WO2005085212A1 - Derivé de la pyrimidine substitué - Google Patents

Derivé de la pyrimidine substitué Download PDF

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Publication number
WO2005085212A1
WO2005085212A1 PCT/JP2005/003535 JP2005003535W WO2005085212A1 WO 2005085212 A1 WO2005085212 A1 WO 2005085212A1 JP 2005003535 W JP2005003535 W JP 2005003535W WO 2005085212 A1 WO2005085212 A1 WO 2005085212A1
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substituted
group
pyrimidine
methanol
compound
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PCT/JP2005/003535
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English (en)
Japanese (ja)
Inventor
Noriyuki Kawano
Yohei Koganemaru
Naoyuki Masuda
Hiroyuki Kaizawa
Wataru Hamaguchi
Takahiro Miyazaki
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Astellas Pharma Inc.
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Publication of WO2005085212A1 publication Critical patent/WO2005085212A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D401/12—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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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

Definitions

  • the present invention relates to a novel substituted pyrimidine derivative, and a medicament containing the same as an active ingredient, particularly a therapeutic agent for an inflammatory disease.
  • Chemokines which are cell chemotactic factors, are broadly classified into two types, CXCZ chemokines and CCZ iS chemokines, depending on their structural characteristics.
  • these chemokine receptors belong to the family of seven transmembrane G-protein coupled receptors, and are composed of CXC chemokine receptor and CC chemokine receptor (Pharmacological Reviews, 52, 145, 2000).
  • CCR4 CC chemokine receptor 4
  • Thymus and activation-regulated chemoine (I'ARC) and macrophage-derived chemokine (MDC) are specific ligands for CCR4 (CCJ chemokines) (Journal of Biological Chemistry, 272, 1503 ⁇ , 1997, Journal of Biological chemistry, 273, 1764, 1998).
  • TARC was found as a T cell chemotactic factor (Journal of Biological Chemistry, 271, 21514, 1996), and MDC was discovered as a chemotactic factor for monocytes' macrophages and ⁇ cells (Journal of Experimental Medicine, 185, 1595, 1997).
  • Chemokines are also known to have the characteristics of both inflammatory chemokines and homeostatic chemokines. Today, 20, 254, 1999).
  • CCR4 and its ligands are involved in various diseases such as inflammatory diseases, allergic diseases, and autoimmune diseases.
  • diseases such as asthma, The Journal of Clinical Investigation, 107, 1357, 2001
  • atopic dermatitis Journal of Investigative Dermatology, 115, 640, 2000
  • psoriasis Laboratory dermatitis
  • CCR4 function modulators are expected as agents for preventing or treating these diseases and the like.
  • Various drugs such as steroids are used as prophylactic or therapeutic agents for the above-mentioned inflammatory diseases, allergic diseases, autoimmune diseases, etc. There is a strong need for the development of drugs based on this.
  • Patent Document 1 A gazette published after the application on which the priority of the present application is based describes that a pyrimidine derivative represented by the following general formula has an anti-inflammatory effect based on the regulation of functions of TARC and the like (Patent Document 1).
  • Ar is a substituted or unsubstituted aryl
  • R 1 is NR 3
  • R 2 is a hydrogen atom or a substituted or unsubstituted lower alkyl
  • R 3 is a substituted or unsubstituted A represents lower alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aromatic heterocyclic aralkyl, etc.
  • A represents formula (III), etc.
  • m 1 is an integer of 0 to 2
  • n is 0 to An integer of 4
  • a 1 represents a number capable of substituting 0 force
  • Q represents -NR 7
  • R 6 and R 7 are the same or different and represent a hydrogen atom or a substituted or unsubstituted lower alkyl, etc. ] Or a substituted or unsubstituted alicyclic heterocyclic group.
  • the application does not include compounds having aryl or heteroalkyl as R 2 or R 3 . It has been reported that a 5-cyanopyrimidine derivative represented by the following general formula has an anti-inflammatory effect based on the regulation of functions such as TARC (Patent Document 2).
  • R 1 and R 3 are the same or different and each represent a hydrogen atom
  • -NR 4 R 5 [R 4 and R 5 are the same or different and each represent a hydrogen atom, a substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, etc.]
  • R 2 represents the above formula (II), etc., where Q is a nitrogen atom or CH, and A is a short bond , Carbonyl, R, etc., R is a substituted or unsubstituted alicyclic heterocyclic group, etc., ma is an integer of 0-2, ya is 0-replaceable integer, na is an integer of 0-4.
  • ya is 0-replaceable integer
  • na is an integer of 0-4.
  • Patent Document 3 It has been reported that a compound represented by the following general formula has a function of regulating the function of TARC or the like (Patent Document 3).
  • Patent Document 4 a compound represented by the following general formula is useful as a therapeutic drug for central diseases based on GPR88 inhibition.
  • R 1 is a hydrogen atom, etc.
  • R 2 is a hydrogen atom, etc.
