FI84058B - Novel 4-(4-phenyl-1-piperazinyl)phenole derivatives useful as intermediates - Google Patents

Abstract

The invention relates to novel 4-(4-phenyl-1- piperazinyl)phenole derivatives useful as intermediates of the formula III <IMAGE> wherein Y is a saturated, substituted, heterocyclic group; a group of the formula -N=A, wherein A is a substituted heterocyclic group, or a substituted carbonylamino or thiocarbonylamino group, and pharmaceutically acceptable acid-addition salts and stereochemical isomerics thereof. Compounds with the structural formula III are suitable as intermediates when preparing therapeutically useful {[4-[4-(4-phenyl-1- piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl}-1H- imidazoles and -1H-1,2,4-triazole derivatives.

Description

84058

New 4- (4-phenyl-1-piperazinyl) phenol derivatives useful as intermediates

Separated from patent application 84 0781 5

The invention relates to novel 4- (4-phenyl-1-piperazinyl) phenol derivatives of the formula III which can be used as intermediates.

15 wherein Y is a group having any of the following formulas 0 0 0 A 1 A 1 A 2 - N NR - N NR - N NR 2 20 \ cH_) \ \ -C 3-1 2 2 0 0 ^ (a) ( c) (d) ~ Ά "'Ό N' N - · 1 'j8

R RX

(G) (h) wherein R 1, R 2 and R 8 represent lower alkyl.

The compounds of formula III can be used as intermediates in the preparation of [[4- [4- (4-phenyl-1-piperazinyl) phenoxymethyl] -1,3-dioxolan-2-yl] methyl as described in the parent patent: 82 FI patent 82 043. ] - 2 1H-imidazole and -1H-1,2,4-triazole derivatives having

is formula I

84058 en 5 I (X) CH 2 - C - Ar I-I-cV ° -fy <γ 10 and pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein Q is -N = or -CH =;

Ar is mono-, di- or trihalogen-substituted phenyl; and 15 Y is as defined above in formula lii.

U.S. Patent No. 4,144,346 describes a number of 1- (1,4-dioxolan-2-ylmethyl) -1H-imidazoles and -1H-1,2,4- (4-phenyl-1-piperazinylaryloxymethyl-1,3-dioxolane). Heterocyclic derivatives of 2-yl) methyl-1H-imidazoles and -1H-1,2,4-20 triazoles which are reported to have antifungal and antibacterial properties.

The compounds of the formula I differ from the prior art compounds not only in their chemical structure but also in that their efficacy against the growth of Candida Albi-.25 cans after systemic and / or topical drug administration is superior, making them particularly suitable for the local and / or vaginal candidiasis. or systemic treatment.

In the above definitions, "halogen" means fluorine, chlorine, bromine or iodine; and "lower alkyl" comprises straight and branched hydrocarbon groups having 1 to 6 carbon atoms; examples thereof are methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.

84058 3

To show more simply the structure of the compounds of formula I and certain starting materials and intermediates used in their preparation, 2-Ar-2- (1H-imidazol-1-ylmethyl or -1H-1,2,4-triazol-1-ylmethyl) - The 1,3-dioxolan-4-yl group in which Ar is as defined above is represented by the following symbol D:

O

10 L _r, = D

CH2-C-Ar 0 o

1 _L

According to claim 15 82 043 of the F1 patent, the compounds of the formula I can be prepared by:

a) o-alkylating in a suitable reaction-inert medium a phenol of formula III

20 HO— ^ -N N —— Y

\ / \ \ = / (lii) with a reagent of formula II D-CH2-W (II) wherein W represents a reactive ester group, or

b) cyclizing an intermediate of formula XII in a suitable reaction-inert medium

D-CH 2 -O-r Λ — N N — f -J— N-C-R (XII) R 5 4 84058

wherein R 5a is hydrogen and R 6a is a suitable leaving group, or R 5 "and R 6" together form a direct bond, with a reagent of formula XIII or XIV

HZABL (XIII) HZABL '(XIV) wherein Z 1 is O, NR 1, NR 2 or NR 4, A is ^ C = O, NR 5, CH 2, 10 C (R 3) 2 or CR 6 R 7, and B is ^ C = O or CH 2, or A and B together form a group -CH 2 -CH 2 -CH 2 -, L is a suitable leaving group and L 'is a precursor of a suitable leaving group, optionally first converting L' to L to give an intermediate of formula XV Or c) cyclizing an intermediate of formula XVII in a suitable reaction-inert medium in a suitable reaction-inert medium. (X) D-CH2-O-N-NH-CZABL (XV)

X

D-CH2-O-Y-N-NH-C-NH-R1 '(XVn) 30

wherein R 1 · is the same as R 1, R 2 or R 4, with a reagent of formula XVIII

35 W-A'-B-W (XVIII) 84058 5 wherein A 'is ^ C = O, NR5, CH2 or C (R3) 2, to give a compound of formula I-a 10, or

d) cyclizing in an acidic aqueous medium containing a carbonyl group donor an intermediate of formula XX

15 S

D-CH2-O-N-NH-C-N-NH2 (XX) R120 to give a compound of formula I-c D-CH2-O-N-N-N-N | 25 2 \ = y \ i \ = 7 n —- n (i-c) R 1 or 30 e) for the preparation of a compound of formula I,

wherein Y is a group of formula (k), (1) or (m), an amine of formula XXVVII

6 84058

ii N

1 'H

w I XXVII) 5 CH2 - C-hr 10 is reacted in a suitable reaction-inert medium with a compound of formula

