SI7910862A8 - Process for the preparation of cycloalkyl-triazole - Google Patents

Description

FIELD OF THE INVENTION

The invention relates to the synthesis of heterocyclic compounds and relates to a process for the preparation of novel cycloalkyltriazole derivatives having interesting physiological activity.

Technical problem

A technical problem that is solved in the present invention is a process for the preparation of novel 5-substituted 3,4-cycloalkyl triazole derivatives of general formula (I) as defined below. The compounds of formula (I) are useful as antiglaucoma and antipsychotic agents and can also be used as medication for patients with psycho-physical dependence on alcohol, tobacco and some drugs. Since the compounds of formula (I) are novel, the previously unspoken compounds, the process itself is novel to obtain and cannot be compared to any known prior art.

The state of the art

The applicant is not aware of any prior art reference to describe a process for the preparation of substituted cycloalkyltriazoles similar to the compounds of formula (I).

A description of how a technical problem is solved with examples of execution

The process of the present invention provides new ones

5-substituted 3,4-cycloalkyl-triazole derivatives which can be represented by the formula:

In the formula, alk is a linear 111 branched bivalent 1111fat1 and a string that is 1 in from 1 to 10 carbon atoms. The symbol alk * * represents a linear 111 branched alpha 1fatlnnl string which 1ma from 1 to 5 carbon atoms 1 R 1 R '(in other cases except when P «R * H) represents two substituents on the aromatic nucleus, which will be the same 111 different and which may be located in any position on the aromatic ring. Thus, the benzene ring may be unsupported by tul san, 111 may 1mat1 be a substituent in o, m 111 p position, 111 horns be dlsupstltulsan on om, op, rap, oo.

Further, the R 1 R 'substituents may be alkyl, halogen, alkyloxy, hydroxy, trifluoromethyl 111 methyl. The term alkyl is intended to mean methyl radical and other simple alkyl radicals having up to 5 carbon atoms, such as ethyl, propyl, isopropyl 1 and the like.

The term halogen refers specifically to fluoro 1 chloro.

The term alkoxy · refers specifically to methoxy, ethoxy

·. * £ isopropoxy.

Non-Toxic "1,. Pharmaceutically Acceptable Salts The invention provides those salts which are known in the art commonly used to trim salts with basic substances which /

should be used as pharmaceutical substances, ie * salts with monobasic 111 pollbasin mineral acids (hydrochloric, sulfuric, phosphoric, etc.) 1 salts with monocarboxylic acid 111 polycarboxylic organic acids (maleic, lactic, methanesulfonic, acetic ).

These salts are made by conventional techniques that begin with the pharmaceutically acceptable acid 1 of the active ingredient bazaar.

Cakes of these horn salts are products which are formed with one 111 two acid molecules. Moreover, some of these salts may crystallize even in anhydrous 1 in hydrated form 1, in some cases, the horn retaining One 111 more solvent molecules for crystallization.

II (where alk ”denotes certain methyl and ethyl).

In the process of the present invention, esters are used

4-ar-1-piperidinyl-1 alkanoic acid, which is well known in the art. 0n1 is then transformed into the corresponding hldrazlds with. hydrazine-hydratoe 111, in the honogenous phase, using a solvent solvent such as ethanol 111 in the double phase, one of which is aqueous, using catalysts suitable for such a reaction.

The hldrazldl thus obtained is treated in a suitable solvent at cloudy temperatures with some alkali-lactam. Adequate aeldrazone (II) is obtained which is separated 1 by cycling with heating, either in the dry state 111 in some solvent, solvent.

Alternatively, the nose may be subjected to two reactions simultaneously, by direct combustion of hydrazide and elbows, either in the presence of 111 in the absence of solvent. In some $ 1 cases, the presence of a basic catalyst, such as sodium s-methylate, finds a rapid reaction. During warm-up, alcohol is eliminated first by trimming amldrazone, which is not isolated 1 subsequently eliminating water from the closed trlazole ring. The reaction can be carried out 111 by removing the alcohol 1 of the water which is formed in the reaction 111 by performing the reaction under reflux conditions.

