A derivative of benzimidazole and a means of having antagonistic activity against substance p and antihistaminas activity

 

(57) Abstract:

The invention relates to a new benzimidazole derivative of the formula (I), where a represents a single bond or C1-2-alkylenes group; R6is a hydrogen atom or a C1-4is an alkyl group; b - C2-3-alkylenes group; X represents an oxygen atom, each of R1and R2is a hydrogen atom; E is C1-2-alkylenes group; R3is a phenyl group (this phenyl group may be optionally substituted by halogen atom), each of R4and R5that are independent from each other, represents a hydrogen atom or a C1-4is an alkyl group; D - C1-2-alkylenes group and Ar is a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group, a C1-4-alkoxygroup or triptorelin group). Also describes a means of having antagonistic activity against substance P and antihistaminas activity. The invention can be used in chemistry and medicine. 2 S. and 4 C.p. f-crystals, 4 PL.

The invention relates to a new benzimidazole derivative having anti-allergic activity, and drug, is of olesna, related to allergies of type I, such as hay fever, urticaria, atopic dermatitis, allergic rhinitis and asthma, are still often used antihistamines and steroids. However, still problems in relation to their clinical utility. The above diseases related to allergies, motivated immune response specific antigen with IgE antibodies and develop into a chronic state of inflammation of the affected part or tissue damage. It was assumed that during this process, various chemical mediators are mutually closely associated with pathological progress. Based on the characteristics of pharmacological action it is believed that among them histamine is involved mainly in the initial stage of the pathological progress. It is believed that this is the reason why remains a problem regarding the clinical utility of antihistamines. On the other hand, steroids, which are used mainly in severe cases, exhibit pharmacological activity in the inhibition of various processes immuno-inflammatory responses in different ways and are believed to exhibit a high level of efficiency. However, when using steroidogenesis or re-introduction. Thus, in the treatment of diseases related to Allergy type I, it is very desirable to develop drugs with a new mechanism of action and a high level of efficiency.

In recent years it was reported that substance P, which is a neuropeptide that acts as a mediator promotion of allergic symptoms and takes a large part in the inflammatory symptoms, especially in the chronic phase (TIPS, 81, 24 (1987); Am. J. Respir. Crit. Care Med., 151, 613 (1995); J. Allergy Clin. Immunol., 92, 95 (1993)). So, I think that the antagonist of the substance P can effectively treat allergic symptoms in the chronic phase (especially chronic inflammation).

Substance P is a member of the family of neurokinins and know that it takes a variety involved in the activation of macrophages or lymphocytes in immunity and inflammation as a factor in the regulation of cytokine production (IL, FNT, IL) and it causes the symptoms of inflammation, such as increased vascular permeability, plasma leakage, and stimulation of the secretory glands. In addition, it functions as a mediator (transmitter) pain from the periphery to the center and adjusts the transmission system of dopamine and epinephrine in the brain.lergicheskie agent, but also as analgesics or psihomimetiki.

In addition, I believe that drug, with not only antagonistic activity against substance P, but also antihistaminas activity, is effective for the treatment of a wide range of allergic symptoms, stretching from the acute phase to the chronic phase, and, thus, it is expected that it is a drug that is clinically good results of treatment.

As a result of extensive studies, the authors of this invention have found that benzimidazole derivatives of this invention have an antagonistic activity against substance P and, moreover, that among the compounds of the present invention, many have also antihistaminas activity.

The benzimidazole with antihistaminas activity, have already been described, for example, in the Japan patent JP-A-59-199679, JP-A-58-79983, European patents EP-B, EP-B and U.S. patent 4219559. However, the compounds of this invention are not included in the number of such described benzimidazole. In addition, in such prior art says nothing about antagonistic activity against substance P.

This invention provides a derivative of benzimidazole of the formula (I) or its salt:

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where a represents a single bond or C1-2-alkylenes group (this Allenova group can be optionally substituted C1-4is an alkyl group), R6represents C1-4is an alkyl group (this alkyl group may be optionally substituted phenyl group), is2-3-alkylenes group (this Allenova group can be optionally substituted C1-4is an alkyl group), X represents an oxygen atom, a sulfur atom or NR7(where R7e depend on each other, represents a hydrogen atom, a halogen atom, a C1-4is an alkyl group or a C1-4-alkoxygroup, E represents C1-2-alkylenes group (this Allenova group can be optionally substituted C1-4is an alkyl group), R3represents a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group or a C1-4-alkoxygroup), C1-4-alkoxygroup or benzyloxy, each of R4and R5that are independent from each other, represents a C1-4is an alkyl group (this alkyl group may be optionally substituted phenyl group), D provides a 1-2-alkylenes group (this Allenova group can be optionally substituted C1-4is an alkyl group and Ar represents a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group, a C1-4-alkoxygroup or triptorelin group), the method of its production and pharmaceutical composition containing it as active ingredient.

Now will be described substituents relating to the connection of the present invention.

In this description, "h" means normaski, "Me" means methyl, "Et" means ethyl, "Bu" means butyl, "Ph" means phenyl and "Bn" means benzyl.

C1-2-Allenova group include methylene and ethylene.

WITH2-3-Allenova group includes ethylene and trimethylene.

C1-4is an alkyl group can be linear, branched or cyclic and include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and cyclobutyl.

WITH1-4-alkoxygroup can be linear, branched or cyclic and includes methoxy, ethoxy, n-propoxy, ISO-propoxy, cyclopropane, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, CYCLOBUTANE.

The halogen atom includes fluorine, chlorine, bromine and iodine.

Now will be described in detail a, b, D, E, Ar, X, R1, R2, R3, R4, R5and R6in compound (I) of this invention.

Specific examples And include a single bond, CH2Snme, CH2CH2and CH2Snme, preferably single bond and CH2.

Specific examples include CH2CH2CH2Snme, Snresn2, Smesne, CH2CH2CH2Snresn2CH2CH2Snresn22CH2and CH2CH2CH2.

Specific examples of D include CH2Snme, CH2CH2and CH2Snme, preferably CH2Snme and CH2CH2.

Specific examples of E include CH2Snme, CH2CH2and CH2Snme, preferably CH2and CH2CH2.

Specific examples of AG include phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-itfeel, 3-itfeel, 4-itfeel, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-were, 3-were, 4-were, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-differenl, 2,4-differenl, 2.5-differenl, 2,6-differenl, 3,4-differenl, 3,5-differenl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2.5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,6-dibromophenyl, 2,3-diiodophenyl, 2,4-diiodophenyl, 2.5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl, 3,5-goodfeel, 2,3-bis(trifluoromethyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,4-bis-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,3 Anil, 2,4-acid, 2,5-acid, 2,6-acid, 3,4-acid, 3,5-acid and 2-chloro-5-Cryptor-were, preferably phenyl, 2-chlorophenyl, 2-methoxy-phenyl, 3, 5dimethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-acid, 2, 5-dichlorophenyl and 2-chloro-5-triptoreline.

Specific examples of X include an oxygen atom, a sulfur atom, N-CN, N-NO2N-OMe, N-OEt and N-OBu, preferably an oxygen atom.

Specific examples of each of R1and R2include a hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropane, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, CYCLOBUTANE, preferably a hydrogen atom.

Specific examples of R3include phenyl, 4-forfinal, 4-chlorophenyl, methoxy, ethoxy and benzyloxy, preferably 4-forfinal, ethoxy.

Specific examples of each of R4and R5include a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl and benzyl, preferably a hydrogen atom, methyl and benzyl.

Specific examples of R6include and the l and benzyl, preferably a hydrogen atom, methyl and benzyl.

The following compounds may be mentioned as preferred compounds among the compounds of formula (I) of the present invention.

(1) Compound of formula (I) or its salt, where a represents a single bond, CH2Snme, CH2H2or CH2Snme, is CH2CH2CH2Snme, Snresn2, CHMeCHMe, CH2CH2CH2Snresn2CH2CH2CHMeCH2CH2CH2Snme, Enmeshment2,

Snresn2Snme, CH2Smesne or CHMeCHMeCHMe, D is CH2Snme, CH2CH2or CH2Snme, E is CH2Snme, CH2CH2or CH2Snme, AG represent phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-itfeel, 3-itfeel, 4-itfeel, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-were, 3-were, 4-were, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-differenl, 2,4-differenl, 2.5-differenl, 2,6-differenl, 3,4-differenl, 3,5-differenl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlor, 2,4-diiodophenyl, 2.5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl, 3,5-diiodophenyl, 2,3-bis(trifluoromethyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 2,3-acid, 2,4-acid, 2,5-acid, 2,6-acid, 3,4-acid, 3,5-acid or 2-chloro-5-Cryptor-were, X represents an oxygen atom, a sulfur atom, N-CN, N-NO2N-OMe, N-OEt or N-OBu, each of R1and R2represents a hydrogen atom, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropane, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy or CYCLOBUTANE, R3represents phenyl, 4-forfinal, 4-chlorophenyl, methoxy, ethoxy or benzyloxy, each of R4and R5represents a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl or benzyl and R6represents a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t is dependent on the oxygen atom.

(3) the Compound or its salt according to above paragraph (2), where each of R1and R2represents a hydrogen atom.

(4) the Compound of formula (I) or its salt, where a represents a single bond or CH2In is CH2CH2or CH2CH2CH2D is CH2Snme or CH2CH2E is CH2or CH2CH2, Ah represents phenyl, 2-chlorophenyl, 2-methoxyphenyl, 3, 5dimethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-acid, 2,5-dichlorophenyl or 2-chloro-5-triptoreline, X represents an oxygen atom, each of R1and R2represents a hydrogen atom, R3is 4-forfinal or ethoxy, each of R4and R5represents a hydrogen atom, methyl or benzyl and R6represents a hydrogen atom, methyl or benzyl.

