US20150259277A1 - Ketamine Derivatives - Google Patents

Ketamine Derivatives Download PDF

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US20150259277A1
US20150259277A1 US14/433,957 US201314433957A US2015259277A1 US 20150259277 A1 US20150259277 A1 US 20150259277A1 US 201314433957 A US201314433957 A US 201314433957A US 2015259277 A1 US2015259277 A1 US 2015259277A1
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compound
chlorophenyl
oxocyclohexyl
amino
alkyl
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James Wallace Sleigh
William Alexander Denny
Jiney Jose
Swarnalatha Akuratiya Gamage
Martyn Gregory Harvey
Logan James Voss
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Auckland Uniservices Ltd
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Assigned to AUCKLAND UNISERVICES LIMITED reassignment AUCKLAND UNISERVICES LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SLEIGH, James Wallace, JOSE, Jiney, VOSS, Logan James, DENNY, WILLIAM ALEXANDER, GAMAGE, SWARNALATHA AKURATIYA, HARVEY, Martyn Gregory
Publication of US20150259277A1 publication Critical patent/US20150259277A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton

Definitions

  • the present invention relates to ketamine derivatives, pharmaceutical compositions comprising them, and their use as anaesthetics, analgesics, or sedatives.
  • (2-o-Chlorophenyl)-2-methylamino-cyclohexanone is an effective non-opioid anaestheticanalgesic drug [Laskowski et al., Can J Anesth 2011, 58, 911: Carstensen & Willer, Br J Anaesth. 2010, 104, 401], with the major advantages over opioids in that it shows no respiratory depression or hyperalgesic effects, and is also free of longer-term effects such as increased tolerance and immune suppression.
  • Ketamine is normally used as the racemate, but more recently the more active (S)-enantiomer has begun to be employed.
  • (S)-Ketamine has similar pharmacological, analgesic and anaesthetic properties to the racemate, but is about twice as potent [Adams & Werner, Anaesthetist 1997, 46, 1026].
  • ketamine has hallucinogenic properties which, together with its relatively long half-life (2-3 h) means that it is normally administered together with sedative or hypnotic drugs like midazolam and/or propofol to control the prolonged period of post-anesthesia hallucinations [Domino, Anesthesiology 2010, 113, 678, Chiaretti et al., Pediatric Blood & Cancer 2011, 57, 1163]. While (S)-ketamine has somewhat faster elimination [Adams & Werner, Anaesthetist 1997, 46, 1026], there is still a need for analogues with much shorter half-lives to avoid the concomitant use of sedativeshypnotics.
  • the present invention provides a compound of formula (I):
  • Y 1 is —C 2-6 aliphaticC(O)OR 1 , C 2-6 aliphaticOC(O)R 1 , C 1-6 aliphaticC(O)OC 1-6 aliphaticC(O)OR 1 , or C 1-6 aliphaticC(O)OC 1-6 aliphaticOR 3 , wherein each aliphatic is optionally substituted with one or more R 2 ;
  • R 1 is C 1-6 aliphatic, optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , and C 1-6 aliphatic;
  • R 2 is C 1-6 aliphatic, optionally substituted with one or more halo, OR 11 , or CN;
  • R 3 is hydrogen or R 1 ;
  • R 11 and R 12 are each independently C 1-6 aliphatic; or R 11 and R 12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring;
  • Y 2 is hydrogen or R 2 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , C 1-6 aliphaticY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1 at any of the available 2-5 positions;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.
  • the present invention provides a method for treating pain in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) to the subject.
  • the invention provides use of a compound of formula (I) in the manufacture of a medicament for treating pain.
  • the invention provides a compound of formula (I) for treating pain.
  • the method, medicament, or compound for treating pain is for providing analgesia.
  • the present invention provides a method for anaesthetizing a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (II) to the subject:
  • Y 11 is —C 1-6 aliphaticC(O)OR 1 , —C 1-6 alpihaticOC(O)R 1 , —C 1-6 aliphaticC(O)OC 1-6 aliphaticC(O)OR 1 , or —C 1-6 alipliaticC(O)OC 1-6 aliphaticOR 3 , wherein each aliphatic is optionally substituted with one or more R 2 : and
  • R 1 , R 3 , Y 2 , X 1 , and X are as defined in the compound of formula (I);
  • the method is for anaesthetizing a subject for a surgical procedure.
  • the method is for inducing general anaesthesia. In other embodiments, the method is for inducing and maintaining general anaesthesia.
  • the present invention provides use of a compound of formula (II) in the manufacture of a medicament for providing anaesthesia.
  • the medicament is for providing anaesthesia for a surgical procedure.
  • the medicament is for inducing general anaesthesia. In other embodiments, the medicament is for inducing and maintaining general anaesthesia.
  • the present invention provides a compound of formula (II) for providing anaesthesia
  • the compound is for providing anaesthesia for a surgical procedure.
  • the compound is for inducing general anaesthesia. In other embodiments, the compound is for inducing and maintaining general anaesthesia.
  • the present invention provides a method for sedating a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of the formula (II) to the subject.
  • the method is for sedating a subject for a medical procedure. In some embodiments, method is for providing conscious sedation.
  • the method is for inducing conscious sedation. In other embodiments, the method is for inducing and maintaining conscious sedation.
  • the present invention provides use of a compound of formula (II) in the manufacture of a medicament for providing sedation.
  • the medicament is for providing sedation for a medical procedure. In some embodiments, the medicament is for providing conscious sedation.
  • the medicament is for inducing conscious sedation. In other embodiments, the medicament is for inducing and maintaining conscious sedation.
  • the present invention provides a compound of formula (II) for providing sedation.
  • the compound is for providing sedation is for a medical procedure. In some embodiments, the compound is for providing conscious sedation.
  • the compound is for inducing conscious sedation. In other embodiments, the compound is for inducing and maintaining conscious sedation.
  • Y 1 is —C 2-6 alkylC(O)OR 1 , —C 2-6 alkylOC(O)R 1 , —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , or —C 1-6 alkylC(O)OC 1-6 alkylOR 3 , wherein each alkyl is optionally substituted.
  • Y 1 is —C 2-6 alkylC(O)OR 1 or —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , wherein each alkyl is optionally substituted.
  • Y 1 is —C 1-6 alkylC(O)OR wherein the alkyl is optionally substituted.
  • Y 1 is —C 2-6 alkylC(O)OR 1 .
  • Y 11 is —C 1-6 alkylC(O)OR 1 , C 1-6 alkylOC(O)R 1 , —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , or —C 1-6 alkylC(O)OC 1-6 alkylOR 3 , wherein each alkyl is optionally substituted.
  • Y 11 is —C 1-6 alkylC(O)OR or C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , wherein each alkyl is optionally substituted.
  • Y 11 is —C 1-6 alkylC(O)OR 1 , wherein the alkyl is optionally substituted. In one specifically contemplated embodiment, Y 11 is —C 1-6 alkylC(O)OR 1 .
  • each alkyl in Y 1 or Y 11 is optionally substituted with from one to three R 2 . In certain embodiments, each alkyl in Y 1 or Y 11 is optionally substituted with one or two R 2 .
  • R 1 is C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl, or cycloalkenyl, wherein each alkyl, alkenyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more halo.
  • each alkyl and alkenyl is optionally substituted with one or more cycloalkyl or cycloalkenyl; and each cycloalkyl and cycloalkenyl is optionally substituted with one or more C 1-6 alkyl or C 2-6 alkenyl.
  • R 1 is C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl, or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 and C(O)R 11 ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each cycloalkyl is optionally substituted with C 1-6 alkyl or C 2-6 alkenyl.
  • R 1 is C 2-6 alkenyl or cycloalkenyl, wherein each alkenyl and cycloalkenvl are optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , and C(O)R 11 ; and each alkyl is optionally substituted with cycloalkyl or cycloalkenyl; and each cycloalkyl is optionally substituted with C 1-6 alkyl or C 2-6 alkenyl.
  • R 1 is C 1-6 alkyl or cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted. In one exemplary embodiment R 1 is C 1-6 alkyl, wherein each alkyl is optionally substituted. In one specifically contemplated embodiment R 1 is C 1-6 alkyl.
  • each alkyl or cycloalkyl in R 1 is optionally substituted with from one to three optional substituents. In certain embodiments, each alkyl or cycloalkyl in R 1 is optionally substituted with one or two optional substituents.
  • R 2 is C 1-6 alkyl or cycloalkyl, optionally substituted with one or more halo, OR 11 , or CN. In other embodiments, R 2 is C 1-6 alkyl, optionally substituted with one or more halo, OR 11 , or CN. In certain exemplary embodiments, R 2 is C 1-6 alkyl.
  • R 11 and R 12 are each independently C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl, or cycloalkenyl; or R 11 and R 12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring. In other embodiments, R 11 and R 12 are each independently C 1-6 alkyl or cycloalkyl; or R 11 and R 12 together with the nitrogen atom to which they are attached are a heteroaryl or heterocyclyl ring. In certain embodiments, R 11 and R 12 are C 1-6 alkyl.
  • Y 2 is hydrogen or C 1-6 alkyl, wherein the alkyl is optionally substituted. In one exemplary embodiment, Y 2 is hydrogen or C 1-6 alkyl. In one specifically contemplated embodiment, Y 2 is hydrogen. In another specifically contemplated embodiment, Y 2 is hydrogen or methyl.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , C(O)R 11 , C 1-6 alkylY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , or C(O)R 11 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , or C(O)R 11 ; or X 2 is C 1-6 alkylY 1 , OY 1 , C(O)Y 1 , SO 2 Y 1 , or C(O)NHY 1 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , or C(O)R 11 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , OR 11 , or C(O)R 11 ; or X 2 is C 1-6 alkylY 1 , OY 1 , C(O)Y 1 , or SO 2 Y 1 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , OR 11 , or C(O)R 11 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions.
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions.
  • X 1 is halo; and X 2 is independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions.
  • X 1 is 2-halo. In another embodiment, X 1 is 2-chloro.
  • X 1 is 2-chloro; and X 2 is hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of positions 3-5.
  • the C 1-6 haloalkyl is CF 3 , CHF 2 , or CH 2 F. In certain embodiments, the C 1-6 haloalkyl is CF 3 . In some embodiments, the C 1-6 haloalkoxy is OCF 3 , OCHF 2 , or OCH 2 F. In certain embodiments, the C 1-6 haloalkoxy is CF 3 .
  • the halo is F, Cl, or Br. In certain embodiments, the halo is F or Cl.
