CS219321B2 - Process for preparing N-substituted N- (heteroaryl) carboxamides - Google Patents

Abstract

A method for preparing N-substituted N-(heteroarylcarboxanides of the general formula I, Ar—N—R1 COR2 (I) in which Ar represents a five-membered heteroaryl group containing two to four nitrogen atoms as individual heteroatoms, wherein the acylimino group —NR1COR2 is attached to a carbon atom of the heteroaryl ring and is substituted by at least one group selected from the group consisting of a hydrogen atom, an alkyl, phenyl, benzyl and a halogen atom, R1 represents C1-10alkyl, C3-6alkenyl, C3-8cycloalkyl and benzyl substituted by at least one group such as a hydrogen atom and a halogen atom, and R2 represents C1-8alkyl, C2-6alkenyl, C3-10cycloalkyl, phenyl, benzyl, C1-4alkoxycarbonyl-C1-6alkyl) C2-8carboxyalkyl or C3-6acyloxyalkyl, consists in by alkylating the corresponding acyl derivative. The compounds are useful for the chemotherapy of hypersensitivity conditions and as intermediates for the preparation of other active derivatives.

Description

The invention relates to a process for the preparation of N-substituted N-(heteroaryl)carboxamides. These compounds are useful for the chemotherapy of acute hypersensitivity states and/or as intermediates for the preparation of active derivatives. Furthermore, pharmaceutical compositions containing pharmacologically active compounds are described herein.

A series of acylamino derivatives with five-membered heteroaryl systems similar to the compounds prepared by the method of the invention have been previously described, see, for example, U.S. Patent No. 3,557,137 and Helv. Chim. Acta, 48, 524 [1965]. It should be noted, however, that these previously discovered compounds either have uses quite different from those prepared by the method of the invention or have been published for academic interest only without further disclosure.

The subject of the invention is a process for the preparation of N-substituted N-(hetercuryl)pyrrolidones of the general formula I,

Ar—N—R ¹

COR ² (I) in which Ar represents a five-membered heteroaryl group containing two to four nitrogen atoms as individual heteroatoms, wherein the acylamino group —NRtCOR ² is attached to a carbon atom of the heteroaryl ring and is substituted with at least one group selected from the group consisting of a hydrogen atom, an phenyl, benzyl and a halogen atom, R ¹ represents C1-10alkyl, _C3-6alkenyl , _{C3-8cycloalkyl} and _benzyl substituted with _at least one group such as a hydrogen atom and a halogen atom, and R ² _represents C1-8alkyl, _C2-6alkenyl , _{C3-10cycloalkyl} , phenyl, benzyl, _{C1-4alkoxycarbonyl -} C1-4alkyl, _{C2-8carboxyalkyl or C3-6acyloxyalkyl ,} with the proviso that when Ar represents a 5-pyrazolyl group, the position The 1-pyrazolyl group cannot be substituted by a phenyl group if both R ¹ and R ² are methyl.

The heteroaryl nucleus is preferably substituted with one or two groups selected from the group consisting of C1-4alkyl, benzyl, phenyl and halogen. Preferred substituents ^R1 are C1-10alkyl, C1-6alkenyl, C3-8cycloalkyl-and benzyl, optionally substituted with halogen. _Preferred substituents ^R2 are C1-8alkyl, _C2-6alkenyl , _{C3-10cycloalkyl} , _{phenyl ,} benzyl, _{C1-4alkyloxycarbonyl - C1-4alkyl} , _{C2-8carboxyalkyl} and _{C3-6acyloxyalkyl} .

The term "C 1-6 alkyl" as used herein means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, n-butyl, sesquibutyl, isobutyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl or 4-methylamyl.

Similarly, the term " _C1-4 alkyl ^" as used herein means a straight or branched chain alkyl group containing 1 to 4 carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl. "C1-4 hydroxyalkyl" and " _{C3-6 acyloxyalkyl} ^" mean the above-mentioned C1-4 alkyl groups substituted with an alkoxy group or at least one halogen atom, such as methoxyethyl, ethoxyethyl, ethoxybutyl, dibromomethyl, trifluoromethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-iodobutyl or pentafluoroethyl.

The term "C _{3 -6} alkenyl ^" is used herein to refer to alicyclic hydrocarbon groups having 3 to 6 carbon atoms and containing a —C=C— group. However, it should be noted that the —C=C— group cannot be directly adjacent to the nitrogen atom of the acylamino group.

"C _3-10 cycloalkyl ^" means a saturated ring with 3 to 10 carbon atoms in _the ring, such as _{cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl or adamantyl. "C 3-10 cycloalkyl} -C _1-6 alkyl" means the above-mentioned saturated ring attached to a C _1-6 alkylene bridge.

As used herein, the term "optionally substituted phenyl" means a phenyl group which is unsubstituted or substituted with one or more groups which do not substantially alter the pharmacological activity of the compounds of formula I, such as halogen, trifluoro, methyl, methyl, methoxy or nitro.

The term "C _2-6 carboxyalkyl" as used herein means a _C 2-6 alkyl group substituted with a carboxylic acid group. Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

Five-membered heteroaryl groups containing 2 to 4 nitrogen atoms as the only heteroatoms falling within the scope of the invention are pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and tetrazolyl. Of these, pyrazolyl, 1,2,4-triazolyl and tetrazolyl groups are preferred.

