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  • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems

Definitions

• the present invention relates to novel condensed imidazole derivatives useful as dipeptidyl peptidase-IV (DPPIV) inhibitors and uses thereof.
• DPPIV dipeptidyl peptidase-IV
• Glucose-dependent, insulin secretion-stimulating hormones known as incretins (GLP-1: Glucagon-Like Peptide-1 and GIP: Glucose-dependent Insulinotropic Polypeptide) secreted in the digestive tract following meals are rapidly hydrolyzed and inactivated by DPPIV.
• DPPIV Glucose-dependent Insulinotropic Polypeptide
• GLP-1 and GIP Glucose-dependent Insulinotropic Polypeptide
• GLP-1 is known to be involved in the suppression of appetite and food intake.
• GLP-l has also been reported to have the effect of protecting the ⁇ cells of the pancreas by enhancing ⁇ cell differentiation and proliferation.
• a DPPIV inhibitor can be a useful therapeutic or preventive agent for diseases with which GLP-1 and/or GIP are associated, such as obesity and diabetes mellitus.
• a DPPIV inhibitor can be a therapeutic agent for diseases such as:
• DPPIV inhibitors are disclosed in the Publication of US patent No. 2002/0161001; International Publication WO 03/004496; and Publication of US patent No.2002/0198205. However, there is no known DPPIV inhibitor having a hypoxanthine or imidazopyridazinone structure backbone.
• an objective of the present invention is to provide compounds having DPPIV-inhibiting activity, which can be used as preventive, therapeutic, or alleviating agents for diabetes mellitus or such diseases.
• the present inventors conducted extensive studies in view of the above background. As a result, they succeeded in synthesizing novel condensed imidazole derivatives, including hypoxanthine and imidazopyridazinone derivatives. To complete the present invention they also found that these compounds had excellent DPPIV-inhibiting activity. Specifically, the present invention comprises:
• T 1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents;
• X represents a C 1-6 alkyl group which may have one or more substituents, a CC 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group which may have one or more substituents, a C 6-10 aryl group which may have one or more substituents, a 5 to 10-membered heteroaryl group which may have one or more substituents, a C 6-10 aryl C 1-6 alkyl group which may have one or more substituents, or a 5 to 10-membered heteroaryl C 1-6 alkyl group which may have one or more substituents;
• Z 1 and Z 2 each independently represent a nitrogen atom or a group represented by the formula —CR 2 ⁇ ;
• R 1 and R 2 each independently represent a group according to the formula -A 0 -A 1 -A 2
• R 1 is a hydrogen atom; Z 1 is a nitrogen atom; and Z 2 is —CH ⁇ ; and [2] Z 1 is a nitrogen atom; and Z 2 is —C(OH) ⁇ ;
• n and m each independently represent 0 or 1) which may have one or more substituents
• a pyrrolidin-1-yl group which may have one or more substituents
• n and m each independently represent 0 or 1
• a pyrrolidin-1-yl group which may have an amino group
• the phenyl group that may have one or more substituents is a phenyl group which may have at the 2-position a substituent selected from the group consisting of a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C 2-7 alkoxycarbonyl group;
• Z 1 is a nitrogen atom
• Z 2 is a group represented by the formula —CR 2 ⁇ (where R is as defined above in [1]);
• Z 2 is a nitrogen atom
• Z 1 is a group represented by the formula —CR 2 ⁇ (where R is as defined above in [1]);
• R 1 represents a hydrogen atom, or a group represented by the formula -A 10 -A 11 -A 12
• R 1 is a hydrogen atom, a C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C 6-10 aryl C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below:
• R 2 is a hydrogen atom, a cyano group, or a group represented by the formula -A 21 -A 22
• R 2 represents a hydrogen atom, a cyano group, a carboxy group, a C 2-7 alkoxycarbonyl group, a C 1-6 alkyl group, a group represented by the formula —CONR D7 R D8 (where R D7 and R D8 each independently represent a hydrogen atom or a C 1-6 alkyl group), or a group represented by the formula -A 23 -A 24
• R2 represents a hydrogen atom, a cyano group, a C 1-6 alkoxy group, or a group represented by the formula -A 25 -A 26
• R 2 is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, or a group represented by the following formula:
• a 27 represents an oxygen atom, a sulfur atom, or —NH—
• a 28 and A 29 each independently represent a hydrogen atom or a C 1-6 alkyl group
• a pharmaceutical agent comprising a compound of any one of [1] to [24];
• a pharmaceutical composition comprising a compound of any one of [1] to [24] and an adjuvant useful for formulation;
• a preventive or a therapeutic agent for diabetes mellitus which comprises a compound of any one of [1] to [24];
• a preventive or therapeutic agent which comprises a compound of any one of [1] to [24], for diabetes mellitus, obesity, hyperlipidemia, AIDS, osteoporosis, a gastrointestinal disorder, angiogenesis, infertility, an inflammatory disease, an allergic disease, or cancer;
• an immunomodulator a hormone modulator, or an anti-rheumatic drug, which comprises a compound of any one of [1] to [24];
• a therapeutic or preventive method for a disease in which the inhibition of dipeptidyl peptidase IV is effective comprises administering to a patient a compound of any one of [1] to [24], or a salt or hydrate thereof, in a pharmaceutically effective amount;
• T 0
• R 1 , R 2 , T 1 , Z 1 and Z 2 are, as defined above in [1];
• R 1 and R 2 independently represent a hydrogen atom, a 4- to 8-membered heterocyclic group which may have one or more substituents, or a group represented by the formula -A 0 -A 1 -A 2
• R 1 and R 2 are hydrogen atoms, and (ii) R 2 is a hydroxyl group.
• a structural formula of a compound sometimes represents a certain isomer for convenience of description.
• compounds of the present invention may include all possible isomers, such as structurally possible geometric isomers, optical isomers generated due to the presence of asymmetric carbons, stereoisomers, tautomers, and mixtures of isomers, and are not limited to formulae being used for the convenience of description, and may be either of two isomers or a mixture of both isomers.
• compounds of the present invention may be either optically active compounds having an asymmetric carbon atom in their molecules or their racemates, and are not restricted to either of them but include both.
• compounds of the present invention may exhibit crystalline polymorphism, but likewise are not restricted to any one of these but may be in any one of these crystal forms or exist as a mixture of two or more crystal forms.
• Compounds of the present invention also include both anhydrous and hydrated forms. Substances produced through in vivo metabolism of compounds of the invention are also within the scope of claims.
• C 1-6 alkyl group refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, which is a monovalent group obtained by removal of any one of the hydrogen atoms from an aliphatic hydrocarbon containing 1 to 6 carbons, and specifically, includes, for example, a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-butyl group, a 2-butyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-1-butyl group, a 3-methyl-1-butyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 2,2-dimethyl-1-propyl group, a 1-hexyl group, a 2-hexyl group,
• C 2-6 alkenyl group refers to a linear or branched alkenyl group containing 2 to 6 carbons, and specifically includes, for example, a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a pentenyl group, and a hexenyl group.
• C 2-6 alkynyl group refers to a linear or branched alkynyl group containing 2 to 6 carbons, and specifically includes, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a butynyl group, a pentynyl group, and a hexynyl group.
• C 3-8 cycloalkyl group refers to a cyclic aliphatic hydrocarbon group containing 3 to 8 carbon atoms, and specifically includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
• C 1-6 alkylene group refers to a divalent group obtained by removal of another arbitrary hydrogen atom from a “C 1-6 alkyl group” defined above, and specifically includes, for example, a methylene group, a 1,2-ethylene group, a 1,1-ethylene group, a 1,3-propylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group.
• C 3-8 cycloalkylene group refers to a divalent group obtained by removal of another arbitrary hydrogen atom from a “C 3-8 cycloalkyl group” defined above.
• C 1-6 alkoxy group refers to an oxy group linked to a “C 1-6 alkyl group” defined above, and specifically includes, for example, a methoxy group, an ethoxy group, a 1-propyloxy group, a 2-propyloxy group, a 2-methyl-1-propyloxy group, a 2-methyl-2-propyloxy group, a 1-butyloxy group, a 2-butyloxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-1-butyloxy group, a 3-methyl-1-butyloxy group, a 2-methyl-2-butyloxy group, a 3-methyl-2-butyloxy group, a 2,2-dimethyl-1-propyloxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, a 2-methyl-1-p
• C 1-6 alkylthio group refers to a thio group linked to a “C 1-6 alkyl group” defined above, and specifically includes, for example, a methylthio group, an ethylthio group, a 1-propylthio group, a 2-propylthio group, a butylthio group, and a pentylthio group.
• C 2-7 alkoxycarbonyl group refers to a carbonyl group linked to a “C 1-6 alkoxy group” defined above, and specifically includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a 1-propyloxycarbonyl group, and a 2-propyloxycarbonyl group.
• C 2-7 alkylcarbonyl group refers to a carbonyl group linked to a “C 1-6 alkyl group” defined above, and specifically includes, for example, a methylcarbonyl group, an ethylcarbonyl group, a 1-propylcarbonyl group, and a 2-propylcarbonyl group.
• halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
• C 6-10 aryl group refers to an aromatic cyclic hydrocarbon group containing 6 to 10 carbon atoms, and specifically includes, for example, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
• heteroatom refers to a sulfur atom, an oxygen atom, or a nitrogen atom.
• the phrase “5 to 10-membered heteroaryl ring” refers to an aromatic 5 to 10-membered ring containing one or more heteroatoms, and specifically includes, for example, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole ring, an isothiazole ring, an imidazole ring, a triazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, an oxadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, indole ring, an isoindole ring, an indazole ring, a chromene ring,
• Preferable “5 to 10-membered heteroaryl rings” include a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a 1,2,4-triazole ring, a thiazole ring, a thiadiazole ring, a pyrazole ring, a furazan ring, a thiadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, an isoquinoline ring, a benzoxazole ring, a benzothiazole ring, and a benzimidazole ring.
• the most preferable example is a pyridine ring.
• the phrase “5 to 10-membered heteroaryl group” refers to a monovalent or divalent group obtained by removal of any one or two hydrogen atoms from a “5 to 10-membered heteroaryl ring” described above.
• the atoms constituting the ring include 1 to 2 heteroatoms
• the ring may contain 1 to 2 double bonds
• the ring may contain 1 to 3 carbonyl groups
• the 4 to 8-membered heterocyclic ring includes, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepan ring, an azocane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a thiazolidine ring, a dioxane ring, an imidazoline ring, a thiazoline ring, and a ring represented by one of the formulae: (where s represents an integer from 1 to 3; T 3x represents a methylene group, an oxygen atom or a group represented by the formula —NT 4x —, wherein T 4x represents a hydrogen atom or C 1-6 alkyl group.
• the “4- to 8-membered heterocyclic rings” include a pyrrolidine ring, a piperidine ring, an azepan ring, a morpholine ring, a thiomorpholine ring, a piperazine ring, a dihydrofuran-2-one ring, and a thiazolidine ring.
• the phrase “4 to 8-membered heterocyclic group” refers to a monovalent or divalent group obtained by removal of any one or two hydrogen atoms from a “4 to 8-membered heterocycle” described above.
• the “4 to 8-membered heterocyclic groups” include a piperidin-1-yl group, a pyrrolidin-1-yl group, and a morpholin-4-yl group.
• C 6-10 aryl C 1-6 alkyl group refers to a group obtained by substitution of a “C 6-10 aryl group” defined above for an arbitrary hydrogen atom in a “C 1-6 alkyl group” defined above, and specifically includes, for example, a benzyl group, a phenethyl group, and a 3-phenyl-1-propyl group.
• the phrase “5 to 10-membered heteroaryl C 1-6 alkyl group” refers to a group obtained by substitution of a “5 to 10-membered heteroaryl group” defined above for an arbitrary hydrogen atom in a “C 1-6 alkyl group” defined above, and specifically, includes for example, a 2-pyridylmethyl and a 2-thienylmethyl group.
• the phrase “4 to 8-membered heterocyclic C 1-6 alkyl group” refers to a group obtained by substitution of a “4 to 8-membered heterocyclic group” defined above for an arbitrary hydrogen atom in a “C 1-6 alkyl group” defined above.
• the phrase “monocyclic or bicyclic 4 to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, that may have one or more substituents” refers to a non-aromatic cyclic group which may have one or more substituents.
• the non-aromatic cyclic groups :
• the atoms constituting the ring of the cyclic group include one or two nitrogen atoms;
• the group is a monocyclic or bicyclic structure.
• the group is represented by the formula: (where n and m each independently represent 0 or 1; R 31 to R 44 independently represent a hydrogen atom or a substituent selected from substituents referred to in the phrase “which may have one or more substituents” (the substituent group S defined below); any two of R 31 to R 44 may in combination form a C 1-6 alkylene group).
• substituents means that a group may have one or more substituents in any combination at replaceable positions.
• substituents include, for example, a substituent selected from the substituent group S defined below.
• This group consists of:
• T 2x represents a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 5 to 10-membered heteroaryl group or a 4 to 8-membered heterocyclic group;
• R T represents a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group or a C 2-6 alkynyl group;
• T 2x and R T each may independently have 1 to 3 substituents selected from the substituent group T defined below)
• This group consists of: hydroxyl, cyano, a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5 to 10-membered heteroaryl, 4 to 8-membered heterocyclic ring, C 1-6 alkoxy, C 1-6 alkylthio, C 2-7 alkoxycarbonyl group, etc.
• the ⁇ substituent group S> preferably consists of:
• the term refers to a group represented by one of the formulae: (where R 31 , R 32 , R 33 , R 34 , and R 35 independently represent a hydrogen atom or a group selected from substituent groups referred to in the phrase “which may have one or more substituents” (the substituent group S defined above)); provided that, at least three of R 31 , R 32 R 33 , R 34 , and R 35 are hydrogen atoms Still more preferably, the term refers to a group represented by one of the formulae:
• the term refers to a group represented by the formula:
• piperidin-1-yl group which may have one or more substituents refers to a “piperidin-1-yl group” which may have one or more substituents selected from the groups referred to in the phrase “which may have one or more substituents” (the substituent group S defined above) at replaceable positions.
• the “piperidin-1-yl group which may have one or more substituents” refers to a group represented by the formula: (where R 31 , R 32 , R 33 , R 34 , and R 35 each independently represent a hydrogen atom or a group selected from the substituents referred to in the phrase “which may have one or more substituents” (the substituent group S defined above)); provided that, at least three of R 31 , R 32 , R 33 , R 34 , and R 35 are hydrogen atoms.
• the term refers to a group represented by one of the formulae:
• the term refers to a group represented by one of the formulae:
• azetidin-1-yl group may have one or more substituents” refers to an “azetidin-1-yl group” which may have one or more groups selected from the substituents referred to in the phrase “which may have one or more substituents” at replaceable positions.
• pyrrolidin-1-yl group may have one or more substituents” refers to a “pyrrolidin-1-yl group” which may have one or more groups selected from the substituents referred to in the phrase “which may have one or more substituents” at replaceable positions.
• piperidin-1-yl group may have one or more substituents” refers to a “piperidin-1-yl group” which may have one or more groups selected from the substituents referred to in the phrase “which may have one or more substituents” at replaceable positions.
• azepan-1-yl group may have one or more substituents” refers to an “azepan-1-yl group” which may have one or more groups selected from the substituents referred to in the phrase “which may have one or more substituents” at replaceable positions.
• piperidin-1-yl group which may have an amino group refers to a “piperidin-1-yl group” which may have an amino group at a replaceable position.
• the “piperidin-1-yl group which may have an amino group” refers to the group represented by one of the formulae: and preferably, to the group represented by one of the formulae:
• azetidin-1-yl group which may have an amino group refers to an “azetidin-1-yl group” which may have an amino group at a replaceable position.
• pyrrolidin-1-yl group which may have an amino group refers to a “pyrrolidin-1-yl group” which may have an amino group at a replaceable position.
• piperidin-1-yl group which may have an amino group refers to a “piperidin-1-yl group” which may have an amino group at a replaceable position.
• azepan-1-yl group which may have an amino group refers to an “azepan-1-yl group” which may have an amino group at a replaceable position.
• C 1-6 alkyl group which may have one or more substituents in the substituent group B defined above refers to a “C 1-6 alkyl group” which may have one or more groups selected from the substituents referred to in the phrase “which may have one or more substituents” at replaceable positions.
• the “C 1-6 alkyl group which may have one or more substituents” refers to a C 1-6 alkyl group which may have one or two substituents selected from the group consisting of a cyano group, a carboxyl group, a C 2-7 alkoxycarbonyl group, a group represented by the formula —NR 3T COR 4T , a group represented by the formula —CONR 3T R 4T (where R 3T and R 4T each independently represent a hydrogen atom or a C 1-6 alkyl group), and a C 1-6 alkoxy group.
• R 1 and R 2 each independently represent a group of the formula -A 0 -A 1 -A 2 (where A 0 , A 1 , and A 2 are as defined above); when both A 0 and A 1 are single bonds, “-A 0 -A 1 -” represents a single bond.
• the phrase “when Z 2 represents a group of the formula —CR 2 ⁇ , R 1 , and R 2 may in combination form a 5 to 7-membered ring” means that compounds represented by formula (I) indicated above includes compounds (II) represented by the formula: (where Z 1 , X, and T 1 are as defined above; A T1 represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a methylene group which may have one or more substituents, or a nitrogen atom which may have one or more substituents; A T2 represents a C 2-6 alkylene group which may have one or more substituents).
• a T1 preferably represents an oxygen atom
• a T2 preferably represents a C 2-4 alkylene group.
• cyanobenzyl group refers to a benzyl group having one cyano group, and specifically, includes, for example, a 2-cyanobenzyl group, a 3-cyanobenzyl group, and a 4-cyanobenzyl group.
