AU733034B2

AU733034B2 - Pyrazolopyridine compound and pharmaceutical use thereof

Info

Publication number: AU733034B2
Application number: AU34621/97A
Authority: AU
Inventors: Atsushi Akahane; Hiromichi Itani; Satoru Kuroda; Yasuyo Shimizu
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1996-07-18
Filing date: 1997-07-17
Publication date: 2001-05-03
Anticipated expiration: 2017-07-17
Also published as: AU3462197A

Description

WO 98/03507 PCT/JP97/02493 PYRAZOLOPYRIDINE COMPOUND AND PHARMACEUTICAL USE THEREOF Field of the Invention The present invention relates to a novel pyrazolopyridine compound and a salt thereof which are useful as medicaments.

Background Art Some pyrazolopyridine compounds to be useful as psychostimulant, remedy for renal failure, or the like are known EP-0299209, EP-0379979, etc.).

Disclosure of the Invention The present invention relates to a novel pyrazolopyridine compound and a salt thereof useful as medicaments; processes for the preparation of said pyrazolopyridine compound and a salt thereof; a pharmaceutical composition comprising, as an -active ingredient, said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof; a use of said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazolopyridine compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazolopyridine compound or pharmaceutically acceptable salt thereof to a human being or an animal.

The pyrazolopyridine compound and a salt thereof are adenosine antagonists (especially, Ai receptor antagonist) and possess various pharmacological actions such as cognitive enhancing action, analgesic action, locomotor action, WO 98/03507 PCT/JP97/02493 antidepressant action, diuretic action, cardioprotective effect, cardiotonic action, vasodilating action cerebral vasodilating action, etc.), the action of increasing the renal blood flow, renal protective effect, improvement action of renal function, enhancing action of lipolysis, inhibition action of anaphylactic bronchoconstriction, acceleration action of the insulin release, the action of increasing the production of erythropoietin, inhibiting action of platelet aggregation, or the like.

They are useful as cognitive enhancer, antidementia drug, psychostimulant, analgesic, cardioprotective agent, antidepressant, ameliorants of cerebral circulation, tranquilizer, drug for heart failure, cardiotonic agent, antihypertensive agent, drug for renal failure (renal insufficiency), drug for renal toxicity, renal protective agent, drug for improvement of renal function, diuretic, drug for edema, antiobesity, antiasthmatic, bronchodilator, drug for apnea, drug for gout, drug for hyperuricemia, drug for sudden infant death syndrome (SIDS), ameliorants of immunosuppressive action of adenosine, antidiabetic agent, drug for ulcer, drug for pancreatitis, drug for Meniere's -syndrome, drug for anemia; drug for thrombosis, drug for myocardial infarction, drug for obstruction, drug for arteriosclerosis obliterans, drug for thrombophlebitis, drug for cerebral infarction, drug for transient ischemic attack, drug for angina pectoris, or the like; WO 98/03507 PCT/JP97/02493 and useful for the prevention and/or treatment of depression, dementia Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, etc.), anxiety, pain, cerebrovascular disease stroke, etc.), heart failure; hypertension essential hypertension, nephrogenous hypertension, etc.); circulatory insufficiency (acute circulatory insufficiency) caused by, for example, ischemia/reperfusion injury (e.g.

myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reperfusion injury, etc.), shock endotoxin shock, hemorrhagic shock, etc.), surgical procedure, or the like; post-resuscitation asystole; bradyarrhythmia; electro-mechanical dissociation; hemodynamic collapse; SIRS (systemic inflammatory response syndrome); multiple organ failure; renal failure (renal insufficiency) acute renal failure, etc.), renal toxicity renal toxicity induced by a drug such as cisplatins, gentamicin, FR-900506 (disclosed in EP- 0184162), cyclosporin cyclosporin A) or the like; glycerol, etc.], nephrosis, nephritis, edema cardiac edema, nephrotic edema, hepatic edema, idiopathic edema, drug edema, acute angioneurotic edema, hereditary angioneurotic edema, carcinomatous ascites, gestational edema, etc.); obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer such as peptic WO 98/03507 PCT/JP97/02493 ulcer gastric ulcer, duodenal ulcer, etc.), pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus mechanical ileus, adynamic ileus, etc.); myocardial infarction, thrombosis arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like.

The novel pyrazolopyridine compound of the present invention can be shown by the following formula

O

N--R

2

N

(I)

R'

N

wherein R' is aryl, and

R

2 is lower alkyl substituted with unsaturated 3 to 8membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), which may have one or more substituent(s); a group of the formula:

R

4 (CH N -R (CHydrogen, lower alkyl, ar(lower)alkyl or acyl, [wherein R 3 is hydrogen, lower alkyl, ar(lower)alkyl or acyl, WO 98/03507 PCT/JP97/02493 R" is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is an integer of 1 or 2]; a group of the formula: \R6 (wherein R 5 and R 6 are each lower alkyl]; or quinuclidinyl, or a salt thereof.

The object compound and a salt thereof of the present invention can be prepared by the following reaction schemes.

Process 1 0 0 NH N-R 2 -N XN

X-R

2 R- xR N N (II) (III) (I) or a salt thereof or a salt thereof WO 98/03507 WO 9803507PCTIJP97/02493 Process 2 03 NCz) R

(IV)

(II)

or a salt thereof NN-R3 I

N

(Ia) or a salt thereof WO 98/03507 WO 9803507PCT/JP97/02493 Process 3

N

elimination reaction of acyl group N-R 2 (lb) (Ic) or a salt thereof or a salt thereof Process 4j

N

dealkylat ion reaction (Id) (Ic) or a salt thereoforaslthef or a salt thereof WO 98/03507 WO 9803507PCT/JP97/02493 Process N-R 2 c

N

N-R 2 e

N

alkylation reaction (Ic) (Ie) or a salt thereof or a salt thereof Process 6

-R

2 c N-R I b

N

acylation reaction (Ic) (Tb) or a salt thereoforaslthrf or a salt thereof WO 98/03507 WO 9803507PCTIJP97/02493 Process 7

NH

formation reaction of thiazole ring

(V)

or a salt thereof 0 S N-A ji N N NN or a salt thereof wherein R' and R' are each as defined above,

R

3 a is acyl, R"b is a group of formula: (CH 2Yn WO 98/03507 WO 9803507PCT/JP97/02493 wherein A, m, n, R 3 and R4b are each as defined above;

R

2 c is a group of formula: wherein A, m, n and R'b are each as defined above and R 3 1 is hydrogen; R" is a group of formula: (CH2)- 3 wherein A, m, n and are each as defined above and R 3, is lower alkyl; R is a group of formula: wherein A, m, n, R 3 c and R4 are each as defi ned above, or a group of formula: -C N 1 0 WO 98/03507 PCT/JP97/02493 wherein

R

5 and R 6 are each as defined above; and X is a leaving group.

In addition to the processes as mentioned above, the object compound and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in a manner similar thereto.

The starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto.

The object compound and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.

It is to be noted that the object compound may include the geometrical isomer(s) due to the double bond(s) and/or the stereo isomer(s) due to the asymmetric carbon atom(s). In this regard, one isomer can be converted to another according to a conventional method in this field of the art.

It is also to be noted that the solvating form of the compound hydrate, etc.) and any form of the crystal of the compound are included within the scope of the present invention.

Suitable salts of the object compound are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt sodium salt, potassium salt, etc.) and an alkaline earth metal salt calcium salt, magnesium WO 98/03507 PCT/JP97/02493 salt, etc.), an ammonium salt, an organic base salt (e.g.

trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), a salt with an amino acid arginine, aspartic acid, glutamic acid, etc.), and the like.

Suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof and which appear in the above and following description in the present specification are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.

Suitable "lower alkyl" may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be (Ci-Ch) alkyl and the more preferred one may be methyl.

Suitable "unsaturated 3 to 8-membered heteromonocyclic group containing 1 or -2 sulfur atom(s) and 1 to 3 nitrogen atom(s)", which group may have 1 to 3 substituent(s) lower alkyl, etc.), may include thiazolyl, isothiazolyl, thiadiazolyl 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, and the like, in WO 98/03507 WO 9803507PCT/JP97/02493 which the preferred one may be 5 or 6-memnbered one, and the more preferred one may be thiazolyl.

Suitable "acyl 1 may include lower alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, etc.); carboxy; protected carboxy; hydroxysulfonyl; and the like.

Suitable "protected carboxy" may be an esterified carboxy, in which concrete examples may be the ones such as lower alkoxycarbonyl g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 1 -cyclopropylethoxycarbonyl, etc.) which may have substituent(s), for example, lower alkanoyloxy- (lower) alkoxycarbonyl acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, butyryloxymethoxycarbonyl, valeryloxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, 1 -acetoxyethoxycarbonyl, 1 -propionyloxyethoxycarbonyl, pivaloyloxymethoxycarbonyl, 2-propionyloxyethoxycarbonyl, hexanoyloxymethoxycarbonyl, etc.]; lower alkanesulfonyl (lower) alkoxycarbonyl [e.g.

2-mesylethoxycarbonyl, etc.]; mono(or di or tri)halo(lower)alkoxycarbonyl 2iodoethoxycarbonyl, 2,2,2-trichioroethoxycarbonyl, etc.]; lower alkenyloxycarbonyl vinyloxycarbonyl, allyloxycarbonyl, etc.]; lower alkynyloxycarbonyl ethynyloxycarbonyl, propynyloxycarbonyl, etc.]; WO 98/03507 WO 9803507PCT/JP97/02493 ar (lower) alkoxycarbonyl [preferably mono-(or di- or tri-)phenyl (lower) alkoxycarbonyl]I which may have substituent(s) (ie. g. benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, benzhydryloxycarbonyl, bis (methoxyphenyl) methoxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4.-hydroxy-3,5-di-tert-butylbenzyloxycarbonyl, etc.]; aryloxycarbony]. which may have substituent(s) [e.g.

phenoxycarbonyl, 1 -chlorophenoxycarbonyl, tolyloxycarbonyl, I4tert-butylphenoxycarbonyl, xylyloxycarbonyl, mesityloxycarbonyl, cumenyloxycarbonyl, etc.] or the like; amidated carboxy, in which concrete examples may be carbamoyl; N- lower) alkylcarbamoyl g. N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbarnoyl, etc.); N- (higher) alkylcarbamoyl N-heptylcarbamoyl, N- (2methylheptyl )carbamoyl, N-nonylcarbamoyl, N-decanylcarbamoyl, N-tricyclo 1.1 1. 7 decanylcarbamoyl, N-undecanylcarbamoyl, N- (bicyclo 3. 2lundecanyl)carbamoyl, N-dodecanylcarbarnoyl, N-tridecanylcarbamoyl, N-tetradecanylcarbamoyl, N-pentadecany icarbamoyl, N-hexadecanylcarbamoyl, N-heptadecanylcarbamoyl, N-octadecanylcarbamoyl, N-nonadecanylcarbamoyl, N-icosanylcarbamoyl, etc.); N ,N-di (lower).alkylcarbamoyl lie. g. N, N-dimethyicarbamoyl, 1 4 WO 98/03507 WO 9803507PCT/JP97/02493 N, N-diethylcai'bamoyl, N-methyl-N-ethylcarbamoyl, NN-dipropylcarbacnoyl, N,N-di (tert-butyl)carbamoyl, N-pentyl-N-hexylcarbamoyl, etc.]; N-lower alkyl-N-ar(lower) alkylcarbamoyl N-methyl-Nbenzylcarbamoyl, etc.); N-carboxy (lower) alkylcarbamoyl g.

N-carboxymethylcarbamoyl, N- (2-carboxyethyl) carbamoyl, N- (2carboxypropyl)carbamoyl, N- (3-carboxypropyl) carbamoyl, N- (1carboxymethylethyl.)oarbamoyl, N- ('-carboxybutyl) carbamoyl, N- (2carboxymethyl-2-methylethyl) carbamoyl, N- (5-carboxypentyl) carbamoyl, N- (3-carboxyhexyl) carbamoyl, etc.); N-protected carboxy(lower)alkylcarbamoyl, in which the preferred one may be N-esterified carboxy(lower)alkylcarbamoyl, and the more preferred one may be N-lower alkoxycarbonyi~lower)alkylcarbamoyl [ie. g.

N- (methoxycarbonylmethyl )carbamoyl, N- (ethoxycarbonylmethyl) carbamoyl, N- (2-ethoxycarbonylethyl )carbamoyl, N- (2-tert-butoxycarbonylethyl) carbamoyl, N- (3-methoxycarbonyipropyl )carbamoyl, N- (1-propoxycarbonyipropyl )carbamoyl, N- (1-isopropoxycarbonylmethylethyl) carbamoyl, N-(Cbutoxycarbonylmethyl) carbamoyl, N-(Ctert-butoxycarbonylmethyl )carbamoyl, N- (4-isobutoxycarbonylbutyl) carbamoyl, N- C2-tert-butoxycarbolylmethyl-2iflethylethyl )carbamoyl, 1 WO 98/03507 WO 9803507PCT/JP97/02493 N- (3-pentyloxycarbonylpentyl) carbamoyl, N- (6 -hexyloxycarbonyihexyl )carbamoyl, N- [(I-cyclopropylethoxy) carbonylmethyl Jcarbamoyl, etc.]; N-lower alkyl-N-carboxy(lower)alkylcarbamoyl [ie. g. Nmethyl-N- (carboxymethyl )carbanoyl, N-methyl-N- (2-carboxyethyl) carbamoyl, N-ethyl-N- (2-carbox ypropyl),carbamoy., N-propyl-N- (3carboxypropyl) carbamoyl, N-isopropyl-N- (1-carboxymethylethyl.) carbamoyl, N-butyl-N- (4f-carboxybutyl )carbamoyl, N-tert-butyl-N-( 2-carboxymethyl-2-methylethyl)carbamoyl, N-pentyl-N- pentyl) carbamoyl, N-hexyl-N- (3-carboxyhexyl) carbamoyl, etc.]; N-lower alkyl-N-protected carboxy (lower)alkylcarbamoyl, in which the preferred one may be N-lower alkyl-N-esterified carboxy(lower)alkylcarbamoyl, and the more preferred one may be N-lower a2lkyl-N-lower alkoxycarbonyl (lower) alkylcarbamoyl [e.g.

N-methyl-N- (methoxycarbonylmethyl) carbamoyl, N-methyl-N- (ethoxycarbonylmethyl )carbamoyl, N-methyl-N-C 2-ethoxycarbonylethyl) carbamoyl, N-ethyl-N- (2-tert-butoxycarbonylethyl )carbamoyl, Npropyl-N- (3-methoxycarbonylpropyl) carbamoyl, N-isopropyl-N- (1propoxycarbonyipropyl) carbanoyl, N-propyl-N- (1-isopropoxycarbonylmethylethyl) carbamoyl, N-butyl (butoxycar'bonylmethyl) carbamoyl, N-isobutyl-N- (tert-butox-ycarbonylmethyl) carbamoyl, N-butyl-N- (J-isobutoxycarbonylbutyl) carbamoyl, N-methyl-N- (2tert-butoxycarbonylmethyl-2-methylethyl) carbamoyl, N-pentyl-N- (3pentyloxycarbonylpentyl) carbamoyl, N-hexyl-N- (6-hexyloxycarbonyl-.

hexyl) carbamoyl, N-ethyl-N- [_(1-cyclo'propylethoxy) carbonylmethyl] carbamoyl, etc.); 1 6 WO 98/03507 PCT/JP97/02493 N-hydroxy(lower)alkylcarbamoyl [e.g.

N-hydroxymethylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, N-(1hydroxyethyl)carbamoyl, N-(3-hydroxypropyl)carbamoyl, N-(1hydroxybutyl)carbamoyl, N-(2-hydroxymethyl-2-methylethyl)carbamoyl, N-(3-hydroxyhexyl)carbamoyl, etc.]; a group of the formula:

-CO-N

wherein a group of the formula:

-NQ

is N-containing heterocyclic group which may have one or more substituent(s), in which N-containing heterocyclic group may contain hetero atom(s) such as N, 0 or S in its ring; or the like; or the like.

Suitable example of the aforesaid "N-containing heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl 1H-azepinyl, etc.), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its Noxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H- 1,2,3-triazolyl, etc.), tetrazolyl 1H-tetrazolyl, 2H- 1 7 WO 98/03507 PCT/JP97/02493 tetrazolyl, etc.) etc.; saturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl perhydro-IH-azepinyl, etc.), pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7-azabicyclo[2.2.1]heptyl, 3azabicyclo[3.2.2]nonanyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s),-for example, dihydrooxazinyl 5,6-dihydro-4H-dihydro-1,3-oxazinyl, etc.), oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.; unsaturated condensed heterocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 or 2 sulfur 1 8 WO 98/03507 PCT/JP97/02493 atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl 1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, thiomorpholinyl, etc.; unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; in which the preferred one may include saturated 3 to 8membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s); and saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s).

The "N-containing heterocyclic group" thus defined may have one or more (preferably 1 to 3) substituent(s) such as lower alkyl as mentioned above; hydroxy(lower)alkyl hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 1-methyl-1hydroxymethylethyl, 4-hydroxypentyl, 3-hydroxyhexyl, etc.); lower alkoxy(lower)alkyl methoxymethyl, 2-methoxyethyl, 1ethoxyethyl, 3-propoxypropyl, 2-(tert-butoxy)butyl, WO 98/03507 WO 9803507PCT/JP97/02493 pentyl, 3-hexyloxyhexyl, etc.); acyloxy(lower)alkyl such as lower alkanoyloxy(lower)alky. (e.g.

acetoxymethyl, I -acetoxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 3-propionyloxypropyl, 2-butyryloxybutyl, 4-pivaloyloxypentyl, 6-hexanoyloxyhexyl, etc.) or the like; protected carboxy such as lower alkoxycarbonyl as mentioned above; carboxy; ar(lower)alkyl such as phenyl(lower)alkyl (e.g.

benzyl, phenethyl, etc.), dipheny. (lower) alkyl benzhydryl, etc.) or triphenyl (lower) alkyl trityl, etc.); lower alkylamino (e.g..methylamino, ethylamino, propylamino, butylamino, tert-butylamino, pentylamino, hexylamino, etc.); acyl such as lower alkanoyl as mentioned above; or the like.

Suitable "~aryl" may include phenyl, naphthyl, anthryl, and the like, in which the preferred one may be (C 6 -Cio) aryl, and the more preferred one may be phenyl.

This £aryll' may have one or more.(preferably I to 3) substituent(s) selected from the group consisting of halogen fluoro, chloro, bromo, iodo), lower alkyl as mentioned above, lower alkoxy methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.), hydroxy, lower alkylsilyloxy trimethylsilyloxy, tert-butyldimethylsilyloxy, etc,), phenyl (lower) alkoxy phenylmethoxy, phenylethoxy, phenylpropoxy, phenylbutoxy, phenylpentyloxy, phenylhexyloxy, etc.), phenyl which may have halo (lower) alkyl trifluoro- .methylphenyl, etc.), and the like.

Suitable Iar (lower) alkylI may include phenyl (lower) alkyl 2 0 WO 98/03507 PCT/JP97/02493 benzyl, phenethyl, etc.), diphenyl(lower)alkyl (e.g.

benzhydryl, etc.) or triphenyl(lower)alkyl trityl, etc.) and the like, in which the preferred one may be phenyl(lower)alkyl, and the more preferred one may be phenyl (Ci-C4) alkyl.

This "ar(lower)alkyl" may have one or more (preferably 1 to 3) substituent(s) such as lower alkoxy as mentioned above, and the like.

Suitable "lower alkylene" may include straight or branched ones such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and the like, in which the preferred one may be (Ci-Ch) alkylene, and the more preferred ones are methylene and ethylene.

Suitable "a leaving group" may include halogen as mentioned above, hydroxy, acyloxy such as alkanoyloxy acetoxy, propionyloxy, etc.), sulfonyloxy mesyloxy, tosyloxy, etc.), and the like.

Of the object pyrazolopyridine compounds the preferred one may be the compound wherein R' is phenyl, and

R

2 is lower alkyl substituted with thiazolyl which may have 1 to 3 lower alkyl; a group of the formula:

R'

N R 3 (CH2).

[wherein R 3 is hydrogen, lower alkyl, phenyl(lower)alkyl, 2 1 WO 98/03507 PCT/JP97/02493 lower alkanoyl, lower alkoxycarbonyl, or phenyl(lower)alkoxycarbonyl, R' is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is an integer of 1 or 2]; a group of the formula: N+ yR S_ \R 6 [wherein R 5 and R' are each lower alkyl]; or quinuclidinyl, and the more preferred one may be the compound wherein R' is phenyl, and

R

2 is lower alkyl substituted with thiazolyl which may have 1 to 3 lower alkyl, and the most preferred one may be the compound wherein R' is phenyl, and

R

2 is a group of the formula:

R

4 N R' CH2)n N [wherein R 3 is hydrogen, lower alkyl, phenyl(lower)alkyl, lower alkanoyl or lower alkoxycarbonyl, R' is hydrogen, 2 2 WO 98/03507 PCT/JP97/02493 A is lower alkylene, m is an integer of 0, and n is an integer of 1 or and the most particularly preferred one may be the compound (I) wherein R' is phenyl, and

R

2 is a group of the formula:

R

4 (H R 3 [wherein R 3 is lower alkyl,

R

4 is hydrogen, A is lower alkylene, m is an integer of 0, and n is an integer of 2].

The processes for the preparation of the object compound and a salt thereof (Process 1 to 7) are explained in detail in the following.

Process 1 The compound and a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.

Suitable salt of the compound (III) can be referred to the ones as exemplified for the compound The present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, 2 3 WO 98/03507 PCT/JP97/02493 nitrobenzene, toluene, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction, preferably in ones having strong polarities. Among the solvents, hydrophillic solvents may be used in a mixture with water. When the compound (III) is in liquid, it can also be used as a solvent.

The reaction is preferably conducted in the presence of a base, for example, inorganic base such as alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal hydride, organic base such as benzyltrimethylammonium hydroxide, trimethylamine, and the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature, under warming or under heating.

The present reaction is preferably carried out in the presence of alkali metal halide sodium iodide, potassium iodide, etc.), alkali metal thiocyanate sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl azodicarboxylate diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like.

When X is -OH, activation of OH with triphenylphosphine and the like may be necessary.

Process 2 2 4 WO 98/03507 PCT/JP97/02493 The compound (Ia) and a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound

(IV).

The reaction of this process can be carried out in a manner similar to that in Process 1.

Process 3 The compound (Ic) and a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to elimination reaction of acyl.

Suitable salts of the compound (Ib) and (Ic) can be referred to the ones as exemplified for the compound This reaction is carried out in accordance with a conventional method such as hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal sodium, potassium, etc.), an alkaline earth metal magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,0]undec-7ene, or the like.

Suitable acid may include an organic acid formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), and an inorganic acid hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, 2 WO 98/03507 PCT/JP97/02493 hydrogen bromide, etc.). The elimination using Lewis acid such as trihaloacetic acid trichloroacetic acid, trifluoroacetic acid, etc.) or the like is preferably carried out in the presence of cation trapping agents anisole, phenol, etc.).

The reaction is usually carried out in a solvent such as water, an alcohol methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, dioxane, a mixture thereof or any other solvent which does not adversely influence the reaction.

A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

The reaction of this process can be also carried out according to a conventional reduction method employed in this field of the art chemical reduction, catalytic reduction, etc.).

Process 4 The compound (Ic) and a salt thereof can be prepared by subjecting the compound (Id) or a salt thereof to dealkylation reaction.

Suitable salts of the compound (Ic) and (Id) can be referred to the ones as exemplified for the compound This reaction can be carried out by reacting the compound (Id) or a salt thereof with a dealkylating agent.

The dealkylating agent is halo(lower)alkyl haloformate and the like.

The reaction is usually carried out in a conventional 2 6 WO 98/03507 PCT/JP97/02493 solvent such as water, alcohol methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.

Process The compound (Ie) and a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to alkylation reaction.

Suitable salts of the compound (Ic) and (Ie) can be referred to the ones as exemplified for the compound This reaction can be carried out by reacting the compound (Ic) or a salt thereof with an alkylating agent.

The alkylating agent is lower alkyl halide and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction temperature is not critical, and the reaction 2 7 WO 98/03507 PCT/JP97/02493 is usually carried out at ambient temperature, under warming or under heating.

The present reaction is preferably carried out in the presence of alkali metal halide sodium iodide, potassium iodide, etc.), alkali metal thiocyanate sodium thiocyanate, potassium thiocyanate, etc.) or the like.

Process 6 The compound (Ib) and a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to acylation reaction.

Suitable salts of the compound (Ib) and (Ic) can be referred to the ones as exemplified for the compound This reaction can be carried out by reacting the compound (Ic) or a salt thereof with an acylating agent.

The acylating agent is acyl halide corresponding to the acyl to be introduced, acyl anhydride corresponding to the acyl to be introduced, and the like.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or 2 8 WO 98/03507 PCT/JP97/02493 under heating.

Process 7 The compound (If) and a salt thereof can be prepared by subjecting the compound or a salt thereof to formation reaction of thiazole ring.

