ZA200501964B - Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory ischaemic and remodelling processes - Google Patents
Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory ischaemic and remodelling processes Download PDFInfo
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- ZA200501964B ZA200501964B ZA200501964A ZA200501964A ZA200501964B ZA 200501964 B ZA200501964 B ZA 200501964B ZA 200501964 A ZA200501964 A ZA 200501964A ZA 200501964 A ZA200501964 A ZA 200501964A ZA 200501964 B ZA200501964 B ZA 200501964B
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- South Africa
- Prior art keywords
- alkyl
- mono
- alkoxy
- alkoxycarbonyl
- compounds
- Prior art date
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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Description
PYRIMIDINONE DERIVATIVES AS THERAPEUTIC AGENTS AGAINST ACUTE AND CHRONIC
INFLAMMATORY, ISCHAEMIC AND REMODELLING PROCESSES
The present invention relates to novel heterocyclic derivatives, processes for their preparation, and their use in medicaments, especially for the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and heart failure development.
The fibrous protein elastin, which comprises an appreciable percentage of all protein content in some tissues, such as the arteries, some ligaments, the lungs and the heart, can be hydrolysed or otherwise destroyed by a select group of enzymes classified as elastases. Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human neutrophil elastase (HNE), is a glycosylated, strongly basic serine protease and is found in the azurophilic granules of human polymorphonuclear leukocytes (PMN). : HNE is released from activated PMN and has been implicated causally im the pathogenesis of acute and chronic inflammatory diseases. HNE is capable of degrading a wide range of matrix proteins including elastin and collagen, and in addition to these actions on connective tissue HNE has a broad range of inflammatory actions including upregulation of IL-8 gene expression, oedema formation, mucus gland hyperplasia and mucus hypersecretion. It also acts as a 20 . mediator of tissue injury by hydrolysing collagen structures, e.g. in the heart after ” acute myocardial infarction or during the development of heart failure, thus damaging endothelial cells, promoting extravasation of neutrophils adhering to the endothelium and influencing the adhesion process itself.
Pulmonary diseases where HNE is believed to play a role include lung fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), pulmonary emphysema, including smoking-induced emphysema, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis. In cardiovascular diseases, HNE is involved in the enhanced generation of ischaemic tissue injury followed by myocardial dysfunction after acute myocardial infarction and in the remodelling processes occurring during the development of heart failure. HNE has also been causally implicated in rheumatoid arthritis, atherosclerosis, brain trauma, cancer and related conditions in which neutrophil participation is involved.
Thus, inhibitors of HLE activity can be potentially useful in the treatment of a number of inflammatory diseases, especially of chromic obstructive pulmonary diseases [R.A. Stockley, Neutrophils and protease/antiprotease imbalance, Am. J.
Respir. Crit. Care 160, S49-S52 (1999)]. Inhibitors of HLE activity can also be potentially useful in the treatment of acute myocardial syndrome, unstable angina pectoris, acute myocardial infarction and coronary artery bypass grafts (CABG) [C.P.
Tiefenbacher et al., Inhibition of elastase improves myocardial function after ’ repetitive ischaemia and myocardial infarction in the rat heart, Eur. J. Physiol. 433, - §563-8570 (1997); Dinerman et al, Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction, J. Am. Coll. Cardiol. 15, 1559- 1563 (1990)], of the development of heart failure [S.J. Gilbert et al., Increased expression of promatrix metalloproteinase-9 and neutrophil elastase in canine "dilated cardiomyopathy, Cardiov. Res. 34, S377-S383 (1997)] and of atherosclerosis [Dollery et al., Neutrophil elastase in human atherosclerotic plaque, Circulation 107, 2829-2836 (2003)]. : :
The synthesis of 5-ethoxycarbonyl-1-phenyl-6-methyl-4-(3-nitrophenyl)-3,4-dihy- , dropyrimidin-2(1H)-one is described in J. Heterocyclic Chem. 38, 1051 (2001). A pharmacological activity of this compound is not mentioned.
