WO1992014733A1 - Produits pharmaceutiques - Google Patents

Produits pharmaceutiques Download PDF

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Publication number
WO1992014733A1
WO1992014733A1 PCT/GB1992/000310 GB9200310W WO9214733A1 WO 1992014733 A1 WO1992014733 A1 WO 1992014733A1 GB 9200310 W GB9200310 W GB 9200310W WO 9214733 A1 WO9214733 A1 WO 9214733A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound according
methyl
alkyl
hydrogen
Prior art date
Application number
PCT/GB1992/000310
Other languages
English (en)
Inventor
Francis David King
Laramie Mary Gaster
Original Assignee
Smithkline Beecham P.L.C.
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 P.L.C. filed Critical Smithkline Beecham P.L.C.
Publication of WO1992014733A1 publication Critical patent/WO1992014733A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof

Definitions

  • This invention relates to novel compounds having useful pharmacological properties, to a process for their
  • EP-A-322016 Duphar international Research B.V.
  • EP-A-307172 Eli Lilly and Company
  • EP-A-323077
  • EP-A-234872 (Adria Laboratories Inc.)
  • EP-A-294292 (Adir et Compagnie)
  • EP-A-339950 (Rorer International
  • Patents 4920219 and 4920227 disclose classes of compounds which have a saturated azabicyclic moiety, such as tropanyl, granatyl or quinuclidinyl, having a -CO-NH- linkage, and are 5-HT 3 receptor antagonists.
  • -CO-NH- moiety is replaced by, for example, guanidino or amidino.
  • These compounds have 5-HT 3 receptor antagonist activity.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X is a phenyl group or a monocyclic 5 or 6 membered
  • heteroaryl group either of which group is optionally fused to a saturated or unsaturated 5-7 membered carbocyclic or heterocyclic ring;
  • Y is NCN, NR x or CR x wherein R x is NO 2 , COR y or SO 2 R y
  • R is C 1-3 alkyl, NH 2 , NH (C 1 _ 3 alkyl), CF 3 or phenyl optionally substituted by one, two or three groups selected from C 1-4 alkyl, C 1-4 alkoxy, nitro, halo, CF 3 and cyano; and
  • Z is a di-azacyclic or azabicyclic side chain, such as a saturated azabicyclic moiety
  • X may be unsubstituted or substituted, usually by one or more substituents selected from halogen, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl, hydroxy, amino, C 1-6 alkylamino, C 1-7 alkanoylamino, or two substituents on X (when fused), may be linked to form a saturated or unsaturated optionally
  • Heteroatoms for heteroaryl and heterocyclic groups are selected from oxygen, nitrogen and sulphur.
  • Halo includes bromo, chloro and fluoro.
  • X is fused), by a carbocyclic ring carbon atom, or by a heterocyclic ring carbon or nitrogen atom.
  • Suitable examples of X are as described in the
  • Z may be any of the values desclosed in the aforementioned Patent references, in particular, the following:- i) GB 2125398A (Sandoz Limited)
  • EP-A-215545 (Beecham Group p.l.c.)
  • EP-A-214772 (Beecham Group p.I.c.)
  • the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof:
  • X 1 is a group of formula (a), (b), (c), (d), (e), (f), (g) or (h):
  • R a to R e and R g to R h are selected from hydrogen, halogen or hydroxy
  • R 1 is hydrogen and R 2 is hydrogen or C 1-4 alkyl
  • R 1 and R 2 together are a bond
  • R 3 to R 7 are independently hydrogen or C 1-6 alkyl
  • R 4 together with R 2 may be C 2-7 polymethylene or C 2-6
  • R 8 and R 9 are independently selected from hydrogen or
  • C 1-6 alkyl or R 8 and R 9 together are C 2-9
  • R 11 is hydrogen, halo, C 1-6 alkoxy or C 1-6 alkyl
  • R 10 and R 11 are joined to form -OCH (R 15 R 16 )-E- wherein E is
  • R 12 is
  • R 13 is halo, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkylthio
  • R 14 is hydrogen or C 1-6 alkyl
  • CY-NH- is in the 1-position and either R 15 is in the
  • R 15 is in the 4-position and is hydrogen, halogen, CF 3 , C 1-6 alkyl, C 1-7 acyl, C 1-7 acylamino, phenyl optionally substituted by one or two C 1-6 alkyl, C 1-6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally substituted by one or two C 1-6 alkyl or C 3-8 cYcloalkyl groups or by C 4-5
  • CY-NH- is in the 3-position and either R 15 is in the
  • R 15 is in the 4-position and is hydrogen or C 1-6 alkoxy;
  • L is CH or N
  • Z is tropane, granatane, oxa/thia/aza-granatane,
  • Y is as defined in formula (I).
  • moieties in alkyl or alkyl containing groups in Z or in R 1 to R 15 include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
  • Cycloalkyl moieties include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl.
  • Halo moieties include fluoro, chloro, bromo and iodo.
  • R 2 and R 4 or R 8 and R 9 when joined include C 2 , C 3 , C 4 , C 5 or C 6 polymethylene, preferably C 2 , C 3 , C 4 or C 5 polymethylene.
  • R a to R e and R g to R h are preferably selected from hydrogen, fluoro, chloro and hydroxy, most preferably hydrogen.
  • R b may be 5-, 6- or 7-chloro or fluoro.
  • one of R 1 and R 3 is preferably hydrogen and one or both of R 2 and R 4 (most preferably both) are alkyl groups, such as methyl, or are joined to form C 2-7 polymethylene; or when one of R 2 and R 4 is hydrogen, the other is preferably ethyl or n- or iso- propyl.
  • R 5 is preferably hydrogen or a methyl or ethyl group.
  • R 6 is attached at the 1-position and the other is attached at the 3-position as depicted in sub-formula (c), and R 6 is preferably methyl or ethyl.
  • R 7 is preferably methyl.
  • R 8 and R 8 are preferably both methyl groups.
  • R 10 is C 1-6 alkoxy or is joined to Y
  • R 12 is preferably amino and R 13 is preferably chloro or bromo, most preferably chloro.
  • R 10 is preferably methoxy when C 1-6 alkoxy.
  • R 11 and R 13 are preferably chloro or methyl and R 10 is preferably hydrogen.
  • Other values of X within sub-formula (f) of interest are those described in EP-A-307172 (Eli Lilly and Company), EP-A-313393 (Yoshitomi Pharmaceutical Industries Limited), PCT/GB91/02173 and 02210 (Beecham Group p. I.e.).
  • R 14 is preferably hydrogen or methyl.
  • R 15 when in the 4-position include the following: hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C 1-4 alkanoylamino such as formylamino, acetylamino,
  • propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or
  • tert-butyl or phenyl groups include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.
  • R 15 when in the 1-position include hydrogen, methyl, ethyl, n- or iso- propyl, or when R 15 is in the 4-position, suitable examples include the following: hydrogen, methoxy and ethoxy.
  • Preferred R 15 groups in any of the positions specified above, include hydrogen, methyl and methoxy.
  • CY-NH- is preferably in the 1-position.
  • R y in Y are as described for R 1 to R 15 when C 1-3 alkyl.
  • suitable substituents are selected from methyl, methoxy, hydroxy, chloro, nitro or cyano.
  • Y is preferably N-CN.
  • R is hydrogen or methyl; and X is oxygen, sulphur or
  • cycloalkyl C 3-8 cycloalkyl C 1-4 alkyl, phenyl, naphthyl, phenyl C 1-4 alkyl or naphthyl C 1-4 alkyl wherein a phenyl or naphthyl moiety is optionally substituted by one or more of halo, C 1-6 alkoxy or C 1-6 alkyl.
  • Side chains Z of particular interest include tropane, oxagranatane and azagranatane, where R is methyl.
  • Suitable values for N-substituents when X is N are as described in PCT/GB91/01629, for example, iso-propyl or ethyl.
  • the pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with
  • salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R z -T wherein R z is C 1-6 alkyl, phenyl-C 1-6 alkyl or C 5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid.
  • R z examples include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl.
  • T examples include halide such as chloride, bromide and iodide.
  • Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
  • the compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable
  • X-CY-NH- in compounds of formula (I) may adopt an ⁇ or ⁇ or configuration with respect to Z.
  • the Y substituent may be in the E or Z (trans or cis) configuration with respect to the X or NHZ substituent.
  • the compounds of formula (I) may be prepared according to the following method; by reacting a compound of formula (II):
  • X 1 a is X 1 when of formula (a) or (d) and Q is a leaving group.
  • Suitable values for Q include SCH 3 , chloro, C 1-6 alkoxy or phenoxy, preferably SCH 3 .
  • the reaction preferably takes place in an inert solvent, such as acetonitrile, preferably at elevated temperatures. Subsequent substituent interconversions within X 1 a , Y and Z may be carried out, as well as salt formation.
  • an inert solvent such as acetonitrile
  • E is a leaving group. Suitable values of E are as described for Q, preferably SCH 3 .
  • Compounds of formula H 2 NZ are prepared according to the methods described in the patent references i) to vii) listed hereinbefore.
  • Suitable activated forms include wherein the compound of formula (VII) is reacted with an alkylating agent to form or S-alkyl leaving group, for example S-methyl, by reaction with dimethylsulphate.
  • R x is CN
  • the reactant is cyanamide
  • R x is SO 2 NH 2
  • the reactant is sulfamide
  • Y is CH-NO 2
  • the reactant is nitromethane in the presence of a base.
  • the reaction preferably takes place in an inert solvent, such as tetrahydrofuran, at -10 to +25°C, preferably around 0°C to ambient, in an inert atmosphere, for example under nitrogen, preferably in the presence of a base, such as diisopropylethylamine.
  • an inert solvent such as tetrahydrofuran
  • the reaction preferably takes place in actonitrile or dimethylformamide, at reflux temperatures.
  • the compounds of the present invention are 5-HT 3 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders.
  • Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain; emesis, includes, in particular, that of preventing vomiting and nausea associated with cancer therapy, post-operative emesis, and nausea associated with migraine.
  • cancer therapy include that using cytotoxic agents, such as platinum complexes including cisplatin, and also doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment.
  • CNS disorders include
  • Gastrointestinal disorders include depression, anxiety, psychosis, cognitive disorders such as senile dementia and age associated memory impairment (AAMI) , and drug dependence. Gastrointestinal disorders include
  • 5-HT 3 receptor antagonists may also be of potential use in the treatment of obesity, arrhythmia, and/or disorders associated with myocardial instability.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions are prepared by admixture and are usually adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional
  • excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art, for example with an enteric coating.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,
  • emulsifying agents for example lecithin, sorbitan
  • non-aqueous vehicles which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents;
  • Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
  • the oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolyed-Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by
  • a surfactant or wetting agent is included in the composition to facilitate uniform
  • the invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or
  • gastrointestinal disorders in mammals such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention.
  • Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or
  • Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED 50 ) is then determined.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés de formule (I) et leurs sels acceptables pharmaceutiquement dans laquelle X représente un groupe phényle ou un groupe monocyclique hétéroaryle à 5 ou 6 éléments, l'un ou l'autre groupe étant éventuellement fusionné avec un noyau hétérocyclique ou carbocyclique à 5-7 éléments, saturé ou insaturé; Y représente NCN, NRx ou CRx, où Rx représente NO2, CORy ou SO2Ry, où Ry représente alkyle C1-3, NH2, NH(alkyle C1-3), CF3 ou phényle éventuellement substitué par un, deux ou trois groupes sélectionnés à partir d'alkyle C1-4, alkoxy C1-4, nitro, halo, CF3 et cyano; et Z représente une chaîne latérale di-azacyclique ou azabicyclique, telle qu'une fraction azabicyclique saturée. Lesdits composés et leurs sels acceptables pharmaceutiquement sont des antagonistes du récepteur de 5-HT3.
PCT/GB1992/000310 1991-02-23 1992-02-20 Produits pharmaceutiques WO1992014733A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9103839.8 1991-02-23
GB919103839A GB9103839D0 (en) 1991-02-23 1991-02-23 Pharmaceuticals

Publications (1)

Publication Number Publication Date
WO1992014733A1 true WO1992014733A1 (fr) 1992-09-03

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GB (1) GB9103839D0 (fr)
WO (1) WO1992014733A1 (fr)

Cited By (44)

* Cited by examiner, † Cited by third party
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WO1994001095A2 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
EP0610553A1 (fr) * 1992-11-17 1994-08-17 E.R. SQUIBB &amp; SONS, INC. Dérivés de quinoline et indoline aminocarbonyliques-(thiocarbonyliques) et cyanoguanidiniques
US5352685A (en) * 1992-03-12 1994-10-04 Mitsubishi Kasei Corporation Thieno[3,2-b]pyridine derivatives
US5399562A (en) * 1994-02-04 1995-03-21 G. D. Searle & Co. Indolones useful as serotonergic agents
US5612370A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phenylglycine and phenylalaninen amido benzopyran derivatives
US5612323A (en) * 1995-06-07 1997-03-18 Bristol-Myers Squibb Company Phosphinic ester substituted benzopyran derivatives
US5629429A (en) * 1995-06-07 1997-05-13 Bristol-Myers Squibb Company Process for preparing 4-arylamino-benzopyran and related compounds
US5869478A (en) * 1995-06-07 1999-02-09 Bristol-Myers Squibb Company Sulfonamido substituted benzopyran derivatives
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
US8476431B2 (en) 2008-11-03 2013-07-02 Itellikine LLC Benzoxazole kinase inhibitors and methods of use
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US8642604B2 (en) 2006-04-04 2014-02-04 The Regents Of The University Of California Substituted pyrazolo[3,2-d]pyrimidines as anti-cancer agents
US8697709B2 (en) 2008-10-16 2014-04-15 The Regents Of The University Of California Fused ring heteroaryl kinase inhibitors
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
US8703777B2 (en) 2008-01-04 2014-04-22 Intellikine Llc Certain chemical entities, compositions and methods
US8785454B2 (en) 2009-05-07 2014-07-22 Intellikine Llc Heterocyclic compounds and uses thereof
US8785470B2 (en) 2011-08-29 2014-07-22 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
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US8980899B2 (en) 2009-10-16 2015-03-17 The Regents Of The University Of California Methods of inhibiting Ire1
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
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US9512125B2 (en) 2004-11-19 2016-12-06 The Regents Of The University Of California Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents
US9629843B2 (en) 2008-07-08 2017-04-25 The Regents Of The University Of California MTOR modulators and uses thereof
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Cited By (87)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352685A (en) * 1992-03-12 1994-10-04 Mitsubishi Kasei Corporation Thieno[3,2-b]pyridine derivatives
WO1994001095A3 (fr) * 1992-07-03 1994-04-14 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
WO1994001095A2 (fr) * 1992-07-03 1994-01-20 Smithkline Beecham Plc Medicaments pour le traitement de douleurs viscerales et de migraines
EP0610553A1 (fr) * 1992-11-17 1994-08-17 E.R. SQUIBB &amp; SONS, INC. Dérivés de quinoline et indoline aminocarbonyliques-(thiocarbonyliques) et cyanoguanidiniques
US5514690A (en) * 1992-11-17 1996-05-07 E. R. Squibb & Sons, Inc. Aminocarbonyl (thiocarbonyl) and cyanoguanidine derivatives of quinoline and indoline
US5399562A (en) * 1994-02-04 1995-03-21 G. D. Searle & Co. Indolones useful as serotonergic agents
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