(5) the Compound or its salt according to the above item (4) where E is CH2and R3is 4-florfenicol group.

(6) the Compound or its salt according to the above item (5) where AG represents 3,5-bis(trifluoromethyl)phenyl.

Typical compounds among the benzimidazole derivatives of the formula (Ia), as the compounds of this invention are presented in tablistener, listed at the end of the description, where Q1 - Q43 represent groups of formulas.

The compound of formula (I) of this invention can be used for the purpose of this invention either in its free form or in the form of pharmacologically acceptable salts. Such an acid additive salt may, for example, be the salt of the mineral acid such as hydrochloride, hydrobromide, sulfate, hydrosulfate, nitrate, phosphate, hydrogen phosphate or dihydrophosphate), salt of organic acid (such as formate, acetate, propionate, succinate, malonate, oxalate, maleate, fumarate, malate, citrate, tartrate, lactate, glutamate, aspartate, picrate or carbonate) or a sulfonate such as methanesulfonate, bansilalpet or toluensulfonate).

Next will be described the methods for producing the compounds of this invention.

Derivatives of benzimidazole of the formula (I) as the compounds of this invention can be obtained by the methods represented by the reaction schemes (1) - (7) (see the end of the description).

The reaction scheme (1) is a method of obtaining the compounds of this invention by the reaction of the compound (IIA) with the compound (IIIa).

This reaction is carried out usually in the presence or absence of inorganic bases Abonat potassium, sodium carbonate, lithium carbonate, potassium bicarbonate and sodium bicarbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride, potassium hydride and n-butillitiyem, alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, and amides of metals, such as sodium amide, diisopropylamide lithium hexamethyldisilazide lithium hexamethyldisilazide sodium, and 2,2,6,6-tetramethylpiperidine.

The organic base includes, for example, trimethylamine, triethylamine, pyridine and diisopropylethylamine.

The solvent for the reaction may be any solvent as long as it is involved in the reaction, it may be, for example, the solvent of the type of hydrocarbon, such as benzene, toluene or hexane, a solvent type simple ether, such as tetrahydrofuran, diethyl ether or 1,4-dioxane, a solvent of the amide type, such as formamide, N,N-dimethylacetamide, N,N-dimethylformamide or N -, an organic solvent type of alcohol, such as methanol, ethanol or propanol, a halogenated solvent type, such as chloroform, methylene chloride or telengard, another solvent, such as acetonitrile or dimethylsulfoxide reaction may be in the range from -78oC to the boiling point of the solvent used for the reaction.

The molar ratio of starting materials may not be firmly established, but the compound (IIIa) can be used in an amount of from 0.8 to 10 moles per mole of the compound (IIA).

The reaction scheme (2) is a method of obtaining the compounds of this invention by the reaction of the compound (IIb) with a compound (IIIb).

This reaction can be carried out in conditions similar to the reaction scheme (1).

The molar ratio of starting materials may not be firmly established, but the compound (IIb) can be used in an amount of from 0.8 to 10 moles per mole of the compound (IIIb).

The reaction scheme (3) is the method of obtaining the compound (I) of this invention by the reaction of the compound (IVa) with a compound (Va).

This reaction can be carried out in conditions similar to the reaction scheme (1).

The molar ratio of starting materials may not be firmly established, but the compound (Va) can be used in amounts of from 0.8 to 1.5 mol per mol of compound (IVa).

The reaction scheme (4) is a method of obtaining the compound (I) of the present invention reaii (I) is a hydrogen atom).

This reaction can be performed by heating or cooling the compound (IVb) and the compound (Vb) or compound (IVb) and connection (Vc) in a solvent or in the absence of solvent, it can be done in conditions similar to the reaction scheme (1).

The molar ratio of starting materials may not be firmly established, but the compound (Vb) or connection (Vc) can be used in amounts of from 0.8 to 1.5 mol per mol of compound (IVb).

The reaction scheme (5) is a method of obtaining the compound (I) of this invention by the reaction of the compound (VIa) with compound (VIIa).

This reaction can be performed by heating or cooling compounds (VIa) and the compound (VIIa) in a solvent or in the absence of solvent, it can be done in conditions similar to the reaction scheme (1).

The molar ratio of starting materials may not be firmly established, but the compound (VIa) can be used in amounts of from 0.8 to 1.5 mol per mol of compound (VIIa).

The reaction scheme (6) is a method of obtaining the compound (I) of this invention by the reaction of the compound (VIb) with compound (VIIb).

This reaction can be conducted under conditions that obtained the WFD established, but the compound (VIb) can be used in amounts of from 0.8 to 1.5 mol per mol of compound (VIIb).

Reaction scheme (7) is a method of obtaining the compound (I) of this invention by the reaction of the compound (VIII) with compound (IX).

