US 5,532,240 AGrant
Condensed Thiophene Compound and Pharmaceutical Use Thereof
Issue Date:1996-07-02
•8 Claims
Abstract
A condensed thiophene compound represented by general formula: ##STR1## or a pharmaceutically acceptable salt thereof, wherein ring S represents a thiophene ring; R.sup.1 represents hydrogen, halogen, alkyl, etc.; R.sup.2 represents hydrogen, alkyl, acyl, etc.; G represents --CH.sub.2 --, --CH(OH)--, --CO--, etc.; Q represents alkylene; T represents --N(Rb)(Rc) (wherein Rb, Rc represents each alkyl etc.; or alternatively Rb and Rc are combined together to form cyclic amino); D represents --CH.sub.2 -- or --S--; A and B represent each carbonyl or thiocarbonyl, or are null; and m and n represent each 0, 1 to 4, provided that m+n represents an integer of 4 or less. This compound is useful as an antipsychotic drug having a reduced extrapyramidal side effect.
Metadata
Assignee
- Yoshitomi Pharmaceutical Industries, Ltd.
Inventors
- Tohru Nakao
- Yuji Ono
- Masahiro Bougauchi
- Yasuto Morimoto
Application Information
Application Number:US 2723204
Filing Date:1994-07-08
Priority Date:1991-12-26
Art Unit:122
Classifications
IPC:
A61K 31435C07D49504
Field of Search:
546514544114301;254362
Patent Drawings
This patent does not have any drawings.
Description
FIELD OF THE INVENTION
The present invention relates to novel and pharmaceutically useful condensed thiophene compounds or salts thereof and pharmaceutical uses thereof, and further synthetic intermediates for said condensed thiophene compounds.
BACKGROUND OF THE INVENTION
The following compounds and the method of preparation thereof are disclosed in (1) Chemical Abstracts, vol. 55, column 23488 (1961), (2) Nippon Kagaku Zassi, vol. 83-3, pp. 343-347 (1962), [Chemical Abstracts, vol. 59, column 3862 (1963)], (3) Chemical Abstracts, vol. 64, column 586 (1966), (4) Chemical Abstracts, vol. 69, 18565.times. (1968), (5) U.S. Pat. No. 4,735,940, column 39, lines 50-51 and (6) Journal of Heterocyclic Chemistry, vol. 13, pp. 1347-1349 (1976). ##STR2##
On the other hand, compounds having antipsychotic activity are known by patent publications such as JP-A S60-84282, JP-A S59-227882, JP-A S58-90583, JP-A S63-132887, JP-A S63-183576, JP-A H1-199967 and JP-A H4-308584.
Antipsychotic drugs introduced in 1950's have been played a large role in treating schizophrenia.
In 1960's "dopamine hypothesis" concerned with schizophrenia has been suggested (Carlsson, A. et al, Acta. Pharmacol. Toxicol. 20, 140-144 (1963)) and the strong correlation between the affinity of antipsychotic drugs for D.sub.2 receptors in striatum and the average clinical dose have been reported (Seeman, P. et al, Nature, 261, 717-719 (1976), Creese, I. et al, Science, 192, 481-483 (1976)). After that, the concept of the development of antipsychotic drugs was the blockade of D.sub.2 receptors. However, typical antipsychotic drugs are effective for the treatment of the positive symptoms such as hallucination and delusions, but not effective for that of the negative symptoms such as apathy and social withdrawal (Zubin, J. et al, Comprehensive Psychiatry, 26, 217-240 (1985)). And the extrapyramidal side-effect (EPS: dystonia, akathidia, tardive dyskinesia) and the elevation in the level of serum prolactin in the acute and chronic treatment of typical antipsychotic drugs are the serious problems for patients.
From these points of view, the development of a typical antipsychotic drugs, produce fewer EPS and are more effective than typical antipsychotic drugs in treating schizophrenia, is desired.
The profile of atypical antipsychotic drug are as follows.
1) It is effective for both positive and negative symptoms.
2) It produces fewer EPS.
3) It has no side-effect of internal secretion.
1. Merits by addition of 5-HT.sub.2 receptor antagonistic activity:
In clinical study, it has been reported that the selective 5-HT.sub.2 antagonist ritanserin ameliorates negative symptoms and reduces the incidence of EPS caused by typical antipsychotic drug therapy (Bersani, G. et al, Curr. Ther. Res., 10, 492-499 (1986)). And in preclinical study, it has also been reported that 5-HT.sub.2 antagonists reduced catalepsy induced by haloperidol (Hicks, P. B., Life Sci., 47, 1609-1615 (1990)). On the other hand, syndrome malin induced by neuroleptics is the unbalance of dopaminergic and serotonergic activity in the center of the regulation of temperature has been proposed (Yamawaki, N., Sinkeiseisinyakuri, 11, 17-24 (1989). Therefore, it is expected that additional 5-HT.sub.2 receptor antagonism reduces the syndrome malin.
Risperidone has extremely potent 5-HT.sub.2 and potent D.sub.2 receptor antagonistic properties (Janssen, P. A. J. et al, J. Pharmacol. Exp. Ther. 244, 685-693 (1988)), and has revealed a clinical profile that is distinct from that of existing neuroleptics. Risperidone proved to be an effective antipsychotic, with low EPS liability and with beneficial effects on the negative symptoms of schizophrenia (The 1st International Risperidone Investigator's Meeting (Conference Review), Paris (France), Mar. 9-10, 1992), but it has not a character of atypical antipsychotic drug yet because EPS is appeared in high dose of risperidone and it has side-effect of internal secretion yet.
2. Merits by addition of 5-HT.sub.1A agonist:
5-HT.sub.1A agonist has been reported to be possible to make up for the disadvantage of typical antipsychotic drugs, because 5-HT.sub.1A agonist buspirone improved the depression and EPS caused by haloperidol therapy in clinical study (McMillen, B. A. et al, J. Pharma. Pharmacol., 40, 885-887 (1988)). And, it is supported to the above mentioned possibility that 5-HT.sub.1A agonist 8-OH DPAT and buspirone reverse catalepsy induced by haloperidol in preclinical study (Goff, D. C. et al, J. Clin. Psychopharmacol. 11, 193-197 (1991)), Invernizzi, R. W. et al, Neuropharmacology, 27, 515-518 (1988)). And then, amplification of antipsychotic effect by additional 5-HT.sub.1A agonistic activity is expected, because administration of 8-OH DPAT with D.sub.2 antagonist inhibit conditioned avoidance response (CAR) more potent than that of D.sub.2 antagonist only (Wadenberg, M. L. et al, J. Neural. Transm. 83, 43-53 (1991)).
3. The functional relationships of 5-HT.sub.1A receptors and 5-HT.sub.2 receptors:
By the study of electrical physiology and biochemistry, it has been revealed that 5-HT.sub.1A and 5-HT.sub.2 receptors regulate the serotonergic activity through the K channel (second messenger system in cell) (Bobker, H. H. et al, Trends Neurosci., 13, 169-173 (1990)). Stimulation of 5-HT.sub.1A receptor makes a hyperpolarization, and stimulation of 5-HT.sub.2 receptor makes a depolarization. Therefore, both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist inhibit the serotonergic activity, and the inhibition of serotonergic activity is amplified if 5-HT.sub.1A agonistic and 5-HT.sub.2 antagonistic activities are occurred at the same time. This is supported by the preclinical pharmacological data that anxiolitic and antidepressant effects of 5-HT.sub.1A agonist are reinforced by addition of 5-HT.sub.2 antagonist (Millan, M. J. et al, J. Neural. Transm. 83, 43-53 (1991)).
As mentioned above, it has been reported that the disadvantages of typical antipsychotic drugs are improved by addition of 5-HT.sub.2 antagonistic and 5-HT.sub.1A agonistic activities to the typical antipsychotic drugs (D.sub.2 antagonists). Especially, negative symptoms must be distinguished from depression, but in either symptoms the desired pharmacological effect is activation, and it is suggested that the addition of 5-HT.sub.1A agonistic activity, that improves the depression, improves the negative symptoms like 5-HT.sub.2 antagonistic activity.
As mentioned above, the amplificational effect of serotonergic activity are expected by addition of both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist, therefore it is expected that the addition of both 5-HT.sub.1A agonist and 5-HT.sub.2 antagonist to D.sub.2 antagonist is more effective to the negative symptoms than the addition of either of them to it.
SUMMARY OF THE INVENTION
The present inventors have found that novel condensed thiophene compounds have D.sub.2, 5-HT.sub.2 antagonistic and 5-HT.sub.1A agonistic activities and are useful as potent antipsychotic drugs according with the above-mentioned purposes, and completed the present invention.
DETAILED DESCRIPTION
The present invention provides:
1. a condensed thiophene compound of the formula: ##STR3## or a pharmaceutical acceptable salt thereof.
In the above formula, the ring S means following condensed thiophenes. ##STR4## R.sup.1 is hydrogen, halogen, alkyl, acyl or hydroxyalkyl. R.sup.2 is hydrogen, alkyl, acyl, carbamoyl, substituted carbamoyl, aryl or arylalkyl.
G is --CH.sub.2 --, --CH(OR.sup.3)-- (R.sup.3 is hydrogen, alkyl or acyl), --CO--, or --S(O)t-- (t is 0, 1 or 2).
Q is straight alkylene or branched chain alkylene.
T is a tertiary amino.
D is --CH.sub.2 -- or --S(O)u-- (u is 0, 1 or 2).
A and B are (i) one is absent and the other is carbonyl or thiocarbonyl, or (if) both absent.
When A, B are the case of above-mentioned (i), m is 0 or 1, and n is 0, 1 or 2. When A, B are the case of above-mentioned (ii), m and n are the same or different and each is 0 or an integer of 1 to 4 with the proviso that m+n is an integer of below 4;
2. the compound of the above-mentioned item 1 or a pharmaceutically acceptable salt thereof, wherein T is a tertiary amino of --N(Rb)(Rc) [Rb and Rc are the same or different and each is alkyl, or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino of the formula: ##STR5## wherein q is an integer of 1 to 4, Z is methylene, or N--R.sup.5 (R.sup.5 is aryl, diarylalkyl, heteroaryl or heteroarylalkyl), substituent V is hydrogen, hydroxyl, heteroaryl, heteroarylalkyl or bisarylmethylene and the number of V is 1 to 4. Cyclic amino of formula (1) may contain carbonyl group in the cycle and further may be condensed with aryl or heteroaryl. Ring Am of formula (2) contain amido bond in the cycle and further may contain oxygen atom, sulfur atom, carbonyl and/or N--R.sup.6 (R.sup.6 is hydrogen, alkyl or phenyl).
3. preferable compound of the above-mentioned item 1 selected from the group consisting of:
2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetra hydro-5H-thieno-3,2-b]azepin-5-one,
3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6, 7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetra hydro-8H-thieno[2,3-c]azepin-8-one,
2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tet rahydro-8H-thieno[2,3-c]azepin-8-one,
6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-2-methylthieno[2,3-c]pyridine,
6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-2-(2-(4-(6fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydro-3-methylthieno[2,3-c]pyridine,
6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4, 5,6,7-tetrahydrothieno[2,3-c]pyridine,
3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetra hydro-2-methyl-6-propionylthieno[2,3-c]pyridine,
6-cyclopropylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine,
3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydro-2-methylthieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine, and
6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)e thyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
or a pharmaceutically acceptable salt thereof;
4. Preferable compound of the above-mentioned item 1 selected from the group consisting of:
6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one,
6-acetyl-3-ethyl-2-(2-(4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-t etrahydrothieno[3,2-c]azepin-4-one,
7-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepine,
6-acetyl-3-ethyl-2-(4-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)butyryl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one,
6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one,
2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrah ydro-8H-thieno[2,3-c]azepin-8-one,
2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydr o-8H-thieno[2,3-c]azepin-8-one,
2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydr o-8H-thieno[2,3-c]azepin-8-one,
2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydr o-8H-thieno[2,3-c]azepin-8-one
or a pharmaceutically acceptable salt thereof;
5. a condensed thiophene compound of the formula: ##STR6## wherein X is hydroxyl, or a reactive atom or group derived from hydroxyl (halogen, methanesulfonyloxy, p-toluenesulfonyloxy and so on), and other symbols are as defined in the above-mentioned item 1;
6. a pharmaceutical composition comprising a compound of the above-mentioned item 1 and pharmaceutical additives;
7. an antipsychotic drug containing a compound of the above-mentioned item 1 as an effective ingredient.
In the definitions of the above symbols and in the present specification, halogen means chlorine, bromine, fluorine, iodine; alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl or octadecyl; arylalkyl means, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, 4-naphthylbutyl, diphenylmethyl or bis(4-fluorophenyl)methyl; acyl means, for example, alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl or octanoyl, aroyl such as benzoyl or naphthoyl, heteroarylcarbonyl such as nicotinoyl, thenoyl or furoyl, or cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl or cycloheptylcarbonyl; hydroxyalkyl means, for example, hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl or 1-, 2-, 3- or 4-hydroxybutyl; aryl means, for example, phenyl or naphthyl; substituted carbamoyl means, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, cyclohexylcarbamoyl or piperidinocarbonyl; straight alkylene means, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene or decamethylene; branched chain alkylene means, for example, alkylene substituted by at least one, preferably 1 to 4 alkyl(s) such as propylene, 1-methyltrimethylene, 3-methyltrimethylene, 1-methyl-tetramethylene, 4-methyltetramethylene, 1,4-dimethyltetramethylene, 6-methylhexamethylene or 4,4-dimethyltetramethylene.
In the formula (I), T is a tertiary amino of --N(Rb)(Rc). Wherein Rb and Rc are the same or different and each is alkyl (same as the above), and --N(Rb)(Rc) is exemplified by dialkylamino (e.g. dimethylamino, diethylamino, dipropylamino, diisoproylamino, dibutylamino, dihexylamino, dioctylamino), or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino of the formula: ##STR7## wherein q is an integer of 1 to 4, Z is methylene or N--R.sup.5. Substituent V is hydrogen, hydroxyl, heteroaryl (e.g. pyridyl, thienyl, furyl, pyrimidinyl, 1,2-benzoisothiazol-3-yl, 1,2-benzisoxazol-3-yl, benzothiophen-2- or 3-yl, benzofuran-2- or 3-yl, quinolyl, isoquinolyl, benzoxazol-2-yl, pyrazinyl, pyridazinyl, imidazolyl, 1H-indazol-3-yl, thieno[3,2-c]pyridin-4-yl, furo[3,2-c]pyridin-4-yl, 2-oxo-1-benzimidazolyl, 2-thioxo-1-benzimidazolyl, 2,4-dioxohexahydropyrimidin-1-yl, hydantoin-1-yl), heteroarylalkyl (which may optionally be hydrogenated and is exemplified by pyridylmethyl, furylmethyl, thienylmethyl or (1,4-benzodioxan-2-yl)methyl), or bisarylmethylene (e.g. bis(4-fluorophenyl)methylene, bis(4-chlorophenyl)-methylene) and the number of V is 1 to 4.
R.sup.5 of N--R.sup.5 is aryl (same as the above), diarylalkyl (e.g. diphenylmethyl, bis(4-fluorophenyl)methyl, 2,2-diphenylethyl, 2,2-bis (4-fluorophenyl)-ethyl), heteroaryl (same as the above), or heteroarylalkyl (same as the above).
Cyclic amino of formula (1) may contain carbonyl group in the cycle and further may be fused with aryl (e.g. benzene, naphthalene) or heteroaryl (e.g. furan, thiophene, pyridine, quinoline) to form fused cyclic amino such as 1,2,3,4-tetrahydroisoquinolin-2-yl or phthalimido. Ring Am of formula (2) contain amido bond in the cycle and further may contain oxygen atom, sulfur atom, carbonyl and/or N--R.sup.6 (R.sup.6 is hydrogen, alkyl or phenyl). The ring Am having amido bond in the cycle includes, for example, thiazolidinone, imidazolidinone, pyrazolidinone or pyrrolidinone.
In the above definitions, the aryl and heteroaryl may optionally be substituted by 1 to 3 substituents (e.g. halogen, nitro, amino, cyano, haloalkyl, hydroxyl, alkyl, alkoxy or alkenyl) on the aromatic ring.
Preferable embodiments of T are the group represented by the formula: ##STR8## wherein R.sup.7 is 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, benzo(b)furan-3-yl, benzo(b)thiophen-3-yl, 1,1-dioxobenzo(b)thiophen-3-yl or 1H-indazol-3-yl, which may have 1 or 2 substituents selected from the group consisting of halogen, C.sub.1-4 alkyl (e.g., methyl, ethyl), C.sub.1-4 alkoxy (e.g., methoxy, ethoxy), C.sub.2-4 alkanoyl (e.g., acetyl, propionyl) and 4-fluorophenyl; benzoyl which may have 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; or bis(4-fluorophenyl)methylene; R.sup.8 is 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, benzo(b)furan-3-yl, benzo(b)thiophen-3-yl or benzothiazol-2-yl, which may have 1 or 2 substituents selected from the group consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy.
More preferable embodiments of T are exemplified by 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl, 4-(1,2-benzisothiazol-3-yl)piperidin-1-yl, 4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl, 4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1-yl, 4-(1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(4-fluoro-2-methoxybenzoyl)piperidin-1-yl, 4-(2,4-difluorobenzoyl)piperidin-1-yl, 4-(2-acetyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(2-methyl-6-fluoro-benzo(b)thiophen-3-yl)piperidin-1-yl, 4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(1,2-benzisoxazol-3-yl)piperazin-1-yl, 4-(1,2-benzisothiazol-3-yl)piperazin-1-yl, 4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl, 4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(6-methoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(6-fluoro-2-methylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-chlorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-methoxybenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-bromobenzo(b)furan-3-yl)piperidin-1-yl, 4-(5,6-dimethylbenzo(b) furan-3-yl)piperidin-1-yl, 4-(4,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(5,7-dimethyl-benzo(b) furan-3-yl)piperidin-1-yl, 4-(bis(4-fluorophenyl)methylene)-piperidin-1-yl, 4-(4-hydroxy-2,6-dimethyl benzoyl)piperidin-1-yl, 4-(5-chloro-6-methylbenzo(b) furan-3-yl)piperidin-1-yl, 4-(6-methyl-benzo(b)furan-3-yl)piperidin-1-yl, 4-(5-chloro-2-hydroxybenzoyl)-piperidin-1-yl, 4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(2-hydroxy-5-methylbenzoyl)piperidin-1-yl, 4-(benzo(b)furan-3-yl)piperidin-1-yl, 4-(4-methylbenzo(b) furan-3-yl)piperidin-1-yl, 4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(5-methylbenzo(b)thioph en-3-yl)piperidin-1-yl, 4-(6-methylbenzo(b)-thiophen-3-yl)piperidin-1-yl, 4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl, 4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl, 4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl, 4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl, 4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(7-fluorobenzo(b)-thiophen-3-yl)piperazin-1-yl, 4-(4-methylbenzo(b)thiophen-3-yl)-piperazin-1-yl, 4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(6-methylbenzo(b)-thiophen-3-yl)piperazin-1-yl, 4-(7-methylbenzo(b)-thiophen-3-yl)piperazin-1-yl, and so on.
The salt of the compound of formula (I) include an acid addition salt such as hydrochloride, hydrobromide, phosphate, sulfate, benzenesulfonate, methanesulfonate, citrate, lactate, maleate, fumarate or tartarate. When the compound of formula (I) contain carboxyl as a substituent, the salt includes a metal salt such as sodium salt, potassium salt, calcium salt, aluminum salt, or an amine salt with triethylamine, or bibasic amino acid salt with lysine etc. The pharmaceutically acceptable salts thereof are preferable. The present invention also includes a hydrate and a solvate of the compound of formula (I).
The compounds of formula (I) or (II) having a chiral carbon atom can be prepared as a racemate or an optically active isomer, and the compound having at least two chiral atoms can be obtained as an individual diastereomer or a mixture thereof. The present invention embraces the mixture thereof and the individual isomers. Furthermore, the present invention embraces stereoisomers.
The methods for preparing the compounds of present invention are described as follows:
Method (1)
The compound of formula (I) can be synthesized by reacting the compound of formula (II) with a compound of the formula:
wherein T is as defined above, or acid addition salt thereof.
The reaction is carried out in an inert solvent such as methanol, ethanol, propanol, benzene, toluene, dimethylformamide, tetrahydrofuran, acetonitrile or acetone in the presence of a suitable acid scavenger (e.g. potassium carbonate, sodium carbonate, sodium hydrogencarbonate, pyridine, triethylamine, sodium acetate or potassium acetate) at 20.degree. C.-150.degree. C. for 30 minutes to 30 hours.
When X in the compound of formula (II) is hydroxyl, the reaction is carried out in a suitable inert solvent such as dimethylformamide or benzene in the presence of an aminophosphonium reagent (e.g. N,N-methyl-phenylaminotriphenylphosphonium iodide)at 20.degree. C.-150.degree. C. for 30 minutes to 5 hours.
Method (2)
The compound of formula (I) can be synthesized by reacting a compound of the formula: ##STR9## wherein each symbol is as defined above, with a compound of the formula:
wherein each symbol is as defined above.
The reaction is carried out in an inert solvent such as methanol, ethanol, propanol, N,N-dimethylformamide, benzene, toluene, acetonitrile, diethyl ether, tetrahydrofuran or n-hexane in the presence of a suitable base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium hydride, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate at -20.degree. C.-150.degree. C. for 30 minutes to 5 hours.
Method (3)
The synthetic intermediate compound of formula (II) wherein G is --CO-- can be prepared by reacting a compound of the formula: ##STR10## wherein each symbol is as defined above, with a compound of the formula:
wherein Z.sup.1 is halogen and other symbols are as defined above.
The reaction is carried out in a suitable and inert solvent such as chloroform, dichloromethane or dichloroethane in the presence of a suitable Lewis acid (e.g. tin chloride, aluminum chloride, iron chloride, zinc chloride) at -10.degree. C. to 100.degree. C. for 30 minutes to 5 hours.
Method (4)
The synthetic intermediate compound of formula (II) wherein G is --S-- can be prepared by lithiation of the compound of formula (VI) using a suitable alkyl-lithium, followed by reaction with a compound of the formula:
wherein X.sup.1 and X.sup.2 are the same as the above-mentioned X, but both of them are not hydroxyl, in the presence of sulfur.
The reaction is carried out by lithiation using a suitable alkyl-lithium such as butyllithium or sec-butyllithium in a suitable and inert solvent such as diethyl ether or tetrahydrofuran at a temperature of from -78.degree. C. to the boiling point of the solvent employed, and followed by reaction with sulfur and the compound of formula (VIII).
Method (5)
The synthetic intermediate compound of formula (II) wherein G is --SO-- or --SO.sub.2 -- can be prepared by oxidizing the compound synthesized in Method (4) using a suitable oxidizing agent (e.g. sodium metaperiodate) in a suitable solvent.
Method (6)
The synthetic intermediate compound of formula (II) wherein G is --CH(OH)-- or --CH.sub.2 -- can be prepared by reducing the compound obtained in Method (3) wherein G is --CO-- using a suitable reducing agent such as sodium borohydride.
The reaction is carried out in a suitable and inert solvent, for example, methanol, ethanol, propanol, isoproyl alcohol, tetrahydrofuran, dichloromethane or dichloroethane, in the presence of a suitable reducing agent (e.g. lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, trifluoroboron diethylate, triethylsilane) at -10.degree. C. to 100.degree. C. for 30 minutes to 10 hours.
The compound of formula (I) wherein G is --CH(OH)-- or --CH.sub.2 -- can be prepared by reducing the compound of formula (I) wherein G is --CO-- in a similar manner as the above-mentioned method.
