Inhibitors of Cancer Cell, T-Cell and Keratinocyte Proliferation

Abstract

The invention relates to compounds of the general formula (I) and salts and physiologically functional derivatives thereof, wherein Y is —NR a R b , —NR c ═ONR a R b , —NR c C═SNR a R b , —NR c C═NR d N a R b , heterocycle, —C═ONR a R b , heterocycle, or aryl; n is 0 to 8; m is 0, or 1; r is 0 to 3; t is 0 to 3; X is O or N; Z is CH 2 , C═O, C═S or a single bond; Z 1 is CO—R 2 , CS—R 2 , (CH 2 ) t —R 2 or the side-chain of a naturally occurring amino acid; Z 2 is CO—R 2 , CS—R 2 or (CH 2 ) t —R 3 or the side-chain of a naturally occurring amino acid; Z 3 is CO—R 2 , CS—R 2 or (CH 2 ) t —R 4 or the side-chain of a naturally occurring amino acid; Z 4 is H, alkyl, alkoxy, or cycloalkyl; R 1 , R 2 , R 3 , and R 4 are independently from each other H, OH, SH, NH 2 , CN, NO 2 , alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkylthio, haloalkyloxy, hydroxyalkyl, hydroxyalkylamino, alkylamino, alkylaryl, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxyalkyl, alkoxy, aryloxy, heteroaryl, aryl, or halogen.

1 . A compound of formula (I), salt or a salt or a stereoisomer thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 Y is —NR a R b , —NR c C═ONR a R b , —NR c C═SNR a R b , —NR c C═NR d N a R b , —C═ONR a R b , heterocycle, or aryl; 
 R a , R b , R c , R d  independently are H, —CN, —OH, alkoxy, —SH, alkyl, alkenyl- or alkynylthio, —CO 2 R 4′ , —C(O)R 4′ , —SO 2 NR 4′ , —SO 2 -alkyl, -alkenyl or -alkynyl, —SO 2 R 4′ , —SO 3 R 4′ , —NO 2 , —NR 4′ R 5′ , alkyl-, alkenyl- or alkynyl amino, —N═CR 4′ R 5′ , —NR 4′ C(O)R 4″ , —NR 4′ —CO-haloalkyl, -alkenyl or -alkynyl, —NR 4′ —SO 2 -haloalkyl, -alkenyl or -alkynyl, —NR 4′ —SO 2 -alkyl, -alkenyl or -alkynyl, —NR 4′ —CO-alkyl, -alkenyl or -alkynyl, —NR 4′ (CH 2 ) n heterocycle, —C(NR 4″ )NR 4′ benzimidazolyl, —C(NR 4″ )NR 4′ benzothiazolyl, —C(NR 4″ )NR 4′ benzoxazolyl, alkyl, alkenyl or alkynyl, cycloalkyl, -alkenyl or -alkynyl, —O(CH 2 ) n [O(CH 2 ) n ] r OCH 3 , hydroxyalkyl(alkenyl, alkynyl)amino, hydroxycycloalkyl, -alkenyl or -alkynyl, hydroxyalkyl, -alkenyl or -alkynyl amino, halogen, haloalkyl, -alkenyl or -alkynyl, haloalkyl, -alkenyl or -alkynyl oxy, aryl, arylalkyl, -alkenyl or -alkynyl or a heterocycle; 
 R 4′ , R 4″ , R 5′  independently are H, halogen, alkyl, alkenyl or alkynyl, —C(NR 7 )NR 7′ R 8 , —(CH 2 ) n aryl, —(CH 2 ) n NR 7 R 8 , —C(O)NR 7 R 8 , —N═CR 7 R 8 , —NR 7 C(O)R 8 , cycloalkyl, -alkenyl or -alkynyl, heterocycloalkyl, -alkenyl or -alkynyl, haloalkyl, -alkenyl or -alkynyl, hydroxyalkyl, -alkenyl or -alkynyl, hydroxyalkyl, -alkenyl or -alkynyl aminoalkyl, -alkenyl or -alkynyl, heteroaryl, alkyl-, alkenyl- or alkynylaryl, or aryl; 
 R 7 , R 7′ , R 8  independently are H, halogen, alkyl, -alkenyl or -alkynyl, cycloalkyl, -alkenyl or -alkynyl, heterocycloalkyl, -alkenyl or -alkynyl, haloalkyl, -alkenyl or -alkynyl, hydroxyalkyl, -alkenyl or -alkynyl, -alkenyl or -alkynyl amino, alkyl-, alkenyl- or alkynylamino, heteroaryl, alkylaryl, or aryl; 
 n is 0 to 8; 
 m is 0, or 1; 
 r is 0 to 3; 
 t is 0 to 3; 
 X is O or N; 
 Z is CH 2 , C═O, C═S or a single bond; 
 Z 1 , Z 2 , Z 3  are independently from each other CO—R 2 , CS—R 2 , (CH 2 ) t —R 2  or a side-chain of the naturally occurring amino acids comprising alanine, arginine, asparagine, asparatic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and/or valine, and in case of proline, Z 1 , Z 2  or Z 3  respectively, the carbon atom to which it is attached, and the —NH group which is attached to said carbon atom are part of the ring system of the proline side-chain; 
 Z 4  is H, alkyl, alkenyl or alkynyl, alkoxy, or cycloalkyl, -alkenyl or -alkynyl; 
 R 1 , R 2 , R 3 , R 4  are independently from each other H, OH, SH, NH 2 , CN, NO 2 , alkyl, alkenyl or alkynyl, cycloalkyl, -alkenyl or -alkynyl, heterocycloalkyl, -alkenyl or -alkynyl, haloalkyl, -alkenyl or -alkynyl, alkyl-, alkenyl- or alkynyl thio, haloalkyl(alkenyl, alkynyl) oxy, hydroxyalkyl, -alkenyl or -alkynyl, hydroxyalkyl(alkenyl, alkynyl)amino, alkyl-, alkenyl- or alkynyl amino, alkyl-, alkenyl- or alkynylaryl, alkyl-, alkenyl- or alkynylsulfinyl, alkyl-, alkenyl- or alkynylsulfonyl, alkyl-, alkenyl- or alkynyl thioalkyl (alkenyl, alkynyl), alkyl-, alkenyl- or alkynyl sulfinylalkyl(alkenyl, alkynyl), alkyl-, alkenyl- or alkynyl sulfonylalkyl(alkenyl, alkynyl), alkoxyalkyl(alkenyl, alkynyl), alkoxy, aryloxy, heteroaryl, aryl, halogen or residues of the following formula 
 
