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

Info

Publication number
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
Authority
NZ
New Zealand
Prior art keywords
group
alkyl
fluorine
chlorine atom
alkoxy
Prior art date
Application number
NZ739273A
Other versions
NZ739273A (en
Inventor
John Russel Falck
Robert Fischer
Anne Konkel
Wolf Hagen Schunk
Tim Wesser
Christina Westphal
Philipp Westphal
Original Assignee
Board Of Regents The University Of Texas System
Max Delbrück Centrum Für Molekulare Medizin
Omeicos Therapeutics Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

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)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
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

Publications (2)

Publication Number Publication Date
NZ739273A NZ739273A (en) 2021-02-26
NZ739273B2 true NZ739273B2 (en) 2021-05-27

Family

ID=

Similar Documents

Publication Publication Date Title
RU2018101439A (en) METABOLICALLY STABLE ANALOGUES OF CYP-EICOSANOIDS FOR TREATMENT OF CARDIOLOGICAL DISEASES
US6639089B2 (en) Anticancer agents, perfumes or foods and drinks
RU2730512C2 (en) New derivatives of cyp-eicosanoids
US6602905B1 (en) N-acyl homoserine lactones for the treatment of cardiac tachyarrhythmias, ischaemic heart disease or congestive heart failure
US6384028B1 (en) N-acylpiperidinylcarbonylaminocarboxylic acids and their use as glycoprotein IIb/IIIa antagonists and fibrinogen-blood platelets binding inhibitors
NZ739273B2 (en) Metabolically robust analogs of cyp-eicosanoids for the treatment of cardiac disease
JP5849336B2 (en) Adenylate cyclase activity regulator
US20150291507A1 (en) Panthenyl docosahexaeneoate and its use for treating and preventing cardiovascular diseases
AU596791B2 (en) New carbonic acid esters
JP2006347942A (en) beta-AMYLOID FORMATION INHIBITOR
JP2013043885A (en) Dehydroamino acid-containing glycerol derivative
JP4504656B2 (en) Novel 1,4-benzenediol carboxylic acid ester derivative or salt thereof, method for producing the same, and skin external preparation containing the same
KR840001917B1 (en) Process for preparing mixtures of glyceryl 1,2-bis(di-n*propylacetate) 1,3-bis(di-n-propylacetate)
WO1986003745A1 (en) New o-acylhydroxamic acid derivatives
RU2018133413A (en) ANALOGUES OF CYP-EICOSANOIDS FOR USE IN TREATMENT OR PREVENTION OF DISORDERS RELATED TO NEOVASCULARIZATION AND / OR INFLAMMATION
OA16321A (en) Panthenyl docosahexaeneoate and its use for treating and preventing cardiovascular diseases.
JPH10175990A (en) New tetrahydroxanthone compound
GB2067999A (en) Epoxysuccinic Acid Derivatives