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WO2010077839A1 - Agonistes de cb2 de type oxindole substitué pour le traitement de la douleur - Google Patents

Agonistes de cb2 de type oxindole substitué pour le traitement de la douleur Download PDF

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Publication number
WO2010077839A1
WO2010077839A1 PCT/US2009/067967 US2009067967W WO2010077839A1 WO 2010077839 A1 WO2010077839 A1 WO 2010077839A1 US 2009067967 W US2009067967 W US 2009067967W WO 2010077839 A1 WO2010077839 A1 WO 2010077839A1
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WIPO (PCT)
Prior art keywords
indol
dioxane
spiro
ylsulfonyl
oxo
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PCT/US2009/067967
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English (en)
Inventor
Paul Jeffrey Dollings
Andrew Forrest Donnell
Adam Matthew Gilbert
Minsheng Zhang
Boyd Lynn Harrison
Charles John Stanton Iii
Steven Victor O'neil
Lisa Marie Havran
Dan Chaekoo Chong
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Wyeth Llc (Formerly Known As Wyeth)
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Publication of WO2010077839A1 publication Critical patent/WO2010077839A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin

Definitions

  • CB 1 and CB2 receptors two subtypes of the cannabinoid receptor, both belong to the G-protein- coupled receptor (GPCR) superfamily
  • GPCR G-protein- coupled receptor
  • the CB 1 receptor is predominantly expressed in brain to mediate inhibition of transmitter release and affects many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination muscle tone, and analgesia, as described by Goutopoulos et al., in the publication Pharmacol Ther (2002) 95- 103
  • the CB2 receptor is primarily expressed in immune cells to modulate immune response Activation of the CB2 receptor is known to induce analgesic effects in inflammatory models involved in neurodegeneration diseases, and plays a role in the maintenance of bone density and progression of atherosclerotic lesions
  • CB2 agonists are potential drug candidates for reducing pain (such as chronic inflammatory pain, post surgical pain, neuropathic pain, and bone pain) and for treating a host of diseases including osteoarthritis, athe
  • the invention relates to a compound of Formula I:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the above-described substituted oxmdole compounds of the invention, oi pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
  • the invention relates to a method of treating a CB2-tnediated disorder by administering to a subject in need of this treatment a therapeutically effective amount of one or more of the compounds described above CB2 -mediated disordeis include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e g , glioma)
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in therapy
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the treatment of a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma)
  • a compound of the invention, or pharmaceutically acceptable salt thereof for use in the preparation of a medicament for use in the treatment of one or more CB2-mediated disorders.
  • the present invention provides substituted oxindole compounds that are CB2 agonists having Formula I
  • R 1 is selected from Q. 6 alkyl, C 2 ⁇ alkenyl, C 2 . 6 alkynyl, C
  • R 2 and R 3 are independently selected from H, halogen, C, 6 alkyl, C 2 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, C, ⁇ hydroxyalkyl, C N6 cyanoalkyl, C 6 . ⁇ o aryl, C 4 . l0 heteroaryl, C 3 . 8 cycloalk>'l, C 3 . g heterocycloalkyl, C 3 .
  • R 4 is selected from C(O)NR 6 R 7 , SO 2 NR 6 R 7 , NR 8 C(O)R 9 , NR 8 SO 2 R 9 and C(O)C(O)NR 6 R 7 ;
  • R 5 is selected from H, halogen and Q 6 alkyl.
  • R 6 and R 7 are independently selected from H, Ci 6 alkyl, C 1 ⁇ haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 6-I 0 aryl, Cm heteroaryl, C 3 8 cycloalkyl, C 3 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl and C,. 6 hydroxyallcyl, wherein said C u alkyl C, 6 haloalkyl, C 2 6 alkenyl, C 2 ⁇ alkynyl, C 6 10 aryl, C 4 10 heteroaryl, C 8 cycloalkyl, C 3 8 heterocycloalkyl, C 3 . ?
  • heterocycloalkenyl and Ci 6 hydroxyalkyl is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, cyano, amino, halo, C
  • C 3 . 8 heterocycloalkenyl or C 6 hydi oxyalkyl is optionally substituted with 1 , 2, 3 4, or 5 substituents independently selected from 0R a , cyano, ammo, halo, NO 2 , Cu alkyl, C 6 - I o aryl, Cm heteroaryl, C 8 cycloalkyl, C, % heterocycloalkyl and C 8 heterocycloalkenyl,
  • R* and R 9 are independently selected from H, C 1 - O alkyl.
  • R ⁇ R b , R c and R f are independently selected from II, C 1 ⁇ alkyl, C
  • R c and R c are independently selected from H, C
  • heteroarylalkyl C 5 .1 2 cycloalkylalkyl and C 5 . 12 heterocycloalkylalkyl, wherein said C,. 6 alkyl. C
  • C 4 .i 4 heteroarylalkyl, C 5 . ⁇ 2 cycloalkylalkyl or C 5 . ⁇ 2 heterocycloalkylalkyl. is optionally substituted with OH, cyano, amino, halogen, Q 6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R c and R d , together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C
  • the invented compounds selected from:
  • R 4 when R 4 is SOjNR 6 R 7 , n is 0, R 2 and R 3 , together with the carbon atom to which they are attached, form a l ,3-dioxan-2,2-diyl ring, and R 6 and R 7 , together with the carbon atom to which they are attached, form a pyrrohdinyl ring, then R 1 is not alkyl substituted with NH 2 , CN, N 3 , bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or cyanoalkyl In related embodiments, R 4 is substituted at the 5-position of the oxindole core.
  • R 1 is selected from C ⁇ alkyl, C 2 . 6 alkenyl, C 2 . ft alkynyl, Q 6 haloalkyl, C,. t , hydroxy alkyl, C, 6 cyanoalkyl, C 6 io aryl, GH 0 heteroaryl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl and C 3 8 heterocycloalkenyl, wherein said Ci 6 alkyl, C 2 . 6 alkenyl, C;.
  • U heteroaryl, C 3 .g cycloalkyl, C 3 8 heterocycloalkyl, or C 3 8 heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, N,, NO 2 , OR a , SR 8 , C 6-I0 aryl, C 4 10 heteroaryl, C 3 8 cycloalkyl, C, 8 heterocycloalkyl, and C 3 . 8 heterocycloalkenyl.
  • R' is selected fiom C 6 alkyl, C
  • R 1 is C
  • R 1 is C t 6 alkyl, optionally substituted with one substituent selected from Q-io aryl, C 4 - I0 heteroaryl, C 3 . s cycloalkyl, C 1 .* heterocycloalkyl, and C 1 .* heterocycloalkenyl.
  • R' is is C 3 . ? cycloalkyl.
  • R' is cyclopropyl
  • R' is C
  • R' is C 6 . io aryl or C 4 .
  • R 1 is C 1 6 cyanoalkyl.
  • R' is C]. 6 haloalky!.
  • halogen is fluoro
  • R' is CF 3 .
  • R 2 and R 3 are independently selected from H, halogen, d. 6 alkyl, C 2 _ 6 alkenyl. C? 6 alkynyl. C]. 6 haloalkyl, C
  • R 2 and R 3 are independently selected from H, halogen, C
  • R 2 and R 3 are independently selected from halogen, Cu alkyl, and OR".
  • one of R 2 and R 3 is Ci ⁇ alkyl.
  • one of R 2 and R 3 is 0R ⁇
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ⁇ ng, said ring comprising 1-3 hetcroatoms selected from N, O and S, optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ⁇ ng
  • R 2 and R 3 together with the carbon atom to which they arc attached, join to form a 5-7 membered cycloalkyl ⁇ ng
  • R 1 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1, 2, or 3 substitucnts independently selected from halogen, Ci.., alkyl, C 2 ⁇ , alkenyl, C 2 .,, alkynyl, C b ., Q aryl, Ci 0 heteroaryl, C 3 . 8 cycloalkyl, C 3 , heterocycloalkyl, C 3 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ⁇ ng.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalky] ⁇ ng.
  • the 6-membered heterocycloalkyl ⁇ ng comprises 1 or 2 heteroatoms
  • At least one heteroatom is O.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 1.3-dioxan-2,2-diyl ring, 1.3-dioxolan-2,2-diyl, or tetrahydropyran-2,2-diyl ring.
  • R 4 is C(O)NR 6 R 7 .
  • At least one of R 6 and R 7 is H.
  • At least one of R 6 and R 7 is C,. 6 alkyl.
  • both of R 6 and R 7 are C
  • one of R 6 and R 7 is C 3 .g cycloalkyl, C 7 . u arylalkyl, or C 6 10 aryl
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C,. o alkyl, C,. 6 alkenyl, C 2 . 6 alkynyl, CN, NO 2 , N 3 , 0R a , and SR a .
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ⁇ ng.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or pipe ⁇ dinyl ⁇ ng.
  • R 4 is SO 2 NR 6 R 7
  • At leabl one of R 6 and R 7 is H
  • At least one of R 6 and R 7 is Ci 6 alkyl.
  • both of R 6 and R 7 are C
  • one of R 6 and R' is C 3 . 8 cycloalkyl, C 7 u arylalkyl, or C 6-I0 aryl.
  • R° and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
  • R 4 is NR 8 C(O)R 9 or NR 8 SO 2 R 9 .
  • R 8 is H or C
  • R 9 is H, C
  • 8 heterocycloalkenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halogen, 0R a , cyano, amino, NO 2 , Cu alkyl, C 1 . 4 haloalkyl, Ci 6 hydroxyalkyl, C 3 g cycloalkyl, and C 3 . 8 heterocycloalkyl.
  • R 9 is Cu alkyl, Cu haloalkyl, or Cu hydroxyalkyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, 0R a , C 3 . 8 cycloalkyl, and C 3 .g heterocycloalkyl.
  • R 9 is cycloalkyl or aryl.
  • R 9 is phenyl or cycloalkyl having 3-8 carbon atoms.
  • R 4 is C(O)C(O)NR 6 R 7 .
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
  • R 5 is H, halo, Cu alkyl, Cu haloalkyl, C 1-6 hydroxyalkyl, Cu cyanoalkyl, CN, NO 2 , N 3 , 0R a , or SR a .
  • R 5 is H, halogen, or C M alkyl.
  • n O or 1.
  • n O
  • the invention includes a compound of Formula (I):
  • R' is C
  • cycloalkyl, C 1 ., heterocycloalkyl or C 3 . 8 heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from C 6 - ⁇ o aryl, C 4 .i 0 heteroaryl, C 3 . g cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, halogen, CN, N 3 , NO 2 , OR", SR a ;
  • R 2 and R 3 are independently selected from H, halogen, C
  • R 4 is C(O)NR 6 R 7 , C(O)C(O)NR 6 R 7 , SO 2 NR 6 R 7 , NR*C(0)R 9 , or NR 8 SO 2 R 9 ;
  • R 5 is H , halogen, or C M alkyl
  • R 6 and R 7 are independently selected from H, C ⁇ _s alkyl, d. 6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C
  • R 8 and R 9 are independently selected from H, C
  • R 2 and R 3 arc independently selected from H, halo, CV 6 alkyl, C 2 . 6 alkenyl, C 2 . o alkynyl, C,. 6 haloalkyl, C 6 hydroxyalkyl, C 6 cyanoalkyl, C 6 . ⁇ aryl, C 6 - I o heteroaryl, C 3 . s cycloalkyl, C 8 heterocycloalkyl, C 3 .
  • R a , R b , R", and R f are each independently selected from H, C
  • 4 heterocycloalkylalkyl is optionally substituted with OH, cyano, amino, halo, C ⁇ . 6 alkyl, C 6 -Io aryl, Ci 4 arylalkyl, C4-10 heteroaryl, C 4 . ⁇ heteroarylalkyl, Cs cycloalkyl, or C 3 . 8 heterocycloalkyl;
  • R c and R d are independently selected from H, Cs > alkyl, C
  • R 4 when R 4 is SO 2 NR 0 R 7 , n is O, R 2 and R 3 , together with the carbon atom to which they are attached, join to form a 1 ,3-dioxan-2,2-diyl ring, and R 6 and R 7 , together with the carbon atom to which they are attached, join to form a pyrrolidinyl ring, R 1 is not alkyl substituted with NH 2 , CN, N 3 , bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or C 6 cyanoalkyl.
  • the invention provides compounds of Formula II:
  • R' is C 6 haloalkyl, Ci ⁇ hydroxyalkyl, or C 6 cyanoalkyl.
  • R' is Ci -6 haloalkyl.
  • halogen is fluoro
  • R' is CF 3
  • one of R 2 and R 3 is C,. 6 alkyl.
  • one of R 2 and R 3 is OR a .
  • R 2 and R 3 together wilh the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
  • the 6-membered helerocycloallcyl ring contains 1 or 2 heteroatoms.
  • At least one heteroatom is O
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a l,3-dioxan-2,2-diyl ring, l ,3-dioxolan-2,2-diyl. or tetrahydropyran-2,2-diyl ring.
  • R" and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperaziny!, or piperidinyl ring.
  • the invention provides compounds of Formula III:
  • the invention includes a compound selected from Formulas IVa, FVb, and
  • R is C 1 ⁇ alkyl. optionally substituted with 1, 2, or 3 substituenls ..elected from C 6 - I O aiyl, C 3 g cycloalkyl, C 6-I0 heteioaryl and C 3 8 heterocycloalkyl
  • R is Ci 6 alkyl substituted with one substituent selected from C 6 , 0 aryl, C, 8 cycloalkyl, C 4 , 0 heteroaryl and C 3 8 heterocycloalkyl
  • Ci 6 alkyl is propyl
  • Cy is C 3 7 cycloalkyl
  • Cy is cyclopropyl
  • R 1 is C . 6 haloalkyl, C 1 * hydroxyalkyl, or Ci 6 cyanoalkyl.
  • R' is C, 6 haloalkyl
  • halogen is fluoro
  • R 1 is CF 3 .
  • one of R 3 and R 1 is C,. 6 alkyl.
  • one of R 2 and R 3 is OR a
  • R : and R 3 together with the carbon atom to which they are attached, join to form a 5-7 membered cycloalkyl ring.
  • R 2 ana R 1 together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
  • the 6-membered heterocycloalkyl ring comprises 1 or 2 heteroatoms.
  • At least one heteroatom is O.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a l ,3-dioxan-2,2-diyl nng, l,3-dioxolan-2,2-diyl, or tet ⁇ ahydropyran-2,2-diyl ring
  • R 6 and R 7 together w ith the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R" and R 7 together with the N atom to which they are attached, join to form a pyrrohdinyl, morphohno, piperazmyl, or pipe ⁇ dmyl nng
  • the invention provides compounds of Formula V:
  • substituents of compounds of the invention are disclosed in groups or m ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1 ⁇ alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • the compounds of the invention are stable. As used herein ' 'stable" refers to a compound tha; is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group, which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et). propyl (e.g.. n- propy] and isopropyl), butyl (e.g., n-b ⁇ tyl, lsobuty ' , t-buryl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl. propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CIICl 2 , C 2 Cl 5 , and the like.
  • -'aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like.
  • aryl groups comprise from 6 to about 20 carbon atoms, including comprising from 6 to 10 carbon atoms,
  • arylalkyl refers to an alkyl group substituted by an aryl group. Examp ' .ary arylalkyl groups include, but are not limited to, benzyl and phenethyl.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl. alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups comprise from 3 to 20 carbon atoms, including comprising from 3 to 14 carbon atoms, 3 to 10 carbon atoms. 3 to 8 carbon atoms or 3 to 6 carbon atoms. Cycloalkyl groups can further comprise 0, 1 or 2 double bonds and/or 0, 1 , or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though cither the aromatic or non-aromatic portion.
  • One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfide substituent.
  • Example cycloalkyl groups include eycl ⁇ propyl, cyelobufyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadier.yl, cyclohcptat ⁇ cnyl. norbornyl, norpinyl, norcarnyl. adamantyl, and the like.
  • a "cycloalkylalkyl” group refers to an alky! group substituted by a eyeloalkyl group
  • An exemplary cycloalkylalkyl group includes, bul is not limited to cyclopentylmethyl and cyclohexylmethyl.
  • heteroaryl refers to an aromatic heterocycle comprising at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • Heteroaryl groups include monocyclic and fused, poiycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom m a heteroaryl group can also be oxidized to form an N-ox o moiety or can be functionahzed to form an N-functionahzed group (e.g. N-alkyl or N-aryl).
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, py ⁇ midinyl, pyrazinyl, py ⁇ dazinyl, triazinyl, furyl.
  • quinolyl isoquinolyl, thienyl. linidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl. benzofuryl, benzothienyl, benzthtazolyl, isoxazolyl, pyrazolyl.
  • the heteroaryl group comprises from 2 to 20 carbon atoms, and in further embodiments comprises from about 4 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 6 to about 10 nng-forming atoms. In some embodiments, the heteroaryl group comprises from 1 to 4 heteroatoms, including comprising from 1 to 3 heteroatoms or 1 to 2 heteroatoms.
  • a heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is py ⁇ dylmethyl.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms comprises a heteroatom selected from O, N and S.
  • '"heterocycloalkenyl refers to a partially-unsaturated heterocycle or a heterocycle comprising at least one unsaturated bonding of carbon atoms or carbon and heteroatoms, where one or more of the ring-forming atoms comprises a heteroatom selected from O, N and S.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused iings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include, but are not limited to, morpholmo, thi ⁇ morphohno, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2.3-dihydrobenzofuryl, 1.3-benzodioxole, benzo-l ,4-dioxane, pipendmyl, pyrrolidinyl, isoxazolidmyl. lsothiazohdinyl, pyrazolidinyl, oxazohdinyl, thiazolidinyl. imidazokdin ⁇ !, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused ( i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthahmidyl. naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non- aiomatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfide groups.
  • the heterocycloalkyl group comprises from 4 to 20 carbon atoms, and in further embodiments from 5 to 10 carbon atoms. In some embodiments, the heterocycloalkyl group comprises 5 to 20. 5 to 14. 5 to 12, or 5 to 10 ring-forming atoms. In some embodiments, the heterocycloalkyl group further comprises 1 to 4 heteroatoms, including comprising from 1 to 3, or 1 to 2 heteroatoms, In some embodiments, the heteroeyeloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds. As used herein, "heterocyeloalkylalkyl" refers to an alkyl group substituted by a heterocycloalkyl group.
  • halo or halogen'- includes fluoro, chloro. bromo. and iodo.
  • haloalkyl refers to an alkyl group substituted by one or more halogen atoms.
  • haloalkyl groups examples include CF 3 and CF 2 CF 3 .
  • alkoxy refers to an -O-alkyl group
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the compounds described herein can be asymmetric (e.g.. having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that comprise asymmetrically substituted carbon atoms can be isolated m optically active or raecmic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C-N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers arc contemplated m the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidie acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • compound as used herein is meant to include all stereoisomers, geometric losomers, tautomers. and isotopes of the structures depicted. All compounds, and pharmaceutical) acceptable salts thereof, are also meant to include solrated or hydra ted forms.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions comprising at least 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which comprises a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, cthanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17* ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, withm the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds of the presen: invention can be prepared from readily available starting materials in a variety of ways known to one skilled in the art of organic synthesis. For example, they can be synthesized via the reaction pathways and techniques as described below. Scheme 1
  • spiro oxindole sulf ⁇ namideb VIII
  • VT spiro oxindole
  • VII sulfonamide compounds
  • Alkylation of the oxindole nitrogen was accomplished using organohalides and organotosylates with K 2 CO 3 in DMF at 60° C, and produced invented compounds (VTII).
  • Oxmdole (XII) was eomerted to oxmdole sulfonamides (XIIT) using ClSO 3 H, followed b> reaction with various amines Deprotonation with LDA in THF followed by trapomg with acrylomt ⁇ le and warming to 23 °C produced the desired imented comrjounds (XIV).
  • oxindole sulfonamides (XXIII) were synthesized according to Scheme 10.
  • Tert- alcohol compounds (XXI) were chlorinated using SOCIi, and produced intermediate chloro compounds, winch were reduced with Zn/IIOAc/THF, and produced the desired invented compounds (XXIII).
  • Ceitain invented oxindole dimethylacetals were prepared according to Scheme 14 Isatm sulfonamides (1) were converted to the corresponding dimethylacetal compounds (XXIX) using MeOWp- TsOH. Alkylation or arylatton of the oxindole nitrogen proceeded using organohalides or organotosylates in therailnce Of K 2 CO 3 in warm DMF, and produced the N-functionahzed dimethylacetal compounds (XXX)
  • oxindote acetal amide compounds were prepared according to Scheme 17. Iodo-isatin (XLII) is converted to the corresponding cyclic acetal using 1 ,3 -propanediol andp-TsOH in benzene solvent with heating. Pd-catalyzed carbonylation of the aryliodide followed by trapping with MeOH produced the corresponding methyl ester compound (XLIV). Alkylation or arylation of the oxindole nitrogen ws accomplished organohalides and K 2 CO 3 m DMF solvent with heating and produced corresponding N-functionalized acetal compounds (XLV). Saponification of the ester compounds produces the corresponding carboxylic acid compounds (XLVI). The invented amide compounds (XLVII) were produced from reaction of amines and peptide coupling agents, EDCI'HOBt.
  • N-Aryl oxmdole compounds were prepared from corresponding 1'- hydro-5'-(pyrrolidin-1-ylsulfonyl)spiro[[1,3]dioxane-2.3'-indolin]-2'-one compounds using aryl boronie acids (Ar is a substituted aryl), copper acetate, amine bases such as Lt 3 N m aprotic solvents such as CH 2 Cl; (Scheme 19) .
  • lodooxindolc acctai (XLIII) was alkylated using alkyl or benzylic halides in the presence of a weak base such as K 2 CO 3 or Cs 2 COi in a polar aprotic solvent such as DMF, DMSO or acetone solvent, and produced N-alkyl- or N-benzyl-functionalized acetal compounds (LLX).
  • Palladium catalyzed carbonylative animation was carried out using piperidine to produce amide oxoindole acetal compounds (LX).
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or ' 3 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or ' 3 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection of certain functional groups attached to the oxoindole core of the invented compounds, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • Suitable solvents can be substantially non-rcacti ⁇ c with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures, which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • An example method includes fractional recrystallization using a "cbiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystalliza ⁇ ' on methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacet)'ltartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • the selection of a suitable elution solvent composition may be determined by one skilled in the art.
