WO2005085253A1 - Pyrrolopyrimidine derivatives - Google Patents

Pyrrolopyrimidine derivatives Download PDF

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Publication number
WO2005085253A1
WO2005085253A1 PCT/JP2005/004266 JP2005004266W WO2005085253A1 WO 2005085253 A1 WO2005085253 A1 WO 2005085253A1 JP 2005004266 W JP2005004266 W JP 2005004266W WO 2005085253 A1 WO2005085253 A1 WO 2005085253A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
ethyl
aryl
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PCT/JP2005/004266
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French (fr)
Inventor
Francois P. Bischoff
Ludo E. J. Kennis
Mirielle Braeken
Gaston S. M. Diels
Atsuro Nakazato
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Taisho Pharmaceutical Co., Ltd.
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Priority to JP2006527200A priority Critical patent/JP2007526906A/en
Priority to US10/591,765 priority patent/US20070270588A1/en
Priority to RU2006135120/04A priority patent/RU2006135120A/en
Priority to CA002556946A priority patent/CA2556946A1/en
Priority to EP05720537A priority patent/EP1725562A1/en
Publication of WO2005085253A1 publication Critical patent/WO2005085253A1/en

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Definitions

  • the present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • CCF corticotropin releasing factor
  • CRF CRF plays a core role in biological reactions against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995).
  • CRF there are the following two paths: a path by which CRF acts on peripheral immune system or sympathetic nervous system through hypothalamus-pituitary- adrenal system, and a path by which CRF functions as a neurotransmitter in central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990).
  • Intraventricular administration of CRF to hypophysectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, there are suggested the participation of CRF in hypothalamus- pituitary-adrenal system and the pathway by which CRF functions as a neurotransmitter in central nervous system.
  • CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immunity-related diseases, etc. It has recently been reported that CRF is involved also in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and cephalic external -wound (Brain Res. 545, 339-342,
  • An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesmal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesmal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
  • R 1 is C ⁇ - 9 alkyl, C 2 - 9 alkenyl, C 3 . 7 cycloalkyl, C 3 - 7 cycloalkyl-Ci- 9 alkyl, di(C 3 - 7 cycloalkyl)-C ⁇ - 9 alkyl, C ⁇ - 6 alkoxy-C ⁇ - 9 alkyl, di(C ⁇ - 6 alkoxy)-C ⁇ - 9 alkyl, hydroxy- -galkyl, cyano-C ⁇ - 9 alkyl, carbamoyl-C ⁇ - 9 alkyl, di(C ⁇ - 6 alkyl)amino-C ⁇ -
  • alkyl, aryl, heteroaryl, aryl-C ⁇ - alkyl or heteroaryl-Ci-galkyl, in wl ich said aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, C ⁇ - 6 alkylthio, C ⁇ alkylsulfonyl, aminosulfonyl, mono(C ⁇ - 6 alkyl)aminosulfonyl, di(C ⁇ -
  • R lb are each independently selected from the group consisting of hydrogen, Ci- 6 alkyl and C ⁇ - 6 alkylcarbonyl; R 2 is C ⁇ - 6 alkyl or C ⁇ - 6 haloalkyl; R 3 is hydrogen, C ⁇ _ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 al-kynyl, C 3 - 7 cycloalkyl, C 3 .
  • C ⁇ - 9 alkyl means a straight chain or branched chain alkyl group of 1 to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, .sec-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, isohexyl, 1- ethylpropyl, 1-ethylbutyl, 1,3-dimethylbutyl, 1-propylbutyT, 1-propylpentyl, 1- butylpentyl or the like.
  • C 2 The term "C 2 .
  • 9 alkenyl means a straight chain or branched chain alkenyl group of 2 to 9 carbon atoms, such as vinyl, isopropenyl, allyl or the like.
  • C 3 . 7 cycloalkyl means a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
  • C 3 - 7 cycloalkyl-C ⁇ - alkyl means a substituted C ⁇ - alkyl group having the above-mentioned C 3 - cycloalkyl as the substituent, such as cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1 -cyclopentyl ethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopropylpropyl, 1- cyclobutylpropyl, 1 -cyclopentylpropyl, 1-cyclopropylmetl ⁇ ylpropyl, 1- cyclopropylmethylbutyl or the like.
  • di(C 3 . cycloalkyl)-C ⁇ - 9 alkyl means a substituted C ⁇ - alkyl group having two above-mentioned C 3 - 7 cycloalkyl groups as the substituents, such as di(cyclopropyl)methyl, di(cyclobutyl)methyl, di(cyclopentyl)methyl or the like.
  • C ⁇ - 6 alkoxy means a straight chain or branched chain alkoxy group of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
  • C ⁇ - 6 alkoxy-C ⁇ - 9 alkyl means a substituted C ⁇ - 9 alkyl group having the above-mentioned d. 6 alkoxy group as the substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 -methoxymethyl-propyl, 1- methoxymethyl-butyl or the like.
  • di(C ⁇ - 6 alkoxy)-C ⁇ - 9 alkyl means a substituted Ci- alkyl group having two above-mentioned C ⁇ - 6 alkoxy groups as the substituents, such as 2,3- di(methoxy)propyl, 2-methoxy-l-methoxymethyl-ethyl, 2,4-(diethoxy)pentyl or the like.
  • hydroxy- -galkyl means a substituted C ⁇ - 9 alkyl group having a hydroxy group, such as hydroxymethyl, 1 -hydroxyethyl, 2 -hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- hydroxypentyl, 1-hydroxymethyl-propyl, 1-hydroxymethyl-butyl, 1- hydroxymethyl-3 -methyl-butyl or the like.
  • cyano-C ⁇ - 9 alkyl means a substituted C ⁇ _ 9 alkyl group having a cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 1- cyanobutyl, 5-cyanopentyl, 2-cyano-l -ethyl-ethyl, 1-cyanomethyl-butyl, 1-cyano- 3 -methyl-butyl, l-cyanomethyl-3 -methyl-butyl or the like.
  • carbamoyl-C ⁇ - alkyl means a substituted C ⁇ - 9 alkyl group having a carbamoyl group, such as carbamoylmethyl, 1-carbamoylethyl, 2- carbamoylethyl, 1-carbamoylpropyl, 1-carbamoylbutyl, 5-carbamoylpentyl, 1- carbamoyl-3 -methyl-butyl, 1-carbamoylmethyl-buty, 1-carbamoylmethyl-propyl, 1- carbamoylmethyl-3 -methyl -butyl or the like.
  • di(C ⁇ - 6 alkyl)amino means an amino group having two above- mentioned C ⁇ _ 6 alkyl groups, such as dimethylamino, diethylamino, dipropylamino or the like.
  • di(C 1 - 6 alkyl)amino-C ⁇ - 9 alkyr ⁇ means a substituted C ⁇ _ alkyl group having an above-mentioned di(C ⁇ - 6 alkyl)amino group, such as 2- dimethylaminoethyl, 3-dimethylaminopropyl or the like.
  • aryl means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl, or the like.
  • heteroaryl means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring having in its ring 1 to 4 atoms which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, furyl, thienyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo[l,2,5]thiadiazolyl, benzo[l-2,5]oxadiazolyl or the like.
  • aryl-C ⁇ - 9 alkyl means a substituted C ⁇ - 9 alkyl group having an above-mentioned aryl group, such as benzyl, phenethyl, 3-phenylpropyl or the like.
  • heteroaryl-Ci- 9 alkyl means a substituted C ⁇ - 9 alkyl group having an above-mentioned heteroaryl group, such as pyridin-2-ylmethyl, pyridin- 3-ylmethyl, pyridm-4-ylmethyl or the like.
  • C ⁇ - 6 alkylthio means a straight chain or branched chain alkylthio group of 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
  • C ⁇ - 6 alkylsulfonyl means a straight chain or branched chain alkylsulfonyl group of 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or the like.
  • the term "mono(C 1 - 6 alkyl)aminosulfonyl” means a substituted aminosulfonyl group having an above mentioned C ⁇ - 6 alkyl, such as methylaminosulfonyl, ethylaminosulfonyl or the like.
  • the term "di(C 1 - 6 alkyl)aminosulfonyl” means a substituted aminosulfonyl group having two above mentioned C ⁇ - 6 alkyl, such as dimethylaminosulfonyl, diethylaminosulfonyl or the like.
  • halogen means fluorine, chlorine, bromine or iodine atom.
  • C ⁇ - 6 haloalkyl means a substituted C ⁇ - 6 alkyl having one to three halogen atoms, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl or the like.
  • C ⁇ - 6 alkylcarbonyl means an acyl group of 1 to 7 carbon atoms acetyl, propionyl, butyryl or the like.
  • C 2 - 6 alkynyl means a straight chain or branched chain alkynyl group of 2 to 6 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
  • C ⁇ - 6 alkylamino means a substituted amino group having an above-mentioned C ⁇ . 6 alkyl group, such as methylamino, ethylamino, propylamino or the like.
  • C ⁇ - 6 alkylcarbonylamino means a substituted amino group having a C ⁇ - 6 alkylcarbonyl group, such as acetylamino, propionylamino, 3- methylbutyrylamino, isobutyrylamino, «-butyrylamino or the like.
  • C 3 - 6 cycloalkylcarbonylamino means a substituted amino group having a C 3 .
  • cycloalkylcarbonyl group such as cyclopropane carbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino or the like.
  • arylcarbonylamino means a substituted amino group having an above mentioned aryl group, such as phenylcarbonylamino or the like.
  • heteroarylcarbonylamino means a substituted amino group having an above mentioned heteroaryl group, such as (furan-2-carbonyl)amino,
  • C ⁇ - 6 alkylaminocarbonyl means a substituted aminocarbonyl group having an above mentioned C ⁇ - 6 alkyl group, such as methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl or the like.
  • C ⁇ _ 6 alkylaminocarbonylamino means a substituted aminocarbonylarnino group having an above mentioned - ⁇ alkyl group, such as 3- methylureido, 3-ethylureido, 3-propylureido, 3-isopropylureido or tlxe like.
  • aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C ⁇ - 6 alkyl, C - cycloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ - 6 alkoxy, Ci-ealkylthio, -ealkylsulfonyl, aminosulfonyl, mono(C ⁇ - 6 alkyl)aminosulfonyl, cyano, C !
  • - 6 haloallcyl, trifluoromethoxy, diflnoromethoxy, fluoromethoxy and -N(R 12 )R 13 , wherein R 12 and R 13 are the same or different, and independently are hydrogen or C ⁇ - 6 alkyl" includes, for example, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4- dibromophenyl, 2-brorno-4-isoproylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 4-methoxy-2-methylphenyl, 2-chloro-4- trifluoromethoxyphenyl, 4-isopropyl-2-methylthiophenyl, 2,4,6-trimethylphenyl, 4- bromo-2,6-dimethylphenyl, 4-bromo-2,6-diethylphenyl, 4-chloro-2,6 - di
  • the "pharmaceutically acceptable salts" in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid,/?-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, maridelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc i
  • isomers such as diastereomers, enantiomers, geometric isomers and tautomeric forms may exist.
  • the compound of the present invention includes the individual isomers and the racemic and non- racemic mixtures of the isomers.
  • Preferable examples of the compound of the present invention are as follows.
  • R 1 is -galkyl, C 2 - 9 alkenyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl-C ⁇ - 9 alkyl, di(C - 7 cycloalkyl)-C ⁇ - 9 alkyl, Ci-ealkoxy-Ci-galkyl, di(C ⁇ - 6 alkoxy)-C ⁇ _ 9 alkyl, hydroxy-C ⁇ - 9 alkyl, cyano-C ⁇ . 9 al-kyl, carbamoyl-C ⁇ - 9 alkyl, di(C ⁇ - 6 alkyl)amino-C ⁇ .
  • R_ la and R lb are each independently selected from the group consisting of hydrogen, C i- 6 alkyl and C ⁇ - 6 alkylcarbonyl; R 2 is C ⁇ alkyl or C ⁇ - 6 haloalkyl; R 3 is hydrogen, Ci-ealk l, C 2 . 6 alkenyl, C - 6 alkynyl, C 3 - cycloalkyl, C 3 .
