AU610841B2 - Unsaturated phosphonic acids and derivatives - Google Patents
Unsaturated phosphonic acids and derivatives Download PDFInfo
- Publication number
- AU610841B2 AU610841B2 AU81455/87A AU8145587A AU610841B2 AU 610841 B2 AU610841 B2 AU 610841B2 AU 81455/87 A AU81455/87 A AU 81455/87A AU 8145587 A AU8145587 A AU 8145587A AU 610841 B2 AU610841 B2 AU 610841B2
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- AU
- Australia
- Prior art keywords
- compound
- lower alkyl
- carboxy
- formula
- substituted
- 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.)
- Ceased
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- 150000003009 phosphonic acids Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 36
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 12
- 239000005557 antagonist Substances 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 3
- -1 2-carboxypyrrolidinyl Chemical group 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 239000000203 mixture Substances 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 23
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 102000018899 Glutamate Receptors Human genes 0.000 claims description 17
- 108010027915 Glutamate Receptors Proteins 0.000 claims description 17
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 150000001299 aldehydes Chemical class 0.000 claims description 11
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000007522 mineralic acids Chemical class 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 150000003007 phosphonic acid derivatives Chemical class 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 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 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical class N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 230000002452 interceptive effect Effects 0.000 claims description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 claims 1
- 206010020649 Hyperkeratosis Diseases 0.000 claims 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 16
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000243 solution Substances 0.000 description 94
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- 229940093499 ethyl acetate Drugs 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 238000003818 flash chromatography Methods 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000009833 condensation Methods 0.000 description 10
- 230000005494 condensation Effects 0.000 description 10
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 229960004373 acetylcholine Drugs 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 206010010904 Convulsion Diseases 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 235000015424 sodium Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 208000028867 ischemia Diseases 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 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 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 208000019901 Anxiety disease Diseases 0.000 description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 230000036506 anxiety Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UIKAPMLQQHMWEB-UHFFFAOYSA-N ethyl 4-(2-hydroxyethyl)piperidine-2-carboxylate Chemical compound CCOC(=O)C1CC(CCO)CCN1 UIKAPMLQQHMWEB-UHFFFAOYSA-N 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- CQCAYWAIRTVXIY-UHFFFAOYSA-N 2-(triphenyl-$l^{5}-phosphanylidene)acetaldehyde Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC=O)C1=CC=CC=C1 CQCAYWAIRTVXIY-UHFFFAOYSA-N 0.000 description 4
- XCXJLWLQQPJVDR-UHFFFAOYSA-N 3-(azepan-2-yl)quinoline Chemical compound C1CCCCNC1C1=CN=C(C=CC=C2)C2=C1 XCXJLWLQQPJVDR-UHFFFAOYSA-N 0.000 description 4
- 201000006474 Brain Ischemia Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 206010008118 cerebral infarction Diseases 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001640 fractional crystallisation Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
- VYXQDROPKKIIOK-UHFFFAOYSA-N 1-o-tert-butyl 2-o-ethyl 4-(2-hydroxyethyl)piperidine-1,2-dicarboxylate Chemical compound CCOC(=O)C1CC(CCO)CCN1C(=O)OC(C)(C)C VYXQDROPKKIIOK-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000763 evoking effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
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- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
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- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
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- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 230000003387 muscular Effects 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
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- 238000005949 ozonolysis reaction Methods 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
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- 125000000405 phenylalanyl group Chemical group 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- HRVXPXCISZSDCC-UHFFFAOYSA-N piperidine-4-carbaldehyde Chemical compound O=CC1CCNCC1 HRVXPXCISZSDCC-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- WDXARTMCIRVMAE-UHFFFAOYSA-N quinoline-2-carbonitrile Chemical class C1=CC=CC2=NC(C#N)=CC=C21 WDXARTMCIRVMAE-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical class O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000028325 tonic-clonic seizure Diseases 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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- 238000009736 wetting Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
Compounds of the formula I <IMAGE> in which one or both of the acidic hydroxyl groups of the phosphonic acid part can be etherified, m is one or zero, R<1> denotes carboxyl, esterified carboxyl or amidated carboxyl, the heterocyclic five- or six-membered ring can additionally be substituted on the carbon and/or nitrogen, can have a carbon-carbon double bond or can be condensed with a carbocyclic 6-membered ring, starting from adjacent carbon atoms, A represents lower alkenylene; and salts thereof. These compounds are suitable as antagonists of the N-methyl-D-aspartate- sensitive amino acid stimulant receptor in mammals.
Description
Prescribied ISY Its Articles of A ssoclation.
D. B. MiscftlewsKi -Regi-stered -Patent A-ttorney TiIE COMMISSIONER OF PATENTS.
Erlkvd. WVaters 4, Sons, Aelbouirne.
®rr Form COMMONWEALTH OF PUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICAT ION
(ORIGINAL)
Class Application Number: Lodged: Int. Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: o 00 oName of Applicant: CIBA-GEIGY AG o o Address of Applicant: Klybeckstrasse 141, 4002 Basle, Switzerland Actual Inventor: Address for Service: ALAN J. HUTCHISON, KENNETH R. SHAW and JOSEF A. SCHNEIDER thDW-D-WA-R-S-&-SE-N-- 50QE F? RTUI-L 5 Cq T ~CC Sf~ j 0N .X -/P Complete Specification for the invention entitled: UNSATURATED PHOSPHONIC ACIDS AND DERIVATIVES The following statement is a lull description of this invention, including the best method of performing it known to us la Unsaturated Phosphonic Acids and Derivatives The present invention is concerned with the'compounds of formula I RC' o R Hi m (I) o o i2 wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or o°fo** lower alkoxy; lower alkanoylcxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, m represents one or zero, A represents lower alkenylene, R 1 is carboxy, esteri- 00 9 o on fied carboxy or amidated carboxy, and R 2 denotes hydrogen, lower alkyl or acyl or, if m stands for 1, represents aryl-lower alkyl, wherein the five-or six-membered heterocyclic ring may be addi- 0o tionally substituted on carbon and/or nitrogen, may have present a carbon-carbon double bond or may be fused on adjacent carbon atoms with a six-membered carbocyclic ring; and salts thereof, which are useful in mammals as antagonists of the N-methyl-D-aspartate sensitive excitatory amino acid receptor.
The instant invention is further concerned with processes for preparing said compounds, with pharmaceutical compositions comprising said compounds, with a method of blocking the N-methyl-D-aspartate sensitive excitatory amino acid receptor, and with a method of treating conditions and diseases in mammals responsive to the effect i i -r PATN 0FIC
AECT.
1 7 2 2 of an excitatory amino acid receptor antagonist by administration of said compounds or of pharmaceutical compositions comprising said compounds.
The compounds of the invention are azvive and useful in mammals as selective antagonists of the N-methyl-D-aspartate (NMDA) sensitive excitatory amino acid receptor. The compounds of the invention are therefore also useful, administered alone or in combination to i omammals, for the treatment of disorders responsive to said blockade of the NMDA receptor, comprising e.g. cerebral ischaemia, muscular ,l o' spasms (spasticity), convulsive disorders (epilepsy) and anxiety.
2 The compounds of the invention are also contemplated to be useful ene for the treatment of Huntington's disease.
o Fusion on adjacent carbon atoms with a six-membered carbocyclic ring is fusion with e.g. cyclohexyl or phenyl such that the fused heterocyclic ring of formula I is represented by a bicyclic i ringsystem containing 9 or 10 ring-forming atoms, depending on the ooa value of the symbol m of formula I.
l The heterocyclic ringsystem of the compounds of formula I as defined hereinbefore, together with substituent R 1 is represented e.g. by optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydroo; pyrrolyl, 2-carboxy-1-2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxytetrahydroquinolinyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl., wherein carboxy may be esterified or amidated.
Etherified hydroxy is represented e.g. by lower alkoxy, benzyloxy, benzyloxy substituted on ph-nyl by halogen, by lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl.
One preferred aspect of the invention relates to the phosphonic acid derivatives of formula I aad derivatives thereof wherein the heterocyclic ring represents optionally substituted 2-carboxypiperidinyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl or 2-carboxy-1,2,5, 6 tetrahydropyridinyl, more specifically the compounds of the formula II
R
R
3
(II)
\R1 C 0 2 O and the compounds of formula II with a double bond present between C-3 and C-4 or between C-4 and C-5 of the piperidinyl ring, in which the phosphono bearing chain is attached at the or 5-position of the piperidinyl or tetrahydropyridinyl ring, and wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, R 1 represents oao carboxy or pharmaceutically acceptable esterified or amidated carboxy; R 2 represents hydrogen, lower alkyl, aryl-lower alkyl, or acyl; R 3 represents hydrogen, lower alkyl or aryl-lower alkyl; A represents lower alkenylene; and salts thereof.
Preferred are the compounds of formula II, wherein R and R' indepeno a0 dently represent hydrogen, lower alkyl, benzyl, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, cyclohexyl or cyclopentyl; RI represents carboxy, carbamoyl or pharmaceutically acceptable esterified carboxy as defined herein;
R
2 and R 3 represent hydrogen or lower alkyl; A represents alkenylene of 2 to 4 carbon atoms; and pharmaceutically acceptable salts thereof.
Further preferred are the compounds of formula II wherein R and R' independently represent hydrogen, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl; R 1 represents carboxy, carbamoyl or lower alkoxycarbonyl, lower alkanoyl-
AV
,I .j o' 4oxymethoxycarbonyl, di-lower alkylamino straight chain Cz- 4 -alkoxycarbonyl or pyridylmethoxycarbonyl, R 2 and R 3 represent hydrogen; A is at the 4-position and represents an alkenylene of 3 or 4 carbon atoms with double bond adjacent to phosphono grouping; and pharmaceutically acceptable salts thereof.
Particularly preferred are the compounds of formula III A oo o o OH (III) S ao t wherein A represents 1,3-propenylene, preferably with the double bond adjacent to the phosphono grouping; R I represents carboxy or pharmaceutically acceptable esterified carboxy as defined herein; and pharmaceutically acceptable salts of said compounds having a c salt-forming functional grouping.
o e Most preferred are the compounds of formula III wherein the 2- and 9 4-substituents are cis to each other.
So Another aspect of the invention relates to the phosphonic acid o derivatives of formula I and derivatives cited above wherein the heterocyclic ring represents optionally substituted 2-carboxy- 1,2,3,4-tetrahydro- or perhydroquinolinyl in which the phosphono bearing chain is preferably located at the 3 or 4 position of the tetrahydro or perhydroquinolinyl ring, i.e. the compounds of formula IV S .A--OR' R' I I
(IV)
I VyS 5 or perhydro derivatives thereof, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, ben:yl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxymethyl, lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, or cycloalkyl; R 1 represents carboxy or pharmaceutically acceptable esterified or amidated carboxy; R 2 represents hydrogen, lower alkyl, aryl--lower alkyl, or acyl; R 4 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A represents lower alkenylene; and salts thereof.
0 3 0 0 onl 0o Preferred are the compounds of formula V Db00 o 00 0 I (V) 0 -OH grouping; RI represents carboxy or pharmaceutically acceptable oan""o able salts of said compounds having a salt-forming functional o0 grouping.
O O O Most preferred are the compounds of formula V wherein the 2- and 4-substituents are cis to each other.
or the perhydroquinoline derivatives thereof wherein A represents A furthe1,3-propenylene with the double bond adjaent to the phosphonic acid derivatives of formula I and derivatives cited above wherein the hete grouping; Rcyclic ring represents carox y or pharmaceuti cally acceptableyoesterified carboxy as defined herein; and pharmaceutically accept-VI able salts of said compounds having a salt-forming functional 0 o grouping.
