CYP-eicosanoid derivatives

Patent metadata

Field	Value
Publication number	US-11130772-B2
Application number	US-201515113139-A
Country	US
Kind code	B2
Filing date	Jan 21, 2015
Priority date	Jan 22, 2014
Publication date	Sep 28, 2021
Grant date	Sep 28, 2021

Abstract

The present invention relates to compounds according to general formula (I) which are analogues of epoxymetabolites produced by cytochrome P450 (CYP) enzymes from omega-3 (n-3) polyunsaturated fatty acids (PUFAs). The present invention further relates to compositions containing one or more of these compounds and to the use of these compounds or compositions for the treatment or prevention of conditions and diseases associated with inflammation, proliferation, hypertension, coagulation, immune function, pathologic angiogenesis, heart failure and cardiac arrhythmias.

First claim

The invention claimed is:

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

Assignees

• Max Delbrueck Centrum Fuer Molekulare Medizin
• Univ Texas

Inventors

• Schunck Wolf-Hagen
• Mueller Dominik
• Fischer Robert
• Wallukat Gerd
• Konkel Anne
• Falck John Russell

Classifications

• C07C323/41

  Y being a hydrogen or an acyclic carbon atom · CPC title

• C07C309/21

  containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton · CPC title

• C07D277/82

  Nitrogen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title