CS196360B2 - Process for preparing derivatives of phenylpiperazine - Google Patents

Abstract

Phenylpiperazine derivatives of formula (I) <IMAGE> as well as their pharmaceutically acceptable salts, are prepared. R<1> represents benzyl, C1-6 alkyl or an optionally substituted phenyl; R<2> represents an optionally substituted phenyl, R<3> represents hydrogen or C1-4 alkyl, Q represents furan, thiophene, oxazole or thiazole, m is an integer from 1 to 3 and n is 0 or 1. When m is 2 and n is 0, R<1> cannot represent a methyl group when Q is the thiazol-5-yl group. The preparation is carried out by condensation of a compound of formula (VII): R<1>-Q-(CH2)m-(CHR<3>)n-L (VII) in which L represents the split group, with a compound of formula (VIII): <IMAGE> The compounds of formula (I) and their pharmaceutically acceptable salts are useful in the prophylactic and therapeutic treatment of diseases of immediate hypersensitiveness, especially asthma in mammals. They have a low toxicity.

Description

R ¹ is benzyl, chlorobenzyl ·, C ₆ alkyl or phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, C ₃ _ ₄ alkyl, C _ ₄ haloalkyl, amino, C2- ₄ aíkanoylaminoskupinu, hydroxy, C ₄ alkoxy , nitro and _< C _1-4 alkylsulfohamido,

R ² represents females, optionally substituted with one or two substituents selected from the group consisting of halogen atom, C ₄ alkyl, C ₄ haloalkyl, amino, Сг- ₄ alkanoylamino, hydroxy, C ₄ alkoxy, nitro and C _'4 alkylsulfonamldoskupinu,

R ³ represents hydrogen or C ₄ alkyl. :

. Q is a furan, thiophene, oxazole or thiazole moiety, r is 1 to 3 and n is 0 or 1, and when m is 2 and n is 0, R ¹ is methyl when Q is thiazol-5-yl, and pharmaceutically acceptable salts thereof.

The term "C _1-4 alkyl" means a straight or branched chain alkyl group having 1 to 4 carbon atoms. for example methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. "C _1-4 haloalkyl" refers to the above-mentioned C _1-4 alkyl group substituted with one or more fluorine, chlorine, bromine or iodine atoms and includes groups such as trifluoromethyl or pentachloroethyl. Similarly, the term "C _1-4 alkoxy" refers to the aforementioned C _1-4 alkyl groups attached via an oxygen atom to a phenyl group,

A preferred group of formula I are compounds having at least one of the following characteristics:.

a) m is l and n is 0;

b) Q is a thiazole residue;

c) Q is an oxazole residue;

d) Q is a thiophene residue;

e) Q is a furan residue;

f) R ¹ represents C _1-3 alkyl, such as methyl or isopropyl;

g) R ¹ is phenyl; . ; '

h). R 1 is benzyl;

i) R ² represents phenyl substituted by one or two methyl groups.

A particularly active group of phenyl derivatives ·

piperazine. . common. of formula I are furans of formula II. . / ...

where. ..

R 1 is phenyl, optionally-substituted once. or two groups selected. from groups; halogen including. C _1-4 alkyl, C _1-4 alkoxy. and C 1-4 haloalkyl,.

R ^{2 is} phenyl, optionally substituted. C 1-6 alkyl; . amine, C 1-4 alkylsulfonamido and C 1-4 alkoxy denote 1 or 2, with the exception of the compounds of formula (I). .kterých. . R 1 is unsubstituted. phenyl, m is 1 and R2. means unsubstituted. phenyl,. or wherein R 1 is methyl, m is 1 and R 2 is phenyl. optionally. . substituted. single group. zě. halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or disubstituted groups. two- and C 1-4 -alkyl groups; thiophenes of formula III,

\ D ** (CH, U-iCHR ³ ) _ft -Nx ^N 'R (IIIl where-.... .... ..... ·., ....

.... R1,. Denotes Тёпу!,; ·.

. . R 2 'denotes phenyl, phenyl once substituted by C 1-4 alkyl. or C 1-6 haloalkyl or double substituted with two groups. elected. from the group consisting of halogen, C1-haloalkyl and C1-4alkyl, and m denotes 1 or 2.

· N denotes .0 or,. where m denotes 1, n denotes i and λ ''

Z 'R3 represents / ethyl, ··,' ·.

oxážoly. object / formula. IV, ..

. / - (IV).

where. · Λ ·. . _ ·

R1 is phenyl. . optionally substituted

Gii-4alkoxylein. or. by halogen, * 'R2' is phenyl, optionally substituted. C 1-4 alkyl, halogen,. amino or C 2-4 alkanoylamino. . and

- · ... m.Marking 1 or. 2, the thiazoles of the general formula (V). .

(V) wherein R 1 is benzyl, R 2 is. phenyl. or p-halophenyl, or thiazoles. of the general formula. ',. ·' ··. ·:

(VI) where. ......... ·· · ·, ..... ·. ·.

R1 is C1-alkyl. or phenyl, optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, nitro. and C 1-4 haloalkyl, and

R2 denotes phenyl optionally substituted with C1-4 haloalkyl;

and their, . pharmaceutically. acceptable salts.

>. Preferably in. of the aforementioned derivatives • m stands for! '......

Especially preferred. the compounds of formula I are:

1- [2- (5-phenylthiophen-2-yl) ethyl] -4-phenyl-piperazine,

1- (5-methylfuran-2-ylmethyl) -4- (3-chlorophenyl) piperazine; [5- (4-methoxyphenyl) -1-furan-2-ylmethyl] -4-phenylpiperazine; · · · · · · ·

1- [5- (3,4-Dimethyl-phenyl) -furan-2-ylme. ethyl] -4-phenylpiperazine, 1- (3- [5- (3,4-dichlorophenyl) furan-2-ol).

-yl] -prop-1H-4- (4-methyl-phenyl) -piperazine.

1- [2- (5-phenylthiophen-2-yl) but-1-yl] -4-phenylpiperazine,

1- (5-Phenylthiophen-2-ylmethyl) -4- (3,4-thi ..

-dimethylphenyl) piperazine, 1- [3- (5-phenyl-furan-2-yl) prop-1-yl] -4- (4- (4-methyl-piperazin-1-yl) -4-piperidin-1-yl) piperazine, .

