Patent
Benzolactam compounds and pharmaceutical uses thereof
| العنوان: | Benzolactam compounds and pharmaceutical uses thereof |
|---|---|
| Patent Number: | 5,055,464 |
| تاريخ النشر: | October 08, 1991 |
| Appl. No: | 07/471,023 |
| Application Filed: | January 25, 1990 |
| مستخلص: | Benzolactam compounds of the general formula ##STR1## or isomers thereof as well as salts thereof inclusive of hydrates and/or solvates forms thereof, and benzolactam compounds of the general formula ##STR2## wherein each of the symbols is as defined in the specification. The compound (I) exhibit antiamnesic activity, and are useful as brain function-improving drugs. The compounds (a) and (b) are useful as an intermediate for said compounds (I). Futher, the compound (a) show diuretic or antiulcer activity, and are useful as a diuretic or antiulcer agent. |
| Inventors: | Murakami, Shu (Fukuoka, JPX); Ikebe, Tsuguo (Oita, JPX); Hakamada, Ichiro (Oita, JPX); Anami, Koretake (Oita, JPX) |
| Assignees: | Yoshitomi Pharmaceutical Industries Ltd. (Osaka, JPX) |
| Claim: | What is claimed is |
| Claim: | 1. A benzolactam compound of the formula ##STR28## wherein A is sulfur atom, oxygen atom, methylene group, --NR.sup.6 -- group (wherein R.sup.6 is hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or benzyloxycarbonyl, tert-butoxycarbonyl or trifluoroacetyl) or carbonyl group; R.sup.1 is hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, a cycloalkyl group having 5 to 7 carbon atoms which may contain double bond on the ring, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms, and an alkoxy group having from 1 to 6 carbon atoms, a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and a alkoxy group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms which is substituted by at least one a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, R.sup.2 is an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, a cycloalkyl group having 5 to 7 carbon atoms which may contain double bond on the ring, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, trifluoromethyl, chloromethyl or 2,2,2-trifluoroethyl, an alkoxy group having 1 to 6 carbon atoms which may be substituted by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms which is substituted by at least one a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or a group representable by the formula ##STR29## which may be fused by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms wherein B is an alkylene having 1 to 6 carbon atoms which may further be substituted by an alkyl group having 1 to 4 carbon atoms, propylidene, butylidene, vinylene, propenylene, --CH.sub.2 OCH.sub.2 --, --CH.sub.2 S(O).sub.n CH.sub.2 -- (n represents an integer of 0 to 2), --CH.sub.2 CON(R.sup.8)-- (wherein R.sup.8 is hydrogen atom or an alkyl group having 1 to 6 carbon atoms) and D is oxygen atoms, methylene group or --N(R.sup.9)-- (wherein R.sup.9 is hydrogen atom or an alkyl group having 1 to 6 carbon atoms); R.sup.3 and R.sup.4 are the same or different and are independently hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or a group which is combined with each other together with the adjacent nitrogen atom to form a heterocycle selected from 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl, which may be substituted by an alkyl or aralkyl group and R.sup.5 is hydrogen atom or one to three halogen atom(s), alkyl group(s) having 1 to 6 carbon atoms which may have unsaturated bond or alkyl group(s) having 1 to 6 carbon atoms which may be substituted by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms (when R.sup.5 is two to three atoms and/or groups, the atoms and/or the groups are the same or different), or an isomer thereof or a pharmaceutically acceptable salt thereof. |
| Claim: | 2. A benzolactam compound as claimed in claim 1, wherein said compounds are trans-3(S)-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-4-oxo-2(R)-pheny l-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3(R)-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-4-oxo-2(S)-pheny l-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis-3-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-4-oxo-2 phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-4-oxo-3-[5-oxo-2(S)-pyrrolidinecarboxamido]-2-phenyl-2,3,4,5-tetrahy dro-1,5-benzothiazepine-5-acetamide, trans-3-(2-indolecarboxamido)-4-oxo-2-phenyl2,3,4,5-tetrahydro-1,5-benzoth iazepine-5-acetamide, trans-3-(4,5-dihydroorotylamino)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-ben zothiazepine-5-acetamide, 2-isopropyl-3-(2-indolecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothia zepine- 5 -acetamide, 3(R)-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-4-oxo-2,3,4,5-tetrahyd ro-1,5-benzothiazepine-5acetamide, trans-3-[.gamma.-bulyrolactone-.gamma.(S)-carboxamido]-4-oxo-2-(2-thienyl) -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3-(2-indolecarboxamido)-4-oxo-2 (2-thienyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans- 3-(2 indolecarboxamido)-4-oxo-2-phenyl-N-(2-phenylethyl)-2,3,4,5-tetrahydr o-1,5-benzothiazepine 5-acetamide, trans-3-(2-indolecarboxamido)-2-phenyl-5-(1-pyrrolidinylcarbonylmethyl)-2, 3-dihydro-1,5-benzothiazepin-4(5H)-one, cis-4-oxo-3(R)-[5-oxo-2(S)-pyrrolidinecarboxamido]-2(R)-phenyl-2,3,4,5-tet rahydro-1,5-benzothiazepine-5-acetamide, cis-4-oxo-3(S)-[5-oxo-2(S)-pyrrolidinecarboxamido]-2(S)-phenyl-2,3,4,5-tet rahydro-1,5-benzothiazepine-5-acetamide, cis-3-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-8-chloro-4-oxo-2-phen yl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, trans-3-[.gamma.-butyrolactone-.gamma.(S)-carboxamido]-8-chloro-4-oxo-2-ph enyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, cis-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1-benzaze pine-1-acetamide and trans-3-(2-indolecarboxamido)-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1-1-benzaz epine-1-acetamide, or an isomer thereof as well as a pharmaceutically acceptable salt thereof. |
| Claim: | 3. A pharmaceutical composition as a brain-function improving and brain function-treating agent which comprises a therapeutically effective amount of the benzolactam compound as claimed in claim 1 or 2 with a pharmaceutically acceptable additive. |
| Claim: | 4. A benzolactam compound of the formula ##STR30## wherein A is sulfur atom, oxygen atom, methylene group, --NR.sup.6 -- group (wherein R.sup.6 is hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or benzyloxycarbonyl, tert-butoxycarbonyl or trifluoroacetyl) or carbonyl group; wherein R.sup.1 a is an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, a cycloalkyl group having 5 to 7 carbon atoms which may contain double bond on the ring, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms which is substituted by at least one monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, and each of the other symbols is as defined in claim 1, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. |
| Claim: | 5. A benzolactam compound as claimed in claim 4, wherein said compounds are 3(R)-[3-cyclopentanone-1(R)-carboxamido]-4-oxo-2(S)-phenyl-2,3,4,5-tetrahy dro-1,5-benzothiazepine-5-acetamide and cis-8-chloro-3-[3-cyclopentanone-1(R)-carboxamido]-4-oxo-2-phenyl-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetamide, or an isomer thereof as well as a pharmaceutically acceptable salt thereof. |
| Claim: | 6. A diuretic composition which comprises a therapeutically effective amount of the benzolactam compound as claimed in claim 4 or 5 with a pharmaceutically acceptable additive. |
| Claim: | 7. An antiulcer composition which comprises a therapeutically effective amount of the benzolactam compound as claimed in claim 4 or 5 with a pharmaceutically acceptable additive. |
| Claim: | 8. A benzolactam compound of the formula ##STR31## wherein Z is a group of the formula: --CH.sub.2 CO.sub.2 O, wherein Q is a carboxy-protecting group, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof wherein A is sulfur atom, oxygen atom, methylene group, --NR.sup.6 -- group (wherein R.sup.6 is hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or benzyloxycarbonyl, tert-butoxycarbonyl or trifluoroacetyl) or carbonyl group; R.sup.2 is an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, a cycloalkyl group having 5 to 7 carbon atoms which may contain double bond on the ring, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, trifluoromethyl, chloromethyl or 2,2,2-trifluoroethyl, an alkoxy group having 1 to 6 carbon atoms which may be substituted by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thizolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms which is substituted by at least one a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or a group representable by the formula ##STR32## which may be fused by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms wherein B is an alkylene having 1 to 6 carbon atoms which may further be substituted by an alkyl group having 1 to 4 carbon atoms, propylidene, butylidene, vinylene, propenylene, --CH.sub.2 OCH.sub.2 --, --CH.sub.2 S(O)CH.sub.2 -- (n represents an integer of 0 to 2), CH.sub.2 CON(R.sup.8)-- (wherein R.sup.8 is hydrogen atom or an alkyl group having 1 to 6 carbon atoms) and D is oxygen atom, or --N(R.sup.9)-- (wherein R.sup.9 is hydrogen atom or an alkyl group having 1 to 6 carbon atoms); R.sup.5 is hydrogen atom or one to three halogen atom(s), alkyl group(s) having 1 to 6 carbon atoms which may have unsaturated bond or alkyl group(s) having 1 to 6 carbon atoms which may be substituted by phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms (when R.sup.5 is two to three atoms and/or groups, the atoms and/or the groups are the same or different); R.sup.1 a is an alkyl group having 1 to 6 carbon atoms which may have unsaturated bond, a cycloalkyl group having 5 to 7 carbon atoms which may contain double bond on the ring, an alkyl group having 1 to 6 carbon atoms substituted by at least one of phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, phenyl, 1-naphthyl or 2-naphthyl which may have on the aromatic ring at least one substituent selected from among halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, a monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms which is substituted by at least one monocyclic or polycyclic aromatic ring containing 1 to 3 nitrogen atom(s), oxygen atom(s) and/or sulfur atom(s) selected from thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl or indolyl, which may have on the aromatic ring at least one substituent selected from among halogen, amino, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, and A is as defined above. |
| Current U.S. Class: | 514/211; 514/213; 514/281; 514/183; 540/490; 540/491; 540/517; 540/523 |
| Current International Class: | A61K 3155; C07D28110 |
| Patent References Cited: | 4564612 January 1986 Sugihara et al. 4692522 September 1987 Parsons et al. 4739066 April 1988 Sugihara et al. 4767756 August 1988 Das et al. |
| Other References: | Derwent Publication--Abstract of Japanese Unexamined Publication 1148171/86. |
| Primary Examiner: | Bond, Robert T. |
| Attorney, Agent or Firm: | Sughrue, Mion, Zinn, Macpeak & Seas |
| رقم الانضمام: | edspgr.05055464 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |