CS219321B2 - Method of making the n-substituted n-/heteroaryl/carboxamide - Google Patents

Abstract

Process for the preparation of N-substituted N- (heterophenylcarboxainines) formula I, Ar — N — R1 COR2 (AND) wherein Ar is a five membered heteroaryl group containing as individual heteroatoms two to four nitrogen atoms, wherein the acyluimino group — NR1COR2 is attached to a carbon atom by a heteroaryl ring and is substituted by at least one group selected from the group they make up a hydrogen atom, an envelope, a phenyl, a benzyl and an atom halogen, R 1 is C 1-10 alkyl, C 3-6 alkenyl, C3-8cycloalkyl and benisyl substituted at least one group such as a hydrogen atom and a halogen atom, and R 2 represents C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, phenyl, benzyl, C 1-4 alkoxycarbonyl-C 1-6 alkyl) C 2-8 carboxyalkyl or C3-6acyloxyalkyl, is based on that the corresponding acyl derivative is alkylated. The compounds are useful for chemotherapy hypersensitivity states and as intermediates for the production of other effective derivatives.

Description

The present invention relates to a process for the preparation of N-substituted N- (heteroaryl) carboxamides which are useful for the chemotherapy of sudden hypersensitivity states and / or as intermediates for the production of active derivatives.

A number of acylamino derivatives with five-membered heteroaryl systems, similar to the compounds of the present invention, have already been described, see, for example, U.S. Patent 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 the compounds prepared by the process of the invention, or have been published for academic interest only, without mentioning any details thereof.

The present invention provides a process for the preparation of N- substituted N- (hetercuryl) fearboixamides of formula I,

Ar — N — R ¹

COR ² (I) wherein Ar is a five-membered heteroaryl group containing two to four nitrogen atoms as individual heteroatoms, wherein the acylaimino group -NRtCOR ² is attached to the carbon atom of the heteroaryl ring and is substituted with at least one group selected from hydrogen; !, phenyl, benzyl, and halo, R ¹ represents C1_10alikyl, C3_óalkenyl, C 3-8 cycloalkyl, and benzyl substituted with at least one group as -is hydrogen and halogen, and R ² represents Ci_8alkyl, € ₂ - _alkenyl, C _{3 '10} cycloalkyl , phenyl, benzyl, C ₄ alkoxycarbonyl »alkylsulfonyl-C ₁ _ ₄ alkyl, C _2-8 carboxyalkyl NETM C ₃ _ ₆ acyloxyalkyl, with the proviso that represents when Air 5-pyrazolyl, 1-position of the pyrazolyl group can be substituted phenyl, iznačí when both R ¹ and R ² methyl.

The heteroaryl core is preferably substituted with one or two groups selected from the group consisting of C 1-4 alkyl, benzyl, phenyl and halogen. Preferred R ¹ substituents are C 1-10 alkyl, C 6-6 alkenyl, C 3-8 cycloalkyl-and benzyl, optionally substituted with haloogen. Preferred substituents R ² are Ci_8alkyl, _C2 -óallkenyl, C ₃ _ ₁₀ cycloalkyl, phenyl, benzyl, C ₄ -C alkioxyka.rbonyl ₁ _ ₄ alkyl, C ₂ _ ₈ carboxyalkyl, and C ₃ _ ₆ acyloxyalikyl.

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

Similarly, the term C ₄ alkyl ,, ^It, as used herein, means an alkyl group with straight or branched chain, containing one to four carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-hutyl, isobutyl, sec , t-butyl. "Cx ^ hydroxyulkyl" and C ,, _{3 "O} acyloxyalkyr ^t denote the above-mentioned C ^ alkyl group substituted with an alkoxy group .or at least one halogen atom, such as methoxyethyl, ethoxyethyl, ethoxybutyl, dibromomethyl, trifluormothyl, 1-chloroethyl, 1,1 -dichloroethyl, 1-iodo-butyl or pentafluoroethyl.

