US 4,558,125 AGrant
Benzothiazoline Compounds Which Contain a Carbonyl Group Useful for Treating Cardiovascular Disease
Issue Date:1985-12-10
•11 Claims
Abstract
The invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, which are useful for (i) treating cardiovascular diseases, and (ii) as the active ingredient of pharmaceutical compositions. Formula [I] follows: ##STR1## wherein R.sup.1 is lower alkanoyl; R.sup.2 is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogenolower alkyl and sulfamoyl; R.sup.3 is --COR.sup.8 ; R.sup.8 is hydroxy, lower alkoxy, ##STR2## Z is straight or branched alkylene containing 1 to 6 carbon atoms; m is 0 or 1; n is 0 or 1; and p is 4 or 5.
Metadata
Assignee
- Santen Pharmaceutical Co., Ltd.
Inventors
- Jun-ichi Iwao
- Tadashi Iso
- Masayuki Oya
Application Information
Application Number:US 6123236
Filing Date:1984-05-21
Priority Date:1981-09-12
Art Unit:122
Classifications
IPC:
C07D41700C07D41300
Field of Search:
424544548514250;270368;135179;180253;367;239
Patent Drawings
This patent does not have any drawings.
Description
SUMMARY OF THE INVENTION
This invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, ##STR3## wherein R.sup.1 is lower alkanoyl;
R.sup.2 is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogeno-lower alkyl and sulfamoyl;
R.sup.3 is ##STR4## or --COR.sup.8 ; R.sup.4 and R.sup.5, which may be same or different, each is hydrogen, lower alkyl, cyclohexyl or substituted lower alkyl wherein the substituent(s) is/are selected from the group consisting of hydroxy, phenyl, pyridyl, piperidyl or phenylcarbonyl, and said phenyl nucleus may be resubstituted by one or more groups selected from lower alkyl, hydroxy, halogen, lower alkoxy, nitro, cyano, acetamino and lower alkylamino;
R.sup.6 is hydrogen, alkyl containing 1 to 8 carbon atoms, alkanoyl containing 2 to 8 carbon atoms, alkenoyl containing 2 to 8 carbon atoms or furylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may be substituted by one or more groups selected from hydroxy, phenyl and phenylcarbonyloxy, and said phenyl nucleus may be resubstituted by one or more groups selected from lower alkyl, hydroxy, halogen, lower alkoxy, nitro, cyano, acetamino and lower-alkylamino;
R.sup.7 is hydrogen, hydroxy, phenyl-lower alkyl or benzoyl;
R.sup.8 is hydroxy, lower alkoxy, ##STR5## Z is straight or branched alkylene containing 1 to 6 carbon atoms; m is 0 or 1;
n is 0 or 1;
p is 4 or 5,
wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbon atoms. These compounds include those wherein m is 0 and R.sup.2 is methoxy or nitro.
BACKGROUND OF THE INVENTION
The compounds of this invention are novel benzothiazoline derivatives wherein the substituent at 3-position on the benzothiazoline ring is lower alkanoyl and that at 2-position is phenyl which is resubstituted by ether group at any position. 2-Phenylbenzothiazoline derivatives were reported by H. Breuer et al. (U.S. Pat. No. 3,720,683), H. D. Cossey et al. (J. Chem. Soc., 1965, 954) and P. J. Palmer et al. (J. Med. Chem., 14, 248). The U.S. Pat. of Breuer et al. relates to 2-phenylbenzothiazoline derivatives in which phenyl nucleus is substituted by alkyl, etc. but not ether group, and the pharmacological effects are for anti-inflammatory and anti-microbial. Cossey et al. and Palmer et al. reported 2-phenylbenzothiazoline derivatives in which phenyl nucleus is substituted by ether group, but the substituent of 3-position is not lower alkanoyl but hydrogen, alkyl, benzyl, etc., and the pharmacological effect is for anti-microbial.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to benzothiazoline derivatives of the formula [I]. ##STR6##
The compounds of this invention are benzothiazoline derivatives wherein the substituent at 3-position on the benzothiazoline ring is lower alkanoyl and that at 2-position is phenyl which is resubstituted by ether group at any position. The compounds of this invention are not only new in chemical structure but also found useful for treatment of cardiovascular diseases and such effect on cardiovascular diseases has not been found in the known benzothiazoline derivatives. Cardiovascular diseases are angina cordis, arrhythmia, thrombosis, etc., and .beta.-blocker, inhibitor of platelet aggregation, calcium antagonist, etc. are used as therapeutic agent. From the pharmacological tests, it is proved that the compounds of this invention possess a superior platelet anti-aggregation effect and calcium antagonization, so they are useful for cardiovascular diseases. Processes for preparing the compounds of this invention are summarized as follows. The reaction of the compound of the formula [II] with the compound of the formula [III], ##STR7## wherein X is halogen (the same shall be applied hereinafter), or the reaction reversed the above reaction order, i.e., the reaction of the compound of the formula [IV] with the amine derivative, ##STR8## wherein Y is halogen, carboxy or formyl, and Y and --OH may be jointed to form epoxy ring;
Amine derivative is ##STR9## q is 0 or 1, the same shall be applied hereinafter.
