3-(PIPERIDINYL)- AND 3-(PYRROLIDINYL)-1H-INDAZOLES, A PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICAMENT

Abstract: Novel 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles, intermediates and processes for the preperation thereof, and their use for treating psychoses and alleviating pain are disclosed.

Description: The present invention relates to novel 3-(piperidinyl)and 3-(pyrrolidinyl)-1H-indazoles of formula 1 EMI1.1 wherein R is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralky EMI1.2 cyano, cyanomethyl, formyl, loweralkanoyl, or a group of the formulae EMI1.3 EMI2.1 R1 is hydrogen, loweralkyl, loweralkenyl, lowercyclo alkylloweralk EMI2.2 diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl, loweralkanoyl, hydroxymethyl, lowercycloalkylloweralkanoyl, or a group of the formulae EMI2.3 R5C0, 2- or 4-pyridinyl or 2-pyrimidinyl; R2 and R2 are independently loweralkyl, 2,2,2-trichloroethyl or phenyl, R3 and R4 are independently hydrogen or loweralkyl; R5 represents the group furyl, thienyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, X, X' and X" are independently hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl; m is 2 or 3; n is 1 or 2; and the sum of m and n is 3 or 4; n' and n" are independently 2 or 3; p, p' and p" are independently 1 or 2; q and q' are independently 1, 2, 3 or 4; the optical antipode thereof, or the pharmaceutically acceptable acid addition salt thereof, which are useful for treating psychoses and alleviating pain, alone or in combination with inert psychoses-treating and pain-alleviating adjuvants. Preferred 3-(piperidinyl)- and 3-(pyrrolidinyl)-1Hindazoles of the present invention are those wherein R is hydrogen, loweralkyl EMI3.1 wherein, X' , p' an q are as above and R1 is hydrogen, loweralkyl, lowercycloalkylloweralkyl, loweralkanoyl, hydroxymethyl, EMI3.2 wherein X" and p" are as above and q' is 1, 2, 3 or 4 or R21 OCO wherein R21 is as above or EMI3.3 wherein X" and pt t are as above. Most preferred are these wherein R is hydrogen or loweralkyl and Rl is EMI3.4 EMI4.1 X", p" and q' are as above. As used thorough the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon radical containing no unsaturation and having 1 to 10 carbon atoms such as methyl, ethyl, 1-propyl, 2propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl, 3-nonyl, 4-decyl and the like; the term "alkenyl" refers to a straight or branched chain hydrocarbon radical having one olefinic bond and containing 3 to 10 carbon atoms such as 2-propenyl, 2-butenyl, 3-pentenyl, 3-hexenyl, 3-hep tenyl, 4-octenyl, 4-nonenyl, 5-decenyl and the like; the term "cycloalkyl" refers to a saturated hydrocarbon group possessing at least one carbocyclic ring, the ring containing from 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl and the like; the term "alkanol'1 refers to a compound formed by a combination of an alkyl group and a hydroxy radical. Examples of alkanols are methanol, ethanol, 1- and 2-propanol, 1,2-dimethylethanol, hexanol, octanol, decanol and the like. The term "alkanoic acid" refers to a compound formed by combination of a carboxyl group with a hydrogen atom or alkyl group. Examples of alkanoic acids are formic acid, acetic acid, propanoic acid, 2,2-dimethylacetic acid, hexanoic acid, octanoic acid, decanoic acid and the like; the term "halogen" refers to a member or the family consisting of fluorine, chlorine, bromine or iodine. The term "alkanoyl" refers to the radical formed by removal of the hydroxyl function from an alkanoic acid. Examples of alkanoyl groups are formyl, acetyl, propionyl, 2,2-dimethylacetyl, hexanoyl, octanoyl, decanoyl and the like. The term "lower" as applied to any of the aforementioned groups refers to a group having a carbon skeleton containing up to and including 7 carbon atoms-. The compounds of the present invention which lack an element of symmetry exist as optical antipodes and as the racemic forms thereof. The optical antipode may be prepared from the corresponding racemic forms by standard optical resolution techniques, involving, for example, the separation of diasteromeric salts of those instant compounds characterized by the presence of a basic amino group and an optically active acid, or by the synthesis from optically active precursors. The present invention comprehends all optical isomers and racemic forms thereof of the compounds disclosed and claimed herein. The formulas of the compounds shown herein are intended to encompass all optical isomers of the compounds so depicted. The novel 3-(piperidinyl) and 3-(pyrrolidinyll)-1H- indazoles of the present invention are synthesized by processes illustrated in Reaction Schemes A to C. To prepare the 3-(piperidinyl)- or 3-(pyrrolidinyl) 1H-inda%ole system of formula 1 wherein R is alkyl, a 1-alkylchloropiperidine 3 or a l-alkylchloropyrrolidine 3 is condensed with a 2-fluorobenzonitrile 4 to a 1-alkyl (2-fluorobenzoyl)piperidine 5 or a 1-(alkyl-(2-fluorobenzoyl)pyrrolidine 5 which is cyclized to a 3-(1-alkylpiperidinyl)- or a 3-(1-alkylpyrrolidinyl)-1H-indazole 8. See Reaction Scheme A. The condensation of a 1-alkylchloropiperidine 3 or a 1-alkylchloropyrrolidine 3 with a 2-fluorobenzonitrile 4 is effected by conventional Grignard techniques. Typically, the benzonitrile 4, dissolved in an ethereal solvent, such as tetrahydrofuran, is treated with a Grignard reagent, prepared from the chloropiperidine 3 or chloropyrrolidine 3 and magnesium turnings in an ethereal solvent, such as tetrahydrofuran, followed by hydrolysis under acidic conditions. An initiator such as ethyl bromide may be employed to facilitate formation of the Grignard reagent. The cyclization of a i-alkyl-(2-fluoro- benzoyl)piperidine 5 or a l-alkyl-(2-fluorobenzoyl)pyrro- lidine 5 to a 3-(1-alkylplperidinyl)-1H-indazole 8 or a 3-(1-alkylpyrrolidinyl)-1H-indaz6le 8 is performed by treating the benzoylpiperidine 5 or benzoylpyrrolidine 5 with hydrazine, generally as the hydrate, at an elevated temperature and pressure within the range of about 100O to about 200"C, and about 14 to about 21 bar, respectively. A cyclization temperature of about 1500C is preferred. A cyclization pressure of about 17.5 bar is also preferred. To synthesize the 3-(piperidinyl)- or 3-(pyrrolidinyl)1H-indazole system of formula 1 wherein R is alkenyl, EMI6.1 wherein R3, X', n', p' and q are as above, a 1-alkyl (2-fluorobenzoyl)piperidine 5 or 1-alkyl-(2-fluorobenzoyl)pyrrolidine 5 is converted to a 1-phenoxycarbonyl-(2 fluorobenzoyl)piperidine 6 or 1-phenoxyearbonyl-(2-fluoro- benzoyl)pyrrolidine 6 followed by hydrolysis of the 1-phenoxycarbonylpiperidine 6 or 1-phenoxyzarbonylpyrrolidine 5 to a (2-fluorobenzoyl)piperidine 7 or (2-fluorobenzoyl) pyrrolidine 7, alkylation of the benzoylpiperidine 7 or benzoylpyrrolidine 7 to an N-substituted benzoylpiperidine 9 or N-substituted benzoylpyrrolidine 9 and cyclization to the indazole 10 wherein R is as immediately above. See Reaction Schemes A and B. The conversion of the 1-alkylpiperidine 5 or 1-alkyl- - pyrrolidine 5 to the phenoxycarbonylpiperidine 6 or phen oxycarbonylpyrrolidine 6 is accomplished by treating a tertiary amine 5 with phenylchloroformate in an aromatic solvent in the presence of an acid scavenger. Included among aromatic solvents are benzene, toluene, xylene and the like. Toluene is the preferred aromatic solvent. Included among acid scavengers are sodium carbonate, potassium carbonate and the like. Potassium carbonate is preferred. While the reaction temperature is not narrowly critical, it is preferred to conduct the conversion at the reflux temperature of the reaction mixture to assure a reasonable rate of formation of the carbamate 6. The hydrolysis of the phenoxycarbonylpiperidine 6 or phenoxycarbonylpyrrolidine 6 to the 1-unsubstituted piperidine 7 or 1-unsubstituted pyrrolidine 7 is performed by methods well-known in the art, involving, for example, treatment of the carbamate 6 with an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at or about the reflux temperature of the reaction mixture. Aqueous potassium hydroxide is preferred. The alkylation of an N-unsubstituted piperidine 7 or N-unsubstituted pyrrolidine 7 to an N-substituted piperidine 9 wherein R is as immediately above defined or an N-substituted pyrrolidine 9 wherein R is also as immediately above defined is performed by means of an alkenyl, cycloalkylalkyl, or cyanomethyl halide, i.e. an iodide, bromide or chloride, or a compound of the formula EMI8.1 wherein R3, X', n', p' and q are as above and Hal is iodo, bromo or chloro, in the presence of a base suspended or dissolved in a polar aprotic solvent. Suitable bases include alkali metal carbonates and bicarbonates such as, for example, sodium and potassium carbonate and sodium and potassium bicarbonate. Suitable polar aprotic solvents include dimethylformamide, dimethylacetamide and hexamethylphosphoramide. Potassium carbonate and dimethylformamide are the preferred base and solvent. A reaction promotor such as potassium iodide and an elevated reaction temperature within the range of about 70" to about 1200C may be employed to facilitate the alkylation. A reaction temperature of about 900C is preferred. To furnish the 3-(piperidinyl)- or D-(pyrrolidinyl)- 1H-indazole of formula 1 wherein R is EMI8.2 wherein n' is as above the corresponding ethylene glycol cyclic ketal thereof, i.e., a compound of formula 1 wherein R is EMI9.1 is hydrolyzed. the hydrolysis is conveniently accomplished by conventional methods involving, for example, the inter- - - action of a mineral acid, such as hydrochloric acid, in an alkanol, such as methanol, at ambient temperature, or an elevated temperature such as the reflux temperature of the reaction system. To introduce the indol-3-ylalkyl function, i.e., to fabricate an N-substituted piperidine or N-substituted pyrrolidine of formula 1 wherein R is a group of the formula EMI9.2 wherein R3, R4, X', n' and p' are as above, one treats an N-unsubstituted piperidine 7 or N-unsubstituted pyrrolidine 7 with a 3-(phenylsulfonylalkyl)indole or 3-(alkylphenylsulfonylalkyl)indole of the formula EMI9.3 wherein Z is a group of the formula EMI9.4 wherein Y is hydrogen or alkyl and R3, R4, X', n' and p' are as above. The reaction involving the displacement of the phenylsulfonyl group of the indole is accomplished by treating an N-unsubstituted piperidine 7 or N-unsubstituted pyrrolidine 7 with the phenylsulfonylindole in an aprotic polar sovlent, such as dimethylformamide, dimethylacetamide and hexamethylphosphoramide, or an alkanone such as acetone, 2-butanone, 3-pentanone and the like, dimethylformamide and 2-butanone being preferred, in the presence of an acid scavenger such as an alkali metal carbonate (sodium or potassium carbonate) or alkali metal bicarbonate (sodium or potassium bicarbonate), potassium carbonate and sodium bicarbonate being prferred, at a temperature of about 70" to about 110 C preferrably a temperature of 90"C, when an aprotic polar solvent is used, and at about the reflux temperature of the reaction system when an alkanol is employed as the solvent. The cyclization of the N-substituted benzoylpiperidine 9 or N-substituted benzoylpyrrolidine 9 to the 1Hindazole 10 is readily achieved by procedures substantially similar to those utilized for the cyclization of benz oylpiperidine 5 or benzoylpyrrolidine 5 to 1H-indazole 8. To prepare IR-indazoles substituted at the 1-position, i.e., compounds of formula 11 wherein R1 is alkyl, alkenyl, cycloalklalkyl, dialkylaminoalkyl, cyano, cyanomethyl, EMI10.1 2- or 4-pyridinyl or 2-pyrimidinyl, R is as hereinabove defined, with the proviso that R is not hydrogen, and X, m, n and p are as hereinbefore defined, a 1-unsubstituted 1H-indazole 8 wherein R is as hereinbefore defined, with the proviso that R is not hydrogen, and X, m and p are as hereinbefore defined, is treated, respectively, with an