Most preferred are the compounds of formula V wherein the 2- and 4-substituents are cis to each other. J A further aspect of the invention relates to the phosphonic acid derivatives of formula I and derivatives cited above wherein the heterocyclic ring represents optionally substituted 2-carboxypy'rolidinyl, i.e. the compounds of formula VI i 6
R
3
(VI)
T 'RI OR and the compounds of formula VI with a double bond present between C-3 and C-4 of the pyrrolidinyl ring, in which the phosphono bearing chain is attached preferably at the 3 or 4 position of the pyrrolidine ring and wherein R and R' independently represent hydrogen, o lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower o alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxy- 0 o methyl substituted on oxymethyl by lower alkyl, or cycloalkyl;
R
I represents carboxy or pharmaceutically acceptable esterified or amidated carboxy; R 2 represents hydrogen, lower alkyl or acyl;
CO
0
R
3 represents hydrogen, lower alkyl or aryl-lower alkyl; A represents lower alkenylene; and salts thereof.
S
00 Preferred are the compounds of formula VI wherein the phosphono Co .oB bearing group is attached at the 3-position; R and R' represent hydrogen; R I represents car: -y or pharmaceutically acceptable o esterified carboxy, e.g. 1 alkoxycarbonyl, lower alkanoyloxy-
C
S" methoxycarbonyl, di-lower alkylamino straighc chain C 2 -4-alkoxycarbonyl or pyridylmethoxycarbonyl; R 2 and R 3 represent hydrogen; A represents 1,3-propenylene with double bond adjacent to the phos- °o phono grouping; and pharmaceutically acceptable salts thereof.
The general definitions used herein have the following meaning in the context of the invention.
The term "lower", when referred to above and hereinafter in connection with organic groups, radicals or compounds respectively, defines such with up to and including 7, preferably up to and including 4 and advantageously one, two or three carbon atoms.
Lower alkyl preferably contains 1 to 4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.
F I__ 7 Lower alkenylene representing A preferably contains 2 to 4 carbon atoms and represents for example ethenylene, 1,3-propenylene, 1,4-but-l-enylene, 1,4-but-2-enylene, advantageously with double bond adjacent to phosphono grouping.
Lower alkoxy preferably contains 1 to 4 carbon atoms and represents for example ethoxy, propoxy or advantageously methoxy.
Lower alkanoyl preferably contains 2 to 7 carbon atoms and repre- So sents advantageously acetyl, propionyl, n-butyryl, isobutyryl or S pivaloyl, but may also be formyl.
SLower alkanoyloxy represents advantageously acetoxy, propionyloxy, a n- or i-butyryloxy or pivaloyloxy.
Cycloalkyl contains preferably 3 to 8 carbon atoms and represents Sor e.g. cyclohexyl or cyclopentyl.
Halogen is preferably fluorine and chlorine, but may also represent o bromine or iodine.
Aroyl represents arylcarbonyl, preferably benzoyl or benzoyl substituted by one to three substituents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen; or pyridylcarbonyl, particularly nicotinoyl.
Aroyloxy represents preferably benzoyloxy, benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy, e.g. methyl, chloro or methoxy respectively; or nicotinoyloxy.
Aryl represents preferably optionally substituted phenyl, e.g. phenyl or phenyl substituted by one to three substitutents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen; or pyridyl, particularly 3-pyridyl.
__i -8- Aryl-lower alkyl represents preferably aryl-C 1 -4-alkyl, aryl having meaning as defined above, advantageously benzyl or 2-phenylethyl.
Acyl represents carboxy derived acyl, preferably lower alkanoyl, aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, alpha-amino-lower alkanoyl or alpha-amlno-aryl-lower alkanoyl.
Aryl-iower alkanoyl represents preferably aryl-C 1 4 -alkanoyl, n advantageously phenylacetyl or 3-phenylpropionyl.
go Lower alkoxycarbonyl preferably contains 1 to 4 carbon atoms in the o alkoxy portion and represents for example methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or adva-,tageously ethoxycarbonyl.
0o o Aryl-lower alkoxycarbonyl represents preferably benzyloxycarbonyl.
Alpha-amino-lower alkanoyl and alpha-amino-aryl-lower alkanoyl represents acyl groups of alpha-aminoacids, e.g. alanyl, glycyl, leucyl, isoleucyl and phenylalanyl.
C 0 An N-mono(lower alkyl)carbamoyl group preferably contains o 1 to 4 carbon atoms in the alkyl portion and is for example n a N-methylcarbamoyl, N-propylcarbamoyl or advantageously N-ethylcarbamoyl.
An N,N-di(lower alkyl)carbamoyl group preferably contains 1 to 4 carbon atoms in each lower alkyl portion and represents for example N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and advantageously N,N-diethylcarbamoyl.
Di-lower alkylamino-N-lower alkylcarbamoyl preferably represents di-Cl- 4 -alkylamino-N-C 2 -4-alkylcarbau )yl, the two nitrogen atoms being separated by 2 to 4 carbon atoms and represents for example N-(2-diethylaminoethyl)carbamoyl or N-(3-diethylaminopropyl)carbamoyl.
9- Mono-lower alkylamino preferably contains 1 to 4 carbon atoms and represents for example methylamino, ethylamino, n- or i-(propylamino or butylamino).
Di-lower alkylamino preferably contains 1 to 4 carbon atoms in each lower alkyl group and represents for example dimethylamino, diethylamino, di-(n-propyl)-amino and di-(n-butyl)-amino.
00 .on Di-lower alkylamino-lower alkoxycarbonyl contains preferably o 0 2 to 4 carbon atoms in the alkoxy portion, the oxygen and nitrogen atoms being separated by 2 to 4 carbon atoms, and for example 000 o represents N,N-diethylaminoethoxycarbonyl or N,N-diethylamino- 00 4 0 0 propoxycarbonyl.
Pharmaceutically acceptable esterified carboxy within the context of the present invention represents an esterified carboxy group R', o preferably a carboxylic acid prodrug ester that may be convertible under physiological conditions to free carboxy.
SPharmaceutically acceptable esterified carboxy preferably repre- 0 sents e.g. lower alkoxycarbonyl; (amino, mono- or di-lower alkylonoo amino)-substituted straight chain C 2 5 lower alkoxycarbonyl, carboxy o0 substituted lower alkoxycarbonyl, e.g. a-carboxy-substituted lower 0 alkoxycarbonyl; lower alkoxycarbonyl-substituted lower alkoxycarbonyl e.g. c-lower alkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted lower alkoxycarbonyl, e.g. unsubstituted or substituted benzyloxycarbonyl or pyridylmethoxycarbonyl; lower alkanoyloxy-substituted methoxycarbonyl, e.g. pivaloyloxymethoxycarbonyl; (lower alkanoyloxy or lower alkoxy)-substituted lower alkoxymethoxy carbonyl; bicyclo[2.2.1]heptyloxycarbonyl-substituted methoxycarbonyl e.g. bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; lower alkoxycarbonyloxy-lower alkoxycarbonyl; e.g. l-(methoxy- or ethoxycarbonyloxy)-ethoxycarbonyl.
I1 *I 10 Most preferred prodrug esters are e.g. the straight chain Ci-4-alkyl esters, e.g. ethyl; the lower alkanoyloxymethyl esters, e.g. pivaloyloxymethyl; the di-lower alkylamino-straight chain C 2 -4-alkyl esters, e.g. 2 -diethyl-aminoethyl; the pyridylmethyl esters, e.g. 3-pyridylmethyl.
Pharmaceutically acceptable amidated carboxy within the context of the present invention represents an amidated carboxy group R 1 preferably a carboxylic acid amide that may be convertible under s o physiological conditions to free carboxy.
0 0o 0 3 0 0 00 0 o000 Preferred amidated carboxy is e.g. carbamoyl, N-mono-lower alkyl- 9 carbamoyl e.g. N-ethylcarbamoyl, N,N-di-lower alkylcarbamoyl e.g.
s N,N-diethylcarbamoyl, or di-lower alkylamino-N-lower alkyl- 0 o 0 carbamoyl e.g. N-(2-diethylaminoethyl)carbamoyl or N-(3-diethylam.inopropyl)carbamoyl.
0o0 on o Salts of the compounds of the invention are preferably pharmaceutically acceptable salts, on the one hand metal or ammonium salts of .,og the compounds of the invention having a free phosphonic or carboxy o group, more particularly alkali or alkaline earth metal salts, 0 0 e.g. the sodium, potassium, magnesium or calcium salt; or advanta- O' o geously crystallizing ammonium salts derived from ammonia or organic o o amines, such as methylamine, diethylamine, triethylamine, dicyclo- 0 00 0 .hexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrimethylammonium hydroxide. On the other hand the compounds of the invention which are basic amines form acid addition salts of preferably pharmaceutically acceptable inorganic or organic acids, such as of strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, aacorbic, maleic, fumaric, pyruvic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.
C- i' r r i r .1 11 For isolation or purification purposes, salts may be obtained which might not be useful for pharmaceutical purposes. However, only pharmaceutically acceptable salts are used for therapeutic purposes and these salts, therefore, are preferred.
The compounds of the invention exhibit valuable pharmacological properties, e.g. by selectively blocking the N-methyl-D-aspartate sensitive excitatory aminoacid receptors in mammals. The compounds o are thus useful for treating diseases responsive to excitatory amino S acid blockade in mammals, comprising e.g. nervous system disorders, as° particularly convulsive disorders (epilepsy) and anxiety.
These effects are demonstrable in in vitro tests or in vivo animal o tests using advantageously mammals or tissues or enzyme preparations thereof, e.g. mice, rats, or monkeys. Said compounds can be admini- C'o stered to them enterally or parenterally, advantageously orally or Soo transdermally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of aqueous suspensions or solutions, respectively. The applied in vivo dosage may range between about 0.01 to 100 mg/kg, preferably between about 0.05 and 50 mg/kg, advantageously between about 0.1 and 10 mg/kg. Said compounds can be applied in vitro in the form Sof e.g. aqueous solutions and the dosage may range between about o -4 -8 molar and 10 molar concentrations.
The inhibitory effect on the NMDA-type excitatory amino acid receptors is determined in vitro by measuring the inhibition of the NMDA-evoked 3 H-acetylcholine 3 H-ACh) release from corpus striatum tissue of rat brain, according to J. Lehmann and B. Scatton, Brain Research 252, 77 89 (1982) and Nature 297, 422 424 (1982).
Antagonists of NMDA-type excitatory amino acid receptors competitively antagonize NMDA-evoked 3 H-acetylcholine 3 H-ACh) release from corpus striatum tissue of the brain.
Li~u; I i a*r~ 12 The inhibition of the NMDA-evoked 3 H-acetylcholine 3 1-ACh) release from rat striaral tissue slices by a compound of the invention is expressed as of release of 3 H-ACh in response to stimulation with pM NMDA compared to control. Tests are two-tailed with a minimum of n 4 in each group. IC 50 values represent the concentration of test compound required to inhibit the NMDA-increased 3 H-ACh release by 50 The inhibitory effect on the NMDA-type excitatory amino acid receptors is demonstrated in vivo by inhibition of NMDA-induced Sconvulsions in the mouse.
Illustrative compounds of the invention prevent NMDA-induced convulsions in the mouse at doses as low as about 1.2 mg/kg i.p.
Further indicative of ne anticonvulsant activity, compounds of the oo invention are effective in preventing audiogenic-induced seizures in 0 DBA/2 mice [Chapman et al., Arzneim.-Forsch. 34; 1261, (1984)].
0a 0o 0 o The effect is determined as follows: Forty-five minutes following compound or vehicle administration, mice are placed individually in 0 a soundproof chamber. After a 30 second accommodation period, the co.o mice are exposed to a sound stimulation of 110 dB for 1 minute or until the appearance of a tonic-clonic seizure. Control seizures o 00 consist of an initial wild running phase. The prevention of wild running is indicative of an anticonvulsant effect.
,1 Test compounds in either distilled water solution or in a 3 (w/v) colloidal cornstarch suspension containing 5 polyethyleneglycol 400 and 0.34 Tween 80, are administered by oral intubation or intraperitoneally in a volume of 10 ml/kg of body weight.
Indicative of anxiolytic activity, compounds of the invention are effective in the Cook/Davidson conflict model [Psychopharmacologia 15, 159 168 (1969)].
13 The cerebral antiischemic activity, that is the effect of the compounds of the invention in preventing or reducing brain damage in mammals due to a transient cerebral ischemia (as in a stroke) can be determined in the mongolian gerbil ischemia model, e.g. the model described by T. Kirino, Brain Research 239, 57-69 (1982).
The inhibitory effect on the observed hyperactivity and on the a4 degeneration of neurons in the hippocampus region of the brain following a 5-minute period of ischemia is measured. The test compound is administered i.p. 15 minutes before the ischemia or 2, 4 and 6 hours post ischemia.
ao*" Illustrative compounds of the invention, at a dose of 10 mg/kg i.p.
administered either before or after the ischemia episode, inhibit the ischemia-induced hyperactivity of the gerbil and reduce the degeneration of cerebral neurons as measured in the hippocampus region of the brain.
The aforementioned advantageous properties render the compounds of oo 00 the invention useful as antagonists of the N-methyl-D-aspartate excitatory amino acid receptor in mammals and for the treatment of conditions responsive thereto, such as anxiety and convulsive o o disorders.
The compounds of the invention, i.e. the compounds cited hereinabove, may be prepared by conventional processes, e.g. by 4 a) condensing an aldehyde or ketone of the formula VII m (VII)
R
P
2 4
T
)7 4i The following statement is a full description of this invention, including the best method of performing it known to uS
LI
I I I -14 wherein m, R 1
R
2 and the heterocyclic ring are as defined for formula I with R 1 and amino groups in protected form, and A' represents oxo substituted lower alkyl having 1 carbon less than the alkenylene group A, with a tetra ester derivative of methylenediphosphonic acid, preferably with a tetra-lower alkyl ester of methylenediphosphonic acid, in the presence of a strong anhydrous base and in an inert polar solvent and if required deprotecting the resulting product to obtain a compound of formula I wherein the double bond within the grouping A is adjacent to the phosphono i, 4 grouping; or r t b) condensing a compound of the formula VIII SX-A a o 2 m
(VIII)
*-RI
wherein A, m, R 1
R
2 and the heterocyclic ring are as defined for formula I, and X represents reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid moiety, having one of formulae IX or X H--OR" (IX) 3
(X)
R" wherein R" represents lower alkyl and represents halogen or Slower alkoxy and, if required, converting the resulting phosphonic acid derivative to the phosphonic acid or other ester derivative thereof; or c) converting to R 1 a substituent other than R I at position 2 of the heterocyclic ring in a compound otherwise identical to a compound of the invention; and carrying out the said processes while, if necessary, temporarily protecting any interfering reactive group(s) in these processes, and then liberating the resulting compound of I" L '9_ 0 01 0 n 000 qo o 4 000 0 000 0 0 0 00 n oo 0 00 a 0 0 can oo, 0 0 0 0 0 0 o i 0 00 00 0 0 1 9 15 the invention into another compound of the invention, and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt; and/or separating a mixture of isomers or racemates obtained into the single isomers or racemates; and/or, if desired, resolving a racemate obtained into the optical antipodes.
Reactive esterified hydroxy, in any of the herein mentioned processes, e.g. X in a compound of formula VIII, is esterified by a strong acid, especially hydrohalic, e.g. hydrochloric, hydrobromic or hydroiodic acid, or sulphuric acid, or by a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, for example methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive esterified hydroxy is especially halo, for example chloro, bromo or iodo, or aliphatically or aromatically substituted sulfonyloxy, for example methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).
In starting compounds and intermediates therefor which are converted to the compounds of the invention in a manner described herein, functional groups present, such as carboxy, amino (including ring NH) and hydroxy groups, are optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected carboxy, amino and hydroxy groups are those that can be converted under mild conditions into free carboxy, amino and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place.
The purpose of introducing protecting groups is to protect the functional groups from undesired reactions with reaction components and under the conditions used for carrying out a desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (carboxy 1 i One preferred aspect of the invention relates to the phosphonic acid derivatives of formula I and derivatives thereof wherein the 16 group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part, and the reaction conditions.
Well-known protecting groups that meet these conditions and their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, and also in "The Pep- Stides", Vol. I, Schroeder and Luebke, Academic Press, London, New York 1965, as well as in Houben-Weyl, "Methoden der Organischen Chemie", Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.
,let The preparation of the compounds of the invention wherein the double 00°° bond is adjacent to the phosphono grouping according to process (a) involving the condensation of an aldehyde or ketone with e.g. a o0 tetra lower alkyl ester of methylenediphosphonic acid is carried 0 00 out according to procedure known in the art for such condensations, 0" in the presence of a strong anhydrous base, e.g. butyl lithium, in an inert polar solvent such as tetrahydrofuran, preferably at reflux S temperature. The starting aldehydes or ketones of formula VII can be prepared e.g. by oxidation of the corresponding alcohols for example 0o o with pyridinium chlorochromate, or other methods e.g. as illustrated S in the examples.
The respective alcohols can in turn be prepared by methods generally known in the art, e.g. by reduction of the corresponding aromatic alcohols using methods known in the art for the reduction of pyrrole, pyridine, indole and quinoline rings. For example, the reduction of the pyridine or quinoline ring is advantageously carried out with an organometallic reducing agent or by catalytic hydrogenation, e.g. in the presence of platinum oxide and an acidic solvent such as acetic acid to give corresponding tetrahydropyridines, piperidines, 1,2,3,4-tetrahydroquinolines or perhydroquinolines of the invention, i.e. of formula II, IV and derivatives alkanoyloxymethyl substituted on oxymethyl by lower alkyl; R 1 represents carboxy, carbamoyl or lower alkoxycarbonyl, lower alkanoyli ii 17 thereof. Quaternary quinolinium and pyridinium compounds, e.g. in which R 2 is lower alkyl or aryl-lower alkyl, may be similarly reduced.
The alcohols, aldehydes or ketones so obtained may also be converted to aldehydes or ketones of longer chain length using conventional methodology, e.g. by a Wittig condensation of an aldehyde with methoxy-methyl-triphenylphosphonium chloride to yield the homologous aldehyde, and by other well-known sequences of reactions described in the examples.
The aromatic 2-carboxy-heterocycle-substituted lower alkanols referred to above, for example the 2-carboxypyridinyl- or 2-carboxyquinolinyl-substituted lower alkanols or derivatives thereof can in turn be prepared by treatment of the 2-unsubstituted pyridinyl- or 2-unsubstituted quinolinyl-substituted lower alkanols in suitably e protected form, with e.g. a peracid, such as m-chloroperbenzoic Sona acid, to give the corresponding pyridine-N-oxides or quinoline-Nl oxides. Condensation with a reactive cyanide, e.g. trialkylsilyl S cyanide such as trimethylsilyl cyanide, preferably under basic a conditions, e.g. in the presence of triethylamine, gives the S corresponding 2-cyanopyridine or 2-cyanoquinoline derivatives which oano are then converted, by methods known in the art, to the 2-R 1 (carboxy, esterified or amidated carboxy) substituted pyridine and i s quinoline derivatives.
The condensation according to process is advantageously used for the preparation of the compounds of formula I wherein the double bond within the alkenylene grouping A is not adjacent to the phosphono grouping.
The condensation according to process of a compound of formula VIII with a compound of formula X, e.g. triethyl phosphite, is carried out, e.g. by heating in an inert solvent, and under conditions known in the art for a Michaelis-Arbuzov reaction according to Angew. Chem. Int. Ed. 16, 477 (1977) and i; it 18 Chem. Rev. 81, 415 (1981). Similarly, condensation with e.g. phosphorus trichloride and subsequent hydrolysis gives a compound of formula I.
The condensation according to process of a compound of formula VIII with a compound of formula IX, e.g. diethylphosphonate (diethyl phosphite), is carried out e.g. in a strong basic medium, for instance in the presence of an alkali metal, e.g. sodium, an alkali metal hydride, e.g. sodium hydride, an alkali metal alkoxide, e.g. potassium t-butoxide, in an inert solvent e.g. toluene or dimethylformamide.
4 1 SThe starting materials of formula VIII and reactive derivatives S' thereof can be prepared by methods well known in the art starting a from intermediates of formula VII wherein A' represents oxo-substituted lower alkyl, the preparation of which is described above.
For example, the starting material of formula VIII wherein A o *o represents propenylene is prepared by condensing an aldehyde of a formula VII, wherein the grouping A' represents formyl with o o a suitable Wittig reagent, e.g. formylmethylene-triphenylphosphoran, 0 o reducing the resulting unsaturated aldehyde (in which the chain has been lengthened by two carbon atoms) to the alcohol e.g. with sodium u*c borohydride, and converting the resulting unsaturated alcohol to a o reactive derivative, e.g. the bromide with triphenylphosphine/Nbromo-succinimide.
Interconversions according to process are carried out by methods well-known in the art.
Groups convertible into R' are, for example, carboxy groups in form of anhydrides or acid halides, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, iminoether groups, including cyclic iminoether groups, e.g. dihydro-2-oxazolinyl or dihydro-2-oxazolinyl groups substituted by lower alkyl, and also hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl,
I
i r"l -19 trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl (CHO), di(lower)alkoxymethyl, alkylenedioxymethyl or vinyl.
Certain terms used in the processes have the meanings as defined below.
Oxo substituted lower alkyl represents preferably formyl, formylmethyl, formylethyl or 2-oxo-propyl.
to "I Trialkoxymethyl represents preferably tri(lower alkoxy)methyl, particularly triethoxy- or trimethoxymethyl.
Etherified hydroxymethyl represents preferably lower alkoxymethyl, a* lower alkoxyalkoxymethyl, e.g. methoxymethoxymethyl or 2-oxa- or 2-thiacyclo-alkoxymethyl, particularly 2-tetrahydropyranyloxyoo methyl.
0 a Halomethyl represents especially chloromethyl but may also be o bromomethyl or iodomethyl.
o B
S
a An alkali metal represents preferably lithium but may also be I oo potassium or sodium.
o O 0 0 Groups convertible into R I representing carboxy include esterified and amidated carboxy and such are not limited to esterified and amidated carboxy as defined herein for R 1 Conversion to carboxy is generally accomplished by solvolysis, with acid or base.
Benzyloxycarbonyl or nitrobenzyloxycarbonyl may be converted into carboxy by catalytic hydrogenation, the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxylic acid. In addition, tert-butyloxycarbonyl may also be cleaved with trifluoroacetic acid.
tor example ethyl, propyl, butyl or advantageously methyl.
I 4 i Acetyl may be oxidatively cleaved to carboxy by conversion first to trihaloacetyl, e.g. tribromo or triiodoacetyl, by treatment e.g. with sodium hypobromite, followed by cleavage with e.g. an aqueous base, e.g. sodium hydroxide.
Formyl, di(lower)-alkoxymethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. the dimethyl acetal, are oxidized with e.g. silver nitrate, pyridinium dichromate or ozone to carboxy.
Vinyl may be converted to carboxy by ozonolysis to formyl, which is in turn oxidized to carboxy.
Hydrolysis of trialkoxymethyl to carboxy is advantageously carried out with inorganic acids, e.g. hydrohalic or sulfuric acid. Hydrolysis of etherified hydroxymethyl to hydroxymethyl is preferably o carried out with solutions of inorganic acids, e.g. a hydrohalic .Oo acid. Hydroxymethyl is in turn oxidized to carboxy with an oxidizing agent, e.g. pyridinium dichromate.
oHalomethyl may also be converted to the corresponding carboxaldehydes with e.g. dimethylsulfoxide in the presence of triethylamine °on and silver tetrafluoroborate, or with chromium trioxide and pyridine 9 in dichloromethane.
