JP4708034B2 - Pyrimidinone derivatives as therapeutic agents for acute and chronic inflammation, ischemia and remodeling processes - Google Patents

Description

Detailed Description of the Invention

  The present invention relates to novel heterocyclic derivatives, methods for their preparation, and their use, especially as agents for treating chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction and development of heart failure.

  In tissues such as arteries, ligaments, lungs and heart, elastin, a fibrous protein that accounts for a significant proportion of all protein content, can be hydrolyzed or classified as elastase Destroyed by a group of selected enzymes. Human leukocyte elastase (HLE, EC 3.4.21.37), also known as human neutrophil elastase (HNE), is a strongly glycosylated serine protease, human polymorphonuclear leukocytes (PMN) has been found in azurophilic granules. HNE is released from activated PMN and has been causally involved in the pathogenesis of acute and chronic inflammatory diseases. HNE can degrade a wide range of matrix proteins, including elastin and collagen, and in addition to these activities in connective tissue, HNE up-regulates IL-8 gene expression (Upregulation), edema formation, mucus gland hyperplasia and mucus hypersecretion. It also hydrolyzes the collagen structure, for example in the heart after acute myocardial infarction, or during the formation of heart failure, concomitantly damages endothelial cells and adheres to the endothelium. It acts as a mediator of tissue damage by promoting migration and affecting the adhesion process itself.

  Pulmonary diseases that HNE is believed to affect include pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema including emphysema caused by smoking, chronic obstructive pulmonary disease (COPD) And cystic fibrosis. In the case of cardiovascular disease, HNE increases the production of ischemic tissue damage that progresses to myocardial insufficiency after acute myocardial infarction and remodeling that occurs during development of heart failure. It is involved in remodeling processes. HNE has also been causally involved in rheumatoid arthritis, atherosclerosis, brain injury, cancer and related conditions where neutrophil involvement is implicated.

Accordingly, inhibitors of HLE activity have been found in many inflammatory diseases, particularly chronic obstructive pulmonary disease [R. A. Stockley, Neutrophils and Protease / Antiprotease Imbalance, Am. J. et al. Respir. Crit. Care 160 , S49-S52 (1999)] may be potentially useful. Inhibitors of HLE activity are also treated for acute myocardial syndrome, unstable angina, acute myocardial infarction and coronary artery bypass grafting (CABG) [C. P. Tiefenbacher et al. Inhibition of elastase improves myocardial function after recurrent ischemia and myocardial infarction in the rat heart. J. et al. Physiol. 433 , S563-S570 (1997); Dinerman et al. , Increased release of neutrophil elastase in unstable angina and acute myocardial infarction (J. Am. Coll. Cardiol. 15 , 1559-1563 (1990)], treatment of the formation of heart failure [S. J. et al. Gilbert et al. , Increased expression of pro-matrix metalloproteinase-9 and neutrophil elastase in canine dilated cardiomyopathy. Res. 34 , S377-S383 (1997)] and the treatment of atherosclerosis [Dollery et al. , Neutrophil elastase in human atherosclerotic plaques, Circulation 107 , 2829-2836 (2003)] in human atherosclerotic plaques.

5-Ethoxycarbonyl-1-phenyl-6-methyl-4- (3-nitrophenyl) -3,4-dihydropyrimidin-2 (1H) -one is described in J. Am. Heterocyclic Chem. 38 , 1051 (2001). No mention is made of the pharmacological activity of this compound.

［式中、
Ａは、アリール環またはヘテロアリール環を表し、
Ｒ^１、Ｒ^２およびＲ^３は、互いに独立して、水素、ハロゲン、ニトロ、シアノ、Ｃ_１−Ｃ_６−アルキル、ヒドロキシまたはＣ_１−Ｃ_６−アルコキシ（前記において、Ｃ_１−Ｃ_６−アルキルおよびＣ_１−Ｃ_６−アルコキシは、更に、ハロゲン、ヒドロキシおよびＣ_１−Ｃ_４−アルコキシから成る群から選択される１から３個の同一または異なる基で置換されてもよい）を表し、
Ｒ^４は、トリフルオロメチルカルボニル、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｃ_１−Ｃ_６−アルケノキシカルボニル（C₁-C₆-alkenoxycarbonyl)、ヒドロキシカルボニル、アミノカルボニル、モノ−またはジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニル、Ｃ_６−Ｃ_１０−アリールアミノカルボニル、アリールカルボニル、ヘテロアリールカルボニル、ヘテロシクリルカルボニル、ヘテロアリール、ヘテロシクリルまたはシアノ（前記において、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニルは、Ｃ_３−Ｃ_８−シクロアルキル、ヒドロキシ、Ｃ_１−Ｃ_４−アルコキシ、Ｃ_１−Ｃ_４−アルコキシカルボニル、ヒドロキシカルボニル、アミノカルボニル、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニル、Ｃ_１−Ｃ_４−アルキルカルボニルアミノ、（Ｃ_１−Ｃ_４−アルキルカルボニル）−Ｃ_１−Ｃ_４−アルキルアミノ、シアノ、アミノ、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノ、ヘテロアリール、ヘテロシクリルおよびトリ−（Ｃ_１−Ｃ_６−アルキル）−シリルから成る群から選択される１から３個の同一または異なる基で更に置換されてもよく、そして、前記において、ヘテロアリールカルボニル、ヘテロシクリルカルボニル、ヘテロアリールおよびヘテロシクリルは、更にＣ_１−Ｃ_４−アルキルで置換されてもよい）を表し、
Ｒ^５は、ハロゲン、ヒドロキシ、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルケノキシ、Ｃ_１−Ｃ_６−アルキルチオ、アミノ、モノ−およびジ−Ｃ_１−Ｃ_６−アルキルアミノ、アリールアミノ、ヒドロキシカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニルおよび基−Ｏ−Ｃ_１−Ｃ_４−アルキル−Ｏ−Ｃ_１−Ｃ_４−アルキルから成る群から選択される１から３個の同一または異なる基で置換されてもよいＣ_１−Ｃ_４−アルキルを表すか、
または、
Ｒ^５は、アミノを表し、
Ｒ^６は、水素、Ｃ_１−Ｃ_６−アルキル、ホルミル、アミノカルボニル、モノ−またはジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニル、Ｃ_３−Ｃ_８−シクロアルキルカルボニル、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｎ−（Ｃ_１−Ｃ_４−アルキルスルホニル）−アミノカルボニル、Ｎ−（Ｃ_１−Ｃ_４−アルキルスルホニル）−Ｎ−（Ｃ_１−Ｃ_４−アルキル）−アミノカルボニル、ヘテロアリール、ヘテロシクリル、ヘテロアリールカルボニルまたはヘテロシクリルカルボニル（前記において、Ｃ_１−Ｃ_６−アルキル、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニル、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、ヘテロアリールおよびヘテロシクリルは、アリール、ヘテロアリール、ヒドロキシ、Ｃ_１−Ｃ_４−アルコキシ、ヒドロキシカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、アミノカルボニル、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノカルボニル、アミノ、モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノ、Ｃ_１−Ｃ_４−アルキルカルボニルアミノ、トリ−（Ｃ_１−Ｃ_６−アルキル）−シリル、シアノ、Ｎ−（モノ−およびジ−Ｃ_１−Ｃ_４−アルキルアミノ−Ｃ_１−Ｃ_４−アルキル）−アミノカルボニル、Ｎ−（Ｃ_１−Ｃ_４−アルコキシ−Ｃ_１−Ｃ_４−アルキル）−アミノカルボニルおよびハロゲンから成る群から選択される１から３個の同一または異なる基で置換されてもよい）を表すか、
または、
Ｒ^６は、式：

（式中、
Ｒ^６Ａは、水素およびＣ_１−Ｃ_６−アルキルから成る群から選択され、
そして、
ｎは、１または２の整数を表す）の部分を表し、
Ｒ^７は、ハロゲン、ニトロ、シアノ、Ｃ_１−Ｃ_６−アルキル、ヒドロキシまたはＣ_１−Ｃ_６アルコキシ（前記において、Ｃ_１−Ｃ_６−アルキルおよびＣ_１−Ｃ_６−アルコキシは、更に、ハロゲン、ヒドロキシおよびＣ_１−Ｃ_４−アルコキシから成る群から選択される１から３個の同一または異なる基で置換されてもよい）を表し、
そして、
Ｙ^１、Ｙ^２、Ｙ^３、Ｙ^４およびＹ^５は、互いに独立して、ＣＨまたはＮを表し、ここで、この環は、０、１または２個の窒素原子を含む］の化合物に関する。 The present invention is directed to general formula (I):

[Where:
A represents an aryl ring or a heteroaryl ring,
R ¹ , R ² and R ³ are independently of each other hydrogen, halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy (wherein C ₁ -C _6- Alkyl and C ₁ -C ₆ -alkoxy may further be substituted with 1 to 3 identical or different groups selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ -alkoxy),
R ⁴ is trifluoromethyl _carbonyl, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - _{alkoxycarbonyl,} C 1 -C ₆ - alkenoxy carbonyl (C ₁ -C ₆ -alkenoxycarbonyl), hydroxycarbonyl, Aminocarbonyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano (wherein C ₁ -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, mono- - and di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 3 -C ₈ - cycloalkyl, _hydroxy, C 1 -C ₄ - alkoxy , _C 1 -C ₄ - Arukokishikaru Alkenyl, hydroxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 1 -C ₄ - _{alkylcarbonylamino, (C} 1 -C ₄ - alkylcarbonyl) _-C 1 -C ₄ - alkylamino, cyano, amino, mono- - and di _-C 1 -C ₄ - alkylamino, heteroaryl, heterocyclyl and tri - _(C 1 -C ₆ - alkyl) - 3 to 1, which is selected from the group consisting of silyl And in the foregoing, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl may be further substituted with C ₁ -C ₄ -alkyl)
R ⁵ is halogen, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkenoxy, C ₁ -C ₆ -alkylthio, amino, mono- and di-C ₁ -C ₆ -alkylamino, arylamino 1 to 3 identical or different groups selected from the group consisting of hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl and the group —O—C ₁ -C ₄ -alkyl-O—C ₁ -C ₄ -alkyl Represents C ₁ -C ₄ -alkyl optionally substituted by
Or
R ⁵ represents amino,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, formyl, aminocarbonyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₁ -C _{6- alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) -N- _(C 1 -C ₄ - Alkyl) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl (wherein C ₁ -C ₆ -alkyl, mono- and di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C _6- Alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, heteroaryl and Heterocyclyl is aryl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, amino, Mono- and di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylcarbonylamino, tri- (C ₁ -C ₆ -alkyl) -silyl, cyano, N- (mono- and di-C ₁ -C ₄ - alkylamino _-C 1 -C ₄ - alkyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkoxy _-C 1 -C ₄ - alkyl) - selected from the group consisting of aminocarbonyl and halogen May be substituted with 1 to 3 identical or different groups), or
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₆ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ is halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ alkoxy (wherein C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are further halogen Which may be substituted with 1 to 3 identical or different groups selected from the group consisting of hydroxy and C ₁ -C ₄ -alkoxy),
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another represent CH or N, wherein the ring contains 0, 1 or 2 nitrogen atoms.

  The compounds according to the invention can also exist in the form of their salts, hydrates and / or solvates.

  Physiologically acceptable salts are preferred in the present invention.

The physiologically acceptable salts according to the invention are non-toxic which are generally obtainable by reacting the compounds (I) with inorganic or organic bases or acids conventionally used for such purposes. Salt. The pharmaceutically acceptable salts of compound (I) are not limited, but examples include alkali metal salts such as lithium, potassium and sodium salts, alkaline earth metal salts such as magnesium and calcium salts, such as , Quaternary ammonium salts such as triethylammonium salt, acetate, benzenesulfonate, benzoate, dicarbonates, disulphates, ditartrates, borate, bromide (Bromides), carbonates, chlorides, citrate, dihydrochloride, fumarate, gluconate, glutamate, hexyl resorcinates, hydrobromide (hydrobromide: hydrobromides), hydrochloride, hydroxynaphthoates, iodides, isothionates, lactate, laur Phosphate, malate, maleate, mandelate, mesylate, methylbromides, methylnitrates, methylsulphates, nitrate, oleate, oxalate , Palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, succinate, tartrate, tosylate, valerate, and for pharmaceutical purposes Other salts used are included.

Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as, for example, hemi-, mono-, or dihydrate.

A solvate of the compound of the present invention or a salt thereof is a stoichiometric composition with the solvent of the compound of the present invention.

  The present invention includes both the respective enantiomers or diastereomers of the compounds of the invention and their individual salts and the corresponding racemates or diastereomeric mixtures thereof. Furthermore, according to the invention, all possible tautomers among the compounds mentioned above are included. Diastereomeric mixtures can be separated into their respective isomers by chromatographic methods. Racemates can be resolved into their respective enantiomers by either chromatographic methods or resolution on chiral phases.

  In the present invention, unless otherwise stated, substituents generally have the following meanings:

Alkyl generally represents a straight-chain or branched hydrocarbon group having 1 to 6, preferably 1 to 4, carbon atoms. Examples are not limited, but examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl. The same applies to groups such as alkoxy, alkylamino, alkoxycarbonyl and alkoxycarbonylamino.

Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylcarbonyl generally represents a straight or branched hydrocarbon group having from 1 to 6, preferably from 1 to 4, carbon atoms having a carbonyl function at the site of attachment. Examples are not limited, but examples include formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl, n-hexanoyl.

Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylamino represents an alkylamino group having one or two (independently selected) alkyl substituents, illustratively and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N- Represents isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl represents an alkylaminocarbonyl group having one or two (independently selected) alkyl substituents, illustratively and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylamino Carbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N -Methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylamino-carbonyl and N- n-he Representing the sill -N- methylaminocarbonyl.

Alkylsulfonyl generally represents a linear or branched hydrocarbon group having 1 to 6, preferably 1 to 4 carbon atoms having a sulfonyl function at the site of attachment. . Examples are not limited, but examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl.

Cycloalkyl generally represents a cyclic saturated hydrocarbon group having from 3 to 8, preferably from 3 to 6, carbon atoms. Examples are not limited, but examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Aryl itself and aryl in arylcarbonyl generally represents a mono- to tricyclic aromatic carbocyclic group having from 6 to 14 carbon atoms, illustratively and preferably phenyl, naphthyl and phenanthrenyl. Represents.

Arylcarbonyl illustratively and preferably represents benzoyl and naphthoyl (naphthoyl).

The heteroaryl itself and the heteroaryl in the heteroarylcarbonyl typically have from 5 to 10, preferably 5 or 6 ring atoms, and from S, O and N Represents an aromatic monocyclic or bicyclic group having up to 5, preferably up to 4, heteroatoms selected from the group consisting of, and illustratively and preferably thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl.

Heteroarylcarbonyl is illustratively and preferably thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrimidylcarbonyl, pyridazinylcarbonyl, indolyl Carbonyl, indazolylcarbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, quinolinylcarbonyl, and isoquinolinylcarbonyl are represented.

Heterocyclyl itself and heterocyclyl in heterocyclylcarbonyl generally have from 4 to 10, preferably from 5 to 8, ring atoms and up to 3, preferably up to 2 Monocyclic or polycyclic, preferably monocyclic or bicyclic having heteroatoms and / or hetero groups selected from the group consisting of N, O, S, SO and SO ₂ Represents a heterocyclic group that is non-aromatic. The heterocyclyl group may be saturated or partially unsaturated. Illustratively and preferably, O, such as tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl, Preference is given to 5- to 8-membered monocyclic saturated heterocyclyl groups having up to 2 heteroatoms selected from the group consisting of N and S.

Heterocyclylcarbonyl illustratively and preferably represents tetrahydrofuran-2-carbonyl, pyrrolidine-1-carbonyl, pyrrolidine-2-carbonyl, pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl, morpholinecarbonyl, perhydroazepinecarbonyl .

Halogen represents fluorine, chlorine, bromine and iodine.

When Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are stated to represent CH or N, CH is also a ring carbon atom substituted with the substituent R ³ or R ⁷ It shall represent.

  The symbol * adjacent to the bond indicates the bond site in the molecule.

（式中、
Ｒ^６Ａは、水素およびＣ_１−Ｃ_６−アルキルから成る群から選択され、
そして、
ｎは、１または２の整数を表す）の部分を表し、
Ｒ^７は、ハロゲン、ニトロ、シアノ、Ｃ_１−Ｃ_６−アルキル、ヒドロキシまたはＣ_１−Ｃ_６アルコキシ（前記において、Ｃ_１−Ｃ_６−アルキルおよびＣ_１−Ｃ_６−アルコキシは、更に、ハロゲン、ヒドロキシおよびＣ_１−Ｃ_４−アルコキシから成る群から選択される１から３個の同一または異なる基で置換されてもよい）を表し、
そして、
Ｙ^１、Ｙ^２、Ｙ^３、Ｙ^４およびＹ^５は、互いに独立して、ＣＨまたはＮを表し、ここで、この環は、０、１または２個の窒素原子を含む］の化合物に関する。 In another embodiment, the present invention provides a compound of general formula (I):
[Wherein, A represents an aryl ring or a heteroaryl ring,
R ¹ , R ² and R ³ are independently of each other hydrogen, halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy (wherein C ₁ -C _6- Alkyl and C ₁ -C ₆ -alkoxy may further be substituted with 1 to 3 identical or different groups selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ -alkoxy),
R ⁴ _is, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - _{alkoxycarbonyl,} C 1 -C ₆ - alkenoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono- - or di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 6 _{-C 10} - arylaminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, in heterocyclyl or cyano _(wherein, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, mono- -And di-C ₁ -C ₄ -alkylaminocarbonyl are C ₃ -C ₈ -cycloalkyl, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono - and di -C ₁ C ₄ - _{alkylaminocarbonyl,} C 1 -C ₄ - alkylcarbonylamino, amino, mono- - and di _-C 1 -C ₄ - alkylamino, heteroaryl, heterocyclyl and tri - _(C 1 -C ₆ - alkyl) - Which may be further substituted with 1 to 3 identical or different groups selected from the group consisting of silyl),
R ⁵ is halogen, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkenoxy, C ₁ -C ₆ -alkylthio, amino, mono- and di-C ₁ -C ₆ -alkylamino, arylamino 1 to 3 identical or different groups selected from the group consisting of hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl and the group —O—C ₁ -C ₄ -alkyl-O—C ₁ -C ₄ -alkyl Represents C ₁ -C ₄ -alkyl optionally substituted by
Or
R ⁵ represents amino,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, formyl, aminocarbonyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₁ -C _{6- alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) -N- _(C 1 -C ₄ - Alkyl) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl (wherein C ₁ -C ₆ -alkyl, mono- and di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C _6- Alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, heteroaryl and Heterocyclyl is aryl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, amino, Mono- and di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylcarbonylamino, tri- (C ₁ -C ₆ -alkyl) -silyl, cyano, N- (mono- and di-C ₁ -C ₄ - alkylamino _-C 1 -C ₄ - alkyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkoxy _-C 1 -C ₄ - alkyl) - selected from the group consisting of aminocarbonyl and halogen May be substituted with 1 to 3 identical or different groups), or
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₆ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ is halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ alkoxy (wherein C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are further halogen Which may be substituted with 1 to 3 identical or different groups selected from the group consisting of hydroxy and C ₁ -C ₄ -alkoxy),
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another represent CH or N, wherein the ring contains 0, 1 or 2 nitrogen atoms.

（式中、
Ｒ^６Ａは、水素およびＣ_１−Ｃ_４−アルキルから成る群から選択され、
そして、
ｎは、１または２の整数を表す）の部分を表し、
Ｒ^７は、ハロゲン、ニトロ、シアノ、トリフルオロメチル、トリフルオロメトキシ、メチルまたはエチルを表し、
そして、
Ｙ^１、Ｙ^２、Ｙ^３、Ｙ^４およびＹ^５は、それぞれ、ＣＨを表す］の化合物に関する。 In another embodiment, the present invention provides a compound of general formula (I):
[Wherein A represents a phenyl, naphthyl or pyridyl ring;
R ¹ , R ² and R ³ independently of one another represent hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,
R ⁴ represents C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono-C ₁ -C ₄ -alkylaminocarbonyl or cyano (in the above, C ₁ -C ₆ -Alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl and mono-C ₁ -C ₄ -alkylaminocarbonyl are C ₃ -C ₈ -cycloalkyl, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - represents alkylamino, from 1 selected from the group consisting of heteroaryl and heterocyclyl three identical or may be substituted with different groups), _- alkoxycarbonyl, amino, mono- - or di -C 1 _-C 4
R ⁵ represents methyl or ethyl,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl or heterocyclylcarbonyl ( in _the, C 1 -C ₆ - alkyl and _C 1 -C ₆ - alkoxycarbonyl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, cyano, amino, mono- - and di _-C 1 -C ₄ - substituted with one selected from the group consisting of alkylamino three identical or different radicals May be)
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl;
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each represent CH].

（式中、
Ｒ^６Ａは、水素およびメチルから成る群から選択される）の部分を表し、
Ｒ^７は、トリフルオロメチルまたはニトロを表し、
そして、
Ｙ^１、Ｙ^２、Ｙ^３、Ｙ^４およびＹ^５は、それぞれ、ＣＨを表す］の化合物に関する。 In another embodiment, the present invention provides a compound of general formula (I):
[Wherein A represents a phenyl or pyridyl ring;
R ¹ and R ³ each represent hydrogen,
R ² represents fluoro, chloro, bromo, nitro or cyano,
R ⁴ is cyano, C ₁ -C ₄ -alkylcarbonyl or C ₁ -C ₄ -alkoxycarbonyl (wherein C ₁ -C ₄ -alkoxycarbonyl is hydroxy, C ₁ -C ₄ -alkoxy, C _1- C 4 _- alkoxycarbonyl, mono- - and di -C 1 _-C 4 _- alkylamino, may be substituted with a group selected from the group consisting of heteroaryl and heterocyclyl) represents,
R ⁵ represents methyl,
R ⁶ is hydrogen, C ₁ -C ₄ -alkyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylcarbonyl or C ₁ -C ₄ -alkoxycarbonyl (wherein C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxycarbonyl are heteroaryl, hydroxy, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-C ₁ -C ₄ -alkylamino. Which may be substituted with a group selected from the group consisting of carbonyl, amino, mono- and di-C ₁ -C ₄ -alkylamino),
Or
R ⁶ has the formula:

(Where
R ^6A represents a moiety selected from the group consisting of hydrogen and methyl;
R ⁷ represents trifluoromethyl or nitro,
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each represent CH].

  In another embodiment, the invention relates to compounds of general formula (I), wherein A is phenyl or pyridyl.

In another embodiment, the present invention is concerned with compounds of general formula (I) wherein R ¹ is hydrogen.

In another embodiment, the present invention relates to a compound of general formula (I) wherein R ² is cyano, in particular A is phenyl or pyridyl and R ² is para to the central dihydropyrimidinone ring. It relates to compounds of general formula (I) which are cyano in position.

In another embodiment, the present invention is concerned with compounds of general formula (I) wherein R ³ is hydrogen.

In another embodiment, the invention relates to C ₁ -C ₄ -alkoxycarbonyl, especially 2-hydroxyethoxycarbonyl, wherein R ⁴ is optionally substituted with hydroxy, or R ⁴ is C ₁ -C ₄ -alkylcarbonyl, In particular it relates to compounds of general formula (I) which are methylcarbonyl.

In another embodiment, the present invention is concerned with compounds of general formula (I) wherein R ⁵ is methyl.

In another embodiment, the present invention is concerned with compounds of general formula (I) wherein R ⁶ is hydrogen.

In another embodiment, the present invention relates to a compound of general formula (I) wherein R ⁷ is trifluoromethyl or nitro, in particular a tri wherein R ⁷ is in the meta position relative to the central dihydropyrimidinone ring. It relates to compounds of general formula (I) which are fluoromethyl.

（式中、
Ｚは、ＣＨまたはＮを表し、そして、
Ｒ^１、Ｒ^３、Ｒ^４およびＲ^６は、上記に示す意味を有する）の化合物に関する。 In another embodiment, the present invention provides compounds of the general formula (IA):

(Where
Z represents CH or N, and
R ¹ , R ³ , R ⁴ and R ⁶ have the meanings indicated above.

Compounds of the invention where R ⁶ is hydrogen can be enolized to the corresponding hydroxyamidine:

(式中、
Ａ、Ｒ^１およびＲ^２は上記に示す意味を有する）の化合物を、一般式（ＩＩＩ）：

(式中、
Ｒ^４およびＲ^５は上記に示す意味を有する)の化合物および一般式（ＩＶ）：

(式中、
Ｒ^３、Ｒ^７およびＹ^１からＹ^５は上記に示す意味を有する)の化合物と、酸の存在下で三成分/一工程反応で縮合させるか、または順々に縮合させて、一般式（ＩＢ）：

(式中、
Ａ、Ｒ^１からＲ^５、Ｒ^７およびＹ^１からＹ^５は上記に示す意味を有する）の化合物を生成させ、所望により続いて一般式（ＩＢ）の化合物を一般式（Ｖ）：
Ｒ^６＊−Ｘ （Ｖ），
（式中、
Ｒ^６＊は上記に示すＲ^６の意味を有するが、ただし水素を意味しない、
そして、
Ｘはハロゲン、トシラート（tosylate)、メシラート(mesylate)またはスルファート(sulfate)のような脱離基を表す）の化合物と塩基の存在下で反応させることにより合成することができる。 The compound of the general formula (I) is represented by the general formula (II):

(Where
A, R ¹ and R ² have the meanings indicated above) for the general formula (III):

(Where
R ⁴ and R ⁵ have the meanings indicated above) and the general formula (IV):

(Where
R ³ , R ⁷ and Y ¹ to Y ⁵ have the meanings indicated above) with a three-component / one-step reaction in the presence of an acid, or in turn condensed to form a compound of the general formula ( IB):

(Where
A, R ¹ to R ⁵ , R ⁷ and Y ¹ to Y ⁵ have the meanings indicated above), optionally followed by conversion of a compound of general formula (IB) to general formula (V):
R ^{6 *} -X (V),
(Where
R ^{6 *} has the meaning of R ⁶ shown above, but does not mean hydrogen,
And
X can be synthesized by reacting in the presence of a base with a compound of halogen, tosylate, mesylate, or a leaving group such as sulfate.

A compound of general formula (I) in which R ⁴ represents cyano, R ⁵ represents amino and R ⁶ represents hydrogen is another option: a compound of general formula (II) is a compound of general formula (IV) and Formula (VI):
_NC-CH 2 -CN (VI)
Can be prepared by condensing in a three-component / one-step reaction in the presence of an acid, or in sequence.

  Suitable solvents for step (II) + (III) / (VI) + (IV) → (IB) are generally customary organic solvents which do not change under the reaction conditions. These solvents include diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, ethers such as dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or methanol, ethanol, n-propanol, isopropanol, Included are alcohols such as n-butanol or t-butanol, or hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene or xylene, or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene. It is also possible to use mixtures of the solvents mentioned above. Tetrahydrofuran is preferred for this step.

  Suitable acids for step (II) + (III) / (VI) + (IV) → (IB) are customary inorganic or organic acids. Preferred such acids include, for example, carboxylic acids such as acetic acid or trifluoroacetic acid, eg sulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid, phosphoric acids such as hydrochloric acid or polyphosphoric acid. Preference is given to polyphosphoric acid ethyl ester. The acid is used in an amount of 0.25 mol to 100 mol with respect to 1 mol of the compound of the general formula (III).

  This step is generally performed in a temperature range from + 20 ° C. to + 150 ° C., preferably from + 60 ° C. to + 100 ° C.

  This step is generally performed at normal pressure. However, it is also possible to carry out under high pressure or reduced pressure (for example in the range from 0.5 bar to 5 bar).

  Suitable solvents for step (IB) + (V) → (I) are generally customary organic solvents which do not change under the reaction conditions. These solvents include ethers such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, or pentane, hexane, cyclohexane, benzene, toluene or Hydrocarbons such as xylene or halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane or chlorobenzene are included. It is also possible to use mixtures of the solvents mentioned above. Tetrahydrofuran is preferred for this step.

Suitable bases for step (IB) + (V) → (I) are common inorganic or organic bases. Preferred such bases include, for example, cyclic amines such as piperidine or 4-N, N-dimethylaminopyridine, or (C ₁ -C ₄ ) -trialkylamines such as triethylamine or diisopropylethylamine, or hydrogenation Hydrides such as sodium are included. Sodium hydride is preferred. Such a base is used in an amount of 0.1 mol to 10 mol, preferably 1 mol to 3 mol, relative to 1 mol of the compound of the general formula (IV).

  This step is generally carried out in the temperature range from 0 ° C. to + 150 ° C., preferably from + 20 ° C. to + 80 ° C., in particular at room temperature.

  This method is generally performed at normal pressure. However, it is also possible to carry out under high pressure or reduced pressure (for example in the range from 0.5 bar to 5 bar).

  The compounds of the general formulas (II), (III), (IV), (V) and (VI) are known per se or can be prepared by customary methods.

The above method can be illustrated by the following diagram:

  The compounds according to the invention exhibit an unpredictable useful pharmacological and pharmacokinetic activity spectrum. These compounds are therefore suitable for use as medicaments for the treatment and / or prevention of human and animal diseases.

  Surprisingly, the compounds of the present invention exhibit human neutrophil elastase (HNE) inhibitory activity and are therefore suitable for producing a medicament for treating diseases associated with HNE activity. Thus, the compounds of the present invention allow acute and chronic inflammatory processes such as rheumatoid arthritis, atherosclerosis, and especially pulmonary fibrosis, cystic fibrosis, pneumonia, acute Provide effective treatment of respiratory distress syndrome (ARDS), especially acute and chronic lung diseases such as emphysema, including emphysema caused by smoking, and chronic obstructive pulmonary disease (COPD), chronic bronchitis and bronchiectasis can do. The compounds of the present invention are further useful for cardiovascular ischemic diseases such as acute coronary syndromes, acute myocardial infarction, unstable and stable angina, coronary artery bypass grafting (CABG) and heart failure development. Prophylactic treatment, atherosclerosis, mitral valve disease, atrial septal defect, percutaneous transluminal coronary angioplasty (PTCA), effective treatment of inflammation after open heart surgery and effective treatment of pulmonary hypertension be able to. The compounds of the present invention are also used in rheumatoid arthritis, acute inflammatory arthritis, cancer, acute pancreatitis, ulcerative colitis, periodontal disease, Churg-Strauss syndrome (allergic granulomatous vasculitis), acute and chronic Atopic dermatitis, psoriasis, systemic lupus erythematosus, bullous pemphigoid, sepsis, alcoholic hepatitis, liver fibrosis, Behcet's disease, allergic fungal sinusitis, allergic sinusitis, clone Disease, Kawasaki disease, glomerulonephritis, acute pyelonephritis, colorectal disease, chronic suppurative otitis media, chronic venous leg ulcers, inflammatory bowel disease, bacterial and viral infections, brain injury, stroke and It can also prove useful for effective treatment of other pathologies where neutrophil involvement is implicated.

The present invention is further a least one of the compounds also show the invention, if preferred, to provide a drug that contains together with one or more pharmacologically safe excipient or carrier substances, It also provides its use for the above purposes.

  This active ingredient can act systemically and / or locally. For this purpose, it can be applied in any suitable manner, for example as oral, parenteral, lung, nasal, sublingual, tongue, buccal, rectal, transdermal, conjunctival, otic route, or implant .

  For these application routes, the active ingredient can be administered in suitable dosage forms.

  Useful oral application forms include, for example, tablets (uncoated tablets and coated tablets with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and Application forms that release active ingredients such as aerosols rapidly and / or in modified form are included.

  For parenteral application, avoid absorption steps (intravenous, intraarterial, intracardiac, intrathecal, or lumbar) or mediate absorption (intramuscular, subcutaneous, intradermal, transcutaneous or intraperitoneal) Can be done. Useful parenteral application forms include injections and infusions in the form of solutions, suspensions, emulsions, lyophilized and sterile powders.

  Suitable forms for other routes of application include, for example, inhaled pharmaceutical forms (including powder inhalers, nebulizers), nasal drops / solutions, sprays; tongues Tablets or capsules for sublingual or buccal administration, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions suspensions), ointments, creams, milks, pastes, dusting powders or implants.

  The active ingredient can be converted into the application forms described above in a manner known per se. This is done using inert non-toxic pharmaceutically suitable excipients. These include, among others, carriers (eg, microcrystalline cellulose), solvents (eg, liquid polyethylene glycol), emulsifiers (eg, sodium dodecyl sulphate), dispersants (eg, polyvinyl pyrrolidone), synthetic and natural Contains biopolymers (eg, albumin), stabilizers (eg, antioxidants such as ascorbic acid), colorants (eg, inorganic pigments such as iron oxide) or flavor and / or odor flavoring agents It is.

  For use in humans, it is recommended that a dosage of 0.001 to 50 mg / kg, preferably 0.01 mg / kg to 20 mg / kg be administered orally. For example, for parenteral administration such as nasal, buccal or inhalation intravenously or via mucosa, it may be recommended to use a dosage of 0.001 mg / kg to 0.5 mg / kg.

  However, in certain circumstances, it may be necessary to deviate from the above-mentioned amounts depending on the body weight, the route of application, the individual response to the active ingredient, the formulation method and the time or interval at which the application takes place. Thus, for example, it may be sufficient to use less than the minimum amount mentioned above, while in other cases the upper limit mentioned above will have to be exceeded. When larger amounts are applied, it may be desirable to divide these amounts into multiple individual dose ranges over the day.

  The percentages in the tests and examples described below are by weight unless otherwise stated, and parts are by weight. Solvent ratios, dilution ratios, and reported concentrations in liquid / liquid solutions are each based on volume.

A. Evaluation of physiological activity The possibility that the compound of the present invention inhibits neutrophil elastase activity can be demonstrated, for example, using the following assay.
I. In vitro enzyme assay of human neutrophil elastase (HNE)
Assay contents
Assay buffer: 0.1 M HEPES-NaOH buffer pH 7.4, 0.5 M NaCl, 0.1% (w / v) bovine serum albumin;
HNE (18 U / mg lyophil., # 20927.01, SERVA Electrophoresis GmbH, Heidelberg, Germany) at an appropriate concentration (see below) in assay buffer;
A substrate at the appropriate concentration in the assay buffer (see below);
Test compound at appropriate concentration diluted in assay buffer using 10 mM stock solution in DMSO.

Example A
In vitro inhibition of HNE using a fluorogenic peptide substrate (continuous read-out signal, 384 MTP assay format):
In the case of this protocol, MeOSuc-Ala-Ala-Pro-Val-AMC (# 324740, Calbiochem-Novabiochem Corporation, Merck KGaA, Darmstadt, Germany) is used as the elastase substrate. The test solution is 10 μl test compound dilution, 20 μl HNE enzyme dilution (final concentration 8-0.4 μU / ml, routinely 2.1 μU / ml) and 20 μl substrate dilution (final) The concentration is 1 mM-1 μM, usually 20 μM). This solution is incubated at 37 ° C. for 0-2 hours (usually 1 hour). The fluorescence of AMC released by the enzyme reaction is measured at 37 ° C. (TECAN fluorescence spectrum and plate reader). The rate of increase in fluorescence (ex. 395 nm, em. 460 nm) is proportional to elastase activity. IC ₅₀ values are determined by relative fluorescence intensity and inhibitory concentration plots (RFU-versus- [I] plots). K _m and K _{m (app.)} Values are determined by Lineweaver-Burk plots and converted to K _i values by Dixon plots.

In this assay, the prepared sample had an IC ₅₀ value in the range of 5 nM-5 μM. Representative data is shown in Table 1.
Table 1

Example B
In vitro inhibition of HNE using a fluorogen, insoluble elastin substrate (discontinuous read-out signal, 96 MTP assay format):
In this protocol, elastin-fluorescein (# 100620, ICN Biomedicals GmbH, Eschwege, Germany) is used as an elastase substrate. The test solution is 3 μl test compound dilution, 77 μl HNE enzyme dilution (final concentration 0.22 U / ml-2.2 mU / ml, usually 21.7 μU / ml) and 80 μl substrate suspension (final concentration 2 mg). / ml). This suspension is incubated at 37 ° C. for 0-16 hours (usually 4 hours) with slight shaking. To terminate the enzymatic reaction, 160 μl of 0.1 M acetic acid is added to the test solution (final concentration 50 mM). The polymerized elastin-fluorescein is precipitated by centrifugation (Eppendorf 5804 centrifuge, 3,000 rpm, 10 minutes). The supernatant is transferred to a new MTP, and then the fluorescence of peptide fluorescein released by the enzymatic reaction is measured (BMG Fluostar plate reader). The rate of fluorescence (ex. 490 nm, em. 520 nm) is proportional to the elastase activity. IC ₅₀ values are determined by relative fluorescence intensity and inhibitory concentration plots (RFU-versus- [I] plots).

II. In vitro human neutrophil assay
Example A
In vitro PMN elastolysis assay:
This assay is used to determine the elastolytic potential of human polymorphonuclear leukocytes (PMNs) and to assess the rate of degradation by neutrophil elastase [Z. W. She et al. , Am. J. et al. Respir. Cell. Mol. Biol. 9 , 386-392 (1993)].

Suspended tritiated elastin is applied to a 96 well plate at 10 μg per well. Test and reference [ZD-0892 (J. Med. Chem. 40 , 1876-1885, 3173-3181 (1997), WO95 / 21855) and α1 protease inhibitor (α1PI)] compounds are added to the wells at appropriate concentrations. Human PMNs are separated from the peripheral vein blood of healthy donors and then resuspended in culture medium. Neutrophils are added to the coated wells at concentrations ranging from 1 × 10 ⁶ to 1 × 10 ⁵ cells per well. Porcine pancreatic elastase (1.3 μM) is used as a positive control for this assay, and α1PI (1.2 μM) is used as a positive inhibitor for neutrophil elastase. Cellular controls are PMNs in the absence of compound at each appropriate cell density. The cells and compounds are incubated at 37 ° C. for 4 hours in a humidified incubator. Centrifuge the plate and collect only the cell supernatant. This supernatant is transferred in 75 μl volumes to the corresponding wells of a 96-well luma plate (Lumaplate ™ name: plate containing solid scintillant). The plate is dried until no liquid is visible in the well, then the information is read into a beta counter for 3 minutes per well.

^{Due to the} elastolysis of ³ H-elastin, the counts increase in the supernatant. Inhibiting this elastosis indicates that the amount of tritium in the supernatant is decreased from the viewpoint of cell control. α1PI is 1.2 μM (n = 3 (different donor) 3.6 × 10 ⁵ cells per well) at 83.46 ± 3.97% (standard error of the mean: mean ± sem). there were. IC ₅₀ value against reference compound ZD-0892 (n = 2 (different donor) 3.6 × 10 ⁵ cells per well) which is 45.50 ± 7.75 nM (mean ± sem) Obtained.

  In addition to this α1PI inhibition data, considering that ZD-0892 is a selective inhibitor of PMN elastase, these results indicate that the majority of elastin degradation by PMNs is due to the release of neutrophil elastase. It is shown that it is not due to other elastolytic enzymes such as matrix metalloproteases (MMPs). The compounds of the present invention are evaluated for the presence or absence of such inhibitory activity in this HNE-dependent model of neutrophil elastosis.

Example B
In vitro inhibition of membrane bound elastase:
Measurement of elastase inhibition binding to the neutrophil membrane is performed using a human neutrophil assay. Neutrophils are stimulated with LPS for 35 minutes at 37 ° C. and then spun at 1600 rpm. Membrane-bound elastase is then fixed to neutrophils with 3% paraformaldehyde and 0.25% glutaraldehyde for 3 minutes at 4 ° C. The neutrophils are then spun, then vehicle and evaluation compound are added, followed by the substrate MeOSuc-Ala-Ala-Pro-Val-AMC (# 324740, Calbiochem-Novabiochem Corporation, Merck). KGaA, Darmstadt, Germany) is added at 200 μM. After 25 minutes incubation at 37 ° C., the reaction is stopped with PMSF (phenylmethanesulfonyl fluoride) and then the fluorescence is read at ex: 400 nm, em: 505 nm. IC ₅₀ values are determined by interpolation from relative fluorescence intensity and inhibitory concentration plots.

III. In vivo model
Example A
In vivo model of acute lung injury in rats:
Human neutrophil elastase (HNE) is injected into the lungs of rats to cause acute lung injury. The extent of this injury can be estimated by measuring pulmonary hemorrhage.

  Rats are anesthetized with Hypnorm / hypnovel / water and HNE or saline is fed with a microsprayer and injected into the lungs. Test compounds are administered at specific times by intravenous injection, oral gavage, or inhalation followed by HNE. Sixty minutes after elastase administration, animals are killed by overdose anesthesia (sodium pentobarbitone) and then the lungs are lavaged with 2 ml of heparinised phosphate buffered saline (PBS). The bronchoalveolar lavage (BAL) volume is recorded and the sample is then placed on ice. Each BAL sample was 900 r. p. m. Centrifuge at. Discard the supernatant, resuspend the cell pellet in PBS, and spin down the sample again. The supernatant is again discarded and the cell pellet is resuspended in 1 ml of 0.1% cetyltrimethylammonium bromide (CTAB) / PBS to lyse the cells. Samples are frozen until assayed for blood content. Thaw and mix samples prior to haemorrhage assay. 100 μl of each sample is placed in a separate well of a 96 well flat bottom plate. All samples are tested in duplicate. 100 μl of 0.1% CTAB / PBS is included as a blank. The absorbance of the well contents is measured at 415 nm using a spectrophotometer. A standard curve is constructed by measuring the absorbance (OD) at 415 nm of different blood concentrations in 0.1% CTAB / PBS. Blood content values are calculated by comparing to a standard curve (included in each plate) and normalized to the recovered BAL fluid volume.

  The compound of the present invention is evaluated for its inhibitory activity in this HNE-induced bleeding model in rats by intravenous, oral or inhalation.

Example B
In vivo model of acute myocardial infarction in rats:
Elastase inhibitors are tested in a rat thread-infarct model. Male Wistar rats (weight> 300 g) are given 10 mg / kg aspirin and operated 30 minutes later. These rats were anesthetized with isofluran and they were ventilated (120-130 beats / min, stroke volume 200-250 μl; MiniVent Type 845, Hugo Sachs Elektronik, Germany) during the entire surgery. ) (Ventilated). After the left thoracotomy at the fourth intercostal space, the pericardium is opened and the heart is exposed briefly. The thread is turned in the left coronary artery (LAD) without occluding the artery. This thread passes under the skin to the animal's neck. The chest is closed and the animal is then allowed to recover for 4 days. On day 5, the rats are anesthetized with ether for 3 minutes, then the thread is tied and the LAD is occluded under ECG (electrocardiogram) control. Test compounds are administered orally, intraperitoneally or intravenously (bolus or continuous infusion) before or after LAD occlusion. After 1 hour occlusion, the thread is reopened and perfused. 48 hours by removing the heart and then coloring the heart re-occluded with Evans blue followed by TTC (triphenyltetrazolium chloride) staining of 2 mm heart sections. We will decide later. Normal oxygen (non-occluded tissue) areas (normoxic areas) are colored blue, ischemic (occluded but surviving tissue) areas (ischemic areas) are colored red and necrotic (occluded) The dead tissue) part (necrotic areas) remains white. Each tissue section is scanned and the infarct size is determined by computer planimetry.

B. Example
Abbreviations:
aq. Aqueous
conc. Concentrated
DMF N, N-dimethylformamide DMSO dimethyl sulfoxide EI Electron impact ionization (mass spectrometry)
ESI Electrospray ionization (mass spectrometry)
HPLC High pressure liquid chromatography LC-MS Liquid chromatograph mass spectrometry Mp. Melting point MS mass spectrometry NMR nuclear magnetic resonance spectrum of th. Theoretical (yield) _Rt retention time (HPLC)
THF tetrahydrofuran

General method:
All reactions were performed under an argon atmosphere unless otherwise stated. For the solvent, the solvent purchased from Aldrich was used without further purification. “Silica gel” or “silica” refers to silica gel 60 (0.040 mm-0.063 mm) from Merck KGaA company. Melting points are obtained using a Büch 512 or similar melting point apparatus and are not corrected.

  The compound purified by preparative HPLC was purified on a RP18-column using acetonitrile and water as eluent and a gradient of 1: 9 to 9: 1.

LC-MS / HPLC method:
LC-MS method 1
Instrument: Micromass Quattro LCZ, HP1100; Column: Upsphere HDO, 50 mm × 2.0 mm, 3 μm; Eluent A: Water + 0.05% formic acid, Eluent B: Acetonitrile + 0.05% formic acid; Gradient: 0.0 min 100 % A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; oven: 55 ° C .; flow rate: 0.8 ml / min; UV detection : 208-400 nm.

LC-MS method 2
Instrument: Waters Alliance 2790 LC; Column: Symmetry C18, 50 mm × 2.1 mm, 3.5 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0 min 5% B → 5.0 minutes 10% B → 6.0 minutes 10% B; temperature: 50 ° C .; flow rate: 1.0 ml / min; UV detection: 210 nm.

LC-MS method 3
Instrument: Micromass Platform LCZ, HP1100; Column: Aquasil C-18, 50 mm × 2.0 mm, 3 μm; Eluent A: Water + 0.05% Formic Acid, Eluent B: Acetonitrile + 0.05% Formic Acid; Gradient: 0.0 Min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; oven: 55 ° C .; flow rate: 0.8 ml / min; UV detection: 208-400 nm.

HPLC method 4
Instrument: HP1100 (with DAD detector); Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent: A = 5 ml HClO ₄ / l H ₂ O, B = acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; flow rate: 0.75 ml / min; temperature: 30 ° C .; UV detection: 210 nm.

LC-MS method 5
Instrument: Micromass TOF-MUX-interface Quadruple parallel injection-HPLC Waters 600; Column: Upsphere HDO, 50 mm × 2.0 mm, 3.0 μm; Eluent B: 1 l acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30 A → 3.1 min 10% A → 4.5 min 10% A → 4.6 min 100% A → 6.5 min 100% A; oven: room temperature; flow rate: 0.8 ml / min; UV detection: 210 nm.

LC-MS method 6
Instrument: Micromass Platform LCZ-HPLC Agilent Series 1100; Column: Grom-SIL 120 ODS-4HE, 50 mm × 2.0 mm, 3 μm; Eluent A: 1 l water + 1 ml 50% formic acid, eluent B: 1 l acetonitrile + 1 ml 50% formic acid; gradient : 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C .; 8 ml / min; UV detection: 208-400 nm.

LC-MS method 7
Instrument: Micromass Quattro LCZ-HPLC Agilent Series 1100; Column: Upsphere HDO, 50 mm × 2.0 mm, 3 μm; Eluent A: 1 l water + 1 ml 50% formic acid, Eluent B: 1 l acetonitrile + 1 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 minutes 100% A → 2.9 minutes 30% A → 3.1 minutes 10% A → 4.5 minutes 10% A; oven: 55 ° C .; flow rate: 0.8 ml / min; UV Detection: 208-400 nm.

