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WO1993014083A1 - Derives de benzimidazole substitues pharmaceutiquement actifs - Google Patents

Derives de benzimidazole substitues pharmaceutiquement actifs Download PDF

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Publication number
WO1993014083A1
WO1993014083A1 PCT/EP1992/003006 EP9203006W WO9314083A1 WO 1993014083 A1 WO1993014083 A1 WO 1993014083A1 EP 9203006 W EP9203006 W EP 9203006W WO 9314083 A1 WO9314083 A1 WO 9314083A1
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Prior art keywords
formula
compound
alkyl
radical
optionally substituted
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PCT/EP1992/003006
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English (en)
Inventor
Frans Eduard Janssens
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Janssen Pharmaceutica N.V.
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Publication of WO1993014083A1 publication Critical patent/WO1993014083A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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 4-piperidinyl derivatives having the formula :
  • radicals (a-1) to (a-7) may each independently be replaced by halo, Ci-6alkyl, Ci ⁇ alkyloxy, hydroxy ortrifluoro- methyl;
  • R 1 is Ar or a radical of formula -D-R 2 wherein D is O or S;
  • R 2 is Ci- ⁇ alkyl optionally substituted with hydroxy, Ci- alkyloxy, carboxyl or Ci ⁇ alkyloxycarbonyl; m is 1, 2, 3 or 4; n is 0, 1 or 2 ;
  • L is hydrogen; Ci ⁇ a-U yl; C3- ⁇ cycloalkyl; C3 ⁇ alkenyl optionally substituted with aryl; C ⁇ alkylcarbonyl; Cx-.galkyloxycarbonyl; arylcarbonyl; arylC ⁇ alkyloxy- carbonyl; or a radical of formula :
  • Alk is Ci-6alkanediyl
  • R 3 is cyano, aryl or Het
  • R 4 is hydrogen, aryl, Het or Ci-6alkyl optionally substituted with aryl or Het;
  • R 5 is hydrogen, aryl, Het or Ci- ⁇ alkyl optionally substituted with aryl or Het
  • R 6 is aryl ornaphthalenyl
  • Y is O, S, NR 7 ; said R 7 being hydrogen, Ci ⁇ alkyl or Ci ⁇ alkylcarbonyl ; Z 1 and Z 2 each independently are O, S, NR 8 or a direct bond; said R 8 being hydrogen or C ⁇ --6alkyl;
  • T 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)amino, nitro, cyano, Ci ⁇ alkyl, Ci ⁇ alkyloxy and hydroxy; pyrimidinyl optionally substituted with one or two substituents each independently selected from halo, amino, Ci-6alkylamino, Ci-6alkyl and C ⁇ --6alkyloxy; pyridazinyl optionally substituted with Ci ⁇ alkyl or halo; pyrazinyl optionally substituted with halo, amino or Ci ⁇ alkyl; thienyl optionally substituted with halo or Ci-6alkyl; fiiranyl optionally substituted with halo or Ci- ⁇ alkyl; pyrrolyl optionally substituted with Ci ⁇ alkyl; thiazolyl optionally substituted with Ci-ealkyl; imidazolyl optionally substituted with one or two
  • X 1 and X 2 each independently are O or S ; each R 10 is hydrogen, Ci- ⁇ alkyl, arylCi- ⁇ alkyl, C ⁇ alkyloxyC ⁇ .-6alkyl, hydroxy-
  • R 11 is hydrogen, Ci ⁇ alkyl, hydroxy, mercapto, Ci-6alkyloxy, Ci- ⁇ alkylthio, halo or 15 Ci-6alkyloxycarbonylCi-6alkyl ;
  • radicals G 1 , G 2 , G 3 or G 4 may be replaced by or halo, when connected to a carbon atom; or by Ci ⁇ alkyl, C ⁇ --6alkyloxycarbonyl or arylCi- ⁇ alkyl when connected to a nitrogen atom; and
  • X * r rQ — is a radical having the formula
  • 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 ⁇ alkylthio, mercapto, amino, mono- and di(Ci-6alkyl)amino, carboxyl, Ci ⁇ alkyloxycarbonyl and Ci-6alkylcarbonyl;
  • Ar is phenyl optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, nitro, cyano, trifluoromethyl, Ci ⁇ alkyl, Ci-galkyloxy, C ⁇ --6alkylthio, mercapto, amino, mono- and di(C ⁇ --6aIkyl)amino, carboxyl, Ci ⁇ alkyloxycarbonyl and Ci ⁇ alkylcarbonyl; thienyl; halothienyl; fiiranyl optionally substituted with Ci ⁇ alkyl and/or hydroxyCi ⁇ alkyl; oxazolyl optionally substituted with Ci- ⁇ alkyl and/or hydroxyCi ⁇ alkyl; pyridinyl optionally substituted with Ci- ⁇ alkyl; pyrimidinyl; pyrazinyl; thiazolyl optionally substituted with Ci ⁇ alkyl; orimidazolyl optionally substituted with C ⁇ -- 6 alkyl.
  • halo is generic to fluoro, chloro, bromo and iodo
  • C ⁇ -_5alkyl 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, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, pentyl, hexyl and the like
  • Ci- ⁇ 2 alkyl defines Ci- ⁇ alkyl radicals as defined hereinabove and the higher homologs thereof having from 7 to 12 carbon atoms
  • C3 ⁇ cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl
  • C3 ⁇ alkenyl 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-oxopro- panoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy- 1 ,2,3-propanetri- carboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzene- sulfonic, 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 (I) 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.
  • More interesting compounds are those interesting compounds wherein X — Q — is
  • R-" is C ⁇ alkyl
  • R 4 is hydrogen or pyrimidinyl
  • Y is O orNH
  • R 5 is Ci ⁇ alkyl, aminophenyl or thiazolyl
  • Z 1 and Z 2 each independently are O, NH or a direct bond and T is O or S.
  • R 1 * is methyl
  • R 4 is hydrogen or 2-pyrimidinyl
  • Y is O or NH
  • R 5 is Ci ⁇ alkyl, 2-aminophenyl or 2-thiazolyl
  • Z 1 is NH
  • Z 2 is NH or a direct bond
  • T is O or S.
  • R 5 is methyl or 2-thiazolyl;
  • Z 1 is NH,
  • Z 2 is NH or a direct bond and T is O or S.
  • said compounds being represented by formula (I-b) can be prepared by dehydration of an intermediate of formula (Ill-a) or (EQ-b) in the presence of an acid.
  • Suitable acids are for example (poly)phosphoric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid and the like.
  • the compounds of formulae (I-a) and (I- b) may also be obtained by refluxing an intermediate of formula (Il-a), (Ill-a) or (IH-b) in hexamethylphosphoric triamide.
  • the compounds of formula (I-b) can 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.
  • a suitable solvent e.g. methanol or ethanol
  • an appropriate catalyst e.g. platinum-on-charcoal, palladium-on-charcoal, Raney nickel and the like, optionally at an increased temperature and/or pressure.
  • Some compounds of formula (I-c) may also be obtained by catalytic dehydroxylation of an intermediate of formula (Hl-a) or (Ul-b) following art-known procedures.
  • the compounds of formula (I) wherein L is other than hydrogen, said L being represented by l ⁇ and said compounds being represented by formula (I-d) can be prepared by H-alkylating a compound of formula (I) wherein L is hydrogen, said compound being represented by (I-e), with an alkylating reagent of formula (IN).
  • 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, a ketone, 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, a ketone, 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
  • an organic base such as, for example, an amine
  • an iodide salt preferably an alkali metal iodide, is appropriate.
  • N_-alkylation may be conducted under an inert atmosphere such as, for example, oxygen-free argon or nitrogen.
  • said £J-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions.
  • Said reductive N-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 ⁇ alkanols, esters, ethers, halogenated hydrocarbons, dipolar aprotic solvents, carboxylic acids, or a mixture of such solvents.
  • the term "art-known reductive N-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.
  • an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like.
  • an appropriate catalyst-poison e.g., thiophene, quinoline-sulphur and the like.
  • an alkali metal salt to the reaction mixture such as, for example, potassium fluoride, potassium acetate and the like salts.
  • the compounds of formula (I) wherein L is 2-hydroxyC2-6alkyl or a radical of formula (b-4), said compounds being represented by formula (I-d-3), can be prepared by reacting a compound of formula (I-e) with an epoxide (VII) wherein R* 2 is hydrogen, C ⁇ _4alkyl or a radical R 6 -O-CH2-.
