WO2006007843A1 - 2-(1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence - Google Patents
2-(1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence Download PDFInfo
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- WO2006007843A1 WO2006007843A1 PCT/DK2005/000491 DK2005000491W WO2006007843A1 WO 2006007843 A1 WO2006007843 A1 WO 2006007843A1 DK 2005000491 W DK2005000491 W DK 2005000491W WO 2006007843 A1 WO2006007843 A1 WO 2006007843A1
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- 0 CC(*)(C=C1)N(C)c2c(*)c(*)c(*)c(*)c2C1(C)Sc1c(*)c(*)c(*)c(*)c1*[C@]1CNCCC1 Chemical compound CC(*)(C=C1)N(C)c2c(*)c(*)c(*)c(*)c2C1(C)Sc1c(*)c(*)c(*)c(*)c1*[C@]1CNCCC1 0.000 description 1
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- C07D401/12—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 chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to compounds, which are serotonin reuptake inhibitors and 5 preferably also norepinephrine reuptake inhibitors and/or dopamine reuptake inhibitors and the medical use of such compounds, e.g., in the treatment of affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD) and stress urinary incontinence.
- compounds which are serotonin reuptake inhibitors and 5 preferably also norepinephrine reuptake inhibitors and/or dopamine reuptake inhibitors and the medical use of such compounds, e.g., in the treatment of affective disorders, pain disorders, attention deficit hyperactivity disorder (ADHD) and stress urinary incontinence.
- ADHD attention deficit hyperactivity disorder
- MAOIs monoamine oxidase inhibitors
- biogenic amine neurotransmitter serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] transporter reuptake blockers
- modulators especially blockers of one or more of the 5 -HT and/or NE receptors.
- 5-HT and/or NE-receptor blockers i.e. 5-HT and or NE-antagonist's
- 5-HT and or NE-antagonist's have not proven very successful in the treatment of depression and anxiety and the preferred and currently most efficient treatments are based on the enhancement of 5-HT and/or NE neurotransmission by 20 blocking their reuptake back from the synaptic cleft (Slattery, D.A. et al, "The evolution of antidepressant mechanisms", fundamental and Clinical pharmacology, 2004, 18, 1-21; Schloss, P. et al, "new insights into the mechanism of antidepressant therapy", Pharmacology and therapeutics, 2004, 102, 47-60).
- SSRJs Selective serotonin reuptake inhibitors
- SNRTs have been shown in clinical studies to have a beneficial effect on pain (e.g. Fibromyalgia syndrome, overall pain, back pain, shoulder pain, headache, pain while awake and during daily activities) and especially pain associated with depression (Berk, M. Expert Rev. Neurotherapeutics 2003, 3, 47-451; Fishbain, D. A., et al. "Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review" Pain Medicine 2000 1:310-316).
- SNRI' s have also been shown in clinical studies to have a beneficial effect in attention deficit hyperactivity disorder (ADHD) (N. M. Mukaddes; Venlafaxine in attention deficit hyperactivity disorder, European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002, Page 421). Furthermore, SNRI' s have been shown to be effective for the treatment of stress urinary incontinence (Dmochowski R.R. et al. "Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence", Journal of Urology 2003, 170:4, 1259-1263.)
- ADHD attention deficit hyperactivity disorder
- SNRI' s have been shown to be effective for the treatment of stress urinary incontinence (Dmochowski R.R. et al. "Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence", Journal of Urology 2003, 170:4, 1259-1263.)
- Diphenyl sulphides of Formula (HA) and variations thereof have been disclosed as serotonin re-uptake inhibitors and have been suggested for use in treatment of depression, cf. e.g. US 5095039, US 4056632, EP 396827 Al and WO 9312080.
- EP 402097 describes halogen substituted diphenylsulfides claimed to be selective serotonin inhibitors for treatment of depression.
- WO 9717325 disclose derivatives of N,N-dimethyl- 2-(arylthio)benzylamine claimed to be selective serotonin transport inhibitors and suggest their use as antidepressants. J. Jilek et al., 1989, Collect. Czeck Chem.
- K. Sindelar et al. "Collection of Czechoslovak Chemical Communications, (1991), 56(2), 449-58, by K. Sindelar et al” disclose compounds of Formula (HB) in which one of the rings is substituted with a thiophene ring with test for selectivity as 5 -HT re-uptake inhibitor and NA re-uptake inhibitor, respectively, for use as antidepressants.
- the present invention provides 2-(lH-indolylsulfanyl)-aryl amine derivatives of formula I which are serotonin reuptake inhibitors.
- a particular aspect of the invention provides compounds possessing the combined effect of serotonin reuptake inhibition and norepinephrine reuptake inhibition.
- Another particular aspect of the invention provides compounds possessing the combined effect of serotonin reuptake inhibition and dopamine reuptake inhibition. Furthermore, some of the compounds are also triple 5 -HT, NE and DA re-uptake inhibitors.
- One object of the invention is the provision of compounds, which are serotonin reuptake inhibitors. Another object of the invention is the provision of compounds, which are both serotonin reuptake inhibitors and noradrenaline reuptake inhibitors. Yet another object of the invention is the provision of compounds, which are both serotonin reuptake inhibitors and dopamine reuptake inhibitors. Yet another object of the invention is the provision of compounds, which are serotonin reuptake inhibitors, noradrenaline reuptake inhibitors and dopamine reuptake inhibitors.
- the compounds of the invention are substituted indole derivatives of the general formula I as the free base or salts thereof
- the invention provides a compound according to the above for use as a medicament.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound according to the above and at least one pharmaceutically acceptable carrier or diluent.
- the invention provides the use of a compound according to the above for the preparation of a medicament for the treatment of affective disorders, pain disorders, ADHD and stress urinary incontinence.
- the invention furthermore concerns the use of a compound according to the above in a method of treatment of affective disorders, pain disorders, ADHD and stress urinary incontinence.
- heteroatom refers to a nitrogen, oxygen or sulphur atom.
- Halo means halogen.
- Halogen means fluoro, chloro, bromo or iodo.
- C 1-6 -alk(en/yn)yl means a Ci- 6 -alkyl, a C 2-6 -alkenyl or a C 2-6 -alkynyl group.
- C 1-6 -alk(en)yl means a C 1-6 -alkyl or a C 2-6 -alkenyl group.
- C 1-6 -alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl- 1 -propyl.
- C 2 - 6 -alkenyl designates such groups having from two to six carbon atoms, including one double bond, including but not limited to ethenyl, propenyl, and butenyl.
- Such C 2-6 -alkenyl group may be branched or unbranched.
- C 2-6 -alkynyl designates such groups having from two to six carbon atoms, including one triple bond, including but not limited to ethynyl, propynyl and butynyl.
- C 2-6 -alkynyl group may be branched or unbranched.
- C 3-8 -cycloalk(en)yl means a C 3-8 -cycloalkyl or a C 3-8 -cycloalkenyl group.
- C 3-8 -cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, and cyclohexyl.
- C 3-8 -cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and one double bond, including but not limited to cyclopropenyl, cyclopentenyl and cyclohexenyl.
- the present invention relates to 2-(lH-indolylsulfanyl)-aryl amine-derivatives which are serotonin reuptake inhibitors, some of the compounds are also noradrenaline reuptake inhibitors. Furthermore, some compounds of the invention are serotonin reuptake inhibitors and dopamine reuptake inhibitors. Furthermore, some compounds of the invention are serotonin reuptake inhibitors, noradrenaline reuptake inhibitors and dopamine reuptake inhibitors. Accordingly, the compounds of the invention are considered to be useful in the treatment of affective disorders such as for example depression and anxiety.
- the present invention relates to a compound represented by the general formula I as the free base or salts thereof
- each of R 1 -R 4 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, amino, C 1-6 -alk(en/yn)ylamino, di-(C 1-6 -alk(en/yn)yl)arnino 5 C 1-6 -alk(en/yn)ylcarbonyl, aminocarbonyl, C 1-6 -alk(en/yn)ylaminocarbonyl, di-(C 1-6 -alk(en)yl)aminocarbonyl, hydroxy, C]_ 6 -alk(en/yn)yloxy, C 1 _ 6 -alk(en/yn)ylsul
- R 5 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3 . 8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, amino, Ci -6 -alk(en/yn)ylamino, di-(C 1-6 -alk(en/yn)yl)amino, C 1-6 -alk(en/yn)ylcarbonyl, aminocarbonyl,
- Z is selected from the group consisting of N, CH and C, with the proviso that the dotted line represents a bond when Z is C and with the proviso that the dotted line does not represent a bond when Z is N or CH.
- the dotted line — represents a bond. In another embodiment of the compound of formula I the dotted line — does not represent a bond.
- the dotted line — does not represent a bond and Z represents a nitrogen atom. In a further embodiment of the compound of formula I, the dotted line — does not represent a bond and Z represents CH. In a further embodiment of the compound of formula I, the dotted line — represents a bond and Z represents a carbon atom.
- each of R 1"4 is independently selected from the group consisting of nitro, amino, C 1-6 -alk(en/yn)ylamino, di-(C 1-6 -alk(en/yn)yl)amino, C 1-6 -alk(en/yn)ylcarbonyl, aminocarbonyl,
- each of R 1'4 is independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3 .
- each of R 1"4 is independently selected from the group consisting of hydrogen, halogen and Ci -6 -alk(en/yn)yl.
- an embodiment concerns such compounds wherein at least one of R 1'4 is hydrogen; in a further embodiment at least one of R 1"4 is halogen such as fluoro; in a further embodiment at least one of R 1'4 is C 1-6 -alk(en/yn)yl such as methyl.
- R 1 is hydrogen.
- R 2 is selected from the group consisting of hydrogen, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl and C 3-8 -cycloalk(en)yl- Ci -6 -alk(en/yn)yl.
- R 2 is selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl.
- an embodiment of R 2 is hydrogen; another embodiment of R 2 is Ci- 6 -alk(en/yn)yl typically Ci -6 -alkyl such as methyl.
- R 3 is hydrogen
- R 4 is selected from the group consisting of hydrogen, halogen and cyano. Typically, R 4 is selected from the group consisting of hydrogen and halogen. To further illustrate without limiting the invention an embodiment of R 4 is hydrogen; another embodiment of R 4 is halogen such as fluoro.
- R 5 is selected from the group consisting of halogen, cyano, amino, C 1-6 -alk(en/yn)ylamino, di-(C 1-6 -alk(en/yn)yl)amino, C i -6 -alk(en/yn)ylcarbonyl, aminocarbonyl, C i -6 -alk(en/yn)ylaminocarbonyl, di-(C 1-6 -alk(en)yl)aminocarbonyl, hydroxy, Ci- ⁇ -alkCen/ynJyloxy, Cj- ⁇ -alkCen/yntylsulfanyl, halo-C 1-6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)ylsulfonyl, halo-C 1-6 -alk(en/yn)ylsulfanyl, halo-C
- R 5 is selected from the group consisting of hydrogen and Ci -6 -alk(en/yn)yl.
- an embodiment of R 5 is hydrogen; another embodiment of R 5 is C 1-6 -alk(en/yn)yl typically Ci ⁇ -alkyl such as methyl.
- R 5 is attached to position 2 of the indole moiety. In a further embodiment of the compound of formula I, R 5 is attached to position 3 of the indole moiety.
- each of R 6"9 is independently selected from the group consisting of amino, C 1-6 -alk(en/yn)ylamino, di-(C i -6 -alk(en/yn)yl)amino, C i -6 -alk(en/yn)ylcarbonyl, aminocarbonyl, C 1-6 -alk(en/yn)ylaminocarbonyl, di-(C 1-6 -alk(en)yl)aminocarbonyl, hydroxy, Ci -6 -alk(en/yn)ylsulfanyl, 1IaIo-C 1 -6 -alk(en/yn)yl, halo-C 1-6 -alk(en/yn)ylsulfonyl, halo- Ci -6 -alk(en/yn)ylsulfanyl and C 1-6 -alk(en/yn)yls
- each of R 6"9 is independently selected from the group consisting of hydrogen, halogen, nitro, C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy and C 1-6 -alk(en/yn)yl-O-CO-.
- an embodiment concerns such compounds wherein at least one of R 6"9 is hydrogen; in a further embodiment at least one of R 6"9 is halogen such as chloro or fluoro; in a further embodiment at least one of R 6"9 is nitro; in a further embodiment at least one of R 6"9 is Ci -6 -alk(en/yn)yl typically C 1-6 -alkyl such as methyl or ethyl; in a further embodiment at least one of R 6'9 is C 1 _ 6 -alk(en/yn)yloxy typically C ⁇ -alkyloxy such as methoxy; in a further embodiment at least one of R 6"9 is Ci. 6 -alk(en/yn)yl-O-CO- typically Ci-6-alkyl-O-CO- such as CH 3 -O-CO- .
- R 6 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl and Q-e-alk ⁇ n/yntyloxy.
- R 6 is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 1--6 -alk(en/yn)yloxy.
- R 6 is hydrogen, another embodiment of R 6 is halogen such as chloro or fluoro; another embodiment of R 6 is C 1-6 -alk(en/yn)yl typically C 1-6 -alkyl such as methyl; another embodiment of R 6 is Ci -6 -alk(en/yn)yloxy typically Q- ⁇ -alkyloxy such as methoxy.
- R 7 is selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 -alk(en/yn)yl, C 3 - 8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-C 1-6 -alk(en/yn)yl, Cj-e-aU ⁇ n/yntyloxy and Ci_ 6 -alk(en/yn)yl-O-CO- .
- R 7 is selected from the group consisting of hydrogen, halogen, nitro, C 1-6 -alk(en/yn)yl, d- ⁇ -alkCen/yntyloxy and C 1-6 -alk(en/yn)yl-O-CO- .
- an embodiment of R 7 is hydrogen, another embodiment of R 7 is halogen such as chloro or fluoro; another embodiment of R 7 is nitro; another embodiment of R 7 is C 1-6 -alk(en/yn)yl typically C ⁇ -alky! such as methyl, another embodiment of R 7 is C !
- R 7 is Ci -6 -alk(en/yn)yl-O-CO- typically Ci -6 -alkyl-O-CO- such as Me-O-CO-.
- R 8 is selected from the group consisting of hydrogen, halogen, cyano, Ci -6 -alk(en/yn)yl, C 3- s-cycloalk(en)yl 5
- R is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl and Q- ⁇ -alk ⁇ n/yntyloxy .
- R 8 is hydrogen; another embodiment of R 8 is halogen such as chloro or fluoro; another embodiment of R 8 is C 1-6 -alk(en/yn)yl typically C 1-6 -alkyl such as methyl; another embodiment of R 8 is C 1-6 -alk(en/yn)yloxy typically C ⁇ -alkyloxy such as methoxy.
- R 9 is selected from the group consisting of hydrogen, halogen, cyano, Ci -6 -alk(en/yn)yl, C 3-8 -cycloalk(en)yl, C 3-8 -cycloalk(en)yl-Ci -6 -alk(en/yn)yl, C 1 _ 6 -alk(en/yn)yloxy and Ci_ 6 -alk(en/yn)yl-O-CO-.
- R 9 is selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, Ci_ 6 -alk(en/yn)yloxy, C 1-6 -alk(en/yn)yl-O-CO-.
- R 9 is hydrogen; another embodiment of R 9 is halogen such as chloro or fluoro; another embodiment of R 9 is C 1-6 -alk(en/yn)yl typically Ci -6 -alkyl such as methyl or ethyl; another embodiment of R 9 is Ci_ 6 -alk(en/yn)yloxy typically Ci_ 6 -alkyloxy such as methoxy; another embodiment of R 9 is Cj. 6 -alk(en/yn)yl-O-CO- typically C 1-6 -alkyl- O-CO- such as Me-O-CO-.
- R 10 is selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl.
- R 10 is hydrogen; another embodiment of R 10 is C 1-6 -alk(en/yn)yl typically C 1-6 -alkyl such as methyl.
- halogen typically is fluoro or chloro.
- C 1-6 -alk(en/yn)yl typically is C 1-6 -alkyl, such as methyl.
- C 3-8 -cycloalk(en)yl typically is C 3-8 -cycloalkyl.
- C 3 ,g-cycloalk(en)yl-C 1-6 -alk(en/yn)yl typically is C 3-8 -cycloalkyl-Ci.. 6 -alkyl.
- Ci. 6 -alk(en/yn)ylamino typically is C 1-6 -alkylamino.
- di-(Ci -6 -alk(en/yn)yl)amino typically is di-(C 1-6 -alkyl)amino.
- C 1-6 -alk(en/yn)ylcarbonyl typically is Ci -6 -alkylcarbonyl.
- Ci -6 -alk(en/yn)ylaminocarbonyl typically is C 1-6 -alkylaminocarbonyl.
- Ci_ 6 -alk(en/yn)yloxy typically is C t - 6 -alkoxy, such as methoxy.
- C 1--6 -alk(en/yn)ylsulfanyl typically is C 1-6 -a ⁇ kylsulfanyl, such as methylsulfanyl.
- halo-C 1-6 -alk(en/yn)yl typically is halo-C 1-6 -alkyl, such as trifluoromethyl.
- halo-C 1-6 -alk(en/yn)ylsulfonyl typically is trifluoromethylsulfonyl.
- halo-C 1-6 -alk(en/yn)ylsulfanyl typically is trifluoromethylsulfanyl
- C 1-6 -alk(en/yn)ylsulfonyl typically is C 1-6 -alkylsulfonyl.
- the invention concerns such compounds wherein 0, 1, 2 or 3 of R 1"10 are different from hydrogen, typically 1 or 2 of R 1"10 are different from hydrogen. In a further embodiment 0 or 1 of R 1"4 is different from hydrogen and 0, 1 or 2 of R "9 is/are different from hydrogen. In a further embodiment, none of R 1"10 is different from hydrogen. In a further embodiment, one of R 1"1 is different from hydrogen. A further embodiment concerns such compounds wherein one of R 1"4 is different from hydrogen and none of R 6"10 is hydrogen; in a further embodiment one of R 6"10 is different from hydrogen and none of R 1"4 is hydrogen. In a further embodiment two of R 1"10 are different from hydrogen.
- an embodiment concerns such compounds wherein zero of R 1"4 are different from hydrogen and two of R 6"9 are different from hydrogen; in another embodiment one of R 1"4 is different from hydrogen and one of R 6"9 is different from hydrogen. In a further embodiment three of R 1"10 are different from hydrogen. To further illustrate without limiting the invention an embodiment concerns such compounds wherein one of R 1"4 is different from hydrogen and two of R 6"9 are different from hydrogen. In each embodiment, as mentioned the remaining substituents are hydrogen.
- an embodiment concerns such compounds wherein R 1 is different from hydrogen; another embodiment concerns such compounds wherein R 2 is different from hydrogen; another embodiment concerns such compounds wherein R 3 is different from hydrogen; another embodiment concerns such compounds wherein R 4 is different from hydrogen; another embodiment concerns such compounds wherein R 5 is different from hydrogen; another embodiment concerns such compounds wherein R 6 is different from hydrogen; another embodiment concerns such compounds wherein R 7 is different from hydrogen; another embodiment concerns such compounds wherein R 8 is different from hydrogen; another embodiment concerns such compounds wherein R 9 is different from hydrogen; another embodiment concerns such compounds wherein R 10 is different from hydrogen.
- R 5 is attached to position 2 of the indole.
- Such compounds are embraced by the below formula IA:
- R 5 is attached to position 3 of the indole.
- Such compounds are embraced by the below formula IB:
- each of R 1"4 is independently selected from the group consisting of hydrogen and C 1-6 -alk(en/yn)yl.
- R 5 is C 1-6 -alk(en/yn)yl
- each of R 6"9 are hydrogen.
- R 10 is hydrogen
- each of R 1"4 is independently selected from the group consisting of hydrogen, halogen and Ci -6 -alk(en/yn)yl.
- R 1 is hydrogen;
- R 2 is hydrogen or C 1-6 -alk(en/yn)yl;
- R 3 is hydrogen and
- R 4 is hydrogen or halogen.
- R 5 is hydrogen or C 1-6 -alk(en/yn)yl.
- each of R 6"9 is independently selected from the group consisting of hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy, C 1-6 -alk(en/yn)yl-O-CO- and NO 2 .
- R 6 is hydrogen, halogen, Ci -6 -alk(en/yn)yl or C 1 _ 6 -alk(en/yn)yloxy
- R 7 is hydrogen, halogen, Ci.
- R 8 is hydrogen, halogen, Ci -6 -alk(en/yn)yl or Ci-e-al ⁇ en/y ⁇ yloxy
- R 9 is hydrogen, halogen, C 1-6 -alk(en/yn)yl, C 1-6 -alk(en/yn)yloxy or C 1-6 -alk(en/yn)yl-O-CO-.
- R 10 is hydrogen or C]. 6 -alk(en/yn)yl.
- each of R 1"10 are hydrogen atoms
- each of R " are hydrogen
- R 5 is hydrogen or C 1-6 -alk(en/yn)yl.
- each of R 6"9 is hydrogen, halogen, C 1-6 -alk(en/yn)yl or C 1 _ 6 -alk(en/yn)yloxy.
- R 6 is hydrogen, halogen or C 1-6 -alk(en/yn)yl;
- R 7 is hydrogen, halogen, C 1-6 -alk(en/yn)yl or Q- ⁇ -alkten/yntyloxy;
- R 8 is hydrogen or halogen;
- R 9 is hydrogen, halogen, Ci -6 -alk(en/yn)yl or C 1 _ 6 -alk(en/yn)yloxy.
- R 10 is hydrogen or C ⁇ -alk ⁇ n/yr ⁇ yl.
- the present invention comprises the free base and salts of the compounds of the invention, typically, pharmaceutically acceptable salts.
- the salts of the invention include acid addition salts, metal salts, ammonium and alkylated ammonium salts.
- the salts of the invention are preferably acid addition salts.
- the acid addition salts of the invention are preferably pharmaceutically acceptable salts of the compounds of the invention formed with non-toxic acids.
- Acid addition salts include salts of inorganic acids as well as organic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
- suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like
- metal salts examples include lithium, sodium, potassium, magnesium salts and the like.
- ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and the like.
- the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
- the compounds of the present invention may have one or more asymmetric centre and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoisomeres, are included within the scope of the invention
- Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can also be resolved into their optical antipodes, e.g. by fractional crystallization. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.
- geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
- the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.
- the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming pharmacologically active substances.
- prodrugs will be functional derivatives of the compounds of the general formula I, IA, IB, IC, ID or IE, which are readily convertible in vivo into the required compound of the formula I, IA, IB, IC, ID or IE.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- the invention also encompasses active metabolites of the present compounds.
- Some compounds according to the invention inhibit the serotonin transporter and are thus serotonin reuptake inhibitors.
- the compounds have an in vitro uptake inhibition (IC50) of 5 ⁇ M or less, typically of 1 ⁇ M or less, preferably less than 50OnM or less than 100 nM or less than 50 nM, preferably as measured by the method described in Example 3 - Measurements of "[ 3 H]-5-HT uptake into rat cortical synaptosomes".
- Some compounds according to the invention inhibit the norepinephrine transporter and are thus norepinephrine reuptake inhibitors.
- the compounds typically have an in vitro uptake inhibition (IC50) of 5 ⁇ M or less, typically of 1 ⁇ M or less, preferably less than 50OnM, less than 100 nM or less than 50 nM, as measured by the method described in Example 3 - Measurements of "[ 3 H]noradrenaline uptake into rat cortical synaptosomes".
- Some compounds according to the invention inhibit the dopamine transporter and are thus dopamine reuptake inhibitors.
- such compounds have an in vitro uptake inhibition (IC50) of 5 ⁇ M or less, typically of 1 ⁇ M or less, preferably less than 50OnM, less than 100 nM or less than 50 nM, preferably as measured by the method described in Example 3 - "Measurements of [ 3 H]dopamine uptake into rat cortical synaptosomes".
- the compounds according to the invention are serotonin reuptake inhibitors and they are thus considered to be applicable in the treatment of one or more of the following disorders: affective disorders, pain disorders, ADHD and stress urinary incontinence.
- An embodiment concerns compounds of the invention having dual action being serotonin reuptake inhibitiors and dopamine reuptake inhibitors at the same time.
- compounds according to the invention having dual action have an in vitro uptake inhibition for the serotonin transporter which is at least 5, preferably at least 10 or even more preferred at least 20 or 30 times higher than the in vitro uptake inhibition for the dopamine transporter as measured by the methods described in Example 3 — “Measurements of [ 3 H]-5-HT uptake into rat cortical synaptosomes” and “Measurements of [ 3 H]dopamine uptake into rat cortical synaptosomes”.
- An embodiment concerns compounds of the invention having dual action being serotonin reuptake inhibitiors and norepinephrine reuptake inhibitors at the same time.
- compounds according to the invention having dual action have an in vitro uptake inhibition for the serotonin transporter which is at least 5, preferably at least 10 or even more preferred at least 20 or 30 times higher than the in vitro uptake inhibition for the norepinephrine transporter as measured by the methods described in Example 3 - "Measurements of [ 3 H]-5- HT uptake into rat cortical synaptosomes" and “Measurements of [ 3 H]noradrenaline uptake into rat cortical synaptosomes".
- a further embodiment concerns compounds of the invention having triple action and thus being serotonin reuptake inhibitors, norepinephrine reuptake inhibitors and dopamine reuptake inhibitors.
- the invention provides a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for use as a medicament.
- An embodiment of the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof and at least one pharmaceutically acceptable carrier or diluent.
- the composition may comprise any one of the embodiments of formula I, IA, IB 3 IC, ID or IE described above.
- a further embodiment of the invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder wherein a serotonin reuptake inhibitor is beneficial.
- Such pharmaceutical composition may comprise any one of the embodiments of formula I, IA 5 IB, IC, ID or IE described above.
- a further embodiment of the invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder, wherein a combined serotonin and norepinephrine reuptake inhibitor is beneficial.
- Such pharmaceutical composition may comprise any one of the embodiments of formula I, IA, IB, IC, ID or IE described above.
- a further embodiment of the invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder, wherein a combined serotonin and dopamine reuptake inhibitor is beneficial.
- Such pharmaceutical composition may comprise any one of the embodiments of formula I, IA, IB, IC, ID or IE described above.
- a further embodiment of the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of a disease or disorder, wherein a combined serotonin, norepinephrine and dopamine reuptake inhibitor is beneficial.
- Such pharmaceutical composition may comprise any one of the embodiments of formula I, IA 3 IB, IC, ID or IE described above.
- a further embodiment of the invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of affective disorders, pain disorders, ADHD and stress urinary incontinence.
- the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of affective disorders.
- the affective disorder to be treated is selected from the group consisting of depressive disorders and anxiety disorders.
- a further embodiment concerns the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of depressive disorders.
- the depressive disorder to be treated is selected from the group consisting of major depressive disorder, postnatal depression, dysthymia and depression associated with bipolar disorder, alzheimers, psychosis or parkinsons.
- an embodiment of the invention concerns the treatment of major depressive disorder; another embodiment concerns the treatment of postnatal depression; another embodiment concerns the treatment of dysthymia; another embodiment concerns the treatment of depression associated with bipolar disorder, alzheimers, psychosis or parkinsons.
- an embodiment of the invention concerns the treatment of depression associated with bipolar disorder; another embodiment concerns the treatment of depression associated with alzheimers; another embodiment concerns the treatment of depression associated with psychosis; another embodiment concerns the treatment of depression associated with parkinsons.
- a further embodiment concerns the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of anxiety disorders.
- the anxiety disorders to be treated are selected from the group consisting of general anxiety disorder, social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.
- an embodiment of the invention concerns the treatment of general anxiety disorder; another embodiment concerns the treatment of social anxiety disorder; another embodiment concerns the treatment of post traumatic stress disorder; another embodiment concerns the treatment of obsessive compulsive disorder; another embodiment concerns the treatment of panic disorder; another embodiment concerns the treatment of panic attacks; another embodiment concerns the treatment of specific phobias; another embodiment concerns the treatment of social phobia; another embodiment concerns the treatment of agoraphobia.
- the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of pain disorders.
- the pain disorder to be treated is selected from the group consisting of fibromyalgia syndrome (FMS), overall pain, back pain, shoulder pain, headache as well as pain while awake and during daily activities.
- FMS fibromyalgia syndrome
- an embodiment of the invention concerns the treatment of fibromyalgia syndrome; another embodiment concerns the treatment of overall pain; another embodiment concerns the treatment of back pain; another embodiment concerns the treatment of shoulder pain; another embodiment concerns the treatment of headache; another embodiment concerns the treatment of pain while awake and during daily activities.
- the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of attention deficit hyperactivity disorder.
- the present invention relates to the use of a compound of formula I, IA, IB, IC, ID or IE as the free base or a salt thereof for the preparation of a pharmaceutical composition for the treatment of stress urinary incontinence.
- treatment as used herein in connection with a disease or disorders includes also prevention as the case may be.
- the present invention relates to a method of preparing a compound of formula I, comprising deprotection or cleavage from a polymer support of a compound of formula VA or VB
- the present invention also relates to a pharmaceutical composition.
- the compounds of the invention as the free base or the salt thereof may be administered alone or in combination with pharmaceutically acceptable carriers or diluents, in either single or multiple doses.
- the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
- compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
- compositions formed by combining the compound of the invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
- the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
- the compounds of this invention are generally utilized as the free substance (base) or as a pharmaceutically acceptable salt thereof.
- base an acid addition salt of a compound having the utility of a free base.
- salts are prepared in a conventional manner by treating a solution or suspension of a free base of the invention with a chemical equivalent of a pharmaceutically acceptable acid. Representative examples are mentioned above.
- compositions for oral administration may be solid or liquid.
- Solid dosage forms for oral administration include e.g. capsules, tablets, dragees, pills, lozenges, powders, granules and tablette e.g. placed in a hard gelatine capsule in powder or pellet form or e.g. in the form of a troche or lozenge.
- pharmaceutical compositions for oral administration may be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
- Liquid dosage forms for oral administration include e.g. solutions, emulsions, suspensions, syrups and elixirs.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
- the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in- water or water-in-oil liquid emulsion.
- Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
- solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, gums and the like.
- liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water.
- the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- any adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
- the amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
- compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. - - -
- solutions of the compound of the invention in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
- aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
- the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
- Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials.
- Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
- Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants, etc.
- a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
- the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
- the formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
- a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.01 to about 1000 mg, such as about 0.01 to 100 mg, preferably from about 0.05 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
- parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
- typically doses are in the order of about half the dose employed for oral administration.
- a compound of the invention is meant any one of the embodiments of formula I, IA, IB, IC 5 ID and IE as described herein.
- the present invention relates to a method of preparing a compound of the invention as described in the following.
- the compounds of the invention may be prepared as follows:
- R is a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, or benzyl-carbamate) or a benzyl-derived protective group, wherein the protective groups may be linked to a solid support, like the Wang resin-based carbamate linker, whereupon the compound of formula I is isolated as the free base or an acid addition salt thereof.
- Intermediates of formula VA and VB can be prepared by the following methods: Method A Chemical transformation of a substituted thiophenol compound of formula VIA or of a substituted diphenyl disulfide compound of formula VIB to the corresponding benzenesulfenyl chloride compound and subsequent reaction with an indole of formula VIII or IX gives the protected intermediates VA or VB, respectively.
- Z is CH or N
- R 1 -R 10 are as previously described and R' is a nitrogen protecting group such as a carbamate group (such as methyl-, ethyl-, tert-butyl-, allyl-, or benzyl-carbamate) or a benzyl-derived protective group, wherein the protective groups may be linked to a solid support, like the Wang resin-based carbamate linker.
- Compounds of formula VIA (with Z being CH) can be prepared by demethylation of the corresponding 4-(2-methoxy-phenyl)-piperidine, protection of the nitrogen of the piperidine ring (with R' as described above), activation of the phenol functionality (with e.g.
- Compounds of formula VIB (with Z being N) can be prepared by the reaction of mono-protected piperazine (with R' as described above) and 2-fluro- 1 -nitrobenzenes, reduction of the nitro functionality, diazonium salt formation, followed by reaction with a xanthate salt (e.g. potassium ethylxanthate). Hydrolysis of the newly formed xanthate moity followed by oxidation gives disulphides of formula VIB.
- a xanthate salt e.g. potassium ethylxanthate
- Indoles of formula VIII and IX are either commercially available or can be prepared according to methods described in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc. New York, namely under reaction conditions such as those which are known and suitable for such reactions.
- R is a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, or benzyl-carbamate) or a benzyl-derived protective group, wherein the protective groups may be linked to a solid support, like the Wang resin- based carbamate linker.
- R 1 -R 10 are as previously described and R is a carbamate (such as methyl-, ethyl-, tert-butyl-, allyl-, or benzyl-carbamate) or a benzyl- derived protective group, wherein the protective groups may be linked to a solid support, like the Wang resin-based carbamate linker.
- Mass spectra were obtained by an alternating scan method to give molecular weight information.
- the molecular ion, MH+ was obtained at low orifice voltage (5V) and fragmentation at high orifice voltage (100V).
- SCX ion-exchange chromatography
- Nonafluoro-butane-1-sulfonyl fluoride (2.71 mL; 15.1 mmol) was added to a mixture of ethyl-diisopropyl-amine (2.87 mL; 16.5 mmol), 4-(iV,N-dimethylamino)-pyridine (25 mg) and 4-(2-hydroxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester (3.81 g; 13.7 mmol) in 50 ml 1,2-dichloro-ethane at O 0 C under argon. The reaction mixture was allowed to warm to room temperature and stirred 16 hours.
- reaction mixture was stirred 15 minutes at room temperature and added dropwise to potassium ethylxanthate (3.87 g; 24.2 mmol) in 30 mL water at 70°C (CAUTION!: gas evolution).
- the reaction mixture was stirred 2 hours at 70°C. 10 mL 28% NaOH and 30 mL ethanol were added and the reaction mixture was stirred 16 hours at 60°C in an open flask, the reaction mixture was cooled to room temperature and extracted with diethyl ether (2 x 250 mL). The organic phase was washed with brine (2 x 100 mL), dried with MgSO 4 and concentrated in vacuo.
- N-chlorosuccinimide 69.9 mmol was suspended in 200 mL dry CH 2 Cl 2 and cooled in an ice bath to 0 0 C. It was slowly treated with 66.6 mmol 2-bromothiophenol. After addition was completed the solution cleared up and turned orange. Stirring was continued at room temperature for 1 hour.
- the combined organic phase was dried over K 2 CO 3 and evaporated under vacuum.
- the compound was applied to a silica column in 1 / 4 ethyl acetate / heptane and filtered through using 1 / 4 ethyl acetate / heptane. The eluent was evaporated under vacuum to give the title compound.
- Example 1 Compounds of the invention of Formula IA Synthesis of 3-(2-piperazin-l-yl-phenylsulfanyl)-lH-indole 3 M HCl-gas in dry ethyl acetate (3 mL) was added to 3-[2-(4-tert-butoxycarbonyl- piperazin-l-yl)-phenylsulfanyl]-indole-l -carboxylic acid fert-butyl ester. The solution was stirred for 1 h at 0 0 C and evaporated under vacuum. The crude product was purified by preparative LC-MS. The isolated product was submitted for testing as DMSO solution. The following compounds were prepared in a similar way and analytical data are shown in table 1:
- [ 3 H]-5-HT are added to 96 well plates and shaken briefly.
- Composition of assay buffer 123 mM NaCl, 4.82 mM KCl 5 0.973 niM CaCl 2 , 1.12 mM MgSO 4 , 12.66 mM Na 2 HPO 4 , 2.97 mM NaH 2 PO 4 , 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid.
- Buffer is oxygenated with 95% 0 2 /5% CO 2 for 10 min at 37 °C and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 0.2 mL.
- composition of assay buffer 123 niM NaCl, 4.82 niM KCl, 0.973 niM CaCl 2 , 1.12 mM MgSO 4 , 12.66 mM Na 2 HPO 4 , 2.97 mM NaH 2 PO 4 , 0.162 niM EDTA, 10 mM glucose and 1 mM ascorbic acid.
- Buffer is oxygenated with 95% 0 2 /5% CO 2 for 10 min at 37 0 C and pH is adjusted 7.4. The incubation is started by adding tissue to a final assay volume of 1 ml.
- Tissue preparation male wistar rats (125-250 g) are sacrificed by decapitated and striatum quickly dissected out and placed in 40 vol (w/v) ice cold 0,40 M sucrose. The tissue is gently homogenised (glass teflon homogeniser) and the P2 fraction is obtained by centrifugation (1000 g, 10 minutes and 40000 g, 20 minutes, 4°C) and suspended in 560 volumes of a modified Krebs-Ringer-phosphate buffer, pH 7.4.
- Tissue 0,25 mg/well(140 ⁇ l) (original tissue) is mixed with test suspension. After 5 minutes pre-incubation 12.5 nM 3H-dopamine is added and the mixture is incubated for 5 minutes at RT.
- the incubation is terminated by filtering the samples under vacuum through Whatman GF/C filters with a wash of 1 ml buffer.
- the filters are dried and appropriate scintillation fluid
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Priority Applications (15)
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DE602005012272T DE602005012272D1 (en) | 2004-07-16 | 2005-07-13 | 2- (1H-INDOLYLSULFANYL) -ARYLAMINE DERIVATIVES FOR USE IN THE TREATMENT OF AFFECTIVE PSYCHOSES, PAIN, THE HYPERKINETIC SYNDROME OF CHILD AGE (ADHD), AND STRESS HARMINE INCONTINENCE |
PL05759183T PL1771415T3 (en) | 2004-07-16 | 2005-07-13 | 2- (1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
RSP-2009/0070A RS50804B (en) | 2004-07-16 | 2005-07-13 | 2-(1h-indolylsulfanyl)-aryl amine derivatives for use in the treatment of affective disorders, pain, adhid and stress urinary incontinence |
UAA200612493A UA82610C2 (en) | 2004-07-16 | 2005-07-13 | 2-(1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
JP2007520664A JP4865710B2 (en) | 2004-07-16 | 2005-07-13 | 2- (1H-Indolylsulfanyl) -arylamine derivatives for use in the treatment of affective disorders, pain, ADHD and stress urinary incontinence |
BRPI0512073-0A BRPI0512073A (en) | 2004-07-16 | 2005-07-13 | compound, pharmaceutical composition, and use thereof |
EA200602180A EA011418B1 (en) | 2004-07-16 | 2005-07-13 | 2-(1h-indolylsulfanyl)-aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
DK05759183T DK1771415T3 (en) | 2004-07-16 | 2005-07-13 | 2- (1H-indolylsulfanyl) arylamine derivatives for use in the treatment of affective disorders, pain, ADHD and stress incontinence |
MXPA06015201A MXPA06015201A (en) | 2004-07-16 | 2005-07-13 | 2-(1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence. |
EP05759183A EP1771415B1 (en) | 2004-07-16 | 2005-07-13 | 2- (1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
US11/629,043 US7678800B2 (en) | 2004-07-16 | 2005-07-13 | 2-(1H-indolylsulfanyl)-aryl amine derivatives for use in the treatment of affective disorders, pain, ADHD and stress urinary incontinence |
CA2570805A CA2570805C (en) | 2004-07-16 | 2005-07-13 | 2-(1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
IL179924A IL179924A0 (en) | 2004-07-16 | 2006-12-07 | 2 - (1h-indolylsulfanyl) - aryl amine derivatives for use in the treatment of affective disorders, pain adhd and stress urinary incontinence |
NO20066010A NO20066010L (en) | 2004-07-16 | 2006-12-27 | 2- (1H-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, ADHD and stress urinary incontinence |
HR20090112T HRP20090112T3 (en) | 2004-07-16 | 2009-02-23 | 2- (1h-indolylsulfanyl) -aryl amine derivatives for use in the treatment of affective disorders, pain, adhd and stress urinary incontinence |
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JP2008546679A (en) * | 2005-06-17 | 2008-12-25 | ハー・ルンドベック・アクチエゼルスカベット | 2- (1H-Indolylsulfanyl) -arylamine derivatives |
US7534791B2 (en) | 2005-06-17 | 2009-05-19 | H. Lundbeck A/S | Benzo[b]furane and benzo[b]thiophene derivatives |
US7629473B2 (en) | 2005-06-17 | 2009-12-08 | H. Lundbeck A/S | 2-(1H-indolylsulfanyl)-aryl amine derivatives |
EA016054B1 (en) * | 2006-06-16 | 2012-01-30 | Х. Лундбекк А/С | Crystalline forms of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of neuropathic pain |
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JP2013216669A (en) * | 2006-06-16 | 2013-10-24 | H Lundbeck As | Crystalline form of 4-[2-(4-methylphenylsulfanyl)-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for treatment of neuropathic pain |
JP2009539890A (en) * | 2006-06-16 | 2009-11-19 | ハー・ルンドベック・アクチエゼルスカベット | Crystalline form of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of neuropathic pain |
WO2007144006A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | Crystalline forms of 4- [2- (4-methylphenylsulfanyl) -phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of neuropathic pain |
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AU2008228639B2 (en) * | 2007-03-20 | 2012-12-13 | H. Lundbeck A/S | 4- [2- (4-methylphenylsulfanyd-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of adhd, melancholia, treatment resistent depression or residual symptoms in depression |
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WO2008113360A2 (en) | 2007-03-20 | 2008-09-25 | H. Lundbeck A/S | 4- [2- (4-methylphenylsulfanyd-phenyl] piperidine with combined serotonin and norepinephrine reuptake inhibition for the treatment of adhd, melancholia, treatment resistent depression or residual symptoms in depression |
WO2010000409A3 (en) * | 2008-07-03 | 2010-03-04 | Bayer Schering Pharma Aktiengesellschaft | Compounds and processes for production of radiopharmaceuticals |
WO2010000409A2 (en) * | 2008-07-03 | 2010-01-07 | Bayer Schering Pharma Aktiengesellschaft | Compounds and processes for production of radiopharmaceuticals |
CN105377189A (en) * | 2013-11-14 | 2016-03-02 | 加州理工学院 | Accommodating intraocular lens |
Also Published As
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MXPA06015201A (en) | 2007-03-15 |
SI1771415T1 (en) | 2009-04-30 |
CY1108942T1 (en) | 2014-07-02 |
PL1771415T3 (en) | 2009-06-30 |
JP2008506640A (en) | 2008-03-06 |
JP4865710B2 (en) | 2012-02-01 |
PT1771415E (en) | 2009-03-16 |
HRP20090112T3 (en) | 2009-03-31 |
BRPI0512073A (en) | 2008-02-06 |
AU2005263324A1 (en) | 2006-01-26 |
RS50804B (en) | 2010-08-31 |
DE602005012272D1 (en) | 2009-02-26 |
ATE420071T1 (en) | 2009-01-15 |
US7678800B2 (en) | 2010-03-16 |
UA82610C2 (en) | 2008-04-25 |
EP1771415B1 (en) | 2009-01-07 |
NO20066010L (en) | 2006-12-27 |
US20080027074A1 (en) | 2008-01-31 |
EA200602180A1 (en) | 2007-04-27 |
KR20070036061A (en) | 2007-04-02 |
CA2570805A1 (en) | 2006-01-26 |
EA011418B1 (en) | 2009-02-27 |
IL179924A0 (en) | 2007-05-15 |
DK1771415T3 (en) | 2009-02-23 |
CN1972911A (en) | 2007-05-30 |
ZA200610162B (en) | 2008-06-25 |
CA2570805C (en) | 2010-08-24 |
EP1771415A1 (en) | 2007-04-11 |
ES2317266T3 (en) | 2009-04-16 |
AR052308A1 (en) | 2007-03-14 |
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