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1. WO2011023795 - (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS

Publication Number WO/2011/023795
Publication Date 03.03.2011
International Application No. PCT/EP2010/062552
International Filing Date 27.08.2010
Chapter 2 Demand Filed 14.12.2010
IPC
C07D 265/30 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
265Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
281,4-Oxazines; Hydrogenated 1,4-oxazines
30not condensed with other rings
C07D 265/32 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
265Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
281,4-Oxazines; Hydrogenated 1,4-oxazines
30not condensed with other rings
32with oxygen atoms directly attached to ring carbon atoms
C07D 413/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
413Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
02containing two hetero rings
12linked by a chain containing hetero atoms as chain links
C07D 419/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
419Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
02containing two hetero rings
12linked by a chain containing hetero atoms as chain links
C07D 471/04 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
471Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/-C07D463/251
02in which the condensed system contains two hetero rings
04Ortho-condensed systems
A61K 31/5377 2006.01
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
535having six-membered rings with at least one nitrogen and at least one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
53751,4-Oxazines, e.g. morpholine
5377not condensed and containing further heterocyclic rings, e.g. timolol
CPC
A61K 31/5375
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
31Medicinal preparations containing organic active ingredients
33Heterocyclic compounds
395having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
535having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
53751,4-Oxazines, e.g. morpholine
A61P 25/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25Drugs for disorders of the nervous system
A61P 25/04
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25Drugs for disorders of the nervous system
04Centrally acting analgesics, e.g. opioids
A61P 25/06
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25Drugs for disorders of the nervous system
06Antimigraine agents
A61P 25/16
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25Drugs for disorders of the nervous system
14for treating abnormal movements, e.g. chorea, dyskinesia
16Anti-Parkinson drugs
A61P 25/18
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
25Drugs for disorders of the nervous system
18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
Applicants
  • ABBOTT HEALTHCARE PRODUCTS B.V. [NL]/[NL] (AllExceptUS)
  • IWEMA BAKKER, Wouter, I. [NL]/[NL] (UsOnly)
  • COOLEN, Hein K.A.C. [NL]/[NL] (UsOnly)
  • MONS, Harmen [NL]/[NL] (UsOnly)
  • STOIT, Axel [NL]/[NL] (UsOnly)
  • RONKEN, Eric [NL]/[NL] (UsOnly)
  • VAN DER KAM, Elizabeth [NL]/[NL] (UsOnly)
  • FRANKENA, Jurjen [NL]/[NL] (UsOnly)
Inventors
  • IWEMA BAKKER, Wouter, I.
  • COOLEN, Hein K.A.C.
  • MONS, Harmen
  • STOIT, Axel
  • RONKEN, Eric
  • VAN DER KAM, Elizabeth
  • FRANKENA, Jurjen
Agents
  • HOGENBIRK, Marijke
Priority Data
09169075.031.08.2009EP
61/238,51831.08.2009US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) (THIO)MORPHOLINE DERIVATIVES AS S1P MODULATORS
(FR) DÉRIVÉS DE (THIO)MORPHOLINE MODULATEURS DE S1P
Abstract
(EN)
The present invention relates to (thio)morpholine derivatives of the formula (I), wherein R1 is selected from cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each optionally substituted with (1-4C)alkyl, phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyloptionally substituted with one or more fluoro atoms, (2-4C)alkynyl, (1-4C)alkoxy optionally substituted with one or more fluoro atoms,amino, di(1-4C)alkylamino, -SO2-(1-4C)alkyl, -CO-(1-4C)alkyl, -CO-O-(1-4C)alkyl, -NH-CO-(1-4C)alkyl and (3-6C)cycloalkyl, phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl, monocyclic heterocycle optionally substituted with halogen, (1-4C)alkyl or with phenyl optionally substituted with (1-4C)alkyl, and bicyclic heterocycle optionally substituted with (1-4C)alkyl; A is selected from -CO-O-, -O-CO-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O- and the linking group –Y-(CH2)n-X- wherein Y is attached to R1 and selected from a bond, -O-, -S-, -SO-, -SO2-, -CH2-O-, -CO-, -O-CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C-and -C≡C-; n is an integer from 1 to 10; and X is attached to the phenylene / pyridyl group and selected from a bond, -O-, -S-, -SO-, -SO2 -, -NH, -CO-, -C=C-and -C≡C-; ring structure B optionally contains one nitrogen atom; R2 is H, (1-4C)alkyl optionally substituted with one or more fluoro atoms, (1-4C)alkoxy optionally substituted with one or more fluoro atoms, or halogen; and R3 is (1-4C)alkylene-R5 wherein the alkylene group may be substituted with (CH2)2 to form a cyclopropyl moiety or one or two halogen atoms, or R3 is is (3-6C)cycloalkylene-R5 or -CO-CH2-R5, wherein R5 is -OH, -PO3H2, -OPO3H2, -COOH, -COO(1-4C)alkyl or tetrazol-5-yl; R4 is H or (1-4C)alkyl; R6 is one or more substituents independently selected from H, (1-4C)alkyl or oxo; W is -O-, -S-, -SO- or -SO2-; or a pharmaceutically acceptable salt, a solvate or hydrate thereof; with the proviso that the derivative of formula (I) is not 2-(4-ethylphenyl)-4-morpholinoethanol or 4-[4-(2-hydroxyethyl)-2-morpholinyl]benzeneacetonitrile or a pharmaceutically acceptable salt, a solvate or hydrate thereof. The compounds of the invention have affinity to S1P receptors and may be used in the treatment, alleviation or prevention of S1P receptor mediated diseases and conditions.
(FR)
Cette invention concerne des dérivés de (thio)morpholine de formule (I). Dans la formule (I), R1 est choisi parmi un groupe cyano, alcynyle (2-4C), alkyle (1-4C), cycloalkyle (3-6C), cycloalcényle (4-6C), bicycloalkyle (6-8C), bicyclique (8-10C), chacun éventuellement substitué par un alkyle (1-4C), un phényle, un biphényle, un naphtyle, chacun éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un atome d'halogène, un alkyle (1-4C) éventuellement substitué par un ou plusieurs atomes fluoro, un alcynyle (2-4C), un alcoxy (1-4C) éventuellement substitué par un ou plusieurs atomes fluoro, un amino, un dialkyl(1-4C)amino, un -SO2-alkyle (1-4C), un -CO-alkyle (1-4C), un -CO-O-alkyle (1-4C), un -NH-CO-alkyle (1-4C) et un cycloalkyle (3-6C), un phényle substitué par un phénoxy, un benzyle, un benzyloxy, un phényléthyle ou un hétérocycle monocyclique, chacun éventuellement substitué par un alkyle (1-4C), un hétérocycle monocyclique éventuellement substitué par un atome d'halogène, un alkyle (1-4C) ou par un phényle éventuellement substitué par un alkyle (1-4C), et un hétérocycle bicyclique éventuellement substitué par un alkyle (1-4C); A est choisi parmi -CO-O-, -O-CO-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O- et le groupe de liaison -Y-(CH2)n-X-, où Y est lié à R1 et choisi parmi une liaison, -O-, -S-, -SO-, -SO2-, -CH2-O-, -CO-, -O-CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C- et -C≡C-; n est un nombre entier de 1 à 10; et X est lié au groupe phénylène/pyridyle et choisi parmi une liaison, -O-, -S-, -SO-, -SO2-, -NH, -CO-, -C=C- et -C≡C-; la structure de cycle B contient éventuellement un atome d'azote; SPW0912 WO150 R2 est H, un alkyle (1-4C) éventuellement substitué par un ou plusieurs atomes fluoro, un alcoxy (1-4C) éventuellement substitué par un ou plusieurs atomes fluoro, ou un groupe halogène; et R3 est un alkylène (1-4C)-R5, où le groupe alkylène peut être substitué par (CH2)2 pour former un fragment cyclopropyle ou un ou deux atomes d'halogène, ou R3 est un cycloalkylène (3-6C)-R5 ou -CO-CH2-R5, où R5 est -OH, -PO3H2, -OPO3H2, -COOH, un -COO-alkyle (1-4C) ou un tétrazol-5-yle; R4 est H ou un alkyle (1-4C); R6 est un ou plusieurs substituants indépendamment choisis parmi H, un groupe alkyle (1-4C) ou oxo; W est -O-, -S-, -SO- ou -SO2 -; ou un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci; à condition que le dérivé de formule (I) ne soit pas un 2-(4-éthylphényl)- 4-morpholino-éthanol ou un 4-[4-(2-hydroxyéthyl)- 2-morpholinyl]benzène- acétonitrile ou un sel pharmaceutiquement acceptable, un solvate ou un hydrate de celui-ci. Les composés selon l'invention ont une affinité pour les récepteurs S1P et peuvent être utilisés pour traiter, soulager ou prévenir les maladies et affections médiées par les récepteurs S1P.
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