Preferred compounds of the invention have the general formula II,

where R ³ represents a substituent selected from the group consisting of hydrogen, C 1-4 alkyl and optionally substituted phenyl, R ⁴ represents a substituent attached to one of the carbon atoms of the pyrazole nucleus which is selected from the group consisting of formyl, carboxyl, hydroxyl, C _1-4 hydroxyalkyl, _{C 1-4} alkyl, C _3-10 cycloalkyl, _{C 3-6 acyloxyalkyl} , optionally substituted phenyl and halogen or 'represents hydrogen.

The acylamino group is preferably attached to the pyrazole nucleus at the 3- or 5-position.

Particularly interesting pyrazoles of formula II are those in which ^R3 represents C1-4alkyl, for example methyl, ^R4 represents hydrogen, C1-4alkyl or phenyl and ^NR1COR2 is a substituent in position 5, where ^R1 represents C3-6alkyl, for example n-butyl, n-hexyl, allyl or benzyl, and ^R2 represents _C3-6alkyl , for example isopropyl and n-hexyl, allyl, benzyl or _{C3-6cycloalkyl} .

Preferred 1,2,4-triazoles according to the invention have the general formula III,

where R ⁵ represents a substituent preferably selected from the group comprising formyl, carboxyl, hydroxyl, C 1-4 hydroxyalkyl, C 1-4 alkyl, C 3-6 alkoxyalkyl, C 3-6 acyloxyalkyl, optionally substituted phenyl with halogen and R ⁶ represents a substituent on one of the nitrogen atoms selected from the group comprising hydrogen, C 1-4 alkyl and optionally substituted phenyl.

Particularly interesting triazoles of general formula III are those in which R ¹ represents C 1-4 alkyl or benzyl, optionally substituted by halogen, and R ² represents C _{1-6 alkyl, C 3-6 cycloalkyl} , phenyl or benzyl.

Preferred tetrazoles are represented by the general formula IV,

N-N

IQ>— /V--N

NftCOR

R ⁷ (IV) where R ⁷ is preferably a substituent selected from the group consisting of _{C 1-4 alkyl} and benzyl. Other tetraisoles tend to be unstable.

Particularly interesting tetrazoles of formula IV are those in which R ⁷ is C 1-6 alkyl, for example methyl, attached in position 2 of the tetrazole nucleus, R ¹ is C 3-6 alkyl, for example hexyl, and R ² is C 3-6 cycloalkyl, for example cyclopentyl or cyclohexyl, or _{C 3-6} alkyl, such as isopropyl.

The essence of the preparation of N-substituted N-(heteroaryl)carboxamides of the above-mentioned general formula I by the method according to the invention is that the a-cyl derivative of the general formula VI,

ArNHCOR ² , in which Ar and R ² have the above-mentioned meaning, is reacted with an alkylating agent of the general formula in which X ¹ represents a halogen atom or an alkyl sulfate group and R ¹ has the above-mentioned meaning.

When Ar represents a tetrazolyl nucleus, it is very advantageous to prepare acylamino derivatives of general formula I in this manner, since tetrazolylalkyl derivatives of general formula IV are difficult to prepare due to quaternization problems with nitrogen atoms in the tetrazolyl ring.

Compounds of formula VI can be alkylated by dissolving the amide in a suitable anhydrous polar solvent, such as dimethylformamide, after forming its alkali metal salt with a hydride, preferably sodium hydride, which is then treated with an alkylating agent of the above formula R ¹ X ¹ , where X ¹ represents a reactive atom, such as a halogen atom, or a reactive group, such as an alkyl sulfate group.

Of course, other alkylating agents and other alkylation reaction conditions than those listed above may be used, the nature of which will be readily apparent to those skilled in the art.

Alkylation of compounds of general formula I, where Ar represents triazolyl or tetrazolyl and where the nitrogen atom in the ring is unsubstituted, can lead to the formation of mixtures of alkylated products, which under certain circumstances may be difficult to separate.

Derivatives of general Formula VI can be obtained by treating the corresponding amines of general formula ArNH2 by standard alkylation procedures.

Amines of the general formula ArNH2 are either known compounds [see, for example, J. Amer. Chem. Soc. 78, 923 (1954); Ang. Chem. Int. 13, 206 (1974); Z. Chem. 10, 386 (1970); Chemical Reviews 61, 87 (1961) and Chemische Berlchte 87, 396 (1964)], or they can be prepared by adaptation of known synthetic methods. In the case of pyrazole amines prepared by the reaction of 2-chloroacrylonitrile with monosubstituted hydrazines, it should be noted that the reaction can produce 3- or 5-aminopyrazoles. The data of G. Ege in Synthesis (1976), 52 indicate that the more likely reaction product is 3-aminopyrazole, and this assumption has therefore been followed in the present invention. However, the structure found is not clear, and if further research confirms that 5-aminopyrazole was indeed produced, it should be understood that the products obtained in the above reaction are similarly substituted at the 5-position.

Intermediates of general formula VI, except for those intermediates where Ar represents

1,2,4-tetrazolyl group and R ² represents methyl or phenyl, and except in cases where Ar (VI) represents pyrazolyl substituted with a pyridyl group, are novel. The invention also relates to these novel intermediates.

