WO2002066443A2 - 2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives - Google Patents

2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives Download PDF

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WO2002066443A2
WO2002066443A2 PCT/JP2002/001471 JP0201471W WO02066443A2 WO 2002066443 A2 WO2002066443 A2 WO 2002066443A2 JP 0201471 W JP0201471 W JP 0201471W WO 02066443 A2 WO02066443 A2 WO 02066443A2
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thioxo
tetrahydropyrimidine
methyl
phenyl
alkyl
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PCT/JP2002/001471
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WO2002066443A3 (en
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Nancy Delaet
John Williams
Dean Wilson
Nagashige Ohmawari
Hisao Nakai
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Ono Pharmaceutical Co., Ltd.
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention is related to: (1) neutral sphingomyelinase inhibitors containing 2-thioxo 1,2,3,4-tetrahydropyrimidine derivatives of the formula (I): wherein all of the symbols have the same meanings as described hereinbefore, or a non-toxic salt thereof, a hydrate thereof, or a prodrug thereof as active ingredient, (2) novel 2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives of the formula (I): wherein all of the symbols have the same meanings as described hereinbefore, or a non-toxic salt thereof, a hydrate thereof, or a prodrug thereof, (3) some novel specific compounds, and (4) process for the preparation of the compounds of the formula (Ia), or a prodrug thereof. The compounds of the present invention of the formulae (I) and (Ia) are neutral sphingomyelinase inhibitors and therefore are useful for the treatment and/or prevention of arteriosclerosis, cerebral ischemia, cardiac ischemia, lung injury, renal injury, GVHD (graft versus host diseases), transplant rejection, HIV, etc.

Description

DESCRIPTION
2-THIOXO-l, 2, 3, 4-TETRΔHYDROPYRIMIDINE DERIVATIVES
TECHNICAL FIELD
This invention relates to 2-thioxo-l, 2, 3, 4- tetrahydropyrimidine derivatives and neutral sphingo yelinase inhibitors containing 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives as active ingredient. More particularly, this invention relates to:
(1) neutral sphingomyelinase inhibitors containing 2-thioxo- 1, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (I):
Figure imgf000002_0001
H
wherein all of the symbols have the same meanings as described hereinafter, or a non-toxic salt thereof, a hydrate thereof, or a prodrug thereof as active ingredient,
(2) novel 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (la) :
Figure imgf000002_0002
wherein all of the symbols have the same meanings as described hereinafter, or a non-toxic salt thereof, a hydrate thereof, or a prodrug thereof,
(3) some novel specific compounds, and
(4) process for the preparation of the compounds of the formula (la), or a prodrug thereof. BACKGROUND ART
Sp ingomyelin and its metabolic products are known to play a role as second messengers in a variety of cellular signaling pathways. Sphingomyelinases (SMase) cleave sphingomyelin to produce ceramide and phosphocholine. Ceramide serves as a second messenger that induces a variety of cell regulatory phenomena such as apoptosis, cell differentiation, cell proliferation, and sterol homeostasis. Neutral SMase (N-SMase) is a Mg2+ sensitive enzyme that can be activated by a host of physiologically relevant and structurally diverse molecules like tumor necrosis factor-alpha (TNF-alpha) , oxidized low density lipoproteins (Ox-LDL) , and several growth factors. Programmed cell death (apoptosis) by proinfla matory cytokines such as TNF-alpha, interleukin (IL) -1, and high concentrations of Ox-LDL occurs via activation of a cell membrane-associated N-Smase (Arterioscler Thromb Vase Biol 1998, 18(10) : 1523-33) . Moreover, an antibody against N-SMase can abrogate Ox-LDL and TNF-alpha induced apoptosis. Overexpression of recombinant human N-SMase in human aortic smooth muscle cells markedly stimulates apoptosis. Since plaque stability is an integral aspect of atherosclerosis management, activation of N-SMase and subsequent apoptosis may be vital events in the onset of plaque rupture, stroke and heart failure (Chem Phys Lipids 1999, 102(1-2) : 79-96).
Lung epithelium plays a significant role in modulating the inflammatory response to lung injury. Exposure of human airway epithelial cells to H202 induces a greater than 2-fold activation of N-SMase activity with concomitant sphingomyelin hydrolysis, ceramide generation, and apoptosis (Am J Respir Cell Mol Biol 2000, 22 (4) : 460-8) . The antigen-specific signal mediated by the T-cell receptor (TCR) is essential for activation of T-cells; however, additional co-stimulatory signals are required for complete T-cell activation. Ligation of CD28 initiated sphingomyelin hydrolysis and generated ceramide. Treatment of T cells with either exogenous SMase or a cell-permeable ceramide analogue, C6- ceramide, mimicked the CD28 signal by inducing T cell proliferation and IL-2 gene transcription (Eur J Immunol 1995, 25 (7) : 1999-2004) . Inhibition of ceramide production by fumonisin BI impaired TCR-induced IL-2 production and programmed cell death. Moreover, specific inactivation of N-SMase by antisense RNA inhibited IL-2 production and mitogen-activated protein kinase activation after TCR triggering. These results suggest that ceramide production by activation of N-SMase is an essential component of the TCR signaling machinery (J Exp Med 1999, 189(10) : 1581-9). Blocking strategies of co-stimulatory signals have been evaluated as targets of therapeutic intervention for graft versus host disease (Ann Hematol 2000 Jun; 79(6) : 83-90) . Moreover, the potential for the inhibition of these co-stimulatory pathways has been reported to induce transplantation tolerance (J Am Soc Nephrol 1999, 10(6) : 1356-65) .
Renal injury dramatically increases total ceramide by approximately 300% (Am J Physiol 1999, 277(5 Pt 2) : F723-33) . Synthetic cell permeable C2-ceramide induced apoptotic death of rat neonatal cardiomyocytes in vitro. In the rat heart left coronary artery occlusion model, the content of ceramide in ischemic area was significantly elevated (Am J Pathol 1997, 151(5) : 1257-63). One of the earliest responses of cardiac myocytes to hypoxia and reoxygenation is the activation of N- SMase and accumulation of ceramide (Circ Res 2000, 86(2) 198-204) .
In the rat middle cerebral artery occlusion model, ceramide was produced in the cerebral cortex by the breakdown of sphingomyelin during early ischemia (Neurol Res 1996, 18(4) : 337-41). An increase of ceramide was found in the ischemic human brain of an acute case of internal carotid artery occlusion (Jpn J Exp Med 1989, 59(2) : 59-64) .
A drastic increase was observed in the ceramide levels after HIV-infection, whereas sphingosine levels were hardly influenced (Biochem Biophys Res Cortimun 1992, 187(1) : 209-16). Ceramide treatment resulted in a 20- to 100-fold enhancement of HIV production in infected myelomonocytic cells (AIDS Res Hum Retroviruses 1994, 10(7) : 775-80).
Neutral sphingomyelinases inhibitors are useful for the prevention and / or treatment of various diseases induced by activation of neutral sphingomyelinase. Such diseases are, for example, arteriosclerosis, cerebral ischemia, cardiac ischemia, lung injury, renal injury, GVHD (graft versus host diseases) , transplant rejection, HIV etc. Related arts
Some 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives are known. For example, in the specification of W096/14846, 2- (thi) oxo-1, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (A) :
Figure imgf000005_0001
wherein AA is
Figure imgf000006_0001
wherein each of Y1A, Y2A, Y3A, Y4AandY5Ais independently -H; straight chained or branched C1-C7 alkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -F, -CI, -Br, or -I; -N02; -OR3A, -OCOR3A, -COR3A etc.; or any two of Y1A, Y2A, Y3A, Y4A and Y5A present on adjacent carbon atoms can constitute a methylenedioxy group; wherein XA is S; 0; or NR3A; wherein R1A is -H etc.; wherein R2A is straight chained or branched C1-C7 alkyl, alkoxyalkyl, C3-C7 cycloalkyl or cycloalkenyl etc.; wherein R3A is -H; straight chained or branched C1-C7 alkyl etc.; wherein R4A is
Figure imgf000007_0001
wherein ZA is CH2; CO; C02; CONR3A etc.; PA is an integer from 1 to 7;
RA is -H; straight chained or branched C1-C7 alkyl etc.; R8A is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl etc.
(with the proviso that definitions not related are omitted.) are disclosed as selective antagonists for human πιc receptors. Also, in the specification of W097/17969, 2- (thi) oxo-1, 2, 3, 4- tetrahydropyrimidine derivatives similar to the above compounds are disclosed as selective antagonists for human Dlc receptors.
In the specification of EP 409223, 2-thioxo-l, 2, 3, - tetrahydropyrimidine derivatives of the formula (B) :
Figure imgf000007_0002
H
wherein R Cl-6 alkoxy, amino or phenylamino; R2B is Cl-6 alkyl or phenyl;
RB is Cl-11 alkyl or phenyl substituted by one or more of substituents selected from halogen, nitro, amino, di(Cl-6 alkyl) amino, Cl-6 alkyl, Cl-6 alkoxy and hydroxy, and the formula (C) :
Figure imgf000008_0001
wherein Rlc is Cl-11 alkyl; R2C is Cl-6 alkyl or phenyl; R4C is Cl-11 alkyl or phenyl substituted by one or more of substituents selected from halogen, nitro, amino, di(Cl-6 alkyl) amino, Cl-6 alkyl, Cl-6 alkoxy and hydroxy, are disclosed as intermediates of anti-inflammatory agents.
In the specification of JP 59-190974, the process for the preparation of 2-thioxo-l, 2, 3, -tetrahydropyrimidine derivatives of the formula (D) :
Figure imgf000008_0002
wherein RD is alkyl, aryl, or aralkyl, are disclosed. Also, the following compounds are known:
1) 4- (4-benzyloxyphenyl) ~5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (MFCD00974754) ,
2) 4- (4-chlorophenyl) -5- (2, 4-dichlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00974757) , 3) 4- (furan-2-yl) -5-phenylcarbamoyl-6-methyl-2~thioxo-
1, 2, 3, 4-tetrahydropyrimidine (MFCD00580265) ,
4) 4- (2-methoxynaphthalen-l-yl) -5-acetyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (MFCD00223150) ,
5) 4- (2-methoxynaphthalen-l-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00223144) , 6) 4, 6-diphenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (MFCD00052358) ,
7) 4, 6-diphenyl-5-benzoyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (MFCD00205392) , 8) 4- (thiophen-2-yl) -5-ethoxycarbonyl-β-methyl-2-thioxo-
1,2, 3, 4-tetrahydropyrimidine (MFCD00112376) ,
9) 4- (2-ethoxyphenyl) -5- (3-methylcyclohexyloxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0147212) , 10) 4- (4-methylphenyl) -5-methyl~6-ethoxycarbonyl-2-thioxo-
1, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382715) ,
11) 4- (4-methoxyphenyl) ~5-methyl-6-methoxycarbonyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
(Asinex catalog No. AS0382673) , 12) 4- (thiophen-2-yl) -5-phenylcarbamoyl-6~methyl-2-thioxo-
1, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340303) ,
13) 4- (2, 4-dichlorophenyl) -5- (4-bromophenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0372009) , 14) 4- (4-bromophenyl) -5- (4-bromophenylcarbamoyl) -6-methyl-
2-thioxo-l, 2,3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0372012) ,
15) 4- (2-methoxyphenyl) -5-methyl-6~methoxycarbonyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382658),
16) 4- (2-methoxyphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382657) ,
17) 4- (2-fluorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382720) , 18) 4- (4-methoxyphenyl) -5-methyl- 6-ethoxycarbonyl-2-thioxo- 1,2,3, -tetrahydropyrimidine (Asinex catalog No. BAS0382714),
19) 4- (2-chlorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382716) ,
20) 4- (4-dimethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0127145) ,
21) 4- (acenaphthen-5-yl) -5-ethoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340287) ,
22) 4- (4-diethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0381636),
23) 4- (2-ethoxyphenyl) -5- (2-methylcyclopentyloxycarbonyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0287844) ,
24) 4- (2, 5-dimethoxyphenyl) -5- (3, 4-dimethylcyclohexyloxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381532) , 25) 4- (2-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0603658),
26) 4- (naphthalen-1-yl) -5-methoxycarbonyl-6~methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0608654) ,
27) 4- (2, 5-dimethoxyphenyl) -5- (2-methylcyclopentyloxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381486) ,
28) 4- (4-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
(Asinex catalog No. BAS0603628),
29) 4- (2-benzyloxyphenyl) -5-ethoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, -tetrahydropyrimidine
(Asinex catalog No. BAS0619649) , 30) 4-phenyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 182170-90-7), 31) 4- (4-diethylaminophenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0326573) , 32) 4- (2-chlorophenyl) -6- (4-chlorophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 101423-56-7),
33) 4-phenyl-6- (1, 5-diphenyl-3-methylpyrazol-4-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 101985-95-9),
34) 4- (4-chlorophenyl) -6- (1, 5-diphenyl-3-methylpyrazol-4- yl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 101985-96-0),
35) 4- (pyridin-3-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
(CAS Registry No. 102989-62-8),
36) 4- (pyridin-4-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
(CAS Registry No. 102989-63-9), 37) 4- (thiophen-2-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine (CAS Registry No. 102989-64-0),
38) 4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (CAS Registry No. 106761-13-1),
39) 4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 112080-23-6),
40 ) 4-cyclohexyl-5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine (CAS Registry No. 112080-25-8),
41) 4- (2- (4-chlorobenzyloxy) phenyl) -5-methoxycarbonyl-6- ethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 114483-50-0),
42) 4- (2- (2-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 114483-54-4),
43) 4- (2- (3-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6-methyl-
2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 114483-55-5), 44) 4- (2- (4-chlorobenzyloxy) -3-methoxyphenyl) -5- ethoxycarbonyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 114483-56-6),
45) 4- (4- (4-chlorobenzyloxy) -3-nitrophenyl) -5- ethoxycarbonyl-6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (CAS Registry No. 114483-57-7),
46) 4- (furan-2-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2, 3, 4-tetrahydropyrimidine (CAS Registry No. 123629-45-8),
47) 4-phenyl-6- (4-aminophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 131138-75-5),
48) 4- (4-chlorophenyl) -6- (4-aminophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 131138-76-6), ) _ (4-methoxyphenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 131555-40-3), 50) 4- (2-chlorophenyl)-6-phenyl-2-thioxo-l,2,3,4- tetrahydropyrimidine (CAS Registry No. 131555-41-4),
51) 4- (4-dimethylaminophenyl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 131555-42-5),
52) 4- (2-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3,4-tetrahydropyrimidine (CAS Registry No. 131555-43-6),
53) 4- (4-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo-
1, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 131555-44-7),
54) 4-methyl-6-phenyl-2-thioxo-l, 2,3, -tetrahydropyrimidine (CAS Registry No. 14095-74-0), 55) 4, 6-diphenyl-5-ethoxycarbonyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 154866-93-0),
56) 4- (4-nitrophenyl) -6- (5-bromo-2-methoxyphenyl) -2-thioxo- 1,2, 3, -tetrahydropyrimidine (CAS Registry No. 169781-32-2),
57) 4- (4-methoxyphenyl) -6- (pyridin-2-yl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 172474-39-4),
58) 4, 6-bis (4-methylphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyri idine (CAS Registry No. 172494-72-3),
59) 4- (4-chlorophenyl) -5- (4-fluorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No . 181058-54-8 ) ,
60) 4- (4-chlorophenyl) -5- (4-chlorophenylcarbamoyl) -6- ιuethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
(CAS Registry No. 181058-55-9), 61) 4- (naphthalen-1-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1, 2, 3, -tetrahydropyrimidine (CAS Registry No. 219815-16-4), 62) 4- (4-methoxynaphthalen-l-yl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine
(CAS Registry No. 219815-18-6), 63) 4- (l,3-diphenylpyrazol-4-yl)-6-phenyl-2-thioxo-l,2,3,4- tetrahydropyrimidine (CAS Registry No. 221619-46-1),
64) 4- (1, 3-benzodioxol-5-yl) -6- (4-bromophenyl) -2-thioxo- 1, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 244178-65-2),
65) 4- (furan-2-yl) -6- (4-methoxyphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 259825-89-3),
66) 4-phenyl-6-ethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 259825-90-6),
67) 4- (acenaphthen-5-yl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine (CAS Registry No. 284664-25-1),
68) 4-phenyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 30570-19-5),
69) 4-methy1-6- (1-methylpropyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 34461-92-2), 70) 4-phenyl-6- (4-chlorophenyl) -2-thioxo-l, 2,3, 4- tetrahydropyrimidine (CAS Registry No. 71834-42-9),
71) 4- (4-methylphenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyri idine (CAS Registry No. 71834-43-0),
72) 4- (3-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 71834-44-1),
73) 4- (4-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 71834-45-2),
74) 4-phenyl-6- (4-methoxyphenyl) -2-thioxo-l, 2, 3, - tetrahydropyrimidine (CAS Registry No. 71834-46-3), 75) 4- (1, 3-benzodioxol-5-yl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 71834-47-4),
76) 4- (4-methylphenyl) -6- (4-methoxyphenyl) -2-thioxo-
1, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 71834-48-5), 77) 4- (4-methoxyphenyl) -6- (4-chlorophenyl) -2-thioxo-
1,2, 3, 4-tetrahydropyrimidine (CAS Registry No. 71834-49-6),
78) 4, 6-bis (4-methoxyphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine (CAS Registry No. 71834-50-9),
79) 4- (1, 3-benzodioxol-5-yl) -6- (4-chlorophenyl) -2-thioxo- 1,2,3,4-tetrahydropyrimidine (CAS Registry No. 71834-51-0),
80) 4, 6-bis (4-chlorophenyl) -2-thioxo-l, 2,3,4- tetrahydropyri idine (CAS Registry No. 71851-30-4),
81) 4, 6-dimethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 98484-90-3), 82) 4- (4, 6-dimethoxypyrimidin-5-yl) -5-rαethoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00196464) , and
83) 4-phenyl-5-ethoxycarbonyl-6- (2-methoxyphenyl) -2-thioxo-
1,2, 3, 4-tetrahydropyrimidine (MFCD00223200) . In parentheses, MFCD number refers to the compound's MDL number in the ACD (Available Chemicals Directory) Database by MDL
Information Systems Inc.
DISCLOSURE OF THE INVENTION Energetic investigations have been carried out to discover a neutral sphingomyelinase inhibitor. As a result, the present inventors have found that 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (I) have inhibitory activity against neutral sphingomyelinase, and have accomplished the present invention.
2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (I) of the present invention are not known as neutral sphingomyelinase inhibitor at all. And 2-thioxo-l, 2, 3, 4- tetrahydropyrimidine derivatives of the formula (la) of the present invention and some specific compounds are novel compounds that are not known at all.
The present invention relates to: (1) neutral sphingomyelinase inhibitors containing 2-thioxo- 1,2,3,4-tetrahydropyrimidine derivatives of the formula (I):
Figure imgf000015_0001
H
wherein
R1 is R1*"1 or R1"2;
R1"1 is 1) phenyl, 2) pyridyl, 3) imidazolyl, 4) benzimidazolyl, 5) benzoxazolyl, 6) benzothiazolyl, 7) benzofurazanyl, 8) benzofuryl,
9) benzothienyl, or 10) indolyl; each ring represented by R1"1 may be optionally substituted by 1~5 of R4; R4 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, or 9) C2-10 acyloxy; or two of R4 that present on adjacent carbon atoms can constitute a methylenedioxy group; R1"2 is
1) Cl-10 alkyl, 2) Cl-10 alkyl substituted by Cl-10 alkylthio,
3) carbocyclic ring 1, 4) carbocyclic ring 2, 5) Cl-10 alkyl substituted by carbocyclic ring 2, 5) hetero ring 1, or 6) hetero ring 2; carbocyclic ring 1 is phenyl; carbocyclic ring 2 is C3-15 mono-, bi- or tri-carbocyclic ring, with proviso that carbocyclic ring 2 does not represent phenyl; hetero ring 1 is pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl or indolyl; hetero ring 2 is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, with proviso that hetero ring 2 does not represent pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl and indolyl; carbocyclic ring 1, carbocyclic ring 2, hetero ring 1 and hetero ring 2 may be optionally substituted by 1 ~ 5 of R5;
R5isl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen, 5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR6R7, 11) -S02R8, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9 or 15) trifluoromethyl; or two of R5 that present on adjacent carbon atoms can constitute a methylenedioxy group; R6 and R7, each independently, are hydrogen or Cl-10 alkyl;
R8 is Cl-10 alkyl;
R9 is phenyl, or Cl-10 alkyl substituted by R10;
R10 is hydroxy, -COOR11, piperidyl, or phenyl optionally substituted by halogen; R11 is hydrogen, or Cl-10 alkyl; with proviso that carbocyclic ring 1 and hetero ring 1 must be substituted by at least one of 10) -NR6R7, 11) -S02R8, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9 or
15) trifluoromethyl; R2 is R2"1 or R2"2;
R2"1 is
1) -COR12, 2) -COOR13, or 3) -CONR14R15;
R12 is Cl-10 alkyl;
R13 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) Cl-10 alkyl substituted by Cl-10 alkoxy or Cl-10 alkylthio, or 4) Cl-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of Rlδ;
R14 is hydrogen, or Cl-10 alkyl;
R15 is 1) Cl-10 alkyl, or 2) C2-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16; R16 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, or 10) -NR17R18;
R17 and R18 each independently, are hydrogen or Cl-10 alkyl; R2"2 is
1) hydrogen, 2) methyl, 3) -COR19, 4) -COOR19, or 5) -CONR19R20;
R19 is 1) carbocyclic ring 3, 2) hetero ring 3, 3) Cl-10 alkyl substituted by -O-carbocyclic ring 3, or 4) Cl-10 alkyl substituted by carbocyclic ring 4; R20 is hydrogen or Cl-10 alkyl; carbocyclic ring 3 is C3-15 mono-, bi- or tri-carbocyclic ring; hetero ring 3 is 3-15 embered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms; carbocyclic ring 4 is phenyl or naphthyl; carbocyclic ring 3, hetero ring 3 and carbocyclic ring 4 may be optionally substituted by 1 - 5 of R21;
R21 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR22R23, 11) -S02R24, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25, or 15) trifluoromethyl; or two of R21 that present on adjacent carbon atoms can constitute a methylenedioxy group;
R22 and R23 each independently, are hydrogen or Cl-10 alkyl; R24 is Cl-10 alkyl;
R25 is phenyl, or Cl-10 alkyl substituted by R26;
R2S is hydroxy, -COOR27, piperidyl, or phenyl optionally substituted by halogen;
R27 is hydrogen or Cl-10 alkyl; with proviso that carbocyclic ring 4 must be substituted by at least one of 11) -S02R24, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25, or 15) trifluoromethyl; or two of R21 that present on adjacent carbon atoms must constitute a methylenedioxy group; R3 is R3"1 or R3"2 ;
R3"1 is
1) Cl-10 alkyl, or 2) Cl-10 alkyl substituted by Cl-10 alkoxy;
R3"2 is 1) -COOR28, 2) carbocyclic ring 5, or 3) hetero ring 4;
R28 is Cl-10 alkyl; carbocyclic ring 5 is C3-15 mono-, bi-, or tri-carbocyclic ring, with proviso that carbocyclic ring 5 do not represent C3-7 cycloalkyl, and C3-7 cycloalkenyl; hetero ring 4 is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms; carbocyclic ring 5 and hetero ring 4 may be optionally substituted by 1 ~ 5 of R29; R29isl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR30R31, 11) -S02R32, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR33, or 15) trifluoromethyl; or two of R29 that present on adjacent carbon atoms can constitute a methylenedioxy group;
R30 and R31 each independently, are hydrogen or Cl-10 alkyl;
R32 is Cl-10 alkyl;
R33 is phenyl, or Cl-10 alkyl substituted by R34;
R34 is hydroxy -COOR35, piperidyl, or phenyl optionally substituted by halogen;
R35 is hydrogen, or Cl-10 alkyl, a non-toxic salt thereof, a hydrate thereof, or a prodrug thereof as active ingredient,
(2) novel 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine derivatives of the formula (la) :
Figure imgf000019_0001
H
wherein
Rla is Rla_1 or Rla-2;
Rla_1 is 1) phenyl, 2) pyridyl, 3) imidazolyl, 4) benzimidazolyl, 5) benzoxazolyl, 6) benzothiazolyl, 7) benzofurazanyl, 8) benzofuryl,
9) benzothienyl, or 10) indolyl; each ring represented by Rla_1 may be optionally substituted by 1~5 of Ra; R4a is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, or 9) C2-10 acyloxy; or two of R4a that present on adjacent carbon atoms can constitute a methylenedioxy group; Rla_2 is
1) Cl-10 alkyl, 2) Cl-10 alkyl substituted by Cl-10 alkylthio,
3) carbocyclic ring la, 4) carbocyclic ring 2, 5) Cl-10 alkyl substituted by carbocyclic ring 2a, 5) hetero ring la, or 6) hetero ring 2a; carbocyclic ring la is phenyl; carbocyclic ring 2a is C3-15 mono-, bi- or tri-carbocyclic ring, with proviso that carbocyclic ring 2a does not represent phenyl; hetero ring la is pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl or indolyl; hetero ring 2a is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, with proviso that hetero ring 2a does not represent pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl and indolyl; carbocyclic ring la, carbocyclic ring 2a, hetero ring la and hetero ring 2a may be optionally substituted by 1 ~ 5 of R5a;
R5aisl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR6aR7a, 11) -S02R8a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9a or 15) trifluoromethyl; or two of R5a that present on adjacent carbon atoms can constitute a methylenedioxy group;
R6a and R7a, each independently, are hydrogen or Cl-10 alkyl; R8a is Cl-10 alkyl;
R9a is phenyl, or Cl-10 alkyl substituted by R10a;
R10 is hydroxy, -COORlla, piperidyl, or phenyl optionally substituted by halogen;
Rlla is hydrogen, or Cl-10 alkyl; with proviso that carbocyclic ring la and hetero ring la must be substituted by at least one of 10) -NRSaR7a, 11) -S02R8a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9a or
15) trifluoromethyl;
R2a is R23"1 or R2a-2 .
R2a" 1 is
1 ) -COR12a, 2 ) -COOR: 13a, or 3 ) -CONR1 aR15a
R12a is Cl- 10 alkyl ;
R13a is 1 ) Cl-10 alkyl, 2 ) C2-10 alkenyl, 3 ) Cl-10 alkyl substituted by Cl-10 alkoxy or Cl-10 alkylthio, or 4 ) Cl-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16a;
R14a is hydrogen, or Cl-10 alkyl ;
R15a is 1 ) Cl-10 alkyl , or 2 ) C2-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16a;
R16a is l ) Cl-10 alkyl , 2 ) C2-10 alkenyl, 3 ) C2-10 alkynyl, 4 ) halogen, 5 ) nitro , 6) hydroxy, 7 ) Cl-10 alkoxy, 8 ) C2-10 acyl , 9) C2-10 acyloxy, or 10 ) -NR17aR18a;
R17a and R18a each independently, are hydrogen or Cl-10 alkyl ;
R2a-2 i s
1 ) hydrogen, 2 ) methyl, 3 ) -COR19a, 4 ) -COOR19a, or 5 ) -CONR19aR20a; R19a is 1) carbocyclic ring 3a, 2) hetero ring 3a, 3) Cl-10 alkyl substituted by -O-carbocyclic ring 3a, or 4) Cl-10 alkyl substituted by carbocyclic ring 4a;
R20a is hydrogen or Cl-10 alkyl; carbocyclic ring 3a is C3-15 mono-, bi- or tri-carbocyclic ring; hetero ring 3a is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms ; carbocyclic ring 4a is phenyl or naphthyl; carbocyclic ring 3a, hetero ring 3a and carbocyclic ring 4 may be optionally substituted by 1 - 5 of R21a;
R21aisl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR2aR3a, 11) -S02R24a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25a, or 15) trifluoromethyl; or two of R21a that present on adjacent carbon atoms can constitute a methylenedioxy group;
R22a and R23a each independently, are hydrogen or Cl-10 alkyl; R24a is Cl-10 alkyl;
R25a is phenyl, or Cl-10 alkyl substituted by R26a;
R26a is hydroxy, -COOR27a, piperidyl, or phenyl optionally substituted by halogen;
R27a is hydrogen or Cl-10 alkyl; with proviso that carbocyclic ring 4 must be substituted by at least one of 11) -S02R2 a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25a, or 15) trifluoromethyl; or two of R21a that present on adjacent carbon atoms must constitute a methylenedioxy group; R3a is R3a_1 or R3a"2;
R3a"x is
1 ) Cl-10 alkyl, or 2 ) Cl-10 alkyl substituted by Cl-10 alkoxy;
R3a"2 is
1) -COOR28a, 2) carbocyclic ring 5a, or 3) hetero ring 4a; R28a is Cl-10 alkyl; carbocyclic ring 5a is C3-15 mono-, bi-, or tri-carbocyclic ring, with proviso that carbocyclic ring 5a do not represent C3-7 cycloalkyl, and C3-7 cycloalkenyl; hetero ring 4a is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms ; carbocyclic ring 5a and hetero ring 4a may be optionally substituted by 1 ~ 5 of R29a; R29a is l ) Cl-10 alkyl , 2 ) C2-10 alkenyl, 3 ) C2-10 alkynyl, 4 ) halogen,
5 ) nitro , 6 ) hydroxy, 7 ) Cl-10 alkoxy, 8 ) C2-10 acyl , 9 ) C2-10 acyloxy, 10 ) -NR30aR 1a, 11 ) -S02R32a, 12 ) phenyl optionally substituted by halogen, 13 ) -C≡C-phenyl , 14 ) -OR33a, or 15 ) trifluoromethyl ; or two of R29a that present on adj acent carbon atoms can constitute a methylenedioxy group;
R30a and R31a each independently, are hydrogen or Cl-10 alkyl ;
R32a is Cl-10 alkyl ;
R33a is phenyl , or Cl-10 alkyl substituted by R3 a; R34a is hydroxy -COOR35a, piperidyl, or phenyl optionally substituted by halogen;
R35a is hydrogen, or Cl-10 alkyl .
With proviso that
(1) Rla, R2a and R3a respectively do not represent Rla_1, R2a_1 and R3a_1 respectively at the same time;
(2) when Rla is Cl-10 alkyl or phenyl substituted by 1 - 5 of Cl-10 alkyl, halogen, nitro, hydroxy, Cl-10 alkoxy, -NR6aRa, and R2a is -COO-Cl-10 alkyl or unsubstituted -CONH-phenyl, then R3a do not represent Cl-10 alkyl or unsubstituted phenyl; (3) when Rla is Cl-10 alkyl or phenyl substituted by 1 ~ 5 of Cl-10 alkyl, halogen, nitro, hydroxy, Cl-10 alkoxy, -NR6aR7a, and R2a is -CO-Cl-10 alkyl or unsubstituted -CO-phenyl, then R3a do not represent Cl-10 alkyl or unsubstituted phenyl; and (4) the following compounds 1) ~ 83) are excluded; 1) 4- (4-benzyloxyphenyl) -5-phenylcarbamoyl~6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
2) 4- (4-chlorophenyl) -5- (2, 4-dichlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 3) 4- (furan-2-yl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
4) 4- (2-methoxynaphthalen-l-yl) -5-acetyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
5) 4- (2-methoxynaphthalen-l-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
6) 4, 6-diphenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
7) 4, 6-diphenyl-5-benzoyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
8) 4- (thiophen-2-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
9) 4- (2-ethoxyphenyl) -5- (3-methylcyclohexyloxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
10) 4- (4-methylphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 11) 4- (4-methoxyphenyl) -5-methyl-6-methoxycarbonyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
12) 4- (thiophen-2-yl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
13) 4- (2, 4-dichlorophenyl) -5- (4-bromophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
14) 4- (4-bromophenyl) -5- (4-bromophenylcarbamoyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
15) 4- (2-methoxyphenyl) -5-methyl-6-methoxycarbonyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 16) 4- (2-methoxyphenyl) -5-methyl- 6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
17) 4- (2-fluorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
18) 4- (4-methoxyphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
19) 4- (2-chlorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
20) 4- (4-dimethylaminophenyl) -5- (2-ethylthioethoxycarbonyl ' -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
21) 4- (acenaphthen-5-yl) ~5-ethoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, -tetrahydropyrimidine,
22) 4- (4-diethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) - 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 23) 4- (2-ethoxyphenyl) -5- (2-methylcyclopentyloxycarbonyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
24) 4- (2, 5-dimethoxyphenyl) -5- (3, 4-dimethylcyclohexyloxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
25) 4- (2-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
26) 4- (naphthalen-1-yl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
27) 4- (2, 5-dimethoxyphenyl) -5- (2-methylcyclopentyloxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 28) 4- (4-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
29) 4- (2-benzyloxyphenyl) -5-ethoxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
30) 4-phenyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
31) 4- (4-diethylaminophenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
32) 4- (2-chlorophenyl) -6- (4-chlorophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
33) 4-phenyl-6- (1, 5-diphenyl-3-methylpyrazol-4-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
34) 4_ (4-chlorophenyl) -6- (1, 5-diphenyl-3-methylpyrazol-4- yl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
35) 4- (pyridin-3-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
36) 4- (pyridin-4-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
37) 4- (thiophen-2-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
38 ) 4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
39) 4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 40) 4-cyclohexyl-5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
41) 4- (2- (4-chlorobenzyloxy) phenyl) -5-methoxycarbonyl-6- ethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
42) 4- (2- (2-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
43) 4- (2- (3-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
44) 4- (2- (4-chlorobenzyloxy) -3-methoxyphenyl) -5-ethoxy carbonyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 45) 4- (4- (4-chlorobenzyloxy) -3-nitrophenyl) -5-ethoxy carbonyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 46) 4- (furan-2-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
47) 4-phenyl-6- (4-aminophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
48) 4- (4-chlorophenyl) -6- (4-aminophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
49) 4- (4-methoxyphenyl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 50) 4- (2-chlorophenyl) -6-phenyl-2-thioxo-l, 2,3, 4- tetrahydropyrimidine,
51) 4- (4-dimethylaminophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
52) 4- (2-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
53) 4- (4-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
54) 4-methyl-6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
55) 4, 6-diphenyl-5-ethoxycarbonyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
56) 4- (4-nitrophenyl) -6- (5-bromo-2-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 57) 4- (4-methoxyphenyl) -6- (pyridin-2-yl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
58) 4, 6-bis (4-methylphenyl) -2-thioxo-l, 2,3, 4- tetrahydropyrimidine,
59) 4- (4-chlorophenyl) -5- (4-fluorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
60) 4- (4-chlorophenyl) -5- (4-chlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
61) 4- (naphthalen-1-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 62) 4- (4-methoxynaphthalen-l-yl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
63) 4- (1, 3-diphenylpyrazol-4-yl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
64) 4- (1, 3-benzodioxol-5-yl) -6- (4-bromophenyl) -2-thioxo- 1,2,3,4-tetrahydropyrimidine,
65) 4- (furan-2-yl) -6- (4-methoxyphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
66) 4-phenyl-6-ethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
67) 4- (acenaphthen-5-yl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
68 ) 4-phenyl-6-methyl-2-thioxo-l , 2,3,4- tetrahydropyrimidine,
69) 4-methyl-6- (1-methylpropyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine, 70) 4-phenyl-6- (4-chlorophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
71) 4- (4-methylphenyl ) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 72) 4- (3-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
73) 4- (4-chlorophenyl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
74) 4-phenyl-6- (4-methoxyphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
75) 4- (1, 3-benzodioxol-5-yl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
76) 4- (4-methylphenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 77) 4- (4-methoxyphenyl) -6- (4-chlorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
78) 4, 6-bis (4-methoxyphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
79) 4- (1, 3-benzodioxol-5-yl) -6- (4-chlorophenyl) -2-thioxo- 1,2,3,4-tetrahydropyrimidine,
80) 4, 6-bis (4-chlorophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
81) 4, 6-dimethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
82) 4- (4, 6-dimethoxypyrimidin-5-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
83) 4-phenyl-5-ethoxycarbonyl-6- (2-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, a non-toxic salt thereof, a hydrate thereof, and a prodrug thereof, (3) the following novel compounds: 1) 4- (4-chloro-3-nitrophenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
2) 4- (2,3-dichlorophenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
3) 4- (4-hydroxy-3-nitro-5-methoxyphenyl) -5-ethoxycarbonyl- 6-phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
4) 4- (3, 4-dichlorophenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
5) 4- (4-diethylaminophenyl) -5-ethoxycarbonyl- 6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
6) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
7) 4- (4-nitrophenyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 8) 4- (6-bromo-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 9) 4- (4-hydroxy-3-methoxy-5-nitrophenyl) -5- (2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 10) 4- (4-diethylaminophenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
11) 4- (3-bromophenyl) -5- (2-methoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
12) 4- (3, 4-dichlorophenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl~2-thioxo-1, 2,3, -tetrahydropyrimidine,
13) 4- (1-ethylpropyl) -5-methoxycarbonyl-6-ethyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
14) 4- (1-ethylpropyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 15) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
16) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
17) 4- (4-methoxyphenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
18) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-benzyloxy carbonyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
19) 4- (4-methoxyphenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 20 ) 4- ( 4-chlorophenyl ) -5- (2-ethoxyethoxycarbonyl ) -6-methyl- 2-thioxo-l, 2 , 3 , 4-tetrahydropyrimidine,
21) 4- (4-diethylaminophenyl) -5-phenylcarbamoyl- 6-methyl-2- thioxo-1 , 2 , 3 , 4-tetrahydropyrimidine, 22 ) 4- ( 6-chloro-l , 3-benzodioxol-5~yl ) -5-benzyloxycarbonyl- 6-methyl-2-thioxo-l , 2 , 3 , 4-tetrahydropyrimidine,
23 ) 4- ( 6-chloro-l , 3-benzodioxol-5-yl ) -5-ethoxycarbonyl- 6-t- butyl-2-thioxo-l , 2 , 3, 4-tetrahydropyrimidine,
24 ) 4- ( 6-chloro-l , 3-benzodioxol-5-yl ) -5- (N, N-diethyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
25) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6- t-butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
26) 4- (6-bromo-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 27) 4- (2-ethoxyphenyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
28) 4- (2-ethoxyphenyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
29) 4- (4-chlorophenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
30) 4- (4-chlorophenyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, -tetrahydropyrimidine,
31) 4- (4-chlorophenyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 32) 4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6-t-butyl-2- thioxo-1,2, 3, 4-tetrahydropyrimidine,
33) 4- (4-chlorophenyl) -5-benzylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
34) 4- (4-chlorophenyl) -5- ( (4-methoxybenzyl) carbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
35) 4- (2, 5-dimethoxyphenyl) -5- (N-benzyl-N-methylcarbamoyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
36) 4- (2, 5-dimethoxyphenyl) -5- ( (2- (4-methoxyphenyl) ethyl) ) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 37) 4- (2, 5-dimethoxyphenyl) -5-phenylcarbamoyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
38) 4- (4-chlorophenyl) -5- (N-benzyl-N-methylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 39) 4- (4-diethylaminophenyl) -5~phenylcarbamoyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
40) 4- (4-diethylamino-2-hydroxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
41) 4- (1-ethylpropyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
42) 4- (l-acetylindol-3-yl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
43) 4- (4-pentylphenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 44) 4- (4-pentylphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
45) 4-pentyl-5-phenylcarbamoyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
46) 4- (4- (2-methylpropyl) phenyl) -5-phenylcarbamoyl-6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
47) 4-pentyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
48) 4- (2-methylpropyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 49) 4- (4- (2-methylpropyl) phenyl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-1, 2,3, 4-tetrahydropyrimidine,
50) 4-propyl-5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine, or
51) 4- (4- (2-methylpropyl) phenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, or (4) process for the preparation of the compounds of the formula (la) , a non-toxic salts thereof, a hydrate thereof, and a prodrug thereof. DETAILED DESCRIPTION OF INVENTION
The present invention as above summarized are described in detail below.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include straight-chain and branched-chain ones. Moreover, the isomers in the structure of a double bond, ring, fused ring (E, Z, cis, trans) , the isomers generated by the presence of asymmetric carbon atom(s) etc. (R, S isomers, α, β isomers, enantiomers, diastereomers) optically active isomers having optical rotation (D, L, d, 1 isomers) , isomers separated by chromatography (more polar or less polar isomers) , equilibrium compounds, compounds of arbitrary ratio of these compounds. In the formulae (I) and (la), Cl-10 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomeric groups thereof.
In the formulae (I) and (la) , C2-10 alkenyl means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and isomeric groups thereof.
In the formulae (I) and (la) , C2-10 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and isomeric groups thereof.
In the formulae (I) and (la) , Cl-10 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomeric groups thereof.
In the formulae (I) and (la) , Cl-10 alkylthio means methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio and isomeric groups thereof.
In the formulae (I) and (la), C2-10 acyl means ethanoyl (acetyl), propanoyl (propionyl) , butanoyl (butyryl) , pentanoyl (valeryl) , hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and isomeric groups thereof. In the formulae (I) and (la), C2-10 acyloxymeans ethanoyloxy
(acetyloxy) , propanoyloxy (propionyloxy) , butanoyloxy
(butyryloxy) , pentanoyloxy (valeryloxy) , hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy and isomeric groups thereof.
In the formulae (I) and (la) , halogen is fluorine, chlorine, bromine and iodine .
In the formulae (I) and (la), C3-7 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the formulae (I) and (la), C3-7 cycloalkenyl means cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl .
In the formulae (I) and (la), carbocyclic ring 1 and carbocyclic ring la means benzene (phenyl) .
In the formulae (I) and (la), carbocyclic ring 2 and carbocyclic ring 2a mean C3-15 mono-, bi- or tri-carbocyclic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, indene, naphthalene, indan, tetrahydronaphthalene, bicyclo [3.3.0] octane, bicyclo [3.3.0]nonane, bicyclo [4.4.0] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5]undecane, fluorene, anthracene, 9, 10-dihydroanthracene, bicyclo [3.1.1] heptane, bicyclo [3.3.1] -2-heptene, adamantane, bicyclo [2.2.0] octane, acenaphthene etc.. In the formulae (I) and (la), carbocyclic ring 3 and carbocyclic ring 3a mean C3-15 mono-, bi- or tri-carbocyclic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, indene, naphthalene, indan, tetrahydronaphthalene, bicyclo [3.3.0] octane, bicyclo [3.3.0] nonane, bicyclo [4.4.0] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5]undecane, fluorene, anthracene, 9, 10-dihydroanthracene, bicyclo [3.1.1] heptane, bicyclo [3.3.1] -2-heptene, adamantane, bicyclo [2.2.0] octane, acenaphthene etc.. In the formulae (I) and (la) , carbocyclic ring 4 and carbocyclic ring 4a mean benzene (phenyl) or naphthalene (naphthyl) .
In the formulae (I) and (la) , carbocyclic ring 5 and carbocyclic ring 5a mean C3-15 mono-, bi- or tri-carbocyclic ring, for example, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, indene, naphthalene, indan, tetrahydronaphthalene, bicyclo [3.3.0] octane, bicyclo [3.3.0] nonane, bicyclo [4.4.0] decane, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, fluorene, anthracene, 9, 10-dihydroanthracene, bicyclo [3.1.1] heptane, bicyclo [3.3.1] -2-heptene, adamantane, bicyclo [2.2.0] octane, acenaphthene etc.. In the formulae (I) and (la) , hetero ring 1 and hetero ring la mean pyridine (pyridyl), imidazole (imidazolyl), benzimidazole (benzimidazolyl) , benzoxazole (benzoxazolyl) , benzothiazole (benzothiazolyl) , benzofurazan (benzofurazanyl) , benzofuran (benzofuryl), benzothiophene (benzothienyl), or indole (indolyl) . In the formulae (I) and (la) , hetero ring 2 and hetero ring 2a mean 3-15 membered mono- or bi-heterocyclic aryl, or mono- or bi-, partially or fully saturated heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms . For example, 3-15 membered mono- or bi-heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, means pyrrole, triazole, tetrazole, pyrazole, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiin (thiopyran) , thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, isoindole, isobenzofuran, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxepin, benzoxazepine, benzoxadiazepine, benzothiepin, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzothiadiazole, benzotriazole etc..
For example, 3-15 membered mono- or bi- partially or fully saturated heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, means pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetraazoline, tetraazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiine (dihydrothiopyran) , tetrahydrothiine (tetrahydrothiopyran) , dihydrooxazole, tetrahydrooxazole (oxazolidine) , dihydroisoxazole, tetrahydroisoxazole (isooxazolidine) , dihydrothiazole, tetrahydrothiazole (thiazolidine) , dihydroisothiazole, tetrahydroisothiazole (isothiazolidine) , dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine) , dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine) , tetrahydrooxadiazine, tetrahydrothiadiazine, tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, benzodioxane, benzodithiolane, benzodithiane etc..
In the formulae (I) and (la), hetero ring 3, hetero ring 3a, hetero ring 4 and hetero ring 4a mean 3-15 membered mono- or bi-heterocyclic aryl, or mono- or bi-, partially or fully saturated heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms.
For example, 3-15 membered mono- or bi-heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, means pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiin (thiopyran) , thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzoxepin, benzoxazepine, benzoxadiazepine, benzothiepin, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, acridine etc..
For example, 3-15 membered mono- or bi- partially or fully saturated heterocyclic aryl containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, means pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetraazoline, tetraazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyridine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiine
(dihydrothiopyran) , tetrahydrothiine (tetrahydrothiopyran) , dihydrooxazole, tetrahydrooxazole (oxazolidine) , dihydroisoxazole, tetrahydroisoxazole (isooxazolidine) , dihydrothiazole, tetrahydrothiazole (thiazolidine) , dihydroisothiazole, tetrahydroisothiazole (isothiazolidine) , dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine) , dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine) , tetrahydrooxadiazine, tetrahydrothiadiazine, tetrahydrooxazepine, tetrahydrooxadiazepine, perhydrooxazepine, perhydrooxadiazepine, tetrahydrothiazepine, tetrahydrothiadiazepine, perhydrothiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dithiolane, dithiane, benzodioxolane, benzodioxane, benzodithiolane, benzodithiane etc..
Preferred R1"1 and Rla_1 are phenyl.
Preferred R1"2 and Rla~2 are carbocyclic ring 1 and la, carbocyclic ring 2 and 2a, Cl-10 alkyl substituted by carbocyclic ring 2 and 2a or hetero ring 2 and 2a. More preferred R1"2 and Rla~2 are carbocyclic ring 1 and la, carbocyclic ring 2 and 2a or hetero ring 2 and 2a. Preferred carbocyclic ring 2 and 2a are C3-7 mono-carbocyclic ring, and more preferred carbocyclic ring 2 and
2a are phenyl. Preferred hetero ring 2 and 2a are 3-10 membered mono- or bi-hetero ring containing 1 ~ 2 of hetero atoms selected form nitrogen, oxygen or sulfur atoms.
Preferred R2"1 and R2a_1 are -COOR13 and -COOR13a. Preferred R13 and R13a are Cl-10 alkyl, or Cl-10 alkyl substituted by Cl-10 alkoxy or Cl-10 alkylthio. Preferred R2"2 and 2a"2 are -COR19 and -C0R19a, -COOR19 and -
C00R19a, or -CONR19R20 and -CONR19aR20a. More preferred R2-2 and R2a"
2 are -CONR19R20 and -CONR19aR20a . Preferred R19 and R19a are carbocyclic ring 3 and 3a, or hetero ring 3 and 3a. Preferred carbocyclic ring
3 and 3a are C3-7 mono-carbocyclic ring. Preferred hetero ring 3 and 3a are 3-10 membered mono- or bi-hetero ring containing 1 ~ 2 of hetero atoms selected from nitrogen, oxygen or sulfur atoms .
Preferred R3"1 and R3a_1 are Cl-10 alkyl.
Preferred R3"2 and R3a"2 are carbocyclic ring 5 and 5a. Preferred carbocyclic ring 5 and 5a are C3-7 mono-carbocyclic ring. More preferred carbocyclic ring 5 and 5a are phenyl.
The compounds of the formulae (I) and (la) of the present inventionmaybe converted to corresponding salts by knownmethods . Non-toxic and water-soluble salts are preferable. Suitable salts include salts of alkali metal (potassium, sodium, etc.), salts of alkali earth metal (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable salts of organic amine
(tetramethylammonium, triethylamine, methylamine, dimeth lamine, cyclopentylamine, benzylamine, phenethyla ine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.).
The compounds of the formulae (I) and (la) of the present invention may be converted to corresponding acid addition salts by known methods . Non-toxic and water-soluble acid addition salts are preferable. Suitable acid addition salts include salts of inorganic acid (e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid) and salts of organic acid (e.g. salts of acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzole acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, , toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid), etc. The compounds of the formulae (I) and (la) of the present invention or salts thereof may be converted to corresponding hydrates by known methods .
The prodrug of the formula (I) means the compound of the formula (I ' )
Figure imgf000039_0001
H
wherein R36 is Cl-10 alkyl, and the other symbols have the same meaning as hereinbefore described.
The prodrug of the formula (la) means the compound of the formula (la' )
Figure imgf000039_0002
H
wherein R36a is Cl-10 alkyl, and the other symbols have the same meaning as hereinbefore described. The preferable specific compounds of the formulae (I) and (la) are the following compounds (1) ~ (83), and those described in the Examples.
Compound (1) : 4- (4-benzyloxyphenyl) -5-phenylcarbamoyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00974754)
Figure imgf000039_0003
Compound (2) : 4- (4-chlorophenyl) -5-phenylcarbamoyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 182170-95-2)
Figure imgf000040_0001
Compound (3) : 4- (4-chlorophenyl) -5- (2, 4- dichlorophenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (MFCD00974757)
Figure imgf000040_0002
Compound (4) : 4- (furan-2-yl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine (MFCD00580265)
Figure imgf000040_0003
Compound (5) : 4- (2-chloro-6-fluorophenyl) -5-phenylcarbamoyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No 183231-05-2)
Figure imgf000040_0004
Compound ( 6 ) : 4- ( 4-chlorophenyl ) -5-ethoxycarbonyl- 6-methyl- 2-thioxo-l , 2 , 3 , 4-tetrahydropyrimidine (MFCD00196753 )
Figure imgf000041_0001
Compound (7) : 4- (2-methoxyphenyl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00227676)
Figure imgf000041_0002
Compound (8) : 4- (2-methoxynaphthalen-l-yl) -5-acetyl-6- methyl-2-thioxo-l,2,3, 4-tetrahydropyrimidine (MFCD00223150)
Figure imgf000041_0003
Compound (9) : 4- (4-hydroxy-3-methoxyphenyl) -5- ethoxycarbonyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00224923)
Figure imgf000042_0001
Compound (10) : 4- (4-dimethylaminophenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (CAS Registry No. 19492-61-6)
Figure imgf000042_0002
Compound (11) : 4- (2-methoxynaphthalen-l-yl) -5- methoxycarbonyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (MFCD00223144)
Figure imgf000042_0003
Compound (12) : 4-phenyl-5-methoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine (MFCD00275315)
Figure imgf000042_0004
Compound (13) : 4, 6-diphenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 6381-55-1)
Figure imgf000043_0001
Compound (14) : 4, 6-diphenyl-5-benzoyl-2~thioxo-l, 2, 3, 4- tetrahydropyrimidine (CAS Registry No. 253328-49-3)
Figure imgf000043_0002
Compound (15) : 4- (2-chloro-6-fluorophenyl) -5-ethoxycarbonyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00112375)
Figure imgf000043_0003
Compound (16) : 4-phenyl-5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine (MFCD00188414)
Figure imgf000043_0004
Compound (17) : 4- (thiophen-2-yl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (MFCD00112376)
Figure imgf000044_0001
Compound (18) : 4- (2-ethoxyphenyl) -5- (2-methyl propoxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (Asinex catalog No. BAS0147211)
Figure imgf000044_0002
Compound (19) : 4- (2-propoxyphenyl) -5-hexyloxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0161659)
Figure imgf000044_0003
Compound (20) : 4- (2-ethoxyphenyl) -5- (3- methylcyclohexyloxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0147212)
Figure imgf000044_0004
Compound (21) : 4- (4-methylphenyl) -5-methyl-6-ethoxycarbonyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382715)
Figure imgf000045_0001
Compound (22) : 4- (4-methoxyphenyl) -5-methyl-6- methoxycarbonyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382673)
Figure imgf000045_0002
Compound (23) : 4- (2-fluorophenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0246374)
Figure imgf000045_0003
Compound (24) : 4- (thiophen-2-yl) -5-phenylcarbamoyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340303)
Figure imgf000046_0001
Compound (25) : 4- (2, 4-dichlorophenyl) -5- (4- bromophenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0372009)
Figure imgf000046_0002
Compound (26) : 4- (4-bromophenyl) -5- (4-bromophenylcarbamoyl) 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0372012)
Figure imgf000046_0003
Compound (27) : 4- (2-methoxyphenyl) -5-methyl-6- methoxycarbonyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382658)
Figure imgf000046_0004
Compound (28) : 4- (2-methoxyphenyl) -5-methyl-6- ethoxycarbonyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382657)
Figure imgf000047_0001
Compound (29) : 4- (1, 3-benzodioxol-5-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381278)
Figure imgf000047_0002
Compound (30) : 4- (2-fluorophenyl) -5-methyl-6-ethoxycarbonyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382720)
Figure imgf000047_0003
Compound (31) : 4- (4-dimethylaminophenyl) -5-methoxycarbonyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 134074-44-5)
Figure imgf000048_0001
Compound (32) : 4- (2-ethoxyphenyl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0380930)
Figure imgf000048_0002
Compound (33) : 4- (4-methoxyphenyl) -5-methyl-6- ethoxycarbonyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382714)
Figure imgf000048_0003
Compound (34) : 4- (2-chlorophenyl) -5-methyl- 6-ethoxycarbonyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0382716)
Figure imgf000049_0001
Compound (35) : 4- (4-dimethylaminophenyl) -5- (2- ethylthioethoxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (Asinex catalog No. BAS0127145)
Figure imgf000049_0002
Compound (36) : 4- (acenaphthen-5-yl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340287)
Figure imgf000049_0003
Compound (37) : 4- (4-diethylaminophenyl) -5- (2- ethylthioethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0381636)
Figure imgf000050_0001
Compound (38) : 4- (2, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381021)
Figure imgf000050_0002
Compound (39) : 4- (3, , 5-trimethoxyphenyl) -5-ethoxycarbonyl- 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0655585)
Figure imgf000050_0003
Compound (40) : 4- (2, 5-dimethoxyphenyl) -5- (2- propenyloxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, - tetrahydropyrimidine (Asinex catalog No. BAS038143S
Figure imgf000051_0001
Compound (41) : 4- (4-bromophenyl) -5-methoxycarbonyl-6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0486131)
Figure imgf000051_0002
Compound (42) : 4- (4-methoxyphenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381302)
Figure imgf000051_0003
Compound (43) : 4- (2-ethoxyphenyl) -5- (2- methylcyclopentyloxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0287844)
Figure imgf000051_0004
Compound (44) : 4- (2, 5-dimethoxyphenyl) -5- (3, 4- di ethylcyclohexyloxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (Asinex catalog No. BAS0381532)
Figure imgf000052_0001
Compound (45) : 4- (4- (1-methylethyl) phenyl) -5-ethoxycarbonyl- 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0417019)
Figure imgf000052_0002
Compound ( 46 ) : 4- ( 3-methoxy-4-propoxyphenyl ) -5- methoxycarbonyl- 6-methyl-2-thioxo-l , 2 , 3 , 4- tetrahydropyrimidine (Asinex catalog No . BAS0603631 )
Figure imgf000052_0003
Compound (47) : 4- (4-methoxyphenyl) -5- (1- methylethoxycarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine (Asinex catalog No. BAS0141626)
Figure imgf000053_0001
Compound (48) : 4- (2, 3-dimethoxyphenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340260)
Figure imgf000053_0002
Compound (49) : 4- (2-methoxyphenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0380855)
Figure imgf000053_0003
Compound (50) : 4- (3-methoxy-4-propoxyphenyl) -5- ethoxycarbonyl-6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0603637)
Figure imgf000053_0004
Compound (51) : 4- (2-benzyloxyphenyl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0603658)
Figure imgf000054_0001
Compound (52) : 4- (4- (1-methylethyl) phenyl) -5- methoxycarbonyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0417020)
Figure imgf000054_0002
Compound (53) : 4- (4-dimethylaminophenyl) -5- (2- ethylbutoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0111575)
Figure imgf000054_0003
Compound (54) : 4- (naphthalen-1-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0608654)
Figure imgf000055_0001
Compound (55) : 4- (2, 5-dimethoxyphenyl) -5- (2- phenylethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0381410)
Figure imgf000055_0002
Compound (56) : 4- (2-propoxyphenyl) -5- (2- propenyloxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0316882)
Figure imgf000055_0003
Compound (57) : 4- (3, 4-dimethoxyphenyl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0486167)
Figure imgf000055_0004
Compound (58) : 4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0340258)
Figure imgf000056_0001
Compound (59) : 4- (2, 5-dimethoxyphenyl) -5- (2- methylcyclopentyloxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0381486)
Figure imgf000056_0002
Compound (60) : 4- (2-propoxyphenyl) -5- (2- phenylethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0381619)
Figure imgf000056_0003
Compound (61) : 4- (4-benzyloxyphenyl) -5-methoxycarbonyl- 6- methyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0603628)
Figure imgf000057_0001
Compound (62) : 4- (3-hydroxyphenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0667373)
Figure imgf000057_0002
Compound (63) : 4- (4-diethylaminophenyl) -5-butoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0135155)
Figure imgf000057_0003
Compound (64) : 4- (2, 5-dimethoxyphenyl) -5- (2- ethylbutoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0111570)
Figure imgf000058_0001
Compound (65) : 4- (2, 4-dimethoxyphenyl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381015)
Figure imgf000058_0002
Compound (66) : 4- (2-ethoxyphenyl) ~5-butoxycarbonyl-6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0147209)
Figure imgf000058_0003
Compound (67) : 4- (2, 4-dimethoxyphenyl) -5-pentyloxycarbonyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0101150)
Figure imgf000058_0004
Compound ( 68 ) : 4- (2-benzyloxyphenyl ) -5-ethoxycarbonyl- 6- methyl-2-thioxo-l , 2 , 3 , 4-tetrahydropyrimidine ( 114483-51-1 ]
Figure imgf000059_0001
Compound (69) : 4- (2-propoxyphenyl) -5~benzyloxycarbonyl-6- methyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381393)
Figure imgf000059_0002
Compound (70) : 4- (2-ethoxyphenyl) -5- (2- ethylthioethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0380972)
Figure imgf000059_0003
Compound (71) : 4- (2-ethoxyphenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0381007)
Figure imgf000060_0001
Compound (72) : 4- (2-methoxyphenyl) -5-butoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0101183)
Figure imgf000060_0002
Compound (73) : 4- (2-methoxyphenyl) -5-pentyloxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0101141)
Figure imgf000060_0003
Compound (74) : 4- (2-ethoxyphenyl) -5-hexyloxycarbonyl-6- methyl-2-thioxo-l, 2,3, -tetrahydropyrimidine (Asinex catalog No. BAS0161659)
Figure imgf000060_0004
Compound (75 ; 4- ( 2-propoxyphenyl ) -5~pentyloxycarbonyl- 6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0147187)
Figure imgf000061_0001
Compound (76) : 4- (2, 5-dimethoxyphenyl) -5-butoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0111565)
Figure imgf000061_0002
Compound (77) : 4- (2, 5-dimethoxyphenyl) -5- (2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0381224)
Figure imgf000061_0003
Compound (78) : 4- (2-ethoxyphenyl) -5-pentyloxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0188351)
Figure imgf000062_0001
Compound (79) : 4- (3-hydroxy-4-methoxyphenyl) -5- ethoxycarbonyl-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine (Asinex catalog No. BAS0287844)
Figure imgf000062_0002
Compound (80) : 4- (4-nitrophenyl) -5-ethoxycarbonyl-6-phenyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine (CAS Registry No. 134074-37-6)
Figure imgf000062_0003
Compound ( 81 ) : 4- ( 4-methoxyphenyl ) -5-ethoxycarbonyl- 6- phenyl-2-thioxo-l, 2 , 3, 4-tetrahydropyrimidine (CAS Registry No . 134074-40-1 )
Figure imgf000063_0001
Compound (82) : 4-phenyl-5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2, 3, 4-tetrahydropyrimidine (CAS Registry No. 182170-90-7)
Figure imgf000063_0002
Compound (83) : 4- (4-diethylaminophenyl) -5- (2- ethoxyethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (Asinex catalog No. BAS0326573)
Figure imgf000063_0003
Process for the preparation
1 ) In the compound of the formula ( la) , R is -COR , -COOR , 13a
-CONR14aR15a, -COR19a, -COOR19a and -CONR19aR20a, that is the compound of the formula ( Ia-1 )
Figure imgf000064_0001
H
wherein R37a is -R12a, -OR13a, -NR1 aR15a, -R ,19>a% -0R ,193aa or
Figure imgf000064_0002
and the other symbols have the same meaning as hereinbefore described, may be prepared by following (a) and (b) methods. (a) The compound of the formula (Ia-1) may be prepared by cyclization of the compound of formula (II)
Figure imgf000064_0003
wherein all the symbols have the same meaning as hereinbefore described, with the compound of formula ( III )
Figure imgf000064_0004
with concomitant S-deprotection.
This reaction may be carried out, for example, in organic solvent (pyridine etc.) at 70 ~ 100°C.
(b) The compound of the formula (Ia-1) may be prepared by reacting the compound of formula (IV)
Figure imgf000064_0005
wherein all the symbols have the same meaning as hereinbefore described, with the compound of formula (V)
Figure imgf000065_0001
wherein Rla has the same meaning as hereinbefore described and the compound of formula (VI)
Figure imgf000065_0002
This reaction may be carried out, for example, in organic solvent (ethoxyethanol etc.) in the presence of an acid (hydrochloric acid etc.) at 60 ~ 100°C.
2) The compound of the formula (la), where R2a is hydrogen and methyl, that is the compound of the formula (Ia-2)
Figure imgf000065_0003
H
wherein R38a is hydrogen or methyl, and the other symbols have the same meaning as hereinbefore described, may be prepared by the following method.
The compound of the formula (Ia-2) may be prepared by reacting the compound of formula (VII)
Figure imgf000065_0004
wherein all the symbols have the same meaning as hereinbefore described, with the above described compound of formula (VI) .
This reaction may be carried out, for example, in organic solvent (methanol, ethanol etc.) , using an alkali metal hydroxide (potassium hydroxide, sodium hydroxide etc.), in an aqueous solution thereof at 60 ~ 100°C.
3) The prodrug of the formula (la), that is the compound of the formula (la' )
Figure imgf000066_0001
H
wherein all the symbols have the same meaning as hereinbefore described, may be prepared by the following method.
The compound of the formula ( la ' ) may be prepared by reacting the compound of formula (la) with the compound of formula (VIII)
Figure imgf000066_0002
wherein R36a has the same meaning as hereinbefore described, or the compound of the formula ( IX)
Figure imgf000066_0003
wherein X is halogen atom, and R36a has the same meaning as hereinbefore described.
This reaction may be carried out, for example, in organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) or without solvent, in the presence of a tertiary amine (pyridine, triethylamine, dimethylaniline, dimethyla inopyridine etc.) at -20 ~ 40°C.
The compounds of the formulae (II), (III), (IV), (V), (VI), (VII) , (VIII) or (IX) are known per se or may be prepared by known methods .
For example, the compound of the formula (II) may be prepared by the following scheme 1 .
Scheme 1
Figure imgf000067_0001
,1a^\ (V)
H
Acetic acid, piperidine, molecular sieves
Figure imgf000067_0002
In the above scheme 1, all the symbols have the same meaning as hereinbefore described. In each reaction in the present specification, products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
The other starting materials and reagents in the present invention are known per se or may be prepared by known methods . Pharmacological An i vi i es
The inhibitory activity against neutral sphingomyelinase was confirmed as follows.
1) Inhibitory activity against neutral sphingomyelinase (in vitro) Assays were conducted at 37°C in a total volume of lOOμL. Firstly,
50 μL of substrate solution (50uM [methyl-14C] sphingomyelin in reaction buffer containing 20mM HEPES NaOH pH7.4, 20mM MgCl2, and 0.1% Triton X-100) and lOμL of a solution of the compound of the present invention (DMSO solution) were mixed and preincubated for 5 min. Next, reactions were initiated by the addition of 40μL of enzyme solution (containing 1U of mouse neutral sphingomyelinase, 20mM HEPES NaOH pH7.4 solution ) , and subsequently terminated after 30min by the addition of 400μL of chlorofor /methanol (1:1 v/v) . After vortex mixing and centrifugation, the mass of hydrolysed [N-methyl-14C]phosphorylcholine in the aqueous phase was determined by measuring of the 14C radioactivity using a liquid scintillation counter.
Using serial logarithmic concentrations of the compound of the present invention as independent variables and corresponding inhibitory percentages as dependent variables, a linear regression analysis by the least squares method was carried out to calculate IC50 values.
The results are shown in Table 1 and 2.
Table 1
Figure imgf000069_0001
Table 2
Figure imgf000070_0001
Inhibitory activities of the compound of the present invention on human neutral sphingomyelinase can also be determined by exchanging mouse neutral sphingomyelinase for human neutral sphingomyelinase.
2) Inhibitory activities of the compound of the present invention on IL-2 secretion in T cells can be measured as follows.
IL-2 secretion in Jurkat cells (cell based)
Jurkat cells (human T cell leukemia cell line, 4 x IO5 cells/well) were incubated in 96-well tissue culture plate with the compound of the present invention for lhr at 37 °C before stimulation with 4 uM Ionomycin, 40 nM Phorbol-myristate-acetate and 4 μg/ml anti-CD28. After stimulation cells were incubated for 6hr at 37 °C and cell culture supernatants were analyzed with IL-2 ELISA.
Using serial logarithmic concentrations of the compound of the present invention as independent variables and corresponding inhibitory percentages as dependent variables, a linear regression analysis by the least squares method was carried out to calculate IC50 value. Toxicity
The toxicity of the compounds of the present invention is very low and therefore, it may be considered safe for pharmaceutical use.
INDUSTRIAL APPLICABILITY
The compounds of the present invention of the formulae (I) and (la) are neutral sphingomyelinase inhibitors and therefore are useful for the treatment and/or prevention of arteriosclerosis, cerebral ischemia, cardiac ischemia, lung injury, renal injury, GVHD (graft versus host diseases) , transplant rejection, HIV etc. For the purposes described above, the compounds of the present invention of formula (I), non-toxic salts, acid addition salts or hydrates thereof may be administered normally, usually systemically or topically, orally or parenterally.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally in the range of from 1 mg to 1000 mg, by oral administration, up to several times per day, and in the range of from 0.1 mg to 100 mg, by parenteral administration (preferably intravenous administration) , up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used. The compounds of the present invention may be administered in the form of, for example, solid forms for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules, etc. Capsules include hard capsules and soft capsules.
In these solid forms, one or more of the active compound (s) maybe admixed with excipients (e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch), binders (e.g. hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate) , disintegrants (e.g. cellulose calcium glycolate) , lubricants (e.g. magnesium stearate), stabilizing agents, and adjuvants to assist dissolution (e.g. glutamic acid, aspartic acid) and prepared according to methods well known to those skilled in the art. The solid forms may, if desired, be coated with coating agents (e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate) , or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable aqueous solutions, suspensions and emulsions, syrups and elixirs, etc. In such forms, one or more of the active compound (s) may be dissolved, suspended or emulsified into diluent (s) commonly used in the art (e.g. purified water, ethanol or a mixture thereof) . Besides such liquid forms may also comprise wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent, etc. Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent (s) for injection immediately before use. In injections, one or more of the active compound (s) may be dissolved, suspended or emulsified into solvent (s) . The solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.
Injections may comprise some additives, such as stabilizing agents, solution adjuvants (e.g. glutamic acid, aspartic acid or POLYSORBATE80 (registered trademark) ) , suspending agents, emulsifying agents, soothing agent, buffering agents, preservatives. They may be sterilized at the final step, or may be prepared and compensated according to sterile methods. They may also be manufactured in the form of sterile solid forms, which may be dissolved in sterile water or some other sterile diluent (s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound (s) and may be prepared by methods known per se. Sprays may comprise additional substances other than diluents, such as stabilizing agents (e.g. sodium sulfate), isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid) . For preparation of such sprays, for example, the method described in the United States Patent No. 2,868,691 or 3,095,355 may be used.
BEST MODE FOR CARRING OUT THE INVENTION The following reference examples and examples illustrate the present invention, but do not limit the present invention. The solvents in the parentheses show the developing or eluting solvents, and the ratios of the solvents used are by volume in chromatographic separations or TLC. The solvents in the parentheses in NMR show the solvents used in the measurement.
Reference example 1
1, 3-diphenyl-2- (thiophen-2-ylmethylene) propane-1, 3-dione
Figure imgf000073_0001
A solution of thiophene-2-carbaldehyde (1.12 g, 10 mmol) in tetrahydrofuran (12.5 ml) was added to a mixture of dibenzoylmethane (2.24 g, 10 mmol) in tetrahydrofuran (12.5 ml) .
Acetic acid (glacial, 180 mg) and piperidine (0.3 ml, 3 mmol) were added, followed by ca. 3 cc of 3 Angstrom molecular sieves. The mixture was then shaken overnight at room temperature using an orbital shaker, decanted from the molecular sieves, and concentrated in vacuo. The residue was purified by silica gel flash chromatography using ethyl acetate / hexane gradients as eluent to give the title compound (1.62 g) .
Example 1
4- (thiophen-2-yl) -5-benzoyl-6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine
Figure imgf000074_0001
The compound prepared in Reference example 1 (48 mg, 0.15 mmol) was dissolved in pyridine (0.6 ml) in a glass vial, and S- (4-methoxybenzyl) thiourea hydrochloride (35 mg, 0.3 mmol) was added as a neat solid. The mixture was heated and shaken at 80°C overnight using an orbital shaker (causing cyclization with concomitant S-deprotection) . The mixture was then cooled, concentrated in vacuo, and the residue was purified by HPLC / MS chromatography to give the title compound (24 mg) having the following physical data. Analytical LC / MS conditions:
HPLC Column : reverse-phase C-18 mobile phase : 10-90% acetonitrile in water over 3.7 min., water containing 0.05% trifluoroacetic acid, acetonitrile containing 0.035% trifluoroacetic acid flow rate : 3.5 ml / min MS condition : ESI (Pos) retention time (min) : 3.60; Mass (ESI, Pos) : m/z 377 (M+H)+. Example 2
4- (4-diethylaminophenyl) -5-phenylcarbamoyl-6- (4- methylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000075_0001
Thiourea (23 mg, 0.3 mmol) was placed in a 1.0 ml glass vial. N-phenyl-3- (4-methylphenyl) -3-oxo-propanamide was suspended in 2-ethoxyethanol at a concentration of approx. 2 M (253 mg, 1 mmol in 0.5 ml ethoxyethanol) , and 0.15 ml of the resulting slurry was added to the thiourea. 4- (diethylamino) benzaldehyde was prepared as an approximately 2 M solution (354 mg, 2.0 mmol per 1.0 ml ethoxyethanol) and 0.15 ml of this solution was added to the reaction, followed by 10 Dl concentrated HCI. The reaction was then heated to 75°C overnight with shaking. The crude reaction mixture was then cooled, diluted with 0.5 ml 1:1 methanol / DMSO, and purified by HPLC / MS to give the title compound (52 mg) having the following physical data. Analytical LC / MS conditions: HPLC Column : reverse-phase C-18 mobile phase : 10-90% acetonitrile in water over 3.7 min., water containing 0.05% trifluoroacetic acid, acetonitrile containing 0.035% trifluoroacetic acid flow rate : 3.5 ml / min MS condition : ESI (Pos) retention time (min) : 2.87; Mass (ESI, Pos) : m/z 471 (M+H)+.
Example 3 4- (4-methylphenyl) -5-methyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000076_0001
(2E) -2-methyl-3- (4-methylphenyl) -l-phenylprop-2-en-l- one (71 mg, 0.3 mmol) was dissolved in absolute ethanol (1.5 ml), treated with thiourea (46 mg, 0.6mmol) and 5.0 eq. aqueous potassium hydroxide (90 μl of a solution of 2.8 g KOH in 3.0 ml water) added. The reaction was then heated to 70 °C for 8 hour, then cooled, concentrated in vacuo, dissolved in 1.0 ml 1:1 methanol / DMSO, and purified by HPLC / MS to give the title compound
(9.0 mg) having the following physical data.
Analytical LC / MS conditions:
HPLC Column : reverse-phase C-18 mobile phase : 10-90% acetonitrile in water over 3.7 min., water containing 0.05% trifluoroacetic acid, acetonitrile containing
0.035% trifluoroacetic acid flow rate : 3.5 ml / min
MS condition : ESI (Pos) retention time (min) : 2.62; Mass (ESI, Pos) : m/z 295 (M+H) +.
Example 3(1)
4- (3, 4-dihydroxyphenyl) -6- (2-hydroxyphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000077_0001
The title compound having the following physical data was obtained by the same procedure as for Example 3, using (2E)- 3- (3, 4-dihydroxyphenyl) -1- (2-hydroxyphenyl) prop-2-en-l-one instead of (2E) -2-methy1-3- (4-methylphenyl) -l-phenylprop-2- en-l-one. retention time (min) : 2.27; Mass (ESI, Pos) : m/z 315 (M+H) + .
Example 4(1) - 4 (228)
The compounds having the following physical data were obtained by the same procedure used in Example 1 or Example2, using the corresponding starting materials.
Example 4(1)
■ 4- (2, 3-dichlorophenyl) -5-methoxycarbonyl-6- (4-fluorophenyl) - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000077_0002
retention time (min) : 3.78;
Mass (ESI, Pos) : m/z 411 (M+H)'
Example 4(2) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000078_0001
retention time (min) : 3.62; Mass (ESI, Pos) : m/z 421 (M+H)+.
Example 4(3)
4- (4-diethylaminophenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000078_0002
retention time (min) : 2.52; Mass (ESI, Pos) : m/z 414 (M+H)+.
Example 4(4) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-phenyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000079_0001
retention time (min) : 3.73; Mass (ESI, Pos) : m/z 417 (M+H) +.
Example 4(5)
4- (6-bromo-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000079_0002
retention time (min) : 3.73; Mass (ESI, Pos) : m/z 461 (M+H)+.
Example 4(6)
4- (3- (4-chlorophenoxy) phenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000079_0003
retention time (min) : 4.31; Mass (ESI, Pos) : m/z 465 (M+H)+.
Example 4(7)
4- (2-phenylethyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000080_0001
retention time (min) : 3.93; Mass (ESI, Pos) : m/z 333 (M+H) +.
Example 4(8)
4- (3- (4-chlorophenoxy) phenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000080_0002
retention time (min) : 4.35; Mass (ESI, Pos) : m/z 431 (M+H) + .
Example 4(9)
4- (2-phenylethyl) -5- (2-methoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000081_0001
retention time (min) : 3.28; Mass (ESI, Pos) : m/z 335 (M+H)+.
Example 4 (10)
4- (3- (4-chlorophenoxy) phenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000081_0002
retention time (min) : 3.86; Mass (ESI, Pos) : m/z 433 (M+H)+.
Example 4 (11)
4- (4-diethylaminophenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000081_0003
retention time (min) : 1.94; Mass (ESI, Pos) : m/z 378 (M+H)+. Example 4(12)
4- (2-phenylethyl) -5-benzyloxycarbonyl-6-methyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000082_0001
retention time (min) : 3.93; Mass (ESI, Pos) : m/z 367 (M+H) + .
Example 4 (13) 4- (4-diethylaminophenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000082_0002
retention time (min) : 2.69; Mass (ESI, Pos) : m/z 410 (M+H)+.
Example 4(14)
4- (3-bromophenyl ) -5-ethoxycarbonyl-6- ( furan-3-yl ) -2-thioxo-
1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000083_0001
retention time (min) : 3.65; Mass (ESI, Pos) : m/z 407 (M+H)+.
Example 4 (15)
4- (2, 3-dichlorophenyl) -5-ethoxycarbonyl-6- (furan-3-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000083_0002
retention time (min) : 3.73; Mass (ESI, Pos) : m/z 397 (M+H)+.
Example 4(16)
4- (1-ethylpropyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000083_0003
retention time (min) : 3.70; Mass (ESI, Pos) : m/z 337 (M+H)+. Example 4 ( 17 )
4- (thiazol-2-yl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000084_0001
retention time (min) : 2.90; Mass (ESI, Pos) : m/z 350 (M+H)+.
Example 4 (18) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000084_0002
retention time (min) : 3.38; Mass (ESI, Pos) : m/z 461 (M+H) +.
Example 4 (19)
4- ( 4-methoxyphenyl ) -5-methoxycarbonyl-6- ( 4-f luorophenyl ) -2- thioxo-1 , 2 , 3 , 4-tetrahydropyrimidine
Figure imgf000085_0001
retention time (min) : 3.42; Mass (ESI, Pos) : m/z 373 (M+H)+.
Example 4 (20)
4- (thiazol-2-yl) -5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000085_0002
retention time (min) : 3.07; Mass (ESI, Pos) : m/z 346 (M+H)+.
Example 4 (21)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6- phenyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine
Figure imgf000085_0003
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 457 (M+H)+.
Example 4 (22) 4- (4-carboxymethoxyphenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000086_0001
retention time (min) : 3.17; Mass (ESI, Pos) : m/z 379 (M+H) +
Example 4 (23)
4- (thiazol-2-yl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000086_0002
retention time (min) : 3.08;
Mass (ESI, Pos) : m/z 312 (M+H)+.
Example 4 (24)
4- (5-methylfuran-2-yl) -5-methoxycarbonyl-6-methoxymethyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000087_0001
retention time (min) : 3.18; Mass (ESI, Pos) : m/z 297 (M+H)+.
Example 4 (25)
4- ( 1-ethylpropyl ) -5- (2-methoxyethoxycarbonyl ) -6-methyl-2- thioxo-1, 2 , 3, 4-tetrahydropyrimidine
Figure imgf000087_0002
retention time (min) : 3.15; Mass (ESI, Pos) : m/z 301 (M+H)+.
Example 4(26)
4- (4-carboxymethoxyphenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1,2, 3, 4-tetrahydropyrimidine
retention time (min) : 3.23; Mass (ESI, Pos) : m/z 413 (M+H) +. Example 4 (27 )
4- ( 1-ethylpropyl ) -5-benzyloxycarbonyl-6-methyl-2-thioxo-
1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000088_0001
retention time (min) : 3.90;
Mass (ESI, Pos) : m/z 333 (M+H)+.
Example 4 (28)
4- (thiazol-2-yl) -5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine
Figure imgf000088_0002
retention time (min) : 3.20; Mass (ESI, Pos) : m/z 346 (M+H)+.
Example 4 (29)
4- (1-ethylpropyl) -5-ethoxycarbonyl- 6- (furan-3-yl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000088_0003
retention time (min) : 3.62; Mass (ESI, Pos) : m/z 323 (M+H) + Example 4 ( 30 )
4- ( 6-chloro-l, 3-benzodioxol-5-yl) ~5~phenylcarbamoyl-6-methyl-
•2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000089_0001
retention time (min) : 3.40; Mass (ESI, Pos) : m/z 402 (M+H)+.
Example 4 (31) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5- (4- methoxyphenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000089_0002
retention time (min) : 3.35; Mass (ESI, Pos) : m/z 432 (M+H)+.
Example 4 (32)
4- ( 6-chloro-l , 3-benzodioxol-5-yl ) -5-methoxycarbonyl- 6- ( 4- trifluoromethylphenyl ) -2-thioxo-l , 2, 3, 4-tetrahydropyrimidine
Figure imgf000090_0001
retention time (min) : 4.13; Mass (ESI, Pos) : m/z 471 (M+H)+.
Example 4 (33)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000090_0002
retention time (min) : 3.80; Mass (ESI, Pos) : m/z 472 (M+H)+.
Example 4 (34)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-methoxycarbonyl-6- (4- trifluoromethylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000091_0001
retention time (min) : 3.91; Mass (ESI, Pos) : m/z 511 (M+H)+.
Example 4 (35)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (4- methylphenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000091_0002
retention time (min) : 3.42;
Mass (ESI, Pos) : m/z 456 (M+H) +
Example 4(36)
4- (2-phenylethyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine
Figure imgf000092_0001
retention time (min) : 3.62; Mass (ESI, Pos) : m/z 352 (M+H)+.
Example 4(37)
4- (2-phenylethyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000092_0002
retention time (min) : 4.26; Mass (ESI, Pos) : m/z 347 (M+H)+.
Example 4 (38)
4- (2-phenylethyl) -5- (4-methoxyphenylcarbamoyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000092_0003
retention time (min) : 3.52; Mass (ESI, Pos) : m/z 382 (M+H)+.
Example 4 (39)
4- (2-phenylethyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000093_0001
retention time (min) : 4.05; Mass (ESI, Pos) : m/z 414 (M+H)+.
Example 4(40)
4- (2-phenylethyl) -5-methoxycarbonyl-6- (4- trifluoromethyIphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000093_0002
retention time (min) : 4.23;
Mass (ESI, Pos) : m/z 421 (M+H) +
Example 4 (41)
4- (2-phenylethyl) -5- (4-methylphenylcarbamoyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000094_0001
retention time (min) : 3.83; Mass (ESI, Pos) : m/z 366 (M+H) +.
Example 4(42)
4- (2-ethoxyphenyl) -5- (4-methoxyphenylcarbamoyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000094_0002
retention time (min) : 3.47; Mass (ESI, Pos) : m/z 398 (M+H)+.
Example 4(43)
4- (2-ethoxyphenyl) -5- (2-methoxyphenylcarbamoyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000094_0003
retention time (min) : 3.67; Mass (ESI, Pos) : m/z 398 (M+H) \ Example 4 ( 44)
4- (2-ethoxyphenyl) -5- ( 4-methylphenylcarbamoyl ) -6-methyl-2- thioxo-1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000095_0001
retention time (min) : 3.72;
Mass (ESI, Pos) : m/z 382 (M+H)+.
Example 4 (45)
4- (4-chlorophenyl) -5-methoxycarbonyl-6- (4- tirfluoromethylphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000095_0002
retention time (min) : 4.18; Mass (ESI, Pos) : m/z 427 (M+H)+.
Example 4(46)
4- ( 4-chlorophenyl) -5- (4-methylphenylcarbamoyl ) -6-methyl-2- thioxo-1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000096_0001
retention time (min) : 3.67; Mass (ESI, Pos) : m/z 372 (M+H)+.
Example 4 (47)
4- (thiophen-2-yl) -5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000096_0002
retention time (min) : 3.80; Mass (ESI, Pos) : m/z 345 (M+H)+.
Example 4(48)
4- (thiophen-2-yl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000096_0003
retention time (min) : 3.73; Mass (ESI, Pos) : m/z 311 (M+H)+.
Example 4 (49) 4- (thiophen-2-yl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000097_0001
retention time (min) : 3.63; Mass (ESI, Pos) : m/z 392 (M+H)
Example 4 (50)
4- (thiophen-2-yl) -5-methoxycarbonyl-6- (4- trifluoromethylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000097_0002
retention time (min) : 3.90; Mass (ESI, Pos) : m/z 399 (M+H)+.
Example 4 (51) 4- (thiophen-2-yl) -5-ethoxycarbonyl-6- (3, 5- ditrifluoromethylphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine
Figure imgf000097_0003
retention time (min) : 4.33;
Mass (ESI, Pos) : m/z 481 (M+H)
Example 4 (52) 4- (4-diethylaminophenyl) -5- (4-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000098_0001
retention time (min) : 2.31; Mass (ESI, Pos) : m/z 425 (M+H)+.
Example 4 (53)
4- (4-diethylaminophenyl) -5- (2-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000098_0002
retention time (min) : 2.47;
Mass (ESI, Pos) : m/z 425 (M+H)
Example 4 (54)
4- (4-diethylaminophenyl) -5-methoxycarbonyl-6- (4- trifluoromethylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000099_0001
retention time (min) : 2.95; Mass (ESI, Pos) : m/z 464 (M+H)+.
Example 4 (55)
4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6- (3, 5-ditrifluoro methyIphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000099_0002
retention time (min) : 3.40; Mass (ESI, Pos) : m/z 546 (M+H) +.
Example 4(56)
4- ( 4-diethylaminophenyl ) -5- ( 4-methylphenylcarbamoyl) -6- methyl-2-thioxo-l , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000100_0001
retention time (min) : 2.50; Mass (ESI, Pos) : m/z 409 (M+H)+.
Example 4 (57)
4- (4-chlorophenyl) -5-cyclohexylcarbamoyl-6-methyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000100_0002
retention time (min) : 3.50; Mass (ESI, Pos) : m/z 364 (M+H)+.
Example 4 (58)
4- ( 4-chlorophenyl) -5- (indolin-1-ylcarbonyl) -6-methyl-2- thioxo-1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000100_0003
retention time (min) : 3. 60 ; Mass (ESI, Pos) : m/z 384 (M+H)+.
Example 4 (59)
4- (4-chlorophenyl) -5-cyclopentylcarbamoyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine
Figure imgf000101_0001
retention time (min) : 3.27; Mass (ESI, Pos) : m/z 350 (M+H)+.
Example 4(60)
4- (4-chlorophenyl) -5- (N-ethyl-N- (2-methyIphenyl) carbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000101_0002
retention time (min) : 3.70; Mass (ESI, Pos) : m/z 400 (M+H) +.
Example 4(61)
4- (4-diethylaminophenyl) -5- (2-methoxyethoxycarbonyl) -6- ( 4- nitrophenyl ) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000102_0001
retention time (min) : 2.70; Mass (ESI, Pos) : m/z 485 (M+H) +.
Example 4 (62)
4- (4-diethylaminophenyl) -5-benzylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000102_0002
retention time (min) : 2.22; Mass (ESI, Pos) : m/z 409 (M+H)+.
Example 4 (63)
4- (4-diethylaminophenyl ) -5-cyclohexylcarbamoyl-6-methyl-2- thioxo-1, 2 , 3, 4-tetrahydropyrimidine
Figure imgf000102_0003
retention time (min) : 2.26; Mass (ESI, Pos) : m/z 401 (M+H)+.
Example 4 (64) 4- (4-diethylaminophenyl) -5- (indolin-1-ylcarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000103_0001
retention time (min) : 2.40; Mass (ESI, Pos) : m/z 421 (M+H)+.
Example 4 (65)
4- (4-diethylaminophenyl) -5- (2- (4-methoxyphenyl) ethyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000103_0002
retention time (min) : 2.39;
Mass (ESI, Pos) : m/z 453 (M+H)+.
Example 4(66)
4- (4-diethylaminophenyl) -5- (N-ethyl-N- (2-methylphenyl) carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000104_0001
retention time (min) : 2.54; Mass (ESI, Pos) : m/z 437 (M+H)+.
Example 4 (67)
4- (4-diethylaminophenyl) -5- ( (4-methoxybenzyl) carbamoyl) -6- methyl-2-thioxo-l, 2,3, -tetrahydropyrimidine
Figure imgf000104_0002
retention time (min) : 2.27; Mass (ESI, Pos) : m/z 439 (M+H)+.
Example 4 (68)
4- (2, 5-dimethoxyphenyl) -5- (2-methoxycarbonylphenylcarbamoyi;
6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000104_0003
retention time (min) : 3.76; Mass (ESI, Pos) : m/z 442 (M+H)+. Example 4(69)
4- (4-chlorophenyl) -5- ( (1, 3-benzodioxol-5-ylmethyl) carbamoyl)
6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000105_0001
retention time (min) : 3.27; Mass (ESI, Pos) : m/z 416 (M+H)+.
Example 4(70) 4- (4-chlorophenyl) -5-phenylcarbamoyl-6- (4-methylphenyl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000105_0002
retention time (min) : 4.05; Mass (ESI, Pos) : m/z 434 (M+H)+.
Example 4(71)
4- ( 4-chlorophenyl) -5- (N-ethyl-N-phenylcarbamoyl) -6-methyl-2- thioxo-6-methyl-l, 2 , 3, 4-tetrahydropyrimidine
Figure imgf000106_0001
retention time (min) : 3.58; Mass (ESI, Pos) : m/z 386 (M+H)+.
Example 4 (72)
4- (4-diethylaminophenyl) -5- (N-benzyl-N-methylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000106_0002
retention time (min) : 2.40; Mass (ESI, Pos) : m/z 423 (M+H)+.
Example 4 (73)
4- (4-diethylaminophenyl) -5- ( ( 1, 3-benzodioxol-5-ylmethyl) carbamoyl) -6-methyl-2-thioxo-l, 2 , 3, 4-tetrahydropyrimidine
Figure imgf000106_0003
retention time (min) 2 .27 ; Mass (ESI, Pos) : m/z 453 (M+H) +.
Example 4(74)
4- (4-diethylaminophenyl) -5- (3-chlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000107_0001
retention time (min) : 2.62; Mass (ESI, Pos) : m/z 429 (M+H)+.
Example 4 (75)
4- (4-diethylaminophenyl) -5- (4-methylpiperidin-l-ylcarbonyl) 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000107_0002
retention time (min) : 2.26; Mass (ESI, Pos) : m/z 401 (M+H) + .
Example 4(76)
4- (4-diethylaminophenyl) -5- (N-ethyl-N-phenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000108_0001
retention time (min) : 2.45; Mass (ESI, Pos) : m/z 423 (M+H)+.
Example 4 (77)
4- (4-diethylaminophenyl) -5- (3-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000108_0002
retention time (min) : 2.47; Mass (ESI, Pos) : m/z 409 (M+H)+.
Example 4(78)
4- (2, 5-dimethoxyphenyl) -5- (N- (4-chlorophenyl) -N-methyl carbamoyl) -6-phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000108_0003
retention time (min) : 3.93; Mass (ESI, Pos) : m/z 494 (M+H)+.
Example 4 (79)
4- (2, 5-dimethoxyphenyl) -5- (3-chlorophenylcarbamoyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000109_0001
retention time (min) : 3.73; Mass (ESI, Pos) : m/z 418 (M+H)+.
Example 4 (80)
4- (2, 5-dimethoxyphenyl) -5- (5-chloro-2-methylphenylcarbamoyl) 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000109_0002
retention time (min) : 3.72; Mass (ESI, Pos) : m/z 432 (M+H)+.
Example 4 (81)
4- (2, 5-dimethoxyphenyl) -5- (2, 3-dimethylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000110_0001
retention time (min) : 3.45; Mass (ESI, Pos) : m/z 412 (M+H)+.
Example 4 (82)
4- (2, 5-dimethoxyphenyl) -5- (perhydroazepin-1-ylcarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000110_0002
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 390 (M+H)+.
Example 4 (83)
4- (2, 5-dimethoxyphenyl ) -5- (2-chlorophenylcarbamoyl ) -6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000110_0003
retention time (min) : 4.01; Mass (ESI, Pos) : m/z 460 (M+H)+.
Example 4(84) 4- (2, 5-dimethoxyphenyl) -5- (3-nitrophenylcarbamoyl) -6-t-butyl - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000111_0001
retention time (min) : 3.91; Mass (ESI, Pos) : m/z 471 (M+H)+.
Example 4(85)
4- (2, 5-dimethoxyphenyl) -5- (2, 6-dimethylpiperidin-l- ylcarbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000111_0002
retention time (min) : 3.70; Mass (ESI, Pos) : m/z 404 (M+H)+.
Example 4(86) 4- (2, 5-dimethoxyphenyl) -5-phenylcarbamoyl-6- (4-methylphenyl) 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000111_0003
retention time (min) : 3.86; Mass (ESI, Pos) : m/z 460 (M+H)+.
Example 4 (87) 4- (2, 5-dimethoxyphenyl) -5- (3, 4-dimethylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000112_0001
retention time (min) : 3.45; Mass (ESI, Pos) : m/z 412 (M+H)+.
Example 4(88)
4- (2, 5-dimethoxyphenyl) -5- (3-methylphenylcarbamoyl) -6-methyl-
2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000112_0002
retention time (min) : 3.53;
Mass (ESI, Pos) : m/z 398 (M+H)+.
Example 4(89)
4- (2, 5-dimethoxyphenyl) -5- (2, 4-dimethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000113_0001
retention time (min) : 3.38; Mass (ESI, Pos) : m/z 444 (M+H)+.
Example 4 (90)
4- (2, 5-dimethoxyphenyl) -5- (2-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000113_0002
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 414 (M+H)+.
Example 4 (91)
4- (2, 5-dimethoxyphenyl) -5- (4-methylphenylcarbamoyl) -6-methyl-
2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000113_0003
retention time (min) : 3.53; Mass (ESI, Pos) : m/z 398 (M+H)+.
Example 4 (92; 4- (4-chlorophenyl) -5- (4-aminophenylcarbamoyl) -6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000114_0001
retention time (min) : 2.65; Mass (ESI, Pos) : m/z 435 (M+H) + .
Example 4 (93)
4- (4-chlorophenyl) -5- (perhydroazepin-1-ylcarbonyl) - 6-methyl -
2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000114_0002
retention time (min) : 3.38; Mass (ESI, Pos) : m/z 364 (M+H) + .
Example 4(94) 4- (4-chlorophenyl) -5- (6-methylpyridin-2-ylcarbamoyl) -6- methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000115_0001
retention time (min) : 2.80; Mass (ESI, Pos) : m/z 373 (M+H)+.
Example 4(95)
4- (4-chlorophenyl) -5- (2-methylpiperidin-l-ylcarbonyl* methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000115_0002
retention time (min) : 3.40; Mass (ESI, Pos) : m/z 364 (M+H)+.
Example 4 (96)
4- (4-chlorophenyl) -5- (3-methylpiperidin-l-ylcarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000115_0003
retention time (min) : 3.45; Mass (ESI, Pos) : m/z 364 (M+H)+.
Example 4(97)
4- (4-chlorophenyl) -5- (4-methylpiperidin-l-ylcarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
retention time (min) : 3.45; Mass (ESI, Pos) : m/z 364 (M+H)+.
Example 4(98)
4- (4-diethylaminophenyl) -5- (4-bromophenylcarbamoyl) -6-methyl- 2-thioxo-l,2, 3, 4-tetrahydropyrimidine
Figure imgf000116_0002
retention time (min) : 2.75; Mass (ESI, Pos) : m/z 475 (M+H)+.
Example 4(99)
4- (4-diethylaminophenyl) -5- (5-chloro-2-methylphenylcarbamoyl)
-6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000117_0001
retention time (min) : 2.64; Mass (ESI, Pos) : m/z 443 (M+H)+.
Example 4(100)
4- (4-diethylaminophenyl) -5- (3,4, 5-trimethoxyphenylcarbamoyl) 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000117_0002
retention time (min) : 2.34; Mass (ESI, Pos) : m/z 485 (M+H)+.
Example 4(101)
4- (4-diethylaminophenyl) -5- (6-ethoxybenzothiazol-2- ylcarbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000117_0003
retention time (min) : 2.90; Mass (ESI, Pos) : m/z 496 (M+H)+.
Example 4 (102)
4- (4-diethylaminophenyl) -5- (benzothiazol-2-ylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000118_0001
retention time (min) : 2.70; Mass (ESI, Pos) : m/z 452 (M+H)+.
Example 4 (103)
4- (4-diethylaminophenyl) -5- (2, 3-dimethylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000118_0002
retention time (min) : 2.47; Mass (ESI, Pos) : m/z 423 (M+H)+.
Example 4 (104)
4- (4-diethylaminophenyl) -5- (2, 6-dimethylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000119_0001
retention time (min) : 2.40; Mass (ESI, Pos) : m/z 423 (M+H)+.
Example 4(105)
4- (4-diethylaminophenyl) -5- (3-nitrophenylcarbamoyl) -6-phenyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000119_0002
retention time (min) : 2.90; Mass (ESI, Pos) : m/z 502 (M+H)+.
Example 4(106)
4- (4-diethylaminophenyl) -5- (4-aminophenylcarbamoyl) -6-phenyl-
2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000119_0003
retention time (min) : 1.78; Mass (ESI, Pos) : m/z 472 (M+H)+.
Example 4(107) 4- (4-diethylaminophenyl) -5- (5-chloro-2-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000120_0001
retention time (min) : 2.84; Mass (ESI, Pos) : m/z 459 (M+H)+.
Example 4(108)
4- (4-diethylaminophenyl) -5- (perhydroazepin-1-ylcarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000120_0002
retention time (min) : 2.21;
Mass (ESI, Pos) : m/z 401 (M+H)+.
Example 4(109)
4- (4-diethylaminophenyl) -5- (2-chlorophenylcarbamoyl) -6-t- butyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine
Figure imgf000121_0001
retention time (min) : 2.97; Mass (ESI, Pos) : m/z 471 (M+H)+.
Example 4 (110)
4- (4-diethylaminophenyl) -5- (2, 4-dichlorophenylcarbamoyl) -6- methyl-2-thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000121_0002
retention time (min) : 2.84; Mass (ESI, Pos) : m/z 463 (M+H)+.
Example 4 (111)
4- ( 4-diethylaminophenyl) -5- (2-methoxyphenylcarbamoyl) -6- (3- aminophenyl ) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000121_0003
retention time (min) : 2.50; Mass (ESI, Pos) : m/z 502 (M+H)+.
Example 4(112) 4- (4-diethylaminophenyl) -5- (3-chloro-2-me thylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000122_0001
retention time (min) : 2.62; Mass (ESI, Pos) : m/z 443 (M+H)+.
Example 4(113)
4- (4-diethylaminophenyl) -5- (3-nitrophenylcarbamoyl) -6-t- butyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000122_0002
retention time (min) : 2.97;
Mass (ESI, Pos) : m/z 482 (M+H)+.
Example 4(114)
4- (4-diethylaminophenyl) -5- (4-chloro-2, 5- dimethoxyphenylcarbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyri idine
Figure imgf000123_0001
retention time (min) : 2.84; Mass (ESI, Pos) : m/z 489 (M+H)+.
Example 4 (115)
4- (4-diethylaminophenyl) -5- (3, 5-dimethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000123_0002
retention time (min) : 2.54; Mass (ESI, Pos) : m/z 455 (M+H)+.
Example 4 (116)
4- (4-diethylaminophenyl) -5- (1, 4-dimethylpentylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000123_0003
retention time (min) : 2.77; Mass (ESI, Pos) : m/z 417 (M+H)+.
Example 4(117)
4- (4-diethylaminophenyl) -5- (6-methylpyridin-2-ylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000124_0001
retention time (min) : 1.72; Mass (ESI, Pos) : m/z 410 (M+H)+.
Example 4(118)
4- (4-diethylaminophenyl) -5- (2-methylpiperidin-l-ylcarbonyi; 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000124_0002
retention time (min) : 2.26;
Mass (ESI, Pos) : m/z 401 (M+H) +
Example 4(119)
4- (4-diethylaminophenyl) -5- (2-ethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000125_0001
retention time (min) : 2.70; Mass (ESI, Pos) : m/z 439 (M+H)+.
Example 4 (120)
4- (4-diethylaminophenyl) -5- (3, 4-dimethylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000125_0002
retention time (min) : 2.75; Mass (ESI, Pos) : m/z 423 (M+H)+.
Example 4 (121)
4- (4-diethylaminophenyl) -5- (2, 5-diethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000125_0003
retention time (min) : 2.95; Mass (ESI, Pos) : m/z 483 (M+H)+.
Example 4(122)
4- (4-diethylaminophenyl) -5- (3-methylpiperidin-l-ylcarbonyl) 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000126_0001
retention time (min) : 2.31; Mass (ESI, Pos) : m/z 401 (M+H)+.
Example 4(123)
4- (4-diethylaminophenyl) -5- (N-ethyl-N- (2-phenoxyethyl) carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000126_0002
retention time (min) : 2.74; Mass (ESI, Pos) : m/z 467 (M+H) + .
Example 4(124)
4- (4-diethylaminophenyl) -5- (2, 4-dimethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000127_0001
retention time (min) : 2.45; Mass (ESI, Pos) : m/z 455 (M+H)+.
Example 4 (125)
4- (4-diethylaminophenyl) -5-t-butylcarbamoyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000127_0002
retention time (min) : 2.14; Mass (ESI, Pos) : m/z 375 (M+H)+.
Example 4 (126)
4- (4-diethylaminophenyl) -5- (2, 5-dichlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000127_0003
retention time (min) : 2.82; Mass (ESI, Pos) : m/z 463 (M+H)+.
Example 4 (127)
4- (4-phenoxyphenyl) -5-methoxycarbonyl- 6- (4-f luorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000128_0001
retention time (min) : 4.18; Mass (ESI, Pos) : m/z 435 (M+H)+.
Example 4 (128)
4- (3-phenoxyphenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000128_0002
retention time (min) : 4.44; Mass (ESI, Pos) : m/z 397 (M+H) + .
Example 4 (129)
4- (4-benzyloxy-3-methoxyphenyl) -5- (2-methylpropoxycarbonyl)
6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000129_0001
retention time (min) : 4.30; Mass (ESI, Pos) : m/z 441 (M+H)+.
Example 4(130)
4-cyclohexyl-5- (2-ethoxyethoxycarbonyl ) -6-methyl-2-thioxo-
1 , 2, 3, 4-tetrahydropyrimidine
Figure imgf000129_0002
retention time (min) : 3.76; Mass (ESI, Pos) : m/z 327 (M+H)+.
Example 4 (131)
4- (3-phenoxyphenyl) -5- (2-ethoxyethoxycarbonyl ) -6-methyl-2- thioxo-1 , 2 , 3 , 4-tetrahydropyrimidine
Figure imgf000129_0003
retention time (min) : 4.11; Mass (ESI, Pos) : m/z 413 (M+H)+. Example 4 (132)
4- (4-benzyloxy-3-methoxyphenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000130_0001
retention time (min) : 3.98;
Mass (ESI, Pos) : m/z 457 (M+H)4.
Example 4 (133)
4- (4-phenoxyphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000130_0002
retention time (min) : 4.10; Mass (ESI, Pos) : m/z 413 (M+H)+.
Example 4 (134)
4- (4-phenylphenyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1,2, 3, 4-tetrahydropyrimidine
Figure imgf000131_0001
retention time (min) : 4.16; Mass (ESI, Pos) : m/z 419 (M+H)+.
Example 4(135)
4- (1-phenylethyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000131_0002
retention time (min) : 3.83; Mass (ESI, Pos) : m/z 371 (M+H)+.
Example 4 (136)
4- (2-methylpropyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000131_0003
retention time (min) : 3.76; Mass (ESI , Pos ) : m/ z 323 (M+H) '
Example 4 (137)
4- (2-phenylethyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000132_0001
retention time (min) : 3.95; Mass (ESI, Pos) : m/z 371 (M+H)+.
Example 4 (138)
4- (2-phenylpropyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000132_0002
retention time (min) : 4.10; Mass (ESI, Pos) : m/z 385 (M+H) +.
Example 4 (139)
4- (quinolin-3-yl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000133_0001
retention time (min) : 2.87; Mass (ESI, Pos) : m/z 356 (M+H)+.
Example 4 (140)
4- (4-phenylphenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000133_0002
retention time (min) : 3.55; Mass (ESI, Pos) : m/z 381 (M+H)+.
Example 4 (141)
4- (1-phenylethyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000133_0003
retention time (min) 4.13; Mass (ES I , Pos ) : m/ z 333 (M+H)
Example 4(142)
4- (4-phenylphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000134_0001
retention time (min) : 3.98; Mass (ESI, Pos) : m/z 397 (M+H)+.
Example 4 (143)
4- (1-ethylpropyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000134_0002
retention time (min) : 3.58; Mass (ESI, Pos) : m/z 315 (M+H)+.
Example 4 (144)
4- (2-methylpropyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000135_0001
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 301 (M+H)+.
Example 4 (145)
4- (2-phenylethyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000135_0002
retention time (min) : 3.70; Mass (ESI, Pos) : m/z 349 (M+H)+.
Example 4 (146)
4- (l-acetylindol-3-yl) -5-methoxycarbonyl-6- (4-fluorophenyl)
2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000135_0003
retention time (min) : 3.68; Mass (ESI, Pos) : m/z 424 (M+H)+. Example 4 ( 147 )
4- (4-pentylphenyl) -5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000136_0001
retention time (min) : 3.75; Mass (ESI, Pos) : m/z 413 (M+H)+.
Example 4(148) 4- (5-chloro-l, 3-dimethylpyrazol-4-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000136_0002
retention time (min) : 3.43; Mass (ESI, Pos) : m/z 357 (M+H)+.
Example 4(149)
4- ( 4- (2-phenylethynyl) phenyl ) -5- (2-ethoxyethoxycarbonyl ) -6- methyl-2-thioxo-l , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000137_0001
retention time (min) : 3.17; Mass (ESI, Pos) : m/z 421 (M+H) +.
Example 4 (150)
4- (4- (2-hydroxyethoxy) phenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000137_0002
retention time (min) : 3.37; Mass (ESI, Pos) : m/z 403 (M+H)+.
Example 4 (151)
4- ( 4- (2-hydroxyethoxy) phenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2 , 3, 4-tetrahydropyrimidine
Figure imgf000138_0001
retention time (min) : 3.58; Mass (ESI, Pos) : m/z 399 (M+H)+.
Example 4 (152)
4- (4-mesylphenyl) -5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000138_0002
retention time (min) : 3.65; Mass (ESI, Pos) : m/z 417 (M+H)+.
Example 4 (153)
4- (3-methylpyrazol-4-yl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000138_0003
retention time (min) : 3.23; Mass (ESI, Pos) : m/z 343 (M+H)+. Example 4 (154)
4- (4- (4-fluorobenzyloxy) phenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000139_0001
retention time (min) : 4.23; Mass (ESI, Pos) : m/z 463 (M+H)+.
Example 4 (155) 4- (4- (2-hydroxyethoxy) phenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000139_0002
retention time (min) : 3.50; Mass (ESI, Pos) : m/z 399 (M+H)+.
Example 4 (156)
4- ( 4-mesylphenyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo-l , 2 , 3 , 4- t etrahydropyr imidine
Figure imgf000140_0001
retention time (min) : 3.62; Mass (ESI, Pos) : m/z 417 (M+H) +.
Example 4 (157)
4- (4- (2-hydroxyethoxy) phenyl) -5-phenylcarbamoyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000140_0002
retention time (min) : 3.50; Mass (ESI, Pos) : m/z 446 (M+H) +.
Example 4 (158)
4- (4- (4-fluorobenzyloxy) phenyl) -5- (2-methylpropoxycarbonyl)
6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000140_0003
retention time (min) : 4.36; Mass (ESI, Pos) : m/z 429 (M+H)+.
Example 4 (159) 4- (4-mesylphenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000141_0001
retention time (min) : 3.62; Mass (ESI, Pos) : m/z 383 (M+H)+.
Example 4 (160)
4- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000141_0002
retention time (min) : 3.23;
Mass (ESI, Pos) : m/z 432 (M+H)+.
Example 4(161)
4- (4- (4-fluorobenzyloxy) phenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
retention time (min) : 4.18; Mass (ESI, Pos) : m/z 445 (M+H)+.
Example 4 (162)
4- (5- (4-chlorophenyl) furan-2-yl) -5- (2-ethoxyethoxycarbonyl) 6-methyl-2-thioxo-l, 2,3, -tetrahydropyrimidine
Figure imgf000142_0002
retention time (min) : 4.25; Mass (ESI, Pos) : m/z 421 (M+H)+.
Example 4 (163)
4- (2-methylthioethyl) -5-methoxycarbonyl- 6- (4-fluorophenyl) -2- thioxo-1 , 2, 3, 4-tetrahydropyrimidine
Figure imgf000142_0003
retention time (min) : 2 .96; Mass (ESI, Pos) : m/z 341 (M+H)
Example 4(164)
4-propyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000143_0001
retention time (min) : 3.04; Mass (ESI, Pos) : m/z 309 (M+H)+.
Example 4 (165)
4-pentyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000143_0002
retention time (min) : 3.37; Mass (ESI, Pos) : m/z 337 (M+H)+.
Example 4 (166)
4-cyclopropyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000143_0003
retention time (min) : 2.87; Mass (ESI, Pos) : m/z 307 (M+H)+.
Example 4 (167) 4-cyclopentyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000144_0001
retention time (min) : 3.27; Mass (ESI, Pos) : m/z 335 (M+H)+.
Example 4(168)
4-cyclopentyl-5-phenylcarbamoyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000144_0002
retention time (min) : 3.29;
Mass (ESI, Pos) : m/z 378 (M+H)+.
Example 4(169)
4-cyclopentyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000145_0001
retention time (min) : 2.84; Mass (ESI, Pos) : m/z 316 (M+H)+.
Example 4 (170)
4-pentyl-5- (2-methoxyphenylcarbamoyl) -6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000145_0002
retention time (min) : 3.22; Mass (ESI, Pos) : m/z 348 (M+H)+.
Example 4 (171)
4-cyclopentyl-5- (2-methoxyphenylcarbamoyl ) -6-methyl-2-thioxo-
1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000145_0003
retention time (min) : 3.04; Mass (ESI, Pos) : m/z 346 (M+H)+.
Example 4(172) 4- (4- (2-methylpropyl) phenyl) -5- (2-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000146_0001
retention time (min) : 3.66; Mass (ESI, Pos) : m/z 410 (M+H)+.
Example 4 (173)
4-propyl-5-benzyloxycarbonyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000146_0002
retention time (min) : 3.29; Mass (ESI, Pos) : m/z 305 (M+H)+.
Example 4(174)
4-cyclopentyl-5-benzyloxycarbonyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000146_0003
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 331 (M+H)+.
Example 4(175) 4-cyclopentyl-5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine
Figure imgf000147_0001
retention time (min) : 3.16; Mass (ESI, Pos) : m/z 331 (M+H)+.
Example 4 (176)
4-cyclopentyl-5- (2-methylpropoxycarbonyl ) -6-methyl-2-thioxo-
1 , 2, 3, 4-tetrahydropyrimidine
Figure imgf000147_0002
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 297 (M+H)+.
Example 4 (177) 4- (2- (2-hydroxyethoxy) phenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000147_0003
retention time (min) : 3.02; Mass (ESI, Pos) : m/z 365 (M+H)+. Example 4 ( 178 )
4- ( 4-chloro-3-nitrophenyl ) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1 , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000148_0001
retention time (min) : 3.81; Mass (ESI, Pos) : m/z 418 (M+H)+.
Example 4 (179) 4- (2, 3-dichlorophenyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000148_0002
retention time (min) : 3.90; Mass (ESI, Pos) : m/z 407 (M+H)+.
Example 4(180)
4- (4-hydroxy-3-nitro-5-methoxyphenyl) -5-ethoxycarbonyl-6- phenyl-2-thioxo-l , 2 , 3, 4-tetrahydropyrimidine
Figure imgf000149_0001
retention time (min) : 3.47; Mass (ESI, Pos) : m/z 430 (M+H)+.
Example 4 (181)
4- (3, 4-dichlorophenyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000149_0002
retention time (min) : 4.01; Mass (ESI, Pos) : m/z 407 (M+H)+.
Example (182)
4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000149_0003
retention time (min) : 2.67; Mass (ESI, Pos) : m/z 410 (M+H)+.
Example 4 (183)
4- (6-chloro-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000150_0001
retention time (min) : 3.80; Mass (ESI, Pos) : m/z 383 (M+H)+.
Example 4 (184)
4- (4-nitrophenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000150_0002
retention time (min) : 3.67;
Mass (ESI, Pos) : m/z 350 (M+H)+.
Example 4 (185)
4- (6-bromo-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxycarbonyl) 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000151_0001
retention time (min) : 3.85; Mass (ESI, Pos) : m/z 427 (M+H)+.
Example 4(186)
4- (4-hydroxy-3-methoxy-5-nitrophenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000151_0002
retention time (min) : 3.47; Mass (ESI, Pos) : m/z 396 (M+H) + .
Example 4 (187)
4- (4-diethylaminophenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000151_0003
retention time (min) 2.59; Mass (ESI, Pos) m/z 376 (M+H) + . Example 4(188)
4- (3-bromophenyl) -5- (2-methoxyethoxycarbonyl) -6-methyl- 2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000152_0001
retention time (min) : 3.28; Mass (ESI, Pos) : m/z 387 (M+H)+.
Example 4(189) 4- (3, 4-dichlorophenyl) -5- (2-methoxyethoxycarbonyl) -6-methyl - 2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000152_0002
retention time (min) : 3.50; Mass (ESI, Pos) : m/z 375 (M+H)+.
Example 4 (190)
4- (1-ethylpropyl) -5-methoxycarbonyl-6-ethyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000152_0003
retention time (min) : 3.42; Mass (ESI, Pos) : m/z 271 (M+H) +.
Example 4 (191) 4- (1-ethylpropyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000153_0001
retention time (min) : 3.83; Mass (ESI, Pos) : m/z 333 (M+H)+.
Example 4 (192)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000153_0002
retention time (min) : 3.47;
Mass (ESI, Pos) : m/z 423 (M+H) +.
Example 4 (193)
4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000154_0001
retention time (min) : 2.90; Mass (ESI, Pos) : m/z 425 (M+H)+.
Example 4 (194)
4- (4-methoxyphenyl) -5- (2-methoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000154_0002
retention time (min) : 2.89; Mass (ESI, Pos) : m/z 337 (M+H)+.
Example 4 (195)
4- (4-acetyloxy-3, 5-dimethoxyphenyl ) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000154_0003
retention time (min) : 3.55; Mass (ESI, Pos) : m/z 457 (M+H)+.
Example 4 (196) 4- (4-methoxyphenyl) -5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000155_0001
retention time (min) : 3.63; Mass (ESI, Pos) : m/z 369 (M+H)+.
Example 4(197)
4- (4-chlorophenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000155_0002
retention time (min) : 3.43;
Mass (ESI, Pos) : m/z 355 (M+H)+.
Example 4 (198)
4- (4-diethylaminophenyl) -5~phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000156_0001
retention time (min) : 2.31; Mass (ESI, Pos) : m/z 395 (M+H)+.
Example 4 (199)
4- (6-chloro-l, 3-benzodioxol-5-yl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000156_0002
retention time (min) : 3.95; Mass (ESI, Pos) : m/z 417 (M+H)+.
Example 4(200)
4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-t-butyl-
2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000156_0003
retention time (min) : 4.01;
Mass (ESI, Pos) : m/z 397 (M+H) +. Example 4 ( 201 )
4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5- (N, N-diethylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000157_0001
retention time (min) : 2.99; Mass (ESI, Pos) : m/z 382 (M+H)+.
Example 4 (202) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000157_0002
retention time (min) : 3.75; Mass (ESI, Pos) : m/z 437 (M+H)+.
Example 4 (203)
4- ( 6-bromo-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-t-butyl-
2-thioxo-l , 2 , 3 , 4-tetrahydropyrimidine
Figure imgf000158_0001
retention time (min) : 4.05; Mass (ESI, Pos) : m/z 443 (M+H)+.
Example 4 (204)
4- (2-ethoxyphenyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000158_0002
retention time (min) : 3.53; Mass (ESI, Pos) : m/z 368 (M+H) +.
Example 4 (205)
4- (2-ethoxyphenyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000158_0003
retention time (min) : 4.15; Mass (ESI, Pos) : m/z 363 (M+H) +. Example 4 (206)
4- (4-chlorophenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
retention time (min) : 4.06;
Mass (ESI, Pos) : m/z 339 (M+H)+.
Example 4 (207)
4- (4-chlorophenyl) -5-ethoxycarbonyl-6-t-butyl~2-thioxo- 1,2,3,4-tetrahydropyrimidine
Figure imgf000159_0002
retention time (min) : 4.13; Mass (ESI, Pos) : m/z 353 (M+H)+.
Example 4 (208)
4- (4-chlorophenyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000160_0001
retention time (min) : 3.91; Mass (ESI, Pos) : m/z 420 (M+H)+.
Example 4(209)
4- (4-diethylaminophenyl) -5-ethoxycarbonyl- 6-t-butyl-2- thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000160_0002
retention time (min) : 2.80; Mass (ESI, Pos) : m/z 390 (M+H)+.
Example 4(210)
4- (4-chlorophenyl) -5-benzylcarbamoyl-6-methyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000160_0003
retention time (min) : 3.37; Mass (ESI, Pos) : m/z 372 (M+H)+.
Example 4 (211)
4- (4-chlorophenyl) -5- ( (4-methoxybenzyl) carbamoyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000161_0001
retention time (min) : 3.33; Mass (ESI, Pos) : m/z 402 (M+H)+.
Example 4 (212)
4- (2, 5-dimethoxyphenyl) -5- (N-benzyl-N-methylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000161_0002
retention time (min) : 3.60; Mass (ESI, Pos) : m/z 412 (M+H)+.
Example 4 (213)
4- (2, 5-dimethoxyphenyl) -5- ( (2- (4- methoxyphenyl) ethyl) ) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine
Figure imgf000162_0001
retention time (min) : 3.30; Mass (ESI, Pos) : m/z 442 (M+H)+.
Example 4 (214)
4- (2, 5-dimethoxyphenyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine
Figure imgf000162_0002
retention time (min) : 3.72; Mass (ESI, Pos) : m/z 446 (M+H)+.
Example 4 (215)
4- (4-chlorophenyl) -5- (N-benzyl-N-methylcarbamoyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000162_0003
retention time (min) : 3.52;
Mass (ESI, Pos) : m/z 386 (M+H)+. Example 4 (216)
4- (4-diethylaminophenyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000163_0001
retention time (min) : 2.77; Mass (ESI, Pos) : m/z 457 (M+H)+.
Example 4 (217) 4- (4-diethylamino-2-hydroxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000163_0002
retention time (min) : 2.77; Mass (ESI, Pos) : m/z 392 (M+H)+.
Example 4 (218)
4- (1-ethylpropyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000164_0001
retention time (min) : 4.16; Mass (ESI, Pos) : m/z 299 (M+H)
Example 4 (219)
4- (l-acetylindol-3-yl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000164_0002
retention time (min) : 3.86; Mass (ESI, Pos) : m/z 386 (M+H)+.
Example 4 (220)
4- (4-pentylphenyl) -5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000164_0003
retention time (min) : 4.13; Mass (ESI, Pos) : m/z 375 (M+H)+. Example 4 (221)
4- (4-pentylphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine
Figure imgf000165_0001
retention time (min) : 3.57;
Mass (ESI, Pos) : m/z 391 (M+H)+.
Example 4 (222)
4-pentyl-5-phenylcarbamoyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000165_0002
retention time (min) : 3.53; Mass (ESI, Pos) : m/z 380 (M+H)
Example 4 (223)
4- (4- (2-methylpropyl) henyl) -5-phenylcarbamoyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000166_0001
retention time (min) : 3.78; Mass (ESI, Pos) : m/z 442 (M+H)+.
Example 4 (224)
4-pentyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine
Figure imgf000166_0002
retention time (min) : 3.11; Mass (ESI, Pos) : m/z 318 (M+H)+.
Example 4 (225)
4- (2-methylpropyl) -5-phenylcarbamoyl-6-methyl-2-thioxo-
1,2,3, 4-tetrahydropyrimidine
Figure imgf000166_0003
retention time (min) : 3.48; Mass (ESI, Pos) : m/z 380 (M+H)+.
Example 4 (226)
4- (4- (2-methylpropyl) phenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine
Figure imgf000167_0001
retention time (min) : 3.95; Mass (ESI, Pos) : m/z 395 (M+H)+.
Example 4 (227)
4-propyl-5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2,3,4- tetra ydropyrimidine
Figure imgf000167_0002
retention time (min) : 3.21; Mass (ESI, Pos) : m/z 305 (M+H)+.
Example 4 (228)
4- ( 4- (2-methylpropyl) henyl ) -5- (2-methylpropoxycarbonyl ) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine
Figure imgf000168_0001
retention time (min) : 3.99; Mass (ESI, Pos) : m/z 361 (M+H)+.
Example 5
3-acetyl-4- (4-diethylaminophenyl) -5- (2-ethylthioethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine
Figure imgf000168_0002
To a solution of 4- (4-diethylaminophenyl) -5- (2- ethylthioethoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine (3.0 g, 7.33 mmol) in pyridine (20 ml), acetic anhydride (20 ml) was added. The mixture was stirred for 2 days at room temperature. The mixture was concentrated. To the residue, ethyl acetate was added. The organic layer was washed with IN-HCl, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ether-hexane to give the title compound (2.8 g) having the following physical data. TLC : Rf 0.50 (Hexane : AcOEt = 2 : 1) ;
NMR (d6-DMSO) : D 11.60 (s, 1H) , 6.98 (d, J=9Hz, 2H) , 6.56 (d, J=9Hz,
2H) , 6.32 (s, 1H) , 4.22 (t, J=6.6Hz,2H), 3.28 (q, J=7.2Hz, 4H) , 2.73 (t, J=6.6Hz,2H), 2.62 (s, 3H) , 2.50 (q, J=7.5Hz, 2H) , 2.36 (s, 3H) , 1.14 (t, J=7.5Hz, 3H),1.04 (t, J=7.2Hz, 6H) .
Formulation example 1 The following components were admixed in conventional method and punched out to obtain 100 tablets each containing 50 mg of active ingredient.
4- (4-diethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine 5.0 g Carboxymethyl Cellulose calcium (disintegrating agent)
0.2 g Magnesium stearate (lubricating agent) 0.1 g
Microcrystalline cellulose 4.7 g
Formulation example 2 The following components were admixed in conventional method. The solution was sterilized in conventional manner, placed 2 ml portions into 5 ml ampoules and freeze-dried to obtain 100 ampoules each containing 20 mg of the active ingredient. 4- (4-diethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine 2.00 g mannitol 20 g distilled water 500 ml

Claims

1. A method for prevention and/or treatment of disease induced by activation of neutral sphingomyelinase, which comprises the administration of an effective amount of a compound of the formula (I) :
Figure imgf000170_0001
H
wherein
R1 is R1"1 or R1"2,
R1"1 is 1) phenyl, 2) pyridyl, 3) imidazolyl, 4) benzimidazolyl, 5) benzoxazolyl, 6) benzothiazolyl, 7) benzofurazanyl, 8) benzofuryl,
9) benzothienyl, or 10) indolyl; each ring represented by R1"1 may be optionally substituted by 1~5 of R4; R4 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, or 9) C2-10 acyloxy; or two of R4 that present on adjacent carbon atoms can constitute a methylenedioxy group; R1"2 is
1) Cl-10 alkyl, 2) Cl-10 alkyl substituted by Cl-10 alkylthio,
3) carbocyclic ring 1, 4) carbocyclic ring 2, 5) Cl-10 alkyl substituted by carbocyclic ring 2, 5) hetero ring 1, or 6) hetero ring 2; carbocyclic ring 1 is phenyl; carbocyclic ring 2 is C3-15 mono-, bi- or tri-carbocyclic ring, with proviso that carbocyclic ring 2 does not represent phenyl; hetero ring 1 is pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl or indolyl; hetero ring 2 is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, with proviso that hetero ring 2 does not represent pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl and indolyl; carbocyclic ring 1, carbocyclic ring 2, hetero ring 1 and hetero ring 2 may be optionally substituted by 1 ~ 5 of R5;
R5isl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen, 5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR6R7, 11) -S02R8, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9 or 15) trifluoromethyl; or two of R5 that present on adjacent carbon atoms can constitute a methylenedioxy group; R6 and R7, each independently, are hydrogen or Cl-10 alkyl;
R8 is Cl-10 alkyl;
R9 is phenyl, or Cl-10 alkyl substituted by R10;
R10 is hydroxy, -COOR11, piperidyl, or phenyl optionally substituted by halogen; R11 is hydrogen, or Cl-10 alkyl; with proviso that carbocyclic ring 1 and hetero ring 1 must be substituted by at least one of 10) -NRSR7, 11) -S02R8, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9 or
15) trifluoromethyl; R2 is R2"1 or R2"2;
R2"1 is
1) -COR12, 2) -COOR13, or 3) -CONR14R15;
R12 is Cl-10 alkyl;
R13 is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) Cl-10 alkyl substituted by Cl-10 alkoxy or Cl-10 alkylthio, or 4) Cl-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16;
R14 is hydrogen, or Cl-10 alkyl;
R15 is 1) Cl-10 alkyl, or 2) C2-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 - 5 of R16; R16 is l ) Cl-10 alkyl , 2 ) C2-10 alkenyl , 3 ) C2-10 alkynyl , 4 ) halogen,
5 ) nitro, 6 ) hydroxy, 7 ) Cl-10 alkoxy, 8 ) C2-10 acyl , 9 ) C2-10 acyloxy, or 10 ) -NR17R18 ;
R17 and R18 each independently, are hydrogen or Cl-10 alkyl; R2"2 is
1) hydrogen, 2) methyl, 3) -COR19, 4) -COOR19, or 5) -CONR19R20;
R19 is 1) carbocyclic ring 3, 2) hetero ring 3, 3) Cl-10 alkyl substituted by -O-carbocyclic ring 3, or 4) Cl-10 alkyl substituted by carbocyclic ring 4; R20 is hydrogen or Cl-10 alkyl; carbocyclic ring 3 is C3-15 mono-, bi- or tri-carbocyclic ring; hetero ring 3 is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms ; carbocyclic ring 4 is phenyl or naphthyl; carbocyclic ring 3, hetero ring 3 and carbocyclic ring 4 may be optionally substituted by 1 ~ 5 of R21;
R21isl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR22R23, 11) -S02R24, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25, or 15) trifluoromethyl; or two of R21 that present on adjacent carbon atoms can constitute a methylenedioxy group;
R22 and R23 each independently, are hydrogen or Cl-10 alkyl; R24 is Cl-10 alkyl;
R25 is phenyl, or Cl-10 alkyl substituted by R26;
R26 is hydroxy, -COOR27, piperidyl, or phenyl optionally substituted by halogen;
R27 is hydrogen or Cl-10 alkyl; with proviso that carbocyclic ring 4 must be substituted by at least one of 11) -S02R24, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25, or 15) trifluoromethyl; or two of R21 that present on adjacent carbon atoms must constitute a methylenedioxy group; R3 is R3"1 or R3"2;
R3"1 is
1) Cl-10 alkyl, or 2) Cl-10 alkyl substituted by Cl-10 alkoxy; R3"2 is
1) -COOR28, 2) carbocyclic ring 5, or 3) hetero ring 4;
R28 is Cl-10 alkyl; carbocyclic ring 5 is C3-15 mono-, bi-, or tri-carbocyclic ring, with proviso that carbocyclic ring 5 do not represent C3-7 cycloalkyl, and C3-7 cycloalkenyl; hetero ring 4 is 3-15 membered mono- or bi-hetero ring containing
1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms ; carbocyclic ring 5 and hetero ring 4 may be optionally substituted by 1 - 5 of R29;
R29isl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR30R31, 11) -S02R32, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR33, or 15) trifluoromethyl; or two of R29 that present on adjacent carbon atoms can constitute a methylenedioxy group;
R30 and R31 each independently, are hydrogen or Cl-10 alkyl;
R32 is Cl-10 alkyl;
R33 is phenyl, or Cl-10 alkyl substituted by R34; R34 is hydroxy -COOR35, piperidyl, or phenyl optionally substituted by halogen;
R35 is hydrogen, or Cl-10 alkyl, a non-toxic salt thereof or a hydrate thereof as active ingredient.
2. A method for prevention and/or treatment of disease induced by activation of neutral sphingomyelinase, which comprises the administration of an effective amount of a compound of the formula
Figure imgf000174_0001
H
wherein R36 is Cl-10 alkyl, and the other symbols have the same meaning as described in claim 1, which is a prodrug of the compound of the formula (I) described in claim 1.
3. A method according to claim 1, for which the disease induced by activation of neutral sphingomyelinase is arteriosclerosis, cerebral ischemia, cardiac ischemia, lung injury, renal injury, GVHD, transplant rejection or HIV.
4. A method according to claim 2, for which the disease induced by activation of neutral sphingomyelinase is arteriosclerosis, cerebral ischemia, cardiac ischemia, lung injury, renal injury, GVHD, transplant rejection or HIV.
5. A pharmaceutical composition for the prevention and / or treatment of a disease induced by activation of neutral sphingomyelinase, which comprises, as active ingredient, an effective amount of a compound of the formula (I) described in claim 1.
6. A pharmaceutical composition for the prevention and / or treatment of a disease induced by activation of neutral sphingomyelinase, which comprises, as active ingredient, an effective amount of a compound of the formula (I') described in claim 2.
7. A compound of formula (la)
Figure imgf000175_0001
H
wherein
Rla i s Rla-1 o r Rla-2
Rla_1 is 1) phenyl, 2) pyridyl, 3) imidazolyl, 4) benzimidazolyl, 5) benzoxazolyl, 6) benzothiazolyl, 7) benzofurazanyl, 8) benzofuryl, 9) benzothienyl, or 10) indolyl; each ring represented by Rla-1 may be optionally substituted by 1~5 of R4a; R4a is 1) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen, 5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, or 9) C2-10 acyloxy; or two of Ra that present on adjacent carbon atoms can constitute a methylenedioxy group; Rla"2 is
1) Cl-10 alkyl, 2) Cl-10 alkyl substituted by Cl-10 alkylthio, 3) carbocyclic ring la, 4) carbocyclic ring 2a, 5) Cl-10 alkyl substituted by carbocyclic ring 2a, 5) hetero ring la, or 6) hetero ring 2a; carbocyclic ring la is phenyl; carbocyclic ring 2a is C3-15 mono-, bi- or tri-carbocyclic ring, with proviso that carbocyclic ring 2a does not represent phenyl; hetero ring la is pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl or indolyl; hetero ring 2a is 3-15 membered mono- or bi-hetero ring containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms, with proviso that hetero ring 2a does not represent pyridyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofurazanyl, benzofuryl, benzothienyl and indolyl; carbocyclic ring la, carbocyclic ring 2a, hetero ring la and hetero ring 2a may be optionally substituted by 1 ~ 5 of R5a;
R5aisl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR6aR7a, 11) -S02R8a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9a or 15) trifluoromethyl; or two of R5a that present on adjacent carbon atoms can constitute a methylenedioxy group;
R6a and R7a, each independently, are hydrogen or Cl-10 alkyl; R8a is Cl-10 alkyl;
R9a is phenyl, or Cl-10 alkyl substituted by R10a;
R10a is hydroxy, -COORlla, piperidyl, or phenyl optionally substituted by halogen;
Rlla is hydrogen, or Cl-10 alkyl; with proviso that carbocyclic ring la and hetero ring la must be substituted by at least one of 10) -NR6aR7a, 11) -S02R8a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR9a or
15) trifluoromethyl;
R2a i s R2a-1 Q r R2a-2 ; R2a_1 is
1 ) -COR12a, 2 ) -COOR13a, or 3 ) -CONR14aR15a;
R12a is Cl-10 alkyl ;
R13a is 1 ) Cl-10 alkyl, 2 ) C2-10 alkenyl, 3 ) Cl-10 alkyl substituted by Cl-10 alkoxy or Cl-10 alkylthio, or 4 ) Cl-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16a;
R1 a is hydrogen, or Cl-10 alkyl ;
R15a is 1 ) Cl-10 alkyl , or 2 ) C2-10 alkyl substituted by phenyl or naphthyl optionally substituted by 1 ~ 5 of R16 ;
R1Sa is l ) Cl-10 alkyl , 2 ) C2-10 alkenyl, 3 ) C2- 10 alkynyl , 4 ) halogen, 5 ) nitro, 6) hydroxy, 7 ) Cl-10 alkoxy, 8 ) C2-10 acyl, 9) C2-10 acyloxy, or 10 ) -NR17aR18a;
R17a and R18a each independently, are hydrogen or Cl-10 alkyl ;
R2a"2 is
1 ) hydrogen, 2 ) methyl, 3 ) -COR19a, 4 ) -COOR19a, or 5 ) -CONR19aR20a; R19a is 1) carbocyclic ring 3a, 2) hetero ring 3a, 3) Cl-10 alkyl substituted by -O-carbocyclic ring 3a, or 4) Cl-10 alkyl substituted by carbocyclic ring 4a;
R20a is hydrogen or Cl-10 alkyl; carbocyclic ring 3a is C3-15 mono-, bi- or tri-carbocyclic ring; hetero ring 3a is 3-15 membered mono- or bi-hetero ring containing
1~4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms; carbocyclic ring 4a is phenyl or naphthyl; carbocyclic ring 3a, hetero ring 3a and carbocyclic ring 4 may be optionally substituted by 1 ~ 5 of R21a;
R21aisl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen,
5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR22aR23a, 11) -S02R24a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25a, or 15) trifluoromethyl; or two of R21a that present on adjacent carbon atoms can constitute a methylenedioxy group;
R22a and R23a each independently, are hydrogen or Cl-10 alkyl;
R24a is Cl-10 alkyl; R25a is phenyl, or Cl-10 alkyl substituted by R26a;
R26a is hydroxy, -COOR27a, piperidyl, or phenyl optionally substituted by halogen;
R2 a is hydrogen or Cl-10 alkyl; with proviso that carbocyclic ring 4 must be substituted by at least one of 11) -S02R24a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR25a, or 15) trifluoromethyl; or two of R21a that present on adjacent carbon atoms must constitute a methylenedioxy group;
R3a is R33"1 or R3a"2 ; R3a_1 is
1) Cl-10 alkyl, or 2) Cl-10 alkyl substituted by Cl-10 alkoxy;
R3a"2 is
1 ) -COOR28a, 2 ) carbocyclic ring 5a, or 3 ) hetero ring 4a;
R2Ba is Cl-10 alkyl ; carbocyclic ring 5a is C3-15 mono-, bi-, or tri-carbocyclic ring, with proviso that carbocyclic ring 5a do not represent C3-7 cycloalkyl, and C3-7 cycloalkenyl; hetero ring 4a is 3-15 membered mono- or bi-hetero ring containing 1 ~ 4 of hetero atoms selected from nitrogen, oxygen or sulfur atoms ; carbocyclic ring 5a and hetero ring 4a may be optionally substituted by 1 ~ 5 of R29a;
R29aisl) Cl-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) halogen, 5) nitro, 6) hydroxy, 7) Cl-10 alkoxy, 8) C2-10 acyl, 9) C2-10 acyloxy, 10) -NR30aR31a, 11) -S02R32a, 12) phenyl optionally substituted by halogen, 13) -C≡C-phenyl, 14) -OR33a, or 15) trifluoromethyl; or two of R29a that present on adjacent carbon atoms can constitute a methylenedioxy group;
R30a and R31a each independently, are hydrogen or Cl-10 alkyl;
R32a is Cl-10 alkyl;
R33a is phenyl, or Cl-10 alkyl substituted by R34a;
R34a is hydroxy -COOR35a, piperidyl, or phenyl optionally substituted by halogen;
R35a is hydrogen, or Cl-10 alkyl.
With proviso that
(1) Rla, R2a and R3a respectively do not represent Rla_1, R2a_1 and R3a-1 respectively at the same time; (2) when Rla is Cl-10 alkyl or phenyl substituted by 1 - 5 of Cl-10 alkyl, halogen, nitro, hydroxy, Cl-10 alkoxy, -NR6aRa, and R2a is
-COO-Cl-10 alkyl or unsubstituted -CONH-phenyl, then R3a do not represent Cl-10 alkyl or unsubstituted phenyl;
(3) when Rla is Cl-10 alkyl or phenyl substituted by 1 ~ 5 of Cl-10 alkyl, halogen, nitro, hydroxy, Cl-10 alkoxy, -NR6aR7a, and R2a is
-CO-Cl-10 alkyl or unsubstituted -CO-phenyl, then R3a do not represent Cl-10 alkyl or unsubstituted phenyl; and
(4) the following compounds 1) ~ 83) are excluded;
1) 4- (4-benzyloxyphenyl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
2) 4- (4-chlorophenyl) -5- (2, 4-dichlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
3) 4- (furan-2-yl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
4) 4- (2-methoxynaphthalen-l-yl) -5-acetyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
5) 4- (2-methoxynaphthalen-l-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
6) 4, 6-diphenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
7) 4, 6-diphenyl-5-benzoyl-2-thioxo-l, 2,3,4- tetrahydropy imidine,
8) 4- (thiophen-2-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
9) 4- (2-ethoxyphenyl) -5- (3-methylcyclohexyloxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
10) 4- (4-methylphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
11) 4- (4-methoxyphenyl) -5-methyl-6-methoxycarbonyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
12) 4- (thiophen-2-yl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
13) 4- (2, 4-dichlorophenyl) -5- (4-bromophenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 14) 4- (4-bromophenyl) -5- (4-bromophenylcarbamoyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
15) 4- (2-methoxyphenyl) -5-methyl-6-methoxycarbonyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
16) 4- (2-methoxyphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
17) 4- (2-fluorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, -tetrahydropyrimidine,
18) 4- (4-methoxyphenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 19) 4- (2-chlorophenyl) -5-methyl-6-ethoxycarbonyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
20) 4- (4-dimethylaminophenyl) -5- (2-ethylthioethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 21) 4- (acenaphthen-5-yl) -5-ethoxycarbonyl-6-methyl-2- thioxo-1 ,2,3, 4-tetrahydropyrimidine,
22) 4- (4-diethylaminophenyl) -5- (2-ethylthioethoxycarbonyl) - 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
23) 4- (2-ethoxyphenyl) -5- (2-methylcyclopentyloxycarbonyl) - 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
24) 4- (2, 5-dimethoxyphenyl) -5- (3, 4-dimethylcyclohexyloxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
25) 4- (2-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2~ thioxo-1, 2, 3, 4-tetrahydropyrimidine, 26) 4- (naphthalen-1-yl) -5~methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
27) 4- (2, 5-dimethoxyphenyl) -5- (2-methylcyclopentyloxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
28) 4- (4-benzyloxyphenyl) -5-methoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
29) 4- (2-benzyloxyphenyl) -5-ethoxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
30) 4-phenyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 31) 4- (4-diethylaminophenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
32) 4- (2-chlorophenyl) -6- (4-chlorophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
33) 4-phenyl-6- (1, 5-diphenyl-3-methylpyrazol-4-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
34) 4- (4-chlorophenyl) -6- (1, 5-diphenyl-3-methylpyrazol-4- yl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
35) 4- (pyridin-3-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine, 36) 4- (pyridin-4-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
37) 4- (thiophen-2-yl) -6- (2-amino-4-methylthiazol-5-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 38) 4- (2, 2-dimethyl-l, 3-dioxolan-4-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
39) 4- (2-trifluoromethylphenyl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
40) 4-cyclohexyl-5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
41) 4- (2- (4-chlorobenzyloxy) phenyl) -5-methoxycarbonyl-6- ethyl-2-thioxo-l, 2,3, -tetrahydropyrimidine,
42) 4- (2- (2-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 43) 4- (2- (3-chlorobenzyloxy) phenyl) -5-ethoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
44) 4- (2- (4-chlorobenzyloxy) -3-methoxyphenyl) -5-ethoxy carbonyl-6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
45) 4- (4- (4-chlorobenzyloxy) -3-nitrophenyl) -5-ethoxy carbonyl-6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
46) 4- (furan-2-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
47) 4-phenyl-6- (4-aminophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine, 48) 4- (4-chlorophenyl) -6- (4-aminophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
49) 4- (4-methoxyphenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
50) 4- (2-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
51) 4- (4-dimethylaminophenyl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
52) 4- (2-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 53) 4- (4-chlorophenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
54) 4-methyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 55) 4, 6-diphenyl-5-ethoxycarbonyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
56) 4- (4-nitrophenyl) -6- (5-bromo-2-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
57) 4- (4-methoxyphenyl) -6- (pyridin-2-yl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
58) 4, 6-bis (4-methylphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
59) 4- (4-chlorophenyl) -5- (4-fluorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 60) 4- (4-chlorophenyl) -5- (4-chlorophenylcarbamoyl) -6- methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine,
61) 4- (naphthalen-1-yl) -5-ethoxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
62) 4- (4-methoxynaphthalen-l-yl) -5-ethoxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
63) 4- (1, 3-diphenylpyrazol-4-yl) -6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
64) 4- (1, 3-benzodioxol-5-yl) -6- (4-bromophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 65) 4- (furan-2-yl) -6- (4-methoxyphenyl) -2-thioxo-l, 2,3, 4- tetrahydropyrimidine,
66) 4-phenyl-6-ethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
67) 4- (acenaphthen-5-yl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 68) 4-phenyl-6-methyl-2-thioxo-l,2,3,4- tetrahydropyrimidine,
69) 4-methyl-6- (1-methylpropyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
70) 4-phenyl-6- (4-chlorophenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
71) 4- (4-methylphenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
72) 4- (3-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
73) 4- (4-chlorophenyl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
74) 4-phenyl-6- (4-methoxyphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine, 75) 4- (1, 3-benzodioxol-5-yl) -6-phenyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
76) 4- (4-methylphenyl) -6- (4-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
77) 4- (4-methoxyphenyl) -6- (4-chlorophenyl) -2-thioxo- 1,2,3,4-tetrahydropyrimidine,
78) 4, 6-bis (4-methoxyphenyl) -2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
79) 4- (1, 3-benzodioxol-5-yl) -6- (4-chlorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 80) 4, 6-bis (4-chlorophenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
81) 4, 6-dimethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
82) 4- (4, 6-dimethoxypyrimidin-5-yl) -5-methoxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 83) 4-phenyl-5-ethoxycarbonyl-6- (2-methoxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, a non-toxic salt thereof or a hydrate thereof.
8. A compound of formula (la')
Figure imgf000183_0001
wherein R36a is Cl-10 alkyl, and the other symbols have the same meaning as described in claim 7, which is a prodrug of the compound of the formula (la) described in claim 7.
9. A compound according to claim 7, which is
1) 4- (thiophen-2-yl) -5-benzoyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine ,
2) 4- (4-diethylaminophenyl) -5-phenylcarbamoyl-6- (4- methylphenyl ) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
3) 4- (4-methylphenyl) -5-methyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
4) 4- (3, 4-dihydroxyphenyl) -6- (2-hydroxyphenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 5) 4- (2, 3-dichlorophenyl) -5-methoxycarbonyl- 6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
6) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5-methoxycarbonyl- 6- ( 4-fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
7) 4- (4-diethylaminophenyl) -5-methoxycarbonyl- 6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
8) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl- 6- phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
9) 4- ( 6-bromo-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl- 6- phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 10) 4- (3- (4-chlorophenoxy) phenyl) -5-ethoxycarbonyl- 6- phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
11) 4- (2-phenylethyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
12) 4- (3- (4-chlorophenoxy) phenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
13) 4- (2-phenylethyl) -5- (2-methoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
14) 4- (3- (4-chlorophenoxy) phenyl) -5- (2-methoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 15) 4- (4-diethylaminophenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, -tetrahydropyrimidine,
16) 4- (2-phenylethyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine, 17) 4- (4-diethylaminophenyl) -5-benzyloxycarbonyl-6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
18) 4- (3-bromophenyl) -5-ethoxycarbonyl- 6- (furan-3-yl) -2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
19) 4- (2, 3-dichlorophenyl) -5-ethoxycarbonyl-6- (furan-3-yl) - 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
20) 4- (1-ethylpropyl) -5-methoxycarbonyl-6- (4-fluorophenyl) - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
21) 4- (thiazol-2-yl) -5-methoxycarbonyl-6- (4-fluorophenyl) - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 22) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-methoxycarbonyl- 6- (4-fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
23) 4- (4-methoxyphenyl) -5-methoxycarbonyl- 6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
24) 4- (thiazol-2-yl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
25) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
26) 4- (4-carboxymethoxyphenyl) -5- (2-methylpropoxycarbonyl) - 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 27) 4- (thiazol-2-yl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
28) 4- (5-methylfuran-2-yl) -5-methoxycarbonyl-6- methoxymethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
29) 4- (1-ethylpropyl) -5- (2-methoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
30) 4- (4-carboxymethoxyphenyl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
31) 4- (1-ethylpropyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine, 32) 4- (thiazol-2-yl) -5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
33) 4- (1-ethylpropyl) -5-ethoxycarbonyl-6- (furan-3-yl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 34) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5-phenylcarbamoyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
35) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5- (4-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
36) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5-methoxycarbonyl-6- (4-trifluoromethyIphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
37) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
38) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-methoxycarbonyl- 6- (4-trifluoromethylphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
39) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (4-methylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
40) 4- (2-phenylethyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
41) 4- (2-phenylethyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
42) 4- (2-phenylethyl) -5- (4-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 43) 4- (2-phenylethyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
44) 4- (2-phenylethyl) -5-methoxycarbonyl-6- (4- trifluoromethylphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
45) 4- (2-phenylethyl) -5- (4-methylphenylcarbamoyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
46) 4- (2-ethoxyphenyl) -5- (4-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
47) 4- (2-ethoxyphenyl) -5- (2-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 48) 4- (2-ethoxyphenyl) -5- (4-methylphenylcarbamoyl) -6- methyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine,
49) 4- (4-chlorophenyl) -5-methoxycarbonyl-6- (4- tirfluoromethylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 50) 4- (4-chlorophenyl) -5- (4-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
51) 4- (thiophen-2-yl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
52) 4- (thiophen-2-yl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
53) 4- (thiophen-2-yl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
54) 4- (thiophen-2-yl) -5-methoxycarbonyl-6- (4-trifluoro methylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 55) 4- (thiophen-2-yl) -5-ethoxycarbonyl-6- (3, 5-ditrifluoro methylphenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
56) 4- (4-diethylaminophenyl) -5- (4-methoxyphenylcarbamoyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
57) 4- (4-diethylaminophenyl) -5- (2-methoxyphenylcarbamoyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
58) 4- (4-diethylaminophenyl) -5-methoxycarbonyl-6- (4- trifluoromethyIphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
59) 4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6- (3,5- ditrifluoromethylphenyl) -2-thioxo-l, 2,3,4- tetrahydropyrimidine,
60) 4- (4-diethylaminophenyl) -5- (4-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
61) 4- (4-chlorophenyl) -5-cyclohexylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 62) 4- (4-chlorophenyl) -5- (indolin-1-ylcarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
63) 4- (4-chlorophenyl) -5-cyclopentylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
64) 4- (4-chlorophenyl) -5- (N-ethyl-N- (2-methylphenyl) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
65) 4- (4-diethylaminophenyl) -5- (2-methoxyethoxycarbonyl) -6- ( 4-nitrophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
66) 4- (4-diethylaminophenyl) -5-benzylcarbamoyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
67) 4- (4-diethylaminophenyl) -5-cyclohexylcarbamoyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
68) 4- (4-diethylaminophenyl) -5- (indolin-1-ylcarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 69) 4- (4-diethylaminophenyl) -5- (2- (4-methoxyphenyl) ethylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
70) 4- (4-diethylaminophenyl) -5- (N-ethyl-N- (2-methylphenyl) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 71) 4- (4-diethylaminophenyl) -5- ( (4-methoxybenzyl) carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
72) 4- (2, 5-dimethoxyphenyl) -5- (2-methoxycarbonylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
73) 4- (4-chlorophenyl) -5- ( (1, 3-benzodioxol-5-ylmethyl) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
74) 4- (4-chlorophenyl) -5-phenylcarbamoyl-6- (4- ethyIphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
75) 4- (4-chlorophenyl) -5- (N-ethyl-N-phenylcarbamoyl) -6- methyl-2-thioxo-6-methyl-l, 2,3, 4-tetrahydropyrimidine, 76) 4- (4-diethylaminophenyl) -5- (N-benzyl-N-methylcarbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 77) 4- (4-diethylaminophenyl) -5- ( (1, 3-benzodioxol-5- ylmethyl) carbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 78) 4- (4-diethylaminophenyl) -5- (3-chlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
79) 4- (4-diethylaminophenyl) -5- (4-methylpiperidin-l- ylcarbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
80) 4- (4-diethylaminophenyl) -5- (N-ethyl-N-phenylcarbamoyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
81) 4- (4-diethylaminophenyl) -5- (3-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
82) 4- (2, 5-dimethoxyphenyl) -5- (N- (4-chlorophenyl) -N-methyl carbamoyl) -6-phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
83) 4- (2, 5-dimethoxyphenyl) -5- (3-chlorophenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
84) 4- (2, 5-dimethoxyphenyl) -5- (5-chloro-2-methylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 85) 4- (2, 5-dimethoxyphenyl) -5- (2, 3-dimethylphenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
86) 4- (2, 5-dimethoxyphenyl) -5- (perhydroazepin-1- ylcarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
87) 4- (2, 5-dimethoxyphenyl) -5- (2-chlorophenylcarbamoyl) -6- t-butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
88) 4- (2, 5-dimethoxyphenyl) -5- (3-nitrophenylcarbamoyl) -6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 89) 4- (2, 5-dimethoxyphenyl) -5- (2, 6-dimethylpiperidin-l- ylcarbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 90) 4- (2, 5-dimethoxyphenyl) -5-phenylcarbamoyl-6- (4- methylphenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
91) 4- (2, 5-dimethoxyphenyl) -5- (3, 4-dimethylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
92) 4- (2, 5-dimethoxyphenyl) -5- (3-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
93) 4- (2, 5-dimethoxyphenyl) -5- (2, 4-dimethoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
94) 4- (2, 5-dimethoxyphenyl) -5- (2-methoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 95) 4- (2, 5-dimethoxyphenyl) -5- (4-methylphenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
96) 4- (4-chlorophenyl) -5- (4-aminophenylcarbamoyl) -6-phenyl- 2-thioxo-l,2, 3, 4-tetrahydropyrimidine,
97) 4- (4-chlorophenyl) -5- (perhydroazepin-1-ylcarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
98) 4- (4-chlorophenyl) -5- ( 6-methylpyridin-2-ylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
99) 4- (4-chlorophenyl) -5- (2-methylpiperidin-l-ylcarbonyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
100) 4- (4-chlorophenyl) -5- (3-methylpiperidin-l-ylcarbonyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
101) 4- (4-chlorophenyl) -5- (4-methylpiperidin-l-ylcarbonyl) - 6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 102) 4- (4-diethylaminophenyl) -5- (4-bromophenylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
103) 4- (4-diethylaminophenyl) -5- (5-chloro-2-methylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
104) 4- (4-diethylaminophenyl) -5- (3,4, 5-trimethoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
105) 4- (4-diethylaminophenyl) -5- ( 6-ethoxybenzothiazol-2- ylcarbamoyl) -6-methyl-2-thioxo-l, 2, 3, -tetrahydropyrimidine,
106) 4- (4-diethylaminophenyl) -5- (benzothiazol-2- ylcarbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 107) 4- (4-diethylaminophenyl) -5- (2, 3-dimethylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
108) 4- (4-diethylaminophenyl) -5- (2, 6-dimethylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
109) 4- (4-diethylaminophenyl) -5- (3-nitrophenylcarbamoyl) -6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
110) 4- (4-diethylaminophenyl) -5- (4-aminophenylcarbamoyl) -6- phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
111) 4- (4-diethylaminophenyl) -5- (5-chloro-2-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 112) 4- (4-diethylaminophenyl) -5- (perhydroazepin-1- ylcarbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
113) 4- (4-diethylaminophenyl) -5- (2-chlorophenylcarbamoyl) -6- t-butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
114) 4- (4-diethylaminophenyl) -5- (2, 4-dichlorophenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
115) 4- (4-diethylaminophenyl) -5- (2-methoxyphenylcarbamoyl) - 6- (3-aminophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
116) 4- (4-diethylaminophenyl) -5- (3-chloro-2-methylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
117) 4- (4-diethylaminophenyl) -5- (3-nitrophenylcarbamoyl) -6- t-butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
118) 4- (4-diethylaminophenyl) -5- (4-chloro-2, 5- dimethoxyphenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
119) 4- (4-diethylaminophenyl) -5- (3, 5-dimethoxyphenyl carbamoyl) -δ-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 120) 4- (4-diethylaminophenyl) -5- (1, 4-dimethylpentyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 121) 4- (4-diethylaminophenyl) -5- (6-methylpyridin-2- ylcarbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
122) 4- (4-diethylaminophenyl) -5- (2-methylpiperidin-l- ylcarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
123) 4- (4-diethylaminophenyl) -5- (2-ethoxyphenylcarbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
124) 4- (4-diethylaminophenyl) -5- (3, 4-dimethylphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
125) 4- (4-diethylaminophenyl) -5- (2, 5-diethoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 126) 4- (4-diethylaminophenyl) -5- (3-methylpiperidin-l- ylcarbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 127) 4- (4-diethylaminophenyl) -5- (N-ethyl-N- (2-phenoxyethyl) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 128) 4- (4-diethylaminophenyl) -5- (2, 4-dimethoxyphenyl carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
129) 4- (4-diethylaminophenyl) -5-t-butylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 130) 4- (4-diethylaminophenyl) -5- (2, 5- dichlorophenylcarbamoyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
131) 4- (4-phenoxyphenyl) -5-methoxycarbonyl-6- (4-- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
132) 4- (3-phenoxyphenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
133) 4- (4-benzyloxy-3-methoxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
134) 4-cyclohexyl-5- (2-ethoxyethoxycarbonyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine, 135) 4- (3-phenoxyphenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
136) 4- (4-benzyloxy-3-methoxyphenyl) -5- (2-ethoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
137) 4- (4-phenoxyphenyl) -5- (2-ethoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
138) 4- (4-phenylphenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
139) 4- (1-phenylethyl) -5-methoxycarbonyl-6- (4-fluorophenyl) - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 140) 4- (2-methylpropyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
141) 4- (2-phenylethyl) -5-methoxycarbonyl-6- (4-fluorophenyl) - 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
142) 4- (2-phenylpropyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
143) 4- (quinolin-3-yl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
144) 4- (4-phenylphenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine,
145) 4- (1-phenylethyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
146) 4- (4-phenylphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
147) 4- (1-ethylpropyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
148) 4- (2-methylpropyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
149) 4- (2-phenylethyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
150) 4- (l-acetylindol-3-yl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
151) 4- (4-pentylphenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 152) 4- (5-chloro-l, 3-dimethylpyrazol-4-yl) -5- (2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
153) 4- (4- (2-phenylethynyl) phenyl) -5- (2-ethoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 154) 4- (4- (2-hydroxyethoxy) phenyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
155) 4- (4- (2-hydroxyethoxy) phenyl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
156) 4- (4-mesylphenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
157) 4- (3-methylpyrazol-4-yl) -5-benzyloxycarbonyl-6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
158) 4- (4- (4-fluorobenzyloxy) phenyl) -5-ethoxycarbonyl-6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 159) 4- (4- (2-hydroxyethoxy) phenyl) -5-ethoxycarbonyl-6- phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
160) 4- (4-mesylphenyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
161) 4- (4- (2-hydroxyethoxy) phenyl) -5-phenylcarbamoyl-6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
162) 4- (4- (4-fluorobenzyloxy) phenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
163) 4- (4-mesylphenyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 164) 4- (4-(2-(piperidin-l-yl)ethoxy)phenyl)-5- (2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
165) 4- (4- (4-fluorobenzyloxy) phenyl) -5- (2-ethoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
166) 4- (5- (4-chlorophenyl) furan-2-yl) -5- (2-ethoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
167) 4- (2-methylthioethyl) -5-methoxycarbonyl-6- (4- fluorophenyl) -2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 168) 4-propyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
169) 4-pentyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
170) 4-cyclopropyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
171) 4-cyclopentyl-5-methoxycarbonyl-6- (4-fluorophenyl) -2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
172) 4-cyclopentyl-5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 173) 4-cyclopentyl-5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
174) 4-pentyl-5- (2-methoxyphenylcarbamoyl) -6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
175) 4-cyclopentyl-5- (2-methoxyphenylcarbamoyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
176) 4- (4- (2-methylpropyl) phenyl) -5- (2-methoxyphenyl carbamoyl) -6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine,
177) 4-propyl-5-benzyloxycarbonyl-6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 178) 4-cyclopentyl-5-benzyloxycarbonyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
179) 4-cyclopentyl-5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
180) 4-cyclopentyl-5- (2-methylpropoxycarbonyl) -6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, or 181) 4- (2- (2-hydroxyethoxy)phenyl)-5-(2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine .
10. A compound which is
1) 4- (4-chloro-3-nitrophenyl) -5-ethoxycarbonyl-6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
2) 4- (2, 3-dichlorophenyl) -5-ethoxycarbonyl- 6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
3) 4- (4-hydroxy-3-nitro-5-methoxyphenyl) -5-ethoxycarbonyl- 6-phenyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
4) 4- (3, 4-dichlorophenyl) -5-ethoxycarbonyl- 6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine, 5) 4- (4-diethylaminophenyl) -5-ethoxycarbonyl- 6-phenyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
6) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
7) 4- (4-nitrophenyl) -5- (2-methylpropoxycarbonyl) - 6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
8 ) 4- ( 6-bromo-l, 3-benzodioxol-5-yl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
9) 4- (4-hydroxy-3-methoxy-5-nitrophenyl) -5- (2- methylpropoxycarbonyl) -6-methyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine,
10) 4- (4-diethylaminophenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
11) 4- (3-bromophenyl) -5- (2-methoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 12) 4- (3, 4-dichlorophenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
13) 4- (1-ethylpropyl) -5-methoxycarbonyl- 6-ethyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
14) 4- (1-ethylpropyl) -5-ethoxycarbonyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
15) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methylpropoxy carbonyl) -6-ιuethyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
16) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5- (2-methoxyethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
17) 4- (4-methoxyphenyl) -5- (2-methoxyethoxycarbonyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
18 ) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-benzyloxy carbonyl-6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 19) 4- (4-methoxyphenyl) -5-benzyloxycarbonyl-6-methyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
20) 4- (4-chlorophenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
21) 4- (4-diethylaminophenyl) -5-phenylcarbamoyl-6-methyl-2- thioxo-1, 2, 3, 4-tetrahydropyrimidine,
22 ) 4- ( 6-chloro-l, 3-benzodioxol-5-yl) -5-benzyloxycarbonyl- 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
23) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 24) 4- (6-chloro-l, 3-benzodioxol-5-yl) -5- (N,N-diethyl carbamoyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
25) 4- (4-acetyloxy-3, 5-dimethoxyphenyl) -5-ethoxycarbonyl-6- t-butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
26) 4- ( 6-bromo-l, 3-benzodioxol-5-yl) -5-ethoxycarbonyl-6-t- butyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
27) 4- (2-ethoxyphenyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
28) 4- (2-ethoxyphenyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine, 29) 4- (4-chlorophenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l,2, 3, 4-tetrahydropyrimidine,
30) 4- (4-chlorophenyl) -5-ethoxycarbonyl-6-t-butyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
31) 4- (4-chlorophenyl) -5-phenylcarbamoyl-6-phenyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
32) 4- (4-diethylaminophenyl) -5-ethoxycarbonyl-6-t-butyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
33) 4- (4-chlorophenyl) -5-benzylcarbamoyl~6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine,
34) 4- (4-chlorophenyl) -5- ( (4-methoxybenzyl) carbamoyl) -6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
35) 4- (2, 5-dimethoxyphenyl) -5- (N-benzyl-N-methylcarbamoyl) - 6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine, 36) 4- (2, 5-dimethoxyphenyl) -5- ( (2- (4-methoxyphenyl) ethyl) ) carbamoyl) -6-methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
37) 4- (2, 5-dimethoxyphenyl) -5-phenylcarbamoyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
38) 4- (4-chlorophenyl) -5- (N-benzyl-N-methylcarbamoyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
39) 4- (4-diethylaminophenyl) -5-phenylcarbamoyl-6-phenyl-2- thioxo-1, 2,3, 4-tetrahydropyrimidine,
40) 4- (4-diethylamino-2-hydroxyphenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine, 41) 4- (1-ethylpropyl) -5- (2-methylpropoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
42) 4- (l-acetylindol-3-yl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
43) 4- (4-pentylphenyl) -5- (2-methylpropoxycarbonyl) -6- methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine,
44) 4- (4-pentylphenyl) -5- (2-ethoxyethoxycarbonyl) -6-methyl- 2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
45) 4-pentyl-5-phenylcarbamoyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, 46) 4- (4- (2-methylpropyl) phenyl) -5-phenylcarbamoyl-6- phenyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
47) 4-pentyl-5-phenylcarbamoyl-6-methyl-2-thioxo-l, 2, 3, 4- tetrahydropyrimidine,
48) 4- (2-methylpropyl) -5-phenylcarbamoyl-6-methyl-2-thioxo- 1,2,3, 4-tetrahydropyrimidine,
49) 4- (4- (2-methylpropyl) phenyl) -5-benzyloxycarbonyl-6- methyl-2-thioxo-l, 2, 3, 4-tetrahydropyrimidine,
50) 4-propyl-5-ethoxycarbonyl-6-phenyl-2-thioxo-l, 2,3,4- tetrahydropyrimidine, or
51) 4- (4- (2-methylpropyl) phenyl) -5- (2-methylpropoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine .
11. A compound according to claim 8, which is 3-acetyl-4- (4-diethylaminophenyl) -5- (2-ethylthioethoxy carbonyl) -6-methyl-2-thioxo-l, 2,3, 4-tetrahydropyrimidine .
12. A pharmaceutical composition for the prevention and / or treatment of a disease induced by activation of neutral sphingomyelinase, which comprises, as active ingredient, an effective amount of a compound of the formula (la) described in claim 7.
13. A pharmaceutical composition for the prevention and / or treatment of a disease induced by activation of neutral sphingomyelinase, which comprises, as active ingredient, an effective amount of a compound of the formula (la') described in claim 8.
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