NZ739273B2 - Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease - Google Patents

Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease Download PDF

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NZ739273B2
NZ739273B2 NZ739273A NZ73927316A NZ739273B2 NZ 739273 B2 NZ739273 B2 NZ 739273B2 NZ 739273 A NZ739273 A NZ 739273A NZ 73927316 A NZ73927316 A NZ 73927316A NZ 739273 B2 NZ739273 B2 NZ 739273B2
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New Zealand
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group
alkyl
fluorine
chlorine atom
alkoxy
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NZ739273A
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NZ739273A (en
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John Russel Falck
Robert Fischer
Anne Konkel
Wolf Hagen Schunk
Tim Wesser
Christina Westphal
Philipp Westphal
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Board Of Regents The University Of Texas System
Max Delbrück Centrum Für Molekulare Medizin
Omeicos Therapeutics Gmbh
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Application filed by Board Of Regents The University Of Texas System, Max Delbrück Centrum Für Molekulare Medizin, Omeicos Therapeutics Gmbh filed Critical Board Of Regents The University Of Texas System
Priority claimed from PCT/EP2016/067601 external-priority patent/WO2017013265A1/en
Publication of NZ739273A publication Critical patent/NZ739273A/en
Publication of NZ739273B2 publication Critical patent/NZ739273B2/en

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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. ds and to the use of these compounds or compositions for the treatment or prevention of cardiovascular diseases.

Description

epoxide hydrolases, that are less prone to autooxidation, and which preferably have anti-atrial fibrillation, anti-ventricular arrhythmia, or anti-heart failure.
In a first embodiment there is provided 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 ) -O-(CH ) -X (II) 2 n 2 k wherein n is an integer of from 3 to 8; and k is 0, 1 or 2; most preferably k is 1; X represents CH OH, CH OAc, CH(O) or a group selected from the group consisting of: h N SO R 2 H ; ; 9 ; HN 5 ; HO C R' S N NH preferably X is ; wherein R and R' each independently represents a hydrogen atom; or a C -C alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); R represents a hydroxyl group, C1-C6alkoxy, —NHCN, —NH(C1-C6alkyl), —NH(C3- 11 11 C cycloalkyl), —NH(aryl), or —O(C -C alkyldiyl)O(C=O)R ; R is a C -C alkyl group which is 6 1 6 1 6 optionally substituted with one or more fluorine or chlorine atom(s), or a C -C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); 2 3 20 21 22 23 R represents -NHR ; -NR R ; -OR ; -(OCH -CH ) -R ; -C -C -heterocyclyl optionally 2 2 i 3 10 substituted with one, two or three substituents independently selected from the group consisting of hydroxyl group, C -C alkoxy, C -C alkyl, and oxo; -(Xaa) ; a mono-, or 1 6 1 6 o 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: 24 24 O R R ; O R ; P(=O)(OH)R P(=O)(OH)R and ; wherein 3 30 31 32 R represents (SO R ); (OR ); -C -C alkanediyl(SO R ); -C -C alkanediyl(CO H), an 2 1 6 2 1 6 2 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 -C alkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine atom, 1 6 1 6 1 6 hydroxyl group, amino group, —NH(C -C alkyl), —N(C -C )dialkyl, and -C(=O)OR ; wherein 1 6 1 6 the heteroaryl group, is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C -C alkylthio, fluorine or 1 6 1 6 1 6 chlorine atom, hydroxyl group, amino group, —NH(C1-C6alkyl), —N(C1-C6)dialkyl and - C(=O)OR ; where the cycloalkyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C - 1 6 1 6 1 C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), —N(C - 6 1 6 1 C6)dialkyl, and -C(=O)OR ; and wherein the heterocycloalkyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of C - C alkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 6 1 6 1 6 NH(C -C alkyl), —N(C -C )dialkyl and -C(=O)OR ; 1 6 1 6 R is a C -C alkyl, or an aryl group, wherein the C -C alkyl group is optionally substituted 1 6 1 6 with -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 C )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 -C alkyl, C -C alkoxy, C -C alkylthio, 1 6 1 6 1 6 fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), and —N(C - 1 6 1 C )dialkyl; R is a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); or a C -C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); R is a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); or a C -C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); 21 R and R each independently represents a hydrogen atom; a C -C alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); a C - C cycloalkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); -C -C alkyldiyl(CO H) or together form a C -C -heterocycloalkyl which may 1 6 2 3 10 be substituted with one or more C -C alkyl group(s), C -C alkoxy group(s), fluorine or chlorine 1 6 1 6 atom(s) or hydroxyl group(s); R is a hydrogen atom, a C -C alkyl group; or a C -C cycloalkyl group; wherein the C - 1 6 3 6 1 C alkyl group or the C -C cycloalkyl group is optionally substituted with -NH , —NH(C - 6 3 6 2 1 C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl- C -C alkoxy, one, two or three fluorine or 6 1 6 1 6 1 6 chlorine atom(s), hydroxyl, or C -C alkoxy, an aralkyl group, a heteroalkyl group or a heteroalkylcycloalkyl group; R is -OH, -O(C -C )alkyl, or -N(C -C )dialkyl; 1 3 1 3 i is an integer of from 1 to 10; 24 25 26 R , R , and R each independently represents a hydrogen atom; —C(=O)C -C alkyl; 11 21 or —C(=O)C -C alkenyl; 11 21 R represents —OH; —O(CH2)2NH2, —OCH2-[CH(NH2)(CO2H)], —O(CH2)2N(CH3)3; or O OH HO OH 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 is selected from the group consisting of: N ; N N ; N ; N N ; ; H H H H N and N ; H ; h is 0, 1, or 2; 51 R represents a hydrogen atom; a fluorine or chlorine atom; -CF ; -C(=O)OR ; 52 53 54 –NHC(=O)R ; -C(=O)NR R ; or –S(O )OH; R represents a hydrogen atom; a C -C alkyl group; or a C -C cycloalkyl group; wherein 1 6 3 6 the C -C alkyl group or the C -C cycloalkyl group is optionally substituted with -NH , —NH(C - 1 6 3 6 2 1 C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl-C -C alkoxy, one, two or three fluorine or 6 1 6 1 6 1 6 chlorine atom(s), hydroxyl, or C -C alkoxy; 52 53 54 R , R and R each independently represents a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s); a C -C 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 -C alkyl, C -C haloalkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine 1 6 1 6 1 6 1 6 atom, hydroxyl group, amino group, —NH(C -C alkyl), —N(C -C )dialkyl, and an oxo 1 6 1 6 substituent; R and R each independently represents a hydroxyl group; an -O(C -C )alkyl group, an -O(C -C )alkenyl group, a, -O(C -C )alkyldiylO(C=O)(C -C )alkyl group, or a -O(C -C )alkyldi- 2 6 1 6 1 6 1 6 ylO(C=O)(C -C )alkenyl group; wherein the C -C alkyl group and the C -C alkenyl group may 2 6 1 6 2 6 be substituted with NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C6alkoxycarbonyloxy-, C1-C6alkylcarbonylthio-, C1-C6 alkylaminocarbonyl-, di(C1- C6)alkylaminocarbonyl-, or one, two or three fluorine or chlorine atom(s); or R represents a hydroxyl group and R represents a group: R represents C -C alkyl, or aryl; wherein the C -C alkyl is optionally substituted with - 1 6 1 6 NH , —NH(C -C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl-C -C alkoxy, one, two or three 2 1 6 1 6 1 6 1 6 fluorine or chlorine atom(s), hydroxy, C -C alkoxy, aryl, aryloxy, —C(=O)-aryl, —C(=O)C - 1 6 1 C alkoxy; and wherein the aryl group is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C - 1 6 1 6 1 C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), 6 1 6 —N(C -C )dialkyl, and an oxo substituent; g is 1 or 2; X represents an oxygen atom; sulfur atom; or NH; X represents an oxygen atom; sulfur atom; NH; or N(CH ); X represents an oxygen atom; sulfur atom; nitrogen atom; carbon atom; or C-OH; and the dashed line represents a carbon-carbon bond or a carbon-carbon double bond; E is a group represented by the general formula (III) or (IV): (IV) (III) wherein R12 and R13 are preferably in cis configuration, and wherein ring A in formula (III) represents a 5-membered or 6-membered carbocyclic or heterocyclic ring containing at least one double bond, including an aromatic carbocyclic or heterocyclic ring, which can be substituted with one to three or one to four substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C -C alkylthio, 1 6 1 6 1 6 fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), and —N(C - 1 6 1 C )dialkyl; and L and T each independently represents a ring atom, wherein L and T are adjacent to another; 12 13 R and R each independently represents a hydrogen atom, a fluorine atom, hydroxyl, -NH , C -C alkyl, C -C alkoxy, —C(=O)-aryl, —C(=O)C -C alkyl, or -SO (C -C alkyl); or - 2 1 6 1 6 1 6 2 1 6 SO aryl; wherein any of the foregoing C -C alkyl, C -C alkoxy, or aryl are optionally substituted 2 1 6 1 6 with one, two or three substituents independently selected from the group consisting of -NH , —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, C1-C6alkylcarbonyloxy-, C1-C6alkoxycarbonyloxy-, C1- C6alkylcarbonylthio-, C1-C6alkylaminocarbonyl-, di(C1-C6)alkylaminocarbonyl-, fluorine or 12 13 chlorine atom, and hydroxyl; or R and R 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 -NH2, —NH(C1-C6)alkyl, —N(C1- C )dialkyl, C -C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C - 6 1 6 1 6 1 6 1 C alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxyl; 6 1 6 I is –(CH ) -Y, wherein m is an integer of from 3 to 6, provided that m is an integer of from 3 to 5 when E is a group according to general formula (III); Y represents a group selected from the group consisting of: 41 42 NR R 44 45 46 47 N NR R NR R N 48 f R O ; ; (oxamide) 49 49 wherein 40 41 43 44 46 48 49 R , R , R , R , R , R and R each independently represents a hydrogen atom, -C - C alkyl, -C -C cycloalkyl, -C -C alkoxy, —C(=O)aryl, or —C(=O)C -C alkyl, wherein any of the 6 3 6 1 6 1 6 foregoing C -C alkyl, C -C cycloalkyl , C -C alkoxy, or aryl are optionally substituted with one, 1 6 3 6 1 6 two or three substituents independently selected from the group consisting of -NH , —NH(C - C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C - 6 1 6 1 6 1 6 1 C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, fluorine or 6 1 6 1 6 40 41 43 44 chlorine atom, and hydroxy; or R and R , or R and R , are taken together to form a 5- membered or 6-membered ring, which ring may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, — 2 1 6 N(C -C )dialkyl, C -C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, 1 6 1 6 1 6 1 6 C -C alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, fluorine or chlorine atom, and 1 6 1 6 hydroxyl; 42 45 47 50 R , R , R and R each independently represents a -C -C alkyl, wherein the C -C alkyl 1 3 1 3 may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 3 1 3 1 3 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C -C )alkyl- 3 1 3 1 3 1 3 40 41 43 44 49 aminocarbonyl-, fluorine or chlorine atom, and hydroxyl; or R and R ; R and R ; R and R are taken together to form a 5-membered or 6-membered ring, which ring may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 C6)alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxyl; f is an integer of from 0 to 2; with the proviso that when X does not comprise a -C(=O)O-motif with the carbonyl carbon in alpha or beta position to the oxygen atom of general formula (II), Y is an oxamide, a carbamate or a carbamide, preferably Y is an oxamide as defined above.
In a second embodiment there is provided a pharmaceutical composition comprising the compound according to the first embodiment in combination with a physiologically acceptable excipient.
In a third embodiment there is provided use of the compound according to the first embodiment, for the manufacture of a medicament for the treatment of a cardiovascular disease.
In a first aspect the above problem is solved by the provision of compounds of the general formula (I):

Claims (16)

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 ) -O-(CH ) -X (II) 2 n 2 k wherein n is an integer of from 3 to 8; and k is 0, 1 or 2; most preferably k is 1; X represents CH OH, CH OAc, CH(O) or a group selected from the group consisting of: N SO R ; H ; ; 9 ; HN 5 ; ; OH N OH HO C R' S N NH (26709027_1):RTK preferably X is ; wherein R and R' each independently represents a hydrogen atom; or a C -C alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); R represents a hydroxyl group, C -C alkoxy, —NHCN, —NH(C -C alkyl), —NH(C - 1 6 1 6 3 11 11 C cycloalkyl), —NH(aryl), or —O(C -C alkyldiyl)O(C=O)R ; R is a C -C alkyl group 6 1 6 1 6 which is optionally substituted with one or more fluorine or chlorine atom(s), or a C - C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); 2 3 20 21 22 23 R represents -NHR ; -NR R ; -OR ; -(OCH -CH ) -R ; -C -C -heterocyclyl 2 2 i 3 10 optionally substituted with one, two or three substituents independently selected from the group consisting of hydroxyl group, C -C alkoxy, C -C alkyl, and oxo; -(Xaa) ; a mono- 1 6 1 6 o , 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: (26709027_1):RTK O O R O R O O R O O O R O O R ; O P(=O)(OH)R O P(=O)(OH)R and ; wherein 3 30 31 32 R represents (SO R ); (OR ); -C -C alkanediyl(SO R ); -C -C alkanediyl(CO H), an 2 1 6 2 1 6 2 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 -C alkyl, C -C alkoxy, C -C alkylthio, fluorine 1 6 1 6 1 6 or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), —N(C -C )dialkyl, 1 6 1 6 and -C(=O)OR ; wherein the heteroaryl group, is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C - 1 6 1 C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 6 1 6 NH(C -C alkyl), —N(C -C )dialkyl and -C(=O)OR ; where the cycloalkyl group is 1 6 1 6 optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine atom, 1 6 1 6 1 6 hydroxyl group, amino group, —NH(C -C alkyl), —N(C -C )dialkyl, and -C(=O)OR ; 1 6 1 6 and wherein the heterocycloalkyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C - 1 6 1 C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 6 1 6 NH(C -C alkyl), —N(C -C )dialkyl and -C(=O)OR ; 1 6 1 6 R is a C -C alkyl, or an aryl group, wherein the C -C alkyl group is optionally 1 6 1 6 substituted with -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, 2 1 6 1 6 1 6 C -C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 1 6 1 6 1 6 1 C )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 -C alkyl, C - 1 6 1 C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 6 1 6 NH(C -C alkyl), and —N(C -C )dialkyl; 1 6 1 6 (26709027_1):RTK R is a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); or a C -C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); R is a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); or a C -C cycloalkyl group which is optionally substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); 20 21 R and R each independently represents a hydrogen atom; a C -C alkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); a C -C cycloalkyl group which may be substituted with one or more fluorine or chlorine atom(s) or hydroxyl group(s); -C -C alkyldiyl(CO H) or together form a C -C - 1 6 2 3 10 heterocycloalkyl which may be substituted with one or more C -C alkyl group(s), C - 1 6 1 C alkoxy group(s), fluorine or chlorine atom(s) or hydroxyl group(s); R is a hydrogen atom, a C -C alkyl group; or a C -C cycloalkyl group; wherein the C - 1 6 3 6 1 C alkyl group or the C -C cycloalkyl group is optionally substituted with -NH , — 6 3 6 2 NH(C -C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl- C -C alkoxy, one, two or 1 6 1 6 1 6 1 6 three fluorine or chlorine atom(s), hydroxyl, or C -C alkoxy, an aralkyl group, a heteroalkyl group or a heteroalkylcycloalkyl group; R is -OH, -O(C -C )alkyl, or -N(C -C )dialkyl; 1 3 1 3 i is an integer of from 1 to 10; 24 25 26 R , R , and R each independently represents a hydrogen atom; —C(=O)C -C alkyl; 11 21 or —C(=O)C -C alkenyl; 11 21 R represents —OH; —O(CH ) NH , —OCH -[CH(NH )(CO H)], —O(CH ) N(CH ) ; 2 2 2 2 2 2 2 2 3 3 O OH HO OH 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; (26709027_1):RTK R is selected from the group consisting of: N ; N N ; N ; N N ; ; H H H H HN N ; ; and N N H h is 0, 1, or 2; 5 51 R represents a hydrogen atom; a fluorine or chlorine atom; -CF ; -C(=O)OR ; 52 53 54 –NHC(=O)R ; -C(=O)NR R ; or –S(O )OH; R represents a hydrogen atom; a C -C alkyl group; or a C -C cycloalkyl group; wherein 1 6 3 6 the C -C alkyl group or the C -C cycloalkyl group is optionally substituted with -NH , 1 6 3 6 2 —NH(C1-C6)alkyl, —N(C1-C6)dialkyl, —NH(C1-C6)alkyldiyl-C1-C6alkoxy, one, two or three fluorine or chlorine atom(s), hydroxyl, or C -C alkoxy; 52 53 54 R , R and R each independently represents a C -C alkyl group which is optionally substituted with one or more fluorine or chlorine atom(s); a C -C 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 -C alkyl, C -C haloalkyl, C -C alkoxy, C -C alkylthio, 1 6 1 6 1 6 1 6 fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), —N(C - 1 6 1 C )dialkyl, and an oxo substituent; R and R each independently represents a hydroxyl group; an -O(C -C )alkyl group, an -O(C -C )alkenyl group, a, -O(C -C )alkyldiylO(C=O)(C -C )alkyl group, or a -O(C - 2 6 1 6 1 6 1 C )alkyldiylO(C=O)(C -C )alkenyl group; wherein the C -C alkyl group and the C - 6 2 6 1 6 2 C alkenyl group may be substituted with NH , —NH(C -C )alkyl, —N(C -C )dialkyl, 6 2 1 6 1 6 C -C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C 1 6 1 6 1 6 1 6 alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, or one, two or three fluorine or chlorine atom(s); or R represents a hydroxyl group and R represents a group: (26709027_1):RTK R represents C -C alkyl, or aryl; wherein the C -C alkyl is optionally substituted with - 1 6 1 6 NH , —NH(C -C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl-C -C alkoxy, one, 2 1 6 1 6 1 6 1 6 two or three fluorine or chlorine atom(s), hydroxy, C -C alkoxy, aryl, aryloxy, —C(=O)- aryl, —C(=O)C -C alkoxy; and wherein the aryl group is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 1 6 1 6 NH(C -C alkyl), —N(C -C )dialkyl, and an oxo substituent; g is 1 or 2; X represents an oxygen atom; sulfur atom; or NH; X represents an oxygen atom; sulfur atom; NH; or N(CH ); X represents an oxygen atom; sulfur atom; nitrogen atom; carbon atom; or C-OH; and the dashed line represents a carbon-carbon bond or a carbon-carbon double bond; E is a group represented by the general formula (III) or (IV): P 13 (IV) (III) wherein R12 and R13 are preferably in cis configuration, and wherein ring A in formula (III) represents a 5-membered or 6-membered carbocyclic or heterocyclic ring containing at least one double bond, including an aromatic carbocyclic or heterocyclic ring, which can be substituted with one to three or one to four substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C - 1 6 1 6 1 C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), 6 1 6 and —N(C -C )dialkyl; and L and T each independently represents a ring atom, wherein L and T are adjacent to another; (26709027_1):RTK 12 13 R and R each independently represents a hydrogen atom, a fluorine atom, hydroxyl, - NH , C -C alkyl, C -C alkoxy, —C(=O)-aryl, —C(=O)C -C alkyl, or -SO (C -C alkyl); 2 1 6 1 6 1 6 2 1 6 or -SO aryl; wherein any of the foregoing C -C alkyl, C -C alkoxy, or aryl are optionally 2 1 6 1 6 substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 12 13 C )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxyl; or R and R 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 , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 C )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxyl; I is –(CH ) -Y, wherein m is an integer of from 3 to 6, provided that m is an integer of from 3 to 5 when E is a group according to general formula (III); Y represents a group selected from the group consisting of: 41 42 NR R 44 45 46 47 NR R NR R N 48 f R O ; (oxamide) O 50 wherein 40 41 43 44 46 48 49 R , R , R , R , R , R and R each independently represents a hydrogen atom, -C - C alkyl, -C -C cycloalkyl, -C -C alkoxy, —C(=O)aryl, or —C(=O)C -C alkyl, wherein 6 3 6 1 6 1 6 any of the foregoing C -C alkyl, C -C cycloalkyl , C -C alkoxy, or aryl are optionally 1 6 3 6 1 6 substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 40 41 43 C )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxy; or R and R , or R (26709027_1):RTK and R , are taken together to form a 5-membered or 6-membered ring, which ring may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C - 2 1 6 1 6 1 6 1 C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C - 6 1 6 1 6 1 C )alkylaminocarbonyl-, fluorine or chlorine atom, and hydroxyl; 42 45 47 50 R , R , R and R each independently represents a -C -C alkyl, wherein the C -C alkyl 1 3 1 3 may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C -C )alkyl, —N(C -C )dialkyl, C - 2 1 3 1 3 1 C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C -C alkylcarbonylthio-, C - 3 1 3 1 3 1 C alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, fluorine or chlorine atom, and 3 1 3 40 41 43 44 49 50 hydroxyl; or R and R ; R and R ; R and R are taken together to form a 5- membered or 6-membered ring, which ring may be substituted with one, two or three substituents independently selected from the group consisting of -NH , —NH(C - C )alkyl, —N(C -C )dialkyl, C -C alkylcarbonyloxy-, C -C alkoxycarbonyloxy-, C - 6 1 6 1 6 1 6 1 C alkylcarbonylthio-, C -C alkylaminocarbonyl-, di(C -C )alkylaminocarbonyl-, 6 1 6 1 6 fluorine or chlorine atom, and hydroxyl; f is an integer of from 0 to 2; with the proviso that when X does not comprise a -C(=O)O-motif with the carbonyl carbon in alpha or beta position to the oxygen atom of general formula (II), Y is an oxamide, a carbamate or a carbamide, preferably Y is an oxamide as defined above.
2. The compound according to claim 1, with the further proviso that when n is 3, 5, 6, 7 or 8, k is 1 and E is a group according to general formula (III) or 12 13 general formula (IV), wherein each of R and R is a hydrogen atom; P represents a group: 81 81 –(CH ) -O-(CH )-X ; –(CH ) -O-(CH )-X ; 2 3 2 2 5 2 wherein X represents a group selected from the group consisting of: (26709027_1):RTK N SO N SO 4' and ; ; H 9'' ; H 9' ; 1' 1 R is defined as R above; 2' 3' 22' 23 R represents -NHR ; -OR ; -(OCH -CH ) -R ; a mono-, or disaccharide, or a 2 2 i 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 wherein R is selected from the group consisting of: O R O R O R O O R O O O R ; R ; ; O P(=O)(OH)R O P(=O)(OH)R and ; wherein 3' 30 31 32 R represents (SO R ); (OR ); -C -C alkanediyl(SO R ); or -C -C alkanediyl(CO H); 2 1 6 2 2 6 2 R is a hydrogen or a C -C cycloalkyl group, which is optionally substituted with -NH2, —NH(C -C )alkyl, —N(C -C )dialkyl, —NH(C -C )alkyldiyl- C -C alkoxy, one, two or 1 6 1 6 1 6 1 6 three fluorine or chlorine atom(s), hydroxy, or C -C alkoxy; R and i are as defined above; 24 25 26 27 R , R , R , and R are as defined above; 4' 4 R is defined as R above; and h is defined as above; 6' 7' 6 7 R and R are defined as R and R above; 9' 9 9'' R is defined as R above; R represents aryl which is optionally substituted with one, two or three substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C -C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, — 1 6 1 6 NH(C -C alkyl), —N(C -C )dialkyl, and an oxo substituent. 1 6 1 6
3. The compound according to claim 1 or 2, wherein X is (26709027_1):RTK 2 22 23 wherein R is -OR ; -(OCH -CH ) -R ; a mono-, or disaccharide, or a derivative 2 2 i 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 wherein R is selected from the group consisting of: O R O R O R O O R O O O R O O R ; O P(=O)(OH)R O P(=O)(OH)R and ; wherein R and i are as defined above; 22 23 27 and wherein R , and R to R are as defined in claim 1.
4. The compound according to any one of claims 1 to 3, wherein X is -C(=O)OH or a suitable salt of the carboxylic acid, preferably a free carboxylic acid.
5. The compound according to any one of claims 1 to 4, wherein Y is one of the oxamides defined according to claim 1.
6. The compound according to any one of claims 1 to 3 and 5, wherein X is 2 22 23 wherein R is -OR ; -(OCH -CH ) -R ; a mono-, or disaccharide, or a derivative thereof, 2 2 i which is joined to -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the saccharide; or wherein R is selected from the group consisting of: (26709027_1):RTK 24 24 O O R O R O O O R O R ; O P(=O)(OH)R O P(=O)(OH)R 22 23 27 wherein and R , R to R and i are as defined in claim 1, and wherein Y is one of the oxamides defined according to claim 1.
7. The compound according to any one of claims 1 to 6, wherein X is C(=O)OH, preferably the free carboxylic acid, and Y is one of the oxamides defined according to claim 1.
8. The compound according to claim 1, with the formula (V): formula (V) or a pharmaceutically acceptable salt thereof, wherein 55 22 23 R represents -OH; -OR ; -(OCH -CH ) -R ; a mono-, or disaccharide, or a derivative 2 2 i thereof, which is joined to -C(=O) by an ester bond via the 1-O-, 3-O-, or 6-O-position of the saccharide; 22 23 22 R , R and i are as defined in claim 1, preferably R is a hydrogen atom or a C -C alkyl group, more preferably a hydrogen atom and i is preferably 2 to 4, more preferably 3; Y represents a group selected from the group consisting of: 41 42 NR R 44 45 46 47 N NR R NR R N 48 f R O ; ; (oxamide) (26709027_1):RTK O 50 40 50 40 wherein R to R are defined in claim 1, preferably R is a hydrogen atom or a C1- C alkyl group, more preferably a hydrogen atom 57 58 R and R are hydrogen; or form together a five- or six-membered ring, preferably an aromatic ring, optionally substituted with one to three or one to four substituents independently selected from the group consisting of C -C alkyl, C -C alkoxy, C - 1 6 1 6 1 C alkylthio, fluorine or chlorine atom, hydroxyl group, amino group, —NH(C -C alkyl), 6 1 6 —N(C -C )dialkyl, and an oxo substituent; 57 58 s is 1 or 2, with the proviso that s is 0 if R and R form together a five- or six-membered ring; the double bond in formula (V) represents a double carbon-carbon bond in cis- 57 58 configuration, if R and R are hydrogen, or this double bond is part of a five- or six- 57 58 membered ring formed together by R and R .
9. The compound according to claim 8, wherein 55 23 23 R represents –OH or-(OCH -CH ) -R ; i is 2 to 4, preferably i is 3; R is preferably 2 2 i Y is an oxamide, a carbamide or a carbamate, preferably a C -C alkyl substituted oxamide, carbamide or carbamate; 57 58 R and R are both H, or together form a substituted or non-substituted five- or six- membered aromatic ring, preferably form a substituted or non-substituted benzyl ring; 57 58 s is 1 or s is 0 if R and R together form a substituted or non-substituted five- or six- membered aromatic ring.
10. The compounds according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of: (26709027_1):RTK O OH NH O NH NH O (26709027_1):RTK ; ; (26709027_1):RTK and pharmaceutically acceptable salts thereof.
11. The compound according to any one of claims 1 to 10, with the formula (VI) O NH NH O formula (VI) or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 in combination with a physiologically acceptable excipient.
13. The composition according to claim 12, formulated for administration orally, topically, subcutaneously, intramuscularly, intraperitoneally, intravenously, or intranasally; preferably orally or intraveneously; more preferably orally.
14. The composition according to claim 12 or 13, wherein the composition is a dosage form selected from the group consisting of a spray, an aerosol, a foam, an inhalant, a powder, a tablet, a capsule, a soft gelatin capsule, a tea, a syrup, a granule, a chewable tablet, a salve, a cream, a gel, a suppository, a lozenge, a liposome composition and a solution suitable for injection. (26709027_1):RTK
15. Use of the compound according to any one of claims 1 to 11, for the manufacture of a medicament for the treatment of a cardiovascular disease.
16. The use according to claim 15, wherein the cardiovascular disease is selected from the group consisting of atrial fibrillation, ventricular arrhythmia, heart failure, coronary artery disease, myocardial infarction, maladaptive cardiac hypertrophy, and cardiac arrhythmias including ventricular extrasystoles, ventricular tachycardia, malignant ventricular tachycardia, atrial tachycardia, atrial flutter and atrial fibrillation, dilatative cardiomyopathy, and hypertensive heart disease; preferably selected from the group consisting of atrial fibrillation, atrial tachycardia, ventricular arrhythmia, and heart failure. OMEICOS Therapeutics GmbH Board of Regents, The University of Texas System Max Delbrück-Centrum für Molekulare Medizin By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (26709027_1):RTK
NZ739273A 2015-07-22 2016-07-22 Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease NZ739273B2 (en)

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US201562195645P 2015-07-22 2015-07-22
US62/195,645 2015-07-22
PCT/EP2016/067601 WO2017013265A1 (en) 2015-07-22 2016-07-22 Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease

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