14-hydroxy-docosahexaenoic acid compounds
The invention describes novel 14-hydroxy docosahexaenoic acid (DHA) analogs, their preparation, isolation, identification, purification and uses thereof.
1. A compound comprising the formula (IV):
wherein
is a double Dona;
wherein each double bond is, independently, in the Z or E configuration, with the exception that when Z is COOH, the double bonds are not in the configuration C4:Z, C7:Z, C9:E, C11:Z; C16:Z and C19:Z
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS(O) 2 R d , —OS (O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt thereof,
provided that when the double bonds have the configuration C4:Z, C7:Z, C9:E, C11:E; C16:Z and C19:Z:
(i) the compound is purified; and/or
(ii) when Z is —C(O)OR d , then R d for Z is not a hydrogen.
2. The compound of claim 1 , wherein:
(i) the compound is purified if, Z is —C(O)OR d and R d of Z is a hydrogen atom; and/or
(ii) the double bonds at the 4, 7, 16 and 19 positions are each of Z configuration.
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
4. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 1 .
5. A compound comprising the formula (II):
wherein each of P 1 and P 2 individually is a protecting group or a hydrogen atom;
wherein
is a double bond;
wherein each double bond is, independently, in the Z or the E configuration;
wherein the carbon at C4 and C14 are, independently, either R or S;
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS (O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt thereof,
provided that when Z is COOH and P 1 and P 2 are H, the double bonds are not in the configuration C5:E, C7:Z, C10:Z, C12:Z; C16:Z and C19:Z or
(i) the compound is purified; and/or
(ii) when Z is —C(O)OR d , then R d for Z is not a hydrogen.
6. The compound of claim 5 , wherein P 1 and P 2 are both hydrogen atoms.
7. The compound of claim 5 , wherein the double bonds at the 7, 16 and 19 positions are each of the Z configuration.
8. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
9. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 5 .
10. A compound comprising the formula (III):
wherein each of P 1 and P 2 individually is a protecting group or a hydrogen atom;
wherein
is a double bond;
wherein each bond is, independently, in the Z or E configuration, with the exception that when Z is COOH and P1 and P2 are H, the double bonds are not in the configuration C4:Z, C7:Z, C9:E, C11:Z; C16:Z and C19:Z;
wherein the carbon at C13 and C14 are, independently, either R or S;
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS (O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt thereof, provided when the compound has the configuration 13R,14S and C4:Z, C7:Z, C9:E, C11:E; C16:Z and C19:Z
(i) the compound is purified; and/or
(ii) Z is —C(O)OR d , then R d for Z is not a hydrogen.
11. The compound of claim 10 , wherein P 1 and P 2 are both hydrogen atoms.
12. The compound of claim 10 , wherein the double bonds at the 4, 7, 16 and 19 positions are each of Z configuration.
13. A pharmaceutical composition comprising a compound of claim 10 and further comprising a pharmaceutically acceptable carrier.
14. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 10 .
15. The compound of claim 10 , wherein the compound has the structure:
wherein each of P 1 and P 2 , individually, is a protecting group or a hydrogen atom;
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS (O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt thereof.
