EP1372644A2 - Verwendung substituierter imidazo[1,2-a]-pyridin-3-yl-amid-und imidazo[1,2-a]-pyridin-3-yl-aminverbindungen als arzneimittel zur behandlung von neurodegenerativen erkrankungen - Google Patents

Verwendung substituierter imidazo[1,2-a]-pyridin-3-yl-amid-und imidazo[1,2-a]-pyridin-3-yl-aminverbindungen als arzneimittel zur behandlung von neurodegenerativen erkrankungen

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Publication number
EP1372644A2
EP1372644A2 EP02730112A EP02730112A EP1372644A2 EP 1372644 A2 EP1372644 A2 EP 1372644A2 EP 02730112 A EP02730112 A EP 02730112A EP 02730112 A EP02730112 A EP 02730112A EP 1372644 A2 EP1372644 A2 EP 1372644A2
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EP
European Patent Office
Prior art keywords
radical
unsubstituted
monosubstituted
general formula
aryl
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EP02730112A
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German (de)
English (en)
French (fr)
Inventor
Corinna Maul
Hagen-Heinrich Hennies
Bernd Sundermann
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of substituted imidazo [1, 2-a] pyridin-3-yl-amide and imidazo [1, 2-a] pyridin-3-yl-amine compounds and their physiologically tolerable salts as inhibitors for the Nitric oxide synthase and for the production of medicaments and a process for their preparation.
  • NO synthase nitrogen monoxide synthase
  • the medicinal products are said to be suitable for the treatment of migraines, septic shock, newly rodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis, fungal diseases or for wound healing.
  • substituted imidazo [1, 2-a] pyridin-3-yl amide and amine compounds of the general formula I below act as inhibitors on the nitrogen monoxide synthase and are particularly useful for the treatment of migraines and septic shock , neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis, fungal diseases or for wound healing.
  • the present invention therefore relates to the use of at least one substituted imidazo [1, 2-a] pyridin-3-yl amide or amine compound of the general formula I,
  • R 2 is an unsubstituted or at least monosubstituted ⁇ -d-alkyl radical, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C 2- 8 alkynyl radical, a C 3 -8- Cycloalkyl radical, one via a C- ⁇ .
  • R 4 for H, for an unsubstituted or at least monosubstituted
  • C ⁇ -8 alkyl radical an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C 3-8 -cycloalkyl radical, a C 3-7 - heterocyclyl radical, an unsubstituted or at least monosubstituted aryl or heteroaryl radical, an a C ⁇ -8 alkylene group bonded C 3-8 cycloalkyl radical, a via a C- ⁇ alkylene substituted aryl or heteroaryl radical bonded group C 3-7 heterocyclyl group, an a C ⁇ - 8 alkylene group bonded, unsubstituted or mono- or, preferably an unsubstituted or at least monosubstituted alkyl radical C ⁇ -8 or an unsubstituted or at least monosubstituted aryl or heteroaryl radical, particularly preferably an unsubstitute
  • R 5 is an unsubstituted or at least monosubstituted C ⁇ -8 alkyl group, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C 3 -8- Cycloalkyl radical, a C 3 bonded via a Ci- ⁇ -alkylene group.