Method (7)
The compound of formula (I) wherein G is --CH(OR.sup.3')-- (R.sup.3' is alkyl or acyl) can be prepared by reacting the compound of formula (I) wherein G is --CH(OH)-- with a compound of the formula:
wherein Z.sup.2 is halogen and R.sup.3' is as defined above.
The reaction is carried out in a suitable and inert solvent such as methanol, ethanol, propanol, butanol, N,N-dimethylformamide, tetrahydrofuran, benzene or toluene in the presence of an acid scavenger (e.g. sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide) at room temperature to 150.degree. C. for 1 to 20 hours.
The compound of formula (VI) wherein one of A and B is absent and the other is carbonyl group can be synthesized by, for example, the following methods.
Method (8)
A method which comprises subjecting a compound of the formula: ##STR11## wherein each symbol is as defined above, to Schmidt rearrangement.
The reaction is carried out by reacting the compound of formula (XVIII) with sodium azide in a suitable and inert solvent such as chloroform, methylene chloride, toluene or benzene or without a solvent in the presence of a suitable acid (e.g. trifluoroacetic acid, polyphosphoric acid, sulfuric acid) at 0.degree. C. to 150.degree. C. for 30 minutes to 10 hours.
Method (9)
A method which comprises subjecting a compound of the formula: ##STR12## wherein R.sup.5 is hydrogen, alkyl, methanensulfonyl group or p-toluene-sulfonyl group and other symbols are as defined above, to Beckmann rearrangement.
The reaction is carried out by reacting the compound of formula (XIX) in a suitable and inert solvent such as benzene, toluene, dimethylformamide or diethyl ether or without solvent in the presence of a suitable acid (e.g. phosphoric acid, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide, polyphosphoric acid, sulfuric acid) at 0.degree. C. to 150.degree. C. for 30 minutes to 10 hours.
The compound of formula (VI) wherein both of A and B are absent can be synthesized by, for example, the following method.
Method (10)
A method which comprises reducing a compound of the formula: ##STR13## wherein each symbol is as defined above.
The reaction is carried out using boron trifluoride-ether complex and sodium borohydride in a suitable and inert solvent such as ether or tetrahydrofuran at 0.degree. C. to the boiling point of the solvent employed for 30 minutes to 10 hours.
Method (11)
The synthetic intermediate compound of the formula: ##STR14## wherein R.sup.1 is as defined above, can be prepared by the following method. ##STR15##
The compound of formula (XXII) can be prepared by a dehydration condensation of the corresponding aldehyde compound with aminoacetoaldehyde dimethyl acetal. The reaction is carried out in a suitable and inert solvent, for example, tetrahydrofuran, diethyl ether, methylene chloride, benzene or toluene, preferably without solvent at 10.degree. C. to 100.degree. C. for 30 minutes to 10 hours.
The compound of formula (XXIII) can be prepared by reducing the compound of formula (XXII) using a reducing agent such as sodium cyano-borohydride, lithium aluminum hydride, aluminum hydride or diisobutylaluminum hydride, preferably sodium borohydride in an inert solvent such as ethanol, butanol, isopropyl alcohol or tetrahydrofuran at -20.degree. C. to 100.degree. C. for 30 minutes to 15 hours.
The compound of formula (XXIV) can be prepared by reacting the compound of formula (XXIII) with an acid such as sulfuric acid, p-toluenesulfonic acid or phosphoric acid, preferably hydrochloric acid, in an inert solvent such as water, tetrahydrofuran, diethyl ether or dioxane, preferably in water at 0.degree. C. to 120.degree. C. for 30 minutes to 15 hours.
The compound of formula (XXI) can be prepared by reacting the compound of formula (XXIV), which usually may not be isolated and purified, with a reducing agent such as a tin(II) chloride in a solvent such as water, tetrahydrofuran, diethyl ether or dioxane, preferably in water, in the presence of an acid such as sulfuric acid, p-toluenesulfonic acid, phosphoric acid, preferably hydrochloric acid at 0.degree. C. to 120.degree. C. for 30 minutes to 15 hours.
The thus obtained compounds of the present invention can be isolated and purified by a conventional method such as recrystallization or column chromatography.
When the obtained compound is a racemate, it can be separated into desired optically active isomers, for example, by means of fractional recrystallization of a salt with an optically active acid or column filled with an optically active carrier. Individual diastereomers can be separated by the method such as fractional crystallization or chromatography. Such compounds can also be obtained by using an optically active starting material. Furthermore, the stereoisomers can be isolated by recrystallization, column chromatography or the like.
The compounds exemplified in the examples and listed in the following tables, or salts thereof are encompassed in the condensed thiophene compounds of formula (I) of the present invention. In the tables, "Me" means methyl, "Et" means ethyl, "C.sub.6 H.sub.5 " means phenyl, and the symbols "I" to "X" in "T" means the following amine molecules: ##STR16##
The pharmacological activities of the compound of formula (I) were examined by a series of receptor binding tests, anti-apomorphine action and anti-ergometrine action as described below.
Experiment Example 1
Affinity for dopamine 2 receptor
A specific binding of dopamine 2 (D.sub.2) receptor was tested according to the method described in Eur. J. Pharmacol. 46, 377 (1977).
A synaptosome fraction was separated from corpus striatum of 9-10 week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.1) containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 10 .mu.M pargyline and 0.1% ascorbic acid for the experiment.
The test compound at several concentrations and tritiated spiperone (final concentration 0.2 nM) were added to the synaptosome suspension, and each mixture was incubated at 37.degree. C. for 20 minutes. After the incubation, the mixture was filtered with suction through Whatman GF/B (trade mark) glass filter. The filter was washed with 50 mM Tris-HCl buffer (pH 7.7), and the radioactivity of the filter was measured by a liquid scintillation counter. Non-specific binding was determined in the presence of 10.sup.-4 M (.+-.)-sulpiride. The concentration necessary for 50% inhibition (IC.sub.50) was determined on a graph, and inhibition constant (Ki value) was calculated. The results are shown in Table 1.
Experiment Example 2
Affinity for serotonin 2 receptor
A specific binding of serotonin 2 (5-HT.sub.2) receptor was tested according to the method described in Mol. Pharmacol. 21, 301 (1981).
A crude synaptosome fraction was separated from hippocampus of 9-10 week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.7) for the experiment. The test compound at several concentration and tritiated ketanserin (final concentration 0.2 nM) were added to the synaptosome suspension, and each mixture was incubated at 37.degree. C. for 20 minutes. After the incubation, the mixture was filtered with suction through Whatman GF/B (trade mark) glass filter. The filter was washed with 50 mM Tris-HCl buffer (pH 7.7), and the radioactivity of the filter was measured by a liquid scintillation counter. Non-specific binding was determined in the presence of 10.sup.-5 M mianserin. The concentration necessary for 50% inhibition (IC.sub.50) was determined on a graph, and inhibition constant (Ki value ) was calculated. The result are shown in Table 1.
Experiment Example 3
Affinity for serotonin 1A receptor
A specific binding of serotonin 1A (5-HT.sub.1A) receptor was tested according to the method described in J. Neurochem. 44, 1685 (1985).
A crude synaptosome fraction was separated from hippocampus of 9-10 week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.4) containing 1 mM manganese chloride for the experiment. The test compound at several concentrations and tritiated 8-hydroxy-2-dipropyl-aminotetralin (8-OH-DPAT, final concentration 0.2 nM) were added to the synaptosome suspension, and each mixture was incubated at 37.degree. C. for 12 minutes. After the incubation, the mixture was filtered with suction through Whatman GF/B (trade mark) glass filter. The filter was washed with 50 mM Tris-HCl buffer (pH 7.7), and the radioactivity of the filter was measured by a liquid scintillation counter. Non-specific binding was determined in the presence of 10.sup.-5 M serotonin (5-HT). The concentration necessary for 50% inhibition (IC.sub.50) was determined on a graph, and inhibition constant (Ki value) was calculated. The results are shown in Table 1.
Experiment Example 4
Anti-apomorphine action (in mouse)
Male dd mice at 3 per group were used for the experiment. The test compound was orally administered to the mice, and 60 minutes later, 0.5 mg/kg of apomorphine hydrochloride was subcutaneously administered. the movement for 20 minutes from immediately after the administration of apomorphine hydrochloride was measured using Valimex (Columbus, USA). Each group was tested four times, and the amount of the test compound necessary to lower the movement by 50% than that of a control group was calculated from a graph and taken as ED.sub.50. The results are shown in Table 2.
Experiment Example 5
Anti-ergometrine action
Male ddY mice at 12 per group were used for the experiment. The test compound was orally administered to the mice, and 60 minutes later, 20 mg/kg of ergometrine maleate was intraperitoneally administered. The amount of the test compound necessary to vanish the head-twitch reaction for 10 minutes from immediately after the administration of ergometrine maleate was calculated as ED.sub.50 value by Probit method. The results are shown in Table 2.
Experimental Example 6
Catalepsy Test
The method of Simon, P. et al (J. Pharm. Pharmacol., 22, 546, 1970) was utilized with a slight modification.
Catalepsy in rats was evaluated at the various time after oral administration of test drugs using a horizontal bar positioned 7 cm above the bench. Cataleptogenic activity was judged to be positive when the forepaws of the rats remained on the bar for more than 30 sec. Ten rats at each dose level were used to determine the ED.sub.50 value required to induce catalepsy in 50% of the animals.
Experiment Example 7
Acute toxicity
Male ddY mice weighing 20-28 g were used at 10 per group. They were orally administered with the compound of Example 24 and observed for 5 days after the administration. The LD.sub.50 (50% lethal dose) was 205 mg/kg.
The compounds of formula (I) were found to have high affinities for dopamine (D.sub.2) receptor and serotonin (5-HT.sub.1A, 5-HT.sub.2) receptors according to the receptor binding assay using the radioligands. And they possessed D.sub.2 antagonistic, 5-HT.sub.2 antagonistic and 5-HT.sub.1A agonistic activities according to the inhibition of apomorphine-induced hyperactivity, ergometrine-induced head-twitches and forskolin-induced adenylate cyclase activity, respectively. Further they were found to have the inhibitory activity of spontaneous locomotor activity, methanphetamine-induced hyperactivity and conditioned avoidance responding. Therefore, these compounds will be effective for the positive symptoms such as hallucination and dellusion. And they were found to be effective for the forced swimming test, an indication of activation, and to have low cataleptogenic activity, an indication of the extrapyramidal side-effects. Therefore, these compounds will also be effective for the negative symptoms, such as apathy and social withdrawal. And they will be effective antipsychotic drugs with the potential for fewer extrapyramidal side-effects. The compounds of formula (II) are useful as synthetic intermediate for the compounds of formula (I).
When the compounds of formula (I) of the present invention are used as pharmaceuticals, a therapeutically effective amount of the compounds and adequate pharmacologically acceptable additives such as excipient, carrier, diluent and so on are mixed to be formulated into a form such as tablets, capsules, granules, syrups, injectable solutions, suppositories, dispersible powders or the like and are administered in the form mentioned above. The dosage may generally range about 5 to about 500 mg per day for an adult in a single dose or divided doses in the case of oral administration.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will be explained in more detail by the following examples, but these examples are not to be construed as limiting the present invention. The following compounds obtained can be identified by the various analysis such as NMR, IR, elemental analysis, mass spectrometry and so on.