The conversion of cyano to lower alkoxycarbonyl is advantageously carried out by treatment first with a lower alkanol, e.g. anhydrous I ethanol, in the presence of a strong acid, e.g. hydrochloric acid preferably at reflux temperature, followed by hydrolysis with water.
Furthermore, the conversion of cyano to carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.
I I 21 Esterified carboxy such as lower alkoxycarbonyl may be amidized with ammonia, mono- or di-(lower)alkylamines e.g. methylamine, dimethylamine in an inert solvent, e.g. a lower alkanol, such as butanol, to unsubstituted, mono- or di(lower) alkylcarbamoyl.
The compounds of the invention may thus also be converted to other compounds of the invention by e.g. functional group transformations well-known in the art.
For example, conversion of carboxylic acid esters and amides to S carboxylic acids is advantageously carried out by hydrolysis with o' inorganic acids such as a hydrohalic or sulfuric acid or with aqueous ,alkalies, preferably alkali metal hydroxides such as lithium or o sodium hydroxide.
00 Free carboxylic acids may be esterified with lower alkanols, such as gn ethanol, in the presence of a strong acid, e.g. sulfuric acid, or on with diazo (lower) alkanes, e.g. diazomethane, in a solvent such as o 0 ethyl ether, advantageously at room temperature, to give the Scorresponding lower alkyl esters.
S Furthermore, the free carboxylic acids may be converted via treatment of a reactive intermediate thereof, e.g. an acyl halide such as the acid chloride, or a mixed anhydride, e.g. such derived from a o lower alkyl halocarbonate such as ethyl chloroformate, with ammonia, mono- or di-(lower) alkylamines, in an inert solvent such as dichloromethane, preferably in the presence of a basic catalyst such as pyridine, to compounds wherein R 1 represents unsubstituted, mono or di-(lower)alkylcarbamoyl.
Phosphonic acid esters are converted to the corresponding phosphonic acids by treatment with acid, such as aqueous hydrochloric acid or hydrobromic acid in glacial acetic acid, or with bromotrimethylsilane according to J. Chem. Soc. Chem. Comm. 1979, 739. Benzyl esters may be converted to the acids by hydrogenolysis.
-e moyl.
I
1 22 Phosphonic acids are converted to esters, e.g. optionally substituted lower alkyl esters, e.g. by cond.nsation with an optionally substituted lower alkyl halide preferably in a basic non-aqueous medium, such as in the presence of triethylamine.
In a preferred embodiment of the invention a compound of formula II, IV or VI, wherein R and R' represent lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, preferably lower alkyl, R I is pharmaceutically acceptable esterified or amidated carboxy, preferably lower alkoxycarbonyl, and R 2 represents acyl, preferably lower alkoxycarbonyl, is converted into a compound of formula II, IV or VI, respectively, wherein R and R' are hydrogen, R I is carboxy and R 2 is hydrogen, by treatment with an inorganic acid, such as a 0 00 o oo hydrohalic acid or sulfuric acid, preferably hydrochloric acid, or with aqueous alkalies, preferably alkali metal hydroxides, such as lithium or sodium hydroxides, preferably at elevated temperatures.
0 o 0 000 o oo The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such o o that are inert to the reagents and are solvents thereof, of cata- 0 °o0 lysts, of condensing or said other agents respectively and/or in o inert atmospheres, at low temperatures, room temperature or elevated 0 0 temperatures, preferably at the boiling point of the solvents used, o 0 and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative examples.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
t o- -I~~IJ-YIL II ILL V~L lr~LUVI JL
I
-23 Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially preferred.
The invention also relates to any novel starting materials and processes for their manufacture.
Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, depending on the number of asymmetrical carbon atomr, as pure optical isomers, such as antipodes, or as mixtures of optical isomers such as racemates or as mixtures of diastereoisomers or of geometric isomers. The aforesaid possible Sisomers or mixtures thereof are within the purview of this inveno o0 °o 0 tion; certain particular isomers are preferred as indicated above.
Any resulting mixtures of diastereoisomers, mixtures of racemates ooo can be separated on the basis of the physicochemical differences of o ot the constituents, in known manner, into the pure isomers, dia- Sstereoisomers, racemates, or geometric isomers, for example by S° chromatography and/or fractional crystallization.
o a 0 oQ Any resulting racemates can be resolved into the optical antipodes soeo by known methods, for example by e.g. reacting an acidic end product o0o with an optically active base that forms salts with the racemic acid, and separating the salts obtained in this manner, for example by fractional crystallization, into the diastereoisomeric salts from which the optically active free carboxylic or phosphonic acid antipodes can be liberated on acidification. The basic racemic products can likewise be resolved into the optical antipodes, e.g. by separation of the diastereoisomeric salts thereof, with an optically active acid, and liberating the optically active basic compound by treatment with a standard base. Racemic products of the invention can thus be resolved into their optical antipodes, e.g., by the fractional crystallization of d- or A-(tartrates, mandelates,
I
i. -I nydroxyethanesuitonic, benzenesulronic, p-toluenesulfonic or naphthalenesulfonic acid.
24 camphorsulfonates) or of d- or-X(a-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine) salts. The acidic compounds of the invention can also be resolved by separating diastereomeric ester or amide derivatives prepared from an optically active alcohol or amine, and regenerating the resolved optically active compound. Advantageously, the more active of the two antipodes is isolated.
Finally the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeutically useful acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or o0 ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide 0 0 or carbonate, or a cation exchange preparation, or an alkylene oxide such as propylene oxide. A compound of the invention with a free carboxylic or phosphonic acid group can thus also be converted into o 00 the corresponding metal or ammonium salts. These or other salts, for °°oeo0 example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are 0 o separated and the bases are liberated from the salts.
o In view of the close relationship beween the free compounds and the o .oo. compounds in the form of their salts, whenever a compound is o "o referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, for blockade of the N-methyl-D-aspartate sensitive excitatory amino acid receptor ml 25 and for the treatment of diseases responsive to blockade of the N-methyl-D-aspartate sensitive excitatory amino acid receptor, such as cerebral ischemia, convulsive disorders and anxiety, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers.
The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
Preferred are tablets and gelatin capsules comprising the active tf ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubri- 0 «cants, e.g. silica, talcum, stearic acid, its magnesium or calcium C 00 0° salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinyl- °oo pyrrolidone; if desired d) disintegrants, e.g. starches, agar, o oo alginic acid or its sodium salt, or effervescent mixtures; and/or S e) absorbents, colorants, flavors and sweeteners. Injectable 0 compositions are preferably aqueous isotonic solutions or suspen- C sions, and suppositories are advantageously prepared from fatty 0a. emulsions or suspensions. Said compositions may be sterilized and/or o e cooao contain adjuvants, such as preserving, stabilizing, wetting or "o emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75 preferably about 1 to 50 of the active ingredient.
Suitable formulations for transdermal application include an effective amount of a compound of formula I with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage throught the skin of the host. Charactelogia 15, 159 168 (1969)].
i 26 ristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device of the skin.
The invention also relates to a method of blocking the N-methyl-Daspartate sensitive excitatory amino acid receptor in mammals, and to a method of treatment of disorders in mammals, e.g. such respon- "I sive to blockade of the N-methyl-D-aspartate excitatory amino acid receptor, such as cerebral ischemia, convulsi;e disorders and anxiety, using an effective amount of a compound of the invention as a pharmacologically active substance, preferably in the form of 0 abu-'e-cited pharmaceutical compositions.
A particular embodiment thereof relates to a method of treating cerebral ischemia and of inhibiting brain damage resulting from o. cerebral ischemia (in a stroke) in mammals which comprises the o",o administration to a mammal in need thereof of an effective amount of an N-methyl-D-aspartate blocking compound of the invention or of a 0 0 pharmaceutical composition comprising a said compound.
0 The dosage of active compound administered is dependent on the cons species of warm-blooded animal (mammal), the body weight, age and °o 0o individual condition, and on the form of administration.
A unit dosage for a mammal of about 50 to 70 kg may contain between about 5 and 100 mg of the active ingredient.
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 2 and 13 kPa.
727 27 Example 1: Ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-tertbutoxycarbonylpiperidine-2-carboxylate is hydrolyzed with 6N hydrochloric acid to yield 4-[1-(3-phosphonoprop-2-enyl)]piperidine- 2-carboxylic acid.
The starting material is prepared as follows: 4-(2-hydroxyethyl)pyridine is oxidized to 4-(2-hydroxyethyl)-pyridine-N-oxide which is in turn treated with trimethylsilyl cyanide to yield 4-(2-hydroxyethyl)-2-cyanopyridine which is converted to ethyl 4-(2-hydroxyethyl)-2-pyridine carboxylate and then hydrogenated to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
1 4# A solution of 2.01 g of ethyl 4-(2-hydroxyethyl)-piperidine-2carboxylate in 5 ml dichloromrethane is added to a solution of 2.20 g 0094+9 O of di-tert-butyl dicarbonate in 10 ml dichloromethane. After o ae ona "standing for 10 minutes the solvent is evaporated and the residue is flash chromatographed with hexane/ethyl acetate (50:50) to afford o ethyl 4-(2-hydroxyethyl)-1-tert-butoxycarbonylpiperidine-2-carboxylate.
0o 0 o 00 To a solution of 1.56 g of dimethyl sulfoxide in 10 ml dichloroa methane is added 2.2 g of oxalyl chloride at -78 0 C. After 20 minutes 00On 2.4 g of ethyl 4-(2-hydroxyethyl)-1-tert-butoxycarbonyl-piperidine- 2-carboxylate in 5 ml dichloromethane is added. The reaction is stirred f-r one hour and 2.2 g of triethylamine is added. The ice bath is removed, the solvent evaporated and the residue is flash chromatographed with hexane/ethyl acetate (70:30) to afford ethyl 1-tert-butoxycarbonylpiperidine-2-carboxylate-4-acetaldehyde.
At -78 0 C, 2.73 ml n-butyllithium is added to 2.02 g bis(diethylphosphono)-methane in 20 ml anhydrous tetrahydrofuran. After minutes 2.08 g ethyl 1-tert-butxycarbonylpiperidine-2-carboxylate-4-acetaldehyde in 5 ml tetrahydrofuran is added. The mixture is then refluxed for 16 hours. The cooled reaction mixture is conceni i- in these processes, and then liberating the resulting compound ot L armr3~ra*?ur~uomrrr~L, 28 trated and flash chromatographed (95:5 dichloromethane/methanol) to yield ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-tert-butoxycarbonylpiperidine-2-carboxylate.
Example 2: The following compounds can be prepared according to methods generally illustrated in the previous example: trans 3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid; trans 3-[1-(4-phosphonobut-2-enyl)]-pyrrolidine-2-carboxylic u g acid.
0 0 0 '3 0.0 0 .o The starting material for compound can be prepared as follows: 0 00 Trans ethyl N-ethoxycarbonyl-pyrrolidine-2-carboxylate-3-acetalde- 0 00 00 0 hyde is condensed with (C 6
H
5 3
P=CHOCH
3 under conditions of the n00 0 Wittig reaction to afford trans ethyl N-ethoxycarbonylpyrrolidine-2carboxylate-3-propionaldehyde. Condensation with bis-(diethylphos- 0 phono)methane under conditions described herein example 1) 00 0 c yields trans ethyl 3-[1-(4-diethylphosphonobut-3-anyl)]-pyrrolidine- 0c" 02-carboxylate.
o The starting material for compound can be prepared as follows: 0 0:00i The alcohol, trans ethyl N-ethoxycarbonyl-3-(2-hydroxyethyl)e~ pyrrolidine-2-carboxylate is oxidized to the aldehyde, trans ethyl oo N-ethoxycarbonylpyrrolidine-2-carboxylate-3-acetaldehyde, which is 0 as condensed with triphenylphosphoranylideneacetaldehyde under conditions of the Wittig reaction; the resulting a,B-unsaturated C 4 -aldehyde is reduced to the corresponding alcohol which is converted to the bromide. Condensation with triethyl phosphite yields ethyl 3-[l1-(4-diethylphosphonobut-2-enyl)]-pyrrolidine-2-carboxylate.
