EP0873322A1 - Novel compounds with analgesic effect - Google Patents

Novel compounds with analgesic effect

Info

Publication number
EP0873322A1
EP0873322A1 EP96943427A EP96943427A EP0873322A1 EP 0873322 A1 EP0873322 A1 EP 0873322A1 EP 96943427 A EP96943427 A EP 96943427A EP 96943427 A EP96943427 A EP 96943427A EP 0873322 A1 EP0873322 A1 EP 0873322A1
Authority
EP
European Patent Office
Prior art keywords
compound
compound according
conr
cor
hydrogen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP96943427A
Other languages
German (de)
English (en)
French (fr)
Inventor
Edward Roberts
Claes Wahlestedt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca Canada Inc
Original Assignee
Astra Pharma Inc
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 Astra Pharma Inc filed Critical Astra Pharma Inc
Publication of EP0873322A1 publication Critical patent/EP0873322A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention is related to novel compounds which are substituted 7-membered nitrogen rings, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds.
  • the novel compounds are used in therapy, and in particular for the treatment of pain.
  • the ⁇ receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the ⁇ receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the ⁇ receptor have also been shown to posess immunomodulatory activities.
  • the problem underlying the present invention was to find new analgesics having excellent analgesic effects, but also with an improved side-effect profile over current ⁇ agonists and potential oral efficacy.
  • Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
  • novel compounds according to the present invention are defined by the general formula (I)
  • A is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, each optionally and independently substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH2) 0 CF3, halogen, CONR 5 R 6 , CO 2 R 5 , COR 5 , (CH 2 )oNR 5 R 6 , (CH 2 )oCH3(CH 2 )oSOR 5 R 6 , (CH 2 ) 0 SO 2 R 5 , (CH 2 ) 0 SO 2 NR 5 , (CH 2 )oNR 5 COR 6 and — NR 5 (CH 2 ) 0 COR 1 ; wherein o is 0, 1, or 2, and R , R and R are as defined below respectively;
  • R is selected from hydrogen, a branched or straight C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C -C6 cycloalkyl; Cg-Cio aryl; and heteroaryl having from 5 to 10 atoms selected from any of C, S, N and O;
  • R and R is each and independently as defined for R above;
  • R is selected from hydrogen, CH3, OR , CO2R , and CH CO 2 R wherein R is as defined above; B is a substituted or unsubstituted aromatic; an optionally substituted C5-C10 hydroaromatic; a heteroaromatic or a heterohydroaromatic moiety having from 5 to 10 atoms selected from any of C, S, N and O, optionally substituted by 1-2 substituents each and independently selected from hydrogen, CH3, CF3, halogen, (CH2) p CONR R ,
  • Preferred compounds according to the invention are compounds of the formula (I) wherein
  • A is selected from phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, and pyrrolidinyl; wherein
  • each A group being optionally substituted by 1 or 2 substituents independently selected from hydrogen, CH3, (CH 2 ) 0 CF3, F, Cl, CONR 5 R 6 , CO 2 R 5 , COR 5 , (CH2) ⁇ SOR 5 , (CH2)oSO 2 R 5 , (CH2) 0 SO 2 NR 5 , (CH 2 )oNR 5 COR 6 and NR 5 (CH 2 ) 0 COR 6 ; wherein R 5 and R are as defined below, and o is 0 or 1; R , R and R is each and independently selected from hydrogen, a branched or straight C1-C4 alkyl, C3-C5 cycloalkyl, C4-C8 (alkyl-cycloalkyl) wherein alkyl is -C2 alkyl and cycloalkyl is C3-C6 cycloalkyl, and phenyl;
  • R is hydrogen, methyl, or OR wherein R is as defined above;
  • B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, pyrryl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl. indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, pyrrolidinyl, indazolinyl, and
  • each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, CH , CF3, halogen, (CH 2 ) p CONR 5 R 6 , (CH 2 )pNR 5 R 6 , (CH 2 ) p COR 5 , (CH 2 ) p CO 2 R 5 , and OR 5 ;
  • R and R are each and independently selected from hydrogen, CH3, CH(Me) 2 ,
  • each A substituent may be optionally and independently substituted by 1 or 2 substituents selected from H, CH3, (CH 2 ) 0 CF3, F, Cl, CONR R , CO 2 R 5 , (CH 2 ) 0 SOR 5 , (CH 2 )oSO 2 R 5 , (CH 2 ) D SO 2 NR 5 R 6 , (CH 2 )oNR 5 COR 6 , and NR (CH ) 0 COR ; wherein R and R are as defined below, and 0 is 0, 1 or 2;
  • R and R is each and independently selected from phenyl, methyl and ethyl; or R and R taken together is -(CH 2 )r- wherein r is 4 or 5;
  • 2 1 R is H, methyl, or OR ;
  • R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R , and R is each and independently as defined forR above;
  • B is selected from phenyl, naphthyl, indolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, furanyl, quinolinyl, isoquinolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydroquinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, indazolinyl, and
  • each B group being optionally substituted by 1-2 substituents independently selected from hydrogen, methyl, CF 3 , halogen, (CH 2 ) p CONR 5 R 6 , (CH 2 )pNR 5 R 6 , (CH2) p COR 5 , (CH 2 ) p CO 2 R 5 , and OR 5 ,
  • R " and R are each and independently selected from H, CH3, CH(Me)2, CH 2 CH(Me)2, CH(Me)CH 2 CH 3 (CH 2 ) p CONR 5 R 6 , (CH 2 )pNR 5 R 6 , (CH 2 ) p CONR 5 R 6 . (CH 2 ) p CO 2 R 5 ,
  • R , R , R and R are as defined above.
  • the substituents A and B respectively, may optionally be substituted at any position of the ring.
  • halogen we mean chloro, fluoro, bromo and iodo.
  • aryl we mean an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
  • heteroaryl we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
  • hydroaromatic we mean a partly or fully saturated aromatic ring structure having 5-10 carbon atoms in the ring.
  • heterohydroaromatic we mean a partly or fully saturated aromatic ring structure in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
  • isomers we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation.
  • orientation we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
  • isoforms we mean compounds of the formula (I) which differ by their crystal lattice, such as crystalline compound and amorphous compounds.
  • prodrug we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug.
  • pharmaceutically acceptable derivatives e.g. esters and amides
  • the novel compounds of the present invention are useful in therapy, especially for the treatment of pain.
  • a further aspect of the invention is the use of a compound of the formula (I) for the manufacture of a medicament for use in any of the diseases disclosed below.
  • the compounds are useful for modulating the analgesic effects acting at the ⁇ opioid receptor subtype, including for modulating side effects seen with agents acting at the ⁇ opioid receptor subtype such as morphine, especially respiratory depression, gut motility and abuse liability.
  • Compounds of the invention are also useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti tumour agents and anti viral agents.
  • Compounds of the invention are useful also in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • An aldehyde or ketone is treated with a nucleophile such as a Grignard or organolithium species to produce the corresponding alcohol.
  • This alcohol may then be converted into a suitable leaving group (X) such as an ester, sulphonate or halide which may in turn be displaced with a nudeophilic species such as a substituted or unsubstituted piperazine.
  • X a suitable leaving group
  • N- (4)-unsubstituted piperazine derivatives may then be suitably substituted with a variety of groups via their organo halide or equivalent species, or acylated with a number of different acylating compounds. This sequence of events will give rise to compounds according to general formula I.
  • N-protected amino acid as its activated ester, may be reacted with a second amino acid ester.
  • this species On treatment with an acid this species may then cyclize to form a piperazinedione.
  • This dione may be reduced via a number of standard methods to the corresponding piperazine (e.g. a reducing agent such as lithium aluminium hydride, by conversion to the thioamide and subsequent desulphurization, hydrogenation in the presence of POCI3 etc.)
  • This piperazine may then be alkylated or acylated on one or more of the nitrogens and/or may be used subsequently in generalized method A.
  • Ar 4-diethylaminocarbonylphenyl (5)
  • Ar 2- naphthyl (6)
  • Ar 4-diethylaminocarbonylphenyl (9)
  • Ar 2-naphthyl (10)
  • novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, intrathecally and intracerebroventricularly.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, cetrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sub
  • Preferred pharmaceutically acceptable salts are the hydrochlorides and citrates.
  • composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid from compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the fmely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art
  • the pharmaceutical compositions is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • Human 293S cells expressing cloned human ⁇ , ⁇ , and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CC ⁇ in shaker flasks containing calcium-free DMEM 10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 ⁇ g/ml geneticin.
  • Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supernatants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again.
  • lysis buffer 50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol
  • the final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS.
  • Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl 2 , 1 mg/ml BSA (Sigma A- 7888), pH 7.4, which was stored at 4°C after filtration through a 0.22 m filter, and to which had been freshly added 5 ⁇ g/ml aprotinin, 10 ⁇ M bestatin, 10 ⁇ M diprotin A, no DTT).
  • binding buffer 50 mM Tris, 3 mM MgCl 2 , 1 mg/ml BSA (Sigma A- 7888), pH 7.4
  • the radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI- soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 ⁇ l MS-20 scintillation fluid/well.
  • TopCount Packard
  • the specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test peptides was expressed as percentage of control SB.
  • Values of IC50 and Hill coefficient (n ⁇ ) for ligands in displacing specifically bound radiohgand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit.
  • Values of Kj were calculated from the Cheng-Prussoff equation. Mean ⁇ S.E.M. values of IC50, Kj and n ⁇ were reported for ligands tested in at least three displacement curves.
  • Radioligand Kg values were determined by perf orming the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kg (up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and Bma from individual experiments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site mode B) BIOLOGICAL MODEL (IN VIVO MODEL)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Optics & Photonics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP96943427A 1995-12-22 1996-12-11 Novel compounds with analgesic effect Withdrawn EP0873322A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9504662 1995-12-22
SE9504662A SE9504662D0 (sv) 1995-12-22 1995-12-22 New compounds
PCT/SE1996/001636 WO1997023467A1 (en) 1995-12-22 1996-12-11 Novel compounds with analgesic effect

Publications (1)

Publication Number Publication Date
EP0873322A1 true EP0873322A1 (en) 1998-10-28

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP96943427A Withdrawn EP0873322A1 (en) 1995-12-22 1996-12-11 Novel compounds with analgesic effect

Country Status (21)

Country Link
EP (1) EP0873322A1 (cs)
JP (1) JP2000502680A (cs)
KR (1) KR19990076649A (cs)
CN (1) CN1209126A (cs)
AU (1) AU706436B2 (cs)
BR (1) BR9612206A (cs)
CA (1) CA2239162A1 (cs)
CZ (1) CZ176798A3 (cs)
EE (1) EE9800195A (cs)
HU (1) HUP9900105A3 (cs)
IL (1) IL124997A0 (cs)
IS (1) IS4768A (cs)
NO (1) NO982863L (cs)
NZ (1) NZ324888A (cs)
PL (1) PL327538A1 (cs)
SE (1) SE9504662D0 (cs)
SK (1) SK81998A3 (cs)
TR (1) TR199801184T2 (cs)
TW (1) TW360641B (cs)
WO (1) WO1997023467A1 (cs)
ZA (1) ZA9610355B (cs)

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Publication number Priority date Publication date Assignee Title
SE9504661D0 (sv) * 1995-12-22 1995-12-22 Astra Pharma Inc New compounds
US6441172B1 (en) 1996-11-07 2002-08-27 Torrey Pines Institute For Molecular Studies Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
GB9804734D0 (en) * 1998-03-05 1998-04-29 Pfizer Ltd Compounds
RU2186295C2 (ru) 1999-10-27 2002-07-27 Беллакем Ою Установка циклического действия для утилизации отходов, содержащих полимерные соединения
EE9900336A (et) 1999-10-27 2000-10-16 Bellakem O� Tsükkeltegevuse seade polümeerühendeid sisaldavate jäätmete utiliseerimiseks
US8473062B2 (en) 2008-05-01 2013-06-25 Autonomic Technologies, Inc. Method and device for the treatment of headache
US8412336B2 (en) 2008-12-29 2013-04-02 Autonomic Technologies, Inc. Integrated delivery and visualization tool for a neuromodulation system
US8494641B2 (en) 2009-04-22 2013-07-23 Autonomic Technologies, Inc. Implantable neurostimulator with integral hermetic electronic enclosure, circuit substrate, monolithic feed-through, lead assembly and anchoring mechanism
US9320908B2 (en) 2009-01-15 2016-04-26 Autonomic Technologies, Inc. Approval per use implanted neurostimulator

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US4826844A (en) * 1987-09-30 1989-05-02 American Home Products Corporation Substituted 1-(aralkyl-piperazinoalkyl) cycloalkanols
GB9202238D0 (en) * 1992-02-03 1992-03-18 Wellcome Found Compounds
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Also Published As

Publication number Publication date
ZA9610355B (en) 1997-06-23
KR19990076649A (ko) 1999-10-15
NO982863D0 (no) 1998-06-19
CZ176798A3 (cs) 1998-09-16
CN1209126A (zh) 1999-02-24
SK81998A3 (en) 1998-11-04
PL327538A1 (en) 1998-12-21
CA2239162A1 (en) 1997-07-03
JP2000502680A (ja) 2000-03-07
BR9612206A (pt) 1999-07-13
IL124997A0 (en) 1999-01-26
AU1216397A (en) 1997-07-17
EE9800195A (et) 1998-12-15
IS4768A (is) 1998-06-10
TR199801184T2 (xx) 1998-09-21
SE9504662D0 (sv) 1995-12-22
NZ324888A (en) 1999-01-28
WO1997023467A1 (en) 1997-07-03
HUP9900105A2 (hu) 1999-04-28
NO982863L (no) 1998-06-19
AU706436B2 (en) 1999-06-17
TW360641B (en) 1999-06-11
MX9804797A (es) 1998-10-31
HUP9900105A3 (en) 2000-05-29

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