Sulfur-containing heterocyclic compounds useful for the treatment of osteoporosis, and their production

• US 5,071,841 A
• Filed: 12/28/1989
• Issued: 12/10/1991
• Est. Priority Date: 12/28/1988
• Status: Expired due to Term

• 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, Tsuda, Masao
• Primary Examiner(s): Shen, Cecilia
• Application Number:
  US07/458,094
• Time in Patent Office: 712 Days
• Field of Search: 549/9, 549/23, 549/5, 549/51, 549/53, 540/596, 540/542, 514/96, 514/363, 514/370, 514/371, 514/79, 514/96, 514/212, 514/228.2, 514/233.5, 514/275, 514/316, 514/324, 514/361, 514/363, 514/364, 514/365, 514/367, 514/370 , 514/377, 514/380, 514/431, 514/432, 514/253, 544/391, 544/57, 544/62, 544/145, 544/243, 544/322, 548/139, 548/194, 548/195, 548/112, 548/128, 548/136, 548/138, 548/159, 548/156, 548/195, 548/233, 548/245, 548/525, 546/22, 546/187, 546/202
• US Class Current: 514/96
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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

The present invention provides a sulfur-containing heterocyclic compound of the formula (I) ##STR1## wherein ring A is a benzene ring which may be substituted; R is a hydrogen atom or a hydrocarbon group which may be substituted; B is a carboxyl group which may be esterified or amidated; X is --CH(OH)-- or --CO--; k is 0 or 1; and k'"'"' is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

Also, it provides a process for producing the compound (I) or a salt thereof and a pharmaceutical preparation for use in the treatment of osteoporosis comprising the compound (I) or salt thereof.

The compounds (I) and salts thereof show excellent bone resorption inhibitory activity.

Claims

1. A sulfur-containing heterocyclic compound of the formula (I) ##STR229## 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 conssitng 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 a 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) C₁₌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 a group consisting of the halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy) phosphoryl group,

(5)(i) thiol, 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 a group consisting of a halogen, hydroxyl, C_1-6 alkoxy and mono- or di(C_1-6 alkoxy)phosphoryl gorup,

(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 substitutent 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 a 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 a 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 a 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, C_1-10 alkoxy carbonyl, C_6-14 aryloxycarbonyl, C_7-19 aralkyloxycarbonyl group

or a group of the formula --CONR₁ R₂ where R₁ and R₂ each is

(1) a hydrogen atom,

(2) a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl or C_7-19 aralkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from a group consisting of (i) a halogen, (ii) hydroxyl, (iii) C_1-6 alkoxy, (iv) amino which may be substituted by C_1-6 alkyl, (v) amino substituted by acyl, (vi) carbamoyl which may be substituted by C_1-6 alkyl, (vii) C_1-6 alkoxycarbonyl, (viii) mono- or dialkoxyphosphoryl (ix) phosphono group and (x) 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms,

(3)

(i) 5- to 7-membered unsubstituted heterocycles containing one sulfur, nitrogen or oxygen atom, 5- or 6-membered heterocycles containing 2 to 4 nitrogen atoms, or 5- or 6-membered heterocycles containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, and each of these heterocycles being optionally fused to a 6-membered ring contaiing a maximum of 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom or

(ii) substituted heterocycles selected from the group consisting of 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazoly, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isooxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl or 4-methyl-2-morpholinyl

or alternatively R₁ and R₂, taken together with the adjacent nitrogen atom, form

morpholine, piperidine, thiomorpholine, homopiperidine, pyrrolidine or thiazolidine,

x is --CH(OH)-- or --CO--;

k is 0 or 1, and k'"'"' is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

3. A compound as claimed in claim 1, wherein B is a group of the formula --CONR₁ R₂ where R₁ and R₁ each is

(1) a hydrogen atom,

(2) a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl or C_7-19 aralkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from a group consisting of (i) a halogen, (ii) hydroxyl, (iii) C_1-6 alkoxy, (iv) amino which may be substituted by C_1-6 alkyl, (v) amino substituted by acyl, (vi) carbamoyl which may be substituted by C_1-6 alkyl, (vii) C_1-6 alkoxycarbonyl, (viii) mono- or dialkoxyphosphoryl (ix) phosphono group and (x) 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms,

(3)

(i) 5- to 7-membered unsubstituted heterocycles containing one sulfur, nitrogen or oxygen atom, 5- or 6-membered heterocycles containing 2 to 4 nitrogen atoms, or 5- or 6-membered heterocycles containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, and each of these heterocycles being optionally fused to a 6-membered ring contaiing a maximum of 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom or

(ii) substituted heterocycles selected from the group consisting of 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazoly, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isooxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl or 4-methyl-2-morpholinyl

or alternatively R₁ and R₂, taken together with the adjacent nitrogen atom, form

morpholine, piperidine, thiomorpholine, homopiperidine, pyrrolidine or thiazolidine.