  • R 6 is an unsubstituted or at least monosubstituted C- ⁇ -8 alkyl group, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C 3-8 cycloalkyl radical, a bound via a Ci- ⁇ alkylene group C 3-8 cycloalkyl radical, an unsubstituted or at least monosubstituted aryl or heteroaryl residue or an a C ⁇ -8 - alkylene group bonded unsubstituted or at least monosubstituted aryl or heteroaryl radical, preferably represents an unsubstituted or at least monosubstituted C ⁇ -8 alkyl radical or an unsubstituted or at least monosubstituted or at least monosubstituted aryl or heteroaryl radical, preferably represents an unsubstituted or
  • R 7 is an unsubstituted or at least monosubstituted C- ⁇ -8 alkyl group, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C3 - 8 cycloalkyl radical, an a C ⁇ -8 alkylene group bonded C 3-8 cycloalkyl radical, an unsubstituted or at least monosubstituted aryl or heteroaryl residue or an a C ⁇ -8 - alkylene group bonded unsubstituted or at least monosubstituted aryl or heteroaryl radical, preferably represents an unsubstituted or at least monosubstituted C ⁇ -8 alkyl radical or an unsubstituted or at least monosubstituted aryl or heteroaryl radical, preferably represents an unsubstituted or at least monosubstitute
  • R 8 is an unsubstituted or at least monosubstituted C ⁇ -8 alkyl group, an unsubstituted or at least monosubstituted C2-8 alkenyl radical, an unsubstituted or at least monosubstituted C2-8 alkynyl radical, a C 3 -8- Cycloalkyl radical, a C 3-8 -cycloalkyl radical bonded via a Ci- ⁇ -alkylene group, an unsubstituted or at least monosubstituted aryl or heteroaryl radical, one via a -C -8 alkylene group bound, unsubstituted or at least monosubstituted aryl or heteroaryl radical, preferably -8 alkyl radical, or substituted for an unsubstituted or at least monosubstituted aryl or heteroaryl radical is an unsubstituted or at least mono-substituted C ⁇ ,
  • Preferred -8- alkyl radicals are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso - pentyl, neo-pentyl, n-hexyl, 2-hexyl and n-octyl.
  • Preferred C 2-8 alkynyl radicals are selected from the group consisting of ethynyl, propynyl (-CH-C ⁇ CH, -C ⁇ C-CH 3 ), butynyl, pentynyl, hexynyl and octynyl.
  • the C ⁇ -8 alkyl radical, the C 2-8 alkenyl group or C 2-8 alkynyl moiety is present singly or multiply substituted, is (are) one or more hydrocarbon radical (s) preferably by a substituent selected from the group F, Cl, Br, I, CN, NH 2 , NH alkyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH alkyl heteroaryl, NH heterocyclyl, NH alkyl OH , N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2) SH, S-alkyl, S- Aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-heterocyclyl, S-alkyl-OH, S
  • C 3-8 cycloalkyl radical encompasses cyclic hydrocarbons having 3 to 8 carbon atoms, which may be saturated or unsaturated, unsubstituted or at least simply substituted, the bond of the cycloalkyl radical to the basic structure of general formula I can take place via any ring member of the cycloalkyl radical.
  • the C 3-8 cycloalkyl radical is preferably selected from the group cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • the C 3-8 cycloalkyl radical is particularly preferably a cyclohexyl radical.
  • C 3-7 heterocyclyl radical includes within the meaning of the present invention, a 3-, 4-, 5-, 6- or 7-membered cyclic organic radical which contains at least 1, optionally also 2, 3, 4 or has 5 heteroatoms in the ring system, where the heteroatoms may be the same or different and the cyclic radical may be saturated or unsaturated, but not aromatic and may be unsubstituted or at least monosubstituted.
  • the heterocyclyl radical can be bound to the basic structure of the general formula I via any ring member of the heterocyclyl radical.
  • the heterocyclyl residue can also be part of a bi- or polycyclic system. Preferred heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur.
  • the C 3-7 heterocyclyl moiety is selected from the group tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • aryl radical means aromatic hydrocarbons which can also be condensed with further saturated, at least partially unsaturated or aromatic ring systems, the bond between the aryl radical and the basic structure of the general formula I being via any ring member of the aryl residue can take place. If the aryl radical has more than one substituent, these can be the same or different and can be in any and possible position of the aryl radical.
  • the aryl radical is preferably selected from the group of unsubstituted or at least monosubstituted phenyl, anthracenyl, 1-naphthyl and 2-naphthyl.
  • the aryl radical is particularly preferably selected from the group of phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 2,3-dihydroxyphenyl, 2,3-dimethoxyphenyl and 1-naphthyl.