The green base products are separated from the reaction mixture and then salivated by known techniques.

The following examples illustrate the invention:

EXAMPLE 1

Preparation of 3- / 3- / 4- (2-tol 11) -1-pipeline level 11 / propyl / -5,6,7, $ / * tetrahydro-s-triazolo / 4,3-a / p1r1d1na /. · ( I alk - - (CH ₂ ) ₃ -; alk *. - (CH ₂ ) ₄ -:

R 1 is 2-CH ₃ ; R * - H

A mixture of 26 g (0.147 mol) of 1- (2-tol11) piperazine, 23 g (0.154 mol) of ethyl 4-chlorobutyrene, 11 g (0.104 tuolft) of anhydrous sodium carbonate and 1 130 ml of absolute ethanol was heated under reflux conditions, with. By stirring, 24 hours.

The reaction mixture was cooled to room temperature 1 cropped sodium filtrate separated filtration!? .. Alcohol was eliminated from the filtrate by heating under reduced pressure.

the oily residue is distilled. 20 o (472) ethyl ester is produced

4- (2-Tolyl) -pyrazole or butyric acid, incl. 185 ° (0.6 mm Kg), which was dissolved in 50 µl of arsenious ethanol. This <

15 g of hydrazinhydrate (932) were added to the solution and the resulting suspension was refluxed for 4 hours. The alcohol was then separated under a foamed press., 1 residue was collected in 50 ml of a solution of 502 potassium carbonate.

The rubbery residue, on standing, becomes a filterable substance ί has a low melting point, which is collected and washed with 1 ether hydrogen: (14 g - 74 :). A small fraction was transformed into chloride hydrate showing mp 202 ° C,. . . , ---- _ ₆ -after crystallization From absolute ethanol. 14 g of the above hldrazld was further mixed with C g (0.05 mol) of O-tsetllvalerolactam, 0.4 g of dry sodium methylcrylate 1 was added and the mixture was heated, with stirring, to 120-130 ° for 45-50 minutes. The mixture is still

cool 1 is collected in absolute ethanol. The insoluble impurities are removed. The filtrate 1 filtrate is treated with an excess solution of hydrochloric acid 1 in acid in ethanol. The precipitate which formed was further separated by filtration of ^ 1 recrystallized from ethanol at 95 °; m.p. 2C6 ° C .; yield 15 g (731). Analysis® product shows forr.ulu .2HC1 .H ^ O.

EXAMPLE 2

Cobylva n is 3- (2- / 4- (2-yl) -1-piperazinyl) ethyl] -C, 7, fc, dtetra hydro- N -s-tri azole / 4,3-a / azepine (1 'alk - '(CH _? ) _? -; alk' «- (CK ₂ ), -;

R «2-CH ,; R '»H)

a) Hi ir d 4- (2-tol 11) -pi r-erazi nll-prop er.ske kjs & l ine

A solution of 23.4 c (0.103 mol) of 4- (2-tolyl) piperazinyl-propionic acid ethyl ester of 1 25 g (0.5 nol) of Mnrazhlldrate (SPI) in 50 ml of ethanol was refluxed for 5 hours.

At the end of the warm-up cycle, the solution is cooled, diluted with three volumes of water, which is separated. from ethyl acetate. Princs

13.c g (soil); m.p. 13 ° C-159 ° C.

Analysis of pct2ujc formula ^C 14 ^H 22 ^; 4 ° '

- *.

b) The mixture formed with a mixture of 4.3 g (0.034 mol) of o-methylcaprol & ktama, 9 g (8.034 r ola) of the previous hldrazld 1 0.9 µ sodium methlate was heated, with vigorous stirring, with the aid of an oil bath kept at 16O-17O ° C. 1 hour 1 15 cin. After cooling, the soluble part in

- 7 ' to the knuckle hexane assisted by three successive washes of 1 decent. The hexane extracts were fused 1 1 to dry. The residue was taken up in ether 1 A double equivalent amount of hydrochloric acid solution in ether was added. The dichlor ·, * hydrate to be precipitated was collected by filtration "and recrystallized from ethanol."; m.p. 2S2 ° C .; yield 11 g (77.55).

The analysis agrees with the formula ». 2HC1.

EXAMPLE 3

Preparation of 3- (2- (4- (2-tolyl) -1-piperazin-11-ethyl) -5,6,7,8-tetrahydro-s-triszol- [4,3-a] pyridir.a.

(I alk - - (CH ₂ ) ₂ -; alk * - - (CH ^ -;

P. - 2-CH ₃ ; R '»H)

S .-. EJs 23.1 g (C.22 riol) o-ethyl 1 va ero! octane, 52.4 g (0.1V roll) of <- (2-toH1) -piperazinyl-propionic acid hydrazic and 20C xylene xylol is heated under r & flux removal, in a suitable apparatus, of alcohol 1 of water formed by azeotrone distillation . When the formation of water ceases (approximately S hours), the resulting solution is allowed to cool 1 the formed substance is separated by filtration, washed with hexano and dried in air. Yield: 41.5 g (675); t_.t. 153-160 C. The values for a 1 Ossentary analysis agree with the clenentary forr-υΐ and CpR- ^ N.-.

i-pnohlcrhi drat

Pf formed 3.25 r / three of the spor-enutc base - in 20 tul of absolute ethanol was added 2 »1 5 solutions of ΗΓ1 in ethanol. The solution was diluted with an equal amount of ethyl acetate, a separating solvent, which was separated by filtration and recrystallized from absolute and

alcohol. Yield 3.1 g; m.p. 2O6-2C7 ° C. The analysis of chlorine ion agrees with the formula »C. _HHCI.

27 f

Dichlorohydrate. .. \ / J · »· '. ·'% Y

To a solution of 3.-25 g of the base described above, dissolved in 20 cyl of absolute ethanol, 4 nor ethanol HCl solution (5 H) was added. The separating substance was filtered off with 1 liter of absolute ethanol. Yield 3.2 g, mp 253-254 ° C. The analysis ^{follows the} formula on ^C 19 ^H 27 ^K 5 ' ^{2,: C} 1 *

If the same hydrochloride is recovered from 1 ° alcohol at 95 °, 3.0 g of product is obtained, m.p. Mp 214-215 ° C., 1a The analysis corresponds to the formula.

Haleat

The solution obtained dissolved 3.25 g of the aforesaid sponge base υ 23 .τ t ethanol absolute t $ s with a solution of 1.16 c maleic acid in 10 nor the ethanol absolute. The solution was distilled off with 30 [mu] l of ethyl acetate 1 substance. The branch was collected by filtration. 1 recrystallized from the ethanol absolute. Yield: 2.5 g; tt 153-15 * ^c C.

The analysis agrees with the formula «Cj § ^ 27 ^ * 5 '^ 4 ^ 4%'

EXAMPLE 4

Preparation of 3- / 4- (2-tolyl} -1-piperazinyl-1-ethyl) -5,5,7, S-tetrahydro-s-triazole- (4,3-a) pyridine (I alkyl »- (CH ₂ ) ₂ -i alk * «- (CH ₂ ) ₄ -s

R is 2-CH2; R '«H) j

a) 4- (2-Tol 11) -piperidine-propionic acid hydrazide with 3,4,5,6-tetrahydro -? - hydrazino-pyridinone.

