Methods for Treating Skin Pigmentation

Abstract

This invention relates to methods and compositions for bringing about changes in skin pigmentation. More particularly, this invention relates to compounds which affect melanogenesis and can be used as depigmenting agents or as agents for darkening skin utilizing the PAR-2 pathway.

1 - 9 . (canceled) 
     
     
         10 . A method of effecting changes in mammalian skin pigmentation comprising administering to a mammal a pigmentation-changing effective amount of a compound which affects the PAR-2-pathway wherein said compound is a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is selected from the group consisting of C 1 -alkyl, carboxyC 1-4 alkyl, C 1-4 alkoxycarbonylC 1-4 alkyl, phenylC 1-4 alkyl, substituted phenylC 1-4 alkyl (where the phenyl substituents are independently selected from one or more of, C 1-4  alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl), formyl, C 1-4 alkoxycarbonyl, C 1-2 alkylcarbonyl, phenylC 1-4 alkoxycarbonyl, C 3-7 cycloakylcarbonyl, phenylcarbonyl, substituted phenylcarbonyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl), C 1-4 alkylsulfonyl, C 1-4 alkoxysulfonyl, perfluoroC 1-4 alkyl-sulfonyl, phenylsulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4  alkoxycarbonyl, 10camphorsulfonyl, phenyl C 1-4 alkysulfonyl, substituted phenyl C 1-4 alkysulfonyl, C 1-4 alkylsulfinyl, perfluoroC 1-4 alkylsulfinyl, phenylsulfinyl, substituted phenylsulfinyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl), phenyl1C 1-4 alkylsulfinyl, substituted pheny1C 1-4 alkylsulfinyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl or substituted naphthylsulfonyl (where the naphthyl substituents are independently selected from one or more of; C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or C 1-4 alkoxy-carbonyl), 1-naphthylsulfinyl, 2-naphthylsulfinyl or substituted naphthylsulfinyl (where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl); a D or L amino acid which is coupled as its carboxy terminus to the nitrogen depicted in formula I and is selected from the group consisting of alanine, asparagine, 2-azetidinecarboxylic acid, glycine, N—C 1-8 alkyglycine, proline, 1-amino-1-cycloC 1-8 alkylcarboxylic acid, thiazzolidine-4-carboxylic acid, 5,5-dimethylthiazolidine-4-carboxylic acid, oxadolidine-4-carboxylic acid, pipecolinic acid, valine, methionine, cysteine, serine, threonine, norleucine, leucine, tert-leucine, isoleucine, phenylalanine, 1-naphthalanine, 2-naphthalamine, 2-thienylalanine, 3-thienylalanine, [1,2,3,4]-tetrahydroisoquinoline-1-carboxylic acid and 1,2,3,4,1-tetrahydroisoquinoline-2-caroboxylic acid 
 where the amino terminus of said amino acid is connected to a member selected form the group consisting of  C1 -4-alkyl,tetrazol-5yl-C 1-2 alkyl, carboxyC 1-4 alkyl, C 1-4 alkoxycarbony1C 1-4 alkyl, phenylC 1-4 alkyl, substituted phenyl C 1-4  alkyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboy or C 1-4 alkoxycarbonyl), 1,1-diphenyl C 1-4 alkyl, 3phenyl-2-hydroxypropionyl, 2,2-diphenyl-1-hydroxyerthylcarbonyl, [1,2,3,4]-tetrahydroisoquinoline-1-carbonyl, [1,2,3,4]-tetrahydroisoquinoline-3,carbonyl, 1-methylamino-1-cyclohexanecarbonyl, 1-hydroxy-1-cyclohexanecarbonyl, 1-hydroxy-1-pheny-lacetyl, 1-cyclohexyl-1-hydroxyacetyl, 3-phenyl2-hydroxypropionyl, 3,3diphenyl-2-hydroxypropionyl, 3-cyclohexyl-2-hydroxypropionyl, formyl, C 1-4 alkoxycarbonyl, C 1-12 alkylcarbonyl, perfluoroC 1-4 alkyl, C 1-4 alkylcarbonyl, phenylC 1-4 alkylcarbonl, substituted phenylC 1-4 alkylcarbonyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo amido, nitro amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl), 1,1diphenylC 1-4 alkylcarbonyl, substituted 1,1-diphenylC 1-4 -alkylcarbonyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4  alkoxycarbanyl), perfluoroC 1-4 alkysulfonyl, C 1-4 alkysulfonyl, C 1-4 alkoxysulfonyl, phenysulfonyl, substituted phenylsulfonyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alklamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxcarbonyl), 10 camphorsulfonyl, phenylC 1-4 alkylsulfonyl, substituted phenyl C 1-4 alkylsulfonyl, perfluoroC 1-4 alkysulfinyl, C 1-4 alkysulfinyl, phenylsulfinyl, substituted phenysulfinyl (where the phenyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4  alkylamino, C 1-4 dialkylamino, carboxy or C 1-4  alkoxycarbonyl), 1-naphthysulfonl, 2-naphthylsulfonyl, substituted naphthylsulfonyl (where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C1-58-4alkoxycarbonyl),1-naphthysulfinyl, 2-naphthysulfinyl, and substituted naphthylsulfinyl (where the naphthyl substituents are independently selected from one or more of, C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamono, carboxy or C 1-4 alkoxycarbonyl): or a poly peptide comprised of two amino acids, 
 
       where the first amino acid is a D or L amino acid, bound via its carboxy terminus to the nitrogen depicted in Formula I and is selected from the group consisting of glycine, N—C 1-8 alkylglycine, alanine, 2-azetidinecarboxylic acid, proline, thiazolidine-4-carboxyliic acid, 5,5 dimethylthiazolidine-4-carboxylic acid, oxazolidine-4-carboxylic acid, 1-amino-1-cycloC 3-8 alkylcarboxylic acid, 3-hydroxypropoline, 4-hydroxyproline, 3-(C 1-4 alkoxy)proline, 4(C 1-4 alkoxy) proline, 3,4-dehydroprline, 2,2-dimethyl-4-thiazolidine carboxylic acid, 2,2-dimethyl-4-oxadolidine carboxylic acid, pipecolinic acid, valine, methionine, cysteine, asparagine, serine, threonine, leucine, tert-leucine, isoleucine, phenylalanine, 1-naphthalanine, 2-naphthalanine, 2-thienylalanine, 3thienylalnine, [1,2,3,4]-tetrahydroisoquinoline-2-carboxylic acid, aspartic acid-4-C 1-4 alkyl ester and glutamic acid 5-C 1-4 alkyl ester and the second D or L amino acid, is bound to the amino terminus of said first amino acid, and is selected from the group consisting of phenylalanine, 4-benzolyphenylalanine, 4-carboxyphenylalanine, 4-(Carboxy C 1-2 alkyl)phenylalanine, substituted phenylalanine (where the phenyl substituents are independently selected from one or more of C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy C 1-4 dialkylamino, carboxy- or C 1-4 alkoxycarbonyl), 3-benzothienylalanine, 4biphenylalanine, homophenylalanine, octahydroindole-2-carboxylic acid, 2-Pyridylalanine, 3-pyridylalanine, 4-thiazolyalanine, 2-thienylalanine, 3-(3-benzothienyl) alanine, 3-thienylalanine, tryptophan, tyrosine, asparagine, 3-triC 1-4 alkylsilylalanine, cyclohexylglycine diphenylglycine, phenylglycine, methionine sulfoxide, methionine sulfone, 2,2-dicyclohexylalanine, 2-(1naphthylalanine), 2-(2-naphthylalanine), phenyl substituted phenylalanine (where the substituents are selected from C 1-4 (alkyl, perfluoro C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialylamino, carboxy or C 1-4 alkoxycarbonyl), aspartic acid, aspartic acid4C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbony), aspartic acid, aspartic acid-4-C 1-4 alkyl ester glutamic acid, glutamic acid-5-C 1-4  alkyl ester, cycloC3-salkylaalanine, substituted cycloC 3-8 alkylalanine (where the ring substituents are carboxy, C 1-4 alkyl ester, cycloC 3-8 alkylalanine, substituted cycloC 3-8 alkylalanine (where the ring substituents are carboxy, C 1-4 alkylcarboxy, C 1-4 alkoxcarbonyl or aminocarbonyl), 2,2-diphenylalanine and all alpha-C 1-5 alkyl of all amino acid derivatives thereof, where the amino terminus of said second amino acid is unsubstituted or monosubstituted with a member of the group consisting of formyl, C 1-12 alkyl, tetrazol-5-y1C 1-2 alkyl, carboxyC 1-8 , alkyl, carboalkoxyC 1-4 alkyl, phenyl C 1-4 alkyl, substituted phenylC 1-4 alkyl (where the phenyl substituents or independently selected from one or more of C 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 -alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4 , dialkylamino, carboxy or C 1-4 alkoxycarbonyl), 1,1-dipheny1C 1-4 alkyl, C 1-6 alkoxycarbonyl, phenylC 1-6 alkoxycarbonyl, C 1-2 alkylcarbonyl, perfluoroC 1-4 alkylC 1-4 alkylcarbonyl, phenyC 1-4 alkylcarbonyl, substituted phenyC 1-4 alkylcarbonyl(where the phenyl substituents are independently selected from one or more of C 1-4 alkyl, perfluoro C 1-4 alkyl, C 1-4  alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino C 1-4 dialkylamino, carboxy or C 1-4 alkoxycarbonyl) 1,1-diphenylC 1-4 alkyl, perfluoroC 1-4 alkyl, C 1-4 alkoxycarbonyl), 10-camphorsulfonyl, phenylC 1-4 alkysulfonyl, substituted phenyl C 1-4 alkylsulfonyl, C 1-4 alkysulfinyl, pertfluoro C 1-4 alkylsulfinyl phenylsulfinyl, substituted phenylsulfinyl (where the phenyl substituents are independently selected from one or more of, C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamono, C1-4dialkylamono, carboxy or C1-4alkoxycarbonyl), phenyC1-4alkylsulfinyl, substituted phenylC1-4alkylsulfinyl l-naphthylsulfonyl, 2-naphthylsulfonyl, substituted naphthylsulfonyl (where the naphthyl substituent is selected from C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl;), 1-naphthyl-sulfinyl, 2naphthylsulfinyl and substituted naphthylsulfinyl (where the naphthyl substituent is selected from C1-4alkyl, perfluoroC1-4alkyl, C1-4alkoxy, hydroxy, halo, amido, nitro, amino, C1-4alkylamino, C1-4dialkylamino, carboxy or C1-4alkoxycarbonyl); R1 is selected from the group consisting of hydrogen and alkyl; R2 is selected from the group consisting of aminoC 2-5 , alkyl, guanidinoC 2-5 alkyl, C 1-4 alkylguanidinoC 2-5 alkyl, diC 1-4 alkylguanidinoC 2-5 alkyl, amidinoC 2-5 alkyl, C 1-4 alky-lamidinoC 2-5 alkyl, diC 1-4 alky-lamidinoC2-5alkyl, C 1-3 alkoxyC2-5alkyl, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidino, C 1-4 alkylamino, C 1-4 dialkylamino, halogen, perfluoro C 1-4 alkyl, C 1-3 alkyl, C 1-3 alkoxy or nitro), benzyl, phenyl substituted benzyl (where the substituents are independently selected from one or more of, amino, amidino, guanidino, C 1-4 alkylamino, C 1-4 dialky-lamino, halogen, pertfluoro C 1-4 alkyl, C1-04alkyl, C 1-3 alkoxy or nitro), hydroxyC 2-5 alkyl, C 1-5 alkylaminoC 2-5  alkyl, C 2-5 dialklaminoC 2-5 alkyl, 4-aminiocyclohexylC O-2 alkyl and C 1-5 alkyl;
 p is 0 or 1: 
 B is 
 