  • heteroaryl radical stands for a 5-, 6- or 7-membered cyclic aromatic radical which has at least 1, optionally also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or can be different and the binding to the basic structure of the general formula I can take place via any and possible ring member of the heteroaryl radical. If the heteroaryl radical has more than one substituent, these heteroaryl substituents can be the same or different and can be present in any and possible position of the heteroaryl.
  • the heterocycle can also be condensed with further saturated, at least partially unsaturated or aromatic ring systems. Preferred heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heteroaryl radical is preferably selected from the group of unsubstituted or at least monosubstituted pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indolyl, indazolyl, purinyl, pyrimidinyl, indolizinyl, quinolinyl, isoquinol Quinazolinyl, carbazolyl, phenazinyl and phenothiazinyl.
  • heteroaryl radicals are selected from the group pyridin-2-yl, pyridin-3-yl, furan-2-yl, furan-3-yl, 5-hydroxymethylene-furan-2-yl, 5-nitro-furan 2- yl, 5- [1,3] dioxolane-furan-2-yl, 5-carboxylic acid furan-2-yl, thien-2-yl (2-thiophene), thien-3-yl (3-thiophene ) and 5-carboxylic acid-2-thiophene (5-carboxylic acid thien-2-yl).
  • the C 3-8 cycloalkyl, the C 3-7 heterocyclyl, the aryl or the heteroaryl radical is mono- or polysubstituted, we preferably include one or more, for example two, three or four times, Substitution of one or more hydrogen atoms of the ring system with a substituent selected from the group F, Cl, Br, I, CN, NH 2 , NH alkyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH alkyl heteroaryl , NH-heterocyclyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (heterocyclyl) 2 , N (alkyl-OH) 2 , NO, NO 2 , SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-
  • substituents particularly preferred substituents are selected from the group F, CF 3 , OH and O-CH 3 .
  • substituents are selected from the group OH, O-CH 3 , CH 2 OH, NO 2 , CO 2 H, CO 2 ethyl and [1, 3] -dioxolane.
  • cycloalkyl radicals particularly preferred substituents are CO 2 H or CO 2 ethyl.
  • the use of the compound 7-methyl-2-thiophene-3-yl-imidazo [1, 2-a] pyrididin-3-yl-amine or a physiologically tolerable salt, preferably the corresponding hydrochloride, as an inhibitor for the is very particularly preferred nitric oxide synthase.
  • the substituted imidazo [1, 2-a] pyridin-3-yl-amide and amine compounds of the general formula I or their physiologically tolerable salts have at least one center of asymmetry, they can be used in the form of their racemates, their pure enantiomers , their pure diastereomers or in the form of a mixture of at least two of the aforementioned stereoisomers.
  • substituted imidazo [1,2-a] pyridin-3-yl amide and amine compounds of the general formula I can also be present in the form of a mixture of their enantiomers or diastereomers. These mixtures can have two or more of the respective stereoisomers in any mixing ratio.
  • Chiral substituted imidazo [1, 2-a] pyridin-3-yl amide or amine compounds of the general formula I are preferably used in enantiomerically pure form.
  • the present invention further provides a process for the preparation of substituted imidazo [1, 2-a] pyridin-3-yl-amine compounds of the general formula I given above, in which the radical R 3 is H and the radicals R 1 , R 2 and R 4 to R 7 have the meaning according to the general formula I given above, by at least one substituted 2-aminopyridine of the general formula
  • radicals R 1 and R 2 have the meaning according to the general formula I given above, in solution with at least one aldehyde of the general formula III,
  • radical R 4 has the meaning according to the general formula I, and at least one alkali metal cyanide reacted with microwave radiation and the compounds of the general formula I thus obtained in which the radical R 3 is H and the radicals R 1 , R 2 and R 4 to R 7 have the meaning according to the general formula I, if necessary, are purified by conventional methods known to the person skilled in the art and optionally isolated.
