WO1996008468A1 - Composes carbamoyloxyamine - Google Patents

Composes carbamoyloxyamine Download PDF

Info

Publication number
WO1996008468A1
WO1996008468A1 PCT/DK1995/000368 DK9500368W WO9608468A1 WO 1996008468 A1 WO1996008468 A1 WO 1996008468A1 DK 9500368 W DK9500368 W DK 9500368W WO 9608468 A1 WO9608468 A1 WO 9608468A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
compound
ring
phenyl
Prior art date
Application number
PCT/DK1995/000368
Other languages
English (en)
Inventor
Erik Falch
Ivan Mikkelsen
Povl Krogsgaard-Larsen
Original Assignee
H. Lundbeck A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to AU34704/95A priority Critical patent/AU3470495A/en
Publication of WO1996008468A1 publication Critical patent/WO1996008468A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a novel class of carbamoyloxypropylamine or carba- moyloxyethylamine derivatives in which the alkyl backbone contains substituents or is partly incorporated into ring structures.
  • the novel compounds are ligands at the central nicotine acetylcholine receptors (nAChRs) and accordingly useful in the treatment of certain cognitive, neurological and mental disorders.
  • nAChRs in the central nervous system (CNS) as pharmacological and therapeutic targets
  • CNS central nervous system
  • ACh central acetylcholine
  • Cortical nAChRs are markedly reduced in brain tissues from Alzheimer patients (Giacobini, J. Neurosci Res.
  • the parietotemporal cortex is the brain area which is most consistently implicated in the cognitive deficits in Alzheimer patients (Gitelman and Prohovnik,Ne ⁇ vrot->/o/. Aging., 1992 13, 313-318). Preclinical and clinical data are consistent with the view that nACh receptor agonists are useful in the treatment of Alzheimer's disease (Sahakian et al., Br.J. Psych. 1989, 154, 797-800; Levin, Psychopharmacology 1992 , 708, 417-431).
  • nAChR ligands have therapeutic potential in schizophrenia (Adler et a ⁇ .,Biol. Psychiat. 1992, 32, 607-616).
  • nicotine and other nAChR agonists have shown effects in animal models of anxiety (Brioni et al., Eur.J. Pharmacol. 1993, 238, 1-8) and pain (Qian et al., Eur. J. Pharmacol. 1993, 250, 13-14; Badio and Daly, Mol. Pharmacol. 1994, 45, 563-569).
  • Tobacco smoke contains a variety of substances, but it is beyond doubt that the addictive nature of smoking is attributable to the content of nicotine. Consequently, nAChR ligands may be useful drugs in therapies for smoking cessation (for referen ⁇ ces, see Williams et al., supra).
  • Nicotine is the classical nACh receptor agonist, but the number of nACh receptor agonists and antagonists, synthesized or isolated from natural sources, is rapidly growing (Williams et al., supra).
  • a number of a analogues of carbamylcholine including N-methylcarbamylcholine (MCC), (Boksa et al., Eur. J. Pharmacol. 1989, 773, 93-108; Abood et al., Pharma ⁇ col. Biochem. Behav. 1988, 30, 403-408) and N,N-dimethylcarbamylcholine (DMCC) (Punzi et al., Biochem. Pharmacol. 1991 , 41, 465-467; Sarawati et a ⁇ .,Drug Dev. Res. 1994, 31, 142-146) have been synthesized and characterized as nAChR ligands.
  • the compounds synthesized included some N-alkyl-, N,N-dialkyl and cycloalkyl carbamate estes of dimethylethanolamine and the N-methyl carbamate ester of dimethylpropanolamine.
  • nAChR ligands Within the compounds found to be nAChR ligands, the qua ⁇ ternary analogues, i.e. carbamate esters of choline, showed markedly higher nAChR affinity than the corresponding tertiary amines, i.e. carbamate esters of N,N- dimethylaminoethanol (Abood et al., supra; Punzi et al., supra). Since the former group of analogues are likely to show a limited ability to penetrate the blood-brain barrier it is desired to obtain novel potent nAChR ligands having a good ability to penetrate the blood-brain barrier.
  • the present invention relates to a novel class of carbamoyloxy amine compounds of the formula I
  • A represents CH 2 or a bond
  • R-i is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or phenyl
  • R 2 is alkyl, alkenyl, alkynyl, cycloalkyl or phenyl; or R-i and R 2 together with the adjacent nitrogen form a 3 to 7 membered monoazacyclic ring