       
         
           
           
               
               
           
         
         where n is 0-3, R, is H or C1-Saikyl and the carbonyl moiety of B is bound to E; E is a heterocycle selected from the group consisting of oxazolin-2-yl, oxazol-2-yl thiazol-2-yl, thiazol-5-yl, thiazol-4-yl, thiazolin-2-yl, imidazol-2-yl, 4-oxo-2quinoxalin-2-yl, 2pyridyl, 3-pyridyl, benzo(b)thiophen-2-yl, triazol-4-yl triazol-6-yl, pyrazol-2-yl, 4,5,6,7-tetrahydrobenzothiazol-2yl, naphtho[2,1-dlthiazol-2-yl, naphtho[1-2-dlthiazoi-2-yl quinoxalin-2-yl, isoquinclin-1-yl, isoquinolin-3-yl, benzo [blfuran-2-yl [pyrazin-2-yl, quinazoiin-2-yl, isothiazol-5-yl, isothiazol-3yl, purin-8yul and a substituted heterocycle where the substituents are selected from C 1-4 alkyl, perfluoro C 1-4 alkyl C 1-4 alkoxy, hydroxy, halo, amido, nitro, amino, C 1-4 alkylamino, C 1-4  dialkylamino, carboxy, C 1-4 alkoxycarbonyl, hydroxy or phenylC 1-4 alkylaminocarbonyl; or pharmaceutically acceptable salts thereof. 
       
     
     
         10 . A method according to claim  9  wherein said compound contains a d-phenylalanine-proline-arginine sequence. 
     
     
         11 . A method according to  claim 10  wherein said compound is (S)-N-Methyl-D-phenylalanyl-N-[4-[(aminoiminomethyl)aminol-1-(2-benzothiazolylcarbonyl)butyl-L-prolinamide. 
     
     
         12 - 68 . (canceled)