  • reaction of (I-e) with respectively (VI) and (VII) may be conducted by stirring and, if desired, heating the reactants in a reaction-inert solvent such as, for example, a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, an ether, e.g., tetrahydrofuran, l,l'-oxybisethane, an alcohol, e.g., methanol, ethanol, 1-butanol, a dipolar aprotic solvent, e.g., N,N-dimethylformamide, N_,N-dimethylacetamide and the like.
  • a reaction-inert solvent such as, for example, a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, an ether, e.g., tetrahydrofuran, l,l'-oxybisethane, an alcohol, e.g., methanol, ethanol,
  • the compounds of formula (I) can also be prepared by N.-alkylating an intermediate of formula (VIII) with an appropriate alkylating reagent of formula (IX).
  • N-alkylation is conveniently conducted following art-known N-alkylation procedures as described hereinabove for the preparation of (I-d) from (I-e) and (IV).
  • the compounds of formula (I) wherein L is a radical of formula (b-2) and R ⁇ is aiyl or Het, said R ⁇ being represented by R 4 " a and said compounds by formula (I-d-4) may • also be prepared by 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-d-5), with a reagent of formula (X-a) .
  • the compounds of formula (I-d-4) may also be prepared by treating a compound of formula (XI) with a reagent of formula (X-b).
  • the alkylation reactions of (I-d-5) with (X-a) and (X-b) with (XI) may conveniently be conducted in an inert organic solvent such as, for example, an aromatic hydrocarbon, a ketone, an ether, an alcohol, or 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.
  • reaction of (XII) with (XIII), or (XIV) with (I-d-8) can generally be conducted in a suitable reaction-inert solvent such as, for example, an ether, e.g., tetrahydrofuran and the like, a halogenated hydrocarbon, e.g., trichloromethane and the like. Elevated temperatures may be suitable to enhance the rate of the reaction.
  • a suitable reaction-inert solvent such as, for example, an ether, e.g., tetrahydrofuran and the like, a halogenated hydrocarbon, e.g., trichloromethane and the like. Elevated temperatures may be suitable to enhance the rate of the reaction.
  • the compounds of formula ⁇ ) wherein L is a radical of formula (b-3), Z 2 is a direct bond, Z 1 is other than a direct bond and T is other than NR 9 , said Z* ⁇ and T being represented by Z*- * ⁇ a and T 2 , said compounds being represented by (I-d-9), can be prepared by reacting a compound of formula (I-d-8) with a reagent of formula (XV) or a reactive functional derivative thereof.
  • the reaction of (XV) with (I-d-8) may generally be conducted following art-known esterif ⁇ cation 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-d-8); or by reacting (XV) and (I-d-8) with a suitable reagent capable of forming amides or esters, e.g., N,N-methanetetraylbis- [cyclohexamine], 2-chloro-l-methylpy ⁇ idinium iodide and the like.
  • Said reactions may most conveniently be conducted in a suitable solvent such as, for example, an ether, e.g., tetrahydrofuran, a halogenated hydrocarbon, e.g., dichloromethane, trichloromethane, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, and the like.
  • a suitable solvent such as, for example, an ether, e.g., tetrahydrofuran, a halogenated hydrocarbon, e.g., dichloromethane, trichloromethane, a dipolar aprotic solvent, e.g. N,N-dimethylformamide, and the like.
  • a base such as, for example, N,N-diethylethanamine and the like may be appropriate.
  • the compounds of formula (I) wherein R3, R ⁇ 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; US-4,342,870 and US-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 procedures 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 can 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, M-alkylation, N-acylation, reductive _N[-alkylation and the like methods.
  • reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art
  • the intermediates of formula (Il-a), (Ill-a) and (IH-b) wherein L is hydrogen and n is 1, said intermediates being represented by (II-a-2), ( ⁇ I-a-2) and (HI-b-2), can be obtained from reduction of the pyridine ring of a compound of formula (XVIE-a), (XVm-b) and (XVIII-c), respectively.
  • the intermediates of formula (XVHI-a), (XVTJI-b) and (XVIII-c) can be reduced by catalytic hydrogenation in a suitable solvent e.g. methanol, ethanol, or acetic acid, in the presence of hydrogen and an appropriate catalyst, e.g. rhodium-on-charcoal and the like, optionally at an increased temperature and/or pressure.
  • a suitable solvent e.g. methanol, ethanol, or acetic acid
  • an appropriate catalyst e.g. rhodium-on-charcoal and the like
  • said compounds of formula (XNQI-a), (XN ⁇ i-b) and (XVIII-c) may be reduced by an alkali metal in liquid ammonia, preferably in the presence of an alcohol (Birch reduction).
  • the intermediates of formula (XVTfl-a) and (XVEH-b) can be prepared by reacting a compound of formula (XLX), wherein R 16 is H or methyl, with an intermediate of formula (XX) in the presence of a base, in a reaction-inert solvent
  • R 16 CH 3 : (XV ⁇ i-b)
  • Suitable bases are, for example, potassium tert butoxide, n. butyllithium, sodium amide, sodium hydride or lithium diisopropylamide.
  • Reaction-inert solvents are, for example, ethers, e.g. tetrahydrofuran, 1,4-dioxane and the like.
  • the intermediates of formula (XX) can be prepared by catalytic hydrogenolysis of the halo compound of formula (XXI), 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 and the like, and in the presence of a suitable base, e.g. calcium oxide, calcium carbonate and the like, optionally at an increased temperature and/or pressure.
  • a suitable solvent e.g. methanol or ethanol
  • an appropriate catalyst e.g. platinum-on-charcoal, palladium- on-charcoal and the like
  • a suitable base e.g. calcium oxide, calcium carbonate and the like, optionally at an increased temperature and/or pressure.
  • 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 anti-histaminic activity over structurally related compounds wherein X ⁇ Q — is CH— CH 2 — ,
  • the compounds of formula ( ) and their acid addition salts are very useful in the treatment of allergic 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.
  • 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.
  • 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 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 die 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 die 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.
  • 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 (I) 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) A mixture of 10 parts of 2-chloro-l-[(4-fluorophenyl)methyl]-lH-benzimidazole, 3 parts of calciumoxide and 200 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 2 parts 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 dissolved in trichloromethane and this solution was washed witii water, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and petroleumether.
  • Example 3 A mixture of 2 parts of intermediate (5) and 15 parts of polyphosphoric acid was stirred for 1 hour at 150-160°C. After cooling to 100°C, the reaction mixture was carefully diluted with water. Next there was added NaOH (aq.) while cooling on ice. The product was extracted wit 4-methyl-2-pentanone and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI 3 / CH 3 OH(NH3) 95:5). The eluent of the desired fraction was evaporated and die residue was converted into die (E)-2-butenedioate salt in ethanol.
  • Example 8 A mixture of 3.35 parts of compound (1), 1 part of polyoxymethylene and 120 parts of methanol was hydrogenated at normal pressure and room temperature in the presence of 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and die filtrate was evaporated. The residue was purified by column chromatography (silica gel ; CHCI3 / CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was converted into die hydrochloride salt in 2,2'-oxybispropane by addition of 2-propanol saturated witii HCl.
  • Example 15 A mixture of 1.03 parts of isotiiiocyanatomethane, 3.6 parts of compound (27) and 90 parts of tetrahydrofuran was stirred for 6 hours at room temperature. The reaction mixture was evaporated and die residue was diluted witii water. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel ; CHCI 3 / CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was converted into die cyclohexanesulfamate salt in 2-propanone.
  • Active ingredient as used diroughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
  • 500 g of the A.I. is dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.51 of the polyediylene glycol at 60 ⁇ 80°C. After cooling to 30 ⁇ 40°C there are added 351 of polyethylene glycol and die 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 metiiyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate are dissolved in 41 of boding 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 widi the remaining part of the former solution and 121 of 1,2,3-propanetriol and 31 of sorbitol 70% solution are added tiiereto. 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 die 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 20 Film-coated tablets
  • a mixture of 100 g of die A.I., 570 g lactose and 200 g starch is mixed well and tiiereafter humidified widi 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 mixture is sieved, dried and sieved again.
  • tiiere 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 die active ingredient. ga ing
  • Example 22 Suppositories 3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 g surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 g are molten togetiier. The latter mixture is mixed well widi die former solution. The thus obtained mixture is poured into moulds at a temperature of 37-38°C to form 100 suppositories each containing 30 mg of the A.I.
  • Suppositories 3 g A.I. is dissolved in a solution of 3 g 2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 g surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 g are molten togetiier. The latter mixture is mixed

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des dérivés de 4-pipéridinyle antihistaminiques de formule (I), dans laquelle α représente (d-3); (d-1); ou (d-2); =A?1-A2=A3-A4¿= représente =CH-CH=CH-CH=, =CH-N=CH-CH=, =CH-CH=N-CH=, 1CH-CH=CH-N=, =N-CH=N-CH= ou =CH-N=CH-N; R1 représente Ar ou -D-R2 dans lequel D représente O ou S; R2 représente alkyle C¿1-6? éventuellement substitué avec hydroxy, alkyloxy C1-6, carboxyle ou alkyloxycarbonyle C1-6; m est égal à 1, 2, 3 ou 4; m vaut 0, 1 ou 2; L représente hydrogène, alkyle C1-12; cycloalkyle C3-6; alcényle C3-6 éventuellement substitué avec aryle; alkylcarbonyle C1-6; alkyloxycarbonyle; arylcarbonyle; aryle C1-6; alkyloxycarbonyle; arylcarbonyle; aryle C1-6alkyloxycarbonyle; ou radical -Alk-R?3¿; -alk-Y-R4; -Alk-Z1-C-(=T)-Z?2-R5; -CH¿2-CHOH-0CH2-O-R6. On décrit également un procédé de préparation de ces dérivés. De plus, l'invention se rapporte aux compositions contenant lesdits composés antihistaminiques et à un procédé de traitement des maladies allergiques.
PCT/EP1992/003006 1992-01-09 1992-12-29 Derives de benzimidazole substitues pharmaceutiquement actifs WO1993014083A1 (fr)

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EP92200041 1992-01-09

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024324A1 (fr) * 1995-12-27 1997-07-10 Janssen Pharmaceutica N.V. Derives 1-(piperidinyl 1,2-disubstitue)-4-substitue-piperidine comme antagonistes des recepteurs de la tachykinine
US6706720B2 (en) 1999-12-06 2004-03-16 Bristol-Myers Squibb Company Heterocyclic dihydropyrimidine compounds
US7160879B2 (en) 2002-01-10 2007-01-09 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 2-(4-benzyl-piperazin-1-ylmethyl)- and 2-(4-benzyl-diazepan-1-ylmethyl)-1H-benzoimidazole analogues
US7772232B2 (en) 2004-04-15 2010-08-10 Bristol-Myers Squibb Company Quinazolinyl compounds as inhibitors of potassium channel function
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
JP2015519381A (ja) * 2012-06-11 2015-07-09 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ−アルファ調節ベンゾイミダゾール
US10705094B2 (en) 2015-06-18 2020-07-07 UCB Biopharma SRL TNF receptor signaling modulator assay
US11174311B2 (en) 2016-12-21 2021-11-16 UCB Biopharma SRL Antibody against trimeric TNFα complex

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EP0151826A1 (fr) * 1984-01-09 1985-08-21 Janssen Pharmaceutica N.V. Pipéridines méthyl-4 dont le groupe méthyl est substitué par un groupe hétérocyclique bicylique et pipéridines avec un hétéroatome lié en position 4 et substitué par un groupe hétérocyclique
EP0282133A2 (fr) * 1987-03-09 1988-09-14 Janssen Pharmaceutica N.V. Dérivés de benzimidazole substitués en 1 par alkyle
EP0363963A1 (fr) * 1988-10-13 1990-04-18 Merrell Dow Pharmaceuticals Inc. Benzimidazoles pipéridinyliques comme antihistaminiques
EP0378254A2 (fr) * 1989-01-09 1990-07-18 Janssen Pharmaceutica N.V. Dérivés de 2-aminopyrimidinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0151826A1 (fr) * 1984-01-09 1985-08-21 Janssen Pharmaceutica N.V. Pipéridines méthyl-4 dont le groupe méthyl est substitué par un groupe hétérocyclique bicylique et pipéridines avec un hétéroatome lié en position 4 et substitué par un groupe hétérocyclique
EP0282133A2 (fr) * 1987-03-09 1988-09-14 Janssen Pharmaceutica N.V. Dérivés de benzimidazole substitués en 1 par alkyle
EP0363963A1 (fr) * 1988-10-13 1990-04-18 Merrell Dow Pharmaceuticals Inc. Benzimidazoles pipéridinyliques comme antihistaminiques
EP0378254A2 (fr) * 1989-01-09 1990-07-18 Janssen Pharmaceutica N.V. Dérivés de 2-aminopyrimidinone

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024324A1 (fr) * 1995-12-27 1997-07-10 Janssen Pharmaceutica N.V. Derives 1-(piperidinyl 1,2-disubstitue)-4-substitue-piperidine comme antagonistes des recepteurs de la tachykinine
US6169097B1 (en) 1995-12-27 2001-01-02 Janssen Pharmaceutica N.V. 1-(1,2-Disubstituted piperidinyl)-4-substituted piperidine derivatives
EA001559B1 (ru) * 1995-12-27 2001-04-23 Жансен Фармасетика Н.В. Производные 1-(1,2-дизамещенный пиперидинил)-4-замещенного пиперидина как антагонисты рецепторов тахикинина
US6346540B1 (en) 1995-12-27 2002-02-12 Janssen Pharmaceutica N.V. 1-(1,2-disubstituted pipeidinyl)-4-substituted piperidine derivatives
CN1131854C (zh) * 1995-12-27 2003-12-24 詹森药业有限公司 作为速激肽受体拮抗剂的1－(1,2－二取代哌啶基)－4－取代哌啶衍生物
US6706720B2 (en) 1999-12-06 2004-03-16 Bristol-Myers Squibb Company Heterocyclic dihydropyrimidine compounds
US7157451B2 (en) 1999-12-06 2007-01-02 Bristol-Myers Squibb Company Heterocyclic dihydropyrimidine compounds
US7541362B2 (en) 1999-12-06 2009-06-02 Bristol-Myers Squibb Company Heterocyclic dihydropyrimidine compounds
US7160879B2 (en) 2002-01-10 2007-01-09 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 2-(4-benzyl-piperazin-1-ylmethyl)- and 2-(4-benzyl-diazepan-1-ylmethyl)-1H-benzoimidazole analogues
US8357704B2 (en) 2004-04-15 2013-01-22 Bristol-Myers Squibb Company Fused heterocyclic compounds as inhibitors of potassium channel function
US7772232B2 (en) 2004-04-15 2010-08-10 Bristol-Myers Squibb Company Quinazolinyl compounds as inhibitors of potassium channel function
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
JP2015519381A (ja) * 2012-06-11 2015-07-09 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ−アルファ調節ベンゾイミダゾール
US9550737B2 (en) 2012-06-11 2017-01-24 Ucb Biopharma Sprl TNF -α modulating benzimidazoles
US10883996B2 (en) 2015-06-18 2021-01-05 UCB Biopharma SRL Methods of identifying signaling modulators of the trimeric TNFa
US10775385B2 (en) 2015-06-18 2020-09-15 UCB Biopharma SRL Treatment of autoimmune and inflammatory disorders with asymmetric TNF alpha trimers
US10705094B2 (en) 2015-06-18 2020-07-07 UCB Biopharma SRL TNF receptor signaling modulator assay
US10969393B2 (en) 2015-06-18 2021-04-06 UCB Biopharma SRL Complexes between anti-TNF antibodies, trimeric TNF proteins and organic molecules binding them
US11022614B2 (en) 2015-06-18 2021-06-01 UCB Biopharma SRL Antibodies binding to trimeric TNF alpha epitopes
US11448655B2 (en) 2015-06-18 2022-09-20 UCB Biopharma SRL Method for identifying a modulator of the TNFα or CD40L interaction with their cognate receptors
US11674967B2 (en) 2015-06-18 2023-06-13 UCB Biopharma SRL Method of identifying potential inhibitors of APO TNFα trimers
US12055549B2 (en) 2015-06-18 2024-08-06 UCB Biopharma SRL Methods of use of anti-TNFα antibodies
US11174311B2 (en) 2016-12-21 2021-11-16 UCB Biopharma SRL Antibody against trimeric TNFα complex

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TW231291B (fr) 1994-10-01
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