CS241020B2

CS241020B2 - Method of aminosubstituted 4,5,6,7-tetrahydro-1h(or 2h)-indazoles' derivatives preparation

Info

Publication number: CS241020B2
Application number: CS794476A
Authority: CS
Inventors: Nicholas J Bach; Edmund C Kornfeld
Original assignee: Lilly Co Eli
Priority date: 1979-01-22
Filing date: 1979-06-28
Publication date: 1986-03-13
Also published as: SU1311620A3; KR830000754B1; PL118568B1; PL118459B1; SU976848A3; HU184624B; KR830000708B1; SU1015823A3; CS447679A2; JPS55100367A

Abstract

Indazol tautomers(I; one of R and R1 is H, and the other is H(R2)2; R2 = H, allyl, Me, Et, n-Pr) were prepd. and they were effective in the treatment of Parkinsonism and in the inhibition of prolactin. Thus, the reaction of 4-acetamidocy-clohexanone with HC(OMe)2NMe2 gave 4-acetamido-2-≮(dimethylamino) methylene≉ cyclohexanone, the latter was treated with N2H4 to give I.

Description

The subject of the invention is a process for the preparation of aminosubstituted 4,5,6,7-tetra-

hydro-1H (or 2H) -indazoles of formulas I and II

wherein one of R and R 1 is hydrogen and the other is N (R 2) 2, wherein R 2 is individually methyl, ethyl or n-propyl and the pharmaceutically acceptable salts thereof

acid salts, which are carried out by reacting tautomeric formulas IB and IIB

wherein one of R 1 and R 1 is hydrogen and the other is NH 2 with the corresponding aldehyde in the presence of a hydride as a reducing agent and optionally converting the compounds of Formula I and II into pharmaceutically acceptable salts.

These compounds and their salts are useful as dopamine agonists for the treatment of Parkihsonism a. for inhibiting secreceprolactin.

The compounds of formulas I and II are tautomeric, that is, in solution they occur in equilibrium, in which the percentage of said tautomer in the mixture depends on both the environment and the electron forces. The compound of formula I above represents 1H-indazole and the compound of formula II 2H-indazole. Many of the intermediates used to prepare compounds of Formula I and II are also tautomeric.

The pharmaceutically acceptable salts of the compounds of Formulas I and II with acids include those derived from non-toxic inorganic acids such as hydrochloric acid, acidic acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphoric acid. and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and dicarboxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids. pharmaceutically acceptable salts include sulphates, pyruvates, hydrogen sulphates, sulphites, hydrogenesulins, nitrates, phosphates, monohydrogeophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates , formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates , suberates, sebacates, fumarates, maleates, mandelates, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, "Benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylensulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, 3-hydroxybutyrates, glycolates, malonates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and similar salts. Examples of compounds within the scope of general formula I are: DL-5-dimethylamino-4,5,6,7-tetrahydro-1,1H-indazole methanesulfonate, DL-5-diethylamino-4,5,6,7-tetrahydro-5 -. 1 H-indazole maleate, DL-5-di (n-propyl amino-4,5,6,7-tetrahydro-1H-indazole hydrochloride. Examples of compounds within the scope of formula II are: DL-6-dimethylamino-4 , 5,6,7-tetrahydro-2H-indazole maleate, N-methyl-N-ethyl-DL-5-amino-4,5,6,7-tetrahydro-2H-indazole hydrochloride, N-methyl-N-propyl- DL-5-amino-4,5,6,7-tetrahydro-2H-indazole sulphate The presence of a substituent at the 5 or 6 position of the indazole ring brings the asymmetric center into the molecule, thus the compounds of formulas I and II include two optical isomers occurring as DL The cleavage of the DL-pair of the compounds of the invention to their optical antipodes can be accomplished by methods known in the literature.

The compounds of formulas I and II have been named DL-5- (or 6) -dialkylamir, o-4,5,6,7-tetrahydro-1H-indazoles and DL-5- (or 6) -di-alkylamino -4,5,6,7-tetrahydro-2K-indazoles. The presence of the amino group at the 5-position or the 6-position of the indazole ring forms a center asymmetry and thus the compounds of formulas I and II are prepared in the form of a racemate or DL-mixture. These racemates can be resolved into the corresponding D- and L-isomers by known methods. It is believed that the dopamine agonist activity exhibited by racemates of Formulas I and II can be predominantly or completely linked to one stereoisomer. The present invention relates not only to dopamine-agonist D-racemates but also to pure stereoisomers that have a dopamine agonist effect.

The invention is further illustrated by the following specific examples. Example 1 Preparation of DL-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazole and DL-5-dimethylamino-4,5,6,7-tetrahydro-2H-indazole A reaction mixture consisting of 630mL of DL was prepared. 5-amino-4,5,6,7-tetrahydro-1H-indazole dihydrochloride and dihydrochloride of its 2H-tautomer, 410 g of sodium acetate and 75 ml of ethanol. Sodium cyanoborohydride (380 mg) was added to the mixture, and aqueous formalin (1 ml, 37%) was added. The mixture was stirred at room temperature for 17 hours and then poured into ice / 1 N hydrochloric acid. The aqueous phase is extracted with chloroform, and the chloroform extract is discarded. The aqueous phase was then basified with 14 N aqueous ammonium hydroxide, and the resulting alkaline solution was extracted several times with a mixture of chloroform and isopropanol. The extracts were combined and washed with saturated aqueous sodium chloride solution and dried. Evaporation of the solvent gave 0.43 g of a residue consisting of DL-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazol and DL-5-dimethylamino-4,5,6,7. -tetra-hydro-2H-indazole formed by the above reaction. The NMR spectrum of this tautomeric mixture provides characteristic peaks at 142 Hz (singletaminomethyl) 432 and 440 Hz (broad singlet C-3H). The spectrum was measured by CDCl3. The compounds were further purified by dissolving the residue in 10 mL of 1N aqueous hydrochloric acid and diluting with anhydrous ethanol. The solution was evaporated to dryness in vacuo and the resulting evaporation was recrystallized from methanol / ether. The DL-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazoliumhydrochloride and DL-5-dimethylamino-4,5,6,7-tetrahydro-2H-indazole dihydrochloride thus prepared melted at 230-238 ° C. for foaming. Yield 430 mg.

Analysis: Calculated: 45.39% C, 7.20% H, 17.64% N, found: 45.26% C, 7.13% H, 17.46% N. Example 2 Preparation of DL-5- di- (n-propyl) amino-4,5,6,7-tetrahydro-1H-indazole and DL-5-di (n-propyl-amino-4,5,6,7-tetrahydro-2H-indazole

Following the procedure of Example 1, but substituting the regionaldehyde for formaldehyde, a mixture of DL-5-di (n-propyl) amino'-4,5,6,7-tetrahydro-1H-indazole and its 2H-tautomer is prepared. in CDCl 3 it gives characteristic peaks at 52 Hz (triplet propyl CH 3) and 432 Hz (singlet C-3 H). The dihydrochloride salts of the tautomeric mixture prepared by this process melted at 154-160 ° C for foaming. Yield 2.97 g (from 2.15 g starting material).

Analysis: Calculated: 53.06 ° C, 8.56% H, 14.28% N, found: 52.83% O / C, 8.83% H, 14.30% N. Example 3

Following the procedure of Example 1, DL-6-amino-4,5,6,7-tetrahydro-1H (and 2H) indazole is alkyl. with propionaldehyde and reacting with NaBH 3 CN to give DL-6-di (n-propyl) amino-4,5,6,7-tetrahydro-1H (a 2H) -indazole. Free base non-crystalline glass, mass spectrum (molecular ion M + at 221).

As evidence of the utility of the compounds of formulas I and II for the treatment of Parkinson's syndrome, it has been found that these compounds rotate in rotation in a 6-hydroxydopamine-injected rat. In this test, rats prepared according to Ungerstedt and Ar-buthnott, Brain Res. 24 (485, 1970). Compounds that have a dopamine agonist effect after injection cause the rats to rotate in circles against the wound side. After a latency period, which is different for different compounds. counts for 15 mi-nut. The compounds were dissolved in water and the aqueous solution formed. injects rats incontinently at a number of doses. The following table shows the results of this test. In Table 1, column 1, the names of the compounds are shown, the column 2 is the reference and the column 3 shows the percentage of the rotational behavior, and column 4 the number of revolutions. 241020 3 TABLE 1

Rotation Behavior Compound Name Dose Level Percentage of Crystals Inducing Turning DL-5-di- (n-propyl) amino-4,5,6,7-tetrahydro-1 mg / kg 67 48 -1H (a 2H J-indazole dihydrochloride 100 µg) / kg 33 6 DL-5 dimethylamino-4,5,6,7-tetrahydro-1 H (a 2 H -indazoldihydrochloride 1 mg / kg 33 5 DL-6-di- (n-propylamino-4,5,6,7) -tetrahydro-1 mg / kg 100 98 -1 H (a 2H) -indazoldihydrochloride 250 µg / kg 50 30 100, µg / kg 0 -

The compounds of formulas I and II are also useful as prolactin inhibitors and can be used as such for the treatment of inadequate lactations, such as postpartum lactation, gaiacore. Prolactin inhibition has been demonstrated as follows to demonstrate the usefulness of the treatment of diseases in which it is desirable to reduce prolactin levels by the compounds of Formulas Ia II:

Adult male Sprague-Dawley rats weighing 200 g are placed in an air-conditioned room with controlled illumination (illumination from 6 to 20 hours) and rats are allowed access to laboratory water feeding ad libitum. Each rat was injected intraperitoneally with 2.0 mg of reserpine in an aqueous suspension 18 hours prior to administration of the insazole. The purpose of reserpine is to maintain prolactin levels in a uniformly elevated level. The test compounds are dissolved in water and injected intraperitoneally with doses ranging from 5 mg / kg to 50 µg / kg. Each compound is administered in a single dose of a group of 10 rats and an equivalent amount of solvent is applied to the 10-well control group. One hour after treatment, all rats are killed by cutting the head and 150 μϊ of serum are analyzed for prolactin levels.

The difference between the treated rat prolactin level and the control rat prolactin level divided by the control rat prolactin level indicates the percent inhibition of prolactin secretion attributable to the compounds of Formulas I and II. These percentages of inhibition are shown in Table 2 below. The table in column 1 lists the names of the compounds, columns 2 to 4 show the percent inhibition of prolactin at the indicated dose. TABLE 2

Percentage of prolactin inhibition at the indicated doses

DL-5-di- (n-propyl) amino-4,5,6,7-tetrahydro-1 H (a 2H) -indazole dihydrochloride DL-5 dimethylamino-4,5,6,7-tetrahydro-1 H DL-6-di- (n-propylamino-4,5,6,7-tetrahydro-1H (a 2H) -indazole dihydrochloride (and 2H) -indazole dihydrochloride

By using the compounds of Formulas I and II to inhibit prolactin secretion or to treat Parkinson's syndrome or other pharmacological effects, a compound of Formula I and II above, or a salt thereof with a pharmaceutically acceptable acid, is administered to a person with Parkinson's or with a need to reduce the level of prolactin. lactin in an amount effective to remove some syndromes or to reduce prolactin levels. Oral administration is preferred. If parenteral administration is used, 5 mg / kg 500, ug / kg 50, ug / kg 94-6611331-31c, the injection is preferably carried out using the appropriate pharmaceutical compositions. Other methods of parenteral administration such as intraperitoneal, intramuscular or intravenous administration are equally effective. Particularly in the case of intravenous or intramuscular administration, pharmaceutically acceptable salts are used. For oral administration, the compound of formula (I) and (II), either in free base form or in salt form, can be admixed with a standard pharmaceutical ingredient and filled with

Claims

241020 10 is pressed into empty telescopic gelatin capsules or compressed into tablets. The oral dose ranges from 0.01 to 10 mg / kg body weight of the mammal and the parenteral dose is from 0.0025 to 2.5 mg / kg. The LD 50 values of DL-5-di (n-propyl) amino-4,5,6,7-tetrahydro-1 H (a 2 H) -indazole dihydrochloride range from 100 to 300 mg / kg for intraperitoneal administration to mice. 10 and 30 mg / kg are non-lethal and the 30 mg / kg dose produces some undesirable side effects.

A process for preparing amino substituted 4,5,6,7-tetrahydro-1H (or 2H) -in-dazoles, tautomers of formulas I and II

(ID where one of R and R 1 is hydrogen and the other is N (R 2) 2, wherein R 2 is individually methyl, ethyl or n-propyl, and pharmaceutically acceptable acid addition salts thereof; by reacting tautomers of formulas IB and IIB

wherein one of R and R 1 is a hydrogen atom and the other is NH 4, with the corresponding aldehyde in the presence of a metal hydride as the reducing agent, and optionally converting the compounds of formula I and II into pharmaceutically acceptable salts.

2. A process as claimed in claim 1, wherein the corresponding starting compounds are reacted to give compounds of general formula (I) wherein R is as defined in (1), R1 is N (R2) 2 wherein R2 is n-propyl.

3. The process of clause 1 for the preparation of tau-tomers of DL-5- (di-n-propyl) amino-4,5,6,7-tetrahydro-2H-indazole and DL-5- (di-n-propane). characterized by the fact that DL-5-amino-4,5,6,7-tetrahydro-1H-indazole and DL-5 are reacted with 5-amino-4,5,6,7-tetrahydro-1H-indazole. -amino-4,5,6,7-tetrahydro-2H-indazole with propionaldehyde and sodium cyanoborohydride.

4. The process of clause 1 for the preparation of TauTers DL-6- (di-n-propyl) amino-4,5,6,7-tetrahydro-1H-indazole and DL-6- (di-n-propane). characterized by reacting DL-6-amino-4,5,6,7-tetrahydro-1H-indazole and DL-- 6-Amino-4,5,6,7-tetrahydro-2H-indazole with propionaldehyde and sodium cyanoborohydride.

5. The process according to claim 1 for preparing tauers of DL-5-dimethylamino-4,5,6,7-tetrahydro-1H-indazole and DL-5-dimethylamino-4,5,6,7-tetrahydro-2H- characterized in that DL-5-amino-4,5,6,7,7-tetrahydro-1H-indazole and DL-5-amino-4,5,6,7-tetrahydro-2H-indazole are reacted formalin with sodium cyanoborohydride.