The compounds of general formula are useful in the prophylactic and therapeutic treatment of acute hypertensive diseases including asthma, and in the alleviation of asthmatic conditions. The compounds have low toxicity.

The compounds or mixtures of the present invention may be administered by various routes ^and may be formulated into various forms for this purpose. The compounds or mixtures can be administered orally or rectally, topically, parenterally, for example by injection and by continuous or continuous intra-arterial injection, for example in the form of tablets, troches, sublingual tablets, sachets, starch wafers with a special closure, elixirs, suspensions, sprays and ointments, for example containing 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in a physiologically suitable medium and sterile packaged powders adsorbed on a carrier for the preparation of injection solutions. Advantageously, for these purposes, mixtures can be prepared in unit dose form, each unit dose preferably containing 5 to 500 mg (5.0 to 50 mg in the case of parenteral administration; 5.0 to 50 mg in the case of inhalation and 25 to 500 mg in the case of inhalation and 25 to 500 mg in the case of inhalation). mg in the case of oral or rectal administration) of the compound of general formula L A dose of 0.5 to 300 mg/kg, preferably 0.5 to 20 mg/kg of active ingredient, may be administered per day, although it is of course to be understood that the amount of compound or compounds of general formula I will be determined by the physician having regard to all relevant circumstances including the conditions of treatment, the choice of compound to be administered and the choice of route of administration, and therefore the above preferred doses are not intended to limit the scope of the present invention in any way.

As used herein, the term "unit dosage form" means physically discrete units containing individual quantities of the active ingredient, usually in admixture with a pharmaceutical diluent or otherwise in association with a pharmaceutical carrier. The amount of active ingredient is such that one or more units are normally required for a single therapeutic administration, or such that in the case of divided units such as scored tablets, at least a portion, such as one-half or one-quarter of the divided unit, is required for a single therapeutic administration.

The dosage forms of the present invention normally consist of at least one compound of the general formula I, mixed or diluted with a carrier or enclosed or coated with the carrier used. They take the form of capsules, sachets, starch wafers with a special closure, paper or other wrappers or ready-to-use packages such as ampoules. The carriers or diluents may be solid, semi-solid or liquid substances which serve as additives, inert substances or media for the therapeutically active substance.

Some examples of diluents and carriers that can be used in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, p-olypropylene glycol, liquid paraffin, white soft paraffin, kaolin, silica, microcrystalline cellulose, calcium silicate, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, acacia, calcium phosphate, cocoa butter, ethoxylated esters, peanut oil, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoromethane. In the case of tablets, glidants may be included to prevent the powdery ingredients from sticking and binding in the dies and on the punch of the tabletting machine. For example, aluminum, magnesium or calcium stearate, talc or mineral oil may be used for this purpose.

The following examples further illustrate the invention.

Example 1 a] 1-Methyl-3-aminopyrazole

175 g (2 moles) of 2-chloroactylonitrile are slowly added to a solution of 92 g (2 moles) of methyl hydrazide and 280 g (2 moles) of potassium carbonate in 1000 ml of water cooled to 0°C under nitrogen. The solution is left at 0-5°C for 1.5 hours and then heated to 40-50°C for 2 hours. Continuous extraction of the reaction mixture with ethyl acetate and evaporation of the extract to dryness gives 145 g of 1-methyl-3-aminopyrazole, at 62-66 ^° C/666.6 Pa, as a pale yellow oil.

Analysis for· C4H7N3:

calculated:

49.5% C, 7.3% H, 43.3% N, found:

49.3% C, 7.5% H, 43.5% N.

b) N-(1-Imethylpyrazol-3-yl)-2-methylpropanamide

23.8 g (0.15 mol) of isobutyric anhydride and 11.7 g (0.12 mol) of 3-amino-1-methylpyrazole are heated together at 78°C in benzene for 2 hours. The solvent and excess reactant are removed in vacuo. The residue is distilled at 124-128°C/6.66 Pa. 14.4 g of the distillate solidifies on standing. The sample, after separation from ether and benzene with a boiling point of 40-60°C, is in the form of needles having a melting point of 82-83°C.

c) N-Benzyl-N-(1-methylpyrazol-3-yl)-2-methylpropanamide g (0.018 mol) of pyrazole in 20 ml of dry dimethylformamide is maintained at 0°C during the addition of 1 g (0.021 mol) of 50% sodium hydride. After a further 1 hour at 0°C, 3.5 g (0.0205 mol) of benzyl bromide are added and the mixture is allowed to cool to room temperature over 2 hours. Water is then added and the oil which has separated is isolated in ether. The extract is evaporated to dryness to give a solid which, on recrystallization from ether and petrol, boiling at 40-60 ^° C, gives 2.9 g of white needles, melting at 81-82°C.

Analysis for CisHiaNsO:

calculated:

70.1% C, 7.45% H, 16.35% N, found:

70.0% C, 7.45% H, 16.6% N.

Examples 2 to 35

The following pyrazoles were prepared using a similar procedure as described in Example 1. All boiling points are relative to the air bath temperature.

