WO2005066142A2 - Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists - Google Patents
Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists Download PDFInfo
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- WO2005066142A2 WO2005066142A2 PCT/JP2005/000319 JP2005000319W WO2005066142A2 WO 2005066142 A2 WO2005066142 A2 WO 2005066142A2 JP 2005000319 W JP2005000319 W JP 2005000319W WO 2005066142 A2 WO2005066142 A2 WO 2005066142A2
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- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- hydrogen
- alkoxy
- different
- Prior art date
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- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 title claims abstract description 12
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 150000003921 pyrrolotriazines Chemical class 0.000 title description 3
- 239000002464 receptor antagonist Substances 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 16
- SHCRKMNTWSCEBT-UHFFFAOYSA-N N1N=NC=C2N=CC=C21 Chemical group N1N=NC=C2N=CC=C21 SHCRKMNTWSCEBT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000005557 antagonist Substances 0.000 claims abstract description 5
- -1 Cι-6alkyl Chemical group 0.000 claims description 119
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 38
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
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- 125000001424 substituent group Chemical group 0.000 claims description 16
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000004677 hydrates Chemical class 0.000 claims description 8
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- YYQGUWHFXVXQOO-GFCCVEGCSA-N 2-chloro-4-[[3-[(2R)-2-hydroxybutyl]-1-methyl-2-oxobenzimidazol-5-yl]amino]pyridine-3-carbonitrile Chemical compound ClC1=C(C#N)C(=CC=N1)NC1=CC2=C(N(C(N2C[C@@H](CC)O)=O)C)C=C1 YYQGUWHFXVXQOO-GFCCVEGCSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052760 oxygen Inorganic materials 0.000 claims description 3
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- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
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- KCTZOTUQSGYWLV-UHFFFAOYSA-N N1C=NC=C2N=CC=C21 Chemical group N1C=NC=C2N=CC=C21 KCTZOTUQSGYWLV-UHFFFAOYSA-N 0.000 claims 3
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
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- 150000002576 ketones Chemical class 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a therapeutic agent for diseases in which corticotropin releasing factor (CRF) is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitides, schizophrenia, pain, etc.
- CCF corticotropin releasing factor
- CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987), and it is suggested that CRF plays a core role in biological reactions against stresses (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol, 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995).
- CRF CRF Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp. 29-52, 1990.
- Intraventricular administration of CRF to hypophy- sectomized rats and normal rats causes an anxiety-like symptom in both types of rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, there are suggested the participation of CRF in hypothalamus-pituitary-adrenal system and the pathway by which CRF functions as a neurotransmitter in central nervous system.
- CRF CRF is involved (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is involved in depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immunity-related diseases, etc. It has recently been reported that
- CRF CRF is involved also in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and cephalic external wound (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170,
- WO98/35967 discloses pyrrolopyrimidines or pyrrolotriazine derivatives respectively as CRF receptor antagonists. However, none disclose the compounds provided in the present invention.
- An object of the present invention is to provide an antagonist against CRF receptors which is effective as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain, etc.
- diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain, etc.
- the present inventors earnestly investigated pyrrolopyrimidines or pyrrolotriazines substituted with a carbamoyl group that have a high affinity for CRF receptors, whereby the present invention has been accomplished.
- the present invention is pyrrolopyrimidine or pyrrolotriazine derivatives substituted with a carbamoyl group explained below.
- E is N or CR 10 ;
- R 1 is -OR 4 , -S(O) ⁇ R 4 or -NR 4 R 5 ;
- R 2 is hydrogen, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, halogen, C ⁇ -6 alkoxy, C 3-7 cycloalkyloxy, C ⁇ -6 alkylthio or -N(R 6 )R 7 ;
- R 3 is hydrogen, C ⁇ -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C ⁇ _ 6 alkyl or aryl;
- R 4 and R 5 are the same or different, and independently hydrogen, Ci.palkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, di(C 3-7 cycloalkyl)-C 1-6 alkyl, C ⁇ -6 alkoxy-C ⁇ .
- R 4 and R 5 are taken together to form - (CH 2 ) m -A-(CH 2 ) n - wherein A is methylene, oxygen, sulfur, NR 8 or CHR 9 ; R and R 7 are the same or different, and independently hydrogen or C ⁇ _ 6 alkyl; R 8 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, aryl or aryl-C 1-6 alkyl; R 9 is hydrogen, hydroxy, hydroxy-C ⁇ -6 alkyl, cyano or cyano-Ci- ⁇ alkyl; R 10 is hydrogen, halogen or C 1-6 alkyl; 1 is an interger selected from 0, 1 and 2; m
- C 1-9 alkyl means a straight chain or branched chain alkyl group of 1 to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, sec-butyl, pentyl, isopentyl, 1-methylbutyl, hexyl, isohexyl, 1-ethylpropyl, 1- ethylbutyl, 1,3-dimethylbutyl, 1-propylbutyl, 1-propylpentyl, 1-butylpentyl or the like.
- C 3 _ 7 cycloalkyl means a cyclic alkyl group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
- Cs ⁇ cycloalkyl-C ⁇ ealkyl means a substituted C 1-6 alkyl group having the above-mentioned C 3-7 cycloalkyl as the substituent, such as cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 1-cyclopropylpropyl, 1- cyclobutylpropyl, 1-cyclopentylpropyl, 1-cyclopropylmethylpropyl, 1- cyclopropylmethylbutyl or the like.
- C 3-8 cycloalkyloxy means a cyclic alkoxy group of 3 to 8 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or the like.
- di(C 3-7 cycloalkyl)-C 1-6 alkyl means a substituted C ⁇ -6 alkyl group having two above-mentioned C 3- cycloalkyl groups as the substituents, such as di(cyclopropyl)methyl, di(cyclobutyl)methyl, di(cyclopentyl)methyl or the like.
- C ⁇ -6 alkoxy means a straight chain or branched chain alkoxy group of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy or the like.
- C 1-6 alkoxy-C ⁇ -6 alkyl means a substituted C 1-6 alkyl group having the above-mentioned C 1-6 alkoxy group as the substituent, such as methoxymethyl, 2- methoxyethyl, 2-ethoxyethyl, 1-methoxymethylpropyl, 1-methoxymethylbutyl or the like.
- di(C ⁇ -6 alkoxy)-C 1-6 alkyl means a substituted C 1-6 alkyl group having two above-mentioned C 1-6 alkoxy groups as the substituents, such as 2,3- di(methoxy)propyl, 2-methoxy-l-methoxymethyl-ethyl, 2,4-di(ethoxy)pentyl or the like.
- hydroxy-C 1-6 alkyl means a substituted d- 6 alkyl group having a hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1- hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 5- hydroxypentyl, l-hydroxymethylpropyl, 1-hydroxymethylbutyl, l-hydroxymethyl-3- methylbutyl or the like.
- cyano-C ⁇ -6 alkyr means a substituted C 1-6 alkyl group having a cyano group, such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl, 1- cyanobutyl, 5-cyanopentyl, 2-cyano-l-ethylethyl, 1-cyanomethylbutyl, l-cyano-3- methylbutyl, l-cyanomethyl-3 -methyl-butyl or the like.
- carbamoyl-C 1-6 alkyl means a substituted C 1-6 alkyl group having a carbamoyl group, such as carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl, 1-carbamoylpropyl, 1-carbamoylbutyl, 5-carbamoylpentyl, l-carbamoyl-3- methylbutyl, 1-carbamoylmethylbuty, 1-carbamoylmethylpropyl, 1- carbamoylmethyl-3-methylbutyl or the like.
- di(C ⁇ -6 alkyl)amino means a amino group having two above- mentioned C 1-6 alkyl groups, such as dimethylamino, diethylamino, dipropylamino or the like.
- di(C ⁇ -6 alkyl)amino-C 2-6 alkyl means a substituted C 2-6 alkyl group having a above-mentioned di(C 1-6 alkyl)amino group, such as 2- dimethylaminoethyl, 3-dimethylaminopropyl or the like.
- aryl means a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl, or the like.
- heteroaryl means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring having in its ring 1 to 4 atoms which may be the same or different and are selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, quinolyl, indolyl, benzofuranyl, quinoxalinyl, benzo[l,2,5]thiadiazolyl, benzo[l,2,5]oxadiazolyl or the like.
- ary-C salkyl means a substituted Ci-salkyl group having the above-mentioned aryl as the substituent, such as benzyl, phenethyl or the like.
- halogen means fluorine, chlorine, bromine or iodine atom.
- C 2-6 alkenyl means a straight chain or branched chain alkenyl group of 2 to 6 carbon atoms, such as vinyl, isopropenyl, allyl or the like.
- C 2-6 alkynyl means a straight chain or branched chain alkynyl group of 2 to 6 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.
- C ⁇ -6 alkylthio means a straight chain or branched chain alkylthio group of 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio or the like.
- aryl or heteroaryl which aryl or heteroaryl is unsubstituted or substituted with 1 or more substituents, which are the same or different, selected from the group consisting of halogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-
- the "pharmaceutically acceptable salts" in the present invention include, for example, salts with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, jp-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc
- isomers such as diastereomers, enantiomers, geometricisomers and tautomeric forms may exist.
- the compound of the present invention includes the individual isomers and the racemic and non- racemic mixtures of the isomers.
- R 1 , R 2 , R 3 and Ar are as defined in formula [I]. More preferable are compounds of the formula [II], wherein R 1 is -OR 4 or -NR 4 R 5 ; R 2 is C 1-6 alkyl; R 3 is hydrogen or C 1-6 alkyl; R 4 and R 5 are the same or different, and independently hydrogen, C 1-9 alkyl, C 3- 7 cycloalkyl, C 3- cycloalkyl-C ⁇ . 6 alkyl, di(C 3-7 cycloalkyl)-C ⁇ -6 alkyl, C 1-6 alkoxy-C ⁇ .
- Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C 1-3 alkyl, C ⁇ -3 alkoxy, C ⁇ _ 3 alkylthio, trifluoromethyl, trifluoromethoxy and -N(R 20 )R 21 (wherein R 20 and R 21 are the same or different, and independently are hydrogen or C ⁇ -3 alkyl); More preferable are compounds of the formula [II], wherein R 1 is -OR 4 or -NR 4 R 5 ; R 2 is C ⁇ -6 alkyl; R 3 is hydrogen or C ⁇ -6 alkyl; R 4 is C ⁇ alkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkyl- C ⁇ -6 alkyl;
- R 1 , R 2 , R 3 and Ar are as defined in formula [I]. More preferable are compounds of the formula [III], wherein R 1 is -OR 4 or -NR 4 R 5 ; R 2 is C ⁇ -6 alkyl; R 3 is hydrogen or C 1-6 alkyl; R 4 and R 5 are the same or different, and independently hydrogen, -palkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl-C 1 _ 6 alkyl, di(C 3 _ 7 cycloalkyl)-C 1-6 alkyl, C 1-6 alkoxy-C ⁇ -6 alkyl, di(C 1- 6 alkoxy)-C ⁇ -6 alkyl, hydroxy-C ⁇ -6 alkyl or cyano-C 1-6 alkyl; Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen, C ⁇
- R 5 is hydrogen
- Ar is phenyl which phenyl is substituted with two or three substituents, which are the same or different, selected from the group consisting of halogen and C 1-3 alkyl.
- the compound of the formula [I] can be produced, for example, by the process shown in the following reaction scheme 1 (in the following reaction scheme, R 1 , R 2 , R 3 and Ar are as defined above, LG is chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group, R a is C 1-6 alkyl or benzyl, p is 1 or 2).
- Step l Compound (2) can be obtained by reacting Compound (1) with the corresponding amine in an inert solvent in the presence or absence of a base.
- the base includes, for example, amines such as triethylamine, N,N- diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium dusopropylamide and the like; and Grignard reagents such as methylmagnesium bromide and the like.
- the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; esters such as ethyl acetate, ethyl formate; amides such as N,N- dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
- alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
- ethers such as diethyl ether, tetrahydr
- Step 2 Conversion of a cyano group in Compound (2) into a carbamoyl group can be achieved in the presence of an acid or a base in the presence or absence of an inert solvent.
- R 1 has a cyano group
- the cyano group can be converted into a carbamoyl group at the same time.
- the acid includes inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid nitric acid and the like; organic acids such as benzenesulfonic acid, toluenesulfonic acid and the like.
- the base includes inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminium hydroxide and the like.
- the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, tert- butyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N- methylpyrrolidone, N,N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
- the compound of the present invention can be converted to a salt with an acid in an inert solvent.
- the acid includes inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and the like; organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid,p- toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid and the like.
- the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons such as benzene, toluene and the like; amides such as N,N-dimethylformamide, N- methylpyrrolidone, N,N-dimethylacetamide and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as acetone, methylethylketone and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
- alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the
- Step 3 Conversion of Compound (4) into Compound (5) can be carried out by treatment of (4) with thiourea in an inert solvent and followed by reacting with an alkylating reagent in the presence or absence of a base in an inert solvent.
- the alkylating reagent includes conventional alkylating reagents such as methyl iodide, methyl bromide, dimethyl sulfate, ethyl iodide, ethyl bromide, diethyl sulfate, benzyl chloride, benzyl bromide and the like.
- the base includes amines such as triethylamine, NN-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium dusopropylamide and the like; and Grignard reagents such as methylmagnesium bromide and the like.
- amines such as triethylamine, NN-diisopropylethylamine, pyridine and the like
- inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like
- the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
- alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
- ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxye
- Step 4 Conversion of Compound (5) into Compound (6) can be achieved in the same manner as step 2.
- Step 5 Conversion of Compound (6) into Compound (7) can be carried out by reacting Compound (6) with an oxidizing reagent in an inert solvent.
- the oxidizing reagent includes conventional oxidizing reagents to oxidize a sulfide group such as peroxyacetic acid, hydrogen peroxide, 3-chloroperoxybenzoic acid, Oxone, sodium periodate, sodium perborate and the like.
- the inert solvent includes, for example, alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; hydrocarbons such as benzene, toluene, xylene and the like; amides such as N,N-dimethylformamide, N-methylpyrrolidone, N,N- dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and mixtures of solvents selected from these inert solvents.
- alcohols such as methanol, ethanol, isopropyl alcohol, ethylene glycol and the like
- ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxye
- Step 6 Conversion of Compound (7) into Compound (8) can be carried out in the same manner as step 1.
- the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved.
- the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by a conventional preparation technique by adding conventional fillers, binders, disintegrators, pH-adjusting agents, solvents, etc.
- the compound of the present invention can be administered to an adult patient in a dose of 0.1 to 500 mg per day in one portion or several portions orally or parenterally. The dose can be properly increased or decreased depending on the kind of a disease and the age, body weight and symptom of a patient.
- Table 1 and table 2 list the compound obtained in Example 1 and compounds obtained by the similar procedure as described in Example 1.
- Table 1 lists the compound obtained in Example 2 and compounds obtained by the similar procedure as described in Example 2.
- EDTA 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin, to obtain a membrane preparation.
- CRF receptor binding test The membrane preparation (0.3 mg protein/ml), 125 I-CRF (0.2 nM) and a test drug were reacted at 25°C for 2 hours. After completion of the reaction, the reaction mixture was filtered by suction through a glass filter (GF/C) treated with
- 1-006, 1-007, 1-008, 1-009, 1-010, 1-011, 1-012, 1-013, 1-016, 1-017, 1-018, 1-019, 1-022, 1-027, 2-001, 2-002, 2-003, 2-004, 2-005 and 2-006 can be exemplified as typical compounds having an IC 5 0 value of 100 nM or less.
- CRF CRF receptors
- These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain, etc.
- diseases in which CRF is considered to be involved such as depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastral diseases, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cephalic external wound, inflammation, immunity-related diseases, alpecia, irritable bowel syndrome, sleep disorders, dermatitides, schizophrenia, pain, etc.
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Abstract
Description
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/584,946 US8106194B2 (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives |
EP05703558A EP1706410A2 (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists |
JP2006546614A JP4742273B2 (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives |
CN2005800020220A CN1910185B (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives as CRF receptor antagon |
CA2552503A CA2552503C (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives |
HK07103339.7A HK1097539A1 (en) | 2004-01-06 | 2007-03-29 | Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists |
Applications Claiming Priority (2)
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JP2004001311 | 2004-01-06 | ||
JP2004-001311 | 2004-01-06 |
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WO2005066142A2 true WO2005066142A2 (en) | 2005-07-21 |
WO2005066142A3 WO2005066142A3 (en) | 2005-10-13 |
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PCT/JP2005/000319 WO2005066142A2 (en) | 2004-01-06 | 2005-01-06 | Pyrrolopyrimidine and pyrrolotriazine derivatives as crf receptor antagonists |
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Country | Link |
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US (1) | US8106194B2 (en) |
EP (1) | EP1706410A2 (en) |
JP (1) | JP4742273B2 (en) |
CN (1) | CN1910185B (en) |
CA (1) | CA2552503C (en) |
HK (1) | HK1097539A1 (en) |
RU (1) | RU2367663C2 (en) |
WO (1) | WO2005066142A2 (en) |
Cited By (5)
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US7365078B2 (en) | 2004-01-06 | 2008-04-29 | Taisho Pharmaceutical Co., Ltd. | Triaza-cyclopenta[cd]indene derivatives |
US7557111B2 (en) | 2004-01-06 | 2009-07-07 | Taisho Pharmaceutical Co., Ltd. | Substituted thieno[3,2-d]pyrimidines as CRF receptor antagonists |
US7951811B2 (en) | 2004-06-25 | 2011-05-31 | Taisho Pharmaceutical Co., Ltd. | Pyrrolo[2,3-D]pyrimidine derivatives substituted with a cyclic amino group |
US8106194B2 (en) | 2004-01-06 | 2012-01-31 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolotriazine derivatives |
WO2017004408A1 (en) * | 2015-07-01 | 2017-01-05 | Northwestern University | Substituted 4-methyl-pyrrolo[1.2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
Families Citing this family (1)
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CA2736018C (en) * | 2008-09-16 | 2015-11-03 | Stephanie Merchant | Compositions for treating or delaying the onset of hair loss |
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KR20010005568A (en) | 1997-03-26 | 2001-01-15 | 우에하라 아끼라 | 4-Tetrahydropyridylpyrimidine Derivatives |
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-
2005
- 2005-01-06 CA CA2552503A patent/CA2552503C/en not_active Expired - Fee Related
- 2005-01-06 US US10/584,946 patent/US8106194B2/en not_active Expired - Fee Related
- 2005-01-06 RU RU2006128581/04A patent/RU2367663C2/en not_active IP Right Cessation
- 2005-01-06 EP EP05703558A patent/EP1706410A2/en not_active Withdrawn
- 2005-01-06 JP JP2006546614A patent/JP4742273B2/en not_active Expired - Fee Related
- 2005-01-06 WO PCT/JP2005/000319 patent/WO2005066142A2/en active Application Filing
- 2005-01-06 CN CN2005800020220A patent/CN1910185B/en not_active Expired - Fee Related
-
2007
- 2007-03-29 HK HK07103339.7A patent/HK1097539A1/en not_active IP Right Cessation
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EP0729758A2 (en) * | 1995-03-02 | 1996-09-04 | Pfizer Inc. | Pyrazolopyrimidines and pyrrolopyrimidines for treatment of neuronal and other disorders |
WO1998008847A1 (en) * | 1996-08-28 | 1998-03-05 | Pfizer Inc. | Substituted 6,5-hetero-bicyclic derivatives |
WO1998035967A2 (en) * | 1997-02-18 | 1998-08-20 | Neurocrine Biosciences, Inc. | Biazacyclic crf antagonists |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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US7365078B2 (en) | 2004-01-06 | 2008-04-29 | Taisho Pharmaceutical Co., Ltd. | Triaza-cyclopenta[cd]indene derivatives |
US7557111B2 (en) | 2004-01-06 | 2009-07-07 | Taisho Pharmaceutical Co., Ltd. | Substituted thieno[3,2-d]pyrimidines as CRF receptor antagonists |
US8106194B2 (en) | 2004-01-06 | 2012-01-31 | Taisho Pharmaceutical Co., Ltd. | Pyrrolopyrimidine and pyrrolotriazine derivatives |
US7951811B2 (en) | 2004-06-25 | 2011-05-31 | Taisho Pharmaceutical Co., Ltd. | Pyrrolo[2,3-D]pyrimidine derivatives substituted with a cyclic amino group |
WO2017004408A1 (en) * | 2015-07-01 | 2017-01-05 | Northwestern University | Substituted 4-methyl-pyrrolo[1.2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
US9802942B2 (en) | 2015-07-01 | 2017-10-31 | Northwestern University | Substituted 4-methyl-pyrrolo[1,2-A]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
US10040799B2 (en) | 2015-07-01 | 2018-08-07 | Northwestern University | Substituted 4-methyl-pyrrolo[1,2-A]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
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US10227352B2 (en) | 2015-07-01 | 2019-03-12 | Northwestern University | Substituted 4-methyl-pyrrolo[1,2-A]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
US10442812B2 (en) | 2015-07-01 | 2019-10-15 | Northwestern University | Substituted 4-methyl-pyrrolo[1,2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity |
Also Published As
Publication number | Publication date |
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JP2007517794A (en) | 2007-07-05 |
RU2006128581A (en) | 2008-02-20 |
HK1097539A1 (en) | 2007-06-29 |
CN1910185A (en) | 2007-02-07 |
US20110137031A1 (en) | 2011-06-09 |
US8106194B2 (en) | 2012-01-31 |
CN1910185B (en) | 2010-05-26 |
CA2552503C (en) | 2011-09-13 |
JP4742273B2 (en) | 2011-08-10 |
CA2552503A1 (en) | 2005-07-21 |
EP1706410A2 (en) | 2006-10-04 |
RU2367663C2 (en) | 2009-09-20 |
WO2005066142A3 (en) | 2005-10-13 |
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