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WO2010069147A1 - Derives de la dihydropyrimidine, leurs compositions et leur utilisation - Google Patents

Derives de la dihydropyrimidine, leurs compositions et leur utilisation Download PDF

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Publication number
WO2010069147A1
WO2010069147A1 PCT/CN2009/001489 CN2009001489W WO2010069147A1 WO 2010069147 A1 WO2010069147 A1 WO 2010069147A1 CN 2009001489 W CN2009001489 W CN 2009001489W WO 2010069147 A1 WO2010069147 A1 WO 2010069147A1
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Prior art keywords
group
dihydropyrimidine
methyl
carboxylate
alkyl
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PCT/CN2009/001489
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English (en)
Chinese (zh)
Inventor
戈尔德曼⋅西格氟里德
卢妍莲
李静
张英俊
符兆林
卢轩
林淘曦
罗忠华
陈燕桂
Original Assignee
张中能
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Publication of WO2010069147A1 publication Critical patent/WO2010069147A1/fr

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    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the present invention provides a novel dihydropyrimidine compound, a process for its preparation and its use as a medicament for the preparation of a medicament for the treatment and prevention of viral diseases, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to the use of these dihydropyrimidine other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B. Background technique
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical signs in pathology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • Interferon and lamivudine are conventional drugs approved for the treatment of chronic hepatitis.
  • interferon is only moderately active and has harmful side effects; although lamivudine has good activity as a new drug, its resistance develops rapidly during treatment and stops treatment.
  • the rebound effect is often followed by WO 99/54312, 99/54326, 99/54329 and US 7074784 relating to the use of a dihydropyrimidine for the treatment and prevention of hepatitis virus infection.
  • the patent US7074784 example discloses a 1,4 dihydropyrimidine compound substituted with a 2-position halopyridyl group and a 6-position basic group.
  • Halogenated ring systems are sensitive to nucleophilic materials such as amines such as morpholine. We have found that the replacement of the two substituents with the other heterocyclic compounds gives better activity and better chemical stability against nucleophilic attack than the previously disclosed compounds.
  • Another object of the present invention is to provide a method for preparing dihydropyrimidine compounds.
  • a further object of the present invention is to provide a medicament containing a dihydropyrimidine compound as a medicament for the preparation of a medicament for the treatment and prevention of a viral disease, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection.
  • 1 represents hydrogen, amino, nitro, cyano, F, Cl, Br, 1, hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or ⁇ -0: 6 thiol, Alkoxy group of C!-Cs, ⁇ oxycarbonyl group of C,-C 6 , alkylamino group of dC 6 , dialkylamino group of -C 6 , amide group of CC 6 , acyloxy group of -C 6 , An acyl group of C 6 , an alkylthio group of dC 6 , an alkylsulfonyl group of C, -C 6 or an alkanoyl group of - or an unsubstituted pyridine group; or a phenyl group, a naphthyl group, a thio group, a pyridyl group, a thienyl group, Oryl, pyrrolidinyl, imidazolyl,
  • R 2 represents hydrogen, amino, nitro, cyano, F, Cl, Br, I , hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or - (6-alkyl, C, -C 6 Alkoxy, C,-C 6 alkoxycarbonyl, dC 6 alkylamino, C r C 6 dinonylamino, C,-C 6 amide, C,-C 6 acyloxy , an acyl group of d-Ce, an alkylthio group of dC 6 , an alkylsulfinyl group of C,-C 6 or an alkylsulfonyl group of -C 6 ; or a phenyl group, a naphthyl group, containing 1-5 selected from N, S a heteroatom of 5-12 atoms substituted by a hetero atom of O, wherein the heteroaryl group is pyridinyl, quinolyl, pyrimidinyl, fu
  • A represents a key, -0-, -S -, or -NRu -, where! ⁇ is an alkoxycarbonyl group of ⁇ -C 6 , or a linear, branched, or cyclic saturated or unsaturated C 8 hydrocarbon group, wherein the hydrocarbon group optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH-(-alkyl), -N-(d-alkyl) 2 , the same or different heterochain units, and optionally halogen, nitro, cyano, hydroxy, having 6-10 An aryl group of carbon atoms, an aralkyl group having 6 to 10 carbon atoms or a heteroaryl group;
  • R 3 represents an alkoxycarbonyl group of H, or a linear, branched, or cyclic saturated or unsaturated C,-C 8 hydrocarbon group, or the hydrocarbon group thereof optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH- (-alkyl), -N-(d-alkyl) 2 , the same or different hetero chain units, and optionally halogen, nitro, cyano, hydroxy, having An aryl group of 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula 1 12 1
  • R represents hydrogen, amino, methyl, and when R is methyl, R is a substituent other than unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl or imidazolyl; or R represents
  • Z represents a halogen, and when Z is Br and X is -CH 2 -, it cannot be a thiazol-2-yl group and an unsubstituted pyridyl group;
  • 1 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocyclic ring, C,-C 8 fluorenyl group, C r C 8 alkoxy group, -Cs alkylthio group, C r C 8 alkylsulfinyl, -Cs sulfonyl, C r C acyl, nitro, trifluoromethyl 8 or -CO-N (R 20) 2 , wherein R 2 o can be H or An alkyl group of CrC 8 ;
  • R is morpholin-4-yl-methyl, thiazol-2-yl, R 3 is -CH3, when A is 0, R 2 is not 2,4-dichloro-phenyl;
  • the C 1 -C8 alkyl group means a group having 1-8 carbon atoms in a straight or branched chain, wherein the alkyl group may be independently and optionally optionally substituted by one or more substituents described in the present invention. Replace. A straight or branched alkyl group having 1 to 4 carbon atoms is preferred.
  • Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl and n-hexyl, etc. .
  • aryl may be used alone or as a large part of "aralkyl” “aralkyloxy” or “aryloxyalkyl", unless otherwise specified, aryl means a total of 6-10 membered rings.
  • aryl may be used interchangeably with the term “aromatic ring”, as an aromatic ring may include phenyl, naphthyl.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thieny
  • aralkyl includes aryl substituted alkyl groups.
  • an arylalkyl group refers to a "lower aralkyl” group, i.e., an aryl group attached to a C1-6 alkyl group.
  • the acyl group of Cr represents a linear or branched acyl group having 1-8 carbon atoms, preferably a linear or branched acyl group having 1 to 6 carbon atoms, and particularly preferred acyl groups are acetyl group and propionyl group.
  • the alkenyl group of C 2 -C 4 represents a linear or branched alkenyl group having 2 to 4 carbon atoms, preferably a vinyl group or a propenyl group.
  • the decyloxy group of -Cs represents a linear or branched alkoxy group having 1-8 carbon atoms, preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, more preferably a methoxy group, Oxy or propoxy.
  • the alkylthio group of -C 8 represents a linear or branched alkylthio group having 1 to 8 carbon atoms, preferably a linear or linear alkylthio group having 1 to 6 carbon atoms, more preferably a methylthio group, Ethylthio or propylthio.
  • the alkoxycarbonyl group of C r C 8 represents a straight-chain or branched playk-like carbonyl group having 1-8 carbon atoms, preferably a linear or linear fluorenyloxycarbonyl group having 1 to 4 carbon atoms, more preferably a methoxy group. Carbonyl, ethoxycarbonyl or propoxycarbonyl.
  • C r C 8 hydrocarbon group include the aforementioned C r C alkyl, C r C 8 alkenyl group 8, C 3 -C 8 cycloalkyl, preferably ( ⁇ - (8 alkyl.
  • the cycloalkyl group of C r C 8 represents a cyclopropyl group, a cyclopentyl group, a cyclobutyl group or a cyclohexyl group, preferably a cyclopropyl group.
  • the compound of the present invention includes the formula (1) or its isomer (la) or a mixture thereof.
  • the isomer of formula (I) generally refers to its tautomer or optical isomer.
  • the isomers (1) and (la) can exist in equilibrium with tautomers. If R4 is hydrogen, the isomers (I) and (la) can exist as tautomers:
  • the compounds of the present invention may exist in the form of optical isomers which are in enantiomeric or diastereomeric relationship between the optical isomer forms.
  • the invention relates to these enantiomers or diastereomers and mixtures thereof.
  • the racemate can be resolved into a single component of a stereoisomer by known methods, such as the introduction of other chiral groups in the molecule of the inventive compound to give optically pure enantiomers. body.
  • the compounds of the invention may also be in the form of a salt, the physiologically acceptable salts of which are preferred in the present invention.
  • the physiologically acceptable salt may be a mineral acid salt or an organic acid salt.
  • inorganic acid salts such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, a salt formed from lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalene-disulfuric acid.
  • the physiologically acceptable salt may also be a metal or ammonium salt of a compound of the invention.
  • Particularly preferred are sodium, potassium, magnesium, or calcium salts, and from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, fine
  • Some of the compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the present invention includes those stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • Z represents halogen, when Z is Br and X is -CH r , R, cannot be thiazol-2-yl and unsubstituted pyridyl;
  • Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl, Or NR 14 R I 5 , wherein R l4 and R l5 may be the same or different and represent a fluorenyl group of CC 4 which is optionally substituted by a hydroxy, alkoxycarbonyl group, or R l4 , R l 5 and The N atom bond synthesizes a heterocyclic ring which is: imidazole, triazole, tetrazole or a group represented by the following formula:
  • Y represents CH r , -CH 2 -CH 2 - , - 0, -8, -50-, 80 2 - or NR 16 , wherein R 16 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , R l 7 , R 18 > R l 9 may be the same or different and represent H or C 1 -C 8 fluorenyl;
  • R 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocycle , d- the embankment group, C r of the embankment group, dC 4 alkylthio, d- alkyl sulfinyl, C r C 4 alkylsulfonyl, dC 4 acyl,
  • Some of the examples are alkyl, nitro, F, Cl, Br, hydroxy, trifluoromethyl, CrC 4 alkyl, or unsubstituted pyridyl in formula (I) and (la); or phenyl , thiazolyl, pyrimidinyl, thienyl, furanyl, pyrrolidinyl, imidazolyl, thiazinyl; or the same or different substituents wherein the above ring system is selected from the group consisting of up to 3 substitutions: Base, amino, F, Cl, Br, hydroxy, trifluoromethyl, benzyl, -alkyl, d-alkoxy, -alkoxycarbonyl, C amide, dC 4 acyloxy; R 2 represents an amino group, a nitro group, a F, Cl, Br, a hydroxyl group, a trifluoromethyl group, an alkyl group of dC 4 ; or a phenyl group, or
  • Z represents halogen, when Z is Br, and X is -CH r , R is not a thiazol-2-yl group and an unsubstituted pyridyl group.
  • Z represents phenylbenzenesulfonyloxy, decanoyloxy, pyridyl, , Or NR 14 R 15, wherein R 14 and R l 5 identical or different, represent alkyl, said alkyl optionally substituted by hydroxy, C r C 3 alkoxycarbonyl substituent, or R 14, R I 5 and N atom bond to synthesize a heterocyclic ring, which is: imidazole, triazole, tetrazole or a group represented by the following formula:
  • Y represents CH 2 -, -CH 2 -CH 2 -, -0, -S, -SO-, S0 2 - or NR 16 , wherein R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , wherein R 17 , R I 8 , R l9 The same or different, representing an alkyl group of ⁇ or -C 4 ; R 20 represents hydrogen, halogen, cyano, azide, amino,
  • Some of the examples are represented by the formula (I) and Ua) ( ⁇ -(: 3 alkyl, or unsubstituted pyridyl; or phenyl, thiazolyl, pyrimidinyl, thienyl, furyl, imidazolyl)
  • the above ring system is the same or different substituents selected from the group consisting of up to 3 substitutions: nitro, amino, F, Cl, Br, trifluoromethyl, -C 3 alkyl;
  • R 2 An alkyl group representing CrC 3 , or a phenyl group, or a C 5 -C 6 heteroaryl group substituted with 1 to 2 hetero atoms selected from N, S, O, which is a pyridyl group or a pyrimidinyl group Or a thienyl group, an oxazolyl group or a thiazolyl group, wherein the above ring system is the same or different substituents selected from the group consisting of up
  • Z represents methyl sulfonyloxy, methylsulfonyloxy, pyridyl, Or a NR 14 R 1
  • Some of the examples are the same or different substituents of the formula U) and (la) which represent a phenyl group, a thienyl group, a furyl group, an imidazolyl group, or a ring system selected from the group consisting of the following groups, up to 2 substitutions.
  • R 2 represents a phenyl group, which is selected from the same or different substituents of the following groups, up to 3 substitutions: F , Cl, Br, trifluoromethyl, C, -C 3 alkyl, the alkyl is substituted by halogen;
  • A represents -0-, -NR u -, wherein R u represents hydrogen or C, -C 4 alkyl group; R.
  • R 3 represents hydrogen, C r C 4 alkyl group;
  • R, R I5 and N atom bond to form a heterocyclic ring which is a group represented by the following formula:
  • Y represents -0, -S, -SO-, SO r or NR I6 , and
  • R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R,7 or CO-NR l8 R l9 , R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or C!-C),
  • R 20 represents hydrogen, halogen;
  • Base represents hydrogen.
  • R1 in the formulae (I) and (la) represents a thienyl group, a furyl group, an imidazolyl group, and the above ring system is the same or different substituents selected from the group consisting of up to 2 substitutions: F, Cl, ⁇ , - ⁇ : 3 alkyl
  • R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br, trifluoromethyl
  • A represents -0-, -NH-
  • R 3 represents hydrogen, C'-alkyl
  • R represents -CH 3 , wherein when R is methyl, it cannot be unsubstituted pyridyl, thiazolyl, substituted phenyl , furanyl, thienyl, imidazolyl
  • R represents -XZ, X represents -CH r ;
  • Z represents Br, when Z is Br, and X is -CH r , it cannot
  • Y represents -0, -S, -SO-, SO r or NR I6 , and
  • R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R l7 or CO-NR 18 R l9 , wherein R l7 , R l8 , R l9 may be the same or different and represent an alkyl group of H or -, and 11 ⁇ 2 represents hydrogen; in the above definition, when R is morpholine 4-yl-methyl, R, is thiazol-2-yl, R 3 is -CH 3 , when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
  • Some of the examples are represented by the formula (1) and (la), wherein the above ring system is the same or different substituents selected from the group consisting of the following groups: up to 2 substitutions: F , CI. Br; R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br; A represents -0-, -NH-; R 3 represents hydrogen, (: alkyl, R 2 represents 1 -CH 3, wherein when R is methyl, ⁇ is not unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl; or represents -XZ, X represents -CH r , Z represents Br, when Z is Br, X is -CH 2 -, it cannot be thiazol-2-yl and unsubstituted pyridyl; or Z represents toluenesulfonyloxy, methyls
  • Y represents -0, -S, -SO-, SO r , NR, 6 , and R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l7 or CO-NR 18 R 19 , wherein R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or d-, and R 20 represents hydrogen; in the above definition, R is morpholin-4-yl-methyl, R is thiazol-2-yl, R 3 is -CH 3 , and when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
  • the compound of the formula (I) and (la) of the present invention or a salt or hydrate thereof may also be a specific compound: 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl) -methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester, 4-(2-chloro-4-fluorophenyl)-6-(morpholine-4 -yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2,4-dichlorophenyl)-6- (morpholine- 4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2-bromophenyl)-6-(monooxythio?
  • the compound of the present invention of the formula (I) or (la) can be produced by the following method:
  • R 2 , R 3 , and R have the same meanings as defined above;
  • R, R4 have the same meaning as before, or
  • R, R 2 , R 3 , , X and Z have the same meanings as defined above, and W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy, And a compound represented by the formula (IX) or (III)
  • a compound represented by the formula (Va) can be reacted with a compound of the formula (IX) or (hydrazine) to prepare a corresponding ⁇ -ketocarboxylic acid.
  • the ester (V), which cannot be prepared by this method, is commercially available.
  • W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy.
  • the aldehyde of the formula (II) used as a starting material is known or can be prepared according to known methods described in the literature [see TD Harris and GP Roth, J. Org. Chem., 44, 146 (1979), published in Germany. 2 165260, July 1972, German publication 2401665, July 1974, Mijano et al., Chemical Abstracts 59, (1963), 13929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), EP Papadopoulos, M. Mardin and Ch.
  • the hydrazine of the formula (V) used as a starting material is known in some cases or can be prepared according to known methods described in the literature [see Houben-Weyl, Organic Chemistry, Vol. 1 1/ 2, 38 pages (1958); RL Shoiner and FW Neumann, Chemical Review 35, 351 (1944)], or may be prepared as described in WO-A-99/54326 and WO-A-99/54329.
  • the compounds (VIII) and (X) can be produced according to the procedure [A] or [B] described in WO-A-99/54326.
  • inert organic solvents are suitable for the eight, B, C and D steps.
  • Preferred among them are alcohols (e.g., methanol, ethanol, isopropanol), ethers (e.g., dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether), carboxylic acids (such as glacial acetic acid). , dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
  • alcohols e.g., methanol, ethanol, isopropanol
  • ethers e.g., dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether
  • carboxylic acids such as glacial acetic acid.
  • dimethylformamide dimethyl sulfoxide, acetonit
  • the reaction temperature can be varied within a relatively wide range.
  • a temperature between 20 and 150 Torr is usually used, but is preferably at the boiling temperature of the selected solvent.
  • the reaction can be carried out under atmospheric pressure or under high pressure. It is usually carried out under atmospheric pressure.
  • the reaction can be carried out in the presence or absence of an acid or a base; however, it is preferred to carry out the reaction in the presence of a weak acid such as acetic acid or formic acid.
  • a weak acid such as acetic acid or formic acid.
  • the column is a silicon limb.
  • Silica gel 300-400 mesh
  • d6-DMSO CD30D or d6-acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard.
  • TMS 0.25 ppm
  • s sensinglet, unimodal
  • d doublet, doublet
  • t triplet, triplet
  • m multiplet, multiplet
  • br broadened, wide
  • Peak dd (doublet of doublets), dt (doublet of triplets).
  • Coupling constant expressed in Hertz (Hz).
  • MS mass spectrometry
  • Pure compounds are characterized by: Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min Flow rate, 5 to 95% (0.1% formic acid in CH3CN) in (0.1 % formic acid in H20). Column was operated at 40 0C.
  • HPLC high performance liquid chromatography
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, muscular, Peritoneal machine, intrathecal, heart Intravenous, intrasternal or intracranial injection or input, or by means of an explanted reservoir, preferably oral, intramuscular, intraperitoneal or intravenous.
  • the compound of the present invention or the pharmaceutical composition containing the compound of the present invention can be administered in unit dosage form, and the dosage form can be a liquid dosage form, a solid dosage form, a liquid dosage form, and can be a true solution, a colloid type, a microparticle dosage form, an emulsion dosage form, and a suspension.
  • Dosage form, other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, stickers Agents, tinctures, etc.
  • the pharmaceutical composition of the present invention may further contain a usual carrier, and the pharmaceutically acceptable carrier herein includes, but is not limited to: ion exchanger, alumina, aluminum stearate, lecithin, serum protein such as human serum albumin, buffer. a substance such as phosphate, glycerol, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, etc., the weight content of the carrier in the pharmaceutical composition It may be from 1% to 98%, usually about 80%. For convenience, local anesthetics, preservatives, buffers and the like may be directly
  • Oral tablets and capsules may contain excipients such as binders (eg, sugars, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (eg, lactose, sucrose, corn, starch, calcium phosphate) , sorbitol, glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol, silica), disintegrants (such as potato starch), or acceptable sizing agents (such as sodium lauryl sulfate) Salts, tablets may be prepared by methods well known in the art of pharmacy.
  • binders eg, sugars, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers eg, lactose, sucrose, corn, starch, calcium phosphate
  • sorbitol, glycine e.glycine
  • lubricants such as magnesium stearate
  • Oral can also be prepared as a suspension of water and oil, a solution, an emulsion, a syrup or an elixir. It can also be made into a dry product, supplemented with water or other suitable medium before use.
  • a liquid preparation may contain conventional additives, such as Suspensions (sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils), emulsifiers (eg lecithin, sorbus) Monosaccharide monooleate, gum arabic); or non-aqueous carrier (may contain edible oils), such as almond oil, oils (such as glycerol, ethylene glycol, or ethanol); preservatives (such as methylparaben) Or propyl ester, sorbic acid), if necessary, add flavoring or coloring agents.
  • Suspensions sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxye
  • the suppository can comprise a conventional suppository base such as cocoa butter or other glycerides.
  • liquid dosage forms are usually made from the compound and a sterile carrier.
  • the carrier is preferred water.
  • the compound can be dissolved in the carrier or in a suspension solution. The compound is dissolved in water before being prepared into an injection solution, filtered and sterilized, and then placed in a sealed bottle or ampoule. .
  • the compound of the invention When applied topically to the skin, the compound of the invention may be in the form of a suitable ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers, wherein the carrier to which the ointment formulation can be applied includes but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams can be used, including but not limited to: mineral oil, sorbitan Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the carrier to which the ointment formulation can be applied includes but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water
  • lotions and creams can be
  • the active compound of the formula (1) in the above pharmaceutical preparation should be present in a concentration of from about 0.1 to 99.5 based on the total amount of the mixture. /. Preferably, it is about 0.5 to 95% by weight.
  • One embodiment of the invention relates to a composition
  • a composition comprising: A) at least one of the above-described dihydropyrimidines, B) at least one other antiviral agent different from A.
  • a detailed embodiment of the invention relates to a composition
  • a composition comprising: A) the above-described dihydropyrimidine, B) HBV polymerase inhibitor, and, where appropriate, C) an immunomodulatory agent.
  • Preferred immunomodulators C) include, for example, all interferons such as alpha-, beta- and gamma-interferons, especially a-2a- and a-2b-interferons, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines. .
  • the present invention also relates to such compositions for the treatment and prevention of HBV infection and their use in the treatment of diseases caused by HBV.
  • compositions of the invention are beneficial for the treatment of HBV-induced diseases relative to a single treatment of a single compound
  • the compositions of the present invention are well tolerated, primarily with enhanced antiviral activity, and with respect to the single component of Tox-50, which has a toxicity range of 50% cell survival.
  • the HBV polymerase inhibitor guanidine used to achieve the object of the present invention is Ph. A. Furman et al., Antimicrobial Agents and Chemotherapy Vol. 36 (No. 12 ), 2688 (1992) Those materials revealed in endogenous polymerase experiments, as well as those described below, inhibit the formation of HBV DNA double strands, resulting in a maximum of 50% of the activity values of zero.
  • HBV virions were transferred from the culture suspension to the positive strand of HBV DNA together with the nucleoside 5'-triphosphate.
  • agarose gel electrophoresis a binding product of 3.2 kb DNA in which [ ⁇ - 32 ⁇ ]-deoxynucleoside 5'-triphosphate and virus were present was found, and there was no potential HBV polymerase-inhibiting property. substance.
  • From the cell culture suspension of HepG2.2.15 cells it was precipitated with polyethylene glycol and concentrated to obtain HBV virions.
  • One part by volume of the clarified cell culture suspension was mixed with 1/4 part by volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M of sodium chloride.
  • the pellet was centrifuged at 2500 xg for 15 minutes, and the precipitate was resuspended in 2 ml of a buffer containing 0.05 Mtris-HCI M (pH 7.5), and dialyzed against the buffer containing 100 mM potassium chloride. The sample was frozen at -80 'C.
  • Each reaction mixture (100) contains at least 10 5 HBV virions, 50 mM tris-HCI (p.sub.H 7.5).
  • the gel is dried or transferred to the membrane using Southern transfer techniques.
  • An HBV polymerase inhibitor is present if there is a maximum 50% concentration of the control group.
  • Abacavir (-)-( 1 S-cis)-4-[2-amino-6-(cyclopropylamine)-9H-indol-9-yl]-2-yl-cyclopentene - Methanol, cf.
  • a further preferred embodiment of the invention relates to the invention comprising A) the above-mentioned dihydropyrimidines (I) and (la) and B) lamivudine Lamivudine ) composition aboard
  • Another preferred HBV antiviral agent B contains, for example, a phenylacrylamide represented by the following formula
  • R 2 are independently independently a C,-C 4 alkyl group or have a nitrogen atom at their position to form a ring having 5 to 6 atoms containing carbon and/or oxygen.
  • R 3 to R l2 are each independently hydrogen, halogen, -C 4 alkyl, optionally substituted C r C 4 alkoxy, nitro, cyano or trifluoromethyl.
  • R l 3 is hydrogen, C, -C 4 alkyl, dC 7 acyl or aralkyl, and X is halogen or optionally substituted -C 4 alkyl, and salts thereof.
  • AT-61 is a compound
  • Preferred immunomodulators C) include, for example, all interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, especially a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, especially a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • Another preferred embodiment of the invention relates to a composition
  • a composition comprising A) the above-described dihydropyrimidines (1) and (la); B) lamivudine; and, where appropriate, C) interferon.
  • the invention includes the preparation of a medicament comprising, in addition to a non-toxic, pharmaceutically acceptable carrier, one or more compounds (1) or (la) or compositions of the invention or one or more A composition consisting of the active ingredient (1) or (la) or a composition consisting of the composition of the invention.
  • the active ingredients (I) and (la) referred to in the above pharmaceutical preparations have a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the entire mixture.
  • the above pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the compounds (1) and (la).
  • the content ratio of the components A, B and the appropriate C in the composition of the present invention may vary within a wide range of limitations, preferably 5 to 500 mg A/10 to 1000 mg B , especially 10 to 200 mg A/20. Up to 400 mg B,
  • Component C if appropriate, can also be used, its total use, preferably 10 million IU (international unit), more preferably 2-7 million IU (international unit), 3 weeks per week over a period of more than 3 years Times.
  • the compound or composition of the present invention as defined by the above pharmaceutical preparations usually has a concentration by weight of from about 0.1 to 99.5%, preferably from about 0.5 to 95% (relative to the entire mixture).
  • the above pharmaceutical preparation can be carried out by a known conventional method such as mixing the active ingredient with a carrier.
  • the single ingredient contains the active ingredient preferably in a total amount of from about 0.1 to about 80 mg/kg body weight, preferably 0.1 Up to 30mg kg body weight. In any case, depending on the above dosages, especially depending on the weight of the individual and the subject, the type of preparation, the manner in which the medication is taken, and the time or interval at which the medication is administered are necessary.
  • the present invention also relates to the above compounds and compositions for use in the control of diseases.
  • the invention further relates to a medicament comprising at least one of the above compounds or compositions and, where appropriate, one or more other active pharmaceutical ingredients.
  • the invention further relates to the use of the above compounds and compositions for the manufacture of a medicament for the treatment and prevention of the above mentioned diseases, in particular viral diseases, in particular hepatitis B.
  • the compound was synthesized by a method similar to that of Example 1 using methyl acetoacetic acid. Yield: 55% (melting point: ⁇ 52-154 ⁇ ),
  • Example 4 Methyl 6-molyl-4-(4-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • the compound obtained in Example 2 was synthesized in a similar manner to that in Example 3.
  • This compound uses methyl 6-methyl-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11.
  • Mp 148-148, 7 ° C
  • This compound uses methyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-acid ester (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11.
  • Mp 165, 8-166, 4 ° C
  • This compound uses ethyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and WO 9954329 mentioned) as a raw material by the method of the synthesis of 11.
  • This compound uses 2,2,2-trifluoroethyl-6-methyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine
  • the -5-carboxylate was synthesized as a raw material by the method of Example 11.
  • This compound was synthesized by a method similar to that of Example 16 using trifluoroacetylpiperazine (Tetrahedron Letters Vol. 36, No. 41, p 7357-7369 (1995) as a starting material.
  • the preparation method is as follows:
  • Hydroxylamine hydrochloride 18.0 g (0.26 mol) was dispersed in 120 ml of formic acid. At 80 ° C, 24 g of 1-methyl-1H-imidazole-2-carbaldehyde (0.22 mol) was added dropwise to the system, and the reaction was completed in 40 minutes. The system was stirred at 80 °C for 2 hours, the reaction was stopped, the solvent was evaporated in vacuo, and then recrystallized from 100 ml of anhydrous ethanol to yield 17.1 g (yield: 62%) of pale yellow crystalline product.
  • reaction was quenched, cooled, filtered, and EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • 2- cyanopyridine 10.4 g (100 mmol) was dissolved in 100 ml of anhydrous methanol, and 18.0 g (100 mmol) of a 30% sodium methoxide solution was added thereto, and 13.4 g (250 mmol) of ammonium chloride was added thereto with stirring at room temperature, and the mixture was stirred at room temperature overnight. . Filtration, the filtrate was concentrated to dryness, stirred with 100 ml of acetone, filtered, and the filter cake was washed with an appropriate amount of acetone, and dried to yield a white solid 18.4 g (yield: 117%).
  • Step 2 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • reaction was quenched, cooled, filtered, and evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 3 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde as a starting material. ) -2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzidine as a starting material.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40. (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-bromo-) by a method similar to that of Example 39 using 2-bromo-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2-au-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate. MS (M+H: 489, 491 )
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-chloro-) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was introduced into the reaction as a starting material, and methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) was synthesized by a method similar to that of Example 40. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4- (2,4-) by a method similar to that of Example 39 using 2,4-dichlorobenzamide and methyl acetoacetate as starting materials.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40 (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-chloro) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzhydrazide and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 0.172 g (2 mmol) of anhydrous piperazine was dissolved in 15 ml of absolute ethanol, and 0.9 g (2 mmol) was added dropwise at room temperature.
  • the methyl-6-bromomethyl-4-(2) prepared by the step 1.
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzaldehyde as a starting material.
  • Step 2 The compound prepared in the first step and 1-trifluoroacetylpiperazine were put into the reaction as a starting material, and the ethyl 4-(2,4-dichlorophenyl) group was synthesized by a method similar to that of Example 45. 2-(Pyridin-2-yl)-6-(4-(1-trifluoroacetyl)piperazinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 Methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • the acid ester will be 1.0 g of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-
  • Step 2 1.3 g (3.6 mmol) methyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-
  • Step 3 1.12 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-
  • the 5-carboxylate was dissolved in 120 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes.
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 2- Chloro-4-fluorobenzaldehyde 1.58 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.30 g (10 mmol) of ethyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 1.59 g (10 mmol), anhydrous Sodium acetate 1. Og (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester
  • Step 3 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 - Carboxylic esters
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate 0.85 g (2 mmol) ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved In 80 ml of carbon tetrachloride, heated to 60 ° C, 0.37 g (2.1 mmol) of N-bromosuccinimide was added in batches, kept at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was steamed at room temperature. The solvent was removed to give a pale yellow crude product, 0.58 g.
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2-indol-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5- post-ester
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-di- ft pyridine, 1,4--5-carboxylate 2,4-Dichlorobenzaldehyde 0.88 g (5 mmol) was dissolved in 50 ml of absolute ethanol, and 0.58 g (5 mmol) of methyl acetoacetate and benzamidine hydrochloride 0.78 g (5 mmol) were added. Anhydrous sodium acetate 0.50 g (6 mmol) was added and the mixture was warmed to reflux for 18 hours.
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 1.3 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 1.5 g of freshly prepared ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 95 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5
  • Example 64 The above title compound was obtained by a preparation method similar to that of Example 64.
  • Example 64 The above title compound was obtained by a preparation method similar to that of Example 64.
  • Step 1 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 77 Prepared by a method similar to that of Example 70 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Example 78 It was prepared by a method similar to the preparation method of Example 71 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Example 78 It was prepared by a method similar to the preparation method of Example 71 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Preparation of ethyl 4-(2-au-4-fluorophenyl)-2-methyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate B Base 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-methyl-1,4-dihydropyrimidine-5-carboxylate crude 1.3 g dissolved in 50 ml of ethanol, added 0.5 g (5.7 mmol) of morpholine.
  • the antiviral effect of the compounds of the invention on hepatitis B virus is based on the methods described by MA Sells et al, Proc. Natl. Acad. Sci. 84, 10051009 (1987) and BE orba et al., Antiviral Research 19, 5570 (1992).
  • Antiviral testing was performed on %-well microtiter plates. The first column only received medium and HepG2.2.15 cells as a virus control.
  • test compound 50 mM was first dissolved in DMSO and then diluted in HepG2.2.15 medium.
  • the compound according to the invention is typically pipetted 100 times at each test concentration (1st test concentration) to the second test column of the microtiter plate and then in a medium supplemented with 2% by weight fetal calf serum (volume 25). Diluted 2'° times in two steps.
  • Each well of the microtiter plate containing 2% by weight of fetal bovine serum contained 225 ⁇ l of HepG2.2.15 cell suspension (5 x 10 4 cells/ml). 37;, 5% C0 2 (v/v) The test mixture was incubated for 4 days.
  • the surface suspension was then aspirated and discarded, and 225 freshly prepared medium was added to the wells.
  • the compounds according to the invention were each refilled with a 10-fold concentrated solution in volume. The mixture is continued to grow for 4 days.
  • cytotoxic or cytostatic changes induced by substances in HepG2.2.15 cells for example, changes in cell morphology under light microscopy.
  • the changes induced by these substances in HepG2.2.15 cells are evident compared to untreated cells, such as changes in cell lysis, vacuoles, or cell morphology.
  • 50% toxicity (TOX.-50) refers to a morphology of cells that are 50% compared to the corresponding control cells.
  • the tolerance of some of the compounds according to the invention is tested on other host cells, such as HeLa cells, primary human peripheral hematopoietic cells or transformed cell lines such as H-9 cells.
  • the intracellular or extracellular suspension of HepG2.2.15 cells was denatured (1.5 MNaCI/0.5 N NaOH), neutralized (3 M NaCl/0.5 M Tris HCI, pH 7.5), then wash (2xSSC). The DNA was returned to the membrane by incubating the filter at 120 ° C for 2-4 hours.
  • Detection of viral DNA obtained from He P G2.2.15 cells treated on a nylon filter was performed on non-radioactive, digoxin-labeled hepatitis B DNA probes, each under the conditions of digoxin labeling, and purified. Hybrid based on operational confidence.
  • Pre-hybridization and hybridization were carried out in 5xSSC, l x blocking reagent, 0.1% by weight of N-lauroyl sarcosine, 0.02% by weight of SDS and 100 //g of herring sperm DNA.
  • Pre-hybridization was carried out at 60 ° C for 30 minutes and then specifically hybridized with 20 to 40 ng/ml of digoxin-labeled, denatured HBV-DNA (14 hours, 60 ° C). Wash the filter. Detection of HBV-DNA with digoxin antibody
  • the wash filter is hybridized in a closed test (according to the manufacturer's information). Hybridization was carried out using an anti-DIG antibody and alkaline phosphate fermentation for 30 minutes. After the washing step, the substrate of alkaline phosphatase, CSPD, was added with a filter for 5 minutes, then coated with a plastic film, and incubated for another 15 minutes at 37 Torr. Exposing the filter to the X-ray layer reveals the luminescent signal of hepatitis B DNA (culture depends on signal strength: 10 minutes to 2 hours).
  • the intracellular or extracellular Hepatitis B population was reduced by the compound according to the invention by a maximum half-inhibitory concentration (IC 5 Q, 50% inhibitory concentration) corresponding to a concentration of 50% of the untreated sample.
  • IC 5 Q 50% inhibitory concentration
  • the antiviral effect value exhibited by the compound of the present invention is 1 C 50 lower than 1 ⁇ ⁇ , which is unexpected.
  • the compounds of the invention are useful in the treatment of viral-induced diseases, particularly acute and chronic persistent HBV viral infections. Chronic viral diseases caused by HBV may cause morbidity to become severe, and chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinogenesis in many cases.
  • the indicated regions that may be mentioned are, for example, the treatment of acute and chronic viral infections that may result in infectious hepatitis, such as hepatitis B virus infection.
  • the compounds of the invention are especially suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
  • the compound of the present invention shows a strong antiviral effect, wherein some of the compounds 1C 5 () are less than 2 ⁇ , the IC 50 value of some compounds is between 2 nM and 20 nM, and the IC 5 o value of some compounds is between 20 nM and 200 nM.
  • the compounds of the present invention have unexpected antiviral activity against hepatitis B (HBV) and are therefore suitable for the treatment of various diseases caused by viruses, particularly those caused by acute and chronic persistent HBV infection.
  • Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma.
  • Treatment can lead to acute and chronic viral infections of infectious hepatitis, such as hepatitis B virus infection.
  • infectious hepatitis such as hepatitis B virus infection.
  • Particularly preferred are the treatment of chronic hepatitis B infection and the treatment of acute hepatitis B virus infection.
  • the present invention provides a dihydropyrimidine compound represented by the general formula (I) and its isomer (la), a preparation method thereof and use thereof as a medicament for preparing a medicament for treating and preventing a viral disease, In particular, it is used as a preparation for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to the use of these dihydropyrimidines together with other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B.
  • the invention has industrial applicability.

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Abstract

L'invention concerne des dérivés de la dihydropyrimidine, leurs isomères, énantiomères, sels et hydrates, ainsi que leur procédé de préparation, et leurs compositions pharmaceutiques. Lesdits composés peuvent être utilisés dans la fabrication de médicaments pour le traitement et la prévention de maladies virales, de préférence l'infection par l'hépatite B.
PCT/CN2009/001489 2008-12-17 2009-12-17 Derives de la dihydropyrimidine, leurs compositions et leur utilisation WO2010069147A1 (fr)

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JP2019535644A (ja) * 2016-11-18 2019-12-12 シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド ジヒドロピリミジン化合物並びにその調製方法及び使用
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