CH623315A5 - Process for the preparation of triazolylbenzophenone derivatives - Google Patents

Description

The present invention relates to a process for the preparation of triazolylbenzophenone derivatives of the formula Ia

N N K4 R8

R-LJL CH-NH-COCHNH,

wherein in the above structural formula M is phthalimido, hydrazinolyzed in an inert solvent.

2. Use of the compounds of the formula Ia prepared by the process of claim 1 for the preparation of a compound of the formula Ib

45

R

N N R R

J M 1

> -CHNH — COCI

11

50

(Ia)

COCHNH-COCHNH,

wherein R is hydrogen, lower alkyl, halogeno lower alkyl, the grouping - (CH2) n-X-R5 or the grouping

(Ib)

55

- (CH2) n-N;

R «

R7

wherein R is hydrogen, lower alkyl, halogeno lower alkyl, the grouping - (CH2) "- X-R5 or the grouping

- (CH2) n-N:

R6

R7

where R5 is hydrogen, lower alkyl, C2-C0-alkenyl, C2-C6-alkynyl, C0-C10-aryl or C2-C8-acyl, X is sulfur or acid-60 substance, n is zero, 1, 2 or 3, R6 and R7 is any hydrogen or

Is lower alkyl, or the group R6-N-R7 represents pyrrolidino, piperidino, morpholino or y-methylpiperazino; R1 is hydrogen or halogen, R2 halogen, nitro or tries fluoromethyl, R1 and R8 are the same or different hydrogen, lower alkyl or C7-C10-aralkyl, and their pharmaceutically acceptable acid addition salts. These compounds of the formula Ia produced according to the invention are known as anxiolys

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tics, sedatives, hypnotics, antispasmodics, muscle relaxants, antidepressants or useful as their synthetic intermediates.

To illustrate the above definitions it can be said that alkyl, e.g. Methyl, ethyl, isopropyl, butyl, pentyl, hexyl; Alkenyl, e.g. Vinyl, allyl, butenyl, pentenyl, hexenyl; Alkynyl, e.g. Ethynyl, propynyl, butynyl, pentenyl; Aryl, e.g. Phenyl, tolyl, xylyl, pyridyl; Aralkyl, e.g. Benzyl, phenethyl, phenylpropyl; Acyl, e.g. Formyl, acetyl, propionyl, benzoyl, carbobenzoxy; a-aminoacyl, e.g. Glycyl, alanyl, leucyl, phenyl, alanyl; and halogen, e.g. Chlorine, bromine, fluorine, iodine.

According to the invention, for example, the following triazolylbenzophenone derivatives of the formula Ia can be produced: 2 ', 5-dichloro-2- (3-L-phenylalanylaminomethyl-5-methyl-4H-

-1,2,4-triazoI-4-yl) benzophenone; 5-chloro-2- (3-glycylaminomethyl-5-dimethylaminomethyl-4H-

-1,2,4-triazol-4-yl) benzophenone; 5-chloro-2- (3-glycylaminomethyl-5-morpholinomethyl-4H-

-1,2,4-triazol-4-yl) benzophenone; 5-chloro-2- (3-glycylaminomethyl-5-piperidinomethyl I-4H-

-l, 2,4-triazol-4-yl) benzophenone; 2 \ 5-dichloro-2- (3-glycylaminomethyl-5-dimethylaminomethyI-

-4H-1,2,4-triazol-4-yl) benzophenone; 2 \ 5-dichloro-2- (3-glycylaminomethyl-5-diethylaminomethyl - 4H-1,2,4-triazol-4-yl) benzophenone;

2 ', 5-dichloro-2- (3-glycylaminomethyl-5-pyrridinomethyl-4H-1,2,4-triazol-4-yl) benzophenone;

2 ', 5-dichloro-2- (3-glycylaminomethyl-5-phenylthiomethyl-4H-l, 2,4-triazol-4-yl) benzophenone; s 2 ', 5-dichloro-2- (3-glycyaminomethyl-5-propylthiomethyl-4H-1,2,4-triazol-4-yl) benzophenone;

2 ', 5-dichloro-2- [3- (Na-glycyl-glycylaminomethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone;

2 \ 5-dichloro-2- | 3- (N <I-L-phenylaIanyl-glycylaminomethyl) -5-io -methyl-4H-l, 2,4-triazol-4-yl] -benzophenone;

5-chloro-2- (3-glycylaminomethyl-5-acetoxymethyl-4H-1,2,4-triazol-4-yl) benzophenone;

5-chloro-2- (3-glycylaminomethyl-5-pyrrolidinomethyl-4H-1,2,4-triazoI-4-yl) benzophenone; 15 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-4H-1,2,4-triazoI-4-yl) benzophenone;

5-chloro-2- (3-glycylaminomethyl-4H-1,2,4-triazol-4-yl) benzophenone;

5-chloro-2- (3-glycylaminomethyl-5-methyl-4H-l, 2,4-triazol-20 -4-yl) benzophenone;

5-chloro-2- (3-glycylaminomethyl-5-propargyoxymethyl-4H-1,2,4-triazol-4-yl) benzophenone;

5-chloro-2'-fluoro-2- (3-glycylaminomethyl-5-morpholinomethyl-4H-1,2,4-triazol-4-yl) -benzophenone and 25 5-chloro-2- (3-L- phenylalanylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl) benzophenone.

The aforementioned triazolylbenzophenone derivatives of the formula

Ia can be prepared by various methods, as can be seen from the following reaction scheme.

Procedure A

h n1 *

Ar

■ NH-C0CHNH-C0CH-Q

. weak OH (uV ^ V. acid

N N R8

R-il ^ JLCH-NH-COCH-Q

| Bydrazinolysis

N N R ^ R8

UJL CH-NH-COCHNH,

-

.v_ weak

"5" CO ar

2 [YY ^ '- 00 ^ SCh ^ ure kJ (IV)

"IJssj ^ LM-NHCOR - -1-2

POII ar

Procedure B

(III)

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A-COCH-Q (VI)

rJ ~ Y ~ C ° ~ Ar

^ (Ia)

or

Reduction / '4

R "8" 11 N — N j R R

R ^ NJ'KMNH-ODCHMÎ-COCHNHj

N N R ° N N IT R ° N N R "* Rö rfS ^ jp-CCHftr rJL_nJLcH-NH2 A-COCH-hal R-l ^ KjLcHMH-COCH-hal rnet-N ^ CHNH-C0CH-N3 Isyjl (Ib)

I (Vü)) I

Procedure C

A-CO-R3 (X) (R3C0 = acyl)

R9-KII-R10 (IX)

N N R

1

Os

'A

N N R

N N r4

R7> N (CHgî ^ lLuJLcH-NH-CO-R3

R J. ILIIHNHCOR3 R6-KH-R7 (Xl), '(R = halo-alkyl)

-CO-Ar (lo)

CO-Ar

(Id)

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4th

In this reaction scheme, A represents a reactive group, e.g. Halogen, an ester radical, Ar phenyl or 2-halophenphenyl, shark stands for halogen, HMT is hexamethylenetetramine, R "is hydrogen, lower alkyl or C7-C10-Ar-alkyl, met means alkali metal, Q is phthalimido and R, R2, R4, R®, R7, R8, R9 and R1 "have the meaning given above.