Suitable salts of the compound and (If) can be referred to the ones as exemplified for the compound This reaction can be carried out by reacting the compound or a salt thereof with a haloacetaldehyde or its reactive derivative.

The haloacetaldehyde or its reactive derivative is bromoacetaldehyde diethyl acetal, and the like.

The object compound of the present invention is an adenosine antagonist and possesses the various pharmacological actions as stated before.

In order to show the usefulness of the compound of the 2 9 WO 98/03507 PCT/JP97/02493 present invention, the pharmacological test result of the representative compound of the present invention is shown in the following.

Test Adenosine antagonistic activity Test Method The adenosine antagonistic activity of the test compound was examined by radioligand binding techniques using 8-cyclopentyl-1,3-dipropylxanthine, [dipropyl-2,3-'H(N)] (3H-DPCPX, 2 x 10-'M) for human A' receptor.

[II] Test Compound 3-[2-(1-Methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-a]pyridine (the compound of Example 2) [III] Test Result The inhibition was more than 90% at the dose of x 10-' The pyrazolopyridine compound and a salt thereof of this invention are usuful as adenosine antagonists and for the prevention and/or the treatment of depression, dementia (e.g.

Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, etc.), anxiety, pain, cerebrovascular disease (e.g.

stroke, etc.), heart failure, and the like.

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyrazolopyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an 3 0 WO 98/03507 PCT/JP97/02493 organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.

The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use.

In addition, auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary. The pyrazolopyridine compound or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce the desired aforesaid pharmaceutical effect upon the process or condition of diseases.

For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the pyrazolopyridine compound varies depending on the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 100 mg of the pyrazolopyridine compound per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 100 mg of the pyrazolopyridine compound

(I)

per kg weight of.a human being or an animal, and in case of oral 3 1 WO 98/03507 WO 9803507PCT/JP97/02493 administration, a daily dose of 0.5 100 mg of the pyrazolopyridine compound MI per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.

The following Preparation and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1 Into a mixture of 3-(2-cyanomethyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-phenllPYrazolo[I ,5-alpyridine (2.0 g) and triethylamine (1.02 ml) in pyridine (10 ml) was introduced hydrogen sulfide at 50*C for 6 hours. The mixture was poured into water. The resulting solid was collected by filtration to give 3-(C3-oxo-2-thiocarbamoylmethyl-2, 3-dihydropyridazin-6-yl) 2-phenylpyrazolo[1 ,5-ailpyridine (2.18 g).

mp 220.0-221.0*C (EtOli) IR (Nujol) :3400, 3270, 3180, 1650, 1610, 1575 cm-' NMR (DMS0-d6, 6 :5.03 (2H, 6.89 (OH, di, J=9.7Hz), 7.03-7.08 (OH, in), 7.06 (OH, d, J=9.7Hz) 7.36-7.50 (J4H, in), 7.64-7-70 (2H, in), 8.04 (11, di, J=8.9Hz) 8.80 (1H, d, J=6.9Hz), 9.42 (lIi 9.86 (OH, s) (t)-APCI/MS :36.2 Anal. Calcd. for Ci9H, 5NsOS .H0 C 61.61, H 4.35, N 18.91 Found :C 61.514, H- 4.25, N 18.85 Preparation 2 3 2 WO 98/03507 PCT/JP97/02493 To a solution of 4-piperidone hydrochloride (25 g) in a mixture of water (200 ml) and tetrahydrofuran (200 ml) was added dropwise benzyl chloroformate (29 ml) at 0 to 10 0 C, and the pH (pH 8.5-9.5) was adjusted with addition of 30% aqueous sodium hydroxide.

To the reaction mixture was added ethyl acetate (250 ml) and organic phase was separated, which was washed two times with 200 ml of saturated sodium chloride in water and dried over magnesium sulfate.

Evaporation of the solvent gave 1-benzyloxycarbonyl-4piperidone (42.5 g, 98.8 yield).

NMR (CDCIa, 6) 2.45 (4H, t, J=6.2Hz), 3.79 (4H, t, J=6.3Hz), 5.18 (2H, 7.36-7.40 (5H, m), (+)-APCI/MS 234 Preparation 3 To a suspension of sodium hydride (7.92 g, 60% dispersion in mineral oil) in dimethyl sulfoxide (250 ml) was added by portions trimethylsulfoxonium iodide (41.63 g) at room temperature under nitrogen atmosphere.

After stirring for 1 hour, to the reaction mixture was added dropwise 1-benzyloxycarbonyl-4-piperidone (42 and the mixture was heated to 55C and stirred for 4 hours.

The reaction mixture was poured into ice water (800 ml) and extracted three times with 800 ml of ethyl acetate.

Organic phase was combined, washed with water (500 ml x 3) and saturated sodium chloride in water, and dried over magnesium 3 3 WO 98/03507 PCT/JP97/02493 sulfate.

Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting with 20% ethyl acetate in n-hexane to give 1-benzyloxycarbonylpiperidine-4-spiro-2'oxirane (23.25 g, 52.2 yield).

NMR (CDClI, 6) 1.39-1.51 (2H, m),-1.76-1.91 (2H, m), 2.69 (2H, 3.41-3.55 (2H, 3.77-3.90 (2H, m), 5.15 (2H, 7.28-7.38 (5H, m) (+)-APCI/MS 248 (M +1) Preparation 4 To a solution of (3R)-3-hydroxypyrrolidine hydrochloride (24.8 g) in a mixture of dioxane (200 ml) and water (200 ml) were added successively with triethylamine (60 ml) and di-tertbutyl dicarbonate (48.2 g) at O0C, which mixture was allowed to warm to ambient temperature and stirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (400 ml), washed successively with 1N aqueous hydrochloric acid (200 ml), saturated sodium hydrogencarbonate in water (200 ml) and saturated sodium chloride in water (200 ml x and dried over magnesium sulfate.

Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give (3R)-1-tertbutoxycarbonyl-3-hydroxypyrrolidine (27.17 g).

NMR (CDC13, 6) 1.46 (9H, 1.89-2.05 (2H, m), 2.77 (1H, 3.30-3.50 (4H, 4.

3 9 -4.4 7 (1H, m) WO 98/03507 PCT/JP97/02493 (+)-APCI/MS 188 Preparation 1-tert-Butoxycarbonyl-4-piperidinol was obtained in 91.2% yield in substantially the same manner as in Preparation 4.

NMR (DMSO-d6, 6) 1.14-1.33 (2H, 1.39 (9H, s), 1.60-1.74 (2H, 2.87-3.01 (2H, m), 3.55-3.71 (3H, 4.67 (1H, d, J=4.1Hz) Preparation 6 1-tert-Butoxycarbonyl-2-(2-hydroxyethyl)piperidine was obtained in substantially the same manner as in Preparation 4.

NMR (CDC13, 6) 1.40-2.05 (8H, 1 .47 (9H, s), 2.60-2.80 (1H, 3.25-3.72 (2H, m), 3.75-4.05 (2H, 4.35-4.50 (1H, m) Preparation 7 To a suspension of lithium aluminum hydride (2.0 g) in tetrahydrofuran (100 ml) was added dropwise a solution of 1tert-butoxycarbonyl-2-(2-hydroxyethyl)piperidine (8.0 g) in tetrahydrofuran (50 ml) at ambient temperature under nitrogen atmosphere.

After stirring for 6 hours, the reaction mixture was refluxed for 3.5 hours.

The reaction mixture was allowed to cool to 5 0 C, and water (2 ml), 4N aqueous sodium hydroxide solution (2 ml) and water (6 ml) were successively added with care.

Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give a residue, which was 3 WO 98/03507 PCT/JP97/02493 chromatographed on silica gel eluting successively with chloroform, a mixture of chloroform and methanol (10:1) and methanol.

Fractions containing desired product were collected and the solvent was removed under reduced pressure to give 2-(2hydroxyethyl)-1-methylpiperidine (2.47 g).

NMR (CDC13, 6) 1.20-1.85 (7H, 1.99-2.12 (2H, m), 2.20-2.35 (1H, 2.37 2.85-2.95 (1H, m), 3.65-3.76 (1H, 3.90-4.04 (1H, m) (+)-APCI/MS 144 (M +1) Preparation 8 To a suspension of 4-hydroxypiperidine (5.0 g) and triethylamine (7.6 ml) in dichloromethane (100 ml) was added dropwise propionyl chloride (4.5 ml) at -70 to -60°C under nitrogen atmosphere.

After stirring for 1 hour, insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give a residue, to which was added ethyl acetate (200 ml), followed by stirring for 30 minutes.

Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give 4-hydroxy-1propionylpiperidine (7.70 g).

NMR (CDCl3, 6) 1.15 (3H, t, J=7.5Hz), 1.37-1.59 (2H, m), 1.82-1.96 (2H, 2.22 (2H, br-s), 2.36 (2H, q, J=7.5Hz), 3.65-4.20 (3H, m) (+)-APCI/MS 158 (M 4 +1) 36 WO 98/03507 PCT/JP97/02493 Preparation 9 To a suspension of lithium aluminum hydride (1.81 g) in tetrahydrofuran (100 ml) was added dropwise a solution of 4hydroxy-1-propionylpiperidine (5.0 g) in tetrahydrofuran (30 ml) at ambient temperature under nitrogen atmosphere.

After stirring for 1 hours, the reaction mixture was refluxed for 4 hours, and then which was allowed to cool to 4°C.

To the resulting mixture were successively added with care water (1.81 ml), 4N aqueous sodium hydroxide solution (1.81 ml) and water (5.43 ml), which was followed by stirring for additional 1 hour.

Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give 4-hydroxy-1propylpiperidine (4.37 g).

NMR (CDC13, 6) 0.89 (3H, t, J=7.4Hz), 1.45-1.69 (4H, m), 1.84-2.19 (5H, 2.24-2.33 (2H, 2.73-2.84 (2H, m), 3.62-3.76 (1H, m) (+)-APCI/MS 144 Preparation 1-Butyryl-4-hydroxypiperidine was obtained in 98.7% yield in substantially the same manner as-in Preparation 8.

NMR (CDCIa, 6) 0.97 (3H, t, J=7.4Hz), 1.40-1.75 (4H, m), 1.80-2.00 (2H, 2.27-2.36 (2H, 2.42 (1H, br-s), 3.10-3.30 (2H, 3.65-3.80 (1H, 3.85-3.98 (1H, m), 4.00-4.15 (1H, m) (+)-APCI/MS 172 (M+1) 3 7 WO 98/03507 PCT/JP97/02493 Preparation 11 1-Butyl-4-hydroxypiperidine was obtained in 98.0% yield in substantially the same manner as in Preparation 9.

NMR (CDC1 3 6) 0.91 (3H, t, J=7.2Hz), 1.20-1.65 (6H, m), 1.80-2.20 (5H, 2.25-2.35 (2H, 2.70-2.80 (2H, m), 3.61-3.75 (1H, m) (+)-APCI/MS 158 Preparation 12 4-Hydroxy-l-pentanoylpiperidine was obtained in 98.3% yield in substantially the same manner as in Preparation 8.

NMR (CDC13, 6) 0.93 (3H, t, J=7.2Hz), 1.20-1.70 (6H, m), 1.80-2.00 (2H, 2.25 (1H, br-s), 2.29-2.38 (2H, m), 3.09-3.27 (2H, 3.65-3.85 (1H, 3.86-4.00 (1H, m), 4.03-4.18 (1H, m) (+)-APCI/MS 186 (MD+1) Preparation 13 4-Hydroxy-l-pentylpiperidine was obtained in 99.4% yield in substantially the same manner as in Preparation 9.

NMR (CDC13, 6) 0.89 (3H, t, J=6.4Hz), 1.20-1.65 (8H, m), 1.85-1.95 (2H, 2.00-2.35 (5H, 2.72-2.83 (2H, m), 3.50-3.75 (1H, m) (+)-APCI/MS 172 Preparation 14 1-Hexanoyl-4-hydroxypiperidine was obtained in 96.7% yield in substantially the same manner as in Preparation 8.

NMR (CDC13, 6) 0.90 (3H, t, J=6.6Hz), 1.20-1.70 (8H, m), 3 8 WO 98/03507 WO 9803507PCT/JP97/02493 1.78-2.00 (2H, in), 2.10 O1H, 2.28-2.37 (2H, in), 3.10-3.30 (2H1, mn), 3.65-3.82 O1Hi) 3.86-3'.99 O1H, mn), ~4.03-4.20 O1H, m) (+)-APCT/MS :200 (MNI+) Preparation 1-Hexyl-4-hydroxypiperidine was obtained in 97.2% yield in substantially the same manner as in Preparation 9.