O S

L-C-O-OR 2 -L-C-NR 1 R 14 or L-C-NR 1 R 14 and, if desired, N-alkylation in a suitable reaction-inert medium of a compound of formula I-d-1

^ _ ^ -NH

D-CH2-0_ ^ yN N ~ Y_y_ "N \ I (I-d-1) 25

with a reagent of formula XXI

R1_a-W (XXI) 30 wherein q R1'® has the same meaning as above for R1 ', except for hydrogen, as a compound of formula Ie-1 x 1- / \ / \ / "' 'Λ ^ - N - R a 35 D- CH2 ~ o —1 / y — NN— (f NI (Ie-1) ^ B —A * 7 84058

or a compound of formula I-d-2 5 I

\ -f \ - / \ 2 = J N - A

B

respectively with a reagent of formula XXI '10 R1' * '-W (XXI') wherein R1_a? represents the same as R 1, R 8 or R 10, to give a compound of formula Ie-2, wherein Y 'is a group of one of formulas (g) to (j), wherein D is a group of formula is a formula

»O

^ N

CH9-C-Ar o "-¾ I_I_ 30 and optionally a compound of formula I is converted into a therapeutically active, non-toxic acid addition salt with a suitable acid, or conversely the acid addition salt is converted into the free base with alkali and / or stereochemically isomeric forms of the compound of formula I are prepared. .

84058 8

The group W denoting the reactive ester residue is, for example, halogen, preferably chlorine, bromine or iodine, or a sulfonyloxy group such as, for example, methylsulfonyloxy or 4-methylphenylsulfonyloxy group.

The o-alkylation according to process variant a) above, in which the phenol of the formula III is used as starting material, is suitably carried out in a reaction-inert solvent or a mixture of such solvents. Suitable reaction-inert solvents include aromatic hydrocarbons, e.g., benzene, methylbenzene, dimethylbenzene and the like; lower alkanols, e.g. methanol, ethanol, 1-butanol and the like; ketones, e.g. 2-propanol, 4-methyl-2-pentanone and the like; ethers, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; N, N-dimethylformamide (DMF); N, N-15 dimethylacetamide (DMA); hexamethylphosphoric triamide (HMPT); dimethyl sulfoxide (DMSO); nitrobenzene; 1-Methyl-2-pyrrolidinone and the like To bind the acid liberated in the reaction, a suitable base such as an alkali metal carbonate or bicarbonate, sodium hydride or an organic base such as N, N-diethylethanamine or N- (1-methylethyl) can be added. ) -2-propanamine. It may be advantageous to convert a substituted phenol of formula III in advance to a metal salt, preferably a sodium salt, by a conventional method, e.g. by reacting a compound of formula III with a metal base such as sodium hydride, sodium hydroxide or the like and then using the resulting metal salt in the reaction. with a compound according to To accelerate the reaction, it is suitably carried out at a somewhat elevated temperature, preferably at about 80 to 130 ° C.

The cyclizations according to process variants b) and c) above can be carried out in a suitable reaction-inert solvent, such as an alcohol, e.g. butanol, an ether, e.g. tetrahydrofuran or 1,4-di-oxane. Although the cyclization can be performed at room temperature, it is preferable to use a somewhat elevated temperature to accelerate the reaction. The reaction is preferably carried out at the reflux temperature of the reaction mixture. Suitable catalysts, e.g. N, N-dimethyl-4-pyridin-5-namine, can also be used to accelerate the reaction.

The acidic aqueous solution used in the above process variant d) is, for example, an aqueous solution of hydrochloric acid, sulfuric acid and the like.

The N-10 alkylations according to process variant e) above can be carried out in a conventional manner, e.g.

by stirring the reactants, preferably at a somewhat elevated temperature in a suitable organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide and the like, in the presence of a suitable base such as an alkali metal hydride or carbonate.

The 1H-imidazole and -1H-1,2,4-triazole derivatives of formula I obtained in the base form in the above preparations can be converted into therapeutically active, non-toxic acid addition salts by treatment with suitable acids, such as inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic, propane, hydroxy-acetic, 2-hydroxypropane, 2-oxopropane, ethanedicarboxylic, propanedicarboxylic, butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) -2-Butenedicarboxyl, 2-hydroxybutanedicarboxylic, 2,3-dihydroxybutanedicarboxylic, 2-hydroxy-1,2,3-propanetricarbox-30-yl, methanesulfonic, ethanesulfonic, benzenesulfonic, 4 -methylbenzenesulfonic, cyclohexanesulfamine, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid and the like.

The salts are in turn converted into the corresponding free bases in the customary manner, e.g. by reaction with an alkali such as sodium or potassium hydroxide.

84058 ίο

It appears from formula I that they have at least two asymmetric carbon atoms in their structure, namely carbon atoms in the 2- or 4-positions of the dioxolane group, and the compounds can thus exist in different stereochemical isomeric forms.

Diastereomeric racemates of the compounds of formula I, denoted as cis and trans forms, are described in J. Org. Chem. 35 (9), ss. 2849-2867 (1970) can be prepared separately by conventional methods. Suitable methods that can be advantageously used include, for example, selective crystallization and chromatographic separation, e.g., column chromatography.

Since the stereochemical configuration has already been determined in several intermediate compounds, for example intermediates of formulas II, XII, XV, XVII and XX, it is possible to distinguish the cis and trans forms at this stage or also at an earlier stage after which the corresponding forms of the compound of formula I are obtained. of them as described above. Separation of the cis and trans forms of such intermediates can be performed in a conventional manner as described above for the separation of the cis and trans forms of Compound I.