Example 3: 4-[1-(3-Phosphonoprop-1-enyl)]piperidine-2-carboxylic acid can be similarly prepared using ethyl 4 -hydroxymethyl-N-ethoxycarbonylpiperidine-2-carboxylate as intermediate.
29 Example 4: At -780C, 20.3 ml of butyllithium (1.64 M) is added to ml of tetraethylmethylenediphosphonate [bis(diethylphosphono)methane] in 100 ml anhydrous tetrahydrofuran. After 5 minutes, 9.26 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4acetaldehyde in 125 ml anhydrous tetrahydrofuran is added. Mixture is refluxed 18 hours, cooled, concentrated and purified by flash chromatography using ethyl acetate/hexane (75:25 to 9:1) to yield ethyl 4-[1-(3-diethylphosphonoprop- 2 -enyl)]-(l-tert-butoxycarbonyl)piperidine-2-carboxylate.
The starting material is prepared as follows: A solution of 4-pyridylacetic acid in 500 ml of anhydrous ethanol containing 75 ml of concentrated sulfuric acid is refluxed 18 hours. The solution is cooled to 0 C and neutralized by addition of sodium hydroxide o a solution and saturated aqueous sodium carbonate. Extraction with ao' ethyl acetate yields on concentration in vacuo ethyl 4-pyridylacetate.
A solution of 23.8 g of ethyl 4-pyridylacetate in 100 ml of an- On ehydrous tetrahydrofuran is added dropwise to 5.5 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran under a D nitrogen. The mixture is heated at 500° (bath) for 40 minutes, then cooled in an ice bath, and the excess lithium aluminum hydride is decomposed by addition of 6.6 ml of water followed by 6.6 ml of 15 o" 0 aqueous sodium hydroxide and 20 ml of water. The solid is filtered "a off and the filtrate concentrated in vacuo to yield 4-pyridylethanol.
A solution of 16.3 g of 4-pyridylethanol, 21.8 g of chloro-tertbutyl-dimethylsilane and 10.9 g of imidazole in 150 ml of dimethylformamide is stirred 1 hour at room temperature. The product is isolated by extraction into ethyl acetate/hexane and washed 4 times with 400 ml of water; the extract is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine.
i i ii" I- 1 -li" 30 To a stirred solution of 28.8 g of 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine in 300 ml of dichloromethane is added 24 g of m-chloroperbenzoic acid. After 4 hours the solution is washed with aqueous sodium carbonate solution and water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide.
A solution of 28.6 g of 4-(tert-butyl-dimethylsilyloxyethyl)pyridine-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml triethylamine is stirred under nitrogen at reflux for 3 hours. The dark solution is cooled in an ice bath, 30 ml of ethanol added, followed by 400 ml ethyl acetate and 200 ml hexane. The solution is washed twice, with 150 ml of water, dried over sodium sulfate, 'r filtered, concentrated in vacuo and purified by flash chromatography 0Z using ethyl acetate/hexane (1:10) to yield 4-(tert-butyl-dimethyl- 0 Coo° silyloxyethyl)-2-cyanopyridine.
A solution of 22.2 g of 4-(tert-butyl-dimethylsilyloxyethyl)-2cyanopyridine in 220 ml anhydrous ethanol containing 0.19 g of 0 sodium is stirred at room temperature for 24 hours. The solution is then cooled to 00C and 22 ml of 6N hydrochloric acid added. The o solution is stirred at room temperature for 16 hours, cooled to 00C and 7.5 ml 6N sodium hydroxide added followed by 75 ml saturated aqueous sodium bicarbonate. Extraction with dichloromethane and flash chromatography using ethyl acetate yields ethyl 4-(2-hydroxyod aethyl)-pyridine-2-carboxylate.
A mixture of 8.37 g of ethyl 4-(2-hydroxyethyl)-pyridine-2carboxylate in 130 ml acetic acid and 4 g platinum oxide is hydrogenated at 345 kPa. Filtration, concentration in vacuo, neutralization with potassium carbonate and extraction with dichloromethane yields an oil that is purified by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1) to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
31 A solution of 7.9 g of ethyl-4-(2-hydroxyethyl)-piperidine-2carboxylate, 9.0 g di-tert-butyl dicarbonate in 80 ml of dichloromethane is stirred for 2 hours at room temperature and then concentrated in vacuo to yield ethyl 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)-piperidine-2-carboxylate.
A solu;ion of 11.8 g of ethyl(1-tert-butoxycarbonyl)-4-(2-hydroxyethyl)-piperidine-2-carboxylate and 12.6 g of pyridinium chlorochromate in 175 ml dichloromethane is stirred under nitrogen at room temperature for 80 minutes. Mixture is filtered and purified by S0 0 flash chromatography using ethyl acetate/hexane (25:75) to yield SO 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acetaldehyde.
0 P Example 5: A mixture of 4.67 g of ethyl 4-[1-(3-diethylphosphono- 6 prop-2-enyl]--(tert-butoxycarbonyl)-piperidine-2-carboxylate and 4m 00 ml 6N hydrochloric acid is refluxed 12 hours. The solution is concentrated in vacuo to dryness. The residue is dissolved in 50 ml ethanol and 3.8 ml of propylene oxide added. The solid that 0 separates is filtered off and dried in vacuo to yield cis-4-[I1-(3- 0 00 0 vphosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, m.p. 163-165 0
C.
Example 6: At -78 0 C, 6.9 ml of butyllithium (1.6 M) is added to 2.9 ml of tetraethylmethylene diphosphonate in 30 ml anhydrous 00 tetrahydrofuran. After 5 minutes, 2.47 g of trans ethyl 1-acetylaee piperidine-2-carboxylate-4-acetaldehyde in 55 ml tetrahydrofuran C (anhydrous) is added. The mixture is refluxed 18 hours, cooled, concentrated and purified by flash chromatography using dichloromethane/ethanol (100:3) to yield trans ethyl 4-[l-(3-diethylphosphonoprop-2-enyl)]-1-acetyl-piperidine-2-carboxylate.
The starting material is prepared as follows: At 0 0 C, 9.4 ml acetic anhydride is added to a stirred solution of 13.5 g of ethyl 4-(2hydroxyethyl)-piperidine-2-carboxylate in 75 ml pyridine. After stirring at room temperature for 30 minutes the solution is concentrated in vacuo and ethyl acetate (300 ml) is added; the solution is washed twice with 2N hydrochloric acid, once with water and once 1iyuroxymeLnyl, eunerinrea nyaroxymethyl, lower alkanoyloxymethyl, iUIY----- ~PCI CglWLIII~ 32 with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 100 ml ethanol, 5 g of powdered potassium carbonate is added and the mixture stirred 1 hour at room temperature. The solution is filtered, concentrated in vacuo and purified by flash chromatography using dichloromethane/methanol (95:5) to yield trans ethyl 1-acetyl- 4-(2-hydroxyethyl)-piperidine-2-carboxylate.
A mixture of 3.7 g of trans ethyl l-acetyl-4-(2-hydroxyethyl)- Sed piperidine-2-carboxylate and 5.4 g of pyridinium chlorochromate in So, 75 ml dichloromethane is stirred under nitrogen for 2 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (7:3 to 8:2) to yield trans ethyl 1-acetylpiperidine- 2-carboxylate-4-acetaldehyde.
0 00 Example 7: A mixture of 2.5 g of trans ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-l-acetylpiperidine-2-carboxylate and 40 ml 6N 0.
Sno hydrochloric acid is refluxed for 12 hours. The solution is conceno0o°o trated in vacuo to dryness. The residue is dissolved in 20 ml of ethanol and 2.3 ml of propylene oxide added. The solid that 0 U separates is filtered off and dried in vacuo to yield trans 4-[1ao U (3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, o 0 m.p. 132-140 0
C.
o o 0 0 1 OO Example 8: A solution of 0.334 g of trans ethyl 4 -[1-(3-bromoprop-lenyl)]-l-(tert-butoxycarbonyl)-piperidine-2-carboxylate and 3.5 ml of triethylphosphite is refluxed under nitrogen for 70 minutes. The cooled solution is concentrated in vacuo and purified by flash chromatography using dichloromethane/methanol (100:3) to yield trans ethyl 4 -[l-(3-diethylphosphonoprop-l-enyl)]-1-(tert-butoxycarbonyl)piperidine-2-carboxylate.
The starting material is prepared as follows: A solution of 20 g 4-pyridylcarbinol, 28.9 g of chloro-tert-butyl-dimethylsilane and 14.4 g imidazole in 200 ml dimethylformamide is stirred 3 hours at room temperature. Product is isolated by extraction into ethyl 33 acetate/hexane and washing extract 4 times with 400 ml of water. The solution is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine.
A solution of 40.6 g of 4-(tert-butyl-dimethylsilyloxymethyl)pyridine and 40 g of m-chloroperbenzoic acid in 500 ml dichloromethane is stirred 16 hours at room temperature. Solution is washed with 2N sodium hydroxide and water, dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyldimethylo o silyloxymethyl)-pyridine-N-oxide.
000 t o c A solution of 37.9 g of 4-(tert-butyl-dimethylsilyloxymethyl)- #too pyridine-N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml tri- 0:09: ethylamine is stirred under nitrogen at reflux for 2 1/2 hours. Dark ooO solution is cooled in an ice bath, then 40 ml of ethanol added o 60 followed by 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, concentrated in Soo, vacuo and purified by flash chromatography using ethyl oo°° acetate/hexane (1:10) to yield 4-(tert-butyl-dimethylsilyloxymethyl)-2-cyanopyridine.
0 Q 0 o«,ouS A solution of 21.7 g of 4-(tert-butyl-dimethylsilyloxymethyl)-2cyanopyridine in 220 ml anhydrous ethanol containing 0.2 g of sodium 0" 00 is stirred at room temperature for 18 hours, cooled to 0 0 C and 22 ml o0 6N hydrochloric acid is then added. The solution is stirred at room temperature for 18 hours, cooled to 0 0 C, 7.5 ml 6N sodium hydroxide added followed by 20 ml saturated aqueous sodium carbonate. Extraction with dichloromethane, then drying, filtering and concentrating the extract yields an oil which crystallizes from ether to yield ethyl 4-(hydroxymethyl)-pyridine-2-carboxylate.
A mixture of 13.9 g of ethyl 4 -(hydroxymethyl)-pyridine-2-carboxylate, 5 g platinum oxide in 250 ml acetic acid is hydrogenated at 345 kPa. Filtration, concentration in vacuo, and neutralization with potassium carbonate in dichloromethane yields an oil that is 34 purified by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1) to yield ethyl 4-(hydroxymethyl)piperidine-2-carboxylate.
A solution of 5.16 g of ethyl 4-(hydroxymethyl)-piperidine-2carboxylate and 6.33 g di-tert-butyl dicarbonate in 100 ml of dichloromethane is stirred at room temperature for 18 hours. The solution is concentrated in vacuo to yield ethyl 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine-2-carboxylate.
o~r O 0 A solution of 7.9 g of ethyl 1-(tert-butoxycarbonyl)-4-(hydroxyo. o methyl)-piperidine-2-carboxylate and 9.9 g of pyridinium chlorochromate in 175 ml of dichloromethane is stirred at room temperature 0 0. for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde.
02 A solution of 1 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl- ,.0D piperidine-4-carboxaldehyde and 2 g of formylmethylene-triphenylphosphoran in 16 ml of toluene is heated to 100 0 C (bath) for 0*0"o 2 hours. The solution is cooled and purified by flash chromatography 00000 using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)- 2-ethoxycarbonyl-piperidine-4-acrylaldehyde.
00 0 0 o 0 0000 0000 A solution of 0.83 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-acrylaldehyde and 0.11 g of sodium borohydride in 8 ml of ethanol is stirred at 0 0 C for 30 minutes; 0.2 ml of acetic acid is added followed by ice cold water and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography using ethylacetate/hexane (25:75) yields trans ethyl 1-(tertbutoxycarbonyl)-4-[l1-(3-hydroxyprop-l-enyl)]-piperidine-2-carboxylate.
35 A solution of 0.367 g of trans ethyl 1-(tert-butoxycarbonyl)-4-[1- (3-hydroxyprop-1-enyl)]-piperidine-2-carboxylate, 0.35 g triphenylphosphine and 0.23 g of bromosuccinimide in 8 ml of dichloromethane is stirred initially at 0 0 C and then at room temperature for minutes. Purification by flash chromatography using ethyl acetate/hexane yields trans ethyl 4-[1-(3-bromoprop-1-enyl)]- 1-(tert-butoxycarbonyl)-piperidine-2-carboxylate.
Example 9: A solution of 0.39 g of trans ethyl 4-[l-(3-diethylphoso phonoprop-1-enyl)]-1-(tert-butoxycarbonyl)--iperidine-2-carboxylate 000 0 and 2.3 ml of trifluoroacetic acid in 8 ml o' dichloromethane is 00 a stirred at room temperature for 30 minutes. Saturated aqueous sodium 0000 oooo bicarbonate is added and the mixture extracted with dichloromethane.
Purification by flash chromatography using dichloromethane/methanol n 'saturated with ammonia (20:1) yields trans ethyl 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylate.
0 ",Example 10: A solution of 0.265 g of trans ethyl 4-[1-(3-diethyl- Sa phosphonoprop-1-enyl)]-piperidine-2-carboxylate in 5 ml of anhydrous ethanol containing 0.074 ml of butyl lithium (1.6 M) is heated at 000008 80 0 (bath) for 72 hours. After cooling, 0.025 ml acetic acid is non* added, followed by excess saturated sodium bicarbonate, and the mixture is extracted with dichloromethane. The dichloromethane extract on concentration in vacuo yields an oil; purification by flash chromatography using dichloromethane/isopropanol saturated with ammonia (20:1) yields cis ethyl -diethylphosphonoprop-lenyl)]-piperidine-2-carboxylate.
Example 11: a) A mixture of 0.142 g of cis ethyl 4-[1-(3-diethylphosphonoprop- 1-enyl)]-piperidine-2-carboxylate and 2.5 ml of 6N hydrochloric acid is refluxed for 12 hours. The solution is concentrated in vacuo to dryness. The residue is dissolved in 2 ml of ethanol and 0.15 ml of propylene oxide is added. The solid that separates is filtered off and dried in vacuo to yield cis 4 -[1-(3-phosphonoprop-l-enyl)]piperidine-2-carboxylic acid, m.p. 175 0 dec.
optically pure antipodes.
36 b) Similarly, hydrolysis of the trans ester of example 9 yields the corresponding trans acid, m.p. 130-1350C.
c) A solution of cis 4-[l-(3-phosphonoprop-l-enyl)]-piperidine-2carboxylic acid in saturated ethanolic hydrochloric acid is heated under reflux overnight. The solvent is removed in vacuo. A solution of the residue in ethanol is treated with propylene oxide and evaporated to dryness to yield cis ethyl 4-[l-(3-phosphonoprop-lenyl)]-piperidine-2-carboxylate.
Example 12: To a solution of 0.234 g of trans l-ethoxycarbonyl-2- 000 -o ethoxycarbonyl-pyrrolidine-3-propionaldehyde in 5 ml of anhydrous 0a0 tetrahydrofuran under nitrogen, cooled to -78 0 C, is added slowly a solution of 0.23 ml of tetraethylmethylenediphosphonate and 0.57 ml 0: o00 of butyllithium (1.6 M) in 5 ml of anhydrous tetrahydrofuran also at -78°C. Solution is refluxed for 14 hours, cooled and treated with 0.15 ml of acetic acid; the reaction mixture is concentrated, diluted with water and extracted with dichloromethane. The extract S0 Soo. is dried over sodium sulfate, filtered and concentrated; purifica- 0aco tion by flash chromatography using ethyl acetate yields trans ethyl l-ethoxycarbonyl-3-[ -(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2- 0o o carboxylate.
000000 The starting material is prepared as follows: A mixture of 50 g of 0 00 0oqo N-(2-cyanoethyl)glycine in 300 ml of ethanol saturated with hydrogen chloride gas is stirred 1 hour at room temperature then refluxed for 1 hour. After cooling the solid is filtered off and the filtrate neutralized with sodium bicarbonate, filtered again and concentrated to yield ethyl N-(ethoxycarbonylmethyl)-B-alaninate.
To a mixture of 49 g of ethyl N-(ethoxycarbonylmethyl)-8-alaninate and 30 ml of water cooled to -10°C is added dropwise 27.6 ml of ethyl chloroformate followed by a solution of 12.7 g of sodium carbonate in 50 ml of water. The mixture is warmed to room temperature then heated at 550C for 50 minutes. The mixture is cooled, extracted with toluene, the extract is washed with 2N hydrochloric by the fractional crystallization of d- or l-(tartrates, mandelates, 37 acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo to yield ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-B-alaninate.
A solution of 53.9 g of ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-P-alaninate in 200 ml of toluene is added dropwise to a stirred solution of potassium hexamethyldisilazide (429 ml, 0.653 M) in 125 ml of toluene under nitrogen and cooled to 0°C. After minutes at 0 C, 21.6 ml of acetic acid is added followed by a solution of 100 g of sodium phosphate (monobasic) in 1 liter of water. The layers are separated, the organic layer is washed with pH 7 buffer, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane to yield ethyl l-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylate.
To a stirred suspension of 24 g of benzyloxycarbonylmethyl-triphenylphosphonium bromide in 2?5 ml of anhydrous tetrahydrofuran ooo under nitrogen and cooled to 0 C is added 73 ml of potassium oO hexamethyldisilazide (0.652 After 10 minutes a solution of 11 g of ethyl l-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylate in 50 ml of a tetrahydrofuran is added and the mixture refluxed 2 1/2 hours. After cooling the mixture is filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, dried over oo0° sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane to yield an oil; this is hydrogenated in 200 ml of ethanol and 5 g of 10 palladium on carbon to yield, after filtering and concentrating the filtrate, 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetic acid.
A solution of 10 g of l-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine- 3-acetic acid in 50 ml tetrahydrofuran is cooled to 0°C and 55 ml of borane/tetrahydrofuran (1 M) is added dropwise. After stirring 2 hours at 0°C, 20 ml of water is added, the mixture is extracted with ethyl acetate, 'ashed twice with water and dried over sodium sulfate. The solution is filtered, concentrated and purified by the N-methyl-D-aspartate sensitive excitatory amino acid receptor ~I~~P~1~PIC~i 38 flash chromatography using ethyl acetate/hexane (1:1 to 7:3) to yield cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.
A solution of 6 g of cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of dichloromethane containing 7.3 ml of diisopropylethylamine, to which is added 5.1 ml of 85 benzyloxymethyl chloride, is stirred 3 1/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfate, S'filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane to yield cis ethyl l-ethoxycarbonyl-3- [2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxy'ate.
4Qt A solution of 6.2 g of cis ethyl l-ethoxycarbonyl-3-[2-(bcnizyloxy- 0 o methoxy)-ethyl]-pyrrolidine-2-carboxylate in 75 ml of anhydrous ethanol containing 1 ml of butyllithium (1.6 M) is refluxed under nitrogen for 6 days. After cooling, 1.7 ml of IN hydrochloric acid 0 c o is added, the solution is concentrated in vacuo, cold water added 0o oand mixture extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by high o a pressure liquid chromatography using ethyl acetate/hexane (15:85) to yield trans ethyl l-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]pyrrolidine-2-carboxylate.
-000 0o A mixture of 1.64 g of trans ethyl l-ethoxycarbonyl-3-[(2-benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate and 2 g of 10 palladium on carbon in 35 ml of acetic acid is hydrogenated at 311 kPa. The mixture is filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (6:4 to 7:3) to yield trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.
A solution of 0.991 g of trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.24 g pyridinium chlorochromate in 20 ml of dichloromethane is stirred under nitrogen for 4 hours. Mixture is solvents to assist passage throught the skin of the host. Characte- -39 filtered and purified by flash chromatography using ethyl acetate/hexane to yield trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.
To 0.4 g of trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3acetaldehyde in 5 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78 0 C, is added dropwise a solution of 1.17 g of methoxymethyl-triphenylphosphonium chloride in 15 ml of anhydrous tetrahydrofuran to which is added 1.55 ml of potassium tert- S'butoxide/tetrahydrofuran (1.6 Solution is stirred at room temperature for 4 hours. 2N hydrochloric acid (11 ml) is added and the mixture is stirred for 45 minutes. The solution is concentrated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and the residue is purified o 4 by flash chromatography using ethyl acetate/hexane (1:5 to 3:7) to yield trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3propionaldehyde.
0oo o0 Example 13: A mixture of 0.193 g of trans ethyl l-ethoxycarbonyl-3- [1-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate and o 4 ml of concentrated hydrochloric acid is refluxed for 16 hours. The solution is cooled and concentrated to dryness in vacuo. The solid that separates is filtered off and dried in vacuo to yield trans o u 3-[l-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid, I m.p. 110-115 0 C dec.
Example 14: To a solution of 0.426 g cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde in 10 ml of anhydrous tetrahydrofuran under nitrogen, cooled to -78°C, is added slowly a solution of 0.45 ml of tetraethylmethylenediphosphonate and 1.06 ml of butyllithium (1.6 M) in 10 ml of anhydrous tetrahydrofuran also at -78 0 C. Solution is refluxed 14 hours, cooled and 0.3 ml acetic acid is added; the reaction mixture is concentrated, water is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by
CI
I
40 flash chromatography using ethyl acetate to yield cis ethyl l-ethoxycarbonyl-3-[l-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2carboxylate.
The starting material is prepared as follows: A solution of 0.908 g of cis 3-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol and 1.14 g pyrldinium chlorochromate in 20 ml of dichloromethane is stirred under nitrogen for 4 hours. Mixture is filtered and purified by flash chromatography using ethyl acetate/hexane to yield cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde.
To 0.663 g of cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3acetaldehyde in 10 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78 0 C, is added dropwise a solution of 2.21 g of methoxymethyl-triphenylphosphonium chloride in 20 ml of anhydrous tetrahydrofuran to which is added 2.6 ml of potassium tertbutoxide/tetrahydrofuran (1.6 Solution is stirred at room temperature for 4 hours; 15 ml of 2N hydrochloric acid is added and the mixture stirred for 45 minutes. The solution is concentrated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated; purification by flash chromatography using ethyl acetate/hexane (1:5 to 3:7) yields cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.
Example 15: A mixture of 0.176 g of cis ethyl l-ethoxycarbonyl-3-[1- (4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate and ml of concentrated hydrochloric acid is refluxed 18 hours. The solution is concentrated in vacuo to dryness, the residue dissolved in 1.5 ml of isopropanol/methanol and 0.2 ml of propylene oxide is added. The solid that separates is filtered off and dried in vacuo to yield cis 3-[l-(4-phosphonobut-3-enyl)]-pyrrolidine-2carboxylic acid, m.p. 132-140 0
C.
00 060 4 a0 0 J j 0 C i- 41 Example 16: A solution of 0.0655 g of trans ethyl 1-ethoxycarbonyl- 3-[l-(4-bromobut-2-enyl)]-pyrrolidine-2-carboxylate in 0.75 ml of triethylphosphite is refluxed 20 minutes. The solution is concentrated in vacuo and the residue purified by flash chromatography using dichloromethane/ethanol (30:1) to yield trans ethyl 1-ethoxycarbonyl-3-[l-(4-disthylphosphonobut-2-enyl)]-pyrrolidine-2-carboxylate.
The starting material is prepared as follows: A solution of 0.225 g S'of trans l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde and 0.4 g of (formylmethylene)-triphenylphosphoran in 2 ml of dichloromethane is refluxed 44 hours. The solution is concentrated and the residue is purified by flash chromatography using ethyl acetate/hexane to yield trans ethyl l-ethoxycarbonyl-3-[1-(4oxobut-2-enyl)]-pyrrolidine-2-carboxylate.
To a stirred solution of 0.102 g of trans ethyl l-ethoxycarbonyl-3- 0 0 o [1-(4-oxobut-2-enyl)]-pyrrolidine-2-carboxylate in 2 ml of ethanol r" ona cooled to 0 C is added 0.035 g of sodium borohydride. After minutes at 0 0 C and 30 minutes at room temperature 0.05 ml of 0 D acetic acid is added, the solution concentrated, water added and mixture extracted with dichloromethane. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield trans ethyl l-ethoxycarbonyl-3-[l-(4-hydroxybut-2-enyl)]-pyrrolidine-2carboxylate.
To a stirred solution of 0.0937 g of trans ethyl l-ethoxycarbonyl-3- S[l-(4-hydroxybut-2-enyl)]-pyrrolidine-2-carboxylate and 0.1 g of triphenylphosphine in 2 ml of dichloromethane at 0 C is added 0.067 g of N-bromosuccinimide. After 30 minutes at room temperature the mixture is purified by flash chromatography using ethyl acetate/hexane to yield trans ethyl l-ethoxycarbonyl-3-[1-'4bromobut-2-enyl)]-pyrrolidine-2-carboxylate.
li.
42 Example 17: A mixture of 0.053 g of trans ethyl l-ethoxycarbonyl-3- [l-(4-diethylphosphonobut-2-enyl)]-pyrrolidine-2-carboxylate and ml of concentrated hydrochloric acid is refluxed for 16 hours.
The solution is concentrated to dryness in vacuo, the residue is dissolved in 1 ml of methanol, 0.2 ml of propylene oxide is added and the solution is concentrated. The residue is purified by ion exchange chromatography eluating with 0.1N ammonium hydroxide to yield trans 3-[l-(4-phosphonobut-2-enyl)]-pyrrolidine-2-carboxylic acid, m.p. 138-145 0
C.
Example 18: Preparation of an injectable formulation containing mg of the active ingredient per 5 ml of solution having a formula as follows: cis 4-[l-(3-phosphonoprop-l-enyl)]piperidine-2-carboxylic acid 10.0 g Propylparaben 0.5 g Water for injection q.s. 5000.0 ml The active ingredient and preservative are dissolved in 3500 ml of S water for injection and the solution is diluted to 5000 ml. The solution is filtered through a sterile filter and filled into injection vials under sterile conditions each vial containing 5 ml of the solution.
oa Example 19: a) Preparation of 10,000 tablets each containing 10 mg of the active ingredient, having the formula as follows: cis 4-[l-(3-phosphonoprop-l-enyl)]piperidine-2-carboxylic acid 100.00 g Lactose 2,535.00 g Corn starch 125.00 g c C I 43 Polyethylene glycol 6,000 150.00 g Magnesium stearate 40.00 g Purified water q.s.
Procedure: All the powders are passed through a screen with openings of 0.6 mm. The the drug substance, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of the polyethylene glycol o in 260 ml of water. The paste formed is added to the powders, which 0o 0 are granulated, if necessary, with an additional amount of water.
,Os The granulate is dried overnight at 35 0 C broken on a screen with a 0 1.2 mm openings and compressed into tablets, using concave punches uppers bisected.
S0 o oo Analogously tablets are prepared, containing about 1-50 mg of one of the other compounds disclosed and exemplified herein.
S'010 b) Preparation of 1,000 capsules each containing 5 mg of the active ingredient, having the formula as follows: o 0
C
on o cis 4-[l-(3-phosphonoprop-l-enyl)]o piperidine-2-carboxylic acid 5.0 g a 0 Lactose 212.0 g 0 o' Modified starch 80.0 g Magnesium stearate 3.0 g Procedure: All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogeneous. No. 2 hard gelatin capsules are filled with 300 mg of said mixture each, using a capsule filling machine.
Analogously capsules are prepared, containing about 1-50 mg of the other compounds disclosed and exemplified herein.
A
Claims (25)
1. A compound of formula I R'O- R(H 2 )M m (I) /*-R1 ca 2 o so 0coQ 0 0 00 00 0 000 0 on wherein R and R' independently represent hydrogen, lower alkyl, 00 00 benzyl, benzyl substituted on phenyl by halogen, lower alkyl or 9lower alkoxy; lower alkanoyloxymethyl or lower alkanoyloxymethyl 1 0 0 00 aooi substituted on oxymethyl by lower alkyl or cycloalkyl, m represents one or zero, A represents lower alkenylene R1 is carboxy, esterified carboxy or amidated carboxy and R' denotes hydrogen, lower alkyl or acyl or, if m stands for 1, represents aryl-lower alkyl, wherein the 0 0,000! five-or six-membered heterocyclic ring may be additionally substi- 9000 0 e tuted on carbon and/or nitrogen, may have present a carbon-carbon 00 0 double bond or may be fused on adjacent carbon atoms with a six- oo00 00 o membered carbocyclic ring; or a salt thereof.
2. A compound of formula I according to claim 1 wherein the hetero- ese cyclic ringsystem, together with substituent R 1 is represented by optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydro- pyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6- tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxytetrahydro- quinolinyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydro- indolyl or 2-carboxyperhydroindolyl, wherein carboxy may be esterified or amidated; or a salt thereof. RAi;, -Y 7J 9 'r o0' iluan~r~-rariu 45
3. A compound according to claim 1 of the formula II -OR' fRR R3-4 (II) or a compound of formula II with a double bond present between C-3 and C-4 or between C-4 and C-5 of the piperidinyl ring, in which the phosphono bearing chain is attached at the or
5-position of the piperidinyl or tetrahydropyridinyl ring, and wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or o0, lower alkoxy; lower alkanoyloxymethyl or lower alkanoyloxymethyl co404 substituted on oxymethyl by lower alkyl or cycloalkyl, R 1 represents 0 4 o 0 a carboxy or pharmaceutically acceptable esterified or amidated a CO carboxy; R 2 represents hydrogen, lower alkyl, aryl-lower alkyl, or acyl; R 3 represents hydrogen, lower alkyl or aryl-lower alkyl; A represents lower alkenylene; or a salt thereof. o So o <ei 4. A compound of formula II according to claim 3 wherein R and R' 00 4 independently represent hydrogen, lower alkyl, benzyl, lower "Bo alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, cyclohexyl or cyclopentyl; R 1 represents carboxy, carbamoyl or pharmaceutically acceptable esterified carboxy as defined herein; R 2 and R 3 represent hydrogen or lower alkyl; A represents alkenylene of 2 to 4 carbon atoms; or a pharmaceutically acceptable salt thereof. A compound of formula II according to claim 3 wherein R and R' independently represent hydrogen, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl; R 1 repre- sents carboxy, carbamoyl or lower alkoxycarbonyl, lower alkanoyl- oxymethoxycarbonyl, di-lower alkylamino straight chain Cz-i-alkoxy- carbonyl or pyridylmethoxycarbonyl, R 2 and R 3 represent hydrogen; A is at the 4-position and represents alkenylene of 3 or 4 carbon 46 atoms with double bond adjacent to the phosphono grouping; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 3 of the formula III A- -FOH /\R i OH (III) 0 00 a 0 0 ell 00M0 0000 0 0. 0' 09 0 0O 0 00 0 0 0O OD 0 tO 0O wherein wherein A represents 1,3-propenylene, preferably with the double bond adjacent to the phosphono grouping; R 1 represents carboxy or pharmaceutically acceptable esterified carboxy as defined herein; or a pharmaceutically acceptable salt of said compound having a salt-forming functional grouping.
7. A compound according to claim 6 being 4-[l-(3-phosphonoprop-2- enyl)]piperidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 6 being 4-[1-(3-phosphonoprop-l- enyl)]piperidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 of the formula IV \R1 R~i i2 (IV) or a perhydro derivative thereof, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxy- methyl, lower alkanoyloxymethyl substituted on oxymethyl by lower il--I II~-M sYICU_-^ 47 alkyl, or cycloalkyl; R 1 represents carboxy or pharmaceutically acceptable esterified or amidated carboxy; R 2 represents hydrogen, lower alkyl, aryl-lower alkyl, or acyl; R 4 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A represents lower alkenylene; or a salt thereof. A compound according to claim 9 of the formula V A- -OH H I i i (v) o* o or a perhydroquinoline derivative thereof wherein A represents o 1,3-propenylene with the double bond adjacent to the phosphono os grouping; R 1 represents carboxy or pharmaceutically acceptable esterified carboxy as defined herein; or a pharmaceutically o o: acceptable salt of said compound having a salt-forming functional c 0 grouping.
11. A compound according to claim 1 of the formula VI R 3 -OR' (VI) \1 R 4 or a compound of formula VI with a double bond present between C-3 and C-4 of the pyrrolidinyl ring, wherein R and R' independent- ly represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy, lower alkanoyloxy- methyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, or cycloalkyl; R' represents carboxy or pharmaceutically acceptable esterified or amidated carboxy; R 2 represents hydrogen, lower alkyl or acyl; R 3 represents hydrogen, lower alkyl or aryl- lower alkyl; A represents lower alkenylene; or a salt thereof. (y^;nq W7l- L- I 48
12. A compound of formula VI according to claim 11 wherein the phosphono bearing group is attached at the 3-position, R and R' represent hydrogen; R I represents carboxy, lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, di-lower alkylamino straight chain C 2 4 -alkoxycarbonyl or pyridylmethoxycarbonyl; R 2 and R 3 represent hydrogen; A represents 1,3-propenylene with double bond adjacent to the phosphono grouping; or a pharmaceutically accept- able salt thereof.
13. A compound according to claim 11 being trans 3-[1-(4-phosphono- but-3-enyl)]-pyrrolidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof. oo 00 0 eo 14. A compound according to claim 11 being trans 3-[l-(4-phosphono- o on but-2-enyl)]-pyrrolidine-2-carboxylic acid or a -harmaceutically ooI acceptable salt thereof. o 0 4 o 15. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 14, in admixture or conjunction with one or more pharmaceutically suitable carriers. 0 OOOo 16. A compound claimed in any one of claims 1 to 14 when used in a So therapeutic method of treating humans and animals. .4 4
17. A compound claimed in any one of claims 1 to 14 when used as an antagonist of the N-methyl-D-aspartate (NMDA) sensitive excitatory amino acid receptor.
18. The use of a compound claimed in any one of claims 1 to 14 in a pharmaceutical composition.
19. The use of a compound claimed in any one of claims 1 to 14 in a ph'rmaceutical composition for application as antagonist of the N-,methyl-D-aspartate (NMDA) sensitive excitatory amino acid receptor. 49 Process for the manufacture of a pharmaceutical composition, wherein a compound claimed in any one of claims 1 to 14 is worked up with a pharmaceutical carrier.
