JPS615068A - Piperazine and piperidine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The prior art has disclosed a large number of 1-((heterocyclyl)alkyl)biperanones having pharmaceutical properties as well as a large number of 1-
Substituted 4-(diarylmethyl)piperazine and 4
-(diarylmethoxy)piperidine derivatives have been found. Such compounds are described in the following references: U.S. Patent 3,362,956 /I 3,472,854 // 3,369,022 // 2 t 8 B 2 + 2711 /
3,956,328 and C.A., 64.3499g (1966).

The essential difference between the compounds of the present invention and the previous ones is that B is present at the 1-position of the piperazine or piperidine group.
It depends on the nature of the -CJ2n- group and/or the nature of the diarylmethyl or diarylmethoxy group present in the 4-position of the piperazine or piperidine group, respectively.

The present invention relates to novel chemical compounds, particularly piperazine and piperidine derivatives represented structurally by the formula and pharmaceutically acceptable acids thereof: where Ar' and Ar2 are respectively independently phenyl,
selected from the group consisting of substituted phenyl and pyridinyl, wherein the substituted phenyl is selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl and nitro. Z is phenyl having a substituent, m is an integer of 0 or 1, and A is a member selected from the group consisting of ':N- and CH-, provided that A is; m is 0 when At least two carbon atoms are present in the linear portion of the chain linking B and the piperidine or piperazine 9 atoms, and [wherein R1 and R2 are each independently hydrogen, halo,
is selected from the group consisting of lower alkyl and trifluoromethyl; lower alkino to lower alkylcarbonyl-level alkyloxycarbonyl-lower alkyl, carboxy-lower, e. alkyl, phenyl, phenylmethyl,
a group having a lower alkylamino group selected from the group consisting of hydroxymethyl and lower alkenyl, and I W [wherein R1 and R2 are each independently hydrogen, halo, lower alkyl , and trifluoromethyl, and M is hydrogen, lower alkyl, phenyl, phenylmethyl,
a member selected from the group consisting of mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino' and cycloalkyl having 8 to 6 carbon atoms; I am a member of the group.

The term "lower alkyl" used in the above description and in the following definitions refers to straight-chain and branched hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, etinope, 1-methylethyl, 111-dimethyl. Ethyl, propyl, butyl, pentyl, hexyl, etc. are all included, and "lower alkenyl" means straight chain and branched alkenyl groups having 2 to 6 carbon atoms, such as evaethynyl, 1-methylethynyl, 1-
7'ropenyl, 2-7'ropenyl, 2-7'tenyl, 1
-Methyl-2-butenyl, 2-pentenyl, 2-hexenyl, etc., and "cycloalkyl" is a cyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl,
cyclobutyl, cyclopentyl and hcyclohexyl, the expression [C,nH2WJ has at least 2 carbon atoms in the linear part of the chain linking the group B and the piperidine or piperazine 9. Straight and branched alkylene chains having 2 to 6 carbon atoms, such as 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-1
3-propanediyl, 1,4-butanediyl, 2-methyl-1,4-butanediyl, 1,5-pentanediyl, 116-hexanediyl, and the term "halo" generally refers to atomic numbers less than 127. halogens, namely fluoro, chloro, bromo and iodo.

The compounds of the present invention of the formula (1), excluding those in which B represents a 2-amino-17H-benzimidazol-1-yl group, are those of the formula (n
), where n is as defined above and B is the hole 7? l R2 (wherein R1 and R2 are as defined above) as defined above except for the 2-amino-IH-benzimidazol-1-yl group, and W is the corresponding A suitable reactive ester function derived from an alcohol, such as halo, methanesulfonyl, 4-methylbenzenesulfonyl, etc.] is replaced with a suitable piperidine or piperazine derivative of formula ([), where A, mXA r ' and Ar2
as defined above]: (U) (III) The above condensation reaction is preferably carried out in a suitable organic solvent inert to the reaction, For example, lower alkanols, such as methanol, ethanol, propatool, butanol and similar alkanols; aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, etc.; ethers, such as 1,4-dioxane, 1,1'-oxybispropane. etc.: ketones such as 4-methyl-2-pentanone: N,
Performed in N-dimethylformamide; nitrobenzene, etc. To remove the acid liberated during the reaction process,
A suitable base can be added, for example an alkali metal or alkaline earth metal carbonate or bicarbonate.

Small amounts of suitable metal iodides, such as sodium or potassium iodide, can also be added as reaction promoters. To increase the reaction rate, somewhat elevated temperatures are suitable, and preferably the reaction is carried out at the reflux temperature of the reaction mixture.

In this and the following preparations, the reaction product is separated from the reaction mixture and it is optionally further purified by applying methods commonly known in the art.

B is 2. In the compound (l-α) of formula CI) representing a -7minor IH-benzimidazol-1-l group, B represents a 2-(lower alkyloxycarbonylamino)-1H-benzimidazol-1-l group. from the corresponding compound (1-6) of I, by decarboxylating the latter under hydrolytic conditions, e.g. by acid hydrolysis using a suitable strong acid such as hydrochloric acid, hydrobromic acid or sulfuric acid; It is easily prepared by alkaline hydrolysis using a suitable strong base such as sodium or potassium oxide.

B group in the compound or intermediate product of formula (1) is 2-(lower alkyloxycarbonylamino)-1H-benzimidazol-1 or 2-(lower alkylcarbonylamino)-1H-benzimidazol-1 When denoting a group -, the group can also exist in different tautomeric forms as noted below: Such tautomeric forms of the compound of formula (,1) are of course also within the scope of the present invention. It is within.

On the other hand, the compound of formula (1) represented by formula (1-c) [R,'', R2, nXAXA r' and Ar2 are as defined above] .ring closure of a suitable intermediate of formula (IV) using a suitable cyclizing agent as methods known in the art for preparing 3-dihydro-2H-benzimidazolone-2-ones; Advantageously suitable cyclizing agents that can be used include, for example, urea, carbonyl dichloride, alkali metal isocyanates, and the cyclization reaction is carried out according to methods generally known in the art.

For example, when urea is used as a cyclizing agent, compound (1-c) can be easily obtained by stirring and heating the reactants together in the absence of a solvent.

The above groaning method is shown below.

Tongue 1-------1" (1-C) Formula (I-C
) is a compound of the corresponding formula (V) [wherein R'', R2,
n, A, m, Ar' and Ar2 are as defined above, and P is a suitable protecting group] by removing the protecting group according to conventional methods. Examples of such protecting groups include lower alkyloxycarbonyl and formula % [wherein R3 and R4 represent different groups, R3 is preferably lower alkyl and R4 is preferably hydrogen,
lower alkyl or phenyl] substituted ethynyl groups. When the protecting group is lower alkyloxycarbonyl, it can be easily removed by alkaline hydrolysis, and when the protecting group is a substituted ethynyl group, it can be removed by acidic hydrolysis of the appropriate intermediate ('V). easily removed. In carrying out the acid hydrolysis to remove the substituted ethynyl group from (V,), a wide variety of protic acids can be conveniently used, including mineral acids such as hydrochloric, hydrobromic, nitric and phosphoric acids; and organic acids such as acetic acid, prono;
Contains ethanedionic acid. Additionally, the reaction may be carried out in an organic solvent inert to the reaction, such as is commonly used in such types of hydrolysis reactions, such as lower alkanols such as methanol, ethanol, 2-nolopanol, etc. It can also be carried out inside.

A method similar to the above-mentioned method for producing compound (1-6') from ([V)] is used one more time to produce IH-benzimidazole from 1,2-benzenediamine, which is known in the art. By reacting (IV) with a suitable cyclizing agent according to a method, formula (id) I R+ R2 (■-d) [wherein 7? I, A! 2, Ru, A, m, Ar'
and Ar2 are as defined above, and M' is selected from the group consisting of lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino and cycloalkyl. can also be manufactured. Depending on the nature of Ml in compound (1-d), for example, the following cyclizing agents can be used.

When A/l represents hydrogen, formic acid or tri(alkyloxy)methane can be used as the cyclizing agent.

When M' represents lower alkyl, phenyl, phenylmethyl or cycloalkyl, a carboxylic acid of the formula 8% () [wherein R5 is lower alkyl, phenyl, phenylmethyl or cycloalkyl], or its Functional 1'' derivatives, such as acyl halides, estenopeamides or nitriles derived from said acids, or iminoesters of the formula, in which R5 is as defined above, or aldehydes of the formula, or Addition products of silane and alkali metal hydrogen sulfates can be used. When the cyclizing agent is an aldehyde, a suitable oxidizing agent is added to the reaction mixture, such as nitrobenzene, mercuric oxide, Cu(l[) and Pb(l salts) or other suitable oxidizing agents known in the art. Alternatively, the aldehyde itself can also act as an oxidizing agent when added in excess.