  • R 3 and R 4 are the same or different and each represent hydrogen, alkyl, alkenyl, alkynyl, mono- or polyhalogenated lower alkyl, cycloalkyl, phenyl, or phenyl-lower alkyl or R 3 and R 4 together form a spirojoined C 4 .
  • R 3 and R 2 may together with the nitrogen and carbon to which they are attached form a 3 to 7 membered monoazacyclic ring;
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or phenyl-lower alkyl; or if R 2 do not form a ring with R-i or R 3 , then R 5 and R 2 may together with the nitrogen atom to which R 2 is attached, the carbon atom substituted with R 3 and R 4 and the carbon atom to which R 5 is attached, form a 3 to 7 membered monoazacyclic ring; or if R 3 is not included in a ring and R 5 do not form a ring together with R 2 , R 5 and R 4 may together with the carbon atoms to which they are attached form a 3 to 7 membered carbocyclic ring; provided that R 5 is hydrogen when A is a bond; R ⁇ is hydrogen
  • the compounds of the invention have been found to have a high affinity for nAChR's. Furthermore, some of the compounds have been found to exhibit nAChR agonist properties. Accordingly, the compounds of the invention are considered use ⁇ ful in the treatment of cognitive, neurological and mental disorders in which nAChR dysfunction is involved, such as pain, dementia, Alzheimers disease, Parkinsons di ⁇ sease, impaired learning ability, impaired memory function, psychosis, schizophre ⁇ nia, pain and anxiety, in particular dementia, Alzheimers disease or impaired lear- ning ability or memory function. Furthermore, they may be used in theraputical treat ⁇ ment for smoking cessation.
  • the invention provides a pharmaceutical composition comprising at least one novel carbamoyloxy amine compound of formula I in a therapeutically effective amount.
  • the present invention provides the use of a carbamoyloxy amine compound of formula I for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders and diseases.
  • Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers as well as any mixture thereof, including the racemic mixtures, are also embraced by the invention.
  • alkyl designates C-i- ⁇ alkyl which may be straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, tert.butyl, pentyl, hexyl, hep- tyl or octyl.
  • alkyl groups lower alkyl groups are preferred.
  • the term lower alkyl designates C 1 - 4 alkyl which may be a straight or branched such as methyl, ethyl, propyl, isopropyl, butyl, tert.butyl.
  • alkenyl and alkynyl, desig ⁇ nate C2-8 groups having at least one double or tripple bond, respectively, and lower alkenyl and lower alkynyl designate such groups having up to 4 carbon atoms.
  • cycloalkyl designates a saturated carbocyclic ring having 3-7 carbon atoms, inclusive.
  • phenyl-lower alkyl designates a lower alkyl group (as herein defined) which, in turn, is substituted with a phenyl group.
  • Preferred phenyl-lower alkyl are benzyl, 1-and 2-phenylethyl, 1-.2-, and 3-phenylpropyl, and 1 -methyl- 1-phenylethyl.
  • halogen designates F, Cl, Br or I, F being preferred.
  • polyhaloge- nated lower alkyl designates lower alkyl, as defined above, substituted with two or more halogen atoms, which may be the same or different.
  • a preferred example of polyhalogenated lower alkyl is trifluoromethyl.
  • a 3 to 7 membered monoazacyclic ring refers to a 3-, 4-, 5-, 6- or 7- membered ring containing one nitrogen atom, such as aziridinyl, azetidinyl, pyrrolidi- nyl, piperidinyl or perhydroazepinyl.
  • Preferred groups are pyrrolidinyl and piperidinyl.
  • 3 to 7 membered carbocyclic ring refers to a 3-, 4-, 5-, 6- or 7-membered carbon ring, for instance cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane.
  • the salts of the compounds of the formula I include any pharmaceutically accept ⁇ able acid addition salt.
  • This term as used herein generally includes the non-toxic acid addition salts of compounds of the formula I, formed with non-toxic inorganic or organic acids.