NMR (CDCl3, 65) :0.88 (3H1, t, J=6.6Hz), 1.20-1.70 (10H, in), 1.80-1.95 (2H1, in), 2.00-2.35 (5H, rn), 2.70-2.85 (2H, in), 3.55-3.75 (1H, m) (+)-APCI/MS :186 (M+1) Preparation 16 1 -Acetylpiperidin- 1 4-ol was obtained in 95.6% yield in substantially the same manner as in Preparation 8.

NMR (DMSO-d(,, 6) :1.10-1.140 (2H1, mn), 1.60-1.80 (2H, mn), 1.97 (31, 2.95 (1H, ddd, J=3.4Hz, 9.6Hz, 13.1Hz), 3.05-3.19 (1H, in), 3.55-3.75 (2H, in), 3.80-3.95 (1H, mn), 4.72 O1H, d, J=4.lHz) Preparation 17 1 -Ethylpiperidin-4-ol was obtained in 87.0% yield in substantially the same manner as in Preparation 9.

NMR (DMS-d6, 65) :0.96 (3H, t, J=7.2Hz), 1.214-1.43 (2H, mn), 1.60-1.75 (211, in), 1.85-2.00 (211, m), 2.26 (211, q, J=7.2Hz), 2.60-2.75 (211, in), 3 9 WO 98/03507 PCT/JP97/02493 (+)-APCI/MS 130 (M+1) Preparation 18 To a solution of isonipecotic acid (5 g) in a mixture of dioxane (50 ml) and water (25 ml) were successively added 38 ml of 1N aqueous sodium hydroxide solution and di-tert-butyl dicarbonate (8.87 g) at O°C, which mixture was allowed to warm to ambient temperature and stirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (200 ml) and water (100 ml).

The pH was adjusted to 2 with 2N aqueous hydrochloric acid.

The organic phase was separated, and dried over magnesium sulfate.

Evaporation of the solvent gave 1-tert-butoxycarbonyl-4piperidinecarboxylic acid (8.4 g).

NMR (DMSO-d6, 6) 1.20-1.50 (2H, 1.39 (9H, s), 1.70-1.90 (2H, 2.30-2.50 (1H, m), 2.65-2.95 (2H, 3.83 (2H, br-d, J=13.2Hz), 12.27 (1H, br-s) Preparation 19 To a suspension of lithium aluminum hydride (350 mg) in tetrahydrofuran (20 ml) was added dropwise a solution of 1-tertbutoxycarbonyl-4-piperidinecarboxylic acid (1 g) at ambient temperature under nitrogen atmosphere.

After stirring for 24 hours, the reaction mixture was allowed to cool to OC, and water (0.35 ml), 4N aqueous sodium hydroxide solution (0.35 ml) and water (1.05 ml) were 4 0 WO 98/03507 PCT/JP97/02493 successively added with care.

Insoluble material was removed by filtration and the filtrate was concentrated in vacuo to give 1-methyl-4piperidinemethanol (600 mg).

NMR (DMSO-ds, 6) 1.00-1.80 (7H, 2.12 (3H, s), 2.72 (2H, br-d, J=11.5Hz), 3.22 (2H, t, J=5.6Hz), 4.40 (1H, t, J=5.3Hz) (+)-APCI/MS 144 Preparation To a stirred suspension of sodium hydride (238 mg) in tetrahydrofuran (50 ml) was added dropwise triethylphosphonoacetate (1.2 ml) at ambient temperature under nitrogen atmosphere.

After stirring for 30 minutes, to the reaction mixture was added dropwise 1-tert-butoxycarbonyl-4-piperidone (1 and the mixture was stirred overnight. To the stirred reaction mixture was added water (1 ml).

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate and washed successively with water (100 ml) and brine (100 ml), and dried over anhydrous magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting with a mixture of nhexane and ethyl acetate to give 1-tert-butoxycarbonyl-4ethoxycarbonylmethylenepiperidine (1.19 g).

NMR (DMSO-d6, 6) 1.17 (3H, t, J=7.1Hz), 1.38 (9H, s), WO 98/03507 WO 9803507PCT/JP97/02493 2.20-2.30 (2H, in), 2.79-2.85 (211, m), 3.314-3.44 (4H, mn), 41.07 (211, q, J=7.lHz), 5.75 (1H, s) Preparation 21 A mixture of 1 -tert-butoxycarbonyl-4-ethoxycarbonylmethylenepiperidine (3 g) and 10% palladium on carbon (50% wet, 600 mng) in methanol (150 ml) was stirred for 2 hours under hydrogen atmosphere.

The catalyst was removed by filtration. Evaporation of the solvent gave 1 -tert-butoxycarbonyl-4-ethoxycarbony lmethy 1piperidine (3.12 g).

NMR (DMSO-dfi, 65) 0.90-1.17 (2H, mn), 1.17 t, J=7.lHz), 1.38 (9H1, 1.55-1.95 (31, m), 2.23 (2H, d, J=7.OHz), 2.55-2.85 (2H1, m), 3.90 (2H1, br-d, J=13.3Hz), 41.05 (2H, q, J=7.lHz) Preparation 22 1 -Methyl-4-piperidineethanol was obtained in 82.0% yield in substantially the same manner as in Preparation 19.

NMR (DMSO-d6i, 6) :1.00-1.40 (511, mn), 1.58 (2H1, br-d, J=12.L4Hz, 1.70-1.90 (2H, in), 2.10 (3H, 2.70 (2H, br-d, J=11.6Hz, 3.41 (2H, q, J=6.51z), 41.31 (1H, t, J=5.1l~z) (+)-APCI/MS :130 Example 1 A mixture of 3- (3-oxo-2-thiocarbamoylmethyl-2, 3-dihydropyridazin-6-yl)-2-phenylpyrazolotl ,5-alpyridine (0.50 g) and broioacetaldehyde.diethyl acetal (0.541 ml) in a mixture of 4 2 WO 98/03507 WO 9803507PCTIJP97/02493 methanol (2.5 ml) and chloroform (5 ml) was refluxed for 514 hours. After evaporating the solvent, the residue was chromatographed on silica gel (40 ml) using a mixture of chloroform and ethyl acetate The desired fractions were collected and evaporated in vacua. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3- [3-oxo-2- (2-thiazolylmethyl) 3-dihydropyridazin-6-yl] (0.23 g) as yellow needles.

mp *-130.0-132.0'C (EtOAc-n-hexane) IR (Nujol) 1665, 1630, 1590, 1520 cm-' NMR (DMS0-d6,(6) 5.68 (2H, 6.96 (OH, d, J=9.7Hz), 7.08 O1H, dt, J=1.3Hz, 6.9Hz), 7.10 (OH, d, J=9.7Hz, 7.37-7.419 (41H, in), 7.58-7.63 (2H1, in), 7.75 (OH, d, J=3.3Hz), 7.84 (1N, d, J=3.3Hz), 7.89 O1H, d, J=8.9Hz), 8.82 (1H, d, J=6.9HzL-.

(+)-APCI/MS (mlz) :386 (M+H)I Anal. Calcd. for C2t ifisNsOS YH2O: C 64.44, H 4.03, N 17.89 Found :C 64.05, H 3.85, N 17.57 Example 2 A stirred mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2phenylpyrazolo[1, 5-alpyridine (2.0 4-chloro-1 -methylpiperidine hydrochloride (1.24 g) and sodium hydride (610 mng, dispersion in mineral oil) in N,N--dimethylformamide (20 ml) was heated at 115 0 C, and stirred for 1 day.

The reaction. mixture was cooled to ambient temperature and 4 3 WO 98/03507 PCT/JP97/02493 water was added thereto.

Evaporation of the solvent gave a residue, which was dissolved in chloroform (300 ml) and washed successively with water (20 ml x saturated sodium hydrogencarbonate in water ml) and saturated sodium chloride in water (20 ml), and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed on silica gel (100 ml) eluting successively with chloroform and a mixture of chloroform and methanol (50:1 40:1-.10:1). Fractions containing desired product were collected and the solvent was removed in vacuo to give a product, which was recrystallized from 50% aqueous ethanol to give 3-[2- (1-methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2- (471 mg).

mp 139.0-140.0°C (aq. EtOH) FT IR (KBr) 1660.4, 1589.1, 1531.2, 1496.5, 1465.6 cm-' NMR (DMSO-ds, c) 1.50-2.10 (6H, 2.20 (3H, s), 2.80-3.00 (2H, 4.70-4.90 (1H, m), 6.87 (1H, d, J=9.7Hz), 7.05-7.13 (2H, 7.40-7:65 (6H, m), 7.90 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS 386 (M+1) Anal. Calcd. for C23H2N50 C 68.47, H 6.25, N 17.36 Found C 68.71, H 6.08, N 17.37 Example 3 4 4 WO 98/03507 PCT/JP97/02493 To a stirred mixture of 3-(3-oxo-2,3-dihydropyridazin-6yl)-2-phenylpyrazolo[1,5-a]pyridine (30 1-methyl-4hydroxypiperidine (15.58 g) and triphenylphosphine (40.94 g) in tetrahydrofuran (1.2 was added dropwise diethyl azodicarboxylate (24.58 ml) at -5 to 0*C under nitrogen atmosphere.

The reaction mixture was allowed to warm to ambient temperature and stirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (2 and extracted two times with 300 ml of 2N aqueous hydrochloric acid. Aqueous phases were combined and the pH was adjusted to 10.7 with 30% aqueous sodium hydroxide solution while keeping the temperature at 5 to Insoluble material was collected by filtration, washed with 500 ml of water and dried to give a crude product.

The crude product was dissolved in chloroform, which was chromatographed on silica gel (800 g) eluting successively with ethyl acetate, chloroform and a mixture of chloroform and methanol (40:1).

Fractions containing desired product were collected and the solvent was removed in vacuo to give crude crystals, which were recrystallized from 50% aqueous ethanol to give methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2- (19.36 g).

Example 4 To a stirred solution of 3-(3-oxo-2,3-dihydropyridazin-6- 4 WO 98/03507 PCT/JP97/02493 yl)-2-phenylpyrazolo[1,5-a]pyridine (1.0 1-methyl-4hydroxypiperidine (520 mg) and triphenylphosphine (1.37 g) in tetrahydrofuran (40 ml) was added dropwise diisopropyl azodicarboxylate (1.03 ml) at -5 to O°C under nitrogen atmosphere.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (100 ml) and extracted two times with ml of 6N aqueous hydrochloric acid. Aqueous phases were combined and the pH was adjusted to 10.0 with 30% aqueous sodium hydroxide solution while keeping the temperature at 5 to 15 0

C.

Insoluble material was collected by filtration, washed with water and dried under reduced pressure to give a crude product.

The crude product was dissolved in chloroform, which was chromatographed on silica gel (75 g) eluting with a mixture of chloroform and methanol (40:1).

Fractions containing desired product were collected and the solvent was removed in vacuo to give crude crystals, which were recrystallized from 50% aqueous ethanol to give methylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]-2- (736 mg).

Example To a suspension of 3-[2-(1-methylpiperidin-4-yl)-3-oxo-2,3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (5.7 g), in ethanol (30 ml) was added 25% hydrochloric acid in ethanol 4 6 WO 98/03507 WO 9803507PCT/JP97/02493 ml), which mixture was stirred overnight at ambient temperature.

Resulting precipitates were collected by filtration, washed with et hanol and dried under reduced pressure to give methyip iperidin-'l-yl) -3-oxo- 2, 3-dihydropyridazin-6-yl] -2--phenylpyzazolo[1 ,5-alipyridine hydrochloride (5.77 g).

mp :271.0-274.0*C (EtOH) FT IR (KBr) :1658.5, 1587.1, 1525.4, 1490.7, 1467.6, 1419.4 cm-' NMR (DMS0-d6, 6) 2.00-2.15 (2H, in), 2.25-2.45 (2H, mn), 2.76 3.15-3.35 (2H, mn), 3.45-3.60 (2H, in), 5.05-5.25 (OH, mn), 6.89 C1H,-d, J=9.7Hz), 7.014-7.14 (2H, in), 7.47-7.64 (6H, mn), 8.10 O1H, d, J=8.9Hz), 8.83 (OH, d, J=6.9Hz), 10.72 O1H, br-s) (+)FAB-MS :386 (M+1) Anal Calcd. for C23H25C1Ns0* 3/2H20 C 61.53, H: 6.06, N: 15.60 Found C :61.39, H: 5.98, N: 15.60 Example 6 (1-tert-Butoxycarbonylpiperidin-l-yl) -3-oxo-2, 3dihydropyridazin-6-yl]--2-phenylpyrazolo [1 ,5-alipyridine was obtained in 45.9% yield in substantially the same manner as in Example 3.

mp 152.0-153.0 0 C (EtOH) FT IR 1675.8, 1660.4, 1-589.1, 1529.3, 1469.5, .4 7 WO 98/03507 WO 9803507PCT/JP97/02493 1417.4 cm- 1 NMR (DMSO-d6, 6) :1.141(9H, 1.60-1.90 (14H, in), 2.80-3.05 (2H1, mn), 4.00-4.15 (2H1, mn), 4.95-5.15 O1H, mn), 6.91 O1H, d, J=9.7Hz), 7.08 (OH, dt, J=1.3Hz and 6.9Hz), 7.18 (OH, d, J=9.7Hz), 7.35-7.55 O4H, mn), 7.56-7.62 (211, mn), 7.85 O1H, d,-J8.9Hz), 8.83 (1H, d, J=6.9Hz) Anal :Calcd. for Cz7H29NS0 3 C: 66.24, H: 6.38, N: 14.30 Found C: 66.66, H: 6.26, N: 141.24 Example 7 A mixture of 3- -1-tert-butoxycarbonylpyrrolid in-3yl )-3-oxo-2, 3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1 pyridine (2.41 g) in 6N-aqueous hydrochloric acid (50 ml) was refluxed for 4.5 hours.

The reaction mixture was cooled and the solvent was removed in vacuo.

To the resultant residue were added ethanol (15 ml) and hydrochloric acid in ethanol (5 ml), which mixture was stirred overnight at ambient temperature.

Resulting precipitates were collected by filtration, washed with ethanol and dried under reduced pressure to give 3- [3-oxo- 2-C (3S)-pyrrolidin-3-yl)-2,3-dihydropyridazin-6-yl]-2hydrochloride C(1.8 g).

mp :211.0-212.5*C (EtOH) FT IR (KBr) 1662.3, 1589.1, 1519.6,9 1492.6, 1465.6, 4 8 WO 98/03507 WO 9803507PCTIJP97/02493 1413.6 cm-' 1 N~MR (DMSO-d6 6) :2.20-2.140 (2H, in), 3.19-3.30 (2H, mn), 3.41 O1H, dd, J=5..2Hz and 12.3Hz), 3.62 O1H, dd, J=7.6Hz and 12.3Hz), 5.56-5.65 (OH, Mn), 6.914 O1H, d, J=9.7Hz), 7.09 OHl, dt, J=1.3Hz and 6.9Hz), 7.19 (OH, d, J=9.7Hz), 7.41-7.52 (J4H, in), 7.60-7.65 (2H, in), 7.93 O1H, d, J=8.9Hz), 8.83 (OH, d, J=6.9Hz), 9.46 (2H, br-s) (+)-FAB/MS (in/z) :358 (M+1) Anal. Calcd. for C21H2aClNsO- 1 4 C 60.58, H 5.45, N 16.82 Found :C 60.31, H 5.47, N 16.62 Example 8 3- [3-Oxo-2- (piperidin-4-yl) 3-dihydropyridazin-6-yl] -2phenylpyrazolo[1 ,5-alpyridine hydrochloride was obtained in 79.5% yield in substantially the same manner as in Example 7.

mp :over 290*C (EtOH) FT IR (KBr) :1658.5, 1587.1, 1521.6, 1492.6, 11465.6, 1415.5 cm-1 NHR (DMS0-dfi, 6) :1.95-2.40 (4H1, in), 3.00-3.25 (2H, mn), 3.30-3.45 (2H, mn), 5.10-5.30 O1H, mn), 6.89 (1H, d, J=9.7Hz), 7.05-7.15 (2H, mn), 7.415-7.64(6H, in), 8.04 (1H, d, J=8.9Hz), 8.83 (1H, d, 3=6.9Hz), 9.16 (2H1, br-s) (+)-FAB/Ms (in/z) :372 Anal Calcd. for C22HzzClNsO -3/4H20 4 9 WO 98/03507 PCT/JP97/02493 C: 62.70, H: 5.62, N: 16.62 Found C: 62.76, H: 5.72, N: 16.53 Example 9 To a stirred mixture of 3-(3-oxo-2,3-dihydropyridazin-6yl)-2-phenylpyrazolo[1,5-alpyridine (3.34 (3R)-1-tertbutoxycarbonyl-3-hydroxypyrrolidine (2.6 g) and triphenylphosphine (4.55 g) in tetrahydrofuran (100 ml) was added dropwise diethyl azodicarboxylate (2.73 ml) at 0 to 5°C under nitrogen atmosphere.

Evaporation of the solvent gave a residue, to which was added 6N aqueous hydrochloric acid (100 ml), and the mixture was refluxed for 8 hours.

The reaction mixture was cooled and washed with ethyl acetate (200 ml x 2).

The pH of the aqueous phase was adjusted to 12 with aqueous sodium hydroxide solution while keeping the temperature at 5 to The resultant was extracted with chloroform (200 ml x 2) and organic phases were combined and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting successively with chloroform and a mixture of chloroform and methanol (40:1 -*20:1 Fractions containing desired product were collected and the 0 WO 98/03507 WO 9803507PCT/JP97/02493 solvent was removed in vacuo, to give a crude product, which was recrystallized from ethanol to give 3-[3oX02-((3S)-pyrrolidin- 3-yl) 3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1 pyridime (2.84 g).

mp 144.0-145.5 0 C (EtOH) FT IR (KBr) :1658.5, 1585.2, 1525.4, 1490.7, 1465.6, 1415.5 cm-' NMR (DMS0-d6, 6) :1.80-2..20 (2H, in), 2.75-3.00 M3, mn), 3.12 O1H, dd, J=7.2Hz and 11.7Hz), 5.37-5.47 O1H, mn), 6.87 (1H, d, J=9.6Hz), 7.07 dt, J=l.3Hz and 6.9Hz), 7.18 (OH, d, J=9.6Hz), 7.40-7.62 (6H, in), 7.89 O1H, d, J=8.9Hz), 8.82 OIH, d, J=6.9Hz), (+)-APCI/Ms :358 Anal. Calcd. for C21Hi9NrO -2/3H 2 0 C 68.28, H 5.55, N 18.96 Found :C 68.47, H 5.28, N 18.90 Example 3- [3-Oxo-2- (piperidin-4-yl) 3-dihydropyridazin-6-yl J-2was obtained in 62.2% yield in substantially the same manner as in Example 9.

mp:115.0-117.0*C (aq. EtOl)_ FT IR (KBr) :1656.6, 1585.2, 1529.3, 1494.6, 1463.7, 1421.3 cm-' NMR (DMS0-d6, 6) :1.70-1.85 (4H, in), 2.50-2.70 (2H, in), 3.00-3.10 (2H, mn), 4.80-5.00 (OH, mn), 6.87 di J=9.6Hz), 7.05-7.13 (2H, in), 1 WO 98/03507 WO 9803507PCT/JP97/02493 7.43-7.63(6H1, in), 7.91 (1H, d, J=8.9HZ), 8.82 (OH, d, J=6.9Hz) (+)-APCI/MS :372 (M-1+1) Anal: Calcd. for Cz2H2lNsO* 2 4 H2O C: 64.21, 11: 6.25, N: 17.02 Found 64.26, H: 6.28, N: 16.94 Example 11 3- (1-Ethylpiperidin-4-yl )-3-oxo-2, 3-dihydropyridazin-6ylil-2-phenylpyrazolo[1,5-ajpyridine was obtained in 28.1% yield in substantially the same manner as in Example 3.

mp 134.0-135.0"C (50% aq. EtOH) IR (KBr) 1660.4, 1589.1, 1529.3, 11492.6, 1465.6, 1415.5 cm-1 NHR (DMSO-d6,6(3) 1.01 M3, t, J=7.lIHz), 1. 80-2.15 (6H, mn), 2.36 (2H, q, J=7.lHz), 2.90-3.10 (2H, in), 4.70-4.90 O1H, mn), 6.87 O1H, d, J=9.7Hz), 7.05-7.15 (2H, in), 7.45-7.60 (6H, mn), 7.89 O1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) Anal: Calcd. for C2 4H2 sNsO Y2H20 C: 70.57, H: 6.42, N: 17.14 Found 71.02, H: 6.35, N: 17.07 Ex apple 12 3- (1 -ropylpiperidin-4-yl) -3-oxo-2, 3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-alpyrjidine was obtained in 44.7% yield in substantially the same manner as in Example 3.

2 WO 98/03507 PCT/JP97/02493 mp 104.0-106.09C (50% aq. EtOH) IR (KBr) 1656.6, 1589.1, 1531.2, 1467.6, 1417.4, 1290.1 cm-' NMR (DMSO-ds, 6) 0.86 (3H, t, J=7.3Hz), 1.35-1.55 (2H, m), 1.70-2.35 (8H, 2.90-3.05 (2H, n), 4.70-4.90 6.89 (1H, d, J=9.7Hz), 7.05-7.30 (2H, 7.40-7.60 (6H, i), 7.88 (1H, d, J=8.9Hz), 8.83 (UI, d, J6.9Hz) (+)-APCI/MS 414 (M+1) Anal. Calcd. for C25H2-rNsO 1/10H20 C 72.58, H 6.60, N 16.86 found C 72.61, H 6.58, N 16.94 Example 13 3-[2-(1-Butylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6yl]-2-phenylpyrazolo(1,5-alpyridine was obtained in 44.6% yield in substantially the same manner as in Example 3.

mp 106.0-108.0*C (50% aq. EtOH) IR (Kr) 1656.6, 1591.0, 1538.9, 1465.6, 1419.4, 1342.2 cm-' NMR (CDC,6) 0.94 (3H, t, J=7.lHz), 1.20-1.65 (4H, 1.90-2.50 (8H, i), 3.05-3.20 (2H, 4.95-5.15 m), 6.74 (1H, d, J=9.6Hz), 6.88-6.96 (1H, m), 6.98 (1H, d, J=9.6Hz), 7.28-7.40 i), 7.43-7.48 (3H, 7.55-7.62 (2H, n), 8.01 (1H, d, J8.9Hz), 8.52 d, J6.9Hz) 3 WO 98/03507 WO 9803507PCT/JP97/02493 (+)-APCI/MS (rn/z) 428 Anal. Calcd. for C26H29NsO* YAHzO C 71.53, H 6.93, N 16.04 found :C 71.39, H 6.87, N 15.99 Example 141 3- [3-Oxo-2- (1 -pentylpiperidin-4-yl) 3-dihydropyridazin-6yl)-2-phenylpyrazolo[1,5-apyridine was obtained in 38.8% yield in substantially the same manner as in Example 3.

mp :105.5-106.0*C (aq. EtOH) FT IR (KBr) :1660.4, 1589.1, 1531.2, 1496.5, 1465.6, 1417.4 cm- 1 NMR (DMSO-d 83-0. 91 (3H, mn), 1. 20-1. 45 (6H, in), 1.75-2.15 (6H, in), 2.20-2.35 (2H, mn), 2.90-3.05 (2H, mn), 4.70-4,90 O1H, mn), 6.88 (OH, d, J=9.6Hz), 7.05-7.15 (2Hj mn), 7.57-7.60 (2H, in), 7.88 (OH, d, J=8.9Hz), 8.83 O1H, d, J=6.9Hz) (+)-APCI/Ms (miz) 442 Anal. Calod. for C27H3iNs0* !/AHzO C 72.70, H 7.12, N 15.70 found C 72.73, H 7.10, N 15.72 Example 3- (1-Hexylpiperidin-4-yl) -3-oxo-2, 3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-alpyridine was obtained in 26.3% yield in substantially the same manner as in Example 3.

mp :106.0-106.59C (aq. EtOH) 4 WO 98/03507 PCT/JP97/02493 FT IR (KBr) 1660.4, 1589.1, 1531.2, 1463.7, 1417.4 cm-' NMR (DMSO-d6,6) 0.82-0.90 (3H, 1.20-1.55 (8H, m), 1.70-2.15 (6H, 2.20-2.35 (2H, m), 2.90-3.05 (2H, 4.70-4,90 (1H, m), 6.88 (1H, d, J=9.6Hz), 7.00-7.15 (2H, m), 7.40-7.65 (6H, 7.88 J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS 456 Anal. Calcd. for C2aH33NsO- 1/8H20 C 73.45, H 7.32, N 15.30 found C 73.35, H 7.39, N 15.28 Example 16 To a suspension of sodium hydride (65 mg, 60% dispersion in mineral oil) in N,N'-dimethylformamide (20 ml) was added dropwise 3-[2-(piperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6-yl]- 2-phenylpyrazolo[1,5-alpyridine (500 mg) at 25°C under nitrogen atmosphere, which was followed by stirring for 30 minutes.

To the reaction mixture was added isopropyl iodide (940 mg) and the mixture was stirred for additional 18 hours.

To the resulting mixture were added excess triethylamine and water. Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (100 ml) and washed with IN-aqueous hydrochloric acid. The aqueous layer was adjusted to pH 10-12 with 4N-aqueous sodium hydroxide solution and extracted with ethyl acetate (100 ml). The organic layer was separated, washed with water (100 ml) and dried over magnesium sulfate.

WO 98/03507 WO 9803507PCT/JP97/02493 Evaporation of the solvent gave a residue, which was recrystallized from 50% aqueous ethanol to give 3-112-(1- .isopropylpiperidin-4-yl) -3-oxo-2, 3-dihydropyridazin-6-yl] -2phenylpyrazolo[ 1,5-alpyridine (350 mng).

mp :157-5-158.3 0 C (50%-aq. Etoll) IR :1660.4, 1589.1, 1531.2, 1467.6, 1417.4 cm- 1 NMR CDMS0-d6, 6) :0.98 (6H, d, 1.75-2.00 (4H, mn), 2.20-2.40 (2H, mn), 2.65-2.95 (314, 4.70-4190 (OH, mn), 6.87 (OH, q, J=9.6Hz), 7.05-7.13 (2H, m) 7.40-7.60 (6H, in), 7.88 (1H, d, J=8.9Hz), 8.83 O1H, d, J=7.OHz) (+)-APCI/HS (in/z) :414 Example 17 3- (1-Methylpiperidin-3-yl) -3-oxo-2, 3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-alpyridine was obtained in 31.0% yield in substantially the same manner as in Example 3.

nip :126.0-127.0'C (50% aq. EtOH) lB (KBr) :1658.5, 1587.1, 1529.3, 1465.6, 1417.4 cm' NMR (DMSQ-d&, 6) :1.50-2.10 (6H, in), 2.18 (OH) s), 2.70-2.95 (2H, mn), 4.80-5.00 (iH, mn), 6.89 (OH, d, J=9.6Hz), 7.00-7.15 (OH, in), 7.19 (OH, d, J=9.6Hz), 7.40-7.65 (6H, mn), 7.88 (OH, d, J=8.9Hz), 8.82 (OH, d, J=6.9Hz) C+)-APCI/MS :386.1 Anal. Calcd. for C23HZ3NsO. 2H20 6 WO 98/03507 PCT/JP97/02493 C 65.54, H 6.46, N 16.61 found C 65.75, H 6.39, N 16.56 Example 18 3-[2-(1-Benzylpiperidin-4-yl)-3-oxo-2,3-dihydropyridazin-6yl]-2-phenylpyrazolo[1,5-a]pyridine was obtained in 60.7% yield in substantially the same manner as in Example 3.

mp 184.1-185.3°C (50% aq. EtOH) IR (KBr) 1662.3, 1589.1, 1525.4, 1490.7, 1459.8 1415.5 cm-' NMR (DMSO-d6, 6) 1.70-2.20 (6H, m), 2.93 (2H, br-d, J=12.4Hz), 3.51 (2H, s), 4.70-4.90 (1H, 6.88 (1H, d, J=9.6Hz), 7.00-7.17 (2H, 7.20-7.65 (11H, m), 7.88 (1H, d, J=8.8Hz), 8.84 (1H, d, (+)-APCI/MS 462 (M +1) Anal. Calcd. for C2ZH27NsO- /2H20 C 74.02, H 6.00, N 14.88 found C 74.37, H 6.08, N 15.36 Example 19 To a stirred solution of 3-(3-oxo-2-(piperidin-4-yl)-2,3dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.5 g) in pyridine (30 ml) was added dropwise acetic anhydride (1.28 ml) at ambient temperature.

The reaction mixture was stirred overnight.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (100 ml) and washed successively with 7 WO 98/03507 WO 9803507PCT/JP97/02493 2N aqueous hydrochloric acid (100 ml) and saturated sodium chloride in water (100 ml), and dried over magnesium'sulfate.

Insoluble material was removed by filtration. The filtrate was concentrated in vacua to give 3-L2-(1-acetylpiperidin-4-yl)..

3-oxo-2, 3-dihydropyridazin-6-yl] 2 phenylpyrazolo [1 ,5-a Ipyridine g).

mp :1 1 4.0-116.9 0 C (EtOH) IR (KBr) 1656.6, 1627.6, 1585.2, 1531.2, 1457.9, 1427.1 cm-' NMR (DMSO-d 6 ,65) :1.50-2.00 (411, in), 2.02 (3M, s), 2.60-2.80 (OH, mn), 3.15-3.35 (iH, mn), 3.90 O1H, br-d, J=12.2Hz), 4.149 (OH, br-d, J=13.2Hz, 5.00-5.20 (1H, in), 6.92 (1H, d, J=9.6Hz), 7.03-7.12 (1H, mn), 7.20 (iH, d, J=9.6Hz), 7.40-7.60 (6H, in), 7.814 (OH, d, J=8.9Hz), 8.83 (OH, d, J=6.9Hz) (+)-APCI/Ms (rn/z) :414 (M+1) Example To a stirred mixture of 3-[3-oxo-2-(piperidin-4-yl.-2,3-.

dihydropyridazin-6-yl] 2 -phenylpyrazolo [1 ,5-ajpyridine (500 mg), potassium tert-butoxide (182 mg) and 18 -crown-6-ether (34 mg) in tetrahydrofuran (20 ml) was added methyl iodide (0.17 ml) at ambient temperature, which mixture was stirred overnight at that temperature.

An insoluble material appeared in the reaction mixture, which was collected by filtration. The crude solid was 8 WO 98/03507 WO 9803507PCrIJP97/02493 recrystallized from ethanol to give 3- 1 -dinethylpiperidinio) -3-oxa-2 S 3-dihydropyridazin-6-yl J -2--phenylpyrazolo(1 .5-alpyridine iodide (730 mg).

mp 225.0-226.5*C (hexane) IR (KBr) :1666.2, 1631.5, 1594.8, 1529.3, 1465.6 cm-' NMR (DMS0-d6, 6) 1.95-2.30 (OH, mn), 2.99 M3, s), 3.17 3.45-3.80 (4H, in), 5.00-5.20 (1H, mn), 6.98 (1H, d, J=9.7Hz), 7.06-7.14 (18, mn), 7.32 (OH, d, J=9.7Hz), 7.40-7.65 (68, mn), 7.91 (1H, d, J=8.9Hz), 8.85 (OH, d, J=6.9Hz) (+)-APCI/MS (in/z) :400 Example 21 3- [2-C (3S) -1-tert-Butoxycarbonylpyrrolidin-3-yl) -3-oxo-2, 3d ihydropyridazin-6-yl] -2-phenylpyrazolo[1i,5-a] pyridine was obtained in 60.9% yield in substantially the same manner as in Example 3.

mp :165.5-167.0*C (EtOH) FT IR (KBr) :1679.7, 1664.3, 1591.0, 1517.7, 1483.0, 14157.9, 1403.9 cm-1 NMR (DMSO-d6, 6)5 1.30-1.40(9H, mn), 2.10-2.30(2H, m), 3.3J4-3.80(41H, in), 5.45-5.60(1H, mn), 7.13(1H, d, J=g.7Hz), 7.341-7.64(68, in), 7.82(1H, d, J=8.9Hz), 8.82(1H, d, J=6.9Hz) Example 22 3- [3-Oxo-2- (3-quinuclidinyl) 3-dihydropyridazin-6-yl] -2- 9 WO 98/03507 PCT/JP97/02493 phenylpyrazolo[ ,5-a]pyridine was obtained in 7.3% yield in substantially the same manner as in Example 3.

mp 191.0-192.7°C (50% aq. EtOH) IR (KBr) 1660.4, 1591.0, 1535.1, 1467.6, 1411.6 cm-' NMR (CDCIa, 6) 1.20-1.50 (1H, 1.55-2.00 (3H, m), 2.15-2.35 (1H, 2.70-3.20 (4H, m), 3.21-3.35 (1H, 3.59 (1H, dd, J=5.6Hz and 13.9Hz), 5.15-5.25 (1H, 6.80 (1H, d, J=9.6Hz), 6.87-6.96 (1H, 7.07 (1H, d, J=9.6Hz), 7.27-7.61 (6H, 7.91 (1H, d, J=8.9Hz), 8.55 (1H, d, (+)-APCI/MS 398 Example 23 3-[2-(1-Methylpiperidin-3-yl)methyl-3-oxo-2,3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine was obtained in 52.1% yield in substantially the same manner as in Example 3.

mp 159.0-160.0°C (50% aq. EtOH) IR (KBr) 1658.5, 1587.1, 1529.3, 1465.6 cm-' NMR (DMSO-ds, 6) 0.90-1.10 (1H, 1.30-2.00 (5H, m), 2.05-2.30 (1H, 2.13 (3H, 2.50-2.60 (2H, m), 3.94-4.15 (2H, 6.87 (1H, d, J=9.6Hz), 7.03-7.13 (2H, 7.40-7.65 (6H, m), 7.92 (1H, d, J=8.9Hz), 8.82 (1H, d, J=6.9Hz) Anal. Calcd. for C24H2sNO 3/10H20 C 71.19, H 6.37, N 17.30 6 0 WO 98/03507 PCTIJP97/02493 Found C 71.40, H 6.34, N 17.30 C+)-AFCI/NS 400.2 (W+i) Example 24 -Methylpiperidin-2-yl)nethyl-3-oxo-2, 3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a)pyridine was obtained in 58.6% yield in substantially the same manner as in Example 3.

mp 154.0-155.0*C (50% aq. EtCH) IR (KBr) 1662.3, 1587.1, 1527.3, 1498.4, 1463.7 cm' NMR (DMSO-d6, 6) 1.10-1.70 (6H, m), 2.05-2.20 (1H, 2.29 (3H, 2.40-2.60 (1H, i), 2.70-2.85 (1H, 4.04 (1H; dd, J=4.7Hz and 12.9Hz), 4.44 (1H, dd, J=4.7Hz and 12.9Hz), 6.87 (1H, d, J=9.6Hz), 7.00-7.15 (2H, m), 7.40-7.65 (6H, 7.98 d, J=8.9Hz), 8.82 (1H, d, J=6.9Hz) (+)-APCI/Ms 400.2 (M+1) Anal. Calcd. for C24H2sN50 C 72.16, H 6.31, N 17.53 Found C 72.30, H 6.41, N 17.53 Example 3-[2-{2-Cl-Methylpiperidin-2-yl)ethyl)-3-oxo-2,3dihydropyridazin-6-ylJ -2-phenylpyrazolo[1 ,5-alpyridine was obtained in 91.0% yield in substantially the same manner as in Example 3.

mp 113.5-116.09C (EtOH-n-Hexane) 6 1 WO 98/03507 WO 9803507PCT/JP97/02493 FT IR (KBr) :1666.2, 1633.4, 1589.1, 1527.3, 11496.5, 1463.7, 1419.4 cm- 1 NMR (DMS0-df, 15) :1.10-1.75 (6H, in), 1.80-2.05 (4H, i) 2.18 M3, 2.76 (Iii, br-d, J=11.J4Hz), 4.10-4.21 (2H, in,6.87 (1H, d, J=9.6Hz), 7.03-7.13 (OH, mn), 7.12 (1H.d, J=9.6Hz), 7.39-7.63 (6H, mn), 7.94 (OH, d, J=8.9Hz), 8.82 O1H, d, J=6.9Hz) Anal. Calcd. for C25H27Ns0* 1/8H20 C 72.22, H 6.61 N 16.84 Found :C 72.03, H 6.55, N 16.81 Example 26 3- [3-Oxo-2-{ 2-C piperidin-2-yl )ethyl 1-2,3dihydropyridazin-6-yl] -2-phenylpyrazolo [1 ,5-aJ pyridine was obtained in 33.3% yield in substantially the same manner as in Example 9.

mp :124.4-125.4 (50% aq. EtOH) IR (KBr) :1662.3, 1585.2, 1527.3, 1496.5, 1463.7, 1446.4, 1421.3 cm-1 NMR (CDCl 3 6) :1.15-2.20 (8H, mn), 2.50-2.70 (2H, in), 3.13 O1H, br-d, J=12.OHz), 4.19-41.33 OH1, in), 4.40-41.55 (11, in), 6.76 (OH, d, J=9.6Hz), 6.90-6.97 (OH, in), 7.03 (1H, d, J=9.6Hz), 7.30-7.65 (6H, in), 7.99 (OH, d, J=9.OHz), 8.54 d, J=6.9Hz) 6 2 WO 98/03507 PCT/JP97/02493 (+)-APCI/NS 400 Anal. Calcd. for C24H2sNs 5 O* HzO C 69.04, H 6.52, N 16.77 Found C 69.53, H 6-33, N 16.83 Example 27 3-[2-(1-Methylpiperidin-4-yl)methyl-3-oxo-2,3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-alpyridine was obtained in 7.9% yield in substantially the same manner as in Example 3.

mp 179.5-181.0oC (EtOH) IR (KBr) 1656.6, 1587.1, 1525.4, 1490.7, 1450.2, 1419.4 cm' NMR (DMS0-ds, 6) 1.15-1.45 (2H, 1.50-1.65 (2H, m), 1.70-1.95 (3H, 2.14 (3H, s), 2.74 (2H, br-d, J=10.9Hz), 4.02 (2H, d, J=7.lHz), 6.88 (21, d, J=9.6Hz), 7.00-7.20 (2H, i), 7.40-7.65 (6H, 7.90 d, J8.9Hz), 8.83 (1H, d, (+)-APCI/MS 400 (M1) Example 28 To a stirred mixture of 3-(3-oxo-2,3-dihydropyridazin-6yl)-2-phenylpyrazolo[1 ,5-a]pyridine (2.7 1-methyl-4piperidineethanol (1.41 g) and triphenylphosphine (3.19 g) in tetrahydrofuran (60 ml) was added dropwise diethyl azodicarboxylate (1.92 ml) at 0 to 5*C under nitrogen atmosphere.

