United States Patent (19) (11) 4,129,735 Sellstedt et al. (45) Dec. 12, 1978

54 PROCESS FOR PREPARING 57 ABSTRACT -5-CARBOXAM DE Anti-allergic agents of N-aromatic 1H-(or 2H) tet- . DERVATIVES razole-5-carboxamide derivation present the following 75 Inventors: John H. Selstedt, Pottstown; Dieter formulae: H. Klaubert, West Chester, both of Pa. X 73 Assignee: American Home Products Corporation, New York, N.Y. G R N-N (21) Appl. No.: 726,707 O A NHC-C and (22 Filed: Sep. 24, 1976 N N-N Related U.S. Application Data R H 62) Division of Ser. No. 669,570, Mar. 23, 1976, Pat. No. X 4,013,647. 51) int. Cl? ...... CO7D 413/02; CO7D 257/04 CGN R 52 U.S. C...... S44/132; 544/58; O NEN 544/331; 544/366; 544/405; 260/306.3 R; M 260/308 D; 546/210,546/276 NHC-C 58 Field of Search ...... 260/247.2 A, 268 PH, Y-h 260/293.69, 308 D, 243 B, 256.4 N, 294.9, 295 R AM,295.5A, 302H,306.8R; 544/132, 58,332, 336,366 in which v. (56) References Cited Ris-CN or -CONH; U.S. PATENT DOCUMENTS R’ is , lower alkyl, lower alkoxy, halo, 2,507,337 5/1950 Harvillet al...... 260/308 D polyhalolower)alkyl, lower alkyl carbonyl or 3,966,965 6/1976 Sellstedt et al...... 424/309 carb(lower)alkoxy; X is FOREIGN PATENT DOCUMENTS 4521833 7/1970 Japan ...... 260/308 D R OTHER PUBLICATIONS -CH, -, -o- -N- Lee et al., "J. Org. Chem." vol. 40, No. 24 (1975) pp. where R is lower alkyl and 3491-349S. R"is hydrogen or lower alkyl; or a pharmaceutically Weygand, "Ber" vol. 101, 1968, pp. 3623-3641. acceptable salt thereof. Primary Examiner-Henry R. Jiles Assistant Examiner-R. W. Ramsuer Attorney, Agent, or Firm-Richard K. Jackson 2 Claims, No Drawings 4,129,735 1. 2 PROCESS FOR PRE PARNG DESCRIPTION OF THE INVENTION TETRAVAOLESCARBOKAM DE DERVATIVES In accordance with this invention, there is provided a This is a division of application Ser. No. 669,570, filed process for preventing the release of pharmacological Mar. 23, 1976, now U.S. Pat. No. 4,013,647. 5 mediators from an immediate hypersensitivity reaction between reaginic type antibodies and an antigen, BACKGROUND OF THE INVENTION thereby preventing the symptoms manifest in bronchial Atopic immediate sensitivity is the chief manifesta asthma, seasonal pollinosis, allergic rhinitis, urticaria, tion found in animals suffering from bronchial asthma, allergic conjunctivitis, food allergy and anaphylactoid seasonal pollinosis (e.g. hay fever), allergic rhinitis, reactions of a sensitized animal, which comprises pro urticaria, allergic conjunctivitis, food allergies and ana phylactically administering to said animal an effective phylactoid reactions. The substances most frequently amount of a compound of the formula: responsible for clinically manifest sensitivities are plant pollen, animal feathers and danders, dust, milk and wheat, whether inhaled or ingested. Atopic hypersensi 15 tivity is found in man, dog, and other animals. Its occur rence is exceptionally found in the lower animals. . N The presence of antibodies associated with atopic R hypersensitivity reactions in the host serum is estab lished by the passive sensitization of the skin of a normal recipient, after injection of serum from a sensitized host into askin site followed by injection of antigen into the R2 same area 24 hours later, resulting in a local hive. This is commonly referred to as the Prausnitz-Kustner (P-K) reaction. 