  • the salts include salts with non-toxic inorganic acids, such as hydrochloric, hydrobromic, sulphuric, sulphamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, stearic, lactic, malic, pamoic, ascorbic, phenylacetic, glutamic, benzoic, salicylic, sulphonic, sulphanilic, and the like.
  • R-i is preferably lower alkyl, most preferably methyl and R 2 is preferably lower alkyl, especially methyl, or designates together with R 3 and the nitrogen and carbon, repectively, to which R 2 and R 3 are attached a pyrrolidinyl ring or R-i and R 2 may together form a pyrrolidinyl ring.
  • R3 is preferably lower alkyl, or together with R 2 forms a ring, cf above. Most preferably R 3 is lower alkyl, especially methyl.
  • R 4 is preferably hydrogen and R 5 is preferably hydrogen or together with R 3 forms a ring, cf. above.
  • Re is preferably hydrogen or lower alkyl, most preferably hydrogen, ethyl or methyl and R 7 is preferably lower alkyl, most preferably ethyl or methyl.
  • Preferred compounds of the invention are compounds of formula II
  • R-i, R 2, R 3, R ⁇ and R 7 are as defined above;
  • Especially preferred compounds of the invention are compounds of formula
  • R-i, R 2 , Re and R 7 are as defined above;
  • Another, subclass of preferred compounds of the invention are compounds of formula IV:
  • R* ⁇ , Re and R 7 are as defined above.
  • Especially preferred compounds are:
  • the compounds of the invention are conveniently administered to a patient, via rectal, oral, parenteral or transdermal dosage forms or by inhalation as one or more daily doses, or other time-presented doses.
  • the dose will, of course, depend on the requirements of the individual under treatment.
  • the effective daily dose of a typical compound is 5.0 ⁇ g to 1.5 mg, preferably 10 ⁇ g to 1.0 mg, in particular 25 ⁇ g to 0.5 mg pr. kg of body weight.
  • the daily dose is generally in the range of 0.3 to 100 mg, preferably 0.6 to 60mg, usually 1.5 to 40 mg for typical compounds regardless of administration form.
  • the daily dose may be administered in 1 to 3 single doses.
  • the compounds of the formula I may be administered in the form of tablets, capsules, suspensions, emulsions, solutions, injectables, suppositories, enema, various drug delivery devices and in other suitable form.
  • the route of administration may be rectally, orally, parenterally or transdermally or by inhalation.
  • the formula ⁇ tion and preparation of any of these dosage forms is well-known to those skilled in the art of pharmaceutical formulation.
  • any one of the compounds of the present invention in a pharmacologically effective amount is combined with any oral nontoxic pharmaceutically acceptable inert carrier such as lactose, starch and microcrystalline cellulose.
  • suitable binders e.g. gelatin
  • lubricants e.g. talc or magnesium stearate
  • disintegrating agents e.g. starch or various cellulose derivatives
  • a compound of the present invention is dissolved in sterile water in a given concentration and sterilized by e.g. membrane filtration, or radiation.
  • the pH of the solution may, if necessary, be adjusted with e.g. hydrochlo ⁇ ric acid, sodium hydroxide or a suitable buffer, and a suitable preservative may optionally be added.
  • agents like sodium chloride may be added in order to adjust the tonicity of the solution.
  • a suitable parenteral preparation may also consist of the compound formulated as a sterile, solid substance distributed in injection vials. Before dispensing, water for injection is added to dissolve the compound.
  • typical dosage forms include suppositories (emulsion and suspension types), rectal gelatin capsules (solutions and suspensions), and enemas or micro-enemas (solutions and suspen ⁇ sions).
  • a compound of the invention is combined with any pharmaceutically acceptable suppository base such as cocoa butter, esterified fatty acids (C-io-C-i ⁇ ), glycerinated gelatin, and various water- soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters.
  • Various additives like salicylates or surfactant materials may be incorporated.
