EP1379502A1 - Ligands du recepteur nicotinique de l'acetylcholine - Google Patents

Ligands du recepteur nicotinique de l'acetylcholine

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Publication number
EP1379502A1
EP1379502A1 EP02732477A EP02732477A EP1379502A1 EP 1379502 A1 EP1379502 A1 EP 1379502A1 EP 02732477 A EP02732477 A EP 02732477A EP 02732477 A EP02732477 A EP 02732477A EP 1379502 A1 EP1379502 A1 EP 1379502A1
Authority
EP
European Patent Office
Prior art keywords
formula
methyl
benzyl
compounds
hept
Prior art date
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Application number
EP02732477A
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German (de)
English (en)
Inventor
Kai Schiemann
Joachim Leibrock
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Merck Patent GmbH
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Merck Patent GmbH
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Publication date
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Publication of EP1379502A1 publication Critical patent/EP1379502A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61P25/14—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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • Nicotinic acetylcholine receptor ligands Nicotinic acetylcholine receptor ligands
  • the invention relates to (2-azabicyclo [2.2.1] hept-7-yl) methyl and (2-
  • AB is a single or a double bond, XO, NR 3 or S, R 1 is hydrogen, A, Ar, arylalkyl, Het, C (O) -R 4 , SO 2 -R 4 , C (S) N (R 4 ) 2 or COOR 4 ,
  • R 2 A Ar, arylalkyl, Het, C (0) -R 4 , SO 2 -R 5 , C (S) N (R 5 ) 2 or
  • R 3 to R 5 each independently of one another are hydrogen, A, cycloalkyl,
  • R 6 is hydrogen or A
  • a linear or branched alkyl group with 1 to 10 carbon atoms is A linear or branched alkyl group with 1 to 10 carbon atoms
  • Phenyl, naphthyl or biphenyl Phenyl, naphthyl or biphenyl
  • Ring members where 1 to 4 N and / or 1 to 4 S and / or 1 to 4 O atoms can be present and the heterocyclic radical once, twice or three times by shark, A, - [C (R 6 ) 2 ] 0 -Ar, - [C (R 6 ) 2 ] 0 -cycloalkyl, OR 6 , N (R 6 ) 2 , N0 2 , CN, COOR 6 , CON (R 6 ) 2 , NR 6 COA, NR 6 CON (R 6 ) 2 , NR 6 SO 2 A, COR 6 , SO 2 NR 6 or 5 (0),.
  • ⁇ And / or carbonyl oxygen may be substituted, Het 1 3-methyl-2,5-dioxopyrrolidin-1-yl or 1, 3-dioxo-1, 3-dihydro-isoindol-2-yl, m is 1 or 2, o 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds have a central nervous system.
  • the compounds are nicotinic acetylcholine receptor ligands.
  • acetylcholine receptors responsible for the nervous system.
  • active ingredients that can interact with the class of acetylcholine receptors are, for example, pilocarpine, nicotine, lobeline and epibatidine. These nicotinic acetylcholine receptors can be divided into two principal classes, depending on the locations where they occur.
  • neuromuscular receptors there are the neuromuscular receptors. These are further divided into (cqc ⁇ ß ⁇ ) and ( ⁇ ⁇ ß ⁇ ) receptors.
  • neuronal nicotinic acetylcholine receptors that are found in the ganglia.
  • ( ⁇ 2 - ⁇ 5 ) receptors and the ( ⁇ 2 - ⁇ 9 ) receptors, see also “Basic Neurochemistry”, Ed. Siegel et. Al., Raven Press, New York 1993.
  • the substances of the formula I are able to interact with each of these receptors. They interact particularly well
  • An in vitro detection of the interaction with the nicotinic ⁇ 7 receptor can, for example, analogously to ÜM. Ward et al, FEBS 1990, 270, 45-48 or DRE Macallan, FEB 1998, 226, 357-363. Further in vitro tests for nicotinic receptors are in FE D'Amour et al, Manual for Laboratory Work in Mammalian Physiology, 3rd Ed., The University of Chicago Press (1965), W. Sihver et al, Neuroscience 1998, 85, 1121 -1133 or B. Latli et al, J. Med. Chem. 1999, 42, 2227-22234.
  • Diseases that can be treated with the substances according to formula I include schizophrenia, depression, anxiety, dementia, in particular Alzheimer's disease and Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory restrictions, Age-related memory loss, relief from Withdrawal symptoms from nicotine addiction. Due to the neuroprotective effect, compounds of the formula I are used for strokes and damage to the brain by toxic compounds.
  • the invention relates to the compounds of the formula I and their physiologically acceptable acid addition salts.
  • the invention also relates to the solvates, e.g. Hydrates or alcoholates, this one
  • Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or addition compounds with alcohols, e.g. with methanol or ethanol.