• fluorocyanobenzyl group refers to a benzyl group having one fluorine atom and one cyano group, and specifically, includes, for example, a 2-cyano-4-fluorobenzyl group and a 2-cyano-6-fluorobenzyl group.
• carbamoylphenoxy group refers to a phenoxy group having a group represented by the formula —CONH 2 , and specifically, includes, for example, a 2-carbamoylphenoxy group, a 3-carbamoylphenoxy group, and a 4-carbamoylphenoxy group.
• salts include, for example, inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.
• Examples of preferred inorganic salts include hydrochloride, hydrobromide, sulfate, nitrate, and phosphate.
• Examples of preferred organic salts include acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, and p-toluene sulfonate.
• Examples of preferred inorganic base salts include: alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts.
• Examples of preferred organic base salts include diethylamine salts, diethanolamine salts, meglumine salts, and N,N′-dibenzylethylenediamine salts.
• Examples of preferred acidic amino acid salts include aspartate and glutamate.
• Examples of preferred basic amino acid salts include arginine salts, lysine salts, and ornithine salts.
• the present invention provides compounds represented by the following formula (I), or salts or hydrates thereof:
• T 1 represents a monocyclic or bicyclic 4- to 12-membered heterocyclic group containing one or two nitrogen atoms in the ring, and may have one or more substituents;
• X represents a C 1-6 alkyl group which may have one or more substituents, a C 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group which may have one or more substituents, a C 6-10 aryl group which may have one or more substituents, a 5- to 10-membered heteroaryl group which may have one or more substituents, a C 6-10 aryl C 1-6 alkyl group which may have one or more substituents, or a 5- to 10-membered heteroaryl C 1-6 alkyl group which may have one or more substituents;
• Z 1 and Z 2 each independently represent a nitrogen atom or a group represented by the formula —CR 2 ⁇ ;
• R 1 and R 2 each independently represent a group of the formula -A 0 -A 1 -A 2
• R 1 and R 2 may in combination form a 5 to 7-membered ring.
• R 1 is a hydrogen atom
• Z 1 is a nitrogen atom
• Z 2 is —CH ⁇
• Z 1 is a nitrogen atom
• Z 2 is —C(OH) ⁇
• the substituent group B represents the group consisting of: a hydroxyl group, a mercapto group, a cyano group, a nitro group, a halogen atom, a trifluoromethyl group, a C 1-6 alkyl group which may have one or more substituents, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a group represented by the formula —SO 2 —NR B1 —R B2 , a group represented by the formula —NR B1 —CO—R B2 , a group represented by the formula —NR B1 —R B2 (where R B1 and R B2 each independently represent a hydrogen atom or a C
• Preferable compounds represented by the formula (I) include, for example, the following compounds:
• Z 1 is a nitrogen atom
• Z 2 is a group represented by the formula —CR 2 ⁇ (where R 2 has the same definition as R 2 defined above);
• Z 2 is a nitrogen atom
• Z 1 is a group represented by the formula —CR 2 ⁇ (where R 2 has the same definition as R 2 defined above);
• T 1 is a group which may have one or more substituents and is represented by the formula: (where n and m each independently represent 0 or 1), an azetidin-1-yl group which may have one or more substituents, a pyrrolidin-1-yl group which may have one or more substituents, a piperidin-1-yl group which may have one or more substituents, or an azepan-1-yl group which may have one or more substituents;
• T 1 is a group represented by the formula: (where n and m each independently represent 0 or 1), an azetidin-1-yl group which may have an amino group, a pyrrolidin-1-yl group which may have an amino group, a piperidin-1-yl group which may have an amino group, or an azepan-1-yl group which may have an amino group;
• T 1 is a piperazin-1-yl group or a 3-amino piperidin-1-yl group
• X is a group represented by the formula —X 1 —X 2 (where X 1 represents a single bond or a methylene group which may have one or more substituents; x 2 represents a C 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group may have one or more substituents, or a phenyl group which may have one or more substituents);
• the phenyl group, which may have one or more substituents, of X represented by the group of the above formula —X 11 —X 12 is a phenyl group which may have, at the 2 position, a substituent selected from the group consisting of: a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, a ethyl group, a fluoromethyl group, a vinyl group, a methoxy group, an ethoxy group, an acetyl group, a cyano group, a formyl group, and a C 2-7 alkoxycarbonyl group;
• the substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR C1 —R C2 , (where each of R C1 and R C2 independently represent a hydrogen atom or a C 1-6 alkyl group), a group represented by the formula —CO—R C3 —R C4 and a group represented by the formula —CH 2 —CO—R C3 —R C4 (where R C3 represents a single bond, an oxygen atom or a group represented by the formula —NR C5 —; R C4 and R C5 each independently represent a hydrogen atom or a C 1-6 alkyl group);
• R 1 is a hydrogen atom, a C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, a 5 to 10-membered heteroaryl C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below, or a C 6-10 aryl C 1-6 alkyl group which may have 1 to 3 substituents selected from the substituent group C described below;
• the substituent group C represents the group consisting of: a hydroxyl group, a nitro group, a cyano group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR C1 —R C2 (where R C1 and R C2 each independently represent a hydrogen atom, or a C 1-6 alkyl group), a group represented by the formula —CO—R C3 —R C4 and a group represented by the formula —CH 2 —CO—R C3 —R C4 (where R C3 represents a single bond, an oxygen atom, or a group represented by the formula —NR C5 —; R C4 and R C5 each independently represent a hydrogen atom or a C 1-6 alkyl group);
• R 1 is a methyl group, a cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a 2-methoxyethyl group or a 4-methoxycarbonyl-pyridin-2-yl group;
• R 2 is a hydrogen atom, a cyano group, or a group represented by the formula -A 21 -A 22 ;
• the substituent group D represents the group consisting of a hydroxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, a trifluoromethyl group, a group represented by the formula —NR D1 —R D2 (where R D1 and R D2 each independently represent a hydrogen atom or a C 1-6 alkyl group), a group represented by the formula —CO—R D3 (where R D3 represents a 4 to 8-membered heterocyclic group), and a group represented by the formula —CO—R 4 —R D5 (where R D4 represents a single bond, an oxygen atom, or a group represented by the formula —NR D6 —; R D5 and R D6 each independently represent a hydrogen atom, a C 3-8 cycloalkyl group or a C 1-6 alkyl group);
• R 2 is a hydrogen atom, a cyano group, a carboxy group, a C 2-7 alkoxycarbonyl group, a C 1-6 alkyl group, a group represented by the formula —CONR D7 R D8 (where R D7 and R D8 each independently represent a hydrogen atom or C 1-6 alkyl group), a group represented by the formula -A 23 -A 24 (where A 23 represents an oxygen atom, a sulfur atom, or a group represented by the formula —NR A3 —; A 24 and R A3 each independently represent a hydrogen atom, a C 1-6 alkyl group which may have a substituent selected from the substituent group D1 described below, a C 3-8 cycloalkyl group which may have a substituent selected from the substituent group D1 described below, a C 2-6 alkenyl group which may have a substituent selected from the substituent group D1 described below, a C 2-6 alkynyl group which may have
• the substituent group D1 represents the group consisting of a carboxy group, a C 2-7 alkoxycarbonyl group, a C 1-6 alkyl group, a group represented by the formula —CONR D7 R D8 (where R D7 and R D8 each independently represent a hydrogen atom or C 1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
• R is a hydrogen atom, a cyano group, a C 1-6 alkoxy group, or a group of the formula -A 25 -A 26 (where A 25 represents an oxygen atom, a sulfur atom, or a group represented by the formula —NR A4 —; A 26 and R A4 each independently represent a hydrogen atom, a C 1-6 alkyl group having a substituent selected from the substituent group D1 described below, a C 3-8 cycloalkyl group having a substituent selected from the substituent group D1 described below, or a phenyl group having a substituent selected from the substituent group D1 described below);
• the substituent group D1 represents the group consisting of a carboxyl group, a C 2-7 alkoxycarbonyl group, a C 1-6 alkyl group, a group represented by the formula —CONR D7 R D8 (where R D7 and R D8 each independently represent a hydrogen atom or a C 1-6 alkyl group), a pyrrolidin-1-ylcarbonyl group, a C 1-6 alkyl group, and a C 1-6 alkoxy group;
• R is a hydrogen atom, a cyano group, a methoxy group, a carbamoylphenyloxy group, a group represented by one of the formulae: (where A 27 represents an oxygen atom, a sulfur atom, or a group represented by the formula —NH—;
• a 28 an A 29 each independently represent a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom, a cyano group, or a carbamoylphenyloxy group.
• the order of preference is (1) to (3) with (3) the most preferable; with respect to T 1 , the order of preference is (4) to (7) with (7) the most preferable; with respect to X, the order of preference is (8) to (12) with (12) the most preferable; with respect to R 1 , the order of preference is (13) to (17) with (17) the most preferable; with respect to R 2 , the order of preference is (18) to (22) with (22) the most preferable.
• preferred compounds represented by above formula (I) include compounds defined by any 2 to 5 embodiments selected from the groups consisting of (1)-(3), (4)-(7), (8)-(12), (13)-(17), and (18)-(22).
• Preferable compounds include, for example, compounds defined by the following specific combinations of embodiments:
• R 31 to R 42 , n, m, R 1 , R 2 , X, A 0 , A 1 , A 2 , R A , and T 1 are the same as defined above.
• U 1 and U 3 each independently represent a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group.
• R p1 , R p2 , and R p3 each independently represent an -NH-protecting group such as a pivalyloxymethyl group and a trimethylsilylethoxymethyl group.
• R p4 represents a hydroxyl group-protecting group such as a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group.
• R p5 represents an NH-protecting group such as N,N-dimethylsulfamoyl, trityl, benzyl, and t-butoxycarbonyl.
• U 2 and U 4 each independently represent a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a group represented by the formula —B(OH) 2 , a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group, or a group represented by the formula —Sn(R Z ) 3 (where R Z represents a C 1-6 alkyl group).
• R x2 is a group represented by the formula —O-A 2 , a group represented by the formula —S-A 2 , a group represented by the formula —N(R A )A 2 , or a 4- to 8-membered heterocyclic group which may have one or more substituents (for example, 1-pyrrolidinyl, 1-morpholinyl, 1-piperazinyl, or 1-piperidyl), etc.
• R x3 represents a group of the formula -A 0 -A 1 -A 2 , such as a cyano group, a C 1-6 alkyl group which may have one or more substituents, a C 3-8 cycloalkyl group which may have one or more substituents, a C 2-6 alkenyl group which may have one or more substituents, a C 2-6 alkynyl group which may have one or more substituents, and a C 6-10 aryl group which may have one or more substituents.
• a 2COOR represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains an ester group.
• a 2COOH represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains a carboxylic acid.
• a 2NO2 represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains a nitro group.
• a 2NH2 represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 610 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains an amino group.
• a 2CN represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains a nitrile group.
• a CONH2 represents a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered heteroaryl C 1-6 alkyl group, or a C 6-10 aryl C 1-6 alkyl group, each of which contains a carboxylic amide group.
• M represents —MgCl, —MgBr, —Sn(R Z ) 3 (where R Z is as defined above), etc.
• room temperature refers to a temperature of about 20 to about 30° C.
• T 1a is defined as the group represented by T 1 , or represents a group of the formula: a group represented by the formula: (where R 31 to R 44 are as defined above, except that any one of R 31 to R 44 represents —NH—R p3 ), or a group represented by the formula: (where R 31 to R 40 are as defined above, except that any one of R 31 to R 40 represents —NH—R p3 ).
• an —NH-protecting reagent is reacted with compound (1a) [CAS No. 56160-64-6] to give compound (2a).
• the reaction conditions are selected depending on the type of —NH-protecting reagent to be used.
• the reaction may be performed under conditions that are generally used to introduce a protecting group using the reagent.
• An —NH-protecting reagent can be a reagent that is generally used to introduce an —NH-protecting group.
• —NH-protecting reagents include, for example, chloromethyl pivalate. It is preferable to use 1 to 2 equivalents of a protecting reagent.
• Solvents for the reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. N,N-dimethylformamide is preferably used.
• the reaction can be achieved in the presence of a base.
• bases to be used in the reaction include cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, and sodium hydride.
• Sodium hydride is preferably used.
• a base is preferably used in an amount of 1 to 5 equivalents.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C. A preferred reaction temperature is room temperature.
• Compound (2a-2) can be any compound that is an electrophilic reagent such as an alkyl halide.
• an electrophilic reagent such as an alkyl halide.
• alkyl halides such as iodomethane, iodoethane, iodopropane, and benzyl bromide
• alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2-butene
• alkynyl halides such as propargyl bromide and 1-bromo-2-butyne.
• One to two equivalents of an electrophilic reagent are preferably used.
• Solvents for the reaction include, for example, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene.
• the reaction can be achieved in the presence or absence of a base.
• bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
• one to two equivalents of a base are preferably used.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (4a) can be prepared from compound (3a) for example, by catalytic reduction under a hydrogen atmosphere in the presence of a metal catalyst, but the reaction conditions are not limited thereto.
• Specific solvents for the reaction include, for example, methanol, ethanol, propanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene.
• metal catalysts include palladium carbon, platinum oxide, and Raney nickel. A metal catalyst is preferably used at 0.5 to 50 weight %. Apreferred hydrogen pressure is 1 to 5 atm.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (4a-2) are: alkyl halides such as iodomethane, iodoethane, iodopropane, and benzyl bromide; alkenyl halides such as allyl bromide and l-bromo-3-methyl-2-butene; or alkynyl halides such as propargyl bromide and 1-bromo-2-butyne. These halides are preferably used in an amount of one to two equivalents.
• Solvents for the reaction include dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, tetrahydrofuran, and toluene.
• the reaction can be carried out in the presence or absence of a base.
• bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
• 1 to 4 equivalents of a base are preferably used.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• Compound (5a) can be obtained by reacting compound (4a) with compound (4a-2) in the presence of a copper catalyst and a base. In this case, it is preferable to use 0.1 to 2 equivalents of a copper catalyst and 1 to 10 equivalents of a base.
• compound (4a-2) may be arylboronic acid, heteroarylboronic acid, or such, in which X is a C 6-10 aryl group which may have one or more substituents or a 5- to 10-membered heteroaryl group which may have one or more substituents, and U 2 is —B(OH) 2 or such.
• X is a C 6-10 aryl group which may have one or more substituents or a 5- to 10-membered heteroaryl group which may have one or more substituents
• U 2 is —B(OH) 2 or such.
• One to three equivalents of compound (4a-2) are preferably used.
• reaction solvents include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, toluene, pyridine, N,N-dimethylformamide, and N-methylpyrrolidone.
• Bases include triethylamine, diisopropyl ethyl amine, pyridine, and N,N-dimethylaminopyridine.
• Copper catalysts include copper (II) acetate, copper (II) trifluoroacetate, copper (II) chloride, and copper (II) iodide. The reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (5a) is reacted with a halogenating agent to give compound (6a).
• halogenating agents include, for example, N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide.
• a halogenating agent is preferably used in an amount of 1 to 4 equivalents.
• Solvents for the reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (6a) is reacted with compound (7a) to give compound (8a).
• compound (8a) 1 to 4 equivalents of compound (7a) are preferably used.
• the reaction can be carried out, for example, in a solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, and xylene, or in the absence of a solvent.
• a solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, and xylene
• a solvent such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, and xylene
• the reaction can be conducted at a temperature ranging from 0° C. to 200° C. in
• the —NH-protecting group at the 3-position of compound (8a) is removed to give compound (9a).
• the reaction conditions are selected depending on the type of —NH-protecting group to be removed.
• the deprotection reaction may be preformed under conditions that are generally used for the protecting group.
• R p2 is a pivalyloxymethyl group
• the reaction can be carried out in methanol, or a mixed solution of methanol and tetrahydrofuran, using a base such as sodium methoxide, sodium hydride, or 1,8-diazabicyclo[5,4,0]-7-undecene at a temperature of 0 to 150° C.
• a base such as sodium methoxide, sodium hydride, or 1,8-diazabicyclo[5,4,0]-7-undecene at a temperature of 0 to 150° C.
• 0.1 to 2 equivalents of a base are preferably used.
• R p2 is a trimethylsilylethoxymethyl group
• the reaction can be carried out in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, using a fluoride reagent such as tetrabutyl ammonium fluoride or cesium fluoride at a temperature of 0 to 150° C.
• a fluoride reagent such as tetrabutyl ammonium fluoride or cesium fluoride at a temperature of 0 to 150° C.
• 1 to 5 equivalents of a fluoride reagent are preferably used.
• reaction conditions there are no particular limitations on the reaction conditions, and the The reaction can be conducted under standard conditions for chlorination.
• the reaction can be carried out at a temperature ranging from 0 to 150° C. in a solvent such as phosphorus oxychloride. In this case, it is preferable to use a 10 to 200 times amount of halogenating agent by weight.
• R p3 is a t-butoxycarbonyl group or such, which is removed under the above-described conditions using phosphorus oxychloride or such, the protecting group should be reintroduced.
• reaction conditions for the protection there are no particular limitations on the reaction conditions for the protection.
• the reaction can be carried out using an —NH— protection reagent such as di-t-butyl dicarbonate, in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine at 0 to 150° C.
• a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine at 0 to 150° C.
• compound (10a) is reacted with compound (11a-2) to give compound (11a).
• Compound (11a-2) includes alcohol compounds or phenol compounds represented by A 2 -OH, amine compounds represented by A 2 (R A )NH or such, and thiol compounds represented by A 2 -SH.
• compound (11a-2) is preferably used in an amount of 1 to 10 equivalents or 5 to 100 times by weight.
• Solvents for the reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
• the reaction can be carried out in the presence or absence of a base.
• Bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, butyllithium, methyllithium, lithium bis (trimethylsilyl)amide, sodium bis (trimethylsilyl)amide, potassium bis (trimethylsilyl)amide, and triethylamine.
• 1 to 10 equivalents of a base is preferably used.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (10a) is reacted with compound (13a) in the presence of a metal catalyst to give compound (12a).
• a metal catalyst In this case, 1 to 50 equivalents of compound (13a) are preferably used.
• Solvents for the reaction include acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
• Metal catalysts include palladium catalyst and copper catalyst.
• Palladium catalysts include tetrakis triphenylphosphine palladium, palladium acetate, and dibenzylideneacetone palladium.
• Copper catalyst include copper iodide. It is preferable to use 0.01 to 2 equivalents of a metal catalyst.
• the reaction can be conducted in the presence of an organophosphorous ligand.
• organophosphorous ligand examples include o-tolyl phosphine and diphenylphosphinoferrocene. In this case, it is preferable to use 1 to 5 equivalents of an organophosphorous ligand to the metal catalyst.
• the reaction can be carried out in the presence or absence of a base.
• Bases to be used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, potassium phosphate, lithium bis trimethylsilyl amide, sodium bis trimethylsilyl amide, potassium bis trimethylsilyl amide, and triethylamine.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (10a) is reacted with a cyanidation reagent to give compound (14a).
• cyanidation reagents include, for example, sodium cyanide and potassium cyanide. It is preferably used in an amount of 1 to 20 equivalents.
• Solvents for the reaction include, for example, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• the cyano group of compound (14a) is hydrolyzed to give compound (15a).
• reaction conditions There are no particular limitations on the reaction conditions, and the reaction can be carried out under conditions generally used for the conversion of a cyano group to a carbamoyl group by hydrolysis.
• Solvents for the reaction include N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, ethanol, and a mixed solvent of tetrahydrofuran and methanol.
• the reaction can be carried out in the presence or absence of a base.
• a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, or ammonia.
• the reaction can be achieved after adding an aqueous solution of hydrogen peroxide (preferably an aqueous solution of 30% hydrogen peroxide).
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• R p3 of compound (16a) is removed to give compound (17a).
• Compounds (11a), (12a), (14a), (15a), and others can be used as compound (16a).
• the deprotection reaction for R p3 can be carried out under standard reaction conditions for removing an —NH-protecting group.
• R p3 is a t-butoxycarbonyl group
• the reaction can be carried out in the presence of an acid such as an anhydrous methanol solution of hydrogen chloride, an anhydrous ethanol solution of hydrogen chloride, an anhydrous dioxane solution of hydrogen chloride, trifluoroacetic acid, or formic acid.
• an acid such as an anhydrous methanol solution of hydrogen chloride, an anhydrous ethanol solution of hydrogen chloride, an anhydrous dioxane solution of hydrogen chloride, trifluoroacetic acid, or formic acid.
• compound (18a) is chlorinated to give compound (19a).
• the reaction conditions can be conducted under standard conditions for chlorination.
• the reaction can be carried out in a solvent such as phosphorus oxychloride at a temperature ranging from 0 to 150° C. Preferably 10 to 200 times by weight of chlorination reagent is used.
• R p3 is a t-butoxycarbonyl group or such, which is removed under the above-described condition using phosphorus oxychloride or such, the protecting group should be reintroduced.
• reaction conditions for the protection there are no particular limitations on the reaction conditions for the protection, and when R p3 is a t-butoxycarbonyl group, the reaction can be carried out using an —NH— protection reagent such as di-t-butyl dicarbonate, in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine at a temperature ranging from 0 to 150° C.
• a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or triethylamine
• compound (19a) is partially hydrolyzed to give compound (20a).
• the reaction is carried out in the presence of a base such as sodium acetate, potassium carbonate, or sodium hydroxide.
• a base such as sodium acetate, potassium carbonate, or sodium hydroxide.
• Solvents for the reaction include dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, water, and mixtures thereof.
• the reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• compound (20a) is reacted with compound (21a) to give compound (22a).
• the reaction can be conducted under the same conditions as used in [Step A2] of production method A.
• the reaction can be conducted under the same conditions as used in [Step A4] of production method A.
• compound (24a) is reacted with a halogenating agent to give compound (25a).
• the reaction can be conducted under the same conditions as used in [Step A5] of production method A.
• compound (25a) is chlorinated to give compound (26a).
• compound (25a) can be reacted with phosphorus oxychloride, phosphorus pentachloride, or a mixture thereof in a solvent or in the absence of a solvent at a temperature of 0 to 150° C.
• Solvents include, for example, toluene, acetonitrile, and dichloroethane.
• compound (1b) is benzylated and the sugar chain is cleaved to give compound (2b).
• Compound (2b) can be obtained by reacting compound (lb) with benzyl bromide in a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, or ethanol, at a temperature of 0 to 150° C., adding 3 to 10 equivalents of hydrochloric acid, and incubating the mixture at a temperature of 0 to 150° C. to cleave the sugar moiety. It is preferable to use 1 to 3 equivalents of benzyl bromide.
• a solvent such as acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, or ethanol
• a solvent such
• compound (2b) is reacted with a halogenating agent to give compound (3b).
• the halogenation reaction can be conducted under the same conditions as used in [Step A5] of production method A.
• compound (3b) is reacted with compound (4b) to give compound (5b).
• the reaction can be conducted under the same conditions as used in [Step A6] of production method A.
• compound (5b) is reacted with compound (5b-2) to give compound (6b).
• the reaction can be conducted under the same condition as used in [Step A2] of production method A.
• Compound (9b) represented by the formula: can be obtained by using compound (8b) represented by H-T 1a , instead of compound (7a) in [Step A6] of production method A described above under the same reaction conditions as used in [Step A6], and then appropriately applying [Step A7] to [Step A13] described above.
• Compound (10b) represented by the formula: can be obtained by using compound (8b) represented by H-T 1a , instead of compound (3b) in [Step B3] of production method B described above under the same reaction conditions as used in [Step B3] and then appropriately applying (Step B4] to [Step B6] described above.
• Preferable examples of compound (8b) include piperidin-3-yl carbamic acid t-butyl ester.
• compound (1c) is reacted with compound (1c-2) to give compound (2c).
• the reaction can be conducted under the same conditions as used in [Step A4] of production method A.
• Compound (3c) can be obtained, for example, by heating an ethanol solution of compound (2c) under reflux in the presence of an acid such as sulfuric acid or hydrochloric acid.
• an acid such as sulfuric acid or hydrochloric acid.
• the reaction conditions are not limited thereto. In this reaction, it is preferable to use one to two equivalents of an acid.
• compound (7c) is thioamidated to give compound (8c).
• Solvents for the reaction include methanol, ethanol, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane.
• Thioamidation reagents include ammonium sulfide, sodium sulfide, and hydrogen sulfide. It is preferable to use 2 to 10 equivalents of a thioamidation reagent.
• the reaction is carried out in the presence of a base such as triethylamine or N,N-diisopropylethylamine.
• a base such as triethylamine or N,N-diisopropylethylamine.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• compound (8c) is reacted with a methylating reagent to give compound (9c).
• Methylating reagents include trimethyl oxonium tetrafluoroborate, methyl sulfate, methyl iodide, and trimethylphosphite. It is preferable to use 1.0 to 1.5 equivalent of the methylating reagent.
• compound (9c) can be obtained by carrying out the reaction in a halogenated solvent such as dichloromethane at a temperature ranging from 0° C. to 50° C.
• a halogenated solvent such as dichloromethane
• compound (9c) can be obtained by carrying out the reaction in the presence of a base such as potassium carbonate, triethylamine, or N,N-diisopropylethylamine. In this case, it is preferable to use 1.0 to 1.5 equivalent of abase.
• Solvents for the reaction include acetone, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane. The reaction can be performed at a temperature ranging from 0° C. to 100° C.
• reaction conditions for the hydrolysis There are no particular limitations on the reaction conditions for the hydrolysis.
• the reaction can be carried out in a mixed solvent of ethanol and water in the presence of an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid, at a temperature ranging from 0° C. to 80° C. In this case, it is preferable to use 5 to 50 equivalents of the acid.
• R p3 is a group, such as a t-butoxycarbonyl group, which is removed under the above-described condition, the protecting group should be reintroduced. There are no particular limitations on the reaction conditions for the introduction of this protecting group.
• R p3 is a t-butoxycarbonyl group
• the reaction can be carried out using a reagent such as t-butyl dicarbonate in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, and N,N-diisopropylethylamine, at a temperature ranging from 0 to 80° C. In this case, it is preferable to use 2 to 3 equivalents of a base.
• reaction conditions for the reduction can be achieved by reacting compound (10c) with hydrogen in the presence of Raney nickel in a solvent such as benzene, ethanol, 2-propanol, or acetone, at a temperature ranging from 0° C. to 50° C., or alternatively reacting compound (10c) with a reducing agent such as sodium borohydride, in a solvent such as methanol, ethanol, or 2-methyl-2-propanol, or in a mixed solvent of water and tetrahydrofuran at a temperature ranging from 0° C.
• a solvent such as benzene, ethanol, 2-propanol, or acetone
• compound (10c) with a reducing agent such as sodium borohydride, in the presence of 1 to 5 equivalents of a mercury salt such as mercuric acetate in a solvent such as methanol, ethanol, or 2-methyl-2-propanol at a temperature ranging from 0° C. to 50° C. It is preferable to use two to three equivalents of a reducing agent.
• a reducing agent such as sodium borohydride
• compound (11c) is subjected to an oxidation reaction to give compound (12c).
• compound (12c) can be obtained by carrying out the reaction in a solvent such as dichloromethane or chloroform, at a temperature ranging from 20° C. to 80° C.
• compound (12c) can also be obtained by carrying out the reaction under standard conditions for the oxidation of a primary alcohol to aldehyde, such as Swern oxidation. It is preferable to use 5 to 20 equivalents of an oxidant.
• compound (12c) is reacted with compound (13c) to give compound (17c).
• compound (12c) is reacted with compound (13c) to give compound (17c).
• Compound (17c) can be obtained, for example, by combining compounds (12c) and (13c) in a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, or in the absence of solvent, and reacting the mixture at a temperature of 20 to 150° C.
• a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane
• the reaction conditions are not limited thereto.
• compound (12c) is reacted with hydrazine to give compound (15c).
• the reaction can be conducted under the same conditions as used in [Step C11] of production method C. It is preferable to use 2 to 10 equivalents of hydrazine.
• a substitution reaction is carried out using compound (15c) and compound (16c) to give compound (17c).
• the reaction can be conducted under the same conditions as used in [Step A2] of production method A. It is preferable to use 1 to 3 equivalents of compound (16c).
• reaction conditions for the hydrolysis there are no particular limitations on the reaction conditions for the hydrolysis.
• compound (19c) can be obtained by incubating compound (18c) in the presence of a base at a temperature ranging from 0° C. to 100° C.
• Solvents for the reaction include methanol, ethanol, tetrahydrofuran, water, or mixtures thereof.
• Bases include lithium hydroxide, sodium hydroxide, and potassium hydroxide. It is preferable to use 1 to 2 equivalents of a base.
• compound (19c) is reacted with a reducing agent to give compound (20c).
• the reduction can be achieved under a standard condition for the reduction of carboxylic acid to methyl alcohol.
• Reducing agents include borane derivatives such as borane-tetrahydrofuran complex and borane-methyl sulfide complex, and sodium borohydride. It is preferable to use 5 to 30 equivalents of a reducing agent.
• compound (20c) can be obtained by carrying out the reaction using a solvent such as 1,4-dioxane, tetrahydrofuran, or dimethoxyethane at a temperature ranging from ⁇ 78° C. to 35° C.
• a solvent such as 1,4-dioxane, tetrahydrofuran, or dimethoxyethane at a temperature ranging from ⁇ 78° C. to 35° C.
• compound (19c) when sodium borohydride is used as a reducing agent, first, compound (19c) is reacted with an activator such as isobutyl chloroformate, at a temperature ranging from ⁇ 78° C. to 20° C., then reacted with a reducing agent such as sodium borohydride at a temperature ranging from ⁇ 78° C. to 35° C., to obtain compound (20c).
• Solvents for the reaction include 1,4-dioxane, tetrahydrofuran, and dimethoxyethane.
• compound (21c) is reacted with a silylating agent in the presence of a base to give compound (22c).
• Solvents for the reaction include dichloromethane, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and dimethoxyethane.
• Bases include imidazole, pyridine, 4-dimethylaminopyridine, triethylamine, and N,N-diisopropylethylamine.
• Silylating agents include t-butyldimethylchlorosilane, and t-butylchlorodiphenylsilane. It is preferable to use 1.0 to 1.5 equivalent of a base and 1.0 to 1.5 equivalent of a silylating agent.
• the reaction can be conducted at a temperature ranging from 0° C. to 80° C.
• the reaction can be conducted under the same condition as used in [Step C7] of production method C.
• compound (23c) is hydrolyzed to give compound (24c).
• Compound (24c) can be obtained by carrying out the reaction in a mixed solvent of ethanol and water in the presence of an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid, at a temperature ranging from 50° C. to 100° C.
• an acid such as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid
• —NH— is re-protected through a protection reaction.
• the reaction can be carried out using a reagent such as t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropyl ethylamine, at a temperature ranging from 0 to 80° C.
• a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropyl ethylamine
• compound (1d-2) includes, for example, alkyl halides such as iodomethane, iodoethane, iodopropane, benzyl bromide, 2-bromoacetophenone, chloromethyl benzyl ether, and bromoacetonitrile; alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl bromide and 1-bromo-2-butyne. It is preferable to use 1 to 1.5 equivalent of compound (1d-2).
• alkyl halides such as iodomethane, iodoethane, iodopropane, benzyl bromide, 2-bromoacetophenone, chloromethyl benzyl ether, and bromoacetonitrile
• alkenyl halides such as allyl bromide and 1-bromo-3-methyl-2
• Solvents for the reaction include N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and dichloromethane.
• the reaction can be carried out in the presence or absence of a base.
• Bases to be used in the reaction include 1,8-diazabicyclo[5,4,0]undecene, triethylamine, N,N-diisopropylethylamine, and sodium hydride. In this case, it is preferable to use 1 to 1.5 equivalent of the base.
• the reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• Solvents for the reaction include a mixed solvent of water and a solvent from N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane.
• Nitrite salts include sodium nitrite and potassium nitrite. It is preferable to use 3 to 5 equivalents of a nitrite.
• the reaction can be conducted at a temperature ranging from 20° C. to 120° C.
• compound (3d) is reacted with ammonia to give compound (4d). It is preferable to use 10 to 20 equivalents of ammonia.
• the reaction can be carried out in a solvent such as methanol, ethanol, or 1,4-dioxane at a temperature ranging from 20° C. to 200° C.
• a solvent such as methanol, ethanol, or 1,4-dioxane
• compound (4d) is subjected to catalytic reduction under hydrogen atmosphere or in the presence of 2 to 3 equivalents of hydrazine using a metal catalyst to give compound (5d).
• Solvents for the reaction include methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, or a mixed solvent thereof.
• Metal catalysts include palladium carbon, platinum oxide, and Raney nickel. It is preferable to use a metal catalyst in the amount of 0.5 to 10% by weight. The reaction can be conducted at a temperature ranging from 0° C. to 150° C.
• the reaction is carried out in the presence of a carboxylic anhydride such as acetic anhydride.
• a carboxylic anhydride such as acetic anhydride.
• Orthoformate esters include methyl orthoformate, and ethyl orthoformate. It is preferable to use 1 to 20 times as much orthoformate ester by weight and 3 to 10 equivalents of carboxylic anhydride.
• the reaction can be conducted at a temperature ranging from 20° C. to 200° C.
• Protecting reagents include N,N-dimethylsulfamoyl chloride, trityl chloride, di-t-butyl dicarbonate, and benzyl bromide. It is preferable to use 1 to 1.5 equivalent of a protecting reagent.
• Solvents for the reaction include dichloromethane, chloroform, carbon tetrachloride, toluene, N,N-dimethylformamide, and tetrahydrofuran.
• Bases include pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0]undecene, triethylamine, and N,N-diisopropylethylamine.
• the protecting reagent is di-t-butyl dicarbonate
• 0.005 to 0.1 equivalent of 4-dimethylaminopyridine is used preferably.
• the reaction can be conducted at a temperature ranging from 20° C. to 200° C.
• reaction conditions there are no particular limitations on the reaction conditions.
• the reaction is carried out as follows.
• Compound (7d) is reacted with a base at a temperature ranging from ⁇ 100° C. to 20° C., and then a chlorinating reagent is reacted thereto.
• This reaction produces compound (8d).
• Compound (8d) can also be obtained by reacting compound (7d) with a base in the presence of a chlorination reagent.
• Solvents for the reaction include, for example, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane.
• Bases include n-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, and magnesium diisopropylamide. It is preferable to use 1 to 1.5 equivalent of a base.
• Chlorinating reagents include hexachloroethane, and N-chloro succinimide. It is preferable to use 1 to 3 equivalents of a chlorination reagent.
• compound (8d) is reacted with compound (9d) to give compound (10d).
• the reaction can be conducted under the same conditions as used in [Step A6] of production method A.
• R p3 of compound (11d) is removed to give compound (12d).
• the reaction can be conducted under the same condition as used in [Step A13] of production method A.
• R 1 is a benzyloxymethyl group
• compound (11d) is reacted with 3 to 10 equivalents of boron tribromide, boron trichloride, or such in a solution such as dichloromethane at a temperature ranging from ⁇ 100° C. to 20° C. This reaction produces compound (13d).
• —NH— is re-protected through a protection reaction.
• the reaction can be carried out using a reagent such as di-t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80° C.
• a reagent such as di-t-butyl dicarbonate
• a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran
• a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80° C.
• the reaction is
• compound (13d) is reacted with compound (13d-2) to give compound (14d).
• the reaction can be conducted under the same conditions as used in [Step D1] of production method D.
• R p3 of compound (14d) is removed to give compound (12d).
• the reaction can be conducted under the same conditions as used in (Step A 13 ] of production method A.
• the deprotection can be achieved under standard reaction conditions depending on the type of protecting group.
• the deprotection can be achieved by carrying out the reaction using a base such as sodium hydroxide, potassium carbonate, and ammonia, in tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, water, or a mixed solvent thereof at a temperature ranging from 0° C. to 100° C.
• a base such as sodium hydroxide, potassium carbonate, and ammonia
• X is introduced into compound (15d) to give compound (16d).
• the reaction can be conducted using X-U 2 under the same conditions as used in [Step A4] of production method A.
• An alcohol (X—OH) can be introduced using Mitsunobu's reaction.
• compound (16d) can be obtained by reacting an alcohol (X—OH) with an azodicarboxylic acid dialkyl ester and triphenylphosphine in a solvent such as tetrahydrofuran, at a temperature ranging from —70° C. to 50° C.
• the reaction can be conducted under the same conditions as used in [Step A6] of production method A.
• Compound (1e) represented by the formula: can be obtained by using compound (8b) represented by H-T 1a , instead of compound (6c), in [Step C5] or [Step C15] of production method C described above under the same reaction conditions as used in [Step C5], and then appropriately applying [Step C6] to [Step C21] described above.
• ester group of compound (1f) is hydrolyzed to give compound (2f).
• the reaction can be conducted under the same conditions as used in [Step C16] of production method C.
• Solvents for the reaction include methanol, ethanol, tetrahydrofuran, water, or mixtures thereof.
• Reducing agents includes, iron, tin, and zinc.
• Catalysts include hydrochloric acid and ammonium salts such as ammonium chloride. The reaction can be conducted at a temperature ranging from 20° C to 120° C.
• reaction conditions there are no particular limitations on the reaction conditions.
• Compound (2h) can be obtained by reacting compound (1h) with hydrogen peroxide in the presence of a base at a temperature ranging from ⁇ 20° C. to 50° C.
• Solvents include methanol, ethanol, tetrahydrofuran, water, or a solvent mixture thereof.
• Bases include ammonia and alkyl amines such as triethylamine.
• compound (1i) is reacted with an alkyl metal agent or an aryl metal agent to give compound (2i).
• reaction conditions there are no particular limitations on the reaction conditions.
• the reaction is carried out as follows.
• Compound (1i) may be reacted with an agent such as alkyllithium, aryllithium, alkyl Grignard reagent, or aryl Grignard reagent, in a solvent such as diethyl ether or tetrahydrofuran, at a temperature ranging from ⁇ 100° C. to 100° C.
• the compound may be reacted with alkylzinc or arylzinc in a solvent such as N,N-dimethylformamide or 1-methyl-2-pyrrolidone, at a temperature ranging from 0° C. to 50° C.
• compound (2i) is oxidized to give compound (3i)
• a typical reagent that is generally used in the oxidation of an alcohol can be used as the oxidant.
• manganese dioxide can be used as the oxidant in a solvent such as dichloromethane or chloroform, at a temperature within the range of 20 to 100° C.
• sulfur trioxide pyridine can be used as the oxidant in a solvent such as dimethyl sulfoxide, at a temperature within the range of 20 to 100° C.
• Dess-Martin periodinane may be used in a solvent such as dichloromethane or chloroform, at a temperature within the range of ⁇ 50 to 50° C.
• compound (1j) is reacted with a cyanidation agent in the presence of a catalyst to give compound (2j).
• Cyanidation agents include sodium cyanide, and potassium cyanide.
• Catalysts include acetic acid.
• Solvents include, for example, acetonitrile. The reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• the nitrile group of compound (2j) is hydrolyzed to give compound (3j).
• the reaction can be conducted under the same conditions as used in [Step H1] of production method H.
• compound (4j) is reacted with compound (5j) to give compound (6j).
• the reaction can be conducted under the same conditions as used in [Step C11] of production method C.
• Dehydrating agents include, for example, phosphorus oxychloride.
• Bases include alkyl amines such as triethylamine.
• Solvents include dichloromethane, and chloroform.
• the reaction can be carried out in the absence of solvent. The reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• Compound (5k) can be obtained, for example, by reacting a mixture of compounds (3k) and (4k) in a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane, or in the absence of solvent at a temperature ranging from 20° C. to 200° C.
• a solvent such as methanol, ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or dimethoxyethane
• the reaction conditions are not limited thereto.
• compound (5k) is chlorinated to give compound (6k).
• the reaction can be conducted under the same conditions as used in [Step D7] of production method D.
• the deprotection reaction for R p5 can be carried out under standard reaction conditions for removing an —NH-protecting group.
• R p5 is a benzyl group
• the reaction can be achieved using a metal such as lithium or sodium in liquid ammonia at a temperature within the range of ⁇ 78° C. to ⁇ 30° C.
• Oxidants include salts such as iron (III) chloride.
• Solvents include methanol, ethanol, and water. The reaction can be conducted at a temperature ranging from 20° C. to 100° C.
• —NH— is re-protected through a protection reaction.
• the reaction can be carried out using a reagent such as di-t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, or tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80° C.
• a base such as pyridine, 4-aminopyridine, triethylamine, or N,N-diisopropylethylamine, at a temperature ranging from 0 to 80° C.
• the reaction is not limited thereto.
• compound (31) is reacted with compound (41) to give compound (51).
• the reaction can be conducted under the same conditions as used in [Step A4] of production method A.
• the reaction can be conducted at a temperature ranging from 20° C. to 150° C.
• Solvents for the reaction include methanol, ethanol, water, and a mixed solvent thereof.
• Reducing agents include tin salts such as tin chloride.
• Solvents include concentrated hydrochloric acid. The reaction can be conducted at a temperature ranging from 20° C. to 150° C.
• the reaction can be achieved using a solvent such as acetonitrile or tetrahydrofuran.
• the reaction can be conducted at a temperature ranging from 20° C. to 100° C.
• Compound (7n) can be obtained, for example, by reacting compound (6n) with osmic acid and sodium periodate in a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or water at a temperature ranging from 20° C. to 100° C.
• a solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or water at a temperature ranging from 20° C. to 100° C.
• the reaction conditions are not limited to this example.
• reaction conditions There are no particular limitations on the reaction conditions.
• the reaction can be conducted under standard reaction conditions to be used for chlorination.
• Compound (8n) can be obtained, for example, by using a reagent such as phosphorus pentachloride in a solvent such as phosphorus oxychloride, at a temperature of 0 to 150° C.
• Bases include sodium hydride and lithium diisopropylamide.
• Solvents include, for example, tetrahydrofuran and N,N-diformamide. The reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• the ester of compound (3o) is hydrolyzed to give compound (4o).
• the reaction can be conducted under the same condition as used in [Step C16] of production method C.
• compound (4o) is reacted with diphenylphosphoryl azide in the presence of a base to give compound (5o).
• Solvents for the reaction include toluene, t-butanol, tetrahydrofuran, and dichloromethane.
• Bases include tertiary amines such as triethylamine and diisopropylethylamine. The reaction can be conducted at a temperature ranging from ⁇ 50° C. to 50° C.
• the reaction can be achieved in t-butanol at a temperature ranging from 50° C. to 100° C.
• Acids include hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
• Solvents include methanol, ethanol, 1,4-dioxane, water, and mixtures thereof. The reaction can be conducted at a temperature ranging from 0° C. to 50° C. Production Method P
• a typical NH group-protecting reagent that is generally used in protecting NH groups can be used as an NH group-protecting reagent.
• R p3 is a t-butoxycarbonyl group
• the reaction can be achieved at a temperature ranging from 0 to 80° C. using a reagent such as di-t-butyl dicarbonate, in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, and tetrahydrofuran, in the presence of a base such as pyridine, 4-aminopyridine, triethylamine, and N,N-diisopropylethylamine.
• Reaction solvents include tetrahydrofuran, methanol, and ethanol.
• Acids include inorganic acids such as hydrochloric acid and sulfuric acid. The reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• Bases include sodium hydride, potassium t-butoxide, and 8-diazabicyclo[5.4.0]-7-undecene.
• Solvents include dichloromethane, tetrahydrofuran, and N,N-dimethylformamide. The reaction can be conducted at a temperature ranging from 0° C. to 100° C.
• Methanol can be used as solvent.
• the reaction can be conducted at a temperature ranging from 0° C. to 80° C.
• Reaction solvents include methanol, ethanol, and water.
• the reaction can be conducted at a temperature ranging from 20° C. to 150° C.
• R p5 represents a t-butoxycarbonyloxy group, a trityl group, or a group represented by the formula —SO 2 NH 2 ;
• T 10 represents a halogen atom or a hydrogen atom]
• T 11 represents a halogen atom or a group represented by the formula:
• the methods indicated above are representative methods for producing compound (I) of the present invention.
• the starting compounds and various reagents to be used in the methods for producing compounds of the present invention may be salts or hydrates, or solvates depending on the type of starting materials, solvents to be used, or such, and are not limited as long as they do not inhibit the reactions.
• the type of solvents to be used depends on the types of starting compounds, reagents to be used, or such, and is not limited as long as it does not inhibit the reactions and dissolves starting materials to some extent.
• compound (I) of the present invention When compound (I) of the present invention is obtained as a salt or a hydrate, such a product can be converted to a free form of compound (I) described above according to a conventional method.
• various isomers of compound (I) of the present invention can be purified and isolated by typical isolation means, for example, including recrystallization, diastereomer salt method, enzyme-based separation, and various chromatographic methods (for example, thin layer chromatography, column chromatography, and gas chromatography).
• Compounds of the present invention, salts thereof, or hydrates thereof can be formulated into tablets, powders, particles, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, epithem, lotions, etc. by conventional methods.
• Such formulation can be achieved by using typical diluting agents, binders, lubricants, colorants, flavoring agents, and if required, stabilizers, emulsifiers, absorbefacients, surfactants, pH modulators, preservatives, antioxidants, etc., and materials commonly used as ingredients of pharmaceutical preparations according to conventional methods.
• an oral preparation can be produced by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a diluting agent, and if required, a binder, a disintegrating agent, a lubricant, a colorant, a flavoring agent, or such, and formulating the mixture into powders, particles, granules, tablets, coated tablets, capsules, or the like according to conventional methods.
• the materials include, for example, animal and vegetable oils such as soya bean oil, beef tallow, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resins; silicone oils; surfactants such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block co-polymer; water-soluble polymers such as hydroxyethyl cellulose, poly-acrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as
• Diluting agents include, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystal cellulose, and silicon dioxide.
• Binders include, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block co-polymer, and meglumine.
• Disintegrating agents include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, and calcium carboxymethyl cellulose.
• Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.
• Colorants include those pharmaceutically acceptable.
• Flavoring agents include cocoa powder, peppermint camphor, aromatic powder peppermint oil, Borneo camphor, and cinnamon powder. Tablets and granules may be coated with sugar, or if required, other appropriate coatings can be made.
• Solution such as syrups or injectable preparations, to be administered can be formulated by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a pH modulator, a solubilizing agent, an isotonizing agent, or such, and if required, with an auxiliary solubilizing agent, a stabilizer, or the like, according to conventional methods.
• Methods for producing an external preparation are not limited and such preparations can be produced by conventional methods. Specifically, various materials typically used for producing pharmaceuticals, quasi drugs, cosmetics, and such can be used as base materials for the external formulation.
• base materials to be used include, for example, animal and vegetable oils, mineral oils, ester oil, wax, higher alcohols, fatty acids, silicone oil, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, and pure water.
• external preparations of the present invention can contain, as required, pH modulators, antioxidants, chelating agents, antibacterial/antifungal agents, coloring matters, odoriferous substances, etc. But this does not limit the type of base materials that are to be used in an external preparation of the present invention.
• the preparation may contain differentiation inducers, blood flow improving agents, antimicrobial agents, antiphlogistics, cell activators, vitamins, amino acids, humectants, keratolytic agents, etc.
• the amount of base materials listed above is adjusted within a concentration range used for producing typical external preparations.
• a compound of the present invention or a salt thereof, or a hydrate thereof is administered
• the forms of a compound are not limited and a compound can be given orally or parenterally by a conventional method.
• a compound can be administered as a dosage form such as tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, epithems, and lotions.
• the dose of a pharmaceutical of the present invention can be selected appropriately based on symptom severity, age, sex, weight, forms of compounds, type of salts, specific type of diseases, etc.
• a pharmaceutical agent of this invention is administered once or several times at a dose of approx. 0.03 to approx. 1000 mg/adult/day, preferably 0.1 to 500 mg/adult/day, more preferably 0.1 to 100 mg/adult/day.
• An injection can be given at a dose of approx. 1 to approx. 3000 ⁇ g/kg, preferably approx. 3 to approx. 1000 ⁇ g/kg.
• reaction solution was concentrated to 50 ml, and washed with 20 ml of t-butyl methyl ether.
• the solution was acidified with concentrated hydrochloric acid.
• the resulting precipitate was collected by filtration, and washed successively with 10 ml of water and 10 ml of t-butyl methyl ether. Thus, 1.03 g of the title compound was obtained.
• reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was triturated with diethyl ether. The crystals were collected by filtration, and washed with diethyl ether. Thus, 3.0 g of the title compound was obtained as a white solid.
• the title compound was obtained by treating (7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl 2,2-dimethylpropionate by the same method as used in Example (1e).
• the mixture was stirred at room temperature for three hours.
• the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
• the solvent was concentrated, and the residue was dissolved in trifluoroacetic acid.
• the mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.89 mg of the title compound.
• the title compound was obtained by treating [7-(2-butynyl)-i-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate by the same method as used in Example (1f).
• the title compound was obtained by treating 7-(2-butynyl)-1-methyl-3,7-dihydropurine-2,6-dione by the same method as used in Example (1e).
• Example 4d Using iodocyclohexane instead of methyl 2-bromophenylacetate in Example (4d), the title compound was obtained by the same method as used in Example 4.
• This solution was poured into a suspension consisting of 7 g of di-t-butyl dicarbonate, 50 ml of tetrahydrofuran, 100 g of sodium bicarbonate, and 200 ml of water, and the mixture was stirred at room temperature for one hour.
• the reaction mixture was diluted with ethyl acetate, and the mixture was washed with water.
• the organic layer was dried over anhydrous magnesium sulfate, then filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography.
• Example (11b) Using ethanol instead of methanol in Example (11b), the trifluoroacetate of the title compound was obtained by the same method as used in Example 11. This compound was purified by chromatography using NH-silica gel. Thus, the title compound was obtained from the fraction eluted with ethyl acetate-methanol (20:1).
• Example 13 Using 2-methoxy ethanol instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 13.
• Example 13 Using ethyl 1-hydroxycyclopropanecarboxylate instead of ethyl 2-hydroxyacetate in Example 13, the trifluoroacetate of the title compound was obtained by the same method as used in Example 13. The compound was purified by chromatography using NH-silica gel. Thus, the title compound was obtained from the fraction eluted with ethyl acetate-methanol (20:1).
• Example 13 Using phenol instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 13.
• Example 13 Using ethyl 2-(t-butoxycarbonyl)acetate instead of ethyl 2-hydroxyacetate in Example 13, the title compound was obtained by the same method as used in Example 13.
• reaction solution was concentrated, and the residue was dissolved in trifluoroacetic acid.
• the mixture was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.38 mg of the title compound.
• the title compound was obtained using a mixed solution consisting of 0.5 ml of benzylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran solution) by the same method as used in Example 23.
• the title compound was obtained using a mixed solution consisting of 0.5 ml of phenethylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran solution) by the same method as used in Example 23.
• Example 30 Using N-methyl glycine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 2.06 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using L-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 1.35 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using N-methyl glycine t-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 3.16 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using D-proline methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 0.74 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using DL-alanine methyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 1.20 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using methyl 2-aminoisobutylate hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 1.18 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using L-alanine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 2.38 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using L-alanine t-butyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 0.76 mg of the title compound was obtained by the same method as used in Example 30.
• Example 30 Using ⁇ -alanine ethyl ester hydrochloride instead of glycine ethyl ester hydrochloride in Example 30, 0.85 mg of the title compound was obtained by the same method as used in Example 30.
• Example 41 Using morpholine instead of 2-ethoxyethylamine in Example 41, 7.31 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using benzylamine instead of 2-ethoxyethylamine in Example 41, 8.40 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using ethyl isonipecotate instead of 2-ethoxyethylamine in Example 41,7.43 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using N-methylbenzylamine instead of 2-ethoxyethylamine in Example 41, 2.38 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using 4-chlorobenzylamine instead of 2-ethoxyethylamine in Example 41, 2.84 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using phenethylamine instead of 2-ethoxyethylamine in Example 41, 2.70 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using N-methylphenethylamine instead of 2-ethoxyethylamine in Example 41, 2.17 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using ethyl nipecotate instead of 2-ethoxyethylamine in Example 41, 2.93 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using ethyl pipecolate instead of 2-ethoxyethylamine in Example 41, 0.97 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using L-proline t-butyl ester instead of 2-ethoxyethylamine in Example 41, 4.07 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using ethyl (R)-nipecotate instead of 2-ethoxyethylamine in Example 41, 0.87 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using ethyl (L)-nipecotate instead of 2-ethoxyethylamine in Example 41, 2.94 mg of the title compound was obtained by the same method as used in Example 41.
• Example 41 Using methylaminoacetonitrile instead of 2-ethoxyethylamine in Example 41, 1.00 mg of the title compound was obtained by the same method as used in Example 41.
• the residue was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was concentrated by flushing with nitrogen gas.
• the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.92 mg of the title compound.
• Example 63 Using DL-alanine methyl ester hydrochloride instead of D-proline methyl ester hydrochloride in Example 63, 1.12 mg of the title compound was obtained by the same method as used in Example 63.

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