IE48359B1 - 4,5-dihydro and 4,5,6,7-tetrahydro-1h(or 2h)-indazoles - Google Patents

Description

This invention provides a group of of the formulae indazoles The compounds of the invention are useful as intermediates in the preparation of tetrahydroindazoles having pharmaceutical activity, described in Patent Specification No. , which relates to a group of tetrahycro-lE {or 2H)-indazoles of. the formulae H N / II 8 3 5 9 wherein one of R and R2, is H and the other is N(R2),; * 2 where each R is individually allyl, methyl, ethyl or n-propyl; and pharmaceutically-acceptable acid addition salts thereof.

These compounds and their salts are useful as dopamine accnists for treating Parkinsonism and for inhibiting prolactin secretion.

A process for preparing the tautcaers of formulae I and II comprises reacting tautomers of the formulae IB 113 wherein one of R and R1 is H and the other is NIR2),; * 2 where both R are H; with an aldehyde in the presence of a metal hydride reducing agent, or with an alkyl halide or anhydride followed by reduction.

Compounds represented by I and II are tautomers? i.e., in solution, they exist in dynamic equilibrium with the percent -of a given tautomer in the mixture depending on both environment and electronic forces. Formula I abcve represents a 1Hindaiole and formula II a 2B-indazole. Many of the intermediates used to prepare formulae I and II are also teutcmers. 8 3 5 9 Compounds of formulae I and II in which R^ is N(R2)2 and R is H are prepared by a synthetic procedure illustrated in the Reaction Scheme below. In the Reaction Scheme R5 is (C^-Cj) alkyl or benzyl. The term (C^-Cj) alkyl includes methyl, ethyl, n-propyl and isopropyl. R^ is H, CH^, or CH=CH2· 8 3 5 8 Reaction Scheme H a==/\-N(CH*R*)» H XIa V S 3 5 9 In accordance with the Reaction Scheme, a 3-enol ether-6-hydroxymethylene-2-cyclohexenone, for example 3-ethoxy-6-hydroxymethylene-2-cyclohexenone, prepared by the method of Wenkert et al. J. Org. Chen·.., 27, 2278 (1962), is reacted with hydrazine hydrate in a mutual inert solvent such as ethanol to yield .dl-6-ethoxy-4,5-dihydro-lH-indazole (VIII) and its 2H tautomer (Villa) of the invention. Hydrolysis with acid, preferably a strong, highly ionized acid such as ID ' p-toluenesulfonic, trifluoroacetic, hydrochloric and others, yields dl-6-oxo-4,5,6,7-tetrahydro-lH-indazole (IX) and the 2H tautomer (IXa), also of the invention. Reductive amination of this oxo compound with ammonium acetate and sodium cyanoborohydride, or other suitable metal hydride reducing agents of sufficient reducing power, in the presence of a mutual inert solvent yields the corresponding dl-6-amino-4,5,6,7-tetrahydro-lHindazole, (X) and dl-6-amino-4,5,6,7-tetrahydro-2Hindazole, compounds coming within the scope of formulae IA and IIA above wherein R is H and R^· is NH2Preparation of compounds of formulae I and II wherein R is H and R^ is N(CH3)2, NiCjHgJj' N(n-propyl)2 or N(allyl)2 is carried out by reductively alkylating the 6-amino compound (X) and (Xa) with an aldehyde in the-presence of a metal hydride reducing agent, such as sodium cyanoborohydride to yield the dl-6-dialkyl (or diallyl)amino-4,5,6,7-tetrahydro-lHindazole (XI) and the corresponding 2H tautomer (Xla). The preparation of compounds in which the 6-amino group is unsymmetrically substituted can be accomplished by reacting the primary amine (X and Xa) with one mole of and IX and ixa formylating at the procedure a compound of an acid chloride or anhydride to yield the 6-acylamino derivative/ reducing the acyl group to an alkyl group (e.g·» acetyl -# ethyl) with a metal hydride, such as LiAlH^ and then alkylating the thus-formed secondary amine at C-6 with an alkylating agent containing a different alkyl group (e.g., methyl or n-propyl in the above example.) The novel intermediates of the invention represented by formulae VIII and Villa in the Reaction Scheme are prepared by C-6 an enolether of cyclohexane-1,3-dione in R5 is (C^-CgJalkyl or benzyl, using of Kenkert, et al (loc. cit.) to yield formula VII. Reaction of VII with hydrazine hydrate yields the tautomers VIII and Villa, de-enolization of which with acid gives the keto compounds IX and IXa.

