SE437662B - Substituted tetrazoles and anti-allergic agents - Google Patents

Abstract

Substituted 8-(1H-tetrazole-5-ylcarbamoyl) quinoline with the formula<IMAGE>and pharmaceutically acceptable salts thereof are described as effective anti-allergenic agents. The compounds are produced by activating an 8-carboxyquinoline and transforming such with an amino tetrazole.

Description

7806673-5 'Üïítïifff t: QUALITY-bli w lO 15 20 25 30 35' - fax g, ï. 2 tautomerism does not occur in those compounds in which the tetrazole ring is substituted with an alkyl group, the substituent group remaining in a spirit position.

The invention also relates to antiallergic compositions containing the compounds. Currently preferred compounds of the invention are those wherein n is 0, i.e. the 2-, 3- and 4-positions of the quinoline moiety are unsubstituted, and R 2 is hydrogen. Another preferred subclass is compounds in which one of the nitrogen atoms in the tetrazole ring is substituted with alkyl of 1-4 carbon atoms and preferably of methyl. When an alkyl or alkoxy substituent is present somewhere in the compound, it preferably contains 1 carbon atom.

The compounds of the invention in which R 2 is chlorine, iodine, methyl or nitro form a preferred subgroup, as do the compounds of the invention in which R 1 is methyl.

The compounds of the invention are prepared by reacting substituted 8-carboxyquinoline with aminotetrazole or an alkylaminotetrazole. At present, it is preferred to activate the δ-carboxy groups by such techniques as are used in peptide chemistry to convert a carboxylic acid group to a substituted carboxamide group. A preferred method of carboxyl activation is reaction of the carboxylic acid group with N, N'-carbonyldiimidazole. Other methods which may be used are reaction with thionyl chloride, reaction with N, N'-dicyclohexylcarbodiimide to give an activated adduct, reaction with ethyl chloroformate, n-butyl chloroformate and the like to give a mixed anhydride, reaction with p nitrophenoxybenzyl chloride to provide a p-nitroenoxybenzyl ester and the like.

The activated 8-carboxyquinoline intermediate is then reacted with an aminotetrazole in an aprotic solvent such as tetrahydrofuran or N, N-dimethylformamide, or in aqueous medium in the presence of an acid acceptor, for example a tertiary organic base such as pyridine or triethylamine, or smiles an alkali metal carbonate or bicarbonate. Reactions in aqueous media may require a co-solvent to achieve reaction. Elevated temperatures can be used if necessary. Preferably, the reaction temperature is 4 20 15 25 25 35 4 4. Treatment may require repeated dosing of the medicine at regular intervals. The amount of medication and the frequency of administration depend on many factors and no exact dosage ranges or sizes can usually be determined. However, as a general clue when the compounds are administered by inhalation to a patient suffering from acute allergic asthma, therapeutically useful results can be obtained when doses of 0.1-20 mg / kg are used. When the compounds are administered orally, larger doses are normally given. The invention thus provides a method of inhibiting the effects of an antibody-antigen reaction, which comprises a prior (preferably) or subsequent application to the known or expected field of the antibody-antigen reaction mechanism of a therapeutically effective amount of a compound of the invention. Other active ingredients may also be present in the compositions of the invention. Thus, in compositions for administration by inhalation, it may be appropriate to include a bronchodilator, such as isoprenaline, adrenaline, carbuterol, rimiterol, orciprenaline, isoetharine or derivatives thereof, especially salts. The amount of bronchodilator used varies over a wide range depending on, among other things, the nature and activity of the bronchodilator and the compound used according to the present invention. However, the use of a minor portion (ie, less than 50% by weight) of the bronchodilator along with 0.1 to 10% by weight of the compound of the present invention is preferred. Such compositions are also encompassed by the invention.

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

EXAMPLE 1 A solution of 1.0 g (6 mmol) of 8-quinolinecarboxylic 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. female åfåålïßhïw-å 7806673-5 3 tours in the area 25-ZOOÛC. The temperature used in a given reaction usually depends on the solvent used and is often the reflux temperature of the mixture. 8- (N-alkyl-1H-tetrazol-5-ylcarbamoyl) quinolines are readily prepared from known N-alkyltetrazoles or by alkylation of the tetrazole moiety of the corresponding unsubstituted compound of the invention with suitable alkylating agents such as alkyl bromides and - iodides. The alkylation usually results in a mixture of N1- and N2-substituted compounds. Separation is performed by crystallization or chromatography.

