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WO1994027992A1 - Derives de piperidine, leur preparation et leur utilisation - Google Patents

Derives de piperidine, leur preparation et leur utilisation Download PDF

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Publication number
WO1994027992A1
WO1994027992A1 PCT/DK1994/000199 DK9400199W WO9427992A1 WO 1994027992 A1 WO1994027992 A1 WO 1994027992A1 DK 9400199 W DK9400199 W DK 9400199W WO 9427992 A1 WO9427992 A1 WO 9427992A1
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WO
WIPO (PCT)
Prior art keywords
fluoro
compound
benzisoxazol
formula
piperidine
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/DK1994/000199
Other languages
English (en)
Inventor
John Bondo Hansen
Frederik Christian GRØNVALD
John Patrick Mogensen
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to AU69239/94A priority Critical patent/AU6923994A/en
Publication of WO1994027992A1 publication Critical patent/WO1994027992A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to piperidine derivatives which are useful for treating CNS-system, cardiovascular system and/or gastrointestinal dis- orders, methods for preparing such compounds and pharmaceutical compositions containing them.
  • DA dopamine
  • clozapine some neuroleptics (e.g. clozapine) show an atypical profile: the compounds are not only beneficial in treating patients, who respond poorly to classical neuroleptic therapy, but the compounds are also relatively devoid of extrapyrimidal side effects (EPS) commonly seen with classical neuroleptics (Ereshefsky et al., Clin.Pharm 8, 691-709, 1989).
  • EPS extrapyrimidal side effects
  • the antipsychotic effect of clozapine and related compounds might be due to its blockade of not only DA-receptors (D-1 , D-2, D-3, D-4, D-5) but also 5HT-receptor subtypes (5HT 2 -, 5HT 3 -, 5HT 1C -, 5HT 1A -), NA- ⁇ , -receptors, histamine and possibly other receptors.
  • 5HT 2 -blockade may also be important (Meltzer, Schizphr. Bull. 17: 263-87, 1991) to counteract the socalled negative symptoms of psycho ⁇ sis (delusions and social withdrawal) which are otherwise difficult to treat with conventional neuroleptics.
  • n and m independently are 0, 1 , 2, or 3;
  • A is cycloalkylene having 3-11 carbon atoms or cycloalkylidene having 3-8 carbon atoms;
  • X is O or NH
  • Y is O, S, NH, NCN, or N-alkyl
  • R 1 is 1 ,2-benzisoxazol-3-yl, 1 H-indazol-3-yl, or 1-methyl-1 H-indazol-3-yl, all of which may be substituted independently with halogen or alkyl in one, two, three or all of the 4-, 5-, 6- and 7-positions;
  • R 2 is hydrogen or alkyl
  • R 3 is phenyl optionally substituted with alkyl, halogen, alkoxy, or perhalome- thyl, or R 3 is
  • Z together with the double bond in the phenyl ring represents a 5- or 6-membered heterocyclic ring comprising one or more nitrogen-, oxy ⁇ gen-, or sulphur atoms; or
  • R 2 and R 3 together with the nitrogen atom form a fused heterocyclic ring system
  • Physiologically and pharmaceutically acceptable salts of the compounds of the invention include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulphonates e.g. mesylates. If desirable, selected salts may be sub ⁇ jected to further purification by recrystallization.
  • the invention includes within its scope all optical isomers of compounds of the general formula I and their mixtures including racemic mixtures thereof.
  • the compound of the formula (I) includes all cis- and trans-isomers as well as mixtures thereof.
  • C ⁇ -alky refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.
  • cycloalkylene denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from each of two different carbon atoms of the ring.
  • Preferred examples of cycloalkylenes having 3-11 carbon atoms are cyclopropylene, 1 ,2-cyclobutylene. 1 ,2-cyclopentylene, 1 ,3-cyclopentylene. 1 ,2-cyclohexyle- ne, 1 ,3-cyclohexylene, 1 ,3-cyclooctylene, 1 ,4-cycloundecylene.
  • cycloalkylidene denotes a bivalent radical derived from a saturated monocyclic hydrocarbon by removal of two atoms of hydrogen from the same carbon atom of the ring.
  • Examples of cycloalkyli- denes having 3-8 carbon atoms are cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene and cyclooctylidene.
  • alkoxy refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.
  • halogen means fluorine, chlorine, bromine and iodine.
  • perhalomethyl means -CF 3 , -CCI 3 , -CBr 3 and -Cl 3 .
  • 5- or 6-membered heterocyclic ring refers to a monocyclic unsaturated ring containing one or more hetero atoms selected from nitrogen, oxygen and sulphur and having 5 or 6 members, e.g. pyrrolo, imidazo, pyrazolo, piperido, piperazino, triazolo, pyrimido, pyridaz- o.oxazino, azino, isothiazolo, isoxazolo, oxazolo, oxadiazolo, thiadiazolo, thiazolo, 1 ,3-dioxolo, 1 ,4-dioxanyl.
  • pyrrolo imidazo, pyrazolo, piperido, piperazino, triazolo, pyrimido, pyridaz- o.oxazino, azino, isothiazolo, isoxazolo, oxazolo
  • fused heterocyclic ring system refers to a multiple heterocyclic ring system preferably having 2 or 3 fused unsaturated or saturated rings in a linear or branched arrangement.
  • the group -N(R 2 )(R 3 ) is preferably a group selected from 1 ,2.3,4-tetrahydro-quinolin-l -yl, 1 ,2,3,4-tetrahydro-5,6-methylenedioxy- quinolin-1-yl, 1 ,2,3,4-tetrahydro-6.7-methylenedioxy-quinolin-1 -yl, 1 ,2,3,4- tetrahydro-7.8-methylenedioxy-quinolin-1 -yl; 1 -indolinyl, 4,5-methylenedioxy- 1 -indolinyl, 5,6-methylenedioxy-1 -indolinyl, 6,7-methylenedioxy-1 -indolinyl; 1 ,2,3,4-tetrahydro-quinolin-l -yl substituted independently in one or more of the 5-, 6-, 7- or
  • halogen, C ⁇ -alkoxy or perhalo- methyl 1 -indolinyl substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C ⁇ -alkyl, halogen, C- ⁇ -alkoxy or perhalomethyl; 3,4- dihydro-2H-1 ,4-benzoxapine substituted independently in one or more of the 4-, 5-, 6- or 7-positions with C ⁇ g -alkyl, halogen, C ⁇ -alkoxy or perhalo ⁇ methyl.
  • R 3 is selected from benzthia- zolyl, benzimidazolyl, benzisoxazol, 1 H-indazolyl, benzofuranyl, indolyl, 3H- indolyl, indolinyl, benzothiophenyl, quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, quinazolinyl and 3,4-methylenedioxyphenyl.
  • Z is selected from the group consisting of thiazolyl, imidazolyl, piperazinyl, morpholino, thiomor- pholino, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, pyrazolyl, and pyrazinyl.
  • R 1 is 6-fluoro-1 H- indazol-3-yl, 6-fluoro-1 ,2-benzisoxazol-3-yl, or 6-fluoro-1 -methyl-1 H-indazol-3- yl;
  • X is O;
  • Y is O; and
  • -A- is cyclopropylene, cyclopropylidene or cyclohexyl- ene.
  • the substituent R 1 is preferably selected from 6-fluoro-1 ,2-benzisoxazol-3-yl, 6-fluoro-1 H-indazol-3-yl, and 6-fluoro-1 -methyl-1 H-indazol-3-yl.
  • Preferred compounds of the invention are:
  • the compounds of the present invention demonstrate high affinity for various receptor subtypes including the 5HT 2 -, the dopamine D and D 2 - receptors or a combination of these.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of CNS-system disorders, cardiovascular disorders or gastrointestinal disorders.
  • the invention also relates to the use of the inventive com ⁇ pounds of formula (I) as medicaments useful for treating CNS-system, cardiovascular system and gastrointestinal disorders, such as treatment of anxiety, sleep disorders, depression, psychosis, schizophrenia, migraine, ischemic neuronal damage, asthma, hypertension, urticaria, analgesia and emesis.
  • the invention relates to a method of preparing the above mentioned compounds.
  • a compound of formula (II) a compound of formula (II)
  • N-ethyl-N-(3,4-methylenedioxyphenyl)carbamoyl chloride prepared by treatment of N-ethyl-3.4-methylenedioxyaniline with phosgene in the presence of triethylamine may be reacted with the desired aminoalkyi piperidine or hydroxyalkyi piperidine intermediate to obtain the desired urea or carbamate of formula I.
  • R 2 and R 3 have the meanings set forth above, prepared by the method described in R. Lee Webb and C.S. Labaw, J. Heterocyclic Chem. U9, 1205 (1982) from R 2 -NH 2 and N-cyanodiphenoxyimidocarbonate.
  • E is a suitable leaving group, e.g. CI-, Br-, I-, p-toluensulfonate-; R 12 is H or a protecting group, and A, n, m and X have the meaning set forth above.
  • compounds of formula (III) can be made by reacting a com- pound of formula (VIII) with one of the compounds of formula (XVa) or
  • p is an integer 1 ,2,3,4,5 or 6.
  • the compounds of the present invention have been tested for binding to various CNS receptor subtypes in vitro in mice.
  • TEST 1 In yjtro inhibition of DOPAMINE D2 receptor binding,
  • Radioactive-labelled ligand 3 H-Spiropehdol is incubated with isolated cell- membrane fragments at 37°C for a given period of time. Following complet- ed incubation, the incubate is filtered through GF/B filters which are rinsed following filtration to remove unspecifically adhered radioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters is indicative of the amount of ligand bound specifically as well as nonspecifically to the mem- branes.
  • the procedure is performed in ice bath. Polytron kinematica is rinsed with milli-Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitat- ed, striatum is removed quickly and weighed (approx. 50 mg). Striatum is transferred to a centrifuging vial containing 10 ml ice-cold D2 buffer. Homo- genization is performed applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifuging vial. The 10 ml rinsing buffer is added to the tissue vial. Centri- fugation at 18,000 rpm for 10 min.
  • polytron kinematica homogenizer
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-SCH 23390 is incubated with isolated cell- membrane fragments in incubation buffer at 30°C for a given period of time. Following completed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered ra ⁇ dioactivity. As opposed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • mice Male Wistar rats, 150-200 g are decapitated. Striatum is removed quickly, weighed (approx. 50 mg) and carefully homogenized in 100 x vol. of buffer I applying glass/teflon homogenizer 10 up/down strokes. Ex.: 50 mg striatum is homogenized in 5,000 ⁇ l buffer I. The homogenate is centrifuged at 18,000 rpm for 20 min. at 4°C, and the supernate is decanted. This step is performed three times, and each time the pellet is resuspended and homogenized in 100 x vol. of buffer I. Following the third centrifugation, the pellet is suspended in 100 x vol. of resuspension buffer and homogenized. The tissue is now ready for use. The tissue is stable at 0°C for 8 hours.
  • the test result is shown in Table I as IC 50 indicating the concentration inhibiting specific binding by 50%.
  • Radioactive-labelled ligand 3 H-Ketanserine is incubated with isolated cell membrane fragments at 37°C for a given period of time. Following complet ⁇ ed incubation, the incubate is filtered through GF/B filters, which are rinsed following filtration to remove unspecifically adhered radioactivity. As op ⁇ posed to low-molecular compounds, membrane fragments are not rinsed through the filters, the radioactivity bound to the filters indicates the amount of ligand bound specifically as well as nonspecifically to the membranes.
  • the preparation is made in ice bath. Polytron kinematica is rinsed with milli- Q-H 2 0 before and after use. Male Wistar rats, 150-200 g are decapitated. Frontal cortex is removed quickly and weighed (approx. 200 mg). Frontal cortex is added to centrifuging vial containing 10 ml ice-cold D2 buffer. Homogenization applying polytron kinematica (homogenizer) setting 6 for 20 sec. The homogenizer is rinsed with 10 ml D2 buffer in another centrifug ⁇ ing vial. The 10 ml rinsing buffer is added to the tissue vial. Centrifuged at 18,000 rpm for 10 min. at 4°C. Final pellet is transferred to 125 x vol. of same buffer. (Ex 200 mg in 25 ml D2 buffer). Can be stored for approx. 30 min. at 0°C.
  • IC 50 i.e. the concentration inhibiting specific binding by 50%.
  • the compounds of the invention may be placed into the form of pharmaceutical composi ⁇ tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, sus ⁇ pensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additio ⁇ nal active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and digly- cerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvi- nylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or like can be used when a sweetened vehicle can be employed.
  • the compound of the invention is dis-claimedd in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains:
  • trans-2,3- methylene-1 ,4-butanol 800 mg, 8 mmol
  • 3,4-methylenedi- oxyphenylisocyanate 1.3 g, 8 mmol
  • (+ trans-2,3-methylene-4-(3,4- methylenedioxyphenylcarbamoyloxy)butanol 750 mg, 28 mmol
  • MS/FAB (8 KV, 2mA): 584 (M + 1), 375, 233, 178, 166, 138.

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

Abstract

L'invention concerne des dérivés de pipéridine selon la formule (I) dans laquelle n et m valent indépendamment 0, 1, 2 ou 3; A représente cycloalkylène ou cycloalkylidènes; X représente O ou NH; Y représente O, S, NH, NCN ou N-alkyle inférieur; R1 représente 1,2-benzisoxazol-3-yle, 1H-indazol-3-yle ou 1-méthyle-1H-indazol-3-yle, pouvant tous être substitués; R2 représente H ou alkyle; et R3 représente phényle optionnellement substitué, ou R3 représente (a) où Z, conjointement avec la double liaison dans la chaîne fermée phényle, représente une chaîne fermée hétérocyclique à 5 ou 6 éléments; ou R2 et R3, conjointement avec l'atome d'azote, forment un système de chaîne fermée hétérocyclique condensé. L'invention décrit également les sels pharmaceutiquement acceptables de ces dérivés. Ces dérivés et leurs sels sont utiles dans le traitement d'affections concernant le système nerveux central, le système cardio-vasculaire et les maladies gastro-intestinales.
PCT/DK1994/000199 1993-05-26 1994-05-25 Derives de piperidine, leur preparation et leur utilisation Ceased WO1994027992A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69239/94A AU6923994A (en) 1993-05-26 1994-05-25 Piperidine derivatives, their preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK60693A DK60693D0 (da) 1993-05-26 1993-05-26 Kemiske forbindelser, deres fremstilling og anvendelse
DK0606/93 1993-05-26

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WO1994027992A1 true WO1994027992A1 (fr) 1994-12-08

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DK (1) DK60693D0 (fr)
WO (1) WO1994027992A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6605623B1 (en) 1998-12-18 2003-08-12 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US20120040972A1 (en) * 2007-07-26 2012-02-16 Luca Gobbi Dual modulators of 5ht2a and d3 receptors
US8877778B2 (en) 2010-12-15 2014-11-04 Hoffmann-La Roche Inc. Benzofurane compounds
US8921397B2 (en) 2011-05-04 2014-12-30 Hoffmann-La Roche Inc. Benzofurane-piperidine compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0377528A1 (fr) * 1989-01-05 1990-07-11 Lipha, Lyonnaise Industrielle Pharmaceutique Pipéridines, procédés de préparation et médicaments les contenant

Patent Citations (1)

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EP0377528A1 (fr) * 1989-01-05 1990-07-11 Lipha, Lyonnaise Industrielle Pharmaceutique Pipéridines, procédés de préparation et médicaments les contenant

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 68, No. 21, 20 May 1968, (Columbus, Ohio, USA), A. BOROVANSKY et al., "New Basic Cycloalkyl Esters of Substituted Carbanilic Acids with Local Anesthetic Activity", page 9103, the Abstract No. 94518d; & EXPERIENTIA 1968, 24 (4), 376-377. *
CHEMICAL ABSTRACTS, Volume 72, No. 8, 23 February 1970, (Columbus, Ohio, USA), BENES LUDEK et al., "Alkoxycarbanilic Acid Esters with High Local Anesthetic Activity", page 163, the Abstract No. 30086m; & ARZNEIM.-FORSCH 1969, 19 (11), 1902-1903. *
CHEMICAL ABSTRACTS, Volume 86, No. 25, 20 June 1977, (Columbus, Ohio, USA), BENES L. et al., "Studies of Local Anesthetics. LX. Basic Cyclohexyl Esters of Alkoxy-Substituted Carbanilic Acids in Cis Configuration", page 585, the Abstract No. 189658k; & CESK. FARM. 1976, 25 (8), 317-320. *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6444686B1 (en) 1998-12-18 2002-09-03 Brsitol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6605623B1 (en) 1998-12-18 2003-08-12 Bristol-Myers Squibb Pharma Co. N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6906066B2 (en) 1998-12-18 2005-06-14 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6897234B2 (en) 1999-12-17 2005-05-24 Bristol-Myers Squibb Pharma Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US20120040972A1 (en) * 2007-07-26 2012-02-16 Luca Gobbi Dual modulators of 5ht2a and d3 receptors
US20130165432A1 (en) * 2007-07-26 2013-06-27 Hoffmann-La Roche Inc. Dual Modulators of 5HT2A and D3 Receptors
US8829029B2 (en) 2007-07-26 2014-09-09 Hoffmann-La Roche Inc. Dual modulators of 5HT2A and D3 receptors
US8877778B2 (en) 2010-12-15 2014-11-04 Hoffmann-La Roche Inc. Benzofurane compounds
US8921397B2 (en) 2011-05-04 2014-12-30 Hoffmann-La Roche Inc. Benzofurane-piperidine compounds

Also Published As

Publication number Publication date
DK60693D0 (da) 1993-05-26
AU6923994A (en) 1994-12-20

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