  • Enemas or micro-enemas of the solution type may simply be prepared by dissolving compounds of this invention in water or in water containing e.g. 0.5% of methylcellulose or another viscosity-increasing agent.
  • the novel and useful compounds of the invention may also be administered by drug delivery systems such as gastrointestinal drug delivery devices and rectally applied osmotic delivery devices, wherein the delivery device is manufactured from naturally occurring or synthetic polymeric materials.
  • the compounds of the present invention may be prepared by : a) Reacting a compound of the formula V
  • R-j' is as R-i defined above or an amino protecting group
  • R2, R3, R4, R5 and A are as defined above, with a compound of the formula VI
  • R 6 ' is as defined above for R 6 except that it may not be hydrogen
  • R 7 is as defined above
  • Z is a leaving group
  • R 7 wherein R 6 and R 7 are as defined above and then, if an amino protecting group has been used, removing the said group.
  • the reaction is carried out without a solvent or in a solvent, e.g. toluene, tetrahydro- furan, diethylether, acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide, or the like.
  • a solvent e.g. toluene, tetrahydro- furan, diethylether, acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide, or the like.
  • a base e.g. sodium hydride, tertiary amine, pyridine, potas ⁇ sium carbonate, or the like, usually has to be present whereas in b) a base may be present if convenient.
  • the temperature during the reaction is usually be ⁇ tween 0°C and the boiling point of the mixture and in c) it is usually between -10°C and the boiling point of the mixture
  • the reaction time is normally from 1 to 96 hours.
  • One way to obtain the compounds of formula VII may be by reacting a compound of formula V with phosgene.
  • Suitable leaving groups Z may easily be selected by a person skilled in the art. As examples may be mentioned chlorine, bromine and iodine.
  • amino protecting group designates groups readily removable by hydrolysis or hydrogenation. Suitable protecting groups may easily be selected. As examples of such groups may be mentioned methyloxycarbonyl, ethyloxycarbonyl, tert.butyl- oxycarbonyl, benzyloxycarbonyl, formyl, acetyl, trityl, benzyl, or the like.
  • Example 1 The present invention is further illustrated by the following examples which, however, may not be construed to be limiting.
  • Example 1
  • T designates tartrate, B hydrobromide, DT dibenzoyi tartrate; M maleate, O oxalate and C hydrochloride. The remaining compounds were isolated as fumarates.
  • the compounds of the invention were tested in the following well recognized and reliable test methods.
  • Rat brains were homogenized (Ultraturrax) in 10 vol (w/v) buffer consisting of Na 2 HP0 4l 8 mM; KH 2 P0 4 , 1.5 mM; KCI, 3 mM; NaCl, 120 mM; EDTA, 2 mM; HEPES, 20 mM; and iodoacetamide, 5mM (pH 7.4).
  • the homogenate was centrifuged (50.000 x g; 20 min.; 0°C) and the pellet resuspended in 10 vol. cold standard assay buffer with the same composition as the buffer preparation described above, except for the addition of MgCl 2, 1 mM and CaCb, 2 mM, and the elimination of EDTA and iodoacetamide. Aliquots (0.1 mg of tissue) were incubated with 5 nM L-[ 3 H]Nicotine (78 Ci/mmol, Amersham) alone or in the presence of test compound in a total volume of 0.6 ml for 60 min. at 0°C.
  • the compounds of the invention have been tested with respect to affini ⁇ ty for muscarinic receptors by the method of Sauerberg, P. et al., J. Med. Chem. 1988, 31, 1312-1316, and some of compounds were tested with respect to agonistic effect at the nAChRs in the Guinea Pig lleum test as described by Amt et al. Eur. J. Pharmacol. 1992, 218, 159-169 or the Nicotine Cue test as described by L. T. Meltzer et al., Psychopharmacology Q8, 283-286, 1980. Some of the compounds were selective towards the nAChRs as compared to muscarinic receptors whereas the compounds tested in the Guinea Pig lleum test or the Nicotine Cue test were found to act as agonists. Formulation Examples
  • compositions of the invention may be prepared by conventional methods in the art as described above.

