DD283619A5 - PROCESS FOR PREPARING NEW 3,4,5-SUBSTITUTED 4H-1,2,4-TRIAZOLE - Google Patents

Abstract

The invention relates to a process for the preparation of novel compounds of the formula (I) according to the invention. (R1, R2, R3, R14 and V are defined in the description). They can be used as drugs with particular PAF-antagonistic effect. Formula (I) {new compounds; PAF antagonistic effect; Application as a medicinal product; inflammatory and allergic diseases}

Description

2 a 3 6 i

Process for the preparation of new 3,4,5-substituted 4H-1,2,4-triazoles

Field of application of the invention

The invention relates to a process for the preparation of novel 3 »4» 5-substituted 4-H-1,2,4-triazoles with valuable pharmacological properties, in particular with PAP-antagonistic activity.

The compounds according to the invention are used as medicaments, for example for the treatment of inflammatory and allergic diseases in which PAP is involved.

Characteristic of the known state of the art

There are no known data on compounds with PAP-antagonistic activity, which are suitable for the treatment of inflammatory and allergic diseases.

There are no reports of processes for the preparation of 3 ', 4,5-substituted 4H-1,2,4-triazoles.

Object of the invention

The aim of the invention is to provide novel compounds having a PAP-antagonistic activity, which are suitable for the treatment of inflammatory and allergic diseases in which PAP is involved.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention: new compounds of the formula

manufactured.

Where R, R2, Ro, R _{1 have} :

R R

(II)

(D

and V have the following meanings:

(III)

(IV)

ΊΟ where

R., Rc for H, R ₁₁ , OR ₁₁ , halogen, CF ^, aryl, I ¹ I (R ₁₁ ) O, together also for a fused-on

" 9 ° '1

C ₅ -C ₇ -CyClOalken-, a fused-on benzene ring or one of the groups bound to adjacent C atoms of the benzene ring -N = CH-NH-, -N = CH-CH = CH-, -O-CH ₂ -O- , -O-CH ₂ -CH ₂ -O-, -NH-CO-NH- and -N = CH-CH = N-,

_{r is} H, R _n , or OR ₁₁ or aryl;

XX XX

R _{7 is} H, R ₁₁ / halogen or aryl;

for H, R, or halogen, R_ and R ₀ together also for one.

/ O

fused C ₅ -C -cycloalkene or benzene ring,

R _g , R ₁₀ for H, R ₁₁ , OR ₁₁ , ₁₁₂

together also for a fused Benzo1ring;

X is S, O, NH or Y is CH, N;

R _{11 is} C 1 -C 4 -alkyl, and when in addition to R ₁₁

or an R-. group containing radicals II, III and IV have no further substituents, also C ₅ -C ₁₂ alkyl or alkoxy;

H, C ₁ -C ₄ -alkyl, CF ₃ , C ₁ -C ₄ -alkoxy, CH ₂ -O- (C ₁ -C ₄ -alkyl), C ₃ -C ₆ -cycloalkyl;

(C.-C, -alkylene) -Het, where Het 1 o

.NO

-N

12

• R

13

R ₁ ,, 12

-N

13

N.

-N

2 3 3: 1

12

(V)

(VI)

(VII)

13 (VIII)

12

(IX)

^C 13-

Z: S, N-R, CH = CH, N = CH or CH = N;

JL / *

: H, C ₁ -C ₄ alkyl or aryl;

R: H, C -C -alkyl,

R ₁ _ and R-_ together, if appropriate

a fused benzene ring;

14 ^{: H>} C 1 -C -alkyl, C 1 -C 4 -alkoxy or halogen; CR t / fk Be

tau.cc je ^ et / ς otTc <

irotkauctm Sei «);

V: O or S;

and the salts of these compounds with acids.

The hydrocarbon chains in the defined radicals can be straight-chain or branched. "Halogen" means fluorine, chlorine, bromine and iodine, "aryl" especially phenyl and naphthyl. As far as multiple substitution in the heterocyclic and aromatic radicals possible

is, the substituents may be the same or different. Up to three alkyl or alkoxy groups may be present, in particular in the case of C ₁ -C ₂ -alkyl or alkoxy, while aryl, CF-, N (R ₁ ) _ is present at most twice, but preferably only once. The group N (R) may contain identical or different radicals R. The group VR 1 is preferably in para position to the triazolyl group. In the above definitions, the following substituent meanings are to be emphasized:

R: the groups II and III, where

R ₄ , R ₅ and R _{6 are} H, C ₁ -C ₄ C -C -alkoxy, halogen, R is also C -C -alkyl or -alkoxy, when R and

R. H are, 6

R. and R _c together also fused 4 b

C -C -cycloalkene, methylenedioxy, ethylenedioxy and, if R. is H, also

a fused benzene ring; X is S, O, NH, N (C ₁ -C ₄ alkyl);

YN when X is NH or N- (C ₁ -C ₄ alkyl), CH when X is S or O;

R, is H, C ₁ -C -alkyl, phenyl, halogen, R_ also C ₁ -C _c --Alkyl when R _n is H; R_ and R _Q together also fused C -C -Cycloalkene or benzene ring;

H, CH _3, C ₂ H _5, 1-C ₃ H _7, cyclopropyl;

(C ₁ -C ₄ alkylene) -Het where Het _f the groups V, VI, or

^ZR 12

means

NO

wherein ^R 12 ^:

^R i3 ^:

Z:

13

H, CH ₃ . Phenyl, H, CH ₃ and

S, NR ₁₂ , CH = CH, N = CH or CH = N j. _s t; H, C 1 -C 4 -alkyl, C 1 -C -alkoxy, halogen, O, S

Particularly noteworthy are those compounds of the invention in which the following substituent meanings are present:

stand by it

R.