The present invention relates to compounds of the general formula (I)
r R®
R:
R* us
R® AN 0 oN 7 MD, ’ v2 iz R
Va wherein
A represents an aryl or heteroaryl ring,
R!, R? and R® independently from each other represent hydrogen, halogen, nitro, cyano, Cy-Cg-alkyl, hydroxy or C;-Cs-alkoxy, wherein C,-Cs-alkyl and
C1-Ce-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C;-Cs- alkoxy, .
R* represents trifluoromethylcarbonyl, C,-Ce-alkylcarbonyl, C;-Cg-alkoxy- carbonyl, C;-Cs-alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C;-Cq-alkylaminocarbonyl, Cg-Cio-arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C;-Cg-alkylcarbonyl, C;-Cg-alkoxycarbonyl, mono- and di-C;-C,- alkylaminocarbonyl can be further substituted with one to three identical or different radicals selected from the group consisting of C3-Cs-cycloalkyl, hydroxy, C;-Cs-alkoxy, C,-Cs-alkoxycarbonyl, hydroxycarbonyl, amino- carbonyl, mono- and di-C;-C,-alkylaminocarbonyl, C;-Cs-alkylcarbonyl- amino, (C;-Cg4-alkylcarbonyl)-C,-Cy-alkylamino, cyano, amino, mono- and di-C,-C;s-alkylamino, heteroaryl, heterocyclyl and tri-(C;-Cg-alky!)-silyl, and wherein heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and hetero- cyclyl can be further substituted with C;-Cg-alkyl,
R? represents C;-Cq-alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy,
C:-Cs-alkoxy, C,-Cs-alkenoxy, C;-Cg-alkylthio, amino, mono- and di-C;-C¢- alkvlamino, arvlamino, hydroxycarbonyl. C;-Cs-alkoxycarbonyl and the radical -O-C,-C;-alkyl-O-C,-C,-alkyl, or E : R® represents amino,
R® represents hydrogen, C;-Cg-alkyl, formyl, aminocarbonyl, mono- or di-C;-C- alkylaminocarbonyl, C;-Cg-cycloalkylcarbonyl, C,-Cs-alkylcarbonyl, Cy-Cg- ~ alkoxycarbonyl, N-(C;-C-alkylsulfonyl)-aminocarbonyl, N-(C;-Cs-alkyl- sulfonyl)-N-(C,;-C,-alkyl)-aminocarbonyl, heteroaryl, heterocyclyl, hetero- arylcarbonyl or heterocyclylcarbonyl, wherein Ci-Ce-alkyl, mono- and di-
C1-Cs-alkylaminocarbonyl, C,-Cs-alkylcarbonyl, C;-Cs-alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C;-Cs-alkoxy, hydroxycarbonyl, C,-Cg-alkoxycarbonyl, amino- carbonyl, mono- and di-C;-C;-alkylaminocarbonyl, amino, mono- and di-
C,-Cy-alkylamino, Cy-Cy-alkylcarbonylamino, tri-(C;-Cg-alkyl)-silyl, cyano,
N-(moene- and di-C;-Cgs-alkylamino-C,;-Cy-alkyl)-aminocarbonyl, N-(C;-C,- alkoxy-C,-Cs-alkyl)-aminocarbonyl and halogen, or
R® represents a moiety of the formula
0 0 0
SA SAN o PNP
LNR™ _o eh wherein
R% is selected from the group consisting of hydrogen and C;-Ce-alkyl, and n represents an integer of 1 or 2,
R’ represents halogen, nitro, cyano, C;-Cg-alkyl, hydroxy or C;-C¢-alkoxy, wherein C;-Cs-alkyl and C,-Cg-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of } halogen, hydroxy and C,-C;-alkoxy, ) and
YY? YP, Y* and Y? independently from each other represent CH or N, wherein the : ring contains either 0, 1 or 2 nitrogen atoms. :
CL The compounds according to this invention can also be present in the form of their salts, hydrates and/or solvates.
Physiologically acceptable salts are preferred in the context of the present invention.
