CS244847B2 - Production method of new substituted phenylalkyl(piperazinyl or homopiprazil)-propylurea or thioureas - Google Patents

Description

The present invention relates to novel substituted phenylalkyl / piperazinyl or homopiperazinyl / propylureas and thioureas, to their non-toxic acid addition salts, to a process for the preparation of these compounds, to pharmaceutical compositions containing said compounds as active ingredients and to their use in the treatment of immunological, inflammatory and allergic diseases.

DE-OS No. 2,727,469 (1978) Chem. Abs., 90, 186989r (1979) discloses, inter alia, 3-substituted 1-phenylpiperazinylpropylureas which are useful as intermediates in the synthesis of 1-phenylpiperazinylpropyl-hexahydropyrimidinedione, which in turn are useful as serotonin antagonists and as thrombocyte aggregation inhibitors.

The present invention is a method for producing the novel phenylalkyl groups / piperazinyl or homopiperazinyl / propyl urea or thiourea of the formula I "2 ·" 3 "(CH _{2) n} -N J L _(CH2)

N- (CH ₂ ) _p -NHCNHR ₄ (1) wherein

R 1, R ₂ , R ₃ are each independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di / lower alkyl / amino, lower alkylthio or trihalomethyl,

R 6 represents a hydrogen atom, a C 1 -C 12 alkyl group, a C 3 -C 8 cycloalkyl group, an allyl group, a benzyl group, a phenol group or

2 · phenyl substituted with lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di / lower alkyl / aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfonyl , tetrazolyl, sulfamoyl, hydroxy or lower alkanoyl, n is 1, 2, 3 or 4, m is 0 or 1, nebo is 2, 3 or 4, and

X is oxygen or sulfur, and non-toxic, pharmacologically acceptable acid addition salts thereof.

The term lower alkyl (whether alone or in combination) means a straight or branched saturated hydrocarbon radical having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.

The term halogen refers to fluorine, chlorine, bromine and iodine. the term lower alkoxy denotes straight or branched saturated aliphatic ether radicals containing from 1 to 4 carbon atoms, for example methoxy, ethoxy, propoxy and butoxy.

The term lower alkanoyl refers to an acylated radical having 1 to 4 straight or branched saturated aliphatic carboxylic acids, such as formyl, acetyl or propionyl.

By lower alkanoyloxy is meant a lower alkanoyl radical having 1 to 4 carbon atoms attached to an oxygen function, such as acetoxy and propionyloxy. By lower alkoxycarbonyl is meant an esterified carboxyl group of the formula Rg-OCO, wherein R ₅ is a straight or branched (C 1 -C 4) alkyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl.

By lower alkoxyethoxycarbonyl is meant a radical of the formula R 8 -OCH 3 CH 3 OOC-, wherein R 8 is methyl or ethyl. By di / lower alkyl / aminoethyl is meant a radical of the formula (Ry) gNCHgCHg-, wherein Ry is methyl or ethyl.

The terms "lower alkylthio", "lower alkylsulfonyl" and "lower alkylsulfinyl" mean groups of the formula RgS-, RgSOg, respectively. R 8 SO-, wherein R 8 is a straight or branched (C 1 -C 4) alkyl group.

It will be understood that the radicals indicated in formula I by Rg, Rg and Rg may be the same or different. The residues represented by the symbols Rg, Rg and Rg can be attached in any possible position of the phenyl ring, but those compounds in which one of the radicals indicated with Rg, Rg or R ₂ is present in the para-position are preferred.

Also preferred are those compounds wherein R 8 represents a hydrogen atom, R 8 represents a residue other than hydrogen and R 8 represents a group other than hydrogen bonded to the para-position. Most preferred are those in which R8 and R8 are hydrogen atoms and R8 is other than hydrogen bonded to the para-position.

Among these most preferred compounds are those wherein R ₂ and R 8 are hydrogen atoms and R 8 is a chlorine atom, preferably attached at the para-position.

A substituted phenyl radical R @ 1 may contain one to five, preferably one to three, substituents selected from the above group. These substituents may occupy any possible position on the phenyl ring, with the exception of substitution by lower alkoxycarbonyl and / or carbonyl.

These substituents cannot be attached at the ortho position of the phenyl ring. The above-defined meanings have the above-mentioned expressions throughout the text.

It will be appreciated that in the formula (I) the number 0, the compounds of formula (1) are piperazine derivatives corresponding to the formula (Ia).

R 1 (CH ₂ ) _n -N * · - (CH ₂ ) _p -NH-C-NHR ₄ (1a)

in which

R ₂ , R ₂ , R 1, R ₄ , X, and n are as defined above.

When R a in the formula I is 1, the compounds of the formula X are homopiperazines corresponding to the formula Ib

Rj *

3 '

- - A (CH ₂ ) n -N »- (CH ₂ ) p-NH-α-I H ₄ (Ib) in which

R _2, 1 * 2 '* ^r 3 ^r 4' X 2 and '£ are as defined above.

Preferred are piperazine derivatives of formula Ia.

The present invention includes the following groups of compounds as described above and their non-toxic pharmaceutically acceptable salts:

(a) Compounds of formula (Ia) or (Ib) wherein

R ^, R ₂ and Rj are each independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di / lower alkyl / amino or trihalomethyl group,

R 4 is hydrogen, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, phenyl or phenyl substituted by lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, cyano or nitro, ^x n is a number of 1, 2, 3 or 4;

X is oxygen or sulfur.

(b) Compounds of formula (Ia) or (Ib) wherein

R ₂ represents chlorine.

244847 4

R ₂ and R ₃ represent hydrogen atoms,

R ₄ is hydrogen, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, allyl, phenyl or phenyl substituted by lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di / lower alkyl / aminoethoxycarbonyl, lower alkylaulfonyl, lower alkylaulfinyl, carbamyl, tetrazolyl, sulfamoyl, hydroxyl or lower alkanoyl, n is 1; hdonotu 3 a

X represents oxygen or sulfur.

c) Compounds of formula IIa or IIb (XXa)

R, <ch ₂ , "- Q - / ch ₂ / _p -nh-1-nhr ₄ (lib) in which

R @ 1 and R @ ₂ independently of one another are hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di / lower alkyl / amino, lower alkylthioacin or trihalogenomethyl group

R ₄ is hydrogen, C 1 -C 12 alkyl, allyl, C 3 -C 8 cycloalkyl, phenyl or phenyl substituted by lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di / lower alkyl / aminoethoxycarbonyl, lower alkylaulfonyl, lower alkylaulfinyl, carbamyl, tetrazolyl, sulfamoyl, hydroxyl or lower aanoyoyl, n is an integer of 1 2, 3 or 4, £ is a number of 2, 3, or 4 and

X is oxygen or sulfur.

(d) Compounds of formula XXa or IXb wherein

R @ 1 and R @ ₂ are each independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower aananoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di / lower alkyl / amino or trihalomethyl .

represents hydrogen, C1-C12alkyl, C3-C8cycloalkyl, phenyl or phenyl substituted by lower alkyl, halogen, lower, alkoxy, carboxyl, lower alkoxycarbonyl, cano or nitro, n is a number of 1, 2, 3 or 4;

X is oxygen or sulfur.

(e) Compounds of formula IIa or IIb, wherein

Rj is chlorine,

R ₂ represents hydrogen,

R ₄ is hydrogen, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, allyl, phenyl or phenyl Substituted by lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di / lower alkyl / aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, carbamoyl, tetrazolyl, sulfamoyl, hydroxyl or lower alkanoyl, n is 1; 3 a

X is oxygen or sulfur.

(f) Compounds of formula (IIa) or (XIb) wherein

R1 is chlorine,

R ₂ represents hydrogen,

R ₄ represents a phenyl group substituted with a lower alkyl group, a halogen, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group. cyano, nitro, lower alkanoyl, lower alkoxyethoxycarbonyl, di / lower alkyl / aminoethoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, carbamoyl, tetrazolyl, sulfamoyl, hydroxyl, or lower alkanoyl n is 1, 1 is 3 and

X is oxygen.

(g) Compounds of formula (IIa) or (IIb) wherein

R ₂ denotes hydrogen, R ₃ is chloro.

R ₄ represents a phenyl group substituted with a carboxyl group or a lower alkoxycarbonyl group, n has a value of 1, δ has a value of 3 and

X is oxygen.

Of the compounds described above, those in which X is oxygen are preferred. Preference is also given to those compounds in which n has a value of 1 and / or δ has a value of 3. If the symbol in the abovementioned compounds represents a lower alkyl group, the chain of this alkyl group preferably contains 1 to 6 carbon atoms.

In accordance with the invention, the compounds of formula (I) above are prepared by preparing a compound of formula (II)

ICH ₂ ) _m in which

R1, R2, R2, _n and m are as defined above, reacted with a compound of formula III

X

X - (CH ₂ ) _p - NHCTIH - R ₄ (111) wherein

R ₄ , R ₆ and X are as defined above and

Y represents a reactive amine-reactive substituent to form a carbon-nitrogen bond, for example halogen, activated ester residue, hydroxyl group, sulfuric acid ester residue, sulfonic acid ester residue and the like.

The reaction of the invention may be carried out in the presence or absence of a solvent.

For that purpose it is. aqueous or organic inert solvents may be used, depending on the nature of the reactants.

These solvents include hydrocarbon solvents, dioxane, tetrahydrofuran, dimethylsulfoxide, dlmethylformamide, ethoxyethanol and lower alkanols containing up to 5 carbon atoms, with or without addition of water. It is preferred, but not necessary, to carry out the reaction in the presence of an acid binding agent such as triethylamine. or an alkali metal carbonate.

The compounds of formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acids, in particular hydrochloric or hydrobromic acid, nitric acid, sulfuric acid, orthophosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

244647

The reaction of the invention may be carried out in the presence or absence of a solvent.

Depending on the nature of the reactants, aqueous or organic inert solvents may be used for this purpose.

Such solvents include hydrocarbon solvents, dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, ethoxyethanol, and lower alkanols containing up to 5 carbon atoms, with or without water.

It is preferred, but not necessary, to carry out the reaction in the presence of an acid binding agent such as triethylamine or an alkali metal carbonate.

The compounds of formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acids, in particular hydrochloric or hydrobromic acid, nitric acid, sulfuric acid, orthophosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid. acetic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

The starting materials for the process according to the invention are either known or can be prepared in a manner known per se.

Except for compounds in which a C 7 -C 12 alkyl group is present, the compounds of Formula I inhibit in vitro histamine-induced contraction of the isolated guinea pig ileum and are useful in warm-blooded animals to antagonize the effect of histamine on histamine H 1 -receptors.

Accordingly, the compounds of formula (I) may be used as natihistamines for the treatment of allergic diseases such as allergic rhinitis, vasomotor rhinitis, conjunctivitis allergic, hay fever, hives, urticaria and food allergies.

Certain compounds of Formula I do not induce central nervous system side effects, such as sedation, that normally occur in the treatment of antihistamines. In particular, 1- [3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl] -3- (4-carboxyphenyl) urea and 1- [3- [4- (4-chlorobenzyl) piprazine] have been found to be particularly useful. 1-yl-2-propyl [-3- (4-ethoxycarbonylphenyl) urea in standard mouse pharmacological tests does not show any significant central nervous system effects.

With the exception of those in which R1 is a phenyl group substituted by a carboxyl group, the compounds of formula I also inhibit in vitro histamine release from leukocytes / basophils / human peripheral blood and from IgE-mediated rat peritoneum mast cells and are useful for inhibiting warm-blooded animals antigen-induced release of histamine and / or other mediators of alleric reactions from cells.

The release of mediators in basophils and fat cells is believed to occur in numerous allergic and inflammatory diseases such as allergic asthma, allergic rhinitis, allergic conjunctivitis, hay fever, urticaria, food allergies, and the like.

For pharmaceutical purposes, the compounds of the invention are administered to warm-blooded animals locally, orally, parenterally, or via the airways as active ingredient in conventional pharmaceutical compositions, i.e. compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient. Oral and topical administration is preferred.

For oral administration, the compounds of the invention may be formulated as syrups, tablets, capsules, pills, and the like. Preferably, the compositions are in unit dosage forms or in a form that allows the patient to administer the unit dose.

Any pharmaceutical carrier suitable for the manufacture of solid compositions may be used in the preparation of a tablet, powder or lozenge.

Examples of such carriers include various starches, lactose, glucose, saeharose, calcium dihydrogen phosphate and chalk. The compositions described may also be in the form of capsules (e.g. gelatin) containing the desired active ingredient in the form of syrups, liquid solutions or suspensions.

Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerin, aqueous sodium chloride solution, water, propylene glycol, and sorbitol solution. These carriers, together with flavoring and coloring agents, may be used to prepare syrups.

The compounds of the invention may also be administered by a non-oral route and, in accordance with standard pharmaceutical practice, appropriate formulations may be prepared, for example for rectal suppository administration, or injectable preparations in aqueous or non-aqueous solutions, suspensions or emulsions in pharmaceutically acceptable form. an acceptable liquid, such as sterile pyrogen-free water or a parenterally acceptable oil or mixture of liquids, which liquids may contain bacteriostatic agents, antioxidants, preservatives, buffers or other soluble substances to render the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives.

These compositions are made in unit dosage forms, such as ampoules or emergency injectable preparations, or in multi-dose containers, such as vials from which the respective dose can always be taken, or in the form of a solid preparation or concentrate which can be used to preparing an injectable preparation.

The compounds of the invention may also be suitably formulated for airway administration, for example as aerosols or solutions for application as a mist, or as a microfine powder, for inhalation, wherein the active ingredient may be contained alone or in combination with an inert carrier such as lactose.

In such a case the particles of active compounds suitably have diameters of less than 20 _(microns, preferably less than 10 / um. If desired, such preparations may contain small amounts of other antiallergics, anti-asthmatic and bronchodilators for example sympathomimetic active amines such as isoprenaline, isoetharin, metaproterenol, salbutamol, phenylephrine, phenoterol and ephedrine, xanthine derivatives such as theophylline and aminophylline, and corticosteroids such as prednisolone and adrenal stimulants such as adreno-corticotropic hormone (ACTH).

The compounds of the invention may also be present in ointments, creams, lotions, gels, aerosols and solutions for topical application to the skin, nose or eye. In addition to these dosage forms, skin coatings can also be prepared for application to the skin.

Solutions for topical application to the nose and eye may contain, in addition to the compounds of the invention, suitable buffers, tonicity agents, microbial preservatives, antioxidants and viscosity enhancers in aqueous media.

Examples of such viscosity enhancers include polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin. The microbial preservatives used may include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol.

Compositions for topical application to the eye may also be in the form of ointments, wherein the active ingredient is contained in a suitable inert mask base consisting of mineral oil, natural vaseline, polyethylene glycols or lanolin derivatives, together with antimicrobial agents.

In all aysteraic compositions, a suitable unit dose of active ingredient may be from 1 to 500 mg, with a unit dose of from 1 to 200 mg being preferred. The effective dose of a compound of the invention will depend upon the particular compound, the nature of the disease being treated and its extent, the condition of the patient, and the frequency and mode of administration.

Generally, the systemic dose for a patient weighing about 70-80 kg ranges from about 1 to 200 mg / day. A daily dose in the range of 1 to 100 mg is preferred.

For topical application, compositions containing from 0.001 to 1.0% active ingredient, preferably 0.01 to 0.1% active ingredient, are preferably used.

For the preparation of pharmaceutical compositions, the compounds of the formula I are conventionally mixed with the appropriate pharmaceutical carriers, flavoring agents and coloring agents and processed, for example, into tablets or capsules or suspended or dissolved in water or oil, for example corn, with the addition of appropriate excipients. oils.

The compounds of the invention may be administered orally or parenterally in liquid or solid form. Water which contains stabilizing agents, solubilizing agents and / or buffers commonly used in the preparation of injectable solutions is preferably used as the injectable medium.

Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, more complex compounds of the above (e.g., ethylenediaminetetraacetic acid), antioxidants (such as sodium sulfite, sodium pyrosulfite or ascorboylic acid), high molecular weight polymers liquid polyethylene oxides / to adjust viscosity, and polyethylene derivatives of sorbitol anhydrides.

If necessary, preservatives such as benzoic acid, methyl or propylparaben, benzalkonium chloride and other quaternary ammonium compounds can also be added.

Useful solid carriers include, for example, starch, lactose, mannitol, methylcellulose, microcrystalline cellulose, talc, silica, dicalcium phosphate, and high molecular weight polymers (such as polyethylene glycol).

Compositions intended for oral administration may optionally contain flavoring and / or sweetening agents. For topical application, the compounds of the invention may also be used in the form of powders or ointments. For this purpose, the compounds are mixed, for example, with powdered, physiologically compatible diluents or conventional ointment bases.

The invention is illustrated by the following non-limiting examples.

Example 1

1- [3- [4- [4- (4-Chloro-phenyl) -propyl} -piperazin-1-yl] -propyl] -3-n-hexylurea dihydro chloride and (K) 39 g (0.3 mol) chloropropylamine hydrochloride, 38.2 g (0.3 mol) of n-hexyl isocyanate and 500 ml of methylene chloride are slowly added with 35 g (35 mmol) of triethylamine. The resulting solution was stirred for 1 hour, then the solvent was evaporated in vacuo.

The residue was stirred with ether and the colorless solid product was filtered off. The ethereal solution was washed with water, dried (MgSO4) and concentrated. 57.0 g (yield 86%) of pure 1- (3-chloropropyl) -3-n-hexylurea are obtained in the form of colorless crystals of m.p. 48-50 ° C.

b) A mixture of 2.21 g (10 mmol) of 1- (3-chloropropyl) -3-n-hexylurea, 2.39 g (10 mmol) of 1- [3- (4244847)].

-chlorophenyl / propyl-piperazine, 1.01 g (10 mmol) of triethylamine and 25 ml of alcohol are heated at reflux for 1 hour. The cooled reaction mixture was diluted with ether, washed with water, dried over sodium sulfate, and concentrated in vacuo. The yellow, viscous oily residue was purified by silica gel column chromatography using a mixture of: methylene chloride and methanol / 93; 7) as eluent.

After precipitation with ethereal hydrochloric acid, 1.6 g (yield 38%) of the title compound is obtained in the form of colorless crystals, m.p. 213 DEG-216 DEG.

Example 2

1- [3- [4- [4- (4-Chloro-phenyl) -propyl] -piperazin-1-yl] -propyl] -3- (4-cyanophenyl) -urea dihydrochloride monohydrate and (K) mixture 17.8 g (137 mmol) 3 -chloropropylamine hydrochloride, 19.7 g (137 mmol) of 4-cyanophenyl isocyanate and 200 ml of methylene chloride are slowly added 13.8 g (137 mmol) of triethylamine. The resulting solution was stirred until a slightly exothermic reaction subsided and the solvent was evaporated. under vacuum.

The product was dissolved in ether, the solution was washed with water and after drying some of the ether was evaporated. The precipitated colorless crystals were filtered off and dried. 17.5 g (yield 54%) of 1- (3-chloropropyl) -3- (4-cyanophenyl) urea are obtained. Recrystallization of a small sample of the product from aqueous acetone gave a pure product melting at 95-97 ° C.

b) A mixture of 3.57 g (15 mmol) of 1- (3-chloropropyl) -3- (4-cyanophenyl) -root, 3.58 g (15 mmol)

1- 3- (4-chlorophenyl) propyl piprazine, 1.52 g (13 mmol) of triethylamine and 100 ml of ethanol were heated under reflux for 35 hours.

The solvent was evaporated in vacuo, water was added to the residue and the product was extracted with ether. The extract was dried and concentrated in vacuo. The resulting reddish-yellow oil was purified by silica gel column chromatography using a 9: 1 mixture of methylene chloride and methanol as eluent.

The title compound is obtained in 2.8 g (42%) of the free base which is dissolved in ether and the title compound precipitates with ethereal hydrochloric acid, which, after recrystallization from water, results in colorless crystals, m.p. 219-221. Deň: 32 ° C.

Example 3

1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (4-carbamoylphenyl) urea dihydrochloride

A solution of 10.0 g (19.9 mmol) of 1- (3 - [[- (4-chlorobenzyl) piperazin-1-yl] propyl] -3- (4-cyanophenyl) urea dihydrochloride monohydrate, 120 mL glacial acetic acid and 80 mL of concentrated hydrochloric acid was heated to 80 ° C for 30 minutes.

The reaction mixture was poured onto ice, basified with aqueous potassium hydroxide solution, and the product was extracted with methylene chloride. The extract was dried over sodium sulfate and the desired salt precipitated with ethereal hydrochloric acid. Recrystallization from ethanol several times afforded 3.54 g (38% yield) of the title compound as colorless crystals, m.p. 224-226 ° C.

Example 4

1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (4-tert-butylphenyl) urea dihydrochloride

To a solution of 2.98 g (20 mmol) of 4-tert-butylaniline in 25 mL of ether was added a solution of 4.22 g (20 mmol) of 3-iodopropylpropyl isocyanate in 25 mL of ether, and the resulting solution was heated at reflux for 3 h.

After evaporation of the solvent, 4-chlorobenzylpiperazine (4.18 g, 20 mmol) and ethanol (50 ml) were added to the residue, and the resulting solution was heated to reflux for 24 hours. Aqueous sodium bicarbonate solution was added to the mixture, and the product was extracted with methylene chloride.

The extract was dried over sodium sulfate and the desired salt precipitated with ethereal hydrochloric acid. Recrystallization from ethanol several times afforded 3.73 g (33% yield) of the title compound as colorless crystals of m.p. 240 DEG-241 DEG.

Example 5

1- (3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3- (4-carboxyphenyl) urea hydrochloride

A solution of 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl-3-propyl) -3- (4-ethoxycarbonylphenyl) urea hydrochloride (2.59 g, 5.6 mmol) in methanol (75 mL) was heated to reflux for 8 h. with 10 ml of 1 N aqueous sodium hydroxide.

The reaction mixture was concentrated in vacuo, the residue was dissolved in water, filtered and acidified with hydrochloric acid. The precipitated solid product was collected and washed with methanol. 1.92 g (yield 80%) of the title compound are obtained in the form of colorless crystals, m.p. 244-246 ° C.

Example 6

The following compounds can also be prepared in an analogous manner to the previous examples:

A. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (3-carboxyphenyl) urea dihydrochloride,

B. 1- [3- (4- (4-Chlorobenzyl) piperazin-1-yl} propyl) -3- (3-ethoxycarbonylphenyl) urea dihydrochloride, m.p. 240 DEG-243 DEG C.,

C. 1- (3- [1-] 4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3- (3-carbamoylphenyl) urea dihydrochloride,

D. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (3-hydroxy-4-carbamoylphenyl) urea dihydrochloride,

E. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (3-hydroxy-4-ethoxycarbonylphenyl) urea dihydrochloride, m.p. 245-247 ° C,

F. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (3-hydroxy-4-carboxyphenyl) urea dihydrochloride,

G. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (3-methoxy-3-ethoxycarbonylphenyl) urea dihydrochloride,

H. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (3-methoxy-4-carboxyphenyl) urea dihydrochloride,

X. dihydrochloride l- / 3- [4- / 4-chlorobenzyl / _pipe> pyrazin-l-yl propyl / 3-carboxy-4-hydroxyphenyl / urea

J. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (3-ethoxycarbonyl-4-hydroxyphenyl) urea dihydrochloride,

K. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (3-carboxy-4-methoxyphenyl) urea dihydrochloride,

L. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (3-ethoxycarbonyl-4-methoxyphenyl) urea dihydrochloride,

M. 1- (3- [4- (4-Cyano-benzyl) -piperazin-1-yl] -propyl) -3- (4-cyanophenyl) -urea dihydrochloride monohydrate, m.p. 220-223 ° C,

N. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (4-sulfamoylphenyl) urea dihydrochloride, m.p. 245 DEG-246 DEG C.,

O. 1- (3- [4- (4-Cyanobenzyl) piperazin-1-yl] propyl) -3- (4-ethoxycarbonylphenyl) urea dihydrochloride, m.p. 241 DEG-245 DEG C.,

P. 1- (3- [4- (4-Methoxybenzyl) piperazin-1-yl] propyl) -3- (4-ethoxycarbonylphenyl) urea dihydrochloride, m.p. 215 DEG-218 DEG C.,

R. 1- [3- [4- (4-Methylthiobenzyl) piperazin-1-yl] propyl] -3- (4-ethoxycarbonylphenyl) urea monohydrate, m.p. 200 DEG-222 DEG C.,

S. 1- [3- [4- (4-Methylbenzyl) piperazin-1-yl] propyl] -3- (4-ethoxycarbonylphenyl) urea monohydrate, m.p. 226-229 ° C,

1- (3- [4- (4-Trifluoromethylbenzyl) piperazin-1-yl] propyl) -3- (4-ethoxycarbonylphenyl) urea dihydrochloride, m.p. 240 DEG-243 DEG C.

U. 1- [3- [4- (4-Ethoxycarbonylbenzyl) piperazin-1-yl] propyl] -3- (4-ethoxycarbonylphenyl) urea monohydrate, m.p. 235-237 ° C,

V. 1- [2- [tert- [4-Chlorobenzyl] pinerazin-1-yl] ethyl] -3- (4-cyanophenyl) urea dihydrochloride, m.p. 217-219 ° C,

X. 1- (4-Q1- (4-chlorobenzyl) piperazin-1-yl) butyl] -3- (4-ethoxycarbonylphenyl) urea hemihydrate, m.p. 227-228 ° C,

Y. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3-cyclohexylurea dihydrochloride, m.p. 184 DEG-187 DEG C.,

Z. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3-methylurea dihydrochloride, m.p. 193-207 ° C,

AA. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3-n-butylurea hemihydrate, m.p. 222-223 ° C,

AB. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3-n-hexylurea dihydrochloride, m.p. 214 DEG-215 DEG C.,

AC. 1- (3-Q4- (4-chlorobenzyl) piperazin-1-yl) propyl] -3-n-octylurea dihydrochloride, m.p. 229-230 ° C;

AD. 1- [3- [[(4-Fluorobenzyl) piperazin-1-yl] propyl] -3-cyclohexylurea monohydrate, m.p. 203 DEG-206 DEG C.,

AE. 1- [3- (4-Benzylpiperazin-1-yl) propyl] -3-cyclohexylurea dihydrochloride, m.p. 202-213 ° C,

AF. 1- [3- (4-Benzylpiperazin-1-yl) propyl] -3-phenylurea, m.p. 45 DEG-47 DEG C.

AG. 1- (3-Q4- (4-chlorobenzyl) piperazin-1-yl) propyl] -3-phenyl urea, m.p. 135-137 ° C;

AH. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl-3- (4-chlorophenyl) urea hydrochloride, m.p. 241 [deg.] C,

AI. 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl} propyl) -3- (4-methylphenyl) urea dihydrochloride monohydrate, m.p. 131-132 ° C,

AJ. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] nropyl) -3- (4-methoxyphenyl) urea hydrochloride, m.p. 237-238 ° C;

AK. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (4-ethoxycarbonylphenyl) urea hydrochloride, m.p. 233 DEG-234 DEG C.,

AL. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (4-fluorophenyl) urea dihydrochloride monohydrate, m.p. 225-228 ° C,

AM. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (4-nitrophenyl) urea dihydrochloride, m.p. 230-231 ° C. ·

AN. 1- (3- [4- (4-Chlorobenzyl) homopiperazin-1-yl] propyl) -3-cyclohexylurea dihydrochloride, m.p. 167-175 ° C,

AO. 1- [3- [4- (4-Chlorobenzyl) homopiperazin-1-yl] propyl] -3-phenylurea dihydrochloride, m.p. 125-135 ° C,

AP. 1- [3- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3-cyclohexylthionurea, m.p. 127 DEG-128 DEG C .;

AR. 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3-phenylthiourea, m.p. 155-156 ° C;

AS. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl) propyl] -3-n-hexylthiourea dihydrochloride hemihydrate, m.p. 182-186 ° C,

AT. 1- (3-Q4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3-benzylurea dihydrochloride, m.p. 203-206 ° C,

AU. 1- (3- [4- (4-chlorophenethyl) piperazin-1-yl) propyl] -3-n-hexylurea dihydrochloride, m.p. 230-233 ° C,

AV. 1- (3-Q4- (4-chlorobenzyl) piperazin-1-yl} propyl) -3- (4-cyanophenyl) urea dihydrochloride monohydrate, m.p. 236-238 ° C,

AX. 1- [3- [4- [p-trifluoromethyl-4-chlorobenzyl] piperazin-1-yl] propyl] -3-n-hexylurea dihydrochloride, m.p. 216-219 ° C,

ΑΪ. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl) propyl] -3-allylurea dihydrochloride, m.p. 232 DEG-234 DEG C.,

AZ. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (4-acetylphenyl) urea dihydrochloride m.p.

BA. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- (4-ethoxyphenyl) urea dihydrochloride, m.p. 225 DEG-227 DEG C.,

BB. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl) -3- [4- (methylthio) phenyl] urea dihydrochloride monohydrate, m.p. 212 DEG-214 DEG C.,

BC. 1- (3- [4- (4-Chloro-benzyl) -piperazin-1-yl) -propyl] -3- (2-chloro-phenyl) -urea dihydrochloride monohydrate, m.p. 222 DEG-224 DEG C.,

BD. 1- (3- [4- (4-Chlorobenzyl) piperazin-1-yl) propyl] -3- (2,6-dichlorophenyl) urea dihydrochloride, m.p. 246 DEG-248 DEG C .;

BE. 1- [3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl] -3- (n-dodecyl) urea dihydrochloride, m.p. 215 DEG-222 DEG.

Example 7

The in vitro inhibitory activity of the compounds of formula I on the release of histamine from human leukocytes (basophils) and from rat peritoneum living cells can be demonstrated by the following hiochemical tests:

A. Determination of in vitro histamine release from human leukocytes (basophils)

1. Leukocyte separation

The modified method described by L. Lichtenstein and A. Osler, J. Exp.

Media 120, 507 (1964). 80 to 100 ml of human blood with heparin added are mixed in polypropylene centrifuge tubes with 20 ml of a 0.2% saline solution containing 0.6 g dextrose and 1.2 g dextran.

The mixture was allowed to stand at room temperature for 60 to 90 minutes to separate the erythrocytes from the supernatant enriched in platelets and leukocytes. The supernatant was collected and centrifuged cold at 110 g for 8 minutes.

The leukocyte pellet obtained by centrifugation is washed twice with tris-buffer and then suspended in a concentration of 1-2 χ 10 ⁶ cells / ml in 150 to 180 ml of tris-ACM buffer.

2. Reaction mixture

The reaction was carried out in plastic tubes (12x75 mm) in a total volume of 1.25 ml. The reaction medium consists of 0.05 ml of rabbit anti-human IgE (antigen), 0.2 ml of a 10-1000 µM solution of the test substance in water and 1.0 ml of the leukocyte suspension.

The reaction mixture was incubated in a 37 ° C water bath with shaking for 60 minutes. After completion of the reaction, the tubes are placed in a centrifuge, centrifuged and the supernatants collected. Protein is removed from the supernatants by precipitation of 0.2 ml of 8% perchloric acid.

3. Histamine test

Histamine release is measured using the automated fluorometric method described by W. Slraganian and W. Hook in Chapter 102 of the Manual of Clinical Immunology, Second Edition, Ed. Rose and H. Friedman, American Society for Microbiology Washington, D. C. 1980.

The percentage inhibition is calculated using the following formula:

/ control - blank _ / test - blank, ........ experiment / .............. sample ....... experiment / —- X 100 / control - blank

Concentrations causing 50% inhibition of histamine release are determined by interpolating a graph of inhibition in percent versus the log of the test compound concentration.

B. Determination of Inhibition of Histamine Release from Rat Peritoneum Mast Cells

1. Obtaining peritoneal mast cells

Rats are sacrificed with ether and injected into their peritoneum with 20 ml MEH (Minimum Essential Meiduro) containing 20 units / ml heparin. Abdomen is kneaded for 1 minute and the effluent is collected. Peritoneal cells are obtained by cold centrifugation for 8 minutes at 1800 rpm. After washing twice with Tris-A buffer, the cells are suspended in 2-4 x 10 6 cells / ml in Tris-ACM buffer.

2. Reaction mixture

The reaction was carried out in plastic tubes (12x75 mm) in a total volume of 1.25 ml. The reaction mixture consists of 0.5 ml (10 to 1000 µg) of sheep anti-rat IgE or ovalbumin,

0.2 ml of a 10-1000 µM solution of the test substance in water, 0.5 ml of a phosphatidylserine solution (20 to 10 µg per tube) and 0.5 ml of cell suspension.

The reaction mixture was incubated in a 37 ° C water bath with shaking for 60 minutes. After completion of the reaction, the tubes are placed in a centrifuge, centrifuged and the supernatants collected. Precipitate 0.2 ml of 8% perchloric acid to remove protein from the supernatants.

3. Histamine test

Histamine release is measured using an automated fluorometric method (cited above).

The concentration causing 50% inhibition of histamine release (IC ₅₀ ) is determined in the same manner as in paragraph A.

The results of tests for the efficacy of compounds of formula I in inhibiting histamine release from human leukocytes (basophils) according to procedure A above are shown in Table A below:

Table A test substance inhibition (example number) ^IC50

6Y

6Z

6AA

6AB> 1,000 50

300 *

244847 / Table A continued

test substance / example number / inhibition of xc ₅₀ ΙρΆΙ 6AC 16 6 AD 50 6AE 240 6AF 400 ,. 6AG 78 6AH 30 6AI 37 6AJ 80 6AK 190 6AL ^{20 May} 6AM 30 6AN 13 6A0 15 Dec 6AP 26 6 AR 37 6 AS int ^x / 6AT 112 6AU 16 6AV 81 6AX int ^{x /} 6AY 120 6AZ 115 6BA 35 Legend:

^{X //} int with Interference a. Test procedure

The results of tests for the efficacy of the compounds of formula I in inhibiting the release of histamine from rat peritoneum mast cells according to procedure B above are shown in Table Bi.

Table B test substance (example number)

6Y

6AB

6AC. 6AG 6AV

Example 8 Inhibition of IC ₅₀ µM

108

110

210> 1 OOO 150

The activity of the compounds of formula I in antagonizing the effects of histamine on contraction of the isolated guinea pig ileum can be determined by the method of G. Possanza, A. Bauen and P. Stewart, Int. Sheet. Allergy Appl. Immunol., 49, 289 (1975).

The degree of inhibition is determined as the difference between the contraction caused by histamine alone (final concentration 0.2 µg / ml) and the contraction that occurs in the presence of both histamine and the test compound.

Efficacy inhibitory action of the test substance is expressed as the concentration of compound causing 50 »suppressing contraction / IC ₅₀ /.

In the above test, the results in Table C were obtained for each compound of Formula I:

Table C test substance example number /

SY

6Z

6AA

6AB

6AC

SAD

6AE

6AP

6AG

6AH

6AX

SAJ

6AK

6AL

6AM

6AN

SAO

6AP

6AR

SAS

6AT

6AU

6AV

6AX

6AY

6AZ

6BA

Example 9

Tablets of ^IC 50 inhibition

0.13

0.11

0.21

0.015

0.63

0.07

0.05

0.75

0.11

0.32

0.21

0.05

0.15

0,065

0.015

0.11

0.06

0.018

0.15

0.55

0.11

0.10

0.08

0.23

0.02

0.008

0.09

0.17

0.02

Ingredients:

ingredient 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl) propyl] -3- (4-carboxyphenyl) urea hydrochloride stearic acid dextrose amount

0.010 parts 0.010 parts 1.890 parts total 1.910 parts

Preparation:

The individual components are mixed in a conventional manner and compressed into tablets of 1.91 g each, each representing a unit dose for oral administration containing 10 mg of active ingredient.

Example 10

Ointment

Ingredients:

Ingredient amount 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3- / 4-

-methoxyphenyl / urea 2,000 part fuming hydrochloric acid 0.011 part sodium pyrosulfite 0.050 part a mixture of equal parts of cetyl alcohol and stearyl alcohol 20,000 part white vaseline 5,000`Share synthetic bergamot oil 0,075 part distilled water make up to 100,000 parts

Preparation:

. The above ingredients are suitably mixed to homogeneity to form an ointment containing 100 g of the active ingredient.

Example 11

Inhalation aerosol

Ingredients:

component 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl) propyl] -3-n-hexylurea dihydrochloride soy lecithin propellant / Freon 11, and 14)

1.00 parts 0.20 parts

100,00 part

Preparation:

The aforementioned components are mixed in a conventional manner and the aerosol canisters are dispensed with a dispensing valve which releases 0.5-2.0 mg of active ingredient per actuation.

Example 12

Ingredients:

Ingredient amount 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl) hydrochloride

-3- (4-carboxyphenyl) ureas 5.0 part sodium pyrosulfite 1.0 part ethylenediamine-sodium tetraacetic acids 0.5 part sodium chloride 8.5 parts redistilled water to make up 1 000.0 parts

*:

Preparation:

Dissolve the components in a sufficient amount of redistilled water, dilute the solution to the above concentration with additional redistilled water, filter the particles to remove the particles, and fill the filtrate under aseptic conditions with a 1 ml vial which is then sterilized and sealed. Each ampoule contains 5 mg of active substance.

Example 13

Topical solution (eye or nasal)

Ingredients:

Ingredient amount 1- [3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl] hydrochloride

-3- (4-cyanophenyl) ureas 0.020 part sodium monohydrogen phosphate 0,758 part sodium dihydrogen phosphate 0.184 part sodium chloride 0.365 aílu polyvinyl alcohol 3,500 part henzalkonium chloride 0.10 parts distilled water make up to 100,000 part

Preparation:

The above components are dissolved in an ordinary manner into an aqueous solution which is filtered, with the solution for ophthalmic application requiring sterile filtration. Each milliliter of the resulting solution contains 0.2 mg of active ingredient.

In Examples 9 to 13, the corresponding active ingredient can in each case be replaced by any of the compounds of formula (X) or its salts. Similarly, the amounts of active ingredients given in these illustrative examples may be varied to provide a unit dose within the above range.

The quantity and nature of inert pharmaceutical carriers and excipients may also be varied to meet specific requirements.

The process of the invention has been illustrated by several specific embodiments, but it will be understood that the invention is by no means limited to these embodiments, but that various changes and modifications may be made thereto which do not depart from the spirit and scope of the invention.

Claims (2)

Process for the preparation of novel substituted phenylalkyl / piperazinyl or homopiperazinyl / propylureas or thioureas of the general formula I - N N- (CH ₂ ) _p X -NH 2 N 1 HR, (1) in which R 1 ₍ r ₂ and R ₃ independently of one another are hydrogen, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkanoyl C 4 -C 4 alkanoyl, halogen, nitro, cyano, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 dialkylamino, C 1 -C 4 alkylthio carbon atoms or trihalomethyl group, R ₄ represents a hydrogen atom, a C 1 -C 12 alkyl group, a C 3 -C 8 cycloalkyl group, an allyl group, a benzyl group, a phenyl group or a phenyl group substituted with one to three of the same or different substituents selected from alkyl; C 1 -C 4 -halogen, halogen atoms, C 1 -C 4 -alkoxy, carboxyl, C 1 -C 4 -alkoxycarbonyl, alkoxyethoxycarbonyl, wherein the alkoxy part is methoxy or ethoxy, cyano, alkyl, nitro C1-C4 carbon atoms, C1-C4 dialkylaminoethoxycarbonyl in each alkyl moiety, C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, carbamoyl, tetrazolyl, sulfamoyl, hydroxy and alkanoyl 1-4 carbon atoms ku, n is a number of 1, 2, 3 or 4, m is a number of 0 or 1, is a number of 2, 3 or 4, and X represents oxygen or sulfur »netoxiokých and their pharmacologically acceptable acid addition salts, characterized in that a compound of the formula II ^{R 2} '] £ K ^<CH 2) n ^{N <X4H} J / HZ (CH ₂ ) _m in which R ₃ , R ₂ , R ₃ , _n and m are as defined above, reacted with a compound of formula III X Y - / CH ₂ / p - nhAsh - _R4 / 111 / in which R ₄ , R ₆ and X are as defined above and Y represents a reactive substituent with an amine to form a carbon-nitrogen bond, for example halogen, activated ester residue, hydroxyl group, sulfuric acid ester residue, sulfonic acid ester residue, and optionally converted to its non-toxic, pharmacologically acceptable acid addition salt . 2. The process according to claim 1, wherein the corresponding starting materials are used. to form the compounds of formula (I) above wherein: R 8, R 8 and R 8 are each independently hydrogen, C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkanoyl, a halogen atom, a nitro group, a cyano group, a (C 1 -C 4) alkoxycarbonyl group, a (C 1 -C 4) dialkylamino group in each alkyl part, or a trihalomethyl group, R ₄ represents a hydrogen atom, a C 1 -C 12 alkyl group, a C 3 -C 8 cycloalkyl group or a phenyl group optionally substituted by one to three identical or different substituents selected from the group consisting of C 1 -C 4 alkyl groups, halogen atoms , (C1-C4) alkoxy, carboxyl, (C1-C4) alkoxycarbonyl, cyano and nitro, n is 1, 2, 3 or 4, m is 0 or 1, 2. is a number of 3 a X is oxygen or sulfur, and non-toxic, pharmacologically acceptable acid addition salts thereof.