The term "C ₃ _ _o ^t -alkenyl is used herein to indicate alicyclic hydrocarbon groups having 3 to 6 carbon atoms and containing a -C = C-. 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 ring carbon atoms like cyclopropyl, cyklolbutyl, cyclopentyl, cyclooctyl, or adamantyl. "C ₃ _i ₀ cycloalkyl-C ₆ alkyl" means the above-mentioned saturated ring _O attached to C alkylene bridge.

As used herein, the term "optionally substituted phenyl" means a phenyl group which is unsubstituted or substituted by one or more groups which do not substantially alter the pharmacological action 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 ^ alkyl group of a substituted carboxylic acid group. Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

Five-membered heteroaryl groups containing from 2 to 4 nitrogen atoms as the only heteroatoms 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,

wherein R ³ represents a substituent selected from hydrogen, C 1-4 alkyl and optionally substituted phenyl, R ⁴ represents a substituent attached to one of the carbons of the pyrazole nucleus which is selected from the group consisting of formyl, carboxyl, hydroxyl, Ci_4hydroxyalkyl C _{1 '-C 4} alkyl, C ₃ _ ₁₀ cycloalkyl, C ₃ _ ₆ 219321 acyl-oxyalkyl, optionally substituted phenyl or halolgen 'represents hydrogen.

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

Particularly interesting pyrazoles of formula II are those in which R @ ³ denotes C1-4 alkyl, for example methyl, R ^{@ 4} denoted hydrogen, C1-4 alkyl or phenyl and NR @ 4 COR @ ² is a substituent at the 5 position where R @ ^{1 is} C3-4 alkyl, e.g. burtyl, n-hexyl, allyl or benzyl, and R ² represents C3 _'6 alkyl, for example isopropyl, and n-hexyl, allyl, benzyl or C ₃ _ ^ cycloalkyl.

Preferred 1,2,4-triazoles of the invention have the formula III,

wherein R ⁵ is a substituent preferably selected from the group consisting of formyl, carboxyl, hydroxyl, C 1-4 hydroxyalkyl, C 1-4 alkyl, C 3-8 cycloalkyl, C 3-6 acyloxyalkyl, optionally substituted phenyl with halogen, and R ⁶ is a substituent on one of the nitrogen atoms selected from hydrogen, C 1-4 alkyl and optionally substituted phenyl.

Particularly interesting triazoles of formula III 'are the lips, in which R ¹ iznačí Ci_4alkyl or benzyl optionally substituted by halogen, and R ² represents Ci_óalkyl, C ₃ _ ₆ cycloalkyl, phenyl or benzyl.

Preferred tetrazoles are represented by formula IV,

N-N

IQ> - / V - N

NftCOR

R ⁷ (IV) wherein R ⁷ is preferably a substituent selected can be any of C ₁ _ ₄ alkyl, and benzyl. Other tetraisols tend to be unstable.

Particularly interesting tetrazoles of formula IV are those in which R ⁷ is C 1-6 alkyl, for example methyl bonded in the 2-position of the tetraisole ring, R ¹ is C 3-6 alkyl, for example hexyl, and R ² is C 3-6 cycloalkyl, for example cyclopentyl or cyiclohexyl; C ₃ _ ₆ alkyl-θ as' isopropyl.

The essence of the preparation of the N-substituted N- (heteroaryl) carhoxaimides of the aforementioned general formula (I) by the method according to the invention is that the α-cylderivir of the general formula (VI)

ArNHCOR ² , wherein Ar and R ² are as defined above, reacts with an alkylating agent of the formula wherein X ¹ is a halogen atom or an alkyl sulphate group and R ¹ is as defined above.

When Ar is a tetrazolyl nucleus, it is very advantageous to produce the acylaminode derivatives of general formula (I) in this manner because the tetrazolylalkyl derivatives of formula (IV) are difficult to produce due to the quaternization problems with the nitrogen atoms in the tetrazolyl ring.

Compounds of formula (VI) may be alkylated by dissolving the amide in a suitable nonaqueous polar solvent such as dimethylformamide to form its alkali salt with a hydride, preferably sodium hydride, which is then treated with an alkylating agent of the above formula R ¹ X ¹ , wherein X ¹ is a reactive atom, such as a halogen atom, or a reactive group, such as an alkyl sulfate group.

Of course, other alkylating agents and reaction conditions for alkylation other than those mentioned above may also be used. Their nature is readily apparent to the garment experts.

Alkylation of compounds of formula I wherein Ar is trialzolyl or tetrazolyl and wherein the ring nitrogen atom is unsubstituted may result in mixtures of alkylated products, which in some circumstances may be difficult to separate.

The derivatives of the formula VI can be obtained by treating the corresponding amines of the formula ArNH 2 with a standard alkylane process.

The amines of the formula ArNH 2 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 may be prepared by adapting known synthesis methods. In the case of pyrazole amines produced by the reaction of 2-chloroacrylonitrile with monosubstituted hydrazines, it should be appreciated that the reaction can produce 3- or 5-aminopyraisols. G. Ege's data in Synthesis (1976), 52 suggest that the more likely reaction product is 3-aminopyrazole and this suggestion has therefore been pursued in the present invention. However, the structure found is unclear, and if further research would confirm that 5-aminopyraisole was indeed produced, it should be understood that the products obtained in the above reaction are similarly substituted at the 5-position.

Intermediates of formula VI, except for those where Ar is

1,2,4-tetrazolyl group and R ² denotes methyl or phenyl, and except where Ar (VI) represents pyrazolyl substitutes Nu-pyridyl group are new. The invention also relates to these novel intermediates.

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

The compounds or mixtures of the invention may be administered by various routes, ^and may be formulated for this purpose. The compounds or mixtures may be administered by the oral or rectal route, topically, parenterally, for example by injection and continuous intra-arterial muse, for example in the form of tablets, lozenges, sublingual tablets, sachets, special-capsule starch wafers, 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, injectable solutions and suspensions in a physiologically acceptable environment, and sterile packed powders adsorbed on a carrier for the preparation of injectable solutions. For this purpose, unit dose compositions may be prepared, preferably each unit dose containing 5 to 500 mg (5.0 to 50 mg for parenteral administration; 5.0 to 50 mg for inhalation and 25 to 50 mg for parenteral administration). 500 mg in the case of oral or rectal administration The dosage of 0.5 to 300 mg / kg, preferably 0.5 to 20 mg / kg of active ingredient can be administered per day, although it will be understood that the amount of the compound or compounds of formula I as determined by the physician in view of all relevant circumstances, including the conditions for treatment, the choice of compound to be administered and the route of administration, and therefore the above-mentioned preferred doses are not intended to limit the scope of the invention in any way.

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

The dosage forms of the invention normally consist of at least one compound of formula I, mixed or diluted with a carrier or sealed or coated with the carrier used. They take the form of capsules, sachets, special-purpose starch wafers, paper or other containers or emergency containers, such as ampoules. The carrier or diluent may be a solid, semi-solid or liquid substance which serves as an additive, inert substance or environment for the therapeutically active substance.

Some examples of diluents and carriers that can be used in the pharmaceutical compositions of this invention include lactose, dextrose, sucrose, sorbitol, mannitol, p-olyleneLenglycol, liquid-paraffin, white soft paraffin, kaolin, silica, microcrystalline cellulose, calcium silicate, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, peanut oil, alginates, traction, gelatin, syrup, methylcellulose, polyoxyeithylene sorbitan monolaurate, ethyl lactate, sorbitol and propyl lactate, sorbitol and propyl acetate , such as trichloronofluoromethane, dichlorodifluoromethane and dichloritetrafluoromethane. In the case of tablets, glidants may be incorporated to prevent adhesion and binding of the powdered components to the nozzles and to the punch of the tablet machine. For example, aluminum, magnesium or calcium stearate, talc or mineral oil may be used.

The following examples further illustrate the invention.

Example 1 a] 1-Methyl-3-aminopyrazole

175 g (2 moles) of 2-chloroactonitrile is slowly added to a solution of 92 g (2 moles) of methylhydrazide and 280 g (2 moles) of potassium carbonate! in 1000 ml of water cooled to 0 ° C under a nitrogen atmosphere. The solution is left at 0-5 ° C for 1.5 hours and then heated at 40-50 ° C for 2 hours. Continuously extracting the reaction mixture with ethyl acetate and evaporating the extract to dryness gave 145 g of L-methyl-3-aminopyrazole of the temperature 62 to 66 ^C C / 666.6 Pa, as a pale yellow oil.

Analysis for · C4H7N3:

calculated:

H, 7.3%; N, 43.3%. 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 µg (0.12 mol) of 3-amino-1-methylpyrazole were heated together at 78 ° C in benzene for 2 hours. The solvent and excess reagent were removed in vacuo. The residue distilled at 124 to 128 ° C / 6.66 Pa. On standing, 14.4 g of distillate solidified. The sample, after separation from ether and tartar, boiling at 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) pyrazole in 20 ml dry dimethylformamide was maintained at 0 ° C during the addition of 1 g (0.021 mol) 50% sodium hydride. After an additional 1 hour at 0 ° C, 3.5 g (0.0205 moles) of benzyl bromide was added and the mixture was allowed to cool to room temperature over 2 hours. Water was then added and the oil which separated was collected into ether. The extract was evaporated to dryness to give a solid which recrystallized from ether and gasoline boiling at 40-60 ^° C to give 2.9 g of white needles having a melting point of 81-82 ° C.

Analysis for CisHiaNsO:

calculated:

% C, 70.1;% H, 7.45;% N, 16.35.

H, 7.45; N, 16.6.

Example 2 to 35

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

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

mp 170 ° C / 13.33 Pa,

N-butyl-N- (1-methylpyrazol-3-yl) -2-methylpropanamide, m.p.

N-butyl-N- (1-methylpyrazol-3-yl) cyclohexanecarboxamide, mp 82-84 ° C,

1-ethoxycarbonyl-N-1 H -imethylpyrazol-3-yl heptanamide, m.p. 83-84 ° C;

N-toenzyl-N- (1-meithylpyrazol-3-yl) benzamide, mp 129-130 ° C,

N-decyl-N- (1-methylpyrazol-3-yl) benzamide, mp 65-67 ° C,

N-butyl-N- (1-methylpyrazol-3-yl) benisamide, mp 63-65 ° C,

N-methyl-N- (1-methylpyridol) -3-yl) -2-methylpropanamide, mp 40-42 ° C, N-butyl-N- (1-methylpyrazol-3-yl) cycloibutylcarboxamide, mp 69 to 71 ° C, N-hexyl-N- (1-methylpyrrole-3-yl) acetamide,

mp 165 áž 170 ° C at 13,33 Pa,

N-Imethyl-N- (1-methylpyrazol-3-yl) adamantanecarboxamide, mp 112-114 ° C, N-butyl-N- (1-methylpyrazol-3-yl) crotonamide, mp 35-38 ° C,

N-benzyl-N ^J (l-methylpyrazole-3-yl) -2-methylpropanamide, mp 81-82 ° C

2-Acethoxy-N- (1-methylpyrazol-3-yl) propanamide, b.p. 170 ° C / 66.66 Pa,

N-methyl-N- (1-methylpyrazol-3-yl) cyclohexanecarboxamide, mp 66-69 ^° C,

1-carboxy-N- (1-methyl-pyrimidin-3-yl) -heptane-amide, m.p. 132-136 ° C,

N- (o-chlorobenzyl) -N- (1-methylpyrazol-3-yl) benzamide, mp 148-149 ° C, N-methyl-N- (1-methylpyrazol-3-yl) heptanamide, mp 23-25 ° C,

N-methyl-N -, (l-methylpyrazole-3-yl Jíenylacetamiíd, m.p. 49-51 ^Q C

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

N-hexyl-N- (1-methylpyrazol-3-yl) phenylacetamide, mp 190 ° C / 66.66 Pa, 2-acetoxy-N-butyl-N- (1-methylpyraeol-3-yl) propanamide, M.p. 50 DEG-52 DEG C., 1-carboxy-N- (1-methylpyrazol-3-yl) propanamide, m.p. 168 DEG-170 DEG.