  • the power at which the microwaves are radiated and the frequency of the microwaves radiated in can vary over a wide range.
  • Microwaves are preferably irradiated with an output of 100 to 1200 watts, particularly preferably 100 to 250 watts.
  • the frequency of the irradiated microwaves is preferably in the range from 850 to 22250 MHz, particularly preferably in the range from 915 ⁇ 25 MHz, 2450 ⁇ 13MHz, 5800 ⁇ 75 MHz or 22125 ⁇ 125 MHz.
  • the reaction time for carrying out the process according to the invention can vary depending on a large number of parameters, for example the type of the particular compounds of the general formula II or III, the type of solvent or the reaction temperature.
  • the optimum reaction time in each case can be determined by a person skilled in the art by simple preliminary tests.
  • the reaction takes place at a temperature up to at most the boiling point of the solvent or solvent mixture used.
  • the reaction or solvent mixture is particularly preferably carried out under reflux.
  • the time at which the radiation of the microwaves begins and the duration of the microwave radiation can also vary.
  • at least one substituted 2-aminopyridine of the general formula II and at least one aldehyde of the general formula III are first reacted with one another with irradiation with microwaves, the reaction mixture thus obtained is cooled and then with at least one alkali metal cyanide, if appropriate at elevated temperature implemented.
  • a substituted 2-aminopyridine of the general formula II, an aldehyde of the general formula III and an alkali metal cyanide are reacted with one another in equimolar amounts.
  • aldehydes of the general formula III given above can be used both in pure form and in the form of their addition compounds, in particular in the form of their bisulfite adducts.
  • the alkali metal cyanide used in the process according to the invention is preferably potassium cyanide, sodium cyanide or mixtures thereof, particularly preferably potassium cyanide.
  • the process according to the invention for the preparation of substituted imidazo [1, 2-a] pyridin-3-yl-amine compounds of the general formula I given above, in which the radical R 3 is H and the radicals R 1 , R 2 and R 4 to R 7 have the meaning according to the general formula I can be carried out both in non-polar and in polar solvents, it being possible for the polar solvents to be both protic and non-protic. Mixtures of the abovementioned solvents can also be used.
  • Water or a water-based solvent mixture is preferably used as the solvent in the process according to the invention.
  • the process according to the invention can be carried out both under normal pressure and under reduced or increased pressure. It can preferably be carried out at elevated pressure, particularly preferably at a pressure of up to 3 bar.
  • substituted 2-aminopyridines of the general formula II and the aldehydes of the general formula III are generally available on the market or can be prepared by customary methods known to the person skilled in the art.
  • the present invention also relates to a process for the preparation of substituted imidazo [1, 2-a] pyridin-3-yl amide compounds of the general formula I given above, in which the radical R 3 is SO 2 R 8 and the R 1 , R 2 and R 4 to R 8 have the meaning according to the general formula I by at least one compound of the general formula I in which the radical R 3 is H and the radicals R 1 , R 2 and R 4 to R 7 have the meaning according to the general formula I, with at least one compound of the general formula R 8 -SO 2 -OH, R 8 -SO 2 -X or R 8 -SO 2 -O-SO 2 -R 8 , in which X represents Cl, Br or I and the radical R 8 each has the meaning according to the general formula I, to give a compound of the general formula I in which the radical R 3 represents SO 2 R 8 and the radicals R 1 , R 2 and R 4 to R 8 have the meaning according to the general formula I and, if necessary, they have been converted by customary methods
  • a non-polar, a polar, protic or a polar, non-protic solvent can preferably be used as the solvent.
  • the temperature can vary over a wide range.
  • the temperature is preferably 0 to 300 ° C., particularly preferably 5 to 250 ° C.
  • the substituted imidazo [1, 2-a] pyridin-3-yl-amine and amide compounds can be prepared in high yield and within short reaction times by the process according to the invention.
  • the compounds obtained by the process according to the invention are furthermore distinguished by a high purity, so that the process according to the invention is excellently suitable for the preparation of substance libraries by combinatorial chemistry.
  • the substituted imidazo [1, 2-a] pyridin-3-yl-amide and amine compounds of the general formula I according to the invention can be isolated by the process according to the invention both in the form of the free base and as a salt.
  • amine compound of the general formula I is usually obtained after its preparation by the process according to the invention described above and, if appropriate, subsequent workup by customary methods known to the person skilled in the art.
  • the free base of the respective imidazo [1, 2-a] -pyridin-3-yl-amide or amine compound of the general formula I thus obtained or formed in-situ without isolation can then, for example by reaction with an inorganic or organic Acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid, converted into the corresponding, physiologically compatible become.
  • the conversion of the respective imidazo [1, 2-a] pyridin-3-yl amide or amine compound of the general formula I into the corresponding hydrochloride can preferably also be carried out by adding a suitable organic solvent, such as, for example, butan-2- on (methyl ethyl ketone), dissolved compound of general formula I can be obtained as a free base with trimethylsilyl chloride (TMSCI).
  • a suitable organic solvent such as, for example, butan-2- on (methyl ethyl ketone)
  • TMSCI trimethylsilyl chloride
  • substituted imidazo [1, 2-a] pyridin-3-yl amide and amine compounds of the general formula I according to the invention can be obtained in the form of their racemates or other mixtures of their various enantiomers and / or diastereomers by the preparation process according to the invention these are separated and, if necessary, isolated by customary methods known to those skilled in the art. Examples include chromatographic separation processes, in particular liquid chromatography processes under normal pressure or under elevated pressure, preferably MPLC and HPLC processes, and processes of fractional crystallization. Individual enantiomers, e.g. diastereomeric salts formed by HPLC on a chiral phase or by crystallization with chiral acids, such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10-camphorsulfonic acid.
  • chiral acids such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10-camphorsulfonic acid.
  • Another object of the present invention is the use of at least one substituted imidazo [1, 2-a] pyridin-3-yl amide or amine compound of the general formula I as an inhibitor for the nitrogen monoxide synthase for the production of a medicament for the treatment of Migraines, septic shock, neurodegenerative diseases, preferably multiple sclerosis, Parkinson's disease, Alzheimer's or Huntington's disease, inflammation, inflammation pain, cerebral ischemia, diabetes, meningitis, arteriosclerosis, fungal diseases or for wound treatment.
  • the present invention also relates to the use of at least one substituted imidazo [1, 2-a] pyridin-3-yl amide or amine compound of the general formula I for the manufacture of a medicament for combating migraines, septic shock, neurodegenerative diseases, preferably multiple sclerosis, Parkinson's disease, Alzheimer's disease or Huntington's disease, Inflammation, inflammation pain, cerebral ischemia, diabetes, miningitis, arteriosclerosis, fungal diseases or for wound treatment.
  • the corresponding pharmaceuticals can be in the form of liquid, semi-solid or solid pharmaceutical forms, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, patches, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, Aerosols or in multiparticulate form, for example in the form of pellets or granules, are present and can also be administered as such.
  • the medicaments according to the invention usually contain further physiologically tolerable pharmaceutical auxiliaries, which can preferably be selected from Group consisting of customary carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically tolerable pharmaceutical auxiliaries can preferably be selected from Group consisting of customary carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically compatible excipients and the amounts to be used depends on whether the medicinal product is oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local, for example on infections on the skin or mucous membranes and to be applied to the eyes.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferably suitable for oral administration, and solutions, suspensions, easily reconstitutable dry preparations and sprays are suitable for parenteral, topical and inhalative administration.
  • the amount of the particular imidazo [1, 2-a] -pyridin-3-yl-amide or amine compound to be administered to the patient may vary and is dependent, for example, on the weight or age of the patient and on the Type of application, the indication and the severity of the disease.
  • 0.1 to 5000 mg / kg, preferably 1 to 500 mg / kg, particularly preferably 2 to 250 mg, per kg body weight of the patient are usually at least one imidazo [1, 2-a] -pyridin-3-yl-amide or -amin compound of general formula I applied.
  • This assay allows the percentage inhibition of NO synthase by a compound of the general formula I according to the invention to be determined by measuring the NOS activity when the compound acts. NO synthase is mixed together with radioactively labeled arginine and the respective compound of general formula I under suitable conditions. After stopping the NO formation reaction at a given point in time, the amount of unreacted arginine is determined directly or indirectly. The comparison of this amount with the amount of arginine remaining in a mixture of NOS and arginine remaining in a mixture of NOS and arginine without addition of a compound according to the invention and under otherwise identical conditions gives the percentage inhibition of NO synthase through the tested compound.
  • This assay can be carried out as follows:
  • the separation takes place via a filter plate membrane.
  • This NOS assay is particularly suitable for high throughput screening (HTS) on microtiter plates (MTP).
  • HTS high throughput screening
  • MTP microtiter plates
  • Radioactive arginine is used as the substrate in this HTS-NOS assay.
  • the assay volume can be selected between 25 ⁇ l and 250 ⁇ l depending on the type of microtiter plate (MTP).
  • MTP microtiter plate
  • cofactors and coenzymes are added.
  • the batches are incubated in this microtiter plate (assay MTP) according to step (a) at room temperature and, depending on the enzyme activity (units) used, is between 5 and 60 minutes.
  • the plate is placed in a cell harvester, which is equipped with an MTP that has a cation exchange membrane as a filter base (filter MTP).
  • NADPH tetrasodium salt
  • Order No. 1585363 R ⁇ CHE company
  • Enzyme preparation buffer 50 mM Tris-HCl with 1 mM EDTA: The pH of the
  • Buffer was set to 7.4 at 4 ° C.
  • Incubation buffer 50 mM HEPES with 1 mM EDTA; 1, 25 mM CaCl 2 and 1 mM dithiothreitol.
  • the pH of the buffer was adjusted to 7.4 at 25 ° C.
  • Rat cerebelli were used as the starting tissue. The animals were anesthetized and sacrificed, the brain tissue, the cerebellum, was dissected out, 1 ml of enzyme preparation buffer (4 ° C.) was added per rat cerebellum, and the mixture was digested with a Polytron homogenizer for 1 min at 6000 rpm. This was followed by centrifugation at 4 ° C for 15 min at 20,000 g and then decanting off the supernatant and portioned freezing at -80 ° C (discarding the precipitate). incubation:
  • the content of the assay MTP was then transferred into a 96-well cation exchanger MTP (filter MTP) with the aid of a 96-well cell harvester and suctioned off.
  • a one-time wash with 200 ml H O (from one
  • the plate was then dried in a drying cabinet at 60 ° C. for 1 h. Then the bottom side of the filter MTP was sealed exactly from below with a "back seal”. Then 35 ⁇ l scintillator were pipetted in per well. Furthermore, the top of the plate was sealed with a "top seal”. After a waiting time of 1 hour, the plate was measured on the ß counter.
  • the substituted 2-aminopyridine of the general formula II was placed in water in a three-necked flask, an equimolar amount of the bisulfite adduct of the aldehyde of the general formula III was added and the mixture was heated under reflux for two hours while irradiating with microwaves.
  • the reaction mixture was cooled to a temperature of 20 to 25 ° C and treated with an equimolar amount of aqueous potassium cyanide solution.
  • the reaction mixture was then stirred for three hours at a temperature of 20 to 25 ° C and then overnight at 50 ° C.
  • reaction mixture was optionally first filtered.
  • the filtrate was then extracted with dichloromethane and diethyl ether, the combined extracts dried over sodium sulfate and concentrated.
  • the crude product thus obtained was dissolved in 2-butanone, precipitated by adding half a molar equivalent of water followed by 1.1 equivalents of chlorotrimethylsilane and then stirring overnight.
  • the primary amine prepared according to general procedure I was mixed with 20 equivalents of acetic anhydride in a Teflon vessel. The jar was capped and treated with 800 watts in the microwave for five to sixty minutes so that the temperature did not exceed 100 ° C. After cooling to 20 to 25 ° C, the reaction solution was poured into ice-cold, approximately five percent potassium carbonate solution and extracted with dichloromethane. The organic phase thus obtained was dried over sodium sulfate and / or potassium carbonate and concentrated. The crude product thus obtained was purified by column chromatography on silica gel and the corresponding hydrochloride was then precipitated in accordance with general working instructions I.
  • Example 1 Example 1 :
  • Example 1 The compound prepared according to Example 1 was tested in the HTS-NOS assay as described above. The inhibition of nitrogen monoxide synthase (10 ⁇ M) by the compound according to the invention according to Example 1 was 89%.

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EP02730112A 2001-04-05 2002-04-05 Verwendung substituierter imidazo[1,2-a]-pyridin-3-yl-amid-und imidazo[1,2-a]-pyridin-3-yl-aminverbindungen als arzneimittel zur behandlung von neurodegenerativen erkrankungen Withdrawn EP1372644A2 (de)

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DE10117184 2001-04-05
DE10117184A DE10117184A1 (de) 2001-04-05 2001-04-05 Substituierte Imidazol[1,2-a]-pyridin-3-yl-amid- und -aminverbindungen
PCT/EP2002/003796 WO2002080911A2 (de) 2001-04-05 2002-04-05 Verwendung substituierter imidazo[1,2-a]-pyridin-3-yl-amid- und imidazo[1,2-a]-pyridin-3-yl-aminverbindungen als arzneimittel zur behandlung von neurodegenerativen erkrankungen

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DE10310106A1 (de) 2003-03-06 2004-09-16 Grünenthal GmbH Substituierte Pyridot [1,2-a]pyrimidin-Verbindungen
DE102004021716A1 (de) * 2004-04-30 2005-12-01 Grünenthal GmbH Substituierte Imidazo[1,2-a]pyridin-Verbindungen und Arzneimittel enthaltend substituierte Imidazo[1,2-a]pyridin-Verbindungen
DE102004044884A1 (de) * 2004-09-14 2006-05-24 Grünenthal GmbH Substituierte bizyklische Imidazo-3-yl-amin-Verbindungen
WO2007075869A2 (en) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Bicyclic heteroaryl compounds
FR2903107B1 (fr) 2006-07-03 2008-08-22 Sanofi Aventis Sa Derives d'imidazopyridine-2-carboxamides, leur preparation et leur application en therapeutique
FR2903105A1 (fr) 2006-07-03 2008-01-04 Sanofi Aventis Sa Derives de 2-benzoyl-imidazopyridines, leur preparation et leur application en therapeutique
FR2903108B1 (fr) * 2006-07-03 2008-08-29 Sanofi Aventis Sa Utilisation de derives d'imidazo[1,2-a] pyridine-2-carboxamides en therapeutique.

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CA1164459A (en) * 1980-11-11 1984-03-27 Yung-Hsiung Yang Process for preparing (imidazo¬1,2-a|pyridine- 2-yl)-carbostyril or -3,4-dihydrocarbostyryl derivatives
DE3269604D1 (en) * 1981-06-26 1986-04-10 Schering Corp Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them
FR2638161B1 (fr) * 1988-10-24 1991-01-11 Centre Nat Rech Scient Nouvelles benzoyl-2 imidazo (1,2-a) pyridines et leurs sels, leur procede de preparation, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant
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JP2004531512A (ja) 2004-10-14
CA2442986A1 (en) 2002-10-17
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