Substituted 4-biphenyl-4-hydroxybutyric acid derivatives as matrix metalloprotease inhibitors

• US 5,939,583 A
• Filed: 10/30/1997
• Issued: 08/17/1999
• Est. Priority Date: 10/31/1996
• Status: Expired due to Fees

• Current Assignee: Bayer Pharmaceuticals Corporation (Bayer AG)
• Original Assignee: Bayer Corporation (Bayer AG)
• Inventors: Bjorge, Susan M., Zadjura, Lisa Marie, Brubaker, William Frederick, Kluender, Harold C. E.
• Primary Examiner(s): Higel, Floyd D.
• Application Number:
  US08/960,921
• Time in Patent Office: 656 Days
• Field of Search: 548/479, 562/469, 514/278, 514/532, 514/543, 514/417
• US Class Current: 562/469
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 323/56 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 323/61 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 59/56 containing halogen
• CPC Class Codes: C07C 59/64 : containing six-membered aromatic rings
• CPC Class Codes: C07C 59/66 : the non-carboxylic part of the ether containing six-membered aromatic rings
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide

Abstract

Inhibitors for matrix metalloproteases, pharmaceutical compositions containing them, and a process for using them to treat a variety of physiological conditions. The compounds of the invention have the generalized formula ##STR1## in which T is a pharmaceutically-acceptable substituent group; A is CH₂, CH, or N; G is CH₂ or CH; and R¹ is any of a variety of disclosed substituent groups. The class of compounds of the invention includes ring-containing materials in which the units A and G are joined. The compounds of the invention are mixtures of diastereomers, or individual diastereomers making up these mixtures.

Claims

1. A compound having matrix metalloprotease inhibitory activity and the formula ##STR40## wherein:

T is a pharmaceutically-acceptable substituent group;

x is 0, 1, or 2;

m is 0 or an integer of 1-4;

n is 0 or 1; and

either

A and G are both CH₂ ;

or

A is a chemical bond and G is CH₂ ;

or

A is CH or N; and

G is CH; and

A is connected to G by a ring-forming linkage of formula;

(CH₂)_0-3 (Q)(CH₂)_0-3;

wherein

Q is a chemical bond, S, or O; and

C, S, and O constitute linking atoms;

resulting in formation of a ring which includes A, said ring-forming linkage, and G;

with the provisos that

the sum of n plus the total number of linking atoms in said ring-forming linkage is an integer of from 1 to 4; and

the number of heteroatoms in said ring is 0 or 1;

R¹ is;

aryl of 6-10 carbons, provided that if this aryl group is phenyl, then x is 1 or 2;

heteroaryl containing 4-9 carbons and at least one N, O or S heteroatom;

aryl-substituted alkenyl wherein the aryl portion contains 6-10 carbons and the alkenyl portion contains 2-5 carbons;

heteraryl-substituted alkenyl wherein the heteroaryl portion contains 4-9 carbons and at least one N, O, or S heteroatom, and the alkenyl portion contains 2-5 carbons;

aryl-substituted alkynyl wherein the aryl portion contains 6-10 carbons and the alkynyl portion contains 2-5 carbons;

heteroaryl-substituted alkynyl wherein the heteroaryl portion contains 4-9 carbons and at least one N, O, or S heteroarom and the alkynyl portion contains 2-5 carbons;

N-phthalimidoyl;

N-(1,2-naphthalenedicarboximidoyl);

N-(2,3-naphthalenedicarboximidoyl);

N-(1,8-naphthalenedicarboximidoyl);

N-indoloyl;

N-(2-pyrrolodinonyl);

N-succinimidoyl;

N-maleimidoyl;

3-hydantoinyl;

1,2,4-urazolyl;

amido;

a urethane;

a urea;

##STR41## wherein Y is O or S, R² is H or alkyl of 1-3 carbon atoms, and u is 0, 1, or2;

an amino; and

ZR⁸ in which

Z represents ##STR42## and R⁸ is;

aryl of 6-10 carbons;

heteroaryl containing 4-9 carbons and at least one N, O, or S heteroatom;

arylalkyl wherein the aryl portion contains 6-12 carbons and the alkyl portion contains 14 carbons;

or

heteroaryl-alkyl wherein the aryl portion contains 4-9 carbons and at least one N, O, or S heteroatom and the alkyl portion contains 1-4 carbons;

or

and with the proviso that

when Z is O, R⁸ may also be alkyleneoxy or polyalkyleneoxy terminated with H, alkyl, or phenyl;

aryl or heteroaryl portions of any of the T or R¹ groups optionally bearing up to two substituents selected from the group consisting of --(CH₂)_y C(R¹¹)(R¹²)OH, --(CH₂)_y OR¹¹, --(CH₂)_y SR¹¹, --(CH₂)_y S(O)R¹¹, --(CH₂)_y S(O)₂ R¹¹, --(CH₂)_y SO₂ N(R¹¹)₂, --(CH₂)_y N(R¹¹)₂, --(CH₂)_y N(R¹¹)COR¹², --OC(R¹¹)₂ O-- in which both oxygen atoms are connected to the aryl ring, --(CH₂)_y COR¹¹, --(CH₂)_y CON(R¹¹)₂, --(CH₂)_y CO₂ R¹¹, --(CH₂)_y OCOR¹¹, -halogen, --CHO, --CF₃, --NO₂, --CN, and --R¹², in which y is 0-4;