This reaction can be carried out in conditions similar to the reaction scheme (1).

The molar ratio of starting materials may not be firmly established, but the compound (IX) can be used in amounts of from 0.8 to 1.5 mol per mol of compound (VIII).

Now will be described the methods of obtaining raw materials for the compounds of this invention.

Among the starting materials for the compounds of this invention, the compound (IIA) and compound (IIb) can be obtained by methods shown by reaction scheme (8).

The compound (IIA) can be obtained by condensation of compound (IIaa) with compound (IX) to obtain compounds (IIab) with subsequent halogenoalkanes (halogenation reagent can be gloriously reagent, such as pentachloride phosphorus, thionyl chloride, sulfurylchloride, chlorine-triphenylphosphine or carbon tetrachloride-triphenylphosphine, pomeroyi reagent, such as tribromide phosphorus, pentabromide phosphorus, minilp is such as idefinitely, or by reaction with R8SO2Cl or halogenoalkanes compound (IIaa) or by reaction with R8SO2Cl to obtain the compound (AC) followed by condensation with the compound (IX).

The compound (IIb) can be obtained by reaction of the compound (IIA) with the compound (b) or by reaction of the compound (IIA) with the compound (Ha) to obtain compound (IIbb) with subsequent removal of the protective group, or by reaction of the compound (A) with compound (Ha) to obtain compounds (IIba), followed by reaction with compound (IX) to obtain compound (IIbb) with subsequent removal of the protective group, or by carrying out the removal of the protective group to obtain the compound (IIbc), followed by reaction with compound (IX), or by reaction of the compound (A) with compound (b) to obtain compounds (IIbc), followed by reaction with compound (IX), or protect it to get the connection (IIba), followed by reaction with compound (IX) to obtain compound (IIbb) with subsequent removal of the protective group.

Among the starting materials for the compounds of this invention, the compound (IVa) can be obtained by the methods shown in reaction scheme (9).

The compound (IVa) can be obtained by reaction of the is blowing halogenoalkanes his or reaction with R8SO2Cl, or by reaction of the compound (A) with compound (XIb), or by reaction of the compound (IIbc) with compound (Chi) to obtain compounds (IVaa), followed by reaction with compound (IX) to obtain compounds (IVab), followed by halogenoalkanes his or reaction with R8SO2Cl.

Among the starting materials for the compounds of this invention, the compound (IVb) can be obtained by the methods shown in reaction scheme (10).

Compound (IVb) can be obtained by removing the protective group of the compound (IVbb) or by reaction of the compound (IIA) with the compound (XIId), Intermediate product (IVbb) can be obtained by reaction of the compound (IIb) with a compound (XIIb), by reaction of the compound (IVa) with a compound (Ha), by reaction of the compound (IVba) with compound (IX) or by reaction of the compound (IIA) with the compound (XIIc).

Among the starting materials for the compounds of this invention, the compound (VIa) can be obtained by the methods shown in reaction scheme (11).

The compound (VIa) can be obtained by reaction of the compound (IIb) with a compound (XIIIb), by reaction of the compound (IVa) with a compound (XIIIa), by reaction of the compound (VIaa) with compound (IX) by reaction of the compound (IIA) with the compound (XIIIc) or by reaction of the compound (IVb) with a compound (XIIId).

The compound (VIb) can be obtained by reaction of the compound (VIa) with compound (XIVa), by reaction of the compound (IVa) with a compound (XIVb), by reaction of the compound (IIA) with the compound (XIVc), by reaction of the compound (IIb) with a compound (XIVd), by reaction of the compound (IVb) with a compound (XIVe), or by reaction of the compound (IVba) with compound (IX).

Among the starting materials for the compounds of this invention, the compound (VIII) can be obtained by the methods shown in reaction scheme (13).

The compound (VIII) can be obtained by reaction of the compound (VIaa) with compound (VIIa), by reaction of the compound (A) with compound (IIIa), by reaction of the compound (VIba) with compound (VIIb), by reaction of the compound (IIbc) with compound (IIIb), removing the protective group of the compound (IVba) to obtain compounds (IVbc) followed by reaction with compound (Vb) or halogenoalkanes connection (IVaa) or by reaction with R8SO2Cl to obtain the compound (IVac) followed by reaction with compound (Va).

The reaction of the following compounds described in reaction schemes from (8) to (13), i.e. (VIaa) and (VIIa), (As) and (IIIa), (IIbc) and (IIIb), (VIba) and (VIIb), (IVbc) and (Vb), (IVac) and (Va), (IVb) and (XIVe), (IIb) and (XIVd), (IIA) and (XIVc), (VIa) and (XIVa), (IVa) and (XIVb), (IVa) and (XIIIa), (IIb) and (XIIIb), (IIA) and (XIIIc), (IVb) and (b), (IIa) and (b), (VIaa) and (IX), (VIba) and (IX), (IVba) and (IX), (IVaa) and (IX), (AA) and (IX), (As) and (IX), (IIb) and (IX) and (IIbc) and (IX) can be carried out in conditions similar to the reaction scheme (1). The reaction can be carried out also in the absence of solvent. Molar ratio of the compounds may not necessarily be firmly established, but they may be in the range from 0.1:1 to 1:0,1.

Intermediate products (IVba), (IVbc), (VIaa) and (VIba) described in the reaction schemes from (10) to (13) can be obtained by the methods set forth in reaction schemes from (14) to (16).

Connection (IVba) can be obtained by reaction of the compound (IIbc) with compound (XIIb), by reaction of the compound (IVac) with compound (Ha) or by reaction of the compound (A) with compound (XIIc).

Connection (IVbc) can be obtained by reaction of the compound (A) with compound (XIId) or by reaction of the compound (A) with compound (XIIc) to obtain compounds (IVba) with subsequent removal of the protective group.

Connection (VIaa) can be obtained by reaction of the compound (IIbc) with compound (XIIIb), by reaction of the compound (IVac) with compound (XIIIa), by reaction of the compound (A) with compound (HS) or by reaction of the compound (IVbc) with compound (XIIId).

Connection (VIba) can be obtained by reaction of the compound (VIaa) with compound (XIVa), reaction seeding (XIVd) or by reaction of the compound (IVbc) with compound (XIVe).

The reaction of the following compounds described in reaction schemes from (14) to (16), i.e. (As) and (HS), (As) and (XIId), (IIbc) and (XIIb), (IVac) and (XIIa), (IVac) and (XIIIa), (IIbc) and (XIIIb), (As) and (XIIIc), (IVbc) and (XIIId), (VIaa) and (XIVa), (IVac) and (XIVb), (As) and (XIVc), (IIbc) and (XIVd) and (IVbc) and (XIVe), can be carried out in conditions similar to the reaction scheme (1). Furthermore, the reaction can be carried out also in the absence of solvent. Molar ratio of the compounds may not necessarily be firmly established, but they may be in the range from 0.1:1 to 1:0,1.

The methods shown in reaction scheme (17), can be used as ways to obtain the structure of benzimidazole.

A derivative of benzimidazole of the formula (XVc) can be obtained by condensation of a derivative diaminobenzene formula (XVa) with compound (XVI). In addition, the benzimidazole derivative of the formula (XVd) can be obtained by condensation of a derivative diaminobenzene formula (XVb) with compound (XVI) or by reaction of the compound (XVc) with compound (IX). The intermediate product (XVb) can be obtained by reaction of the compound (XVa) with compound (IX) or the condensation of compounds (A) in reducing conditions.

With regard to conditions obtain, then a reference can be made to the methods described, for example, in J. Org. Chem., 28, 1931 (1963); J. Chem. Soc., 2238 (1953); J. ); J. Org. Chem., 56 (6), 2260 (1991); Synth. Commnn., 16(1), 35 (1986); Khim. Geterotsikl. Soedin. , 71 (1980); Chem. Soc. C., 20 (1967); Chim. Ther., 2, 95 (1967); J. Org. Chem. , 27, 2163 (1962); Chem. Pharm. Bull., 12, 773 (1964); J. Chem. Soc. , 2296 (1959); J. Am. Chem. Soc., 79, 4391 (1957); J. Chem. Soc., 1401 (1949).

The above methods of connection (A), (AC), (IIbc), (IIba), (IVac), (IVaa), (IVbc), (IVba), (VIaa), (VIba) and (VIII) can be obtained directly from compound (XVa). In addition, compounds (IIab), (IIA), (IIb), (IIbb), (IVa), (IVab), (IVbb), (IVb), (VIa), (VIb) and (I) can be obtained directly from compound (XVb).

To obtain compound (XVa) and (XVb), you can use the methods shown in reaction scheme (18).

The compound (XVa) can be obtained by reaction of the compound (XVIIa) with ammonia to obtain the compound (XVIIb), and then recover. In addition, compound (XVb) can be obtained by reaction of the compound (XVIIa) with compound (IXb) to obtain compounds (XVIIc) and then restore it.

As described above, the authors of the present invention it was found that the compound of formula (I) of the present invention is a excellent connection as a strong anti-allergic agent and it can be used not only as an active ingredient of a prophylactic or therapeutic agent for hay fever, kropiwnicka against other diseases related to substance P, for example, eye diseases such as conjunctivitis, spring catarrh of the eyes; inflammatory diseases such as chronic rheumatoid arthritis; pain, such as migraine, headache, dental pain and prolonged dull pain accompanying various diseases; gastrointestinal diseases such as ulcerative colitis and Crohn's disease, and mental illness, such as depression and dysthymia. Thus, this invention provides a pharmaceutical composition comprising a compound of this invention in amounts effective to treat these diseases.

