CN100575346C - Pyrimidone derivatives is acute and chronic inflammatory, ischemia and reconstruction capability pathology as the medicine treatment - Google Patents
Pyrimidone derivatives is acute and chronic inflammatory, ischemia and reconstruction capability pathology as the medicine treatment Download PDFInfo
- Publication number
- CN100575346C CN100575346C CN03824983A CN03824983A CN100575346C CN 100575346 C CN100575346 C CN 100575346C CN 03824983 A CN03824983 A CN 03824983A CN 03824983 A CN03824983 A CN 03824983A CN 100575346 C CN100575346 C CN 100575346C
- Authority
- CN
- China
- Prior art keywords
- compound
- general formula
- carbonyl
- alkyl
- group
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to new Hete rocyclic derivatives, their preparation method and their purposes in medicine, especially the purposes in the treatment chronic obstructive pulmonary disease.
Description
The present invention relates to new Hete rocyclic derivatives, their preparation method and their purposes in medicine, especially treat the purposes of chronic obstructive pulmonary disease, acute coronary syndrome, Acute Myocardial Infarction and development in heart failure.
The fibrous protein elastin accounts for the suitable proportion of all proteins content in some tissues (as artery, some ligaments, lung and heart), can chosenly be categorized as one group of enzymic hydrolysis or otherwise destroyed of elastoser.Human leukocyte elastase (HLE, EC 3.4.21.37) is also referred to as people's neutrophilic granulocyte elastoser (HNE), for glycosylated strong basicity serine protease and be found in the azurophilic granule of human polymorphonuclear leukocyte (PMN).HNE is discharged by activation of PMN and participates in the pathogeny of acute and chronic inflammatory disease.The HNE stromatin widely of degrading, comprise elastin and collagen protein, and except that these effects to reticular tissue, HNE has inflammatory effects widely, comprises just adjusting, oedema formation, mucous gland hyperplasia and the Polyblennia of IL-8 genetic expression.It is also by the amboceptor of Collagen Hydrolysate structure as tissue injury, for example, the heart in heart after Acute Myocardial Infarction or the evolution in heart failure so damages epithelial cell, acceleration is exosmosed attached to the neutrophilic granulocyte on the endothelium, and influences adhesion process itself.
Think that tuberculosis that HNE works comprises pulmonary fibrosis, pneumonia, adult respiratory distress syndrome (ARDS), pulmonary emphysema (pulmonary emphysema that comprise smoking-bring out), chronic obstructive pulmonary disease (COPD) and cystic fibrosis.In cardiovascular disorder, after HNE and the Acute Myocardial Infarction ischemic tissue damage the enhancing generation of myocardial dysfunction subsequently relevant and with evolution in heart failure in the reconstruction pathology that occurs relevant.HNE also involves rheumatoid arthritis, atherosclerosis, cerebral trauma, cancer and relates to the cause of disease that neutrophilic granulocyte participates in associated conditions.
Therefore, the HLE activity inhibitor can be used for treatment [R.A.Stockley, neutrophilic granulocyte and proteolytic enzyme/protease inhibitor imbalance, the Am.J.Respir.Crit.Care of treatment, the especially chronic obstructive pulmonary disease of many inflammatory diseasess potentially
160, S49-S52 (1999)].The HLE activity inhibitor also can be used for the treatment of [C.P.Tiefenbacher etc. in acute myocardium syndrome, unstable angina pectoris, Acute Myocardial Infarction and the coronary artery bypass graft surgery (CABG) potentially, elastoser is improved the rat heart inhibition of myocardial function after ischemic and the myocardial infarction repeatedly, Eur.J.Physiol.
433, S563-S570 (1997); Dinerman etc. increase the release of neutrophilic granulocyte elastoser in unstable angina pectoris and the Acute Myocardial Infarction, J.Am.Coll.Cardiol.
15, 1559-1563 (1990)], development in heart failure [S.J.Gilbert etc., the expression of matrix metalloproteinase-9 and neutrophilic granulocyte elastoser before being increased in dog and expanding in the myocardosis, Cardiov.Res.
34, S377-S383 (1997)] and atherosclerosis [Dollery etc., the neutrophilic granulocyte elastoser in human artery's atherosclerotic plaque, Circulation
107, 2829-2836 (2003)].
At J.Heterocyclic Chem.
38, 5-ethoxycarbonyl-1-phenyl-6-methyl-4-(3-nitrophenyl)-3 has been described in 1051 (2001), 4-dihydro-pyrimidin-2 (1H)-ketone synthetic.Do not mention the pharmacologically active of this compound.
The present invention relates to general formula (I) compound
Wherein
A represents aromatic ring or hetero-aromatic ring,
R
1, R
2And R
3Hydrogen, halogen, nitro, cyano group, the C of representing independently of one another
1-C
6-alkyl, hydroxyl or C
1-C
6-alkoxyl group, wherein C
1-C
6-alkyl and C
1-C
6-alkoxyl group can be selected from following identical group or different group further replaces: halogen, hydroxyl and C by one to three
1-C
4-alkoxyl group,
R
4Represent trifluoromethyl carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, C
1-C
6-allyloxycarbonyl, hydroxycarbonyl group, aminocarboxyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
6-C
10-aromatic yl aminocarbonyl, aryl carbonyl, heteroaryl carbonyl, heterocyclic radical carbonyl, heteroaryl, heterocyclic radical or cyano group, wherein C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, list-and two-C
1-C
4-alkyl amino-carbonyl can be selected from following identical group or different group further replaces: C by one to three
3-C
8-cycloalkyl, hydroxyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, hydroxycarbonyl group, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, C
1-C
4-alkyl-carbonyl-amino, (C
1-C
4-alkyl-carbonyl)-C
1-C
4-alkylamino, cyano group, amino, list-and two-C
1-C
4-alkylamino, heteroaryl, heterocyclic radical and three-(C
1-C
6-alkyl)-silyl, and wherein heteroaryl carbonyl, heterocyclic radical carbonyl, heteroaryl and heterocyclic radical can be by C
1-C
4-alkyl further replaces,
R
5Representative can be by one to three C that is selected from following identical group or the replacement of different group
1-C
4-alkyl: halogen, hydroxyl, C
1-C
6-alkoxyl group, C
1-C
6-alkene oxygen base, C
1-C
6-alkylthio, amino, list-and two-C
1-C
6-alkylamino, arylamino, hydroxycarbonyl group, C
1-C
6-alkoxy carbonyl and group-O-C
1-C
4-alkyl-O-C
1-C
4-alkyl,
Or
R
5Represent amino,
R
6Represent hydrogen, C
1-C
6-alkyl, formyl radical, aminocarboxyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
3-C
8-naphthene base carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, N-(C
1-C
4-alkyl sulphonyl)-aminocarboxyl, N-(C
1-C
4-alkyl sulphonyl)-N-(C
1-C
4-alkyl)-aminocarboxyl, heteroaryl, heterocyclic radical, heteroaryl carbonyl or heterocyclic radical carbonyl, wherein C
1-C
6-alkyl, list-and two-C
1-C
4-alkyl amino-carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, heteroaryl and heterocyclic radical can be selected from following identical group or the replacement of different group by one to three: aryl, heteroaryl, hydroxyl, C
1-C
4-alkoxyl group, hydroxycarbonyl group, C
1-C
6-alkoxy carbonyl, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, amino, list-and two-C
1-C
4-alkylamino, C
1-C
4-alkyl-carbonyl-amino, three-(C
1-C
6-alkyl)-silyl, cyano group, N-(single-and two-C
1-C
4-alkylamino-C
1-C
4-alkyl)-aminocarboxyl, N-(C
1-C
4-alkoxy-C
1-C
4-alkyl)-aminocarboxyl and halogen,
Or
R
6Represent the following formula part
Wherein
R
6ABe selected from hydrogen and C
1-C
6-alkyl, and
N represents 1 or 2 integer,
R
7Represent halogen, nitro, cyano group, C
1-C
6-alkyl, hydroxyl or C
1-C
6-alcoxyl
Base, wherein C
1-C
6-alkyl and C
1-C
6-alkoxyl group can be selected from following by one to three
Identical group or different group further replace: halogen, hydroxyl and C
1-C
4-alkoxyl group,
And
Y
1, Y
2, Y
3, Y
4And Y
5Represent CH or N independently of one another, wherein this ring contains
0,1 or 2 nitrogen-atoms are arranged.
The compounds of this invention also can their form of salt, hydrate and/or solvate exist.
Acceptable salt on the preferred in the context of the present invention physiology.
Acceptable salt is nontoxic salt on the physiology of the present invention, generally can obtain by compound (I) and the mineral alkali, organic bases or the acid-respons that are generally used for this purpose.The non-limiting example of the pharmacy acceptable salt of compound (I) comprises an alkali metal salt (lithium salts for example, sylvite and sodium salt), alkaline earth salt (as magnesium salts and calcium salt), quaternary ammonium salt (as triethyl ammonium salt), acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, carbonate, muriate, Citrate trianion, dihydrochloride, fumarate, gluconate, glutaminate, Sucrets salt, hydrobromate, the hydrogen chlorate, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, lauroleate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphoric acid salt, diphosphate, Polygalacturonate, salicylate, stearate, vitriol, succinate, tartrate, tosylate, valerate and other are made the salt of medicinal purpose.
The hydrate of The compounds of this invention or their salt is the stoichiometric composition of these compounds and water, as half, one or two hydrates.
The solvate of The compounds of this invention or their salt is the stoichiometric composition of these compounds and solvent.
The present invention includes independent enantiomorph or diastereomer and corresponding raceme or the non-enantiomer mixture and their salt separately of The compounds of this invention.In addition, according to the present invention includes all possible tautomeric form of above-claimed cpd.Non-enantiomer mixture goes out independent isomer by chromatographic process is separable.Raceme can be by isolating separately enantiomorph based on the chromatographic process of chirality phase or by Split Method.
In the context of the present invention, generally speaking, if not explanation in addition, substituting group has following implication:
Alkyl general proxy has the straight or branched alkyl of individual, preferred 1-4 the carbon atom of 1-6.Non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl.This is equally applicable to as groups such as alkoxyl group, alkylamino, alkoxy carbonyl and alkoxycarbonyl aminos.
Illustrative and the preferred representation methoxy of alkoxyl group, oxyethyl group, positive propoxy, isopropoxy, tert.-butoxy, n-pentyloxy and positive hexyloxy.
What alkyl-carbonyl general proxy had 1-6, a preferred 1-4 carbon atom has carbonyl functional group's straight or branched alkyl at its link position.Non-limiting example comprises formyl radical, ethanoyl, positive propionyl, positive butyryl radicals, isobutyryl, valeryl, positive caproyl.
Illustrative and the preferred representation methoxy carbonyl of alkoxy carbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, tert-butoxycarbonyl, n-pentyloxy carbonyl and positive hexyloxy carbonyl.
The alkylamino representative has the alkylamino group of one or two (independent selection) alkyl substituent, illustrative and preferred represent methylidene amino, ethylamino, n-propyl amino, sec.-propyl amino, tertiary butyl amino, n-pentyl amino, n-hexyl amino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propyl amino, N-sec.-propyl-N-n-propyl amino, the N-tertiary butyl-N-methylamino, N-ethyl-N-n-pentyl amino and N-n-hexyl-N-methylamino.
The alkyl amino-carbonyl representative has the alkyl amino-carbonyl group of one or two (independent selection) alkyl substituent, illustrative and preferred represent methylidene aminocarboxyl, the ethylamino carbonyl, the n-propyl aminocarboxyl, the sec.-propyl aminocarboxyl, tertiary butyl aminocarboxyl, the n-pentyl aminocarboxyl, the n-hexyl aminocarboxyl, N, N-dimethylamino carbonyl, N, N-diethylamino carbonyl, N-ethyl-N-base aminocarboxyl, N-methyl-N-n-propyl aminocarboxyl, N-sec.-propyl-N-n-propyl aminocarboxyl, the N-tertiary butyl-N-methylamino carbonyl, N-ethyl-N-n-pentyl amino-carbonyl and N-n-hexyl-N-methylamino carbonyl.
What alkyl sulphonyl general proxy had 1-6, a preferred 1-4 carbon atom has the straight or branched alkyl of alkylsulfonyl functional group at its link position.Non-limiting example comprises methyl sulphonyl, ethylsulfonyl, n-propyl alkylsulfonyl, sec.-propyl alkylsulfonyl, normal-butyl alkylsulfonyl, tertiary butyl alkylsulfonyl.
Cycloalkyl general proxy has the cyclic saturated hydrocarbon base of individual, preferred 3-6 the carbon atom of 3-8.Non-limiting example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
The monocycle that the aryl representative generally has 6-14 carbon atom in aryl itself and the aryl carbonyl is to trinucleated aromatic carbocyclic group, and is illustrative and preferably represent phenyl, naphthyl and phenanthryl.
Aryl carbonyl is illustrative and preferably represent benzoyl and naphthoyl.
The heteroaryl representative has 5-10, preferred 5 or 6 annular atomses and can reach 5 at most, preferably can reach 4 heteroatomic aromatic monocyclic or bicyclic radicals that are selected from S, O and N at most in heteroaryl itself and the heteroaryl carbonyl, and is illustrative and preferably represent thienyl, furyl, pyrryl, thiazolyl, oxazolyl, imidazolyl, oxadiazole base, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, indyl, indazolyl, benzofuryl, benzothienyl, benzothiazolyl, quinolyl, isoquinolyl.
The heteroaryl carbonyl is illustrative and preferably represent thienyl carbonyl, furyl carbonyl, pyrryl carbonyl, thiazolyl carbonyl, oxazolyl carbonyl, imidazolyl carbonyl, pyridyl carbonyl, pyrimidyl carbonyl, pyridazinyl carbonyl, indole carbonyl, indazolyl carbonyl, benzofuryl carbonyl, benzothienyl carbonyl, quinolyl carbonyl, isoquinolyl carbonyl.
Heterocyclic radical represent monocycle or many rings, preferred monocycle or dicyclo non-aromatic heterocyclic group in heterocyclic radical itself and the heterocyclic radical carbonyl, generally has 4-10 and preferred 5-8 annular atoms and can reach 3 at most, preferably can reach 2 at most and be selected from N, O, S, SO and SO
2Heteroatoms and/or assorted base.Heterocyclic radical can be saturated or part is unsaturated.Preferably have and to reach two heteroatomic 5-8 unit monocycle saturated heterocyclyls that are selected from O, N and S at most, as illustrative and preferred tetrahydrofuran (THF)-2-base, tetramethyleneimine-1-base, tetramethyleneimine-2-base, tetramethyleneimine-3-base, pyrrolinyl, piperidyl, morpholinyl, perhydro-azepine
Base.
The heterocyclic radical carbonyl is illustrative and preferably represent tetrahydrofuran (THF)-2-carbonyl, tetramethyleneimine-1-carbonyl, tetramethyleneimine-2-carbonyl, tetramethyleneimine-3-carbonyl, pyrroline carbonyl, piperidinyl carbonyl, morpholine carbonyl, perhydro-azepine
Carbonyl.
Halogen is represented fluorine, chlorine, bromine and iodine.
As explanation Y
1, Y
2, Y
3, Y
4And Y
5When representing CH or N, CH also represents by R
3Or R
7The ring carbon atom that substituting group replaces.
By key
*Link position in the symbolic representation molecule.
In another embodiment, the present invention relates to general formula (I) compound, wherein
A represents aromatic ring or hetero-aromatic ring,
R
1, R
2And R
3Hydrogen, halogen, nitro, cyano group, the C of representing independently of one another
1-C
6-alkyl, hydroxyl or C
1-C
6-alkoxyl group, wherein C
1-C
6-alkyl and C
1-C
6-alkoxyl group can be selected from following identical group or different group further replaces: halogen, hydroxyl and C by one to three
1-C
4-alkoxyl group,
R
4Represent C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, C
1-C
6-allyloxycarbonyl, hydroxycarbonyl group, aminocarboxyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
6-C
10-aromatic yl aminocarbonyl, heteroaryl carbonyl, heterocyclic radical carbonyl, heteroaryl, heterocyclic radical or cyano group, wherein C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, list-and two-C
1-C
4-alkyl amino-carbonyl can be selected from following identical group or different group further replaces: C by one to three
3-C
8-cycloalkyl, hydroxyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, hydroxycarbonyl group, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, C
1-C
4-alkyl-carbonyl-amino, amino, list-and two-C
1-C
4-alkylamino, heteroaryl, heterocyclic radical and three-(C
1-C
6-alkyl)-silyl,
R
5Representative can be by one to three C that is selected from following identical group or the replacement of different group
1-C
4-alkyl: halogen, hydroxyl, C
1-C
6-alkoxyl group, C
1-C
6-alkene oxygen base, C
1-C
6-alkylthio, amino, list-and two-C
1-C
6-alkylamino, arylamino, hydroxycarbonyl group, C
1-C
6-alkoxy carbonyl and group-O-C
1-C
4-alkyl-O-C
1-C
4-alkyl,
Or
R
5Represent amino,
R
6Represent hydrogen, C
1-C
6-alkyl, formyl radical, aminocarboxyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
3-C
8-naphthene base carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, N-(C
1-C
4-alkyl sulphonyl)-aminocarboxyl, N-(C
1-C
4-alkyl sulphonyl)-N-(C
1-C
4-alkyl)-aminocarboxyl, heteroaryl, heterocyclic radical, heteroaryl carbonyl or heterocyclic radical carbonyl, wherein C
1-C
6-alkyl, list-and two-C
1-C
4-alkyl amino-carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, heteroaryl and heterocyclic radical can be selected from following identical group or the replacement of different group by one to three: aryl, heteroaryl, hydroxyl, C
1-C
4-alkoxyl group, hydroxycarbonyl group, C
1-C
6-alkoxy carbonyl, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, amino, list-and two-C
1-C
4-alkylamino, C
1-C
4-alkyl-carbonyl-amino, three-(C
1-C
6-alkyl)-silyl, cyano group, N-(single-and two-C
1-C
4-alkylamino-C
1-C
4-alkyl)-aminocarboxyl, N-(C
1-C
4-alkoxy-C
1-C
4-alkyl)-aminocarboxyl and halogen,
Or
R
6Represent the following formula part
Wherein
R
6ABe selected from hydrogen and C
1-C
6-alkyl, and
N represents 1 or 2 integer,
R
7Represent halogen, nitro, cyano group, C
1-C
6-alkyl, hydroxyl or C
1-C
6-alkoxyl group, wherein C
1-C
6-alkyl and C
1-C
6-alkoxyl group can be selected from following identical group or different group further replaces: halogen, hydroxyl and C by one to three
1-C
4-alkoxyl group,
And
Y
1, Y
2, Y
3, Y
4And Y
5Represent CH or N independently of one another, wherein this ring contains 0,1 or 2 nitrogen-atoms.
In another embodiment, the present invention relates to general formula (I) compound, wherein
A represents phenyl ring, naphthalene nucleus or pyridine ring,
R
1, R
2And R
3Hydrogen, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, trifluoromethyl or the trifluoromethoxy represented independently of one another,
R
4Represent C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl, hydroxycarbonyl group, aminocarboxyl, list-C
1-C
4-alkyl amino-carbonyl or cyano group, wherein C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl and list-C
1-C
4-alkyl amino-carbonyl can be selected from following identical group or different group replacement: C by one to three
3-C
8-cycloalkyl, hydroxyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, amino, list-or two-C
1-C
4-alkylamino, heteroaryl and heterocyclic radical,
R
5Represent methylidene or ethyl,
R
6Represent hydrogen, C
1-C
6-alkyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
1-C
6-alkyl-carbonyl, C
1-C
6-alkoxy carbonyl or heterocyclic radical carbonyl, wherein C
1-C
6-alkyl and C
1-C
6-alkoxy carbonyl can be selected from following identical group or the replacement of different group by one to three: heteroaryl, hydroxyl, C
1-C
4-alkoxyl group, hydroxycarbonyl group, C
1-C
6-alkoxy carbonyl, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, cyano group, amino, list-and two-C
1-C
4-alkylamino,
Or
R
6Represent the following formula part
Wherein
R
6ABe selected from hydrogen and C
1-C
4-alkyl, and
N represents 1 or 2 integer,
R
7Represent halogen, nitro, cyano group, trifluoromethyl, trifluoromethoxy, methyl or ethyl,
And
Y
1, Y
2, Y
3, Y
4And Y
5Represent CH separately.
In another embodiment, the present invention relates to general formula (I) compound, wherein
A represents phenyl ring or pyridine ring,
R
1And R
3Represent hydrogen separately,
R
2Represent fluorine, chlorine, bromine, nitro or cyano group,
R
4Represent cyano group, C
1-C
4-alkyl-carbonyl or C
1-C
4-alkoxy carbonyl, wherein C
1-C
4-alkoxy carbonyl can be selected from following group and be replaced: hydroxyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, list-and two-C
1-C
4-alkylamino, heteroaryl and heterocyclic radical,
R
5Represent methylidene,
R
6Represent hydrogen, C
1-C
4-alkyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
1-C
4-alkyl-carbonyl or C
1-C
4-alkoxy carbonyl, wherein C
1-C
4-alkyl and C
1-C
4-alkoxy carbonyl can be selected from following group and be replaced: heteroaryl, hydroxyl, C
1-C
4-alkoxyl group, hydroxycarbonyl group, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, amino, list-and two-C
1-C
4-alkylamino,
Or
R
6Represent the following formula part
Wherein
R
6ABe selected from hydrogen and methyl,
R
7Represent trifluoromethyl or nitro,
And
Y
1, Y
2, Y
3, Y
4And Y
5Represent CH separately.
In another embodiment, the present invention relates to general formula (I) compound, wherein A is phenyl or pyridyl.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
1Be hydrogen.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
2Be cyano group, especially wherein A is phenyl or pyridyl and R
2For being positioned at cyano group with respect to the right-position of center dihydropyrimidinonesand ring.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
3Be hydrogen.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
4For choosing wantonly by hydroxyl, the especially C of 2-hydroxyl-oxethyl carbonyl substituted
1-C
4-alkoxy carbonyl, or R wherein
4Be C
1-C
4-alkyl-carbonyl, especially methyl carbonyl.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
5Be methyl.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
6Be hydrogen.
In another embodiment, the present invention relates to general formula (I) compound, wherein R
7Be trifluoromethyl or nitro, especially wherein R
7For be positioned at respect between the dihydropyrimidinonesand ring of center-position trifluoromethyl.
In another embodiment, the present invention relates to general formula (IA) compound
Wherein
Z represents CH or N, and
R
1, R
3, R
4And R
6Has above-mentioned appointment implication.
The compounds of this invention, wherein R
6Be hydrogen, but enol changes into corresponding hydroxyamidines:
General formula (I) compound can be in the presence of acid by three kinds of composition/single step reactions or successively general formula (II) compound, general formula (III) compound and general formula (IV) compound condensation are obtained general formula (IB) compound, optional next synthetic by general formula (IB) compound and the reaction of logical formula V compound in the presence of alkali subsequently
General formula (II) compound
Wherein
A, R
1And R
2Have above-mentioned appointment implication,
General formula (III) compound
Wherein
R
4And R
5Have above-mentioned appointment implication,
General formula (IV) compound
Wherein
R
3, R
7And Y
1-Y
5Have above-mentioned appointment implication,
General formula (IB) compound
Wherein
A, R
1-R
5, R
7And Y
1-Y
5Have above-mentioned appointment implication,
Logical formula V compound
R
6*-X (V)，
Wherein
R
6*Has above-mentioned specified R
6Implication, but do not represent hydrogen, and
X represents leavings group, as halogen, tosylate, methanesulfonates or sulfuric ester.
On the other hand, R wherein
4Represent cyano group, R
5Represent amino and R
6Represent general formula (I) compound of hydrogen can be in the presence of acid by three kinds of composition/single step reactions or successively general formula (II) compound, general formula (IV) compound and general formula (VI) compound condensation are prepared.
NC-CH2-CN (VI)
The suitable solvent that is used for method (II)+(III)/(VI)+(IV) → (IB) is generally organic solvent common usefulness, that do not change under this reaction conditions.These solvents comprise ether (as ether, isopropyl ether, 1,2-glycol dimethyl ether, diox or tetrahydrofuran (THF)), ethyl acetate, acetone, acetonitrile, methyl-sulphoxide, dimethyl formamide, alcohol (as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol), hydrocarbon (as pentane, hexane, hexanaphthene, benzene, toluene or dimethylbenzene) or halohydrocarbon (as methylene dichloride, ethylene dichloride, trichloromethane or chlorobenzene).Also may use the mixture of above-mentioned solvent.The solvent that is preferred for this method is a tetrahydrofuran (THF).
The appropriate acid that is used for method (II)+(III)/(VI)+(IV) → (IB) is generally mineral acid or organic acid.These acid preferably include carboxylic acid (as acetate or trifluoroacetic acid), sulfonic acid (as methylsulfonic acid or right-toluenesulphonic acids), hydrochloric acid or phosphoric acid (as Tripyrophosphoric acid).Preferred Tripyrophosphoric acid ethyl ester.With respect to general formula (III) compound of 1mol, the amount that acid is used is 0.25mol-100mol.
This method is carried out under+20 ℃-+150 ℃, preferred+60 ℃ of-+100 ℃ of temperature ranges usually.
This method is carried out under normal pressure usually.Yet, also may under pressurization or decompression, carry out (for example in the 0.5-5bar scope).
The suitable solvent that is used for method (IB)+(V) → (I) is generally the conventional organic solvent that does not change under this reaction conditions.These solvents comprise ether (as ether, isopropyl ether, 1,2-glycol dimethyl ether, diox or tetrahydrofuran (THF)), ethyl acetate, acetone, acetonitrile, methyl-sulphoxide, dimethyl formamide, hydrocarbon (as pentane, hexane, hexanaphthene, benzene, toluene or dimethylbenzene) or halohydrocarbon (as methylene dichloride, ethylene dichloride, trichloromethane or chlorobenzene).Also may use the mixture of above-mentioned solvent.The solvent that is preferred for this method is a tetrahydrofuran (THF).
The appropriate base that is used for method (IB)+(V) → (I) is generally mineral alkali or organic bases.These alkali preferably include cyclammonium (as piperidines or 4-N, the N-dimethyl aminopyridine), (C
1-C
4)-trialkylamine (as triethylamine or diisopropyl ethyl amine) or hydride (as sodium hydride).Preferred sodium hydride.With respect to 1mol general formula (IV) compound, the amount that alkali uses is 0.1mol-10mol, preferred 1mol-3mol.
This method usually 0 ℃-+150 ℃, preferred+20 ℃-+80 ℃ especially carry out under the room temperature.
This method is carried out under normal pressure usually.Yet, also may under pressurization or decompression, carry out (for example scope of 0.5-5bar).
General formula (II), (III), (IV), (V) and (VI) compound this as known compound, or they can prepare by ordinary method.
Aforesaid method can be used following process description:
The compounds of this invention shows unforeseeable, effective pharmacology and pharmacokinetics field of activity.Thereby they are suitable as the medicine that treats and/or prevents the humans and animals illness.
Surprising is that The compounds of this invention demonstrates people's neutrophilic granulocyte elastoser (HNE) and suppresses active, thereby is applicable to the active relevant treatment of diseases medicine of preparation and HNE.Therefore they can be following acute and chronic inflammatory pathology effective treatment are provided: as rheumatoid arthritis, atherosclerosis; And especially provide effective treatment: as pulmonary fibrosis, cystic fibrosis, pneumonia, adult respiratory distress syndrome (ARDS), particularly pulmonary emphysema (pulmonary emphysema that comprise smoking-bring out) and chronic obstructive pulmonary disease (COPD), chronic bronchitis and bronchiectasis for following acute, chronic lung disease.The compounds of this invention also can be following ischemic cardiovascular disease effective treatment is provided: as acute coronary syndrome, Acute Myocardial Infarction, unstable and stable stenocardia, coronary artery bypass graft surgery (CABG) and development in heart failure, provide effective treatment for inflammation after atherosclerosis, mitral valvular disease, atrial septal defect, percutaneous transluminal coronary angioplasty (PTCA), the open heart operation and for pulmonary hypertension.They also are proved can provide effective treatment to following disease: rheumatoid arthritis, acute inflammation sacroiliitis, cancer, acute pancreatitis, ulcerative colitis, periodontopathy, Chury-Strauss comprehensively demonstrate,proves, acute and chronic atopic dermatitis, psoriatic, systemic lupus erythematous, BP, Sepsis, alcoholic hepatitis, hepatic fibrosis, the BehcetShi disease, supersensitivity fungi sinusitis paranasal sinusitis, the allergic sinusitis, Crohn disease, kawasaki disease, glomerulonephritis, acute pyelonephritis, the colorectum disease, chronic suppurative otitis media, chronic venous property leg ulcer, enteritis, bacillary and viral infection, cerebral trauma, the illness that apoplexy and other neutrophilic granulocyte participate in.
The present invention also provides and contains at least a The compounds of this invention, preferably also has the vehicle of one or more pharmacology safety or the medicine of carrier substance, and also provides them to be used for the purposes of above-mentioned purpose.
But activeconstituents whole body and/or effect partly.For this purpose, it can suitable manner be used, for example per os, through parenteral, through lung, intranasal, through the hypogloeeis, through tongue, per os cheek, per rectum, through skin, through conjunctiva, use through ear or as implant.
For these route of administration, the administration form administration that activeconstituents can be suitable.
Useful Orally administered form comprises rapidly and/or with the administration form of improved procedure release of active ingredients, as tablet (non-coated tablet and coated tablet, for example enteric coated tablet), capsule, sugar coated tablet, granule, pill, powder, emulsion, suspensoid, solution and aerosol.
Parenteral administration can be avoided absorption step (in the intravenously, intra-arterial, heart, in the backbone or in the waist marrow) to carry out or comprise that absorption (intramuscular, subcutaneous, intracutaneous, transdermal or intraperitoneal) carries out.Useful parenteral administration forms comprises the injection preparation of injection and solution, suspensoid, emulsion, freeze-dried and sterile powder form.
The form that is applicable to other route of administration comprises for example imbedibility medicament forms (comprising powder inhalator, atomizer), nose drops/solution, sprays; Tablet or capsule, suppository, ear and ophthalmic preparation, vaginal capsule agent, aqueous suspensions (lotion, shake mixture), lipotropy suspensoid, ointment, ointment, emulsion (milk), paste, applying medicinal powder or implant through tongue, hypogloeeis or buccal administration.
Activeconstituents can change into the administration form of narration with known method itself.This finishes by using inertia, nontoxic, suitable medicinal vehicle.Wherein these vehicle comprise carrier (for example Celluloasun Microcrystallisatum), solvent (for example liquid macrogol), emulsifying agent (for example sodium lauryl sulphate), dispersion agent (for example polyvinylpyrrolidone), synthetic and natural biological polymer (for example albumin), stablizer (antioxidant for example, as xitix), tinting material (for example mineral dye, as ferric oxide) or taste and/or smell correctives.
For human, under case of oral administration, recommending pharmaceutical quantities is 0.001-50mg/kg, preferred 0.01mg/kg-20mg/kg.Under the situation of administered parenterally, as intravenously or through nasal mucosa, per os cheek or through inhalation, the recommendation using dosage is 0.001mg/kg-0.5mg/kg.
Even now needs to depart from mentioned amount in some cases, promptly as body weight, route of administration, to activeconstituents individual behavior, preparation way and use time or the function at interval that carries out.For example, use in some cases be less than aforesaid minimum may be enough, and will have to exceed the upper limit of aforementioned quantities in other situation.In the situation of using bigger amount, can suitably be divided into intraday a plurality of single dose.
In following test and embodiment, unless otherwise indicated, otherwise percentages; Part by weight.The concentration of the liquid/liquid solution of solvent ratio, thinning ratio and report is separately based on volumeter.
A. physiologically active evaluation
For example, use the provable The compounds of this invention of following test to suppress the activity of neutrophilic granulocyte elastase activity:
I.
The vitro enzyme test of people's neutrophilic granulocyte elastoser (HNE)
Content of the test:
Test damping fluid: 0.1M HEPES-NaOH pH of buffer 7.4,0.5M NaCl, 0.1% (w/v) bovine serum albumin;
The solution of the test damping fluid of the HNE of suitable concn (referring to following) (18U/mg lyophile, #20927.01, SERVAElectrophoresis GmbH, Heidelberg, Germany);
The solution of the test damping fluid of the substrate of suitable concn (referring to following);
The test compound solution by test damping fluid (from 10mM DMSO stock solution) dilution of suitable concn.
Embodiment A
Use fluorescence peptide substrates vitro inhibition HNE (continuous read output signal, 384MTP measuring method):
In this scheme, use elastin enzyme substrates MeOSuc-Ala-Ala-Pro-Val-AMC (#324740, Calbiochem-Novabiochem Corporation, Merck KgaA, Darmstadt, Germany).By mixing 10 μ L test compound diluents, 20 μ L HNE enzyme diluents (ultimate density 8-0.4 μ U/ml is generally 2.1 μ U/ml) and 20 μ L substrate diluents (ultimate density 1mM-1 μ M is generally 20 μ M) preparation test solution respectively.Gained solution was in 37 ℃ of incubation 0-2 hours (being generally one hour).In the fluorescence (TECAN wave spectrum fluorescence add card reader) of 37 ℃ of mensuration by the AMC of enzymatic reaction release.(ex.395nm, em.460nm) speed of Zeng Jiaing and elastase activity are proportional for fluorescence.By RFU-right-[I] mapping can determine IC
50Value.Can determine K by making Lineweaver-Burk figure
mAnd K
M (app.)Value also is converted into the Ki value by Dixon figure.
In this test, the IC of preparation embodiment compound
50Value is in 5nM-5 μ M scope.Representative data provides in table 1:
Table 1
| The embodiment numbering | IC 50[nM] |
| 1 | 8 |
| 9 | 40 |
| 14 | 5 |
| 15 | 8 |
| 16 | 10 |
| 20 | 700 |
| 24 | 13 |
| 26 | 10 |
| 28 | 50 |
| 58 | 1100 |
| 60 | 5 |
| 72 | 6 |
| 73 | 60 |
| 74 | 20 |
| 103 | 60 |
| 109 | 15 |
| 110 | 50 |
Embodiment B
Use insoluble fluorescence elastin substrate (being interrupted read output signal, the 96MTP measuring method) vitro inhibition HNE:
In this scheme, use elastin enzyme substrates elastin-luciferin (#100620, ICN Biomedicals GmbH, Eschwege, Germany).By mixing 3 μ L test compound diluents, 77 μ L HNE enzyme diluents (ultimate density 0.22U/ml-2.2mU/ml is generally 21.7 μ U/nl) and 80 μ L substrate suspension (ultimate density is 2mg/ml) preparation test solution.Gained suspension under the condition of slight jolting in 37 ℃ of incubation 0-16 hours (being generally four hours).The acetic acid (ultimate density is 50mM) that adds 160 μ L 0.1M in test solution is to stop enzymatic reaction.By centrifugal settling polymeric elastin-luciferin (Eppendorf 5804 whizzers, 3.000rpm, 10min).Supernatant liquid is transferred among the new MTP, and measures the fluorescence (BMG Fluostar card reader) of the peptide fluorescein that is discharged by enzymatic reaction.(ex.490nm, em.520nm) speed and elastase activity are proportional for fluorescence.By RFU-right-[I] mapping can determine IC
50Value.
II.
The in vitro tests of people's neutrophilic granulocyte
Embodiment A
The in vitro tests of PMN elastolysis:
This test be used to measure the elastolytic potentiality of people's polymorphonuclear cell (PMN) and estimate because the ratio of neutrophilic granulocyte elastin enzyme liberating [referring to Z.W.She etc., Am.J.Respir.Cell.Mol.Biol.
9,386-392 (1993)].
The tritiated elastin that is dissolved in the suspension is coated on 96 orifice plates with every hole 10 μ g.With test compound and control compound [ZD-0892 (J.Med.Chem.
40,1876-1885,3173-3181 (1997), WO 95/21855) and α 1 proteinase inhibitor (α 1PI)] join in the hole with suitable concentration.From the peripheric venous blood of healthy donors, isolate people PMN and be suspended in the substratum.With neutrophilic granulocyte with every hole 1 * 10
6-1 * 10
5The concentration of individual cell joins in the coated hole.With the positive control of porcine pancreatic elastase (1.3 μ M) as this test, and with the positive inhibitor of α 1PI (1.2 μ M) as the neutrophilic granulocyte elastoser.Cell contrast is for the PMN of the no compound of suitable cell density separately.With cell and compound in moistening thermostat container in 37 ℃ of incubations 4 hours.Plate is centrifugal to allow a harvested cell supernatant liquor.75 μ L volume supernatant liquors are transferred to 96 hole Lumaplate
TMIn the respective aperture of (plate that contains solid scintillator).Drying plate was read three minutes every hole until the visible liquid of Kong Zhongwu and with beta-counter.
3The elastolysis of H-elastin causes the reading in the supernatant liquor to increase.Compare with cell, suppress this elastolysis and show that then the tritium in the supernatant liquor reduces.In 1.2 μ M (n=3 different donors, every hole 3.6 * 10
5Individual cell), the α 1PI (inhibition of mean value ± s.e.m.) that produces 83.46 ± 3.97%.Obtain the IC of reference compound ZD-0892
50Value is 45.50 ± 7.75nM (mean value ± s.e.m.) (n=2 different donors, every hole 3.6 * 10
5Individual cell).
Known ZD-0892 is that the selective depressant of PMN elastoser adds the data results that α 1PI suppresses, and shows the most because release of neutrophilic granulocyte elastoser of the elastin Degradation that is produced by PMN but not because in addition short elastolysis enzyme such as matrix metalloproteinase (MMP).Estimate the inhibition activity of The compounds of this invention to this HNE-dependent form neutrophilic granulocyte elastolysis.
Embodiment B
Film is in conjunction with the vitro inhibition of elastoser:
The test method of end user's neutrophilic granulocyte is measured the restraining effect of the elastoser that is attached to the neutrophilic granulocyte film.Stimulate neutrophilic granulocyte 35min in 37 ℃ with LPS, centrifugal with 1600rpm then.Then, film is fixed to neutrophilic granulocyte on 3min with 3% Paraformaldehyde 96 and 0.25% glutaraldehyde in 4 ℃ in conjunction with elastoser.Centrifugal then this neutrophilic granulocyte, and add solvent and compound to be evaluated, add substrate MeOSuc-Ala-Ala-Pro-Val-AMC (#324740 with 200 μ M subsequently, Calbiochem-Novabiochem Corporation, Merck KgaA, Darmstadt, Germany).Then, use PMSF (phenylmethylsulfonyl fluoride) termination reaction, and read fluorescence in ex:400nm and em:505nm in 37 ℃ of incubation 25min.In mapping to inhibitor concentration, relative fluorescence determines IC with interpolation technique
50Value.
III.
The body inner model
Embodiment A
Acute Lung Injury body inner model:
People's neutrophilic granulocyte elastoser (HNE) is instilled into induced lung causes acute lung injury.Degree of injury can be estimated by measuring pulmonary apoplexy.
With Hypnorm/Hypnovel/ water anesthetized rat and by micro-sprayer release HNE or physiological saline are instilled in the lung.Before giving HNE, test compound gives through intravenous injection, per os tube feed or through suction at setting-up time.Give elastoser and put to death animal with excessive narcotic (vetanarcol) after 60 minutes, and with 2ml heparinization phosphate buffered saline(PBS) (PBS) lavation lung.Write down bronchoalveolar lavage (BAL) volume and sample is positioned over preservation on ice.Each BAL sample in 4-10 ℃ with 900r.p.m. centrifugal 10 minutes.Abandoning supernatant and the cell pellet is suspended among the PBS and with the sample recentrifuge again precipitates.Abandoning supernatant and the cell pellet is suspended in 0.1% cetyl trimethylammonium bromide (CTAB)/PBS of 1ml again with dissolved cell once more.When measuring blood content, take out sample is freezing.Sample is thawed before hemorrhage and mix measuring.Each sample is got 100 μ l and is presented in the independent hole in the 96 hole flat undersides.All samples is all measured in duplicate.Comprise that 0.1%CTAB/PBS with 100 μ l is as blank.Measure the absorbancy of material in the hole in the 415nm place with spectrophotometer.The 0.1%CTAB/PBS solution of the blood by measuring different concns is set up typical curve in the OD of 415nm value.The value of blood content is by relatively calculating with typical curve (be included in each plate in), and makes its stdn for the BAL fluid volume that reclaims.
The compounds of this invention is estimated their inhibition activity in the hemorrhage model of this rat HNE-inductive through intravenously, per os or through sucking.
Embodiment B
The body inner model of rat acute myocardial infarction:
Testing elastic proteinase inhibitor in rat threading cerebral infarction models.30min before operation gives male Wistar rat (weight＞300g) with the 10mg/kg acetylsalicylic acid.With isoflurane (isofluran) anesthesia and ventilation in the whole surgery process (120-130 is rich/min, 200-250 μ L stroke output; MiniVent Type 845, Hugo Sachs Elektronik, Germany).Then thoracotomy is carried out in the 4th root gap in the left side, opens pericardium and heart is temporarily taken out.With wire-wound arteria coroaria sinistra (LAD) wrapping but do not make arterial occlusion.This root line is arrived the animal neck from subcutaneous passing.Closed-chest also allows animal restore 4 days.The 5th day,, control down the LAD closure with the line knotting and in ECG with etherization rat 3min.Test compound is before the LAD closure or closed back per os, give through intraperitoneal or through intravenously (disposable large vol injection or continuous infusion).After closed 1 hour, line is reopened to pour into again.The excision heart, and after 48 hours, dye by the heart with Evans Blue counterweight closure, it is big or small then with TTC (triphenyltetrazolium chloride) infraction to be measured in the heart section statining of 2mm.Blueness is dyed in normoxic (do not have closed tissue) zone, ischemic (closed but the tissue of survival), and redness is dyed in the zone and downright bad (closed dead tissue) zone still is white.Scan the section of every block organization and determine the infraction size with the computer planimetry.
B. embodiment
Abbreviation:
Aq. the aqueous solution
Conc. spissated
DMF N, dinethylformamide
The DMSO methyl-sulphoxide
EI electron impact ionization (being used for MS)
ESI electron spray ionisation (being used for MS)
The HPLC high pressure liquid chromatography
The LC-MS liquid chromatograph mass spectrography
Mp. fusing point
The MS mass spectrum
NMR nucleus magnetic resonance POP
Ofth. theoretical (productive rate)
Rt retention time (being used for HPLC)
The THF tetrahydrofuran (THF)
Universal method:
Except as otherwise noted, otherwise institute respond and all under argon gas atmosphere, carry out.The solvent that uses all is not further purified available from ALdrich." silica gel " or " silicon-dioxide " is meant the silica gel 60 (0.040mm-0.063mm) from Merck KGaA company.Measurement of melting point adopts B ü chi 512 or similarly surveys the fusing point device, and does not proofread and correct.
Compound is elutriant purifying through the RP18-post with acetonitrile and water by the preparation HPLC purifying, adopts 1: 9-9: 1 gradient.
The LC-MS/HPLC method:
LC-MS method 1
Instrument: Micromass Quattro LCZ, HP 1100; Post: Uptisphere HDO, 50mm * 2.0mm, 3 μ m; Elutriant A: water+0.05% formic acid, elutriant B: acetonitrile+0.05% formic acid; Gradient: 0.0min100%A → 0.2min100%A → 2.9min 30%A → 3.1min 10%A → 4.5min10%A; Baking oven: 55 ℃; Flow velocity: 0.8ml/min; UV-detects: 208-400nm.
LC-MS method 2
Instrument: Waters Alliance 2790LC; Post: Symmetry C18,50mm * 2.1mm, 3.5 μ m; Elutriant A: water+0.1% formic acid, elutriant B: acetonitrile+0.1% formic acid; Gradient: 0.0min 5%B → 5.0min 10%B → 6.0min10%B; Temperature: 50 ℃; Flow velocity: 1.0ml/min; UV-detects: 210nm.
LC-MS method 3
Instrument: Micromass Platform LCZ, HP1100; Post: Aquasil C-18,50mm * 2.0mm, 3 μ m; Elutriant A: water+0.05% formic acid, elutriant B: acetonitrile+0.05% formic acid; Gradient: 0.0min 100%A → 0.2min100%A → 2.9min 30%A → 3.1min 10%A → 4.5min 10%A; Baking oven: 55 ℃; Flow velocity: 0.8ml/min; UV-detects: 208-400nm.
HPLC method 4
Instrument: HP 1100 band DAD-detectors; Post: Kromasil RP-18,60mm * 2mm, 3.5 μ m; Elutriant: A=5mlHClO
4/ 1H
2O, the B=acetonitrile; Gradient: 0min2%B, 0.5min 2%B, 4.5min 90%B, 6.5min 90%B; Flow velocity: 0.75ml/min; Temperature: 30 ℃; UV-detects: 210nm.
LC-MS method 5
Instrument: 4-(fold) parallel injection in Micromass TOF-MUX-interface and HPLCWaters 600; Post: Uptisphere HDO, 50mm * 2.0mm, 3.0 μ m; Elutriant A:1l water+1ml 50% formic acid, elutriant B:1l acetonitrile+1ml50% formic acid; Gradient: 0.0min100%A → 0.2min 100%A → 2.9min 30%A → 3.1min 10%A → 4.5min 10%A → 4.6min 100%A → 6.5min 100%A; Baking oven: room temperature; Flow velocity: 0.8ml/min; UV-detects: 210nm.
LC-MS method 6
Instrument: Micromass Platform LCZ and HPLC Agilent series 1100; Post: Grom-SIL 120 ODS-4HE, 50mm * 2.0mm, 3 μ m; Elutriant A:1l water+1ml50% formic acid, elutriant B:1l acetonitrile+1ml50% formic acid; Gradient: 0.0min100%A → 0.2min 100%A → 2.9min 30%A → 3.1min 10%A → 4.5min 10%A; Baking oven: 55 ℃; Flow velocity: 0.8ml/min; UV-detects: 208-400nm.
LC-MS method 7
Instrument: Micromass Quattro LCZ and HPLC Agilent series 1100; Post: Uptisphere HDO, 50mm * 2.0mm, 3 μ m; Elutriant A:1l water+1ml 50% formic acid, elutriant B:1l acetonitrile+1ml 50% formic acid; Gradient: 0.0min 100%A → 0.2min 100A → 2.9min 30%A → 3.1min 10%A → 4.5min 10%A; Baking oven: 55 ℃; Flow velocity: 0.8ml/min; UV-detects: 208-400nm.
Starting raw material:
Embodiment 1A
2-bromo-5-(1,3-dioxolane-2-yl) pyridine
With 6-bromo-3-pyridylaldehyde (500mg, 2.7mmol) and 1, (200mg 3.2mmol) is dissolved in the toluene (50ml) 2-ethylene glycol, adds in the round-bottomed flask that reflux exchanger and Dean-Stark water trap are housed with macroporous resin (Amberlyst) 15 (100mg).This solution spends the night in refluxing to stir down, is cooled to room temperature then, filters and vacuum concentration.With this crude product with hexanaphthene and ethyl acetate be elutriant through silica gel column chromatography, obtain titled reference compound, be colorless oil.
Productive rate: 0.489g (theoretical yield 79%)
HPLC (method 4): 3.46min.
MS(ESIpos)：m/z＝231(M+H)
+
1H-NMR(300MHz，CDCl
3)：δ＝8.46(d，1H)，7.64(m，1H)，7.49(m，1H)，4.15-4.00(m，4H)ppm.
Embodiment 2A
5-(1,3-dioxolane-2-yl)-2-pyridine carbonitrile
With embodiment 1A (2.8g, 12.5mmol), zinc cyanide (1.6g, 13.8mmol) and four-(triphenylphosphine) close palladium (0) (1.4g 1.3mmol) is dissolved in dimethyl formamide (among the 100ml and in 80 ℃ of stirrings spend the night (18h).Add four-(triphenylphosphine) again and close palladium (0) (0.1g) and will react again and spend the night (18h), then 2 days (48 hours) of room temperature placement in 80 ℃ of stirrings.Solvent removed in vacuo adds entry (100ml) and uses ethyl acetate (1L) extraction product in residue.With salt solution (200ml) washing organic phase,, filter and vacuum concentration with sal epsom monohydrate drying.With this crude product with hexanaphthene and ethyl acetate be elutriant through silica gel column chromatography, obtain titled reference compound, be white amorphous solid.
Productive rate: 0.94g (theoretical yield 42%)
HPLC (method 4): 3.21min.
MS(ESIpos)：m/z＝177(M+H)
+
1H-NMR(400MHz，DMSO-d
6)：δ＝8.81(s，1H)，8.09(s，2H)，5.95(s，1H)，4.13-3.94(m，4H)ppm.
Embodiment 3A
5-formyl radical-2-pyridine carbonitrile
Method A):
With being similar to Dodd, the method preparation of D. etc. [J.Org.Chem.1992,57,7226-7234]: 5-(1,3-dioxolane-2-yl)-2-pyridine carbonitrile (the embodiment 2A under stirring; 850mg, acetone 4.8mmol) (85: 15,59.5ml) add in the solution tosic acid (102mg, 0.59mmol).To be reflected at refluxes to stir down spends the night (18h), and then adds tosic acid (50mg) and water (5ml).To be reflected at the restir 48h down that refluxes.This solution is cooled to room temperature and uses the saturated sodium bicarbonate solution quencher.(3 * 100ml) extraction products with sal epsom monohydrate drying, filter and vacuum concentration with ethyl acetate.With this crude product preparation HPLC purifying, obtain faint yellow solid.
Productive rate: 0.66g (theoretical yield 93%)
Fusing point: 80-82 ℃
HPLC (method 4): 2.13min.
MS(ESIpos)：m/z＝133(M+H)
+
1H-NMR(400MHz，DMSO-d
6)：δ＝10.18(s，1H)，9.21(m，1H)，8.49(m，1H)，8.27(m，1H)ppm.
Method b):
1.04g (8.2mmol) oxalyl chloride is dissolved in the 8ml methylene dichloride.Be added dropwise to 1.28g (16.4mmol) methyl-sulphoxide in-78 ℃.This solution was stirred 20 minutes in-78 ℃, add the solution that 1g (7.46mmol) embodiment 5A compound is dissolved in the 7ml methylene dichloride then, and in-78 ℃ of continuously stirring 2 hours again.Be added dropwise to 3.4g (33.6mmol) triethylamine then, be warming up to room temperature after, this mixture of column chromatography purification (silicon-dioxide, elutriant are hexanaphthene to cyclohexane/ethyl acetate 2: 1).
Productive rate: 0.76g (theoretical yield 77%)
Data analysis: on seeing.
Embodiment 4A
5-methyl-2-pyridine carbonitrile
36g (209mmol) 2-bromo-5-picoline and 37.5g (418mmol) cupric cyanide were refluxed two hours in the 500ml dimethyl formamide.After being cooled to 50 ℃, stir adding 10% ammonia soln (500ml) down.Use the dichloromethane extraction product, organic phase is with dried over mgso and solvent removed in vacuo.With column chromatography (silicon-dioxide, elutriant: cyclohexane/ethyl acetate 9: 1) purified product.
Productive rate: 18g (theoretical yield 73%)
1H-NMR(300MHz，CDCl
3)：δ＝2.4(s，3H)，7.6(m，2H)，8.6(s，1H)ppm.
Embodiment 5A
5-(methylol)-2-pyridine carbonitrile
(13g 110mmol) is dissolved in the 400ml tetracol phenixin, and adds 29.4g (165mmol) N-bromosuccinimide and 0.4g (1.6mmol) dibenzoyl peroxide with embodiment 4A compound.Reaction mixture refluxed three hours is cooled to room temperature and filtration.Wash this solution with sodium thiosulfate solution, dried over mgso, and solvent removed in vacuo.Residue is dissolved in 200ml diox and the 200ml water, and (44g 440mmol), and stirs this mixture 2 hours down in refluxing to add lime carbonate.After being cooled to room temperature, filter this mixture, and add methylene dichloride.After being separated, organic phase dried over mgso, and solvent removed in vacuo.With column chromatography (silicon-dioxide, elutriant: cyclohexane/ethyl acetate 2: 1) purified product.
Productive rate: 5.2g (theoretical yield 35%)
1H-NMR(300MHz，DMSO-d
6)：δ＝4.7(d，2H)，5.6(t，1H)，8.0(m，2H)，8.7(s，1H)ppm.
Preparation embodiment:
Embodiment 1
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 7.0g (34.29mmol) N-[3-(trifluoromethyl) phenyl] urea, 8.99g (68.58mmol) 4-cyanobenzaldehyde, 8.92g (68.58mmol) ethyl 3-oxobutanoate and 20g Tripyrophosphoric acid ethyl ester be suspended among the 250mlTHF.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo, and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 13.4g (91%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；4.0(q，2H)；5.4(d，1H)；7.6(m，3H)；7.7(m，3H)；7.9(m，2H)；8.4(d，1H)ppm.
Embodiment 2
4-{5-ethanoyl-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-4-pyrimidyl } cyanobenzene
With 265mg (1.3mmol) N-[3-(trifluoromethyl) phenyl] urea, 131mg (1.0mmol) 4-cyanobenzaldehyde and 100mg (1.0mmol) 2, the 4-diacetylmethane is suspended among the 2mlTHF, and adds the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 29mg (7%)
1H-NMR(200MHz，DMSO-d
6)：δ＝2，0(s，3H)；2.2(s，3H)；5.5(d，1H)；7.5(m，1H)；7.6(m，3H)；7.7(m，1H)；7.8(m，1H)；7.9(m，2H)；8.5(d，1H)ppm.
Embodiment 3
4-(4-bromophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 204mg (1.0mmol) N-[3-(trifluoromethyl) phenyl] urea, 142mg (0.77mmol) 4-bromobenzaldehyde and 100mg (0.77mmol) ethyl 3-oxobutanoate be suspended among the 2mlTHF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 23mg (6%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；4.0(q，2H)；5.3(d，1H)；7.4(m，2H)；7.6(m，3H)；7.7(m.3H)；8.3(d，1H)ppm.
Embodiment 4
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[4-fluorophenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 154mg (1.0mmol) N-[4-fluorophenyl] urea, 101mg (0.77mmol) 4-cyanobenzaldehyde and 100mg (0.77mmol) ethyl 3-oxobutanoate be suspended among the 2mlTHF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 40mg (14%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；4.0(q，2H)；5.3(d，1H)；7.3(m，4H)；7.5(m，2H)；7.9(m，2H)；8.3(d，1H)ppm.
Embodiment 5
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-chloro-phenyl-]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 170mg (1.0mmol) N-[3-chloro-phenyl-] urea, 100mg (0.77mmol) 4-cyanobenzaldehyde and 100mg (0.77mmol) ethyl 3-oxobutanoate be suspended among the 2mlTHF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 13mg (4%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.1(s，3H)；4.0(q，2H)；5.3(d，1H)；7.2(m，1H)；7.4(m，3H)；7.5(m，2H)；7.9(m，2H)；8.3(d，1H)ppm.
Embodiment 6
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid (1S)-2-methoxyl group-1-methyl-2-oxoethyl ester
With 200mg (0.98mmol) N-[3-(trifluoromethyl) phenyl] urea, 129mg (0.98mmol) 4-cyanobenzaldehyde, 92mg (0.49mmol) 3-ketobutyric acid (1S)-2-methoxyl group-1-methyl-2-oxoethyl ester and 295mg Tripyrophosphoric acid ethyl ester be suspended among the 3mlTHF.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.Obtain non-enantiomer mixture.
Productive rate: 96mg (40%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.3(d，3h)；1.4(d，3H)；2.0(s，3H+3H)；3.6(s，3H)；3.6(s，3H)；5.0(m，1H+1H)；5.4(m，1H+1H)；7.6-7.9(m，8H+8H)；8.4(m，1H+1H)ppm.
Embodiment 7
4-{6-methyl-5-(4-morpholinyl carbonyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-4-pyrimidyl } cyanobenzene
With 150mg (0.73mmol) N-[3-(trifluoromethyl) phenyl] urea, 96mg (0.73mmol) 4-cyanobenzaldehyde, 63mg (0.37mmol) 4-(4-morpholinyl)-4-oxo-2-butanone and 220mg Tripyrophosphoric acid ethyl ester be suspended among the 3ml THF.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the methylene chloride with silicon-dioxide column chromatography purification residue.
Productive rate: 28mg (16%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.5(s，3H)；3.1(m，4H)；3.6(m，4H)；5.3(br.s，1H)；7.6(m，2H)；7.7(m，1H)；7.8(m，2H)；7.9(m，2H)；8.0(br.s，1H)ppm.
Embodiment 8
4-(4-cyano-phenyl)-N, N-diethyl-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidine carboxamide
With 200mg (0.98mmol) N-[3-(trifluoromethyl) phenyl] urea, 128mg (0.98mmol) 4-cyanobenzaldehyde, 77mg (0.49mmol) 4-(4-diethylamino)-4-oxo-2-butanone and 295mg Tripyrophosphoric acid ethyl ester be suspended among the 3ml THF.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the methylene chloride with silicon-dioxide column chromatography purification residue.
Productive rate: 106mg (47%)
1H-NMR(300MHz，DMSO-d
6)：δ＝0.9(m，6H)；3.1(m，4H)；5.2(br.s，1H)；7.6(m，2H)；7.7(m，1H)；7.8(m，2H)；7.9(m，2H)；8.0(brs，1H)ppm.
Embodiment 9
6-amino-4-(4-cyano-phenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidine formonitrile HCN
With 400mg (1.97mmol) N-[3-(trifluoromethyl) phenyl] urea, 199mg (1.51mmol) 4-cyanobenzaldehyde and 100mg (1.51mmol) propane dinitrile be suspended among the 2ml THF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the methylene chloride with silicon-dioxide column chromatography purification residue.
Productive rate: 4mg (1%)
1H-NMR(400MHz，DMSO-d
6)：δ＝5.2(d，1H)；6.0(s，2H)；7.6(m，3H)；7.7(m，2H)；7.8(m，1H)；7.9(m，2H)8.4(d，1H)ppm，
Embodiment 10
4-(4-cyano-phenyl)-3-formyl radical-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
100mg (0.23mmol) embodiment 1 compound is dissolved in the 1ml dimethyl formamide, and adds 35.7mg (0.23mmol) phosphoryl chloride.This reaction mixture stirred two hours in 70 ℃.After being cooled to room temperature, product separates with preparation HPLC.
Productive rate: 43mg (41%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.1(s，3H)；4.1(q，2H)；6.4(s，1H)；7.6(m，2H)；7.7(m，1H)；7.8(m，1H)；7.9(m，4H)；9.2(s，1H)ppm.
Embodiment 11
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid
Embodiment 1 compound of 3g (7mmol) is dissolved in the mixture of ethanolic soln of 50ml water and 100ml 5%KOH.This reaction mixture was in stirring at room 18 hours.Solvent removed in vacuo and be elutriant with the methylene chloride with silicon-dioxide column chromatography purification residue.
Productive rate: 1.27g (45%)
1H-NMR(300MHz，DMSO-d
6)：δ＝2.0(s，3H)；5.4(d，1H)；7.6(m，1H)；7.6(m，2H)；7.7(m，1H)；7.8(m，1H)；7.9(m，3H)；8.3(d，1H)；12.5(s，1H)ppm.
Embodiment 12
4-(4-cyano-phenyl)-6-methyl-2-oxo-N-propyl group-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidine carboxamide
Embodiment 11 compounds of 40mg (0.1mmol) are dissolved in the 2ml dimethyl formamide, and add 7mg (0.11mmol) Tri N-Propyl Amine, 15mg (0.11mmol) 1-hydroxyl-1H-benzotriazole hydrate and 12mg (0.1mmol) 4-dimethylaminopyridine.This reaction mixture adds 21mg (0.11mmol) hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide then in 0 ℃ of stirring.This reaction mixture adds entry and ethyl acetate then in stirring at room 18 hours.The saturated KHSO of organic phase
4The aqueous solution, water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 29mg (66%)
1H-NMR(300MHz，DMSO-d
6)：δ＝0.7(t，3H)；1.3(sext，2H)；1.7(s，3H)；3.0(q，2H)；5.4(d，1H)；7.6(m，3H)；7.7(m，2H)；7.8(m，2H)；7.9(m，1H)；8.1(d，1H)ppm.
Embodiment 13
4-(4-cyano-phenyl)-N-(2-methoxy ethyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidine carboxamide
Embodiment 11 compounds of 48mg (0.12mmol) are dissolved in the 2ml dimethyl formamide, add 10mg (0.13mmol) 2-methoxyethyl amine, 18mg (0.13mmol) 1-hydroxyl-1H-benzotriazole hydrate and 15mg (0.12mmol) 4-dimethylaminopyridine.This reaction mixture adds 25mg (0.13mmol) hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide then in 0 ℃ of stirring.This reaction mixture adds entry and ethyl acetate then in stirring at room 18 hours.The saturated KHSO of organic phase
4Solution, water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 22mg (40%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.7(s，3H)；3.2(s，3H)；3.3(m，4H)；5.4(d，1H)；7.6(m，3H)；7.7(m，3H)；7.9(m，2H)；8.1(m，1H)ppm.
Embodiment 14
4-(4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 1 compound of 89mg (0.21mmol) is joined in the suspension of 2ml THF of 12.4mg (0.31mmol) 60% sodium hydride (in mineral oil).This mixture was in stirring at room two hours.Add 26mg (0.21mmol) methyl-sulfate then, and with this mixture in room temperature restir two hours.Add entry and ethyl acetate then, organic phase water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 85mg (93%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；2.8(s，3H)；4.0(q，2H)；5.5(s，1H)；7.6(m，3H)；7.7(m，1H)；7.8(m，2H)；7.9(m，2H)ppm.
Embodiment 15
3-ethanoyl-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 1 compound of 100mg (0.23mmol) is joined in the suspension of 2ml THF of 12mg (0.28mmol) 60% sodium hydride (in mineral oil).This mixture was in stirring at room two hours.Add 91mg (1.16mmol) Acetyl Chloride 98Min. then, and with this mixture in room temperature restir two hours.Add entry and ethyl acetate then, organic phase water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 93mg (85%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.2(t，3H)；2.1(s，3H)；2.5(s，3H)；4.2(m，2H)；6.7(s，1H)；7.4(m，1H)；7.5(m，2H)；7.6(m，1H)；7.7(m，1H)；7.8(m，1H)；7.9(m，2H)ppm.
Embodiment 16
6-(4-cyano-phenyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl) phenyl]-3,6-dihydro-1,5 (2H)-pyrimidine dicarboxylate
Embodiment 1 compound of 100mg (0.23mmol) is joined in the suspension of 2ml THF of 12mg (0.28mmol) 60% sodium hydride (in mineral oil).This mixture was in stirring at room two hours.Add 126mg (1.16mmol) chlorine ethyl-carbonate then, and with this mixture in room temperature restir two hours.Add entry and ethyl acetate then, organic phase water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 92mg (79%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.2(t，3H；t，3H)；2.1(s，3H)；4.2(m，2H)；4.3(q，2H)；6.4(s，1H)；7.4(m，1H)；7.5(m，3H)；7.7(m，1H)；7.8(m，1H)；7.9(m，2H)ppm.
Embodiment 17
4-(4-cyano-phenyl)-6-methyl isophthalic acid-(3-aminomethyl phenyl)-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 150mg (1.0mmol) N-[3-aminomethyl phenyl] urea, 101mg (0.77mmol) 4-cyanobenzaldehyde and 100mg (0.77mmol) ethyl 3-oxobutanoate be suspended among the 2ml THF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 8mg (3%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；2.3(s，3H)；4.0(q，2H)；5.3(d，1H)；7.0(m，2H)；7.2(m，1H)；7.3(m，1H)；7.6(m，2H)；7.9(m，2H)；8.2(d，1H)ppm.
Embodiment 18
4-(4-chloro-phenyl-)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 204mg (1.0mmol) N-[3-(trifluoromethyl) phenyl] urea, 108mg (0.77mmol) 4-chlorobenzaldehyde and 100mg (0.77mmol) ethyl 3-oxobutanoate be suspended among the 2ml THF, and add the concentrated hydrochloric acid of catalytic amount.This mixture stirred 18 hours down in refluxing.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 29mg (9%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；4.0(q，2H)；5.3(d，1H)；7.5(m，5H)；7.6(m，1H)；7.7(m，2H)；8.3(d，1H)ppm.
Embodiment 19
6-(brooethyl)-4-(4-cyano-phenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 1 compound of 3g (7mmol) is dissolved in the 100ml chloroform.Be added dropwise to 558mg (3.48mmol) bromine in 0 ℃.This mixture is in stirring at room two hours, solvent removed in vacuo then.With the cyclohexane/ethyl acetate is elutriant silicon-dioxide column chromatography purification residue.
Productive rate: 3.2g (90%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)；4.0(q，2H，d，1H)；4.6(br d，1H)；5.4(d，1H)；7.6(m，3H)；7.7(m，2H)；7.8(m，1H)；7.9(m，2H)；8.6(d，1H)ppm.
Embodiment 20
4-(4-cyano-phenyl)-6-[(diethylamino) methyl]-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 19 compounds of 20mg (0.04mmol) are dissolved in the 2ml acetone, and add 8mg (0.10mmol) diethylamine.This mixture is in stirring at room 18 hours, solvent removed in vacuo then.With preparation HPLC purifying residue.
Productive rate: 15mg (75%)
1H-NMR(300MHz，DMS0-d
6)：δ＝0.6(t，6H)；1.1(t，3H)；2.0(m，2H)；2.2(m，2H)；3.1(br d，1H)；3.9(br d，1H)；4.1(q，2H)；5.4(d，1H)；7.5(m，1H)；7.6(m，4H)；7.7(m，1H)；7.9(m，2H)ppm.
Embodiment 21
6-(anilino methyl)-4-(4-cyano-phenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 19 compounds of 50mg (0.10mmol) are dissolved in the 2ml acetone, and add 18mg (0.20mmol) aniline.This mixture is in stirring at room 18 hours, solvent removed in vacuo then.With preparation HPLC purifying residue.
Productive rate: 28mg (55%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.1(t，3H)；3.6(d/d，1H)；4.1(q，2H)；4.4(d/d，1H)；5.4(m，2H)；6.2(m，2H)；6.5(m，1H)；6.9(m，2H)；7.6(m，6H)；7.9(m，2H)；8.4(d，1H)ppm.
Embodiment 22
(+)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With preparation HPLC with the be separated enantiomer of embodiment 1 of chirality: the 100mg compound is dissolved in the 1.5ml ethyl acetate, and post KBD 8361 is (based on monomer N-methacryloyl-L-leucine-1-
The chirality silica gel selector switch of base acid amides is referring to EP-A-379917), 250mm * 20mm, eluent ethylacetate, flow velocity 25ml/min, 23 ℃ of temperature, sampling volume 2500 μ l detect 254nm.
1H-NMR(300MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；4.0(q，2H)；5.4(d，1H)；7.6(m，3H)；7.7(m，2H)；7.8(m，1H)；7.9(m，2H)；8.4(d，1H)ppm.
[α]
20=+3.3 ° (λ=589nm, methylene dichloride, c=535.0mg/100ml)
Embodiment 23
(-)-4-(4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 22 compounds of 100mg (0.23mmol) are joined in the suspension of 2ml THF of 14mg (0.35mmol) 60% sodium hydride (in mineral oil).This mixture was in stirring at room two hours.Add 29mg (0.23mmol) methyl-sulfate then, and with this mixture in room temperature restir two hours.Add entry and ethyl acetate then, organic phase water and salt water washing, dried over sodium sulfate and vacuum-evaporation are to doing.Product is elutriant silicon-dioxide column chromatography purification with the cyclohexane/ethyl acetate.
Productive rate: 76mg (74%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t,3H)；2.0(s，3H)；2.8(s，3H)；4.0(q，2H)；5.5(s，1H)；7.6(m，3H)；7.7(m，1H)；7.8(m，2H)；7.9(m，2H)ppm.
[α]
20=-18.1 ° (λ=589nm, methylene dichloride, c=530.0mg/100ml)
Embodiment 24
4-(6-cyano group-3-pyridyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
To the embodiment 3A compound that is stirring (76mg, add in tetrahydrofuran (THF) 0.58mmol) (5ml) solution ethyl 3-oxobutanoate (75mg, 0.58mmol), N-[3-(trifluoromethyl) phenyl] urea (118mg, 0.58mmol) and Tripyrophosphoric acid ethyl ester (200mg; According to Cava etc., J.Org.Chem.1969,34,2665 method prepared fresh).This reaction mixture refluxed two days (48 hours), this solution is used DMSO (2ml) dilution and is used the preparation HPLC purifying then.Vacuum concentration product part and be elutriant silicon-dioxide column chromatography once more with the cyclohexane/ethyl acetate.
Productive rate: 92mg (theoretical yield 35%)
MS(ESIpos)：m/z＝431(M+H)
+
HPLC (method 4)=4.63min
1H-NMR (300MHz, DMSO-d
6): δ=8.76 (s, 1H), 8.36 (d, 1H), 8.16-8.00 (m, 2H), 7.83-7-74 (m, 2H), 7.75-7.58 (m, 2H), 5.47 (d, 1H), 4.03 (quartet, 2H), 2.06 (s, 3H), 1.08 (t, 3H) ppm.
Embodiment 25
4-{5-(1H-imidazoles-1-base carbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-4-pyrimidyl } cyanobenzene
In the 5ml anhydrous dimethyl formamide solution of 501mg (1.25mmol) embodiment 11 compounds, add 567mg (3.5mmol) N, N-carbonyl dimidazoles.With this reaction mixture place spend the night after, solvent is fallen in vacuum-evaporation.Residue obtained with acetic acid ethyl dissolution and water and salt water washing.After dried over mgso, solvent is fallen in vacuum-evaporation.
Productive rate: 500mg (theoretical yield 88.6%)
MS(EI)：m/z＝452(M+H)
+
1H-NMR(200MHz，DMSO-d
6)：δ＝1.40(d，3H)，5.5(d，1H)，7.0(s，1H)，7.55-8.0(m，9H)，8.4(s，1H)，8.45(d，1H)ppm.
Embodiment 26
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-hydroxy methacrylate
45.1mg (0.1mmol) embodiment 25 compounds are joined in the 0.5ml ethylene glycol.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, this reaction mixture preparation HPLC purifying (post: Agilent Zorbax Extend C1820mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min 10%A, 2min 10%A, 6min 90%A, 7min 90%A, 7.1min10%A, 8min 10%A; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge and contain product part and vacuum concentration.
Productive rate: 22mg (theoretical yield 49.4%)
MS(EI)：m/z＝446(M+N)
+
1H-NMR (300MHz, DMSO-d
6): δ=2.05 (d, 3H), 3.5 (quartet, 2H), 3.95-4.15 (m, 2H), 4.75 (tr, 1H), 5.45 (d, 1H), 7.55-7.75 (m, 5H), 7.75 (d, 1H), 7.85 (d, 2H), 8.35 (d, 1H) ppm.
Embodiment 27
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(dimethylamino) ethyl ester
45.1mg (0.1mmol) embodiment 25 compounds are joined in 0.5ml2-(dimethylamino) ethanol.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, this reaction mixture preparation HPLC purifying (post: Agilent Zorbax Extend C18 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min 10%A, 2min 10%A, 6min90%A, 7min90%A, 7.1min10%A, 8min 10%A; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 24mg (theoretical yield 50.8%)
MS(EI)：m/z＝473(M+H)
+
1H-NMR(300 MHz，DMSO-d
6)：δ＝2.05(d，3H)，2.1(s，6H)，2.4(m，2H)，4.1(m，2H)，5.35(d，1H)，7.55(d，1H)，7.6(d，2H)，7.7(m，2H)，7.8(d，1H)，7.85(d，2H)，8.35(d，1H)ppm.
Embodiment 28
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(4-pyridyl) ethyl ester
45.1mg (0.1mmol) embodiment 25 compounds are joined in 0.5ml 2-(4-pyridyl) ethanol.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, this reaction mixture preparation HPLC purifying (post: Agilent Zorbax Extend C1820mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min 10%A, 2min 10%A, 6min90%A, 7min 90%A, 7.1min 10%A, 8min 10%A; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 17mg (theoretical yield 33.5%)
MS(EI)：m/z＝507(M+H)
+
1H-NMR(300MHz，DMSO-d
6)：δ＝2.0(d，3H)，2.9(tr，2H)，4.3(tr，2H)，5.25(d，1H)，7.15(d，2H)，7.45(d，2H)，7.5(d，1H)，7.65(tr，2H)，7.8(m，3H)，8.35(d，1H)，8.4(d，2H)ppm.
Embodiment 29
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(2-pyridyl) ethyl ester
The compound of 45.1mg (0.1mmol) embodiment 25 is joined in 0.5ml2-(2-pyridyl) ethanol.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, this reaction mixture preparation HPLC purifying (post: Agilent Zorbax Extend C18 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min 10%A, 2min 10%A, 6min 90%A, 7min 90%A, 7.1min 10%A, 8min 10%A; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 22mg (theoretical yield 43.4%)
MS(EI)：m/z＝507(M+H)
+
1H-NMR(300MHz，DMSO-d
6)：δ＝2.0(d，3H)，3.0(tr，2H)，4.4(tr，2H)，5.25(d，1H)，7.15-7.25(m，2H)，7.4(d，2H)，7.5(d，1H)，7.6-7.75(m，3H)，7.8(m，3H)，8.3(d，1H)，8.45(d，1H)ppm.
Embodiment 30
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(2-OXo-1-pyrrolidine base) ethyl ester
45.1mg (0.1mmol) embodiment 25 compounds are joined in 0.5ml 1-(2-hydroxyethyl)-2-Pyrrolidone.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, this reaction mixture preparation HPLC purifying (post: Agilent Zorbax Extend C1820mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min10%A, 2min 10%A, 6min 90%A, 7min 90%A, 7.1min 10%A, 8min10%A; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 25mg (theoretical yield 48.8%)
MS(EI)：m/z＝513(M+H)
+
1H-NMR (300MHz, DMSO-d
6): δ=1.8 (quintet, 2H), 2.0 (d, 3H), 2.1 (tr, 2H), 3.2 (tr, 2H), 3.4 (tr, 2H), 4.0-4.2 (m, 2H), 5.35 (d, 1H), 7.55 (d, 1H), 7.6 (d, 2H), 7.7 (tr, 2H), 7.8 (d, 1H), 7.9 (d, 2H), 8.4 (d, 1H) ppm.
Prepare following compound with the method that is similar to embodiment 14-16:
Prepare following compound with the method that is similar to embodiment 6-8:
Embodiment 59
4-(4-cyano-phenyl)-6-methyl-3-[2-(4-morpholinyl)-2-oxoethyl]-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Embodiment 44 compounds of 80mg (0.16mmol) are dissolved in the 2ml dimethyl formamide, add 16mg (0.18mmol) morpholine, 24mg (0.18mmol) 1-hydroxyl-1H-benzotriazole hydrate and 20mg (0.16mmol) 4-dimethylaminopyridine.This reaction mixture adds 35mg (0.18mmol) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride then in 0 ℃ of stirring.This reaction mixture adds entry and ethyl acetate then in stirring at room 18 hours.Organic phase is extremely done with dried over sodium sulfate and vacuum-evaporation.As needs, product is further purified with column chromatography or preparation HPLC.
