IE46796B1 - Substituted tetrazole compounds - Google Patents

Description

This invention relates be represented by the formula to physiologically active compounds which can wherein R1 is alkyl or alkoxy of one or two carbon atoms, R is alkyl or alkoxy of one or two carbon atoms, hydrogen, nitro or halogen, R-\ is hydrogen or alkyl of one to four carbon atoms and n is zero, one or two, and pharmaceutically acceptable salts thereof (including alkali metal salts, e.g. sodium, and organic base salts, e.g. dimethyl aminoethanol). R^ in the foregoing formula is bonded to a carbon atom of the ring.

In the foregoing formula, the circle in the tetrazoie ring signifies a pair of double bonds which, together with the bonds shown, satisfy all of the valences of the ring carbon atom and all but one valence of the four ring nitrogen atoms. That remaining nitrogen 3 valence is satisfied by R .

In the compounds of the invention in which the tetrazole ring is unsubstituted, the hydrogen atom exists in tautomeric form on 1 ? either the N or the.N atom, i.e.

H -N.

-N For convenience, however, this has been depicted herein simply as appearing on the N1 atom. Such tautomerism does not occur in the compounds in which the tetrazole ring is substituted by an alkyl group (the substituent group remaining in a single location).

The invention also relates to anti-allergic compositions containing the compounds and to an anti-allergic method which comprises applying a compound of the invention to a non-human mammalian organism in need thereof.

Presently preferred compounds of the invention are those wherein n is zero (i.e. the 2, 3 and 4 positions of the quinoline moiety are 2 unsubstituted) and R is hydrogen. Another preferred subclass 4679 G is compounds wherein one of the nitrogens of the tetrazole ring is substituted by alkyl of one to four carbon atoms and most preferably by methyl. When an alkyl or alkoxy substituent is present anywhere in the compound, it preferably contains one carbon atom. The compounds of the invention wherein R is chloro, iodo, methyl or nitro form a preferred subclass as do those compounds of the invention wherein R^ is methyl.

The compounds of the invention are prepared by the interraction of an activated Rz, R^^substituted 8-carboxyquinoline (where 2 1 R , R and n are as in Formula (I)) with aminotetrazole or a C.| to alkyl aminotetrazole. It is presently preferred to activate the 8-carboxy groups by techniques such as are used in peptide chemistry to convert a carboxylic acid group to an N-substituted carboxamide group. One preferred method for carboxyl activation is reaction of the carboxylic acid group with Ii,N'-carbonyl diimidazole. Other methods which may be used are reaction with thionyl chloride, reaction with ti,II'-dicyclohexyl carbodiimide to provide the activated adduct, reaction with ethyl chloroformate or n-butyl chloroformate to provide a mixed anhydride, and reaction with ji-nitrophenoxybenzyl chloride to provide a £-fiitrophenoxybenzyl ester.

The activated 8-carboxyquinoline intermediate is then reacted with an aminotetrazole in an aprotic solvent such as tetrahydrofuran or Ii,ii-dimethylformamide, or in aqueous madia in the presence of an acid acceptor, for example 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 in order to obtain reaction. Elevated temperatures may be used if necessary. Preferably the reaction temperatures are in the range of 25-200°C.

The temperature used in the particular reaction will normally depend upon the solvent used, and will frequently be the reflux temperature of the mixture.

- (N - Alkyl - IH - 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. Alkylation will generally result in a mixture of 1 2 N and N substituted compounds. Separation is carried out by crystallization or chromatography.

The salts are prepared by reaction with the organic or inorganic base in a non-reactive solvent, e.g. with sodium hydroxide or dimethyl aminoethanol.

The compositions of the invention 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 upon the desired mode of administration which may be, for example, orally by inhalation (orally or nasally), parenterally (as by intradermal or intravenous injection) or by topical application. They may be formulated in the conventional manner with conventional ingredients, e.g. they may be put up as solutions, suspensions, syrups, dry powders, tablets or, when intended for topical application, as creams, lotions or pastes.

The compositions of the invention generally comprise a minor proportion of the active compound and a major proportion of carrier or diluent. 6 7 9 6 The new compounds are useful in the treatment of so-called intrinsic asthma (in which no sensitivity to extrinsic antrigen can be demonstrated) or any condition in which non-specific factors trigger the release of allergic mediators and in the treatment of other conditions in which antigen-antibody reactions are responsible for disease, for example extrinsic asthma, food allergies, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hay fever, uticaria and auto-immune diseases. The treatment may be one which requires repeated dosages of the medicament at regular intervals. The amount of medicament and frequency of administrat ion will depend upon many factors, and no concise dosage rate or regimen can be generally stated. However, as a general guide, where the compounds are administered by inhalation to a subject suffering from acute allergic asthma, therapeutically useful results may be achieved when doses of 0.1 to 20 mg/kg are used. When the compounds are administered by oral routes, larger dosages are normally given.

The method according to the invention may thus involve inhibiting the effects of the antibody-antigen reaction, other than in man, which comprises the prior (preferably) or subsequent application to the known or expected area 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 beneficial to include a bronchodilator such as isoprenaline, adrenaline, carbuterol, rimiterol, orciprenaline, isoethraine or derivatives thereof, particularly salts. The amount of bronchodilator used will, vary over a broad range, depending, inter alia, 4679C upon the nature and activity of the bronchodilator and the compound of the present invention which is used. However, the use of a minor proportion (i.e. less than 50 percent by weight) of the bronchodilator together with from 0.1 to 10 percent by weight of the compound of the present invention is preferred. Such compositions constitute an additional aspect of the invention.

The effectiveness of the compounds of the invention is evaluated by inhibiting passive cutaneous anaphylaxis in a standard test method substantially as described in Immunology, 16, 749 (1969).

EXAMPLE 1 A solution of 1.0 g. (6 mmole) of 8-quinoline carboxylic acid and 0.98 g. (6 mmole) of N,N'-carbonyl di imidazole in 40 ml. of Ν,Ν-dimethylformamide is stirred at 100°C. for six hours. To this mixture is added 0.62 g. (6 mmole) of 5-aminotetrazole monohydrate in 10 ml. of Ν,Ν-dimethylformamide. 100°C., the solution is evaporated, water and about 3 ml. of ten percent hydrochloric acid and stirred for one hour. The solid product, separated by filtration, dried and recrystallized from Ν,Ν-dimethylformamide, is - (1H - tetrazol - 5 - ylcarbamoyl) - quinoline, m.p. 310-315°C. (dec.).

EXAMPLE 2 After stirring for one hour at The residue is diluted with A mixture of 2.4 g (0.020 mole) of 8-quinolinecarboxylic acid and 3.0 g. (0.030 mole) of 5-amino-1-methyltetrazole is stirred in 30 ml. of pyridine at 20°C. while adding 2.0 ml. of thionyl chloride 6 7 9 6 dropwise. The mixture is heated at 70°C. for one hour. The reaction mixture is evaporated to provide a residue which is diluted with water. The solid is separated by filtration and recrystallized from acetic acid with decolorizing charcoal. The product is recrystall5 ized a second time from acetic acid to provide 8-(1- methyl IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 224-225°C.

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

Examples 3. 5 - chloro - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 305°C. 4. 6 - iodo - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 295 - 297°C. . 5 - methyl - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 296-297°C. 6. 5 - methoxy - 8 - (IH - tetrazol - 5 - ylcarbamoylJquinoline, m.p. 276 - 279°C. 7. 6 - nitro - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 307 - 309°C. 8. 2 - methyl - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 303 - 307°C. 9. 4 - methyl - 8 - (IH .- tetrazol - 5 - ylcarbamoyl)quinoline, m.p. > 290°C. . 6 - methyl - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 289°C. 6 7 9 - chloro - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 300-301¾. - chloro - 4 - methyl - 8 - (IH - tetrazol -5ylcarbamoyl)quinoline, m.p. 276-279°C. - methoxy - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline. 14. 8 - (1 - n - butyl - IH - tetrazol - 5 - ylcarbamoyl)quinoline EXAMPLE 15 To a solution of 1.7 g (10 mmole) of 8-quinoline carboxylic acid in 50 ml. of Ν,Ν-dimethylformamide is added 1.6 g. (10 mmole) of Ν,Ν'-carbonyldiimidazole, and the mixture is stirred for four hours at 100¾.

The reactive intermediate which is formed is reacted with 1.0 g. (10 mmole) 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 reactive intermediate and heating for four hours at 140-150¾. The solution is then evaporated. Water is added to the residue, the mixture is cooled, then filtered. The solid product is recrystallized from ethanol to provide 8-(2- methyl - IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 222-223¾.

EXAMPLE 16 Using the method of Example 2, but adding 50 ml. of chloroform as solvent, 7 - methyl - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline m.p. 285 - 287¾., is obtained. 67 9 6 EXAMPLE 17 To a stirred ice bath-cooled solution of 4.0 g. (0.020 mole) of 2,4-dimethyT-'8-quinoline carboxylic acid in 20 ml. of Ν,Ν-dimethylformamide is added 2.8 ml. of triethylamine. To this solution is added dropwise 2 ml. of ethyl chloroformate. The mixture is stirred for one hour, then 2 g. (0.020 mole) of 2-aminotetrazole monohydrate in 10 ml. of N,N-dimethylformainide is added. The mixture is stirred at 20°C. for about 16 hours then evaporated to provide a residue which is washed with water.

The residue is recrystallized twice from acetic acid to provide 2,4 - dimethyl - 8 - (IH - tetrazol - 5 - ylcarbamoyl)quinoline, m.p. 300-305°C.

Claims (5)

CLAIMS I. A compound of the formula N-Ν' wherein is alkyl or alkoxy of one or two carbon atoms, 5 R2 is alkyl or alkoxy of one or two carbon atoms, hydrogen, nitro or halogen, R is hydrogen or alkyl of one to four carbon atoms and n is zero, one or two, and pharmaceutically acceptable salts thereof.

1. Π 3 wherein R , R, R and n are as defined in claim 1. 5 6. A process according to claim 5 wherein the 8-carboxyquinoline reactant is activated by reaction of the carboxylic acid group thereof with N,N 1 -carbonyl diimidazol:;, thionyl chloride, N,Ν'-dicyclohexyl carbodiimide, ethyl chloroformate, n-butyl chloroformate or ])-nitrophenoxybenzyl chloride. 10 7. A process according to claim 5 for the preparation of 8 - (1H - tetrazol - 5 - ylcarbamoyl)quinoline. 8. A process according to claim 5 for the preparation of 6 - iodo - 8 - (1H - tetrazol - 5 - ylcarbamoyl)quinoline. 9. A process according to claim 5 for the preparation of 8-(2- methyl - IH - tetrazol - 5 - ylcarbamoylJquinoline. 10. A method of treating an allergyin a non-human mammal which comprises administering thereto as an anti-allergic agent a compound 5 according to ary of claims 1 to 4. 11. A method according to claim 10 wherein the method of administration is by inhalation. 12. A method according to claim 10 wherein the method of administration is oral. 10 13. A substituted tetrazole compound substantially as hereinbefore described in Example 1 or 15 herein. 14. A substituted tetrazole compound substantially as hereinbefore described in any one of Examples 2, 10 to 14, 16 and 17 herein. 15. A substituted tetrazole compound substantially as 15 hereinbefore described in any one of Examples 3 to 9 herein. 16. A process for preparing a substituted tetrazole compound, the process being substantially as hereinbefore described in Example 1 or 15 herein. 17. A process for preparing a substituted tetrazole compound, 20 the process being substantially as hereinbefore described in any one of Examples 2, 10 to 14, 16 and 17 herein. 18. A process for preparing a substituted tetrazole compound, the process being substantially as hereinbefore described in any one of Examples 3 to 9 herein. ι'ΐ 19. A pharmaceutical composition comprising a compound according to any of claims 1 to 4 and 13 and a pharmaceutically acceptable diluent. 20. A pharmaceutical composition comprising a compound according to claim 14 and a pharmaceutically acceptable diluent. 21. A pharmaceutical composition comprising a compound according to claim 15 and a pharmaceutically acceptable diluent.

2. 8 - (1H - tetrazol - 5 - ylcarbamoyl)quinoline. 10

3. 6 - iodo - 8 - (1H - tetrazol - 5 - ylcarbamoyl)quinoline.

4. 8-(2- methyl - 1H - tetrazol - 5 - ylcarbamoyl)quinoline. 5. A process for the preparation of a compound according to claim 1 which comprises activating an 8-carboxyquinoline of the formula and reacting it with an aminotetrazole of the formula N-:—N “ 3 — 4-0 /- “ 2 N- N

5. 22. A composition according to any of claims 19 to 21 including a bronchodilator.