Patent ID: 6825232
Filing Date: 2004-11-30
Classification: A61K,A61P

Abstract:
A method of treating ophthalmic inflammatory disorders in a patient that is not suffering from dry eye, wherein the ophthalmic inflammatory disorder is selected from the group consisting of conjunctivitis; iritis; uveitis; episcleritis; scleritis; keratitis; endophthalmitis; blepharitis; and iatrogenic inflammatory conditions, and wherein the method comprises topically administering to the patient a composition comprising a HETE compound of formulas I-XI:I-III: wherein:X is Oâˆ’M+, OR or NHRâ€²; M+ is Na+, K+, Li+, Cs+, and (A)4N+; and A is independently H, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)4N+ forms a heteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of: alkyl, halogen, hydroxy and functionally modified hydroxy; Râ€² is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is made with a moiety selected from the group consisting of: alkyl, halogen, hydroxy and functionally modified hydroxy; and Y is wherein Râ€³ is H or C(O)R; wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2â€”Hal, CH2NO2, CH2SR20, COSR21, or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H, or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; K is C2-C8 alkyl, alkenyl, or alkynyl, or a C3-C8 allenyl group; A and X are the same or different and are a direct bond, CH2, NR7, O, or S, with the proviso that at least one of A and X is NR7, O, or S; B is H, or BB together comprises a double bonded O, S, or NR8, with the proviso that BB comprises a double bonded O, S, or NR8 when A and X are the same or different and are NR7, O, or S; wherein: NR7 and NR8 are the same or different and comprise a functionally modified amino group, e.g., R7 and R8 are the same or different and are H, alkyl, cycloalkyl, aryl, aralkyl, acyl, OH, or alkoxy; p is 0 or 1; D-E, G-H are the same or different and are CH2CH2, CH&boxH;CH, or Câ‰¡C; and Y is C(O) (i.e. a carbonyl group) or Y is wherein R9O constitutes a free or functionally modified hydroxy group; wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21, or 2,3,4,5-tetrazol-1-yl, where: R is H or a pharmaceutically acceptable cation, or CO2R forms a pharmaceutically acceptable ester moiety; NR2R3, NR5R6 are the same or different and comprise a free or functionally modified amino group; OR4 comprises a free or functionally modified hydroxy group; Hal is F, Cl, Br, or I; R20 is H, alkyl, acyl; R21 is H or a pharmaceutically acceptable cation, or COSR21 forms a pharmaceutically acceptable thioester moiety; A is L1-A1-L2, L1-A2-L2, L3-A2-L4, or L5-A2â€”L3; A1 is CH2CH2; A2 is L1 is CH2-B-D; B and D are the same or different and are CH2CH2, CH&boxH;CH, or Câ‰¡C; L2 is CH2-K-CH2CH2; K is CH2CH2, CH&boxH;CH, or Câ‰¡C; L3 is CH2CH2CH2, CH2CH&boxH;CH, CH2Câ‰¡C, CH&boxH;CHCH2, Câ‰¡CCH2, or CH&boxH;C&boxH;CH; L4 is Xâ€”CH2CH2; X is CH2CH2CH&boxH;CH, CH2CH2Câ‰¡C, CH2CH2CH2CH2, CH2CH&boxH;CHCH2, CH2Câ‰¡CCH2, CH&boxH;CHCH2CH2, Câ‰¡CCH2CH2, CH2CH&boxH;C&boxH;CH, or CH&boxH;C&boxH;CHCH2; L5 is CH2CH2-B-D; and Y is C(O) (i.e. a carbonyl group) or Y is wherein R9O constitutes a free or functionally modified hydroxy group; wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21 or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; X is C2-C5 alkyl, alkynyl, or alkenyl or a C3-C5 allenyl group; Y is H, free or functionally modified hydroxy group, halo, trihalomethyl, free or functionally modified amino group, free or functionally modified thiol group, C(O)R7, or alkyl; R7 is H, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino; A is a direct bond or C1-3 alkyl; B is CH2CH2, cis- or trans-CH&boxH;CH, or Câ‰¡C; and one of D and D1 is H and the other is a free or functionally modified OH group, or DD1 together comprises a double bonded oxygen; wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21 