Productive rate: 78mg (85%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.1(t，3H)；2.0(s，3H)；3.4(m，4H)；3.6(m，4H)；3.7(d，1H)；4.1(m，2H)；4.5(d，1H)；5.5(s，1H)；7.6(m，5H)；7.8(m，1H)；7.9(m，2H)ppm.
Prepare following compound with the method that is similar to embodiment 59:
Prepare following compound with the method that is similar to embodiment 6-8:
Embodiment 70
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidine carboxamide
Embodiment 11 compounds of 200mg (0.5mmol) are dissolved in the 5ml tetrahydrofuran (THF), and adding 6mg (0.05mmol) 4-N, N-dimethyl aminopyridine, 77mg (0.6mmol) N, N-diisopropyl ethyl amine and 115mg (0.6mmol) phosphofluoric acid benzotriazole-1-base oxygen base-three (tetramethyleneimine-1-yl) is Phosphonium (pyrrolidino).This reaction mixture adds 5ml (2.5mmol) ammonia (for the 0.5M dioxane solution) then in stirring at room 15 minutes.This reaction mixture adds entry and ethyl acetate then in stirring at room 1 hour.Organic phase is extremely done with dried over sodium sulfate and vacuum-evaporation.Product is further purified with preparation HPLC.
Productive rate: 55mg (theoretical yield 28%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.8(s，3H)；5.4(d，1H)；7.2(br.s，1H)；7.4(br.s，1H)；7.6(m，5H)；7.7(m，1H)；7.9(m，2H)；8.1(d，1H)ppm.
Embodiment 71
(+)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid
Being separated with chirality with preparation HPLC, [post KBD8361 is (based on monomer N-methacryloyl-L-leucine-1-for the enantiomer of embodiment 11
The chirality silica gel selector switch of base acid amides is referring to EP-A-379917), 250mm * 20mm, elutriant: ethyl acetate → methyl alcohol → ethyl acetate, flow velocity 25ml/min, 23 ℃ of temperature detect 254nm].
1H-NMR(300MHz，DMSO-d
6)：δ＝2.0(s，3H)；5.4(d，1H)；7.6(m,1H)；7.6(m，2H)；7.7(m，1H)；7.8(m，1H)；7.9(m，3H)；8.3(d，1H)；12.5(s，1H)ppm.
[α]
20=+2.5 ° (λ=589nm, methyl alcohol, c=505mg/100ml).
Embodiment 72
(+)-4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-hydroxyethyl ester
Under argon gas, 1560mg (3.89mmol) embodiment 71 compounds are joined among the 19.6mlDMF.After adding 1.095ml (7.86mmol) triethylamine and 1.11ml (15.7mmol) ethylene bromohyrin, this reaction mixture stirred 8 hours in about 70 ℃.After the cooling, this reaction mixture vacuum concentration.With the acetic acid ethyl dissolution residue and wash with water.After dried over mgso, organic phase vacuum-evaporation.The residue obtained 8ml of using dissolve with methanol is also used preparation HPLC purifying (post: Nucleosil 100-5 C 18 Nautilus, 20 * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.3% formic acid; Gradient: 0min 10%A, 2min 10%A, 6min 90%A, 7min90%A, 7.1min 10%A, 8min 10%A; Wavelength: 220nm; Sampling volume: about 500 μ 1; Sample introduction number of times: 18).Merge the part and the freeze-drying that contain product.
Productive rate: 1290mg (theoretical yield 74.5%)
MS(EI)：m/z＝446(M+H)
+
1H-NMR (300MHz, DMSO-d
6): δ=2.05 (d, 3H); 3.5 (quartet, 2H); 3.95-4.15 (m, 2H); 4.75 (tr, 1H); 5.45 (d, 1H); 7.55-7.75 (m, 5H); 7.75 (d, 1H); 7.85 (d, 2H); 8.35 (d, 1H) ppm.
[α]
20=+14.3 ° (λ=589nm, methyl alcohol, c=455mg/100ml).
Embodiment 73
5-{5-ethanoyl-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-4-pyrimidyl }-the 2-pyridine carbonitrile
To the embodiment 3A compound (75mg that is stirring, 0.57mmol) tetrahydrofuran (THF) (5ml) solution in add 2,4-diacetylmethane (57mg, 0.57mmol), N-[3-(trifluoromethyl) phenyl] urea (116mg, 0.57mmol) and Tripyrophosphoric acid ethyl ester (200mg) according to Cava etc., J.Org.Chem.34,2665 (1969) described method prepared fresh].This reaction mixture refluxed 24 hours, this solution is used DMSO (2m1) dilution and is used the preparation HPLC purifying then.
Productive rate: 101mg (theoretical yield 44%)
1H-NMR(200MHz，DMSO-d
6)：δ＝2.02(s，3H)；2.24(s，3H)；5.54(d，1H)；7.52-7.90(m，4H)；8.08(d，2H)；8.50(d，1H)；8.81(s，1H)ppm.
Embodiment 74
(+)-5-{5-ethanoyl-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-4-pyrimidyl }-the 2-pyridine carbonitrile
Being separated with chirality with preparation HPLC, [post KBD8361 is (based on monomer N-methacryloyl-L-leucine-1-for the enantiomer of embodiment 73
The chirality silica gel selector switch of base acid amides is referring to EP-A-379917), 250mm * 20mm, elutriant: ethyl acetate → methyl alcohol → ethyl acetate, flow velocity 25ml/min, 23 ℃ of temperature detect 254nm].
1H-NMR(300MHz，CDCl
3)：δ＝2.06(s，3H)；2.35(s，3H)；5.69(d，1H)；6.02(d，1H)；7.29-7.50(m,2H)；7.57-7.75(m，3H)；7.83(dd，1H)；8.74(d，1H)ppm.
MS(ESIpos)：m/z＝401(M+H)
+
[α]
20=+25.1 ° (δ=589nm, methyl alcohol, c=505mg/100ml).
Embodiment 75
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(2-pyridyl) methyl ester
In the 0.4ml anhydrous dimethyl formamide solution of 40.1mg (0.1mmol) embodiment 11 compounds, add 48.6mg (0.3mmol) N, N-carbonyl dimidazoles.This reaction mixture was placed after one hour, and the dilute with water reaction mixture is also used dichloromethane extraction.After dried over mgso, solvent is fallen in vacuum-evaporation.In residue, add 0.5ml (2-pyridyl) methyl alcohol.This reaction mixture stirred 1 hour in about 100 ℃.After the cooling, with this reaction mixture of preparation HPLC purifying (post: Nucleosil 100-5 C 18Nautilus 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% formic acid; Gradient: 0min 10%A, 2min 10%A, 6min 90%A, 7min 90%A, 7.1min 10%A, 8min 10%A; Flow velocity: 25ml/min; Wavelength: 220nm; Sampling volume: about 550 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 17mg (theoretical yield 34.5%)
MS(EI)：m/z＝493(M+H)
+
1H-NMR(300MHz，DMSO-d
6)：δ＝2.1(d，3H)；5.15(dd，2H)；5.45(d，1H)；7.05(d，1H)；7.3(dd，1H)；7.5-7.85(m，9H)；8.35(d，1H)；8.5(d，2H)ppm.
Embodiment 76
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid 2-(3-pyridyl) ethyl ester
In the 0.57ml anhydrous dimethyl formamide solution of 60.2mg (0.15mmol) embodiment 11 compounds, add 72.9mg (0.45mmol) N, N-carbonyl dimidazoles.This reaction mixture was placed after one hour, and the dilute with water reaction mixture is also used ethyl acetate extraction.After dried over mgso, solvent is fallen in vacuum-evaporation.In residue, add 185mg (1.5mmol) 2-(3-pyridyl) ethanol and 20 μ L (0.27mmol) triethylamines.This reaction mixture stirred 1 hour in 100 ℃.Dilute this reaction mixture with 0.4ml methyl alcohol then, filter and with preparation HPLC purifying (post: Nucleosil 100-5 C 18Nautilus 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% formic acid; Gradient: 0min10%A, 2min 10%A, 6min90%A, 7min 90%A, 7.1min 10%A, 8min10%A; Flow velocity: 25ml/min; Wavelength: 220nm; Sampling volume: about 550 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 44mg (theoretical yield 57.9%)
LC-MS (EI, method 5): m/z=507 (M+H)
+, R
t=3.19min.
Embodiment 77
4-(4-cyano-phenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid
Embodiment 14 compounds of 4.1g (9.25mmol) are dissolved in the 100ml ethanol.In this solution, add 6.2ml (27.6mmol) potassium hydroxide aqueous solution (25% weight).Placed 18 hours under this reaction mixture room temperature.And then add 12.4ml (55.2mmol) potassium hydroxide aqueous solution (25% weight) also with this reaction mixture stirring 2 hours.This reaction mixture of dilute with water is also used ethyl acetate extraction three times.The water order is with the 1N hcl acidifying and use ethyl acetate extraction.This latter's extraction liquid falls solvent with dried over mgso and vacuum-evaporation.Residue is elutriant silicon-dioxide column chromatography purification with the cyclohexane/ethyl acetate.
Productive rate: 1.5g (theoretical yield 39%)
MS(EI)：m/z＝416(M+H)
+
1H-NMR(300MHz，DMSO-d
6)：δ＝2.0(s，3H)；2.8(s，3H)；5.5(d，1H)；7.6-7.8(m，6H)；7.9(d，2H)；12.6(s，1H)ppm.
Prepare following compound with the method that is similar to embodiment 76:
1)In this case, the alcohol that uses is as solid and be reflected at 0.4ml DMF and advance under existing
Embodiment 102
4-(4-cyano-phenyl)-1-(3, the 5-dichlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
Under argon gas; 30.8mg (0.15mmol) N-(3, the 5-dichlorophenyl) urea was stirred 4 hours in 80 ℃ in the 0.5ml diox with 39.3mg (0.3mmol) 4-formyl radical cyanobenzene, 39mg (0.3mmol) ethyl 3-oxobutanoate and 90mg three silyl polyphosphates (trimethylsilylpolyphosphate).After adding a small amount of DMSO, filter this reaction mixture and use preparation HPLC purifying (post: Agilent Zorbax Extend C18 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% strong aqua; Gradient: 0min 10%A, 2min10%A, 6min 90%A, 7min 90%A, 7.1min 10%A, 8min 10%A; Flow velocity 25ml/min; Wavelength: 220nm; Sampling volume: about 500 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 38.1mg (theoretical yield 59%)
LC-MS (EI, method 7): m/z=431 (M+H)
+, R
t=4.14min.
Embodiment 103
6-methyl-4-(3-nitrophenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid ethyl ester
With 30.6mg (0.15mmol) N-[3-(trifluoromethyl) phenyl] urea and 45.3mg (0.3mmol) 3-nitrobenzaldehyde, 39mg (0.3mmol) ethyl 3-oxobutanoate and 90mg Tripyrophosphoric acid ethyl ester be [according to Cava etc., J.Org.Chem.
34, 2665 (1969) method prepared fresh] together in 0.5ml diox and 0.1ml DMF in 80 ℃ of joltings 18 hours.After adding 200 μ lDMF, filter this reaction mixture and use preparation HPLC purifying (post: Nucleosil 100-5C 18 Nautilus 20mm * 50mm, 5 μ m; Solvent orange 2 A: acetonitrile, solvent B: water+0.1% formic acid; Gradient: 0min 10%A, 2min 10%A, 6min 90%A, 7min 90%A, 7.1min 10%A, 8min 10%A; Flow velocity 25ml/min; Wavelength: 220nm; Sampling volume: about 800 μ l; Sample introduction number of times: 1).Merge the part and the vacuum concentration that contain product.
Productive rate: 34mg (theoretical yield 50.4%)
LC-MS (EI, method 6): m/z=450 (M+N)
+, R
t=3.94min.
Prepare following compound with the method that is similar to embodiment 102:
Embodiment 108
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-pyrimidine-5-formic acid 2-cyano ethyl ester
With 9.87g (48.3mmol) N-[3-(trifluoromethyl) phenyl] urea, 12.68g (96.68mmol) 4-cyanobenzaldehyde, 15g (96.68mmol) 3-ketobutyric acid (2-cyano ethyl) ester and 37.5g Tripyrophosphoric acid ethyl ester be suspended among the 250ml THF.This mixture refluxes and stirred 18 hours down.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 25g (theoretical yield 100%)
1H-NMR(200MHz，DMSO-d
6)：δ＝2.1(s，3H)；2.8(m，2H)；4.2(m，2H)；5.4(d，1H)；7.6(m，4H)；7.7(m，2H)；7.9(m，2H)；8.5(d，1H)ppm.
Embodiment 109
4-(4-cyano-phenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydrochysene-pyrimidine-5-formonitrile HCN
0.609g (1.52mmol) embodiment 70 compounds are dissolved in 60ml THF and add 1.24g (12.93mmol) (methoxycarbonyl sulfamyl)-triethyl ammonium-N-trimethyl-glycine.Stirred solvent removed in vacuo and be elutriant with the methylene chloride/methanol mixture with silicon-dioxide column chromatography purification residue under this reaction mixture room temperature 1 hour.
Productive rate: 249mg (theoretical yield 43%)
1H-NMR(300MHz，DMSO-d
6)：δ＝1.8(s，3H)；5.4(d，1H)；7.7(m，4H)；7.8(m，2H)；8.0(m，2H)，8.4(d，1H)ppm.
Embodiment 110
6-methyl-4-(4-nitrophenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3,4-tetrahydropyrimidine-5-ethyl formate
With 7.84g (38.4mmol) N-[3-(trifluoromethyl) phenyl] urea, 5.81g (38.4mmol) 4-nitrobenzaldehyde, 5.0g (38.4mmol) ethyl 3-oxobutanoate and 15g Tripyrophosphoric acid ethyl ester be suspended among the 100ml THF.This mixture refluxes and stirred 18 hours down.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the toluene/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 8.75g (theoretical yield 51%)
1H-NMR(200MHz，DMSO-d
6)：δ＝1.1(t，3H)，2.1(s，3H)；4.0(m，2H)；5.4(d，1H)；7.5-7.8(m，6H)；8.3(m，2H)；8.5(d，1H)ppm.
Embodiment 111
5-ethanoyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1-[3-(trifluoromethyl) phenyl]-1,2,3, the 4-tetrahydropyrimidine
With 0.407g (2.0mmol) N-[3-(trifluoromethyl) phenyl] urea, 0.302g (2.0mmol) 4-nitrobenzaldehyde, 0.2g (2.0mmol) 2,4-diacetylmethane and 0.4g Tripyrophosphoric acid ethyl ester are suspended among the 20ml THF.This mixture refluxes and stirred 18 hours down.After being cooled to room temperature, solvent removed in vacuo and be elutriant with the cyclohexane/ethyl acetate with silicon-dioxide column chromatography purification residue.
Productive rate: 0.302g (theoretical yield 36%)
1H-NMR(200MHz，DMSO-d
6)：δ＝2.0(s，3H)；2.2(s，3H)；5.5(d，1H)；7.5-7.8(m，6H)；8.3(m，2H)；8.5(d，1H)ppm.
The operation embodiment of C. relevant medicinal compositions
The compounds of this invention can be converted into medicinal preparations as follows:
Tablet
Form
(from BASF, Ludwigshafen is Germany) with the 2mg Magnesium Stearate for 100mg embodiment 1 compound, 50mg lactose (monohydrate), 50mg W-Gum (locality), 10mg polyvinylpyrrolidone (PVP 25).
The heavy 212mg of sheet, diameter 8mm, radius-of-curvature 12mm.
Preparation
The mixture of activeconstituents, lactose and starch is granulated with the 5%PVP aqueous solution (m/m).After the drying, with particle and Magnesium Stearate mixing 5min.This mixture is with conventional tabletting machine compressing tablet (tablet specification see on).The used pressure of compressing tablet is generally 15kN.
Oral suspensions
Form
1000mg embodiment 1 compound, 1000mg ethanol (96%), 400mg Rhodigel (from FMC, Pennsylvania, the xanthan gum of USA) and 99g water.
The 10ml oral suspensions provides the 100mg The compounds of this invention of single dose.
Preparation
Rhodigel is suspended in the ethanol and with activeconstituents joins in this suspension.Add entry under stirring.It is complete until the Rhodigel swelling to continue stir about 6h.
Claims (17)
1. general formula (I) compound or its salt,
Wherein
A represents phenyl ring or pyridine ring,
R
1And R
3Represent hydrogen separately,
R
2Represent fluorine, chlorine, bromine, nitro or cyano group,
R
4Represent cyano group, C
1-C
4-alkyl-carbonyl or C
1-C
4-alkoxy carbonyl, wherein C
1-C
4-alkoxy carbonyl can be selected from following group and be replaced: hydroxyl, C
1-C
4-alkoxyl group, C
1-C
4-alkoxy carbonyl, list-and two-C
1-C
4-alkylamino, heteroaryl and heterocyclic radical,
R
5Represent methylidene,
R
6Represent hydrogen, C
1-C
4-alkyl, list-or two-C
1-C
4-alkyl amino-carbonyl, C
1-C
4-alkyl-carbonyl or C
1-C
4-alkoxy carbonyl, wherein C
1-C
4-alkyl and C
1-C
4-alkoxy carbonyl can be selected from following group and be replaced: heteroaryl, hydroxyl, C
1-C
4-alkoxyl group, hydroxycarbonyl group, aminocarboxyl, list-and two-C
1-C
4-alkyl amino-carbonyl, amino, list-and two-C
1-C
4-alkylamino,
Wherein, the heteroaryl representative has 5-10 annular atoms and can reach 5 heteroatomic aromatic monocyclic or bicyclic radicals that are selected from S, O and N at most; Heterocyclic radical is represented monocycle or is encircled the non-aromatic heterocyclic group more, has 4-10 annular atoms and can reach 3 at most to be selected from N, O, S, SO and SO
2Heteroatoms and/or group,
Or
R
6Represent the following formula part
Wherein
R
6ABe selected from hydrogen and methyl,
R
7Represent trifluoromethyl or nitro,
And
Y
1, Y
2, Y
3, Y
4And Y
5Represent CH separately.
2. the general formula of claim 1 (I) compound, wherein A is phenyl or pyridyl.
3. claim 1 or 2 general formula (I) compound, wherein R
1Be hydrogen.
4. claim 1 or 2 general formula (I) compound, wherein R
2Be cyano group.
5. claim 1 or 2 general formula (I) compound, wherein R
3Be hydrogen.
6. claim 1 or 2 general formula (I) compound, wherein R
4Be the optional C that is replaced by hydroxyl
1-C
4-alkoxy carbonyl, or R wherein
4Be C
1-C
4-alkyl-carbonyl.
7. claim 1 or 2 general formula (I) compound, wherein R
5Be methyl.
8. claim 1 or 2 general formula (I) compound, wherein R
6Be hydrogen.
9. claim 1 or 2 general formula (I) compound, wherein R
7Be trifluoromethyl or nitro.
10. the compound of general formula (IA)
Wherein
Z represents CH or N, and
R
1, R
3, R
4And R
6Has among the claim 1-9 specified implication in each.
11. each the defined general formula (I) or (IA) method of compound among the synthetic respectively claim 1-10, described method is included in acid and exists down by single step reaction or successively general formula (II) compound, general formula (III) compound and general formula (IV) compound condensation are obtained general formula (IB) compound, optional general formula (IB) compound reacts with logical formula V compound in the presence of alkali subsequently
General formula (II) compound
Wherein
A, R
1And R
2Have among the claim 1-10 specified implication in each,
General formula (III) compound
Wherein
R
4And R
5Have among the claim 1-10 specified implication in each,
General formula (IV) compound
Wherein
R
3, R
7And Y
1-Y
5Have among the claim 1-10 specified implication in each,
General formula (IB) compound
Wherein
A, R
1-R
5, R
7And Y
1-Y
5Have among the claim 1-10 specified implication in each,
Logical formula V compound
R
6*-X (V)，
Wherein
R
6*Has among the claim 1-10 specified R in each
6Implication, but do not represent hydrogen, and
X represents leavings group, and it is selected from halogen, tosylate, methanesulfonates or sulfuric ester.
12. composition, described composition contain among at least a claim 1-10 general formula (I) that defines in each or (IA) acceptable diluent on compound and the pharmacology.
13. the composition of claim 12, described composition are used for the treatment of acute and chronic inflammatory, ischemia and/or reconstruction capability pathology.
14. preparation claim 12 and 13 method for compositions, it is characterized in that making among the claim 1-10 general formula (I) that defines in each or (IA) compound form suitable administration form with auxiliary material commonly used.
15. the general formula (I) that defines in each among the claim 1-10 or (IA) compound be used to prepare the purposes of medicine.
16. the purposes of claim 15, described purposes are used to prepare medicine acute and chronic inflammatory, ischemia and/or reconstruction capability pathology.
17. the purposes of claim 16, wherein said pathology are chronic obstructive pulmonary disease, acute coronary syndrome, Acute Myocardial Infarction or development in heart failure.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0220962.5 | 2002-09-10 | ||
| GB0220962A GB0220962D0 (en) | 2002-09-10 | 2002-09-10 | Heterocyclic derivatives |
| GB0226609.6 | 2002-11-14 | ||
| GB0315870.6 | 2003-07-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1732159A CN1732159A (en) | 2006-02-08 |
| CN100575346C true CN100575346C (en) | 2009-12-30 |
Family
ID=9943787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN03824983A Expired - Fee Related CN100575346C (en) | 2002-09-10 | 2003-08-28 | Pyrimidone derivatives is acute and chronic inflammatory, ischemia and reconstruction capability pathology as the medicine treatment |
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 |
|---|---|---|---|---|
| ES2433228T3 (en) * | 2009-07-10 | 2013-12-10 | Bayer Intellectual Property Gmbh | Indazolyl substituted dihydroisoxazolopyridines and methods of use thereof |
| WO2016146607A1 (en) * | 2015-03-18 | 2016-09-22 | Bayer Pharma Aktiengesellschaft | Method for producing (4s)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro pyrimidine-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
Non-Patent Citations (1)
| Title |
|---|
| A Combinatorial Approach of Highly EnantioselectiveAryl-Dihydropyrimidine Selectors for Chiral HPLC. FRECHET J M J ET AL.JOURNAL OF COMBINATORIAL CHEMISTRY,Vol.1 No.1. 1999 * |
Also Published As
| Publication number | Publication date |
|---|---|
| GT200300189A (en) | 2004-04-19 |
| GB0220962D0 (en) | 2002-10-23 |
| ZA200501964B (en) | 2006-05-31 |
| CN1732159A (en) | 2006-02-08 |
| GB0226609D0 (en) | 2002-12-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4708034B2 (en) | Pyrimidinone derivatives as therapeutic agents for acute and chronic inflammation, ischemia and remodeling processes | |
| US11685721B2 (en) | Human plasma kallikrein inhibitors | |
| EP1546113B1 (en) | Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory, ischaemic and remodelling processes | |
| JP5134248B2 (en) | Dihydropyridinone derivatives | |
| ES2314276T3 (en) | DERIVATIVES OF DIHYDROPIRIDINE FOR USE AS INHIBITORS OF ELASTASE OF HUMAN NEUTROPHILES. | |
| JP4825195B2 (en) | 1,4-Diaryl-dihydropyrimidin-2-one compounds and their use as human neutrophil elastase inhibitors | |
| DE69727308T2 (en) | HETEROCYCLENE DERIVATIVES INHIBIT FACTOR Xa | |
| JP4825194B2 (en) | 1,4-Diaryl-dihydropyrimidin-2-one compounds and their use as human neutrophil elastase inhibitors | |
| CN1582274B (en) | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade | |
| JP4619122B2 (en) | Dihydropyridinone derivatives as HNE inhibitors | |
| SK1272000A3 (en) | Heterocyclic derivatives which inhibit factor xa | |
| CN105073724A (en) | Phthalazines as potassium ion channel inhibitors | |
| JPH0710848B2 (en) | Pyridine-3-carboxamide derivative | |
| CN100575346C (en) | Pyrimidone derivatives is acute and chronic inflammatory, ischemia and reconstruction capability pathology as the medicine treatment | |
| BRPI0618231A2 (en) | benzene derivatives or their salts | |
| RU2376295C2 (en) | Derivatives of pyrimidinone and pharmaceutical composition on their basis, which has properties of human neutrophil elastase inhibitor | |
| JP4708025B2 (en) | Heterocyclic derivatives | |
| DE60103342T2 (en) | New pyridazines as endothelin antagonists | |
| WO2000061579A1 (en) | New endothelin converting enzyme inhibitors, their production and their use | |
| CZ2000293A3 (en) | Heterocyclic derivatives inhibiting Xa factor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1088304 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1088304 Country of ref document: HK |
|
| ASS | Succession or assignment of patent right |
Owner name: BAYER INTELLECTUAL PROPERTY GMBH Free format text: FORMER OWNER: BAYER PHARMACEUTICALS AG Effective date: 20130326 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: BAYER PHARMACEUTICALS AG Free format text: FORMER NAME: BAYER SCHERING PHARMA AG |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Berlin Patentee after: BAYER PHARMA AG Address before: Berlin Patentee before: Bayer Schering Pharma AG |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130326 Address after: German Monheim Patentee after: BAYER INTELLECTUAL PROPERTY GmbH Address before: Berlin Patentee before: BAYER PHARMA AG |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20091230 Termination date: 20180828 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |