EP1355909A2 - Dihydropyrazolopyridine compounds and pharmaceutical use thereof - Google Patents

Dihydropyrazolopyridine compounds and pharmaceutical use thereof

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Publication number
EP1355909A2
EP1355909A2 EP02710458A EP02710458A EP1355909A2 EP 1355909 A2 EP1355909 A2 EP 1355909A2 EP 02710458 A EP02710458 A EP 02710458A EP 02710458 A EP02710458 A EP 02710458A EP 1355909 A2 EP1355909 A2 EP 1355909A2
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EP
European Patent Office
Prior art keywords
dihydro
pyrazolo
pyridine
ethyl
carboxylate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02710458A
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German (de)
French (fr)
Inventor
Toshiyuki c/o MITSUBISHI PHARMA CORP. KOHARA
Kenji c/o MITSUBISHI PHARMA CORP. FUKUNAGA
Masatake c/o MITSUBISHI PHARMA CORP. FUJIMURA
Tokushi c/o MITSUBISHI PHARMA CORP. HANANO
Hirotaka c/o MITSUBISHI PHARMA CORP. OKABE
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Mitsubishi Pharma Corp
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Mitsubishi Pharma Corp
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Publication date
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Publication of EP1355909A2 publication Critical patent/EP1355909A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
  • glycogen synthase kinase-3 beta (GSK-3 ⁇ ), a protein kinase, is involved in the causes of various diseases as noted in the following.
  • Type-II diabetes is a disease in which the insulin reactivity of pancreatic ⁇ cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced.
  • GSK-3 ⁇ acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GS -3 ⁇ -inhibitory activity actually lowers glucose in blood by a GSK-3 ⁇ -inhibitory activity (Proc. Nat. Acad. Sci, 93, 8455 (1996)). Therefore, medicaments having a GSK-3 ⁇ -inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.
  • GSK-3 ⁇ is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)).
  • Tat which is a protein produced by HIV virus that causes AIDS, enhances GSK-3 ⁇ activity in neurons to induce neuronal death (J. Neurochem., 73, 578 (1999)).
  • GSK-3 ⁇ inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
  • Lithium and valproic acid which have anti-manic- depressive activity, have a GSK-3 ⁇ inhibitory activity (J. Neurochem., 72, 1327 (1999)).
  • the relationship between anti- manic-depressive activity and GSK-3 ⁇ inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998)).
  • GS -3 ⁇ inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.
  • NF-AT a transcription factor
  • calcineurin a transcription factor
  • 3 ⁇ inhibitors are considered to be medicaments effective for immunopotentiation.
  • JP-A-3-272189 invention drawn to an improved synthesis method of mevalolacton intermediates
  • JP- A-2-275878 therapeutic agents for hyperlipoproteinemia and atherosclerosis
  • JP-A-1-272584 therapeutic agents for hyperlipoproteinemia
  • JP-A-59-65089, JP-A-59-118786, JP- A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4- substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5- carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods.
  • the present inventors reproduced the following reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[l,5-a]pyrimidine derivative represented by the formula (V) could be produced.
  • An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3 ⁇ ), and further, medicaments comprising them.
  • the present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo[ 3, 4-b] yridine derivatives have a selective and strong inhibitory activity on GSK-3 ⁇ , which resulted in the completion of the present invention.
  • the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-3 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
  • formula (I) dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-3 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
  • R° is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group optionally having substituent( s) , phenylalkyl optionally having substituent(s) , or a group of the formula: -COOR 8 (wherein R 8 is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)) ; R 1
  • aromatic heterocyclic group (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
  • R 6 and R 7 are each phenyl optionally having substituent( s) or an aromatic heterocyclic group, or R 2 and R 3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent( s) ;
  • R 4 is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and
  • R 5 is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalk l, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s) (particularly phenyl), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, or R 4 and R 5 in conjunction may form a 5 or 6 membered
  • R 5 is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituent( s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a medicament comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • a pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.
  • a glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.
  • Alzheimer's disease ischemic cerebrovascular disorder
  • Down's syndrome cerebral ischemia due to cerebral amyloid angiopathy
  • progressive supranuclear paralysis progressive supranuclear paralysis
  • subacute sclerosing panencephalitic Parkinsonism postencephalitic Parkinsonism
  • boxer's encephalopathy Parkinson dementia complex of Guam
  • Lewy body disease Pick's
  • Fig. 1 shows the GSK-3 ⁇ -inhibitory activity of the compounds of Example 47 and Example 137.
  • Fig. 2 shows the effect of the compound of Example 66 on amyloid ⁇ -induced cytotoxicity.
  • Fig. 3 shows the GSK-3 ⁇ -inhibitory effect of the compound of Example 27 in a gerbil brain ischemia model.
  • the formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring.
  • the present invention encompasses each isomer of formulas (I-a) and (I-b), and a mixture of these isomers.
  • Alkyl means a linear or branched carbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl(a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s).
  • the alkyl of R 5 is preferably alkyl having 2 to 8 carbon atoms.
  • alkyl having 2 to 8 carbon atoms concretely includes ethyl, propyl, butyl, pentyl(amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-butyl and the like.
  • Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
  • Acyl includes alkylcarbonyl having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, and aromatic acyl having 7 to 12 carbon atoms, such as benzoyl, naphthoyl, cinnamoyl, benzylcarbonyl and the like.
  • the benzene and naphthalene rings may have 1 to 5 substituent( s) .
  • Cycloalkyl means a cyclic carbon chain of 3 to 8 carbon atoms.
  • Cycloalkyl concretely includes, for example, cyclopropyl, eyelobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl having 3 to 6 carbon atoms.
  • Halogen represents fluorine, chlorine, bromine or iodine.
  • Amino is primary amino, or secondary or tertiary amino having the above alkyl, and includes, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and the like, with a preference for tertiary amino containing alkyl having 1 to 4 carbon atom(s).
  • Alkylthio is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio(amylthio) , hexylthio and structural isomers thereof, such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom(s).
  • Haloalkyl is the above alkyl substituted by 1 to 5 halogen(s), and represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2, 2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like.
  • Aminoalkyl is the above-mentioned alkyl having the above amino, and includes, for example, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, 2- methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2- diethylaminoethyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom(s) having tertiary amino.
  • Acylamino is acylamino having the above acyl, and represents, for example, acetylamino, propion lamino, butyrylamino, valerylamino, pivaloylamino, benzoyla ino, phenyla ⁇ etylamino, phenylpropionylamino, phenylbutyrylamino and the like.
  • Alkoxy is alkoxy having the above alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy(amyloxy) , hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, ter -pentyloxy and the like, with a preference for alkoxy having 1 to 4 carbon atom(s).
  • Cycloalkoxy is alkoxy having the above cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms.
  • Phenylalkoxy is phenylalkoxy having the above alkoxy, and includes, for example, benzyloxy, 1-phenylethoxy, 2- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl-l- phenylethoxy, l-methyl-2-phenylethoxy, 1-phenylpropoxy, 2- pheylpropoxy, 1-methyl-1-phenylpropoxy, l-methyl-2- phenylpropoxy, 1-methyl-3-phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s) .
  • aminoalkoxy is aminoalkoxy consisting of the above alkoxy and amino, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- di ethylaminoethoxy, 3-dimethylaminopropoxy, 4- dimethylaminobutoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s), and alkoxy having 1 to 4 carbon atom(s) .
  • Alkoxyalkyl is alkoxyalkyl consisting of the above alkoxy and alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).
  • Phenoxyalkyl is phenoxyalkyl containing the above alkyl, and includes, for example, phenoxy ethyl, 2- phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
  • Dialkoxyalkyl is dialkoxyalkyl consisting of the above alkyl and alkoxy, and includes, for example, dimethoxymethy1, diethoxymethy1, 2, 2-dimethoxyethyl, 2,2-diethoxyethyl and the like, with a preference for dialkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
  • Hydroalkyl is hydroxyalkyl having the above alkyl, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl and the like, with a preference for hydroxylalkyl containing alkyl having 1 to 4 carbon atom(s).
  • Alkoxycarbonyl is alkoxycarbonyl having the above alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, see- butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s). However, R 4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms.
  • Aminocarbonyl is aminocarbonyl having the above amino, and includes, for example, aminocarbonyl (carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl, phenylcarbamoyl, benzylcarbamoyl and the like, with a preference for tertiary-aminocarbonyl containing alkyl having 1 to 4 carbon atom(s).
  • Alkylthiocarbonyl is alkylthiocarbonyl having the above alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert- butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms .
  • Carboxyalkyl is carboxyalkyl having the above alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s).
  • Cycloalkoxyalkyl is cycloalkoxyalkyl having the above cycloalkoxy and alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl and the like, with a preference for cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s) .
  • Alkylsulfinyl is alkylsulfinyl having the above alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 4 carbon atom(s).
  • Alkylsulfonyl is alkylsulfonyl having the above alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 4 carbon atom(s) .
  • Mercaptoalkyl is mercaptoalkyl having the above alkyl, and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).
  • Alkylthioalkyl is alkylthioalkyl having the above alkylthio and alkyl, and includes, for example, methylthiomethy1, methylthioethyl, methylthiopropy1, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
  • Aryl is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and the like. They may have 1 to 5 substituent( s) and substitution sites are not particularly limited.
  • Alkyl is aralkyl wherein the above alkyl is substituted by the above aryl, and includes benzyl, 2- phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent( s) on the aryl moiety.
  • Acyloxyacetyl is acyloxyacetyl having the above acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxya ⁇ etyl and the like.
  • “Acyloxyalkyl” is acyloxyalkyl having the above acyl and alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2- acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2- benzoyloxyethyl and the like.
  • Aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic ring optionally containing 1 to 3 heteroatom( s) of nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • the substituent of the "aromatic heterocyclic ring optionally having substituent( s) " is exemplified by those mentioned for the "substituent” below, wherein the number of the substituent is generally 1 to 5, preferably 3.
  • Phenylalkyl is phenylalkyl having the above alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1- phenylpropyl, 2-phenylpropyl, 1-methy1-1-phenylpropyl, 1- methyl-2-phenylpropyl, l-methyl-3-phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s).
  • Alkoxycarbonylalkyl is alkoxycarbonylalkyl having the above alkoxycarbonyl and alkyl, and includes, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3- ethoxycarbonylpropyl and the like.
  • Alkoxycarbonylethenyl is alkoxycarbonylethenyl having the above alkoxycarbonyl, and includes, for example, 2- methoxycarbonylethenyl, 2-ethoxycarbonylethenyl, 2- butoxycarbonylethenyl, 2-tert-butoxycarbonylethenyl and the like.
  • Dialkylphosphinyl is dialkylphosphinyl having the above alkyl, and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).
  • Dialkylphosphonyl is dialkylphosphonyl having the above alkyl, and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
  • substituted includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic ring, phenylalkyl, hydroxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like.
  • Ring optionally containing heteroatom(s) is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) consisting of nitrogen atom, oxygen atom and sulfur atom, with particular preference given to a ring containing sulfur atom.
  • the ring may be substituted by one or more of the above substituents or oxo groups.
  • the substitution site is not particularly limited.
  • This ring is formed by R and R in the formula (I) together with the attached carbon atom. By forming this ring, a spiro ring is formed in the compound of the formula (I) .
  • the above ring can be fused with a benzene ring optionally having substituent( s) .
  • Such a ring includes, for example, 2,3-dihydrobenzo[b]thiophene, 2,3- dihydrobenzo[b]thiophen-l-oxide and the like.
  • a group derived from a benzene ring, which is fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indan and the like, with preference given to naphthalene (namely naphthyl) and particular preference given to 1-naphthyl.
  • a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom( s) includes the following groups and the like.
  • 2 ,1 ,3-benzoxadiazole and 3 ,4-dihydro-2H- benzopyrane are preferable, and 2 ,1 ,3-benzoxadiazol-4-yl and 3 ,4-dihydro-2H-benzopyran-8-yl are particularly preferable.
  • a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom (s) , which is fused with a benzene ring includes the following groups and the like.
  • the "5 or ⁇ -membered ring optionally containing heteroatom (s) " is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom (s) consisting of nitrogen atom, oxygen atom and sulfur atom.
  • heteroatom s
  • Examples thereof include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, pyrroline, pyrrolidine, imidazoline and imidazolidine.
  • furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan and pyridine are preferable.
  • the compounds, represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention.
  • acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like.
  • the compounds of the present invention can form hydrates, solvates with ethanol and the like, and crystal polymorphs.
  • optical isomers and racemates thereof can be present, and all of these are encompassed in the present invention.
  • a compound wherein R° is hydrogen can be synthesized as shown in the following according to the method described in J. Chem. Soc, Perkin Trans. 1, 947 (1996) and the like. (First Production Method)
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • Meldrum's acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII) to give an amide derivative of the formula (IX).
  • the reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction.
  • a carboxylic acid solvent inert to the reaction.
  • the solvent formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • the obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X) .
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethyIformamide, dimethyl sulfoxide and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • the compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine.
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • the carbonyl derivative of the formula (VII), which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983).
  • the carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993). (Second Production Method)
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • the compounds (I) of the present invention can be produced by reacting aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII).
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent inert to the reaction.
  • ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used.
  • the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
  • a compound wherein R° is a substituent other than hydrogen can be synthesized as follows. (Third Production Method)
  • R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and X represents halogen, provided that R° is not hydrogen.
  • the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base.
  • a base includes, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like.
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like.
  • the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
  • R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, provided that R° is not hydrogen.
  • the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) in the presence of a base.
  • a base includes, for example, triethyla ine, pyridine, 4-dimethylaminopyridine and the like.
  • the reaction is carried out in the presence of a solvent inert to the reaction.
  • a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like.
  • the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
  • the compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography and the like. When the purified product obtained is a racemate, a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column packed with optically active carrier.
  • the present invention also encompasses optically active compounds.
  • the compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3 ⁇ such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3 ⁇ .
  • the compounds of the present invention have a GSK-3 ⁇ -selective inhibitory activity and can be medicaments with small side-effect for diabetes, diabetic complications and neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic- depressive psychosis and the like) .
  • Alzheimer's disease ischemic cerebrovascular disorders
  • Down's syndrome cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism,
  • Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation.
  • the carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and other conventionally used substances.
  • Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration of injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like.
  • the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1 - 1,000 mg, preferably 50 - 200 mg per day for an adult person, which is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.
  • solid compositions for oral administration tablet, powder, granule and the like are used.
  • one or more active substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid and magnesium aluminate.
  • the composition may contain, according to a conventional method, inert additives other than diluent, for example, a lubricant such as magnesium stearate, a disintegrator such as cellulose and calcium glycolate, a stabilizer such as lactose and a solubilizer such as glutamic acid and aspartic acid.
  • Tablet and pill may be coated with a gastric or enteric coating film of, for example, sucrose, gelatin, hydroxypropylcellulose and the like.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like, and contain an inert diluent generally used, such as purified water and ethanol. This composition may contain an adjuvant such as wetting agent and suspending agent, a sweetener, a flavor, an aromatic and an antiseptic, in addition to the inert diluent.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solution, suspension and emulsion.
  • the aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
  • a composition may contain adjuvants such as antiseptic, wetting agent, emulsifier, dispersant, stabilizer and solubilizer. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of an antimicrobial agent, irradiation of ultraviolet ray and the like.
  • a sterile solid composition may be prepared and used upon dissolution in sterile water or sterile solvent for injection prior to use.
  • Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples .
  • Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples .
  • the title compound was prepared from 2- methoxybenzaldehyde , 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
  • the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
  • IR(KBr) :v 3277, 3209, 3094, 1668, 1593, 1514, 1313, 1213,1153, 1097, 765cm _1 .
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl acetoacetate in the same manner as in Example 1.
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and t-butyl acetoacetate in the same manner as in Example 1.
  • the title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and isopropyl acetoacetate in the same manner as in Example 1. MP:218-220°C.
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and benzyl acetoacetate in the same manner as in Example 1. MP:234°C.
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and N,N-dimethylacetamide in the same manner as in Example 1. MP:229°C.
  • IR(KBr):v 3375, 3175, 3067, 1707, 1606, 1533, 1278, 1206, 1197, 1167cm -1 .
  • the title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
  • IR(KBr):v 3290, 3178, 3069, 1703, 1608, 1537, 1280, 1232, 1174, 1138,
  • the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
  • IR(KBr) :v 3321, 3178, 3070, 1703, 1610, 1535, 1278, 1224, 1184, 1145cm "1 .
  • IR(KBr):v 3263,3194,3080, 1668, 1591, 1520, 1286, 1232, 1149, 1095, 1062cm -1 .
  • the title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
  • the title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1. MP:119-120°C.
  • IR(KBr):v 3263, 3209, 3194, 3080, 1668, 1591, 1520, 1286, 1232, 1149, 106 2,750cm -1 .
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- met ylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- propoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- isopropyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- butoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- benzyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:128°C.
  • the title compound was prepared from 2,3- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2, 3- dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 3-fluoro-2- methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2,3- dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2-chloro-3- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:236-238°C.
  • the title compound was prepared from 2-chloro-4- fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2,5- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2,5- diehlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 5-fluoro-2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2-chloro-5- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
  • the title compound was prepared from pyridine-3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
  • the title compound was prepared from furan-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:121-123°C.
  • the title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:129-131°C.
  • the title compound was prepared from 5-chlorothiophene- 2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from thiophene-3- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
  • the title compound was prepared from naphthalene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 1, 3-benzdioxazole- 4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2, 3-dihydro-l, 4- benzodioxin-6-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from benzo[b]furan-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl (thiophen-2- carbonyl) acetate in the same manner as in Example 1.
  • the title compound was prepared from 2- propylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
  • the title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 25. MP:228°C.
  • the title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.

Abstract

The present invention provides dihydropyrazolopyridine compounds represented by the formula (I): wherein each symbol is as defined in the specification,optically active forms thereof, and pharmaceutically acceptable salts thereof and hydrates thereof. The compounds of the present invention show a selective and strong inhibitory activity on glycogen synthase kinase-3 beta (GSK-3β), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications and neurodegenerative diseases or as immunopotentiators.

Description

DESCRIPTION DIHYDROPYRAZOLOPYRIDINE COMPOUNDS AND PHARMACEUTICAL USE
THEREOF Technical field The present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
(GSK-3β) -inhibitory activity, and use thereof.
Background art It has been reported that glycogen synthase kinase-3 beta (GSK-3β), a protein kinase, is involved in the causes of various diseases as noted in the following.
Type-II diabetes is a disease in which the insulin reactivity of pancreatic β cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced. GSK-3β acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GS -3β-inhibitory activity actually lowers glucose in blood by a GSK-3β-inhibitory activity (Proc. Nat. Acad. Sci, 93, 8455 (1996)). Therefore, medicaments having a GSK-3β-inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof. The developmental mechanism of Alzheimer's dementia has not yet been elucidated. However, it is considered that amyloid aggregation and neurofibril changes are closely related to the cause of the development. GSK-3β is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)). In addition to the above, (3) the direct involvement of GSK-3β in nuronal death through inactivation of pyruvate dehydrogenase by phosphorylation to decrease the production amount of acetylcholine necessary for maintaining cell activity (Proc. Nat. Acad. Sci., 93, 2719 (1996)) has been reported.
In addition, the effectiveness for AIDS encephalopathia as a neurodegenerative disease other than Alzheimer has been suggested. Tat, which is a protein produced by HIV virus that causes AIDS, enhances GSK-3β activity in neurons to induce neuronal death (J. Neurochem., 73, 578 (1999)). From the above,
GSK-3β inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
Lithium and valproic acid, which have anti-manic- depressive activity, have a GSK-3β inhibitory activity (J. Neurochem., 72, 1327 (1999)). The relationship between anti- manic-depressive activity and GSK-3β inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998)).
Based on the foregoing, GS -3β inhibitors are considered to be medicaments effective for improving manic-depressive psychosis. NF-AT, a transcription factor, is dephosphorylated by calcineurin to increase immunological responses (Science, 275,
1930 (1997)). GS -3β acts for suppressing immunological function by conversely phosphorylating NF-AT. Therefore, GSK-
3β inhibitors are considered to be medicaments effective for immunopotentiation.
Incidentally, JP-A-3-272189 (invention drawn to an improved synthesis method of mevalolacton intermediates) , JP- A-2-275878 (therapeutic agents for hyperlipoproteinemia and atherosclerosis) and JP-A-1-272584 (therapeutic agents for hyperlipoproteinemia) disclose pyrazolo[3, 4-b]pyridine compounds wherein the 6-position is either methyl, isopropyl or cyclopropyl. These publications do not disclose or suggest any action of these compounds on GSK-3β or the central nervous system.
The specifications of JP-A-59-65089, JP-A-59-118786, JP- A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4- substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5- carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods. The present inventors reproduced the following reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[l,5-a]pyrimidine derivative represented by the formula (V) could be produced. They measured IR, NMR and the melting point of the compound of the formula (V) and found them to be identical with IR, NMR and the melting point described in the specification of this publication. It is therefore concluded that an erroneous structural formula has been disclosed in these publications. In other words, 6- methyl-4-substituted phenyl-4, 7-dihydropyrazolo[3,4- b]pyridine-5-carboxylate cannot be synthesized according to the methods described in these publications.
The compound of the above formula (IV) can be synthesized according to the method described in J. Chem. Soc, Perkin Trans. 1, 947 (1996), and this publication discloses methyl 4-(2-chlorophenyl)-6-methyl-4, 7-dihydro-lH- pyrazolo[3,4-b]pyridine-5-carboxylate and the like. Disclosure of the invention
An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3β), and further, medicaments comprising them. The present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo[ 3, 4-b] yridine derivatives have a selective and strong inhibitory activity on GSK-3β, which resulted in the completion of the present invention. That is, the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-3β-inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
The present invention provides the following. 1. A dihydropyrazolopyridine compound of the formula (I):
wherein
R° is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group optionally having substituent( s) , phenylalkyl optionally having substituent(s) , or a group of the formula: -COOR8 (wherein R8 is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)) ; R1 and R2 are the same or different and each is hydrogen, alkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acyla ino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkox alkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group or phenylalkyl; R3 is
(1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) phenyl optionally having substituent( s) ,
(4) aromatic heterocyclic group, (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
(6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s) , or
(7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent(s) , or a group selected from the groups represented by the following formulas (II) and (III),
(II) (III) wherein R6 and R7 are each phenyl optionally having substituent( s) or an aromatic heterocyclic group, or R2 and R3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent( s) ;
R4 is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and
R5 is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalk l, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s) (particularly phenyl), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, or R4 and R5 in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s) , provided that when R°, R1 and R2 are each hydrogen, R4 is methoxycarbonyl and R5 is methyl, then R3 should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4- carboxyphenyl or 4-methoxycarbonylphenyl, or an optically active form thereof,, a pharmaceutically acceptable salt thereof or a hydrate thereof.
2. The dihydropyrazolopyridine compound of the above-described 1, wherein R5 is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituent( s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
3. The dihydropyrazolopyridine compound of the above-described 1, wherein R1 is hydrogen, alkyl, phenyl optionally having substituent( s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
4. The dihydropyrazolopyridine compound of the above-described 1, wherein R2 is hydrogen or alkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
5. The dihydropyrazolopyridine compound of the above-described 1, wherein R3 is phenyl optionally having 1 to 3 substituent( s) , naphthyl, 2,1, 3-benzoxadiazol-4-yl or 3, 4-dihydro-2H- benzopyran-8-yl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
6. The dihydropyrazolopyridine compound of the above-described 1, wherein R4 is alkoxycarbonyl having 2 to 5 carbon atoms, cyano or nitro, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
7. The dihydropyrazolopyridine compound of the above-described 1, wherein R5 is alkyl having 2 to 4 carbon atoms, cyclopropyl, phenyl, thienyl or hydroxyalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
8. The dihydropyrazolopyridine compound of the above-described 1, wherein R2 and R3 in conjunction form a ring containing sulfur atom and the ring is condensed with a benzene ring optionally having substituent(s) , or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
9. The dihydropyrazolopyridine compound of the above-described 1, wherein R° is hydrogen or a group of the formula: -COOR8
(wherein R8 is alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent( s) ) , or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof. 10. The dihydropyrazolopyridine compound of the above- described 1, which is selected from
(32) ethyl 4,7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carbox late,
(47) ethyl 4-(2-chloro-3-trifluoromethylphenyl)-4,7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate,
(66) ethyl 4,7-dihydro-4-(naphthalen-l-yl)-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
(73) ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4,7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate, (87) ethyl 4-(2-chlorophenyl)-4,7-dihydro-6-(thiophen-2-yl)-
2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
(116) ethyl 4-(2, l,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-
2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
( 122 ) 4-(2, 3-dichlorophenyl)-4, 7-dihydro-5-nitro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine,
( 140) 4-(2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine,
( 147 ) 4-( 2-bromo-3-cyanophenyl)-5-cyano-4, 7-dihydro-6-phenyl- 2H-pyrazolo[ 3 , 4-b]pyridine,
( 158 ) 4- ( 2 , 1 , 3-benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- phenyl-2H-pyrazolo[ 3, 4-b]pyridine,
(171) 4-( 2 , 1 , 3-benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6- (thiophen-2-yl)-2H-pyrazolo[ 3, 4-b]pyridine,
(182) ethyl 4-(2-bromo-3-nitrophenyl)-4,7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
(183) ethyl 4-(2-bromo-3-cyanophenyl)-4,7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, ( 189 ) 4-(2-bromo-3-nitrophenyl) -5-cyano-4, 7-dihydro-6-propyl- 2H-pyrazolo[ 3, 4-b]pyridine,
(205) ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7- dihydro-6-propyl-2H-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, (240) ethyl 4-(2, l,3-benzoxadiazol-4-yl)-6-ethyl-4,7-dihydro- 2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
( 257 ) 4-( 2 , 1, 3-benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- hydroxymethyl-2H-pyrazolo[ 3 , 4-b]pyridine, (260) 4- ( 2-bromo-3-cyanophenyl) -5-cyano-4 , 7-dihydro-6- isopropyl-2H-pyrazolo[ 3, 4-b]pyridine, (264) 4-(2,l,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6- isopropyl-2H-pyrazolo[ 3 , 4-b]pyridine, and
(268 ) 4- ( 2-bromo-3-cyanophenyl) -5-cyano-6-cyclopropyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine, a tautomer, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
11. A medicament comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
12. A pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive. 13. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.
14. The medicament of the above-described 11, which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.
15. The medicament of the above-described 11, which is used for prevention and/or treatment of a neurodegenerative disease.
16. The medicament of the above-described 15, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinson dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic-depressive psychosis.
17. The medicament of the above-described 11, which is used for prevention and/or treatment of diabetes and diabetic complications .
18. The medicament of the above-described 11, which is used as an immunopotentiator.
Brief Description of The Drawings
Fig. 1 shows the GSK-3β-inhibitory activity of the compounds of Example 47 and Example 137.
Fig. 2 shows the effect of the compound of Example 66 on amyloid β-induced cytotoxicity.
Fig. 3 shows the GSK-3β-inhibitory effect of the compound of Example 27 in a gerbil brain ischemia model. Detailed Description of The invention The formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring. The present invention encompasses each isomer of formulas (I-a) and (I-b), and a mixture of these isomers.
(I-a) (I-b)
The compounds represented by the formula (I) in the present specification are described in detail in the following. "Alkyl" means a linear or branched carbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl(a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s). The alkyl of R5 is preferably alkyl having 2 to 8 carbon atoms. The "alkyl having 2 to 8 carbon atoms" concretely includes ethyl, propyl, butyl, pentyl(amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-butyl and the like. Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
"Acyl" includes alkylcarbonyl having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, and aromatic acyl having 7 to 12 carbon atoms, such as benzoyl, naphthoyl, cinnamoyl, benzylcarbonyl and the like. The benzene and naphthalene rings may have 1 to 5 substituent( s) . "Cycloalkyl" means a cyclic carbon chain of 3 to 8 carbon atoms. Cycloalkyl concretely includes, for example, cyclopropyl, eyelobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl having 3 to 6 carbon atoms.
"Halogen" represents fluorine, chlorine, bromine or iodine.
"Amino" is primary amino, or secondary or tertiary amino having the above alkyl, and includes, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and the like, with a preference for tertiary amino containing alkyl having 1 to 4 carbon atom(s).
"Alkylthio" is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio(amylthio) , hexylthio and structural isomers thereof, such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom(s).
"Haloalkyl" is the above alkyl substituted by 1 to 5 halogen(s), and represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2, 2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like. "Aminoalkyl" is the above-mentioned alkyl having the above amino, and includes, for example, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, 2- methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2- diethylaminoethyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom(s) having tertiary amino.
"Acylamino" is acylamino having the above acyl, and represents, for example, acetylamino, propion lamino, butyrylamino, valerylamino, pivaloylamino, benzoyla ino, phenylaσetylamino, phenylpropionylamino, phenylbutyrylamino and the like.
"Alkoxy" is alkoxy having the above alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy(amyloxy) , hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, ter -pentyloxy and the like, with a preference for alkoxy having 1 to 4 carbon atom(s). "Cycloalkoxy" is alkoxy having the above cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms. "Phenylalkoxy" is phenylalkoxy having the above alkoxy, and includes, for example, benzyloxy, 1-phenylethoxy, 2- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl-l- phenylethoxy, l-methyl-2-phenylethoxy, 1-phenylpropoxy, 2- pheylpropoxy, 1-methyl-1-phenylpropoxy, l-methyl-2- phenylpropoxy, 1-methyl-3-phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s) .
"Aminoalkoxy" is aminoalkoxy consisting of the above alkoxy and amino, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- di ethylaminoethoxy, 3-dimethylaminopropoxy, 4- dimethylaminobutoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s), and alkoxy having 1 to 4 carbon atom(s) . "Alkoxyalkyl" is alkoxyalkyl consisting of the above alkoxy and alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).
"Phenoxyalkyl" is phenoxyalkyl containing the above alkyl, and includes, for example, phenoxy ethyl, 2- phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
"Dialkoxyalkyl" is dialkoxyalkyl consisting of the above alkyl and alkoxy, and includes, for example, dimethoxymethy1, diethoxymethy1, 2, 2-dimethoxyethyl, 2,2-diethoxyethyl and the like, with a preference for dialkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
"Hydroxyalkyl" is hydroxyalkyl having the above alkyl, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl and the like, with a preference for hydroxylalkyl containing alkyl having 1 to 4 carbon atom(s).
"Alkoxycarbonyl" is alkoxycarbonyl having the above alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, see- butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s). However, R4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms.
"Aminocarbonyl" is aminocarbonyl having the above amino, and includes, for example, aminocarbonyl (carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl, phenylcarbamoyl, benzylcarbamoyl and the like, with a preference for tertiary-aminocarbonyl containing alkyl having 1 to 4 carbon atom(s). "Alkylthiocarbonyl" is alkylthiocarbonyl having the above alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert- butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms .
"Carboxyalkyl" is carboxyalkyl having the above alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s).
"Cycloalkoxyalkyl" is cycloalkoxyalkyl having the above cycloalkoxy and alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl and the like, with a preference for cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s) . "Alkylsulfinyl" is alkylsulfinyl having the above alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 4 carbon atom(s). "Alkylsulfonyl" is alkylsulfonyl having the above alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 4 carbon atom(s) . "Mercaptoalkyl" is mercaptoalkyl having the above alkyl, and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s). "Alkylthioalkyl" is alkylthioalkyl having the above alkylthio and alkyl, and includes, for example, methylthiomethy1, methylthioethyl, methylthiopropy1, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
"Aryl" is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and the like. They may have 1 to 5 substituent( s) and substitution sites are not particularly limited.
"Aralkyl" is aralkyl wherein the above alkyl is substituted by the above aryl, and includes benzyl, 2- phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent( s) on the aryl moiety.
"Acyloxyacetyl" is acyloxyacetyl having the above acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxyaσetyl and the like. "Acyloxyalkyl" is acyloxyalkyl having the above acyl and alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2- acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2- benzoyloxyethyl and the like. The substituent of the "phenyl optionally having substituent(s) " is exemplified by those mentioned for the "substituent" below, wherein the number of the substituent is generally 1 to 5, preferably 3. Phenyl having 1 or 2 substituent( s) is particularly preferable. "Aromatic heterocyclic group" is a 5- or 6-membered aromatic heterocyclic ring optionally containing 1 to 3 heteroatom( s) of nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine and the like. The substituent of the "aromatic heterocyclic ring optionally having substituent( s) " is exemplified by those mentioned for the "substituent" below, wherein the number of the substituent is generally 1 to 5, preferably 3.
"Phenylalkyl" is phenylalkyl having the above alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1- phenylpropyl, 2-phenylpropyl, 1-methy1-1-phenylpropyl, 1- methyl-2-phenylpropyl, l-methyl-3-phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s).
The kind and the number of the substituent of the "phenylalkyl optionally having substituent( s) " are the same as those for the above-mentioned "aromatic heterocyclic ring" .
"Alkoxycarbonylalkyl" is alkoxycarbonylalkyl having the above alkoxycarbonyl and alkyl, and includes, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3- ethoxycarbonylpropyl and the like.
"Alkoxycarbonylethenyl" is alkoxycarbonylethenyl having the above alkoxycarbonyl, and includes, for example, 2- methoxycarbonylethenyl, 2-ethoxycarbonylethenyl, 2- butoxycarbonylethenyl, 2-tert-butoxycarbonylethenyl and the like.
"Dialkylphosphinyl" is dialkylphosphinyl having the above alkyl, and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).
"Dialkylphosphonyl" is dialkylphosphonyl having the above alkyl, and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
In the present specification, "substituent" includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic ring, phenylalkyl, hydroxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like. "Ring optionally containing heteroatom(s) " is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) consisting of nitrogen atom, oxygen atom and sulfur atom, with particular preference given to a ring containing sulfur atom. The ring may be substituted by one or more of the above substituents or oxo groups. The substitution site is not particularly limited. This ring is formed by R and R in the formula (I) together with the attached carbon atom. By forming this ring, a spiro ring is formed in the compound of the formula (I) . The above ring can be fused with a benzene ring optionally having substituent( s) . Such a ring includes, for example, 2,3-dihydrobenzo[b]thiophene, 2,3- dihydrobenzo[b]thiophen-l-oxide and the like.
"A group derived from a benzene ring, which is fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring" represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indan and the like, with preference given to naphthalene (namely naphthyl) and particular preference given to 1-naphthyl. "A group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom( s) " includes the following groups and the like.
Of these, 2 ,1 ,3-benzoxadiazole and 3 ,4-dihydro-2H- benzopyrane are preferable, and 2 ,1 ,3-benzoxadiazol-4-yl and 3 ,4-dihydro-2H-benzopyran-8-yl are particularly preferable.
"A group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom (s) , which is fused with a benzene ring" includes the following groups and the like.
The "5 or β-membered ring optionally containing heteroatom (s) " is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom (s) consisting of nitrogen atom, oxygen atom and sulfur atom. Examples thereof include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, pyrroline, pyrrolidine, imidazoline and imidazolidine. Of these, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan and pyridine are preferable.
The compounds, represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention. Such acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like. Furthermore, the compounds of the present invention can form hydrates, solvates with ethanol and the like, and crystal polymorphs. When an asymmetric carbon atom exists, optical isomers and racemates thereof can be present, and all of these are encompassed in the present invention. Of the compounds (I) of the present invention, a compound wherein R° is hydrogen can be synthesized as shown in the following according to the method described in J. Chem. Soc, Perkin Trans. 1, 947 (1996) and the like. (First Production Method)
wherein R2, R3, R4 and R5 are as defined above.
Meldrum's acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII) to give an amide derivative of the formula (IX). The reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction. As the solvent, formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
wherein R2, R3, R4 and R5 are as defined above. The obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X) . The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethyIformamide, dimethyl sulfoxide and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
(X) wherein R1 represents hydrogen, and R2, R3, R4 and R5 are as defined above.
The compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
The carbonyl derivative of the formula (VII), which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983). The carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993). (Second Production Method)
wherein R1, R2, R3, R4 and R5 are as defined above.
The compounds (I) of the present invention can be produced by reacting aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII). The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used. The reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C. Of the compounds (I) of the present invention, a compound wherein R° is a substituent other than hydrogen can be synthesized as follows. (Third Production Method)
(XI) (XII) (I)
wherein R°, R1, R2, R3, R4 and R5 are as defined above, and X represents halogen, provided that R° is not hydrogen.
The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base. Suitable base includes, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like. The reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C. (Fourth Production Method)
(Xi) ( iii) (i)
wherein R°, R1, R2, R3, R4 and R5 are as defined above, provided that R° is not hydrogen.
The compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) in the presence of a base. Suitable base includes, for example, triethyla ine, pyridine, 4-dimethylaminopyridine and the like. The reaction is carried out in the presence of a solvent inert to the reaction. As the solvent, one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like. The reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
The compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography and the like. When the purified product obtained is a racemate, a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column packed with optically active carrier. The present invention also encompasses optically active compounds.
The compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3β such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3β. Therefore, the compounds of the present invention have a GSK-3β-selective inhibitory activity and can be medicaments with small side-effect for diabetes, diabetic complications and neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic- depressive psychosis and the like) . In addition, the compounds of the present invention are useful as immunopotentiators . Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation. The carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and other conventionally used substances. Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration of injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like. While the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1 - 1,000 mg, preferably 50 - 200 mg per day for an adult person, which is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.
As solid compositions for oral administration according to the present invention, tablet, powder, granule and the like are used. In such a solid composition, one or more active substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid and magnesium aluminate. The composition may contain, according to a conventional method, inert additives other than diluent, for example, a lubricant such as magnesium stearate, a disintegrator such as cellulose and calcium glycolate, a stabilizer such as lactose and a solubilizer such as glutamic acid and aspartic acid. Tablet and pill may be coated with a gastric or enteric coating film of, for example, sucrose, gelatin, hydroxypropylcellulose and the like. Liquid compositions for oral administration include pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like, and contain an inert diluent generally used, such as purified water and ethanol. This composition may contain an adjuvant such as wetting agent and suspending agent, a sweetener, a flavor, an aromatic and an antiseptic, in addition to the inert diluent. Injections for parenteral administration contain sterile aqueous or non-aqueous solution, suspension and emulsion. The aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such a composition may contain adjuvants such as antiseptic, wetting agent, emulsifier, dispersant, stabilizer and solubilizer. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of an antimicrobial agent, irradiation of ultraviolet ray and the like. Alternatively, a sterile solid composition may be prepared and used upon dissolution in sterile water or sterile solvent for injection prior to use.
Examples The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples . Example 1
Ethyl 4- (2-chlorophenyl) -4 , 7-dihydro-6-methyl-2H-pyrazolo [3 , 4- b] pyridine-5-carboxylate
A solution of 2-chlorobenzaldehyde (1.7 g) , 3- aminopyrazole (1.0 g) and ethyl acetoacetate (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane- ethyl acetate (8:2)) to give the title compound (850 mg) as colorless crystals.
Melting Point (MP) : 217-221°C. Anal. Calcd. for : Cι6Hι6N302Cl: C, 60.47 ;H, 5.08 ;N,13.22.
Found: C, 60.15 ;H, 5.07 ;N, 13.53.
MS (El) :317 (M+) .
V-NMR (400MHz, DMSO-d6)δ (ppm) : 1.00 (3H,t,J=6.8Hz) , 2.25 (3H,s),
3.72-3.82(2H,m) , 5.57(lH,s), 7.07-7.12 (2H,m) , 7.18 (lH,d,J=7.3Hz) , 7.26(lH,s), 7.34 (lH,d,J=7.9Hz) ,
9.53(lH,br.s) , 11.98 (lH,br. s) .
IR(KBr) :v=3393, 3267, 1670, 1589, 1518, 1278, 1217cm-1. Example 2
Ethyl 4 , 7-dihydro-4- (2-methoxyphenyl) -6-methyl-2H- pyrazolo [3 ,4-b]pyridine-5-carboxylate
The title compound was prepared from 2- methoxybenzaldehyde , 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
MP:196-200°C. Anal. Calcd. for : Cι7Hι9N30 1/5 H20:C,64.42 ;H,6.17 ;N,13.26. Found: C, 64.08 ;H, 6.05 ;N, 13.68. MS (El) :313(M+) .
^- MR (400MHz,DMSO-d6)δ(ppm) : 1.00 (3H, t,J=6.8Hz) , 2.81(3H,s), 3.72(3H,s), 3.87 (2H,q,J=6.8Hz) , 5.54(lH,s), 6.80 (lH,dd,J=7.3Hz and 7.4Hz), 6.90 (lH,d,J=7.8Hz) , 7.04 (lH,d,J=7.4Hz) , 7.13-
7.15(2H,m), 9.99 (lH,b . s) , 11.98 (lH,br. s) .
IR(KBr) :v=3362, 3267, 3204, 3090, 1662, 1589, 1516, 1275, 1097cm"1. Example 3
Ethyl 4 , 7-dihydro-6-methyl-4- (2-trifluoromethylphenyl) -2H- pyrazolo [3 ,4-b]pyridine-5-carboxylate
The title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
MP:259-262°C.
Anal. Calcd. for:Cι7Hι6F3N302 1/5 H20:C,57.53 ;H,4.66;N, 11.84. Found: C, 57.56 ;H, 4.68 ;N, 11.86. MS (El) :352(M++1) . ^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.74 (3H, t,J=6.9Hz) , 2.40(3H,s), 3.68-3.81 (2H,m) , 5.42(lH,s), 7.00 (lH,s) , 7.28 (lH,dd,J=7.3Hz and 7.4Hz), 7.33 (lH,d,J=7.2Hz) , 7.51 (lH,dd,J=7.3Hz and 7.4Hz), 7.60 (lH,d,J=7.8Hz) , 9.58 (lH,br . s) , 12.00 (lH,br. s) .
IR(KBr) :v=3277, 3209, 3094, 1668, 1593, 1514, 1313, 1213,1153, 1097, 765cm_1.
Example 4
Methyl 4- (2-chlorophenyl) -4 , 7-dihydro-6-methyl-2H- pyrazolo [3 ,4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl acetoacetate in the same manner as in Example 1.
MP:235°C.
Anal. Calcd.' for : Cι5Hι4ClN302 2^5 H20: C,57.94 ;H,4.80 ;N, 13.51.
Found: C, 58.03 ;H, 4.55, -N, 13.43. MS(EI) :303(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 2.40(3H,s) , 3.34(3H,s) , 5.55(lH,s) , 7.09-7.11 (2H,m) , 7.18 (lH,dd, J=7.3Hz and 7.4Hz) , 7.29(lH,s) , 7.34(lH,d,J=7.3Hz) , 9.57 (lH,br . s) , 12.00 (lH,br . s) . Example 5 t-Butyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-methyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and t-butyl acetoacetate in the same manner as in Example 1.
MP:207°C.
Anal. Calcd. for:C18H20ClN302:C,62.52;H,5.83;N,12.15.
Found:C,62.51;H,5.79;N,12.17. MS(EI) :345(M+) .
XH-NMR ( 400MHz, DMSO-d6)δ(ppm) : 1.07(9H,s), 2.36(3H,s),
5.50(1H,S), 7.11-7.15(2H,m), 7.20( lH,d, J=7.3Hz) , 7.25(lH,s),
7.37(lH,d,J=7.3Hz) , 9.35 ( lH,br .s) , 11.93( lH,br .s) .
Example 6 Isopropyl 4-( 2-fluorophenyl) -4, 7-dihydro-6-methyl-2H- pyrazolo[ 3, 4-b] yridine-5-carboxylate
The title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and isopropyl acetoacetate in the same manner as in Example 1. MP:218-220°C.
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.66 (3H,d, =6.3Hz) ,
1.02(3H,d,J=6.3Hz) , 2.37(3H,s), 4.66( lH,q, J=6.3Hz) , 5.40(lH,s),
7.01-7.14(4H,m), 7.19(lH,s), 9.46( lH,br .s) , 11.97( lH,br.s) .
Example 7 Benzyl 4-(2-chlorophenyl) -4, 7-dihydro-6-methyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and benzyl acetoacetate in the same manner as in Example 1. MP:234°C.
Anal. Calcd. for:C2ιHι8ClN302:C,66.40;H,4.78;N,11.06.
Found:C,66.16;H,4.86;N,10.92.
MS(EI) :319(lf) . ^-NMR (400MHz,DMSO-d6)δ(ppm) : 2.43(3H,s), 4.81( lH,d,J=12.6Hz) , 4.92(lH,d,J=12.6Hz), 5.62(lH,s), 6.86-6.88(2H,m) , 7.13- 7.18(6H,m), 7.31-7.34(2H,m), 9.65( lH,br.s) , 12.01( lH,br.s) . Example 8 4-(2-Chlorophenyl) -5-dimethylaminocarbonyl-4, 7-dihydro-6- methyl-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and N,N-dimethylacetamide in the same manner as in Example 1. MP:229°C.
Anal. Calcd. for:C16Hi7ClN40 1/2 H20:C,58.99;H,5.57;N, 17.20.
Found:C,58.90;H,5.46;N,16.84.
MS(EI) :316(M+) .
1H-MMR ( 400MHz, DMSO-d6 ) δ(ppm) : 1.77(3H,s), 2.72(6H,s), 5.39(lH,s), 7.10-7.22(4H,m), 7.30( lH,d, J=7.3Hz) , 8.40( lH,br .s) ,
11.83(lH,br.s) .
