WO2007098356A1 - Congeners of milnacipran as monoamine re-uptake - Google Patents

Congeners of milnacipran as monoamine re-uptake Download PDF

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Publication number
WO2007098356A1
WO2007098356A1 PCT/US2007/062187 US2007062187W WO2007098356A1 WO 2007098356 A1 WO2007098356 A1 WO 2007098356A1 US 2007062187 W US2007062187 W US 2007062187W WO 2007098356 A1 WO2007098356 A1 WO 2007098356A1
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Prior art keywords
substituted
thiophen
compound
alkyl
aminomethyl
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PCT/US2007/062187
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French (fr)
Inventor
Chen Chen
Brian Dyck
Jonathan Grey
Florence Jovic
Junko Tamiya
Troy D. Vickers
Mingzhu Zhang
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Neurocrine Biosciences, Inc.
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Publication of WO2007098356A1 publication Critical patent/WO2007098356A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates generally to monoamine re-uptake inhibitors and more specifically to serotonin and noradrenaline re-uptake inhibitors, and to methods of treating disorders by administration of such inhibitors to a warm-blooded animal in need thereof.
  • Decreased concentrations of monoamine neurotransmitters are implicated in a number of disorders of the central or peripheral nervous system. These disorders include depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders.
  • serotonin also known as 5-hydroxytryptamine or 5-HT
  • noradrenaline noradrenaline
  • dopamine dopamine
  • these disorders include depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders.
  • neurotransmitters travel from the terminal of a ' neuron across a small gap (i.e., the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of the neurotransmitter back into the presynaptic neuron. Enhancing the . amount of one or more of these monoamines has been shown to have utility in the treatment of disorders such as depression, anxiety, neuropathic pain, fibromyalgia, urinary incontinence and attention deficit hyperactivity disorder (ADHD).
  • One advantageous method to increase the amount of a monoamine or monoamines is by administering a re-uptake inhibitor which has a particular selectivity/affinity to.one or more monoamine transporters.
  • Selective serotonin re-uptake inhibitors function by inhibiting the reuptake of serotonin by afferent neurons.
  • SSRIs well known in the art include sertraline (Zoloft®), fluoxetine (Prozac®) and paroxetine (Paxil®).
  • Selective noradrenaline (or norepinephrine) re-uptake inhibitors function by increasing noradrenaline levels and include drugs known in the art including reboxetine (Edronax®), atomoxetine (Strattera®), and bupropion (Wellbutrin®).
  • Dual serotonin-noradrenaline reuptake inhibitors which inhibit the reuptake of both serotonin and norepinephrine include venlafaxine (Effexor®), duloxetine (Cymbalta®), milnacipran and imipramine (Tofranil®).
  • inhibitors may advantageously possess characteristics such as enhanced selectively toward one or more monoamine- 'transporters, enhanced pharmacokinetic properties (such as half-life, bioavailability, and minimal interaction with liver enzymes such as the cytochrome P450 family), and/or enhanced potency.
  • pharmaceutical compositions containing such monoamine re-uptake inhibitors as well as methods relating to the use thereof to treat, for example, conditions caused by low concentrations of a monoamine or monoamines.
  • the present invention fulfills these needs, and provides other related advantages.
  • this invention is generally directed to monoamine re-uptake inhibitors, in particular, serotonin and/or noradrenaline reuptake inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the monoamine re-uptake inhibitors of this invention are compounds having the following general structure (I):
  • the monoamine reuptake inhibitors of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders of the central or peripheral nervous system in both men and women, as well as a mammal in general (also referred to herein as a "subject").
  • disorders include, but are not limited to, depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, . fibromyalgia and.sleep.: disorders.
  • Conditions of particular interest which may be treated by administration of compounds.
  • the compounds may. also be useful in combination with antipsychotic agents for the treatment of schizophrenia, as well as in combination with dopaminergic agents for use in Parkinson's disease. ' ' . . .
  • the methods of this invention include administering an effective amount of a monoamine re-uptake inhibitor, preferably in the form of a pharmaceutical composition, to a mammal in need thereof.
  • a monoamine re-uptake inhibitor preferably in the form of a pharmaceutical composition
  • pharmaceutical compositions are disclosed containing one or more monoamine re-uptake inhibitors of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. . .
  • the present invention is directed generally to compounds useful as monoamine reuptake inhibitors.
  • the compounds of this invention have the following structure (I):
  • Ri, R 2 are independently H 1 Ci.i O alkyl, Ci.i O alkyl substituted by 1 to 4 R 9 , aryl, aryl substituted by 1 to 4 R 10 , heterocycleC-i ⁇ alkyl, heterocycleC 1-4 alkyl substituted by 1 to 4 R 10 , arylC-i- 4 alkyl, or arylC ⁇ alkyl substituted by 1 to 4 R 10 ; or Ri and R 2 taken together with the nitrogen to which they are attached form a 5-14 member heterocycle or 5-14 member heterocycle substituted by 1 to 4 R 1 O!
  • R ⁇ a , Rs b are independently and at each occurrence, H, F, OH, Ci-4alkyl substituted by 1 to 4 R 9 , substituted by 1 to 4 R 9 ;
  • R 6 is aromatic heterocyclic ring or aromatic heterocyclic ring substituted by 1 to 4 R 10 ;
  • R 7 is H, C ⁇ alkyl, C 1-4 alkyl substituted by 1 to 4 R 9 , F, OH, C 1-4 alkoxy, d ⁇ alkoxy substituted by 1 to 4 R 9 , or phenyl;
  • R 8 is or C-,. 4 alkyl substituted by 1 to 4 R 9 ;
  • R 9 is halo, OH, C 1-4 alkoxy, CN, or NR-IiR 12 ;
  • R 10 is C ⁇ alkyl, halo, OH, C 1-4 alkoxy, CN, or NR 11 R 12 ;
  • R 1 - I , R 12 are independently and at each occurrence, H or C 1-4 alkyl; and n is 1 or 2.
  • Alkyl and C 1-10 alkyl mean a straight chain or branched, noncyclic or. cyclic,, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the terms “lower alkyl” and “Ci. 4 alkyl” have the same meaning as alkyl but contain from 1 to 4 carbon atoms.
  • Representative saturated straight chain alkyls include methyl,.
  • saturated branched alkyls include isopropyl, sec-butyl, isobutyl, terf-butyl, isopentyl, and the like.
  • saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHa-cyclopropyl, -CH ⁇ cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Cyclic alkyls include di- a ⁇ d poly-homocyclic rings such as decalin and adamantyl.
  • Unsaturated alkyls contain at least ohe double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or “alkynyl", respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1- butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.
  • Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl. having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH 2 ) 2 Phenyl, -(CH 2 )3Phenyl, -CH(phenyl) 2 , and the like.
  • 5-6 Member carbocycle means a ring composed of 5 or 6 carbon atoms, either saturated, unsaturated or aromatic.
  • Heteroaryl means an aromatic heterocycle ring of 5- to 10-members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
  • Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazol
  • Heterocycle (also referred to herein as a “heterocycle ring”) means a 5- to 7- membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Heterocycles include heteroaryls as defined above.
  • heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrqpyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, . tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • HeterocycleCi_ 4 alkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl, -CH 2 pyridyl and the like.
  • Aromatic heterocyclic ring means heterocycle wherein at least one ring of the heterocycle is aromatic and includes heteroaryls and nonaromatic heterocycles which are fused to aryl or heteroaryl moieties. .
  • aromatic heterocyclic ring includes 2,3-dihydro-benzofuran, 1,3-dihydro-isoindole, 2,3-dihydro-indole, dihydro-4H-thieno[3,2- c]pyridine, 3,4-dihydro-2H-quinoline, 3,4-dihydro-1 H-isoquinoline, benzo[1,3]dioxple, and the like.
  • Halogen or "halo" means fluoro, chloro, bromo and iodo.
  • Alkoxy means an alkyl moiety attached through an oxygen bridge (Ae., -O-alkyl), such as -O-methyl, -O-ethyl, and the like. has the same meaning as alkoxy but contains from 1 to 4 carbon atoms.
  • substituted means any of the above groups (Ae., alkyl ' , carbocycie, aryl, or heterocycle) wherein at least one hydrogen atom is replaced with a substituent.
  • R Sa and R 5b of structure (I) are H and n is 1 or 2, as shown in structures (II) and (III), respectively.
  • R ⁇ of structure (I) is H, F and methyl, as shown in structures (IV), (V) and (IV), respectively.
  • R 5a> R 5b and R 7 of structure (I) are H, n is ,1 , . and R 3 and R 4 are both H or both C-i ⁇ alkyl (specifically methyl) as. shown. in. structures (VIl), and; (VIII), : respectively.
  • R 7 of structure (I) is H
  • R 1 is C ⁇ alkyl (specifically ethyl)
  • R 2 is (specifically benzyl) as showri in structure (IX)
  • R 7 of structure (I) is H while both R 1 and R 2 are C 1-4 alkyl (specifically propenyl and propynyl) as shown in structure (X).
  • R 1 and R 2 taken together with the nitrogen to which they are attached form a heterocycle such as 3,4-dihydro-2H-quinolin-1-yl as shown in structure (Xl) and form a substituted heterocycle such as 4-phenyl-piperidin-1-yl as shown in structure (XII).
  • R 6 of structure (I) is aromatic heterocyclic rings thiophen-2-yl and benzo[1,3]dioxol-5-yl as shown in structures (XIII) and (XIV), respectively.
  • the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.
  • the compounds of structure (I) above may be made by the following reaction schemes, wherein all substituents are as defined above unless indicated otherwise.
  • Substituted acetonitrile / may be condensed with epichlorohydrin under basic conditions (such as NaHMDS, THF). Alkaline hydrolysis of the nitrile (such as reflux in potassium hydroxide in ethanol) followed by acidic workup gives the lactone //.
  • Substituted acetic acid /77 is alkylated with an allyl halide (such as allyl bromide with cesium, carbonate as base) yielding /V which is converted to alpha diazo ester with reagent acetomidobenzensulfonylazide under basic conditions (DBLJ) to give v.
  • allyl halide such as allyl bromide with cesium, carbonate as base
  • Lactone ring // is opened by reaction with potassium phthalimide in hot DMF to give vi.
  • Ring opening of // with a lithium salt of an amine (such as produced from an amine and tert-butyl lithium at -78 0 C) produces alcohol x.
  • x is converted to azide xi using sodium azide followed by reduction with a platinum or palladium catalyst under hydrogen atmosphere yielding ix.
  • Monoalkylation is performed first by BOC protection with di-fe/t-butyl dicarbonate followed by alkylation with an alkyl halide to yield xii after deprotection. Without BOC protection, reductive alkylation with an appropriate aldehyde or ketone or acylation with acid chloride or amino acid derivative gives xii.
  • Alcohol x is oxidized by, for example, Swem oxidation to give aldehyde xii.
  • Particular individual compounds of the present invention include:
  • the compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
  • Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like).
  • the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
  • prodrugs are also included within the context of this invention.
  • Prodrugs are any covalently bonded carriers that release a compound of.structure .(l), / ⁇ .wvo .when, such .prodrug is . administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent : compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like. .
  • the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms, of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
  • the compounds of this invention and their salts may inhibit the uptake of one or more of the monoamine neurotransmitters serotonin, noradrenaline and dopamine.
  • these compounds and their salts may have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders which are caused by or linked to decreased neurotransmission of one or more of these monoamines. These disorders include disorders of the central and/or peripheral nervous system.
  • the compounds of the present invention may selectively inhibit the re-uptake of serotonin and noradrenaline over the re-uptake of dopamine.
  • Other compounds of the present invention may selectively inhibit noradrenaline over both serotonin and dopamine.
  • compounds of the present invention may selectively inhibit the re-uptake of serotonin over both noradrenaline and dopamine.
  • conditions which may be treated by compounds of the current invention include, but are not limited to, depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders.
  • Pain may generally be divided into two categories: acute pain and chronic (or persistent) pain.
  • Acute pain is self-limiting and generally results from injured or diseased tissue and is considered nociceptive in nature. Examples of nociceptive pain include post-operative pain, pain associated with trauma, and the pain of arthritis.
  • Chronic pain can be defined as pain that persists beyond the usual course of the acute injury or disease. Chronic pain is generally neuropathic in nature and can be continuous or recurring. Chronic pain is generally caused by prolonged and sometimes permanent dysfunction of the central or peripheral nervous system.
  • Examples include post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy / causalgia (nerve trauma), components of cancer pain, phantom limb pain, entrapment neuropathy (e.g., carpal tunnel syndrome), and peripheral neuropathy (widespread nerve damage due to, for instance, diabetes or excessive alcohol use).
  • post herpetic or post-shingles
  • reflex sympathetic dystrophy / causalgia nerve trauma
  • components of cancer pain phantom limb pain
  • entrapment neuropathy e.g., carpal tunnel syndrome
  • peripheral neuropathy widespread nerve damage due to, for instance, diabetes or excessive alcohol use.
  • a compound of structure (I) may be administered along with an antipsychotic to treat schizophrenia.
  • the antipsychotic may be typical or atypical.
  • a compound of structure (I) could also be administered with a dopaminergic agent such as levodopa to treat Parkinson's disease and/or the side effects associated with such therapy. . ⁇ ⁇
  • compositions containing one or more monoamine re-uptake inhibitors are disclosed.
  • the compounds of the present invention may be formulated as pharmaceutical compositions.
  • Pharmaceutical compositions of the present invention comprise a monoamine re-uptake inhibitor of the present invention and a pharmaceutically acceptable carrier and/or diluent.
  • the monoamine re-uptake inhibitor is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve monoamine re-uptake inhibition, and preferably with acceptable toxicity to the patient.
  • Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a monoamine re-uptake inhibitor, diluents, dispersing and surface active agents, binders, and lubricants.
  • One skilled in this art may further formulate the monoamine re-uptake inhibitor in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
  • the present invention provides a method for treating disorders of the central or peripheral nervous system.
  • Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
  • "treat” includes prophylactic administration.
  • Such methods include systemic administration of a monoamine re-uptake inhibitor of this invention, preferably in the form of a pharmaceutical composition as discussed above.
  • systemic administration includes oral and parenteral methods of administration.
  • suitable pharmaceutical compositions of monoamine re-uptake inhibitors include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions.
  • compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the monoamine re-uptake inhibitor, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
  • the monoamine re-uptake inhibitors of this invention may be assayed by the methods disclosed in Examples 13 to 17, while the following Examples 1 to 12 disclose the synthesis of representative compounds of this invention.
  • Agilent 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCl); .
  • HPLC column Phenomenex Synergi-Max RP 8OA, 2.0 x 50 mm column;
  • HPLC gradient 1.0 n ⁇ L/minute, from 10% acetonitrile in water to 90% acetonitrile in water in 2.5 minutes, maintaining 90% for 1 minute. Both acetonitrile and water have 0.025% TFA.
  • Agilent 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI);
  • HPLC column Phenomenex Synergi-Max RP 80A, 2.0 x 50 mm column;
  • Agilent 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (electrospray);
  • HPLC column XTerra MS, C 18 , 5 ⁇ , 3.0 x 250 mm column;
  • HPLC gradient 1.0 mL/minute, from 10% acetonitrile in water to 90% acetonitrile in water in 46 minutes, jump to 99% acetonitrile and maintain 99% acetonitrile for 8.04 minutes. Both acetonitrile and water have 0.025% TFA.
  • Agilent 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI) and Berger FCM 1200 CO 2 pump module;
  • HPLC column Berger Pyridine, PYR 6OA, 6 ⁇ , 4.6 x 150 mm column;
  • HPLC gradient 4.0 mL/minute, 120 bar; from 10% methanol in supercritical CO 2 to 60% methanol in supercritical CO 2 in 1.67 minutes, maintaining 60% for 1 minute. Methanol has 1.5% water. Backpressure regulated at 140 bar.
  • HPLC gradient 1.5 mL/min, from 5% acetonitrile in water to 90% acetonitrile in water in
  • Agilent 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI); . . ' . .. - .
  • HPLC column BHK Laboratories, Inc. alpha C18 (O/B), 4.6 X 150 mm column;
  • UV detector and a PE Sciex APH 50EX mass detector UV detector and a PE Sciex APH 50EX mass detector
  • Dionex P680A and P680P pumps Dionex PAD 100 photodiode array detector, Jasco CD 2095 plus chiral detector, Gilson 215 liquid handler.
  • Analytical Columns are 0.46 x 25 cm, 5 ⁇ m; preparative columns are 2 x 25 cm, 5 ⁇ m.
  • Step 1A (1R,5R)-1-Thiophen-2-yl-3-oxa-bicyclo[3.1.01hexan-2-one (1-1)
  • the material was extracted (3 x 100 mL dichloromethane and 3 x 100 mL ethyl acetate) and the combined organic fractions were concentrated under reduced pressure.
  • the resulting black tar residue was washed twice with aqueous sodium bicarbonate (100 mL) and twice with brine (50 mL).
  • Step 2A AIIvKI H-lndol-S-vhacetate (2aV
  • Step 2B fert-Butyl 3-(Allyloxycarbonyl)methylindole-1-carboxylate (2b> : Ester 2a (1.04 g, 4.83 mmol) was dissolved in acetonitrile (20 ml_) and treated with di-tert-butyl dicarbonate (1.27 g, 5.82 mmol) and dimethylaminopyridine (DMAP 59 mg). The mixture was stirred for 1 h, diluted with ethyl acetate (75 mL), and then washed with 0.1 N HCI (75 mL), water (2 x 50 ml_), and aqueous sodium chloride (2 x 50 mL). The mixture was dried (MgSO 4 ) and concentrated to afford 1.45 g (95%) of 2b as an amber oil: LC-MS 216 (MH+-100).
  • Ester 2b (1.43 g, 4.52 mmol) and p-acetamidobenzenesulfonyl azide (1.16 g, 4.83 mmol) were dissolved in acetonitrile (8 mL).
  • DBU (0.72 mL, 4.8 mmol) in acetonitrile (4 mL) was added over 30 minutes and stirring was continued for 16 h.
  • the mixture was poured into aqueous ammonium chloride (40 mL) and extracted twice with ethyl acetate (50 mL). The combined extracts were washed with water (3 x 50 mL) and aqueous sodium chloride (50 mL), dried (MgSO 4 ), and concentrated.
  • the residue was purified by flash chromatography (elution with 8% ethyl acetate in hexanes) to afford 0.70 g (46%) of 2c as red crystals.
  • Step 2D fert-Butyl 3-(2-Oxo-3-oxa-bicyclor3.1.0lhex-1-yl)indole-1-carboxylate (2-1)
  • Step 3A AIIvI 5-Chloro-3-methylbenzorblthiophene-2-yl)acetate (3b)
  • Step 3B S-Chloro-S-methylbenzorblthiophene ⁇ -vO-S-oxa-bicyclore.i .OIhexan-2-one (3-1 )
  • Step 4A (1 R,2R)-2-(1.3-Dioxo-1 ,3-dihvdroisoindol-2-ylmsthylV1-thiophene-2-ylcvclopropanecarboxylic acid (4a)
  • Step 4B 2-1 ⁇ 1 R.2R)-2-(1.S-Dihvdroisoindole- ⁇ -carbonvD- ⁇ -thiophene- ⁇ -ylcvclopropylmethyll-isoindole- 1.3-dione (4c)
  • Step 4C 2-K1 R.2R)-2-Aminomethyl-1-thiophen-2-ylcvclopropyl)-(1 ,3-dihvdroisoindol-2-yl)methanone (4-1 )
  • Step 5A (1 S.2f?)-2-Hvdroxymethyl-1-thiophen-3-yl-cvclopropanecarboxylic acid diethylamide (5a)
  • Step 5B (1S.2RV2-Azidomethyl-1-thiophen-3-yl-cvclopropanecarboxylicacid diethylamide (5b)
  • triphenylphosphine 620 mg, 2.36 mmol
  • carbon tetrabromide 790 mg, 2.38 mmol
  • 5a 204 mg, 0.805 mmol
  • dry DMF 4 mL
  • the reaction mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere.
  • the mixture was cooled to 0 0 C, sodium azide (158 mg, 2.43 mmol) added and the solution stirred at room temperature for 4 hours under a nitrogen atmosphere. Water was added (10 mL) and almost all solvents removed in vacuo.
  • the oily/aqueous residue was dissolved in ethyl acetate (50 mL) and a solution of saturated aqueous sodium chloride (50 mL).
  • the biphasic mixture was placed in a separatory funnel, the layers separated and the aqueous layer extracted with fresh portions of ethyl acetate (2 x 50 mL).
  • the extracts were combined and washed with a solution of saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and solvent removed /n vacuo to give an oil.
  • Step 5C (1R,2SV2-Diethylcarbamoyl-2-thiophen-3-yl-cvcloDropylmethylammonium trifluoroacetate (5-
  • Step 6A (H R2Sy2-Diethylcarbamoyl-24hiophen ⁇ 3-yl-cvclopropylmethyl)methylammonium . trifluoroacBtate (6-1)
  • This oil (0.142 mmol) was dissolved in THF (1 mL) and sodium hydride (60% dispersion in mineral oil, 50 mg, 1.2 mmol) added. The mixture was stirred at room temperature for 1.5 hours, lodomethane (10 ⁇ L, 0.161 mmol) was added and the reaction stirred for 20 hours at room temperature in a sealed vial. Methanol (1 mL) was added, all solvents removed under a stream of nitrogen gas, water (1 ml.) added and the solution extracted into ethyl acetate (3 x 2mL). The combined extracts were concentrated and purified by preparative TLC using an eluting solvent of 1 :1 hexanes: ethyl acetate.
  • Step 7A (M R ⁇ SV ⁇ -Diethylcarbamoyl ⁇ -thiophen-S-yl-cvcloDropylmethvD-dimethylammonium trifluoroacetate (7-1)
  • Step 8A Diethyl (1R.2Ry2-Aminomethyl-1-(5-bromothiophen-2-yl)cyclopropranecarboxamide (8-1) To a solution of the starting material 8a (60 mg, 0.16 mmol) in 1 mL of DMF was added a solution of N-bromosuccinimid ⁇ (NBS 1 31 mg, 1.1 eq) in 1 mL of DMF. The resulting solution was stirred at room temperature overnight with some protective foil wrapped around the flask to avoid degradation.
  • N-bromosuccinimid ⁇ N-bromosuccinimid ⁇
  • Step 1OA Diethyl (1 R,2R)-2-Aminomethyl-1-(4,5-dichlorothiophen-2-v0cvclopropranecarboxamide (10- 1) and Diethyl (1R,2R)-2-Aminomethyl-1-(3A5-trichlorothiophen-2 ⁇ 0cvclopropranecarboxamide (10-2)
  • Step 11 A Diethyl (1 R,2RV2-r(Aminoacetylamino)methv ⁇ -i4hiophen-2-ylcvclopropranecarboxamide (11-11
  • Step 12A Diethyl (1 Rv2R)-2-Formyl-1-thiophen-2-ylcvclopropranecarboxamide C ⁇ 2b)
  • Step 12B Diethyl (1 R,2R)-2-((S.RV1-Hvdroxy-2-nitroethylH-thiophen-2-ylcyclopropranecarboxamide (12c) ⁇
  • Step 12B Diethyl (1 R ⁇ R ⁇ -ffS.R ⁇ -Amino-i-hvdroxy ⁇ thvD-i-thioDhen- ⁇ -ylcvclopropranecarboxamide (12-1)
  • the norepinephrine, dopamine, and serotonin transporters were individually expressed in stably transfected HEK293 cell lines and grown in Dulbecco's Modified Eagles Medium (DMEM) (Cellgro, 15- 013-CV) with the following supplements: 1% HEPES (Cellgro, MT 25-060-CI); 1% L-glutamine (Cellgro, MT 25-005-CI); 1% sodium pyruvate (Cellgro, MT 25-OOOCI); 1% Pen/Strep (Cellgro, MT 30-001-CI); 10% heat-inactivated fetal bovine serum (FBS) (Hyclone, Logan, UT); 250 ⁇ g/ml G418 (Cellgro, 61-234-. RG).
  • DMEM Dulbecco's Modified Eagles Medium
  • the cells were then incubated at room temperature for 20 minutes with varying concentrations of competing liga ⁇ d in a total volume of 150 ⁇ l transport buffer (20 m M HEPES, 122 mM NaCI, 3 rtiM KCl, 1.3 mM CaCI 2 ,.1.2 mM KH 2 PO 4 , 0.4. mM MgSO 4 , 1 mM ascorbic acid, 0.1 mM pargylin ⁇ j 0.1 mM tropolone). Radioligand was then added to the cells for a total volume of 200 ⁇ l, and cells were incubated at room temperature for an additional 20 minutes.
  • transport buffer 20 m M HEPES, 122 mM NaCI, 3 rtiM KCl, 1.3 mM CaCI 2 ,.1.2 mM KH 2 PO 4 , 0.4. mM MgSO 4 , 1 mM ascorbic acid, 0.1 mM pargylin ⁇ j 0.1 mM tropolone
  • the formalin test was conducted using the Automated Nociception Analyzer (Department of Anesthesiology, University of California, San Diego, Yaksh et al, 2001). One hour prior to testing, a metal band was glued to a rat's left hind paw. The animal was then put in a testing chamber. Animals were dosed with compound orally at volumes equal to or less than 10 mL/kg with either vehicle (5% Cremophor ® in milliQ water) or active compounds (1-100 mg/kg) one hour prior to formalin injection. As a positive control, rats were dosed with ethosuximide at 600 mg/kg orally.
  • Neuropathy was induced by Spinal Nerve Ligation (SNL) surgery (Kim and Chung, 1992). Briefly, in rats, the left L5 and L6 spinal neurons distal to the dorsal root ganglion were tightly ligated with 6-0 silk suture. At 4-12 weeks post-surgery, the rats were tested for mechanical hyperalgesia using the pin prick method (Koch et al, 1996). The length of time the paw was held off the grid-floor was measured with the computer program Xnote Stopwatch ver1.4. Zero seconds was assigned when there was no paw withdrawal. The baseline score was determined from the average of five trials. Baselines were counterbalanced for assignments into treatment groups.
  • Guide cannulae were lowered into the brain at a rate of ⁇ 0.2 mm/min and at an angle of 5° to the following depths: 2.0 mm (left frontal cannula) and 3.0 mm (right striatal cannula).
  • the dialysis membranes of the microdialysis probes have a 3.0 mm length and extend 3.0 mm past the ends of the implanted cannulae so the final depths of inserted probes were 3.0 mm and 6.0 mm for the PFG and striatal probes respectively.
  • the sampled brain regions correspond to (1 ) left prefrontal cortex (PFC), including mainly anterior cingulate and prelir ⁇ bic cortices, and (2) right striatum (caudate-putamen) mainly, but also including to a small degree in some animals, lateral globus pallidus.
  • Cannulae were secured with dental cement to the skull and bone screws. The skin incision was closed with 4-Q suture and Vetbond (3-M). Animals received immediate post-operative care and were allowed, one full week to recover from surgery. Animals were housed in 12:12 light-dark room (lights off at 7AM).
  • Microdialysis procedure After a 1-week recovery, animals were placed in individual Raturn bowls for microdialysis sampling (Bioanalytical Systems, Inc., West Lafayette, IN). The capped stylets that cover the cannulae and maintain their patency. were removed, and microdialysis probes were inserted manually at a slow rate. Probe membranes protruded 3.0 mm from the cannula tips and sampled extracellular fluid over this entire 3.0 mm length. The input tube of each microdialysis probe was connected to a syringe pump (CMA/102, CMA Microdialysis, North Chelmsford, MA) that delivered artificial cerebrospinal fluid (aCSF).
  • CMA/102 CMA Microdialysis, North Chelmsford, MA
  • aCSF had the following composition: 154.7mM Na + , 2.9mM K + , H mM Ca 2+ , 0.82 mM Mg 2+ , 132.49 rnM CP (pH 7.4).
  • the output tubes of each probe were connected to a refrigerated fraction collection system (Honeycomb, Bioanalytical Systems, Inc.). Animals were allowed 14-16 hrs to recover from probe insertion and to habituate to the bowl and tether. Probes were perfused over this time period at a slow rate of 0.2 ⁇ L/min. On the following morning, pump perfusion rates were increased to 1.1 ⁇ L/min at the time of lights off (7 AM). Dialysate sampling began 1 hr later.
  • Brain areas of interest (left frontal region, ⁇ 2-4 mm rostral to bregma, and right midline region, ⁇ 0-2 mm caudal to bregma) were sectioned coronally with a cryostat and sections were prepared for histological examination of probe placement and depth.
  • Peak values for each sample were normalized to the mean peak value of the first three baseline samples for each monoamine using Micosoft Excel. Normalized data were imported info GraphPad Prism (GraphPad Software, San Diego, CA) for ⁇ graphical analysis arid to test for significant differences between treatment groups using repeated measures, two-way ANOVA for treatment (different dose-groups: vehicle, 1 , 3 and 10 mg/kg) and time (15 time points). If significant interaction effects were observed, pair-wise post-hoc group comparisons were made using Tukey's least significant difference procedure to test for significant effects of treatment at each time point. As an example, compound 4-77 at 10 mg/kg was found to significantly increase extracellular norepinephrine concentrations in the prefrontal cortex by 250% over vehicle control.

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Abstract

Monoamine re-uptake inhibitors and more specifically serotonin and noradrenaline re-uptake inhibitors are disclosed that have utility in the treatment of disorders of the central or peripheral nervous system in both men and women. The compounds of this invention have the structure: wherein R1, R2, R3, R4, R5a, R5b, R6, R7, and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts, esters and solvates thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for inhibiting monoamine re-uptake in a subject in need thereof.

Description

CONGENERS OP MILNACIPRAN AS MONOAMINE RE-UPTAKE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application No. 60/774,016 filed February 16, 2006, which application is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
This invention relates generally to monoamine re-uptake inhibitors and more specifically to serotonin and noradrenaline re-uptake inhibitors, and to methods of treating disorders by administration of such inhibitors to a warm-blooded animal in need thereof.
BACKGROUND OF THE INVENTION
Decreased concentrations of monoamine neurotransmitters, such as serotonin (also known as 5-hydroxytryptamine or 5-HT), noradrenaline (norepinephrine), and dopamine, are implicated in a number of disorders of the central or peripheral nervous system. These disorders include depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders. These neurotransmitters travel from the terminal of a ' neuron across a small gap (i.e., the synaptic cleft) and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport (i.e., reuptake) of the neurotransmitter back into the presynaptic neuron. Enhancing the . amount of one or more of these monoamines has been shown to have utility in the treatment of disorders such as depression, anxiety, neuropathic pain, fibromyalgia, urinary incontinence and attention deficit hyperactivity disorder (ADHD). One advantageous method to increase the amount of a monoamine or monoamines is by administering a re-uptake inhibitor which has a particular selectivity/affinity to.one or more monoamine transporters.
Selective serotonin re-uptake inhibitors (SSRIs) function by inhibiting the reuptake of serotonin by afferent neurons. SSRIs well known in the art include sertraline (Zoloft®), fluoxetine (Prozac®) and paroxetine (Paxil®).. Selective noradrenaline (or norepinephrine) re-uptake inhibitors function by increasing noradrenaline levels and include drugs known in the art including reboxetine (Edronax®), atomoxetine (Strattera®), and bupropion (Wellbutrin®). Dual serotonin-noradrenaline reuptake inhibitors (SNRIs) which inhibit the reuptake of both serotonin and norepinephrine include venlafaxine (Effexor®), duloxetine (Cymbalta®), milnacipran and imipramine (Tofranil®).
While significant strides have been made in this field, there remains a need in the art for effective small molecule monoamine re-uptake inhibitors. These, inhibitors may advantageously possess characteristics such as enhanced selectively toward one or more monoamine- 'transporters, enhanced pharmacokinetic properties (such as half-life, bioavailability, and minimal interaction with liver enzymes such as the cytochrome P450 family), and/or enhanced potency. There is also a need for pharmaceutical compositions containing such monoamine re-uptake inhibitors, as well as methods relating to the use thereof to treat, for example, conditions caused by low concentrations of a monoamine or monoamines. The present invention fulfills these needs, and provides other related advantages.
BRIEF SUMMARY OF THE INVENTION
In brief, this invention is generally directed to monoamine re-uptake inhibitors, in particular, serotonin and/or noradrenaline reuptake inhibitors, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the monoamine re-uptake inhibitors of this invention are compounds having the following general structure (I):
Figure imgf000003_0001
(I) including stereoisomers, prodrugs and pharmaceutically acceptable salts, esters and solvates thereof, wherein R1, R2, R3, R4, Rsa, Rsb, Re, R7> and n are as defined below.
The monoamine reuptake inhibitors of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders of the central or peripheral nervous system in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such conditions include, but are not limited to, depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, . fibromyalgia and.sleep.: disorders. Conditions of particular interest which may be treated by administration of compounds. of structure (I) include depression, anxiety, neuropathic pain, fibromyalgia, Urinary incontinence and attention deficit hyperactivity disorder (ADHD). The compounds may. also be useful in combination with antipsychotic agents for the treatment of schizophrenia, as well as in combination with dopaminergic agents for use in Parkinson's disease. ' ' . . .
. The methods of this invention include administering an effective amount of a monoamine re-uptake inhibitor, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a. further embodiment, pharmaceutical compositions are disclosed containing one or more monoamine re-uptake inhibitors of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. . .
These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the present invention is directed generally to compounds useful as monoamine reuptake inhibitors. The compounds of this invention have the following structure (I):
Figure imgf000004_0001
(I) and stereoisomers, prodrugs and pharmaceutically acceptable salts, esters and solvates thereof, wherein:
Ri, R2 are independently H1 Ci.iOalkyl, Ci.iOalkyl substituted by 1 to 4 R9, aryl, aryl substituted by 1 to 4 R10, heterocycleC-i^alkyl, heterocycleC1-4alkyl substituted by 1 to 4 R10, arylC-i- 4alkyl, or arylC^alkyl substituted by 1 to 4 R10; or Ri and R2 taken together with the nitrogen to which they are attached form a 5-14 member heterocycle or 5-14 member heterocycle substituted by 1 to 4 R1O!
R3, R4 are independently H, C^alkyl, C^alkyl substituted by 1 to 4 R10, or -C(=O)R8;
Rδa, Rsb are independently and at each occurrence, H, F, OH,
Figure imgf000004_0002
Ci-4alkyl substituted by 1 to 4 R9,
Figure imgf000004_0003
substituted by 1 to 4 R9;
R6 is aromatic heterocyclic ring or aromatic heterocyclic ring substituted by 1 to 4 R10;
R7 is H, C^alkyl, C1-4alkyl substituted by 1 to 4 R9, F, OH, C1-4alkoxy, d^alkoxy substituted by 1 to 4 R9, or phenyl;
R8 is
Figure imgf000004_0004
or C-,.4alkyl substituted by 1 to 4 R9;
R9 is halo, OH, C1-4alkoxy, CN, or NR-IiR12;
R10 is C^alkyl, halo, OH, C1-4alkoxy, CN, or NR11R12;
R1-I, R12 are independently and at each occurrence, H or C1-4alkyl; and n is 1 or 2.
As used herein, the above terms have the following meaning: .
"Alkyl" and "C1-10alkyl." mean a straight chain or branched, noncyclic or. cyclic,, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the terms "lower alkyl" and "Ci.4alkyl" have the same meaning as alkyl but contain from 1 to 4 carbon atoms. Representative saturated straight chain alkyls include methyl,. ethyl, n-propyl,, n-butyl, n-pehtyi; n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, terf-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHa-cyclopropyl, -CH^cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls include di- aήd poly-homocyclic rings such as decalin and adamantyl. Unsaturated alkyls contain at least ohe double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1- butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like.
"Aryl" means an aromatic carbocyclic moiety such as phenyl or naphthyl.
Figure imgf000005_0001
having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH2)2Phenyl, -(CH2)3Phenyl, -CH(phenyl)2, and the like.
"5-6 Member carbocycle" means a ring composed of 5 or 6 carbon atoms, either saturated, unsaturated or aromatic.
"Heteroaryl" means an aromatic heterocycle ring of 5- to 10-members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.
"Heterocycle" (also referred to herein as a "heterocycle ring") means a 5- to 7- membered monocyclic, or 7- to 14-membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrqpyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, . tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"HeterocycleCi_4alkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH2morpholinyl, -CH2pyridyl and the like.
"Aromatic heterocyclic ring" means heterocycle wherein at least one ring of the heterocycle is aromatic and includes heteroaryls and nonaromatic heterocycles which are fused to aryl or heteroaryl moieties. . Thus, in addition to the heteroaryls listed above, aromatic heterocyclic ring . includes 2,3-dihydro-benzofuran, 1,3-dihydro-isoindole, 2,3-dihydro-indole, dihydro-4H-thieno[3,2- c]pyridine, 3,4-dihydro-2H-quinoline, 3,4-dihydro-1 H-isoquinoline, benzo[1,3]dioxple, and the like.
"Halogen" or "halo" means fluoro, chloro, bromo and iodo.
"Alkoxy" means an alkyl moiety attached through an oxygen bridge (Ae., -O-alkyl), such as -O-methyl, -O-ethyl, and the like.
Figure imgf000005_0002
has the same meaning as alkoxy but contains from 1 to 4 carbon atoms.
Lastly, the term "substituted" as used herein means any of the above groups (Ae., alkyl', carbocycie, aryl, or heterocycle) wherein at least one hydrogen atom is replaced with a substituent. In the case of an oxo substituent ("=O") two hydrogen atoms are replaced. "Substituents" within the context of this invention include halogen, hydroxy, oxo, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, thioalkyl, haloalkyl, hydroxyalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaRb , - NRaC(=O)ORb -NR3SO2Rb, -ORa, -C(=O)Ra -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb) -SH, -SRa, - SORa, -S(=O)2Ra, -OS(=O)2Ra, -S(=O)2ORa, wherein R3 and Rb are the same or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.
In an embodiment of the present invention, RSa and R5b of structure (I) are H and n is 1 or 2, as shown in structures (II) and (III), respectively.
Figure imgf000006_0001
(H) (III)
In another embodiment, Rγ of structure (I) is H, F and methyl, as shown in structures (IV), (V) and (IV), respectively.
Figure imgf000006_0002
(IV) (V) (IV)
In an embodiment of the present invention, R5a> R5b and R7 of structure (I) are H, n is ,1 , . and R3 and R4 are both H or both C-i^alkyl (specifically methyl) as. shown. in. structures (VIl), and; (VIII), : respectively.
Figure imgf000006_0003
(VIl) (VIlI)
In additional embodiments, R7 of structure (I) is H, R1 is C^alkyl (specifically ethyl), and R2 is (specifically benzyl) as showri in structure (IX) and R7 of structure (I) is H while both R1 and R2 are C1-4alkyl (specifically propenyl and propynyl) as shown in structure (X).
Figure imgf000006_0004
(IX) (X)
In other embodiments, R1 and R2 taken together with the nitrogen to which they are attached form a heterocycle such as 3,4-dihydro-2H-quinolin-1-yl as shown in structure (Xl) and form a substituted heterocycle such as 4-phenyl-piperidin-1-yl as shown in structure (XII).
Figure imgf000007_0001
(Xl) (XII)
In another embodiment, R6 of structure (I) is aromatic heterocyclic rings thiophen-2-yl and benzo[1,3]dioxol-5-yl as shown in structures (XIII) and (XIV), respectively.
Figure imgf000007_0002
(XIII) (XIV)
The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, the compounds of structure (I) above may be made by the following reaction schemes, wherein all substituents are as defined above unless indicated otherwise.
Reaction Scheme 1
Figure imgf000007_0003
Substituted acetonitrile / may be condensed with epichlorohydrin under basic conditions (such as NaHMDS, THF). Alkaline hydrolysis of the nitrile (such as reflux in potassium hydroxide in ethanol) followed by acidic workup gives the lactone //.
Reaction Scheme 2
Figure imgf000007_0004
Substituted acetic acid /77 is alkylated with an allyl halide (such as allyl bromide with cesium, carbonate as base) yielding /V which is converted to alpha diazo ester with reagent acetomidobenzensulfonylazide under basic conditions (DBLJ) to give v. Intramolecular cyclization with a catalyst such as rhodium acetate dimer results in //.
Reaction Scheme 3
Figure imgf000008_0001
Lactone ring // is opened by reaction with potassium phthalimide in hot DMF to give vi.
Reaction with oxalyl or sulfonyl chloride yields the acid chloride vii which gives viii after condensation with an appropriate amine. Deprotection with hydrazine or a substituted hydrazine gives ix.
Reaction Scheme 4
Figure imgf000008_0002
// x xi ix
Ring opening of // with a lithium salt of an amine (such as produced from an amine and tert-butyl lithium at -780C) produces alcohol x. x is converted to azide xi using sodium azide followed by reduction with a platinum or palladium catalyst under hydrogen atmosphere yielding ix.
Reaction Scheme 5
Figure imgf000008_0003
ix xϋ
Monoalkylation is performed first by BOC protection with di-fe/t-butyl dicarbonate followed by alkylation with an alkyl halide to yield xii after deprotection. Without BOC protection, reductive alkylation with an appropriate aldehyde or ketone or acylation with acid chloride or amino acid derivative gives xii.
Figure imgf000008_0004
Alcohol x is oxidized by, for example, Swem oxidation to give aldehyde xii. Reaction with nitromethane in the presense of base such as sodium hydride followed by reduction with nickel boride or other reagent yields xv.
Particular individual compounds of the present invention include:
((1R,2R)-2-Aminomethyl-1-thiophenr2-yl-cyclopropyl)-(1 ,3-dihydro-isoindol-2-yl)-methanone (Ex. 4-1); (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(2-hydroxy-ethyl)-amide 4-2; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(2,3-dihydro-indol-1-yl)-methanone 4-3; ((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropylHS^-dihydro-IH-isoquinolin^-yO-methanone 4-4; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-phenyl-amide 4-5; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid benzyl-ethyl-amide 4-6; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid butyl-ethyl-amide 4-7; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid propyl-ethyl-amide 4-8; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-o-tolyl-amide 4-9; ((1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropyl)-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone 4-10; [(1R,2R)-2-Aminomethyl-1-(5-chloro-thiophen-2-yl)-cyclopropyl]-(3,4-dihydro-2H-quinolin-1-yl)- methanone 4-11 ;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(4-phenyl-piperazin-1-yl)-methanone 4-12; ((IS^R^-Aminomethyl-i-pyridin^-yl-cyclopropylHS^-dihydro-IH-isoquinolin^-ylJ-methanone 4-13; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone 4-14; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(3,6-dihydro-2H-pyridin-1-yl)-methanone 4-15; ((IR^R^-Aminomethyl-i-thiopheπ^-yl-cyclopropylJ^.S-dihydro-benzoti ^loxazin^-yO-methanone 4- 16;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(5-methanesulfonyl-2,3-dihydro-indol-1-yl)- methanone 4-17;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(2-methyl-allyl)-amide 4-18; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)- methanone 4-19;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid allyl-but-2-ynyl-amide 4-20; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid but-2-ynyl-propyl-amide 4-21.;' ((1S,2R)-2-Aminomethyl-1-benzo[1,3]dioxol-5-yl-cyclopropyl)-(1 ,3-dihydro-isoindol-2-yl)-methanone 4- 22;
(1 S,2R)-2-Aminomethyl-1-benzo[b]thiophen-5-yl-cyclopropanecarboxylic acid allyl-ethyl-amide 4-23; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid allyl-ethyl-amide 4-24; ((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropylHS-fluoro^.S-dihydro-indol-i-y^-methanone 4-25; ((1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(5-chloro-2,3-dihydro-indol-1-yl)-methanone 4-26; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(5-bromo-2,3-dihydro-indol-1-yl)-methanone 4-27; ((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropylHδ-methyl-S^-dihydro^H-quinolin-i-yl)- methanone 4-28;
(1 R,2R)-2τAminomethyl-1-thiophen-2-yl-eyclopropanecarboxylic acid diallylamide 4-29; (1 R,2R)-2-Aminomethyl-1~thiophen-2-yl-cyclopropanecarboxylic acid allyl-propyl-arriide 4-30; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(2,5-dihydro-pyrrpl-1-yl)-methanone 4-31; ((1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(5-fluoro-1 ,3-dihydro-isoindol-2-y!)-methanone A- 32; . . . . . . .
2-((1R,2R>2i-Aminomethyl-1-thiophen^2-yl^cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinoiine-7- . carbonitrile 4-33;
(1 S,2R)-2-Aminomethyl-1-thiophen-3-yI-cyciopropanecarboxylic acid allyl-ethyl-amide 4-34;
((1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropyl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone 4-35;
((1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropyl)-(3,6-dihydro-2H-pyridin-1-yl)-methanone 4-36;
((1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropyl)-(1 ,3-dihydro-isoindol-2-yl)-methanone 4-37;
((1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropyl)-(2,3-dihydro-benzo[1 ,4]oxa∑in-4-yl)-methanone 4-
38;
((1S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropyl)-(2,3-dihydro-indol-1-yl)-methanone 4-39; (1S,2R)-2-Aminomethyl-1-benzo[b]thiophen-5-yl-cyclopropanecarboxylic acid ethylamide 4-40; ((1S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)- methanone 4-41;
((1S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropyl)-(3,4-dihydro-1H-isoquinolin-2-yl)- methanone 4-42;
((1S,2R)-2-Aminomethyl-1-benzo[1 )3]dioxol-5-yl-cyclopropyl)-(2,3-dihydro-benzo[1 ,4]oxazin-4-yl)- methanone 4-43;
(1 S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropanecarboxylic acid di-prop-2-ynyl-amide 4-44; (1S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropanecarboxylic acid diallylamide 4-45; (1 S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropanecarboxylic acid allyl-prop-2-ynyl-amide 4-46; (1 S,2R)-2-AminomethyM-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid diallylamide 4-47; (1S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid allyl-propyl-amide 4-48;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid allyl-prop-2-ynyl-amide 4-49; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid phenethyl-propyl-amide 4-50; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone 4-51;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropaπecarboxylic acid cyclopropylmethyl-prppyl-amide 4- 52;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid di-prop-2-ynyl-amide 4-53; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid di-but-2-ynyl-amide 4-54; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-prop-2-ynyl-amide 4-55.;' . (1 S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyc|opropanecarboxylic acid allyl-ethyl-amide 4-56;
(1 R,2R)-2-AminomethyI-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(3-methyl-but-2-enyl)-amide 4-57; ' ■ ■ ' • ' '
((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropylHΘ^-dimethoxy-S^-dihydro-IH-isoquinolin^-yl)- methanone 4-58;
((1R)2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(7,8-dihydro-5H-1 ,6,9-triaza-anthracen-6-yl)- methanone 4-59;
(1 R,2R)-2-Aminomethyl-1rthiophen-2-yl-cyclopropanecarboxylic acid but-2-ynyl-ethyl-amide 4-60; (1 S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid di-prop-2-ynyl- amide 4-61 ; ' • • •. •. •. • ■ • • • • •-- • ■ .. -. • • ..- ..•
(1 S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid al!yl-but-2-ynyl- amide 4-62; . .
(1 S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid but-2-ynyl-propyl- amide 4-63; .
(1 S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yI-cycIopropanecarboxylic acid allyl-ethyl-amide 4-64; (1 S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropanecarboxyiic acid diallylamide 4-65; (1 S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropanecarboxyli.c.acid diτprop-2τ-ynyl-.amide 4-66;. (1 S,2R)-2-Aminomethyl-1-benzo[1 ,3]dioxol-5-yl-cyclopropanecarboxylic acid allyl-but-2-ynyl-amide A- 67;
(1S,2R)-2-Aminomethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid allyl-prop-2-ynyl- amide 4-68;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid bis-pyridin-2-ylmethyl-amide 4-69; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-thiazol-4-yl methyl-amide 4- 70;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid benzo[1 ,2,5]oxadiazol-5-ylmethyl- ethyl-amide 4-71 ;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(1-methyl-1 H-benzotriazol-5- ylmethyl)-amide 4-72;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid (3,5-dimethyl-isoxazol-4-ylmethyl)- ethyl-amide 4-73;
(1 R,2R)-2-Aminomethyl-1-benzo[b]thiophen-2-yl-cyclopropanecarboxylic acid diallylamide 4-74; (1 R,2R)-2-Aminomethyl-1-benzo[b]thiophen-2-yl-cyclopropanecarboxylic acid allyl-ethyl-amide 4-75; (1 R,2R)-2-Aminomethyl-1-benzo[b]thiophen-2-yl-cyclopropanecarboxylic acid di-prop-2-ynyl-amide A- 76;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(2-fluoro-allyl)-amide 4-77; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-phenethylτamide 4-78; ((1R,2R)-2-Aminomethyl-1-thiopheή-2-yl-cyclopropyl)-(2-methyl-piperidin-1-yl)-methanone 4-79; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(3-methyl-piperidin-1-yl)-methanone 4-80; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(4-methyl-piperidinτ:1^yl)-methanone 4-81; • , - ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(2-ethy!τpiperidin-1-yl)-methanone 4-82; -. - - . ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone . 4-83; . ((1R,2R)-2-Aminomethyt-1-thiophen-2-yl-cyclopropyI)-(4a,8a)-octahydro-isoquinolin-2-y!-methanone 4-
84; . . . . . . . . ' . . .. . . . .
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(4aR,8aR)-octahydro-isoquinolin-2ryl-methanone 4-85; . . ■ . . . . .. - ,
((IR^R^-AminomΘthyl-i-thiophen^-yl-cyclopropyO^aS.δaS^octahydro-isoquinolin^-ylrmethanone
4-86;
((1R,2R)-2-Amiπomethyl-1-thiophen-2-yl-cyclopropyl)-(4-phenyl-piperidin-.1-yl)-methaπone 4-87;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyI)-(3-phe:nyl-piperidin-1-yI)-methanone 4-88;'
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(2-phenyl-piperidin-1-yl)-methanone 4-89;
((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropyl^fi ^'lbipiperidinyl-i '-yl-methanone 4-90;
(1 R,2R)-2-Aminomethyi-1-thiophen-2-yl-cyclopropanecarboxylic acid (1-phenyl-ethyl)-prop-2-ynyl-amide
4-91;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(4-benzyl-piperidin-1-yl)-methanone 4-92;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(3-benzy.Kmorpholin-4-yl)-methanone 4-93;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(3-benzykpiperidin-1-yl)rmethanone 4-94;
((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-(2R-phenyl-pyrrolidin-1-yl)-methanone 4-95; ((IR^R^-Aminomethyl-i-thiophen^-yl-cyclopropylHZS-phenyl-pyrrolidin-i-ylJ-methanone 4-96; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ((E)-but-2-enyl)-ethyl-amide 4-97; (1 R,2R)-2-Aminomethyl-1-(5-chloro-thiophen-2-yl)-cyclopropanecarboxylic acid diallylamide 4-98; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid methyl-prop-2-ynyl-amide 4-99; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid benzyl-methyl-amide 4-100; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid methyl-naphthalen-1-ylmethyl- amide 4-101;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid but-2-ynyl-prop-2-ynyl-amide 4- 102;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid allyl-(but-2-enyl)-amide 4-103; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid (but-2-enyl)-prop-2-ynyl-amide 4- 104;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(pent-2-enyl)-amide 4-105; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ethyl-(4-methoxy-benzyl)-amide 4- 106;
(1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid ((Z)-but-2-enyl)-ethyl-amide 4-107; ((1R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropyl)-((2R,6S)-2,6-dimethyl-piperidin-1-yl)-methanone 4-108;
(1 S,2R)-2-Aminomethyl-1-thiophen-3-yl-cyclopropanecarboxylic acid diethylamide 5-1 ; . (1S,2R)-2-Aminomethyl-1-pyridin-2-yl-cyclopropaneca'rboxylic acid diethylamide 5-2; (1 R,2R)-2-Aminomethyl-1-benzothiazol-2-yl-cyclopropanecarboxylic acid diethylamide 5-3; (1 R,2R)-2-Aminomethyl-1-thiophen-2-yl-cyclopropanecarboxylic acid diethylamide 5-4; (1 S,2R)-2-Aminomethyl-1-benzo[b]thiophen-3-yl-cyclopropanecarboxylic acid diethylamide 5-5; (1S,2R)-2-Aminomethyl-1-benzo[b]thiophen-5-yl-cyclopropanecarboxylic acid diethylamide.5-6; , . _, .. . (1S,2R)-2-Aminomethyl-1-benzo[1,3]dioxol-5-yl-cyclopropanecarbqxylic acid diethylamide 5-7; (1 S,2R)-2-Aminαmethyl-1-(2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid diethylamide 5-8; (1 R,2R)-2-Aminomethyl-1-(5-fluoro-benzo[b]thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 5-
(1 R,2R)-2-Aminomethyl-1-benzo[b]thiophen-2-yl-cyclopropanecarboxylic acid diethylamide 5-10; 3-((1S,2R and 1R,2S)-2-Aminomethyl-1-diethylcarbamoyl-cyclopropyl)-indole-1-carboxyiic acid tert-butyl ester 5-11 ; . . . .
(1 S.2R and 1 R,2S)-2-Aminomethyl-1-(1H-indol-3-y.l)-cyclopropanecarboxylic acid diethylamide 5-12; (1 S.2R and 1 R,2S)-2-Aminomethyl-1-thiophenr3-yI-cycloprobanecarboxyIic aeid diethyiamide 5-13; • (1 S,2R and 1 R,2S)-2-Aminomethyl-1-(3-methyl-benzo[b]thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 5-14; .
(1 S.2R and 1 R,2S)-2-Amiήόmethyl-i-benzo[b]thiophen-2-yl-cyclopropaήecarbbxylic acid diethylamide 5-15;
(1 S,2R and 1 R,2S)-2-Aminomethyl-1-(1H-inden-2-yl)-cyclopropanecarboxylic acid diethylamide 5-16; (1 S,2R and 1 R,2S)-2-Aminomethy|τ1-(5-chloro-3-methyl-benzo[b]thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 5-17; (1 S,2R)-2-Methylaminomethyl-1-thiophen-3-yl-cycloρropanecarboxylic acid diethylamide 6-1 ; (1 S,2R)-2-Dimethylaminomethyl-1-thiophen-3-yl-cyclopropanecarboxylic acid diethylamide 7-1; (1 R,2R)-2-Aminomethyl-1-(5-bromo-thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 8-1 ; (1 R,2R)-2-Aminomethyl-1-(5-chloro-thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 9-1; (1 R,2R)-2-Aminomethyl-1-(4,5-dichloro-thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 10-1 ; (1 R,2R)-2-Aminomethyl-1-(3,4,5-trichloro-thiophen-2-yl)-cyclopropanecarboxylic acid diethylamide 10-2; (1 R,2R)-2-[(2-Amino-acetylamino)-methyl]-1-thiophen-2-yl-cyclopropanecarboxylic acid diethylamide 11-1; and (1 R,2R)-2-(2-Amino-1-hydroxy-ethyl)-1-thiophen-2-yl-cyclopropanecarboxylic acid diethylamide 12-1.
The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of.structure .(l), /α .wvo .when, such .prodrug is . administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent : compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. .
■ With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms, of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
As mentioned above, the compounds of this invention and their salts may inhibit the uptake of one or more of the monoamine neurotransmitters serotonin, noradrenaline and dopamine. As such, these compounds and their salts may have utility over a wide range of therapeutic applications, and may be used to treat a variety of disorders which are caused by or linked to decreased neurotransmission of one or more of these monoamines. These disorders include disorders of the central and/or peripheral nervous system.
In an embodiment, the compounds of the present invention may selectively inhibit the re-uptake of serotonin and noradrenaline over the re-uptake of dopamine. Other compounds of the present invention may selectively inhibit noradrenaline over both serotonin and dopamine. In another embodiment, compounds of the present invention may selectively inhibit the re-uptake of serotonin over both noradrenaline and dopamine.
In an embodiment, conditions which may be treated by compounds of the current invention include, but are not limited to, depression, eating disorders, schizophrenia, inflammatory bowel disorders, pain, addiction disorders, urinary incontinence, dementia, Alzheimer's, memory loss, Parkinsonism, anxiety, attention-deficit disorder, social phobia, obsessive compulsive disorder, substance abuse and withdrawal, cognitive disorders, fibromyalgia and sleep disorders.
Pain may generally be divided into two categories: acute pain and chronic (or persistent) pain. Acute pain is self-limiting and generally results from injured or diseased tissue and is considered nociceptive in nature. Examples of nociceptive pain include post-operative pain, pain associated with trauma, and the pain of arthritis. Chronic pain can be defined as pain that persists beyond the usual course of the acute injury or disease. Chronic pain is generally neuropathic in nature and can be continuous or recurring. Chronic pain is generally caused by prolonged and sometimes permanent dysfunction of the central or peripheral nervous system. Examples include post herpetic (or post-shingles) neuralgia, reflex sympathetic dystrophy / causalgia (nerve trauma), components of cancer pain, phantom limb pain, entrapment neuropathy (e.g., carpal tunnel syndrome), and peripheral neuropathy (widespread nerve damage due to, for instance, diabetes or excessive alcohol use).
In another embodiment, a compound of structure (I) may be administered along with an antipsychotic to treat schizophrenia. The antipsychotic may be typical or atypical. A compound of structure (I) could also be administered with a dopaminergic agent such as levodopa to treat Parkinson's disease and/or the side effects associated with such therapy. . ■ ■
In another embodiment of the invention, pharmaceutical compositions containing one or more monoamine re-uptake inhibitors are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a monoamine re-uptake inhibitor of the present invention and a pharmaceutically acceptable carrier and/or diluent. The monoamine re-uptake inhibitor is present in the composition in an amount which is effective to treat a particular disorder— that is, in an amount sufficient to achieve monoamine re-uptake inhibition, and preferably with acceptable toxicity to the patient. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a monoamine re-uptake inhibitor, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the monoamine re-uptake inhibitor in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
In another embodiment, the present invention provides a method for treating disorders of the central or peripheral nervous system. Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, "treat" includes prophylactic administration. Such methods include systemic administration of a monoamine re-uptake inhibitor of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of monoamine re-uptake inhibitors include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the monoamine re-uptake inhibitor, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
The following examples are provided for purposes of illustration, not limitation. In summary, the monoamine re-uptake inhibitors of this invention may be assayed by the methods disclosed in Examples 13 to 17, while the following Examples 1 to 12 disclose the synthesis of representative compounds of this invention.
EXAMPLES
HPLC Methods for analyzing the samples
Retention time, tR, in minutes
Analytical HPLC-MS Method 1
Platform: Agilent 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCl); .
HPLC column: Phenomenex Synergi-Max RP 8OA, 2.0 x 50 mm column;
HPLC gradient: 1.0 nϊL/minute, from 10% acetonitrile in water to 90% acetonitrile in water in 2.5 minutes, maintaining 90% for 1 minute. Both acetonitrile and water have 0.025% TFA.
Analytical HPLC-MS Method 2 ' ■ ■
Platform: Agilent 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI);
HPLC column: Phenomenex Synergi-Max RP 80A, 2.0 x 50 mm column;
HPLC gradient: 1.0 mL/minute, from 5% acetonitrile in water to 95% acetonitrile in water in 13.5 minutes, maintaining 95% for 2 minute. Both acetonitrile and water have 0.025% TFA. . Analytical HPLC-MS Method 3
Platform: Agilent 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (electrospray);
HPLC column: XTerra MS, C18, 5μ, 3.0 x 250 mm column;
HPLC gradient: 1.0 mL/minute, from 10% acetonitrile in water to 90% acetonitrile in water in 46 minutes, jump to 99% acetonitrile and maintain 99% acetonitrile for 8.04 minutes. Both acetonitrile and water have 0.025% TFA.
Analytical HPLC-MS Method 4
Platform: Agilent 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI) and Berger FCM 1200 CO2 pump module;
HPLC column: Berger Pyridine, PYR 6OA, 6μ, 4.6 x 150 mm column;
HPLC gradient: 4.0 mL/minute, 120 bar; from 10% methanol in supercritical CO2 to 60% methanol in supercritical CO2 in 1.67 minutes, maintaining 60% for 1 minute. Methanol has 1.5% water. Backpressure regulated at 140 bar.
Analytical HPLC-MS Method 5
Platform: Gilson 215 Auto-sampler, Dionex Thermostatted Column Compartment TCC-
100 held at 30 0C, Dionex PDA-100 Photodiode Array Detector (220 nm and 254 nm), Dionex P680
HPLC pump, Thermo Finnigan MSQ single quad Mass Spectrometer (APCI)
HPLC column: Phenomenex Gemini 5μ C18 110A, 3.0 x 150 mm
HPLC gradient: 1.5 mL/min, from 5% acetonitrile in water to 90% acetonitrile in water in
9.86 minutes, from 90% acetonitrile in water to 95% acetonitrile in water in 0.1 minutes, hold at 95% for
1.19 minutes. Both acetonitrile and water have 0.04% NH4OH.
Analytical HPLC-MS Method 6
Platform: Agilent 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (APCI); . . ' . .. - .
HPLC column: BHK Laboratories, Inc. alpha C18 (O/B), 4.6 X 150 mm column;
HPLC gradient: 3.6 mL/minute, sample was loaded with 5% acetonitrile in water, and eluted with 10 to 95% acetonitrile in water over 12.75 minutes, water and acetonitrile used contained 0.05% and 0,035% TFA.by volume, respectively.
Preparative HPLC-MS •
Platform: Shimadzu HPLC equipped with a Gilson 215 auto-sampler/fraction collector,
UV detector and a PE Sciex APH 50EX mass detector;
HPLC column: BHK ODS-O/B, 5 μ, 30x75 mm . • ■
HPLC gradient: 35 mL/minute, 10% acetonitrile in water to 100% acetonitrile in 7 minutes, maintaining 100% acetonitrile for 3 minutes, with 0.025% TFA. Chiral HPLC
Platform: Dionex P680A and P680P pumps, Dionex PAD 100 photodiode array detector, Jasco CD 2095 plus chiral detector, Gilson 215 liquid handler. Analytical Columns are 0.46 x 25 cm, 5 μm; preparative columns are 2 x 25 cm, 5 μm.
EXAMPLE 1 (1 R.δRJ-i-THIOPHEN^-YL-S-OXA-BICYCLOβ.i .0]HEXAN-2-ONE
Figure imgf000017_0001
1-1
Step 1A: (1R,5R)-1-Thiophen-2-yl-3-oxa-bicyclo[3.1.01hexan-2-one (1-1)
2-Thiopheneacetonitrile (40.0 g, 0.325 mol) was dissolved in tetrahydrofuran (THF, 160 mL) and added dropwise (53 min) to a stirred solution of sodium hexamethyldisilazane (NaHMDS, 715 mL, 1M in THF) at 0 0C under a nitrogen atmosphere. After an additional 5 minutes, (R)-(-)-epichlorohydrin (29.92 g, 0.325 mol) in solution (THF, 180 mL) was added drop wise over 49 minutes while maintaining a reaction temperature below 8 0C. The mixture was stirred for at least 2 h at 0 0C and then was allowed to come to room temperature overnight. KOH (1 mL, 1 N) and EtOH (2 mL) were added to the reaction mixture and solvent volume was reduced under vacuum leaving approximately 200 mL of THF. KOH (31 mL, 1 N) and EtOH (80 mL) were added and the mixture was refluxed under a nitrogen atmosphere (8 h) and then stirred at room temperature (13 h). The reaction mixture was placed in an ice bath and HCI (12 N) was added dropwise (30 min) under a stream of nitrogen until the pH was between 1 and 2. The mixture was stirred (2 h) as it was allowed to come to room temperature and then stored at -4 0C (48 h). The material was extracted (3 x 100 mL dichloromethane and 3 x 100 mL ethyl acetate) and the combined organic fractions were concentrated under reduced pressure. The resulting black tar residue was washed twice with aqueous sodium bicarbonate (100 mL) and twice with brine (50 mL). The aqueous fractions were extracted with ethyl acetate (50 mL), and the combined organic fractions were dried (Na2SO4), filtered and concentrated to give thick black oil that was dissolved in.25/mL of dichloromethane and purified by chromatography (silica gel 20% ethyl acetate/hexanes) to afford 29.4 g (50 %) of 1-1 as a dark red oil.
The following compounds were synthesized Using the above procedure with (R)-H" epichlorohydrin. chiral
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000018_0002
The following compounds were synthesized using the above procedure with (+/-)-epichlorohydrin.