  • the compounds of the formula I have at least one asymmetric carbon atom which can have different configurations. They can therefore be present in various optically active forms or as racemates. In the case of the compounds of the formula I, there are stereoisomers due to the bridgehead carbon atom, which are referred to as endo- or exo-isomers. Exo-isomers are compounds of formula I on which the substituent, ie -CH 2 -XR 2 , is further removed from the functional group NR 1 .
  • the invention relates to the compounds of the formula I and their salts and solvates according to Claim 1 and to a process for the preparation of compounds of the formula I and their salts and solvates, characterized in that a) a compound of the formula II
  • R 4 has the meaning given in claim 1, where free amino or hydroxyl groups are protected during the reaction and the protective groups are cleaved off after esterification and L is Cl, Br, I or a free or reactive functional OH group and the rest R optionally converts to a radical R 1 , where R 1 has the meaning given in claim 1, or b) a compound of the formula II wherein AB represents a single or a double bond, X NR 3 ,
  • R 3 has the meaning given in claim 1 and
  • L denotes Cl, Br, I or a free or reactive functional OH group, reacted and optionally converting the radical R into a radical R 1 , where R has the meaning given in claim 1, or c) a compound of the formula II
  • R 3 has the meaning given in claim 1 and
  • R 5 has the meaning given in claim 1 implemented and optionally converting the radical R into a radical R 1 , where R 1 has the meaning given in claim 1, or d) optionally one of the radicals R, R 1 and / or a substituent of the aryl group into another radical R, R 1 and / or a substituent of
  • Aryl group converted for example by cleaving an OA group to form an OH group and / or converting a CHO group into a CN group and / or hydrogenating a benzyl group and / or a base of the formula I obtained by treatment with an acid converted into one of their salts.
  • the invention also relates to the compounds of the formula I according to claim 1, and to their physiologically acceptable salts and solvates as active pharmaceutical ingredients.
  • the invention also relates to the compounds of the formula I according to claim 1 and their physiologically acceptable salts or solvates as ligands of the nicotinic acetylcholine receptor.
  • A-B represents a single or a double bond, with the single bond being preferred.
  • X represents O, NR 3 or S, where R 3 has one of the meanings mentioned below.
  • O and NH are particularly preferred for X.
  • A means linear or branched alkyl having 1 to 10 C atoms and preferably has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
  • Alkyl having 1 to 10 carbon atoms is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, and also also n-pentyl, 1-, 2- or 3-methylbutyl , n-hexyl, 1-, 2-, 3- or 4-methylpentyl, n-heptyl, n-octyl, n-
  • Nonyl or n-decyl is particularly preferred.
  • Ar means unsubstituted or one or more times by shark, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, COOR 6 , CON (R 6 ) 2 , NR 6 COR 6 , NR 6 CON (R 6 ) 2 , NR 6 S0 2 A,
  • Ar is preferably unsubstituted or substituted phenyl, naphthyl or biphenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p- isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-aminophenyl, o-, m- or p- Hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p- (trifluoromethoxy) phenyl, o-, m- or p-cyanophenyl, o-, m- or p-
  • Ar is particularly preferred phenyl, o-aminophenyl, p-methoxyphenyl, 2-amino-5-bromophenyl, 2-amino-5-fluorophenyl, 2-amino-5-chlorophenyl, 2-amino-3-methylphenyl, 2-amino- 5-nitrophenyl, 2-amino-4,5-dimethoxyphenyl, 3-methyl-2,5-dioxopyrrolidin-1-phenyl, 5-fluoro-2- (3-methyl-2,5-dioxo -pyrrolidin-1 -yl) -phenyl, 5-bromo-2- (3-methyl-2,5-dioxopyrrolidin-1 -yl) - phenyl, 2- (3-methyl-2,5-dioxopyrrolidin-1-yl) -5-nitrophenyl, 4-chloro-2- (3-methyl-2,5-dioxopyrrolidin-1-yl)
  • Arylalkyl with 7 to 14 carbon atoms preferably means benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,
  • Arylalkyl benzyl is particularly preferred.
  • Cycloalkyl with 3 to 10 carbon atoms preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cycloalkyl also means mono- or bicyclic terpenes, preferably p-menthan, menthol, pinan, bornan or camphor, including any known stereoisomeric form or adamantyl. For campers, this means both L-campers and D-campers.
  • Shark means fluorine, chlorine, bromine or iodine, particularly preferably fluorine, chlorine or bromine.