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

N- (1-hexyl) -N- (1-methylpyrazol-3-yl) -2-imethylpropanamide, m.p. 34-35 ° C, N- (4-bromophenyl) methyl-N- (1-methylcyclopentanecarboxamide, mp 88 ° C, pyrazol-3-yl) acetamide, mp 59 to 60 ° C,

N-phenylmethyl-N- (1-phenylpyrrol-3-yl) cyclohexanecarboxamide, mp 109-110 ° C,

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

N- (1-butyl) -N- (1-methylpyrazol-3-yl) cyclopentanecarboxamide, m.p. 62-64 ° C and 68-69 ° C,

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

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

mp 67-67.5 ° C,

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

N- (2-methylprop-1-yl) -N- (1-methylpyrazol-3-yl) -heptanamide, mp 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 are treated with 8.9 g of heptanoic acid and stirred overnight at room temperature. Water was then added and the resulting solid was collected and recrystallized from chloroform and hexane. Yield 6.4 g, mp 78-79 ° C.

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

Analysis for C20H29N3O:

Calculated:

% C, 13.35;% H, 8.9;% N, 12.8.

C, 1.3.55; 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 treated with 5.37 g of cyclohexanicarboxylic acid chloride in 40 ml of dry pyridine at room temperature for 2.5 hours. After addition of water precipitated 4.7 g of N- (l, 3,5-trimethyl-4-yl) cyclohexanecarboxamide the ^Q mp 182 C.

2.5 g of the amide is suspended in 50 ml of dimethylformamide and 0.61 g of a 50% sodium hydride dispersion is slowly added. After 1 hour the mixture was cooled with ice and 2.13 g of butyl iodide was added. After 3 hours. water is added and the product is isolated in ethyl acetate as an oil, b.p. 135 ° C (air bath) / 0.1 mm Hg, 2.7 g.

Analysis for C17H29N3O:

calculated:

H, 10.0%; N, 14.4%;

H, 9.8; N, 14.4. Example 38

N- (2-chlorophenyl) methyl-N- (1,3,5-trimethylpyrazol-4-yl) cyclohexanecarboxamide, m.p. 121 DEG-122 DEG C., was ground 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 STST ⁵

5-amino-1-methyl-3-phenylpyrazole, mp 128-129 ° C, was prepared according to Gazz, 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-phenylpyrazole in dry pyridine are 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 are then alkylated with hexyl iodide as described in Example 37 above.

The product is isolated as a solid of tt 2 ^! 7 to 37 ^c, C.

Example 42

N-methyl-N- (1-methyl-3-phenylpyrazol-5-yl) cyclopentanecarboxamide, m.p. 65-69 ° C, was 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 one hour. After cooling and stirring at 0 ° 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 of m.p. 120-121 ° C.

0.025 mol of acetylated derivative was dissolved in 15 ml of dry dimethylformamide and added dropwise with stirring and cooling to a suspension of 1.2 g (0.025 mol) of sodium hydride (50% oil dispersion) in 10 ml of dry dimethylformamide. When gas evolution is complete, the resulting clear solution is added dropwise with 5 g (i.e., approximately 10% excess 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. The ethereal extract was dried to constant weight at 40 DEG C./2 mm Hg to give 4.8 g of the title compound as a colorless liquid.

Analysis for C10H19N5O:

calculated:

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

% C, 53.2;% H, 8.26;

N-benisyl-N- (4-methyltetrazol-S-yl) -2-methylpropanamide

The procedure of Example 43 was repeated except that benzyl bromide was used in place of n-butyl iodide. The product, after drying to constant weight at 70 ° C / 66.66 Pa, is obtained in the form of a pale yellow oil which, upon prolonged standing, completely transforms into a crystalline form of m.p. 65 ° C.

