CYP-eicosanoid derivatives

1. A compound of the general formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein P is a group represented by the general formula (II):

—(CH 2 ) n —B—(CH 2 ) k —X   (II)

wherein X represents:

wherein k is 0 or 1; and

B represents a bond, —O—, or —S—;

n is 0 or an integer of from 3 to 8; and

k is 0 or 1, provided that when n is 0 or 3, then k is 1 and when n is 3, B is —O— or —S—;

wherein

R 1 represents a hydroxyl group, C 1 -C 6 alkoxy, —NHCN, —NH(C 1 -C 6 alkyl), —NH(C 3 -C 6 cycloalkyl), —NH(aryl), or —O(C 1 -C 6 alkyldiyl)O(C═O)R 11 ;

R 11 is a C 1 -C 6 alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s), or with a C 3 -C 6 cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);

R 2 represents —NHR 3 , —NR 20 R 21 , —OR 22 , or —(OCH 2 —CH 2 ) i —R 23 ;

wherein

R 3 represents (SO 2 R 30 ), (OR 31 ), —C 1 C 6 alkanediyl(SO 2 R 32 ), or —C 1 -C 6 alkanediyl(CO 2 H);

R 30 is a C 1 -C 6 alkyl group which is optionally substituted with —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 6 alkylcarbonyloxy-, C 1 -C 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-, one, two or three fluorine or chlorine atoms, or a hydroxyl group,

or an aryl group which is optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 )dialkyl;

R 31 is a C 1 -C 6 alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);

or a C 3 -C 6 cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);

R 32 is a C 1 -C 6 alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s),

or a C 3 -C 6 cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);

R ° and R 21 each independently represents a hydrogen atom, a C 1 -C 6 alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s), a C 3 -C 6 cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s) or —C 1 -C 6 alkyldiyl(CO 2 H);

R 22 is a hydrogen atom, a C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group, wherein the C 1 -C 6 alkyl group or the C 3 -C 6 cycloalkyl group is optionally substituted with —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, —NH(C 1 -C 6 )alkyldiyl, —C 1 -C 6 alkoxy, one, two or three fluorine or chlorine atom(s), hydroxy, or C 1 -C 6 alkoxy;

R 23 is —OH, —O(C 1 -C 3 )alkyl, or —N(C 1 -C 3 )dialkyl;

i is an integer of from 1 to 10;

R 4 represents

h is 0, 1, or 2;

R 6 and R 7 each independently represent a hydroxyl group, an —O(C 1 -C 6 )alkyl group, an —O(C 2 -C 6 )alkenyl group, a —O(C 1 -C 6 )alkyldiylO(C═O)(C 1 -C 6 )alkyl group or a —(C 1 -C 6 )alkyldiylO(C═O)(C 2 -C 6 )alkenyl group, wherein the C 1 -C 6 alkyl group and the C 2 -C 6 alkenyl group are optionally substituted with NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 5 alkylcarbonyloxy-, C 1 -C 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-; or with one, two or three fluorine or chlorine atom(s);

R 8 and R 8′ each independently represents a hydrogen atom, a C 1 -C 6 alkyl group, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 6 cycloalkyl, —C(═O)aryl; or —C(═O)heteroaryl, wherein the C 1 -C 6 alkyl, the C 3 -C 6 cycloalkyl, the aryl, or the heteroaryl group may be substituted with one, two or three substituents selected from the group consisting of fluorine atom, chlorine atom, hydroxy, —NH 2 , —NH(C 1 -C 6 )alkyl, -N(C 1 -C 6 )dialkyl, —NH(C 1 -C 6 )alkanediyl-C 1 -C 6 alkoxy, and C 1 -C 6 alkoxy;

X 1 represents an oxygen atom; sulfur atom; or NH;

X 2 represents an oxygen atom; sulfur atom; NH; or N(CH 3 );

wherein

R 12 and R 13 of formula (IV) each independently is

a hydrogen atom, a fluorine atom, hydroxy, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)-aryl, —C(═O)C 1 -C 6 alkyl, —SO 2 (C 1 -C 6 alkyl) or —SO 2 aryl,

wherein any of the foregoing C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -—(═O)-aryl, or —SO 2 aryl are optionally substituted with one, two or three substituents independently selected from the group consisting of:

—NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 6 alkylcarbonyloxy-, C 1 -C 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-, fluorine atom, chlorine atom, and hydroxy;

or R 12 and R 13 form together a 5-membered or 6-membered ring, which is optionally substituted with one, two or three substituents independently selected from the group consisting of:

—NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 6 alkylcarbonyloxy-, C 1 -C 6 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-, fluorine atom, chlorine atom, and hydroxy;

I is —(CH 2 ) 3 —Y,

wherein

Y represents a group:

wherein

R 40 , R 41 , R 43 , and R 44 each represents a hydrogen atom; R 42 is a methyl group and R 45 is an ethyl group;

with the proviso that

when:

(i) n is 3 and each of R 12 and R 13 is a hydrogen atom;

(ii) n is 4 and k is 1 and each of R 12 and R 13 is a hydrogen atom;

or

(iii) n is 5, 6, 7, or 8, and each of R 12 and R 13 is a hydrogen atom then, P represents one of the following groups:

—(CH 2 ) 3 —O—(CH 2 )—X 81 , —(CH 2 ) 3 —S—(CH 2 )—X 81 , —(CH 2 ) 5 —O—(CH 2 )—X 81 , —(CH 2 ) 5 —S—(CH 2 )—X 81 , —(CH 2 ) 5 —O—X 82 , —(CH 2 ) 5 —X 83 ; —(CH 2 ) 7 —O—X 82 ; or —(CH 2 ) 7 —X 83 , wherein

X 81 represents a group:

X 82 represents a group:

X 83 represents a group:

R 1′ is defined as R 1 above;

R 2′ represents —NHR 3′ , —OR 22′ , —(OCH 2 —CH 2 ) i —R 23 ,

wherein

R 3′ represents (SO 2 R 30 ), (OR 31 ), —C 1 -C 6 alkanediyl(SO 2 R 32 ), or —C 2 -C 6 alkanediyl(CO 2 H),

R 22′ is a C 3 -C 6 cycloalkyl group, which is optionally substituted with —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, —NH(C 1 -C 6 )alkyldiyl-C 1 -C 6 alkoxy, one, two or three fluorine or chlorine atom(s), hydroxy, or C 1 -C 6 alkoxy,

R 23 and i are as defined above, provided that when i=3, R 23 is not —OH;

R 4′ is defined as R 4 above; and h is defined as above;

R 6′ and R 7′ are defined as R 6 and R 7 above;

R 8″ and R ′″ are defined as R 8 and R 8′ above;

R 9′ is defined as R 9 above; R 9″ represents aryl which is optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 )dialkyl, and an oxo substituent.

2. The compound according to any one of claim 1 , wherein X is

3. The compound according to claim 1 , wherein one of R 12 and R 13 represents a hydrogen atom and the other represents a fluorine atom, hydroxy, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(═O)-aryl, —C(═O)C 1 -C 6 alkyl, or —SO 2 (C 1 -C 6 alkyl); or —SO 2 aryl; wherein any of the foregoing C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or aryl are optionally substituted with one, two or three substituents independently selected from the group consisting of —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 6 alkylcarbonyloxy-, C 1 -C 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxy; or R 12 and R 13 are taken together to form a 5-membered or 6-membered ring, which ring is optionally substituted with one, two or three substituents independently selected from the group consisting of —NH 2 , —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 )dialkyl, C 1 -C 6 alkylcarbonyloxy-, C 1 -C 6 alkoxycarbonyloxy-, C 1 -C 6 alkylcarbonylthio-, C 1 -C 6 alkylaminocarbonyl-, di(C 1 -C 6 )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxy.

4. The compound according to claim 1 , wherein P is —(CH 2 ) 3 —O—(CH 2 )—X 81 ; —(CH 2 ) 5 —O—(CH 2 )—X 81 ; —(CH 2 ) 3 —S—(CH 2 )—X 81 ; —(CH 2 ) 5 —S—(CH 2 )—X 81 ; —(CH 2 ) 5 —O—X 82 ; —(CH 2 ) 7 —O—X 82 ; —(CH 2 ) 5 —X 83 or —(CH 2 ) 7 —X 83 .

5. (Withdrawn- Currently Amended) The compound according to claim 4 , wherein P represents —(CH 2 ) 5 —X 83 or —(CH 2 ) 7 —X 83 .

6. The compound according to claim 1 , wherein X 83 represents a group selected from the groups consisting of:

7. The compound according to claim 1 , wherein n is 3 and R 1′ is a hydroxyl group; and R 2′ represents —NHR 3′

wherein

R 3′ is (SO 2 R 30 ), R 30 is —C 1 -C 6 alkyl or phenyl;

R 6′ and R 7′ each independently represents a hydroxyl group; an —O(C 1 -C 6 )alkyl group; or an —O(CH 2 )O(C═O)(C 1 -C 6 )alkyl group;

R 8″ is hydrogen atom; and R 8′″ is —C(═O)C 1 -C 6 alkyl.

8. A compound selected from the group consisting of:

9. A pharmaceutical composition that comprises at least one compound according to claim 1 , and, optionally, a carrier substance and/or an adjuvant.

10. The compound according to claim 1 , wherein said compound is part of a medicament.

11. A method comprising:

administering to a patient that suffers from a cardiovascular disease or has suffered in the past from a cardiovascular disease an effective amount of at least one of the compounds of claim 1 .

12. The method of claim 11 , wherein the cardiovascular disease is ventricular arrhythmia or atrial fibrillation.

13. The method of claim 12 , wherein at least 0.5 mg of the at least one compound is administered to the patient in one day.

14. A method for providing omega-3 (n-3) polyunsaturated fatty acids (PUFA) derivatives to a persons at risk to develop a condition or disease associated with inflammation, proliferation, hypertension, coagulation, immune function, pathologic angiogenesis, or cardiac disease comprising:

providing orally or parenterally to the person at risk at least one of the compounds of claim 1 in an amount considered effective to reduce the risk of developing said condition or disease.