| 摘要 |
#CMT# #/CMT# Nitrogen substituted heterocyclic compounds (I) and their salts, solvates or solvates of the salts, are new. #CMT# : #/CMT# Nitrogen substituted heterocyclic compounds of formula (I) and their salts, solvates or solvates of the salts, are new. U 1>N; W 1>N or CR 1>6>; V 1>CR 1>2>or N; A : CR 1>5>or N; R 1>2>e.g. H, OH or amino; R 1>5>e.g. H, halo or CN; R 1>6>H or CH 3; R1 : e.g. piperidine groups or pyrrolidine groups; and R 2>6-10C-aryl or 5-10-membered heteroaryl. Full Definitions are given in the DEFINITIONS (Full Definitions) Field. An independent claim is included for the preparation of (I). #CMT#[Image]#/CMT# #CMT#ACTIVITY : #/CMT# ACTIVITY -Antianemic; Immunostimulant; Neuroprotective; Nootropic; Antiparkinsonian; Neuroleptic; Antidepressant; Tranquilizer; Cerebroprotective; Vasotropic; Hypnotic; Anticonvulsant; Antidiabetic; Analgesic; Antianginal; Anorectic; Nephrotropic; Ophthalmological; Cardiovascular-Gen.; CNS-Gen.; Gastrointestinal-Gen.; Calcium antagonist; Antisickling; Hemostatic; Anticoagulant; Thrombolytic; Immunosuppressive; Immunomodulator; Cytostatic; Antiasthmatic; Antiinflammatory; Respiratory-Gen.; Antiarthritic; Antirheumatic; Antibacterial; Virucide; Fungicide; Anti-HIV; Hepatotropic; Antiparasitic; Antimalarial; Endocrine-Gen.; Vulnerary; Osteopathic; Cardiant; Antiarrhythmic; Antiarteriosclerotic; Hypotensive. #CMT#MECHANISM OF ACTION : #/CMT# Glycogen synthase kinase 3-beta -inhibitor. The ability of (I) to inhibit glycogen synthase kinase 3-beta was tested using biochemical assay. The results showed that (I), preferably 4-amino-2-[(2-{[6-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrazin-8-yl]amino}ethyl)amino]-1,3-thiazol-5-carbonitrile exhibited an IC 50value of 3.2 nM. #CMT#USE : #/CMT# (I) is useful for: the treatment and/or prophylaxis of diseases, preferably hematological disease, preferably leukopenia and neutropenia; and the efficient ex-vivo increase of adult hematopoietic stem cells from bone marrow and/or peripheral blood, and/or embryonic stem cells from umbilical cord blood (all claimed). (I) is useful for: the treatment and/or prophylaxis of Alzheimer's disease, Parkinson's disease, schizophrenia, degeneration, dementia, depression, aggression, cerebrovascular ischemia, insomnia, Huntington's chorea, neurotraumatic diseases e.g. stroke, type II diabetes mellitus and associated diseases and metabolic syndrome or obesity, type 1 diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, glomerulonephritis, hypercalcemia, neutropenia, chemotherapy-induced neutropenia, granulocytopenia, acquired and innate leukopenia, acquired and innate anemia, hemolytic anemia, sickle cell anemia, thrombocytopenia, leukocyte function disease, blood clotting disorder, graft-versus-host-reaction, cancer (e.g. liver tumor and pancreas tumor), leukemia (e.g. acute/chronic lymphatic leukemia and acute/chronic myeloid leukemia), asthma, pneumonia, lung diseases, inflammatory diseases, autoimmune disorder, preferably multiple sclerosis, rheumatoid arthritis, infections caused by gram-negative and gram-positive bacteria, viral infections, fungal infection caused by Candida albicans, HIV or HIV associated infections, hepatitis A, B and C, parasite infections, malaria, alopecia, wound healing, glaucoma, osteoporosis, bone marrow diseases, bone and joint diseases, and circulatory heart disease, preferably cardiac defect, heart attack, cardiac fibrosis, cardiac arrhythmias or myocardial infarction, medicament or substance induced cardiotoxicity, atherosclerosis and hypertension. #CMT#ADVANTAGE : #/CMT# (I) exhibits high pharmacological and pharmacokinetic activity. #CMT#ORGANIC CHEMISTRY : #/CMT# Preparation (Claimed): Preparation of (I) comprises reacting a nitrogen substituted heterocyclic compound of formula (II) with a compound of formula (R1-H) (III). X 1>halo, preferably Cl or F. #CMT#[Image]#/CMT# #CMT#DEFINITIONS : #/CMT# Full Definitions: U 1>N; W 1>N or CR 1>6>; V 1>CR 1>2>or N; A : CR 1>5>or N; R 1>2>H, OH, amino, hydroxycarbonyl, amino carbonyl, CF 3, CF 3O, CN, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl-amino, 5- or 6-membered heterocyclylcarbonyl, CH 2R 1>3>or -CH 2CH 2R 1>4>, where: the heterocyclylcarbonyl is optionally substituted by 1-3 substituents halo, oxo, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkylaminocarbonyl, the alkoxy, alkyl amino, alkyl carbonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino or alkylsulfonylamino are substituted by hydroxy, amino, hydroxycarbonyl, amino carbonyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, 5- or 6-membered heterocyclyl or phenyl, the phenyl is optionally substituted by 1-3 substituents of halo, CN, CF 3, CF 3O, amino carbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl or 1-4C-alkylcarbonylamino, and the heterocyclyl is optionally substituted by 1-3 substituents of halo, oxo, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkylaminocarbonyl; R 1>3>, R 1>4>OH, amino, CN, hydroxycarbonyl, amino carbonyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino or 5- or 6-membered heterocyclyl, where the alkoxy, alkyl amino, alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino is optionally substituted by OH, amino, hydroxycarbonyl, amino carbonyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl or 1-4C-alkylcarbonylamino, and the heterocyclyl is optionally substituted by 1-3 substituents of halo, oxo, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkylaminocarbonyl; R 1>5>H, halo, CN, CF 3, 1-3C-alkyl, CH 3O, methylthio or cyclopropyl; R 1>6>H or CH 3; R 1>-X-C(R 4>)(R 5>)-C(R 6>)(R 7>)-(C(Y 1>-R 3>)(R 8>)-R 9>) n(a), piperidine group of formula (b) or (c), pyrrolidine group of formula (d) or (e); aa : connection to heterocycle; n : 0 or 1; X : R 1>0>, S or O; Y 1>NR 1>1>or S; R 1>0>, R 1>1>H, 1-3C-alkyl or cyclopropyl; R 3>pyrid-2-yl, pyrimid-2-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-thiazol-2-yl or 1,3-thiazol-4-yl (all optionally substituted by 1-2 substituents of halo, CN, NO 2, amino, CF 3, CF 3O, amino carbonyl, trifluoromethylcarbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 3-4C-cycloalkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl or 3-6C-cycloalkylcarbonyl), or 2-aminopyrimid-4-yl, 2-(mono-1-4C-alkylamino)pyrimid-4-yl, 2-(mono-3-4C-cycloalkylamino)pyrimid-4-yl, pyridazin-3(2H)-on-6-yl, 1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1H-1,2,4-triazol-5-yl, 2,4-dihydro-3H-1,2,4 triazol-3-on-5-yl) or 1,2-pyrazol-5-yl (all optionally substituted by halo, CN, nitro, amino, CF 3, CF 3O, amino carbonyl, trifluoromethylcarbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 3-4C-cycloalkylamino, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl or 3-6C-cycloalkylcarbonyl), where the alkyl, alkoxy, alkyl amino, alkyl carbonyl, alkoxycarbonyl, alkylaminocarbonyl or cycloalkylcarbonyl is optionally substituted by halo, CN, OH, amino, CF 3or 3-6C-cycloalkyl; R 4>, R 6>, R 8>H, 1-3C-alkyl or cyclopropyl; R 5>, R 7>, R 9>H or 1-3C-alkyl; and R 2>6-10C-aryl or 5-10-membered heteroaryl (both optionally substituted by 1-3 substituents of OH, hydroxymethyl, amino, halo, CN, CF 3, CF 3O, amino carbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxymethyl, 1-4C-alkylamino, 1-4C-alkylaminomethyl, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkylsulfonylamino, 1-4C-alkylaminosulfonyl, phenyl, benzyloxy, 5- or 6-membered heterocyclyl, 5- or 6-membered heterocyclylcarbonyl, 5- or 6-membered heterocyclylmethyl or 5- or 6-membered heteroaryl, where: phenyl, benzyloxy, heterocyclyl, heterocyclylcarbonyl, heterocyclylmethyl or heteroaryl is optionally substituted by 1-3 substituents of halo, CN, CF 3, CF 3O, amino carbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylamino, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl, 1-4C-alkylaminocarbonyl or 1-4C-alkylcarbonylamino, and two of the substituents at the aryl together with C forms a 1,3-dioxolane or 1,4-dioxane. Preferred Definitions: R 1>2>-R 1>6>, R 4>-R 1>1>H; R 1>(a); n : 0; X : NR 1>0>; Y 1>NR 1>1>; R 3>substituted pyridin-2-yl group of formula (f); aaa : connection with Y 1>; L : CN, nitro or trifluoromethylcarbonyl; M : H or amino; and R 2>phenyl, which is optionally substituted by 1-2 substituents of F, Cl or CF 3. #CMT#[Image]#/CMT# #CMT#[Image]#/CMT# #CMT#ADMINISTRATION : #/CMT# Administration of (I) is oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, or via implant or stent. No dosage details given. #CMT#SPECIFIC COMPOUNDS : #/CMT# 28 Compounds (I) are disclosed e.g. 6-[(2-{[6-(2,4-dichlorophenyl)[1,2,4]triazolo[3,4-f][1,2,4]triazin-8-yl]-amino}ethyl)amino]pyridin-3-carbonitrile of formula (Ia), 2-amino-6-[(2-{[6-(2,4-dichlorophenyl)[1,2,4]triazolo[3,4-f][1,2,4]triazin-8-yl]amino}ethyl)-amino]pyridin-3-carbonitrile, 2-amino-6-{[2-{6-[(4-trifluoromethyl)phenyl][1,2,4]triazolo[3,4-f][1,2,4]triazin-8-yl}amino-ethyl]amino}pyridin-3-carbonitrile, 6-{[2-({6-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[3,4-f][1,2,4]triazin-8-yl}amino)ethyl]-amino}pyridin-3-carbonitrile and 6-[(2-{[6-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-a]pyrazin-8-yl]amino}ethyl)amino]pyridin-3-carbonitrile. #CMT#[Image]#/CMT# #CMT#EXAMPLE : #/CMT# Butyl-[(Z)-(2)4-dichlorophenyl-(4H-1,2,4-triazol-4-yl-imino)methyl]carbamate (4.7 g) was stirred in phenol (25 ml) for 5 hours. The reaction mixture was diluted with dichloromethane to obtain 8-chloro-6-(2,4-dichlorophenyl)[1,2,4]triazolo[3,4-f][1,2,4]triazine (3 |
