DE19616471A1 - Phosphonic acid ester for the treatment of brain disorders and depression - Google Patents
Phosphonic acid ester for the treatment of brain disorders and depressionInfo
- Publication number
- DE19616471A1 DE19616471A1 DE19616471A DE19616471A DE19616471A1 DE 19616471 A1 DE19616471 A1 DE 19616471A1 DE 19616471 A DE19616471 A DE 19616471A DE 19616471 A DE19616471 A DE 19616471A DE 19616471 A1 DE19616471 A1 DE 19616471A1
- Authority
- DE
- Germany
- Prior art keywords
- phosphonic acid
- dimethyl ester
- trichloroethane
- acid dimethyl
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000003008 phosphonic acid esters Chemical class 0.000 title claims abstract description 14
- 208000014644 Brain disease Diseases 0.000 title claims description 4
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 210000004556 brain Anatomy 0.000 claims abstract description 4
- -1 difluorochloromethyl Chemical group 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 125000004673 propylcarbonyl group Chemical group 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229910052717 sulfur Chemical group 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 claims description 4
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 150000002366 halogen compounds Chemical class 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- BHVWDFJQEHZKIY-UHFFFAOYSA-N dimethoxy(sulfanylidene)-lambda5-phosphane Chemical compound COP(=S)OC BHVWDFJQEHZKIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910017464 nitrogen compound Inorganic materials 0.000 claims description 2
- 150000002830 nitrogen compounds Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- BTHJBFGTISSYAM-UHFFFAOYSA-N ethyl (1,1,1-trichloro-2-methylpropan-2-yl) carbonate Chemical compound CCOC(=O)OC(C)(C)C(Cl)(Cl)Cl BTHJBFGTISSYAM-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000003085 diluting agent Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 208000010877 cognitive disease Diseases 0.000 description 4
- 230000001149 cognitive effect Effects 0.000 description 4
- 229960001952 metrifonate Drugs 0.000 description 4
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 4
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000019022 Mood disease Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010048650 Cholinesterase inhibition Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- OEBRKCOSUFCWJD-UHFFFAOYSA-N dichlorvos Chemical compound COP(=O)(OC)OC=C(Cl)Cl OEBRKCOSUFCWJD-UHFFFAOYSA-N 0.000 description 2
- 229950001327 dichlorvos Drugs 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229960003975 potassium Drugs 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XGINAUQXFXVBND-UHFFFAOYSA-N 1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidine Chemical compound N1CC=CN2CCCC21 XGINAUQXFXVBND-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
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- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
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- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- 239000003921 oil Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
Description
Die Erfindung betrifft die Verwendung von Phosphonsäureestern zur Behandlung und Prävention von Hirnleisungsstörungen und Depressionen, neue Stoffe und deren Herstellung.The invention relates to the use of phosphonic acid esters for the treatment and Prevention of brain disorders and depression, new substances and their Manufacturing.
Aus DE 10 78 370 sind Phosphonsäureester bekannt, die zur Bekämpfung von Insekten eingesetzt werden.DE 10 78 370 discloses phosphonic acid esters which are used to control insects be used.
Außerdem ist bekannt, daß das Anthelmintikum Metrifonat zur Behandlung von Alzheimer geeignet ist (US 4 950 658). Als Wirkmechanismus wird vermutet, daß Metrifonat langsam in den Organophosphorsäureester Dichlorvos umgewandelt wird und dadurch eine lang anhaltende Cholinesterasehemmung induziert. In Weiterführung dieses Konzeptes wurde Butonat als geeignete Vorstufe für Metrifonat/Dichlorvos vorgeschlagen (B.R. Holmstedt und I. Nordgren) in Cholinergic Basis for Alzheimer Therapy (R.E. Becker und E. Giaco bini, eds.), Birkhäuser, Boston, pp. 155-161, 1991).It is also known that the anthelmintic metrifonate is used to treat Alzheimer's is suitable (US 4 950 658). As a mechanism of action, it is believed that metrifonate is slow is converted into the organophosphoric acid ester dichlorvos and thereby a long persistent cholinesterase inhibition induced. In continuation of this concept Butonate proposed as a suitable precursor for metrifonate / dichlorvos (B.R. Holmstedt and I. Nordgren) in Cholinergic Basis for Alzheimer Therapy (R.E. Becker and E. Giaco bini, eds.), Birkhauser, Boston, pp. 155-161, 1991).
Es wurde nun überraschenderweise gefunden, daß Phosphonsäureester der allgemeinen Formel (I)It has now surprisingly been found that phosphonic esters of the general Formula (I)
in welcher
R für geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoffatomen steht, das
gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,
R¹ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoff
atomen steht,
R² für Wasserstoff oder geradkettiges oder verzweigtes Alkyl, Alkylcarbonyl,
Alkoxycarbonyl oder Alkylsulfonyl mit jeweils bis zu 6 Kohlenstoffatomen in der
Alkylgruppe steht, oder für Alkyl- oder Dialkylaminocarbonyl mit jeweils bis zu 4
Kohlenstoffatomen in den Alkylgruppen steht,
R³ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoff
atomen und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹
für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff
bedeutet,
deren Salze sowie deren Isomere,
zur Behandlung und Prävention von Hirnleistungsstörungen und Depressionen eingesetzt
werden können, auch ohne daß eine Umwandlung zu einem Cholinesterasehemmer
eintritt.in which
R represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by one or more halogen atoms,
R¹ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl each having up to 6 carbon atoms in the alkyl group, or represents alkyl- or dialkylaminocarbonyl each having up to 4 carbon atoms in the alkyl groups,
R³ for hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and their isomers,
can be used for the treatment and prevention of brain disorders and depression, even without a conversion to a cholinesterase inhibitor.
Aufgrund der Versuchsergebnisse sind die Verbindungen der Formel (I) geeignet zur Behandlung und Prävention kognitiver und affektiver Erkrankungen, insbesondere zur Behandlung von seniler und präseniler Demenz, Demenz des Alzheimer-Typs, AIDS- bezogener Demenz, kognitiven Defiziten bei Parkinson oder Huntington oder Hirn leistungsstörungen in Folge von Infarktgeschehen, und zur Behandlung von Depressionen.Based on the test results, the compounds of formula (I) are suitable for Treatment and prevention of cognitive and affective disorders, especially for Treatment of senile and presenile dementia, dementia of the Alzheimer type, AIDS related dementia, cognitive deficits in Parkinson's or Huntington's or brain performance disorders as a result of infarction, and for the treatment of Depressions.
Besonders geeignet zur Behandlung und Prävention von kognitiven und affektiven Stö
rungen sind die Verbindungen der Formel (I)
in welcher
R für geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen oder für
Trifluormethyl, Trichlormethyl, Difluormethyl, Dichlormethyl, Fluormethyl,
Chlormethyl, Difluorchlormethyl oder Dichlorfluormethyl steht,
R¹ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoff
atomen steht,
R² für Wasserstoff oder geradkettiges oder verzweigtes Alkyl, Alkylcarbonyl, Alkoxy
carbonyl oder Alkylsulfonyl mit jeweils bis zu 4 Kohlenstoffatomen in der
Alkylgruppe steht, oder für Alkyl- oder Dialkylaminocarbonyl mit jeweils bis zu 3
Kohlenstoffatomen in den Alkylgruppen steht,
R³ für geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen
und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹
für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff
bedeutet,
deren Salze sowie Isomere.The compounds of the formula (I) are particularly suitable for the treatment and prevention of cognitive and affective disorders
in which
R represents straight-chain or branched alkyl having up to 4 carbon atoms or trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, difluorochloromethyl or dichlorofluoromethyl,
R¹ represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl each having up to 4 carbon atoms in the alkyl group, or represents alkyl- or dialkylaminocarbonyl each having up to 3 carbon atoms in the alkyl groups,
R³ for straight-chain or branched alkyl with up to 4 carbon atoms
and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and isomers.
Besonders bevorzugt werden Verbindungen der allgemeinen Formel (I) verwendet,
in welcher
R für Methyl, Chlormethyl, Dichlormethyl, Trichlormethyl, Trifluormethyl, Dichlor
fluormethyl oder Difluorchlormethyl steht,
R¹ für Wasserstoff oder Methyl steht,
R² für Wasserstoff- Methyl, Ethyl, Methylcarbonyl, Ethylcarbonyl, Propylcarbonyl,
t-Butylcarbonyl, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Methylsulfonyl,
Ethylsulfonyl, Propylsulfonyl, Methylaminocarbonyl, Dimethylaminocarbonyl oder
für Propylaminocarbonyl steht,
R³ für Methyl, Ethyl oder Propyl steht
und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹
für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff
bedeutet,
deren Salze sowie Isomere.Compounds of the general formula (I) are particularly preferably used
in which
R represents methyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, dichlorofluoromethyl or difluorochloromethyl,
R¹ represents hydrogen or methyl,
R² represents hydrogen, methyl, ethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl or propylaminocarbonyl,
R³ represents methyl, ethyl or propyl
and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and isomers.
Weiterhin betrifft die Erfindung folgende neue Stoffe:
(1-tert.-Butylcarbonyloxy-2,2,2-tichlorethan)-phosphonsäure-dimethyl-ester
(1-Methansulfonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethyleste-r
(1-Ethansulfonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethylester-
(1-Methoxycarbonylo xy-2,2,2-trichlorethan)-phosphonsäure-dimethylester
(1-Acetyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethylester
(1-Methoxycarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethylest-er
(1-Propylcarbonyloxy-2,2,2-trifluorethan)-phosphonsäuredimethylester-
(1-Methansulfonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethyleste-r
(1-Dimethylaminocarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimet-hylester
(1-Propylaminocarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethy-lester
(1-A cetyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethylester
(1-Methoxycarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethy-lester
(1-Dimethylaminocarbonyloxy-2,2,2-trichlorethan)thiophosphonsäure-di-methylester
2,2,2-Trifluorethan-thio phosphonsäure-dimethylester
(1-Propylaminocarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dim-ethylester
(1-Methansulfonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethyl-ester
(1-Propylcarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäuredimethyle-ster
(1-tert.-Butylcarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dim-ethylester
(1-Ethoxycarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethyl-ester.The invention further relates to the following new substances:
(1-tert-Butylcarbonyloxy-2,2,2-tichloroethane) -phosphonic acid dimethyl ester
(1-methanesulfonyloxy-2,2,2-trichloroethane) -phosphonic acid dimethyl ester-r
(1-ethanesulfonyloxy-2,2,2-trichloroethane) -phosphonic acid dimethyl ester-
(1-Methoxycarbonylo xy-2,2,2-trichloroethane) phosphonic acid dimethyl ester
(1-Acetyloxy-2,2,2-trifluoroethane) phosphonic acid dimethyl ester
(1-methoxycarbonyloxy-2,2,2-trifluoroethane) phosphonic acid dimethyl ester
(1-propylcarbonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester-
(1-methanesulfonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester-r
(1-Dimethylaminocarbonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester
(1-Propylaminocarbonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester
(1-A cetyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-methoxycarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-Dimethylaminocarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
2,2,2-trifluoroethane thio phosphonic acid dimethyl ester
(1-Propylaminocarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-Methanesulfonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-Propylcarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-tert-Butylcarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-Ethoxycarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester.
Die erfindungsgemäß verwendeten Verbindungen der Formel (I) werden hergestellt,
indem man
1-Hydroxy-phosphonsäureester der Formel (II)The compounds of the formula (I) used according to the invention are prepared
by one
1-hydroxy-phosphonic acid ester of the formula (II)
mit Halogenverbindungen der Formel (III)with halogen compounds of the formula (III)
Hal-R² (III)Hal-R² (III)
gegebenenfalls in Gegenwart von säurebindenden Mitteln oder gegebenenfalls in Form der Alkali-, Erdalkali- oder Ammoniumsalze und gegebenenfalls in Gegenwart von Lösemitteln oder, für den Fall, daß R² für Alkylcarbonyl steht, alternativ mit Carbonsäureanhydriden der Formel (IV)optionally in the presence of acid-binding agents or optionally in the form the alkali, alkaline earth or ammonium salts and optionally in the presence of Solvents or, in the event that R² is alkylcarbonyl, alternatively with Carboxylic anhydrides of the formula (IV)
R² -O-R² (IV)R² -O-R² (IV)
gegebenenfalls in Gegenwart katalytischer Mengen Mineralsäure in an sich bekannter Weise umsetzt.optionally in the presence of catalytic amounts of mineral acid in a known manner Implemented wisely.
Die Ausgangsstoffe der Formeln (II), (III) und (IV) sind bekannt oder nach bekannten Methoden herstellbar.The starting materials of the formulas (II), (III) and (IV) are known or according to known ones Methods can be produced.
Das Verfahren zur Herstellung der Verbindungen der Formel (I) durch Umsetzung mit den Halogenverbindungen der Formel (II) wird vorzugsweise unter Verwendung von Verdünnungsmitteln durchgeführt. Als Verdünnungsmittel kommen dabei praktisch alle inerten organischen Lösungsmittel in Frage. Hierzu gehören vorzugsweise aliphatische und aromatische, gegebenenfalls halogenierte Kohlenwasserstoffe wie z. B. Pentan, Hexan, Heptan, Cyclohexan, Petrolether, Benzin, Ligroin, Benzol, Toluol, Methylenchlorid, Ethylenchlorid, Chloroform, Tetrachlorkohlenstoff, Chlorbenzol und Dichlorbenzol, Ether wie z. B. Diethyl- und Dibutylether, Methyl-tert.-butylether und Methyl-tert.- amylether, Glykoldimethylether und Diglykoldimethylether, Tetrahydrofuran und Dioxan, Ketone wie z. B. Aceton, Methyl-ethyl-, Methyl-isopropyl- und Methyl-isobutyl-keton, Ester wie z. B. Essigsäuremethylester und -ethylester, Nitrile wie z. B. Acetonitril und Propionitril, Amide wie z. B. Dimethylformamid, Dimethylacetamid und N-Methyl pyrrolidon, sowie Dimethylsulfoxid, Tetramethylensulfon und Hexamethyl phosphorsäuretriamid.The process for the preparation of the compounds of formula (I) by reaction with the halogen compounds of formula (II) is preferably used using Diluents performed. Practically all of them come as diluents inert organic solvents in question. These preferably include aliphatic ones and aromatic, optionally halogenated hydrocarbons such as. B. pentane, hexane, Heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, Ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and dichlorobenzene, Ethers such as B. diethyl and dibutyl ether, methyl tert-butyl ether and methyl tert.- amyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, Ketones such as B. acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, Esters such as B. methyl acetate and ethyl ester, nitriles such as. B. acetonitrile and Propionitrile, amides such as e.g. B. dimethylformamide, dimethylacetamide and N-methyl pyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethyl phosphoric triamide.
Als Säureakzeptoren können die üblicherweise für derartige Umsetzungen verwendbaren Säurebindemittel eingesetzt werden. Vorzugsweise in Frage kommen Alkalimetall- und Erdalkalimetallhydride, wie Lithium-, Natrium-, Kalium- und Calciumhydrid, Alkali metall- und Erdalkalimetallhydroxide wie Lithium-, Natrium-, Kalium- und Calcium hydroxid, Alkalimetali- und Erdalkalimetallcarbonate und -hydrogencarbonate, wie Natrium- und Kaliumcarbonat oder -hydrogencarbonat sowie Calciumcarbonat, Alkalimetallacetate wie Natrium- und Kaliumacetat, Alkalimetall-alkoholate wie Natrium- und Kalium-tert.-butylat, ferner basische Stickstoffverbindungen wie Trimethylamin, Triethylamin, Tripropylamin, Tributylamin, Ethyldiisopropylamin, Ethyldicyclohexylamin, N,N-Dimethylbenzyiamin, N,N-Dimethylanilin, Pyridin, 2-Methyl-, 3-Methyl-, 4-Methyl-, 2,4-Dimethyl, 2,6-Dimethyl, 4,6-Dimethyl-, 2-Ethyl-, 4-Ethyl- und 5-Ethyl-2-methyl-pyridin, 1,5-Diazabicyclo[4,3,0]nonen (DBN), 1,8- Diazabicycio-[5,4,0]undec-7-en (DBU) und 1,4-Diazabicyclo[2,2,2]octan (DABCO).The acid acceptors which can be used conventionally for such reactions Acid binders are used. Alkali metal and Alkaline earth metal hydrides such as lithium, sodium, potassium and calcium hydride, alkali metal and alkaline earth metal hydroxides such as lithium, sodium, potassium and calcium hydroxide, alkali metal and alkaline earth metal carbonates and hydrogen carbonates, such as Sodium and potassium carbonate or hydrogen carbonate and calcium carbonate, Alkali metal acetates such as sodium and potassium acetate, alkali metal alcoholates such as Sodium and potassium tert-butoxide, also basic nitrogen compounds such as Trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, Ethyldicyclohexylamine, N, N-dimethylbenzyiamine, N, N-dimethylaniline, pyridine, 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl, 2,6-dimethyl, 4,6-dimethyl, 2-ethyl, 4-ethyl and 5-ethyl-2-methyl-pyridine, 1,5-diazabicyclo [4,3,0] nonen (DBN), 1,8- Diazabicycio- [5,4,0] undec-7-ene (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO).
Die Reaktionstemperaturen können in einem größeren Bereich variiert werden. Im all gemeinen arbeitet man bei Temperaturen zwischen 0°C und 100°C, vorzugsweise bei Temperaturen zwischen 10°C und 80°C.The reaction temperatures can be varied over a wide range. In all generally one works at temperatures between 0 ° C and 100 ° C, preferably at Temperatures between 10 ° C and 80 ° C.
Das Verfahren wird im allgemeinen unter Normaldruck durchgeführt. Es ist jedoch auch möglich, unter erhöhtem oder vermindertem Druck zu arbeiten.The process is generally carried out under normal pressure. However, it is also possible to work under increased or reduced pressure.
