CS200494B2 - Process for preparing therapeutical acylaminosubstituted five-memberd heterocyclic compounds - Google Patents

Abstract

Acylamino heteroaryl compounds in which the heteroaryl nucleus is a 5-membered nucleus which contains, as the sole heteroatoms, two nitrogen atoms, and a further heteroatom selected from oxygen and sulphur, methods of making the compounds and pharmaceutical formulations containing the compounds. The compounds have anti-allergy activity.

Description

The invention relates to a process for the preparation of therapeutically active acylamino-substituted five-membered heterocyclic compounds.

Compounds similar to the compounds of the invention have been previously described, see, for example, Buui. Soc. Chim. 1219 (1967), Belgian Patent No. 736,854 and British Patent No. 1,333,495. However, the publications on this type of compounds have either patented a use completely different from that of the compounds of the present invention, or are academic publications only. in which the panability of these substances is not described.

It is an object of the present invention to provide a method for producing compounds useful in the chemotherapy of sudden hypersensitivity states.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of therapeutically active acelamino substituted heterocyclic heterocyclic compounds of formula I

Ar — N — R ^{* 1} . | - (I ⁾ >

COR ² 'wherein Ar is a five-membered heterocyclic ring containing as the only heteroatom 2 nitrogen atoms and another heteroatom selected from the group consisting of oxygen and sulfur, wherein said heteroaryl ring is substituted with at least one group selected from C 1-4 alkyl, C 1-4 alkyl gcykloaltyl phenyl and ^F ^ ^BC ICEM ac.y amino group- @ ¹ COR @ ² is attached to a carbon atom of the heteroaryl ring, and R * is selected from the group zahrnuuící C_g200494

2004-94 alkyljCj-galkenyl, C3 gcyklohLkyl and benzyl substituted with at least one group selected from s ^to u ^{p s} in mitigating hydrogen atom hategenu,. And R ² represents C _1-8 alkyl, C _1-8 cycloalkyl, benzyl and phenyl substituted with at least one group selected from hydrogen, halogen and C 1-4 alkoxy, with the proviso that

2 (a) when Ar is 1,3,4-Uiadiazolyl, R is C] _jalkyl and R is selected from the group consisting of C_, y, ^and alkyl and Cj_gCykloalkyy, said 1,3,4-thiadiazolyl group can be any of substituováu the above groups except group zahrnuíící hydrogen and alkyl C_3 ^ol,

2 (b) when Ar is 1,3,4-thiediazolyl substituted with methyl and R is p-bromoenny, R has any of the above meanings except methyl, and (c) when Ar is 1,2,4-oxadiazolyl R 1 has any of the above meanings except methyl or benzyl when R is methyl.

The optional substituents on the heteroaromatic nucleus are preferably selected from the group consisting of C 1-6 -alkyl, C 1-6 -cycloalkyl and phenyl. As a substituent r ', C 1-6 alkyl, C 8-6 alkenyl, C 8-6 cycloalkyl and benzyl groups optionally substituted by halogen, C 1-4 alkyl or C 1-4 alkoxy may be used. As the substituent R 2, C 3 -C 6 cycloalkyl, benzyl or phenyl groups optionally substituted by halogen or C 1-6 alkoxy may advantageously be used.

The term C1-4 alkyl as used herein denotes a straight or branched chain alkyl group having 1 to 4 carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-butyl, n-butyl, secondary butyl or a tertiary butyl group.

It will be apparent to those skilled in the art that under the term five-membered heterocyclic nucleus containing, on the one hand, two nitrogen atoms and, on the other hand, another one selected from. Oxygen and sulfur groups include the 1,2,4- and 1,3,4-oxadiazolyl and the 1,2,4- and 1,3,4-trifluidyl ring systems.

The compounds of the present invention containing the above-mentioned Uttroarvic nuclei in the molecule may be represented by the following general structural formulas II to VII:

NR 2 OR ² (II)

NR1COR1 (III)

RkOR ²

N —— N (IN) ^{R with} NR ¹ COR ² (VI) S- _N RICOR2 S — N rAA ^ cor ² (VII)

Wherein R @ 1 and R @ 2 are as hereinbefore defined and R is hydrogen or optionally tubstitutute on the U-cyclic ring.

Of interest are those compounds of formulas (1) to (VII) in which the aryl group is a C 1-6 alkyl group, especially a methyl group, R 1 is a C 1-6 alkyl group, especially a C 1-6 alkyl group, or a C 1-6 alkenyl group or benzyl group. R2 denotes a C3- (5alkyl, C3-8cycloalkyl or benzyl group).

According to the invention, the compounds of formula (I) may be prepared by acylating an alkyl derivative of formula (VIII)

ArMHR ¹ (· VII) wherein Ar and R ¹ are ^H with Ora Uve ^d Eny importance.

The acylation of the compound of formula VIII is preferably carried out by treatment with an acid halide of the formula RCO-X in which X is chlorine or bromine and R is as defined above in the presence of a proton acceptor such as pyridine or triehlyphamine in an inert solvent such as benzene . The acylation can also be carried out by heating an alkyl derivative of formula (VIII) with an appropriate acid anhydride of formula (RCO) gO in an inert solvent. '

Those skilled in the art will appreciate that many other methods of acylation may be used (see, for example, monngrraie The Chhmissry of Arian, 1971 by AJ Bedith; Survey of Organic Synthesis, 19'70, by Бее ^ З-егэ and Pearson; Organic Functional Group Preparatisns). ^, 1968, by Sandler and Kara; reagents for Organic Synttiheis, 1968, by Rleser and Fieser, etc.

The starting compounds of formula VIII can be prepared from the corresponding amines of formula ArNHg by standard alkylation procedures.

The amines of the formula ArNHg are either known compounds or can be prepared by mooification of known synthetic methods.

The present inventors have found that the compounds of formula (I) may be used in the prophylaxis and therapy of sudden diseases of the sensitivity, including asthma, and in alleviating the status of asthmaticus. The compounds have low toxicity.

The compounds prepared by the method of the invention or the therapeutic preparations based thereon may be administered orally, rectally, topically, parenterally, for example by injection and continuous or by intra-arterial infusion, for example tablets, lozenges, sublingual tablets, sachets, capsules, elixirs, suspension, aerosols, ointments, for example, ointments containing 1 to 10% by weight of the active compound in a suitable base, in the form of soft and hard yellow capsules, suppositories, injectable solutions and suspensions in a physiologically acceptable environment, and in the form of sterile packed powders adsorbed onto a suitable carrier; intended for solution for injection. Particularly preferred are therapeutic formulations in dosage unit form, each dosage unit containing preferably 5 to 500 mg of the compound prepared by the method of the invention (5 to 50 mg for parenteral administration, 5.0 to 50 mg for inhalation, and 25 to 500 mg for inhalation). orally or rectally). In the treatment, doses ranging from 0.5 to 300 mg of active ingredient per kg of hormone per day, preferably 0.5 to 20 ms / kg per day, may be administered; however, it is readily understood that the active compound or compounds which can be administered must be determined by the physician on the basis of all relevant circumstances, such as the type of compound to be treated, the compound to be administered, and the selected mode of administration of the preparation, and therefore the above dosage range is not intended to limit the scope of the invention in any way.

In the description of the invention, the form of dosage units refers to a physically discrete dosage unit containing an alpha-lilac amount. the compound, usually in admixture with a pharmaceutically acceptable diluent, or in conjunction with a pharmaceutically acceptable carrier; the active ingredient is such that one or more units are required for a single therapeutic administration, or, in the case of divisible units, such as scored tablets, at least one part, such as half or quarter, of a range is required for a single therapeutic administration. other units.

The therapeutic compositions of the invention normally consist of one compound of the invention and a pharmaceutically acceptable carrier; the active substance is mixed with or dissolved in the cell, or is enclosed or encapsulated in a digestible carrier, which may take the form of a capsule, sachet, capsule, paper or other container, or is filled in a suitable container, such as ampoule. As carriers or diluents, a solid, semi-solid, or liquid material may be used as a vehicle, excipient or medium for the therapeutically active agent.

Lactose, glucose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white petrolatum, kaolin, anhydrous can be used as suitable diluents or carriers in the pharmaceutical preparations according to the invention. silicon dioxide, microcrystalline cellulose, calcium silicate, silica gel, polyvinyl pyrrolidine, cetostearyl alcohol, starch, modified starches, gum arabic, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, peanut oil, alginates, tragacanth, alginates, tragacanth, . P. (British Pharmacopoeia), methylcellulose, polyoxyethylesorbitol monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitol trioleate, sorbitol sesquioleate and olevanol and propellants such as trichlorofluorofluoromethane, dichlorodifluoromethane and dichlorodifluoromethane. In the case of tablets, a glidant may be added in their preparation to prevent sticking and joining of the sprayed components in the embossing matrix and the punch of the tabletting machine. Aluminum, magnesium or calcium stearate, talc or mineral oil may be used for this purpose.

Capsules, tablets, suppositories, aerosols, injectable solutions, creams and ointments are preferably used as preferred forms of the pharmaceutical compositions of the invention.

The invention is illustrated by the following examples:

Example 1

N-Methyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzamide

To a solution of 2- (N-methylamino) -5-methyl-1,3,4-thiadiazole (6 g, 0.046 mol) in pyridine (190 mL) was added benzoyl chloride (9.7 g, 0.069 mol) and the mixture was heated 6 hours to reflux. The pyridine was distilled off under reduced pressure, the residue was stirred with water, basified with sodium hydroxide solution and shaken with chloroform. The chloroform extracts were combined, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried, the desiccant was filtered off and the solvent was distilled off. The title compound is obtained, which is recrystallized from ethanol.

Example 2

N-2-Propenyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzamide

The title compound was prepared as described in Example 1 but using 2- [N- (2-propenyl) amino] -5-methyl-1,3,4-thiadiazole as a starting material, which was obtained by cyclization of 4- (2- propenyl) thiosemicarbazide.

Example 3

N-Phenylmethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -phenylacetamide

a) N- (5-Methyl-1,3,4-thiadiazol-2-yl) benzylamine

A mixture of 2-amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) and benzaldehyde (29.6 mL, 0.3 mol) was refluxed in ethanol (200 mL) for 1 L /2 hours. The solution was cooled to room temperature and sodium borohydride (11.35 g, 0.3 mol) was added over 5-10 minutes. The mixture was refluxed for 4 hours, then additional sodium borohydride (5 g) was added and the mixture was refluxed overnight. Ethanol was distilled off, the residue was stirred with water and the mixture was shaken with ether. The ethereal extract with sodium sulphate is filtered and the solvent is distilled off; The solid was triturated with ether, filtered, washed with petroleum ether (to 40-60 ° C, re-stirred with ether and filtered) to give Ν- (5-η 4 -1,3-1,3), 4-thiophiazol-2-yl) -enenzylminine (30.95 g), having a melting point of 140 ° C after recrystallization from ether.

b) Κ-Εβηη1 [η 4] 1-Ν- (5-methyl-1,3,4-thaadaazol-2-yl) phosphinamide

To a solution of N- (5-methyl-1,3,4-thiaphiazol-2-yl) benzamine (15 g, 0.073 mol-1) in pyridine. (200 mL) was added phthylacetyl chloride and the mixture was heated at reflux for 6 hours. The pyridine is filtered off under reduced pressure, the residue is stirred with water and the mixture is shaken with ether. The ether extract was dried, filtered and the solvent was removed. The residue was recrystallized from ethanol to give the title compound, mp 128 ° C.

Examples4 to 6

The following compounds were prepared as described in Example 3:

N- (5-Methyl-1,3,4-thiadiazole-2-1l) -N-o-chlorobenzyl) -N- (o-chlorophenyl) -N- (5-methyl-1,3,4-thiadiazole-2-1l) N-(5-phenyl-1,3,4'-thiadiazol-21-yl) -cycloeenaankaboxoxide.

Example 7 (R, N-methyl-1,3 ₎ 4-thiadiazol-2-1 (phthylacceamide)

a) Ν- (5-η 5 - (-, 3,4-thiadiazol-21y)) exaanaeid

To a solution of 2-amino-5-methyl-1,3,4'-thiaphiazole (23 g, 0.2 mol) in toluene (100 mL) was added n-hexanoic anhydride (50 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture is left to crystallize overnight at room temperature, the precipitated product is filtered and recrystallized from ethyl acetate; - (5-Methyl-1,3,4-thiadiazole-2-1-thexylanide (20.68 g), m.p. 203 DEG C.).

(b) - (5-Methyl-1,3,4-thiaphiazsl-2-yl) eexylmin,

To a suspension of lithium aluminum hydride (2.9 g, 0.076 mol) in tetrahidrofuran (THF) (120 mL) was added portionwise under stirring at a temperature below 15 ° C - (5-methyl-113,44-htadfazo). -2-yl) hexanamide (16 g, 0.075 mL). The reaction mixture was heated under reflux for 2 hours with stirring, then cooled with ice, and the excess reducing agent was quenched with a solution of water (2.9 mL) in THF (29 mL). To the solution was added a solution of 2 N sodium hydroxide (2.9; U) and water (5.8 m), and after addition of diatomaceous earth (Supercel brand) the solution was filtered. From the filtrate the solvent is distilled off and the residue was ^ e * ^ς tk y1talizujt of 50% aqueous methanol; title product (9.5 g), m.p. 101-105 ° C.

c) -]. Heχ1l (N (5'meehh1l (1,3,4-thiaphiazlb (2-yl))

To a solution of - (5-methyl-3,4,4-thiadiazol-22-yl-hexylmine) (5.98 g, 0.03 mol) in toluene (60 mL) was added triethylaein (4.59 mL) and phthyl acetyl chloride (4 mL) with stirring. 64 g, 0.03 moD, and the solution was heated at reflux overnight. Additional amine (4.6 mL) and phenylacetyl acetate (4 mL) were added and the mixture was heated to reflux. The solvent was removed from the reaction mixture, the residue was stirred with water and the mixture was shaken with chloroform, the extract was washed with 2N sodium hydroxide solution and water, dried over sulfate. The title compound is obtained as an oily liquid, b.p. 190 ° C / 13 Fa (8.03 g), after solidifying with ethanol to give a solid product, m.p. mp 90 ° C.

Example 8

N- (5-Methyl-1,3,4-thiadiazol-2-yl) -2-methylpropanamide

To _2-Amano-5-t mettyhl1 З, 44triadiazolu (15 g, '0.13 mol) was added isobutyric gears (70 mL) and the reaction SMSS We heated with stirring for 1 1/2 hour under reflux in an oil bath 180-200 ° C warm. The excess anhydride is distilled off under reduced pressure, and the solid residue is recrystallized from ethyl acetate to give N- (5-methyl-1,3,4-thiadiazol-2-yl) -2-methylpropanamide as gold-yellow needle-like crystals.

Examples 9a10.

In the same way, the following compounds are prepared:

N- (5-methyl-1,3,4-thiadiazol-2-yl) butanamide, cream colored crystalline solid, m.p.

Mp 231-233 ° C; e

N- (5-Methyl-1,3,4-thiadiazol-2-yl) heptanamine, cream-colored crystalline solid.

example _ 11

N- (5-Methyl-1,3,4-thiazol-2-yl) butllamine

N- (5-Methyl-1,3,4-thiaeiazol-2-yl) -butanamide (1.85 g, 0.01 mol) was added in small portions under nitrogen atmosphere at 0-5 ° C in small portions. to a suspension of lithium aluminum hydride (0.38 g, 0.01 mol) in anhydrous Etrahidrof uranium (25 mL). The reaction mixture was heated to reflux with stirring for 2 hours, then cooled and added dropwise to the solution.

solution of water (0.38 g) in THF (3.8 mL). Then 2 N sodium hydroxide solution (0.30 mL) and water (0.76 mL) were added and the mixture was stirred for 1/2 hour. The solution is filtered through a pad of diatomaceous earth (Suuetcet), the solvent is removed under reduced pressure from the filtrate and the residue is recrystallized from aqueous ethanol. There was thus obtained N- (5-methyl-1,3,4-thiazol-2-yl) bulylamine as a pale yellow crystalline solid, mp 100-102 ° C. ^;

Example 12

N (5-Methyl-113-4-thiaeiazol-2-yl) -heptidine * Prepared as described in Example 11.

Example 13

N-Bu JYL-N- _(5-meehhl-1> 3,4-thiaάiazol - yl) -2-] ehtlyerrepanιmid

A mixture of N- (5-methyl-1,1,4,4-thiadiazol-2-yl) butylamine (3 g, 0.0175 mol) and itobutyl anhydride (15 ml) was heated on a boiling bath for 1 1/2 hours. The excess isobutyric anhydride st is decanted off under reduced pressure and the residue is precooled under reduced pressure to give the title compound as an oily liquid (3.6 g, 55%) having a boiling point of 132 DEG C./40 mbar. upon cooling, it solidifies to a white solid of mp 54-57 ° C.

Example. 14a 15

The diluent compounds are prepared in a similar manner:

- ~ (Hxyl- (N (η 5 - η 5 -1,1,4,4-hexadiazol-1-yl) -2-methylthioearamide)

It forms a colorless oily liquid, m.p. 152-154 ° C at 67 Pa; ng; 1,5108. The structure was confirmed by NMR, IR and UF spectra.

Analysis: Calculated: C, 57.99; H, 8.55; N, 15.61. Found: 57.81% С 8.67% H, 15.76% N.

N-Heptyl-N- (5-methyl-1,3,4-thiadiasol-2-yl) -2-methylpropana-.ru Л

He did

N-Butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide

To a solution of N- (5-methyl-1,3,4-thiadiazol-2-yl) butylamine (1.7 g, 0.01 mol) in benzene (20 mol) was added triethylamine (1.53 mL) and chloride. cyclopropanecarboxylic acid (1.15 g), and the reaction mixture was refluxed for 20 hours. The solvent was distilled off and the residue was dissolved in ether. The solution was filtered, the filtrate was washed with water, dried, decolourised with charcoal, filtered and the solvent was distilled off. Recrystallization of the residue from pelrolether (m.p. 40-60 ° C) gave N-butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide as a colorless crystalline solid, mp 82-84 ° C. C.

Example 17

N-Butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopentanecarboxamide

The title compound is prepared as described in Example 16. It forms a colorless oil.

infrared liquid with IR and UF spectra. boiling 162 to 1 64 ° C at 53 Pa. The structure was confirmed by NMR Analysis: for C ^ HH ^N ^O OS calculated: 58.4 «C, 7.9% H, 5,7 % N; found: 58.5% C, 7.6% H, 15.9 % N.

Example 18

N- (5-Methyl-1,3,4-thiadiazol-2-yl) -1-methylethylamine

To a solution of 2-amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) in a mixture of osopropariol (700 mL) with acetone (100 mL) was added portionwise with stirring and cooling sodium borohydride ( 20 g). The reaction mixture was heated under stirring for 3 1/2 hours at reflux, then cooled, poured into water (3 L) and the solution was shaken with ether (3x). The combined ether extracts were dried, filtered and the solvent was distilled off. The title compound is obtained as a cream colored solid, m.p. 145 ° C.

Example 19

N- (5-Methyl-1,3,4-thiadiazol-2-yl) cyclohexylamine

This compound was prepared as described in Example 18. It formed a colorless crystalline solid, m.p. 192-194 ° C (from ethyl acetate).

Example 20

N- (1-Methylthyl) -N- (5-methyl-1,3,4-thiadiazol-2-yl) benzamide

To a solution of N- (5-methyl-1,3,4-thiadiazol-2-yl) -1-methylethylamine (5 g, 0.032 mol) in pyridine (100 mL) was added benzoyl chloride (4.1 mL) and the reaction mixture. with stirring, reflux for 5 1/2 hours. The pyridine was distilled off under reduced pressure, the residue was stirred with water and the mixture was extracted with ether (3.times.). The ether extracts were combined, dried, filtered and the solvent was distilled off. The residue was recrystallized from a mixture of ether and pstroletheeee (b.p. 40-60 ° C) to give the title compound as a pale yellow crystalline solid, mp 82.5-83.5 ° C.

Examples 21 and 22

The following compounds are prepared in a similar manner:

N- (1-ethyl-ethyl) -N- (5-ethyl-1,3,4-thiaeiazol-2-yl) -phenyl acyl, a pale yellow crystalline solid, m.p. 83-85 ° C; and

N-cyclohesyl-N- (5-methyl-1,3,4-thiazolol-2-yl) -cyclopropanecarboxaeid, a yellow colored crystalline solid, m.p. 76.5-78.5 ° C.

P'ř'í klad. 23 ‘

a) 5-Chloro-3-methyl-1,2,2-thiadiazole

A 3 ml flask equipped with a stirrer, a dropping funnel and a thermometer was charged with dichloromethane (500 mL, acetamidine hydrochloride (47.0 g, 0.50 mol) and trichloro-n-sulfonyl sulfide (83.0 g, 0.45 moo)). A solution of sodium hydroxide (100 g, 2.50 mol) in 150 ml of water is slowly added dropwise under stirring and cooling with dry ice in an acetone bath at a temperature below -8 [deg.] C. After adding about half of the caustic solution, the reaction After the dropwise addition of sodium hydroxide solution (about 5 hours), the precipitated sodium chloride was filtered off, washed with dichloromethane, the organic layer was separated and the aqueous layer was shaken with dichloromethane (3 x 30 ml). All dichloromethane fractions were washed, washed with water until neutral, and dried over magnesium sulfate, and the solvent was evaporated and the red colored liquid residue was distilled off under reduced pressure to give 5-chloro. r-3-ethyl-1,2,4,4-thiazole azole as a colorless liquid, bp 25 ° C / 467 Pa; yield 27 g (45%).

b) 5-Buylamino-methyl-1H-thiadiazole

Dissolve 5-CCl-3-trans-1,2,4-triazole (27 g, 0.20 mol) in 200 mL of ethanol and add an ethanolic solution of butylamine (44 g, 0.25 mL) while cooling in an ice bath. (60 mol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume, ether added, the precipitated white butylamine hydrochloride was filtered off and the yellow colored filtrate was washed with water. The ethereal layer was dried (MgSO4), the solvent was distilled off, and the resulting oil was distilled under reduced pressure. There was obtained 5-butylamino-3-ethyl-1,2,2,4-thiazolyl as a light yellow colored liquid, b.p. 101-102 at 18.7 Pa; yield 29.9 g (87.2%).

c) N- (3-Methyl-1,2,4-thiazol-5-yl) -N-methylcyclohexanecarboxamides

To a solution of 5-methyl-1-amino-methyl-1,24,4-thiazole (7.0 g, 0.054 mol) in THF. anhydrous benzene (6.87 g, 0.068 mol) was added dropwise, then cyclohexanecarboxylic acid chloride (9.92 g, 0.068 mol) was slowly added dropwise and the mixture was heated under reflux for 1 1/2 hours. The reaction mixture was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered, and the solvent redistilled to give a yellow oil which was crystallized by standing (recrystallization twice). 60-80 [deg.] C.), N- (3-ethyl-112,4-thiadiazolyl) -N-ethyl-yl-hexaacarboxide is obtained in the form of an almost colorless crystalline solid, m.p. 96 [deg.] C .; 23 g (63.8%.

and

Examples 24 to 33

In a similar manner to Example 23, the following compounds were prepared:

N- (3-methyl-12,4,4 ^- triazol-5-yl) -4-butyl-2-methylpropanamide, b.p. 115-117 ° C / 13 Pa. Analysis: For C18H25N2O4 calculated: 54.74% C, H, 7.33; N, 17.41. <5.33% 0 13.28% S; found: 54 _Э 64% C, H, 7.97; N, 17.37. <5 »48% 0 13,36% s,

N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-butylcycloproannecarboxamide, m.p. 43 ° C, N- (3-methyl-1,2,4-thiadiazole-5- yl) -N-butylfeyykaabooxímid, mp 77 ° C, N- _{(3-iykiObrbuy-II1)} 2 _{II-4-UУiadiazol} 5yyl) -NrokУylckkrrokaш · k £ arbQχamid, N- (3-methyl-l, 2,4-thiadiazole -5-11) -N-methylphenyl-acetamide, mp 86 ° C, N- (3-methyl-11,2,4'-hexadiazol-5-yl) -N-2-prooenyl) acetamide, mp 61 ° C. N- (3-LL1 METUJE ^{1 1 2} 4lthiadizool-llyl) -N-meth ^l 22 ^{1-methyl benzenesulfonamide} lyllp ^OP t · ⁵⁴ ° ^C N-L3- ^ i ^ eežiili-1, 2, 4-chloro-thiazol-5-yl) N-bulylelylhexamide, b.p. 130-135 ° C / -20 Pa, purified by column chromatography,.

Analysis: Calculated: C, 59.33; H, 8.89; N, 14.83; S, 5.65; S, 11.31. Found:% C, 59.39;% H, 8.82;% N, 15.19;

N- (3-methyl-1,2,4-1H-thiaziazol-5-yl) -1-2-prooenylphenylacetimide, m.p. 70 ° C. N- (3-methyl-1,2,4-thididizo-1-5-yl) -2-2-oropelylycyclopropeylPoxoximide, m.p. · T. 77 ° C.

Example 34

3-Phenyl-5-pyridylmethyl-1,2,4-dioxadiazole

To a solution of benzamidoxime (34.0 g, 0.25 mole in anhydrous trichloroacetic acid (160 g with stirring at 60 ° C) is added tert-rich chloroacetic anhydride (154.5 g, 0.5 mole and the mixture). The mixture is cooled, poured into ice water (400 ml, the organic portion is separated, washed with water and taken up in UetaacУ0omethεnb (500 µl). The solution is neutralized by boiling with a saturated aqueous solution. The reaction mixture was concentrated in vacuo, dried over magnesium sulfate, and the solvent was evaporated.

Example 35 ’

3-Ethyl-1-tricyl-1-methyl-1,2,4-dioxadiazole was prepared in a similar manner.

Example 1 and d 36

5lBujylaminel) зmetУyl-1,2,4llxadiazll-

3-Methyl-1-nitro-methyl-1,2,4-iodadiazole (43 g, 0.21 mol) was added to trifluoromethylbenzyl (46.75 g, 0.63 mol) and the mixture was stirred at matt overnight. The mixture was distilled and the residue was pre-dried under reduced pressure (110 ° C oil bath, 67 ° C.). After recrystallizing the product from PET (60 ° C to 80 ° C), the title compound (26 g) was obtained. as white plate-like crystals, mp 62-65 ° C.

Example 37

NeBujul N-N) of 3-methyl-4- _J l12) lxadiazoll5lyl) enrbutenmid

A mixture of 5-benzylamino-3-methyl-11,4,4-oxadiazl-b (4.2 g, 0.03 mole and ruthyric anhydride (4.75 g, 0.033 mmol) was refluxed in toluene (30 m) for 3 hours. The residue was heated to boiling with methanol (60 ml) for 1 hour in the presence of a few drops of triethylamine, methanol was distilled off under reduced pressure, the residue was taken up in dichloromethane, washed twice with 2 N hydrochloric acid and twice with saturated sodium chloride. sodium bicarbonate solution and dried over anhydrous magnesium sulfate. the product was purified by column chromatography (120 g silica gel) using initially petroleum ether (TV 40-60 ° C) _T later petroleum ether to 10% ether к eluting substances. fractions containing the desired product Combine, evaporate the solvent and distill the product in a bead distillation tube at an air bath temperature of 119 ° C and at 440 Pa.>

Anal calcd for: C C jH ^ NN ^Og calculated; % C, 58.64;% H, 8.50;% N, 18.65; Found: C 58.78, H 8.30, N 18.40, O 14.18%.

Example 1 and d 38 to 44 *

The following oxadiazoles were prepared as described in Example 37:

N-ethyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide, m.p. 92 ° C / 400 Pa.

Analysis: For ^C 9 ^H 15 ^N 3 ° 2 calculated: 54, βϋ% C, 7.66% H, 21.30% N, 16.22% O, found: 54.68% C, 7.46% H N, 21.14%.

N-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) acetamide, liquid, η ₂ θ 1.4748; N-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide, boiling point (air bath temperature) 98 ° C / 200Pa.

H, 8.50; N, 18.66; N, 14.20. Found: C, 58.49; H, 8.22. N, 18.40; N, 14.18%.

N, N-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) hexanamide, Analysis: Calculated: C, 61.63; H, 9.15; H, 46.58. % N, 12.63%. Found:% C, 61.89;% H, 9.39;% N, 16.33.

N-ethyl-N- (3-phenyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide, m.p. 48 [deg.] C .;

N-butyl-N- (3-phenyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide, boiling point 140 ° C (air bath temperature) at 933 Pa, analysis for ^C 16 ^H 21 ^N 3 ° C calculated: 66.88%, 7.37% H, 14.62% N, 11.14% O, found: 67.07% C, 7.38% H, 14.36% N, 11% 06% 0.

N-ethyl-N- (3-phenyl-1,2,4-oxadiazol-5-yl) -n-butanamide, m.p. 74 ° C.

Example 45

N-r-Hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) acetamide

A solution of 5-n-hexylamino-3-methyl-1,2,4-oxadiazole (4.6 g, 0.025 mol) in acetic anhydride (25 ml) was heated at reflux for 3 hours and then the excess anhydride was distilled off. under reduced pressure. The residue is taken up in chloroform (50 ml) and the solution is washed twice

N hydrochloric acid and twice saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Boiling point 113-114 ° C / 133 Pa.

Analysis: for C —HH ^ ^ I —Og calculated: 58.64% C, 8.50% H, 18.65% N, 14.20% 0, found: 58.66% C, 8.76% H, N 18.57%, O 14.48%.

Example 4o

N- (3-Methyl-1,2,4-oxadiazol-5-yl) -N-2-propenylacetemide

The oxadiazole of the ^{p ip} Ravi Úsobí from ^{p p p} o Sanyo in pfakl ^ u 45 · Boiling point ⁸² ° C ^(t e ^p - lota vzduchné bath) at 200 Pa. Analysis: Pro ^C 8 11 11 ^H 3 ° 2 calculated: 53.02% C, 6.12% H, 23.19% N, 17.66% O, found: 52.78% C, 5.90% H, N, 23.03 17.69% 0.,

Example 47

N- (3-Methyl-1,2,4-oxadiazoo-5-yl) -N- (4-methenylphenyl) ethanol-cyclopropanecarboxamide

To a solution of 5- (4-methenylphenyl) methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mol) and triethylamine (3.45 g 0.035 mol) in anhydrous benzene was added at poi at 10 ° C was added cyclopropanecarboxylic acid chloride (3,45.g, 0.033 mo) After addition of chloride the ^temperature; The mixture was allowed to warm to room temperature and then heated to reflux overnight. After cooling, the solution was washed with 2 N hydrochloric acid ivate and twice with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and decolorized with activated carbon. The crude product was purified by column chromatography on silica gel (110 g), first using petroleum ether and then petroleum ether with increasing ether up to 10% to elute the materials. Recrystallization from petroleum ether (bp 60-80 ° C) gave the title compound as colorless needles, mp 49.5-50.5 ° C.

Example -1 and d 48 to 59

The following oxadiazoles were prepared as described in Example 47:

N-menoh-N- (3-ethyl-1,2,4-oxadiazol-5-yl) benzamide, mp 74 ° C; N-Buyl-N- (3-enyl-1,2,4-oxadiazol-5-yl) -cyclopropanecarboxboxid, u- ⁶ liquid 1.4882; N-heterocyclyl-N- (3-enyl) thiol-12,4-oxadiazol-5-yl) cyclopentunctorboxeand boiling point · 121 ° C (air bath temperature) at 187 Pa.

for C: CH25NNNO °: calculated: 64.48% C, 9.02% H, 15.04% N, 11.52% O; Found: 64.76% C. H, 8.86; N, 14.82. O, 11.52;

N-hexy-N- (3-mono-1,2,4-oxadiazol-5-yl) ωkohhneaakcaroxoxide, boiling point 157 ° C · (air bath temperature) at 200 Pa.

analysis: for

H, 9.77; N, 14.32; C, 10.9;

Found:% C, 65.58;% H, 9.05;% N, 10.19;

N-Hexa-N- (3-methyl-1,2,4-oxadiazol-5-yl) -benzamide, boiling point 126 ° C (air bath temperature) at 27 Pa · Analysis: Calculated for C 8 H 8 H 2 O 3: 66.87 % H, 7.36; N, 14.62; N, 11.13. Found:% C, 66.8;% H, 7.35;% N, 14.58;

N- (3-methyl-1,2,4-oxadiazol-3-yl) -N-2-poopenyl-cyclopoopanecarboxamide, boiling point 120 ° C (air bath temperature) at 1333 Pa.

N- (3-methyl-1, 2,4-oxadiezoI-3-yl) M ^T -fenyliiethylcykoohexnnkerboxamid, mp 73 ° C; N- (3'-methyl-1,2,4-oxadiazol-3-yl) -N-phenylmethylbenzamide, mp 75 ° C;

N- (3-methyl-2,4-oxadiazol-3-yl) -N-phenylmethyl-3-methyl-propanol amide, b.p. 127 DEG C./0.4 mbar; .

N- (4-methoxylC-fnC) methyl-N- (3-methyl-1,2,4-oxadiazol-3-yl) cyclohexanecarboxamides (1, mp 70 ° C; N- (4-methoxylphenyl) -C-N) - (3-methyl-1,2,4-oxadiazol-3-yl) --- ethylpropanamide, boiling point 118 ° C (air bath temperature at 27 Pa;

N- (4-Methylphenyl) -methyl-N- (3-methyl-1,2,4) oxadiazol-5-yl) -cyclohexa-1-carboxamide, m.p.

Deň: 32 ° C.

She said d, 60

N- (3,6,6,4,5 / -1,2,4-oe) -2- (2-chloro-2-carboxylic acid) (m) -N-isopropyl-amino-2-methylpoopane (mie

Isobutyric anhydride (7.9 g, 0.05 mol) was added isopropylleino-3-ethoxy-1,2,4-oxathiazole and the mixture was heated at 100 ° C overnight. After cooling, methanol (60 [mu] L) and a few drops of trimethylminine were added to the reaction mixture, and the mixture was heated under reflux for 1 hour. The methanol is distilled off under reduced pressure, the residue is taken up in ether and the solution is washed twice with a saturated solution of sodium hydrogen carbonate. After de-distillation of the solvent, the product is pre-distilled in a spherical distillation tube; boiling point 90 ° C (air bath temperature) at 173 Pa.

Example 61

N- (3-Methyl-1,3,4-oxadiazol-2-yl) -Ne _n -rrPCyCckblobcarbbxxamide

a) 1-Accey-4-allylsemi-carboxylic acid

To a boiling solution of acetyrazrazine (22.2 g, 0.30 mol) in anhydrous benzene (300 mL) was slowly added ethyl acetate (25 g, 0.30 mol) and the mixture was heated to boiling for 1 hour; two layers are formed. The benzene was removed by filtration, the residue was triturated with ether and filtered off; title compound as a white crystalline solid, m.p. 71-74 ° C.

b) 3-Methyl-2-n-propylamino-13,4-oxadiisole

1-AAethyl-4-e-propyl-semicarbazide (35 g, 0.22 moo), prepared as described in (i), was refluxed with phosphorus oxychloride virus for 2 hours. m (150 ml) until no more hydrogen chloride is released. Excess phosphorus oxychtoride is distilled off under a water pump vacuum, the residue is poured into 200 ml of ice water and the mixture is neutralized with 50% sodium hydroxide solution to pH 7. Shake off the red colored oily product into dichloromethane (2 x 180 ml). the organic extracts are combined, dried, filtered and the solvent is distilled off. The oily residue was filtered using a Vigreux column; A pink colored liquid is obtained which crystallizes to a solid by melting at 46.5 DEG-47.5 DEG.

c) Ν- (5-β-β 5 / -1,4-oxaldazol-4-yl) -N-n-propylcyclobutanecarboximide

5-Methyl-2- (2-n-propylamino) -1- (1,3-oxo-1,4-oxazo; L (6 g, 0.04 moo), prepared as described in (b)) is refluxed in both benzene (25 µL) and in the presence of treethylamine (4.72 g, 0.05 mol) with cyclobutanecarboxylic acid chloride (5.5 g, 0.05 mol) for 2 hours. The reaction mixture was filtered, washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and the solvent was distilled off. A reddish brown liquid is obtained which, after distillation twice under reduced pressure over a Vigreux column, affords the title compound as a slightly pink colored liquid, b.p. 110-111 DEG C./36 mbar.

Examples 62 to 69

The following additional oxadiazoles were prepared as described in Example 61: N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-2-methylpropanamide, b.p.

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propylcyclohexanecarboxemide, boiling point 120-121 ° C / 27 Pa.

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-cyclopentanecarboxamide, boiling point 110 to

112 ° C / l Pa.

N- (5-methyl-1,3,4-oxadiazol-1-yl) -N-2-propenyl-2-methylpropanamide, b.p. 93 DEG C./0.4 mbar; N- (5-methyl-1,3,4-oxadiazol-2-yl) -1,4-2-propenyl-2-cyclopentanecarboxamide, bp 114-116 ° C / 16 Pa.

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-hexyl-n-hexanamide, b.p. N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-butyl-2-methylpropanamide, bp 82-84 ° C / 13 Pa;

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-butylacetamide, bp 82-84 ° C / 13 Pa.

Example 70

N-n-hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide

The 1,2,4-oxadiazole was prepared as described in Example 37; boiling point 90 ° C / 147 Pa.

Anal. Calc'd for C 23 H 23 N 3 O 2: C 61.63, H 9.15, N 16.58, O 12.63. Found: C 61.47, H 8.98, N 16.84, O 12.70;

Examples 71 to 73

The following oxadiazoles are similarly prepared as described in Example 47 generally:

N-methyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclohexanecarboxamide,

For C 7 HH ^ NN ^Og requires C, 59.17; H, 7.67; N, 14.82; O, 14.33; Found:% C, 59.05;% H, 7.59;% N, 18.41;

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-2-propenyl-heptanamide, b.p. 104 ° C / 200 Pa. % C, 62.12;% H, 8.42;% N, 16.71;

found:. % C, 62.16;% H, 8.20;% N, 16.54;

N- (3-methyl-1,2,4-oxadiazol-5-yl) -Nn-butyl-2-ethylbutanamide, b.p. 71 ° C / 7.3 Pa. % C, 61.63;% H, 9.15;% N, 16.59; Found: C 61.46, H 8.90, N 16.57, 12.47% 0;

Example 74

N- (3-methyl-1,2,4-thiacliazol-5-yl) -N-phenylinethyyl-n-hexanimide

This material was prepared as described in Example 23. Melting point 72 ° C.

Example 1 to 75

The following additional 1,2,4-thiadiazole was prepared as described in Example 23

N- (3-Minyl-1,2,4-thiadiazolinyl) -N-hydrogenation, mp 38 ° C;

N- (4-methyl-1'-4-thiadiadiazole-5-yl) -N-methyl-2-carboxylic acid, mp 57 ° C;

^ O Hhhyl- ^{1, d} i and ^y 2J4lt thiazol-5lyl) -N- ^h enyllnt ^{yn l-ll} FNE -acntεmi ^d, triols TAM is ¹ 34 ° C.

Examples. 78 to 86

Following the procedure described in Example 47, a further 1,2,4-oeadiazole was prepared

N butnl-N- (3-Mn ^М у 1 ~ 1 2.4 - oxedčazzlL ^ -yl) neylkarbceamid analysis: for vnpočtnno: 64.44% C 6.61% ,, Η, 16 _t 1 .% N, 12.44% 0 naLnznno 65> 99% C, 6 _t 55% H, 15.99% N, 12>, O7 0%;

Nb-yl-methyl-N-n-ethyl-l, 2,4-oeadiazol-5-il) ^-4-cy lorhenylkarboezlid analysis: for C ^ ₁ ^ C1N ₂ O vnpočtnno 57> 44% C 7, 5, 99% 7 H7 12.07% Cl7 14 _t 37% 7 N, 10.97% 7 0, including: 574 55% C, 5.33 H, 12.37% Cl, 1 4.1 7% N, П ^^ О;

^N -butyl- ^N - ^(3-methyl-e h · ^l-yl 1, ^2, - oxadizzol 5- ⁿ⁾ -L-LTE ^h hox ⁿ phen ^l lkarboezli ^d Topi bp ¹⁰⁵ ° C / ² Pa Analysis % for C C HH ^ ^N N-O O: C, 62.27; H, 6.62; N, 14.5 .2%, 16.59%. Found: C, 61.99; 6.47%. H, 14.42%. N, 16.74%.

N bbtyllN- (3-supine ^y tl-1,2 - oeadiazll55ly)) lkklh ezenkarloxвlid ^y, ^ mperature bp 70 ° C / 1 mbar, the analysis' for ^θΐ4Η.23 Ν 2 ^Ο 3 vnpočtnno: 63.37 % C, 8.47% H, 15.84% N, found:% C, 63.54;% H, 557;% N, 15.60;

^N -butyll ^N - (3 'Ine ^H H ^{l-yl-1, 2,} - oxadizzoll5- ⁿ l) cyclohexyl ⁰ OBU ^from enkarboealid idiot boiling point of ⁶⁷ ° C / 3 ^{p _z;} * analysis: for ^^ ^ 2 ° 3 ^ ² ^ what NO: 60.74% C 83.77% H,% N, 13% @ 19 0 ezlnznel: 60.44% 7 7.88% H N 17 13 217% 0;

^ - (3-1 ^ '^ Уу: 1- ^ 1, 2,4-lezdizzll55l l)) -! ^^ prlPl; LL22 _{met.tl.Ίlpropznaliά-J} ^ mperature boiling point 62 ° C / 20 mbar, the analysis : for CjqH | Calc'd: C 56.85, H 8.11, N 19.89

low: 56% 3% 814% H7 19 »64« N5

N-butyl-N- (J-butyl-1) 2,4-oxadiazol-5-yl) cyclopropaiicarboxamide, Anal. Calcd: for C ^ HHg ^N ^Og: C, 63.37; C, 8.74%. H, 15.84% N, 12.06% O, found: C 63% 19, 8.51% 7 H, 15.58% N, 11 »82% 0;

N-butyl-N- (3-ethic-1,2,4-lxadiazol-5-yl) -cyclopropanecarboxamide, boiling point 65 ° C / 1 Pa, analysis: for C 18 H 18 N 4 O 6 · calculated: 60.74% C, 8 H, 07.1; N, 17.1; N, 13.49. Found: C, 60.5; C, 7.78; N, 13.33;

N buUyl -N- (3 "Ciklohexxl-1, 2,4-oxadiazolb5byl1 lklooρooankPpUlxamid _C, Analysis: CjgHggN ^ Og

I calculated: C 65.95, H 8.65, found: C 66.15, H 8.83,

Examples 83 to 89

As described in Example 60

N-butyl-N- (3'-ethyl-1 (Z, 4-oxadiazol-5 ')

N 14.42%, 10.98% 0,

N, 14.51; O, 10.86;

the following additional oxadiazoles are prepared:

‘Yl) 2-methyl chloroopanpmide, boiling point 65 ° C / 3 Pa,

Anaalysis: calculated for: C 18 H 8 N 4 O 6: C, 60.22; H, 8? 5%; N, 13.56. 13 > 37% O;

Found:% C, 59.96;% H, 8.68;% N, 36%;

N-butyl-N- (3-butyl-1,2,4-lxadiazol-5-yl) 22-methyloplopanamide, boiling point 64 ° C / 3 Pa, analysis: calcd. ^ 9% of C, S> 4 H 42% 15> 72% N, 11.93% O found: 62 _F 55% C, 9 »20% HL 15446% N 11> 72 0%;

Ы-ЬНуУ-М-Л 3 -cyclohexyl-1,2,4-lxadiazol-5-yl) -2-methyl-10-pentanediol, boiling point 92 ° C / 3 Pa, analysis: calcd. H, 28%; N, 14.32; O, 10.91;

Found: 65 », 26% 0, S,> 09% _f H ^ 14-0 7% N, 11.05% O;

The following Examples 90 to 97 illustrate the preparation of pharmaceutical formulations containing N-n-hexyl-N- (3-bethyl-112,4-ololazol-5-yl) cycloentanecarboxamide as the active ingredient.

Example 90

Soft gelatine capsules are prepared by incorporating the following ingredients: Mooss (active ingredient) active compound 30 butyl hydrated oxyanosol B. P.0.02 distilled coconut hey B.P.C. 30____

100.02

The ingredients are mixed and filled into soft gelatin capsules, the shell of which is mainly composed of gelatin and glycerin.

Example 91

The procedure was as described in Example 90, but with the same propp-gallate as an antioxidant instead of butylated hydroxyanisole.

Example 92

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mm / capsule) Active Compound23 Silica (anhydrous) 23 Lactose48 Butylated H 2 O 4 N 2 O 3 N P

The butylated hydroxyannsol is dissolved in the active compound and the resulting solution is adsorbed onto silica (anhydrous). Lactose is added, mixed well and the mixture is filled into hard ielltin capsules.

Example 93

The ointment is prepared from the following components: hydroxy active compound hydroxyanisole butylated B.P. white paraffin vaseline

1.5 wt.

0.02% wt.

ad 100%

The butylated is dissolved in molten paraffinic vaseline, the compound and the mixture allowed to cool.

add to effect 94

A topical cream containing 1.0% active compound is prepared as follows:

active compound 1.0 g nonionic emu Uí ^ ^ i ^ i ^ i ^ J ^ reagent of the formula _{CH3. [CH2]} n. [o.CH ₂ .CHH _m .OE, where m is 15 or 17 and n is 20 to (Cetomacrogol 1,000) 3.0 g of citric acid 11.5 g paraffin oil 9.0 g butylated hyúroxyaaisol BP 0.02 g distilled water up to 100.0

The active compound is mixed with butylated hydroxyenisole and the mixture is stirred. suspended in paraffin oil. Cetostarlalcohol is added to the suspension and the mixture is heated to 70 ° C with stirring. At the same time, dissolve Cetommarogol 1000 in 60 ml of water heated to 70 ° C. In the case of an aqueous solution of Cetomaarogol 1000, the above mixture of o-alcohol, paraffin oil and the active ingredient is mixed with stirring, and the cream is stirred until cool. Thereafter, the cream is adjusted to the desired moisture content by adding water and passed through a 0.38 mm slit in a stainless steel coioid mill.

Example 95

Suppositories containing 25 mg or 50 mg of active compound are prepared as follows: 2.5 g of active compound

Henkkl's base 97.5 g

The active compound is mixed with the melted Henkel substrate, using as little as possible to lie.

The molten mixture is poured into suppository molds having a nominal capacity of 1 g and 2 g, respectively, to give suppositories containing 25 mg and 50 mg, respectively, of the active compound.

Example 96

An aerosol formulation can be made using the following ingredients:

Amounts per ml of the active compound 10.00 mg propylene glycol 11.00 mg tetrotortuum fluoride (propellant 114) 550.00 mg diclorodifluoromethane (propellant 12) 830.00 mg

The active compound is mixed with propylene glycol, the solution is added to the propellant gas 114, the mixture is cuhaadC at -1 ^° C and 20 ^° C and transferred to a filling device. At the same time, the propellant gases 111a 02, which have been pre-cooled to -15 ° C and -20 ° C, are filled into the second filling device. Ccd ené mi mi!!! the propellant gas from the second filling device is introduced into a stainless steel container and then the necessary amount of the mixture from the first filling device is added. The vial is then replaced with a valve and sealed. Vv-li! it is provided with a measuring device which, in a single operation. softening of the valve releases about 0.15 mg of the active compound. _w

Example 1 'and d 97.

Tablets are prepared using the following ingredients:

active compound 10.00 mg microcyssalic c-Iu-osc 250.00 mg sodium salt of starch bexylmethyl 25,00 mg st-cnami Učř -nntý 3.00 mg butylated hydroxy salt B.P. 0,002 mg

The butylated hydroxysilicol is dissolved in the active compound and the solution is adsorbed per ml of c-l-axis. The resulting mixture was mixed with sodium starch carbonyl sodium, magnesium stearate was added, and after thorough mixing, the mixture was compressed into tablets.

In the above examples, 90 ai. 97. The liquid active compound may be either wholly or partially other liquid active compound obtainable by the process of the invention. If a solid is used in place of the liquid active compound, of course these processes must be suitably treated.

Claims (2)

OBJECT OF THE INVENTION (B) when Ar is 1,3,4-thiidiisolyl substituted with methyl; and R6 is p-bromofewl, R has any of the above meanings except meetyl; i ⁽ c ⁾ if. Ar ^ C ^ -oxidiizolyl substi.tuovený phen ^l rim ^R 'has any of the above-mentioned ^{characterized} У ^h 2 meanings except methyl or benzyl when R is methyl, characterized in that the alkyl is alkylated. a derivative of formula VIII ArNHR ¹ ^ 111 ^ n MŽ ^of Ar and ^R1 MMIII defined above. 2. Method of claim 1, confessed ^ said non · whereby a compound of formula VII in ^them ^ ^ Target MŽ toteroi this Ar is a substituted ^ · _ · C i-iltylem jillenyl bennyl or will be indicated in the compound of reilci of formula R ¹ is γ-C 1-6 alkyl, R ² C0X wherein R represents Y ^^ illil, У ^ __ cylloalkyl or benzyl and X · · represents a chlorine, bromine or Groups - ^ ^{-OCOR 2e.} 3. A method according to claim 1 or 2, wherein the compound of the above formula VIII, wherein the heteroiryl ring Ar is a 1,2,4-oxidiisolil system substituted with at least one group selected from the group consisting of: hydrogen, Oj ^ alkyl, C ^ cC ¹ ^^ shaved and ^phenyl and ^Rd has .shora Uve · ^d Eny meanings indicated in the compound is generally reiksi ^ o formula 'f R ² C0X 1 · 2 (i) when Ar is 1,3,4-thiidiisolyl, R is O 1 and H 1; substituted with any of the abovementioned groups, except for the group consisting of hydrogen atom and γ-illyl; A process for the preparation of therapeutically active icylamino-substituted five-membered heterocyclic compounds of formula I. · Ar-NR ¹ I, ^(I > · COR) v.němž pětičlerný Ar is a heterocyclic ring obssahjicí as heteroatoms two nitrogen atoms and · a further heteroatom selected from the group consisting of oxygen and sulfur, wherein said heteroaryl ring is substituted by at least one group selected from the group zOimnjící hydrogen, C ^ ^ la gCykLiol ^{phenyl. p} c řLčemž ^yl eminosku ina ^p -NR c ^{OR 2} is attached and the carbon atom ⁿ · heteroirylového ring, and R 'is selected from the group comprising β-Ο ^ΙΙ-1, C-gclkenyl, y ^ gCykloaUkyL and benzyl substituted with at least one group selected that. groups zOhnuící · vodíkα hydrogen ^atom, a ^{C h} alo ^ene C- ^ ^»111 /! and ^Y ₁ _ ^J l ^il OXYS ^{the UPIN} and ^{R2 is?} Ο | _ ⁸¹ ^ 11]. · ^ C ^^ cykloOLkyl, benzyl and phenyl substituted with at least one selected from Groups · Groups zahrnuící hydrogen, halogen and yj i iiloxy, provided that,. r ' Wherein R is as defined above and X is a chlorine, bromine or group atom -OCOR ·