Example 9
4-(2-Chlorophenyl) -5-hydrazinocarbonyl-4, 7-dihydro-6-methyl-
2H-pyrazolo[ 3, 4-b]pyridine To a solution of 4-(2-chlorophenyl) -4, 7-dihydro-5- dimethylaminocarbonyl-6-methyl-2H-pyrazolo[3, 4-b]pyridine (200 mg) in acetonitrile (200 mL) was added hydrazine (200 mg) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound as colorless crystals (150 mg).
MP:220°C.
Anal. Calcd. for:C14Hi4ClN50 3/10 H20:C,54.39;H,4.76;N,22.65. Found:C,54.36;H,4.56;N,22.65.
MS(EI) :303(M+) .
^- MR (400MHz, DMSO-d6)δ(ppm) : 1.85(3H,s), 3.20-3 ,80(3H,br.s) ,
5.15(lH,s), 6.81(lH,s), 7.16-7.028(3H,m) , 7.34( lH,d, J=7.3Hz) , 10.05-11.07(2H,brs) .
Example 10
4-(2-Fluorophenyl) -4,7-dihydro-6-methyl-5- isopropylthiocarbonyl-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and acetoacetic acid isopropyl thioester in the same manner as in Example 1.
MP:192-194°C.
^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 1.03(3H,d,J=6.9Hz) , 1.15(3H,d,J=6.9Hz) , 2.43(3H,S), 3.35( lH,q,J=6.9Hz) , 5.55(lH,s),
7.04-7.15(4H,m), 7.33(lH,s), 9.81( lH,br.s) , 12.11( lH,br.s) .
Example 11
4, 7-Dihydro-6-methyl-5-nitro-4-(2-trifluoromethylphenyl) -2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and 1- nitropropan-2-one in the same manner as in Example 1.
MP:257-258°C.
^- MR ( 400MHz, DMSO-d6 ) δ(ppm) : 2.65(3H,s), 5.75(lH,s), 7.19(1H,S), 7.30-7.35(2H,m), 7.51( lH,dd, J=7.3Hz and 7.8Hz),
7.66(lH,d,J=7.8Hz), 10.87( lH,br.s) , 12.45( lH,br.s) .
Example 12
Ethyl 4, 7-dihydro-4-phenyl-6-trifluoromethyl-2H-pyrazolo[3, 4- b]pyridine-5-carboxylate The title compound was prepared from benzaldehyde, 3- aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:110-115°C.
Anal. Calcd. for:C16Hι4N302F3 1/2 H20:C,55.49;H,4.37;N, 12.13. Found:C,55.84;H,4.70;N,11.89.
MS(EI) :337(M+) .
^-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.84(3H,t, J=6.9Hz) ,
3.90(2H,q,J=6.8Hz) , 5.54(lH,s), 7.13-7.17 (3H,m) , 7.24- 7.28(3H,m), 9.78(lH,br.s), 12.20( lH,br .s) .
IR(KBr):v=3375, 3175, 3067, 1707, 1606, 1533, 1278, 1206, 1197, 1167cm-1.
Example 13
Ethyl 4-(2-fluorophenyl) -4, 7-dihydro-6-trifluoromethyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:119-120°C. Anal. Calcd. for:C16H13F4N302:C, 54.09;H,3.69;N, 11.84.
Found:C, 53.84;H, 3.57;N, 11.79.
MS(EI) :356(M++1) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.94 (3H,t, J=6.8Hz) ,
3.89(2H,q,J=6.8Hz), 5.46(lH,s), 7.11-7.20(4H,m) , 7.28- 7.30(lH,m), 9.92(lH,br.s), 12.27 ( lH,br .s) .
IR(KBr):v=3290, 3178, 3069, 1703, 1608, 1537, 1280, 1232, 1174, 1138,
756cm-1.
Example 14
Ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-trifluoromethyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate maleate The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:171-172°C. MS(EI) :371(M+) .
^- MR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.91 (3H,t, J=7.3Hz) ,
3.50(3H,br.s), 3.87 (2H,q, J=6.8Hz) , 5.66(lH,s), 6.26(2H,s),
7.15-7.18(2H,m), 7.27( lH,d, J=7 -8Hz) , 7.30(lH,s),
7.40(lH,d,J=7.8Hz), 9.65(lH,br.s) . IR(KBr):v=3297, 2935, 1730, 1624, 1550, 1479, 1186cm-1. Example 15
Ethyl 4, 7-dihydro-4-( 2-methoxyphenyl) -6-trifluoromethy1-2H- pyrazolo[3,4-b]pyridine-5-carboxylate The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:144-146°C. Anal. Calcd. for:C17Hι5F3N303:C,55.59;H,4.39;N,11.44.
Found:C,55.55;H,4.38;N,11.43.
MS (El) :367(M+) .
^- MR (400MHz,DMSO-d6)δ(ppm) : 0.94(3H,t,J=6.8Hz) , 3.83(3H,s),
3.89(2H,q,J=6.8Hz),5.51(lH,s), 6.84( lH,dd,J=7.3Hz and 7.4Hz), 6.94-6.97(2H,m), 7.13( lH,dd,J=7.3Hz and 7.4Hz), 7.20(lH,s),
9.70(lH,br.s), 12.13(lH,br.s) .
IR(KBr) :v=3431, 3173, 3067, 2993, 2924, 1689, 1610, 1527, 1286, 1226,
1145cm-1.
Example 16 Ethyl 4, 7-dihydro-6-trifluoromethyl-4- (2- trifluoromethylphenyl) -2H-pyrazolo[ 3 , 4-b]pyridine-5- carboxylate
The title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:182-186°C.
Anal. Calcd. for:Cι7Hι3N3O2F6:C,50.38;H,3.23;N,10.37.
Found:C,50.21;H,3.15;N,10.39.
MS (FAB) :406(M++1) . ^Η-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.83 (3H,t, J=6.8Hz) ,
3.83(2H,q,J=6.8Hz), 5.49(lH,s), 7.08(lH,s), 7.35-7.39 (2H,m) ,
7.62(lH,dd,J=7.3Hz and 7.4Hz), 7.66( lH,d, J=7.8Hz) ,
9.97(lH,br.s), 12.30(lH,br.s) .
IR(KBr) :v=3339, 3177, 3067, 1711, 1608, 1537, 1313, 1280, 1182, 1141cm"1. Example 17
Ethyl 4- ( 3-chlorophenyl) -4 , 7-dihydro-6-trifluoromethyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 3- chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1. MP:144-145°C.
Anal. Calcd. for:C16Hi3N3O2F3Cl:C,51.69;H,3.52;N,11.30. Found:C,51.33;H,3.74;N,11.10. MS(EI) :371(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.98 (3H,t, J=6 ,8Hz) , 3.92(2H,q,J=6.8Hz), 5.21(lH,s), 7.11( lH,d, J=7.8Hz) , 7.17(lH,s), 7.23(lH,d,J=8.7Hz), 7.29-7.33(2H,m) , 9.92 ( lH,br .s) , 12.30(lH,br.s) .
IR(KBr) :v=3321, 3178, 3070, 1703, 1610, 1535, 1278, 1224, 1184, 1145cm"1.
Example 18
Ethyl 4-( 4-chlorophenyl) -4, 7-dihydro-6-trifluoromethyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 4- chlorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:176-178°C.
Anal. Calcd. for :Cι6Hι3F3N302Cl:C,51.69;H,3.52;N, 11.30. Found:C,51.91;H,3.77;N,11.08.
MS(EI) :371(M+) .
^- MR ( 400MHz, DMSO-d6 )δ(ppm) : 0.98 (3H,t, J=6.8Hz) ,
3.90(2H,q,J=7.3Hz), 5.92(lH,s), 7.16(2H,d, J=8.2Hz) , 7.27(lH,s),
7.31(2H,d,J=8.2Hz), 9.87( lH,br .s) , 12.27( lH,br .s) . IR(KBr) :v=3476, 3368, 3178, 3078, 1714, 1695, 1606, 1537, 1278, 1172,
1134cm"1.
Example 19
Ethyl 4 , 7-dihydro-4- ( 4-methoxyphenyl) -6-trifluoromethyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 4- methoxybenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:159-161°C. Anal. Calcd. for :C17Hι6FN303:C,55.59;H,4.39;N, 11.44.
Found:C,55.49;H,4.54;N,11.33.
MS(EI) :367(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.99 (3H,t, J=7.3Hz) , 3.68(3H,s), 3.89(2H,q,J=7.3Hz) , 5.12(lH,s), 6.82(2H,d, J=8.7Hz) ,
7.03(2H,d,J=8.7Hz), 7.22-7.24( lH,m) , 9.71( lH,br .s) ,
12.19(lH,br.s) .
IR(KBr) :v=3323, 3231, 3173, 3067, 1699, 1610, 1535, 1510, 1302, 1248, 118
4,1145cm"1. Example 20
Ethyl 4- ( 4-ethoxycarbonylphenyl) -4, 7-dihydro-6- trifluoromethyl-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 4- ethoxycarbonylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:157-160°C.
Anal. Calcd. for :Cι9Hι8F3N3O4:C,55.75;H,4.43;N,10.26.
Found:C,55.68;H,4.39;N,10.43.
MS (FAB) :410(M++1) . ^-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.96 (3H,t, J=6.9Hz) , 1.28
(3H,t,J=7.3Hz), 3.89(2H,q,J=6.8Hz), 4.27 ( 2H,q,J=7.3Hz) ,
5.28(lH,s), 7.27(1H,S), 7.29(2H,d, J=8.3Hz) , 7.87 (2H,d,J=8.2Hz) ,
9.92(lH,br.s), 12.28( lH,br.s) .
IR(KBr):v=3393, 3188, 3082, 1692, 1612, 1539, 1284cm"1. Example 21
Ethyl 4-(2-chlorophenyl) -4, 7-dihydro-3-methyl-6- trifluoromethyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate The title compound was prepared from 2- chlorobenzaldehyde, 3-amino-5-methylpyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:165-168°C. MS(EI) :385(M+) .
^- R (400MHz,DMSO-d6)δ(ppm): 0.94 (3H,t,J=7.3Hz) , 1.81 (3H,s), 3.85(2H,q,J=6.8Hz), 5.54(lH,s), 7.17-7.20 (2H,m) ,
7.27(lH,dd,J=7.3Hz and 7.4Hz), 7.36( lH,d, J=8.3Hz) ,
9.79(lH,br.s), 11.96(lH,br .s) .
IR(KBr):v=3263,3194,3080, 1668, 1591, 1520, 1286, 1232, 1149, 1095, 1062cm-1.
Example 22
Ethyl 4, 7-dihydro-4~(thiophen-2-yl)-6-trifluoromethyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP: 157-161°C.
Anal. Calcd. for:C14Hι2F3N3θ2S :C,49.27;H,2.95;N, 12.31.
Found:C,49.10;H,3.28;N,12.13. MS(EI) :343(M+) .
^- MR (400MHz,DMSO-d6)δ(ppm) : 1.08 ( 3H,t, J=7.4Hz) , 4.00
(2H,q,J=7.4Hz), 5.52(lH,s), 6.76 ( lH,d, =2 -9Hz) ,
6.87(lH,dd,J=2.9Hz and 5.4Hz), 7.30( lH,d, J=5.4Hz) , 7.43(lH,s),
9.96(lH,br.s), 12.35( lH,br.s) . IR(KBr):v=3350,3240,3180, 1693, 1612, 1535, 1396, 1371, 1304, 1153, 109
3,1057,694cm"1.
Example 23
Ethyl 4, 7-dihydro-4-(thiophen-3-yl)-6-trifluoromethyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from thiophene-3- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
MP:140-145°C.
Anal. Calcd. for :Cι4Hι2F3N302S:C,49.27;H,2.95;N, 12.31. Found:C,49.65;H,2.64;N,12.19. MS (El) :343(M+) .
XH-NMR (400MHz, DMSO-ds)δ(ppm): 1.03 (3H,t, J=7.3Hz) , 3.96 (2H,q,J=7.3Hz), 5.30(lH,s), 6.87( lH,d, J=4.8Hz) , 7.05(lH,s), 7.35(lH,s), 7.39(lH,dd,J=2.9Hz and 4.8Hz), 9.76( lH,br .s) ,
12.25(lH,br.s) .
IR(KBr) :v=3356, 3182, 2982,2932, 1689, 1614, 1537, 1304, 1224, 1153cm-1.
Example 24 Ethyl 4, 7-dihydro-4-( 1-naphthyl)-6-trifluoromethyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1. MP:119-120°C.
Anal. Calcd. for:C2oHι6F3N302 1/2 H2O:C,60.45;H,4.57;N, 10.57.
Found:C,60.20;H,4.77;N,10.39.
MS(FAB) :388(M++1) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.69 (3H,t,J=6.8Hz) , 3.73(2H,q,J=6.8Hz), 6.04(lH,s), 7.09(lH,s), 7.26( lH,d,J=6.8Hz) ,
7.41(lH,dd,J=7.3Hz and 7.4Hz), 7.52-7.58(2H,m) ,
7.75(lH,d,J=8.3Hz), 7.92( lH,dd,J=7.3Hz and 7.4Hz), 8.33(lH,s),
9.87(lH,br.s), 12.14( lH,br.s) .
IR(KBr) :v=3173, 1670, 1606, 1138 , 1095cm"1. Example 25
Ethyl 4,7-dihydro-4-phenyl-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate maleate
A solution of benzaldehyde (1.6 g), 3-aminopyrazole (1.0 g) and ethyl 3-ketohexanoate (1.9 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate
(8:2)) to give the title compound (720 mg) as colorless crystals.
MP:139-141°C.
Anal. Calcd. for:C18H2iN302C4H404 1/2 H2O:C,60.54;H,6.00;N,9.63.
Found: C,60.16;H,5.60;N, 10.01. MS(EI) :311(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.94-0.95 (6H,m), 1.62
(2H,q,J=7.8Hz), 2.66-2.77(2H,m) , 3.50(3H,br .s) ,
3.83(2H,q,J=6.8Hz) , 5.10(lH,s), 6.25(2H,S), 7.05-7.20 (6H,m) , 9.37(lH,br.s) .
IR(KBr) :v=3337, 3042, 1699, 1593, 1467, 1539, 1361, 1203cm"1
Example 26
Ethyl 4-(2-fluorophenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate The title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:192-194°C.
Anal. Calcd. for :CιsH2oFN302 1/2 H20:C,63.89;H,6.26;N,12.42. Found:C,63.85;H,6.01;N,12.36.
MS (El) :329(M+).
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.93 (3H,t, J=7.3Hz) , 0.97
(3H,t,J=7.3Hz), 1.62-1.68(2H,m), 2.71-2 -83(2H,m) ,
3.82(2H,q,J=7.3Hz) , 5.43(lH,s), 7.05-7. ll(4H,m) , 7.21(lH,s), 9.48(lH,br.s), 11.97( lH,br .s) .
IR(KBr) :v=3265, 3198,2964, 1591, 1514, 1224, 1209, 1093cm"1.
Example 27
Ethyl 4-(2-chlorophenyl)-4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b] yridine-5-carboxylate The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:202-205°C.
Anal. Calcd. for:C18H20ClN3O2:C,62.52;H,5.83;N, 12.15. Found:C,62.28;H,5.76;N,12.37. MS(FAB) :346(M++1) .
1H-NM (400MHz, DMSO-d6)δ(ppm) : 0.85 (3H,t, J=6.8Hz) , 0.95 (3H,t,J=7.3Hz), 1.62-1.68(2H,m), 2.67-2.87(2H,m) , 3.78(2H,q,J=6.8Hz), 5.58(lH,s), 7.07-7. ll(2H,m) ,
7.18(lH,dd,J=7.3Hz and 7.4Hz), 7.25(lH,s), 7.34( lH,d, J=7.8Hz) ,
9.49(lH,br.s), 11.97( lH,br.s) .
IR(KBr):v=3263, 3209, 3194, 3080, 1668, 1591, 1520, 1286, 1232, 1149, 106 2,750cm-1.
Example 28
Methyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl 3-ketohexanoate in the same manner as in Example 25.
MP:203-207°C.
Anal. Calcd. for :Cι7Hι8ClN302 1/5 H2O:C,60.88;H,5.53;N, 12.53.
Found: C, 60.73 ;H, 5.36 ;N, 12.14. MS(EI) :331(M+) .
^-NMR ( 400MHz, DMSO-de )δ(ppm) : 0.97 (3H,t, J=7.3Hz) , 1.64-
1.66(2H,m), 2.72-2.83(2H,m), 3.31(3H,s), 5.57(lH,s),
7.10(lH,d,J=7.3Hz), 7.09-7.11( lH,m) , 7.17-7.18 ( lH,m) ,
7.27(lH,s), 7.34(lH,d,J=7.8Hz), 9.54( lH,br .s) , 11.97( lH,br .s) . IR(KBr):v=3260, 3190, 1672, 1591, 1516, 1232cm-1.
Example 29
Ethyl 4-( 2-bromophenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:223°C.
Anal. Calcd. for:C18H2oBrN302:C,55.40;H,5.17;N, 10.77.
Found:C,55.08;H,5.14;N,10.85. MS(EI) :390(M+) .
^Η- MR (400MHz,DMSO-d6)δ(ppm) : 0.86(3H,t,J=7.3Hz) , 0.97(3H,t,J=7.3Hz), 1.63-1.69(2H,m) , 2.71-2.74( lH,m) , 2.80- 2.83(lH,m), 3.77(2H,q,J=7.3Hz) , 5.67(lH,s), 7.00( lH,dd,J=7.3Hz and 7.4Hz), 7.10(lH,d,J=7.3Hz) , 7.22( lH,dd, J=7.3Hz and 7.4Hz),
7.28(lH,s), 7.51(lH,d,J=7.3Hz), 9.50( lH,br.s) , 11.97( lH,br.s) .
Example 30
Ethyl 4 , 7-dihydro-4-(2-methylphenyl) -6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- met ylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:178°C. Anal. Calcd. for:Cι9H23N3O2:C,70.13;H,7.12;N, 12.91.
Found:C,70.12;H,7.35;N,12.99.
MS(EI) :325(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.83(3H,t,J=7.3Hz) ,
0.96(3H,t,J=7.3Hz), 1.62-1.66(2H,m) , 2.44(3H,s), 2.64- 2.66(lH,m), 2.76-2.79(lH,m), 3.77 (2H,q,J=7.3Hz) , 5.31(lH,s),
6.93(lH,d,J=7.3Hz) , 6.99-7.05( 3H,m) ,7.18( lH,s) , 9.34( lH,br.s) ,
11.87(lH,br.s) .
Example 31
Ethyl 4, 7-dihydro-6-propyl-4-( 2-trifluoromethylphenyl) -2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:198-202°C. Anal. Calcd. for:Ci9H2oF3N302 1/2 H20: C,58.76;H,5.45;N, 10.81.
Found:C,58.82;H,5.92;N,10.62.
MS (El) :379(M+).
^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 0.76 (3H,t, J=7.3Hz) ,
0.98(3H,t,J=7.3Hz) , 1.64-1.68(2H,m) , 2.76-2.79(2H,m) , 3.80(2H,q,J=7.3Hz) , 5.44(lH,s), 7.00( 1H,S) ,7.27-7.30( lH,m) ,
7.33(lH,d,J=7.8Hz), 7.53( lH,dd,J=7.3Hz and 7.4Hz),
7.61(lH,d,J=7.3Hz), 9.54( lH,br .s) , 11.99 ( lH,br .s) .
IR(KBr):v=3265, 3198, 2964, 1591, 1514, 1224, 1209, 1093cm"1. Example 32
Ethyl 4, 7-dihydro-4-(2-methoxyphenyl) -6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:169°C.
Anal. Calcd. for:C19H23N303:C,66.84;H,6.79;N, 12.31. Found:C,66.58;H,6.50;N,12.34. MS(EI) :341(M+) .
1H-MM ( 400MHz,DMSO-d6)δ(ppm) : 0.85(3H,t,J=7.3Hz) ,
0.97(3H,t,J=7.3Hz) , 1.66-1.68(2H,m) , 2.66-2.70( lH,m) , 2.81-
2.88(lH,m), 3.80(2H,q,J=7.3Hz), 3.85(3H,s), 5.47(lH,s),
6.76(lH,dd,J=7.3Hz and 7.4Hz), 6.89-6.94(2H,m) , 7.04(lH,dd,J=7.3Hz and 7.4Hz), 7.14(lH,s), 9.29 ( lH,br -s) ,
11.82(lH,br.s) .
Example 33
Ethyl 4-(2-ethoxyphenyl)-4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate The title compound was prepared from 2- ethoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:203°C.
Anal. Calcd. for:C2oH25N303:C,67.58;H,7.09;N,11.82. Found:C,67.48;H,7.06;N,11.81.
MS(EI) :355(M+).
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.85(3H,t, J=7.3Hz) , 0.97(3H,t,J=7.3Hz) , 1.41(3H,t, J=7.3Hz) , 1.64-1.67(2H,m) , 2.68- 2.71(lH,m), 2.78-2.81(lH,m), 3.79 (2H,q, J=7.3Hz) , 4.03- 4.05(lH,m), 4.10-4.12(lH,m), 5.48(lH,s), 6.74( lH,dd, J=7.3Hz and 7.4Hz), 6.87( lH,d, J=7.3Hz) , 6.94(lH,d, J=7.3Hz) , 7.01(lH,dd,J=7.3Hz and 7.4Hz), 7.14(lH,s), 9.28( lH,br .s) , 11.79(lH,br.s). Example 34
Ethyl 4 , 7-dihydro-4-( 2-propoxyphenyl) -6-propyl-2H- pyrazolo[ 3, -b]pyridine-5-carboxylate
The title compound was prepared from 2- propoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:205°C.
Anal. Calcd. for:C2ιH27N303:C,68.27;H,7.37;N,11.37. Found:C,68.05;H,7.39;N,11.35. MS(EI) :369(M+) .
XH-NMR ( 400MHz, DMSO-d6 )δ(ppm) : 0.84(3H,t,J=7.3Hz) ,
0.97(3H,t,J=7.3Hz) , 1.05(3H,t, J=7.3Hz) , 1.64-1.67(2H,m) , 1.81-
1.84(2H,m), 2.70-2.73( lH,m) , 2.78-2.82( lH,m) ,
3.77(2H,q,J=7.3Hz), 3.92( lH,q, J=7.3Hz) , 4.07( lH,q, J=7.3Hz) , 5.52(lH,s), 6.75(lH,dd,J=7.3Hz and 7.4Hz), 6.88( lH,d, J=7.3Hz) ,
6.94(lH,d,J=7.3Hz) , 7.01( lH,dd,J=7.3Hz and 7.4Hz), 7.11(lH,s),
9.28(lH,br.s), 11.79( lH,br.s) .
Example 35
Ethyl 4, 7-dihydro-4-( 2-isopropyloxyphenyl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- isopropyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:210°C. Anal. Calcd. for:C2ιH27N303:C, 68 ,27;H,7.37;N, 11.37.
Found:C,67.93;H,7.39;N,11.32.
MS (El) :369(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.84 (3H,t, J=7.3Hz) ,
0.97(3H,t,J=7.3Hz) , 1.25(3H,d, J=6.8Hz) , 1.39 (3H,d, J=6.8Hz) , 1.64-1.69(2H,m), 2.68-2.72( lH,m) , 2.78-2.82( lH,m) ,
3.77(2H,q,J=7.3Hz), 4.64-4.67( lH,m) , 5.45(lH,s),
6.73(lH,dd,J=7.3Hz and 7.4Hz), 6.89-6.90(3H,m) , 7.15(lH,s),
9.27(lH,br.s), 11.77(lH,br.s) . Example 36
Ethyl 4-(2-butoxyphenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- butoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:171°C.
Anal. Calcd. for:C22H29N3O3:C,68.90;H,7.62;N,10.96. Found:C,68.66;H,7.63;N,10.89. MS(EI) :383(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.84(3H,t,J=7.3Hz) , 0.95- 0.99(6H,m), 1.52-1.80( 6H,m) , 2.69-2.71( lH,m) , 1.76-1.80( lH,m) , 3.77(2H,q,J=7.3Hz), 3.95-3.98 ( lH,m) ,4.07-4.10 ( lH,m) , 5.51(lH,s), 6.74(lH,dd,J=7.3Hz and 7.4Hz), 6.88-6.94(2H,m) , 7.01(lH,dd,J=7.3Hz and 7.4Hz), 7.10(lH,s), 9.28( lH,br .s) , 11.79(lH,br.s) . Example 37
Ethyl 4-( 2-cyclopentyloxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 2- cyclopentyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:195°C.
Anal. Calcd. for:C23H29N3O3:C,69.85;H,7.39;N,10.62. Found:C,69.63;H,7.28;N,10.61.
MS(EI) :395(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.83(3H,t,J=7.3Hz) ,
0.97(3H,t,J=7.3Hz), 1.65-1.98( 8H,m) , 2.66-2.78(2H,m) ,
3.76(2H,q,J=7.3Hz), 4.89-4.93( lH,m) , 5.43(lH,s), 6.72(lH,dd,J=7.3Hz and 7.4Hz), 6.88-6.93(2H,m) ,
7.00(lH,dd,J=7.3Hz and 7.4Hz), 7.10(lH,s), 9.28( lH,br .s) ,
11.77(lH,br.s) .
Example 38 Ethyl 4-( 2-benzyloxyphenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- benzyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:128°C.
Anal. Calcd. for:C25H27N303:C,71.92;H,6.52;N, 10.06. Found:C,71.66;H,6.73;N,9.85. MS (El) :417(M+). XH-NMR ( 400MHz, DMSO-d6)δ (ppm ) : 0.84(3H,t, J=7.3Hz) ,
0.97(3H,t,J=7.3Hz), 1.64-1.67 (2H,m) , 2.70-2.73( lH,m) , 2.80- 2.83(lH,m), 3.80(2H,q, J=7.3Hz) , 5.20(2H,d, J=30Hz) , 5.60(lH,s), 6.78(lH,dd,J=7.3Hz and 7.4Hz), 6.96-7.03( 3H,m) , 7.08(lH,s), 7.35(lH,dd,J=7.3Hz and 7.4Hz), 7.40-7.43(2H,m) , 7.52- 7.55(2H,m), 9.30( lH,br.s) , 11.79( lH,br.s) . Example 39
Ethyl 4, 7-dihydro-4-( 2-methylthiophenyl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
A solution of 2-methylthiobenzaldehyde (20 g), Meldrum's acid (19 g), ethyl 3-ketohexanoate (21 g) and ammonium acetate (11 g) in acetic acid (130 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (9.7 g). To a solution of dimethylformamide (1.3 g) in chloroform (5 mL) were added phosphorus oxychloride (1.7 L) and a solution of the obtained colorless crystals (1.5 g) in chloroforom (10 mL) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (18.5 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals (0.9 g). To a solution of the obtained colorless crystals (0.9 g) in pyridine (10 mL) was added hydrazine (0.27 g) and the mixture was stirred with heating for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give the title compound (230 mg) as colorless crystals. MP:198°C. Anal. Calcd. for:C19H23N302S:C,63.84;H,6.49;N,11.75. Found:C, 63.56 ;H, 6.45;N, 11.64. MS (El) :357(M+) .
^Η-NMR ( 400MHz,DMSO-d5) δ(ppm) : 0.82(3H,t,J=7.3Hz) ,
0.96(3H,t,J=7.3Hz), 1.62-1.68 (2H,m) , 2.48(3H,s), 2.67- 2.71(lH,m), 2.79-2.83(lH,m), 3.74(2H,q, J=7.3Hz) , 5.54(lH,s),
6.99-7.06(3H,m), 7.22-7.25(2H,m) , 9.38 ( lH,br .s) ,
11.86(lH,br.s) .
Example 40
Ethyl 4, 7-dihydro-4-( 2-methylsulfinylphenyl) -6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
To a solution of ethyl 4,7-dihydro-4-(2-methylthio)-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (100 mg) in tetrahydrofuran (3.0 mL) was added metachloroperbenzoic acid
(60 mg) and the mixture was stirred at -78°C for 30 minutes. An aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give colorless crystals.
By recrystallization from ethyl acetate, the title compound
(50 mg) was obtained as colorless crystals. MP:216°C.
Anal. Calcd. for:Cι9H23N3O3S:C,61.10;H,6.21;N,11.25.
Found:C,61.32;H,6.18;N,10.99.
MS(EI) :373(M+) . 1H-MMR (400MHz,DMSO-d6)δ(ppm) : 0.91( 3H,t, J=7.3Hz) , 0.97(3H,t,J=7.3Hz), 1.64-1.68(2H,m) , 2.69-2.72(lH,m) , 2.72(3H,s), 2.76-2.79(lH,m), 3.90(2H,q,J=7.3Hz) , 5.36(lH,s), 7.15(lH,dd,J=7.3Hz and 7.4Hz), 7.20(lH,s), 7.37-7.39(2H,m) , 7.85(lH,dd,J=7.3Hz and 7.4Hz), 9.59( lH,br .s) , 12.04(lH,br.s) . Example 41
Ethyl 4, 7-dihydro-4- ( 2-nitrophenyl) -6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2-nitrobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39. MP:218°C.
Anal. Calcd. for:Cι8H20N404:C,60.66;H,5.66;N,15.72. Found:C,60.25;H,5.65;N,15.44. MS (El) :356(M+) . 1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.80(3H,t, J=7.3Hz) ,
0.95(3H,t,J=7.3Hz) , 1.59-1.64(2H,m) , 2.69-2.73( lH,m) , 2.77- 2.80(lH,m), 3.72(2H,q,J=7.3Hz) , 5.45( lH,s) ,7.28-7.33(3H,m) , 7.56(lH,dd,J=7.3Hz and 7.4Hz), 7.76( lH,d, J=7.3Hz) , 9.64(lH,br.s), 10.07(lH,br.s) . Example 42
Ethyl 4-( 2-cyanophenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2-cyanobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39. MP:211°C.
Anal. Calcd. for:C19H20NO2:C,67.84;H,5.99;N,16.66.
Found:C,67.49;H,6.14;N,16.23.
MS (El) :336(M+) .
^- R ( 400MHz,DMSO-d6)δ(ppm) : 0 ,89(3H,t, J=7.3Hz) , 0.94(3H,t,J=7.3Hz), 1.61-1.67(2H,m) , 2.71-2.73( lH,m) , 2.79- 2.82(lH,m), 3.80(2H,q,J=7.3Hz), 5.48 ( IH, s) ,7.21-7.29(2H,m) , 7.28(lH,dd,J=7.3Hz and 7.4Hz), 7.55( lH,dd,J=7.3Hz and 7.4Hz), 7.70(lH,d,J=7.3Hz), 9.63( lH,br.s) , 12.07( lH,br.s) . Example 43
Ethyl 4-(2, 3-difluorophenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,3- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:207°C.
Anal. Calcd. for:d8Hι9F2N302 1/5 H2O:C,61.60;H,5.57;N, 11.97.
Found: C, 61.41 ;H, 5.56 ;N, 11.59. MS(EI) :347(M+) .
XH-NMR ( 400MHz, DMSO-d6)δ (ppm ) : 0.90-0.97 ( 6H,m) , 1.60-1.66(2H,m) ,
2.68-2.71(lH,m),2.79-2.82(lH,m), 3.83(2H,q, J=7.3Hz) ,
5.45(lH,s), 6.87(lH,dd,J=7.3Hz and 7.4Hz), 7.03-7.13(2H,m) ,
7.76(lH,s), 9.55(lH,br.s), 12.03( lH,br.s) . Example 44
Ethyl 4-(2 , 3-dichlorophenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2, 3- dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:220°C.
Anal. Calcd. for :Cι8Hι9Cl2N302 :C,56.85;H,5.04;N, 11.05.
Found:C,56.35;H,5.00;N,11.01.
MS(EI) :380(M+) . XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.88(3H,t,J=7.3Hz) ,
0.99(3H,t,J=7.3Hz), 1.66-1.69(2H,m) , 2.74-2.77( lH,m) , 2.82-
2.86(lH,m), 3.81(2H,q,J=7.3Hz), 5.66(lH,s), 7 ,10(lH,d,J=7.3Hz) ,
7.24(lH,dd,J=7.3Hz and 7.4Hz), 7.31(lH,s), 7.38( lH,d,J=7.3Hz) ,
9.59(lH,br.s), 12.04(lH,br.s). Example 45
Ethyl 4-( 3-fluoro-2-methylphenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 3-fluoro-2- methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:159-162°C.
Anal. Calcd. for:Cι9H22FN303 3/10 H20:C,65.42;H,6.53;N, 12.05. Found:C,65.56;H,6.29;N,12.40.
MS (El) :343(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm): 0.89 (3H,t, J=7.3Hz) , 0.97
(3H,t,J=7.3Hz), 1.64(2H,m), 2.36(3H,s), 2.67-2.84(2H,m) ,
3.80(2H,q,J=7.3Hz) , 5.35(lH,s), 6.86(2H,d, J=8.8Hz) , 7.07(lH,dd,J=7.3Hz and 7.4Hz), 7.23 (lH,s), 9.42( lH,br .s) ,
11.94(lH,br.s) .
IR(KBr) :v=3265, 3193, 2966, 2934, 1668, 1591, 1520, 1466, 1240cm"1.
Example 46
Ethyl 4-( 2 , 3-dimethoxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2,3- dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:205-206°C. Anal. Calcd. for:C2oH25N304:C,64.67;H,6.78;N, 11.31.
Found:C,64.76;H,6.81;N,11.15.
MS(EI) :371(M+) .
^-NMR ( 400MHz,DMSO-d5)δ(ppm) : 0.90(3H,t, J=7.4Hz) ,
0.98(3H,t,J=7.3Hz), 1.66-1.68 (2H,m) , 2.68-2.70( lH,m) , 2.80- 2.83(lH,m), 3.77(3H,s), 3.80(3H,s), 3.80-3.85(2H,m) ,
5.44(lH,s), 6.58(lH,d,J=7.3Hz) , 6.76 ( lH,d, J=6.8Hz) ,
6.88(lH,dd,J=7.3Hz and 7.4Hz) ,7.11( lH,s) , 9.32( lH,br.s) ,
11.83(lH,br.s) .
Example 47 Ethyl 4-( 2-chloro-3-trifluoromethylphenyl) -4, 7-dihydro-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-chloro-3- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:236-238°C.
Anal. Calcd. for:Cι9H19ClF3N302:C,55.15;H,4.63;N, 10.15. Found: C,55.07;H,4.55;N, 10.13. MS(EI) :413(M+) .
XH-NMR ( 400MHz,DMS0-d6)δ(ppm) : 0.82(3H,t,J=7.3Hz) ,
0.97(3H,t,J=7.3Hz), 1.65(2H,m), 2.70-2.90 (2H,m) , 3.65-
3.85(2H,m), 5.72(lH,s), 7.29(lH,s), 7.41-7.42(2H,m) , 7.59-
7.61(lH,m), 9.62(lH,br.s), 12.05( lH,br.s) . Example 48
Ethyl 4-( 2-chloro-4-fluorophenyl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-chloro-4- fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MS(EI) :363(M+) .
XH-NMR ( 400MHz , DMSO-de ) δ ( ppm) : 0 . 88 ( 3H, t, J=7 .3Hz ) ,
0 .96 ( 3H,t , J=7 .3Hz ) , 1.62-1 .67 ( 2H,m) , 2 . 66-2 .80 ( 2H,m) ,
3.77(2H,q,J=7.3Hz) , 5.54( lH,s) ,7.08-7.13(2H,m) , 7.25(lH,s), 7.32(lH,dd,J=2.5Hz and 8.8Hz), 9.53( lH,br .s) , 11.99( lH,br.s) .
Example 49
Ethyl 4-( 2 , 5-difluorophenyl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,5- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:168-169°C.
MS (El) :347(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.92-0.99 ( 6H,m) , 1.62-1.68 (2H,m) , 2.67-2.71(lH,m), 2.85-2.88(lH,m) , 3.80-3.91(2H,m) ,
4.03(lH,q,J=6.8Hz) , 5.40(lH,s), 6.77-6.80( lH,m) , 6.98-
7.00(lH,m), 7.12-7.16(lH,m), 7.26(lH,s), 9.59( lH,br.s) ,
12.06(lH,br.s) . Example 50
Ethyl 4- (2 , 5-dichlorophenyl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2,5- diehlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:162°C.
Anal. Calcd. for:C18H19Cl2N302 1/2 H20:C,55.54;H,5.18;N, 10.79.
Found:C,55.50;H,5.50;N,11.17. MS(EI) :380(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.89 ( 3H,t, J=7.3Hz) ,
0.98(3H,t,J=7.3Hz) , 1.62-1.66 (2H,m) , 2.64-2.67( lH,m) , 2.86-
2.90(lH,m), 3.81(2H,q,J=7.3Hz) , 5.55(lH,s), 7.04(lH,s),
7.18(lH,d,J=7.3Hz), 7.28(lH,s), 7.41( lH,d, =7.3Hz) , 9.61(lH,br.s), 12.06( lH,br.s) .
Example 51
Ethyl 4- ( 5-fluoro-2-methoxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 5-fluoro-2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:164-167°C.
Anal. Calcd. for:C19H22FN303: C,63.50;H,6.17;N, 11.69.
Found:C,63.24;H,6.09;N,11.70. MS(EI) :359(M+) .
XH-NMR (400MHz, DMSO-d6)δ(ppm) : 0.87(3H,t, J=7.3Hz) , 0.98(3H,t,J=7.3Hz) , 1.64-1.69(2H,m) , 2.62-2.91(2H,m) , 3.79(2H,q,J=7.3Hz) , 3.85(3H,s), 5.44(lH,s), 6.33( lH,dd, J=3.0Hz and 7.8Hz), 6.83-6.91(2H,m) , 7.17(lH,s), 9.41( lH,br.s) , 11.89(lH,br.s) .
IR(KBr):v=3252, 2955, 1657, 1510, 1232, 1074cm-1. Example 52
Ethyl 4- (2-chloro-5-methoxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-chloro-5- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
Anal. Calcd. for:Cι9H22ClN3O3:C,60.72;H,5.90;N,11.18.
Found:C,60.58;H,5.88;N,11.07.
MS(EI) :375(M+).
XH-NMR ( 400MHz, DMSO-d6)δ (ppm ) : 0.88(3H,t, J=7 ,3Hz) , 0.99(3H,t,J=7.3Hz), 1.64-1.69(2H,m) , 2.64-2.67 ( lH,m) , 2.87-
2.90(lH,m), 3.79(2H,q,J=7.3Hz), 3.86(3H,s), 5.44(lH,s),
6.85(lH,d,J=7.3Hz), 6 ,94( lH,d, J=7.3Hz) , 7.10(lH,dd,J=2.9Hz and
7.3Hz), 7.17(lH,s), 9 ,43( lH,br .s) , 11.91( lH,br .s) .
Example 53 Ethyl 4-( 2 , 5-dimethoxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b] yridine-5-carboxylate
The title compound was prepared from 2,5- dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:169-170°C.
MS(EI) :371(M+) .
XH-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.88 (3H,t,J=7.3Hz) , 0.98(3H,t,J=7.3Hz), 1.68-1.70(2H,m) , 2.49-2.54( lH,m) , 2.94- 2.97(lH,m), 3.57(3H,s), 3.79-3.83(2H,m) , 3.80(3H,s), 4.02(lH,q,J=7.3Hz), 5.43(lH,s), 6.49( lH,d,J=2.9Hz) ,
6.59(lH,dd,J=2.9Hz and 8.8Hz), 6.82( lH,d, J=8.8Hz) , 7.14(lH,s),
9.32(lH,br.s), 11.83( lH,br.s) .
Example 54
Ethyl 4-( 2 , 6-difluorophenyl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,6- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP : 185°C .
Anal. Calcd. for:C18H19F2N302 1/2 H20:C, 60.67;H,5 ,66;N, 11.79.
Found:C,60.68;H,5.46;N,11.61.
MS(EI) :347(M+). ^- R ( 400MHz, DMSO-d6)δ(ppm) : 0.90-0.97( 6H,m) , 1.54-1.58(2H,m) ,
2.51-2.54(lH,m), 2.76-2.81( lH,m) , 3.82(2H,q,J=7.3Hz) ,
5.53(1H,S), 6.90(2H,dd,J=7.3Hz and 7.3Hz), 7.16( lH,d, J=7.3Hz) ,
7.20(lH,s), 9.50(lH,br.s), 11.96 ( lH,br.s) .
Example 55 Ethyl 4-(2 , 6-dichlorophenyl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,6- dichlorobenzaldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39. MP:202°C.
Anal. Calcd. for:Cι8Hι9Cl2N302 3/10 H20:C,56.06;H,5.12;N, 10.90.
Found:C,56.28;H,5.46;N,10.78.
MS(EI) :380(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 0.83( 3H,t, J=7.3Hz) , 0.92(3H,t,J=7.3Hz) , 1.57-1.62(2H,m) , 2.47-2.51( lH,m) , 2.77-
2.80(lH,m), 3.74(2H,q,J=7.3Hz), 6.03(lH,s), 7.05(lH,s),
7.13(lH,dd,J=7.3Hz and 7.4Hz), 7.22 ( lH,d, J=7.3Hz) ,
7.39(lH,d,J=7.3Hz), 9.53( lH,br.s) , 11.93( lH,br.s) .
Example 56 Ethyl 4-(2-chloro-6-fluorophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2-chloro-6- fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:180-183°C. MS (El) :363(M+).
XH-NMR ( 400MHz , DMSO-d6 ) δ ( ppm) : 0 .92 ( 3H,t, J=6 .9Hz ) , 0 .94 ( 3H, t, J=7 .3Hz ) , 1 .56-1 . 61 ( 2H,m) , 2 .50-2 .85 ( 2H,m) , 3.80 ( 2H, q, J=7 .3Hz ) , 5.75 ( lH, s ) , 7.01-7.17 ( 4H,m) , 9 .52 ( lH,br . s ) , 11.97 ( lH,br . s ) .
IR(KBr) :v=3265 , 1591, 1518 , 1456 , 1228 , 1097cm"1.
Example 57 Ethyl 4, 7-dihydro-6-propyl-4-(pyridin-3-yl) -2H-pyrazolo[3,4- b]pyridine-5-carboxylate dihydrocloride
The title compound was prepared from pyridine-3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
MP:251°C. Anal. Calcd. for:C17H20N4O2-2HCl:C,52.99;H,5.76;N,14.54.
Found:C,52.99;H,5.67;N,14.44.
MS(EI) :312(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.91(3H,t, J=7.3Hz) ,
1.09(3H,t,J=7.3Hz) , 1.52-1.61(2H,m) , 2.66-2.71(2H,m) , 3.93- 4.00(2H,m), 5.24(1H,S), 7.90( lH,dd,J=7.3Hz and 7.4Hz), 8.31-
8.35(2H,m), 8.66-8.69(2H,m), 10.35( lH,br.s) .
Example 58
Ethyl 4 , 7-dihydro-6-propyl-4-(pyridin-4-yl) -2H-pyrazolo[3,4- b]pyridine-5-carboxylate dihydrocloride The title compound was prepared from pyridine-4-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
MP:266°C.
Anal. Calcd. for:C17H0N4O2 2HC1:C,52.99;H,5.76;N, 14.54.
Found:C, 52.63 ;H, 5.65;N, 14.69. MS(EI) :312(M+) .
^-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.91(3H,t,J=7.3Hz) ,
1.12(3H,t,J=7.3Hz), 1.52-1.59(2H,m) , 2.64-2.72 (2H,m) ,
4.01(2H,q,J=7.3Hz) , 5.30(lH,s), 7.76 (2H,d, J=6 ,4Hz) , 8.66(lH,s),
8.72(2H,d,J=6.4Hz), 10.39 ( lH,br.s) . Example 59
Ethyl 4- ( furan-2-yl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate maleate
The title compound was prepared from furan-2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:108-111°C. MS(EI) ^OlfM*) . 1H- MR ( 400MHz,DMSO-d6) δ(ppm) : 0.92(3H,t,J=7.3Hz) ,
1.05(3H,t,J=6.8Hz) , 1.58(2H,q, J=7.3Hz) , 2.66-2.72 (2H,m) , 3.50(3H,br.s), 3.94(2H,q,J=6.8Hz) ,5.21 ( 1H,S) ,5.78 ( lH,d, J=2.9Hz),6.23(lH,s), 6.24(2H,s), 7.75(lH,s), 7.38(lH,s), 9.42(lH,br.s) . IR(KBr) :v=3207, 2962, 1703, 1479, 1348, 1205, 1076, 866cm"1. Example 60
Ethyl 4-( furan-3-y1) -4 , 7-dihydro-4-( furan-3-yl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from furan-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:121-123°C.
Anal. Calcd. for :Cι6Hι9N303C4H404:C,57.54;H,5.55;N, 10.07. Found:C,57.14;H,5.55;N,10.37. MS(EI) :301(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.90(3H,t,J=7.3Hz ) , 1.08(3H,t,J=7.4Hz) , 1.55-1.57(2H,m) , 2.62-2.70(2H,m) , 3.36(lH,br.s), 3.50(2H,br.s) , 3.97(2H,q,J=7.3Hz) , 5.06(lH,s), 6.16(1H,S), 6.24(2H,s), 7.13(lH,s), 7.35(lH,s), 7.40(lH,s), 9.31(lH,br.s) .