16. A purified compound of claim 10 , wherein the compound has the structure:
wherein each of P1 and P2, individually, are a protecting group or a hydrogen atom;
wherein Z is C(O)ORd, C(O)NRcRc, C(O)H, C(NH)NRcRc, C(S)H, C(S)ORd, C(S)NRcRc, or CN;
each Ra, is independently selected from hydrogen, (C1 C6) alkyl, (C3 C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5 C10) aryl, phenyl, (C6 C16) arylalkyl, benzyl, 2 6 membered heteroalkyl, 3 8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4 11 membered cycloheteroalkylalkyl, 5 10 membered heteroaryl or 6 16 membered heteroarylalkyl;
each Rc, is independently a protecting group or Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rb is independently selected from ═O, ORd, (C1 C3) haloalkyloxy, OCF3, ═S, SRd, ═NRd, ═NORd, NRcRc, halogen, CF3, CN, NC, OCN, SCN, NO, NO2, ═N2, N3, S(O)Rd, S(O)2Rd, S(O)2ORd, S(O)NRcRc, S(O)2NRcRc, OS(O)Rd, OS(O)2Rd, OS(O)2ORd, OS(O)2NRcRc, C(O)Rd, C(O)ORd, C(O)NRcRc, C(NH)NRcRc, C(NRa)NRcRc, C(NOH)Ra, C(NOH)NRcRc, OC(O)Rd, OC(O)ORd, OC(O)NRcRc, OC(NH)NRcRc, OC(NRa)NRcRc, [NHC(O)]nRd, [NRaC(O)]nRd, [NHC(O)]nORd, [NRaC(O)]nORd, [NHC(O)]nNRcRc, [NRaC(O)]nNRcRc, [NHC(NH)]nNRcRc or [NRaC(NRa)]nNRcRc;
each n, independently is an integer from 0 to 3; and
each Rd, independently is a protecting group or Ra;
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 16 a pharmaceutically acceptable carrier.
18. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 16 .
19. A compound comprising the formula (V)
wherein each of P 1 , P 2 and P 3 individually is a protecting group or a hydrogen atom;
wherein
is a double bond and wherein each double bond is, independently in the Z or E configuration;
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS (O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt or ester thereof,
provided that when Z is COOH and P 1 , P 2 and P 3 are H, the double bonds are not in the configuration C5:E, C7:Z, C9:E, C11:Z, C16:Z, C19:Z or
(i) the compound is purified; and/or
(ii) Z is —C(O)OR d , then R d for Z is not a hydrogen.
20. The compound of claim 19 , wherein P 1 , P 2 and P 3 are all hydrogen atoms.
21. The compound of claim 19 , wherein the double bonds at the 7, 16 and 19 positions are each of Z configuration.
22. The compounds of claim 19 , wherein the compounds have the structure:
23. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier.
24. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 22 .
25. A compound comprising one of the formula (IIIa, IIIb or IIIC):
wherein each of P 1 and P 2 individually is a protecting group or a hydrogen atom;
wherein
is a double bond;
wherein each double bond is, independently in the Z or the E configuration;
wherein Z is —C(O)OR d , —C(O)NR c R c , —C(O)H, —C(NH)NR c R c , —C(S)H, —C(S)OR d , —C(S)NR c R c , or —CN;
each R a , is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R c , is independently a protecting group or R a , or, alternatively, each R c is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R a or suitable R b groups;
each R b is independently selected from ═O, —OR d , (C1-C3) haloalkyloxy, —OCF 3 , ═S, —SR d , ═NR d , ═NOR d , —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R d , —OS (O) 2 R d , —OS(O) 2 OR d , —OS(O) 2 NR c R c , —C(O)R d , —C(O)OR d , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R d , —OC(O)OR d , —OC(O)NR c R c , —OC(NH)NR c R c , —OC(NR a )N R c R c , —[NHC(O)] n R d , —[NR a C(O)] n R d , —[NHC(O)] n OR d , —[NR a C(O)] n OR d , —[NHC(O)] n NR c R c , —[NR a C(O)] n NR c R c , —[NHC(NH)] n NR c R c or —[NR a C(NR a )] n NR c R c ;
R 1 and/or R 2 , is/are each independently selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl or 6-16 membered heteroarylalkyl;
each n, independently is an integer from 0 to 3; and
each R d , independently is a protecting group or R a ;
or a pharmaceutically acceptable salt or ester thereof.
26. The compound of claim 25 , wherein P 1 and P 2 are both hydrogen atoms.
27. The compound of claim 25 , wherein the double bonds at the 4, 7, 16 and 19 positions are each of Z configuration.
28. The compound of claim 25 , wherein R 1 and/or R 2 are independently or both, a methyl group.
29. The compound of any of claim 25 , wherein Z is COOH.
30. A pharmaceutical composition comprising a compound of claim 25 and a pharmaceutically acceptable carrier.
31. A method of treating or preventing inflammation comprising administrating to a subject in need thereof an effective amount of a compound according to claim 25 .