When Ml represents mercapto, for example, carbon disulfide,
Cyclizing agents such as thiourea, dichlorinated carbochionic acid, ammonium thiocyanate, and the like can be used.

When Ml is an amino group, the ring closure can be carried out using 7-anamide or a metal salt thereof, preferably an alkali or alkaline earth metal salt, or BrCN.

When Ml represents lower alkyloxycarbonylamino, the cyclizing agent is, for example, a suitable lower argyl (iminomethoxymethyl) carbamate of formula (IX) or formula (X) (X) [wherein R6 is hydrogen or methyl] lower alkyl [(lower alkoxylbonyl fumino) (R6-thio)]
methylene] carbamate, or lower alkyl carbonothiocyanatidate of formula (XI) (lower furkyl) -0-C-NC8(XI), or lower alkyl carbonothiocyanatidate of formula (XI) S (lower alkyl) -NH-C-0- (Low grade 7A4 le)
□Ql) lower alkyl lower alkyl carbamothioate, di-lower alkyl cyanimide dicarbonate can be used.

All of the above cyclization reactions can be carried out according to known methods as described in text i+ij:.

On the other hand, the compound of formula (he) R' R2(1-,) can be prepared by preparing a suitable 2-amino-IH-benzimidazoly-container of formula (■-〇) according to standard N-acylation methods.
For example, (1-4
) and an appropriate primary alkyl carbonyl halide or a representative alkyl carboxylic acid to form 1.14.

Formula (1-f) [wherein A'', R2, n, AXmXAr' and Ar
2 is as defined above and L' is lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-
selected from the group consisting of lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroquinemethyl and lower alkenyl, with the proviso that the unsaturation in the lower alkenyl is in a position other than α ) can be produced by introducing L' into the compound.

Depending on the nature of the L1 group added, the following methods can be used.

When Z and I represent lower alkyl, lower alkyloxycarbonyl-lower alkyl, phenylmethyl or lower alkenyl (in this case the symbol L1α is used), (1
-C) The introduction of Llα into (I-C) and the formula L'a -
A suitable reactive ester of W (X ■) [wherein L1α
is as defined above and W is the formula (n)
has the same meaning as given in the definition of starting materials].

The condensation of (XIV) and (1-C) is the reactive ester (II
) and the intermediate product of formula (1) can be carried out under the same conditions as those described in -F. In order to increase the reaction rate, small amounts of suitable macrocyclic polyethers, such as 2,8,
11.12-dibenzo-1,4,7,10,18,16
-hexaoxacyclooctadeca-2,11-diene,
Adding is the N value.

When the L1 group to be introduced is lower alkyloxycarbonylethyl, the introduction of the group is carried out by formula (1-C) and formula (XV
) (lower alkyl)00C-CH-=CH2(Xv) (
(lower alkyl) 2-norobenoate. The reaction is conveniently carried out in an organic solvent inert to the reaction, such as aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; ethers such as 1,1'-oxybisethane, 2,2' -oxyxpropane, tetrahydrofuran, 1,4-dioxane, etc., preferably in the presence of a suitable aminium hydroxide such as, for example, N,N,N-triethylbenzene methanaminium hydroxide.

Formula (1-f) in which Z and I represent carboxy-lower alkyl
The compound has the corresponding lower alkyloxycarbonyl-
The latter can be readily derived from lower alkyl-substituted compounds by hydrolysis of the latter in conventional manner, for example with aqueous alkali, liberating the acid from the ester.

When the L1 group is lower alkylcarbonyl, it is conveniently combined with a suitable acylating agent derived from the lower alkylcarboxylic acid corresponding to (1-C), such as a halide,
It is preferably introduced according to standard N-acylation methods by reaction with chloride or anhydride.

When Ll represents lower alkylaminocarbonyl, it can be dissolved in a suitable organic solvent which is inert to the reaction.
For example, the reaction of (1-17) with a suitable isocyanatoalkane in an ether such as 1,1'-oxybisethane, 2,2'-oquinpispropane, 1,4-dioxane, etc. Introduced by n.

When Ll is a hydroxymethyl group, its introduction can be easily carried out by combining (J-C) with 71, lumaldehyde in a suitable organic bath such as N, N-, 'methylformamide, etc. It is carried out by reaction.

On the other hand, the compound of formula (1-g) [wherein B, n, Ar' and Ar2 are as defined above] is a compound of formula (■) and ([) for the production of compound (11). Under the same conditions as mentioned above, the formula (XV
I) are prepared by condensing the piperazine derivative of formula (X) with a suitable reactive ester of formula (X), where Ar', Ar2 and W are as defined above: -h) compounds are conveniently prepared from the corresponding 18H-substituted congeners by standard S-alkylation methods, e.g.
'Lshi', in medium, 1. Produced by the reaction of a mercago compound with a suitable halo-lower alkane in a sand alkanol such as ethanol, 2-propanol, butanol, etc.

A number of intermediates of formula (n) are known compounds, and some of them are described in U.S. Patent Application Nos. 597-793 and 1975, filed July 21, 1975.
U.S. Patent Application No. 62, filed October 8,
No. 0,727, and they can all be manufactured according to methods known per se. Depending on the nature of B in the intermediates (11), the following methods can be used for their preparation.

Formula (11-+z) 0 The intermediate product can be produced as follows.

A suitable substituted 2-□chloromitrobenzene of formula (X) is combined with a suitable aminoalkanol (XIX) and the reactants are combined in a suitable organic solvent inert to the reaction, e.g. a lower alkanol, e.g. When reacted by refluxing in ethanol, 2-propanol, butanol, etc., the (2-nitrophenyl)aminocoalkanol of formula (XX) is obtained; - Nitro-amine reduction by catalytic hydrogenation using a nickel catalyst. The intermediate product (XM) thus obtained is then reacted with a suitable cyclizing agent (as described for the preparation of compounds (I-C) from The alcohol of formula (XXn) obtained from f is then converted into the desired reactive ester (n-+z) by application of methods known in the art. Phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride, etc. When the reactive ester is an iodide, it is preferably prepared from the corresponding chloride or bromide by reaction of the Other reactive esters, such as methanesulfonate and 4-methylbenzenesulfonate, are derived by substituting the alcohol with a suitable sulfonyl halide, such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively. Obtained by reaction with

The above reaction is clearly illustrated by the following schematic representation.

RI R2(XX) (X■) (XX) (XXI) (xxn) On the other hand, the intermediate product of formula (■-α) is 1) the compound of formula (xxm) [wherein R3 and R4 are defined above [as described above] is reacted with a haloalkanol of formula (XXIV) by a common N-alkylation method to obtain an alcohol of formula (XXV); and converted into a reactive ester group by conventional methods such as 111)
(XXVI) thus obtained is prepared by removing the substituted ethynyl group by acid hydrolysis as described for the preparation of (1-C) from (V).

The introduction of a hydroxyalkyl chain into (XXlfl) to obtain (XXIV) can be carried out by converting (XX[) into a suitable 2-(haloalkyloxy)tetrahydro 2H-
React with pyran to obtain intermediate S proboscis of formula (XX■),
This is carried out by hydrolytically removing its ether functionality, for example by treatment with aqueous hydrochloric acid.

When reactive ester (■-α) is mixed with no-ride (■
-α-1), it is possible to prepare (XX[ll) with an equal amount of the appropriate dihaloalkane (XXIX) in the presence of a suitable strong base such as e.g. sodium methoxide or an aqueous alkali and e.g. N-)! By the Macko Sza method using a quaternary ammonium catalyst such as J ethylbenzenemethanaminium chloride, the substituted ethynyl group can be reacted to give an intermediate of formula (XXM-u), which then converts the substituted ethynyl group into It is produced by removal by acid hydrolysis to give the desired halide (■-α-1).

When the substituted ethynyl group is substituted with another suitable protecting group, the same procedure is followed except that its removal must be carried out according to the method appropriate for the removal of the particular group involved. It should be noted that it can also be applied.

The above reaction is clearly explained by the following schematic representation. and L2 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkyloxycarbonyl-lower alkyl, phenyl, phenylmethyl and lower alkylaminocarbonyl. For convenience, (xxnr)
is prepared by introducing a reactive ester side chain into the starting material of formula (XXX) following a method similar to that described above for the preparation of intermediate (XX■) from .

The intermediate product of is prepared from the corresponding (■-α) by hydroxymethylation of the latter with formaldehyde in a conventional manner.

Intermediates of formula (II-d) other than those in which M represents a mercapto or lower alkylthio group are conveniently obtained by introducing a reactive ester side chain into the starting material of formula (XXXI). '727L -W group is introduced by the formula (x
Regarding the introduction of the group into the starting material of xn+) -F
T1 is carried out according to a method similar to that used.

Intermediates of the formula (ll-e) AI', in which R', R', A/', n and W are as defined above, can be prepared by a suitable compound of the formula (XXI). It is produced by ring-closing the alcohol using a suitable cyclizing agent as described above, and then converting the hydroxyl group of the intermediate product of the formula <XXXI thus obtained into a reactive ester group.

The intermediate product of (XXXIr) is (X
XXII-α), the intermediate product of formula (X It can be easily obtained by converting the hydroxyl functional group of (XXX[I[) into a reactive ester group.

(XXXII-ff) (XXX
[II) Reactive ester formation (n-f).

The intermediate product of formula (H-17) NH-Co-(lower alkyl) is the corresponding amine-substituted homolog RI
R2 according to methods known to those skilled in the art, e.g.
II-IL) with an appropriate lower alkyl carbonyl halide or an anhydride derived from an appropriate lower alkyl carboxylic acid, and is easily produced by N-acylation.

Intermediate products of formula (IV) can be obtained by condensing a suitable reactive ester of formula (XXXIV) with piperazine or piperidine derivatives of formula ([1)], followed by condensation of the intermediate product (XXXV) thus obtained. Reducing the nitro group to an amine group according to standard nitro-amine reduction methods, e.g. by reaction of the nitro compound with nascent ice cream, or by catalytic hydrogenation in the presence of a suitable catalyst, e.g. Raney nickel. It is obtained by

(XXXIV) Formula (XXXIV) used here as starting material
The reactive ester of formula (XX) is readily prepared from the alcohol of formula (XX) by converting its hydroxyl functionality to a reactive ester group according to standard methods such as those described above.

Intermediate products of formula (V) are obtained by condensing reactive esters of formula (XXXVI) with piperazine or piperidine derivatives of formula ([1)].

The reactive ester (XXXVI
) can convert the CnN2rLIV group to the formula (X
XX■) into the starting material.

Intermediates of formula (XVI) are prepared by combining a reactive ester of formula (II) with a piperazine derivative of formula (XXX), where Q is a suitable protecting group, such as phenylmethyl or lower alkyloxycarbonyl. reaction and then catalyzing the protecting group Q from the intermediate product thus obtained (XXXDO) according to standard methods known in the art, for example using a palladium catalyst on charcoal when Q represents phenylmethyl. by hydrogenation or, when Q represents lower alkyloxycarbonyl, by alkaline hydrolysis;
Manufactured by removing.

(XXX■) (XXXIX) Removal of Q -> (X Vl ) The intermediate product of formula (XVI-42) is obtained by reacting (XXXVI) with (XXX■) to obtain the intermediate product of formula CXL), and then It is prepared by removing the protecting groups P and Q by suitable methods generally known in the art.

IR2 (XL) (XVI-α) Intermediates (In) of the formula ([[) where A is :N- and m is 0 are generally known, and they are all known in the art. Manufactured by applying a method.

Such intermediate products can be obtained, for example, by first subjecting a suitable aroyl halide to a Friedel-Craf reaction with a suitable allene to give Ar',Ar2-methanone, which is then subjected to conventional methods, e.g. borohydration. Produced by reduction to the corresponding methanol using sodium. The latter is then converted into the reactive ester (X■) according to standard methods for the preparation of reactive esters from alcohols, and then reaction of (X■) with piperazine yields the desired intermediate ('l[ I-CL) is obtained.

The intermediate product ([-1+) of formula ([), where A is CH- and m is 1, is a 4-piperiditeur of formula (XL I ) where Q is a suitable protecting group as described above. X■
) with a suitable reactive ester of
Next, the protecting group of (XLII) thus obtained is removed by a conventional method to easily produce it.

(XZ, I) (X■) CXL old (
[[-b) The main starting materials used in all the above preparations are generally known, and they are all prepared according to general methods known to those skilled in the art.

Compounds of formula , such as hydrohalic acids, such as hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxyprohanonic acid, 2-oxopropanone. acid, propanedioic acid, butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutenedioic acid, 2,3-dihydroxybutenedioic acid, 2
-hydroxy-1,2,8-propanetricarboxylic acid,
Benzoic acid, 8-phenyl-2-propenoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, Thunzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexasulfamic acid, 2-hydroxybenzoic acid , 4-amino-2-hydroxybenzoic acid, and similar acids. Conversely, the salt form can also be converted to the free base form by treatment with an alkali.

The compounds of the present invention of formula (1) and their pharmaceutically acceptable acid addition salts have strong antianaphylactic and antihistamine properties, and they are suitable as such for human and animal treatment. It is a useful agent for The useful anti-anaphylactic and anti-histamine properties of the compounds of the invention were determined by the test methods described below. This is clearly shown by the results.

The compounds listed in the accompanying table are not intended to serve the purposes of the present invention, but rather include all useful anti-anaphylactic and anti-anaphylactic properties of all compounds within the scope of formula (1). It is emphasized that it is mentioned to illustrate histamine properties.

A. Materials and Methods The anti-anaphylactic and anti-histamine effects of the compound (1) of the present invention and its salts were studied in vivo in guinea pigs. Guinea pigs weighing 400-5001 F were sensitized to ovalbumin by intraplantar injection of 0.05 ml of antiserum into the left hind paw. The animals were then fasted and 24 hours after sensitization they were treated orally with saline (=control animals) or with specified doses of the compound.

Two hours after pretreatment with the compound, a histamine injection (at a dose of 50 μm) was given plantarly into the right hind paw. The diameter of both hindpaws was measured before and 10 minutes after the histamine injection. Thirty minutes after the histamine injection, the animals were given 0.6 kg of ovalbumin intravenously. All control animals developed typical anaphylactic shock symptoms (cough, dyspnea, convulsions) and 85 of these control animals died 15 minutes after the J11 albumin injection. ? The protection against F-death was used as a criterion for examining the effectiveness of the drug, and the evaluated ED5
The o value, that is, the oral intake when the guinea pig's protection was established at 50φ is shown on the lower garment.

The average histamine-induced edema in 200 control animals 10 minutes after histamine injection was 15 units (1
unit -0, I Tl1m). A response of less than 10 units occurring at a rate of 5 or less in control animals is defined as effective inhibition of histamine edema in animals treated with the compound, and the oral dose levels at which this effective inhibition is seen are also shown in the table below. .

b) Antihistamine activity in vitro Guinea pig ileum pieces were suspended in 100 ml of 87.5' O Tyrode bath with a preload of 0.75 S' and 95% of 02 and 5 T. A gas consisting of CO2 was supplied. Histamine (0,5'llf/l
) induced spasticity was recorded by wave photography using isotonic criteria giving 5x magnification. The interaction of the compound to be tested with the working muscle (5 min incubation time) was investigated and significant inhibition of histamine-induced contractions (5 min incubation time) was investigated.
%) is the effective concentration of the compound (In'i/
l) are shown in the table below.

The results of the above tests indicate that the compound (1) of the present invention and its pharmaceutically acceptable salts, when administered systemically to warm-blooded animals, are effective at doses ranging from about 0.25 to about 20 mg/Kg of body weight. were generally found to be active as anti-allergic agents.

Because of their useful antihistamine and antianaphylactic activity, the compounds of the present invention can be formulated into a variety of pharmaceutical forms for administration. To prepare the pharmaceutical compositions of the present invention, an antihistamine in base or addition salt form as the active ingredient or an anti-anaphylactic effective amount of the specified compound is intimately mixed with a pharmaceutically acceptable carrier. . The carrier may take a variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably prepared in a single unit suitable for oral, rectal or parenteral injection administration.
Preferably in dosage form. For example, in the preparation of compositions for oral dosage forms, any common pharmaceutical vehicle may be used, such as for oral overnight preparations such as suspensions, suspensions, syrups, elixirs and solutions. Water, glycol, oil, alcohol, etc., powders, pills,
In the case of capsules and tablets, it can be a solid carrier such as starch, sugar, kaolin, lubricants, binders, leavening agents and the like. Because of their ease of administration, tablets and capsules represent the most useful oral dosage unit forms, in which case solid pharmaceutical carriers are employed. Carriers for parenteral administration will normally consist of sterile water, at least in large part, although other ingredients may also be included, such as ingredients to aid solubility. Injectable solutions can also be prepared in which the carrier is a saline solution, a glucose solution, or a mixture of saline and glucose solutions. Suitable liquid carriers, suspending agents and the like may also be used.

Because of its greater water solubility than the corresponding base form (1)
The acid addition salts of are clearly more suitable for the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.

Dosage unit form, as used in the specification and claims, refers to physically discrete units suitable for single administration, each unit containing the desired pharmaceutical carrier(s). Contains a predetermined amount of active ingredient calculated to produce a therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packages, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls. etc. as well as their separated compounds.

The following examples illustrate the invention but are not intended to limit the scope of the invention.

All parts are by weight unless otherwise noted.

Example 1 54 parts of 1,8-dihydro-1-(phenylmethyl)-
2H-benzimidazolone-2-one, 47.25 parts of 1-
To a stirred hot mixture consisting of bromo-3-chloropropane and 6 parts of N,N,N-triethylbenzene methanaminium chloride at 60'O was added dropwise 450 parts of a 60% solution of sodium hydroxide. . After completion, stirring was continued for 6 hours at 60°C. The oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane to give, after drying, 42 parts (58%) of 1-(8-chloro-propyl)-1,8-dihydro-8-(phenylmethyl)-2H-benz. An imidazolone-2-one was obtained.

In a similar manner, the following compounds were prepared: Example 2 The procedure of Example 1 was carried out and an equal amount of
Using the correct IH-benzimidazole, the following was obtained as a residue: Example 3 20 parts of 8-CC2-amino-4-chloro-phenyl)
Aminoco-1-propertool, 50 parts acetic acid and 150 parts
A mixture of 1 part 4N hydrochloric acid solution was stirred overnight and brought to reflux. The reaction mixture was cooled and evaporated. , the residue was dissolved in water and the solution was alkalized using ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. 4-
6.5 parts (28%) when crystallized from a mixture of methyl-2-pentanone and 212'-oxybispropane
5-chloro-2-methyl-IH-benzimidazole-1-propatol was obtained.

Similarly, 5-chloro-2-ethyl-1H-benzimidazole-1-propatol was produced by reaction with 8-(:(2-amino-4-chlorophenyl)amine)-1-nolobanoltofuropanoic acid. manufactured.

Example 4 A stirred solution containing 30 parts of 8-[(2-amino-4-chlorophenyl)aminoco-1-propatol and 0.1 part of 4-methylbenzenesulfonic acid in 405 parts of methylbenzene. A solution of 34 parts of cyclohexanecarboxaldehyde in 45 parts of methylbenzene was added dropwise to the refluxing (water separator) mixture.

After completion, stirring was continued for 1 hour using a water separator at reflux temperature. The methylbenzene was removed by vacuum distillation and the residue was triturated in 2,2'-oxybispropane.

When the product is separated and dried, 16.5 parts (88%) of 5
-Chloro-2-cyclohexyl-IH-benzimidazole-1-propatol (melting point 95C) was obtained.

Example 5 A mixture of 30 parts of 8-[:(2-amino-4-chloro-phenyl)7mi/ )-1-propatur, 44.8 parts of sodium α-hydroxybenzenethanesulfonate and 120 parts of ethanol The mixture was stirred and refluxed for 30 minutes. The reaction mixture was evaporated and the residue was taken into water. The oily product was extracted with trichloromethane. The extract was dried, filtered, and evaporated to a residual liquid of 45 parts (100%
) 5-chloro-2-(phenyl-methyl)-1H-benzimidazole-1-propatol was obtained.

Similarly, 8-((2-amino-5-chlorophenyl)
6-
Chlor-2-7 chlorohexyl-IH-benzimidazole-1-propatol (melting point 120.1'O) was produced.

Example 6 To a stirred mixture of an 85% aqueous solution of 93 parts of 8-(2-amino-phenyl)amino-1-propatur, 45.5 parts of potassium hydroxide and 600 parts of ethanol, 608 parts of Carbon disulfide was added warmly. After completion, stirring was continued at reflux temperature for 6 hours. The reaction mixture was evaporated and the residue was added to 1500 parts of water. The whole thing
It was filtered over h1/-flo and the P solution was acidified using acetic acid. The oily product solidified upon stirring. When the pieces are distributed door to door, washed with water, and dried, 92 parts (7
8.9%) of 2-mercapto-I If-benzimidazole-1-propatol (melting point 110C) was obtained.

A mixture of 208 parts of 2-mercapto-IH-benzimidazole-1-propatol, 15.62 parts of iodomethane and 120 parts of methanol was heated overnight at room temperature.
The company was agitated. The reaction mixture was evaporated and the residue was dissolved in 500 parts of water. The solution was washed with high flow 1/75 and the P solution was alkalized using solid potassium hydroxide. The oily product was extracted with trichloromethane. Dry the extract;
After filtering and evaporating, 19 parts (85.5 parts) of 2-(
methylthio) -L H-benzimidazole-1-
Pronoknol was obtained as a residue.

19 parts of 2-(methylthio)-1H-benzimidazole-1-propatol to 152 parts of N.

11.5 parts of methanesulfonyl chloride were added dropwise to a stirred mixture of N-diethyluecumamine and 195 parts of dichloromethane.

After completion stirring was continued for 1 hour at reflux temperature. After cooling water was added and the layers were separated. The organic phase is dried, filtered and evaporated to give 19 parts of 8-C2-(methylthio)-L.
H-benzimidazol-1-l]propyl methanesulfonate was obtained as an oily residue.

Example 7 80 parts of IH-benzimidazole, 49 parts of 2-(4
-chlorobutoxy)-tetrahydro-2H-pyran, 2
A mixture of 1 part potassium hydroxide and 200 parts ethanol was stirred and refluxed overnight.

The reaction mixture was cooled to room temperature, filtered and the P solution was evaporated. The residue was stirred in water and acidified using dilute hydrochloric acid solution. The whole was stirred and heated in a water bath for 80 minutes. After cooling to room temperature, the product was extracted with methylbenzene. The aqueous phase was separated for 7 i and alkalized with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, dried and evaporated to give 50 parts of IH-benzimidazole-1-butanol as an oily residue.

Example 8 To a stirred mixture of 5 parts of 4-chloro-1,8-dihydro-3-(3-hydroxypropyl)-2H-benzimidazolone-2-one and 75 parts of trichloromethane, 8 A portion of sulfinyl chloride was added dropwise. After completion, stirring was continued for 8 hours at flow temperature. The reaction mixture was cooled and evaporated. The residue was dissolved in a small amount of 4-methyl-2-
Stirred in pentanone. The product was filtered and dried to give 3.5 parts of 4-chloro-3-(3-chloropropyl).
-1,8-dihydro-2H-benzimidazolone-2-one was obtained.

In a similar manner, the following 1-(chloro-alkyl)-1H-
2 Example 9 in which benzimidazole was prepared 1132 parts of 1.2.4-)dichloro-5-nitrobenzene, 75 parts of 3-amino-1-propatol, 0.2
A mixture of 1 part potassium iodide and 200 parts Q butanol was stirred and refluxed overnight. The dichlor was removed by vacuum distillation and water was added to the residue. The product was extracted with 4-methyl-2-pentanone. The extract was washed 2-3 times with water, dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 2,2'-oxybispropane. The product was furnaced and crystallized from a mixture of 2°2'-oxybispropane and 2-propane to give 8.
1.7 parts of 8-('(4°5-dichloro-2-nitrophenyl)aminoco-1-propatol (melting point 97'0
)was gotten.

Similarly, 8-([2-nitro-4-(trifluoromethyl)phenylcoamino)-1-propatur and 2-([:2-
Nitro-4-()lifluoromethinotetraphenyl]amino)ethanol (melting point 74.9'O) was produced.

Example 10 39.2 parts of 3-(2-nitro-phenyl)ami/-1
- 85.7 parts of sulfinyl chloride were added dropwise to a stirred mixture of propatool and 225 parts of trichloromethane (exothermic reaction: temperature rose to 45'O)
. After completion, stirring was continued for 6 hours at reflux temperature. Evaporation of the reaction mixture yielded 43 parts (100%) of N-(3-
Chloro-propyl)-2-nitrobenzenamide was present as a residue. (XX■-1) In the same manner, the following residues were produced: N-(3-chloropropyl)-2-nitro-4-(trifluoromethyl)benzenamine, 4.5-dichloro-
N-(3-chloropropyl)-2-nitrobenzeneamine (melting point 78'o), and N-(2-chloroethyl)-2-nitro-4-(trifluoromethyl)benzenamine.

Example 11 21.5 parts of N-(3-chloropropyl)-2-nitrobenzeneamine, 22.68 parts of 1-(diphenylmethyl)-piperazine, 20 parts of NlN-diethylethanamine and 180 parts of The mixture of NlN-dimethylacetamide was stirred and heated at io'c for 6 hours. The reaction mixture was evaporated and the residue was taken into water. The oily product was extracted using trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propatol, ethanol and 2,2'-oxybispropane. When the product is separated and dried, 1
5.5 parts (86.9%) of 4-(diphenylmethyl)-
N-(2-nitrophenyl)-t-piperazinepropanamine hydrochloride (melting point 228°C) was obtained.

Similarly, the following was prepared: N-(4,5-dichloro-2-nitrophenyl)-4-
(diphenylmethyl)-1-piperazinepropanamine (residue), 4-(diphenylmethyl)-#-[2-nitro-4-
()-lifluoromethyl)-phenyl]-t-piperazinepropanamine (melting point z 3.7 °C) and 4-(diphenylmethyl)-#-[2-nitro-4-(
trifluoromethyl)-phenyl] = tQ piperazineethanamine (melting point 152.1 °C).

Example 12 15 parts of 4-(diphenylmethyl)-N-(2-nitrophenyl)-,1-piperazinepropanaminej/@
A mixture of 160 parts of methanol and salt was hydrogenated at normal pressure and room temperature using 5 parts of Raney nickel catalyst. After the calculated amount of ice cream had been absorbed, the catalyst was The P solution was evaporated. The solid residue was crystallized from a mixture of 2-propanol and 2°2'-oxybispropane. The product was separated and dried to give 12 parts (78,9 %) of N-(2-aminophenyl)-
4-(diphenylmethyl)-1-piperazinepropanamine hydrochloride (melting point 223.1 c ) was obtained.

The following was prepared in the same way: 4.5-Dichloro-N'-(8-C4-(diphenylmethyl)-1-piperazinyl]-propyl) = 1.2-benzenediamine (oily residue), N '-(8-[4-(diphenylmethyl)-1-piperazinyl]propyl) -
4-()-lifluoromethyl)-1,2-benzenediamine, and N'-(2-C4-(diphenylmethyl)-
i-Piperazinyl]ethyl)-4-()lifluoromethyl)-1,2-benzenediamine (oily residue).

Example 13 605 parts of 1-(8-chloropropyl)-1°8-dihydro-8-(1-methylethynyl)-2H-benzimidazolone-2-one, 81.68 parts of 1-(phenylmethyl ) A mixture of piperazine, 21.2 parts of sodium carbonate, 0.1 part of potassium iodide and 400 parts of 4-methyl-2-pentanone was stirred and refluxed for 20 hours using a water separator. The reaction mixture was cooled, water was added, and the layers were separated. The organic phase is dried, filtered and evaporated to give 70 parts (100%) of t,s-dihydro-1-(l-methyl-
ethynyl)-8-(8-(4-(phenylmethyl)-x
-piperazinyl]furovir)-2H-benzimidazolone-2-one was obtained as a residue.

Similarly, 1,3-dihydro-1-(2-[4-(phenylmethyl)-1-piperazinyl]ethyl)-2H-benzimidazolo-2-70111 points 186, 5°C) was obtained. .

Example 1 also contains 70 parts of 1,1-dihydro-1-(1-methylethynyl)-8-(8-[4-(phenylmethyl)-1-piperazinyl]-propyl)-2H-benzimidazolo-2 −
55 parts of a 6N hydrochloric acid solution were added to a stirred solution of 240 parts of 6N hydrochloric acid in ethanol. The whole was stirred for 2 hours at 40-50°C.

The reaction mixture was evaporated and the residue was taken up in dilute ammonium hydroxide solution. The oily product was extracted using trichloromethane. The extract was dried, filtered, and evaporated to yield 68 parts (100 parts) of 1°8-dihydro-1-(
8-(4-(phenylmethyl)-1-piperazinyl]propyl)-2H-benzimidazolone-2-one was obtained as a residue.

Example 15 A mixture of 63 parts of 1,3-dihydro-t-(8-[4-(phenylmethyl)-1-piperazinyl]propyl)-2H-benzimidazolone-2-one in 400 parts of methanol was Descaling was carried out using 10 parts of charcoal and 10% palladium catalyst at pressure and room temperature. After the calculated amount of hydrogen had been absorbed, the catalyst was separated on Hyflo and the P liquid was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2-propanol. When the product was separated and dried, 29.5 parts (63%) of 1.3-
dihydro-1-IJ-(1-piperazinyl)propyl)
-2If-Penzimita Thorone (melting point 157.
50) was slipped.

Similarly, i,s-dihydro-1-(2-(l-piperazinyl)ethyl)-2H-benzimidazolone-2-one (melting point 122.6°0) was obtained.

Example 16 To a stirred mixture of 20 parts aluminum chloride and 100 parts fluorobenzene was added dropwise 20,s parts of 2,4-dichlorobenzoyl chloride. After completion, the mixture was heated to reflux and stirred at reflux temperature for 5 minutes.

The reaction mixture was poured onto crushed ice and the product was extracted with 1,1'-oxybisethane. The extract was dried and evaporated to give 80 parts of (2,4-dichlorophenyl>(4-fluorophenyl)methanone) as an oily residue.

Similarly, (4-fluorophenyl)(4-pyridinyl)methanone (melting point 85.5°C) was produced.

Example 17 23.4 parts of (4-1
37 parts of sodium borohydride were added dropwise to the stirred and refluxing mixture containing the fluorophenyl)(2-fluorophenyl)methanone. Reflux temperature after completion (±
800) for 2 hours. The reaction mixture was cooled and decomposed by the addition of water. The 2-propertool was evaporated and the remaining product was extracted with trichloromethane. Drying, filtering and evaporating the extract yields 2
36 parts of 4-chloro-α-(2-fluorophenyl)benzene methanol were obtained as a residue.

Similarly, the following were prepared: 2I4-dichloro-α-(4-fluorophenyl)benzene methanol (residue), α-(4-fluorophenyl)-4-pi+)dine methanol (melting point 188. 2'O), α-(4-fluorophenyl)-g-hyridinemethanol hydrochloride (melting point 1583°C), and 4-methoxy-
α-[8-()Lifluoromethyl)phenyl]benzene methanol (residue).

Example 18 A mixture of 22 parts of 2,4-dichloro-α-(4-fluorophenyl)benzene methanol and 240 parts of 12N hydrochloric acid solution was stirred at room temperature for 40 hours. The reaction mixture was poured onto ice water and the product was extracted using trichloromethane. The extracts were washed with water, dried, filtered and evaporated. Distillation of the residue yields 13.2 parts of 2,4-dichloro-
1-[chloro-(4-fluorophenyl)methyl]Hensen (boiling point 0.15 146'O at +run pressure
)was gotten.

Similarly, the following was prepared: 1-[α-chloro-α-(4-methoxyphenyl)methyl]-8-()
(lifluoromethyl)benzene (residue) and 1-[chloro-(4-methylphenyl)methylcy4-
Fluorobenzene (remainder i: tl.

Example 19 236 parts of 4-chloro-α-(
24 parts of sulfinyl chloride were added dropwise to the stirred mixture containing the 2-fluorophenyl)benzene methanol. After completion, the whole was heated to reflux and stirred without stirring at reflux temperature for 5 hours and then at room temperature for an additional night. Evaporating the benzene and distilling the residue gives 16.5
part of 1-chloro-4-[α-chloro-α-(2-fluorophenyl)-mefyl]benzene (boiling point, 0.1 tr
122-125c) was obtained at an pressure of

The following items were manufactured in the same manner. .

8-[α-chloro-α-(4-fluorophenyl)methylcopyridine hydrochloride (oil residue), 8-[α-chloro-α-(4-chlorophenyl)methylcopyridine hydrochloride (residue) , 4-[α-chloro-α-(4-fluorophenyl)methylcopyridine hydrochloride (melting point 198-200'O), 1-
(Chlorphenylmethyl) -2,8'') methylbenzene (boiling point, 137 °C at 0.7 m pressure), 1-
(Chlorphenylmethyl)-2,4-cymerhenzene (n point 187 °C at 0.7 ran pressure),
2-(chlorophenylmethyl)-1,4-dimethylbenzene (boiling point 136'O at 0.7 mm), 1-
(Chlorphenylmethyl)-2-fluorobenzene (boiling point 108-109°C at 0.4m pressure).

Example 20 121 parts of piperazine, 54 parts of 3-[α-chloro-α
A mixture of -(4-ly10ulfenyl)methyl]hyridine hydrochloride and 315 parts of NlN-dimethylbormamide was stirred at room temperature for 20 minutes. The reaction mixture was evaporated and 250 parts of water were added directly to the residue. The product was extracted with methylbenzene.

The organic phase was washed with water and extracted with 10% acetic acid solution. The acidic aqueous phase was made alkaline using 60% sodium hydroxide solution and the product was extracted again with methylbenzene.

The extract was dried, filtered and evaporated. The oily residue was converted to the nitrate in ethanol. When the salt is separated, washed with ethanol and 2,2'-oxybispropane, and crystallized from the ethanol, 48 parts of 1-[α-(4-chlorophenyl)-α-(3-pyridinyl)methyl] are obtained. Hyperazine trinitrate (melting point 132.9'O) was obtained.

The following were prepared in the same way: 1-[α-(4-chlorophenyl)-α-(2-fluorophenyl)methyl]hyperazine, 1-[α-(4-fluorophenyl)-α- (4-pyridinyl)methylcopiperazine (melting point 108.40), 1-[(2-chlorophenyl)(8-40ruphenyl)
Methylcopiperazine, 1-[(2-fluorophenyl)phenylmethylcopiperazine ethanedioate (1:1), (melting point 195, 5
°C), 1-[(4-fluorophenyl)(4-methoxyphenyl)methylcopiperazine ethanedioate (1:2),
(melting point 280.1'0), and 1-((4-nitrophenyl)phenylmethyl]viverazine dihydrochloride.

Example 21 A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidine carboxylate, 85.2 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate in an oil bath at 140'O The mixture was stirred and heated for 3 hours.

The reaction mixture was allowed to cool to room temperature and water was added. The product was extracted with methylbenzene. The extracts were washed successively with water, dilute hydrochloric acid solution and sodium bicarbonate solution, dried, filtered through P7 and evaporated. When the point is removed by distillation, 1 point is 0.5-1, l! 148'O at m pressure
), 29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy]-t-piperidinecarboxylate were obtained in the form of an oily residue.

Same as above, ethyl 4-(diphenylmethoxy)-1-hehe+)dine carboxylate (boiling point 0.4 M at 15 M pressure)
Manufactured by 0C), i4santa.

Example 22 A mixture of 29 parts of ethyl 4-[bis(4-fluorophenyl)methoxy-1-piperidine carboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-nolopanol was stirred for 4 hours. , refluxed. The solvent was evaporated and water was added to the residue. The product was extracted with methylbenzene. The extract was washed 2-3 times with water, dried, and strained.
Evaporated. The oily residue was converted to the hydrochloride salt in 4-methyl-2-pentanone and 2-propatol at room temperature. When salt is distributed door to door and dried, 205 parts (78%) of 4-
[Bis(4-fluorophenyl)-methoxy]piperazine hydrochloride (melting point 161.8C) was obtained.

Similarly, 4-(diphenylmethoxy)piperidine hydrochloride (melting point 2
09. s a ) was produced.

Example 23 5.3 parts of 1-(8-chloropropyl)-i,s-dihydro-2H-penzimitasorone, 5 parts of 1-(
A mixture of diphenylmethyl)piperazine, 6.4 parts of sodium carbonate, and 200 parts of 4-methyl-2-pentanone was stirred using a water dispenser and passed through at high speed. After cooling water was added and the layers were separated. The 4-methyl-2-pentanone phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propatol. The product is separated into furnaces,
Upon drying, 2 parts (28%) of 1-(a-(4-(diphenylmethyl)-1-piperazinyl]propyl)-1,
8-dihydro-2H-benzimidazolone-2-one (11
A temperature of 153.6°C was obtained.

In a similar manner the compounds of No. F were prepared in the free base form or, after treatment of the free base with the appropriate acid, in the addition salt form.

Example 24 The following were prepared in a manner similar to that described in Example 23: 1,a-)Hydro-1-(8-hydroxypropy, tt
1-[8-(4-(bis(4-fluorophenyl)methyl) 1- by reaction of 1-2H-pene imitasol 2-ene methanesulfonate 1-[bis(4-fluorophenyl)methyl]piperazine piperazinyl)propyl] ~1,3-dihydro-2H-benzimidazolo-2
(melting point 197, .9°C), 1,3-dihydro-1-(3-iodopropyl)-3
1-(8-
(4-(diphenylmethyl)-1-piperazinyl]propyl)-1,8-dihydro-3-methyl-2H-benzimidazol-2-dihydrochloride hydrate (melting point 201.8°C
), 5-(a-[4-(diphenylmethyl)-
1-Piperazinyl]clovir)-2(811)-benzothiazolone dihydrochloride hemihydrate (melting point 186.1°C), 3-(8-chloropropyl)-2(a#)-benzoxazolone and 1-(diphenyl) a-(a-[4-(diphenylmethyl)-1-
hiberazinyl(propyl)-2(8H)-benzoxazolone dihydrochloride (melting point 212.4°C).

Example 25 6.95 parts of 1-(5-chloropentyl)-1°8-dihydro-3-(1-methylethynyl)-2H-benzimidazolone-2-one, 5.15 parts of 1-( A mixture of diphenylmethyl)piperazine, 5.80 parts of sodium carbonate, 0.1 parts of potassium iodide, and 160 parts of 4-methyl-2-pentanone was stirred overnight using a water separator and refluxed. The reaction mixture was cooled to room temperature, water was added and the layers were separated. The organic phase was dried, filtered and evaporated.

The residue was stirred with a solution of 12 parts of hydrochloric acid in 40 parts of ethanol and brought to reflux. Evaporation of the whole and crystallization of the residue from ethanol yielded 5 parts (46%) of 1-(5-(4-(diphenylmethyl)-1-piperazinyl]pentyl)-t.

3-dihydro-2H-benzimidazolone-2-one dihydrochloride hydrate (melting point 215.3°C) was obtained.

The following was prepared in the same way: Example 26 76 parts of 1-(s-[4-.
(diphenylmethyl)-1-piperazinyl]propyl)
-1,8-dihydro-3-(1-methylethynyl)-2
To the stirred solution containing H-penzimitasolone 2-one was added 120 parts of hydrochloric acid solution and 250 parts of water. The whole was stirred at room temperature for 30 minutes. Upon cooling in a water bath, the product precipitated. Sort it by furnace, 2-
After washing with 1-methane and 2,2'-oxybis-propane and drying, 43 parts (55%) of 1-, (3
[4-(diphenylmethyl)-1-piperazinyl]propyl)-1,8-dihydro-2H-benzimidazolone-2-in dihydrochloride hydrate (melting point 287.5"c)' was obtained.

Similarly, the following were prepared; Example 27 3.6 parts of #'-(2-(4-(diphenylmethyl)-
A mixture of 1-piperazinyl]ethyl)-L4-()lifluoromethyl)-1,2-benzenediamine and 1,8 parts of urea was stirred in an oil bath at 190°C for 3 hours. The reaction mixture was cooled, water and trichloromethane were added, and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. collection of pure distillates,
Evaporation of the eluent yields 15 parts (41.5%) of 1-(
2-(4-(diphenylmethyl)-1piperazinyl]ethyl l-1,3-dihydro-5-(trifluoromethyl)-2H-benzimidasorol-2-one (melting point 1637°C
)was gotten.

Similarly, the following was prepared: 1-(8-(4-(diphenylmethyl)-1-piperazinyl]propyl)-1% l-dihydro-5-(trifluoromethyl)-2H-benzimidazolo -2-one (melting point 152.7°C), 5,6-dichloro-1-(8-(4-(diphenylmethyl)-1-piperazinylceflovir)-1,3-dihydro-2H-benzimidazo Loan (melting point 214.
7℃).

Example 28 23 parts of 1-(3-(4-(diphenylmethyl)-1-
piperazinyl]propyl)-X, a-dihydro-2H-
Ben/zimidazolone, 4.5 parts formaldehyde 40% solution and 45 parts N.

The mixture of N-dimethylformamide was stirred and heated at 100° C. for 2 hours. The reaction mixture was cooled and diluted with water. The precipitated product is filtered off and crystallized from methylbenzene, yielding 1.5 parts (66%) of 1-(8-
(4-(diphenylmethyl)-1-piperazinyl]-propyl)-1,1-dihydro-3-(hydroxymethyl)-2H-benzimidazolone-2-one (melting point 102.5
°C) was obtained.

Example 29 1.55 parts acetic anhydride, 3 parts 1-(8-[:4-(diphenylmethyl)-1-bizaradinyl]propyl)-1
, s-dihydro-2H-benzimidazolone-2-one and 22.5 parts of methylbenzene was stirred and refluxed overnight. Water was added to the reaction mixture and the layers were separated.

The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol as eluent. After collecting the pure fraction and evaporating the eluent, 1.
1 part (83,5%) of 1-acetyl-8-(8-(4-
(diphenylmethyl)-1-piperazinyl]propyl)
-i,s-dihydro-2H-benzimidazolone-2-one (melting point 124.4°C) was obtained.

Example 80 1,1 part ethyl 2-noropenoate, 3 parts 1-(
8-(4-(Diphenymethyl)-1-piperazinyl]propyl)-1,8-dihydro-2M-benzimidazolone-2-one, N,N,N-trimethylbenzenemethanaminium hydroxide 40% in methanol 2-3 drops of solution,
and 25 parts of 1°4-dioxane was stirred and refluxed for 24 hours. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol and ethanol.

The salt was filtered off and dried to give 1.4 parts (82.5%) of ethyl 8-[3-(:4-(diphenylmethyl)-1-piperazinyl]propyl)-2,a-dihydro-2- Oxo-IH-benzimidazole-1-propanoate dihydrochloride trihydrate (melting point 204°C) was obtained.

Example 31 3 parts of 1-(3-(4-(diphenylmethyl)-1-piperazinyl]propyl)-1,8-dihydro-2H-benzimidazolone-2-one, 1 part of incyanatomethane and 25 of 1,4-dioxane was stirred overnight;
It refluxed. The reaction mixture was evaporated and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of methylbenzene and 2,2'-oxybispropane to yield 0.8 parts (23
,5%) of 8-(,9-(4-(diphenylmethyl)-
1-piperazinyl]-furovir)-2,3-dihydro-
N-methyl-2-oxo-IH-benzimidazole-
1-carboxamide (melting point 153.1°C) was obtained.

Example 32 9.4 parts of 1-(8-[:4-(diphenylmethyl)-
1-piperazinyl]propyl)-1,a-dihydro-2
To a stirred mixture of H-benzimidazolone-2-one and 180 parts of methylbenzene was added 0.8 parts of a 75% dispersion of sodium hydride, and the whole was stirred and heated at 90 DEG C. for 60 minutes.

After cooling to 80°C, 0.2 parts of 2.8 s 11
#12-dibenzo1.4,7,10,18.16-hexaoxacyclooctadeca-2,11-diene was added and stirring continued for 10 minutes. Then 4.2 parts tv ethyl 2-bromoacetate were added and the mixture was stirred and refluxed overnight. The reaction mixture was cooled to 90°C, 50 parts of water were added, and the layers were separated hot. Evaporation of the organic phase yields 10 parts of ethyl-(8-[4-(diphenylmethyl)-1-piperazinylcupropyl)-2
, 8-dihydro-2-oxo-IH-benzimidazole-1-acetate was obtained as a residue.

98 parts of ethyl 8-(8-(4-(diphenylmethyl))
-1-piperazinyl]propyl)-2゜3-dihydro-
A mixture of 2-oxo-IH-benzimidazole-1-acetate, 1.2 parts of sodium hydroxide and 150 parts of water was stirred for 5 minutes and brought to reflux (±80° C.). The reaction mixture was filtered and Part F was acidified with acetic acid to pH 5.8-6, producing a sticky precipitate. It was isolated and crystallized from ethanol and water. The product was separated in F and dried in vacuo at 100°C for 8 hours to yield 6 parts of 8-(8-(4-(diphenylmethyl)-1).
-piperazinyl]propyl)-2,8-dihydro-2-
Oxo-IH-benzimidazole-1-acetic acid hemihydrate (
A melting point of 188.7°C was obtained.

Example 88 5.2 parts of 1,8-dihydro-1-(:8-(1-piperazinyl)propyl]-zH-penzimidaso0-2-
5.28 parts of 2-(chlorphenylmethyl)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,
The N-dimethylformamide mixture was stirred and heated at 50° C. overnight.

The reaction mixture was cooled and poured onto ice water. The product was extracted with methylbenzene. Dry and filter the extract;
Evaporated. The residue was dissolved in 4-methyl-2-pentanone and 2
．． Crystallized from a mixture of 2'-oxybispropanes. The product was separated by F and dried to yield 2 parts (23.4%) of 1,8-dihydro-■-(8-(4-(phenyl(2-
pyridinyl)methyl)-1-piperazinyl)propylcou 2H-benzimidazolone-2-one (melting point 141.7°C
)was gotten.

The following was prepared in the same way: Example 84 4.9 parts of 1-(8-chloropropyl)-1H-benzimidazole, 5.76 parts of 1-[bis(4-fluorophenyl)methyl] A mixture of hiberazine, 5.1 parts of sodium carbonate, 0.1 part of potassium iodide and 200 parts of 4-methyl-2-pentanone was added using a water separator.
Stir for an hour and reflux.

The reaction mixture was cooled, water was added, and the layers were separated.

Dry the organic phase 1. Filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybisprone.

When the product is taken from house to house and dried, 5.5 parts (5 (1,8%)
) of 1-[8-(4-(bis(4-fluorophenyl)
1H-benzimidazole hydrate (melting point 108.4°C) was obtained.

Similarly, the following were prepared: Example 35 The method of Example 34 was repeated to prepare 8-[2-,(methylthio)-1H-benzimidazol-1-l]propyl methanesulfonate and 1-( L 1-(8-"["4-(diphenylmethyl)-1-piperazinyl]propyl)-2-(methylthio)-1H,-henzimidazole trihydrochloride hydrate (melting point 203.4°C) was produced.

Example 36 4.37 parts of N-(2-aminophenyl)-4-(diphenylmethyl), -1,-hiverazinepronosinamine hydrochloride, 38 parts of carbon disulfide, 2 parts of sodium carbonate, and A mixture of 40 parts of ethanol was stirred and refluxed for 20 hours. The reaction mixture was evaporated and water was added to the residue. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The solution was dried, filtered and evaporated.

Crystallization of the residue from 4-methyl-2-pentanone yields 2 parts (45,5) of 1-' (8-[4-(diphenylmethyl)-1-piperazinyl]furovir)-X,a
-dihydro-2H-benzimidazole-2-thione (
A melting point of 181.8°C was obtained.

Example 37 60 parts of N-(2-aminophenyl)-4-(diphenylmethyl)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl) carbamate, 42 parts of acetic acid and 450 parts of trichloromethane. The mixture was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was stirred in water.

The latter was decanted and the residue was added back into the water.

The whole was made alkaline using dilute ammonium hydroxide solution and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated.

The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5) as eluent.

The pure fractions were collected and the eluent was evaporated. The residue was dissolved in 4-methyl-2-pentanone and 2. When crystallized from a mixture of '2'-oxybispropane, 13.5 parts of methyl[1-(3-[4-(diphenylmethyl)-x-piperazinyl]furovir)-IH-penzimigzoly2 -L]carbamate (melting temperature: 187.8°C) was obtained.

12 parts of methyl [1-(8-4:4-(diphenylmethyl)-1-piperazinyl]furovir)-IH-benzimidazol-2-yl]-carbamate, 60 parts of concentrated hydrochloric acid solution and 80 parts of the mixture was stirred and refluxed overnight. The reaction mixture was evaporated and water was added to the residue. The free base was liberated using ammonium hydroxide in the usual manner and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from ethanol. The product is oven-separated and dried to yield 4.3 parts (40%) of 1-(8-
(4-(diphenylmethyl)-1-piperazinyl]propyl)-IH-penzimitazole-2-amine (melting point 228.7°C) was obtained.

10.7 parts of 1-(8-(4-(diphenylmethyl)-
A mixture of 1-piperazinyl]furovir)-IH-benzimidazol-2-amine, 5.1 parts of acetic anhydride, and 90 parts of methylbenzene was stirred for 5 hours and refluxed. The reaction mixture was evaporated and the residue was stirred in water. The whole was made alkaline using ammonium hydroxide and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from ethanol. The product is oven-separated and dried to yield 6.6 parts (55.5%) of #-
(1-(8-(4-(diphenylmethyl)-1-piperazinyl)propyl)-1,3-dihydro-2H-be/zimidazoly 2-denacetamide (melting point 143 J°C)
was gotten.

Example 38 13 parts of 1,3-dihydro-1-(8-(1-piperazinyl)propyl)-2H-benzimidazolone-2-one,
12.4 parts of 1, 1'-(bromethylene)bis[benzene], 6.6 parts of sodium carbonate and 200 parts of 4
-Methyl-2-pentanone mixture was stirred and refluxed overnight using a water separator.

After cooling to room temperature, water was added and the layers were separated.

The organic layer was dried, filtered and evaporated. 2,2' residue
-1-(8-44-(diphenylmethyl)-1-piperazinyl]propyl)-1,8-
Dihydro-12H-benzimidazolone-2-one (melting point 1
58°C) was obtained.

Example 39 Following the method of Example 88 and using equal amounts of the appropriate starting materials, the following compound was prepared: 1-(2-(4-[bis(4-fluorophenyl)methyl)-1 -piperazinyl)ethyl]-t,a-dihydro-2H-penzimitasorone 2-one hemihydrate (melting point 18
1.5°C), 1-(2-(4-(diphenylmethyl)-1-piperazinyl]ethyl)-1,8-dihydro-2H-benzimidazolone-2-one (melting point 218°C), and 1- (8-(4
-(bis(4-fluorophenyl)methyl]-1-piperazinyl)-propyl-1,8-dihydro-2H-benzimidazolone-2-one (melting point 198°C).

Example 40 4.8 parts of 1-(3-chloropyropyl)-1,8-2hydro-2H-penzimitasorone, 6.1 parts of 4-(diphenylmethoxy)piperidine hydrochloride, 75 parts carbonate) and 200 parts of 4-methyl-2-
The pentanone mixture was stirred and refluxed overnight using a water separator. The reaction mixture was cooled and water was added. The layers were separated and the 4-methyl-2-pentanone phase was dried, filtered and evaporated. The oily residue was purified by column chromatography on silica gel using a mixture of trichloromethane and 5% methanol as eluent. The pure fractions were collected and the eluent was evaporated. 4 residues
- When crystallized from methyl-2-pentanone, 4.2
(48%) of 1-(8-[4-(diphenylmethoxy)-1-piperidinyl]propyl)-1,8-dihydro-2H-benzimidazolone-2-one (melting point 149.2°C
)was gotten.

The following items were manufactured in the same manner. :Related aspects of the present invention are described below.

1. Formula Ar'' [wherein Ar' and Ar2 are each independently phenyl, substituted]enyl and pyridinyl, wherein the substituted phenyl is halo, lower alkyl, lower phenyl having 1 to 2 substituents independently selected from the group consisting of alkoxy, trifluoromethyl and nitro, m is an integer of 0 or l, A is 〉N- and 〉CH - a member selected from the group consisting of
is an integer from 2 to 6, provided that when CnH2,rL represents a branched alkylene chain, at least two carbon atoms are the linear portion of the chain connecting B and the piperidine or piperazine nitrogen atom. It exists in A! l R2 (where R1 and R2 each independently represent hydrogen, halo,
is selected from the group consisting of lower alkyl and trifluoromethyl, and Y is a member selected from the group consisting of oxygen, sulfur and substituted nitrogen of the formula >y −r, L
is a member selected from the group consisting of hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl) and b) 2 M summer Rr R2 (where R1 and R2 each independently represent hydrogen, halo,
selected from the group consisting of lower alkyl and trifluoromethyl, and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amine, lower alkylcarbonylamino, lower alkyloxycarbonylamino and having 3 to 6 carbon atoms. a member selected from the group consisting of cycloalkyl), and pharmaceutically acceptable acid addition salts thereof. In the process for producing a chemical compound of formula α), preferably in the presence of a reaction-inert organic solvent and a suitable base and at elevated temperature, 2B'-CnH2n-W [In the formula, Bt is 2 N
F2 is the same as B as defined above except for the 2-amino-1H-pendimidazolyl group of R2, and W is a suitable reactive ester function derived from the corresponding alcohol. or b) under hydrolysis conditions to prepare a compound of formula NH2.
-Coo (lower alkyl) RI The compound of R2 is decarboxylated, or or MlC, where M'' is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl. To prepare a compound of formula %, a compound of formula or d) removing the protecting group P from a compound of formula by conventional methods in order to prepare a compound of formula; or C) preparing a compound of formula NJi-CO-(lower alkyl) RI R2. In order to prepare a suitable compound of formula (1-a) above is diacylated by standard N-acylation methods or f) lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl and lower alkenyl, with the proviso that the unsaturation in the lower alkenyl is in a position other than α. In order to produce the compound, the group L1 is introduced into the compound of the above formula (1-c) by a known method, or in order to produce the compound, preferably a reaction-inert organic In the presence of a solvent and a suitable base and at elevated temperature a compound of formula is condensed with a suitable reactive ester of formula where W is as defined above, or h ) 2 S-
<lower alkyl) Compounds of RI R2 are prepared from the corresponding 18H-substituted congeners by known S-alkylation methods and, if desired, the products of steps α) to h) are pharmaceutically acceptable. A method for producing an acid addition salt.

2. Reaction of 1-(8-chloropropyl)-1,,11-dihydro-2H-penzimitasorone with 1-(diphenylmethyl)piperazine and, if desired, the pharmaceutical production of the product. ■-(3-[4-diphenylmethyl)-
1-piperazinyl]propyl)-1,a-dihydro-2
A method for producing a chemical compound according to 1 above selected from the group consisting of H-benzimidazolone-2-one and pharmaceutically acceptable acid addition salts thereof.

3.1.8-Dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate is reacted with 1-[bis(p-fluorophenyl)methylcopiperazine and optionally its characterized in that it produces a pharmaceutically acceptable acid addition salt of the product,
l-43-(j-[bis(4-fluorophenyl)methyl]-1-piperazinyl)propyl)-1,8"dihydro-2H-benzimidazolone-2-one and its pharmaceutically acceptable acid 1 above selected from the group consisting of addition salts;
A method of manufacturing a chemical compound according to.

4.1-(4-chlorobutyl)-1,8-dihydro-2
characterized by reacting H-benzimidazolone-2-one with 1-(bis(p-fluorophenyl)methyl)hyperesin and optionally preparing a pharmaceutically acceptable acid addition salt of the product. , 1-[4-(4-(bis(4
-fluorophenyl)methyl)-i-piperazinyl)butyl]-1,3-dihydro-2H-benzimidazolo-
A method for producing a chemical compound according to 1 above selected from the group consisting of 2-one and a pharmaceutically acceptable acid addition salt thereof.

5.1-(4-chlorobutyl)-1,3-dihydro-2
1-(4 -(4-(diphenylmethyl)-1-
A method for producing a chemical compound according to 1 above selected from the group consisting of (piperazinyl]butyl)-1,8-dihydro-2H-benzimidazolone-2-one and pharmaceutically acceptable acid addition salts thereof.

6. x-(8-[4-(diphenylmethyl)-1-piperazinyl]propyl, characterized by reacting 1-(8-chloropropyl)-1H-benzimidazole with 1-(diphenylmethyl)piperazine )-1H-Benzimidazole and its pharmaceutically acceptable acid addition salts.

7. Reacting 1-(4-chlorobutyl)-1H-benzimidazole with 1-[(4-fluorophenyl)phenylmethylcopiperazine and producing a pharmaceutically acceptable acid addition salt of the product. Characterized by 1-(
a chemical according to 1 above selected from the group consisting of 4-(4-((4-fluorophenyl)phenylmethyl)-1-piperazinyl)butyl]-IH-benzimidazole and pharmaceutically acceptable acid addition salts thereof; Method of manufacturing the compound.

8. Reacting 1-(4-chlorobutyl)-1H-benzimidazole with 1-[bis(p-fluorophenyl)methyl]piperazine and optionally forming a pharmaceutically acceptable acid addition salt of the product. characterized by manufacturing,
1-[4-(4-[bis(4-fluorophenyl)methyl]-1-piperazinyl)butyl)-jH-benzimidazole and pharmaceutically acceptable acid addition salts thereof; 1. A method for producing a chemical compound according to 1.

P

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, Ar^1 and Ar^2 are each independently from the group consisting of phenyl, substituted phenyl, and pyridinyl. selected, wherein the substituted phenyl is phenyl having 1 to 2 substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl, and nitro, and m is is an integer of 0 or 1, A is a member selected from the group consisting of >N- and >CH-, provided that when A is >N-, m is 0;
and when A is >CH-, m is 1 and n is an integer from 2 to 6, provided that when CnH_2n represents a branched alkylene chain, at least two carbon atoms are B and piperidine or piperazine. It exists in the linear part of the chain that connects the nitrogen atom, and B has ▲mathematical formulas, chemical formulas, tables, etc.▼ (Here, R^1 and R^2 each independently represent hydrogen, selected from the group consisting of halo, lower alkyl and trifluoromethyl, and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino and having 3 carbon atoms -6 cycloalkyl) and pharmaceutically acceptable acid addition salts thereof. 2,1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1H-benzimidazole and pharmaceutically acceptable acid addition salts thereof; Compound according to item 1. 3,1-[4-{4-[(4-fluorophenyl)phenylmethyl]-1-piperazinyl}butyl]-1H-
A compound according to claim 1 selected from the group consisting of benzimidazole and pharmaceutically acceptable acid addition salts thereof. 4,1-[4-{4-[bis(4-fluorophenyl)
A compound according to claim 1 selected from the group consisting of methyl]-1-piperazinyl}butyl]-1H-benzimidazole and pharmaceutically acceptable acid addition salts thereof. 5. Inert carrier substance and antihistamine or antianaphylaxis as active ingredients - The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, Ar^1 and Ar^2 are each independent] is selected from the group consisting of phenyl and pyridinyl, wherein said substituted phenyl is substituted with one to two substituents independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, trifluoromethyl and nitro. phenyl having a group, m is an integer of 0 or 1, A is a member selected from the group consisting of >N- and >CH-, provided that when A is >N-, m is 0 and can be,
and when A is >CH-, m is 1 and n is an integer from 2 to 6, provided that when CnH_2n represents a branched alkylene chain, at least two carbon atoms are B and piperidine or piperazine. It exists in the linear part of the chain that connects the nitrogen atom, and B is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R^1 and R^2 each independently represent hydrogen , halo, lower alkyl, and trifluoromethyl, and M is hydrogen, lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino, and carbon number is a member selected from the group consisting of 3 to 6 cycloalkyl) and pharmaceutically acceptable acid addition salts thereof. A pharmaceutical composition.