1- (5- (4-Methoxyphenyl) furan-2-ylmethyl) -4- (4-methylphenyl) piperazine;

(R, 5-Phenyloxazol-2-ylmethyl) -4- (4-methylphenyl) piperazine,

1- (2-Benzylthiazol-4-ylmethyl) -4-phenyl-piperazoline.

and pharmaceutically acceptable addition thereof. salts with acids ..

Other illustrative examples of the novel compounds of the invention. are:.

1- (5-Phenylthiophen-2-ylmethyl) -4- (3-chlorophenyl) piperazine;

1- (5-Methylthiophen-2-ylmethyl) -4- (4-methyl-).

thoxyphenyl Jpiperazine,. . 5

1- (5- (3-Trifluoromethyl-4-chlorophenyl) furan-2-ylmethyl) -4- (4-fluorophenyl) piperazine.

1- [3- (5-phenylfuran-2-yl) prop-1-yl] -4- (3-trifluoromethyl) piperazine, 1- (2-methylthiazol-4-ylmethyl) 4- (3 • - chlorophenyl (piperazine, 1- [2- (4-phenylthiazol-2-yl) ethyl] -4-

- (4-aminophenyl (piperazine, 1- [2- (4-phenylthiazol-2-yl) ethyl) -4-, 4-aminophenyl) piperazine;

- (4-nitrophenyl) piperazine,

1- (5-Phenyloxazol-2-ylmethyl) -4-phenylpiperazip;

1- (4- (3-Trifluoromethylphenyl) thiazol-2-ylmethyl) -4-phenylpiperazine.

1- (4-Phenylthiazol-2-ylmethyl) -4-phenylpiperazine.

1- (2- [5- (4-chlorophenyl) oxazol-2-yl] ethyl) -4-phenylpiperazine,

1- [2- (5-fluoro-2 _{enyíoxažol:} yl (ethyl] -4- (4-chlorophenyl) piperazine · ......

1- [2- (5-Phenyloxazin-1-yl) ethyl (-4- (4-methoxyphenyl) piperazine, 1- [1- (5-phenylpxazol; 2-yl) prop-2-yl] -

- (4-methyl-phenyl ^lf! ^ Piperazine,

1- [1- (5-Phenyl-oxazol-2-yl) -ethyl] -4- (4-methyl-phenyl) -piperazine,

1- (5-Phenyloxazb-2-ylmethyl) -3-methyl-4-.

(4-Methylphen-1-piperpzine, ...

. 1- (5-Phenyloxazin-2-ylmethyl) -2,3-dimethyl-4- (4-methylphenyl (piperazine) -1- (2- [4- (chlorophenyl) thiazole; -yl JethyJj-

-4-phenylpiperazin). 1- [2- (4- (4-methoxyphenyl) piperazin-4- (4-chlorophenyl) piperazin-4-ylphenylthiazol-4-yl) ethyl] - (4-methoxyphenyl) piperazine,

1- [1- (4-Phenyl-thiazol-2-yl) -prop-2-yl] -4- • - (4-methylphenyl) - (piperazine, 1- [1- (4-phenylthiazol-2-yl) ethyl] -4- {4-.

1- (4-phenylthiazol ^; 2-ylmethyl) -4- (4-methanesulfonamidophenyl) piperazine, 1- [2- (5-chlorophenyl (furan-2-yl) ethyl) ethyl] -methyl-phenyl] piperazine; 4-phenylpiperazine,

1- (2- (5-phenylfuran-2-yl) ethyl) -4- (4-chlorophenyl) piperazine, 1H-1- (2- (5-phenylfuran-2-yl) ethyl) -4- ( 4-methoxyphenyl (piperazine), 1- [1- (5-phenylfuran-2-yl) prop-2-yl (-4- (4-methylphenyl) piperazine),

1- (1- (5-Phenylfuran-2-yl) ethyl) -4- (4-methylphenyl) piperazine

1- (5-phenylfuran-2-ylmethyl) -4- (4-methylphenylpiperazine).

1- (5-phenylphenyl-2-methylmethyl) -4- (4-methanesulfonamidophenyl (piperazine, 1- [4- (4-phenylthiazol-2-yl) but-1-yl) -4-phenylpiperazine] ·

1- (5 ^: phenylthiophen-2-ylmethyl) -4- (4-methylphenyl (piperazine,

N- (5-phenylthiophenyl-2-methylmethyl) -4-phenylpiperazine, 1- (5-methylsulfonyl) -2-phenyl-4-phenyl-.

piperazine, - ^! 1- (2- (5-methyloxazol-2-yl) ethyl) -4- (4-methylphenyl) piperazine, 1- (2- (5-methyloxazol-2-ylmethyl) -4- (4-methylphenyl) piperazine), 1- [2- (4-Methyl-oxazol-2-yl) -ethyl] -4- (3-methyl-phenyl) -piperazine,

1- [3- (5-methyl-oxazol-2-yl) -prop-1-yl (-4- (2-chloro-phenyl) -piperazine,

1- (5-benzyloxy-2-ylmethyl (-4- (4-nitrophenyl) piperazine), 1- [4-benzyioxazol-2-ylmethyl (-4- (3-acetylaminophenyl) piperazine),

1- [2- (5-benzyloxazol-2-yl) ethyl (-4- (4-nitrophenyl) piperazine;

1- (2- (5-benzyloxazol-2-yl) ethyl) -4- (4-ethylphenyl) piperazine, 1- [3- (5-benzyloxazol-2-yl) prop-1-yl] - 4- (4-ethoxyphenyl (piperazine),

1- (5-methylthiazol-2-ylmethyl (-4-phenylpiperazin), 1- (4-methylthiazol-2-ylmethyl) -4- (4-methylphenyl) piperazine,.

1- (2- (5-methylthlazol-2-yl) ethyl) -4- (4-chlorophenyl) piperazine,

1- (2- (4-methylthiazol-2-yl) ethyl) -4- (3-methylphenyl (piperazine, 1- [3- (5-methylthiazol-2-yl) prop-1-yl) -4 - (2-chlorophenyl (piperazine),

1- (5-Benzylthiazol-2-ylmethyl) -4- (4-nitrophenyl) piperazine.

1- (4-benzylthiazol-2-ylmethyl) -4- (3-acetylaminophenyl) piperazine,

1- [2- (5-benzylthiazol-2-yl) ethyl] -4- (4-aminophenyl) piperazine,

1- [2- (5-benzylthlazol-2-yl) ethyl (-4- (4-ethylphenyl) piperazine;

1- (3- (5-benzylthiazol-2-yl) prop-1-yl) -4- (4-ethoxyphenyl) piperazine; 1- (5-methylfuran-2-ylmethyl) -4- phenylpiperazine, ·.

1- (4-Methylfuran-2-ylmethyl) -4- (4-methylphenyl) piperazine,

1- (2- (5-methylfuran-2-yl) ethyl) -4- (4-chlorophenyl (piperazine);

1: (2- (4-Methylfuran-2-yl) ethyl) -4- (3-methylphenyl (piperazine, 1- [3- (5-methylfuran-2-yl) prop-1-yl) -4 - (2-chlorophenyl (piperazine,

1- (5-benzylfuran-2-ylmethyl) -4- (4-nitrophenyl) piperazine,

1- (4-Benzylfuran-2-ylmethyl (-4- (3-acetyl, aminophenyl) piperazine)

1- (2- (5-benzylfuran-2-yl) ethyl) -4- (4-ethylphenyl (piperazine, 1- [3- (5-benzylfuran-2-yl) prop-1-yl) -4- (4-ethoxyphenyl (piperazine,

1- (5-Methylthiophen-2-ylmethyl) -4-phenylpiperazine

1- (4-Methylthiophen-2-ylmethyl) -4- (4-methylphenyl) piperazine, 1- [2- (5-methylthiophen-2-yl) ethyl (-4- (4-chlorophenyl ( piperazine,

1- [2- (4-Methylthiophen-2-yl) ethyl] -4- (3-methylphenyl) piperazine

13; (5-methylthiophen-2-yl) prop-1-yl) -4- (2-chlorophenyl) piperazine,

1- (5-Benzylthiophen-2-ylmethyl) -4- (4-nitrophenyl) piperazine

1 '

1- (4-Benzylthiophen-2-ylmethyl) -4- (3-acetylaminophenyl) piperazine

1- (2- (5-benzylthiophen-2-yl) ethyl] -4-.

- (4-nitrophenyl) piperazine, 1- [2- (5-benzylthiophen-2-yl) ethyl] -4-

- (4-ethylphenyl) plperazine,

1- [3- (5-benzylthiophen-2-yl) prop-1-yl] -4- (4-ethoxyphenyl) piperazine, and pharmaceutically acceptable acid addition salts thereof.

The process for the preparation of phenyl piperazine derivatives of the above general formula (1) is described above. bem ^: according to the invention, the compound of the formula

R ¹ -O- (CH2) m- (CHR ³⁾ n L. (VII) wherein L represents a halogen atom, methylsulfonyl or substituted benzenesulfonyl, R ¹ , R ³ , m and n as defined above, is condensed with a compound of formula VIII,

HN NR ^z \ ___ r (I wherein. R ² is as defined above, and the compound of formula I is optionally converted by reaction with an acid into an acid addition salt.

The above condensation is preferably carried out in the presence of a proton acceptor, such as a base, for example sodium carbonate. Suitable solvents for the reaction are polar solvents, such as alkanols, for example ethanol, and the reaction is preferably completed under heating to reflux. The leaving group L may be any group known to be effective in such condensation reactions. It should be noted that halogen atoms such as chlorine, or methylsulfonyl or substituted benzenesulfonyl groups provide good results in this reaction. The reaction is preferably carried out at a temperature range of 20 to 150 ° C.

The compounds of formula (I) prepared by the above process can be isolated as such or in the form of acid addition salts.

Acid addition salts are, preferably, pharmaceutically acceptable non-toxic acid addition salts with suitable acids such as inorganic acids such as hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, or with organic acids such as organic carboxylic acids such as glycolic acid , maleic, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulfonic ký «3 80 ⁸ petroleum jelly, for example methanesulfonic acid, ethanesulfonic acid, 2-hyidroxyethansulfonová, p-toluenesulfonic, or naphthalene-2 -sulfone. In addition to pharmaceutically acceptable acid addition salts, other salts are also included within the scope of acid addition salts, such as picric or oxalic acid salts. These salts may serve as intermediates in the purification of the compounds or in the preparation of other, for example, pharmaceutically acceptable acid addition salts, or are suitable for the identification, characterization or purification of bases.

The resulting acid addition salts may be converted to the free compounds according to known methods, for example by treatment with a base such as a metal hydroxide or alkoxide, for example an alkali or alkaline earth metal hydroxide, for example lithium, sodium, potassium or calcium hydroxide, a metal carbonate such as an alkali metal or alkaline earth metal carbonate or an acidic carbonate. ammonia or ion exchange resin (OH-form) or other suitable reagent.

The resulting acid addition salt may be converted to another acid addition salt by known methods, for example, an inorganic acid salt may be treated with a metal salt such as sodium, barium or silver salts derived from an acid in a suitable diluent in which the resulting inorganic salt is insoluble and thus removed from the reaction medium. The acid addition salt can also be converted to another acid addition salt by treatment with an acid.

The present invention further provides obtaining pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

The compounds of formula I and their pharmaceutically acceptable salts have been found suitable for the prophylactic and terepeutic treatment of immediate hypersensitivity diseases, including asthma in mammals. . The compounds have low toxicity.

The compound or mixture of the invention may be delivered in various ways and may be formulated in various forms for this purpose. Thus, the compounds or mixtures may be administered orally, rectally, locally, or parenterally (e.g., by injection or continuous or continuous non-intravenous infusion), in the form of, for example, tablets, lozenges, sublingual tablets, sachets, special-purpose starch wafers, elixirs, suspensions, suppositories, sprays, ointments (e.g., containing 1-10 wt ^fl / o of the active compound in a suitable .základě), soft and hard gelatin capsules, injectable solutions and suspensions in a 'physiologically acceptable media, and sterile packaged powders adsorbed \ il, carriers for injectable solutions:

Mixtures preferred for these purposes may be

860 in dosage unit forms, each dosage unit preferably containing 5 to 500 mg. (5.0 to 50 mg for parenteral administration, 5.0 to 50 mg for inhalation and 25 to 500 mg for oral or rectal administration) of a compound of Formula I. Doses of the active ingredient, 0.5 to 300 mg, may be administered. / kg per day, and preferably 0.5 to 20 mg / kg, although it will be understood that the amount of the compound of Formula I to be administered will be determined by the physician having regard to all relevant circumstances, including treatment conditions. , the choice of compound to be administered and the route of administration, and therefore the above preferred dosage range is not intended to limit the scope of the invention in any way.

The formulations of the present invention typically comprise at least one compound of formula I mixed with a carrier or dilute carrier or enclosed or encapsulated in an edible carrier in the form of a capsule, sachet, special closure starch wafer, paper or other container or disposable container such as an ampoule. The carrier or diluent may be a solid, semi-solid, or liquid material which serves as an additive, carrier or medium for the therapeutically active agent.

Examples of diluents or carriers that can be used in the pharmaceutical compositions of this invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, purified silica, microcrystalline cellulose, carbonate. calcium, natural silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, acacia, calcium phosphate, cocoa butter, ethoxylated esters, cocoa oil, peanut oil, alginates, tragacanth, gelatin, syrup В. P., methylcellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propylhydroxybenzoate, sorbitan trioleate, sorbitanskioleate and oleyl alcohol and propellants such as trichloromethane fluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a glidant may be incorporated to prevent sticking and bonding of powder particles in the die and punch of the tabletting machine. For example, aluminum, magnesium or calcium stearate, talc or mineral oil may be used for this purpose.

The activity of the compounds prepared by the process of the invention was examined by the following test to verify the antiallergic activity of the compounds. The test is based on allergic bronchospasm induced in guinea pigs and is similar to that described by Herxheimer in the Journal of Physiology (Lopdyn) 117,251 (1952),

Male guinea pigs, sensitized to egg albumin, are exposed to an egg albumin aerosol. nu (1% w / v solution) produced by Wright's fogging device using air at 0.11 MPa The symptoms observed in guinea pigs exposed to the disease are increased velocity and depth of breath followed by hypoxia seen in the eyes and skin, and The time between the initial exposure to antigen and cough is known as the "collapse time" and is characteristic and reproducible for the animal. Antihistamine mepyramine was used to detect the non-histaminic component of the bronchial contracting agents and to emphasize the observed symptoms.

The results are summarized in the following table:

2; .з? · Ώ R2. ·· Dose M / C D / C M-. D / M

198380 yT y

N-R *

R1

СНз—

PI1-CH2 t-Bu-p-NOzPh-

Ph—

Ph—

Ph—

Me - 'p - OMe - Ph—

Ph—, -.

CHsO — Ph—

Ph—

Ph—

Ph—

m-BrPh - 100 p-ClPh -

Ph - 'Pii - m-CF3Ph—

3,4-diClP'h—

3,4-diM-ePh1 m-CIPh -

Ph - · p - MePh - p - MePh -

Ph— m-CF3Ph—

Ph—

3.2

5,5 '. 3.8 '5.0

505.8

100 ..5,8.

50 '5,6

506.2

503.4

505.6

504.7 .50- 6.2

505.4

1005.7

100 .5,7

100 6.6.

1.0. 1.7

0.7 · 1.9

2,0 - 2

1,73,8

1,22,6

0.6. 3.5

2,02,0

1,11,7

1,72,5

1,12,4

4.7. · 2,2

1,42,2

7.3 1.6

19636O *. - mg / kg p. O. 2 hours before disease induction

C. - control (mean collapse time) M '- mepyramine (mean collapse time). administered at 0.5 mg / kg subcutaneously half an hour prior to disease induction D - A compound of the invention. (average collapse time).

Column 1 shows the protective effect of mepyr amine and Column 1. 2 test compounds of the invention. In column 3, the additional protective effect of the compound of formula I is expressed as a ratio. . invention. after previous administration of mepyramine.

The following examples illustrate the invention.

Example 1

(a) 2-Acetoxythioacetamide

The stream of dry hydrogen sulphide is rapidly introduced into a solution of 150 g (1.52 mol) of 2-acttoxyx acetonitrile a. 20 ml triethanalamine. in 500 tons. dry ethanol with vigorous stirring. The internal temperature rises to 55 ° C. . Flow. The gas was held for 3 hours and then subjected to interface chromatography. gas-liquid. find that the reaction is complete ... The excess hydrogen sulfide is removed by bubbling a stream of nitrogen and ethanol, the solvent, is evaporated to dryness. The remaining sticky crystalline mass is extracted. boiling ether and a small amount of insoluble residue. postpone. The combined extracts were treated with decolorizing charcoal, filtered and evaporated to approximately 400 ml. Cooling to 0.1 ° C gave about 170 g of somewhat sticky 2-acetoxythioacetamide, which was used in the next step. without further characterization.

b) 2-Hydroxymethyl-4-phenylthiazole

39.9. g (0.2 mol) of 2-bromoacetophenone and 30 g (0.225 mol) of 2-acetoxythioacetamide are dissolved in 150 ml of dioxane. The mixture was stirred. a. The mixture is heated on a steam bath for 15 minutes and a crystalline mass is obtained. Then 40 ml is added. 5N aqueous hydrochloric acid; warming up. 'continues for another 30 minutes. Dioxane was evaporated in vacuo and residue. is neutralized with an aqueous solution. sodium carbonate. The solid was collected, washed with water and dried. After recrystallization from benzene, the product weighs 33.5 g (87%) and has a melting point of 88-89 ° C.

(c) 2-Chloromethyl-4-phenylthiazole; . . '

6.25 g (0.052 mol) of thionyl chloride are added. 9.55 grams (0.05 moles) is added dropwise to the stirred solution.

2-hydroxymethyl-4-phenylthiazole and 4.0 g (0.051 mol). dry 'pyridine in' 60 'ml' dry. benzene maintained at room temperature. The mixture was further stirred and heated to boiling for 1 hour. Cooled. the reaction mixture is then twice. shake with 70 ml of water and dry with anhydrous magnesium Iran. Remove the solvent. in vacuum and. the remaining red. the oil is extracted 100. ml of petroleum ether having a boiling point of 40 to 60 ° C and a small amount of tar residue is discarded. The extract is treated with decolorizing charcoal, filtered and evaporated; There is a yellow-red oil that. crystallizes by cooling.

The yield was 9.9 g (94.5%).

None. further purification of the product was not carried out and the material was used directly in the next step. .

d) 1 ((4-Phenyl-2-thiazolylmethyl) -4-methyl-piperazine.

A mixture of 4.19 g (0.02 mol) of crude, 2-chloromethyl-4-phenylthiazole, 3.24 g (0.02 mol) of N-phenylpiperazine and finely powdered anhydrous sodium carbonate in 60 ml of absolute. of ethanol was stirred and refluxed for 8 hours. The solvent is evaporated to dryness, the solid residue is suspended in 100 ml of water and then extracted twice with 100 ml of dichloromethane each time. The extracts are washed with water and dried. anhydrous magnesium sulphate. After evaporation of the solvent, recrystallize the residue from the mixture. of benzene and petroleum ether at a boiling point of 60 to 80 ° C (and treatment with activated carbon) were obtained. 5.03. . g (75%) of the desired product. m.p. 142-143 ° C,

EXAMPLE 1 A d 2. 19 Dec

Similarly, it is produced:.

(2) '1- (4-phenyl-2-thiazolylmethyl) -4- (3-bromophenyl) piperazine, mp 127.5-128.5 ° C;

(3) 1- (4-phenyl-2-thiazolylmethyl) -4- (3,4-di-fluorophenyl) piperazine, para. mp 144-146 ° C;

(4) 1- (4-Phenyl-2-thiazolylmethyl) -4- (3-trifluoromethylphenyl) piperazine, m.p. 112-113 ° C; 4-chloro-3-trifluoromethylphenyl] piperazine, m.p.

(6) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methyl-phenylphenyl) piperazine, m.p. 141-143 ° C;

(7) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methoxyphenyl) piperazine, m.p. 148-149 ° C;

(8) 1- [4l (4-chloro-phenyl) -thiazol-11-yl] piperazine, m.p. 164-165 ° C;

(9) 11- [4- (4-chlorophenyl) --- thiazolimethyl) -1-4- (3-bromophentyl) piperazine, m.p. 100-101 ° C; (10) 1- [4-. (4-bromophenyl). -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 166 ° C;

(11) 1- (4- (3-chlorophenyl) -2-thiazolylmethyl) -1-phenylpiperazine, m.p.

131 [deg.] C .;

(12) 1- [4 J 2-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p.

101 [deg.] C .; .

(13) 1- [4- (3,4-dichlorophenyl) -2-thiazolyl-. methyl] -4-phenylpiperazine, para. mp 138-139.5 ° C;

(14) 1- (4- (3-trifluoromethylphenyl) -2-thiazolylmethyl) -4-phenylpiperazine, m.p. 110-111 ° C; .

115) 1- [4f (4-Methoxyphenyl) -2-thiazolylmethyl] -4-phenylpiperazine hydrochloride, m.p. 201 ° C;

(16) 1- [4- (4-methylphenyl) -2-thiazolylmethyl] -4-phenylpiperazine hydrochloride, m.p. 175-180 ° C; (17) 1- [4- (3-methylphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p.

113.5 ° C; . .

(18) 1- [4- (4'hydrooyphenyl] -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 228-230 ° C;

(19) 1- (4- (4-nitrophenyl) -2-thiazolylmethyl) -

-4-phenylpiperazine, melting point. Mp 195-198 ° C.

Example 20

a) N-Phenylchloroacetamide (0.226 mol) chloroacetyl chloride was slowly added to a stirred solution of 25.9 g (0.151 mol) of phenacylammonium hydrochloride in 80 ml of anhydrous dimethylformamide at room temperature. The internal temperature was raised to about 40 ° C. . The mixture was stirred for 4 hours after the addition was complete and most of the dimethylformamide was evaporated under vacuum. The residue is treated with 200 ml of water and the crystalline precipitate is collected, washed with water and dried. Yield 24.75 g (77%), mp 118-119 ° C.

b) 2-Chloromethyl-5-phenylooazole

22.6 g (0.107 mol) of N-phenylacylchloroacetamide are mixed with 200 g of polyphosphoric acid and the mass is stirred for 30 minutes at 150 ° C. The 'hot liquid' is then poured out intensively. mixing · up to 800 ml of water. The mixture thus obtained is extracted three times. in each case 100 ml of chloroform and the extracts were washed with water and shaken with magnesium sulfate. The chloroform is evaporated and the remaining oil is extracted with 400 ml of boiling petroleum ether having a boiling point of 60-80 ° C. The resulting solution is treated with decolorizing charcoal to remove the tar and evaporate. A pale yellow oil is obtained which crystallizes rapidly. Yield 18.8 g (91%), m.p. 70-71 ° C.

c) 1- (5-Phenyloxazol-2-ylmethyl) -4-phenyl-1-piperazinyl.

3.87 g (0.02 mol) · 2-chloromethyl-5-phenyloazazole and 3.25 g (0.02 mol) of N-phenylpiperazine in 60 ml of absolute ethanol · cook and stir with · 5 g gently powdered sodium carbonate for 6 hours.

Evaporate the solution to dryness and treat with · ml of water. The suspension thus obtained is extracted twice with 70 ml of dichloromethane each time. The extracts are dried over magnesium sulphate and evaporated to dryness. The solid residue is recrystallized from petroleum ether at a boiling point of 80 to 100 ° C using decolorizing charcoal. The yield was 4.67 g and the melting point was 96 ° C.

Examples 21 to 35.

Similarly, ..

(21) 1- (5-phenyloazol-2-ylmethyl) -4- (4-methylphthyl) piptrazine, mp 113-114 ° C; .

(22) 1- (5-phenyloazol-2-ylmethyl) -4- (3-chlorophenyl) piptrazine, m.p. 73 ° C;

(23) 1- (5-phenylooazol-2-ylmethyl) -4- (4-chlorophenyl) piperazine, mp 125-126 ° C;

(24) 1- (5-Phenylooazol-2-ylmethyl) -4- (3-

69-70 ° C; (trifluoromethylthiphenyl) piptrazine; (25) 1- (5-phenylooazol-2-ylmethyl) -4- (3,4-dichlorophenyl) piptrazine, m.p. 134-135 ° C;

(26) 1- (5-Feryrlooazol-2-ylmethyl) -4- (4-

mp 121-122 ° C; .

(27) 1- (5-phenylooazol-2-ylmethyl) -4- (3-methylphenyl) piperazine, m.p. 100 ° C;

(28) 1- (5-phenyloazol-2-ylmethyl) -4- (2,4-dimethooyphenyl) piptrazine, m.p. 89-91 ° C;

(29) 1- (5-trnyloxazol-2-ylmethyl) -4- (3,4-dimethooyphenyl) piperazine, m.p. 93-95 ° C;

(30) 1- (5-Phenylooazol-2-ylmethyl) -4- (4-

-piperazine, mp 98 ° C;

(31) 1- (5- (4-fluorophenyl) ooazol-2-ylmethyl) -4-phenylpiperazine, m.p.

116 ° C; (32) 1- [5- (4-fluorophenyl) ooazol-2-ylmethyl] -4- (4- (4-fluorophenyl) piperazine) m.p.

- 112 ° ^C; (33) 1- [5- (4-methoxyphenyl) oxazo-2-ylmethyl] -4-phenylpiperazine, m.p. 112-115 ° C;

(34) 1- [5- (4-Methoxy-phenyl) -oxazol-2-ylmethyl] -4- (4-methoxy-phenyl) -piperazine, m.p. 148-150 ° C;

(35) 1- (5-Phenylooazol-2-ylmethyl) -4- (4-

(1) piperazine, m.p. 170-172 ° C.

1- (5- (3-Trifluoromethylphenyl) furan-2-ylmethyl) -4-phenylpiperazine

(a) 2-Hydrooymethyl-5- (3-trifluoromethylphenyl) furan.

21.2. g (0.1 · mol) of 2- (3-trifluoromethylphenyl) furan · (f. Chem. · Soc./C) 1968, 2737; and

Acta Chem. · Scand. . 24, 2379 (1970) is stirred in 100 ml of tetrahydrofuran, cooled to -40 ° C and added dropwise with 0.1 mole of n-butyl lithium196360 hia as a solution in hexane. After stirring for one hour at -40 ° C, 3.3 g (0.11 mol) of paraformaldehyde is slowly added. The mixture was stirred at -40 ° C for 30 minutes and then allowed to rise in temperature. At 10 ° C, the exothermic reaction begins and the temperature gradually rises to 40 ° C over 10 minutes and then gradually drops to 20 ° C. After further stirring for 1 hour, the clear brown solution was poured on ice and water, adjusted to pH 4 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulphate and evaporated to give a brown, viscous brown oil which, by distillation in vacuo, gave 16.2 grams of 2-hydroxymethyl-5- (3-trifluoromethylphenyl) uranium as a colorless boiling liquid. 125 ° C (66.6 Pa) from which crystals having a melting point of 45 ° C are obtained on standing.

b) 2-Bromomethyl-5- (3-trifluoromethylphenyl) furan

4.84 g (0.02 mol) of the hydroxymethyl compound prepared in a) above are dissolved in 30 ml of dimethylformamide, cooled to 0-5 ° C, and 1.7 ml (0.02 mol) of thionyl bromide are added dropwise with stirring. After 2 hours, the yellowish green solution is poured onto ice and water and extracted with diethyl ether. The ether extract was washed with saturated sodium chloride solution and dried on a molecular sieve Z 2 and evaporated. 4.6 g of a light brown oil are obtained, which crystallizes slowly.

c) 1- (5- (3-Trifluoromethylphenyl) furan-2-ylmethyl) -4-phenylpiperazine

0.015 mol of the bromomethyl product obtained from b) above is stirred in 50 ml of dioxane and 2.75 g (0.017 mol) of N-phenylpiperazine in the presence of 1.5 g of anhydrous sodium carbonate and the mixture is refluxed for 7 hours, poured onto ice and water and extracted with chloroform. The chloroform extract was washed with water, then saturated brine, and finally evaporated to give an oil which was treated with ethereal hydrochloric acid to give 2.1 g of a cream colored crystalline solid. 2 g of this hydrochloride are dissolved in 15 ml of chloroform, mixed with 15 ml of water and then saturated sodium carbonate solution is added dropwise until the resulting solution is alkaline. The phases were separated and the chloroform layer was evaporated. 1.7 g of a straw-colored oil are obtained, which crystallizes slowly. This material was recrystallized from petroleum ether, b.p. 60-80 ° C to give 1.2 g of the title compound, 1- [5- (3-trifluoromethylphenyl) furan-2-ylmethyl] -4-phenylpiperazine, m.p. 94 ° C.

In a similar manner, the following compounds were prepared except that the hydroxymethyl derivatives obtained as intermediates were converted to the chloromethyl compounds by treatment with thionyl chloride. '

Example 37

1- [5- (4-Chloro-phenyl) -furan-2-ylmethyl] -4-phenyl-piperazine, m.p. 140 ° C.

Example 38

1- (5- (4-Chloro-phenyl) -furan-2-ylmethyl) -4- (3-trifluoromethyl-phenyl) -piperazine monohydrochloride.

The free base is obtained as a very viscous oil and is converted to the monohydrochloride with a melting point of 220 ° C.

Example 39

1- (5- (4-Chloro-phenyl-furan-2-ylmethyl) -4- (3-chloro-phenyl) -piperazine, monohydrochloride, m.p. 215 ° C.

Example 40

1- [5- (4-chlorophenyl) furan-2-ylmethyl) -4- (3-bromophenyl) piperazine monohydrochloride.

6.67 g (0.03 mol) of 5- (4-chlorophenyl) -2-pyrosylic acid (Australian Journal of Chemistries, 26, 1147 (1973)) with ref lux is in 100 ml of benzene with 4.5 ml of thionyl chloride After removing the excess thionyl chloride, the remaining acid chloride in benzene was added dropwise with stirring to a cold mixture of 7.23 g (0.03 mol) of N- (3-bromophenyl) piperazine and 4.5 ml (about 0.03 mol). After stirring for one hour at room temperature, the mixture was shaken with 100 ml of water, and the separated benzene phase was further washed with a saturated saline solution, then evaporated to give an oil which crystallized immediately and recrystallized from ethyl acetate / petroleum ether. boiling point 60-80 ° C (1: 3 v / v) and 12.3 g of 1- [5- (4-chlorophenyl) -2-furoyl] -4- (3-bromophenyl) -piperazine, m.p. C.

4.45 g (0.01 mol) of the above tertiary amide is dissolved in 30 ml of dry tetrahydrofuran and added dropwise with stirring and cooling to 0 ° C and to 20 ml of a 1H solution of diborane in tetrahydrofuran (note: reaction under nitrogen) ). The temperature rises to about 8 ° C and the resulting cloudy solution is refluxed for 1 hour. The clear pale yellow solution was cooled and then heated on a steam bath for 15 minutes with 20 mL of 5N hydrochloric acid. After cooling again, the solution was basified with 4N sodium hydroxide and extracted with diethyl ether. The ethereal extract was dried (MgSO4) to give an oil which was converted to 2.8 g of the title compound monohydrochloride at a melting point of 217 ° C.

The following compounds are produced in a similar manner:

190360

Example 41

1- (5- (4-Chlorophenyl) furan-2-ylmethyl) -4- (3-trifluoromethyl-4-chlorophenyl) piperazine, m.p. 104 ° C.

