+

WO1999016431A1 - Melanges d'enantiomeres d'aminocyclohexylamides permettant de produire une analgesie simultanee avec anesthesie locale ou antiarythmie - Google Patents

Melanges d'enantiomeres d'aminocyclohexylamides permettant de produire une analgesie simultanee avec anesthesie locale ou antiarythmie Download PDF

Info

Publication number
WO1999016431A1
WO1999016431A1 PCT/CA1998/000905 CA9800905W WO9916431A1 WO 1999016431 A1 WO1999016431 A1 WO 1999016431A1 CA 9800905 W CA9800905 W CA 9800905W WO 9916431 A1 WO9916431 A1 WO 9916431A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
pynolidinyl
acetamide
cyclohexyl
benzo
Prior art date
Application number
PCT/CA1998/000905
Other languages
English (en)
Inventor
Allen I. Bain
Original Assignee
Nortran Pharmaceuticals 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 Nortran Pharmaceuticals Inc. filed Critical Nortran Pharmaceuticals Inc.
Priority to BR9814048-5A priority Critical patent/BR9814048A/pt
Priority to AU92486/98A priority patent/AU9248698A/en
Priority to MXPA00002969A priority patent/MXPA00002969A/es
Publication of WO1999016431A1 publication Critical patent/WO1999016431A1/fr

Links

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates generally to the use of mixtures of enantiomers of vicinal ammocyclohexylamides to produce local anaesthesia and/or antiarrhythmia, while at the same time producing an approp ⁇ ate level of analgesia
  • This invention is more particularly related to the treatment of cardiac arrhythmias and the inducement of local anaesthesia, with an approp ⁇ ate amount of analgesia
  • the present invention provides compositions and methods for providing analgesia du ⁇ ng the treatment of cardiac arrhythmias or the induction of local anaesthesia in a patient in need thereof
  • the present invention provides a composition comprising a plurality of vicinal aminocyclohexylamide enantiomers, wherein said composition of enantiomers is between about 85% to 99 99% R,R configuration and between about 15% to 0 01% S,S configuration
  • the compositions may optionally include a pharmaceutically acceptable earner or diluent.
  • the plurality of enantiomers are compounds of the formula
  • n is either 0 or 1
  • Rj , R2, R3, R4 are hydrogen, hydroxy, alkoxy of from one to four carbon atoms, or points of attachment of a spiro- or fused five- or six-membered heterocychc nng containing one oxygen or sulfur atom
  • R5 and R5 are either alkyl of from one to five carbon atoms or, when taken together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl, tetrahydroisoquinolinyl, or hexahydro- azepinyl ring
  • Q is selected from the group of substituents comprising: 3,4,5-trimethylphenoxy;
  • R7 is hydrogen, fluorine, chlorine, alkyl of from one to six carbon atoms, or aryl
  • Z is -CH2-, -O-, -S-, or N-Rg where Rg is hydrogen, alkanoyl of from one to six carbon atoms, or alkyl of from one to six carbon atoms;
  • X is CH2, O or S, and R9 and RJ Q are independently hydrogen, fluorine, bromine, alkyl of from one to six carbon atoms, or alkoxy of from one to four carbon atoms;
  • R ⁇ ⁇ and R ⁇ 2 are independently hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, or aryl.
  • compositions of the present invention are provided for use as a medicament, and for use for the manufacture of a medicament to provide analgesia during the treatment of cardiac anhythmias or the induction of local anaesthesia.
  • the present invention further provides for a method comprising the administration, to a patient in need of treatment for cardiac anhythmias or the induction of local anaesthesia, of a composition according to the present invention.
  • the present invention is directed toward mixtures of enantiomers of vicinal aminocyclohexylamides which have a variety of uses.
  • uses include the inducement of local anaesthesia, treatment of anhythmias and the blockade of ion channels in vitro and in vivo.
  • Aminocyclohexylamides are known in the literature and include those disclosed in U.S. Patent No. 5,506,257 and the patent and technical literature cited therein. As disclosed within the present invention, compositions that include mixtures of at least two enantiomers of vicinal aminocyclohexylamides produce, surprisingly, a combination of desirable effects.
  • Examples of vicinal aminocyclohexylamides include the class of substituted aminocyclohexylamide compounds depicted in formula I above.
  • One nitrogen atom is an amine nitrogen substituted with R5 and Rg as defined above.
  • R5 is methyl and Rg is a lower alkyl, more preferably methyl, or, when taken together with the nitrogen atom to which they are attached.
  • R5 and Rg preferably form a py ⁇ olidinyl ring, a morpholinyl ring or a hexahydroazepinyl ring.
  • the other nitrogen atom is an N-methylamide substituted as described above, wherein n is preferably 1.
  • Ri , R2, R3 and R4 are hydrogen or, R3 and R4 are hydrogen and R ⁇ and R2 are an oxaspiran ring.
  • aryl means phenyl; phenyl substituted with alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, or trifluromethyl; 2- or 3-thienyl; and, 2- or 3-thienyl substituted with alkyl of from one to four carbon atoms or alkoxy of from one to four carbon atoms.
  • Aminocyclohexylamides are depicted above in formula I by a structural formula.
  • Such structural formula contains one or more asymmetric carbon atoms and therefore the compounds exist in various stereoisomeric forms
  • the compound is capable of existing in different geomet ⁇ c lsome ⁇ c forms
  • the substituent R ⁇ of the cyclohexane ring may be positioned on the same side of the average plane of the ring as the amide nitrogen, or on the side opposite
  • the two nitrogens (ammo and N-methylamide substituents) attached to the cyclohexyl ring are in a trans onentation
  • the present invention contemplates the use of geometnc and stereoisome ⁇ c forms of the compounds of formula I
  • the compounds of formula I may be prepared by known methods, including those described in the aforementioned United States patents to Horwell (all references cited in the present application, including those of Horwell, are incorporated herein in their entirety by reference). Suitable methods for the synthesis of diaminocyclohexane intermediates useful for preparation of a variety of compounds identified above are described in Szmuszkovicz, J., and Von Voightlander, P.F. (1982) J. Med. Chem. 25: 1 125-1 126. The oxaspiro and methoxy-cyclohexanediamine intermediates useful for syntheses of compounds 7, 10, 18, and 19 are described in Halfpenny, P.R., et al. (1990) J. Med. Chem.
  • the synthetic method for the compounds can be modified in order to obtain the desired mixture of enantiomers.
  • a prescribed ratio of enantiomers can be used in order to produce the desired mixture of enantiomers in the product.
  • the conditions of synthesis can also affect the degree of enantiomeric purity for some compounds.
  • a chiral compound can be synthesized as a pure enantiomer under certain conditions, but alteration of these conditions can result in some racemization.
  • a mixture of the present invention is made possible through such alteration of the conditions of chiral synthesis in order to produce the desired mixture of enantiomers in the product.
  • Another procedure for obtaining the desired mixture of enantiomers entails the chiral synthesis of the two enantiomers, followed by admixture of the two enantiomers in the desired ratio.
  • Another procedure for obtaining the desired mixture of enantiomers requires (a) chiral synthesis of the enantiomer that is required in the smaller quantity in the final mixture, (b) synthesis of the racemate, and (c) admixture of the racemate to the single enantiomer to give the desired final enantiomer ratio.
  • Another procedure for obtaining the desired mixture of enantiomers is to separate a racemate solution using chiral separation techniques, such as preparative liquid chromatography with a chiral column, then mixing the enantiomers in the desired ratio.
  • the compounds of formula I may be in the form of a pharmaceutically acceptable acid addition salt.
  • Such salts include the hydrochloride, sulfate, phosphate, citrate, and other salts known in the art.
  • Pharmaceutical compositions of enantiomers of compound I or salts of compound I may contain pharmaceutically acceptable carriers or diluents, which are well known in the art.
  • Compositions of the present invention are prepared by mixing together two or more vicinal aminocyclohexylamide enantiomers. The aminocyclohexylamides may be vicinal at positions 1,2; 2,3; 3,4; 4,5; 5,6; 6,7; 7,8; etc.; depending on the rest of the structure of the compound as a whole.
  • the aminocyclohexylamide enantiomers are present such that about 85%-99.99% are R,R configuration and about 15%-0.01% are S,S configuration.
  • an R,R enantiomer is present in a mixture at about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% (and numbers in between the integers) or up to 99.99%, with the remaining % as an S,S enantiomer.
  • about 99.5% are R,R and about 0.5% are S,S.
  • the antianhythmic activity of a compound may be estimated against the anhythmias induced by coronary artery occlusion in anaesthetized rats. It is expected that a good antiarrhythmic compound will have antianhythmic activity at doses which have minimal effects on either the ECG, blood pressure or heart rate.
  • a mixture may be assessed as an anaesthetic using a standard test for local anaesthetic effects.
  • a standard test for local anaesthetic effects The following is a general description of such a test.
  • a 20 microliter injection of the drug or the canier vehicle as a control
  • the needle is advanced until the tip contacts the caudal vertebra, then the solution is injected.
  • the pin prick test is conducted both proximally and distally on either side of the injection site. If there is a tail flick response, a "Yes" is recorded. If there is no response, a "No" is recorded, indicating local anaesthesia.
  • a mixture may be assessed as an analgesic using a standard test for analgesic effects.
  • a standard test for analgesic effects The following is a general description of such a test.
  • Compounds over a range of doses are typically administered intravenously to mice weighing 20-30 g.
  • a clip is placed at the base of the animal's tail and each animal is observed for a maximum period of 40 seconds; if the animal turns and bites the clip this indicates a lack of analgesia; whereas failure to turn and bite the clip indicates analgesia.
  • the number of responders in each group is then determined and a dose which produces analgesia in 50% of animals (ED50) is then calculated.
  • ED50 50% of animals
  • the mixtures of the present invention may be employed to treat the rhythm of a heart or prevent anhythmias occurring in a heart that is susceptible to anhythmia.
  • Methods of administering effective amounts of antianhythmic agents are well known in the art and include the administration of an oral or parenteral dosage form.
  • Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, sustained release implants, and transdermal delivery systems.
  • oral or intravenous administration is prefened.
  • the dosage amount and frequency is selected to create an effective level of the agent without harmful effects.
  • a 0.1% to 1% solution injected into a local site is typical.
  • the means of administration may be the same as described above in the case of treatment of anhythmia, except that use of oral administration in the form of tablets or capsules will generally not be appropriate.
  • Topical application of the local anaesthetic agent for example in the form of an ointment or an aerosol spray, may be employed.
  • Means of administering local anaesthetics are well known in the art.
  • Administration of the mixtures of this invention may be carried out in combination with the administration of other agents.
  • it may be desired to administer another antianhythmic agent or local anaesthetic.
  • the present invention also includes a commercial kit containing a pharmaceutical composition which includes two or more isomeric compounds of formula I or, pharmaceutically acceptable salts thereof, in addition to any desired, pharmaceutically acceptable, carriers or diluents.
  • the commercial kit also includes instructions for the use of the pharmaceutical composition for the treatment of anhythmia or for the inducement of local anaesthesia.
  • the commercial package will contain one or more unit doses of the pharmaceutical composition.
  • such a unit dose may be an amount sufficient for the preparation of an intravenous injection.
  • compounds which are light and/or air sensitive may require special packaging and/or formulation.
  • packaging may be used which is opaque to light, and/or sealed from contact with ambient air, and/or formulated with suitable coatings or excipients.
  • This compound was prepared based on the method in U.S. Patent No. 4,579,863.
  • the racemic diamine (Example 1) (16.0 g, 87.9 mmol) was dissolved in boiling methanol (400 mL). A solution of 2,3-di- -toluoyl-D- tartaric acid (35.6 g, 92.1 mmol) in boiling methanol (400 mL) was added. A white precipitate formed immediately. The mixture was cooled to room temperature then the solid (40.4 g) was filtered off. This procedure was repeated twice more to obtain a total of 120 g of crude tartaric acid salt. The salt was washed with hot methanol (1 L) but the specific rotation of the free diamine was only -74 (lit. value: -96).
  • the acid chloride solution was added via cannula to a cooled solution of the (-) diamine (2.90 g, 16 mmol) in dichloromethane (15 mL). The reaction was stined at 0°C for 15 minutes and then stined at room temperature for a further 45 minutes. Ether (40 mL) was added to the solution. An off-white solid precipitated from solution. The solid was filtered off and washed it with fresh ether (3 x 10 mL). The solid was recrystallized from hot methanol/ether (4.79 g, 77%). Specific rotation of the free acetamide (not the HC1 salt):+29.3 (lit. value: +30).
  • Antianhythmic efficacy was assessed by investigating the activity of the compounds on the incidence of cardiac anhythmias in pentobarbital anaesthetized rats subject to coronary artery occlusion. Anhythmias were recorded as ventricular tachycardia (VT) and ventricular fibrillation (VF) and according to Curtis, M.J. and Walker, M.J.A. (1988) Cardiovasc. Res. 22:656.
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • Table 1 describes the result of tests of Compound 7 described therein as an ED50 value (which is the doses required to produce 50% reductions in the anhythmic activity refened to therein).
  • ED50 value which is the doses required to produce 50% reductions in the anhythmic activity refened to therein.
  • ANALGESIA A compound or compounds over a range of dose (or vehicle control) were administered intravenously to mice weighing 20-30 g At 5 and/or 15 minutes after injection a clip was placed at the base of the animal's tail and each animal observed for a maximum period of 40 seconds, if the animal turned and bit the clip this indicated a lack of analgesia whereas failure to turn and bite the clip indicated analgesia The number of responders in each group was then determined and a dose which produces analgesia in 50% of animals (ED50) was then calculated
  • analgesic activity of certain of the compounds used in the compositions of the present invention is desc ⁇ bed in Halfpenny, P R , et al (1990) J Med Chem 33 286-291 It was determined that Compound 10 (the S,S-enant ⁇ omer) with a MPE50 (the dose required to produce 50% of the maximum possible analgesic effect using a rat paw pressure assay) value of 0 024 mg/kg is about 100 times more effective than Compound 7 (the R,R- enantiomer) with a MPE50 value of 2 5 mg/kg EXAMPLE 6
  • a 20 microliter injection of the drug was made close to the base of the tail of a mouse.
  • the needle was advanced until the tip contacts the caudal vertebra, then the solution was injected.
  • the pin prick test was conducted both proximally and distally on either side of the injection site. If there was a tail flick response, a "Yes” was recorded. If there was no response, a "No” was recorded, indicating local anaesthesia.
  • Compound 2, tested at 0.05%, 0.1%, 0.2%, 0.4%, 1% resulted in local anaesthesia in 0%, 33%, 60%, 100%, and 100%, of the mouse population, respectively. Saline injection failed to produce local anaesthesia.
  • Lidocaine as a positive control, at 0.1%, 0.5%, and 1%, produced local anaesthesia in 17%, 17% and 100% of the mouse population.
  • the local anaesthetic activity of certain of the compounds used in the compositions of the present invention is described in U.S. Patent No. 5,506,257.
  • Compound 2 was evaluated for local anaesthetic effects in a Phase II human clinical trial. It was compared with lidocaine in a randomized, double-blind, placebo-controlled trial. Drugs at various concentrations (Compound 2: 0.05%, 0.15% and 0.25%; lidocaine: 0.2%, 0.6% and 1.0%) were injected intradermally in one of either forearms of 40 healthy male subjects. Local anaesthesia in the eight intradermal wheals (four wheals/ forearm) was determined by a pin-prick score system and recorded at 1 , 10, 30, 60 and 120 minutes post-injection.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions et des procédés permettant d'assurer une analgésie pendant le traitement d'arythmies cardiaques ou l'induction de l'anesthésie locale. Les compositions faisant l'objet de cette invention renferment une pluralité d'énantiomères vicinaux aminocyclohexylamides dans des rapports à configurations de type stéréo.
PCT/CA1998/000905 1997-09-26 1998-09-25 Melanges d'enantiomeres d'aminocyclohexylamides permettant de produire une analgesie simultanee avec anesthesie locale ou antiarythmie WO1999016431A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
BR9814048-5A BR9814048A (pt) 1997-09-26 1998-09-25 "misturas de enantiÈmetros de aminociclohexil amidas para produzir de modo simultâneo analgesia com anestesia local ou antiarritmia "
AU92486/98A AU9248698A (en) 1997-09-26 1998-09-25 Mixtures of enantiomers of aminocyclohexylamides to produce simultaneous analgesia with local anaesthesia or antiarrhythmia
MXPA00002969A MXPA00002969A (es) 1997-09-26 1998-09-25 Mezclas de enantiomeros de aminociclohexilamidas para producir analgesia simultanea con anestesia local o antiarritmia.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6015497P 1997-09-26 1997-09-26
US60/060,154 1997-09-26

Publications (1)

Publication Number Publication Date
WO1999016431A1 true WO1999016431A1 (fr) 1999-04-08

Family

ID=22027715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1998/000905 WO1999016431A1 (fr) 1997-09-26 1998-09-25 Melanges d'enantiomeres d'aminocyclohexylamides permettant de produire une analgesie simultanee avec anesthesie locale ou antiarythmie

Country Status (5)

Country Link
CN (1) CN1278166A (fr)
AU (1) AU9248698A (fr)
BR (1) BR9814048A (fr)
MX (1) MXPA00002969A (fr)
WO (1) WO1999016431A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7057053B2 (en) 2000-10-06 2006-06-06 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7101877B2 (en) 1998-04-01 2006-09-05 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7345087B2 (en) 2003-10-31 2008-03-18 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7345086B2 (en) 2003-05-02 2008-03-18 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US7507545B2 (en) 1999-03-31 2009-03-24 Cardiome Pharma Corp. Ion channel modulating activity method
US7524879B2 (en) 2000-10-06 2009-04-28 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7674820B2 (en) 2003-08-07 2010-03-09 Cardiome Pharma Corp. Ion channel modulating activity I
US7767830B2 (en) 2003-05-02 2010-08-03 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof
US8058304B2 (en) 2004-04-01 2011-11-15 Cardiome Pharma Corp. Merged ion channel modulating compounds and uses thereof
US8263638B2 (en) 2004-11-08 2012-09-11 Cardiome Pharma Corp. Dosing regimens for ion channel modulating compounds
US10160727B2 (en) 2014-08-06 2018-12-25 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10533006B2 (en) 2016-02-04 2020-01-14 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10640495B2 (en) 2015-07-07 2020-05-05 Shionogi & Co., Ltd. Heterocycle derivatives having TrkA inhibitory activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4212878A (en) * 1978-01-26 1980-07-15 The Upjohn Company Phenylacetamide derivative analgesics
EP0110869A1 (fr) * 1982-11-26 1984-06-13 Laevosan-Gesellschaft m.b.H. Dérivés d'amide thiénylacétique, sels d'addition pharmaceutiquement acceptables et procédé pour leur préparation
US5506257A (en) * 1992-03-26 1996-04-09 University Of British Columbia Aminocyclohexylamides for antiarrhythmic and anaesthetic uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4212878A (en) * 1978-01-26 1980-07-15 The Upjohn Company Phenylacetamide derivative analgesics
EP0110869A1 (fr) * 1982-11-26 1984-06-13 Laevosan-Gesellschaft m.b.H. Dérivés d'amide thiénylacétique, sels d'addition pharmaceutiquement acceptables et procédé pour leur préparation
US5506257A (en) * 1992-03-26 1996-04-09 University Of British Columbia Aminocyclohexylamides for antiarrhythmic and anaesthetic uses

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7875611B2 (en) 1998-04-01 2011-01-25 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7101877B2 (en) 1998-04-01 2006-09-05 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7534790B2 (en) 1998-04-01 2009-05-19 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7507545B2 (en) 1999-03-31 2009-03-24 Cardiome Pharma Corp. Ion channel modulating activity method
US7259184B2 (en) 2000-10-06 2007-08-21 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US8008342B2 (en) 2000-10-06 2011-08-30 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7057053B2 (en) 2000-10-06 2006-06-06 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7524879B2 (en) 2000-10-06 2009-04-28 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7345086B2 (en) 2003-05-02 2008-03-18 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US7767830B2 (en) 2003-05-02 2010-08-03 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7820712B2 (en) 2003-05-02 2010-10-26 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US8188140B2 (en) 2003-05-02 2012-05-29 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US8163938B2 (en) 2003-05-02 2012-04-24 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7674820B2 (en) 2003-08-07 2010-03-09 Cardiome Pharma Corp. Ion channel modulating activity I
US8207219B2 (en) 2003-08-07 2012-06-26 Cardiome Pharma Corp. Ion channel modulating activity I
US7345087B2 (en) 2003-10-31 2008-03-18 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof
US8058304B2 (en) 2004-04-01 2011-11-15 Cardiome Pharma Corp. Merged ion channel modulating compounds and uses thereof
US8263638B2 (en) 2004-11-08 2012-09-11 Cardiome Pharma Corp. Dosing regimens for ion channel modulating compounds
US10160727B2 (en) 2014-08-06 2018-12-25 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10532985B2 (en) 2014-08-06 2020-01-14 Shionogi & Co., Ltd. Heterocycle and carbocycle derivatives having TRKA inhibitory activity
US10640495B2 (en) 2015-07-07 2020-05-05 Shionogi & Co., Ltd. Heterocycle derivatives having TrkA inhibitory activity
US10533006B2 (en) 2016-02-04 2020-01-14 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US10781210B2 (en) 2016-02-04 2020-09-22 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity
US11008320B2 (en) 2016-02-04 2021-05-18 Shionogi & Co., Ltd. Nitrogen-containing heterocycle and carbocycle derivatives having TrkA inhibitory activity

Also Published As

Publication number Publication date
CN1278166A (zh) 2000-12-27
BR9814048A (pt) 2000-10-03
MXPA00002969A (es) 2002-06-21
AU9248698A (en) 1999-04-23

Similar Documents

Publication Publication Date Title
US5506257A (en) Aminocyclohexylamides for antiarrhythmic and anaesthetic uses
CA2172513C (fr) Aminocyclohexylesters et leurs utilisations
JP3205343B2 (ja) ジアリールジアミン誘導体およびそれらのデルタオピオイド（アント）−アゴニストとしての使用
SK285908B6 (sk) Aminocyklohexyléterová zlúčenina, kompozícia obsahujúca túto zlúčeninu, použitie tejto zlúčeniny pri výrobe liečiva a pri liečbe
WO1999016431A1 (fr) Melanges d'enantiomeres d'aminocyclohexylamides permettant de produire une analgesie simultanee avec anesthesie locale ou antiarythmie
KR20010014279A (ko) 뮤 오피오이드 화합물의 호흡 저하 및 수반되는 부작용을감소시키기 위한 조성물 및 그 방법
EP2867219B1 (fr) Agents bloquants neuromusculaires asymétriques réversibles de durée ultra-courte, courte ou intermédiaire
EP0632806B1 (fr) Aminocyclohexylamides destines a des utilisations antiarythmiques et anesthesiques
AU599954B2 (en) 3-alkoxy-2-aminopropylamines useful as cardiovascular agents
IE60267B1 (en) Centrally-acting muscle relaxants
Lu et al. Molecular modification of anticholinergics as probes for muscarinic receptors. 1. Amino esters of. alpha.-substituted phenylacetic acid and related analogs
EP0302757A2 (fr) Agents de dépletion de la sérotine ayant une activité antiémétique
CA1162544A (fr) Derives de naphthyridine
EP0171912B1 (fr) Composés de pyrrolizidine, leurs méthodes de préparation et leur utilisation
US3868463A (en) Method of treating arrhythmia
US3907999A (en) Substituted dibenzocyclooctene compositions
US3988454A (en) Phenylalkylaralkylamines for pharmaceutical use
US3290212A (en) Antitussive composition
US3896237A (en) Method of treating cardiac arrythmia with phenylalkylaralkylamines
JPS6322070A (ja) Ｎ−〔３−（２，４，６−トリメトキシベンゾイル）プロピル〕ピペリジンの新規誘導体、その製造方法及びそれらを用いた治療剤
EP1611888A1 (fr) Antitussifs
CA1056730A (fr) Preparations pharmaceutiques et veterinaires pour le traitement de la maladie de parkinson et des troubles extrapyramidaux causes par les neuroleptiques
JPH03181419A (ja) イミダゾピリジンを含有する麻酔薬
JPH07508739A (ja) 新規な鎮痛ならびにヌートロピック剤
JPH041183A (ja) イソオキサゾロン化合物およびその用途

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 98810770.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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

Ref document number: PA/a/2000/002969

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载