WO2008092785A1 - Novel 2-aminooxazolines as taar1 ligands for cns disorders - Google Patents
Novel 2-aminooxazolines as taar1 ligands for cns disorders Download PDFInfo
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- WO2008092785A1 WO2008092785A1 PCT/EP2008/050765 EP2008050765W WO2008092785A1 WO 2008092785 A1 WO2008092785 A1 WO 2008092785A1 EP 2008050765 W EP2008050765 W EP 2008050765W WO 2008092785 A1 WO2008092785 A1 WO 2008092785A1
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- WO
- WIPO (PCT)
- Prior art keywords
- dihydro
- oxazol
- ylamine
- phenyl
- chloro
- Prior art date
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- YAXGBZDYGZBRBQ-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazol-2-amine Chemical class NC1=NCCO1 YAXGBZDYGZBRBQ-UHFFFAOYSA-N 0.000 title description 11
- 239000003446 ligand Substances 0.000 title description 6
- -1 phenyloxy, benzyl Chemical group 0.000 claims abstract description 269
- 150000001875 compounds Chemical class 0.000 claims abstract description 219
- 238000011282 treatment Methods 0.000 claims abstract description 67
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 60
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 60
- 239000002253 acid Substances 0.000 claims abstract description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 51
- 150000002367 halogens Chemical group 0.000 claims abstract description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 45
- 239000001257 hydrogen Substances 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 32
- 208000035475 disorder Diseases 0.000 claims abstract description 23
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- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 4
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- 238000000034 method Methods 0.000 claims description 45
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 38
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
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- OHEHXHSMXPWYQM-UHFFFAOYSA-N 4-(4-chloro-2-cyclopropylphenyl)-4,5-dihydro-1,3-oxazol-2-amine Chemical compound C1OC(N)=NC1C1=CC=C(Cl)C=C1C1CC1 OHEHXHSMXPWYQM-UHFFFAOYSA-N 0.000 claims description 6
- XDMSIROORZZAAB-UHFFFAOYSA-N 4-[4-(4-chlorophenyl)phenyl]-4,5-dihydro-1,3-oxazol-2-amine Chemical compound C1OC(N)=NC1C1=CC=C(C=2C=CC(Cl)=CC=2)C=C1 XDMSIROORZZAAB-UHFFFAOYSA-N 0.000 claims description 6
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- XHYQTLTVGVCDGI-SNVBAGLBSA-N (4r)-4-[[dimethyl(phenyl)silyl]methyl]-4,5-dihydro-1,3-oxazol-2-amine Chemical compound C=1C=CC=CC=1[Si](C)(C)C[C@H]1COC(N)=N1 XHYQTLTVGVCDGI-SNVBAGLBSA-N 0.000 claims description 5
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- AVGWRGDAZGWNGF-RORZRARGSA-N (4S)-4-(2-chlorophenyl)-4,5-dihydro-1,3-oxazol-2-amine 4-(4-chlorophenyl)-4,5-dihydro-1,3-oxazol-2-amine 4-(2,4-difluorophenyl)-4,5-dihydro-1,3-oxazol-2-amine Chemical compound FC1=C(C=CC(=C1)F)C1N=C(OC1)N.ClC1=CC=C(C=C1)C1N=C(OC1)N.ClC1=C(C=CC=C1)[C@@H]1N=C(OC1)N AVGWRGDAZGWNGF-RORZRARGSA-N 0.000 claims description 4
- PAACREJBUSVNHS-NIFFTEIASA-N (4S)-4-[4-chloro-2-(trifluoromethyl)phenyl]-4,5-dihydro-1,3-oxazol-2-amine 4-[4,5-dichloro-2-(trifluoromethyl)phenyl]-4,5-dihydro-1,3-oxazol-2-amine Chemical compound ClC1=CC(=C(C=C1)[C@@H]1N=C(OC1)N)C(F)(F)F.ClC1=CC(=C(C=C1Cl)C1N=C(OC1)N)C(F)(F)F PAACREJBUSVNHS-NIFFTEIASA-N 0.000 claims description 4
- KYRYRWLINOBGSL-LLVKDONJSA-N (4r)-4-(3-phenylpropyl)-4,5-dihydro-1,3-oxazol-2-amine Chemical compound C1OC(N)=N[C@@H]1CCCC1=CC=CC=C1 KYRYRWLINOBGSL-LLVKDONJSA-N 0.000 claims description 4
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- HRJZCHBCNRFJIB-SNVBAGLBSA-N (4s)-4-(5-chloro-2-fluorophenyl)-4-methyl-5h-1,3-oxazol-2-amine Chemical compound C=1C(Cl)=CC=C(F)C=1[C@@]1(C)COC(N)=N1 HRJZCHBCNRFJIB-SNVBAGLBSA-N 0.000 claims description 4
