IP Library › Granted Patent US 7,872,052

Granted Patent B2

US 7,872,052 · App. 10/559,322 · Granted Jan 18, 2011

Use of heterocyclic compounds as SCCE inhibitors

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Quick Facts

Patent No.: US 7,872,052
App. No.: 10/559,322
Granted: Jan 18, 2011
Kind: B2

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Abstract

The present invention relates to heterocyclic inhibitors of stratum corneum chymotryptic enzyme (SCCE). More particularly, the invention relates to the use of compounds with the formula (I) or (II) for treatment of certain diseases, in particular skin diseases such as pruritus, as well as cancer such as ovarian cancer.

Claims (248)

1. A method for treatment of a skin disease in a mammal, wherein the skin disease is selected from the group consisting of atopic dermatitis, contact dermatitis, eczema, psoriasis, acne, epidermal hyperkeratosis, acanthosis, epidermal inflammation, dermal inflammation and pruritus, and wherein the mammal has symptoms of the skin disease and the treatment reduces the symptoms wherein the method comprises topically administering to the mammal an effective amount of at least one compound with formula I or II:

wherein

X is O or S; Y is independently O, S, NH or N if the nitrogen atom is bonded to an adjacent carbon atom via a double bond; Z is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom via a double bond;

W, Q, V, and T are independently CH, CH 2 , S, N, or O;

ring A, ring B, ring C and ring D may be aromatic, saturated or partly saturated;

R 1 and R 2 are optional substitutents independently selected from C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl, each optionally substituted with halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 -alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 or CON(R 4 ) 2 , H, halogen, CF 3 , C 1-6 -alkoxy, C 1-6 alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , CON(R 4 ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole;

or R 1 and R 2 , when bonded to adjacent atoms in ring A or ring C, optionally together form a moiety —(CH 2 ) n —, where n=1-5, and wherein 1, 2 or 3 CH 2 units in said moiety are optionally replaced by 1, 2 or 3 heteroatoms, wherein each heteroatom is individually selected from the group consisting of O, S, NH and N if the nitrogen atom is bonded to an adjacent atom via a double bond, and wherein said moiety may optionally be substituted with 1, 2 or 3 substitutents individually selected from the group consisting of halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 , or CON(R 4 ) 2 ;

R 3 is aryl or heteroaryl, each optionally substituted with one or more halogen, CF 3 , C 1-6 -alkoxy, C 1-6 -alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , CON(R 4 ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 -alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, tetrazole, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl, each C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl being optionally substituted with halogen, CF 3 , OCF 3 , COOH, CN, CONH 2 , CONHR 4 , CON(R 4 ) 2 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 alkoxy, or carbamoyl; and

R 4 is C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylthio, aryl, aryloxy, heteroaryl, or heteroaryloxy;

or a pharmaceutical acceptable salt thereof.

2. The method according to claim 1 , wherein said skin disease is selected from the group consisting of atopic dermatitis, contact dermatitis, eczema, psoriasis, acne, epidermal hyperkeratosis, acanthosis, and pruritus.

3. A method for treatment of a skin disease in a mammal, wherein said skin disease is selected from the group consisting of psoriasis and pruritus, which method comprises topically administering to the mammal an effective amount of at least one compound with formula I or II:

wherein

W, Q, V, and T are independently CH, CH 2 , S, N, or O;

ring A, ring B, ring C and ring D may be aromatic, saturated or partly saturated;

R 1 and R 2 are optional substituents independently selected from C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl, each optionally substituted with halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 -alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 or CON(R 4 ) 2 ; H, halogen, CF 3 , C 1-6 -alkoxy, C 1-6 -alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , CON(R 4 ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 -alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole;

or R 1 and R 2 , when bonded to adjacent atoms in ring A or ring C, optionally together form a moiety —(CH 2 ) n —, where n=1-5, and wherein 1, 2 or 3 CH 2 units in said moiety are optionally replaced by 1, 2 or 3 heteroatoms, wherein each heteroatom is individually selected from the group consisting of O, S, NH and N if the nitrogen atom is bonded to an adjacent atom via a double bond, and wherein said moiety may optionally be substituted with 1, 2 or 3 substituents individually selected from the group consisting of halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 , or CON(R 4 ) 2 ;

R 3 is aryl or heteroaryl each optionally substituted with one or more halogen, CF 3 , C 1-6 -alkoxy, C 1-6 -alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , CON(R 4 ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 -alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, tetrazole, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl, each C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl or C 3-6 -cycloalkyl being optionally substituted with halogen, CF 3 , OCF 3 , COOH, CN, CONH 2 , CONHR 4 , CON(R 4 ) 2 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 alkoxy, or carbamoyl; and

R 4 is C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, aryl, aryloxy, heteroaryl, or heteroaryloxy;

or a pharmaceutical acceptable salt thereof.

4. The method according to claim 1 , wherein the compound is selected from compounds of formula Ia and IIa

wherein

T and W are CH, CH 2 , or S, wherein one of T and W is S;

ring A, ring B, ring C and ring D may be aromatic, saturated or partly saturated; and

R 1 , R 2 and R 3 are as defined in claim 1 .

5. The method according to claim 4 , wherein X is O; Y is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom via a double bond; Z is independently O, NH or N if the nitrogen atom is bonded to an adjacent carbon atom via a double bond.

6. The method according to claim 5 , wherein ring A and ring C are aromatic and wherein ring B and ring D are partly saturated.

7. The method according to claim 6 , wherein the compound is selected from compounds having the below listed formulas:

wherein R 1 , R 2 and R 3 are as defined in claim 1 .

8. The method according to claim 7 , wherein R 1 and R 2 , if present, are independently C 1-8 -alkyl optionally substituted with halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 -alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 or CON(R 4 ) 2 ; halogen, C 1-6 -alkoxy;

or R 1 and R 2 , when bonded to adjacent atoms, optionally together form a moiety —(CH 2 ) n —, where n=3, 4 or 5, and wherein said moiety may optionally be substituted with 1, 2 or 3 substituents individually selected from the group consisting of halogen, OH, NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , C 1-6 -alkoxy, trifluoromethoxy, carbamoyl, CONHR 4 , or CON(R 4 ) 2 .

9. The method according to claim 8 , wherein R 1 and R 2 , if present, are independently chlorine or O—CH 3 .

10. The method according to claim 8 , wherein the compound is selected from compounds having the below listed formulas:

wherein R 3 is as defined in claim 1 .

11. The method according to claim 1 , wherein R 3 is phenyl, 1-naphthyl, 4-pyridinyl, 2-furanyl or 2-thienyl, each optionally substituted with halogen, CF 3 , OCF 3 , COOH, CN, CONH 2 , CONHR 4 , CON(R 4 ) 2 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 alkoxy, or carbamoyl; halogen, CF 3 , C 1-6 -alkoxy, C 1-6 -alkylthio, OCF 3 , COOH, CN, CONH 2 , CONHR 4 , OH, NO 2 , NH 2 , NHR 4 , N(R 4 ) 2 , NHCOR 4 , NHSO 2 R 4 , CON(R 4 ) 2 , CONHSO 2 R 4 , SO 2 NH 2 , SO 2 NHR 4 , SO 2 R 4 , SOR 4 , C 1-4 -alkoxycarbonyl, aryl, aryloxy, heteroaryl, heteroaryloxy, alkylphenyl, or tetrazole.

12. The method according to claim 1 , wherein the compound is selected from the group consisting of

2-Phenyl-benzo[d][1,3]oxazin-4-one,

7-Chloro-2-(2-chloro-4-nitro-phenyl)benzo[d][1,3]oxazin-4-one,

2-(2-Iodo-phenyl)-6,7-dimethoxy-benzo[d][1,3]oxazin-4-one,

7-Chloro-2-thiophen-2-yl-benzo[d][1,3]oxazin-4-one,

2-(2-Chloro-4-nitro-phenyl)-6,7-dimethoxy-benzo[d][1,3]oxazin-4-one,

2-(2-Chloro-5-nitro-phenyl)-benzo[d][1,3]oxazin-4-one,

5,7-Dichloro-2-(dimethylamino-benz[d][1,3]oxazin-4-one,

2-Pyridin-4-yl-benzo[d][1,3]oxazin-4-one,

2-Thiophen-2-yl-benzo[d][1,3]oxazin-4-one,

2-(2-Hydroxy-phenyl)-benzo[d][1,3]oxazin-4-one,

2-(2-Fluoro-phenyl)-6,7-dimethoxy-benzo[d][1,3]oxazin-4-one,

7-Chloro-2-(4-ethyl-phenyl)benzo[d][1,3]oxazin-4-one,

7-Chloro-2-(3-methyl-4-nitro-phenyl)-benzo[d][1,3]oxazin-4-one,

N-[4-(6,7-Dimethoxy-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl]-acetamide,

Acetic acid 4-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-phenyl ester,

2-(2-Chlorophenyl)-6,7-dimethoxy-benzo[d][1,3]oxazin-4-one,

6-Chloro-2-thiophen-2-yl-benzo[e][1,3]oxazin-4-one,

6-Chloro-2-furan-2-yl-benzo[e][1,3]oxazin-4-one,

2-(2-Chlorophenyl)-benzo[e][1,3]oxazin-4-one,

2-Thiophen-2-yl-benzo[e][1,3]oxazin-4-one,

2-Furan-2-yl-benzo[e][1,3]oxazin-4-one,

6-Ethyl-2-(2-fluoro-phenyl)-thieno[2,3-d][1,3]oxazin-4-one,

6-Methyl-2-naphthalen-1-yl-thieno[2,3-d][1,3]oxazin-4-one,

6-Ethyl-2-o-tolyl-thieno[2,3-d][1,3]oxazin-4-one,

6-Ethyl-2-(4-fluoro-phenyl)-thieno[2,3-d][1,3]oxazin-4-one,

2-(2-chloro-phenyl)-4H-thieno[3,2-d][1,3]oxazin-4-one,

2-phenyl-4H-thieno[3,2-d][1,3]oxazin-4-one,

2-Furan-2-yl-5,6-dimethyl-thieno[2,3-d][1,3]oxazin-4-one,

2-(4-fluoro-phenyl)-4H-thieno[3,2-d][1,3]oxazin-4-one,

2-(4-Bromo-phenyl)-6-ethyl-thieno[2,3-d][1,3]oxazin-4-one,

6-(2-Chloro-phenyl)-2,3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta[a]indene-4-one,

6-Furan-2-yl-2,3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta[a]inden-4-one,

6-Phenyl-2,3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta[a]inden-4-one,

6-(4-Fluoro-phenyl)-2,3-dihydro-1H-5-oxa-8-thia-7-aza-cyclopenta[a]inden-4-one,

6-Thiophen-2-yl-2,3-dihydro-1H-5-oxo-8-thia-7-aza-cyclopenta[a]inden-4-one,

2-(2-Fluoro-phenyl)-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-(2-Methoxy-phenyl)-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-Phenyl-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-Naphthalen-1-yl-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-Thiophen-2-yl-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-(3-Methoxy-phenyl)-5,6,7,8-tetrahydro-3-oxa-9-thia-1-aza-fluoren-4-one,

2-Pyridin-4-yl-6,7,8,9-tetrahydro-5H-3-oxa-10-thia-1-aza-benzo[a]azulen-4-one,

and pharmaceutical acceptable salts thereof.

13. The method according to claim 12 , wherein the compound is selected from the group consisting of

7-Chloro-2-(2-chloro-4-nitro-phenyl)-benzo[d][1,3]oxazin-4-one,