The above procedures are illustrated below

Procedure A

This process is carried out by treating the quinazoline derivative II or III with a weak acid, e.g. Acetic acid, monochloroacetic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, and the phthalimide derivative IV is obtained, and after subsequent hydrazinolysis of the product IV, the triazolylbenzophenone derivative of the formula Ia is obtained. The first reaction can generally be carried out using an excess of a weak acid, preferably without a solvent, at room temperature or with heat treatment. Said hydrazinolysis of the phthalimide derivative of formula IV can be carried out in a conventional manner, such as by treatment with hydrazine hydrate in a suitable solvent, e.g. Ethanol, methanol, s dimethylformamide, benzene, dimethyl sulfoxide, chloroform, with heating, are accomplished. This hydrazinolysis can achieve a high yield with a high degree of purity of the product of the formula Ia. The product of formula Ia obtained can also be treated with a phthalyl derivative of a-amino-ionic acid, e.g. Glycine, phenylalanine, alanine, leucine, or with their reactive derivative, e.g. Chloride, ester, in a manner customary for amino acid condensation, such as in the presence of a condensing agent, e.g. Dicyclohexylcarbodiimide, in a suitable inert solvent, e.g. Dimethylform-15 amide, dioxane, dimethyl sulfoxide, are condensed, and then the phthalyl product thus obtained is hydrazinolyzed as described above and provides the second product of formula Ib. The starting quinazoline derivatives of the formulas II and III can be derived, for example, from the amino-20 benzophenone derivative of the formula XII or from the quinazoline derivative of the formula XV, as can be seen from the following scheme:

where Cbz stands for the carbobenzoxy radical and A, Ar, Q, R, 55 R2, R4 and R8 have the above meaning.

Procedure B

The starting triazole V, which is in the form of a salt of an acid, e.g. Hydrochloride, hydrobromide, is used, 60 is first reacted with a reactive derivative of a-haloacetic acid VII. The reactive derivative is understood to mean an active derivative of the carboxy group, including the acid halide, acid anhydride, acid azide and active ester. The reaction is carried out in a conventional manner for the formation of the amido bond, such as in an inert solvent, e.g. Dimethylformamide, hexamethyl-phosphoric acid triamide, pyridine, at room temperature or under cooling or heating. The resulting intermediate

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Product halide VIII can be converted to product Ia from process A by treatment with ammonia or hexamethylenetetramine in a solvent, e.g. Methanol, ethanol, diglyme, dimethylformamide, at room temperature or warming; or by treatment 5 with alkali metal azide, e.g. Sodium azide, potassium azide, in an inert solvent, e.g. Dimethylformamide, dimethyl sulfoxide, pyridine, chloroform, at room temperature or with heating and after reducing the azido compound Ic thus obtained with a reducing agent, e.g. Stannous chloride, in sodium hydroxide, zinc dust, or by hydrogenation over a catalyst, e.g. Raney nickel, palladium-carbon, platinum oxide, in a conventional manner, such as in an inert solvent, e.g. Methanol, ethanol, dimethylformamide, benzene, tetrahydrofuran, at room temperature or 15 with cooling or heating.

The intermediate halide VIII is treated with an amine IX, e.g. Methylamine, dimethylamine, diethylamine, pyrrolidine, morpholine, piperidine, y-methylpiperazine, in an inert solvent, e.g. Dimethylformamide, methanol, ethanol, acetone, hexamethylphosphoric triamide, reacted at room temperature or with heating and provides the product Id.

The starting triazole V is also reacted with a reactive derivative of phthalyl-a-amino acid VI and provides the phthalimide derivative IV, which already results from process A mentioned; and the triazole V can be converted to the product Ib by condensation with a protected peptide, e.g. Phthalylglycyl-glycine, whereupon the protective group of the product thus obtained is applied in the usual way, e.g. is split off by hydrazinolysis.

The starting triazole V can be prepared, for example, from aminobenzophenone XVIII, as can be seen from the following scheme:

0

NH ^ CII-CN.H ^ SO ^ Cbz-Cl Cbz-NHCHCN BtOH-HCl ^

NaOH

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where Ac means acetyl, Et ethyl and A, Ar, Cbz, R, R2 and R4 have the above meaning.

Procedure C

The triazole V is reacted with an acylating agent X R3-CO = acyl in the usual way to give the product Ie. The acylating agents are acetyl chloride, acetic anhydride, propionyl chloride, butyryl bromide, isobutyryl chloride, benzoyl chloride and pyruvoyl chloride. If R of the product Ie is halo-genalkyl, the substance Ie can subsequently be incorporated into the product

If converted by treatment with the amine XI. This conversion takes place as in stage VIII - »Id of procedure B.

The starting compound V, R = haloalkyl,

R8

RT

; N (CHo) n- or R5-X- (CH2) n-,

XV

A — CO— (CH) -liai

2'il

\ T —NHCO (CH2) n-ial

(xxrx)

weak acid io used in method B and method C can be prepared according to the following scheme:

R ^> (CH2) a -U-i E2ÏH — Cbz

R

(XXXa)

ïÂïHR7

N N |

O-Ar

HBrr / AcOH, Va

1 11 - ——>

"^ (XXTb)

R5-X-A °

CO — Ai »

H3r / AcOH ^ Vb

V T>

K N I

R5-X- (CH) - - «u ENE-Cbz

Z'XL

(XXIc)

O — Ar

H3r- / AcOH; Vc wherein A ° is hydrogen, alkali metal or an active metal, e.g. Silver, tallium, and A, Ac, Ar, Cbz, R2, R4, R5, X and n have the above meaning.

65 Product Ia can be converted to its pharmaceutically acceptable acid addition salts, such as that of an inorganic acid, e.g. Hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid

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or those of an organic acid such as acetic acid, succinic acid, oxalic acid, maleic acid, malic acid, phthalic acid, methanesulfonic acid, citric acid, toluenesulfonic acid, tartaric acid; this generation takes place for reasons of production, crystallization, solubility or to improve stability.

The triazolylbenzophenone derivatives of the formula Ia or their pharmaceutically acceptable acid addition salts thus produced according to the invention are useful as anxiolytics, sedatives, anticonvulsants, hypnotics, muscle relaxants, antidepressants or their synthetic intermediates. For example, 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl) benzophenone shows an ED50 of 0.23 mg / kg in mice, peros , in the anticonvulsant activity against pententenentetrazole and an ED50 of 0.25 mg / kg in mice, peros, in the potentized anesthetic against sodium thiopental; and 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazoI-4-yl) -benzophenone shows an ED50 of 0.75 mg / kg in mice, peros , with the mentioned anti-seizure effectiveness. The other triazolylbenzophenone derivatives Ia showed similar pharmacological effects.

The triazolylbenzophenone derivatives produced according to the invention and their pharmaceutically acceptable acid addition salts are used alone or in combination with pharmaceutically acceptable carriers, e.g. Wheat starch, grain starch, potato starch, gelatin, etc. applied. The choice of carriers is determined by the preferred route of administration, the solubility of the substance and standard pharmaceutical practice. Examples of pharmaceutical preparations are tablets, capsules, pills, suspensions, syrups, powders and solutions. These compositions can be prepared in the usual way. A suitable dose of the above-mentioned triazolylbenzophenone derivatives Ia or their pharmaceutically acceptable acid addition salts for adults is of the order of about 0.2 mg to about 30 mg / day.

In addition, the triazolylbenzophenone derivatives Ia produced according to the invention or their acid addition salts are useful as growth promoters for cattle and poultry.

The presently preferred and practical embodiments of the present invention are set forth in the following examples.

example 1

(1) To a solution of 1.5 g of 2-phthalimidoacetyl chloride in 20 ml of benzene and 10 ml of dimethylformamide, 2.3 g of 5-chloro-2- (3-aminomethyl-5-methyl-4H-l, 2,4- triazol-4-yl) - benzophenone dihydrobromide is added while cooling with ice and stirring and the temperature inside the flask is gradually raised to room temperature. The reaction mixture is then left to stand at room temperature, neutralized with saturated aqueous sodium bicarbonate solution and shaken with ethyl acetate. The precipitated crystals were filtered, washed with methanol and dried, and 1.68 g of 5-chloro-2- [3- (2-phthalimidoacetamidomethyl) -5-methyl-4H-l, 2,4-triazole- 4-yI] -benzophenone as crystals with F from 251 to 253 ° C.

Analysis for C2TH, 0N5O4Cl:

calculated: C 63.10 H 3.92 N 13.62 Cl 6.90

found: C 63.08 H 4.03 N 13.80 Cl 7.07

(2) A solution of 2.3 g of 5-chloro-2- [3- (2-phthalimido-acetamidomethyI) -5-methyl-4H-l, 2,4-triazoI-4-yI] benzophenone in 20 ml of ethanol was added with 0.92 g of hydrazine hydrate and the resulting mixture was heated at reflux for one hour. The precipitated phthalohydrazide was filtered and the filtrate under reduced pressure

Pressure evaporated. The residue was then dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated under reduced pressure. The precipitate formed was chromatographed on a silica gel column and the product obtained by evaporation from the eluate was recrystallized from ethyl acetate and 5-chloro-2 - (3-glycylaminomethyl-5-methyl-4H) was obtained in a 94% yield -1,2,4-triazol-4-yl) benzophenone hydrate as crystals with F from 110 to 113 ° C.

Analysis for C, BHiSN5OaCl. H20:

calculated: C 56.79 H 5.01 N 17.82 Cl 8.80 found: C 57.12 H 5.07 N 17.52 Cl 9.00 oxalate dihydrate, F 112 to 114 ° C (recrystallized from water-acetonitrile ).

Example 2

(1) Using 2 ', 5-dichloro-2- (3-aminomethyl-5-methyl-4H-l, 2,4-triazol-4-yl) -benzophenone.dihydro-bromide the procedure was according to Example 1 (1) was carried out, using 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl] benzophenone as crystals with F of 219 to 231 ° C was obtained.

(2) Using 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-methyl-4H-l, 2,4-triazoI-4-yl] benzophenone, the Reaction according to Example 1 (2) carried out, wherein 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-l, 2,4-triazol-4-yl) benzophenone as crystals with F from 163 to 165 ° C was obtained.

Analysis for C19H17N502C12:

calculated: C 54.56 H 4.10 N 16.74 Cl 16.95 found: C 54.37 H 4.13 N 16.45 CI 17.00 dihydrochloride monohydrate, F 178.5 to 181.5 ° C (recrystallized from ethanol / ethyl acetate).

Example 3

(1) A solution of 0.7 g of 3- [Na- (2-phthalimidoacetyl) glycyamino] -4-hydroxy-4-phenyl-6-chloro-3,4-dihydroquinazoline in 5 ml acetic acid was refluxed for 2% hours. The reaction mixture obtained was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution and then with water, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column and after elution with ethyl acetate / methanol 20: 1, 5-chloro-2- [3- (2-phthalimidoacetamidomethyl) -4H-l, 2,4-triazol-4- yl] -benzophenone as crystals with F from 214 to 215 ° C. IR (CHCIS), 1780, 1720, 1690 cm "1.

(2) Using the product obtained above, the reaction was carried out as described in Example 1 (2) and the colorless oil obtained was 5-chloro-2- (3-glycyI-aminomethyl-4H-1,2,4-triazole- 4-yl) benzophenone.

Example 4

(1) A solution of 2.36 g of 2-carbobenzoxyamino-methyl-3-amino-4-hydroxy-4- (2-chlorophenyl) -6-chloro-3,4-dihydroquinazoline in 15 ml of dimethylformamide was 0. 79 g of acetyl chloride was added and the resulting mixture was stirred at room temperature for five hours and left overnight. The reaction mixture was then neutralized with aqueous sodium bicarbonate solution and shaken with ethyl acetate. The organic layer was then washed with water and evaporated to give

5

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2.1 g of 2-carbobenzoxyaminomethyl-3-acetamido-4- (2-chlorophenyl) -6-chloro-3,4-dihydroquinazoline.

(2) A mixture of 2.7 g of the above product and 6 ml of 30% hydrogen bromide acetic acid was stirred at room temperature for one hour and 20 minutes. The reaction mixture was then washed with ether and 2.85 g of 2-aminomethyl-3-acetamido-4-bromo-4- (2-chlorophenyl) -6-chIoro-3,4-dihydroquinazoline.dihydrobromide were obtained. dihydrate as crystals with F at 169 to 175 ° C (dec.).

Analysis for Ci7H1!; N4Cl2BrO. 2HBr. 2H20:

calc .: C 32.00 H 3.32 N 8.78 Cl 11.11 Br 37.26 found: C 32.28 H 3.11 N 8.99 Cl 11.40 Br 37.54

(3) To a solution of 1.65 g of 2-phthalimidoacetyl chloride in 20 ml of hexamethylphosphoric acid triamide was added 2.3 g of the above product, and the resulting mixture was stirred at room temperature for three hours. The reaction mixture was then mixed with ether and neutralized with aqueous sodium bicarbonate solution. The resulting precipitate was filtered and shaken with chloroform. The chloroform layer was then evaporated to remove the chloroform and the residue treated with ether to give 1.15 g of 2- (2-phthalimidoacetamidomethyl) -3-acetamido-4-hyroxy-4- (2-chlorophenyl) ) -6-chloro-chiazoline. This substance was recrystallized from ethyl acetate and crystals with F of 165 to 168 ° C. were obtained.

Analysis for C27H21Nr) 05Cl2:

calculated: C 57.26 H 3.74 N 12.36 Cl 12.52 found: C 57.33 H 4.01 N 11.73 CI 12.15

UV X (log) 219, 286 mn (4,852,4,141).

(4) A solution of 1.15 g of the above product in 11 ml of acetic acid was refluxed for 2% hours and the reaction mixture was then evaporated to remove the acetic acid. The residue was shaken with chloroform and the resulting chloroform layer was washed with aqueous sodium bicarbonate solution and then with water, dried and evaporated to remove the chloroform. The resulting residue was treated with ethyl acetate and finally 0.4 g of 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamido-methyl) -5-methyl-4H-l, 2,4-triazole- 4-yl] benzophenone.

(5) The above product was treated with hydrazine hydrate as described in Example 1 (2), whereby 2 ', 5-di-chloro-2- (3-glycylaminomethyl 1-5-methyl-4H-1,2,4- triazoI-4 - yl) benzophenone.

Example 5

(1) To a solution of 1.32 g of 2 ', 5-dichloro-2- (3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) benzophenone in 20 ml of methanol and 20 ml of chloroform were added 0.4 g of potassium iodide and 3 ml of diethylamine and the resulting mixture was refluxed for five hours. The reaction mixture was then evaporated under reduced pressure and the residue extracted with ethyl acetate. The ethyl acetate layer was then washed with water, dried and evaporated under reduced pressure. The residue was then treated with ether and 1.1 g of 2 ', 5-dichloro-2- (3-carbo-benzoxyaminomethyl-5-diethylaminomethyl-4H-1,2,4-triazole - 4-yJ) were obtained. benzophenone. The product was then recrystallized from ether / ethyl acetate and crystals with F of 89 to 94 ° C. were obtained.

(2) A mixture of 1.41 g of the above product and 2.5 ml of 30% hydrobromic acetic acid was stirred at room temperature for two hours and washed twice with 50 ml of ether. The free base obtained was then mixed with 15 ml of benzene, 1.12 g of 2-phthalimidoacetyl chloride and 8 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for two hours and left to stand overnight. This reaction mixture was then mixed with ethyl acetate, neutralized with aqueous sodium bicarbonate solution, and the ethyl acetate layer was washed with water, dried and evaporated under reduced pressure. The resulting residue was treated with ether and 1.4 g of 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-diethylaminomethyl-4H-l, 2,4-triazole- 4-yl] benzophenone. The product was finally recrystallized from ethanol and crystals with an F of 212 to 214 ° C. are obtained.

UV X (log) 218.5, 294 mn (4.85, 3.954).

(3) A suspension of 1.12 g of the above product and 0.234 g of hydrazine hydrate in 10 ml of ethanol was heated at reflux for 25 minutes. The resulting precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the ethyl acetate layer was washed successively with aqueous sodium bicarbonate solution and then with water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column and, after elution with methanol, resulted

0.8 g of 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-diethylamino-methyl-4H-l, 2,4-triazol-4-yl) benzophenone in the form of an oil. NMR (CDC13), 5, 0.73 (t., J = 15, CH2CH, J, 3.53 (s "CH2-NEt2), 4.37 (ABX, NHCH2), 8.13 (br., NH2 ).

Example 6

The reaction according to Example 5 was carried out using dimethylamine instead of diethylamine, the following products being obtained:

(1) 2 ', 5-dichloro-2- (3-carbobenzoxyaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazol-4-yl) benzophenone with F from 123 to 125 ° C after recrystallization Ethyl acetate;

uv * (log e) 253, 291 mji, (4.01, 3.837).

(2) 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-dimethylaminomethyl-4H-1,2,4-triazol-4-yl] benzophenone with F from 226 to 227 ° C after recrystallization from ethanol.

(3) 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazol-4-yl) benzophenone with F at 179 to 183 ° C after recrystallization Ethyl acetate;

UV X ™ H (log e) 214, 250, 290, m [i (4,056, 3,984, 3,438).

Example 7

(1) To a suspension of 0.08 g of sodium hydroxide in 8 ml of dimethylformamide, 0.33 g of thiophenol was added while cooling with ice, and the resulting mixture was stirred under cooling with ice for five minutes. Then 1.06 g of 2 ', 5-dichloro-2- (3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) -benzo-phenone was added to the mixture, which was stirred at room temperature for V / i hours. This reaction mixture was then shaken with ethyl acetate and the ethyl acetate layer was washed with water, dried and evaporated under reduced pressure. The residue was then washed with n-hexane and a gelatinous product resulted, which was mixed with 2 ml of 30% hydrobromic acetic acid

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was mixed. The mixture was then stirred at room temperature for two hours and washed with ether. The resulting crystals were filtered, washed with 50 ml of ether and successively mixed with 10 ml of benzene, 0.672 g of 2-phthalimidoacetyl chloride and finally with 7 ml of dimethylformamide. The mixture was stirred at room temperature for three hours and shaken with ethyl acetate. The ethyl acetate layer was then washed with aqueous sodium bicarbonate solution and then with water, dried and evaporated under reduced pressure to give 1.05 g of 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamido-methyl) -5-phenylthiomethyl- 4H-l, 2,4-triazol-4-yl] benzophenone were obtained. The product was recrystallized from ethanol and crystals with F at 220 to 221 ° C. are obtained.

UV X £ ° H (log e) 219, 290 mfi (4.902, 3.702).

(2) A suspension of 0.84 g of the above product and 0.196 g of hydrazine hydrate in 9 ml of ethanol was treated at reflux for 30 minutes and the resulting precipitate was filtered off. The filtrate was then evaporated under reduced pressure and the residue extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution and then with water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column, which was eluted with methanol, and 0.55 g of 2 ', 5-dichloro-2- (3-glpcylaminomethyl-5-phenylthiomethyl-4H-l, 2,4-triazole-4 was obtained -yl) -benzophenone as a powder.

Analysis for C2riH21N5Cl2S02. % H, 0:

calculated: C 56.55 H 4.08 N 13.19 Cl 13.35 S 6.04 found: C 56.58 H 4.18 N 12.84 Cl 12.87 S 6.06

UV X E '° H (log e) 253 mix (4.137).

Example 8

The reaction was carried out as described in Example 7 using propyl mercaptan instead of thiophenol, the following products being obtained:

(1) 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-propylthiomethyl-4H-1,2,4-triazol-4-yl] benzophenone with F from 172 to 184 ° C after recrystallization from ethanol; Analysis for C30H23NöSCl2O4. Yi H20:

calculated: C 57.05 H 4.15 N 11.09 Cl 11.23 S 5.08 found: C 57.21 H 4.39 N 10.72 CI 11.54 S 5.17

(2) 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-propylthio-methyl-4H-l, 2,4-triazol-4-yl) benzophenone oxalate dihydrate with F from 109 to 113 ° C after recrystallization from dilute acetonitrile;

Analysis for C22H23NÖSC1202. (COOH) 2. 2H, 0:

calculated: C 46.61 H 4.73 N 11.32 CI 11.46 S 5.18 found: C 46.85 H 4.39 N 10.96 CI 11.33 S 5.74

Example 9

Using pyrrolidine instead of diethylamine, the reaction was carried out as described in Example 5, the following products being obtained:

(1) 2 ', 5-dichloro-2- (3-carbobenzoxyaminomethyl-5-pyrro-lidinomethyl-4H-l, 2,4-triazol-4-yl) benzophenone, with F at 143 to 145 ° C after recrystallization from ethyl acetate; Yield 97.4%.

(2) 2 ', 5-dichloro-2- [3- (2-phthalimidoacetamidomethyl) -5-pyrrolidinomethyl-4H-l, 2,4-triazol-4-yl] benzophenone with F of about 193 ° C; Yield 90.8%.

(3) 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-pyrrolidino-methyl-4H-l, 2,4-triazol-4-yl) -benzophenone with F from 181 to 183 ° C after recrystallization Ethanol;

Analysis for C23H24NcCl202:

calculated: C 56.68 H 4.96 N 17.24 CI 14.55 found: C 56.66 H 5.06 N 17.09 CI 14.72 yield 75%.

Example 10

The reaction was carried out as described in Example 5 using 5-chloro-2- (3-carbobenzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl) benzophenone and pyrrolidine. the following products were obtained:

(1) 5-Chloro-2- (3-carbobenzoxyaminomethyl-5-pyrrolodinomethyl-4H-l, 2,4-triazol-4-yl) -benzophenone with F from 174.5 to 175.5 ° C after recrystallization from methylene chloride / 95% ethanol; Yield 92.1%.

(2) 5-Chloro-2- [3- (2-phthalimidoacetamidomethyl) -5-pyrrolidinomethyI-4H-l, 2,4-triazol-4-yl] -benzophenone with F from 245 to 247 ° C (dec .) after recrystallization from methylene chloride / 95% ethanol; Yield 68.7%.

(3) 5-chloro-2- (3-glycylaminomethyl-5-pyrrolidinomethyl-4H-l, 2,4-triazoI-4-yl) -benzophenone with F from 182 to 183 ° C after recrystallization from isopropanol;

Analysis for C23H25O2N0Cl:

calculated: 'C 60.99 H 5.56 N 18.56 Cl 7.83 found: C 61.08 H 5.61 N 18.56 Cl 8.13 yield 72.3%.

Example 11

(1) To a solution of 1.51 g of sodium iodide in 30 ml of acetonitrile was added 5.0 g of 5-chloro-2- (3-carbobenzoxyamino-methy 1-5-chloromethyl I-4H-1,2,4-triazole- 4-yl) benzophenone was added and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into 100 ml of water and shaken twice with 50 ml of benzene. The benzene layer was then washed twice with 100 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on a silica gel column and after elution with ethyl acetate, 3.61 g of 5-chloro-2- (3-carbobenzoxyaminomethyl-5-iodomethyl-4H-l, 2,4-triazol-4-yl) benzophenone were obtained . The product was recrystallized from methylene chloride / ether and there were crystals with F of 133 to 134 ° C (dec.).

(2) To a solution of 1.53 g of thalloethoxide in 60 ml of dry benzene, 0.354 ml of propargyl alcohol was added and the resulting mixture was stirred at room temperature for one hour. The mixture was then evaporated under reduced pressure and thallium propargyl oxide was obtained in the form of white crystals, which were dissolved in 60 ml of dry acetonitrile. 3j00 g of the benzophenone product obtained above was added to the solution, which was stirred for 42 hours at room temperature. The resulting precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was then dissolved in 50 ml of benzene, washed three times with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was then chromatographed on a silica gel column and after elution with 10 to 50% ethyl acetate / methylene chloride, 817 mg of 5-chloro-2- (3-

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-carbobenzoxyaminomethyl-5-propargyloxymethyl-4H-l, 2,4-triazoI-4-yl) -benzophenone in the form of an oil.

(3) A mixture of 817 mg of the above product and 3 ml of 27.5% hydrobromic acetic acid was stirred at room temperature for 1 ½ hours. The resulting solution was then mixed with 32 ml of dry ether, resulting in a precipitate. This precipitate was washed twice with 20 ml of dry ether and 5-chloro-2- (3-aminomethyl-5-pro-pargy loxy methy 1-4H-1,2,4-triazol-4-yl) -benzophenone was obtained .hydro-bromide. 1.6 g of 2-phthalimidoacetyl chloride were added to a suspension of this hydrobromide in 20 ml of dry benzene at room temperature. The resulting mixture was then mixed with 10 ml of dry dimethylformamide and stirred at room temperature for three hours. The reaction mixture was then poured into a solution of 50 ml of saturated aqueous sodium bicarbonate and

Poured 50 ml of water and stirred under ice cooling for 30 minutes. The precipitate was filtered and then washed with ether and then with water and dissolved in about 50 ml of methylene chloride. The organic layer was then dried over magnesium sulfate and evaporated. The residue was recrystallized from methylene chloride / ethanol and 682 mg of 5-chloro-2- [3- (2-phthalimidoacetamidomethyl) -5-propargyloxymethyl-4H-l, 2,4-tri-azol-4-ylJ were obtained -benzophenone as crystals with F from 245 to 246 ° C (dec.).

(4) A solution of 600 mg of the above product and 1.0 ml of hydrazine hydrate in 10 ml of 95% ethanol was heated under reflux for two hours. The precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was then extracted with methylene chloride and the methylene chloride layer was shaken twice with 50 ml of 2N hydrochloric acid. Then the hydrochloric acid layer was alkalized with aqueous ammonia and shaken three times with methylene chloride. The methylene chloride layer obtained was then dried over potassium carbonate and 5-chloro-2 - (3-glycyaminomethyl-5-propargyloxymethyl-4H-1,2,4-triazol-4-yl) benzophenone hydrate was obtained as a colorless oil . The product was crystallized from isopropanol / ether and crystals with F of 93 to 95 ° C. were obtained.

Analysis for C.,., H2l, 03Nr, CI. H20:

calculated: "" C 57.96 H 4.87 N 15.36 Cl 7.78

found: C 58.32 H 4.88 N 15.44 Cl 8.15

Example 12

Using 5-chloro-2'-fiuoro-2- (3-carbo-benzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl) benzophenone with F from 148 to 149 ° C and of morpholine, the reaction was carried out as described in Example 5, the following products being obtained:

(1) 5-Chloro-2'-f luoro-2- (3-carbobenzoxyaminomethyl-5 - morpholinomethyl-4H-l, 3,4-triazol-4-yl) benzophenone with F from 182 to 184.5 ° C after recrystallization from ethyl acetate.

(2) 5-Chloro-2'-fluoro-2- [3- (2-phthalimidoacetamidomethyl) -5-morpholinomethyl-4H-l, 2,4-triazol-4-yl] benzophenone with F at 269 to 270 ° C after recrystallization from methylene chloride / methanol.

(3) 5-ChIoro-2'-fluoro-2- (3-glycylaminomethyl-5-morpho-linomethyl-4H-l, 2,4-triazol-4-yl) benzophenone in amorphous form.

10th

Example 13

(1) A solution of 1.18 g of 2 ', 5-dichloro-2- (3-glycylamino-methyl-5-methyl-4H-l, 2,4-triazoI-4-yl) benzophenone, 1.00 g of phthalylglycine and 1.05 g of dicyclohexylcarbodiimide in 23 ml of 5 dimethylformamide were stirred at room temperature for three hours and the reaction mixture thus obtained was left to stand overnight. The precipitate of urea formed was filtered off, the filtrate was mixed with an excess of aqueous sodium carbonate and the precipitate formed was decanted off. The residue was then dissolved in methylene chloride, washed with water, dried and concentrated. The crude product was chromatographed through a silica gel column and after elution with ethyl acetate / methanol 1: 4, the product obtained was recrystallized from 15 chloroform / methanol and finally 1.35 g of 2 ', 5-dichloro-2- [3- (Na-2-phthalimidoacetylglycylaminomethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone as crystals with F at 269 to 270 ° C.

20 (2) A suspension of 1.10 g of the above product and 0.25 ml of hydrazine hydrate in 10 ml of ethanol was stirred at reflux for 2% hours. The reaction mixture was then allowed to cool to room temperature and the precipitate of phthalyl hydrazide formed was filtered off. The filtrate was then concentrated under reduced pressure and the residue extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure. The residue obtained was recrystallized from ethyl acetate / 30 n-hexane and 210 mg of 2 ', 5-dichloro-2- [3- (N a-glycyl-glycylaminomethyl) -5-methyl-4H-1,2 were obtained , 4-triazol-4-yl] benzophenone as hygroscopic crystals with F at 60 to 65 ° C.

35 Example 14

(1) A solution of 1.08 g of 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-4H-l, 2,4-triazol-4-yl) benzophenone and 80 mg phthalyl -L-phenylalanine in 13 ml of dimethylformamide was mixed with a solution of 450 mg of dicyclohexyl-40 carbodiimide in 3 ml of dimethylformamide at room temperature. The resulting mixture was stirred at room temperature for four hours and left overnight. The reaction mixture obtained was treated as described in Example 30 (1), 1.12 g 45 of 2 ', 5-dichloro-2- {3- [Na- (L-2-benzyl-2-phthalimidoacetyl) glycylaminomethyl ] -5-methyl-4H-l, 2,4-triazol-4-yl} -benzo-phenone as crystals with F at 138 to 140 ° C after recrystallization from methylene chloride / n-hexane were obtained.

50 (2) The product obtained above was treated with hydrazine hydrate as described in Example 13 (2), 2 ', 5-dichloro-2- [3- (Na-L-phenylalanylglycylaminomethyl) -5-methyl-4H -l, 2,4-triazol-4-yll-benzophenone were obtained as hygroscopic crystals with F from 65 to 70 ° C. 55 The dihydrochloride hydrate had an F of 187 to 190 ° C after recrystallization from ethanol ether.

Example 15

(1) A suspension of 1.0 g of 5-chloro-2- (3-carbobenz-60 oxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl) benzophenone and 0.5 g of silver acetate in 20 ml of acetonitrile was heated at reflux for two hours. The silver chloride which separated out was filtered off and the filtrate was evaporated under reduced pressure. The residue was then dissolved in ethyl acetate, the ethyl acetate solution washed with water, dried and evaporated under reduced pressure to give a light yellow oil. The residue was then chromatographed on a silica gel column

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and after elution with ethyl acetate, 0.65 g of 5-chloro-2- (3-carbobenzoxyaminomethyl-5-acetoxymethyl-4H-l, 2,4-triazol-4-yl) benzophenone was obtained as a colorless oil.

IR (film), 3280 (wide), 1745, 1715, 1660, 1595 cm "1

(2) A mixture of 650 mg of the above product and

2 ml of 30% hydrobromic acetic acid was stirred at room temperature for one hour. The resulting mixture was then mixed with an excess of ether and the precipitate formed was washed three times with ether by decantation to give 5-chloro-2- (3-aminomethyl-5-acetoxymethyl-4H-l, 2,4-triazole- 4-yl) benzophenone hydrobromide. A suspension of the above product and 1.0 g of 2-phthalimidoacetyl chloride in 10 ml of benzene were added to 5 ml of dimethylformamide at room temperature and the resulting mixture was stirred for three hours. The reaction mixture obtained was then mixed with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The ethyl acetate layer was then washed thoroughly with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual oil was triturated with ethyl acetate and 700 mg of a crystalline 5-chloro-2- [3 - (2-phthalimidoacetamidomethyI) -5-acetoxymethyl-4H-l, 2,4-triazol-4-yl] -benzophenone were obtained . The product was then recrystallized from ethanol to give crystals with F at 225 to 228 ° C.

(3) A suspension of 522 mg of the above product and 45 mg of 100% hydrazine hydrate in 20 ml of ethanol was heated at reflux for two hours. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium carbonate solution. The methylene chloride layer was then separated, dried over aqueous sodium sulfate and evaporated. The resulting residue was chromatographed on a silica gel column and, after eluting with ethyl acetate / methanol 4/1 v / v. 120 mg of 5-chloro-2- (3-glycylaminomethyl-5-acetoxymethyl-4H-l, 2,4-triazol-4-yl) benzophenone were obtained. yz H20. The product was then recrystallized from ethyl acetate to give crystals with F at 123 ° C (with shrinkage).

IR (Nujol), 3220, 1745, 1655 (broad), 1590 cm "1.

Analysis for C21H20N5C1.1 / 7l H20:

calculated: C 55.94 H 4.69 N 15.53

found: C 55.76 H 4.52 N 15.71

Example 16

(1) To a solution of 2.7 g of L-2-phthalimido-3-phenyl-propionyl chloride in 26 ml of benzene and 13 ml of dimethylformamide was added 3 g of 2 ', 5-dichloro-2- (3-aminomethyl-5-methyl --4H-l, 2,4-triazol-4-yl) -benzophenon.dihydrobromid added at 0 ° C in an ice bath with stirring. The reaction mixture was gradually warmed to room temperature and left overnight. An aqueous saturated sodium bicarbonate solution was then poured into the mixture and the benzene layer was separated off, dried over anhydrous sodium sulfate and evaporated under reduced pressure; 2.5 g of 2 ', 5-dichloro-2- [3- (L-2-benzyl-2-phthalimidoacetamidomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl) were obtained. -benzophenone as crystals with F at 238 to 240 ° C.

IR (Nujol), 3190, 1780, 1715, 1680 (broad), 1590 cm-1.

(2) A suspension of 2.4 g of the above product and 0.2 g of 100% hydrazine hydrate in 20 ml of ethanol was heated at reflux for one hour. The precipitate was filtered off and the filtrate was reduced under reduced pressure

. Pressure evaporated. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer was then dried over anhydrous sodium sulfate and evaporated. The viscous oil was treated with 400 mg oxalic acid in 15 ml acetate and a white precipitate resulted. The precipitates were washed several times with ethyl acetate and finally 1.9 g of 2 ', 5-dichloro-2- (3-L-phenylalanylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl were obtained ) - benzophenone oxalate hydrate.

Analysis for C28H27N507CI2:

calculated: C 54.55 H 4.41 N 11.36 Cl 11.50 found: C 54.13 H 4.34 N 11.06 Cl 11.31 [a] D + 29 ° (EtOH).

Example 17

Using 5-chloro-2- (3-carbobenzoxy-aminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) benzophenone and dimethylamine, the reaction was carried out as described in Example 5, where the following products have been obtained.

(1) 5-chloro-2- (3-carbobenzoxyaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazol-4-yl) benzophenone with F from 123 to 125 ° C;

IR (CHC1S), 3210, 1708, 1655 cm "1.

(2) 5-Chloro-2- | 3- (2-phthaIimidoacetamidomethyl) -5-dimethylaminomethyl-4H-l, 2,4-triazoI-4-yl] -benzophenone with F from 229 to 231 ° C (recrystallized from ethanol);

IR (Nujol), 3200, 1770, 1715, 1680, 1658 cm "1.

(3) 5-chloro-2- (3-glycylaminomethyl-5-dimethylamino-methyl-4H-l, 2,4-triazol-4-yl) benzophenone with F from 188 to 190 ° C;

IR (Nujol), 3340, 3200, 1680 cm "1.

Analysis for C21H23N (i02CI:

calculated: C 59.08 H 5.48 N 19.69 Cl 8.30 found: C 59.21 H 5.25 N 19.56 Cl 8.43

Example 18

Using 5-chloro-2- (3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) benzophenone and piperidine, the reaction was carried out as described in Example 5, giving the following products:

(1) 5-chloro-2- (3-carbobenzoxyaminomethyl-5-piperidino-methyl-4H-l, 2,4-triazol-4-yl) benzophenone with F from 169 to 171 ° C (recrystallized from ethyl acetate);

IR (Nujol), 3180, 1705, 1670 cm "1.

(2) chloro-2- [3-phthalimidoacetamidomethyl-5-piperidino-methyl-4H-l, 2,4-triazoI-4-yl] benzophenone with F from 246 to 248 ° C (recrystallized from ethanol);

IR (Nujol), 3220, 1765, 1715, 1695, 1660 cm "1.

(3) 5-chloro-2- (3-glycylaminomethyl-5-piperidinomethyl-4H-1,2,4-triazoI-4-yl) benzophenone, C2H5OCOCH3, F = 288 ° C;

IR (Nujol), 3220, 1730, 1680, 1660, 1590 cm "1.

Analysis for C2 (iH3, NBOj3Cl:

calculated: C 61.11 H 6.11 N 16.44 Cl 6.94

found: C 60.88 H 6.23 N 16.30 Cl 7.14

Example 19

Using 5-chloro-2- (3-carbobenzoxyaminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) -benzo-

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phenon and morpholine, the reaction was carried out as described in Example 5 and the following products were obtained:

(1) 5-ChIoro-2- (3-carbobenzoxyaminomethyI-5-morpho-linomethyl-4H-l, 2,4-triazol-4-yl) benzophenone, F = 175 to 176 ° C (recrystallized from ethyl acetate);

IR (Nujol), 3220, 1710, 1670 cm-1.

(2) 5-Chloro-2- [3- (2-phthalimidoacetamidomethyl) -5-mor-phoIinomethyI-4H-l, 2,4-triazol-4-yl] -benzophenone, F = 248 to 250 ° C (recrystallized from ethanol);

IR (Nujol), 3200, 1765, 1710, 1695, 1660 cm "1.

(3) 5-chloro-2- (3-glycylaminomethyl-5-morpholinomethyl-4H-l, 2,4-triazol-4-yl) benzophenone, oil;

IR (CHCL), 3200, 1660 (broad), 1590 cm "1;

NMR (CDCI3), 5, 2.0-2.9 (4H, m.), 3.1-3.9 (4H, m.), 3.4 (2H, s.), 4.37 (2H , ABX), 8.07 (1H, br. M.).

Example 20

Using 5-chloro-2- (3-carbobenzoxy-aminomethyl-5-chloromethyl-4H-l, 2,4-triazol-4-yl) -benzophe-non and dimethylamine, the reaction was carried out according to Example 5, whereupon the following products resulted:

(1) 5-Chloro-2- (3-carbobenzoxyaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazol-4-yl) benzophenone, F = 123 to 125 ° C.

(2) 5-ChIoro-2- [3- (L-2-benzyl-2-phthalimidoacetamido-methyl) -5-dimethylaminomethyl-4H-1,2,4-triazol-4-yl) benzophenone, oil ;

IR (CHClj), 3300, 3200, 1780, 1715, 1670 cm "1.

(3) 5-chloro-2- (3-L-phenylalanylaminomethyl-5-dimethylaminomethyl-4H-l, 2,4-triazol-4-yl) benzophenone, oil; Md -4.0 ° (EtOH);

IR (CHCla), 3340, 1665 (broad), 1595 cm-1;

s NMR (CDCy, 5, 1.75 (6H, s.), 2.42 (2H, br. m.), 2.5-3.8 (3H, m.), 4.43 (2H, buckled ABX), 8.25 (1H, br. M.). Analysis for C28H ^ 9N0O2Cl:

calculated: C 65.05 H 5.65 N 16.25 Cl 6.86 found: C 64.81 H 5.56 N 16.00 CI 6.95

io

Example 21

(1) To a solution of 2.56 g of 2 ', 5-dichloro-2- (3-amino methyl-5-methyl-2H-l, 2,4-triazol-4-yl) -benzophenone dihydro-bromide in 20 ml of dimethylformamide, 0.8 ml of pyridine

15 while cooling at -10 ° C and the resulting mixture was stirred at -10 ° C to -13 ° C for 20 minutes. Thereafter, 4.0 g of 2- (2-phthalimidoacetamido) acetyl chloride were added in portions and the mixture was stirred at -10 ° C. for three hours. The reac

The mixture was then mixed with an excess of aqueous sodium bicarbonate solution and the product which separated out was separated off by filtration and dissolved in 100 ml of methylene chloride. The organic layer was then washed with water, dried and to remove the

25 methylene chloride evaporated. The residue was then recrystallized from methanol / chloroform and 2.0 g of 2 ', 5-dichloro-2- [3- (Na-phthalyl-glycyl-glycylamino-methyl) -5-methyl-4H-1, 2, were obtained. 4-triazol-4-yl] benzophenone as crystals with F at 269 to 270 ° C.

30th

(2) The above product was hydrazinolyzed as described in Example 13 (2), 2 ', 5-dichloro-2- [3- (Na - glycyI-glycylaminomethyl) -5-methyl-4H-l, 2.4 -triazol-4-yl] - benzophenone obtained as crystals with F at 60 to 65 ° C.

Was 35.

Claims (2)

623315 2nd PATENT CLAIMS 1. Process for the preparation of a compound of formula Ia N N R R R —CH-NH-COÌKNH (la) wherein R is hydrogen, lower alkyl, halogeno lower alkyl, the grouping - (CH2) n-X-Rn or the grouping - (CH2) n-N: R6 R7 is, where R5 is hydrogen, lower alkyl, C2-CG-alkenyl, C2-C "- alkynyl, Ci; -C] (, - aryl or C2-Cs-acyl, X is sulfur or oxygen, n 0, 1,2 or 3, R "and R7 are each hydrogen or I. Lower alkyl means or the group R "-N-R7 represents pyrrolidino, piperidino, morpholino, or y-methylpiperazino; R1 is hydrogen or halogen, R2 halogen, nitro or trifluoromethyl, R1 and R8 are identical or different hydrogen, lower alkyl or C-- C, "- Aralkyl; characterized in that a phthalyl derivative of the formula IV is, wherein R5 is hydrogen, lower alkyl, C2-CG alkenyl, C2-Cc-alkynyl, C "-C] 0-aryl or C2-C8-acyl, X is sulfur or oxygen, n zero, 1. 2 or 3, Rß and R7, identical or different, each represents hydrogen or lower alkyl, or the group 5 I pation R,: - N-R7 is pyrrolidino, piperidino, morpholino or y-methylpiperazino, R1 is hydrogen or halogen, R2 is halogen, nitro or trifluoromethyl, R4, R8 and R11, identical or different, hydrogen, lower alkyl or C7-C, 0 -Ar- io alkyl, characterized in that a compound of formula Ia obtained 15 20th condensed with a phthalyl derivative of an a-amino acid or its re-25 active derivative in a suitable solvent, and the resulting phthalyl product is hydrazinolyzed in an inert solvent. 3. Use according to claim 2, characterized in that one carries out the condensation reaction of the compound of formula Ia with a phthalyl derivative of an a-amino acid or its reactive derivative in the presence of a condensing agent. R R 8th .N / ^ - CH-NH-COCH-M R1 35 (IV) 40