Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3

Definitions

• the present disclosure relates generally compounds useful for the treatment of central nervous system disorders, such as mood disorders (e.g., depression), anxiety disorders, and neurodegenerative diseases.
• central nervous system disorders such as mood disorders (e.g., depression), anxiety disorders, and neurodegenerative diseases.
• the subject disclosure enables the manufacture of medicaments as well as compositions containing same for use in methods of therapy and prophylaxis of central nervous system disorders.
• a neurite is any projection or outgrowth emanating from the cell body of a neuron or nerve cell.
• Neurons are the core components of the nervous system, which includes the brain, spinal cord, and peripheral ganglia.
• Compounds inducing neurite outgrowth have neuroprotective properties and the induction of neurite outgrowth is a surrogate of the ability of a compound to induce neurogenesis.
• Neurotrophins are critical mediators of neuronal survival during development and are involved in the regulation of neurogenesis (axonal and dendritic outgrowth), synapse formation and function, cell migration and cell proliferation, plasticity, survival and differentiation in adult neurons and glia. Although the majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis.
• TrkA is a signaling receptor for nerve growth factor (NGF)
• TrkB is a signaling receptor for the related neurotrophin brain-derived neurotrophic factor (BDNF)
• BDNF neurotrophin 4/5 and, with lower affinity, for neurotrophin-3
• TrkC is a receptor for neurotrophin-3 (NT3).
• Trk receptors The activation of Trk receptors by the binding of specific neurotrophins triggers receptor dimerization and consequent trans-phosphorylation of tyrosine residues of the tyrosine kinase domain.
• Phosphorylated receptors undergo conformational changes which promote the recruitment of intracellular substrates such SHC1, PI-3 kinase and PLCy-1 to activate signaling cascades.
• the recruitment and tyrosine phosphorylation of PLOy-l activates this enzyme and catalyzes the breakdown of lipids to diacyl glycerol and inositol(l,4,5)triphosphate (IP3).
• IP3 IP3 binding protein
• diacyl glycerol allows maximal activation of several protein kinase C isoforms.
• the phospholipase pathway can indirectly activate MAP kinases and phosphatidylinositol 30-kinase (PI3 kinase) by changes in intracellular calcium.
• MAP kinases MAP kinases
• PI3 kinase phosphatidylinositol 30-kinase
• Antidepressants e.g., SSRIs and tricyclics
• mood stabilisers sodium valproate, lithium
• G-protein coupled receptors initiates signalling from many downstream effector proteins, such as phospholipases and ion channels, thus permitting the release of second messenger molecules within the cell, such as IP3 or calcium ions to promote neurogenesis.
• Neurodegenerative diseases are characterised by a loss of neurons from specific regions of the central nervous system.
• Current research has provided evidence that neurogenesis is impaired in neurodegenerative diseases such as Parkinson's disease, Lewy body disease, and Huntington's disease, and amyotrophic lateral sclerosis, and that stimulation of neurogenesis is associated with restored function in animal models of these diseases, suggesting that neurogenesis is functionally important.
• neurite outgrowth is a critical event in neuronal development, the formation and remodelling of synapses, response to injury, and regeneration. Changes in the pattern of neurite outgrowth have been implicated in neurodegenerative disorders including traumatic brain injury.
• the discovery of new compounds that can positively affect neurite outgrowth by directly modulating neurotrophic pathways is important for the development of new therapeutic agents for treating certain central nervous system disorders (including mood disorders, such as depression, anxiety disorders, neurodegenerative diseases, and brain injury).
• compounds of formula (I) act as effective enhancers of neurite outgrowth in animals including mammals (such as human) and are therefore therapeutically useful in the prophylaxis and treatment of certain central nervous system (CNS) disorders, such as mood disorders (e.g., depression) and neurodegenerative diseases, such as, for instance, multiple sclerosis.
• CNS central nervous system
• disorder includes an adverse condition, trauma or other adverse manifestation of the CNS.
• a compound of formula (I) or pharmaceutically acceptable salt thereof comprising the step of administering an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof:
• Ri represents hydrogen, or optionally substituted Ci-Ce alkyl
• R 2 represents -C(0)NR'R" (where R' is -H or optionally substituted C r C 6 alkyl and R" is optionally substituted C
• R 3 represents optionally substituted aryl or optionally substituted heteroaryl
• R4 represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and
• R 5 represents H, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substituted aryl).
• the compound of formula (I) is not 6-(2,3-dihydro-l H-inden-2- ylamino)-2-methyl-4-phenylquinoline-3-carboxylic acid.
• the present invention also provides methods for treating central nervous system disorders, such as anxiety disorders, mood disorders (e.g., depression), and/or neurodegenerative diseases (e.g., multiple sclerosis) comprising the step of administering to a patient in need thereof a compound of formula (la) or a pharmaceutically acceptable salt thereof; wherein Ri, R 2 , R 3 , and R4 are as described herein; and
• R5' represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C
• the present invention also provides the use of a compound of formula (I) or a salt thereof:
• Ri, R 2 , R3, R4, and R5 are as described herein, in the manufacture of a medicament for enhancing neurite outgrowth in a subject in need thereof.
• the present invention also provides the use of a compound of formula (la) or a salt thereof:
• , R 2 , R 3 , and R4 are as described herein; and R 5 ' represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C ⁇ - C 3 ⁇ 4 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substituted aryl), in the manufacture of a medicament for the treatment of central nervous system disorders, such as anxiety disorders and/or depression.
• R 5 ' represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally
• the present invention also provides the use of a compound of formula (I) or a salt thereof:
• Ri, R 2 , R 3 , R4, and R5 are as described herein, for enhancing neurite outgrowth in a subject in need thereof.
• the present invention also provides the use of a compound of formula (la) or a salt thereof: wherein R
• R 5' represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted Ci- C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substituted aryl), for the treatment of central nervous system disorders, such as anxiety disorders, mood disorders (e.g. , depression), and/or neurodegenerative diseases (e.g., multiple sclerosis).
• central nervous system disorders such as anxiety disorders, mood disorders (e.g. , depression), and/or neurodegenerative diseases (e.g., multiple sclerosis).
• the present disclosure contemplates the treatment or -prophylaxis of a disease of the central nervous system, such as mood disorders (e.g., depression), anxiety disorders, and neurodegenerative diseases.
• a disease of the central nervous system such as mood disorders (e.g., depression), anxiety disorders, and neurodegenerative diseases.
• neurodegenerative disease encompasses a condition leading to the progressive loss of structure or function of neurons, including death of neurons.
• neurodegenerative diseases contemplated herein include AIDS dementia complex, adrenoleukodystrophy, alexander disease, Alpers' disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familial insomnia, frontotemporal lobar degeneration, Huntington's disease, infantile Refsum disease, Kennedy's disease, Krabbe disease, Lyme disease, Machado-Joseph disease, monomelic amyotrophy, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, neurodegeneration with brain iron accumulation, opsoclonus myoclonus, Parkinson's disease, Pick's disease, primary lateral sclerosis, progranulin, progressive multifocal leukoencephalopathy, progressive supranucle
• the compounds of formula (I) treat, ameliorate the symptoms of, prevent, or otherwise delay the onset or development of the CNS disease, disorder, or condition.
• the invention is also based on the discovery that the compounds of the general formula (la) as described herein have useful properties as possible ligands for biological receptors and biological targets that elicit an effect on the central nervous system. Such compounds have significant potential for the treatment of a variety of disorders of the central nervous system, and in particular disorders such as anxiety and depression.
• Alkyl refers to a saturated monovalent hydrocarbon radical which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms or 1 to 9 carbon"atoms (i.e., Ci-Gj alkyl).
• alkyl groups include methyl, ethyl, ⁇ -propyl, wo-propyl, rt-butyl, wo-butyl, «-hexyl, and the like.
• Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
• Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
• aryl groups include phenyl, naphthyl and the like.
• Aryloxy refers to the group aryl-O- wherein the aryl group is as described above.
• Arylalkyl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
• Arylalkoxy refers to the group arylalkyl-O- wherein the arylalkyl group are as described above. Such arylalkoxy groups are exemplified by benzyloxy and the like.
• Alkoxy refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, H-propoxy, /so-propoxy, rc-butoxy, tert-butoxy, sec- butoxy, «-pentoxy, «-hexoxy, 1,2-dimethylbutoxy, and the like.
• Alkenyl refers to a monovalent hydrocarbon radical with at least one site of unsaturation, i.e.
• a carbon-carbon, sp 2 double bond which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds.
• Alkenyloxy refers to the group alkenyl-O- wherein the alkenyl group is as described above.
• Alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 , and preferably from 1-2, carbon to carbon, triple bonds.
• alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), pent-2-ynyl (-CH 2 C ⁇ CCH 2 -CH 3 ), and the like.
• Alkynyloxy refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
• Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Oxyacyl refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Amino refers to the group -NR A R A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Aminoacyl refers to the group -C(0)NR A R A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Acylamino refers to the group -NR A C(0)R A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-aryl, -C(0)0-heteroaryl, and -C(0)0-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Aminoacyloxy refers to the groups -OC(0)NR A -alkyl, -OC(0)NR A -aryl, -OC(0)NR A -heteroaryl, and -OC(0)NR A -heterocyclyl where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Oxyacylamino refers to the groups -NR A C(0)0-alkyl, -NR A C(0)0-aryl, -NR A C(0)0-heteroaryl, and NR A C(0)0-heterocyclyl where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Oxyacyloxy refers to the groups -OC(0)0-alkyl, -0-C(0)0-aryl, -OC(0)0- heteroaryl, and -OC(0)0-heterocyclyl where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Acylimino refers to the groups -C(NR A )-R A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Acyliminoxy refers to the groups -0-C( R A )-R A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Oxyacylimino refers to the groups -C(NR A )-OR A where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 1 1 carbon atoms.
• Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like.
• the term also includes poiycyclic ring systems where the cycloalkyl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, such as adamantanyl, indanyl, 1 ,2,3,4-tetrahydronapthalenyl and the like.
• a cycloalkyl may be attached via an alkylene moiety to form a "cycloalkylalkyl" group.
• the alkylene moiety of a cycloalkylalkyl group contains between 1 and 10 carbon atoms.
• the alkylene moiety of a cycloalkylalkyl group contains between 1 and 3 carbon atoms.
• a cycloalkylalkyl group is optionally substituted on the alkylene moiety and/or on the cycloalkyl.
• Cycloalkenyl refers . to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 1 1 carbon atoms.
• suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.
• Heteroaryl refers to a monovalent aromatic heterocyclic group which fulfills the Htickel criteria for aromaticity (ie. contains 4n + 2 ⁇ electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen).
• Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg.
• indolizinyl benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).
• R 2 is an optionally substituted heteroaryl which has one or more ring heteroatoms
• the heteroaryl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
• a heteroaryl may be attached via an alkylene moiety to form a "heteroarylalkyl" group.
• the alkylene moiety of a heteroarylalkyl group contains between 1 and 10 carbon atoms. In certain embodiments, the alkylene moiety of a heteroarylalkyl group contains between 1 and 3 carbon atoms. In some embodiments, a heteroarylalkyl group is optionally substituted on the alkylene moiety and/or on the heteroaryl.
• Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring.
• the heteroatom is nitrogen. It will be understood that where, for instance, R 2 is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
• a heterocyclyl may be attached via an alkylene moiety to form a "heterocyclylalkyl" group.
• the alkylene moiety of a heterocyclylalkyl group contains between 1 and 10 carbon atoms.
• the alkylene moiety of a heterocyclylalkyl group contains between 1 and 3 carbon atoms.
• a heterocyclylalkyl group is optionally substituted on the alkylene moiety and/or on the heterocyclyl.
• heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7
• Thio refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Thioacyl refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Oxythioacyl refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Oxythioacyloxy refers to groups HO-C(S)-0-, alkylO-C(S)-0-, cycloalkylO-C(S)-0-, arylO-C(S)-0-, heteroarylO-C(S)-0-, and heterocyclylO-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Phosphorylamino refers to the groups -NR A -P(0)(R B )(OR c ) where R A represents H, alkyl, cycloalkyl, alkenyl, or aryl, R represents OR or is hydroxy or amino and R is alkyl, cycloalkyl, aryl or arylalkyl, where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are as described herein.
• Thioacyloxy refers to groups H-C(S)-0-, alkyl-C(S)-0-, cycloalkyl-C(S)-0-, aryl- C(S)-0-, heteroaryl-C(S)-0-, and heterocyclyl-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
• Sulfinyl refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-,. and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• Sulfonyl refers to groups H-S(0) 2 -, alkyl-S(0) 2 -, cycloalkyl-S(0) 2 -, aryl-S(0) 2 -, heteroaryl-S(0) 2 -, and heterocyclyl-S(0)2-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
• “Sulfinylamino” refers to groups H-S(0)-NR A -, alkyl-S(0)-NR A -, cycloalkyl-S(O)- NR A -, aryl-S(0)-NR A -, heteroaryl-S(0)-NR A -, and heterocyclyl-S(0)-NR A -, where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Sulfonylamino refers to groups H-S(0) 2 -NR A -, alkyl-S(0) 2 -NR A , cycloalkyl-S(0) 2 - NR A -, aryl-S(0) 2 -NR A -, heteroaryl-S(0) 2 -NR A -, and heterocyclyl-S(0) 2 -NR A -, where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Oxysulfinylamino refers to groups HO-S(0)-NR A -, alkylO-S(0)-NR A -, cycloalkylO- S(0)-NR A -, arylO-S(0)-NR A -, heteroarylO-S(0)-NR A -, and heterocyclylO-S(0)-NR A -, where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Oxysulfonylamino refers to groups HO-S(0) 2 -NR A -, alkylO-S(0) 2 -NR A -, cycloalkylO-S(0) 2 -NR A -, arylO-S(0) 2 -NR A -, heteroarylO-S(0) 2 -NR A -, and heterocyclylO-S(0) 2 -NR A -, where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Aminothioacyl refers to groups R A R A N-C(S)-, where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Thioacylamino refers to groups H-C(S)-NR A -, alkyl-C(S)-NR A -, cycloalkyl-C(S)- NR A -, aryl-C(S)-NR A -, heteroaryl-C(S)-NR A -, and heterocyclyl-C(S)-NR A -, where R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Aminosulfinyl refers to groups R A R A N-S(0)-, where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• Aminosulfonyl refers to groups R A R A N-S(0) 2 -, where each R A is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
• a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl
• the "optionally substituted" group is selected from halo (e.g. , chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 C,. 6 alkyl, -CONH 2 , -CONH(C,. 6 alkyl), - CONH(Ci.6alkyl) 2 , -OH, hydroxyCi- 6 alkyl, Ci. 6 alkoxy, Ci ⁇ alkyl, Ci-eacyl, carboxyCi. 6 alkyl, acetyl, trifiuoromethyl, benzyloxy, phenyl, phenoxy, -NH 2 , -NH(Ci. 6 alkyl) or -
• the present invention also provides compounds of formula (la) and salts thereof,
• Ri represents hydrogen, or optionally substituted Ci-C 6 alkyl
• R 2 represents -C(0)NR'R" (where R' is -H or optionally substituted C
• R4 represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and
• R 5 represents H, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted Ci-C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substituted aryl).
• R 3 when R 3 is optionally substituted phenyl, R 5 is not optionally substituted cycloalkyl or optionally substituted cycloalkenyl.
• Ri represents H and C1-C4 alkyl
• R 2 represents -C(0)NR'R" (where R' is H or Ci-C 4 alkyl and R" is C1-C4 alkyl, OH or CN), -C(0)OR' (where R' is H or C r C 4 alkyl), -C(0)NHS0 2 R"' (where R'" is aryl or C,-C 3 alkyl), -S(0) 2 NHR”" (where R"" is H, C,-C 3 alkyl, or aryl), optionally substituted heteroaryl or optionally substituted heterocyclyl;
• R 3 represents optionally substituted heteroaryl
• R4 represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and
• Rs represents H, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally " substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substiuted aryl).
• Ri represents H and C1-C4 alkyl
• R 2 represents -C(0)NR'R" (where R' is H or C1-C4 alkyl and R" is C,-C 4 alkyl, OH or CN), -C(0)OR' (where R' is H or C,-C 4 alkyl), -C(0)NHS0 2 R m (where R"' is aryl or C,-C 3 alkyl), -S(0) 2 NHR”" (where R"" is H, C,-C 3 alkyl, or aryl), optionally substituted heteroaryl or optionally substituted heterocyclyl;
• R 3 represents optionally substituted aryl
• R4 represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and R 5 is R 5 ' and represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted Ci- C 6 alkyl, or -C(0)NR'R' (wherein each
• Ri represents C1-C4 alkyl
• R 2 represents -C(0)NR'R" (where R' is H or C,-C alkyl and R" is C
• R 3 represents optionally substituted heteroaryl
• Rj represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and
• R 5 represents H, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C,-C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted C
• Ri represents C1-C4 alkyl;
• R 2 represents -C(0)NR'R" (where R' is H or C 1-C4 alkyl and R" is C G, alkyl, OH or CN), -C(0)OR' (where R * is H or C,-C 4 alkyl), -C(0)NHS0 2 R m (where R"' is aryl or C,-C 3 alkyl), -S(0) 2 NHR ,m (where R ,m is H, C]-C 3 alkyl, or aryl), optionally substituted heteroaryl or optionally substituted heterocyclyl;
• R 3 represents optionally substituted aryl
• R4 represents H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; and
• R 5 is R 5 ' and represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 -optionally substituted C ⁇ - C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted C)-C 6 alkyl or optionally substituted aryl).
• Ri is C1-C4 alkyl. In some embodiments, Ri is methyl, ethyl, isopropyl, n-propyl, or butyl. In certain embodiments, R
• R 2 represents -C(0)NR'R" (where R' is -H or optionally substituted Ci-C 6 alkyl and R" is optionally substituted Ci-C 6 alkyl, -OH or -CN, or R' and R" together form an optionally substituted heterocyclyl), -C(0)OH, -C(0)NHS0 2 R"' (where R'" is optionally substituted aryl or optionally substituted C)-C 6 alkyl), - S(0) 2 NHR”" (where R"" is -H, optionally substituted Ci-C 6 alkyl, or optionally substituted aryl), optionally substituted heteroaryl or optionally substituted heterocyclyl.
• R 2 is -C(0)NR'R", wherein R' is H or C1-C4 alkyl, and R" is C1-C4 alkyl, -OH, or -CN. In certain embodiments, R 2 is -C(0)NR'R", wherein R' is H and R" is -OH or -CN. In certain embodiments, R 2 is -C(0)NHOH. In certain embodiments, R 2 is - C(0)NHCN. In certain embodiments, R 2 is -C(0)NH(C
• R 2 is -C(0)NR'R", wherein R' and R" taken together form an optionally substituted heterocyclyl.
• R' and R" taken together form a 5-7 membered heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.
• R' and R" taken together form a 5-membered heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.
• R' and R" taken together form a 6-membered heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur.
• R' and R" taken together form a 5-membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur.
• R' and R" taken together form a 6- membered heterocyclyl having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R' and R" taken together form a 6-membered heterocyclyl having two heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, R' and R" taken together form a morpholine ring.
• R 2 is -C(0)OR', wherein R' is hydrogen or optionally substituted C
• R 2 is -C(0)OH.
• R 2 is -C(0)NHS0 2 R"', wherein R'" is aryl or C1 -C3 alkyl. In certain embodiments, R 2 is -C(0)NHS0 2 (phenyl). In certain embodiments, R 2 is - C(0)NHS0 2 (Ci-C 3 alkyl). In certain embodiments, R 2 is -C(0)NHS0 2 Me, - C(0)NHS0 2 Et, or -C(0)NHS0 2 iPr.
• R 2 is -S(0) 2 NHR"", wherein R"" is H, C
• R 2 is -S(0) 2 NH 2 .
• R 2 is -S(0) 2 NH(Ci-C 3 alkyl).
• R 2 is -S(0) 2 NHMe, -S(0) 2 NHEt, or -S(0) 2 NHiPr.
• R 2 is -S(0) 2 NH(aryl).
• R 2 is optionally substituted heteroaryl or optionally substituted heterocyclyl. In some embodiments, R 2 is substituted or unsubstituted 5-6 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is a substituted or unsubstituted 5 -membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 6-membered heteroaryl having 1-3 nitrogens. In some embodiments, R 2 is a substituted or unsubstituted 4-7 membered heterocycle having 1 -3 heteroatoms selected from nitrogen, oxygen, and sulfur.
• R 2 is a substituted or unsubstituted 4-membered heterocycle having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 5-membered heterocycle having one heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 6-membered heterocycle having 1 -2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is a substituted or unsubstituted 7-membered heterocycle having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, R 2 is one of the following:
• R y is H or Ci -6 alkyl.
• R 3 represents optionally substituted phenyl.
• R 3 represents wherein 3 ⁇ 4 is selected from carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally, substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminoacyl
• n is 0. In other embodiments, n is an integer from 1 to 4, inclusive. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In the above embodiments R6, when present, includes the following groups:
• R 6 is halogen, cyano, nitro, or amino. In certain embodiments, R6 is bromo or chloro. In some embodiments, R 6 is fluoro.
• 3 ⁇ 4 is an optionally substituted alkyl group.
• R 6 is an unsubstituted alkyl group.
• Re is a substituted alkyl group.
• Re is optionally substituted C i -C 6 alkyl.
• R 6 is optionally substituted Q-C3 alkyl.
• R 6 is methyl or ethyl.
• Re is 1-hydroxyethyl, 1-thioethyl, methoxyiminomethyl, ethoxyiminomethyl, l-(hydroxyimino)ethyl, 1 -
• R6 is trihalomethyl. In certain embodiments, R6 is trifluoromethyl. In certain embodiments, R 6 is pentahaloethyl.
• R 6 is an optionally substituted aryl group. In certain embodiments, R 6 is unsubstituted aryl. In certain embodiments, R 6 is phenyl or napthyl. In certain embodiments, R 6 is substituted aryl. In certain embodiments, Re is halophenyl (for instance, fluorophenyl), aminophenyl, ⁇ carboxyphenyl, hydroxyphenyl, cyanophenyl, nitrophenyl, trihaloalkylphenyl, or alkylphenyl. '
• Re is an optionally substituted acyl group.
• R6 is unsubstituted acyl.
• Re is substituted acyl.
• R 6 is formyl, acetyl, propionyl, or benzoyl.
• R6 is formyl, acetyl, propionyl, or benzoyl, optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano.
• Re is a substituted or unsubstituted alkoxy group.
• Re is Ci-C 6 alkoxy.
• R 6 is C1-C3 alkoxy.
• R6 is methoxy or ethoxy.
• R 6 is dihalomethoxy.
• R6 is trifluoromethoxy.
• R6 is a substituted or unsubstituted oxyacyl group.
• 3 ⁇ 4 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, or i sobuty loxycarbonyl .
• R 3 ⁇ 4 is a substituted or unsubstituted acyloxy group.
• R is Ci-C 6 acyloxy.
• R6 is acetoxy or propioxy.
• R 3 ⁇ 4 is an optionally substituted arylalkyl group.
• R 6 is an unsubstituted arylalkyl group.
• R ⁇ is benzyl.
• R6 is a substituted arylalkyl group.
• R 3 ⁇ 4 is 1-hydroxybenzyl or 1 -thiobenzyl.
• R 6 is an optionally substituted sulfinyl group.
• R 6 is alkylsulfinyl or arylsulfinyl.
• R is alkoxy sulfinyl.
• Rfi is methylsulfinyl, ethylsulfinyl, benzene sulfinyl, methoxysulfinyl, or ethoxysulfinyl.
• ⁇ is benzene sulfinyl, optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano.
• R6 is an optionally substituted sulfonyl group.
• R ⁇ is alkylsulfonyl or arylsulfonyl.
• R3 ⁇ 4 is methylsulfonyl, ethylsulfonyl, or benzenesulfonyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano).
• R6 is an optionally substituted oxyacylamino group.
• Re is C
• R6 is methoxycarbonylamido or ethoxycarbonylamido.
• R 6 is an optionally substituted oxythioacyl group.
• R6 is Ci-C 6 alkoxythiocarbonyl.
• R $ is methoxythiocarbonyl or ethoxythiocarbonyl.
• R 6 is an optionally substituted thioacyloxy group.
• R(, is thionoacetoxy or thionopropionoxy.
• R6 is an optionally substituted sulphinylamino group.
• R6 is alkylsulfinylamino or arylsulfinylamino.
• R 3 ⁇ 4 is methylsulfinylamino, ethylsulfinylamino, or benzenesulfinylamino.
• R6 is benzenesulfinylamino optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano.
• R 6 is an amino group.
• R* is alkylamino or dialkylamino.
• R6 is N-methylamino or ⁇ , ⁇ '-dimethylamino.
• R6 is a substituted amino group, such as a residue of L-valine, D- valine, L-alanine, D-alanine, aspartic acid, or alanylserine.
• R6 is an optionally substituted sulphonylamino group.
• R6 is alkylsulfonylamino or arylsulfonylamino.
• R $ is Ci-C 6 alkylsulfonylamino.
• R ⁇ is methylsulfonylamino, ethylsulfonylamino, or benzenesulfonylamino.
• R6 is benzenesulfonylamino optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano.
• R 6 is an optionally substituted thio group. In certain embodiments, R 6 is a substituted thio group. In certain embodiments, R is alkylthio. In certain embodiments, R 6 is Ci-C 6 alkylthio. In certain embodiments, R 6 is thiomethyl or thioethyl. In certain embodiments, R ⁇ is trihalomethanethio. In some embodiments, is an optionally substituted oxysulfinylamino group. In certain embodiments, is alkoxysulfinylamino. In certain embodiments, R ⁇ is methoxy sulfinylamino or ethoxysulfinylamino.
• R 6 is an optionally substituted oxysulfonylamino group. In certain embodiments, R6 is alkoxylsulfonylamino. In certain embodiments, R 6 is methoxysulfonylamino or ethoxysulfonylamino.
• R 6 is an optionally substituted alkenyl group. In some embodiments, R 6 is unsubstituted alkenyl. In some embodiments, R is substituted alkenyl. In certain embodiments, R is 1-propenyl, vinyl, nitrovinyl, cyano vinyl, or trifluorovinyl, or styryl. In certain embodiments R6 is styryl optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl, or cyano. In certain embodiments, R6 is trihaloethenyl.
• Re is an optionally substituted alkynyl group.
• R$ is substituted C)-C 6 alkynyl.
• R $ is unsubstituted Ci-C 6 alkynyl.
• R 6 is 1-propynyl, ethynyl, or trimethylsilylethynyl .
• n is 1 and R « is selected from halogen, -CN, -CF 3 , -CHF 2 , -CH 2 F, amino, hydroxyl, -NHC1-C3 alkyl, -N(Ci-C 3 alkyl) 2 , -COOH, -COO(Ci-C 3 alkyl), phenyl, benzyl, Ci-C 3 alkyl, or C1-C3 alkoxy.
• n is 2 and each R6 is independently selected from halogen, -CN, - CF 3 , -CHF 2 , -CH 2 F, amino, hydroxyl, -NHC1-C3 alkyl, -N(C,-C 3 alkyl) 2 , -COOH, - COO(C
• n is 3 and each R6 is independently selected from halogen, -CN, - CF 3 , -CHF 2 , -CH 2 F, amino, hydroxyl, -NHC 1 -C3 alkyl, -N(C,-C 3 alkyl) 2 , -COOH, - COO(C
• R4 is C
• R4 is H.
• R4 is methyl, ethyl, n-propyl, or isopropyl.
• R 2 is -COOH
• R4 is H
• R5 is a benzofused C5-C7 cycloalkyl (wherein the benzene ring may be optionally substituted). In certain embodiments, R 5 is an optionally substituted indanyl or optionally substituted 1 ,2,3,4-tetrahydronaphthalenyl. In certain embodiments, R5 is unsubstituted indanyl or 1 ,2,3,4-tetrahydronaphthalenyl.
• R5 is an optionally substituted benzofused C5-C7 cycloalkyl, such as indanyl or 1 ,2,3,4- tetrahydronaphthalenyl, wherein the optional substitutents are independently selected from the group consisting of halo (e.g., chloro, fluoro, or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 Ci.
• halo e.g., chloro, fluoro, or bromo
• R5 is: wherein t is 1 , 2, or 3; q is 1 , 2, 3, or 4; and R* is halo (e.g., chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 C
• R* is halo (e.g., chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 C
• t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In certain embodiments, t is 1 and q is 1.
• R5 is: wherein t is 1 , 2, or 3; q is 1 , 2, 3, or 4; and R x is halo (e.g. , chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 Ci -6 alkyl, -CONH 2 , -CONH(C, -6 alkyl), - CONH(Ci. 6 alkyl) 2 , -OH, hydroxyalkyl, alkoxy, alkyl, acyl, carboxyalkyl, acetyl, trifluoromethyl, benzyloxy, phenoxy, -NH 2 , -NH(C
• R x is halo (e.g. , chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 Ci
• R 5 is a benzofused C 5 -C 7 cycloalkenyl (wherein the benzene ring may be optionally substituted). In certain embodiments, R 5 is optionally substituted indenyl. In certain embodiments, R 5 is unsubstituted indenyl.
• R 5 or R 5 ⁇ is H, optionally substituted acyl, optionally substituted aryl, -(CH 2 ) m -optionally substituted aryl, optionally substituted heteroaryl, -(CH 2 ) m - optionally substituted heteroaryl, optionally substituted heterocyclyl, -(CH 2 ) m -optionally substituted heterocyclyl, -(CH 2 ) m -optionally substituted cycloalkyl, -S(0) 2 -optionally substituted Ci-C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl, or optionally substituted aryl); wherein m is 1 , 2, or 3.
• R 5 or R 5 ' is:
• optionally substituted acyl selected from -C(0)-optionally substituted heteroaryl, -C(O)- optionally substituted alkyl, -C(0)-optionally substituted aryl, -C(0)-optionally substituted heterocyclyl or -C(0)-optionally substituted cycloalkyl.
• R 5 or R 5 > is selected from -C(0)-heteroaryl, -C(0)-alkyl, -C(O)- aryl, -C(0)-heterocyclyl or -C(0)-cycloalkyl, optionally substituted 1 or 2 times by halo (e.g., chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 Ci -6 alkyl, -CONH 2 , -CONH(C,.
• halo e.g., chloro, fluoro or bromo
• R 5 or R 5 > is optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, or optionally substituted cycloalkylalkyl.
• R 5 or Ry is -(CH 2 ) m -optionally substituted aryl, -(CH 2 ) m - optionally substituted heteroaryl, -(CH 2 ) m -optionally substituted heterocyclyl, or -(CH 2 ) m - optionally substituted cycloalkyl; and m is an integer of 1 to 3.
• R 5 or Ry is -(CH 2 ) m -optionally substituted heteroaryl wherein m is 1 or 2.
• R 5 or Ry is -(CH 2 ) m -optionally substituted heteroaryl wherein m is 1.
• R5 or Rs- is -(CH 2 ) m -heteroaryl, optionally substituted 1 or 2 times by halo (e.g. , chloro, fluoro or bromo), -CN, -N0 2 , -C0 2 H, -C0 2 C, -6 alkyl, -CONH 2 , - CONH(C
• halo e.g. , chloro, fluoro or bromo
• R5 or R5' is -S(0 2 )-C
• R 5 or Ry is -C(0)-NH-optionally substituted phenyl.
• R $ or R5' is H.
• R4 is hydrogen, and R 5 is a benzofused C5-O7 cycloalkyl.
• R4 is C 1-C3 alkyl, and R 5 is a benzofused C 5 -C 7 cycloalkyl.
• R4 is hydrogen, and R5 is a benzofused Cs-C 7 cycloalkenyl.
• R4 is Ci-C 3 alkyl, and R5 is a benzofused C 5 -C 7 cycloalkenyl.
• R4 is hydrogen, and R5 is indanyl.
• R4 is methyl, and R 5 is indanyl. In certain embodiments, R4 is hydrogen, and R5 is indenyl. In certain embodiments, R4 is methyl, and R 5 is indenyl. In certain embodiments, R4 is hydrogen, and R 5 is 1 ,2,3,4-tetrahydronaphthalenyl. In certain embodiments, R4 is methyl, and R 5 is 1 ,2,3,4-tetrahydronaphthalenyl.
• R4 is hydrogen, and R5 or Ry is optionally substituted acyl.
• R4 is C 1-C3 alkyl, and R 5 or Ry is optionally substituted acyl.
• R4 is hydrogen, and R 5 or Ry is -C(0)-optionally substituted heteroaryl.
• R is C
• R4 is hydrogen, and R5 or Ry is -C(0)-optionally substituted alkyl.
• R4 is methyl, and R5 or Ry is -C(0)-optionally substituted alkyl.
• R4 is hydrogen, and R5 or R 5 > is -C(0)-optionally substituted aryl. In certain embodiments, R4 is methyl, and R5 or Ry is -C(0)-optionally substituted aryl. In certain embodiments, R4 is hydrogen, and R 5 or Ry is -C(0)-optionally substituted phenyl. In certain embodiments, R4 is methyl, and R 5 or Ry is -C(0)-optionally substituted phenyl. In certain embodiments, R is hydrogen, and R 5 or Ry is -C(0)-unsubstituted phenyl. In certain embodiments, R4 is methyl, and R 5 or Ry is -C(0)-unsubstituted phenyl.
• R is hydrogen, and R5 or Ry is -C(0)-optionally substituted pyridyl.
• R4 is methyl, and R5 or Ry is -C(0)-usubstituted pyridyl.
• R4 is hydrogen, and R5 or Ry is -C(0)-unsubstituted pyridyl.
• R4 is methyl, and R 5 or R 5' is -C(0)-unsubstituted pyridyl.
• R4 is hydrogen and R 5 or Ry is -S(0 2 )-Ci. 6 alkyl.
• R4 is methyl and R 5 or Ry is -S(02)-C i -6 alkyl. In certain embodiments, R4 is hydrogen and R5 or Ry is -C(0)-NH-optionally substituted phenyl. In certain embodiments, R4 is methyl and R5 or Ry is -C(0)-NH-optionally substituted phenyl.
• the aryl, heteroaryl, alkyl, or phenyl groups are, in some embodiments, optionally substituted 1 or 2 times by halo (e.g., chloro, fluoro or bromo), - CN, -NO2, -C0 2 H, -C0 2 C,. 6 alkyl, -CONH 2 , -CONH(C, -6 alkyl), -CON(C 1-6 alkyl)2, -OH, hydroxyalkyl, alkoxy, alkyl, acyl, carboxyalkyl, acetyl, trifluoromethyl, benzyloxy, phenoxy, -NH 2 , -NH(C,. 6 alkyl), or -N(C 1-6 alkyl) 2 .
• halo e.g., chloro, fluoro or bromo
• n is 0 or 1 ;
• R is C
• R 2 is -C(0)OH, -C(0)OCH 3 , -C(0)OCH 2 CH 3 , -C(0)OCH 2 CH 2 CH 3 , or - C(0)NR'R" (where R' and R" together form an optionally substituted morpholinyl);
• R 3 is phenyl optionally substituted 1 or 2 times by a substituent independently selected from the group consisting of halogen, -CN, -CF 3 , amino, hydroxyl, - NHC,-C 3 alkyl, -N(C,-C 3 alkyl) 2 , -COO(C,-C 3 alkyl), phenyl, benzyl, C,-C 3 alkyl or Ci-C 3 alkoxy;
• R is H or Ci-C 3 alkyl
• R5 is R 5 ' and represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) 2 - optionally substituted Ci-C 6 alkyl, or -C(0)NR'R' (wherein each R' is independently H, optionally substituted Ci-C 6 alkyl or optionally substituted afyl).
• n is 0 or 1 ;
• Ri is C
• R 2 is -COOR' (where R * is H or C1 -C4 alkyl);
• R 3 is phenyl optionally substituted 1 or 2 times by a substituent independently selected from the group consisting of halogen, -CN, -CF 3 , amino, hydroxyl, - NHC,-C 3 alkyl, -N(C,-C 3 alkyl) 2 , -COO(C,-C 3 alkyl), phenyl, benzyl, C,-C 3 alkyl or C 1 -C3 alkoxy;
• R4 is H or C 1 -C3 alkyl
• R5 is R 5' and represents H, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted cycloalkylalkyl, -S(0) - optionally substituted C
• the invention provides compounds of formula (la) or salts thereof, wherein R, is methyl, R 2 is -C(0)OH, -C(0)OCH 3 , -C(0)OCH 2 CH 3 , R4 is H, and R 5 is R 5 ' and is -C(0)-optionally substituted heteroaryl (in particular pyridyl, -C(0)-C
• the invention provides compounds of formula (la), or salts thereof, provided that the compounds wherein R 3 is optionally substituted phenyl, one of R and R5 is H, and the other of R4 and R 5 is optionally substituted bicyclic cycloalkyl or optionally substituted bicyclic cycloalkenyl, are specifically excluded.
• the invention provides compounds of formula (la), or salts thereof, provided that the compounds wherein R 3 is optionally substituted phenyl, one of R4 and R5 is H, and the other of R and R 5 is indanyl, are specifically excluded.
• the invention provides compounds of formula (la), provided that the following compounds, and pharmaceutically acceptable salts thereof, are specifically excluded:
• the present invention provides compounds of formula (lb) or salts thereof:
• R 2 is -C(0)OH, -C(0)OCH 3 , or -C(0)OCH 2 CH 3 ,
• R4 is H
• R 5 ' represents optionally substituted acyl, -(CH 2 ) m -optionally substituted aryl, - (CH 2 ) m -optionally substituted heteroaryl, -(CH 2 ) m -optionally substituted heterocyclyl, or -(CH2) m -optionally substituted cycloalkyl, wherein m is an integer of 1 to 3, inclusive.
• the present invention also provides pharmaceutical compositions comprising a compound of formula (la) or (lb), or a salt thereof, and optionally a pharmaceutically acceptable excipient.
• Representative compounds of the present invention and compounds which can be used in the methods of the present invention include:
• Representative compounds of the present invention include:
• Compounds of formula F (where R is alkyl,) of the invention may be prepared by initially reacting 2-amino-5-nitrobenzophenone of formula A with an alkyl acetoacetate of formula B to afford quinolines C. Reduction of the nitro group may afford D which can subsequently be coupled to carbonyl substrates of formula E to prepare compounds of formula F.
• the compounds of formula I (where R5 is optionally substituted aryl or heteroaryl) can be prepared by reacting compounds of formula D using Buchwald or Ullmann coupling conditions.
• the compounds of formula J (where R5 is optionally substituted aryl or heteroaryl) can be prepared by reacting compounds of formula D with alkyl isocynates.
• the anilines of formula D can be converted to corresponding isocynates that can be further reacted with primary or secondary amines.
• esters of formula F to J can be further converted to their corresponding acids (where R is H) using methods such as alkali metal hydroxide mediated hydrolysis.
• the compounds of formula F to J (where R is H) can be further modified to give the corresponding primary, secondary, or tertiary amides by one skilled in the art.
• 3-Bromo-quinolin-4-ol derivatives of formula K are known (e.g., 3-bromo-6-(N,N'-dimethylamino)-2-(trifluoromethyl)- quinolin-4-ol: J. Chem. Info. Comp. Sci.
• 3-(l,2,4-oxadiazole)-quinoline derivative of formula Q can be synthesized by reacting 3-cyano-quinoline derivative of formula R (prepared according to Scheme 8) with hydroxylamine and formamide (e.g., J. Org. Chem., 1979, 44, 1695) or hydroxyl amine and triethyl orthoformate (e.g., WO2005/097750).
• 3-cyano-quinoline derivative of formula R can be reacted with hydroxyl amine and a suitable ester of chloroforrhic acid (e.g., methyl ester: J. Med.
• compounds of the formula W can be prepared by reacting esters of formula V with hydroxylamine and potassium hydroxide.
• Compounds of the formula Y can be prepared by converting compounds of the formula X to the corresponding acid chloride, for example, with oxalyl chloride and dimethylformamide, then by treatment with cyanoamide (NCNH 2 ).
• Compounds of the formula Z can be formed by treating these acid chlorides with a primary sulphonamide.
• Compounds of the formula AI can be prepared by the route shown in Scheme 8 (e.g., Bioorg. Med. Chem. Lett. 201 1, 19 (15) 4482). Reaction of 2-aminobenzophenones AA or AF with alpha-cyanoketones can form 3-cyanoquinolines AC or AG respectively. Compounds AC or AG can be reacted with sodium azide to give tetrazoles AD or AH. 6- Nitro-3-tetrazolylquinolines of the formula AD can be reduced, for example, by hydrogenation, to give the 6-aminoquinolines AE. Either one or two successive reductive aminations of compounds of the formula AE with aldehydes or ketones can give compounds of the formula AI. Alternatively compounds of the formula AH can undergo Buchwald coupling with amines to give compounds of the formula AI.
• Scheme 8 e.g., Bioorg. Med. Chem. Lett. 201 1, 19 (15) 4482.
• protecting group it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
• a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group should be selectively removable in good yield by readily available, preferably non-toxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
• oxygen, sulfur, nitrogen, and carbon protecting groups may be utilized.
• Oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxy methyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetra
• the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1- phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4- dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1 -methoxyethylidene ortho
• Amino-protecting groups include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl- [9-( 10, 10-dioxo- 10, 10, 10, 10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l -adamantyl)-l - methylethyl carbamate (Adpoc), l,l-dimethyl-2-haloethyl carbamate,
• Mbs 2,4,6- trimethylbenzenesulfonamide
• Mts 2,6-dimethoxy-4-methylbenzenesulfonamide
• Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonamide
• Ms methanesulfonamide
• SES ⁇ - trimethylsilylethanesulfonamide
• DNS 4-(4 ⁇ 8'- dimethoxynaphthylmethyl)benzenesulfonamide
• benzylsulfonamide trifluoromethylsulfonamide
• phenacylsulfonamide benzylsulfonamide
• protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in Protective Groups in Organic Synthesis, Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
• a compound that enhances neurite outgrowth is a compound that increases neurite outgrowth by at least 5% (e.g., at least 10%, at least 20%, at least 50%, or more in comparison to a control) in a neurite outgrowth assay, for example, a neurite outgrowth assay described herein.
• compounds disclosed herein enhance neurite outgrowth in primary cortical neurons which contain TrkB but do not appear to have any significant effect in PC 12 cells which lack the TrkB receptor.
• TrkB and its ligand BDNF in limbic brain regions including the hippocampus have a critical role in the pathology of mood (affective) disorders and neurodegeneration.
• BDNF the most abundant neurotrophin in the brain, in the action of antidepressant compounds.
• Exposure to stress, which is associated with the onset of many mood disorders, has consistently been shown to decrease hippocampal neurotrophin expression, in particular BDNF, while chronic antidepressant administration and /or electro-convulsive therapy, increases the expression of BDNF and its receptor TrkB, in the brain.
• Evidence is accumulating for the neurotrophic and neuroprotective effects of other psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics. They also promote neurogenesis and are protective in models of neurodegenerative disease and ischemia. These effects are achieved by activation of particular intracellular signaling pathways and up-regulation of the expression of neurotrophic/neuroprotective molecules such as BDNF, NGF, Bcl-2, and AKT.
• other psychotropic agents such as mood stabilizers, antidepressants, and antipsychotics. They also promote neurogenesis and are protective in models of neurodegenerative disease and ischemia. These effects are achieved by activation of particular intracellular signaling pathways and up-regulation of the expression of neurotrophic/neuroprotective molecules such as BDNF, NGF, Bcl-2, and AKT.
• central nervous system disorders such as mood disorders (e.g., depression), anxiety disorders, or neurodegenerative diseases
• methods of treating or preventing central nervous system disorders such as- mood disorders (e.g., depression), anxiety disorders, or neurodegenerative diseases comprising the administration of an effective amount of at least one compound of formulae (I), (la), (lb) or an embodiment thereof described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
• mood disorders are broadly recognized and clearly defined by the relevant DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition, Text Revision) criteria.
• depressive disorders of which the best known and most researched is major depressive disorder (MDD) commonly called clinical depression or major depression, and bipolar disorder (BD), formerly known as manic depression and characterized by intermittent episodes of mania or hypomania, usually interlaced with depressive episodes.
• MDD major depressive disorder
• BD bipolar disorder
• depressive disorders include: atypical depression, melancholic depression, psychotic major depression, catatonic depression, postpartum depression, seasonal affective disorder), dysthymia, depressive disorder not otherwise specified (DD- NOS) (e.g., recurrent brief depression, minor depressive disorder), substance induced mood disorders (e.g., alcohol induced mood disorders, benzodiazepine induced mood disorders, interferon-alpha induced mood disorders).
• DD- NOS depressive disorder not otherwise specified
• substance induced mood disorders e.g., alcohol induced mood disorders, benzodiazepine induced mood disorders, interferon-alpha induced mood disorders.
• the compounds described herein can be administered to a subject in need thereof as a substitute or replacement for traditional antidepressant medication.
• compounds described herein can be administered to a subject in need thereof as a supplement to traditional antidepressant medication.
• a method for treating or preventing depression in a subject including the step of administering to said subject a compound of formula (I), (la), or (lb), or an embodiment thereof described herein, or a pharmaceutically acceptable salt thereof, in the absence of adjunct antidepressant therapy.
• Replacing traditional antidepressant medication with the present compounds can be advantageous, particularly where the traditional medication is associated with one or more adverse effects (e.g., anxiety, nausea, headaches, erectile dysfunction, early-onset suicidal tendencies, etc).
• SSRJ selective serotonin re-uptake inhibitors
• serotonin/noradrenalin re-uptake inhibitors selective noradrenalin reuptake inhibitors
• monoamine oxidase inhibitors tricyclic antidepressants
• lithium and other mood stabilisers atypical antidepressants
• hormones such as estrogen or progestogen.
• the present compounds are administered to a subject in need thereof, together with traditional antidepressants for a period of about 2-4 weeks, to address the symptoms of depression, with the option of discontinuing treatment with the present compounds whilst continuing with the traditional therapy.
• the subject is treated with both a present compound and one or more traditional antidepressant medications (administered sequentially or in combination) for the duration of the treatment period.
• Such combination therapy may be particularly useful, for example, where the combination of a present compound and one or more traditional antidepressant medications provides relief from depression in the acute lag phase of the treatment period and/or where an additive or synergistic antidepressant therapeutic effect is desired.
• a subject according to the methods of the present invention does not suffer from an anxiety disorder.
• a subject does not suffer from a phobia.
• a subject does not suffer from one or more of agoraphobia, agoraphobia without history of panic disorder, animal phobia, and social phobia.
• a subject does not suffer from one or more of obsessive- compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and substance-induced anxiety disorder.
• a subject does not suffer from generalized anxiety disorder.
• a subject does not suffer from social anxiety disorder.
• a subject according to the methods of the present invention does not suffer from one or more of neuroses, convulsions, migraine, depressive disorder, bipolar disorder, psychotic disorder, neurodegeneration arising from cerebral ischemia, attention deficit hyperactivity disorder, Tourette's syndrome, speech disorder, and disorders of circadian rhythm.
• a subject does not suffer from one or more of single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I or bipolar II manic disorder, and cyclothymic disorder.
• a subject does not suffer from schizophrenia.
• a subject does not suffer from stuttering.
• a subject according to the methods of the present invention does not suffer from one or more of pain or nociception, emesis, eating disorder, premenstrual syndrome, muscle spasm or spasticity, hearing disorder, urinary incontinence, and the effects of substance abuse or dependency.
• a subject does not suffer from one or more of acute emesis, delayed emesis, anticipatory emesis, emesis induced by chemotherapy or radiation, motion sickness, and post-operative nausea and vomiting.
• a subject does not suffer from anorexia nervosa or bulimia nervosa.
• a subject does not suffer from tinnitus or age- related hearing impairment.
• a subject does not suffer from alcohol withdrawal.
• a subject does not suffer from Alzheimer's disease.
• a subject according to the methods of the present invention does not display one or more symptoms, e.g., one, two, three, four, five, six, seven, eight, nine, or ten symptoms of one or more of the following diseases or conditions: anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivit disorder; Tourette's syndrome; speech disorders, including stuttering; and disorders of circadian rhythm, e.g.
• anxiety disorders such as panic disorder with or without agor
• emesis including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting
• eating disorders including anorexia nervosa and bulimia nervosa
• premenstrual syndrome muscle spasm or spasticity, e.g., in paraplegic patients
• hearing disorders including tinnitus and age-related hearing impairment
• urinary incontinence and the effects of substance abuse or dependency, including alcohol withdrawal; dementing conditions; and Alzheimer's disease.
• Depression relapse can also occur in patients treated with traditional antidepressant medication. Many such compounds are administered for anywhere from months to years and a reduction in efficacy is often seen with such long-term use, leading to significant continuing depression and dysfunction. Depression relapse may be sudden onset for some patients, while for others it might be evident as a gradual decline in mood and function, which diminishes over time as the patient approaches the state of relapse. Thus, patients who experience sudden onset of depression relapse or a gradual depression relapse would benefit from the methods disclosed herein, as the present compounds of formula (I) or (la), or a subformula thereof described herein, can offset the diminishing effect of traditional antidepressant therapy. Thus, the use of the present compounds may prevent or partly alleviate depression relapse often seen in patients taking traditional antidepressant medication.
• a method for treating or preventing relapse in a subject receiving antidepressant therapy including the step of administering to said subject a compound of formula (I), (la), or (lb), or an embodiment thereof described herein, or a pharmaceutically acceptable salt thereof.
• the traditional antidepressant therapies that are associated with potential depression relapse in a subject would be known to those skilled in the art.
• Examples include, but are not limited to, dosage increases, alternative SSRIs or SNRIs, and non-SSRI antidepressants such as noradrenaline re-uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and other mood stabilisers, atypical antidepressants and hormones such as estrogen and progestogen, also referred to herein as "second antidepressant compounds”.
• non-SSRI antidepressants such as noradrenaline re-uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and other mood stabilisers, atypical antidepressants and hormones such as estrogen and progestogen, also referred to herein as "second antidepressant compounds”.
• Treating refers to alleviating or abrogating the cause and/or the effects of the disorder or disease.
• the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of condition, or the amelioration of one or more symptoms (e.g. , one or more discemable symptoms) of said condition (i.e., "managing” without “curing” the condition), resulting from the administration of one or more therapies (e.g. , one or more therapeutic agents such as a compound or composition of the invention).
• therapies e.g. , one or more therapeutic agents such as a compound or composition of the invention.
• the terms “treat”; “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a condition described herein. In other embodiments the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a condition described herein, either physically by, e.g. , stabilization of a discemable symptom or physiologically by, e.g. , stabilization of a physical parameter, or both.
• the desired therapeutic activity, or effect will typically depend on the condition being treated.
• the therapeutic effect may be a reduction in at least one clinical symptom of depression, including, but not limited to, cognitive impairment, loss of appetite, mood, and/or inactivity.
• preventing refers to administering a medicament beforehand to avert or forestall the appearance of one or more symptoms of a disease or disorder.
• prevent is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, or symptom of the condition and this is the sense intended in this disclosure.
• the Physician's Desk Reference a standard text in the field, uses the term “prevent” hundreds of times.
• the terms "prevent”, “preventing” and “prevention” with regard to a disorder or disease refer to averting the cause, effects, symptoms or progression of a disease or disorder prior to the disease or disorder fully manifesting itself.
• the present compounds of formula (I) or (la), or an embodiment thereof described herein, or a pharmaceutically acceptable salt thereof are administered to said subject sequentially (i.e., before or after) or in combination with a second antidepressant compound (e.g. , with existing antidepressant therapy).
• the present compounds have the further added advantage over traditional therapy in that they exhibit reduced sedative side effects which may adversely affect a patient's quality of life. In certain embodiments, the present compounds are free of measurable sedative side effects.
• Sudden discontinuation of antidepressant medication may produce withdrawal effects caused by physical dependence on the drug.
• Compounds can be evaluated for physical dependence in a simple animal model where, following a period of chronic dosing (e.g., for 14-20 days), the study drug is stopped and measurements of food intake, body weight and body temperature are taken over the next 5 days. The symptoms of abrupt discontinuation of the drug are manifest as significantly reduced appetite, weight loss, and drop in body temperature.
• This model is suitable for detecting the effects across a broad range of drug classes including opiates, antidepressants, and benzodiazepines. Abrupt withdrawal of the present compounds tested did not produce any changes in these parameters indicating that the compounds do not produce physical dependence and supporting their suitability for chronic use to treat mood disorders such as depression.
• the compounds encompassed herein may also be used as a combination therapy, e.g., combining the treatment with other antidepressants such as benzodiazepines (e.g., alprazolam, diazepam, lorazepam, clonezepam), selective serotonin re-uptake inhibitors (SSRI) (e.g., citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, zimelidine, vilaxodone), serotonin norepinephrine reuptake inhibitors (SNRI) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran), monoamine oxidase inhibitors (e.g., phenelzine, moclobemide), tricyclic antidepressants (e.g., trimipramine, imipramine), tetracycl
• atypical antidepressants e.g., bupropion
• acetylcholinesterase inhibitors e.g., donepezil, galantamine, rivastigmine
• atypical antipsychotics e.g., risperidone, aripiprizole, quetiapine, olanzapine
• hormones such as estrogen and progestogen.
• neurode outgrowth-responsive any disease state, disorder, or condition which may be ameliorated by enhancement of neurite outgrowth.
• diseases, disorders, and conditions are referred to herein as "neurite outgrowth-responsive.”
• the neurite outgrowth-responsive disease is a neurodegenerative disease.
• the neurodegenerative disease is multiple sclerosis or Parkinsonian related disorders.
• the neurodegenerative disease is multiple sclerosis.
• the neurodegenerative disease may involve a condition which involves neural damage including wound healing, spinal cord injury, peripheral nerve disorders.
• a sub-threshold disease, condition, state, disorder or trauma is a sub-threshold disease, condition, state, disorder or trauma.
• the disease, condition, state, disorder, or trauma is defined by its symptoms.
• the compounds contemplated herein are useful in ameliorating the symptoms of a disease, condition, state, disorder, or trauma of the CNS.
• trauma this includes stroke, brain haemorrhage, or another condition or event of the systemic vasculature which affects the CNS.
• the symptoms of a disease, condition, state, disorder, or trauma of the CNS would be familiar to those skilled in the art. Examples of such symptoms include mood disorders, such as depression.
• the compounds herein are used in the treatment of depression attributed to (or associated with) a neurodegenerative disease in the subject.
• the compounds encompassed herein may also be used as therapy, e.g., combining the treatment with other neurodegenerative treatments, such as acetylcholineesterase inhibitors (e.g., Aricept, Exelon), and treatments for multiple sclerosis (e.g., Avonex, Betaseron, Copaxone, Tysabri, Gilenya).
• acetylcholineesterase inhibitors e.g., Aricept, Exelon
• multiple sclerosis e.g., Avonex, Betaseron, Copaxone, Tysabri, Gilenya
• the neurodegenerative disease is not Alzheimer's disease. In another embodiment, the neurodegenerative disease is not a neurodegenerative disease arising from cerebral ischemia.
• the neurodegenerative disease is not Alzheimer's disease, Pick's disease, Lewy body dementia, Basal ganglia Huntington's disesase, Parkinson's disease, Brainstem & cerebellum atrophy, Freidrich's ataxia, multiple system atrophy, types 1 , 2, 3, 6, 7 spinocerebellr ataxia, Motor amyotrophic lateral sclerosis, familial spastic paraparesis, spinal muscular atrophy, or spinal & bulbar muscular atrophy.
• a method of treatment of disorders of the central nervous system comprising the administration of an effective amount of at least one compound of formula (la) or (lb), or a salt thereof, to a subject in need thereof.
• an anxiety disorder is classified as one of the following: • panic disorder,
• OCD obsessive-compulsive disorder
• GAD generalized anxiety disorder
• ASD acute stress disorder
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of a panic disorder.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of obsessive-compulsive disorder (OCD).
• OCD obsessive-compulsive disorder
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of post-traumatic stress disorder (PTSD).
• PTSD post-traumatic stress disorder
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of social phobia (or social anxiety disorder - SAD).
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of specific phobias.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of substance-induced anxiety disorder.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of acute stress disorder (ASD).
• ASD acute stress disorder
• GAD generalized anxiety disorder
• Generalised anxiety disorder criteria include:
• a subject to be treated with a compound of formula (la) or (lb) as described herein may be identified by one or more of the above criteria for generalized anxiety disorder.
• the compounds of formula (la) or (lb) as described herein may be used to treat or prevent one or more symptoms associated with an anxiety disorder.
• Each anxiety disorder has different symptoms, but all the symptoms cluster around excessive, irrational fear and dread.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of depression, for instance, major depressive disorder.
• Major depressive disorder criteria include:
• At least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: at least one of the symptoms is either
• the symptoms are not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism).
• a substance e.g. a drug of abuse, a medication
• a general medical condition e.g., hypothyroidism
• a subject to be treated with a compound of formula (la) or (lb) as described herein may be identified by one or more of the above criteria for major depressive disorder.
• the compounds of formula (la) or (lb) as described herein may be used to treat or prevent one or more symptoms associated with depression.
• disorders for which compounds of formula (la) or (lb) as described herein may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; hearing disorders, including tinnitus and age-related hearing impairment; urinary incontinence; and the effects of substance abuse or dependency, including alcohol withdrawal.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of cerebral ischemia.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of disorders of the circadian rhythm.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of pain and nociception.
• the compounds of formula (la) or (lb) as described herein may be used in the treatment of Alzheimer's disease.
• a treatment effective amount is a therapeutically effective amount or a prophylactically effective amount.
• therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.
• the therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure, or treat the disease or disorder or one or more of its symptoms.
• prophylactically effective amount refers to an amount effective in preventing or substantially lessening the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder before it is acquired or reducing the severity of one or more of its symptoms before the symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease or symptom) and secondary prophylaxis (whereby the disease or symptom has already developed and the patient is protected against worsening of this process). As used herein, the term “effective amount” relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity.
• Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
• the dosage may be in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage.
• the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage.
• the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage.
• the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
• the method comprises administering to a subject in need thereof the present compound in a dosage to provide an effective amount in vivo that will enhance neurite outgrowth (neurogenesis), including, but not limited to the acute stages of treatment (e.g., within 1, 2, 3, or 4 weeks from the commencement of treatment).
• an effective amount in vivo has an in vitro equivalent concentration that is sufficient to increase neurite outgrowth by at least 5%, at least 10%, at least 20%, or at least 50% in a neurite outgrowth assay, for example, a neurite outgrowth assay described herein. Methods of determining an in vitro equivalent concentration of the present compounds would be familiar to the skilled artisan.
• a blood sample is taken and assayed by HPLC, ELISA, gas chromatography, or by other suitable assay to determine the concentration per ml of blood.
• An equivalent effective concentration can then be used in an in vitro assay once factors such as the weight of the subject, the appropriate blood volume of the subject and the appropriate rate of diffusion of the present compound across the blood-brain barrier are taken into account.
• an approximate in vivo effective amount can be determined for a subject by extrapolating the in vitro concentration to an in vivo equivalent.
• Factors such as the weight of the subject, the appropriate blood volume of the subject and the appropriate rate of diffusion of the present compound across the blood-brain barrier may be used to extrapolate an in vivo effective amount and hence the appropriate dosage amount that would give rise to said in vivo effective amount.
• treatment with the present compounds may be continued throughout the treatment period or it may be ceased or replaced with traditional therapeutic compounds.
• Methods of determining the effective amount of the present compounds that is required for enhancing neurite outgrowth (neurogenesis) in vivo would be familiar to those skilled in the art.
• enhancement of neurogenesis can be determined by measuring a symptom of the CNS disorder including, but not limited to, cognitive impairment, degree and frequency of seizures or tremors, motordysfunction, headaches and mood (e.g., degree of happiness).
• administer in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the animal in need of treatment.
• administration and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
• an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
• the compounds of the invention may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
• Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject. It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
• the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
• the active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
• the formulation of such compositions is well known to those skilled in the art.
• the composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
• the compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents.
• the active agents may be administered separately or in conjunction.
• the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
• an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed.
• compounds described herein can be administered to a subject in a dosage range from between about 0.01 to about 10,000 mg/kg body weight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01 to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg body weight/day, about 0.01 to about 500 mg/kg body weight/day, about 0.01 to about 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg body weight/day.
• an effective amount can be achieved using a first amount of a compound of Formula (I), (la), or (lb) or a pharmaceutically acceptable salt thereof, and a second amount of an additional suitable therapeutic agent.
• the compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone).
• the compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose).
• the compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose.
• the compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof can be administered in a sub-therapeutic dose, while the additional therapeutic agent is administered in an effective amount.
• the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
• the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
• Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
• coadministration also encompasses use of each compound in a sequential manner in either order.
• co-administration involves the separate administration of the first amount of a compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof, and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect.
• the period of time between each administration which can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life, and kinetic profile.
• a compound of formula (I), (la), or (lb) as described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent can be administered in any order within about 24, hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
• a first therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
• a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours* 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy to a subject.
• a second therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
• therapeutic agents that may be combined with a compound of this disclosure, either administered separately or in the same pharmaceutical composition, include, but are not limited to, muscle relaxants, anticonvulants, hypnotics, anaesthetics, analgesics, cholinergics, antidepressants, mood stabilisers, anxiolytics, etc.
• the second therapeutic agent is a SSRI selected from the following: citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)
• citalopram Cyclona, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital
• escitalopram (Lexapro, Cipralex, Seroplex, Esertia)
• paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor,
• the second therapeutic agent is a tetracyclic antidepressant (TeCA) selected from the group consisting of:
• Amoxapine (Amokisan, Asendin, Asendis, Defanyl, Demolox, Moxadil)
• the second therapeutic agent is a serotonin-noradrenaline reuptake inhibitor (SNRI) selected from the group consisting of:
• Duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela) Milnacipran (Ixel, Savella, Dalcipran, Toledomin)
• the second therapeutic agent is a Noradrenaline reuptake inhibitor NRI) selected from the group consisting of:
• Atomoxetine (Tomoxetine, Strattera, Attentin)
• the second therapeutic agent is a monoamine oxidase inhibitor (MAOI) selected from the group consisting of:
• Nialamide (Niamid)
• Furazolidone (Furoxone, Dependal-M)
• Tranylcypromine (Parnate, Jatrosom) Brofaromine (Consonar)
• the second therapeutic agent is a tricyclic antidepressant (TCA) selected from the group consisting of:
• Amitriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Sarotex, Lentizol)
• Desipramine Napramin, Pertofrane
• Doxepin (Aponal, Adapine, Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, Silenor)
• Imipramine Antideprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil
• the compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
• enteral e.g., oral
• parenteral intravenous, intramuscular, intra-arterial, intramedullary
• intrathecal subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal
• topical as by powders, ointments, creams, and/or drops
• mucosal nasal,
• Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site.
• intravenous administration e.g., systemic intravenous injection
• regional administration via blood and/or lymph supply e.g., via blood and/or lymph supply
• direct administration e.g., direct administration to an affected site.
• the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
• the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
• the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
• the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
• compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous, and intradermal) administration.
• the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired.
• General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington 's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
• compositions described herein can be prepared by any method known in the art of pharmacology.
• preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
• compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
• a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
• the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
• Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
• the composition may comprise between 0.1% and 100% (w/w) active ingredient.
• compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
• Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
• Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
• crospovidone cross-linked poly(vinyl-pyrrolidone)
• sodium carboxymethyl starch sodium starch glycolate
• Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulos
• Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcry stall ine cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and
• Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
• antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
• Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
• EDTA ethylenediaminetetraacetic acid
• salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
• citric acid and salts and hydrates thereof e.g., citric acid mono
• antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
• antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
• Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
• Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
• preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 1 15, Germaben II, Neolone, Kathon, and Euxyl.
• the preservative is an anti-oxidant.
• the preservative is a chelating agent.
• Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate.
• pentanoic acid dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.
• Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium Iauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
• Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckt
• Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
• compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., inert diluent, preservative disintegrant (e.g., sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
• a binder e.g., inert diluent, preservative disintegrant (e.g., sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• the active ingredient can be in micro-encapsulated form with one or more excipients.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
• Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• opacifying agents include polymeric substances and waxes.
• Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils ⁇ e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art such as, for example, water or other solvents,
• the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
• compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like.
• suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
• Transdermal patches may also be used to administer the compounds of the invention.
• compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.
• suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.
• compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lypphilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• An injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
• compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
• suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
• Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
• Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
• Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
• Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
• Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
• Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
• pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a provided compound.
• the salts of the provided compounds will be pharmaceutically acceptable salts.
• Other salts may, however, be useful in the preparation of provided compounds or of their pharmaceutically acceptable salts.
• Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. (1977) 66: 1-19, incorporated herein by reference in its entirety.
• a pharmaceutically acceptable salt involves the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
• the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
• a pharmaceutically acceptable salt may have more than one charged atom in its structure. When multiple charged atoms are present in the parent drug, its pharmaceutically acceptable salts will have multiple counter ions and these can be several instances of the same counter ion or different counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms in the parent compound and/or one or more counter ions.
• Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.
• suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
• Quarternary ammonium salts such as N + (Ci
• salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, carbonic, boric, sulfamic, propionic, butyric, hydroxymaleic, mucic, phenylacetic, sulfanilic, aspartic, edetic, stearic, palmitic, oleic, lauric, ascorbic, valeric, perchloric, malonic, p-
• Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
• Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, palmoate (i.e., l , l'-methylene-bis-(2-hydroxy-3-
• Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• the compounds and pharmaceutical formulations described herein may be contained in a kit.
• the kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination.
• one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container.
• the container or containers are placed within a package, and the package can optionally include administration or dosage instructions.
• a kit can include additional components such as syringes or other means for administering the agents, as well as diluents or other means for formulation.
• kits can comprise: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) a container or packaging.
• the kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g. preventing or treating one or more of the diseases and disorders described herein).
• the kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents described herein for co therapy use, a pharmaceutically acceptable carrier, vehicle or diluent.
• the pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.
• a kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
• the container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.
• Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
• the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
• the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
• a "daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day.
• a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another or more compositions of the kit can consist of several tablets or capsules.
• a kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen.
• a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed.
• a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
• pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group (for instance at the CR' position) is converted into an ester, such as an acetate or phosphate ester, or where a free amino group is (for instance at the CR' position) converted into an amide (e.g., a-aminoacid amide).
• Procedures for esterifying, e.g. , acylating, the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
• the compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g., hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
• compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
• the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres e.g.; greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
• Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, e.g., chromatography, or use of a resolving agent.
• the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention.
• the synthetic methods and processes described herein to prepare the compounds of the present invention are amenable to solid phase synthetic techniques and/or combinatorial chemistry to produce individual compounds or libraries of compounds.
• Example 2 A mixture of Example 2 (0.98g, 2.4 mmol), 2M KOH aq (3.6 ml, 7.2 ml) and 18-crown-6 ether (0.63 g, .0.24 mmol) in EtOH (50 ml) was refluxed for 30 hours under N 2 . After cooling to room temperature the organic solvent was removed under reduced pressure and the residue was diluted to 5 ml with H 2 0, filtered and the filtrate was acidified to pH ⁇ 5 with 10% aqueous citric acid. The precipitate formed was filtered off, washed with H 2 0, small volume of EtOH, Et 2 0 and evaporated under reduced pressure to give pure product as a deep yellow solid (0.89 g, 93%).
• Example 1 NaBH(OAc) 3 (91.4 mg, 0.43 mmol) was added to a solution of Example 1 (80.8 mg, 0.26 mmol), cyclopentanone (25 ⁇ , 0.28 mmol) and glacial AcOH (100 ⁇ ) in anhydrous 1,2- dichloroethane (3 ml). The resulting mixture was stirred overnight at room temperature under N 2 . The mixture was quenched by addition of sat.NaHC0 3 aq (5 ml) and extracted with EtOAc. The extracts were dried over anhydrous, MgS0 4 , filtered and the filtrate evaporated to dryness under reduced pressure.
• Example 1 (88.4 mg, 0.29 mmol), 6-(trifluoromethyl)nicotinaldehyde (53.7mg, 0.31 mmol) and glacial AcOH (100 ⁇ .) in anhydrous 1 ,2-dichloroethane (3 ml).
• the resulting mixture was stirred overnight at room temperature under N 2.
• the mixture was quenched by addition of sat.NaHC0 3a q (5 ml) and extracted with EtOAc.
• the extracts were dried over anhydrous MgS0 4 , filtered and the filtrate evaporated to dryness under reduced pressure.
• Triethylamine (20 ⁇ , 0.14 mmol) was added to a solution of Example 1 (18.8 mg, 0.06 mmol) and isonicotinoyl chloride hydrochloride (1 1.9 mg, 0.07 mmol) in anhydrous DCM (1 mL). The resulting mixture was stirred overnight at room temperature under N 2 . The mixture was quenched by addition of sat.NaHC0 3aq (1 ml) and extracted with EtOAc. The extracts were dried over anhydrous MgS0 4 , filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by colurhn chromatography (Si0 2 , 20- 70% EtOAc/DCM) (22.0 mg, 88%).
• Triethylamine (20 ⁇ , 0.14 mmol) was added to a solution of Example 1 (27.8 mg, 0.09 mmol) and benzoyl chloride (15 ⁇ , 0.13mmol) in anhydrous DCM (1 mL). The resulting mixture was stirred for 1 hour at room temperature under N 2 The mixture was quenched by addition of sat.NH 4 Cl aq (1 ml) and extracted with EtOAc. The extracts were dried over anhydrous MgS0 4 , filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by column chromatography (Si0 2 , 80% Et 2 0/n-hexane) (28.2mg, 76%).
• Phenyl isocyanate (20 ⁇ , 0.184 mmol) was added to a solution of Example 1 (50.1 mg, 0.164 mmol) and triethylamine (30 ⁇ iL, 0.215 mmol) in anhydrous 1 ,2-dichloroethane (2 mL). The resulting mixture was stirred at 65°C for 18 hours under N 2 . The reaction was evaporated to dryness and the residue purified by column chromatography (Si0 2 , 40-60% Et 2 0/DCM) (23.3mg, 33.4%).
• Methanesulfonyl chloride (15 ⁇ , 0.194 mmol) was added to a solution of Example 1 (48.0 mg, 0.157 mmol) and triethylamine (30 ⁇ -, 0.215 mmol) in anhydrous DCM (2 mL). The resulting mixture was stirred for 1 hour at room temperature under N 2 . The mixture was quenched by addition of sat.NaHC0 3a q (1 ml) and extracted with EtOAc. The extracts were dried over anhydrous MgS0 4 , filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by column chromatography.
• Example 11 (Si0 2 , 10-40% Et 2 0/DCM) to afford Example 11 (51.4 mg, 70.8%).
• the suspension was triturated with a 10-ml pipette and using a 21G needle and syringe, and centrifuged at 350 x g for 10 min at room temperature.
• the pellet of dissociated cells was resuspended in medium consisting of Neurobasal (Gibco) supplemented with 2% B27 supplement (Gibco), 0.5 mM L-Glutamine (Gibco), an antibiotic-antimicotic mixture.
• Viable cells were counted in a Neubauer cytometer using the trypan blue exclusion test (Sigma). Cells were seeded on the basis of 30000 cells per Petri dish ( ⁇ 35 mm, Nunc) precoated with poly-L-lysine. a. Treatment
• Examples 1-9 show a significant enhancement in neurite outgrowth in Biological Protocol 1., at concentrations of 100 nM or less.
• the light dark paradigm is based on a conflict between the innate aversion of rodents to brightly illuminated areas and on the spontaneous exploratory behaviour of the mice. If given a choice between a large brightly compartment versus a small dark compartment they spontaneously prefer the dark part.
• Anxiolytic compounds have been found to increase the number of entries into the bright compartment and the total time spent there. Anxiogenic compounds were observed to work in the opposite way.
• the apparatus consists of two PVC (polyvinylchloride) boxes (19 x 19 x 15 cm) covered with Plexiglas. One of these boxes is darkened. The other box is illuminated by 100 W desk lamp placed 15 cm above and providing an illumination of about 4400 Lux. An opaque plastic tunnel (5 x 7 x 10 cm) separates the dark box from the illuminated one.
• PVC polyvinylchloride
• Test compounds may be prepared in aqueous vehicle containing 0.5% w/v hydroxypropylmethyl cellulose, 0.5% v/v benzyl alcohol and 0.4% v/v Tween 80. The compounds may be administrated per os 1 hour before the implementation of the test.
• EPM Elevated Plus Maze
• the apparatus is made of polyvinylchloride materials and consists of four equal exploratory arms (45 ⁇ 10 cm) which are all interconnected by a small platform (10 ⁇ 10 cm). Two arms are open and two others are closed with walls (30 cm high). The apparatus is placed 66 cm above the floor. A videotracking system is used to record the test (ViewPoint, France). The video camera is placed at 2.50 m above the equipment and connected to the computer via a video capture card (Pinnacle Systems, France).
• a trial consists of placing an animal on the central platform facing a closed arm.
• the number of entries and the duration spent in open arms are automatically recorded by a videotrack system during an 5 minutes period.
• the Marble Burying test is used as a model for both anxiety and obsessive compulsive disorders. Mice have a natural tendency to bury marbles under the bedding when placed in a cage with rows of evenly spaced marbles on the floor. Suppression of this spontaneous burying has been used as a measure of anxiolytic drug action. Mice pre-treated with benzodiazepines and different classes of antidepressants bury less marbles when compared to the control mice
• the apparatus consists of transparent polycarbonate cages (30 cm x 18 cm x 19 cm) containing a 5 cm layer of fine sawdust bedding and 20 glass marbles (diameter: 1.5 cm) spaced evenly along the walls of the cage. Each animal is placed individually in the cage where it remains for a 20 min test session. On termination of the test session the animals are removed from the cage and the number of marbles at least two-thirds buried in the sawdust is recorded. a. Test compounds and treatment
• the open field (dark) is used to measure the spontaneous motor activity of mice in a quiet, dark environment. This system is useful for discriminating the sedating or stimulating properties of test compounds on spontaneous locomotion and can thus provide a preliminary indication of potentially adverse effects such as sedation.
• the apparatus is an open plexiglass cage (52 x 52 cm) with 40 cm walls.
• the animal's movements are tracked by a computerised video tracking system, consisting of an overhead camera, diode sensors placed underneath the floor of the cage, computer and video analyser software (ViewPoint, France).
• the video camera is placed at 2.50 m above the cage and connected to the computer via a video capture card (Pinnacle Systems, France).
• the video tracking system is set in a way that the floor of the OF is divided into nine equal squares. The total number of crossed squares and the total walked distance are recorded.
• Each animal is singly placed in a corner of the apparatus and its locomotor activity is automatically recorded over a period of 20 minutes.
• the forced swim test is the most widely used paradigm for the evaluation of potential antidepressant effect of drugs.
• Animals placed in a container filled with water show periods of increased swimming activity and periods of relative immobility.
• Immobile posture reflects a state of tiredness, fatigue, reduced stamina or a lowered mood (hopelessness) similar to the core symptoms observed in depressed patients and in individuals under intense stress.
• Clinically active anti-depressants have been found to delay the onset of the first phase of immobility and to reduce the total time of relative immobility.
• the test has some predictive value for anti-depressant drugs.
• the apparatus consists of a glass cylinder (height 35 cm; diameter 24 cm) filled with water (depth: 25 cm, temperature: 25 ⁇ 1 °C).

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