It will be appreciated that cis and trans diastereomeric racemates may be further subdivided into optical isomers, cis (+), cis (-), trans (+) and trans (-) forms according to methods known in the art.

Many of the intermediates and starting materials used in the above preparation methods are known compounds and others can be prepared by methods known in the art for the preparation of similar compounds; some of these compounds are novel and their preparation is described below.

The intermediates of formula III of the invention may generally be prepared in a manner known in the art from an intermediate of formula XXII wherein P is a suitable protecting group; 11 84058 '• o-ö-GO'1 (XXII) 5 ^ deprotection 10 ^ == / x (III)

The method by which the protecting group P is removed depends on the nature of 15 P. For example, when P is a methyl group, the reaction may be carried out in an acid hydrolysis medium containing a strong non-oxidizing mineral acid, e.g. hydrobromic acid in glacial acetic acid.

Intermediates of formula XXII can be prepared by cyclization of an intermediate of formula XXIII with an amine of formula V: H w P'0 ~ O_V “+" i (xxii) 25 —'h - (XXIII) w (V)

The reaction is carried out by stirring the reactants in a suitable polar solvent, e.g. a mixture of water and a suitable water-miscible organic solvent such as water and 2-propanol, 2-propanol and the like, preferably at elevated temperature to improve the reaction rate and most preferably a suitable alkali or alkaline earth. in the presence of lime metal iodide, e.g. potassium iodide.

35 Starting materials of the formula V in which Y

is a group of 84058 12 according to any one of formulas (a), (c), (d), (g) or (h), may be prepared by cyclizing a reagent of formula XXIV with a reagent of formula XXV following the cyclization procedure previously described for the preparation of method b) compound of formula I from compounds of formulas XII and XIII: r P '-NH- (^) - NH-BAL + -NCR - 10 (XXIV) (XXV) (V)

In formula XXIV P 'is hydrogen or a suitable protecting group, in which case the protecting group should be removed after the cyclization reaction.

The starting materials of formula V can also be prepared from the corresponding nitro derivatives by reduction by a known reduction method used for the reduction of a nitro group to an amine.

Intermediates of formula XXII can also be prepared from an intermediate of formula XXVI

By reacting it with a compound of formula XIII by the cyclization process described above used to prepare a compound of formula I by method b) from compounds of formulas XII and XIII.

Intermediates of formula XII can be prepared from an amine of formula XXVII by reacting it with a reagent of formula XXVIII or carbon black to give intermediate ΧΙΙ-a or intermediate X11-b, respectively: 13 84058; 6 oc „2-of> / - ^ - 6 5 LC-R6 (XXVIII) ^ \ = J \ - / \ == / + '(X11-a) o-cu ^ ohQ-nQxH ^' N" 2 ( XXVII) 10 \ + cs2 "x *« - «, - β-οΟ1 '©' N'c's (XII-b) 15

Intermediates of formulas XVII, XIX and XX may conveniently be prepared by reacting an intermediate of formula XII with a suitable amine derivative.

The compounds of formula 1, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms of these compounds are useful as antifungal and antibacterial agents. These compounds have been found to be highly active against a variety of fungi, examples of which are Microsporum canis,

Stenomyces mentagrophytes, Trichophyton rubrum,

Phialophora verrucosa, Cryptococcus neoformans, Candida tropicalis, Candida albicans, Mucor species, Aspergillus fumigatus, Sporotricum schenckii and Saprolegnia species, 30 and against bacteria, examples of which are:

Ervsipelotrix insidiosa, staphylococci such as Staphylococcus hemolyticus, and streptococci such as Streptococcus pyogenes. Due to their strong local and systemic antimicrobial activity, the compounds of the formula I are useful in killing or inhibiting the growth of i4 84058 fungi and bacteria, and in particular can be used for the treatment of patients suffering from diseases caused by microorganisms.

Experimental results showing the strong antimicrobial activity of the compounds of the formula I are shown in FI patent 82,043.

vThe following examples illustrate the invention. Unless otherwise stated, all parts are by weight.

Examples 10 Λ. Manufacture of intermediate products

Example I

A mixture of 1 - (4 - n i. T ro f envy 1 i) - 2-imidic acid (21 parts), iodomethane (16 parts), potassium hydroxide (10 parts) and dimethyl sulfoxide (200 parts) was stirred. at room temperature for 3 hours. An additional 16 parts of iodomethane and 10 parts of potassium hydroxide were then added and stirring was continued overnight. To the reaction mixture was added 300 parts of water, and the mixture was stirred. The precipitated product was filtered and crystallized from 4-methyl-2-Penta-20-nono to give 16.5 parts (74%) of 1-methyl-3-

(4-nitrophenyl) -2-imidazolidinone, m.p. 214.1 to 215.5 ° C

(7).

In a similar manner there were prepared: 1-ethyl-3- (4-nitrophenyl) -2-imidazolidinone, m.p. 175.2 ° C 25 (8); 1- (1-methylethyl) -3- (4-nitrophenyl) -2-imidazolidinone, m.p. 161.7 ° C (9); 1-butyl-3- (4-nitrophenyl) -2-imidazolidinone, m.p. 130.0 ° C (10); and 3Q 1- (4-nitrophenyl) -3-propyl-2-imidazolidinone, m.p. 128.2 ° C (11).