６−ブロモ−３−ピリジンカルバルデヒド（6-Bromo-3-pyridinecarbaldehyde)（５００ｍｇ，２．７ｍｍｏｌ）と１，２−エタンジオール（２００ｍｇ，３．２ｍｍｏｌ）を、還流冷却器およびディーンスタークトラップ（Dean-Stark trap)を備えた丸底フラスコ中でアンバーリスト１５（Amberlyst 15)（１００ｍｇ）とともにトルエン（５０ｍｌ）中に溶解する。この溶液を終夜還流下で撹拌し、そのあと室温まで冷却し、濾過し、真空下で濃縮する。粗生成物を溶出剤としてシクロヘキサンと酢酸エチルを用いてシリカゲルでクロマトグラフィー処理すると、表題化合物を無色油状物として得る。
収量：０．４８９ｇ（理論収量の７９％）
ＨＰＬＣ（方法４）：３．４６分
ＭＳ（ＥＳＩｐｏｓ）：ｍ/ｚ＝２３１（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, CDCl₃): δ = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) ppm. Starting material:
Example 1A
2-Bromo-5- (1,3-dioxolan-2-yl) pyridine

6-Bromo-3-pyridinecarbaldehyde (500 mg, 2.7 mmol) and 1,2-ethanediol (200 mg, 3.2 mmol) were added to a reflux condenser and Dean Stark trap (Dean Dissolve in toluene (50 ml) with Amberlyst 15 (100 mg) in a round bottom flask equipped with a -Stark trap). The solution is stirred overnight at reflux, then cooled to room temperature, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel using cyclohexane and ethyl acetate as eluent to give the title compound as a colorless oil.
Yield: 0.489 g (79% of theoretical yield)
HPLC (Method 4): 3.46 min MS (ESIpos): m / z = 231 (M + H) ^+
1 H-NMR (300 MHz, CDCl ₃ ): δ = 8.46 (d, 1H), 7.64 (m, 1H), 7.49 (m, 1H), 4.15-4.00 (m, 4H) ppm.

実施例１Ａ（２．８ｇ，１２．５ｍｍｏｌ）、シアン化亜鉛（１．６ｇ，１３．８ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（１．４ｇ，１．３ｍｍｏｌ）をジメチルホルムアミド（１００ｍｌ）に溶解し、８０℃で終夜（１８時間）撹拌する。更にテトラキス（トリフェニルホスフィン）パラジウム（０）（０．１ｇ）を加え、反応を再び終夜（１８時間）８０℃で撹拌して行い、次いで、２日間（４８時間）室温で放置する。溶媒を真空下で除去し、残渣に水（１００ｍｌ）を加え、生成物を酢酸エチル（１ｌ）で抽出する。有機相を塩水（２００ｍｌ）で洗浄し、硫酸マグネシウム一水和物で乾燥し、濾過し、真空下で濃縮する。粗生成物を溶出剤としてシクロヘキサンと酢酸エチルを用いてシリカゲルでクロマトグラフィー処理すると、表題化合物を白色非晶形固形物として得る。
収量：０．９４ｇ（理論収量の４２％）
ＨＰＬＣ（方法４）：３．２１分
ＭＳ（ＥＳＩｐｏｓ）：ｍ/ｚ＝１７７（Ｍ＋Ｈ）^＋
1H-NMR (400 MHz, DMSO-d₆): δ = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4.13-3.94 (m, 4 H) ppm. Example 2A
5- (1,3-Dioxolan-2-yl) -2-pyridinecarbonitrile

Example 1A (2.8 g, 12.5 mmol), zinc cyanide (1.6 g, 13.8 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.4 g, 1.3 mmol) were added to dimethylformamide (100 ml). ) And stirred at 80 ° C. overnight (18 hours). Further tetrakis (triphenylphosphine) palladium (0) (0.1 g) is added and the reaction is again stirred overnight (18 hours) at 80 ° C. and then left at room temperature for 2 days (48 hours). The solvent is removed in vacuo, water (100 ml) is added to the residue and the product is extracted with ethyl acetate (1 l). The organic phase is washed with brine (200 ml), dried over magnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel using cyclohexane and ethyl acetate as eluents to give the title compound as a white amorphous solid.
Yield: 0.94 g (42% of theoretical yield)
HPLC (Method 4): 3.21 min MS (ESIpos): m / z = 177 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.81 (s, 1H), 8.09 (s, 2H), 5.95 (s, 1H), 4.13-3.94 (m, 4 H) ppm.

方法ａ）：
Ｄｏｄｄ，Ｄ．ｅｔ ａｌ．［Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９９２，５７，７２２６−７２３４］の手順に準じて製造される：アセトン/水 ８５：１５（５９．５ｍｌ）中の５−（１，３−ジオキソラン−２−イル）−２−ピリジンカルボニトリル（実施例２Ａ；８５０ｍｇ，４．８ｍｍｏｌ）の撹拌溶液に、パラ−トルエンスルホン酸（１０２ｍｇ，０．５９ｍｍｏｌ）を加える。反応を終夜（１８時間）還流下で撹拌し、次いで、更にパラ−トルエンスルホン酸（５０ｍｇ）および水（５ｍｌ）を加える。反応は更に４８時間還流下で撹拌する。この溶液を室温まで冷却し、次に、飽和重炭酸ナトリウム溶液でクエンチ（quenched)する。この生成物を酢酸エチル（１００ｍｌで３回）で抽出し、硫酸マグネシウム一水和物で乾燥し、濾過し、真空下で濃縮する。粗生成物を分取ＨＰＬＣで精製すると、淡黄色固形物を得る。
収量：０．６６ｇ（理論収量の９３％）
融点：８０−８２℃
ＨＰＬＣ（方法４）：２．１３分
ＭＳ（ＥＳＩｐｏｓ）：ｍ/ｚ＝１３３（Ｍ＋Ｈ）^＋
1H-NMR (400 MHz, DMSO-d₆): δ = 10.18 (s, 1H), 9.21 (m, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm. Example 3A
5-formyl-2-pyridinecarbonitrile

Method a):
Dodd, D.D. et al. [J. Org. Chem. 1992, 57, 7226-7234]: 5- (1,3-Dioxolan-2-yl) -2-pyridinecarbonitrile in acetone / water 85:15 (59.5 ml) ( To a stirred solution of Example 2A; 850 mg, 4.8 mmol) is added para-toluenesulfonic acid (102 mg, 0.59 mmol). The reaction is stirred overnight (18 hours) under reflux, then more para-toluenesulfonic acid (50 mg) and water (5 ml) are added. The reaction is stirred at reflux for a further 48 hours. The solution is cooled to room temperature and then quenched with saturated sodium bicarbonate solution. The product is extracted with ethyl acetate (3 x 100 ml), dried over magnesium sulfate monohydrate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC to give a pale yellow solid.
Yield: 0.66 g (93% of theoretical yield)
Melting point: 80-82 ° C
HPLC (Method 4): 2.13 min MS (ESIpos): m / z = 133 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.18 (s, 1H), 9.21 (m, 1H), 8.49 (m, 1H), 8.27 (m, 1H) ppm.

Method b):
1.04 g (8.2 mmol) of oxalylchloride is dissolved in 8 ml of dichloromethane. At −78 ° C., 1.28 g (16.4 mmol) of dimethyl sulfoxide are added dropwise. The solution is stirred at −78 ° C. for 20 minutes, then 1 g (7.46 mmol) of the compound of Example 5A dissolved in 7 ml of dichloromethane is added and stirring at −78 ° C. is continued for a further 2 hours. 3.4 g (33.6 mmol) of triethylamine are then added dropwise and then after warming to room temperature, the mixture is purified by column chromatography (silica, eluent cyclohexane to cyclohexane / ethyl acetate 2: 1).
Yield: 0.76 g (77% of theoretical yield)
Analysis data: see above

３６ｇ（２０９ｍｍｏｌ）の２−ブロモ−５−メチルピリジンと３７．５ｇ（４１８ｍｍｏｌ）のシアン化銅（copper cyanide)を５００ｍｌのジメチルホルムアミド中で２時間還流する。５０℃まで冷却した後、１０％アンモニア水溶液（５００ｍｌ）を撹拌しながら加える。生成物をジクロロメタンで抽出し、有機相を硫酸マグネシウムで乾燥し、次に、真空下で溶媒を除去する。生成物をカラムクロマトグラフィー（シリカ、溶出剤 シクロへキサン/酢酸エチル ９：１）によって精製する。
収量：１８ｇ（理論収量の７３％）
¹H-NMR (300 MHz, CDCl₃): δ= 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm. Example 4A
5-methyl-2-pyridinecarbonitrile

36 g (209 mmol) of 2-bromo-5-methylpyridine and 37.5 g (418 mmol) of copper cyanide are refluxed in 500 ml of dimethylformamide for 2 hours. After cooling to 50 ° C., 10% aqueous ammonia solution (500 ml) is added with stirring. The product is extracted with dichloromethane, the organic phase is dried over magnesium sulphate and then the solvent is removed under vacuum. The product is purified by column chromatography (silica, eluent cyclohexane / ethyl acetate 9: 1).
Yield: 18 g (73% of theoretical yield)
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 2.4 (s, 3H), 7.6 (m, 2H), 8.6 (s, 1H) ppm.

実施例４Ａの化合物（１３ｇ，１１０ｍｍｏｌ）を４００ｍｌのテトラクロロメタンに溶解し、次に、２９．４ｇ（１６５ｍｍｏｌ）のＮ−ブロモスクシンイミド（N-bromosuccinimide)と０．４ｇ（１．６ｍｍｏｌ）のジベンゾイルペルオキシド(dibenzoylperoxide)を加える。反応混合物を３時間還流し、そして室温まで冷却し、濾過する。この溶液を水性チオ硫酸ナトリウムで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空下で除去する。残渣を２００ｍｌのジオキサンおよび２００ｍｌの水に溶解し、炭酸カルシウム（４４ｇ，４４０ｍｍｏｌ）を加え、次に、この混合物を２時間還流下で撹拌する。室温まで冷却した後、混合物を濾過し、次に、ジクロロメタンを加える。相分離の後、有機相を硫酸マグネシウムで乾燥し、溶媒を真空下で除去する。生成物をクロマトグラフィー（シリカ、溶出剤 シクロヘキサン/酢酸エチル ２：１）によって精製する。
収量：５．２ｇ(理論収量の３５％）
¹H-NMR (300 MHz, DMSO-d₆): δ = 4.7 (d, 2H), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 (s, 1H) ppm. Example 5A
5- (Hydroxymethyl) -2-pyridinecarbonitrile

The compound of Example 4A (13 g, 110 mmol) was dissolved in 400 ml of tetrachloromethane, then 29.4 g (165 mmol) of N-bromosuccinimide and 0.4 g (1.6 mmol) of dichloride. Add dibenzoylperoxide. The reaction mixture is refluxed for 3 hours and cooled to room temperature and filtered. The solution is washed with aqueous sodium thiosulfate, dried over magnesium sulfate and the solvent removed in vacuo. The residue is dissolved in 200 ml dioxane and 200 ml water, calcium carbonate (44 g, 440 mmol) is added and the mixture is then stirred at reflux for 2 hours. After cooling to room temperature, the mixture is filtered and then dichloromethane is added. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed under vacuum. The product is purified by chromatography (silica, eluent cyclohexane / ethyl acetate 2: 1).
Yield: 5.2 g (35% of theoretical yield)
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 4.7 (d, 2H), 5.6 (t, 1H), 8.0 (m, 2H), 8.7 (s, 1H) ppm.

７．０ｇ（３４．２９ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素（N-[3-(trifluoromethyl)phenyl]urea)、８．９９ｇ（６８．５８ｍｍｏｌ）の４−シアノベンズアルデヒド、８．９２ｇ（６８．５８ｍｍｏｌ）のエチル ３−オキソブタノアート（ethyl 3-oxobutanoate)および２０ｇのポリリン酸エチルエステル（polyphosphoric acid ethyl ester)を２５０ｍｌのＴＨＦ中で懸濁させる。この混合物を１８時間還流下で撹拌する。室温まで冷却した後、溶媒を真空下で除去し、次に、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：１３．４ｇ（９１％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Manufacturing example:
Example 1
Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

7.0 g (34.29 mmol) N- [3- (trifluoromethyl) phenyl] urea (N- [3- (trifluoromethyl) phenyl] urea), 8.99 g (68.58 mmol) 4-cyanobenzaldehyde, 8.92 g (68.58 mmol) of ethyl 3-oxobutanoate and 20 g of polyphosphoric acid ethyl ester are suspended in 250 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is then purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 13.4 g (91%)
¹ H-NMR (200 MHz, 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.

２６５ｍｇ（１．３ｍｍｏｌ）のＮ−［３−（トリフルオロメチル)フェニル］尿素、１３１ｍｇ（１．０ｍｍｏｌ）の４−シアノベンズアルデヒド、および１００ｍｇ（１．０ｍｍｏｌ）の２，４−ペンタンジオンを２ｍｌのＴＨＦ中で懸濁させ、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：２９ｍｇ（７％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 2
4- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzonitrile

2 ml of 265 mg (1.3 mmol) N- [3- (trifluoromethyl) phenyl] urea, 131 mg (1.0 mmol) 4-cyanobenzaldehyde, and 100 mg (1.0 mmol) 2,4-pentanedione Suspend in THF and then add a catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 29 mg (7%)
¹ H-NMR (200 MHz, 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.

２０４ｍｇ（１．０ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、１４２ｍｇ（０．７７ｍｍｏｌ）の４−ブロモベンズアルデヒド、および１００ｍｇ（０．７７ｍｍｏｌ）のエチル ３−オキソブタノアートを２ｍｌのＴＨＦ中で懸濁させ、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：２３ｍｇ（６％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 3
Ethyl 4- (4-bromophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

2 ml of 204 mg (1.0 mmol) N- [3- (trifluoromethyl) phenyl] urea, 142 mg (0.77 mmol) 4-bromobenzaldehyde, and 100 mg (0.77 mmol) ethyl 3-oxobutanoate In THF and then a catalytic amount of concentrated hydrochloric acid is added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 23 mg (6%)
¹ H-NMR (200 MHz, 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.

１５４ｍｇ（１．０ｍｍｏｌ）のＮ−［４−フルオロフェニル］尿素、１０１ｍｇ（０．７７ｍｍｏｌ）の４−シアノベンズアルデヒド、および１００ｍｇ（０．７７ｍｍｏｌ）のエチル ３−オキソブタノアートを２ｍｌのＴＨＦ中で懸濁させ、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：４０ｍｇ（１４％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 4
Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [4-fluorophenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

154 mg (1.0 mmol) N- [4-fluorophenyl] urea, 101 mg (0.77 mmol) 4-cyanobenzaldehyde, and 100 mg (0.77 mmol) ethyl 3-oxobutanoate in 2 ml THF Suspend and then add a catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 40 mg (14%)
¹ H-NMR (200 MHz, 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.

１７０ｍｇ（１．０ｍｍｏｌ）のＮ−［３−クロロフェニル］尿素、１００ｍｇ（０．７７ｍｍｏｌ）の４−シアノベンズアルデヒドおよび１００ｍｇ（０．７７ｍｍｏｌ）の
エチル ３−オキソブタノアートを２ｍｌのＴＨＦ中で懸濁させ、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：１３ｍｇ（４％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 5
Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3-chlorophenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

170 mg (1.0 mmol) N- [3-chlorophenyl] urea, 100 mg (0.77 mmol) 4-cyanobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate were suspended in 2 ml THF. Then a catalytic amount of concentrated hydrochloric acid is added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 13 mg (4%)
¹ H-NMR (200 MHz, 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.

２００ｍｇ（０．９８ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、１２９ｍｇ（０．９８ｍｍｏｌ）の４−シアノベンズアルデヒド、９２ｍｇ（０．４９ｍｍｏｌ）の（１Ｓ）−２−メトキシ−１−メチル−２−オキソエチル ３−オキソブタノアート、および２９５ｍｇのポリリン酸エチルエステルを３ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。ジアステレオアイソマーの混合物が得られる。
収量：９６ｍｇ（４０％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 6
(1S) -2-Methoxy-1-methyl-2-oxoethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3 , 4-Tetrahydro-5-pyrimidinecarboxylate

200 mg (0.98 mmol) N- [3- (trifluoromethyl) phenyl] urea, 129 mg (0.98 mmol) 4-cyanobenzaldehyde, 92 mg (0.49 mmol) (1S) -2-methoxy-1- Methyl-2-oxoethyl 3-oxobutanoate and 295 mg of polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent. A mixture of diastereoisomers is obtained.
Yield: 96 mg (40%)
¹ H-NMR (200 MHz, 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.

１５０ｍｇ（０．７３ｍｍｏｌ）のＮ−［３−（トリフルオロメチル)フェニル］尿素、９６ｍｇ（０．７３ｍｍｏｌ）の４−シアノベンズアルデヒド、６３ｍｇ（０．３７ｍｍｏｌ）の４−（４−モルホリニル）−４−オキソ−２−ブタノンおよび２２０ｍｇのポリリン酸エチルエステルを３ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてジクロロメタン/メタノールを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：２８ｍｇ（１６％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 7
4- {6-Methyl-5- (4-morpholinylcarbonyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} benzo Nitrile

150 mg (0.73 mmol) N- [3- (trifluoromethyl) phenyl] urea, 96 mg (0.73 mmol) 4-cyanobenzaldehyde, 63 mg (0.37 mmol) 4- (4-morpholinyl) -4- Oxo-2-butanone and 220 mg of polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using dichloromethane / methanol as eluent.
Yield: 28 mg (16%)
¹ H-NMR (300 MHz, 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.

２００ｍｇ（０．９８ｍｍｏｌ）のＮ−［３−（トリフルオロメチル)フェニル］尿素、１２８ｍｇ（０．９８ｍｍｏｌ）の４−シアノベンズアルデヒド、７７ｍｇ（０．４９ｍｍｏｌ）の４−（４−ジエチルアミノ）−４−オキソ−２−ブタノンおよび２９５ｍｇのポリリン酸エチルエステルを３ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてジクロロメタン/メタノールを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：１０６ｍｇ（４７％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 8
4- (4-Cyanophenyl) -N, N-diethyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

200 mg (0.98 mmol) N- [3- (trifluoromethyl) phenyl] urea, 128 mg (0.98 mmol) 4-cyanobenzaldehyde, 77 mg (0.49 mmol) 4- (4-diethylamino) -4- Oxo-2-butanone and 295 mg of polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using dichloromethane / methanol as eluent.
Yield: 106 mg (47%)
¹ H-NMR (300 MHz, 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.

４００ｍｇ（１．９７ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、１９９ｍｇ（１．５１ｍｍｏｌ）の４−シアノベンズアルデヒドおよび１００ｍｇ（１．５１ｍｍｏｌ）のマロノニトリル（malononitrile)を２ｍｌのＴＨＦ中に懸濁し、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてジクロロメタン/メタノールを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：４ｍｇ（１％）
¹H-NMR (400 MHz, DMSO-d₆): 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. Example 9
6-amino-4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarbonitrile

400 mg (1.97 mmol) N- [3- (trifluoromethyl) phenyl] urea, 199 mg (1.51 mmol) 4-cyanobenzaldehyde and 100 mg (1.51 mmol) malononitrile in 2 ml THF. Suspend and then add a catalytic amount of concentrated hydrochloric acid. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using dichloromethane / methanol as eluent.
Yield: 4 mg (1%)
¹ H-NMR (400 MHz, 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.

１００ｍｇ（０．２３ｍｍｏｌ）の実施例１を１ｍｌのジメチルホルムアミドに溶解し、次に、３５．７ｍｇ（０．２３ｍｍｏｌ）のホスホリルクロリド（phosphorylchloride)を加える。反応混合物を７０℃で２時間撹拌する。室温まで冷却した後、生成物を分取ＨＰＬＣによって単離する。
収量：４３ｍｇ（４１％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 10
Ethyl 4- (4-cyanophenyl) -3-formyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

100 mg (0.23 mmol) of Example 1 is dissolved in 1 ml dimethylformamide and then 35.7 mg (0.23 mmol) phosphorylchloride is added. The reaction mixture is stirred at 70 ° C. for 2 hours. After cooling to room temperature, the product is isolated by preparative HPLC.
Yield: 43 mg (41%)
¹ H-NMR (300 MHz, 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.

３ｇ（７ｍｍｏｌ）の実施例１を５０ｍｌの水とエタノール中の１００ｍｌの５％水酸化カリウムの混合物に溶解する。反応混合物を室温で１８時間撹拌する。溶媒を真空下で除去し、残渣を溶出剤としてジクロロメタン/メタノールを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：１．２７ｇ（４５％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 11
4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

3 g (7 mmol) of Example 1 is dissolved in a mixture of 100 ml of 5% potassium hydroxide in 50 ml of water and ethanol. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by column chromatography on silica using dichloromethane / methanol as eluent.
Yield: 1.27 g (45%)
¹ H-NMR (300 MHz, 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.

４０ｍｇ（０．１ｍｍｏｌ）の実施例１１を２ｍｌのジメチルホルムアミドに溶解し、７ｍｇ（０．１１ｍｍｏｌ）のｎ−プロピルアミン、１５ｍｇ（０．１１ｍｍｏｌ）の１−ヒドロキシ−１Ｈ−ベンゾトリアゾール水和物（1-hydroxy-1H-benzotriazole hydrate)および１２ｍｇ（０．１ｍｍｏｌ）の４−ジメチルアミノピリジンを加える。反応混合物を０℃で撹拌し、次いで、２１ｍｇ（０．１１ｍｍｏｌ）の１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩を加える。この反応混合物を室温で１８時間撹拌し、次いで、水と酢酸エチルを加える。有機相を飽和水性硫酸水素カリウム（saturated aqueous KHSO₄)、水および塩水で洗浄し、硫酸ナトリウムで乾燥し、真空下で蒸発させ乾燥する。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：２９ｍｇ（６６％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 12
4- (4-Cyanophenyl) -6-methyl-2-oxo-N-propyl-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

40 mg (0.1 mmol) of Example 11 was dissolved in 2 ml of dimethylformamide, 7 mg (0.11 mmol) of n-propylamine, 15 mg (0.11 mmol) of 1-hydroxy-1H-benzotriazole hydrate ( 1-hydroxy-1H-benzotriazole hydrate) and 12 mg (0.1 mmol) of 4-dimethylaminopyridine are added. The reaction mixture is stirred at 0 ° C. and then 21 mg (0.11 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at room temperature for 18 hours and then water and ethyl acetate are added. The organic phase is washed with saturated aqueous KHSO ₄ , water and brine, dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 29 mg (66%)
¹ H-NMR (300 MHz, 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.

４８ｍｇ（０．１２ｍｍｏｌ）の実施例１１を２ｍｌのジメチルホルムアミドに溶解し、１０ｍｇ（０．１３ｍｍｏｌ）の２−メトキシエチルアミン、１８ｍｇ（０．１３ｍｍｏｌ）の１−ヒドロキシ−１Ｈ−ベンゾトリアゾール水和物および１５ｍｇ（０．１２ｍｍｏｌ）の４−ジメチルアミノピリジンを加える。反応混合物を０℃で撹拌し、次いで、２５ｍｇ（０．１３ｍｍｏｌ）の１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩を加える。この反応混合物を室温で１８時間撹拌し、次いで、水と酢酸エチルを加える。有機相を飽和水性硫酸水素カリウム、水および塩水で洗浄し、硫酸ナトリウムで乾燥し、真空下で蒸発させ乾燥する。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：２２ｍｇ（４０％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 13
4- (4-Cyanophenyl) -N- (2-methoxyethyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 -Pyrimidinecarboxamide

48 mg (0.12 mmol) of Example 11 was dissolved in 2 ml of dimethylformamide, 10 mg (0.13 mmol) of 2-methoxyethylamine, 18 mg (0.13 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 15 mg (0.12 mmol) 4-dimethylaminopyridine is added. The reaction mixture is stirred at 0 ° C. and then 25 mg (0.13 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at room temperature for 18 hours and then water and ethyl acetate are added. The organic phase is washed with saturated aqueous potassium hydrogen sulfate, water and brine, dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 22 mg (40%)
¹ H-NMR (300 MHz, 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.

８９ｍｇ（０．２１ｍｍｏｌ）の実施例１をＴＨＦ２ｍｌ中の６０％水素化ナトリウム（鉱物油中の）１２．４ｍｇ（０．３１ｍｍｏｌ）懸濁液に加える。この混合物を室温で２時間撹拌する。次いで、２６ｍｇ（０．２１ｍｍｏｌ）の硫酸ジメチルを加え、次に、この混合物を室温で更に２時間撹拌する。次いで、水と酢酸エチルを加え、有機相を水および塩水で洗浄し、硫酸ナトリウムで乾燥し、次に、真空下で蒸発させ乾燥させる。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：８５ｍｇ（９３％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 14
Ethyl 4- (4-cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

89 mg (0.21 mmol) of Example 1 is added to a suspension of 12.4 mg (0.31 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for 2 hours. Then 26 mg (0.21 mmol) of dimethyl sulfate are added and the mixture is then stirred for a further 2 hours at room temperature. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and then evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 85 mg (93%)
¹ H-NMR (200 MHz, 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.

１００ｍｇ（０．２３ｍｍｏｌ）の実施例１をＴＨＦ２ｍｌ中の６０％水素化ナトリウム（鉱物油中の）１２ｍｇ（０．２８ｍｍｏｌ）懸濁液に加える。この混合物を室温で２時間撹拌する。次いで、９１ｍｇ（１．１６ｍｍｏｌ）の塩化アセチル（acetylchloride)を加え、次に、この混合物を室温で更に２時間撹拌する。次いで、水と酢酸エチルを加え、有機相を水および塩水で洗浄し、硫酸ナトリウムで乾燥し、次に、真空下で蒸発させ乾燥させる。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：９３ｍｇ（８５％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 15
Ethyl 3-acetyl-4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

100 mg (0.23 mmol) of Example 1 is added to a suspension of 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for 2 hours. 91 mg (1.16 mmol) of acetylchloride are then added and the mixture is then stirred for a further 2 hours at room temperature. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and then evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 93 mg (85%)
¹ H-NMR (200 MHz, 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.

１００ｍｇ（０．２３ｍｍｏｌ）の実施例１をＴＨＦ２ｍｌ中の６０％水素化ナトリウム（鉱物油中の）１２ｍｇ（０．２８ｍｍｏｌ）懸濁液に加える。この混合物を室温で２時間撹拌する。次いで、１２６ｍｇ（１．１６ｍｍｏｌ）のクロロ炭酸エチル（エチル クロリドカルボナート：ethyl chloridocarbonate)を加え、次に、この混合物を室温で更に２時間撹拌する。次いで、水と酢酸エチルを加え、有機相を水および塩水で洗浄し、硫酸ナトリウムで乾燥し、次に、真空下で蒸発させ乾燥させる。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：９２ｍｇ（７９％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 16
Diethyl 6- (4-cyanophenyl) -4-methyl-2-oxo-3- [3- (trifluoromethyl) phenyl] -3,6-dihydro-1,5 (2H) -pyrimidine dicarboxylate

100 mg (0.23 mmol) of Example 1 is added to a suspension of 12 mg (0.28 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for 2 hours. 126 mg (1.16 mmol) of ethyl chloridocarbonate are then added and the mixture is then stirred for a further 2 hours at room temperature. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and then evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 92 mg (79%)
¹ H-NMR (200 MHz, 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.

１５０ｍｇ（１．０ｍｍｏｌ）のＮ−［３−メチルフェニル］尿素、１０１ｍｇ（０．７７ｍｍｏｌ）の４−シアノベンズアルデヒドおよび１００ｍｇ（０．７７ｍｍｏｌ）の３−オキソブタン酸エチル（エチル ３−オキソブタノアート：ethyl 3-oxobutanoate)を２ｍｌのＴＨＦ中に懸濁し、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：８ｍｇ（３％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 17
Ethyl 4- (4-cyanophenyl) -6-methyl-1- (3-methylphenyl) -2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

150 mg (1.0 mmol) N- [3-methylphenyl] urea, 101 mg (0.77 mmol) 4-cyanobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate (ethyl 3-oxobutanoate: ethyl 3-oxobutanoate) is suspended in 2 ml of THF and then a catalytic amount of concentrated hydrochloric acid is added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 8 mg (3%)
¹ H-NMR (200 MHz, 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.

２０４ｍｇ（１．０ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、１０８ｍｇ（０．７７ｍｍｏｌ）の４−クロロベンズアルデヒドおよび１００ｍｇ（０．７７ｍｍｏｌ）の３−オキソブタン酸エチルを２ｍｌのＴＨＦ中に懸濁し、次に、触媒量の濃塩酸を加える。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：２９ｍｇ（９％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 18
Ethyl 4- (4-chlorophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

204 mg (1.0 mmol) N- [3- (trifluoromethyl) phenyl] urea, 108 mg (0.77 mmol) 4-chlorobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate in 2 ml THF And then a catalytic amount of concentrated hydrochloric acid is added. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 29 mg (9%)
¹ H-NMR (200 MHz, 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.

３ｇ（７ｍｍｏｌ）の実施例１を１００ｍｌのクロロホルムに溶解する。０℃で、５５８ｍｇ（３．４８ｍｍｏｌ）の臭素を滴下する。この混合物を室温で２時間撹拌し、次いで、溶媒を真空下で除去する。残渣を溶出剤としてシクロヘキサン/酢酸エチルを用いて、シリカによるカラムクロマトグラフィーによって精製する。
収量：３．２ｇ（９０％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 19
Ethyl 6- (bromomethyl) -4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

3 g (7 mmol) of Example 1 is dissolved in 100 ml of chloroform. At 0 ° C., 558 mg (3.48 mmol) of bromine are added dropwise. The mixture is stirred at room temperature for 2 hours and then the solvent is removed in vacuo. The residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 3.2 g (90%)
¹ H-NMR (200 MHz, 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.

２０ｍｇ（０．０４ｍｍｏｌ）の実施例１９を２ｍｌのアセトンに溶解し、次に、８ｍｇ（０．１０ｍｍｏｌ）のジエチルアミンを加える。この混合物を室温で１８時間撹拌し、次いで、溶媒を真空下で除去する。残渣を分取ＨＰＬＣによって精製する。
収量：１５ｍｇ（７５％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 20
Ethyl 4- (4-cyanophenyl) -6-[(diethylamino) methyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxy Rat

20 mg (0.04 mmol) of Example 19 is dissolved in 2 ml of acetone and then 8 mg (0.10 mmol) of diethylamine is added. The mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is purified by preparative HPLC.
Yield: 15 mg (75%)
¹ H-NMR (300 MHz, DMSO-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.

５０ｍｇ（０．１０ｍｍｏｌ）の実施例１９を２ｍｌのアセトンに溶解し、次に、１８ｍｇ（０．２０ｍｍｏｌ）のアニリンを加える。この混合物を室温で１８時間撹拌し、次いで、溶媒を真空下で除去する。残渣を分取ＨＰＬＣによって精製する。
収量：２８ｍｇ（５５％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 21
Ethyl 6- (anilinomethyl) -4- (4-cyanophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

50 mg (0.10 mmol) of Example 19 is dissolved in 2 ml of acetone and then 18 mg (0.20 mmol) of aniline is added. The mixture is stirred at room temperature for 18 hours and then the solvent is removed in vacuo. The residue is purified by preparative HPLC.
Yield: 28 mg (55%)
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 1.1 (t, 3H); 3.6 (d / d, 1H); 4.1 (q, 2H); 4.4 (d / d, 1H); 5.4 ( 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.

実施例１のエナンチオマーをキラル相分取ＨＰＬＣによって分離する：
１．５ｍｌの酢酸エチルに溶解された化合物１００ｍｇ、カラムＫＢＤ８３６１（モノマー Ｎ−メタクリロイル−Ｌ−ロイシン−１−メンチルアミドに基づくキラルシリカゲルセレクター、欧州特許公開公報ＥＰ−Ａ−３７９９１７参照）、２５０ｍｍ×２０ｍｍ、溶出剤 酢酸エチル、流速 ２５ｍｌ/分、温度 ２３℃、注入量 ２５００μｌ、検出 ２５４ｎｍ。
¹H-NMR (300 MHz, DMSO-d₆): 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、ジクロロメタン、ｃ＝５３５．０ｍｇ/１００ｍｌ） Example 22
(+)-Ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

The enantiomers of Example 1 are separated by chiral phase preparative HPLC:
Compound 100 mg dissolved in 1.5 ml ethyl acetate, column KBD8361 (chiral silica gel selector based on the monomer N-methacryloyl-L-leucine-1-menthylamide, see European Patent Publication EP-A-379917), 250 mm × 20 mm , Eluent ethyl acetate, flow rate 25 ml / min, temperature 23 ° C., injection volume 2500 μl, detection 254 nm.
¹ H-NMR (300 MHz, 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 = 589 nm, dichloromethane, c = 535.0 mg / 100 ml)

１００ｍｇ（０．２３ｍｍｏｌ）の実施例２２をＴＨＦ２ｍｌ中の６０％水素化ナトリウム（鉱物油中の）１４ｍｇ（０．３５ｍｍｏｌ）懸濁液に加える。この混合物を室温で２時間撹拌する。次いで、２９ｍｇ（０．２３ｍｍｏｌ）の硫酸ジメチルを加え、次に、この混合物を室温で更に２時間撹拌する。次いで、水と酢酸エチルを加え、有機相を水および塩水で洗浄し、硫酸ナトリウムで乾燥し、次に、真空下で蒸発させ乾燥させる。生成物を溶出剤としてシクロヘキサン/酢酸エチルを用い、シリカによるカラムクロマトグラフィーによって精製する。
収量：７６ｍｇ（７４％）
¹H-NMR (200 MHz, DMSO-d₆): 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、ジクロロメタン、ｃ＝５３０．０ｍｇ/１００ｍｌ） Example 23
(−)-Ethyl 4- (4-cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidine Carboxylate

100 mg (0.23 mmol) of Example 22 is added to a suspension of 14 mg (0.35 mmol) of 60% sodium hydride (in mineral oil) in 2 ml of THF. The mixture is stirred at room temperature for 2 hours. 29 mg (0.23 mmol) of dimethyl sulfate are then added and the mixture is then stirred for a further 2 hours at room temperature. Water and ethyl acetate are then added and the organic phase is washed with water and brine, dried over sodium sulfate and then evaporated to dryness under vacuum. The product is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 76 mg (74%)
¹ H-NMR (200 MHz, 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 = 589 nm, dichloromethane, c = 530.0 mg / 100 ml)

テトラヒドロフラン（５ｍｌ）中の実施例３Ａ（７６ｍｇ，０．５８ｍｍｏｌ）の撹拌溶液に、３−オキソブタン酸エチル（７５ｍｇ，０．５８ｍｍｏｌ）、Ｎ−［３−（トリフルオロメチル）フェニル］尿素（１１８ｍｇ，０．５８ｍｍｏｌ）およびポリリン酸エチルエステル（２００ｍｇ；Ｃａｖａ ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．１９６９，３４，２６６５の手順に従って新たに調製された）を加える。反応混合物を２日間（４８時間）還流し、その後、溶液をＤＭＳＯ（２ｍｌ）で希釈し、次に、分取ＨＰＬＣによって精製する。生成物フラクションを真空下で濃縮し、溶出剤としてシクロヘキサンと酢酸エチルを用いてシリカによるクロマトグラフィー処理を再びおこなう。
収量：９２ｍｇ（理論収量の３５％）
ＭＳ（ＥＳＩｐｏｓ）：ｍ/ｚ＝４３１（Ｍ＋Ｈ）^＋
ＨＰＬＣ（方法４）＝４．６３分
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 24
Ethyl 4- (6-cyano-3-pyridinyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

To a stirred solution of Example 3A (76 mg, 0.58 mmol) in tetrahydrofuran (5 ml) was added ethyl 3-oxobutanoate (75 mg, 0.58 mmol), N- [3- (trifluoromethyl) phenyl] urea (118 mg, 0.58 mmol) and polyphosphoric acid ethyl ester (200 mg; freshly prepared according to the procedure of Cava et al., J. Org. Chem. 1969, 34, 2665). The reaction mixture is refluxed for 2 days (48 hours), after which the solution is diluted with DMSO (2 ml) and then purified by preparative HPLC. The product fraction is concentrated under vacuum and rechromatographed on silica using cyclohexane and ethyl acetate as eluent.
Yield: 92 mg (35% of theoretical yield)
MS (ESIpos): m / z = 431 (M + H) ⁺
HPLC (Method 4) = 4.63 min
¹ H-NMR (300 MHz, 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.

５ｍｌの乾燥ジメチルホルムアミド中の実施例１１の化合物５０１ｍｇ（１．２５ｍｍｏｌ）溶液に、５６７ｍｇ（３．５ｍｍｏｌ）のＮ，Ｎ−カルボニルジイミダゾール（N,N-carbonyldiimidazole)を加える。この反応混合物を一晩放置した後、溶媒を真空下で蒸発して除去する。残渣を酢酸エチル中に入れ、次に、水および塩水で洗浄する。硫酸マグネシウムで乾燥した後、溶媒を真空下で蒸発して除去する。
収量：５００ｍｇ（理論収量の８８．６％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４５２（Ｍ＋Ｈ）^＋
1H-NMR (200 MHz, DMSO-d₆): 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. Example 25
4- {5- (1H-imidazol-1-ylcarbonyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl } Benzonitrile

To a solution of 501 mg (1.25 mmol) of the compound of Example 11 in 5 ml dry dimethylformamide, 567 mg (3.5 mmol) N, N-carbonyldiimidazole is added. After leaving the reaction mixture overnight, the solvent is removed by evaporation under vacuum. The residue is taken up in ethyl acetate and then washed with water and brine. After drying over magnesium sulfate, the solvent is removed by evaporation under vacuum.
Yield: 500 mg (88.6% of theoretical yield)
MS (EI): m / z = 452 (M + H) ^+
1 H-NMR (200 MHz, 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.

実施例２５の化合物４５．１ｍｇ（０．１ｍｍｏｌ）をエチレングリコール０．５ｍｌに加える。反応混合物を約１００℃で１時間撹拌する。冷却後、この反応混合物を分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数（number of injection)：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：２２ｍｇ（理論収量の４９．４％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４４６（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 26
2-Hydroxyethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of ethylene glycol. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 min 10% A, 2 min 10 % A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; number of injection: 1) Purify. Fractions containing product are collected and concentrated under vacuum.
Yield: 22 mg (49.4% of theoretical yield)
MS (EI): m / z = 446 (M + H) ^+
1 H-NMR (300 MHz, 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.

実施例２５の化合物４５．１ｍｇ（０．１ｍｍｏｌ）を２−（ジメチルアミノ）エタノール０．５ｍｌに加える。反応混合物を約１００℃で１時間撹拌する。冷却後、この反応混合物を分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：２４ｍｇ（理論収量の５０．８％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４７３（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 27
2- (Dimethylamino) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidine Carboxylate

Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 2- (dimethylamino) ethanol. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 min 10% A, 2 min 10 Purify by% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 24 mg (50.8% of theoretical yield)
MS (EI): m / z = 473 (M + H) ^+
1 H-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.

実施例２５の化合物４５．１ｍｇ（０．１ｍｍｏｌ）を２−（４−ピリジニル）エタノール０．５ｍｌに加える。反応混合物を約１００℃で１時間撹拌する。冷却後、この反応混合物を分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：１７ｍｇ（理論収量の３３．５％）
ＭＳ（ＥＩ）：ｍ/ｚ＝５０７（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 28
2- (4-Pyridinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 Pyrimidine carboxylate

Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 2- (4-pyridinyl) ethanol. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 min 10% A, 2 min 10 Purify by% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 17 mg (33.5% of theoretical yield)
MS (EI): m / z = 507 (M + H) ^+
1 H-NMR (300 MHz, 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.

実施例２５の化合物４５．１ｍｇ（０．１ｍｍｏｌ）を２−（２−ピリジニル）エタノール０．５ｍｌに加える。反応混合物を約１００℃で１時間撹拌する。冷却後、この反応混合物を分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：２２ｍｇ（理論収量の４３．４％）
ＭＳ（ＥＩ）：ｍ/ｚ＝５０７（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 29
2- (2-pyridinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 Pyrimidine carboxylate

Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 2- (2-pyridinyl) ethanol. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 min 10% A, 2 min 10 Purify by% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 22 mg (43.4% of theoretical yield)
MS (EI): m / z = 507 (M + H) ^+
1 H-NMR (300 MHz, 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.

実施例２５の化合物４５．１ｍｇ（０．１ｍｍｏｌ）を１−（２−ヒドロキシエチル）−２−ピロリジノン０．５ｍｌに加える。反応混合物を約１００℃で１時間撹拌する。冷却後、この反応混合物を分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：２５ｍｇ（理論収量の４８．８％）
ＭＳ（ＥＩ）：ｍ/ｚ＝５１３（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 30
2- (2-oxo-1-pyrrolidinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4 Tetrahydro-5-pyrimidinecarboxylate

Add 45.1 mg (0.1 mmol) of the compound of Example 25 to 0.5 ml of 1- (2-hydroxyethyl) -2-pyrrolidinone. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated ammonia; gradient: 0 min 10% A, 2 min 10 Purify by% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 25 mg (48.8% of theoretical yield)
MS (EI): m / z = 513 (M + H) ^+
1 H-NMR (300 MHz, 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.

The following compounds are prepared according to the procedures of Examples 14-16.

The following compounds are prepared according to the procedures of examples 6-8.

８０ｍｇ（０．１６ｍｍｏｌ）の実施例４４を２ｍｌのジメチルホルムアミドに溶解し、１６ｍｇ（０．１８ｍｍｏｌ）のモルホリン、２４ｍｇ（０．１８ｍｍｏｌ）の１−ヒドロキシ−１Ｈ−ベンゾトリアゾール水和物および２０ｍｇ（０．１６ｍｍｏｌ）の４−ジメチルアミノピリジンを加える。反応混合物を０℃で撹拌し、次いで、３５ｍｇ（０．１８ｍｍｏｌ）の１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩を加える。この反応混合物を室温で１８時間撹拌し、次いで、水と酢酸エチルを加える。有機相を硫酸ナトリウムで乾燥し、真空下で蒸発させ乾燥する。必要に応じて、生成物を更にカラムクロマトグラフィーまたは分取ＨＰＬＣによって精製する。
収量：７８ｍｇ（８５％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 59
Ethyl 4- (4-cyanophenyl) -6-methyl-3- [2- (4-morpholinyl) -2-oxoethyl] -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2 , 3,4-Tetrahydro-5-pyrimidinecarboxylate

80 mg (0.16 mmol) of Example 44 was dissolved in 2 ml dimethylformamide and 16 mg (0.18 mmol) morpholine, 24 mg (0.18 mmol) 1-hydroxy-1H-benzotriazole hydrate and 20 mg (0 .16 mmol) of 4-dimethylaminopyridine. The reaction mixture is stirred at 0 ° C. and then 35 mg (0.18 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added. The reaction mixture is stirred at room temperature for 18 hours and then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness under vacuum. If necessary, the product is further purified by column chromatography or preparative HPLC.
Yield: 78 mg (85%)
¹ H-NMR (300 MHz, 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.

The following compounds are prepared according to the procedure of Example 59:

The following compounds are prepared according to the procedures of examples 6-8.

２００ｍｇ（０．５ｍｍｏｌ）の実施例１１を５ｍｌのテトラヒドロフランに溶解し、次に、６ｍｇ（０．０５ｍｍｏｌ）の４−Ｎ，Ｎ−ジメチルアミノピリジン、７７ｍｇ（０．６ｍｍｏｌ）のＮ，Ｎ−ジイソプロピルエチルアミンおよび１１５ｍｇ（０．６ｍｍｏｌ）のベンゾトリアゾール−１−イルオキシ−トリス（ピロリジノ）ホスホニウムヘキサフルオロホスファート（benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate)を加える。反応混合物を室温で１５分間撹拌し、次いで、５ｍｌ（２．５ｍｍｏｌ）のアンモニア（ジオキサン中で０．５Ｍ溶液として）を加える。この反応混合物を室温で１時間撹拌し、次いで、水と酢酸エチルを加える。有機相を硫酸ナトリウムで乾燥し、真空下で蒸発させて乾燥する。生成物を分取ＨＰＬＣによって更に精製する。
収量：５５ｍｇ（理論収量の２８％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 70
4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxamide

200 mg (0.5 mmol) of Example 11 was dissolved in 5 ml of tetrahydrofuran, then 6 mg (0.05 mmol) of 4-N, N-dimethylaminopyridine, 77 mg (0.6 mmol) of N, N-diisopropyl. Add ethylamine and 115 mg (0.6 mmol) benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate. The reaction mixture is stirred at room temperature for 15 minutes and then 5 ml (2.5 mmol) of ammonia (as a 0.5 M solution in dioxane) is added. The reaction mixture is stirred at room temperature for 1 hour and then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness under vacuum. The product is further purified by preparative HPLC.
Yield: 55 mg (28% of theoretical yield)
¹ H-NMR (200 MHz, 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.

実施例１１のエナンチオマーをキラル相分取ＨＰＬＣ［カラムＫＢＤ８３６１（モノマー Ｎ−メタクリロイル−Ｌ−ロイシン−１−メンチルアミドに基づくキラルシリカゲルセレクター、欧州特許公開公報ＥＰ−Ａ−３７９９１７参照）、２５０ｍｍ×２０ｍｍ、溶出剤：酢酸エチル→メタノール→酢酸エチル、流速 ２５ｍｌ/分、温度 ２３℃、検出 ２５４ｎｍ］によって分離する。
¹H-NMR (300 MHz, DMSO-d₆): 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、メタノール、ｃ＝５０５ｍｇ/１００ｍｌ） Example 71
(+)-4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

The enantiomer of Example 11 was subjected to chiral phase preparative HPLC (column KBD8361 (chiral silica gel selector based on the monomer N-methacryloyl-L-leucine-1-menthylamide, see European Patent Publication EP-A-379917), 250 mm × 20 mm, Eluent: ethyl acetate → methanol → ethyl acetate, flow rate 25 ml / min, temperature 23 ° C., detection 254 nm].
¹ H-NMR (300 MHz, 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 = 589 nm, methanol, c = 505 mg / 100 ml)

アルゴン下で、１５６０ｍｇ（３．８９ｍｍｏｌ）の実施例７１の化合物を１９．６ｍｌのＤＭＦに加える。１．０９５ｍｌ（７．８６ｍｍｏｌ）のトリエチルアミンおよび１．１１ｍｌ（１５．７ｍｍｏｌ）の２−ブロモエタノールを加えた後、反応混合物を約７０℃で８時間撹拌する。冷却後、この反応混合物を真空下で濃縮する。残渣を酢酸エチルに入れ、次に、水で洗浄する。硫酸マグネシウムで乾燥した後、有機相を真空下で蒸発させる。この残渣を８ｍｌのメタノールに入れ、次に、分取ＨＰＬＣ（カラム：Ｎｕｃｌｅｏｓｉｌ １００−５ Ｃ１８ Ｎａｕｔｉｌｕｓ、２０×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．３％ギ酸；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１８）によって精製する。生成物を含んでいるフラクションを集め、凍結乾燥する。
収量：１２９０ｍｇ（理論収量の７４．５％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４４６（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): δ = 2.05 (d, 3H); 3.5 (quartett, 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、メタノール、ｃ＝４５５ｍｇ/１００ｍｌ） Example 72
(+)-2-Hydroxyethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 Pyrimidine carboxylate

Under argon, 1560 mg (3.89 mmol) of the compound of Example 71 is added to 19.6 ml of DMF. After adding 1.095 ml (7.86 mmol) of triethylamine and 1.11 ml (15.7 mmol) of 2-bromoethanol, the reaction mixture is stirred at about 70 ° C. for 8 hours. After cooling, the reaction mixture is concentrated under vacuum. The residue is taken up in ethyl acetate and then washed with water. After drying over magnesium sulfate, the organic phase is evaporated under vacuum. This residue was taken up in 8 ml of methanol and then preparative HPLC (column: Nucleosil 100-5 C18 Nautulus, 20 × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.3% formic acid; gradient: 0 min. 10% A, 2 minutes 10% A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; wavelength: 220 nm; injection volume: about 500 μl; number of injections: 18 ). Fractions containing product are collected and lyophilized.
Yield: 1290 mg (74.5% of theoretical yield)
MS (EI): m / z = 446 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 2.05 (d, 3H); 3.5 (quartett, 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 = 589 nm, methanol, c = 455 mg / 100 ml)

テトラヒドロフラン（５ｍｌ）中の実施例３Ａ（７５ｍｇ，０．５７ｍｍｏｌ）の撹拌溶液に、２，４−ペンタンジオン（５７ｍｇ，０．５７ｍｍｏｌ）、Ｎ−［３−（トリフルオロメチル）フェニル］尿素（１１６ｍｇ，０．５７ｍｍｏｌ）およびポリリン酸エチルエステル（２００ｍｇ）［Ｃａｖａ ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．３４，２６６５（１９６９）の手順に従って新たに調製された］を加える。反応混合物を２４時間還流し、その後、溶液をＤＭＳＯ（２ｍｌ）で希釈し、次に、分取ＨＰＬＣによって精製する。
収量：１０１ｍｇ（理論収量の４４％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 73
5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} -2-pyridinecarbonitrile

To a stirred solution of Example 3A (75 mg, 0.57 mmol) in tetrahydrofuran (5 ml) was added 2,4-pentanedione (57 mg, 0.57 mmol), N- [3- (trifluoromethyl) phenyl] urea (116 mg). , 0.57 mmol) and polyphosphoric acid ethyl ester (200 mg) [Cava et al. , J .; Org. Chem. 34 , 2665 (1969)]. The reaction mixture is refluxed for 24 hours, after which the solution is diluted with DMSO (2 ml) and then purified by preparative HPLC.
Yield: 101 mg (44% of theoretical yield)
¹ H-NMR (200 MHz, 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.