or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; E-D is CH2CH2CH2 or cis-CH2CH&boxH;CH; or E is trans-CH&boxH;CH and D is CH(OH) in either configuration, wherein the OH is free or functionally modified; or E is CH2CH2 and D is a direct bond; p is 1 or 3 when E-D is CH2CH2CH2 or cis-CH2CH&boxH;CH, or when E is trans-CH&boxH;CH and D is CH(OH) in either configuration, wherein the OH is free or functionally modified; or p is 0 when E is CH2CH2 and D is a direct bond; G-T is CH2CH2, CH(SR7)CH2 or trans-CH&boxH;CH; R7 is H, alkyl, aryl, aralkyl, cycloalkyl or acyl; Y is CH(OH) in either configuration, in which the OH is free of functionally modified, or C&boxH;O (i.e., a carbonyl group); n is 0, 2 or 4; and Z is CH3, CO2R, CONR2R3 or CH2OR4; wherein:R1 is (CH2)nCO2R, (CH2)nCONR2R3, (CH2)nCH2OR4, (CH2)nCH2NR5R6, (CH2)nCH2N3, (CH2)nCH2Hal, (CH2)nCH2NO2, (CH2)nCH2SR20, (CH2)nCOSR21 or (CH2)n-2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; n is 0 or 2; X is O, S(O)p, NR7 or CH2, with the proviso that X cannot be CH2 when n is 0; p is 0, 1 or 2; NR7 comprises a free or functionally modified amino group, e.g., R7 is H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy, A-B, D-E, G-T and J-K are the same or different and are CH2CH2, CH&boxH;CH or Câ‰¡C, with the proviso that at least one of A-B, D-E, G-T and J-K must be CH&boxH;CH or Câ‰¡C; and Y is C(O) (i.e., a carbonyl), or Y is wherein R9O constitutes a free or functionally modified hydroxy group; wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21 or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; A, B, C and D are the same or different and are C1-C5 alkyl, alkenyl, or alkynyl or a C3-C5 allenyl group; X is C(O) (i.e. a carbonyl group) or X is wherein R9O constitutes a free or functionally modified hydroxy group; wherein:R1 is (CH2)nCO2R, (CH2)nCONR2R3, (CH2)nCH2OR4, (CH2)nCH2NR5R6, (CH2)nCH2N3, (CH2)nCH2Hal, (CH2)nCH2NO2, (CH2)nCH2SR20, (CH2)nCOSR21 or (CH2)n-2,3,4,5-tetrazol-1-yl, wherein: R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester; NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same or different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy; OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR20 comprises a free or functionally modified thiol group; R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester; n is 0 or 2; A, B, C and D is C1-C5 alkyl, alkenyl, or alkynyl or a C3-C5 allenyl group; Y is wherein R8 is H or CH3, and X is CH2, CH(CH3) or C(CH3)2; or Y is CH2, CH(CH3) or C(CH3)2, and X is wherein R8 is H or CH3, with the proviso that Y cannot be CH2 when X is andR7O comprises a free or functionally modified hydroxy group; and wherein:R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21, or 2,3,4,5-tetrazol-1-yl, where: R is H or a pharmaceutically acceptable cation, or CO2R forms a pharmaceutically acceptable ester moiety; NR2R3, NR5R6 are the same or different and comprise a free or functionally modified amino group; OR4 comprises a free or functionally modified hydroxy group; Hal is F, Cl, Br, or I; SR20 comprises a free or functionally modified thiol group; R21 is H or a pharmaceutically acceptable cation, or COSR21 forms a pharmaceutically acceptable thioester moiety; A, B, C, D are the same or different and are C1-C5 alkyl, C2-C5 alkenyl, C1-5 cyclopropyl, C2-C5 alkynyl, or a C3-C5 allenyl group; E is where OR7 comprises a free or functionally modified hydroxy group; X&boxH;(CH2)m or (CH2)mO, where m=1-6; and Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, amino, or thiol group; or Xâ€”Y&boxH;(CH2)pY1; where p=0-6; and wherein:W&boxH;CH2, O, S(O)q, NR8, CH2CH2, CH&boxH;CH, CH2O, CH2S(O)q, CH&boxH;N, or CH2NR8; where q=0-2, and R8&boxH;H, alkyl, or acyl; Z&boxH;H, alkyl, acyl, halo, trihalomethyl, or a free or functionally modified amino, thiol, or hydroxy group; and â€” &boxH; single or double bond; or Xâ€”Y=cyclohexyl.