Landscapes

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

Abstract

La présente invention concerne des composés carbamoyloxypropylamine ou carbamoyloxyéthylamine représentés par la formule générale (I). Dans cette formule générale, A représente CH2 ou une liaison, R1 représente hydrogène, alkyle, alcényle, alkynyle, cycloalkyle ou phényle, et R2 représente alkyle, alcényle, alkynyle, cycloalkyle ou phényle, ou bien R1 et R2 forment ensemble un noyau; R3 et R4 représentent hydrogène, alkyle, alcényle, alkynyle, alkyle halogéné, cycloalkyle, phényle ou phénylalkyle ou bien R3 et R4 forment ensemble un carbocycle en C4-7 à jonction spiro, ou bien, lorsque R1 et R2 ne sont pas liés, R3 et R4 peuvent constituer un noyau; R5 représente hydrogène, alkyle, alcényle, alkynyle, cycloalkyle, phényle ou phénylalkyle ou forme un noyau avec R2; ou bien R5 forme un noyau avec R4; R6 et R7 représentent hydrogène, alkyle, alcényle, alkynyle, cycloalkyle, phényle ou phénylalkyle; ou bien R6 forme avec R7 un noyau. Ces composés sont des ligands au niveau des récepteurs centraux de la nicotine acéthylcoline (nACgRs). Ces composés sont utilisables dans le traitement des troubles d'origine cognitive, neurologique ou mentale associés à un dysfonctionnement du nAChR.
PCT/DK1995/000368 1994-09-14 1995-09-14 Composes carbamoyloxyamine WO1996008468A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34704/95A AU3470495A (en) 1994-09-14 1995-09-14 Carbamoyloxy amine compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1056/94 1994-09-14
DK105694 1994-09-14

Publications (1)

Publication Number Publication Date
WO1996008468A1 true WO1996008468A1 (fr) 1996-03-21

Family

ID=8100490

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1995/000368 WO1996008468A1 (fr) 1994-09-14 1995-09-14 Composes carbamoyloxyamine

Country Status (4)

Country Link
AU (1) AU3470495A (fr)
IL (1) IL115305A0 (fr)
WO (1) WO1996008468A1 (fr)
ZA (1) ZA957746B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085727A1 (fr) * 2000-05-05 2001-11-15 Novartis Ag Carbamates azabicycliques et leur utilisation comme agonistes des recepteurs nicotiniques alpha-7 de l'acetylcholine
WO2002020016A1 (fr) * 2000-09-06 2002-03-14 Fujisawa Pharmaceutical Co, Ltd Agent de modulation de la transmission synaptique excitatrice comprenant un compose dote d'une propriete d'activation du recepteur d'acetylcholine nicotinique alpha $g(a)7
JP2004509851A (ja) * 2000-07-14 2004-04-02 ターガセプト，インコーポレイテッド 神経疾患治療用医薬組成物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2794810A (en) * 1952-03-08 1957-06-04 Searle & Co Aminoalkyl cycloalkylcarbamates
FR2704M (fr) * 1961-03-29 1964-09-04 Siegfried Ag
US3287471A (en) * 1964-05-05 1966-11-22 Searle & Co Pyrrolidinyl nu-phenyl-nu-benzylcarbamates
US3347856A (en) * 1965-02-08 1967-10-17 Robins Co Inc A H 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives
CH467755A (de) * 1963-04-18 1969-01-31 Siegfried Ag Verfahren zur Herstellung von spasmolytische und tremolytische Eigenschaften aufweisenden Carbamaten
CH468978A (de) * 1963-08-05 1969-02-28 Siegfried Ag Verfahren zur Herstellung von spasmolytisch und tremolytisch wirkenden Carbaminaten

