EP1404321A1 - 1-alkyl-2-aryl-benzimidazolderivate, deren verwendung zur herstellung von arzneimitteln sowie diese derivate enthaltende pharmazeutische präparate - Google Patents
1-alkyl-2-aryl-benzimidazolderivate, deren verwendung zur herstellung von arzneimitteln sowie diese derivate enthaltende pharmazeutische präparateInfo
- Publication number
- EP1404321A1 EP1404321A1 EP02762333A EP02762333A EP1404321A1 EP 1404321 A1 EP1404321 A1 EP 1404321A1 EP 02762333 A EP02762333 A EP 02762333A EP 02762333 A EP02762333 A EP 02762333A EP 1404321 A1 EP1404321 A1 EP 1404321A1
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- Prior art keywords
- oxy
- benzimidazole
- pentyl
- group
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- 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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention relates to new benzimidazole derivatives and the use of benzimidazole derivatives for the production of medicaments for the treatment of diseases associated with microglia activation and for the prophylaxis against these diseases, as well as pharmaceutical preparations which contain the new benzimidazole derivatives.
- EP 0 104 727 A1 gives benzimidazole derivatives which are not substituted in the 1 position and have an alkyl group in the 2 position.
- Substituents on the benzene ring of the derivatives include Pyridyloxy, pyridylalkyl, pyridylalkyloxy and pyridyloxyalkanediyl radicals.
- EP 0520200 A2 specifies benzimidazole derivatives which have aryl radicals substituted in the 1 position and mono-, di-substituted or in the 2-position have unsubstituted amino groups.
- the benzene ring of the benzimidazole backbone can be substituted with halogen, trifluoromethyl and / or cyano. These compounds are used to treat diseases that are associated with an increased activation of Ca channels.
- WO 01/21634 A1 also describes benzimidazole derivatives which have an alkanediylamido group in the 1-position, in the 2-position and others.
- a substituted phenyl or heteroaryl radical and on the fused benzene ring, etc. can be substituted with at least one substituted alkoxy, alkylamino, alkylsulfonyl and alkylsulfoxide radical. It is stated that these substances can be used as active ingredients in pharmaceutical preparations for a large number of possible indications.
- substituted benzimidazoles which in the 1-position include an alkyl radical and in the 2-position i.a. have a phenyl or heteroaryl radical.
- the fused benzene ring of the benzimidazoles is preferably substituted with an alkoxy or aminoalkoxy radical.
- Such compounds are said to be effective against diseases associated with a ⁇ -amyloid peptide.
- the benzene ring of the backbone of the derivatives can be mixed with nitro, alkanoyl, amino, alkyl, alkoxy, cycloalkyl, heterocycle, unsaturated heterocycle, halogeno, alkylthio, hydroxyalkylidenyl, hydroxyalkylidenylamino, aminoalkylidenyl, Aminoalkoxy, hydroxyalkyl, heterocycle alkoxy, aminoalkylidenyl or trifluoromethyl radicals can be substituted.
- Various anti-inflammatory and atherosclerosis-preventing agents are described in WO 97/12613 A1.
- benzimidazole derivatives are given as active substances which are substituted in the 1 position with an alkyl radical and in the 2 position with a phenyl, naphthyl or heteroaryl radical.
- the substituent on the benzene ring of the active compound can be an alkoxy or alkylthio group.
- EP 0 531 883 A1 specifies condensed five-membered heterocycles, for example substituted benzimidazole derivatives which are substituted in the 1 position, for example with an alkyl radical, and in the 2 position, for example with a substituted phenyl radical. Furthermore, the derivatives described can have further substituents on the benzene ring of the benzimidazole skeleton. The fused benzene ring can then be substituted with an alkyleneoxy or alkylene amine group with a terminal carboxyl group.
- non-steroidal anti-inflammatory drugs have been possible for a possible therapy of neuroinflammation [McGeer, PL, Roger, Neurology 42, 447.449 (1992), Rogers, J., Kirby, LC, Hempleman, SR, Berry, DL McGeer, PL, Kaszniak, AW, Zalin-ski, J., Cofield, M., Mansukhani, L, Wilson, P., Kogan, F., Neurology 43, 1609-1611 (1993), Andersen, K., Launer, LJ, Ott, A.,
- the new benzimidazole derivatives have the following general formula I:
- R 1 is an aryl group, a five- or six-membered heteroaryl group with one or two heteroatoms selected from the group comprising N, S and O, a benzothienyl group or one
- R 4 where X is a bond, CH 2 , (CH 2 ) 2 , or CH (CH 3 ), the radicals R 4 and R 4 'furthermore being selected independently of one another in accordance with the meanings given below and where two radicals at R 1 , if they are ortho to one another, can be linked to one another in such a way that they together form a methanediylbisoxy, ethane-1, 2-diylbisoxy, propane-1, 3-diyl or butane-1,4- form diyl group,
- heteroaryl radical containing one or two heteroatoms selected from the group comprising N, S and O, the phenyl and heteroaryl radicals having up to two radicals being selected from the group comprising F, Cl, Br,
- CH 3 , C 2 H 5) OH, OCH 3 , OC 2 H 5 , NO 2 , N (CH 3 ) 2 , CF 3) C 2 F 5 and SO 2 NH 2 may be substituted and / or a fused one Can carry methanediylbisoxy or ethane-1,2-diylbisoxy group, where the piperazine residue on a second nitrogen atom can also be substituted by R 7 , COR 7 or S0 2 R 7 , where R 7 and R 7 'can be selected independently of one another in accordance with the meanings given below,
- R 3 is one or two substituents that can be independently selected from the group comprising:
- a ring member ring-N or ring-O can be and in a six- or seven-membered cycloalkyl ring one or two ring members Ring-N- and / or Ring-O-
- N (C ⁇ -3- alkyl) (C ⁇ - alkanoyl) may be substituted,
- Y is a group selected from the group comprising O, NH,
- R 4 , R 4 ', R 5 , R 5 ', R e , R 7 and R 7 ' have the following meanings; in it are:
- R 4 and R 4 ' are each independently a residue selected from the group
- alkyl radicals optional can be substituted with a radical selected from the group comprising OH, OCH 3 and SCH 3 and wherein in a five-membered cycloalkyl ring a ring member can be Ring-N or Ring-O and in a six- or seven-membered cycloalkyl ring one or two ring members each
- Ring N and / or ring O atoms can be, where the ring N atoms can optionally be substituted with C 3 alkyl or C 1 alkanoyl,
- R 5 and R 5 ' are each independently a residue selected from the group
- Group comprising C ⁇ -6 alkyl, C 2-6 alkenyl, and C 2 - 6 -alkynyl, where one C atom from O, S, SO, SO 2, NH, Nds alkyl or NC. 1 3 - Alkanoyl can be exchanged, further (Co-3-alkanediyl-C3-7-cycloalkyl), where in a five-membered cycloalkyl ring a ring member can be Ring-N or Ring-O and in a six- or seven-membered cycloalkyl ring one or two ring members each ring -N and / or ring O atoms can be, where ring N atoms can optionally be substituted with C -3 alkyl or C 3 -3 alkanoyl, and also (Co-3-alkanediyl aryl) and ( C 0-3 -alkanediyl heteroaryl), the heteroaryl group being five or six members and containing one or
- Aryl and heteroaryl groups can be substituted with up to two radicals, selected from the group comprising F, Cl, Br, CH 3 , C 2 H 5 , OH, OCH 3 , OC 2 H 5 , NO 2 1 N (CH 3 ) 2 , CF 3 , C 2 F 5 and SO 2 NH 2 , and / or also a fused methane diyl bisoxy or ethane 1, Can carry 2-diylbisoxy group,
- R 7 and R 7 'independently of one another R 4 or R 6 .
- those derivatives can be excluded in which R 2 is C 1-6 alkyl, in particular methyl, and R 1 is substituted by CN or by C (NH) NH 2 if Y is R 4 and ⁇ is COOH or COOK 5 are available.
- the present invention also includes physiologically acceptable salts and esters of the abovementioned compounds, in particular the acid salts of the nitrogen bases of the benzimidazole derivatives according to the invention, furthermore the salts of carboxylic acids of the derivatives according to the invention with bases and the esters of the carboxylic acids of the derivatives and of carboxylic acids derived from carboxylic acid derivatives are, for example of carboxylic acid amides.
- the aryl radicals are in particular the phenyl radical, but also the naphthyl radical.
- the aryl and heteroaryl radicals can be bound in any way to the benzimidazole backbone or another group, for example as 1- or 2-naphthyl, as 2-, 3- or 4-pyridinyl, 2-benzothienyl, 2-thienyl, 3 -Thienyl, Indol-3-yl, 2-Furyl, 3-Furyl, 2-Pyrimidinyl or Imidazol-1 -yl.
- Alkyl groups can be straight-chain or branched. Examples of alkyl groups are methyl, ethyl, n-propyl, / so-propyl, / 7-butyl, se-butyl, tert-butyl, n-pentyl, se-pentyl, fe / t-pentyl, ⁇ eo-pentyl, n- Hexyl, se -hexyl, heptyl, octyl, nonyl, decyl.
- the higher homologues also include both the linear and the branched alkyl groups, for example 2-ethylhexyl for octyl and 3-propyl-hexyl for nonyl.
- Perfluorinated alkyls are preferably CF 3 and C 2 F 5 .
- Alkenyl groups can be straight-chain or branched.
- vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl and 3-methyl-2-propenyl are akenyl radicals in the sense of the invention.
- Alkynyl groups can be straight-chain or branched. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and 2-butynyl. Under cycloalkyl groups are each preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl to understand (corresponds to C 3-7 - cycloalkyl).
- Alkanediyl, alkenediyl, alkindiyl and cycloalkanediyl radicals mentioned in the description of the invention are synonymous with alkylene, alkenylene, alkynylene or cycloalkylene. Insofar as the number of carbon atoms contained is given in the general formulas of the alkanediyl radicals and the value 0 is given as the lower limit of this number, this alkanediyl radical is not included in the respective case.
- alkanes, alkenes and alkynes for A are: straight-chain or branched alkanediyl having one to eight carbon atoms, for example methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, furthermore 1-methylethanediyl, 1-ethylethanediyl, 1-methylpropanediyl, 2-methyl propanediyl, 1-methyl butanediyl, 2-methyl butanediyl, 1-ethyl butanediyl, 2-ethyl butanediyl, 1-methyl pentanediyl, 2-methyl pentanediyl, 3-methyl pentanediyl and analogous compounds.
- Straight-chain or branched alkenediyl and alkynediyl with two to eight carbon atoms are alkenediyl groups or alkynediyl groups with double and triple bonds in all possible positions and with all possible methyl or ethyl substitutions.
- one or two carbon atoms can each be replaced by O, NH, N-C ⁇ -3 alkyl or NC 1-3 alkanoyl, the exchanged group being separated from Y by at least two C atoms. If two residues are ortho-standing, they can form a common ring with the neighboring aromatic.
- physiologically compatible acid salts of the nitrogen bases of the benzimidazole derivatives according to the invention can be formed with inorganic and organic acids, for example with oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid and methanesulfonic acid.
- the inorganic or organic bases which are known for the formation of physiologically tolerable salts, such as, for example, alkali metal hydroxides, in particular sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, furthermore ammonia and amines, such as, are also suitable for salt formation of acid groups, in particular carboxylic acid groups Ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and tris (hydroxymethyl) methylamine.
- physiologically tolerable salts such as, for example, alkali metal hydroxides, in particular sodium and potassium hydroxide, alkaline earth metal hydroxides, such as calcium hydroxide, furthermore ammonia and amines, such as, are also suitable for salt formation of acid groups, in particular carboxylic acid groups Ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and tris (hydroxymethyl) methylamine.
- All lower monohydric, dihydric and trihydric alcohols are suitable for ester formation, in particular methanol, ethanol, / so-propanol and tert-butanol as well as ethylene glycol and glycerol.
- Benzothienyl group which can be independently substituted with up to two of the following radicals, selected from the group comprising:
- K 3 is a radical selected from the group comprising hydrogen, F,
- K 4 and K 6 have the meanings given below,
- ß a residue selected from the group comprising COOH, COOK 5 ,
- radicals K 4 , K 4 ', K 5 , K 5 ', K 6 and K 7 have the following meanings; mean:
- C atom can be replaced by O, S, SO, SO 2 , NH, NC 1-3 alkyl or N-C ⁇ -3 -alkanoyl, furthermore (C 0- 3-alkanediyl-C 3- 7-cycloalkyl), wherein in a five-membered cycloalkyl ring a ring member can be Ring-N or Ring-O and in a six- or seven-membered cycloalkyl ring one or two ring members each ring-N- and / or
- ring N atoms can optionally be substituted with C -3 alkyl or C 3 alkanoyl, and also (C 0-3 alkanediylphenyl) and (Co- 3 alkanediyl) Heteroaryl), the heteroaryl group being five or six-membered and containing one or two heteroatoms selected from the group comprising N, S and O, all of the aforementioned alkyl and cycloalkyl radicals having a radical selected from the group comprising CF 3 , C 2 F 5 , OH, Od-3-alkyl, NH 2 , NH-d -3 -alkyl, NH-C 1-3 -alkanoyl, N (C ⁇ -3 -alkyl) 2 , N (C 1-3 -Alkyl) (C ⁇ - 3 -alkanoyl), COOH, CONH 2 and COO-C ⁇ -3 -alkyl, and all the aforementioned
- N (CH 3 ) 2 , CF 3> C 2 F 5 and SO 2 NH 2 may be substituted and / or may also carry a fused methanediylbisoxy or ethane-1,2-diylbisoxy group, the piperazine residue on a second nitrogen atom also can be substituted with K 7 , COK 7 or S0 2 K 7 , where K 7 and R 7 'can be selected independently of one another in accordance with the meanings given below, R 3 is hydrogen,
- K 5 and R 5 ' are each independently a radical selected from the group comprising ds-alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, (C 0-3 -. Alkanediyl-C 3 7 cycloalkyl ), (C 0 -3-alkanediylphenyl) and (C 0-3
- Any liquid carrier in which the compounds according to the invention are dissolved or emulsified can be used to formulate an injectable preparation.
- These liquids often also contain substances for regulating the viscosity, surface-active substances, preservatives, solubilizers, thinners and other additives with which the solution is adjusted isotonic.
- Other active substances can also be administered together with the benzimidazole derivatives.
- the nitro group (C _> D or F ⁇ * ⁇ G) is preferred by hydrogenation in polar solvents such as acetic acid, lower alcohols or ethyl acetate with the addition of catalysts such as Raney nickel or palladium on carbon, or by chemical reduction, for example with tin in hydrochloric acid, SnCl 2 [FD Bellamy, Tet. Lett., (1984)] or Fe / acetic acid [DC Owslly, JJ Bloomfield, Synthesis, 118, 150 (1977)].
- polar solvents such as acetic acid, lower alcohols or ethyl acetate
- catalysts such as Raney nickel or palladium on carbon
- the type C compounds are converted into the amides F using known acid derivatives, such as, for example, with acid anhydrides or acid chlorides, in suitable solvents, such as aromatic hydrocarbons or halogenated hydrocarbons, with or without the addition of auxiliary bases such as triethylamine or pyridine ,
- suitable solvents such as aromatic hydrocarbons or halogenated hydrocarbons
- auxiliary bases such as triethylamine or pyridine
- the ring closure of the type G compounds to £ takes place according to methods known per se, for example using hydrochloric acid, optionally with the addition of a solubilizer, such as a lower alcohol, preferably methanol, or with dehydrating agents, such as polyphosphoric acid, phosphorus oxychloride or the like, optionally under Add inert solvents, such as aromatic or halogenated hydrocarbons, at temperatures from 0 ° C to 150 ° C, preferably from 10 ° C to 120 ° C.
- nitrobenzene is the
- a second approach uses direct N-alkylation of prefabricated benzimidazoles, for example according to Roth et al .; J. Med. Chem., 40, 4199-4207 (1997).
- a 1 H-benzimidazole is first deprotonated with a base such as sodium hydride and then reacted with the electrophile component such as alkyl halides.
- Hydroxyl function can be prepared by known methods, optionally with an end group ß (formula I) or a precursor containing alkyl , Allyl and benzyl halides to convert the ethers, the reaction with the alkylating agents preferably in polar solvents such as dimethylformamide, dimethyl sulfoxide, ethers such as tetrahydrofuran or lower ketones such as acetone or methyl ethyl ketone, with the addition of bases such as alkali - And alkaline earth hydrides, but preferably sodium hydride, or with the addition of alkali carbonates, such as potassium or cesium carbonate, is carried out in a temperature range from 0 ° C to 120 ° C.
- polar solvents such as dimethylformamide, dimethyl sulfoxide, ethers such as tetrahydrofuran or lower ketones such as acetone or methyl ethyl ketone
- bases such as alkali - And al
- the ester can be cleaved by acidic or alkaline hydrolysis by methods known to those skilled in the art, such as, for example, using basic catalysts such as, for example, alkali metal or alkaline earth metal carbonates or hydroxides in an alcohol or the aqueous solution of an alcohol.
- Aliphatic alcohols such as, for example, methanol, ethanol, butanol, etc. are suitable as alcohols, but preferably methanol.
- Aqueous solutions of ethers such as tetrahydrofuran are also used.
- Lithium, sodium and potassium salts may be mentioned as alkali carbonates and hydroxides.
- the lithium and sodium salts are preferred.
- suitable alkaline earth carbonates and hydroxides are calcium carbonate, calcium hydroxide and barium carbonate.
- the reaction is generally carried out at -10 ° C to 70 ° C, but preferably at 25 ° C.
- the ester cleavage can also be carried out under acidic conditions, such as in aqueous hydrochloric acid.
- a solubilizer such as a lower alcohol, preferably methanol.
- the alkylation reagents can also carry phosphonic or sulfonic acid groups in protected form, from which the corresponding suifonic or phosphonic acids can then be released.
- the alkylation reagents can carry a tetrazole in a protected form, for example tritylated, as a further functional group, from which the tetrazole is then released after the alkylation.
- a tetrazole can later also be produced from a nitrile present in the alkylation reagent or also generated subsequently.
- Y OSO 2 C n F 2n + 1
- alkene, alkyne, allyl, benzyl or also cyano substituents see. see, for example, FJ McQuillin et al, "Transition metal organometallics for organic synthesis", Cambridge University Press 1991, and literature cited there, Chem Rev., 1989, 43 (89) and literature cited there, Adv. Chem. ser., 1974, 252 (132) or Tet. Lett., 1986, 1171 (27).
- the substituents K 3 are contained in the synthesis building blocks from the outset or, if required, are established at a suitable point in the synthesis sequence in question or generated from suitable precursors brought along.
- the nitro groups brought in can be reduced to the corresponding amines by the processes already described above and converted into carboxy amino groups.
- Sulfonylamino groups are accessible from the amino compounds by standard procedures.
- an amine or its hydrochloride is in a suitable inert solvent such as an aromatic hydrocarbon such as toluene or a
- Haloalkane for example dichloromethane
- a base such as triethylamine or pyridine
- a sulfonic acid halide at 0 ° C. to 120 ° C.
- Nitriles can, for example, be converted into ketones using Grignard reagents or lithium organylenes or hydrolyzed to acids or amides. It is self-evident to the person skilled in the art that the reaction conditions used here must be compatible with the remaining groups in the molecule.
- the free acid derivatives of the formula I can be converted into amide derivatives or ester derivatives of the formula I by various processes known from the literature.
- the carboxylic ester derivatives of the formula I can be reduced to the alcohol derivatives of the formula I by various processes known from the literature, which in turn can be converted to the acylated alcohol derivatives or to urethane or thiourethane derivatives of the formula I by various processes known from the literature.
- the free acid derivatives of the formula I can also be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization.
- suitable amounts of the corresponding inorganic bases for example, when the corresponding acids are dissolved in water which contains stoichiometric amounts of the base, after evaporation of the water or after the addition of a water-miscible solvent, for example alcohol or acetone, the solid salt is obtained.
- the amine salts can be prepared in the usual way.
- the corresponding acid is dissolved in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and one to five equivalents of the respective amine are added to this solution.
- a suitable solvent such as ethanol, acetone, diethyl ether or benzene
- the salt is usually obtained in solid form or is isolated in a customary manner after evaporation of the solvent.
- ⁇ -cyclodextrin The clathrates with ⁇ -, ⁇ - or ⁇ -cyclodextrin are obtained analogously to the procedure in WO-A-87/05294. ⁇ -cyclodextrin is preferably used. Liposomes are produced according to the method described in Pharmacy in Our Time, 11, 98 (1982).
- a mixture of 20 mmol of a 3-fluoro-4-nitro-phenol derivative is heated to 70 ° C. for four hours with 80 mmol of a primary amine without solvent. After cooling, the mixture is mixed with ethyl acetate / water cast. It is washed with saturated ammonium chloride solution, extracted with
- a solution of 1.85 mmol of the phenol derivative in 12 ml of NN-dimethylformamide is mixed with 1.85 mmol of cesium carbonate and 2.24 mmol of alkyl bromide or alkyl iodide.
- 1.85 mmol sodium iodide are optionally added.
- the mixture is stirred for 12 to 96 hours, then poured onto water, taken up in ethyl acetate, the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo.
- the reaction mixture can be mixed with dichloromethane, separated from the precipitated salts by filtration and the filtrate concentrated in vacuo. Regardless of the processing method, the residue is purified by crystallization or column chromatography on silica gel.
- the compound to be reduced is dissolved in ethyl acetate, tetrahydrofuran, methanol or ethanol or mixtures of the solvents and hydrogenated on 2 to 5% (based on the nitro compound) of palladium on carbon (10%) at normal pressure.
- the product is filtered off with suction, the residue is washed with ethyl acetate or methanol or ethanol, and the The filtrate was concentrated in vacuo.
- the raw product is usually implemented without further purification.
- 0.11 ml of a 2 normal trimethylaluminum solution [2 N in toluene] is added dropwise to a solution of 0.22 mmol of a primary or secondary amine in 2 ml of toluene at room temperature.
- the mixture is stirred for 15 minutes and then a solution of 0.2 mmol of the corresponding ester in 2 ml of toluene is added dropwise.
- the mixture is heated to 95 ° C. for 3 to 8 hours (depending on the conversion).
- the raw products are drawn up directly onto diatomaceous earth without further processing and separated by chromatography.
- N-Benzyl-5-methoxy-2-ni-troaniline is obtained as an orange solid.
- N-Benzyl-5-methoxy-2-nitroaniline is hydrogenated according to general procedure 3.
- N 2 -Benzyl-4-methoxybenzene-1, 2-diamine is obtained as a black oil.
- N 2 -Benzyl-4-methoxybenzene-1, 2-diamine is reacted with trimethyl orthobenzoate according to general working instructions 10 to give the benzimidazole.
- 1-Benzyl-6-methoxy-2-phenylbenzimidazole is obtained as a solid.
- 1-Benzyl-6-hydroxy-2-phenylbenzimidazole is obtained as a solid.
- 1-Benzyl-6-hydroxy-2-phenylbenzimidazole is alkylated according to general procedure 2 with 6-bromo-hexanoic acid methyl ester.
- 1-Benzyl-6 - [(5- (methoxycarbonyl) pentyl) oxy] -2-phenylbenzimidazole is obtained as a resin.
- 1-Benzyl-6-hydroxy-2-phenylbenzimidazole is alkylated according to general procedure 2 with 6-bromo-hexanoic acid isopropyl ester.
- 1-Benzyl-2-phenyl-6 - [(5 - (/ so-propyl-oxycarbonyl) pentyl) oxy] benzimidazole is obtained as a resin.
- 6- [3- (3-methoxypropylamino) -4-nitro-phenoxy] hexanoic acid methyl ester is hydrogenated according to general procedure 3. This gives 6- [3- (3-methoxypropylamino) -4-aminophenoxy] hexanoic acid methyl ester as a black oil.
- 6- [3- (3-methoxypropylamino) -4-aminophenoxy] hexanoic acid methyl ester is converted to tri-methyl orthobenzoate according to general procedure 10 to
- Example compound 65 6 [(5-carboxypentyl) oxy] -2- (fur-3-yl) -1- (3-methoxypropyl) benzimidazole
- 6- [3- (3,3-Diethoxypropyl) -4-nitro-phenoxy] hexanoic acid methyl ester is hydrogenated according to the general procedure 3. This gives 6- [3- (3,3-diethoxypropyl) -4-amino-phenoxy] hexanoic acid methyl ester as a black oil, d) 6- [3- (3,3-diethoxypropyl) -4-amino-phenoxy] hexanoic acid methyl ester with 4-methoxybenzaldehyde according to general working instructions 4 for
- benzimidazole 1- (3,3-Diethoxypropyl) -6 - [(5- (methoxycarbonyl) pentyl) oxy] -2- (4-methoxyphenyl) benzimidazole is obtained as a brown oil.
- e) 1- (3,3-Diethoxypropyl) -6 - [(5- (methoxycarbonyl) pentyl) oxy] -2- (4-methoxyphenyl) benzimidazole (13 mmol) are dissolved in 600 ml acetone. 33 ml of 6 N hydrochloric acid are added dropwise at room temperature.
- Example connection 91 The following example compounds 91, 95, 98 and 102 were prepared analogously to example 96 using the corresponding amines: Example connection 91
- Primary rat microglia are harvested from mixed glia cultures obtained from P3 rat brains. For the production of mixed
- FCS Serum
- FCS Serum incubated at 37 ° C and 5% CO2.
- a compound according to the invention is added in various concentrations (0.1, 0.3.1.3, and 10 ⁇ M).
- the metabolic activity is reduced by reducing MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3carboxymethoxyphenyl) -2- (sulfophenyl) -2H-tetrazolium), Owen's Reagent, Baltrop, JA et al., Bioorg. & Med. Chem. Lett, 1, 6111 (1991)).
- the percent inhibition refers to a control treated with DMSO only.
- the compounds according to the invention inhibit microglia activation.
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DE10134775A DE10134775A1 (de) | 2001-07-06 | 2001-07-06 | 1-Alkyl-2.aryl-benzimidazolderivate, deren Verwendung zur Herstellung von Arzneimitteln sowie diese Derivate enthaltende pharmazeutische Präparate |
PCT/EP2002/007597 WO2003004023A1 (de) | 2001-07-06 | 2002-07-06 | 1-alkyl-2-aryl-benzimidazolderivate, deren verwendung zur herstellung von arzneimitteln sowie diese derivate enthaltende pharmazeutische präparate |
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DE10207843A1 (de) * | 2002-02-15 | 2003-09-04 | Schering Ag | Mikrolia-Inhibitoren zur Unterbrechung von Interleukin 12 und IFN-gamma vermittelten Immunreaktionen |
AU2003257329C1 (en) | 2002-08-19 | 2010-07-22 | Lorus Therapeutics Inc. | 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents |
WO2004035549A1 (en) | 2002-10-17 | 2004-04-29 | Amgen Inc. | Benzimidazole derivatives and their use as vanilloid receptor ligands |
DK1692113T3 (en) | 2003-11-14 | 2018-01-08 | Lorus Therapeutics Inc | ARYLIMIDAZOLES AND USE THEREOF AS ANTICANCES |
DE102004026590A1 (de) * | 2004-06-01 | 2006-01-12 | Siemens Ag | Assistenzsystem für Kraftfahrzeuge |
ES2473597T3 (es) | 2005-05-25 | 2014-07-07 | Lorus Therapeutics Inc. | Derivados de 2-indolil imidazo[4,5-d]fenantrolina y su uso en el tratamiento del cáncer |
WO2010036908A1 (en) * | 2008-09-26 | 2010-04-01 | Eisai R & D Management Co., Ltd. | Use of benzoxazole compounds in the treatment of malaria |
US8354400B2 (en) | 2008-09-26 | 2013-01-15 | Eisai R&D Co., Ltd. | Benzoxazole compounds and methods of use |
ES2620177T3 (es) * | 2009-10-15 | 2017-06-27 | Guerbet | Agentes de formación de imágenes y su uso para el diagnóstico in vivo de enfermedades neurodegenerativas, particularmente la enfermedad de Alzheimer y enfermedades derivadas |
US9309247B2 (en) | 2013-03-20 | 2016-04-12 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
WO2015051302A1 (en) | 2013-10-04 | 2015-04-09 | Aptose Biosciences Inc. | Compositions and methods for treating cancers |
KR20180094989A (ko) * | 2015-12-15 | 2018-08-24 | 더 보드 오브 트러스티스 오브 더 리랜드 스탠포드 주니어 유니버시티 | 노화 관련 인지장애 및 신경염증의 예방 및/또는 치료 방법 |
JP2021501203A (ja) | 2017-10-30 | 2021-01-14 | アプトース バイオサイエンシズ インコーポレイテッド | がん治療用のアリールイミダゾール |
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US5552426A (en) * | 1994-04-29 | 1996-09-03 | Eli Lilly And Company | Methods for treating a physiological disorder associated with β-amyloid peptide |
EA006302B1 (ru) * | 2000-01-14 | 2005-10-27 | Шеринг Акциенгезельшафт | 1,2-диарилбензимидазолы для лечения заболеваний, связанных с активацией микроглии |
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