IR(KBr) :v=3350, 2972, 1591, 1467, 1361, 1203, 1089cm"1. Example 61
Ethyl 4, 7-dihydro-4-( 2-methylfuran-3-yl) -6-propyl-2H- pyrazolo[ 3, 4-b] yridine-5-carboxylate The title compound was prepared from 2-methylfuran-3- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:123-125°C. Anal. Calcd. for:Cι7H21N303 2/5 H20:C,63.30;H, 6.81;N, 13.03. Found: C,63.51;H,6.64;N, 12.96. MS (El) :315(M+) .
1H- MR ( 400MHz,DMSO-d6) δ(ppm) : 0.93(3H,t,J=7.3Hz) , 1.08(3H,t,J=7.3Hz) , 1.58-1.60(2H,m) , 2.20(3H,s), 2.55- 2.75(2H,m), 3.92(2H,q, J=7.3Hz) , 4.99(lH,s), 5.96(lH,s), 7.21(2H,s), 9.26(lH,br.s), 11.91( lH,br.s) .
IR(KBr) :v=3265, 3198, 2964, 1591, 1514, 1224, 1209, 1093cm"1. Example 62 Ethyl 4, 7-dihydro-6-propyl-4-(thiophen-2-yl) -2H-pyrazolo[ 3, 4- b]pyridine-5-carboxylate maleate
The title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:129-131°C.
Anal. Calcd. for:C16Hι9N3θ2SC4H404 1/4 H20: C,54.85;H,5.41;N,9.59.
Found:C,54.59;H,5.22;N,9.97.
MS(EI) :317(M+) .
XH-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.92 ( 3H,t, J=7.4Hz) , 1.06(3H,t,J=7.3Hz) , 1.58-1.60(2H,m) , 2.72-2.74(2H,m) ,
3.50(3H,br.s), 3.94(2H,q,J=7.4Hz), 5.44(lH,s), 6.25(2H,s),
6.69(1H,S), 6.81(lH,d), 7.15(lH,d), 7.37(lH,s), 9.50( lH,br .s) .
Example 63
Ethyl 4, 7-dihydro-4-( 3-methylthiophen-2-yl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 3-methylthiophene-
2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:125°C. Anal. Calcd. for:Cι7H2ιN302S H20: C,58.43;H,6.63;N, 12.02.
Found: C,58.59;H,6.33;N,12.12.
MS(EI) :331(M+) .
^- MR (400MHz, DMSO-de)δ(ppm) : 0.96(3H,t, J=7.4Hz) , 0.98(3H,t,J=7.3Hz) , 1.60-1.63(2H,m) , 2.22(3H,s), 2.83- 2.90(2H,m), 3.88(2H,q,J=7.3Hz), 5.42(lH,s), 6.68( lH,d, J=4.9Hz) , 7.02(lH,d,J=5.4Hz) , 7.29(lH,s), 9.45( lH,br.s) , 11.98( lH,br.s) . IR(KBr) :v=3267, 3196, 2968, 1664, 1510, 1267, 1201, 1091cm"1. Example 64
Ethyl 4- ( 5-chlorothiophen-2-yl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from 5-chlorothiophene- 2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:129-131°C.
Anal. Calcd. for:C16Hι8N302SC4H404:C,51.33;H,4.74;N,8.98.
Found:C,51.34;H,4.54;N,9.03.
MS(EI) :351(M+). XH-NMR ( 400MHz, DMSO-dg ) δ(ppm) : 0.92(3H,t, J=7.3Hz) ,
1.10(3H,t,J=6.9Hz), 1.59-1.61(2H,m), 2.57-2.82(2H,m) ,
3.50(2H,br.s), 3.38(lH,s), 3.98 (2H,q, J=6.9Hz) , 5.36(lH,s),
6.25(2H,s), 6.53(lH,d,J=3.9Hz), 6.80( lH,d, J=3 -4Hz) , 7.42(lH,s),
9.60(lH,br.s) . IR(KBr) :v=3205, 2964, 2629, 1618, 1471, 1363, 1205, 1080, 889, 652cm"1.
Example 65
Ethyl 4, 7-dihydro-6-propyl-4-(thiophen-3-yl)-2H-pyrazolo[3,4- b]pyridine-5-carboxylate maleate
The title compound was prepared from thiophene-3- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:141-143°C.
Anal. Calcd. for:Cι6Hi9N302SC4H04:C,54.42;H,5.35;N,9.69.
Found:C, 54.17 ;H, 5.23 ;N, 9.66. MS(EI) :317(M+).
XH-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.92(3H,t,J=7 -3Hz) , 1.03(3H,t,J=6.8Hz), 1.59-1.61(2H,m) , 2.60-2.78 (2H,m) , 3.50(2H,br.s), 3.91(2H,q,J=6.8Hz), 5.22(2H,s), 6.26(2H,s), 6.84-6.88(2H,m), 7.29( lH,dd, J=3.0Hz and 4.9Hz) , 7.33(lH,s), 12.0(lH,br.s).
IR(KBr) :v=3346, 2980, 2611, 1697, 1467, 1361, 1205, 1087cm-1. Example 66 Ethyl 4,7-dihydro-4-(naphthalen-l-yl)-6-propyl-2H- pyrazolo[ 3, 4-b] yridine-5-carbox late
The title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
Anal. Calcd. for:C22H23N302:C,73.11;H,6.41;N, 11.63. Found:C, 72.95;H, 6.47 ;N, 11.40. MS(EI) :361(M+) .
^- MR ( 400MHz,DMSO-d6)δ(ppm) : 0.62(3H,t,J=7.3Hz) , 1.00(3H,t,J=7.3Hz) , 1.69-1.73(2H,m) , 2.73-2.76( lH,m) , 2.84-
2.87(lH,m), 3.67(2H,q,J=7.3Hz), 5.95(lH,s), 7.03(lH,s),
7.23(lH,d,J=7.3Hz) , 7.36( lH,dd,J=7.3Hz and 7.4Hz),
7.49(lH,dd,J=7.3Hz and 7.4Hz), 7.57( lH,dd,J=7.3Hz and 7.4Hz),
7.65(lH,d,J=7.3Hz) , 7.88( lH,d, J=7.3Hz) , 8.40( lH,d, J=7 ,3Hz) , 9.45(lH,br.s), 11.82(lH,br.s) .
Example 67
Ethyl 4, 7-dihydro-4-(naphthalen-2-yl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from naphthalene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:136-138°C.
Anal. Calcd. f or : C22H23N302C4H04 1/4 H20:C, 64.79;H,5.75;N,8.72.
Found:C,64.86;H,5.57;N,8.99. MS(EI) :361(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.92-0.98( 6H,m) , 1.64-1.68(2H,m) , 2.72-2.80(2H,m), 3.50(2H,br .s) , 3.80(2H,q, J=7.3Hz) , 5.27(lH,s), 6.25(2H,s),7.23(lH,s), 7.31( lH,d, J=8.3Hz) , 7.41-7.43(2H,m) , 7.57(1H,S), 7.73-7.77(2H,m), 9.47( lH,br .s) .
IR(KBr):v=3202, 2962, 1701, 1464, 1359, 1222cm"1. Example 68
Ethyl 4, 7-dihydro-4- ( 2-methoxynaphthalen-1-yl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- methoxynaphthalene-1-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:188-191°C. Anal. Calcd. for:C23H25N303 2/5 H20:C,69.29;H,6.52;N, 10.54. Found:C,69.35;H,6.62;N,10.21. MS(EI) :391(M+) .
XH-NMR ( 400MHz, DMSO-dg)δ(ppm) : 0.71( 3H,t, J=7.3Hz) , 0.95(3H,t,J=7.3Hz), 1.62-1.63( 2H,m) , 2.49-2.86 (2H,m) , 3.61(2H,q,J=7.3Hz), 3.97(3H,s), 6.27(lH,s), 6.89(lH,s), 7.16- 7.51(3H,m), 7.71-7.77(2H,m), 7.98(lH,s), 9.43( lH,br.s) , 11.77(lH,br.s) .
IR(KBr) :v=3258, 1655, 1593, 1082cm"1.
Example 69 Ethyl 4-( 2 , 3-dihydobenzo[b] furan-7-yl) -4, 7-dihydro-6-propyl-
2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,3- dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:194-196°C.
Anal. Calcd. for :C2oH23 3θ3:C,67.97;H,6.56;N, 11.89.
Found:C,67.97;H,6.68;N,11.77.
MS (El) :353(M+) .
1H-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.92(3H,t, J=7.4Hz) , 0.97(3H,t,J=7.3Hz) , 1.66(2H,m), 2.67-2.70 ( lH,m) , 2.82-
2.84(lH,m), 3.15(2H,t,J=8.8Hz), 3.83-3.86 (2H,m) , 4.55-
4.58(2H,m), 5.29(lH,s), 6.64( lH,dd, J=7.3Hz and 7.4Hz),
6.72(lH,d,J=6.9Hz) , 6.93( lH,dd, J=7.3Hz and 7.4Hz), 7.20(lH,s), 9.32(lH,br.s), 11.86( lH,br .s) . Example 70
Ethyl 4-( 5-bromo-2 , 3-dihydobenzo[b] furan-7-yl) -4 , 7-dihydro-6- propyl-2H-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate The title compound was prepared from 5-bromo-2,3- dihydobenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:200-210°C.
Anal. Calcd. for :C20H22BrN3O3: C,55.57;H,5.13;N,9.72. Found:C,55.23;H,5.09;N,9.89. MS(EI) :432(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.93-0.98(6H,m) ,
1.64(2H,q,J=7.3Hz), 2.63(lH,m), 2.88-2.90 ( lH,m) ,
3.16(2H,t,J=8.3Hz), 3.85-3.87 (2H,m) , 4.57-4.60(2H,m) , 5.23(1H,S), 6.78(lH,s), 7.11(lH,s), 7.22(lH,s), 9.44( lH,br.s) ,
11.94(lH,br.s) .
Example 71
Ethyl 4-(5-chloro-2 , 3-dihydo-2-methylbenzo[b] furan-7-yl) -4, 7- dihydro-6-propyl-2H-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from 5-chloro-2,3- dihydo-2-methylbenzo[b]furan-7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:155-158°C. Anal. Calcd. for:C21H24N303C4H404:C,57.95;H,5.45;N,8.11.
Found:C, 57.57 ;H, 5.28 ;N, 8.47.
MS(EI) :401(M+) .
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.94(6H,t,J=6.8Hz) ,
1.03(3H,d,J=6.3Hz) , 1.65(2H,m), 2.40-2.73 (2H,m) , 2.87(lH,m), 3.29(lH,m), 3.50(3H,br.s), 3.84(2H,q,J=6.8Hz) , 5.05(lH,m),
5.23(lH,s), 6.25(2H,s), 6.64(lH,s), 6.95(lH,s),
7.20(lH,d,J=4.4Hz), 9.43( lH,br .s) .
IR(KBr) :v=3207,2976, 1589, 1462, 1201, 1082cm"1. Example 72
Ethyl 4-(2H-l-benzopyran-8-yl)-4,7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2H-l-benzopyran-8- aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
MP:194°C.
Anal. Calcd. for:C21H23N3O3:C,69.02;H,6.34;N,11.50.
Found:C,68.60;H,6.43;N,11.25. MS(EI) :194(M+) .
XH-NMR (400MHz, DMSO-d6)δ(ppm) : 0.90(3H,t, J=7.3Hz) ,
0.96(3H,t,J=7.3Hz), 1.64-1.68(2H,m) , 2.62-2.66(lH,m) , 2.80-
2.84(lH,m), 3.81(2H,q,J=7.3Hz), 4.85(2H,dd,J=2.0Hz and 9.8Hz),
5.39(1H,S), 5.89(lH,d,J=9.8Hz), 6.46( lH,d,J=9.8Hz) , 6.67- 6.80(3H,m), 7.18(lH,s), 9.31( lH,br.s) , 11.86 ( lH,br.s) .
Example 73
Ethyl 4-( 3 , 4-dihydro-2H-benzopyran-8-yl) -4, 7-dihydro-6-propyl-
2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 3 , 4-dihydro-2H- benzopyran-8-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
MP:208°C.
Anal . Calcd . for :C21H25N303 1/2 H20:C, 67.01 ;H, 6 .96 ;N, 11 . 16 .
Found:C, 67 .41;H, 6 .84;N, 10 .93 . MS (EI ) : 367 (M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.89( 3H,t, J=7.3Hz) ,
0.97(3H,t,J=7.3Hz) , 1.63-1.68 (2H,m) , 1.92-1.96(2H,m) , 2.67-
2.82(4H,m), 3.80(2H,q,J=7.3Hz) , 4.22-4.26 (2H,m) , 5.41(lH,s),
6.61(lH,dd,J=7.3Hz and 7.4Hz), 6.71-6.75(2H,m) , 7.17(lH,s), 9.25(lH,br.s), 11.80(lH,br.s) .
Example 74
Ethyl 4, 7-dihydro-6-propyl-4-( quinolin-4-yl) -2H-pyrazolo[3,4- b]pyridine-5-carboxylate The title compound was prepared from quinoline-4- aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39. MP:198°C. Anal. Calcd. for:C21H22N402 2/5 H20:C,68.24;H,6.22;N, 15.16. Found:C, 68.39 ;H, 6.04;N, 14.83. MS(EI) :362(M+).
XH-NMR ( 400MHz,DMSO-d6)δ(ppm): 0.61(3H,t, J=7.3Hz) ,
1.02(3H,t,J=7.3Hz), 1.68-1.72(2H,m) , 2.76-2.78 ( lH,m) , 2.86- 2.89(lH,m), 3.66-3.68(2H,m), 5.97(lH,s), 7.07(lH,s),
7.17(lH,d,J=4.4Hz), 7.65( lH,dd, J=7.3Hz and 7.4Hz),
7.74(lH,dd,J=7.3Hz and 7.4Hz), 7.99( lH,d, J=7.3Hz) ,
8.48(lH,d,J=7.8Hz) , 8.73( lH,d, J=4.4Hz) , 9.61( lH,br .s) ,
11.94(lH,br.s) . Example 75
Ethyl 4-(benzo[b]thiophen-3-yl)-4,7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from benzo[b]thiophene-
3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
MP:222°C.
Anal. Calcd. for:C20H21N302S:C,65.37;H,5.76;N, 11.44.
Found:C, 65.11;H, 5.31;N, 11.83.
MS(EI) :238(M+) . XH-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.64(3H,t,J=7.3Hz) ,
1.20(3H,t,J=7.3Hz), 1.56-1.58( 2H,m) , 2.66-2.78(2H,m) ,
4.11(2H,q,J=7.3Hz), 4.89(lH,s), 7.42-7.50 (2H,m) , 7.55(lH,s),
7.61(lH,s), 7.96-8.01(2H,m), 10 -32( lH,br . s) , 12.13( lH,br .s) .
Example 76 Ethyl 4- ( 2 , 1, 3-benzoxadiazol-4-yl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 39.
MP:207°C.
Anal. Calcd. for:C18Hι9N503:C, 61.18;H,5.42;N,19.82.
Found:C, 61.06;H, 5.50;N, 19.66. MS(EI) :353(M+).
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.77(3H,t,J=7.3Hz) ,
0.97(3H,t,J=7.3Hz), 2.72-2.77( lH,m) , 2.82-2.86( lH,m) ,
3.79(2H,q,J=7.3Hz), 5.68(lH,S), 7.11( lH,d,J=7.3Hz) , 7.22(lH,s),
7.51(lH,dd,J=7.3Hz and 7.4Hz), 7.78 ( lH,d,J=7.3Hz) , 9.66(lH,br.s), 12.01( lH,br.s) .
Example 77
Ethyl 4-( 1, 3-benzdioxazol-4-yl)-4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 1, 3-benzdioxazole- 4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:203-207°C.
Anal. Calcd. for:C19H2ιN304 1/10 H20:C,63.89;H,5.98;N,11.76.
Found:C,63.72;H,5.86;N,12.01. MS(EI) :355(M+) .
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.94(3H,t, J=7.3Hz) ,
0.96(3H,t,J=7.4Hz) , 1.61.1.67(2H,m) , 2.64-2.82(2H,m) , 3.80-
3.88(2H,m), 5.28(lH,s), 5.99(1H,S), 6.00( lH,d, J=9.7Hz ) ,
6.50(lH,d,J=5.9Hz), 6.65(lH,s), 6.65-6.69 ( lH,m) , 7.25(lH,s), 9.40(lH,br.s), 11.94( lH,br.s) .
IR(KBr) :v=3265,3188, 2962, 1662, 1587, 1514, 1462, 1253, 1215, 1066cm"1. Example 78
Ethyl 4-(6-chloro-3, 4-dihydro-2, 2-dimethyl-2H-l, 4-benzoxazin- 8-yl)-4, 7-dihydro-6-propyl-2H-pyrazolo[ 3, 4-b]pyridine-5- carboxylate maleate
The title compound was prepared from 6-chloro-3,4- dihydro-2,2-dimethyl-2H-l,4-benzoxazine-8-aldehyde, 3- aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MS(EI) :430(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.92(3H,t,J=7.4Hz) ,
0.96(3H,t,J=7.3Hz) , 1.18(3H,S), 1.32(3H, s) , 1.62-1.64(2H,m) , 2.66-2.82(2H,m), 2.99(2H,s), 3.80(2H,t,J=7.3Hz) , 5.32(lH,S),
6.01(2H,s), 6.14(lH,s), 6.32(lH,s), 7.14(lH,s), 9.31( lH,br .s) ,
11.82(lH,br.s) .
IR(KBr):v=3281,2974, 1672, 1599, 1520, 1207, 1155, 1091cm"1.
Example 79 Ethyl 4- ( 6-chloro-3 , 4-dihydro-2 , 2 , 4-trimethyl-l, 4-benzoxazin-
8-yl)-4,7-dihydro-6-propyl-2H-pyrazolo[3,4-b]pyridine-5- carboxylate maleate
The title compound was prepared from 6-chloro-3,4- dihydro-2 , 2 , 4-trimethyl-2H-l, 4-benzoxazine-8-aldehyde, 3- aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MS (El) :444(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.91(3H,t,J=7.3Hz) ,
0.96(3H,t,J=7.3Hz), 1.20(6H,s), 1.35(3H,s), 1.63-1.65 (2H,m) , 2.83(2H,s), 3.00(2H,q,J=7.3Hz), 5.34(lH,s), 6.26(2H,s),
6.43(lH,d,J=2.5Hz), 7.13(lH,s), 9.33(lH,s), 11.82( lH,br .s) .
IR(KBr):v=3273, 2974, 1666, 1597, 1518, 1458, 1259, 1211cm"1.
Example 80
Ethyl 4-( 2 , 3-dihydro-l , 4-benzodioxin-6-yl) -4 , 7-dihydro-6- propyl-2H-pyrazolo [ 3 , 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from 2, 3-dihydro-l, 4- benzodioxin-6-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:147-149°C. Anal. Calcd. for:C2oH23N304C4H404:C,59.37;H,5.60;N,8.66.
Found:C,59.12;H,5.63;N,8.57.
MS(EI) :369(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.93(3H,t, J=7.3Hz) , 1.02(3H,t,J=6.8Hz), 1.60(2H,q, J=7.3Hz) , 2.64-2.68(2H,m) , 3.50(2H,br.s), 3.86(2H,q, J=7.3Hz) , 4.14(4H,s), 4.99(lH,s), 6.26(2H,s), 6.54(lH,s), 6.57 ( lH,d, J=7.8Hz) , 6.65( lH,d, J=7.8Hz) , 7.21(lH,s), 11.97(lH,br.s) . IR(KBr):v=3211, 2694, 2878, 2658, 1697, 1506, 1466, 1363, 1302, 1082cm-1.
Example 81
Ethyl 4-(benzo[b]furan-2-yl)-4,7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate maleate
The title compound was prepared from benzo[b]furan-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:123-125°C.
Anal. Calcd. for:C20H21N3O3C4H4O4 1/2 H20:C, 61.19;H,5.43;N,8.92.
Found:C,61.02;H,5.41;N,9.27. MS(EI) :351(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.96(3H,t, J=7.3Hz) ,
1.02(3H,t,J=6.8Hz) , 1.63(2H,q, J=7.3Hz) , 2.73-2.76 (2H,m) ,
3.50(3H,br.s), 3.93(2H,q, J=7.3Hz) , 5.36(lH,s), 6.24(2H,s),
6.43(lH,s), 7.10-7.21(2H,m), 7.41-7.48 (3H,m) , 9.51( lH,br .s) . IR(KBr) :v=3190, 3080, 2962, 1705, 1581, 1454, 1359, 1195, 883cm"1.
Example 82
Ethyl 4-( 2-chlorophenyl) -6-ethyl-4, 7-dihydro-2H-pyrazolo[3,4- b] yridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketopentanoate in the same manner as in Example 1.
MP:213°C.
Anal. Calcd. for:C17Hι8ClN302:C,61.54;H,5.47;N, 12.66.
Found:C,61.54;H,5.46;N,12.68. MS(EI) :331(M+) .
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.85(3H,t, J=7.3Hz) , 1.21(3H,t,J=7.3Hz), 2.78-2.84(2H,m) , 3.78 (2H,q, J=7.3Hz) , 5.58(lH,s), 7.07-7.12(2H,m), 7.18 ( lH,dd, J=7.3Hz and 7.4Hz) ,7.25(1H,S), 7.34( lH,d,J=7.3Hz) , 9.52( lH,br .s) ,
11.97(lH,br.s) .
Example 83
Ethyl 6-butyl-4-( 2-chlorophenyl) -4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketoheptanoate in the same manner as in Example 1.
MP:209°C. Anal. Calcd. for:Cι9H22ClN302 1/5 H20:C,62.79;H,6.21;N, 11.56.
Found:C, 62.78 ;H, 6.11;N, 11.45.
MS (El) :359(M+) .
^-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.85(3H,t, J=7.3Hz) ,
0.92(3H,t,J=7.3Hz) , 1.36-1.42(2H,m) , 1.60-1.64(2H,m) , 2.72- 2.76(lH,m), 2.83-2.86(lH,m), 3.78(2H,q, J=7.3Hz) , 5.58(lH,s),
7.07-7.11(2H,m), 7.18 ( lH,dd, J=7.3Hz and 7.4Hz), 7.24(lH,s),
7.34(lH,d,J=7.3Hz), 9.49 ( lH,br .s) , 11.96( lH,br.s) .
Example 84
Methyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-methoxymethyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl 4- methoxyacetoacetate in the same manner as in Example 1.
MP:160°C. Anal. Calcd. for:C16Hι6ClN303:C,57.33;H,4.83;N, 12.59.
Found:C, 57.53 ;H, 4.86 ;N, 12.58.
MS (El) :333(M+) .
^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 3.36(3H,S), 3.38(3H,s),
4.67(2H,s), 5.58(1H,S), 7.08-7.13(2H,m) , 7.19( lH,dd,J=7.3Hz and 7.4Hz), 7.32-7.36(2H,m) , 9.14( lH,br.s) , 12.08(lH,br.s) .
Example 85
Ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-phenyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl benzoylacetoacetate in the same manner as in Example 1.
MP:214°C. Anal. Calcd. for:C21H18ClN302 3/10 H20:C,65.47;H,4.87;N, 10.91.
Found:C, 65.29 ;H, 4.73 ;N, 10.93.
MS(EI) :379(M+) .
1H-NM (400MHz,DMSO-d6)δ(ppm) : 0.57 (3H,t, J=7.3Hz) ,
3.52(2H,q,J=7.3Hz), 5.65(lH,s), 7.14( lH,dd,J=7.3Hz and 7.4Hz), 7.27(lH,dd,J=7.3Hz and 7.4Hz), 7.37-7.40( 8H,m) , 9.53( lH,br.s) ,
12.04(lH,br.s) .
Example 86
Ethyl 4-(2-chlorophenyl) -4 , 7-dihydro-6-( 4-methoxyphenyl) -2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl (4- methoxybenzoyl)acetate in the same manner as in Example 1.
MP:211°C.
Anal. Calcd. for:C22H20ClN303:C,64.47;H,4.92;N, 10.25. Found:C,64.30;H,5.00;N,10.24.
MS (El) :409(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0 ,64(3H,t, J=7.3Hz) ,
3.56(2H,q,J=7.3Hz), 3.79( 3H,s) ,5.63( IH, s) , 6.95(2H,d, J=7.3Hz) ,
7.13(lH,dd,J=7.3Hz and 7.4Hz), 7.24-7.38( 6H,m) , 9.45( lH,br.s) , 12.03(lH,br.s) .
Example 87
Ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-(thiophen-2-yl) -2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl (thiophen-2- carbonyl) acetate in the same manner as in Example 1.
MP:200°C.
Anal . Calcd. for :Cι9Hι6ClN302S :C, 59 . 14 ;H, 4. 18 ;N, 10.89 . Found: C, 59.04 ;H, 4.31 ;N, 11.14.
MS(EI) :385(M+) .
XH- MR ( 00MHz,DMSO-de)δ(ppm) : 1.02( 3H,t,J=7.3Hz) ,
4.04(2H,q,J=7.3Hz) , 5.16(lH,s), 6.58( lH,d,J=7.3Hz) , 7.18- 7.70(7H,m), 9.60(lH,br.s), 12.74( lH,br.s) .
Example 88
Ethyl 6-benzyl-4-( 2-chlorophenyl) -4 , 7-dihydro-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 4- phenylacetoacetate in the same manner as in Example 1.
MP:247°C.
Anal. Calcd. for:C22H20ClN3O2O 1/5 H20:C,66.48;H,5.17;N, 10.57.
Found:C, 66.30 ;H, 5.17 ;N, 10.37. MS(EI) :393(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.81( 3H,t, J=7.3Hz) ,
3.76(2H,q,J=7.3Hz), 4.25(2H,s), 5.65(lH,s), 7.06-7.41( 10H,m) ,
9.68(lH,br.s), 12.01( lH,br .s) .
Example 89 Ethyl 6-ethyl-4, 7-dihydro-4-( 2-methoxyphenyl) -2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketopentanoate in the same manner as in Example 1. MP:169°C.
Anal. Calcd. for:Cι8H21N303 3/10 H20:C,64.97;H,6.54;N, 12.63.
Found:C,64.86;H,6.84;N,12.33.
MS(EI) :327(M+) .
^-NMR ( 400MHz, DMS0-d6 ) δ(ppm) : 0.85(3H,t, J=7.3Hz) , 1.18(3H,t,J=7.3Hz) , 2.73-2.76( lH,m) ,2.81-2.85(lH,m) ,
3.74(2H,q,J=7.3Hz), 3.85(3H,s), 5.46(lH,s), 6.76 ( lH,dd, J=7.3Hz and 7.4Hz), 6.89-6.94(2H,m) , 7.04( lH,dd, j=7.3Hz and 7.4Hz),
7.14(lH,s), 9.32(lH,br.s), 11.82( lH,br .s) . Example 90
Ethyl 6-butyl-4, 7-dihydro-4- ( 2-methoxyphenyl) -2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketoheptanoate in the same manner as in Example 1. MP:190°C.
Anal. Calcd. for:C2oH25N303 1/2 H20:C,65.91;H,7.19;N, 11.53. Found:C,65.92;H,7.07;N,11.88. MS(EI) :355(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.85(3H,t, J=7.3Hz) , 0.93(3H,t,J=7.3Hz) , 1.38-1.44(2H,m) , 1.59-1.64(2H,m) , 2.64- 2.68(lH,m), 2.85-2.90(lH,m), 3.81(2H,q, =7.3Hz) , 3.85(3H,s), 5.47(lH,s), 6.76(lH,dd,J=7.3Hz and 7.4Hz), 6.89-6.94(2H,m) , 7.04(lH,dd,J=7.3Hz and 7.4Hz), 7.14(lH,s), 9.29( lH,br .s) , 11.82(lH,br.s) . Example 91
Methyl 4, 7-dihydro-6-methoxymethyl-4-( 2-methoxyphenyl) -2H- pyrazolo[3 , 4-b] yridine-5-carboxylate The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and methyl 4- methoxyacetoacetate in the same manner as in Example 1.
MP:186°C.
Anal. Calcd. for:C17Hι9N304 1/5 H20:C,61.32;H,5.87;N, 12.62. Found:C,61.34;H,5.84;N,12.52. MS (El) :329(M+) .
^Η- MR ( 400MHz, DMSO-d6 ) δ(ppm) : 3.36(3H,s), 3.38(3H,S), 3.86(3H,s), 4.68(2H,s), 5.46(lH,s), 6.77 ( lH,dd, J=7.3Hz and 7.4Hz), 6.90-6.94(2H,m) , 7.06( lH,dd, J=7.3Hz and 7.4Hz), 7.22(lH,s), 8.94(lH,br.s), 11.94(lH,br.s) . Example 92
Ethyl , 7-dihydro-4-( 2-methoxyphenyl) -6-phenyl-2H- pyrazolo[3, 4- ] yridine-5-carboxylate The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1. MP:195°C. Anal. Calcd. for:C22H2ιN3O3:C,70.38;H,5.64;N,11.19. Found:C,70.41;H,5.71;N,11.27. MS(EI) :375(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.55(3H,t,J=7.3Hz) , 3.53(2H,q,J=7.3Hz), 3.88(3H,s), 5.52(lH,s), 6.84( lH,dd,J=7.3Hz and 7.4Hz), 6.94( lH,d,J=7.3Hz) , 7.09(lH,dd,J=7.3Hz and 7.4Hz), 7.18(lH,d,J=7.3Hz), 7.23(lH,s), 7.37-7.40(5H,m) , 9 ,33( lH,br.s) , 11.90(lH,br.s) . Example 93 4-( 2-Chlorophenyl) -4, 7-dihydro-5-nitro-6-propyl-2H- pyrazolo[3, 4-b]pyridine
To an aqueous solution (50 mL) of nitromethane (50 g) was added an aqueous solution (50 mL) of n-butylaldehyde (59 g) , and the mixture was stirred with heating at 60°C for 6 hours. The reaction mixture was allowed to cool to ambient temperature, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give a brown oil (58 g) . To a mixed solution of the obtained oil (50 g) in water (50 mL) and acetone (50 mL) was added sodium chromate (70 g) . Under ice-cooling, concentrated sulfuric acid (46 mL) was added dropwise and the mixture was stirred for 5 hours. Ice- water (200 L) was added and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give l-nitropentan-2-one (40 g) as a brown oil. A solution of 2- chlorobenzaldehyde (1.8 g), 3-aminopyrazole (1.0 g) and 1- nitropentan-2-one (1.4 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give the title compound (680 mg) as yellow crystals. MP:228°C.
Anal. Calcd. for :Cι5Hι5ClN402:C,56.52;H,4.74;N, 17.58.
Found:C,56.26;H,4.91;N,17.64.
MS(EI) :318(M+).
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 1.02 (3H,t,J=7.3Hz) , 1.70- 1.73(2H,m), 2.89-2.91(lH,m), 2.99-3 ,02( lH,m) , 5.90(lH,s), 7.09-7.21(3H,m), 7.39( lH,d,J=7 ,3Hz) , 7.44(lH,s), 10.84(lH,br.s), 12.43( lH,br.s) . Example 94 4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
To a solution of acetonitrile (4.8 g) in THF (150 mL) was added n-BuLi (67 mmol) at -78°C. Further, methyl butanoate (10 g) was added and the mixture was stirred for one hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give l-cyanopentan-2-one (5.5 g) as a colorless oil. A solution of 2-chlorobenzaldehyde (1.9 g), 3-aminopyrazole (1.0 g) and l-cyanopentan-2-one (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (1.3 g) as colorless crystals. MP:248°C.
Anal. Calcd. for :Cι6H15ClN4:C, 64.32 ;H, 5.06;N, 18.75.
Found:C,64.49;H,5.18;N,18.81.
MS(EI) :298(M+) . XH-NMR (400MHz,DMSO-d5)δ(ppm) : 0.95(3H,t,J=7.3Hz) , 1.64- 1.70(2H,m), 2.38-2.42(2H,m), 5.36(1H,S), 7.23-7.26(3H,m) , 7.32(lH,dd,J=7.3Hz and 7.4Hz), 7.42( lH,d, J=7.3Hz) , 9.83(lH,br.s), 12.15(lH,br.s) . Example 95
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- ( 4-methoxyphenyl) -2H- pyrazolo[3, 4-b]pyridine
To a solution of acetonitrile (76 g) in DMSO (100 mL) was added methyl p-anisate (100 g) and the mixture was stirred with heating at 60°C for one hour. The reaction mixture was allowed to cool, and cold water (500 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the ,_, precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give benzoylacetonitrile (60 g) as colorless crystals. A solution of 2- chlorobenzaldehyde (1.7 g), 3-aminopyrazole (1.0 g) and benzoylacetonitrile (1.8 g) in acetonitrile (20 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.63 g) as colorless crystals. MP:124°C. Anal. Calcd. for:C20Hι5ClN4O 8/5 H20:C,61.34;H,4.68;N, 14.31. Found:C,61.32;H,4.88;N,14.31. MS (El) :362(M+) .
^-NMR (400MHz,DMSO-de)δ(ppm) : 3.81(3H,s), 5.48(lH,s), 7.04(2H,d,J=7.3Hz), 7.26( lH,dd,J=7.3Hz and 7.4Hz), 7.32(lH,s), 7.35-7.39(4H,m), 7.45( lH,d,J=7.3Hz) , 9.99 ( lH,br.s) , 12.22(lH,br.s) . Example 96 4-( 2-Chlorophenyl) -2, 4, 7 , 8-tetrahydrofurano[3,4- b]pyrazolo[ 4, 3-e]pyridin-5-one
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 4- chloroacetoacetate in the same manner as in Example 1. MP:>270°C.
Anal. Calcd. for:C14Hι0ClN3O2 2/5 H20:C,57.02;H,3.69;N, 14.25.
Found:C,57.13;H,3.39;N,14.38.
MS (FAB) :288(M++1) .
1H- M ( 400MHz, DMSO-ds)δ (ppm ) : 4.91(2H,dd, J=5.6Hz and 26.6Hz), 5.34(1H,S), 7.15-7.24(3H,m), 7.34(lH,s), 7.41( lH,d, J=6.8Hz) ,
10.31(lH,br.s), 12.20( lH,br .s) .
IR(KBr) :v=3167,2966, 1722, 1637, 1608, 1510, 1026cm"1.
Example 97
5 ' -Ethoxycarbonyl-4 ' ,7 '-dihydro-6 ' -propyl- spiro[benzo[b]thiophene-3(2H) , 4 ' -2 'H-pyrazolo[3, 4-b]pyridine] -
5-oxide
A solution of 2-methylthiobenzaldehyde (62 g), Meldrum's acid (58.7 g), ethyl 3-ketohexanoate (64.4 g) and ammonium acetate (40 g) in acetic acid (400 mL) was heated under reflux overnight. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure to give colorless crystals (40.2 g) . To a solution of dimethylformamide (26.3 g) in chloroform (100 mL) were added, under ice-cooling, phosphorus oxychloride (33.6 mL) and a solution of the obtained colorless crystals (30 g) in chloroform (200 mL), and the mixture was stirred overnight.
Under ice-cooling, an aqueous sodium acetate (370 g) solution was added and the mixture was stirred for one hour. The reaction mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals. To a solution of the obtained crystals in acetone (500 mL) was added diammonium cerium nitrate (42 g) and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The solvent was evaporated under reduced pressure to give colorless crystals. To a solution of the obtained colorless crystals in tetrahydrofuran (500 mL) was added metachloroperbenzoic acid (12 g) at -78°C and the mixture was stirred for 30 minutes. TAn aqueous sodium thiosulfate solution was added, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give colorless crystals. By recrystallization from ethyl acetate, colorless crystals (15 g) were obtained. To a solution of the obtained colorless crystals in tetrahydrofuran (100 mL) was added lithium diisopropylamide (2.5 eq.) at -78°C. Immediately thereafter, methanol and an aqueous ammonium chloride solution were added. The mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. To a solution of the obtained oil in pyridine (50 mL) was added hydrazine (4.2 g) and the mixture was stirred with heating for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give title compound (0.8 g) as colorless crystals. MP:246°C.
Anal. Calcd. for:C19H2ιN3O3S:C,61.44;H,5.70;N, 11.31.
Found:C, 61.58;;H,5.81;N, 11.16.
MS(EI) :371(M+) .
^-NMR (400MHz,DMSO-d5)δ(ppm) : 0.70(3H,t,J=7.3Hz) , 0.96(3H,t,J=7.3Hz), 1.63-1.68 (2H,m) , 2.67-2.76(2H,m) ,
3.07(lH,d,J=14.9Hz), 3.64(2H,q,J=7.3Hz) , 4.00( lH,d,J=14.9Hz) , 7.05-7.09(2H,m), 7.40( lH,dd,J=7 ,3Hz and 7.4Hz), 7.50(lH,dd,J=7.3Hz and 7.4Hz), 7.81( lH,d,J=7.3Hz) , 9.83(lH,br.s), 12.11( lH,br.s) . Example 98
Ethyl 4, 7-dihydro-4-(2-hydroxyphenyl) -6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate A solution of 2-methoxybenzaldehyde (15 g), Meldrum's acid (16 g), ethyl 3-ketohexanoate (17.4 g) and ammonium acetate (9.4 g) in acetic acid (110 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give colorless crystals (8.0 g). To a solution of the obtained colorless crystals (5.2 g) in dichloromethane (150 mL) were added ethanedithiol (20 mL) and aluminum chloride (32 g), and the mixture was stirred for 2 hours. After neutralization with IN aqueous sodium hydroxide solution, the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give colorless crystals (2.0 g) . To a solution of dimethylformamide (1.9 g) in chloroform (10 mL) were added phosphorus oxychloride (2.5 mL) and a solution of the obtained crystals in chloroform (20 mL) under ice- cooling, and the mixture was stirred overnight. Under ice- cooling, an aqueous sodium acetate (27 g) solution was added and the mixture was stirred for one hour. The mixture was extracted with chloroform and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give a colorless oil (1.4 g). To a solution of the obtained oil in pyridine (10 mL) was added hydrazine (0.7 g), and the mixture was stirred with heating for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give the title compound (0.2 g) as colorless crystals. MP:177°C
Anal. Calcd. for:Cι8H2ιN303:C, 66.04;H,6.47;N,12.84. Found:C,65.96;H,6.21;N,12.66. MS(EI) :327(M+) .
1H-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 0.80(3H,t,J=7.3Hz) ,
0.96(3H,t,J=7.3Hz) , 1.56-1.59(2H,m) , 2.70-2.80(2H,m) ,
3.76(2H,q,J=7.3Hz) , 5.50(lH,s), 7.28-7.33 (3H,m) , 7.63(lH,dd,J=7.3Hz and 7.4Hz), 7 -76( lH,d, J=7.3Hz) ,
9.64(lH,br.s), 9.68( lH,br.s) , 10.12(lH,br .s) .
Example 99
Ethyl 4-( 2-aminophenyl) - , 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate To a solution of ethyl 4,7-dihydro-4-(2-nitrophenyl)-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.68 g) in methanol (30 mL) was added 5% palladium-carbon (500 mg), and the mixture was stirred under 10 atm for 3 hours. After removing palladium-carbon by Celite filtration, the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography
(eluent: hexane-ethyl acetate (1:1)) to give the title compound (120 mg) as colorless crystals.
MP:179°C. Anal. Calcd. for :Cι8H22N402:C,66.24;H,6.79;N, 17.17.
Found:C,65.96;H,6.62;N,17.16.
MS (El) :326(M+) .
XH-NMR ( 400MHz, DMS0-d6 ) δ(ppm) : 0.82(3H,t, J=7.3Hz) ,
0.98(3H,t,J=7.3Hz), 1.58-1.64(2H,m) , 2.72-2.78(2H,m) , 3.78(2H,q,J=7.3Hz) , 5.52(lH,s), 6.35-6.38 (2H,br .s) , 7.28-
7.36(3H,m), 7.58(lH,dd,J=7.3Hz and 7.4Hz), 7.78 ( lH,d, J=7.3Hz) ,
9.58(lH,br.s), 11.48( lH,br.s) .
Example 100 Ethyl 4-( 2-ethylphenyl) -4 , 7-dihydro-6-propyl-lH-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2-ethylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:186°C.
Anal. Calcd. for:C20H25N3O2 1/5 H2O:C,70.03;H,7.46;N, 12.25. Found:C,69.91;H,7.53;N,11.98. MS (El) :339(M+) . ^- R ( 400MHz, DMSO-d6)δ(ppm): 0.86(3H, t, J=7.3Hz) ,
0.94(3H,t,J=7.3Hz), 1.24( 3H,t, J=7.3Hz) , 1.64(2H,q,J=7.3Hz) ,
2.64-2.68(lH,m), 2.77-2.86(3H,m) , 3.78 (2H,q,J=7.3Hz) ,
5.34(lH,s), 6.98-7.01(3H,m), 7.07-7.10(2H,m) , 9.34(lH,s),
11.89(lH,s) . Example 101
Ethyl 4, 7-dihydro-6-propyl-4-( 2-propylphenyl) -IH-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2- propylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:197°C.
Anal. Calcd. for:C21H27N302:C,71.36;H,7.70;N, 11.89.
Found:C,71.07;H,7.73;N,11.84.
MS(EI) :353(M+) . XH-NMR (400MHz,DMSO-d5)δ(ppm) : 0.87 (3H,t, J=7.3Hz) , 0.94-
1.00(6H,m), 1.64(2H,q,J=7.3Hz), 2.68-2.80(4H,m) ,
3.79(2H,q,J=7.3Hz) , 5.33(lH,s), 6.98-7.06(5H,m) , 9.34(lH,s),
11.88(1H,S) .
Example 102 Ethyl 4-(2-butylphenyl) -4, 7-dihydro-6-propyl-lH-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from 2-butylbenzaldehyde,
3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:175°C.
Anal. Calcd. for:C22H29N3O2:C,71.90;H,7.95;N,11.43. Found:C,71.50;H,7.94;N,11.36. MS(EI) :367(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.87 (3H,t,J=7.3Hz) , 0.92-
0.97(6H,m), 1.40(2H,q,J=7.3Hz), 1.60-1.66 (4H,m) , 2.70-
2.82(4H,m), 3.80(2H,q,J=7.3Hz), 5.33(lH,s), 6.97-7.06 (5H,m) ,
9.34(1H,S), 11.88(1H,S). Example 103
Ethyl 4, 7-dihydro-4-(indan-4-yl) -6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was prepared from indan-4-aldehyde,
3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.
MP:181-183°C.
Anal. Calcd. for:C2ιH25N302:C, 71.77;H,7.17;N, 11.96.
Found:C,71.66;H,7.14;N,11.88.
MS(EI) :351(M+) . XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0.90 ( 3H,t, J=7.3Hz) ,
0.90(3H,t,J=7.3Hz), 1.62(2H,m), 1.80-2.10(2H,m) , 2.52-
3.10(6H,m), 3.77(2H,q,J=7.3Hz), 5.17(lH,s),
6.81(lH,d,J=6.8Hz),6.91-6.96(2H,m), 7.14(lH,s), 9.33( lH,br .s) ,
11.87(lH,br.s) . Example 104
Ethyl 4, 7-dihydro-6-propyl-4-(1,2,3, 4-tetrahydronaphthalen-5- yl)-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate
Example 105
Ethyl 4-(benzo[b]furan-7-yl) -4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
Example 106
Ethyl 4-(benzo[b]thiophen-7-y1) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b] yridine-5-carboxylate The title compound was prepared from benzo[b]thiophene-
7-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:166°C. 5 Anal. Calcd. for:C20H2ιN3O2S 2H20:C,59.53;H,6.25;N, 10.41.
Found:C,59.77;H,6.46;N,9.95.
MS(El) :367(M+) .
XH-NMR ( 400MHz, DMSO-dg ) δ(ppm ) : 0.74(3,t, J=7.3Hz) ,
0.97(3H,t,J=7.3Hz), 1.65-1.69(2H,m) , 2.70-2.80(2H,m) , O 3.71(2H,q,J=7.3Hz), 5.48( lH,s) , 7.11-7.13(2H,m) ,
7.26(lH,dd,J=7.4Hz and 7.5Hz), 7.39( lH,d, J=5.4Hz) ,
7.63(lH,d,J=7.3Hz) , 7.68( lH,d, J=5.4Hz) , 9.57(lH,s),
11.91(1H,S) .
Example 107 5 5 '-Ethoxycarbonyl-4 ' , 7 '-dihydro-6 '-propyl- spiro[benzo[b]thiophene-3(2H) , 4 '-2 'H-pyrazolo[ 3, 4-b]pyridine] To a solution of 5 ' -ethoxycarbonyl-4 ' , 7 '-dihydro-6 '- propyl-spiro[benzo[b]thiophene-3 (2H) , 4 '-2 'H-pyrazolo[3, 4- b]pyridine]-l-oxide (100 mg) in carbon tetrachloride (20 mL) 0 was added trimethylsilane iodide (0.1 g), and the mixture was stirred with heating for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, and the mixture was extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified 5 by silica gel column chromatography (eluent: hexane-ethyl acetate (8:2)) to give the title compound (20 mg) as colorless crystals.
MP:147°C.
Anal. Calcd. for :C19H21N302S :C,64.20;H,5.95;N, 11.82. 0 Found:C,64.18;H,6.14;N, 11.56.
MS (El) :355(M+) .