25 in which The antibody associated with atopic hypersensitivity Ris-CN or -CONH2: possess distinctive features in that it does not in all forms R is hydrogen, lower alkyl, lower alkoxy, halo, precipitate with its antigen, fails to pass the placenta polyhalo(lower)alkyl, lower alkyl carbonyl or from nother to fetus, has special affinity for the skin, 30 carb(lower)alkoxy; X is frequently lacks specificity toward an individual anti genic factor and is usually labile at about 56' C. after 2 R3 hours. The homocytotropic antibody found in or induced in -CH-, -o- or -N- the rat is related in function and reaction to immuno globulin E (reagin or IgE) found in the human. The where R is lower alkyl; and correlation between honocytotropic antibody in the rat Rishydrogen or lower alkyl; or a pharmaceutically and IgE in the human has been established through the acceptable salt thereof. connanoa effects obtained from chemical reactions, im In accordance with the compound aspect of this in munological reactions and drug responses in the two 40 vention, there is provided a group of N-aromatic 1H-(or species hosting those antibodies. In the human, reagin is 2H) tetrazole-5-carboxamide derivatives of the follow the antibody responsible for atopic immediate hypersen ing structural formulae: sitive reactions. In the rate, the homocytotropic anti body is responsible for atopic immediate hypersensitive In theory, reagin, influences the cell membrane of a mast cell by reacting with an antigen, to initiate the N-N reaction(s) within the mast cell which ultimately re M leases a mediator such as Bradykinin, SRS-A (slow NC-C and reacting substance-A), histamine and other unknown 50 N substances. The mediator effects a change in surround NN ing cell wall permeability permitting a rapid change in R flow or exudance of mediator(s) from the cells, resulting X in an allergic attack sympton. The various methods 4. commonly employed to relieve the symptons of allergic attack, none of which are considered to be quite accept 55 CGN 1 R able, are to (1) avoid attack by the antigen, (2) block the O NE production of antibody with an immuno-suppresent, / (3) block the action of the mediators on the cell under NHC attack by administration of anti-histaminics, anti-5- 60 NaNH hydroxy-tryptamines(5-HT) or anti-inflammatories, or R (4) stimulate the cell under attack to negate the action of the mediator through the action of bronchodilators in which such as suprel (R) or a Xanthine. Ris-CN or CONH2: A compound typifying anti-allergic activity by block R is hydrogen, lower alkyl, lower alkoxy, halo, ing reaction(s) within the mast cells, thereby preventing polyhalo(lower)alkyl, lower alkyl carbonyl or the production and release of mediators, is disodium carb(lower)alkoxy; cronoglycate. (INTAL (R). X is 4,129,735

-CH2-, -o- or -N- where R is lower alkyl; and Ris hydrogen or lower alkyl; or a pharmaceutically where Rand R", independently represent hydro acceptable salt thereof. gen, lower alkyl, lower alkenyl, lower alkynyl, In addition, this invention provides a process for the cycloalkyl of 5 or 6 carbon atoms, aralkyl of 7 to 9 production of N-aromatic and N-heterocyclic 1H-(or 10 carbon atoms, aryl of 6 to 10 carbon atoms or, R 2H) tetrazole-5-carboxamide derivatives in general. and R', taken together with the atom to Basically, the process involves the reaction of an amine which they are attacked form a heterocyclic group ANH2, where A represents the aromatic or heterocy selected from aziridinyl, azetidinyl, pyrrolidinyl, clic moiety, with a 1-protected-1H-tetrazole-5-carbonyl piperidino, piperazinyl, 4-lower alkylpiperazinyl, chloride followed by deprotection (hydrogenolysis) 15 morpholino, this morpholino and a ring substituted and conversion to a pharmaceutically acceptable non lower alkyl analogue of said heterocyclic group. toxic salt as desired. In the preceding paragraph, the definition of Ror More specifically, the process involved in producing R" as aralkyl of 7 or 8 carbon atoms is intended to em the N-aromatic and N-heterocyclic 1H-(or 2H) tet brace the benzyl and phenethyl radicals. The cycloalkyl razole-5-carboxamide derivatives may be described as a 20 groups of 5 to 6 carbon atoms embrace cyclopenty as process which comprises: well as cyclohexyl. Where either Ror Riis hydrogen, a reacting an N-protected oxamic acid ester with undesired acylation of the amino group -NHR" is ac PCls in the presence of an acid acceptor to obtain complished conventionally by protecting that group the imidochloride with a standard protecting group such as the trimethyl 25 silyl group, which is readily removed upon completion of the reaction between the amine ANH2 and the tet razole-5-carbonyl chloride. Roc-d=NHR The chlorinating agent employed in step (d) of the process may be any conventional agent employed in the in which Ris lower alkyl and R is a protecting group; 30 production of a carboxylic acid chloride such as SOC2, b. cyclizing the imido-chloride with hydrazoic acid PCls, PCl3, oxalyl chloride, and the like. to produce the lower alkyl ester of 1-R-5-carboxy-1H The term "lower' used throughout this application to tetrazole; modify alkyl, alkoxy, alkenyl, alkynyl, and the like, is c. saponifying said ester to obtain an salt intended to embrace those univalent aliphatic hydrocar of said tetrazole; 35 bon radicals having 1 to 6 carbon atoms. The term d, converting said tetrazole salt to the 5-chlorocarbo "halo" is used to embrace , bromine, and nyl-1-R-1H-tetrazole by reaction with a chlorinating fluorine. The expression "pharmaceutically acceptable agent; salts' is intended to embrace acid addition salts, where e. reacting said 5-chlorocarbonyl-1-R-1H-tetrazole 40 applicable as well as 1H-(or 2H) tetrazole alkalimetal or with an amine of the formula ANH2; amine salts. Examples of acids with which pharmaceuti f removing the 1-R group from the product of step cally acceptable non-toxic salts may be produced in (e) to obtain the N-substituted-1H-(or 2H) tetrazole-5- clude both organic and inorganic acids such as hydro carboxamide of the formula: chloric. hydrobromic, sulfuric, phosphoric, methane 45 sulfonic, nitric, p-toluene sulfonic, acetic, citric, maleic, succinic acid, and the like. The alkali metal or amine salts of the 1H-(or 2H) include salts of so ANHCO-C dium, potassium, lower alkylamine, di(lower alkyl)a- mine, tri(lower alkyl)amine and the corresponding omega-hydroxy analogues (e.g. methylamine, ethyl amine, propylamine, dimethylamine, diethylamine, di in which propylamine, trimethylamine, triethylamine, tripropyla A is a member selected from the group consisting of mine, di(hydroxyethyl)amide, and the like) as well as 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, more complex amines which are employed in depot 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2- 55 administration, such as N,N-dibenzylethylenediamine, pyrimidinyl, 2-pyrazinyl, a-naphthyl, g-naphthyl, and the like. Furthermore, applicants intend throughout phenyl, 2,6-dichlorophenyl, and substituted phenyl this application, by either structural presentation or by moieties having from one to three substituents in compound name referring to either the 1H- or 2H-tet any of the 2,3,4 and 5 positions of the phenyl ring, razole configuration of the final products, to embrace independently selected from the group consisting both of those tautomeric forms of the unsubstituted of lower alkyl, lower alkylsulfinyl, lower alkoxy, tetrazole nucleus. hydroxy(lower)alkoxy, 2-(lower alkoxy oxalylox The protecting group -R- employed in prepara y)ethoxy, N-mono- and di-lower alkyl amino tion of the 1H-tetrazole-5-carbonyl chloride intermedi (lower)alkoxy, halo, , polyhalolower)al ate is selected for its stability during reaction of the kyl, carbamyl, N-lower alkylcarbamyl, carboxy, 65 lower alkyl oximidoyl chloride with hydrazoic acid lower alkylcarbonyl, cyano, carb(lower)alkoxy, while possessing the attribute of easy removal after phenoxy(lower)alkoxy, lower alkoxyoxalamido, formation of the carboxamide product. Examples of lower alkoxyoxalamidophenoxy and such protecting groups are benzyl, 4-methoxybenzyl, 4,129,735 5 6 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, 2,4,6- cutaneous anaphylaxis test (PCA) using rat homocyto trimethoxybenzyl, trichloroethyl, and the like. tropic antibody - a known correlate of human reaginic The preparation of the 1H-tetrazole-5-carboxylic antibody. acid lower alkyl esters is quite unique in itself and forms By analogy to disodium cromoglycate and its activity an additional aspect of this invention. Thus, applicants correlation between standard test animals, domestic have discovered, unexpectedly, that a N-protected animals and man, the compounds of this invention have lower alkyl ester of oximidoyl chloride reacts with been established as anti-allergic agents suitable for the hydrazoic acid to afford the 1H-tetrazole-5-carboxylic same uses at analogous doses and through the same acid lower alkyl esters and that the combination of the routes of administration as INTAL (E). N-protecting group with the presence of a lower alkyl 10 Thus, there is provided herewith a method for sup ester functional group in the intermediate imido chlo pressing allergic manifestations of atopic immediate ride, cooperate in such manner as to direct the attack of sensitivity in warm-blooded, human and non-human hydrazoic acid in the desired fashion without interfer animals, the latter including domesticated animals such ence by the ester function. as the mouse, rat, hamster, gerbil, dog, cat, sheep, goat, In that sense, applicants provide a process for pro 15 ducing H-tetrazole-5-carboxylic acid lower alkyl es horse, cow, and the like, by administering an effective ters which comprises reacting a N-protected oxamic amount of one or more of the compounds disclosed in acid lower alkyl ester such as N-benzyloxamic acid this application by oral, topical, parenteral, rectal, vagi ethyl ester with PCls in the presence of an acid acceptor nal or inhalation routes. The compounds of this inven to afford the corresponding imidoyl chloride intermedi 20 tion may be administered in conjunction with known ate, which reacts with hydrazoic acid to yield the de compounds effecting anti-histaminic, anti-hypertensive, sired N-protected-1H-tetrazole-5-carboxylic acid esters. analgesic, central nervous system depressant, immuno In the formation of the 1H-tetrazole-5-carboxylic suppressive, anti-serotonin, anti-Bradykinin or endocri acid ester from the imido-chloride precursor, the reac nological responses. In addition, those conventional tant hydrazoic acid may be produced in situ from, for 25 adjuvants known to the art may be combined with the example, a metal , trimethylsilylazide or ammo anti-allergics of this invention to provide compositions nium azide. It is intended, throughout this specification and solutions for administrative purposes, although it is that the expression hydrazoic acid should be interpreted considered desirable and feasible to employ the anti as encompassing the metal , trimethylsilylazide allergics as neat or pure compounds without additives and . 30 other than for purposes of providing suitable pharma The compounds of this invention relieve atopicaller ceutical solution or liquid or vapor suspensions, the gic manifestations, when administered orally and paren latter for use as inhalants. terally to sensitized rats. The oral dose range lies from below 0.1 milligram per The technique employed to establish the anti-allergic kilogram to about 50 milligrams per kilogram host body activity of the 1H-tetrazole-5-carboxamide derivatives 35 weight. As an inhalant the dose is from that of IN of this invention is reported in Immunology, vol. 16, pp. TAL(R), (about 20 milligrams) to 1/2th that quality 749–760 (1969) and involves four male Charles River administered as needed prior to attack. Thus the dosage rats (200-250 grams body weight) per group to provide contemplated for human use based upon the potency of a control, a host for administration of a standard anti the compounds administered lies from about 5 milli allergic compound (disodium cromoglycate) and ani grams to 1 gram, preferably 50 milligrams to about 750 mals for the test compound. The rats were injected milligrams in unit dosage form to be administered when intracutaneously on their shaved backs with sera from necessary and to the degree of the desired response, in rats immunized with egg albumin and pertussis vaccine. single or plural doses under the guidance of a physician. Twenty-four hours after the initial injections, the test compound is administered intraperitoneally or orally at 45 EXAMPLE I a dosage level of 200 milligrams per kilogram host body N-(2-Cyano-3-(4-morpholinyl)phenyl)-1H-tetrazole-3- weight or less. Five minutes later 1 milliliter of a 0.5 carboxamide percent solution of Evans blue dye and 8 milligrams of eggs albumin is injected intravenously. After 40 min To a solution of 20.72 g (0.1 mol) of benzyloxamic utes, the animal is sacrificed and the bleb size on its back 50 acid ethyl ester and 9.89 g (0.125 mol) of pyridine in 95 is measured. The mean bleb size for the animals adminis ml. of methylene chloride is added 26.03 g (0.125 mol) tered the test compound is calculated and the percent of PCls slowly through a Gooch tube at 30° C. or less. inhibition is determined by comparison with the control Stir 1 hour at room temperature, add 112 ml. of 1.78 animal. molar hydrazoic acid in , stir 1 hour at room Although the mechanism by which the compounds of 55 temperature, and slowly bring to reflux. After 4 hour this invention function is not absolutely known, appli of reflux, keep the reaction mixture over night at room cants have found that the compounds of this invention, temperature. The reaction mixture is poured into a cold in a manner believed to be similar to the function of NaHCO3 solution, is added and separate INTAL (R), block reaction(s) in the mast cell leading to the layers. The organic layer is washed again with a the production and release of mediators. 60 NaHCO3 solution, with NHCl, with brine and dried The compounds of this invention permit the occur with CaCl2. Evaporation of the solvent gives 22.46g, of rence of a non-productive antigen-antibody interaction. oil which is distilled in a falling film molecular still at They effectively block the IgE type reaction and have 135° C. and 0.15mm, giving 11.12g of product. The oil little or no effect on the other immunoglobulins such as is crystallized from diethyl ether-pentane to give 6.88 g. IgG, IgM, IgA and go. of 1-benzyl-1H-tetrazole-5-carboxylic acid ethyl ester, In other words, the compounds of this invention mp. 51-55 C. block the release of mediators commonly resulting from Anal. Calcd. for CH2N4O2: C, 56.89; H, 5.21; N, the antigen-antibody reaction as exemplified in a passive 24.13. Found: C, 56.58; H, 5.11; N, 24.13. 4,129,735 7 The ethyl ester (11.61 g, 0.05 mol) is dissolved in 60 cyano-3-(1-piperidinyl)phenyl)-1H-tetrazole-5-carboxa ml. of warm absolute ethyl alcohol. Addition of 3.96 g. mide, (0.06 mol) of KOH in 7 ml. of water causes crystalliza In a manner similar to Example I the benzyl group is tion of the potassium salt. The mixture is kept at room hydrogenolyzed from the above tetrazole giving the temperature over night, filtered, and the filter cake is 5 title compound. washed with cold absolute ethyl alcohol and diethyl ether, giving 11 g of 1-benzyl-l-tetrazole-5-carboxy EXAMPLE II lic acid potassium salt, N-2-Cyano-3-(4-methyl-1-piperazinyl)phenyl)-1H-tet Anal. Calcd. for C9HKNO2: C, 44.61; H, 2.91; N, razole-5-carboxamide 23.13. Found: C, 44.26; H, 2.91; N, 23.27. 10 In a manner similar to Example I, 1-benzyl-1H-tet The potassium salt (7.27 g., 0.03 mol) and 1.5 ml. of razole-5-carbonyl chloride is condensed with 2-amino pyridine are stirred at 0°C. in 135 ml. of benzene, and 25 6-(4-methyl-1-piperazinyl)benzonitrile to give 1-benzyl ml. of oxalyl chloride is rapidly added. After stirring N-2-cyano-3-(4-methyl-1-piperazinyl)phenyl)-1H-tet hour at 15° C. the mixture is stripped at 15 C., and razole-5-carboxamide. scrubbed with two portions of 130 ml. of benzene at 15 15 In a manner similar to Example I the benzyl group is C. giving a crude mixture of 1-benzyl-1H-tetrazole-5- hydrogenolyzed from the above tetrazole giving the carbonyl chloride. This preparation of the acid chloride title compound. is kept cold and used immediately for acylation. The crude acid chloride (0.03 mol.) from above is EXAMPLE IV dissolved in 130 ml. Cl2Cl2 and poured into a solution of 20 N-2-carbamoyl-3-(4-morpholinyl)phenyl)-1H-tet 2-amino-6-(4-morpholinyl)benzonitrile (6.10 g., 0.03 razole-5-carboxamide mol.) and 2.73 g of pyridine in 130 ml. of CH2Cl at 5-10 C. The solution is allowed to come to room In a manner similar to Example I, 1-benzyl-1H-tet temperature during 2 hours, and then wash twice with razole-5-carbonyl chloride is condensed with 2-amino water, with brine, and dry with CaCl2. The solution is 25 6-(4-morpholinyl)benzamide to give 1-benzyl-N-(2-car evaporated in dryness giving 10.7 g. (m.p. 176'-180° C) bamoyl-3-(4-morpholinyl)phenyl)1H-tetrazole-5-car of a white solid which is crystallized from 100 ml. of boxamide. acetonitrile, giving 7.65 g. of 1-benzyl-N-(2-cyano-3-(4- In a manner similar to Example I the benzyl group is morpholinyl)phenyl)-1H-tetrazole-5-carboxamide as hydrogenolyzed from the above tetrazole giving the white crystals, m.p. 184-187 C. 30 title compound. Anal. Calcd. for C20H19NO2: Found: C, 61.68; H, EXAMPLE V 4.92; N, 25.18. C, 61.57; H, 4.78; N, 25.11. The N-benzyl derivative above (1.95 g., 0.005 mol.) is N-2-Cyano-3-(2-methyl-4-morpholinyl)phenyl)-1H dissolved in warm acetic acid and 0.9 g of 10% Pd/C is tetrazole-5-carboxanide added. The mixture is hydrogenated at 35 lbs. over 35 In a manner similar to Example I, 1-(4-methoxyben night, and the mixture is filtered and the cake is washed zyl)-1H-tetrazole-5-carbonyl chloride is condensed with hot acetic acid. The filtrate is stripped to dryness with 2-amino-6-(2-methyl-4-morpholinyl)benzonitrile and the residue is triturated with a warm solution of 10 to give 1-(4-methoxybenzyl)-N-(2-cyano-3-(2-methyl-4- ml. concentrated ammonium hydroxide in 60 ml. of . morpholinyl)phenyl)-1H-tetrazole-5-carboxamide. water. The mixture is filtered and the filtrate is acidified 40 By a process similar to those revealed by D. L. Lee to pH2 with concentrated HC. The acidified mixture is and H. Rappaport in J. Org. Chem, 40,3491(1975) and kept in ice for 2 hours, filtered, and the white product is F. Weygand, et al., in Chem. Ber. 101,3623(1968) the dried. Crystallization of the product from acetonitrile 4-methoxybenzyl group is removed from the above gives 0.42 g of N-(2-cyano-3-(4-morpholinyl)phenyl)- tetrazole. 1-tetrazole-5-carboxamide, m.p. 253'-256' C. (dec.). 45 The corresponding thio morpholino analogue is pre Anal. Calcd. for C3H3NO2: C, 52.17; H, 4.38; N, pared by the method of Example V employing the 4 32.76 Found: C, 52.04; H, 4.34; N, 32.76. methoxybenzyl protecting group to ultimately obtain The title compound exhibited 60 percent inhibition of N-(2-Cyano-3-(thio morpholino)phenyl)-1H-tetrazole the mean bleb size when administered orally at 0.1 milli 5-carboxamide. grams per kilogram and 97% inhibition when adminis- 50 The amine reactants ANH2 are generally known tered orally at 50 milligrams/kilogram host body compounds or they may be readily produced by known. weight in accordance with the rat PCA test described, methods. Typical examples of the production of various supra. applicable amines may be found in copending U.S. ap plications Ser. No. 620,626, filed Oct. 3, 1975, now EXAMPLE I 55 abandoned and Ser. No. 542,465, filed Jan. 20, 1975, N-2-Cyano-3-(1-piperidinyl)phenyl)-1H-tetrazole-5- now U.S. Pat. No. 3,966,965 disclosures of said applica carboxanide tions being incorporated herein for the purpose of illus trating the various intermediates involved. In a manner similar to Example I, 1-benzyl-1H-tet The amines-ANH-listed below readily enter into razole-5-carbonyl chloride is condensed with 2-amino reaction with an N-protected -1H-tetrazole-5-carbo 6-(1-piperidinyl)benzonitric give 1-benzyl-N-(2- nyl chloride to yield the final products listed below:

ANH2 Final Product 2-aminothiazole N-(2-thiazolyl)-1H-tetrazole-5- carboxanide 2-aminopyridine N-(2-Pyridyl-1H-tetrazole-5- carboxamide 2-aminonicotinonitrile N-3-cyano-2-pyridyl-1H-tetrazole

4,129,735 * 11 12 -continued ANH2 Final Product carboxamide 4-dimethylaminoaniline N-(4-dimethylaminophenyl)-1H tetrazole-5-carboxamide 2-amino-6-dimethylamino- N-(2-carbamoyl-3-dimethylamino benzamide phenyl)-1H-tetrazole-5-carboxanide

What is claimed is: 10 R8 1. A process for the production of a 1H-tetrazole-5- / carboxamide which comprises -N a reacting an N-protected oxamic acid lower alkyl R7 ester with PCls in the presence of an acid acceptor to obtain the imidochloride 15 where Rand R", independently represent hydro gen, lower alkyl, lower alkenyl, lower alkynyl, C1 cycloalkyl of 5 or 6 carbon atoms, aralkyl of 7 to 9 Roc -NR' carbon atoms, aryl of 6 to 10 carbon atoms or, R 2 and R", taken together with the nitrogen atom to in which R is lower alkyl and R is a member 20 gif ESSEE selected from the group consisting of benzyl, 4- piperidino, piperazinyl, 4-lower ifiyiperatiny, methoxybenzyl, 2,4-dimethoxybenzyl, 2,6-dime- morpholino thiomorpholino and a ring substituted thoxybenzyl, 2,4,6-trimethoxybenzyl and trichloro- lower alkyl analogue of said heterocyclic group. ethyl; 25 2. The process of claim 1 in which said 1H-tetrazole b. cyclizing said imido-chloride with hydrazoic acid to produce the ester 1-R-5-carbo(lower)alkoxy 5-carboxanide is of the formula 1H-tetrazole; c. saponifying said ester to obtain an alkali metal salt of said tetrazole; 30 d. converting said tetrazole salt to the 5-chlorocarbo C N 3' nyl-1-R-1H-tetrazole by reaction with a chlorinat R1 ing agent; O N-N e. reacting said 5-chlorocarbonyl-1-R-1H-tetrazole M NHC-C with an aromatic amine of the formula ANH2; 35 2 N f removing the 1-R group from the product of step R NN (e); wherein H A is a member selected from the group consisting of 2-thiazolyl, 2-pyridyl, 6-(lower)alkyl-2-pyridyl, in which 3-cyano-2-pyridyl, 3-pyridyl, 4-pyridyl, 2 Ris-CN or -CONH2; pyrimidinyl, 2-pyrazinyl, a-naphthyl, f-naphthyl, 40 R’ is hydrogen, lower alkyl, lower alkoxy, halo, phenyl, 2,6-dichlorophenyl, and substituted phenyl polyhalolower)alkyl, lower alkylcarbonyl or moieties having from one to three substituents in carb(lower) alkoxy; any of the 2,3,4 and 5 positions of the phenyl ring, X is independently selected from the group consisting of lower alkyl, lower alkylsulfinyl, lower alkoxy, 45 hydroxy(lower)alkoxy, 2-(lower alkoxy oxalylox R3 y)ethoxy, N-mono- and di-lower alkyl amino -CH2-, -o- or -- (lower)alkoxy, halo, sulfamyl, polyhaloclower)al kyl, carbamyl, N-lower alkylcarbamyl, carboxy, where R is lower alkyl; and lower alkylcarbonyl, cyano, carb(lower)alkoxy, 50 R'is hydrogen or lower alkyl; or a pharmaceutically phenoxy(lower)alkoxy, lower alkoxyoxalamido, acceptable salt thereof. lower alkoxyoxalamidophenoxy and

55