  • -NR 4 [wherein, R 3 and R 4 are hydrogen atoms, etc. Or R 3 and R 4 together with an adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group]
  • X is 1,2,3,4-tetrazole-5-yl and the like.
  • Y represents a hydrogen atom or the like
  • r represents an integer of 0 to 4.
  • Patent Document 1 International Publication No. 04Z074260 pamphlet
  • Patent Document 2 International Publication No. 03Z082855 pamphlet
  • Patent Document 3 International Publication No. 03Z104230 pamphlet
  • Patent Document 4 WO 04Z054617 pamphlet
  • An object of the present invention is to provide a safe and powerful preventive / therapeutic agent for inflammatory diseases, allergic diseases, autoimmune diseases and the like, which has a function of regulating CCR4 function and replaces conventional steroids. .
  • the present inventors have diligently studied compounds having a CCR4 function regulating action. As a result, a pyrimidine derivative CCR4 having a saturated 6-membered heterocyclic group such as substituted piperidino at the 2-position, a substituted amino group at the 4-position, and a ring group at one of the 5- or 6-position. The present inventors have found that they are useful as function regulators, and have completed the present invention.
  • the compound of the present invention is different from the compound described in Patent Document 1 in that a ring group is directly bonded to the 4-position of the pyrimidine ring via a nitrogen atom. Further, the compound of the present invention is a 5- or 6-position of the pyrimidine skeleton. And has a basic structure different from the compounds described in Patent Documents 2 and 3.
  • the present invention relates to the following compounds.
  • a substituted pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.
  • A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl,
  • R 1 -R °, halogen, -OH, -OR °, halogeno lower alkyl
  • R 3 — H, — R. Or— CN,
  • L bond, -CO-, lower alkylene, -CO- (lower alkylene)-or-(lower alkylene) -CO-,
  • R 2 same or different, -R °, halogen, -OH, -0R °, halogeno lower alkyl, -R °° -0H, -CON (R 8 ) (R 9 ), -R 00 -OR ° ,-R QQ -N (R 8 ) (R 9 ),-R QQ -CN,-R QQ -N (R 8 )-CO- R °,
  • R 8 and R 9 same or different, -H or -R °,
  • R 11 and R 12 same or different from each other, - 0H, -0R °, halogen, - N (R 8) ( R 9), - CN, - N (R 8) - CO- R °, - N ( R 8 ) -SO-R °, -0-CO-R °, -CO-R. Or a group consisting of -CON (R 8 ) (R 9 )
  • R QQ lower alkylene
  • a preferred embodiment of the present invention is a derivative shown below.
  • a substituted pyrimidine derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof represented by the following general formula (II) or a pharmaceutically acceptable salt thereof.
  • A: substituted !, may! /, Aryl or substituted !, may! /, Cycloalkyl,
  • R 1 -R °, halogen, -OH, -OR °, halogeno lower alkyl
  • Y CR 4 or N, where X force CR 3 indicates Y, and X indicates N, Y indicates CR 4 .
  • R 2 same or different, -R °, halogen, -OH, -0R °, halogeno lower alkyl, -R °° -0H, -CON (R 8 ) (R 9 ), -R 00 -OR ° ,-R QQ -N (R 8 ) (R 9 ),-R QQ -CN,-R QQ -N (R 8 )-CO- R °, -R 00 -N (R 8 ) -SO-R ° , -R °°-0-CO-R °, -R °° -CO-R. Or - R °° - CON (R 8 ) (R 9),
  • R 8 and R 9 same or different, -H or -R °,
  • R 5 and R 6 the same or different, the groups described in H or R 2 or R 5 and R 6 are
  • R 7 -H ⁇ -R °,-R °°-OH ⁇ -CON (R 8 ) (R 9 ),-R °°-0- R °,-R °°-N (R 8 ) (R 9), - R °° - CN ⁇ -R °° - N (R 8) - CO- R. , -R. . - N (R 8) - SO - R. , -R. . -0-CO-R. , -R. . -CO-R. Or -R. . -C0N (R 8
  • R QQ lower alkylene
  • B is substituted, may be, pyridyl, substituted !, may be, chel, substituted, may be, furyl or substituted, may be, The derivative according to the above [5], which is a phenol.
  • R 2 is halogeno lower alkyl, -R °° -OH, -R °° -OR. Or -CON (R 8
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the substituted pyrimidine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a CCR4 or a modulator of TARC and Z or MDC function, more preferably an inflammatory disease, an allergic disease or an autoimmune disease, particularly preferably asthma or atopic dermatitis
  • the above-mentioned pharmaceutical composition which is a prophylactic or therapeutic agent for rheumatoid arthritis.
  • a substituted pyrimidine derivative represented by the general formula (I) according to [1]-[10] for the manufacture of a prophylactic or therapeutic agent for an inflammatory disease, an allergic disease or an autoimmune disease.
  • a pharmaceutically acceptable salt thereof, wherein the substituted pyrimidine derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof according to (1)-(10) is used in an effective amount, It is a method for preventing or treating an inflammatory disease, an allergic disease or an autoimmune disease, which is administered to a mammal.
  • the substituted pyrimidine derivative of the present invention has a function of regulating the function of CCR4 or TARC and Z or MDC, and has an advantage that it has a strong effect in a model of an inflammatory disease, an allergic disease or an autoimmune disease.
  • alkyl and “alkylene” mean a straight or branched hydrocarbon chain.
  • “Lower alkyl” is preferably an alkyl group having 116 carbon atoms, more preferably an alkyl group having 114 carbon atoms, and still more preferably methyl and ethyl.
  • “Lower alkylene” means a divalent group formed by removing one arbitrary hydrogen atom from the above “lower alkyl”, preferably alkylene having 114 carbon atoms, more preferably methylene, ethylene and It is propylene.
  • Halogen refers to F, Cl, Br and I.
  • Halogeno lower alkyl means preferably alkyl having 1 to 6 carbon atoms substituted with one or more halogen, more preferably C alkyl substituted with one or more F, Preferably, fluoromethyl, diflu
  • Cycloalkyl is preferably cycloalkyl having 3 to 10 carbon atoms, and may be crosslinked. More preferred are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • Aryl means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and includes a phenyl group fused with “cycloalkyl”. Preferably, they are phenyl and naphthyl, and more preferably, phenyl.
  • the “monocyclic or bicyclic hydrocarbon ring group” includes both monocyclic or bicyclic “cycloalkyl” and monocyclic or bicyclic “aryl”.
  • the term "monocyclic heterocyclic group” refers to a monocyclic 3- to 8-membered, preferably 5- to 7-membered cyclic group containing 1 to 4 hetero atoms selected from 0, S and N forces. And includes a monocyclic heteroaryl which is an unsaturated ring, a monocyclic heterocycloalkyl which is a saturated ring, and a ring group in which the monocyclic heteroaryl is partially hydrogenated.
  • the monocyclic heteroaryl preferably, pyridyl, pyrazul, pyrimidyl, pyridazyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxaziazolyl and the like. No.
  • a monocyclic heterocycloalkyl or a ring group in which a heteroaryl group is partially hydrogenated preferably, piberidyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, Trahydroviral, morpholinyl and the like.
  • the “bicyclic heterocyclic group” is a ring group in which the above-mentioned monocyclic heterocycles are fused together or a benzene ring and a monocyclic heterocycle are condensed.
  • the ring atom S or N may be oxidized to form an oxoxide-dioxide.
  • an arbitrary carbon atom may be substituted with an oxo group.
  • May be substituted means “unsubstituted” or “having 115 identical or different substituents”.
  • the substituent in "substituted or may be aryl" and “substituted or may be cycloalkyl” is preferably halogen, lower alkyl, -OH, -0-lower alkyl, -CN , -S-lower alkyl, NO, more preferably halogen, lower alkyl, -OH
  • Substituents in the “optionally substituted monocyclic or bicyclic hydrocarbon ring group” and the “optionally substituted monocyclic or bicyclic heterocyclic group” are preferably halogen, lower Alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, -CN, NO,
  • NH and preferably 2 is halogen, lower alkyl, or halogeno lower alkyl.
  • the compound of the present invention represented by the formula (I) may have a geometric isomer or a tautomer depending on the type of a substituent. Or a mixture of the isomers.
  • the compound (I) may have an asymmetric carbon atom, and an (R) -form or (S) -form optical isomer based on this may exist.
  • the present invention includes all of the optical isomers as a mixture or an isolated one.
  • the compound (I) also includes a pharmacologically acceptable prodrug.
  • a pharmacologically acceptable prodrug is defined as the NH4 of the present invention by solvolysis or under physiological conditions. It is a compound having a group that can be converted to OH, COH, and the like. As a base to form a prodrug
  • Compound (I) may form an acid addition salt or a salt with a base depending on the type of substituent.
  • the strong salt is a pharmaceutically acceptable salt, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and propion.
  • Acid addition salts with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid, sodium And inorganic bases such as potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ortin; and ammonium salts.
  • the present invention also encompasses pharmaceutical compositions containing various hydrates and solvates of compound (I) and salts thereof and polymorphic substances.
  • Compound (I) which is an active ingredient of the present invention, and pharmaceutically acceptable salts thereof are produced by applying various known synthetic methods, utilizing characteristics based on the basic skeleton or the type of substituent. can do.
  • Such functional groups include, for example, amino groups, hydroxyl groups, carboxyl groups, and the like, and their protecting groups are described, for example, in Protective Groups in Organic Synthesis (Third Edition) by Green (TW Greene) and Utz (PGM Wuts). , 1999) ", which may be appropriately selected and used according to the reaction conditions.
  • a desired compound can be obtained by introducing the protective group and performing a reaction, and then removing the protective group or converting it to a desired group as necessary.
  • the prodrug of the compound (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate or by carrying out a reaction using the obtained compound (I) as in the case of the above-mentioned protective group.
  • the reaction is carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Can be performed.
  • This production method is a method for producing a compound (I) of the present invention by subjecting a pyrimidine derivative (1) having a leaving group at the 2-position to a cyclic amine diversion compound (2) by ibuso substitution.
  • Examples of the leaving group represented by L include a halogen, an alkylsulfiel group, an alkylsulfol
  • reaction is carried out by subjecting compound (1) to a solvent inert to the reaction, in the presence or absence of a base or acid (preferably hydrogen chloride), using an equivalent or excess amount of (2) under cooling and heating under reflux. It usually takes place for one hour and five days.
  • a base or acid preferably hydrogen chloride
  • the solvent is not particularly limited as long as it is inert to the reaction, but, for example, aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy Ethers such as ethane (DME) and 1,2-dietoxetane (DEE); halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, methanol, ethanol, 2-propanol, butanol, etc.
  • aromatic hydrocarbons such as benzene, toluene, xylene, getyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy Ethers such as ethane (DME) and 1,2-dietoxetane (DEE); halogenated hydrocarbons such as dichloromethan
  • Bases include organic bases such as triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo- [5.4.0] -7-indene (DBU), 2,6-lutidine, sodium carbonate, and carbonate.
  • organic bases such as triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo- [5.4.0] -7-indene (DBU), 2,6-lutidine, sodium carbonate, and carbonate.
  • IPEA diisopropylethylamine
  • DBU 1,8-diazabicyclo- [5.4.0] -7-indene
  • Inorganic bases such as potassium, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be mentioned.
  • This production method is a method for producing a compound (la) of the present invention by subjecting a pyrimidine derivative (3) having a piperazino group (3) and a carboxylic acid conjugate (4) to an amidoni reaction.
  • the reaction is carried out by using the compound (3) and the compound (4) in an equal amount or one of them in excess, and using a condensing agent (eg, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), -Ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1-carbylbis-1H-imidazole (CDI), etc., and in some cases, further additives (eg, N-hydroxysuccinimide ( (HONSu), 1-hydroxybenzotriazole (HOBt), etc.) with stirring under cooling and heating, preferably at room temperature, usually for 1 hour to 1 day.
  • a condensing agent eg, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), -Ethyl-3- (3-dimethylaminopropyl) carbodiimide (
  • the active ester form of the compound (4) and the above additive may be isolated and then reacted with the compound (3).
  • the solvent is not particularly limited as long as it is inert to the reaction.For example, aromatic hydrocarbons, ethers, halogenated hydrocarbons, ⁇ , ⁇ -dimethylformamide (DMF), N-methylpyrrolidone (NMP) , Dimethyl sulfoxide (DMSO) and the like. These solvents are used alone or in combination of two or more. In some cases, it is advantageous to carry out the reaction in the presence of a base such as triethylamine, DIPEA, pyridine or the like in order to make the reaction proceed smoothly.
  • a base such as triethylamine, DIPEA, pyridine or the like in order to make the reaction proceed smoothly.
  • the compound of the present invention having an NH group can be produced by a reduction reaction of a compound having a nitro group.
  • L is -C1 or -Br
  • U is -Br, -Cl, -I or -O-SO-CF
  • Q is -B (OH), -B (0-
  • the starting compound (1) can be produced by subjecting a pyrimidine derivative (5) to an ipamine substitution reaction with an amine compound (6), and then performing a coupling reaction using the adduct (7) and the compound (8). You. The same conditions as in the first production method can be applied to the ipso substitution reaction.
  • the coupling reaction can be performed, for example, by the method described in “Chemical Experiment Course (4th edition)”, edited by The Chemical Society of Japan, Vol. 25 (1992) (Maruzen). [Formula 11]
  • R 1Q represents a lower alkyl group. The same applies hereinafter.
  • the compound (la) wherein L 1 is a methylsulfinyl group can be produced according to the above reaction route.
  • methyl and ethyl are preferable as the lower alkyl of R 1Q.
  • the coupling reaction is described in the above-mentioned Nippon Dani Gakkai, “Experimental Chemistry Course (4th edition)”, Vol. 25 (1992) (Maruzen) It can be carried out by the method described.
  • the alkylation is carried out using an alkylating agent such as methyl iodide or dimethyl sulfate in a solvent such as aromatic hydrocarbons, ethers, or halogenated hydrocarbons, or a mixed solvent thereof.
  • Halogenide uses a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, or salty chloride, or a brominating agent such as phosphorus oxybromide in an equimolar excess to obtain an aromatic hydrocarbon or halogenated hydrocarbon.
  • the reaction is carried out in a solvent inert to the reaction or the like or without a solvent.
  • the same conditions as in the first production method can be applied to the ipso substitution reaction.
  • Oxidation can be carried out by using an ordinary method of oxidation reaction of the sulfur group. For example, the method described in The Chemical Society of Japan, “Experimental Chemistry Course (4th edition)”, Vol. 23 (1992) (Maruzen) can be mentioned. . [Formula 12]
  • the starting compound (3) can be produced by subjecting the pyrimidine derivative (1) to a piperazine (14) by an ipso substitution reaction.
  • the same conditions as in the first production method can be applied to the ipso substitution reaction.
  • the cyclic amine conjugates (2a) and (2b) can be produced by the method shown in the above formula.
  • the method described in the above-mentioned “Protective Groups in Organic Synthesis (3rd edition)” for the amino group deprotection reaction and the like can be applied.
  • the reductive alkylation a conventional method of reductive alkylation can be used. For example, it is described in “Experimental Chemistry Lecture (4th edition)” edited by The Chemical Society of Japan, Vol. 20 (1992) (Maruzen). Method.
  • cyclic amine conjugates (2c) and (2d) can be produced by the method shown in the above formula.
  • various cyclic amine compounds (2) can be prepared by, for example, alkylating a compound having a hydroxyl group with an alkylating agent (eg, alkyl halide ⁇ sulfonic acid alkyl ester) or an alkyl ether group by a Mitsunobu reaction to form a fluorinating agent.
  • the compound can be converted to a compound having a phthalimido group by a Mitsunobu reaction with a fluorimido group and phthalimide, respectively.
  • reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate.
  • the salt can be produced by subjecting it to a usual salt-forming treatment.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers can be isolated by a conventional method utilizing physical differences between the isomers.
  • the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Further, the optical isomer is produced from an appropriate optically active starting compound.
  • a vector (including the neomycin resistance gene) with the human CCR4 gene inserted downstream of the EF-1a promoter was prepared and transferred to the mouse pre B cell line B300-19 cells by the electoporation method. Transformation These cells were cultured in a medium supplemented with G418, and a single cell line that constantly and stably expresses human CCR4 was obtained by the limiting dilution method.
  • Human CCR4 expressing cells were collected, washed with PBS, and suspended in Lysis Buffer (10 mM Hepes pH 7.5, 2 mM EDTA, protainase inhibitor). After placing the suspension on ice for 15 minutes, the cells were disrupted with a homogenizer and centrifuged (20000 rpm, 10 min, 4 ° C). 0 The supernatant was ultracentrifuged (22K, 30 min, 4 ° C). Thereafter, the pellet suspended in PBS was used as a membrane fraction in subsequent experiments.
  • Lysis Buffer 10 mM Hepes pH 7.5, 2 mM EDTA, protainase inhibitor
  • Test compounds were prepared at 20 mM Hepes pH 7.05, 100 mM NaCl, 5 mM MgCl,
  • the compounds of Examples 2, 3, 6, 10, 16, 19, 20, 22, and 24 showed an inhibitory activity of 50% or more at 1 M concentration.
  • the compound of Example 3 had an IC of 120 nM.
  • the abdomen of Balb / c mice (6-10 weeks old, female, Nippon Chillers' Riva) was sensitized by applying 150 L of 3% oxazolone / ethanol solution (Sigma-Aldrich Japan).
  • 10 L of a 1% oxazolone / ethanol solution was applied to both sides of the right ear.
  • the test drug was administered 12 hours after application of the oxazolone solution (test drug administration group), and the control group received only the solvent used to dissolve the test drug.
  • the inhibition rate was calculated by the following formula using the group to which the oxazolone solution was applied without sensitization as the normal group. The above test was performed on 5 animals per group.
  • Inhibition rate (swelling of control group swelling of test drug administration group) xl00 / (swelling of control group-swelling of normal group)
  • the compounds of Examples 2, 6, 10, 19 and 20 showed significant inhibitory activity at 30 mg / kg oral administration.
  • the compound of the present invention has a strong CCR4 function regulating action, and a favorable pharmacological action was confirmed in models of inflammatory diseases and the like.
  • a preparation containing one or more of compound (I) or a salt thereof as an active ingredient is prepared using a carrier, an excipient, and other additives that are usually used for formulation.
  • parenteral injections such as intravenous injections, intramuscular injections, suppositories, transdermals, nasal formulations, inhalants, etc. Any of the forms may be used.
  • the dose is determined as appropriate depending on the individual case, taking into account the symptoms, age, sex, etc. of the administration subject.However, for oral administration, it is usually about 0.001 mg / kg to 100 mg / kg per day for an adult. This should be given once or in 2-4 doses.
  • the dose is usually in the range of 0.0001 mg / kg to 10 mg / kg per adult once or more times a day.
  • the dose is usually in the range of 0.0001 mg / kg to 1 mg / kg for an adult once or more times a day.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substance (s) at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone, magnesium aluminate metasilicate and the like.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, or a solubilizer according to a conventional method.
  • Tablets or pills may be coated with sugar coating or a gastric or enteric coating agent, if necessary.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups. Agents, elixirs, etc., and generally used inert solvents such as purified water and ethanol.
  • the composition may contain, in addition to the inert solvent, auxiliaries such as solubilizers, wetting agents and suspending agents, sweeteners, flavoring agents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solvents include, for example, distilled water for injection and physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may further include a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizing agent, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these are prepared by preparing a sterile solid composition, dissolving and suspending it in sterile water or a sterile injection solvent before use.
  • Transmucosal agents such as inhalants and transnasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • an excipient and as Ratatosu Ya starch furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate.
  • P H adjusting agent a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like
  • an appropriate inhalation or insufflation device can be used. Solutions or suspensions of the compounds, alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier, using known devices or nebulizers, such as metered dose inhalers.
  • Can be administered as A dry powder inhaler or the like can utilize a dry powder or a powder-containing capsule that can be used for single or multiple doses.
  • a dry powder or a powder-containing capsule that can be used for single or multiple doses.
  • it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or diacid carbon, etc. .
  • External preparations include ointments, plasters, creams, jellies, cataplasms, sprays, lotions, eye drops, eye ointments and the like. It contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions and the like.
  • ointment or lotion bases include polyethylene glycol, carboxybutyl polymer, white petrolatum, beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl Anore konore, cetyl alcohol, lauromacrogol, sonolebitan sesquioleate and the like.
  • N- (4-chlorophenol) -5- (4-fluorophenyl) -6-methyl-2- (methylsulfuryl) pyrimidin-4-amine was added to dichloromethane in dichloromethane under ice-cooling. Treatment with oral benzoic acid gave N- (4-chlorophenyl) -5- (4-fluorophenyl) -6-methyl-2- (methylsulfuryl) pyrimidin-4-amine. ES: 376.
  • N- (4-chlorophenol) -2- (methylsulfur) -6-phenylpyrimidin-4-amine is treated with m-chlorobenzoic acid in dichloromethane at room temperature to give N There was obtained-(4-chlorophenol) -2- (methylsulfol) -6-phenylpyrimidin-4-amine.
  • tert-butyl 4-oxopiperidine-1-carboxylate and (3S) -ethyl ethyl pecotate in the same manner as in Reference Example 10 to obtain tert-butyl (3S) -3- (ethoxycarbol) -1, 4′-Bipiperidine-1′-carboxylate (ES: 341) was obtained.
  • the THF solution was added to a suspension of lithium hydroxide boron in THF, and the mixture was stirred under reflux with heating to give tert-butyl (3S) -3- (hydroxymethyl) -1,4′-bipiperidine-1 ′.
  • -A carboxylate was obtained.
  • the compound of Reference Examples 13-24 was prepared in the same manner as in Reference Example 2, the compound of Reference Examples 25-29 was prepared in the same manner as in Reference Example 3, and the compound of Reference Example 30- was prepared in the same manner as in Reference Example 4.
  • the compound of Reference Example 38 and the compound of Reference Example 38 in the same manner as in Reference Example 11 was obtained by using the corresponding raw materials. Manufactured.
  • Table 14 shows the structure and physical data of the compound of Reference Example (13-40).
  • 6-Isopropyl-2-mercaptopyrimidin-4-ol is reacted with methane in ethanol in the presence of an aqueous sodium hydroxide solution at room temperature for 2 hours to give 6-isopropyl-2- (methylsulfuryl) pyrimidine-4- (3H )-Got on. EI: 184.
  • 5-cyanouracil was reacted with a 50% aqueous solution of hydroxylamine in methanol at 70 ° C for 2.5 hours to give ⁇ '-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxyimidine. Damide was obtained. This compound was reacted with acetic anhydride in a mixed solvent of THF and DMF at 100 ° C for 1.5 days to give 5- (5-methyl-1,2,4-oxaziazol-3-yl) pyrimidine-2,4 (1H , 3H) -Zion was obtained.
  • the compound of Reference Example 49-54 (the solvent was THF) and the compound of Reference Example 69 (the solvent was DEE) were used in the same manner as in the method of Reference Example 2.
  • the compound of Reference Example 61 was treated in the same manner as in Reference Example 9 using the compound of 55-60 and the compound of 63-66 (the solvent was DME), and the compound of Reference Example 62 was treated in the same manner as in Reference Example 44.
  • the compound of Reference Example 67 (the solvent is trifluoromethanesulfonic acid) and the compound of Reference Example 67 and the compound of Reference Example 68 in the same manner as in the method of Reference Example 4 (4 M hydrogen chloride-ethyl acetate solution instead of 1 M hydrochloric acid)
  • the compound of Reference Example 70 was treated in the same manner as in Reference Example 5, and the compounds of Reference Examples 71 and 72 were treated in the same manner as in Reference Example 10.
  • Example 73- The compound of Reference Example 76 was used in the same manner as in the method of Reference Example 48, and the compound of Reference Example 76 was used. Manufactured using The structures and physical data of the compounds of Reference Examples 49-76 are shown in Tables 5-8, respectively.
  • N- (4-chlorophenol) -5-phenyl-2-pyrazine-1-ylpyrimidine-4-amine and (2R) -l- (t-butoxycarbol) piperidine- 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole were added to a THF solution of 2-carboxylic acid and reacted at room temperature for 17 hours to give tert-butyl (2R)- 2-[(4- ⁇ 4-[(4-chlorophenyl) amino] -5-phenylpyrimidine-2-yl ⁇ piperazine-1-yl) carbol] piperidine-1-carboxylate Obtained. ES: 577.
  • Example compounds shown in Tables 9 to 10 below were produced in the same manner as in Example 17 using the corresponding starting materials.
  • Example 2 Using the same method as in Example 1 except that 250 mg of 2-chloro-N-cycloheptyl-5-phenylpyrimidine-4-amine was used (however, the reaction was carried out at 120 ° C. for 2 days using DEE as a solvent). ) Then, add 178 mg of (1 '-[4- (cycloheptylamino) -5-phenylpyrimidine-2-yl] -1,4, -bipiperidin-3-yl) methanol dihydrochloride to pale yellow Obtained as crystals.
  • the medium was distilled off.
  • the obtained residue was purified by silica gel column chromatography (form-form-methanol-28% aqueous ammonia) to give (1,- ⁇ 4-[(4-form-methyl) amino] -6-isopropyl -5-Phenylpyrimidine-2-yl ⁇ -1,4'-bipiperidin-3-yl) methanol (125 mg) was obtained.
  • This compound was dissolved in 5 ml of methanol, and 0.2 ml of a 4 M hydrogen chloride-dioxane solution was heated to form a hydrochloride, and then the solvent was distilled off.
  • Tables 13 to 15 show the structures of other compounds of the present invention. These are based on the above-mentioned manufacturing methods and examples.
  • the compounds can be easily synthesized by using the methods described and those obvious to those skilled in the art, or variations thereof.
  • the substituted pyrimidine derivative of the present invention has a function of modulating the function of CCR4 or TARC and / or MDC, and therefore has various inflammatory diseases, allergic diseases, autoimmune diseases and the like (eg, asthma, allergic rhinitis).
  • Allergic conjunctivitis hay fever, dermatitis (atopic dermatitis, contact dermatitis), psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis Disease, insulin-dependent diabetes mellitus (IDDM), organ transplant rejection, cancer, inflammatory bowel disease (ulcerative colitis, Crohn's disease), interstitial cystitis, sepsis, pain) It is for. In particular, it is useful as a prophylactic / therapeutic agent for asthma, atopic dermatitis or rheumatoid arthritis.

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Abstract

Nouveau dérivé de la pyrimidine caractérisé par le fait qu’il comporte un groupe hétérocyclique à 6 chaînons saturé (par exemple un groupe pipéridino saturé) en position 2, un groupe amino substitué en position 4 et un groupe cyclique en l’une des positions 5 et 6, ou son sel. Du fait qu’il a un effet de contrôle sur la fonction du récepteur 4 de la chémokine CC (CCR4) et qu’il présente un effet anti-inflammatoire excellent, le composé précédent est utile en tant qu’agent préventif ou que remède pour les maladies inflammatoires, les maladies allergiques, les maladies auto-immunes et ainsi de suite dans lesquelles, en particulier, CCR4 ou TARC et/ou MDC prennent part.
PCT/JP2005/003535 2004-03-04 2005-03-02 Derivé de la pyrimidine substitué WO2005085212A1 (fr)

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Cited By (12)

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WO2007111227A1 (fr) 2006-03-24 2007-10-04 Astellas Pharma Inc. Compose d'acylaminopiperidine
WO2008146914A1 (fr) * 2007-06-01 2008-12-04 Mitsubishi Tanabe Pharma Corporation Composition hétérocyclique
JP2008546698A (ja) * 2005-06-14 2008-12-25 タイゲン バイオテクノロジー カンパニー，リミテッド ピリミジン化合物
WO2009037454A2 (fr) 2007-09-18 2009-03-26 Cancer Research Technology Ltd Marqueur du cancer et cible thérapeutique
EP2092824A1 (fr) 2008-02-25 2009-08-26 Bayer CropScience AG Hétérocyclyl-pyrimidines
EP2120573A1 (fr) * 2007-02-12 2009-11-25 Merck & Co., Inc. Dérivés de la pipéridine
JP2012500278A (ja) * 2008-08-20 2012-01-05 シェーリング コーポレイション 置換ピリジン誘導体および置換ピリミジン誘導体ならびにそれらのウイルス感染の治療における使用
US8193206B2 (en) 2005-06-14 2012-06-05 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
US8501739B2 (en) 2005-07-04 2013-08-06 High Point Pharmaceuticals, Llc Medicaments
EP2805947A4 (fr) * 2012-01-16 2015-05-27 Inst Pharm & Toxicology Amms Dérivés pipérazinyl pyrimidines, procédé de préparation et utilisation associées
WO2021063852A1 (fr) * 2019-09-30 2021-04-08 F. Hoffmann-La Roche Ag Pyrimidine substituée pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
WO2022007869A1 (fr) * 2020-07-10 2022-01-13 浙江海正药业股份有限公司 Dérivé de pyridine ou de pyrimidine, son procédé de préparation et son utilisation

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PT2479165T (pt) * 2009-09-16 2017-12-19 Astellas Pharma Inc Composto de glicina
WO2021143823A1 (fr) * 2020-01-16 2021-07-22 浙江海正药业股份有限公司 Dérivé de pyridine ou de pyrimidine, son procédé de préparation et son utilisation

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JPS5049288A (en) * 1973-08-20 1975-05-01 Thomae Gmbh Dr K Shinkina pirimijinkagobutsuno seizohoho
JP2003500477A (ja) * 1999-05-31 2003-01-07 エフ．ホフマン−ラ ロシュ アーゲー ５−フェニル−ピリミジン誘導体
WO2004074260A1 (fr) * 2003-02-21 2004-09-02 Kyowa Hakko Kogyo Co., Ltd. Dérivés de pyrimidine

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JPS5049288A (en) * 1973-08-20 1975-05-01 Thomae Gmbh Dr K Shinkina pirimijinkagobutsuno seizohoho
JP2003500477A (ja) * 1999-05-31 2003-01-07 エフ．ホフマン−ラ ロシュ アーゲー ５−フェニル−ピリミジン誘導体
WO2004074260A1 (fr) * 2003-02-21 2004-09-02 Kyowa Hakko Kogyo Co., Ltd. Dérivés de pyrimidine

Cited By (21)

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Publication number Priority date Publication date Assignee Title
EP1890703A4 (fr) * 2005-06-14 2010-11-03 Taigen Biotechnology Co Ltd Composes pyrimidine
US8193206B2 (en) 2005-06-14 2012-06-05 Taigen Biotechnology Co., Ltd. Pyrimidine compounds
JP2008546698A (ja) * 2005-06-14 2008-12-25 タイゲン バイオテクノロジー カンパニー，リミテッド ピリミジン化合物
AU2006259525B2 (en) * 2005-06-14 2012-05-24 Gpcr Therapeutics, Inc Pyrimidine compounds
US8846677B2 (en) 2005-07-04 2014-09-30 High Point Pharmaceuticals, Llc Medicaments
US8501739B2 (en) 2005-07-04 2013-08-06 High Point Pharmaceuticals, Llc Medicaments
WO2007111227A1 (fr) 2006-03-24 2007-10-04 Astellas Pharma Inc. Compose d'acylaminopiperidine
US7790884B2 (en) 2006-03-24 2010-09-07 Astellas Pharma Inc. Acylaminopiperidine compound
EP2120573A4 (fr) * 2007-02-12 2011-05-25 Merck Sharp & Dohme Dérivés de la pipéridine
EP2120573A1 (fr) * 2007-02-12 2009-11-25 Merck & Co., Inc. Dérivés de la pipéridine
WO2008146914A1 (fr) * 2007-06-01 2008-12-04 Mitsubishi Tanabe Pharma Corporation Composition hétérocyclique
WO2009037454A2 (fr) 2007-09-18 2009-03-26 Cancer Research Technology Ltd Marqueur du cancer et cible thérapeutique
EP2533047A1 (fr) 2007-09-18 2012-12-12 Cancer Research Technology Ltd CCR4 en tant que cible thérapeutique pour le cancer.
EP2535716A2 (fr) 2007-09-18 2012-12-19 Cancer Research Technology Limited Marqueur de cancer et cible thérapeutique
EP2092824A1 (fr) 2008-02-25 2009-08-26 Bayer CropScience AG Hétérocyclyl-pyrimidines
JP2012500278A (ja) * 2008-08-20 2012-01-05 シェーリング コーポレイション 置換ピリジン誘導体および置換ピリミジン誘導体ならびにそれらのウイルス感染の治療における使用
EP2805947A4 (fr) * 2012-01-16 2015-05-27 Inst Pharm & Toxicology Amms Dérivés pipérazinyl pyrimidines, procédé de préparation et utilisation associées
US9493453B2 (en) 2012-01-16 2016-11-15 The Institute of Pharmacology and Toxicology Academy of Military Medical Science P.L.A. China Piperazinyl pyrimidine derivatives, preparation method and use thereof
WO2021063852A1 (fr) * 2019-09-30 2021-04-08 F. Hoffmann-La Roche Ag Pyrimidine substituée pour le traitement et la prophylaxie d'une infection par le virus de l'hépatite b
WO2022007869A1 (fr) * 2020-07-10 2022-01-13 浙江海正药业股份有限公司 Dérivé de pyridine ou de pyrimidine, son procédé de préparation et son utilisation
CN115916765A (zh) * 2020-07-10 2023-04-04 浙江海正药业股份有限公司 吡啶或嘧啶类衍生物及其制备方法和用途

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