By way of introducing the compounds of this invention may be parenteral, injection (hypodermic, intravenous, intramuscular or intraperitoneal injection), ointment, suppository or aerosol, or oral administration of tablets, capsules, granules, pills, syrup, liquid, emulsion or suspension.

Pharmaceutical or veterinary composition comprising a compound of this invention contains the compound of the present invention in an amount of from about 0.01 to 99.5%, preferably from about 0.1 to 30%, counting on the total weight of the composition.

In addition to the connection gannovka composition can contain several compounds of this invention.

An effective dose of a compound of this invention typically ranges from about 0.003 to 1.5 g, preferably from about 0.01 to 0.6 g per adult patient per day, although its clinical dose depends on age, weight, susceptibility and conditions of the patient. However, if necessary, the dose may be outside the above range.

The compounds of this invention can be made in the form of various preparative forms suitable for administration in accordance with pharmaceutically conventional ways.

Namely, tablets, capsules, granules or pills for oral administration can be obtained with filler, such as sugar, lactose, glucose, starch or mannitol; a binder such so hydroxypropylcellulose, syrup, Arabian gum, gelatin, sorbitol, tragakant, methylcellulose or polyvinylpyrrolidone; dezintegriruetsja tools, such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose or polyethylene glycol; a cross-linking agent, such as talc, magnesium stearate or calcium or silicon dioxide; or lubricating agents, such as sodium laurate or glycerin.

Injections, solutions, AMTA, such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butyleneglycol or polyethylene glycol; surfactants such as ether sorbitan and fatty acids, polyoxyethylene ether sorbitan and fatty acids, polyoxyethylene a fatty acid ester, polyoxyethylene simple ester of hydrogenated castor oil or lecithin; a suspending agent, such as a derivative of cellulose, such as sodium salt of carboxymethyl or methyl cellulose, or natural rubber, such as tragakant or Arabian gum; or preservative, such as ether, peroxybenzoyl acid, benzalkonium chloride or a salt of sorbic acid.

Ointment for percutaneous absorption can be obtained by using white soft paraffin, paraffin oil, higher alcohol, macrogol ointment, hydrophilic ointment or filler type water gel.

Suppositories can be obtained using, for example, cocoa butter, polyethylene glycol, lanolin, triglycerides of fatty acids, coconut oil or Polysorbate.

The best way of implementation examples of the invention

Now the invention will be described in further detail with reference to The clear this invention is in any case is not limited to these specific examples.

The symbol "so square" means "melting point".

REFERENCE EXAMPLE 1: N-Methyl-N-(benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine

A solution containing 1.1 g of 2-chlorobenzimidazole and 1.6 g of N,N'-dimethyl-1,3-projektionen, was heated at a temperature of from 120 to 130oC for two hours. After cooling, the solution was diluted with 50 ml of chloroform and washed with 30 ml of 1 N. aqueous solution of potassium carbonate. It was dried over anhydrous sodium sulfate and the solvent is then drove away under reduced pressure. The obtained residue was dissolved in 50 ml of chloroform and to it was added 5 g of di-tert-BUTYLCARBAMATE. The mixture was left standing at room temperature for one hour and then the solvent is kept at reduced pressure. The obtained residue was recrystallized from diethyl simple ether, obtaining 2.1 g fileidentifier connection in the form of pale brown crystals.

REFERENCE EXAMPLE 2: N-Methyl-N-(benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine

In the same manner as in reference example 1, there was obtained 1.1 g of the above compound in view of CNY EXAMPLE 3: N-Methyl-N-(benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine

2-Chloromethylbenzene in the amount of 4.0 g) was added under ice cooling to a solution comprising 5.0 g of N,N'-dimethyl-1,3-Propylenediamine and 30 ml of ethanol, and the mixture was stirred for one hour. The mixture after returning to room temperature, stirred overnight, after which the solvent is kept at reduced pressure. To the obtained residue were added 50 ml of water and 50 ml of chloroform and potassium carbonate was added until, until the mixture became basic. The organic layer was separated and dried over anhydrous potassium sulfate and the solvent is then drove away under reduced pressure. To the obtained residue were added 50 ml of chloroform and to this solution was added 8 g of di-tert-butyl-dicarbonate. The mixture was stirred at room temperature for one hour and then the solvent is kept at reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/ethanol=9/1) to give 7.0 g of the above compound as a brown oily substance.

REFERENCE EXAMPLE 4: N-Methyl-N-(benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine

In the same manner as in reference example 3 was obtained 6.5 g of the above soedinitelnotkannye.

REFERENCE EXAMPLE 5: N-Methyl-N-(1-(4-terbisil)benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine

A solution comprising 1.0 g of N-methyl-N-(benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine, 540 mg of 4-formanilide, 3 g of potassium carbonate and 20 ml of dimethylformamide was subjected to reaction at room temperature overnight with stirring. Then he was subjected to reaction at a temperature of from 50 to 60oC for 10 hours. Then thereto was added 50 ml of water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate (30 ml) and the solvent is then drove away under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate) to give 1.4 g of the above compound as a colorless oily substance.