Example 1 a d 42

1- [5- (4-Methylphenyl) furan-2-ylmethyl] -4-phenylpiperazine, m.p. 87 ° C.

Fifth 1 a d 43

1- (5- (2-Methylphenyl) furan-2-ylmethyl) -4-phenylpiperazine, mp 67 ° C.

Example 44

1- [5- (3,4-Dichloro-phenyl) -furan-2-ylmethyl) -4-phenyl-piperazine, m.p. 92 ° C.

Example 1 a d 45

1- (5- (3-Trifluoromethyl-4-chlorophenyl) furan-2-ylmethyl) -4-phenylpiperazine, m.p. 102 DEG.

Example 46

1- (5- (3-Trifluoromethyl-4-chlorophenyl) furan-2-ylmethyl) -4- (3-chlorophenyl) piperazine monohydrochloride, m.p. 216 ° C.

Example 1 a d 47

1- (5- (3-Trifluoromethyl-4-chlorophenyl) furan-2-ylmethyl) -4- (4-methylphenyl) piperazine, mp 126 ° C.

Example 48

1- (5-Phenyl-furan-2-ylmethyl) -4- (3-chloro-phenyl) -piperazine, monohydrate, m.p. 208 ° C.

Example 49

1- (2-Methylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine

A mixture of 7.4 g (0.05 mol) of 4-chloromethyl-2-methylthiazole, 12.05 g (0.05 mol) of 1- (3-bromophenyl) piperazine and 10 g of anhydrous sodium carbonate is suspended in 150 ml of absolute ethanol. After stirring for 8 hours, the solvent is evaporated to dryness and 100 ml of water are added, the emulsion is extracted with dichloromethane, the organic extracts are dried over magnesium sulphate and evaporated to an oil which is dissolved in hot benzene and treated with decolorizing active. The filtrate was evaporated to give the title compound as an oil which crystallized quantitatively, mp 82 ° C (ether).

Similarly, the following compounds are prepared:

Example 50

1- (2-Methylthiazol-4-ylmethyl) -4- (3-trifluoromethylphenyl) pepirazine dihydrochloride, m.p. 176-178 ° C.

Example 51 '

1- (2-Methylthiazol-4-ylmethyl) -4- (3-chlorophenyl) piperazine, m.p. 71-72 ° C.

Example 52

1- (2-Methylthlazol-4-ylmethyl) -4- (3-methoxyphenyl) piperazine, m.p. 71.5-72.5 ° C.

Example 53

1- (2-Methylthiazol-4-ylmethyl) -4- (4-bromophenyl) piperazine, m.p. 114-115 ° C.

Example 54

1- (2-Methylthiazol-4-ylmethyl) -4- (2-bromophenyl) piperazine, m.p. 85-86.5 ° C.

Example 55

1- (2-Methyl-thiazol-4-ylmethyl) -α-N, N-dichloro-phenyl-piperazine dihydrochloride, m.p. 175-176 ° C.

Example. 56

1- (2-Methylthiazol-4-ylmethyl) -4- (3-nitrophenyl) piperazine Hydrochloride, m.p. 218-222 ° C.

Example 1 a d 57

1- (2-Methylthiazol-4-ylmethyl) -4- (4-methylphenyl) piperazine hydrochloride, m.p. 190-192 ° C.

Example 58

1- (2-Methylthiazol-4-ylmethyl) -4- (3-methylphenyl) piperazine hydrochloride, m.p. 158-160 ° C.

Example 59

1- (2-Methylthiazol-4-ylmethyl) -4- (4-chloro-phenyl) piperazine, m.p. 98 ° C.

Example 1 a d 60

1- (2-Methylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) plperazine hydrochloride, m.p. 185-187 ° C.

Example 61

1- (2-Methylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine hydrochloride, m.p. 134-135 ° C.

Example 62

2-n-Propyl-4-chloromethylthiazole

To a solution of 30.96 g (0.3 mol) of thiabutanamide in 200 ml of absolute ethanol was slowly added a solution of 38.1 g (0.3 mol) of 1,3-dichloroacetone in 100 ml of ethanol and refluxed for 1 hour. The residue was treated with an excess of saturated sodium bicarbonate solution and extracted with ether, dried and evaporated to a brown oil which was distilled in vacuo to give a light yellow oil, b.p. This oil is converted to the hydrochloride of the title compound by treatment with ethereal hydrogen chloride, melting point 60 DEG C. with decomposition.

b) 2-benzyl-4-chloromethylthiazole, bp 116-118 ° C / 12.0 Pa;

c) 2-isopropyl-4-chloromethylthiazole hydrochloride, m.p. 58 DEG C. with decomposition.

• Example 63

1- (2-n-Propylthiazol-4-ylmethyl) -4-phenylpiperazine

A mixture of 3.18 g (0.015 mol) of hydrochloride

2-n-propyl-4-chloromethylthiazole, 2.43 g (0.015 mol) of 1-phenylpiperazine and 10 g of anhydrous sodium carbonate in 60 ml of absolute ethanol are stirred and refluxed for 6 hours. The suspension was filtered and the filtrate evaporated to a yellow oil. This oil was dissolved in boiling benzene and treated with decolorizing charcoal. After filtration, benzene was removed to give 4.27 g of a yellow oil which crystallized. The solid obtained is recrystallized from petroleum ether, b.p. 60-80 ° C at 0 ° C. A white crystalline solid is obtained with a melting point of 38-39 ° C.

Similarly, the following compounds are prepared:

EXAMPLE 64 1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine, m.p. 51-54 ° C.

Example 65

1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-methylphenyl) piperazine, m.p. 41-44 ° C.

Example 66

1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine, m.p. 46-47 ° C.

Example 67 '

1- (2-n-Propylthiazol-4-ylmethyl) -4- (3-trifluoromethylphenyl) piperazine hydrochloride, m.p. 162-166 ° C.

Example 1 and 68

1- (2-n-propylthiazol-4-ylmethyl) -4- (4,4-dichlorophenyl) piperazine dihydrochloride, m.p. 158-160 ° C.

Example 1 a d 69

1- (2-n-propylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine dihydrochloride, m.p. 174-178 ° C.

Example 70

1- (2-Benzylthiazol-4-ylmethyl) -4-phenylpiperazine, m.p. 60-62 ° C.

