; and
vii) 5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-furancarbonitrile;
7. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzonitrile;
ii) 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile;
iii) 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile;
iv) 3-(1′-Diethoxymethyl-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile;
v) 3-(7′-Bromo-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile;
vi) 3-(7′-Nitro-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile;
vii) 3-(7′-Amino-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile;
viii) 4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile; and
ix) 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)phenylacetonitrile;
8. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(H)-one;
ii) 5′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
iii) 5′-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
iv) 5′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
v) 5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
vi) 5-[3-(Methylthio)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
vii) 5′-[3-(Methylsulfonylphenyl]spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
viii) 5-[3-(Methylsulfonyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
ix) 5′-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol-2′(1′H)-one;
x) 5′-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one; and
xi) 5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
9. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5-(3-Bromo-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indo]]-2(1H)-one;
ii) 5′-(3-Fluoro-5-methylphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
iii) 5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
iv) 5-(3-Fluoro-5-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
v) 5′-(3-Hydroxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
vi) 5-[4-Fluoro-3-nitrophenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
vii) 5-(3-cyano-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
viii) 5′-(4-Cyano-3-fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
ix) 2,3,5,6-Tetrahydro-5-(3-nitrophenyl)spiro[3H-indole-3,4-[4H]pyran]-2(1H)-one;
x) 5′-(Pyrimidin-5-yl)-spiro[cyclohexane]-1,3′-[3H]indol-2′(1H)-one;
xi) 5′-(1H-Indol-4-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
xii) 5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
xiii) 5-(5-Acetyl-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one; and
xiv) 5′-(5-Nitro-1-methyl-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one;
10. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-thiophenecarbonitrile;
ii) 4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophene carbonitrile;
iii) 4-Ethyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile;
iv) 5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl)-2-nitro-thiophene;
v) 5′-(3-Chlorophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one;
vi) 5′-(3-Nitrophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one;
vii) 5′-(5-Chloro-3-methylbenzo[b]thien-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one; and
viii) 5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one;
11. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5′-(4-Cyano-3-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
ii) 5′-(3-cyano-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
iii) 5′-(3-Chloro-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
iv) 5′-(3-Cyanophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
v) 4-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile;
vi) 5′-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
vii) 4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-2-thiophene carbonitrile;
viii) 5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′yl-2-nitrothiophene; and
ix) 5′-(3-nitrophenyl)spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one;
12. The method according to claim 1, wherein the anti-progestin is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
i) 5-(3-Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;
ii) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile;
iii) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methyl thiophene-2-carbonitrile;
iv) 5-(3-Chloro-5-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;
v) 5-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;
vi) 4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;
vii) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;
viii) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-fluoro-benzonitrile;
ix) 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole;
x) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile;
xi) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile;
xii) 3,3-Dimethyl-5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one;
xiii) 5′-(3-Chlorophenyl)spiro[1,3-dioxolane-2,3′-[3H]indol]-2′(1H)-one; and
xiv) 5′-(3-Chlorophenyl)spiro[1,3-dioxane-2,3′-[3H]indol]-2′(1′H)-one;
13. The method according to claim 1 wherein the progestational agent is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, and (17-deacetyl)norgestimate.
14. The method according to claim 1, which comprises:
a) a first phase of 21 daily dosage units of said progestational agent;
b) a second phase of 3 daily dosage units of said antiprogestin compound; and
c) optionally, 4 daily dosage units of said orally and pharmaceutically acceptable placebo to be administered on each day of the 28-day cycle following the first phase and second phase.