Reference Example 1
To a solution of 171 g of 2-methylthiophene in 1500 ml of methylene chloride were added dropwise 500 g of tin(IV) chloride and 300 g of ethyl succinyl chloride under ice-cooling and the mixture was stirred for 1.5 hours. The mixture was poured into water, extracted with chloroform and the organic layer was washed with water, dried over magnesium sulfate and distilled away. To the residue was added isopropyl ether and the precipitated crystals were collected by filtration to give 299 g of white crystals. The resulting crystals were dissolved in 1600 ml of diethylene glycol and 264 g of 100% hydrazine monohydrate was add thereto and the mixture was stirred at 110.degree. C. for 45 minutes. After cooling to 60.degree. C., 445 g of potassium hydroxide was added thereto and the mixture was stirred at 140.degree. C. for 1.5 hours. The mixture was poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled away. The residue was dissolved in 500 ml of acetic anhydride, 5 ml of phosphoric acid was added thereto and the mixture was refluxed with stirring for 80 minutes. The mixture was poured into water, made alkaline with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The mixture of 164 g of the residue, 103 g of hydroxylamine hydrochloride and 124 g of sodium hydrogencarbonate in 500 ml of ethanol was refluxed with stirring for 1.5 hours. The mixture was concentrated in vacuo, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, dried and distilled away. The residue was recrystallized from ethanol to give 152 g of white crystals. The resulting crystals were portionwise added to polyphosphoric acid at 60.degree. C. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel to give 30 g of 2-methyl-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one (m.p. 133.degree.-135.degree. C.) and 93 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one (m.p. 119.degree.-120.degree. C).
Reference Example 2
To a mixture of 61 g of thiophene in 800 ml of tetrahydrofuran was added 500 ml of n-butyllithium dropwise at -25.degree. C. and the mixture was stirred for an hour. To the mixture was added 24.4 g of sulfur at -25.degree. C., the mixture was stirred for 1.5 hours and 111.1 g of 3-bromopropionic acid in 50.1 g of potassium carbonate solution was added dropwise thereto, and then the mixture was stirred at room temperature for 4 hours. The aqueous layer was collected fractionally, washed with toluene, acidified with hydrochloric acid and extracted with chloroform. The organic layer was washed with water, dried and concentrated to give 135 g of a pale yellow oil. To a solution of 125 g of the oil in 1200 ml of toluene was added 153.6 g of trifluoroacetic anhydride dropwise, the mixture was stirred at room temperature for an hour and stirred at 40.degree. C. for further 2 hours. The mixture was poured into ice-cold water and neutralized with sodium hydroxide solution. The toluene layer was washed with water, dried and concentrated in vacuo to give 103 g of a brown oil. To a solution of 103 g of the oil in 1000 ml of ethanol were added 49.9 g of hydroxylamine hydrochloride and 60.3 g of sodium hydrogencarbonate and the mixture was refluxed with stirring for 2 hours. Inorganic substances were filtered off and the filtrate was concentrated. To the residue was added isopropyl ether and the crystals were collected by filtration to give 77 g of white crystals. The resulting crystals were added portionwise to 100% polyphosphoric acid at 70.degree. C. and the mixture was stirred at 80.degree. C. for an hour. After the mixture was poured into water, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 63 g of 2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as pale brown crystals, m.p. 157.degree.-158.degree. C.
EXAMPLE 1
To a mixture of 13 g of 2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one and 21.5 g of 4-chlorobutyryl chloride in 200 ml of dichloroethane was added 21.5 g of aluminum chloride under cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 12 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 124.degree.-125.degree. C.
EXAMPLE 2
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 5 g of 4-chlorobutyryl chloride in 50 ml of dichloroethane was added 8.6 g of aluminum chloride under ice-cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 1.2 g of 3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-o ne as white crystals, m.p. 113.degree.-115.degree. C.
EXAMPLE 3
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one and 4.5 g of 3-chloropropionyl chloride in 50 ml of dichloroethane was added 9.2 g of aluminum chloride and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 5.6 g of 3-(3-chloropropionyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5 -one as white crystals, m.p. 86.degree.-87.degree. C.
EXAMPLE 4
The mixture of 1.0 g of 4-(1,2-benzisothiazol-3-yl)piperazine hydrochloride, 1.5 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one, 2.5 g of potassium carbonate and 0.8 g of potassium iodide in 25 ml of N,N-dimethylformamide and 25 ml of toluene was stirred at 100.degree. C. for 24 hours. After the mixture was cooled in a water bath, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel, dissolved in isopropyl alcohol and oxalic acid was added thereto to make oxalate. The resulting crystals were recrystallized from isopropyl alcohol to give 0.12 g of 7-(4-(4-(1,2-benzisothiazol-3-yl) piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one oxalate 1/2 hydrate as white crystals, m.p. 118.degree.-120.degree. C.
EXAMPLE 5
The mixture of 2.0 g of 4-(1,2-benzisothiazol-3-yl)piperazine hydrochloride, 2.0 g of 3-(4-chlorobutyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-o ne, 2.1 g of potassium carbonate and 1.2 g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60.degree. C. for 3 hours. After the mixture was cooled in a water bath, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel, dissolved in isopropyl alcohol and ethanol-maleic acid was added thereto to make maleate. The resulting crystals were recrystallized from ethanol to give 0.90 g of 3-(4-(4-(1,2-benzisothiazol-3-yl) piperazin-1-yl)butyryl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin -4-one maleate as white crystals, m.p. 150.degree.-152.degree. C.
EXAMPLE 6
The mixture of 2.1 g of 4-(1,2-benzisothiazol-3-yl)piperazine hydrochloride, 2.0 g of 3-(3-chloropropionyl)-2-methyl-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5 -one, 2,2 g of potassium carbonate and 1.2 g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60.degree. C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel, dissolved in isopropyl alcohol and crystallized from isopropyl alcohol-isopropyl ether. The resulting crystals were recrystallized from ethanol to give 1.30 g of 3-(3-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)propionyl)-2-methyl-4,6,7, 8-tetrahydro-5H-thieno[3,2-b]azepin-5-one as white crystals, m.p. 146.degree.-147.degree. C.
EXAMPLE 7
The mixture of 2.4 g of 4-(bis(4-chlorophenyl)methyl)piperazine, 2.0 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one, 1.9 g of potassium carbonate and 1.2 g of potassium iodide in 15 ml of N,N-dimethylformamide and 15 ml of toluene was stirred at 60.degree. C. for 5 hours. After the mixture was cooled in a water bath, water was added thereto. The precipitated crystals were filtered off and the filtrate was extracted with toluene. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and the resulting crystals were recrystallized from isopropyl alcohol-isopropyl ether to give 0.18 g of 7-(4-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)butyryl)-2,3-dihydrothie no[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 185.degree.-187.degree. C. (decomposition).
The following compounds can be prepared in a similar manner as the above.
EXAMPLE 8
2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-4,6,7,8-tetrahydro-5H-thie no[3,2-b]azepin-5-one, m.p. 161.degree.-162.degree. C.
EXAMPLE 9
2-(4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)butyryl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one, m.p. 192.degree.-194.degree. C.
EXAMPLE 10
2-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propionyl)-4,6,7,8-tetrahydro-5H-th ieno[3,2-b]azepin-5-one, m.p. 161.degree.-162.degree. C.
EXAMPLE 11
2-(3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propionyl)-4,6,7,8-tetrahyd ro-5H-thieno[3,2-b]azepin-5-one, m.p. 137.degree.-138.degree. C.
EXAMPLE 12
7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-2,3-dihydrothieno[3,2-f][1 ,4]thiazepin-5(4H)-one, m.p. 197.degree.-198.degree.C.
EXAMPLE 13
2-methyl-3-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyryl)-5,6,7,8-tetrahydr o-4H-thieno[3,2-c]azepin-4-one hydrochloride, m.p. 220.degree.-222.degree. C.
EXAMPLE 14
7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2,3-dihydro thieno[3,2-f][1,4]thiazepin-5(4H)-one, m.p. 186.degree.-187.degree. C.
EXAMPLE 15
2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetra hydro-5H-thieno[3,2-b]azepin-5-one, m.p. 210.degree.-212.degree. C. (decomposition)
EXAMPLE 16
2,4-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)- 4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one hydrochloride, m.p. 250.degree. C. (decomposition)
EXAMPLE 17
3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2-methyl-4, 6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one oxalate 3/2 hydrate, m.p. 115.degree.-118.degree. C.
EXAMPLE 18
2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-3-methyl-4, 6,7,8-tetrahydro-5-thieno[3,2-b]azepin-5-one, m.p. 172.degree.-175.degree. C.
EXAMPLE 19
3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6, 7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one hydrochloride, m.p. 184.degree.-186.degree. C. (decomposition)
EXAMPLE 20
3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2-methyl-5, 6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one oxalate, m.p. 114.degree.-117.degree. C.
EXAMPLE 21
3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-y)piperidin-1-yl)acetyl)-2-methyl-4,6, 7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one hydrochloride 1/2 hydrate, m.p. 208.degree.-210.degree. C. (decomposition)
EXAMPLE 22
3-(2-(4-(6-fluoro-1,2-benzoxazolyl-3-yl)piperidin-1-yl)ethyl)-2-methyl-4,6, 7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 165.degree.-167.degree. C.
EXAMPLE 23
2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetra hydro-4H-thieno[3,2-c]azepin-4-one, m.p. 182.degree.-184.degree. C.
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,6,7,8-te trahydro-5H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,6,7,8,-t etrahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-2,3-dihydr othieno[3,2-f][1,4]thiazepin-5(4H)-one
.circleincircle. 7-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-3,4-dihydr othieno[2,3-b][1,4]thiazepin-2(1H)-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-hydroxybutyl)-5, 6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-5,6,7,8-tetr ahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-5,6,7,8-tet rahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,6,7,8-tet rahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetr ahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetr ahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 2-(4-N,N-dimethylamino)butyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin- 4-one
.circleincircle. 2-(4-(N,N-dimethylamino)butyryl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin -5-one
.circleincircle. 2-(2-(N,N-dimethylamino)acetyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin- 4-one
.circleincircle. 2-(2-(N,N-dimethylamino)acetyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin- 5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-5,6,7,8 -tetrahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-5,6 ,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-5,6 ,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4,6,7,8 -tetrahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-4,6 ,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-4,6 ,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydr othieno[2,3-b]pyridin-6(7H)-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydr othieno[2,3-c]pyridin-7(6H)-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5-dihydr o-7H-thieno[3,2-c]pyridin-6-one
.circleincircle. 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-6,7-dihydr o-4H-thieno[2,3-c]pyridin-5-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,5-dihydro -7H-thieno[3,2-c]pyridin-6-one
.circleincircle. 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-6,7-dihydro -4H-thieno[2,3-c]pyridin-5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-6,7-dih ydro-4H-thieno[2,3-c]pyridin-5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfinyl)-6,7 -dihydro-4H-thieno[2,3-c]pyridin-5-one
.circleincircle. 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylsulfonyl)-6,7 -dihydro-4H-thieno[2,3-c]pyridin-5-one
Reference Example 3
A mixture of 50 g of 5-methyl-2-thiophenealdehyde and 42 g of aminoacetoaldehyde dimethyl acetal was stirred at 60.degree.-70.degree. C. for an hour and concentrated to give 71 g of oil. The resulting oil was dissolved in 450 ml of methanol, 25 g of sodium borohydride was added thereto under cooling and the mixture was stirred for 10-20 minutes, and then concentrated. To the residue was added water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. To the residue were added 264 ml of water and 132 ml of conc. hydrochloric acid and the mixture was stirred at 50.degree. C. for 2 hours. After cooling, 50 ml of conc. hydrochloric acid and 265 g of tin(II) chloride dihydrate were added thereto and the mixture was stirred at 60.degree. C. for 2 hours. The mixture was poured into water, made alkaline with 40% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in 200 ml of tetrahydrofuran, and 80 ml of triethylamine and 40 ml of acetic anhydride were added thereto under cooling, and then the mixture was stirred for an hour. The mixture was poured into water, extracted with ethyl acetate and the extract was washed with water, dried and concentrated. The residue was subjected to column chromatography to give 27 g of 6-acetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine.
Reference Example 4
To a solution of 20 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as an oil obtained by a known method in 100 ml of tetrahydrofuran were added 30 ml of triethylamine and 15 ml of acetic anhydride under cooling. The mixture was stirred for an hour, poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 10 g of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
Preparative Example 1
To a mixture of 27 g of 6-acetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 16 g of acetyl chloride in 250 ml of dichloroethane was added 42 g of aluminum chloride under cooling and the mixture was stirred for 30 minutes. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was dissolved in 300 ml of methanol, 20 g of bromine was added thereto at 30.degree. C. and the mixture was stirred for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give 28 g of 6-acetyl-3-bromoacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine.
Preparative Example 2
A mixture of 28 g of 6-acetyl-3-bromoacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 42 ml of triethylsilane and 140 ml of trifluoroacetic acid was stirred at room temperature for 5 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the residue was added isopropyl ether and the precipitated crystals were collected by filtration to give 14 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as white crystals, m.p. 93.degree.-95.degree. C.
The following compounds were prepared in a similar manner as the above. Figures mean .delta. value of .sup.1 H-NMR (CDCl.sub.3).
.circleincircle. 5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 6.66(s, 1H), 4.60(d,2H), 4.00-3.00(m,6H), 2.80(b,2H), 2.15(s,3H)
.circleincircle. 6-acetyl-3-(3-chloropropyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridi ne
466(d,2H), 4.00-3.30(m,4H), 2.50(b,4H), 2.33(s,3H), 2.15(s,3H), 1.50(m,2H)
.circleincircle. 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridin
4.60(d,2H), 4.00-3.40(m,4H), 3.15(t,2H), 2.50(b,4H), 2.15(s,3H), 2.05(s,3H)
.circleincircle. 6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e
4.66(d,2H), 4.00-3.40(m,4H), 2.70-2.30(b,4H), 2.33(s,3H), 2.15(s,3H), 2.00-1.30(m,4H),
.circleincircle. 6-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine 6.70(s,1H), 4.60(d,2H), 4.00-3.00(m,6H), 2.66(b,2H), 2.10(s,3H)
.circleincircle. 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e
4.65(d,2H), 4.05-3.40(m+t,4H), 2.95(t,2H), 2.65(b,2H), 2.40(s,3H), 2.20(s,3H)
.circleincircle. 3,6-bisacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro[2,3-c]pyridine 4.66(d,2H), 4.00-3.50(m+t,4H), 3.40(t,2H), 2,85(b,2H), 2.50(s,3H), 2.15(s,3H)
.circleincircle. 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-propylthieno[2,3-c]pyridin e
4.66(d,2H), 4.00-3.33(m+t,4H), 3.00-2.33(m,6H), 2.15(s,3H), 1.65(m,2H), 1.00(t,3H)
.circleincircle. 6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine
4.75(d,2H), 4.50(s,2H), 3.75(t,2H), 2.65(t,2H), 2.50(s,3H),2.20(s,3H)
EXAMPLE 24
A mixture of 5.9 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine , 5 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 6.7 g of potassium carbonate and 3.2 g of potassium iodide in 50 ml of dimethylformamide and 50 ml of toluene was stirred at 50.degree. C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and crystallized from isopropyl ether. The resulting crystals were recrystallized from acetonitrile to give 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, m.p. 70.degree.-75.degree. C.
EXAMPLE 25
A mixture of 4 g of 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 4 ml of conc. sulfuric acid and 80 ml of water was refluxed under heating for 3 hours. The mixture was poured into water, made alkaline and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated. To the residue was added isopropyl ether and the crystals were collected by filtration to give 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetr ahydro-2-methylthieno[2,3-c]pyridine, m.p. 88.degree.-90.degree. C.
EXAMPLE 26
To a mixture of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetr ahydro-2-methylthieno[2,3-c]pyridine in 0.5 ml of triethylamine and 10 ml of chloroform was added 0.18 g of benzoyl chloride under cooling and the mixture was stirred for an hour, and then poured into water. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography to give 0.4 g of 6-benzoyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4, 5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 192.degree.-195.degree. C. as oxalate 1/4 hydrate thereof.
EXAMPLE 27
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.48 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylothieno[2,3-c]pyridin e and 0.5 g of 4-((6,7-dimethoxy-1,2-benzisoxazol-3-yl)methyl)piperidine hydrochloride to give 0.4 g of 6-acetyl-3-(2-(4-((6,7-dimethoxy-1,2-benzisoxazol-3-yl)methyl)piperidin-1- yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 197.degree.-200.degree. C. as oxalate thereof.
EXAMPLE 28
The reaction and procedure were conducted in a similar manner as in Example 26 using 0.19 g of cyclohexanecarbonyl chloride in stead of benzoyl chloride to give 0.06 g of 6-cyclohexylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 205.degree.-208.degree. C. as oxalate 1/2 hydrate thereof.
EXAMPLE 29
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.4 g of 6-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyrid ine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.4 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.85-2.30(m,8H), 2.15(s,3H), 2.30-2.70(m,2H), 2.60(s,3H), 2.70-3.30(m,5H), 3.65(m,4H), 4.60(d,2H), 7.05(dt,1H), 7.25(dd, 1H), 7.70(dd, 1H)
EXAMPLE 30
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 6-acetyl-3-(4-chlorobutyryl-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridin e and 1.2 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine as an oil, m.p. 93.degree.-95.degree. C. as oxalate 1/4 hydrate thereof.
EXAMPLE 31
The reaction and procedure were conducted in a similar manner as in Example 24 using 4.0 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 3.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 3.3 g of 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydrothieno[2,3-c]pyridine as white crystals, m.p. 130.degree.-132.degree. C.
EXAMPLE 32
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.5 g of 6-acetyl-3-(2-bromoethyl)-2-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 2.2 g of 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)et hyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 191.degree.-201.degree. C. as oxalate 1/2 hydrate thereof.
EXAMPLE 33
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 5-acetyl-2-(2-bromoethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.61 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 5-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydrothieno[ 2,3-c]pyridine as an oil, m.p. 170.degree.-172.degree. C. as oxalate thereof.
EXAMPLE 34
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 0.6 g of 4-(bis(4-fluorophenyl)-methylene)piperidine to give 0.5 g of 6-acetyl-3-(2-(4-bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl)-4,5,6, 7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 209.degree.-211.degree. C. as axalate thereof.
EXAMPLE 35
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.95 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.9 g of 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-oxoethy l)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 92.degree.-94.degree. C. as 3/2oxalate 1/2 hydrate thereof.
EXAMPLE 36
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.7 g. of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-propylthieno[2,3-c]pyridin e and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-2-propyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)e thyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 178.degree.-180.degree. C. (decomposition) as oxalate 1/2 hydrate thereof.
EXAMPLE 37
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-(4-chlorobutyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 0.9 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5 ,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 158.degree.-160.degree. C. as 3/2oxalate thereof.
EXAMPLE 38
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 6-acetyl-(3-chloropropyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propionyl) -4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 180.degree.-182.degree. C. as oxalate thereof.
EXAMPLE 39
To a solution of 0.5 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine hydrochloride in ethanol was added 0.3 ml of 37% formaldehyde solution and the mixture was stirred at room temperature for an hour. To the mixture was added 0.2 g of sodium cyanoborohydride, the mixture was stirred for an hour, and then concentrated. To the residue was added water and extracted with chloroform. The extract was washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography and recrystallized from isopropyl ether to give 2,6-dimethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine 1/2 hydrate as white crystals, m.p. 100.degree.-103.degree. C.
EXAMPLE 40
A mixture of 0.8 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 20 ml of 16.8% dimethylamine-ethanol solution in a pressure bottle was stirred at 80.degree. C. for 5 hours and then the solvent was distilled away. To the residue was added water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to give 0.4 g of 6-acetyl-3-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c] pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:2.17(s,3H), 2.30(s,6H), 2.40(s,3H), 2.50-2.80 (m,6H), 3.80(m,2H), 4.66(d,2H)
EXAMPLE 41
The reaction and procedure were conducted in a similar manner as in Example 40 using 2.3 g of 5-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine to give 5-acetyl-2-(2-dimethylaminoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride 1/4 hydrate, m.p. 201.degree.-203.degree. C. (decomposition).
EXAMPLE 42
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridin e and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.80-3.50(m,15H), 2.10(s,3H), 2.25(s,3H), 3.80(m,2H), 4.70(d,2H), 7.10(dt,1H), 7.30(dd,1H), 7.75(dd,1H)
EXAMPLE 43
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.2 g of 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.3 g of 6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydrothieno[2,3-c]pyridine as white crystals, m.p. 145.degree.-147.degree. C.
EXAMPLE 44
The reaction and procedure were conducted in a similar manner as in Example 26 using 0.12 g of propionyl chloride instead of benzoyl chloride to give 0.4 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetr ahydro-2-methyl-6-propionylthieno[2,3-c]pyridine as an oil, m.p. 192.degree.-195.degree. C. (decomposition) as oxalate 1/2 hydrate thereof.
EXAMPLE 45
The reaction and procedure were conducted in a similar manner as in Example 26 using 0.15 g of isobutyryl chloride instead of benzoyl chloride to give 0.4 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetr ahydro-6-isobutyryl-2-methylthieno[2,3-c]pyridine as an oil, m.p.200.degree. C. (decomposition) as oxalate 1/2 hydrate thereof.
EXAMPLE 46
The reaction and procedure were conducted in a similar manner as in Example 26 using 0.14 g of cyclopropylcarbonyl chloride instead of benzoyl chloride to give 0.4 g of 6-cyclopropylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1- yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 188.degree.-190.degree. C. (decomposition) as oxalate 1/4 hydrate thereof.
EXAMPLE 47
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.5 g of 3,6-diacetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)e thyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.80-2.60(m,7H), 2.20(s,3H), 2.50(s,3H), 2.60-3.40 (m,8H), 3.65(m,2H), 4.60(d,2H), 7.05(dt,1H), 7.25(dd,1H), 7.70(dd,1H)
EXAMPLE 48
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridin e and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.25 g of 5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.60-2.50(m,8H), 2.20(s,3H), 2.40(s,3H), 2.50-2.90 (m,4H), 3.16(m,3H), 3.80(m,2H), 4.50(d,2H), 7.05(dt,1H), 7.25(dd,1H), 7.70(dd,2H)
EXAMPLE 49
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.4 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 0.9 g of 4-(1,2-benzisothaizol-3-yl)piperazine to give 1.0 g of 6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-te trahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 190.degree.-192.degree. C. (decomposition) as oxalate thereof.
EXAMPLE 50
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyrid ine and 1.4 g of 4-(6-fluoro-1,2,-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.80-3.30(m,16H), 2.02(s,3H), 2.18(s,3H), 3.75(m,3H), 4.70(d,2H), 7.04(dd,2H), 7.70(dd,1H)
EXAMPLE 51
A mixture of 334 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine , 420 mg of 4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidine hydrochloride, 500 mg of potassium carbonate and 216 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 85.degree. C. for 8 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 360 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1- yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 193.degree.-196.degree. C. as oxalate thereof.
EXAMPLE 52
A mixture of 334 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine , 308 mg of 4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 500 mg of potassium carbonate and 220 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90.degree. C. for 25 hours and concentrated in vacuo. To the residue were added ethyl acetate and water and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 100 mg of 6-acetyl-3-(2-(4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 167.degree.-172.degree. C. as oxalate thereof.
EXAMPLE 53
A mixture of 210 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine , 200 mg of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride, 250 mg of potassium carbonate and 140 mg of potassium iodide in 5 ml of dimethylformamide and 5 ml of toluene was stirred at 90.degree. C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 160 mg of 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
.sup.1 H-NMR(CDCl.sub.3) .delta.:2.20(s, 3H), 2.40(s, 3H), 3.10(m,2H), 1.8-2.8 (m,13H), 3.75(m,2H), 4.60(d,2H), 7.02(s,1H), 7.10(dt,1H), 7.50 (dd,1H), 7.70(dd,1H)
m.p. 223.degree.-225.degree. C. as oxalate thereof.
EXAMPLE 54
A mixture of 514 mg of 6-acety-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3,-c]pyridine , 511 mg of 4-(6-fluoro-1H-indazol-3-yl)piperidine hydrochloride, 690 mg of potassium carbonate and 365 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90.degree. C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel and recrystallized from the mixture of diisopropyl ether and isopropyl alcohol to give 170 mg of 6-acetyl-3-(2-(4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl)ethyl-4,5,6,7-te trahydro-2-methylthieno[2,3-c]pyridine monohydrate, m.p. 116.degree.-119.degree. C.
EXAMPLE 55
A mixture of 590 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine , 580 mg of 4-(6-fluoro-1-methyl- 1H-indazol-3-yl) piperidine, 780 mg of potassium carbonate and 415 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90.degree. C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 540 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 213.degree.-216.degree. C. as oxalate thereof.
EXAMPLE 56
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride. The mixture was stirred for 30 minutes, refluxed under heating for an hour and then poured into water. The precipitated crystals were collected by filtration and washed with isopropyl alcohol to give 2 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, m.p. 221.degree.-223.degree. C. (decomposition).
EXAMPLE 57
A mixture of 1.9 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at 50.degree. C. for 12 hours. The mixture was poured into water, alkalified and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 0.85 g of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 156.degree.-158.degree. C.
EXAMPLE 58
A mixture of 800 mg of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, 920 mg of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.45 g of potassium carbonate and 580 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90.degree. C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel and recrystallized from ethyl acetate to give 0.65 g of 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetr ahydro-8H-thieno[2,3-c]azepin-8-one, m.p. 192.degree.-194.degree. C.
EXAMPLE 59
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2.5 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under cooling. The mixture was stirred for 30 minutes, refluxed under heating and poured into water, and then extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was crystallized from ethyl acetate-isopropyl ether to give 1.2 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 163.degree.-165.degree. C.
EXAMPLE 60
A mixture of 1.1 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, 1.1 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.68 g of potassium carbonate and 670 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90.degree. C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel and recrystallized from ethyl acetate-isopropyl ether to give 0.55 g of 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-te trahydro-8H-thieno[2,3-c]azepin-8-one 1/2 hydrate, m.p. 186.degree.-187.degree. C.
EXAMPLE 61
To a mixture of 6.7 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 4.5 g of sodium borohydride in 70 ml of tetrahydrofuran was added boron trifluoride-ether complex dropwise under ice-cooling and the mixture was refluxed under heating for an hour. The mixture was poured into water, washed with chloroform, made alkaline with 10% potassium hydroxide solution and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4.1 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
EXAMPLE 62
To a mixture of 4 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 4 g of pyridine in 20 ml of chloroform was added 4.1 g of acetic anhydride under ice-cooling and the mixture was stirred at room temperature for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
EXAMPLE 63
To a solution of 2 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 1.7 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes and refluxed under heating for an hour. The mixture was poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated to give 2.2 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
EXAMPLE 64
A mixture of 2.1 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at room temperature for 12 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 1.8 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
EXAMPLE 65
A mixture of 1.6 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine, 1.8 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine hydrochloride, 2.6 g of potassium carbonate and 1 g of potassium iodide in 15 ml of dimethylformamide and 15 ml of toluene was stirred at 90.degree. C. for 5 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 1.5 g of 7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6 ,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil. The oil was treated with hydrochloric acid in isopropyl alcohol and recrystallized from ethanol-isopropyl ether to give 7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine hydrochloride 3/2 hydrate, m.p. 210.degree. C. (decomposition).
EXAMPLE 66
To a solution of 2.5 g of 7-acetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine and 2.7 g of 4-chlorobutyryl chloride in 25 ml of dichloromethane was added 6.0 g of aluminum chloride under ice-cooling. The mixture was stirred for 30 minutes, poured into water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 2.9 g of 7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
EXAMPLE 67
A mixture of 2.8 g of 7-acetyl-2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine, 2.6 g of 4-(6-fluoro-1,2-benzisoxazol- 3-yl)piperidine hydrochloride, 3.9 g of potassium carbonate and 1.55 g of potassium iodide in 30 ml of dimethylformamide and 30 ml of toluene was stirred at 70.degree. C. for 20 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 3.0 g of 7-(acetyl-2-(4-(4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)- 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil. The oil was treated with hydrochloric acid in isopropyl alcohol and recrystallized from ethanol-ethyl acetate to give 7-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5 ,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine hydrochloride, m.p. 230.degree. C. (decomposition).
EXAMPLE 68
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyrid ine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 116.degree.-118.degree. C. as an oxalate monohydrate thereof.
EXAMPLE 69
The reaction and procedure were conducted in a similar manner as in Example 14 using 1.0 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 0.88 g of 1-(1,2-benzoisothiazol- 3-yl)piperazine to give 1.0 g of 6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-te trahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 190.degree.-192.degree. C. (decomposition) as an oxalate 1/2 hydrate thereof.
EXAMPLE 70
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.9 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 1.0 g of 4-(5-chloro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.7 g of 6-acetyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 122.degree.-124.degree. C. (decomposition) as a hydrochloride thereof.
EXAMPLE 71
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.2 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridin e and 0.2 g of 1-(6-chlorobenzothiazol-2-yl)piperazine to give 0.04 g of 6-acetyl-3-(2-(4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl)ethyl)-4,5,6,7- tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 180.degree. C. (decomposition) as an oxalate thereof.
EXAMPLE 72
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridin e and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.25 g of 5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5 ,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 198.degree.-200.degree. C. (decomposition) as an oxalate thereof.
EXAMPLE 73
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.7 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.67 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-3-e thyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 165.degree.-167.degree. C. (decomposition) as hydrochloride dihydrate thereof.
EXAMPLE 74
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.8 g of 5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.0 g of 5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4 ,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an oil, m.p. 235.degree. C. as hydrochloride 1/2 hydrate thereof.
EXAMPLE 75
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.1 g of 2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.21 g of 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-te trahydro-4H-thieno[3,2-c]azepin-4-one, m.p. 142.degree.-143.degree. C.
EXAMPLE 76
To a solution of 0.4 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-2-methyl-5, 6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one (m.p. 175.degree.-176.degree. C. as oxalate thereof) in 20 ml of methanol was added 0.5 g of sodium borohydride under cooling. The mixture was stirred for 10 minutes and concentrated. Water was added thereto and the solution was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled away. The residue was treated with fumaric acid in ethanol and recrystallized from ethanol to give 0.22 g of 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-hydroxyethyl)-2- methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one difumarate monohydrate, m.p. 116.degree.-118.degree. C.
EXAMPLE 77
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.5 g of 6-acetyl-3-bromo-2-(2-chloroethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 0.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.05 g of 6-acetyl-3-bromo-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)et hyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil, m.p. 114.degree.-117.degree. C. as an oxalate thereof.
EXAMPLE 78
The reaction and procedure were conducted in a similar manner as in Example 24 using 0.5 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one and 0.5 g of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 0.2 g of 2-(2-(4-(6-fluoro-benzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetr ahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 191.degree.-193.degree. C.
EXAMPLE 79
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine.
EXAMPLE 80
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(4-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)butyryl)-4, 5,6,7-tetrahydrothieno[2,3-c]pyridine.
EXAMPLE 81
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridin e and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-3-methylthieno[2,3-c]pyridine.
EXAMPLE 82
A mixture of 0.5 g of 2-((3-chloropropyl)thio)-4-oxo-4,5,6,7-tetrahydrobenzo(b)thiophene, 0.5 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 0.6 g of potassium carbonate and 0.4 g of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was mixed at 100.degree. C. for 4 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 0.5 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4-oxo-4 ,5,6,7-tetrahydrobenzo(b)-thiophene. The resulting compound was dissolved in 20 ml of ethanol, and 0.1 g of hydroxylamine hydrochloride and 0.12 g of sodium hydrogencarbonate were added thereto. After the mixture was refluxed for 3 hours, the solvent was distilled away in vacuo and water was added to the residue, and then extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. To the residue was added isopropyl ether to give 0.5 g of an oxime compound as crystals. A mixture of 0.35 g of the oxime compound and 3.5 g of 115% polyphosphoric acid was stirred at 100.degree. C. for 5 hours, poured into water and extracted with chloroform. The extract was washed with water, dried and concentrated. The residue was separated and purified by column chromatography on a silica gel and each of resulting crystals was recrystallized from isopropyl ether to give 0.06 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-5,6,7,8 -tetrahydro-4H-thieno[3,2-c]azepin-4-one, m.p. 119.degree.-121.degree. C. and 0.019 g of 2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propylthio)-4,6,7,8 -tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 125.degree.-127.degree. C.
EXAMPLE 83
A mixture of 1.0 g of 2-(2-chloroethyl)-3-ethyl-4,6,7,8-tetrahydro- 5H-thieno[3,2-b]azepin-5-one, 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 4.0 g of potassium carbonate and 1.5 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 100.degree. C. for 3 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and recrystallized from isopropyl alcohol to give 0.45 g of 3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,6, 7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one 3/4 hydrate, m.p. 115.degree.-117.degree. C.
EXAMPLE 84
A mixture of 0.7 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine , 0.7 g of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride, 1.8 g of potassium carbonate and 0.6 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70.degree. C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium and concentrated. The residue was purified by column chromatography on a silica gel and dissolved in ethanol to convert hydrochloride thereof, and then recrystallized from methanol to give 0.45 g of 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo-(b)thiophen-3-yl)piperidin-1-yl)et hyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 240.degree. C. (decomposition).
EXAMPLE 85
A mixture of 1.0 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine , 0.95 g of 4-(6-fluorobenzo(b)furan-3-yl) piperidine hydrochloride, 3.0 g of potassium carbonate and 1.0 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70.degree. C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and dissolved in ethanol to convert hydrochloride thereof, and then recrystallized from isopropyl alcohol to give 0.5 g of 6-acetate-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl )-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 205.degree. C. (decomposition).
EXAMPLE 86
A mixture of 0.5 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine , 0.5 g of 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine hydrochloride, 1.5 g of potassium carbonate and 0.5 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70.degree. C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel to give 0.5 g of 6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine as an oil.
.sup.1 H-NMR (CDCl.sub.3) .delta.:1.10 (t,3H), 2.00-2.40 (m,4H), 2.20 (d,3H), 2.50 (q,2H), 2.60-2.70 (m,4H), 3.00 (m,2H), 3.15 (m,1H), 3.20 (m,4H), 3.80 (dt,2H), 4.50 (d,2H), 7.20 (dt,1H), 7.60(dd,1H), 7.95 (dd,1H) m.p. 156.degree.-160.degree. C. as oxalate 1/3 hydrate thereof.
The following compounds can be prepared in a similar manner as the above.
EXAMPLE 87
6-formyl-3-isobutyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate 1/4 hydrate, m.p. 165.degree.-167.degree. C.
EXAMPLE 88
6-formyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride 1/2 hydrate, m.p. 220.degree. C. (decomposition).
EXAMPLE 89
3-ethyl-6-formyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate 1/4 hydrate, m.p. 188.degree.-190.degree. C.
EXAMPLE 90
6-acetyl-3-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7- tetrahydro-2-methylthieno[2,3-c]pyridine oxalate 1/3 hydrate, m.p. 210.degree.-212.degree. C.
EXAMPLE 91
6-acetyl-3-ethyl-2-(2-(4-(4-fluoro-2-methoxybenzoyl)piperidin-1-yl)ethyl)-4 ,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 134.degree.-136.degree. C.
EXAMPLE 92
6-acetyl-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propionyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 215.degree. C. (decomposition).
EXAMPLE 93
6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyl)-4,5, 6,7-tetrahydrothieno[2,3-c]pyridine oxalate 1/4 hydrate, m.p. 186.degree.-188.degree. C.
EXAMPLE 94
6-acetyl-2-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propyl)-4,5 ,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 150.degree.-152.degree. C.
EXAMPLE 95
6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)acetyl)-4,5 ,6,7-tetrahydrothieno[2,3-c]pyridine, m.p. 141.degree.-144.degree. C.