""-A racemic
Figure imgf000018_0003
EXAMPLE 2
GENERAL SYNTHESIS OF LACTONE INTERMEDIATES FROM DIAZO COMPOUNDS
Figure imgf000018_0001
Step 2A: AIIvKI H-lndol-S-vhacetate (2aV
AlIyI bromide (1.4 mL, 16 mmol) and cesium carbonate (5.11 g, 15.7 mmol) were added to a stirred solution of 1 H-indole-3-carbqxylic acid (3.60 g, 20.5 mmol) in acetone. The mixture was stirred at room temperature for 3 days and then concentrated under vacuum. The residue was taken up in dichloromethane (75 mL), washed with aqueous sodium chloride (75 mL), dried (MgSO4), and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0-30% ethyl acetate and 0.1% triethylamine in hexanes) to afford 1.04 g (24%) of 2a as an amber oil which was used in the next step without further purification.
Step 2B: fert-Butyl 3-(Allyloxycarbonyl)methylindole-1-carboxylate (2b> : Ester 2a (1.04 g, 4.83 mmol) was dissolved in acetonitrile (20 ml_) and treated with di-tert-butyl dicarbonate (1.27 g, 5.82 mmol) and dimethylaminopyridine (DMAP 59 mg). The mixture was stirred for 1 h, diluted with ethyl acetate (75 mL), and then washed with 0.1 N HCI (75 mL), water (2 x 50 ml_), and aqueous sodium chloride (2 x 50 mL). The mixture was dried (MgSO4) and concentrated to afford 1.45 g (95%) of 2b as an amber oil: LC-MS 216 (MH+-100).
Step 2C: tert-Butyl 3-(Allyloxycarbonvndiazomethylindole-1-carboxylate (2c)
Ester 2b (1.43 g, 4.52 mmol) and p-acetamidobenzenesulfonyl azide (1.16 g, 4.83 mmol) were dissolved in acetonitrile (8 mL). DBU (0.72 mL, 4.8 mmol) in acetonitrile (4 mL) was added over 30 minutes and stirring was continued for 16 h. The mixture was poured into aqueous ammonium chloride (40 mL) and extracted twice with ethyl acetate (50 mL). The combined extracts were washed with water (3 x 50 mL) and aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (elution with 8% ethyl acetate in hexanes) to afford 0.70 g (46%) of 2c as red crystals.
Step 2D: fert-Butyl 3-(2-Oxo-3-oxa-bicyclor3.1.0lhex-1-yl)indole-1-carboxylate (2-1)
Using a syringe pump, 2c (632 mg, 1.85 mmol) in dichloromethane (10 mL) was added to a refluxing solution of rhodium(ll) acetate dimer (20 mg, 0.045 mmol) in dichloromethane (10 mL) over 3 h. Once the addition was completed, heating was continued for 30 minutes and the mixture was concentrated under vacuum. The residue was purified by flash chromatography (elution with 20% ethyl acetate in hexanes) to afford 332 mg (57%) of 2-1 as a brown oil: LC-MS 214 (MH+-100).
racemic
Figure imgf000019_0001
Figure imgf000019_0002
• EXAMPLE 3
GENERAL SYNTHESIS OF LACTONE INTERMEDIATES FROM DIAZO COMPOUNDS
Figure imgf000020_0001
Step 3A: AIIvI 5-Chloro-3-methylbenzorblthiophene-2-yl)acetate (3b)
To a solution of 5-chloro-3-methylbenzo[b]thiophene-2-acetic acid 3a (1.92 g, 8 mmol) in acetone (50 mL) was added cesium carbonate (2.73 g, 8.4 mmol). The reaction was stirred overnight at room temperature. The acetone was removed under reduced pressure and the solid was partitioned between methylene chloride and water. The layers were separated and the aqueous layer was extracted twice with methylene chloride. The combined organic layers were washed once with 1 :1 saturated sodium chloride/water, dried over magnesium sulfate and concentrated to dryness to give 1.94 g of 3b (6.9 mmol) in 87 % yield.
Step 3B: S-Chloro-S-methylbenzorblthiophene^-vO-S-oxa-bicyclore.i .OIhexan-2-one (3-1 )
To an ice-cooled solution of 3b (0.78 g, 2.8 mmol) in acetonitrile (5.6 mL) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 2.09 mL, 13.9 mmol) followed by 4-acetamidobenzenesuifonyl azide (1.33 g, 5.6 mmol). After 25 minutes the reaction was diluted with chloroform (50 mL) and washed with 1N HCI (3 x 50 mL). The solution was dried over magnesium sulfate and filtered.. The crude solution of 3c was heated to 80 0C for 3 hours at which time the solvent was evaporated and the crude material was purified by column chromatography (2:1 hexane/ethyl acetate) to give, 0.387 g of 3-1 (i .39 mmol) in 50 % yield.
Using the appropriate starting materials, the following compounds were prepared according to the above procedures. racemic
Figure imgf000020_0002
Figure imgf000020_0003
EXAMPLE 4 2-[(1 R,2R)-2-AMINOMETHYL-1 -THIOPHEN-2-YLCYCLOPROPYL)-(1 ,3-DIHYDROISOINDOL-2-YL)METHANONE
Figure imgf000021_0001
Step 4A: (1 R,2R)-2-(1.3-Dioxo-1 ,3-dihvdroisoindol-2-ylmsthylV1-thiophene-2-ylcvclopropanecarboxylic acid (4a)
A mixture of lactone 1-1 (3.5 g, 19 mmol) and 3.3 g (1 eq) of potassium phthalimide in 15 mL of DMF was heated at 140 "C in a sealed vial overnight. The mixture was allowed to cool to room temperature and poured over 150 mL of cold water. It was washed with ethyl acetate (X 3), acidified at 0 0C with 40 mL of 1 M HCl and extracted with ethyl acetate (X 3). The solvent was evaporated and the , crude product obtained was heated up to reflux in 40 mL of ethanol and 40 mL of 4% HCI for 1 hour. The ethanol was then evaporated and the material extracted with ethyl acetate' (X 3). • Purification on silica gel using a mixture of ethyl acetate: hexane: acetic acid 100: 200: 1.5 as eluent produced 2.75 g . (45%) of carboxylic acid 4a: LC-MS 328 (MH+)
Step 4B: 2-1Ϊ1 R.2R)-2-(1.S-Dihvdroisoindole-Σ-carbonvD-Σ-thiophene-Σ-ylcvclopropylmethyll-isoindole- 1.3-dione (4c)
Thionyl chloride (5 mL, 10 eq) was added at room temperature to a solution of 2.2 g (6.7 mmol) of the carboxylic acid 4a. in 20 mL of dichloromethane. The solution was stirred for 2 hours and was evaporated. The resulting crude acid chloride 4b was taken up in 30 mL of dichloromethane and added at 0 0C to a solution of isoindoline (2.4 g, 3 eq) in 25 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight. The solution was then washed with 0.1 N HCl (X 3) and . saturated sodium bicarbonate (X 3), dried over magnesium sulfate and evaporated. Purification on silica gel using 35% ethyl acetate in hexane as eluent gave 2.3 g (79%) of amide 4c: LC-MS 429 (MH+).
Step 4C: 2-K1 R.2R)-2-Aminomethyl-1-thiophen-2-ylcvclopropyl)-(1 ,3-dihvdroisoindol-2-yl)methanone (4-1 )
To a solution of 2.3 g (5.4 mmol) of the amide 4c in 40 mL of ethanol at 0 0C, was added hydrazine (3 mL, 20 eq). The solution was stirred at room temperature overnight then filtered using ethanol to wash the solid phthalimide derivative. The filtrate was evaporated at room temperature and taken up with dichloromethane and water, lnsolubles were filtered. The product was extracted using 0.5 M HCI (X 3) then washed with dichloromethane. A solution of 1 M KOH was slowly added at 0 °C to basify the aqueous solution. The product was then extracted in dichloromethane (X 3), washed with water and dried over magnesium sulfate. The dry solution was cooled at 0 °C and a solution of 2 M HCI in ether (6 mL, 2 eq) was added. The solution was stirred at room temperature for 15 minutes and then evaporated to give 1.1 g (68%) of 4-1 : LC-MS 299 (MH+).
Using the appropriate starting materials, the following compounds were prepared according to the above procedures.
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0002
EXAMPLE 5
(I R^S^-DlETHYLCARBAMOYL-Z-THIOPHEN-S-YL-CYCLOPROPYLMETHYLAMMONIUM TRIFLUOROACETATE
Figure imgf000025_0001
Step 5A: (1 S.2f?)-2-Hvdroxymethyl-1-thiophen-3-yl-cvclopropanecarboxylic acid diethylamide (5a)
To a solution of diethylamine (0.710 mL, 6.86 mmol) in tetrahydrofuran (2.3 ml_) was added n- butyllithium (4.3 mL of a 1.6M solution in hexanes, 6.88 mmol) at 0 0C under a nitrogen atmosphere. The resulting mixture was cooled to -780C and a solution of 1-4 (411 mg, 2.27 mmol) in tetrahydrofuran (2.3 mL) was slowly added. The reaction mixture was stirred at -780C for 2 hours under a nitrogen atmosphere. To the cold mixture was added a solution of saturated aqueous ammonium chloride (20 ml_). The solution was warmed to room temperature and dried overnight under a stream of nitrogen gas. To the residue was added ethyl acetate (50 ml_) and a solution of saturated aqueous sodium chloride (50 ml_). The biphasic mixture was sonicated, the organic layer separated and washed sequentially with saturated aqueous solutions of sodium potassium tartrate (50 ml.) and ammonium chloride (50 ml_). The organic extract was dried over anhydrous magnesium sulfate, filtered and solvent removed in vacuo to give an oil. Purification by flash chromatography using an eluting solvent of 1 :1 hexanes: ethyl acetate gave 5a (244 mg, 42%) as a yellow oil. 1H NMR (300 MHz, CDCI3): 0.95 (t, 3H), 1.11 (m, 1H), 1.15 (t, 3H), 1.50-1.66 (m, 2H)1 3.11 (t, 1H), 3.27-3.60 (m, 4H), 4.03 (m, 1H), 4.71 (d, 1H), 6.9-6.94 (m, 2H), 7.25 (m, 1H). GCMS, m/z: 253 (M+).
Step 5B: (1S.2RV2-Azidomethyl-1-thiophen-3-yl-cvclopropanecarboxylicacid diethylamide (5b)
To a 10 mL round-bottomed flask was added triphenylphosphine (620 mg, 2.36 mmol), carbon tetrabromide (790 mg, 2.38 mmol), 5a (204 mg, 0.805 mmol) and dry DMF (4 mL). The reaction mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. The mixture was cooled to 0 0C, sodium azide (158 mg, 2.43 mmol) added and the solution stirred at room temperature for 4 hours under a nitrogen atmosphere. Water was added (10 mL) and almost all solvents removed in vacuo. The oily/aqueous residue was dissolved in ethyl acetate (50 mL) and a solution of saturated aqueous sodium chloride (50 mL). The biphasic mixture was placed in a separatory funnel, the layers separated and the aqueous layer extracted with fresh portions of ethyl acetate (2 x 50 mL). The extracts were combined and washed with a solution of saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and solvent removed /n vacuo to give an oil. Purification by flash chromatography using an eluting solvent of 5:1 hexanes: ethyl acetate gave 5b (166 mg, 74%) as a cream colored solid. LC-MS 279 (MH+). GCMS, m/z: 278 (M+).
Step 5C: (1R,2SV2-Diethylcarbamoyl-2-thiophen-3-yl-cvcloDropylmethylammonium trifluoroacetate (5-
To a 10 mL round-bottomed flask was added 5b (166 mg, 0.596 mmol), ethanol (5mL) and 10% palladium on carbon (50 mg). The atmospheric gases were evacuated and the solution stirred at room temperature under 1 atmosphere of hydrogen-gas for 1:5 hours. The mixture was filtered through celite and solvent removed in vacuo to give the crude amine (138 mg, 92%). Purification (of ~46 rηg crude amine) by preparative HPLC gave the TFA salt of 5-1 (46.8 mg, 69%) as an oil. LCMS, UV purity: 100% (220 nm and 254 nm). LC-MS 253 (MH+). chiral
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0003
racemic
Figure imgf000027_0001
Figure imgf000027_0004
EXAMPLE 6
((I R^S^-DlETHYLCARBAMOYL^-THIOPHEN-S-YL-CYCLOPROPYLMETHYLjMETHYLAMlVlONIUM
TRIFLUOROACETATE .
Figure imgf000027_0002
■ ' .5-.1 . . .' . . . , .. , . . . . . 6-1
Step 6A: (H R2Sy2-Diethylcarbamoyl-24hiophen~3-yl-cvclopropylmethyl)methylammonium . trifluoroacBtate (6-1)
To a screw cap vial was added 5-1 (46.0 mg, 0.182 mmol), dichloromethane (1 ml_), triethylamine (0.10 mL, 0.70 mmol) and di-tert-butyl dicarbonate (75 mg, 0.344 mmol). The vial was sealed and stirred at room temperature for 3 hours. An LCMS showed desired BOC-protected product had formed and no 5-1 remained. The mixture was concentrated under a stream of nitrogen gas. Purification by preparative TLC plate using an eluting solvent of 2:1 hexanes: ethyl acetate gave the BOC protected intermediate (50.2 mg, 78%) as colorless oil. This oil (0.142 mmol) was dissolved in THF (1 mL) and sodium hydride (60% dispersion in mineral oil, 50 mg, 1.2 mmol) added. The mixture was stirred at room temperature for 1.5 hours, lodomethane (10 μL, 0.161 mmol) was added and the reaction stirred for 20 hours at room temperature in a sealed vial. Methanol (1 mL) was added, all solvents removed under a stream of nitrogen gas, water (1 ml.) added and the solution extracted into ethyl acetate (3 x 2mL). The combined extracts were concentrated and purified by preparative TLC using an eluting solvent of 1 :1 hexanes: ethyl acetate. The purified material was dissolved in dichloromethane (4 ml_), TFA (1 mL) added and the solution stirred for 30 min at room temperature. All solvents were removed under a stream of nitrogen gas and the crude material purified by preparative HPLC to give the TFA salt of 6-1 (10.2 mg, 15 % over 4 steps) as an oil. LCMS, UV purity: 100% (220 nm and 254 nm). LC-MS (method 5) 267.1 (MH+), tR = 10.79 min.
EXAMPLE 7
((IR^S^-DlETHYLCARBAMOYL^-THIOPHEN-S-YL-CYCLOPROPYLMETHYLj-DlMETHYLAMMONIUM
TRIFLUOROACETATE
Figure imgf000028_0001
Step 7A: (M RΣSVΣ-Diethylcarbamoyl^-thiophen-S-yl-cvcloDropylmethvD-dimethylammonium trifluoroacetate (7-1)
To a screw cap vial was added 5-1 (46.0 mg, 0.182 mmol), dichloroethane (DCE, 1 mL) and formaldehyde (30 μL of a 37 wt% solution in water, 1.08 mmol). The vial was sealed and the solution was stirred at room temperature for one hour. Sodium triacetoxyborohydride (250 mg, 1.18 mmol) was added and the mixture stirred for a further 17 hours at room temperature. The DCE was removed under a stream of nitrogen gas, water (1 mL) and ethyl acetate (2mL) added and the mixture sonicated for 5 minutes. The organic extract was separated, the aqueous layer extracted with fresh portion of ethyl acetate (2 x.2 mL) and the combined organic extracts dried under a stream of nitrogen gas. The oil residue was dissolved in methanol and purified by preparative. HPLC to give the TFA salt of 7-1 (10.5 .. mg, 15 %) as an oil. LCMS, UV purity: 98% (220 nm and 254 nm). LC-MS (method 5) 281 (MH+), tj, = 7.55 min.
. • • EXAMPLE 8
DIETHYL (1 R,2R)-2-AMINOMETHYL-1-(5-BROMOTHIOPHEN-2-YL)CYCLOPROPRANECARBOXAMIDE .
Figure imgf000028_0002
Step 8A: Diethyl (1R.2Ry2-Aminomethyl-1-(5-bromothiophen-2-yl)cyclopropranecarboxamide (8-1) To a solution of the starting material 8a (60 mg, 0.16 mmol) in 1 mL of DMF was added a solution of N-bromosuccinimidθ (NBS1 31 mg, 1.1 eq) in 1 mL of DMF. The resulting solution was stirred at room temperature overnight with some protective foil wrapped around the flask to avoid degradation. The solution was then poured into cold water, extracted with dichloromethane (3X) and evaporated to give 80 mg (100% yield) of the desired 2-bromothiophene 8c, LC-MS (method 2) 333 (MH+), tR = 4.47 min. This material was converted to the free amine 8-1 as described in Step 4C.
EXAMPLE 9
DIETHYL (I R1ZR)-Z-AMINOMETHYL-I-(S-CHLOROTHIOPHEN^-YL)CYCLOPROPRANECARBOXAMIDE
Figure imgf000029_0001
Step 9A: Diethyl (1R.2RV2-Aminomethyl-1-(5-chlorothiophen-2-v0cyclopropranecarboxarnide (9-1) To a solution of the starting material 5-2 (25 mg, 0.1 mmol) in 1 mL of dichloromethane was added 12 μL (1.5 eq) of sulfuryl chloride. The resulting solution was stirred at room temperature for 1 h. The solution was then evaporated and purified on preparative HPLC to give 9 mg (30% yield) of 9-1 , LC-MS (method 2) 287 (MH+), tR = 4.23 min.
EXAMPLE 10 . . DIETHYL (1 R,2R)-2-AMINOMETHYL-1 -(4,5-DICHLOROTHIOPHEN^-YL)CYCLOPROPRANECARBOXAMIDE
Figure imgf000029_0002
Step 1OA: Diethyl (1 R,2R)-2-Aminomethyl-1-(4,5-dichlorothiophen-2-v0cvclopropranecarboxamide (10- 1) and Diethyl (1R,2R)-2-Aminomethyl-1-(3A5-trichlorothiophen-2^0cvclopropranecarboxamide (10-2)
. To a solution of the starting material 5-2 (80 mg, 0.21 mmol) in 2 mL of dichloromethane was added 36 μL (20 eq) of sulfuryl chloride. The resulting solution was stirred at.room temperature for 3h and evaporated. The resulting crude products were purified on preparative HPLC to give 10-1, LC-MS (method 2) 320.9 (MH+), tR = 4.66 min and 10-2, LC-MS (method 2) 354.9 (MH+), tR = 5.20 min. EXAMPLE 11 DIETHYL (1 R,2R)-2-[(AMINOACETYLAMlNO)METHYL]-1-THIOPHEN-2-YLCYCLOPROPRANECARBOXAMIDE
Figure imgf000030_0001
Step 11 A: Diethyl (1 R,2RV2-r(Aminoacetylamino)methvπ-i4hiophen-2-ylcvclopropranecarboxamide (11-11
To a solution of the starting material 5-2 (50 mg, 0.2 mmol) and triethylamine (60 μl_, 2 eq) in 1 mL of dioxane at 0 0C was added phthalyl-glycyl chloride (44 mg, 1 eq) in 1 ml_ of dioxane. The resulting solution was stirred at room temperature overnight. The solution was then evaporated. Water was added and the product was extracted in ethyl acetate (X3) to give 77 mg (88% yield) of 11a, LC-MS 440 (MH+). This material was converted to the free amine 11-1 as described in Step 4C. LC-MS (method 2) 310.1 (MH+), tR = 3.44 min. ; . . .
EXAMPLE 12 DIETHYL (1 R,2R)-2-((S,R)-2-AMINO-1-HYDROXYETHYL)-1-THIOPHEN-2-YLCYCLOPROPRANECARBOXAMIDE
Figure imgf000030_0002
Step 12A: Diethyl (1 Rv2R)-2-Formyl-1-thiophen-2-ylcvclopropranecarboxamide C\2b)
DMSO (0.26 mL , 4 eq) in 1mL of dichloromethane was added dropwise to a solution of 0.15 mL of oxalyl chloride (1 eq) in 1mL of dichloromethane at -78 0C. A solution of the alcohol 12a (0.23 g, 0.9 mmol) in 1 mL dichloromethane was then added slowly. The solution was stirred at -780C for 2h and triethylamine (0.53 mL, 4 eq) was added.. The reaction mixture was stirred at -78 0C for 1 hour. then was quenched with saturated NH4CI. The temperature was allowed to warm up to RT and the product, was extracted with ethyl acetate (X3), and washed with water yielding 0.19 g (80%) of 12b, LC-MS 252
Step 12B: Diethyl (1 R,2R)-2-((S.RV1-Hvdroxy-2-nitroethylH-thiophen-2-ylcyclopropranecarboxamide (12c) ■
Nitromethane (19 μL, 1 eq) was added at 0 °C to a suspension of sodium hydride (17 mg, 1.2 eq) in 2 mL of THF. After 15 minutes at room temperature, the 12b (90 mg, 0.36 mmol) was added in 1mL of THF. The reaction mixture was stirred at room temperature for 40 minutes and then quenched with saturated NH4Cl. The solution was evaporated and then extracted with ethyl acetate to give after evaporation 0.1 g (90%) of crude 12c, LC-MS 313 (MH+).
Step 12B: Diethyl (1 R^R^-ffS.R^-Amino-i-hvdroxyΘthvD-i-thioDhen-Σ-ylcvclopropranecarboxamide (12-1)
NiCI2 (31 mg, 3 eq) was added at room temperature to a solution of 25 mg (0.08 mmol) of 12c in 0.5 mL of THF. Methanol (0.5 mL) was then added and the reaction mixture was cooled to 0 °C. Sodium borohydride (36 mg, 12 eq) was then added in portions and the reaction mixture was stirred at 0 °C for 30 minutes. HCI was added until pH 1 and the mixture was stirred at room temperature for 2 hours. The solution was filtered and ammonium hydroxide was added until pH 9. The solution was extracted with ethyl acetate and evaporated. Purification on preparative HPLC gave 12-1. LC-MS (method 2) 283.1 (MH+), tR = 4.22 min.
EXAMPLE 13
INHIBITION OF RADIOLIGAND TRANSPORT BY HEK293 CELLS EXPRESSING HUMAN NOREPINEPHRINE, DOPAMINE,
OR SEROTONIN TRANSPORTERS
The norepinephrine, dopamine, and serotonin transporters were individually expressed in stably transfected HEK293 cell lines and grown in Dulbecco's Modified Eagles Medium (DMEM) (Cellgro, 15- 013-CV) with the following supplements: 1% HEPES (Cellgro, MT 25-060-CI); 1% L-glutamine (Cellgro, MT 25-005-CI); 1% sodium pyruvate (Cellgro, MT 25-OOOCI); 1% Pen/Strep (Cellgro, MT 30-001-CI); 10% heat-inactivated fetal bovine serum (FBS) (Hyclone, Logan, UT); 250 μg/ml G418 (Cellgro, 61-234-. RG).
The day before the assay, solid white 96-well TC-treated sterile plates (Costar, 3917) that had been coated with 0.01% poly-D-lysine (Sigma, P6407) and 0.01% collagen (BD Biosciences, 354236) were seeded with cells at a density of 20,000 cells/well. The cells were allowed to attach overnight in a 37 0C incubator (7.5% CO2). On the day of the assay, media was removed, and cells were washed with phosphate buffered saline. The cells were then incubated at room temperature for 20 minutes with varying concentrations of competing ligaήd in a total volume of 150 μl transport buffer (20 m M HEPES, 122 mM NaCI, 3 rtiM KCl, 1.3 mM CaCI2,.1.2 mM KH2PO4, 0.4. mM MgSO4, 1 mM ascorbic acid, 0.1 mM pargylinβj 0.1 mM tropolone). Radioligand was then added to the cells for a total volume of 200 μl, and cells were incubated at room temperature for an additional 20 minutes. (Levo-[ring-2,5,6-3H] Norepinephrine (52 Ci/mmol, PerkinElmer, NET-678) was used for NET, 3,4r[ring-2,5,6-3H] Dihydroxyphenylethylamine (50 Ci/mmol, PerkinElmer, NET-673) was used for DAT, and [alpha, beta- 3H(N)] 5-Hydrόxytryptamine (30 Ci/mmol, PerkinElmer, NET-498) was used for SERT.) After incubation, the transport buffer was quickly aspirated from the plates, and the cells were washed twice with 4 0C wash buffer (20 mM HEPES, 280 mM D-mannitol, 5.4 mM KCI, 1.8 mM CaCI2, 0.8 mM MgSO4, 1 mM ascorbic acid, 0.1 mM pargyline, 0.1 mM tropolone)! Cells were treated with 50 μl 5% sodium dodecyl sulfate solution (Sigma, L4522) and 200 μl Microscint scintillation fluid. Plates were shaken vigorously overnight before monitoring radioligand in a TopCount-NXT (Packard) microplate scintillation counter. Data were analyzed by nonlinear, least-squares curve fitting algorithms using ActivityBase (IDBS, Guildford, Surrey, UK).
EXAMPLE 14
RADIOLIGAND BINDING TO HUMAN NET TRANSPORTER EXPRESSED IN MAMMALIAN CELL LINES Crude membranes were prepared by differential centrifugation from HEK293 cells stably transfected with the human norepinephrine transporter. Membranes (3 μg of protein) were incubated for 2 hours with 1.5 nM [3H] Nisoxetine (86 Ci/mmol, PerkinElmer, NET-1084) in the presence of varying concentrations of competing ligaπd. Non-specific binding was determined in the presence of excess (1 μM) desipramine. Reactions were terminated by rapid vacuum filtration using a Packard 96-well cell harvester over PEI soaked (1%) (Sigma, P3143) GF/C membrane filter plates (Packard, 6005174). The filter plates were then washed with 600 μl phosphate buffered saline containing 0.01% (v/v) Triton-X100 and dried under forced air fans. Microscint scintillation fluid was added to each well before monitoring bound radioligand in a TopCount-NXT (Packard) microplate scintillation counter. Binding data were analyzed by nonlinear, least-squares curve fitting algorithms using ActivityBase (IDBS, Guildford, Surrey, UK).
EXAMPLE 15
FORMALIN FLINCH ASSAY
The formalin test was conducted using the Automated Nociception Analyzer (Department of Anesthesiology, University of California, San Diego, Yaksh et al, 2001). One hour prior to testing, a metal band was glued to a rat's left hind paw. The animal was then put in a testing chamber. Animals were dosed with compound orally at volumes equal to or less than 10 mL/kg with either vehicle (5% Cremophor® in milliQ water) or active compounds (1-100 mg/kg) one hour prior to formalin injection. As a positive control, rats were dosed with ethosuximide at 600 mg/kg orally. Animals were injected with • 50 μl of 5% formalin solution (20-fold dilution of a 37% stock from Fisher Chemicals) subcutaneously on dorsal surface of the left hind paw. The number of flinches was recorded for each minute for one hour . by detecting the movement.of a metal paw band with a localized low strength sinusoidal electromagnetic field. Drug effects were analyzed by a one-way ANOVA on each phase {Phase I (0-9 minutes), Phase HA (10-40 minutes), and Phase HB (41-60 minutes)}. Significant effects were analyzed by Durinett's post hoc comparison to vehicle. As an example, compound 4-24 administered at 60 mg/kg was found to decrease flinches during Phase HA by 40% compared to vehicle, similar to positive control.
EXAMPLE 16
SPINAL NERVE LIGATION ASSAY ■ • ■
Neuropathy was induced by Spinal Nerve Ligation (SNL) surgery (Kim and Chung, 1992). Briefly, in rats, the left L5 and L6 spinal neurons distal to the dorsal root ganglion were tightly ligated with 6-0 silk suture. At 4-12 weeks post-surgery, the rats were tested for mechanical hyperalgesia using the pin prick method (Koch et al, 1996). The length of time the paw was held off the grid-floor was measured with the computer program Xnote Stopwatch ver1.4. Zero seconds was assigned when there was no paw withdrawal. The baseline score was determined from the average of five trials. Baselines were counterbalanced for assignments into treatment groups. Animals were dosed with compound orally at volumes equal to or less than 10 mL/kg with either vehicle (5% Cremophor® in milliQ water) or active compounds (1-100 mg/kg) one hour prior to assessment of withdrawal in response to the pin prick. Drug effects were analyzed by a two-way ANOVA with treatment and time as variables. Significant effects were analyzed by Dunnett's post hoc comparison. As an example, compound 4-29 administered at 30 mg/kg was found to decrease hyperalgesia responses by approximately 70% compared to vehicle.
Kim SH, Chung JM., An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat., Pain. 1992 Sep;50(3):355-63.
Koch BD, Faurot GF, McGuirk JR, Clarke DE, Hunter JC, Modulation of mechano-hyperalgesia by clinically effective analgesics in rats with a peripheral mononeuropathy. Analgesia. 1996; VoI 2:157-164. Yaksh TL, Ozaki G, McCumber D, Rathbun M, Svensson C, Malkmus S, Yaksh MC, An automated flinch detecting system for use in the formalin nociceptive bioassay. J Appl Physiol. 2001 Jun;90(6):2386-402.
EXAMPLE 17
MlCRODIALYSIS PROCEDURE FOR THE DETERMINATION OF MONOAMINE LEVELS
Surgery: Animals were anaesthetized with isoflorane, and a servo-controlled heating pad maintained body temperature throughout the surgery. Animals were placed in a stereotaxic instrument and an incision was made down the mid-line over the skullcap. Miniature bone screws were inserted individually into the occipital, parietal and frontal skull plates. Two small holes (1.8 mm diameter) were drilled with micro-trephines for stereotaxic insertion of guide cannulae, one in the left frontal plate (3.1 mm anterior and 1.2 mm lateral to bregma) and a second in the right parietal plate (0.5 mm posterior and 4.4 mm lateral to bregma). Guide cannulae were lowered into the brain at a rate of ~0.2 mm/min and at an angle of 5° to the following depths: 2.0 mm (left frontal cannula) and 3.0 mm (right striatal cannula). The dialysis membranes of the microdialysis probes have a 3.0 mm length and extend 3.0 mm past the ends of the implanted cannulae so the final depths of inserted probes were 3.0 mm and 6.0 mm for the PFG and striatal probes respectively. The sampled brain regions, correspond to (1 ) left prefrontal cortex (PFC), including mainly anterior cingulate and prelirήbic cortices, and (2) right striatum (caudate-putamen) mainly, but also including to a small degree in some animals, lateral globus pallidus. Cannulae were secured with dental cement to the skull and bone screws. The skin incision was closed with 4-Q suture and Vetbond (3-M). Animals received immediate post-operative care and were allowed, one full week to recover from surgery. Animals were housed in 12:12 light-dark room (lights off at 7AM). Microdialysis procedure: After a 1-week recovery, animals were placed in individual Raturn bowls for microdialysis sampling (Bioanalytical Systems, Inc., West Lafayette, IN). The capped stylets that cover the cannulae and maintain their patency. were removed, and microdialysis probes were inserted manually at a slow rate. Probe membranes protruded 3.0 mm from the cannula tips and sampled extracellular fluid over this entire 3.0 mm length. The input tube of each microdialysis probe was connected to a syringe pump (CMA/102, CMA Microdialysis, North Chelmsford, MA) that delivered artificial cerebrospinal fluid (aCSF). aCSF had the following composition: 154.7mM Na+, 2.9mM K+, H mM Ca2+, 0.82 mM Mg2+, 132.49 rnM CP (pH 7.4). The output tubes of each probe were connected to a refrigerated fraction collection system (Honeycomb, Bioanalytical Systems, Inc.). Animals were allowed 14-16 hrs to recover from probe insertion and to habituate to the bowl and tether. Probes were perfused over this time period at a slow rate of 0.2 μL/min. On the following morning, pump perfusion rates were increased to 1.1 μL/min at the time of lights off (7 AM). Dialysate sampling began 1 hr later. Individual samples were collected over a 30 min time period. After 1.5 hrs of baseline sampling (3 samples), either vehicle (5% Cremophor in MiIIQ water) or NBI compound, which was prepared in vehicle solution, was administered orally at doses of either 1, 3 or 10 mg/kg and at a dose volume of 5 mL/kg. Sampling was continued for 6 hrs after dosing (12 post-dose samples). At the end of the study, sampling carousels were removed and transported to the HPLC-electrochemical detection system. Animals were euthanized with CO2 and decapitation. Brains were immediately removed and prepared for histology by inserting the brains briefly (1 min) into -40 0C 2-methylbutane. Brain areas of interest (left frontal region, ~2-4 mm rostral to bregma, and right midline region, ~0-2 mm caudal to bregma) were sectioned coronally with a cryostat and sections were prepared for histological examination of probe placement and depth.
HPLC-EC detection and analysis: Monoamine levels in microdialysis samples were measured by HPLC-electrochemical detection (EC). 27 uL was withdrawn from individual microdialysis samples and injected onto an HPLC-EC system consisting of a pulse-free pump (Model 582 Solvent Delivery System; ESA Instruments, Chelmsford, MA), a 2 mm x 15 cm, 3 um particle size LC column (70-4129; ESA Instruments), and an electrochemical detector (Coulochem III; ESA Instruments). The mobile phase consisted of 0.05 M citrate, 1.00 mM OSA, 0.1 rnM EDTA, 6.5% methanol, and pH = 4.85, and resulted. '. in retention times of approximately 4", 12" and 34" for NE, DA and 5-HT; respectively. The optimal detection settings for the detector were the following: working electrode = +300 mV, reference electrode #1 = +200 mV, reference electrode #2 = -120 mV, signal filter = 0.1 Hz, range = 1.0 nA. Chromatograms were analyzed manually off-line (EZChrome Elite software; Agilent Technologies, Pleasantown, CA) to determine peak areas for NE (norepinephrine), DA (dopamine) and 5-HT. Daily analysis of monoamine standards showed the quantitative limits for NE, DA and 5-HT was approximately 0.2-0.5 pg per 27 uL of sample. Peak values for each sample were normalized to the mean peak value of the first three baseline samples for each monoamine using Micosoft Excel. Normalized data were imported info GraphPad Prism (GraphPad Software, San Diego, CA) for ■ graphical analysis arid to test for significant differences between treatment groups using repeated measures, two-way ANOVA for treatment (different dose-groups: vehicle, 1 , 3 and 10 mg/kg) and time (15 time points). If significant interaction effects were observed, pair-wise post-hoc group comparisons were made using Tukey's least significant difference procedure to test for significant effects of treatment at each time point. As an example, compound 4-77 at 10 mg/kg was found to significantly increase extracellular norepinephrine concentrations in the prefrontal cortex by 250% over vehicle control.
It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

CLAIMSWe claim:
1. A compound having the following structure:
Figure imgf000035_0001
(I) or a stereoisomer, prodrug or pharmaceutically acceptable salt, ester or solvate thereof, wherein:
R1, R2 are independently H, C1-10alkyl, Ci-iOalkyl substituted by 1 to 4 R9, aryl, aryl substituted by 1 to 4 R10, heterocycleC^alkyl, heterocycleC1-4alkyl substituted by 1 to 4 R10, arylC-i. 4alkyl, or substituted by 1 to 4 Ri0; or R1 and R2 taken together with the nitrogen to which they are attached form a 5-14 member heterocycle or 5-14 member heterocycle substituted by 1 to 4 Ri0;
R3, R4 are independently H, C1-4alkyl, C^alkyl substituted by 1 to 4 Rio, or -C(=O)R8;
Rsa. Rβb ar6 independently and at each occurrence, H1 , F, OH, C^alkyl, C^alkyl substituted by 1 to 4 R9, Ct.4alkoxy, or C-^alkoxy substituted by 1 to 4 R9;
R6 is aromatic heterocyclic ring or aromatic heterocyclic ring .substituted by 1 to 4 Ri0; >■
R7 is H1 C1^aIkVl, C^alkyl substituted by 1 to 4 R9, F, OH, C-^alkoxy, C-^alkoxy substituted by 1 to 4 R9, or phenyl; ;
R8 is C-t^alkyl or Chalky! substituted by 1 to 4 R9;
R9 is halo, OH, C1^aIkOXy, CN, or NR11Ri2;
R10 is Chalky!, halo, OH, CMalkoxy, CN, or NR11R12; • R11, R-12 are independently and at each occurrence, H or C^alkyl; and n is 1 or 2.
2. The compound of claim 1 wherein n is 1.
3. The compound of claim 1 wherein R3 and R4 are independently H or Ci^alkyl.
4. The compound of claim 1 wherein R1 and R2 are C1-10alkyl or C1-10alkyl substituted by 1 to 4 R9. . ' •
5. The compound of claim 1 wherein R1 and R2 taken. together with the nitrogen to which they are attached form a 5-14 member heterocycle or 5-14 member heterocycle substituted by 1 to 4 R10.
6. The compound of claim 1 wherein R7 is H.
7. The compound of claim 1 wherein R6 is nonaromatic heterocycle fused to an aryl or heteroaryl moiety.
8. The compound of claim 1 wherein R6 is heteroaryl or heteroaryl substituted by 1 to 4 R10.
9. The compound of claim 8 wherein n is 1.
10. The compound of claim 9 wherein R7 is H.
11. The compound of claim 1 wherein R8 is thiophen-2-yl, thiophen-2-yl substituted by 1-3 R10, thiophen-3-yl, or thiophen-3-yl substituted by 1-3 R10-
12. The compound of claim 1 wherein Ri and R2 are independently
Figure imgf000036_0001
substituted by 1 to 4 R9.
13. The compound of claim 12 wherein R6 is thiophen-2-yl, thiophen-2-yl substituted by 1-3 R-io, thiophen-3-yl, or thiopheη-3-yl substituted by 1-3 R10-
14. The compound of claim 13 wherein R3 and R4 are independently H or methyl. . ,
15. The compound of claim 1 wherein R1 is unsaturated
Figure imgf000036_0002
substituted by 1 to 4 R9.
16. The compound of claim 1 wherein R5a and R5b are H.
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
18. A method of treating a disorder of the central or peripheral nervous system comprising administering to. a subject in need thereof an effective amount of the pharmaceutical composition of claim 17. •
19. The method of claim 18 wherein the disorder is depression, anxiety, pain, fibromyalgia, urinary incontinence or attention deficit hyperactivity disorder (ADHD).
20. The method of claim 19 wherein the disorder is depression, anxiety, neuropathic pain, fibromyalgia or urinary incontinence.
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WO2020007902A1 (en) 2018-07-05 2020-01-09 Bayer Aktiengesellschaft Substituted thiophenecarboxamides and analogues as antibacterials agents
WO2021001331A1 (en) 2019-07-03 2021-01-07 Bayer Aktiengesellschaft Substituted thiophene carboxamides and derivatives thereof as microbicides
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WO2020007902A1 (en) 2018-07-05 2020-01-09 Bayer Aktiengesellschaft Substituted thiophenecarboxamides and analogues as antibacterials agents
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WO2021001331A1 (en) 2019-07-03 2021-01-07 Bayer Aktiengesellschaft Substituted thiophene carboxamides and derivatives thereof as microbicides
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