CA2138331A1 - Use of phosphoric acid esters and phosphonic acid esters for treating disorders of cognitive function and depressions - Google Patents
Use of phosphoric acid esters and phosphonic acid esters for treating disorders of cognitive function and depressionsInfo
- Publication number
- CA2138331A1 CA2138331A1 CA002138331A CA2138331A CA2138331A1 CA 2138331 A1 CA2138331 A1 CA 2138331A1 CA 002138331 A CA002138331 A CA 002138331A CA 2138331 A CA2138331 A CA 2138331A CA 2138331 A1 CA2138331 A1 CA 2138331A1
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- pyrimidin
- tert
- butyl
- carbon atoms
- 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.)
- Abandoned
Links
- 150000003008 phosphonic acid esters Chemical class 0.000 title claims abstract description 21
- 230000003920 cognitive function Effects 0.000 title claims abstract description 11
- 150000003014 phosphoric acid esters Chemical class 0.000 title claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 39
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 150000005690 diesters Chemical class 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 150000005691 triesters Chemical class 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- -1 phosphoryl halides Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000008081 1H-pyrimidin-4-ones Chemical class 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 230000000875 corresponding effect Effects 0.000 claims 1
- 208000035475 disorder Diseases 0.000 abstract description 6
- 230000004970 emotional disturbance Effects 0.000 abstract description 2
- 208000024827 Alzheimer disease Diseases 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000012549 training Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 241001465754 Metazoa Species 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- KNCHDRLWPAKSII-UHFFFAOYSA-N 4-ethyl-2-methylpyridine Chemical group CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- 230000009182 swimming Effects 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- WTRJNJSYUUFXIL-UHFFFAOYSA-N 2-tert-butyl-4-methoxy-1h-pyrimidin-6-one Chemical compound COC1=CC(O)=NC(C(C)(C)C)=N1 WTRJNJSYUUFXIL-UHFFFAOYSA-N 0.000 description 2
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 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
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 101150114843 Mgll gene Proteins 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
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 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
- 238000010171 animal model Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 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
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000001145 hydrido group Chemical class *[H] 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N n-cyclohexyl-n-ethylcyclohexanamine Chemical compound C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
- 150000002830 nitrogen compounds Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 125000006368 phosphonoyl group Chemical group [*:1]P([*:2])=O 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
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 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
- 230000003449 preventive effect Effects 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
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 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
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
The use of phosphoric acid esters and phosphonic acid esters for treating disorders of cognitive function and depressions Abstract The present invention relates to the use of phosphoric acid esters and phosphonic acid esters for preparing medicaments for the treatment of disorders of cognitive function and of emotional disturbances, in particular of Alzheimers disease, and of depressions.
Description
` 2138331 ;`
, ., ~
The invention relates to the use of phosphoLlc acid esters and phosphonic acid esters for the treatment and prevention of disorders of co~nitive function and depressions, and to pharmaceutical agents and their preparation.
DE 2 642 981, DE 2 209 554, EP 305 840 and EP 279 259 disclose phosphoric acid esters and phosphonic acid esters which are employed for controlling insects.
It has now been found that phosphoric acid esters and 10 phosphonic acid esters of the general.formula (I) . .:.
X
Il ~OR
XJ~N (I) ~ ~`
R3 NJ\R2 in which R - represents straight-chain or branched alkyl having up to 6 carbon atoms, Rl - represents straight-chain or branched alkyl or .
lS alkoxy having up to 6 carbon atoms, R2 _ represents hydrogen, or . -:-' ~: :: ~,:. `
~. ~
''`,'`.,'','.' '-''`...:-'`".'' . : ' :~ . '~` -` ,' ~ :, :: ': .: :` ' - :' : ::: :.: ':
q~P102 - 1- ;~.. ;:'`"'`'.. `.'.'.-'`
21~83~1 .
represents straight-chain or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms, or represents dialkylamino having up to.4 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 7 carbon atoms, R3 - represents straight-chain or branched alkoxy or ;~
alkyl having up to 6 carbon atoms which can be substituted by alkoxy having up to 4 carbon atoms, or represents hydrogen, R~ - represents halogen, hydrogen or straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, and X -- denotes oxygen or sulphur, and their physiologically tolerated salts, as well as their isomers, can be employed for the treatment and prevention of disorders of cognitive function and ,, 20 depressions. .
On the basis of the experimental results, the compounds of the formula (I) are suitable for the treatment and ::~
prevention of disorders of cognitive . function, in par~
ticular for the treatment of senile and presenile '`'', '' ~ ,''''''''`'~
,' "~ ' '' ,~',' ,' '- ' ' `,','`, `',.`' ~`,''', TP 1_2 - 2 -. - - ~.: .:
dementia, dementia of the Alzheimer type, AIDS-related dementia, cognitive deficiencies in cases of Parkinson's disease or consequence of infarction events, and for the treatment 5 of depressions. ~ :-: .:::
:: :.: : .
Particularly suitable for treating and preventing dis~
orders of cognitive function and depressions are those compounds of the formula (I) in which ~ ;
::
10 R represents straight-chain or branched alkyl -~
having up to 4 carbon atoms, ;~
R~ represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, R2 represents hydrogen,.or represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or ::
represents dialkylamino having in each case up to 3 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 6 carbon .`
atoms, :~
R3 represents straight-chain or branched alkyl or ; ~.
alkoxy having up to 4 carbon atoms, or represents .--:
methoxymethyl, or represents hydrogen,:~
. .,,..... - .,~i.
''. :'-'','' TP 102 ~ 3 ~
;: ~.. ,'.. ,.~ `, :,',.
` 21~3~1 R4 represents hydrogen or methoxy, and .
X represents sulphur, ;~
and salts thereof.
5 Particularly preferably used are compounds of the formula , ~ . .; ,, in which R represents methyl, R' represents methyl, ethyl, propyl or methoxy, 10 R2 represents cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, or represent~ methoxy or ethoxy, or represents dimethylamino, R3 represent~ methyl, ethyl, alkoxy having up to 4 carbon atoms or methoxymethyl, R4 represents hydrogen or methoxy, and 6alts thereof.
Over and above this, the present invention relates to the .~. ..' - ' ` ~' TP 102 - 4 ~
.,,~ ~ . ~ . . .
, ., ~
The invention relates to the use of phosphoLlc acid esters and phosphonic acid esters for the treatment and prevention of disorders of co~nitive function and depressions, and to pharmaceutical agents and their preparation.
DE 2 642 981, DE 2 209 554, EP 305 840 and EP 279 259 disclose phosphoric acid esters and phosphonic acid esters which are employed for controlling insects.
It has now been found that phosphoric acid esters and 10 phosphonic acid esters of the general.formula (I) . .:.
X
Il ~OR
XJ~N (I) ~ ~`
R3 NJ\R2 in which R - represents straight-chain or branched alkyl having up to 6 carbon atoms, Rl - represents straight-chain or branched alkyl or .
lS alkoxy having up to 6 carbon atoms, R2 _ represents hydrogen, or . -:-' ~: :: ~,:. `
~. ~
''`,'`.,'','.' '-''`...:-'`".'' . : ' :~ . '~` -` ,' ~ :, :: ': .: :` ' - :' : ::: :.: ':
q~P102 - 1- ;~.. ;:'`"'`'.. `.'.'.-'`
21~83~1 .
represents straight-chain or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms, or represents dialkylamino having up to.4 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 7 carbon atoms, R3 - represents straight-chain or branched alkoxy or ;~
alkyl having up to 6 carbon atoms which can be substituted by alkoxy having up to 4 carbon atoms, or represents hydrogen, R~ - represents halogen, hydrogen or straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, and X -- denotes oxygen or sulphur, and their physiologically tolerated salts, as well as their isomers, can be employed for the treatment and prevention of disorders of cognitive function and ,, 20 depressions. .
On the basis of the experimental results, the compounds of the formula (I) are suitable for the treatment and ::~
prevention of disorders of cognitive . function, in par~
ticular for the treatment of senile and presenile '`'', '' ~ ,''''''''`'~
,' "~ ' '' ,~',' ,' '- ' ' `,','`, `',.`' ~`,''', TP 1_2 - 2 -. - - ~.: .:
dementia, dementia of the Alzheimer type, AIDS-related dementia, cognitive deficiencies in cases of Parkinson's disease or consequence of infarction events, and for the treatment 5 of depressions. ~ :-: .:::
:: :.: : .
Particularly suitable for treating and preventing dis~
orders of cognitive function and depressions are those compounds of the formula (I) in which ~ ;
::
10 R represents straight-chain or branched alkyl -~
having up to 4 carbon atoms, ;~
R~ represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, R2 represents hydrogen,.or represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or ::
represents dialkylamino having in each case up to 3 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 6 carbon .`
atoms, :~
R3 represents straight-chain or branched alkyl or ; ~.
alkoxy having up to 4 carbon atoms, or represents .--:
methoxymethyl, or represents hydrogen,:~
. .,,..... - .,~i.
''. :'-'','' TP 102 ~ 3 ~
;: ~.. ,'.. ,.~ `, :,',.
` 21~3~1 R4 represents hydrogen or methoxy, and .
X represents sulphur, ;~
and salts thereof.
5 Particularly preferably used are compounds of the formula , ~ . .; ,, in which R represents methyl, R' represents methyl, ethyl, propyl or methoxy, 10 R2 represents cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, or represent~ methoxy or ethoxy, or represents dimethylamino, R3 represent~ methyl, ethyl, alkoxy having up to 4 carbon atoms or methoxymethyl, R4 represents hydrogen or methoxy, and 6alts thereof.
Over and above this, the present invention relates to the .~. ..' - ' ` ~' TP 102 - 4 ~
.,,~ ~ . ~ . . .
2 1 3 ~
. .
novel substances which are listed below:
0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, -0-(6-n-Butyloxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- ~:
thionoethanephosphonic acid diester, 0-~6-Methyl-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionopropanephosphonic acid diester, ~ :
10 0-(6-Methyl-2-isopropyl-pyrimidin-4-yl)-0-methyl- :
thionomethanephosphonic acid diester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- .
thionoethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- ~ -thionomethanephosphonic acid diester, . `.
0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Methyl-2-cyclopropyl-pyri m; din-4-yl)-0,0-dimethyl- :~
thionophosphoric acid triester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl- : -thionophosphoric acid triester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl~
thionophosphoric acid triester, 0-(6-Propoxy-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-. ~ ,. . --: .:
~ .''`'. ~''' ''' " ' ''' ~ 5 --' ::: :
2 ~ 3 1 : ; ~
thionophosphoric acid triester, 0-(5-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester. -~
The novel and known compounds of the formula (I), used in ~-accordance with the invention, are prepared by [A] Reacting phosphonoyl or phosphoryl halides of the formula (II) . .~ - .
H I l ~OR
a~
D ~ ~: ::: ~ - .:.:
in which R, Rl and X have the given meaning, and Hal represents halogen, preferably chlorine, .. ..... ~, -: -: ~ -with 4-hydroxy-pyrimidines of the formula (III) OH
R3 N~R2 (111 in which R2, R3 and R4 have the given meaning, optionally in the presence of acid-binding agents or : ~
. ~-` 2i38331 .
optionally in the form of the alkali metal, alkaline earth metal or ammonium salts and optionally in the presence of solvents.
The starting compounds of the formulae (II) and (III) are known or can be prepared by known methods.
The process for preparing the compounds of the formula (I) is preferably carried out using diluents. Practically all inert organic solvents are suitable for use a6 diluents in this context. The solvents preferably include aliphatic and aromatic, optionally halogenated hydro~
carbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloro-form, carbon tetrachloride, chlorobenzene and o-dichloro-benzene, ethers, such as diethyl ether, dibutyl ether,glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, esters, such as methyl acetate and ethyl acetate, nitriles, such as, for example, acetonitrile and propionitrile, amides, such as, for example, dimethyl-for ~ de, dimethylacet~m;de and N-methylpyrrolidone, as well as dimethyl sulphoxide, tetramethylene sulphone and hexamethylphosphoric triamide.
~ 25 Acid-binding agents which are customarily utilizable for ;~ reactions of this nature may be employed as acid ~ acceptors. Those which are preferable are alkali metal ~ , . ~ . .
21383~1 hydrides and alkaline earth metal hydrides, such as lithium, sodium, potassium and calcium hydride, alkali metal hydroxides and alkaline earth metal hydroxides, such as lithium, sodium, potassium and calcium hydroxide, alkali metal carbonates and hydrogen carbonates and alkaline earth metal carbonates and hydrogen carbonates, such as sodium carbonate or sodium hydrogen carbonate and potassium carbonate or potassium hydrogen carbonate, as well as calcium carbonate, alkali metal acetates, such as sodium and potassium acetate, alkali metal alcoholates, such as sodium and potassium tert-butoxide, and, additionally, basic nitrogen compounds, such as tri~
methylamine, triethylamine, tripropylamine, tributyl-amine, t.riisobutylamine, ethyldiiso-propylamine, ethyldicyclohexylamine, N,N-dimethylbenzyl-amine, N,N-dimethyl-aniline, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 2,6-dimethyl-, 2-ethyl-, 4-ethyl- and 5-ethyl-2-methyl-pyridine, 1,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 1,8-diazabicyclo-[5.4.0~-undec-7-ene (DBU) and 1,4-diaza-bicyclo-t2.2.2]-octane (DABCO).
The reaction temperatures can be varied over a relatively wide range. In general, temperature of between 0C and 100C, preferably temperatures of between 10C and 80C, are employed.
In general, the process is carried out under standard pressure. However, it is also possible to carry it out under elevated or reduced pressure.
! : .
-TP 102 - 8 - ~ ~
:. .:
. ' ' . .
21~8331 For carrying out the process, the starting compounds ~ A .:
which are required in each case are generally employed in approximately equimolar quantities. However, it is also possible to use one of the two components employed in 5 each case in a relatively large excess. In general, the ~ ;
reaction is carried out in a suitable diluent in the presence of an acid acceptor, and the reaction mixture is stirred for several hours at the temperature which is required on each occasion. The working up is in each case effected in accordance with the customary methods (cf.
the preparation examples). -~
In most cases, the compounds result in the form of oils, some of which cannot be distilled without decomposing;
however, these oils can be freed of the remaining vola~
tile constituents, and in this way purified, by so-called ~incipient distillation~, i.e. by being heated for a relatively long time, under reduced pressure, at mode-rately elevated temperatures. They are characterized on `-the basis of their refractive indices. `-The efficacy of the compounds of the formula (I) in the treatment and prevention of disorders of cerebral function is verified using an animal model which is based on spatial memory. In this test, originally described by Morris (R.G.M. Morris, J. Neurosci. Methods 11: 47-60, 1984), rats have to learn to locate a platform which they cannot see and which represents the only possible route of escape from a pool of water. For this, the animals (young, adult male rats, approximately 3 months old) are . ': ~:
TP 102 - 9 - ~
21~8331 given 4 training runs a day over a period of 3 days. The latency to locate the platform, and the distance covered, are the parameters which are measured.
As training progresses, both the escape latency and the distance swum diminish as the result of the acquisition of a strategy for spatially locating the goal. The effect of test substances in improving cognitive power is manifested in an acceleration of the time required for the learning process, i.e. the learning curve becomes steeper. Test substances are administered once a day (60 min prior to the first training run). Control animals receive an equivalent quantity of the vehicle.
":
At the end of the training phase, i.e. once the 12th training run has been completed, the platform is taken out of the water and it is investigated, in a further swimming experiment, whether the experimental animals look for the platfoxm in a defined naxrow area around the training position of the platform (retention test). - -~-The test results demonstrate that the described compounds have a positive influence both on the learning behaviour of the animals and on the retention of that which has been learnt. The esters described can, therefore, be used both for the therapeutic and the preventive treatment of cognitive disturbances in general, and of dementias of the Alzheimer type in particular.
The efficacy of the compounds of the formula (I) in the ~- -treatment and prevention of depressions is verified using '' ~
' ~ ~:
. ~' the "Rat Forced Swimming Test". This behavioural model was described for the first time by Porsolt et al. (R.D.
Porsolt, M. Le Pichon, M. Jalfre, Nature 266: ~30-732, 1977), and is nowadays a generally recognized in-vivo screening model for identifying novel antidepressants. It is based on the observation that, in a situation where there is no escape, rats persist in an immobile attitude ("behavioural despair"). In a pretest session, young adult rats (3-4 months old) are placed individually for 20 min in glass cylinders (height 40 cm, diameter 20 cm) which are filled with water to a height of 15 cm.
24 h after this pretest session , the animals are once again transferred into the cylinders and the duration of immobility is measured over a period of 5 min. The described esters are administered in the time interval between the two swimming sessions . Controls are given the vehicle.
In an analogous manner to clinically active antidepres~
sants described in the literature, the compounds of the formula (I) decrease the duration of immobility and lead to behavioural activation. On the basis of these results, the tescribed compounds are also suitable for use in the treatment of emotional disturbances, in particular of depression.
I . -: ~ . .:
~: . , :, , ,:,:
' ~ : ' :, TP 102 - ll -~: - :' ~---............................. . .
. .
2 1 3 8 3 ~
Te s t r e s u l t s ~
Il/C;~13 R, ~ N
R3 N C4H9-t . ._ .. . ~ . = ED o . ~ cn or~lly acti ve doses, .
~atForced given.orally . . .___ . Swim Test Mo~rts Ma7e . . --CH~ -OCH7 0.11 mg/kg 0.~1 mgll~g_ -C~Hc -OCHl 3.0 m~g 30 mg/kg -CH~ -CHl 0.24 mg~C~ 0.14.3 mg/l~g -C2H5 OC4Hg-n 0.17 mg/~g 0.1 mgll~g -CH3 ~C3Hrn 0.015 mg/k~5 not tested .... _ _ ..... . _ . l -C~H~ ~C3Hrn 0.014 mg/~g ~
-__ ~
-OCH3 -OCH3 0.55 mg/kg1-3 mg/kg -OCH3 -OC2H5 2.3 mglkg not~¦
-OCH3 -OC3H7 1.3 mg/kg 1-3 n~g/kg : -~ . " ~ . ~ . _ _ ,: , ': ' The invention likewise embraces pharmaceutical : -compositions which contain an effective quantity of the ;- .
said compounds, and the preparation and use of these : ~ :::
5 compositions for treating and preventing the abovemen~
tioned diseases.
The novel active compounds may be .converted in a known . ::
manner, into the customary formulations, such as tablets, .. ~
': ::
,, ~
~ ;~: TP 102 - 12 ~
.. .. .' ~ .
., . . ,, . ., ~, . . . .
2138331 ~:
coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inërt, non~
toxic, pharmaceutically suitable carrier substances or solvents. In this context, the therapeutically active 5 compound should in each case be present in a concen- ~ s tration range of approximately 0.5 to 90% by weight of the total mixture, i.e. in quantities which are sufficient to provide the given dosage scope.
The formulations are prepared, for example, by extending 10 the active compounds with solvents and/or carrier sub-stances, where appropriate ùsing emulsifying agents -~
and/or dispersing agents, it being possible, for example when using water as a diluent, to use organic solvents or `solubilizing agents where this is appropriate.
15 Administration is effected in a customary manner, prefer-ably orally or parenterally, in particular perlingually or intravenously. Transdermal administration is also possible, for example using a plaster.
. . ~
When the parenteral route is used, solutions of the 20 active compound can be employed which make use of suit- -able carrier materials.
In general, it has been found to be advantageous to administer quantities of about 0.001 to 1 mg/kg, preferably 0.01 to 0.5 mg/kg, of body weight in order to achieve effective results in the case of intravenous administration, while, in the case of oral ":-. : .' ' . '' ':
21~8331 ~: ~
. , . . ~
administra~ion, the dosage is about 0.01 to 20 mg/kg, preferahly 0.1 to 10 mg/kg, of body weight. ;~
Despite this, it can, where appropriate, be necessary to deviate from the said quantities, depending on the body weight and the nature of the route of admlnistration, on the individual reaction to the medicament, on the nature of its formulation and on the time or interval at which administration -is effected. Thus, in some cases, it can be sufficient to administer less than the abovementioned lowest quantity while, in other cases, the said upper limit has to be exceeded. Where relatiyely large quantities are being administered, it can be advisable to divide these into several smaller doses given over -~ --the course of the day.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for the treatment of diseases of the cognitlve function and depression.
' ' 2 1 3 8 ~ 3 i . .. ~
Preparation examples~
~xample 1 Il /OCH3 ; ~ ~ ~
O--P ~
~N CH3 CH30N~C4H9-tert. , .,- -7.3 g (0.05 mol) of thionomethanephosphonoyl chloride methyl ester are added, at 20C and while stirring, to a mixture of 9.1 g (0.05 mol) of 4-hydroxy-6-methoxy-2 tert-butyl-pyrimidine (preparation, see EP 279 259), 10.3 g (0.075 mol) of potassium carbonate and 80 ml of acetonitrile. The reaction mixture is subsequently ~tirred at 20C for 15 hours and the solvent i8 then distilled off in vacuo. The residue is taken up in 100 ml of methyl tert-butyl ether, and this mixture is washed twice with 50 ml of water on each occasion, dried with sodium sulphate and filtered. The ~olvent i~ distilled off from the filtrate in vacuo at approximately 50C.
., ~
7.7 g (53% of theory) of 0-(6-methoxy-2-tert-butyl~
pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester are obtained as an oily residue having a refractive index n23 of 1.5121.
~''-'' ~'~.:-' ` 213~3~1 -,~
Example 2~
II ~OCH3 ,~ C2Hs n-C4Hg-O N~C4Hg~tert.
6.85 g (0.05 mol) of n-butyl bromide are added, at 20C
and while stirring, to a mixture of 11.6 g (0.04 mol) of 0-(6-hydroxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester (preparation, seeBP 279 259~, 6.9 g (0.05 mol) of potassium carbonate and ml of acetonitrile. The reaction mixture is subsequently stirred at 20C for 15 hours and the solvent is then distilled off in vacuo. The residue is taken up in 100 ml of methyl tert-butyl ether, and this mixture i5 washed once with 50 ml of a 5 percent solution of sodium hydroxide and once with 50 ml of water, dried with sodium sulphate and filtered. The solvent is distilled from the filtrate in vacuo at approximately 50C.
6.55 g (47% of theory) of 0-(6-n-butyloxy-2-tert-butyl~
pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester are obtained as an oily residue having a refrac~
tive index n25 of 1.4961.
: :
`~ .`
The following compounds of the formula Il~OR
4~ P~R~
R3~NJ~R2 ;, l .. ,.~__ ___ EL R Rl R2 R3 R' X Rd~ve -~
N~ . (~rc I _ _ "~
1 3 CH3 CH3 L-C~Hg ~H3 H S 15092/27 . . ~ ~ ~
4 CH3 n C3H7 L-C4H9 OCH~ H S 15042/23 S CH3 CH3 i-C3H7 -CH3 H S
6 CH3 CH3 ~ C~H~ ~ H S 1.5058/20 7 CH~ C~ ~ C4Hs OC~H7~) H S 1.5028/20 ~ ;
8 CH3 CH3 t.-C~T{9 -OC~H7(n) H S 1.5032/20 : ~
_ ... . : -, .::-:
9 CH3 C~3 ~ C~H9 -OC4~(n) H S 1.4987/23 are obtained in analogy with ~xample 1 -. -:
~ . ': :, : '~ . .;
-: ~
, ~ ~ - .. ..
:- -: -:. :.
. :: ~;
21~8~
Preparation examples:
~xample_10 Il ~OCH3 O-P~ .
,~ OCH3 CH30 NJ\C4Hg-tert. ;; ~ ~;
16 g (0.1 mol) of thionophosphoryl chloride dimethyl ester are added, at 20C and while stirringr to a mixture of 18.2 g (0.10 mol) of 4-hydroxy-6-methoxy-2-tert-butyl-pyrimidine, 20.8 g (0.15 mol) of potassium carbonate and ` ~ ~`
80 ml of acetonitrile. The reaction mixture i~ subse-guently ~tirred at 20C for 15 hours and the solvent i8 then di6tilled off in vacuo. The re~idue is taken up in 100 ml of toluene and this mixture is washed twice with 100 ml of water on each occasion, dried with sodium sulphate and filtered. The solvent is distilled off from the filtrate in vacuo at approximately 50C. The residue is freed of volatile constituents at 70C under high vacuum.
27.6 g (90% of theory) of 0-(6-methoxy-2-tert-butyl~
pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester are obtained as an oily residue having a refrac~
tive index n2' of 1.5069. ;~
.
;~ TP_102 - 18 -, ,'. .:
21383~
:.
The following compounds of the ~ormula Il OR - ~ ;
O--P~
R4~N OR
R~ R Rl R~ ~3R~ X _ _ C~l, CH, --~¦ C13, H S
12 CH3 Cll, C4Hg~ C,ll,O _ S lA970/20 13 CH3 CH3 C~Hg t st. Il-C3H,0 H S lA9~6/20 i ~ .
14 CH3 C~3 C~H9 t~rL Il-C~H90 H S
L~
_ _ _ . ., .. ,.,.,. :_ __ ::
are obtained in analogy with Example 1 . ~ ~ . . - ,.
,: "
. :.- -:. -.:: ~ -:
: ~' ' . ' - ' .;~-..~,..- ~.,:' :~ TP 102 - 19 - ~
. .
novel substances which are listed below:
0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, -0-(6-n-Butyloxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- ~:
thionoethanephosphonic acid diester, 0-~6-Methyl-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionopropanephosphonic acid diester, ~ :
10 0-(6-Methyl-2-isopropyl-pyrimidin-4-yl)-0-methyl- :
thionomethanephosphonic acid diester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- .
thionoethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl- ~ -thionomethanephosphonic acid diester, . `.
0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thiono-methanephosphonic acid diester, 0-(6-Methyl-2-cyclopropyl-pyri m; din-4-yl)-0,0-dimethyl- :~
thionophosphoric acid triester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl- : -thionophosphoric acid triester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl~
thionophosphoric acid triester, 0-(6-Propoxy-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-. ~ ,. . --: .:
~ .''`'. ~''' ''' " ' ''' ~ 5 --' ::: :
2 ~ 3 1 : ; ~
thionophosphoric acid triester, 0-(5-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester. -~
The novel and known compounds of the formula (I), used in ~-accordance with the invention, are prepared by [A] Reacting phosphonoyl or phosphoryl halides of the formula (II) . .~ - .
H I l ~OR
a~
D ~ ~: ::: ~ - .:.:
in which R, Rl and X have the given meaning, and Hal represents halogen, preferably chlorine, .. ..... ~, -: -: ~ -with 4-hydroxy-pyrimidines of the formula (III) OH
R3 N~R2 (111 in which R2, R3 and R4 have the given meaning, optionally in the presence of acid-binding agents or : ~
. ~-` 2i38331 .
optionally in the form of the alkali metal, alkaline earth metal or ammonium salts and optionally in the presence of solvents.
The starting compounds of the formulae (II) and (III) are known or can be prepared by known methods.
The process for preparing the compounds of the formula (I) is preferably carried out using diluents. Practically all inert organic solvents are suitable for use a6 diluents in this context. The solvents preferably include aliphatic and aromatic, optionally halogenated hydro~
carbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, xylene, methylene chloride, ethylene chloride, chloro-form, carbon tetrachloride, chlorobenzene and o-dichloro-benzene, ethers, such as diethyl ether, dibutyl ether,glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, esters, such as methyl acetate and ethyl acetate, nitriles, such as, for example, acetonitrile and propionitrile, amides, such as, for example, dimethyl-for ~ de, dimethylacet~m;de and N-methylpyrrolidone, as well as dimethyl sulphoxide, tetramethylene sulphone and hexamethylphosphoric triamide.
~ 25 Acid-binding agents which are customarily utilizable for ;~ reactions of this nature may be employed as acid ~ acceptors. Those which are preferable are alkali metal ~ , . ~ . .
21383~1 hydrides and alkaline earth metal hydrides, such as lithium, sodium, potassium and calcium hydride, alkali metal hydroxides and alkaline earth metal hydroxides, such as lithium, sodium, potassium and calcium hydroxide, alkali metal carbonates and hydrogen carbonates and alkaline earth metal carbonates and hydrogen carbonates, such as sodium carbonate or sodium hydrogen carbonate and potassium carbonate or potassium hydrogen carbonate, as well as calcium carbonate, alkali metal acetates, such as sodium and potassium acetate, alkali metal alcoholates, such as sodium and potassium tert-butoxide, and, additionally, basic nitrogen compounds, such as tri~
methylamine, triethylamine, tripropylamine, tributyl-amine, t.riisobutylamine, ethyldiiso-propylamine, ethyldicyclohexylamine, N,N-dimethylbenzyl-amine, N,N-dimethyl-aniline, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 2,6-dimethyl-, 2-ethyl-, 4-ethyl- and 5-ethyl-2-methyl-pyridine, 1,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 1,8-diazabicyclo-[5.4.0~-undec-7-ene (DBU) and 1,4-diaza-bicyclo-t2.2.2]-octane (DABCO).
The reaction temperatures can be varied over a relatively wide range. In general, temperature of between 0C and 100C, preferably temperatures of between 10C and 80C, are employed.
In general, the process is carried out under standard pressure. However, it is also possible to carry it out under elevated or reduced pressure.
! : .
-TP 102 - 8 - ~ ~
:. .:
. ' ' . .
21~8331 For carrying out the process, the starting compounds ~ A .:
which are required in each case are generally employed in approximately equimolar quantities. However, it is also possible to use one of the two components employed in 5 each case in a relatively large excess. In general, the ~ ;
reaction is carried out in a suitable diluent in the presence of an acid acceptor, and the reaction mixture is stirred for several hours at the temperature which is required on each occasion. The working up is in each case effected in accordance with the customary methods (cf.
the preparation examples). -~
In most cases, the compounds result in the form of oils, some of which cannot be distilled without decomposing;
however, these oils can be freed of the remaining vola~
tile constituents, and in this way purified, by so-called ~incipient distillation~, i.e. by being heated for a relatively long time, under reduced pressure, at mode-rately elevated temperatures. They are characterized on `-the basis of their refractive indices. `-The efficacy of the compounds of the formula (I) in the treatment and prevention of disorders of cerebral function is verified using an animal model which is based on spatial memory. In this test, originally described by Morris (R.G.M. Morris, J. Neurosci. Methods 11: 47-60, 1984), rats have to learn to locate a platform which they cannot see and which represents the only possible route of escape from a pool of water. For this, the animals (young, adult male rats, approximately 3 months old) are . ': ~:
TP 102 - 9 - ~
21~8331 given 4 training runs a day over a period of 3 days. The latency to locate the platform, and the distance covered, are the parameters which are measured.
As training progresses, both the escape latency and the distance swum diminish as the result of the acquisition of a strategy for spatially locating the goal. The effect of test substances in improving cognitive power is manifested in an acceleration of the time required for the learning process, i.e. the learning curve becomes steeper. Test substances are administered once a day (60 min prior to the first training run). Control animals receive an equivalent quantity of the vehicle.
":
At the end of the training phase, i.e. once the 12th training run has been completed, the platform is taken out of the water and it is investigated, in a further swimming experiment, whether the experimental animals look for the platfoxm in a defined naxrow area around the training position of the platform (retention test). - -~-The test results demonstrate that the described compounds have a positive influence both on the learning behaviour of the animals and on the retention of that which has been learnt. The esters described can, therefore, be used both for the therapeutic and the preventive treatment of cognitive disturbances in general, and of dementias of the Alzheimer type in particular.
The efficacy of the compounds of the formula (I) in the ~- -treatment and prevention of depressions is verified using '' ~
' ~ ~:
. ~' the "Rat Forced Swimming Test". This behavioural model was described for the first time by Porsolt et al. (R.D.
Porsolt, M. Le Pichon, M. Jalfre, Nature 266: ~30-732, 1977), and is nowadays a generally recognized in-vivo screening model for identifying novel antidepressants. It is based on the observation that, in a situation where there is no escape, rats persist in an immobile attitude ("behavioural despair"). In a pretest session, young adult rats (3-4 months old) are placed individually for 20 min in glass cylinders (height 40 cm, diameter 20 cm) which are filled with water to a height of 15 cm.
24 h after this pretest session , the animals are once again transferred into the cylinders and the duration of immobility is measured over a period of 5 min. The described esters are administered in the time interval between the two swimming sessions . Controls are given the vehicle.
In an analogous manner to clinically active antidepres~
sants described in the literature, the compounds of the formula (I) decrease the duration of immobility and lead to behavioural activation. On the basis of these results, the tescribed compounds are also suitable for use in the treatment of emotional disturbances, in particular of depression.
I . -: ~ . .:
~: . , :, , ,:,:
' ~ : ' :, TP 102 - ll -~: - :' ~---............................. . .
. .
2 1 3 8 3 ~
Te s t r e s u l t s ~
Il/C;~13 R, ~ N
R3 N C4H9-t . ._ .. . ~ . = ED o . ~ cn or~lly acti ve doses, .
~atForced given.orally . . .___ . Swim Test Mo~rts Ma7e . . --CH~ -OCH7 0.11 mg/kg 0.~1 mgll~g_ -C~Hc -OCHl 3.0 m~g 30 mg/kg -CH~ -CHl 0.24 mg~C~ 0.14.3 mg/l~g -C2H5 OC4Hg-n 0.17 mg/~g 0.1 mgll~g -CH3 ~C3Hrn 0.015 mg/k~5 not tested .... _ _ ..... . _ . l -C~H~ ~C3Hrn 0.014 mg/~g ~
-__ ~
-OCH3 -OCH3 0.55 mg/kg1-3 mg/kg -OCH3 -OC2H5 2.3 mglkg not~¦
-OCH3 -OC3H7 1.3 mg/kg 1-3 n~g/kg : -~ . " ~ . ~ . _ _ ,: , ': ' The invention likewise embraces pharmaceutical : -compositions which contain an effective quantity of the ;- .
said compounds, and the preparation and use of these : ~ :::
5 compositions for treating and preventing the abovemen~
tioned diseases.
The novel active compounds may be .converted in a known . ::
manner, into the customary formulations, such as tablets, .. ~
': ::
,, ~
~ ;~: TP 102 - 12 ~
.. .. .' ~ .
., . . ,, . ., ~, . . . .
2138331 ~:
coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inërt, non~
toxic, pharmaceutically suitable carrier substances or solvents. In this context, the therapeutically active 5 compound should in each case be present in a concen- ~ s tration range of approximately 0.5 to 90% by weight of the total mixture, i.e. in quantities which are sufficient to provide the given dosage scope.
The formulations are prepared, for example, by extending 10 the active compounds with solvents and/or carrier sub-stances, where appropriate ùsing emulsifying agents -~
and/or dispersing agents, it being possible, for example when using water as a diluent, to use organic solvents or `solubilizing agents where this is appropriate.
15 Administration is effected in a customary manner, prefer-ably orally or parenterally, in particular perlingually or intravenously. Transdermal administration is also possible, for example using a plaster.
. . ~
When the parenteral route is used, solutions of the 20 active compound can be employed which make use of suit- -able carrier materials.
In general, it has been found to be advantageous to administer quantities of about 0.001 to 1 mg/kg, preferably 0.01 to 0.5 mg/kg, of body weight in order to achieve effective results in the case of intravenous administration, while, in the case of oral ":-. : .' ' . '' ':
21~8331 ~: ~
. , . . ~
administra~ion, the dosage is about 0.01 to 20 mg/kg, preferahly 0.1 to 10 mg/kg, of body weight. ;~
Despite this, it can, where appropriate, be necessary to deviate from the said quantities, depending on the body weight and the nature of the route of admlnistration, on the individual reaction to the medicament, on the nature of its formulation and on the time or interval at which administration -is effected. Thus, in some cases, it can be sufficient to administer less than the abovementioned lowest quantity while, in other cases, the said upper limit has to be exceeded. Where relatiyely large quantities are being administered, it can be advisable to divide these into several smaller doses given over -~ --the course of the day.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for the treatment of diseases of the cognitlve function and depression.
' ' 2 1 3 8 ~ 3 i . .. ~
Preparation examples~
~xample 1 Il /OCH3 ; ~ ~ ~
O--P ~
~N CH3 CH30N~C4H9-tert. , .,- -7.3 g (0.05 mol) of thionomethanephosphonoyl chloride methyl ester are added, at 20C and while stirring, to a mixture of 9.1 g (0.05 mol) of 4-hydroxy-6-methoxy-2 tert-butyl-pyrimidine (preparation, see EP 279 259), 10.3 g (0.075 mol) of potassium carbonate and 80 ml of acetonitrile. The reaction mixture is subsequently ~tirred at 20C for 15 hours and the solvent i8 then distilled off in vacuo. The residue is taken up in 100 ml of methyl tert-butyl ether, and this mixture is washed twice with 50 ml of water on each occasion, dried with sodium sulphate and filtered. The ~olvent i~ distilled off from the filtrate in vacuo at approximately 50C.
., ~
7.7 g (53% of theory) of 0-(6-methoxy-2-tert-butyl~
pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester are obtained as an oily residue having a refractive index n23 of 1.5121.
~''-'' ~'~.:-' ` 213~3~1 -,~
Example 2~
II ~OCH3 ,~ C2Hs n-C4Hg-O N~C4Hg~tert.
6.85 g (0.05 mol) of n-butyl bromide are added, at 20C
and while stirring, to a mixture of 11.6 g (0.04 mol) of 0-(6-hydroxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester (preparation, seeBP 279 259~, 6.9 g (0.05 mol) of potassium carbonate and ml of acetonitrile. The reaction mixture is subsequently stirred at 20C for 15 hours and the solvent is then distilled off in vacuo. The residue is taken up in 100 ml of methyl tert-butyl ether, and this mixture i5 washed once with 50 ml of a 5 percent solution of sodium hydroxide and once with 50 ml of water, dried with sodium sulphate and filtered. The solvent is distilled from the filtrate in vacuo at approximately 50C.
6.55 g (47% of theory) of 0-(6-n-butyloxy-2-tert-butyl~
pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester are obtained as an oily residue having a refrac~
tive index n25 of 1.4961.
: :
`~ .`
The following compounds of the formula Il~OR
4~ P~R~
R3~NJ~R2 ;, l .. ,.~__ ___ EL R Rl R2 R3 R' X Rd~ve -~
N~ . (~rc I _ _ "~
1 3 CH3 CH3 L-C~Hg ~H3 H S 15092/27 . . ~ ~ ~
4 CH3 n C3H7 L-C4H9 OCH~ H S 15042/23 S CH3 CH3 i-C3H7 -CH3 H S
6 CH3 CH3 ~ C~H~ ~ H S 1.5058/20 7 CH~ C~ ~ C4Hs OC~H7~) H S 1.5028/20 ~ ;
8 CH3 CH3 t.-C~T{9 -OC~H7(n) H S 1.5032/20 : ~
_ ... . : -, .::-:
9 CH3 C~3 ~ C~H9 -OC4~(n) H S 1.4987/23 are obtained in analogy with ~xample 1 -. -:
~ . ': :, : '~ . .;
-: ~
, ~ ~ - .. ..
:- -: -:. :.
. :: ~;
21~8~
Preparation examples:
~xample_10 Il ~OCH3 O-P~ .
,~ OCH3 CH30 NJ\C4Hg-tert. ;; ~ ~;
16 g (0.1 mol) of thionophosphoryl chloride dimethyl ester are added, at 20C and while stirringr to a mixture of 18.2 g (0.10 mol) of 4-hydroxy-6-methoxy-2-tert-butyl-pyrimidine, 20.8 g (0.15 mol) of potassium carbonate and ` ~ ~`
80 ml of acetonitrile. The reaction mixture i~ subse-guently ~tirred at 20C for 15 hours and the solvent i8 then di6tilled off in vacuo. The re~idue is taken up in 100 ml of toluene and this mixture is washed twice with 100 ml of water on each occasion, dried with sodium sulphate and filtered. The solvent is distilled off from the filtrate in vacuo at approximately 50C. The residue is freed of volatile constituents at 70C under high vacuum.
27.6 g (90% of theory) of 0-(6-methoxy-2-tert-butyl~
pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester are obtained as an oily residue having a refrac~
tive index n2' of 1.5069. ;~
.
;~ TP_102 - 18 -, ,'. .:
21383~
:.
The following compounds of the ~ormula Il OR - ~ ;
O--P~
R4~N OR
R~ R Rl R~ ~3R~ X _ _ C~l, CH, --~¦ C13, H S
12 CH3 Cll, C4Hg~ C,ll,O _ S lA970/20 13 CH3 CH3 C~Hg t st. Il-C3H,0 H S lA9~6/20 i ~ .
14 CH3 C~3 C~H9 t~rL Il-C~H90 H S
L~
_ _ _ . ., .. ,.,.,. :_ __ ::
are obtained in analogy with Example 1 . ~ ~ . . - ,.
,: "
. :.- -:. -.:: ~ -:
: ~' ' . ' - ' .;~-..~,..- ~.,:' :~ TP 102 - 19 - ~
Claims (12)
1. Use of phosphoric acid esters and phosphonic acid esters of the general formula (I) (I) in which R - represents straight-chain or branched alkyl having up to 6 carbon atoms, R1 - represents straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, R2 - represents hydrogen, or represents straight-chain or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms, or represents dialkylamino having up to 4 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 7 carbon atoms, R3 - represents straight-chain or branched alkoxy or alkyl having up to 6 carbon atoms which can be substituted by alkoxy having up to 4 carbon atoms, or represents hydrogen, R4 - represents halogen, hydrogen or straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, and X - denotes oxygen or sulphur, and their physiologically tolerated salts, as well as their isomers, for the treatment and prevention of disorders of cognitive function and of de-pressions.
2. Use according to Claim 1, where, in the general formula, R represents straight-chain or branched alkyl having up to 4 carbon atoms, R1 represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, R2 represents hydrogen, or represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or represents dialkylamino having in each case up to 3 carbon atoms in each alkyl group, or represents cycloalkyl having from 3 to 6 carbon atoms, R3 represents straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or repre-sents methoxymethyl, or represents hydrogen, R4 represents hydrogen or methoxy, and X represents sulphur, and salts thereof.
3. Use according to Claim 1, where, in the general formula, R . represents methyl, R1 represents methyl, ethyl, propyl or methoxy, R2 represents cyclopropyl, methyl, ethyl, iso-propyl, tert-butyl, or represents methoxy or ethoxy, or represents dimethylamino, R3 represents methyl, ethyl, alkoxy having up to
4 carbon atoms or methoxymethyl, R4 represents hydrogen or methoxy, and salts thereof.
4. Phosphoric acid esters and phosphonic acid esters of the group 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-n-Butyloxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester, 0-(6-Methyl-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionopropanephosphonic acid diester, 0-(6-Methyl-2-isopropyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Methyl-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Methoxy-2-tert-butyl-pyrimidino4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(5-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester.
4. Phosphoric acid esters and phosphonic acid esters of the group 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-n-Butyloxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester, 0-(6-Methyl-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionopropanephosphonic acid diester, 0-(6-Methyl-2-isopropyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionoethanephosphonic acid diester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0-methyl-thionomethanephosphonic acid diester, 0-(6-Methyl-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Methoxy-2-tert-butyl-pyrimidino4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Ethoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Butoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(6-Propoxy-2-cyclopropyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester, 0-(5-Methoxy-2-tert-butyl-pyrimidin-4-yl)-0,0-dimethyl-thionophosphoric acid triester.
5. Medicaments containing the phosphoric acid esters and phosphonic acid esters according to Claim 4.
6. Phosphoric acid esters and phosphonic acid esters according to Claim 4 for the treatment of diseases.
7. Process for preparing phosphoric acid esters and phosphonic acid esters according to Claim 4, charac-terized in that the relevant phosphoryl halides or phosphonoyl halides are reacted with the corres-ponding 4-hydroxy-pyrimidines, optionally in the presence of acid-binding agents or optionally in the form of alkali metal, alkaline earth metal or ammonium salts, and optionally in the presence of a solvent.
8. A pharmaceutical composition for the treatment and prevention of disorders of cognitive function and of depression, which composition comprises a phosphonic acid ester or phosphonic acid ester as defined in any one of claims 1 to 4, or a physiologically tolerated salt or isomer thereof, together with a suitable diluent or carrier.
9. A process for preparing a pharmaceutical composition for the treatment and prevention of disorders of cognitive function and of depression, which process comprises admixing a phosphonic acid ester or phosphonic acid ester as defined in any one of claims 1 to 4, or a physiologically tolerated salt or isomer thereof, with a suitable diluent or carrier.
10. Use of a phosphonic acid ester or phosphonic acid ester as defined in any one of claims 1 to 4, or a physiologically tolerated salt or isomer thereof, for the treatment and prevention of diseases of cognitive function and depression.
11. Phosphonic acid esters and phosphonic acid esters as defined in any one of claims 1 to 4, and the physiologically tolerated salts and isomers thereof, for the treatment and prevention of diseases of cognitive function and depression.
12. A commercial package containing, as active pharmaceutical ingredient, a phosphonic acid ester or phosphonic acid ester as defined in any one of claims 1 to 4, or a physiologically tolerated salt or isomer thereof, together with instructions for its use for the treatment of diseases of cognitive function and depression.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4343599A DE4343599A1 (en) | 1993-12-21 | 1993-12-21 | Use of new and known pyrimidyl phosphonate ester and thio-ester cpds. |
| DE4343600A DE4343600A1 (en) | 1993-12-21 | 1993-12-21 | Use of new and known phosphate ester(s) |
| DEP4343599.8 | 1993-12-21 | ||
| DEP4343600.5 | 1993-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2138331A1 true CA2138331A1 (en) | 1995-06-22 |
Family
ID=25932276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002138331A Abandoned CA2138331A1 (en) | 1993-12-21 | 1994-12-16 | Use of phosphoric acid esters and phosphonic acid esters for treating disorders of cognitive function and depressions |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0659434A1 (en) |
| JP (1) | JPH07206883A (en) |
| CA (1) | CA2138331A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19736539A1 (en) * | 1997-08-22 | 1999-02-25 | Bayer Ag | Use of cycloalkyl-substituted phosphonic acid ester(s) for treating cognitive and affective disorders |
| JP6557020B2 (en) * | 2014-02-14 | 2019-08-07 | ステラケミファ株式会社 | Method for producing phosphoric acid diester salt and method for producing phosphoric acid diester |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK130683B (en) * | 1971-03-04 | 1975-03-24 | Sandoz Ag | Pesticidally active pyrimidinylphosphoric acid esters. |
| US4012506A (en) * | 1975-07-03 | 1977-03-15 | Ciba-Geigy Corporation | Pyrimidyl thio- and dithio-phosphoric acid esters |
| DE2642981C2 (en) * | 1976-09-24 | 1984-11-08 | Bayer Ag, 5090 Leverkusen | Alkoxy-substituted pyrimidinyl-thionophosphonic acid esters, process for their preparation and their use as insecticides and acaricides |
| DE3704689A1 (en) * | 1987-02-14 | 1988-08-25 | Bayer Ag | THIONOPHOSPHONIC ACID ESTER |
| DE3729264A1 (en) * | 1987-09-02 | 1989-03-23 | Bayer Ag | PYRIMIDINYL (THIONO) (THIOL) PHOSPHORIC ACID ESTER |
| US4950658A (en) * | 1988-12-06 | 1990-08-21 | Board Of Trustees Of Southern Illinois Univ. | Method of medical treatment of Alzheimer's disease |
-
1994
- 1994-12-08 EP EP94119398A patent/EP0659434A1/en not_active Withdrawn
- 1994-12-15 JP JP6332901A patent/JPH07206883A/en active Pending
- 1994-12-16 CA CA002138331A patent/CA2138331A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07206883A (en) | 1995-08-08 |
| EP0659434A1 (en) | 1995-06-28 |
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