14-hydroxy-docosahexaenoic acid compounds

Patent metadata

Field	Value
Publication number	US-9611240-B2
Application number	US-201414557230-A
Country	US
Kind code	B2
Filing date	Dec 1, 2014
Priority date	Sep 16, 2008
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

The invention describes novel 14-hydroxy docosahexaenoic acid (DHA) analogs, their preparation, isolation, identification, purification and uses thereof.

First claim

What is claimed is:

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

Assignees

• Brigham & Womens Hospital Inc

Inventors

• Serhan Charles N
• Yang Rong

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title