The salts are prepared by reaction with the organic or inorganic base in an inert solvent, for example with sodium hydroxide or dimethylaminomethanol. The compositions of the invention normally comprise a compound of the invention in association with a pharmaceutically acceptable carrier or diluent. The nature of the composition and the carrier or diluent will, of course, depend on the mode of administration desired, which may be, for example, orally by inhalation (orally or nasally), parenterally (such as by intradermal or intravenous injection) or by topical application. They may be mixed in a conventional manner with conventional ingredients, for example in the form of solutions, suspensions, syrups, dry powders, tablets, or when they are intended for topical application as creams, lotions or pastes. The compositions of the invention usually comprise a minor portion of the active compound and a major portion of the carrier or diluent. The new compounds are useful in the treatment of so-called "intrinsic" asthma (where no hypersensitivity to extrinsic antigen can be detected) or any other conditions, in which non-specific factors trigger the release of allergenic agents and in the treatment of other conditions in which antigen-antibody responses are responsible for the disease, eg extrinsic asthma, food allergies, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hay fever, urticaria and autoimmune disease mixture 15 20 25 30 35 7806673-5 0.62 g (6 mmol) of 5-aminotetrazole monohydrate is added to 10 ml of N, N-dimethylformamide. After stirring for 1 h at 10 [deg.] C., the solution is evaporated. The residue is diluted with water and about 3 ml of 10% hydrochloric acid and stirred for 1 h. , separated by filtration, dried and recrystallized from N, N-dimethylformamide, is 8- (1H-tetrazol-5 -sylcarbamoyl) quinoline, mp 31o-31s ° C (decomposition).

EXAMPLE 2 A mixture of 2.4 g (0.02 mol) of 8-quinolinecarboxylic acid and 3.0 g (0.030 mol) of 5-amino-1-methyltetrazole is stirred in 30 ml of pyridine at 20 ° C with the addition of 2 g. 0 ml thionyl chloride dropwise. The mixture is heated at 70 ° C for 1 hour.

The reaction mixture is evaporated to give a residue which is diluted with water. The solid is separated by filtration and recrystallized from acetic acid with decolorizing charcoal. The product is recrystallized a second time from acetic acid to give 8- (1-methyl-1H-tetrazol-5-ylcarbamoyl) quinoline, mp 224-225 ° C.

Using the method of Example 2, the following compounds of the invention are prepared from the starting compounds aminotetrazole or N-alkylaminotetrazoles and substituted 8-carboxyquinolines.

Example gel 3 5-chloro-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 305 ° C. 4-iodo-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 295-297 ° C. 5-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 296-297 ° C. 6 5-methoxy-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 276-279 ° C. 7-nitro-S- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 307-309 ° C. 2-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 303-307 ° C. 4-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp> 290 ° C. 10 6-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 287-2s9 ° C. 7806673-5 10 15 20 25 30 35 6 11 6-chloro-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 300-3o1 ° c. 12 5-chloro-4-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 276-279 ° C. 13 4-methoxy-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, 14 8- (1-n-butyl-1H-tetrazol-5-ylcarbamoyl) quinoline.

EXAMPLE 15 To a solution of 1.7 g (10 mmol) of 8-quinoline-carboxylic acid to 50 ml of N, N-dimethylformamide is added 1.6 g (10 mmol) of N, N'-carbonyldiimidazole and the mixture is stirred for 4 hours. at 100 ° C.

The reactive intermediate formed is reacted with 1.0 g (10 mmol) is carried out by adding the solution and two drops of 5-amino-2-methyltetrazole. The reaction 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 first product is recrystallized from ethanol to give 8- (2-methyl-1H-tetrazol-5-ylcarbamoyl) quinoline, mp 222-223 ° C.

EXAMPLE 16 Using the method of Example 2 but adding 50 ml of chloroform as solvent, 7-methyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline is obtained, mp 285-28700.

EXAMPLE 17 To a stirred ice bath-cooled solution of 4.0 g (0.020 mol) of 2,4-dimethyl-8-quinolinecarboxylic acid in 20 ml of N, N-dimethylformamide 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 ml) of 2-aminotetrazole monohydrate in 10 ml of N, N-dimethylformamide are added. The mixture is stirred at 20 ° C for about 16 hours and then evaporated to give a residue which is washed with water. The residue is recrystallized twice from acetic acid to give 2,4-dimethyl-8- (1H-tetrazol-5-ylcarbamoyl) quinoline, mp 300-30 ° C.

Claims (8)

A compound of the formula (I) R fee yr / w N'-fN wherein R 1 is alkyl. or alkoxy having 1 or 2 carbon atoms, 2 R is alkyl or alkoxy having 1 or 2 carbon atoms, hydrogen, nitro or halogen, R 3 is hydrogen or alkyl having 1-4 carbon atoms and n is 0, 1 or 2, and pharmaceutically acceptable salts thereof. The compound 8- (1H-tetrazol-5-ylcarbamoyl) quinoline according to claim 1. The compound 6-iodo-8- (1H-tetrazol-5-ylcarbamoyl) -quinoline according to claim 1. The compound 8- (2-methyl-1H-tetrazol-5-ylcarbamoyl) quinoline according to claim 1. An antiallergic agent, characterized in that it comprises a compound of the formula R 2 R 1 // n (I) is alkyl or alkoxy having 1 or 2 carbon atoms, hydrogen, is hydrogen or alkyl having 1-4 carbon atoms and n is 0, 1 or 2, in combination with a pharmaceutically acceptable carrier. .aa m ... dßlfšåeàgmmmml 7806673-5 8 An antiallergic agent according to claim 5, characterized in that it comprises the compound 8- (1H- -tetrazol-5-ylcarbamoyl) quinoline. The antiallergic agent according to claim 5, characterized in that it comprises the compound 6-iodo-8- (1H-tetrazol-5-ylcarbamoyl) quinoline. The antiallergic agent according to claim 5, characterized in that it comprises the compound 8- (2-methyl-1H-tetrazol-5-ylcarbamoyl) quinoline.