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WO1999059997A1 - Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide - Google Patents

Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide Download PDF

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Publication number
WO1999059997A1
WO1999059997A1 PCT/DK1999/000266 DK9900266W WO9959997A1 WO 1999059997 A1 WO1999059997 A1 WO 1999059997A1 DK 9900266 W DK9900266 W DK 9900266W WO 9959997 A1 WO9959997 A1 WO 9959997A1
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WIPO (PCT)
Prior art keywords
phenyl
spiro
triaza
oxo
alkyl
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PCT/DK1999/000266
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English (en)
Inventor
Brett Watson
Rolf Hohlweg
Christian Thomsen
Original Assignee
Novo Nordisk 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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP2000549615A priority Critical patent/JP2002515503A/ja
Priority to AU38099/99A priority patent/AU3809999A/en
Priority to EP99920561A priority patent/EP1080091A1/fr
Publication of WO1999059997A1 publication Critical patent/WO1999059997A1/fr

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Classifications

    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • the present invention relates to use of small organic compounds acting as opioid receptor ligands for the treatment of vasomotor disturbances.
  • the present invention relates to the compounds of the general formula la or lb for the
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical composi-
  • a "hot flush” is a sudden transient sensation ranging from warmth to intense heat and typically accompanied by flushing and perspiration. It is the classic sign of the
  • nociceptin a novel heptadecapeptide, nociceptin.
  • Nociceptin and analogues thereof have been disclosed in WO 97/07212 , EP 813065 and in WO 97/07208.
  • These peptides and inhibitors thereof are said to be useful for antagonising physiologic effects of an opioid in an animal, and for treating/preventing a disease related to: hyperalgesia, neuroendocrine secretion, stress, locomotor activity, anxiety etc.
  • triaza-spiro compounds are vasodilating agents and morphinelike analgesics as disclosed in US 3,238,216 and US 3,155,670 by Janssen.
  • the present invention provides a compound of the formula la or lb as disclosed below or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of Type II diabetes, septic shock, inflammation, incontinence and vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes.
  • the present invention relates to use of a small organic compound acting as an opioid receptor ligand for the preparation of a pharmaceutical composition for the treatment of a disease selected from migraine, non insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence, vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes and/or for alleviating symptoms of drug withdrawal, in particular abstinence symptoms occurring during withdrawal from abusive drugs.
  • the invention relates to use of a small organic compound acting as a Nociceptin receptor ligands with a molecular weight of less than 1000 or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to use of small organic compounds acting as Nociceptin receptor ligand with a molecular weight less than 600 or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand with less than 5 amide bonds or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to use of a small organic compound acting as a Nociceptin receptor ligands wherein said compound has no amide bonds or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to use of a compound wherein said compound comprises a triaza-spiro compound acting as a Nociceptin receptor ligand or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to use of a small organic compound acting as a Nociceptin receptor ligand with an IC 50 less than 1 ⁇ M or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of vasomotor disturbances.
  • the invention relates to a compound of the general formula
  • R 1 is phenyl, arylalkyl or thienyl, optionally substituted with one or more of halo- gene, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C ⁇ -alkoxy or NR 6 R 8 wherein R 6 and R 8 independently are hydrogen or C ⁇ -alkyl, or R 1 is C ⁇ -alkyi; R 2 is aminophenyl, C ⁇ s-monoalkylaminophenyl, C ⁇ -dialkylaminophenyi, cyanophenyl, C 2.6 -alkylphenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, coumarinyl, said groups may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C ⁇ -alkyl,
  • R 2 is phenyl, phenoxy, benzodioxinyl or cyanodiphenylmethyl, any of which may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C ⁇ -alkoxy, C(0)R 7 , wherein R 7 is -OH, C ⁇ -alkoxy or -NR 12 R 13 , wherein R 12 and R 13 independently are hydrogen or C ⁇ s alkyl, provided that R 1 is not phenyl, R 3 is not methyl or hydrogen or R 4 is not hydrogen, acetyl, methyl, hy- droxymethyl, ethyl, 2-cyanoethyl, propionyl or methoxymethyl;
  • R 3 is hydrogen, C ⁇ -alky!, phenyl, benzyl or acetyl;
  • R 4 is hydrogen or (CH 2 ) m -(CHR 9 )-(CH 2 )p-AR 11 , wherein m and p independently are 0-4 and R 9 is hydrogen, C ⁇ -alkyl, phenyl or arylalkyl, R 11 is C ⁇ -alkyl, hydroxy, C.,.
  • R 5 is hydrogen or C ⁇ -alkyl
  • z is CHR wherein R 1 is hydrogen, C ⁇ -alkyl, phenyl or arylalkyl - or z is C 2 -8 alkylene, C 2 . 8 -alkenylene or C 2 . 8 -alkynyiene;
  • n 1 or 2 or a pharmaceutically acceptable salt thereof.
  • R is phenyl, arylalkyl or thienyl, optionally substituted with one or more of halogene, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C ⁇ -alkoxy or NR 6 R 8 wherein R 6 and R 8 independently are hydrogen or C, . 6 -alkyl, or R 1 is C ⁇ -alkyl.
  • R 2 is aminophenyl, C ⁇ -monoalkylaminophenyl, C ⁇ -dialkylaminophenyl, cya- nophenyl, C 2 . 6 -alkylphenyl, naphthyl, tetrahydronaphthyl, furanyl, indanyl, ben- zothienyl, benzofuranyl, said groups may be substituted with one or more of halo- gene, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C ⁇ -alkoxy, C(0)R 7 , wherein R 7 is -OH, -NR 12 R 13 , wherein R 2 and R 13 independently are hydrogen or C ⁇ e alkyl , or C ⁇ -alkoxy or R 2 is phenyl provided that R 1 is not phenyl, R 3 is not methyl or hydrogen and R 4 is not hydrogen, acetyl, methyl, hydroxy methyl, ethyl, 2-
  • R 3 is hydrogen, C ⁇ -alkyl, phenyl, benzyl or acetyl.
  • R 4 is hydrogen or (CH 2 ) m -(CHR 9 )-(CH 2 )p-AR 11 , wherein m and p independently are 0-4 and R 9 is hydrogen, C ⁇ -alkyl, phenyl or arylalkyl, R 11 is C ⁇ -alkyl, hydroxy, C, .
  • R 5 is hydrogen or C 1 . 4 -alkyl.
  • z is CHR 10 wherein R 10 is hydrogen, C ⁇ -alky!, phenyl or arylalkyl - or z is C 2.8 - alkylene, C 2 . 8 -alkenylene or C 2 . 8 -alkynylene.
  • n 1 or 2 or a pharmaceutically acceptable salt thereof.
  • R is C ⁇ -alkyl, phenyl, arylalkyl or thienyl.
  • R 2 is aminophenyl, C L e-monoalkylaminophenyl, C ⁇ -dialkylaminophenyl, cyanophenyl, C 2 . 6 -alkylphenyl, naphthyl, tetrahydronaphthyl, furanyl, indanyl, benzothienyl, benzofuranyl, said groups may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C,. 6 -alkyl, hydroxy, C ⁇ -alkoxy, C(0)R 7 , wherein R 7 is -OH, - NR 12 R 13 , wherein R 12 and R 13 independently are hydrogen or C,. 6 alkyl, or
  • R 2 is cyanophenyl or naphthyl, said groups may be substituted with one or more of fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C ⁇ - alkoxy, C(0)R 7 , wherein R 7 is -OH, C ⁇ -alkoxy or -NR 12 R 13 wherein R 12 and R 13 independently are hydrogen or C,_ 6 alkyl.
  • n is 2.
  • Another preferred embodiment of the invention comprises compound la wherein R ⁇ R 2 , R 3 , R 4 , R 5 , z and n are defined as above.
  • R 1 is phenyl
  • the invention comprises use of a compound of the general formula
  • R 1 is phenyl, arylalkyl or thienyl, optionally substituted with one or more of halo- gen, cyano, nitro, trifluoromethyl, C 1 6 -alkyl, hydroxy, C ⁇ -alkoxy or NR 6 R 8 wherein R 6 and R 8 independently are hydrogen or C ⁇ -alkyl, or R 1 is C,.
  • R 2 is phenyl, phenoxy, benzodioxinyl, cyanodiphenylmethyl, aminophenyl, C ⁇ - monoalkylaminophenyl, naphthyl, tetrahydronaphthyl, anthryl, furanyl, indanyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, coumari- nyl, said groups may be substituted with one or more of halogen, cyano, nitro, trifluoromethyl, C ⁇ -alkyl, hydroxy, C.,. 6 -alkoxy, C(0)R 7 , wherein R 7 is -OH, C ⁇ - alkoxy or -NR 12 R 13 , wherein R 12 and R 13 independently are hydrogen or C _ 6 alkyl;
  • R 3 is hydrogen, C.,_ 6 -alkyl, phenyl, benzyl or acetyl;
  • R 4 is hydrogen or (CH 2 ) m -(CHR 9 )-(CH 2 )p-AR 11 , wherein m and p independently are 0-4 and R 9 is hydrogen, C 1-6 -alkyl, phenyl or arylalkyl, R 11 is C ⁇ -alkyl, hydroxy, C g-alkoxy, guanidino, an amino acid residue or a 2-4 peptidyl residue with a C- terminal group consisting of either OCH 3 , or NH 2 ; R 11 can also be a group NR 1 R 15 wherein R 14 and R 15 independently are hydrogen, C ⁇ alkyl, (CH 2 )qR ) 1 16 where q can be 0 to 6 and R 16 can be a C3-C7 membered cycloalkyl ring, an optionally substituted aromatic or heteroaromatic ring, an aliphatic ring containing one or more heteroatoms, an alkoxy or aryloxy group, an amino or a
  • R 5 is hydrogen or C ⁇ -alkyl
  • z is CHR 10 wherein R 10 is hydrogen, C ⁇ -alkyl, phenyl or arylalkyl - or z is C 2.8 - alkylene, C 2.8 -alkenylene or C 2 . 8 -alkynylene;
  • n is 1 or 2 or a pharmaceutically acceptable salt thereof for the treatment of migraine, non insulin dependent diabetes mellitus (type II diabetes), sepsis, inflammation, incontinence and/or vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes.
  • composition in another embodiment of the invention is in a form suitable for oral, nasal, transdermal, pulmonal, or parenteral administration.
  • the compound of the formula la or lb is administered as a dose in the range from about 0.01 to about 5000 mg per patient per day, preferably from about 1 to about 1000 mg per patient per day, especially from about 10 to about 100 mg per patient per day, e.g. about 100 mg per patient per day.
  • the invention in a fourth aspect relates to a method for the treatment or prevention of migraine, Type II diabetes, sepsis, inflammation, incontinence and/or vasomotor disturbances, in particular the peripheral vasomotor effects known as hot flushes or hot flashes, the method comprising administering to a patient in need thereof an effective amount of compound of the formula la or lb or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising triaza-spiro compounds with high affinity to the nociceptin receptor, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method of treatment symptoms of drug withdrawal, in particular abstinence symptoms occurring during withdrawal from abusive drugs.
  • the effective such as the therapeutically effective amount of a compound of the formula la or lb 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 term "patient” comprises any mammal which may benefit from treatment or prevention of vasomotor disturbances, such as a human, especially if the mammal is a female, such as a woman. However, “patient” is not intended to be limited to a woman.
  • small organic compounds refers to compounds with a molecular weight below 1000 and with less than 5 amide bonds or no amide bonds.
  • triaza-spiro represents a compound of formula with various substituents as defined above.
  • high affinity represents an IC 50 below 1 ⁇ M.
  • arylalkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic hydrocarbon; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like.
  • C ⁇ -alky! 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.
  • C L g-alkoxy alone or in combination is intended to include those groups of the designated length in either a linear or branched or cyclic configuration linked thorugh 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.
  • halogen means fluorine, chlorine, bromine or iodine.
  • amino acid residue or peptidyl residues is also meant to comprise naturally occurring or synthetically produced amino acids linked to the compound by an amide bond.
  • C 2 8 .-alkylene represent a branched or straight alkyl group having from one to the specified number of carbon atoms.
  • Typical C 2 _ 8 - alkylene groups include, but are not limited to, ethylene, n-propylene, iso- propylene, butylene, iso-butylene, sec-butylene, tert-butylene, pentylene, iso- pentylene, hexylene, iso-hexylene and the like.
  • C 2 . 8 .-alkenylene represents an olefinicaily unsatu- rated branched or straight group with at least one double bond.
  • groups include, but are not limited to, vinyl, 1 -propenylene, allylene, iso- propenylene, 1 ,3-butadienylene, 1 -butenylene, hexenylene, pentenylene, and the like.
  • C 2 . 8 .-alkynylene represent an unsaturated branched or straight group having at least one triple bond. Examples of such groups include, but are not limited to, 1 -propynylene, 1 -butynylene, 2-butynylene, 1 - pentynylene, 2-pentynylene and the like.
  • ligand is also meant to comprise a compound with agonistic, partial agonistic or antagonistic activity specifically binding to receptor proteins.
  • treatment is also meant to comprise prophylactic treatment.
  • the preparation of compounds of formula la may include, but are not limited to the following methods:
  • a compound of formula (II) wherein R 1 , R 3 , R R 5 and n are as defined above may be allowed to react with a compound of formula (III), wherein R 2 and z are defined as above and X is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride and a catalyst, e.g.
  • a compound of formula (II) wherein R 1 , R 3 , R 4, R 5 , and n are as defined above may be allowed to react with an aldehyde of formula (IV), wherein R 2 is as defined above and the linker y is one C-atom shorter than linker z, where z is as defined above, to form an imine of formula (V).
  • the reaction may be carried out in a suitable solvent like a lower aliphatic alcohol as e.g. ethanol or an ether as e.g. tetrahydrofuran or a mixture of these.
  • the formed iminium derivative of formula (V) is then reduced to an amine of formula (la) by the addition of a suitable reducing agent, e.g. a hydride as sodium cyanoborohydride or sodium borohydride in e.g. 1 to 120 h at 20° C to reflux temperature.
  • a suitable reducing agent e.g. a hydride as sodium cyanoborohydride or sodium
  • Compounds of formula (la) may also be prepared in a parallel fashion using solid phase technology, e.g. as described by F. Zaragoza and S.V. Petersen, Tetrahedron, 52, 10823 (1996).
  • R 4 in a compound of formula (II) is replaced by (CH 2 ) m -(CHR 9 )-(CH 2 ) p -C(0)R 7b , wherein m, p and R 9 are as defined above and R 7 is a resin-O- or a resin-NH-residue.
  • a compound of formula (VI) wherein R ⁇ R 2 , R 3 , R 5 , z and n are as defined above, may be deprotonated at N3 with a suitable base, as sodium hydride, n-butyl lith- ium or potassium tert.-butoxide in an aprotic solvent as e.g. dimethyl formamide or dimethylsulfoxide and subsequently allowed to react with a reagent of formula (VII), wherein R 4 and X are as defined above.
  • the reaction may be carried out at temperatures from 0 °C to reflux temperature, preferably at room temperature in 1 to 24 hours, to form a compound of formula (la).
  • a compound of formula (la) may further be synthesized by allowing a compound of formula (VIII), wherein R 1 , R 2 , R 3 , R 5 , R 9 , m, p, n an z are as described above, to react with a compound of formula (IX), in which the R 11 group bears a residue which is coupled to a resin and may be subsequently cleaved from the resin as an ester or amide moiety.
  • the coupling reaction between (VIII) and (IX) may be carried out in a suitable solvent as e.g. dimethyl formamide or N-methyl pyrrolidone using e.g.
  • the compound of the formula la or lb may be prepared in the form of pharmaceutically acceptable salts such as base or acid addition salts, especially acid-addition salts, including salts of organic acids and min- eral acids.
  • pharmaceutically acceptable salts such as base or acid addition salts, especially acid-addition salts, including salts of organic acids and min- eral 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, maleic 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.
  • Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compound of the formula la or lb are able to form.
  • 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 appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the formula la or lb of this invention may form solvates with standard low molecular weight solvents using methods known to a person skilled in the art.
  • the compound of the formula la or lb 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.
  • a pharmaceutical composition for use in accordance with the present invention comprises, one or more compound of the formula la or lb as active ingredient(s), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing compounds of the formula la or lb 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., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include Compound of formula la or lb 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 which may be in the form of a 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, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol 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 auxiliary 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, transdermai or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula la or lb dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • 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, corn starch, and/or po- tato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound 100 mg Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Ad.
  • mice Male Sprague Dawley rats ( 300 ⁇ 25 g) were anaesthetized with pentobarbital sodium (50 mg/kg i.p.) and polyethylene catheters were positioned in both femoral veins for the intravenous administration of drugs, such as nociceptin and analogues, and into the left femoral artery in order to measure arterial blood pressure and heart rate.
  • drugs such as nociceptin and analogues
  • the trachea was cannulated with polyethylene tubing and the rat was pithed, ventilated and drug treated as described by Nuki Y. et al. (Effects of Dorsal Rhizotomy on Depressor Response to Spinal Cord Stimulation Mediated by Endogenous Calcitonin Gene-related Peptide in the Pithed Rat. J. Neurosurg. 1993; 79:899-904).
  • HPLC-MS analyses were performed on a PE Sciex API 100 LC/MS System using Method 1 : a WatersTM 3 mm x 150 mm 3.5 ⁇ C-18 Symmetry column and positive ionspray with a flow rate of 20 ⁇ L/minute.
  • Method 2 a YMC ODS-A 120 A s - 5 ⁇ 3 mm x 50 mm column and positive ionspray with a flow rate of 20 ⁇ L/minute.
  • the column was eluted with a linear gradient of 5-90% A, 85-0% B and 10% C in 7.5 minutes at a flow rate of 1.5 ml/min.
  • solvent A acetonitrile
  • solvent B water
  • solvent C 0.5% trifluoroacetic acid in water).
  • M.p. is melting point and is given in °C and is not corrected.
  • Column chromatography was carried out using the technique described by W.C. Still et al,
  • the resin was agitated with 20% piperidine in N,N- dimethylformamide (10 ml) for 30 minutes. The solution was removed by suction, the resin was washed with N,N-dimethylformamide (2x 10 ml), dichloromethane (4x 10 ml) and methanol (3x 10 ml) and dried. This yielded the Wang resin (2.53 g) with attached 3-carboxy-1-phenyl-1 ,3,8-triazaspiro[4.5]decan-4-one (0.67 mmol/g).
  • the resin was drained, washed with dimethyl sulfoxide (2x 1 ml), dichloromethane (4x 1 ml) and methanol (2x 1 ml).
  • a solution of sodium methoxide (0.009 mmol) in a mixture of tetrahydrofu- ran/methanol 4:1 (2 ml) was added to the resin and the suspension was agitated at 50 °C for 16 h.
  • the mixture was neutralized by addition of a solution of acetic acid (0.01 mmol) in a mixture of tetrahydrofuran/methanol 4:1 (1 ml), the solution was drained and the resin was washed with tetrahydrofuran (1 ml).
  • the combined filtrates were concentrated in vacuo to yield the title compounds.
  • the formed precipitate was collected by filtration, washed successively with water (800 ml), toluene (600 ml) and icecold acetone (2 X 200 ml) and dried affording the title compound as a powder (191.20 g, 68% yield).
  • Teflon tube equipped with a frit on a mechanical shaker.
  • the resin was allowed to swell in dimethyl formamide (1.5 ml) for 1 h.
  • the solvent was removed by suction and the resin was agitated with 20% pipehdine in N,N-dimethylformamide (1.5 ml) for 30 minutes.
  • the solution was removed by suction and the resin was washed with N,N-dimethylformamide (3x 1.5 ml).
  • the resin was filtered and washed with dimethylformamide (2 x 1.5 ml), dichloromethane (4 x 1.5 ml), methanol (2 x 1.5 ml) and tetrahydrofuran/methanol 4:1 (2 x 1.5 ml).
  • a solution of sodium methoxide (0.009 mmol) in a mixture of tetrahydrofuran/methanol 4:1 (2 ml) was added to the resin and the suspension was agitated at 50 °C for 16 h.
  • Rink Amide (AM) resin (0.69 mmol/g, pur- chased from Novabiochem) was suspended in piperidine/N,N-dimethylformamide (20%) (all volumes are calculated as 10 ml/gram of resin) and shaken on a mechanical shaking apparatus for 0.5 h.
  • the resin was filtered, rinsed with N,N- dimethylformamide, suspended in piperidine/N,N-dimethylformamide (20%) and shaken for 0.5 h.
  • the resin was filtered and washed as follows: 3 x N,N- dimethylformamide /water (90%), 2 x ethanol, 3 x N,N-dimethylformamide, 5 x methylene chloride.
  • the resin was dried in vacuo and suspended in N,N- dimethylformamide.
  • Fmoc-Arg(Pbf).OH 1.7 g, 01.7 mmol, 4 equivalents
  • EDAC N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole
  • the resin was filtered and washed successively with 3 x N,N-dimethylformamide /water (90%), 3 x N,N-dimethylformamide, 3 x methylene chloride, was suspended in piperidine/N,N-dimethylformamide (20%) and shaken for 0.5 h.
  • the resin was filtered and washed as follows: 3 x N,N-dimethylformamide /water (90%), 2 x ethanol, 3 x N,N-dimethylformamide, 5 x methylene chloride.
  • the resin was dried in vacuo and suspended in N,N-dimethylformamide and (8- naphthalen-1-ylmethyl-4-oxo-1-phenyi-1 ,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid (1.08 g, 2.51 mmol, 3.6 equivalents) was added followed by EDAC (0.47 g, 2.51 mmol, 3.6 equivalents), HOBT (0.33 g, 2.51 mmol, 3.6 equivalents) and the reac- tion was allowed to stir at room temperature for 20 h.
  • the resin was filtered and washed 3 x N,N-dimethylformamide /water (90%), 3 x N,N-dimethylformamide, 3 x methylene chloride and dried in vacuo.
  • the resin was suspended in trifluoroacetic acid/water (95%) and shaken for 2 h.
  • the filtrate was collected and added dropwise to cyclohexane/ether (50%) after which a white precipitate was observed.
  • This white solid was collected and washed 3 x cyclohexane/ether (50%) with the aid of a centrifuge. This was dissolved in a minimum amount of acetonitrile/water (10%) and lyophiiized affording the title compound (273 mg, 50% yield), as a white powder.
  • HPLC retention time 11.01 minutes (5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 30 minutes at 35 °C).
  • This compound was prepared and purified analogously to EXAMPLE 8 using Rink Amide (AM) Resin (0.69 mmol/g) (0.200 g, 0.138 mmol, 1 equivalent), Fmoc- .D-Arg(Pbf).OH (0.358 g, 0.552 mmol, 4 equivalents) to yield the title compound (73 mg, 59% yield) as a white powder. This powder was assumed to be salted with two equivalents of trifluoroacetic acid.
  • AM Rink Amide
  • the resin was suspended in dimethylformamide, treated with (8-naphthalen-1 -ylmethyl-4-oxo-1 -phenyl-1 ,3,8-triaza-spiro[4.5]dec-3-yl)- acetic acid (0.274 g, 0.640 mmol), 1-hydroxybenzotriazole (0.099 g, 0.640 mmol) and N,N'-diisopropylcarbodiimide (0.081 g, 0.640 mmol).
  • the reaction was al- lowed to shake for 20 h at room temperature.
  • the resin was filtered, suspended in dimethylsulfoxide and heated to 40 °C for 1 h.
  • the resin was again filtered, suspended in dimethylsulfoxide (8 ml) and heated to 40 °C for 1 h.
  • the resin was filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml); 3 x dimethylformamide (8 ml); 3 x dichloromethane (8 ml) and air-dried.
  • the resin was treated with trifluoroacetic acid/water (95/5) (8 ml) for 1 h at room temperature. The filtrate was collected and concentrated in vacuo to give the desired product.
  • EXAMPLE 10A 2-. SV[2-(8-Naphthalen-1-ylmethyl-4-oxo-1 -phenyl-1.3.8-triaza-spiro[4.51dec-3-yn- acetylamino]-5-ureido-pentanoic acid amide
  • Rink Amide (AM) resin (Novabiochem) (0.200 g, 0.138 mmol) was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature. The resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for
  • the resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1-
  • the resin was filtered and washed as follows: 3 x dimethylforma- mide/water (90/10) (8 ml); 3 x dimethylformamide (8 ml); 3 x dichloromethane (8 ml) and air-dried.
  • the resin was treated with trifluroacetic acid/water (95/5) (8 ml) for 2 h at room temperature.
  • the filtrate was collected and concentrated in vacuo to give the desired product.
  • Rink Amide (AM) resin (Novabiochem) (0.200 g, 0.138 mmol) was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room tem- perature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylforma- mide/water (90/10) (8 ml), 3 x dimethylformamide(8 ml), 3 x dichloromethane.
  • the resin was suspended in dimethylformamide (8 mL), L-Fmoc-Arg(Pbf)-OH (0.358 g, 0.552 mmol) and 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) were added. N,N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) was added and the reaction was allowed to shake for 20 h at room temperature. The resin was filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml), Fmoc.Gly.OH (0.163 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'- diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added. The reaction was allowed to shake 20 h at room temperature. The resin was filtered and washed as follows: 3 x dimethylformamide/water (80/20) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml). The resin was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room tem- perature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml); (8-naphthaien-1-ylmethyl-4-oxo-1- phenyl-1 ,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid (0.269 g, 0.552 mmol), 1- hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added.
  • the reaction mixture was allowed to shake at room temperature for 20 h and filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml); 3 x dimethylformamide (8 ml); 3 x dichloromethane (8 ml) and air-dried.
  • the resin was treated with trifluoroacetic acid/water (95/5) (8 ml) for 2 h at room temperature.
  • the filtrate was collected and added dropwise to cyclohexane/ether at 0 °C to form a white precipitate.
  • EXAMPLE 12 5-Guanidino-2-. S 2- ⁇ 2-[2-( 8-naphthalen-1 -ylmethyl-4-oxo-1 -phenyl-1.3.8-triaza- spiro[4.5]dec-3-yl)-acetylamino]-acetylamino ⁇ -acetylamino.-pentanoic acid amide
  • Rink Amide (AM) resin (Novabiochem) (0.200 g, 0.138 mmol) was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room tem- perature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml), L- Fmoc-Arg(Pbf)- OH (0.358 g, 0.552 mmol) and 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) were added. N,N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) was added and the reaction was allowed to shake for 20 h at room temperature. The resin was filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethyGformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was sus- pended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml), Fmoc-Gly-Gly-OH (0.195 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'- diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added and the reaction was allowed to shake for 20 h at room temperature.
  • the resin was filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room tem- perature.
  • the resin was filtered and rinsed with dimethylformamide and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1- ylmethyi-4-oxo-1 -phenyl-1 ,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid (0.269 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'- diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added.
  • the reaction mixture was allowed to shake at room temperature for 20 h, filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml); 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was treated with trifluoroacetic acid/water (95/5) (8 ml) for 2 h at room temperature.
  • the filtrate was collected and added dropwise to cyclohexane/diethylether (50/50) at 0 °C to form a white precipitate which was collected and washed with the cyclohexane/diethylether solution. 32.5 mg of product were collected.
  • the compound was synthesized using 3-(7-bromo-heptyl)-8-naphthalen-1- ylmethyl-1 -phenyl-1 , 3, 8-triaza-spiro[4.5]decan-4-one, prepared as described in Example 13.
  • the 1 ,3-diaminopropyl Wang resin was prepared using the procedure described above.
  • N-(2-aminoethyl)-2-(8-naphthalen-1-ylmethyl-4-oxo-1-phenyl- 1 ,3,8-triazaspiro[4.5]dec-3-yl)acetamide dihydrochloride (0.203 g, 0.40 mmol) in dimethylformamide (1.5 ml) was added diisopropylethylamine (0.046 g, 3.6 mmol) and 1-H-pyrazole-1-carboxamidine hydrochloride (0.088 g, 0.60 mmol). The mixture was stirred at room temperature for 1 h and the same amount of 1-H- pyrazole-1-carboxamidine hydrochloride was added.
  • Rink Amide (AM) resin (Novabiochem) (0.200 g, 0.138 mmol) was suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature.
  • the resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 25 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml), L Fmoc-Lys(Boc)- OH (0.258 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'-diisopropylcarbodiimide (0.071 g, 0.552 mmol) were added and the reaction was allowed to shake for 20 h at room temperature. The resin was filtered and
  • the resin was filtered and rinsed with dimethylformamide (8 ml) and again suspended in dimethylformamide/piperidine (80/20) (8 ml) and shaken for 30 min at room temperature; the resin was washed as follows: 3 x dimethylformamide/water (90/10) (8 ml), 3 x dimethylformamide (8 ml), 3 x dichloromethane (8 ml).
  • the resin was suspended in dimethylformamide (8 ml); (8-naphthalen-1- ylmethyl-4-oxo-1-phenyl-1 ,3,8-triaza-spiro[4.5]dec-3-yl)-acetic acid (0.269 g, 0.552 mmol), 1-hydroxybenzotriazole (0.085 g, 0.552 mmol) and N,N'- diisopropylcarbodiim.de (0.071 g, 0.552 mmol) were added.
  • the reaction mixture was allowed to shake at room temperature for 20 h, filtered and washed as follows: 3 x dimethylformamide/water (90/10) (8 ml); 3 x dimethylformamide; 3 x di- chloromethane (8 ml).
  • the resin was treated with trifluoroacetic acid/water (95/5) (8 ml) for 2 h at room temperature.
  • the filtrate was collected and added dropwise to heptane/diethylether at 0 °C to form a white precipitate which was collected and washed with the heptane/diethylether solution. 13.7 mg of product were isolated.

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Abstract

L'invention concerne l'utilisation de petits composés organiques agissant comme des ligands du récepteur opioïde, pour le traitement de troubles vasomoteurs. Elle se rapporte notamment à des composés triaza-spiro de formule générale (Ia) ou (Ib), dans lesquelles R1 est choisi parmi phényle, arylalkyle ou thiényle; R2 est choisi parmi aminophényle, monoalkylaminophényle C¿1-6?, dialkylaminophényle C1-6, cyanophényle, alkylphénylenaphtyle C2-6, tétrahydronaphtyle, furanyle, indanyle, benzothiényle ou benzofuranyle; R?3¿ représente hydrogène, alkyle C¿1-6?, phényle, benzyle ou acétyle; R?4¿ représente hydrogène ou (CH¿2?)m-(CHR?9)-(CH¿2)p-AR11; R5 représente hydrogène ou alkyle C¿1-4?; z représente CHR?10, R10¿ représentant hydrogène, alkyle C¿1-6?, phényle ou arylalkyle - ou z représente alkylène C2-8, alcénylène C2-8 ou alkynylène C2-8; n vaut 1 ou 2. Elle peut encore se rapporter à un sel acceptable au plan pharmaceutique desdits composés, ledit sel et les composés étant utilisés pour le traitement de la migraine, du diabète non-insulinodépendant (diabète de type II), la septicémie, l'inflammation, l'incontinence et/ou les troubles vasomoteurs, notamment les effets vasomoteurs périphériques connus sous le nom de bouffées de chaleur.
PCT/DK1999/000266 1998-05-18 1999-05-14 Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide WO1999059997A1 (fr)

Priority Applications (3)

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JP2000549615A JP2002515503A (ja) 1998-05-18 1999-05-14 オピオイド受容体のサブタイプへの高い親和性を有する新規１，３，８−トリアザスピロ〔４，５〕デカノン
AU38099/99A AU3809999A (en) 1998-05-18 1999-05-14 Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes
EP99920561A EP1080091A1 (fr) 1998-05-18 1999-05-14 Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide

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DK0681/98 1998-05-18
DK68198 1998-05-18
DK71198 1998-05-20
DK0711/98 1998-05-20
DKPA199800729 1998-05-26
DK72998 1998-05-26
DKPA199800927 1998-07-10
DKPA199800927 1998-07-10
DKPA199900111 1999-01-29
DKPA199900111 1999-01-29

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EP0997464A1 (fr) * 1998-10-23 2000-05-03 Pfizer Inc. 1,3,8-Triazaspiro[4,5] decanones utiles comme agonistes du récepteur orl1
WO2001036418A1 (fr) * 1999-11-17 2001-05-25 Novo Nordisk A/S Nouvelles triazaspirodecanones a affinite elevee pour des soustypes de recepteurs opioides
WO2001046192A1 (fr) * 1999-12-22 2001-06-28 Meiji Seika Kaisha, Ltd. COMPOSES SPIRO UTILES EN TANT QU'AGONISTES DES RECEPTEURS DES OPIOIDES $g(d)
EP1256575A1 (fr) * 2000-02-18 2002-11-13 Meiji Seika Kaisha Ltd. Derives de phenoxyalkylamine utiles en tant qu'agonistes du recepteur opioide delta
WO2002100861A1 (fr) * 2001-06-13 2002-12-19 Akzo Nobel N.V. Derives de 1-(3-phenyloxypropyl)piperidine
WO2002013759A3 (fr) * 2000-08-15 2003-07-10 Cpd Llc Methode de traitement du syndrome du diabete de type ii humain
WO2003082333A1 (fr) 2002-03-29 2003-10-09 Mitsubishi Pharma Corporation Remede contre les troubles du sommeil
US6635653B2 (en) 2001-04-18 2003-10-21 Euro-Celtique S.A. Spiropyrazole compounds
US6686370B2 (en) 1999-12-06 2004-02-03 Euro-Celtique S.A. Triazospiro compounds having nociceptin receptor affinity
WO2004022558A2 (fr) * 2002-09-09 2004-03-18 Janssen Pharmaceutica, N.V. Derives de 1,3,8-triazaspiro[4.5]decan-4-one a substitution hydroxyalkyle utiles pour traiter des maladies associees au recepteur orl-1
EP1402899A1 (fr) * 2001-05-08 2004-03-31 Toray Industries, Inc. Remedes contre la sepsie
US6777421B2 (en) 2001-04-10 2004-08-17 Ortho-Mcneil Pharmaceutical, Inc. 1,3,8-Triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
WO2004104004A2 (fr) * 2003-05-23 2004-12-02 Zealand Pharma A/S Analogues de nociceptine et leurs utilisations
US6828440B2 (en) 2001-04-18 2004-12-07 Euro-Celtique, S.A. Spiroindene and spiroindane compounds
US6846831B2 (en) 2000-08-15 2005-01-25 Cpd, Llc Method of treating the syndrome of lipodystrophy
US6861421B2 (en) 2001-04-18 2005-03-01 Euro-Celtique S.A Nociceptin analogs
US6867222B2 (en) 2001-04-18 2005-03-15 Euro-Celtique, S.A. Nociceptin analogs
US6872733B2 (en) 2001-04-18 2005-03-29 Euro-Celtique S.A. Benzimidazolone compounds
US6919310B2 (en) 2000-08-15 2005-07-19 Cpd, Llc Method of treating the syndrome of coronary heart disease risk factors in humans
US6969712B2 (en) 2000-11-15 2005-11-29 Banyu Pharmaceutical Co., Ltd. Benzimidazole derivatives
US6979436B2 (en) 1999-11-19 2005-12-27 Palatin Technologies, Inc. Opioid metallopeptide compositions and methods
US6984664B2 (en) 1999-12-06 2006-01-10 Euro-Celtique, S.A. Tertiary amino compounds having opioid receptor affinity
US6995168B2 (en) 2002-05-31 2006-02-07 Euro-Celtique S.A. Triazaspiro compounds useful for treating or preventing pain
US7125877B2 (en) 2002-05-14 2006-10-24 Banyu Pharmaceutical Co., Ltd. Benzimidazole derivatives
US7456198B2 (en) 1999-12-06 2008-11-25 Purdue Pharma L.P. Benzimidazole compounds having nociceptin receptor affinity
WO2011160084A1 (fr) * 2010-06-18 2011-12-22 Altos Therapeutics, LLC Antagonistes d2, procédés de synthèse et méthodes d'utilisation
US8354434B2 (en) 2006-01-30 2013-01-15 Purdue Pharma L.P. Cyclourea compounds as calcium channel blockers
US8399474B2 (en) 2006-10-20 2013-03-19 Neurendo Pharma, Llc Method of restoring the incretin effect
US8703948B2 (en) 2006-11-28 2014-04-22 Janssen Pharmaceutica Nv Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
US10034871B2 (en) 2014-11-07 2018-07-31 Regents Of The University Of Minnesota Salts and compositions useful for treating disease
US11472777B2 (en) * 2015-09-14 2022-10-18 The National Institute for Biotechnology in the Negev Ltd. Piperazine and piperidine derivatives, their synthesis and use thereof in inhibiting VDAC oligomerization, apoptosis and mitochondria dysfunction

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