R¹¹ represents H or lower alkyl of 1-4 carbon atoms; and

R¹² represents lower alkyl of 1-4 carbon atoms;

said compound being a mixture of diastereomers, or the single diastereomer which has the greater matrix metalloprotease inhibitory activity of the diastereomers constituting said mixture of diastereomers;

or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1 wherein

A is CH₂ ;

G is CH₂ ; and

n is O;

said compound having the formula ##STR43## wherein T, x, m, and R¹ are as defined in claim 1.

3. The compound of claim 2 wherein

m is 0, 1, or 2;

and

when m is 0, R¹ is ##STR44## when m is 1, R¹ is ##STR45## when m is 2, R¹ is ##STR46##

4. The compound of claim 3 wherein T is halogen or OR⁶ wherein R⁶ is alkyl of 1-6 carbons or benzyl;

x is 1;

m is 0or2;

when m is 0, R¹ is ##STR47## and when m is 2, R¹ is ##STR48##

5. A compound of claim 2 having the name 4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2-(phenylthiomethyl)butanoic acid;

2S, 4R!-4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2-(phenylthiomethyl)-butanoic acid;

4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2- (4-hydroxyphenyl)-thiomethyl!-butanoic acid;

4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2-(3-phenylpropyl)butanoic acid;

4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2- 2-(3-N,N-diethylcarbamoyl)-phenylethyl!butanoic acid;

4- 4-(4-pentyloxyphenyl)phenyl!-4-hydroxy-2-(3-phenylpropyl)butanoic acid;

4- 4-(4-benzyloxyphenyl)phenyl!-4-hydroxy-2-(3-phenylpropyl)butanoic acid;

4- 4-(4-chlorophenyl)phenyl!-4-hydroxy-2-(2-phthalimidoethyl)butanoic acid.

6. The compound of claim 1 wherein

n is 0 or 1;

and

A is CH or N; and

G is CH; and

A is connected to G by a ring-forming linkage of formula;

(CH₂)_0-3 (Q)(CH₂)_0-3 ;

wherein

Q is a chemical bond, S, or O; and

C, S, and O constitute linking atoms;

resulting in formation of a ring which includes A, said ring-forming linkage, and G;

said compound having the formula ##STR49## with the provisos that the sum of n plus the total number of linking atoms in said ring-forming linkage is an integer of from 1 to 4; and

the number of heteroatoms in said ring is 0 or 1;

T, x, m, and R¹ being as defined in claim 1.

7. The compound of claim 6 wherein

n is 0;

A is CH;

Q is a chemical bond; and

said ring-forming linkage is --(CH₂)₂ --; and

said compound having the formula ##STR50##

8. The compound of claim 7 wherein T is halogen or OR⁶ wherein R⁶ is alkyl of 1-6 carbons or benzyl;

x is 1;

m is 0 or 1; and

when m is 0, R¹ is ##STR51## when m is 1, R¹ is ##STR52##

9. A compound of claim 6, having the name trans-5- (4-(4-chlorophenyl)phenyl)hydroxymethyl!-trans-2-phenylthio-cyclopentanecarboxylic acid;

trans-5- (4-(4-chlorophenyl)phenyl)hydroxymethyl!-cis-2-(2-methoxycarbonyl-phenylthio)cyclopentanecarboxylic acid; and

trans-5- (4-(4-chlorophenyl)phenyl)hydroxymethyl!-trans-2-phthalimidomethylcyclopentanecarboxylic acid.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier.

13. A method for treating a matrix metalloprotease-mediated condition in a mammal comprising administering to said mammal an amount of a compound of claim 1 which is effective to treat said condition.

14. The method of claim 13 wherein said mammal is a human.

15. The method of claim 13 wherein the effect the treatment of is:

alleviation of osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurysmal aortic disease, dystrophobic epidermolysis bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, or demyelating diseases of the nervous system;

retardation of tumor metastasis or degenerative cartilage loss following traumatic joint injury;

reduction of coronary thrombosis from atherosclerotic plaque rupture;

or improved birth control; and

said amount of a compound of claim 1 is effective to inhibit the activity of at least one matrix metalloprotease in said mammal, thereby to achieve said effect.

16. A method of preparing a compound of formula ##STR53## comprising:

reducing to a hydroxyl group the ketone carbonyl in a compound of formula ##STR54## wherein T, x, G, n, A, m, and R¹ are as defined in claim 1.