This invention is further illustrated by the following specific examples: Example 1 Preparation of dl-6-Ethoxy-4,5-dihydro-lH-indazole and dl-6-Ethoxy-4,5-dihydro-2H-indazole A solution was prepared from 5 g. of 3etIicxy-6-hydroxymethylene-2-cyclohexenone [prepared by the method of Kenkert et al., J. Org. Chen., 27, 2278, (1962)] and 150 ml. of ethanol. 1.9 ml. of hydrazine hydrate were added and the resulting mixture stirred at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was 8 3 5 9 evaporated in vacuo and the residue dissolved in chloroform. The chloroform solution was chromatographed over 100 g. of florisil using chloroform containing increasing amounts (0-2%) of ethanol as the eluant. Fractions shown by TLC to contain a major spot different from starting material were combined and the solvents evaporated from the combined fractions in vacuo. The resulting residue was crystallized from a mixture of ether and hexane. dl-6-Ethoxy-4,5-dihydro-lH-indazole and its 2H tautomer thus prepared melted at 118-120cC.; yield = 3.64 g.

Analysis Calc.: C, 65.83; H, 7.37; N, 17.06 Found: C, 66.03, H, 7.25; N, 16.81.

Example 2 Preparation of dl-6-Oxo-4,5,6,7-tetrahydro-lHindazole and dl-6-Oxo-4,5,6,7-tetrahydro-2H-indazole A mixture of 3.2 g. of dl-6-ethoxy-4,5dihydro-lH-indazole and its 2H tautomer and 150 ml. of IN aqbeous hydrochloric acid were stirred at ambient temperature under a nitrogen atmosphere for 1.25 hours. TLC indicated that a new major spot (not starting material) was present. An infrared spectrum of this major spot showed absorption at 1710 cm. indicating formation of a keto group. The reaction mixture was saturated with solid sodium bicarbonate and the aqueous alkaline mixture extracted several times with chloroform. The chloroform solutions were ccrbined and the combined solutions washed with saturated acueous sodium chloride and then dried. 8 3 3 9 Evaporation ol the chloroform yielded a residue which was dissolved in chloroform and chromatographed over 30 g. of Florisil (Registered Trade Mark) using chloroform containing 2% methanol as the eluant. Fractions shown to contain dl-6-oxo-4,5,6,7-tetrahydro-lH-inda2ole and dl-6-oxo-4,5,6,7-tetrahydro-2K-indazole formed in tha above reaction were combined and dissolved in methanol. 0.7 ml. of methane sulfonic acid were added and the resulting mixture diluted to a volume of about 125 ml. with ether. The solution was cooled and the volatile constituents were removed by evaporation in vacuo. The residue was dissolved in ethanol, and the ethanol solution diluted with ether.

On cooling an oil.formed. The oil was redissolved in ethanol, ether added to the point of incipient precipitation and the mixture allowed to cool. Crystalline dl-6-oxo-4,5,6,7-tetrahydro-lH(and 2H)-inda2ole methane sulfonate was obtained which melted in the range 95-105*C. after recrystallization from an ether/ethanol solvent mixture; yield « 1.86 g.

Analysis Calc.: C, 41.37; H, 5.21; N, 12.06, S, 13.81 Found: C, 41.57; H, 5.38; N. 11.77; S, 13.53.

Example 3 Preparation of dl-6-Amino-4,5,6, 7-tetrahydro-1Hindazole and dl-6-amino-4,5,6,7-tetrahydro-2Hindazole 8 3 5 9 Eight grains of dl-6"OXO*4 9 5* 6 b 7—fc©tr&" hydro-lH-indazole hydrochloride plus the hydrochloride of the 2H-tautomer (formed by metathesis from the above methane sulfonate of Example 2) and g. of ammonium acetate were dissolved in 400 ml. of methanol to which was added 2.9 g. of sodium cyanoborohydride. The reaction mixture was stirred at room temperature under a nitrogen atmosphere- for about 1 day after which time it was poured into an excess of IN aqueous hydrochloric acid. The aqueous layer was extracted with ether and the ether extract discarded. The aqueous layer was then made basic with dilute aqueous sodium hydroxide and the basic layer extracted several times with a chloroform15 isopropanol solvent mixture. The organic extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded a residue comprising dl-6-amino-4,5,6,7-tetrahydro-lH-indazole and dX-6-amino-4,5,6,7-tetrahydro-2H-indazole. The residue was dissolved in 200 ml. of ethanol and the ethanol solution added dropwise with stirring to 7.7 ml of 12N aqueous hydrochloric acid. The resulting mixture was concentrated in vacuo to yield an equi25 librium mixture of dl-6-ami no-4,5,6,7-tetrahydroIH-indazole dihydrochloride and dl-6-amino-4,5,6,7tetrahydro-2H-indazole dihydrochloride melting at 275-230®C. with decomposition after recrystallization from ethanol. Yield =· 4.20 g.

Analysis Calc.: C, 40.02. K, 6.24,- N, 20.00 Found: C, 39.74; Ή, 6.04; N, 19.60.

Claims (4)

1. Tautomers of the formula VIII Villa wherein R' is

2. alkyl or benzyl Tautomers of the formulae

3. A tautomeric mixture of formulae VIII and Villa as defined in claim 1 substantially as hereinbefore described.

4. A tautomeric mixture of formulae IX and Iia as defined in claim 2 substantially as hereinbefore described