WO2001032178A1 - Utilisation de piperidines 3,4-substituees - Google Patents

Utilisation de piperidines 3,4-substituees Download PDF

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Publication number
WO2001032178A1
WO2001032178A1 PCT/DK2000/000595 DK0000595W WO0132178A1 WO 2001032178 A1 WO2001032178 A1 WO 2001032178A1 DK 0000595 W DK0000595 W DK 0000595W WO 0132178 A1 WO0132178 A1 WO 0132178A1
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Prior art keywords
alkyl
treatment
trans
cyano
halogen
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PCT/DK2000/000595
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English (en)
Inventor
Christian Thomsen
Rolf Hohlweg
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Novo Nordisk A/S
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Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU10188/01A priority Critical patent/AU1018801A/en
Publication of WO2001032178A1 publication Critical patent/WO2001032178A1/fr

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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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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

Definitions

  • the present invention relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of conditions in which there is alteration of blood pressure, hypotension, excessive vasodilation or migraine.
  • the present invention also relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of memory and attention deficits resulting from but not limited to Alz- heimer's disease, Parkinson's disease, trauma and stroke.
  • the present invention also relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of painful conditions such as acute pain, chronic pain, arthritic pain or migraine.
  • the present invention also relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression.
  • the present invention further relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of conditions in which there is symptoms of addictive drug withdrawal, including alcoholism.
  • the present invention further relates to the use of compounds of the general formula I for the treatment, prevention, alleviation or amelioration of metabolic disorders such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • Opioid receptors consist of a family of G-protein coupled receptors termed ⁇ , ⁇ , K, and the recently discovered nociceptin receptor (also termed orphan opioid receptor-like (ORL1) receptor).
  • Nociceptin also known as orphanin FQ (OFQ)
  • ORL1 receptor and its mRNA are widely distributed throughout the central nervous system (CNS) and nociceptin has many cellular effects in vitro on ORL1 receptor- expressing tissue.
  • the ORL1 receptor is also expressed in the supraoptic nucleus and subfomical organ and in the cortical areas and the hippocampus as well as expressed in e.g., the periagueductal grey and raphe nuclei) and in spinal cord (upper layers of the dorsal horn).
  • Nociceptin as well as its receptor, ORL1 is also expressed in the ventral tegmental area, substantia nigra, locus coeruleus and in the dorsal raphe. These nuclei represent the major sources of monoamine neurotransmitters in the brain and the regulation of monoamine-transmission by nociceptin has widespread implications for many types of behaviours.
  • the present invention relates to the use of 4-arylpiperidine compounds and their salts with pharmaceutically acceptable acids, acting as nociceptin antagonists,
  • a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of memory and attention deficits resulting from but not limited to Alzheimer's disease, Parkinson's disease, trauma and stroke;
  • a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of painful conditions such as acute pain, chronic pain, arthritic pain or migraine
  • a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression
  • R 1 represents hydrogen, a straight or branched C ⁇ -alkyl or C 3 . 7 -cycloalkyl group
  • R 2 and R 3 independently represent hydrogen, alkyl, alkynyl, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio, cyano, or aralkyloxy;
  • R 4 and R 5 independently represent hydrogen, alkyl, C 3 . 7 -cycloalkyl, alkynyl, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio, cyano, acylamino, methylsulfonyl, methylenedioxy, aryloxy or aralkyloxy: or R 4 and R 5 together represent a methylenedioxy group; and Ar independently represents a phenyl, tetrahydronaphthyl or thienyl group, or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of painful conditions such as but not limited to acute pain, chronic pain, arthritic pain or migraine; or - for the preparation of a pharmaceutical composition for the treatment and/or prevention of increased blood pressure, hypotension, excessive vasodilation or migraine; or - for the preparation of a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression.;
  • a pharmaceutical composition for the treatment, prevention, alleviation or amelioration of metabolic disorders such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • metabolic disorders such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • Nociceptin antagonists are furthermore useful for treating hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • the nociceptin antagonists reduce food-intake under several conditions including food- deprivation, spontaneous feeding, glucoprivic conditions and introduction of highly palatable food.
  • the antagonists are particular effective against excessive food-intake induced by palatable food and high-fat diet.
  • the compounds of the present invention may have two or more asymmetric centres and it is intended that stereoisomers and optical isomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention.
  • the compounds of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like
  • pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which are known to the skilled artisan
  • the acid addition salts may be obtained as the direct products of compound synthesis
  • the free base may be dissolved in a suitable solvent containing the ap- propnate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan
  • C-, 6 -alkyl represent a branched or straight saturated hydrocarbon chain having 1 to 8 carbon atoms
  • Typical C-, 6 -alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso- pentyl, hexyl, iso-hexyl and the like
  • C3-7'-cycloalkyl represents a carbonylic group having from 3 to 7 carbon atoms e g cycloproyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and the like