Analysis for C31H17N5O:

calculated:

% H, 6.61;% N, 27.0%.

η λ l.ťV7i3 η η *

60.0% C, 6.41% Η, 26.7% Ν, Example 45

N-ihexyl-N- (2-methyltetrazol-5-yl) -2-methyl-propanamide

The procedure of Example 43 was repeated except that 1-iodo-hexane was used. The product is finally distilled on a device equipped with a condenser. A pale yellow oil is obtained with a boiling point of 120 DEG C. at 13.33 Pa.

Analysis for C12H23N5O:

calculated:

% C, 56.9%;% H, 9.15;% N, 27.6%.

H, 9.39; N, 27.8. Example 46

N-n-butyl-N- (2-methyltetraisol-5-yl) cyclopentanecarboxamide

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. After one hour of gentle reflux at the reflux temperature, the reaction is complete and the product is worked up as in Example 43. 17.9 g of an acylated derivative of mp 150 ^° C are obtained, which is then alkylated as in Example 43 to give the desired compound which is to a constant weight, in the form of a pale yellow liquid.

Analysis for C12H21N5O:

vypolčteno:

H, 8.42; N, 27.8. Found:

H, 8.65; N, 27.6. Example 47

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

The procedure of Example 46 was repeated except that benzyl bromide was used in the final step and the reaction was carried out for 6 hours. The title compound, initially obtained as a pale yellow oil, suddenly crystallized. After recrystallization from ethyl acetate and petroleum ether, m.p. 40-60 ° C, 1: 3 (v / v), mp 54 ° C.

Analysis for C15H19N5O:

calculated:

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

% C, 63.1;% H, 6.59;% N, 24.7

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

The procedure of Example 46 was repeated except that 1-iodohexane was used and the reaction lasted 24 hours. The final product was obtained as a pale yellow liquid, which was dried to constant weight at 25 ^Q C / 13.33 Pa.

Analysis for C14H25N5O;

calculated:

% C, 60.2%;% H, 9.02;% N, 25.1%.

60.4% C, 9.33% H, 24.8% N. Example 49

N-benzyl-N- ^(2-benzyl-L zyltetrazol 5-yl) -2-methyipropanamid

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

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

Example 1 and d 50

N-n-Butyl-N- (Z-benzyltetrazol-5-yl) -2-methylpropanamide

The procedure of Example 49 was repeated except that n-butyl iodide was used instead of benzyltoromide. 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, m.p. 135-140 [deg.] C./13.3 Pa (B / W).

Analysis for C10H11N5O: calculated:

H, 5.11; N, 32.2. Found:

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

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

calculated:

5.3% C, 7.68% H, 31.4% N, found:

% C, 53.7%;% H, 7.47%;

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

Analysis for C5H9N5O:

calculated:

38.7% C, 5.85% H, 45.1% N, found:

38.6% C, 5.76% H, 45.4 θ / ο N.

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

Analysis for C 7 H 11 N 5 O: 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, m.p. 160 ° C / 20 Pa (spherical cooler).

Analysis for * C 11 H 15 BrN 5 Q: calculated:

42.6 o / o c, 3.90 ° / o H, N 22.6%, Br 25.8%, found:

H, 4.16; N, 22.5; Br, 25.8.

N-methyl-N- (2-methyltetrazol-5-yl) heptanamide, m.p. 118 DEG C./0.6 mbar.

Analysis for * C10H19N5O: calculated:

53.3% 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, bp 126 ° C / 6.6 Pa.

N-allyl-N- (2-methyltetrazol-5-yl) diphenylacetamide, m.p. 140 ^DEG C./0.13 mm Hg (ball condenser).

Analysis for C 13 H 15 N 5 O: calculated:

H, 5.88%; N, 27.2%.

% H, 5.97;% N, 27.0%.

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 1-iodopropane; sodium hydride in dimethylformamide to give the title compound.

Similarly produced:

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 acyllated with isobutyric acid and the resulting amide is alkylated as in the above examples to give the title compound.

Similarly produced:

N-butyl-N- [1-methyl-1 (1H) -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-buityl 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, 1-ethoxycarbonyl-Nn-butyl-N- (1-methylpyrazol-3-yl) heptanamide, 1-carboxy-Nn-butyl -N- (1-methylpyrazol-3-yl) heptanamide; and 1-carlbexyl-N-butyl-N-1-methylpyrazol-3-yl) propanamide.

Example 71

Similarly, the amide of Example 58 is butyl-n-buityl bromide to give N-n-butyl-N- [4-butyl-3-methyl-4 (H) -1,2,4-trlazole] -α-methylpropanamide.

Examples 72 to 74

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

Ν- (2-Butyl) -N- (1-methylpyrazol-3-yl) heptanamide, m.p. 138-141 ° C / 13.3 Pa,

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

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

Examples 75 to 88

The following triaisols were prepared by methods similar to those of Examples 59 and 71:

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

N-methyl-N- [3-phenyl-1 (H) -1,2,4-triazol-5-yl] cyclopropanecanboxamide, mp 169 ° C, N-butyl-N- [3-phenyl-1-1 [H] -1,2,4-triazol-5-yl] butanamide, mp 113.5-114 ° C, N-ethyl-α-methyl-N- [3denyl-T (H) -1,2,4-It-thiazole- S-ylproipanamide, mp 120-121 °

Ce lsi a

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

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

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

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

N-butyl-N- [3-phenyl-1 (H) -1,2,4-triazol-5-yl] -2-methylpropanamide, gum, structure verified 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] benzamide, (M / e 326/8);

N- (4-chlorobenzyl) -N- [3-methyl-1 (H) -1,4-triazol-5-ylcyclohexanecarboxamide, mp 143 ° C;

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

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

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

Example 89

Soft latin capsules are made using:

Quantity (mg / capsule)

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

Example 90

Hard gelatine capsules are produced using the following ingredients:

Quantity (mg / capsule)

Active ingredient 25 Silicon dioxide 25 Lactose 50 Butylated hydroxyanisole 0.02

The 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%

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

Example 92

Topical cream, containing 1% of the compound, is prepared as follows:

grams

Active compound

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

Cetostearyl alcohol .10

K a p a lný p ar aine 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 was added to the flask and the mixture was 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 the active compound is then poured into an aqueous solution of cetomacrogol 1000 with stirring and continued until the cream has cooled. The cream is then adjusted to the required weight by the active compound 20

Ptopylígalát 0,03

The fractionated coconut oil 70 doubles and passes to a stainless steel colloid mill with 0.0381 cm holes.

Example 93

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

Active ingredient 3 g

Henkel base 17 g

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

Example 94

An aerosol spray is produced which contains the following components:

Quantity (per ml)

Active compound 10,00 mg Propylene glycol 10,00 mg Dichlortetrafluoroethane 500.00 mg (propellant 114) Dichlordifluoromethane 900 mg (propellant 12)

The active compound is mixed with propylene glycol and the mixture is added to propellant 114. The resulting mixture is cooled to -15 to -20 ° C, and transferred to a first charging apparatus. At the same time, the mixture of propellant 114 and 12, pre-cooled to -15 to -20 ° C, is charged to the second filling device. A measured amount of propellant from the second charging device is introduced into the stainless steel containers and then the desired amount of substance from the first charging device is added. It is then fitted with a valve element and the reservoir is secured with a tight closure. These valve elements may be provided with a metering device, thus releasing approximately 0.15 mg of active compound per actuation of the valve.

Example 95

Tablets are made from the following ingredients:

Active compound 15.00 mg Microcrystalline cellulose 240,00 mg Sodium salt of carboxy- methyl starch 20,00 mg Magnesium stearate 2.5 mg Butylated hydroxyanisole 0,002 mg

The butylated hydroxyanisole is dissolved in the active ingredient and the resulting solution is adsorbed onto microcrystalline cellulose. The resulting mixture is mixed with sodium carboxymethylated starch, and then magnesium stearate is injected. 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.