  • Het means a saturated, unsaturated or aromatic mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 to 4 N and / or 1 to 4 S and / or 1 to 4 O atoms can be present and the heterocyclic radical is one -, two or three times by shark, A, - [C (R 6 ) 2 ] 0 -Ar, - [C (R 6 ) 2 ] 0 -cycloalkyl, OR 6 , N (R 6 ) 2 , NO 2 , CN, COOR 6 , CON (R 6 ) 2 , NR 6 COA, NR 6 CON (R 6 ) 2 , NR ⁇ OA COR 6 , SO 2 NR 6 or 5 (0) ⁇ and / or carbonyl oxygen can be substituted, where A, shark, ar and Cycloalkyl have one of the meanings given above and R 6 , o and m have the meaning given below.
  • Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4 -Pyhdyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, - 4 or -5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl 1, 2,4-oxadiazol-3- or -5-yl, 1, 3,4 -Thiadiazol-2- or -5-yl, 1, 2,4-
  • Benzoxazolyl 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 4- or 5-benzothiadiazolyl, 2-, 4-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8 -Chinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
  • heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro -2- or -3-furyl, 1, 3- dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5
  • Het 1 means 3-methyl-2,5-dioxopyrrolidin-1-yl or 1,3-dioxo-1,3-dihydro-isoindol-2-yl.
  • R 1 represents hydrogen, A, Ar, arylalkyl, het, C (0) -R 4 , SO 2 -R 4 , C (S) N (R 4 ) 2 or COOR 4 , where A, Ar, arylalkyl and Het are one have the meanings mentioned above and R 4 has one of the meanings mentioned below.
  • R 1 is preferably hydrogen, A or arylalkyl.
  • R 1 is particularly preferably arylalkyl.
  • R 2 represents A, Ar, arylalkyl, Het, C (O) -R 4 , SO 2 -R 5 , C (S) N (R 5 ) 2 or COOR 4 , where A, Ar, arylalkyl and Het are one of the previously have meanings mentioned and R 4 and R 5 have one of the meanings mentioned below.
  • R 1 is preferably A, C (0) -R 4 , SO 2 -R 5 or C (S) N (R 5 ) 2 .
  • R 2 is particularly preferably C (O) -R 4 , where R 4 has one of the meanings mentioned below.
  • R 2 is particularly preferably C (0) -R 4 or S0 2 -R 5 , where R 4 and R 5 have one of the meanings mentioned below.
  • R 3 to R 5 each independently represent hydrogen, A, cycloalkyl, ar or arylalkyl, where A, cycloalkyl, ar or arylalkyl have one of the meanings mentioned above.
  • R 3 is preferably hydrogen or alkyl having 1 to 10 carbon atoms, as described above.
  • R 3 is particularly preferably hydrogen.
  • R 4 is preferably Ar or cycloalkyl, as previously described.
  • R 4 is particularly preferably phenyl, o-aminophenyl, p-methoxyphenyl, 2-amino-5-bromophenyl, 2-amino-5-fluorophenyl, 2-amino-5-chlorophenyl, 2-amino-3-methylphenyl, 2-amino -5-nitrophenyl, 2-amino-4,5-dimethoxy-phenyl, 3-methyl-2,5-dioxopyrrolidin-1-yl-phenyl, 5-fluoro-2- (3-methyl-2,5- dioxopyrrolidin-1 -yl) phenyl, 5-bromo-2- (3-methyl-2,5-dioxopyrrolidin-1 -yl) phenyl, 2- (3-methyl-2,5-dioxo- pyrrolidin-1-yl) -5-nitrophenyl, 4-chloro
  • R 6 represents hydrogen or alkyl having 1 to 10 carbon atoms, as described above.
  • R 6 is preferably hydrogen, methyl or ethyl.
  • R represents A, Ar, arylalkyl, het, C (O) -R 4 , SO 2 -R 4 , C (S) N (R 4 ) 2 , COOR 4 or an amino protecting group, wherein A, Ar, arylalkyl, het and R 4 has one of the meanings described above and the amino protecting group has one of the meanings mentioned below.
  • R denotes benzyl, methyl, tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) or benzoyl.
  • m is 1 or 2, particularly preferably 2.
  • o is 0, 1, 2, 3 or 4, particularly preferably 0 or 1.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • Ic R 1 is hydrogen, A, or arylalkyl
  • R 2 is A or C (O) R 4 , SO 2 R 5 or C (S) N (R 5 ) 2 ;
  • R 4 represents A, Ar or cycloalkyl
  • R 1 is hydrogen or arylalkyl
  • R 4 Ar or cycloalkyl
  • R 5 represents hydrogen or arylalkyl
  • R 5 represents arylalkyl
  • R 1 is hydrogen or arylalkyl
  • R 4 Ar or cycloalkyl
  • R 5 represents hydrogen or arylalkyl
  • R 5 means arylalkyl
  • the invention relates in particular to the compounds a) 2-amino-5-bromo-benzoic acid (2'-benzyl-2'-azabicyclo [2.2.1] hept-7'-yl-methyl) ester, b) 2- Benzyl-7-methoxymethyl-2-azabicyclo [2.2.1] heptane, c) cyclopropanecarboxylic acid (2'-benzyl-2'-azabicyclo [2.2.1] hept-7'-ylmethyl) ester, i.e.
  • Manufacture is otherwise produced according to methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; ) are described, namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • the starting materials for the claimed process can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I. On the other hand, it is possible to carry out the reaction in stages.