Physiologically acceptable salts according to the invention are non-toxic salts which in general are accessible by reaction of the compounds (I) with an inorganic or organic base or acid conventionally used for this purpose. Non-limiting examples of pharmaceutically acceptable salts of compounds (I) include the alkali metal salts, e.g. lithium, potassium and sodium salts, the alkaline earth metal salts such as magne- sium and calcium salts, the quaternary ammonium salts such as, for example, triethyl ammonium salts, acetates, benzene sulphonates, benzoates, dicarbonates, disulphates,
ditartrates, borates, bromides, carbonates, chlorides, citrates, dihydrochlorides, fumarates, gluconates, glutamates, hexyl resorcinates, - hydrobromides, hydro- chlorides, hydroxynaphthoates, iodides, isothionates, lactates, laurates, malates, maleates, mandelates, mesylates, methylbromides, methylnitrates, methylsulphates, nitrates, oleates, oxalates, palmutates, pantothenates, phosphates, diphosphates, ~ polygalacturonates, salicylates, stearates, sulphates, succinates, tartrates, tosylates, valerates, and other salts used for medicinal purposes.
Hydrates of the compounds of the invention or their salts are stoichiometric com- positions of the compounds with water, such as for example hemi-, mono-, or dihydrates.
Solvates of the compounds of the invention or their salts are stoichiometric com- positions of the compounds with solvents. :
The present invention includes both the individual enantiomers or diastereomers and the corresponding racemates or diastereomeric mixtures of the compounds according to the invention and their respective salts. In addition, all possible tautomeric forms of the compounds described above are included according to the present invention.
The diastereomeric mixtures can be separated into the individual isomers by chromatographic processes. The racemates can be resolved into the respective . enantiomers either by chromatographic processes on chiral phases or by resolution.
In the context of the present invention, the substituents, if not stated otherwise, in general have the following meaning:
Alkyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to radicals such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino.
Alkoxy illustratively and preferably represents methoxy, ethoxy, N-PTOPOXY, : " 1s0propoxy, tert.-butoxy, n-pentoxy and n-hexoxy.
Alkylcarbonyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms which has a carbonyl function at the position of attachment. Non-limiting examples include formyl, acetyl, n-propionyl, n- butyryl, i1sobutyryl, pivaloyl, n-hexanoyl. iE 10 Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxy- carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert.-butoxycarbonyl, n-pentoxy- carbonyl and n-hexoxycarbonyl. :
Alkylamino represents an alkylamino radical baving one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, isopropylamino, tert.-butylamino, n-pentylamino, n-hexyl- amino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N- n-propylamino, N-isopropyl-N-n-propylamino, N-tert.-butyl-N-methylamino, N-ethyl-
N-n-pentylamino and N-n-hexyl-N-methylamino.
Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylamino- carbonyl, tert.-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl,
N N-dimethylaminocarbonyl, ~ N,N-diethylaminocarbonyl, ~N-ethyl-N-methylamino- carbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl,
N-tert.-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl and N-n- hexyl-N-methylaminocarbonyl.
Alkylsulfonyl in general represents a straight-chain or branched hydrocarbon radical having 1 to 6, preferably 1 to 4 carbon atoms which has a sulfonyl function at the position of attachment. Non-limiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 1sopropylsulfonyl, n-butylsulfonyl, tert.-butylsulfonyl.
Cycloalkvl in general represents a cyclic saturated hydrocarbon radical having 3 to 8, preferably 3 to 6 carbon atoms. Non-limiting examples include cyclopropyl, cyclo- butyl, cyclopentyl, cyclohexyl and cycloheptyl.
Aryl per se and in arylcarbonyl represents a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, illustratively and preferably representing phenyl, naphthyl and phenanthrenyl.
Arylcarbonyl] illustratively and preferably represents benzoyl and naphthoyl.
Heteroaryl per se and in heteroarylcarbonyl represents an aromatic mono- or bicyclic radical having generally 5 to 10 and preferably 5 or 6 ring atoms and up to 5 and - preferably up to 4 heteroatoms selected from the group consisting of S, O and N, llustratively and preferably representing thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, _ imudazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl.
Heteroarylcarbonyl illustratively and preferably represents thienylcarbonyl, furyl- caibonyl, pynolylearbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl, pyndylcarbonyl, pyrimidylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl, indazolyl- carbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, quinolinylcarbonyl, iso- quinolinylcarbonyl.
Heterocyclyl per se and in heterocyclylcarbonyl represents a mono- or polycyclic, preferably mono- or bicyclic, nonaromatic heterocyclic radical having generally 4 to © 10 and preferably 5 to 8 ring atoms and up to 3 and preferably up to 2 heteroatoms and/or hetero groups selected from the group consisting of N, O, S, SO and SO,. The heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to
5- to 8-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms selected from the group consisting of O, N and S, such as illustratively and preferably tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.
Heterocyclylcarbonyl Ulustratively and preferably represents tetrahydrofuran- 2-carbonyl, pyrrolidine-1-carbonyl, pyrrolidine-2-carbonyl, pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl, morpholinecarbonyl, perhydroazepine- } carbonyl.
Halogen represents fluorine, chlorine, bromine and iodine. : When stated, that Y?!, Y2. Y3, Y* and Y° represent CH or N, CH. shall also stand for a ring carbon atom, which is substituted with a substituent R> or R’. : )
A * symbol next to a bond denotes the point of attachment in the molecule.
In another embodiment, the present invention relates to compounds of general formula (I), wherein :
A represents an aryl or heteroaryl ring,
R!, R? and R? independently from each other represent hydrogen, halogen, nitro, cyano, C;-Cg-alkyl, hydroxy or Cy-Ce-alkoxy, wherein C;-Cg-alkyl and
C1-Cs-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C,-C.- alkoxy, :
R* represents C;-Ce-alkylcarbonyl, C,-Cs-alkoxycarbonyl, C;-Ce-alkenoxy- carbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C,-C4-alkylamino- carbonyl, Cé-Cio-arylaminocarbonyl, heteroarylcarbonyl, heterocycly]-
carbonyl, heteroaryl, heterocyclyl or cyano, wherein C;-Cs-alkylcarbonyl,
C,-Cs-alkoxycarbonyl, mono- and di-C;-Cs-alkylaminocarbonyl can be oo further substituted with one to three identical or different radicals selected X from the group consisting of C3-Cg-cycloalkyl, hydroxy, C;-Cs-alkoxy,
C;-C4-alkoxycarbonyl, hvdroxycarbonyl, aminocarbonyl, mono- and di-
C,-C;s-alkylaminocarbonyl, C,-C,-alkylcarbonylamino, amino, mono- and di-
C,-Cs-alkylamino, heteroaryl, heterocyclyl and tri-(C;-Cg-alkyl)-silyl, ~ R® represents C,-Cs-alkyl, which can be substituted with one to three identical or ) different radicals selected from the group consisting of halogen, hydroxy, 'Cy-Ce-alkoxy, C;-Cs-alkenoxy, C;-C¢-alkylthio, amino, mono- and di-C;-Cg- alkylamino, arylamino, hydroxycarbonyl, C,-Ce-alkoxycarbonyl and the radical -O-C;-Cy-alkyl-O-C;-Ca-alkyl, or
R® represents amino, :
RS represents hydrogen, C,-Ce-alkyl, formyl, aminocarbonyl, mono- or di-C,-C,- alkylaminocarbonyl, C;-Cg-cycloalkylcarbonyl, C,-Cs-alkylcarbonyl, C;-Cs- alkoxycarbonyl, N-(C;-C,-alkylsulfonyl)-aminocarbonyl, N-(C;-Cs-alkyl- sulfonyl)-N-(C,-C,4-alkyl)-aminocarbonyl, heteroaryl, heterocyclyl, hetero- arylcarbonyl or heterocyclylcarbonyl, wherein C,-Cg-alkyl, mono- and di-
C,-Cs-alkylaminocarbonyl, C,-Cs-alkylcarbonyl, C1-Ce-alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C,-Cs-alkoxy, hydroxycarbonyl, C,-Cs-alkoxycarbonyl, amino- carbonyl, mono- and di-C;-Cy4-alkylaminocarbonyl, amino, mono- and di-
C,-Cs-alkylamino, C,-Cs-alkylcarbonylamino, tri-(C;-Cg-alkyl)-silyl, cyano,
N-(mono- and di-C;-Cs-alkylamino-C;-Cs-alkyl)-aminocarbonyl, N-(C,-C,- alkoxy-C,;-C;-alkyl)-aminocarbonyl and halogen,
Claims (1)
- We claim1. Compounds of the general formula (I) Rr? R— A R? NR oo R® “No AN 7 OF TR YY \ | R wherein A represents an aryl or heteroaryl ring, ‘R!, R? and R® independently from each other represent hydrogen, halogen, nitro, cyano, Cy-Cg-alkyl, hydroxy or C;-Cs-alkoxy, wherein C,-Cg- alkyl and C;-Ce-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C,-Cs-alkoxy, : R* represents trifluoromethylcarbonyl, C,-Ce-alkylcarbonyl, C,-Cg¢- alkoxycarbonyl, C,-Cg-alkenoxycarbonyl, hydroxycarbonyl, amine- carbonyl, mono- or di-C,-C4-alkylaminocarbonyl, Cg-Cjo-arylamino- carbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C;-Cg-alkylcarbonyl, C,-C¢-alkoxycarbony!, mono- and di-C;-Cy-alkylaminocarbonyl can be further substituted with one to three identical or different radicals selected from the group consisting of C;-Cg-cycloalkyl, hydroxy,C1-Ce-alkoxy, C,-Cs-alkoxycarbonyl, hydroxycarbonyl, amino- carbonyl, mono- and di-C,-C;-alkylaminocarbonyl, C;-Cs-alkyl- carbonylamino, (C;-Cs-alkylcarbonyl)-C,-Cq-alkylamino, cyano, ' amino, mono- and di-C;-C;-alkylamino, heteroaryl, heterocyclyl and tri-(C;-Cg-alkyl)-silyl, and wherein heteroarylcarbonyl, heterocyclyl- carbonyl, heteroaryl and heterocyclyl can be further substituted with Cy-Cs-alkyl,R® represents C,-Cy-alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy, C,;-Cg-alkoxy, C,-Cs-alkenoxy, C;-Ce-alkylthio, amino, mono- and di-C;-Cg¢-alkylamino, arylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbony] and the radical -O-C,-Cy-alkyl-O-C,-Cq-alkyl,or :R® represents amino, R® represents hydrogen, C,-Cg-alkyl, formyl, aminocarbonyl, mono- or di-C;-Cs-alkylaminocarbonyl, C;-Cs-cycloalkylcarbonyl, Ci-Ce-alkyl- carbonyl, C;-Cs-alkoxycarbonyl, N-(C;-Cs-alkylsulfonyl)-amino- carbonyl, N-(C;-Cs-alkylsulfonyl)-N-(C;-Cs-alkyl)-aminocabonyl, heteroaryl. heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, : wherein C,-Cs-alkyl, mono- and di-C,-C;-alkylaminocarbonyl, C;-Cg-alkylcarbonyl, C;-Cg-alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, Cy-Cs-alkoxy,hydroxycarbonyl, C;-Cs-alkoxycarbonyl, aminocarbonyl, mono- and . di-C,-Cs-alkylaminocarbonyl, amino, mono- and di-Cy-Cy-alkyl-amino, C,-Cy-alkylcarbonylamino, tri-(Cy-Cg-alkyl)-silyl, cyano,mono- and di-C;-Cs-alkylamino-C;-Cy-alkylaminocarbonyl, Cy-Cs- alkoxy-C,-Cs-alkylaminocarbonyl and halogen, or : : RS represents a moiety of the formula i : (NR ) Lo or [Lh wherein : R* is selected from the group consisting of hydrogen and C;-Cg- alkyl, and n represents an integer of 1 or 2, R’ represents halogen, nitro, cyano, C;-Cg-alkyl, hydroxy or Cy-Ce- alkoxy, wherein C;-Cg-alkyl and Ci-Ce-alkoxy can be further sub- stituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C,;-C,-alkoxy, and Yh Y3 YY and YP independently from cach other represent CII or N, wherein the ring contains either 0, 1 or 2 nitrogen atoms, and their salts, hydrates and/or solvates and their tautomeric forms.2. Compounds of general formula (I) according to Claim 1, whereinA represents an aryl or heteroaryl ring, R', R? and R® independently from each other represent hydrogen, halogen, nitro, cyano, Cy-Cg-alkyl, hydroxy or C;-Cg-alkoxy, wherein C;-Cs- alkyl and C;-Cg-alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C,-Cy4-alkoxy, R* represents C,-Ce-alkylcarbonyl, C;-Cs-alkoxycarbonyl, C;-C¢- alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di- oo Cy-Cs-alkylaminocarbonyl, C¢-Cyo-arylaminocarbonyl, heteroaryl- carbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C,-Cs-alkylcarbonyl, C,-Ce-alkoxycarbonyl, mono- and di- C)-Cy-alkylaminocarbonyl can be further substituted with one to three identical or different radicals selected from the group consisting of Cs-Cs-cycloalkyl, hydroxy, C;-Cs-alkoxy, C;-Cs-alkoxycarbonyl, hy- droxycarbonyl, aminocarbonyl, mono- and di-C;-C4-alkylamino- carbonyl, C;-Cs-alkylcarbonylamino, amino, mono- and di-C;-C,- alkylamino, heteroaryl, heterocyclyl and tri-(C;-Cg-alkyl)-silyl, rR 1epiesents C1-Cs-alkyl, which van Le substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy, C,-C¢-alkoxy, C,-Ce-alkenoxy, C,-Cg-alkylthio, to amino, mono- and di-C,-Cg-alkylamino, arylamino, hydroxycarbonyl, C,-Ce-alkoxycarbonyl and the radical -O-C;-Cs-alkyl-O-C-Ci-alkyl, or R® represents amino,RS represents hydrogen, C;-Cq-alkyl, formyl, aminocarbonyl, mono- or di-Cy-Cs-alkylaminocarbonyl, Cs-Cg-cycloalkylcarbonyl, C,-Cg-alkyl- carbonyl, C;-C¢-alkoxycarbonyl, N-(C,-Cs-alkylsulfonyl)-amino- carbonyl, = N-(C;-C;-alkylsulfonyl)-N-(C,-C4-alkyl)-aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C,;-Ce-alkyl, mono- and di-C,-C,-alkylaminocarbonyl, C;-Ce- alkylcarbenyl, C,-Ce-alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or ditterent radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C,-Cs-alkoxy, hydroxycarbonyl, C,-Cs-alkoxycarbonyl, aminocarbonyl, mono- and di-C,-Cs-alkylaminocarbonyl, amino, mono- and di-C,-C;-alkyl- amino, C;-Cq-alkylcarbonylamino, tri-(C;-Cg-alkyl)-silyl, cyano, mono- and di-C,-Cs-alkylamino-C,-C4-alkylaminocarbonyl, Ci-Cs- alkoxy-C,-C;-alkylaminocarbonyl and halogen, or R® represents a moiety of the formula 0) 0 00 . “0 o “AN AAR | © Lo wherein R® is selected from the group consisting of hydrogen and C;-Cs- alkyl, and n represents an integer of 1 or 2,R’ represents halogen, nitro, cyano, C;-Cg-alkyl, hydroxy or C;-Cs- alkoxy, wherein C,-Ce-alkyl and C,-Cg-alkoxy can be further sub- stituted with one to three identical or different radicals selected from ‘ the group consisting of halogen, hydroxy and C;-C;-alkoxy, and Y', Y% Y?, Y* and Y* independently from each other represent CH or N, wherein the ring contains either 0, 1 or 2 nitrogen atoms.: 3." Compounds of general formula (I) according to Claim 1 or 2, wherein : A represents a phenyl, naphthyl or pyridyl ring, R!, R? and R® independently from each other represent hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoro- methoxy, rR? represents C,-Cs-alkylcarbonyl, C,-Ce-alkoxycarbonyl, hydroxy- carbonyl, aminocarbonyl, mono-C;-C4-alkylaminocarbonyl or cyano, wherein C;-Cg¢-alkylcarbonyl, C,-Cs-alkoxycarbonyl and mono-C;-C,- allcylaminocarbonyl] can be substituted with one to three identical or different radicals selected from the group consisting of C;-Cs- cycloalkyl, hydroxy, C;-Cs-alkoxy, C,-Cs-alkoxycarbonyl, amino, mono- or di-C;-C,-alkylamino, heteroaryl and heterocyclyl, R® represents methyl or ethyl, R® represents hydrogen, C,-Cg-alkyl, mono- or di-C,-Cs-alkylamino- © carbonyl, Cy-Ce-alkylcarbonyl, C,-Cg-alkoxycarbonyl