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WO1998014430A1 - Derives de pyrimidine - Google Patents

Derives de pyrimidine Download PDF

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Publication number
WO1998014430A1
WO1998014430A1 PCT/JP1997/003476 JP9703476W WO9814430A1 WO 1998014430 A1 WO1998014430 A1 WO 1998014430A1 JP 9703476 W JP9703476 W JP 9703476W WO 9814430 A1 WO9814430 A1 WO 9814430A1
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WIPO (PCT)
Prior art keywords
group
optionally substituted
lower alkyl
acceptable salt
alkyl group
Prior art date
Application number
PCT/JP1997/003476
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English (en)
Japanese (ja)
Inventor
Jun-Etsu Igarashi
Hiroyuki Katsumi
Tamiki Nishimura
Original Assignee
Sumitomo Pharmaceuticals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP28178896A external-priority patent/JPH10109937A/ja
Priority claimed from JP8453797A external-priority patent/JPH10259181A/ja
Application filed by Sumitomo Pharmaceuticals Co., Ltd. filed Critical Sumitomo Pharmaceuticals Co., Ltd.
Publication of WO1998014430A1 publication Critical patent/WO1998014430A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—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

Definitions

  • the present invention relates to novel pyrimidine derivatives and psychotropic drugs containing them as active ingredients.
  • Psychotropic drugs such as phenothiazines (chlorpromazine, etc.), petit mouth phenones (haloperidol, etc.), benzamides (sulpiride), etc. are used for schizophrenia, manic depression, Parkinson's disease, and psychiatric symptoms due to substance abuse. It has been used as a useful therapeutic agent for psychiatric symptoms associated with senile dementia or Alheimer's disease, but is known to have side effects such as extrapyramidal disorders. In addition, psychotropic drugs such as chlorpromazine, haloperidol, and tiapride also have side effects such as a decrease in the level of consciousness and orthostatic hypotension in addition to the ⁇ 1 receptor-blocking action.
  • Clozapine is a psychotropic drug with preferential affinity for the D4 receptor, has no side effects such as extrapyramidal disorders, and is resistant to treatment for typical psychotropic drugs. It is also effective for severe schizophrenia, etc., but is known to have a serious side effect of granulocytopenia.
  • Japanese Patent Application Laid-Open No. Hei 6-504054 describes that an aminomethylphenylimidazole derivative is a useful compound having a psychotropic effect as a specific ligand of a new type of dopamine receptor subtype, and WO95 / 18118 describes a bicyclic compound. It is described that a sex aromatic amine derivative is a useful medicine for central nervous system and cardiovascular diseases. WO 96/31488 describes pyrimidine derivatives which are effective as psychotropic drugs. Disclosure of the invention
  • the present inventors have found a novel pyrimidine derivative having a strong affinity for the D4 receptor and completed the present invention.
  • the present invention is as follows.
  • W represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group.
  • X represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.
  • Y represents an oxygen atom or a sulfur atom.
  • A, G and Z have the following meanings in the group (1) or (2).
  • A represents an optionally substituted amino group or an optionally substituted lower alkyl group.
  • G represents a nitrogen atom.
  • a 2 represents a hydrogen atom or a lower alkyl group which may be substituted.
  • W 1 may represent a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, a aryl group which may be substituted or substituted.
  • m and n are the same or different and each represents 0, 1 or 2.
  • RR 2 , R 3 and R 4 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkynyl group which may be substituted, Represents a cycloalkyl group which may be substituted, a aryl group which may be substituted or a heterocyclic group which may be substituted.) Represents a ring represented by:
  • Z is the formula: — N (Q l ) Q 2
  • Q 1 and Q 2 are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group, or Q 1 and Q 2 Q 2 represents a 5- or 7-membered nitrogen-containing heterocyclic group which may be substituted together with the nitrogen atom bonded to each other.
  • a 1 represents an optionally substituted amino group or an optionally substituted lower alkyl group.
  • W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, 1 to 5 groups independently selected from the group consisting of an aryl group and an optionally substituted heterocyclic group are phenyl groups which may be substituted [2] or [ 3] The compound of the above or a pharmacologically acceptable salt thereof.
  • W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, A phenyl group optionally substituted at the 4-position, wherein the group independently selected from the group consisting of an aryl group and an optionally substituted heterocyclic group is [2] or [3].
  • W is an optionally substituted lower alkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group or an optionally substituted naphthyl group [ [9] The compound according to [10] or a pharmacologically acceptable salt thereof.
  • a medicament comprising, as an active ingredient, the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof.
  • a psychotropic drug comprising, as an active ingredient, the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof.
  • the lower alkyl group includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms.
  • alkyl groups such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 1-ethylbutyl, hexyl, Examples include 1-methylpentyl, 1-ethylbutyl, 2-methylpentyl and the like.
  • cycloalkyl group examples include a cycloalkyl group having 5 to 7 carbon atoms, and specific examples include cyclopentyl, cyclohexyl, and cycloheptyl.
  • alkenyl for example, an alkenyl group having 1 to 3 linear or branched double bonds having 2 to 6 carbon atoms can be mentioned, and specific examples thereof include vinyl, 1-propyl, and 2-propyl. Nyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl and the like.
  • Examples of the lower alkynyl include an alkynyl group having 1 to 3 straight-chain or branched triple bonds having 2 to 6 carbon atoms, and specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. , 1-pentynyl, 1-hexynyl and the like.
  • aryl group examples include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthranyl, 2-anthranyl, and the like.
  • heterocyclic group examples include a 5- to 7-membered monocyclic, 9 to 10-membered cyclic, including 1 to 4 heteroatoms arbitrarily selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Or a 12- to 14-membered tricyclic, saturated or unsaturated heterocyclic group.
  • the nitrogen atom and the sulfur atom may be oxidized as the case may be.
  • the point of attachment of the heterocyclic group is on any nitrogen or carbon atom.
  • a 6-membered monocyclic saturated heterocyclic group containing one or two heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms such as piperidyl, piperazinyl, and morpholinyl, pyridyl, and pyridazinyl 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 heteroatoms arbitrarily selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom such as 5-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms, such as phenol and pyrrolidinyl, imidazolyl, furyl, 2-oxo-1 5-membered monocyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen and sulfur atoms such as, 3-dioxorenyl and pyrrolyl, quinolyl
  • Examples of the 5- to 7-membered nitrogen-containing heterocyclic group include at least one nitrogen atom, and one or two hetero atoms arbitrarily selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom.
  • a 5- to 7-membered monocyclic saturated or unsaturated heterocyclic group which may further be included, and a 5- to 7-membered monocyclic saturated heterocyclic group is preferable.
  • Specific examples include a 6-membered monocyclic saturated heterocyclic group such as piperidyl, piperazinyl and morpholinyl, and a 5-membered monocyclic saturated heterocyclic group such as pyrrolidinyl.
  • Examples of the substituted lower alkyl group include a cycloalkyl group which may be substituted, a aryl group which may be substituted, a heterocyclic group which may be substituted, a halogen atom, an oxo group, --OP 1 (P 1 is a hydrogen atom, Represents a lower alkyl, cycloalkyl, aryl or hydroxyl modifying group), —OCOP 2 (P 2 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group) ), — — ( ⁇ 3) ⁇ 4 ( ⁇ 3 represents a hydrogen atom or a lower alkyl group, and P 4 is a modification of a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group or an amino group.
  • NHP 6 (where P 5 and P 6 are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or a guanidino group modifying group).
  • NHP 6 (P 5 Contact Fine P 6 are as defined above.)
  • One COOP 7 (P 7 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, Represents a modifying group for an aryl group, a heterocyclic group or a carboxyl group.
  • P 8 represents a hydrogen atom or a lower alkyl group
  • P 9 represents a hydrogen atom, a lower alkyl group or an amide group modifying group.
  • One SP 1Q represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a modifying group of a thiol group.
  • —COP 11 is a hydrogen atom, a lower alkyl group, a cycloalkyl group,
  • — NHCOP 12 represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aryl group.
  • — S (O) s P 13 P 13 represents a lower alkyl group, a cycloalkyl group or a Ariru group, s is 1 or represents 2;.), - S0 2 N (P 14) P 15 (P
  • substituted lower alkyl groups include benzyl, 2-phenyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-indolylmethyl , 2- (3-Indolyl) ethyl, bromomethyl, Bivaloyloxymethyl, 1-Ethoxycarbonyloxethyl, 5-Methyl_2-Oxo-1,3-Dioxolen-1-ylmethyl, 2-Chloroethyl , 2-dimethylaminoethyl, getylaminoethyl, 3-dimethylamino 2- (dimethylaminomethyl) propyl, 2- (1-morpholinyl) ethyl, 1-acetoxetil, 1-methoxycarbonyloxetyl, acetoxmethyl , 1-acetoxy-1-phenylmethyl, methoxycarbonylmethyl, 1-pivaloyloxityl, etc
  • the substituted lower alkenyl group, a cycloalkyl group, Ariru group, a heterocyclic group, a halogen atom, - OP 17 (P 17 is a hydrogen atom, a lower alkyl group or hydroxyl group of the modifying group.), - OCOP 18 (P 18 Represents a hydrogen atom or a lower alkyl group.), Nitro group, cyano group, COOP 19 (P 19 is a hydrogen atom or a carboxyl group) Represents a decoration group.
  • P 21 represents a lower alkyl group, for example, a lower alkenyl group substituted with 1 to 5 substituents arbitrarily selected from the group Specific examples include 3-phenyl-12-propenyl, 5-methoxy-2-pentenyl, 2-carboxyvinyl and the like.
  • Examples of the substituted lower alkynyl group include a cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom, one OP 17 (P 17 has the same meaning as described above.), — OCOP 18 (P 18 has the same meaning as described above.) ), Nitro group, cyano group, —COO P 19 (P 19 is as defined above), —CON (P 8 ) P 9 (P 8 and P 9 are as defined above), one COP 20 (P 20 has the same meaning as described above.) And —OCOOP 21 (P 21 has the same meaning as described above.) And a lower alkynyl group substituted with 1 to 5 substituents arbitrarily selected from the group And specifically, 3-phenyl-2-propynyl and the like.
  • the substituted cycloalkyl group, a lower alkyl group, Ariru group, a heterocyclic group, c androgenic atom, One ⁇ _P 17, (P 17 is as defined above.) - OCO P 18 (P 18 before Symbol synonymous ), — N (P 22 ) P 23 (P 22 represents a hydrogen atom or a lower alkyl group, and P 23 represents a hydrogen atom, a lower alkyl group or a modifying group of an amino group.), One C ( NP 24) NHP 25 (wherein, P 24 and P 25 are the same or to different dates, represents a modifying group of a hydrogen atom or Guanijino group), -.
  • NHC N HP 25 (P 24 and P 25 is as defined above.), a nitro group, Shiano group, one CO OP 19 (P 19 is as defined above.), one CON (P 8) P 9 ( P 8 and P 9 are a front stories ),
  • One SP 26 P 26 represents a hydrogen atom, a lower alkyl group or a thiol modifying group.
  • —CO P 20 P 20 has the same meaning as described above.
  • —NHCO P 27 P 27 represents a hydrogen atom or a lower alkyl group.
  • S (0) s P 28 P 28 represents a lower alkyl group, and s has the same meaning as described above.
  • SO 2 N P 29
  • P 3Q P 29 and P 3Q are the same or different and are each a hydrogen atom or a lower alkyl group.
  • —OCOOP 21 (P 21 has the same meaning as described above.), And a cycloalkyl group substituted with 1 to 3 substituents arbitrarily selected from the group of).
  • Specific examples include 4-chlorochlorohexyl, 4-cyanocyclohexyl, 2-dimethylaminocyclohexyl, 4-methoxycyclohexyl and the like.
  • one NHCOP 27 (P 27 is as defined above.), one S (0) s P 28 ( s and P 28 are as defined above. :) one SO 2 NP 29 P 30 (P 29 and P 30 are as defined above.)
  • —O A heterocyclic group substituted with 1 to 3 substituents arbitrarily selected from the group of COOP 21 (P 21 has the same meaning as described above.) Specifically, 1-acetyl-4- Piperidinyl, 1-benzyl-4-imidazolyl, 1-methyl-3-indolinyl, 5_methyl-12_oxo-1,1,3-dioxolen-14-yl, 5-oxo-12-tetrahydrofuranyl, 1, 3-dihydro-3-oxo-11-isobenzofuranyl and the like.
  • Examples of the substituent in the substituted 5- to 7-membered nitrogen-containing heterocyclic group include the same substituents as those in the substituted heterocyclic group.
  • Examples of the substituted aryl group include an aryl group substituted with 1 to 5 substituents arbitrarily selected from the group consisting of the following (a), (b) and (c).
  • substituted phenyl group examples include a phenyl group substituted with 1 to 5 substituents arbitrarily selected from the group consisting of the above (a), (b) and (c).
  • substituted aryl group examples include 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-hydrophenyl, and 2,4-dichlorophenyl.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • Examples of the amino group which may be substituted include those represented by the following formula: N (Q 3 ) Q 4 (wherein Q 3 and Q 4 are the same or different and each are a hydrogen atom, a lower alkyl group which may be substituted, A cycloalkyl group or an optionally substituted heterocyclic group, or Q 3 and Q 4 are bonded to each other together with the nitrogen atom to which they are bonded, and And a 5- or 7-membered nitrogen-containing heterocyclic group, which may be substituted.
  • N (Q 3 ) Q 4 wherein Q 3 and Q 4 are the same or different and each are a hydrogen atom, a lower alkyl group which may be substituted, A cycloalkyl group or an optionally substituted heterocyclic group, or Q 3 and Q 4 are bonded to each other together with the nitrogen atom to which they are bonded, and And a 5- or 7-membered nitrogen-containing heterocyclic group, which may be substituted.
  • methylamino group N, N-dimethylamino group, N-ethyl-N-methylamino group, N-cyclohexyl-N-methylamino group, N, N-dicyclohexylamino group, N— (4 —Methylcyclohexyl) — N-ethylamino group, piperidyl group, pyridyl group, N-methylbiperazyl group, pyridazyl group, piperazyl group, pyrrolidyl group, morphonyl group, imidazolidinyl group, pyridazolidinyl group and the like.
  • Examples of the modifying group for the hydroxyl group, the modifying group for the amino group, the modifying group for the guanidino group, the modifying group for the carboxyl group, the modifying group for the amide group, and the modifying group for the thiol group include protecting groups that are usually used in the reaction. For example, Izumiya et al., Amino acids described in “Basic and Experimental Peptide Synthesis” (Maruzen, 1985) or “Protective Groups in Organic Synthesis” by Green et al. (Jillon Willett & Sons, 1991) Side chain protecting groups and the like can be used.
  • Examples of the hydroxyl-modified group include an ether-type modified group and an acyl-type modified group.
  • the ether-type modifying group include benzyl, 2-nitrobenzyl, 2,6-dichlorobenzyl, t-butyl, and the like
  • examples of the acyl-type modifying group include a lower alkanol group.
  • Examples of the lower alkanoyl group include a straight-chain or branched-chain alkanoyl group having 5 or less carbon atoms, and specific examples include acetyl, propanoyl, and butanoyl.
  • Examples of the modifying group for the amino group include a urethane-type modifying group and an acyl-type modifying group.
  • Examples of the urethane-type modifying group include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl. , 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, t-butyloxycarbonyl, fluorenyloxycarbonyl and the like.
  • Examples of the acyl-type modifying group include formyl and acetyl Benzoyl, trifluoroacetyl, methanesulfonyl and the like.
  • modifying group for the guanidino group examples include urethane-type modifying groups such as benzyloxycarbonyl and t-butyloxycarbonyl, 4-toluenesulfonyl, 4-methoxybenzenesulfonyl, and nitro group.
  • carboxyl group-modifying group examples include ester-type modifying groups, such as lower alkyl, 2,2,2-trichloroethyl, benzyl, 4-methoxybenzyl, diphenylethyl and the like.
  • Examples of the modifying group for the amide group include 2,4-dimethoxybenzyl.
  • Examples of the thiol group-modifying group include a sulfide-type modifying group. Examples thereof include jyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, and acetamidomethyl.
  • X is preferably a halogen atom, more preferably a chlorine atom, a bromine atom, or an iodine atom, and particularly preferably a chlorine atom or a bromine atom.
  • X is preferably an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.
  • W is preferably an optionally substituted lower alkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group or an optionally substituted naphthyl group. More preferably, a lower alkyl group such as a methyl group, an ethyl group, and a propyl group, cyclohexyl, benzyl, acetoxmethyl, 1-acetoxityl, 1-acetox-1-phenylmethyl, pivaloyloxymethyl, and 1-bivaloyl Kishechiru etc. - OCOP 2 (.
  • P 2 are as defined above) substituted lower alkyl group, 1 - main butoxycarbonyl O key Chez chill, 1 one ethoxycarbonyl O key share one OCOOP 1 chill like 6 (where P 16 is as defined above), a lower alkyl group substituted with, 5-methyl-2-oxo_1,3-dioxolen-4- Lower alkyl group substituted by a substituted complex such as ylmethyl, 2- (1-morpholinyl) ethyl, 5-oxo-12-tetrahydrofuranyl, 1,3-dihydro-3-oxo-1-isobenzofuranyl Heterocyclic group such as group, substituted aryl group such as 5-indanyl group, 3 -dimethylamino-2- (dimethylaminomethyl) propyl, 2-dimethylaminoethyl, 2-getylaminoethyl, methoxycarbonylmethyl, 2-dimethyl Examples include aminocyclohexyl and
  • a 1 preferably includes an amino group which may be substituted, and specific examples thereof include a methylamino group, a dimethylamino group, and an N-methylbiperazinone group.
  • a 2 is preferably a hydrogen atom and a lower alkyl group such as a methyl group, an ethyl group, and a propyl group.
  • W 1 is preferably an optionally substituted aryl group or an optionally substituted heterocyclic group, and particularly preferably an optionally substituted phenyl group.
  • Q 1 and Q 2 in Formula 3 each include a secondary or tertiary amino group.
  • preferred examples of N (Q 1 ) Q 2 include an optionally substituted pyrazinyl group , Formula:
  • any of the isomers or a mixture thereof may be used, and when two or more asymmetric carbons are present, the compound may be used as an enantiomer. It may exist as a diastereomer or as a mixture thereof, for example, as a racemate.
  • pharmacologically acceptable salts include pharmacologically acceptable addition salts with inorganic acids and organic acids, and addition salts with inorganic bases and organic bases. Examples of the addition salt with an inorganic acid include hydrochloride, hydrobromide, hydroiodide, sulfate and the like.
  • addition salts with organic acids include acetate, oxalate, citrate, malate, tartrate, maleate, fumarate, methanesulfonate, 4-toluenesulfonate, etc. Is mentioned.
  • examples of the addition salt with an inorganic base include a sodium salt, a potassium salt, a calcium salt and the like.
  • examples of the addition salt with an organic base include amine salts such as arginine salt, lysine salt, and triethylamine salt.
  • the compound represented by the formula 1 and the pharmacologically acceptable salts thereof also include solvates such as hydrates thereof.
  • the compound represented by the formula 2 can be produced, for example, by the following production method.
  • AAW, W 1 m and n are as defined above.
  • X 1 represents a halogen atom.
  • R 5 represents a lower alkyl group.
  • This production method 1 can be carried out in the same manner as the method described in J. Med. Chem., 25, 1459 (1982). Specifically, it can be carried out as follows.
  • Compound (6) can be obtained by reacting malonic ester (4) with amidine or guanidine (5) in the presence of a base in a reaction inert solvent at room temperature to 80 ° C. it can.
  • a base for example, a metal base such as sodium ethoxide can be used.
  • a solvent inert to the reaction for example, an organic solvent such as ethanol can be used.
  • compound (7) By reacting compound (6) with a brominating agent such as bromine at room temperature or the like, compound (7) is converted to Obtainable.
  • a reaction solvent for example, glacial acetic acid or the like can be used.
  • the compound (9) can be obtained by reacting the compound (7) with the compound (8) in a solvent inert to the reaction at room temperature to 150 ° C in the presence of a base.
  • a metal base such as sodium hydride can be used as the base used in this reaction, and N, N-dimethylformamide (DMF) or the like can be used as a solvent inert to the reaction.
  • the compound (10) can be obtained by reacting the compound (9) with a halogenating agent at 0 to 120 ° C.
  • a halogenating agent include thionyl chloride such as thionyl chloride and thionyl bromide, phosphorus halide such as phosphorus oxychloride and phosphorus oxybromide, and hydrogen halide such as hydrogen chloride and hydrogen bromide.
  • the solvent used in the reaction include solvents that do not affect the reaction, and for example, solvents such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, DMF, and methyl ether can be used.
  • the reaction can also be carried out without a solvent. If necessary, the reaction can be carried out in the presence of an amine such as pyridine, quinoline, dimethylaniline, triethylamine or diisopropylamine. Further, a halogen exchange reaction can be performed.
  • an amine such as pyridine, quinoline, dimethylaniline, triethylamine or diisopropylamine. Further, a halogen exchange reaction can be performed.
  • the compound of the present invention represented by (12) can be obtained by reacting the compound (10) with the amine (11) in the presence of a base, for example, at 0 to 85 ° C.
  • a base for example, an inorganic base such as potassium carbonate can be used, and as a solvent, for example, dimethoxetane, a mixed solvent of dimethoxetane and water, ethanol and the like can be used.
  • the compound (9) can be obtained by halogenating the malonic ester (4), reacting the compound (8), and then reacting it with amidine or guanidine (5).
  • Manufacturing method 2
  • a 2 , X 1 , W, W 1 , m and n are as defined above.
  • a 3 represents an amino group which may be substituted, and R 6 represents a lower alkyl group.
  • This Production Method 2 can be carried out in the same manner as the method described in J. Med. Chem., ⁇ 8, 553 (1975). Specifically, it can be carried out as follows.
  • Compound (14) can be obtained by oxidizing compound (13) at 0 ° C. to room temperature.
  • the oxidizing agent used in the reaction include hydrogen peroxide, sodium periodate and the like.
  • the compound (16) can be obtained by reacting the compound (14) with the barbituric acid (15) at 60 to 120 ° C.
  • the solvent used in the reaction include acetic acid and the like, and it is also preferable to add acetic anhydride as a dehydrating agent.
  • Compound (17) is obtained by reacting compound (16) with a halogenating agent be able to. This reaction can be carried out under the same conditions as for the production of compound (10) in Production method 1.
  • the compound (19) can be obtained by reacting the compound (17) and the amine (18) regiospecifically by limiting the molar ratio or suppressing the reaction temperature. Subsequently, in the same manner as in the production of compound (12) from compound (10) in production method 1, compound (20) can be obtained from compound (19). Manufacturing method 3
  • W, W 1 , AA 2 , X 1 , R 5 , Y, m and n are as defined above.
  • X 2 represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.
  • X 3 represents a chlorine atom, a bromine atom, methanesulfonyloxy or 4-toluenesulfonyloxy.
  • Compound (21) is inactivated with benzene, xylene, dichloromethane, chloroform, carbon tetrachloride, methyl ether, tetrahydrofuran (THF), dioxane, etc.
  • Compound (22) is obtained by adding 1-2 equivalents of sodium hydride and 1-1.2 equivalents of compound (8) in a neutral solvent and reacting at room temperature to 90 ° C for 5 minutes to 2 hours. Can be obtained.
  • compound (22) is dissolved in an alcohol such as methanol or ethanol, or in an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, THF, dioxane, or the like.
  • Compound (23) can be obtained by adding an equivalent amount of amidine or guanidine (5) and reacting at room temperature to 60 ° C for 1 to 2 hours.
  • compound (25) can be obtained from compound (23) in the same manner as in the production of compound (12) from compound (9) in production method 1. Manufacturing method 4
  • the compound of the present invention represented by the formula 3 can be carried out in the same manner as in the method described in W096 / 31488 and J. Med. Chem., 25, 1459 (1982). Specifically, for example, it can be implemented as follows.
  • the compound (27) can be obtained by reacting the aniline derivative (26) with a malonic ester in the presence of a base in a solvent inert to the reaction at room temperature to 80 ° C, and then closing the ring by heating.
  • a base used in this reaction for example, a metal base such as sodium ethoxide can be used.
  • a solvent inert to the reaction for example, an organic solvent such as ethanol can be used.
  • the reaction temperature at the time of ring closure includes, for example, a range of 50 to 120 ° C.
  • compound (29) can be obtained from compound (27) in the same manner as in the production of compound (12) from compound (6) in production method 1.
  • the halogen atom represented by X 1 is converted to a substituted, lower alkyl or optionally substituted cycloalkyl group.
  • these compounds are reacted with a metal magnet in a ether solvent such as THF or getyl ether to obtain a Grignard reagent, which is then reacted with a ketone, aldehyde, epoxide, or the like corresponding to the target compound. It can be carried out by combining a reduction reaction, an oxidation reaction and the like according to the conditions.
  • halogenated aryl compounds corresponding to the target compound and these compounds can be prepared in the presence of t-butyllithium and trisacetylacetylacetonate iron (J. Org. Chem., 48, 4728 (1983)), or In the presence of nickel tetrakistriphenylphosphine (J. Med. Chem., 26, 1653 (1983); J. Am. Chem. So, 103, 6460 (1981)), THF, DMF or dimethoxyethane It can be carried out by reacting in an inert solvent.
  • the compound of the present invention represented by the formula 1 can be purified by a usual purification method, for example, recrystallization, thin-layer chromatography, high-performance liquid chromatography and the like.
  • the pharmacologically acceptable salt of the compound of the present invention can be produced by a usual method. TJP97 / 03476
  • Administration of the medicament of the present invention can be carried out by a usual administration route, for example, oral, intramuscular, intravenous, subcutaneous, intraperitoneal, or intranasal administration.
  • the dose and frequency of administration vary depending on the animal species, administration route, symptom severity, sex difference, body weight, etc., and are not particularly limited. In humans, it is usually 1 mg to 100 mg per adult day, preferably 2 mg to 20 mg is administered once or more times a day.
  • Examples of the dosage form include powders, fine granules, tablets, capsules, suppositories, injections, nasal preparations and the like. At the time of formulation, it is manufactured by a usual method using an ordinary formulation carrier.
  • a binder, a disintegrant, a lubricant, a coloring agent, etc. are added as necessary, and then tablets, granules, powders, capsules, etc. are prepared in a conventional manner.
  • a PH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. as necessary, and use it as an injection in the usual manner.
  • the medicament of the present invention can be applied not only to humans but also to various mammals such as mice, rats, dogs, cats, cats, pomas, goats, sheep, peas, pigs, etc. .
  • 5- (4-chlorophenethylthio) 1,4,6-dichloro-12-methylpyrimidine 500 mg, 4-amino-1-benzylpiperidine 470 mg, potassium carbonate 113 mg are dissolved in 10 ml of methylethyl ketone to which lOmg of water is added. And heated to reflux for 4 hours. Water was added to the reaction solution and extracted with toluene. The organic layer was acidified by adding dilute hydrochloric acid, and the aqueous layer was separated. Toluene and aqueous ammonia were added to the aqueous layer to make it basic, and the organic layer was separated.
  • N-methyldanidine hydrochloride 27.5 g was added to the mixture (prepared from 12 g and 300 ml of dehydrated ethanol), followed by stirring at room temperature for 1 hour. Next, a dehydrated ethanol solution (300 ml) of 43.5 g of getyl malonate was added dropwise, and the mixture was refluxed for 5 hours. After cooling to room temperature, the reaction solution was added to ice water, acetic acid was added, and the mixture was made acidic to precipitate crystals. The crystals were collected by filtration, washed with water, and dried to obtain crude crystals. By recrystallizing this from water, 19.5 g of 2-methylamino-1,4,6-dihydroxypyrimidine was obtained as white crystals.
  • the precipitated crystals were collected by filtration, washed with cold water and diethyl ether, and dried under reduced pressure to obtain 2.3 g of 4,6-dihydroxy-12-methylamino-15-phenylthiopyrimidine as white crystals. .
  • To 2.0 g of the mixture 3.3 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 1 hour.
  • the reaction solution was cooled, added to ice water, made basic with ammonia water, and then extracted with chloroform. After the organic layer was washed with a small amount of water, it was dried over anhydrous magnesium sulfate.
  • 4,6-Dichloro mouth_2-Methylamino-5-phenylthiopyrimidine 44 mg, 1-benzyl-4-methylaminopiperidine 47 mg, lium carbonate 1 lmg were added to 5 ml of methylethyl ketone to which a small amount of water was added. The mixture was refluxed for 9 hours. Water was added to the reaction solution, extracted with toluene, diluted hydrochloric acid was added to the organic layer, and the aqueous layer was separated. The aqueous layer was made basic by adding toluene and aqueous ammonia, and the organic layer was separated.
  • the activity of the compound was determined using a D4 receptor membrane preparation prepared from CH0-K1 cells transfected with human D4 receptor cDNA according to the method described in Nature, 350, 610-614 (1991).
  • the inhibitory rate of the radioligand [ 3 H] -spiperone to the binding reaction to the D 4 receptor membrane standard by a predetermined concentration of the test compound was determined.
  • the inhibition rate was determined in the same manner as described above using the human D2 receptor cDNA.
  • Table 1 shows the binding activity of the compounds as Ki values.
  • the novel pyrimidine derivative of the present invention is a psychotropic drug having a strong affinity for the D4 receptor and no affinity for the ⁇ 1 receptor, for example, schizophrenia, manic depression, Parkinson's disease, substance abuse It is useful as a remedy for psychiatric symptoms caused by senile dementia or psychiatric symptoms associated with Alzheimer's disease.

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Abstract

Cette invention se rapporte à de nouveaux dérivés de pyrimidine, représentés par la formule générale (I), où W représente aryle éventuellement substitué, etc.; X représente halogéno, etc.; Y représente soufre; et A, G et Z ont la signification définie dans les cas (1) ou (2) suivants: (1) A représente amino éventuellement substitué, etc.; G représente azote; et Z représente un groupe représenté par la formule générale (II) (où A2 représente hydrogène ou alkyle éventuellement substitué; W1 représente aryle éventuellement substitué, etc.; et m et n, qui sont identiques ou différents, représentent chacun 0, 1 ou 2); ou (2) A et G forment avec l'atome de carbone auquel ils sont liés un cycle benzène éventuellement substitué et Z représente un groupe représenté par la formule générale -N(Q?1)Q2) (où Q1 et Q2¿, qui sont identiques ou différents, représentent chacun hydrogène, alkyle inférieur éventuellement substitué, etc.). Ces composés constituent des médicaments psychotropes ayant une puissante affinité pour le récepteur D4 mais n'ayant aucune affinité pour le récepteur α1 et ils sont utiles comme remèdes notamment contre les symptômes psychiques de la schizophrénie, de la psychose maniacodépressive, de la maladie de Parkinson ou de la toxicomanie ou contre les symptômes psychiques accompagnant la démence sénile ou la maladie d'Alzheimer.
PCT/JP1997/003476 1996-10-02 1997-09-29 Derives de pyrimidine WO1998014430A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP28178896A JPH10109937A (ja) 1996-10-02 1996-10-02 向精神薬として有効なピリミジン誘導体
JP8/281788 1996-10-02
JP9/84537 1997-03-17
JP8453797A JPH10259181A (ja) 1997-03-17 1997-03-17 アミノキノリン誘導体

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WO1998014430A1 true WO1998014430A1 (fr) 1998-04-09

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6107313A (en) * 1998-10-02 2000-08-22 Combichem, Inc. Dopamine receptor antagonists
US7576215B2 (en) 2003-12-12 2009-08-18 Wyeth Quinolines and pharmaceutical compositions thereof
JP2009541421A (ja) * 2006-06-29 2009-11-26 エフ．ホフマン−ラ ロシュ アーゲー ピリミジン及びキナゾリン誘導体

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4992080A (fr) * 1972-09-08 1974-09-03
JPS63280066A (ja) * 1987-04-24 1988-11-17 エギシュ　ヂョヂセルヂャール ３―アミノ―４―エチルチオキノリンまたは製薬的に使用しうるその酸付加塩を含む抗不安薬
JPH02255662A (ja) * 1989-02-22 1990-10-16 Hoechst Ag 置換ピリミジン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4992080A (fr) * 1972-09-08 1974-09-03
JPS63280066A (ja) * 1987-04-24 1988-11-17 エギシュ　ヂョヂセルヂャール ３―アミノ―４―エチルチオキノリンまたは製薬的に使用しうるその酸付加塩を含む抗不安薬
JPH02255662A (ja) * 1989-02-22 1990-10-16 Hoechst Ag 置換ピリミジン誘導体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6107313A (en) * 1998-10-02 2000-08-22 Combichem, Inc. Dopamine receptor antagonists
US7576215B2 (en) 2003-12-12 2009-08-18 Wyeth Quinolines and pharmaceutical compositions thereof
JP2009541421A (ja) * 2006-06-29 2009-11-26 エフ．ホフマン−ラ ロシュ アーゲー ピリミジン及びキナゾリン誘導体

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