Zur Durchführung des Verfahrens werden die jeweils benötigten Ausgansstoffe im allgemeinen in angenähert äquimolaren Mengen eingesetzt. Es ist jedoch auch möglich, eine der beiden jeweils eingesetzten Komponenten in einem größeren Überschuß zu verwenden. Die Reaktion wird im allgemeinen in einem geeigneten Verdünnungsmittel in Gegenwart eines Säureakzeptors durchgeführt, und das Reaktionsgemisch wird mehrere Stunden bei der jeweils erforderlichen Temperatur gerührt. Die Aufarbeitung erfolgt nach üblichen Methoden (vergl. die Herstellungsbeispiele).To carry out the process, the starting materials required in each case are generally used in approximately equimolar amounts. However, it is also possible one of the two components used in each case in a larger excess use. The reaction is generally carried out in a suitable diluent Presence of an acid acceptor performed, and the reaction mixture is several Stirred for hours at the required temperature. The processing takes place according to usual methods (see the manufacturing examples).
Das Verfahren zur Herstellung der Verbindungen der Formel (I) durch Umsetzung mit den Carbonsäureanhydriden der Formel (IV) kann auch ohne Verwendung von Verdünnungsmitteln durchgeführt werden. Als Katalysator können alle üblichen Mineralsäuren eingesetzt werden. Vorzugsweise in Frage kommen Schwefelsäure, Salzsäure oder Phosphorsäure. Sie werden in einer Menge von 0,001 bis 10 Mol% eingesetzt. The process for the preparation of the compounds of formula (I) by reaction with the carboxylic anhydrides of the formula (IV) can also be used without Diluents are carried out. All the usual catalysts can be used Mineral acids are used. Sulfuric acid are preferred, Hydrochloric acid or phosphoric acid. They are used in an amount of 0.001 to 10 mol% used.
Die Verbindungen fallen meist in Form von Ölen an, die sich zum Teil nicht unzersetzt destillieren lassen, jedoch durch sogenanntes "Andestillieren", d. h. durch längeres Erhitzen unter vermindertem Druck auf mäßig erhöhte Temperaturen von den letzten flüchtigen Anteilen befreit und auf diese Weise gereinigt werden. Zu ihrer Charakterisierung dient der Brechungsindex. Die kristallinen Verbindungen werden durch ihren Schmelzpunkt charakterisiert.The compounds mostly come in the form of oils, some of which do not decompose Allow to distill, but by so-called "distillation", d. H. through longer Heat under reduced pressure to moderately elevated temperatures from the last volatile components are freed and cleaned in this way. To their The refractive index is used for characterization. The crystalline compounds are characterized by their melting point.
Die Wirksamkeit der beschriebenen Phosphonsäureester bei der Behandlung und Prävention kognitiver und affektiver Störungen wird mit Hilfe von Tiermodellen belegt. Die Testergebnisse zeigen, daß die Verbindungen das Lernverhalten der Tiere wie auch die Retention des Gelernten positiv beeinflussen. Der besondere Vorteil liegt darin, daß die Verbindungen im aktiven Dosisbereich keine Hemmung der Cholinesteraseaktivität im Hirn induzieren. Dies führt zu einer besseren Verträglichkeit verglichen mit procholinergen Referenzsubstanzen, wie z. B. Tetrahydroaminoacridin, Physostigmin oder Metrifonat. Die beschriebenen Phosphonsäureester können daher sowohl zur therapeutischen als auch zur präventiven Behandlung von kognitiven Störungen allgemein, insbesondere von Demenzen des Alzheimer-Typs, verwendet werden.The effectiveness of the described phosphonic acid esters in the treatment and Prevention of cognitive and affective disorders is demonstrated with the help of animal models. The test results show that the compounds improve the learning behavior of the animals as well positively influence the retention of what has been learned. The particular advantage is that the compounds in the active dose range did not inhibit cholinesterase activity induce in the brain. This leads to better tolerability compared to procholinergic reference substances, such as. B. tetrahydroaminoacridine, physostigmine or metrifonate. The phosphonic acid esters described can therefore both therapeutic as well as preventive treatment of cognitive disorders in general, in particular of dementias of the Alzheimer type.
Analog zu den in der Literatur beschriebenen, klinisch aktiven Antidepressiva, führen die beschriebenen Phosphonsäureester im Tierversuch zu einer Verhaltensaktivierung. Auf Grund dieser Ergebnisse sind die Verbindungen auch zur Behandlung affektiver Störungen, insbesondere der Depression geeignet. Wie im Falle der kognitiv verbessernden Wirkung ist auch diese antidepressive Komponente nicht über eine Cholinesterasehemmung zu erklären.Analogous to the clinically active antidepressants described in the literature, the described phosphonic esters in animal experiments to activate behavior. On Because of these results, the compounds are also more affective for the treatment Disorders, particularly suitable for depression. As in the case of the cognitive this antidepressant component does not have an improving effect either To explain cholinesterase inhibition.
Die Erfindung umfaßt ebenfalls pharmazeutische Mittel, die die genannten Verbindungen in einer wirksamen Menge enthalten, deren Herstellung und Verwendung zur Behandlung und Prävention der vorstehenden Krankheiten.The invention also encompasses pharmaceutical compositions containing the compounds mentioned contained in an effective amount, their preparation and use for Treatment and prevention of the above diseases.
Die neuen Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überführt werden, wie Tabletten, Dragees, Pillen, Granulate, Aerosole, Sirupe, Emulsionen und Lösungen, unter Verwendung inerter, nicht toxischer, pharmazeutischer Trägerstoffe oder Lösemittel. Hierbei soll die therapeutisch wirksame Verbindung jeweils in einer Konzentration von etwa 0,5 bis 90 Gew.-% der Gesamtmischung vorhanden sein, d. h. in Mengen, die ausreichend sind, um den angegebenen Dosierungsspielraum zu erreichen. The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, coated tablets, pills, granules, aerosols, syrups, Emulsions and solutions using inert, non-toxic, pharmaceutical Carriers or solvents. Here, the therapeutically effective compound each in a concentration of about 0.5 to 90% by weight of the total mixture be present, d. H. in amounts sufficient to meet the specified Achieve dosage range.
Die Formulierungen werden beispielsweise hergestellt durch Verstrecken der Wirkstoffe mit Lösemitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/oder Dispergiermitteln, wobei z. B. im Fall der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösemittel als Hilfslösemittel verwendet werden können.The formulations are produced, for example, by stretching the active ingredients with solvents and / or carriers, optionally using Emulsifiers and / or dispersants, z. B. in the case of using Water as a diluent, optionally organic solvents as auxiliary solvents can be used.
Die Applikation erfolgt in üblicher Weise, vorzugsweise oral oder parenteral, insbesondere perlingual oder intravenös. Die Applikation kann auch transdermal z. B. durch Pflaster erfolgen. Für den Fall der parenteralen Anwendung können Lösungen des Wirkstoffs unter Verwendung geeigneter flüssiger Trägermaterialien eingesetzt werden.The application is carried out in the usual way, preferably orally or parenterally, especially perlingually or intravenously. The application can also be transdermally z. B. done by plaster. In the case of parenteral use, solutions of the Active ingredient can be used using suitable liquid carrier materials.
Im allgemeinen hat es sich als vorteilhaft erwiesen, bei intravenöser Applikation Mengen von etwa 0,001 bis 1 mg/kg, vorzugsweise etwa 0,01 bis 0,05 mg/kg Körpergewicht zur Erzielung wirksamer Ergebnisse zu verabreichen, und bei oraler Applikation beträgt die Dosierung etwa 0,01 bis 20 mg/kg, vorzugsweise 0,1 bis 10 mg/kg Körpergewicht.In general, it has proven to be advantageous in the case of intravenous administration from about 0.001 to 1 mg / kg, preferably about 0.01 to 0.05 mg / kg body weight for To achieve effective results, and when administered orally, the Dosage about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht bzw. der Art des Applikationsweges, vom individuellen Verhalten gegenüber dem Medikament, der Art der Formulierung und dem Zeitpunkt bzw. dem Intervall, zu welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Menge überschritten werden muß. Im Fall der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen.Nevertheless, it may be necessary from the amounts mentioned deviate, depending on the body weight or the type of Application route, from individual behavior towards the drug, the type the formulation and the time or interval at which administration he follows. So it may be sufficient in some cases, with less than the above Minimum quantity to get by, while in other cases the above mentioned quantity must be exceeded. In the case of application of larger quantities, it can it is advisable to distribute them in several single doses throughout the day.
Zu einer Mischung aus 12,87 g (0,05 Mol) (1-Hydroxy-2,2,2-trichlorethan)- phosphonsäure-dimethylester, 6 g (0,06 Mol) Triethylamin und 100 ml Methylenchlorid tropft man unter Kühlen bei 5°C 6,3 g (0,055 Mol) Methansulfonsäurechlorid und rührt dann 18 Stunden bei Raumtemperatur nach. Man extrahiert das Reaktionsgemisch zweimal mit je 30 ml Wasser. Die organische Phase wird abgetrennt, über Natriumsulfat getrocknet und im Vakuum vom Lösungsmittel befreit. Zurück bleiben 14,5 g (86% d. Th.) (1-Methansulfonyloxy-2,2,2-trichlorethan)-phosphonsäure- dimethylester in Form farbloser Kristalle mit dem Schmelzpunkt 74 bis 75°C.To a mixture of 12.87 g (0.05 mol) (1-hydroxy-2,2,2-trichloroethane) - dimethyl phosphate, 6 g (0.06 mol) triethylamine and 100 ml methylene chloride 6.3 g (0.055 mol) of methanesulfonic acid chloride are added dropwise while cooling at 5 ° C. and the mixture is stirred then after 18 hours at room temperature. The reaction mixture is extracted twice with 30 ml of water each. The organic phase is separated off Dried sodium sulfate and freed from the solvent in vacuo. Stay back 14.5 g (86% of theory) (1-methanesulfonyloxy-2,2,2-trichloroethane) -phosphonic acid- dimethyl ester in the form of colorless crystals with a melting point of 74 to 75 ° C.
Eine Mischung aus 12,87 g (0,05 Mol) (1-Hydroxy-2,2,2-trichlorethan)- phosphonsäure-dimethylester, 60 ml Toluol, 9,5 g (0,05 Mol) Pivalinsäureanhydrid und 0,05 g konz. Schwefelsäure wird 15 Stunden bei 40°C gerührt. Dann gibt man 50 ml gesättigte Natriumhydrogencarbonatlösung zu und rührt so lange weiter, bis die CO₂- Entwicklung aufhört. Die organische Phase wird abgetrennt, über Natriumsulfat getrocknet und im Vakuum eingedampft. Der Rückstand wird über Kieselgel chromatographiert (Eluent: Petrolether/Aceton 7 : 3). Man erhält 6,85 g (40% d.Th.) (1- tert.-Butylcarbonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethyles-ter in Form eines farblosen Öles mit dem Brechungsindex =1.4655.A mixture of 12.87 g (0.05 mol) (1-hydroxy-2,2,2-trichloroethane) - dimethyl phosphate, 60 ml of toluene, 9.5 g (0.05 mol) of pivalic anhydride and 0.05 g conc. Sulfuric acid is stirred at 40 ° C for 15 hours. Then you give 50 ml saturated sodium bicarbonate solution and continue to stir until the CO₂- Development stops. The organic phase is separated off over sodium sulfate dried and evaporated in vacuo. The residue is over silica gel chromatographed (eluent: petroleum ether / acetone 7: 3). 6.85 g (40% of theory) are obtained (1- tert-Butylcarbonyloxy-2,2,2-trichloroethane) -phosphonic acid dimethyl ester in the form of a colorless oil with the refractive index = 1.4655.
Zu einer Mischung aus 5,5 g (0,02 Mol) (1-Hydroxy-2,2,2-trichlorethan)- thiophosphonsäure-dimethylester, 2,5 g (0,025 Mol) Triethylamin und 30 ml Diethylether tropft man unter Kühlen bei 5°C 2,3 g (0,02 Mol) Methansulfonsäurechlorid und rührt dann 3 Stunden bei Raumtemperatur nach. Man extrahiert das Reaktionsgemisch zweimal mit je 20 ml Wasser. Die organische Phase wird abgetrennt, über Natriumsulfat getrocknet und im Vakuum vom Lösungsmittel befreit. Zurück bleiben 6,5 g (86% d. Th.) (1-Methansulfonyloxy-2,2,2-trichlorethan)- thiophosphonsäure-dimethylester in Form farbloser Kristalle mit dem Schmelzpunkt 47,5 bis 50,5°C. To a mixture of 5.5 g (0.02 mol) (1-hydroxy-2,2,2-trichloroethane) - dimethyl thiophosphate, 2.5 g (0.025 mol) of triethylamine and 30 ml Diethyl ether is added dropwise with cooling at 5 ° C. to 2.3 g (0.02 mol) of methanesulfonic acid chloride and then stir for 3 hours at room temperature. You extract that Reaction mixture twice with 20 ml of water. The organic phase is separated off, Dried over sodium sulfate and freed from solvent in vacuo. Back remain 6.5 g (86% of theory) (1-methanesulfonyloxy-2,2,2-trichloroethane) - thiophosphonic acid dimethyl ester in the form of colorless crystals with a melting point of 47.5 up to 50.5 ° C.
Analog einem der Beispiele 1 bis 3 können die folgenden Verbindungen hergestellt werden.The following compounds can be prepared analogously to one of Examples 1 to 3 will.
Claims (10)
R für geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoffatomen steht, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist,
R¹ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoff atomen steht,
R² für Wasserstoff oder geradkettiges oder verzweigtes Alkyl, Alkylcarbonyl, Alkoxycarbonyl oder Alkylsulfonyl mit jeweils bis zu 6 Kohlenstoffatomen in der Alkylgruppe steht, oder für Alkyl- oder Dialkylaminocarbonyl mit jeweils bis zu 4 Kohlenstoffatomen in den Alkylgruppen steht,
R³ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 6 Kohlenstoff atomen
und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹ für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff bedeutet,
deren Salze sowie Isomere,
zur therapeutischen Anwendung.1. Phosphonic acid esters of the general formula in which
R represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by one or more halogen atoms,
R¹ represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl each having up to 6 carbon atoms in the alkyl group, or represents alkyl- or dialkylaminocarbonyl each having up to 4 carbon atoms in the alkyl groups,
R³ for hydrogen or straight-chain or branched alkyl with up to 6 carbon atoms
and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and isomers,
for therapeutic use.
R für geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen oder für Trifluormethyl, Trichlormethyl, Difluormethyl, Dichlormethyl, Fluormethyl, Chlormethyl, Difluorchlormethyl oder Dichlorfluormethyl steht,
R¹ für Wasserstoff oder geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoff atomen steht,
R² für Wasserstoff oder geradkettiges oder verzweigtes Alkyl, Alkylcarbonyl, Alkoxy carbonyl oder Alkylsulfonyl mit jeweils bis zu 4 Kohlenstoffatomen in der Alkylgruppe steht, oder für Alkyl- oder Dialkylaminocarbonyl mit jeweils bis zu 3 Kohlenstoffatomen in den Alkylgruppen steht,
R³ für geradkettiges oder verzweigtes Alkyl mit bis zu 4 Kohlenstoffatomen
und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹ für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff bedeutet,
deren Salze sowie Isomere
zur therapeutischen Anwendung.2. Phosphonic acid ester according to claim 1, wherein
R represents straight-chain or branched alkyl having up to 4 carbon atoms or trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, difluorochloromethyl or dichlorofluoromethyl,
R¹ represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl each having up to 4 carbon atoms in the alkyl group, or represents alkyl- or dialkylaminocarbonyl each having up to 3 carbon atoms in the alkyl groups,
R³ for straight-chain or branched alkyl with up to 4 carbon atoms
and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and isomers
for therapeutic use.
R für Methyl, Chlormethyl, Dichlormethyl, Trichlormethyl, Trifluormethyl, Dichlor fluormethyl oder Difluorchlormethyl steht,
R¹ für Wasserstoff oder Methyl steht,
R² für Wasserstoff, Methyl, Ethyl, Methylcarbonyl, Ethylcarbonyl, Propylcarbonyl, t-Butylcarbonyl, Methoxycarbonyl, Ethoxycarbonyl, Propoxycarbonyl, Methylsulfonyl, Ethylsulfonyl, Propylsulfonyl, Methylaminocarbonyl, Dimethylaminocarbonyl oder für Propylaminocarbonyl steht,
R³ für Methyl, Ethyl oder Propyl steht
und
X für Sauerstoff oder Schwefel steht, jedoch für den Fall, daß R für Trichlormethyl, R¹ für Wasserstoff und R³ für Wasserstoff oder Propylcarbonyl steht, nicht Sauerstoff bedeutet,
deren Salze sowie Isomere
zur therapeutischen Anwendung.3. Phosphonic acid ester according to claim 1, wherein
R represents methyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, dichlorofluoromethyl or difluorochloromethyl,
R¹ represents hydrogen or methyl,
R² stands for hydrogen, methyl, ethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, t-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, methylaminocarbonyl, dimethylaminocarbonyl or for propylaminocarbonyl,
R³ represents methyl, ethyl or propyl
and
X represents oxygen or sulfur, but does not mean oxygen if R represents trichloromethyl, R¹ represents hydrogen and R³ represents hydrogen or propylcarbonyl,
their salts and isomers
for therapeutic use.