or hetero- cyclylcarbonyl, wherein C,-Cg-alkyl and C;-Cg-alkoxycarbonyl can be~~ substituted with one to three identical or different radicals selected from the group consisting of heteroaryl, hydroxy, Ci-Cs-alkoxy, hydroxycarbonyl, C;-Ce-alkoxycarbonyl, aminocarbonyl, mono- and di-C,-Cy-alkylaminocarbonyl, cyano, amino, mono- and di-C;-Cs- alkylamino, or RS represents a moiety of the formula0 IL 0 Lr L_o Loh EE wherein R* is selected from the group consisting of hydrogen and C,-C,- alkyl, and n represents an integer of 1 or 2, R’ represents halogen, nitro, cyano, tnfluoromethyl, trifluoromethoxy, methyl or ethyl, and v! Y?, Y? , Y* and Y* each represent CH.4, Compounds of general formula (I) according to Claim 1, 2 or 3, wherein A represents a phenyl or a pyridyl ring,Rand R? each represent hydrogen, R? represents fluoro, chloro, bromo, nitro or cyano,R* represents cyano, (;-Cy-alkylcarbonyl or C;-Cs-alkoxycarbonyl, wherein C,-Cs-alkoxycarbonyl can be substituted with a radical selected from the group consisting of hydroxy, C;-Cs-alkoxy, C;-Cs- alkoxycarbonyl, mono- and di-C;-Cs-alkylamino, heteroaryl and heterocyclyl, rR represents methyl, R® represents hydrogen, C;-Cs-alkyl, mono- or di-C;-C4-alkylamino- carbonyl, C,-Cy-alkylcarbonyl or C;-Cs-alkoxycarbonyl, wherein C1-Cs-alkyl and C,-Cs-alkoxycarbonyl can be substituted with a "radical selected from the group consisting of heteroaryl, hydroxy, C,-C4-alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and -di-C,-Cy4- alkylaminocarbonyl, amino, mono- and di-C;-C;-alkylamino,or : R® represents a moiety of the formula _L I Nw Se NR L_o > wherein R* is selected from the group consisting of hydrogen and methyl,'R’ represents trifluoromethyl or nitro, and Co vv? Y?, Y* and Y® each represent CH.- 5. Compounds of general formula (I) according to at least one of Claims 1 to 4, wherein A 1s phenyl or pyridyl.6. Compounds of general formula (I) according to at least one of Claims 1 to 5, wherein R! is hydrogen.1. Compounds of general formula (I) according to at least one of Claims 1 to 6, wherein R? is cyano.:8. Compounds of general formula (I) according to at least one of Claims 1 to 7, wherein R? is hydrogen.9. Compounds of general formula (I) according to at least one of Claims 1 to 8, wherein R’ is Ci-Cs-alkoxycarbony! optionally substituted by hydroxy or wherein R* is Cy-Cs-alkylcarbonyl.10. Compounds of general formula (I) according to at least one of Claims 1 to 9, wherein R® is methyl.11. Compounds of general formula (I) according to at least one of Claims 1 to 10, wherein R® is hydro gen. © 12. Compounds of general formula (I) according to at least one of Claims 1 to 11, wherein R’ is tnfluoromethyl or nitro.13. Compounds of general formula (IA) : CN : ) 1 A, R _ R? 6 ig H,C™ "N” So (1A), R '- CF, ~ wherein Zz represents CH or N, and R', R?, R* and R® have the meaning indicated in Claims 1 to 12.14. Process for synthesizing the compounds of general formula (I) or (IA), respectively, as defined in Claims 1 to 13 by condensing compounds of general formula (II) Rr? £1) LA (1D, wherein A, R' and R? have the meaning indicated in Claims 1 to 13, with compounds of general formula (IIT)R® O 1), wherein R* and R® have the meaning indicated in Claims 1 to 13,5 . aud compounds of general fomula TV),. NH, No FPN 5 I Y Rr YY : av), . R® wherein } R3 , rR’, and Y' to Y* have the meaning indicated in Claims 1 to 13, in the presence