Metabolically robust analogs of CYP-eicosanoids for the treatment of cardiac disease

Patent metadata

Field	Value
Publication number	US-11096910-B2
Application number	US-201615746246-A
Country	US
Kind code	B2
Filing date	Jul 22, 2016
Priority date	Jul 22, 2015
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

Abstract

The present invention relates to compounds according to general formula (I) which are metabolically robust analogues of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids (n-3 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 cardiovascular diseases.

First claim

The invention claimed is:

1. A compound of the general formula (I):
P-E-I  (I)

or a pharmaceutically acceptable salt thereof, wherein

P is a group represented by the general formula (II):
(CH 2 ) n —O—(CH 2 ) k —X  (II)

wherein
n is an integer of from 3 to 8; and
k is 0, 1 or 2;
X represents CH 2 OH, CH 2 OAc, CH(O) or a group selected from the group consisting of:

wherein
R and R′ each independently represents a hydrogen atom; or a C 1 -C 6 alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s);
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 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 ; —(OCH 2 —CH 2 ) i —R 23 ; —C 3 -C 10 -heterocyclyl optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl group, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and oxo; —(Xaa) o ; a mono-, or disaccharide, or a derivative thereof, which is joined to —C(O) by an ester bond via the 1-O, 3-O-, or 6-O-position of the saccharide;
or is selected from the group consisting of:

wherein
R 3 represents (SO 2 R 30 ); (OR 31 ); —C 1 -C 6 alkanediyl(SO 2 R 32 ); —C 1 -C 6 alkanediyl(CO 2 H), an aryl group, a heteroaryl group, a cycloalkyl group or a heterocycloalkyl group, wherein the aryl group 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 —C(═O)OR 51 ; wherein the heteroaryl group, 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 —C(═O)OR 51 ; where the cycloalkyl group 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 —C(═O)OR 51 ; and wherein the heterocycloalkyl group 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 —C(═O)OR 51 ;
R 30 is a C 1 -C 6 alkyl, or an aryl group, wherein the C 1 -C 6 alkyl group is optionally substituted with —NH2, —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;
and wherein the aryl group 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 20 and R 21 each independently represents a hydrogen atom; a C 1 -C 6 alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); a C 3 -C 6 cycloalkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); —C 1 -C 6 alkyldiyl(CO 2 H) or together form a C 3 -C 10 -heterocycloalkyl which may be substituted with one or more C 1 -C 6 alkyl group(s), C 1 -C 6 alkoxy group(s), fluorine or chlorine atom(s) or hydroxyl group(s);
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 —NH2, —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), hydroxyl, or C 1 -C 6 alkoxy, an aralkyl group, a heteroalkyl group or a heteroalkylcycloalkyl group;
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 24 , R 25 , and R 26 each independently represents a hydrogen atom; —C(═O)C 11 -C 21 alkyl; or
—C(═O)C 11 -C 21 alkenyl;
R 27 represents —OH; —O(CH 2 ) 2 NH 2 , —OCH 2 —[CH(NH 2 )(CO 2 H)], —O(CH 2 ) 2 N(CH 3 ) 3 ; or

Xaa represents Gly, a conventional D,L-, D- or L-amino acid, a non-conventional D,L-, D- or L-amino acid, or a 2- to 10-mer peptide; and is joined to —C(═O) by an amide bond;
o is an integer of from 1 to 10;
R 4 is selected from the group consisting of:

h is 0, 1, or 2;
R 5 represents a hydrogen atom; a fluorine or chlorine atom; —CF 3 ; —C(═O)OR 51 ;
—NHC(═O)R 52 ; —C(═O)NR 53 R 54 ; or —S(O 2 )OH;
R 51 represents 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), hydroxyl, or C 1 -C 6 alkoxy;
R 52 , R 53 and R 54 each independently represents a C 1 -C 6 alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s); a C 3 -C 6 cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s); 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 haloalkyl, 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;
R 6 and R 7 each independently represents 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 —O(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 may be 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 )alkylaminocarbo

Assignees

• Omeicos Therapeutics Gmbh
• Univ Texas
• Max Delbruck Centrum Fur Molekulare Medizin

Inventors

• Fischer Robert
• Konkel Anne
• Wesser Tim
• Westphal Philipp
• Schunk Wolf-Hagen
• Westphal Christina
• Falck John Russell

Classifications

• C07D309/14

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D307/68

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D295/192

  from aromatic carboxylic acids · CPC title

• C07D263/48

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D257/04

  Five-membered rings · CPC title