  • R 10 is hydrogen or d- 6 alkyl
  • R 11 is hydrogen, C ⁇ - 6 alkyl or di(C ⁇ - 6 alkyl)arnino-C ⁇ _ 6 alkyl
  • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C ⁇ - 6 alkyl, C - 7 cycloalkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, -ealko y, C ⁇ - 6 alkylthio, C ⁇ _ 6 alkylsulfonyl, aminosulfonyl, mono(C ⁇ _ 6 alkyl)aminosulfonyl, di(C ⁇ - 6 alkyl)aminosulfonyl, cyano, haloC ⁇ alkyl, trifluo
  • Ci- ⁇ alkyl is hydrogen, C ⁇ - 6 alkyl or di(C 1 - 6 alkyl)aminoC 1 - 6 alkyl;
  • Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, C ⁇ - 6 alkyl, C 3 - 7 cycloalkyl, C . 6 alkenyl, C 2 - 6 alkynyl, Ci- 6 alkoxy, Q-
  • R 2 is C ⁇ - 6 alkyl
  • R 3 is hydrogen or Ci- ⁇ alkyl
  • R 10 is hydrogen or C ⁇ - 6 alkyl
  • R 11 is hydrogen or Ci- ⁇ alkyl
  • Ar is phenyl which phenyl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Q-salkyl, C ⁇ - 3 alkoxy, Ci- 3 alkylthio, trifluoromethyl and -N(R )R , wherein R and R are the same or different, and independently are hydrogen or C ⁇ alkyl.
  • R 1 is C ⁇ - 9 alkyl, C - 7 cycloalkyl, C 3 . 7 cycloalkyl-C ⁇ - 6 alkyl, di(C 3 - 7 cycloalkyl)-C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy-C ⁇ - 6 alkyl, di(C ⁇ - 6 alkoxy)-Ci- 6 alkyl or aryl-C ⁇ alkyl;
  • R 2 is C ⁇ .
  • R 3 is C ⁇ alkyl
  • R 10 is hydrogen
  • R 11 is hydrogen
  • Ar is phenyl which phenyl is substituted with 2 or 3 substituents, which are the same or different, selected from the group consisting of halogen or C ⁇ alkyl.
  • the preferable bond between X and Y is a double bond.
  • the preferable R is C ⁇ - 6 alkyl. More preferable R is methyl.
  • the preferable R is C ⁇ - 6 alkyl. More preferable R is ethyl.
  • the preferable R 10 is hydrogen.
  • the preferable R 11 is hydrogen.
  • the preferable Ar is phenyl which phenyl is substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, C ⁇ - 3 alkyl, C ⁇ alkoxy, C ⁇ alkylthio, trifluoromethyl and -N(R 12 )R 13 , wherein R 12 and R 13 are the same or different, and independently are hydrogen or C ⁇ -3alkyl.
  • the more preferable Ar is phenyl which phenyl is substituted with 2 or 3 substituents, which are the same or different, selected from the group consisting of halogen or C ⁇ - 3 alkyl.
  • the compound of the formula [I] can be produced, for example, by the process shown in the following reaction schemes 1-3 (in the following reaction schemes, R , R , R , R and Ar are as defined above, L and L are the same or different, selected from the group consisting of chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group, L 3 is chloro, bromo or iodo, R a is C ⁇ - 6 alkyl, R b is d- 6 alkyl, R c is Ci- ⁇ alkyl, C 3 - 6 cycloalkyl, aryl or heteroaryl, R d is hydrogen or Ci _ salkyl).
  • Reaction Scheme 1 Reaction Scheme 1
  • Compound (7) and (8) the compounds in the present invention, can be prepared by the method shown in reaction scheme 1.
  • Compound (1) can be transformed to (2) by using a reagent for conversion of amine to guanidine in the presence or absence of a base in an inert solvent.
  • Treatment of compound (2) with compound (3) can provide compound (4) in the presence or absence of a base in an inert solvent.
  • Compound (4) can be converted to compound (5) using a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without using a solvent.
  • Compound (5) can be treated with compound (6) to form compound (7) in the presence or absence of a base in an inert solvent.
  • the reagent for conversion of a nine to guanidine includes, for example, cyanamide, S-alkylthiouronium salt and its derivatives, aminoiminosulfonic acids, 3,5-dimethylpyrazole-l-carboxamidine nitrate, pyrazole-1-carboxamidine hydrochloride and the like.
  • the base includes, for example, amines such as triethylamine, N.N-diisopropylethylamine, pyridine, N,N- dimethylaniline, N,N-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; nxetal amides such as sodium amide, lithium diisopropylamide and the like; and Grign-ard reagents such as methyl magnesium bromide and the like.
  • amines such as triethylamine, N.N-diisopropylethylamine, pyridine, N,N- dimethylaniline, N,N-diethylaniline and the like
  • inorganic bases such as sodium carbonate
  • the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like.
  • the sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methansuk onic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis trifluoromethanesulfonimide) and the like.
  • the oxidizing agent includes, for example, manganese dioxide, potassium permanganate, palladium and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylforrnamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide * pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropy
  • Compound (15), the compound in the present invention can be prepared by the method shown in reaction scheme 2.
  • Compound (2), synthesized in the same manner as shown in reaction scheme 1, can be converted to compound (10) by reacting with compound (9) in the presence or absence of a base in an inert solvent.
  • Treatment of compound (10) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without using a solvent can provide compound (11).
  • Compound (11) can be reacted with compound (12) in the presence or absence of a base in an inert solvent to form compound (13).
  • Introduction of an iodine atom on the pyrimidine ring of compound (13) can be carried out in an inert solvent by using a conventional reagent for introducing an iodine atom such as iodine, iodine monochloride or the like.
  • Compound (14) can be converted to compound (15) using a palladium catalyst, such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0) or the like, under a cabon oxide atomosphere in the presence or absence of a base and a ligand in an inert solvent.
  • a palladium catalyst such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0) or the like
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N- diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert- butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like.
  • amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N- diethylaniline and the like
  • inorganic bases such as sodium carbonate, potassium carbon
  • the halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like.
  • the sulfonating reagent includes, for example, p-toluenesulfonyl chloride, n ethanesulfonyl chloride, p- toluenesulfonic anhydride, methansulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide) and the like.
  • the ligand includes, for example, triphenylphosphine, l,3-bis(ddphenylphosphono)propane and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the ILke; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as methanol, ethanol, isopropy
  • Compound (19), (21), (23), (25), (26), (28), (29), (30), (32), (34), (35), (36), (37), (38) and (39), the compounds in the present invention, can be prepared by the method shown in reaction scheme 3.
  • Compound (2) can be prepared in the same manner as shown in reaction scheme 1.
  • Compound (17) was given by reacting compound (2) with compound (16) in the presence or absence of a base in an inert solvent. Preparation of compound (17) from compound (1) may be performed in one pot continuously. Conversion of compound (17) to compound (18) can be carried out in the same method for the conversion of compound (4) to compound (5) in reaction scheme 1. Treatment of compound (18) with amine (6) in the presence or absence of a base in an inert solvent can provide compound (19).
  • Compound (19) can be transformed to compound ( 1) by treatment with a base and an alkylating reagent (20) in an inert solvent. Reacting compound (19) with aldehyde (22) in the presence of a base in an inert solvent gave an alkylidene compound (23).
  • Compound (25) can be provided by acylation of compound (19) with isocyanate (24) in the presence of " base in an inert solvent. Reduction of a carbonyl group in compound (19) with a reducing agent in an inert solvent can provide compound (26).
  • Compound (28) can be produced by Mannich reaction of compound (26) using an amine (27) and formaldehyde.
  • Conversion of compound (19) to oxime (29) can be performed by reacting compound (19) with a nitrite derivative in the presence or absence of an acid in an inert solvent.
  • a reducing agent in an inert solvent can give compound (30).
  • Acylation of the amino group in compound (30) by using an acylating agent (31) in an irxert solvent can give compound (32).
  • Urea derivatives (34) can be produced by reacting compound (30) with an isocyanate (33) in an inert solvent.
  • Reacting a mixture of compound (30) and an aldehyde (22) in the presence of a catalyst for hydLrogenation under hydrogen atmosphere or in the presence of a reducing agent in an- inert solvent can provide compound (35).
  • Compound (36) can be provided by oxidation of compound (19) with an oxidizing agent in an inert solvent. Treatment of compound (36) with a Grignard reagent or alkyl lithium in an inert solvent can give compound (37). Reduction of compound (37) with a reducing agent in an inert solvent can provide compound (38) and/or compound (39).
  • the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine l,S-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide a-nd the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potasshrrn hexamethyldisilazanide and the like.
  • amines such as triethylamine, N,N-diisopropylethylamine, pyridine l,S-diaza
  • the acid includes, for example, includes inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, ⁇ -toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gli conic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid and the like.
  • inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like
  • organic acids such as acetic acid, oxalic acid, lactic acid,
  • the reducing agent includes, for example, lithium borohydride, sodium borohydride, calcium bororxydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, potassium tri-sec- butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride;, lithium aluminum hydride, sodium aluminum hydride, sodium bis(2- methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, trichlorosilane and the like.
  • the oxidizing agent includes, for example, manganese dioxide, potassium permanganate, palladium and the like.
  • the catalyst for- hydrogenation includes, for example, palladium, nickel and the like.
  • the Grigna-rd reagent includes, for example, methylmagnesium iodide, methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium chloride.
  • the alkyl lithium includes, for example, methyllithium, ethyllithiurn, butyllithium and the like.
  • the nitrite derivative includes, for example, nitrite salts such as sodium nitrite, potassium nitrite and the like; organic nitrite derivatives such as butyl nitrite, isobutylnitrite, isoamylnitrite and the like.
  • the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol-- ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahycirofuran, 1 ,4 ⁇ dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as enzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimet-hylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetoni ⁇ trile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as
  • the compound of the present invention can be converted to a salt with an acid in an inert solvent.
  • the acid includes inorgani c acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-si-ilfonic acid and the like.
  • the inert solvent includes, for example, alcohols such as -methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylfo ⁇ namide, N-methylpyrrolidone, NN-dimethylacetamide and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
  • alcohols such as -methanol, ethanol, isopropyl alcohol, ethylene glyco
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved.
  • the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents., etc.
  • the compound of the present invention can " be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally. The dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient.
  • Step 1 Synthesis of (2-bromo-4-isopropyl-phenyl)-[7-(2-methoxy-ethyl)-4— methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-yl]-amine (Step 1)
  • a mixture of 2- bromo-4-isopropyl aniline (50 g) and cyanamide (39 g) in ethyl acetate (850 oil) and ethanol (110 ml) was stirred at room temperature.
  • a solution of 1M HC 1 in ether was added and the reaction mixture was stirred for 1 h.
  • the ether was distillated and the reaction mixture was stirred and refluxed overnight.
  • the reaction mixture was cooled to room temperature and diluted with ether (1 OOO ml) to give a solid.
  • the solid was filtered off, washed with acetonitrile and dried to give 40 g of N-(2-bromo-4-isopropyl-phenyl)-guanidine hydrochloride.
  • the filtrate was concentrated under reduced pressure and the residue was crystallized from acetonitrile to provide a second fraction (8 g) of the product.
  • Step 3 A mixture of 2-(2-bromo-4-isopro ⁇ yl-pheoylamino)-5-(2- hydroxy-ethyl)-6-methyl-3H- ⁇ yrimidin-4-one (23.5 g) and pliosphorus oxychloride (300ml) was stirred at 60°C overnight. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated.
  • Step 4 A mixture of (2-bromo-4-isopropyl-phenyl)-[4-chloro-5-(2- chloro-ethyl)-6-methyl-pyrimidin-2-yl]-amine (6 g) and 2-methoxyethylamine (1.5 g) in dioxane (50 ml) was stirred at 120°C overnight.
  • reaction mixture was cooled and filtered over decalite.