^- R (400MHz, DMSO-d6)δ(ppm) : 0.73(3H,t, J=7.3Hz) ,
0.95(3H,t,J=7.3Hz), 1.64-1 -67(2H,m) , 2.56-2.64(2H,m) , 3.03(lH,d,J=10.2Hz), 3.72(2H,q, J=7.3Hz) ,4.03( lH,d,J=10.2Hz^ 6.69(lH,d,J=7.3Hz), 6.91( lH,dd,J=7.3Hz and 7.4Hz), 7.03(lH,dd,J=7.3Hz and 7.4Hz), 7.08(lH,s), 7.15 ( lH,d, J=7.3Hz) , 9.65(lH,br.s), 11.96( lH,br .s) . Example 108
Ethyl 4, 7-dihydro-4-methyl-4-phenyl-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
To a solution of 5 ' -ethoxycarbonyl-4 ' , 7 ' -dihydro-6 ' - propyl-spiro[benzo[b]thiophene-3 ( 2H) , 4 ' -2 'H-pyrazolo[3,4- b]pyridin]-l-oxide (100 mg) in tetrahydrofuran (10 mL) were added disodium hydrogenphosphate (1.2 g) and methanol (5 mL) under ice-cooling, and 10% sodium amalgam (3.0 g) was added. The mixture was stirred for 5 hours, filtered through Celite and extracted with chloroform. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent: hexane- ethyl acetate (8:2)) to give the title compound (80 mg) as colorless crystals. MP:207°C. Anal. Calcd. for:C19H23N3O2:C,70.13;H,7.12;N,12.91. Found:C,69.89;H,7.18;N,12.99. MS(EI) :325(M+) .
^- MR (400MHz,DMSO-d6)δ(ppm) : 0.71(3H,t,J=7.3Hz) ,
0.96(3H,t,J=7.3Hz), 1.64-1.68(2H,m) , 2.28(3H,s), 2.48- 2.56(2H,m), 3.71(2H,q,J=7.3Hz), 6.73-7.01 (5H,m) , 7.10(lH,s),
9.71(lH,br.s), 11.87( lH,br.s) .
Example 109
Ethyl 4, 7-dihydro-6-propyl-4-(2,3, 5-trichlorophenyl) -pyrazolo
[ 3 , 4-b]pyridine-5-carboxylate The title compound was prepared from 2,3,5- trichlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:218-220°C (decomposition). Anal. Calcd. for:CιsH18Cl3N302:C,52.13;H, 4.37;N, 10.13.
Found:C,51.76;H,4.37;N,10.07.
MS (El) :414(M+) .
XH-NMR ( 400MHz, DMSO-d6)δ(ppm) : 0.89(3H,t, J=6.9Hz) , 0.97(3H,t,J=7.3Hz), 1.62-1.67(2H,m) , 2.65-2.71( lH,m) , 2.85-
2.92(lH,m), 3.76-3.88(2H,m), 5.62(lH,s), 7.03( lH,d, J=1.6Hz) ,
7.33(lH,s), 7.59(lH,d,J=2.4Hz) , 9.69(lH,s), 12.12(lH,s).
Example 110
Ethyl 4, 7-dihydro-6-propyl-4-(2,3,4,5- tetrahydrobenzo[b] oxepin-9-yl) -2H-pyrazolo[ 3 , 4-b]pyridine-5- carboxylate
Example 111
Ethyl 4-( 3-chloro-2-methylphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 3-chloro-2- methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 1.
MP:185°C.
Anal. Calcd. for :C19H22C1N302:C,63.42;H,6.16;N, 11.68. Found:C,63.37;H,6.12;N,11.65.
MS(EI) :359(M+) .
^Η- R (400MHz,DMSO-d6)δ(ppm): 0.87(3H,t,J=7.3Hz) ,
0.95(3H,t,J=7.3Hz) , 1.60-1.66(2H,m) , 2.67-2.69 ( lH,m) , 2.74-
2.78(lH,m), 3.78(2H,q,J=7.3Hz), 5.39(lH,s), 6.95( lH,d, J=7.3Hz) , 7.04(lH,dd,J=7.3Hz and 7.4Hz), 7.12( lH,d, J=7.3Hz) , 7.24(lH,s),
9.44(lH,br.s), 11.94( lH,br.s) .
Example 112
Ethyl 4-( 2 , 1, 3-benzothiadiazol-4-yl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate The title compound was prepared from 2,1,3- benzothiadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:180°C. Anal. Calcd. for :Cι8Hι9N502S:C,58.52;H,5.18;N, 18.96.
Found:C,58.51;H,5.19;N,18.81.
MS(EI) :369(M+).
1H-N R (400MHz,DMSO-d6)δ(ppm) : 0.62(3H,t, J=7.3Hz) , 1.00(3H,t,J=7.3Hz) , 1.68-1.72(2H,m) , 2.76-2.89 (2H,m) ,
3.72(2H,q,J=7.3z), 6.02(lH,s), 7.16(lH,S), 7.20( lH,d, J=7.3Hz) ,
7.60(lH,dd,J=7.3Hz and 7.4Hz), 7.83(lH,d, J=7.3Hz) , 9.55(lH,s),
11.89(lH,s) .
Example 113 Ethyl 4-( 2 , 1 , 3-benzoxadiazol-4-yl) -4, 7-dihydro-6-methyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 25. MP:228°C.
Anal. Calcd. for:Ci6Hi5N5O3:C,59.07;H,4.65;N,21.53.
Found:C,58.85;H,4.75;N,21.17.
MS (El) :325(M+) .
^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 0.75(3H,t,J=7.3Hz) , 2.42(3H,s), 3.79(2H,q,J=7.3Hz) , 5.67(lH,s), 7.14( lH,d,J=6.6Hz) ,
7.23(lH,s),7.49(lH,dd,J=9.0Hz and 6.6Hz), 7.78( lH,d,J=9.0Hz) ,
9.69(lH,s), 12.02(lH,s).
Example 114
Ethyl 4- ( 2 , 1 , 3-benzoxadiazol-4-yl) -4, 7-dihydro-6-phenyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.
MP:190°C. Anal. Calcd. for:C21Hι7N503:C,65.11;H,4.42;N,18.08.
Found:C,64.99;H,4.59;N,18.06.
MS (El) :387(M+) .
^-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.54 (3H,t,J=7.3Hz) , 3.56(2H,q,J=7.3Hz), 5.68(lH,s), 7.24(lH,s), 7.26-7.42 ( 6H,m) , 7.72(lH,dd,J=7.3Hz and 7.2Hz), 7.94( lH,d,J=7 ,3Hz) , 9.71(lH,s),12.08(lH,s). Example 115 Ethyl 4-(2, 3-dichlorophenyl)-4, 7-dihydro-6-phenyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2,3- dichlorobenzaldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1. MP:214°C.
Anal. Calcd. for:C21Hι7N5O3:C,65.11;H,4.42;N,18.08.
Found:C,64.85;H,4.48;N,17.92.
MS(EI) :387(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.57(3H,t, J=7.3Hz) , 3.52(2H,q,J=7.3Hz), 5.70(lH,s), 7.30-7.40(9H,m) , 9.61(lH,s),
12.12(1H,S) .
Example 116
(+)Ethyl 4-( 2 , 1, 3-benzoxadiazol-4-yl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The compound described in Example 76 was separated using a semi-preparative column for optical resolution (CHIRALPAK AS,
1.0 cmχ25 cm, eluent n-hexane/2- propanol/diethylamine=90/10/0.1, flow rate 2.0 mL/min, UV 254 nm, retention time 40 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.) to give the title compound as colorless crystals.
MP: 159°C.
MS(El) : 353 (M+) .
Specific rotation: [ ]D=+260°(EtOH,c=0.5) .
Example 117 (-)Ethyl 4-(2, l,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The compound described in Example 76 was separated using a semi-preparative column for optical resolution (CHIRALPAK AS, 1.0 cmχ25 cm, eluent n-hexane/2- propanol/diethylamine=90/10/0.1, flow rate 2.0 mL/min, UV 254 nm, retention time 55 minutes, DAICEL CHEMICAL INDUSTRIES, LTD.) to give the title compound as colorless crystals. MP: 160°C.
MS(El): 353(M+).
Specific rotation: [α]D=-277°(EtOH,c=0.5) .
Example 118
4-(2-Bromophenyl)-4, 7-dihydro-5-nitro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from n-butylaldehyde, 2- bromobenzaldehyde and 3-aminopyrazole in the same manner as in
Example 93.
MP:226°C. Anal. Calcd. for:C15Hι5BrN402:C,49.60;H,4.16;N, 15.43.
Found:C,49.57;H,4.28;N,14.96.
MS (El) :363(M+) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 1.02(3H,t,J=7.3Hz) , 1.72-
1.76(2H,m), 2.85-3.05(2H,m), 5.89(lH,s), 7.07-7. l(2H,m) , 7.25(lH,dd,J=7.5Hz and 7.4Hz), 7.47(lH,s), 7.56( lH,d,J=7.3Hz) ,
10.84(lH,s), 12.43(1H,S).
Example 119
4, 7-Dihydro-4-(2-methoxyphenyl)-5-nitro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from n-butylaldehyde, 2- methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.
MP:223°C.
Anal. Calcd. for:C16Hι8N03:C,61.13;H,5.77;N,17.82. Found:C,61.01;H,5.87;N,17.92.
MS(EI) :314(M+).
^- R (400MHz,DMSO-d6)δ(ppm) : 1.03(3H,t,J=7.3Hz) , 1.72-
1.78(2H,m), 2.82-3.04(2H,m), 3.86(3H,s), 5.76(lH,s), 6.78(lH,dd,J=7.5Hz and 7.4Hz), 6.90( lH,d, J=7.3Hz) , 6.95(lH,d,J=7.3Hz), 7.10( lH,dd,J=7.5Hz and 7.4Hz) , 7.33(lH,s), 10.68(1H,S), 12.29(1H,S). Example 120 4, 7-Dihydro-4- ( 2-methylthiophenyl) -5-nitro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from n-butylaldehyde, 2- methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93. MP:211°C.
Anal. Calcd. for:Cι6Hι8N402S:C,58.16;H,5.49;N, 16.96.
Found:C,57.94;H,5.47;N,16.53.
MS(EI) :330(M+) .
1H-NM ( 400MHz,DMSO-de)δ(pp ) : 1.02 ( 3H,t,J=7.3z) , 1.71- 1.76(2H,m), 2.8-3.00(2H,m), 5.89(lH,s), 6.98( lH,d, J=7.3Hz) ,
7.03(lH,dd,J=7.5Hz and 7.4Hz), 7.13 ( lH,dd, J=7.5Hz and 7.4Hz),
7.28(lH,d,J=7.3Hz), 7.41(lH,s), 10.74(lH,s), 12.34(lH,s).
Example 121
4, 7-Dihydro-5-nitro-4-( 2-nitrophenyl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from n-butylaldehyde, 2- nitrobenzaldehyde and 3-aminopyrazole in the same manner as in
Example 93.
MP:204°C. Anal. Calcd. for:C15H15N504:C,54.71;H,4.59;N,21.27.
Found:C,54.50;H,4.77;N,21.32.
MS(EI) :329(M+) .
1H-NM (400MHz,DMSO-d6)δ(ppm) : 1.01(3H,t,J=7.3Hz) , 1.69- 1.74(2H,m), 2.85-2.99(2H,m), 5.67(lH,s), 6.94( lH,d,J=7.3Hz) , 6.98-7.03(2H,m), 7.09(lH,d, J=7.3Hz) , 7.38(lH,s), 10.69(lH,s), 12.34(lH,s) . Example 122
4-( 2 , 3-Dichlorophenyl) -4 , 7-dihydro-5-nitro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from n-butylaldehyde,
2 , 3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93. MP:239°C.
Anal. Calcd. for:C15Hι4Cl2N4O2:C,51.01;H,4.00;N,15.86.
Found:C,50.70;H,4.06;N,15.60.
MS(EI) :353(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 1.02(3H,t, J=7.3Hz) , 1.70- 1.74(2H,m), 2.89-2.92(lH,m), 2.96-3.02( lH,m) , 5.96(lH,s),
7.09(lH,d,J=7.3Hz) , 7.24( lH,dd, =7.5Hz and 7.4Hz),
7.43(lH,d,J=7.3Hz), 7.49(lH,s), 10.98(lH,s), 12.49(lH,s).
Example 123
4, 7-Dihydro-4-(naphthalen-1-yl) -5-nitro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from n-butylaldehyde, naphthalen-1-aldehyde and 3-aminopyrazole in the same manner as in Example 93.
MP:226°C. Anal. Calcd. for:C19H18N402:C,68.25;H,5.43;N,16.76. Found:C,68.29;H,5.20;N,16.67. MS(EI) :334(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.06(3H,t,J=7.3Hz) , 1.76-
1.82(2H,m), 2.95-3.06(2H,m) , 6.33(lH,s), 7.18-7.22(2H,m) , 7.36(lH,dd,J=7.5Hz and 7.4Hz), 7.54(lH,dd,J=7.5Hz and 7.4Hz),
7.60(lH,dd,J=7.5Hz and 7.4Hz), 7.71( lH,d,J=7.3Hz) ,
7.92(lH,d,J=7.3Hz) , 8.46( lH,d, J=7.3Hz) , 10.80(1H,S),
12.29(1H,S).
Example 124 4, 7-Dihydro-4-( 3 , 4-dihydro-2H-benzopyran-8-yl) -5-nitro-6- propyl-2H-pyrazolo [3, 4-b]pyridine
The title compound was prepared from n-butylaldehyde,
3,4-dihydro-2H-benzopyran-8-aldehyde and 3-aminopyrazole in the same manner as in Example 93. MP:234°C.
Anal. Calcd. for:C18H20N4O3:C,63.52;H,5.92;N,16.46. Found:C,63.22;H,5.94;N,16.44. MS(EI) :340(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 1.02(3H,t, J=7.3Hz) , 1.71- 1.77(2H,m), 1.92-1.95(2H,m), 2.69-2 ,73(2H,m) , 2.85-3.02(2H,m) , 4.23-4.28(2, m), 5.71(lH,s), 6.61-6.67 (2H,m) , 6.80(lH,d,J=7.3Hz), 7.37(lH,s), 10.64(lH,s), 12.28(lH,s). Example 125
4- ( 2 , 3-Dichlorophenyl) -4 , 7-dihydro-6-methyl-5-nitro-2H- pyrazolo [ 3 , 4-b ] pyridine
The title compound was prepared from acetaldehyde, 2,3- dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.
MP:>270°C.
Anal. Calcd. for :C13Hι0Cl2N4O2:C,48.02;H,3.10;N,17.23.
Found:C,48.05;H,3.12;N,17.24.
MS(EI) :325(M+) . XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 2.66(3H,s), 5.94(lH,s),
7.13(lH,d,J=7.2Hz), 7.22 ( lH,dd, J=7.3Hz and 7.2Hz),
7.42(lH,d,J=7.3Hz), 7.50(lH,s), 10.94(lH,s), 12.49(lH,s).
Example 126
4-( 2 , 3-Dichlorophenyl) -6-ethyl-4 , 7-dihydro-5-nitro-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from propionaldehyde,
2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.
MP:250°C. Anal. Calcd. for:Cι4H12Cl2N402:C,49.58;H,3.57;N,16.52.
Found:C,49.54;H,3.62;N,16.73.
MS(EI) :339(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.29(3H,t,J=7.3Hz) , 2.98- 3.01(2H,m), 5.94(1H,S), 7.10 ( lH,d,J=7.3Hz) , 7.24( lH,dd,J=7.3Hz and 7.2Hz), 7.42( lH,d, J=7.2Hz) , 7.49(lH,s), 10.93(lH,s), 12.49(lH,s). Example 127 6-Butyl-4-( 2 , 3-dichlorophenyl) -4 , 7-dihydro-5-nitro-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from pentylaldehyde, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93 . MP:220°C.
Anal. Calcd. for:C16H16Cl2N402:C,52.33;H,4.39;N,15.26.
Found:C,52.64;H,4.61;N,14.51.
MS (El) :367(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.94 ( 3H,t,J=7.3Hz) , 1.41- 1.46(2H,m), 1.63-1.68(2H,m), 2.94-3.04(2H,m) , 5.95(lH,s),
7.08(lH,d,J=7.2Hz) , 7.23( lH,dd, J=7.3Hz and 7.2Hz),
7.42(lH,d,J=7.2Hz) , 7.48(lH,s), 10.97(lH,s), 12.28(lH,s).
Example 128
4-( 2-Bromophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butanoate,
2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:237°C. Anal. Calcd. for:Cι6H15BrN4:C,55.99;H,4.41;N,16.32.
Found:C,55.97;H,4.45;N, 16.40.
MS(EI) :343(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.95( 3H,t,J=7 ,3Hz) , 1.64-
1.70(2,m), 2.40-2.44(2H,m), 5.35(lH,s), 7.15( lH,dd,J=7.5Hz and 1 .4Hz ) , 7.22(lH,d,J=7.3Hz), 7.27(lH,s), 7.36( lH,dd,J=7 ,5Hz and
7.4Hz), 7.59(lH,d,J=7.3Hz), 9.84(lH,s), 12.16(lH,s).
Example 129
5-Cyano-4, 7-dihydro-4-( 2-methoxyphenyl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butanoate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:203°C.
Anal. Calcd. for:Cι7Hι8N4O:C,69.37;H,6.16;N,19.03.
Found:C,69.34;H,6.25;N,19.01.
MS(EI) :294(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.96 (3H,t,J=7.3Hz) , 1.65- 1.70(2H,m), 2.38-2.43(2H,m), 3.83(3H,s), 5.22(lH,s),
6.89(lH,dd,J=7.5Hz and 7.4Hz), 6.99 ( lH,d, J=7.3Hz) ,
7.05(lH,d,J=7.3Hz) , 7.15-7.18(2H,m) , 9.65(lH,s), 12.02(lH,s).
Example 130
5-Cyano-4, 7-dihydro-4- (2-methylthiophenyl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butanoate,
2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:216°C. Anal. Calcd. for:Cι7H18N4S:C,65.78;H,5.84;N,18.05.
Found:C,65.68;H,5.81;N,17.83.
MS(EI) :310(M+) . H-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.96(3H,t,J=7.3Hz) , 1.65-
1.70(2H,m), 2.40-2.46(2H,m), 2.48(3H,s), 5.34(lH,s), 7.13- 7.21(4H,m), 7.30(lH,d,J=7.3Hz), 9.75(lH,s), 12.07(lH,s).
Example 131
5-Cyano-4, 7-dihydro-4-( 2-methylphenyl) -6-propyl-2H-pyrazolo
[ 3, 4-b] yridine
The title compound was prepared from methyl butanoate, 2-methylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:230°C.
Anal . Calcd . for :C17Hι8N4 :C, 73 .35 ;H, 6.52 ;N, 20.13. 12.22(1H,S). Example 134
5-Cyano-4-(2, 3-dichlorophenyl) -4, 7-dihydro-6-propy1-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl butanoate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:242°C.
Anal. Calcd. for:C16H14Cl2N4 1/5 H20:C,57.05;H, 4.31;N, 16.63. Found:C,57.23;H,4.49;N,16.25.
MS (El) :333(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.94(3H,t,J=7 -3Hz) , 1.62-
1.68(2H,m), 2.40-2.46(2H,m) , 5.44(lH,s), 7.22( lH,d,J=7 -3Hz) ,
7.30(1H,S), 7.35(lH,dd,J=7.5Hz and 7.4Hz), 7.51( lH,d, J=7.3Hz) , 9.89(lH,s), 12.19(lH,s).
Example 135
5-Cyano-4, 7-dihydro-4-(naphthalen-1-y1) -6-propyl-2H- pyrazolo[ 3,4-b]pyridine
The title compound was prepared from methyl butanoate, naphthalene-1-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:263°C.
Anal. Calcd. for:C20Hι8N4:C,76.41;H,5.77;N, 17.82.
Found : C , 76.05 ; H, 5.85 ;N, 17.73. MS(EI) :314(M+) .
XH-NMR ( 400MHz, DMSO-de )δ (ppm) : 0.97(3H,t, J=7.3Hz) , 1.68-
1.73(2H,m), 2.44-2.48(2H,m), 5.71( lH,s) ,7.04( lH,s) , 7.39-
7.46(4H,m), 7.81(lH,d,J=7.3Hz), 7.94(lH,d, J=7.3Hz) , 9.83(lH,s),
12.02(lH,s) . Example 136
5-Cyano-4-( 3, 4-dihydro-2H-benzopyran-8-yl)-4, 7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl butanoate, 3, 4-dihydro-2H-benzopyran-8-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:230°C.
Anal. Calcd. for:C19H20N4O:C,71.23;H,6.29;N,17.49. Found:C,71.20;H,6.48;N,17.55. MS(EI) :320(M+).
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.95(3H,t,J=7.3Hz) , 1.64-
1.70(2H,m), 1.92-1.95(2H,m), 2.38-2.43(2H,m) , 2.72-2.76(2H,m) ,
4.16-4.27(2H,m), 5.16(lH,s), 6.74( lH,dd, J=7.5Hz and 7.4Hz), 6.83-6.88(2H,m), 7.20(1H,S), 9.62(lH,s), 12.01(lH,s).
Example 137
4-(2, 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6-propyl-2H- pyrazolof 3, 4-b]pyridine
The title compound was prepared from methyl butanoate, 2,l,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:194°C.
Anal. Calcd. for:Cι6H14N60:C,62.73;H,4.61;N,27.44.
Found:C,62.52;H,4.78;N,27.19. MS(EI) :306(M+) .
^- MR (400MHz,DMSO-d6)δ(ppm) : 0.92 ( 3H,t,J=7.3Hz) , 1.63-
1.68(2H,m), 2.38-2.43(2H,m), 5.40(lH,s), 7.25(lH,s),
7.40(lH,d,J=7.3Hz), 7.58 ( lH,dd, J=7.5Hz and 7.4Hz),
7.92(lH,d,J=7.3z), 9.93(lH,s), 12.13(lH,s). Example 138
4-( 2 , 1 , 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6-propyl-
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butanoate,
2,l,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:195°C.
Anal. Calcd. for:C16H14N6S:C,59.61;H,4.38;N,26.07.
Found:C,59.33;H,4.48;N,25.76. MS (El ) : 322 ( M+ ) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.98(3H,t,J=7.3Hz) , 1.68- 1.74(2H,m), 2.45-2.50(2H,m), 5.72(lH,s), 7.19(lH,s), 7.43(lH,d,J=7.3Hz) , 7.72( lH,dd,J=7.5Hz and 7.4Hz), 7.97(lH,d,J=7.3Hz) , 9.87(lH,s), 12.06(lH,s). Example 139
5-Cyano-4, 7-dihydro-4-( 2-methylbenzoxazol-4-yl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butanoate, 2-methylbenzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:208°C.
Anal. Calcd. for :Cι8H17N50 1/5 H20:C,66.94;H,5.43;N,21.68. Found:C,66.85;H,5.52;N,22.09. MS(EI) :319(M+) .
1H-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.97 ( 3H,t,J=7.3Hz ) , 1.67- 1.72(2H,m), 2.40-2.45(2H,m) , 2.63(3H,s), 5.51(lH,s), 7.06(lH,d,J=7.3Hz), 7.16(lH,s), 7.29 ( lH,dd,J=7.3Hz and 7.2Hz) , 7.47(lH,d,J=7.3Hz) , 9.77(lH,s), 12.06(lH,s). Example 140
R(-) 4-(2, l,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6- propyl-2H-pyrazolo [ 3 , 4-b]pyridine
To a solution of the compound described in Example 137 (64.5 g) in THF (1000 mL) was added (-)camphorsulfonic acid (49 g) at room temperature and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure to give an oil. The obtained oil was recrystallized from acetonitrile twice to give colorless crystals (11 g). To a solution of the obtained colorless crystals in methanol (50 mL) was added water (50 mL) . The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The residual methanol solution was added dropwise to water (1000 mL) and the crystals were collected by filtration to give the title compound (11 g) as pale-yellow crystals.
(CHIRALPAK AS, 0.25 cmχ25 cm, eluent n-hexane/2- propanol/diethylamine =80/20/0.1, flow rate 1.5 mL/min, UV 254 nm, retention time 10 minutes, DAICEL CHEMICAL INDUSTRIES,
LTD.)
MP: 170°C.
MS(EI): 306(M+). Specific rotation: [α]D=-80°(EtOH,c=1.0) .
Example 141
S (+) 4-(2, 1, 3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine
To a solution of the compound (54 g), which was recovered from the mother liquor obtained in Example 140, in
THF (600 mL) was added (+)camphorsulfonic acid (41 g) at room temperature and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure to give an oil.
The obtained oil was recrystallized from acetonitrile twice to give colorless crystals (12 g) . To a solution of the obtained colorless crystals in methanol (50 mL) was added water (50 mL) .
The mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate.
The solvent was evaporated under reduced pressure and the residual methanol solution was added dropwise to water (1000 mL) . The crystals were collected by filtration to give the title compound (11 g) as pale-yellow crystals.
(CHIRALPAK AS, 0.25 cmχ25 cm, eluent n-hexane/2- propanol/diethylamine =80/20/0.1, flow rate 1.5 mL/min, UV 254 nm, retention time 13 minutes, DAICEL CHEMICAL INDUSTRIES,
LTD.)
MP: 170°C.
MS (El): 306 (M+). Specific rotation: [ ]D=+82°(EtOH,c=1.0) .
Example 142
4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-phenyl-2H- pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl benzoate, 2- chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:158°C.
Anal. Calcd. for:Cι9Hι3ClN4 H2O:C,65.05;H,4.31;N, 15.97. Found:C,65.35;H,4.19;N,16.21.
MS(EI) :332(M+).
XH-NMR ( 400MHz, DMSO-de ) δ(ppm ) : 5.51(lH,s), 7.25-7.51(8H,m) ,
7.59-7.61(2H,m), 10.07(lH,s), 12.24(lH,s).
Example 143 5-Cyano-4, 7-dihydro-4-(2-methylthiophenyl)-6-phenyl-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl benzoate, 2- methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:146°C.
Anal. Calcd. for:C20Hι6N4S 4/5 H20:C,66.94;H, 4.94;N, 15.61.
Found:C,66.85;H,4.81;N,15.65.
MS (El) :344(M+) .
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 2.48(3H,s), 5.48(1H,S), 7.19- 7.33(5H,m), 7.48-7.50(3H,m) , 7.59-7.61(2H,m) , 9.99(lH,s),
12.16(lH,s) .
Example 144
5-Cyano-4-( 2-cyanophenyl)-4, 7-dihydro-6-phenyl-2H- pyrazolo[3,4-b]pyridine The title compound was prepared from methyl benzoate, 2- cyanobenzaldehyde and 3-aminopyrazole in the same manner as in
Example 95.
MP:148°C. Anal. Calcd. for:C2oHι3N5 3/5 H20:C,71.89;H, 4.28;N,20.96. Found:C,71.89;H,4.33;N,20.91. MS(EI) :323(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 5.38(lH,s), 7.31(lH,s), 7.44- 7.59(7H,m), 7.70(lH,dd,J=7.3Hz and 7.2Hz) , 7.83( lH,d, J=7.3Hz) , 10.21(1H,S), 12.31(lH,s). Example 145
5-Cyano-4-(2 ,3-dichlorophenyl) -4, 7-dihydro-6-phenyl-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl benzoate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:162°C.
Anal. Calcd. for:C19Hι2Cl2N4:C,62.14;H,3.29;N, 15.26. Found:C,61.57;H,3.93;N,17.19. MS(EI) :367(M+).
XH-NMR ( 400MHz, DMSO-d6 )δ (ppm ) : 5.59(lH,s), 7.37-7.42(3H,m) ,
7.48-7.55(4H,m), 7.59-7.62(2H,m) , 10.14(lH,s), 12.28(lH,s).
Example 146 5-Cyano-4, 7-dihydro-4-(naphthalen-1-yl) -6-phenyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl benzoate, naphthalene-1-benzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:174°C.
Anal. Calcd. for:C23H16N4:C,79.29;H,4.63;N,16.08.
Found:C,79.50;H,4.85;N,16.58.
MS (El) :348(M+) .
XH-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 5.87( lH,s) ,7.12( lH,s) ,7.50- 7.63(9H,m), 7.82( lH,d, J=7.3Hz) ,7.96(lH,d, J=7.3Hz) ,
8.34(lH,d,J=7.3Hz), 10.09 ( lH,s) , 12.12 ( IH, s) .
Example 147
4- (2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6-phenyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl benzoate, 2- bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:>270°C.
Anal. Calcd. for:C20H12BrN5:C,59.72;H,3.01;N,17.41.
Found:C,59.53;H,3.17;N,17.30.
MS(EI) :402(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 5.63(lH,s), 7.39 (lH,s), 7.49- 7.51(3H,m), 7.60-7.63(3H,m),7.75(lH,d,J=7.3Hz),
7.85(lH,d,J=7.3Hz) , 10.21(lH,s), 12.33(lH,s).
Example 148
5-Cyano-4-( 3 , 4-dihydro-2H-benzopyran-8-yl) -4, 7-dihydro-6- phenyl-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl benzoate,
3,4-dihydro-2H-benzopyran-8-benzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:255°C.
Anal. Calcd. for:C22HιsN40:C,74.56;H,5.12;N, 15.81. Found:C,74.27;H,5.11;N,15.82.
MS (El) :354(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm): 1.94-1.97(2H,m) , 2.75-2.78(2H,m) ,
4.20-4.30(2H,m), 5.30(lH,s), 6.80( lH,dd,J=7.3Hz and 7.2Hz),
6.91(lH,d,J=7.3Hz), 7.02( lH,d, J=7 ,3Hz) , 7.28(lH,s), 7.49- 7.51(3H,m), 7.60-7.63(2H,m) , 9.88(lH,s), 12.11(lH,s).
Example 149
5-Cyano-4- ( 2 , 3-difluorophenyl) -4 , 7-dihydro-6-phenyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl benzoate, 2 , 3-difluorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:165°C.
Anal. Calcd. for:C19H12F2N4 3/5 H20:C,66.12;H,3.86;N, 16.23. Found:C,65.87;H,3.81;N,16.46. MS (El) :334(M+) .
XH-NMR ( 400MHz, DMSO-d5 )δ (ppm) : 5.40(lH,s), 7.16-7.38(4H,m) , 7.48-7.50(3H,m), 7.57-7.59(2H,m) , 10.11(lH,s), 12.30(lH,s). Example 150
5-Cyano-4, 7-dihydro-4-( 2-methoxyphenyl)-6-phenyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl benzoate, 2- methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:206°C.
Anal. Calcd. for:C20HιeN4O:C,73.15;H,4.91;N, 17.06.
Found:C,73.23;H,5.14;N,17.19.
MS(EI) :328(M+) . XH-NMR ( 400MHz, DMSO-dg ) δ(ppm ) : 3.86(3H,s), 5.36(lH,s),
6.94(lH,dd,J=7.3Hz and 7.2Hz), 7.02( lH,d, J=7.3Hz) , 7.19-
7.25(3H,m), 7.48-7.51(3H,m), 7.60-7.63(2H,m) , 9.91(lH,s),
12.12(lH,s).
Example 151 5-Cyano-4, 7-dihydro-4, 6-bis( 2-methoxyphenyl) -2H-pyrazolo[3,4- b]pyridine
The title compound was prepared from methyl o-anisate,
2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:220°C.
Anal. Calcd. for:C2ιHι8N402:C, 70.38;H,5.06;N, 15.63.
Found:C,69.97;H,5.13;N,16.15.
MS (El) :358(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 3.86(3H,s), 3.88(3H,s), 5.32(1H,S), 6.95-7.06(3H,m), 7.14-7 -25(3H,m) ,
7.37(lH,d,J=7.3Hz), 7.45( lH,dd, J=7.3Hz and 7.2Hz), 9.74(lH,s), 12.05(1H,S) . Example 152 5-Cyano-4, 7-dihydro-4-(2-methoxyphenyl)-6-( 3-methoxyphenyl) - 2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl m-anisate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:192°C.
Anal. Calcd. for:C2ιHι8N4O2:C,70.38;H,5.06;N,15.63. Found:C,69.97;H,5.09;N,15.54. MS (El) :358(M+) . XH-NMR ( 400MHz, DMSO-de )δ (ppm ) : 3.81(3H,s), 3.86(3H,s),
5.35(lH,s), 6.95(lH,dd,J=7.3Hz and 7.2Hz), 7.01( lH,d, J=7.3Hz) ,
7.07(lH,d,J=7.3Hz), 7.14 ( lH,s) ,7.18-7.23(5H,m) ,
7.41(lH,dd,J=7.3Hz and 7.2Hz), 9.88(lH,s), 12.12(lH,s).
Example 153 5-Cyano-4, 7-dihydro-4-(2-methoxyphenyl)-6-( 4-methoxyphenyl)-
2H-pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl p-anisate,
2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:149°C.
Anal. Calcd. for:C21Hι8N402 1/2 H20:C,68.65;H,5.21;N,15.25.
Found:C, 68.67;H, 4.99;N, 15.35.
MS(EI) :358(M+) .
XH-NMR ( 400MHz, DMSO-de )δ( ppm) : 3.81(3H,s), 3.86(3H,s), 5.33(lH,s), 6.94(lH,dd,J=7.3Hz and 7.2Hz), 7.01-7.05( 3H,m) ,
7.18-7.24(3H,m), 7.56 (2H,d, J=7.2Hz) , 9.82(lH,s), 12.10(lH,s).
Example 154
5-Cyano-4, 7-dihydro-4-(2-nitropheny1)-6-pheny1-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl benzoate, 2- nitrobenzaldehyde and 3-aminopyrazole in the same manner as in
Example 95.
MP:221°C. Anal. Calcd. for:Cι9Hι3N5O2:C,66.47;H,3.82;N,20.40.
Found:C,66.48;H,4.08;N,20.41.
MS(EI) :343(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 5.54(lH,s), 7.34(lH,s), 7.49- 7.52(4H,m), 7.59-7.64(3H,m), 7.74( lH,dd,J=7.3Hz and 7.2Hz) ,
7.91(lH,d,J=7.3Hz), 10.16(lH,s), 12.30(lH,s).
Example 155
5-Cyano-4, 7-dihydro-6- ( 2-methoxyphenyl) -4-( 2-nitrophenyl) -2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl o-anisate,
2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:207°C.
Anal. Calcd. for:C2oHι5N503:C,64.34;H,4.05;N,18.76. Found:C,64.03;H,4.21;N,18.68.
MS(EI) :373(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 3.85 ( 3H, s) , 5.50 ( IH, s) ,
7.03(lH,dd,J=7.3Hz and 7.2Hz), 7.14( lH,d, J=7.3Hz) , 7.33(lH,s),
7.37(lH,d,J=7.3Hz), 7.44-7 -52(2H,m) , 7.74-7.80(2H,m) , 7.92(lH,d,J=7.3Hz), 10.02(lH,s), 12.25(lH,s).
Example 156
5-Cyano-4, 7-dihydro-6-( 3-methoxyphenyl) -4-( 2-nitrophenyl) -2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl m-anisate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:220°C.
Anal. Calcd. for :C2oHι5N503:C,64.34;H,4.05;N, 18.76. Found:C,63.92;H,4.14;N,18.74. MS(EI) :373(M+) .
XH-NMR (400MHz, DMSO-d6)δ(ppm) : 381(3H,s), 5.53(lH,s), 7.07(lH,d,J=7.3Hz), 7.14-7.18(2H,m) , 7.33(lH,s), 7.40(lH,dd,J=7.3Hz and 7.2Hz), 7.50( lH,dd, J=7.3Hz and 7.2Hz), 7.63(lH,d,J=7.3Hz) , 7.74( lH,dd, J=7.3Hz 7.2Hz), 7.91(lH,d,J=7.3Hz), 10.13(lH,s), 12.30(lH,s). Example 157
5-Cyano-4, 7-dihydro-6-( 4-methoxyphenyl)-4-(2-nitrophenyl)-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl p-anisate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:215°C. Anal. Calcd. for:C20Hι5N5O3:C, 64.34;H,4.05;N,18.76. Found:C,64.13;H,4.12;N,18.69. MS (El) :373(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 3.81(3H,s), 5.51(1H,S),
7.03(2H,d,J=7.3Hz), 7.33(lH,s), 7.47-7.55 (3H,m) , 7.61(lH,d), 7.74(lH,dd,J=7.3Hz and 7.2Hz), 7.91( lH,d,J=7.3Hz) , 10.07(lH,s),
12.28(1H,S) .
Example 158
4-(2, 1,3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-phenyl-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl benzoate,
2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:231°C.
Anal. Calcd. for:Cι9Hι2N60:C,67 ,05;H,3.55;N,24.69. Found:C,66.76;H,3.90;N,24.71.
MS (El) :340(M+) .
XH-NMR ( 400MHz,DMSO-de)δ( pm) : 5.55(lH,s), 7.33(lH,s), 7.50- 7.64(7H,m), 7.95(lH,d,J=7.3Hz) , 10.20(lH,s), 12.23(lH,s). Example 159 4-(2 , 1,3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-(2- methoxyphenyl)-2H-pyrazolo[3,4-b]pyridine
The title compound was prepared from methyl o-anisate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:180°C.
Anal. Calcd. for:C20Hι4NeO2:C,64.86;H,3.81;N,22.69.
Found:C,64.11;H,3.98;N,22.34. MS(EI) :370(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 3.84(3H,s), 5.56(lH,s),
7.03(lH,dd,J=7.3Hz and 7.2Hz), 7.14(lH,d, J=6.8Hz) , 7.33-
7.35(2H,m), 7.45(lH,dd,J=7.3Hz and 7.2Hz), 7.54( lH,d, =7.3Hz) ,
7.65(lH,dd,J=8.8Hz and 6.8Hz),u 7.94( lH,d,J=8.8Hz) , 10.04(lH,s), 12.18(lH,s).
Example 160
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-( 3- methoxyphenyl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl m-anisate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:198°C.
Anal. Calcd. for:C20Hι4NeO2 4/5 H20:C,62.43;H,4.09;N,21.84.
Found:C,62.60;H,3.99;N,22.15. MS(EI) :370(M+) .
XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 3.80(3H,s), 5.55(lH,s), 7.06-
7.17(3H,m), 7.33(lH,s), 7.40( lH,dd, J=7.3Hz) ,
7.52(lH,d,J=6.6Hz) , 7.62( lH,dd, J=8.8Hz and 6.8Hz),
7.95(lH,d,J=6.8Hz) , 10.18(lH,s), 12.24(lH,s). Example 161
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6-( 4- methoxyphenyl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl p-anisate,
2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:244°C.
Anal. Calcd. for:C20Hι4N6O2:C,64.86;H,3.81;N,22.69.
Found:C,64.77;H,3.91;N,22.49. MS (El) :370(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 3.80(3H,s), 5.53(lH,s),
7.02(2H,d,J=7.3Hz), 7.32(lH,s), 7.50-7.53 (3H,m) ,
7.61(lH,dd,J=8.8Hz and 6.8Hz), 7.94(lH,d,J=8.8Hz) , 10.11(lH,s), 12.21(lH,s).
Example 162
4-(2, 1 , 3-Benzothiadiazol-4-yl)-5-cyano-4, 7-dihydro-6-phenyl-
2H-pyrazolo[ 3, 4-b] yridine
The title compound was prepared from methyl benzoate, 2,l,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:258°C.
MS(EI) :356(M+).
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 5.85(lH,s), 7.27(lH,s), 7.51- 7.52(3H,m), 7.61-7.67(3H,m) , 7.76 ( lH,dd, J=8.8Hz and 6.8Hz) ,
8.00(lH,d,J=8.8Hz)> 10.13(lH,s), 12.16(lH,s).
Example 163
4-(2, 1, 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6-(2- methoxyphenyl)-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl o-anisate,
2, l,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:231°C.
Anal. Calcd. for:C20Hι4N6OS 3/10 H2O:C,61.30;H,3.76;N,21.45. Found:C,61.24;H,3.74;N,22.09.
MS(EI) :386(M+) . H-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 3.89(3H,s) ,5.85( lH,s) , 706(lH,dd,J=7.6Hz and 7.3Hz), 7.17( lH,d, J=8.3Hz) , 7.28(lH,s), 7.43-7.49(2H,m), 7.69(lH,d, J=6.8Hz) , 7.80 ( lH,dd, J=8.8Hz and 6.8Hz), 7.99(lH,d,J=8.8Hz), 9.97(lH,s), 12.11(lH,s). Example 164
4-(2, 1, 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6-( 3- methoxyphenyl)-2H-pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl m-anisate, 2,l,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:220°C. Anal. Calcd. for :C20H14N6OS:C, 62.16;H,3.65;N,21.75. Found:C, 61.98 ;H, 3.70;N, 21.66. MS (El) :386(M+) .
XH-NMR ( 400MHz,DMSO-de ) δ(ppm) : 3.82(3H,S), 5.85(lH,s),
7.08(lH,d,J=8.3Hz), 7.19(lH,s), 7.23-7.27 (2H,m) , 7.42(lH,dd,J=7.8Hz and 7.2Hz), 7.61( lH,d, J=6.6Hz) ,
7.75(lH,dd,J=8.8Hz and 6.8Hz), 7.99( lH,d,J=8.1Hz) , 10.10(lH,s),
12.16(lH,s) .
Example 165
4- ( 2 , 1 , 3-Benzothiadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- ( 4- methoxyphenyl) -2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl p-anisate,
2,l,3-benzothiadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:238°C. MS(EI) :386(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 3.81(3H,s), 5.83(lH,s),
7.04(2H,d,J=8.8Hz) , 7.26(lH,s), 7.73-7.77 (3H,m) ,
7.75(lH,dd,J=8.8Hz and 6.8Hz), 7.99(lH,d,J=8.8Hz) , 10.04(lH,s),
12.14(1H,S) . Example 166
4-( 2 , 1 , 3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-( yridin-4- yl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl isonicotinate, 2,l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 95.
MP:236°C.
MS(EI) :341(M+).
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 5.58 ( lH,s) , 7.35( 1H,S) , 7.54- 7 .64 ( 4H,m) , 7 .96 ( lH,d, J=8 .1Hz ) , 8 .72 ( 2H, d, J=5 .9Hz ) , 10.40 ( lH, s ) , 12 .29 ( lH, s ) . Example 167
4-( 2 , 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-( 4-pyridin- 5 3-yl) -2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl nicotinate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:216°C. O Anal. Calcd. for:C18HnN70 1/5 H20:C,62.68;H,3.33;N,28.43.
Found:C,62.73;H,3.43;N,28.30.
MS(EI) :341(M+) .
XH-NMR ( 400MHz, DMSO-d6)δ(ppm) : 5.59(lH,s), 7.35(lH,s), 7.52-
7.63(3H,m), 7.95-8.00(2H,m), 8.69( lH,d,J=4.9Hz) , 8.76(lH,s), 5 10.39(1H,S), 12.28(lH,s).
Example 168
4- ( 2 , 1, 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6-( 4-pyridin-
2-yl) -2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl picolinate, 0 2, l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:188°C.
MS(EI) :341(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 5.59(lH,s), 7.34(1H,S), 7.51- 5 7.53(2H,m), 7.63(lH,dd,J=9.0Hz and 6.6Hz), 7.75( lH,d, J=6 ,6Hz) ,
7.95-7.97(2H,m), 8.69 ( lH,d, J=5.4Hz) , 10.20(lH,s), 12.26(lH,s).
Example 169
4- (2 , 1, 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6-
( aphthalen-1-yl) -2H-pyrazolo[ 3, 4-b]pyridine 0 The title compound was prepared from methyl 1-naphthoate,
2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:213°C. Anal. Calcd. for:C23Hι4NeO:C,70.76;H,3.61;N,21.53.
Found: C, 70.33 ;H, 3.74 ;N, 21.23.
MS(EI) :390(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 5.65(lH,s), 7.35-7.66(7H,m) , 7.96-8.21(4H,m), 10.35(lH,s), 12.23(lH,s).
Example 170
4-( 2, 1, 3-Benzoxadiazol-4-yl)-5-cyano-6-(furan-2-yl)-4, 7- dihydro-2H-pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl furan-2- carboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 95.
MP:241°C.
Anal. Calcd. for:C17H10N6O2:C, 61.82;H,3.05;N,25.44.
Found:C,61.72;H,3.19;N,25.34. MS(EI) :330(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm) : 5.54(1H,S), 6.69(1H,S),
7.22(lH,d,J=3.4Hz), 7.32 (1H,S), 7.48( lH,d, J=6.3Hz) ,
7.61(lH,dd,J=9.0Hz and 6.3Hz), 7.89(lH,s), 7.94( lH,d, J=9.OHz) ,
10.17(1H,S), 12.26(lH,s). Example 171
4-(2, 1, 3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-(thiophen-
2-yl)-2H-pyrazolo[ 3, 4-b] pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2,l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 95.
MP:230°C.
Anal. Calcd. for :C17Hι0N6OS:C,58.95;H,2.91;N,24.26.
Found:C,58.71;H,3.08;N,24.03.
MS (El) :346(M+) . XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 5.54(lH,s), 7.17( lH,dd, J=4.9Hz and 4.8Hz), 7.33(1H,S), 7.49 ( lH,d, J=6.6Hz) , 7.58-7.64(2H,m) ,
7.77(lH,d,J=4.9Hz), 7.95( lH,d, J=9 ,0Hz) , 10.21(lH,s),
12.27(1H,S) . Example 172
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- (naphthalen-2-yl)-2H-pyrazolo[ 3, 4-b] yridine
The title compound was prepared from methyl 2-naphthoate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:228°C.