of an acid either in a three-component / one-step reaction or sequentially to give compounds of the general formula (IB) R’ R R* NH Rr’ No NEN (IB), R’ Vas rR’ v wherein . AR to RS, R’, and Y! to Y* have the meaning indicated in Claims 1 to 13, t optionally followed by reaction of the compounds of general formula (IB) with compounds of the general formula (V) R¥-X v), wherein : R® has the meaning of R® as indicated in Claims 1 to 13, but does not represent hydrogen, and X represents a leaving group, such as halogen, tosylate, mesylate or . sulfate, in the presence of a base.15. The composition containing at least one compound of general formula (I) or (1A) as defined in Claims 1 to 13 and a pharmacologically acceptable diluent.16. A composition according to Claim 15 for the treatrnent of acute and chronic inflammatory, ischaemic and/or remodelling processes. :17. The process for the preparation of compositions according to Claim 15 and 16 characterized in that the compounds of general formula (I) or (IA) as defined in Claims 1 to 13 together with customary auxiliaries are brought into a suitable * application form.18. Use of the compounds of general formula (I) or (IA) as defined in Claims 1 to 13 for the preparation of medicaments.19. Use according to Claim 18 for the preparation of medicaments for the treat- ment of acute and chronic inflammatory, ischaemic and/or remodelling processes. :20. Use according to Claiw 19, wherein the process 1s chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or development of heart failure.21. Process for controlling chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or development of heart failure in humans and animals by administration of a neutrophil elastase inhibitory amount of at least one compound according to any of Claims 1 to 13.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0220962A GB0220962D0 (en) | 2002-09-10 | 2002-09-10 | Heterocyclic derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200501964B true ZA200501964B (en) | 2006-05-31 |
Family
ID=9943787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200501964A ZA200501964B (en) | 2002-09-10 | 2005-03-08 | Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory ischaemic and remodelling processes |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN100575346C (en) |
| GB (2) | GB0220962D0 (en) |
| GT (1) | GT200300189A (en) |
| ZA (1) | ZA200501964B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2451817B1 (en) * | 2009-07-10 | 2013-09-04 | Bayer Intellectual Property GmbH | Indazolyl-substituted dihydroisoxa-zolopyridines and methods of use thereof |
| JP7390100B2 (en) * | 2015-03-18 | 2023-12-01 | ピーエイチ・ファーマ・カンパニー・リミテッド | (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4 -Production method of tetrahydropyrimidine-5-carbonitrile |
-
2002
- 2002-09-10 GB GB0220962A patent/GB0220962D0/en not_active Ceased
- 2002-11-14 GB GB0226609A patent/GB0226609D0/en not_active Ceased
-
2003
- 2003-08-28 CN CN03824983A patent/CN100575346C/en not_active Expired - Fee Related
- 2003-09-04 GT GT200300189A patent/GT200300189A/en unknown
-
2005
- 2005-03-08 ZA ZA200501964A patent/ZA200501964B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GT200300189A (en) | 2004-04-19 |
| GB0226609D0 (en) | 2002-12-24 |
| CN100575346C (en) | 2009-12-30 |
| CN1732159A (en) | 2006-02-08 |
| GB0220962D0 (en) | 2002-10-23 |
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