EP0853626A1 - Composes phosphiniques substitues et leur utilisation pharmaceutique - Google Patents
Composes phosphiniques substitues et leur utilisation pharmaceutiqueInfo
- Publication number
- EP0853626A1 EP0853626A1 EP96928599A EP96928599A EP0853626A1 EP 0853626 A1 EP0853626 A1 EP 0853626A1 EP 96928599 A EP96928599 A EP 96928599A EP 96928599 A EP96928599 A EP 96928599A EP 0853626 A1 EP0853626 A1 EP 0853626A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- group
- alkyl
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 238
- 239000003814 drug Substances 0.000 title claims description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims abstract description 36
- 125000003118 aryl group Chemical group 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 21
- 150000002148 esters Chemical class 0.000 claims abstract description 20
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 20
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- -1 3-carboxyphenyl Chemical group 0.000 claims description 211
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 150
- 125000000217 alkyl group Chemical group 0.000 claims description 141
- 239000000203 mixture Substances 0.000 claims description 105
- 238000006243 chemical reaction Methods 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 71
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000004185 ester group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 13
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000006483 4-iodobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1I)C([H])([H])* 0.000 claims description 7
- 229910015900 BF3 Inorganic materials 0.000 claims description 7
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 claims description 7
- 230000000638 stimulation Effects 0.000 claims description 7
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 6
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000001544 thienyl group Chemical class 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001475 halogen functional group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 4
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 4
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- 125000006480 iodobenzyl group Chemical group 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 150000001266 acyl halides Chemical class 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 241001516584 Andrya Species 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 66
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- 239000005711 Benzoic acid Substances 0.000 description 51
- 235000010233 benzoic acid Nutrition 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 230000002829 reductive effect Effects 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 33
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 238000003818 flash chromatography Methods 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- 239000000377 silicon dioxide Substances 0.000 description 25
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- 239000011574 phosphorus Substances 0.000 description 23
- 229910052698 phosphorus Inorganic materials 0.000 description 23
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 description 13
- 238000004255 ion exchange chromatography Methods 0.000 description 13
- 229920005989 resin Polymers 0.000 description 13
- 239000011347 resin Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- 229940125810 compound 20 Drugs 0.000 description 11
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000004949 mass spectrometry Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 229940125797 compound 12 Drugs 0.000 description 8
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 5
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 5
- 229940125773 compound 10 Drugs 0.000 description 5
- 229940125758 compound 15 Drugs 0.000 description 5
- 229940127204 compound 29 Drugs 0.000 description 5
- 229940127573 compound 38 Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 238000002523 gelfiltration Methods 0.000 description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 5
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 5
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
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Classifications
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- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates to chemical compounds which are substituted phosphinic acids or salts or esters thereof, their preparation and their use as pharmaceuticals.
- R j and R 2 are both H, R 1 and R 2 are both methyl or R 1 and R 2 together with the attached carbon atom are cyclopentyl. These compounds are said to act as GABA B antagonists.
- the present invention provides compounds which are substituted phosphinic acids of formula
- R 1 is a monovalent aromatic or araliphatic group connected through a carbon atom thereof to the indicated carbon atom
- R 2 is an unsubstituted or substituted hydrocarbyl group
- R x is hydrogen or an unsubstituted or substituted hydrocarbyl group
- R y is hydrogen, R y a or a NH- protecting group
- R y a is an unsubstituted or substituted hydrocarbyl group.
- R 1 as an aromatic group may have up to 40 carbon atoms and may be an aryl group such as a phenyl, tolyl, xylyi or naphthyl group or a heterocyclic aromatic group such as a thienyl, furyl, indolyl or pyridyl group, which groups may be unsubstituted or substituted by one or more substituents such as halogen, hydroxy, to C 4 alkoxy, carboxyl, functionally modified carboxyl including esterified carboxyl, amidated carboxyl and cyano, carboxy-C r C 8 alkyl, functionally modified carboxy-C C 8 alkyl or nitro.
- aryl group such as a phenyl, tolyl, xylyi or naphthyl group or a heterocyclic aromatic group such as a thienyl, furyl, indolyl or pyridyl group, which groups may be unsubstituted or substituted
- R 1 as an aromatic group is an aryl group of 6 to 15 carbon atoms which may be unsubstituted or substituted in one or more positions by halogen, carboxyl, functionally modified carboxyl, carboxy-C r C 8 alkyl, functionally modified carboxy-C r C 8 alkyl or nitro, or R 1 as an aromatic group is a 5 to 10-membered heterocyclic aromatic group having one or two nitrogen atoms in the ring system.
- R 1 as unsubstituted or substituted aryl is phenyl or phenyl substituted in one or more of the meta and para positions, with respect to the carbon atom thereof linked to the indicated morpholine ring, by halogen, carboxyl, functionally modified carboxyl, or nitro.
- substituted phenyl groups include phenyl mono-or di-substituted by chloro; bromo; iodo; carboxyl; -COOR 3 where R 3 is to C 8 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl optionally substituted by halogen, hydroxy or Ci to C 4 alkoxy; carbamoyl; N-C r C 4 alkyl carbamoyl, such as methyl- or ethyl-carbamoyl, N, N-di(C 1 -C 4 alkyl) carbamoyl such as dimethyl- or diethyl-carbamoyl; cyano; carboxy-C r C 4 alkyl such as carboxymethyl; Ci to C 8 alkoxy-carbonyl-C r C 4 alkyl such as methoxy- or ethoxy- carbon
- R 1 as an araliphatic group may have 7 to 40 carbon atoms and may be phenyl-lower alkyl, for example benzyl or 2-phenylethyl, ⁇ , ⁇ -diphenyl-lower alkyl such as diphenylmethyl, or ⁇ -naphthyl-lower alkyl such as naphthylmethyl, any of which groups may be unsubstituted or substituted in one or more positions, which may be ortho, meta or para positions, by a substituent chosen from those hereinbefore specified for R 1 as an aromatic group.
- R 1 as an araliphatic group is ⁇ -phenyl-C ⁇ -C 4 alkyl, which is unsubstituted or substituted in one or more positions by halogen, carboxyl, functionally modified carboxyl or nitro.
- R 1 is phenyl, 3-iodophenyl, 3, 4-dichlorophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-(methoxycarbonyl)phenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxy benzyl, 4-ethoxycarbonylbenzyl or indol-3-yl.
- R 2 as an unsubstituted or substituted hydrocarbyl group may, in general, have 1 to 40 carbon atoms. It may be for example an alkyl, cycloalkyl, alkenyl or alkynyl group or an alkyl, cycloalkyl or alkenyl group substituted by one or more substituents such as halogen, hydroxy, Cj to C 8 alkoxy, thio, Cj to Cg alkylthio, cyano, acylamino, C3 to C 8 cycloalkyl, C 3 to C 8 cycloalkyl substituted for example by one or more substituents such as hydroxy, Cj to C 8 alkoxy, thio or Ci to C 8 alkylthio, C 3 to C 8 cycloalkenyl, C 6 to C 15 aryl, C 6 to C 15 aryl substituted for example by one or more substituents such as hydroxy, Ci to C 8 alkoxy, halogen or trifiu
- Aliphatic radicals R 2 are, for example, lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or poly-halo-lower alkyl, mono-, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo- (hydroxy)-lower alkyl, mono-, di- or poly-halo(hydroxy)-lower alkenyl, lower alkoxy- lower alkyl, di-lower alkoxy-lower alkyl, lower alkoxy(hydroxy)-lower alkyl, lower alkoxy(halo)-lower alkyl, lower alkylthio-lower alkyl and di-lower alkylthio-lower alkyl.
- Cycloaliphatic radicals R 2 are, for example, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-, thia- and dithia-cycloalkyl.
- Cycloaliphatic-aliphatic radicals R 2 are, for example, cycloalkyl-lower alkyl, cyclo- alkenyl-lower alkyl, cycloalkyl(hydroxy)-lower alkyl and (lower alkylthio)cycloalkyl- (hydroxy)-lower alkyl.
- Araliphatic radicals R 2 are, for example, phenyl-lower alkyl radicals that are unsubstituted or mono-, di- or tri-substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifiuoromethyl, preferably ⁇ -phenyl-lower alkyl substituted as indicated or unsubstituted ⁇ , ⁇ -diphenyl- or ⁇ -naphthyl-lower alkyl.
- Heteroarylaliphatic radicals R 2 are, for example, thienyl-, furyl- or pyridyl-lower alkyl radicals that are unsubstituted or substituted, especially mono- or di-substituted, by halogen, preferably unsubstituted ⁇ -thienyl-, ⁇ -furyl- or ⁇ -pyridyl-lower alkyl.
- lower radicals and compounds are to be understood, for example, as those containing up to and including 7, preferably up to and including 4, carbon atoms.
- Lower alkyl is, for example, C r C alkyl, preferably C ⁇ -C 4 alkyl, such as methyl, ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec-butyl, tert-butyl or a C C ⁇ - kyl group, such as a pentyl, hexyl or heptyl group.
- Lower alkenyl is, for example, C 2 -C 4 alkenyl, such as vinyl, allyl or but-2-enyl, but may also be a C 5 -C alkenyl group, such as a pentenyl, hexenyl or heptenyl group.
- Lower alkynyl is, for example, C 2 -C 7 alkynyl, preferably C 3 -C 5 alkynyl, that carries the double bond in a position higher than the ⁇ , ⁇ -position, for example 2-propynyl (propargyl), but-3-yn-l-yl, but-2-yn-l-yl or pent-3-yn-l-yl.
- Oxo-lower alkyl carries the oxo group preferably in a position higher than the ⁇ -position and is, for example, oxo-C 2 -C 7 alkyl, especially oxo-C 3 -C 6 alkyl, such as 2-oxopropyl, 2- or 3-oxobutyl or 3-oxopentyl.
- Phenyl-lower alkyl is, for example, benzyl, 1 -phenylethyl, 2-phenylprop-2-yl or, in the second place, 2-phenylethyl, 2-phenylprop-l-yl or 3-phenylprop-l-yl.
- Thienyl-, furyl- or pyridyl-lower alkyl is, for example, thienyl-, furyl- or pyridyl-methyl, 1-thienyl-, l-furyl- or 1-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-pyridyl-prop-2-yl, or, in the second place, 2-thienyl-, 2-furyl- or 2-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-pyridyl- prop-1-yl or 3-thienyl-, 3-furyl- or 3-pyridyl-prop-l-yl.
- Hydroxy-lower alkyl carries the hydroxy group preferably in the ⁇ - or ⁇ -position and is, for example, corresponding hydroxy-C 2 -C 7 alkyl, such as 1 -hydroxyethyl, 1- or 2-hydroxy- propyl, 2-hydroxyprop-2-yl, 1- or 2-hydroxybutyl, 1-hydroxyisobutyl or 2-hydroxy-3- methylbutyl.
- Dihydroxy-lower alkyl carries the hydroxy groups especially in the ⁇ , ⁇ -position and is, for example, ⁇ , ⁇ -dihydroxy-C 3 -C 7 alkyl, such as 1 ,2-dihydroxyprop-2-yl.
- Hydroxy-lower alkenyl carries the hydroxy groups preferably in the ⁇ -position and the double bond preferably in a position higher than the ⁇ , ⁇ -position and is, for example, corresponding ⁇ -hydroxy-C 3 -C 5 alkenyl, for example l-hydroxybut-2-enyl.
- Mono-, di- or poly-halo-lower alkenyl is, for example, mono- di- or tri-fluoro-C 2 -C 5 - alkenyl, such as l-fluorobut-2-enyl.
- Mono-, di- or p ⁇ lyhalo(hydroxy)-lower alkyl carries the hydroxy group preferably in the ⁇ -position and the halogen atoms preferably in a position higher than the ⁇ -position and is, for example, corresponding mono- di- or tri-fluoro- ⁇ -hydroxy-C 2 -C 7 alkyl, such as 4,4,4- trifluoro- 1 -hydroxybutyl.
- Mono-, di- or poly-halo-lower alkyl is, for example, mono- di- or tri-fluoro-C2-C5alkyl, such as 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1,1-difluorobutyl.
- Lower alkoxy is, for example, C r C 7 alkoxy, preferably C r C 4 alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also be isobutoxy, sec-butoxy, tert- butoxy or a C 5 -C 7 alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
- Acylamino-lower alkyl is, for example C r C 4 alkylcarbonylamino-C 1 -C 4 alkyl such as acetylaminopropyl or C 6 -C 10 arylcarbonylamino-C r C 4 alkyl such as benzoylaminomethyl.
- Cyano-lower alkyl is, for example cyano-C r C 4 alkyl, such as cyanomethyl or 2-cyanoethyl.
- Mono-, di- or poly-halo(hydroxy)-lower alkenyl carries the hydroxy group preferably in the ⁇ -position and the halogen atoms preferably in a position higher than the ⁇ -position and is, for example, corresponding mono-, di- or tri-fluoro- ⁇ -hydroxy-C 2 -C 5 alkenyl, such as 2-fluoro-l-hydroxybuten-2-yl.
- Lower alkoxy-lower alkyl is, for example, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, such as methoxy- or ethoxy-methyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxy- or 3-ethoxy-propyl or 1- or 2-methoxybutyl.
- Di-lower alkoxy-lower alkyl is, for example, di-C 1 -C 4 -alkoxy-C 1 -C 4 alkyl, for example dimethoxymethyl, dipropoxymethyl, 1,1- or 2,2-diethoxyethyl, diisopropoxymethyl, dibutoxymethyl or 3,3-dimethoxypropyl.
- Lower alkoxy(hydroxy)-lower alkyl is, for example, C r C 4 alkoxy-C 2 -C 7 -(hydroxy)alkyl, such as 2-hydroxy-3-methoxyprop-2-yl.
- Lower alkoxy(halo)-lower alkyl is, for example, C 1 -C 4 alkoxy-C 2 -C5-(halo)alkyl, such as 2-fluoro-3-methoxybutyl.
- Lower alkylthio-lower alkyl is, for example, C 1 -C alkylthio-C 1 -C 4 alkyl, such as methyl ⁇ thio- or ethylthio-methyl, 2-methylthioethyl, 2-ethylthioethyl, 3-methylthio- or 3-ethylthio-propyl or 1- or 2-methylthiobutyl.