Solution £ c {S.07 roll} P-met 11-wave erolcktarc. 17.5 - (C.067 rolls) of 4- (2tcl and 1) -piperazine or 1-prone or.sl acid is added to 120 ml of benzene. The suspension was vigorously stirred for 3 hours at room temperature. The resulting substance was collected by filtration, 1 Washed with benzene. Yield: 20 o (87?); mp 110 ° C. with decomposition »(pre-bathed bath). Elemental analysis agrees with the empirical formula ^C 19 ^H 29 ^W 5 ° ·

- ^ 3

b) 18 g (0.053 mol · *) of the above aoldrazone was suspended in 200 ml of benzene. The Snela was refluxed for 3 hours with azeotropic acid removal of the formed water. At the end of the warm-up cycle, the substance cools down, the substance being formed is separated and the mixture is dissolved in benzene. Yield: 15 g (S3l) j.p. i61-152 ° C.

Elemental analysis was sent from eir.p1 rij.?. formula om EXAMPLE ⁵

One of the procedures described in Examples 1-4 were made:

3- / 2- / 4- (2,5-11 hicrofεπΠ) -1-pyrrolidinyl-ethyl / -6,7,8,9te trachydro-5H-s-tri azole / 4, For / azei n (I alk - - (CH ₂ ) ₂ -i alk '»·'.« = 2-C »; k '= 5 Cl)? Cnochlorhydrate. H ^ C mp 220 ° C. (from alcohol at 95 ° C)

H prefers d 4- (?, 5-d1h1oref «i» i 1) -p1 crosslinks or l-proplOr.sk e acids, not necessary for the sfr.thesis the mentioned product was made according to the pre-plated element and 1rse m.p. 13E-137 ° C (From ethyl acetate).

Elemental analysis shows the formula C, AcUJLC.

o 1 fc? 4

The 4- (2,5-d1 chlorofen.11) -piperazine-11-propionic acid ethyl ester required for the synthesis of the pre-chlorofrazole was prepared according to method 1 described above. 19P-2QG ° C / 1 r: s.

Elemental analysis shows the formula ^r j ς ^Η 20 ^ 2 ^? '2 ° 2'

3- / 2- / 4- (2,5-dichlorophenyl) -1-piperazinyl-ethyl / -5,6,7,8 tetrahydro-s-triazole / 4,3-a / pyridine (I alkyl · - ( .CH ₂ ) ₂ -; alk ·. - (CK ₂ ) ₄ -;

R-2-C1; R '»5-C1)

Dichlorohydrate. H _with 0 mp - 218 ° C. (from alcohol at 95 ° C)

3- / 2- / 4- (3-chlorophenes 1) -1-piperazinyl-1-yl11-6,7,8,9-tetra * ♦ · »A-4

Mdro-5H-s-trisazole / 4,3-a / azeplene (I alk - - (CH ₂ ) _2- alk * - (CH ₂ ) ₅ -j R - 3-C1; R * - H)

Chlorhydrate m.p. 234 ° C. (1z of absolute ethanol)

3- (3-) 4- (2-Tolyl) -1-piperazinyl-1-propyl-6,7,8,9-tetrahydro5H-s-triazole-4,3-azeplene.

(I alk - - {CH ₂ ) ₃ -; alk »· - (CKJ, -;

R · 2-CK-; P '* H) •' onohlcrhldrat m.p. 271 ° C. (From absolute ethanol).

3- / 2- / 4- (2-cethenylphenyl) -1-piperazinyl-1-yl] -6,7,8,9tetrahydro-5H-s - three azole / 4,3-a / azepline (I alkyl - - ( CH alk '' - (CHJ.-;

C C Cm. p. «2-OCH .; R '- K)

Honohlorh! Drat m.p. Z30 ° C. (1z of absolute ethanol).

As indicated earlier, the compounds of the present invention, administered in effective amounts, are effective

·. \ - · are for treatment:

a) h1pertenzlic states of cka, including glaucoma, when z * are given topically 111 systemically;

b) pslhopatoldtklh symptoms of psychophrenia of the Johfrenl type psychosis »certain hallucination of 1 dellfcljutpa, by means of oral 111 parenternl administration; and,

c) abstinence syndrome in patients with the condition, the name of the psyllophilic drug, which is 111 alcohol dependent alcohol producing tobacco, 111 pharmaceutical substances, oral 111 parenteral drugs.

In pc · the latter n states (c) the co-treatment with ?, does drain cblike currently lor 1? (e h treats the wound, but the syndrome? af with tir.encf j «is mitigated by the effect on psyhloSke p: ehi.r.1xne the quays cause it. Zeto the present compound can be sisatrated with additional i11 depot agents to be used in conjunction with other For example, such as psychotherapy, such as facilitating the process of unwinding.

The therapeutic value of the compounds of the present invention for each of the preparations depicted is determined using experimental models at 1 agodated to demonstrate the «effects of each of the various symptoms outlined above. The ability to lower eye pressure was studied with 1 rz norralnir rabbit *, using the experimental conditions described previously (Ourbery et al, “Effects of sys ter 1 cal ly · adninlstsred drugs on intrsocular pressure in rabblts”, Arznein. Fcrsch., 20. 1143-1147 (1970);

Oe ^ ^{e0 e} * »Effects of top1 ^! ca1ly 1nst1lled drups on intraocular pressure in rabblts, Arnzel «. Forsch., 25, 806-809 (1975)) 1 in animals with cynon hypertension.

- 12 One example of ocular hypertension used in the test is one that is produced by the introduction of a single suspension of betanetazone into One 111 two eyes. Thus, it is possible to obtain stable ocular hypertension that is indistinguishable from glaucoma in humans.

The products tested have been shown to have heart defects. pressure in normal rabbits 1 in rabbits with ocular hypertension, 1 when given topically, in the form of eye wash fluid at a concentration of 0.25-0.5)., 1 when administered parenterally at doses Between 0.1-1 κο / kg l.v.

In ocular hypertension product! Compared with pilocar? 1no, in the form of eye irrigation fluid at a concentration of 0.5-li 1 it has been shown that they have the same activity, ^w edjut1m, over the last product have the advantage of not causing ftiosis and other irritation.

Furthermore, it has been shown to produce other similar activity with neurol eptl cilia in the formulated laboratory test kit for the study of a whole class of drugs.

Amphetamine toxicity in niches can be cited as an example of coricheroids (Lagerspetz etal, Amphetar.ine toxicity in geneticallv agoressive and non-agaressive rrics ¹ ·, J. Fharm. Phcrmacc-l., £ 2, S <2 (1S71)). The products are chloroproriazine-coupled and exhibit similar barrier activity. " ,

- ··.

As compared to the last 1 to other traditional neuroleptics, the products of the present invention provide two major advantages, namely, lower toxicity and lack of catatonia.

On the basis of the last Indented Indication, nowSodnja Jedlnje \ - -ι ₃ . · -:

these may be considered free from the side effects of the extraplural type, which, in turn, are common features of other neuroleots.

Finally, the tests that led to the use of the present compounds in the treatment of alcohol 111 habituation to alcohol, tobacco 1. farc «aceutic substances that create lining, were done using a completely new operative theory.

It is well known that other substances are considered to be a manifestation of alcohol addiction 111 «psychological adjustments that are developed in the world to compensate for the early deprirriating effects of noaenutl relatives.

When administration of the latter is discontinued, the adjustments made by the organism are no longer balanced against the η-effective agents mentioned, and therefore, sympathetic reactions occur.

As is well known, the reaction of cheering reverberates as a result of syrtodic hyperhexitability, tenuous tension and shivering, excitement, nausea 1, in some serious cases, cramps. For these tests, a working theory was used that meets ds, based on the phonener adlkclje 1 dependence, and therefore 1 siridrora spstinsndje, postcjl common physiological rehanizar kcj1 orcar.lzar used to adapt a variety of srccstvlra ^l tc what st logger », alcohol, narcotics analgeticl, etc.

To confirm this is produced by the life-affirming syneron or addiction-tl to the following substances: alcohol, nicotine, morphine and clonldine.

The results obtained show that abstinence syndromes that occur when the above treatments are reversed can be treated.

-K not only with case-by-case alternative treatments (e.g., lobelln is only active in the case of nicotine, while methadone is only active in the case of morphine), · z ♦ ve.Č also 1 with sunstannans that do not -soeciflly in all pores sporulated by tlps of the apsti nenci syndrome is ..

V

These latter substances are those which are shielded in the present invention and are iodine, of the numerous proBČover.ih products, possessed by oyu ojoMmi. Thus ·: οπυ can be used as a donor remedy for 7s of treating patients who suffer from cd additions 111 depending on the nature and nature of the use of “completely irritating” effects.

In fact. izi ', l ^a da to act on the physiological system used by aranier to balance the de ^ res 1 hot effect of such substances as sr alcohol 1 rcrfir.

How can this rrrrrrrrrrrrrrrrrrrrr? against with 1 moto abstinence is n? suustitncio np "" teranijcn, which is the one time cr-esra as 1 agent that produces an acyclic (as in the "case of methadone used for the treatment of morphine and crure drugs), more direct effects: on the physiological system kcj1 is odeovortn with? abstinence syndrome is.

Therapeutic treatments return short of the use regime ?: Oral, products are given an average of 25-5Γ - *? * Three routes? c '' - iv * c. ΓΗ lik er tretirarjz 'i zcfrzni is also worm rsi

O r 2 s o i h si

209 he three sharp features, k i o i ??. the third ra :, j c n * manual d roma a ^ stint 'dje, cross doses' emu particle times to o v no.

For oral waxing, n-cie used oral formulation type sake, r.e-Vxical 1 common uses, such as solutions, suspensions, tablets, capsules, powders, formula

--15.ce 1 aptrdt; fired 1 similarly. '

For parenteral tanning, the products may be administered at an average dcfzl 25-5G r <g ', 2 111 3 times daily. For the treatment of glaucon 1 other hypertensive eye forms, products>

are given in the form of eyewash fluid (concentration 0.25-G.5T} 2 to 4 times daily. To achieve this, an aqueous 111 oil formulation selected from those commonly used in the area of target treatment is used.

the floor is "the compounds of the invention sadaSnjec ^w abandoned to wander istovrc-chlorides with drujir .farmaeeutski '' sredstvira, imajuči u joke orireejeri tif kcja disease is treated.

Teuton 33S-442

The best way to use the invention in prlvredl, which .is ^ known

Applicant

The invention can best be applied if the following procedure is used:

A mixture of 4.3 g (0.034 mol) of o-methylcaprolactam, 9 g (0.034 mol) of 4- (2-tolyl) -piperazinyl-propionic acid hydrazide and 0.9 g of sodium methylate was heated with vigorous stirring at 160-170 ° C. 1 hour and 15 min. After cooling, a soluble hexane-containing portion of the balloon is extracted from the balloon with three successive rinses and decantation. The hexane extracts were combined and evaporated to dryness. The residue was dissolved in ether and a double amount of an equivalent, hydrochloric acid solution in ether was added.

The dichlorhydrate was filtered off and recrystallized from ethanol to give 3- (2- (4-(2-tolyl) -1-piperazinyl) ethyl) -6,7,8,9-tetrahydro-5H-s- triazole / 4,3-a / azepine.

Claims (1)

Process for the preparation of cycloalkyltriazoles of the general formula: in which: an alkylene alkylene linear array containing 1 to 3 carbon atoms, alk an divalent alkylene linear chain containing 4-5 carbon atoms, and R and R 'which are identical or different represent a radical selected from the group consisting of hydrogen, methyl. methoxy or chlorine, wherein the cyclic alkylactam of the general formula: alk J O-alk 'where alk' as defined above and alk '' is methyl or ethyl, is heated with the aryl-piperazinyl-alkanoic acid hydrazide of the formula: