KR890000174B1 - Substituted phenylalkyl(homo-piperazinyl,propyl-(ureas or thioureas)and process for preparing thereof - Google Patents

Abstract

Title compd. of formula (I) and its acid addn. salt, useful as antihistamines and inhibitors of mediator release are prepd. In (I), R1, R2 and R3 are each H, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di (lower alkyl) amino, lower alkylthio or trihalomethyl; R4 is H, C1-12 alkyl, C3-8 cycloalkyl, allyl, phenyl or substd. phenyl; n is 1,2,3 or 4; m is 1; P is 2, 3 or 4; X is O or S.

Description

Substituted phenyl alkyl (homopiperazinyl) propyl- (urea or thiourea) and processes for their preparation.

The present invention relates to novel substituted phenylalkyl (homopiperazinyl) propyl- (urea and thiourea) of formula (I) and pharmaceutically acceptable acid addition salts thereof and methods for preparing the same, and agents containing them as active ingredients. The pharmaceutical compositions and methods of using them in the treatment of immune diseases, inflammations and allergic diseases.

Wherein R ₁ , R ₂ and R ₃ are each independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alcoholcarbonyl, di (lower) Alkyl) amino, lower alkylthio or trihalomethyl, R ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl, or hydroxyl, lower alkyl, halogen, lower alkoxy, Lower alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy ethoxycarbonyl, cyano, nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsuponyl, lower alkylsulfinyl, carbamyl Phenyl substituted by tetrazolyl, or sulfamoyl, n is 1, 2, 3 or 4, m is 1, p is 2, 3 or 4 and x is oxygen or sulfur.

JP 2,727,469 (1978) (Chem-AbS., 90,186989r (1979)) is useful as an intermediate in the synthesis of 1-phenyl-piperazinylpropyl hexahydropyrimidine-dione, serotonin 3-Substituted-1-phenylpiperazinylpropyl-ureas are described which are useful as antagonists and platelet aggregation inhibitors.

As used herein, "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tertiary butyl. "Halogen" refers to fluorine, chlorine, bromine and iodine, and "lower alkoxy" refers to a straight or branched chain saturated aliphatic ether group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy. . "Lower alkanoyl" refers to an acyl moiety derived from a straight or branched chain saturated aliphatic carboxylic acid having 1 to 4 carbon atoms, for example formyl, acetyl or propionyl. "Lower alkanoyloxy" means lower alkanoyl residues having 1 to 4 carbon atoms, such as acetoxy and propionyloxy, bonded to an oxygen functional group. "Lower alkoxycarbonyl" is an esterified carboxy group, such as methoxycarbonyl, ethoxy, of the general formula R ₅ -OCO-, wherein R ₅ is a straight or branched chain alkyl group having 1 to 4 carbon atoms Carbonyl, propoxycarbonyl, butoxycarbonyl. "Lower alkoxyethoxycarbonyl" means a group of the general formula R ₅ -OCH ₂ CH ₂ OCO-, wherein R ₅ is methyl or ethyl. "Di (lower alkyl) aminoethyl" refers to a group of the general formula (R ₇ ) ₂ NCH ₂ CH ₂ -wherein R ₇ is methyl or ethyl. "Lower alkylthio" and "lower alkylsulfinyl" represent groups of the general formula R ₈ S-, R ₈ SO-, wherein R ₈ is a straight or branched alkyl group having 1 to 4 carbon atoms, respectively.

Those skilled in the art will understand that the groups represented by R ₁ , R ₂ and R ₃ in formula (I) may be the same or different from one another. The groups represented by R ₁ , R ₂ and R ₃ may be substituted at the effective positions of the phenyl ring. However, preference is given to compounds in which one of the groups represented by R ₁ , R ₂ and R ₃ is in the para-position. Also preferred are compounds in which R ₂ is hydrogen, R ₃ is not hydrogen, and R ₁ is not hydrogen substituted at the para position. More preferred are compounds in which R ₂ and R ₃ are each hydrogen and R ₁ is not hydrogen substituted at the para position. Most preferred are compounds wherein R ₂ and R ₃ are hydrogen, R ₁ is chlorine and is preferably substituted in the para position. When R ₄ is substituted phenyl in the general formula (I), the phenyl ring may include one or two substituents at the possible positions of the phenyl ring. However, except that R ₄ is phenyl substituted with lower alkoxycarbonyl or carboxyl, the substituent cannot be located at the ortho position of the phenyl ring.

If m is 0 in Formula (I), those skilled in the art will know that the compound of Formula (I) is piperazine of Formula (Ia).

Wherein R ₁ , R ₂ , R ₃ , R ₄ , x, n and p are as defined above.

When m is 1 in general formula (I), the compound of general formula (I) is homopiperazine of the following general formula (Ib).

Wherein R ₁ , R ₂ , R ₃ , R ₄ , x, n and p are as defined above. Piperazine compounds of formula (Ia) are preferred.

In a similar aspect, the present invention encompasses the following classes of compounds or their pharmaceutically acceptable salts: (a) R ₁ , R ₂ and R ₃ are independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alka Noyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di (lower alkyl) amino or trihalomethyl, R ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cyclo of 3 to 8 carbon atoms Phenyl substituted by alkyl, phenyl or lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, cyano or nitro, n is 1, 2, 3 or 4, p is 3 and x is oxygen or sulfur A compound of formula (Ia) or formula (Ib); (b) R ₁ is chlorine, R ₂ and R ₃ are each hydrogen, R ₄ is hydrogen, alkyl having 1 to 12 carbons, cycloalkyl having 3 to 8 carbons, allyl, phenyl or hydroxyl, lower alkyl, halogen , Lower alkoxy, carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulphyl A compound of formula (Ia) or formula (Ib) wherein phenyl is substituted by niyl, carbamyl, tetrazolyl or sulfamoyl, n is 1, p is 3 and x is oxygen or sulfur; (c) a compound of the following general formula (Ia ') or general formula (Ib'),

Wherein R ₁ and R ₂ 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 ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl or hydroxyl, lower alkyl, halogen, lower alkoxy, lower alkanoyl, Carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, carbamyl, tetrazolyl, Or phenyl substituted with sulfamoyl, n is 1, 2, 3 or 4, p is 2, 3 or 4 and x is oxygen or sulfur; (d) R ₁ and R ₂ are each independently hydrogen, lower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, lower alkanoyl, halogen, nitro, cyano, lower alkoxycarbonyl, di (lower alkyl) amino Or trihalomethyl, R ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl, pedyl, or lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, cyano or nitro A compound of formula (Ia ') or (Ib') wherein substituted phenyl, n is 1, 2, 3 or 4, p is 3 and x is oxygen or sulfur; (e) R ₁ is chlorine, R ₂ is hydrogen, R ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl or hydroxyl, lower alkyl, halogen, lower alkoxy, Lower alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxy ethoxycarbonyl, cyano, nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, carbamyl , Tetrazolyl, or phenyl substituted with sulfamoyl, n is 1, p is 3, and x is oxygen or sulfur; a compound of formula (Ia ') or formula (Ib'); (f) R ₁ is chlorine, R ₂ is hydrogen, R ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl or hydroxyl, lower alkyl, halogen, lower alkoxy, Lower alkanoyl, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinylcarbamyl, A compound of formula (Ia ') or formula (Ib') wherein phenyl is substituted with tetrazolyl or sulfamoyl, n is 1, p is 3 and x is oxygen; (g) R ₂ is hydrogen, R ₃ is chlorine, R ₄ is phenyl substituted by carboxyl or lower alkoxycarbonyl, n is 1, p is 3, and x is oxygen (Ia ') Or a compound of formula (lb).

Among the above compounds, compounds in which x is oxygen are preferred. Also preferred are compounds wherein n is 1 and / or p is 3. In the above compounds, when R ₄ is a lower alkyl group, the preferred chain length of the alkyl group is 1 to 6 carbon atoms.

The compound contained in general formula (I) can be manufactured by the following method.

Method A

Reaction of Compound of Formula (II) with Compound of Formula (III)

R ₄ -N = C = X (III)

Method B

Reaction of Compound of Formula (IV) with Compound of Formula (V)

Wherein R ₁ , R ₂ , R ₃ , R ₄ , n, m, p and x are as defined above.

Y is a reactive substituent that reacts with an amine to form a carbon-nitrogen bond, for example halogen, active ester, hydroxyl, sulfur ester, sulfone ester and the like.

Method C

Reaction of Compound of Formula (VI) with Compound of Formula (VII)

Wherein R ₁ , R ₂ , R ₃ , R ₄ , n, m, p and x are as defined above.

The reaction of Method A can be carried out in the presence or absence of a solvent. Aprotic organic solvents such as toluene or other hydrocarbon solvents, methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide can be used. The reaction temperature depends on the starting compound and the solvent used in the reaction and is usually between room temperature and the reflux temperature of the mixture. The reaction time depends on the temperature and may be several minutes to several hours. Although not essential, it is preferred to carry out the reaction in the presence of an acid binder such as triethylamine or alkali metal carbonate.

The reaction of methods B and C can be carried out in the presence or absence of a solvent. Depending on the nature of the reactants, either aqueous or organic inert solvents can be used. Such solvents include hydrocarbon solvents, dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, ethoxyethanol and lower alkanols with up to 5 carbon atoms, added or not added to water. Preference is given to carrying out the reaction in the presence of an acid binder such as triethylamine or alkali metal carbonate.

Compounds included in general formula (I) are basic and thus form addition salts with inorganic or organic acids. Non-toxic and pharmaceutically acceptable acid addition salts include hydrochloric acid, in particular hydrochloric or hydrobromic acid, nitric acid, sulfuric acid, O-phosphoric acid, citric acid, maleic acid, fumaric acid, propionic acid, butyric acid, acetic acid, succinic acid, methanesulfonic acid, benzene It is formed with sulfonic acid, p-toluene sulfonic acid and the like.

Starting compounds for methods A-C are known compounds or can be prepared by known methods.

Compounds of formula (I), except compounds wherein R ₄ is a lower alkyl group having 7 to 12 carbon atoms, inhibit histamine-induced spasticity of the guinea pig ileum isolated in vitro and inhibit the histamine (H ₁ ) receptor in warm blooded animals Antagonizes histamine action. Thus, the compounds of general formula (I) can be used as antihistamines for the treatment of allergic diseases such as allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, high fever, dwarf and food allergy. have. Certain compounds of formula (I) have few side effects on the central nervous system such as sedation associated with antihistamine therapy. In particular, 1- (3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl) -3- (4-carboxyphenyl) -urea and 1- (3- [4- (4-chlorobenzyl A) piperazin-1-yl] propyl) -3- (4-ethoxycarbonylphenyl) urea has been found to be free of side effects on the central nervous system in drug testing on standard mouse nervous systems.

Compounds of formula (I), except compounds wherein R ₄ is phenyl substituted with a carboxyl group, inhibit IgE-regulated release of histamine from human peripheral blood leukocytes (basic) and peritoneal mast cells of rats in vitro, Inhibits release from histamine and / or other mediators of allergic responses from antigen-induced cells in warm-blooded animals. The release of mediators from basophilic and mast cells is associated with many allergic diseases and inflammations, such as allergic asthma, allergic rhinitis, allergic conjunctivitis, high fever, mumps, food allergy and the like.

For pharmaceutical purposes, the compounds of the present invention are topically, orally, orally or via the respiratory tract as active ingredients in conventional pharmaceutical compositions, i.e., compositions comprising an inert pharmaceutical carrier and an effective amount of the active ingredient. Administration to warm-blooded animals. Oral and topical administration are preferred.

When administering the compound of this invention, it can administer with a syrup, a tablet, a capsule, a pill, etc. The composition is preferably in unit dose form, or in a form that a patient can take by himself in a single dose. Pharmaceutical compositions suitable for formulating solid compositions can be used when the compositions are tablets, powders or antifoams. Examples of such carriers are various starches, lactose, glucose, sucrose, cellulose, dicalcium phosphate and whistle. The composition may be in the form of an intake capsule (eg gelatin), syrup, liquid or suspension containing the compound. Suitable pharmaceutical liquid carriers include ethyl alcohol, glycerin, saline, water, propylene glycol or sorbitan solutions, and the like, which can be mixed with flavors or pigments to form syrups.

The compounds of the present invention can be administered by other methods than oral. According to conventional pharmaceutical methods, the composition may be formulated. For example, in rectal dosage forms such as suppositories, in the form of injections in the form of aqueous solutions or non-aqueous solutions, suspensions in the form of pharmaceutically acceptable liquids such as sterile pyrogen-free water, parenterally acceptable oils or liquids. It may be an agent or an emulsion, and they may contain bactericides, antioxidants, preservatives, buffers or other solvents, thickeners, suspensions or other pharmaceutically acceptable additives which make blood and isotonic solution. Such forms may be in dosage unit form, eg, in multiple dose forms, such as in ampoules, in disposable syringes, or in containers with suitable dosages, or in concentrate or solid form for use in injectable formulations.

The compounds of the present invention may also be present in the form for administration to the respiratory tract, either alone or in admixture with an inert carrier such as lactose, as aerosols or solutions for nebulizers, fine powders for aeration. In such cases, the diameter of the particles of the active compound is suitably 20 microns or less, preferably 10 microns or less. Optionally, small amounts of other anti-allergic agents such as sympathetic excitatory amines (e.g., isoprenelin, isotarin, metaproterenol, salbutamol, phenylephrine, phenoterol and epadrin) and Anti-asthmatic bronchodilators; Xanthine derivatives such as theophylline and aminophylline; And corticosteroids such as prednisolone and adrenal stimulants such as ACTH and the like.

The compounds of the present invention may also be present as ointments, creams, lotions, gels, aerosols or solutions for topical administration to the skin, nose or eye. In addition to these dosage forms, it may be formulated with a skin coating for application to the skin.

Liquids for topical administration to the nose and eyes may contain, in addition to the compounds of the invention, suitable buffers, isotonicity modifiers, microbial preservatives, antioxidants and thickeners in aqueous excipients. Examples of agents for increasing the viscosity include polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbate or glycerin and the like. Microbial preservatives include benzalkonium chloride, thimerosal, chlorobutanol or phenylethyl alcohol. Topical preparations for the eye may be present as ointments in a suitable inert base consisting of mineral oil, petrolatum, polyethylene glycol or ranoltin derivatives with microbial preservatives.

In systemic formulations, a suitable dosage unit will contain from 1 to 500 mg of active ingredient, with a dosage unit of from 1 to 200 mg being preferred. The effective dosage of a compound of the present invention depends on the compound used, the nature of the treatment state, the severity of the disease, the condition of the patient, the route of administration and the frequency of administration. Typically, the palliative dose is about 1 to about 200 mg per day for a patient weighing about 70 to about 80 kg of body weight. A dosage range of about 1 mg to about 100 mg per day is preferred.

In the case of topical administration, formulations containing 0.001 to 1.0%, preferably 0.01 to 0.1%, of the active ingredient are preferred.

In the preparation of pharmaceutical compositions, the compounds of the present invention are formulated into tablets or capsules by mixing with a suitable pharmaceutical carrier, fragrance, flavoring agent and pigment in a conventional manner, or as water or oil (e.g. corn oil) Add to a suitable medium dissolved or suspended in the mixture and mix.

The compounds of the present invention can be administered orally or parenterally in the form of liquids or solids. As an injection medium, preference is given to using water containing stabilizers, solubilizers and / or buffers conventionally used in injection solutions. Additives of this type include tartarate, citrate, acetate buffers, ethanol, propylene glycol, polyethylene glycols, complexing agents (e.g. EDTA), antioxidants (e.g. sodium bisulfite, sodium metabisulfite and ascorbate) Acid), high molecular weight polymer for viscosity adjustment (for example, polyethylene oxide liquid), polyethylene derivative of sorbitol anhydride, and the like.

Preservatives such as benzoic acid, methyl or propyl parabens, benzalkonium chloride and other quaternary ammonium compounds can be added as needed.

Solid carrier materials that can be used include starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic potassium phosphate and high molecular weight polymers (e.g. polyethylene glycol).

Compositions suitable for oral administration may optionally contain flavoring and / or sweetening agents. For topical administration, the compounds according to the invention can be used in the form of dispersed physically compatible diluents or powders or ointments mixed with conventional ointment substrates.

The starting compounds of Methods A to C are known compounds or can be prepared by known methods.

The following examples are intended to practice the present invention and to enable those skilled in the art to more fully understand the present invention. However, it should be understood that the invention is not limited to the specific examples described below.

Example 1

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-cyclohexylurea dihydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) -piperazine (2.0 g; 7.5 mmol) and cyclohexyl isocyanate (1.6 g; 12.8 mmol) solution in tetrahydrofuran (5 ml) at room temperature Stir for minutes. The reaction mixture is evaporated under reduced pressure and the residual oil is dissolved in ethanol (10 ml). The crude product was added to water to precipitate as a white solid, collected by filtration and recrystallized twice with cyclohexane to give 1- {3- [4- (4-chlorobenzyl) pipe, which is a white crystalline solid with a melting point of 109 to 112 ° C. Razin-1-yl] -propyl} -3-cyclohexylurea (1.62 g; yield 56%) is obtained. This product in methylene chloride (20 ml) is precipitated as dihydrochloride by addition of excess anhydrous salt under hydrogen. Recrystallization from water gives the title compound as colorless crystals with a melting point of 184 to 187 ° C.

Example 2

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-methylurea dihydrochloride

A solution of 1- (3-aminopropyl) -4- (4-chlorobenzyl) -piperazine (2.68 g; 10 mmol) and methyl isocyanate (0.57 g; 10 mmol) in methylene chloride (10 ml) is stirred overnight at room temperature . The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on silica gel column (1 "x 24") using methanol-ammonium hydroxide (3-6%) with methylene chloride as eluent. The product (1.0 g; yield 31%) is dissolved in methylene chloride / ether (1: 1; 20 ml) and the solution is treated with anhydrous hydrogen chloride to precipitate the title compound as colorless crystals having a melting point of 193 to 207 DEG C (decomposition). .

Example 3

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-butylurea dihydrochloride hemihydrate

A 1- (3-aminopropyl) -4- (4-chlorobenzyl) -piperazine solution (2.67 g; 10 mmol) in methylene chloride (50 ml) was added to n-butyl isocyanate (1.09 g; 11 mmol) for 2 hours. Reflux. The reaction mixture is concentrated in vacuo and the residue is treated with ethereal hydrogen chloride. The precipitate is recrystallized from methylene chloride / methanol to give the title compound as colorless crystals (3.2 g; yield 71%) having a melting point of 222 to 223 ° C.

Example 4

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-hexylurea dihydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmol) and n- It is carried out according to the method described in Example 3 using hexyl isocyanate (1.41 g; 10 mmol). Recrystallization from ethanol affords the title compound (4.00 g; yield 83%) as colorless crystals having a melting point of 214 to 215 캜.

Example 5

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-octylurea dihydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmol) and n- It is carried out according to the method described in Example 3 using octyl isocyanate (1.55 g; 10 mmol). Recrystallization from methanol / ethanol / water affords the title compound (3.1 g; yield 62%) as colorless crystals with a melting point of 229 to 230 < 0 > C.

Example 6

1- {3- [4- (4-fluorobenzyl) piperazin-1-yl] propyl} -3-cyclohexylurea dihydrochloride monohydrate

A solution of 1- (3-aminopropyl) -4- (4-fluorobenzyl) -piperazine (2.0 g; 8 mmol) and cyclohexyl isocyanate (1.0 g; 8 mmol) in methylene chloride (20 ml) overnight at room temperature Stir. The reaction mixture is evaporated and the residue is mixed with ether (20 ml). The ether solution is filtered and the filtrate is applied to a silica gel column (300 g) and developed with the same solvent. Fractions containing product were eluted with methylene chloride / methanol / ammonium hydroxide (45: 5: 1) and evaporated to yield 1- {3- [4- (4-fluorobenzyl) as pale yellow oil (2.6 g; 85% yield). ) -Piperazin-1-yl] propyl} -3-cyclohexylurea is obtained. The product is dissolved in ether, precipitated with etheric hydrochloric acid and recrystallized with ethanol to give the title compound (2.96 g; yield 80%) as colorless crystals having a melting point of 203 to 206 캜.

Example 7

1- [3- (4-benzylpiperazin-1-yl) propyl] -3-cyclohexylurea dihydrochloride

A solution of 1- (3-aminopropyl) -4-benzylpiperazine (2 g; 12.9 mmol) and cyclohexyl isocyanate (1.6 g; 12.9 mmol) in methylene chloride (50 ml) is stirred overnight at room temperature. The reaction mixture is concentrated and the crude product is precipitated from ether into dihydrochloride by the method described in Example 6. Recrystallization with ethanol affords the title compound as colorless crystals (3.62 g; yield 65%) having a melting point of 202 to 213 ° C.

Example 8

1- [3- (4-benzylpiperazin-1-yl) propyl] -3-phenylurea

A solution of 1- (3-aminopropyl) -4-benzylpiperazine (3.0 g; 12.9 mmol) and phenyl isocyanate (1.54 g; 12.9 mmol) in methylene chloride (20 ml) is stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is recrystallized from aqueous acetone to give the title compound as colorless crystals (2.77 g; yield 61%) having a melting point of 45 to 47 ° C.

Example 9

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-phenylurea

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (2.0 g; 7.5 mmol) and phenyl isocyanate (1.6 g; 13.4 mmol) in tetrahydrofuran (5 ml) are stirred at room temperature for 30 minutes. . Ethanol (50 ml) is added and the reaction mixture is stirred for 3 hours and then concentrated under reduced pressure. The residue is crystallized from aqueous ethanol to give crude product (2.7 g). Recrystallization from the same solvent gives the title compound as colorless crystals (0.62 g; yield 21%) having a melting point of 135 to 137 占 폚.

Example 10

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4- (chlorophenyl) urea hydrochloride

Example using 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (2.67 g; 10 mmol), methylene chloride (50 ml) and 4-chlorophenyl isocyanate (1.54 g; 10 mmol) Perform the method described in 3. Recrystallization from methanol gives the title compound (1.1 g; yield 25%) as colorless crystals having a melting point of 241 DEG C.

Example 11

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-methylphenyl) urea dihydrochloride monohydrate

Example 3 using 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (2.67 g; 10 mmol), methylene chloride (50 ml) and 4-tolyl isocyanate (1.33 g; 10 mmol) It is carried out by the method described in. Recrystallization from methanol / methylene chloride affords the title compound (0.81 g; yield 17%) as colorless crystals having a melting point of 131 to 132 ° C.

Example 12

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] -propyl} -3- (4-methoxyphenyl) urea hydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (5.09 g; 19 mmol), methylene chloride (50 ml) and 4-methoxyphenyl isocyanate (2.83 g; 19 mmol) It is performed by the method described in Example 3. Recrystallization from methanol / methylene chloride affords the title compound (3.57 g; yield 45%) of off-white crystals having a melting point of 237 to 238 ° C.

Example 13

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-ethoxycarbonylphenyl) urea hydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (7.54 g); 20 mmol, methylene chloride (50 ml), tetrahydrofuran (50 ml), triethylamine (8.4 ml; 60 mmol) were used in the method described in Example 3. Recrystallization from methanol yields the title compound (3.11 g; yield 34%) as colorless crystals having a melting point of 233 to 234 ° C.

Example 14

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

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-ethoxycarbonylphenyl) urea hydrochloride (2.59 g; 5.6 mmol) in methanol (75 ml) The solution is refluxed with aqueous sodium hydroxide (1N; 10 ml) for 8 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in water. After filtration, the solution is acidified with hydrochloric acid, the precipitated solid is collected and washed with methanol to give the title compound (1.92 g; yield 80%) as colorless crystals having a melting point of 244 to 246 ° C.

Example 15

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-fluorophenyl) urea dihydrochloridemonohydrate

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (50 ml), tetrahydrofuran (10 ml), triethylamine (4.2 ml; 30 mmol) and 4-fluorophenyl isocyanate (1.37 g; 10 mmol) are carried out according to the method described in Example 3. Recrystallization from methanol / methylene chloride affords the title compound (3.75 g; yield 76%) as colorless crystals having a melting point of 225 to 228 ° C.

Example 16

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-nitrophenyl) urea dihydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), tetrahydrofuran (50 ml), trimethylamine (4.2 ml; 30 mmol) and 4-nitro It is carried out according to the method described in Example 3 using phenyl isocyanate (1.64 g; 10 mmol). Recrystallization from methanol / water affords the title compound (2.79 g; yield 55%) as off-white crystals having a melting point of 203 to 231 ° C. (decomposition).

Example 17

1- {3- [4- (4-chlorobenzyl) homopiperazin-1-yl] propyl} -3-cyclohexylurea dihydrochloride

A solution of 1- (3-aminopropyl) -4- (4-chlorobenzyl) -homopiperazine (2.16 g; 7.7 mmol) in methylene chloride (30 ml) with cyclohexyl isocyanate (1.05 g; 8.5 mmol) at room temperature Stir for 1 hour. The reaction mixture was concentrated to an oil under reduced pressure and chromatographed on silica gel (methylene chloride / methol / ammonium hydroxide; 97 / 2.5 / 0.5) to give a colorless oil, 1- {3- [4- (4-chlorobenzyl) homopiperazine. -1-yl] propyl} -3-cyclohexylurea is obtained. This oil is dissolved in ether and precipitated with ethereal hydrogen chloride to afford the title compound (2.25 g; yield 61%) as a white crystalline solid with a melting point of 167 to 175 ° C. (decomposition).

Example 18

1-3- {3- [4- (4-chlorobenzyl) homopiperazin-1-yl] propyl} -3-phenylurea dihydrochloride

1- (3-aminopropyl) -4- (4-chlorobenzyl) homopiperazine (1.03 g; 3.7 mmol) in ethylene chloride (15 ml) using phenyl isocyanate for 2 hours according to the method described in Example 17 React for a while. The crude product was isolated and purified on silica gel and converted to hydrochloride in a similar manner to give the title compound (1.23 g; yield 83%) as colorless crystals at melting points 125 to 135 ° C.

Example 19

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-cyclohexylthiourea

1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (5.36 g; 20 mmol) was carried out in methylene chloride (35 ml) using cyclohexyl isothiocyanate (2.82 g; 20 mmol) The reaction is carried out for 2 hours by the method described in Example 17. The crude product is separated and chromatographed on silica gel in a similar manner. The product was recrystallized from ethanol to give the title compound (2.98 g; yield 36%) as colorless crystals having a melting point of 127 to 128 ° C.

Example 20

1- {3- [4- (chlorobenzyl) piperazin-1-yl] propyl} -3-phenylthiourea

Reaction of 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine (5.36 g; 20 mmol) in methylene chloride (35 ml) using phenylisothiocyanate in the method described in Example 17 Let's do it. The crude product is isolated and chromatographed on silica gel in a similar manner and crystallized from ethanol to give the title compound (2.39 g; yield 30%) as an off-white crystalline solid with a melting point of 155-156 ° C.

Example 21

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-hexylthiourea dihydrochloride hemihydrate

N-hexylisothiocyanate (1.57 g; 10 mmol) in methylene chloride (100 ml) was added to 1- (3-aminopropyl) -4- () in methylene chloride (100 ml) and triethylamine (4.3 ml; 31 mmol). Add slowly to 4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol) solution. The resulting mixture is refluxed for 2 hours, washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and filtered to precipitate the salt with etheric hydrochloric acid. Recrystallization from ethanol affords the title compound (0.80 g; yield 16%) as an off-white powder with a melting point of 182 to 186 ° C.

Example 22

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-benzylurea dihydrochloride

Benzyl isocyanate (1.33 g; 10 mmol), 1- (3-aminopropyl) -4- (4-clobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (250 ml) and triethylamine ( 4.3 ml; 31 mmol) was used according to the method described in Example 21 to obtain the title compound (3.65 g; yield 77%) as colorless crystals having a melting point of 203 to 206 ° C.

Example 23

1- {3- [4- (4-chlorophenethyl) piperazin-1-yl] propyl} -3-n-hexylurea dihydrochloride

A solution of n-hexyl isocyanate (1.27 g; 10 mmol) in methylene chloride (25 ml) was added to 1- (3-aminopropyl) -4- (4-chlorophenethyl) piperazine (2.82 g; 10 in methylene chloride (50 ml). Millimolar) solution. The resulting mixture was refluxed for 6 hours, concentrated in vacuo and chromatographed on silica gel (methylene chloride / methanol / ammonium hydroxide; 45/5/1) to give a yellow oil. Precipitate with dihydrochloride and recrystallize from ethanol to give the title compound (0.91 g; yield 19%) as colorless crystals with a melting point of 230 to 233 ° C.

Example 24

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-cyanophenyl) urea dihydrochloride monohydrate

4-cyanophenyl isocyanate (1.44 g; 10 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (75 ml) and Triethylamine (4.3 ml; 31 mmol) was carried out by the method described in Example 21. Recrystallization from metaol / ethanol affords the title compound (3.87 g; yield 77%) having a melting point of 236 to 238 ° C. as colorless crystals.

Example 25

1- {3- [4- [3- (4-chlorophenyl) propyl] piperazin-1-yl] -propyl} -3-n-hexylurea dihydrochloride

(a) Triethylamine (35 g; 35 mmol) is added slowly to a mixture of chloropropylamine hydrochloride (39 g; 0.3 mol), n-hexyl isocyanate (38.2 g; 0.3 mol) and methylene chloride (500 ml). The resulting solution is stirred for 1 hour and then the solvent is removed in vacuo. The residue is treated with ether to filter the colorless solid. The ether solution was washed with water, dried (magnesium sulfate) and concentrated to give pure 1- (3-chloropropyl) -3-n-hexylurea (57.0 g; 86% yield) as colorless crystals with a melting point of 48 to 50 ° C. do.

(b) 1- (3-chloropropyl) -3-n-hexylurea (2.21 g; 10 mmol), 1- [3- (4-chlorophenyl) propyl] piperazine (2.39 g; 10 mmol), tri A mixture of ethylamine (1.01 g; 10 mmol) and alcohol (25 ml) was refluxed for 18 hours. The cooled reaction mixture is diluted with ether, washed with water, dried (sodium sulfate) and concentrated in vacuo. The resulting yellow viscous oil is purified on a silica gel column (methylene chloride / methanol; 93; 7) and precipitated with etheric hydrochloric acid to give the title compound (1.6 g; yield 38%) as colorless crystals with a melting point of 213 to 216 ° C. .

Example 26

1- {3- [4- (3-trifluoromethyl-4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-hexylurea dihydrochloride

(a) A mixture of 1- (3-chloropropyl) -3-n-hexylurea (11.0 g; 50 mmol), piperazine (43.0 g; 500 mmol) and ethanol (250 ml) is refluxed for 2 hours. The solvent is removed in vacuo and the solid residue is dissolved in water. The resulting solution was extracted with methylene chloride and concentrated in vacuo and the residue was chromatographed on silica gel to give 1- (3-piperazinylpropyl) -3-n-hexylurea (6.7 g; 39% yield) as a pale yellow oil. To obtain.

(b) 1- (3-piperazinylpropyl) -3-n-hexylurea (2.7 g; 10 mmol), 3-trifluoromethyl-4-chlorobenzyl chloride (2.29 g; 10 mmol), triethyl A mixture of amine (1.01 g; 10 mmol) and ethanol (30 ml) is refluxed for 3 hours. The solvent is evaporated in vacuo and water is added to the residue. The product is extracted with ether, and the extract is dried (sodium sulfate) and concentrated. The oily residue is precipitated with etheric hydrochloric acid and recrystallized with alcohol to give the title compound (3.1 g; yield 58%) as colorless crystals with a melting point of 216 to 219 ° C.

Example 27

1- {3- {4- [3- (4-chlorophenyl) propyl] piperazin-1-yl} propyl} -3- (4-cyanophenyl) urea dihydrochloridemonohydrate

(a) a mixture of triethylamine (13.8 g; 137 mmol) of 3-chloropropylamine hydrochloride (17.8 g; 137 mmol), 4-cyanophenyl isocyanate (19.7 g; 137 mmol) and methylene chloride (200 ml) Slowly add to. The resulting solution is stirred until a gentle exothermic reaction subsides and the solvent is removed in vacuo. The product is dissolved in ether, washed with water and dried to remove some ether. Precipitated colorless crystals were filtered and dried to afford 1- (3-chloropropyl) -3- (4-cyanophenyl) -urea (17.5 g; yield 54%). A small amount of product is recrystallized from water / acetone to give a pure product with a melting point of 95-97 ° C.

(b) 1- (3-chloropropyl) -3- (4-cyanophenyl) -urea (3.57 g; 15 mmol), 1- [3- (4-chlorophenyl) propyl] piperazine (3.58 g; 15 mmol), triethylamine (1.52 g; 15 mmol) and ethanol (100 ml) were refluxed for 35 hours. The solvent is removed in vacuo and water is added to the residue. The product is extracted with ether, dried and concentrated in vacuo. The resulting red yellow oil is purified on a silica gel column (methylene chloride / methanol 9: 1) to give the product as a free base (2.8 g; yield 42%). The product is dissolved in ether, precipitated with etheric hydrochloric acid and recrystallized with water to give the title compound as colorless crystals with a melting point of 219 to 221 ° C.

Example 28

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-allylurea dihydrochloride

Triethylamine (2.0 g; 20 mmol) solution in methylene chloride was added to 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (7.54 g; 20 mmol) and allyl isocyanate in methylene chloride. (1.66 g; 20 mmol) is added dropwise. After the addition is complete, the mixture is washed with water and the solvent is removed. The resulting yellow oil was purified on a silica gel column (methylene chloride / methanol; 9; 1), precipitated with etheric hydrochloric acid and recrystallized with ethanol / water to give the title compound (2.1 g; yield) as colorless crystals with a melting point of 232 to 234 ° C. 25%) is obtained.

Example 29

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-acetylphenyl) urea dihydrochloride dihydrate

A solution of 4-acetylphenyl isocyanate (1.61 g; 10 mmol) in methylene chloride (100 ml) was added to 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol). To methylene chloride (50 ml) and triethylamine (4.3 ml; 31 mmol). The resulting mixture is refluxed for 3 hours, washed with aqueous sodium bicarbonate solution, dried (sodium sulfate) and precipitated with etheric hydrochloric acid. Recrystallization from ethanol yields the title compound (4.13 g; yield 82%) as a white powder having a melting point of 197 DEG C or more (slow decomposition).

Example 30

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-ethoxyphenyl) urea dihydrochloride

4-ethoxyphenyl isocyanate (1.63 g; 10 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (16 ml) and Triethylamine (4.3 ml; 31 mmol) was used following the method described in Example 29. Recrystallization from ethanol affords the title compound (3.42 g; yield 68%) as colorless crystals with a melting point of 225 to 227 ° C.

Example 31

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- [4- (methylthio) phenyl] urea dihydrochloride monohydrate

4- (methylthio) phenylisocyanate (10.0 g; 60.5 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (22.8 g; 60.5 mmol), methylene chloride (400 ml ) And triethylamine (25.8 ml; 185 mmol) according to the method of Example 29. Recrystallization from methanol / water affords the title compound (27.3 g; yield 89%) as colorless crystals at melting points 212-214 ° C.

Example 32

3- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (2-chlorophenyl) urea dihydrochloride monohydrate

2-chlorophenylisocyanate (1.54 g; 10 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (50 ml) and tri It is carried out according to the method described in Example 29 using ethylamine (4.3 ml; 31 mmol). Recrystallization from ethanol affords the title compound (2.63 g; yield 53%) as colorless crystals with a melting point of 222 to 224 ° C.

Example 33

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (2,6-dichlorophenyl) urea dihydrochloride

2,6-dichlorophenyl isocyanate (1.88 g; 10 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (50 ml) And triethylamine (4.3 ml; 31 mmol) according to the method described in Example 29. Recrystallization from methanol gives the title compound (2.75 g; yield 52%) as colorless crystals with a melting point of 246 to 248 ° C.

Example 34

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (n-dodecyl) urea dihydrochloride

n-dodecyl isocyanate (2.11 g; 10 mmol), 1- (3-aminopropyl) -4- (4-chlorobenzyl) piperazine trihydrochloride (3.77 g; 10 mmol), methylene chloride (100 ml) and tri Ethylamine (3.03 g; 30 mmol) was used following the method described in Example 29. Recrystallization with water gives the title compound (3.21 g; yield 58%) as colorless crystals with a melting point of 215 to 222 캜.

Example 35

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-carbamylphenyl) urea dihydrochloride

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-cyanophenyl) urea dihydrochloride monohydrate (10.0 g; 19.9 mmol), glacial acetic acid (120 ml ), And concentrated hydrochloric acid (80 ml) solution is heated at 80 ° C for 30 minutes. The mixture is poured on ice and basified with aqueous potassium hydroxide solution. The product is extracted with methylene chloride and dried (sodium sulfate) to precipitate the salt with etheric hydrochloric acid. Recrystallization from ethanol several times affords the title compound (3.54 g; yield 38%) having a melting point of 224 to 226 ° C. as colorless crystals.

Example 36

1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-tert-butylphenyl) urea dihydrochloride

A solution of 3-iodopropyl isocyanate (4.22 g; 20 mmol) in ether (25 ml) is added to 4-tert-butylaniline (2.98 g; 20 mmol) in ether (25 ml) and the resulting solution is refluxed for 3 hours. After the solvent was removed, 4-chlorobenzylpiperazine (4.18 g; 20 mmol) in ethanol (50 ml) was added and the resulting solution was refluxed for 24 hours. An aqueous sodium bicarbonate solution is added to the mixture, the product is extracted with methylene chloride, dried (sodium sulfate), and the salt is precipitated with etheric hydrochloric acid. Recrystallization from ethanol several times affords the title compound (3.73 g; yield 33%) as colorless crystals at melting point 240-241 ° C.

Example 37

The following compounds can be prepared from equimolar amounts of 3-iodopropylisocyanate, suitably substituted aniline and 4-chlorobenzylpiperazine in a similar manner to the method described in Example 36; A. 1- {3- [4-4- (4-chlorobenzyl) piperazin-1-yl, propyl} -3- (3-carboxyphenyl) urea dihydrochloride.

B. 1- {3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl} -3- (3-ethoxycarboxyphenyl) urea dihydrochloride.

C. 1- {3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl} -3- (3-carbamylphenyl) urea dihydrochloride.

D. 1- {3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl} -3- (3-hydroxy-4-carbamylphenyl) urea dihydrochloride.

E. 1- {3- [4- (4-Chlorobenzyl) piperazin-1-yl] propyl} -3- (3-hydroxy-4-ethoxycarbamylphenyl) urea dihydrochloride.

F. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-hydroxy-4-carboxyphenyl) urea dihydrochloride.

G. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-methoxy-4-ethoxycarbonylphenyl) urea dihydrochloride.

H. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-methoxy-4-carboxyphenyl) urea dihydrochloride.

I. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-carboxy-4-hydroxyphenyl) urea dihydrochloride.

J. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-ethoxycarbonyl-4-hydroxyphenyl) urea dihydrochloride.

K. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3 (3-carboxy-4-methoxyphenyl) urea dihydrochloride.

L. 1- {3- [4- (4-Chlorophenyl) piperazin-1-yl] propyl} -3- (3-ethoxycarbonyl-4-methoxyphenyl) urea dihydrochloride.

Example 38

In vitro inhibition of histamine release from human leukocytes (basophils) and peritoneal mast cells of rats by the compound of formula (I) can be explained by the following biochemical test method; A. In vitro measurement of histamine release inhibition from human leukocytes (basic).

1. Isolation of white blood cells; Improved Methods of Liechtenstein and Osler [L. Lichtenstein and A. Osler. J. Exp. Med. 120, 507 (1964). Heparinized human blood (80-100 ml) is mixed with 20 ml brine (0.2%) containing 0.6 gm of dextrose and 1.2 gm of dextran in a propylene centrifuge tube. The mixture is left at ambient temperature for 60-90 minutes to separate red blood cells from the platelet, leukocyte-rich supernatant. Remove the supernatant and centrifuge for 8 min at 110 x g at cold. Leukocyte pellets are washed twice with Tris buffer and finally suspended in 150-180 ml of Tris-ACM buffer at 1-2 × 10 ⁶ cell counts / ml.

2. reaction mixture; The reaction is carried out in a plastic tube with a total volume of 1.25 ml of 12 × 75 mm. The reaction medium contains 0.05 ml rabbit anti-human IgE (antigen), 0.2 ml test compound in water at a concentration of 10-1000 μM, 1.0 ml leukocyte suspension. The reaction mixture is incubated for 60 minutes in a 37 ° C. shaking water bath. Once the reaction is complete, centrifuge the tube and collect the supernatant. Protein is precipitated with 0.2 ml of 8% perchloric acid and removed from the supernatant.

3. Histamine Assay: Histamine release is measured by automated fluorescence assays in the literature. See W. Siraganian and W. Hook in Chapter 102 of the Manual of Clinical Immunology, 2nd Edition, Edited by R. Rose and H. Frideman , Published by the American Society for Microbiology, Washington, DC1980). The percentage for inhibition is calculated as follows:

Concentrations that inhibit the release of histamine by 50% (IC 50) are plotted as a plot of% inhibition versus drug concentration.

B. Measurement of Histamine Release Inhibition in Peritoneal Mast Cells of Rats.

1. Peritoneal mast cell odor: After rats are sacrificed with ether, 20 ml of MEM (Minimum Essential Medium) containing 20 units / ml of heparin is injected intraperitoneally. Massage the abdomen for 1 minute and collect the gastric lavage fluid. Peritoneal cells are centrifuged at 1800 rpm for 8 minutes under cooling. After washing twice with Tris A buffer, cells are resuspended in Tris ACM buffer at 2-4 × 10 ⁶ cell counts / ml.

2. Reaction mixture: The reaction is carried out in a 12 x 75 mm plastic tube with a total volume of 1.25 ml. The reaction mixture is 0.5 ml (10-1000 μg) of positive-rat IgE or ovalbumin, 0.2 ml of test compound in water at a concentration of 10-1000 μM, 0.5 ml of phosphatidylserine solution (20-60 μg in each tube), and 0.5 ml of cell suspension It contains. The reaction mixture is incubated for 60 minutes in a shaking bath at 37 ° C. After the reaction is complete, the tubes are centrifuged and the supernatant collected. The protein is removed from the supernatant by precipitation with 0.2 ml of 8% perchloric acid.

3. Histamine Assay: Histamine release is measured by the above-described automatic fluorescence assay of Shiraganian.

Enter a Part A concentration that inhibits histamine release by 50% (IC ₅₀ ).

The results of testing compounds of formula (I) for the inhibition of histamine release from human leukocytes according to Method A are shown in Table A.

* Int = interrupt the test

The results of testing the compounds of formula (I) for inhibition of histamine release from rat peritoneal mast cells according to Method B are shown in Table B.

Example 39

The antagonism of histamine action on the contraction of isolated guinea pigs by the compounds of formula (I) can be measured by the method of reference. G. Possanza, A Bauen. And P.stewart.Int Arch. Allergy Appl. Immunol., 49 289 (1975). Inhibitory concentrations are determined by the difference between the contraction by histamine (final concentration 0.2 μg / ml) and the contraction seen when both histamine and test compound are present. The inhibitory activity of the test compound is represented by (IC ₅₀ ) of the compound which causes a 50% reduction in the contraction reaction.

When tested according to the methods described above, the results for compounds of formula (I) are shown in Table C.

Example 40

refine

Tablet compositions are synthesized from the following components: 1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-ethoxycarbonylphenyl) urea

0.0010 parts hydrochloride

Stearic Acid 0.0010 part

Dextrose Part 1.890

1.910 total

Preparation: The ingredients are mixed in a conventional manner and the mixture is compressed into tablets of 1.91 gm which is an oral dosage unit composition containing 10 mg of active ingredient.

Example 41

Ointment

Ointment compositions are synthesized from the following components: 1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-methoxyphenyl) -urea

Hydrochloride 2.000 parts

0.011 fuming hydrochloric acid

Sodium pyrosulphite0.05part

20.000 parts of a mixture of cetyl alcohol and stearyl alcohol (1: 1)

White Vaseline 5.000 part

Synthetic bergamot oil 0.075 parts

Add an appropriate amount of distilled water to make 100.000 parts.

Preparation: The above ingredients are uniformly mixed in a conventional manner with 100 g of an ointment containing 2.0 gm of the active ingredient.

Example 42

Inhalation aerosols

The aerosol composition is synthesized from the following components. 1- {4- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3-n-hexylurea dihydro

Chloride 1.00

Soybean LecithinPart 0.20

Appropriate amount of blowing gas mixture is added (freon 11, 12 and 14) to 100.000 parts.

Preparation: The components are mixed in a conventional manner and the composition is filled in an aerosol container equipped with a metering valve which releases 0.5 to 2.0 mgm of active ingredient per actuation of the valve.

43 on implementation

Hypodermic injection

The solution is synthesized from the following components: 1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-carboxyphenyl) urea hydro

Chloride 5.0 parts

Sodium Pyrosulphite 1.0 part

0.5 parts of sodium salt of EDTA

Sodium chloride 8.5 parts

Distilled water is added in an appropriate amount to make 100.0 parts.

Preparation: Dissolve each component in an appropriate amount of double distilled water, dilute the solution with additional double distilled water to the above-mentioned concentration, filter the resulting solution until the suspended particles are freed, and then filter the filtrate under sterile conditions. Fill ampoules, sterilize and seal. Each ampoule contains 5 mg of active ingredient.

44 in real

Topical liquids (for eyes and nose)

The liquid composition is synthesized from the following components: 1- {3- [4- (4-chlorobenzyl) piperazin-1-yl] propyl} -3- (4-cyanophenyl) urea hydro

Chloride 0.020 parts

Disodium hydrogen phosphate0.758part

Dihydrogen Sodium Phosphate0.184part

Sodium chloride0.365part

3.500 parts of polyvinyl alcohol

Benz Alkonium Chloride0.010part

Add an appropriate amount of distilled water to make 100.000 parts.

Preparation: The above components are mixed in a conventional manner to form an aqueous solution. The solution is filtered with an ophthalmic solution that requires sterile filtration. It contains 0.2 mg of active ingredient per ml of solution.

Other compounds included in Formula (I) or their non-toxic and pharmaceutically acceptable acid addition salts may replace certain active ingredients of Examples 40-44. In addition, in this embodiment, the amount of the active ingredient can be adjusted to the dosage unit in the above-described range, and the specific requirements can be satisfied by changing the properties and the amount of the inert pharmaceutical carrier component.

While the invention has been described by way of specific embodiments, it will be understood by those skilled in the art that the invention is not limited to such specific embodiments, and various changes and modifications may be made without departing from the spirit or scope of the invention. I understand that it is possible.

Claims (7)

Compounds of the following general formula (I) and acid addition salts thereof.

Wherein R ₁ , R ₂ and 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 ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl, or lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, Nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, carbamyl, tetrazolyl, sulfamoyl, hydroxyl or lower phenyl substituted with lower alkanoyl; n is 1, 2, 3 or 4; m is 1; p is 2, 3 or 4; x is oxygen or sulfur. Compounds of the following general formula (IIb) and acid addition salts thereof.

Wherein R ₁ , R ₂ , R ₄ , n, p and x are the same as defined in claim 1. The compound according to claim 1, further comprising 1- [3- [4- (4-chlorobenzyl) homopiperazin-1-yl] propyl] -3-cyclohexylurea; And 1- [3- [4- (4-chlorobenzyl) homopiperazin-1-yl] propyl] -3-phenylurea and acid addition salts thereof. A method for preparing a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof, characterized by reacting a compound of formula (II) with a compound of formula (III).

Wherein R ₁ , R ₂ and 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 ₄ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, allyl, phenyl, or lower alkyl, halogen, lower alkoxy, carboxyl, lower alkoxycarbonyl, lower alkoxyethoxycarbonyl, cyano, Nitro, lower alkylthio, di (lower alkyl) aminoethoxycarbonyl, lower alkylsulfonyl, lower alkylsulfinyl, carbamyl, tetrazolyl, sulfamoyl, hydroxyl or lower phenyl substituted with lower alkanoyl; n is 1, 2, 3 or 4; m is 1; p is 2, 3 or 4; x is oxygen or sulfur. A compound of formula (IV) is characterized by reacting with a compound of formula (V) to prepare a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , n, m, p and x are as defined in claim 4 and Y is a reactive substituent which reacts with an amine to form a carbon-nitrogen bond, for example For example, halogen, activated ester, hydroxyl, sulfuric acid ester, sulfonic acid ester and the like. A process for preparing a compound of formula (I) or a pharmaceutically acceptable non-toxic acid addition salt thereof, characterized by reacting a compound of formula (VI) with a compound of formula (VII).

Wherein R ₁ , R ₂ , R ₃ , R ₄ , n, m, p and Y are as defined above. Pharmaceutically useful pharmaceutical agents for the treatment of immune diseases, inflammations and allergic diseases, characterized by containing an effective amount of a compound of formula (I) as defined in claim 1 or a physiologically acceptable acid addition salt thereof. Composition.