alkyl, alkenyl, cycloalkylalkyl, dialkylaminoalkyl, cyanogen, cyanomethyl, 2- or 4-pyridinyl or 2-pyrimidinyl halide, i.e., an iodide, bromide or chloride, or a compound of the formula EMI11.1 wherein X", n", q' and p" are as defined above and Hal is iodo, bromo or chloro, in the presence of an alkali metal hydride suspended in a polar aprotic solvent. Among alkali metal hydrides, there may be mentioned lithium hydride, potassium hydride and sodium hydride. Sodium hydride s preferred. Among polar aprotic solvents, there may be mentioned dimethylformamide, dimethylacetamide and hexamethylphosphoramide. Dimethylformamide is preferred. While the alkylation normally proceeds readily at ambient temperature, the reaction may be conducted at an elevated temperature of about 50 to about 100 C to facilitate the conversion. See Reaction Scheme C. Alternatively, 1H-indazoles substituted at the 1-position by a group of the formula EMI12.1 i.e., compounds of the formula 11 wherein R1 is EMI12.2 wherein X" is hydrogen, halogen, alkyl, alkoxy, hydroxy or amino and p" is 1 or 2, may be prepared from the corresponding compounds wherein X" is nitro by conventional methods involving, for example, reduction of nitro group to an amino function, diazotization and subsequent displacement or reduction of the diazonium moiety. To provide a 1-hydroxymethyl-3-(piperidinyl)-1H- indazole 13 or 1-hydroxymethyl-3-(pyrrolidinyl)-1H-inda- zole 13, a 1-unsubstituted 3-(piperidinyl)-1H-indazole 8 or 1-unsubstitubed 3-(pyrrolidinyl)-1E-indazole 8 wherein R is as hereinbefore defined, with the exception that R is not hydrogen, is treated with formaldehyde in the form or paraformaldehyde or trioxane in an alkanol such as methanol, ethanol, 2-propanol and the like, preferably ethanol, in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, sodium hydroxide being preferred, at an elevated temperature of about the reflux temperature of the reaction mixture. To prepare the hydroxymethyl-iH-indazole 13 wherein R is hydrogen, one conducts the condensation on, for example, an N-phenoxycarbonyl-1H-indazoel of formula 10 and then removes the carbamoyl group under conventional mild hydrolysis conditions. To fabricate the 3-(piperidinyl)- or3-(pyrrolidinyl) 1H-indazole system of formula 1 wherein R is EMI12.3 alkanoyl, formyl or RêOCO wherein Rê, X', p' and q are as defined above, a 3-(piperidinyl)- or 3-(pyrrolidinyl)1H-indazole of formula 18, i.e., a compound wherein the nitrogen atom of the D-(piperidinyl) or 3-(pyrrolidinyl) groups and the nitrogen atom occupying the 1-position of the indazole system are unsubstituted, is treated with an alkanoyl or formyl halide, i.e., an alkanoyl or formyl iodide, bromide or chloride, or halide or the formulas EMI13.1 and R20C0Hal, wherein R2, X', p' and q are as above and Hal is iodo, bromo or chloro, in a halocarbon such as dichloromethane or trichloromethane, or a polar aprotic solvent such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide in the presence of an acid scavenger such as sodium or potassium carbonate, or sodium or potassium bicarbonate to provide a D-(piperidinyl)- or )-(pyrrolidinyl)-1H-indazole of formula 19 wherein R, X, m, n and p are as above. Trichloromethane and dimethylformamide are the preferred solvents, and potassium bicarbonate is the preferred scavenger. To minimize formation of disubstituted products, i.e., compounds of formula 20 wherein R, X, m, n and p are as above, one generally performs the acylation reaction, i.e., the conversion of 18 to 19, at about ambient temperature, at which temperature only minor amounts of the N,N'-di- substituted product 20 are usually formed. The N-substituted and N,N'-disubstituted products 19 and 20 may be separated by conventional techniques such as recrystallization. In the event substantial amounts of the N,N'disubstituted product are formed, or the separation proves to be difficult, one may transform the N,N'-disubstituted compound 20 to the monosubstituted product 19 by alcoho isis. The acoholysis is conveniently accomplished by means of an alkali metal alkoxide in an alkanol. Suitable alkali metal alkoxides include lithium, sodium or potassium methoxide, ethoxide, 1-propoxide and the like. Suitable alkanols include methanol, ethanol, 1-propanol and the like. Sodium methoxide in methanol is preferred. To provide the 1H-indazole 10 wherein R is hydrogen and X, m, n and p are as defined above an N-unsubs-tituted benzoylpiperidine 7 or N-unsubstituted benzoylpyrrolidine 7 is cyclized with hydrazine hydrate by the hereinbefore described process. 3-(Piperidinyl)- or 3-(pyrrolidinyl)-1H-indazol systems'of formula 1 wherein R is cyano are also prepared by treating a 1-substituted 1H-indazole of formula 11 wherein R is alkyl and R1 is formyl, alkanoyl or EMI14.1 wherein X" , p" and q' are as above with cyanogen bromide or chloride as hereinbefore described. Por example, treatment of a solution of 1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11 wherein R is methyl, R1 is benzoyl, X is hydrogen, m and n are 2 and p is 1) and chloroform with cyanogen bromide in the presence of potassium carbonate provides 1-benzoyl-3-(1-cyano-4-piperidinyl)-1E- indazole (1 wherein R is cyano, R1 is benzoyl, X is hydrogen, m and n are 2 and p is 1). To prepare 1-substituted 1H-indazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl EMI14.2 wherein R21, R5, X" , pi' and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodide, a compound of the formula EMI15.1 R2 OCOHal or R5COHal wherein RX R5, X11, p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1Hindazol 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100 C yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl. Alternatively, the synthesis of 1-substituted 1Hindazoles of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl, EMI15.2 RêOCO or R5CO wherein Rê, R5, X', p' and q are as above is accomplished by contacting a formyl, cycloalkylalkanoyl or alkanoyl halide or compound of the formula EMI15.3 R21OCOHal or R5COHal wherein R2 , 1 X", p" and q' are as above, with a 1-unsubstituted-1Hindazole 8 in a halocarbon such as dichloromethane or trichloromethane, preferably trichloromethane, in the presence of an acid scavenger such as sodium or potassium carbonate, or sodium or potassium bicarbonate, preferably potassium carbonate. The reaction proceeds readily at moderate temperatures. To promote the conversion however, elevated temperatures, i.e., the reflux temperature of the reaction medium are generally employed. To provide 1-substituted lH-indazoles 11, wherein R1 is EMI16.1 wherein X" and p" are described hereinbefore, a 1-unsubstituted 1H-indazole 8 is treated with a benzenesulfonyl halide of the formula EMI16.2 wherein X" and p" are as described and Hal is chloride or bromide at an elevated temperature within the range of about 80" to about 1500C. a reaction temperature of about 100"C being preferred. 1H-indazoles of formula 11 wherein R1, X, m, n and p are as above and R is hydrogen are prepared from 1Hindazoles of formula 11 wherein R1, X, m, n and p are as above and R is alkyl by the conversion of a 3-(1-alkyl- piperidinyl)- or D-(1-alkylpyrrolidinyl)-1H-indazole 11 wherein R is alkyl and R1, X, m, n and p are as above to a 3-(1-cyanopiperidinyl) or 3-(1-cyanopyrrolidinyl)-1Hindazole 11 wherein R is cyano and R1, X, m and p are as above followed by removal of the cyano group to a 1Hindazole of formula 11 wherein R is hydrogen and R1, X, m, n and p are as above. The conversion of a 1-alkylpiperidine 11 or 1-alkylpyrrolidine 11 wherein R is alkyl to the corresponding 1-cyano compound 11 wherein R is cyano is accomplished by treating the alkylpiperidine 11 or alkylpyrrolidine 11 with a cyanogen halide such as cyanogen bromide or chloride in the presence of a acid acceptor such as sodium or potassium carbonate or sodium or potassium bicarbonate in a suitable solvent. Suitable solvents include halocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane and the like, and dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, and dimethylsulfoxide. Cyanogen bromide is the preferred halide and dimethyl sulfoxide containing potassium carbonate is the preferred reaction medium. The conversion temperature is not critical. To avoid side-reactions, however, it is preferred to perform the reaction at reduced temperatures between about 0 and about 30 C. A temperature of about 25"C is preferred. The removal of the cyano group of compounds of for mulÅa 11 wherein R is cyano may be effected under conventional hydrolytic conditions, utilizing for example, aqueous organic acids such as aqueous acetic, or mineral acids such as dilute hydrochloric acid or sulfuric acid. N-unsubstituted 1H-indazoles, i.e., 1H-indazoles of formula 18 wherein both the indazole and piperidine (or pyrrolidine) nitrogen atoms are unsubstituted, are prepared by an alternative synthesis involving the condensat ion of an appropriately substituted fluorobenzene of formula 15 wherein X and p are selected from the groups described above with an N-formyl- or N-alkanoyl-(piperidinyl)- or (pyrrolidinyl)carbonyl halide of formula 16 wherein R is formyl or alkanoyl and Hal is chloro or bromo, followed by cyclization of the resulting (2-fluorobenzoyl)piperidine 17 or (2-fluorobenzoyl)pyrrolidine 17 to the 1H-indazole 18. The condensation of fluorobenzene 15 with a carbonyl halide 16 is accomplished under Friedel-Crafts conditions as described in U.S. Patent 4,355,037. The cyclization of a (2-fluorobenzoyl)piperidine 17 or (2-fluorobenzoyl)pyrrolidine 17 to a 1H-indazole 18 is performed with hydrazine hydrate in an alkanol at an elevated temperature, conditions under which the N formyl or N-alkanoyl group of the piperidine or pyrrolidine ring is removed. Suitable alkanols include ethanol, 2-propanol, 1-butanol, 3-pentanol and the like. 1-Butanol is preferred. A cyclization temperature of the boiling point of the reaction medium is also preferred. The synthesis of 3-(3-haloalkyl)-6-fluoro-1,2-benz- isoxazoles, 4,4-bis(4-fluorophenyl)butyl halides,3 (phenylsulfonylalkyl) indoles and 3-(alkylphenylsulfonylalkyl)-indoles, 1-(3-haloalkyl) 1 , 2- dihydro-2H-benzimidazol-2-ones; and 4-fluorobenzoylalkyl halides ethylene glycol ketals requisite precursors for the preparation of 3-(4-piperidinyl)-1H-indazoles and 3-(3-pyrrolidinyl)-1H-indazoles of the present invention, substituted at the indazole and/or piperidine or pyrrolidine nitrogen atoms, are described in U.S. Patent 4,352,811. The 3-(piperidinyl)- and 3-(pyrrolidinyl)-lH-indazoles of the present invention are useful for treating psychoses by virtue of their ability to elicit a antipsychotic response in mammals. Antipsychotic activity is determined in the climbing mice assay by methods similar to those described by P. Protais, et al., Psychopharmacol., 50 1 (1976) and iB. Costall, Eur. J. Pharmacol., 50 39 (1978). The subject CK-1 male mice (23 - 27 grams) are grouphoused under standard laboratory conditions. The mice are individually placed in wire mesh stick cages (4" x 4" by 10) and are allowed one hour for adaptation and exploration of the new environment. Then apomorphine is injected subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 30 minutes. Compounds to be tested for antipsychotic activity are injected intraperitoneally 30 minutes prior to the apomorphine challenge at a screening dose of 10 mg/kg. For evaluation of climbing, 3 readings are taken at 10, 20 and 30 minutes after apcmorphine administration according to the following scale: Climbing Behavior Score Mice with: 4 paws on bottom (no climbing) 0 2 paws on the wall (rearing) 1 4 paws on the wall (full climb) 2 Mice consistently climbing before the injection of apomorphine will be discarded. With full-developed apomorphine climbing, the animals are hanging onto the cage walls, rather motionless, over longer periods of time. By contrast, climbs due to mere moor