実施例７３のエナンチオマーをキラル相分取ＨＰＬＣ［カラムＫＢＤ８３６１（モノマー Ｎ−メタクリロイル−Ｌ−ロイシン−１−メンチルアミドに基づくキラルシリカゲルセレクター、欧州特許公開公報ＥＰ−Ａ−３７９９１７参照）、２５０ｍｍ×２０ｍｍ、溶出剤：酢酸エチル→メタノール→酢酸エチル、流速 ２５ｍｌ/分、温度 ２３℃、検出 ２５４ｎｍ］によって分離する。
ＭＳ（ＥＳＩｐｏｓ）：ｍ/ｚ＝４０１（Ｍ＋Ｈ）^＋
［α］^２０＝＋２５．１°（δ＝５８９ｎｍ、メタノール、ｃ＝５０５ｍｇ/１００ｍｌ） Example 74
(+)-5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} -2-pyridine Carbonitrile

The enantiomer of Example 73 was subjected to chiral phase preparative HPLC (column KBD8361 (chiral silica gel selector based on the monomer N-methacryloyl-L-leucine-1-menthylamide, see European Patent Publication EP-A-379917), 250 mm × 20 mm, Eluent: ethyl acetate → methanol → ethyl acetate, flow rate 25 ml / min, temperature 23 ° C., detection 254 nm].
MS (ESIpos): m / z = 401 (M + H) ⁺
[Α] ²⁰ = + 25.1 ° (δ = 589 nm, methanol, c = 505 mg / 100 ml)

０．４ｍｌの乾燥ジメチルホルムアミド中の実施例１１の化合物４０．１ｍｇ（０．１ｍｍｏｌ）溶液に、４８．６ｍｇ（０．３ｍｍｏｌ）のＮ，Ｎ−カルボニルジイミダゾールを加える。この反応混合物を１時間放置した後、この反応混合物を水で希釈し、次に、ジクロロメタンで抽出する。硫酸マグネシウムで乾燥した後、溶媒を真空下で蒸発して除去する。この残渣に、０．５ｍｌの（２−ピリジニル)メタノールを加える。この反応混合物を約１００℃で１時間撹拌する。冷却後、反応混合物を分取ＨＰＬＣ（カラム：Ｎｕｃｌｅｏｓｉｌ １００−５ Ｃ１８ Ｎａｕｔｉｌｕｓ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％ギ酸；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；流速 ２５ｍｌ/分；波長：２２０ｎｍ；注入量：約５５０μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：１７ｍｇ（理論収量の３４．５％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４９３（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 75
2- (2-pyridinyl) methyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 Pyrimidine carboxylate

To a solution of 40.1 mg (0.1 mmol) of the compound of Example 11 in 0.4 ml of dry dimethylformamide is added 48.6 mg (0.3 mmol) of N, N-carbonyldiimidazole. After allowing the reaction mixture to stand for 1 hour, the reaction mixture is diluted with water and then extracted with dichloromethane. After drying over magnesium sulfate, the solvent is removed by evaporation under vacuum. To this residue is added 0.5 ml of (2-pyridinyl) methanol. The reaction mixture is stirred at about 100 ° C. for 1 hour. After cooling, the reaction mixture was subjected to preparative HPLC (column: Nucleosil 100-5 C18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 min 10% A, 2 min 10 % A, 6 minutes 90% A, 7 minutes 90% A, 7.1 minutes 10% A, 8 minutes 10% A; flow rate 25 ml / min; wavelength: 220 nm; injection volume: about 550 μl; injection number: 1) Purify. Fractions containing product are collected and concentrated under vacuum.
Yield: 17 mg (34.5% of theoretical yield)
MS (EI): m / z = 493 (M + H) ^+
1 H-NMR (300 MHz, 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.

０．５７ｍｌの乾燥ジメチルホルムアミド中の実施例１１の化合物６０．２ｍｇ（０．１５ｍｍｏｌ）溶液に、７２．９ｍｇ（０．４５ｍｍｏｌ）のＮ，Ｎ−カルボニルジイミダゾールを加える。この反応混合物を１時間放置した後、この反応混合物を水で希釈し、次に、酢酸エチルで抽出する。硫酸マグネシウムで乾燥した後、溶媒を真空下で蒸発させて除去する。この残渣に、１８５ｍｇ（１．５ｍｍｏｌ）の２−（３−ピリジル)エタノールおよび２０μｌ（０．２７ｍｍｏｌ）のトリエチルアミンを加える。反応混合物を１００℃で１時間撹拌する。次いで、この反応混合物を０．４ｍｌのメタノールで希釈し、濾過し、次に、分取ＨＰＬＣ（カラム：Ｎｕｃｌｅｏｓｉｌ １００−５ Ｃ１８ Ｎａｕｔｉｌｕｓ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％ギ酸；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；流速 ２５ｍｌ/分；波長：２２０ｎｍ；注入量：約５５０μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：４４ｍｇ（理論収量の５７．９％）
ＬＣ−ＭＳ（ＥＩ、方法５）：ｍ/ｚ＝５０７（Ｍ＋Ｈ）^＋、Ｒ_ｔ＝３．１９分 Example 76
2- (3-pyridinyl) ethyl 4- (4-cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5 Pyrimidine carboxylate

To a solution of 60.2 mg (0.15 mmol) of the compound of Example 11 in 0.57 ml of dry dimethylformamide is added 72.9 mg (0.45 mmol) of N, N-carbonyldiimidazole. After the reaction mixture is left for 1 hour, the reaction mixture is diluted with water and then extracted with ethyl acetate. After drying with magnesium sulfate, the solvent is removed by evaporation under vacuum. To this residue is added 185 mg (1.5 mmol) 2- (3-pyridyl) ethanol and 20 μl (0.27 mmol) triethylamine. The reaction mixture is stirred at 100 ° C. for 1 hour. The reaction mixture was then diluted with 0.4 ml methanol, filtered, and then preparative HPLC (column: Nucleosil 100-5 C18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0. Gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; flow rate 25 ml / min; wavelength Purify by: injection: about 550 μl; number of injections: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 44 mg (57.9% of theoretical yield)
LC-MS (EI, method 5): m / z = 507 (M + H) ⁺ , R _t = 3.19 min.

４．１ｇ（９．２５ｍｍｏｌ）の実施例１４を１００ｍｌのエタノールに溶解する。この溶液に、水に溶解した水酸化カリウム（２５重量％）溶液６．２ｍｌ（２７．６ｍｍｏｌ）を加える。反応混合物を室温で１８時間放置する。次いで、更に、水に溶解した水酸化カリウム（２５重量％）溶液１２．４ｍｌ（５５．２ｍｍｏｌ）を加え、反応混合物を２時間撹拌する。この反応混合物を水で希釈し、酢酸エチルで３回抽出する。水相を１Ｎ塩酸で酸性にし、次いで、酢酸エチルで抽出する。この最後の抽出物を硫酸マグネシウムで乾燥し、真空下で蒸発させる。残渣を溶出剤としてシクロヘキサン/酢酸エチルを用い、シリカによるカラムクロマトグラフィーによって精製する。
収量：１．５ｇ（理論収量の３９％）
ＭＳ（ＥＩ）：ｍ/ｚ＝４１６（Ｍ＋Ｈ）^＋
1H-NMR (300 MHz, DMSO-d₆): 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. Example 77
4- (4-Cyanophenyl) -3,6-dimethyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid

4.1 g (9.25 mmol) of Example 14 is dissolved in 100 ml of ethanol. To this solution is added 6.2 ml (27.6 mmol) of potassium hydroxide (25% by weight) solution in water. The reaction mixture is left at room temperature for 18 hours. Then, further 12.4 ml (55.2 mmol) of a solution of potassium hydroxide (25% by weight) dissolved in water is added and the reaction mixture is stirred for 2 hours. The reaction mixture is diluted with water and extracted three times with ethyl acetate. The aqueous phase is acidified with 1N hydrochloric acid and then extracted with ethyl acetate. This last extract is dried over magnesium sulphate and evaporated under vacuum. The residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 1.5 g (39% of theoretical yield)
MS (EI): m / z = 416 (M + H) ^+
1 H-NMR (300 MHz, 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.

^１）この場合、使用されるアルコールは固体であり、反応は０．４ｍｌのＤＭＦの存在下でおこなわれる。 The following compound is prepared according to the procedure of Example 76:

^{1) In} this case, the alcohol used is a solid and the reaction is carried out in the presence of 0.4 ml of DMF.

アルゴン下で、３０．８ｍｇ（０．１５ｍｍｏｌ）のＮ−（３，５−ジクロロフェニル）尿素を０．５ｍｌのジオキサン中の３９．３ｍｇ（０．３ｍｍｏｌ）の４−ホルミルベンゾニトリル、３９ｍｇ（０．３ｍｍｏｌ）のエチル ３−オキソブタノアートおよび９０ｍｇのトリメチルシリルポリホスファート（trimethylsilylpolyphosphate)とともに、８０℃で４時間撹拌する。少量のＤＭＳＯを添加した後、この反応混合物を濾過し、次に、分取ＨＰＬＣ（カラム：Ａｇｉｌｅｎｔ Ｚｏｒｂａｘ Ｅｘｔｅｎｄ Ｃ１８ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％濃アンモニア水；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；流速 ２５ｍｌ/分；波長：２２０ｎｍ；注入量：約５００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：３８．１ｍｇ（理論収量の５９％）
ＬＣ−ＭＳ（ＥＩ、方法７）：ｍ/ｚ＝４３１（Ｍ＋Ｈ）^＋、Ｒ_ｔ＝４．１４分 Example 102
Ethyl 4- (4-cyanophenyl) -1- (3,5-dichlorophenyl) -6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

Under argon, 30.8 mg (0.15 mmol) N- (3,5-dichlorophenyl) urea was converted to 39.3 mg (0.3 mmol) 4-formylbenzonitrile, 39 mg (0. 3 mmol) of ethyl 3-oxobutanoate and 90 mg of trimethylsilylpolyphosphate are stirred at 80 ° C. for 4 hours. After adding a small amount of DMSO, the reaction mixture was filtered and then preparative HPLC (column: Agilent Zorbax Extended C18 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% concentrated aqueous ammonia. Gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; flow rate 25 ml / min; wavelength: 220 nm; Purify by injection volume: approx. 500 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 38.1 mg (59% of theoretical yield)
LC-MS (EI, method 7): m / z = 431 (M + H) ⁺ , R _t = 4.14 min.

３０．６ｍｇ（０．１５ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素を、０．５ｍｌのジオキサンと０．１ｍｌのＤＭＦ中の４５．３ｍｇ（０．３ｍｍｏｌ）の３−ニトロベンズアルデヒド、３９ｍｇ（０．３ｍｍｏｌ）のエチル ３−オキソブタノアートおよび９０ｍｇのポリリン酸エチルエステル［Ｃａｖａ ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．３４，２６６５（１９６９）の手順に従って新たに調製された］とともに、８０℃で１８時間振とうする。２００μｌのＤＭＦを添加した後、この反応混合物を濾過し、分取ＨＰＬＣ（カラム：Ｎｕｃｌｅｏｓｉｌ １００−５ Ｃ１８ Ｎａｕｔｉｌｕｓ ２０ｍｍ×５０ｍｍ、５μｍ；溶媒Ａ：アセトニトリル、溶媒Ｂ：水＋０．１％ギ酸；グラジエント：０分 １０％Ａ、２分 １０％Ａ、６分 ９０％Ａ、７分 ９０％Ａ、７．１分 １０％Ａ、８分 １０％Ａ；流速 ２５ｍｌ/分；波長：２２０ｎｍ；注入量：約８００μｌ；注入数：１）によって精製する。生成物を含んでいるフラクションを集め、真空下で濃縮する。
収量：３４ｍｇ（理論収量の５０．４％）
ＬＣ−ＭＳ（ＥＩ、方法６）：ｍ/ｚ＝４５０（Ｍ＋Ｈ）^＋、Ｒ_ｔ＝３．９４分 Example 103
Ethyl 6-methyl-4- (3-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

30.6 mg (0.15 mmol) N- [3- (trifluoromethyl) phenyl] urea was added to 45.3 mg (0.3 mmol) 3-nitrobenzaldehyde in 0.5 ml dioxane and 0.1 ml DMF. , 39 mg (0.3 mmol) ethyl 3-oxobutanoate and 90 mg polyphosphoric acid ethyl ester [Cava et al. , J .; Org. Chem. 34 , 2665 (1969)] and shaken at 80 ° C. for 18 hours. After adding 200 μl of DMF, the reaction mixture was filtered and preparative HPLC (column: Nucleosil 100-5 C18 Nautilus 20 mm × 50 mm, 5 μm; solvent A: acetonitrile, solvent B: water + 0.1% formic acid; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; flow rate 25 ml / min; wavelength: 220 nm; injection volume: Purify by approximately 800 μl; injection number: 1). Fractions containing product are collected and concentrated under vacuum.
Yield: 34 mg (50.4% of theoretical yield)
LC-MS (EI, method 6): m / z = 450 (M + H) ⁺ , R _t = 3.94 min.

The following compound is prepared according to the procedure of Example 102:

９．８７ｇ（４８．３ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、１２．６８ｇ（９６．６８ｍｍｏｌ）の４−シアノベンズアルデヒド、１５ｇ（９６．６８ｍｍｏｌ）の（２−シアノエチル） ３−オキソブタノアート((2-cyanoethyl) 3-oxobutanoate)および３７．５ｇのポリリン酸エチルエステルを２５０ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロヘキサン/酢酸エチルを用い、シリカによるカラムクロマトグラフィーによって精製する。
収量：２５ｇ（理論収量の１００％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 108
4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid 2-cyanoethyl ester

9.87 g (48.3 mmol) N- [3- (trifluoromethyl) phenyl] urea, 12.68 g (96.68 mmol) 4-cyanobenzaldehyde, 15 g (96.68 mmol) (2-cyanoethyl) 3 Suspend (2-cyanoethyl) 3-oxobutanoate and 37.5 g of polyphosphoric acid ethyl ester in 250 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 25 g (100% of theoretical yield)
¹ H-NMR (200 MHz, 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.

０．６０９ｇ（１．５２ｍｍｏｌ）の実施例７０を６０ｍｌのＴＨＦに溶解し、１．２４ｇ（１２．９３ｍｍｏｌ）の（メトキシカルボニルスルファモイル)−トリエチルアンモニウム−Ｎ−ベタイン（(methoxycarbonylsulfamoyl)-triethylammonium-N-betaine)を加える。反応混合物を室温で１時間撹拌し、溶媒を真空下で除去し、次いで、残渣を溶出剤としてジクロロメタン/メタノール混合液を用いたシリカによるカラムクロマトグラフィーによって精製する。
収量：２４９ｍｇ（理論収量の４３％）
¹H-NMR (300 MHz, DMSO-d₆): 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. Example 109
4- (4-Cyanophenyl) -6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carbonitrile

0.609 g (1.52 mmol) of Example 70 was dissolved in 60 ml of THF and 1.24 g (12.93 mmol) of (methoxycarbonylsulfamoyl) -triethylammonium-triethylammonium- Add N-betaine). The reaction mixture is stirred at room temperature for 1 hour, the solvent is removed in vacuo, and the residue is then purified by column chromatography on silica using a dichloromethane / methanol mixture as eluent.
Yield: 249 mg (43% of theoretical yield)
¹ H-NMR (300 MHz, 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.

７．８４ｇ（３８．４ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、５．８１ｇ（３８．４ｍｍｏｌ）の４−ニトロベンズアルデヒド、５．０ｇ（３８．４ｍｍｏｌ）のエチル ３−オキソブタノアートおよび１５ｇのポリリン酸エチルエステルを１００ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてトルエン/酢酸エチルを用いたシリカによるカラムクロマトグラフィーによって精製する。
収量：８．７５ｇ（理論収量の５１％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 110
Ethyl 6-methyl-4- (4-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine-5-carboxylate

7.84 g (38.4 mmol) N- [3- (trifluoromethyl) phenyl] urea, 5.81 g (38.4 mmol) 4-nitrobenzaldehyde, 5.0 g (38.4 mmol) ethyl 3-oxo Butanoate and 15 g of polyphosphoric acid ethyl ester are suspended in 100 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using toluene / ethyl acetate as eluent.
Yield: 8.75 g (51% of theoretical yield)
¹ H-NMR (200 MHz, 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.

０．４０７ｇ（２．０ｍｍｏｌ）のＮ−［３−（トリフルオロメチル）フェニル］尿素、０．３０２ｇ（２．０ｍｍｏｌ）の４−ニトロベンズアルデヒド、０．２ｇ（２．０ｍｍｏｌ）の２，４−ペンタンジオンおよび０．４ｇのポリリン酸エチルエステルを２０ｍｌのＴＨＦ中で懸濁させる。この混合物を還流下で１８時間撹拌する。室温まで冷却した後、溶媒を真空下で除去し、残渣を溶出剤としてシクロへキサン/酢酸エチルを用いたシリカによるカラムクロマトグラフィーによって精製する。
収量：０．３０２ｇ（理論収量の３６％）
¹H-NMR (200 MHz, DMSO-d₆): 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. Example 111
5-acetyl-6-methyl-4- (4-nitrophenyl) -2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydropyrimidine

0.407 g (2.0 mmol) N- [3- (trifluoromethyl) phenyl] urea, 0.302 g (2.0 mmol) 4-nitrobenzaldehyde, 0.2 g (2.0 mmol) 2,4- Pentanedione and 0.4 g of polyphosphoric acid ethyl ester are suspended in 20 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica using cyclohexane / ethyl acetate as eluent.
Yield: 0.302 g (36% of theoretical yield)
¹ H-NMR (200 MHz, 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.

C. Suitable examples of use for pharmaceutical compositions The compounds of the invention can be converted into pharmaceutical formulations as follows.
tablet
Composition Example 1 100 mg, lactose (monohydrate) 50 mg, corn starch (natural) 50 mg, polyvinylpyrrolidone (PVP25) (BASF, Ludwigshafen, Germany) 10 mg and magnesium stearate 2 mg.
Tablet weight 212mg, diameter 8mm, curvature radius 12mm.
The mixture of manufacturing active ingredient, lactose and starch is granulated with 5% PVP solution (m / m) in water. The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is formed on a conventional tablet press (tablet format: see above). The molding force applied is typically 15 kN.

Suspension for oral administration
1000 mg of the compound of Composition Example 1, 1000 mg of ethanol (96%), 400 mg of Rodigel (Xanthan gum (FMC, Pennsylvania, USA)) and 99 g of water.
A 100 mg dose of a compound according to the invention is provided by 10 ml of oral suspension.
The manufactured Logigel is suspended in ethanol and the active ingredient is added to the suspension. Add water with stirring. Stirring is continued for about 6 hours until the logigel is fully swelled.

Claims (21)

Formula (I):

[Where:
A represents a phenyl or pyridyl ring;
R ¹ , R ² and R ³ are independently of each other hydrogen, halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy (wherein C ₁ -C _6- Alkyl and C ₁ -C ₆ -alkoxy may further be substituted with 1 to 3 identical or different groups selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ -alkoxy),
R ⁴ is trifluoromethylcarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C ₁ -C ₄ - _{alkylaminocarbonyl,} C 6 _{-C 10} - arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, in heterocyclyl or cyano _(wherein, C 1 -C ₆ - alkylcarbonyl, _{C 1} -C ₆ - alkoxycarbonyl, mono- - and di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 3 -C ₈ - cycloalkyl, _hydroxy, C 1 -C ₄ - _alkoxy, C 1 -C ₄ - alkoxycarbonyl , Hydroxyca Boniru, aminocarbonyl, mono- - and di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 1 -C ₄ - _{alkylcarbonylamino, (C} 1 -C ₄ - alkylcarbonyl) _-C 1 -C ₄ - alkylamino, cyano, amino, mono- - and di _-C 1 -C ₄ - alkylamino, heteroaryl, heterocyclyl and tri - _(C 1 -C ₆ - alkyl) - from 1 selected from the group consisting of silyl 3 identical or Which may be further substituted with different groups, and in the foregoing, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl may be further substituted with C ₁ -C ₄ -alkyl),
R ⁵ is halogen, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkenoxy, C ₁ -C ₆ -alkylthio, amino, mono- and di-C ₁ -C ₆ -alkylamino, arylamino 1 to 3 identical or different groups selected from the group consisting of hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl and the group —O—C ₁ -C ₄ -alkyl-O—C ₁ -C ₄ -alkyl Represents C ₁ -C ₄ -alkyl optionally substituted by
Or
R ⁵ represents amino,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, formyl, aminocarbonyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₁ -C _{6- alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) -N- _(C 1 -C ₄ - Alkyl) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl (wherein C ₁ -C ₆ -alkyl, mono- and di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C _6- Alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, heteroaryl and Heterocyclyl is aryl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, amino, Mono- and di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylcarbonylamino, tri- (C ₁ -C ₆ -alkyl) -silyl, cyano, mono- and di-C ₁ -C ₄ 1 to 3 identical or different groups selected from the group consisting of -alkylamino-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkylaminocarbonyl and halogen Which may be substituted)
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₆ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ is halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ alkoxy (wherein C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are further halogen Which may be substituted with 1 to 3 identical or different groups selected from the group consisting of hydroxy and C ₁ -C ₄ -alkoxy),
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another represent CH or N, wherein the ring contains 0, 1 or 2 nitrogen atoms] Salts, hydrates and / or solvates, and tautomers thereof. A represents a phenyl or pyridyl ring;
R ¹ , R ² and R ³ are independently of each other hydrogen, halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ -alkoxy (wherein C ₁ -C _6- Alkyl and C ₁ -C ₆ -alkoxy may further be substituted with 1 to 3 identical or different groups selected from the group consisting of halogen, hydroxy and C ₁ -C ₄ -alkoxy),
R ⁴ _is, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - _{alkoxycarbonyl,} C 1 -C ₆ - alkenoxy carbonyl, hydroxycarbonyl, aminocarbonyl, mono- - or di _-C 1 -C ₄ - _{alkylaminocarbonyl,} C 6 _{-C 10} - arylaminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, in heterocyclyl or cyano _(wherein, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, mono- -And di-C ₁ -C ₄ -alkylaminocarbonyl are C ₃ -C ₈ -cycloalkyl, hydroxy, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono - and di -C ₁ C ₄ - _{alkylaminocarbonyl,} C 1 -C ₄ - alkylcarbonylamino, amino, mono- - and di _-C 1 -C ₄ - alkylamino, heteroaryl, heterocyclyl and tri - _(C 1 -C ₆ - alkyl) - Which may be further substituted with 1 to 3 identical or different groups selected from the group consisting of silyl),
R ⁵ is halogen, hydroxy, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkenoxy, C ₁ -C ₆ -alkylthio, amino, mono- and di-C ₁ -C ₆ -alkylamino, arylamino 1 to 3 identical or different groups selected from the group consisting of hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl and the group —O—C ₁ -C ₄ -alkyl-O—C ₁ -C ₄ -alkyl Represents C ₁ -C ₄ -alkyl optionally substituted by
Or
R ⁵ represents amino,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, formyl, aminocarbonyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₃ -C ₈ -cycloalkylcarbonyl, C ₁ -C _{6- alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) - aminocarbonyl, N- _(C 1 -C ₄ - alkylsulfonyl) -N- _(C 1 -C ₄ - Alkyl) -aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl (wherein C ₁ -C ₆ -alkyl, mono- and di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C _6- Alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, heteroaryl and Heterocyclyl is aryl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, amino, Mono- and di-C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -alkylcarbonylamino, tri- (C ₁ -C ₆ -alkyl) -silyl, cyano, mono- and di-C ₁ -C ₄ 1 to 3 identical or different groups selected from the group consisting of -alkylamino-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkylaminocarbonyl and halogen Which may be substituted)
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₆ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ is halogen, nitro, cyano, C ₁ -C ₆ -alkyl, hydroxy or C ₁ -C ₆ alkoxy (wherein C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy are further halogen Which may be substituted with 1 to 3 identical or different groups selected from the group consisting of hydroxy and C ₁ -C ₄ -alkoxy),
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ independently of one another represent CH or N, wherein the ring contains 0, 1 or 2 nitrogen atoms. A compound of general formula (I) A represents a phenyl or pyridyl ring;
R ¹ , R ² and R ³ independently of one another represent hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,
R ⁴ represents C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono-C ₁ -C ₄ -alkylaminocarbonyl or cyano (in the above, C ₁ -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl and mono _-C 1 -C _4, - _{alkylaminocarbonyl,} C 3 -C ₈ - cycloalkyl, _hydroxy, C 1 -C ₄ - _alkoxy, C 1 -C ₄ -alkoxycarbonyl, amino, mono- or di-C ₁ -C ₄ -alkylamino, heteroaryl and heterocyclyl may be substituted with 1 to 3 identical or different groups selected from ,
R ⁵ represents methyl or ethyl,
R ⁶ is hydrogen, C ₁ -C ₆ -alkyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkoxycarbonyl or heterocyclylcarbonyl ( in _the, C 1 -C ₆ - alkyl and _C 1 -C ₆ - alkoxycarbonyl, heteroaryl, _hydroxy, C 1 -C ₄ - alkoxy, _{hydroxycarbonyl,} C 1 -C ₆ - alkoxycarbonyl, aminocarbonyl, mono- - and di _-C 1 -C ₄ - alkylaminocarbonyl, cyano, amino, mono- - and di _-C 1 -C ₄ - substituted with one selected from the group consisting of alkylamino three identical or different radicals May be)
Or
R ⁶ has the formula:

(Where
R ^6A is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;
And
n represents an integer of 1 or 2,
R ⁷ represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl;
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are each a compound of the general formula (I) according to claim 1 or 2, wherein each represents CH. A represents a phenyl or pyridyl ring;
R ¹ and R ³ each represent hydrogen,
R ² represents fluoro, chloro, bromo, nitro or cyano,
R ⁴ is cyano, C ₁ -C ₄ -alkylcarbonyl or C ₁ -C ₄ -alkoxycarbonyl (wherein C ₁ -C ₄ -alkoxycarbonyl is hydroxy, C ₁ -C ₄ -alkoxy, C _1- C 4 _- alkoxycarbonyl, mono- - and di -C 1 _-C 4 _- alkylamino, may be substituted with a group selected from the group consisting of heteroaryl and heterocyclyl) represents,
R ⁵ represents methyl,
R ⁶ is hydrogen, C ₁ -C ₄ -alkyl, mono- or di-C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkylcarbonyl or C ₁ -C ₄ -alkoxycarbonyl (wherein C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxycarbonyl are heteroaryl, hydroxy, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-C ₁ -C ₄ -alkylamino. Which may be substituted with a group selected from the group consisting of carbonyl, amino, mono- and di-C ₁ -C ₄ -alkylamino),
Or
R ⁶ has the formula:

(Where
R ^6A represents a moiety selected from the group consisting of hydrogen and methyl;
R ⁷ represents trifluoromethyl or nitro,
And
Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are each a compound of the general formula (I) according to claim 1, 2 or 3, wherein each represents CH. A compound of general formula (I) according to one of claims 1 to 4, wherein R ¹ is hydrogen. R ² is cyano, compounds of general formula (I) according to one of claims 1 to 5. R ³ is hydrogen, compounds of general formula (I) according to one of claims 1 to 6. R ⁴ is _C 1 -C ₄ substituted with hydroxy, optionally - or alkoxycarbonyl, or, ^{R 4} is _C 1 -C ₄ - alkylcarbonyl, generally according to one of claims 1 to 7 A compound of formula (I). R ⁵ is methyl, the compound of the general formula (I) according to one of claims 1 to 8. R ⁶ is hydrogen, compounds of general formula (I) according to one of claims 1 to 9. R ⁷ is trifluoromethyl or nitro, compounds of general formula (I) according to one of claims 1 to 10. General formula (IA):

(Where
Z represents CH or N, and
R ¹ , R ³ , R ⁴ and R ⁶ have the meanings indicated in one of claims 1 to 11).   5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} -2-pyridinecarbonitrile and its 2. A compound according to claim 1 which is a salt, hydrate and / or solvate and tautomer.   (+)-5- {5-acetyl-6-methyl-2-oxo-1- [3- (trifluoromethyl) phenyl] -1,2,3,4-tetrahydro-4-pyrimidinyl} -2-pyridine The compound according to claim 1, which is carbonitrile and its salts, hydrates and / or solvates, and tautomers. General formula (II):

(Where
A, R ¹ and R ² have the meanings given in one of claims 1 to 12) of the general formula (III):

(Where
R ⁴ and R ⁵ have the meaning indicated in one of claims 1 to 12) and the general formula (IV):

(Where
R ³ , R ⁷ and Y ¹ to Y ⁵ have the meanings indicated in one of claims 1 to 12) in the presence of an acid in a three-component / one-step reaction or in turn By condensation, the general formula (IB):

(Where
A, R ¹ to R ⁵ , R ⁷ and Y ¹ to Y ⁵ have the meanings given in one of claims 1 to 12), optionally followed by the compound of general formula (IB) Formula (V):
R ^{6 *} -X (V),
(Where
R ^{6 *} has the meaning of R ⁶ as defined in one of claims 1 to 12, but does not denote hydrogen, and
X represents a general formula (I) as defined in one of claims 1 to 14 or IA), synthesis method of each compound.   A pharmaceutical composition comprising at least one compound of general formula (I) or (IA) as defined in one of claims 1 to 14 and a pharmacologically acceptable excipient. 16. The pharmaceutical composition according to treat more acute and chronic inflammation and / or imaginary Chiyogi.   18. A compound of general formula (I) or (IA) as defined in one of claims 1 to 14, together with conventional auxiliaries, is in suitable application form. The manufacturing method of the pharmaceutical composition of.   Use of a compound of general formula (I) or (IA) as defined in one of claims 1-14 for the manufacture of a medicament. The use of claim 19, wherein for the manufacture of a medicament for the treatment of the more acute and chronic inflammation and / or imaginary Chiyogi.   21. Use according to claim 20, wherein the process is the formation of chronic obstructive pulmonary disease, acute coronary syndrome, acute myocardial infarction or heart failure.