EXAMPLE 96
6-acetyl-3-ethyl-2-(2-(4-(2,4-difluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7 -tetrahydrothieno[2,3-c]pyridine 1/2 oxalate 1/2 hydrate, m.p. 128.degree.-131.degree. C.
EXAMPLE 97
6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-3-propylthieno[2,3-c]pyridine fumarate, m.p. 197.degree.-199.degree. C. (decomposition).
EXAMPLE 98
6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl)ethyl)-4, 5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine 3/2oxalate, m.p. 218.degree. C. (decomposition).
EXAMPLE 99
6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4, 5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 129.degree.-131.degree. C.
EXAMPLE 100
6-acetyl-3-(1-hydroxyethyl)-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperid in-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate monohydrate, m.p. 168.degree.-170.degree. C.
EXAMPLE 101
6-acetyl-3-ethyl-2-(2-(4-(2-acetyl-6-fluorobenzo(b)thiophen-3-yl)piperidin- 1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 232.degree. C (decomposition).
EXAMPLE 102
6-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1 -yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate,
.sup.1 H-NMR(CDCl.sub.3) .delta.:1.10 (t,3H), 1,30 (t,3H), 1.60-2.00 (m,4H), 2.10 (s,3H), 2.20-3.40 (m, 14H), 3.50-3.90 (m, 3H), 4.63 (d,2H), 7.00 (dt,1H), 7.36 (dd,1H), 7.80 (dd,1H)
EXAMPLE 103
6-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl )ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 232.degree. C. (decomposition).
EXAMPLE 104
6-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)thiophen-3-yl)piperidin- 1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 105
6-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride dihydrate, m.p. 205.degree. C. (decomposition)
EXAMPLE 106
5-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1 -yl)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 107
6-acetyl-3-ethyl-2-(2-(4-(1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydrothieno[2,3-c]pyridine oxalate monohydrate, m.p. 152.degree.-155.degree. C.
EXAMPLE 108
6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tet rahydrothieno[2,3-c]pyridine
EXAMPLE 109
6-acetyl-3-ethyl-2-(2-(4-(6-methoxybenzo(b)fu ran-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 110
6-acetyl-3-ethyl-2-(2-(4-(6-hydroxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 111
5-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)thiophen-3-yl)piperidin- 1-yl)ethyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine
EXAMPLE 112
5-acetyl-3-ethyl-2-(2-(4-(2-methyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-y l)ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 113
5-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 114
5-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl) piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 115
5-acetyl-3-ethyl-2-(2-(4-(1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 116
5-acetyl-3-ethyl-2-(2-(4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl )ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 117
5-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl)-4,5,6,7-tet rahydrothieno[3,2-c]pyridine
EXAMPLE 118
5-acetyl-3-ethyl-2-(2-(4-(6-methoxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 119
5-acetyl-3-ethyl-2-(2-(4-(6-hydroxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 120
5-acetyl-3-ethyl-2-(2-(4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 121
5-acetyl-3-ethyl-2-(2-(4-(5-chloro-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 122
5-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-2-yl)piperidin-1-yl)ethyl-4,5,6,7-t etrahydrothieno[3,2-c]pyridine
EXAMPLE 123
5-acetyl-3-ethyl-2-(2-(4-(benzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 124
5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-2-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, m.p. 218.degree. C. (decomposition)
EXAMPLE 125
5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-2-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 126
5-acetyl-3-ethyl-2-(2-(4-(7-bromo-5-methoxybenzo(b)furan-2-yl)piperidin-1-y l)ethyl)-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine
EXAMPLE 127
6-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-2-yl)piperidin-1-yl)ethyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine
EXAMPLE 128
6-acetyl-3-ethyl-2-(2-(4-(benzo(b)thiophen-2-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 129
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-2-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 130
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-2-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 131
6-acetyl-3-ethyl-2-(2-(4-(7-bromo-5-methoxybenzo(b)furan-2-yl)piperidin-1-y l)ethyl)-4, 5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 132
6-acetyl-3-ethyl-2-(2-(4-(6,7-difluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl )ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 133
6-acetyl-3-ethyl-2-(2-(4-(5,6-difluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl )ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 134
6-acetyl-3-ethyl-2-(2-(4-(6-methyl-1,2-benzisoxazol-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 135
6-acetyl-3-ethyl-2-(2-(4-(6-hydroxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)et hyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 136
6-acetyl-3-ethyl-2-(2-(4-(6,7-dihydroxy-1,2-benzisoxazol-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 137
6-acetyl-3-ethyl-2-(2-(4-(5,6-dihydroxy-1,2-benzisoxazol-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 138
N-ethyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-6-carboxamide oxalate 1/2 hydrate, m.p. 159.degree.-162.degree. C.
EXAMPLE 139
6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin -1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride dihydrate, m.p. 240.degree. C. (decomposition)
EXAMPLE 140
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-t etrahydrothieno[2,3-c]pyridine dihydrochloride 1/4 hydrate, m.p. 240.degree.-243.degree. C.
EXAMPLE 141
6-acetyl-3-ethyl-2-(2-(4-(6-methoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl)et hyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 142
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-t etrahydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 143
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl-4,6,7,8-te trahydro-5H-4-methylthieno[3,2-b]azepin-5-one
EXAMPLE 144
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-t etrahydro-8H-thieno[2,3-c]azepin-8-one
EXAMPLE 145
A mixture of 5.0 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine , 4.9 g of 4-(5-methylbenzo(b)furan-3-yl) piperidine hydrochloride, 2.5 g of potassium carbonate, 3.0 g of potassium iodide, 30 ml of dimethylformamide and 30 ml of toluene was stirred at 70.degree. C. for 7 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and then dissolved into ethanol to make a hydrochloride. The resulting crystals were recrystallized from isopropyl alcohol to give 6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)-furan-3-yl)piperidin-1-yl)ethyl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 222.degree.-225.degree. C.
EXAMPLE 146
A mixture of 0.9 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine , 1.0 g of 4-(4,6-dichlorobenzo(b)furan-3-yl)piperidine hydrochloride, 0.5 g of potassium carbonate, 0.5 g of potassium iodide, 25 ml of dimethylformamide and 25 ml of toluene was stirred at 80.degree. C. for 6 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and then dissolved into ethanol to make a hydrochloride. The resulting crystals were recrystallized from isopropyl alcohol to give 6-acetyl-2-(2-(4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-3-e thyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 260.degree. C. (decomposition).
EXAMPLE 147
A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-54H-thieno[3,2-b]azepin-5-one, 2.2 g of 4-(6-fluorobenzo(b)furan-3-yl)piperidine hydrochloride, 2.6 g of potassium carbonate, 1.44 g of potassium iodide, 20 ml of dimethylformamide and 20 ml of toluene was stirred at 80.degree. C. for 8 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahyd ro-5H-thieno[3,2-b]azepin-5-one, m.p. 176.degree.-178.degree. C.
EXAMPLE 148
A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, 2.1 g of 4-(5-methylbenzo(b)furan-3-yl)piperidine hydrochloride, 2.6 g of potassium carbonate, 1.5 g of potassium iodide, 20 ml of dimethyl formamide and 20 ml of toluene was stirred at 80.degree. C. for 8 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahyd ro-5H-thieno[3,2-b]azepin-5-one, m.p. 156.degree.-158.degree. C.
EXAMPLE 149
6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,1-dioxobenzo(b)thiophen-3-yl)piperidin -1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride dihydrate, m.p. 240.degree. C. (decomposition)
EXAMPLE 150
3-ethyl-2-(2-(4-(6-fluoro-1,2-benzoisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydrothieno[2,3-c]pyridine-6-carboxylic acid ethyl amide oxalate 1/2 hydrate, m.p. 159.degree.-162.degree. C.
EXAMPLE 151
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-t etrahydrothieno[2,3-c]pyridine dihydrochloride 1/4 hydrate, m.p. 240.degree.-243.degree. C.
EXAMPLE 152
6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-2-methylbenzo(b)furan-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride dihydrate, m.p. 205.degree. C. (decomposition)
EXAMPLE 153
6-acetyl-3-ethyl-2-(2-(4-(1,2-benzoisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydrothieno[2,3-c]pyridine oxalate monohydrate, m.p. 152.degree.-155.degree. C.
EXAMPLE 154
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-t etrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 160.degree.-162.degree. C.
EXAMPLE 155
b 6-acetyl-3-ethyl-2-(2-(4-(5-chlorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride dihydrate, m.p. 209.degree.-211.degree. C. (decomposition)
EXAMPLE 156
5-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine oxalate 1/2 hydrate, m.p. 148.degree.-151.degree. C.
EXAMPLE 157
6-acetyl-3-ethyl-2-(2-(4-(5-methoxybenzo(b)furan-3-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate 1/2 hydrate, m.p. 109.degree.-112.degree. C.
EXAMPLE 158
5-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, m.p. 218.degree. C. (decomposition)
EXAMPLE 159
6-acetyl-3-ethyl-2-(2-(4-(5-bromobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4 ,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 124.degree.-126.degree. C.
EXAMPLE 160
6-acetyl-3-ethyl-2-(2-(4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride 1/4 hydrate, m.p. 210.degree. C. (decomposition)
EXAMPLE 161
6-acetyl-3-ethyl-2-(2-(4-(bis(4-fluorophenyl)methylene)piperidin-1-yl)ethyl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 212.degree.-213.degree. C.
EXAMPLE 162
6-acetyl-3-ethyl-2-(2-(4-(4-hydroxy-2,6-dimethylbenzoyl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate 1/2 hydrate, m.p. 198.degree.-200.degree. C.
EXAMPLE 163
6-acetyl-3-ethyl-2-(2-(4-(5-chloro-6-methylbenzo(b)furan-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride 1/2 hydrate, m.p. 230.degree. C. or above (decomposition)
EXAMPLE 164
6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride 1/4 hydrate, m.p. 200.degree. C. (decomposition)
EXAMPLE 165
3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 5,6,7,8-tetrahydrothieno[3,2-c]azepin-4-one hydrochloride, m.p. 260.degree. C. or above (decomposition)
EXAMPLE 166
7-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepine hydrochloride monohydrate, m.p. 201.degree.-203.degree. C.
EXAMPLE 167
7-acetyl-3-ethyl-2-(2-(4-(5-chloro-6-methylbenzo(b)furan-3-yl)piperidin-1-y l)ethyl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepine hydrochloride 1/2 hydrate, m.p. 203.degree.-205.degree. C.
EXAMPLE 168
6-acetyl-3-ethyl-2-(2-(4-(5-methoxybenzo(b)furan-2-yl)piperidin-1-yl)ethyl) -4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride monohydrate, m.p. 215.degree.-218.degree. C.
EXAMPLE 169
6-acetyl-3-ethyl-2-(4-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)butyryl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride 3/2 hydrate
.sup.1 H-NMR (CDCl.sub.3): 1.20-1.40 (m, 3H), 2.05-2.50 (m, 6H), 2.50-3.18 (m, 13H), 3.64-3.92 (m, 5H), 4.60-4.83 (m, 2H), 7.05 (dd, 1H), 7.19 (d, 1H), 7.48 (s, 1H), 7.65-7.80 (b, 1H)
EXAMPLE 170
3,6-diacetyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 233.degree.-235.degree. C. (decomposition)
EXAMPLE 171
6-acetyl-3-(1-hydroxyethyl)-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1 -yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate, m.p. 193-196.degree. C.
EXAMPLE 172
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 255.degree. C. or above (decomposition)
EXAMPLE 173
6-acetyl-3-ethyl-2-(2-(4-(5-chloro-2-hydroxybenzoyl)piperidin-1-yl)ethyl)-4 ,5,6,7-tetrahydrothieno[2,3-c]pyridine oxalate monohydrate, m.p. 172.degree.-175.degree. C.
EXAMPLE 174
6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 229.degree.-231.degree. C.
EXAMPLE 175
6-acetyl-3-ethyl-2-(2-(4-(5,7-dimethylbenzo(b)furan-3-yl)piperidin-1-yl)eth yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 242.degree.-245.degree. C.
EXAMPLE 176
6-acetyl-3-ethyl-4,5,6,7-tetrahydro-2-(2-(4-(4,6-dimethylbenzo(b)furan-3-yl )piperidin-1-yl)ethyl)thieno[2,3-c]pyridine hydrochloride 1/4 hydrate, m.p. 230.degree. C. or above
EXAMPLE 177
6-acetyl-3-ethyl-4,5,6,7-tetrahydro-2-(2-(4-(2-hydroxy-5-methylbenzoyl)pipe ridin-1-yl)ethyl)thieno[2,3-c]pyridine fumarate 1/2 hydrate, m.p. 218.degree.-220.degree. C. (decomposition)
EXAMPLE 178
2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one, m.p. 188.degree.-190.degree. C.
EXAMPLE 179
2-(2-(4-(benzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thi eno[3,2-b]azepin-5-one
EXAMPLE 180
2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 181
2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 182
2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 183
2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 184
2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 185
2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 186
2-(2-(4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 187
2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3 2-b]azepin-5-one
EXAMPLE 188
2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 189
2-(2-(4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 190
2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 191
2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 192
2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 193
2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahydr o-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 194
2-(2-(4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 195
2-(2-(4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 196
2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5H-thieno[3,2-b]azepin-5-one
EXAMPLE 197
2-(2-(4-(7fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrahy dro-5-thieno[3,2-b]azepin-5-one
EXAMPLE 198
2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5-thieno[3,2-b]azepin-5-one
EXAMPLE 199
2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5-thieno[3,2-b]azepin-5-one
EXAMPLE 200
2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6 7,8-tetrahydro-5-thieno[3,2-b]azepin-5-one
EXAMPLE 201
2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl)-4,6,7,8-tetrah ydro-5-thieno[3,2-b]azepin-5-one
EXAMPLE 202
6-acetyl-3-ethyl-2-(2-(4-(benzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine
EXAMPLE 203
6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 204
6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 205
6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 206
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 207
6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperidin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 208
6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzo(b) furan-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 209
6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 210
6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazinyl)ethyl)-4,5 ,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 211
6-acetyl-3-ethyl-2-(2-(4-(7fluorobenzo(b)furan-3-yl)piperazin-1-yl)ethyl)-4 ,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 212
6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 213
6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2 3-c]pyridine
EXAMPLE 214
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 215
6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperazin-1-yl)ethyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 216
6-acetyl-3-ethyl-2-(2-(4-(4-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 217
6-acetyl-3-ethyl-2-(2-(4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 218
6-acetyl-3-ethyl-2-(2-(4-(6fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 219
6-acetyl-3-ethyl-2-(2-(4-(7fluorobenzo(b)thiophen-3-yl)piperazin-1-yl)ethyl )-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 220
6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 221
6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 222
6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 223
6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)thiophen-3-yl)piperazin-1-yl)ethy l)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine
EXAMPLE 224
2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrah ydro-8H-thieno[2,3-c]azepin-8-one
EXAMPLE 225
2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydr o-8H-thieno[2,3-c]azepin-8-one
EXAMPLE 226
2-(2-(4-(5-methylbenzo(b)furan3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro -8H-thieno[2,3-c]azepin-8-one
EXAMPLE 227
2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydr o-8H-thieno[2,3-c]azepin-8-one
Formulation Example 1
Tablets containing 10 mg of a compound of the formula (I) are prepared in accordance with the following formulation:
The compound of the formula (I) is pulverized by an atomizer into fine powders below 10.mu. in average particle diameter, which are admixed with lactose, corn starch and crystalline cellulose sufficiently in a kneading machine, and further kneaded with polyvinylpyrrolidone paste. The kneaded mixture is passed through a sieve of 200 mesh, dried at 50.degree. C. and passed through a sieve of 24 mesh. Talc and magnesium stearate are mixed therewith and the mixture is compressed into 120.0 mg tablets with a punch of 8 mm in diameter. These tablets are, if desired, subjected to sugar-coating or film-coating.
While the present invention has been adequately and sufficiently described in the foregoing specification including examples, the description can be changed or modified within the spirit and scope of this invention.
Claims
What is claimed is:
1. A condensed thiophene compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR34## wherein the ring S is selected from the group consisting of the following fused thiophenes: ##STR35## wherein R.sup.1 represents a hydrogen atom, a halogen atom, an alkyl group, an acyl group or a hydroxyalkyl group; R.sup.2 represents a hydrogen atom, an alkyl group, an acyl group, a carbamoyl group, a substituted carbamoyl group, an aryl group or an arylalkyl group; G represents a --CH.sub.2 -- group, a --CH(OR.sup.3)-- group (wherein R.sup.3 represents a hydrogen atom, an alkyl group or an acyl group), a --CO-- group or a --S(O).sub.t group (t is 0, 1 or 2); Q represents a straight alkylene group or a branched chain alkylene group; T represents a tertiary amino group; D represents a --CH.sub.2 -- group; both A and B are absent; m is 2; and n is 0.
2. The compound of claim 1 selected from the group consisting of: 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 6-acetyl-2-ethyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5, 6,7-tetrahydro-3-methylthieno[2,3-c]pyridine, 6-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl) butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetra hydro-2-methyl-6-propionylthieno[2,3-c]pyridine, 6-cyclopropylcarbonyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 3,6-diacetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6 ,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, and 6-acetyl-3-ethyl-2-(2-(4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine or a pharmaceutically acceptable salts thereof.
3. The compound of claim 1 selected from the group consisting of: 6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(4-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl) butyryl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(7-methylbenzo(b)furan-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperidin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperazin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(4-methylbenzo(b)furan-3-yl)piperazin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, and 6-acetyl-3-ethyl-2-(2-(4-(6-methylbenzo(b)thiophen-3-yl)piperazin-1-yl) ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, or pharmaceutically acceptable salt thereof.
4. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein T represents a --N(Rb)(Rc) tertiary amino group; Rb and Rc are the same or different and each represents an alkyl group, or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino group of the formula: ##STR36## wherein q is an integer of 1 to 4, Z represents a methylene group or N--R.sup.5 (wherein R.sup.5 represents an aryl group, a diarylalkyl group, a heteroaryl group or a heteroarylalkyl group), V represents a hydrogen atom, a hydroxyl group, a heteroaryl group, a heteroarylalkyl group or a bisarylmethylene group and the number of V is 1 to 4; the cyclic amino group of formula (1) may contain a carbonyl group in the cyclic group and further may be condensed with an aryl group or a heteroaryl group; and the ring Am in formula (2) is a carbocyclic ring that may contain an amido bond in the ring and further may contain an oxygen atom, a sulfur atom, a carbonyl group and/or an N--R.sup.6 group (wherein R.sup.6 represents a hydrogen atom, an alkyl group or a phenyl group) in the ring.
5. The compound of claim 1 or pharmaceutically acceptable salts thereof, wherein T is represented by either of the following formulae: ##STR37## wherein R.sup.7 is 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, benzo(b)furan-3-yl, benzo(b)thiophen-3-yl, 1,1,-dioxobenzo (b)thiophen-3-yl or 1H-indazol-3-yl, which may have 1 or 2 substituents selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.2-4 alkanoyl and 4-fluorophenyl; benzoyl which may have 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; or bis(4-fluorophenyl) methylene; R.sup.8 is 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, benzo(b)furan-3-yl, benzo(b)thiophen-3-yl or benzothiazol-2-yl, which may have 1 or 2 substituents selected from the group consisting of halogen, C.sub.1-4 alkyl and C.sub.1-4 alkoxy.
6. The compound of claim 1 as pharmaceutically acceptable salts thereof, wherein T represents a group selected from the group consisting of: 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(5-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidin-1-yl, 4-(1,2-benzisothiazol-3-yl)piperidin-1-yl, 4-(6-fluorobenzo(b)thiophen-3-yl) piperidin-1-yl, 4-(6-fluoro-1H-indazol-3-yl)piperidin-1-yl, 4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1-yl, 4-(1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(6-fluorobenzo(b)furan-3-yl) piperidin-1-yl, 4-(4-fluoro-2-methoxybenzoyl)piperidin-1-yl, 4-(2,4-difluorobenzoyl) piperidin-1-yl, 4-(2-acetyl-6-fluorobenzo(b)thiophen-3-yl) piperidin-1-yl, 4-(2-ethyl-6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(2-methyl-6-fluoro-benzo(b)thiophen-3-yl)piperidin-1-yl, 4-(2-ethyl-6-fluorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(1,2-benzisoxazol-3-yl) piperazin-1-yl, 4-(1,2-benzisothiazol-3-yl)piperazin-1-yl, 4-(6-chlorobenzothiazol-2-yl)piperazin-1-yl, 4-(6-fluoro-1,1-dioxobenzo (b)thiophen-3-yl)piperidin-1-yl, 4-(6-methoxy-1,2-benzisoxazol-3-yl)piperidin-1-yl, 4-(5-methylbenzo(b)furan-3-yl) piperidin-1-yl, 4-(4,6-dichlorobenzo(b)furan-3-yl)piperidin-1-yl, 4-(6-fluoro-2-methylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-chlorobenzo (b)furan-3-yl)piperidin-1-yl, 4-(5-fluorobenzo(b)furan-3-yl) piperidin-1-yl, 4-(5-methoxybenzo(b)furan-3-yl)piperidin-1-yl, 4-(5-bromobenzo (b)furan-3-yl)piperidin-1-yl, 4-(5,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(4,6-dimethylbenzo(b)furan-3-yl)piperidin-1-yl, 4-(5,7-dimethyl-benzo(b)furan-3-yl)piperidin-1-yl, 4-(bis(4-fluorophenyl) methylene)-piperidin-1-yl, 4-(4-hydroxy-2,6-dimethylbenzoyl) piperidin-1-yl, 4-(5-chloro-6-methylbenzo(b)furan-3-yl) piperidin-1-yl, 4-(6-methyl-benzo(b)furan-3-yl)piperidin-1-yl, 4-(5-chloro-2-hydroxybenzoyl)-piperidin-1-yl, 4-(7-methylbenzo(b)furan-3-yl) piperidin-1-yl, 4-(2-hydroxy-5-methylbenzoyl)piperidin-1-yl, 4-(benzo (b)furan-3-yl)piperidin-1-yl, 4-(4-methylbenzo(b)furan-3-yl) piperidin-1-yl, 4-(4-methylbenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(5-methylbenzo(b)thiophen-3-yl)piperidin-1-yl, 4-(6-methylbenzo(b)-thiophen-3-yl)piperidin-1-yl, 4-(7-methylbenzo(b)thiophen-3-yl) piperidin-1-yl, 4-(4-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(5-fluorobenzo b)furan-3-yl)piperazin-1-yl, 4-(6-fluorobenzo(b)furan-3-yl) piperazin-1-yl, 4-(7-fluorobenzo(b)furan-3-yl)piperazin-1-yl, 4-(4-methylbenzo (b)furan-3-yl)piperazin-1-yl, 4-(5-methylbenzo(b)furan-3-yl) piperazin-1-yl, 4-(6-methylbenzo(b)furan-3-yl)piperazin-1-yl, 4-(7-methylbenzo (b)furan-3-yl)piperazin-1-yl, 4-(4-fluorobenzo(b)thiophen-3-yl) piperazin-1-yl, 4-(5-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(6-fluorobenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(7-fluorobenzo(b)-thiophen-3-yl)piperazin-1-yl, 4-(4-methylbenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(5-methylbenzo(b)thiophen-3-yl)piperazin-1-yl, 4-(6-methylbenzo (b) -thiophen-3-yl) piperazin-1-yl and 4-(7-methylbenzo (b) thiophen-3-yl)piperazin-1-yl.
7. A pharmaceutical composition comprising a compound of claim 1 and pharmaceutical additives.
8. An antipsychotic drug containing a compound of claim 1 as an effective ingredient.
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