  • C-, 6 -alkoxy as used herein, alone or in combination is intended to include those C-i 6 -alkyl groups of the designated length in either a linear or branched or cyclic configuration linked through an ether oxygen having its free valence bond from the ether oxygen
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy
  • C ⁇ . 6 -alkylth ⁇ o refers to a straight or branched monovalent substituent comprising a lower alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e g methylthio, ethylthio, propylthio, butylthio, pentylthio
  • Ar resembles "aryl” is intended to include aromatic rings, such as carboxychc aromatic rings selected from the group consisting of phenyl, naphthyl, (1-naphtyl or 2-naphtyl), tetrahydronaphthyl or thienyl
  • halogen means fluorine, chlorine, bromine or iodine.
  • alkynyl means e.g.ethynyl, propynyl or butynyl.
  • acylamino means e.g. acetylamino, propionylamino or butyrylamino.
  • aryloxy means an aryl group as defined above linked through an ether oxygen having its free valence bond from the ether oxygen. Examples of aryloxy groups are phenoxy or naphthyloxy. Certain of the above-defined terms may occur more than once in the above formula I, and upon such occurrence each term shall be defined independently of the other. In the compound of the above formula I, R 1 is preferably methyl.
  • R 2 and R 3 is preferably halogen, most preferably fluorine.
  • R 4 and R 5 is preferably an alkyl or cyano group, most preferably in ortho position.
  • compound I has the trans- configuration with respect to the substituents in 3- and 4-position of the piperidine ring.
  • compound I has the cis-configuration with respect to the substituents in 3- and 4-position of the piperidine ring.
  • compound I represents the (+) enantiomer.
  • compound I represents the (-) enantiomer.
  • Preferred compounds of the invention are:
  • the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
  • the compounds of formula I may be prepared from the corresponding carbinols which can be prepared by reducing a compound of formula II
  • R1 , R2, R3, and Ar are as hereinbefore defined, preferably with a complex metal hydride reducing agent, especially lithium aluminium hydride, as described in US 3,912,743 which is hereby incorporated in its entirety,
  • Plasmids containing ORL1 in a pcDNA 3.1 (In Vitrogen, U.S.A.) was transfected into baby hamster kidney (BHK) cells and cultured in Dulbecco's modified Eagles media (incl. glu- tamax) supplemented with 10% foetal bovine serum, 50 ⁇ g streptomycin, 50 U/ml penicillin in an incubator at 37°C (95 % air, 5% CO2). Cells were initially selected using 0.75 mg/ml G418 and 0.5 mg/ml was used in the culture media.
  • Membrane preparation BHK cells expressing ORL1 was harvested with phosphate buffered saline supplemented with 1 mM EDTA, pH 7.4 and centrifuged (1000 x g, 5 min, 4 °C). The pellet was homogenised in assay buffer (50 mM TRIS-HCI, pH 7.8, 5 mM MgCI 2 , 0.2 mM EGTA, 1 mg/ml BSA, 0.2 mg/ml bacitracin.) and centrifuged (40000 x g, 4°C, 20 min). The resulting pellet was homogenised in assay buffer supplemented with 10% sucrose (w/vol) and membranes were frozen in aliquots at -80°C.
  • assay buffer 50 mM TRIS-HCI, pH 7.8, 5 mM MgCI 2 , 0.2 mM EGTA, 1 mg/ml BSA, 0.2 mg/ml bacitracin.
  • [ 125 l]-Tyr 14 -Nociceptin binding assay- Frozen membranes were thawed, homogenised briefly and kept on ice until use.
  • test compounds 0.05 mg protein/well
  • 1.0 mg SPA beads/well WGA PVT beads, Amersham
  • buffer was added to 96 well plates at 25°C in a final volume of 200 ⁇ l.
  • testcompounds were determined using a [ 35 S]-GTP-g-S binding assay as detailed: Membranes (see above) were thawed, homogenised briefly and kept on ice until use. Test compounds, membranes (0.1 mg protein/well), 2.0 mg SPA beads/well (WGA PVT beads, Amersham), 1 ⁇ M GDP (Sigma, St. Louis, U.S.A.) and buffer was added to 96 well plates at 25°C in a volume of 175 ⁇ l.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed., 995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier that may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material, which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaeryth tol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilized and mixed, if desired, with auxil- iary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, trans- dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscu- lar, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, comstarch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and for the treatment and/or prevention of increased blood pressure, hypotension, excessive vasodilation or migraine; memory and attention deficits resulting from, but not limited to, Alzheimer's disease, Parkinson's disease, trauma and stroke; acute pain, chronic pain, arthritic pain or migraine; conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression; conditions in which the- re is symptoms of addictive drug withdrawal, including alcoholism; metabolic disorders such such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 0.1 mg to about 70 mg per day.
  • dosage In choosing a regimen for patients it may frequently be necessary to begin with a dosage of from about 20 to about 70 mg per day and when the condition is un- der control to reduce the dosage as low as from about 0.1 to about 10 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a method of treating and/or preventing increased blood pressure, hypotension, excessive vasodilation or migraine; memory and attention deficits resulting from, but not limited to, Alzheimer's disease, Parkinson's disease, trauma and stroke; acute pain, chronic pain, arthritic pain or migraine; conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression; conditions in which there is symptoms of addictive drug withdrawal, including alcoholism; metabolic disorders such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.
  • the present invention relates to the use of one or more com- pounds of the general formula I or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of increased blood pressure, hypotension, excessive vasodilation or migraine; memory and attention deficits resulting from, but not limited to, Alzheimer's disease, Parkinson's disease, trauma and stroke; acute pain, chronic pain, arthritic pain or migraine; conditions in which there is excessive dopamine such as Schizophrenia, Parkinson's disease and depression; conditions in which there is symptoms of addictive drug withdrawal, including alcoholism; metabolic disorders such as hyperglycaemia, dyslipidemia, Type 1 diabetes, Type 2 diabetes, hypertriglyceridemia, syndrome X, insulin resistance, IGT or obesity.