21. A compound according to claim 6 selected from the group con- sisting of cis-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carbo- xylic acid, trans 4-[l-(3-phosphonoprop-2-enyl)]-piperidine-2- carboxylic acid, cis 4-[1-(3-phosphonoprop-l-enyl)]-piperidine- 2-carboxylic acid and trans 4-[1-(3-phosphonoprop-l-enyl)]-piperi- dine-2-carboxylic acid or a pharmaceutically acceptable salt thereof. °o 22. A compound according to claim 11 being cis 3-[l-(4-phosphonobut- 0o 3-enyl)]-pyrrolidine-2-carboxylic acid or a pharmaceutically accept- co o able salt thereof. 9000 0 °0o00 23. A pharmaceutical composition comprising a compound claimed in a 0oo any one of claims 21 and 22, in admixture or conjunction with one or more pharmaceutically suitable carriers.
24. A compound claimed in any one of claims 21 and 22 when used in a therapeutic method of treating humans and animals. 0000 o 0 00 0
25. A compound claimed in any one of claims 21 and 22 when used as 00 00 o" an antagonist of the N-methyl-D-aspartate (NMDA) sensitive excit- atory amino acid receptor. 0 00 0 26. The use of a compound claimed in any one of claims 21 and 22 in a pharmaceutical composition.
27. The use of a compound claimed in any one of claims 21 and 22 in a pharmaceutical composition for application as antagonist of the N-methyl-D-aspartate (NMDA) sensitive excitatory amino acid receptor. 50
28. Process for the manufacture of a pharmaceutical composition, wherein a compound claimed in any one of claims 21 and 22 is worked up with a pharmaceutical carrier.
29. Process for the manufacture of a compound of formula I shown in claim 1, in which formula all symbols have the meanings given in claim 1, or a salt thereof, which consists in a) condensing an aldehyde or ketone of the formula VII ~H) 2 (VII) 0 00 0 0 .000 0 00 0 0e I a 0 0 o 0 0 0 0 o 0r wherein m, R I R 2 and the heter.cyclic ring are as defined for formula I with R 1 and amino groups in protected form, and A' represents oxo substituted lower alkyl having 1 carbon less than the alkenylene group A, with a tetra ester derivative of methylene- diphosphonic acid, in the presence of a strong anhydrous base and in an inert polar solvent, and if required deprotecting the resulting product to obtain a compound of formula I wherein the double bond within the grouping A is adjacent to the phosphono grouping; or b) condensing a compound of the formula VIII X \i) 2 (VIII) 0 00 6 wherein A, m, R 2 and the heterocyclic ring are as defined for formula I, and X represents reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid moiety, having one of formulae IX or X, VN7SI 'Vy' U A l' or alcn±oromeunane is suirrea unaer nlnrogen tor 4 hours. Mixture is 51 51 H- -OR" (IX) (X) OR" wherein R" represents lower alkyl and represents halogen or lower alkoxy and, if required, converting the resulting phosphonic acid derivative to the phosphonic acid or other ester derivative thereof; or c) converting to R I a substituent other than R 1 at position 2 of the heterocyclic ring in a compound otherwise identical to i compound of the invention; and carrying out the said processes while, if necessary, temporarily protecting any interfering reactive group(s) in these processes, and then liberating the resulting compound of 9 oi oa 0 the invention; and, if desired, converting a resulting compound of o 00 o) the invention into another compound of the invention, and/or, if a ,s desired, converting a resulting free compound into a salt or a 0on, resulting salt into the free compound or into another salt; and/or o0 R on separating a mixture of isomers or racemates obtained into the single isomers or racemates; and/or, if desired, resolving a racemate obtained into the optical antipodes.
30. A compound of formula I according to the process of claim 29. 0 0
31. Process according to claim 29 characterized in that a compound .o oo of formula I 0 0* SR'O- H2 S* R H Y m (I) -R 1 wherein R and R' represent lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyl- oxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by -1 .1 0U4.L0aLt!' L1LwLt:U, LOIl eI1LLat UU cALLU -j I 52 lower alkyl or cycloalkyl, R 1 is carboxy or esterified or amidated carboxy, and R 2 represents acyl, is converted into a compound of formula I, wherein R and R' are hydrogen, R 1 is carboxy and R 2 is hydrogen, by treatment with an inorganic acid, or with aqueous alkalies.
32. Process according to claim 31 characterized in that a compound of formula I, wherein R and R' represent lower alkyl, R' and R 2 represent lower alkoxycarbonyl, is converted into a compound of formula I, wherein R and R' are hydrogen, R I is carboxy and R 2 is hydrogen, by treatment with an inorganic acid, or with aqueous alkalies. a; t si 4 1 a 0 6 0 o o 0 o 0 0 0 0 0 0 0o0000 0 00 00 0 0 P4 o a 04 a v t, 1 .v" "^DS 1: G q i I 53
33. A compound of formula I as shown in claim 1, said compound substantially as herein described with reference to any one of Examples 1 to 17.
34. A pharmaceutical formulation substantially as herein described with reference to either of Examples 18 or 19. DATED this 6th day of March, 1991. CIBA-GEIGY AG By Their Patent Attorneys ARTHUR S. CAVE CO. a t 4 4 4 44 o l 0 0 4 *004 0
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US93370286A | 1986-11-21 | 1986-11-21 | |
US933702 | 2001-08-20 |
Publications (2)
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AU8145587A AU8145587A (en) | 1988-05-26 |
AU610841B2 true AU610841B2 (en) | 1991-05-30 |
Family
ID=25464377
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU81455/87A Ceased AU610841B2 (en) | 1986-11-21 | 1987-11-20 | Unsaturated phosphonic acids and derivatives |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP0275820B1 (en) |
JP (1) | JPH0686470B2 (en) |
KR (1) | KR880006195A (en) |
AT (1) | ATE60776T1 (en) |
AU (1) | AU610841B2 (en) |
CA (1) | CA1312608C (en) |
DD (1) | DD273837A5 (en) |
DE (1) | DE3768000D1 (en) |
DK (1) | DK609487A (en) |
ES (1) | ES2031927T3 (en) |
FI (1) | FI86638C (en) |
GR (1) | GR3001443T3 (en) |
HU (1) | HU199857B (en) |
IE (1) | IE60534B1 (en) |
IL (1) | IL84492A0 (en) |
MX (1) | MX9437A (en) |
NO (1) | NO170853C (en) |
NZ (1) | NZ222607A (en) |
PH (1) | PH25465A (en) |
PT (1) | PT86168B (en) |
ZA (1) | ZA878699B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4968678A (en) * | 1988-02-19 | 1990-11-06 | Eli Lilly And Company | Tetrazole excitatory amino acid receptor antagonists |
CA2000901A1 (en) * | 1988-10-21 | 1990-04-21 | Alexis A. Cordi | Phosphono-hydroisoquinoline compounds useful in reducing neurotoxic injury |
US4902695A (en) * | 1989-02-13 | 1990-02-20 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
EP0424179A3 (en) * | 1989-10-20 | 1991-12-27 | John William Olney | Use of combined excitatory amino acid and cholinergic antagonists to prevent neurological deterioration |
US5238958A (en) * | 1990-02-26 | 1993-08-24 | Warner-Lambert Company | Substituted α-amino acids having selected acidic moieties for use as excitatory amino acid antagonists in pharmaceuticals |
US5194430A (en) * | 1990-05-17 | 1993-03-16 | Merrell Dow Pharmaceuticals Inc. | Heterocyclic-nmda antagonists |
SE9003652D0 (en) * | 1990-11-15 | 1990-11-15 | Astra Ab | NEW HETEROCYCLIC COMPOUNDS |
US5260286A (en) * | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
WO1998056788A1 (en) | 1997-06-12 | 1998-12-17 | Rhone-Poulenc Rorer Limited | Imidazolyl-cyclic acetals |
EP3427729A1 (en) | 2017-07-13 | 2019-01-16 | Paris Sciences et Lettres - Quartier Latin | Probenecid for use in treating epileptic diseases, disorders or conditions |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203891A2 (en) * | 1985-05-24 | 1986-12-03 | Ciba-Geigy Ag | Certain phosphonic acids and derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2104079B (en) * | 1981-08-14 | 1985-08-21 | London Polytech | New aminoacid isomers, their production and their medicinal use |
-
1987
- 1987-11-16 AT AT87810662T patent/ATE60776T1/en active
- 1987-11-16 IL IL84492A patent/IL84492A0/en unknown
- 1987-11-16 ES ES198787810662T patent/ES2031927T3/en not_active Expired - Lifetime
- 1987-11-16 EP EP87810662A patent/EP0275820B1/en not_active Expired - Lifetime
- 1987-11-16 DE DE8787810662T patent/DE3768000D1/en not_active Expired - Lifetime
- 1987-11-18 FI FI875097A patent/FI86638C/en not_active IP Right Cessation
- 1987-11-18 PH PH36083A patent/PH25465A/en unknown
- 1987-11-19 PT PT86168A patent/PT86168B/en not_active IP Right Cessation
- 1987-11-19 NZ NZ222607A patent/NZ222607A/en unknown
- 1987-11-19 CA CA000552204A patent/CA1312608C/en not_active Expired - Fee Related
- 1987-11-19 DD DD87309215A patent/DD273837A5/en not_active IP Right Cessation
- 1987-11-20 NO NO874854A patent/NO170853C/en unknown
- 1987-11-20 AU AU81455/87A patent/AU610841B2/en not_active Ceased
- 1987-11-20 KR KR870013064A patent/KR880006195A/en not_active Application Discontinuation
- 1987-11-20 JP JP62292195A patent/JPH0686470B2/en not_active Expired - Lifetime
- 1987-11-20 IE IE314987A patent/IE60534B1/en not_active IP Right Cessation
- 1987-11-20 DK DK609487A patent/DK609487A/en not_active Application Discontinuation
- 1987-11-20 ZA ZA878699A patent/ZA878699B/en unknown
- 1987-11-20 HU HU875161A patent/HU199857B/en not_active IP Right Cessation
- 1987-11-23 MX MX943787A patent/MX9437A/en unknown
-
1991
- 1991-02-07 GR GR90401113T patent/GR3001443T3/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203891A2 (en) * | 1985-05-24 | 1986-12-03 | Ciba-Geigy Ag | Certain phosphonic acids and derivatives |
AU593553B2 (en) * | 1985-05-24 | 1990-02-15 | Novartis Ag | Certain phosphonic acids and derivatives |
Also Published As
Publication number | Publication date |
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NO874854L (en) | 1988-05-24 |
DD273837A5 (en) | 1989-11-29 |
NO170853C (en) | 1992-12-16 |
ATE60776T1 (en) | 1991-02-15 |
JPH01135791A (en) | 1989-05-29 |
IE60534B1 (en) | 1994-07-27 |
PT86168A (en) | 1987-12-01 |
PT86168B (en) | 1990-08-31 |
DE3768000D1 (en) | 1991-03-14 |
EP0275820A2 (en) | 1988-07-27 |
HUT46331A (en) | 1988-10-28 |
AU8145587A (en) | 1988-05-26 |
MX9437A (en) | 1994-01-31 |
EP0275820B1 (en) | 1991-02-06 |
NO170853B (en) | 1992-09-07 |
NO874854D0 (en) | 1987-11-20 |
ZA878699B (en) | 1988-05-23 |
GR3001443T3 (en) | 1992-09-25 |
DK609487A (en) | 1988-05-22 |
PH25465A (en) | 1991-07-01 |
KR880006195A (en) | 1988-07-22 |
EP0275820A3 (en) | 1988-08-03 |
JPH0686470B2 (en) | 1994-11-02 |
DK609487D0 (en) | 1987-11-20 |
FI875097A0 (en) | 1987-11-18 |
ES2031927T3 (en) | 1993-01-01 |
FI86638C (en) | 1992-09-25 |
IL84492A0 (en) | 1988-04-29 |
FI86638B (en) | 1992-06-15 |
CA1312608C (en) | 1993-01-12 |
FI875097A (en) | 1988-05-22 |
HU199857B (en) | 1990-03-28 |
NZ222607A (en) | 1990-10-26 |
IE873149L (en) | 1988-05-21 |
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