  • Modulation is meant to refer to an ability to increase or decrease aclivity of an the receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell.
  • compounds of the invention can be used in methods of modulating the activity of the CB2 receptor, by contacting the receptor with one or more of the compounds or compositions described herein.
  • contacting refers to bringing together of indicated moieties m an in vitro system or an in vivo system.
  • "contacting" a compound of the invention with the CB2 receptor includes the administration of a compound of the present invention to an individual or patient, such as a human, as well as, for example, introducing a compound of the invention into a sample comprising a cellular or purified preparation of the receptor.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the present invention can act as CD2 receptor agonists.
  • these compounds can be used to treat CB2-mediated disorders, such as CB2 agonists are potential drug candidates for reducing treating pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
  • the treatment includes administration of a therapeutically effective amount of one or more of the invented 3-substitutcd oxindole compounds described above to a patient in need thereof,
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, vetc ⁇ narian, medical doctor or other clinician,
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/'or symptomatology) such as decreasing the severity of disease.
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease
  • inhibiting the disease for example, inhibiting a disease, condition or disorder
  • Examplary cancers treatable by the invented compounds herein include, but are not limited to, glioma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, cancer of the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, sjTio vial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, or WiIm' s tumor, and the like.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment of the diseases, disorders or conditions described herein.
  • one or more of the above-described 3-substituted oxindolc compounds can be used together with an anti-inflammatory agent, an anti-cancer agent, an analgesic, or other therapeutic agent useful in treating pain, cancer, osteoarthritis, atherosclerosis, osteoporosis or other disease.
  • the agents or therapies can be administered together with the compounds of the invention (e.g., combined into a single dosage form), or the agents or therapies and may be administered simultaneously or sequentially by separate routes of administration.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions, which is a combination of a compound of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier
  • compositions can be prepared in a manner well known m the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g.. by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • Methods for ocular deliver, 1 can include topical administration (eye drops), subconjunctival, periocular or mtravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • This invention also includes pharmaceutical compositions, which comprise, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an cxc ⁇ ient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient when it serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient,
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or m a liquid medium), ointments comprising, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to an average particle size of less than 200 mesh. If the active compound is substantially water- soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. an average particle size of about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by methods described in International Patent Application No. WO 2002/000196.
  • suitable exeipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient, l he term "unit dosage forms 1' refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit comprising a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like,
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above comprising from, for example. 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed m release,
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described supra, and in some embodiments, the compositions are administered by an oral or nasal respiratory route for local or systemic effect.
  • compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices, which deliver the formulation in an appropriate manner.
  • the amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the seventy of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophihzed. the lyophihzed preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5 to 9 and most preferably from 1 to 8, It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution comprising about 0.1 to about 10% w/ ' v (weight/volume) of the compound for parenteral adrninstration. Some typical dose ranges are from about 1 mg/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • kits useful for example, in the treatment or prevention of diseases, such as pain or cancer and other diseases referred to herein, which include one or more containers comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/'or guidelines for mixing the components can also be included in the kit.
  • the invention will be described in greater detail by way of specific examples.
  • the gradient was held at 100% eluent B for an additional 1.5 minutes (total time 4,0 minutes).
  • the HPLC rapidly equilibrated the column back to 100% eluent A for an additional 1.5 minutes for subsequent injections.
  • the total HPLC 7 MS ran time was 5.5 minutes.
  • Compounds were diluted to -1.0 mg/mL in DMSO.
  • the analysis injection volume was 5 ⁇ L.
  • the HPLC column used was a Thermo Electron Corporation. Aquasil Cl 8, 50 x 2, 1 mm, 5 ⁇ m particle size.
  • Step 2 3-[2'-Oxo-5' ⁇ pyrrolidin-l-yhulfonyl)spiro ⁇ t ⁇ clohexane-l,3'-ind ⁇ l/ ⁇ l '(2 ⁇ )-ylJpropanenitriIe
  • Step 2 3-[3-Cyclohexyl-2- ⁇ xo-5-(p ⁇ rolidin-l-ylsulfonyl ⁇ -2y3-dih ⁇ o-lU-indol-3- ⁇ ilpr#panenitrile
  • Example 12 A procedure similar to that of Example 12, using different G ⁇ gnard reagents, provided Examples 13-20. The compounds and their analytical data are shown in Table 1.
  • Example 21 ⁇ procedure similar to that of Example 21 provided Examples 22-30.
  • the compounds and their analytical data are shown in Table 2.
  • Example 44 A procedure similar to that of Example 43, using different alkyl halides, provided Examples 44- 59.