4. A compound as claimed in claim 1, wherein ring A is a benzene ring which may be substituted by 1 or 2 substituents, which are the same or different, selected from a group consisting of a halogen, ac_1-10 alkyl and a C_1-6 akoxy;

R is a hydrogen atom, a C_1-10 alkyl or a phenyl group;

B is a C_1-10 alkoxycarbonyl group of a group of the formula --CONR₁ R₂ where R₁ and R₂ each is

(1) a hydrogen atom,

(2) a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl or C_7-19 aralkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from a group consisting of (i) a halogen, (ii) hydroxyl, (iii) C_1-6 alkoxy, (iv) amino which may be substituted by C_1-6 alkyl, (v) amino substituted by acyl, (vi) carbamoyl which may be substituted by C_1-6 alkyl, (vii) C_1-6 alkoxycarbonyl, (viii) mono- or dialkoxyphosphoryl (ix) phosphono group and (x) 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms,

(3)

(i) 5- to 7-membered unsubstituted heterocycles containing one sulfur, nitrogen or oxygen atom, 5- or 6-membered heterocycles containing 2 to 4 nitrogen atoms, or 5- or 6-membered heterocycles containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, and each of these heterocycles being optionally fused to a 6-membered ring contaiing a maximum of 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom or

(ii) substituted heterocycles selected from the group consisting of 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazoly, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isooxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl or 4-methyl-2-morpholinyl

or alternatively R₁ and R₂, taken together with the adjacent nitrogen atom, form

morpholine, piperidine, thiomorpholine, homopiperidine, pyrrolidine or thiazolidine,

and each of K and k'"'"' is 0.

5. A compound as claimed in claim 1 wherein ring A is a benzene ring which may be substituted by 1 or 2 substituents, which are the same or different, selected from a group consisting of a halogen, a C_1-10 alkyl and a C_1-6 alkoxy.

6. A compound as claimed in claim 1 wherein ring A is a benzene ring which may be substituted by 1 or 2 C_1-10 alkyl groups, which are the same or different.

7. A compound as claimed in claim 1 wherein ring A is a benzene ring which may be substituted by a C_3-7 cycloalkyl group.

8. A compound as claimed in claim 1 wherein R is a hydrogen atom, a C_1-10 alkyl or a phenyl group.

9. A compound as claimed in claim 1 wherein R is a hydrogen atom or a methyl group.

11. A compound as claimed in claim 1, namely 6-cyclohexyl-N-(4-diethoxyphosphorylmethylphenyl)-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide.

12. A compound as claimed in claim 1, namely 6,7-dimethyl-N-(4-diethoxyphosphorylphenyl)-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide.

13. A compound as claimed in claim 1, namely 6,7-dimethyl-N-(4-diethoxyphophorylmethylphenyl)-3,4-dihydro-1H-2-benzothipyran-4-one-1-carboxamide.

14. A pharmaceutical preparation for use in the treatment of osteoporosis comprising an effective anti-osteoporotic amount of a compound or pharmaceutically acceptable salt claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.

2. A compound as claimed in cliam 1, wherein B is a C_1-10 alkoxycarbonyl group or a group of the formula --CONR₁ R₂ where R₁ and R₂ each is

(1) a hydrogen atom,

(2) a C_1-10 alkyl, C_2-10 alkenyl, C_6-14 aryl or C_7-19 aralkyl group which may be substituted by 1 to 3 substituents, which are the same or different, selected from a group consisting of (i) a halogen, (ii) hydroxyl, (iii) C_1-6 alkoxy, (iv) amino which may be substituted by C_1-6 alkyl, (v) amino substituted by acyl, (vi) carbamoyl which may be substituted by C_1-6 alkyl, (vi) carbamoyl which may be substituted by C_1-6 alkyl, (vii) C_1-6 alkoxycarbonyl, (viii) mono- or dialkoxyphosphoryl (ix) phosphono group and (x) 5- or 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen and/or sulfur atoms,

(3)

(i) 5- to 7-membered unsubstituted heterocycles containing one sulfur, nitrogen or oxygen atom, 5- or 6-membered heterocycles containing 2 to 4 nitrogen atoms, or 5- or 6-membered heterocycles containing 1 to 2 nitrogen atoms and one sulfur or oxygen atom, and each of these heterocycles being optionally fused to a 6-membered ring contaiing a maximum of 2 nitrogen atoms, a benzene ring, or a 5-membered ring containing one sulfur atom or

(ii) substituted heterocycles selected from the group consisting of 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, 5-methyl-2-benzothiazoly, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isooxazolyl, 4-(4-chlorophenyl)-5-methyl-2-oxazolyl, 3-phenyl-1,2,4-thiadiazol-5yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl, 4,5-dimethyl-2-furanyl or 4-methyl-2-morpholinyl

or alternatively R₁ and R₂, taken together with the adjacent nitrogen atom, form

morpholine, piperidine, thiomorpholine, homopiperidine, pyrrolidine or thiazolidine.

10. A compound as claimed in laim 2 wherein R₁ is a hydrogen atom and R₂ is a group of the formula C₆ C₄ (CH₂)_n P(O)(OR'"'"')₂ where n is 0 or 1 and R'"'"' is a C_1-6 alkyl group.