The processes are explained in detail as follows. The reaction of the hydroxy derivative of the formula [II] with the halide of the formula [III] needs no specific conditions, and known methods which are generally used for a reaction or hydroxy derivative with halide can be employed, but preferably the reaction is carried out in organic solvent (for example, dimethylformamide) in the presence of base (for example, NaH). The reaction of the compound of the formula [IV] with amine derivative is divided into the following (a)-(d) reactions. ##STR10## Specific conditions are unnecessary for the above-mentioned reactions. Methods which are generally used for a reaction of amine derivative with halide, carboxylic acid derivative, aldehyde derivative or epoxy derivative can be employed.
The compounds of this invention can be converted to acid salts. Said salts are obtained by general methods using inorganic acids or organic acids. Examples of pharmaceutically acceptable salts of the compounds are hydrochloride salt, sulfuric acid salt, phosphoric acid salt, lactic acid salt, maleic acid salt, fumaric acid salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, oxalic acid salt, etc.
The compounds of the formula [I] have stereoisomers because of the existence of one or more asymmetric carbon atoms, and these isomers are included in this invention.
Examples are shown below, and the compounds of this invention are listed in Table I-IX.
The assignments of the NMR spectra in Table X are made according to the numbers of the formula [IX]. ##STR11## But, protons (aromatic), not be assigned, are named as aromatic H (Ar--H). Proton of --OCH.sub.3 group is assigned as --OCH.sub.3 (P) when the group is attached to C.sub.2 '-C.sub.6 ' position of the formula [IX], and assigned as --OCH.sub.3 (A) when the group is attached to the phenyl group which is the substituent of amine moeity of the side chain.
EXAMPLE 1
3-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 86)
1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and 4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and the solution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethyl acetate is added to the reaction mixture and the solution is concentrated in vacuo. To the residue ether is added to produce crystals. Crystals are collected by filtration to give 1.3 g (81%) of the titled compound.
Physical data are shown in Table VII.
The compounds shown in Table VII are prepared by the similar method descrived above using corresponding amine derivatives.
EXAMPLE 2
3-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 86)
1.64 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline, 1.82 g of 3-acetyl-2-[2-(3-chloro-2-hydroxypropoxy)phenyl]benzothiazoline and 10 ml of t-butylamine are dissolved in 30 ml of ethanol and the solution is refluxed for 3 hours. The solution is concentrated in vacuo, and the residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. To this solution 2N HCl/ether is added to produce crystals. Crystals are filtered to give 3.5 g (80%) of the titled compound.
The physical constant of the crystals is the same of the compound obtained in Example 1.
EXAMPLE 3
3-Acetyl-2-[2-(3-dimethylaminopropoxy)phenyl]benzothiazoline (Compound No. 7)
To the suspension of 0.26 g of the sodium hydride in anhydrous DMF, the solution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 5 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF is added. The reaction mixture is stirred for 2 hours at 80.degree. C., and washed with n-hexane after cooling and poured into ice-water. The separated oil is extracted with ethyl acetate. The organic layer is washed with N--NaOH solution, water and saturated sodium chloride solution in the order named and dried over anhydrous magnesium sulfate. Ethy acetate is removed off in vacuo to give 1.0 g (56%) of the titled compound.
Physical data are shown in Table I.
The compounds shown in Table I, II and III are prepared by the similar method described above using corresponding benzothiazoline derivatives and substituted aminoalkyl halides.
EXAMPLE 4
3-Acetyl-2-[2-(3-aminopropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 1)
By substituting 0.83 g of 3-aminopropyl bromide for 3-dimetylaminopropyl chloride in the procedure of Example 3, 1.2 g of the titled compound is obtained.
