Patent ID: 6353032
Filing Date: 2002-03-05
Classification: A61K,A61P,C07F,Y10S

Abstract:
A method for the treatment of dry eye and other disorders requiring the wetting of the eye which comprises stimulating ocular mucin production by administering to a mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of one or more compounds of the following formula I: wherein:R20 is H or CH&boxH;CH(CH2)12CH3; X is O or S; R1 is H, (C&boxH;O)R4 or CH2R4; J is O or NH; R2 is (C&boxH;O)R5; A is CH2 or O; R3 is OCH2CH(NH3+)COOâˆ’, OCH2CH2NH3+, OCH2CH2N+(CH3)3, OCH2CH(OH)CH2OH, O-inositol, OH, H, or alkyl; R4 and R5 are independently a HETE derivative; substituted or unsubstituted C12-30 alkyl or alkenyl (the alkenyl group containing one or more double bonds); alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or alkyl-Mâ€”Q; wherein the substitution is alkyl, halo, hydroxy, or functionally modified hydroxy; wherein: M is O or S;and Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or alkyl(heteroaryl)alkyl; with the proviso that at least one of R4 and R5 must be a HETE derivative; wherein the HETE derivative is a structural fragment of formulas II-XIV: wherein:Y is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; V: wherein:Z and Z1 are H, or ZZ1 is CH2; B5â€”D5, E5â€”G5 and T5â€”K5 are the same or different and are CH2CH2, CH&boxH;CH, or Câ‰¡C; Y5 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; VI: wherein:X6 is CH2CH2CH&boxH;CH, CH2CH2C&boxH;C, CH2CH2CH2CH2, CH2CH&boxH;CHCH2, CH2Câ‰¡CCH2, CH&boxH;CHCH2CH2, C&boxH;CCH2CH2, CH2CH&boxH;C&boxH;CH, or CH&boxH;C&boxH;CHCH2; K6â€”T6â€”L6 is CH2CH2CH2, CH2CH&boxH;CH, CH2C&boxH;C, CH&boxH;CHCH2, Câ‰¡CCH2, or CH&boxH;C&boxH;CH; Y6 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; VII: wherein:X7 is CH2CH2CH2, CH2CH&boxH;CH, CH2C&boxH;C, CH&boxH;CHCH2, C&boxH;CCH2, or CH&boxH;C&boxH;CH; D7â€”E7 and G7â€”T7 are the same or different and are CH2CH2, CH&boxH;CH, or Câ‰¡C; Y7 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy fine indicates the point of attachment; VIII: wherein:X8 is C2-C5 alkyl, alkynyl, or alkenyl, or a C3-C5 allenyl group; J8 is H, free or functionally modified hydroxy group, halo, trihalomethyl, free or functionally modified amino group, free or functionally modified thiol group, C(O)R8, or alkyl; R8 is H, OH, alkyl, alkoxy, amino, alkylamino, or alkoxyamino; A8 is direct bond or C1-3 alkyl; D8 is CH2CH2, cis- or trans-CH&boxH;CH, or Câ‰¡C; Y8 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; IX: wherein:E9â€”D9 is CH2CH2CH2 or cis-CH2CH&boxH;CH; or E9 is trans-CH&boxH;CH and D9 is CH(OH) in either configuration, wherein the OH is free or functionally modified; or E9 is CH2CH2 and D9 is a direct bond; p is 1 or 3 when E9â€”D9 is CH2CH2CH2 or cis-CH2CH&boxH;CH, or when E9 is trans-CH&boxH;CH and D9 is CH(OH) in either configuration, wherein the OH is free or functionally modified; or p is 0 when E9 is CH2CH2 and D9 is a direct bond; G9â€”T9 is CH2CH2, CH(SR)CH2, or trans-CH&boxH;CH; SR comprises a free or functionalized thiol group; n is 0, 2, or 4; Z9 is CH3, CO2R0, CONR2R3, or CH2OR4; R9 is H or CO2R9 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 forms a free or functionally modified amino group; OR4 forms a free or functionally modified hydroxy group; Y9 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; X: wherein:K10 is C2-C7 alkyl, alkenyl, or alkynyl, or a C3-C7 allenyl group; A10 and X10 are the same or different and are a direct bond, CH2, NR11, O, or S, with the proviso that at least one of A and X is NR11, O, or S; B10 are both H, or B10B10 together forms a double bonded O, S, or NR12, with the proviso that B10B10 is a double bonded O, S, or NR12 when A10 and X10 are the same or different and are NR11, O, or S; NR11 and NR12 are the same or different and comprise a free or functionally modified amino group, D10â€”E10 and G10 â€”T10 the same or different and are CH2CH2, CH&boxH;CH, or Câ‰¡C; Y10 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; XI: wherein:A11, B11, C11 and D11 are the same or different and are C1-C5 alkyl, alkenyl, or alkynyl, or a C3-C5 allenyl group; Y11 is C&boxH;O or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; XII: wherein:A12, B12, C12 and D12 are the same or different and are C1-C5 alkyl, alkenyl, or alkynyl, or a C3-C6 allenyl group; Y12 is CH(OH) or CCH3(OH) in either configuration, wherein the hydroxy group can be free or functionally modified, and X12 is CH2, CH(CH3) or C(CH3)2; or Y12 is CH2, CH(CH3) or C(CH3)2, and X12 is CH(OH) or CCH3(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and the wavy line indicates the point of attachment; XIII: wherein:A13, B13, C13 and D13 are the same or different and are C1-C5 alkyl, C2-C5 alkenyl, C1-C5 cyclopropyl, C2-C5 alkynyl, or a C3-C5 allenyl group; E13 is CH(OH), where the hydroxy group is free or functionally modified; X13 is (CH2)m or (CH2)mO, wherein m is 1-6; and Y13 is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, amino, or thiol group; or X13â€”Y13 is (CH2)pY21; wherein p is 0-6; and â€ƒwherein: W13 is CH2, O, S(O)q, NR18, CH2CH2, CH&boxH;CH, CH2O, CH2S(O)q, CH&boxH;N, or CH2NR18; wherein q is 0-2, and R18 is H, alkyl, or acyl; Z13 is H, alkyl, acyl, halo, trihalomethyl, or a free or functionally modified amino, thiol, or hydroxy group; and - - - - is a single or double bond; or X13â€”Y13 is cyclohexyl; and the wavy line indicates tho point of attachment; XIV: wherein:OR14 and OR15 are the same or different and comprise a free or functionally modified hydroxy group; G14, T14, and Z14 are the same or different and are CH2CH2, cis- or trans-CH&boxH;CH, or Câ‰¡C;  is Câ‰¡C or cis-CH&boxH;CH; one of A11, B11 is H or CH3, and the other is a free or functionally modified hydroxy group, or A14â€”B14 comprises a double bonded oxygen as a carbonyl, or A14â€”B14 is OCH2CH2O; X14 is CR16R17(CH2)q or CR16R17R17(CH2)qO, with q is 0-6; R10 and R17 are the same or different and are H or CH3; Y11 is CH3, or a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, thiol, or amino group; or X14â€”Y14 is (CH2)pY20, p is 0-6, â€ƒwherein: W14 is CH2, O, S(O)m, NR21, CH2CH2, CH&boxH;CH, CH2O, CH2S(O)m, CH&boxH;N, or CH2NR21; m is 0-2; NR21 is NH or a functionally modified amino group; J14 is H, alky, acyl, halo, trihalomethyl, or a free or functionalized hydroxy, thiol, or amino group; and - - - - is a single or double bond; or X14â€”Y14 is cyclohexyl; and the wavy line indicates the point of attachment.