DK142576B - INDAZOL DERIVATIVES USED AS INTERMEDIATES FOR THE PREPARATION OF INDAZOL DERIVATIVES WITH BETA RECEPTOR BREAKING EFFECT - Google Patents

Description

(§ (11) PRESENTATION 142576 DENMARK (si) int.er.3 c 07 b 231/56 "(21) Application No. 1996/78 (22) Submitted on May 8, 1978/24) Day of Living 27" Βφ ¥ · 1977 (44) The note presented and _

the petition published on dPtm nOV. 1 9oU

Dl THE RECTORATE OF _ u PATENT AND TRADEMARKET (30) Pnggritet gassed from the

JO. April 1976, 2619165, DE

(71) BOEHRINGER MANNHEIM GMBH., Mannheim ^ Waldhof, DE.

(72) Inventor: Fritz Wiedemann, Weinheimerstr. 82, Weinheim-Laetzel = Saxony, DE: Wolfgang Kampe, Zedernstr. 49, Heddesheim, DE.

(74) Plenipotentiary:

The company Chas. Hude.

---; - 1 1 ----- '' 1- - (64) Indazole derivatives for use as intermediates for the preparation of indazole derivatives having fceta receptor blocking effect.

The present invention relates to indazole derivatives for use as intermediates in the preparation of indazole derivatives having a fJ receptor blocking effect and of the general formula o-ch2-ch-ch2-nh-r2

OH &

Ί (II) y

H

Wherein R is hydrogen or an alkyl group having 1-3 carbon atoms and R is a straight or branched alkyl group having 3-4 carbon atoms which may be optionally substituted with a methyl mercapto group

The compounds of the invention are peculiar in that they have the general formula

9-ch 2 -O

I - (I)

i

in R 'wherein R 1 is as defined above and R' is hydrogen or an acyl group of 1-7 carbon atoms.

It has been found that the novel compounds of general formula I are valuable intermediates for the preparation of useful pharmacologically active compounds of general formula II.

Thus, by hydrogenolysis of the compounds of the general formula I to form compounds of the general formula

OH

Λ— JCv, m)

Ac wherein R 1 is as defined above and Ac is acetyl, and subsequently reacting the compounds of general formula III with reactive compounds of formula 3

Hal - CH- - CH - CH_, / T

2 \ / 2 (IV)

ISLAND

wherein Hal represents a halogen atom, intermediates which are then obtained with alkylamines of 3-4 carbon atoms, such as isopropylamine and tert-butylamine, result in suitable 3-indazolyl (4) -oxy-propanol (2) amines. as inhibitors of the adrenergic $ receptors for the treatment and prevention of cardiovascular disease. By reacting 1-acetyl-4- (2,3-epoxypropoxy) -indazole with isopropylamine, e.g. 1- [indazolyl- (4) -oxy] -3-isopropylaminopropanol- (2), cf. Example 1 of Danish Patent Specification No. 137,956. By means of turnovers with other components, circuit active and anti-allergic active obstructions can also be prepared from these, cf. pages 2-3 of said presentation document and the accompanying table of test results.

The compounds of the general formula I can be prepared in a manner known per se, preferably by nitrosating and cyclizing a compound of the general formula XCH * 0 / v CH 3 (V),> C

R

wherein R 1 is as defined above and R "is an acyl group having from 1 to 7 carbon atoms, and then, as desired, the acyl group decomposes, after which the compounds of formula I thus obtained can also be converted to other compounds of the general formula if desired. formula I.

As mentioned, the substituent R1 in the sense a lower alkyl group may contain 1-3 carbon atoms, with the methyl group being preferred.

As mentioned, the protecting groups R 'and R "in the meaning of" acyl "are meant groups having 1-7 carbon atoms, preferably the acetyl group or the benzoyl group.

4 1425 76

In the process, 3-acylamino-2-methyl-phenyl-benzyl ether of the general formula IV in the presence of the anhydride and an alkali salt of the acid corresponding to the acyl group is nitrosated (e.g. with isoamyl-nitrite) in an aprotic solvent (e.g. toluene) and then cy = clised by heating.

An analog of indazole synthesis described by the method is described in German Patent Specification No. 2,155,545.

A subsequent conversion of the compounds of formula I to other compounds of formula I can also be carried out. Thus, from the compounds of general formula I wherein R 1 represents an acyl group, this group can be selectively removed under mild conditions by aminolysis or hydrolysis, i.e. without changing the other functional groups.

In the following examples, the preparation of the compounds of the invention is further described.

Example 1.

l-acetyl-4-benzyloxy-indazole

A mixture of 64 g (3-acetamino-2-methyl-phenyl) -benzyl ether, 25 g of sodium acetate, 69 ml of acetanhydride, 50 ml of isoamyl nitrite and 2 liters of toluene is stirred for 15-20 hours at 80-90 ° C. After cooling to 10 ° C, the salts are suctioned off and the filtrate evaporated to dryness in vacuo. Rubbing the residue with 300 ml of methanol gives 47.5 g of almost colorless crystals, m.p. 97 ° C.

The starting material (3-acetamino-2-methyl-phenyl) -benzyl ether is obtained in two reaction steps as follows: (3-amino-2-methyl-phenyl) -benzyl ether

By reduction of (2-methyl-3-nitro-phenyl) -benzyl ether with hydrazine = hydrate and Raney nickel in methanol the crude product is obtained as a green oil.

142576 5 sr * ·; τ- t · ·.

(3-acetamino-2-methyl-phenyl) -benzyl ether

Acetylation of the above-described product with acetanhydride in toluene: colorless crystals, mp 142-143 ° C (from toluene).

Example 2.

l-acetyl-4-benzyloxy-6-methyl-i.ndazol

A mixture of 149 g of (3-acetamino-2,5-dimethyl-phenyl) -benzyl ether, 50 g of sodium acetate, 138 ml of acetic anhydride, 50 ml of isoamyl nitrite and 3 liters of toluene is stirred for 15-20 hours at 80-90 °. After cooling, suction is filtered off, the filtrate is evaporated to dryness in vacuo, the residue is taken up for approx. 300 ml of methanol and crystallize the product in the cold. Yield 103 g of yellow crystals, mp 91-93 ° C.

The (3-acetamino-2,5-di-methyl-phenyl) -benzyl ether used as starting material in Example 2 is prepared by the following reaction. from 2,5-dimethyl-3-nitro-phenol: (2,5-dimethyl-3-nitro-phenyl) -benzyl ether

A mixture of 433 g of 2,5-dimethyl-3-nitro-phenol, 360 g of K2 CO3, 326 ml of benzyl chloride and 2 liters of DMF is stirred overnight at 50 ° C. The filtrate is extracted, evaporated to dryness in vacuo, the residue is poured into 4 liters of ice water, and after extraction and drying in the air 668 g of yellow crystals are obtained, mp 66-68 ° C.

(3-amino-2,5-dimethy1-phenyl) -benzyl ether

The above-described nitro compound is reduced with hydrazine hydrate-Raney nickel in methanol. As a crude product, a brown oil is obtained in good yield.

(3-acetamido-2,5-dimethyl-phenyl) -benzyl ether

Acetylation of the above-described product with acetanhydride in toluene: colorless crystals, mp 169-171 ° C (from toluene).

6 U2576 By analogy one obtains

a) from (3-acebamino-2,6-dimethyl-phenyl) -benzyl ether (m.p. 161-162 ° G) (prepared via (2,6-dimethyl-3-nitro-phenyl) -benzyl) ether and (3- amino-2,6-dimethyl-phenyl) -benzyl ether): 1-acetyl-4-benzyloxy-5-methyl-indazole, mp 108-109 ° C

b) out phta (3-acetamino-2,4-dimethyl-phenyl) -benzyl ether (m.p. 160-162 ° C) (prepared via (2,4-dimethyl-3-nitro-phenyl) -benzyl ether (m.p. 65-67) ° C) and (3-amino-2,4-dimethyl-phenyl) -benzyl ether):

1-acetyl-4-benzyloxy-7-methyl-indazole, m.p. 90-92 ° C

c) from (2-methyl-3-acetamino-5-ethyl-phenyl) -benzyl ether (mp 139-140 ° C) (prepared via (2-methyl-3-nitro-5-ethyl-phenyl) -benzyl ether and (2-methyl-3-amino-5-ethyl-phenyl) -benzyl ether): 1-acetyl-4-benzyloxy-6-ethyl-indazole, mp 109.5-110.5 ° C.

Example 3.

4-benzyloxy-6-methyl-indazole

0.5 g of 1-acetyl-4-benzyloxy-6-methyl-indazole is allowed to stand for 1 hour at room temperature in 10 ml of isopropylamine, evaporated to dryness in vacuo and recrystallized from methanol-water using activated carbon. Yield 0.2 g of colorless crystals, mp 105 DEG-107 DEG.

By analogy one obtains:

a) 4-Benzyloxy-5-methyl-indazole, m.p. 94-95 ° C

b) 4-benzyloxy-7-methyl-indazole, mp 175-177 ° C

c) 4-benzyloxy-6-ethyl-indazole.