- Di-lower alkylthio-lower alkyl is, for example, di-C 1 -C alkylthio-C 1 -C alkyl, for example dimethylthiomethyl, dipropylthiomethyl, 1,1- or 2,2-diethylthioethyl, diisopropylthio- methyl, dibutylthiomethyl or 3,3-dimethylthiopropyl.
- Halogen is halogen having an atomic number of up to and including 53, i.e. fluorine, chlorine, bromine or iodine.
- Cycloalkyl is, for example, C 3 -C 8 cycloalkyl, especially C 3 -C 6 cycloalkyl, such as cyclo ⁇ propyl, cyclobutyl, cyclopentyl or cyclohexyl.
- Hydroxycycloalkyl is, for example, ⁇ -hydroxy-C 3 -C 6 cycloalkyl, such as 1-hydroxycyclo- propyl, 1-hydroxycyclobutyl or 1-hydroxycyclohexyl.
- Oxa- or thia-cycloalkyl is, for example, oxa- or thia-C 3 -C 8 cycloalkyl, especially oxa- or thia-C 3 -C 6 cycloalkyl, such as 2-oxacyclopropyl (oxiranyl), 2- or 3-oxacyclobutyl (oxetan- yl), 2- or 3-thiacyclobutyl (thietanyl), 2- or 3-oxacyclopentyl (tetrahydrofuranyl), 2- or 3-thiacyclopentyl (thiolanyl) or 2-oxacyclohexyl (tetrahydropyranyl).
- 2-oxacyclopropyl oxiranyl
- 2- or 3-oxacyclobutyl oxetan- yl
- 2- or 3-thiacyclobutyl thietanyl
- 2- or 3-oxacyclopentyl tetra
- Dioxacycloalkyl is, for example, l,3-dioxa-C 3 -C 8 cycloalkyl, such as l,3-dioxolan-2-yl or l,3-dioxan-2-yl.
- Dithiacycloalkyl is, for example, l,3-dithia-C 3 -C 8 cycloalkyl, such as l,3-dithiolan-2-yl or l,3-dithian-2-yl.
- Cycloalkyl-lower alkyl is, for example, C 3 -C 8 -cycloalkyl-C 1 -C 4 alkyl, especially C 3 -C 6 - cycloalkyl-C r C 4 alkyl, such as ⁇ -(C 3 -C 6 cycloalkyl)-C r C alkyl, for example cyclopropyl- methyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.
- Cycloalkenyl-lower alkyl is, for example, C 3 -C 8 cycloalkenyl-C r C 4 alkyl, especially C 3 -C 6 cycloalkenyl-C C 4 alkyl, such as ⁇ -(C 3 -C 6 cycloalkenyl)-C r C 4 alkyl, for example cyclopent-1-enylmethyl, cyclopent-2-enylmethyl, cyclopent-3-enylmethyl, cyclohex-1- enylmethyl, cyclohex-2-enylmethyl or cyclohex-3-enylmethyl.
- Cycloalkyl(hydroxy)-lower alkyl is, for example, C 3 -C 6 cycloalkyl-C r C 4 (hydroxy)alkyl, such as ⁇ -(C 3 -C 6 cycloalkyl)- ⁇ -hydroxy-C C 4 alkyl, for example cyclopropyl(hydroxy)- methyl, cyclobutyl(hydroxy)methyl, or cyclohexyl(hydroxy)methyl.
- (Lower alkylthiocycloalkyl) ⁇ ydroxy)-lower alkyl is, for example, l-(C r C 4 alkylthio- C 3 -C 6 cycloalkyl)-l-hydroxy-C r C 4 alkyl, such as (2-methylthiocycloprop-l-yl)hydroxy- methyl.
- R 2 is lower alkyl, lower alkenyl, lower alkynyl, oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- or poly-halo-lower alkyl, mono-, di- or poly-halo-lower alkenyl, mono-, di- or poly-halo- (hydroxy)-lower alkyl, mono-, di- or poly-halo(hydroxy)-lower alkenyl, lower alkoxy- lower alkyl, di-lower alkoxy-lower alkyl, lower alkoxy(hydroxy)-lower alkyl, lower alkoxy(halo)-lower alkyl, lower alkylthio-lower alkyl, di-lower alkylthio-lower alkyl, cyano-lower alkyl, acylamino-lower alkyl, cycloalkyl, hydroxycycloalkyl, hydroxycycl
- R 2 is C ⁇ -C alkyl, such as methyl, ethyl, propyl, isopropyl, butyl isobutyl or pentyl, ⁇ , ⁇ -di-C 1 -C 4 alkoxy-C 1 -C alkyl, especially ⁇ , ⁇ -di- or ethyl, such as dimethoxy- or diethoxy-methyl or 1, 1-diethoxyethyl, cyano-C ⁇ -C 4 alkyl such as cyanomethyl or 2-cyanoethyl, acylamino-Cj-Cs alkyl such as acetylaminoethyl, acetylaminopropyl, acetylaminopentyl or benzoylaminomethyl, C 3 -C 6 cycloalkyl-C 1 -C alkyl, such as cyclopropyl- or cyclo- hexyl-methyl, C 3 -C
- R 2 is -C5 alkyl such as methyl, ethyl or butyl, ⁇ , ⁇ -di-(C r C 4 alkoxy)methyl such as diethoxymethyl, ⁇ , ⁇ -di-(C r C 4 alkoxy)ethyl such as 1, 1-diethoxyethyl, C 3 -C 6 cycloalky l-C r C 4 alkyl such as cyclopropylmethyl or cyclohexylmethyl, benzyl or 4-methoxybenzyl.
- R 2 is cyclohexylmethyl or 4-methoxybenzyl.
- R x as an unsubstituted or substituted hydrocarbyl group may have up to 40 carbon atoms and may be a Ci to C 10 alkyl, C 2 to C 10 alkenyl, C 3 to C 8 cycloalkyl, C 4 to C 13 cycloalkylalkyl, C 6 to o aryl or C 7 to C 13 aralkyl group, any of which groups may be substituted by one or more substituents chosen from those hereinbefore specified for R 1 .
- R is hydrogen, lower alkyl, C 3 to C 6 cycloalkyl, C 6 to C 8 aryl or C 7 to C 9 aralkyl, especially hydrogen or isopropyl.
- R y as an unsubstituted or substituted hydrocarbyl group R y a may have up to 40 carbon atoms and may be, for example, a C j to C 10 alkyl, C 3 to C 8 cycloalkyl or C 7 to C 13 aralkyl group, any of which groups may be unsubstituted or substituted by hydroxy or C t to C alkoxy.
- R y as a NH-protecting group may be, for example, an acyl group such as acetyl, trifluoroacetyl, benzoyl or p-nitrobenzoyl or an alkoxycarbonyl or aralkoxycarbonyl group such as tert-butoxycarbonyl or benzyloxycarbonyl.
- R y is hydrogen, lower alkyl, C 7 to C 9 aralkyl, acetyl, benzoyl, tert-butoxycarbonyl or benzyloxycarbonyl, especially hydrogen, methyl, ethyl, benzyl, acetyl, benzoyl, tert-butoxycarbonyl or benzyloxycarbonyl.
- R 1 is phenyl, 3-iodophenyl, 3, 4-dichlorophenyl, 3-cyanophenyl, 3-(methoxycarbonyl)phenyl, 3-carboxyphenyl, 3-nitrophenyl, benzyl, 4-iodobenzyl, 4-carboxybenzyl, 4-ethoxycarbonylbenzyl or indol-3-yl
- R 2 is cyclohexylmethyl or 4-methoxybenzyl
- R is hydrogen or isopropyl
- R y is hydrogen, methyl or benzyloxycarbonyl, and salts and esters thereof.