       
         
           
           
               
               
           
         
         wherein 
         W is N, CR e ; 
         R e  is H, halogen, alkyl, -alkenyl or -alkynyl, cycloalkyl, -alkenyl or -alkynyl, heterocycloalkyl, -alkenyl or -alkynyl, haloalkyl, -alkenyl or -alkynyl, hydroxyalkyl, -alkenyl or -alkynyl, -alkenyl or -alkynyl amino, alkyl-, alkenyl- or alkynylamino, heteroaryl, alkylaryl, or aryl; 
         R 6 , R 6′  is independently H, OH, SO 3 H, CO 2 H, N(CH 3 ) 2 , OPO 3 H. 
       
     
     
         2 . The compound of  claim 1 , wherein Y is imidazolidine-2,4-dione. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is aryl. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is phenyl. 
     
     
         5 . The compound according to  claim 1 , wherein Z 1 , Z 2 , Z 3  are independently from each other (CH 2 ) t —R 2  or a side-chain of the naturally occurring amino acids, which are alanine, arginine, asparagine, asparatic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and/or valine, and in case of proline, Z 1 , Z 2  or Z 3  respectively, the carbon atom to which it is attached, and the —NH group which is attached to said carbon atom are part of the ring system of the proline side-chain, wherein t and R 2  are as defined in  claim 1 . 
     
     
         6 . The compound according to  claim 5 , wherein R 2  is independently aryloxy, heteroaryl, aryl or residues of the following formula 
       
         
           
           
               
               
           
         
       
       wherein W, R 6  and R 6′  are as defined in  claim 1 . 
     
     
         7 . The compound according to  claim 1 , wherein m is 1 and X is O. 
     
     
         8 . The compound according to  claim 1 , wherein n is 1. 
     
     
         9 . The compound according to  claim 1 , wherein r is 1. 
     
     
         10 . The compound according to  claim 1 , wherein Z 4  is H. 
     
     
         11 . The compound according to  claim 1 , wherein the configuration of the chiral centers is “S”. 
     
     
         12 . The compound according to  claim 1 , wherein Z 1 , Z 2 , Z 3  are independently a side chain of histidine, phenylalanine, tryptophane, or tyrosine. 
     
     
         13 . A method of treatment or prevention of a disease characterized by hyperproliferation of cells which comprises administering a compound according to  claim 1 , in desired with one or more appropriate adjuvants and additives, to a mammal. 
     
     
         14 . The method according to  claim 13 , wherein the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, alopecia totalis, alopecia subtotalis, alopecia universalis, alopecia diffusa, lupus erythematodes of the skin, lichen planus, dermatomyostis of the skin, atopic eczema, morphea, sklerodermia, psoriasis vulgaris, psoriasis capitis, psoriasis guttata, psoriasis inversa, alopecia areata ophiasis-type, androgenetic alopecia, allergic contact eczema, irritative contact eczema, contact eczema, pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, scarring mucosal pemphigoid, bullous pemphgoid, mucous pemphigoid, dermatitis, dermatitis herpetiformis duhring, urticaria, necrobiosis lipoidica, erythema nodosum, lichen vidal, prurigo simplex, prurigo nodularis, prurigo acuta, linear IgA dermatosis, polymorphic light dermatoses, erythema solaris, lichen sclerosus et atrophicans, exanthema of the skin, drug exanthema, purpura chronica progressiva, dihidrotic ekzema, Ekzema, fixed drug exanthema, photoallergic skin reaction, lichen simplex eriorale, dermatitis and “Graft versus Host-Disease”, acne, rosacea, scarring, keloids, and vitiligo. 
     
     
         15 . The method according to  claim 13  for the treatment of cancer, wherein said cancer is selected from adenocarcinome, acinic cell adrenal cortical carcinomas, alveoli cell carcinoma, anaplastic carcinoma, basaloid carcinoma, basal cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, renaladinol carcinoma, embryonal carcinoma, anometroid carcinoma, fibrolamolar liver cell carcinoma, giant cell carcinomas, follicular carcinomas, hepatocellular carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, leptomanigio carcinoma, medullary carcinoma, melanotic carcinoma, menigual carcinoma, mesometonephric carcinoma, oat cell carcinoma, squamal cell carcinoma, sweat gland carcinoma, transitional cell carcinoma, tubular cell carcinoma, amelioblastic sarcoma, immunoblastic sarcoma, angiolithic sarcoma, botryoid sarcoma, endometrial stoma sarcoma, ewing sarcoma, fascicular sarcoma, giant cell sarcoma, granulositic sarcoma, juxaccordial osteogenic sarcoma, coppices sarcoma, leukocytic sarcoma (leukemia), lymphativ sarcoma (lympho sarcoma), medullary sarcoma, myeloid sarcoma (granulocitic sarcoma), austiogenci sarcoma, periosteal sarcoma, reticulum cell sarcoma (histiocytic lymphoma), round cell sarcoma, synovial sarcoma, telangiectatic audiogenic sarcoma, Hodgkin's disease, lymphocytic lymphomas, Burkitt's lymphoma, NPDL, NML, NH and diffuse lymphomas. 
     
     
         16 . The method according to  claim 13 , wherein the disease is selected from the group consisting of Psoriasis, atopic dermatitis, actinic keratoses, hyperkeratoses like epidermolytic hyperkeratosis, Hyperkeratosis Lenticularis Perstans, Keratosis pilaris and Ichthyoses. 
     
     
         17 . The method according to  claim 13 , wherein the disease is selected from the group comprising disease caused by viruses, including AIDS, HIV, SCID, Epstein Barr virus associated diseases such as Sjorgren's syndrome, virus associated B cell lymphoma, in particular AIDS or EBV associated B cell lymphoma. 
     
     
         18 . A method for the treatment or prevention of a disease characterized by hyperproliferation of ketatinocytes which comprises administering a compound according to  claim 1 , if desired with one or more with appropriate adjuvants and additives, to a mammal.