Granted Patent B2

US 7,964,591 · App. 12/794,575 · Granted Jun 21, 2011

Assignees: Novartis Pharma AG; Xenon Pharmaceuticals Inc.

Abstract

Claims (50)

1. A method of treating a skin disorder mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:

x and y are each independently 1, 2 or 3, provided that x and y are not both 1;

W is —C(O)N(R 1 )—, —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— or —N(R 1 )C(O)—;

V is —C(O)—, —C(S)—, or —C(R 10 )H;

each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl;

R 1a is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl;

R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;

R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;

R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ;

R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;

or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together, or R 8 and R 8a together, do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;

one of R 6 , R 6a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 7 , R 7a a, R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;

R 10 is hydrogen or C 1 -C 3 alkyl; and

each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl;

a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,

wherein the skin disorder is selected from the group consisting of acne, rosacea, seborrheic skin, and any combination of these.

2. The method of claim 1 , wherein the mammal is a human.

3. The method of claim 1 , wherein the administering is by topical administration.

4. The method of claim 1 , wherein the pharmaceutical composition of the compound of formula (I) comprises a percutaneous penetration enhancer.

5. The method of claim 4 , wherein the percutaneous penetration enhancer is SEPA-9.

6. The method of claim 1 , wherein the skin disorder is selected from the group consisting of acne, rosacea, seborrheic skin, and any combination of these.

7. The method of claim 6 , wherein the skin disorder is rosacea.

8. The method of claim 6 , wherein the skin disorder is seborrheic skin.

9. The method of claim 1 ,

wherein

V is —C(O)— or —C(S)—;

W is selected from —C(O)N(R 1 )— and —N(R 1 )C(O)—;

R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 6 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;

R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 11 ) 2 , —OC(O)R 11 , —C(O)OR 11 , —S(O) 2 N(R 11 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl;

R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl;

R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and

R 11 is hydrogen or C 1 -C 3 alkyl.

10. The method of claim 1 ,

wherein

V is —C(O)—;

W is selected from —C(O)N(R 1 )— and —N(R 1 )C(O)—;

R 2 is selected from the group consisting of C 7 -C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 13 -C 19 aralkyl, C 3 -C 12 heterocyclylalkyl, and C 3 -C 12 heteroarylalkyl;

R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 5 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;

R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy and trifluoromethyl; and

R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl.

11. The method of claim 10 ,

Wherein:

V is —C(O)—;

W is —N(R 1 )C(O)—;

R 2 is C 3 -C 12 cycloalkyl;

R 3 is aryl or C 5 -C 12 heteroaryl.

12. The method of claim 1 , wherein the skin disorder is rosacea.

13. The method of claim 1 , wherein the skin disorder is seborrheic skin.

14. The method of claim 1 , wherein the skin disorder is acne.

Assignments (3)

Continuity (14)