- the compounds of formula I may be in the form of internal salts and can form both acid addition salts and salts with bases by conventional salt-forming reactions.
- Acid addition salts of compounds of formula I are, for example, their pharmaceutically acceptable salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).
- suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benz
- Salts of compounds of formula I with bases are, for example, their salts with pharmaceut ⁇ ically acceptable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, Ila and lib, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as unsubstituted or C-hydroxylated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or tri- (hydroxy-lower alkyl)amines, such as ethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)methylamine or 2- hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamine
- the hydroxy group attached to phosphorus in formula I may also be esterified.
- the invention includes compounds of formula I in the form of their esters with an alcohol, which may be a Cj to C 10 alkanol in which the alkyl radical is unsubstituted or substituted, for example by halogen, cyano or Ci to C 4 alkoxy, such as methanol, ethanol, isopropanol, isobutanol, 2-ethylhexanol, 2-chloroethanol, 2-cyanoethanol, 2-ethoxyethanol or 2-n-butoxyethanol, a C 3 to C 8 cycloaliphatic alcohol such as cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, methylcyclohexanol or cyclooctanol, or a C 7 to C 13 araliphatic alcohol such as benzyl, a Cj to C 10
- the compounds according to the invention may be in the form of isomeric mixtures, especially in the form of racemates, or in the form of pure isomers, especially optical antipodes.
- Preferred isomers of compounds of formula I are those in which R 1 and the group attached to the 2- position of the indicated morpholine ring are trans with respect to each other,i.e. those of formula
- R 1 , R 2 , R x and R y are as hereinbefore defined.
- R 1 , R 2 , R x and R y are as hereinbefore defined.
- the compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. They exhibit an effective binding to the GAB A B receptor and have been found to be antagonists of GABA ( ⁇ -aminobutyric acid) at that receptor.
- GABA ⁇ -aminobutyric acid
- antagonism at GABA B receptors can increase the release of rapid stimulant amino acid transmitters, that is to say, glutamate and aspartate, and thus improve information processing in the brain. This is in keeping with the finding that the late post-synaptic inhibition potential in the hippocampus, which is attributed to a GABA B mechanism, is broken down by the antagonists and thus permits a faster nerve impulse transmission sequence.
- the GABA B antagonists according to the invention interact at the GABA B receptor with IC5 0 values from 10 "7 to 10" 10 M (mole/litre) on cerebral cortex membranes of rats.
- GAB A B agonists such as baclofen
- they do not potentiate the stimulation by noradrenalin of adenylate cyclase on sections of the cerebral cortex of rats but act as antagonists of the baclofen action.
- the antagonists not only exhibit antagonism towards baclofen but also have an independent action as antagonists of endogenous GABA.
- the compounds of the invention are suitable for use in the treatment or prevention of conditions characterised by stimulation of GABA B receptors.
- they are suitable for use as nootropics, antidepressants and anxiolytics, for example in the treatment of central nervous system disorders such as anxiety, depression, cerebral insufficiency, epilepsy of the "petit mal” type, i.e. absence epilepsy in children and adolescents, atypical absences such as the Lennox-Gastant syndrome, in the treatment of conditions requiring enhancement of cognitive performance and as an antidote to baclofen.
- R 4 is R 1 as hereinbefore defined except that R 4 may not be substituted by carboxyl
- R x is as hereinbefore defined except that it may not be substituted by carboxyl with a compound of formula
- R 2 is as hereinbefore defined, X is halogen, e.g. chlorine or bromine, and R 5 is C j to C 8 alkyl, e.g. n-hexyl, n-octyl, preferably Cjto C 4 alkyl such as methyl, ethyl, isopropyl or isobutyl, especially ethyl, in the presence of a base, to give a compound of formula
- R 4 and R are as defined in formula II, followed, where required, by one or more substitution reactions to change the nature of a substituent in R 4 and/or R x and/or by hydrolysis of an ester substituent in R 4 and/or R to carboxyl and/or by conversion of the ester group -OR 5 to -OH.
- the reaction of compounds of formulae II and III which proceeds by monoalkylation of the amino group followed by cyclisation, may be effected in a one-step procedure.
- the reaction is carried out in two stages.
- a weak base for example a hindered amine such as 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) is added slowly to a mixture of the compounds of formulae II and IH in a solvent, preferably a hydrocarbon such as benzene, toluene or xylene, at a temperature of 70 to 110°C, to give a novel intermediate product of formula
- R 2 , R 4 , R 5 and R are as hereinbefore defined.
- This intermediate is then treated with a base under harsher conditions than those employed in its formation, for example with a similar base at a higher temperature or, preferably, with a stronger base such as an alkali metal hydride at a temperature from 10 to 50°C.
- the treatment of the intermediate with base may be carried out in a solvent, preferably a hydrocarbon such as toluene, benzene or xylene.
- Intermediate compounds of formula V may also themselves be used as pharmaceuticals, for example in the treatment or prevention of a condition characterised by stimulation of a GABA B receptor, particularly in de-esterified form, i.e. where R 5 as alkyl has been replaced by hydrogen and any carboxylic ester group in R 4 and/or R x has been converted into a carboxyl group. Accordingly, the invention includes novel compounds of formula
- R 1 , R 2 and R x are as hereinbefore defined, or salts or esters thereof.
- Compounds of formula I or IV in which R x and or R 1 or R 4 respectively contains a cyano substituent on an aryl or heteroaryl ring may be prepared by reacting an alkali metal cyanide with a compound of formula I or IV where R x and/or R 1 or R 4 respectively contains a halogen substituent on an aryl or heteroaryl ring, which compound may be prepared by diazotisation, followed by reaction with an alkali metal halide, of a compound of formula I or IV where R x and/or R 1 or R 4 respectively contains an amino group on an aryl or heteroaryl ring, which compound may be prepared by reduction of a compound of formula I or IV in which R x and/or R 1 or R 4 respectively contains a nitro group on an aryl or heteroaryl ring. All of these reactions can be effected using known procedures.
- R x and/or R 1 or R 4 respectively contains an esterified carboxyl substituent can also be prepared from other compounds of formula I or IV respectively.
- they may be prepared by reacting a compound of formula I or IV in which R and/or R 1 or R 4 respectively contains a halogen substituent on an aryl or heteroaryl ring with carbon monoxide and an alcohol in the presence of a palladium complex as catalyst, using known procedures.
- R 4 contains an esterified carboxyl group
- this may be hydrolysed to a free carboxyl group using conventional methods.
- R 4 in the compound of formula IV contains a nitro group on an aryl or heteroaryl ring
- this group may be converted in turn to amino by reduction, to halo by diazotisation of amino followed by reaction with an alkali metal halide, to cyano by reaction of halo with an alkali metal cyanide and thence to carboxyl by hydrolysis of cyano, these reactions conveniently being carried out using known procedures.
- the conversion of the ester group -OR 5 in a compound of formula IV or V into -OH can be effected by treatment with a suitable basic or acidic agent, such as an alkali metal hydroxide, for example sodium hydroxide or lithium hydroxide, an alkali metal halide, especially an alkali metal bromide or iodide, such as lithium bromide or sodium iodide, thiourea, an alkali metal thiophenolate, such as sodium thiophenolate, or a protonic acid or a Lewis acid, such as a mineral acid, for example hydrochloric acid, or a tri-lower alkyl-halosilane, for example trimethylchlorosilane.
- the replacement reaction can be effected in the absence or presence of a solvent and, if necessary, with heating or with cooling in a closed vessel and/or under an inert gas atmosphere.
- the conversion of -OR 5 in a compound of formula IV or V into -OH can also be carried out by treatment with an acid under hydrolytic conditions, especially with a mineral acid, such as a hydrohalic acid, for example hydrochloric acid, which is used in dilute or concentrated aqueous form, or by treatment with an organic silyl halide, such as trimethylsilyl iodide or bromide, and, if necessary, by subsequent hydrolysis.
- the reaction is preferably carried out at elevated temperature, for example by maintaining the reaction mixture at reflux temperature, and, where appropriate, using an organic diluent in a closed vessel and/or under an inert gas atmosphere.
- Compounds of formula II are in some instances commercially available, e.g. (R) - and (S) - phenyl glycinols.
- Compounds of formula II may be prepared by reduction of an aminocarboxylic acid of formula R 4 C(R x )(NH 2 )COOH, where R 4 and R are as hereinbefore defined in formula II, by reaction with borane dimethyl sulphide in the presence of a boron trifluoride complex such as boron trifluoride diethyl etherate. This reaction may be carried out using known procedures.
- Novel compounds of formula ⁇ where (i) R 4 is iodobenzyl, particularly 4-iodobenzyl, and R x is hydrogen and (ii) R 4 is phenyl and R x is isopropyl, may be prepared by this method.
- the compounds of formula II where R 4 is substituted by nitro may be prepared from an aminocarboxylic acid of formula R 4 C(R x )(NH 2 )COOH where R 4 is otherwise unsubstituted by nitration to introduce a nitro group into R 4 , converting the amino group in the product into a protected amino group, for example by reaction with di-tert-butyl dicarbonate to form a tert-butylcarbamate group, esterifying the carboxyl group in the protected product for example by conversion into a methyl ester, then reducing the ester group to -CH 2 OH by treatment with an appropriate reducing agent such as an alkali metal borohydride and finally removing the amino-protecting group by treatment with acid to re-form a free amino group.
- R 4 is nitrophenyl may be prepared by such a reaction sequence.
- R 4 , R 6 and R are as hereinbefore defined, reacting the compound of formula VI with an alcohol of formula R 7 OH, where R 7 is an alkyl group of 1 to 10 carbon atoms, e.g. n-hexyl, 2-ethylhexyl, n-octyl or decyl, preferably C j to C alkyl such as methyl, ethyl, isopropyl or n-butyl, especially methyl or ethyl, in the presence of an acid to form a compound of formula
- R 7 is an alkyl group of 1 to 10 carbon atoms, e.g. n-hexyl, 2-ethylhexyl, n-octyl or decyl, preferably C j to C alkyl such as methyl, ethyl, isopropyl or n-butyl, especially methyl or ethyl, in the presence of an acid to form a
- R x where R 4 , R 6 , R 7 and R x are as hereinbefore defined, removing R 6 , when this is other than hydrogen, from the compound of formula VII using, for example, known procedures to give a compound of formula
- R 4 , R 7 and R x are as hereinbefore defined, for example, where R 6 is an optionally substituted benzyl group, by catalytic hydrogenation in the presence of an organic acid, e.g. acetic acid, to give a compound of formula VIII in the foim of a salt thereof with the organic acid, reacting the compound of formula VIII with an amino-protecting agent such as tert-butyl dicarbonate to convert the amino group into a protected amino group, reducing the ester group -COOR 7 in the protected compound to -CH 2 OH by reaction with an appropriate reducing agent such as an alkali metal borohydride, and finally removing the protecting group to form a free amino group.
- an amino-protecting agent such as tert-butyl dicarbonate
- R 4 is substituted by a carboxylic ester group
- the protected amino group formed should be a group such as a tert-butyl carbamate group which will permit the ester group -COOR 7 to be reduced to -CH 2 OH while leaving the ester group in R 4 and then be removable by a reaction, for example in a non-aqueous medium, which leaves the ester group in R 4 .
- the compound of formula VI may be subjected to acid hydrolysis, for example using conventional procedures, to convert the indicated cyano group to carboxyl and the resulting aminocarboxylic acid may be reduced to a compound of formula II by reaction with borane dimethyl sulphide in the presence of a boron trifluoride complex such as boron trifluoride diethyl etherate, for instance using known procedures.
- a boron trifluoride complex such as boron trifluoride diethyl etherate
- R 4 is a monovalent araliphatic group as hereinbefore defined and R is an unsubstituted or substituted hydrocarbyl group as hereinbefore defined other than methylol
- R is methyl and R 4 is benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 2-phenylethyl, l,3-benzodioxol-5-methyl, 3-phenyl-l-aminopropyl, ⁇ -hydroxybenzyl, ⁇ -hydroxy- ⁇ -methylbenzyl, or ⁇ -hydroxy- ⁇ -methyl-4-nitrobenzyl, and with the exception of compounds of formula II where R 4 is benzyl and R x is allyl or -CH 2 CH 2 SCH 3 .
- a silylating agent such as a bis(trialkylsilyl) derivative of an amide, which agent undergoes reaction with the compound of formula DC to form a P(III) silyl compound which then reacts with the compound of formula X.
- the reaction may be carried out at a temperature from 0 to 50°C; it is preferably carried out in a solvent, for example a hydrocarbon such as toluene or a halohydrocarbon such as dichloromethane.
- Esters of formula EX may be prepared by reacting a protected phosphinate ester of formula
- R 5 is as hereinbefore defined and Q is a P-H-protecting group, with a compound of formula
- the leaving moiety Z may be, for example, a halogen atom or an organic sulphonate group.
- Z is chlorine, bromine, iodine, or a methanesulphonate, trifluoromethanesulphonate or p-toluenesulphonate group.
- Protected phosphinate esters of formula XI may be prepared by known methods, for example as described in US 4 933 478. Compounds of formula XII are either commercially available or may be prepared by known procedures.
- R is R y a
- R y a may be prepared by reacting a compound of formula I where R y is hydrogen with a compound of formula R y a Z, where R y a and Z are as hereinbefore defined, or by reductive alkylation using an aldehyde of formula R y b CHO, where R y b is hydrogen or R y a as hereinbefore defined, and a reducing agent which reduces imines to amines, for example sodium cyanoborohydride.
- a reducing agent which reduces imines to amines, for example sodium cyanoborohydride.
- R y is a NH-protecting group
- a compound of formula I where R y is hydrogen may be prepared by reacting a compound of formula I where R y is hydrogen with a reagent known to introduce the desired protecting group.
- the protecting group is an acyl group
- the compound of formula I where R y is hydrogen may be reacted with an acyl halide or carboxylic acid anhydride such as acetyl chloride, acetic anhydride or benzoyl chloride, for instance using known procedures.
- the compound of formula I where R y is hydrogen may be reacted with an alkoxycarbonyl or aralkoxycarbonyl halide or an alkyl or aralkyl dicarbonate such as benzyl chloroformate or di-tert-butyl dicarbonate, for example using known procedures.
- compounds of formula I where R y is R a or a NH-protecting group may also be prepared by the method hereinbefore described for the preparation of compounds of formula I where R y is hydrogen, in which method the compound of formula II is replaced by a compound of formula
- R 4 and R x are as defined in formula II, R 2 and R 5 are as hereinbefore defined and R y is R y a as hereinbefore defined or a NH-protecting group.
- This reaction may be carried out in a solvent, usually a hydrocarbon such as benzene, toluene or xylene, and is generally carried out under harsher conditions than those used for the reaction of compounds of formulae II and IH, for example using sodium hydride as the base and at a temperature of 10°C to 70°C.
- This reaction may be followed, where required, by one or more substitution reactions to change the nature of a substituent in R 4 and/or R x and/or by hydrolysis of an ester substituent in R 4 and/or R x to carboxyl and/or by conversion of the ester group -OR 5 to -OH.
- R 2 , R 4 , R 5 , R and R y are as hereinbefore defined followed, where required, by replacement of R y as an NH-protecting group by hydrogen and/or by one or more substitution reactions to change the nature of a substituent in R 4 and/or R x and/or by hydrolysis of an ester substituent in R 4 and/or R to carboxyl and/or by conversion of the ester group -OR 5 to -OH.
- the conversion of the primary hydroxyl group in the compound of formula XIV into Z may be carried out using known procedures.
- Z is an iodine atom
- the conversion may be effected by reacting the compound of formula XIV with triphenylphosphine, imidazole and iodine in a solvent such as acetonitrile or tetrahydrofuran at 0°C to 50°C
- Z is a trifluoromethanesulphonate group
- the conversion may be effected by reacting the compound of formula XIV with trifluoromethanesulphonic anhydride in pyridine at -100°C to 50°C.
- R y is an acyl group such as acetyl or benzoyl
- replacement by hydrogen may be effected by reaction with aqueous hydrochloric acid
- R y is trifluoroacetyl
- replacement by hydrogen may be effected by reaction with aqueous potassium carbonate.
- R 2 , R 4 , R 5 and R x are as hereinbefore defined, and replacing the indicated hydrogen attached to nitrogen by a NH-protecting group R y as hereinbefore defined, for example using known procedures such as those hereinbefore described.
- the reaction between the compounds of formula II and XVI may be carried out, for example, at a temperature of 20 to 100°C, preferably in an organic solvent such as an alcohol, especially ethanol.
- the hindered base may be, for example, a diazabicyclo compound such as 1,5-diazabicyclo [4.3.0]non-5-ene or 1,8-diazabicyclo [5.4.0]undec-7-ene or preferably, a tertiary amine such as dicyclohexyl(ethyl)amine or, especially, diisopropylethylamine.
- a diazabicyclo compound such as 1,5-diazabicyclo [4.3.0]non-5-ene or 1,8-diazabicyclo [5.4.0]undec-7-ene
- a tertiary amine such as dicyclohexyl(ethyl)amine or, especially, diisopropylethylamine.
- Compounds of formula XIV or XVII may themselves be used as pharmaceuticals, for example in the treatment or prevention of a condition characterised by stimulation of a GABA B receptor, particularly in de-esterified form, i.e. where R 5 as alkyl has been replaced by hydrogen and any carboxylic ester group in R 4 and/or R x has been converted into a carboxyl group, for example using known procedures.
- the invention includes novel compounds of formula where R 1 , R 2 , R x and R y are as hereinbefore defined, or salts or esters thereof.
- Compounds of the invention obtained as salts can be converted into the free compounds in a manner known per se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or ammonia, or another of the salt-forming bases mentioned hereinbefore, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another of the salt-forming acids mentioned hereinbefore.
- a base such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or ammonia
- an acid such as a mineral acid, for example with hydrochloric acid, or another of the salt-forming acids mentioned hereinbefore.
- Salts of the invention can be converted into different salts of the invention in a manner known per se; for example, acid addition salts can be converted by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of another acid in a suitable solvent in which an inorganic salt being formed is insoluble and is thus excluded from the reaction equilibrium, and base salts can be converted by freeing the free acid and converting into a salt again.
- a suitable metal salt such as a sodium, barium or silver salt
- the compounds of formula I may also be obtained in the form of hydrates or may include the solvent used for crystallisation.
- the free compounds and their salts are also optionally to be understood as being the corresponding salts and free compounds, respec ⁇ tively, where appropriate and where the context so allows.
- diastereoisomeric mixtures and mixtures of racemates can be separated in known manner into the pure diastereoisomers and racemates, respectively, on the basis of the physico ⁇ chemical differences between their constituents, for example by chromatography and/or fractional crystallisation.
- Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of micro- organisms or, by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example according to the acidic, basic or functionally modifiable groups contained in compounds of formula I, with an optically active acid, base or an optically active alcohol, into mixtures of diastereoisomeric salts or functional derivatives, such as esters, separation of the same into the diastereoisomers from which the desired enantiomer can be freed in customary manner.
- an optically active auxiliary compound for example according to the acidic, basic or functionally modifiable groups contained in compounds of formula I, with an optically active acid, base or an optically active alcohol, into mixtures of diastereoisomeric salts or functional derivatives, such as esters, separation of the same into the diastereoisomers from which the desired enanti
- Suitable bases, acids and alcohols for the purpose arc, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similar bases that can be obtained by synthesis, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-toluoyltartaric acid, D- or L-malic acid, D- or L-mandelic acid, or D- or L-camphor- sulfonic acid, or optically active alcohols, such as borneol or D- or L-(l-phenyl)ethanol.
- optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecoline, e
- Compounds of formula I, VA or XVIII may be isotopically labelled, particularly with ⁇ C, 14 C, 2 H, 3 H or 125 I, for use in diagnostics.
- the compounds of formula I, VA or XVIII may be used, for example, in the form of pharmaceutical compositions that comprise a therapeutically effective amount of the active ingredient, where appropriate together with pharmaceutically acceptable carriers that are suitable for enteral, for example oral, or parenteral administration, which carriers may be solid or liquid and organic or inorganic.
- pharmaceutically acceptable carriers that are suitable for enteral, for example oral, or parenteral administration, which carriers may be solid or liquid and organic or inorganic.
- tablets or gelatin capsules are used that contain the active ingredient together with diluents, for example lactose, dex ⁇ trose, saccharose, mannitol, sorbitol, cellulose and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
- Tablets may also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl ⁇ cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, for example sodium alginate, and/or effervescent mixtures, or absorbents, colourings, flavourings and sweeteners.
- the compounds of formula I can also be used in the form of parenterally administrable compositions or in the form of infusion solutions.
- Such solutions are prefer ⁇ ably isotonic aqueous solutions or suspensions which, for example in the case of lyophilised compositions that comprise the active ingredient on its own or together with a carrier, for example mannitol, can be prepared before use.
- the pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preserv ⁇ atives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
- compositions which, if desired, may comprise other pharmacologically active substances, may be prepared in a manner known per se, for example by conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and may comprise approximately from 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, and, in the case of lyophilisates, up to approximately 100 %, active ingredient.
- the invention relates also to the use of the compounds of formula I, VA or XVIII, or salts or esters thereof, preferably in the form of pharmaceutical compositions.
- the dose may depend on various factors, such as the mode of administration, species, age and/or individual condition.
- the doses to be administered daily may, in the case of oral administration, be from approximately 1 to approximately 50 mg kg, especially from 5 to approximately 25 mg/kg, and, in the case of warm-blooded animals having a body weight of approximately 70 kg, preferably from approximately 70 mg to approximately 3500 mg, especially from approximately 350 to approximately 1750 mg, expediently divided into from 2 to 6, for example 3 or 4, single doses.
- the invention accordingly includes a method of treating or preventing a condition in warm-blooded mammals, particularly humans, characterised by stimulation of a GABA B receptor which comprises administering to the warm-blooded mammal a compound of formula I, VA or XVIII, or a pharmaceutically acceptable salt or ester thereof.
- Phenyl glycine (42g) is dissolved in concentrated sulphuric acid (210ml) and the solution is cooled to 0°C. Fuming nitric acid (15.5ml) is added dropwise to the cooled solution over 30 minutes and the mixture is stirred for a further 30 minutes at 0°C, then 18 hours at room temperature. The solution obtained is poured over 1 litre of ice and carefully adjusted to pH7 by adding approximately 875ml of 10M aqueous sodium hydroxide whilst keeping the temperature of the solution below 20°C. The resulting mixture is stirred for 3 hours at room temperature and the precipitate obtained is filtered off. The precipitate is washed three times with water and recrystalized from 1 litre of water to afford 3-nitrophenylglycine, mpt 165-6°C.
- 3-Nitrophenyl glycine (5g) is added to a mixture of methanol (200ml) and triethylamine (20ml) and the mixture is stirred vigorously for 10 minutes at room temperature.
- Di-tert-butyl dicarbonate (U.13g) is added and the reaction mixture is heated under reflux for 2 hours.
- the solution obtained is cooled to room temperature and then concentrated to dryness under reduced pressure to afford a dark orange residue.
- the residue is purified by flash chromatography [silica gel, CH 2 C1 2 (95%), CH 3 OH (2.5%), CH 3 COOH (2.5%)] to afford Compound A as an orange foam.
- Trifluoroacetic acid 60ml is added to a flask containing Compound C (5g) cooled to 0°C.
- the resulting solution is stirred for 20 minutes at 0°C, then allowed to warm to room temperature and stirred for a further 3 hours.
- the solvent is removed under reduced pressure and the residue is purified by ion exchange chromatography (Dowex 50WX 2-200 (H + form) resin, elutant 3% aqueous ammonium hydroxide solution) to afford Compound D as a pale brown foam.
- Trifluoroacetic acid (3.0ml, 39.17mM) is added to a stirred solution of Compound F (2.2g, 7.45mM) in dry dichloromethane (25ml) under argon at room temperature. The mixture is stirred for 5 hours at room temperature. On completion of the reaction (tic), the mixture is evaporated under reduced pressure without heating and the residue is co-evaporated with chloroform (2 x 20ml). After drying under high vacuum, the residue is purified by ion exchange chromatography on Amberlyst A21 resin using water as eluant to afford Compound 4 as a colourless oil.
- Compound 7 (4.7, 15.35mM) is reacted with trifluoroacetic acid (75ml) using substantially the same procedure as described for the preparation of Compound D from Compound C.
- the crude product is purified by ion exchange chromatography on Dowex 50WX 2-200 (H + form) resin using methanol: water: aqueous ammonia solution (50%: 47%: 3%) as eluant to afford Compound 8 as a cream coloured solid, m.p. 65-67°C.
- Bis(trimethylsilyl)acetamide (28.51ml) is added dropwise to a solution of 18.22g of ethyl cyclohexylmethylphosphinate, prepared as described in EP 0569333, in 100ml of dry CH 2 C1 2 under argon. The solution is stirred at room temperature for 1 hour, then trimethyl phosphate (13.42ml) is added, followed by 1,3-dibromopropene (mixture of cis/trans isomers) (9.57ml). After stirring the solution at room temperature for 18 hours, it is poured into saturated aqueous NaHCO 3 solution (100ml) and stirred for 10 minutes.
- the reaction mixture is allowed to warm to room temperature and stirred for 20 hours.
- Saturated aqueous ammonium chloride solution (5ml) is added, then the reaction mixture is partitioned between ethyl acetate and water.
- the aqueous layer is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulphate, filtered and evaporated.
- the residue is purified by flash chromatography on silica using 5% methanol in dichloromethane as eluant to afford Compound 15 as a mixture of diastereomers at phosphorus.
- Sodium cyanide impregnated alumina (5mM NaCN per gram of alumina) is prepared by the procedure of S. L. Regen, S. Quici and S. J. Liaw described in the Journal Organic Chemistry, 1979, 44(12), 2029.
- a suspension of sodium hydride (0.105g, 4.4mM) in dry toluene (5ml) is added portionwise over 30 seconds to a stirred solution of Compound 37 (2.0g, 4.0mM) in dry toluene (25ml).
- the mixture is stirred for 30 minutes at 0°C and then for 3 hours at room temperature.
- Glacial acetic acid (1ml) is added, then the reaction mixture is diluted with ethyl acetate (75ml).
- the organic phase is washed with saturated sodium bicarbonate solution, water and then brine.
- the combined organic phases are dried over magnesium sulphate, filtered and evaporated.
- the resulting product is further purified by gel filtration on a Bio-Gel P2 column using water as eluant to afford trans-2, 5-disubstituted morpholine racemic Compound 40, m.p. >250°C (dec).
- a buffered stock solution of formaldehyde is prepared by dissolving sodium acetate (1.8g, 21.4mM), acetic acid (1.3ml, 22.7mM) and 40% aqueous formaldehyde solution (7.0ml; lOlmM) in water (5ml). An aliquot (10ml) of the above stock solution is added to a mixture of Compound 29 (0.10g, 0.262mM) in methanol (2ml) and the mixture is stirred for 10 minutes at room temperature. Sodium cyanoborohydride (0.165g, 2.62mM) is added portionwise over 2 minutes. The mixture is stirred for 24 hours at room temperature.
- the mixture is extracted with ethyl acetate and the combined organic phases are washed with water then brine, dried over magnesium sulphate, filtered and evaporated.
- the residue is purified by flash chromatography on silica using acetic acid: methanol: chloroform (2% :10%: 88%) as eluant.
- the product is further purified by ion exchange chromatography on Dowex 50 WX 2-200 resin (H + form) using THF: water (3:1) as eluant.
- a mixmre of compound 45 (15.0g, 69.4mM) and bis(triphenylphosphine) palladium (II) chloride (4.0g, 5.70mM) in methanol (100ml) and triethylamine (25ml) is degassed by sparging with argon for 5 minutes.
- the mixture is saturated with carbon monoxide and then pressurised to 30 psi in a pressure vessel.
- the mixture is slowly heated to 100°C whilst maintaining the pressure below 50psi for 5 hours.
- the mixmre is cooled to room temperature, filtered and evaporated.
- the residue is triturated with ethyl acetate and the filtrate evaporated.
- the residue is purified by flash chromatography on silica using a gradient from 10% to 20% methanol in chloroform as eluant to afford compound 4.
- (2R/S)-2-amino-2- (lH-indol-3-yl)ethanol is prepared by the procedure of A.H. Katz et.al described in the Journal Medicinal Chemistry, 1988, 31, 1244.
- a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (50ml, 25mM) is added dropwise to a cooled (-70°C) solution of ethyl 1,1-diethoxyethylphosphinate (5.25g, 25mM) in dry THF (30ml). The mixture is stirred for 0.5 hours at -70°C. The resulting solution is added dropwise over ten minutes to a cooled solution of 4-methoxybenzyl chloride (3.9g, 25mM) in THF (30ml). The resulting mixture is stirred for 1 hour at -70°C and then allowed to warm to room temperature. Reaction is stirred for 18 hours at room temperature.
- Chlorotrimethylsilane (3.8ml, 30.3mM) is added to a solution of Compound 55 (l.Og, 3.03mM) in a 9:1 mixture of chloroform: ethanol (10ml) and the mixture is stirred for 18 hours at room temperature. The mixture is evaporated under reduced pressure and the residue is co-evaporated with chloroform. After drying under high vacuum, the residue is purified by flash chromatography on silica using ethyl acetate as eluant to afford Compound 56 as a colourless oil.
- Bromotrimethylsilane (0.074ml, 0.55mM) is added to a solution of Compound 59 (50mg, 0.1 ImM) in dichloromethane (1 ml) and the reaction is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the residue is co-evaporated with a 1:1 mixture of methanol: water. The resulting residue is dissolved in 6M hydrochloric acid (2ml) and the mixture is heated under reflux for 4 hours. The solvent is removed under reduced pressure and the residue is co-evaporated three times with water.
- the resulting residue is purified by ion exchange chromatography on Dowex 50 WX 2-200 resin (H + form) using methanol : 2% sodium hydroxide solution (1:1) to elute the product.
- the resulting product is further purified by gel filtration on a BIO-GEL P2 column using water as eluant to afford the trans-2,5-disubstituted morpholine racemic Compound 60. 31 P nmr (202.5MHz; D 2 O) ⁇ (ppm) 37.4.
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Abstract
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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GBGB9518186.3A GB9518186D0 (en) | 1995-09-07 | 1995-09-07 | Chemical Compounds |
GB9518186 | 1995-09-07 | ||
GB9613047 | 1996-06-21 | ||
GBGB9613047.1A GB9613047D0 (en) | 1996-06-21 | 1996-06-21 | Chemical compounds |
PCT/GB1996/002113 WO1997009335A1 (fr) | 1995-09-07 | 1996-08-30 | Composes phosphiniques substitues et leur utilisation pharmaceutique |
Publications (1)
Publication Number | Publication Date |
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EP0853626A1 true EP0853626A1 (fr) | 1998-07-22 |
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ID=26307695
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Application Number | Title | Priority Date | Filing Date |
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EP96928599A Withdrawn EP0853626A1 (fr) | 1995-09-07 | 1996-08-30 | Composes phosphiniques substitues et leur utilisation pharmaceutique |
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EP (1) | EP0853626A1 (fr) |
JP (1) | JPH11512111A (fr) |
KR (1) | KR19990044452A (fr) |
CN (1) | CN1196057A (fr) |
AR (1) | AR004682A1 (fr) |
AU (1) | AU6831996A (fr) |
CA (1) | CA2229036A1 (fr) |
CZ (1) | CZ66498A3 (fr) |
HU (1) | HUP9802260A3 (fr) |
IL (1) | IL123191A0 (fr) |
NO (1) | NO980994L (fr) |
PL (1) | PL324987A1 (fr) |
SK (1) | SK30198A3 (fr) |
TR (1) | TR199800414T1 (fr) |
WO (1) | WO1997009335A1 (fr) |
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WO1998028313A1 (fr) * | 1996-12-24 | 1998-07-02 | Novartis Ag | Acides carboxyliques et phosphiniques a substitution (thio)morpholine |
EP1618098B1 (fr) | 2003-04-11 | 2014-11-19 | PTC Therapeutics, Inc. | Composes d'acide benzoique 1,2,4-oxadiazole et utilisation de ceux-ci dans la suppression non-sens et le traitement de maladies |
CA2647903C (fr) | 2006-03-30 | 2016-12-13 | Ptc Therapeutics, Inc. | Methodes de production d'une proteine fonctionnelle a partir d'un adn presentant une mutation non-sens et traitement des troubles associes |
CN112979575A (zh) | 2014-03-06 | 2021-06-18 | Ptc医疗公司 | 1,2,4-噁二唑苯甲酸的药物组合物和盐 |
WO2017075312A1 (fr) | 2015-10-30 | 2017-05-04 | Ptc Therapeutics, Inc. | Méthodes de traitement de l'épilepsie |
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BE787617A (fr) * | 1971-08-16 | 1973-02-16 | Bristol Myers Co | Imidazolines et procede pour les preparer |
US4551526A (en) * | 1984-09-26 | 1985-11-05 | American Hospital Supply Corporation | Synthesis of alpha-aminonitriles |
US5929236A (en) * | 1993-03-26 | 1999-07-27 | Schering Corporation | 2-substituted morpholine and thiomorpholine derivatives as GABA-B antagonists |
-
1996
- 1996-08-30 CZ CZ98664A patent/CZ66498A3/cs unknown
- 1996-08-30 HU HU9802260A patent/HUP9802260A3/hu unknown
- 1996-08-30 AU AU68319/96A patent/AU6831996A/en not_active Abandoned
- 1996-08-30 CA CA002229036A patent/CA2229036A1/fr not_active Abandoned
- 1996-08-30 WO PCT/GB1996/002113 patent/WO1997009335A1/fr not_active Application Discontinuation
- 1996-08-30 SK SK301-98A patent/SK30198A3/sk unknown
- 1996-08-30 IL IL12319196A patent/IL123191A0/xx unknown
- 1996-08-30 KR KR1019980701700A patent/KR19990044452A/ko not_active Application Discontinuation
- 1996-08-30 PL PL96324987A patent/PL324987A1/xx unknown
- 1996-08-30 CN CN96196806A patent/CN1196057A/zh active Pending
- 1996-08-30 TR TR1998/00414T patent/TR199800414T1/xx unknown
- 1996-08-30 JP JP9510936A patent/JPH11512111A/ja active Pending
- 1996-08-30 EP EP96928599A patent/EP0853626A1/fr not_active Withdrawn
- 1996-09-05 AR ARP960104238A patent/AR004682A1/es unknown
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1998
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Title |
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See references of WO9709335A1 * |
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NO980994L (no) | 1998-04-30 |
CZ66498A3 (cs) | 1998-07-15 |
AR004682A1 (es) | 1999-03-10 |
AU6831996A (en) | 1997-03-27 |
PL324987A1 (en) | 1998-07-06 |
HUP9802260A2 (hu) | 1999-05-28 |
NO980994D0 (no) | 1998-03-06 |
CA2229036A1 (fr) | 1997-03-13 |
IL123191A0 (en) | 1998-09-24 |
CN1196057A (zh) | 1998-10-14 |
MX9801839A (es) | 1998-08-30 |
WO1997009335A1 (fr) | 1997-03-13 |
SK30198A3 (en) | 1998-08-05 |
JPH11512111A (ja) | 1999-10-19 |
KR19990044452A (ko) | 1999-06-25 |
HUP9802260A3 (en) | 1999-10-28 |
TR199800414T1 (xx) | 1998-05-21 |
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