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US 6,271,232 B1Granted
Collagenase-1 and stromelysin-1 inhibitors, pharmaceutical compositions comprising same and methods of their use
AssigneeAffymax Technologies N.V.
InventorsDavid Campbell, Gary C. Look, Anna Katrin Szardenings, Dinesh V. Patel
Life of this patent
Estimating the term…
Abstract
Novel inhibitors of metalloproteases, in particular collagenase-1 and stromelysin-1, are disclosed. Such compounds are useful in pharmaceutical compositions and methods for treating or controlling disease states or conditions which involve tissue breakdown, such as rheumatoid arthritis.
Claims14
A compound of formula:
- wherein R1 is selected from the group consisting of —CH2R8 and —CHR8R9, and R4 is selected from the group consisting of hydrogen and —CH2R8 and —CHR8R9;
- R2, R3, R5, R6 and R8 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) an alkyl group of from 1 to 12 carbon atoms, optionally substituted;
- (iii) —NR′C(O)—X—R″ where R′ and R″ are independently selected from the group consisting of hydrogen, alkyl of from 1 to 12 carbon atoms, substituted alkyl of from 1 to 12 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2, and X is selected from the group consisting of a bond, O, and NR′ where R′ is as defined above;
- (iv) —OC(O)Y—R″ where R″ is selected from the group consisting of alkyl of from 1 to 12 carbon atoms, substituted alkyl of from 1 to 12 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2, and Y is selected from the group consisting of a bond and NR′ where R′ is as defined above;
- (v) alkenyl groups of from 2 to 10 carbon atoms;
- (vi) alkynyl groups of from 3 to 10 carbon atoms;
- (vii) carboxyl groups;
- (viii) carboxyl ester groups wherein the ester group comprises from 1 to 12 carbon atoms;
- (ix) heterocycles, either saturated, unsaturated or aromatic, having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted;
- (x) R—C(O)— groups where R is hydrogen or an alkyl group of from 1 to 12 carbon atoms, optionally substituted on the alkyl group;
- (xi) aryl group of from 6 to 10 carbon atoms optionally substituted with 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2;
- and
- (xii) arylalkyl, optionally substituted on the aryl group and/or the alkyl group;
- or wherein
- R2, R3 and the carbon to which they are attached form a cycloalkyl or heterocyclic group;
- or
- R1 and R2 and the carbon and nitrogen to which they are attached, respectively, form a heterocyclic group;
- R4 and R5 and the carbon and nitrogen to which they are attached, respectively, form a heterocyclic group;
- R7 is hydrogen;
- R9 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic or substituted heterocyclic;
- and
- n is an integer from 1 to 3;
- and a pharmaceutical salt thereof.
22 more elements
A method for treating a patient suffering from rheumatoid arthritis, said method comprising administering to said patient an effective amount of a compound of the formula
- wherein:
- R1 and R4 are independently selected from the group consisting of hydrogen and —CH2R8 and —CHR8R9;
- R2, R3, R5, R6 and R8 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) an alkyl group of from 1 to 12 carbon atoms, optionally substituted;
- (iii) —NR′C(O)—X—R″ where R′ and R″ are independently selected from the group consisting of hydrogen, alkyl of from 1 to 12 carbon atoms, substituted alkyl of from 1 to 12 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2, and X is selected from the group consisting of a bond, O, and NR′ where R′ is as defined above;
- (iv) —OC(O)Y—R″ where R″ is selected from the group consisting of alkyl of from 1 to 12 carbon atoms, substituted alkyl of from 1 to 12 carbon atoms, aryl groups of from 6 to 10 carbon atoms optionally substituted with from 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2, and Y is selected from the group consisting of a bond and NR′ where R′ is as defined above;
- (v) alkenyl groups of from 2 to 10 carbon atoms;
- (vi) alkynyl groups of from 3 to 10 carbon atoms;
- (vii) carboxyl groups;
- (viii) carboxyl ester groups wherein the ester group comprises from 1 to 12 carbon atoms;
- (ix) heterocycles, either saturated, unsaturated or aromatic, having from 2 to 6 carbon atoms and 1 to 3 ring hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted;
- (x) R—C(O)— groups where R is hydrogen or an alkyl group of from 1 to 12 carbon atoms, optionally substituted on the alkyl group;
- (xi) aryl group of from 6 to 10 carbon atoms optionally substituted with 1 to 3 substituents on the aryl moiety selected from the group consisting of hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amido, amino, aryloxy, carboxyl, halo, mercapto, cyano, nitro, —SO3, and —SO2NH2;
- and
- (xii) arylalkyl, optionally substituted on the aryl group and/or the alkyl group;
- or wherein R2, R3 and the carbon to which they are attached form a cycloalkyl or heterocyclic group;
- or
- R1 and R2 and the carbon and nitrogen to which they are attached, respectively, form a heterocyclic group;
- R4 and R5 and the carbon and nitrogen to which they are attached, respectively, form a heterocyclic group;
- R7 is hydrogen and alkyl of from 1 to 12 carbon atoms, R8C(O)— and R8S— where R8 is as defined above;
- R9 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic or substituted heterocyclic;
- and
- n is an integer from 1 to 3;
- or a pharmaceutical salt thereof.
22 more elements
Dependencies are inferred from the claim text.