Phospholipids of hydroxyeicosatetraenoic acid-like derivatives and methods of use

A method for the treatment of dry eye and other disorders requiring the wetting of the eye which comprises 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:

• 10
• wherein:
• R20 is H or Ch═CH(CH2)12CH3;
• X is O or S;
• R1 is H, (C═O)R4 or CH2R4;
• J is O or NH;
• R2 is (C═O)R5;
• A is CH2 or O;
• R3 is OCH2CH(NH3+)COO−, 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-M-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 formula II:
• 11
• wherein:
• OR6 and OR7 are the same or different and comprise a free or functionally modified hydroxy group;
• T and Z are the same or different and are CH2CH2, cis- or trans-CH═CH, or C≡C;
• 12
• one of A1, B1 is H or CH3, and the other is a free or functionally modified hydroxy group, or A1-B1 comprises a double bonded oxygen as a carbonyl, or A1-B1 is OCH2CH2O;
• X1 is CR16R17(CH2)q or CR16R17(CH2)qO, with q is 0-6;
• R16 and R17 are the same or different and are H or CH3;
• Y1 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 X1-Y1 is (CH2)pY20, p is 0-6,
• 13
• wherein:
• W14 is CH2, O, S(O)m, NR21, CH2CH2, Ch═CH, CH2O, CH2S(O)m, Ch═N, or CH2NR21;
• m is 0-2;
• NR21 is NH or a functionally modified amino group;
• J14 is H, alkyl, acyl, halo, trihalomethyl, or a free or functionalized hydroxy, thiol, or amino group;
• and
• —is a single or double bond;
• or X1-Y1 is cyclohexyl;
• and
• the wavy line indicates the point of attachment.

A compound of formula I:

• 14
• wherein:
• R20 is H or Ch═CH(CH2)12CH3,
• X is O or S;
• R1 is H, (C═O)R4 or CH2R4;
• J is O or NH;
• R2 is (C═O)R5;
• A is CH2 or O;
• R3 is OCH2CH(NH3+)COO−, 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-M-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 formula II:
• 15
• wherein:
• OR6 and OR7 are the same or different and comprise a free or functionally modified hydroxy group;
• T and Z are the same or different and are CH2CH2, cis- or trans-CH═CH, or C≡C;
• 16 one of A1, B1 is H or CH3, and the other is a free or functionally modified hydroxy group, or A1-B1 comprises a double bonded oxygen as a carbonyl, or A1-B1 is OCH2CH2O;
• X1 is CR16R17(CH2)q or CR16R17(CH2)qO, with q is 0-6;
• R16 and R17 are the same or different and are H or CH3;
• Y1 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 X1-Y1 is (CH2)pY20, p is 0-6,
• 17
• wherein:
• W14 is CH2, O, S(O)m, NR21, CH2CH2, Ch═CH, CH2O, CH2S(O)m, Ch═N, or CH2NR21;
• m is 0-2;
• NR21 is NH or a functionally modified amino group;
• J14 is H, alkyl, acyl, halo, trihalomethyl, or a free or functionalized hydroxy, thiol, or amino group;
• and
• —is a single or double bond;
• or X1-Y1 is cyclohexyl;
• and
• the wavy line indicates the point of attachment.