Abstract

La présente invention concerne l'utilisation de composés de formule (I). Dans la formule, R1 représente hydrogène, un alkyle C¿1-8? linéaire ou ramifié ou un groupe cycloalkyle C3-7; et R?2 et R3¿ représentent indépendamment hydrogène, alkyle, alcynyle, alcoxy, trifluoroalkyle, hydroxy, halogène, méthylthio, cyano, ou aralkyloxy; et R4 et R5 représentent indépendamment hydrogène, alkyle, cycloalkyle C¿3-7?, alcynyle, alcoxy, trifluoroalkyle, hydroxy, halogène, méthylthio, cyano, acylamino, méthylsulfonyle, méthylènedioxy, aryloxy ou aralkyloxy, ou R?4 et R5¿ représentent ensemble un groupe méthylènedioxy; et Ar représente indépendamment un groupe phényle, tétrahydronaphtyle ou thiényle. Ces composés ou un de leurs sels pharmaceutiquement acceptables sont utiles pour préparer une formulation pharmaceutique permettant de: traiter, prévenir, soulager ou améliorer des états dans lesquels il existe une altération de la pression sanguine, de l'hypotension, une vasodilatation excessive ou de la migraine ; traiter, prévenir, soulager ou améliorer les pertes de la mémoire et de l'attention liées entre autres à la maladie d'Alzheimer, à la maladie de Parkinson, aux traumatismes et aux accidents cérébrovasculaires ; traiter, prévenir, soulager ou améliorer les états douloureux tels que la douleur aiguë, la douleur chronique, la douleur arthritique ou la migraine ; traiter, prévenir, soulager ou améliorer des états dans lesquels on retrouve une quantité excessive de dopamine tels que la schizophrénie, la maladie de Parkinson et la dépression; traiter, prévenir, soulager ou améliorer des états associés à des symptômes de sevrage d'une drogue toxicomanogène, y compris l'alcoolisme; traiter, prévenir, soulager ou améliorer des troubles du métabolisme tels que l'hyperglycémie, la dyslipidémie, le diabète de Type 1, le diabète de Type 2, l'hypertriglycéridémie, le syndrome X, la résistance à l'insuline, la tolérance diminuée au glucose ou l'obésité. La présente invention concerne également des compositions pharmaceutiques comprenant ces composés et des procédés d'utilisation de ces mêmes composés et des compositions pharmaceutiques les contenant.
PCT/DK2000/000595 1999-10-29 2000-10-26 Utilisation de piperidines 3,4-substituees WO2001032178A1 (fr)

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Cited By (9)

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WO2002022572A2 (fr) * 2000-09-11 2002-03-21 Sepracor, Inc. Ligands pour les recepteurs de monoamine et transporteurs, et procedes d'utilisation de ces derniers
WO2003014114A2 (fr) * 2001-08-08 2003-02-20 Neurosearch A/S Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine
WO2005004896A1 (fr) * 2003-07-01 2005-01-20 Ufpeptides S.R.L. Antagonistes du recepteur nop pour le traitement de la maladie de parkinson
WO2007072150A2 (fr) * 2005-12-20 2007-06-28 Pfizer Products Inc. Derives de piperidine
US7294637B2 (en) 2000-09-11 2007-11-13 Sepracor, Inc. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter
CN112105610A (zh) * 2018-03-13 2020-12-18 朱比连特普罗德尔有限责任公司 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物
JP2021138744A (ja) * 2015-09-02 2021-09-16 トレベナ・インコーポレイテッドTrevena, Inc. ６員アザヘテロ環を含有するデルタ−オピオイド受容体調節化合物、同化合物を使用する方法、および同化合物を作る方法
US11702408B2 (en) 2017-02-17 2023-07-18 Trevena, Inc. 5-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
US11912713B2 (en) 2017-02-17 2024-02-27 Trevena, Inc. 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same

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WO2002022572A2 (fr) * 2000-09-11 2002-03-21 Sepracor, Inc. Ligands pour les recepteurs de monoamine et transporteurs, et procedes d'utilisation de ces derniers
WO2003014114A2 (fr) * 2001-08-08 2003-02-20 Neurosearch A/S Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine
WO2003014114A3 (fr) * 2001-08-08 2004-03-04 Neurosearch As Derives d'amine substitues et leur utilisation en tant qu'inhibiteurs du recaptage des neurotransmetteurs de monoamine
WO2005004896A1 (fr) * 2003-07-01 2005-01-20 Ufpeptides S.R.L. Antagonistes du recepteur nop pour le traitement de la maladie de parkinson
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JP7463318B2 (ja) 2015-09-02 2024-04-08 トレベナ・インコーポレイテッド ６員アザヘテロ環を含有するデルタ－オピオイド受容体調節化合物、同化合物を使用する方法、および同化合物を作る方法
JP2021138744A (ja) * 2015-09-02 2021-09-16 トレベナ・インコーポレイテッドTrevena, Inc. ６員アザヘテロ環を含有するデルタ−オピオイド受容体調節化合物、同化合物を使用する方法、および同化合物を作る方法
US11702408B2 (en) 2017-02-17 2023-07-18 Trevena, Inc. 5-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
US11912713B2 (en) 2017-02-17 2024-02-27 Trevena, Inc. 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
JP2021518338A (ja) * 2018-03-13 2021-08-02 ジュビラント プローデル エルエルシー Ｐｄ１／ｐｄ−ｌ１相互作用／活性化の阻害剤としての二環式化合物
US11529341B2 (en) * 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
JP7279063B2 (ja) 2018-03-13 2023-05-22 ジュビラント プローデル エルエルシー Ｐｄ１／ｐｄ－ｌ１相互作用／活性化の阻害剤としての二環式化合物
CN112105610B (zh) * 2018-03-13 2024-01-26 朱比连特普罗德尔有限责任公司 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物
JP7279063B6 (ja) 2018-03-13 2024-02-15 ジュビラント プローデル エルエルシー Ｐｄ１／ｐｄ－ｌ１相互作用／活性化の阻害剤としての二環式化合物
CN112105610A (zh) * 2018-03-13 2020-12-18 朱比连特普罗德尔有限责任公司 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物

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