R ,, R _{r is} H, CH, OCH _n , Cl, F;

R. and R_

together also for -O-CH -O- or -O-CH-CH-O, bound to adjacent C atoms of the phenyl ring (R, then H);

is H, CH _3, OCH _3; for H, C ₁ -C ₄ -alkyl, Cl, Br; together also for a fused cycloalkene ring with 5 or 6 carbon atoms;

H, CH _3, C ₂ H _5, 1-C ₃ H _7, cyclopropyl; C -C alkylene-Het, when Het for

it Q

12

.N

-N

-R, or -N

13

12 "

^R 13 ^: and

H, CH _3, C ₆ H ₅ H, CH,

C - C alkylene-Het, if Het for

2 83 p

or

stands;

R ₁₄ : H,

O, S.

The compounds according to the invention are prepared by processes known per se. The methods used may be, e.g. in "Chemistry of Heterocyclic compounds". Vol. 37, Wiley, New York (1981), p. 34 et seq. And 69 et seq., Or described in F. Clemence et al. Eur. J. Med., Formerly Chem. Ther. 20, 257-266 (1985).

1. 1-Acylamidrazone of the formula

(XI)

in which R ₁ , R ₂ , R ^ ^ d V have the abovementioned meaning (the substituents R, and R_ can, as indicated, also be arranged in reverse) are heated without solvent or in a solvent inert under the reaction conditions, the ring closure enters I. The reaction temperature during the reaction in the melt is preferably 150-20O ⁰ C. As solvents are suitably used those whose boiling point is in the range mentioned, so that the reaction can take place under reflux.

The compounds of formula XI can be obtained by conventional methods, e.g. as follows:

(a) Imino ethers are reacted with hydrazides to give substituted imino ethers which give acylamidrazones with anilines. In the last step, 1,3,4-oxadiazoles can occur as intermediates. Further reaction to the compounds of the formula I does not necessarily require intermediate isolation of the 1-acylamidrazones.

(R ₂ ) R ₁

(XII)

HN-NH

it

(XIII)

(R ₂ ) R ₁

(XIV)

N-NH

OR O

N N

xiv Ibzw. R

In the above formulas R is a lower alkyl radical, the other symbols have the meanings given above. R and R ₂ may be arranged reversely, as before and in the following.

(b) Corresponding amidrazines are reacted with acid halides, acid anhydrides or orthoesters:

N-NH.

XI

(XVI)

D = halogen or

-0-COR ₂ .

instead of XVI (RO) CR is also usable

(XV)

2 θ 3 ύ

(C) Thioamides or S-methylisothioamides are reacted with hydrazides:

XI

(XVII)

(XVIII)

(d) imide chlorides are reacted with hydrazides:

+ (XIX)

XI

2. Compounds of the formula (I) in which R is the same

it

CH or CH is, by reaction of

Amidrazonen be obtained with diethylamino or ethoxyethynes or -propines at temperatures between 120-180 ⁰ C in aprotic solvents such as xylene:

+ E-C = C-R

e:

or CHO

¹⁴ R: H, CH.

^C 2 ^H 5

(XX)

3. Compounds of the formula (I) in which R 1 is a lower alkyl can be obtained from hydrazones (formed from amidrazones with 8-keto acid esters or β-diketones) by heating in the melt state or in aprotic solvents such as xylene:

/ Ζ "

.N-N / O

C-CH.-C ^ 2 \

(XXII)

(XXIII)

R ¹ : alkyl or alkoxy (preferably with 1 to 8

C atoms) R " ₂ : C ₁ -C ₄ -alkyl

4. Compounds of the formula I in which "Het" in R

 3

is one of the groups V, VI, VII or VIII, can be prepared by reacting compounds of the formula

R.

in the R,

(XXIV)

V- (C.C. -alkylene) -G 1 o

V have the above meaning

V "21 and G for a" leaving group ", preferably halogen or a sulfo acid radical, with the V, VI, VII or VIII corresponding heterocycles in polar solvents.

The heterocycle is preferably used in the form of a sodium salt. Suitable solvents are, for example, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or hexamethylphosphoric triamide (HMPT). The reaction temperature is preferably 20-10O ⁰ C.

The compounds of formula XXIV can be selected from the compounds of formula

N N

R

(XXV)

V-M

(M alkali metal, R, R as defined above) by reaction with compounds of the formula

Halogen (C ₁ -C ₄ alkylene) -G (XXVI) can be obtained.

The compounds of formula XXV can be prepared from the corresponding methoxy compounds by demethylation and conversion of the resulting phenols into the alkali metal salts. The phenols can be converted by known methods into the thiophenols and these are converted into the alkali metal salts.

5. Reaction of compounds of formula XXV with compounds of the formula

GR ₃ (XXVII)

wherein G and R have the above meanings. The reaction takes place in polar solvents such as lower alcohols such as ethanol, ketones such as methyl ethyl ketone, DMF, HMPT, DMSO, at room temperature or slightly elevated temperature.

6. Compounds of the formula I in which R as heterocycle contains a linked via the 4-position 4H-1,2,4-triazole ring can be prepared from amines of the formula

N N

R, Jl '] -R.,

(XXVIII)

V- (C ₁ -C, alkylene) -NH_

be prepared by ring closure reaction by the methods given in Methods 1, 2 and 3.

The examples described below are intended to explain the methods in more detail.

The compounds according to the invention are valuable drugs, in particular due to PAF-antagonistic action. They are therefore particularly suitable for the treatment of diseases in which inflammatory and / or allergic processes play a role, such as in asthma, aspirin-induced asthma, chronic bronchitis, allergic rhinitis and ARDS (adult respiratory distress symptoms); Inflammatory and autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, multiple sclerosis, glomerulonephritis, psoriasis, pruritus, rejection of kidney, liver and other transplants, inflammatory bowel disease, scleroderma and other autoimmune diseases (such as M. Werlhof); cardiovascular diseases such as myocardial infarction, reperfusion injury, heart failure, unstable angina pectoris, stroke, pulmonary (ischemia-related) hypertension, other ischemic and hypoxic conditions; Shock and shock prophylaxis, cardio-vascular disorders in shock (sepsis, septic shock, polytraumatic shock, anaphylactic shock); Organ failure in shock (ARDS, kidney failure,

Gastrointestinal ulcers), DIC (Disseminated Xntravascular Coagulation), Thrombosis / Thromboembolism; further spread of metastases, agoraphobia, depressive illnesses, side effects of medicines (immunological intolerance, ischemia-inducing effect,

fabric damage effect). They can also be used in combinations for which PAF antagonists are suitable, for example with β-adrenergics, parasympatholytics, corticosteroids, antiallergic agents, secretolytics. In combination with TNF (Tumor Necrosis Factor), a better tolerability (elimination of interfering side effects) of the TNF is achieved; If desired, TNF can therefore also be used in higher doses than when it is used alone. (Under "combination" is here also the application of the two active ingredients in separate preparations and at a certain time interval to understand). When the compounds according to the invention are used together with β-etherergic agents, a synergistic effect can be achieved, e.g. in broncholysis.

As a measure of the PAF-antagonistic effect, the inhibitory concentrations (IC ₅₀ ) in PAF-induced platelet aggregation are given (compounds of the formula I where R_ is CH ₃ , VR ₃ in the para position to the triazolyl ring and R, is H):

2 a 3 ό 1 9

-V-R.

χ ίο

-6

-N

-O-CH ₂ -CH ₂ -N

\ -

1.1

.N

-O-CH ₂ -CH ₂ -N

OCH,

0.8

.N

> _ -0-CH, -CH - N

YY ^{2 2} V

0.7

-O-CH ₂ -CH ₂ -N 0.7

CH-

-O-CH - CH - N

0.2

CH.

-N

-S-CH

2 "\

0.2

CH.

-O-CH-CH-N

CH, 0.09

-V-R.

IC ₅₀ X 10

-6

-O-CH-CH-N

-N

.N

0.1

CH.

2 Λ 3 ο

The new compounds can be administered topically, orally, transdermally, parenterally or by inhalation. The compounds are present as active ingredients in common dosage forms, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, e.g. Tablets, dragees, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, ointments, emulsions, syrups, suppositories.

The therapeutic and prophylactic dose depends on the nature and severity of the condition.

An effective dose of the compounds according to the invention is between 1 and 100, preferably between 10 and 80 mg / dose when administered orally, between 0.001 and 50, preferably between 0.1 and 30 mg / dose when administered intravenously or intramuscularly. For inhalation, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% of active ingredient should be used.

Formu1ierungsbeispiele

1. tablets

Composition:

Active ingredient according to the invention 30 parts by weight

Stearic acid 6 parts by weight

Grape sugar 564 parts by weight

The ingredients are processed in the usual way into tablets of 600 mg weight. If desired, the active ingredient content can be increased or decreased and the amount of glucose reduced or increased accordingly.

2. Suppositories

Composition:

Active substance according to the invention 80 parts by weight

Lactose, powdered 45 parts by weight

Cocoa butter 1575 parts by weight

The ingredients are processed in the usual way to suppositories of 1.7 g in weight.

3. Inhalation powder

Micronised active ingredient powder (compound of formula I, particle size about 0.5 to 7 microns) are filled in an amount of 0.02 mg with 10 mg micronized lactose and optionally suitable amounts of other active ingredients in hard gelatin capsules. The powder is prepared from conventional inhalers, e.g. according to DE-A 3345 722, inhaled.

19 4. Metered dose inhaler

Active substance according to the invention 0.5% by weight

Sorbitan trioleate 0.5% by weight monofluorotrichloromethane and

Difluorodichloromethane (2: 3) 99.0% by weight

The mixture is filled into metered dose inhalers of conventional type. The dosing device is designed, for example, so that 0.05 ml of the preparation are dispensed per stroke.

embodiment

The invention is explained in more detail below with reference to some examples.

". j O -J ·

example 1

5- (5-bromo-2-thienyl) -4- [4- [2- [4- (3,5-dimethyl-l, 2,4-triazolyl)] ethoxy]] phenyl-3-methyl-4 H l, 2,4-triazole

3 g of acetic acid [2- (5-bromo-2-thenoyl) -hydrazonid] ethyl ester, m.p. 134-7 ° C (prepared from 5-bromothiophene-2-carboxylic acid hydrazide, mp. 142-4 ° C, by reaction with Ethyl acetimidate hydrochloride), and 2 g of 4- [2- (4-aminophenoxy) ethyl] -3,5-dimethyl-4H-1,2,4-triazole, m.p. 151-3 ° C (prepared by reacting 2 - (4-nitrophenoxy) ethylamine with acetic acid (2-acetylhydrazonid) ethyl ester and catalytic reduction of the nitro compound, mp. 212-4 ° C, with Pd / carbon) are heated with stirring for 2 hours at 150 ⁰ C. The oily residue is dissolved in 150 ml of chloroform / methanol mixture (4: 1), decolorized by addition of activated charcoal and silica gel and filtered. The solvent is distilled off, the residue dissolved in 20 ml of ethyl acetate, cooled, the precipitated title compound (2.1 g, 57% of theory) is filtered off with suction and recrystallized from acetonitrile; Mp 224-6 ° C.

Example 2

5- (3,4-Dimethoxyphenyl) -4- [4- [2- (l ~ imidazolyl) ethoxyphenyl-3-trifluoromethyl-4H-l, 2,4-triazole

3.4 g of 3,4-Dimethoxybenzoesäure- (2-trifluoracetylhydrazonid) methylester (m.p. 103-4 ⁰ C;. Prepared by reacting 3,4-Dimethoxybenzoesäureiminomethylesterhydrochlorid and Trifluoressigsäurehydrazid) and l- [2- (4-aminophenoxy) ethyl] imidazole (mp 87-9 ° C; prepared by reacting ethyl 2- (4-nitrophenoxy) -ptoluenesulfonate with imidazole and

catalytically ^ reduction of the nitro compound, mp. Oxalate: 131-4 ° C, with Pd / carbon) are stirred for 2 hours at 150 ⁰ C. The oily residue is dissolved in 50 ml of ethanol, filtered through activated charcoal and concentrated. The residue is dissolved by heating in ethyl acetate and diluted with ether. The title compound precipitated (1.5 g, 32.6% of theory); it is filtered off with suction and purified by recrystallization from ethyl acetate, mp 165-7 ° C.

Example 3

4_ [4_ [2- (l-imidazolyl) ethoxy]] phenyl-3-methyl-5- (2-thienyl) -4H-l, 2,4-triazole

1.95 g of imidazole are dissolved in 25 ml of dimethylformamide, portionwise with 1.37 g

Sodium hydride (55-60% in oil) and stirred for one hour. After completion of the hydrogen evolution, 8.3 g of 4- [4- (2-chloroethoxy) phenyl] -3-methyl-5- (2-thienyl) -4H-l, 2,4-triazole (mp. 149-51 ° C ; made of

4- (4-hydroxyphenyl) -3-methyl-5- (2-thienyl) -4H-l, 2,4-triazole, mp. 278 ° C, with p-toluenesulfonic acid (2-chloroethyl ester) in dimethylformamide was added and with the addition of potassium carbonate for 2 hours at 80 to 90 ⁰ C stirred. The dimethylformamide is distilled off, the residue is dissolved in chloroform, the solution is washed with dilute sodium hydroxide solution, dried with sodium sulfate and distilled off. The residue is dissolved by heating in ethyl acetate, after cooling, the precipitated title compound is filtered off with suction and recrystallized from acetonitrile; Mp 170-2 ⁰ C. The hydrochloride of the compound crystallized from isopropyl alcohol / ether with addition of the calculated amount of hydrochloric acid. Mp 213-33 ° C (decomp.).

Ί j 3 6 ί

Example 4

3-methyl-4- [4- (3-pyridyl) methoxy] phenyl-5- (2-thieny) -4H-l, 2,4-triazole

5.14 g of 4- (4-hydroxyphenyl) -3-methyl-5- (2-thienyl) -4H-1,2,4-triazole, 50 ml of ethanol, 40 ml of 1N sodium ethylate solution and 3.3 g of 3-picolyl chloride hydrochloride are refluxed for 5 hours. After distilling off the ethanol, the residue is dissolved in 150 ml of chloroform, the solution is washed with dilute sodium hydroxide solution, dried and distilled off. The residue is dissolved in ethyl acetate, the solution is cooled and the precipitated title compound is filtered off with suction. Recrystallization from acetonitrile gives the pure compound, mp. 158 ° C.

Example 5

4- [4- [2- [4- (3,5-dimethyl-l, 2,4-triazolyl)] ethoxy]] - phenyl-3-methyl-5-phenyl-4H-l, 2,3,4 triazole

2.94 g of 4- [4- (2-aminoethoxy) phenyl-3-methyl-5-phenyl-4H-1,2,4-triazole, m.p. 125-6 ° C (prepared from 4- (4-hydroxyphenyl ) -3-ethyl-5-phenyl-4H-l, 2,4-triazole by reaction with Ν, Ν-dibenzylaminoethyl chloride and catalytic hydrogenation with Pd / charcoal) and 1.85 g of acetic acid (2-acetylhydrazonide) ethyl ester boiled in 10 ml of ethanol for 30 minutes under reflux, then the ethanol is distilled off and the melt is heated to about 150 ⁰ C for 30 minutes. The crystalline residue is dissolved in ethanol, filtered through activated charcoal and the solvent distilled off. There remains an oil which is dissolved in acetonitrile. It cools and sucks the

c 3 6 I 9

failing title connection. After recrystallization from 95% acetonitrile, the compound (hydrate) melts at 245 ° C.

Example 6

3-methyl-4- [4- (3-pyridinylmethyl-thio) phenyl] -5-phenyl-4H-l, 2,4-triazole

a) 3 - [(4-aminophenyl) thiomethyl] -pyridine

A solution of 25 g (0.2 mol) of 4-mercaptoaniline in 100 ml of ethanol is added dropwise with stirring to a solution of sodium ethylate in ethanol [10.2 g (0.44 gatom) of sodium in 200 ml of absolute ethanol]. Subsequently, 32.8 g (0.2 mol) of 3-chloromethyl-pyridine hydrochloride are added in portions, wherein the temperature rises to 40-50 ⁰ C. The reaction mixture is stirred overnight at room temperature, treated with water and extracted with methylene chloride. The inorganic phase is dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude product is filtered through a silica gel column in methylene chloride / methanol 95: 5. The remaining after distilling off the solvent crystals are acetonitrile / diisopropyl ether

-J

j 6 1

recrystallized.

Yield: 31 g (72% of theory); Mp. 120-123 ⁰ C.

b) 3 - [(4-Benzoylaminophenyl) thioraethyl] pyridine

To 17.3 g (0.08 mol) of [(4-aminophenyl) thioraethyl] pyridine and 8.91 g (0.088 mol) of triethylamine in 250 ml of chloroform is added dropwise at 20-25 ⁰ C, a solution of 11.25 g (0.08 mol) of benzoyl chloride in 50 ml of chloroform. After completion of the addition, the reaction mixture is stirred for two hours at room temperature, with 200 ml of water and then with 300 ml of petroleum ether (40-60 ⁰ C). The resulting crystals are separated, suspended in ethyl acetate, filtered off with suction and dried. Yield: 20.4 g (79% of theory); Mp. 148-150 ⁰ C.

c) 3-Methyl-4- [4- (3-pyridinylmethyl-thio) -phenyl] -5-phenyl-4H-1, 2,4-triazole

A suspension of 9.6 g (0.03 mol) of the product obtained according to b) and 6.25 g (0.03 mol) of phosphorus pentachloride in 150 ml of toluene is stirred for four hours at reflux temperature. The reaction mixture is then evaporated, 100 ml of toluene are added and concentrated again to dryness. The residue is suspended in 200 ml of toluene. After the addition of .5 / 56 g (0.075 mol) of acethydrazide and 5.56 g (0.075 mol) of triethylamine, the reaction mixture is refluxed for five hours on a water separator and evaporated at reduced pressure. The residue is partitioned between methylene chloride and water. The

2 83 6 i 9

organic phase is separated, washed successively with 5% acetic acid, dilute ammonia and water and dried over sodium sulfate. The residual oil after distilling off the solvent is chromatographed on silica gel with acetone as the eluent. This gives 3.9 g (36% of theory) of the abovementioned compound; Mp 118-119 ° C (acetonitrile / diisopropyl ether).

1 ~>"> f £ JOO

Analogously to the above examples, the compounds listed in the tables below can be prepared:

Table I

Compounds of the formula

R.

O - R.

No. R.

Fp- [ ⁰ C] for base salt with

.N

1 H - (CH ₂ ) ₂ -N

127-9

2 CH ₃ - (CH ₂ ) ₂ -N

105

190-2 (HCl)

.N

3 CH ₃ - ( ^CH 2 ⁾ 3 ^N

118-21

206-9 (HCl)

c. υ \ j O I

No. R

Mp [ ⁰ C] for base salt with

-N

4 _o . H - (CH ₂ ) ₄ -N

116

5 CH.

: ^} 2- ^N

CH. 140-2

125-30 (HCl + H ₂ O)

6 CH.

- (CH ₂ J ₂ -N

184-6

180-4 (2 HCl)

7 CH.

- (CH ₂ ) ₂ -N

175-6 262-4 (HCl)

8 CH.

(CH ₂ ) ₂ -N

N. 126-8

CH.

9 CH ₃ - (CH ₂ ) ₂ -N

245 (hydrate)

CH.

No. R.

Fp- [ ⁰ C] for base salt with

10 CH.

CH.

- (CH ₂ ) ₂ -N

^C 6 ^H 5 168-70

11 CH.

92-5 (hydrate)

12 CH.

CH.

- <CH ₂ ) ₂ -N

178-80

13 H -CH.

120-2

14CH-CH

162-3

15 C ₂ H ₅ -CH ₂ .

118-9

16 iC ₃ H ₇ -CH ₂

145-6

υ -j -j i

No. R.

Mp [ ⁰ C] for base salt with

CH.

93-6 (hydrate)

CH.

139-41

19CH, -CH.

126-7

CH.

138-9

20 CH ₃ - <CH ₂ ) ₂ .

91-2

22 CH ₃ " ^(CH 2 ⁾ 2

127-9

23! -CH ₃ H ₇ - ^(CH 2 ⁾ 2

124-5

No. R

R.

Mp [ ⁰ C] for base salt with

CF.

-CH

141-2

Table II

Compounds of the formula

S N

CH.

O - R.

0:: i \

Mp [ ⁰ C] for base salt with

170-2 231-3 (HCl)

- (CH _) .- N 2 2 \ 145-7

CH.

- (CH ₂ ) ₂ -N

CH. 175-8 (hydrate)

-N

CH.

158

2 S36 i 9

Mp [ ⁰ C] for base salt with

CH.

126-8

-N

- (CH) -N 2 2 _χ

^k NZZL

CH.

CH.

CH. 145-7

207-9

- (CH ₂ ) ₅ -N

192-4 (HCl)

CH.

CH.

Table III

Compounds of the formula N N

CH.

-Ν '

O - R.

No. R,

Mp [ ⁰ C] for base salt with

S

.N

134-6

\ -

158-60

O / \

CH.

190-1

-N

(CH ₂ J ₂ -N

OCH.

(Hydrate)

No. R.

R.

Fp- [ ⁰ C] for base salt with

CH ₃ OCH ₃ .N

(CH ₂ ) ₂ -N

130

CH ₃ OCH ₃

CH.

202-4 (2 HCl XH ₂ O)

CH ₃ OCH ₃

CH.

.N

.N

194-6 (X 1/2 H ₂ O)

CH ₂ J

134-5

OCH, -N

145-6

Cl

10

-N 154-6

• N

(X2h ₂ O)

Mp [ ⁰ C] for base salt with

Cl

CH.

CH. 235 (X 1/2 CH ₃ OH)

Cl

CH.

(CH ₂ ) ₂ -N

CH. 184-5

CH.

CH ₃ O CH 0

CH.

(CH ₂ ) ₂ -N

OCH.

218-20

121-3 (X H "<

- (CH ₂ ) ₂ -N

CH.

- (CH) -N

: h 155-7

195-7

I 3 ώ 1 9

No. Mp. [° C] for base salt with

17

CH.

.N

-N

258-60 (X CH ₃ OH)

CH.

18

CH.

- (CH ₂ ) ₂ -N

.N

CH.

213-5 (XH ₂

  Ν

112-4

20

-N

192-4 (HCl)

21

.N

-N

160-2

CH, 22 CH.

\ 1

CH.

- (CH ₂ ) ₂ -N

230-3

CH.

2 C 3 Π 9

No. R, mp. [ ⁰ C] for base salt with

23 CH.

-N

- (CH ₂ ) ₂ -N

130-8

24 CH.

CH.

168-70

25 CH.

CH.

- (CH ₂ ) -N

-N

CH.

212-4

26 CH.

¹ T.

- (CH ₂ ) ₂ -N

-N

134-6

CH.

IN

  N

27 CH.

122-4

-N

28 CH.

-CH

2 \ v

129-31

2 j 3 6 ί

No.

Fp- [ ⁰ C] for base salt with

29 Br-

-N

(CH) -N'2

118-20

30 Br

CH.

(CH ₂ ) ₂ -N

CH.

224-6

  N

- (CH ₂ ) ₂ -N-

118-20

CH.

100-2

CH.

- (CH ₂ ) ₂ -1

.N

CH.

151-3 (χ 1 vinegar)

- (CH ₂ ) ₂ -N

155-7

y- ^N

163-5

2 i j 6 1

No. R,

Mp [ ⁰ C] for base salt with

CH.

167-8

-N

.169-70

Ύ.

CH.

(CH ₂ ) ₂ -N

.N

.N

(O

CH.

CH.

.N

(CH ₂ ) ₂ -N

CH.

232-4 243-5

: N

(CH ₂ ) ₂ -N

157-9

N.

2 ^; 2

181-3

No. R,

R. Fp- [ ⁰ C] for base salt with

OJ

»- -CH.

CH.

43

CH.

.N

95-7

145-7

Cl

CH.

116-7 (hemihydrate)

Cl

CH.

156-8

to

OCH.

CH.

141-2

i 3 6 1 9

No. R, m.p. [° C] for base salt with

CH.

CH.

178-80

CH.

140-2

OCH.

CH.

78-80 (hemihydrate)

CH ₃ O

CH.

OCH. 146-48

\ -

130-2

140-2

2 5 3 6 i 9

R. Fp. [ ⁰ C] for base salt with

CH.

155-6

-N

CH.

105

S N

55 Cl-Z ⁷ ^ V- CH.

160-2

56 CU ·

123-5

57 H-C- /

 j

CH.

(CH ₂ ) ₂ -N

CH.

H ₃ C

CH.

- (CH ₉ ), - N

OCH,

No. R ₁

Mp [ ⁰ C] for base salt with

CH,

CH.

162-3

Cl

CH.

175-6

- ^C 6 ^H 5

CH,

112-4 (Zers.)

Cl CH.

132

(Zers.) (Fumaric acid)

Cl

Cl Cl

Cl

CH,

-CH ₂ -CH ₂ -N

-N

Z j .. 'i 9

No. R ₁

R-Fp. [ ⁰ C] for base salt with

Cl

Cl

CH-

-CH ₂ -CH ₂ -

: N

Cl

Cl Cl

Cl

-CH ₂ -CH ₂ -

-N

CH,

CH.

N =

rN

CH.

OCH.

-JH

-CH ₂ -CH ₂ -N

OCH.

CH-

-CH "-CH -.- N 2 2 \

-N

OCH.

=! · Ί ο ό 1 J

No.

Mp [ ⁰ C] for base · salt with

OCH.

OCH.

: N

-CH ₂ -CH ₂ -N

141-3

N =

72

OCH.

OCH.

CH.

-CH ₂ -CH ₂ -N

: N

166-9

CH.

73

OCH.

OCH.

-CH ₂ -CH ₂ -N

116-8

74

OCH.

OCH.

rN

-CH - CH., - N 2 2 \

145-7

rN

C ₆ H ₅

-CH _O -CH "-N

'-' ο 3 6 i 9

No. R.

Mp [ ⁰ C] for base salt with

76 cl.

^X. -CH ₀ -CH ₀ -N

2 2 \ 209-11

77 H ₅ C ₂ -

CH.

105

: N

-CH - CH ₀ -N

^{2 2 N} 225-8

: N

-CH ₀ -CH ₀ -N 2 2 \ 191-3

: N

80 H ₃ C

-CH ₂ -CH ₂ -

191-2

OCH,

146-8

) CH

i: j 6 i 9

No. R ₁

Mp [ ⁰ C] for base salt with

: N

-CH ₀ -CH ₀ -N

\ 2 \ 130-2

^ _ -CH ₀ -CH ₀ -N 140-2

: N

S .. N

-CH ₀ .

Ii ir

155-6

 )

j J 6 1 9

TABLE

Compounds of the formula

N N

• A.A.,

S-R.

No. R.

R. Fp. [ ⁰ C] base salt with

1 CH.

CH.

118-9

2 iC ₃ H ₇

CH.

113-5

3 CH.

OCH.

CH.

151-3

4 CH.

N X

CH-

No. R. mp. [° C] Base salt rait

5 CH,

CH.

CH.

118-9

6 CH.

CH.

7 CH.

CH.

-N

8 CH ₃ H ₃ C.

CH.

9 CH ₃ Cl

Cl CH.

- (CH ₂ ) ₂ -N

CH.

No. R.

Mp ["C] base salt

rait

10 CH.

H ₃ C _ / \ -N

-CH

11 C ₂ H ₅

CH.

OCH.

CH.

12 CF.

CH.

CH.

14 CH ₃ H ₃ C- / V- CH ₂ .

15 CH.

Oi

.0CH

OCH.

16 CH.

-N

UC ₂ H ₅ -CH ₂

2 '; 3 6 1 5

No. RR Fp. C ⁰ C] Base salt

With

17 CH.

18 CH.

19 CH.

H ₃ C_

CH.

) ₂ -N

CH.

.N

-N

• N

-N

CH.

20 · CH.

CH.

(CH ₂ ) ₂ -N

-N

H.

.N

CH.

-N

CH.

O <-) · L j L xj - j -j J

No. R.

Mp [ ⁰ C] base salt with

CH,

(CH ₂ ) ₂ -N

CH.

24 CH.

25 i-

- (CH.

155-6 (1.5

fumaric acid)

26 CH.

CH.

OCH.

100-1

CH.

OCH.

OCH.

- (CH ₂ ) ₂ -N (

2 3361 9

No. R,

Mp [ ⁰ C] base salt

With

30 CH,

(CH ₂ ) ₂ -Π

= N

CH,

- (CH ₂ ) ₂ -N

rN

CH,

CH,

33 iC ₃ H ₇

CH,

Cl

N _s

CH.

147-9

CH,

OCH,

OCH, -CH,

2: 3 ') I

No. R, mp. [ ⁰ C] base salt

With

CH,

CH,

CH,

-CH

98-100 (Zers.)

37 CH,

OCH,

CH,

-CH

126

(Zers.) (Fumaric acid)

38 CH,

^C 6 ^H 5

CH,

-CH-

146-8 (Zers.)

(Fumaric acid)

According to the invention can also be obtained

Mp 165-7 ° C

-N

O - (CH ₂ ) ₂ -N

IJ CF,

S - (CH ₂ ) ₂ -l: N

: N

N, N

Il OCH,

Mp 144-6 ° C

-N

0 - CH.

Further compounds of the formula I which can be obtained according to the invention:

OCH,

N N

Oech

O - CH ₂ -Het

Het:

-CH ₂ -

CH,

-CH ₂ -N

-N

: N

CH,

Claims (4)

Pat ent to the test 1. A process for the preparation of compounds of the formula (D, wherein R R ^. and V have the following meaning part: (H) * TV > (III) (IV), in which R ^, R ₅ for H, R ₁₁ , OR ₁₁ , halogen, CF ^, aryl, IT (R ₁₁ ) ₂ , together also for a fused-on 2: 3 <! J -St ₇ -, a fused benzene ring or one of the groups bound to adjacent C atoms of the benzene ring -N = CH-NH-, -N = CH-CH = CH-, -O-CH ₂ -O-, -O-CH ₂ -CH ₂ -O-, -NH-CO-NH- and -N = CH-CH = N-, R ₁ , for H, R ₁ . or OR ₁ . or aryl; b XX XX R _{7 is} H, R 1, halogen or aryl; R - for H, R ,, or halogen, R_ and R ₀ together also for a / O fused C ₅ -C ₇ ~ cycloalkene or benzene ring, R _g , R ₁₀ for H, R ₁₁ , OR ₁₁ , N (R _{i; l} ) _{2 /} together also for a fused benzene ring; for S, O, NH or
for CH, N; for C ₁ -C.-alkyl, and when in addition to R ₁₁ or a R ₁₁ -containing radical II, III or IV have no further substituents, also C ₅ -C ₁₂ ~ alkyl or alkoxy stand; H, C ₁ -C ₄ -alkyl, CF ₃ , C ₁ -C ₄ -alkoxy, C-j-Cg-cycloalkyl; (C.sub.1-C.sub.-alkyl-O-Het, wherein He.t Ί2 - Η _R (V) 13 (VI) IT (VII) 13 -II IT, .R -JR ₁₃ , 12 13 (VIII) Z: S, NR ₁₂ , CH = CH, H = CH or CH = IT; R _{19 is} H, C.-C, alkyl or aryl; (X) _{3 4}
R ₁₂ and R ₁ -, together optionally represent a fused benzene ring; R ..: H, C ₁ -C ₄ -AlkJl, C ₁ -C ₄ -alkoxy or halogen, and may also be present twice; V: 0 or S;
and the salts of these compounds with acids, 36 - 6o- characterized in that a) by heating 1-acylamidrazones of the formula IT - HH R ₂ (R ₁ ) in the R .., Rp, R ,, R ₁ / and V are as defined above, or heated b) an amidrazone of the formula R. (XX), in the R., R ,, R .. ¹ . and V have the above meaning, with an ethyne derivative of the formula E-C ^ C-R 2 ö 3 6 1 9 -M- in the E or OC ₂ H ₅ , RH or CH ₃ , reacted with ring closure or that one c) a hydrazone of the formula (XXII) in the R ₁ , R, and V the obiqe meaning and R ^{1 is} C ¹ -C 4 alkyl or alkoxy and 1 O R ₂ "C ₁ -C ₄ -AlKyI means, heated or that one d) a compound of the formula -Ν R. (XXIV) V- (C 1 -C 6 -alkylene) -G 1 o '}. \ 3 6 1 -U- in which R, R and V have the abovementioned meaning and G is a leaving group leaving group, reacts with cloud-deprotonated heterocycles R, which are to be connected to the alkylene chain via a nitrogen atom, or that one e) a compound of the formula XXV in which R, R and V have the above meaning and M is an alkali metal, with a compound G-R (XXVII) implements G and R have the above meaning, or that one f) for the preparation of compounds of the formula I in which R represents an optionally substituted 4H-1,2,4-triazole ring linked via the 4-position, an amine of the formula (XXVIII) V- (C ₁ -C -alkylene) -NH_ 10 2 i j 3 j I in which R, R and V are as defined above, subjected to a ring closure reaction by the methods given in Methods 1, 2 and 3 to form a corresponding 4H-1,2,4-triazole compound, and that the salts obtained by the processes a) to f) are converted, if desired, into free bases, initially obtained salts into the free bases. 2. The method according to claim 1, characterized in that compounds are prepared according to claim 1, wherein R _{1 represents} the groups II and III, in which R ₄ , R (- and Rr H, C ₁ -C ₄ -alkyl, C _Λ -C. Alkoxy, halogen, R ₇ , also Cc-C, "- alkyl or alkoxy when R ₁ - and Rg are H, Ra and Rj- together also fused Cc-Cy-cycloalkene, methylenedioxy, ethylenedioxy and, when Rg is H, also a fused benzene ring; Z is S, O, NH, IT (C ₁ -C ₄ alkyl); Y IT ₁ when X is NH or IT- (C ₁ -C ₄ -alkyl)
CH, when X is S or O; R ₇ , R ₈ H, C ₁ -C ₄ -alkyl, phenyl, halogen, R ₇ also C ₅ -C ₁₂ -alkyl when R g is H; R ₇ and Rg together too fused C, -C ₇ cycloalkene or benzene ring; R _{2 is} H, CH ₂ , C ₂ H ₅ , 1-C ₃ H ₇ , cyclopropyl; R ^ is (C ₁ -C ₄ -alkylene) -Het, wherein
Het the groups V, VI or
R ₁₂ means 3 b 3 c ί worm R ₁₂ : II, CH ₃ , phenyl, R ₁₃ : H, CH ₃ and Z: S, ITR ₁₂ , CH = CH, N = CH or CH = K, R _{14 is} H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or halogen, V is 0, S. 3. The method according to claim 1, characterized in that compounds prepared according to claim 1 v / ground, in which R ₁ : or ^R 8 in which R ₄ , R _{5 is} for Ii, CH ₃ , OCH ₃ , Cl, P; R ₄ and Rr together also for -O-CH ₂ -O- or -O-CH ₂ -CH ₂ -O attached to adjacent C atoms of the phenyl ring (Rr then equal to H); R _{6 is} H, CH ₃ , OCH ₃ ; R ₇ , R _{8 is} H, C ₁ -C ₄ -alkyl, Ci, Br; together for one fused Cycloalkene ring with 5 or C atoms are; ,: H, CH ₃ , C ₂ H ₅ , 1-C ₃ H ₇ , cyclopropyl is j - (dc - Alkylene-Het is when Het for R ₁₂ -N j 'R-ip ° ^ ^he R, o 13 R ₁₃ R _{12 is} H, CH ₃ , C ₆ H ₅ , R _{13 is} H, CH ₃ ; and C - C ₂ -alkylene-Het is when Het for or stands; R _{14 is} H;
V 0, S is. 4. The method according to claim 1, characterized in that compounds according to claim 1, 2 or 3 prepared v / earth, in which
R- for or Cl (R _4: H, CH _3, OCH _3, Br, Cl, P, R _5: H, CH _3, OCH _3, Cl, R _7: H, CH _3, Cl, Br); R _{2 is} CH ₃ , C ₃ H ₅ , 1-C ₃ H ₇ or cyclopropyl 2 3 Z i 9 -CH _o - ( -CH ₂ -CH ₂ -IT [ CH, CH -CH ₂ -CH ₂ -II CH, CH, or -CH ₂ -CH ₂ - (Q. H is and V stands for 0 or S «