  • the radical L is preferably Cl or Br; however, it can also mean I, OH or, preferably, a reactively modified OH group, in particular alkylsulfonyloxy with 1-6 (for example methanesulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalene sulfonyloxy) or also trichloromethoxy, alkoxy, such as methoxy, ethoxy, propoxy or butoxy, and also phenoxy.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or synthesis sequence), their type and size is otherwise not critical; however, those with 1-20 C atoms are preferred.
  • acyl group is in
  • acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxy carbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (aloe),
  • Aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr).
  • Preferred amino protecting groups are Boc, Fmoc and aloe, furthermore Z and acetyl.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkyl groups, alkyl, aryl or aralkylsilyl groups or 0.0- or 0, S-acetals.
  • the nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or synthesis sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, Alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene, cyclopentylidene, cyclopentylidene, cyclopentyl Me
  • Activated acids of formula III are commercially available or can be easily analogous to conditions known to those skilled in the art
  • Formula III is an esterification. Reaction conditions of an esterification are known to the person skilled in the art.
  • an acid chloride of the formula III can be reacted with an alcohol of the formula II in the presence of a base at temperatures between 0 ° and 100 ° C., preferably between 20 ° and 50 ° C.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, N-methyl-pyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon dis
  • Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • NR 6 CON (R 6 ) 2 , NR 6 S0 2 A, COR 6 , S0 2 NR 6 , S (0) means, where R 6 represents hydrogen or alkyl having 1 to 10 carbon atoms, as described above , When esterified under the conditions specified above free amino or hydroxy groups must be protected during the reaction. After esterification, the protective groups can be split off and the substituent R can optionally be converted into a radical R 1 , where R 1 can have the meaning given in claim 1.
  • RA Ar, arylalkyl, Het, C (0) -R 4 , S0 2 -R 4 , C (S) N (R 4 ) 2 , COOR 4 or an amino protecting group, D Hai, A, OR 6 , N (R 6 ) 2 , N0 2 , CN, COOR 6 , CON (R 6 ) 2 , NR 6 COR 6 ,
  • NR 6 CON (R 6 ) 2 , NR 6 S0 2 A, COR 6 , S0 2 NR 6 or and R 6 is hydrogen or alkyl having 1 to 10 carbon atoms, with a compound of the formula VI or VII
  • the reaction temperature is between about 30 ° and 150 °, preferably between 60 ° and 100 °.
  • the reaction time is between a few minutes and several days depending on the conditions used.
  • the reaction preferably takes place in the presence of a base.
  • the reaction conditions of this sulfonation are known to the person skilled in the art, for example according to P. Pinho et al., Chem. Commun. 1999, 7, 597-598.
  • the reaction preferably takes place in the presence of a base.
  • the reaction conditions of this reaction are known to the person skilled in the art, for example according to F. Fueloep et al, Chem. Ber. 1990, 123, 803-809.
  • the base can be, for example, an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or
  • Bases which are bound to a polymeric carrier are also particularly suitable, for example tris (2-aminoethyl) amine polystyrene (NovaBiochem, Art. No. 01-64-0170).
  • a base of the formula I obtained can be converted into the associated acid addition salt using an acid.
  • Acids which provide physiologically acceptable salts are suitable for this reaction.
  • inorganic acids can be used, for example sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic
  • the free bases of the formula I can be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, provided that no further acidic groups are present in the molecule.
  • strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, provided that no further acidic groups are present in the molecule.
  • Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.
  • the invention further relates to the active pharmaceutical ingredients according to the invention as nicotinic acetylcholine receptor ligands for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairment, age-related memory impairment, relief of withdrawal symptoms from nicotine addiction, stroke or damage to the brain due to toxic compounds.
  • nicotinic acetylcholine receptor ligands for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairment, age-related memory impairment, relief of withdrawal symptoms from nicotine addiction, stroke or damage to the brain due to toxic compounds.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts or solvates.
  • the compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.
  • Organic come as carriers or inorganic substances that are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch , Magnesium stearate, talc,
  • Vaseline Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • the substances according to the invention are generally in
  • Analogously to known, commercially available preparations for example Tae-rin administered, preferably in doses between about 5 mg and 100 mg, in particular between 10 and 40 mg per dosage unit.
  • the daily dosage is preferably between about 0.5 and 1 mg / kg body weight.
  • the specific dose for each individual patient depends on various factors, for example on the effectiveness of the special compound used, on the age, body weight, general health, gender, on the diet, on Time and route of administration, the rate of excretion, combination of drugs and the severity of the disease to which the therapy applies. Oral use is preferred.
  • the compounds of formula I set out above are used for the production of medicaments which are used for the treatment of diseases which are based on dysfunction or degeneration of nicotinic acetylcholine receptors.
  • the invention also relates to the use of compounds of the formula I according to claim 1 and / or their physiologically acceptable salts or solvates for the manufacture of a medicament, in particular for the manufacture of a medicament for the treatment of diseases in which the stimulation of the nicotinic acetylcholine receptors to improve the clinical picture leads.
  • the invention furthermore relates to the use of compounds of the formula I according to claim 1 and / or of their physiologically acceptable salts and solvates for the manufacture of a medicament for the prophylaxis or treatment of schizophrenia, depression, anxiety, dementia, Alzheimer's disease, Lewy bodies dementia, neurodegenerative Diseases, Parkinson's disease, Huntington's disease, Tourette's syndrome, learning and memory impairments, age-related memory loss, relief from
  • methanol is obtained from the reaction of (2-benzyl-2-azabicyclo [2.2.1] hept-7-yl) 4-methoxy-benzoic acid chloride 4-methoxy-benzoic acid (2'-benzyl-2'-azabicyclo [2.2.1] hept-7'-yl-methyl) ester; ESI 352; salt precipitation with 0.5M HCl solution gives 4-methoxy-benzoic acid (2'-benzyl-2'-aza-bicyclo [2.2.1] hept-7'-yl-methyl) ester hydrochloride,
  • Example 8 Analogously to Example 3, methylamine is obtained from the reaction of (2-benzyl-2-azabicyclo [2.2.1] hept-7-yl)
  • Example 9 Analogously to Example 1, methylamine is obtained from the reaction of (2-benzyl-2-azabicyclo [2.2.1] hept-7-yl)
  • DIEA N, N- Diisopropylaminomethylpolystyrene
  • phenylmethanesulfonyl chloride 0.06 mmol phenylmethanesulfonyl chloride
  • Example 13 To a solution of 0.1 mmol (2-benzyl-2-aza-bicyclo [2.2.1] hept-7-yl) methanol in 2 ml of tetrahydrofuran (THF), 0.110 mmol of isothiocyanatomethyl-benzene is added at room temperature. It is stirred for 6 hours at room temperature and 0.30 mmol of Ths- (2-aminoethyl) amine polystyrene (NovaBiochem, Item No. 01-64-0170) and 0.30 mmol
  • Methyl isocyanate polystyrene (NovaBiochem, Art. No. 01-64-0169) was added and the mixture was stirred at 50 ° C. for 12 hours. The solution is filtered and the solvent is removed. 0- (2-Benzyl-2-aza-bicyclo [2.2.1] hept-7-yl-methyl) -N-benzyl-thiocarbamate is obtained; ESI 368. Salt precipitation with 0.5M HCl solution gives 0- (2-benzyl-2-azabicyclo [2.2.1] hept-7-yl-methyl) -N-benzyl-thiocarbamate hydrochloride.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool.
  • Each Suppositohum contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 PO 4 ⁇ 2 H 2 O, 28.48 g of NaH 2 PO 4 ⁇ 12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water.
  • pH 6.8 make up to 1 I and sterilize by irradiation. This solution can be used in the form of eye drops.
  • Example D Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F Dragees 5 Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G Capsules Q 2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is transferred into c ampoules, lyophilized under aseptic conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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Abstract

L'invention concerne des composés de formule (I), dans laquelle A-B, X, R<1> et R<2> ont les significations spécifiées dans la revendication 1. Ces composés sont des ligands du récepteur nicotinique de l'acétylcholine et peuvent être utilisés en prévention ou traitement de maladies ou de troubles tels que schizophrénie, dépression, anxiété, démence, maladie d'Alzheimer, démence à corps de Lewy, maladies neurodégénératives, maladie de Parkinson, chorée de Huntington, syndrome de la Tourette, troubles de l'apprentissage et de la mémoire, troubles de la mémoire liés à l'âge, en soulagement de symptômes de sevrage liés à une dépendance à la nicotine ou en traitement d'accident vasculaire cérébral ou de lésions du cerveau occasionnées par des composés toxiques.
EP02732477A 2001-04-14 2002-03-13 Ligands du recepteur nicotinique de l'acetylcholine Withdrawn EP1379502A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10118551 2001-04-14
DE10118551A DE10118551A1 (de) 2001-04-14 2001-04-14 Nikotinische Acetylcholinrezeptor Liganden
PCT/EP2002/002729 WO2002083640A1 (fr) 2001-04-14 2002-03-13 Ligands du recepteur nicotinique de l'acetylcholine

Publications (1)

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EP1379502A1 true EP1379502A1 (fr) 2004-01-14

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US (1) US20040110788A1 (fr)
EP (1) EP1379502A1 (fr)
JP (1) JP2004527534A (fr)
AR (1) AR033156A1 (fr)
CA (1) CA2443577A1 (fr)
CZ (1) CZ20032999A3 (fr)
DE (1) DE10118551A1 (fr)
HU (1) HUP0303980A3 (fr)
SK (1) SK13722003A3 (fr)
WO (1) WO2002083640A1 (fr)

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SE0400970D0 (sv) * 2004-04-14 2004-04-14 Astrazeneca Ab Nicotinic acetylcholine receptor ligands
US20090137623A1 (en) * 2005-12-30 2009-05-28 Naresh Kumar Muscarinic receptor antagonists

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9020051D0 (en) * 1990-09-13 1990-10-24 Pfizer Ltd Muscarinic receptor antagonists
CA2287223A1 (fr) * 1997-04-26 1998-11-05 Tomohiro Toyoda Composes 2-azabicyclo
GB9822945D0 (en) * 1998-10-20 1998-12-16 Isis Innovations Ltd Epibatidine analogues
DE10044905A1 (de) * 2000-09-12 2002-03-21 Merck Patent Gmbh (2-Azabicyclo[2.2.1]hept-7-yl)methanol-Derivate als nikontinische Acetylcholinrezeptor Agonisten

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Title
See references of WO02083640A1 *

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US20040110788A1 (en) 2004-06-10
HUP0303980A3 (en) 2005-09-28
HUP0303980A2 (hu) 2004-04-28
CA2443577A1 (fr) 2002-10-24
JP2004527534A (ja) 2004-09-09
DE10118551A1 (de) 2002-10-17
AR033156A1 (es) 2003-12-03
SK13722003A3 (sk) 2004-02-03
CZ20032999A3 (cs) 2004-02-18

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