stimulation usually only least a few seconds. The climbing scores are individually totaled (maximals score: 6 per mouse over 3 readings) and the total score of the control group (vehicle intraperitoneally - apomorphine subcutaneously) is set to 100 . ED50 values with 95 % confidence limits, calculated by a Linear Regression Analysis of some of the instant 3-(piperidinyl)- 1E-indazoles and 3-(pyrrolidinyl)-1H-indazoles as well as standard antipsychotics, are presented in Table 1. Table 1 Antipsychotic activity Compound (ED50 mg/kg) 3-(1-methyl-4-piperidinyl)-1H- 4.5 indazole 3-(1-methyl-4-piperidinyl)-1- 46 % (10 mg/kg*) indazole 1-ethyl-3-±1-methyl-4- 41 % (10 mg/kg*) piperidinyl)-1 H-indazole 1-acetyl-3-(1-methyl-4- 5.4 piperidinyl)-1H-indazole 1-benzoyl-3-(t-methyl-4- 6.5 piperidinyl)-1E-indazole 9-(1-[4,4-bis(4-fluorophenyl)- 7.4 1-butyl]-4-piperidinylj-1H- indazole 1-C; ;yclopropylmethyl-3- 36 % (io mg/kg*) (1-methyl-4-piperidinyl)-1H- indazole haloperidol (standard) 0.11 sulpiride (standard) 14.5 * decrease in climbing score at indicated dose Antipsychotic response is achieved when the present 3 (piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of from 0.01 to 50 mg/kg of body weight per day. A particularly preferred effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the adminstration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and they do not, to any extent, limit the scope or practice of the invention. The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-inda zoles of the present invention are useful as analgetlcs due to their ability to alleviate pain in mammals. The analgetic utility is demonstrated in the phenyl-p-quinone writhing assay in mice, a standard assay for analgesia [Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)]. Thus, for instance, the subcutaneous dose effecting an approximately 50 % inhibition of writhing (ED50) in mice produced in this assay is as follows: Compound ED50 mg/kg 3-(1-methyl-4-piperidinyl)-1H- 0.26 indazole 1-ethyl-3-(1-methyl-4- 0.65 piperidinyl)-1-indazole 1-acetyl-3-(1-methyl-4- 0.71 piperidinyl)-1H-indazole 1-benzoyl-3-(1-methyl-4- 0.85 piperidinyl)-1H-indazole 1-phenylmethyl-3-(1-methyl- 75 % (20 mg/kg*) 4-piperidinyl)-1H-indazole 96 % (20 mg/kg*) 3-[1-[4,4-bis(4-fluorophenyl)-1- 31 % (20 mg/kg*) butyl]-4-piperidinyl}-1H-indazole 1-cyclopropylmethyl-3-(1-methyl- 1.1 4-piperidinyl)-1H-indazole 1-[3-(dimethylamino)propyl]-3- 15 ffi (20 mg/kg*) (1 -methyl-4-piperidinyl)-1 H- indazole 1-(4-trifluoromethyl-1-phenyl)- 9.8 <RTI ID=21.6> 3-(1-methyl-4-piperidinyl)-1H- indazole propoxyphene (standard) 3.9 pentazocine (standard) 1.3 * inhibition of writhing at indicated dose Analgesia production is achieved when the present 3-(pi peridinyl)-and 3-(pyrrolidinyl)-1H-indazoles are administered to a subject requiring such treatment as an effective oral, parenteral or intravenous dose of from 0.01 to 100 mg/kg of body weight per day. A particularly effective amount is about 25 mg/kg of body weight per day. It is to be understood, however, that for any particular subject, specific dosage regimens should be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compound. It is to be further understood that the dosages set forth herein are exemplary only and that they do not, to any extent, limit the scope or practice of the invention. Compounds of the present invention include: (a) 3-(3-(pyrrolidinyl)-1H-indazole (b) 3-( 1-propenyl-4-piperidinyl)-1H-indazole (c) 3-(4-cyclopropylmethyl-3-piperidinyl)-6-methyl-1 (2-pyrimidinyl ) -1 H-indazole (d) 3-[1-butyl-3-pyrrolidnyl]-4-methoxy-1-(2-pyridinyl) 1 H-indazole (e) 3- (1 -cyanomethyl-3-piperidinyl )-7-trifluoromethyl- 1 H-indazole (f) 1-(4-fluorobenzoyl)-3-[4-piperidinyl]-5-nitro-1H indazole (g) 3-(1-acetyl-4-piperidinyl)-4-amino-1-(4-fluoroben zoylethyl)]-1H-indazole (h) 3-[1-(1-methylindol-3-propyl)-3-piperidinyl]-1H- indazole (i) 1-formyl-3-(1-formyl-4-piperidinyl)-1H-indazole (j) 5,6-dichloro-3-[1-(4-fluorobenzoylpropyl)-4-piperi- dinyl]-1-(propen-1-yl)-1H-indazole (k) 1-cyano-3-[1-(4-fluorobenzoylpropyl)-3-pyrrolidinyl]- 1H-indazole ethylene ketal (1) 1-cyanomethyl-3-[1-(6-fluoro-1 ,2-benzisoxazol-3-pro pyl)-3-piperidinyl]-1 H-indazole (m) 3-(1-phenoxyearbonyl-4-piperidinyl)-1-(4-picolinoyl)- 1 H-indazole (n) 3-{1-[1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1- ylpropyl]-4-piperidinyl}-1 -(2-thiazolylcarbonyl)-1 H- indazole (o) 3-{1-(3-phenylpropyl)-4-piperidinyl}-1H-indazole (p) 3-[1-(1-methylindol-3-propyl)-3-piperidinyl]-1H- indazole Effective amounts of the present invention may be administered to a subject by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The 3-(piperidinyl)- and 3-(pyrrolidinyl)-1H-indazoles of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes or stability, convenience or crystallization, increased solubility and the like. Preferred pharmaceutically acceptable addition salts include salts of mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid and the like, salts of monobasic carboxylic acids such as, for example, acetic acid, propionic acid and the like, salts of dibasic acids such as, for example, maleic acid, fumaric acid and the like, and salts of tribasic carboxylic acdis such as, for example, carboxysuccinic acid, citric acid and the like. Effective quantities of the compounds of the invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be en closed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5 76 of active compound, but may be varied depending upon the particular form and may conveniently be between 4 < , to about 70 ffi of the weight of the unit. The amount of active compound in such composition is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0 - 300 milligrams of the active compound. The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragancanth or gelatin; an excipient such as s tarch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or a flavoring agent such as peppermint, methyl salicylate, or organge flavoring may be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such a s a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1 % of active compound, but may be varied between 0.5 and about 50 % of the weight thereof. The amount of active compounds in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.5 to 100 milligrams of active compound. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glykols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffer such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. The following examples are for illustrative purposes only and are not to be construed as limiting the invention. All temperatures are given in degreed centrigrade (DC). Example 4-(2-Fluorobenzoyl)-1-methylpiperidine hydrochloride To a suspension of 7.6 g of magnesium turnings in 25 ml of tetrahydrofuran was added a few drops of ethyl bromide, with stirring under nitrogen. After the reaction began approximately 50.0 g of N-methyl-4-chloropiperidine in 125 ml of tetrahydrofuran was added dropwise at a rate such that noderate reflux was maintained. The reaction was heated under reflux for an additional hour. A solution of 37.2 g of o-fluorobenzonitrile in 30 ml of tetrahydrofuran was added dropwise. After completion of the reaction mixture was heated under reflux for two hrs and stirred overnight at room temperature. The reaction mixture was poured into a solution of 85 g of ammonium chloride in 1200 ml of ice water and heated on a steam bath for 3 hrs. The mixture was cooled, extracted with benzene (3x, 250 ml) and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave an oil. A 1.0 g-portion of the oil was dissolved in ether and a solution of etheral hydrogen chloride was added. The precipitate was collected, dried and twice recrystallized from ethanol ether to give 0.5 g (42 ) of product, mp 167 - 169 . Analysis: Calculated for C13H17clS0: 60.58 %C 6.65 %H 5.43 %N 7.37 %F Found: 60.30 %i: 6.78 %H 5.43 %N 7.59 %F Example 2 1-Phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine To a solution of 57.5 g of 4-(2-fluorobenzoyl-)-1methyl piperidine and 68.7 g of potassium carbonate in 750 mi of toluene was added with stirring 47 g of phenylchloroformate. The reaction mixture was heated under reflux for 5 hrs, colled to room temperature, filtered, and the solvent removed under reduced pressure to give an oil. Trituration of the oil with hexane gave 48.6 g (46 %) of product. Recrystallization of 1.0 g of product from ethanolwater (2x) and from ethanol gave the analytical sample, mp 95 - 96 . Analysis: Calculated for C19YH18FNO3: 69.71 %C 5.54 %H 4.28 %N 5.81 %F Found: 69.45 gge 5.67 , 4.13 %N 6.10 %F Example 3 4-(2-Fluorobenzoyl)piperidine hydrochloride A solution of 40.5 g of 1-phenoxycarbonyl-4-(2-fluoro- benzoyl)piperidine, 500 ml of ethanol and 500 ml of 30 % of potassium hydroxide solution was stirred at a temperature slightly below reflux overnight. The reaction temperature was colled to room temperatur, diluted with 250 ml of water, and the ethanol partially removed under reduced pressure. The aqueous suspension was extracted with ether (2x 150 ml) and the ether fraction subsequently extracted with 1N hydrochloric acid (2 x 200 ml). The aqeuous solution was basified with 25 % sodium hydroxide solution, extracted with ether (2 x 150 ml) and dried over anhydrous sodium sulfate. The solvent was removed under redduced pressure to give an oil. The oil was dissolved in a minimum amount of ethanol and a solution of ethereal hydrogen chloride was added dropwise until a precipitate formed. The solid was collected and dried to give 9.7 g (40 k) of product. Recrystallization twice from ethanolether gave the analytical sample, mp 185 - 187 . Analysis: Calculated for C 2H 5ClFNO: 59.14 %C 6.2() %H 5.74 %N 7.80 %F Found: 58.90 %C 6.36 %H 5.50 %N 7.56 %F Example 4 1-Methyl-4-piperidinyl)-1H-indazole An autoclave was charged with 10.0 g of 4-(2-fluorobenzoyl)-1-methylpiperidine and 14 ml of hydrazine hydrate. The reaction was heated at 1500 for 20 hrs, cooled, and poured into water. The resultant solid was collected. -The solid was recrystallized twice from toluene to yield 2.4 g (23.7 %) of product, mp 168 - 1700. Analysis: Calculated for C13H17N: 72.52 %C 7.96 %H 19.52 o°N Found: 72.60 %C 8.04 %H 19.51 %N Example 5 3-{1-[4,4-bis(4-Fluorophenyl)-1-butyl]-4-piperidinyl]-1Hindazole A mixture of 10.0 g of 4-(2-fluorobenzoyl)piperidine 16.9 g of potassium carbonate, 28.8 g of 4-chloro-1,1bis(4-fluorophenyl)butane, 250 ml of dimethylformamide and a few crystals of potassium iodide was heated at 90" for 8 hrs with stirring. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sufate and the solvent removed in vacuo to yield an oil. The oil was dissolved in ether, and oxalic acid was added. Recrystallization of the resultant solid from ethanol gave 10.6 g (34.6 %) of 1-[4,4-bis(4-fluorophenyl)-1-butyl]-4-(2-fluorobenzoyl)piperidine oxalate, mp 179 - 181 . A solution of 8.0 g of 1-[4,4-bis(4-fluorophenyl)1-butyl]-4-(2-fluorobenzoyl)-piperidine and 110 ml of hydrazine hydrate was heated at 1500 in an autoclave for 20 huts, with stirring. The resultant solid was diluted with water, and the mixture extracted with dichloromethane. The dichloromethane was evaporated in vacuo to yield a solid. The solid was recrystallized from toluene to give 3.8 g (47.4 %) of product, mp 154 - t56". Analysis: Calculated for C28H29F2N3: 75.48 %C 6.56 %H 9.43 XN Found: 75.29 %C 6.59 %H 9.40 %N Example 6 1-Ethyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrobromide To a stirred suspension of 0.86 g of sodium hydride (50 % oil dispersion) in 50 ml of dimethylformamide was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H- indazole in 15 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature and 1.34 ml of ethyl bromide in 10 ml of dimethylformamide was added, dropwise. The reaction was stirred overnight at ambient temperature and poured into water. The aqueous suspension was extracted with ethyl acetate (2X, 100 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo to yield an oil. The oil was dissolved in a minimum amount of ethanol-ether, and a saturated solution of ether-hydrogen bromide was added. The salt was recrystallized from ethanol-ether to yield 2.4 g (52.8 %) of product, mp 240 - 242". Analysis: Calculated for C15H21N3HBr: 55.56 C 6.84 %H 12.96 %N Found: 55.39 %C 6.68 %H 12.59 %N Example 7 1-[4-Nitro-1-phenyl]-3-(1-methyl-4-piperidinyl)-1H- indazole hydrochloride To a stirred suspension, under nitrogen, of 0.86 g of sodium hydride (50 % cil dispersion) was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After completion of the addition, the reaction mixture was stirred at ambient temperature for 1 hr and then 2.2 g of 1fluoro-4-nitrobenzene was added, dropwise. The reaction mixture was stirred at ambient temperature for 16 hr and then poured into water. The resultant solid was collected and dried. The solid was dissolved in absolute ethanol and the solution was treated with saturated hydrogen chloride/ether solution to precipitate a salt. Recrystallization of the salt from methanol-ether (twice) gave 3.0 g (52 %) of product, mp 272 - 274C. Analysis: Calculated for C19H20N402-HCl 61.20 %C 5.68 %H 15.03 %N Found: 61.09 C 5.70 H 14.82 N Example 8 1-[3-(Dimethylamino)propyl]-3-(1-methyl-4-piperidinyl)-1H- indazole difumarate To a stirred suspension of 1.15 g of sodium hydride (50 % oil dispersion) in 30 ml of dimethylformamide, under nitrogen, was adedd dropwise 4.3 g of 3-(1-methyl-4-piperi dinyl)-1H-indazole dissolved in 30 ml of hot dimethylformamide. After stirring at ambient temperature for 1 hr, a solution of 3.3 g of dimethylaminopropylchloride in 30 ml of toluene was added dropwise. The reaction was then heated at 60 for 1 hr and then stirred at ambient temperature for 16 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate (3x 150 ml The organic extracts were combined, washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo to yield an oil. the oil was dissolved in 25 ml of acetonitrile and 4.6 g of fumaric acid was added. The mixture was warmed on the steam bath (ca. 15 min), and then left at ambient temperature for 15 hrs. The resultant solid was filtered and recrystallized from dimethylformamide (thrice) with cooling (ca. 5 ) to yield 1.4 g (18.7 %) of product, mp 161 - 163 . Analysis: Calculated for C18H28N4.2C4H4O4: 58.61 %C 6.81 %H 10.52 %N Found: 58.82 %C 6.91 %H 11.51 % Example 9 1-(4-Trifluoromethyl-1-phenyl)-3-(1-methyl-4-piperidinyl)1H-indazole hydrochloride To a stirred suspension of 1.15 g of sodium hydride (50 % oil dispersion) in 30 ml of dimethylformamide, under nitrogen, was added dropwise 4.3 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 30 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 1 hr and then 3.9 g of 4-fluorobenzotrifluoride was added. The temperature was raised to 90" and held there for 16 hrs. the reaction mixture was poured into water and the aqueous suspension extracted with ethyl acetate (2X, 150 ml). The extracts were combined, washed with water, brine, dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield an oil. The oil was dissolved in ether and saturated ether-hydrogen chloride solution was added to precipitate a salt. Recrystallization (twice) from isopropanol-ether gave 3.3 g (41.7 ) of product, mp 221 223". Analysis: Calculated for C20H20F3N3.HCl: 60.68 %C 5.34 %H 10.62 XN Found: 60.86 %C 5.55 H 10.62 %N Example 10 1-Hydroxymethyl-3-(1-methyl-4-piperidinyl)-1E-indazole A solution of 0.52 g of paraformaldehyde, 3.0 g of 3 (1-methyl-4-piperidinyl)-1H-indazole, 15 ml of ethanol and 0.34 ml of 5 ffi aqueous sodium hydroxide was refluxed for 3 hrs. The ethanol ws removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with dichloromethane (2x, 50 ml) and the combined extracts were washed with water and dried over anhydrous magnesium sulfate. The dichloromethane was evaporated in vacuo to yield an oil, which crystallized upon standing. Th-e solid was recrystallized twice from ethyl acetate to yield 1.3 g (57.8 %) of product, mp 128 - 1300. Analysis: Calculated for C14H19N30: 68.54 %C 7.81 %H 17.13 N Found: 68.41 C 7.81 %H 17.24 %N Example 11 1-(6-Fluoro-1,2-benzisoxazole-3-propyl)-3-(1-methyl-4piperidinyl)-1H-indazole maleate To a stirred suspension under nitrogen of 0.8 g of sodium hydride (50 % oil dispersion) in 45 ml of dimethylformamide, was added dropwise, 3.0 g of 3-(1-methyl-4- piperidinyl)-1H-indazole dissolved in 50 ml of hot dimethylformamide. The reaction mixture was stirred at am bient temperature for 45 min and then 3.9 g of 3-3-chloroprop-1-yl)-6-fluoro-1,2-benzisoxazole was added. The reaction mixture was stirred at ambient temperature overnight (ca. 16 hr) and then poured into water. The aqueous suspension was extracted with ether and the ether extract was washed with water, dried over anhydrous magnesium sulfate, and filtered. Treatment of the etheral solution with 2.0 g of maleic acid suspended in 10 ml of ethanol resul- ted in an oil. Decantation of the supernatant ether solution and subsequent trituration of the oil will ethyl acetate gave a solid. Recrystallization of the solid from ethyl acetate yielded 3.0 g (43 %) of product, mp 127 - 129 . Analysis: Calculated for C23H25FN40.C4H404: 63.77 %C 5.75 %H 11.02 %N Found: 63.53 %C 5.71 %H 11.15 %j1 Example 12 1-Cyclopropylmethyl-3-(1-methyl-4-piperidinyl)-1Hindazole hydrobromide EMI32.1 To a stirred mixture of 1.19 g of sodium hydride (50 % oil dispersion) in 65 ml of dimethylformamide was added, dropwise, 4.0 g of D-(1-methyl-4-piperidinyl)-1H- indazole in 20 ml of dimethylformamide. The mixture was stirred for 1 hr at ambient temperature and then 1.40 g of chloromethylcyclopropane in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred 2 1/2 days at ambient temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and saturated hydrogen bromide/ether solution was added dropwise to precipitate a salt. The salt was recrystallized from toluene and ethyl acetate to yield 2.8 g (32 ) of product, mp 177- 179 C. Analysis: Calculated for C17H23N3.HBr: 58.29 C 6.86 H 12.00 %N Found: 58.20 %C 6.59 %H 11.82 %N Example 13 1-Phenylmethyl-3-(1-methyl-4-piperidinyl)-1H-indazolehydrobromide To a stirred suspension of 0.86 g of sodium hydride (50 % oil dispersion) in 50 ml of dimethylformamide under nitrogen, was added, dropwise, 3.0 g of 3-(1-methyl-4piperidinyl)-1H-indazole dissolved in 15 ml of hot dimethylformamide. After stirring one hr at ambient temperature, 2.6 g of benzyl bromide in 5 ml of diemthyl- formamide was added. The reaction mixture was stirred at ambient temperature for 15 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine and dried over anyhdrous magnesium sulfate. The ethyl acetate was evaporated in vacuo to yield an oil. The oil was dissolved in ether and gaseous hydrogen bromide was passed through the solution to yield an oily material. The oily material was triturated with boiling ethyl acetate. The solid was collected and recrystallized from absolute ethanol to yield 2.4 g (44.3 ) of product, mp 218 - 220". Analysis: Calculated for C2oH23NHBr: 62.18 %C 6.00 %H 10.88 %N Found: 62.13 %C 6.24 %H 10.87 XN Example 14 1-Phenethyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrobromide To a stirred mixture of 0.86 g of sodium hydride (50 % oil dispersion) in 50 ml of diemthylformamide was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H indazole in 15 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 1 hr and then a solution of 3.33 g of (2-bromoethyl)benzene in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 2 1/2 days at ambient temperature, cooled to 0 , and water was added dropwise. The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and a saturated bromide/ether solution was added dropwise. The resultant solid was recrystallized two times from ethanol to yield 2.0 g (36 ) of product, mp 163 - 164 . Analysis: Calculated for C21H25N3.HBr: 63.00 %C 6.50 %H 10.50 XN Found: 62.93 %C 6.58 %H 10.55 %N Example 15 1-Acetyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride A mixture of 2.0 g of 3-(1-methyl-4-piperidinyl)1H-indazole, 20 ml of acetic anhydride and a few drops of pyridine was stirred under reflux for 2 hrs. Most acetic anhydride was evaporated in vacuo and the resultant solution was poured into 80 ml of water. The solution was made basic with ammonium hydroxide solution. A white solid precipitated. The solid was collected, dried and dissolved in ether. Saturated ether-hydrogen chloride solution was added. The salt was reprecipitated from cold methanol with ether to yield 1.6 g (60.5 %) of product, mp 238 - 2390. Analysis: Calculated for C15H19ND0-HCl: 61.32 %C 6.86 H 14.30 %N Found: 61.08 C 6.76 %H 14.32 %N Example 16 1-Benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-in- dazole and 3.2 ml of benzoyl chloride was heated at 100 for 2 hrs. The resultant solid was triturated with ether and collected. The salt was twice recrystallized from ethanolether to yield 3.1 g (62.2 %) of product, mp 234 - 236 . Analysis: Calculated for C20H21N30.HCl: 67.50 %C 6.23 %H 11.81 N Found: 67.22 %C 6.15 %H 11.82 %N Example 17 3-(1-Methyl-4-piperidirXyl)-1-trichloroethoxyearbony'-1H- indazole hydrochloride A mixture of 2.3 g of trichloroethyl chloroformate, 3.0 g of potassium carbonate, 2.1 g of 3-(1-methyl-4-piperidyl)-1H-indazole and chloroform was heated under reflux for 16 hrs. The reaction mixture was cooled, filtered, and the filtrate was concentrated to a solid in vacuo. The solid was triturated with ethyl acetate, collected, and recrystallized from ethanol to yield 3.9 g (91 %) of product, mp 190 - 192 . Analysis: Calculated for C16H18Cl3N302XCl 44.99 %C 4.48 %H 9.85 %N Pound: 44.64 SgC 4.46 %H 9.84 %N Example 18 1 -Phenylsulfonyl-3- (1 -methyl-4-piperidinyl )-1 H-indazole hydrochloride A mixture of 2.5 g of 3-(1-methyl-4-piperidinyl)-1H- indazole and 50 ml of benzenesulfonyl chloride was heated on a steam bath for 1 hr. The solution was cooled to ambient temperature and then poured into ether. The precipitate was collected and triturated with ethyl acetate to yield a solid. The solid was combined with 1.5 g of solid from another experiment and recrystallized twice from isopropanol to yield 2.3 g (36 %) of product, mp 222 - 224 . Analysis: Calculated for C1gH21Nfi02S 58.24 %C 5.66 %H 10.72 %N Found: 58.17 C 5.77 %H 10.80 %N Example 19 1-(4-?luorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazole A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1Hindazole in 15 ml of 4-fluorobenzoyl chloride was heated at 100 for 2 hrs. The reaction mixture was poured into ether and the precipitate was collected. The precipitate was treated with dilute aqueous sodium hydroxide solution and extracted EMI36.1 with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 2.5 g (53 %) of product, mp 132 - 133 . Analysis: Calculated for C20H20FN30: 71.20 %C 5.98 %X 12.45 N Found: 71.42 %C 6.21 t 12.50 %N Example 20 1-Ethoxyearbonyl-3-(1-methyl-4-piperidinyl)-1X-indazole hydrochloride To a stirred mixture of the 3.5 g of 3-(1-methyl-4piperidinyl)-1H-indazole, 2.7 g of potassium carbonate and 40 ml of chloroform was added, dropwise, 21.1 g of ethyl chloroformate. The reaction mixture was stirred under reflux for 16 hr, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was triturated with ether. Recrystallization from ethanol-ether and then from isopropyl alcohol-ether gave 2.3 g (43.8 ) of product, mp 181 - 1830C (gas evolution). Analysis: Calculated for C16H21N3OHCl: 59.34 %C 6.85 %H 12.98 %N Found: 58.76 %C 7.05 %H 12.80 N Example 21 1-(4-Methoxybenzoyl)-3-(1-methyl-4-piperidinyl)-1E-indazole hydrochloride A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1Hindazole in 10 ml of p-anisoyl chloride was heated at 100 C for 3 hr. The reactions mixture was cooled to ambient temperature, ether was adedd and the solid was