N-butyl-N-(1-methylpyrazol-3-yl)acetamide,

b.p. 170 °C/13.33 Pa,

N-butyl-N-(1-methylpyrazol-3-yl)-2-methylpropanamide, m.p. 43 to 47 °€,

N-butyl-N-(1-methylpyrazol-3-yl)cyclohexanecarboxamide, m.p. 82 to 84 °C,

1- ethoxycarbonyl-N-methylpyrazol-3-yl heptanamide, m.p. 83 to 84 °C,

N-thoenzyl-N-'(1-methylpyrazol-3-yl)benzamide, m.p. 129 to 130 °C,

N-decyl-N-(1-methylpyrazol-3-yl)'benzamide, m.p. 65 to 67 °C,

N-butyl-N-(1-methylpyrazol-3-yl)benzamide, m.p. 63 to 65 °C,

N-methyl-N-(1-methyl'pythazol-3-yl)-2-methylpropanamide, m.p. 40 to 42°C, N-butyl-N-(1-methylpyrazol-3-yl)cyclobutylcarboxamide, m.p. 69 to 71°C, N-hexyl-N-(1-methylpyr a,zol-3-yl)acetamide,

b.p. 165 to 170 °C at 13.33 Pa,

N-imethyl-N-(1-methylpyrazol-3-yl)adamantanecarboxamide, m.p. 112 to 114 °C, N-butyl-N-(1-methylpyrazol-3-yl)crotonamide, m.p. 35 to 38 °C,

N-benzyl-N ^J (1-methylpyrazol-3-yl)-2'-methylpropanamide, mp 81 to 82 °C,

2-acet'Oxy-N-(1-methylpyraZ'Ol-3-yl)propanamide, b.p. 170 °C/66.66 Pa,

N-methyl-N-(1-methylpyrazol-3-yl)cyclohexanecarboxamide, 1.p. 66 to 69 ^C C,

1-k'carboxy-N-(1-methylpyraizol-3-yl)heptanamide, m.p. 132–136 °C,

N-(o-chlorobenizyl)-N-(1-methylpyrazol-3-yl)benzamide, m.p. 148 to 149 °C, N-methyl-N-(1-methylpyrazol-3-yl)heptanamide, m.p. 23 to 25 °C,

N-methyl-N-(1-methylpyrazol-3-yl)phenylacetamide, mp 49 to 51 ^° C,

N-hexyl-N-(1-methylpyrazol-3-yl)heptanamide, mp 160 °C/26.66 Pa,

N-hexyl-N-(1-methylpyrazol-3-yl)phenylacetamide, m.p. 190 °C/66.66 Pa, 2-acetoxy-N-butyl-N-(1-methylpyraeol-3-yl)propanamide, 1.1.50 to 52 °C, 1-carboxy-N-(1-methylpyrazol-3-yl)propanamide, m.p. 168 to 170 °C,

N-(1-methylpyrazol-3-yl)-N-(2-propenyl)cyclohexanecarboxamide, 1.1. 82 to 83 °C,

N-(1-hexyl)-N-(1-methylpyrazol-3-yl)-2-dimethylpropanamide, 1.1. 34 to 35 °C, N-(4-bromophenyl)methyl-N-(1-methylcyclopentanecarboxamide, mp 88 °C, pyrazinol-3-yl)acetamide, mp 59–60 °C,

N-phenylmethyl-N-(1-phenylpyrazol-3-yl)cyclohexanecarboxamide, m.p. 109 to 110 °C,

N-(1-butylpyrazol-3-yl)-N-(hexyl)cyclopropanecarboxamide, b.p. 150 °C/17.33 Pa,

N-(1-butyl)-N-(1-methylpyrazol-3-yl)cyclopentanylcarboxamide, m.p. of one part is 62 to 64 °C and of the other part 68 to 69 °C,

N-(1-butylpyrazol-3-yl)-N-(methyl Jcyclopropanecarboxamide, b.p. 130 °C/20 Pa,

N-(1-methylpyrazol-3-yl)-N-(phenylmethyl)N-methyl-N-(1-phenylpyrazol-3-yl)acetamide,

mp 67 to 67.5 °C,

N-(1-hexyl)-N-(1-enylpyrazol-3-yl)cyclohexanecarboxamide, mp 57-58°C,

N-(2-methylprop-1-yl)-N-(1-methylpyrazol-3-yl)heptanamide, m.p. 123-126°C.

Example 3Θ

N-phenylmethyl-N-(1,3,5-trimethylpyrazol-3-yl)heptanamide

4.17 g of 1,3,5-trimethyl-4-pyrazolamine in ml of pyridine was treated with 8.9 g of heptanoic acid and stirred overnight at room temperature. Water was then added and the resulting solid was separated and recrystallized from chloroform and hexane. The yield was 6.4 g and m.p. 78-79°C.

2.37 g of 1,3,5-trimethylpyrazol-4-ylheptanamide are dissolved in 40 ml of dry dimethylformamide at 0 °C and 0.58 g of sodium hydride in the form of a 50% dispersion are slowly added. After 1 hour at 0 °C, 11.88 g of beosyl bromide are added. After a further 4 hours, water is added and the product is isolated into ethyl acetate. Evaporation of the extract gives an oil with a b.p. of 170 °C (Air bath)/20 Pa.

