Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
  • C07C45/46—Friedel-Crafts reactions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D235/12—Radicals substituted by oxygen atoms

Definitions

• the invention relates to substituted heterocyclyl compounds, in particular benz-substituted benzimidazole-2 derivatives of the formula wherein R is an optionally esterified or amidated carboxy group or an optionally etherified or esterified hydroxylmethyl group, R i represents an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, R 2 represents hydrogen or an aliphatic radical, and Ph one den Radical R 1 -X-containing 1,2-phenylene group, X is lower alkylidene or a direct bond, and pharmaceutically acceptable salts of compounds of the formula I with salt-forming properties for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body, containing pharmaceutical preparations, their use and new compounds of formula 1 and salts of compounds of formula I with salt-forming properties, with the proviso that R is different from alkoxymethyl or R 1 -X from lower alkyl when R 2 is hydrogen, al
• the invention relates, for example, to compounds of the formula I in which R, Ri, Ph and R 2 have the meanings given and either X is methylene, where R i has at least 2 carbon atoms if Ph is otherwise unsubstituted, R 2 is ethyl and R is acetoxymethyl , or X denotes a direct bond, where R 1 has at least 2 carbon atoms if Ph is otherwise unsubstituted, R 1 -X is different from alkyl if R is unsubstituted carbamyl and R 2 is hydrogen or alkyl or R alkoxymethyl and R 2 is hydrogen, alkyl or alkenyl, and R 1 -X-Ph- is different from 1,2-phenylene substituted by methyl in the 4- and / or 5-position when R is carboxy or hydroxymethyl and R 2 is hydrogen, and salts of such compounds with salt-forming Properties, processes for their preparation, pharmaceutical preparations containing them and their use as medicines.
• organic radicals and compounds denoted by “lower” contain in particular up to and with 7, preferably up to and with 4 carbon atoms.
• the etherified hydroxyl group means, for example, an etherified hydroxyl group, for example an aliphatic or araliphatic radical, such as an optionally substituted aliphatic or araliphatic hydrocarbon radical.
• B corresponding lower alkoxy or phenyl-lower alkoxy.
• Lower alkoxy substituents include: a. Hydroxy, lower alkoxy and / or di-lower alkylamino, and those of phenyl-lower alkoxy, e.g. B. lower alkyl, lower alkoxy and / or halogen, where one or more substituents may be present.
• the amino group means, for example, amino monosubstituted by hydroxyl, mono- or disubstituted by lower alkyl or disubstituted by lower alkylene.
• esterified hydroxymethyl R the esterified hydroxy group means, for example, hydroxy esterified with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid, e.g. B. corresponding lower alkanoyloxy or benzoyloxy optionally substituted by lower alkyl, lower alkoxy and / or halogen.
• Lower alkanoyloxy is e.g. B. acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeroyloxy, caproyloxy or pivaloyloxy.
• Aliphatic, cycloaliphatic, aromatic and araliphatic radicals R 1 and R 2 are primarily optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as corresponding lower alkyl, lower alkenyl, cycloalkyl, phenyl, naphthyl or phenyl-lower alkyl. Substituents are e.g. B.
• Heterocyclyl in a heterocyclic or heterocyclic-aliphatic radical R i is primarily monocyclic heterocyclyi aromatic character with a heteroatom, such as oxygen, sulfur or nitrogen, as a ring member, such as furyl, thienyl or pyridyl.
• the aliphatic part is, for. B. a corresponding aliphatic hydrocarbon radical, in particular lower alkyl.
• Lower alkylidene X is, for example, methylene.
• 1,2-phenylene can also be mono- or polysubstituted, inter alia by lower alkyl, lower alkoxy, hydroxy and / or halogen.
• Lower alkoxy means e.g. B. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or n-hexyloxy.
• Phenyl lower alkoxy is e.g. B. benzyloxy or 1- or 2-phenylethoxy.
• Hydroxy, lower alkoxy or di-lower alkylamino lower alkoxy is in particular 2- and / or 3-hydroxy-lower alkoxy, e.g. B. 2-hydroxyethoxy, 3-hydroxypropyloxy or 2,3-dihydroxy-propyloxy, and 2- or 3-lower alkoxy-lower alkoxy, e.g. B. 2-methoxyethoxy, 2-ethoxyethoxy or 3-methoxypropyloxy, or Diniederalkylaminoniederalkoxy, z. B. dimethylamino or diethylaminoethoxy.
• Lower alkyl is e.g. B.
• Halogen is in particular halogen with atomic numbers up to 35, i.e. H. Fluorine, chlorine or bromine.
• Lower alkylene is e.g. B. 1,4-butylene, 1,5-pentene or 1,6-hexylene.
• Niederalkenyl is e.g. B. vinyl, 1-methyl-vinyl, 1-ethyl-vinyl, allyl, 2- or 3-methyl-allyl or 3,3-dimethyl-allyl.
• Cycloalkyl preferably contains 3 to 8 ring atoms and is e.g. B. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• Lower alkylthio is e.g. As methylthio or ethylthio, while Niederalkansulfinyl and Niederalkansulfonyl z.
• Lower alkyl substituted by lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl is e.g. B. methylthio- or ethylthiomethyl, 1- or 2-methylthio- or 1- or 2-ethylthioethyl, or 2- or 3-methylthio- or 2- or 3-ethylthiopropyl, methanesulfinyl- or ethanesulfinylmethyl, 1- or 2-methanesulfonyl- or 1- or 2-ethanesulfonyl-ethyl, or 2- or 3-methanesulfonyl or 2- or 3-ethanesulfonylpropyl.
• Lower alkyl substituted by phenylthio, benzenesulfinyl or benzenesulfonyl is e.g. As phenylthio, benzenesulfinyl or benzenesulfonylmethyl, or 1- or 2-phenylthio, 1- or 2-benzenesulfinyl, or 1 - or 2-benzenesulfonylethyl.
• Phenyl lower alkyl is e.g. B. benzyl, 1 - or 2-phenylethyl or 1-, 2- or 3-phenylpropyl.
• Furyl is e.g. B. 2-furyl, and thienyl z.
• Furyl-lower alkyl, thienyl-lower alkyl and pyridyl-lower alkyl are in particular appropriately substituted methyl radicals, such as furfuryl, 2-thenyl or picolyl, e.g. B. 2- or 4-pyridylmethyl.
• Salts are e.g. B. those of compounds of the formula wherein R is carboxy, with bases.
• Such salts are in particular pharmaceutically usable, non-toxic salts, such as alkali metal or alkaline earth metal, e.g. As sodium, potassium, magnesium or calcium salts, also ammonium salts with ammonia or amines, such as lower alkylamines, e.g. As trimethylamine or triethylamine, or mineral acid salts of compounds of formula I with a basic side chain, for. B. corresponding hydrohalides, such as chlorides.
• British Patent No. 766749 describes a number of structurally similar compounds, namely 5-methyl and 5,6-dimethylbenzimidazole-2 derivatives, which have carboxy, carbamyl or hydroxymethyl as a substituent in the 2-position, as starting materials for the preparation of benzimidazole cobobalamines described. Furthermore, in U.S. Patent No. 3,325,271 and. a. 2-Alkoxyalkyl-benzimidazoles alkylated in the benzo part are proposed as crop protection agents and described in the published Dutch patent application No. 7004376 benzimidazole-2-carboxyamides alkylated in the benzo part as intermediates.
• the compounds of formula 1 have valuable pharmacological properties.
• they show antiallergic effects, e.g. B. on the rat in doses of about 10 to about 100 mg / kg when administered orally in the passive cutaneous anaphylaxis test (PCA reaction), which is analogous to that of Goose and Blair, Immunology, vol. 16, p. 749 (1969 ) described method can be detected, wherein the passive cutaneous anaphylaxis is generated according to the method described by Ovary, Prog. Allergy, Vol. 5, p. 459 (1958).
• the antiallergic, in particular the degranulation-inhibiting, effect can also be determined in an in vitro experiment on the basis of the histamine release from peritoneal cells of the rat in the case of immunologically induced release (using, for example, rats infested with Nippostrongylus brasiliensis) and in the case of chemically induced release (whereby these e.g. B. is effected with a polymer of N-4-methoxy-phenylethyl-N-methyl-amine).
• the compounds of the present invention are therefore inhibitors of allergic reactions, e.g. B.
• allergic diseases such as asthma, both extrinsic and intrinsic asthma, or other allergic diseases, such as allergic rhinitis, e.g. B. hay fever, conjunctivitis, or allergic dermatitis, e.g. B. urticaria or eczema can be used.
• allergic rhinitis e.g. B. hay fever, conjunctivitis, or allergic dermatitis, e.g. B. urticaria or eczema
• allergic rhinitis e.g. B. hay fever, conjunctivitis
• allergic dermatitis e.g. B. urticaria or eczema
• the invention relates in particular to those of the compounds of the formula I defined above, in which R represents free carboxy or hydroxymethyl, as etherified hydroxy group lower alkoxy, Hydroxyniederalkoxy, Niederalkoxyniederalkoxy or Diniederalkylaminoniederalkoxy is exhibiting esterified carboxyl or etherified hydroxymethyl, exhibiting as amino group amino, hydroxyamino, lower alkylamino, di-lower alkylamino or lower alkyleneamino amidated carboxy or have, as esterified hydroxyl group, lower alkanoyloxy or optionally substituted by lower alkyl, lower alkoxy and / or halogen-substituted benzoyloxy esterified hydroxymethyl, R i lower alkyl optionally substituted by lower alkoxy, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, phenylthio, benzenesulfiny
• the invention relates in particular to those of the compounds of formula I defined above, wherein R for free carboxy, as etherified hydroxy group, lower alkoxy or hydroxy lower alkoxy having up to and with 4 carbon atoms, e.g. B. methoxy, ethoxy, 2-hydroxyethoxy or 2,3-dihydroxypropyloxy, having esterified carboxy, or as an amino group amino or hydroxyamino, lower alkylamino or di-lower alkylamino, wherein lower alkyl contains up to and with 4 carbon atoms, e.g. B.
• methylamino, ethylamino, dimethylamino or diethylamino having amidated carboxy or hydroxymethyl, as etherified hydroxy group lower alkoxy with up to 4 carbon atoms, for.
• R 1 is lower alkyl of up to 7 carbon atoms, e.g. B.
• B phenylthio-, benzenesulfinyl- or benzenesulfonylmethyl, 1- or 2-phenylthio-, 1- or 2-benzenesulfinyl- or 1- or 2-benzenesulfonylethyl, or 1-, 2- or 3-phenylthio-, 1-, 2- or 3-benzenesulfinyl- or 1-, 2- or 3-benzenesulfonylpropyl, lower alkenyl with up to and with 5 carbon atoms, e.g. B. 1-methyl or 1-ethyl vinyl or allyl, cycloalkyl with up to 7 carbon atoms, e.g. B.
• cyclopropyl or cyclohexyl optionally by lower alkyl having up to and with 4 carbon atoms, for. B. methyl, lower alkoxy with up to 4 carbon atoms, for. B. methoxy, and / or halogen with atomic number up to 35, z. B. chlorine or bromine, substituted phenyl or phenyl-lower alkyl having up to and with 4 carbon atoms in the lower alkyl radical, for. B. benzyl or 1- or 2-phenylethyl, furyl, thienyl or pyridyl, e.g. B.
• the invention relates primarily to compounds of the formula wherein R 'on the one hand primarily for carboxy or further as etherified hydroxy group lower alkoxy with up to and with 4 carbon atoms, e.g. B. methoxy or ethoxy, having esterified carboxy and on the other hand primarily hydroxymethyl or further as etherified hydroxy group lower alkoxy with up to 4 carbon atoms, for. B. methoxy or ethoxy, having etherified hydroxymethyl, and wherein R ' 1 lower alkyl having up to and with 7 carbon atoms, for. B.
• cycloalkyl with up to and with 6 ring carbon atoms for.
• B. represents cyclopropyl or cyclohexyl or phenyl
• X ' is methylene
• R' 2 is hydrogen or lower alkyl having up to 4 carbon atoms, e.g. B. methyl
• R 3 is hydrogen, lower alkyl having up to and with 4 carbon atoms, for. B. methyl, lower alkoxy with up to 4 carbon atoms, for. B. methoxy, or halogen with atomic number up to 35, z. B.
• chlorine means the rest of the formula R ' 1 -X'- and the group R 3 , if this is other than hydrogen, preferably occupy the 5- and 6-positions of the benzimidazole ring, and pharmaceutically acceptable salts of compounds of the formula la, in which R 'is carboxy, with bases for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body, pharmaceutical preparations containing them and compounds of the formula la, with the proviso that R' of as etherified hydroxy group lower alkoxy with up to and having 4 carbon atoms, lower alkoxymethyl is different if R ' l is lower alkyl with up to and with 6 carbon atoms, and pharmaceutically acceptable salts of compounds of the formula Ia, in which R' is carboxy, with bases themselves and processes their manufacture.
• the invention relates primarily to those of the compounds of formula la defined above, wherein R 'for carboxy or for etherified hydroxy group lower alkoxy with up to and with 4 carbon atoms, for. B. methoxy or ethoxy, having esterified carboxy, and wherein R ' 1 -X' lower alkyl having 2 to 7 carbon atoms, e.g. B. ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl, cycloalkylmethyl with up to 6 ring carbon atoms, for. B.
• R ' 2 for hydrogen or in particular for lower alkyl having up to and with 4 carbon atoms, for. B. methyl
• R 3 is hydrogen or lower alkyl having up to 4 carbon atoms, e.g. B. methyl, lower alkoxy with up to 4 carbon atoms, for. B. methoxy, or halogen with atomic number up to 35, z. B.
• chlorine means where the radicals R ' 1 -X'- and R 3 preferably occupy the 5- or 6-position of the benzimidazole ring, and pharmaceutically acceptable salts of compounds of formula la in which R' is carboxy, with Bases for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body, pharmaceutical preparations containing them, and compounds of the formula Ia and pharmaceutically acceptable salts of this compound with salt-forming properties, and methods for their preparation.
• the invention relates primarily to those of the compounds of formula la defined above, wherein R 'is carboxy, hydroxymethyl or lower alkoxycarbonyl or lower alkoxymethyl with a total of up to 5 carbon atoms, e.g. B. methoxy or ethoxycarbonyl or methyl, R ' i ⁇ X' lower alkyl having up to 8, for example with up to 5, carbon atoms, for. B.
• R ' 2 and R 3 are independently hydrogen or lower alkyl having up to 4 carbon atoms, such as methyl, and pharmaceutically acceptable salts of compounds of the formula la in which R 'is carboxy, with bases for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body, pharmaceutical preparations containing them, and compounds of the formula la and pharmaceutically acceptable salts of these compounds with salt-forming properties, in which R 'is carboxy, with bases themselves, with the proviso that R is different from lower alkoxymethyl having up to and with 5 carbon atoms if R' 1 -X'- lower alkyl having up to and with 7 carbon atoms, and with the further proviso that a methyl group R ' 1 -X'- does not take the 5 (6) position of the benzimidazole ring when R 3 is
• the invention relates primarily to e.g. B.
• R ' is either carboxy or lower alkoxycarbonyl with a total of up to 5 carbon atoms, such as methoxy or ethoxycarbonyl, and wherein R' 1 -X'- lower alkyl with up to 7 carbon atoms, e.g. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or n-hexyl, and R ' 2 and R 3 lower alkyl having up to and with 4 carbon atoms, for. B.
• the radical R ' 1 -X'- the 5- and the lower alkyl radical R 3 occupies the 6-position of the benzimidazole ring, and salts of such compounds in which R' is carboxy, with bases and methods their manufacture, the aforementioned Compounds and pharmaceutically acceptable salts of such compounds in which R 'is carboxy, with bases for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body and pharmaceutical preparations containing them.
• the invention relates primarily to e.g. B. further compounds of formula la, wherein R 'is carboxy, R' i lower alkyl with up to 7, z. B. with up to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl or n-butyl, X 'is methylene, R' 2 is hydrogen and R 3 is hydrogen or lower alkyl having up to 4 carbon atoms, such as Represents methyl, the radical R ' 1 -X'- being the 5- and a lower alkyl radical R 3 the 6-position of the benzimidazole ring, and processes for their preparation, the compounds mentioned and pharmaceutically acceptable salts of those compounds in which R' Carboxy means with bases for use in a method for the prophylactic and / or therapeutic treatment of the human or animal body and pharmaceutical preparations containing them.
• the invention relates in particular to the compounds of the formula 1 mentioned in the examples.
• salts of starting materials of formula 11 come, for example, acid addition salts such as hydrohalides, e.g. B. the hydrochlorides of compounds in which R is optionally etherified or esterified hydroxymethyl, or alkali metal or ammonium salts, for. B. the sodium salts of compounds in which R is carboxy, into consideration.
• acid addition salts such as hydrohalides, e.g. B. the hydrochlorides of compounds in which R is optionally etherified or esterified hydroxymethyl, or alkali metal or ammonium salts, for. B. the sodium salts of compounds in which R is carboxy, into consideration.
• the cyclization is carried out in the usual way, in the case of normal or, in particular, for the preparation of compounds in which R is optionally etherified hydroxymethyl, elevated temperature, for. B. at about 50 ° C to about 160 ° C, especially at about 110 ° C to 140 ° C, if necessary in the presence of an acidic condensing agent such as a hydrohalic acid, e.g. B. of hydrochloric acid, and / or a water-binding agent, for. B. of dicyclohexylcarbodiimide, and advantageously under inert gas, for. B. under nitrogen.
• an acidic condensing agent such as a hydrohalic acid, e.g. B. of hydrochloric acid, and / or a water-binding agent, for. B. of dicyclohexylcarbodiimide, and advantageously under inert gas, for. B. under nitrogen.
• the above process variant is particularly suitable for the preparation of compounds of the formula I in which R is optionally etherified hydroxymethyl, which can then be conveniently converted into other compounds of the formula 1 in a conventional manner.
• the starting materials of the formula 11 are expediently prepared in situ, for example by adding a corresponding 1,2-phenylenediamine which is substituted by the radical R 1 -X- and which may also contain further substituents, ie a compound of the formula or an acid addition salt thereof, e.g. B. its hydrochloride, with an acid of the formula R-COOH (IIb) or a suitable reactive derivative, preferably esters, such as lower alkyl esters, amide, anhydride, such as acid halide, imino ethers, such as imino lower alkyl ethers or imino esters, such as iminochloride, thereof, for. B.
• 1,2-phenylenediamines to be used as starting materials for this can be, for example, by conventional reduction, for. B. reaction with a chemical reducing agent, such as sodium dithionite, or with suitably activated hydrogen, such as by a noble metal catalyst in a basic medium, for. B.
• this 1,2-nitraniline intermediate can also be treated with the above-mentioned acid, e.g. B. with glycolic or oxalic acid, or with a suitable derivative thereof, e.g. B. with an ethoxyacetic acid or chloroxalic acid lower alkyl ester, and then the nitro group, for. B. with water in the presence of Raney nickel) reduce.
• the above-mentioned acid e.g. B. with glycolic or oxalic acid
• a suitable derivative thereof e.g. B. with an ethoxyacetic acid or chloroxalic acid lower alkyl ester
• the 1,2-nitraniline compounds to be used for the preparation of the starting materials of the formula II can, if they are not known, for. B. can be prepared from the corresponding chlorobenzenes of the formula H - PhH - Cl by using these in a conventional manner, for. B.
• a preferred embodiment of the process described above is that a compound of the formula with an acid of the formula R-COOH (Ilb) or a suitable functional derivative thereof, and, if desired, converting a compound thus obtainable into another compound of the formula 1 and / or an obtained free salt-forming compound into a salt or an obtained one Salt converted into the free compound or into another salt.
• Suitable functional derivatives of acids of formula IIb are z. B. their esters, such as lower alkyl esters, amides or anhydrides, such as acid halides.
• Suitable acids of the formula IIb and their functional derivatives to be used in the above process variant are, for example, the optionally etherified glyoxylic acid and ethyl chloro or bromoxalate.
• the reaction takes place in particular in the presence of a solvent or diluent, such as a lower alkanol, e.g. B. of methanol or ethanol, if necessary with heating to about 50 ° C to 160 ° C, z. B. to about 110 ° C to about 140 ° C.
• a solvent or diluent such as a lower alkanol, e.g. B. of methanol or ethanol
• the new compounds can also be prepared by working in a compound of formula wherein X 3 represents a group which can be converted into group R, transfers X 3 to group R and, if desired, converts a compound of the formula thus obtainable into another compound of formula I and / or, if desired, a salt obtained the free compound or converted into another salt and / or a free salt-forming compound into a salt.
• a group X 3 is primarily a radical which can be converted oxidatively into the carboxy group or reductively into hydroxymethyl R, and in particular the formyl group, these also being carried out in situ in the course of the oxidation reaction, e.g. B. from the methyl or aminomethyl group or with an inorganic acid such as a hydrohalic acid, for. B. with hydrochloric acid, esterified or with a cyclic 2-hydroxy ether, e.g. B. with 2-hydroxytetrahydropyran, or a cyclic 2- or 4-hydroxythioether, e.g. B.
• the oxidation can be carried out in a manner known per se, e.g. B. by treatment with an oxidizing heavy metal compound, in the case of starting materials of the formula 11, in which X 3 represents the formyl group or an oxidatively convertible radical, such as one of the esterified or etherified hydroxymethyl groups mentioned, or optionally substituted 2-furyl, preferably with a Chromium VI or manganese VII containing oxidizing compound, e.g. B. chromium trioxide or, in particular, potassium permanganate, and in the case of starting materials of the formula 11 in which X 3 represents one of the etherified hydroxymethyl groups mentioned, furthermore containing a manganese IV, oxidizing compound such as manganese dioxide.
• an oxidizing heavy metal compound in the case of starting materials of the formula 11, in which X 3 represents the formyl group or an oxidatively convertible radical, such as one of the esterified or etherified hydroxymethyl groups mentioned, or optionally substituted 2-fury
• a suitable solvent or diluent e.g. B. of acetone or pyridine, or one, preferably aqueous, mixture thereof, if necessary, with cooling or heating, e.g. B. in a temperature range from about 0 ° C to about 80 ° C.
• a formyl group can e.g. B. also by reduction with a light metal or di-light metal hydride, such as a boron, sodium boron or lithium aluminum hydride, e.g. B. with sodium borohydride or with sodium cyanoborohydride in a lower alkanol, lithium aluminum hydride in ether, or diisoamylborane in tetrahydrofuran, if necessary with cooling or gentle heating, e.g. B. at about 0 ° C to about 100 ° C, and / or under an inert gas such as nitrogen to hydroxymethyl.
• a light metal or di-light metal hydride such as a boron, sodium boron or lithium aluminum hydride
• e.g. B. with sodium borohydride or with sodium cyanoborohydride in a lower alkanol, lithium aluminum hydride in ether, or diisoamylborane in tetrahydrofuran if necessary with
• Further radicals X 3 which can be converted into the groups of the formula R are different from the optionally esterified or amidated carboxyl group of the formula R and can be converted into this functionally modified carboxyl group, such as cyano, halogen, e.g. B. chlorocarbonyl, reactive esterified carboxyl groups, such as mono-, di- or trihalogen, z. B. chloro, di-chloro or trichloroethoxycarbonyl, phenoxy or 4-nitrophenoxy or 2,4-dinitrophenoxycarbonyl, or reactive carbamyl groups, such as) midazotyi-2-carbony !, open-chain or cyclic imino ether groups, e.g. B.
• These groups can be solvolytically, e.g. B. hydrolytically, usually in the presence of an acidic or preferably alkaline hydrolysis agent, such as an organic sulfonic acid, e.g. B. p-toluenesulfonic acid or mesitylenesulfonic acid, or a mineral acid, e.g. B.
• a tri-lower alkoxymethyl or imino ether group can also be converted into esterified carboxy or a cyano group X 3 into the carbamyl group.
• the hydrolysis of cyano and trihalomethyl is preferably carried out in a basic manner, and the hydrolysis of imino ether groups is preferably acidic.
• the reactive esterified carboxyl groups and carbamyl groups mentioned can likewise be solvolysed to form amidated carboxy groups by reaction with ammonia or a corresponding amine.
• the above reactions can be carried out according to methods known per se, usually in the presence of a solvent or diluent or a mixture thereof and, if necessary, with cooling or heating, e.g. B. a temperature range from about 0 ° C to about 120 ° C.
• Further radicals X 3 which can be converted solvolytically into groups of the formula R are, for example, hydroxymethyl groups which are different from any esterified or etherified hydroxymethyl and which are esterified or etherified hydroxymethyl groups which can be converted into these.
• esterified hydroxymethyl groups are, for example, hydroxymethyl groups esterified with inorganic acids such as hydrohalic acids, e.g. B. chlorine or bromomethyl.
• Etherified hydroxymethyl groups of the type defined above are, for example, with a cyclic, preferably 5- or 6-membered 2- or 4-hydroxyether or thioether, e.g. B.
• a silanol such as a tri-lower alkylsilanol, e.g. B. with trimethylsilanol, etherified hydroxymethyl groups.
• the groups mentioned can be used in a conventional manner, for example in the presence of an acidic or, above all, basic hydrolysis agent, such as an organic sulfonic acid, e.g. B. of p-toluenesulfonic acid or mesitylenesulfonic acid, or a mineral acid, e.g. B.
• hydroxymethyl groups etherified with hydroxy ethers or hydroxythioethers is preferably effected in a mildly acidic manner, e.g. B. using p-toluenesulfonic acid in methanol or toluene.
• Thioether compounds can also be neutral hydrolyzed in the presence of silver salts such as silver nitrate.
• Hydroxymethyl groups esterified in the stated manner can furthermore be reacted with a corresponding alcohol, such as a lower alkanol, or preferably a corresponding metal alcoholate, such as an alkali metal, e.g. B. the sodium lower alkanolate, to be etherified hydroxymethyl groups R solvolysed.
• a corresponding alcohol such as a lower alkanol
• a corresponding metal alcoholate such as an alkali metal, e.g. B. the sodium lower alkanolate
• the starting materials can be prepared in a manner known per se.
• the compounds of the formula IIIa used for this purpose are advantageously prepared in situ by working in a compound of the formula wherein Hal is chlorine, bromine or iodine and Y 1 is carboxy, cyano or hydroxymethyl, first the group Y 1 is converted into a radical X 3 and then Hal by reaction with the corresponding metal, for. B. with magnesium, in the group Y, z. B. the formula - MgHal.
• Compounds of the formula IIla in which Y is different from magnesium and z. B. means a group -Cd / 2 can also by reacting the corresponding Halogenmagnesiumverbindurgen with a salt of formula MHal 2 , z. B. with cadmium chloride.
• Carboxy can, for example, either initially, e.g. B. by means of thionyl chloride in methylene chloride, converted into halocarbonyl and then by reaction with the aminoalkanol in question, for. B. with aminoisobutanol, or by reaction with the aziridine in question, for. B. with 2,2-DimethyJaziridin, and subsequent acid-catalyzed ring expansion, in one of the imino ether groups mentioned, for. B. in 4,4- or 5,5-dimethyl-4,5-dihydro-oxazolyl- (2) - are converted.
• Cyano can be reacted with the aminoalkanol or alkanediol in question, e.g. B. with 4-amino-2-methyl-pentan-2-ol or 2-methyl-pentan-2,4-diol, with acid catalysis also in an imino ether group, for. B. in 4,4,6-trimethyl-5,6-dihydro-oxazinyl- (2).
• Hydroxymethyl can, for example, by reaction with a chlorosilane, e.g. B. with trimethylchlorosilane in pyridine, etherified or with an appropriate unsaturated cyclic ether or thioether, e.g. B.
• compounds of the formula III in which X 3 is formyl can also be prepared by converting Hal into a group Y and then into a group in a compound of the formula IIIb in which Y 1 is acetalized formyl, such as lower alkylenedioxy- or di-lower alkoxymethyl Group R 1 -X- transferred and the acetalized formyl group, e.g. B. acid catalytic, hydrolyzed.
• starting materials of the formula 111 can, starting from the corresponding 1,2-phenylenediamines, which are substituted by the rest of the formula R 1 -X- and optionally contain further substituents and which can be obtained from the corresponding nitroanilino compounds by reducing the nitro group, e.g. B. with hydrogen in the presence of Raney nickel, are prepared in an analogous manner as described for their treatment with glycolic acid or a suitable reactive derivative thereof, for. B. by reaction with an acid of formula X 3 -COOH, such as a mono- or trihaloacetic acid, diniederalkoxyacetic acid or 5-dinederalkoxymethylfuran-2-carboxylic acid, or a reactive derivative such as a lower alkyl ester thereof.
• an acid of formula X 3 -COOH such as a mono- or trihaloacetic acid, diniederalkoxyacetic acid or 5-dinederalkoxymethylfuran-2-carboxylic acid, or a reactive derivative such as
• starting materials of the formula III in which X 3 is formyl or cyano can also be obtained by adding a benzimidazole which is unsubstituted in the 1- and 2-position and contains the group R 1 -X and optionally further substituted in the carbocyclic ring with 2 -Chlor-1,1,2-trifluoro-ethene, and the available 1- (2-chloro-1,1,2-trifluoroethyl) benzimidazole, which is unsubstituted in the 2-position and which contains the group R 1 in the carbocyclic part and optionally contains further substituents, with an alcohol such as a lower alkanol, e.g. B.
• an alcohol such as a lower alkanol, e.g. B.
• a base such as an alkali metal hydroxide, e.g. B. sodium hydroxide, or with a hydroxylamine acid addition salt, e.g. B. the hydrochloride, in the presence of a base, e.g. B. pyridine.
• X 3 represents an acetalized formyl group, such as diniederalkoxymethyl, e.g. B. diethoxymethyl, or the hydroximinomethyl group, which is known in a conventional manner, for. B. by hydrolysis in the formyl group X 3 or by dehydration, for. B. with phosphorus pentoxide or 4-methylphenylsulfonyl chloride, can convert into the cyano group X 3 .
• a starting material of formula 111, wherein X 3 is cyano can e.g. B. also by treating a compound of formula 111, wherein X 3 trihalomethyl, e.g. B. trichloromethyl means, can be obtained with aqueous ammonia.
• the new compounds can also be prepared by using a compound of the formula with a reactive derivative of carbonic acid, e.g. B. with carbon dioxide or a compound of the formula RX 5 (V), in which X 4 is a metal radical and Xs is a halogen atom, and, if desired, converts a compound of the formula I thus obtainable into another compound of the formula I, and / or if desired, a salt obtained is converted into the free compound or into another salt and / or a free salt-forming compound into a salt.
• a compound of the formula with a reactive derivative of carbonic acid e.g. B. with carbon dioxide or a compound of the formula RX 5 (V), in which X 4 is a metal radical and Xs is a halogen atom, and, if desired, converts a compound of the formula I thus obtainable into another compound of the formula I, and / or if desired, a salt obtained is converted into the free compound or into another salt and / or a free salt
• Metal radicals are, for example, groups -M 1 , -M II -Hal or -M II / 2, where M 'is a metal atom from Group I, M "is a metal atom from Group II of the Periodic Table of the Elements and Hal is halogen, such as chlorine, bromine or Preferred metal radicals of the type mentioned are those of the formulas - Li, - MgHal and - Cd / 2.
• Compounds of formula V are, for example, corresponding haloformates, e.g. B. Lower alkyl chloroformate.
• Halogen atoms are, for example, chlorine, bromine or iodine atoms.
• reaction of compounds of formulas IV and V is carried out in a conventional manner, advantageously in an inert solvent, such as an ether, for. B. in diethyl ether or tetrahydrofuran, a hydrocarbon, for. B. benzene, or mixtures thereof, if necessary with cooling or gentle heating, e.g. B. at about -30 ° C to about 100 ° C, e.g. B. at boiling temperature, and / or under inert gas, for. B. under nitrogen.
• Preferred embodiments of this method are in particular the reaction of lithium or halogen magnesium compounds of the formula IV with carbon dioxide, a halogen, for. B. chloro- or bromoformic acid lower alkyl ester or a carbamyl halide, e.g. B. with carbamyl chloride or N, N-di-lower alkyl carbamyl chlorides.
• the organometallic compounds of formula IV to be used as starting materials are advantageously prepared in situ by using a corresponding halogen, eg. B. chlorine, iodine or especially bromine compound, preferably in an ether, for. B. in diethyl ether or tetrahydrofuran, with lithium or especially magnesium or the corresponding 2-unsubstituted compound in a conventional manner, with a hydrocarbon metal compound such as butyllithium, butyl magnesium bromide or phenyllithium.
• a corresponding halogen eg. B. chlorine, iodine or especially bromine compound
• a hydrocarbon metal compound such as butyllithium, butyl magnesium bromide or phenyllithium.
• Other organometallic compounds can be obtained from the halogen, especially bromine, magnesium compounds, by reaction with a corresponding metal halide, e.g. B. with cadmium chloride, copper chloride or zinc chloride can be obtained.
• the halogen compounds to be used for this can e.g. B. can be prepared by a corresponding, optionally substituted on an amino group by a radical R 2 R 1 -X-1,2-phenylenediamine, accessible z. B. from the corresponding halodinitrobenzene by reducing the nitro groups, for. B. with hydrogen and Raney nickel, with a reactive derivative of carbonic acid, for. B. with a di-lower alkyl carbonate or with phosgene and the initially obtained 2-hydroxy compound in a conventional manner, for. B. halogenated with phosphorus tri- or pentachloride or thionyl chloride.
• starting materials of the formula IV corresponding 2-unsubstituted compounds can be prepared by reacting a corresponding 1,2-diaminohalobenzene, aminonitro- or R 2 -aminonitrohalobenzene with formic acid or an ester thereof and optionally reducing the nitro group, ring closure entry.
• R 1 -X- is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heterocyclic-aliphatic radical
• R 1 -X- is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heterocyclic-aliphatic radical
• X 6 is a group reducible to the group of the formula R 1 -X, or a salt thereof the group X 6 reduces to the desired group of the formula R 1 -X-, and if desired, a compound of the formula I thus obtainable in a converts another compound of formula I and / or, if desired, converts a salt obtained into the free compound or into another salt and / or a free salt-forming compound.
• the groups of the formula R 1 -X- which can be reduced are, for example, aliphatic, cycloaliphatic, araliphatic, cycloaliphatic-aliphatic ones which have at least one double or triple bond or at least one X 7 radical which can be reductively replaced by hydrogen or heterocyclic aliphatic radicals.
• At least one double or triple bond radicals of the type mentioned are, for example, corresponding alkenyl or alkynyl radicals, cycloalkenyl, cycloalkenylalkyl or cycloalkenylalkenyl radicals, aralkyl radicals or heteroarylalkenyl radicals.
• substituted radicals of the type mentioned are, for example, X 7 alkyl radicals, X 7 cycloalkylalkyl or cycloalkyl X 7 alkyl radicals, aryl X 7 alkyl radicals or heteroaryl-X 7 aryl radicals, preferably of the formula R 1 - CH (X 7 ) -, such as R 1 -CH (OH) -.
• the compounds of formula VI to be used as starting materials can, for. B. be prepared by, in a manner known per se, a corresponding chlorobenzene of the formula H-PhH-Cl by reaction with a compound introducing the radical X 6 , for. B. of the formula R 1 -COHal or (R 1 CO) 2 O in the presence of aluminum trichloride, the compound of the formula X 6 -PhH-Cl thus nitrated with nitric acid / sulfuric acid and the chlorine nitro compound of the formula X 6 -Ph (Cl) -NO 2 , e.g. B.
• a compound of the formula obtainable according to the invention can be converted into another compound of the formula I in a manner known per se.
• diethyl (pyro) carbonate or with organic sulfite or phosphite, such as diniederalkyl sulfite or tri-lower alkyl phosphite, in the presence of a suitable acidic agent, such as p-toluenesulfonic acid, or with an alcohol in the presence of a suitable condensing agent, such as a dehydrating agent, e.g. B. dicyclohexylcarbodiimide, or, to form a hydroxy lower alkyl group, with an epoxy lower alkane, e.g. B. ethylene oxide, esterify.
• a suitable acidic agent such as p-toluenesulfonic acid
• a suitable condensing agent such as a dehydrating agent, e.g. B. dicyclohexylcarbodiimide, or, to form a hydroxy lower alkyl group, with an epoxy lower alkane, e.g. B
• thionyl chloride can react with a metal alcoholate or an alcohol in the presence of an acid-binding base, and so arrive at a compound of formula 1, wherein R is esterified carboxy.
• Any substituents present in an esterification reagent may be present in a functionally modified form and then in a compound of the formula in which R is z.
• B. stands for substituted lower alkoxycarbonyl, in which substituents are present in a functionally modified form, are released. So you can as an esterification reagent z.
• B. use the 2,3-epoxy-propyl chloride and subsequently hydrolyze a 2,3-epoxy-propyloxy grouping R in the resulting ester to the desired 2,3-dihydroxy-propyloxy grouping.
• R is esterified carboxy
• e.g. B. is also p-nitro or 2,4-dinitrophenoxy or benzyloxycarbonyl
• this can by transesterification, for. B. by treatment with an alcohol, if necessary in the presence of a suitable transesterification catalyst, such as an optionally substituted alkali metal, for.
• a suitable transesterification catalyst such as an optionally substituted alkali metal, for.
• sodium or potassium alkanolate can be converted into another esterified carboxy group.
• ammonium salt or an amine salt of a compound of the formula in which R is carboxy can be converted by dehydration with a suitable dehydrating agent, such as sulfuric acid, into a compound of the formula I in which R is optionally substituted carbamyl.
• R is carboxy in halide form
• a thionyl halide such as thionyl chloride.
• R 2 is hydrogen
• Such an intermediate can e.g. B. by treatment with a suitable alcoholate, such as an alkali metal, e.g. As sodium or potassium alcoholate, or with an alcohol in the presence of a mineral acid, e.g. B. hydrogen chloride, or with ammonia, hydroxylamine or a primary or secondary amine, are converted into a compound of formula 1, wherein R represents esterified carboxy or optionally substituted carbamyl.
• an esterified carboxyl group or an optionally substituted carbamyl group R can be converted into the free carboxyl group in a conventional manner, e.g. By hydrolysis, usually in an alkaline medium, such as by treatment with water in the presence of an alkali metal or alkaline earth metal hydroxide, e.g. B. sodium hydroxide.
• an alkali metal or alkaline earth metal hydroxide e.g. B. sodium hydroxide.
• An optionally esterified or present in halide or salt form carboxy group R can also be reduced to hydroxymethyl by reaction with a light metal borohydride or with hydrogen in the presence of a hydrogenation catalyst.
• a light metal hydride such as a borane, e.g. As diborane or the borantetrahydrofuran complex or a di-light metal hydride, such as lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride.
• Halocarbonyl groups such as chlorocarbonyl are preferably reduced with hydrogen in the presence of palladium, preferably on a support such as barium sulfate, and, if necessary, a sulfur-containing cocatalyst, e.g. B. of thiourea.
• Etherifying agents are, for example, reactive esters of corresponding alcohols, for example their esters with inorganic acids, such as hydrochloric, bromic or hydroiodic acid or sulfuric acid, or with organic sulfonic acids, for. B. with methane, benzene, p-bromobenzene or p-toluenesulfonic acid, and epoxides derived from corresponding 1,2-diols.
• reaction with the etherifying agents mentioned can be carried out in a customary manner, for example in the presence of an alkali metal hydride or alcoholate, for. B. of sodium hydride or sodium methoxide, or by using the compound to be etherified as a salt, for. B. sodium salt.
• this can be esterified in a conventional manner, e.g. B. by direct esterification with a corresponding carboxylic acid in the presence of a mineral acid, for. B. of hydrochloric acid or sulfuric acid, or by reaction with a reactive derivative, e.g. B.
• an anhydride such as the anhydride or chloride
• an ester such as lower alkyl or o-nitrophenyl, 2,4-dinitrophenyl ester
• the carboxylic acid if necessary in the presence of an acidic or especially basic condensing agent, in the reaction with an acid anhydride , e.g. B. of pyridine, and in the reaction with an ester, for. B. an alkali metal, such as sodium or potassium alcoholates, into an esterified hydroxymethyl group R.
• the etherification or esterification of a hydroxymethyl group can, however, also be carried out in such a way that these are initially in the usual manner, for. B.
• esterified hydroxymethyl groups R can be further oxidized to carboxy groups and etherified hydroxymethyl groups to esterified carboxy groups.
• the oxidation can be carried out in a manner known per se, e.g. B. by reaction with an oxidizing heavy metal compound, starting from hydroxymethyl, preferably with a chromium VI or manganese VII containing oxidizing compound, for. B. with chromium trioxide or, in particular, potassium permanganate, starting from etherified hydroxymethyl R, can also be carried out with a compound containing manganese IV, such as manganese dioxide. It is preferably carried out in the presence of a suitable solvent or diluent, for. B. of acetone or pyridine, or a preferably aqueous, mixture thereof, if necessary with cooling or heating, for. B. in a temperature range from about 0 ° C to about 80 ° C.
• Obtained free salt-forming compounds of formula 1 can be converted into salts in a manner known per se, acids z. B. with a base or with a suitable salt of a carboxylic acid and bases with a mineral acid, usually in the presence of a solvent or diluent.
• Salts obtained can be converted into the free compounds in a manner known per se, e.g. by treating with an acidic reagent such as a mineral acid.
• the compounds, including their salts, can also be obtained in the form of their hydrates or include the solvent used for the crystallization.
• the invention also relates to those embodiments of the process in which one starts from a compound which is obtainable as an intermediate at any process stage and carries out the missing process steps, or forms a starting material under the reaction conditions or uses it in the form of a derivative thereof, optionally a salt.
• the present invention also relates to pharmaceutical preparations which contain compounds of the formula I or pharmaceutically acceptable salts thereof.
• the pharmaceutical preparations according to the invention are those for enteral, such as oral, nasal or rectal, as well as parenteral or topical administration to warm-blooded animals, which contain the pharmacologically active substance alone or together with a pharmaceutically usable carrier material.
• the dosage of the active ingredient depends on the warm-blooded species, the age and the individual condition, as well as on the mode of administration.
• the new pharmaceutical preparations contain e.g. B. up to about 95%, preferably from about 5% to about 90% of the active ingredient.
• Pharmaceutical preparations according to the invention are e.g. B. those in unit dosage forms, such as dragées, tablets, capsules or suppositories, and ampoules, also inhalation preparations, and topical and local (z. B. for insufflation) usable pharmaceutical preparations.
• compositions of the present invention are manufactured in a manner known per se, e.g. B. by means of conventional mixing, granulating, coating, solution or lyophilization processes produced.
• pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, into tablets or dragee cores after adding suitable auxiliaries .
• Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B.
• fillers such as sugar, e.g. B. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. As tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch paste using z. B.
• Dragee kernels are provided with suitable, optionally gastric juice-resistant coatings, u. a.
• Concentrated sugar solutions which optionally contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate.
• suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate.
• the tablets or dragee coatings can contain dyes or pigments, e.g. B. for identification or for labeling different doses of active ingredient.
• compositions which can be used orally are plug-in capsules made of gelatin, and soft, closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
• the capsules can contain the active ingredient in the form of granules, e.g. B. in a mixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers.
• the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being able to be added.
• suppositories into consideration, which consist of a combination of the active ingredient with a suppository base.
• suppository base z.
• Gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; come as base materials z.
• aqueous solutions of an active ingredient in water-soluble form e.g. B. a water-soluble salt
• further suspensions of the active ingredient such as corresponding oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, e.g. B. sesame oil, or synthetic fatty acid esters, e.g. B. ethyl oleate or triglycerides, or aqueous injection suspensions, which viscosity-increasing substances, for. B. sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also contain stabilizers.
• Inhalation preparations for the treatment of the respiratory tract by nasal or buccal administration are e.g. B. aerosols or sprays, which can distribute the pharmacological agent in the form of a powder or in the form of drops of a solution or suspension.
• preparations with powder-distributing properties usually contain a liquid propellant with a boiling point below room temperature, and, if desired, carriers, such as liquid or solid nonionic or anionic surface-active agents and / or solid diluents.
• Preparations in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and, if necessary, an additional solvent and / or a stabilizer.
• compressed air can also be used, which can be generated as required by means of a suitable compression and expansion device.
• compositions for topical and local use are e.g. B. for the treatment of the skin lotions and creams which contain a liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (preferably containing a preservative), for the treatment of the eyes eye drops, which contain the active compound in aqueous or oily solution and eye ointments, which are preferably produced in sterile form, for the treatment of nose powders, aerosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse powder, which is produced by rapid Inhalation through the nostrils, and nasal drops containing the active compound in aqueous or oily solution, or for local treatment of the mouth, lozenges containing the active compound in a mass generally formed from sugar and gum arabic or tragacanth, which flavorings can be added, as well as pastilles, the active substance in an inert mass, for. B. from gelatin and glycerin or sugar and gum arabic
• the invention also relates to the use of the new compounds of the formula I or salts thereof as pharmacologically active compounds, in particular as antiallergics, preferably in the Form of pharmaceutical preparations.
• the daily dose which is administered to a warm-blooded animal of approximately 70 kg, is, depending on the form of administration, from approximately 2 mg to approximately 7000 mg.
• the mixture is cooled to about 15 ° by adding ice, the crystalline precipitate is filtered off, washed with water, taken up in methylene chloride, dried over sodium sulfate, steamed under reduced pressure, finally with the addition of cyclohexane and petroleum ether (boiling range 60-80 ° ), the methylene chloride, cools and sucks the 2-methyl-4-methylamino-5-nitrobutyrophenon of mp. 105-107 °.
• the starting material can be prepared in a manner analogous to that described in Example 3, starting from chlorobenzene via 4-chlorobutyrophenone and 4-chloro-3-nitrobutyrophenone.
• Concentrated sulfuric acid (1275 ml), cooled to -20 ° to -25 ° by means of a carbon dioxide / chloroform mixture, is added dropwise with good stirring within 28 minutes with 285.5 g of the mixture of 4-chloro-2-methyl-butyrophenone and 2-chloro-4-methyl-butyrophenone were added.
• the resulting solution is treated at -20 ° to -25 ° within 30 minutes with a mixture of 240 ml of concentrated sulfuric acid and 75 ml of 100% nitric acid (d: 1.52) and then stirred for a further 15 minutes, keeping the temperature can be increased to -15 °. You pour on.
• 2-hydroxymethyl-5-butyl-1,6 is obtained by reacting 25 g of 5-butyl-6-methyl-2-methylamino-aniline-bis-hydrochloride with 11.5 g of glycolic acid -dimethyl-benzimidazole in the form of a viscous oil.
• 5-Butyl-1 is obtained in an analogous manner to that described in Example 2 by oxidizing 8.5 g of 2-hydroxymethyl-5-butyl-1,6-dimethyl-benzimidazole with 24 g of potassium permanganate in 200 ml of 95% aqueous acetone , 6-dimethyl-benzimidazole-2-carboxylic acid.
• a 2% aqueous solution of the sodium salt of 5 (6) -methyl-benzimidazole-2-carboxylic acid suitable for inhalation can be prepared as follows:
• the sodium salt of 5 (6) -methyl-benzimidazole-2-carboxylic acid is dissolved in freshly distilled water, and the solution with the disodium salt of ethylenediamine-tetraacetic acid and the benzalkonium chloride (mixture of alkyl-dimethyl-benzyl-ammonium chlorides, in which alkyl of 8 contains up to 18 carbon atoms). After the components have completely dissolved, the solution obtained is brought to a volume of 100 ml with water, filled and sealed gas-tight.
• capsules containing 5-butyl-1,6-dimethyl-benzimidazole-2-carboxylic acid ethyl ester suitable for insufflation can be prepared as follows:
• the 5-butyl-1,6-dimethyl-benzimidazole-2-carboxylic acid ethyl ester and the lactose are mixed well.
• the powder obtained is then sieved and the portions of 0.05 g each are filled into gelatin capsules.
• Tablets containing 100 mg of butyl 1,6-dimethyl-benzimidazole-2-carboxylic acid ethyl ester can be prepared, for example, in the following composition:
• the active ingredient is mixed with the milk sugar, part of the wheat starch and with colloidal silica and the mixture is passed through a sieve.
• Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weak plastic mass has formed.
• the mass is passed through a sieve of approx. 3 mm mesh size, dried and the dry granules are again passed through a sieve. Then the remaining wheat starch, talc and magnesium stearate added.
• the mixture obtained is pressed into tablets of 250 mg with a notch (s).

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