Example n

Ethyl 2 - [(4-aminophenyl) amino] acetate hydrochloride (2.7 parts), acetic anhydride (1.1 parts), sodium hydrogen carbonate (0.98 parts), dichloromethane 15 84058 (65 parts) and a mixture of water (50 parts) was stirred for 30 minutes at room temperature, the organic phase was separated, washed with water, dried, filtered and evaporated, and the residue was crystallized from a mixture of 4-methyl-2-penta-5-non and 2,2'-oxybispropane. 1.9 parts (68%) of ethyl 2- [Y ”4- (acetylamino) -phenylaminoacetate were obtained, mp 119.5 ° C (12).

Example III

Ethyl 2- [4- (acetylamino) phenyl] amino} acetyl-10-tin (25 parts), 1-isocyanatobutane (20 parts), N, N-dimethyl-4-pyridinamine (2 parts) and trichloromethane The mixture (300 parts) was stirred and refluxed for 48 hours. The reaction mixture was evaporated and 180 parts of dimethylbenzene were added to the residue, and the mixture was heated under reflux with stirring for 8 hours. After cooling, the precipitated product was filtered, washed with 2-propanol and dried to give 25.5 parts (83%) of N- [1- (3-butyl-2,4-dioxo-1-imidazolidinyl) phenyl] acetamide, m.p. . 192.8 ° C (13).

In a similar manner there were prepared: N- [3- (3-methyl-2,4-dioxo-1-imidazolidinyl) phenyl] acetamide, m.p. 262.7 ° C (14); N- [4- [3- (1-methylethyl) -2,4-dioxo-1-imidazolidinyl] phenyl] acetamide, m.p. 215 ° C (15); N- [3- (3-ethyl-2,4-dioxo-1-imidazolidinyl) phenyl] -acetamide, m.p. 250.5 ° C (16); and N- [4- [4- (2,4-dioxo-3-propyl-1-imidazolidinyl) phenyl] acetamide, m.p. 212.3 ° C (17).

Example IV

A mixture of 1-ethyl-3- (4-nitrophenyl) -2-imidazolidinone (12 parts), a 4% ethanolic solution of thiophene (1 part) and methanol (200 parts) was hydrogenated under normal pressure at room temperature to 10%. in the presence of a palladium / carbon catalyst (2 parts). After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 9.6 parts (93%) of 1- (4-aminophenyl) -3-ethyl-2-imidazolidinone (18).

In a similar manner there were prepared: 1- (4-aminophenyl) -3- (1-methylethyl) -2-imidazolidinonione (19); 1- (4-aminophenyl) -3-butyl-2-imidazolidinone (20); 1- (4-aminophenyl) -3-propyl-2-imidazolidinone (21); and 1q 1- (4-aminophenyl) -3 - * - methyl-2-imidazolidinone (22).

Example y A mixture of N- [4- [4- (2,4-dioxo-3-propyl-1-imidazolidinyl) -phenyl] acetamide (19.5 parts) and concentrated hydrochloric acid (480 parts) was stirred and heated to reflux. 5 hours. The reaction mixture was cooled, the precipitated product was filtered and dissolved in a mixture of methanol and water. The solution was neutralized with sodium hydrogen carbonate solution and the product was extracted with trichloromethane.

The extract was dried, filtered and evaporated, yielding 15 parts (90%) of 1- (4-aminophenyl) -3-propyl-2,4-imidazolidinedione, m.p. 133.2 ° C (23).

In a similar manner there were prepared: 1- (4-aminophenyl) -3- (1-methylethyl) -2,4-imidazolidinedione, m.p. 109.4 ° C (24); 1- (4-aminophenyl) -3-methyl-2,4-imidazolidinedione, m.p. 201.5 ° C (25); 1- (4-aminophenyl) -3-ethyl-2,4-imidazolidinedione, m.p. 14 9.30 (2 (26); and 1- (4-aminophenyl-3-butyl-2,4-imidazolidinedione, mp 114.8 ° C (27)).

Example VI

Ν, Ν-bis (2-chloroethyl) -4-methoxybenzeneamine (16.5 parts), 1- (4-aminophenyl) -3-methyl-2-imidazo-1-quinone (12.5 parts) , a mixture of sodium hydrogen carbonate (11 parts) and 1-butanol (240 parts) was heated under reflux with cooling and stirring for 24 hours. The mixture was cooled, 100 parts of water were added, and the resulting mixture was stirred. The precipitated product was filtered, washed with water and 1-butanol and dried to give 17.5 parts of 5 (73%) 1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -1- 3-methyl-2-imidazolidinone, m.p. 240.9-241.0 ° C (28).

In a similar manner were prepared:

1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3- (1-methylethyl) -2,4-imidazolidinedione, m.p. 214.2 ° C

10-[3-ethyl-1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2H-imidazolidinedione, m.p. 228.0 ° C (30); 3-butyl-11- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -7-2,4-imidazolidinedione, m.p. 206.7 ° C (31); 1 1- 1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl} -3-methyl-2,4-imidazolidinedione, m.p. 258.7 ° C (32); ιγ (Λ - ((4-methoxyphenyl) -1-piperazinyl) phenyl] -3-propyl-2,4-imidazolidinedione, m.p. 200.8 ° C (33); 1-ethyl-3- [4- [4- (4-methoxyphenyl) -1-piperazinyl] -2'-phenyl] -2-imidazolidinedione, m.p. 246.3 ° C (34); 1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3- (1-methylethyl) -2-imidazolidinone, m.p. 234.5 ° C (35); 1-butyl-3- [4- (4- (4-methoxyphenyl) -1-piperazinyl] -phenyl] -2-imidazolidinone, mp 240.4 ° C (36); 4- (4-methoxyphenyl) -1-piperazinyl-1-phenyl] -3-propyl-2-imidazolidinone, mp 252.0 ° C (37).

Example yjp

Phenyl [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] carbamate (5 parts), ethyl [(1-methylethyl) amino] acetate (3 parts), N A mixture of N-dimethyl-4-pyridinamine (1 part) and 1,4-dioxane (100 parts) was heated to reflux with stirring overnight. The warm solution was saturated with water and allowed to cool. The solution was poured into water and extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel filtration eluting with a mixture of trichloromethane and methanol (98: 2, v / v). The filtrate was evaporated and the residue was crystallized from methylbenzene to give 3.7 parts (73%) of 3- [4- [4- (4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -1- (1- methyl) -2,4-imidazolidinedione, mp 193.7 ° C (38).

Phenyl-4- [4- (4-methoxyphenyl) -1-piperazinyl] -phenylcarbamate (24 parts), ethyl N-butylglycine (15.9 parts), N, N-dimethyl-4-pyridinamine (2 parts) and 1,4-dioxane (200 parts) were heated to reflux and stirred overnight. Water was then added to the mixture, and stirring was continued for some time. The reaction mixture was cooled and poured into water with stirring. The precipitated product was filtered, washed with water and dissolved in 150 parts of trichloromethane. The resulting solution was stirred with silica gel (3 parts) for 30 minutes, the silica gel was filtered off and the filtrate was evaporated. The residue was crystallized from butanol. The product was filtered off and dried in vacuo at 60 ° C to give 2.3 parts of 1-butyl-3- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2, 4-imidazolidinedione, m.p. 183.7 ° C (39).

Example VIII

A mixture of 1- (4-isothiocyanatophenyl) -4- (4-methoxyphenyl) piperazine (15 parts), 2,2-dimethoxy-N-methylethanamine (6.5 parts) in dichloromethane (195 parts) was stirred for 1 hour. time at room temperature. The reaction mixture was evaporated and the residue was triturated in 4-methyl-2-pentane. The product was filtered off and dried, yielding 19.4 parts (95%) of N- (2,2-dimethoxyethyl) -N '- [N- (N- (4-methoxyphenyl) -1-piperazinyl] phenyl] -N-methyl -lithiourea, m.p. 155.0 ° C (40).

is 84058

In a similar manner there were prepared: N- (2,2-dimethoxyethyl) -N-ethyl-N1- [4- [4- (4-methoxy-phenyl) -1-piperazinyl] phenyl] thiourea (41); N- (2,2-dimethoxyethyl) -N1- [4- [4- (4-methoxyphenyl) -1-5] piperazinyl] phenyl] -N - (] - methylethyl) thiourea, m.p. 139.7 ° C (42); and N- (2,2-dimethoxyethyl) -N '- [N- (4- (4-methoxyphenyl) -1-piperazinyl] phenyl) -N- (1-methylpropyl) thiourea, mp 140 ° C (43).

10 Example IX

A mixture of 1- (4-isothiocyanatophenyl) -4- (4-methoxyphenyl) piperidine (10 parts), 3-butylamino) -1-propanol (6.3 parts) and dichloromethane (130 parts) was stirred at room temperature. at 3 hours. The reaction mixture was evaporated and the residue was triturated in 2-propanone.

The product was filtered off and dried, yielding 12.7 parts (92%) of N-butyl-N- (3-hydroxypropyl) -N 1 - (4- [4- [2-oxoxyphenyl] -1-piperazinyl] phenyl} thiourea, mp. 153.9 ° C (44).

B. Preparation of compounds of formula III

Example X

A small amount of sodium hydrogen sulfite was added to a 48% aqueous solution of hydrogen sulfide (75 parts). Then 1.7 parts of N-butyl-N- (3-hydroxypropyl) -25N '- (4- 4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl) were added. - thiourea. The mixture was heated to reflux with stirring for 3 hours, then the mixture was evaporated. The residue was dissolved in a mixture of methanol and water, and the solution was neutralized with sodium hydrogencarbonate solution. The product was extracted with dichloromethane, the extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (92: 2 by volume). The pure fractions were collected and the eluent was evaporated. brick. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.6 parts (38%) of 4- {4- [4- [4- (3-butyltetrahydro-1,3-thiazin-2-ylidene) amino] phenyl} -1-piperazinyl}. tenolia, sp. 143.0 ° C (45).

Example XI_ 5 A mixture of 1- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -3-propyl-2-imidazolidinone (7 parts) and 48% hydrobromic acid (225 parts) was stirred and heated. at reflux for 5 hours. The mixture was cooled, the precipitated product was filtered, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was neutralized with sodium bicarbonate solution. The product was extracted with trichloromethane, the extract dried, filtered and evaporated. The residue was triturated in dichloromethane, the product was filtered off and dried, yielding 6 parts of 15 (89%) of 1- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] -phenyl] -3-propyl-2-imidazolidinone. (46).

In a similar manner there were prepared: 1-ethyl-3- [4- [4- (4-hydroxyphenyl) -1-piperazyl] -4-phenyl] -2-imidazolidinone, m.p. + 300 ° C (dec.) (47); 1'-butyl-3- [4- [4- (4-hydroxyphenyl) -1-piperazinyl, 7-phenyl] -2-imidazolidinone, m.p. 217.5 ° C (48); 1- (N- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3- (1-methylethyl) -2-imidazolidinone, mp 250.0 ° C (49); 1-butyl-3- 4- [4- (4-hydroxyphenyl) -1-piperazinyl] -25-phenyl] -2,4-imidazolidinedione (50); 3- {4- [1- (4-hydroxyphenyl) -1-piperazinyl] phenyl} -1- (1-methylethyl) -2,4-imidazolidinedione, mp 244.1 ° C (51); 1- [4- (4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3-30 propyl -2,4-imidazolidinedione, mp 210.9 ° C (52); 1- [4- (4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -1,3- (1-methylethyl) - 2,4-imidazolidinedione, mp 249 ° C (53); 3-ethyl-11- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2,4-imine dazolidinidione, mp 287.1 ° C (54); 21,84058 3-butyl-1- [N- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2,4- imidazolidinedione, mp 212.2 ° C (55), 1- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3-methyl-2,4-imidazolidinedione (56), and 5Z- (N- (hydroxyphenyl) -1-piperazinylphenyl] -1,3-methyl-2-imide azolidinone (57).

Example XII

HBr gas was introduced into a cold 48% aqueous HBr solution (150 parts). To the solution was added 18.3 parts of 10 N- (2,2-dimethoxyethyl) -N 1 '/ * 4- / 4- (4-methoxyphenyl) -1-piperazinyl / phenyl O'-N- (1-methyl lie style) thiourea, and the mixture was stirred first for 1 hour at room temperature and then for 2 hours at reflux temperature. The mixture was allowed to cool overnight, the precipitated product was filtered, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was neutralized with sodium hydrogen carbonate solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was boiled in methanol. After cooling, the product was filtered and purified by column chromatography on silica gel eluting with a mixture of trichloromethane and methanol (98: 2, v / v). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol. The product was filtered off and dried, yielding 10.5 parts (68%) of 4- [4- [4- [4- [3- (1-methylethyl) -2 (311) -thiazolylidene] amino] phenyl] -1-piperazinyl. li / -phenol, m.p. 215.7 ° C (58).

Example XIII

HBr gas was introduced with stirring into a mixture of 48% aqueous HBr (150 parts) and sodium sulfite (1 part). To the mixture was added 16.5 parts of N- (2,2-dimethoxyethyl) -N '- [N- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -N-methylthiourea, and the mixture was stirred and stirred. heated for 1 h with cooling for 3 h. The mixture was cooled, the precipitated product was filtered off, washed with 2-propunol-84058 and dissolved in a mixture of methanol and water. The solution was treated with sodium hydrogen carbonate. The product was extracted with dichloromethane. The precipitated product was filtered and purified by chromatography on a silica gel column 5 eluting with a mixture of trichloromethane and methanol (98: 2, v / v). The pure fractions were collected and the eluent was evaporated. The residue was triturated in dichloromethane. The product was filtered off and dried, yielding 6 parts (44%) of 4- [4- [4 - [(3-methyl-2- (3H) -thiazol-10-ylidene) amino] phenyl] -1-pipers. inyvli 7fenolia, m.p. 225 ° C (59).

In a similar manner there were prepared: N- [4- (3-ethyl) -2H-thiazolylidene-amino-phenyl] -1-piperazinyl] -phenol, m.p. 198.6 ° C (60); and 15 4 - [4- [4- [4- (3- (1-methylpropyl) -2 (3H) -thiazolylidene] amino] phenyl] -1-piperazinyl] phenol, m.p. 160 ° C (61).

C. Preparation of compounds of formula I from compounds of formula III_

20 Example XIV

3- [4- [4- (4-Hydroxyphenyl) -1-piperazinyl] -1H-phenyl] -1- (1-methylethyl) -2,4-imidazolidinedione (4.2 parts), cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanoylmethanesulfonate ester (4.3 parts), potassium carbonate ( 1.4 parts) and a mixture of 4-methyl-2-pentanone (120 parts) were stirred and refluxed for 72 hours. The reaction mixture was cooled and poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (99.5: 0.5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentano-35. The product was filtered off and dried at 120 ° C, yielding 1.9 parts (25%) of cis-3- / 4- [4- [4 - [(2- (2,4-dichlorophenyl) -2- ( 1H-imidazol-1-ylmethyl) -1,3-dioxolan-23,84058 4-ylmethoxy7phenyl-1-diperazinyl >> 7-phenyl-1- (1-

methylethyl) -2,4-imidazolidinedione, m.p. 177.6 ° C

(compound 25).

5

Example XV

1- [4- (4- (4-hydroxyphenyl) -1-piperazinyl] -7-phenyl] -3-methyl-2,4-imidazolidinedione (3.4 parts), cis-2- (2,4-dichlorophenyl ) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanoylmethanesulfonate ester (3.4 parts), potassium carbonate (2.8 parts) parts), a mixture of dimethyl sulfoxide (20 parts) and 1-butanol (64 parts) was stirred and refluxed for 3 hours. To the cooled mixture was added 200 parts of water.

The precipitated product was filtered, washed with water and 1-Buta-15 ...

dried, and purified by column chromatography on silica gel, eluting with a mixture of trichloromethane and methanol (99.5: 0.5, v / v). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 160 parts of 1-butanol to give 2.1 parts of 20 (33%) of cis-1- [4- [4- [4- [4- (2,4-dichlorophenyl) -2- (1H-1 , 2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl-methoxy-phenyl-1-piperazinyl-phenyl-3-methyl-2,4-imidazolidinedione, m.p. 236.8 ° C (comp. 26).

In a similar manner there were prepared: 2- [cis - [(4- [4- [4- [{2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4- Yyl-methoxy-phenyl-1-piperazinyl-phenyl-3-methyl-2,4-imidazolidinedione, mp 237.9 ° C (comp. 27).

Example XVI

* 3 H 1- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -3- (1-methylethyl) -2,4-imidazolidinedione (3.6 parts), cis- 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanoyl methanesulfonate ester (5.5 parts), potassium carbonate ( 2 parts) A mixture of 35 and 1-butanol (160 parts) was stirred and refluxed for 3 hours. To the mixture was added a second portion of cis-2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanoylmethanesulfonate ester (2 , 5 parts) and stirring for 5 hours and heating under reflux was continued for 2 hours.

The reaction mixture was cooled, and 200 parts of water were added thereto. The precipitate formed on stirring was filtered and crystallized from 1-butanol to give 4.2 parts (65%) of cis-1- [4- [4- [4- [4- [2- (2,4-dichlorophenyl) -2- (1H-10]]. 1,2,4-Triazol-1-ylmethyl) -1,3-dioxolan-4-yl-7-methoxy / phenyl} -1-piperazinyl} phenyl, 7-3- (1-methylethyl) -2,4- imidazolidinedione, m.p. 227.1 ° C (comp. 28).

Following the same procedure and using 15 equivalent amounts of suitable starting materials, the following compounds were prepared: fj Cl 20 1 // λ cls CH; -cvt> cl V, I-L cv „_0_nQn, 0JH'-r '25

Compound n ° · Q R1 Sp. (° C) 30 29 CH (CH 3) 2 CH 232.2 30 N n.C 2 Hg 180.7 31 CH C 7 H 5 235.4 32 N C 2 H 5 228.6 33 N n.C 3 H? 195.4 35 34 CH n.C3H7 199f5 25 84058

Example XVII

1- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] -4-phenyl] -3-methyl-2-imidazolidinone (5 parts), cis-2- (2,4-dichlorophenyl) -2- (1H A mixture of 1,2,4-triazol-1-ylmethyl) -5,3-dioxolane-4-methanol methanesulfonate ester (8.7 parts), potassium carbonate (3 parts) and 1-butanol (160 parts) was stirred and heated. return to cool overnight. The reaction mixture was cooled and 100 parts of water were added thereto. The precipitated product was filtered off, dried and purified by column chromatography on silica gel, eluting with a mixture of trichloromethane and methanol (99: 1 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol to give 7.8 parts (82%) of 15 cis-1- [4- [4- [4- [2- (2,4-dichlorophenyl) -2- (1H-1,2 , 4-thiazol-1-ylmethyl) -1,3-dioxolan-4-yl-methoxy-7-phenyl-1-piperazinyl / phenyl-3-methyl-2-imidazolidinone, m.p. 205.8 ° C (comp. 35).

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compounds were prepared:

O

0-l c „2-o- 84058 26

Compound no · Q R1 m.p. (° C) δ 36 N C 2 H 5 198.3 37 CH C 2 H 5 205.3 38 CH n-C 4 H 9 159, 5 39 N n.C 3 H 7 179.8-181.0 40 CH n.C 3 H 7 189.2-191.3 10 41 CH 1 .C 3 H 7 209.8-217.5 42 N i.C 3 H 7 199.0-200.0 43 CH CH 3 215.4 ^ In a similar manner the following compounds were also prepared: Γ1 cis

20 CH., - C ^ --Ar O

0? / \ / \ a — λ y N-R

I-1 — cH, -O 2 Vhn ^ N- <y ^) ~ N \

Compound 25 no. Q Ar R 'Sp * (° C) 44 N 2,4-Cl2-C6H3 n.C4H9 152.2 45 N 4 -Cl-CH, nCH7 194.3 46 N 2 -Br, 4-Cl-C6H3 n.C3H ? 181.0 .30 47 CH 4 -F-C.H, n.C.H, 175.1 48 N 2 -Cl-C 6 H 4 n.C 3 H 7 162.2 49 N 4 -Br-C 6 H 4 n.C 3 H? 201.5 and 50 CH 2 -Cl, 4-F-C 6 H 3 n.C ^ 161f6 _---------- 35 27 84058

Example XVIII

4- {4- [4- (3- (3-butyltetrahydro-1,3-thiazin-2-ylidene) amino] phenyl] -1-piperazinyl] phenol (3.3 parts), cis-2- (2,4-dichlorophenyl) - 2- (1H-1,2,4-triazol-1-yl-5-methyl) -1,3-dioxolane-4-methanol methanesulfonate ester (4.2 parts), potassium carbonate (1.4 parts) and 2 -propanol (160 parts) was stirred and refluxed for 3 days. A second portion (2.1 parts) of cis-2- (2,4-dichlorophenyl) -2- (1H-1,2,4-tri-10-azol-1-ylmethyl) -1,3-dioxolane-4- methanol-methanesulfonate ester and stirring was continued at reflux for 2 days. To the cooled mixture was added 300 parts of water. The precipitated product was filtered, washed with water and 2-propanol, dried and filtered. The residue was purified by filtration on a silica gel column using a mixture of trichloromethane and methanol (99: 1, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.8 parts (66%) of ¢ 15-4- [4- [4 - ((2- (2,4-dichlorophenyl) -2- (1H-1,2,4- Triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-phenyl-1-piperazinyl-N- (3-butyltetrahydro-2H-1,3-thiazin-2-ylidene) ) benzenamine, mp 190.8 ° C (comp. 51).