  • Step 1 is analogous to (Reference example 1, step 1).
  • Step 3 A mixture of 6-methyl-2-(2,4,6-trimethyl-phenylamino)- pyrimidine-4-ol (15 g) and phosphorus oxychloride (200 ml) was stirred and refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. Water was added and the mixture was alkalified with potassium carbonate. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated.
  • Step 5 To a solution of N 4 -(l-ethyl-propyl)-6-methyl-N 2 -(2,4,6- trimethyl-phenyl)-pyrimidine-2,4-diamine (3.1 g) in methanol (30 ml) at room temperature was added dropwise a 1M solution of iodine monochloride in dichloromethane (10 ml). The reaction mixture was stirred for 1 h and concentrated under reduced pressure.
  • Step 6 A mixture of N 4 -(l-ethyl-propyl)-5-iodo-6-methyl-N 2 -(2,4,6- trimethyl-phenyl)-pyrimidine-2,4-diamine (0.5 g), palladium(II) acetate (0.02 g), l,3-bis(diphenylphosphino)propane (0.08 g) and triethylamine (1 g) in tetrahydrofuran (50 ml) was stirred under 60 atmosphere CO pressure, at 75°C for 16 h.
  • Stepl and step 2 A mixture of ethyl-(2,4,6-trimethyl-phenyl)-amine (50 g) and cyanamide (21 g) in N-methylpyrrolidone (50 ml) was stirred at 150°C for 1 h. The reaction mixture was cooled to room temperature. Ethanol (500 ml), ethyl acetoacetate (65 g) and potassium carbonate (37 g) were added and the mixture was stirred and refluxed for 16 h. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate (2x). The combined organic layers were washed with water, dried over magneshun sulfate and concentrated under reduced pressure.
  • Ethanol 500 ml
  • ethyl acetoacetate 65 g
  • potassium carbonate 37 g
  • Step 3 A mixture of 2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-6-methyl- pyrimidin-4-ol (2.7 g) and N,N-diisopropylethylamine (1.6 g) in dichloromethane (100 ml) was stirred under nitrogen at 0°C. Triflic anhydride (3.4 g) was added dropwise. The reaction mixture was brought to room temperature and stirred for 1 h.
  • Step 4 is analogous to (example 4, step 4).
  • Step 5 is analogous to (example 4, step 5).
  • Step 6 A mixture ofN 2 -ethyl-N 4 -(l-ethyl-propyl)-5-iodo-6-methyl-N 2 - (2,4,6-trimemyl-phenyl)-pyrimidine-2,4-diamine (0.5 g), palladium(II) acetate (0.02 g), l,3-bis(diphenylphosphino)propane (0.08 g) and diethylamine (25 ml) in tetrahydrofuran (50 ml) was stirred under 60 atmosphere CO pressure, at 75°C for 16 h.
  • Step 7 N,N-diethyl-2- ⁇ 4-(l-ethyl-propylamino)-2-[ethyl-(2,4,6- frimethyl-phenyl)-ammo]-6-methyl-pyrimidin-5-yl ⁇ -2-oxo-acetamide (0.05 g) and a solution of 6M hydrochloric acid in 2-propanol (1 ml) were stirred at 150°C for
  • Step 1 and step 2 A mixture of ethyl-(2,4,6-trimethyl-phenyl)-amine (50 g) and cyanamide (21 g) in N-methylpyrrolidone (50 ml) was stirred at 150°C for 1 h. The reaction mixture was cooled to room temperature. Ethanol (1000 ml), diethyl acetylsuccinate (65 g) and potassium carbonate (74 g) were added and the mixture was stirred and refluxed for 16 h. Diethyl acetylsuccinate (65 g) was added a second time and the reaction mixture was stirred and refluxed for 24 h.
  • Step 3 is analogous to (example 5, step 3)
  • Step 4 A mixture of ⁇ 2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4- methyl-6-trifluoromethanesulfonyloxy-pyrimidin-5-yl ⁇ -acetic acid ethyl ester (10 g), 1-ethyl-propylamine (4 g) and potassium carbonate (4 g) in acetonitrile (100 ml) was stirred at 125°C for 72 h. The solvent was evaporated and the residue was dissolved in water and extracted with dichloromethane.
  • Step 2 A solution of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione (0.15 g) in tetrahydrofuran (1.5 ml) under nitrogen was stirred at -20°C. 1 M ethylmagnesium bromide in tetrahydrofuran (0.5 ml) was added. The reaction mixture was brought to room temperature and stirred for 1 h. A solution of ammonium chloride (1 ml) was added and the product was extracted with dichloromethane.
  • reaction mixture was stirred for 1 h, poured out into water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to provide 7-(l-ethyl-propyl)-2-[ethyl- (2,4,6-trimethyl-phenyl)-amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione 5-oxime (1.4 g) as a mixture of the geometric isomers.
  • Step 1 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4- methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione 5-oxime (0.5 g) was hydrogenated with Raney Nickel in tetrahydrofuran (50 ml).
  • reaction mixture was filtered over decalite and the filtrate was concentrated under reduced pressure to give 5- amino-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-methyl-5,7- dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.5 g).
  • Step 2 A mixture of 5-amino-7-(l -ethyl-propyl)-2-[ethyl-(2,4,6- trimemyl-phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g), propionyl chloride (0.055 g) and triethylamine (0.1 g) in dichloromethane (2 ml) was stirred at room temperature for 16 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 A solution of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 g) in tetrahydrofuran (20 ml) was stirred at 0°C under nitrogen. Borane- tetrahydrofuran complex, 1M solution in tetrahydrofuran (12.5 ml) was added dropwise and the reaction mixture was stirred for 2 h at room temperature. Methanol/acetic acid 1 : 1 was added and the solvent was evaporated.
  • Step 2 A mixture of ethyl-[7-(l-ethyl-propyl)-4-methyl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl-phenyl)-amine (60%) and ethyl-[7- (l-ethyl-propyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl- phenyl)-amine (32 %) (1 g) and manganese(IN) oxide (5 g) in dichloromethane were stirred at room temperature for 76 h.
  • the washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl 2 , 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation.
  • CRF receptor binding test The membrane preparation (0.3 mg protein/ml), I-CRF (0.2 nM) and a test drug were reacted at 25°C for 2 h. After completion of the reaction, the reaction mixture was filtered by suction through a glass filter (GF/C) treated with
  • An inhibition curve was obtained by reacting a definite concentration (0.2 nM) of 125 I-CRF with various concentrations of each test drug under the conditions described above. A concentration of the test drug at which binding of 125 I-CRF is inhibited by 50% (IC 50 ) was determined from the inhibition curve. As a result, it was found that compounds 1-003, 1-004, 1-008 and 1-011 can be exemplified as typical compounds having an IC 50 value of 200 nM or less.
  • CRF CRF receptors
  • diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.

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Abstract

According to the present invention, there is provided an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc. A pyrrolopyrimidine derivative represented by the following formula [I]: has a high affinity for CRF receptors and is effective against diseases in which CRF is considered to be involved.

Description

DESCRIPTION PYRROLOPYRIMIDINE DERIVATIVES
TECHNICAL FIELD The present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
DESCRIPTION OF THE PRIOR ART CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397,
1981; and J. Neurosci., 7, 88-100, 1987), and it is suggested that CRF plays a core role in biological reactions against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). For CRF, there are the following two paths: a path by which CRF acts on peripheral immune system or sympathetic nervous system through hypothalamus-pituitary- adrenal system, and a path by which CRF functions as a neurotransmitter in central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990). Intraventricular administration of CRF to hypophysectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, there are suggested the participation of CRF in hypothalamus- pituitary-adrenal system and the pathway by which CRF functions as a neurotransmitter in central nervous system. The review by Owens and Nemeroff in 1991 summarizes diseases in which CRF is involved (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immunity-related diseases, etc. It has recently been reported that CRF is involved also in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and cephalic external -wound (Brain Res. 545, 339-342,
1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997). Accordingly, antagonists against CRF receptors are useful as therapeutic agents for the diseases described above. US2004224964 discloses 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine derivatives as CRF receptor antagonists. However, none disclose the compounds provided in the present invention.
PROBLEM(S) TO BE SOLVED BY THE INVENTION An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesmal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
MEANS FOR SOLVING THE PROBLEM The present inventors earnestly investigated pyrrolopyrimidines that have a high affinity for CRF receptors, whereby the present invention has been accomplished. The present invention is pyrrolopyrimidine derivatives explained below. A pyrrolopyrimidine derivative represented by the following formula [I]:
Figure imgf000003_0001
(wherein R1 is Cι-9alkyl, C2-9alkenyl, C3.7cycloalkyl, C3-7cycloalkyl-Ci-9alkyl, di(C3-7cycloalkyl)-Cι-9alkyl, Cι-6alkoxy-Cι-9alkyl, di(Cι-6alkoxy)-Cι-9alkyl, hydroxy- -galkyl, cyano-Cι-9alkyl, carbamoyl-Cι-9alkyl, di(Cι-6alkyl)amino-Cι-
9alkyl, aryl, heteroaryl, aryl-Cι- alkyl or heteroaryl-Ci-galkyl, in wl ich said aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of Cι-6alkyl, Cι-6alkoxy, Cι-6alkylthio, Cμ alkylsulfonyl, aminosulfonyl, mono(Cι-6alkyl)aminosulfonyl, di(Cι-
6alkyl)aminosulfonyl, halogen, Cι-6haloalkyl, cyano, nitro, -NRlaRlb, where Rla and
Rlb are each independently selected from the group consisting of hydrogen, Ci- 6alkyl and Cι-6alkylcarbonyl; R2 is Cι-6alkyl or Cι-6haloalkyl; R3 is hydrogen, Cι_6alkyl, C2-6alkenyl, C2-6al-kynyl, C3-7cycloalkyl, C3. cycloalkyl-Cι-6alkyl, benzyl; the bond between X and Y is a single bond or a double bond; wherein (1) when the bond between X and Y is a single bond, X is CR4R5 or C=O; Y is CR6R7, C=O, C=N-OR8 or C=CH-R9; (2) when the bond between X and Y is a double bond, X is CR10; Y is CR11; R4 and R5 are the same or different, and independently are hydrogen or -ealkyl; R6 and R7 are the same or different, and independently are hydrogen, Cι_
6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, hydroxy, -βalkylamino, di(C!- 6alkyl)amino, di(Cι-6alkyl)amino-Cι-6alkyl, Ci-ealkylcarbonylamino, C3- 6cycloalkylcarbonylamino, arylcarbonylamino, heteroaxylcarbonylamino, Ci- 6alkylaminocarbonyl or Cι-6alkylaminocarbonylamino; or R and R are taken together to form C3- cycloalkyl, with the proviso that not both of CR4R5 and CR6R7 are CH2; R8 is hydrogen or Ci-βalkyl; R9 is Cι-6alkyl, C3-6cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen or Cι-6alkyl; R10 is hydrogen or Cι-6alkyl; R11 is hydrogen, Cι_6alkyl or di(Cι-6alkyl)amino-Cι-6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, Cι-6alkyl, C3-7cyclo alkyl, C2.6alkenyl, C2_
6alkynyl, Cι-6alkoxy, Ci-δalkylthio,
Figure imgf000005_0001
aminosulfonyl, mono(Cι-
6alkyl)aminosulfonyl, di(Cι-6alkyl)aminosulfonyl, cyano, Cι-6haloalkyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -NT(R12)R13, wherein R12 and R13 are the same or different, and independently are hydrogen or Chalky!). individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof. The terms used in the present specification have the following meanings. The term "Cι-9alkyl" means a straight chain or branched chain alkyl group of 1 to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, .sec-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, isohexyl, 1- ethylpropyl, 1-ethylbutyl, 1,3-dimethylbutyl, 1-propylbutyT, 1-propylpentyl, 1- butylpentyl or the like. The term "C2.9alkenyl" means a straight chain or branched chain alkenyl group of 2 to 9 carbon atoms, such as vinyl, isopropenyl, allyl or the like. The term "C3.7cycloalkyl" means a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like. The term "C3-7cycloalkyl-Cι- alkyl" means a substituted Cι- alkyl group having the above-mentioned C3- cycloalkyl as the substituent, such as cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1 -cyclopentyl ethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopropylpropyl, 1- cyclobutylpropyl, 1 -cyclopentylpropyl, 1-cyclopropylmetlιylpropyl, 1- cyclopropylmethylbutyl or the like. The term "di(C3. cycloalkyl)-Cι-9alkyl" means a substituted Cι- alkyl group having two above-mentioned C3-7cycloalkyl groups as the substituents, such as di(cyclopropyl)methyl, di(cyclobutyl)methyl, di(cyclopentyl)methyl or the like. The term "Cι-6alkoxy" means a straight chain or branched chain alkoxy group of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like. The term "Cι-6alkoxy-Cι-9alkyl" means a substituted Cι-9alkyl group having the above-mentioned d.6alkoxy group as the substituent, such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 -methoxymethyl-propyl, 1- methoxymethyl-butyl or the like. The term "di(Cι-6alkoxy)-Cι-9alkyl" means a substituted Ci- alkyl group having two above-mentioned Cι-6alkoxy groups as the substituents, such as 2,3- di(methoxy)propyl, 2-methoxy-l-methoxymethyl-ethyl, 2,4-(diethoxy)pentyl or the like. The term "hydroxy- -galkyl" means a substituted Cι-9alkyl group having a hydroxy group, such as hydroxymethyl, 1 -hydroxyethyl, 2 -hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- hydroxypentyl, 1-hydroxymethyl-propyl, 1-hydroxymethyl-butyl, 1- hydroxymethyl-3 -methyl-butyl or the like. The term "cyano-Cι-9alkyl" means a substituted Cι_9alkyl group having a cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 1- cyanobutyl, 5-cyanopentyl, 2-cyano-l -ethyl-ethyl, 1-cyanomethyl-butyl, 1-cyano- 3 -methyl-butyl, l-cyanomethyl-3 -methyl-butyl or the like. The term "carbamoyl-Cι- alkyl" means a substituted Cι-9alkyl group having a carbamoyl group, such as carbamoylmethyl, 1-carbamoylethyl, 2- carbamoylethyl, 1-carbamoylpropyl, 1-carbamoylbutyl, 5-carbamoylpentyl, 1- carbamoyl-3 -methyl-butyl, 1-carbamoylmethyl-buty, 1-carbamoylmethyl-propyl, 1- carbamoylmethyl-3 -methyl -butyl or the like. The term "di(Cι-6alkyl)amino" means an amino group having two above- mentioned Cι_6alkyl groups, such as dimethylamino, diethylamino, dipropylamino or the like. The term "di(C1-6alkyl)amino-Cι-9alkyrι means a substituted Cι_ alkyl group having an above-mentioned di(Cι-6alkyl)amino group, such as 2- dimethylaminoethyl, 3-dimethylaminopropyl or the like. The term "aryl" means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl, or the like. The term "heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring having in its ring 1 to 4 atoms which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, furyl, thienyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo[l,2,5]thiadiazolyl, benzo[l-2,5]oxadiazolyl or the like. The term "aryl-Cι-9alkyl" means a substituted Cι-9alkyl group having an above-mentioned aryl group, such as benzyl, phenethyl, 3-phenylpropyl or the like. The term "heteroaryl-Ci-9alkyl" means a substituted Cι-9alkyl group having an above-mentioned heteroaryl group, such as pyridin-2-ylmethyl, pyridin- 3-ylmethyl, pyridm-4-ylmethyl or the like. The term "Cι-6alkylthio" means a straight chain or branched chain alkylthio group of 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio or the like. The term "Cι-6alkylsulfonyl" means a straight chain or branched chain alkylsulfonyl group of 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or the like. The term "mono(C1-6alkyl)aminosulfonyl" means a substituted aminosulfonyl group having an above mentioned Cι-6alkyl, such as methylaminosulfonyl, ethylaminosulfonyl or the like. The term "di(C1-6alkyl)aminosulfonyl" means a substituted aminosulfonyl group having two above mentioned Cι-6alkyl, such as dimethylaminosulfonyl, diethylaminosulfonyl or the like. The term "halogen" means fluorine, chlorine, bromine or iodine atom. The term "Cι-6haloalkyl" means a substituted Cι-6alkyl having one to three halogen atoms, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl or the like. The term "Cι-6alkylcarbonyl" means an acyl group of 1 to 7 carbon atoms acetyl, propionyl, butyryl or the like. The term "C2-6alkynyl" means a straight chain or branched chain alkynyl group of 2 to 6 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like. The term "Cι-6alkylamino" means a substituted amino group having an above-mentioned Cι.6alkyl group, such as methylamino, ethylamino, propylamino or the like. The term "Cι-6alkylcarbonylamino" means a substituted amino group having a Cι-6alkylcarbonyl group, such as acetylamino, propionylamino, 3- methylbutyrylamino, isobutyrylamino, «-butyrylamino or the like. The term "C3-6cycloalkylcarbonylamino" means a substituted amino group having a C3.6cycloalkylcarbonyl group, such as cyclopropane carbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino or the like. The term "arylcarbonylamino" means a substituted amino group having an above mentioned aryl group, such as phenylcarbonylamino or the like. The term "heteroarylcarbonylamino" means a substituted amino group having an above mentioned heteroaryl group, such as (furan-2-carbonyl)amino,
(pyridine-2-carbonyl) amino, (pyridine-3-carbonyl)amino, (pyridine-4- carbonyl)amino or the like. The term "C ι-6alkylaminocarbonyl" means a substituted aminocarbonyl group having an above mentioned Cι-6alkyl group, such as methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl or the like. The term "Cι_6alkylaminocarbonylamino" means a substituted aminocarbonylarnino group having an above mentioned -βalkyl group, such as 3- methylureido, 3-ethylureido, 3-propylureido, 3-isopropylureido or tlxe like. The phrase "aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, Cι-6alkyl, C - cycloalkyl, C2-6alkenyl, C2- 6alkynyl, Cι-6alkoxy, Ci-ealkylthio, -ealkylsulfonyl, aminosulfonyl, mono(Cι- 6alkyl)aminosulfonyl,
Figure imgf000008_0001
cyano, C!-6haloallcyl, trifluoromethoxy, diflnoromethoxy, fluoromethoxy and -N(R12)R13, wherein R12 and R13 are the same or different, and independently are hydrogen or Cι-6alkyl" includes, for example, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4- dibromophenyl, 2-brorno-4-isoproylphenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 4-methoxy-2-methylphenyl, 2-chloro-4- trifluoromethoxyphenyl, 4-isopropyl-2-methylthiophenyl, 2,4,6-trimethylphenyl, 4- bromo-2,6-dimethylphenyl, 4-bromo-2,6-diethylphenyl, 4-chloro-2,6 - dimethylphenyl, 2,4,6-tribromophenyl, 2,4,5-tribromophenyl, 2,4,6-trichlorophenyl, 2,4,5-trichlorophenyl, 4-bromo-2,6-dichlorophenyl, 6-chloro-2,4-dibromophenyl, 2,4-dibromo-6-fluoropxιenyl, 2,4-dibromo-6-methylphenyl, 2,4-dibromo-6- methoxyphenyl, 2,4-di" romo-6-methylthiophenyl, 2,6-dibromo-4-isopropylphenyl, 2,6-dibromo-4-trifluoromethylphenyl, 2-bromo-4-trifluoromethylphenyl, 4-bromo- 2-chlorophenyl, 2-bromo-4-chloroρhenyl, 4-bromo-2-methylphenyl, 4-chloro-2- methylphenyl, 2,4-dimethoxyphenyl, 2,6-dimethyl-4-methoxyphenyl, 4-chloro-2,6- dibromophenyl, 4-bromo-2,6-difluorophenyl, 2,6-dichloro-4-trifluororrxethylphenyl, 2,6-dichloro-4-trifluoromethox phenyl, 2,6-dibromo-4-trifluoromethoxyphenyl, 2- chloro-4,6-dimethylphenyl, 2-bromo-4,6-dimethoxyphenyl, 2-bromo-4-isopropyl- 6-methoxyphenyl, 2,4-dimethoxy-6-methylphenyl, 6-dimethylamino-4- methylpyridin-3 -yl, 2-chloro-6-trifluoromethylpyridin-3 -yl, 2-chloro-6- trifluoromethoxypyridin-3 -yl, 2-chloro-6-methoxypyridin-3 -yl, 6-methoxy-2- trifluoromethylpyridin-3-yl, 2-chloro-6-difluoromethylpyridin-3-yl, 6-methoxy-2- methylpyridin-3-yl, 2,6-dimethoxypyridin-3-yl, 4,6-dimethyl-2- trifluoromethylpyrimidin-5-yl, 2-dimethylamino-6-methylpyridin-3 -yl. The "pharmaceutically acceptable salts" in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid,/?-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, maridelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminium ion or the like; salts with an amine such as arnrrαonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylarnine, 2- aminoethanol, benzathine or the like. In a compound of the present invention, isomers such as diastereomers, enantiomers, geometric isomers and tautomeric forms may exist. The compound of the present invention includes the individual isomers and the racemic and non- racemic mixtures of the isomers. Preferable examples of the compound of the present invention are as follows. The pyrrolopyrimidine derivative represented by the following formula [II]:
Figure imgf000010_0001
(wherein R1 is -galkyl, C2-9alkenyl, C3-7cycloalkyl, C3-7cycloalkyl-Cι-9alkyl, di(C -7cycloalkyl)-Cι-9alkyl, Ci-ealkoxy-Ci-galkyl, di(Cι-6alkoxy)-Cι_9alkyl, hydroxy-Cι-9alkyl, cyano-Cι.9al-kyl, carbamoyl-Cι-9alkyl, di(Cι-6alkyl)amino-Cι. 9alkyl, aryl, heteroaryl, aryl-Cι-s>alkyl or heteroaryl-Cι-9alkyl, in which said aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of C^aUcyl, Cι- alkoxy, Ci-ealkylthio, Cι_ 6alkylsulfonyl, aminosulfonyl, mono(Cι.6alkyl)aminosulfonyl, di(Cμ 6alkyl)aminosulfonyl, halogen, Ci-βhaloalkyl, cyano, nitro, -NRlaRlb, where R_la and Rlb are each independently selected from the group consisting of hydrogen, C i- 6alkyl and Cι-6alkylcarbonyl; R2 is C^alkyl or Cι-6haloalkyl; R3 is hydrogen, Ci-ealk l, C2.6alkenyl, C -6alkynyl, C3- cycloalkyl, C3. 7cycloalkyl-Cι-6alkyl, benzyl; R10 is hydrogen or d-6 alkyl; R11 is hydrogen, Cι-6alkyl or di(Cι-6alkyl)arnino-Cι_6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, Cι-6alkyl, C -7cycloalkyl, C2-6alkenyl, C2- 6alkynyl, -ealko y, Cι-6alkylthio, Cι_6alkylsulfonyl, aminosulfonyl, mono(Cι_ 6alkyl)aminosulfonyl, di(Cι-6alkyl)aminosulfonyl, cyano, haloC^alkyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -N(R12)R13, wherein 12 and R13 are the same or different-- and independently are hydrogen or Cι-6alkyl). More preferable are the compound represented by the formula [II], wherein R1 is Cι-9alkyl, C3-7cyclo alkyl, C3- cycloalkyl-Cι-6alkyl, di(C3-7cycloal-kyl)- Cι-6alkyl, Cι-6alkoxy-Cι-6alkyl, di(Cι-6alkoxy)-C1-6alkyl, hydroxy-Q-βalkyl, c ano- Cι-6alkyl, carbamoyl-Cι-6alkyl, di(C1-6alkyl)amino-C1-6alkyl, aryl-Cι-6alkyl or heteroaryl-Cι-6alkyl; R2 is Cι-6alkyl; R3 is hydrogen or Cι-6alkyl; R10 is hydrogen or
Ci-βalkyl; R11 is hydrogen, Cι-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Cι-6alkyl, C3-7cycloalkyl, C .6alkenyl, C2-6alkynyl, Ci-6alkoxy, Q-
6alkylthio, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -N(R )R , wherein R and R are the same or different, and independently are hydrogen or Cι-6alkyl. More preferable are the compound represented by the formula [II], wherein R1 is Cχ-9alkyl, C3_7cycloalkyl, C3- cycloalkyl-Cι-6alkyl, di(C3-7cycloalkyl)-C1-6alkyl, Cι-6alkoxy-Cι-6alkyl, di(Cι_
6alkoxy)-C1-6alkyl or aryl-Cι-6alkyl; R2 is Cι-6alkyl; R3 is hydrogen or Ci-βalkyl; R10 is hydrogen or Cι-6alkyl; R11 is hydrogen or Ci-βalkyl; Ar is phenyl which phenyl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Q-salkyl, Cχ-3alkoxy, Ci- 3alkylthio, trifluoromethyl and -N(R )R , wherein R and R are the same or different, and independently are hydrogen or C^alkyl. More preferable are the compound represented by the formula [II], wherein R1 is Cι-9alkyl, C -7cycloalkyl, C3.7cycloalkyl-Cι-6alkyl, di(C3-7cycloalkyl)-Cι-6alkyl, Cι-6alkoxy-Cι-6alkyl, di(Cι- 6alkoxy)-Ci-6alkyl or aryl-C^alkyl; R2 is Cι.3alkyl; R3 is C^alkyl; R10 is hydrogen; R11 is hydrogen; Ar is phenyl which phenyl is substituted with 2 or 3 substituents, which are the same or different, selected from the group consisting of halogen or C^alkyl. The preferable bond between X and Y is a double bond. The preferable R is Cι-6alkyl. More preferable R is methyl. The preferable R is Cι-6alkyl. More preferable R is ethyl. The preferable R10 is hydrogen. The preferable R11 is hydrogen. The preferable Ar is phenyl which phenyl is substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Cι-3alkyl, C^alkoxy, C^alkylthio, trifluoromethyl and -N(R12)R13, wherein R12 and R13 are the same or different, and independently are hydrogen or Cι-3alkyl. The more preferable Ar is phenyl which phenyl is substituted with 2 or 3 substituents, which are the same or different, selected from the group consisting of halogen or Cι-3alkyl. The compound of the formula [I] can be produced, for example, by the process shown in the following reaction schemes 1-3 (in the following reaction schemes, R , R , R , R and Ar are as defined above, L and L are the same or different, selected from the group consisting of chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group, L3 is chloro, bromo or iodo, Ra is Cι-6alkyl, Rb is d-6alkyl, Rc is Ci-βalkyl, C3-6cycloalkyl, aryl or heteroaryl, Rd is hydrogen or Ci _ salkyl). Reaction Scheme 1
Figure imgf000012_0001
Compound (7) and (8), the compounds in the present invention, can be prepared by the method shown in reaction scheme 1. Compound (1) can be transformed to (2) by using a reagent for conversion of amine to guanidine in the presence or absence of a base in an inert solvent. Treatment of compound (2) with compound (3) can provide compound (4) in the presence or absence of a base in an inert solvent. Compound (4) can be converted to compound (5) using a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without using a solvent. Compound (5) can be treated with compound (6) to form compound (7) in the presence or absence of a base in an inert solvent. Treatment of compound (7) with an oxidizing agent in an inert solvent can give compound (8). When R3 in compound (7) [or (8)] is hydrogen, treatment of compound (7) [or (8)] with an alkyLating reagent in the presence or absence of a base in an inert solvent can provide the N-alkylated compound (R3 =
Cι-6alkyl). Herein, the reagent for conversion of a nine to guanidine includes, for example, cyanamide, S-alkylthiouronium salt and its derivatives, aminoiminosulfonic acids, 3,5-dimethylpyrazole-l-carboxamidine nitrate, pyrazole-1-carboxamidine hydrochloride and the like. The base includes, for example, amines such as triethylamine, N.N-diisopropylethylamine, pyridine, N,N- dimethylaniline, N,N-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; nxetal amides such as sodium amide, lithium diisopropylamide and the like; and Grign-ard reagents such as methyl magnesium bromide and the like. The halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like. The sulfonating reagent includes, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic anhydride, methansuk onic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis trifluoromethanesulfonimide) and the like. The oxidizing agent includes, for example, manganese dioxide, potassium permanganate, palladium and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylforrnamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide* pyridine; water; and mixtures of solvents selected from these inert solvents. Reaction Scheme 2
Figure imgf000014_0001
(2) (10) (11)
Figure imgf000014_0002
(13) (14) (15)
Compound (15), the compound in the present invention, can be prepared by the method shown in reaction scheme 2. Compound (2), synthesized in the same manner as shown in reaction scheme 1, can be converted to compound (10) by reacting with compound (9) in the presence or absence of a base in an inert solvent. Treatment of compound (10) with a halogenating reagent or a sulfonating reagent in the presence or absence of a base in an inert solvent or without using a solvent can provide compound (11). Compound (11) can be reacted with compound (12) in the presence or absence of a base in an inert solvent to form compound (13). Introduction of an iodine atom on the pyrimidine ring of compound (13) can be carried out in an inert solvent by using a conventional reagent for introducing an iodine atom such as iodine, iodine monochloride or the like. Compound (14) can be converted to compound (15) using a palladium catalyst, such as palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0) or the like, under a cabon oxide atomosphere in the presence or absence of a base and a ligand in an inert solvent. Herein, the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N- diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert- butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide and the like; and Grignard reagents such as methyl magnesium bromide and the like. The halogenating reagent includes, for example, phosphoryl chloride, phosphoryl bromide, phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide and the like. The sulfonating reagent includes, for example, p-toluenesulfonyl chloride, n ethanesulfonyl chloride, p- toluenesulfonic anhydride, methansulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide) and the like. The ligand includes, for example, triphenylphosphine, l,3-bis(ddphenylphosphono)propane and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the ILke; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
Reaction Scheme 3
Figure imgf000016_0001
(32)
Compound (19), (21), (23), (25), (26), (28), (29), (30), (32), (34), (35), (36), (37), (38) and (39), the compounds in the present invention, can be prepared by the method shown in reaction scheme 3. Compound (2) can be prepared in the same manner as shown in reaction scheme 1. Compound (17) was given by reacting compound (2) with compound (16) in the presence or absence of a base in an inert solvent. Preparation of compound (17) from compound (1) may be performed in one pot continuously. Conversion of compound (17) to compound (18) can be carried out in the same method for the conversion of compound (4) to compound (5) in reaction scheme 1. Treatment of compound (18) with amine (6) in the presence or absence of a base in an inert solvent can provide compound (19). Compound (19) can be transformed to compound ( 1) by treatment with a base and an alkylating reagent (20) in an inert solvent. Reacting compound (19) with aldehyde (22) in the presence of a base in an inert solvent gave an alkylidene compound (23). Compound (25) can be provided by acylation of compound (19) with isocyanate (24) in the presence of "base in an inert solvent. Reduction of a carbonyl group in compound (19) with a reducing agent in an inert solvent can provide compound (26). Compound (28) can be produced by Mannich reaction of compound (26) using an amine (27) and formaldehyde. Conversion of compound (19) to oxime (29) can be performed by reacting compound (19) with a nitrite derivative in the presence or absence of an acid in an inert solvent. Following reduction of the oxime group in compovαnd (29) with a reducing agent in an inert solvent can give compound (30). Acylation of the amino group in compound (30) by using an acylating agent (31) in an irxert solvent can give compound (32). Urea derivatives (34) can be produced by reacting compound (30) with an isocyanate (33) in an inert solvent. Reacting a mixture of compound (30) and an aldehyde (22) in the presence of a catalyst for hydLrogenation under hydrogen atmosphere or in the presence of a reducing agent in an- inert solvent can provide compound (35). Compound (36) can be provided by oxidation of compound (19) with an oxidizing agent in an inert solvent. Treatment of compound (36) with a Grignard reagent or alkyl lithium in an inert solvent can give compound (37). Reduction of compound (37) with a reducing agent in an inert solvent can provide compound (38) and/or compound (39). Herein, the base includes, for example, amines such as triethylamine, N,N-diisopropylethylamine, pyridine l,S-diazabicyclo[5.4.0]undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide a-nd the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazanide, sodium hexamethyldisilazanide, potasshrrn hexamethyldisilazanide and the like. The acid includes, for example, includes inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, ^-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gli conic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid and the like. The reducing agent includes, for example, lithium borohydride, sodium borohydride, calcium bororxydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, potassium tri-sec- butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride, tetramethylammonium borohydride;, lithium aluminum hydride, sodium aluminum hydride, sodium bis(2- methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, trichlorosilane and the like. The oxidizing agent includes, for example, manganese dioxide, potassium permanganate, palladium and the like. The catalyst for- hydrogenation includes, for example, palladium, nickel and the like. The Grigna-rd reagent includes, for example, methylmagnesium iodide, methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium bromide, ethylmagnesium chloride. The alkyl lithium includes, for example, methyllithium, ethyllithiurn, butyllithium and the like. The nitrite derivative includes, for example, nitrite salts such as sodium nitrite, potassium nitrite and the like; organic nitrite derivatives such as butyl nitrite, isobutylnitrite, isoamylnitrite and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol-- ethylene glycol and the like; ethers such as diethyl ether, diisopropyl ether, tetrahycirofuran, 1 ,4~ dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as enzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; amides such as N,N-dimet-hylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetoni~trile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents. The compound of the present invention can be converted to a salt with an acid in an inert solvent. The acid includes inorgani c acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-si-ilfonic acid and the like. The inert solvent includes, for example, alcohols such as -methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylfoπnamide, N-methylpyrrolidone, NN-dimethylacetamide and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved. For this purpose, the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents., etc. The compound of the present invention can "be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally. The dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient.
PREFERRED EΝBODIMEΝTS OF THE INVENTION The present invention is concretely explained with reference to the following examples and a test example, but is not limited thereto. Reference example 1
Figure imgf000020_0001
Synthesis of (2-bromo-4-isopropyl-phenyl)-[7-(2-methoxy-ethyl)-4— methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-yl]-amine (Step 1) In a flask, equipped with a Dean Stark apparatus, a mixture of 2- bromo-4-isopropyl aniline (50 g) and cyanamide (39 g) in ethyl acetate (850 oil) and ethanol (110 ml) was stirred at room temperature. A solution of 1M HC 1 in ether was added and the reaction mixture was stirred for 1 h. The ether was distillated and the reaction mixture was stirred and refluxed overnight. The reaction mixture was cooled to room temperature and diluted with ether (1 OOO ml) to give a solid. The solid was filtered off, washed with acetonitrile and dried to give 40 g of N-(2-bromo-4-isopropyl-phenyl)-guanidine hydrochloride. The filtrate was concentrated under reduced pressure and the residue was crystallized from acetonitrile to provide a second fraction (8 g) of the product. (Step 2) A mixture of N-(2-bromo-4-isopropyl-phenyl)-guanidine hydrochloride (48 g), 2-acetylbutyrolactone (30 g) and triethylamine (33 g) in ethanol (170 ml) was stirred and refluxed overnight. The solvent was evaporated and the residue purified by a silica gel column chromatography (eluent: dicWoromemane/ammonia 7M in methanol = 95 : 5) to give 2-(2-bromo-4- isopropyl-phenylamino)-5-(2-hydroxy-ethyl)-6-methyl-3H-pyrimidin-4-one (25 g) as a solid.
(Step 3) A mixture of 2-(2-bromo-4-isoproρyl-pheoylamino)-5-(2- hydroxy-ethyl)-6-methyl-3H-ρyrimidin-4-one (23.5 g) and pliosphorus oxychloride (300ml) was stirred at 60°C overnight. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by a silica gel column chromatography (eluent: dichloromethane = 100) to give (2-bromo-4-isopropyl-ρhenyl)-[4-chloro-5- (2-chloro-ethyl)-6-methyl-pyrimidin-2-yl] -amine (22 g) as a solid. (Step 4) A mixture of (2-bromo-4-isopropyl-phenyl)-[4-chloro-5-(2- chloro-ethyl)-6-methyl-pyrimidin-2-yl]-amine (6 g) and 2-methoxyethylamine (1.5 g) in dioxane (50 ml) was stirred at 120°C overnight. The solvent was evaporated and the residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 97 : 3) to give (2-bromo-4-isopt-opyl-phenyl)-[7-(2- methoxy-ethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrinιidine-2-yl]-amine (3-6 g).
Reference example 2
Figure imgf000021_0001
Synthesis of (2-bromo-4-isopropyl-phenyl)-ethyl- [7— (2-methoxy-ethyl)-4- methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine A mixture of (2-bromo-4-isopropyl-phenyl)-[7-(2-n -ethoxy-ethyl)-4- methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-yl]-amine (0.6 g), iodoethane (0.3 g) and sodium hydride (0.3 g) in tetrahydrofuran (20 ml) "was stirred at 60°C for 4 h. Ethyl acetate (40 ml) and a solution of sodium hydroxide 0.5M (40 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, separated, dried over magnesium sulfate, filtered and the solvent was evaporated.
The residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 97 : 3) to give (2-bromo-4-isopropyl-phenyl)-ethyl-
[7-(2-methoxy-ethyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]- amine (0.46 g).
Example 1
Figure imgf000022_0001
Synthesis of (2-bromo-4-isopropyl-phenyl)- [7-(2-methoxy-ethyl)-4- methyl-7H-pyrrolo [2,3 -d]pyrimidin-2-yl]-amine (1-010) A mixture of (2-bromo-4-isopropyl-phenyl)-[7-(2-methoxy-ethyl)-4- methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-2-yl]-amine (1.7 g) and manganese(IN) oxide (1.5 g) in dioxane (25 ml) was stirred and refluxed for 4 h. The reaction mixture was cooled and filtered over decalite. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 99 : 1) to give (2-bromo-4- isopropyl-phenyl)-[7-(2-methoxy-ethyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2- yl]-amine (0.31 g). Example 2
Figure imgf000023_0001
Synthesis of (2-bromo-4-isopropyl-phenyl)-ethyl-[7-(l -ethyl-propyl)-4- memyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine (1-003) A mixture of (2-bromo-4-isopropyl-phenyl)-ethyl-[7-(l -ethyl-propyl)-4- methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine (0.4 g) and manganese(IN) oxide (0.4 g) in dioxane (10 ml) was stirred and refluxed for 3 h. The reaction mixture was cooled and filtered over decalite. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 99 : 1) to give (2-bromo-4- isopropyl-phenyl)-ethyl-[7-(l -ethyl-propyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin- 2-yl]-amine (0.37 g).
Example 3
Figure imgf000023_0002
Synthesis of (2 -bromo-4-isopropyl-phenyl)-ethyl-[7-(2-methoxy-ethyl)-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine (1-002) A mixture of (2-bromo-4-isopropyl-phenyl)- [7-(2-methoxy-ethyl)-4- methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-amine (0.9 g), iodoethane (0.4 g) and sodium hydride (0.4 g) in tetrahydrofuran (20 ml) was stirred at 60°C for 4 h.
Ethyl acetate (50 ml) and a solution of sodium hydroxide 0.5M (50 ml) were added.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 98 : 2) to give (2-bromo-4-isopropyl-phenyl)-ethyl-
[7-(2-methoxy-ethyl)-4-methyl-7H-pyrrolo[2,3 -d]pyrimidin-2-yl] -amine (0.32 g) .
Example 4
Figure imgf000024_0001
Synthesis of 7-(l -ethyl-propyl)-4-methyl-2-(2,4,6-trimethyl- phenylamino)-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione (4-002)
(Step 1) is analogous to (Reference example 1, step 1).
(Step 2) A mixture of N-(2,4,6-trimethyl-phenyl)-guanidine hydrochloride (14.8 g), ethyl acetoacetate (39 g) and potassium carbonate (14 g) in ethanol (300 ml) was stirred and refluxed for 16 h. The solvent was evaporated and the residue purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 98 : 2). The product was crystallized from hexane, filtered and dried to provide 6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrimidine-
4-ol (15 g).
(Step 3) A mixture of 6-methyl-2-(2,4,6-trimethyl-phenylamino)- pyrimidine-4-ol (15 g) and phosphorus oxychloride (200 ml) was stirred and refluxed for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. Water was added and the mixture was alkalified with potassium carbonate. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by a silica gel column chromatography (eluent: dichloromethane = 100) to give (4-chloro-6-methyl-pyrimidine-2-yl)-(2,4,6-trimethyl-phenyl)-amine (llg).
(Step 4) A mixture of (4-chloro-6-methyl-pyrimidine-2-yl)-(2,4,6- trimethyl-phenyl)-amine (7.5 g), 3-ethyl-propylamine (3.5 g) and potassium carbonate (3.5 g) in acetonitrile was stirred at 125°C for 2 days. The solvent was evaporated and the residue was dissolved in water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (eluent: dichloromethane/7M ammonia in methanol = 98 : 2). The product was crystallized from isopropyl ether, filtered and dried to give N -(l-ethyl-propyl)-6-methyl-N -(2,4,6-trimethyl-ρhenyl)- pyrimidine-2,4-diamine (3-1 g).
(Step 5) To a solution of N4-(l-ethyl-propyl)-6-methyl-N2-(2,4,6- trimethyl-phenyl)-pyrimidine-2,4-diamine (3.1 g) in methanol (30 ml) at room temperature was added dropwise a 1M solution of iodine monochloride in dichloromethane (10 ml). The reaction mixture was stirred for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 98 : 2), crystallized from isopropyl ether, filtered and dried to provide N4-(l-ethyl-propyl)-5-iodo-6- methyl-N -(2,4,6-trimethyl-phenyl)-pyrimidine-2,4-diamine (2.6 g).
(Step 6) A mixture of N4-(l-ethyl-propyl)-5-iodo-6-methyl-N2-(2,4,6- trimethyl-phenyl)-pyrimidine-2,4-diamine (0.5 g), palladium(II) acetate (0.02 g), l,3-bis(diphenylphosphino)propane (0.08 g) and triethylamine (1 g) in tetrahydrofuran (50 ml) was stirred under 60 atmosphere CO pressure, at 75°C for 16 h. The solvent was evaporated and the residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 95 : 5) to give 7-(l- ethyl-propyl)-4-methyl-2-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3- d]pyrimidine-5,6-dione (0.12 g).
Example 5
Figure imgf000026_0001
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-7H-pyrrolo [2,3 -d]pyrimidine-5 ,6-dione (4-001 )
(Stepl and step 2) A mixture of ethyl-(2,4,6-trimethyl-phenyl)-amine (50 g) and cyanamide (21 g) in N-methylpyrrolidone (50 ml) was stirred at 150°C for 1 h. The reaction mixture was cooled to room temperature. Ethanol (500 ml), ethyl acetoacetate (65 g) and potassium carbonate (37 g) were added and the mixture was stirred and refluxed for 16 h. The solvent was evaporated and the residue was dissolved in water and extracted with ethyl acetate (2x). The combined organic layers were washed with water, dried over magneshun sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether, filtered and dried to provide 2-[ethyl-(2,4,6-trimethyl-phenyl)- amino]-6-methyl-pyrimidin-4-ol (29 g). The filtrate was concentrated under reduced pressure and purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give a second fraction of the product (7.7 g). (Step 3) A mixture of 2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-6-methyl- pyrimidin-4-ol (2.7 g) and N,N-diisopropylethylamine (1.6 g) in dichloromethane (100 ml) was stirred under nitrogen at 0°C. Triflic anhydride (3.4 g) was added dropwise. The reaction mixture was brought to room temperature and stirred for 1 h. Water was added and the organic layer was dried over magnesium sulfate, filtered and evaporated to give trifluoro-methanesulfonic acid 2-[ethyl-(2,4,6- trimethyl-phenyl)-amino]-6-methyl-pyrimidin-4-yl ester (4.1 g).
(Step 4) is analogous to (example 4, step 4).
(Step 5) is analogous to (example 4, step 5).
(Step 6) A mixture ofN2-ethyl-N4-(l-ethyl-propyl)-5-iodo-6-methyl-N2- (2,4,6-trimemyl-phenyl)-pyrimidine-2,4-diamine (0.5 g), palladium(II) acetate (0.02 g), l,3-bis(diphenylphosphino)propane (0.08 g) and diethylamine (25 ml) in tetrahydrofuran (50 ml) was stirred under 60 atmosphere CO pressure, at 75°C for 16 h. The solvent was evaporated and the residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 95 : 5) to give N,N- diethyl-2-{4-(l-ethyl-propylarmno)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-6- methyl-pyrimidin-5-yl}-2-oxo-acetamide (0.2 g).
(Step 7) N,N-diethyl-2-{4-(l-ethyl-propylamino)-2-[ethyl-(2,4,6- frimethyl-phenyl)-ammo]-6-methyl-pyrimidin-5-yl}-2-oxo-acetamide (0.05 g) and a solution of 6M hydrochloric acid in 2-propanol (1 ml) were stirred at 150°C for
30 minutes. The product was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 7-(l-ethyl- propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-methyl-7H-pyrrolo[2,3- d]pyrimidine-5,6-dione (0.006 g).
Example 6
Figure imgf000028_0001
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6-one (3-001)
(Step 1 and step 2) A mixture of ethyl-(2,4,6-trimethyl-phenyl)-amine (50 g) and cyanamide (21 g) in N-methylpyrrolidone (50 ml) was stirred at 150°C for 1 h. The reaction mixture was cooled to room temperature. Ethanol (1000 ml), diethyl acetylsuccinate (65 g) and potassium carbonate (74 g) were added and the mixture was stirred and refluxed for 16 h. Diethyl acetylsuccinate (65 g) was added a second time and the reaction mixture was stirred and refluxed for 24 h. A solution of 6M hydrochloric acid in 2-propanol was added and the mixture was stirred at 60°C for 24 h. The solvent was evaporated and water was added. The mixture was alkalified with a solution of potassium carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 95 : 5) to provide {2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-hydroxy-6-methyl-pyrimidin-5-yl}- acetic acid ethyl ester (78 g).
(Step 3) is analogous to (example 5, step 3)
(Step 4) A mixture of {2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4- methyl-6-trifluoromethanesulfonyloxy-pyrimidin-5-yl} -acetic acid ethyl ester (10 g), 1-ethyl-propylamine (4 g) and potassium carbonate (4 g) in acetonitrile (100 ml) was stirred at 125°C for 72 h. The solvent was evaporated and the residue was dissolved in water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to give 7-(l-ethyl-propyl)-2-[ethyl- (2,4,6-trimethyl-phenyl)-amino]-4-methyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6- one (8 g).
Example 7
Figure imgf000029_0001
Synthesis of 5-ethyl-7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)- amino] -5-hydroxy-4-methyl-5 ,7-dihydro-pyrrolo [2,3 -d]pyrimidin-6-one (3 -020) (Step 1) A mixture of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.6 g) and manganese(IN) oxide (0.5 g) in dichloromethane (2 ml) was stirred at room temperature for 16 h. The reaction mixture was filtered over decalite and the filtrate was concentrated under reduced pressure to give 7-(l-ethyl-propyl)-2- [ethyl-(2,4,6-frimethyl-phenyl)-amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6- dione (0.1 g).
(Step 2) A solution of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione (0.15 g) in tetrahydrofuran (1.5 ml) under nitrogen was stirred at -20°C. 1 M ethylmagnesium bromide in tetrahydrofuran (0.5 ml) was added. The reaction mixture was brought to room temperature and stirred for 1 h. A solution of ammonium chloride (1 ml) was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 5- ethyl-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-5-hydroxy-4- methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.034 g).
Example 8
Figure imgf000030_0001
Synthesis of ethyl-[7-(l -ethyl-propyl)-4,5-dimethyl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl-ρhenyl)-amine (2-001) and ethyl-[7- (l-ethyl-proρyl)-4,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]- (2,4,6-trimethyl- phenyl)-amine (1-015) 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-5-hydroxy- 4,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.8 g), prepared in the similar method as example 7, in tetrahydrofuran (20 ml) was stirred at 0°C under nitrogen. Borane-tetrahydrofuran complex, 1M solution in tetrahydrofuran (14 ml) was added and the reaction mixture was stirred for 16 h. The solvent was evaporated, water and potassium carbonate were added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give ethyl-[7-(l-ethyl-propyl)-4,5-dimethyl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-yl]- (2,4,6-trimethyl-phenyl)-amine (0.035 g) and ethyl- [7-(l-ethyl-propyl)-4,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]- (2,4,6- trimethyl-phenyl)-amine (0.011 g).
Example 9
Figure imgf000031_0001
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione 5-oxime (6-001) A solution of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)- amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1.3 g) in acetic acid (20 ml) was stirred at room temperature. Sodium nitrite (0.5 g) was added and 3 drops of water were added. The reaction mixture was stirred for 1 h, poured out into water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to provide 7-(l-ethyl-propyl)-2-[ethyl- (2,4,6-trimethyl-phenyl)-amino]-4-methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione 5-oxime (1.4 g) as a mixture of the geometric isomers.
Example 10
Figure imgf000031_0002
Synthesis of N-{7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)- amino]-4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}- propionamide (3-005)
(Step 1 ) 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4- methyl-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione 5-oxime (0.5 g) was hydrogenated with Raney Nickel in tetrahydrofuran (50 ml). The reaction mixture was filtered over decalite and the filtrate was concentrated under reduced pressure to give 5- amino-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-methyl-5,7- dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.5 g). (Step 2) A mixture of 5-amino-7-(l -ethyl-propyl)-2-[ethyl-(2,4,6- trimemyl-phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g), propionyl chloride (0.055 g) and triethylamine (0.1 g) in dichloromethane (2 ml) was stirred at room temperature for 16 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give N-{7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}- propionamide (0.034 g).
Example 11
Figure imgf000032_0001
Synthesis of 1 -{7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)- amino]-4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-3- isopropyl-urea (3-007) A mixture of 5-amino-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g), 2- isocyanato-propane (0.042 g), dimethylaminopropylamine (cat.) in dioxane (3 ml) was stirred at room temperature for 16 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give l-{7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-3- isopropyl-urea (0.015 g).
Example 12
Figure imgf000033_0001
Synthesis of 5-dimethylamino-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6- trimethyl-phenyl)-amino] -4-methyl-5 ,7-dihydro-pyrrolo [2,3 -d]pyrimidin-6-one (3 - 010) A mixture of 5-amino-7-(l-ethyl-proρyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.1 g), paraformaldehyde (0.1 g), palladium on activated carbon, 10 % (0.1 g) and thiophene 4% in diisopropylether (0.1 ml) in methanol (40 ml) was hydrogenated at 50°C. The reaction mixture was filtered over decalite and the filtrate was concentrated under reduced pressure. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 5-dimethylamino-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6- trimethyl-phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.013 g).
Example 13
Figure imgf000033_0002
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-
4,5,5-trimethyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6-one (3-009) A mixture of 7-(l -ethyl -propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-
4-methyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g) and sodium hydride 50% (0.04 g) in tetrahydrofuran was stirred at room temperature for 15 minutes.
Iodomethane (0.12 g) was added and the reaction mixture was stirred for 1 h.
Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 7-(l-ethyl- propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4,5,5-trimethyl-5,7dihydro- pyrrolo[2,3-d]pyrimidin-6-one (0.004 g).
Example 14
Figure imgf000034_0001
Synthesis of 5,5-diethyl-7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (3-018) A mixture of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.015 g) and sodium bis(trimethylsilyl)amide in dioxane (2 ml) was stirred at room temperature for 15 minutes under nitrogen. Bromoethane (0.087 g) was added and the reaction mixture was stirred at 60°C for 1 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 5,5-diethyl-7-(l-ethyl-propyl)-2-[ethyl-(2,4,6- trimethyl-phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.018 g). Example 15
Figure imgf000035_0001
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 5-isobutylidene-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (5-001) A mixture of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g), isobutyraldehyde (0.057 g) and piperidine in dioxane (1.5 ml) was stirred at 65°C for 16 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6- trimethyl-phenyl)-amino]-5-isobutylidene-4-methyl-5,7-dihydro-pyrrolo[2,3- d]pyrimidin-6-one (0.071 g) as a mixture of the geometric isomers.
Example 16
Figure imgf000035_0002
Synthesis of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-carboxylic acid isopropylamide (3-022) A mixture of 7-(l -ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]- 4-methyl-5,7dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.15 g), 2-isocyanato propane (0.042 g) and sodium bis(trimethylsilyl)amide in dioxane (2 ml) was stirred at 85°C for 16 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give 7-(l-ethyl- propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-carboxylic acid isopropylamide (0.114 g).
Example 17
Figure imgf000036_0001
step 2
Figure imgf000036_0002
Synthesis of ethyl-[7-( 1 -ethyl-ρropyl)-4-methyl-7H-pyrrolo[2,3 - d]pyrimidin-2-yl]-(2,4,6-trimethyl-phenyl)-amine (1-008)
(Step 1) A solution of 7-(l-ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl- phenyl)-amino]-4-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (1 g) in tetrahydrofuran (20 ml) was stirred at 0°C under nitrogen. Borane- tetrahydrofuran complex, 1M solution in tetrahydrofuran (12.5 ml) was added dropwise and the reaction mixture was stirred for 2 h at room temperature. Methanol/acetic acid 1 : 1 was added and the solvent was evaporated. The residue was dissolved in water, alkalified with potassium carbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a mixture of ethyl- [7-(l -ethyl- propyl)-4-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl- phenyl)-amine (60%) and ethyl-[7-(l-ethyl-propyl)-4-methyl-7H-pyrrolo[2,3- d]pyrimidin-2-yl]-(2,4,6-trimethyl-phenyl)-amine (32 %) (1 g). The residue was used without further purification. (Step 2) A mixture of ethyl-[7-(l-ethyl-propyl)-4-methyl-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl-phenyl)-amine (60%) and ethyl-[7- (l-ethyl-propyl)-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl- phenyl)-amine (32 %) (1 g) and manganese(IN) oxide (5 g) in dichloromethane were stirred at room temperature for 76 h. The reaction mixture was filtered over decalite and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: dichloromethane/methanol = 98 : 2) to give ethyl- [7-( 1 -ethyl-propyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-2-yl]-(2,4,6-trimethyl-phenyl)-amine (0.119 g) and 7-(l- ethyl-propyl)-2-[ethyl-(2,4,6-trimethyl-phenyl)-amino]-4-methyl-7H-pyrrolo[2,3- d]pyrimidine-5,6-dione.
Example 18
Figure imgf000037_0001
Synthesis of [5-dimethylaminomethyl-7-(l-ethyl-propyl)-4-methyl-7H- pyrrolo[2,3-d]pyrimidin-2-yl]-ethyl-(2,4,6-trimethyl-phenyl)-amine (1-014) Formaldehyde, 37wt% solution (0.5 ml) was stirred at room temperature.
Dimethylamine in water was added and the reaction mixture was stirred for 15 minutes . Ethyl- [7-( 1 -ethyl-propyl)-4-methyl-7H-pyrrolo [2,3 -d]pyrimidin-2-yl] - (2,4,6-trimethyl-phenyl)-amine (0.05 g) in methanol (0.5 ml) was added and the reaction mixture was stirred at 60°C for 3 h. Water was added and the product was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a reversed phase column chromatography (eluent: ammonium acetate/acetonitrile) to give [5-dimethylaminomethyl-7-(l-ethyl-propyl)-4-methyl- 7H-pyrrolo[2,3-d]pyrimidin-2-yl]-ethyl-(2,4,6-trimethyl-phenyl)-amine (0.015 g). Tables 1-6 list the compounds obtained in Examples 1-20 and compounds obtained by the similar procedure as in Examples 1-20. Table l*1
Figure imgf000038_0001
Com. Ex. 10 RJ RJ R R1 MS R.T.
No. No. / Ar (min
Figure imgf000038_0002
1-002 >Me Et H H 7.3
Figure imgf000038_0003
Figure imgf000038_0004
1-006 „OMe Et H H .Cl El 6.0 378 (M+) Cl
Figure imgf000038_0005
1-008 17 Et H H 19.2
Figure imgf000038_0006
Figure imgf000038_0007
1-010 .OMe H H H 6.2
Figure imgf000039_0001
1-011 1 ^ Et H H Br ESI ! l .OMe U 481 (M++Na)
1-012 1 If ! H H H r-Cl ESI 8-3 T 383 (iv +l) Cl
1-013 1 sOUe H H H yCI El 5.2 \ 350 Qyf) Cl
1-014 18 10.2
Figure imgf000039_0002
Figure imgf000039_0003
*1: Com. No. = compound number, Ex. No. = example number, MS = mass spectrum, ESI = elecfrospray ionization, El = electron ionization, Me = methyl, Et = ethyl, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M amumonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
Figure imgf000040_0001
*1: Com. No. = compound number, Ex. No. = example number, Me = methyl, Et = ethyl, MS = mass spectrum, ESI = elecfrospray ionization, El = electron ionization, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm x 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M ammonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
Table 3*1
Figure imgf000040_0002
Com. Ex. R3 R6 R7 MS R.T. No. No. M1 Ar (min
3-001 6 Et H H El 9.9 JC 380 M*) Me
3-002 *2 10 l) 4.6
Figure imgf000040_0003
-003 10 Et l) 4.4
-004 10 / Et l) 4.3
Figure imgf000041_0001
-005*2 10 / Et E o H l) 4.3
Figure imgf000041_0002
-006*2 10 Et l) 4.2
Figure imgf000041_0003
Figure imgf000041_0004
-009 13 M Et Me Me El 17.1 408 (M++l) Me
Figure imgf000041_0005
-013 7 ,. Et OH e VMe ESI 8.5 H^ \J 445 (M÷+Na) Me
Figure imgf000041_0006
Figure imgf000042_0001
-017 7 Et OH 9.3
Figure imgf000042_0003
-021 14 t -CH2CH2- 21.6
Figure imgf000042_0004
-022 16 , Et M 5.8
Figure imgf000042_0005
* 1 : Com. No. = compound number, Ex. No. = example number, Me = methyl, Et = ethyl, MS = mass spectrum, ESI = elecfrospray ionization, El = electron ionization, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M ammonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
*2: HPLC conditions: X Terra MS C18 2.5μm, 4.6 mm x 50 mm; Waters; Flow rate: 1.2 ml/min; mobile phase: A = 0.5 % ammonium acetate in H2O/CH3CN (90/10); B = methanol; C = acetonitrile; gradient: start: 90% A + 10% B; end: 10% A + 90% C Table 4*1
Figure imgf000043_0001
Com. Ex. R3 MS R.T. No. No. Ar (min)
4-001 5 Et ESI Me vMe 7.9, 9.6 . 417 (M++Na) Me
4-002 4 H Me-γ4γMe ESI 4.1 . 389 (M++Na) Me
*1 : Com. No. = compound number, Ex. No. = example number, Me = methyl, Et = ethyl, MS = mass spectrum, ESI = elecfrospray ionization, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm x 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M ammonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
Table 5*1
Figure imgf000044_0001
Com. Ex. M1 R3 MS R.T. No. No. \ Ar (min)
5-001 15 Et 31.8, 42.2
Figure imgf000044_0002
5-002 15 Et Me- .Me ESI 21.6, 38.1 481 (M++Na) Me
5-003 15 23.5, 26.2
Figure imgf000044_0003
5-004 15 . Et Me- .Me ESI 13.1, 16.7 492 (M++Na) Me
Figure imgf000044_0004
*1: Com. No. = compound number, Ex. No. = example number, Me = methyl, Et = ethyl, MS = mass spectrum, ESI = elecfrospray ionization, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm x 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M ammonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid. Table 6*1
Figure imgf000045_0001
Com. Ex.
No. No. M' R3 R8 J S R.T. Ar (min)
6-001 9
Figure imgf000045_0002
*1: Com. No. = compoimd number, Ex. No. = example number, Me = methyl, Et = ethyl, MS = mass spectrum, ESI = elecfrospray ionization, R.T. = retention time on HPLC, HPLC conditions: Capcell Pak UG120, 4.6 mm x 150 mm, Shiseido; Flow rate: 1.0 ml/min; mobile phase: acetonitrile / 0.05M ammonium acetate aqueous solution (80 : 20), pH of the solvent was adjusted to 7.4 with aqueous ammonia or acetic acid.
Test Example [CRF receptor binding test] Monkey amygdala membranes were used as a receptor preparation. 125I-CRF was used as 125I-labeled ligand. Binding reaction using the I-labeled ligand was carried out by the following method described in The Journal of Neuroscience, 7, 88 (1987). Preparation of receptor membranes: Monkey amygdala was homogenized in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl2, 2 mM EDTA and centrifuged at 48,000 x g for 20 min, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in 50 mM Tris-HCl buffer (pH 7.0) containing 10 mM MgCl2, 2 mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation. CRF receptor binding test: The membrane preparation (0.3 mg protein/ml), I-CRF (0.2 nM) and a test drug were reacted at 25°C for 2 h. After completion of the reaction, the reaction mixture was filtered by suction through a glass filter (GF/C) treated with
0.3% polyethylene imine, and the glass filter was washed three times with phosphate-buffered saline containing 0.01% Triton X-100. After the washing, the radioactivity of the filter paper was measured in a gamma counter. i oc The amount of I-CRF bound when the reaction was carried out in the presence of 1 μM CRF was taken as the degree of nonspecific binding of 125I-CRF, and the difference between the total degree of 125I-CRF binding and the degree of nonspecific 125I-CRF binding was taken as the degree of specific 125I-CRF binding. An inhibition curve was obtained by reacting a definite concentration (0.2 nM) of 125I-CRF with various concentrations of each test drug under the conditions described above. A concentration of the test drug at which binding of 125I-CRF is inhibited by 50% (IC50) was determined from the inhibition curve. As a result, it was found that compounds 1-003, 1-004, 1-008 and 1-011 can be exemplified as typical compounds having an IC50 value of 200 nM or less.
ADVANTAGEOUS EFFECT OF THE INVENTION According to the present invention, compounds having a high affinity for CRF receptors have been provided. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastro-intesinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.

Claims

1. A pyrrolopyrimidine derivative represented by the following formula [I] :
Figure imgf000047_0001
(wherein R1 is Cι- alkyl, C -9alkenyl, C - cycloalkyl, C3-7cycloalkyl-Cι-9alkyl, di(C3-7cycloalkyl)-C1-9alkyl, -βalkoxy-Ct-galkyl, di(Cι-6alkoxy)-Cι-9alkyl, hydroxy-C1-9alkyl, cyano-C^alkyl, carbamoyl-Ci-ξialkyl, di(C1-6alkyl)amino-Cι. alkyl, aryl, heteroaryl, aryl-C^alkyl or heteroaryl-Cι_9alkyl, in which said aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of Cι-6alkyl, Cι_6alkoxy, Cι-6alkylthio, C\. 6alkylsulfonyl, aminosulfonyl, mono(C1-6alkyl)aminosulfonyl, di(Cι- 6alkyl)aminosulfonyl, halogen, Ci-βhaloalkyl, cyano, nitro, -NRlaRlb, where Rla and Rl are each independently selected from the group consisting of hydrogen, . 6alkyl and Ci-6alkylcarbonyl; R2 is Cι-6alkyl or -βhaloalkyl; R3 is hydrogen, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3- cycloalkyl-Cι-6alkyl, benzyl; the bond between X and Y is a single bond or a double bond; wherein (1 ) when the bond between X and Y is a single bond, X is CR4R5 or OO; Y is CR6R7, C=O, C=N-ORs or C=CH-R9; (2) when the bond between X and Y is a double bond, X is CR10; Y is CR11; R4 and R5 are the same or different, and independently are hydrogen or Cι-6alkyl; R6 and R7 are the same or different, and independently are hydrogen, - 6alkyl, C3-6cycloalkyl, C2.6alkenyl, C2.6alkynyl, hydroxy, C^alkylamino, di(Cι- 6alkyl)amino, di(Cι_6alkyl)amino-Cι-6alkyl, Cι-6alkylcarbonylamino, C3- 6cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, Ci-
6alkylaminocarbonyl or Cι-6alkylaminocarbonylamino; or
Figure imgf000047_0002
are taken together to form C3-6cycloalkyl, with the proviso that not both of CR4R5 and CR6R7 are CH ; R8 is hydrogen or Cι-6alkyl; R9 is Ci-βalkyl, C3-6cycloalkyl, aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of halogen or Cι-6alkyl; R10 is hydrogen or Cι-6alkyl; R11 is hydrogen, Cι-6alkyl or di(Cι_ alkyl)amino-C1-6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, -βalkyl, C3- cycloalkyl, C -6alkenyl, C2. 6alkynyl, Cι-6alkoxy- Cι-6alkylthio, Ct-δalkylsulfonyl, aminosulfonyl, mono(C1. 6alkyl)aminosulfonyl, di(C1-6alkyl)aminosulfonyl, cyano, Cι-6haloalkyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -N(R12)R13, wherein R12 and R13 are the same or different, and independently are hydrogen or Cι-6alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
2. The pyrrolopyrimidine derivative according to claim 1 represented by the following formula [II]:
Figure imgf000048_0001
(wherein R is Cι-9alkyl, C2-9alkenyl, C3-7cycloalkyl,
Figure imgf000048_0002
di(C3. cycloalkyl)-C i _9alkyl, Ci -6alkoxy-C i -9alkyl, di(C \ -6alkoxy)-C i _ alkyl, hydroxy-Cι- alkyl, cyano-Cι-9alkyl, carbamoyl-Ci-galkyl, di(C1-6alkyl)amino-Cι- 9alkyl, aryl, heteroaryl, aryl- -galkyl or heteroaryl-Cι-9alkyl, in which said aryl and heteroaryl optionally substituted with one to three substituents independently selected from the group consisting of -ealkyl, Cι-6alkoxy, Cι-6alkylthio, Ci- 6alkylsulfonyl, aminosulfonyl, mono(Cι-6alkyl)aminosulfonyl, di(Cι- 6alkyl)aminosulfonyl, halogen, Cι-6haloalkyl, cyano, nitro, -NRlaRlb, where Rla and R1 are each independently selected from the group consisting of hydrogen, Ci. 6alkyl and 0-6alkylcarbonyl; R2 is Ci-ealkyl or -βhaloalkyl; R3 is hydrogen, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C - 7cycloalkyl-C1-6alkyl, benzyl; R10 is hydrogen or Ci-όalkyl; Ru is hydrogen, Cι-6alkyl or di(C1-6alkyl)amino-Cι-6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C^a-kyl, C3-7cycloalkyl, C -6alkenyl, C2- 6alkynyl, Cι-6alkoxy, d-βalkylthio, Ci-ealkylsulfonyl, aminosulfonyl, mono^- 6alkyl)aminosulfonyl, di(Cι-6alkyl)aminosulfonyl, cyano, haloCι-6alkyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -N(R12)R13, wherein R12 and R are the same or different, and independently are hydrogen or Cι-6alkyl), individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
3. The pyrrolopyrimidine derivative according to claim 2 represented by the formula [II], wherein R1 is Cι- alkyl, C3.7cycloalkyl,
Figure imgf000049_0001
di(C3- 7cycloalkyl)-C!-6alkyl, Cι-6alkoxy-Cι_6alkyl, di(C1.6alkoxy)-Cι-6alkyl, hydroxy-Ci- 6alkyl, cyano-Cι-6alkyl-, carbamoyl-Cι-6alkyl, di(C1-6alkyl)amino-C1-6alkyl, aryl-Ci- 6alkyl or heteroaryl-Cι_6alkyl; R2 is Cι-6alkyl; R3 is hydrogen or C^a-kyl; R10 is hydrogen or Cι_6alkyl; R11 is hydrogen, Cι-6alkyl or di(C1.6alkyl)aminoC1-6alkyl; Ar is aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Cι-6alkyl, C3.7cycloalkyl, C -6alkenyl, C -6alkynyl, - 6alkoxy, C!-6alkylthio, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy and -N(R )R , wherein R and R are the same or different, and independently are hydrogen or -βalkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
4. The pyrrolopyrimidine derivative according to claim 2 represented by the formula [II], wherein R-1 is Cι-9alkyl, C -7cycloalkyl, C3-7cycloalkyl-Cι-6alkyl, di(C3-
Figure imgf000049_0002
Cι-6alkoxy-Cι-6alkyl, di(Cι-6alkoxy)-C1-6alkyl or aryl-Ci- βalkyl; R2 is d-6alkyl; R3 is hydrogen or Cι_6alkyl; R10 is hydrogen or Chalky!; R11 is hydrogen or Cι-6alkyl; Ar is phenyl which phenyl is unsubstituted or substituted with one to three substituents, which are the same or different, selected from the group consisting of halogen, Cι-3alkyl, C^alkoxy, Cι-3alkylthio, trifluoromethyl and -N(R12)R13, wherein R12 and R13 are the same or different, and independently are hydrogen or Cι-3alkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
5. The pyrrolopyrimidine derivative according to claim 2 represented by the formula [II], wherein R1 is Cι-9alkyl, C3-7cycloalkyl, C3-7cycloalkyl-Cι-6alkyl, di(C3- 7cycloalkyl)-Cι-6alkyl- Cι_6alkoxy-Cι-6alkyl, di(Cι-6alkoxy)-C1-6alkyl or aryl-Cϊ- 6alkyl; R2 is Cι- alkyl; R3 is Chalky!; R10 is hydrogen; R11 is hydrogen; Ar is phenyl which phenyl is substituted with 2 or 3 substituents, which are the same or different, selected from the group consisting of halogen or Ci-3alkyl, individual isomers thereof or racemic or non-racemic mixtures of isomers thereof, or pharmaceutically acceptable salts and hydrates thereof.
6. An antagonist for CRF receptors, comprising a pyrrolopyrimidine derivative, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claims 1 to 5, as an active ingredient.
7. Use of a pyrrolopyrimidine derivative, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claim 1 to 5, for the manufacture of an antagonist for CRF receptors.
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US7557111B2 (en) 2004-01-06 2009-07-07 Taisho Pharmaceutical Co., Ltd. Substituted thieno[3,2-d]pyrimidines as CRF receptor antagonists
EP2273882A1 (en) * 2008-05-13 2011-01-19 Poniard Pharmaceuticals, Inc. Bioactive compounds for treatment of cancer and neurodegenerative diseases
US7951811B2 (en) 2004-06-25 2011-05-31 Taisho Pharmaceutical Co., Ltd. Pyrrolo[2,3-D]pyrimidine derivatives substituted with a cyclic amino group
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US8420657B2 (en) 2008-02-06 2013-04-16 Novartis Ag Pyrrolo[2,3-D]pyrimidines and use thereof as tyrosine kinase inhibitors
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US8957074B2 (en) 2010-02-19 2015-02-17 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
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US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
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US8324225B2 (en) 2006-05-26 2012-12-04 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8420657B2 (en) 2008-02-06 2013-04-16 Novartis Ag Pyrrolo[2,3-D]pyrimidines and use thereof as tyrosine kinase inhibitors
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US8685980B2 (en) 2008-08-22 2014-04-01 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US9416136B2 (en) 2008-08-22 2016-08-16 Novartis Ag Pyrrolopyrimidine compounds and their uses
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US8957074B2 (en) 2010-02-19 2015-02-17 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
US9309252B2 (en) 2010-02-19 2016-04-12 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
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