REFERENCE EXAMPLE 6: N-Methyl-N-(1-(4-terbisil)benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine

In the same manner as in reference example 5 was obtained 1.3 g of the above compound as a pale-yellow oily substance from 1.0 g of N-methyl-N-(benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine.

REFERENCE EXAMPLE 7: N-Methyl-N-(1-(4-terbisil)Ben example 5 there was obtained 5.0 g of the above compound as a pale-yellow oily substance from 6.5 g of N-methyl-N-(benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine.

REFERENTIAL EXAMPLE 8: N-Methyl-N-(1-(4-terbisil)benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine

In the same manner as in reference example 5 was obtained with 6.1 g of the above compound as a pale-yellow oily substance from 6.0 g of N-methyl-N-(benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine.

Example of GETTING a 1: Hydrochloride of N-Methyl-N-(1-(4-fluoro-benzyl) benzimidazole - 2 - yl) - N' - methyl - N' - (3,5 - bis (trifluoromethyl) benzylaminocarbonyl)-1,3-Propylenediamine

Triperoxonane acid at 2 ml) was added to 1.3 g of N-methyl-N-(1-(4-terbisil)benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,3-Propylenediamine and the mixture was stirred at room temperature for one hour. Then thereto was added 50 ml water and 50 ml of chloroform and potassium carbonate was added thereto until then, until the mixture became basic. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent is kept at reduced pressure, obtaining 970 mg of colorless maslany the a and the mixture was heated and stirred at 120oC for two hours. After cooling, the obtained oily substance was purified column chromatography on silica gel (eluent:ethyl acetate/ethanol = 9/1) to give 500 mg of a colorless oily substance. 250 mg of This oily substance was dissolved in 3 ml of ethanol and thereto was added 3 ml of 28% of a mixture of chloride-hydrogen acid-ethanol. The solvent is kept under reduced pressure and the residue was led from diethyl simple ester, getting 280 mg of the above compound as colorless crystals (so pl. 170,0-172,0oC).

Example of GETTING a 2: Hydrochloride of N-methyl-N-(1-(4-terbisil) benzimidazole-2-yl)-N'-methyl-N'-(3,5-bis(trifluoromethyl) benzylaminocarbonyl)-1,2-Ethylenediamine

In the same way as in the example of obtaining 1 that has received the above-mentioned compound as colorless crystals from N-methyl-N-(1-(4-terbisil)benzimidazole-2-yl)-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine (so pl. 182,0-to 185.0oC).

An EXAMPLE of OBTAINING 3: Hydrochloride of N-methyl-N-(1-(4-terbisil) benzimidazole-2-yl)methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl) benzylaminocarbonyl)-1,3-Propylenediamine

In the same way as in the example of obtaining 1 that has received the above-mentioned compound in the form of a pale yellow oily S="ptx2">

EXAMPLE 4: the Hydrochloride of N-methyl-N-(1-(4-fluoro-benzyl) benzimidazole-2-yl)-methyl-N'-methyl-N'-(3,5-bis(trifluoromethyl) benzylaminocarbonyl)-1,2-Ethylenediamine

In the same way as in the example of obtaining 1 that has received the above-mentioned compound as colorless crystals from N-methyl-N-(1-(4-terbisil)benzimidazole-2-yl)methyl-N'-methyl-N'-tert-butoxycarbonyl-1,2-Ethylenediamine (so pl. 144, 0mm-145,0oC).

EXAMPLES GET 5-13.

In the same way as in the example of obtaining 1, there were obtained compounds are shown in table 2, in the form of their hydrochloride.

PRESCRIPTION EXAMPLE 1: Tablets, g:

The compound of this invention - 10

Lactose - 260

Microcrystalline cellulose - 600

Corn starch - 350

Hydroxypropylcellulose - 100

Carboxymethylcellulose-Sa - 150

Magnesium stearate - 30

Just - 1500

The above ingredients were mixed conventional way and turned in 10000 covered sugar tablets containing 1 mg of active ingredient per tablet.

PRESCRIPTION EXAMPLE 2: Capsules, g:

The compound of this invention - 10

Lactose - 440

Microcrystalline cellulose - 1000

Magnesium stearate - 50

Just - 1500

Visayas, containing 1 mg of active ingredient per capsule.

PRESCRIPTION EXAMPLE 3: Soft elastic capsules, g

The compound of this invention - 10

PEG 400 - 479

The glycerides of saturated fatty acids - 1500

Peppermint oil - 1

Polysorbate 80 - 10

Just - 2000

The above ingredients were mixed and then filled into soft gelatin capsules 3 accepted way to get 10000 soft elastic capsules containing 1 mg of active ingredient per capsule.

PRESCRIPTION EXAMPLE 4: Ointment, g:

The compound of the present invention to 1.0

Liquid paraffin - 10,0

Cetanol - 20,0

White soft paraffin - 68,4

Ethylparaben - 0,1

1-Menthol - 0,5

Just 100,0

The above ingredients were mixed by a common way to obtain a 1% ointment.

PRESCRIPTION EXAMPLE 5: Suppository, g:

The compound of this invention - 1

Watersol n* - 478

Watersol W35* - 520

Polysorbate 80 - 1

Just - 1000

* Brand name connection type triglyceride

The above ingredients were mixed in the melting accepted way and poured into a container for suppository followed by cooling and solidification to obtain 1000 PCs/BR> The compound of the present invention, mg - 1

Distilled water for injection, ml - 5

Whenever required, the injection is obtained by dissolving the compounds in distilled water.

EXAMPLES TEST

Inhibitory effect on induced by substance P and histamine reduction allocated ileum of the Guinea pig.

Connection

Compound was dissolved and diluted in 100% dimethyl sulfoxide (DMSO). Substance P (SP, Peninsula Laboratories or Peptide Institute) and histamine dihydrochloride (Wako Pure Chemicals) was dissolved and diluted with distilled water. The content of DMSO in the bath for body did not exceed 0.25%. /about.

Ways

Male Hartley Guinea pigs (300-400 g) were killed by a blow to the head. Remove the terminal ileum and ileum strips (15-20 mm) suspended at a voltage of 0.5 g in the tub for body 20 ml solution containing modified Tyrode, which was kept at 30oWith and aeronavali a mixture of 95%O2+5%CO2. Responses were recorded as a result of isotopically. Tissue was balanced for 15 min and then received a permanent response to histamine (1 μm). Then received induced by substance P (0.01 µm) or histamine (0.1 MKN) is a substance P or histamine with the test compound was expressed as a percentage of the contractile reactions without the test compounds. IC50was the concentration of test compound required to prevent 50% of the contractile response induced by substance P or histamine. Rooms compounds of the tested compounds correspond to the numbers of examples of the preparation (see tab.3)

Industrial applicability

The compounds of this invention exhibit antagonistic activity against substance P and can be used as anti funds.

Example of getting

Example 14 (see tab.4)

1. A derivative of benzimidazole of the formula (I)

< / BR>
or its salt,

where a represents a single bond or C1-2-alkylenes group;

R6is a hydrogen atom or a C1-4is an alkyl group;

B - C2-3-alkylenes group;

X is an oxygen atom;

each of R1and R2is a hydrogen atom;

E - C1-2-alkylenes group;

R3is a phenyl group (this phenyl group may be optionally substituted by a halogen atom);

each of R4and R5that are independent from each other, represents a hydrogen atom or a C1-4is an alkyl group;

D - C1-2-alkylenes group

Ar is a phenyl group (this phenyl group may be the stylish group).

2. The compound or its salt under item 1, where a is single bond, CH2CH2CH2;- CH2CH2CH2CH2CH2D - CH2or CH2CH2E - SN2or CH2CH2; Ar is phenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-itfeel, 3-itfeel, 4-itfeel, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2-were, 3-were, 4-were, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-differenl, 2,4-differenl, 2.5-differenl, 2,6-differenl, 3,4-differenl, 3,5-differenl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2.5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl, 2,4-diiodophenyl, 2.5-diiodophenyl, 2,6-diiodophenyl, 3,4-diiodophenyl, 3,5-diiodophenyl, 2,3-bis-(trifluoromethyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl, 2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 2,3-dimetilfenil, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 2,3-acid, 2,4-acid, 2,5-acid, 2nd from R1and R2is a hydrogen atom; R3- phenyl, 4-forfinal, 4-chlorophenyl, and each of R4and R5is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl and R6is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl.

3. The compound or its salt under item 1, where a represents a single bond or CH2;- CH2CH2or CH2CH2CH2; D is CH2; E - SN2or CH2CH2; Ar is phenyl, 2-chlorophenyl, 2-methoxyphenyl, 3, 5dimethylphenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-acid, 2,5-dichlorophenyl or 2-chloro-5-triptoreline; X is an oxygen atom; each of R1and R2is a hydrogen atom; R3- 4-forfinal; each of R4and R5is a hydrogen atom or methyl and R6is a hydrogen atom or methyl.

4. The compound or its salt according to p. 3, where E is CH2, R3- 4-Fortunella group.

5. The compound or its salt according to p. 4, where Ar is 3,5-bis(trifluoromethyl)phenyl.

6. The tool, which has antagonistic activity against substance P and antihistaminas activity, which contains a compound or its sostavljaet phenyl group (this phenyl group may be optionally substituted by a halogen atom, C1-4is an alkyl group, a C1-4the alkoxy group).

 

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