Pyridazine derivatives and their use as therapeutic agents in the treatment of skin disorders

Abstract

Methods of treating an SCD-mediated skin disorder or condition in a mammal, preferably a human, including administering to a mammal in need thereof a compound of formula (I): where x, y, W, V, R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are defined herein, and compositions including a compound of formula (I).

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; 
         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; 
         or R 2  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         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; 
         or R 3  is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; 
         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 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 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 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; 
         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. 
       
     
     
         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 3 , 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™ (2-n-nonyl-1,3-dioxolane). 
     
     
         6 . The method of  claim 1 , wherein the skin disorder is selected from the group consisting of acne, rosacea, seborrheic skin, oily skin (syn seborrhea) and seborrheic dermatitis, and any combination of these. 
     
     
         7 . The method of  claim 6 , wherein the skin disorder is rosacea or acne. 
     
     
         8 . The method of  claim 6 , wherein the skin disorder is seborrheic skin, oily skin (syn seborrhea) or seborrheic dermatitis. 
     
     
         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; 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.   
     
     
         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; and   R 3  is aryl or C 5 -C 12 heteroaryl.   
     
     
         12 . The method of  claim 11 , wherein the skin disorder is selected from the group consisting of acne, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, and any combination of these. 
     
     
         13 . The method of  claim 12 , wherein the skin disorder is acne or rosacea. 
     
     
         14 . The method of  claim 12 , wherein the skin disorder is seborrheic skin, oily skin (syn seborrhea) or seborrheic dermatitis. 
     
     
         15 . The method of  claim 1 , wherein the skin disorder is selected from the group consisting of acne, rosacea, seborrheic skin, oily skin (syn seborrhea), seborrheic dermatitis, and any combination of these, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide. 
     
     
         16 . A formulation suitable for topical administration, including the compound of formula (I) as described in  claim 1 , and one or more penetration enhancers. 
     
     
         17 . The formulation suitable for topical administration as claimed in  claim 16 , including:
 a) the compound of formula (I) as described in  claim 1 ;   b) one or more penetration enhancers;   c) optionally one or more antioxidants;   d) optionally one or more solvents;   e) optionally one or more co-solvents;   f) optionally one or more surfactants;   g) optionally one or more preservatives; and   h) optionally one or more gelling agents.   
     
     
         18 . The formulation as claimed in  claim 17 , wherein the compound of formula (I) is 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide. 
     
     
         19 . The formulation as claimed in  claim 17 , wherein the penetration enhancer is present and is diethylene glycol monoethylether or SEPA-9™ (2-n-nonyl-1,3-dioxolane). 
     
     
         20 . The formulation as claimed in  claim 17 , wherein at least one antioxidant is present and is butylated hydroxytoluene or a combination of butylated hydroxytoluene and butylated hydroxyanisole. 
     
     
         21 . The formulation as claimed in  claim 17 , wherein at least one solvent is present and is diisopropyl adipate. 
     
     
         22 . The formulation as claimed in  claims 17 , wherein at least one co-solvent is present and is benzyl alcohol, propylene glycol, ethanol, or a combination thereof. 
     
     
         23 . The formulation as claimed in  claim 17 , wherein at least one surfactant is present and is sorbitan monolaureate, polysorbate20, or a mixture of sorbitan monolaureate and polysorbate20. 
     
     
         24 . The formulation as claimed in  claim 17 , wherein at least one preservative is present and is benzyl alcohol. 
     
     
         25 . The formulation as claimed in  claim 17 , wherein at least one gelling agent is present and is Carbopol 974P. 
     
     
         26 . The formulation as claimed in  claim 18 , including:
 a) 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide;   b) diethylene glycol monoethylether or SEPA-9™ (2-n-nonyl-1,3-dioxolane);   c) butylated hydroxytoluene, or a combination of butylated hydroxytoluene and butylated hydroxyanisole;   d) benzyl alcohol; and   e) optionally including sorbitan monolaureate.   
     
     
         27 . The formulation as claimed in  claim 18 , including:
 a) 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide;   b) diethylene glycol monoethylether;   c) butylated hydroxytoluene;   d) benzyl alcohol; and   e) sorbitan monolaureate.   
     
     
         28 . The formulation as claimed in  claim 18 , comprising:
 a) from about 0.05% w/w to about 5.0% w/w of 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide;   b) from about 1.0% w/w to about 25.0% w/w of penetration enhancers selected from one or more of diethylene glycol monoethylether, SEPA-9™ (2-n-nonyl-1,3-dioxolane), Brij® 93, and diethylene glycol;   c) from about 0.01% w/w to about 5.0% w/w butylated hydroxytoluene, or a combination of butylated hydroxytoluene and butylated hydroxyanisole;   d) from about 0.03% w/w to about 10.0% w/w benzyl alcohol; and   e) optionally including from about 0.1% w/w to about 10.0% w/w sorbitan monolaureate.   
     
     
         29 . The formulation as claimed in  claim 28 , comprising:
 a) from about 0.05% w/w to about 5.0% w/w 6-[4-(5-Fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropyl-ethyl)-amide;   b) from about 1.0% w/w to about 25.0% w/w diethylene glycol monoethylether;   c) from about 0.01% w/w to about 5.0% w/w butylated hydroxytoluene, or a combination of butylated hydroxytoluene and butylated hydroxyanisole;   d) from about 0.03% w/w to about 10.0% w/w benzyl alcohol; and   e) from about 0.1% w/w to about 10.0% w/w sorbitan monolaureate.