Sulfur-containing heterocyclic compounds

• US 5,158,943 A
• Filed: 05/23/1991
• Issued: 10/27/1992
• Est. Priority Date: 12/28/1988
• Status: Expired due to Fees

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Sohda, Takashi, Yamazaki, Iwao
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US07/704,962
• Time in Patent Office: 523 Days
• Field of Search: 549/5, 549/12, 514/96, 514/337, 514/371, 514/431, 546/274, 548/195
• US Class Current: 514/96
• CPC Class Codes: C07D 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans
• CPC Class Codes: C07D 335/08 Naphthothiopyrans; Hydrogenated naphthothiopyrans
• CPC Class Codes: C07D 337/08 condensed with one six-membered ring
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4021 Esters of aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/4056 Esters of arylalkanephosphonic acids C07F9/4025 takes precedence
• CPC Class Codes: C07F 9/655372 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65539 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

A sulfur-containing hetrocyclic compound of the formula (I) ##STR1## wherein the ring A is an optionally substituted benzene ring, R is a hydrogen atom or an optionally substituted hydrocarbon residue, B is a carboxyl group which may be esterified or amidated, X is --CH(OH)-- or --CO--, and n is an integer of 0, 1 or 2, or its salt, which is useful in the prevention or treatment of osteoporosis.

Claims

1. A sulfur-containing heterocyclic compound of the formula (I):

##STR73## wherein ring A is a benzene ring which may be substituted by 1 to 4 substituents, which are the same or different, selected from the group consisting of;

(1) halogen;

(2) nitro,

(3) C_1-10 straight-chain or branched alkyl or C_3-7 cycloalkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy, mono- or di(C_1-6 alkoxy)phosphoryl and phosphono group,

(4) (i) hydroxyl, or

(ii) C_1-10 straight-chain or branched alkoxy, C_4-6 cycloalkoxy, C_2-10 alkenyloxy, C_6-19 aralkyloxy, C_2-10 alkanoxyloxy or C_6-14 aryloxy group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy)phosphoryl group,

(5) (i) mercapto, or

(ii) C_1-10 straight-chain or branched alkylthio, C_4-6 cycloalkylthio, C_7-19 aralkylthio or C_2-10 alkanoylthio group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy)phosphoryl group,

(6) amino group which may be substituted by 1 or 2 substituents, which are the same or different, selected from a group consisting of a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl and C_7-19 aralkyl group wherein the substituent may be further substituted by a halogen, C_1-3 alkoxy, mono- or di(C_1-6 alkoxy)phosphoryl or phosphono group,

(7) C_1-19 acyl group,

(8) mono- or dialkoxyphosphoryl,

(9) phosphono,

(10) aryl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a C_1-6 alkyl, halogen, hydroxyl and C_1-6 alkoxy group,

(11) C_7-19 aralkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a C_1-6 alkyl, halogen, hydroxyl and C_1-6 alkoxy group and

(12) 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms, which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a C_1-6 alkyl, halogen, hydroxyl and C_1-6 alkoxy group;

R is (i) a hydrogen atom or (ii) a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl or C_7-19 aralkyl group which may be substituted by a 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms, halogen, dialkoxyphosphoryl or phosphono group;

B is a carboxyl group which may be esterified or amidated, X is --CH(OH)-- or --CO--, and n is an integer of 0, 1 or 2, or its salt.

2. A compound of claim 1, wherein the ring A is a benzene ring substituted by 1 to 4 substituents, which are the same or different, selected from the group consisting of:

(1) halogen,

(2) C_1-10 straight-chain or branched alkyl or C_3-7 cycloalkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy, mono- or di(C_1-6 alkoxy)phosphoryl and phosphono group,

(3) (i) hydroxyl, or

(ii) C_1-10 straight-chain or branched alkoxy, C_4-6 cycloalkoxy, C_2-10 alkenyloxy, C_6-19 aralkyloxy, C_2-10 alkanoxyloxy or C_6-14 aryloxy group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy)phosphoryl group,

(4) (i) mercapto, or

(ii) C_1-10 straight-chain or branched alkylthio, C_4-6 cycloalkylthio, C_7-19 aralkylthio or C_2-10 alkanoylthio group which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of a halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy)phosphoryl group,

(5) amino group which may be substituted by 1 or 2 substituents, which are the same or different, selected from the group consisting of a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl and C_7-19 aralkyl group wherein the substituent may be further substituted by a halogen, C_1-3 alkoxy, mono- or di(C_1-6 alkoxy)phosphoryl or phosphono group, or its salt.