collected. The solid, suspended In ether, was stirred for 16 hr. The mixture was filtered and dried. Recrystallization from ethanol (twice) yielded 4.0 g (74.4 %) of product, mp 235 -- 237 C. Analysis: Calculated for C21H23N302.HCl: 65.36 %C 6.27 %H 10.89 %N Found: 64.83 %C 6.16 %H 10.82 %N Example 22 1-(2-Chlorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole fumarate To a stirred suspension of 1.1 g of sodium hydride 50 % oil dispersion) in 40 ml of dimethylformamide under nitrogen was added, dropwise, 4.0 g of 3-(1-methyl-4piperidinyl)-1H-indazole in 25 ml of hot dimethylformamide. The reaction was stirred at ambient temperautre for 1 hr and then 3.6 g of 1-chloro-2-fluorobenzene was added. The temperature was then raised to 120C and held at 120C for 20 hrs. The reaction was poured into water and the aqueous suspension was extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate, and the ether was removed in vacuo. The residue was chromatographed on a Water's preparative high-pressure liquid ch roinatograph using a silica gel columns eluted with tetra hydrofuran-(C2H5)2SH (99:1). Evaporation of the appropriate fractions yielded an oil. The oil was dissolved in ether and 1.5 g of fumaric acid was added. The mixture was stirred at ambient temperature for 16 hr, and the solid was collected. Recrystallization from isopropyl alcohol-ether and then from ethanol-ether gave 2.5 g (31.4 %) of product, mp 179 - 181 C. Analysis: Calculated for C19H20ClN3.C4H404: 62*51 %C 5.47 %H 9.51 %] Found: 62.46 %C 5.50 %H 9.43 % Example 23 1-Benzoyl-3-(1-cyano-4-piperidinyl)-1H-indazole A sample of 8.4 g of 1-benzoyl-3-(1-methyl-4-piperidinyl) 1H-indazole hydrochloride was converted to its free base and the base was dissolved in 135 ml of chloroform. The solution was stirred and 4.0 g of potassium carbonate was added followed by 2.7 g of cyanogen bromide. The reaction mixture was stirred under reflux for 16 hrs. The mixture was filtered, and the solvent was removed in vacuo. The mixture was chromatographed on a high-pressure column chromatography apparatus (silica gel), eluting with 0.3 ffi methanol/dichloroethane. Evaporation of the appropriate fraction followed by recrystallization from toluene hexane yielded 2.2 g (28 %) of the product, mp 144 - 146 . Analysis: Calculated for C20H18N40: 72.71 %C 5.59 H 16.97 N Found: 72.56 %C 5.57 XH 17.18 %N Example 24 6-Fluoro-3-(4-piperidinyl)-1H-indazole A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 60 ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs. The reaction was poured into 11 to water, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. Recrystallization of the residue from isopropanolwater and then from isopropanol yielded 3.3 g (20.1 %) of product, mp 214 - 216 . Analysis: Calculated for C12H14N3F: 65.73 %C 6.44 %H 19.17 N Found: 65.55 %C 6.35 %H 19.30 %N Example 25 1-(2-Puroyl)-3-(1-methyl-4-piperidingl)-1H-indazole hydrochloride A mixture of 4.0 g of 3-(4-piperidinyl)-1H-indazole, 2.7 mol of 2-furoyl chloride (95 % pure) and 60 ml of chloroform was refluxed for 3 hrs. The mixture was filtered. The filtrate was evaporated under reduced pressure, the residue was triturated with ethyl acetate and the solid was collected. The solid and filtrate were combined and recrystallized twice from ethanol to yield 3.3 g (51.5 %) of product, mp 268 - 270 C. Analysis: Calculated for C18H19N302.HCl: 62.51 XC 5.83 5SH 12.15 ,oN Pound: 62.78 %C 6.00 %H 12.11 , Example 26 1-(4-Chlorophenyl)-3-(1-methyl-4-piperidinyl)-1E-indazole furmar ate To a stirred suspension of 1.1 g of sodium hydride (50 ffi oil dispersion) in 40 ml of dimethylformamide was added, dropwise, under nitrogen, 4.0 g of 3-(1-methyl-4 piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. The reaction was stirred at ambient temperature for 45 min, and 2.9 ml of 4-fluorochlorobenzene was added. The temperature was increased to 1200 and the reaction proceeded at this temperature for 24 hr. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was heated (steam bath) with 3N hydrochloric acid and the salt was collected. The salt was immediately recrystallized from water. The wet salt was treated with ammonium hydroxide and the base was extracted Into dichloromethane. Evaporation of the dichloromethane in vacuo gave an oil. the oil solidified on standing. The solid was dissolved in ether and 1.4 g of fumaric acid was added. Recrystallization from 2-propanol gave 3.9 g (47.5 %) of product, mg 176 - 178 . Analysis: Calculated for C19H20ClN ;O*C4H404: 62.25 C 5.47 5H 9.51 N Found: 62.32 %C 5.40 %H 9.56 XN Example 27 6-Fluoro-3-[1-(prop-1-yl)-4-piperidinyl]-1H-indazole A mixture of 3.0 g of 6-fluoro-2-(4-piperidinyl)-1Hindazole, 1.8 g of 1-bromopropane, 2.5 g of sodium bicarbonate and 30 ml of dimethylformamide was stirred and heated at 60 for 2 hr. After stirring at ambient temperature for 14 hr, the reaction was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate yielded 2.3 g (63 ) of product. This material was combined with a sample from another experiment and recystallized from ethyl acetate to yield the analytical sample, mp 175 - 177 . Analysis: Calculated or C15H20FN3: 68.94 %C 7.71 %H 16.08 %N Found: 69.24 %C 7.62 %H 16.15 N Example 28 6-Fluoro-2-( 1 -pheneth-2-yl-4-piperidinyl)-1H-indazole A mixture of 5.0 g of 6-fluoro-3-(4-piperidinyl)-1Hindazole, 4.6 g of (2-bromoethyl)benzene, 4.2 g of sodium bicarbonate and 50 ml of dimethylformamide was stirred at 60C for 3 hr and at ambient temperature for 15 hr. The reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized twice from 2-propanol (one charcoal treatment) to yield 2.6 (35 %) of product, mp 163 - 165 . Analysis: Calculated for C22H22FN3: 74.27 %C 6.86 %H 12.99 %N Pound: 74.45 C 6.96 %H 13.49 %N Example 29 1-Benzoyl-3-( 1-pheneth-2-yl-4-piperidinyl)-1 H-indazole hydrochloride A mixture of 1.6 g of 3-(1-pheneth-2-yl-4-piperidinyl)- 1H-indazole and 7 ml of benzoyl chloride was heated at 100 for 2 hr. After cooling, ether was added and the solid was collected. The solid was combined with material from a prior experiment and recrystallized from methanol to yield 2.4 g (51 %) of product, inp 248 - 250 . Analysis: Calculated for C27H26FN30.HCl: 69.89 %C 5.86 H 9.06 %N Found: 70.03 %C 5.96 %H 9.22 %N Example 30 1-(3-Chlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1Hindazole and 8 ml of 3-chlorobenzoyl chloride was heated at 100 for 2 hr. The reaction was allowed to cool, and ether was added. The resultant solid was collected and recrystallized twice from isopropyl alcohol to yield 3.7 g (67.7%) of product, mp 209 - 211 . Analysis: Calculated for C20H20ClN30-HCl: 61.54 %C 5.42 %H 10.77 N Found: 61.54 %C 5.57 %H 10.66 egN Example 31 1-(2-Chlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H indazole-fumarate A mixture of 3.0 g of 3-(4-piperidinyl)-1H-indazole and 8 ml of 2-chlorobenzoyl chloride was heated at 100 (steam bath) for 2 hr. The reaction was cooled to ambient temperature, and ether was added. The oil, which separated, solidified upon scratching. The solid was treated with ammonium hydroxide and the precipitate was dissol- ved in ether ethanol (350 : 10 ml). Fumaric acid (1.4 g) was added, and the mixture was stirred at ambient temperature for 4 hr. The resultant solid was collected, dried, triturated with hot acetone, and recrystalllized from isopropyl alcohol to yield 3.6 g (54.7 5) of the product, mp 182 - 184 . Analysis: Calculated for C20H20ClN3O.C4H4O4: 61.34 %C 5.15 %H 8.94 , Found: 61.54 %C 5.30ll 8.96, Example 32 6-Fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole To a stirred suspension, under nitrogen, of 4.7 g of lithium aluminum hydride (50 - 55 % oil dispersion) in 90 ml of tetrahydrofuran was added, dropwise, 8.9 g of 6-fluoro-3-( 1 -methoxycarbonyl-4-piperidinyl)-i H-inda- zole, dissolved in 50 ml of tetrahydrofuran. After the addition was complete, the reaction was heated under reflux for 2 hr. The reaction was cooled in an ice-salt bath and water was carefully added. the mixture was filtered and the filter cake was washed with tetrahydrofuran and twice with hot methanol. The filtrate was concentrated ifl vacuo. The residue was triturated with ethyl acetate to yield 5.1 g (68 ) of product, mp 217 - 220 . Recrystallization from ethanol (twice) provided the analytical sample, mp 218 - 220 . Analysis: Calculated for C13H16N3: 66.93 %C 6.91 5sH 18.01 %N Found: 67.08 %C 6.97 %H 18.09 5N Example 33 1-(2-Nitrophenyl)-3-(1-methyl-4-piperidinyl)-1X-indazole fumarate To a stirred suspension, under nitrogen, of 0.86 g (0.018 mole) of a 50 oil dispersion of sodium hydroxide in 20 ml of dimethylformamide was added, dropwise, 3.2 g (0.015 mole) of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hr and a solution of 2.2 g (0.0115 mole) of 1-fluoro-2-nitrobenzene in 5 ml of dimethylformamide was added slowly. The reaction mixture was stirred at ambient temperature for 2 hrs and then poured into water. The precipitate was collected and then dissolved in ethanol-ether. To the stirred solution, 1.7 g of fumaric acid was added. After stirring at ambient temperature for four hrs, the mixture was filtered and the filter cake was recrystallized from methanol-ether (twice) to yield 4.3 g (67.8) of product, inp 210-212 C. Analysis: Calculated for C19H20N4O2.C4H4O4: 61.05C 5.35H 12.38N Found: 61.08% 5.43%H 12.47%N Example 34 1-(2-Chlorophenyl)-3-(4-piperidinyl)-1H-indazole fumarate To a stirred mixture cf 4.2 g (0.04 mole) of cyanogen bromide, 6.3 g of potassium carbonate and 125 ml of dimethylsulfoxide was added, dropwise, 12.0 g (0.037 mole) of 1-(2-chlorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 30 ml.of dimethylsulfoxlde. The reaction mixture was stirred at ambient temperature for two hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to give an oil. The oil was triturated with ether to give 7.1 g (57%) of 1-(2chlorophenyl)-3-(1-cyano-4-piperidinyl)-1H-indazole, mp 109-111 0C. A stirred mixture of 6.5 g (0.0019 mole) of 1-(2chlorophenyl)-3-(1-cyano-4-piperidinyl)-1H-indazole and 60 ml of 25% aqueous sulfuric acid was heated under reflux for 16 hr. The reaction mixture was cooled in an ice-bath and 50% aqueous sodium hydroxide solution was added dropwise until the mixture was basic. The aqueous mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and te solvent removed in vacuo to give an oil. The oil was dissolved in ethanol-ether and 2.2 g of fumaric acid was added. After stirring at ambient temperature for 6 hrs, the salt was collected. The salt was recrystallized twice from methanol-ether to yield 2.4 g (3o) of product, mp 213 215 C. Analysis: Calculated for C18H18ClN3.C4H4O4: 61.75%C 5.18%H 9.82%N Found: 61.55%C 5.48%H 9.62%N Example 35 1-(2-Aminophenyl)-3-(1-methyl-4-piperidinyl)-indazole fumarate To a cooled (5 C), stirred solution. of 9.5 g (0.042 mole) of stannous chloride dihydrate in 20 ml of conc hydrochloric acid and 10 ml of tetrahydrofuran was added, dropwise, 3.6 g (0.01 mole) of 1-(2-nitrophenyl)-3 (1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of tetrahydrofuran. After completion of the addition, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was poured into ice water and made basic with 10 sodium hydroxide solution. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was dissolved in ethanol (warming) and 2.0 g of fumaric acid was added. The mixture was then warmed on the steam bath for a few mins. The salt was collected to give 3.4 g (80) of product. The salt was combined with 1.1 g of another experiment and recrystallized first frorn dimethylformamide-ethyl acetate (twice) and then from methanol-ether to yield the analytical sample, mp 208-210C. Analysis: Calculated for C19H22N4C4ll404: 65.40C 6.21%H 13.24 N Found: 65.46%C 6.40%H 13.35%N Example 36 1-(2-Fluorophenyl)-3-(1-methyl-4-piperidinyl)-iH-indazole hydrochloride To a stirred suspension of 1.0 g (0.021 mole) of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide, under nitrogen, was added, dropwise, 3.2 g (0.015 mole) of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After ageing at ambient temperature for 45 mins, 3.6 g (0.032 mole) of 1,2-difluorobenzene was added and the temperature was raised to 1200C and held there for 6 hrs. The reaction mixture was quenched with water and the aqueous mixture extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield an oil. The oil was combined with 2.7 g of oil from another experiment and the combined sample (6.9 g) was chromatographed. Flash chromatography was utilized with 210 g of silica gel and 10% ethyl acetate-diethylamine as the eluent. Evaporation of the appropriate fractions gave 4.3 g (57%) of product, as an oil. Treatment of the oil with ethereal hydrogen chloride gave the hydrochloride salt. The salt was recrystallized from ethanol-ether and then from acetonitrile to yield the analytical sample, mp 215-217 C. Analysis: Calculated for C19H20FN3.HCl: 65.98%C 6.11%H 12.16%N Found: 65.79%C 6.16%H 12.21%N Example 37 1-(3-Pluoropnenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride To a suspension of 2.0 g (0.04-2 mole) of a 50 oil dispersion of sodium hydride in 40 ml of dimethylformamide was added, dropwise, 6.4 g (0.030 mole) of 3-(1-methyl-4- piperidinyl)-1f1-indazole in 50 ml of hot dimethylformaxnide. After stirring for 40 mins at ambient temperature, 7.2 g (0.06) nole) of 1,3-difluorobenzene was added. The mixture was heated at 1200C for 20 hrs, cooled and poured into water. The mixture was extracted with ether. The extracts were dried over anhydrous magnesium sulfate and concen trated to yield an oil. The oil was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9, Rf = 0.43). Evaporation of appropriate fractions gave an oil. The oil was dissolved in anhydrous ether and hydrogen chloride gas was bubbled into the solution, The ether was decanted and the solid was recrystallized twice from ethanol-ether to yield 2.6 g (25%) of product, mp 254256 C. Analysis: Calculated for C19H20FN3.HCl: 65.99%C 6.12H 12.15N Found: 65.83%C 6.09H 12.15%N Example 38 6-Fluoro-1-(2-fluorophenyl)-3-(1-methyl-4-piperidinyl)- IH-indazole fumarate To a stirred suspension, under nitrogen, of 1.2 g (0.025 mole) of a 50 oil dispersion of sodium hydride in 25 ml of dimethylformamide was added, dropwise, 4.2 g (0.018 mole) of 6-fluoro-3-(1-methyl-4-piperidinyl)-1Hindazole dissolved in 30 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 45 mins and then 4.4 g (0.038 mole) of 1,2-difluorobenzene was added. The temperature was raised to 1200C and held there for 6 hrs. The reaction mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to yield an oil. The oil was triturated with hexane to yield 1.3 g of the indazol starting material. The filtrate was concentrated to an oil. The oil was purified by flash chromatography utilizing a silica gel column (50 x 145 mm) and 10 ethyl acetate-diethylamine es the eluent. Concentration of the appropriate fractions gave 2.0 g (33%) of product, as an oil. The oil was dissolved in ether, stirred, and 0.8 g of fumaric acid was added. The salt was collected, dried and had mp 181-183 C. Analysis: Calculated for C19H19F2N3-C4H4o4: 62.29%C 5.23%H 9.487SN Found: 62.15%C 5.40%H 9.47%N Example 39 3-( 1 -Acetyl-4-piperidinyl)-6-fluoro-i -phenyl-1 H-indazole To a stirred solution of 3.0 g (o.oo8 mole) of 1acetyl-4-(2,4-difluorobenzoyl)piperidlne phenylhydrazone in 30 ml of dimethylformamide, under nitrogen, was added 0.44 g (o.009 mole) of a 50% oil dispersion of sodium hydride. The reaction mixture was heated, and at about 40 C a vigorous solution of hydrogen occurred. The tempera-. ture was then raised to 80 C and held there for 1.5 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated to yield an oil. The oil was combined with the oil from another experiment and a total of 13.5 g of material was chromatographed on a Water's Prep LC 500. Two silica gel columns were uti-- lized and 3% dichloromethane-methanol was used as the eluent. The appropriate fractions were evaporated. The residue was recrystallized twice from isopropyl alcohol-water (one charcoal treatment) to yield 2.4 g (18%) of product, mp 126-128 C. Analysis: Calculated for C20H20FN3O: 71.20%C 5.98%H 12.45%N Found: 70.98?,C 5.997NE 12.48%N Example 40 1-(2-Trifluoromethylphenyl)-3-(1-methyl-4- piperidinyl) H-indazole To a stirred suspension of 1.0 g (0.021 mole) of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g (0.0145 mole) of 3-(1-methyl-4-piperidinyl)-1E-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml (0.029 mole) of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90 C and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamineethyl acetate, 1:9, Rf = 0.47). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110-1110C. Analysis: Calculated for C20H20F3N3: 66.84%C 5.61%H 11.695EN Found: 66.65%C 5.59%H 11.82%N Example 41 1-(2-Fluorophenylmethyl)-3-( l-methyl-4-piperidinyl)-1H- indazole hydrobromide To a suspension of 0.86 g (0.0179 mole) of a 50 oil dispersion of sodium hydride in 50 ml of dimethylformamide was added, dropwise, 3.0 g (0.014 mole) of 3-(1-methyl-4- piperidinyl)-1H-indazole dissolved in 15 ml of hot dimethylformamide. After stirring for 1 hr, 2.19 g (0.015 mole) of 2-fluorobenzyl chloride was added. The reaction mixture was stirred at ambient temperature for 17 hrs and then poured into 250 ml of water. The mixture was extracted with ether. The extract was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was dissolved in anhydrous ether and hydrogen bromide gas was bubbled through the solution. The salt was triturated with ether and recrystallized from ethanol-ether and then ethanol to yield 3.06 g (54%) of product, mp 205-206 C. Analysis: Calculated for C20H22FN3.HBr: 59.41%C 5.73%H 10.39%N Found: 59.02%C 5.68%H 10.29%N Example 42 1-Benzoyl-6-chloro-3-( 1 -methyl-4-piperidinyl)-1H-indazole hydrochloride A mixture of 3.0 g (0.012 mole) of 6-chloro-3-(1- methyl4-piperidinyl)-1H-indazole and 8 ml of benzoyl chloride was heated at 10000 on a steam bat for 4 hrs. The reaction mixture was cooled to ambient temperature and ether was added. The precipitate was filtered, washed with ether and dried. Recrystallization from ethanol (twice) yiclded 2.6 g (56ss) cf product, mp 248-250 C. Analysis: Calculated for C20H20ClN3O.HCl: 61.54%C 5.42%H 10.77%N Found: 61.34%C 5.46%H 10.67%N Example 43 1-(4-Chlorobenzoyl)-3-(I-ethyl-4-piperidinyl)-6-fluoro-1H- indazole hydrochloride ¯¯¯¯ ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ A mixture of 3.0 g (0.012 mole) of 3-(1-ethyl-4-pi- peridinyl)-6-fluoro-1H-Indazole ad 8 ml of 4-chloroben zoyl chloride was heated at 100 C in a steam bath for 4 hrs. Ether was added and the solid was collected. The solid was recrystallized twice from ethanol-ether to yield 2.9 g (57%) of product, mp 240-242 C. Analysis: Calculated for C21H21ClFN3O.HCl: 59.72%C 5.01%H 9.95%N Found: 59.69%C 5.39%H 9.92%N Example 44 1-(4-Chlorobenzoyl)-6-fluoro-3-(1-methyl-4-piperidinyl)1H-indazole hydrochloride A mixture of 2.0 g (0.0086 mole) of 6-fluoro-3-(1- methyl-4-piperidinyl)-1H-indazole and 5 ml of 4-chlorobenzoyl chloride was heated at 100 C in a steam bath for 2 hrs. After cooling, ether was added and the solid was collected. The solid was combined with a 2.5 g sample from another experiment and recrystallized twice from ethanol-ether to yield 4.7 g (56%, calculated on the combination of both experiments) of product, mp 258-260 C. Analysis: Calculated for C20H19ClN3.HCl: 58.83%C 4.69%H 10.29%N Found: 59.02%C 5.07%H 10.30%N Example 45 1-(4-Methylbenzoyl)-3 methyl-4-piperidinyl)-1H-indasole fumarate A mixture of 3.0 g (0.014 mole) of 3-(l-methyl-4- piperidinyl)-1H-indazole and 8 ml of 4-toluoyl chloride was heated at 1000C in a steam bath for 4 hrs. Ether was added to the cooled mixture and the salt was collected. The salt was converted to its free base by means of ammonium hydroxide solution. The base was dissolved in ethanol (90 ml)-ether (175 ml) and 1.5 g of fumaric acid was added. The mixture was stirred at ambient temperature for 16 hrs, and the resultant fumarate salt was collected. Re crystallization twice from methanol-ether yielded 3.8 g (60%) of product, mp 205-2070C. Analysis: Calculated for C21H23N3O.C4H4O4: 66.80%C 6.06%H 9.35%N Found: 66.98%C 6.14%H 9.44ssN Example 46 1-(2,3-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1Hindazole A mixture of 3.0 g (0.014 mole) of 3-(1-methyl-4- piperidinyl)-1H-indazole and 8 ml of 3,4-dichlorobenzoyl chloride was heated at 100 C in a steam bath for 4 hrs. After the reaction mixture cooled to ambient temperature, ether was added and the salt was collected. The salt was mixed with water and ammonium hydroxide solution was added until the mixture was basic. The mixture was warmed on the steam bath for about 5 mins, cooled and extracted with dichloromethane. Evaporation of the dichloromethane in vacuo provided the free base. The base was recrystallized from methanol-trichloromethane (with concentration of the mother liquor) to yield 3.0 g (57ss) of product, mp 187189 C. Analysis: Calculated for C20H19Cl2N3O: 61.86%C 4.93%H 10.82%N Found: 61.83%C 5.02%H 10.84%N Example 47 1-Benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole fumarate A mixture of 3.1 g (0.013 mole) of 6-fluoro-3-(l- methyl-4-piperidinyl)-1H-indazole and 8 ml of benzoyl chloride was heated at 100 C in a steam bath for 8 hrs. After colling, ether was added and the solid was collected. The solid was treated with ammonium hydroxide solution to give an oil. The oil was dissolved in 300 ml of ether, stirred and 1.2 g of fumaric acid was added. After four hrs at ambient temperature, the fumarate salt was collected. Recrystallization from ethanol-ether yielded 3.0 g (50.9) of product, mp 180-182 C. Analysis: Calculated for C20H20FN3O.C4H4O4: 63.57%C 5.33%H 9.27%N Found: 63.51%C 5-43XH 9-55%N Example 48 1-(4-Trifluoromethylbenzoyl)-3-(1-methyl-4-piperidinyl)-1Hindazole fumarate A mixture of D.0 g (0.014 mole) of 3-(l-methyl-4- piperidinyl)-1lI-indazole and 8 ml of 4-trifluoromethylben- zoyl chloride was heated at 100 C on a steam bath. After 2 hrs, an additional 5 ml of 4-trifluoromethylbenzoyl chloride was added and heating was continued for 2 additional hrs. After cooling to ambient temperature, ether was added and the salt was collected. The salt was converted to its free base by means of ammonium hydroxide solution. The free base was dissolved in ethanol-ether and 0.75 g of fumaric acid was added to give 2.7 g (38%) of product. Two samples of the salt were combined and recrystallized from ethanol (twice) to yield the analytical sample, mp 212 214 C. Analysis: Calculated for C21H20F3N30C4H404: 59.64%C 4.80%H 8.35%N Found: 59.57%C 4.86%H 8.41%N Example 49 i-(4-Chlorobenzoyl)-3-(l-methyl-4-piperidinyl)-IH-indazole fumarate A solution of 3.0 g (0.014 mole) of 3-(1-methyl-4 piperidin-l)-1H-indazole and 8 ml of 4-chlorobenzoyl chloride was heated at 100 C in a steam bath for 4 hrs. After cooling to ambient temperature, ether was added and the salt was collected. The salt was converted into its free base by means of ammonium hydroxide solution and extractive isolation with dichloromethane. The base was dissolved in 150 ml of hot ethanol and 1.6 g of fumaric acid was added. Ether (200 ml) was added to the solution and the fumarate salt was collected. Two recrystalizations from ethanol yielded 3.5 g (54%) of product, mp 216-218 Analysis: Calculated for C20H20ClN3O.C4H4O4 : 61.34%C 5.15%H 8.94%N Found: 61.42%C 5.18%H 9.00%N Exaile 50 6-Chloro-3-(1-methyl-4-piperidinyl)-1H-indazole To a stirred solution, under nitrogen, of 13.0 g (0.044 mole) of 4-(6-chloroindazol-3-yl)piperidinyl-1- carboxylic acid methyl ester in 150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution of lithium aluminium hydride (0.048 mole) in tetrahydrofuran. The solution was stirred under reflux for 1 hr. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered, the filter cake washed with tetrahydrofuran and methanol, and the filtrate was concentrated. Recrystallization of the residue from ethanol-water yielded 7.6 g (69%) of product, mp 211-213 C. Analysis: Calculated for C13H16C1N3: 62.52%C 6.46%H 16.83%N Found: 62.73%C 6.61%H 16.96%N Example 51 3-(1-Ethyl-4-piperidinyl)-6-fluoro-1H-indazole To a stirred suspension, under nitrogen, of 14.0 g (0.053 mole) of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1H- indazole in 180 ml of tetrahydrofuran was added, dropwise, 55 ml of a 1M solutions of lithium aluminium hydride (0.055 mole) in tetrahydrofuran. The reaction mixture was stirred under reflux for 1 hr and then stirred at ambient temperature for 15 hrs. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the filtrate was concentrated. Recrystallization of the residue from toluene afforded 9.0 g (68%) of product. Recrystallization of a 3.0 g sample from toluene yielded the analytical sample, mp 175-178 C. Analysis: Calculated for C14H1E3FN3: 67.997NC 7.34%H 16.99%N Found: 68.07%C 7.33%H 17.11%N Example 52 6-Chloro-3-(4-piperidinyl)-1R-indaole A solution of 18.0 g (0.063 mole) of 1-acetyl-4-(4- chloro-2-fluorobenzoyl)piperidine, 130 ml of n-butanol and 51 ml of hydrazine monohydrate was stirred under reflux for 48 hrs. Most of the n-butanol was evaporated in vacuo and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonltrile to yield 3.0 g (20%) of product. This product was combined with a 1.3 g sample from another experiment and the combined samples (4.3 g) were recrystallized from acetonitrile to yield the analytical sample, mp 174-176 C. Analysis: Calculated for C12H14ClN3: 61.14%C s.99%H 17.88%N Found: 61.02%C 5.94%H 17.94%N Example 53 3-(1-Methyl-4-piperidinyl)-1H-indazole A solution of 4.7 g (0.018 mole) of 4-(1H-indazole3-yl)-piperdine-1-carboximidie acid methyl ester and 80% of acetic acid was heated under reflux for 48 hrs. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ether and then made basic by the slow addition cf a 50% aqueous sodium hydroxide solution. A solid separated from the solution. The sold was collected and dried. Recrystallization from ethanol yielded 1.7 g (46%) of product. Concentration of the mother liquors from this and another experiment gave additional product, mp 213-215 C. Analysis: Calculated for C12H15N3: 71.61%C 7.51%H 20.88%N Found: 70.89C 7.48%H 20.74ssN Example 54 6-Bromo-1-methyl-3-(4-piperidinyl)-1H-indazole hydrochloride A solution of 3.3 g (0.01 mole) of 4-(3-bromo-2 fluorobenzoyl)-l-acetylpiperidine, 1.1 g (0.013 mole) of methylhydrazine and 30 ml of n-butanol was heated under reflux for 16 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The aqueous suspension was made basic with ammonium hydroxide solution and extracted with dichloromethane. The extract was washed with water, dried over anhydrous potassium carbonate and the solvent was concentrated to give 3- acetyl-4-piperidinyl)-6-bromo-1H-indazole, as an oil. A solution of 3.0 g (0.009 mole) of 3-(1-acetyl-4- piperidinyl)-6-bromo-1H-indazole and 30 ml of 6N hydro- chloric acid was heated under reflux for 4 hrs. The reaction mixture was cooled in an ice-bath, stirred and 50% aqueous sodium hydroxide solution was added dropwise until the reaction mixture was basic. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate and the solvent was concentrated to yield 1.6 g (62%) of product, as an oil. The product from three experiments were combined and converted to the hydrochloride salt with ethereal hydrogen chloride. The salt was recrystallized twice from ethanol-ether and then once from trichloroeethane-ether to yield the analytical sample, mp 238-240 C. Analysis: Calculated for C13H16BrN3.HCl: 47.22%C 5.18%H 12.71%N Found: 46.96%C 5.12%H 12.66%N Example 55 3-(1-Acetyl-4-piperidinyl)-6-fluoro-1H-indazole A solution of 15.0 g (0.069 mole) of 4-(2,4-di fluorobenzoyl)-l-acetylpiperidine, 6.9 g (0.14 mole) of hydrazine hydrate and 140 ml of ethanol was heated under reflux for 4 hrs. The ethanol was removed in vacuo to give a solid. The solid was triturated with water, filtered and dried to yield 12.5 g (64ffi) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine hydrazone, mp 159-142 C. A mixture of 12.1 g (0.046 mole) of 1-acetyl-4-(2,4difluorobenzoyl)piperidine hydrazone, 11.8 g of potassium carbonate and 120 ml of dimethylformamide was stirred and heated at 1200C for 16 hrs. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give a solid. Recrystallization of the solid from ethyl acetate (twice) yielded 4.1 g (42% with concentration of mother liquor) of product, mp 162-164 C. Analysis: Calculated for C14H16FN3O: 62.35%C 6.17%H 16.08%N Found: 64.10%C 6.31%H 15.89%N Example 56 3-(1-Acetyl-4-piperidinyl)-6-chloro-1H-indazole A mixture of 19.6 g (0.066 mole) of 1-acetyl-4-(2fluoro-4-chlorobenzoyl)piperidine hydrazone, 48.2 g (0.13 mole) of potassium carbonate and 200 ml of dimethylformamide was stirred, under nitrogen, at 1200C for 16 hrs. After cooling to ambient temperature, the reaction mixture was poured into water and the aqueous mixture was extract-ed with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. Upon standing, a solid formed. The solid was triturated with ethyl acetate to yield 3.8 g (21%) of product. Recrystallization from acetonitrile gave the analytical sample, mp 172-174 C. Analysis: Calculated for C14H16ClN30: 60.54%C s.81%H 15.13%N Found: 60.55%C s.83%H 15.33%N Example 57 4-(6-Chloroindazol-3-yl)piperidine-1-carboxylic acid methyl ester To a stirred suspension of 5.8 g (0.025 mole) of 6chloro-3-(4-piperidinyl)-1H-indazole, 4.6 g (0.055 mole) of sodium bicarbonate and trichloromethane (25 ml)-te'sra- hydrofuran (25 ml) was added, dropwise, 5.2 g (0.055 mole) of methyl chloroformate. The reaction mixture was stirred at ambient temperature for 16 hrs and then poured into water. The organic layer was collected, washed with water, dried over anhydrous potassium carbonate and the solvent concentrated to give 4-(6-chloro-1-methyoxycarbonyl-3-yl) piperidine-1-carboxylic acid methyl ester, as an oil. The oil was dissolved in 50 ml of methanol and 1.5 ml of a 25% sodium methoxide-methanol solution was added. The reaction mixture was stirred at ambient temperature for 0.5 hrs, poured into water and the aqueous mixture extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated to an oil. The oil was triturated with hexane. Recrystallization from toluenehexane (twice) yielded 3.5 g (47%) of product, mp 132134 C. Analysis: Calculated for C14H16ClN3O2: 57.24%C 5.49%H 14.30%N Found: 57.22%C 5.46%H 14.33%N Example 58 1-(4-Pyridinyl)-3-(1-methyl-4-piperidinyl)-1H-indazole sesquifumarate To a stirred suspension of 1.72 g (0.036 mole) of a 50% oil dispersion of sodium hydride, under nitrogen, in 30 ml of dimethylformamide was added, dropwise, 3.2g (0.0148 mole) of 3-(1-methyl-4piperidinyl)-1H-indazole in 25 ml of hot dimethylformamide. After stirring at ambient temperature for 45 mins, 2.3 g (0.0155 mole) of 4-chloropyridine hydrochloride was added portionwise. The reaction mixture was stirred at ambient temperature for 16 hrs and then heated under reflux for 12 hrs. The reaction mixture was cooled to ambient temperature and 0.43 g of a 50% oil dispersion of sodium hydride was added followed by 0.6 g of 4-chloropyridine. The reaction mixture was then heated under reflux for an additional 4 hrs, cooled to ambient temperature and poured into water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was purified in two runs by flash chromatography (silica gel, 150 x 50 mm), eluting with ethyl acetate-diethylamine (9:1). Similar fractions were combined and evaporated. The residue was converted to the fumarate salt by dissolution in ethanol (25 ml)-ether (175 ml) and by adding 1.9 g of fumaric acid. Recrystallization from dimethylformamide yielded 3.2 g (465S) of product, mp 205-207 C. Analysis: Calculated for C18H20N4.1.5C4H4O4: 61.79%C 5.62%H 12.01%N Found: 61.50C 5.785CH 12.187SN Example 59 1-(2-Pyridinyl)-3-(1-methyl-4-piperidinyl)-1X-indazole fumarate To a stirred suspension, under nitrogen, of 0.85 g (0.018 mole) of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g (0.015 mole) of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. The reaction mixture was stirred at ambient temperature for 1 hr and then 1.5 g (0.0155 mole) of 2-fluoropyridine was added. The temperature was raised to 95-100"C and held there for 6 hrs. The reaction mixture was allowed to cool and was then poured into water. A solid separated from the solution. The solid was collected and dried to yield 3.5 g (79.8%) of product, mp 123-125"C, as the free base. The fumarate salt was prepared by dissolving the product in hot ethanol, adding 2.7 g of fumaric acid and heating the mixture on the steam bath. After a few mins, the fumarate salt precipitated from the solution. The mixture was allowed to stand overnight at ambient temperature and the salt was collected. Two recrystallizations from methanolether yielded 2.8 g (46%) of product, mp 203-205 C. Analysis: Calculated for C18H20N4 C4H404: 64.69%C 5.92%H 13.72%N Found: 64.69XC 6.00%H 15-77XN Example 60 1-(3-Hydroxy-1-propyl)-3-(1-methyl-4-piperidinyl)-1H- indazole To a stirred suspension of 0.35 g (0.0046 mole) of a 50-55 oil disperison of lithium aluminum hydride in 50 ml of tetrahydrpfuran was added, dropwise, under nitrogen, 2.4 g (0.007 mole) of 1-(3-ethoxycarbonyl-1-ethyl)-3-(1- methyl-4-piperidinyl)-1H-indazole in 25 ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 1.5 hrs, cooled in an ice-salt bath, and water was added dropwise. The reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the filtrate concentrated in vacuo to give an oil. The oil was taken up in dichloromethane. The dichloromethane was washed with water, dried over anhydrous magnesium sulfate and the solvent removed in vacuo to yield 1.7 g (81%) of product. The product was combined with that from another experiment (total 3.2 g) and recrystallized twice from ethyl acetatehexane to yield the analytical sample, mp 9698C C. Analysis: Calculated for C16H23N0: 70.29%C 8.48%H 15.37%N Found: 70.53%C 8.34%H 15.47%N Example 61 4-(4-Bromo-2-fluorobenzoyl)-1-acetylpiperidine To a stirred suspension of 21.1 g (0.16 mole) of aluminum chloride and 63 ml of 3-fluorobromobenzene was added, portionwise, 16.0 g (0.08 mole) of 1-acetyl-isonipecotoyl chloride. The reaction mixture was stirred under reflux for 4 hrs. Host of the supernatant 3-fluorobromobenzene was decanted and ice water was added. The aqueous mixture was extracted with dichloromethane and the extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give an oil. The cil was triturated with ether. Recrystallization from cyclohexane gave 4.9 g (19%) of product. Recrystallization from cyclobexane yielded the analytical sample, mp ii 1- I 130C. Analysis: Calculated for C14H15BrFN02: 51.23C 4.61%H 4.24%N Found: sI.40%C 4.61%H 4.92%N Example 62 1 -(3-Ethoxycarbonyl-1 -ethyl)-3-( 1 -methyl-4-piperidinyl) 1 H-indazole To a stirred suspension, under nitrogen, of 1.7 g of a 50% oil dispersion of sodium hydride in 75 ml of dimethylformamide was added, dropwise, 6.0 g of 3-(1-methyl4-piperidinyl)-1H-indazole in 30 ml of hot dimethylformamide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for 1 hr and a solution of 6.5 g of ethyl 3-bromopropionate was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate and the extracts were washed with water, dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate under vacuum gave 6.5 g (70.8%) of product, as an oil. REACTION SCHEME A EMI65.1 EMI65.2 wherein R, X, m, n and p are as hereinbeforedsecribed. REACTION SCHEME B EMI66.1 wherein R, X, m, n and p are as hereinbeforedescribed. REACTION SCHEME C EMI67.1 wherein R, RÚ, Rê, R6, X, m, n and p are as hereinbeforedescribed. REACTION SCHEME D EMI68.1 wherein R, RÚ, X, Hal, m, n and p are as before.

