WO1993014088A1 - Antihistaminic piperazinyl derivatives - Google Patents

Antihistaminic piperazinyl derivatives Download PDF

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Publication number
WO1993014088A1
WO1993014088A1 PCT/EP1992/003000 EP9203000W WO9314088A1 WO 1993014088 A1 WO1993014088 A1 WO 1993014088A1 EP 9203000 W EP9203000 W EP 9203000W WO 9314088 A1 WO9314088 A1 WO 9314088A1
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Prior art keywords
formula
alkyl
compound
methyl
optionally substituted
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PCT/EP1992/003000
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French (fr)
Inventor
Frans Eduard Janssens
Joseph Elisabeth Leenaerts
Gaston Stanislas Marcella Diels
François Maria SOMMEN
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Janssen Pharmaceutica N.V.
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Publication of WO1993014088A1 publication Critical patent/WO1993014088A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with novel piperazinyl derivatives having the formula :
  • R 1 is (hydroxyC ⁇ alkyl)furanyl, (C ⁇ alkyl)oxazolyl or (hydroxyC ⁇ alkyl)oxazolyl;
  • radicals (a-1) to (a-7) may each independently be replaced by halo, Ci ⁇ alkyl, Ci ⁇ alkyloxy, hydroxy or triflu ⁇ ro- methyl; m is 1, 2, 3 or 4;
  • L is hydrogen; Chalky!; C3 ⁇ cycloalkyl; C3 ⁇ alkenyl optionally substituted with aryl; carbonyl; or a radical of formula :
  • Alk is Ci ⁇ alkanediyl
  • R 3 is cyano, aryl or Het
  • R 4 is hydrogen, aryl Het or Ci ⁇ alkyl optionally substituted with aryl or Het;
  • R 5 is hydrogen, aryl, Het or Ci-6alkyl optionally substituted with aryl or Het;
  • R 6 is aryl or naphthalenyl;
  • Y is O, S, NR 7 ; said R 7 being hydrogen, Ci- ⁇ alkyl or Ci-6alkylcarbonyl ;
  • Z 1 and Z 2 each independently arc O, S, NR 8 or a direct bond; said R 8 being hydrogen or Ci-6alkyl;
  • X is O, S or NR 9 ; said R 9 being hydrogen, Ci ⁇ alkyl or cyano;
  • each Het is selected from pyridinyl optionally substituted with one or two substituents each independently selected from halo, amino, mono- and di(C ⁇ alkyl)-arnino, nitro, cyano, Ci ⁇ alkyl, Ci-6alkyloxy and hydroxy; pvrirnidinyl optionally substituted with one or two substituents each independently selected from halo, amino, Ci ⁇ alkylamino, Ci- ⁇ al yl and Ci ⁇ alkyloxy; pyridazinyl optionally substituted with Ci ⁇ alkyl or halo; pyrazinyl optionally substituted with halo, amino or Ci ⁇ alkyl; thienyl optionally substituted with halo or Ci ⁇ alkyl; furanyl optionally substituted with halo or Ci-ealkyl; pyrrolyl optionally substituted with C ⁇ aU yl; thiazolyl optionally substituted with C ⁇ - 6 alkyl; irnid
  • X 1 and X 2 each independently are O or S ; each R 10 is hydrogen, hydroxy- Ci-6alkyl or Ci ⁇ alkyloxycarbonyl;
  • R 11 is hydrogen, Ci- ⁇ alkyl, hydroxy, mercapto, Ci- ⁇ alkyloxy, Ci ⁇ alkylthio, halo or Ci ⁇ alkyloxycarbonylCi ⁇ alkyl ;
  • radicals G 1 , G 2 , G 3 or G 4 may be replaced by C
  • each aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci-6alkyl, Ci-6alkyloxy, Ci-6alkylthio, mercapto, amino, mono- and di(C ⁇ alkyl)amino, carboxyl, C ⁇ .6alkyloxycarbonyl and Ci ⁇ alkylcarbonyl.
  • the compounds of formula (I) wherein Het is substituted with hydroxy, mercapto or arnino may also exist in their tautomeric forms. Such forms although not explicitly indicated hereinabove, are intended to be included within the scope of the invention.
  • Ci- ⁇ alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, lJ-dimethylethyl, 1-methylpropyl, 2-methylpropyl, pentyl, hexyl and the like;
  • Ci-i2alkyl defines Ci ⁇ alkyl radicals as defined hereinabove and the higher homologs thereof having from 7 to 12 carbon atoms;
  • C ⁇ - ⁇ cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • C3-6alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-buten
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
  • Said salt forms can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g.
  • hydrochloric, hydrobromic and the like acids sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricar- boxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
  • the salt form can be converted by treatment with alkali into the free base form.
  • acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula CO are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds of this invention may have several asymmetric carbon atoms in their structure. As usual, each of these chiral centers may be indicated by the stereochemical descriptors R and S.
  • the stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.
  • Preferred compounds comprise those compounds of formula (I) wherein
  • R 3 is cyano, Ci- ⁇ alkyloxy- phenyl, 2-oxo-3-oxazolidi ⁇ yl, Ci ⁇ alkyloxazolyl or a bicyciic heterocyclic radical of formula
  • R 11 being Ci- 6 alkyl
  • R 4 is hydrogen, nitropyridinyl or imidazopyridinyl
  • R 5 is Ci ⁇ alkyl, aminophenyl, halophenyl, furanyl, l-methyl-2-indolyl or Ci-6alkylpyrrolyl
  • Y is NH
  • Z 1 and Z 2 each independently are NH or a direct bond and X is O.
  • R 4 is nitropyridinyl or iinidazopyridinyl;
  • R 5 is Ci ⁇ alkyl, fluorophenyl, furanyl, l-methyI-2-indolyl or l-methyl-2-py ⁇ olyl.
  • R 1 is 2-methyl-5-oxazolyl
  • L is hydrogen, methyl or a radical of formula
  • the compounds of formula 0 wherein L is other than hydrogen, said L being represented by lA and said compounds being represented by formula (I-a) can be prepared by N-alkylating a compound of formula (I) wherein L is hydrogen, said compound being represented by (I-b), with an alkylating reagent of formula (II).
  • W represents an appropriate leaving group such as, for example, halo, e.g. chloro, bromo and the like; or a sulfonyloxy group such as, for example, methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the like.
  • Said N-alkylation reaction can conveniently be conducted in a reaction-inert solvent such as, for example, water, an aromatic hydrocarbon, an alkanol, an ether, a dipolar aprotic solvent, or a mixture of such solvents.
  • a reaction-inert solvent such as, for example, water, an aromatic hydrocarbon, an alkanol, an ether, a dipolar aprotic solvent, or a mixture of such solvents.
  • an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction.
  • an iodide salt, in alkali metal iodide is appropriate.
  • Somewhat elevated temperatures and stirring may enhance the rate of the reaction.
  • it may be advantageous to conduct said N-alkylation under an inert atmosphere such as, for example, oxygen-free argon
  • said N-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions.
  • reductive ⁇ -alkylation reaction may conveniently be carried out by reducing a mixture of the reactants in a suitable reaction-inert solvent following art-known reductive N-alkylation procedures.
  • the reaction mixture may be stirred and or heated in order to enhance the reaction rate.
  • Suitable solvents are, for example, water; Ci-6alkanols, esters, ethers, halogenated hydrocarbons, dipolar aprotic solvents, carboxylic acids, or a rnixture of such solvents.
  • the compounds of formula (I) can also be prepared by iN-alkylating an intermediate of formula (IV) with an appropriate alkylating reagent of formula (V).
  • the compounds of formula 0-) wherein L is a radical of formula (b-2) and R 4 is aryl or Het, said R 4 being represented by R 4 "-- 1 and said compounds by formula (I-a-2) can also be prepared by alkylating a compound of formula (I) wherein L is a radical of formula (b-2) and R 4 is hydrogen, said compound being represented by formula (I-a-3), with a reagent of formula (VI).
  • the alkylation reaction of (I-a-3) with (VT) can conveniently be conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, a ketone, an ether, a halogenated hydrocarbon, and a dipolar aprotic solvent.
  • an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction. Somewhat elevated temperatures may enhance the rate of the reaction.
  • the compounds of formula (I) wherein L is a radical of formula (b-3), Z 2 is a direct bond, _Z is other than a direct bond and X is other than NR ⁇ , said Z and X being represented by Zl ⁇ a and X 2 , said compounds being represented by (I-a-4), can be prepared by reacting a compound of formula (I-a-5) with a reagent of formula (VII) or a reactive functional derivative thereof.
  • the reaction of (VII) with (I-a-5) may generally be conducted following art-known esterification or amidation reaction procedures.
  • the carboxylic acid may be converted into a reactive derivative, e.g., an anhydride or a carboxylic acid halide, which subsequently is reacted with (I-a-5); or by reacting (VII) and (I-a-5) with a suitable reagent capable of forming amides or esters, e.g., N,N-methanetetraylbis[cyclohexamine], 2-chloro-l-methylpyridinium iodide and the like.
  • Said reactions may most conveniently be conducted in a suitable solvent such as, for example, an ether, a halogenated hydrocarbon, a dipolar aprotic solvent and the like.
  • the addition of a base may be appropriate.
  • the compounds of formula (I-a-4) wherein Z 1 '- is NH, X 2 is O and R 5 is 2-arninophenyl or a derivative thereof, said compounds being represented by (I-a-4-1) can be obtained by reacting a compound of formula (I-a-5) wherein Z 1 ' 3 is NH, said compounds being represented by (I-a-5-1), with a reagent of formula (Vm):
  • the compounds of formula (I) can also be prepared by H-alkylating a reagent of formula (DC) with an intermediate of formula (X).
  • N-alkylation is conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (D).
  • R 1 is (hydroxyC ⁇ aJ ⁇ l)furanyl or (hydroxy- Ci-6alkyl)oxazolyl
  • said R 1 being represented by R 1* - 1
  • said compounds being represented by formula ( -c) can be obtained from the reduction of an intermediate of formula (XI) wherein R 2 is furanyl or oxazolyl substituted with a carboxylic ester or a (Ci-5alkyl)carboxylic ester group, with an appropriate reducing agent
  • reducing agents are, for example, lithium borohydride, lithium aluminum hydride, and the like.
  • the compounds of formula (I) can also be converted into each other following art- known procedures of functional group transformation. Some examples of such proce ⁇ dures are cited hereinafter.
  • the compounds of formula (I) containing a cyano substituent can be converted into the corresponding amines by stirring and, if desired, heating the starting cyano compounds in a hydrogen containing medium in the presence of an appropriate catalyst such as, for example, platinum-on-charcoal, Raney nickel and the like catalysts.
  • Suitable solvents are, for example, methanol, ethanol and the like.
  • the compounds of formula (I) containing an amino group may also be obtained by hydrolysis of the corresponding carbamate derivative in acidic medium.
  • Amino groups may be alkylated or acylated following art-known procedures such as, for example, N-alkylation, N-acylation, reductive N-alkylation and the like methods.
  • the compounds of formula (I) wherein L is hydrogen can be obtained from compounds of formula (I) wherein L is phenylmethyl or Ci ⁇ alkyloxycarbonyl following art-known procedures like catalytic hydrogenation or hydrolysis in an acidic or alkaline medium depending on the nature of L.
  • reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art.
  • Some intermediates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or similar compounds.
  • the intermediates of formula (IV) can be prepared by N-alkylating an intermediate of formula (DC) with an alkylating reagent of formula (XII).
  • the intermediates of formula (IV) wherein L is other than hydrogen, said compounds being represented by formula (TV-a), may also be obtained by N.-alkylating a compound of formula (XuT) with an alkylating reagent of formula 01).
  • N-alkylations are conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (JT).
  • the intermediates of formula (DC) can be obtained from an intermediate of formula (XIV) wherein L 2 is phenylmethyl or Ci-6alkyloxycarbonyl following art-known procedures like catalytic hydrogenation or hydrolysis in an acidic or alkaline medium depending on the nature of L.
  • intermediates of formula (XIV) wherein L is a radical of formula -Alk-Y-R 4 (b-2) wherein Y is NH and R 4 is a radical of formula (c-3), said intermediates being represented by the formula (XTV-a) can be prepared by reacting an intermediate of formula (XV), with an appropriate metal oxide or salt in an appropriate solvent following art-known procedures.
  • Said appropriate metal oxides or salts are for example mercury(II) or lead( ⁇ ) oxides or salts, such as, for example, mercuryoxide, mercurychloride, mercuryacetate, leadoxide, leadacetate and the like. In certain instances it may be appropriate to supplement the reaction mixture with a small amount of sulfur.
  • the intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XVI) with a reagent of formula (XVII), in a reaction-inert solvent.
  • the intermediates of formula (XVI) can be prepared by reacting an intermediate of formula (XVIII) with carbon disulfide in a reaction-inert solvent, preferably in the presence of e.g. dicyclohexylcarbodiimide (DCC).
  • a reaction-inert solvent preferably in the presence of e.g. dicyclohexylcarbodiimide (DCC).
  • the intermediates of formula (X) can be prepared by reacting an intermediate of formula (XIX) with a reagent of formula (XX) wherein R 12 is Ci-4alkyl, in a reaction- inert solvent.
  • Appropriate solvents are, for example, water, an aromatic hydrocarbon, a ketone, an ether, a dipolar aprotic solvent, or a mixture of such solvents.
  • an appropriate base such as, an alkali metal carboxylate, e.g. sodium acetate, potassium acetate, sodium propionate and the like, may be utilized to pick up the acid which is liberated during the course of the reaction.
  • the nitro derivative of formula (XXI) may be reduced by catalytic hydrogenation in a suitable solvent, e.g. methanol or ethanol, in the presence of hydrogen and an appropriate catalyst, e.g. platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like, optionally at an increased temperature and/or pressure. In some instances it may be useful to add an appropriate catalyst poison such as thiophene to the reaction mixture.
  • said nitro derivative may also be reduced by a reducing agent such as, for example, sodium sulfide, sodium hydrogen sulfide, sodium hydrosulfite, titanium trichloride, formic acid, N,N-diethylethanamine, and the like.
  • the intermediates of formula (XXI) can be prepared by reacting a compound of formula (XXJT with a reagent of formula (XXHI) in a reaction-inert solvent.
  • Suitable solvents are, for example, alkanols, e.g. methanol, ethanol and the like.
  • an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction.
  • the intermediates of formula (XI) can be prepared by N-alkylating an intermediate of formula (IV) with an alkylating reagent of formula (XXIV).
  • the intermediates of formula (XI) may also be prepared by N-alkylating an intermediate of formula (IX) with an alkylating reagent of formula (XXV).
  • the intermediates of formula (XI) may be obtained from N-alkylating an intermediate of formula (XXVI) with an alkylating reagent of formula (II).
  • N-alkyla ⁇ ons are conveniently conducted following art-known H-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (II).
  • Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like; and enantiomers may be separated from each other following art-known resolution methods, for example, by the selective crystallization of their diastereomeric salts with chiral acids. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof possess useful pharmacological properties. More particularly, they are active antihistaminics which can clearly be demonstrated by, e.g., the results obtained in the test "Protection of Rats from Compound 48/80-induced lethality". Surprisingly, some of the present compounds have improved antiallergic activity over structurally related compounds, known from e.g. EP-A-0,393,738, published October 24, 1990, and US-4,946,843.
  • the compounds of formula (I) and their acid addition salts are very useful in the treatment of diseases such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and or may be helpful for preparing the desired compositions.
  • compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
  • Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • the present invention also relates to a method of treating warm-blooded animals suffering from said allergic diseases by administering to said warm-blooded animals an antiallergically effective amount of a compound of formula (J) or a pharmaceutically acceptable acid addition salt form thereof.
  • an antiallergically effective amount would be from about 0.001 mg/kg to about 20 mg/kg body weight, and more preferably from about 0.01 mg/kg to about 5 mg/kg body weight.
  • Example 2 a) To a stirred and cooled ( ⁇ -5°C) solution of 254 g of carbon disulfide and 103 g of M, N-methanetetraylbis[cyclohexanamine] in 1170 g of tetrahydrofuran there was added dropwise a solution of 109.7 g of 4-(phenylmethyl)-l-piperazineethanarnine in 180 g of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature, stirred for a few hours and then evaporated.
  • Example 4 To and 1.05 g of a dispersion of sodium hydride in mineral oil (50%) there was added dropwise a solution of 5.8 g of intermediate (12) in and, after 1 hour, a solution of 3.95 g of ethyl 5-(chloromethyl)-2-furancarboxylate in some H- ⁇ ! - ⁇ - ⁇ thylformamide. Stirring at room temperature was continued for 1 1 2 hours. After the addition of NaHCO 3 (aq.), the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH C1 2 / C 2 HsOH 97 :3).
  • Example 7 A mixture of 24 g of ethyl 1 -piperazinecarboxylate, 41.7 g of intermediate (5) , 16 g of sodium carbonate and 600 ml of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / C2H5OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from 4-methyl-2-pentanone.
  • Example 11 A mixture of 3J g of compound (10), 1 g of polyoxymethylene, 1 ml of a solution of thiophene in methanol 4% and 150 ml of methanol were hydrogenated at normal pressure and at room temperature in the presence of 2 g of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between dichloromethane and NH4OH (aq.). The aqueous layer was separated and re-extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was converted into the (E)-2-butenedioate (1 :2) salt in ethanol.
  • compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.
  • Active ingredient as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
  • Example 20 Film-coated tablets Preparation pf a let core A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl- pyrrolidone (Kollidon-K 90®) in about 200 ml of water. The wet powder rnixture is sieved, dried and sieved again. Then there are added 100 g microcrystalline cellulose (Avicel®) and 15 g hydrogenated vegetable oil (Sterotex ®). The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient. Coating
  • 1,2,3-propanetriol 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concen ⁇ trated colour suspension (Opaspray K-l-2109®) and the whole is homogenated.
  • the tablet cores are coated with the thus obtained mixture in a coating apparatus.

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Abstract

Antihistaminic piperazinyl derivatives having formula (I) wherein R1 is (hydroxyC¿1-6?alkyl)furanyl, (C1-6alkyl)oxazolyl or (hydroxyC1-6alkyl)oxazolyl; -A?1=A2-A3=A4¿- is a bivalent radical having the formula -CH=CH-CH=CH- (a-1), -N=CH-CH=CH- (a-2), -CH=N-CH=CH- (a-3), -CH=CH-N=CH- (a-4), -CH=CH-CH=N- (a-5), -N=CH-N=CH- (a-6) or -CH=N-CH=N- (a-7); m is 1, 2, 3 or 4; L is hydrogen; C¿1-12?alkyl; C3-6cycloalkyl; C3-6alkenyl optionally substituted with aryl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; arylcarbonyl; arylC1-6alkyloxycarbonyl; or a radical of formula: -Alk-R?3¿ (b-1); -Alk-Y-R4 (b-2); -Alk-Z1-C(=X)-Z2-R5 (b-3); or -CH¿2?-CHOH-CH2-O-R?6¿ (b-4). Process for preparing the same, compositions containing said antihistaminic derivatives and a method of treating allergic diseases.

Description

A TimSTAfflNIC PIPERAZI YL DERIVATIYES
Background of the invention In US-4,695,575; US-5,041,448; US-4,943,580; US-4,988,689; US-5,008,268;
US-4,946,843; US-5,011,842 and EP-0,468,884-A there are disclosed methylenebenzimidazole and methyleneimidazopyridine derivatives useful as antihistaminics and serotonin antagonists.
Description of the invention
The present invention is concerned with novel piperazinyl derivatives having the formula :
Figure imgf000003_0001
the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein
R1 is (hydroxyCι^alkyl)furanyl, (Cι^alkyl)oxazolyl or (hydroxyCι^alkyl)oxazolyl;
-A--=A2-A3=A4- is a bivalent radical having the formula
Figure imgf000003_0002
wherein one or two hydrogen atoms in said radicals (a-1) to (a-7) may each independently be replaced by halo, Ci^alkyl, Ci^alkyloxy, hydroxy or trifluόro- methyl; m is 1, 2, 3 or 4;
L is hydrogen; Chalky!; C3^cycloalkyl; C3^alkenyl optionally substituted with aryl;
Figure imgf000004_0001
carbonyl; or a radical of formula :
Figure imgf000004_0002
Alk is Ci^alkanediyl;
R3 is cyano, aryl or Het;
R4 is hydrogen, aryl Het or Ci^alkyl optionally substituted with aryl or Het;
R5 is hydrogen, aryl, Het or Ci-6alkyl optionally substituted with aryl or Het; R6 is aryl or naphthalenyl;
Y is O, S, NR7; said R7 being hydrogen, Ci-βalkyl or Ci-6alkylcarbonyl ;
Z1 and Z2 each independently arc O, S, NR8 or a direct bond; said R8 being hydrogen or Ci-6alkyl;
X is O, S or NR9; said R9 being hydrogen, Ci^alkyl or cyano;
each Het is selected from pyridinyl optionally substituted with one or two substituents each independently selected from halo, amino, mono- and di(Cι^alkyl)-arnino, nitro, cyano, Ci^alkyl, Ci-6alkyloxy and hydroxy; pvrirnidinyl optionally substituted with one or two substituents each independently selected from halo, amino, Ci^alkylamino, Ci-^al yl and Ci^alkyloxy; pyridazinyl optionally substituted with Ci^alkyl or halo; pyrazinyl optionally substituted with halo, amino or Ci^alkyl; thienyl optionally substituted with halo or Ci^alkyl; furanyl optionally substituted with halo or Ci-ealkyl; pyrrolyl optionally substituted with C^aU yl; thiazolyl optionally substituted with Cι-6alkyl; irnidazolyl optionally substituted with one or two substituents each independently selected from Ci-ealkyl, arylCi^alkyl and nitro; 1,3,4-thiadiazolyl optionally substituted with Ci-ealkyl or amino; oxazolyl optionally substituted with Ci-^alkyl; 2-oxo-3-oxazolidinyl; l-methyl-2-indolyl; 2,3-dihydro-l,4-benzodioxinyl optionally substituted with Ci-ealkyl or halo; 2-oxo-2H-l-benzopyranyl and 4-oxo-4H-l- benzopyranyl both being optionally substituted with Ci-6alkyl; 3,7-dihydro-l,3- dimethyl-2,6-dioxo- lH-purin-7-yl optionally substituted with Cj^alkyl; and a bicyclic heterocyclic radical of formula
Figure imgf000005_0001
wherein
X1 and X2 each independently are O or S ; each R10 is hydrogen,
Figure imgf000005_0002
hydroxy- Ci-6alkyl or Ci^alkyloxycarbonyl;
R11 is hydrogen, Ci-^alkyl, hydroxy, mercapto, Ci-^alkyloxy, Ci^alkylthio, halo or Ci^alkyloxycarbonylCi^alkyl ;
G1 is -CH=CH-CH=CH-; -S-CH=CH- or -N=CH-NH- ;
G is -CH=CH-CH=CH-, -(CH2)4-, -S-(CH2)2-, -S-(CH2)3-, -S-CH=CH-,
-CH=CH-O-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-CH=CH-, -NH-CH=N-, -NH-N=CH- or -NH-N=CH-CH2-;
G3 is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,
-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ;
G4 is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,
-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ;
wherein one or two hydrogen atoms in said radicals G1, G2, G3 or G4 may be replaced by C|_6alkyl,
Figure imgf000005_0003
or halo, when connected to a carbon atom; or by Chalky!,
Figure imgf000005_0004
when connected to a nitrogen atom;
each aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci-6alkyl, Ci-6alkyloxy, Ci-6alkylthio, mercapto, amino, mono- and di(Cι^alkyl)amino, carboxyl, Cι.6alkyloxycarbonyl and Ci^alkylcarbonyl. The compounds of formula (I) wherein Het is substituted with hydroxy, mercapto or arnino, may also exist in their tautomeric forms. Such forms although not explicitly indicated hereinabove, are intended to be included within the scope of the invention. As used in the foregoing definitions halo is generic to fluoro, chloro, bromo and iodo; Ci-^alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, lJ-dimethylethyl, 1-methylpropyl, 2-methylpropyl, pentyl, hexyl and the like; Ci-i2alkyl defines Ci^alkyl radicals as defined hereinabove and the higher homologs thereof having from 7 to 12 carbon atoms; Cβ-δcycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C3-6alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyI, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C3^alkenyl being connected to a nitrogen atom preferably is saturated; Ci^alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentane- diyl, 1,6-hexanediyl and the branched isomers thereof.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salt forms can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-l,2,3-propanetricar- boxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The term acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula CO are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The compounds of this invention may have several asymmetric carbon atoms in their structure. As usual, each of these chiral centers may be indicated by the stereochemical descriptors R and S. The stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.
Aryl as used in the definition of R3, R4 and R-5, in particular is phenyl optionally substituted with halo, Ci-.galkyl, hydroxy or C^galkyloxy; aryl as used in the definition of R6 in particular is phenyl optionally substituted with halo.
Interesting compounds are those compounds of formula (I) wherein R1 in particular represents a radical of formula
Figure imgf000007_0001
Preferred compounds comprise those compounds of formula (I) wherein
-A1=A2-A3=A4- is a bivalent radical of formula -CH=CH-CH=CH- (a-1), or -N=CH-CH=CH- (a-2); m is 1; R1 is (hydroxyCι^alkyl)furanyl or (Cι^alkyl)oxazolyl; L is hydrogen, Cι_ι alkyl, Ci^alkyloxycarbonyl or a radical of formula -Alk-R3 (b-1),
-Alk-Y-R4 (b-2), or -Alk-Z1-C(=X)-Z2-R-5 (b-3), wherein R3 is cyano, Ci-βalkyloxy- phenyl, 2-oxo-3-oxazolidiπyl, Ci^alkyloxazolyl or a bicyciic heterocyclic radical of formula
Figure imgf000007_0002
R11 being Ci-6alkyl, G2 being -CH=CH-CH=CH-, -S-(CH2)2- or -S-CH=CH-; R4 is hydrogen, nitropyridinyl or imidazopyridinyl; R5 is Ci^alkyl, aminophenyl, halophenyl, furanyl, l-methyl-2-indolyl or Ci-6alkylpyrrolyl; Y is NH; Z1 and Z2 each independently are NH or a direct bond and X is O.
More preferred compounds are those preferred compounds wherein R1 is 5-hydroxymethyl-2-furanyl; L is methyl or a radical of formula -Alk-R3 (b- 1 ), -Alk-Y-R4 (b-2), or -Alk-Z1-C(=X)-Z2-R5 (b-3), wherein R3 is methoxyphenyl, 2-oxo-3-oxazolidinyl or a bicyciic heterocyclic radical of formula
Figure imgf000008_0001
G2 being -CH=CH-CH=CH-, -S-( R- 2- or -S-CH=CH-; R4 is nitropyridinyl or iinidazopyridinyl; R5is Ci^alkyl, fluorophenyl, furanyl, l-methyI-2-indolyl or l-methyl-2-pyπolyl.
Another group of more preferred compounds are those preferred compounds wherein R1 is 2-methyl-5-oxazolyl; L is hydrogen, methyl or a radical of formula
Figure imgf000008_0002
The most preferred compounds of formula (I) are :
5-[[2-[(4-methyl-l-piperazinyl)methyl]- IH-benzimidazol- l-yl]nτethyl-2-furanmethanol;
N-[2-[4-[[3-[[5-(hyσ^xymeΛyl)-2-i-ur^ yl]methyl]-l-piperazinyl]e yl]-3-furancarboxarnide;
2 -dihydro-6-[2-[4-[[3-[[5-(hydroxymethyl)-2-furanyl]memyl]-3H-iιrύda∞ pyridin-2-yl]methyl]-l-piperazinyl]ethyl]-7-methy
N-[2-[4-[[l-[[5-(hydroxymemyl)-2-furanyl]m^ piperazinyl]emyl]-3-furancarboxamide; 7-meftyl-6-[2-[4-[[3-[(2-methyl-5-oxazo^ yl]methyl]-l-pipeι^zinyl]ethyl]-5H-tMazolo[3,2-a]pyriιmdin-5-one
2-[[4-[2-(4-methoxyphenyl)ethyl]-l-piperazinyl]methyl]-3-[(2-methyl-5- oxazolyl)methyl]-3H-iιnidazo[4,5-b]pyridine; the solvates and the pharmaceutically acceptable addition salts thereof.
The compounds of formula 0 wherein L is other than hydrogen, said L being represented by lA and said compounds being represented by formula (I-a) can be prepared by N-alkylating a compound of formula (I) wherein L is hydrogen, said compound being represented by (I-b), with an alkylating reagent of formula (II).
Figure imgf000009_0001
In formula (II) and hereinafter W represents an appropriate leaving group such as, for example, halo, e.g. chloro, bromo and the like; or a sulfonyloxy group such as, for example, methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the like.
Said N-alkylation reaction can conveniently be conducted in a reaction-inert solvent such as, for example, water, an aromatic hydrocarbon, an alkanol, an ether, a dipolar aprotic solvent, or a mixture of such solvents. The addition of an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction. In some instances the addition of an iodide salt, preferat in alkali metal iodide, is appropriate. Somewhat elevated temperatures and stirring may enhance the rate of the reaction. Additionally, it may be advantageous to conduct said N-alkylation under an inert atmosphere such as, for example, oxygen-free argon or nitrogen.
Alternatively, said N-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions.
The compounds of formula (I-a) wherein L1 is Ci-l2alkyl, C3-6cycloalkyl, a radical of formula (b- 1 ), (b-2) or (b-3), said radicals being represented by the radical L^H- and said compounds by formula (I-a-1), can also be prepared by the reductive N-alkylation reaction of (I-b) with an appropriate ketone or aldehyde of formula L^=O (IE), said L,2=O being an intermediate of formula L^H2 wherein two geminal hydrogen atoms are replaced by =O, and !?■ is a geminal bivalent radical comprising Ci-i2alkylidene, C3-6cycloalkylidene, R3-C 1 -6alkylidene, R4- Y-C 1 -6alkylidene and R5-Z2-C(=X)-Z1 -Ci -όalkylidene.
Figure imgf000009_0002
(ffl) (I-a-1) Said reductive ϋ-alkylation reaction may conveniently be carried out by reducing a mixture of the reactants in a suitable reaction-inert solvent following art-known reductive N-alkylation procedures. In particular, the reaction mixture may be stirred and or heated in order to enhance the reaction rate. Suitable solvents are, for example, water; Ci-6alkanols, esters, ethers, halogenated hydrocarbons, dipolar aprotic solvents, carboxylic acids, or a rnixture of such solvents. The term "art-known reductive M-alkylation procedures" means that the reaction is carried out either with sodium cyanoborohydride, sodium borohydride, formic acid or a salt thereof, e.g. ammonium formate and the like reducing agents, or alternatively under hydrogen atmosphere, optionally at an increased temperature and/or pressure, in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may be advantageous to add an appropriate catalyst- poison to the reaction mixture, e.g., thiophene, quinoline-sulphur and the like. In some instances it may also be advantageous to add an alkali metal salt to the reaction rnixture such as, for example, potassium fluoride, potassium acetate and the like salts.
The compounds of formula (I) can also be prepared by iN-alkylating an intermediate of formula (IV) with an appropriate alkylating reagent of formula (V).
Figure imgf000010_0001
σv) ©
Said Ν-alkylation is conveniently conducted following art-known Ν-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (JT).
The compounds of formula 0-) wherein L is a radical of formula (b-2) and R4 is aryl or Het, said R4 being represented by R4"--1 and said compounds by formula (I-a-2) can also be prepared by alkylating a compound of formula (I) wherein L is a radical of formula (b-2) and R4 is hydrogen, said compound being represented by formula (I-a-3), with a reagent of formula (VI).
Figure imgf000011_0001
The alkylation reaction of (I-a-3) with (VT) can conveniently be conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, a ketone, an ether, a halogenated hydrocarbon, and a dipolar aprotic solvent. The addition of an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction. Somewhat elevated temperatures may enhance the rate of the reaction.
The compounds of formula (I) wherein L is a radical of formula (b-3), Z2 is a direct bond, _Z is other than a direct bond and X is other than NR^, said Z and X being represented by Zl~a and X2, said compounds being represented by (I-a-4), can be prepared by reacting a compound of formula (I-a-5) with a reagent of formula (VII) or a reactive functional derivative thereof.
Figure imgf000011_0002
The reaction of (VII) with (I-a-5) may generally be conducted following art-known esterification or amidation reaction procedures. For example, the carboxylic acid may be converted into a reactive derivative, e.g., an anhydride or a carboxylic acid halide, which subsequently is reacted with (I-a-5); or by reacting (VII) and (I-a-5) with a suitable reagent capable of forming amides or esters, e.g., N,N-methanetetraylbis[cyclohexamine], 2-chloro-l-methylpyridinium iodide and the like. Said reactions may most conveniently be conducted in a suitable solvent such as, for example, an ether, a halogenated hydrocarbon, a dipolar aprotic solvent and the like. The addition of a base may be appropriate.
The compounds of formula (I-a-4) wherein Z1'- is NH, X2 is O and R5 is 2-arninophenyl or a derivative thereof, said compounds being represented by (I-a-4-1) can be obtained by reacting a compound of formula (I-a-5) wherein Z1'3 is NH, said compounds being represented by (I-a-5-1), with a reagent of formula (Vm):
Figure imgf000012_0001
The compounds of formula (I) can also be prepared by H-alkylating a reagent of formula (DC) with an intermediate of formula (X).
Figure imgf000012_0002
Said N-alkylation is conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (D).
The compounds of formula (I) wherein R1 is (hydroxyCι^aJ^l)furanyl or (hydroxy- Ci-6alkyl)oxazolyl, said R1 being represented by R1*-1 and said compounds being represented by formula ( -c) can be obtained from the reduction of an intermediate of formula (XI) wherein R2 is furanyl or oxazolyl substituted with a carboxylic ester or a (Ci-5alkyl)carboxylic ester group, with an appropriate reducing agent
re redduucctitioonn
Figure imgf000013_0002
Figure imgf000013_0001
(XI) (I-c)
Appropriate reducing agents are, for example, lithium borohydride, lithium aluminum hydride, and the like.
The compounds of formula (I) wherein R3, R4 or R-5 are Het, may also be prepared following art-known procedures for preparing heterocyclic ring systems or following analogous methods. A number of such cyclization procedures are described in for example, US-4,695,575 and in the references cited therein, in particular US-4,335,127; 4,342,870 and 4,443,451.
The compounds of formula (I) can also be converted into each other following art- known procedures of functional group transformation. Some examples of such proce¬ dures are cited hereinafter. The compounds of formula (I) containing a cyano substituent can be converted into the corresponding amines by stirring and, if desired, heating the starting cyano compounds in a hydrogen containing medium in the presence of an appropriate catalyst such as, for example, platinum-on-charcoal, Raney nickel and the like catalysts. Suitable solvents are, for example, methanol, ethanol and the like. The compounds of formula (I) containing an amino group may also be obtained by hydrolysis of the corresponding carbamate derivative in acidic medium. Amino groups may be alkylated or acylated following art-known procedures such as, for example, N-alkylation, N-acylation, reductive N-alkylation and the like methods. The compounds of formula (I) wherein L is hydrogen can be obtained from compounds of formula (I) wherein L is phenylmethyl or Ci^alkyloxycarbonyl following art-known procedures like catalytic hydrogenation or hydrolysis in an acidic or alkaline medium depending on the nature of L.
In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art. Some intermediates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or similar compounds.
The intermediates of formula (IV) can be prepared by N-alkylating an intermediate of formula (DC) with an alkylating reagent of formula (XII).
Figure imgf000014_0001
The intermediates of formula (IV) wherein L is other than hydrogen, said compounds being represented by formula (TV-a), may also be obtained by N.-alkylating a compound of formula (XuT) with an alkylating reagent of formula 01).
Figure imgf000014_0002
Q__U) QV-a)
Said N-alkylations are conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (JT).
The intermediates of formula (DC) can be obtained from an intermediate of formula (XIV) wherein L2 is phenylmethyl or Ci-6alkyloxycarbonyl following art-known procedures like catalytic hydrogenation or hydrolysis in an acidic or alkaline medium depending on the nature of L.
L — N N— L2 *~ L — N NH
(XIV) (TX)
The intermediates of formula (XIV) wherein L is a radical of formula -Alk-Y-R4 (b-2) wherein Y is NH and R4 is a radical of formula (c-3), said intermediates being represented by the formula (XTV-a) can be prepared by reacting an intermediate of formula (XV), with an appropriate metal oxide or salt in an appropriate solvent following art-known procedures.
Figure imgf000015_0001
(XW-a)
Said appropriate metal oxides or salts are for example mercury(II) or lead(ϋ) oxides or salts, such as, for example, mercuryoxide, mercurychloride, mercuryacetate, leadoxide, leadacetate and the like. In certain instances it may be appropriate to supplement the reaction mixture with a small amount of sulfur.
The intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XVI) with a reagent of formula (XVII), in a reaction-inert solvent.
__-
Figure imgf000015_0002
(xvπ)
Figure imgf000015_0003
The intermediates of formula (XVI) can be prepared by reacting an intermediate of formula (XVIII) with carbon disulfide in a reaction-inert solvent, preferably in the presence of e.g. dicyclohexylcarbodiimide (DCC).
/ — CS2 — \
L2— N N— Alk— NH2 *~ L2— N N— Alk— N=C=S ^ ___ (XVffl) (XVI)
The intermediates of formula (X) can be prepared by reacting an intermediate of formula (XIX) with a reagent of formula (XX) wherein R12 is Ci-4alkyl, in a reaction- inert solvent.
Figure imgf000016_0001
(X)
Appropriate solvents are, for example, water, an aromatic hydrocarbon, a ketone, an ether, a dipolar aprotic solvent, or a mixture of such solvents. The addition of an appropriate base such as, an alkali metal carboxylate, e.g. sodium acetate, potassium acetate, sodium propionate and the like, may be utilized to pick up the acid which is liberated during the course of the reaction.
The intermediates of formula (XIX) can be obtained from the corresponding nitro derivatives of formula (XXI) following art-known reduction procedures.
Figure imgf000016_0002
(XXI)
Figure imgf000016_0003
For example, the nitro derivative of formula (XXI) may be reduced by catalytic hydrogenation in a suitable solvent, e.g. methanol or ethanol, in the presence of hydrogen and an appropriate catalyst, e.g. platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like, optionally at an increased temperature and/or pressure. In some instances it may be useful to add an appropriate catalyst poison such as thiophene to the reaction mixture. Alternatively, said nitro derivative may also be reduced by a reducing agent such as, for example, sodium sulfide, sodium hydrogen sulfide, sodium hydrosulfite, titanium trichloride, formic acid, N,N-diethylethanamine, and the like.
The intermediates of formula (XXI) can be prepared by reacting a compound of formula (XXJT with a reagent of formula (XXHI) in a reaction-inert solvent.
Figure imgf000017_0001
(xxm) (XXD
Suitable solvents are, for example, alkanols, e.g. methanol, ethanol and the like. The addition of an appropriate base such as, for example, an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide, or an organic base may be utilized to pick up the acid which is liberated during the course of the reaction.
The intermediates of formula (XI) can be prepared by N-alkylating an intermediate of formula (IV) with an alkylating reagent of formula (XXIV).
Figure imgf000017_0002
(XI)
The intermediates of formula (XI) may also be prepared by N-alkylating an intermediate of formula (IX) with an alkylating reagent of formula (XXV).
Figure imgf000017_0003
(XD
Alternatively, the intermediates of formula (XI) may be obtained from N-alkylating an intermediate of formula (XXVI) with an alkylating reagent of formula (II).
Figure imgf000018_0001
(XXVQ (XI)
Said N-alkylaύons are conveniently conducted following art-known H-alkylation procedures as described hereinabove for the preparation of (I-a) from (I-b) and (II).
The intermediates of formula (TV), (IX), (XI), and (XTV) can also be converted into each other following art-known procedures of functional group transformation as described hereinbefore for the compounds of formula (I).
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like; and enantiomers may be separated from each other following art-known resolution methods, for example, by the selective crystallization of their diastereomeric salts with chiral acids. Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reactions occur stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof possess useful pharmacological properties. More particularly, they are active antihistaminics which can clearly be demonstrated by, e.g., the results obtained in the test "Protection of Rats from Compound 48/80-induced lethality". Surprisingly, some of the present compounds have improved antiallergic activity over structurally related compounds, known from e.g. EP-A-0,393,738, published October 24, 1990, and US-4,946,843.
In view of their antiallergic properties, the compounds of formula (I) and their acid addition salts are very useful in the treatment of diseases such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like. In view of their useful antiallergic properties the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the antiallergic compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in 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 herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The present invention also relates to a method of treating warm-blooded animals suffering from said allergic diseases by administering to said warm-blooded animals an antiallergically effective amount of a compound of formula (J) or a pharmaceutically acceptable acid addition salt form thereof.
Those of skill in treating allergic diseases in warm-blooded animals could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an antiallergically effective amount would be from about 0.001 mg/kg to about 20 mg/kg body weight, and more preferably from about 0.01 mg/kg to about 5 mg/kg body weight.
The following examples are intended to illustrate and not to limit the scope of the present invention in all its aspects.
Experimental part
A. Preparation of the intermediates
Example 1 a) A mixture of 19.61 g of 5-(arninomethyl)-2-furanmethanol, 23.78 g of 2-chloro-3- nitropyridine, 16.8 g of sodium hydrogen carbonate and 80 g of ethanol was stirred for 6 hours at reflux temperature. After cooling, the reaction rnixture was evaporated and the residue was taken up in water. The product was extracted with trichloromethane and the extract was dried, filtered and co-evaporated with methylbenzene (4x), yielding 37.2 g (100%) of 5-[[(3-nitro-2-pyridinyl)amino]methyl]-2-furanmethanol (interm. 1).
In a similar way, but using sodium carbonate instead of sodium hydrogen carbonate, there was prepared :
5-[[(2-nitrophenyl)amino]methyl]-2-furanmethanol; mp. 88.9°C (interm.2). b) A πiixture of 37.2 g of intermediate (1), 2 g of a solution of thiophene in methanol 4% and 320 g of methanol was hydrogenated at normal pressure and at 50°C in the presence of 3 g of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, . yielding 32.9 g (100%) of 5-[[(3-amino-2-pyriώnyl)amino]methylJ-2- ranmethanol
(interm. 3). In a similar way there was also prepared :
5-[[(2-arninophenyl)an ino]methyl]-2-fiιranmethanol (interm.4). ' c) To a stirred rnixture of 32.9 g of interrnediate (3), 700 ml of methanol and 18 g of sodium acetate there were added portionwise 34.8 g of ethyl 2-cWoroethaneimidate. The whole was stirred for 19 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. After basifying with R2CO3, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 41.6 g (100%) of 5-[[2-(chloromethyl)-3H-imidazo[4,5-b]pyridin- 3-yl]methyl]-2-furanmethanol (interm.5). In a similar way there were also prepared :
5-[[2-(chloromemyl)-lH-benzimidazol-l-yl]methyl]-2-furannieth (interm. 6); and 2-(chloromethyl)-3-[(2-ιnethyl-5-oxazolyl)me
Example 2 a) To a stirred and cooled (<-5°C) solution of 254 g of carbon disulfide and 103 g of M, N-methanetetraylbis[cyclohexanamine] in 1170 g of tetrahydrofuran there was added dropwise a solution of 109.7 g of 4-(phenylmethyl)-l-piperazineethanarnine in 180 g of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature, stirred for a few hours and then evaporated. The residue was triturated in lJ'-oxybis-ethane, yielding 151.5 g (100%) of l-(2-isothiocyanatoethyl)- -(phenylmethyl)piperazine (interm. 8). b) To a stirred solution of 125.4 g of intermediate (8) and 1080 g of tetrahydrofuran there were added 43.6 g of 3,4-pyridinediamine. The whole was stirred overnight at reflux temperature and was then evaporated. The residue was crystallized from ethanol (2x), yielding 110 g (74%) of ϋ-(4-amino-3-pyridinyl)-ι\,-[2-[4-(phenylmethyl)-l- piperazinyl]ethyl]thiourea; mp. 164.0°C (interm.9). c) To a stirred solution of 37 g of intermediate (9) in 240 g of ethanol there were added 32.5 g of mercury(II)oxide and 0.5 g of sulfur. Stirring was continued for 2 hours at reflux temperature. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 90:10). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 22.2 g (65.9%) of H-[2-[4-(phenylmethyl)-l-piperazinyl]ethyl]-3H- imidazo[4,5-c]pyridin-2-amine; mp. 133.0°C (interm. 10).
A mixture of 20 g of intermediate (10) and 200 g of methanol was hydrogenated at normal pressure and room temperature in the presence of 3 g of palladium-on-charcoal catalyst 10% and 3 g of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in 2,2'-oxybispropane, filtered off and converted into the trihydrochloride salt in ethanol by addition of 2-propanol saturated with HC1. The salt was filtered off and dried, yielding 23.2 g (100%) of N-[2-(l-piperazinyl)ethyl]-lM-irnidazo[4,5-c]pyridin- 2-amine trihydrochloride; mp.287.9°C (interm. 11).
Exam le 3 A mixture of 52.3 g of ethyl l-piperazinecarboxylate, 55.6 g of 2-chloromethyl-lH- benzimidazole, 31.8 g of sodium carbonate and 1000 ml of ethanol was stirred for 19 hours at reflux temperature. The reaction rnixture was evaporated and the residue was partitioned between water and dichk>romethane. The aqueous layer was separated and re- extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol, yielding 49 g (56.6%) of ethyl 4-(lH-benzimidazol-2-ylmethyl)- l-piperazine¬ carboxylate; mp. 199.9°C (interm. 12).
Example 4 To
Figure imgf000022_0001
and 1.05 g of a dispersion of sodium hydride in mineral oil (50%) there was added dropwise a solution of 5.8 g of intermediate (12) in
Figure imgf000022_0002
and, after 1 hour, a solution of 3.95 g of ethyl 5-(chloromethyl)-2-furancarboxylate in some H-α! -ώ-πκthylformamide. Stirring at room temperature was continued for 1 1 2 hours. After the addition of NaHCO3 (aq.), the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH C12 / C2HsOH 97 :3). The eluent of the desired fraction was evaporated and the residue was crystallized from lJ'-oxybisethane. The product was filtered off and dried, yielding 4.8 g (53.4%) of ethyl 4-[[l-[[5-(ethoxycarbonyl)-2- furanyl]memyl]-lH-benzimidazol-2-yl]methyl]-l-piperazinecarboxylate hemihydrate; mp. 105.5°C (interm. 13). In a similar way there was also prepared : ethyl 5-[[2-[(4-methyl-l-piperazinyl)methyl]-lH-rjenzimidazol-l-yl]methyl]-2- furancarboxylate (E)-2-butenedioate (1:2); mp. 178.8°C (interm. 14).
B. Preparation of the final compounds
Example 5
To a solution of 4.4 g of intermediate (13) in 150 ml of dry tetrahydrofuran there were added dropwise 3.75 ml of a solution of lithium borohydride in tetrahydrofuran 2M under a nitrogen atmosphere. After refluxing overnight, there were added 2-propanone and water. The whole was evaporated and the residue was taken up in water. There was added some K2CO3 and then the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel ; CH2Cl2 / C2H5OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.8 g (20.1%) of ethyl 4-[[l-[[5-(hydroxymethyl)-2- furanyl]methyl]-lH-benzinτidazol-2-yl]meώyl]-l-piperazinecarboxylate; mp. 155.7°C (comp. 1).
In a similar way, but using lithium aluminumhydride instead of lithium borohydride, there was prepared :
5-[[2-[(4-methyl-l-piperazinyl)methyl]-lH^ mp. 167.5°C (comp. 2).
Example 6
To a stirred mixture of 75 g of intermediate (12) and
Figure imgf000023_0001
under nitrogen, there were added portionwise 13.7 g of a dispersion of sodium hydride in mineral oil (50%). Stirring at room temperature was continued for 1 hour. There was added dropwise a solution of 53 g of 5-(bromomethyl)-2-methyloxazole in some N,N-dimethylformamide, while cooling on ice. The mixture was stirred for 2 hours at room temperature and was then diluted with water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2C12 / Q2H5OH 95:5). The eluent of the desired fraction was evaporated, yielding 81 g (81.3%) of ethyl 4-[[l-[(2-methyl-5- oxazolyl)methyl]- lH-benzimidazol-2-yl]methyl]- 1 -piperazinecarboxylate (comp. 3).
Example 7 A mixture of 24 g of ethyl 1 -piperazinecarboxylate, 41.7 g of intermediate (5) , 16 g of sodium carbonate and 600 ml of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / C2H5OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 5.4 g (9.0%) of ethyl 4-[[3-[[5-(hydJoxymethyl)-2-furanyl]memyl]-3H-imidazo[4,5-b]pyridin-2- yl]methyl]-l -piperazinecarboxylate; mp.92.5°C (comp. 4). In a similar way there was also prepared : ethyl 4-[[3-[(2-methyl-5-oxazolyl)methyl]-3H-imidazo[4,5-b]pvridin-2-yl]methyl]- 1 - piperazinecarboxylate; mp. 121.9°C (comp.5). In a similar way but using methanol instead of ethanol, there were also prepared : 5-[[2-[[4-[2-[QH-mιidazo[4,5-c]pyri mπdaτzo[4,5-b]pyriάιn-3-yl]rrιethyl]-2-furarιr∞ (E)-2-butenedioate (2:5); mp. 180J°C (comp. 6); and 5-[[2-[[4-[2-[(lH-iπώiazo[4,5--c]^ benzinτiά^zol-l-yl]n-ethyl]-2-furamnethanoI (E)-2-butenedioate (1:3) hemihydrate; mp. 174.3°C (comp.7).
Example 8
A mixture of 26 g of compound (4), 37 g of potassium hydroxide and 170 ml of 2-propanol was stirred overnight at reflux temperature. The reaction rnixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / CH3OH / CH3OH(NH3)
80:10: 10). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 10 g
(45.7%) of 5-[[2-(l -piperazinylmethyl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2- furanmethanol hemihydrate; mp. 117.8°C (comp. 8).
In a similar way there was also prepared :
5-[[2-(l-piperazmyj^ethyl)-lH-benzimidazol-l-yl]methyl]-2-furanmeti^ hemihydrate; mp. I29.8°C (comp.9).
Example 9
A mixture of 4.5 g of compound (3) and 100 ml of hydrobromic acid 48% was stirred for 1 1/2 hour at reflux temperature. The reaction rnixture was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.5 g
(58.9%) of l-[(2-methyl-5-*oxazolyl)πιeΛyl]-2-(l-piperazin^ tetrahydrobromide monohydrate; mp. 215.7°C (comp. 10).
In a similar way there was also prepared :
3-[(2-methyl-5-Oxazolyl)meΛyl]-2-(l-piperam mp. 128.9°C (comp. 11).
Example 10
A mixture of 1.5 g of 3-chloro-H-(l-rnethylethyl)propanamide, 2.3 g of compound (9), 0.8 g of sodium carbonate, 0.01 g of potassium iodide and 200 ml of 4-methyl-2- pentanone was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and re-extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was crystallized from a rnixture of acetonitrile and ethanol, yielding 2.6 g (84.5%) of 4-[[l-[[5-(hydroxymethyl)- 2-furanyl]methyl]- lH-berιzirnida72θl-2-yl]me yl]-]S-(l-π» hylethyl)- 1-piperazine- propanamide; mp. 177.2°C (comp. 12). The compounds listed in Table 1 hereinbelow were prepared in a similar way.
Table 1
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000026_0001
: (E>2-butenedioate
The compounds listed in Table 2 hereinbelow were prepared in a similar way but using N^-dimethylacetamide instead of 4-methyl-2-pentanone without the addition of potassium iodide. labje *
Figure imgf000027_0002
In a similar way but using N_^-dimethylfσrmamide instead of 4-methyl-2-pentanone and without the addition of potassium iodide, there were also prepared : ~~
4-[[3-[[5-(hydroxyme yl)-2-furanyl]memyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-l- piperazineacetonitrile; mp. 126.6°C (comp. 32); and
4-[[l-[[5-(hydroxymethyl)-2-furanyl]methyl]-lH-benzimidazol-2-yl]methyl]-l- piperazineacetonitrile; mp. 163.9°C (comp. 33).
Example 11 A mixture of 3J g of compound (10), 1 g of polyoxymethylene, 1 ml of a solution of thiophene in methanol 4% and 150 ml of methanol were hydrogenated at normal pressure and at room temperature in the presence of 2 g of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between dichloromethane and NH4OH (aq.). The aqueous layer was separated and re-extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was converted into the (E)-2-butenedioate (1 :2) salt in ethanol. The salt was filtered off and dried, yielding 3.56 g (63.8%) of l-[(2-methyl-5-oxazolyl)methyl]-2-[(4- methyl-l-piperazmyl)rnethyl]-lH-benzimidazole (E)-2-butenedioate (1:2); mp.207 -5°C (comp. 34).
In a similar way there were also prepared : 5-[[2-[(4-methyl-l-pipCTazώyl)methy^ furanmethanol cyclohexanesulfamate (1:2); mp. 142.2°C (comp. 35); and
3-[(2-memyl-5-oxazolyl)methyI]-2-[(4-π^
[4,5-b]pyridine (E)-2-butenedioate (1:2); mp. 168.2°C (comp. 36).
Example 12
A mixture of 11 g of compound (33) and 300 ml of methanol saturated with ammonia was hydrogenated at normal pressure and room temperature in the presence of 2 g of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 11 g (99.2%) of 5-[[2-[[4-(2- aminc«Λyl)-l-piperazmyl]methyl]-lB-b^
(comp. 37).
In a similar way there was also prepared :
5-[[2-[[4-(2-aminoetfιyl)-l-piperazinyl]rjιe&^
2-furanmethanol (comp.38).
Example 13
To a stirred mixture of 1.3 g of N_-rnethyl-2-pyrrolecarboxylic acid, 2.02 g of
N^-ώethylethanamine and 200 ml of dichloromethane there were added portionwise .2.5 g of 2-chloro-l-methylpyridinium iodide and, after 1 hour, 3.7 g of compound (37). Stirring at room temperature was continued overnight. The reaction mixture was washed with water (3x) and the washings were re-extracted with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / CH3OH / CH3OH(NH3) 90:8:2). The eluent of the desired fraction was evaporated and the residue was converted into the (E)-2-butene- dioate (2:1) salt in ethanol. The salt was filtered off and dried, yielding 1J g (20.6%) of
N-[2-[4-[[l-[[5-(hydroxymethyl)-2-furanyl]me piperazinyl]ethyl]-l-methyl-lH-pyrrole-2-carboxamide (E)-2-butenedioate (2:1); mp.
185.5°C (comp.39).
The compounds listed in Table 3 were prepared in a similar way : Table ?
Figure imgf000029_0001
Figure imgf000029_0002
: (E)-2-butenedioate
Example 14
To a stirred mixture of 3.7 g of compound (38), 1.2 g of M,N-diethylet anamine and 50 ml of trichloromethane there were added portionwise 1.5 g of 4-chloro-3-nitropyridine. Stirring at room temperature was continued overnight. The reaction mixture was diluted with water and extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / CH3OH(NH3) 97:3). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.7 g (34.5%) of 5-[[2-[[4-[2-[(3-nitro-4-pyrid^ imidazo[4,5-b]pyridin-3-yl]methyl]-2-furanmethanol; mp. 154.2°C (comp. 44). Example l5
To a stirred and heated (50°C) mixture of 3.9 g of compound (37) and 150 ml of M-H-dimethylformamide there was added dropwise a solution of 1.72 g of
Figure imgf000030_0001
After stirring for 3 hours at 75°C, the reaction mixture was evaporated. The residue was purified by column chromatography (silica gel ; CH2CI2 / CH3OH / CH3OH(NH3) 90: 10: 1). The eluent of the desired fraction was evaporated and the residue was converted into the (E)- 2-butene-dioate (2: 1) salt in ethanol. The salt was filtered off and dried, yielding 1.5 g (24.9%) of2-am o-H-[2-[4-[[l-[[5-(hydroxymeΛyl)-2-furanyl]methyl]-lH- benzimidazol-2-yl]-methyl]-l-piperazmyl]ethyl]rjenzamide (E)-2-butenedioate (2:1); mp. 196.6°C (comp.45).
C. Pharmacological example Example 16 The useful antiallergic properties of the compounds of formula (I) can be demonstrated in the test "Protection of rats from compound 48/80-induced lethality", which is described in US-4,556,660. The ED50-value (in mg/kg) for the compounds 2, 16, 25, 26, 42 and 44 was found to range from 0.02 mg kg to 0.08 mg/kg.
D. Composition Examples
The following formulations exemplify typical pharmaceutical compositions in dosage unit form suitable for systemic or topical administration to warm-blooded animals in accordance with the present invention.
"Active ingredient" (A.I.) as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
Example 17 : Oral drops
500 g of the A.I. is dissolved in 0.51 of 2-hydroxypropanoic acid and 1.5 1 of the polyethylene glycol at 60~80°C. After cooling to 30~40°C there are added 351 of polyethylene glycol and the mixture is stirred well. Then there is added a solution of 1750 g of sodium saccharin in 2.51 of purified water and while stirring there are added 2.51 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg ml of the A.I. The resulting solution is filled into suitable containers. Example 18 : Oral solutions
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 4 1 of boiling purified water. In 3 1 of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g of the A.I. The latter solution is combined with the remaining part of the former solution and 121 of 1 ,2,3-propanetriol and 3 1 of sorbitol 70% solution are added thereto.40 g of sodium saccharin are dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence are added. The latter solution is combined with the former, water is added q.s. to a volume of 201 providing an oral solution comprising 5 mg of the A.I. per teaspoonful (5 ml). The resulting solution is filled in suitable containers.
Example 19 : Capsules
20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate are vigorously stirred together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of the A.I..
Example 20 : Film-coated tablets Preparation pf a let core A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl- pyrrolidone (Kollidon-K 90®) in about 200 ml of water. The wet powder rnixture is sieved, dried and sieved again. Then there are added 100 g microcrystalline cellulose (Avicel®) and 15 g hydrogenated vegetable oil (Sterotex ®). The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient. Coating
To a solution of 10 g methyl cellulose (Methocel 60 HG®) in 75 ml of denaturated ethanol there is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps ®) in 150 ml of dichloromethane. Then there are added 75 ml of dichloromethane and 2.5 ml
1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolved in 75 ml of dichloromethane. The latter solution is added to the former and then there are added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concen¬ trated colour suspension (Opaspray K-l-2109®) and the whole is homogenated. The tablet cores are coated with the thus obtained mixture in a coating apparatus.

Claims

Claims
1. A compound having the formula
Figure imgf000032_0001
a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein
R1 is (hydroxyCι^alkyl)furanyl, (Ci-6alkyl)oxazolyl or (hydroxyCi-6alkyl)oxazolyl;
-A1=A2-A3=A4- is a bivalent radical having the formula
Figure imgf000032_0002
wherein one or two hydrogen atoms in said radicals (a-1) to (a-7) may each independently be replaced by halo, Ci^alkyl, Ci^alkyloxy, hydroxy or trifluoro- methyl; m is 1, 2, 3 or 4; L is hydrogen; C]_ι2alkyl; C3^cycloalkyl; C3^alkenyl optionally substituted with aryl; C^alkylcarbonyl; C^alkyloxycarbonyl; arylcarbonyl; arylC-:_galkyloxy- carbonyl; or a radical of formula :
Figure imgf000032_0003
Alk is Ci^alkanediyl; R3 is cyano, aryl or Het;
R4 is hydrogen, aryl, Het or Ci-6alkyl optionally substituted with aryl or Het; R5 is hydrogen, aryl, Het or Ci^alkyl optionally substituted with aryl or Het; R6 is aryl or naphthalenyl;
Y is O, S, NR7; said R7 being hydrogen, Ci^alkyl or Ci^alkylcarbonyl ; Z1 and Z2 each independently are O, S, NR8 or a direct bond; said R8 being hydrogen or Ci-6alkyl;
X is O, S or NR9; said R9 being hydrogen, Ci^alkyl or cyano;
each Het is selected from pyridinyl optionally substituted with one or two substituents each independently selected from halo, amino, mono- and di(Cι^alkyl)-amino, nitro, cyano, Ci^alkyl, Cι.6alkyloxy and hydroxy; pyrimidinyl optionally substituted with one or two substituents each independently selected from halo, amino, Ci-^alkylamino, Ci-6alkyl and Ci^alkyloxy; pyridazinyl optionally substituted with Ci-^alkyl or halo; pyrazinyl optionally substituted witii halo, amino or Ci^alkyl; diienyl optionally substituted with halo or Ci^alkyl; furanyl optionally substituted with halo or Ci-βalkyl; pyrrolyl optionally substituted with Ci^alkyl; thiazolyl optionally substituted with Ci^alkyl; imidazolyl optionally substituted with one or two substituents each independently selected from Ci^alkyl, arylCi^alkyl and nitro; 1,3,4-thiadiazolyl optionally substituted with Ci-βalkyl or amino; oxazolyl optionally substituted with Ci-6alkyl; 2-oxo-3-oxazolidinyl; l-methyl-2-indolyl; 2,3-dihydro-l,4-benzodioxinyl optionally substituted with Ci^alkyl or halo; 2-oxo-2H-l-benzopyranyl and 4-oxo-4H-l- benzopyranyl both being optionally substituted with Ci^alkyl; 3,7-dihydro-l,3- dimethyl-2,6-dioxo-lH-purin-7-yl optionally substituted with Cι. alkyl; and a bicyciic heterocyclic radical of formula
Figure imgf000033_0001
wherein χl and X2 each independently are O or S ; each R10 is hydrogen, Ci-6alkyl, arylCi-ealkyl, Cι^alkyloxyCι^allg-1, hydroxy- Ci-6alkyl or Ci^allryloxycarbonyl;
R11 is hydrogen, Ci-^alkyl, hydroxy, mercapto, Cχ^alkyloxy, Ci^alkylthio, halo or Ci^alkyloxycarbonylCi^alkyl ;
G1 is -CH=CH-CH=CH-; -S-CH=CH- or -N=CH-NH- ;
G2 is -CH=CH-CH=CH-, -(CH2)4-, -S-(CH2)2-, -S-(CH2)3-, -S-CH=CH-,
-CH=CH-O-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-CH=CH-, -NH-CH=N-,
-NH-N=CH- or -NH-N=CH-CH2-; G3 is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,
-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ; G4 is -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-,
-CH=CH-CH=N-, -N=CH-N=CH- or -CH=N-CH=N- ;
wherein one or two hydrogen atoms in said radicals G1, G2, G3 or G4 may be replaced by C-^alkyl, C-^aUcylthio, C-^alkyloxy or halo, when connected to a carbon atom; or by C-^alkyl, C^alkyloxycarbonyl or arylCj^alkyl when connected to a nitrogen atom;
each aryl is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci^alkyl,
Ci^alkyloxy, Ci-galkylthio, mercapto, amino, mono- and di(Ci-6alkyl)amino, carboxyl, Ci-6aIkyloxycarbonyl and Ci-6alkylcarbonyl.
2. A compound according to claim 1 wherein -A^A^-A^A^- is a bivalent radical of formula -CH=CH-CH=CH- (a-1), or -N=CH-CH=CH- (a-2); m is 1; R1 is (hydroxyCi-6alkyl)furanyl or (Ci-6alkyl)oxazolyI; L is hydrogen, Cι_ι2alkyl, C-^alkyloxycarbonyl or a radical of formula -Alk-R3 (b-1), -Alk-Y-R4 (b-2), or -Alk- Z1-C(=X)-Z2-R5 (b-3), wherein R3 is cyano, Ci^alkyloxy-phenyl, 2-oxo-3- oxazolidinyl, Ci-^alkyloxazolyl or a bicyciic heterocyclic radical of formula
O
R11 being Ci-ealkyl, G2 being -CH=CH-CH=CH-, -S^CH^- or -S-CH=CH-; R4 is hydrogen, nitropyridinyl or imidazopyridinyl; R5 is Ci^alkyl, aminophenyl; halophenyl; furanyl, l-methyl-2-indolyl or Ci-6alkylpyrrolyl; Y is NH; Z1 and Z2 each independently are NH or a direct bond and X is O.
3. A compound according to claim 2 wherein R1 represents a radical of formula
Figure imgf000035_0001
4. A compound according to claim 3 wherein the compound is :
5-[[2-[(4-methyl-l-piperaanyl)meth^
N-[2-[4-[[3-[[5-(hyάiOxyrrιethyl)-2^ yl]methyl]- 1 -piperazinyl]ethyl]-3-furancarboxamide; 2,3-d ydro-6-[2-[4-[[3-[[5-(hydroxymemyl)-2-furanyl]methyl]-3jH-imidazo[4,5-b]- pvridin-2-yl]methyl]-l-piperazinyl]ethyl]-7-methyl-5^
N-[2-[4-[[l-[[5-(hydroxymethyl)-2-furanyl]meι^^^ piperazinyl]ethyl]-3-furancarboxamide;
7-memyl-6-[2-[4-[[3-[(2-methyl-5-oxazolyl)methyl]-3H-iπιidazo[4,5-b]pyridin-2- yl]memyl]-l-piperazmyl]etnyl]-5H-thiazoto^^ and
2-[[4-[2-(4-methoxyphenyl)ethyl]-l-piperazinyl]methyl]-3-[(2-methyl-5- oxazolyl)methyl]-3H-iιnidazo[4,5-b]pyridine; a solvate or a pharmaceutically acceptable addition salt thereof.
5. An antiallergic composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective antiallergic amount of a compound as claimed in any of claims 1 to 4.
6. A process for preparing an antiallergic composition as claimed in claim 5, characterized in that a therapeutically effective antiallergic amount of a compound of formula (I) as claimed in any of claims 1 to 4 is intimately mixed with a pharmaceutically acceptable carrier.
7. A compound as claimed in any of claims 1 to 4 for use as a medicine.
8. A process for preparing a compound as claimed in any of claims 1 to 4 characterized to a) ϋ-alkylating a compound of formula (I) wherein L is hydrogen, said L being represented by L1 and said compound being represented by (I-b), with an alkylating reagent of formula (II), wherein W represents a reactive leaving group, thus yielding a compound of formula (I) wherein L is other than hydrogen, said compounds being represented by formula (I-a);
Figure imgf000036_0001
b) reductively N-alkylating (I-b) with a ketone or aldehyde of formula L2=O (IH), said L2=O being an intermediate of formula L-^H2 wherein two geminal hydrogen atoms are replaced by =O, and L**-- is a geminal bivalent radical comprising Ci-I2alkylidene, C3-6cycloaIkylidene, R3-Cl-6alkylidene, R4-Y-Cl-.6alkylidene and R-5-z2-C(=X)-Z1-Ci-6all^lidene, thus yielding a compound of formula (I-a) wherein L1 is Ci-I2alkyl, C3-6cycloalkyl, a radical of formula (b-1), (b-2) or (b-3), said radicals being represented by the radical L-^H- and said compounds by formula (I-a-1);
Figure imgf000036_0002
c) N-alkylating an intermediate of formula (TV) with an alkylating reagent of formula (V);
Figure imgf000036_0003
0V) 0)
d) alkylating a compound of formula (I) wherein L is a radical of formula (b-2) and R^ is hydrogen, said compound being represented by formula (I-a-3), with a reagent of formula (VI), thus yielding a compound of formula (I) wherein L is a radical of formula
(b-2) and R^ is aryl or Het, said R4 being represented by R4"a and said compounds by formula (I-a-2);
Figure imgf000037_0001
e) reacting a compound of formula (I-a-5) with a reagent of formula (VII) or a reactive functional derivative thereof, thus yielding a compound of formula (I) wherein L is a radical of formula (b-3), 7?- is a direct bond, iS is other than a direct bond and X is other than NR9, said Z-- and X being represented by Z-~a and X^, said compounds being represented by (I-a-4);
Figure imgf000037_0002
f) reacting a compound of formula (I-a-5) wherein Z1_a is NH, said compounds being represented by (I-a-5-1), with a reagent of formula (VIII), thus yielding a compound of formula (I-a-4) wherein Z1_a is NH, X2 is O and R5 is 2-aminophenyl or a derivative thereof, said compounds being represented by (I-a-4-1);
Figure imgf000037_0003
g) H-alkylating a reagent of formula (IX) with an mterrnediate of formula (X)
Figure imgf000038_0001
h) reducing an intermediate of formula (XT) wherein R2 is furanyl or oxazolyl substituted with a carboxylic ester or a (Cι_5alkyl)carboxylic ester group, with a reducing agent, thus yielding a compound of formula (I) wherein R1 is
Figure imgf000038_0002
or (hydroxy-Ci-6alkyl)oxazolyl, said R1 being represented by R1*2 and said compounds being represented by formula (I-c);
Figure imgf000038_0003
( D α<)
and, if desired, converting the compounds of formula (I) into each other following art- known functional group transformation reactions, and further, if desired, converting the compounds of formula Q) into a therapeutically active acid addition salt form by treatment with an acid; or conversely, converting the salt into the free base with alkali; and/or preparing stereochemically isomeric forms thereof.
PCT/EP1992/003000 1992-01-09 1992-12-29 Antihistaminic piperazinyl derivatives WO1993014088A1 (en)

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Publication number Priority date Publication date Assignee Title
US7030150B2 (en) 2001-05-11 2006-04-18 Trimeris, Inc. Benzimidazole compounds and antiviral uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0307014A1 (en) * 1987-07-10 1989-03-15 Janssen Pharmaceutica N.V. Anti-allergic 2-(heterocyclyl alkyl) imidazo pyridines and 2-(heterocyclyl alkyl) purines
EP0393738A1 (en) * 1989-04-07 1990-10-24 Janssen Pharmaceutica N.V. Hydroxyalkylfuranyl derivatives
WO1992001687A1 (en) * 1990-07-19 1992-02-06 Janssen Pharmaceutica N.V. Novel oxazolyl derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0307014A1 (en) * 1987-07-10 1989-03-15 Janssen Pharmaceutica N.V. Anti-allergic 2-(heterocyclyl alkyl) imidazo pyridines and 2-(heterocyclyl alkyl) purines
EP0393738A1 (en) * 1989-04-07 1990-10-24 Janssen Pharmaceutica N.V. Hydroxyalkylfuranyl derivatives
WO1992001687A1 (en) * 1990-07-19 1992-02-06 Janssen Pharmaceutica N.V. Novel oxazolyl derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7030150B2 (en) 2001-05-11 2006-04-18 Trimeris, Inc. Benzimidazole compounds and antiviral uses thereof

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