  • the compounds and their analytical data are shown in Table 4.
  • Step 2 5 '-A ⁇ nm ⁇ irolll,3]dioxane-2,3 '-indolinJ-2 '-one
  • Step I neopentyl 1 '-(cycl ⁇ propyI ⁇ nethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3 ⁇ dioxane-2,3 '-mdolej-5 'sulfonate
  • DMF dimethylfo ⁇ namide
  • Step 4 l '-(cyclopropylmethyl)-4'-[oxo(piperidin-l-yl)acetyl] ⁇ iroll,3-dioxane-2,3'-indoll-2'(l ⁇ )-one
  • Example 161 A procedure similar to that of Example 161 , using different alkyl halides, provided Examples 162 - 166.
  • the compounds and their analytical data are shown in Table 12.
  • Step 1 7-(piperidin-l-ylcarhonyl)-lH-ind ⁇ le-2,3-dione
  • Step 2 7'-(piperidin-l-ykarb ⁇ nyl)spiro[l,3-di ⁇ xane-2,3 '-ittdolJ-2 '(I 'H)-one
  • Example 167 A procedure similar to that of Example 167, using different alkyl hahdes, provided Examples 168 - 172, The compounds and their analytical data are shown in Table 13.
  • Step 2 r-(cycl()propylmeth ⁇ l)-4'-(piperidm-l- ⁇ lcarbonyl) ⁇ iro(l,3-dioxane-2,3'- ⁇ ndol]-2 '(l ⁇ )-one
  • Step l 6 '-iodospiro(l,3-dioxane-2,3 '-indoIJ-2 '(I 'H)- ⁇ ne
  • Step 3 6 '-(piperidin-l-ylcarbonyl)spir ⁇ [l,3-dioxane-2,3 '-indolJ-2 '(I ⁇ )-one
  • Step 3 / '-(cyclopropylmethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxolane-2,3 '-indole J -5 'suifonyl chloride
  • Step 4 l '-( ⁇ ciopropylmethyl)-5'-f(2,6-dimethylpiperidin-l-yI)sulfo» ⁇ ijsph" ⁇ fl,3-di ⁇ xolane-2,3'-ind»Ij-2'(r one
  • Example 185 A procedure similar to that of Example 185, using different amines, provided Examples 186- 196.
  • the compounds and their analytical data are shown in Table 16.
  • Examples 202-207 were prepared from 5 '-(piper dm-1-ylsullbnyl)spiro[1.3-dioxanc-2,3'-indolJ- 2'(l ⁇ )-one (prepared m procedure similar to Example 151) according to the procedure for Example 198,
  • Examples 210-215 were prepared from 5'- ⁇ pipe ⁇ dm-l ,3-dio ⁇ olane -2,3'- indol]-2 ( 1 II)-one and different alkjl hahdes according to the procedure for Example 198 The compounds and their analytical data are shown m Table 19 Table 19 Compounds Prepared According to the Procedure of Example 198
  • Step 3 4-chIoro-N-(l '-(cyclopropylmethyl)-2 ' ⁇ oxospiro[[l,3]dioxane-2,3 '-indolineJ-5 '-yljbenzenesulfonamide
  • Example 21 A procedure similar to that of Example 221, using different boronic acids, provided Examples 221 - 259 The compounds and their analytical data are shown m Table 21 Table 21 : Compounds Prepared According to the Procedure of Example 221.
  • Step 2 5'-(3-Fluoropyrrotidin-l-ytsutfonyi)spiro([l ⁇ 3]dioxane-2,3'-indolin]-2'-one
  • Step 2 S'-(3J-Diflu ⁇ ropyrrolidin-l-ykulfonyl)spiro([l,3]dioxane-2,3'-indotin]-2'-one
  • Step 3 5'-(3,3-Difluoropyrrolidin-l-ylsulf ⁇ nyI)-] '-pIienylspir ⁇ //l,3Jdi ⁇ xane-2,3'-lndolinJ-2'-o ⁇ e
  • Example 271 A procedure similar to that of Example 271 , using different borome acids, provided Examples 272 - 274. The compounds and their analytical data are shown in Table 23. Table 23: Compounds Prepared According to the Procedure of Example 271.
  • Example 275 A procedure similar to that of Example 275, using different boronic acids, prouded Examples 276 - S ⁇ The compounds and their analjtical data are shown m Table 24 Table 24: Compounds Prepared According Io the Procedure of Example 275.

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Abstract

L'invention porte sur des dérivés oxindoles substitués en position 3 qui sont des agonistes du récepteur CB2, sur des compositions pharmaceutiques les contenant et sur des procédés de traitement concernant des troubles à médiation par CB2 (par exemple la douleur, le cancer, etc.) à l'aide des dérivés oxindoles substitués en position 3 et des compositions décrites par les présentes.
PCT/US2009/067967 2008-12-15 2009-12-15 Agonistes de cb2 de type oxindole substitué pour le traitement de la douleur WO2010077839A1 (fr)

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WO2015049351A1 (fr) * 2013-10-04 2015-04-09 Bayer Cropscience Ag Utilisation de sulfonamides dihydro-oxindolyle substitués ou de sels de ces derniers pour améliorer la tolérance au stress chez les plantes
CN107235992A (zh) * 2017-07-06 2017-10-10 中国人民解放军第四军医大学 吲哚酮螺四氢噻吩类化合物及其盐、制备方法和应用
WO2018108627A1 (fr) 2016-12-12 2018-06-21 Bayer Cropscience Aktiengesellschaft Utilisation d'indolinylméthylsulfonamides substitués ou de leurs sels pour accroître la tolérance au stress chez les plantes
JP2018527293A (ja) * 2015-06-16 2018-09-20 オリオン コーポレーション ブロモドメイン阻害剤としてのスピロ［シクロブタン−１，３’−インドリン］−２’−オン誘導体
WO2022076496A1 (fr) * 2020-10-08 2022-04-14 Merck Sharp & Dohme Corp. Préparation de dérivés d'oxindole servant de nouveaux inhibiteurs de diacylglycéride o-acyltransférase 2

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US9278924B2 (en) 2011-10-25 2016-03-08 The Johns Hopkins University 5-nonyloxytryptamine and related intracellular PH acidifiers for the treatment and prevention of cancer
WO2013063216A1 (fr) * 2011-10-25 2013-05-02 The Johns Hopkins University 5-nonyloxytryptamine et autres agents d'acidification du ph intracellulaire pour le traitement et la prévention du cancer
AU2014331111B2 (en) * 2013-10-04 2018-05-31 Bayer Cropscience Aktiencesellschaft Use of substituted dihydro-oxindolyl sulfonamides, or the salts thereof, for increasing the stress tolerance of plants
CN105764341A (zh) * 2013-10-04 2016-07-13 拜耳作物科学股份公司 取代的二氢羟吲哚磺酰胺或其盐用于提高植物的胁迫耐受性的用途
JP2016533350A (ja) * 2013-10-04 2016-10-27 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 植物のストレス耐性を増大させるための置換されているジヒドロオキシインドリルスルホンアミド類又はその塩の使用
WO2015049351A1 (fr) * 2013-10-04 2015-04-09 Bayer Cropscience Ag Utilisation de sulfonamides dihydro-oxindolyle substitués ou de sels de ces derniers pour améliorer la tolérance au stress chez les plantes
US10065926B2 (en) 2013-10-04 2018-09-04 Bayer Cropscience Aktiengesellschaft Use of substituted dihydrooxindolylsulfonamides, or the salts thereof, for increasing the stress tolerance of plants
JP2018527293A (ja) * 2015-06-16 2018-09-20 オリオン コーポレーション ブロモドメイン阻害剤としてのスピロ［シクロブタン−１，３’−インドリン］−２’−オン誘導体
WO2018108627A1 (fr) 2016-12-12 2018-06-21 Bayer Cropscience Aktiengesellschaft Utilisation d'indolinylméthylsulfonamides substitués ou de leurs sels pour accroître la tolérance au stress chez les plantes
CN107235992A (zh) * 2017-07-06 2017-10-10 中国人民解放军第四军医大学 吲哚酮螺四氢噻吩类化合物及其盐、制备方法和应用
CN107235992B (zh) * 2017-07-06 2019-08-20 中国人民解放军第四军医大学 吲哚酮螺四氢噻吩类化合物及其盐、制备方法和应用
WO2022076496A1 (fr) * 2020-10-08 2022-04-14 Merck Sharp & Dohme Corp. Préparation de dérivés d'oxindole servant de nouveaux inhibiteurs de diacylglycéride o-acyltransférase 2
JP2023541714A (ja) * 2020-10-08 2023-10-03 メルク・シャープ・アンド・ドーム・エルエルシー 新規なジアシルグリセリドｏ－アシルトランスフェラーゼ２阻害剤としてのオキシインドール誘導体の製造
JP7482324B2 (ja) 2020-10-08 2024-05-13 メルク・シャープ・アンド・ドーム・エルエルシー 新規なジアシルグリセリドｏ－アシルトランスフェラーゼ２阻害剤としてのオキシインドール誘導体の製造

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