The reaction mixture was allowed to warm to ambient 6 3 WO 98/03507 PCT/JP97/02493 temperature and stirred overnight.

Evaporation of the solvent gave a residue, to which was added 2N aqueous hydrochloric acid, and the mixture was under stirring for 1 hour.

The reaction mixture was washed with ethyl acetate.

Aqueous phase was separated. The pH of the aqueous phase was adjusted to 12 with 15% aqueous sodium hydroxide solution while keeping the temperature at 5 to 15"C. The resulting solution was extracted with ethyl acetate.

Organic phase was separated, washed with water and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was added in ethanol (2 ml). 25% Hydrochloric acid in ethanol (1 ml) was added thereto and the mixture was stirred overnight.

Insoluble material was collected and washed with ethanol to give 3-[2-(1-methylpiperidin-4-yl)ethyl-3-oxo-2,3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine hydrochloride (2.93 g).

mp over 250"C (50% aq. EtOH) IR (KBr) 1654.6, 1583.3, 1527.3, 1467.6, 1417.4 cm-' NMR (DMSO-d 6 6) 1.30-2.00 (7H, 2.69 (3H, s), 2.75-3.00 (2H, 3.20-3.50 (2H, m), 4.17 (2H, t, J=6.8Hz), 6.89 (1H, d, J=9.6Hz), 7.05-7.18 (2H, 7.40-7.65 (6H, m), 7.92 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS 414 6 4 WO 98/03507 PCT/JP97/02493 Anal. Calcd. for CzsHzBCiN s O 1/10HzO C 66.46, H 6.29, N 15.50 Found C 66.18, H 6.34 N 15.34 Example 29 To a stirred solution of 3-[2-(1-methylpiperidin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenyl- (300 mg) in 1,2-dichloroethane (50 ml) was added dropwise 1-chloroethyl chloroformate (324 The reaction mixture was refluxed under stirring for 16 hours.

Evaporation of the solvent gave a residue, which was dissolved in ethyl acetate (100 ml) and extracted with 100 ml of 2N aqueous hydrochloric acid. Aqueous phase was separated, and the pH was adjusted to 12 with 30% aqueous sodium hydroxide solution while keeping the temperature at 5 to 15 0

C.

This aqueous phase was extracted with ethyl acetate (100 ml). The organic phase was washed with saturated sodium chloride in water (100 ml), and dried over magnesium sulfate.

Evaporation of the solvent gave a crude product. The crude product was dissolved in chloroform, which solution was chromatographed on silica gel eluting with a mixture of chloroform and methanol (40:1).

Fractions containing desired product were collected and the solvent was removed in vacuo to give a crude solid, which was recrystallized from 50% aqueous ethanol to give 3-[3-oxo-2- (piperidin-3-yl)methyl-2,3-dihydropyridazin-6-yl]-2- 6 WO 98/03507 PCT/JP97/02493 (75 mg).

mp 250.0-251.3 0 C (EtOH) IR (KBr) 1656.6, 1587.1, 1525.4, 1465.6, 11419.4 cm- 1 NMR (DMSO-dB, 6) 1.20-1.80 (J4H, 2.10-2.50 (1H, m), 2.55-2.80 (2H, 3.00-3.30 (3H, m), 4.08 (2H, d, J=7.lHz), 6.90 d, J=9.7Hz), 7.00-7.15 (2H, 7.40-7.65 (6H, m), 7.95 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS (mlz) 386 Example (Piperidin-2-yl)methyl}-3-oxo-2,3-dihydropyridazin- 6-yl]-2-phenylpyrazolo[1,5-alpyridine was obtained in 17.3% yield in substantially the same manner as in Example 29.

mp 141.0-142.5 0 C (50% aq. EtH) IR (KBr) 1666.2, 1633.4, 1591.0, 1527.3, 1494.6 cm-' NMR (DMS0-ds, 6) 0.86-1.80 (6H, 2.40-2.60 (1H, i), 2.90-3.10 (3H, 4.05 (2H, d, J=6.1Hz), 6.87 (1H, d, J=9.6Hz), 7.00-7.15 (2H, m), 7.40-7.65 (6H, 7.97 (1H, d, J=9.OHz), 8.82 (1H, d, J=6.9Hz) (+)-APCI/MS Cm/z) 386 Anal. Calcd. for C23H2 3 N50* V C 70.03, H 5.88, N 17.75 Found C 70.31, H 6.12, N 18.19 Example 31 3-[2-{((2S)--Methylpyrrolidin-2-yl)methyll-3-oxo-2,3- 6 6 WO 98/03507 PCT/JP97/02493 dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-alpyridine was obtained in 74.6% yield in substantially the same manner as in Example 3.

mp 114.5-117.0 C (n-Hexane-CHCl3) FT IR (KBr) 1664.3, 1635.3, 1589.1, 1529.3, 1496.5, 1463.7, 1423.2 cm-' NMR (DMSO-d 6 1.50-2.00 (4H, 2.15-2.30 (1H, m), 2.30 (3H, 2.60-2.80 (1H, 2.90-3.10 (1H, m), 4.05 (1H, dd, J=7.2Hz and 12.7Hz), 4.27 (1H, dd, J=4.6Hz and 12.7Hz), 6.88 (1H, d, J=9.6Hz), 7.00-7.14 (2H, m), 7.40-7.60 (6H, 8.00 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS 386 Anal. Calcd. for C23H2Ns0 Y 2 C 70.03, H 6.13, N 17.75 Found C 70.06, H 5.97, N 17.67 Example 32 3-[3-0xo-2-((2S)-pyrrolydin-2-yl)methyl-2,3dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine was obtained in 62.3% yield in substantially the same manner as in Example 9.

mp 111.5-113.5"C (50% aq. EtOH) IR (KBr) 1662.3, 1633.4, 1589.1, 1529.3, 1496.5, 1467.6 cm-' NMR (DMSO-d6,6) 1.20-1.90 (4H, 2.70-3.00 (2H, m), WO 98/03507 PCT/JP97/02493 3.45-3.65 (1H, 4.05-4.10 (2H, m), 6.90 (1H, d, J=9.6Hz), 7.00-7.15 (2H, m), 7.30-7.65 (6H, 8.02 (1H, d, J=8.9Hz), 8.82 (1H, d, J=6.9Hz) (+)-APCI/MS 372 Anal. Calcd. for C22H21NsO C 67.85, H 5.95, N 17.98 Found C 68.21, H 5.73, N 17.64 Example 33 To a solution of sodium hydroxide (300 mg) in a mixture of water (20 ml) and toluene (20 ml) were added successively 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[l,5-a]pyridine (1.94 benzyltriethylammonium chloride (155 mg) and 1-benzyloxycarbonylpiperidine-4-spiro-2'-oxirane (5 and the mixture was refluxed for 5 hours.

The reaction mixture was cooled and extracted with chloroform (200 ml). Organic phase was separated, which was washed successively with 1N-aqueous sodium hydroxide (20 ml) and saturated sodium chloride in water, and dried over magnesium sulfate.

Evaporation of the solvent gave a residue, which was chromatographed on silica gel (250 ml) eluting successively with ethyl acetate in n-hexane and ethyl acetate.

Fractions containing desired product were collected and the solvent was removed under reduced pressure to give a crude product, which was recrystallized from ethanol to give 6 8 WO 98/03507 WO 9803507PCT/JP97/02493 benzyloxycarbonyl-4-hydroxypiperidin-4vyl)methyl 3 oxo- 2 ,3dihydropyridazin-6-yl] -2-phenylpyrazolo [1 ,5-alpyridin'e (2.8 g, 79.8% yield).

mp :175.5-177.0'2C (EtOH) FT IR (KBr) :1697.1, 1650.8, 1583.8, 1527.3, 1490.7, 1469.5 cm-1 NMR (DMSO-d 6 ,65) :1.42-1.60 (M4, mn), 3.00-3.30 (2H, in), 3.70-3.90 (2H, in), 4.21 (2H, 4[95 (1H, s), 5.06 O1H, 6.89 (1H, d, J=9.6Hz), 7.03-7.12 (2Hf,i) 7.28-7.64 (10H, mn), 8.07 (OH, d, J=8.9HZ), 8.81 (OH, d, J=6.9Hz) (+)-APCI/MS: 536 (M4+1) Anal. Calcd. for C31H29NsO4 C 69.52, H 5.46, N 13.08 Found C 69.32, H 5.40, N 13.01 Example 34 A mixture of 3- [2-Cl -benzyloxycarbonyl-J4-hydroxypiperidin- 4-yl )methyl-3-oxo-2, 3-dihydropyridazin-6-yll -2-phenylpyrazolo- (2.5 10% palladium on carbon (500 mg, wet) and concentrated hydrochloric acid (100 in N,Ndirnethylformamide (100 ml) was stirred under hydrogen atmosphere.

On confirmation of the absence of the starting material by TLC check, the catalyst was removed by filtration and to the filtrate was added triethylamine.

The solvent was removed under reduced pressure to give a residue, which was chromatographed on silica gel (100 ml) 6 9 WO 98/03507 PCT/JP97/02493 eluting successively with chloroform, 9% and 20% methanol in chloroform.

Fractions containing desired product were collected and concentrated in vacuo to give a crude product, which was recrystallized from ethanol to give 3-[2-(4-hydroxypiperidin-4yl)methyl-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo- (817 mg, 42.6% yield).

mp over 260°C (EtOH) FT IR (KBr) 1648.8, 1581.3, 1517.7, 1490.7 cm-' NMR (DMSO-ds, 6) 1.60-1.90 (4H, 2.90-3.20 (4H, m), 4 24 (2H, 5.18 (1H, 6.90 (1H, d, J=9.6Hz), 7.05-7.12 (2H, 7.39-7.63 (6H, m), 8.10 (1H, d, J=8.9Hz), 8.83 (1H, d, J=6.9Hz) (+)-APCI/MS 402 (M+1) Example A mixture of 3-[2-(4-hydroxypiperidin-4-yl)methyl-3-oxo- 2, 3 -dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (650 mg) and acetic anhydride (1.53 ml) in pyridine (30 ml) was stirred overnight at room temperature.

Evaporation of the solvent gave a residue, which was dissolved in chloroform (150 ml) and washed succesively withIN aqueous hydrochloric acid, saturated sodium hydrogencarbonate in water and saturated sodium chloride in water, and dried over magnesium sulfate.

Evaporation of the solvent gave a crude product, which was recrystallized from ethanol to give 3-[2-(1-acetyl-4- 7 0 WO 98/03507 PCTIJP97/02493 hydroxypiperidin-4-yl)methyl-3-oxo-2,3-dihydropyridazin-6-ylJ-2- (284 mig, 39.6% yield).

mp 163.0-165.0 0 C (EtOH) FT IR (KBr) 1646.9, 1581.3, 1527.3, 1490.7 cm-' NMR (DMSO-df, 6) 1.40-1.62 (4H, 1.97 (3H, s), 2.80-3.00 (1H, 3.20-340 m), 3.50-3.70 (1H, 4.00-4.20 (1H, 4.22 (2H, i), 4.93 (1H, 6.88 (1H, d, J=9.'6Hz), 7.05-7.10 (2H, i), 7.39-7.51 (4H1, 7.58-7.62 (2H, m), 8.09 (1H, d, J=8.9Hz), 8.81 (1H, d, J=6.9Hz) (+)-APCI/MS 444 Anal. Calcd. for C2sH2SNs03- C 65.06, H 5.90, N 15.17 Found C 65.26, H 5.80, N 15.15 Example 36 3-[2-(2-Methylthiazol-4-yl)methyl-3-oxo-2,3dihydropyridazin-6-yl l-2-phenylpyrazolo E ,5-a]pyridine was obtained in 51.9% yield in substantially the same manner as in Example 3.

mp 196.0-197.5 0 C (EtOH) FT IR (KBr) 1666.2, 1631.5, 1592.9, 1531.2, 1494.6, 1469.5, 1452.1, 1419.4 cm-' NMR (DMSO-d6, 6) 2.67 (3H, 5.38 (2H, s), 6.89 (1H, d, J=9.6Hz), 7.05 d, J=9.6Hz), 7.05-7.10 (1H, 7.30-7.41 (2H, m), 7.45-7.50 (3H, 7.59-7.65 (2H, m), 7 1 WO 98/03507 PCT/JP97/02493 71.85 (OH, d, J=8.9Hz), 8.80 (OH, d, J=6.9Hz) (+)-APCI/MS (mlz) :400 (M t +1) Anal. Calcd. for C 2 2 Hi ?NsOS C 65.Lf1, H 4.37, N 17.34 Found C 65.41, H 4.18, N 17.18 7 2 P~kOPER\PDBSpi\3462 I.97.sp-d-7O2/OI 72A Comparative Example 1 A comparison of antagonising CPA-induced hypolocomnotion activity and toxicity was 2 conducted for the compound of Example 2. (R N-methylpiperidine) and Example 2 of US 5,204,346.

The results are depicted in Table 1.

Table 1 Present Invention Example 2 of (Example 2) US 5,204,346 R

CH

3

N_

activity of antagonising CPA-induced 0.21 0.54 hypolocomotion [ED5O Plasma Dose (mg/kg) Concentration (nM) in rats after 30 min or 3.2 389 23 N. T.

p.o. administration 10 N.T. 165±14 3388 ±651 N.T.

Toxicity (chromosornal aberration) (at 200 ug/ml) (at2 tg/ml) S. I. *5

S

S. S

S

10 Not tested Methods 1. Activity of antagonising CPA-induced hypolocomotion Spontaneous locomnoter activity of fasted rats was monitored using a double infrared beamn system. Clear polycarbonate cages were mounted on the measuring box, P:\OPER\PDBSpeci\34621-97.spc.doc-06/02/01 -72Bthrough which two infrared beams passed each cage 3 cm above the floor of the cage and cm from each end. Each beam was connected to a detection system, which registered beam interruptions. This information was converted to digital interface and the data were analysed with PC. Each rat was pre-treated with adenosine antagonist administered p.o., and 25 min after the treatment, 0.056 mg/kg of CPA (adenosine Al antagonist) was administered i.p. Five min after the CPA challenge, the locomoter activity of each rat was measured for 20 min. For comparison of the drug potency, ED 5 0 values of selected compounds were determined by the least squares liner regression analysis.

2. Plasma concentration (nM) in rats after 30 min of p.o. administration.

Fasted rats were orally administered with an adenosine antagonist. Thirty min after the administration, animals were anaesthetised with 4% halothane in oxygen and nitrous oxide (30:70 and venous blood was collected from the inferior vena cava. Blood was allowed to clot at 4 °C overnight, and the resulting serum was stored at -20 "C in 200 ml 15 aliquots. Serum samples were denatured by boiling the sample at 80 'C for 15 min. After denaturation, drug concentration of each sample was measured by adenosine receptor binding assay.

3. Toxicity (chromosomal aberration) The test was performed in 4 test series consisting of the direct method 24- and 48-hour treatment without S9 Mix) and the metabolic activation method (6-hour treatment without S9 Mix). Positive control substances for the direct method and metabolic activation method were Mitomycin C and Dimethylnitrosamine, respectively. After a preculture of the cells derived from Chinese hamster lung, the culture medium (BCS- 25 MEM) was exchanged with the fresh BCS-MEM (with or without S9 Mix) including the test substance, and the cells were incubated at 37'C in a CO 2 incubator for 6, 24 or 48 hours. The media for 6 hour treatments were rinsed twice and exchanged with fresh BCS- MEM and incubated further for 18 hours. After incubation, cells were washed, treated with hypotonic solution, fixed and stained with Giemsa's solution. Specimens of each series were examined microscopically and the number of chromosomes was determined.

The number of the cells with structural aberrations or the cells with polyploid in 100 P:\OPER\PDB\SpcrA3462 dc-06/02/O1 72C metaphase cells per specimen was recorded, and thus, 200 cells in total were examined in each group. The test compound was judged to be clastogenic when the incidence of the cells with structural aberrations or the cells with polyploid increased dose-dependently and differed significantly from the solvent control.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Unless the context indicates otherwise, the reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

o *o

Claims

1. A pyrazolopyridine compound of' the following formula N R 2 N N S *5 S S S S S S S S S *5 5*55 S S S wherein R' is aryl, and R' is lower alkyl substituted with unsaturated 3 to 8- membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) which may have one or more substituent(s); a group of the formula: [wherein R 3 is hydrogen, lower alkyl, ar(lower)alkyl or acyl, R4 is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n isan integer of Icr 2]; a group of' the formula: KR6 7 3 WO 98/03507 PCT/JP97/02493 [wherein R 5 and R 6 are each lower alkyl]; or quinuclidinyl, or a salt thereof.

2. A compound of claim 1, wherein R' is phenyl, and R 2 is lower alkyl substituted with thiazolyl which may have 1 to 3 lower alkyl; a group of the formula: R 4 N R 3 (CH2). [wherein R' is hydrogen, lower alkyl, phenyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, or phenyl(lower)alkoxycarbonyl, R* is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is an integer of 1 or 2]; a group of the formula: R6 [wherein R 5 and R 6 are each lower alkyl]; or quinuclidinyl, or a salt thereof.

3. A compound of claim 2, wherein R 2 is lower alkyl substituted with thiazolyl which may have 1 to 3 lower alkyl, or a salt 7 4 WO 98/03507 PCT/JP97/02493 thereof.

4. A compound of claim 2, wherein R 2 is a group of the formula: R 4 N R 3 (CHz)22 [wherein R 3 is hydrogen, lower alkyl, phenyl(lower)alkyl, lower alkanoyl, lower alkoxycarbonyl, or phenyl(lower)alkoxycarbonyl, R' is hydrogen or hydroxy, A is lower alkylene, m is an integer of 0 or 1, and n is an integer of 1 or or a salt thereof. A compound of claim 4, wherein R 2 is a group of the formula: R' -N R (CH2). [wherein R 3 is hydrogen, lower alkyl, phenyl(lower)alkyl, lower alkanoyl, or lower alkoxycarbonyl, R' is hydrogen, A is lower alkylene,.. m is an integer of 0, and n is an integer of 1 or or a salt thereof. 7 WO 98/03507 PCT/JP97/02493

6. A compound of claim 5, wherein R 2 is a group of the formula: R 4 (CH2) [wherein R 3 is hydrogen, lower alkyl, phenyl(lower)alkyl, lower alkanoyl, or lower alkoxycarbonyl, R" is hydrogen, A is lower alkylene, m is an integer of 0, and n is an integer of or a salt thereof.

7. A compound of claim 6, wherein R 2 is a group of the formula: R 4 N R 3 (CH2) [wherein R 3 is lower alkyl, R' is hydrogen, A is lower alkylene, m is an integer of 0, and n is an integer of or a salt thereof.

8. A compound of claim 4, wherein R 2 is a group of the formula: R 4 C N R' ^(CH2)n WO 98/03507 PCT/JP97/02493 [wherein R 3 is hydrogen, lower alkyl, lower alkanoyl, or phenyl(lower)alkoxycarbonyl, R' is hydrogen or hydroxy, A is lower alkylene, m is an integer of 1, and n is an integer of 1 or or a salt thereof.

9. A compound of claim 8, wherein R 2 is a group of the formula: R' N R2) [wherein R' is hydrogen, or lower alkyl, RI is hydrogen, A is lower alkylene, m is an integer of 1, and n is an integer of 1 or or a salt thereof. 7 7 WO 98/03507 PCT/JP97/02493 A process for the preparation of the pyrazolopyridine compound of claim 1 or a salt thereof, which comprises, reacting a compound of the formula (II): (II) N wherein R' is as defined in claim 1, or a salt thereof, with a compound of the formula (III): X-R 2 (III) wherein R 2 is as defined in claim 1 and X is a leaving group, to give a compound of the formula N -R 2 N wherein R' and R 2 are each as defined in claim 1, or a salt thereof, 7 8 WO 98/03507 PCT/JP97/02493 reacting a compound of the formula (II): (II) wherein R' is as defined in claim 1, or a salt thereof, with a compound of the formula (IV): 0 >-CHN-R' (IV) wherein n is as defined in claim 1 and R 3a is acyl, to give a compound of the formula (Ia): (CH2) (Ia) wherein R' and R 3 are each as defined above, or a salt thereof, 7 9 WO 98/03507 PCT/JP97/02493 subjecting a compound of the formula (Ib): N -R 2 b (Ib) wherein R' is as defined in claim 1 and R b is a group of the formula: wherein A, m, n and R 4 are each as defined in claim 1 and is as defined above, or a salt thereof, to elimination reaction of acyl group, to give a compound of the formula (Ic): N -R 2 (Ic) wherein R' is as defined in claim 1 and R 2 c is a group of the formula: 8 0 WO 98/03507 PCT/JP97/02493 R 4 -N N-R 3 b (CHz), wherein A, m, n and R' are each as defined above, R 3 b is hydrogen, or a salt thereof, subjecting a compound of the formula (Id): N R2L I N (Id) wherein R' is as defined in claim 1 and Rzd is a group of the formula: R 4 CH2 N -R 3 (CH2) wherein A, m, n and R 4 are each as defined above and R 3 is lower alkyl, or a salt thereof, to dealkylation reaction, to give a compound of the formula (Ic): 8 1 WO 98/03507 PCT/JP97/02493 -_R2c (Ic) wherein R' and R2 are each as defined above, or a salt thereof, subjecting a compound of the formula (Ic): N -R2c I N (Ic) wherein R' and R 2 c are each as defined above, or a salt thereof, to alkylation reaction, to give a compound of the formula (Ie): N -R 2 e N N (Ie) wherein R' is as defined in claim 1 and R 2e is a group of the formula: 8 2 WO 98/03507 PCT/JP97/02493 R 3 c wherein A, m, n, R 3 and RI are each as defined above, or a group of the formula: R wherein Rs and R 6 are each as defined in claim 1, or a salt thereof, subjecting a compound of the formula (Ic): N -R 2 N (Ic) wherein R I and R 2 c are each as defined above, or a salt thereof, to acylation reaction, to give a compound of the formula (Ib): N -R 2 b I -N (Ib) 8 3 WO 98/03507 PCT/JP97/02493 wherein R' and R 2b are each as defined above, or a salt thereof, or subjecting a compound of the formula S NH2 (V) wherein R' and A are each as defined in claim 1, or a salt thereof, to formation reaction of thiazole ring, to give a compound of the formula (If): N-A I N N (If) wherein R' and A are each as defined above, or a salt thereof.

11. A pharmaceutical composition comprising the compound of claim 1 or a salt thereof in association with pharmaceutically acceptable carriers or excipients.

12. A method for preventing or treating a disease selected from 8 4 WO 98/03507 PCT/JP97/02493 the group consisting of depression, dementia, anxiety, pain, cerebrovascular disease, heart failure, hypertension, circulatory insufficiency, post-resuscitation, asystole, bradyarrhythmia, electro-mechanical dissociation, hemodynamic collapse, SIRS (systemic inflammatory response syndrome), multiple organ failure, renal failure (renal insufficiency), renal toxicity, nephrosis, nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotention, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack and angina pectoris, which comprises administering the compound of claim 1 or a salt thereof to a human being or an animal.

13. Use of the compound of claim 1 or a salt thereof as a medicament.

14. Use of the compound of claim 1 or a salt thereof as an adenosine antagonist. A process for preparing a pharmaceutical composition which comprises admixing the compound of claim 1 or a salt thereof with pharmaceutically acceptable carriers or excipients. 8 P::OPERTPDB'Spa2 133549 s2 065.dow-07;03.O -86-

16. Use of the compound of claim 1 or a salt thereof for the production of a pharmaceutical composition for the therapy of diseases on which an adenosine antagonist is therapeutically effective.

17. A compound of claim 1 substantially as hereinbefore described.

18. A process of claim 10 substantially as hereinbefore described.

19. A composition of claim 11 substantially as hereinbefore described. A method according to claim 12 substantially as hereinbefore described.

21. A use according to any one of claims 13, 14 or 16 substantially as hereinbefore described.

22. A process according to claim 15 substantially as hereinbefore described. Dated this 7 th day of March 2001 Fujisawa Pharmaceutical Co., Ltd. 20 By Its Patent Attorneys DAVIES COLLISON CAVE a a a a a a a ao a a *oooo o