Analysis for C20H29N3O:

Calculated:

13.35% C, 8.9% H, 12.8% N, found:

1.3.55% C, 9.1% H, 12.7% N. Example 37

N-(n-butyl)-N-(1,3,5-trimethylpyrazol-4-yl)cyclohexanecarboxamide

4.17 g of 4-amino-1,3,5-trimethylpyrazole are reacted with 5.37 g of cyclohexanecarboxylic acid chloride in 40 ml of dry pyridine for 2.5 hours at room temperature. After addition of water, 4.7 g of N-(1,3,5-trimethylpyrazol-4-yl)cyclohexanecarboxamide with a melting point of 182 ^° C. precipitate.

2.5 g of the amide is suspended in 50 ml of dimethylformamide and 0.61 g of a 50% dispersion of sodium hydride is slowly added. After 1 hour, the mixture is cooled with ice and 2.13 g of butyl iodide is added. After 3 hours, water is added and the product is isolated in ethyl acetate as an oil with a b.p. of 135 °C (air bath)/ /6.66 Pa in an amount of 2.7 g.

Analysis for C17H29N3O:

calculated:

70.1% C, 10.0% H, 14.4% N, found:

70.3% C, 9.8% H, 14.4% N. Example 38

N-(2-chlorophenyl)methyl-N-(1,3,5-trimethylpyrazol-4-yl)cyclohexanecarboxamide, m.p. 121-122°C, was prepared as in Example 36.

Example 39

I. ! ,

N-(4-Chlorophenyl)methyl-N-(1,3,5-trimethylpyrazol-4-yl)heptanamide, m.p. 187-191°C (air bath)/20 Pa, was prepared similarly.

Example 40 icST ⁵

5-amino-1-methyl-3-phenylpyrazole, m.p. 128-129°C, is prepared according to Gažz, Chim. Ital. 98, 569 (1968).

Example 41

N-(1-hexyl)-N-1-methyl-3-phenylpyrazol-5-yl)cyclopentanecarboxamide

3.75 g of 5-amino-1-methyl-3-phenylpyraazole in dry pyridine was treated with 3.14 g of cyclopentanecarboxylic acid chloride and kept at room temperature for 2 hours. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate. The washed and dried solution was then evaporated to give 4.8 g of a solid, m.p. 160°C.

2.0 g of the amine is then alkylated with hexyl iodide as described above in Example 37.

The product is isolated as a solid with a melting point of ^2.7 to 37 ^° C.

Example 42

N-Methyl-N-(1-methyl-3-phenylpyrazol-5-yl)cyclopentanecarboxamide, melting point 65-69°C, is prepared as described in Example 41.

Example 43

N-n-butyl-N-(2-methyltetrazol-5-yl)-2-methylpropanamide

3.3 g (0.033 mol) of 2-methyl-5-aminotetrazole were heated to reflux in 40 ml of benzene with 3.7 g of isobutyryl chloride for 1 hour. After cooling and stirring at 0 to 10 °C overnight, the resulting white crystalline solid was filtered off and washed with a small amount of cold benzene. Drying gave 4.2 g of the acetylated derivative, m.p. 120 to 121 °C.

0.025 mol of the acetylated derivative is dissolved in 15 ml of dry dimethylformamide and a suspension of 1.2 g (0.025 mol) of sodium hydride (50% oil dispersion) in 10 ml of dry dimethylformamide is added dropwise, with stirring and cooling. When the evolution of gas has ceased, the resulting clear solution is mixed dropwise with 5 g (i.e. approximately 10% excess) of n-butyl iodide. After 3 hours at room temperature, the mixture is poured onto 100 ml of ice water and the resulting neutral mixture is extracted three times with 30 ml of diethyl ether. The ether extract is dried to constant weight at 40°C/26.66 Pa. 4.8 g of the desired compound is obtained as a colorless liquid.

Analysis for C10H19N5O:

calculated:

53.3% -C, 8.50% H, 31.0% N, found:

53.2% C, 8.26% H, 30.8% N. Example 44

N-benizyl-N-^-methyltetrazol-S-yl)-2-methylpropanamide

The procedure of Example 43 is repeated, but benzyl bromide is used instead of n-butyl iodide. The product, after drying to constant weight at 70 °C/66.66 Pa, is obtained in the form of a light yellow oil, which on standing for a longer period completely changes to a crystalline form with a melting point of 65 °C.

Analysis for C31H17N5O:

calculated:

60.2% C, 6.61% H, 27.0% N.

η λ l.ťV7i3 η η *

60.0% C, 6.41% H, 26.7% N, Example 45

N-hexyl-N-(2-methyltetrazol-5-yl)-2-methyl'propanamide

The procedure of Example 43 is repeated, but 1-iodohexane is used. The product is finally distilled in a condenser to give a pale yellow oil with a boiling point of 120°C at 13.33 Pa.

Analysis for C12H23N5O:

calculated:

56.9% C, 9.15% H, 27.6% N, found:

56.8% C, 9.39% H, 27.8% N. Example 46

N-n-butyl-N-(2-methyltetraizol-5-yl)cyclopentane carihoxamide

9.9 g (0.1 mol) of 2-methyl-5-aminotetrazole are dissolved in 100 ml of warm* benzene and 13.2 g (0.1 mol) of cyclopentanecarboxylic acid chloride are added dropwise to the solution. After one hour of gentle refluxing, the reaction is terminated and the product is worked up as in Example 43. 17.9 g of the acylated derivative with a melting point of 150 ^° C. is obtained, which is then alkylated as in Example 43 to the desired compound, which is, after drying to constant weight, in the form of a light yellow liquid.

Analysis for C12H21N5O:

read out:

57.3% C, 8.42% H, 27.8% N, found:

57.6% C, 8.65% H, 27.6% N. Example 47

N-Benzyl-N-(2-methyltetrazol-5-yl)cyclopentanecarboxamide

The procedure of Example 46 is repeated, but benzyl bromide is used in the final step and the reaction is carried out for 6 hours. The desired compound, obtained initially as a light yellow oil, crystallizes suddenly. After recrystallization from ethyl acetate and petroleum ether, b.p. 40-60 °C in a ratio of 1:3 (v/v), it has a m.p. of 54 °C.

Analysis for C15H19N5O:

calculated:

63.1% C, 6.71% H, 24.6% N, found;

63.1% C, 6.59% H, 24.7% N. Example 48

N-hexyl-N-(2-methyltetrazol-5-yl)cyclopentanecarboxamide

The procedure of Example 46 is repeated, but 1-iodohexane is used and the reaction is carried out for 24 hours. The final product is obtained as a light yellow liquid which is dried to constant weight at 25 ^° C/13.33 Pa.

Analysis for C14H25N5O;

calculated:

60.2% C, 9.02% H, 25.1% N, found:

60.4% C, 9.33 θ/ο H, 24.8% N. Example 49

N-benzyl-N-(2- ^{benzyltetrazol} -5-yl)-2-methylpropanamide

8.75 g (0.05 mol) of 2-benzyl-5-aminotetrazole are refluxed in 100 ml of benzene with 5.5 g of isobutyryl chloride for 2 hours. Working up as in Example 43 gives 9.3 g of the acetylated derivative, m.p. 151-152°C.

The thus acetylated derivative is reacted and worked up as in Example 44 to give the desired compound, which is initially in the form of a pale yellow oil which slowly crystallizes. After recrystallization from ethyl acetate and petroleum ether of * b.p. 40-60 °C in a ratio of 1:4 (v/v) it has a melting point of 68 °C.

Example 50

N-n-'butyl-N-(Z-benzyltetrazol-5-yl)-2-methylpropanamide

The procedure of Example 49 is repeated, but n-butyl iodide is used instead of benzyl torimide. The final product is dried to constant weight at 25°C/13.3 Pa.

Analysis for C16H231N5O:

calculated:

63.7% C, 7.89% H, 23.2 θ/ο N, found:

63.9% C, 8.10% H, 23.2% N.

Examples 51 to 58

The following compounds are produced in the same way:

N-methyl-N-(2-methyltetrazol-5-yl)benzamide, b.p. 135 to 140°C/13.3 Pa (ball condenser).

Analysis for C10H11N5O: calculated:

55.3% C, 5.11% H, 32.2% N, found:

55.1% C, 4.91 O/o H, 32.0% N.

N-n-toluyl-N-(2-methyltetrazol-5-yl)cyclopropanecarboxamide, b.p. 124°C/26.6 Pa. Analysis for* C10H17N5O:

calculated:

5.3.8% C, 7.68% H, 31.4% N, found:

53.7% C, 7.47 0/0 H, 31.3% N.

N-methyl-N-(2-methyltetrazol-5-yl)acetamide, m.p. 75°C/9.33 Pa. On standing, crystals with a m.p. of approximately 35°C are obtained.

Analysis for C5H9N5O:

calculated:

38.7 θ/o C, 5.85 θ/ο H, 45.1% N, found:

38.6% C, 5.76% H, 45.4 θ/ο N.

N-allyl-N-(2-methyltetrazol-5-yl)acetamide, mp 85 °C/20 Pa.

Analysis for C7H11N5O: calculated:

46.4% C, 6.12 0/0 H, 38.7 θ/ο N, found:

46.1% C, 6.20 o/ ₀ H, 38.8% N.

N - (4-bromobenzyl) -N- (2-methyltetrazol-5-yl) acetamide, b.p. 160 °C/20 Pa (spherical condenser).

Analysis for* CnHizBrNsQ: calculated:

42.6 % C, 3.90 % H, 22.6 % N, 25.8 % Br, found:

42.6 °/o C, 4.16% H, 22.5% N, 25.8% Br.

N-methyl-N-(2-methyltetrazol-5-yl)heptanamide, mp 118 °C/6.6 Pa.

Analysis for* C10H19N5O: calculated:

53.3 0/0 C, 8.50% H, 31.1% N, found:

53.8 o/o G, 8.56% H, 30.4% N.

N-allyl-N-(2-methyltetra'zol-5-yl)heptanamide, mp 126 °C/6.6 Pa.

N-allyl-N-(2-methyltetrazol-5-yl)phenylacetamide, mp 140 ^° C/13.33 Pa (ball condenser).

Analysis for C13H15N5O: calculated:

60.7 0/0 C, 5.88% H, 27.2% N, found:

60.8 0/0 C, 5.97% H, 27.0% N.

Examples 59 to 61

N-[1,4-diphenyl-1 ^: (H)-1,2,3-triazol-5-yl]

-N-propylacetamide,

N-[1,4-Diphenyl-1(H)-1,2,3-triazol-5-yl]acetamide is alkylated with 1-iodopropane in the presence of sodium hydride in dimethylformamide to give the title compound.

Similarly, the following is made:

N-[1,4-diphenyl-1(H)-1,2,3-triazol-5-yl]-N-methylcyclopropanecarboxamide and

N-[1,4-diphenyl'-1(H)-1,2,3-triazol-5-yl]-N-benzylheptanamide.

Examples 62 to 64

N-butyl-N-[2-phenyl-2(H)-1,2,3-triazol-4-yl]-2-methylpropionamide

4-Amino-2-phenyl-(H)-1,2,3-triazole is acylated with isobutyric acid and the resulting amide alkylated as in the above examples to give the title compound.

Similarly, it is produced:

N-butyl-N-[1-methyl-1(H)-1,2,3-triazol-5-yl]cyclopentanecarboxamide from the corresponding [5-amino-1-methyl-1(H)-1,2,3-triazole] and

N-butyl-N-[5-methyl-1-phenyl-1(H)-triazol-4-yl]acetamide from the corresponding amine [4-amino-5-methyl-1-phenyl-1(H)-1,2,3-triazole].

Examples 65 to 70

The amides of Examples 5, 17 and 24 are alkylated with methyl iodide or n-butyl bromide in the presence of sodium hydride, *using the procedure generally outlined in Example 1. The following alkylated products are obtained:

1-ethoxycarbonyl-N-methyl-N-(1-methylpyrazol-3-yl)heptanamide, 1-carboxy-N-methyl-N-(1-methylpyrazol-3-yl)heptanamide,

1-carboxy-N-imethyl-N-(1-methylpyrazol-3-yl)propanamide, l-ethoxycarbonyl-N-n-butyl-N-(l-methylpyrazol-3-yl)heptanamide, l-carboxy-N-n-butyl-N-(l-methylpyrazol-3-yl)heptanamide and l-carboxy-N-n-butyl-N-fl-methylpyrazol-3-yl) propanamide.

Example 71

Similarly, the amide from Example 58 was butylated with n-butyl bromide to give N-n-butyl-N-[4-butyl-3-methyl-4(H)-1,2,4-triazol]-α-methylpropanamide.

Examples 72 to 74

The following pyrazoles were prepared by methods similar to those of Example 1:

Ν-(2-butyl)-N-(1-tmethylpyrazol-3-yl)heptanamide, mp 138 to 141 °C/13.3 Pa,

N-cyclohexyl-N-(1-methylpyrazol-3-yl)pentanamide, mp 97.5 to 98°C,

N-(2-butyl)-N-(1-methylpyrazol-3-yl)cyclohexane-carboxamide, mp 98-99°C.

Examples 75 to 88

The following triaazoles were prepared by methods similar to those described in Examples 59 and 71:

N-methyl-N-[3-phenyl-1(H)-1,2,4-triazol-5-yl]heptanamide, m.p. 170 °C,

N-methyl-N-[ 3-phenyl-1 (H)-1,2,4-triazol-5-yl]cyclopropanecanboxamide, m.p. 169 °C, N-butyl-N-[3-phenyl 1-1 [H )-1,2,4-triazol-5-yl]butanamide, m.p. 113.5–114 °C, N-ethyl-a-methyl-N-[ 3-denyl-T(H)-1,2,4-It Thiazol-S-ylproipanamide, m.p. 120–121°

Celsi and

N-butyl-N-[3-phenyl-1(H)-1,2,4-triazol-5-yl]benzeneacetamide, m.p. 120 m.p. 122 ^C C,

N-benzyl-N-[3-methyl-1(H)-1,2,4-triazol-5-yl]heptanamide, colorless oil, structure confirmed by mass spectroscopy data,

N-butyl-N-[3-methyl-1(H)-1,2,4-triazol-5-yl]-2-methylpropionamide, mp 92.5 to °C,

N-butyl-N-{3-phenyl-1(H)-1,2,4-triazol-5-yl]cyclohexanecarboxamide, mp 110.5-112°C;

N-butyl-N-[3-phenyl-1(H)-1,2,4-triazol-5-yl]-2-methylpropanamide, gum, structure confirmed by NMR (M/e 286);

N-(4-Chlorobenzyl)-N-[3-methyl-1(H)-1,2,4-triazol-5-yl]acetamide, mp 124°C;

N-(4-Chlorobenzyl)-N-[3-methyl-1(H)-1,2,4-triazol-5-yl behzamide, (M/e 326/8);

N-(4-Chlorobenzyl)-N-[3-methyl-1(H)-1^-triazol-S-ylcyclohexanecarboxamide, mp 143°C;

N-Methyl-N-[3-phenyl-1(H)-1,2,4-triazol-5-yl]benzamide, m.1. 147 °C;

N-Methyl-N-[3-phenyl-1(H)-1,2,4-triazol-5-yl]acetamide, mp 196 °C.

Examples 89 to 95 below illustrate pharmaceutical compositions containing N-(n-butyl)-N-(1,3,5-trimethylpyrazol-4-yl)cyclohexanecarboxamide as the active ingredient.