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2794810A (en) * 1952-03-08 1957-06-04 Searle & Co Aminoalkyl cycloalkylcarbamates
FR2704M (fr) * 1961-03-29 1964-09-04 Siegfried Ag
CH405266A (de) * 1961-03-29 1966-01-15 Siegfried Ag Verfahren zur Herstellung von als Antiparkinsonmittel verwendbaren Verbindungen
CH467755A (de) * 1963-04-18 1969-01-31 Siegfried Ag Verfahren zur Herstellung von spasmolytische und tremolytische Eigenschaften aufweisenden Carbamaten
CH468978A (de) * 1963-08-05 1969-02-28 Siegfried Ag Verfahren zur Herstellung von spasmolytisch und tremolytisch wirkenden Carbaminaten
US3287471A (en) * 1964-05-05 1966-11-22 Searle & Co Pyrrolidinyl nu-phenyl-nu-benzylcarbamates
US3347856A (en) * 1965-02-08 1967-10-17 Robins Co Inc A H 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 55, 25 December 1961, (Columbus, Ohio, USA), Abstract No. 6375a; & JP,B,36 007 464, (DAINIPPON PHARMACEUTICAL CO., LTD), 20 June 1961. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085727A1 (fr) * 2000-05-05 2001-11-15 Novartis Ag Carbamates azabicycliques et leur utilisation comme agonistes des recepteurs nicotiniques alpha-7 de l'acetylcholine
US6780861B2 (en) 2000-05-05 2004-08-24 Novartis Ag Azabicyclic carbamates and their use as α-7 nicotinic acetylcholine receptor agonists
JP2004509851A (ja) * 2000-07-14 2004-04-02 ターガセプト，インコーポレイテッド 神経疾患治療用医薬組成物
WO2002020016A1 (fr) * 2000-09-06 2002-03-14 Fujisawa Pharmaceutical Co, Ltd Agent de modulation de la transmission synaptique excitatrice comprenant un compose dote d'une propriete d'activation du recepteur d'acetylcholine nicotinique alpha $g(a)7

Also Published As

Publication number Publication date
IL115305A0 (en) 1995-12-31
AU3470495A (en) 1996-03-29
ZA957746B (en) 1996-07-25

Similar Documents

Publication Publication Date Title
AU707325B2 (en) 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one derivatives for use as 5-HT4 or H3 receptor ligands
KR101019313B1 (ko) Ｎ-[페닐(피페리딘-2-일)메틸]벤즈아미드의 유도체, 그의제조 방법 및 치료법에서의 그의 용도
RU2382032C2 (ru) Соли донепезила, подходящие для получения фармацевтических композиций
US20050153963A1 (en) N-[phenyl (piperidin-2-yl) methyl]benzamide derivatives, preparation thereof, and use thereof in therapy
JP3038155B2 (ja) 神経保護剤を用いる耳鳴治療
WO1993018002A1 (fr) Sels quaternaires de piperidines 4-substitues, leur preparation et compositions pharmaceutiques les contenant
EA014370B1 (ru) Циклопропиламины в качестве модуляторов рецептора гистамина н
SK280905B6 (sk) 3-metylamino-6-karboxamido-1,2,3,4-tetrahydrokarbazol, spôsob jeho prípravy, farmaceutický prípravok s jeho obsahom a jeho použitie
HU221726B1 (hu) Piperazinszármazékok, e vegyületeket tartalmazó gyógyászati készítmények és eljárás a vegyületek előállítására
FR2696178A1 (fr) Amides basiques quaternaires, procédé pour leur préparation et compositions pharmaceutiques en contenant.
BG61120B2 (bg) Производни на 1,2,5,6-тетрахидропиридин-3-карбоксалдехид оксим,метод за получаването им,приложението им като лекарствени средства и съдържащите ги състави
JP2013517326A (ja) κオピオイド受容体結合リガンド
JPH0411559B2 (fr)
US5292745A (en) Use of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine derivatives as free radical scavengers
CZ114299A3 (cs) N-Substituované azaheterocyklické sloučeniny
WO1996008468A1 (fr) Composes carbamoyloxyamine
ES2354968T3 (es) Derivados de piperidina antihistamínicos e intermedios para la preparación de los mismos.
JPWO2002030896A1 (ja) ２，２−ジフェニルブタンアミド誘導体及びこれを含有する医薬
JPH01186866A (ja) 分割化アミノピロリジン神経防護剤
JPH07119189B2 (ja) 光学活性なベンジルアルコール誘導体及びその用途
FR2753970A1 (fr) Derives de n-(benzothiazol-2-yl) piperidine-1-ethanamine, leur preparation et leur application en therapeutique
SI9300217A (sl) Farmacevtiki, ki vsebujejo ariloksialkilamino in ariltioalkilamino derivate
AU751592B2 (en) Ureidopiperidine derivatives as selective human NK3 receptor antagonists
WO2009138734A2 (fr) Utilisation de composés opiacés pour les douleurs périphériques, la cicatrisation des plaies et la formation de cicatrices
EP0869954B1 (fr) Composes heterocycliques utiles dans le traitement d'une inflammation neurogenique

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase