14-hydroxy-docosahexaenoic acid compounds

Patent metadata

Field	Value
Publication number	US-9611239-B2
Application number	US-201414557212-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) analogues, their preparation, isolation, identification, purification and uses thereof.

First claim

What is claimed is:

1. A compound comprising the formula (I):

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 E configuration, with the exception that when Z is COOH and P 1 and P 2 are H, the double bonds are not in the configuration C4:Z, C8:E, C 10:Z, C12:Z; C16:Z and C19:Z;
wherein the carbon at C7 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 or ester thereof, provided that: when the compound has the configuration 7R,14S- C4:Z, C8:E, C10:E, C12:Z; C16:Z or C19:Z or 7S,14S C4:Z, C8:E, C10:Z, C12:E, C16:Z, 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:
when
(i) P 1 and P 2 are both hydrogen atoms; and/or
(ii) the compound is purified, Z is —C(O)OR d and R d of Z is a hydrogen atom; and/or
(iii) the C-7 hydroxy has an S configuration; and/or
(iv) the C-14 alcohol has an S configuration; and/or
(v) the double bonds at the 4, 10, 16 and 19 positions are each of Z configuration.

3. A pharmaceutical composition comprising a compound and/or a purified compound of claim 1 and a pharmaceutically acceptable carrier.

4. A method of treating or preventing inflammation comprising administering to an subject in need thereof an effective amount of a compound according to claim 1 .

5. A purified compound of claim 1 comprising a formula selected from:

or a pharmaceutically acceptable salt or ester thereof, optionally wherein one or both of the hydroxyls are converted into a protecting group.

6. A purified compound of claim 1 comprising a formula selected from:

or a pharmaceutically acceptable salt or ester thereof.

7. A pharmaceutical composition comprising a purified compound of claim 6 and a pharmaceutically acceptable carrier.

8. A method of treating or preventing inflammation comprising administering to an subject in need thereof an effective amount of a compound according to claim 6 .

9. A compound comprising one of the formula (Ic, Id or Ie):

wherein each of P 1 and P 2 individually is a protecting group or a hydrogen atom;
wherein is a double bond;
wherein the double bonds are, 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 )NR 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.

10. The compound of claim 9 , wherein the double bonds are at the 4, 16 and 19 positions are each of the Z configuration and the double bond at the 10 position is in the E configuration.

11. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

12. A method of treating or preventing inflammation comprising administering to a subject in need thereof an effective amount of a compound according to claim 9 .

13. The compound of claim 9 , wherein:
(i) P 1 and P 2 are both hydrogen atoms; and/or
(ii) R 1 and/or R 2 , is/are a methyl group; and/or
(iii) Z is COOH; and/or
(iv) the C-14 alcohol has an S configuration.

14. The compound of claim 9 , comprising a formula selected from:

Assignees

• Brigham & Womens Hospital Inc
• The Brigham & Women'S Hospital Inc

Inventors

• Serhan Charles N
• Yang Rong

Classifications

• 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

• A61P37/08

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

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title