3. The compound of claim 1, wherein B is an amidated carboxyl group of the formula --CON(R¹)(R²) in which R¹ and R² are independently selected from the group consisting of (a) hydrogen, (b) a hydrocarbon group selected from the group consisting of C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl and C_7-19 aralkyl and (c) a heterocyclic group selected from the group consisting of 5- to 7-membered heterocyclic groups containing 1 sulfur, nitrogen or oxygen atom, a 5- or 6-membered heterocyclic group containing 2 to 4 nitrogen atoms and a 5- or 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, any of which can be optionally condensed with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom, the hydrocarbon and heterocyclic groups being optionally substituted with up to three members, which may be the same or different, selected from the group consisting of halogen, hydroxy, C_1-6 alkoxy, amino which may be substituted with C_1-6 alkyl or C_1-10 acyl, carbamoyl which may be substituted with C_1-6 alkyl, C_1-6 alkoxy carbonyl, mono- or di-alkoxyphosphoryl, phosphono or a 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms, which may be substituted by 1 to 3 substituents, which are the same or different, selected from the group consisting of halogen, C_1-6 alkyl, hydroxyl and C_1-6 alkoxy, or its salt.

4. A compound of claim 1 wherein the ring A is a benzene ring substituted by one or two substituents of a straight or branched cain alkyl having 1 to 10 carbon atoms, an alkoxy having 1 to 10 carbon atoms, an alkylthio having 1 to 10 carbon atoms and/or halogen, or its salt.

5. A compound of claim 1 wherein the ring A is a benzene ring substituted by an alkylenedioxy having 1 to 3 carbon atoms, or its salt.

6. A compound of claim 1 wherein the ring A is a benzene ring substituted by methyl, methoxy or methylthio, or its salt.

7. A compound of claim 1 wherein the ring A is a benzene ring substituted by a chlorine, or its salt.

8. A compound of claim 1 wherein R is hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenyl group, or its salt.

9. A compound of claim 1 wherein B is carboxyl or C_1-10 alkoxycarbonyl group, or its salt.

10. A compound of claim 3 wherein R¹ is hydrogen atom or an alkyl group having 1 to 10 carbon atom, and R² is a phenyl or phenyl-C_1-3 alkyl group which may be substituted by a halogen, a C_1-6 alkoxy, a mono- or di-alkoxyphosphoryl, a mono- or di-alkoxyphosphoryl-C_1-3 alkyl or a C_1-6 alkoxycarbonyl or a 5- or 6-membered heterocyclic group having one or two nitrogen atoms, or one nitrogen atom and one sulfur atom which may be substituted by a phenyl, or its salt.

11. A compound of claim 1 wherein X is --CO--, and n is 0, or its salt.

12. A compound of claim 1 which is N-(diethoxyphosphorylmethylphenyl)-7,8-dimethoxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide, N-(4-diethoxyphosphorylphenyl)-7-methyl-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide, N-benzyl-N-methyl-7-methyl-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide or trans-N-(4-chlorophenyl)-4,7,8-trimethyl-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide.

13. A prophylactic or therapeutic composition for osteoporosis which comprises a bone resorption inhibitory amount of a compound of the formula (I) as claimed in claim 1 or its pharmaceutically salt and a pharmaceutically acceptable carrier or excipient.

14. A composition of claim 13 wherein the compound of the formula (I) is one as claimed in any one of claims 4, 9, 10-12, 2 or 3.

15. A method for preventing or treating osteoporosis comprising administering an effective amount of a compound of the formula (I) of claim 1 or its pharmaceutically acceptable salt optionally together with a pharmaceutically acceptable carrier or excipient to a patient suffering from osteoporosis.