Anal. Calcd. for:C23H14N6O:C,70.76;H,3.61;N,21.53. Found:C,70.66;H,3.81;N,20.94. MS(EI) :390(M+) .
XH-NMR ( 400MHz, DMSO-d6 )δ (ppm) : 5.48(lH,s), 7.24(lH,s), 7.44-
7.55(5H,m), 7.85-7.92(4H,m) , 8.05(lH,s), 10.21(lH,s),
12.14(1H,S) .
Example 173 4- ( 2, 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6- ( furan-2-yl)-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl furan-3- carboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 95. MP:237°C.
Anal. Calcd. for:C17H10N6O2:C,61.82;H,3.05;N,25.44.
Found:C,61.59;H,3.27;N,25.01.
MS(EI) :330(M+) .
XH-NMR (400MHz, DMSO-de )δ( ppm) : 5.52(lH,s), 6 -93( lH,d, J=1.0Hz) , 7.31(lH,s), 7.48(lH,d,J=6.6Hz), 7.60( lH,dd, J=9.OHz and 6.6Hz) ,
7.80(lH,dd,J=1.0Hz), 7.94( lH,d, J=9 ,0Hz) , 8.24(lH,s),
10.07(1H,S), 12.25(1H,S).
Example 174
4- ( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-(thiophen- 3-yl)-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-3- carboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 95. MP:242°C.
Anal. Calcd. for :C17H10NeOS:C,58.95;H,2.91;N,24.26.
Found:C,58.52;H,3.15;N,23.92.
MS(EI) :346(M+) . XH-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 5.54(lH,s), 7.32(lH,s),
7.42(lH,d,J=5.1Hz), 7.50( lH,d, J=6.6Hz) , 7.61-7.66(2H,m) ,
7.94(lH,d,J=9.0Hz), 8.00(lH,s), 10.13(lH,s), 12.24(lH,s).
Example 175
6-(Benzo[b] furan-2-yl) -4-(2,1, 3-benzoxadiazol-4-yl) -5-cyano- 4, 7-dihydro-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl benzo[b] furan-2-carboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:>270°C. Anal. Calcd. for:C21H12N6O2:C,66.31;H,3.18;N,22.09.
Found:C, 66.26;H, 3.3 ;N, 21.53.
MS(EI) :380(M+) .
XH-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 5.62(lH,s), 7.31-7.36(2H,m) ,
7.45(lH,dd,J=9.0Hz and 6.7Hz), 7.53( lH,d, J=6.7Hz) , 7.61- 7.65(3H,m), 7.77( lH,d,J=7.3Hz) , 7.96( lH,d,J=9.OHz) ,
10.44(1H,S), 12.33(lH,s).
Example 176
4- ( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-methyl-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from ethyl acetate,
2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:212°C.
Anal. Calcd. for:Cι4Hι0N60 3/5 H20:C,58.17;H,3.91;N,29.07. Found:C,58.45;H,4.08;N,28.61.
MS(EI) :278(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 2.14(3H,s), 5.40(lH,s),
7.25(lH,s), 7.40(lH,d,J=6.6Hz) , 7.59( lH,dd, J=9.OHz 6.6Hz) , 7.92 ( lH,d,J=9 .0Hz ) , 9 .98 ( lH, s) , 12 . 13 ( lH, s) . Example 177
4-(2 , 1 , 3-Benzoxadiazol-4-yl) -6-butyl-5-cyano-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl pentanoate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:200°C. Anal. Calcd. for:Cι7H16NeO:C,63.74;H,5.03;N,26.23. Found:C,63.85;H,5.01;N,26.26. MS(EI) :320(M+) .
XH-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.88( 3H,t,J=7.3Hz) , 1.30- 1.39(2H,m), 1.57-1.65(2H,m), 2.06-2.40(2H,m) , 5.39(lH,s), 7.25(1H,S), 7.39(lH,d,J=6.6Hz) , 7.59 ( lH,dd,J=9.OHz and 6.6Hz), 7.91(lH,d,J=9.0Hz) , 9.94(lH,s), 12.13(lH,s). Example 178
Ethyl 4- ( 2-chloro-3-methylphenyl)-4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
A suspension of 2-chloro-m-xylene (15 ml), N- bromosuccinimide (23.3 g) and benzoyl peroxide (200 mg) in carbon tetrachloride (150 ml) was heated under reflux for 6 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane) to give 2-bromomethyl-l-chloro-6- methylbenzene (16.0 g) as a colorless oil. 2-Bromomethyl-l- chloro-6-methylbenzene (25.4 g) and hexamethylenetetramine (32.4 g) were dissolved in acetic acid-water (1:1, 10 ml) and the mixture was heated under reflux for 5 hours. To the reaction mixture was added concentrated hydrochloric acid (40 ml) and the mixture was heated under reflux for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-3-methyIbenzaldehyde (19.4 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chloro-3- methyIbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:198-200°C.
Anal. Calcd. for:Cι9H22ClN302:C,63.42;H,6.16;N,11.68. Found:C,63.19;H,6.14;N,11.71. MS(EI) :359(M+) .
1H-NMR ( 400MHz,DMSO-d6)δ(ppm): 0.85(3H,t,J=7.3Hz) , 0.97(3H,t,J=7.3Hz) , 1.65(2H,m , 2.33(3H,s), 2.68-2.71( lH,m) , 2.79-2.84(lH,m), 3.72-3.82(2H,m) , 5.63(lH,s), 6.93-6.96 ( lH,m) , 7.05-7.07(2H,m), 7.24(lH,s), 9.46(lH,s), 11.94(lH,s). Example 179
Ethyl 4-(2-chloro-3-nitrophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
To a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in THF (50 ml) was added borane-tetrahydrofuran complex ( IM THF solution, 30 ml) under ice-cooling and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a pale-yellow solid (3.7 g) . The obtained pale-yellow solid (1.6 g) and manganese dioxide (1.7 g) were heated under reflux in toluene for 4.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane- ethyl acetate (4:1)) to give 2-chloro-3-nitrobenzaldehyde (1.3 g) as a pale-yellow solid. Subsequently, the title compound was prepared from 2-chloro-3-nitrobenzaldehyde, 3- aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MS(EI) :390(M+) . XH-NMR (400MHz,DMSO-de)δ(ppm) : 0.85 (3H,t,J=6.8Hz) ,
0.97(3H,t,J=7.3Hz), 1.64-1.68(2H,m) , 2.70-2.85(2H,m) , 3.73- 386(2H,m), 5.67(lH,s), 7.31(lH,s), 7.39-7.47(2H,m) , 7.73(lH,dd,J=1.5,7.8Hz), 9.67(1H,S), 12.10(lH,s). Example 180 Ethyl 4-( 2-chloro-3-cyanophenyl) -4,7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
To a solution of 2-chloro-3-methyIbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10-ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) to give 2-cyano-6- ethyIchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methyIchlorobenzene (10.9 g), N-bromosuccinimide
(12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:213-215°C.
Anal. Calcd. for:C19H19ClN402:C,61.54;H,5.16;N, 15.11. Found:C,61.25;H,5.36;N,14.71. MS(EI) :370(M+) .
XH-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.86(3H,t,J=6.9Hz) , 0.96(3H,t,J=7.3Hz), 1.65(2H,m), 2.70-2.80(2H,m) , 3.73- 3.81(2H,m), 5.63(lH,s), 7.31(lH,s), 7.42-7.44(2H,m) , 7.72(lH,dd, J=3.0,6.4Hz), 9.65(lH,s), 12.08(lH,s). IR(KBr) :v=3344, 3292,2985,2954,2242,1652cm-1. Example 181
Ethyl 4-( 2 , 3-dibromophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
A suspension of 2-bromo-3-nitrotoluene (5.0 g), iron (3.9 g) and ammonium chloride (3.7 g) in ethanol (50 ml) -water (17 ml) was heated under reflux for 2 hours. The insoluble matter was filtered off. To the filtrate was added ethyl acetate (100 ml) and the mixture was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) to give a pale-yellow oil (4.8 g) . The obtained pale-yellow oil (4.8 g) was dissolved in 47% hydrobro ic acid (50 ml). Under ice- cooling, an aqueous sodium nitrite (1.6 g) solution (18 ml) was added and the mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was added dropwise to a solution of cuprous bromide (2.0 g) in 47% hydrobromic acid (20 ml) over 30 minutes and the mixture was stirred at 60°C for 4.5 hours. To the reaction mixture was added water (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (9:1)) to give 2,3-dibromotoluene (2.6 g) as a brown oil. A suspension of 2,3-dibromotoluene (2.6 g), N- bromosuccinimide (1.85 g) and benzoyl peroxide (50 mg) in carbon tetrachloride (30 ml) was heated under reflux for 2 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane) to give a colorless oil (1.1 g) . To a solution of the obtained colorless oil (1.1 g) in dimethyl sulfoxide (8.6 ml) - methylene chloride (2 ml) was added trimethylamine-N-oxide (1.0 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml) and the mixture was extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2, 3-dibromobenzaldehyde (0.5 g) as a brown oil. Then the title compound was prepared from 2,3-dibromobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:180-183°C (decomposition). MS(EI) :469(M+) .
XH-NMR (400MHz, DMSO-de )δ (ppm) : 0.86(3H,t, J=7.3Hz) , 0.96(3H,t,J=7.3Hz) ,1.65(2H,m), 2.70-2.80(2H,m) , 3.72- 3.83(2H,m), 5.67(1H,S), 7.07 ( lH,d, J=5.8Hz) , 7.18(lH,dd,J=5.8,7.8Hz), 7.48 ( lH,d, J=7.8Hz) , 9.57(lH,s), 12.02(1H,S).
IR(KBr):v=3344, 3292, 2985, 2954, 2242, 1652cm"1. Example 182
Ethyl 4-(2-bromo-3-nitrophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 H2Q
A suspension of 2-bromo-3-nitrotoluene (5.1 g), N- bromosuccinimide (4.2 g) and benzoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g) . The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid- water (1:1, 16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-bromo-3-nitrobenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-bromo-3-nitrobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:213-215°C.
Anal. Calcd. for:Cι8Hι9BrN404 1/2 H20:C,48.66; H, 4.54;N, 12.61. Found: C, 48.34 ;H, 4.20 ;N, 13.04. MS(EI) :435(M+) .
^- MR ( 400MHz, DMSO-de ) δ(ppm ) : 0 ,87(3H,t, J=7.3Hz) , 0.97(3H,t,J=7.3Hz) , 1.63-1.68 (2H,m) , 2.77-2.81(2H,m) , 3.72- 3.85(2H,m), 5.68(lH,s), 7.33-7 -36(2H,m) ,
7.47(lH,dd,J=7.8,7.8Hz), 7.66( lH,d, J=7.8Hz) , 9.67(lH,s), 12.09(1H,S) . Example 183
Ethyl 4-(2-bromo-3-cyanophenyl )-4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was prepared from 2-bromo-m-xylene, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 180.
MP:210-212°C (decomposition).
Anal. Calcd. for:Cι9H19BrN402:C,54.95;H,4.61;N,13.49. Found:C,54.98;H,4.94;N,13.11. MS(EI) :415(M+) .
XH-NMR ( 400MHz, DMSO-de )δ (ppm) : 0.85(3H,t, J=6.8Hz) ,
0.97(3H,t,J=7.3Hz), 1.62-1.68 (2H,m) , 2.75-2.80(2H,m) , 3.72-
3.83(2H,m), 5.63(lH,s), 7.32(lH,s), 7.39-7.48 (2H,m) ,
7.68(lH,dd,J=1.9,7.3Hz), 9.65(lH,s), 12.07(1H,S). Example 184
4-( 2-Chloro-3-cyanophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[3 , 4-b]pyridine
The title compound was prepared from methyl butanoate,
2-chloro-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for:C17Hα4Cl3N5:C,63.06;H,4.36; N,21.63.
Found:C, 63.10 ;H, 4.42 ;N, 21.61.
MS (El) :323(M+) . ^- MR ( 400MHz,DMSO-de )δ(ppm) : 0.94(3H,t,J=7.3Hz) , 1.61- 1.71(2H,m), 2.35-2.49(2H,m), 5.47(lH,s), 7.32(lH,s), 7.52- 7.59(2H,m), 7.87(lH,dd,J=2.0,7.3Hz), 9.95(lH,s), 12.24(lH,s). Example 185 4- ( 2-Chloro-3-nitrophenyl) -5-cyano-4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butanoate, 2-chloro-3-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:234-235°C.
Anal. Calcd. for:C16H14ClN502: C,55.90;H,4.10;N,20.37.
Found:C,55.93;H,4.34;N,20.72.
MS (El) :343(M+) . 1H-NMR ( 400MHz, DMSO-de )δ (ppm ) : 0.94(3H,t, J=7.3Hz) , 1.64-
1.69(2H,m), 2.37-2.45(2H,m), 5.52(lH,s), 7.34(lH,s), 7.54-
7.60(2H,m), 7.89(lH,dd,J=2.0,6.9Hz), 9.97(lH,s), 12.25(lH,s).
Example 186
4- (2-Bromo-3-cyanophenyl)-5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine 1/5 H2Q
The title compound was prepared from methyl butanoate,
2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:275-279°C (decomposition). Anal. Calcd. for :Cι7H14BrN5 1/5 H2O:C,55.05;H,3.89;N,18.88.
Found:C,54.98;H,3.91;N,18.81.
MS(EI) :368(M+) .
1H-N R ( 400MHz,DMSO-de )δ(ppm) : 0.94(3H,t, J=7.3Hz) , 1.64- 1.69(2H,m), 2.38-2.43(2H,m), 5.47(lH,s), 7.33(lH,s), 7.54- 7.60(2H,m), 7.83(lH,dd,J=2.0,7.4Hz), 9.95(lH,s), 12.24(lH,s). Example 187
( +)Ethyl 4- ( 3 , 4-dihydro-2H-benzopyran-8-yl) -4, 7-dihydro-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate
To a solution of the compound (1.94 g) described in Example 73 in acetonitrile (15 ml) was added (-)-10- camphorsulfonic acid (1.23 g) at 50°C and the mixture was stirred under ice-cooling for 30 minutes. The precipitated crystals were collected by filtration and recrystallized (ethanol-ethyl acetate (2:1), 30 ml) to give white crystals (0.81 g). The obtained white crystals were suspended in water and a saturated aqueous sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate and the extract was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a colorless transparent oil. The obtained colorless transparent oil was crystallized from ethyl acetate to give the title compound (470 mg) as white crystals.
MP:159-161°C.
Anal. Calcd. for:C2ιH25N303:C,68.64;H,6.86;N,11.44. Found:C,68.37;H,6.86;N,11.26. Spec if ic rotation : [ α ] D=+200 ° ( EtOH , c=0.5 ) . MS(EI) :367(M+) .
^-NMR (400MHz, DMSO-de )δ (ppm) : 0.91( 3H,t, J=6.8Hz ) , 0.98(3H,t,J=7.3Hz), 1.60-1.70(2H,m) , 1.90-2 ,00(2H,m) , 2.67- 2.82(4H,m), 3.81(2H,m), 4.25(2H,m), 5.42(lH,s), 6.62(lH,dd,J=7.4,7.8Hz), 6.72-6.76(2H,m) , 7.18(lH,s), 9.26(lH,s), 11.81(1H,S). Example 188
(-)Ethyl 4-( 3, 4-dihydro-2H-benzopyran-8-yl) -4,7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate
The filtrate obtained by filtering off the (-)-10- camphorsulfonate salt in Example 187 was concentrated under reduced pressure and suspended in water. To the suspension was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give white crystals (780 mg) . By the same process as in Example 187 using the obtained white crystals and (+)-10-camphorsulfonic acid, the title compound (150 mg) was obtained as white crystals.
MP:160-161°C.
Anal. Calcd. for:C2ιH25N303:C,68.64;H,6.86; N, 11.44.
Found:C,68.49;H,6.81;N,11.42. Specific rotation: [ ]D=-202°(EtOH,c=0.5)
MS(EI) :367(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm ) : 0.91(3H,t, J=6.8Hz) ,
0.98(3H,t,J=7.3Hz) , 1.60-1.70(2H,m) , 1.90-2.00(2H,m) , 2.67- 2.82(4H,m), 3.81(2H,m), 4.25(2H,m), 5.42(lH,s), 6.62(lH,dd,
J=7.4,7.8Hz), 6.72-6.76(2H,m), 7.18(lH,s), 9.26(lH,s),
11.81(lH,s) .
Example 189
4-(2-Bromo-3-nitrophenyl)-5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl butanoate,
2-bromo-3-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:250-255°C (decomposition). Anal. Calcd. for:C16HιBrN502:C,49.50;H,3.63;N,18.04.
Found:C,49.37;H,3.76;N,18.02.
MS(EI) :388(M+) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.95(3H,t,J=7.6Hz) , 1.64-
1.70(2H,m), 2.39-2.44(2H,m), 5.53(1H,S), 7.34(1H,S), 7.49(lH,d,J=7.8Hz) , 7.60( lH,dd, J=7.8,8.OHz) ,
7.82(lH,d,J=8.0Hz) , 9.97(lH,s), 12.25(lH,s).
Example 190
Ethyl 4 , 7-dihydro-4-( 2-methoxy-3-methylphenyl) -6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate A suspension of 2, 6-dimethylphenol (19.5 g), iodo ethane
(31 ml) and potassium carbonate (33.2 g) in dimethylformamide
(200 ml) was stirred at 60°C for 10 hours. The reaction mixture was poured into water (300 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane) to give 2-methoxy-m-xylene (12 g) as a colorless oil. A suspension of 2-methoxy-m-xylene (5.1 g), N-bromosuccinimide (4.2 g) and bezoyl peroxide (229 mg) in carbon tetrachloride (50 ml) was heated under reflux for 3 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give a yellow solid (5.4 g) . The obtained yellow solid (5.4 g) and hexamethylenetetramine (5.1 g) were dissolved in acetic acid- water (1:1,16 ml) and the mixture was heated under reflux for 2 hours. To the reaction mixture was added concentrated hydrochloric acid (6 ml) and the mixture was heated under reflux for 15 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) and crystallized (hexane-ethyl acetate (5:1)) to give 2-methoxy-3-methyIbenzaldehyde (1.2 g) as yellow crystals. Subsequently, the title compound was prepared from 2-methoxy-3-methyIbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:220-222°C. Anal. Calcd. for:C2oH25N303:C,67.58;H,7.09; N, 11.82. Found:C,67.47;H,7.02;N,11.91. MS(EI) :355(M+) .
^Η- MR ( 400MHz,DMSO-de ) δ(ppm) : 0.89 (3H,t,J=7.OHz) , 0.97(3H,t,J=7.3Hz) , 1.60-1.70(2H,m) , 2.23(3H,s), 2.66- 2.85(2H,m), 3.81(3H,S), 3.81-3.85(2H,m) , 5.43(lH,s), 6.82- 6.91(3H,m), 7.13(1H,S), 9.31(lH,s), 11.82(lH,s). Example 191 Ethyl 4- ( 3-cyano-2-methoxyphenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-methoxy-3- ethyIbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 180. MP:220-222°C.
Anal. Calcd. for:C20H22N4O3:C,65.56;H,6.05; N,15.29.
Found:C,65.20;H,6.10;N,15.23.
MS(EI) :366(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.89 (3H,t, J=7.1Hz) , 0.96(3H,t,J=7.3Hz), 1.60-1.70(2H,m) , 2.70-2.80(2H,m) , 3.75-
3.90(2H,m), 4.02(3H,s), 5.46(lH,s), 7.14-7.19 (2H,m) ,
7.32(lH,d,J=6.lHz), 7.53( lH,d, J=7.8Hz) , 9.51(lH,s),
11.97(lH,s) .
Example 192 5-Cyano-6-ethyl-4 , 7-dihydro-4- ( 2-nitrophenyl) -2H-pyrazolo[ 3 , 4- b]pyridine
The title compound was prepared from methyl propionate,
2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:228-230°C (decomposition).
Anal. Calcd. for:Cι5Hι3N5O2:C,61.01;H,4.44;N,23.72.
Found:C, 60.72 ;H, 4.51;N, 23.78.
MS (El) :295(M+).
^-NMR (400MHz,DMSO-d6)δ(ppm) : 1.21(3H,t,J=7.4Hz) , 2.42- 2.49(2H,m), 5.37(lH,s), 7.27(lH,s), 7.43-7.49(2H,m) ,
7.70(lH,dd,J=7.6,8.0Hz), 7.89 ( lH,d, J=8.OHz) , 9.94(lH,s),
12.21(1H,S) .
Example 193
5-Cyano-4-( 2 , 3-dichlorophenyl) -6-ethyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl propionate,
2,3-dichlorobenzaldehyde, 3-aminopyrazole and l-cyanobutan-2- one in the same manner as in Example 94. MP:>300°C.
Anal. Calcd. for:C15Hι2Cl2N4:C,56.44;H,3.79;N, 17.55.
Found: C, 56.33 ;H, 3.86 ;N, 17.67.
MS(EI) :319(M+) . XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 1.21(3H,t, J=7 ,6Hz) , 2.38-
2.49(2H,m), 5.43(lH,s), 7.23( lH,d, J=6.8Hz) , 7.31-7.37 (2H,m) ,
7.51(lH,dd,J=1.7,8.lHz), 9.92(1H,S), 12.19(lH,s).
Example 194
5-Cyano-6-ethyl-4, 7-dihydro-4- ( 2-methoxyphenyl)-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl propionate,
2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:230-232°C. Anal. Calcd. for:Cι6Hι6N40:C,68.55;H,5.75;N, 19.99.
Found:C,68.16;H,5.97;N,20.39.
MS(EI) :280(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 1.22(3H,t, J=7.6Hz) , 2.42-
2.49(2H,m), 3.84(3H,s) ,5.21( 1H,S) , 6.86-6.91 ( lH,m) , 6.99(lH,d,J=8.3Hz) , 7.05( lH,d, J=7.6Hz) ,7.15-7.19(2H,m) ,
9.68(lH,s), 12.02(lH,s).
Example 195
4-(2-Chloro-3-cyanophenyl)-5-cyano-6-ethyl- , 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl propionate,
2-chloro-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>300°C.
Anal. Calcd. for:C16Hι2ClN5:C,62.04;H,3.90;N,22.61. Found:C,61.74;H,4.14;N,22.93.
MS(EI) :309(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.21(3H,t,J=7.6Hz) , 2.42- 2.49(2H,m), 5.45(1H,S), 7.33(lH,s), 7.52-7.60(2H,m) , 7.87 ( lH,dd, J=2 .0, 7 .3Hz ) , 9 .97 ( lH, s ) , 12 .23 ( lH, s) .
Example 196
4- ( 2 , 1 , 3-Benzoxazol-4-yl) -5-cyano-6-ethyl-4 , 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl propionate,
2,l,3-benzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:206-208°C (decomposition).
Anal. Calcd. for:C15Hι2N60:C,61.64;H,4.14;N,28.75. Found:C,61.43;H,4.41;N,28.85.
MS (El) :292(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.20(3H,t, J=7.6Hz) , 2.40-
2.50(2H,m), 5.40(lH,s), 7.26(lH,s), 7.40( lH,d,J=6.6Hz) ,
7.58(lH,dd,J=6.6,9.0Hz), 7.92( lH,d,J=9.OHz) , 9.97(lH,s), 12.14(lH,s).
Example 197
4-(2-Chlorophenyl) -5-cyano-6-ethyl-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl propionate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>300°C.
Anal. Calcd. for:C15Hι3ClN4:C,63.27;H,4.60; N,19.68.
Found:C,63.14;H,4.69;N,19.67. MS(EI) :284(M+) .
^-NMR ( 400MHz,DMSO-de) δ(ppm) : 1.21( 3H,t, J=7.6Hz) , 2.42-
2.49(2H,m), 5.35(lH,s), 7.22-7.26 (3H,m) , 7.30-7.34( lH,m) ,
7.42(lH,d,J=7.8Hz), 9.85(lH,s), 12.15(lH,s).
Example 198 4- ( 2-Bromo-3-cyanophenyl) -5-cyano-6-ethyl-4 , 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl propionate,
2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:>300°C.
Anal. Calcd. for:Cι6Hι2BrN5:C,54.25;H,3.41; N,19.77. Found:C,54.13;H,3.56;N,19.98. MS(EI) :354(M+) .
1H-NMR (400MHz,DMSO-de)δ(ppm) : 1.21(3H,t,J=7.6Hz ) , 2.43(2H,m), 5.46(1H,S), 7.33(lH,s), 7.56-7.60(2H,m) , 7.82-7.84( lH,m) , 9.98(1H,S), 12.24(1H,S). Example 199 4-(2-Bromophenyl) -5-cyano-6-ethyl-4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine
The title compound was prepared from methyl propionate, 2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:250-253°C (decomposition).
Anal. Calcd. for:C15Hι3BrN4:C,54.73; H,3.98; N, 17.02.
Found:C,54.28;H,3.96;N,16.94.
MS (El) :329(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.21(3H,t, J=7.6Hz) ,2.42- 2.45(2H,m), 5.34(lH,s), 7.16( lH,dd,J=7.5, 7.6Hz) ,
7.22(lH,d,J=6.6Hz), 7.27(lH,s), 7.36( lH,dd, J=6.3,7.3Hz) , 7.59(lH,d,J=6.8Hz), 9.86(lH,s), 12.15(lH,s). Example 200
Ethyl 4-( 2-chlorophenyl) -6-cyano-4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine-5-carboxylate 1/4 hydrate
A solution of l,l'-carbonylbis-lH-imidazole (22.5 g), ethanol (8.1 ml) and toluene (100 ml) was stirred at room temperature for 1.5 hours. To the reaction mixture was added ice-water ( 100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give a colorless oil (19.3 g) . A solution of the obtained residue (19.3 g) and pyruvic aldehyde dimethyl acetal (11.1 ml) in toluene (50 ml) was added dropwise to a suspension of sodium hydride (8.44 g) in toluene (250 ml) under reflux with heating, over 15 minutes, and the mixture was heated under reflux for 1.5 hours. To the reaction mixture was added a 10% aqueous citric acid solution (610 ml) and1the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (5:1)) to give ethyl 4, 4-dimethoxy-3-oxobutanoate (15.1 g) as a colorless oil. Subsequently, ethyl 4-(2- chlorophenyl)-6-dimethoxymethyl-4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine-5-carboxylate was obtained as a yellow solid from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4, 4-dimethoxy- 2-oxobutanoate in the same manner as in Example 1. To a solution of ethyl 4-(2-chlorophenyl)-6-dimethoxymethyl-4, 7- dihydro-2H-pyrazolo[3,4-b]pyridine-5-carboxylate (463 mg) in tetrahydrofuran (5 ml) was added IN hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give ethyl 4-(2-chlorophenyl)- 6-for y1-4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate (290 mg) as a yellow solid. A solution of ethyl 4-(2- chlorophenyl)-6-formyl-4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine- 5-carboxylate (290 mg) and hydroxylamine-O-sulfonic acid (128.5 mg) in water (10 ml) -ethanol (10 ml) was stirred at 80°C for 2 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and crystallized from ethanol-ethyl acetate to give the title compound (53 mg) as yellow crystals.
MP:275-278°C (decomposition).
Anal. Calcd. for:Cι6Hι3ClN402 1/4 H2O:C,57.66;H,4.08;N, 16.81.
Found:C, 57.54 ;H, 4.06 ;N, 16.66.
MS(EI) :328(M+) . ^- MR ( 400MHz, DMSO-de )δ (ppm) : 0.93( 3H,t, J=7.1Hz) , 3.91(2H,m),
5.67(1H,S), 7.15-7.19(2H,m), 7.25( lH,dd, J=7.3, 8 ,3Hz) ,
7.33(lH,s), 7.39(lH,d,J=8.3Hz), 10.81(lH,s), 12.34(lH,s).
Example 201
4-(2-Chloro-3-trifluoromethylphenyl) -5-cyano-4, 7-dihydro-6- propy1-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butanoate,
2-chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C. Anal. Calcd. for:Cι7Hι4ClF3N4:C,55.67;H,3.85;N, 15.28.
Found:C,55.81;H,3.97;N,15.44.
MS(EI) :366(M+) .
^-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.95( 3H,t,J=7.3Hz) , 1.64- 1.70(2H,m), 2.40-2.43(2H,m), 5.55(lH,s), 7.31(lH,s), 7.54- 7.56(2H,m), 7.74( lH,dd,J=3.6,5 ,6Hz) , 9.93(1H,S), 12.22(lH,s). Example 202
4-( 2-Chloro-3-trifluoromethylphenyl)-5-cyano-4, 7-dihydro-6- phenyl-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from benzoic acid, 2- chloro-3-trifluoromethylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:>250°C. Anal. Calcd. for :C20H12C1F3N4:C,59.94;H,3.02;N, 13.98.
Found:C, 59.74 ;H, 3.18 ; , 13.95.
MS(EI) :400(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 570(lH,s), 7.39(lH,s), 7.49-
7.51(3H,m), 7.57-7.62(3H,m), 7.75-7.79(2H,m) , 10.18(lH,s), 12.31(lH,s).
Example 203
4- ( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-isopropyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl isobutyrate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for:C16Hι5ClN4:C,64.32;H,5.06;N,18.75.
Found:C,64.18;H,5.12;N,18.84. MS(EI) :298(M+) .
XH-NMR ( 400MHz,DMSO-d6) δ(ppm) : 1.23(3H,d,J=6.8Hz) ,
1.27(3H,d,J=6.8Hz), 3.06(lH,m), 5.34(lH,s), 7.22-7.26 (3H,m) ,
7.30-7.34(lH,m), 7.42( lH,d,J=7.1Hz) , 9.63(lH,s), 12.16(lH,s).
Example 204 Ethyl l-tert-butoxycarbonyl-4- ( 2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
To a solution of the compound (1.2 g) described in
Example 27 and dimethylaminopyridine (128 mg) in THF (40 ml) was added di-tert-butyldicarbonate (830 mg) and the mixture was stirred at room temperature for one day. The solvent was evaporated under reduced pressure and the title compound (102 mg) was obtained as colorless crystals by silica gel column chromatography (eluent: hexane-ethyl acetate (3:1)). MP:112-116°C.
Anal. Calcd. for:C23H28ClN304:C,61.95;H,6.33;N,9.42.
Found:C, 61.84 ;H, 6.33 ;N, 9.34.
MS (El) :445(M+) . ^- MR ( 400MHz, DMSO-de ) δ(ppm ) : 0.87 ( 3H,t, J=6.9Hz) ,
0.98(3H,t,J=7.3Hz), 1.56(9H,s), 1.62-1.72 (2H,m) , 2.80-
2.92(2H,m), 3.85(2H,q, J=6.9Hz) , 5.56(lH,s), 7.14-7.17 (2H,m) ,
7.23(lH,dd,J=7.3 and 7.8Hz), 7.30(lH,s), 7.39 ( lH,d, J=7.4Hz) ,
8.75(1H,S) . Example 205
Ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4 , 7-dihydro-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 204 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound (300 mg) was obtained as colorless crystals.
MP:144-147°C.
Anal. Calcd. for :C23H28ClN304:C,61.95;H,6.33;N,9.42.
Found:C,61.93;H,6.35;N,9.40. MS(EI) :445(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.85(3H,t,J=6.9Hz) , 0.97(3H,t,J=7.3Hz) , 1.49(9H,s), 1.63-1.69 (2H,m) , 2.66- 2.85(2H,m), 3.80(2H,q,J=6.9Hz) , 5.57(lH,s), 7.10-7.15 ( lH,m) , 7.17(lH,ddd,J=1.5, 7.3 and 7.8Hz), 7.23(lH,dd,J=6.4 and 7.3Hz), 7.41(lH,d,J=7.2Hz) , 7.67(lH,s), 10.01(lH,s). Example 206
Ethyl 4-(2-chlorophenyl) -4, 7-dihydro-l-methoxycarbonyl-6- propyl-IH-pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4- (2-chlorophenyl) -4, 7-dihydro-6-propyl-IH- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and methyl chloroformate in the same manner as in Example 204. MS (El) :403(M+) . IR(KBr) :v=3422, 1736, 1699, 1531, 1450, 1232, 1086 cm"1.
1H-NMR (400MHz,DMSO-de)δ(ppm) : 0.87(3H,t, J=7.1Hz) ,
0.97(3H,t,J=7.3Hz), 1.60-1.66(2H,m) , 2.86-2.89(2H,m) ,
3.83(2H,q,J=7.lHz), 3.94(3H,s), 5.55( 1H,S) ,7.13-7.38(4H,m) , 7.35(1H,S), 8.67(1H,S).
Example 207
Ethyl 4-( 2-chlorophenyl)-4, 7-dihydro-2-methoxycarbonyl-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 206 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as colorless crystals.
MP:141-143°C.
MS (El) :403(M+) . IR(KBr):v=3290, 1774, 1695, 1633, 1597, 1523, 1444, 1364, 1307, 1209 cm"1.
^-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.86 (3H,t,J=7.1Hz) ,
0.95(3H,t,J=7.3Hz), 1.64-1.70.(2H,m) , 2.71-2.85(2H,m) ,
3.78(2H,q,J=7.1Hz), 3.85(lH,s), 5.57( 1H,S) ,7.10-7.24( 3H,m) , 7.42(lH,d,J=1.4Hz), 7.72(lH,s), 9.94(lH,s).
Example 208
Ethyl 1-benzyloxycarbonyl-4-(2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from ethyl 4- (2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[ 3 , 4-b] yridine-5-carboxylate, dimethylaminopyridine and benzyl chloroformate in the same manner as in Example 204,
MP:80°C.
Anal. Calcd. for:C26H26ClN3O4:C,65.07;H,5.46;N,8.75. Found:C,65.24;H,5.71;N,8.50.
MS(EI) :479(M+) .
IR(KBr) :v=3344, 1745, 1701, 1527, 1451, 1226, 1084, 1060 cm"1.
XH-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.88(3H,t,J=7.OHz) , 0.94(3H,t,J=7.3Hz), 1.56-1.62(2H,m) , 2.81-2.88 (2H,m) ,
3.82(2H,q,J=7.0Hz), 5.41(2H,s), 5.55(lH,s), 7.13-7.24 (3H,m) ,
7.36(lH,s), 7.37(6H,m), 8.62(lH,S).
Example 209 Ethyl 2-benzyloxycarbonyl-4-( 2-chlorophenyl) -4, 7-dihydro-6- propyl-2H-pyrazolo [ 3, 4-b]pyridine-5-carboxylate
Further elution using the column of silica gel column chromatography in Example 208 and hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.
MS(EI) :479(M+) .
IR(KBr) :v=3294, 1759, 1697, 1601, 1383, 1363, 1300, 1201 cm-1.
^-N R ( 400MHz,DMSO-de ) δ(ppm) : 0.85 (3H,t,J=7.OHz) ,
0.95(3H,t,J=7.3Hz), 1.61-1.67(2H,m) , 2.72-2.82(2H,m) , 3.79(2H,q,J=7.0Hz) , 5.30(2H,s), 5.56(1H,S), 7.09-7.41(9H,m) ,
7.73(1H,S), 9.95(lH,s).
Example 210
Ethyl l-benzoyl-4- ( 2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was obtained as colorless crystals from ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and benzoyl chloride in the same manner as in Example 204.
MP:115°C. Anal. Calcd. for:C25H24ClN303:C,66.74;H,5.38;N,9.34.
Found:C,66.58;H,5.41;N,9.28.
MS (El) :449(M+) .
IR(KBr) :v=3414, 1680, 1641, 1516, 1095 cm"1.
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.90(3H,t, J=6.3Hz) , 1.00(3H,t,J=7.3Hz), 1.65-1.71( 2H,m) , 2.90-2.93(2H,m) ,
3.85(2H,q,J=7.3Hz), 5.63(lH,s), 7.16-7.22 (2H,m) ,
7.29(lH,d,J=7.3Hz) , 7 ,40( lH,d, J=7.8Hz) , 7.46(lH,s), 7.50-
7.54(2H,m), 7.65( lH,dd, J=6.3 and 7.8Hz) , 7.98( lH,d,J=6.3Hz) , 9 .10 ( 1H, S ) . Example 211
Ethyl 2-benzoyl-4- ( 2-chlorophenyl) -4, 7-dihydro-6-propyl-2H- pyrazolo[ 3 , -b]pyridine-5-carboxylate Through the column of silica gel column chromatography used in Example 210 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.
MP:119-121°C. Anal. Calcd. for:C25H24ClN303:C,66.74;H,5.38;N,9.34. Found:C, 66.58 ;H, 5.43;N, 9.30. MS(EI) :479(M+) .
IR(KBr) :v=3406, 1670, 1628, 1601, 1481, 1348, 1084 cm-1. XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.87 (3H,t, J=6.8Hz) , 0.97(3H,t,J=7.3Hz) , 1.65-1.67(2H,m) , 2.74-2.83(2H,m) , 3.82(2H,q,J=7.3Hz) , 5.65(lH,s), 7.13-7.26 (3H,m) , 7.44(lH,d,J=7.8Hz) , 7.47-7.51(2H,m) , 7.60(lH,dd,J=7.3 and 7.3Hz), 7.91(2H,d,J=7.8), 8.00(lH,s), 10.06(lH,s). Example 212 Ethyl l-benzylcarbonyl-4-( 2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenylacetyl chloride in the same manner as in Example 204. XH-NMR ( 400MHz, DMSO-de )δ(ppm) : 0.89 (3H,t, J=6.8Hz) , 0.94(3H,t,J=7.3Hz) , 1.60-1.61(2H,m) , 2.84-2.86(2H,m) , 3.82(2H,q,J=6.8Hz), 4.47(2H,s), 5.59(lH,s), 7.20-9.44 ( 10H,m) , 8.90(1H,S) . Example 213
Ethyl 2-benzylcarbonyl-4- ( 2-chlorophenyl) -4, 7-dihydro-6- propyl-2H-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 212 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.
MS(EI) :463(M+) . IR(KBr):v=3308, 1699, 1628, 1630, 1599, 1523 cm-1.
^Η-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.87 (3H,t,J=6.8Hz) ,
0.98(3H,t,J=7.3Hz), 1.65-1.71(2H,m) , 2.77-2.84(2H,m) ,
3.83(2H,q,J=6.8Hz), 4.25(2H,s), 5.60(lH,s), 7.11-7.31(8H,m) ,
7.41(lH,d,J=7.8Hz), 7.84(lH,s), 10.30(lH,s). Example 214
Ethyl 4-(2-chlorophenyl) -4, 7-dihydro-l-phenylcarbamoy1-6- propyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.
MS(EI) :464(M+) .
IR(KBr) :v=3310, 1699, 1597, 1518, 1448, 1369, 1228, 1194, 1093 cm-1.
XH-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.98 (3H,t,J=7.1Hz) , 0.97(3H,t,J=7.3Hz), 1.96(2H,m), 2.87(2H,m), 3.83(2H,q,J=7.1Hz) ,
5.61(1H,S), 7.11-7.69(8H,m), 7.67 (2H,d,J=7.8Hz) , 8.86(lH,s),
10.31(1H,S) .
Example 215
Ethyl 4- ( 2-chlorophenyl) -4, 7-dihydro-2-phenylcarbamoyl-6- propyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 214 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as colorless crystals. MP:145-147°C.
Anal. Calcd. for:C25H25ClN403:C,64.58;H,5.42;N, 12.05.
Found:C,64.10;H,5.41;N,12.30.
MS(EI) :464(M+) . IR(KBr) :v=3341, 1697, 1653,1630, 1597, 1520, 1367, 1197, 1093 cm-1.
1H-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.88(3H,t, J=7.OHz) ,
0.97(3H,t,J=7.3Hz),1.68(2H,m), 2.80-2.92(2H,m) ,
3.82(2H,q,J=7.0Hz), 5.62 ( lH,s) ,7.10-7.20(3H,m) , 7.22(lH,dd,J=7.1 and 7.1Hz), 7.31-7.33(2H,m) ,
7.41(lH,d,J=7.1Hz),7.58-7.60(2H,m), 7.85(lH,s), 9.67(1H,S),
9.83(1H,S) .
Example 216
Ethyl l-benzylcarbamoyl-4-( 2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and benzyl isocyanate in the same manner as in Example 204. MS(EI) :478(M+) .
IR(KBr):v=3402, 1699, 1637, 1525, 1226, 1091 cm"1.
XH-NMR ( 400MHz,DMSO-d6)δ(ppm): 0.88(3H,t,J=7.0Hz) ,
0.96(3H,t,J=7.3Hz), 1.61-1.63(2H,m) , 2.83(2H,m),
3.82(2H,q,J=7.0Hz), 4.37(2H,d), 5.58(lH,s), 7.11-7.31(9H,m) , 7.38(lH,d,J=7.8Hz), 8.74(lH,s), 9.01(lH,s).
Example 217
Ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-l-phenoxycarbonyl-6- propyl-IH-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4- (2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenyl chloroformate in the same manner as in Example 204.
MS(EI) :465(M+) .
IR(KBr) :v=3339, 1728, 1633, 1525, 1371, 1302, 1224, 1091 cm-1. ^-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.83(3H,t,J=7.1Hz) ,
0.96(3H,t,J=7.3Hz), 1.70(2H,m), 2.94(2H,m), 3.82(2H,q, J=7.1Hz) ,
5.62(1H,S), 7.12-7.53(9H,m), 8.26(lH,s), 9.30(lH,s).
Example 218 Ethyl 4-(2-chlorophenyl) -4, 7-dihydro-2-phenoχycarbonyl-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 217 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.
MP:156-157°C.
Anal. Calcd. for:C25H24ClN3O4:C,64.44;H,5.19;N,9.02.
Found:C,64.42;H,5.31;N,9.04. MS(EI) :465(M+) .
IR(KBr) :v=3325, 1765, 1685, 1597, 1525, 1373, 1205, 1099 cm-1.
-Η-NMR (400MHz,DMSO-d5)δ(ppm) : 0.87 (3H,t,J=7.1Hz) ,
1.00(3H,t,J=7.3Hz), 1.67-1.69(2H,m) , 2.76-2.85(2H,m) ,
3.82(2H,q,J=7.lHz), 5.61(lH,s), 7.15( lH,dd, =1.7 and 6.8Hz), 7.15(lH,dd,J=1.7 and 6.8Hz), 7.17( lH,dd, J=2.0 and 7.6Hz),
7.24(lH,dd,J=1.3 and 7.4Hz), 7.27-7.31(3H,m) , 7.41-7.45(3H,m) ,
7.89(1H,S), 10.01(lH,s).
Example 219
Ethyl 4-( 2-chlorophenyl) -l-ethoxycarbonyl-4, 7-dihydro-6- propyl-IH-pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from ethyl 4- (2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and ethyl chloroformate in the same manner as in Example 204. MP:88-89°C.
Anal. Calcd. for:C21H24ClN3O4:C,60.36;H,5.79;N, 10.06.
Found:C, 60.2 ;H, 5.72 ;N, 10.05.
MS(EI) :417(M+) .
IR(KBr) :v=3422, 1734, 1705, 1647, 1591, 1531, 1228, 1086, 1062 cm-1. XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.87(3H,t,J=7.1Hz) ,
0.96(3H,t,J=7.3Hz), 1.31(3H, t,J=7.lHz), 1.61-1.66 (2H,m) ,2.83-
2.92(2H,m), 3.83(2H,q,J=7.lHz), 4.41(2H,q,J=7.1Hz) , 5.55(lH,s),
7.13-7.16(2H,m), 7 ,25( lH,dd,J=7.0 and 7.6Hz), 7.34(lH,s), 7 .38 ( lH, d, J=7 .6Hz ) , 8 .65 ( lH, s ) . Example 220
Ethyl 4-(2-chlorophenyl)-2-ethoxycarbonyl-4, 7-dihydro-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate Throug the column of silica gel column chromatography used in Example 219 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid. MS (El) :417 (M+) . IR(KBr) :v=3325, 1765, 1685, 1631, 1597, 1525, 1373, 1205, 1099 cm"1. XH-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 0.87 (3H,t,J=7.1Hz) , 0.97(3H,t,J=7.3Hz), 1.26(3H,t, J=7.OHz) , 1.63-1.69 (2H,m) , 2.74- 2.81(2H,m), 3.81(2H,q,J=7.1Hz), 4.29(2H,q,J=7.OHz) , 5.57(lH,s), 7.12(lH,dd,J=6.3 and 7.5Hz), 7.17 ( lH,d,J=7.8Hz) , 7.23(lH,dd,J=6.3 and 7.4Hz), 7.40( lH,d,J=7.8Hz) , 7.71(lH,s), 9.96(1H,S) . Example 221
Ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-l-propoxycarbonyl-6- propyl-lH-pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[ 3, 4-b]pyridine-5-carboxylate, dimethylaminopyridine and propyl chloroformate in the same manner as in Example 204. MP:66-68°C. MS(EI) :431(M+) .
IR(KBr) :v=3356, 1738, 1695, 1527, 1282, 1084 cm"1. ^- MR ( 400MHz,DMSO-de ) δ(ppm) : 0.88 (3H,t,J=7.0Hz) , 0.92(3H,t,J=7.3Hz), 0.97 (3H,t, =7.3Hz) , 1.62-1.67(2H,m) , 1.70- 1.75(2H,m) , 2.85-2.92(2H,m) ,3.83(2H,q,J=7.OHz) , 4.32(2H,t,J=6.5Hz), 5.57(lH,s), 7.14-7.18 (2H,m) ,
7.26(lH,dd,J=6.3 and 7.6Hz), 7.35(lH,s), 7.39( lH,d,J=7.8Hz) 9.10(lH,s) . Example 222 Ethyl 4-( 2-chlorophenyl) -4, 7-dihydro-2-propoxycarbony1-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 221 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.
MP:59°C.
Anal. Calcd. for:C22H26ClN3O4:C,61.18;H,6.07;N,9.73.
Found:C,60.81;H,5.98;N,9.74. MS(EI) :431(M+) .
IR(KBr) :v=3296, 1761, 1697, 1633, 1599, 1523, 1365, 1218, 1089 cm-1. ^Η-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.87(3H,t,J=7.1Hz) , 0.89(3H,t,J=7.5Hz), 0.97(3H,t,J=7.3Hz) , 1.63-1.69(4H,m) , 2.74- 2.81(2H,m), 3.81(2H,q,J=7.lHz), 4.21(2H,t,J=6.6Hz) , 5.58(lH,s), 7.12(lH,dd,J=1.8 and 7.6Hz), 7.17 ( lH,ddd,J=1.9, 7.3 and 7.6Hz), 7.22(lH,ddd,J=1.2, 7.3 and 7.6Hz), 7.41( lH,dd,J=1.2 and 7.8Hz), 7.72(lH,s), 9.99(1H,S). Example 223 Ethyl 4- ( 2-chlorophenyl) -4, 7-dihydro-2-isobutylyl-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-lH- pyrazolo[3, 4-b]pyridine-5-carboxylate, dimethylaminopyridine and isobutyryl chloride in the same manner as in Example 204. XH-NMR (400MHz,DMSO-de)δ(ppm) : 0.84(3H,t,J=7.OHz) ,
0.96(3H,t,J=7.3Hz), 1.10(3H,d, J=6.9Hz) , 1.14(3H,d,J=6.8Hz) , 1.64-1.70(2H,m), 2.75-2.83(2H,m) , 3.53( lH,q, J=7.OHz) , 3.83(2H,t,J=6.9Hz), 5.59(lH,s), 7.12(lH,s), 7.16 ( lH,dd,J=5.8 and 7.8Hz), 7.24(lH,dd, =6.3 and 7.5Hz), 7.41(lH,s), 7.81(1H,S), 10.05(lH,s). Example 224
Ethyl l-acetyl-4-( 2-chlorophenyl)-4, 7-dihydro-6-propyl-IH- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was obtained as colorless crystals from ethyl 4- (2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[3,4-b]pyridine-5-carboxylate, dimethylaminopyridine and acetyl chloride in the same manner as in Example 204. MP:75-76°C.
Anal. Calcd. for:C20H22ClN3O3:C,61.93;H,5.72;N,10.83.
Found:C, 61.77 ;H, 5.78;N, 10.90.
MS(EI):387(M+).
-Η-NMR ( 400MHz , DMSO-de ) δ(ppm) : 0 .89 ( 3H,t, J=7 .3Hz ) , 0.97 ( 3H,t, J=7 .3Hz ) , 1.60-1.66 ( 2H,m) , 2 .66 ( 3H, s ) , 2 .85-
2.90(2H,m), 3.81(2H,q,J=7.3Hz) , 5.57 ( 1H,S) ,7.14-7.18(2H,m) , 7.26(lH,dd,J=7.3 and 7.6Hz), 7.38(lH,s), 7.39 ( lH,d,J=8.1Hz) , 8.90(lH,s). Example 225 Ethyl 2-acetyl-4-( 2-chlorophenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 224 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as a colorless amorphous solid. MS (El) :387(M+) .
IR(KBr):v=3306, 1699, 1633, 1601, 1523, 1371, 1197, 1086 cm-1. XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.87 (3H,t,J=7.OHz) , 0.96(3H,t,J=7.3Hz), 1.66(2H,m), 2.44(3H,s), 2.65-2.85 (2H,m) , 3.80(2H,q,J=7.0Hz), 5.58(lH,s), 7.09-7.22(3H,m) , 7.40(lH,d,J=7.9Hz), 7.80(lH,s), 10.0(lH,s). Example 226
Ethyl l-butoxycarbonyl-4-( 2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-IH- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate, dimethylaminopyridine and butyl chloroformate in the same manner as in Example 204. MS ( El ) : 445 ( M+ ) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.87 (3H,t, J=7.3Hz) ,
0.88(3H,t,J=7.lHz) , 1.33-1.38 (2H,m) , 1.60-1.69(4H,m) , 2.85-
2.87(2H,m), 3.82 (2H,q,J=7.3Hz) , 4.36 (2H,t,J=6.5Hz) , 5.55(lH,s), 7.13-7.17(2H,m), 7.25( lH,dd,J=6.4 and 6.5Hz), 7.34(lH,s),
7.37(lH,d,J=7.5Hz), 8.61(lH,s).
Example 227
Ethyl 2-butoxycarbonyl-4-( 2-chlorophenyl) -4, 7-dihydro-6- propyl-2H-pyrazolo[3 , 4-b]pyridine-5-carboxylate Through the column of silica gel column chromatography used in Example 226 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as a colorless amorphous solid.
MS (El) :445(M+) . 1H-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.86(3H,t,J=7 -3Hz) ,
0.87(3H,t,J=7.3Hz), 0.96(3H,t, J=7.3Hz) , 1.31-1.32(2H,m) ,
1.61(4H,m), 2.73-2.80(2H,m),3.80(2H,q,J=7.3Hz),
4.24(2H,t,J=6.5Hz) , 5.57(lH,s), 7.09-7.22 (3H,m) ,
7.39(lH,d,J=7.8Hz) , 7.70(lH,s), 9.98(lH,s). Example 228
Ethyl 4-( 2-chlorophenyl) -l-cinnamoyl-4 , 7-dihydro-6-propyl-1H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 4-(2-chlorophenyl) -4, 7-dihydro-6-propyl-1H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate, dimethylaminopyridine and cinnamoyl chloride in the same manner as in Example 204.
MP:131-134°C.
Anal. Calcd. for:C27H26ClN303:C,68.13;H,5.51;N,8.83. Found:C, 68.04;H, 5.58 ;N, 8.75. MS(EI) :475(M+) .
IR(KBr) :v=3396, 1687, 1624, 1521, 1394, 1207, 1087 cm"1. XH-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.89(3H,t,J=7 ,0Hz) , 0.98(3H,t,J=7.lHz), 1.62-1.68 (2H,m) , 2.89-2.91(2H,m) , 3.84(2H,q,J=7.0Hz), 5.60(lH,s), 7.16( lH,dd,J=7.4 and 7.8Hz),
7.18(lH,d,J=6.3Hz), 7.26( lH,dd,J=6.3 and 7.4Hz),
7.39(lH,d,J=7.8Hz), 7.45(lH,s), 7.46(3H,m), 7.67( lH,d,J=6.1Hz) ,
7.69-7.76(2H,m), 7.91( lH,d,J=7.4Hz) , 9.01(lH,s). Example 229
Ethyl 4-( 2-chlorophenyl)-l-cinnamoyl-4, 7-dihydro-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
Through the column of silica gel column chromatography used in Example 228 was further flowed hexane-ethyl acetate (3:1) as an eluent, the title compound was obtained as colorless crystals.
MS (El) :475(M+) .
IR(KBr) :v=3304, 1695, 1674, 1601, 1521, 1365, 1168, 1095 cm"1.
^-NMR ( 400MHz, DMSO-de )δ(ppm) : 0.86(3H,t, J=7.OHz) , 0.98(3H,t,J=7.3Hz), 1.65-1.70(2H,m) , 2.76-2.87(2H,m) ,
3.82(2H,q,J=7.0Hz), 5.62(lH,s), 7.12-7.18 (2H,m) ,
7.24(lH,dd,J=7.3 and 7.3Hz), 7.42( lH,d, J=7.8Hz) , 7.45-
7.46(3H,m), 7.60(lH,d,J=6.lHz) , 7.62-7.70 (2H,m) ,
7.86(lH,d,J=6.lHz) , 7.85(lH,s), 10.09(lH,s). Example 230
Ethyl 4-(2-chlorophenyl)-4, 7-dihydro-3-methyl-6-propyl-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from 2-ethyIbenzaldehyde, 3-amino-5-methylpyrazol and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:164-165°C.
MS (El) :359(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.94(3H,t,J=7 ,0Hz) ,
1.02(3H,t,J=7.3Hz), 1.61(2H,m), 1.89(3H,s), 2.60-2.85 (2H,m) , 3.80(2H,q,J=7.0Hz), 5.44(lH,s), 7.00-7.30(4H,m) , 9.39(lH,s),
11.66(1H,S).
Example 231
Ethyl 4-(2-chlorophenyl)-4, 7-dihydro-2-methyl-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
A solution of ethyl 3-ketohexanoate (7.5 g) , 2- chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean- Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-( 2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2- (2-chlorophenyl)methylene-3-oxohexanoate ( (E) /( Z)=1: 1 mixture, 2.8 g) , 3-amino-l-methylpyrazole (0.25 g) and p- toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals. MP:150-151°C. MS(El) :359(M+) . ^-N R ( 400MHz,DMSO-de)δ(ppm) : 0.83(3H,t,J=7.OHz) ,
0.96(3H,t,J=6.5Hz), 1.65(2H,m), 2.67-2.85(2H,m) , 3.58(3H,s), 3.77(2H,q,J=7.0Hz), 5.55(lH,s), 7.07-7.ll(2H,m) , 7.19(lH,dd,J=7.4 and 7.8Hz), 7.24(lH,d,J=8.3Hz) , 9.45(lH,s). Example 232 Ethyl 4-(2-chlorophenyl)-4, 7-dihydro-l-methyl-6-propyl-lH- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as a colorless amorphous solid from ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ( (E) /( Z)=1 : 1 mixture) , 3-amino-2-methylpyrazole and p- toluenesulfonic acid. MS(EI) :359(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.84(3H,t,J=7.OHz) , 1.00(3H,t,J=7.lHz), 1.67-1.69(2H,m), 2.70-2.88 (2H,m) ,
3.65(3H,s), 3.80(2H,q,J=7.0Hz),5.55(lH,S), 6.96(lH,S), 7.08- 7.12(2H,m), 7.20(lH,dd,J=6.8 and 7.8Hz), 7.35( lH,d,J=7.8Hz) , 9.31(1H,S). Example 233 Ethyl 4, 7-dihydro-l-methyl-4- ( naphthalen-1-yl) -6-propyl-lH- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
A solution of ethyl 3-ketohexanoate (6.6 g), 1- naphthaldehyde (7.34 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 mL) was heated under reflux for 3 hours and the reaction mixture was dehydrated using a Dean- Stark condenser. The solvent was evaporated and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2- (naphthalen-1-yl)methylene-3-oxohexanoate ( (E)/(Z)=1:1 mixture) as a yellow oil. The title compound was obtained as a colorless amorphous solid from ethyl 2-(naphthalen-l- yl)methylene-3-oxohexanoate ( (E)/(Z)=1:1 mixture) , 3-amino-2- methylpyrazole and p-toluenesulfonic acid. MS(EI) :375(M+) . XH-NMR (400MHz,DMSO-de )δ(ppm) : 0.60 ( 3H,t,J=6.9Hz) ,
1.03(3H,t,J=6.9Hz) ,1.74(2H,m), 2.78-2.85(2H,m) , 3.65(3H,s), 3.68(2H,q,J=6.9Hz),5.94(lH,s), 6.76(lH,s), 7.20( lH,d, J=7.3Hz) , 7.37(lH,dd,J=7.4 and 7.8Hz), 7 -50(lH,dd, =6.9 and 7.8Hz), 7.58(lH,m), 7.67(lH,d,J=8.3Hz), 7.88 ( lH,d,J=8 ,3Hz) , 8.42(lH,d,J=8.8Hz) , 9.26(lH,s). Example 234
Ethyl 4-( 3-chlorophenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- ]pyridine-5-carboxylate The title compound was obtained as colorless crystals from 3-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanpate in the same manner as in Example 25.
MP:140-143°C. Anal. Calcd. for :Cι8H20ClN3O2 2/5 H20:C,61.24;H,5.94;N, 11.90.
Found:C,61.50;H,5.94;N,11.99.
MS (El) :345(M+) .
IR(KBr) :v=3263, 1736, 1666, 1591, 1514, 1275, 1222, 1207, 1087 cm"1.
^-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.95(3H,t,J=7.0Hz) , 1.04(3H,t,J=7.1Hz), 1.58-1.63(2H,m) , 2.63-2.81(2H,m) ,
3.86(2H,q,J=7.0Hz) , 5.11(lH,s), 7.08( lH,d,J=7.8Hz) , 7.12(2H,m),
7.21(lH,d,J=8.3Hz), 7.26(lH,s), 9.84(lH,s), 11.99(lH,s).
Example 235
Ethyl 4-( 4-chlorophenyl) -4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from 4-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:159-161°C. Anal. Calcd. for :Cι8H20ClN3O2 1/5 H20:C,61.87;H,5.88;N, 12.03.
Found:C,61.92;H,6.23;N,11.95.
MS (El) :345(M+) .
IR(KBr) :v=3263, 1730, 1662, 1593, 1516, 1207, 1091 cm"1.
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.92(3H,t,J=7.OHz) , 0.95(3H,t,J=7.3Hz) , 1.60(2H,m), 2.64-2.80 (2H,m) ,
3.84(2H,q,J=7.0Hz) , 5.10(1H,S), 7.13(2H,d, J=7.3Hz) , 7.22(lH,s),
7.25(2H,d,J=7.3Hz), 9.45(lH,s), 11.96(lH,s).
Example 236
Ethyl 4 , 7-dihydro-4-( 4-methyl-lH-imidazol-5-yl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from 4-methyl-5-imidazolecarboxaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:219-220°C.
Anal. Calcd. for:C16H2ιN502 1/2 H20:C,59.61;H,6.25;N,21.72.
Found: C, 59.34 ;H, 6.48 ;N, 22.06.
MS(EI) :315(M+) . IR(KBr):v=3113, 2980, 1687, 1620, 1568, 1244, 1159 cm"1.
^-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.94(3H,t,J=7.3Hz) ,
1.08(3H,t,J=7.0Hz), 1.58-1.59 (2H,m) , 2.21(3H,s), 2.58-
2.79(2H,m), 3.97(2H,q,J=7.3Hz), 5.50(lH,s), 6.14(lH,s),
7.14(1H,S), 7.19(1H,S), 9.78(lH,s), 11.53(lH,s). Example 237
Ethyl 4, 7-dihydro-4-( 1-methyl-lH-imidazol-2-yl)-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from 1-methy1-2-imidazolecarboxaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
MP:209°C.
Anal. Calcd. for:Cι6H21N502 3/5 H20:C,59.28;H, 6.28;N,21.60.
Found:C,59.00;H,6.52;N,21.55.
MS(EI) :315(M+) . IR(KBr) :v=3254, 3184, 3080, 1685, 1593, 1518, 1278, 1207, 1078 cm"1.
^- MR ( 400MHz, DMSO-de )δ (ppm) : 0.91 ( 3H,t, J=6.8Hz) ,
0.93(3H,t,J=7.3Hz) , 1.55-1.61(2H,m) , 2.57-2.80(2H,m) ,
3.44(3H,s), 3.87(2H,q,J=6.8Hz), 5.29(lH,s), 6.56(lH,s),
6.84(1H,S), 7.27(1H,S), 9.38(lH,s), 11.97(lH,s). Example 238
Ethyl 4, 7-dihydro-4-( lH-imidazol-5-yl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from 3-imidazolecarboxyaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
MP:200°C.
Anal. Calcd. for:Ci5Hi7N502 1/2 H20:C,58.43;H,5.88;N,22.71.
Found:C,58.53;H,6.25;N,22.93. MS(EI) :301(M+) .
IR(KBr) :v=3217, 1655, 1585, 1506, 1226, 1205, 1084 cm"1. 1H-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.92(3H,t,J=7.3Hz) , 1.01(3H,t,J=7.3Hz), 1.57-1.59 (2H,m) , 2.59-2.74(2H,m) , 3.90(2H,q,J=7.3Hz), 5.12(1H,S), 6.35(1H,Ξ), 7.35(lH,s), 7.38(1H,S), 9.21(1H,S), 11.91(lH,s). Example 239
Ethyl 4-(2,1, 3-benzoxadiazol-4-yl) -6-butyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3- ketoheptanoate in the same manner as in Example 1.
MP:213°C.
Anal. Calcd. for:C19H21N5θ3:C,62.11;H,5.76;N,19.06. Found:C,62.08;H,5.75;N,18.95.
MS(EI) :367(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.77 (3H,t,J=7.3Hz) ,
0.92(3H,t,J=7.3Hz), 1.32-1.40(2H,m) , 1.60-1.64(2H,m) , 2.76-
2.86(2H,m), 3.76-3.82(2H,m), 5.68(lH,s), 7.11( lH,d, J=6.6Hz) , 7.22(lH,s), 7.51(lH,dd,J=9.0Hz and 6.6Hz), 7.77( lH,d, J=9.OHz) ,
9.65(1H,S), 12.00(1H,S).
Example 240
Ethyl 4-(2, 1 , 3-benzoxadiazol-4-yl)-6-ethyl-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate The title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl 3- ketopentanoate in the same manner as in Example 1.
MP:196°C.
Anal. Calcd. for:Cι7Hι7N503:C, 60.17;H,5.05;N,20.64. Found:C,60.09;H,5.15;N,20.41. MS (El) :339(M+).
XH-NMR ( 400MHz, DMSO-d6 )δ (ppm) : 0.75 (3H,t, J=7.3Hz), 1.21 (3H, t, J=7.3Hz), 2.83(2H,q,J=7.3Hz), 3.73-3.84(2H,m) , 5.68(lH,s), 7.12(lH,d,J=6.6Hz), 7.22(lH,s), 7.50( lH,dd,J=9.OHz and 6.6Hz) ,
7.77(lH,d,J=9.0Hz), 9.68(lH,s), 12.01(lH,s).
Example 241
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-6- (thiophen-2-yl) -2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:174°C. Anal. Calcd. for :Cι7HnClN4S 1/10 H20:C,59.94;H, 3.31;N, 16.45.
Found:C,59.82;H,3.48;N,16.93.
MS(EI) :338(M+) .
^- MR ( 400MHz,DMSO-dg)δ(ppm) : 5.50(lH,s), 7.18( lH,dd, J=7.3Hz and 7.2Hz), 7.24-7.35(4H,m) , 7.45( lH,d, J=7.8Hz) , 7.60(lH,d,J=3.6Hz) , 7.77 ( lH,d, J=3.9Hz) , 10.08(lH,s),
12.29(lH,s) .
Example 242
5-Cyano-4 , 7-dihydro-4-( 2-methoxyphenyl) -6-(thiophen-2-yl) -2H- pyrazolo[ 3 , 4-b] yridine The title compound was prepared from methyl thiophene-2- carboxylate, 2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:215°C.
Anal. Calcd. for:C18H14N4OS:C,64.65;H,4.22;N, 16.75. Found:C,64.66;H,4.32;N,17.02.
MS(EI) :334(M+) .
^-NMR ( 400MHz,DMSO-de)δ(ppm): 3.85(3H,S), 5.34(lH,s), 6.93(lH,dd,J=7.3Hz and 7.2Hz), 7.01(lH,d, J=7.3Hz) , 7.14- 7.25(4H,m), 7.60(lH,d,J=3.6Hz), 7.77( lH,d,J=5.1Hz) , 9.91(lH,s), 12.17(1H,S). Example 243
5-Cyano-4, 7-dihydro-4-( 2-methylthiophenyl) -6-(thiophen-2-yl) - 2H-pyrazolo[ 3, 4-b] yridine The title compound was prepared from methyl thiophene-2- carboxylate, 2-methylthiobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:222°C. 5 Anal. Calcd. for:C18Hι4N4S2 2/5 H2O:C,60.44;H,4.17;N,15.66. Found:C,60.58;H,4.44;N,15.35. MS(EI) :350(M+) . H-NMR ( 400MHz, DMSO-de )δ(ppm) : 2.49(3H,s), 5.48(1H,S), 7.17-
7.28(5H,m), 7.33(lH,d,J=7.3Hz), 7.60( lH,d,J=3.7Hz) , o 7.77(lH,d,J=3.9Hz) , 10.01(lH,s), 12.22(lH,s).
Example 244
5-Cyano-4, 7-dihydro-4-( 2-nitrophenyl) -6-(thiophen-2-yl) -2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-2- 5 carboxylate, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:165°C.
Anal. Calcd. for:C17HnN502S:C,58.44;H,3.17;N,20.05.
Found:C, 58.15;H, 3.42 ;N, 20.38. 0 MS(EI) :349(M+) .
XH-NMR (400MHz, DMSO-de)δ(ppm) : 5.54(lH,s), 7.18( lH,dd, J=7.3Hz and 7.2Hz), 7.34(lH,s), 7.48-7.55(2H,m) ,
7.60(lH,d,J=3.7Hz),7.72-7.79(2H,m), 7.92( lH,d,J=8.1Hz) ,
10.16(1H,S), 12.35(lH,s). 5 Example 245
4- ( 2 , 1 , 3-Benzothiadiazol-4-yl) -5-cyano-4, 7-dihydro-6-
(thiophen-2-yl) -2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2,l,3-benzothiadiazol-4-aldehyde and 3- 0 aminopyrazole in the same manner as in Example 95.
MP:254°C.
Anal. Calcd. for:C17HioN6S2:C,56.34;H,2.78;N,23.19.
Found:C, 56.01;H, 2.91;N, 23.19. MS(EI) :362(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 5.84(lH,s), 7.19 ( lH,dd, J=4.4Hz and 4.3Hz), 7.28(lH,s), 7.55( lH,d,J=6.8Hz) , 7.65( lH,d, J=3.7Hz) , 7.72-7.79(2H,m), 7.99 ( lH,d, J=8.8Hz) , 10.14(lH,s), 12.21(lH,s). Example 246
5-Cyano-4,7-dihydro-4-(naphthalen-l-yl)-6-(thiophen-2-yl)-2H- pyrazolo[3 , 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, naphthalene-1-aldehyde and 3-aminbpyrazole in the same manner as in Example 95.
MP:214°C.
Anal. Calcd. for:C21Hι4N4S:C,71.16;H,3.98;N,15.81.
Found:C, 70.75 ;H, 3.96 ;N, 15.85.
MS (El) :354(M+) . XH-NMR (400MHz,DMSO-de)δ(ppm) : 5.87( IH, s) , 7.13( 1H,S) ,
7.18(lH,dd,J=4.6Hz and 3.9Hz), 7.45-7.54( 4H,m) ,
7.62(lH,d,J=3.9Hz), 7.78 ( lH,d, J=4.9Hz) , 7.83( lH,d,J=8.1Hz) ,
7.95(lH,d,J=9.3Hz) , 8.31( lH,d, J=7.3Hz) , 10.09(lH,s),
12.17(1H,S) . Example 247
5-Cyano-4- ( 2 , 3-dichlorophenyl) -4 , 7-dihydro-6-(thiophen-2-yl) -
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:232°C.
Anal. Calcd. for:C17Hι0Cl2N4S 1/10 H20:C,54.44;H,2.74;N, 14.94.
Found:C,54.08;H,2.90;N,15.29.
MS (El) :373(M+). 1H-M ( 400MHz, DMSO-de ) δ(ppm) : 5.58(lH,s), 7.18( lH,dd, J=7.3Hz and 7.2Hz), 7.32-7.41(3H,m), 7.54(lH,dd, J=7.3Hz and 1.5Hz),
7.60(lH,d,J=3.7Hz), 7.78( lH,d, J=4.9Hz) , 10.14(lH,s),
12.32(lH,s) . Example 248
5-Cyano-4, 7-dihydro-4-(2-methylphenyl) -6-phenyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl benzoate, 2- methylbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:246°C.
Anal. Calcd. for:C20H16N 1.0 H20:C,72.71;H,5.49;N, 16.96. Found:C, 72.50;H, 5.26;N, 17.20. MS(EI) :312(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 2.38(3H,s), 5.29(lH,s), 7.11-
7.23(5H,m), 7.47-7.49(3H,m), 7.55-7.58 (2H,m) , 9.94(lH,s),
12.17(1H,S).
Example 249 5-Cyano-4, 7-dihydro-4-(2-methylphenyl)-6-(thiophen-2-yl)-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2-methyIbenzaldehyde and 3-aminopyrazole in the same manner as in Example 95. MP:276°C.
Anal. Calcd. for:Cι8H14N4S:C,67.90;H,4.43;N, 17.60.
Found:C,67.93;H,4.54;N,17.64.
MS(EI) :318(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 2.36(3H,s), 5.28(lH,s), 7.11- 7.18(5H,m), 7.24(lH,s), 7.55( lH,dd,J=3.7Hz and 1.0Hz),
7.74(lH,dd,J=5.9Hz and 1.0Hz), 9.95(lH,s), 12.22(lH,s).
Example 250
4-(2-Chlorophenyl) -5-cyano-6-dimethoxymethyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl dimethoxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
^-H-NMR (400MHz,DMSO-de )δ(ppm) : 3.39(6H,s), 5.18(lH,s), 5.43(lH,s), 7.23-7.27(3H,m), 7.32-7.35( lH,m) ,
7.44(lH,d,J=7.8Hz) , 9.65(lH,s), 12.21(lH,s).
Example 251
4-(2-Chlorophenyl) -5-cyano-6-formyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine
4-(2-Chlorophenyl) -5-cyano-6-dimethoxymethyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine (4.4 g) was added to trifluoroacetic acid (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and crystallized from ethyl acetate (50 ml) to give the title compound (1.9 g) as yellow crystals.
1H-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 5.63(lH,s), 7.27-7.46(5H,m) ,
7.48(lH,d,J=7.lHz), 9.73(lH,s), 10.17(lH,s), 12.34(lH,s). Example 252
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-hydroxymethyl-2H- pyrazolo[ 3, 4-b]pyridine
To a suspension of 4-(2-chlorophenyl)-5-cyano-6-formy1-
4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine (400 mg) in methanol (10 ml) was added sodium borohydride (53 mg) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. 10% Hydrochloric acid was added to the reaction mixture, and a saturated sodium hydrogencarbonate solution was added. The precipitated crystals were collected by filtration and washed with ethanol to give the title compound (295 mg) as yellow crystals.
MP:205-210°C (decomposition).
Anal. Calcd. for:Ci4HuClN40 1/4 H20:C,57.74;H,3.98;N, 19.24.
Found:C, 57.38 ;H, 3.93;N, 18.94. MS(EI) :286(M+) . αH-NMR (400MHz, DMSO-de )δ (ppm) : 4.29(2H,d, =5.6Hz) , 5.38(lH,s),
5.49(lH,t,J=5.6Hz), 7.22-7.34( 4H,m) , 7.43( lH,d, J=8 ,0Hz) ,
9.60(1H,S), 12.17(lH,s). Example 253
4-(2-Chlorophenyl)-5-cyano-4, 7-dihydro-6-(trans-2- ethoxycarbonylethenyl) -2H-pyrazolo[ 3 , 4-b]pyridine To a suspension of sodium hydride (94 mg) in dimethoxyethane (10 ml) was added ethyl diethylphosphonoacetate (528 mg) and the mixture was stirred at room temperature for 15 minutes. Under ice-cooling, 4-(2- chlorophenyl) -5-cyano-6-formyl-4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine (670 mg) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give the title compound (560 mg) as yellow crystals. MP:240-243°C (decomposition). Anal. Calcd. for :Cι8Hι5ClN402 1/2 H20:C,59.43;H,4.43;N, 15.40. Found:C,59.53;H,4.26;N,15.31. MS(EI) :354(M+).
1H- MR ( 400MHz,DMSO-d6 ) δ(ppm) : 1.25(3H,d, J=7.1Hz) , 4.21(2H,q,J=7.lHz), 5.52(lH,s), 6.93( lH,d,J=15.9Hz) , 7.27- 7.46(6H,m), 10.09(lH,s), 12.31(lH,s). Example 254
4-( 2-Chlorophenyl) -5-cyano-6-( 2-ethoxycarbonylethyl) -4, 7- dihydro-2H-pyra2olo[ 3, 4-b]pyridine
A suspension of 4- (2-chlorophenyl) -5-cyano-4,7-dihydro- 6-(trans-2-ethoxycarbonylethenyl) -2H-pyrazolo[ 3 , 4-b]pyridine (260 mg) and 5% palladium on carbon (110 mg) in ethanol was subjected to catalytic hydrogenation at room temperature for 5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give a yellow solid. The yellow solid was crystallized from ethyl acetate-diisopropyl ether to give the title compound (160 mg) as pale-yellow crystals. MP:172-174°C. MS(EI) :356(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 1.18(3H,t,J=7.3Hz) ,2.60-
2.80(4H,m), 4.08(2H,q,J=7.3Hz) , 5.35(lH,s), 7.20-7.31 (4H,m) , 7.42(lH,d,J=8.0Hz) , 9.84(lH,s), 12.16(lH,s).
Example 255
4-(2 , 1, 3-Benzoxadiazol-4-yl) -5-cyano-6-dimethoxymethyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl dimethoxyacetate, 2,l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 94.
^- MR ( 400MHz,DMSO-d6)δ(ppm) : 3.35(3H,s), 3.38(3H,s), 5.16(lH,s), 5.47(1H,S), 7.26(lH,s), 7.42( lH,d,J=6.6Hz) , 7.60(lH,dd,J=6.6,8.5Hz), 7.94( lH,d,J=8.5Hz) , 9.77(lH,s), 12.19(lH,s). Example 256 o
4-( 2, 1, 3-Benzoxadiazol-4-yl)-5-cyano-6-formy1-4, 7-dihydro-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from 4-(2, 1,3- benzoxadiazol-4-yl)-5-cyano-6-dimethoxymethyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine in the same manner as in Example 251.
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 5.71(lH,s), 7.33(1H,S), 7.56(lH,d,J=6.6Hz), 7.62( lH,dd,J=6.6,8.8Hz) , 7.98(lH,d,J=8.8Hz), 9.73( lH,s) , 10.32( 1H,S) , 12.32(lH,s). Example 257
4-(2, 1,3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- hydroxymethyl-2H-pyrazolo[3, 4-b]pyridine
The title compound was prepared from 4-(2, 1,3- benzoxadiazol-4-yl) -5-cyano-6-formyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine in the same manner as in Example 252. MP:215-220°C (decomposition).
Anal. Calcd. for:C14H10N6O2 1/2 H20:C,55.44;H,3.66;N,27.71. Found:C,55.32;H,3.68;N,27.31. MS(EI) :294(M+) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 4.30(2H,s), 5.45(lH,s),
5.52(lH,brs), 7.27(lH,s), 7.42( lH,d,J=6.6Hz) ,
7.59(lH,dd,J=6.6,9.0Hz), 7.93( lH,d,J=9.OHz) , 9.71(lH,s), 12.16(lH,s).
Example 258
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6-(trans-2- ethoxycarbonylethenyl) -2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from 4- ( 2 , 1 , 3- benzoxadiazol-4-yl)-5-cyano-6-formyl-4,7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine in the same manner as in Example 253.
XH-NMR ( 400MHz, DMSO-de )δ(ppm) : 1.24( 3H,d, J=7.1Hz) ,
4.21(2H,q,J=7.1Hz) , 5.59(lH,s), 6.96( lH,d, J=16.1Hz) ,
7.32(lH,s), 7.39(lH,d,J=16.lHz), 7.50(lH,m), 7.59(lH,m), 7.96(lH,d,J=8.3Hz) , 10.21(lH,s), 12.29(lH,s).
Example 259
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-( 2- ethoxycarbonylethy1) -4, 7-dihydro-2H-pyrazolo[ 3, 4-b] yridine The title compound was prepared from 4-(2, 1,3- benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(trans-2- ethoxycarbonylethenyl)-2H-pyra2θlo[3, 4-b]pyridine in the same manner as in Example 254.
MS(EI) :364(M+) .
1H-NMR ( 400MHz , DMSO-de ) δ(ppm) : 1 . 18 ( 3H, t, J=7 . 1Hz ) , 2 .66- 2 .80 ( 4H,m) , 4 .08 ( 2H, q, J=7 . lHz ) , 5 .40 ( lH, s ) , 7 .26 ( lH, s ) ,
7.42(lH,d,J=6.6Hz) , 7.58( lH,dd,J=6.6, 9.OHz) ,
7.92(lH,d,J=9.0Hz), 9.96(lH,s), 12.16(lH,s).
Example 260 4-(2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6-isopropyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl isobutyrate,
2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for:C17H14BrN5:C,55.45;H,3.83;N,19.02.
Found:C,55.30;H,3.91;N,18.98.
MS(EI) :368(M+) . -NMR ( 400MHz,DMSO-dg)δ(ppm) : 1.23(3H,d,J=6.8Hz) ,
1.27(3H,d,J=6.8Hz) , 3.03( lH,m) ,5.45( IH, s) , 7.33(lH,s), 7.55-
7.82(2H,m), 7.83(lH,dd,J=2.0,7.1Hz), 9.76(lH,s), 12.25(lH,s).
Example 261
4- ( 2-Bromophenyl) -5-cyano-4, 7-dihydro-6-isopropyl-2H- pyrazolo[ 3, 4-b]pyridine acetonitrile
The title compound was prepared from methyl isobutyrate,
2-bromobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C. Anal. Calcd. for:Cα6H15BrN4C2H3N:C,56.26;H, 4.72;N, 18.22. Found:C,56.05;H,4.56;N,17.09. MS(EI) :343(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.24(3H,d, J=7.1Hz) ,
1.27(3H,d,J=7.1Hz), 2.06(3H,s), 3.06(lH,m), 5.23(lH,s), 7.13- 7.18(lH,m), 7.22(lH,d,J=7.6Hz) , 7.27(lH,s),
7.36(lH,dd,J=1.2,7.6Hz), 7.59( lH,dd, J=l .2,8.OHz) , 9.64(lH,s),
12.17(lH,s) .
Example 262
5-Cyano-4, 7-dihydro-6-isopropyl-4-( 2-nitrophenyl) -2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl isobutyrate,
2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:224°C.
MS(EI) :309(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 1.23(3H,d,J=7.1Hz) ,
1.28(3H,d,J=7.lHz), 3.03(lH,m), 5.36(lH,s), 7.27(lH,s), 7.43- 7.49(2H,m), 7.70(lH,dd,J=1.2,8.8Hz), 7.89 ( lH,dd,J=1.2,8.3Hz) ,
9.71(lH,s), 12.23(lH,s).
Example 263
5-Cyano-4- ( 2 , 3-dichlorophenyl) -4 , 7-dihydro-6-isopropyl-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl isobutyrate,
2,3-dichlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for:C16Hi4Cl2N4:C,57.67;H,4.23;N, 16.89. Found:C,57.74;H,4.27;N,16.89.
MS(EI) :333(M+) .
XH-M ( 400MHz,DMSO-de)δ(ppm) : 1.23 ( 3H,d,J=7.1Hz) ,
1.27(3H,d,J=7.1Hz), 3.04(lH,m), 5.42(lH,s), 7.23( lH,d, J=7.6Hz) ,
7.31(lH,s), 7.35(lH,dd,J=7.6,7.8Hz), 7.51( lH,dd, =1.5, 7.8Hz) , 9.70(1H,S), 12.21(1H,S).
Example 264
4- ( 2, 1, 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-isopropyl-
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl isobutyrate, 2, l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:222-223°C (decomposition).
Anal. Calcd. for:C16Hι4NeO:C,62.71;H,4.61;N,27.44.
Found:C,62.71;H,4.65;N,27.45. MS(EI) :306(M+) .
XH-NMR ( 400MHz,DMSO-de)δ(ppm): 1.24(3H,d,J=7.1Hz) ,
1.25(3H,d,J=7.lHz), 3.03(lH,m), 5.39(lH,s), 7.26(lH,s),
7.40(lH,d,J=6.6Hz), 7.58 ( lH,dd,J=6.6,8.8Hz) , 7.92(lH,d,J=8.8Hz) , 9.74(lH,s), 12.15(lH,s).
Example 265
5-Cyano-4, 7-dihydro-6-isopropy1-4-(2-methoxyphenyl)-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl isobutyrate,
2-methoxybenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for:Cι7H18N4O:C,69.37;H,6.16;N,19.03. Found:C,69.13;H,6.21;N,19.54.
MS (El) :294(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 1.23( 3H,d, J=7.1Hz) ,
1.28(3H,d,J=7.lHz) , 3.09(lH,m), 3.83(3H,s), 5.19(lH,s),
6.90(lH,dd,J=7.4,7.6Hz), 6.99 ( lH,d,J=7.6Hz) , 7.05(lH,dd,J=1.7,7.4Hz), 7.15-7.19(2H,m) , 9.47(lH,s),
12.04(1H,S) .
Example 266
4-( 2-Chlorophenyl) -5-cyano-6-cyclopropyl-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl cyclopropanecalboxylate, 2-chlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for :Cι6H13ClN4:C, 64.76;H,4.42;N, 18.88. Found:C,64.71;H,4.50;N,19.05. MS(EI) :296(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm ) : 0.89-0.93(2H,m) , 1.00-1.15(2H,m) , 2.01(lH,m),5.35(lH,s), 7.22-7.26(3H,m) , 7.31-7.34( lH,m) , 7.42(lH,d,J=7.8Hz), 9.14(lH,s), 12.16(lH,s). Example 267
4- ( 2-Bromophenyl) -5-cyano-6-eyelopropy1-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl cyclopropanecalboxylate, 2-bromobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. for :Cι6Hι3BrN4:C,56.32;H,3.84;N, 16.42. Found:C,56.18;H,3.90;N,16.48.
MS (El) :341(M+) .
1H-NMR ( 400MHz, DMSO-d6)δ (ppm) : 0.90-0.93 (2H,m) , 1.00-1.15(2H,m) ,
2.01(lH,m), 5.34(lH,s), 7.13-7.22(2H,m) ,7.27(lH,s) , 7.34-
7.38(lH,m), 7.59(lH,d,J=6.8Hz) , 9.15(lH,s), 12.16(lH,s). Example 268
4- ( 2-Bromo-3-cyanophenyl) -5-cyano-6-cyclopropyl-4, 7-dihydro-
2H-pyrazolo[ 3, -b]pyridine 1/4 acetonitrile
The title compound was prepared from methyl cyclopropanecalboxylate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:>250°C.
Anal. Calcd. f or : Cι7Hι2BrN5H20 1/4 CH3CN:C,53.28;H,3.77;N, 18.64.
Found.: C,53.28;H, 3.72;N, 18.81.
MS(EI) :366(M+) . 1H-NMR ( 400MHz, DMSO-de )δ (ppm ) : 0.90-0.93 ( 2H,m) , 1.03-1.08 (2H,m) ,
1.96-2.00(lH,m), 5.45(lH,s), 7.32(lH,s), 7.54-7.60(2H,m) ,
7.83(lH,dd,J=1.7,7.1Hz), 9.27(lH,s), 12.25(lH,s).
Example 269
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-cyclopropyl-4 , 7- dihydro-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl cyclopropanecalboxylate, 2,1, 3-benzoxadiazole-4-aldehyde and
3-aminopyrazole in the same manner as in Example 94.
MP:200-201°C (decomposition). Anal. Calcd. for:C16Hι2N60 H20:C,59.62;H,4.38;N,26.07.
Found:C,59.93;H,4.05;N,26.19.
MS(EI) :304(M+) .
1H-NMR ( 400MHz, DMSO-de )δ(ppm) : 0.88-0.93( 2H,m) , 1.01-1.12 ( 2H,m) , 1.99(lH,m), 5.39(lH,s), 7.25(lH,s), 7.40 ( lH,d, J=6.6Hz) ,
7.59(lH,dd,J=6.6,9.0Hz), 7.92( lH,d, J=9.OHz) , 9.26(lH,s),
12.15(1H,S) .
Example 270 4-( 2-Methoxyphenyl) -5-cyano-6-cyclopropyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine 1/4 acetonitrile
The title compound was prepared from methyl cyclopropanecalboxlate, 2-methoxybenzaldehyde and 3- aminopyra2ole in the same manner as in Example 94. MP:241-243°C.
Anal. Calcd. for :Cι7Hι6N40 1/4 CH3CN:C, 69.46;H,5.58;N,19.67.
Found:C, 69.35;H, 5.56 ;N, 19.64.
MS(EI) :292(M+) .
1H- M ( 400MH2, DMSO-de )δ (ppm) : 0.90-0.92 ( 2H,m) , 0.99-1.10(2H,m) , 2.01-2.06(lH,m), 3.84(3H,s), 5.21(lH,s),
6.90(lH,dd,J=7.3,7.6Hz), 6.98-7.05(2H,m) , 7.15-7.19(2H,m) ,
8.97(1H,S), 12.04(lH,s).
Example 271
5-Cyano-6-cyclopropyl-4- ( 2 , 3-dichlorophenyl) -4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine 1/4 acetonitrile
The title compound was prepared from methyl cyclopropanecalboxylate, 2,3-dichlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:>250°C. Anal. Calcd. for:C16H12Cl2N4 1/4 CH3CN:C,58.04;H,3.76;N, 17.43.
Found:C,57.87;H,3.79;N,17.44.
MS(EI) :331(M+) .
XH-NMR ( 400MHz, DMSO-de )δ (ppm ) : 0.90-0.93 (2H,m) , 1.03-1.08(2H,m) ,
1.98-2.03(lH,m), 5.43(lH,s), 7.22( lH,d, J=7.8Hz) , 7.31(lH,s), 7.35(lH,t,J=7.8Hz), 7.51( lH,dd, J=1.5,7.8Hz) , 9.21(lH,s),
12.20(lH,s).
Example 272
5 -Cyano- 6 -cyclopropyl- 4 , 7-dihydro-4- ( 2-nitrophenyl) -2 H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl cyclopropanecalboxylate, 2-nitrobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94. MP:236-238°C (decomposition).
Anal. Calcd. for:Cι6Hι3N502:C,62.53;H,4.26;N,22.79.
Found:C,62.54;H,4.29;N,22.85.
MS(EI) :307(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm ) : 0.90-0.93 (2H,m) , 1.01-1.09 (2H,m) , 1.99(lH,m), 5.37(lH,s), 7.27(lH,s), 7.42-7.49(2H,m) ,
7.70(lH,dd,J=7.5,7.6Hz), 7.90( lH,d, J=8.1Hz) , 9.23(lH,s),
12.22(1H,S) .
Example 273
Ethyl 4-(2-chlorophenyl)-6-dimethoxymethy1-4,7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl 4, 4-dimethoxy-3- oxobutanoate in the same manner as in Example 1.
XH-NMR (400MHz,DMSO-de )δ(ppm) : 0.87(3H,t,J=7.1Hz) , 3.35(3H,s), 3.46(3H,s) ,3.82(2H,m), 5.64(lH,s), 6.11( 1H,S) ,7.10-7.14(2H,m) , 7.20-7.24(lH,m),7.27(lH,s), 7.36( lH,d,J=8.3Hz) , 8.94(lH,s), 12.05(lH,s) . Example 274
Ethyl 4-(2-chlorophenyl)-6-formy1-4, 7-dihydro-2H-pyrazolo[3,4- b]pyridine-5-carboxylate
To a solution of ethyl 4-(2-chlorophenyl) -6- dimethoxymethyl-4, 7-dihydro-2H-pyrazolo[3 , 4-b] yridine-5- carbox late (463 mg) in tetrahydrofuran (5 ml) was added IN hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography ( eluent: hexane-ethyl acetate (1:1)) to give the title compound (290 mg) as a yellow solid. XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.89 (3H,t,J=7.3Hz) , 3.91(2H,m), 5.70(lH,s), 7.14-7.24(3H,m), 7.31(lH,s), 7.40( lH,d,J=7.8Hz) , 9.64(lH,s), 10.23(lH,s), 12.19(lH,s). Example 275 Ethyl 4- (2-chlorophenyl)-4, 7-dihydro-6-isopropyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
2-Chlorobenzaldehyde (1.41 g), 3-aminopyrazole (0.83 g) and ethyl isobutyrylacetate (1.58 g) were stirred in acetic acid (10 ml) at 80°C for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The insoluble material was filtered off, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)). The purified product was crystallized from hexane-ethyl acetate to give the title compound (115 mg) as white crystals. MP:211-213°C. XH-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 0.85(3H,t,J=7.1Hz) , 1.16(3H,m), 1.28(3H,d,J=7.lHz), 3.76(2H,m), 4.35(lH,m), 5.59(lH,s), 7.07- 7.13(2H,m), 7.18-7.22(lH,m),7.24(lH,s), 7.35(lH,dd,J=1.2,8.lHz), 9.14(lH,s), 11.97(lH,s). Example 276 Ethyl 4-( 2-bromophenyl) -4, 7-dihydro-6-isopropyl-2H- pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275. MP:214-215°C.
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.84(3H,t, J=6.8Hz) , 1.16(3H,m), 1.28(3H,d,J=6.8Hz), 3.76(2H,m), 4.35(lH,m), 5.56(lH,s), 7.07- 7.13(2H,m), 7.02(lH,dd,J=7.3,7.8Hz), 7.11( lH,d, J=6.4Hz) , 7.24(lH,dd,J=7.4,7.8Hz), 7.28(lH,s), 7.52 ( lH,d,J=7.8Hz) , 9.15(lH,s), 11.98(1H,S). Example 277 Ethyl 4-( 2-chlorophenyl)-6-cyclopropyl-4,7-dihydro-2H- pyrazolo[3,4-b]pyridine-5-carboxylate
To a solution of 2-oxazolydone (20.8 g) in tetrahydrofuran (750 ml) was added n-butyllithium (1.56 M hexane solution, 153 ml) at -78°C and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclopropanecarbonyl chloride (25 g) in tetrahydrofuran (50 ml) at -78°C over 30 minutes. The mixture was stirred for 14 hours while gradually raising the temperature to room temperature. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give white crystals (26 g) . A mixture of the obtained white crystals (10 g), ethyl bromoacetate (21.5 ml) and zinc powder (25.3 g) in tetrahydrofuran (300 ml) was ultrasonicated for 2 hours and heated under reflux for 2 hours. To the reaction mixture was added 10% hydrochloric acid and the insoluble material was filtered off through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give ethyl 3-cyclopropyl-3-oxopropionate
(5.7 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl
3-cyclopropyl-3-oxopropionate in the same manner as in Example
275.
MP:190-192°C.
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.83-0.93(4H,m) , 1.10(lH,m), 3.14(lH,m), 3.80(2H,m), 5.60(lH,s), 7.08-7.12(2H,m) , 7.18-
7.22(lH,m), 7.25(1H,S), 7.34( lH,d, J=8.3Hz) , 8.62(lH,s),
11.99(lH,s) .
Example 278
4- ( 2-Bromo-3-cyanophenyl) -5-cyano-4, 7-dihydro-6- (thiophen-2- yl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:>280°C. • Anal. Calcd. for:Cι8H10BrN5S:C,52.95;H,2 ,47;N, 17.15. Found:C,52.72;H,2.69;N,17.21. MS (El) :408(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 5.62(lH,s), 7.18 ( lH,dd, J=5.1Hz and 3.7Hz), 7.40(lH,s), 7.59-7.67(3H,m) , 7.79( lH,d,J=3.9Hz) , 7.86(lH,dd,J=7.6Hz and 2.0Hz), 10.20(lH,s), 12.37(lH,s).
Example 279
4-(2-Chlorophenyl)-5-cyano-4, 7-dihydro-3-methyl-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butanoate 2- chlorobenzaldehyde and 3-amino-5-methylpyrazole in the same manner as in Example 94.
MP:260°C.
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.91(3H,t,J=7.3Hz) , 1.60- 1.65(2H,m), 1.71(3H,s), 2.33(2H,q, J=7.3Hz) , 5.27(lH,s), 7.20-
7.24(2H,m), 7.31(lH,dd,J=7.3Hz and 7.2Hz), 7.39( lH,d, J=7.3Hz) ,
9.68(lH,s), 11.83(1H,S).
Example 280 4-( 2-Chloropheny1) -5-cyano-4, 7-dihydro-3-pheny1-6-propy1-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl butanoate 2- chlorobenzaldehyde and 3-amino-5-phenylpyrazole in the same manner as in Example 94. MP:262°C.
XH-NMR (400MHz,DMSO-de)δ(ppm) : 0.89 (3H,t,J=7.3Hz) , 1.61-
1.63(2H,m), 2.36(2H,q,J=7.3Hz) , 5.61(lH,s), 7.09-7.34(9H,m) ,
9.89(1H,S), 12.62(lH,s).
Example 281 l-tert-Butoxycarbonyl-4-(2-chlorophenyl) -5-cyano-4,7-dihydro-
6-propyl-lH-pyrazolo[3, 4-b]pyridine
The title compound was obtained as a colorless amorphous solid from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H- pyrazolo[3, 4-b] yridine, dimethylaminopyridine and di-tert- butyl dicarbonate in the same manner as in Example 204.
MP:98-102°C.
MS(EI) :398(M+) .
IR(KBr) :v=3391, 2199 , 1723, 1643 , 1529, 1394, 1149 cm-1.
XH-NMR ( 400MHz, DMSO-de )δ (ppm) : 0.95(3H,t, J=7.3Hz) , 1.57(3H,s), 1.60-1.67(2H,m), 2.53-2.61(2H,m) , 5.38(lH,s), 7.25-7.31(3H,m) ,
7.35(lH,ddd,J=1.4,7.3 and 7.8Hz), 7.45( lH,d,J=8.1Hz) ,
9.20(1H,S) .
Example 282
2-tert-Butoxycarbonyl-4-(2-chlorophenyl)-5-cyano-4,7-dihydro- 6-propyl-2H-pyrazolo[3, 4-b]pyridine
Through the column of silica gel column chromatography used in Example 281 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as colorless crystals .
MP:175°C (decomposition).
Anal. Calcd. for:C2ιH23ClN402:C,63.23;H,5.81;N, 14.05.
Found:C,62.91;H,5.80;N,13.82. MS(EI) :398(M+) .
IR(KBr):v=3329,2197, 1747, 1612, 1523, 1369, 1311, 1151, 949 cm-1.
XH-NMR (400MHz,DMSO-de)δ(ppm): 0.93(3H,t,J=7.4Hz) ,
1.65(2H,q,J=7.3Hz) , 2.40-2.44(2H,m) , 2.48(9H,s), 5.32(lH,s),
7.27-7.36(3H,m), 7.45( lH,d,J=7.8Hz) , 7.68(lH,s), 10.32(lH,s). Example 283
4-(2-Chlorophenyl) -5-cyano-4,7-dihydro-l-phenylcarbamoyl-6- propyl-lH-pyrazolo[3, 4-b]pyridine
The title compound was obtained as a colorless amorphous solid from 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.
MP:138-140°C.
Anal. Calcd. for:C23H2oClN50 1/4 H20:C, 654;H,4.89;N, 16.58.
Found:C,65.20;H,5.05;N,16.17 MS(EI) :417(M+) .
IR(KBr) :v=3387, 3294,2202, 1712, 1537 cm-1.
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.95(3H,t,J=7.3Hz) ,
1.63(2H,q,J=7.4Hz) , 2.58(2H,m), 5.43(1H,S), 7.13( lH,dd,J=7.4 and 7.5Hz), 7.24-7.36(6H,m), 7.46( lH,d,J=7.8Hz) , 7.69(2H,d,J=7.8Hz), 9.46(1H,S), 10.38(lH,s).
Example 284
4-(2-Chlorophenyl) -5-cyano-4,7-dihydro-2-phenylcarbamoyl-6- propyl-2H-pyrazolo[3, 4-b]pyridine
Through the column of silica gel column chromatography used in Example 283 was further flowed hexane-ethyl acetate
(3:1) as an eluent, the title compound was obtained as a colorless oil.
MP:167-171°C. MS (El ) : 417 (M+ ) .
IR(KBr) :v=3215,2204, 1732, 1631, 1523, 1375 cm"1.
XH-NMR ( 400MHz, DMSO-de )δ(ppm) : 0.97(3H,t,J=7.4Hz) ,
1.65(2H,q,J=7.3Hz), 2.48(2H,m), 5.39(lH,s), 6.95( lH,dd, J=7.3 and 7.3Hz), 7.ll(2H,dd,J=7.3 and 7.6Hz), 7.24-7.49(4H,m) ,
7.61(2H,d,J=7.8Hz), 7.88(lH,s), 8.63(lH,s), 9.77(lH,s),
10.17(1H,S).
Example 285
2-Acetoxyacetyl-4-( 2-chlorophenyl) -5-cyano-4 , 7-dihydro-6- propyl-2H-pyrazolo [ 3 , 4-b]pyridine
The title compound was obtained as colorless crystals from 4-( 2-chlorophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine, dimethylaminopyridine and acetoxyacetyl chloride in the same manner as in Example 204. MP:149-150°C.
Anal. Calcd. for:C20H19ClN4O3:C,60.23;H,4.80;N,14.05.
Found:C,60.17;H,4.83;N,13.90.
MS(EI) ^SfM1") .
IR(KBr):v=3281, 3238, 2197, 1745, 1630, 1608, 1523, 1385, 1344, 1236, 1172 cm"1.
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.95(3H,t,J=7.3Hz) , 1.64-
1.70(2H,m), 2.44(2H,q,J=7.3Hz), 3.33(3H,s), 5.26(2H,s),
5.37(1H,S), 7.29-7.35(3H,m),7.46(lH,d,J=7.8Hz), 7.86(lH,s),
10.45(1H,S). Example 286
Ethyl l-acetoxyacetyl-4-( 2-chlorophenyl) - , 7-dihydro-6-propyl-
IH-pyrazolo[ 3 , 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from ethyl 4- ( 2-chlorophenyl) -4 , 7-dihydro-6-propy1-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate, dimethylaminopyridine and acetoxyacetyl chloride in the same manner as in Example
204.
MP:130-131°C. Anal. Calcd. for:C22H24ClN305:C,59.26;H,5.43;N,9.42.
Found:C,59.17;H,5.39;N,9.31.
MS(EI) :445(M+) .
IR(KBr) :v=3337, 1732, 1529, 1390, 1246, 1086 cm"1. XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.88(3H,t,J=7.0Hz) ,
0.97(3H,t,J=7.3Hz), 1.64-1.70(2H,m) , 2.76-2.82(2H,m) ,
3.31(3H,s), 3.85(2H,q,J=7.0Hz), 5.27(2H,dd,J=3.0 and 9.8Hz),
5.60(lH,s), 7.10-7.25(3H,m), 7.41( lH,dd,J=1.4 and 8.0Hz),
7.82(lH,s), 10.1(1H,S). Example 287
Ethyl l-benzylcarbonyl-4-(2-chlorophenyl) -4, 7-dihydro-6- propyl-lH-pyra2θlo[3, 4-b]pyridine-5-carboxylate
The title compound was obtained as colorless crystals from ethyl 4-(2-chlorophenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate, dimethylaminopyridine and phenylacetyl chloride in the same manner as in Example 204.
MS(EI) :463(M+) .
IR(KBr):v=3418, 1701, 1521, 1392, 1228cm-1.
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.88 (3H,t, J=7.OHz) , 0.93(3H,t,J=7.3Hz), 1.57-1.62(2H,m) , 2.80-2.87 (2H,m) ,
3.82(2H,q,J=7.0Hz), 4.33(2H,s), 5.57(lH,S), 7.15( lH,dd, J=7.4 and 7.8Hz), 7.18-7.31(7H,m) , 7.39( lH,d, J=7.8Hz) , 7.44(lH,s),
8.94(1H,S) .
Example 288 4-( 2, 1, 3-Benzoxadiazol-4-yl)-2-tert-butoxycarbonyl-5-cyano-
4, 7-dihydro-6-propy1-2H-pyrazolo[3, 4-b]pyridine
The title compound was obtained as colorless crystals from 4-( 2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- propyl-IH-pyrazolo[3, 4-b]pyridine, dimethylaminopyridine and tert-butyldicarbonate in the same manner as in Example 204.
MP:168-170°C.
Anal. Calcd. for:C21H22N6O3:C,62.06;H,5.46;N,20.68.
Found:C,61.92;H,5.44;N,20.52. MS (El) :406(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.89(3H,t, =7.3Hz) , 1.47(9H,s), 1.65(2H,m), 2.40(2H,m), 5.39(lH,s), 7.49 ( lH,d,J=6 ,3Hz) , 7.60(lH,dd,J=6.6 and 9.0Hz), 7.79(lH,s), 7.96( lH,d,J=6.6Hz) , 10.43(1H,S). Example 289
4- ( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-l- phenylcarbamoyl-6-propyl-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was obtained as colorless crystals from 4-(2,l,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine, dimethylaminopyridine and phenyl isocyanate in the same manner as in Example 204.
MP:138-140°C.
Anal. Calcd. for :C23H19N702:C, 64.93;H,4.50; N,23.05. Found:C,65.07;H,5.05;N,21.24. MS (El) :425(M+) .
1H-NMR ( 400MHz, DMSO-d6)δ(ppm) : 0.91(3H,t, J=7.3Hz) , 1.62(2H,m), 2.58(2H,m), 5.47(lH,s), 7.13( lH,dd, J=6.3 and 6.6Hz), 7.32- 7.39(3H,m), 7.49(lH,d,J=6.5Hz) , 7.61-7.91(3H,m) , 7.98(lH,d,J=9.lHz), 9.54(lH,s), 10.34(lH,s).
The compounds of the above-described Examples are as follows .
Example Example 12 Example 13 Example 14 Example 15
Example 16 Example 17 Example Example 19 Example 2C
Example 26 E x amp 1 e 27 Example 28 Example 29 Example 30
Example 31 Example 32 Example 33 Example 34 Example 35
Example 36 Example 37 Example 38 Example 39 Example 40
Example 41 Example 42 Example 43 Example 44 Example 45
Example 46 Example 47 Example 48 Example 49 Example 50
Example 56 Example 57 Example 58 Example 59 Example Example 63 Example 64 Example 65
Example 66 Example 70
Example 94
Example 101 Example 102 Example 103 Example 104
Example 108
Example 109 Example 110 Example 111
Example 117 Example 118 Example 119 Example 120 Example 121
Example 122 Example 123 Example 124 Example 125 Example 126
Example 127 Example 128 Exampl e 129 Example 130
Exampl e 132 Example 133 Example 134 Example 135 Exampl e 136
Exampl e 137 Example 138 Example 139 Example 140 Example 141
Example 142 Example 143 Example 144 Example 145 Example 146
Example 147 Example 148 Example 149
Example 152 Example 153 Example 154 Example 155 Example 156
Example 157 Example 158
Example 162 Example 163 Example 164 Example 165 Example 166
Example 167 Example 166 Example 169 Example 170 Example 171
Example 187 Example 188
Example 192 Example 193 Example 194 Example 195 Example 196
Example 197 Example 198
Example 202 Example 203
Exampl e 220 ample 218 Example 219
Example 225
Example 230 Example 231 Example 232 Example 233
Example 234 Example 235 Example 236 Example 237
Example 238
Example 239 Example 240 Example 241 Example 242 Example 243
Example 244 Example 245 Example 246 Example 247 Example 248
Example 249 Example 250 Example 251 Example 252 Example 253
Exampl e 254 Example 255 Example 256 Example 257 Example 258
Example 259 Example 260 Example 261 Example 262 Example 263
Example 264 Example 265 Example 266 Example 267 Example 268
Example 269 Example 270 Example 271 Exampl e 272 Example 273
Example 274 Example 275 Example 277 Example 278
Example 288 Example 289
Example 290
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- ( 4-methoxyphenyl) -6- propyl-2H-pyrazolo[ 3, 4-b]pyridine
To a solution of acetonitrile (15 g) in DMSO (25 mL) was added methyl p-anisate (25 g) and the mixture was stirred with heating at 60°C for 1 hour. The reaction mixture was allowed to cool and cold water (100 mL) was added dropwise. The mixture was acidified with hydrochloric acid and the precipitated crystals were collected by filtration. The obtained crystals were extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4- methoxybenzoylacetonitrile (21 g) as colorless crystals. To a solution of the obtained crystals in toluene was added hydrazine monohydrate (13 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the precipitated crystals were collected by filtration to give 5- amino-3-( 4-methoxyphenyl) yrazole (22 g) . Subsequently, the title compound was prepared from methyl butyrate, 2- chlorobenzaldehyde and 5-amino-3-( 4-methoxyphenyl)pyrazole in the same manner as in Example 94. MP:284°C.
Anal. Calcd. for:C23H2ιClN40:C,68.23;H,5.23;N, 13.84. Found:C,68.17;H,5.29;N,13.86. MS(EI) :404(M+) . -NMR (400MHz,DMSO-d6)δ(ppm) : 0.89(3H,t, J=7.3Hz) , 1.58- 1.63(2H,m), 2.32-2.38(2H,m),3.70(3H,s), 5.56(lH,s), 6.81(2H,d,J=7.2Hz) , 7.09-7.12(2H,m) , 7.17 ( lH,dd, J=7.3Hz and 7.2Hz), 7.24-7.30(3H,m), 9.85( lH,brs) , 12.46 ( lH,brs) . Example 291
4- ( 2 , 1, 3-Benzoxadiazol-4-yl) -6- ( 2-bromothiophen-5-yl) -5-cyano- 4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl 5- bromothiophene-2-carboxylate, 2,1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:208°C.
Anal. Calcd. for :C17H9BrN6OS:C, 48.01; H, 2.13 ;N, 19.76. Found:C,47.94;H,2.36;N,19.78. MS (El) :425(M+).
2H-NMR (400MHz, DMSO-d6)δ(ppm) : 5.54(lH,s), 7.32-7.34(2H,m) ,
7.42(lH,d,J=3.9Hz), 7.50( lH,d, J=6.6Hz) , 7.61(lH,dd, J=9.OHz) ,
7.95(lH,d,J=9.0Hz), 10.32(lH,brs) , 12 -32( lH,brs) . Example 292
4-( 2, 1,3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-( 3- methylthiophen-2-yl)-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl 3- methylthiophene-2-carboxylate, 2,1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:202°C.
Anal. Calcd. for :C18Hι2N6OS:C,59.99;H,3.36;N,23.32.
Found:C,59.89;H,3.53;N,23.06.
MS(EI) :360(M+) . } ^Η-NMR ( 400MHz,DMSO-dg)δ(ppm) : 2.17(3H,s), 5.54(lH,s),
6.96(lH,d,J=5.lHz), 7.32(lH,s), 7.49 ( lH,d,J=6.6Hz) , 7.60-
7.64(2H,m), 7.96(lH,d,J=9.0Hz) , 10.19 ( lH,brs) , 12.25( lH,brs) .
Example 293
4-(2, 1 , 3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-( 1- methoxymethylindol-3-yl)-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl 1- methoxymethylindol-3-carboxylate, 2,1, 3-benzoxadiazole-4- aldehyde and 3-aminopyrazole in the same manner as in Example
95. MP:200°C.
MS(El) :423(M+) .
^- R ( 400MHz,DMSO-d6)δ(ppm) : 3.19(3H,s), 5.55-5.63(3H,m) ,
7.15(lH,dd,J=7.3Hz and 7.2Hz), 7.25( lH,dd,J=7.3Hz and 7.2Hz), 7.34(1H,S), 7.54(lH,d,J=7.3Hz), 7.60-7.66 (3H,m) , 7.93- 7.97(2H,m), 10.12( lH,brs) , 12.22( lH,brs) . Example 294
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-propyl-3-(thiophen-2- yl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl thiophene-2- carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:256°C. Anal. Calcd. for:C20Hι7ClN4S:C,63.07;H,4.50;N,14.71.
Found:C,62.98;H,4.52;N,14.68.
MS (El) :380(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.86(3H,t, J=7.3Hz) , 1.56-
1.62(2H,m), 2.31-2.36(2H,m), 5.46(lH,s), 7.00-7.24(5H,m) , 7.36(lH,d,J=7.3Hz), 7.50( lH,d, J=4.9Hz) , 9.95( lH,brs) ,
12.74(lH,brs) .
Example 295
4- ( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- ( furan-2-yl) -6- propyl-2H-pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl furan-2- carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:253°C.
Anal. Calcd. for:C20Hι7ClN4O:C,65.84?H,4.70;N, 15.36. Found:C,65.81;H,4.84;N,15.49.
MS(EI) :364(M+) .
^-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.88(3H,t, J=7.3Hz) , 1.58-
1.63(2H,m), 2.32-2.36(2H,m) , 5.48(lH,s), 6.31(lH,d,J=3.2Hz) ,
6.45(lH,d,J=1.5Hz) , 7.14-7.23(3H,m) , 7.36 ( lH,d,J=7.3Hz) , 7.59(lH,s), 9.93(lH,brs), 12.76(lH,brs) .
Example 296
4-( 2-Chlorophenyl) -5-cyano-4 , 7-dihydro-3- (2-methoxyphenyl) -6- propyl-2H-pyrazolof 3, -b] yridine The title compound was prepared from methyl 2- methoxybezoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:>270°C. Anal. Calcd. for:C23H21ClN40:C,68.23;H,5.23;N,13.84.
Found:C,68.23;H,5.31;N,13.87.
MS(El) :404(M+) .
1H-NM ( 400MHz,DMSO-d6 )δ(ppm) : 0.90(3H,t,J=7.3Hz) , 1.60-
1.65(2H,m), 2.32-2.36(2H,m), 3.70(3H,s), 5.41(lH,s), 6.76(lH,dd,J=7.3Hz and 7.2Hz), 6.90-6.94(2H,m) , 6.98-
7.04(2H,m), 7.08-7.15(2H,m), 7.22( lH,dd,J=7.3Hz and 7.2Hz),
9.83(lH,brs), 12 ,21( lH,brs) .
Example 297
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- ( 3-methoxyphenyl) -6- propyl-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl 3- methoxybenzoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:239°C. Anal. Calcd. for :C23H2ιClN40:C,68.23;H,5.23;N, 13.84.
Found:C,68.16;H,5.31;N,13.80.
MS (El) :404(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.88(3H,t,J=7.3Hz) , 1.58-
1.63(2H,m), 2.31-2.36(2H,m), 3.68(3H,s), 6.78 ( lH,d,J=7.3Hz) , 6.87-6.89(2H,m), 7.11-7.20(4H,m) , 7.29 ( lH,d,J=7.3Hz) ,
9.92(lH,brs), 12.64( lH,brs) .
Example 298
4-( 2 , 1, 3-Benzoxadiazol-4-yl) -6- ( 2-chlorothiophen-5-yl) -5- cyano-4, 7-dihydro-2H-pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl 5- chlorothiophene-2-carboxylate, 2,1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:210°C. Anal. Calcd. for :Cι7H9ClN6OS:C,53.62;H,2.38;N,22.07.
Found:C,53.51;H,2.67;N,22.13.
MS(EI) :380(M+) .
XH-NMR ( 400MHz,DMSO-d6)δ(ppm) : 5.54(lH,s), 7.23( lH,d,J=3.9Hz) , 7.33(1H,S), 7.46(lH,d,J=3.9Hz), 7.50( lH,d,J=6.6Hz) ,
7.60(lH,dd,J=9.0Hz and 6.6Hz), 7.95( lH,d, J=9.OHz) ,
10.31(lH,brs), 12.30( lH,brs) .
Example 299
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-4, 7-dihydro-6-( 2- methylthiophen-5-yl) -2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl 5- methylthiophene-2-carboxylate, 2 , 1, 3-benzoxadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:192°C. MS(EI) :360(M+) .
"Η-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 2.50(3H,s), 5.52(lH,s),
6.87(lH,d,J=3.6Hz) , 7.32(lH,s), 7.40( lH,d, J=3.7Hz) ,
7.48(lH,d,J=6.6Hz) , 7 -61( lH,dd, J=9.OHz and 6.6Hz),
7.95(lH,d,J=9.0Hz), 10.12( lH,brs) , 12.26( lH,brs) . Example 300
4- ( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- (naphthalen-1-yl) -6- propyl-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl naphthalene-
1-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:254°C.
Anal. Calcd. for:C26H2ιClN :C,73.49;H,4.98;N,13.19.
Found:C,73.81;H,5.05;N,13.08.
MS (El) :424(M+) . 1H-NMR (400MHz,DMSO-d6)δ(ppm) : 0.95(3H,t,J=7.3Hz) , 1.64-
1.70(2H,m), 2.46-2.49(2H,m), 5.25(lH,s), 6.88-7.02(5H,m) ,
7.31(lH,dd,J=7.3Hz and 7.2Hz), 7.42-7.47(3H,m) , 7.83-
7.88(2H,m), 9.95(lH,brs), 12.46( lH,brs) . Example 301
4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- (naphthalen-2-yl) -6- propyl-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl naphthalene- 2-carboxylate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 290.
MP:>270°C.
Anal. Calcd. for:C26H2ιClN4:C, 73.49;H,4.98;N, 13.19. Found:C,73.23;H,5.01;N,13.26. MS(EI) :424(M+) .
^Η-NMR ( 400MHz,DMSO-de ) δ(ppm) : 0.91(3H,t,J=7.3Hz) , 1.61- 1.66(2H,m), 2.31-2.41(2H,m), 5.76(1H,S), 7.05( lH,dd, J=7 -3Hz and 7.2Hz), 7.12-7.16(2H,m) , 7.28( lH,d,J=7.3Hz) , 7.45- 7.52(2H,m), 7.57(lH,d,J=7.3Hz), 7.77-7.84(4H,m) , 9.94( lH,brs) , 12.79(lH,brs) . Example 302
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3, 6-dipropyl-2H- pyrazolo[ 3 , 4-b]pyridine
To a solution of acetonitrile (4.8 g) in THF (150 mL) was added n-BuLi (67 mmol) at -78°C. Methyl butyrate (10 g) was added and the mixture was stirred for 1 hour. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give l-cyanopentan-2-one (5.5 g) as a colorless oil. To a solution of the obtained colorless oil in toluene was added hydrazine monohydrate (5.0 g) and the mixture was heated under reflux for 3 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform-methanol (10:1)) to give 5-amino-3-propylpyrazole (5.0 g). A solution of 2-chloroaldehyde (1.7 g), 5-amino-3- propylpyrazole (1.5 g) and l-cyanopentan-2-one (1.6 g) in acetonitrile (20 mL) was heated under reflux overnight. The mixture was cooled to room temperature and the precipitated crystals were collected by filtration to give the title compound (2.1 g) as colorless crystals.
MP:237°C.
Anal. Calcd. for:C19H2ιClN4:C,66.95;H,6.21;N, 16.44.
Found:C,66.98;H,6.26;N,16.41.
MS(EI) :340(M+) . ^-NMR (400MHz, DMSO-de )δ( ppm) : 0.57(3H,t, J=7.3Hz) ,
0.91(3H,t,J=7.3Hz), 1.02-1.07 (2H,m) , 1.59-1.65(2H,m) , 2.01-
2.12(2H,m), 2.30-2.38(2H,m), 5.28(lH,s), 7.20-7.23(2H,m) ,
7.30(lH,dd,J=7.3Hz and 7.2Hz), 7.38 ( lH,d, J=7.3Hz) ,
9.70(lH,brs), 11.85(lH,brs) . Example 303
4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-3-hydroxy-6-propyl-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl butyrate, 2- chlorobenzaldehyde and 3-amino-5-hydroxypyrazole in the same manner as in Example 94.
MS(EI) :314(M+) .
^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 0.89 (3H,t,J=7.3Hz ) , 1.56-
1.60(2H,m), 2.26-2.38(2H,m), 5.11(lH,s), 7.14-7.21(3H,m) ,
7.27(lH,dd,J=7.3Hz and 7.2Hz), 7.34(lH,d, J=7.3Hz) , 9.64(lH,brs), 10.45( lH,brs) .
Example 304
3-Butyl-4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl pentanoate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in -Example 302.
MP:212°C.
Anal. Calcd. for:C20H23ClN4:C, 67.69;H,6.53;N, 15.79. Found:C,67.58;H,6.46;N,15.75. MS (El) :354(M+) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.64(3H,t,J=7.3Hz) , 0.89- 0.98(6H,m), 1.10-1.14(lH,m), 1.59-1.64(2H,m) ,2.05-2.16 (2H,m) , 2.31-2.35(2H,m), 5.28(lH,s), 7.20-7.24(2H,m) ,
7.29(lH,dd,J=7.3Hz and 7.2Hz), 7 ,38( lH,d, J=7.3Hz) , 9.70(lH,brs), 11.85( lH,brs) . Example 305
4-( 2, 1, 3-Benzoxadiazol-4-yl) -6-(benzothiophen-2-yl) -5-cyano- 4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl benzothiophene-2-carboxylate, 2,1, 3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 95.
MP:220°C. Anal. Calcd. for:C21H12N6OS:C,63.62;H,3.05;N,21.20. Found:C,63.58;H,3.29;N,21.09. MS (El) :396(M+) .
XH-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 5.60(lH,s), 7.36(lH,s), 7.44-
7.46(2H,m), 7.54( lH,d,J=6.3Hz) , 7.64( lH,dd,J=9.OHz and 6.6Hz) , 7.88(1H,S), 7.94-7.98(2H,m), 8.05( lH,d,J=9.OHz) , 10.40( lH,brs) ,
12.31(lH,brs).
Example 306
4-( 2-Chlorophenyl) -5-cyano-6-cyclohexyl-4 , 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl cyclohexanecarboxylate, 2-chlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:163°C.
Anal. Calcd. for:C19Hι9ClN4 1/2 H2O:C,65.61;H,5.80;N, 16.11. Found:C,65.40;H,5.77;N,15.86.
MS(EI) :338(M+) .
^-NMR ( 400MHz, DMSO-de )δ (ppm) : 1.16-1.30(3H,m) , 1.66-1.85(7H,m) , 2.66-2.72(lH,m), 5.33(lH,s), 7.21-7.25(3H,m) , 7.32(lH,dd,J=7.3Hz and 7.2Hz), 7 -41( lH,d,J=7.3Hz) , 9.60(lH,brs), 12.15( lH,brs) . Example 307
6-t-Butyl-4- ( 2-chlorophenyl) -5-cyano-4, 7-dihydro-2H-pyrazolo [ 3 , 4-b]pyridine
The title compound was prepared from methyl pivalate, 2- chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:198°C. Anal. Calcd. for:Cι7Hι7ClN4:C, 65.28;H,5.48;N, 17.91.
Found:C,64.98;H,5.47;N,17.78.
MS (El) :312(M+) .
^-NMR ( 400MHz,DMSO-de) δ(ppm) : 1.41(9H,s), 5.33(lH,s), 7.21-
7.33(4H,m), 7.41(lH,d,J=7.3Hz) , 8.88 ( lH,brs) , 12.20( lH,brs) . Example 308
4- ( 2-Chlorophenyl) -5-cyano-3-cyclopropy1-4, 7-dihydro-6-propy1-
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl eyelopropanecarboxylate, methyl butyrate and 2- chlorobenzaldehyde in the same manner as in Example 302.
MP:270°C.
Anal. Calcd. for:C19Hι9ClN4:C,67.35;H,5.65;N,16.54.
Found:C, 67.34;H, 5.66 ;N, 16.62.
MS(EI) :338(M+) . ^- MR (400MHz,DMSO-d6)δ(ppm) : 0.22-0.25( lH,m) , 0.41-0.44( lH,m) ,
0.50-0.54(lH,m), 0.62-0.66( lH,m) , 0.90(3H,t, J=7.3Hz) , 1.25-
1.29(lH,m), 1.58-1.63(2H,m),2.31-2.36(2H,m), 5.33(lH,s), 7.18-
7.23(2H,m), 7.30(lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d, J=7.3Hz) ,
9.69(lH,brs), 11.73(lH,brs). Example 309
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3-ethyl-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl propionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.
MP:269°C.
Anal. Calcd. for:C18Hι9ClN4:C, 66.15;H,5.86;N, 17.14. Found:C,66.27;H,5.86;N,17.25. MS (El) :326(M+) .
^-NMR ( 400MHz,DMSO-d6 ) δ(ppm) : 0.72(3H,t, J=7.3Hz) ,
0.91(3H,t,J=7.3Hz), 1.59-1.64(2H,m) , 2.09-2. ll(2H,m) , 2.31-
2.40(2H,m), 5.29(lH,s), 7.20-7.24(2H,m) , 7.30( lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d,J=7.3Hz) , 9.70( lH,brs) , 11.86(lH,brs) .
Example 310
3-t-Butyl-4-( 2-chlorophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl pivalate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.
MP:>270°C.
Anal. Calcd. for:C20H23ClN4:C,67.69;H,6.53;N,15.79.
Found:C,67.55;H,6.56;N,15.66. MS(EI) :354(M+) .
1H-MMR ( 400MHz,DMSO-dg) δ(ppm) : 0.84(3H,t,J=7.3Hz) , 0.95(9H,s),
1.53-1.59(2H,m), 2.26-2.30(2H,m) , 5.39(lH,s),
6.97(lH,d,J=7.3Hz) , 7 ,20( lH,dd,J=7.3Hz and 7.2Hz),
7.27(lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d, J=7.3Hz) , 9.73(lH,brs), 11.87(lH,brs) .
Example 311
4-( 2-Chlorophenyl) -5-cyano-3-cyclohexyl-4 , 7-dihydro-6-propy1-
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl cyclohexanecarboxylate, methyl butyrate and 2- chlorobenzaldehyde in the same manner as in Example 302.
MP:>270°C.
Anal. Calcd. for :C22H25C1N4:C,69.37;H,6.62;N,14.71. Found : C, 69 . 17 , - H, 6 . 62 , -N, 14.91 . MS (EI ) : 380 (M+ ) .
1H-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 0.89-1.17 (9H,m) , 1.47-1.64(6H,m) , 2.06-2.08(lH,m), 2.31-2.38(2H,m) , 5.30(lH,s), 7.19-7.23(2H,m) , 7.29(lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d, J=7.3Hz) , 9.71(lH,brs), 11.83( lH,brs) . Example 312
4- ( 2-Chlorophenyl) -5-cyano-6-cyclohepty1-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine The title compound was prepared from methyl eyeloheptanecarboxylate, 2-chlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94. MP:146°C. MS(EI) :352(M+) . ^Η-NMR (400MHz,DMSO-d6)δ(ppm) : 1.42-1.98( 12H,m) , 2.78-
2.81(lH,m), 5.33(lH,s), 7.21-7.24(3H,m) , 7.32( lH,dd,J=7.3Hz and 7.2Hz), 7.41( lH,d, J=7.3Hz) , 9.61( lH,brs) , 12.18( lH,brs) .
Example 313
4-( 2-Chlorophenyl) -5-cyano-6-cyclobutyl-4 , 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl eyelobutanecarboxylate, 2-chlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:188°C. Anal. Calcd. for:Cι7H15ClN4:C,65.70;H,4.86;N,18.03.
Found:C, 65.51,-H, 5.21;N, 18.27.
MS(EI) :310(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 1.72-1.77( lH,m) , 1.93-1.97( lH,m) ,
2.09-2.12(2H,m), 2.38-2.43(2H,m) , 2.58-2.61( lH,m) , 5.33(lH,s), 7.20-7.32(4H,m), 7.41( lH,d, J=7.3Hz) , 9.72 ( lH,brs) ,
12.18(lH,brs) .
Example 314
4- ( 2-Chloropheny1) -5-cyano-3-eyelopenty1-4, 7-dihydro-6-propy1- 2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl cyclopentanecarboxylate, methyl butyrate and 2- chlorobenzaldehyde in the same manner as in Example 302. MP:>270°C.
Anal. Calcd. for:C2ιH23ClN4:C,68.75;H,6.32;N,15.27.
Found:C,68.56;H,6.36;N,15.22.
MS(EI) :366(M+) .
XH-NMR ( 400MHz,DMSO-de) δ(ppm) : 0.89 (3H,t, J=7.3Hz) , 1.31- 1.74(10H,m), 2.30-2.37(2H,m) , 2.52-2.54( lH,m) ,
5.30(lH,s),7.17-7.22(2H,m), 7.28 ( lH,dd, J=7.3Hz and 7.2Hz),
7.37(lH,d,J=7.3Hz) , 9 ,71( lH,brs) , 11.86 ( lH,brs) .
Example 315
4-( 2-Chlorophenyl)-5-cyano-4,7-dihydro-6-propyl-3-isopropyl- 2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl 2- methyIpropionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.
MP:>270°C. Anal. Calcd. for:Cι9H2ιClN :C, 66.95;H,6.21;N, 16.44.
Found:C,66.90;H,6.27;N,16.44.
MS(EI) :340(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.67 (3H,d,J=7.2Hz) ,
0.90(3H,t,J=7.3Hz), 0.95(3H,d, J=7.3Hz) , 1.57-1.63(2H,m) , 2.30- 2.35(2H,m), 5.30(lH,s), 7.19-7.23(2H,m) , 7.29 ( lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d,J=7.3Hz) , 9.71(lH,brs) , 11.88( lH,brs) .
Example 316
4-( 2-Chlorophenyl) -5-cyano-6-cyclopenty1-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl cyclopentanecarboxylate, 2-chlorobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:225°C. Anal. Calcd. for:C18Hι7ClN4 1/5 H20:C,65.83;H,5.34;N, 17.06.
Found : C, 66.02 ;H, 5.51, -N, 16.62.
MS(EI) :324(M+) .
1H-HMR ( 400MHz,DMSO-de)δ(pp ) : 1.56-1.60(2H,m) , 1.78-1.87(6H,m) , 3.06-3.10(lH,m), 5.34(lH,s), 7.22-7.26 (3H,m) ,
7.32(lH,dd,J=7.3Hz and 7.2Hz), 7.42( lH,d, J=7.3Hz) ,
9.61(lH,brs), 12.16( lH,brs) .
Example 317
4- ( 2-Bromo-3-cyanophenyl) -5-cyano-6-cyclopentyl-4, 7-dihydro- 2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl cyclopentanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:247°C. MS(EI) :394(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm) : 1.52-1.58 ( 2H,m) , 1.75-1.82(6H,m) ,
3.01-3.06(lH,m), 5.46(lH,s), 7.33(lH,s), 7.54-7.58(2H,m) ,
7.84(lH,d,J=7.3Hz) , 9.73( lH,brs) , 12.25( lH,brs) .
Example 318 4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-cyclopentyl-4, 7- dihydro-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl cyclopentanecarboxylate, 2, l,3-benzoxadiazole-4-aldehyde and
3-aminopyrazole in the same manner as in Example 94. MP:193°C.
Anal. Calcd. for:C18Hι6N6O:C,65.05;H,4.85;N,25.29.
Found:C,64.72;H,4.98;N,24.86.
MS (El) :332(M+) .
XH-NMR ( 400MHz, DMSO-d6 )δ (ppm ) : 1.55-1.58 (2H,m) , 1.80-1.86(6H,m) , 3.06-3.09(lH,m), 5.39(lH,s), 7.26(lH,s), 7.38( lH,d, J=6.6Hz) ,
7.60(lH,dd,J=9.0Hz and 6.6Hz), 7.91(lH,d, J=9.0Hz) ,
9.72(lH,brs), 12.15( lH,brs) . Example 319
4-( 2-Bromo-3-cyanopheny1) -6-t-buty1-5-cyano-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl pivalate, 2- bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:251°C.
Anal. Calcd. for:C18Hι6BrN5 1/2 H20:C,55.25;H,4.38;N,17.90. Found:C,55.55;H,4.30;N,18.14. MS(EI) :382(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 1.41(9H,s), 5.46(lH,s),
7.33(lH,s), 7.54-7.60(2H,m), 7.82 ( lH,d,J=7.3Hz) , 9.00 ( lH,brs) ,
12.29(lH,brs) .
Example 320 4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -6-t-butyl-5-cyano-4 , 7-dihydro-2H- pyrazolo[ 3, 4-b] yridine
The title compound was prepared from methyl pivalate,
2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:204°C.
Anal. Calcd. for:Cι7Hι5N60 1/2 H2O:C,63.03;H,5.10;N,25.94.
Found:C,63.08;H,5.08;N,26.00.
MS (El) :320(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm): 1.40(9H,S), 5.37(lH,s), 7.26(1H,S), 7.38(lH,d,J=6.6Hz),7.59(lH,dd,J=9.0Hz and 6.6Hz),
7.91(lH,d,J=9.0Hz), 9.02( lH,brs) , 12.20( lH,brs) .
Example 321
4- ( 2-Bromo-3-cyanopheny1) -5-cyano-6-cyclobutyl-4, 7-dihydro-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl eyelobutanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:278°C. Anal. Calcd. for :Cι8Hι4BrN5:C,56.86;H,3.71;N, 18.42. Found:C,56.57;H,3.79;N,18.48. MS (El) :380(M+) .
1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 1.71(lH,m), 1.88-1.95( lH,m) , 2.06-2.13(2H,m), 2.38-2.47(2H,m) , 3.56-3.60( lH,m) , 5.45(lH,s), 7.33(lH,s), 7.57-7.59(2H,m), 7.82( lH,d, J=7.3Hz) , 9.84( lH,brs) , 12.27(lH,brs) . Example 322
4-(2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-cyclobutyl-4, 7-dihydro- 2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl eyelobutanecarboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:194°C. Anal. Calcd. for :Cι7Hι4N6O:C,64.14;H,4.43;N,26.40.
Found:C,64.08;H,4.51;N,26.26.
MS(EI) :318(M+) .
^Η-NMR ( 400MHz,DMSO-de )δ(ppm) : 1.72-1.76 ( lH,m) , 1.90-1.97( lH,m) ,
2.10-2.14(2H,m), 2.39-2.46 (2H,m) , 3.56-3.60( lH,m) , 5.38(1H,S), 7.26(lH,s), 7.37(lH,d,J=6.6Hz), 7.58( lH,dd,J=9.0Hz and 6.6Hz) ,
7.91(lH,d,J=9.0Hz), 9.82( lH,brs) , 12.17( lH,brs) .
Example 323
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-cyclohexyl-4, 7-dihydro-
2H-pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl eyelohexanecarboxylate, 2, l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:210°C.
Anal. Calcd. for:Cι9H18N60:C,65.88;H,5.24;N,24.26. Found:C,65.88;H,5.25;N,24.19.
MS (El) :346(M+) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 1.21-1.26(3H,m) , 1.62-1.80(7H,m) ,
2.66-2.70(lH,m), 5.38(lH,s), 7.25(1H,S), 7.38( lH,d,J=6.6Hz) , 7.59(lH,dd,J=9.0Hz and 6.6Hz), 7.91( lH,d, J=9.OHz) , 9.72(lH,brs), 12.15( lH,brs) . Example 324
4-( 2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6-cycloheptyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl cycloheptaneearboxylate, 2,l,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:228°C. Anal. Calcd. for:C2oH2oNeO:C,66.65;H,5.59;N,23.32. Found:C,66.45;H,5.70;N,22.97. MS(EI) :360(M+) .
1H-NM ( 400MHz,DMSO-de ) δ(ppm) : 1.38-1.98 ( 12H,m) , 2.76-
2.79(lH,m), 5.37(lH,s), 7.24(1H,S), 7.38 ( lH,d,J=6.6Hz) , 7.58(lH,dd,J=9.0Hz and 6.6Hz), 7.91( lH,d,=9.0Hz) , 9.72 ( lH,brs) ,
12.13(lH,brs) .
Example 325
4- ( 2-Bromo-3-cyanopheny1) -5-cyano-6-cyclohexyl-4 , 7-dihydro-2H- pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl cyclohexanecarboxylate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:193°C.
Anal . Calcd. for:C2oH18BrN5 1/2 H20:C, 57 .56 ;H, 4.59 ;N, 16 .78. Found:C, 57.25 ; H, 4.37 ;N, 16.56 .
MS (El ) : 408 (M+) .
1H-NM ( 400MHz,DMSO-d6 )δ(ppm) : 1.21-1.26 ( 3H,m) , 1.66-1.80(7H,m) , 2.66-2.69(lH,m), 5.45(lH,s), 7.33(lH,s), 7.55-7.60(2H,m) , 7.82(lH,d,J=7.3Hz), 9.73( lH,brs) , 12.24( lH,brs) . Example 326
4-( 2-Bromo-3-cyanopheny1) -5-cyano-6-cycloheptyl-4 , 7-dihydro- 2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl cycloheptaneearboxylate, 2-bromo-3-cyanobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94. MP:252°C.
Anal. Calcd. for:C21H20BrN5 1/2 H20:C,58.48;H,4.91;N, 16.24. Found:C,58.53;H,4.73;N,16.19. MS(El) :422(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 1.44-1.58( 12H,m) , 2.76-
2.79(lH,m), 5.44(lH,s), 7.31(lH,s), 7.54-7.60(2H,m) ,
7.83(lH,d,J=7.3Hz), 9.73( lH,brs) , 12.23( lH,brs) . Example 327
5-Cyano-4, 7-dihydro-6-propyl-4-(pyridin-3-yl)-2H-pyrazolo[3,4- b]pyridine
The title compound was prepared from methyl butyrate, pyridine-3-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:201°C.
Anal. Calcd. for:C15Hι5N5:C,67.90;H,5.70;N,26.40.
Found:C,67.42;H,5.74;N,26.72.
MS(EI) :265(M+) . 1H-NM ( 400MHz, DMSO-de ) δ(ppm) : 0.92 (3H,t, J=7.3Hz) , 1.62-
1.67(2H,m), 2.36-2.39(2H,m), 4.98(lH,s), 7.27(lH,s),
7.35(lH,dd,J=7.3Hz and 2.9Hz), 7.54(lH,d, J=7.3Hz) ,8.41-
8.44(2H,m), 9.81(lH,brs), 12.18( lH,brs) .
Example 328 3-t-Butoxycarbonyloxy-4-( 2-chlorophenyl)-5-cyano-4,7-dihydro-
6-propyl-IH-pyrazolo[3, 4-b]pyridine
To a solution of 4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-
3-hydroxy-6-propyl-2H-pyrazolo[3, 4-b]pyridine (12.5 g) in THF
(400 mL) was added triethylamine (4.5 g), dimethylaminopyridine (0.5 g) and di-t-butylcarbonate (9.6 g) and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (12 g) as colorless crystals. MP:182°C.
Anal. Calcd. for:C21H23ClN4O3:C,60.79;H,5.59;N,13.50. Found:C,60.60;H,5.50;N,13.44. MS (El) :414(M+).
-■H-NMR ( 400MHz,DMSO-de)δ(ppm): 0.91(3H,t,J=7.3Hz) , 1.54(9H,s),
2.49-2.51(2H,m), 5.18(lH,s), 7.23-7.27 (2H,m) ,
7.32(lH,dd,J=7.3Hz and 7.2Hz), 7.38( lH,d, J=7.3Hz) , 9.15(lH,brs), 10.99(lH,brs) .
Example 329
4-(2 , 1 , 3-Benzoxadiazol-4-yl) -5-cyano-6- ( 2 , 2-dimethoxyethyl) -
4, 7-dihydro-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl 3,3- dimethoxypropionate, 2,l,3-benzoxadiazole-4-aldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:115°C.
Anal. Calcd. for :Cι7Hi6 e03 1.0 H2O:C,55.13;H,4.90;N,22.69.
Found:C,55.30;H,4.51;N,22.99. MS(EI) :352(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 2.71(2.75(2H,m) , 3.28(3H,s),
3.31(3H,s), 4.74(lH,t,J=5.9Hz) , 5.43(lH,s), 7.28(lH,s),
7.40(lH,d,J=6.6Hz), 7.61( lH,dd, J=9.OHz and 6.6Hz),
7.92(lH,d,J=9.0Hz), 9.99( lH,brs) , 12.18 ( lH,brs) . Example 330
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3- ( 2 , 2-dimethoxyethyl) -
6-propyl-2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl 3,3- dimethoxypropionate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.
MP:180°C.
Anal. Calcd. for:C20H23ClN4O2:C,62.09;H,5.99;N,14.48.
Found:C,62.35;H,6.02;N,14.50. MS(EI) :386(M+) .
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.91(3H,t, J=7.3Hz) , 1.59-
1.64(2H,m), 2.28-2.35(4H,m), 3.00(3H,s), 3.02(3H,s),
3.81(lH,t,J=7.3Hz), 5.31(lH,s), 7.24-7.31(3H,m) , 7.40(lH,d,J=7.3Hz) , 9.75( lH,brs) , 11.92 ( lH,brs) .
Example 331
4- ( 2 , l-Benzoisoxazol-4-yl) -5-cyano-4 , 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butyrate, 2, l-benzoisoxazole-4.aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:239°C.
MS(EI) :305(M+) .
^Η-NMR ( 400MHz, DMSO-d6 ) δ(ppm) : 0 -91(3H,t, J=7.3Hz) , 1.64- 1.67(2H,m), 2.40-2.43(2H,m), 5.23(lH,s), 6.91( lH,d, J=6.6Hz) ,
7.28(lH,s), 7.36(lH,dd,J=9.3Hz and 6.6Hz), 7.52 ( lH,d, J=9.3Hz) ,
9.37(lH,s), 9.96(lH,brs), 12.21( lH,brs) .
Example 332
4- ( 2 , l-Benzoisoxazol-4-yl) -5-cyano-4 , 7-dihydro-6-isopropyl-2H- pyrazolo[ 3 , 4-b] yridine
The title compound was prepared from methyl isobutyrate,
2, l-benzoisoxazole-4.aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:245°C. MS(EI) :305(M+) .
^-NMR ( 400MHz, DMSO-de ) δ(ppm) : 1.23-1.26(6H,m) ,
3.03(lH,t,J=5.9Hz), 5.21(1H,S), 6.92( lH,d, J=6.6Hz) , 7.30(lH,s),
7.37(lH,dd,J=9.3Hz and 6.6Hz), 7.53( lH,d, J=9.3Hz) , 9.34(lH,s),
9.78(lH,brs), l2.23( lH,brs) . Example 333
4-(2,l-Benzoisoxazol-4-yl)-5-cyano-6-cyclopropyl-4,7-dihydro-
2H-pyrazolo[ 3 , 4-b] yridine
The title compound was prepared from methyl eyelopropanecarboxylate, 2, l-benzoisoxazole-4.aldehyde and 3- aminopyrazole in the same manner as in Example 94. MP:248°C. MS(EI) :303(M+) . 1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.89-0.91(2H,m) , 1.05-1.08 (2H,m) ,
1.94-1.98(2H,m), 5.20(lH,s), 6.91( lH,d,J=6.6Hz) ,7.28( IH, s) ,
7.36(lH,dd, J=9.3Hz and 6.6Hz), 7.52( lH,d, J=9.3Hz) , 9.26(lH,s),
9.36(lH,brs) , 12.22 ( lH,brs) .
Example 334 4-(2, 1,3-Benzoxadiazol-4-yl)-5-cyano-6-( 1-t- butoxycarbonylindol-3-yl)-4,7-dihydro-2H-pyrazolo[3,4- b]pyridine
The title compound was prepared from methyl 1-t- butoxycarbonylindole-3-carboxylate, 2,1, 3-benzoxadiazole-4- aldehyde and 3-aminopyrazole in the same manner as in Example
95.
MP:202°C.
MS(El) :479(M+) .
^-NMR (400MHz,DMSO-de)δ(ppm) : 1.65(9H,s), 5.60(lH,s), 7.27- 7.41(3H,m), 7.54-7.58(2H,m), 7.64( lH,dd,J=7.3Hz and 7.2Hz) ,
7.97(lH,d,J=7.3Hz), 8.03(lH,s), 8.10( lH,d,J=7.3Hz) ,
10.23(lH,brs), 12.26( lH,brs) .
Example 335
4-(2 , 1, 3-Benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-(indol-3- yl)-2H-pyrazolo[ 3, 4-b]pyridine
( l-t-Butoxycarbonylindol-3-yl) -4, 7-dihydro-2H- pyrazolo[3, 4-b]pyridine (0.6 g) was added to trifluoroacetic acid (15 mL) under ice-cooling and the mixture was stirred for
3 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to neutralize the mixture. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.4 g) as colorless crystals. MP:238°C.
Anal. Calcd. for :C2ιHι3N70 3/5 H20:C, 64.64;H,3.67;N,25.13. Found:C,64.77;H,4.05;N,25.59. MS(EI) :379(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 5.56(lH,s), 7.08 ( lH,dd, J=7.3Hz and 7.2Hz), 7.15(lH,dd,J=7.3Hz and 7.2Hz), 7.44(lH,s), 7.44-
7.54(3H,m), 7.65(lH,dd,J=7.3Hz and 7.2Hz), 7.76(lH,s), 7.95(lH,d,J=7.3Hz) , 9.98( lH,brs) , 11.63( lH,brs) , 12 ,20( lH,brs) .
Example 336
4- ( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-3-dimethoxymethyl-6- propyl-2H-pyrazolo [ 3, 4-b]pyridine
The title compound was prepared from methyl dimethylacetate, methyl butyrate and 2-chlorobenzaldehyde in the same manner as in Example 302.
MP:212°C.
Anal. Calcd. for:C19H21ClN4O2:C,61.21;H,5.68;N,15.03.
Found:C, 61.25;H, 5.69,-N, 15.17. MS(EI) :372(M+) .
-Η-NMR ( 400MHz,DMSO-de )δ(ppm) : 0.88 (3H,t,J=7.3Hz) , 1.57-
1.63(2H,m), 2.28-2.35(2H,m), 2.93(6H,s) , 4.93( IH, s) , 5.30(lH,s),
7.10(lH,d,J=7.3Hz), 7.19 ( lH,dd,J=7.3Hz and 7.2Hz),
7.25(lH,dd,J=7.3Hz and 7.2Hz), 7.35( lH,d, J=7.3Hz) , 9.80(lH,brs), 12.29( lH,brs) .
Example 337
5-Cyano-4, 7-dihydro-6-propyl-4-(pyridin-4-yl) -2H-pyrazolo[ 3, 4- b]pyridine
The title compound was prepared from methyl butyrate, pyridine-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:224°C.
Anal. Calcd. for:Cι5Hι5N5:C,67.90;H,5.70;N,26.40. Found: C, 67.90 ;H, 5.79 ;N, 26.31. MS(EI) :265(M+) .
^- MR ( 400MHz,DMSO-de)δ(ppm) : 0.92 (3H,t,J=7.3Hz) , 1.62- 1.67(2H,m), 2.35-2.43(2H,m), 4.95(lH,s), 7.20(2H,dd,J=4.6Hz and 1.5Hz), 7.29(lH,s), 8.50(2H,dd,J=4.6Hz and 1.5Hz), 9.84(lH,brs) , 12.20( lH,brs) . Example 338
5-Cyano-4,7-dihydro-4-(3-methyl-2-nitrophenyl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl butyrate, 3- methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:250°C.
Anal. Calcd. for:C17Hι7N502:C, 63.15;H,5.30;N,21.66. Found:C,62.89;H,5.51;N,22.11.
MS (El) :323(M+).
1H- MR ( 400MHz,DMSO-de)δ(ppm) : 0.94( 3H,t,J=7.3Hz) , 1.63-
1.68(2H,m), 2.26(3H,s), 2.36-2.42(2H,m) , 4.83(lH,s),
7.17(1H,S), 7.20(lH,d,J=7.3H), 7.32( lH,d, J=7.3Hz) , 7.48(lH,dd,J=7.3Hz and 7.2Hz), 9.91(lH,brs) , 12.22(lH,brs) .
Example 339
5-Cyano-4,7-dihydro-4-(3-methyl-2-nitrophenyl)-6-isopropyl-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl isobutyrate, 3-methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:261°C.
Anal. Calcd. f or : Cι7H17N502 1/2 H20:C,61.43;H,5.46;N,21.07. Found: C, 61.82, -H, 5.32 ;N, 21.31. MS(EI) :323(M+) .
1H-NMR ( 400MHz, DMSO-de )δ (ppm ) : 1.21(3H,d, =7.2Hz) , 1.26(3H,d,J=7.2Hz), 2.25(3H,s), 3.01( lH,t, J=7.2Hz) , 4.84(1H,S), 7.17(1H,S), 7.22(lH,d,J=7.3Hz), 7.32( lH,d, J=7.3Hz) , 7.48(lH,dd,J=7.3Hz and 7.2Hz), 9.71( lH,brs) , 12.24( lH,brs) .
Example 340
5-Cyano-6-cyclopropyl-4,7-dihydro-4-( 3-methyl-2-nitrophenyl)-
2H-pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl cyclopropanecarboxylate, 3-methyl-2-nitrobenzaldehyde and 3- aminopyrazole in the same manner as in Example 94. MP:265°C.
Anal. Calcd. for:C17H15N502:C,63.54;H,4.71;N,21.79. Found:C,63.44;H,4.85;N,22.04.
MS(EI) :321(M+) . αH-NMR (400MHz,DMSO-de)δ(ppm) : 0.90-1.07 ( 4H,m) , 1.96-
1.99(lH,m),2.26(3H,s), 4.81(lH,s), 7.17(lH,s),
7.20(lH,d,J=7.3Hz), 7.32( lH,d,J=7.3Hz) , 7.48 ( lH,dd,J=7.3Hz and 7.2Hz), 9.23(lH,brs), 12.23( lH,brs) .
Example 341
Ethyl 4-( 2 , 1, 3-benzoxazol-4-yl)-4, 7-dihydro-6-( 1-methylethyl)-
2H-pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 ethyl acetate
The title compound was prepared from 2, 1,3-benzoxazole- 4-aldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.
MP:190-193°C (decomposition)
^Η-NMR (400MHz,DMSO-de )δ(ppm) : 0.7.3(3H,t, J=7.1Hz) ,
1.19(3H,d,J=7.1Hz), 1.29(3H,d,J=7.lHz) , 3.77(2H,m), 4.37(lH,m), 5.69(1H,S), 7.12(lH,d,J=6.6Hz), 7.22(lH,s),
7.51(lH,dd,J=6.6,9.0Hz), 7.78( lH,d,J=8.8Hz) , 9.31( lH,brs) ,
12.02(lH,brs) .
Example 342
Ethyl 4-(2-nitrophenyl)-4, 7-dihydro-6-( 1-methylethyl) -2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from 2-nitrobenzaldehyde,
3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275. MP:205-206°C.
^- MR ( 400MHz, DMSO-de )δ (ppm): 0.78 (3H,t, J=6.8Hz) ,
1.15(3H,d,J=7.lHz), 1.26(3H,d, J=7.1Hz) , 3.71(2H,m), 4.33(lH,m),
5.44(lH,s), 7.29-7.34(3H,m), 7.58(lH,m), 7.78( lH,d, J=8.OHz) , 9.33(lH,brs), 12.11(lH,brs) .
Example 343
Ethyl 4-(2-methoxyphenyl)-4, 7-dihydro-6-( 1-methylethyl)-2H- pyrazolo[3,4-b]pyridine-5-carboxylate 1/2 ethyl acetate The title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.
MP:179-180°C.
^Η-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.81(3H,t,J=7.1Hz) ,
1.17(3H,d,J=7.lHz) , 1.27(3H,d,J=7.IHz) , 3.76(2H,m), 3.85(3H,s), 4.31(lH,m), 5.46(lH,s), 6.77(lH,m), 6.89( lH,d,J=8.OHz) ,
6.94(lH,d,J=7.6Hz) , 7.04(lH,m), 7.14(lH,s), 8.98 ( lH,brs) ,
11.86(lH,brs) .
Example 344
Ethyl 4-( 2-bromophenyl) -4,7-dihydro-6-cyclopropyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate
The title compound was prepared from cyclopropanecarbonyl chloride, 2-bromobenzaldehyde and 3- aminopyrazole in the same manner as in Example 277.
MP:168-170°C ^Η-NMR (400MHz,DMSO-de)δ(ppm) : 0.86(3H,t,J=7. IHz) , 0.87-
0.90(2H,m), 1.10-1.14(2H,m), 3.16(lH,m), 3.78(2H,m),
5.57(1H,S), 7.01(lH,dd,J=5.8,7.6Hz), 7.09 ( lH,d,J=7.8Hz) ,
7.24(lH,m), 7.29(lH,s), 7.51(lH,d,J=6.8Hz) , 8.65( lH,brs) ,
12.01(lH,brs) . Example 345
Ethyl 4-(2-bromo3-cyanopheny1)-4, 7-dihydro-6-cyclopropyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from cyclopropanecarbonyl chloride, 2-bromo-3-cyanobenzaldehyde and 3-aminopyrazole in the same manner as in Example 277. MP:168-170°C
1H-NMR ( 400MHz,DMSO-d6)δ(ppm) : 0.86 (3H,t,J=7. IHz) , 0.88- 1.00(2H,m), 1.10-1.18(2H,m), 3.14(lH,m), 3.80(2H,m), 5.64(lH,s), 7.33(lH,s), 7.34-7.49 (2H,m) , 7.68(lH,m), 8.77(lH,brs), 12.10( lH,brs) . Example 346 4-(2-Chlorophenyl)-5-cyano-7-methyl-6-propy1-4, 7-dihydro-2H- pyrazolo[3, 4-b]pyridine
A solution of 3-aminopyrazole (3.0 g), di-t-butyl dicarbonate (17.3 g) and dimethylaminopyridine (1.3 g) in tetrahydrofuran (360 ml) was stirred at room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give a mixture (7.9 g) of l-(t-butoxycarbonyl)-3-(t- butoxycarbonylamino) yrazole and 2-(t-butoxycarbonyl)-3-(t- butoxycarbonylamino)pyrazole as a white amorphous solid. To a suspension of the obtained white amorphous solid (7.9 g) and sodium hydride (1.1 g) in DMF (80 ml) was added methyl iodide (4.0 g) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water under ice-cooling and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (10:1)) to give a white solid (5.3 g) . The obtained white solid (5.3 g) was dissolved in methylene chloride (50 ml), and trifluoroacetic acid (7 ml) was added. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol (10:1)) to give 3- methylaminopyrazole (1.54 g) as a colorless transparent oil. Subsequently, the title compound was prepared from methyl butyrate, 2-chlorobenzaldehyde and 3-methylaminopyrazole in the same manner as in Example 94.
MP:170-171°C
Anal. Calcd. for:Cι7Hι7N4Cl: C,65.28;H,5.48;N, 17.91. Found:C,65.14;H,5.52;N,17.72.
MS(EI) :312(M+) .
1H-NMR (400MHz,DMSO-d6)δ(ppm) : 1.00( 3H,t,J=7.3Hz) , 1.68(2H,m),
2.62(2H,m), 3.36(3H,s), 5.36(lH,s), 7.22-7.26 (2H,m) , 7.30-
7.32(2H,m), 7.42(lH,d,J=8.lHz), 12.31( lH,brs) . Example 347
4-( 2, 1,3-Benzoxazol-4-yl)-5-cyano-7-methyl-6-propyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butyrate,
2,l,3-benzoxazole-4-aldehyde and 3-methylaminopyrazole in the same manner as in Example 346.
MP:198-200°C
Anal. Calcd. for:Cι7Hι6N60: C, 63.74;H,5.03;N, 26.23.
Found:C,63.78;H,5.12;N,26.47.
MS (El) :320(M+) . XH-NMR ( 400MHz, DMSO-de )δ (ppm) : 0.97 (3H,t, J=7.4Hz) , 1.61(2H,m),
2.63(2H,m), 3.41(3H,s), 5.40( 1H,S) ,7.32 ( lH,s) ,
7.40(lH,d,J=6.6Hz), 7.59 ( lH,dd, J=6.5,6 ,6Hz) ,
7.92(lH,d,J=9.3Hz), 12.30( lH,brs) .
Example 348 4-( 2-Bromo-3-cyanophenyl)-5-cyano-7-methyl-6-propyl-4, 7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butyrate, 2- bromo-3-cyanobenzaldehyde and 3-methylaminopyrazole in the same manner as in Example 346.
MP:218-220°C
Anal. Calcd. for:C18H16N5Br: C,56.56;H,4.22;N, 18.32. Found:C,56.60;H,4.41;N,18.18. MS(EI) :382(M+) .
2H-NMR (400MHz,DMSO-de)δ(ppm) : 1.00(3H,t,J=7.3Hz) , 1.63(2H,m), 2.62(2H,m), 3.37(3H,s), 5.47(lH,s), 7.39(lH,s), 7.56- 7.58(2H,m), 7.83(lH,m), 12.41( lH,brs) . Example 349 4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-methy1-2H- pyrazolo[ 3, 4-b] yridine
The title compound was prepared from ethyl acetate, 2- chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. 1H-NMR ( 400MHz,DMSO-de)δ(ppm) : 2.14(3H,s), 5.35(lH,s), 7.21- 7.33(4H,m), 7.42(lH,d,J=8.lHz) , 9.87( lH,brs) , 12.15( lH,brs) . Example 350
4-(2-Chlorophenyl) -5-cyano-4,7-dihydro-6-(morpholin-4- yl)methyl-2H-pyrazolo[ 3, 4-b]pyridine dihydrochloride A solution of 4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-6- methyl-2H-pyrazolo[ 3, 4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2- (t-butoxycarbonyl) -4-( 2-chlorophenyl)-5-cyano-4, 7-dihydro-6- methyl-2H-pyrazolo[3, 4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-6- methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g) , N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t- butoxycarbonyl) -4- (2-chlorophenyl)-5-σyano-4, 7-dihydro-2H- pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t- butoxycarbonyl) -4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-2H- pyrazolof3, 4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t- butoxycarbonyl)-4-( 2-chlorophenyl)-5-cyano-4, 7-dihydro-6- (morpholin-4-yl)methyl-2H-pyrazolo[3, 4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2- chloropheny1)-5-cyano-4, 7-dihydro-6-(morpholin-4-yl) ethyl-2H- pyrazolo[3, 4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals. MP:210-214°C (decomposition). ^-NMR ( 400MHz,DMSO-de)δ(ppm) : 3.20-3. 0 ( 3H,m) , 3.84-4.00(3H,m) , 4.17-4.40(4H,m), 5.49(lH,s), 7.26-7.37 (4H,s) , 7.45(lH,d,J=7.8Hz) , 10.22( lH,brs) , 11.05( lH,brs) , 12.33(lH,brs) . Example 351 6-Benzyloxymethyl-4-(2-Chlorophenyl)-5-cyano-4,7-dihydro-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from ethyl benzyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. MP:165-166°C
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 4.35(2H,d,J=2.9Hz) , 4.57(2H,s), 5.42(lH,s), 7.24-7.45(10H,m), 10.03( lH,brs) , 12.22( lH,brs) . Example 352
4-(2-Chlorophenyl) -5-cyano-4,7-dihydro-6-(methylpiperazin-1- yl)methyl-2H-pyrazolo[3, 4-b]pyridine dihydrochloride
4-(2-Chlorophenyl) -5-cyano-6-(t-butyldimethylsilyloxy)- methyl-4,7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2- chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6- (t-butyldimethylsilyloxy)methyl-4, 7-dihydro-2H-pyrazolo[3, 4- b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5- cyano-6-hydroxymethyl-4, 7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2- chlorophenyl)-5-cyano-6-hydroxymethyl-4, 7-dihydro-2H- pyrazolo[ 3, 4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was. added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6- bromomethyl-4,7-dihydro-2H-pyrazolo[ 3, 4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2- chlorophenyl)-5-cyano-6-bromomethyl-4, 7-dihydro-2H- pyrazolo[3, 4-b]pyridine (200 mg) in DMF (3 ml) under ice- cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol (4:1)) . The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals. MP:222-225°C (decomposition)
XH-NMR ( 400MHz,DMSO-de)δ(ppm) : 2.66-2.75 (2H,m) , 2.75(3H,s), 3.00-3.10(4H,m), 3.41-3.55(4H,m) , 5.42(lH,s), 7.24-7.36(4H,m) , 7.43(lH,d,J=8.0Hz), 9.77( lH,brs) , 12.17 ( lH,brs) . Example 353 4-(2-Chlorophenyl) -5-cyano-4, 7-dihydro-6-(piperidin-1- yl)methyl-2H-pyrazolo[3, 4-b]pyridine hydrochloride
The title compound was prepared from 4-(2-chlorophenyl)- 5-cyano-6-bromomethyl-4, 7-dihydro-2H-pyrazolo[3, 4-b]pyridine and piperidine in the same manner as in Example 352. ^- R (400MHz,DMSO-d6)δ(ppm) : 1.43(lH,m), 1.67-1.82(5H,m) , 3.05-3.25(2H,m), 3.48(2H,m), 4.10(2H,m), 5.49(lH,s), 7.26- 7.35(4H,m), 7.45(lH,d,J=8.0Hz), 10.28( lH,brs) , 10.59( lH,brs) . Example 354 Ethyl 4-(2-nitrophenyl)-4, 7-dihydro-6-cyclopropyl-2H- pyrazolo[ 3, 4-b]pyridine-5-carboxylate
The title compound was prepared from cyclopropanecarbonyl chloride, 2-nitrobenzaldehyde and 3- aminopyrazole in the same manner as in Example 277. MP:162-164°C (decomposition)
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.81(3H,t, J=7.4Hz) , 0.85-
0.95(2H,m), 1.10-1.18(2H,m), 3.12(lH,m), 3.72(2H,m),
5.46(lH,s), 7.27-7.34(3H,m), 7.58(lH,m), 7.78 ( lH,d, J=8.OHz) , 8.78(lH,brs), 12.12(lH,brs) .
Example 355
Ethyl 4-( 2 , 1, 3-benzoxazol-4-yl) -4, 7-dihydro-6-cyclopropyl-2H- pyrazolo[ 3 , 4-b] yridine-5-carboxylate
The title compound was prepared from cyclopropanecarbonyl chloride, 2, l,3-benzoxazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 277.
MP:109-111°C (decomposition).
^- MR (400MHz,DMSO-de)δ(ppm) : 0.76(3H,t,J=6.8Hz) , 0.85-
0.86(2H,m), 1.14-1.18(2H,m), 3.12(lH,m), 3.80(2H,m), 5.69(lH,s), 7.13(lH,d,J=6.6Hz) , 7.23(lH,s), 7.51(lH,m),
7.79(lH,d,J=9.0Hz), 8.83( lH,brs) , 12.05( lH,brs) .
Example 356
4- ( 2 , 1, 3-Benzoxazol-4-yl) -5-cyano-4, 7-dihydro-2-
( henylcarbamoyl) -6-propyl-2H-pyrazolo[3 , 4-b]pyridine The title compound was obtained as colorless crystals from 4-( 2 , 1, 3-benzoxadiazol-4-yl) -5-cyano-4 , 7-dihydro-6- propyl-2H-pyrazolo[ 3, 4-b]pyridine, dimethylaminopyridine and phenylisocyanate in the same manner as in Example 204.
MS(EI) :425(M+) . ^-NMR ( 400MHz,DMSO-de)δ(ppm) : 0.91(3H,t, J=7.3Hz) , 1.64(2H,m), 2.58(2H,m), 5.44(lH,s), 7.10( lH,dd, J=6.3 and 7.6Hz), 7.31- 7.34(2H,m), 7.52(lH,d,J=6.6Hz), 7.59-7.64(3H,m), 7.95(lH,s), 7.97(lH,d,J=9.0Hz) , 9.83( lH,brs) , 10.30( lH,brs) . Example 357 4-( 2-Chlorophenyl) -5-cyano-4 , 7-dihydro-l- ( 4-pentenoyl) -6- propyl-lH-pyrazolo[ 3, 4-b]pyridine
The title compound was obtained as colorless crystals from 4-(2-chlorophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3, 4-b]pyridine, dimethylaminopyridine and 4-pentenoyl chloride in the same manner as in Example 204.
MP:140°C.
Anal. Calcd. for:C2ιH2ιClN0:C,66.22;H,5.62;N,14.71. Found:C,66.20;H,5.60;N,14.65. MS(EI) :380(M) .
XH-NMR ( 400MHz,DMSO-de )δ(ppm) : 0 ,95(3H,t,J=7.3Hz) , 1.62(2H,m),
2.39-2.58(4H,m), 3.ll(2H,t,J=7.6Hz) , 4.98 ( lH,d,J=7.1Hz) ,
5.06(lH,d,J=10.3Hz), 5.40(lH,s), 5.85(lH,m), 7.27-7.37(4H,m) , 7.46(lH,d,J=7.0Hz), 9.58 ( lH,brs) .
Example 358
4-( 2-Chlorophenyl) -5-cyano-4, 7-dihydro-2- ( 4-pentenoyl) -6- propy1-2H-pyrazolo [ 3 , 4-b]pyridine
The title compound was obtained as colorless crystals from 4-(2-chlorophenyl)-5-cyano-4, 7-dihydro-6-propy1-2H- pyrazolo[3, 4-b]pyridine, dimethylaminopyridine and 4-pentenoyl chloride in the same manner as in Example 204.
MP:176-177°C.
Anal. Calcd. for:C2ιH2ιClN40:C,66.22;H,5.56N, 14.71. Found:C,66.15;H,5.63;N,14.55.
MS(EI) :380(M) .
1H-NMR ( 400MHz,DMSO-d6 )δ(ppm) : 0.95(3H,t,J=7.3Hz) , 1.67(2H,m),
2.34-2.49(4H,m), 3.00(2H,t,J=7.6Hz) , 4.96 ( lH,d,J=10.6Hz) ,
5.02(lH,d,J=27.lHz), 5.36(lH,s), 5.82(lH,m), 7.30-7.35(3H,m) , 7.46(lH,d,J=7.8Hz) , 7.83(lH,s), 10.39( lH,brs) .
Example 359
5-Cyano-4, 7-dihydro-4-( 6-methylpyridin-2-yl) -6-propyl-2H- pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl butyrate, 6- methylpyridine-2-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:177-181°C.
Anal . Calcd . for :C16Hι7N5 4/5 H20 :C, 65.42 ; H, 6 .38 ;N, 23.84 . Found:C,65.52;H,6.31;N,24.19. MS(EI) :279(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.95(3H,t,J=7.6Hz) , 1.66(2H,m),
2.41(2H,m), 2.43(3H,s), 4.94(lH,s), 6.98( lH,d,J=7.6Hz) , 7.06(lH,d,J=7.5Hz), 7.21(lH,s), 7.62( lH,dd,J=7.6 and 7.7Hz),
9.71(lH,brs), 12.09(lH,brs) .
Example 360
4- ( 5-Cyano-4, 7-dihydro-6-propyl-2H-pyrazolo[3,4- b]pyridine)pyridine-N-oxide The title compound was prepared from methyl butyrate, pyridine-4-aldehyde-N-oxide and 3-aminopyrazole in the same manner as in Example 94.
MP:110-115°C.
Anal. Calcd. for:Cι5Hi5N5O:C,62.01;H,6.18;N,24.11. - Found:C,61.94;H,5.85;N,23.73. MS(EI) :283(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.91(3H,t,J=7.3Hz) , 1.62(2H,m),
2.36(2H,m), 4.98(lH,s), 7.18 (2H,d,J=6.6Hz) , 7.31(lH,s),
8.14(2H,d,J=6.3Hz), 9.86( lH,brs) , 12.2( lH,brs) . Example 361
5-Cyano-4 , 7-dihydro-4-( 3-( 4-morpholinomethyl)phenyl) -6-propy1-
2H-pyrazolo[ 3 , 4-b]pyridine
The title compound was prepared from methyl butyrate, 3-
( 4-morpholinomethyl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MS(EI) :363(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 0.92(3H,t, J=7.3Hz) , 1.63(2H,m), 2.30(4H,m), 2.30(2H,m), 3.40(2H,s), 3.53(4H,m), 4.86(lH,s), 7.05(lH,d,J=7.8Hz), 7.10( lH,d,J=7.6Hz) , 7.14(lH,s), 7.19(1H,S), 7.23(lH,dd,J=7.5 and 7.6Hz), 9.70( lH,brs) , 12.10( lH,brs) . Example 362
4-( 3-Bromophenyl) -5-cyano-4, 7-dihydro-6-propyl-2H- pyrazolo[ 3 , 4-b]pyridine The title compound was prepared from methyl butyrate, 3- bromobenzaldehyde and 3-aminopyrazole in the same manner as in
Example 94.
MP:202-205°C. Anal. Calcd. for:C16Hι5BrN4:C,55.99;H,4.41;N,16.32.
Found:C,55.82;H,4.46;N,17.03.
MS(EI) :343(M+) .
XH-NMR (400MHz,DMSO-de)δ(ppm) : 0.91(3H,t,J=7.3Hz) , 1.63(2H,m),
2.37(2H,m), 4.92(1H,S), 7.18( lH,d,J=7.9Hz) , 7.25(lH,s), 7.28(lH,d,J=7.8Hz), 7.33(lH,s), 7.39 ( lH,d,J=8.3Hz) ,
9.80(lH,brs), 12.18(lH,brs) .
Example 363
5-Cyano-4, 7-dihydro-4-(4-fluoro-2-chlorophenyl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine The title compound was prepared from methyl butyrate, 2- chloro-4-fluorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:209-212°C.
Anal. Calcd. for :Cι6H14ClFN4: C,60.67;H, 4.45;N, 17.69. Found:C, 60.48, -H, 4.48 ;N, 17.87. MS(EI):316(M+).
XH-NMR ( 400MHz, DMSO-de ) δ(ppm) : 0.93( 3H,t, J=7.3Hz) , 1.64(2H,m),
2.39(2H,m), 5.33(lH,s), 7.17-7.40(3H,m) , 7.41( lH,dd, J=2.7 and
6.1Hz), 9.85(lH,brs), 12.17 ( lH,brs) . Example 364
5-Cyano-4, 7-dihydro-4-( 3-(morpholin-4-yl)phenyl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl butyrate, 3-
(morpholin-4-yl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:196-200°C.
Anal. Calcd. for:C20H23N5O:C,68.47;H,6.63;N,20.04.
Found:C,68.41;H,6.77;N,20.16. MS(EI) :349(M+) .
^-NMR (400MHz,DMSO-d6)δ(ppm) : 0.92(3H,t,J=7.3Hz) , 1.63(2H,m),
2.32(2H,m), 3.05(4H,t,J=4.6Hz), 7.71(4H,t,J=4.6Hz) , 4.80(lH,S),
6.59(lH,d,J=7.5Hz) , 6.74(lH,m), 6.76(lH,s), 7.13( lH,dd,J=7.8 and 7.8Hz), 7.21(lH,s), 9.67( lH,brs) , 12.02( lH,brs) .
Example 365
5-Cyano-4, 7-dihydro-4-( 3-(morpholin-4-yl)phenyl)-6-isopropyl-
2H-pyrazolo[ 3, 4-b]pyridine
The title compound was prepared from methyl isobutyrate, 3-(morpholin-4-yl)benzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
MP:254-257°C.
Anal. Calcd. for :C2oH23N50:C,68.47;H,6.63;N,20.04.
Found:C,68.56;H,6.73;N,20.30. MS(EI) :349(M+) .
XH-NMR (400MHz,DMSO-d6)δ(ppm) : 1.20(3H,d, J=7.OHz) ,
1.22(3H,d,J=7.lHz), 3.02(2H,m), 3.04(4H,t, J=4.8Hz) ,
3.70(4H,t,J=4.8Hz), 4.78(1H,S), 6.59( lH,d, J=7.6Hz) , 7.74(lH,s),
7.13(lH,dd,J=7.5 and 8.1Hz), 7.22(lH,s), 9.48( lH,brs) , 12.09(lH,brs) .
Example 366
5-Cyano-6-cyclopropyl-4, 7-dihydro-4-( 3-(morpholin-4- yl)phenyl)-2H-pyrazolo[3, 4-b]pyridine
The title compound was prepared from methyl eyelopropanecarboxylate, 3-(morpholin-4-yl)benzaldehyde and 3- aminopyrazole in the same manner as in Example 94.
MP:>260°C. MS(EI) :347(M+) .
XH-NMR ( 400MHz, DMSO-de)δ(ppm) : 0.86(4H,m), 1.93-1 -98( lH,m) , 3.05(4H,t,J=4.6Hz), 3.70(4H,t, J=4.6Hz) , 4.79(lH,s),
6.56(lH,d,J=7.5Hz), 6.74(lH,s), 6.77(lH,s), 7 ,13( lH,dd, J=7.8 and 7.8Hz), 7.20(lH,s), 8.98(lH,brs) ,12.09(lH,brs) .
The compounds of the above-described Examples are as follows .
Example 294 Example 295 Example 296 Example 297
Example 298 Example 299 Example 300 Example 301
Example 302 Example 303
Example 306 Example 307 Example 308 Example 309
Example 310 Example 311 Example 312 Example 313
Example 314 Example 315 Example 316 Example 317
Example 318 Example 319 Example 320 Example 321
Example 322 Example 323 Example 324 Example 325
Example 326 Example 327 Example 328 Example 329
Example 330 Example 331 Example 332 Example 333
Example 335 Example 336 Example 337
Example 338 Example 339 Example 340 Example 341
Example 342 Example 343 Example 344 Example 345
Example 347 Exa pl e 348 Example 349
Example 350 Example 351 Example 352 Example 353
Example 354 Example 355 Example 356
Example 357
Example 358 Example 359 Example 360 Example 361
Example 362 Example 363 Example 364 Example 365
Example 366 Formulation Example 1
The compound of Example 1 (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were thoroughly mixed and kneaded well with a binder made of corn starch (2 parts). The kneaded product was passed through a 16 mesh sieve, dried in an oven at 50°C and passed through a 4 mesh sieve. The kneaded powder thus obtained, corn starch (8 parts), crystalline cellulose (11 parts) and talc (9 parts) were thoroughly mixed and compression-punched to give tablets containing 0.5 mg of the active ingredient per tablet. Formulation Example 2
The compound of Example 1 ( 1.0 mg) and sodium chloride (9.0 mg) were dissolved in water for injection and the solution was filtered to remove pyrogen. The filtrate was transferred into ampoules under sterile conditions. After sterilization, the ampoules were weld-sealed to give injections each containing 1.0 mg of the active ingredient.
The effects of the compounds of the present invention on glycogen synthase kinase-3 beta (GSK-3β) were evaluated and confirmed as follows.
Experimental Example 1: GSK-3β-inhibitory activity
CREB phosphopeptide (4.6 nmol), rabbit GSK-3β (0.5 unit),
ATP (5 nmol), [γ-32P]ATP (12.3 kBq) and a test compound were reacted in a GSK-3β buffer solution (25 μL) (20 mmol/L Tris-HCl (pH 7.5), 10 mmol/L magnesium chloride, 5 mmol/L dithiothreitol) containing 1% dimethyl sulfoxide, at 30°C for 20 minutes. The reaction product (10 μL) was adsorbed on a P81 ion-exchange paper, and the paper was washed with phosphoric acid (100 mmol/L) and measured for cpm on a scintillation counter. As a result, the compounds of the present invention showed the IC50 values of 1 to 1000 nmol/L. For example, the IC50 values of the compounds of Examples 1, 14, 27, 66 and 140 were 210, 170, 25, 51 and 24 nmol/L, respectively. CREB Phosphopeptide is Lys-Arg-Arg-Glu-Ile-Leu-Ser-Arg- Arg-Pro-Ser(P)-Tyr-Arg.
Experimental Example 2: GSK-3β-inhibitory activity in rat cultured hippoeampal neurons Hippoeampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippoeampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor) and the culture was continued for 3 hours, whereby phosphorylation of Tau protein was induced. After the completion of culture, the level of phosphorylation of Tau protein was determined by EIA method using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β) and the inhibitory effect of the GSK-3β inhibitor on the neurons was evaluated. Fig. 1 shows the GSK-3β-inhibitory activity of the compounds of Example 47 and Example 137.
Experimental Example 3: Effect on amyloid β-induced cytotoxicity in rat cultured hippoeampal neurons
Hippoeampal neurons were obtained from rat embryos on the 18th day after conception. After culturing the hippoeampal neurons for 7 days, the neurons were treated with amyloid β (25-35) (20 μmol/L) and a test compound (GSK-3β inhibitor) and the culture was continued for 24 hours, whereby cytotoxicity (decreased activity of intracellular dehydrogenases) was induced. After the completion of culture, activity of intracellular dehydrogenases was determined and the effect of the GSK-3β inhibitor on the amyloid β-induced cytotoxicity was evaluated. Fig. 2 shows the effect of the compounds of Example
66 on amyloid β-induced cytotoxicity. Experimental Example 4: GSK-3β-inhibitory effect in gerbil brain ischemia model
A test compound (GSK-3β inhibitor) was intraperitoneally administered to gerbils and 30 minutes later, brain ischemia was created by shutting off (for 4 minutes) all carotid arteries, whereby phosphorylation of Tau protein in the brain was induced. Three hours after the brain ischemia, the hippocampus, was obtained from the gerbil brain and the level of phosphorylation of Tau protein was determined by Western blot using phosphorylated Tau-recognizing antibody (phosphorylated site by GSK-3β), based on which the GSK-3β- inhibitory effect of the GSK-3β inhibitor in the gerbil brain was evaluated. Fig. 3 shows the GSK-3β-inhibitory effect of the compounds of Example 27 in gerbil brain ischemia model.
Industrial Applicability
The compounds of the present invention show a selective and strong inhibitory action on glycogen synthase kinase-3 beta (GSK-3β), and are useful as medicaments for prevention and/or treatment of diabetes, diabetic complications and neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitie Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinson dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic-depressive psychosis and the like), or as immunopotentiators .
This application is based on patent application Nos. 2001-304707, 2001-26379 and 2001-081238 filed in Japan, the contents of which are hereby incorporated by reference.

Claims

1. A dihydropyrazolopyridine compound of the formula (I):
wherein
R' is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group optionally having substituent( s) , phenylalkyl optionally having substituent( s) , or a group of the formula: -COOR8 (wherein R8 is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent( s)) ; R1 and R2 are the same or different and each is hydrogen, alkyl, acyl, cycloalkyl, hydroxy, thiol, halogen, amino, formyl, carboxy, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group or phenylalkyl; R3 is
(1) alkyl or haloalkyl,
(2) cycloalkyl,
(3) phenyl optionally having substituent( s) , (4) aromatic heterocyclic group,
(5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
(6) a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom(s) , or
(7) a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, wherein the groups of (2) to (7) may have one or more substituent( s) , or a group selected from the groups represented by the following formulas (II) and (III),
(ID (ill)
wherein R6 and R7 are each phenyl optionally having substituent(s) or an aromatic heterocyclic group, or R2 and R3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent( s) ;
R4 is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and R5 is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalkyl, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s) , an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, or R4 and RΞ in conjunction may form a 5 or 6 membered ring optionally containing heteroatom(s) , provided that when R°, R1 and R2 are each hydrogen, R4 is methoxycarbony1 and R5 is methyl, then R3 should not be phenyl, 2-chloropheny, 3-nitrophenyl, 4- carboxyphenyl or 4-methoxycarbonylphenyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
2. The dihydropyrazolopyridine compound of claim 1, wherein R5 is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituen ( s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
3. The dihydropyrazolopyridine compound of claim 1, wherein R1 is hydrogen, alkyl, phenyl optionally having substituent(s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
4. The dihydropyrazolopyridine compound of claim 1, wherein R2 is hydrogen or alkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
5. The dihydropyrazolopyridine compound of claim 1, wherein R3 is phenyl optionally having 1 to 3 substituent( s) , naphthyl, 2,l,3-benzoxadiazol-4-yl or 3, 4-dihydro-2H-benzopyran-8-yl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
6. The dihydropyrazolopyridine compound of claim 1, wherein R4 is alkoxycarbonyl having 2 to 5 carbon atoms, cyano or nitro, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
7. The dihydropyrazolopyridine compound of claim 1, wherein R5 is alkyl having 2 to 4 carbon atoms, cyclopropyl, phenyl, thienyl or hydroxyalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof .
8. The dihydropyrazolopyridine compound of claim 1, wherein R2 and R3 in conjunction form a ring containing sulfur atom and the ring is condensed with a benzene ring optionally having substituent( s) , or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
9. The dihydropyrazolopyridine compound of claim 1, wherein R° is hydrogen or a group of the formula: -COOR8 (wherein R8 is alkyl, aryl optionally having substituent( s) or aralkyl optionally having substituent( s)) , or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
10. The dihydropyrazolopyridine compound of claim 1, which is selected from the group consisting of
(32) ethyl 4, 7-dihydro-4-(2-methoxyphenyl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate,
(47) ethyl 4-(2-chloro-3-trifluoromethylphenyl)-4, 7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate,
(66) ethyl 4,7-dihydro-4-(naphthalen-l-yl)-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate,
(73) ethyl 4-(3,4-dihydro-2H-benzopyran-8-yl)-4, 7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine-5-carboxylate, (87) ethyl 4-(2-chlorophenyl)-4, 7-dihydro-6-(thiophen-2-yl)-
2H-pyrazolo[3, 4-b]pyridine-5-carboxylate,
(116) ethyl 4-(2, l,3-benzoxadiazol-4-yl)-4,7-dihydro-6-propyl-
2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
( 122) 4-(2,3-dichlorophenyl)-4,7-dihydro-5-nitro-6-propyl-2H- pyrazolo[3, 4-b]pyridine,
( 140) 4-(2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- propyl-2H-pyrazolo[3, 4-b]pyridine,
( 147) 4-(2-bromo-3-cyanopheny1) -5-cyano-4, 7-dihydro-6-pheny1-
2H-pyrazolo[3, 4-b]pyridine, (158) 4-(2, l,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6- phenyl-2H-pyrazolo[3, 4-b]pyridine,
(171) 4-( 2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6-
(thiophen-2-yl)-2H-pyrazolo[3, 4-b] yridine,
(182) ethyl 4-(2-bromo-3-nitrophenyl)-4,7-dihydro-6-propyl-2H- pyrazolo[3, 4-b]pyridine-5-carboxylate,
( 183) ethyl 4-(2-bromo-3-cyanophenyl)-4, 7-dihydro-6-propyl-2H- pyrazolo[3, 4-b] yridine-5-carboxylate,
( 189 ) 4-(2-bromo-3-nitrophenyl)-5-cyano-4, 7-dihydro-6-propy1- 2H-pyrazolo[ 3, 4-b]pyridine,
(205) ethyl 2-tert-butoxycarbonyl-4-(2-chlorophenyl)-4,7- dihydro-6-propyl-2H-pyrazolo[3 , 4-b]pyridine-5-carboxylate, (240) ethyl 4-(2, l,3-benzoxadiazol-4-yl)-6-ethyl-4,7-dihydro- 2H-pyrazolo[ 3, 4-b]pyridine-5-carboxylate,
(257 ) 4-(2, 1, 3-benzoxadiazol-4-yl)-5-cyano-4, 7-dihydro-6- hydroxymethyl-2H-pyrazolo[ 3, 4-b]pyridine, (260) 4-(2-bromo-3-cyanopheny1)-5-cyano-4, 7-dihydro-6- isopropyl-2H-pyrazolo[ 3, 4-b]pyridine, (264) 4-(2,l,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6- isopropyl-2H-pyrazolo[ 3, 4-b]pyridine, and
(268 ) 4-(2-bromo-3-cyanophenyl)-5-cyano-6-cyclopropyl-4,7- dihydro-2H-pyrazolo[ 3, 4-b]pyridine, a tautomer, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
11. A medicament comprising a dihydropyrazolopyridine compound of claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
12. A pharmaceutical composition comprising a dihydropyrazolopyridine compound of claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.
13. A glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of claim 1, an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.
14. The medicament of claim 11, which is used for prevention and/or treatment of a disease caused by glycogen synthase kinase-3 beta hyperactivity.
15. The medicament of claim 11, which is used for prevention and/or treatment of a neurodegenerative disease.
16. The medicament of claim 15, wherein the disease is selected from the group consisting of Alzheimer's disease, ischemic cerebrovascular disorder, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitie Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinson dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease and manic-depressive psychosis.
17. The medicament of claim 11, which is used for prevention and/or treatment of diabetes and diabetic complications.
18. The medicament of claim 11, which is used as an immunopotentiator.
EP02710458A 2001-02-02 2002-02-01 Dihydropyrazolopyridine compounds and pharmaceutical use thereof Withdrawn EP1355909A2 (en)

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