  • Y 1 is —C 2-6 alkylC(O)OR 1 , —C 2-6 alkylOC(O)R 1 , —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , or —C 1-6 alkylC(O)OC 1-6 alkylOR 1 , wherein each alkyl is optionally substituted with one or more R 2 ;
  • R 1 is C 1-6 alkyl, C 2-6 alkenyl, cycloalkyl, or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , and C(O)R
  • Y 11 is —C 3-6 alkylC(O)OR 1 , —C 1-6 alkylOC(O)R 1 , —C 1-6 alkylC(O)OC 1-6 alkylC(O)OR 1 , or —C 1-6 alkylC(O)OC 1-6 alkylOR 3 , wherein each alkyl is optionally substituted with one or more R 2 ; R 1 is cycloalkyl or cycloalkenyl, wherein each alkyl and cycloalkyl are optionally substituted with one or more halo, CN, NO 2 , NH 2 , NHR 11 , NR 11 R 12 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 11 , C(O)NR 11 R 12 , SO 2 R 11 , OR 11 , and C(O)R 11 ; and each alkyl is optionally substituted with cycl
  • Y 1 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 , —(CR A R B ) m (CR C R D ) n OC(O)R 1 , —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o C(O)OR 1 , or —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o OR 3 ; m is an integer from 2 to 6; o is an integer from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p is 6 or less; and R A , R B , R C , R D , R E , R F , R G , and R H at each
  • Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 , —(CR A R B ) m (CR C R D ) n OC(O)R 1 , —(CR A R B ) m (CR C R D ) n C(O)O(CR G R H ) p (CR E R F )C(O)OR 1 , or —(CR A R B ) m (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o OR 3 ; m and o are each independently an integer from 1 to 6; n and p are each independently 0 or 1; the sum of m and n and the sum of o and p is 6 or less; and R A , R B , R C , R D , R E , R F , R G , and R 14 at each instance of m, n,
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 or —(CR A R B ) m (CR C R D ) n C(O)O(CR G R H ) p (CR E R F ) o C(O)OR 1 .
  • Y 1 or Y 11 is —(CR A R B ) m (CR A R D ) n C(O)OR 1 .
  • R A , R B , R E , and R F at each instance of m and o are each independently hydrogen; and R C , R D , R G , and R H at each instance of n and p are each independently hydrogen or R 2 .
  • Y 1 is —(CH 2 ) m (CR C R D ) n C(O)OR 1 , —(CH 2 ) m (CR C R D ) n OC(O)R 1 , (CH 2 ) m-1 C(O)O(CR G R H ) p (CH 2 ) o C(O)OR 1 , or —(CH 2 ) m-1 C(O)O(CH 2 ) o OR 3 .
  • Y 11 is —(CH 2 ) m (CR C R D ) n C(O)OR 1 , —(CH 2 ) m CR C R D ) n OC(O)R 1 , —(CH 2 ) m C(O)O(CR G R H ) p (CH 2 ) o C(O)OR 1 , or —(CH 2 ) n C(O)O(CH 2 ) o OR 3 .
  • Y 1 is —(CH 2 ) m (CR C R D ) n C(O)OR 1 or —(CH 2 ) m-1 C(O)O(CR G R H ) p (CH 2 ) o C(O)OR 1 .
  • Y 11 is (CH 2 ) m (CR C R D ) n C(O)OR 1 or —(CH 2 ) m C(O)O(CR G R H ) p (CH 2 ) o C(O)OR 1 .
  • Y 1 is —(CH 2 ) m C(O)OR 1 or —(CH 2 ) m-1 C(O)O(CH 2 ) o C(O)OR 1 .
  • Y 11 is —(CH 2 ) m C(O)OR 1 or —(CH 2 ) m C(O)O(CH 2 ) o C(O)OR 1 .
  • Y 1 or Y 11 is —(CH 2 ) m C(O)OR 1 .
  • Y 1 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 , —(CR A R B ) m (CR C R D ) n OC(O)R 1 , —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R H ) p (CR E R F )C(O)OR 1 , or —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R B ) p (CR E R F ) o OR 3 .
  • Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 , —(CR A R B ) m (CR C R D ) n OC(O)R 1 , —(CR A R B ) m (CR C R D ) n C(O)OH, —(CR A R B ) m (CR C R D ) n C(O)O(CR G R H ) p (CR E R F )C(O)OR 1 , or —(CR A R B ) m (CR C R D ) n C(O)O(CR G R B ) p (CR E R F ) o OR 3 .
  • Y 1 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 or —(CR A R B ) m-1 (CR C R D ) n C(O)O(CR G R B ) p (CR E R F )C(O)OR 1 ; and X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , OR 11 , or C(O)R 11 at any of the available 2-5 positions.
  • Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 or —(CR A R B ) m (CR C R D ) n C(O)O(CR G R H ) p (CR E R F )C(O)OR 1 ; and X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , OR 11 , or C(O)R 11 at any of the available 2-5 positions.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ; and X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions; and
  • Y 2 is hydrogen or C 1-6 alkyl.
  • Y 1 or Y 11 is (CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions; and
  • Y 2 is hydrogen or methyl.
  • Y 1 or Y 11 is (CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions; and
  • Y 2 is hydrogen.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions;
  • R A and R B at each instance of m are hydrogen;
  • Y 2 is hydrogen or C 1-6 alkyl.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions;
  • R A and R B at each instance of m are hydrogen;
  • Y 2 is hydrogen or methyl.
  • Y 1 or Y 11 is (CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 and X 2 are each independently hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 2-5 positions;
  • R A and R B at each instance of m are hydrogen; and
  • Y 2 is hydrogen.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 is 2-chloro;
  • X 2 is hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 3-5 positions;
  • R A and R B at each instance of m are hydrogen;
  • Y 2 is hydrogen or C 1-6 alkyl.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 is 2-chloro;
  • X 2 is hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 3-5 positions;
  • R A and R B at each instance of m are hydrogen; and
  • Y 2 is hydrogen or methyl.
  • Y 1 or Y 11 is —(CR A R B ) m (CR C R D ) n C(O)OR 1 ;
  • X 1 is 2-chloro;
  • X 2 is hydrogen, R 2 , halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, SO 2 R 11 , or OR 11 at any of the available 3-5 positions;
  • R A and R B at each instance of m are hydrogen; and
  • Y 2 is hydrogen.
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the stereochemical configuration at position 2 of the cyclohexyl ring in the compound is (S).
  • the compound comprises 95% or more of a single stereoisomer. In certain embodiments, the compound is stereoisomerically pure.
  • the compound is a pharmaceutically acceptable salt.
  • the salt is a hydrochloride salt.
  • the compound of formula (II) is a compound of formula (I) as defined in the first aspect or in any of the embodiments described above.
  • Asymmetric centers may exist in the compounds of formula (I) and (II).
  • the asymmetric centers may be designated as (R) or (S), depending on the configuration of substituents in three dimensional space at the chiral carbon atom. All stereochemical isomeric forms of the compounds, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof, including enantiomerically enriched and diastereomerically enriched mixtures of stereochemical isomers, are included herein.
  • Individual enantiomers can be prepared synthetically from commercially available enantiopure starting materials or by preparing enantiomeric mixtures and resolving the mixture into individual enantiomers.
  • Resolution methods include conversion of the enantiomeric mixture into a mixture of diastereomers and separation of the diastereomers by, for example, recrystallization or chromatography, and any other appropriate methods known in the art.
  • Starting materials of defined stereochemistry may be commercially available or made and, if necessary, resolved by techniques well known in the art.
  • the compounds of formula (I) and (II) may also exist as conformational or geometric isomers, inlcuding cis, trans, syn, anti,
  • Z) isomers All such isomers and any mixtures thereof are included herein.
  • tautomeric isomers or mixtures thereof of the compounds are also included.
  • tautomeric isomers or mixtures thereof of the compounds include, but are not limited to, ketoenol, imineenamine, and thioketoneenethiol.
  • the compounds of formula (I) and (II) may also exist as isotopologues and isotopomers, wherein one or more atoms in the compounds are replaced with different isotopes.
  • Suitable isotopes include, for example, 1 H, 2 H (D), 3 H (T), 12 C, 13 C, 14 C, 16 O, and 18 O. Procedures for incorporating such isotopes into the compounds described herein will be apparent to those skilled in the art. Isotopologues and isotopomers of the compounds are thus included herein.
  • salts and solvates including hydrates of the compounds.
  • Such salts include, acid addition salts, base addition salts, and quaternary salts of basic nitrogen-containing groups.
  • Acid addition salts can be prepared by reacting compounds, in free base form, with inorganic or organic acids. Examples of inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • organic acids include, but are not limited to, lauric, acetic, trifluoroacetic, formic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, stearic, salicylic, mandelic, methanesulfonic, benzenesulfonic, isoethonic, sulfanilic, adipic, butyric, oxalic, and pivalic.
  • Base addition salt can be prepared by reacting compounds, in free acid form, with inorganic or organic bases.
  • inorganic base addition salts include alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal salts, for example, aluminium, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • organic base addition salts include amine salts, for example, salts of trimethylamine, diethylamine, ethanolamine, diethanolamine, and ethylenediamine.
  • Quaternary salts of basic nitrogen-containing groups in the compounds may be may be prepared by, for example, reacting the compounds with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, and the like.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, and the like.
  • aliphatic is intended to include saturated and unsaturated, nonaromatic, straight chain, branched, acyclic, and cyclic hydrocarbons. Those skilled in the art will appreciate that aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups.
  • alkyl is intended to include straight chain and branched chain alkyl groups. In some embodiments, alkyl groups have from 1 to 12, from 1 to 10, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.
  • alkenyl is intended to include straight and branched chain alkyl groups having at least one double bond between two carbon atoms. In some embodiments, alkenyl groups have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms. In some embodiments, alkenyl groups have one, two, or three carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, —CH ⁇ CH(CH 3 ), —CH ⁇ C(CH 3 ) 2 , —C(CH 3 ) ⁇ CH 2 , and —C(CH 3 ) ⁇ CH(CH 3 ).
  • alkynyl is intended to include straight and branched chain alkyl groups having at least one triple bond between two carbon atoms.
  • the alkynyl group have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms.
  • alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, —C ⁇ CH, —C ⁇ CH 3 , —CH 2 C ⁇ CH 3 , and —C ⁇ CH 2 CH(CH 2 CH 3 ) 2 .
  • cycloalkyl is intended to include mono-, bi- or tricyclic alkyl groups.
  • cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s).
  • cycloalkyl groups have 5 or 6 ring carbon atoms.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms.
  • Bi- and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.
  • cycloalkenyl is intended to include non-aromatic cycloalkyl groups having at least one double bond between two carbon atoms. In some embodiments, cycloalkenyl groups have one, two or three double bonds. In some embodiments, cycloalkenyl groups have from 4 to 14, from 5 to 14, from 5 to 10, from 5 to 8, or from 5 to 6 carbon atoms in the ring(s). In some embodiments, cycloalkenyl groups have 5, 6, 7, or 8 ring carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.
  • aryl is intended to include cyclic aromatic hydrocarbon groups that do not contain any ring heteroatoms.
  • Aryl groups include monocyclic, bicyclic and tricyclic ring systems. Examples of aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl. In some embodiments, aryl groups have from 6-14, from 6 to 12, or from 6-10 carbon atoms in the ring(s). In some embodiments, the aryl groups are phenyl or naphthyl.
  • Aryl groups include aromatic-aliphatic fused ring systems. Examples include, but are not limited to, indanyl and tetrahydronaphthyl.
  • heterocyclyl is intended to include non-aromatic ring systems containing 3 or more ring atoms, of which one or more is a heteroatom.
  • the heteroatom is nitrogen, oxygen, or sulfur.
  • the heterocyclyl group contains one, two, three, or four heteroatoms.
  • heterocyclyl groups include mono-, bi- and tricyclic rings having from 3 to 16, from 3 to 14, from 3 to 12, from 3 to 10, from 3 to 8, or from 3 to 6 ring atoms.
  • Heterocyclyl groups include partially unsaturated and saturated ring systems, for example, imidazolinyl and imidazolidinyl.
  • Heterocyclyl groups include fused and bridged ring systems containing a heteroatom, for example, quinuclidyl.
  • Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolidinyl, and trithianyl.
  • heteroaryl is intended to include aromatic ring systems containing 5 or more ring atoms, of which, one or more is a heteroatom.
  • the heteroatom is nitrogen, oxygen, or sulfur.
  • heteroaryl groups include mono-, bi- and tricyclic ring systems having from 5 to 16, from 5 to 14, from 5 to 12, from 5 to 10, from 5 to 8, or from 5 to 6 ring atoms.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridinylxanthinyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxaliny
  • halo or halogen is intended to include F, Cl, Br, and I.
  • substituted is intended to mean that one or more hydrogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituents are attached is not exceeded, and that the substitution results in a stable compound.
  • FIG. 1A and FIG. 1B are graphs showing time-course for anaesthesia (loss and recovery of righting reflex) with ketamine and rac-C2nPr ( FIG. 1A ) and rac-C4Me ( FIG. 1B ).
  • the grey panel shows the duration of drug infusion (measurement taken every minute). ••••: test compound. ⁇ : ketamine.
  • FIG. 2A and FIG. 2B are graphs showing time-course for analgesia (pedal withdrawal reflex score) with ketamine and rac-C2nPr ( FIG. 2A ) and rac-C4Me ( FIG. 2B ).
  • the grey panel shows the duration of drug infusion (measurement taken every minute). Error bars are SEM. •• 500 •: test compound. ⁇ : ketamine.
  • FIG. 3 is a plot (log 10) of effective potency (dose [mg/kg] to LRR) vs. duration (time to RRR) for ketamine and compounds of the invention.
  • the present invention generally relates to ketamine derivatives and their use as anaesthetics, analgesics, or sedatives.
  • ketamine derivatives of the formula (I) as defined above which can provide anaesthetic and/or analgesic effects similar to ketamine, but at least in some embodiments have the advantage of shortening the period of recovery after administration of the derivative has ceased.
  • the method comprises reacting a compound of the formula (III):
  • Y 2 , X 1 , and X 2 are as defined above with an alkylating agent of the formula Y 1 —Z or Y 11 —Z, wherein Z is a suitable leaving group and Y 1 and Y 11 are as defined above, to provide the compound of the formula (I) or (II), respectively.
  • Z is halo
  • the reaction is carried out in the presence of a base. In certain embodiments, the reaction is carried out in the presence of an inorganic base, for example, a carbonate base.
  • the reaction is carried out in the presence of a suitable solvent, for example, an aprotic solvent.
  • the reaction may be carried out at any suitable temperature. In some embodiments, the reaction is carried out in the presence of a suitable solvent at reflux. In other embodiments, the reaction is carried out at ambient temperature.
  • the compound of formula (III) is prepared by a method comprising heating a compound of the formula (IV)
  • X 1 and X 2 are as defined above in a suitable liquid reaction medium to provide a compound of the formula (III), wherein Y 2 is hydrogen.
  • the method comprises heating the compound of the formula (IV) in a suitable solvent.
  • the compound is heated at a temperature of 75, 100, 125, 150, 175, or 200° C. or more.
  • the compound of formula (IV) is prepared by a method comprising reacting a compound of the formula (V)
  • X 1 and X 2 are as defined above and Z 1 is halo with NH 3 NH 4 OH.
  • the compound of formula (V) is prepared by a method comprising reacting a compound of the formula (VI)
  • X 1 and X 2 are as defined above with a halogenating agent.
  • the halogenating agent is copper (II) bromide.
  • the reaction is carried out in a suitable solvent.
  • (2-chlorophenyl)(cyclopentyl)methanone (31) is brominated by refluxing with CuBr 2 in EtOAc.
  • the brominated intermediate (22) is converted to the corresponding imino cyclopentanol (23) by stirring in NH 4 OH solution saturated with NH 3 gas.
  • the (S)-enantiomer of norketamine (S-24) is obtained by resolution with L-(R,R)-(+)-tartaric acid.
  • the (R)-enantiomer of norketamine (R-24) may be obtained in an analogous fashion from D-(S,S)-( ⁇ )-tartaric acid.
  • the compounds may be converted to hydrochloride salts using HCl gas.
  • Alkyl halides corresponding to Y 1 are commercially available or may be prepared by methods known in the art or analogous thereto.
  • Y 2 is R 2
  • Such compounds may also be prepared by reductive amination with an aldehyde (e.g. formaldehyde when R 2 is methyl) or ketone corresponding to R 2 .
  • Preparation of the compounds may involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by a person skilled in the art.
  • Protecting groups and methods for protection and deprotection are well known in the art [see e.g. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999)].
  • the compounds of formula (I) and (II) have analgesic, anaesthetic, and/or sedative activity and are therefore useful for treating pain and/or anaesthetizing and/or sedating subjects.
  • treatment in the context of treating pain, relates generally to treatment, of a human or a non-human subject, in which some desired therapeutic effect is achieved.
  • the therapeutic effect may, for example, be inhibition, reduction, amelioration, halt, or prevention of the pain.
  • Analgesia is the alleviation or elimination of the sensation of pain.
  • Pain encompasses a wide range of clinical manifestations, and it has a broad meaning. Pain perception is highly subjective, and different people experience pain in different ways and with greatly different intensities. The International Association for the Study of Pain defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Non-limiting types and causes of pain include neuralgia, myalgia, hyperalgesia, hyperpathia, neuritis, and neuropathy. Pain may also be caused by physical trauma, such as burns or surgery. In one embodiment, the pain is pain resistant to treatment with opioids.
  • anaesthetize and related terms such as “anaesthetizing” as used herein means to induce a loss of sensation and usually of consciousness without loss of vital functions artificially produced by the administration of one or more agents that block responses of the body to painful stimuli, for example the absence of a response to a surgical incision.
  • sedate and related terms such as “sedating” as used herein means to induce a state of depressed consciousness in which a patient or subject retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands. Sedation may be evaluated using, for example, the Ramsay Sedation Scale.
  • the methods of the present invention comprise administering compounds of formula (I) or (II) to a subject.
  • the subject may be a human or non-human animal.
  • Non-human animals include, for example, production animals, such as, cattle, sheep, swine, deer, and goats; companion animals, such as, dogs, cats, and horses; zoo animals, such as, zebras, elephants, giraffes, and large cats; research animals, such as, mice, rats, rabbits, and guinea pigs; fur-bearing animals, such as, mink; birds, such as, ostriches, emus, hens, geese, turkeys, and ducks; fresh- and salt-water fish, such as, trout, salmon, carp, and eels; and reptiles, such as lizards and snakes.
  • the subject is a human.
  • the methods comprise administering a therapeutically effective amount of the compound to the subject.
  • a “therapeutically effective amount” of a compound is an amount effective to demonstrate a desired therapeutic effect either alone or in combination with other agents.
  • the therapeutically effective amount of the compound to be administered to a subject depends on, for example, the purpose for which the compound is administered, mode of administration, nature and dosage of any co-administered compounds, and characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. A person skilled in the art will be able to determine appropriate dosages having regard to these any other relevant factors.
  • the dose of administered is from about 0.01 mg per kg of body weight (0.01 mg/kg) to about 100 mg/kg.
  • the compounds may be administered by any suitable route.
  • the route may depend on the therapeutic purpose for which the compound is administered.
  • the compound is administered intravenously.
  • the compound is administered by intravenous bolus. In another specifically contemplated embodiment, the compound is administered intravenously by continuous infusion.
  • the compound is administered as an intravenous bolus and by intravenous infusion. In one embodiment, the compound is administered as an intravenous bolus and by continuous intravenous infusion.
  • the compound is administered as an intravenous bolus at a dose from about 0.01 mg per kg of body weight (0.01 mg/kg) to about 100 mg/kg.
  • the compound is administered by continuous intravenous infusion at a dose from about 0.1 mg/kg/min to about 10 mg/kg/min.
  • the compound is administered for anesthesia as an intravenous bolus at a dose from about 0.01 mg per kg of body weight (0.01 mg/kg) to about 100 mg/kg and as a continuous intravenous infusion at a dose from about 0.1 mg/kg/min to about 10 mg/kg/min Smaller doses would be used for sedation and analgesia.
  • the compounds of formula (I) and (II) are generally prepared in a formulation or pharmaceutical composition appropriate for administration by a particular route.
  • administration route include transdermal, transmucosal (e.g. nasal, transbuccal, sublingual, vaginal, and rectal), oral, pulmonary (i.e. inhalation), and parenteral (e.g. intravenous, intraarterial, intraperitoneal, intradermal, intramuscular, intraventricular, or subcutaneous).
  • the formulations generally comprise a pharmaceutically acceptable diluent, excipient, or carrier. Any suitable diluent, excipient, or carrier can be used provided that it is non-toxic and compatible with the other ingredients of the composition.
  • the diluent, excipient, or carrier used depends on the intended route of administration.
  • the formulation or pharmaceutical composition may be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping, or compression. Numerous diluents, excipients, and carriers and methods for preparing pharmaceutical compositions are known in the art [see e.g. Remington's Pharmaceutical Sciences, Mack Publishing Co., (2000)].
  • Suitable formulations for administering the compounds include, for example, tablets, capsules, suppositories, solutions, and powders etc.
  • the content of the pharmaceutically active compound(s) is typically in the range from 0.05 to 90 wt.-% of the composition as a whole. In one embodiment, the content is from 0.1 to 50 wt.-% of the composition as a whole.
  • compositions include for example tablets, capsules, suppositories, solutions and powders etc.
  • Tablets may comprise a solid carrier or diluent.
  • Liquid pharmaceutical compositions may comprise a liquid carrier, for example, water, petroleum, animal or vegetable oils, mineral oil or synthetic oil.
  • Liquid compositions may also comprise physiological saline solution, dextrose or other carbohydrate solution, glycols e.g. ethylene glycol, propylene glycol or polyethylene glycol, etc.
  • Capsules may comprise a solid carrier e.g. gelatin. Such formulations will be well known to a person skilled in the art.
  • the pharmaceutical composition may be formulated for intravenous, cutaneous or subcutaneous injection.
  • the active ingredient is generally in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability.
  • the solutions may comprise isotonic vehicles e.g. sodium chloride injection, Ringer's injection, etc.
  • Preservatives, stabilisers, buffers antioxidants and/or other suitable additives may be included as required.
  • composition of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.
  • the composition may be formulated as described above.
  • the formulations may comprise or be used or administered in combination, for example sequentially or simultaneously, with one or more additional therapeutic agents, for example alpha-2 adrenergic drugs such as clonidine or dexmedetomidine.
  • additional therapeutic agents for example alpha-2 adrenergic drugs such as clonidine or dexmedetomidine.
  • the composition further comprises a buffer, stabiliser, or adjuvant.
  • the uses of the present invention involve the manufacture of medicaments.
  • the medicaments are also formulated as described above.
  • Ketamine has a measured (Volgyi, G. et al. Anal. Chim. Acta 2007, 583, 418-428) aqueous pKa of 7.49 and a calculated clogP of 2.22.
  • the closest match to this were the acetates (rac-C3OAc and (S)—C3OAc).
  • Next closest in physicochemical properties were the C4 methyl esters (rac-C4Me and (S)—C4Me).
  • the esters overall showed a range of both pKa values (from 4.35 to 6.29) and lipophilicities (from 2.77 to 3.92).
  • the mobile phase was 85% hexanes/15% EtOH with a flow rate of 0.6 mL/min.
  • the purity was determined by monitoring at 254 and 280 nm and was ⁇ 95% unless otherwise stated.
  • the final product purity was also assessed by combustion analysis carried out in the Campbell Micro analytical Laboratory, University of Otago (Dunedin, New Zealand). Melting points were determined on an Electrothermal 2300 Melting Point Apparatus and are uncorrected.
  • DCM refers to dichloromethane
  • DMF refers to N,N-dimethylformamide
  • EtOAc refers to ethyl acetate
  • EtOH refers to ethanol.
  • Ammonium hydroxide 200 mL was cooled to 0° C. in an ice bath and was saturated with NH 3 gas for 5 min.
  • the solution was added to a flask containing 22 (12.74 g, 44.5 mmol) and stirred vigorously at 25° C. for 5 days.
  • the brown clumps formed were separated from the solvent and resuspended in hexanes (150 mL).
  • the precipitate formed was filtered and dried to obtain 23 (8.15 g, 81%) as a pale yellow solid. This was suspended in 8 mL of 2-propanol and cooled to 0° C. in an ice bath. HCl gas was bubbled through the solution for 2 min.
  • the solvent was evaporated under reduced pressure to obtain the desired product as yellow oil (173 mg, 59%).
  • the yellow oil was dissolved in diethyl ether (5 mL) and was cooled to 0° C. in an ice bath. Dry HCl gas was bubbled through the solution at 0° C. for 2 min. The solvent was evaporated under reduced pressure to obtain a yellow solid.
  • the yellow solid was dissolved in EtOAc (1 mL) and sonicated at 25° C. for 2 min.
  • the white precipitate formed was diluted with EtOAc (5 mL) and filtered, washed with EtOAc and dried under vacuum to give rac-C3OAc.HCl (107 mg, 33%), mp 180-183° C.
  • the (S)-norketamine tartrate salt was dissolved in water (200 mL) and neutralized with 2 N NaOH. The aqueous layer was extracted with DCM (3 ⁇ 100 mL). The combined DCM layer was washed with brine (100 mL) and dried over Na 2 SO 4 . Evaporation of solvent under reduced pressure afforded (S)-norketamine free base [(S)-24] (4.96 g) as a pale yellow viscous oil.
  • the solvent was evaporated under reduced pressure to obtain the desired product as yellow oil. This was dissolved in diethyl ether (5 mL) and was cooled to 0° C. in an ice bath. Dry HCl gas was bubbled through the solution at 0° C. for 2 min. The solvent was evaporated under reduced pressure to obtain a yellow solid. The yellow solid was dissolved in EtOAc (2 mL) and sonicated at 25° C. for 2 min. The white precipitate formed was diluted with EtOAc (10 mL) and filtered, washed with EtOAc and dried under vacuum to obtain the product as hydrochloride salt.
  • (R)-24 was prepared by a procedure analogous to that described above for the preparation of (S)-24 using D-(S,S)-( ⁇ )-tartaric acid, rather than L-(R,R)-(+)-tartaric acid.
  • Norketamine ester (0.9 mmol) was dissolved in MeOH (20 mL) and cooled to 0° C. in an ice bath. Acetic acid (0.2 mL, 3.6 mmol) and NaCNBH 3 (112 mg, 1.8 mmol) was added to the above solution and stirred at 0° C. for 5 min. Formaldehyde (37% in H 2 O, 2.2 mmol) was added at 0° C. and reaction mixture allowed to stir at 25° C. for 24 h. The reaction mixture was quenched with NaHCO 3 and diluted with water. The aqueous layer was extracted with CH 2 Cl 2 (3 ⁇ 20 mL), washed with brine and dried over Na 2 SO 4 .
  • Three rats were used in each study, with each group of rats also acting as their own ketamine control.
  • the order of study drug administration was determined by prior oddsevens randomisation with a recovery interval of at least one hour afforded between experiments.
  • PWR and RR were recorded at 1 minute intervals throughout. The times from cessation of infusion to return of righting reflex (RRR), and from cessation of infusion to the animals displaying independent locomotion (walk) were recorded.
  • Nociceptive testing in animals was conducted via 1 second application of constant pressure (firm digital pressure) over the forepaw of the animal.
  • Pedal withdrawal reflex testing is primarily used to assess analgesic effect, and responses are graded accordingly: 0, absent; 1, flicker; 2, moderate withdrawal; 3, fast withdrawal; 4, Fast withdrawal with crypreceding apnoea (modified from Buitrago, S. et al. J. Amer. Assoc. Lab. Animal. Sci. 2008, 47, 11-17).
  • Righting reflex is considered absent when the animal fails to right from a position of dorsal recumbency to a position of sternal recumbency on three attempts performed in rapid succession.
  • b PWR Pedal withdrawal reflex
  • a PWR 1 (a flicker of response) indicates a satisfactory level of analgesia (nociception).
  • c RRR Recovery of righting reflex; ability to right from dorsal recumbency).
  • d Walk (ability to sustain independent locomotion).
  • FIGS. 1 and 2 Representative plots of the performance of two representative compounds of the invention compared to ketamine in are shown in FIGS. 1 and 2 . Loss of righting (anaesthesia) for rac-C2nPr and rac-C4Me are shown in FIGS. 1A and 1B , respectively, and pedal withdrawal scores are shown in FIGS. 2A and 2B .
  • FIG. 3 shows a scatter-plot of effective potency (dose [mg/kg] to loss of righting reflex) versus duration (time to return of righting reflex) for ketamine and representative compounds of the invention.
  • Acetate (S)—C3OAc was the most potent of the compounds (about as potent as ketamine), but showed only moderately faster recoveries (1.5-2 fold) than ketamine itself. Without wishing to be bound by theory, the applicant believes that this is most likely not due to slow acetate hydrolysis, but to the fact that the corresponding alcohol product is itself a potent hypnoticanalgesic.
  • rac-C2Et, rac-C2iPr, rac-C3Et, rac-C3iPr, rac-C4Me, rac-C4Et and rac-C4iPr comprised a mixture of chain lengths (thus a range of pKas) and a variety of Me, Et and iPr esters.
  • rac-C2nPr, rac-C3nPr and rac-C4nPr were also a mixture of chain lengths, but were all n-Pr esters, and at the higher end of the lipophilicity range. Since dose-potency and rapidity of recovery from both LRR and PWR are broadly reciprocal, it is not surprising that these less potent compounds resulted in the fastest recoveries (20-25 fold faster than ketamine).

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WO2017087388A1 (en) * 2015-11-18 2017-05-26 Mitchell Woods Pharmaceuticals, Inc. Phenyl cyclohexanone derivatives and methods of making and using them
CN112125816A (zh) * 2020-03-17 2020-12-25 国药集团工业有限公司 一种氯胺酮、其衍生物或其盐的消旋化方法
US11440874B2 (en) 2018-01-10 2022-09-13 XWPharma Ltd. Ketamine derivatives and compositions thereof
CN115108927A (zh) * 2016-03-25 2022-09-27 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮和(2s,6s)-羟基去甲氯胺酮的晶型和合成方法
US11690811B2 (en) 2021-08-13 2023-07-04 XWPharma Ltd. Pharmaceutical compositions and oral dosage forms of ketamine derivatives
US11827606B2 (en) 2015-11-18 2023-11-28 Spirify Pharma Inc. Phenyl cyclohexanone derivatives and methods of making and using them

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JP6309957B2 (ja) * 2012-10-08 2018-04-11 オークランド ユニサービシーズ リミティド ケタミン誘導体
US20160332962A1 (en) * 2015-05-13 2016-11-17 Janssen Pharmaceutica Nv (s)-csa salt of s-ketamine, (r)-csa salt of s-ketamine and processes for the preparation of s-ketamine
EP3297620A4 (en) 2015-06-27 2019-01-09 Shenox Pharmaceuticals, LLC TRANSDERMAL DELIVERY SYSTEM FOR KETAMINE
WO2019186357A1 (en) * 2018-03-26 2019-10-03 Cellix Bio Private Limited Compositions and methods for the treatment of neurological diseases
CA3102387A1 (en) * 2018-06-04 2019-12-12 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Process for synthesis and purification of (2r,6r)-hydroxynorketamine
CN115677444A (zh) * 2022-10-26 2023-02-03 公安部第三研究所 同位素毒品代谢物标记化合物及其制备方法、用途

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087388A1 (en) * 2015-11-18 2017-05-26 Mitchell Woods Pharmaceuticals, Inc. Phenyl cyclohexanone derivatives and methods of making and using them
US11111210B2 (en) 2015-11-18 2021-09-07 Spirify Pharma Inc. Phenyl cyclohexanone derivatives and methods of making and using them
US11827606B2 (en) 2015-11-18 2023-11-28 Spirify Pharma Inc. Phenyl cyclohexanone derivatives and methods of making and using them
CN115108927A (zh) * 2016-03-25 2022-09-27 美国政府健康及人类服务部 (2r,6r)-羟基去甲氯胺酮和(2s,6s)-羟基去甲氯胺酮的晶型和合成方法
US11613514B2 (en) * 2016-03-25 2023-03-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Crystal forms and methods of synthesis of (2R, 6R)-hydroxynorketamine and (2S, 6S)-hydroxynorketamine
US11440874B2 (en) 2018-01-10 2022-09-13 XWPharma Ltd. Ketamine derivatives and compositions thereof
CN112125816A (zh) * 2020-03-17 2020-12-25 国药集团工业有限公司 一种氯胺酮、其衍生物或其盐的消旋化方法
US11690811B2 (en) 2021-08-13 2023-07-04 XWPharma Ltd. Pharmaceutical compositions and oral dosage forms of ketamine derivatives

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