15. A method of contraception, which comprises administering to a female of child bearing age for 28 consecutive days:
or a pharmaceutically acceptable salt thereof; and
a) a first phase of from 14 to 24 daily dosage units of about 35 to about 100 μg of levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound of the formula:
wherein:
R5is (i), (ii), or (iii):
(i) a substituted benzene ring of the formula:
wherein:
X is selected from the group consisting of halogen, CN, C1to C3alkoxy, C1to C3alkyl, NO2, C1to C3perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms and C1to C3thioalkoxy; and
Y is on the 4′ or 5′ position and is selected from the group consisting of H, halogen, CN, NO2, C1to C3alkoxy, C1to C4alkyl, and C1to C3thioalkyl;
(ii) a five membered ring of the structure:
wherein
U is O, S, or NR6;
R6is selected from the group consisting of H, C1to C3alkyl, and C1to C4CO2alkyl,
X′ is selected from the group consisting of halogen, CN, NO2, C1to C3alkyl and C1to C3alkoxy; with the proviso that when X′ is CN, U is not NR6;
Y′ is selected from the group consisting of H, F, CN, NO2and C1to C4alkyl; or
(iii) a six membered ring having the structure shown
wherein:
X1is N or CX2;
X2is halogen, CN or NO2;
c) optionally, a third phase of daily dosage units of an orally and phamaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28.
16. The method according to claim 15, wherein the antiprogestin is 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester, or a pharmaceutically acceptable salt thereof.
Patent Citations (66)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3635964(A) | 1972-01-01 | Skorcz et al. | Applicant |
| US3917592(A) | 1975-11-01 | Kobzina | Applicant |
| US4093730(A) | 1978-06-01 | Butti | Applicant |
| US4440785(A) | 1984-04-01 | Walsh | Applicant |
| US4666913(A) | 1987-05-01 | Kubla et al. | Applicant |
| US4670566(A) | 1987-06-01 | Walsh | Applicant |
| US4721721(A) | 1988-01-01 | Kuhla | Applicant |
| US4822794(A) | 1989-04-01 | Spada | Applicant |
| US4831027(A) | 1989-05-01 | Narr et al. | Applicant |
| US4853473(A) | 1989-08-01 | Fischer et al. | Applicant |
| US5007952(A) | 1991-04-01 | Kume et al. | Applicant |
| US5171851(A) | 1992-12-01 | Kim et al. | Applicant |
| US5414088(A) | 1995-05-01 | Von Der Saal et al. | Applicant |
| US5453516(A) | 1995-09-01 | Fischer et al. | Applicant |
| US5475020(A) | 1995-12-01 | Johnson et al. | Applicant |
| US5521166(A) | 1996-05-01 | Grubb | Applicant |
| US5681817(A) | 1997-10-01 | Hodgen et al. | Applicant |
| US5688808(A) | 1997-11-01 | Jones et al. | Applicant |
| US5688810(A) | 1997-11-01 | Jones et al. | Applicant |
| US5693646(A) | 1997-12-01 | Jones et al. | Applicant |
| US5693647(A) | 1997-12-01 | Jones et al. | Applicant |
| US5696127(A) | 1997-12-01 | Jones et al. | Applicant |
| US5696130(A) | 1997-12-01 | Jones et al. | Applicant |
| US5696133(A) | 1997-12-01 | Pooley et al. | Applicant |
| US5719136(A) | 1998-02-01 | Chwalisz et al. | Applicant |
| US5733902(A) | 1998-03-01 | Schneider | Applicant |
| US5808139(A) | 1998-09-01 | Pathirana | Applicant |
| US5874430(A) | 1999-02-01 | Christ | Applicant |
| US6077840(A) | 2000-06-01 | Kurihara | Applicant |
| DE3633861 | 1988-04-01 | Applicant | |
| DE4330234 | 1995-03-01 | Applicant | |
| DE4344463 | 1995-06-01 | Applicant | |
| EP22317 | 1981-01-01 | Applicant | |
| EP208510 | 1987-01-01 | Applicant | |
| EP311135 | 1989-04-01 | Applicant | |
| EP385850 | 1990-09-01 | Applicant | |
| EP483077 | 1991-09-01 | Applicant | |
| EP454330 | 1991-10-01 | Applicant | |
| EP535529 | 1992-09-01 | Applicant | |
| EP510235 | 1992-10-01 | Applicant | |
| EP947507 | 1999-10-01 | Applicant | |
| EP978279 | 2000-02-01 | Applicant | |
| JP63112584 | 1988-05-01 | Applicant | |
| WO86/03749 | 1986-07-01 | Applicant | |
| WO91/04974 | 1991-04-01 | Applicant | |
| WO91/06545 | 1991-05-01 | Applicant | |
| WO93/12085 | 1993-06-01 | Applicant | |
| WO94/14434 | 1994-07-01 | Applicant | |
| WO94/29272 | 1994-12-01 | Applicant | |
| WO95/11013 | 1995-04-01 | Applicant | |
| WO95/20389 | 1995-08-01 | Applicant | |
| WO95/20972 | 1995-08-01 | Applicant | |
| WO95/33746 | 1995-12-01 | Applicant | |
| WO96/15794 | 1996-05-01 | Applicant | |
| WO96/19458 | 1996-06-01 | Applicant | |
| WO96/19997 | 1996-07-01 | Applicant | |
| WO97/13767 | 1997-04-01 | Applicant | |
| WO97/49407 | 1997-12-01 | Applicant | |
| WO98/10765 | 1998-03-01 | Examiner | |
| WO98/14436 | 1998-04-01 | Applicant | |
| WO98/27059 | 1998-06-01 | Applicant | |
| WO98/55116 | 1998-12-01 | Applicant | |
| WO99/10325 | 1999-03-01 | Applicant | |
| WO99/11264 | 1999-03-01 | Applicant | |
| WO99/15500 | 1999-04-01 | Applicant | |
| WO99/44608 | 1999-09-01 | Applicant |
Non-Patent Literature (42)
- Katzung, Basic & Clinical Pharmacology, 6th edition, 1995, p. 620.Applicant
- Mamaev, V.P., et al., “Synthesis of 4H-Thieno [3,2-B] Pyrrol-5(6H)-One” Bulletin of the Academy of Sciences on the USSR. Division of Chemical Science, US, Consultants Bureau. New York. vol. 9, p. 1549-1553, 1966.Applicant
- Derwent WPI Abstract, Chwalisz, K., et al. “Female Contraceptive Method Comprises Gestation Treatment with Intermittent Progesterone Antagonist Administration.”, DE 4,330,234, (Mar. 1995).Applicant
- Derwent WPI Abstract, Chwalisz, K., et al. “Contraceptive Pack for Implantation Inhibition—Contains Competitive Progesterone Antagonist and Gestagen for Sequential Oral Administration.”, DE 4,344,463, (Jun. 1995).Applicant
- Kolasa, K., et al., “Preliminary Pharmacological Studies of the Central Action of Phenyl and Piperidinomethyl Derivatives of 2-Benzoxazolone.” Chemical Abstracts, vol. 99, No. 1, Abst. No. 157a, Jul. 4, 1983.Applicant
- Meanwell N.A., et al., “Regiospecific Functionalization of 1,3-dihydro-2H-Benzimidazol-2-One and Structurally Related Cyclic Urea Derivatives” J. Organic Chem., 60(6): 1565-82 (Mar. 24, 1995).Applicant
- Singh, B., et al., “An Efficient and Novel Synthesis of Fused Thiazol-2(3H)-ones” Heterocycles, 36(1): 133-134, p. 136, compounds 16a, 18a, Jan. 1993.Applicant
- Vernin, G., et al., “Etude Dans la Serie des Radicaux Heterocycliques. Partie XV. Decomposition aprotique de 1′ amino-6-ethyl-2-benzothiazole dans des substrats aromatiques et heteroaromatiques: preparation des mesityl-6- et furyl-6-ethyl-2-benzothiazoles, des sels quaternaires et des spiropyrannes correspondants” Helvetica Chimica Acta, 62(1/3):21-30 Jan. 24, 1979.Applicant
- K. Horwitz et al., “Progestin, Progesterone Receptors, and Breast Cancer”, “Hormones and Cancer”, publisher: Birkhaeuser, Boston, Mass., ed. Vedeckis, p. 283-306 (1996).Applicant
- R.M. Evans, “The Steroid and Thyroid Hormone Receptor Superfamily”, Science, 240:889 (May 13, 1988).Applicant
- A. Ulmann et al., “Clinical Uses of Mifepristone (MFP)”, Ann. N.Y. Acad. Sci., 261:248 (Jun. 12, 1995).Applicant
- R. Kekkonen et al., “Sequential Regiment of the Antiprogesterone RU486 and Synthetic Progestin for Contraception”, Fertility and Sterility, 60(4):610 (Oct. 1993).Applicant
- K. Horwitz et al., “Progestin, Progesterone Receptors, and Breast Cancer”, “Horm. Cancer”, publisher: Birkhaeuser, Boston, Mass., ed. Vedeckis, p. 283-306 (1996) abstract only.Applicant
- A. A. Murphy et al., “Regression of Uterine Leiomyomata in Response to the Antiprogesterone RU 486”, J. Clin. Endo. Metab., 76(2):513 (Feb. 1993).Applicant
- L. M. Kettel et al., “Endocrine Responses to Long-Term Administration of the Antiprogesterone RU486 in Patients with Pelvic Endometriosis”, Fertility and Sterility, 56(3):402 (Sep. 1991).Applicant
- H. Michna et al., “Differentiation Therapy with Progesterone Antagonists”, Ann. N.Y. Acad. Sci., 761:224 (Jun. 1995).Applicant
- L. Zhi et al., “5-Aryl-1,2-Dihydrochromeno[3,4-f]quinolines: A Novel Class of Nonsteroidal Human Progesterone Receptor Agonists”, J. Med. Chem., 41(3):291 (Oct. 22, 1998).Applicant
- D. W. Combs et al., “Nonsteroidal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors”, J. Med. Chem., 38:4880 (Dec. 8, 1995).Applicant
- K. L. Perlman et al., “20-Oxopregnacalciferols: Vitamin D Compounds that Bind the Progesterone Receptor”, Tet. Letters, 35(15):2295 (1994).Applicant
- L. G. Hamann et al., “Synthesis and Biological Activity of Novel Nonsteroidal Progesterone Receptor Antagonists”, Ann. N.Y. Acad. Sci., 761:383 (Jun. 12, 1995).Applicant
- R. H. K. Chen et al., “Synthesis and SAR of a Novel Series of Spirobenzothlzaepine Derivatives with Antiprogestin Activity”, POI-37, 16th Int. Cong. Het. Chem., Montana (1997).Applicant
- B. Narr et al., “Preparation, Testing, and Formulation of Imidazobenzoxazinones as Cardiotonics”, Chemical Abstracts, 109:22973 (1988).Applicant
- R. J. Hartmann et al., “Effects of Brofoxine, A New Anxiolytic on Experimentally Induced Conflict in Rats”, Proc West. Pharmacol. Soc., 21:51-55 (1978).Applicant
- B. Singh et al., “Novel cAMP PDE III Inhibitor: Imidazo[4,5-b]pyridin-2(3H)-ones and Thiazolo[4,5-b]pyridin-2(3H)-ones and Their Analogs”, J. Med. Chem., 37:248 (Jan. 21, 1994).Applicant
- A. Andreani et al., “Potential Antitumor Agents XVII (1). Cytotoxic Agents from Indole Derivatives and Their Intermediates”, Acta. Pharm. Nord., 2(6):407 (1990).Applicant
- Sakata et al., “Silver Halide Photographic Materials Useful for Platemaking”, Chemical Abstracts, 123:301431 (1993).Applicant
- P. Pflegel et al., “Polarografie con 7-Chlor-5-phenyl-2-thioxo-1H-e,3-dihydro-1,3,4-benzotriazepinen”, Pharmazie, 37(10): 714-717 (1982).Applicant
- E. I. Barengolts et al., “Progesterone Antagonist RU 486 Has Bone-Sparing Effects in Ovariectomized Rats”, Bone, 17(1):21 (Jul. 1995).Applicant
- E. V. Gromachevskaya et al., “Studies of 4H-3, 1-Benzoxazines”, Chem. Heterocycl. Cmpds. 33(10):1209-1214 (1997).Applicant
- D. Cjoaromp et a;/. “2, 1-Benzisothiazoline 2, 2-Dioxide and Derivatives”, J. Heterocycl. Chem., 23(6):1645-1649 (Nov.-Dec. 1986).Applicant
- A. Turck et al., “On the Metabolism of 3-Substituted and 3,6-Dissustituted Pyridazines”, Tetrahedron, 49(3):599-606 (1993).Applicant
- V. Kumar et al., “Synthesis of 7-Azaindole and 7-Azaoxindole Derivatives through a Palladium-Catalyzed Cross-Coupling Reaction”, J. Org. Chem., 57(25):6995-6998 (1992).Applicant
- P. Canonne et al., “Spirocyclization of 1-(o-Aminophenyl)cycloalkanols and 1-(2′-Amino-3′-pyridinyl)cycloalkanols”, J. Heterocyclic Chem., 26:113 (Jan.-Feb. 1989).Applicant
- M-C. Forest et al., “A Novel Class of Cardiotonic Agents: Synthesis and Biological Evaluation of 5-Substituted 3,6-Dihydrothiadiazin-2-ones with Cyclic AMP Phosphodiesterase Inhibiting and Myofibrillar Calcium Sensitizing Properties”, J. Med. Chem., 35163-172 (Jan. 1992).Applicant
- D. W. Combs et al., “Heteroatom Analogues of Bemoradan: Chemistry and Cardiotonic Activity of 1, 4-Benzothiazinylpyridaziones”, J. Med. Chem., 35:172-176 (Jan. 1992).Applicant
- Kurihari et al., “Synthesis of (±)-PF1092A, B, and C; New Nonsteroidal Progesterone Receptor Ligands”, J. Antibiotics, 50(4):360 (Apr. 1997).Applicant
- A. Kende et al., “Regioselective C-3 Alkylation of Oxindole Dianion”, Synth. Commun. 12(1):1 (1982).Applicant
- T. Tucker et al., “Synthesis of a Series of 4-(Arylethylnyl)-6-Chloro-4-Cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones as Novel Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors”, J. Med. Chem., 37:2347-2444 (Jul. 22, 1994).Applicant
- J. P. Edwards et al., “5-Aryl-1,2-Dihydro-5H-Chromeno[3,4-f]Quinolines as Potent, Orally Active, Nonsteroidal Progesterone Receptor Agonists: The Effect of D-Ring Substituents”, J. Med. Chem., 41:303-310 (Jan. 29, 1998).Applicant
- Derwent WPI abstract, “New Imidazo-Pyridine Derivatives—Useful as Platelet Agglutination Inhibitor, Antiallergic, Antiinflammatory Sedative, Cardiac, and Cardiovascular Vasodilators”, JP 63112584 (May 1988).Applicant
- Derwent WPI abstract, N. Brumagniez et al., “Benzimidazole and Azabenzimidazole(s)—Having Cardiotonic, Vasodilating, Anti-Hypertensive, Anti-Aggregation, and Anti-Ulcer Activity”, EP 385850 (Feb. 1990).Applicant
- Derwent WPI abstract, F. Arndt et al., “New Heterocycle substituted Benzo-Fused Azine and Azole Derivatives—Useful as Selective Herbicides for Pre or Post-Emergence Application”, EP 311135 (Oct. 1988).Applicant