DK142649B - Analogous process for the preparation of substituted tetrazoles. - Google Patents

Description

\ OD | OD ODM PUBLICATION WRITING 142649 DENMARK w int ci.3 c o7 o 401/12 § (21) Application No. 1686/78 (22) Filed on 1 8 Apr. 1978 (24) Race day l8. April 1978 (44) The application submitted and the submission document published on o · deC. 1 9o0

DIRECTORATE OF

PATENT AND TRADE MARKETING <30> Pnettet commanded from (71) RIKER LABORATORIES INC., 19901 Nordhoff Street, Northridge, Cali =

Tornia 91324, US.

U2) Inventor: Edward Herbert Erickson, 5M Center, St. Paul, Minnesota 55101, US.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Bout engineering firm ._______ (54) Analogous process for the production of substituted tetrazoles.

The present invention relates to an analogous process for the preparation of novel substituted tetrazoles having the general formula I or pharmaceutically acceptable salts thereof as set forth in the preamble of claim. Such salts may e.g. be salts with alkali metals such as sodium or with organic bases such as dimethylaminoethanol. In Formula I, the group R1 is bonded to a ring carbon atom.

the formula denotes the circle in the tetrazole ring a pair of double bonds which, together with the bonds shown, fulfill the valence requirements of the ring carbon atom and all valences except one for the four ring nitrogen atoms. The last nitrogen valence is satisfied by the group R 2.

In those compounds in which the tetrazole ring is unsubstituted, the hydrogen atom exists in tautomeric form attached to η 2 to either the N - or the N-atom, i.e.

Η H

N- N>. _ N-N ^ _ N- W ^^ N = N //> ~

For convenience, it is illustrated herein as if the hydrogen atom is bonded to the ^ atom. Such a tautomerism does not occur in compounds where the tetrazole ring is substituted by an alkyl group, the group then sitting in a single position.

The present compounds, all of which are 8-substituted quinolines, are useful in anti-allergic agents, as well as in treatment methods for allergies, in which a compound prepared according to the invention is administered to a mammalian organism as required.

Danish Patent Application No. 3663/73 discloses similar 2-substituted quinolines which have anti-allergic properties, but experiments have shown that they have a far poorer activity than the compounds of the invention.

Preferred compounds are those wherein n is zero, i.e., the 2-, 3- and 4-positions of the quinoline moiety are unsubstituted, and

ISLAND

R represents hydrogen. Another preferred group of compounds are those wherein one of the nitrogen atoms in the tetrazole ring is substituted by an alkyl group of 1-4 carbon atoms, preferably methyl. When alkyl or alkoxy substituents are present anywhere in the formula, they preferably contain 1 carbon atom.

island

Compounds in which R represents chloro, iodo, methyl or nitro form a preferred subgroup, as do compounds in which R 2 represents methyl.

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The process according to the invention is characterized by the characterizing part of the claim. Thus, the compounds are prepared by reacting a substituted 8-carboxyquinoline with aminotetrazole or an alkylaminotetrazole. It is preferred to activate the 8-carboxy groups by methods used in the peptide chemistry to convert a carboxylic acid group to an N-substituted carboxyamido group. A preferred method of carboxyl activation is reacting the carboxylic acid group with N, N1-carbonyldiimidazole.

Other methods are e.g. reaction with thionyl chloride, reaction with N, N * -dicyclohexylcarbodiimide to form an activated adduct, reaction with ethyl chloroformate or n-butyl chloroformate to form a mixed anhydride, and reaction with p-nitro-phenoxybenzyl chloride to form a p-nitrophenoxy

The activated 8-carboxyquinoline intermediate is reacted with an aminotetrazole in an aprotic solvent such as tetrahydrofuran or Ν, Ν-dimethylformamide, or in aqueous media in the presence of an acid acceptor, e.g. a tertiary organic base such as pyridine or triethylamine, or an alkali metal carbonate or bicarbonate. Reactions in aqueous media may require a co-solvent to achieve the reaction. If necessary, elevated temperatures can be used. Preferably, the reaction temperature is 25-200 ° C. The temperature of a particular reaction will usually depend on the solvent used and will frequently be the reflux temperature of the mixture.

8- (N-alkyl-1H-tetrazol-5-ylcarbamoyl) quinolines can be readily prepared from known N-alkyltetrazoles or by alkylation of the tetrazole moiety in the corresponding unsubstituted compound of the invention with appropriate alkylating agents such as alkyl bromides and iodides. The alkylation will usually result in a mixture of N - and N-substituted compounds. Separation can be accomplished by crystallization or chromatography.

Salts of the subject compounds are prepared by reaction with the organic or inorganic base in a non-reactive solvent, e.g. sodium hydroxide or dimethylaminomethanol is used.

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The compounds of this invention are useful in the treatment of so-called "intrinsic" asthma (where no hypersensitivity to extrinsic antigens can be demonstrated) or any other condition where non-specific factors trigger the release of allergy agents and in the treatment of other circumstances where The antigen-antibody response is responsible for diseases such as extrinsic asthma, food allergies, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hay fever, urticaria and autoimmune diseases. Treatment may require repeated dosing of the agent at regular intervals. The amount administered and the frequency of administration will depend on many factors and no precise dose range or size can be specified. However, as a general rule, when the compounds are administered by inhalation in a patient suffering from acute allergic asthma, therapeutically useful results can be achieved at doses of from 0.1 to 20 mg / kg.

The efficacy of the subject compounds is assessed by inhibiting passive cutaneous anaphylaxis by a standard test method, essentially as described in "Immunology", 16, 749 (1969).

The following examples further illustrate the process of the invention.

EXAMPLE 1

A solution of 1.0 g (6 mmol) of 8-quinoline carboxylic acid and 0.98 g (6 mmol) of N, N-carbonyldiimidazole in 40 ml of N, N-dimethylformamide is stirred at 100 ° C for 6 hours. To this mixture is added 0.62 g (6 mmol) of 5-aminotetrazole monohydrate in 10 ml of N, N-dimethylformamide.

After stirring for one hour at 100 ° C, the solution is evaporated.

Dilute the residue with water and ca. 3 ml of 10% hydrochloric acid and stir for 1 hour. The solid product which is separated by filtration, dried and recrystallized from N, N-dimethylformamide is 8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 310-315 ° C (dec.).

EXAMPLE 2

A mixture of 2.4 g (0.020 mol) of 8-quinoline carboxylic acid and 3.0 g (0.030 mol) of 5-amino-1-methyltetrazole is stirred in 30 ml of pyridine at 20 ° C with dropwise addition of thionyl chloride. The mixture is heated to 70 ° C for one hour. The reaction mixture is evaporated to give a residue diluted with water. The solid is separated by filtration and recrystallized from acetic acid using decolorizing coal. The product is recrystallized again from acetic acid to give 8- (1-methyl-1H-tetrazol-5-ylcarbamoyl) -quinoline, m.p. 224 - 225 ° C.

Analogously to Example 2, the following compounds are prepared from appropriate aminotetrazoles or N-alkylaminotetrazoles and substituted carboxyquinolines:

EXAMPLE

3 5-Chloro-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 305 ° C, 4 6-iodo-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 295-297 ° C, 5-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 296-297 ° C, 6 5-methoxy-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 276-279 ° C, 7 6-nitro-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 307-309 ° C, 8 2-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 303-307 ° C, 9 4-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp> 290 ° C, 6-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. . 287-289 ° C, 11 6-Chloro-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 300-301 ° C, 12 5-Chloro-4-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p.

276-279 ° C, 13 6-hydroxy-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. EXAMPLE 14

To a solution of 1.7 g (10 mmol) of 8-quinoline carboxylic acid in 50 ml of Ν, Ν-dimethylformamide is added 1.6 g (10 mmol) of N, N'-carbonyl diimidazole and the mixture is stirred for 4 hours at 100 ° C.

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The steamed reactive intermediate is reacted with 1.0 g (10 mmol) of 5-amino-2-methyltetrazole. The reaction is carried out by adding the solution and two drops of trifluoroacetic acid to the stirred solution of the reactive intermediate and heating for 4 hours at 140-150 ° C. The solution is then evaporated. Water is added to the residue, the mixture is cooled and then filtered. The solid is recrystallized from ethanol to give 8- (2-methyl-1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 222-223 ° C.

EXAMPLE 15

Analogously to Example 2, but using 50 ml of chloroform as the solvent, 7-methyl-8- (1H-tetrazol-5-ylcarbamoyl) -quinoline is obtained, m.p. 285-287 ° C.

EXAMPLE 16

To a stirred solution of 4.0 g (0.020 mol) of 2,4-dimethyl-8-quinoline carboxylic acid in 20 ml of Ν, Ν-dimethylformamide in an ice bath is added 2.8 ml of triethylamine. To this solution is added dropwise 2 ml of ethyl chloroformate. The mixture is stirred for 1 hour, then 2 g (0.020 mol) of 2-aminotetrazole monohydrate is added in 10 ml of Ν, Ν-dimethylformamide. The mixture is stirred at 20 ° C for approx. 16 hours and then evaporated to form a residue which is washed out with water. The residue is recrystallized twice from acetic acid to give 2,4-dimethyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, m.p. 300-305 ° C.