Physical data are shown in Table I.
EXAMPLE 5
3-Acetyl-2-[2-(3-diethylaminopropoxy)phenyl]benzothiazoline hydrochloride (Compound No. 10)
To the solution of 3.48 g of 3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline in 20 ml of ethanol, 10.3 ml of diethylamine is added and the mixture is refluxed for 2 hours. After removal of ethanol and excess amount of diethylamine in vacuo, ethyl acetate and water are added to the residue. The organic layer is extracted with N-hydrochloric acid, the acidic layer is alkalinized with N-sodium hydroxide solution and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo and the resulting oil is dissolved in methanol. To the solution hydrochloric acid in ethyl acetate is added to give 3.4 g (80%) of the titled compound.
Physical data are shown in Table I.
The compounds shown in Table I, II, III and VIII are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.
EXAMPLE 6
3-Acetyl-2-[2-(3-methylaminopropoxy)phenyl]benzothiazoline fumarate (Copmpound No. 2)
To the solution of 6.55 g of 3-acetyl-2-[2-(3-oxopropoxy)phenyl]benzothiazoline in 100 ml of methanol, 8.10 g of methylamine hydrochloride and 10.0 g of molecular sieves(3A), smashed into fine pieces, are added. To the suspension 1.26 g of sodium cyano borohydride is added and the mixture is stirred for 1 hour at room temperature. 2N-Hydrochloric acid is added to the reaction mixture and methanol is removed off in vacuo. The aqueous layer is washed with ethyl acetate and alkalinized with 2N-sodium hydroxide solution and extracted wiht ethyl acetate. The organic layer is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo and the resulting oil is dissolved in methanol. To the solution fumaric acid and ethyl acetate are added to give 4.9 g (65%) of the titled compound.
Physical data are shown in Table I.
EXAMPLE 7
3-Acetyl-2-[2-[5-(N-cyclohexyl-N-methlamino)pentyloxy]-5-methoxyphenyl]benz othiazoline fumarate (Compound No. 21)
By substituting 4.50 g of 3-acetyl-2-[2-(5-bromopentyloxy)-5-methoxyphenyl]benzothiazoline for 3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline and 3.40 g of N-methylcyclohexylamine for diethylamine in the procedure of Example 5, 4.2 g (70%) of the titled compound is obtained.
Physical data are shown in Table I.
The compounds shown in Table I are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.
EXAMPLE 8
3-Acetyl-2-[3-[3-(N-cyclohexyl-N-methylamino)propoxy]-4-hydroxyphenyl]benzo thiazoline fumarate (Compound No. 37)
3.64 g of 3-acetyl-2-[3-(3-chloropropoxy)-4-hydroxyphenyl]benzothiazoline and 3.40 g of N-methylcyclohexylamine are stirred at 100.degree. C. for 1 hour. After cooling to room temperature, the reaction mixture is dissolved in 50 ml of chloroform, the solution is washed with N-hydrochloric acid, N-sodium hydroxide solution and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. Chloroform is removed off in vacuo and the residue is purified by silica gel column chromatography. The oily product is dissolved in 20 ml of ethyl acetate. To the solution 0.71 g of fumaric acid in 3 ml of methanol is added to give 2.78 g (50%) of the titled compound.
Physical data are shown in Table II.
The compounds shown in Table II and III are prepared by the similar method described above using corresponding bnezothiazoline derivatives and amine derivatives.
EXAMPLE 9
3-Acetyl-2-[2-[2-[4-(3,4-dimethoxyphenetyl)-1-piperazinyl]ethoxy]phenyl]ben zothiazoline dimaleate (Compound No. 57)
3.34 g of 3-acetyl-2-[2-(2-chloroethoxy)phenyl]benzothiazoline and 5.01 g of 1-(3,4-dimethoxyphenetyl)piperazine are stirred at 110.degree. C. for 1 hour. After cooling to room temperature, the reaction mixture is dissolved in 50 ml of chloroform, the solution is washed with N-hydrochloric acid, N-sodium hydroxide solution and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. Chloroform is removed off in vacuo and the resulting oil is dissolved in 50 ml of ethyl acetate. To the solution 2.32 g of maleic acid in 30 ml of ethyl acetate is added to give 6.24 g (80%) of the titled compound.
Physical data are shown in Table IV.
The compounds shown in Table I, IV, V, VI and VIII are prepared by the similar method described above using corresponding benzothiazoline derivatives and amine derivatives.
EXAMPLE 10
3-Acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline (Compound No. 97)
To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF, the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMF is added and stirred for 5 hours at 70.degree. C. After cooling to room temperature the reaction mixture is poured into ice-water and extracted with ethyl acetate.
The organic layer is washed with N-potassium hydroxide solution, water, N-hydrochloric acid and saturated sodium chloride solution in the named order and dried over anhydrous magnesium sulfate. The solvent is removed off and the resulting oil is purified by silica gel column chromatography to give 8.67 g (75%) of the titled compound.
Physical data are shown in Table IX.
EXAMPLE 11
3-Acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline (Compound No. 96)
To the solution of 7.71 g of 3-acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline in 50 ml of methanol, 2N-sodium hydroxide solution is added and the reaction mixture is stirred for 2 hours at room temperature. Methanol is removed off in vacuo. The residue is acidified with 2N-hydrochloric acid to give 5.72 g (80%) of the titled compound.
Physical data are shown in Table IX.
EXAMPLE 12
3-Acetyl-2-[2-[3-(morpholinocarbonyl)propoxy]phenyl]benzothiazoline (Compound No. 100)
To the solution of 1.79 g of 3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g of triethylamine in 20 ml of anhydrous methylene chloride, 0.68 g of isobutyl chloroformate is added dropwise while stirring at -13.degree. C. and stirred additional 10 minutes at the same temperature. To the solution 0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.
After the addition, the reaction mixture is stirred for 1 hour under ice-water cooling and for 1 hour at room temperature. The reaction mixture is washed with 5% citric acid solution, water, N-potassium hydroxide solution and saturated sodium chloride solution in the named oder and dried over anhydrous magnesium sulfate. The solvent is removed off in vacuo to give 1.60 g (75%) of the titled compound.
Physical data are shown in Table IX.
The compounds shown in Table IX are prepared by the similar method described above using corresponding amine derivatives.
Pharmacological Activities
Calcium antagonists have not only potentially beneficial effects in the treatment of many diseases but also serve as valuable research tools to elucidate excitation-contraction coupling in various muscle types (A. Fleckenstein, Ann. Rev. Pharmacol., 17, 149-166, 1977). Therefore, we examined the calcium-antagonistic activity of the compounds of this invention.
Pharmacological test I
The action potentials on the smooth muscles of uterus, teania coli and portal vein are dependent on calcium ion, and therefor these smooth muscle preparations are useful for screening of calcium antagonists. We measured the calcium-antagonistic activity of the compounds by the method using guinea-pig teania coli preparation.
Isolated guinea-pig teania coil was suspended in a 20 ml organ bath with Krebs solution at 32.degree. C. and bubbled with 5% carbon dioxide in oxygen. After equilibration, the muscle was washed with Ca.sup.++ -free Krebs solution, and when the muscle had relaxed to basal level, it was suspended in Ca.sup.++ -free-high-K Krebs solution.
The muscle was exposed to test compounds for 5 minutes before addition of CaCl.sub.2, and the contraction evoked by CaCl.sub.2 (3.times.10.sup.-4 M) was recorded isotonically. The calcium-antagonistic activity was represented by the concentration of test compound which elicited 50% inhibition of Ca.sup.++ -evoked contraction (IC.sub.50).
As shown in Table XI, the compounds of this invention had calcium-antagonistic activity.
Blood platelet plays an important role only in hemostasis but also in thrombosis. Platelet hyperaggregability leads to an inclease in the number of circulating platelet aggregates, which may contribute toward the development of cardiac arrythmias, cardiac arrest or myocardial infarction. These cardiovascular diseases can be prevented by inhibition of platelet aggregation. Therefor, we screened the influence of test compounds on platelet aggragation in vitro, and found that they have anti-aggregatory activity.
Pharmacological test II
Blood was obtained from an anesthetized rabbit using 0.1 volumes of 3.8% sodium citrate as anticoagulant. Platelet rich plasma(PRP) was isolated by centrifugation at 650 rpm for 10 minutes at room temperature. After preincubation of PRP (0.25 ml) with various concentrations of test compounds (14 .mu.l) for 1 minute at 37.degree. C., collagen (3 .mu.g/ml:final concentration) or ADP (3 .mu.M:final concentration) was added to induce aggregation and the aggregation profiles were monitored with RIKADENKI six-channel aggregometer. The control experiment contained saline instead of test compound.
The anti-aggregatory activity was represented by the concentration of test compound which elicited 50% inhibition of control response.
As shown in the Table XII, the compounds of this invention had anti-aggregatory activity.
Toxicity test
Acute toxicity of the compounds of this invention is shown in Table XIII.
(animal)
Male ddy-SLC strain rats (4 weeks of age, weighing 19-21 g) were placed in a breeding room of constant temperature and huminity (23.+-.1.degree. C., 55.+-.5%) and fed freely pellet diet and water ad. libitum for a week. Rats showing normal growth were selected for the test.
(method of administration)
Test compounds are suspended in 0.5% tragacanth suspention and administered orally in a dose of 0.5 ml/20 g body weight.
The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, powder, suppository, injection, etc. The dose is adjusted depending on symptom, dosage form, etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000 mg, in one or a few divided doses.
Examples of formulation are shown below.
The tablets may be treated with the common film-coating and further with sugar-coating.
UTILITY IN AN INDUSTRIAL FIELD
This invention offers novel compounds which are useful for therapeutic agent.
Claims
What we claim is:
1. A compound of the formula (I) and salts thereof, ##STR283## wherein R.sup.1 is lower alkanoyl; R.sup.2 is one to three groups selected from hydrogen, lower n-alkyl, lower n-alkoxy, hydroxy, chloro, bromo, nitro, halogeno-lower alkyl and sulfamoyl; R.sup.3 is --COR.sup.8 ; R.sup.8 is hydroxy, lower alkoxy, ##STR284## R.sup.4 and R.sup.5, which may be same or different, each is hydrogen, lower alkyl, cyclohexyl or substituted lower alkyl, said substituted lower alkyl has at least one substituent selected from the group consisting of hydroxy, phenyl, pyridyl, piperidyl and phenylcarbonyl, and said phenyl nucleus may be substituted by one to three groups selected from lower n-alkyl, hydroxy, chloro, bromo, lower n-alkoxy, nitro, cyano, acetamino and lower n-alkylamino; R.sup.6 is hydrogen, alkyl having 1 to 8 carbon atoms, alkanoyl having 2 to 8 carbon atoms, alkenoyl having 2 to 8 carbon atoms or furylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may be substituted by one to three groups selected from hydroxy, phenyl and phenylcarbonyloxy, and said phenyl nucleus may be substituted by one to three groups selected from lower n-alkyl, hydroxy, chloro, bromo, lower n-alkoxy, nitro, cyano, acetamino and lower n-alkylamino; Z is straight or branched alkylene having 1 to 6 carbon atoms; m is 0 or 1; wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbon atoms.
2. A compound as in claim 1 wherein m is 0.
3. A compound as in claim 1 wherein m is 1 , n is 1 and Z is --CH.sub.2 --.
4. A compound as in claim 1 wherein R.sup.1 is acetyl.
5. A compound as in claim 1 wherein R.sup.2 is hydrogen.
6. A compound as in claim 2 wherein R.sup.2 is methoxy or nitro.
7. A compound as in claim 2 wherein R.sup.8 is --N(R.sup.4) (R.sup.5), R.sup.4 is hydrogen and R.sup.5 is 2-(3,4-dimethoxyphenyl)ethyl.
8. A compound as in claim 2 wherein R.sup.8 is ##STR285## and R.sup.6 is methyl.
9. 3-Acetyl-2-[2-[3-(4- methyl-1-piperazinylcarbonyl)propoxy]phenyl]benzothiazoline of the formula of claim 1.
10. A pharmaceutical composition comprising (i) a compound as in claim 1 in an amount sufficient for treatment for cardiovascular diseases and at least one pharmaceutically acceptable excipient.
11. A method of treatment for cardiovascular diseases which comprises administering a composition comprising a compound as in claim 1 and at least one pharmaceutically acceptable excipient.
Patent Citations (4)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3574218 | 1971-04-01 | Kalman et al. | |
| US3720683 | 1973-03-01 | Hermann et al. | |
| US4479949 | 1984-10-01 | Iwao et al. | |
| WOXWO83/00865 | 1983-03-01 |
Non-Patent Literature (1)
- Stanten Pharmaceutical Co. Ltd. Chem. Abst. 99:22453w Eqiv. BE 894358 Burger, Medicinal Chemistry, 3rd Edition.