Claims: Claims: EMI69.1 wherein R is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, ¯ EMI69.2 cyano, cyanomethyl, formyl, loweralkanoyl, or a group of the formulae EMI69.3 EMI70.1 EMI70.2 R1 is hydrogen, loweralkyl, loweralkenyl, lowercyclo alkylloweralkyl, EMI70.3 diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl, loweralkanoyl, hydroxymethyl, lowercycloalkylloweralkanoyl, or a group of the formulae EMI70.4 R5CO or 2- or 4-pyridinyl or 2-pyrimidinyl; R2 and R2 are independently loweralkyl, 2,2,2-trichloroethyl or phenyl; R and R4 are independently hydrogen or lower alkyl; iR5 is a member selected from the group furyl, thienyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, X, X' and X" are independently hydro gen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl; m is 2 or 3, n is I or 2, and the sum of m and n is 3 or 4; n' and nt' are in dependently 2 or 3; p, p' and p" are independently I or 2; q and q' are independently 1, 2, 3 or 4; the optical antipode thereof; or the pharmaceutically ac ceptable salt thereof. 2. A compound according to claim 1 wherein R is hydrogen or loweralkyl or EMI71.1 and R1 is hydrogen, loweralkyl, lowercycloalkylloweralkyl, loweralkanoyl, hydroxymethy EMI71.2 wherein X' and " are independently hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl, p' and p" are 1 or 2 and 1 and q' are independently 1, 2, 3 or 4; or R1 is R210C0 wherein R2 is loweralkyl, 2,2,2-trichloroethyl, or phenyl or R1 is EMI71.3 wherein X" ist hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl; and p " is 1 o 2. 3. A compound according to claim 2 wherein R is hydrogen or loweralkyl and R1 is hydrogen, loweralkyl or a group of the formulae EMI72.1 wherein X" is hydrogen, loweralkyl, loweralkoxy, hy droxy, nitro, amino or trifluoromethyl; p" is 1 or 2; and q' is 1. 4. The compound of claim 1 which is 3-(1-methyl-4-piperi dinyl)-1H-indazole. 5. The compound of claim 1 which is 1ethyl-3-(1-methyl- 4-piperidinyl)-1H-indazole. 6. The compound of claim 1 which is 1-acetyl-3-(1-inethyl- 4-piperidinyl)-1H-indazole. 7. The compound of claim 1 which is 1-benzoyl-3-(1-methyl- 4-piperdinyl)-1H-indazole. 8. The compound of claim 1 which is 1-phenylmethyl-3-(1- methyl-4-piperidinyl)-1H-indazole. 9. The compound of claim 1 which is 1-cyclopropylmethyl- 3-(1-methyl-4-piperidinyl)-1H-indazole. 10. A compound as defined in claim 1 for use as a medica ment. 11. A pharmaceutical composition comprising as active in gredient compound of the formula 1 or a pharmaceuti cally aceptable salt thereof as defined in claim 1 in association with a pharmaceutically acceptable carrier. 12. A process for the preparation of a compound of the formula EMI73.1 wherein R is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, EMI73.2 cyano, cyanomethyl, formyl, loweralkanoyl, or a group of the formulae EMI73.3 EMI74.1 R1 is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, EMI74.2 diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl, loweralkanoyl, hydroxymethyl, lowercycloalkylloweralkanoyl, or a group of the formulae EMI74.3 R5CO, 2- or 4-pyridinyl or 2-pyrimidinyl; R2 and R2 are independently loweralkyl, 252,2-trichloroethyl or phenyl, R3 and R4 are independently hydrogen or loweralkyl; R5 represents the group furyl, thienyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, X, X' and X" are independently hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl; m is 2 or 3; n is 1 or 2; and the sum of m and n is 3 or 4; n' and n" are independently 2 or 3; p, p' and p" are independently 1 or 2; q and q' are independently 1, 2, 3 or 4; the optical antipode thereof, or the pharmaceutically acceptable acid addition salt thereof, which comprises cyclizing a compound of the formula EMI75.1 wherein R, X, m, n and p are as above with hydrazine or hydrazine hydrate, to yield a compound of the formula 1 wherein R1 is hydrogen and R, X, m, n and p are as defined above optionally treating a compound of the formula 1 wherein R1 is hydrogen and R is as defined above with the proviso that R is not hydrogen, with an alkyl halide, alkenyl halide, cycloalkylalkyl halide, alkenyl halide, cycloalkylalkyl halide, dialkylaminoalkyl halide, cyanogen halide, cyanomethyl halide, 2- or 4-pyridyl halide, 2-pyrimidinyl halide, a compound of the formulae EMI75.2 herein X", n", q' and p" are as defined above and Hal is iodo, bromo or chloro in the presence of an alkali metal hydride to yield a compound of the formula 1 wherein R1 is loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, diloweralkylaminoloweralkyl, cyan, cyanomethyl or a group of the formulae EMI76.1 2- or 4-piperidinyl or 2-pyrimidinyl, and X, m, n and p are as defined above, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defied above with the proviso that R is not hydrogen, and X, m, n and p are as defined above, with a formyl-, alkanoyl- or cycloalkylalkanoyl chloride, bromide or iodide or a compound of the formula EMI76.2 R21OCO Hal or R5Co Hal, where R2 , R5, X. , p and q are as defined above and Hal is chloro, bromo or iodo, or the corresponding acid anhydrides to yield a compound of the formula 1 wherein R1 is formyl, lower alkanoyl, lowercycloalkylloweralkanoyl or a group of the formulae EMI76.3 R2,OCO or R5CO, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defined above with the proviso that R is not hydrogen, with formaldehyd to yield a compound of the formula 1 wherein R1 is hy-droxymethyl or reacting a compound of the formula I wherein R1 is hydrogen and R is phenoxycarbonyl with formaldehyde and then removing the carbamoyl group by hydrolysis to yield a compound of the formula 1 wherein R1 is hydroxymethyl and R is hydrogen, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defined above but is not hydrogen, with a benzenesulfonyl halide of the formula EMI77.1 wherein X" and p" are defined above and Hal is chlorine or bromine, to yield a compound of the formula 1 wherein R1 is the group EMI77.2 optionally converting a compound of the formula 1 wherein R1 is a group of the formulae EMI77.3 wherein X" is the nitro group, by reduction of the nitro group to an amino function, diazotization and subsequent displacement or reduction of the diazonium moiety to a compound of the formula 1 wherein R1 is a group of the formula EMI78.1 where X" is hydrogen, halogen, alkyl, alkoxy, hydroxy or amino and p" is I or 2, optionally reacting a compound of the formula 1 wherein R and R1 are both hydrogen with a lower alkanoyl chloride, bromide or iodide or with a halide of the formulae EMI78.2 or R2,OCO Hal where R2, X', p' and q are as defined above and Hal is chlorine, bromine or iodine, to yield a compound of the formula 1 wherein R is lower alkanoyl or a group of the formulae EMI78.3 or R20C0, or optionally reacting a compound of the formula 1 where R is lower alkyl and R1 is formyl, lower alkanoyl or a group of the formula EMI78.4 wherein X", p" and q' are as defined above with cyanogen bromide or chloride to yield a compound of the formula 1 wherein R is cyano and R1 is as hereinbefore described, or optionally removing the cyano group from a compound of the formula 1 wherein R1 is as defined above and R is cyano by hydrolysis to yield a compound of the formula 1 wherein R is hydrogen, or optionally hydrolyzing a compound of the formula 1 wherein R is a group of the formula EMI79.1 to yield a compound of the formula 1 wherein R is a group of the formula EMI79.2 wherein n' is as defined above, and optionally preparing in a conventional way the pharmaceutically acceptable salts thereof. 13. The process of claim 12 wherein the cyclization is performed with hydrazine hydrate. 14. The process of claim 12 wherein the cyclization is performed at a temperature within the range of 100" to 2000C and a pressure of 14 to 21 bar and in a solvent. 15. A pharmaceutical composition comprising as active ingredient a compound of the formula I as claimed in claim 1 or a pharmaceutically acceptable acid addi tion salt thereof in association with a pharmaceu tically acceptable carrier. 16. A compound of the formula 1 or a pharmaceutically acceptable acid addition salt thereof for use as a medicament. Claims for Austria: 1 . A process for the preparation of a compound of the formula EMI80.1 wherein R is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, EMI80.2 cyano, cyanomethyl, formyl, loweralkanoyl, or a group of the formulae EMI80.3 EMI81.1 R1 is hydrogen, loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, EMI81.2 diloweralkylaminoloweralkyl, cyano, cyanomethyl, formyl, loweralkanoyl, hydroxymethyl, lowercycioalkylloweralkanoyl, or a group of the formulae EMI81.3 R.5CO, 2- or 4-pyridinyl or 2-pyrimidinyl; R2 and R2 are independently loweralkyl, 2,2, 2-trichloroethyl or phenyl, R3 and R4 are independently hydrogen or loweralkyl; R5 represents the group furyl, thienyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, X, X' and X" are independently hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino or trifluoromethyl; m is 2 or 3; n is 1 or 2; and the sum of m and n is 3 or 4; n' and n" are independently 2 or 3; p, p' and p" are independently 1 or 2; q and q' are independently 1, 2, 3 or 4; the optical antipode thereof, or the pharmaceutically acceptable acid addition salt thereof, which comprises cyclizing a compound of the formula EMI82.1 wherein R, X, m, n and p are as above with hydrazine or hydrazine hydrate, to yield a compound of the formula 1 wherein R1 is hydrogen and R, X, m, n and p are as defined above optionally treating a compound of the formula 1 wherein R1 is hydrogen and R is as defined above with the proviso that R is not hydrogen, with an alkyl halide, alkenyl halide, cycloalkylalkyl halide, alkenyl halide, cycloalkylalkyl halide, dialkylaminoalkyl halide, cyanogen halide, cyanomethyl halide, 2- or 4-pyridyl halide, 2-pyrimidinyl halide, a compound of the formulae EMI82.2 wherein X", n", q' and p" are as defined above and Hal is iodo, bromo or chloro in the presence of an alkali metal hydride to yield a compound of the formula 1 wherein R1 is loweralkyl, loweralkenyl, lowercycloalkylloweralkyl, diloweralkylaminoloweralkyl, cyano, cyanomethyl or a group of the formulae EMI83.1 2- or 4-piperidinyl or 2-pyrimidinyl, and X, m, n and p are as defined above, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defined above with the proviso that R is not hydrogen, and X, m, n and p are as defined above, with a formyl-, alkanoyl- or cycloalkylalkanoyl chloride, bromide or iodide or a compound of the formula EMI83.2 R2,OCO Hal or R5CO Hal, where R2?, R5, X , p and q are as defined above and Hal is chloro, bromo or iodo, or the corresponding acid anhydrides to yield a compound of the formula 1 wherein R1 is formyl, lower alkanoyl, lowercycloalkylloweralkanoyl or a group of the formulae EMI83.3 Rê'OCO or R5CO, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defined above with the proviso that R is not hydrogen, with formaldehyd to yield a compound of the formula 1 wherein R1 is hy droxymethyl or reacting a compound of the formula 1 wherein R1 is hydrogen and R is phenoxycarbonyl with formaldehyde and then removing the carbamoyl group by hydrolysis to yield a compound of the formula 1 wherein R1 is hydroxymethyl and R is hydrogen, or optionally reacting a compound of the formula 1 wherein R1 is hydrogen and R is as defined above but is not hydrogen, with a benzenesulfonyl halide of the formula EMI84.1 wherein X" and p" are defined above and Hal is chlorine or bromine, to yield a compound of the formula 1 wherein R1 is the group EMI84.2 optionally converting a compound of the formula 1 wherein R1 is a group of the formulae EMI84.3 wherein X" is the nitro group, by reduction of the nitro group to an amino function, diazotization and subsequent displacement or reduction of the diazonium moiety to a compound of the formula 1 wherein R1 is a group of the formula EMI85.1 where X" is hydrogen, halogen, alkyl, alkoxy, hydroxy or amino and p" is 1 or 2, optionally reacting a compound of the formula 1 wherein R and R1 are both hydrogen with a lower alkanoyl chloride, bromide or iodide or with a halide of the formulae EMI85.2 or R2 OCO Hal where R2, X', p' and q are as defined above and Hal is chlorine, bromine or Iodine, to yield a compound of the formula 1 wherein R is lower alkanoyl or a group of the formulae EMI85.3 or R20CO, or optionally reacting a compound of the formula 1 where R is lower alkyl and R1 is formyl, lower alkanoyl or a group of the formula EMI85.4 wherein X", p" and q' are as defined above with cyanogen bromide or chloride to yield a compound of the formula 1 wherein R is cyano and R1 is as hereinbefore described, or optionally removing the cyano group from a compound of the formula 1 wherein R1 is defined above and R is cyano by hydrolysis to yield a compound of the formula 1 wherein R is hydrogen, or optionally hydrolyzing a compound of the formula 1 wherein R is a group of the formula EMI86.1 to yield a compound of the formula 1 wherein R is a group of the formula EMI86.2 wherein n' is as defined above, and optionally preparing in a conventional way the pharmaceutically acceptable salts thereof. 2. The process of claim 12 wherein the cyclization is performed with hydrazine hydrate. 3. The process of claim 12 wherein the cyclization is performed at a temperature within the range of 100" to 2000C and a pressure of 14 to 21 bar and in a solvent.

Inventors: STRUPCZEWSKI, JOSEPH T.
Applicants: HOECHST-ROUSSEL PHARMACEUTICALS INCORPORATED
Application year: 1984
Main classification: C07D401
IPC codes: C07D401, C07D231, A61K31, A61P25, C07D211, C07D413, C07D403, C07D405, C07D417