Example 89

Softgels that are made from Latin are made using the following ingredients:

Quantity (mg/capsule)

The above ingredients are mixed and filled into soft gelatin capsules. The main components of the capsule are gelatin and glycerin.

Example 90

Hard gelatin capsules are made using the following ingredients:

Quantity (mg/capsule)

Active ingredient 25 Silicon dioxide 25 Lactose 50 Butylated hydroxyanisole 0.02

Butylated hydroxyanisole is dissolved in the active ingredient and the resulting solution is adsorbed onto silica. Lactose is then added and mixed. Finally, the mixture is filled into hard gelatin capsules.

Example 91

The ointment is made from the following ingredients:

Active compound 2% by weight

Butylated hydroxyanisole 0.04% by weight ¹ %

White soft paraffin up to 100%

Hydroxyanisole is dissolved in molten paraffin, then the active compound is added and the mixture is allowed to cool.

Example 92

A cream for topical use, containing 1% of the compound, is prepared as follows:

grams

Active compound 1

Cetomacrogol 1000 (polyethylene glycol monoacetyl ether of the formula CH3[CH2] _m [OCH2CH2] _n OH, in which m = 15 or 17 and n = 20 to 24).

Cetostearyl alcohol .10

Liquid paraffin 7

Butylated hydroxyanisole 0.04

Distilled water up to 100.0

The active compound is mixed with hydroxyanisole and suspended in liquid paraffin. Cetostearyl alcohol is added in half and the mixture is heated to 70°C with stirring. Cetomacrogol 1000 is then dissolved in 60 g of water heated to 70°C. The mixture of -cetostearyl alcohol, liquid paraffin and active compound is then poured into the aqueous solution of cetomacrogol 1000 with stirring, which is continued until the cream has cooled. The cream is then adjusted to the required weight in Active compound 20

Ptopolygallate 0.03

Fractionated coconut oil 70 dou and fed into a stainless steel colloid mill with 0.0381 cm holes.

Example 93

Suppositories containing 30 and 60 mg of the compound are manufactured as follows:

Active ingredient 3 g

Henkel base 17 g

The active compound is mixed with Hemkel's base, which has been previously melted using the minimum amount of heat necessary. The mixture is then poured into suppository molds of nominal capacity of 1 g, 2 g, as required. The produced suppositories always contain 30 or 60 mg of active compound.

Example 94

An aerosol spray is produced that contains the following ingredients:

Quantity (per ml)

Effective compound 10.00 mg Propylene glycol 10.00 mg Dichlorotetrafluoroethane 500.00 mg (propellant 114) Dichlorodifluoromethane 900 mg (propellant 12)

The active compound is mixed with propylene glycol and the mixture is added to the propellant 114. The resulting mixture is cooled to -15 to -20 °C and transferred to the first filling device. At the same time, the mixture of propellants 114 and 12, previously cooled to -15 to -20 °C, is filled into the second filling device. A measured amount of propellant from the second filling device is introduced into stainless steel containers and then the required amount of substance from the first filling device is added. It is then equipped with a valve element and the container is secured with a tight closure. These valve elements can be provided with a metering device, so that approximately 0.15 mg of active compound is released with one actuation of the valve.

Example 95

The tablets are made from the following* ingredients:

Effective compound 15.00 mg Microcrystalline cellulose 240.00 mg Sodium carboxy- methyl starch 20.00 mg Magnesium stearate 2.5 mg Butylated hydroxyanisole 0.002 mg

Butylated hydroxyanisole is dissolved in the active ingredient and the resulting solution is adsorbed onto microcrystalline cellulose. This resulting mixture is mixed with sodium carboxymethyl starch and then magnesium stearate is kneaded in. Finally, the mixture is compressed into tablets.

Claims (1)

Subject A process for the preparation of N-substituted N- (heteroaryl) carboxamides of formula I, Ar — N — Rl COR ² (I) in which Ar is a five-membered heteroaryl group containing heteroatoms as individual two to four nitrogen atoms, wherein the acylamino group -NR COR ² is attached to the carbon atom of the heteroaryl ring is substituted by one sufostituentem substituents selected from the group consisting of hydrogen, C ₁ _ ₄ alkyl, phenyl , benzyl and halogen, R ¹ represents a C ₁₀ alkyl, C ₃ _ ₆ alkenyl, C ₃ _ ₈ cykloalikyl berizyl and substituted by at least one substituent selected from the group consisting substlltuentů hydrogen and halogen, and the invention R ² represents a C ₈ alkyl, C ₂ -6alkenyl, C ₃ _ ₁₀ cycloalkyl, phenyl, benzyl, C ₁ '-C álkoxyJkarbonyl ₄ alkyl, C ₂ _ ₈ karboxyal'kyl or C ₃ _ ₆ acyloxyalkyl subject, that when Ar represents a 5-pyrazolyl group, the position of the 1-pyrazolyl group cannot be substituted by a phenyl group when both R ¹ and R ² are both methyl, characterized in that the acyl derivative of the general formula VI, ArNHCOR ² (VI) wherein Ar and R ² have the above meanings, is reacted with an alkylating agent of formula PX ¹ wherein X ¹ is a halogen atom or an alkyl sulfate group and R ¹ is as defined above.