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WO1992015304A2 - Agonistes des recepteurs kappa pour le traitement de l'ischemie cerebrale - Google Patents

Agonistes des recepteurs kappa pour le traitement de l'ischemie cerebrale Download PDF

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Publication number
WO1992015304A2
WO1992015304A2 PCT/EP1992/000492 EP9200492W WO9215304A2 WO 1992015304 A2 WO1992015304 A2 WO 1992015304A2 EP 9200492 W EP9200492 W EP 9200492W WO 9215304 A2 WO9215304 A2 WO 9215304A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
acetyl
alkyl
formula
pyrrolidin
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.)
Ceased
Application number
PCT/EP1992/000492
Other languages
English (en)
Other versions
WO1992015304A3 (fr
Inventor
Giuseppe Giardina
Geoffrey Douglas Clarke
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.)
GlaxoSmithKline SpA
Dr L Zambeletti SpA
Original Assignee
Smithkline Beecham Farmaceutici SpA
Dr L Zambeletti SpA
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 Smithkline Beecham Farmaceutici SpA, Dr L Zambeletti SpA filed Critical Smithkline Beecham Farmaceutici SpA
Publication of WO1992015304A2 publication Critical patent/WO1992015304A2/fr
Publication of WO1992015304A3 publication Critical patent/WO1992015304A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/33—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
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the present invention relates to the use of certain compounds for the manufacture of medicaments for the treatment of cerebral ischaemia; to a method of treatment of cerebral ischaemia; and to pharmaceutical compositions for the treatment of cerebral ischaemia.
  • EP-A-370732 and EP-A-361791 (both Dr. Lo. Z combitti S.p.a.) describe classes of azacyclic and heterocyclic derivatives which exhibit kappa receptor agonism and are of potential therapeutic utility as analgesics.
  • formula (la) being:
  • RCO is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring;
  • R 1 and R 2 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 eycloalkylalkyl groups, or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a hetero-atom,
  • R 3 is hydrogen , C 1-6 alkyl, preferably methyl or ethyl, or phenyl, or R 3 together with R 1 form a -(CH 2 ) 3 - or -(CH 2 ) 4 - group;
  • R 4 and R 5 are independently hydrogen, hydroxyl, halogen, preferably fluorine, C 1-6 alkyl, preferably methyl or ethyl, or aryl, preferably phenyl, provided both R 4 and R 5 are not simultaneously hydrogen; and p is an integer from 1 to 4, preferably 2;
  • R x is the remainder of a heterocyclic group, or an optionally substituted phenyl group
  • R a and R b are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl or C 4-12 cycloalkylalkyl groups, or together form a C 2-8 branched or linear polymethylene or C 2-6 alkenylene group, optionally substituted with a hetero-atom;
  • R c is hydrogen , C 1-6 alkyl, preferably methyl or ethyl, or phenyl, or R c together with R a form a -(CH 2 ) 3 - or -(CE 2 ) 4 - group;
  • R d and R e which may be located on the same or different carbon atoms, are independently hydrogen, C 1-6 alkyl, preferably methyl or ethyl, or phenyl; m is 1, 2 or 3, preferably 2;
  • R f is hydrogen or C 1-6 alkyl, such as methyl or ethyl; n is O, 1 or 2 preferably 1;
  • each of R g and R h is C 1-6 alkyl, or
  • R g and R h are linked together and Rg represents -(Z) p - where p is 0 or 1 and Z is O, S or NR Z where R z is hydrogen or C 1-6 alkyl,
  • R h represents -(CH 2 ) q - where q is an integer of from 1 to 4, preferably 2 or 3.
  • R 4 and R 5 may be located on the same or different carbon atoms of the azacyclic nucleus.
  • the term 'carbocyclic aromatic group' includes single or fused rings, having 6 to 12 ring carbon atoms
  • the term 'heterocyclic aromatic group includes single or fused rings having 5 to 12 ring atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur.
  • one or both rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • the C 1-6 alkyl groups may be either straight or branched chain and examples are methyl, ethyl, propyl, n-butyl, n-pentyl or n-hexyl, preferably methyl.
  • Examples of C 2-6 alkenyl groups are 1- and 2-propenyl; an example of a C 3-6 cycloalkyl group is cyclopropyl, and an example of a C 4-12
  • cycloalkylalkyl group is cyclopropyl methyl.
  • R 1 and R 2 together form a linear or branched polymethylene group, examples are propylene, butylene, pentylene or hexylene, preferably butylene or 1-methyl-butylene.
  • hetero-atoms are oxygen and sulphur, particularly oxygen, and a suitable hetero-atom substituted polymethylene group is -CH 2 CH 2 OCH 2 CH 2 -.
  • the group R in formula (la) preferably has the formula (III):
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • n' is 0, 1 or 2, provided m + m' ⁇ 2
  • X is a direct bond, or O, S or NR 8 in which R 8 is hydrogen or C 1-6 alkyl,
  • Ar is a substituted or unsubstituted carbocyclic or heterocyclic group
  • each of R 6 and R 6 a is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, optionally substituted phenyl, optionally substituted phenyl C 1-6 alkyl, hydroxy, C 1-6 alkoxy, thiol, C 1-6 alkylthio, C 1-6 haloalkoxy, C 1-6 haloalkylthio, halogen, NO 2 , CN, CF 3 , -OCF 3 , -OCHF 2 , -OCF 2 CF 2 H, -OCCl 2 CF 3 , -COOR 9 ,
  • each of R 9 to R 15 is independently hydrogen, C 1-6 alkyl, optionally substituted phenyl or optionally substituted phenyl C 1-6 alkyl;
  • R 6 's form a C 3-6 polymethylene group
  • R 7 is hydrogen or C 1-6 alkyl, such as methyl or ethyl.
  • Preferred halogens are F, Cl and Br.
  • R 6 's When two R 6 's are linked they preferably form a fused cyclopentyl or cyclohexyl ring.
  • Ar is phenyl and R 6 or R 6 a is preferably in the meta and/or para position.
  • R 6 or R 6 a is bromine, chlorine, or CF 3 , particularly in the meta- or para- position.
  • X is typically oxygen or a direct bond, and n is typically 0 or 1.
  • a further preferred group R has the formula (IV)
  • each of R x and R y is C 1-6 alkyl, or
  • R x and R y are linked together and R x represents -(Z) m - where m is 0 or 1 and Z is O, S or NR Z where R z is hydrogen or C 1-6 alkyl,
  • R y represents -(CH 2 ) q - where q is an integer of from 1 to 4, preferably 2 or 3.
  • a preferred sub-group of formula (IV) is a group of formula (V)
  • q is 2 when Z is oxygen and m is 1, and q is 3 when m is 0.
  • a further preferred sub-group of formula (IV) is the group of formula (VI)
  • each of R x and R y is C 1-6 alkyl, preferably methyl, and the position of -CH 2 - is as defined in formula (IV)
  • substituents are one or more of C 1-6 alkyl, preferably methyl, halogen, hydroxy, C 1-6 alkoxy, thiol or C 1-6 alkyl thio.
  • R x represents unsubstituted phenyl.
  • R x When R x forms a heterocyclic group, it may be a single or fused ring group, preferably having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from oxygen, nitrogen and sulphur.
  • R x forms a fused two ring system
  • one or both rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • R x is a single ring heterocyclic group
  • examples are thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl and pyridyl
  • examples are benzofuranyl, benzo thienyl, indolyl and quinolyl.
  • a preferred sub-group of compounds of formula (lb) is a group of compounds of formula (VII)
  • q is 2 when Z is oxygen and p is 1, and q is 3 when p is 0.
  • q is 2 when Z is oxygen and p is 1, and q is 3 when p is 0.
  • a irther preferred sub-group of compounds of formula (lb) is the group of compounds of formula (VIII)
  • each of R g and R h is C 1-6 alkyl, preferably methyl
  • the position of -CH 2 - is as defined in formula (lb)
  • the C 1-6 alkyl groups mentioned above may be either straight or branched chain and examples are methyl, ethyl, propyl, n-butyl, n-pentyl or n-hexyl, preferably methyl.
  • Examples of C 2-6 alkenyl groups are 1- and 2-propenyl; an example of a C 3-6 cycloalkyl group is cyclopropyl, and an example of a C 4-12
  • cycloalkylalkyl group is cyclopropyl methyl.
  • R a and R b together form a linear or branched polymethylene group
  • examples are propylene, butylene, pentylene or hexylene, preferably butylene or 1-methyl-butylene.
  • hetero-atoms are oxygen and sulphur, particularly oxygen, and a suitable hetero-atom substituted polymethylene group is -CH 2 CH 2 OCH 2 CH 2 -.
  • a particularly preferred group of compounds of formula (lb) are those in which R x represents phenyl or mono- or di- hydroxy substituted phenyl, or represents thieno.
  • compositions for use in the treatment of cerebral ischaemia in mammals which comprises a compound of formula (la) or (lb) (as hereinbefore defined) or a pharmaceutically acceptable salt or solvate thereof,
  • the invention further provides a method for the treatment and/or prophylaxis of cerebral ischaemia in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of the Compound.
  • the Compound is in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter aliaj of a pharmaceutically acceptable level of purity excluding normal
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the Compound.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • the Compound in the form of a pharmaceutically acceptable salt include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • An example of the Compound in the form of a pharmaceutically acceptable solvate includes the hydrate.
  • the Compounds have at least two asymmetric centres and therefore exist in more than one stereoisomeric form.
  • the invention extends to the use of all such forms and to mixtures thereof, including racemates.
  • Medicaments and compositions containing the Compounds may be prepared by admixture of a Compound with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • an appropriate carrier which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a medicament or pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent for treating cerebral ischaemia.
  • the suitable dosage range for a Compound depends on the Compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the Compound may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or
  • Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroiidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate;
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroiidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrroiidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired
  • compositions may also be administered by a non-oral route.
  • the compositions may be formulated, for example for rectal administration as a suppository.
  • They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a
  • liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.
  • the effective dose of Compound depends on the particular Compound employed, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the activity of the Compounds in treating cerebral ischaemia may be determined using the gerbil model of ischaemic stroke, as described in P. Lysko et al Stroke, 23(3), 1992.

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  • 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)

Abstract

On décrit des dérivés azacycliques et hétérocycliques présentant une activité agoniste kappa et utiles pour le traitement de l'ischémie cérébrale.
PCT/EP1992/000492 1991-03-05 1992-03-04 Agonistes des recepteurs kappa pour le traitement de l'ischemie cerebrale Ceased WO1992015304A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919104656A GB9104656D0 (en) 1991-03-05 1991-03-05 Pharmaceuticals
GB9104656.5 1991-03-05

Publications (2)

Publication Number Publication Date
WO1992015304A2 true WO1992015304A2 (fr) 1992-09-17
WO1992015304A3 WO1992015304A3 (fr) 1993-06-24

Family

ID=10691041

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/000492 Ceased WO1992015304A2 (fr) 1991-03-05 1992-03-04 Agonistes des recepteurs kappa pour le traitement de l'ischemie cerebrale

Country Status (8)

Country Link
EP (1) EP0574477A1 (fr)
CA (1) CA2105589A1 (fr)
GB (1) GB9104656D0 (fr)
IE (1) IE920679A1 (fr)
MX (1) MX9200948A (fr)
PT (1) PT100188A (fr)
WO (1) WO1992015304A2 (fr)
ZA (1) ZA921575B (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366981A (en) * 1989-11-24 1994-11-22 Dr Lo Zambeletti S.P.A. N-acyl-substituted azacyclic compounds, processes for their preparaion, and their use as pharmaceuticals
US5428042A (en) * 1990-04-28 1995-06-27 Dr Lo Zambeletti S.P.A. 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
WO2005090286A1 (fr) 2004-03-12 2005-09-29 Eli Lilly And Company Antagonistes de recepteur opioide
US7601844B2 (en) 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
US8299098B2 (en) 2008-06-25 2012-10-30 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8804104D0 (en) * 1988-02-23 1988-03-23 Glaxo Group Ltd Chemical compounds
EP0330468A3 (fr) * 1988-02-23 1991-04-03 Glaxo Group Limited Utilisation de dérivés hétérocycliques comme agonistes des récepteurs kappa aux opioides dans le traitement de l'ischémie cérébrale
EP0330467A1 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Composés hétérocycliques
GB8813714D0 (en) * 1988-06-09 1988-07-13 Glaxo Group Ltd Chemical compounds
DE68924751T2 (de) * 1988-09-26 1996-04-11 Smithkline Beecham Farma Azacyclische Verbindungen, verwendbar als Arzneimittel.

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366981A (en) * 1989-11-24 1994-11-22 Dr Lo Zambeletti S.P.A. N-acyl-substituted azacyclic compounds, processes for their preparaion, and their use as pharmaceuticals
US5428042A (en) * 1990-04-28 1995-06-27 Dr Lo Zambeletti S.P.A. 1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists
WO2005090286A1 (fr) 2004-03-12 2005-09-29 Eli Lilly And Company Antagonistes de recepteur opioide
US8609664B2 (en) 2006-01-27 2013-12-17 Bristol-Myers Squibb Co. Piperazinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
US7985861B2 (en) 2006-01-27 2011-07-26 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7601844B2 (en) 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US8299098B2 (en) 2008-06-25 2012-10-30 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8633226B2 (en) 2008-06-25 2014-01-21 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8598164B2 (en) 2010-05-06 2013-12-03 Vertex Pharmaceuticals Incorporated Heterocyclic chromene-spirocyclic piperidine amides as modulators of ion channels
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
US8916565B2 (en) 2011-02-02 2014-12-23 Vertex Pharmaceuticals Incorporated Pyrrolopyrazine-spirocyclic piperidine amides as modulators of ion channels
US9511067B2 (en) 2011-02-02 2016-12-06 Vertex Pharmaceuticals Incorporated Substituted spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]s as modulators of ion channels
US10385070B2 (en) 2011-02-18 2019-08-20 Vertex Pharmaceuticals Incorporated Chroman-spirocyclic piperidine amides as modulators of ion channels
US8828996B2 (en) 2011-03-14 2014-09-09 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels
US9181273B2 (en) 2011-03-14 2015-11-10 Vertex Pharmaceuticals Incorporated Morpholine-spirocyclic piperidine amides as modulators of ion channels

Also Published As

Publication number Publication date
IE920679A1 (en) 1992-09-09
ZA921575B (en) 1992-12-30
CA2105589A1 (fr) 1992-09-06
MX9200948A (es) 1992-11-01
WO1992015304A3 (fr) 1993-06-24
EP0574477A1 (fr) 1993-12-22
GB9104656D0 (en) 1991-04-17
PT100188A (pt) 1993-05-31

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