EP0465254A1
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EP
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Fused thiophene compounds and uses thereof
Assignee: Tanabe Pharma Corp
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Filing: 1991-07-04
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Granted: —
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Expires: 2011-07-04
Abstract
Abstract A fused thiophene compound of the formula: or a pharmaceutically acceptable acid addition salt thereof. In the above formula, one of E¹, E² and E³ is sulfur atom and other two of them are C-R¹ and C-R² respectively. R¹ and R² are the same or different and each is hydrogen, halogen, nitro, amino, cyano, hydroxyl, formyl, alkyl, alkoxy, haloalkyl, arylalkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, halosulfonyl, sulfamoyl, substituted sulfamoyl, carboxyl, acylamino, alkoxycarbonyl, carbamoyl, substituted carbamoyl or substituted amino. D is -CH₂- or -S(0) m - (m is 0, 1 or 2). Q is straight or branched chain alkylene. T is primary amino, secondary amino or tertiary amino. A and B are the same or different and each is carbonyl or thiocarbonyl, or one of A and B is absent and the other of them is carbonyl or thiocarbonyl, or A is -CH₂- and B is carbonyl or thiocarbonyl, and n is 1, 2 or 3 with the proviso that n is 2 or 3 when one of A and B is absent and the other of them is carbonyl or thiocarbonyl, and n is 1 or 2 when A and B are other combinations. In the above definitions, (hetero)aromatic ring and heterocyclic ring may optionally be substituted by 1 to 3 substituents. Said compounds have selective affinity for 5-HT 1A receptor, or high affinity for 5-HT 1A and dopamine D₂ receptors so that they are useful as antianxietic drug, antipsychotic drug or drug for the disease of circulatory system. The intermediates for said fused thiophene compounds are also disclosed.
Inventors
- 👤 Tohru Nakao
- 👤 Hiroshi Tanaka
- 👤 Hirotake Yamato
- 👤 Takeshi Akagi
- 👤 Shuzo Takehara
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-07 16:11
CPC Classifications
C; C07; C07D; C07D495/00; C07D495/02; C07D495/04; C07D513/00; C07D513/02; C07D513/04
Claims Analysis
Total Claims: 19
Claim 1
Independent Claim
224 words
A fused thiophene compound of the formula: or a pharmaceutically acceptable acid addition salt thereof, wherein in the above formula, one of E¹, E² and E³ is sulfur atom and other two of them are C-R¹ and C-R² respectively; R¹ and R² are the same or different and each is hydrogen, halogen, nitro, amino, cyano, hydroxyl, formyl, alkyl, alkoxy, haloalkyl, arylalkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl, haloalkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, halosulfonyl, sulfamoyl, substituted sulfamoyl, carboxyl, acylamino, alkoxycarbonyl, carbamoyl, substituted carbamoyl or substituted amino; D is -CH₂- or -S(O) m - (m is 0, 1 or 2; Q is straight or branched chain alkylene. T is primary amino, secondary amino or tertiary amino: A and B are the same or different and each is carbonyl or thiocarbonyl, or one of A and B is absent and the other of them is carbonyl or thiocarbonyl, or A is -CH₂- and B is carbonyl or thiocarbonyl, and n is 1, 2 or 3 with the proviso that n is 2 or 3 when one of A and B is absent and the other of them is carbonyl or thiocarbonyl, and n is 1 or 2 when A and B are other combinations; and wherein the foregoing (hetero)aromatic ring and heterocyclic ring may optionally be substituted by 1 to 3 substituents.
Claim 2
Dependent Claim
233 words
The compound or pharmaceutically acceptable acid addition salt thereof of claim 1 wherein T is primary amino of -NH₂, T is secondary amino of -NHRa wherein Ra is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl, or T is tertiary amino of -N(Rb)(Rc) wherein Rb and Rc are the same or different and each is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl, or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino of the formula: wherein q is an integer of 1 to 4, Z is methylene, oxygen atom, sulfur atom or N-R5 (R5 is hydrogen, alkyl, cyanoalkyl, hydroxyalkyl, aryl, arylalkyl, alkoxycarbonyl, diarylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, acyl, cinnamyl or adamantanemethyl), substituent V is hydrogen, hydroxyl, amino, carbamoyl, mono or di-substituted amino, cyclic amino, acyl, aryl, arylalkyl, arylalkylamino, alkyl, alkoxy, hydroxyalkyl, alkoxycarbonyl, heteroaryl, phenoxyalkyl, anilinoalkyl, alkylaminoalkyl, alkanoylaminoalkyl or bisarylmethylene and the number of V is 1 to 4, and the cyclic amino of formula (1) may contain carbonyl group in the ring and further may be fused with aryl or hetereoaryl; the ring Am of formula (2) may contain amido bond and further may contain oxygen atom, sulfur atom, carbonyl and/or N-R⁶ (R⁶ is hydrogen, alkyl or phenyl), and also the ring Am may be fused with a 5 to 7 membered saturated or unsatured ring, and wherein the (hetero)aromatic ring and the heterocyclic ring may optionally be substituted by 1 to 3 substituents.
Claim 3
Dependent Claim
32 words
The compound or pharmaceutically acceptable acid addition salt thereof of claim 1 or 2 wherein T is -NHRa where Ra is heteroarylalkyl which may be optionally substituted by 1 to 3 substituents.
Claim 4
Dependent Claim
182 words
The compound or pharmaceutically acceptable acid addition salt thereof of claim 1 or 2 wherein T is -N(Rb)(Rc) where Rb and Rc are the same or different and each is alkyl, arylalkyl or heteroarylalkyl, or Rb and Rc together with the adjacent nitrogen atom form a cyclic amino of the formula: or wherein q is an integer of 1 to 4, Z is methylene or N-R⁵ (R⁵ is aryl, diarylalkyl, heteroaryl, heteroarylalkyl or acyl), substituent V is hydrogen, hydroxyl, carbamoyl, cyclic amino, aryl, arylalkylamino, heteroaryl or bisarylmethylene and the number of V is 1 to 4, wherein the cyclic amino of formula (1) may contain carbonyl group in the ring and further may be fused with aryl or heteroaryl; the ring Am of formula (2) may contain an amido bond in the cycle and further may contain a sulfur atom, and/or N-R⁶ (R⁶ is phenyl), and further the ring Am may be fused to a 5 to 7 membered saturated or unsatured ring, and in the foregoing (hetero)aromatic ring and the heterocyclic ring may optionally be substituted by 1 to 3 substituents.
Claim 5
Dependent Claim
41 words
The compound or pharmaceutically acceptable acid addition salt thereof of claim 1 or 2 wherein T is a cyclic amino of the formula: where Z is N-R⁵ (R⁵ is pyrimidinyl or substituted pyrimidinyl), substituent V is hydrogen, and q is 2.
Claim 6
Dependent Claim
43 words
The compound of claim 1 or 2 of the formula: or pharmaceutically acceptable acid addition salt thereof, wherein R 3′ is hydrogen, halogen, nitro, amino, cyano, hydroxyl, alkyl, alkoxy or haloalkyl and the other symbols are as defined in claim 1 or 2.
Claim 7
Dependent Claim
114 words
The compound of claim 1 or 2 of the formula: or pharmaceutically acceptable acid addition salt thereof, wherein R¹ and R² are the same or different and each is hydrogen, halogen, nitro, amino, cyano, hydroxyl, formyl, alkyl, alkoxy, haloalkyl, aralkyl, acyl, alkoxyalkyl, acyloxyalkyl, hydroxyalkyl, acyloxyalkanoyl, alkoxyalkanoyl, hydroxyalkanoyl, aryloxyalkanoyl or haloalkanoyl, R 3′ is as defined in claim 6, A and B are carbonyl groups, or one of A and B is absent and the other is carbonyl group, n′ is 2 or 3 when A and B are carbonyl groups and n′ is 3 or 4 in the other case, and Q is straight or branched chain alkylene having 1 to 10 carbon atoms.
Claim 8
Dependent Claim
60 words
The compound of claim 1 or 2 of the formula: or pharmaceutically acceptable acid addition salt thereof, wherein R¹ and R² are as defined in claim 7, R 3′ is as defined in claim 6, t is an integer of 1 to 8, A and B are absent or carbonyl group, and when A is carbonyl group, B is absent.
Claim 9
Dependent Claim
80 words
The compound of claim 1 or 2 or pharmaceutically acceptable acid addition salt thereof, wherein T is a group of the formula: and Z is methylene or N-R⁵ (R⁵ is aryl, diarylalkyl, heteroaryl except pyrimidinyl, heterarylalkyl or acyl). Substituent V is hydrogen, hydroxyl, carbamoyl, cyclic amino, aryl, arylalkylamino, heteroaryl or bisarylmethylene and the number of V is 1 to 4. q is 2, and wherein the (hetero)aromatic ring and heterocyclic ring may optionally be substituted by 1 to 3 substituents.
Claim 10
Dependent Claim
38 words
A compound as claimed in claim 1 which is 2-bromo-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-methyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-ethyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-acetyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-(1-hydroxyethyl)-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 5-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl]-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 5-(4-[(1,4-benzodioxan-2-yl)methylamino]butyl]-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno(3,2-f]-1,4-thiazepin-5(4H)-one, 7-bromo-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 7-ethyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 4-[4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl]-2,3-dihydro-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 4-[4-(4-(bis(4-fluorophenyl)methyl)-1-piperazinyl)butyl]-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-methyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepine-4,6-dione, 7-methyl-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-2,3-dihydro-4H-thieno[3,2-f][1,4]thiazepine-4,5-dione, 5-[4-(4-(3-trifluoromethylphenyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 5-[4-(4-(2,3-dimethylphenyl)-1-piperazinyl)butyl]-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 5-[4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl]-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2,3-dihydro-4-[4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl]-7-methyl-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, or 4-[4-(4-(bis(4-fluorophenyl)methylene)piperidino)butyl]-2,3-dihydro-7-methylthieno[3,2-f]-1,4-thiazepin-5(4H)-one or a pharmaceutically acceptable acid addition salt thereof.
Claim 11
Dependent Claim
29 words
A compound as claimed in claim 1 which is 2-bromo-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-methyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-ethyl-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-acetyl-5-[4-(4-(2-pyrididinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2-(1-hydroxyethyl)-5-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, 2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 7-bromo-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 7-acetyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 7-ethyl-2,3-dihydro-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-thieno[3,2-f]-1,4-thiazepin-5(4H)-one, 2-methyl-5-[4-(4-(2-pyrididinyl)-1-piperazinyl)butyl]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4,6-dione or 7-methyl-4-[4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl]-2,3-dihydro-4H-thieno[3,2-f][1,4]thiazepin-3,5-dione, or a pharmaceutically acceptable acid addition salt thereof.
Claim 12
Dependent Claim
41 words
A fused thiophene compound of the formula: wherein X is hydroxyl, a reactive atom or group derived from hydroxyl, a group of -CO-R³ (R³ being hydrogen or alkyl), cyano, carbamoyl or nitro, and other symbols are as defined in claim 1.
Claim 13
Dependent Claim
19 words
The compound of claim 12 of the formula: wherein each symbol is as defined in claims 1 and 12.
Claim 14
Dependent Claim
16 words
A fused thiophene compound of the formula: wherein each symbol is as defined in claim 1.
Claim 15
Dependent Claim
17 words
The compound of claim 14 of the formula: wherein each symbol is as defined in claim 1.
Claim 16
Dependent Claim
34 words
A pharmaceutical composition comprising a fused thiophene compound of pharmaceutically acceptable acid addition salt thereof as claimed in any one of claims 1 to 11 and one or more pharmaceutical carrier, diluent or excipient.
Claim 17
Dependent Claim
30 words
The use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for treating anxiety, the compound being an antianxietic drug.
Claim 18
Dependent Claim
31 words
The use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for treating psychosis, the compound being an an antipsychotic drug.
Claim 19
Dependent Claim
29 words
The use of a compound as claimed in any one of claims 1 to 11 in the preparation of a medicament for treating a disease of the circulatory system.
References Cited (Backward Citations)
EP0324610A2
Cited
EP0329168A2
Cited
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