(1-tert.-Butylcarbonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethy-lester
(1-Methansulfonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethyleste-r
(1-Ethansulfonyloxy-2,2,2-trichlorethan)-phosphonsäure-dimethylester-
(1-Methoxycarbonylox y-2,2,2-trichlorethan)-phosphonsäure-dimethylester
(1-Acetyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethylester
(1-Methoxycarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethylest-er
(1-Propylcarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-d imethylester
(1-Methansulfonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethyleste-r
(1-Dimethylaminocarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimet-hylester
(1-Propylaminocarbonyloxy-2,2,2-trifluorethan)-phosphonsäure-dimethy-lester
(1-Ac etyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethylester
(1-Methoxycarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethy-lester
(1-Dimethylaminocarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-d-imethylester
2,2,2-Trifluorethan-thiophosphonsäure-dimethylester
(1-Propylaminocarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dim-ethylester
(1-Methansulfonyloxy-2,2,2-tr ichlorethan)-thiophosphonsäure-dimethylester
(1-Propylcarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dimethyl-ester
(1-tert.-Butylcarbonyloxy-2,2,2-trichlorethan)-thiophosphonsäure-dim-ethylester
(1-Ethoxycarbonyloxy-2,2,2-trichlorethan)-t hiophosphonsäure-dimethylester.8. series of phosphonic acid esters
(1-tert-Butylcarbonyloxy-2,2,2-trichloroethane) phosphonic acid dimethyl ester
(1-methanesulfonyloxy-2,2,2-trichloroethane) -phosphonic acid dimethyl ester-r
(1-ethanesulfonyloxy-2,2,2-trichloroethane) -phosphonic acid dimethyl ester-
(1-Methoxycarbonylox y-2,2,2-trichloroethane) phosphonic acid dimethyl ester
(1-Acetyloxy-2,2,2-trifluoroethane) phosphonic acid dimethyl ester
(1-methoxycarbonyloxy-2,2,2-trifluoroethane) phosphonic acid dimethyl ester
(1-Propylcarbonyloxy-2,2,2-trifluoroethane) phosphonic acid dimethyl ester
(1-methanesulfonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester-r
(1-Dimethylaminocarbonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester
(1-Propylaminocarbonyloxy-2,2,2-trifluoroethane) -phosphonic acid dimethyl ester
(1-Acethyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-methoxycarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-Dimethylaminocarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid d-imethyl ester
2,2,2-trifluoroethane thiophosphonic acid dimethyl ester
(1-Propylaminocarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
Dimethyl (1-methanesulfonyloxy-2,2,2-trichloroethane) thiophosphonic acid ester
(1-Propylcarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
(1-tert-Butylcarbonyloxy-2,2,2-trichloroethane) thiophosphonic acid dimethyl ester
Dimethyl (1-ethoxycarbonyloxy-2,2,2-trichloroethane) -t hiophosphonic acid ester.
dadurch gekennzeichnet, daß man
1-Hydroxy-phosphonsäureester der Formel (II) mit Halogenverbindungen der Formel (III)Hal-R² (III)gegebenenfalls in Gegenwart von säurebindenden Mitteln oder gegebenenfalls in Form der Alkali-, Erdalkali- oder Ammoniumsalze und gegebenenfalls in Gegenwart von Lösemitteln oder, für den Fall, daß R² für Alkylcarbonyl steht, alternativ mit Carbonsäureanhydriden der Formel (IV)R²-O-R² (IV)gegebenenfalls in Gegenwart katalytischer Mengen Mineralsäure in an sich bekannter Weise umsetzt.9. A process for the preparation of phosphonic acid esters according to claim 8,
characterized in that one
1-hydroxy-phosphonic acid ester of the formula (II) with halogen compounds of the formula (III) Hal-R² (III), if appropriate in the presence of acid-binding agents or if appropriate in the form of the alkali metal, alkaline earth metal or ammonium salts and if appropriate in the presence of solvents or, if R 2 is alkylcarbonyl, alternatively with carboxylic anhydrides of the formula (IV) R²-O-R² (IV), if appropriate in the presence of catalytic amounts of mineral acid, in a manner known per se.
Priority Applications (19)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19616471A DE19616471A1 (en) | 1996-04-25 | 1996-04-25 | Phosphonic acid ester for the treatment of brain disorders and depression |
| CA002252567A CA2252567A1 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| EP97920431A EP0896540A1 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| PL97333464A PL333464A1 (en) | 1996-04-25 | 1997-04-17 | Application of phosphonic esters in treatment and prophylactics of cerebral functional disorders and depressions |
| JP09538197A JP2000510455A (en) | 1996-04-25 | 1997-04-17 | Use of phosphonates for the treatment of brain dysfunction and depression |
| SK1463-98A SK146398A3 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| TR1998/02137T TR199802137T2 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters in relation to functional dysregulations of the brain and depression. |
| BR9709300A BR9709300A (en) | 1996-04-25 | 1997-04-17 | Application of phosphonic acid esters for the treatment of functional brain diseases and depression |
| KR1019980708502A KR20000010611A (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| IL12669897A IL126698A0 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| HU9903366A HUP9903366A3 (en) | 1996-04-25 | 1997-04-17 | Phosphonic acid ester derivatives, method for producing them and medicaments containing the same |
| PCT/US1997/006469 WO1997039756A1 (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression |
| AU24623/97A AU2462397A (en) | 1996-04-25 | 1997-04-17 | Use of phosphonic acid esters for the treatment of functional disorder s of the brain and depression |
| CZ983434A CZ343498A3 (en) | 1996-04-25 | 1997-04-17 | Esters of phosphonic acid, process of their preparation, pharmaceutical composition and use of these compounds for treating functional disorders of brain and depressions |
| ZA9703538A ZA973538B (en) | 1996-04-25 | 1997-04-24 | Use of phosphonic acid esters for the treatment of functional disorders of the brain and depression. |
| IDP971362A ID16678A (en) | 1996-04-25 | 1997-04-24 | USE OF PHOSPHORIC ESTER ACID FOR TREATMENT OF FUNCTIONS OF DISEASES IN THE BRAIN AND DEPRESSION |
| ARP970101724A AR006870A1 (en) | 1996-04-25 | 1997-04-25 | PHOSPHONIC ACID ESTERS FOR THE TREATMENT OF FUNCTIONAL DISORDERS OF THE BRAIN AND DEPRESSION, PROCEDURE FOR THE PREPARATION OF THE SAME, DRUGS THAT CONTAIN THEM, USE OF THE COMPOUNDS FOR THE PREPARATION OF DRUGS |
| BG102864A BG102864A (en) | 1996-04-25 | 1998-10-22 | Application of phosphonic acid esters for the treatment of functional disorders of the brain and depressions |
| NO984964A NO984964L (en) | 1996-04-25 | 1998-10-23 | Use of phosphonic esters for the treatment of functional disorders of the brain and in depression |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19616471A DE19616471A1 (en) | 1996-04-25 | 1996-04-25 | Phosphonic acid ester for the treatment of brain disorders and depression |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19616471A1 true DE19616471A1 (en) | 1997-10-30 |
Family
ID=7792381
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19616471A Withdrawn DE19616471A1 (en) | 1996-04-25 | 1996-04-25 | Phosphonic acid ester for the treatment of brain disorders and depression |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0896540A1 (en) |
| JP (1) | JP2000510455A (en) |
| KR (1) | KR20000010611A (en) |
| AR (1) | AR006870A1 (en) |
| AU (1) | AU2462397A (en) |
| BG (1) | BG102864A (en) |
| BR (1) | BR9709300A (en) |
| CA (1) | CA2252567A1 (en) |
| CZ (1) | CZ343498A3 (en) |
| DE (1) | DE19616471A1 (en) |
| HU (1) | HUP9903366A3 (en) |
| ID (1) | ID16678A (en) |
| IL (1) | IL126698A0 (en) |
| NO (1) | NO984964L (en) |
| PL (1) | PL333464A1 (en) |
| SK (1) | SK146398A3 (en) |
| TR (1) | TR199802137T2 (en) |
| WO (1) | WO1997039756A1 (en) |
| ZA (1) | ZA973538B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1078370B (en) * | 1958-09-16 | 1960-03-24 | Norddeutsche Affinerie | Pest repellants |
| US3069312A (en) * | 1960-09-28 | 1962-12-18 | California Research Corp | N-substituted dimethyl 1-carbamoyloxy-2, 2, 2-trichloroethyl phosphonates as insecticidal compositions |
| BE632366A (en) * | 1962-05-16 | 1900-01-01 | ||
| DE1193044B (en) * | 1963-08-05 | 1965-05-20 | Bayer Ag | Process for making phosphorylated urethanes |
| DE2512375A1 (en) * | 1975-03-21 | 1976-09-30 | Bayer Ag | 1-HYDROXY-2,2,2-TRICHLORAETHANE THIONOPHOSPHONIC ACID DIAL KYLESTER, METHOD FOR THEIR PRODUCTION AND THEIR USE AS INSECTICIDES |
| US4950658A (en) * | 1988-12-06 | 1990-08-21 | Board Of Trustees Of Southern Illinois Univ. | Method of medical treatment of Alzheimer's disease |
-
1996
- 1996-04-25 DE DE19616471A patent/DE19616471A1/en not_active Withdrawn
-
1997
- 1997-04-17 WO PCT/US1997/006469 patent/WO1997039756A1/en not_active Application Discontinuation
- 1997-04-17 PL PL97333464A patent/PL333464A1/en unknown
- 1997-04-17 IL IL12669897A patent/IL126698A0/en unknown
- 1997-04-17 KR KR1019980708502A patent/KR20000010611A/en not_active Application Discontinuation
- 1997-04-17 TR TR1998/02137T patent/TR199802137T2/en unknown
- 1997-04-17 HU HU9903366A patent/HUP9903366A3/en unknown
- 1997-04-17 EP EP97920431A patent/EP0896540A1/en not_active Withdrawn
- 1997-04-17 SK SK1463-98A patent/SK146398A3/en unknown
- 1997-04-17 CA CA002252567A patent/CA2252567A1/en not_active Abandoned
- 1997-04-17 CZ CZ983434A patent/CZ343498A3/en unknown
- 1997-04-17 AU AU24623/97A patent/AU2462397A/en not_active Abandoned
- 1997-04-17 JP JP09538197A patent/JP2000510455A/en active Pending
- 1997-04-17 BR BR9709300A patent/BR9709300A/en not_active Application Discontinuation
- 1997-04-24 ZA ZA9703538A patent/ZA973538B/en unknown
- 1997-04-24 ID IDP971362A patent/ID16678A/en unknown
- 1997-04-25 AR ARP970101724A patent/AR006870A1/en unknown
-
1998
- 1998-10-22 BG BG102864A patent/BG102864A/en unknown
- 1998-10-23 NO NO984964A patent/NO984964L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2462397A (en) | 1997-11-12 |
| KR20000010611A (en) | 2000-02-25 |
| IL126698A0 (en) | 1999-08-17 |
| NO984964L (en) | 1998-12-22 |
| WO1997039756A1 (en) | 1997-10-30 |
| ID16678A (en) | 1997-10-30 |
| BG102864A (en) | 1999-09-30 |
| SK146398A3 (en) | 1999-06-11 |
| TR199802137T2 (en) | 1999-02-22 |
| CA2252567A1 (en) | 1997-10-30 |
| JP2000510455A (en) | 2000-08-15 |
| HUP9903366A2 (en) | 2000-07-28 |
| HUP9903366A3 (en) | 2000-08-28 |
| NO984964D0 (en) | 1998-10-23 |
| ZA973538B (en) | 1997-11-18 |
| CZ343498A3 (en) | 1999-02-17 |
| BR9709300A (en) | 1999-08-10 |
| PL333464A1 (en) | 1999-12-20 |
| AR006870A1 (en) | 1999-09-29 |
| EP0896540A1 (en) | 1999-02-17 |
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Legal Events
| Date | Code | Title | Description |
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| 8127 | New person/name/address of the applicant |
Owner name: MAURER, FRITZ, DR., 40789 MONHEIM, DE |
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| 8139 | Disposal/non-payment of the annual fee |