Example 71

1- (2-Benzylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine, m.p. 74 ° C.

Example 72

1- (2-Benzylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine, m.p. 65 ° C.

Example 73

1- (2-Benzylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine, m.p. 69 DEG C.

Example 74 '

1- (2-Benzylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine, colorless oil.

Example 75

1- [2- (4-Chloro-benzyl) -thiazol-4-ylmethyl] -4-phenyl-piperazine dihydrochloride, m.p. 150 ° C (dec.).

Example 76

1- (2-Isopropylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine, m.p.

Example 77 1- (2-Isopropylthiazol-4-ylmethyl) -4-phenylpiperazine, m.p. 42 ° C.

Example 78

196380

Example 84

1- (2-Iso-propylthiazol-4-ylmethyl) -4- (3-methoxyphenyl) piperazine, m.p.

Example 79

1- (2-Isopropylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine, colorless oil.

Example 80 ‘

1- (2-Isopropylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenylpiperazine) Colorless oil.

The following examples illustrate the preparation of pharmaceutical compositions containing the compounds of the invention. 1- (2-Benzylthiazol-4-ylmethyl) -4-phenylpiperazine is used as the active ingredient, although it will be appreciated by those skilled in the art that other active solid compounds of the invention would be equally useful.

Example 81

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg / capsule)

Active substance250

Dried starch200

Magnesium stearate10

These ingredients are mixed and filled into hard gelatin capsules.

Example 82 '

The above procedure was repeated, but instead of starch, microcrystalline cellulose was used.

Example 83

Tablets are prepared using the following ingredients:

Qty. , (mg / tablet)

Active substance,

100

Magnesium stearate7

Resin "Amberlit XE 88" 5

The starch and the active ingredient are mixed together and sufficient water is added to obtain a uniform dispersion. The mixture is then wet-sieved and dried. After drying, the material is sieved again and then magnesium stearate and "Ambcrlit" resin are added. • Finally, the mixture is compressed into tablets.

Another tablet formulation is prepared using the following ingredients:

Amount (mg / tablet

Active substance - 250 Cellulose crystalline 400 Chemically purified oxide Silica 10 Stearic acid . 5. The ingredients are mixed and compressed to · tablets.

Example 85

An aerosol solution is prepared containing the following components:

Weight ·%

Active substance 0,25

Ethanol '29.75

Chlorodifluoromethane ·. 70 (Propellant 22)

The active ingredient is mixed with ethanol and added to Propellant 22. cooled to -30 ° C and transferred to the filling equipment. The required amount is then fed into stainless steel containers and diluted with a further metered amount of propellant. The cartridge is then provided with a valve unit.

Example 86

A suppository formulation containing 200 mg of compounds is prepared using the following ingredients:

Active Substance 200 mg

Polyethylene glycol 1-000 750 mg

Polyethylene glycol 4000 250 mg

The active ingredient is mixed in molten glycol bases and the mixture is then poured into suitable suppository forms to achieve a suitable weight of the active ingredient.

Example 87

An ointment of the following composition is prepared:

Active substance 1% by weight

Soft white paraffin up to 100%

The active ingredient is added to the molten paraffin and allowed to cool.

Example 88

Prepare cream for. topical use containing the following components: .....

19ВЗВ0

grams Active compound 0.5 Cetomacrogol 1000 2.8 eetostearyl alcohol 11.2 Liquid paraffin 8.0 Water to 100

The active ingredient is suspended in liquid paraffin. Eetostearyl alcohol was added and the mixture was heated to 70 ° C with stirring. Cetomacrogol 1000 is dissolved in 60 g of water and heated to 70 ° C. The two solutions are then mixed with stirring and stirring is continued until the temperature has dropped to room temperature. The cream is then adjusted to the desired weight with water and passed through a colloidal stainless steel mill with a gap between rotor and bulge of 38.1 x 10 -3 cm.

...

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of phenylpiperazine derivatives. of the general formula I, in which R ¹ is benzyl, chlorobenzyl, C ₆ alkyl or phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, C _C4 alkyl, C ₄ haloalkyl, amino, C ₂ _ ₄ alkanoylamino, hydroxy, C ₄ alkoxy, nitro, and C _1-4 alkylsulfonamido, R ² represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, C! _ ₄ alkyl, C ₄ haloalkyl, amino, C ₂ _ ₄ alkanoylamino, hydroxy, C ₄ alkoxy, nitro and C ₄ alkylsulfonamido, R 5 is hydrogen or C _1-4 alkyl, Q is a furan, thiophene, oxazole or thiazole moiety, m is 1 to 3 and n is 0 or 1, wherein when m is 2 and n is 0, R ¹ is methyl. If Q whose thiazol-5-yl group, and pharmaceutically acceptable salts thereof, wherein the compound of formula VII, _R l_Q_ _(C H _{2) m} - (CHR ³⁾ _n -L (VII) wherein L is halogen, methylsulfonyl or substituted benzenesulfonyl, R ¹ , R ³ , Q, m and n are as defined above, condensed with a compound of formula (VIII), Wherein R ² is as defined above, and the compound of formula (I) obtained is optionally converted into an acid addition salt by treatment with an acid. 2. The process according to item 1 for the preparation of phenylpiperazine derivatives of the general formula Ia, R-G1- (CH3 (CH3) in which R ^Ia represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, C _C4 alkyl, C ₄ haloalkyl, amino, C _2-4 alkanoylamino, hydroxy, C ₄ alkoxy, nitro and C ₄ alkylsulfonamido, R ² represents phenyl optionally substituted with one or two substituents selected from the group consisting of halogen, C _'4 alkyl, C ₄ haloalkyl, amino, C _2-4 alkanoylaminoskuplnu, hydroxy, C ₄ alkoxy, nitro and C ₄ alkylsulfonamido, and R ³ represents hydrogen or C ₄ alkyl, Q is a furan, thiophene, oxazole or thiazole moiety, m is 1 to 3 and n is 0 or 1, and when m is 2 and n is 0, R ^1a is methyl when Q is thiazol-5-yl and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (VIIa), R ^1a -Q- (CH 2) m - (CHR ³ ) n L (VI'Ia) wherein L represents a halogen atom, methylsulfonyl or substituted benzenesulfonyl,. R ^1a , R ³ , Q, m and n are as defined above, condensed with a compound of formula VIII, (IIIa) in which R ² is as defined above, and the compound of formula I obtained is optionally converted into an a-