25 Example XIX

4 - [- [4 - ((3-methyl-2 (3H) -thiazolylidene) amino] -phenyl] -1-piperazinyl] -phenol (3 parts), cis-2- (2,4-dichlorophenyl) - 2- (11-imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester (3.5 parts), potassium carbonate (1.4 parts) and 2-propanol (160 parts) The mixture was stirred and refluxed over the weekend, and a second portion (3.5 parts) of cis-2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4 was added. -methanol-methanesulfonate and 1.4 parts of potassium carbonate, and stirring was continued at reflux for 24 hours, 200 parts of water were added to the mixture, and the precipitated product was filtered, washed with water and 2-propanol and purified on a silica gel column using elution. 5 mixtures of trichloromethane and methanol (99: 1, v / v) The pure fractions were collected and the eluent was evaporated, the residue was crystallized from 1-butanol to give 4.1 parts (74%). cis-4- [4- [4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-10] ethoxy]? phenyl-1H-piperazinyl-N- (3-methyl-2- (311) -t-thiazolene) benzene amine, m.p. 192.3 ° C (comp. 52).

In a similar manner there were prepared: 013-4- ^ 4- ^ 4- ^ 2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-15-ylmethyl) -1,3- dioxolan-4-ylmethoxyphenyl-1-piperazinyl-N- (3-ethyl-2 (311) -thiazolylidene) benzeneamine, m.p. 196.8 ° C (comp. 53); cis-4- [4- [4- [2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-20 piperazinyl] -N - (3-ethyl-2 (3H) -thiazolylidene) -benzenamine, m.p. 163.0 ° C (comp. 54); cis-4- [4- [4- [4- (2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl (methoxy) 7-phenyl-1-piperazinyl-N- (3-methyl-2 (3H) -thiazolyl-25-ene) benzeneamine, mp 177.5 ° C (comp. 55); 2- [4- [4- (2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl] -1-piperazinyl] -N - (3- (1-methylpropyl) -2 (3H) -thiazolylidene) benzeneamine, mp 160.4 ° C (comp. 56); 30 cis-4- [4- [4- [2- [2- 4-Dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy-phenyl-1-piperazinyl-N- (3- (1-methylpropyl) -2 (311) -thiazolylidene) benzeneamine, mp 151.4 ° C (compound 57); cis-4- [4- [4- [2- (2,4-dichloro]. enyl) -2- (1H-1,2,4-triazol-35-ylmethyl), 3-dioxan-4-ylmethoxy / phenyl] -1-29,84058 piperazinyl7- N- [3- (1-methylethyl) -2 (3H) -thiazolylidene] benzeneamine, mp 176.1 ° C (Compound 58) and cis-4- [4- (4-) 4- (2- (4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl / methoxy-phenyl-1- (5-piperazinyl) -N- [3- (1-methylethyl) -2 (3H) -thiazolylidene / benzeneamine, m.p. 178.6 ° C (comp. 59).

Example 1-1-Butyl-3- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2,4-imidazolidinedione (4.1 parts), 10 cis-2- (4-Bromophenyl) ) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester ethanedicarboxylate (1: 1) (6.5 parts), potassium carbonate (6 .0 parts), a mixture of 1-propanol (160 parts) and 1,4-dioxane (25 parts) was stirred and refluxed for 3 days. The reaction mixture was diluted with water and the product was extracted 3 times with dichloromethane. The combined organic extracts were washed with water, dried and evaporated in vacuo. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol (99: 1 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 1.7 parts (25%) of propyl cis-N, N-N - (4-bromophenyl) -2- (1H-1,2,4). -triazol-1-ylmethyl) -1,3-dioxolan-4-yl-ethoxy-phenyl-1- (1-piperazinyl) -phenyl} -carbamate, m.p. 214.4 ° C (comp. 175).

In a similar manner there were prepared: cis-4- [4- [4 - [] [2- (2,4-dichlorophenyl) -2- (1H-1,2,4-30 '' triazol-1-ylmethyl ) -1,3-dioxolan-4-yl-methoxy-7-phenyl-1-piperazinyl-4-N- (1-methyl-2-imidazolidinylidene) benzeneamine, m.p. 161.9 ° C (comp. 176); and cis -4-phenyl-β (β- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl N-methoxy-phenyl-1-yl-porcine 1-N- (1-ethyl) -2-imidazolidinylidene) -benzamine, mp 184.0 ° C (comp. 177) .

Claims (2)

Novel 4- (4-phenyl-1-piperazinyl) phenol derivatives of the formula III which are useful as intermediates and in which Y is a group having one of the following formulas: 0 SA! Ai A 2 —N N-R —N N-R —N N-R 15 V'CH2> 2 ^ - ^ 0 oi- ^ (a) (c) (d) 20 "RR Is RR 25 (g) (h) in which R1, R2 and R8 denote lower alkyl. 31 84058 Nya, säsom mellanprodukter anhandbar 4- (4-phenyl-1-piperazinyl) phenol derivative of formula III 5 10 color Y is an group with a formulation of the form 0 0 0 1. n 15 ^ -R —N N-R1 - N N-R2 (CH2 > 2 ^ 0) -1 20 <a) <C) <d> ~ N = 0 ~ n ^ sJ N 1 NJ 25 i8 KRR (9) (h) color R1, R2 and R8 are alkyl.