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- DOWVMJFBDGWVML-UHFFFAOYSA-N n-cyclohexyl-n-methyl-4-(1-oxidopyridin-1-ium-3-yl)imidazole-1-carboxamide Chemical compound C1=NC(C=2C=[N+]([O-])C=CC=2)=CN1C(=O)N(C)C1CCCCC1 DOWVMJFBDGWVML-UHFFFAOYSA-N 0.000 description 1
- NNKPHNTWNILINE-UHFFFAOYSA-N n-cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxopyrazin-1-yl]benzamide Chemical compound CNCCOC1=CC=CC=C1C1(NC=2C(N(C=3C(=C(F)C=C(C=3)C(=O)NC3CC3)C)C=CN=2)=O)CC1 NNKPHNTWNILINE-UHFFFAOYSA-N 0.000 description 1
- OFYAYGJCPXRNBL-LBPRGKRZSA-N naphthalen-2-yl-3-alanine Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-LBPRGKRZSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 1
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229960001576 octopamine Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- RXTGSQFXDQCOSV-OSMGYRLQSA-N tert-butyl (4r)-2,2-dimethyl-4-(2-phenoxycarbothioyloxy-1-phenylpropan-2-yl)-1,3-oxazolidine-3-carboxylate Chemical compound C1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C(C)(OC(=S)OC=1C=CC=CC=1)CC1=CC=CC=C1 RXTGSQFXDQCOSV-OSMGYRLQSA-N 0.000 description 1
- FCLVDRIIBXBDNK-MRXNPFEDSA-N tert-butyl (4s)-2,2-dimethyl-4-(1-phenylprop-1-en-2-yl)-1,3-oxazolidine-3-carboxylate Chemical compound CC([C@@H]1N(C(C)(C)OC1)C(=O)OC(C)(C)C)=CC1=CC=CC=C1 FCLVDRIIBXBDNK-MRXNPFEDSA-N 0.000 description 1
- CSDSDTSZBFUEAU-ZDUSSCGKSA-N tert-butyl (4s)-2,2-dimethyl-4-[2-[6-(trifluoromethyl)pyridin-2-yl]ethynyl]-1,3-oxazolidine-3-carboxylate Chemical compound C1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C#CC1=CC=CC(C(F)(F)F)=N1 CSDSDTSZBFUEAU-ZDUSSCGKSA-N 0.000 description 1
- HZQALADXFQOHNV-FEAKQIBJSA-N tert-butyl (4s)-4-[(e)-2-(3-chlorophenyl)ethenyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1\C=C\C1=CC=CC(Cl)=C1 HZQALADXFQOHNV-FEAKQIBJSA-N 0.000 description 1
- GWGDDPVPRFYBNN-KRWDZBQOSA-N tert-butyl (4s)-4-[[benzyl(ethyl)amino]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate Chemical compound C=1C=CC=CC=1CN(CC)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C GWGDDPVPRFYBNN-KRWDZBQOSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/28—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Definitions
- the invention relates to the use of compounds of formula
- R 1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, or is phenyloxy, benzyl, benzyloxy, -COO-lower alkyl, -O-(CH 2 ) o -O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents for n> 1 may be the same or different;
- X is a bond, -CHR-, -CHRCHR'-, -OCH 2 -, -CH 2 OCHR-, -CH 2 CH 2 CH 2 -, -SCH 2 -, -S(O) 2 CH 2 -, -CH 2 SCH 2 -, -CH 2 N(R)CH 2 -, -cycloalkyl-CH 2 - or SiRR'-CH 2 -;
- R/R' may be independently from each other hydrogen, lower alkyl or lower alkyl substituted by halogen
- R 2 is hydrogen, phenyl or lower alkyl
- Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl, 1,2,3,4-tetrahydro- naphthalen-2-yl, 2,3-dihydrobenzo[l,4]dioxin-6-yl or benzo[l,3]dioxol-5-yl;
- n O, 1, 2 or 3;
- o 2 or 3
- diseases related to the biological function of the trace amine associated receptors which diseases are depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological diseases, Parkinson's disease, neurodegenerative disorders
- Pop/26.11.2007 disorders Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
- the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
- 2-Aminooxazolines are described in the literature as hypertensive agents with good affinity to the adrenergic receptor or as intermediates in processes for preparation of pharmaceutical active agents, for example in
- the compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAARl.
- the compounds may be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
- ADHD attention deficit hyperactivity disorder
- Some of the physiological effects i.e. cardiovascular effects, hypotension, induction of sedation
- cardiovascular effects i.e. cardiovascular effects, hypotension, induction of sedation
- WO02/076950, WO97/12874 or EP 0717 037 may be considered to be undesirable side effects in the case of medicaments aimed at treating diseases of the central nervous system as described above. Therefore it is desirable to obtain medicaments having selectivity for the TAARl receptor vs adrenergic receptors.
- Objects of the present invention show selectivity for TAARl receptor over adrenergic receptors, in particular good selectivity vs the human and rat alpha 1 and alpha2 adrenergic receptors.
- biogenic amines The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system [I]. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions [2- 5].
- a second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlap with the classical biogenic amines regarding structure, metabolism and subcellular localization.
- the TAs include p-tyramine, ⁇ -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines [6] .
- TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10,11]. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by "crossreacting" with their receptor systems [9,12,13]. This view changed significantly with the recent identification of several members of a novel family of GPCRs, the trace amine associated receptors (TAARs) [7,14]. There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse
- TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment.
- the phylogenetic relationship of the receptor genes in agreement with an in-depth GPCR pharmacophore similarity comparison and pharmacological data suggest that these receptors form three distinct subfamilies [7,14].
- TAARl is in the first subclass of four genes (TAARl-
- TAs activate TAARl via Gas.
- Dysregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, - A - metabolic disorders and therefore TAARl ligands have a high potential for the treatment of these diseases.
- Objects of the present invention are the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to the biological function of the trace amine associated receptors, new specific compounds falling into the scope of formula I, their manufacture and medicaments based on a compound in accordance with the invention in the control or prevention of illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
- illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, substance abuse and
- the preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
- lower alkyl denotes a saturated straight- or branched- chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
- Preferred alkyl groups are groups with 1 - 4 carbon atoms.
- lower alkoxy denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.
- lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
- halogen denotes chlorine, iodine, fluorine and bromine.
- cycloalkyl is an alkylene ring, containing from 3 to 6 carbon ring atoms.
- pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
- Preferred compounds of formula I are those, wherein X is a bond.
- Preferred compounds of this group of formula I are those, wherein Y is phenyl, substituted by one or more halogen atoms:
- R 1 is halogen, for n> 1 the halogen atom may be the same or different;
- R 2 is hydrogen, phenyl or lower alkyl; n is 1, 2 or 3; or a pharmaceutically suitable acid addition salt, for example (S)-4-(2-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(4-chloro-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(2,4-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (S)-4-(2,3-difluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(3,4-dichlorophenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(2,5-difluoro-phenyl)-4,5
- R 1 is CH 3 , CF 3 , OCH 3 , OCF 3 or OCH 2 -phenyl;
- R 2 is hydrogen, phenyl or lower alkyl; n is 1, 2 or 3; or a pharmaceutically suitable acid addition salt, for example the following compounds (RS)-4-(2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-o-tolyl-4,5-dihydro-oxazol-2-ylamine
- R 2 is hydrogen, phenyl or lower alkyl; or a pharmaceutically suitable acid addition salt, for example the following compounds (RS)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine (S)-4-biphenyl-4-yl-4,5-dihydro-oxazol-2-ylamine or (RS)-4-(4'-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine.
- Y is phenyl substituted by halogen and CF 3 , halogen and CH 3 , halogen and cycloalkyl or by halogen and OCH 3
- R 1 is halogen and CF 3 , or is halogen and CH 3 , or is halogen and cycloalkyl, or is halogen and OCH 3 ;
- R 2 is hydrogen, phenyl or lower alkyl; n is 1, 2 or3; or a pharmaceutically suitable acid addition salt, for example the following compounds (RS)-4-(3-chloro-4-methoxyphenyl)-4,5-dihydro-oxazol-2-ylamine (S)-4-(3-chloro-4-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (S)-4-(2-fluoro-4-trifluoromethyl-phenyl)-4-methyl-4,5-dihydro-oxazol-2-ylamine (RS)- 4-(4-fluoro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(5-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (RS)-4-(4-chloro-2-trifluoromethyl-
- Preferred compounds of formula I are further those, wherein X is CHR.
- Preferred compounds from this group are those, wherein Y is phenyl:
- R 1 is halogen, CF 3 or CH 3 ,
- R 2 is hydrogen, phenyl or lower alkyl
- R may be independently from each other hydrogen, lower alkyl or lower alkyl substituted by halogen
- n 1 or 2;
- Preferred compounds of formula I are further those, wherein X is CHRCHR'.
- Preferred compounds from this group are those, wherein Y is phenyl,
- R 1 is hydrogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or is halogen, wherein the substituents for n> 1 may be the same or different; R/R' may be independently from each other hydrogen, lower alkyl or lower alkyl substituted by halogen;
- R 2 is hydrogen, phenyl or lower alkyl
- n 0, 1, 2 or 3;
- Preferred compounds of formula I are further those, wherein X is OCH 2 . and Y is phenyl.
- R 1 is lower alkyl, lower alkyl substituted by halogen or halogen, wherein the substituents for n> 1 may be the same or different;
- R 2 is hydrogen, phenyl or lower alkyl
- n 0, 1, 2 or 3;
- Preferred compounds of formula I are further those, wherein X is CH 2 OCHR.
- Preferred compounds from this group are those, wherein Y is phenyl:
- R 1 is hydrogen or halogen; n is 0 or 1;
- - Preferred compounds of formula I are further those, wherein X is -(CH 2 ) 3 - Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds (S)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine or (R)-4-(3-Phenyl-propyl)-4,5-dihydro-oxazol-2-ylamine.
- Preferred compounds of formula I are further those, wherein X is -SCH 2 -, -S(O) 2 CH 2 -, or -CH 2 SCH 2 -.
- Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
- Preferred compounds of formula I are further those, wherein X is -CH 2 N(R)CH 2 -, cycloalkyl-CH 2 - or SiRR'-CH 2 -;
- Preferred compounds from this group are those, wherein Y is phenyl, for example the following compounds
- Preferred compounds of formula I are further those, wherein X is described above and Y is naphthyl, pyridyl, cyclohexyl, 2,3-dihydrobenzo[l,4]dioxin or 1,2,3,4- tetrahydronaphthalen.
- R 1 is hydrogen, deuterium, tritium, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, halogen, phenyl optionally substituted by halogen, or is phenyloxy, benzyl, benzyloxy, or -COO-lower alkyl;
- X is a bond, -CHR- Or -CHRCH 2 -;
- R is hydrogen or lower alkyl; R is hydrogen or lower alkyl;
- Y is aryl, heteroaryl, l,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[l,4]dioxin-( yl or benzo[l,3]dioxol-5-yl; n is 0, 1, 2 or 3; or pharmaceutically suitable acid addition salt with the exception of (S)-4-phenyl-4,5-dihydro-oxazol-2-ylamine,
- the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
- Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
- the reaction sequence is not limited to the one displayed in schemes 1 to 9, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
- Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
- suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at -78°C -> reflux for 1 - 24 hrs.
- Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight, or LiBH 4 /Me 3 SiCl in methanol at 0 0 C -> r.t. overnight.
- Step B Cyclisation of the aminoalcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K2CO3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0 0 C to r.t. overnight.
- Step A Wittig reaction between Garner's aldehyde IV and a benzyl-substituted phosphonic acid diethyl ester V can be accomplished by using a base such as NaH, KOtBu, NaOMe, NaOEt, n-BuLi, LiHMDS, NaHMDS, KHMDS, LDA in a solvent such as THF, dioxane, acetonitrile, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from -78°C - 80 0 C for 15 min - 8 hrs and if appropriate optional addition of a crown ether for ylide generation and then condensing the ylide with the carbonyl compound in the same solvent at temperature between 0 and 80 0 C for 1 - 24 hrs.
- the base, the carbonyl compound and the base and the optional crown ether can be added to the reaction mixture at the same time without preformation of the yl
- Preferred conditions are ylide formation at 0 0 C using n-buthyl lithium solution in hexane as base and 1,2-dimethoxyethane as solvent, reacting the phosphonic acid ester for 5 min at 0 0 C, and then condensation with the carbonyl component at reflux overnight.
- Step B Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as Pt ⁇ 2, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
- the reduction of the alkene can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
- Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SCU or H3PO4 or an organic acid such as CF 3 COOH,
- Preferred conditions are 2N HCl in EtOH at reflux for 1 -3 hrs or 4N HCl in dioxane at r.t. overnight.
- Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 C ⁇ 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at O 0 C to r.t. overnight.
- Step A The synthesis of the Julia reagent (benzothiazole-2-sulfonyl derivative) IX from 'Garner's alcohol' VIII was accomplished as described in literature (Dandanpani, S. et al., Journal of Organic Chemistry 2005, 70(23), 9447).
- Step B Julia reaction between an Y-aldehyde or ketone and and the benzothiazole sulfonyl compound can be accomplished by using a base such as LiHMDS, NaHMDS, KHMDS, LDA, KOtBu, DBU in a solvent such as THF, diethyl ether, 1,2- dimethoxyethane, dichloromethane, DMF or mixtures thereof at temperatures from - 10O 0 C - r.t. for 15 min - 8 hrs for anion generation and then condensing the ylide with the carbonyl compound in the same solvent at temperatures between -100 0 C and r.t. for 1 - 24 hrs.
- a base such as LiHMDS, NaHMDS, KHMDS, LDA, KOtBu, DBU
- a solvent such as THF, diethyl ether, 1,2- dimethoxyethane, dichloromethane, DMF or mixtures thereof at temperatures from - 10O 0
- Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SCU or H3PO4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCI3, THF, MeOH, EtOH or H 2 O at O to 6O 0 C.
- Preferred conditions are 2N HCl in EtOH at reflux for 1 -3 hrs or 4N HCl in dioxane at r.t. overnight.
- Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 C ⁇ 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at O 0 C to r.t. overnight.
- Step A Mitsunobu reaction of 'Garner's alcohol' VIII with phenol derivatives X or thiophenol derivatives X can be accomplished by using a phosphine such as triphenylphosphine and an azodicarboxylate reagent such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-tert-butylazodicarboxylate in a solvent such as THF at temperatures from 50 0 C - 70 0 C for 1 - 18 hrs.
- a phosphine such as triphenylphosphine
- an azodicarboxylate reagent such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-tert-butylazodicarboxylate
- Preferred conditions are triphenylphosphine and di-tert-butylazodicarboxylate in THF at
- Step B Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SCU or H3PO4 or a organic acid such as CF 3 COOH,
- Preferred conditions are 2N HCl in EtOH at reflux for 1 -3 hrs or 4N HCl in dioxane at r.t. overnight.
- Step C Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 C ⁇ 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0 0 C to r.t. overnight.
- Step A Conversion of Garner's aldehyde IV to the dibromo-alkene derivative XII can be accomplished by using a brominating agent such as carbon tetrabromide in the presence of a phosphine such as triphenylphosphine in a chlorinated solvent such as dichloromethane at temperatures between 0 0 C and room temperature.
- a brominating agent such as carbon tetrabromide
- a phosphine such as triphenylphosphine
- a chlorinated solvent such as dichloromethane
- Step B Suzuki reaction of dibromo-alkene derivative XII with an arylboronic acid XIII can be accomplished using a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0) in the presence of a phosphine such as tris(2- furyl) phosphine and a base such as aqueous sodium carbonate in a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from 50 0 C - 100 0 C for 1 - 18 hrs.
- a palladium catalyst such as tris(dibenzylideneacetone)dipalladium (0)
- a phosphine such as tris(2- furyl) phosphine
- a base such as aqueous sodium carbonate
- a solvent such as THF, dioxane, 1,2-dimethoxyethan, DMF,
- Negishi reaction of bromo-alkene derivative XIV with a dialkylzinc reagent XV can be accomplished using a palladium catalyst such as bis(tri-tert- butylphosphine)dipalladium (0) in a solvent such as THF, dioxane, 1,2-dimethoxyethan,
- Preferred conditions are a THF-toluene mixture at room temperature.
- Step D Reduction of the alkene can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as Pt ⁇ 2, Pd-C or Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
- the reduction of the alkene can be effected by Mg in
- R 1 ⁇ chlorine is hydrogenation in the presence of Pd/C as catalyst with EtOH as solvent.
- Step E Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH,
- Steps D and E can also be carried out in the opposite order, in which case the stereochemical preference of the hydrogenation step is typically reversed.
- Step F Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at O 0 C to r.t. overnight.
- Step A Coupling of 4-ethinyl-2,2-dimethyl-l,3-oxazolidine-3-carboxylate XVIII
- Preferred conditions are the use of copper(I) -iodide and bis(triphenylphosphine)palladium(II) chloride with triethylamine as solvent at room temperature.
- Step B Reduction of the alkyne XX can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as hydrogen source with a catalyst such as PtO 2 , Pd-C or
- Raney nickel in solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
- solvents such as MeOH, EtOH, H 2 O, dioxane, THF, HOAc, EtOAc CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
- the reduction of the alkyne can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
- Preferred conditions are transfer hydrogenation using ammonium formiate in the presence of Pd/C as catalyst with MeOH as solvent.
- Step C Simultaneous cleavage of the amino alcohol protecting groups can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or an organic acid such as CF 3 COOH, CHCI2COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCI3, THF, MeOH, EtOH or H 2 O at O to 60 0 C.
- a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
- organic acid such as CF 3 COOH, CHCI2COOH, HOAc or p-toluonesulfonic acid
- a solvent such as CH 2 Cl 2 , CHCI3, THF, MeOH, EtOH or H 2 O at O to 60 0 C.
- Step D Cyclisation of the amino alcohol to the corresponding 2-aminooxazoline can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 C ⁇ 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at O 0 C to r.t. overnight.
- Step A Deprotonation of bis-lactimether XXI (also called “Sch ⁇ llkopf s chiral auxiliary”) with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the organic halide XXII and reaction for several hours leads to product XXIII (Vassiliou, S. et al Synlett 2003, 2398-2400; Schollkopf, U. Topics Curr. Chem. 1983, 109, 65).
- Step B Cleavage of bis-lactim ether product XXIII under acidic conditions using a mineral acid such as HCl, H 2 S ⁇ 4 or H3PO4 or an organic acid such as CF 3 COOH, CHCI2COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at O to 6O 0 C.
- a mineral acid such as HCl, H 2 S ⁇ 4 or H3PO4
- an organic acid such as CF 3 COOH, CHCI2COOH, HOAc or p-toluonesulfonic acid
- a solvent such as acetonitrile, CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at O to 6O 0 C.
- Preferred conditions are a 10% trifluoro acetic acid in a mixture of water and acetonitrile (1 :3) at 40 0 C overnight.
- Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight.
- Step D Cyclisation of the amino alcohol II-4 to the corresponding 2-aminooxazoline 1-4 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at O 0 C to r.t. overnight.
- Homochiral alcohols of formula XXVIII may be prepared by a variety of methods reported in the chemical literature, for instance starting from carboxylic acids of formula XXV and using the methodologies of Evans et al. (ref [ 1 ] ) or Meyers et al. (ref [2] ) . According to these procedures, introduction of a chiral auxilliary, such as the Evans oxazolidinone auxiliary (ref [I]) or the Meyers pseudoephedrine-derived auxiliary (ref
- Step A Homochiral alcohol XXVIII may be converted to the corresponding alkyl iodide
- XXIX using a reagent system comprising imidazole, triphenylphosphine and iodine in dichloromethane (Muller, P. & Bolea, C. HeIv. Chim. Acta 2002, 85, 483-494) or sequential treatment with p-toluensulphonyl chloride/pyridine and sodium iodide in acetone (Taber, D. F. et al. J. Am. Chem. Soc. 1985, 107, 196-199).
- Step B Deprotonation of bis-lactimether XXI (also called "Sch ⁇ llkopf s chiral auxiliary") with a suitable base such as n-butyl-lithium or tert-butyl-lithium in an appropriate organic solvent such as tetrahydrofuran at a low temperature followed by addition of the homochiral alkyl iodide XXIX and reaction for several hours leads to product
- Preferred conditions are the use of n-butyllithium at -78 0 C and allowing the mixture to reach room temperature overnight.
- Step C Cleavage of bis-lactim ether product XXX under acidic conditions using a mineral acid such as HCl, H 2 SCU or H3PO4 or an organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as acetonitrile, CH 2 Cl 2 , CHCI3, THF,
- Preferred conditions are a 10% trifluoro acetic acid in a mixture of water and acetonitrile
- Step D Reduction of the ester XXXI can be effected by treatment with LiAlH 4 , LiBH 4 , NaBH 4 or Red- Al in a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at -78 0 C -> reflux for 1 - 24 hrs.
- a suitable solvent such as 1,2-dimethoxyethane, THF, diethylether, toluene, MeOH or EtOH at -78 0 C -> reflux for 1 - 24 hrs.
- Preferred conditions for acids and esters are LiAlH 4 in THF at r.t. overnight.
- Step E Cyclisation of the amino alcohol II-5 to the corresponding 2-aminooxazoline 1-5 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 C ⁇ 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0 0 C to r.t. overnight.
- a primary amine compound of formula XXXII-I can be accomplished by a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating pro tic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr) 4 at a temperature of -10 to 60 0 C for 1 - 4O h.
- a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3
- a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating pro tic acid such as HCl or a carboxylic acid
- Step B Alkylation of the compound of formula XXXIII-I to compound of formula XXXIII-2 can by accomplished by treatment with a suitable aldehyde RCHO in the presence of a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc) 3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating pro tic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr) 4 at a temperature of -10 to 60 0 C for 1-4O h.
- Step C Preparation of a compound of formula XXXIII-2 may alternatively be accomplished by reductive amination
- XXXIII-2 and Garner's aldehyde (from L- or D-serine; Garner, P.; Park, J.M. Org. Synth. 1998, IX, 300) in the presence of a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc)3 or Na(CN)BH 3 in a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF, dioxane or mixtures thereof in the presence of an activating protic acid such as HCl or a carboxylic acid or an activating Lewis acid such as ZnCl2 or Ti(OiPr) 4 at a temperature of -10 to 60 0 C for 1-40 h.
- a reducing agent such as NaBH 4 , LiBH 4 , NaBH(OAc)3 or Na(CN)BH 3
- a solvent such as MeOH, EtOH, dichloromethane, 1,2-dichloroethane, THF,
- Step D Simultaneous cleavage of the amino alcohol protecting groups of the compound of formula XXXIII-2 can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60 0 C.
- a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
- a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
- a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60 0 C.
- Step E Cyclisation of the amino alcohol II-6 to the corresponding 2-aminooxazoline 1-6 can be accomplished by treatment with cyanogen bromide in THF as solvent and K 2 CO 3 as base at r.t. overnight, or by treatment with cyanogen bromide in methanol as solvent and sodium acetate as base at 0 0 C to r.t. overnight.
- Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
- suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
- Salts of compounds of formula I The compounds of formula I are basic and may be converted to a corresponding acid addition salt.
- the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
- organic acids such as acetic acid, propi
- the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
- an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like.
- the temperature is maintained between 0 0 C and 50 0 C.
- the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
- the acid addition salts of the basic compounds of formula I maybe converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
- a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
- the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a good affinity to the trace amine associated receptors (TAARs), especially TAARl.
- TAARs trace amine associated receptors
- the compounds were investigated in accordance with the test given hereinafter.
- HEK293 cells (ATCC # CRL- 1573) were cultured essentially as described Lindemann et al. (2005).
- HEK293 cells were transfected with the pIRESneo2 expression plasmids containing the TAAR coding sequences
- Cells at confluence were rinsed with ice-cold phosphate buffered saline without Ca 2+ and Mg 2+ containing 10 mM EDTA and pelleted by centrifugation at 1000 rpm for 5 min at 4 0 C. The pellet was then washed twice with ice-cold phosphate buffered saline and cell pellet was frozen immediately by immersion in liquid nitrogen and stored until use at -80 0 C. Cell pellet was then suspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 s.
- PT 3000, Kinematica Polytron
- the homogenate was centrifuged at 48,000xg for 30 min at 4 0 C and the pellet resuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (buffer A), and homogenized with a Polytron at 10,000 rpm for 10 s. The homogenate was then centrifuged at 48,000xg for 30 min at 4 0 C and the pellet resuspended in 20 ml buffer A, and homogenized with a Polytron at 10,000 rpm for 10 s. Protein concentration was determined by the method of Pierce (Rockford, IL).
- the homogenate was then centrifuged at 48,000xg for 10 min at 4 0 C, resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl 2 (10 mM) and CaCl 2 g protein per ml and (2 mM) (buffer B) at 200 homogenized with a Polytron at 10,000 rpm for 10 s.
- Binding assay was performed at 4 0 C in a final volume of 1 ml, and with an incubation time of 30 min.
- the radioligand [ 3 H]-rac-2-(l,2,3,4-tetrahydro-l-naphthyl)-2- imidazoline was used at a concentration equal to the calculated Kd value of 60 nM to give a bound at around 0.1 % of the total added radioligand concentration, and a specific binding which represented approximately 70 - 80 % of the total binding.
- Non-specific binding was defined as the amount of [ 3 H]-rac-2-(l,2,3,4-tetrahydro-l-naphthyl)-2- imidazoline bound in the presence of the appropriate unlabelled ligand (lO ⁇ M). Competing ligands were tested in a wide range of concentrations (10 pM - 30 ⁇ M). The final dimethylsulphoxide concentration in the assay was 2%, and it did not affect radioligand binding. Each experiment was performed in duplicate.
- the preferred compounds show a Ki value ( ⁇ M) in mouse or rat on TAARl in the range of ⁇ 0.01 ⁇ M as shown in the table below.
- the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
- the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
- Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
- Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
- the most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
- disorders of the central nervous system for example the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and attention deficit hyperactivity disorder (ADHD).
- ADHD attention deficit hyperactivity disorder
- the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
- the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
- the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
- Example 2 In analogy to example 1 and starting from the respective amino acid or amino acid derivative were prepared: Example 2
- the total activity was 98.29 mCi and the radiochemical purity was 100 % and 98 % according to radio-HPLC and radio-TLC respectively.
- the specific activity was 17.5 Ci/mole according to mass spectrometry.
- the enantiomeric purity was over 99 % according to HPLC (column: Chiralpak AD 10 ⁇ m 4.6 x 250 mm; mobile phase: 10 % ethanol in n-heptane; flow rate: 1 ml/min; UV: 220 nm).
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Priority Applications (14)
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CA2675221A CA2675221C (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands |
CN2008800039235A CN101600700B (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands for CNS disorders |
EP08701646.5A EP2114906B1 (en) | 2007-02-02 | 2008-01-23 | 2-aminooxazolines as taar1 ligands for cns disorders |
KR1020127008523A KR101275405B1 (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
BRPI0806940-9A2A BRPI0806940A2 (en) | 2007-02-02 | 2008-01-23 | 2-AMINO-OXAZOLINES AS TAAR1 LEADERS FOR CNS DISORDERS |
JP2009547642A JP5248528B2 (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as TAAR1 ligands for CNS diseases |
AU2008209860A AU2008209860A1 (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as TAAR1 ligands for CNS disorders |
NZ578260A NZ578260A (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
ES08701646.5T ES2510546T3 (en) | 2007-02-02 | 2008-01-23 | New 2-aminooxazolines as TAAR1 ligands for CNS disorders |
RU2009128619/04A RU2473545C2 (en) | 2007-02-02 | 2008-01-23 | New 2-aminooxazolines as taar1 ligands for cns diseases |
MX2009008255A MX2009008255A (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands for cns disorders. |
KR1020097018315A KR101174191B1 (en) | 2007-02-02 | 2008-01-23 | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
IL199783A IL199783A0 (en) | 2007-02-02 | 2009-07-09 | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
MA32143A MA31165B1 (en) | 2007-02-02 | 2009-08-04 | NOVEL 2-AMINOOXAZOLINS AS TAAR1 LIGANDS FOR CNS DISORDERS |
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