SK8892001A3 - Organo-phosphorus compounds and their utilization - Google Patents
Organo-phosphorus compounds and their utilization Download PDFInfo
- Publication number
- SK8892001A3 SK8892001A3 SK889-2001A SK8892001A SK8892001A3 SK 8892001 A3 SK8892001 A3 SK 8892001A3 SK 8892001 A SK8892001 A SK 8892001A SK 8892001 A3 SK8892001 A3 SK 8892001A3
- Authority
- SK
- Slovakia
- Prior art keywords
- substituted
- group
- unsubstituted
- alkyl
- hydroxy
- Prior art date
Links
- 150000002903 organophosphorus compounds Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 241000700605 Viruses Species 0.000 claims abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- 241000894006 Bacteria Species 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 244000045947 parasite Species 0.000 claims abstract description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 208000015181 infectious disease Diseases 0.000 claims abstract description 11
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 10
- 241000233866 Fungi Species 0.000 claims abstract description 9
- 125000004185 ester group Chemical group 0.000 claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 5
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 3
- -1 hydroxy, amino Chemical group 0.000 claims description 117
- 239000000203 mixture Substances 0.000 claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 21
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 150000003863 ammonium salts Chemical class 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 201000004792 malaria Diseases 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 230000000855 fungicidal effect Effects 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000004437 phosphorous atom Chemical group 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 150000003868 ammonium compounds Chemical class 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 230000000737 periodic effect Effects 0.000 claims description 5
- 208000000230 African Trypanosomiasis Diseases 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 230000002363 herbicidal effect Effects 0.000 claims description 4
- 208000029080 human African trypanosomiasis Diseases 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 201000002612 sleeping sickness Diseases 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 206010001935 American trypanosomiasis Diseases 0.000 claims description 3
- 206010001986 Amoebic dysentery Diseases 0.000 claims description 3
- 208000024699 Chagas disease Diseases 0.000 claims description 3
- 208000008953 Cryptosporidiosis Diseases 0.000 claims description 3
- 206010011502 Cryptosporidiosis infection Diseases 0.000 claims description 3
- 208000004554 Leishmaniasis Diseases 0.000 claims description 3
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 claims description 3
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 claims description 3
- 201000005485 Toxoplasmosis Diseases 0.000 claims description 3
- 208000005448 Trichomonas Infections Diseases 0.000 claims description 3
- 206010044620 Trichomoniasis Diseases 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 208000007456 balantidiasis Diseases 0.000 claims description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 3
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 3
- 201000000317 pneumocystosis Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000002739 metals Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 10
- 206010000349 Acanthosis Diseases 0.000 claims 4
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 claims 1
- 125000004450 alkenylene group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 229910052797 bismuth Inorganic materials 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 1
- 241001465754 Metazoa Species 0.000 abstract description 27
- 241000282414 Homo sapiens Species 0.000 abstract description 16
- 239000000417 fungicide Substances 0.000 abstract description 3
- 239000003899 bactericide agent Substances 0.000 abstract description 2
- 239000004009 herbicide Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 239000003921 oil Substances 0.000 description 33
- 235000019198 oils Nutrition 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 238000001816 cooling Methods 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 19
- 239000000047 product Substances 0.000 description 16
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 230000008029 eradication Effects 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 241000282412 Homo Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 241000607734 Yersinia <bacteria> Species 0.000 description 8
- 239000000654 additive Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 8
- CJVHLUSZUITNOF-UHFFFAOYSA-N 2-(1-hydroxy-5-oxopyrrolidin-2-yl)ethylphosphonic acid Chemical compound ON1C(CCP(O)(O)=O)CCC1=O CJVHLUSZUITNOF-UHFFFAOYSA-N 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- UCGAMSQKUYTLPJ-UHFFFAOYSA-N 2-(1,5-dihydroxypyrrol-2-yl)ethylphosphonic acid Chemical compound OC1=CC=C(CCP(O)(O)=O)N1O UCGAMSQKUYTLPJ-UHFFFAOYSA-N 0.000 description 6
- VMMFXTABTYOCGF-UHFFFAOYSA-N 2-(1-hydroxy-2-oxopyridin-3-yl)ethylphosphonic acid Chemical compound ON1C=CC=C(CCP(O)(O)=O)C1=O VMMFXTABTYOCGF-UHFFFAOYSA-N 0.000 description 6
- CHTLYANSXRWMEV-UHFFFAOYSA-N 3-(hydroxymethyl)-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NC(CO)CC2=C1 CHTLYANSXRWMEV-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229910004298 SiO 2 Inorganic materials 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- SMYSVBXFACBZBP-UHFFFAOYSA-N (1-hydroxy-2-oxopyrrolidin-3-yl)methylphosphonic acid Chemical compound ON1CCC(CP(O)(O)=O)C1=O SMYSVBXFACBZBP-UHFFFAOYSA-N 0.000 description 5
- MWHJWRGVJKZREO-UHFFFAOYSA-N 2-(2-isocyano-3-phenylpropoxy)oxane Chemical compound C=1C=CC=CC=1CC([N+]#[C-])COC1CCCCO1 MWHJWRGVJKZREO-UHFFFAOYSA-N 0.000 description 5
- STVVMTBJNDTZBF-UHFFFAOYSA-N 2-amino-3-phenylpropan-1-ol Chemical compound OCC(N)CC1=CC=CC=C1 STVVMTBJNDTZBF-UHFFFAOYSA-N 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 208000006454 hepatitis Diseases 0.000 description 5
- 231100000283 hepatitis Toxicity 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229960002317 succinimide Drugs 0.000 description 5
- FCUWSPGCSCSCHK-UHFFFAOYSA-N (1-hydroxy-5-oxopyrrolidin-3-yl)methylphosphonic acid Chemical compound ON1CC(CP(O)(O)=O)CC1=O FCUWSPGCSCSCHK-UHFFFAOYSA-N 0.000 description 4
- FRLDLZDJVBQJDA-UHFFFAOYSA-N (4-amino-1-hydroxy-5-oxopyrrolidin-3-yl)methylphosphonic acid Chemical compound NC1C(CP(O)(O)=O)CN(O)C1=O FRLDLZDJVBQJDA-UHFFFAOYSA-N 0.000 description 4
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- LZKLEUSNFMFXEA-UHFFFAOYSA-N 1-(oxan-2-yloxy)-3-phenylpropan-2-amine Chemical compound C=1C=CC=CC=1CC(N)COC1CCCCO1 LZKLEUSNFMFXEA-UHFFFAOYSA-N 0.000 description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 4
- ZGKDIFYIVDOHOG-UHFFFAOYSA-N 2-bromo-6-(2-dimethoxyphosphorylethyl)-1-oxidopyridin-1-ium Chemical compound BrC1=[N+](C(=CC=C1)CCP(=O)(OC)OC)[O-] ZGKDIFYIVDOHOG-UHFFFAOYSA-N 0.000 description 4
- LMRJQCOMFFQSHG-UHFFFAOYSA-N 3-(2-diethoxyphosphorylethyl)-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NC(CCP(=O)(OCC)OCC)CC2=C1 LMRJQCOMFFQSHG-UHFFFAOYSA-N 0.000 description 4
- NORGAQQNXXECPC-UHFFFAOYSA-N 3-(bromomethyl)-3,4-dihydro-2h-isoquinolin-1-one Chemical compound C1=CC=C2C(=O)NC(CBr)CC2=C1 NORGAQQNXXECPC-UHFFFAOYSA-N 0.000 description 4
- LBVPELDKXOICSH-UHFFFAOYSA-N 3-(dibenzylamino)-4-(dimethoxyphosphorylmethyl)oxolan-2-one Chemical compound COP(=O)(OC)CC1COC(=O)C1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 LBVPELDKXOICSH-UHFFFAOYSA-N 0.000 description 4
- YZJCCPVCZMBTHQ-UHFFFAOYSA-N 3-methyl-1-(2-trimethylsilylethoxy)pyrrolidin-2-one Chemical compound CC1CCN(OCC[Si](C)(C)C)C1=O YZJCCPVCZMBTHQ-UHFFFAOYSA-N 0.000 description 4
- GXUKWDZQNLZDKH-UHFFFAOYSA-N 4-(2-dimethoxyphosphorylethyl)-1-phenylmethoxypyrrol-2-ol Chemical compound C1=C(CCP(=O)(OC)OC)C=C(O)N1OCC1=CC=CC=C1 GXUKWDZQNLZDKH-UHFFFAOYSA-N 0.000 description 4
- XIPKRMKNGMSLTA-UHFFFAOYSA-N 4-(bromomethyl)-3-(dibenzylamino)oxolan-2-one Chemical compound BrCC1COC(=O)C1N(CC=1C=CC=CC=1)CC1=CC=CC=C1 XIPKRMKNGMSLTA-UHFFFAOYSA-N 0.000 description 4
- BVMUOARBOUMJBI-UHFFFAOYSA-N 5-(2-dimethoxyphosphorylethyl)pyrrolidin-2-one Chemical compound COP(=O)(OC)CCC1CCC(=O)N1 BVMUOARBOUMJBI-UHFFFAOYSA-N 0.000 description 4
- 206010059313 Anogenital warts Diseases 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
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- HMEYVGGHISAPJR-IAHYZSEUSA-N rolitetracycline Chemical compound O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCCC1 HMEYVGGHISAPJR-IAHYZSEUSA-N 0.000 description 1
- 229960005009 rolitetracycline Drugs 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000000697 sensory organ Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- YQDGWZZYGYKDLR-UZVLBLASSA-K sodium stibogluconate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].O1[C@H]([C@H](O)CO)[C@H](O2)[C@H](C([O-])=O)O[Sb]21([O-])O[Sb]1(O)(O[C@H]2C([O-])=O)O[C@H]([C@H](O)CO)[C@@H]2O1 YQDGWZZYGYKDLR-UZVLBLASSA-K 0.000 description 1
- 229960001567 sodium stibogluconate Drugs 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 1
- 229960001114 temocillin Drugs 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-S tobramycin(5+) Chemical compound [NH3+][C@@H]1C[C@H](O)[C@@H](C[NH3+])O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H]([NH3+])[C@H](O)[C@@H](CO)O2)O)[C@H]([NH3+])C[C@@H]1[NH3+] NLVFBUXFDBBNBW-PBSUHMDJSA-S 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
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- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
- A01N57/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds
- A01N57/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having phosphorus-to-carbon bonds containing heterocyclic radicals
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/5537—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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Abstract
Description
Vynález sa týka organických zlúčenín fosforu, ich solí, esterov a amidov, a ich použitia v terapeutickej a profylaktickej liečbe infekcií ľudí a živočíchov vyvolaných vírusmi, baktériami, hubami a parazitmi, a ich použitia ako fungicídnych, baktericídnych a herbicídnych prostriedkov aplikovaných na rastliny. Organické zlúčeniny podľa vynálezu zahrnujú fosfinoyl-deriváty, deriváty kyseliny fosfínovej a deriváty kyseliny fosfónovej.The invention relates to organic phosphorus compounds, their salts, esters and amides, and their use in the therapeutic and prophylactic treatment of human and animal infections caused by viruses, bacteria, fungi and parasites, and their use as fungicidal, bactericidal and herbicidal compositions applied to plants. Organic compounds of the invention include phosphinoyl derivatives, phosphinic acid derivatives and phosphonic acid derivatives.
Doterajší stav technikyBACKGROUND OF THE INVENTION
3-hydroxy-2-oxo-4-dimetylfosfóno- a 3-hydroxy-2-oxo-4-difenylfosfinyl-1,2-dihydrochinolíny a ich príprava sú opísané v Tetrahedron Letters, č.38, 1972, str. 3979-39823-hydroxy-2-oxo-4-dimethylphosphono- and 3-hydroxy-2-oxo-4-diphenylphosphinyl-1,2-dihydroquinolines and their preparation are described in Tetrahedron Letters, No. 38, 1972, p. 3979-3982
N-substituované-alkylaminofosfáty sú opísané v Chemical Abstracts, Vol. 093, č. 19, 10 november 1989 a Curr. Chemother. Infect. Dis. Proc. Int. Congr. Chemother., llth, 1980, Vol.l, str. 355-8; v Chemical Abstracts, Vol.105, č.19, 10. november 1986 a v JP 61 106504 A, US-A-4 206 156, US-A4 693 742 a WO 99 525 15 A. O týchto zlúčeninách sa uvádza, že sú vhodné na liečbu bakteriálnych infekcií. Vo WO 99 525 15 A je ďalej opísané ich použitie pri infekciách vyvolaných vírusmi, hubami a parazitmi.N-substituted-alkylaminophosphates are described in Chemical Abstracts, Vol. 093, no. 19, 10 November 1989 and Curr. Chemother. Infect. Dis. Proc. Int. Congr. Chemother., 11 th , 1980, Vol.1, p. 355-8; in Chemical Abstracts, Vol.105, No.19, 10 November 1986 and in JP 61 106504 A, US-A-4 206 156, US-A4 693 742 and WO 99 525 15 A. These compounds are said to be suitable for the treatment of bacterial infections. WO 99 525 15 A further describes their use in infections caused by viruses, fungi and parasites.
Na rozšírenie možností voľby spôsobov liečby ľudí a živočíchov existuje naliehavá potreba prostriedkov, ktoré by boli nielen vysoko účinné, ale na rozdiel od iných liečivých prostriedkov, by tiež vykazovali znížený výskyt vedľajších účinkov a tým by predstavovali pre ľudské zdravie menšie riziko.There is an urgent need for agents that are not only highly effective, but, unlike other medicines, also have a reduced incidence of side effects and thus pose a lower risk to human health to expand the choice of treatments for humans and animals.
Podstata vynálezuSUMMARY OF THE INVENTION
Cieľom vynálezu je poskytnúť univerzálne pôsobiacu liečivú látku použiteľnú na infekcie vyvolané vírusmi, baktériami, hubami a parazitmi u ľudí a živočíchov, ktoré by spĺňali vyššie uvedené požiadavky.It is an object of the invention to provide a universally acting drug substance useful for infections caused by viruses, bacteria, fungi and parasites in humans and animals that meet the above requirements.
Tento cieľ bol prekvapujúco a vyčerpávajúcim spôsobom dosiahnutý skupinou zlúčenín podľa nároku 1. Táto skupina zlúčenín vykazuje antiinfekčné účinky voči vírusom, baktériám, hubám a jedno- a viacbunkovým parazitom. Na rastlinách bol zistený fungicídny, baktericídny a herbicídny účinok uvedených zlúčenín.This object was surprisingly and exhaustively achieved by the group of compounds according to claim 1. This group of compounds exhibits anti-infective effects against viruses, bacteria, fungi and mono- and multicellular parasites. The fungicidal, bactericidal and herbicidal activity of the compounds was found on the plants.
Organické zlúčeniny fosforu podľa vynálezu majú nasledujúci všeobecný vzorec (I):The organic phosphorus compounds of the invention have the following general formula (I):
O 11 (I)O 11 (I)
Rx-A-P-Ra 'Rx-A-P-Ra '
R« kde A znamená skupinu zo skupiny zahrnujúcej (Ci-9)alkylénové zvyšky, ktoré môžu obsahovať jednu alebo viac dvojitých väzieb a môžu byť substituované hydroxy-, halogén-, amino-, a oxoskupinami, rozvetvenými alebo nerozvetvenými (Ci.9)alkylovými a (C2-9)alkenylovými skupinami, kde uvedené (Ci.9)alkylové a (C2-9)alkenylové skupiny môžu byť substituované skupinami zo skupiny zahrnujúcej vodík, hydroxy, amino, halogén a oxo, a skupiny -C-O-C- a -C-N-C-, kde atómy uhlíka v uvedených skupinách -C-O-C- a -C-N-C- môžu byť substituované skupinami zo skupiny zahrnujúcej alkyl s až 7 atómami uhlíka alebo hydroxy, alebo A znamená skupinu nasledujúceho všeobecného vzorca (II):Wherein R represents a group selected from the group consisting of (C 1-9) alkylene radicals which may contain one or more double bonds and may be substituted by hydroxy-, halogen-, amino-, and oxo groups, branched or unbranched (C 1-9) alkyl and (C 2-9) alkenyl groups, wherein said (C 1-9) alkyl and (C 2-9) alkenyl groups may be substituted with a group selected from hydrogen, hydroxy, amino, halogen and oxo, and -COC- and -CNC groups - wherein the carbon atoms in said -COC- and -CNC- groups may be substituted by a group consisting of alkyl of up to 7 carbon atoms or hydroxy, or A represents a group of the following formula (II):
Bi Ej B5 B7 BgBi Ej B5 B7 Bg
I I I IIII
-C1“C2”C3—C4-C5I I III-C1 “C2” C3-C4-C5I I III
B2 E i Bg BgB10 (II) • ·· ·· ·· ·· ···· ···· ··· ··* ···· · · • · · ···· · · ····· ·· ·· · · · kde jeden alebo viac atómov uhlíka zo skupiny zahrnujúcej C3, C4, C5, spoločne so substituentami, ktoré obsahujú nemusia byť prítomné, a najmenej jeden substituent v rámci skupín B] až B10 znamená (C3-8)cykloalkyl-(Co-9)alkylovú skupinu, kde ako (C3.s)cykloalkylová tak (Co-9)alkylová skupina môže obsahovať jednu alebo viac dvojitých väzieb a jeden alebo dva atómy uvedenej cykloalkylovej skupiny môžu byť nahradené atómom zo skupiny zahrnujúcej dusík, kyslík alebo síru, a kde ako cykloalkylovú skupina, tak alkylová skupina môžu byť substituované hydroxy-, halogén-, amino-, a oxoskupinami, rozvetvenými alebo nerozvetvenými (Ci-9)alkylovými a (C2-9)alkenylovými skupinami, kde uvedené (Ci-9)alkylové a (C2-9)alkenylové skupiny môžu byť substituované skupinami zo skupiny zahrnujúcej vodík, hydroxy, amino, halogén a oxo, a zostávajúce prítomné substituenty Bi až B10 sa zvolia zo skupiny zahrnujúcej vodík, hydroxy, halogén, aminoskupiny, (Cj-C26)alkyl, (Ci-C26)alkoxy, (CiC26)alkoxy-(Ci-C26)alkyl, alebo oba substituenty atómu C spoločne tvoria oxoskupinu, a kde každá (Ci.C26)alkylová alebo (Ci-C26)alkoxyskupina môže byť rozvetvená alebo nerozvetvená a môže byť nasýtená alebo nenasýtená s jednou alebo viac dvojitými väzbami, a môže byť substituovaná hydroxy-, amino-, halogén- alebo oxo- skupinami, kde Ri znamená skupinu zvolenú zo skupiny zahrnujúcej 5-členné a 6členné heterocyklické skupiny obsahujúce najmenej jeden atóm dusíka v kruhu, alebo polykarbocyklickú skupinu zahrnujúcu najmenej jeden z uvedených heterocyklov, kde najmenej jeden z uvedených atómov dusíka je súčasťou skupiny tvoriacej hydroxámovú kyselinu alebo ester kyseliny hydroxámovej a uvedený kruh môže byť nasýtený alebo nenasýtený, keď môže obsahovať jednu alebo viac dvojitých alebo trojitých väzieb a tiež môže byť aromatický a môže byť substituovaný hydroxy-, halogén-, amino-, a oxoskupinami, a rozvetvenými alebo nerozvetvenými (Ci-9)alkylovými a (Cí.gjalkenylovými skupinami, kde uvedené (Ci.gjalkylové a (C2.g)alkenylové skupiny môžu byť nasýtené alebo môžu byť tiež nenasýtené a môžu obsahovať jednu alebo viac dvojitých alebo trojitých väzieb, a môžu byť substituované skupinou zo skupiny zahrnujúcej vodík, hydroxy, amino, halogén, a oxo, a kde atóm dusíka hydroxámovej kyseliny alebo esteru hydroxámovej kyseliny je substituovaný OR5, aB 2 E and Bg BgB10 (II) •····································· Wherein one or more carbon atoms of the group consisting of C3, C4, C5, together with substituents which may not be present, and at least one substituent within groups B] to B10 represents (C3-8) a cycloalkyl- (Co-9) alkyl group, wherein both the (C 3-8) cycloalkyl and the (Co-9) alkyl group may contain one or more double bonds and one or two atoms of said cycloalkyl group may be replaced by a nitrogen atom , oxygen or sulfur, and wherein both the cycloalkyl group and the alkyl group may be substituted by hydroxy-, halo-, amino-, and oxo, branched or unbranched (C 1-9) alkyl and (C 2-9) alkenyl groups, wherein said ( C 1-9) alkyl and (C 2-9) alkenyl groups may be substituted by hydrogen, hydroxy, amino, halogen and oxo, and the remaining present substituents of Bi to B10 are selected from hydrogen, hydroxy, halogen, amino, (C 2 -C 6) alkyl, (Cl-C26) alkoxy, (6 -C 2) alkoxy- ( Cl-C26) alkyl, or both substituents together form a C atom of the oxo group, and wherein each (2 Ci.C 6) alkyl or (C 2 -C 6) alkoxy group may be branched or unbranched and may be saturated or unsaturated with one or more and may be substituted by hydroxy-, amino-, halogen- or oxo-groups, wherein R 1 is a group selected from the group consisting of 5-membered and 6-membered heterocyclic groups containing at least one ring nitrogen atom, or a polycarbocyclic group comprising at least one of said heterocycles wherein at least one of said nitrogen atoms is part of a hydroxamic acid or hydroxamic acid ester group, and said ring may be saturated or unsaturated when both may have one or more double or triple bonds and may also be aromatic and may be substituted with hydroxy, halogen, amino, and oxo groups, and branched or unbranched (C 1-9) alkyl and (C 1-8) alkenyl groups, wherein said (C 1-6) .gjalkylové a (C 2 .g) alkenyl groups can be saturated or can also be unsaturated and contain one or more double or triple bonds and may be substituted by hydrogen, hydroxy, amino, halo, and oxo, and wherein the nitrogen atom of the hydroxamic acid or hydroxamic acid ester is substituted with OR 5, and
Rs znamená skupinu zvolenú zo skupiny zahrnujúcej vodík, substituovaný a nesubstituovaný (Ci.g)alkyl, substituovaný a nesubstituovaný hydroxy-(C]. 9)alkyl, substituovaný a nesubstituovaný (Ci-9)alkenyl, substituovaný a nesubstituovaný (Ci-9)alkinyl, substituovaný a nesubstituovaný aryl, substituovaný a nesubstituovaný acyl, substituovaný nesubstituovaný cykloalkyl, substituovaný a nesubstituovaný aralkyl, substituovaný a nesubstituovaný heterocyklyl, a kde R3 a R4 majú rovnaký alebo rôzny význam a sú zvolené zo skupiny zahrnujúcej vodík, substituovaný a nesubstituovaný (C 1-26)alkyl, substituovaný a nesubstituovaný hydroxy-(Ci-26)alkyl, substituovaný a nesubstituovaný aryl, substituovaný a nesubstituovaný acyl, substituovaný a nesubstituovaný aralkyl, substituovaný a nesubstituovaný (C].2c,)alkenyl, substituovaný a nesubstituovaný (Ci-26)alkinyl, substituovaný a nesubstituovaný cykloalkyl, substituovaný a nesubstituovaný heterocyklyl, halogén, OX3 a OX4, kde X3 a X4 majú rovnaký alebo rôzny význam a znamenajú skupinu zvolenú zo skupiny zahrnujúcej vodík, substituovaný a nesubstituovaný (Ci. 26)alkyl, substituovaný a nesubstituovaný hydroxy-(Ci-26)alkyl, substituovaný a nesubstituovaný aryl, substituovaný a nesubstituovaný aralkyl, substituovaný a nesubstituovaný (Ci.2e)alkenyl, substituovaný a nesubstituovaný (Cj.26)alkinyl, substituovaný a nesubstituovaný cykloalkyl, substituovaný a nesubstituovaný heterocyklyl, silyl, katión organickej a anorganickej bázy, predovšetkým kovov hlavných skupín I, II alebo III periodického systému, amónium, substituovanú amóniovú skupinu a amóniové zlúčeniny odvodené od etyléndiamínu alebo aminokyselín, a ich farmaceutický prijateľné soli, estery a amidy a soli uvedených esterov.R 5 represents a group selected from hydrogen, substituted and unsubstituted (C 1-9) alkyl, substituted and unsubstituted hydroxy- (C 1-9) alkyl, substituted and unsubstituted (C 1-9) alkenyl, substituted and unsubstituted (C 1-9) alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclyl, and wherein R 3 and R 4 have the same or different meanings and are selected from the group consisting of hydrogen, substituted and unsubstituted (C 1) -26) alkyl, substituted and unsubstituted hydroxy- (C 1-6) alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted (C 1-2) alkenyl, substituted and unsubstituted (C 1-6) 26) alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, hal Ogen, OX 3 and OX 4 , wherein X 3 and X 4 have the same or different meanings and are a group selected from the group consisting of hydrogen, substituted and unsubstituted (C 1-6 alkyl); 26) alkyl, substituted and unsubstituted hydroxy- (C, 26) alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted (2alkyl) alkenyl, substituted and unsubstituted (C. 2 6) alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclyl, silyl, organic and inorganic base cations, in particular metals of the main groups I, II or III of the periodic system, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of said esters.
Ak heterocyklická skupina vo význame Rj obsahuje dva alebo viac heteroatómov, potom môže obsahovať atómy kyslíka a síry.If a heterocyclic group R 1 contains two or more heteroatoms, it may contain oxygen and sulfur atoms.
Organické zlúčeniny fosforu podľa vynálezu majú výhodne všeobecný vzorec (III)The organic phosphorus compounds of the invention preferably have the general formula (III)
Ο IIΟ II
Ri-A-P-R3 (ΙΙΙ)Ri-APR 3
ΟΧ 4 kde R3 výhodne znamená skupinu zo skupiny zahrnujúcej vodík, metyl, amidový zvyšok alebo OX3, a X4 znamená skupinu zvolenú zo skupiny zahrnujúcej vodík, sodík, draslík, metyl, etyl, a kde X3 má význam uvedený vyššie, a zvlášť výhodné zlúčeniny podľa vynálezu majú všeobecný vzorec (IV)Kde 4 wherein R 3 is preferably hydrogen, methyl, amide or OX 3 , and X 4 is selected from hydrogen, sodium, potassium, methyl, ethyl, and wherein X 3 is as defined above, and particularly preferred compounds of the invention have the formula (IV)
OABOUT
Ri-A-P-OXa <IV>R 1 -AP-OXa < IV >
I OX4 kde X3 a X4 majú rovnaký alebo rôzny význam a sú zvolené zo skupiny zahrnujúcej vodík, (C].3)alkylovú skupinu, kov hlavnej skupiny I, II, alebo III periodickej sústavy prvkov, amónium, substituovanú amóniovú skupinu alebo amóniové zlúčeniny odvodené od etyléndiamínu alebo aminokyselín.I OX 4 in which X 3 and X 4 are the same or different and selected from hydrogen, (C]. 3) alkyl, a metal of main group I, II or III of the periodic table, ammonium, substituted ammonium, or ammonium compounds derived from ethylenediamine or amino acids.
X3 a X4 výhodne znamenajú kov hlavnej skupiny I, II, alebo III periodickej sústavy prvkov, amónium, substituovanú amóniovú skupinu alebo amóniové zlúčeniny odvodené od etyléndiamínu alebo aminokyselín. Inak vyjadrené, soli organických zlúčenín fosforu sú soli s organickými alebo s anorganickými bázami (ako je napríklad sodná soľ, draselná soľ, vápenatá soľ, hlinitá soľ, amóniová soľ, horečnatá soľ, trietylamínová soľ, etanolamínová soľ, dicyklohexylamínová soľ, etyléndiamínová soľ, Ν,Ν'-dibenzyletyléndiamínová soľ) a ďalej soli s aminokyselinami (napríklad arginínová soľ, asparaginátová soľ, glutámová soľ atď.) a podobne.X 3 and X 4 preferably represent a metal of the main group I, II, or III of the periodic table, ammonium, substituted ammonium or ammonium compounds derived from ethylenediamine or amino acids. In other words, salts of organic phosphorus compounds are salts with organic or inorganic bases (such as sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine, ethylenediamine). , Ν'-dibenzylethylenediamine salt) and amino acid salts (e.g., arginine salt, asparaginate salt, glutamic salt, etc.) and the like.
X3 a X4 majú obzvlášť výhodne rovnaký alebo rôzny význam, a znamenajú skupinu zvolenú zo skupiny zahrnujúcej vodík, sodík, draslík, metylovú a etylovú skupinu • ·· ·· ·· ·· ··· · · · · · · · · • · · · · ·· · · ·· · · · ·· ··· · ··· ···· · · ····· ·· ·· ·· ·X 3 and X 4 are particularly preferably the same or different, and are selected from the group consisting of hydrogen, sodium, potassium, methyl and ethyl. · · · · · · · · · · · · · · · · · · · · · · ·
A sa výhodne volí tak, aby vznikol trojčlenný spojovací reťazec medzi atómom fosforu a atómom dusíka heterocyklu A napríklad výhodne znamená skupinu zo skupiny zahrnujúcej metylén, hydroxymetylén, etylén, etenylén, hydroxyetylén, substituovanú predovšetkým oxo-skupinou.A is preferably selected to form a three-membered linking chain between the phosphorus atom and the nitrogen atom of the heterocycle A, for example, preferably represents a group selected from the group consisting of methylene, hydroxymethylene, ethylene, ethenylene, hydroxyethylene, especially substituted by oxo.
Uhlíkový reťazec A všeobecného vzorca (II) tiež výhodne spojuje atóm dusíka, spoločne s ostatnými atómami heterocyklu, a atóm fosforu trojatómovým reťazcom. Ak atóm uhlíka v polohe a vzhľadom k atómu dusíka alebo k atómu fosforu je substituovaný oxo-skupinou, je tiež výhodné, keď spojovací reťazec obsahuje štyri atómy uhlíka. Ak v spojovacom reťazci ako jedna oxoskupina je v polohe a voči atómu dusíka tak aj ďalšia oxo-skupina je v polohe a voči atómu fosforu, je tiež výhodné, keď spojovací reťazec obsahuje päť atómov uhlíka. Ak atóm uhlíka v polohe a vzhľadom k atómu fosforu je substituovaný hydroxyskupinou, výhodné je, keď spojovací reťazec obsahuje štyri atómy. V tomto prípade je tiež výhodné, keď R3 a R4 znamenajú metylénové skupinyThe carbon chain A of formula (II) also preferably connects the nitrogen atom, together with the other heterocycle atoms, and the phosphorus atom with a tri-atomic chain. If the carbon atom in position a relative to the nitrogen or phosphorus atom is substituted with an oxo group, it is also preferred that the linker chain contains four carbon atoms. If in the linker as one oxo group is in position and relative to the nitrogen atom, and the other oxo group is in position and relative to the phosphorus atom, it is also preferred that the linker chain contains five carbon atoms. If the carbon atom in position a relative to the phosphorus atom is substituted with a hydroxy group, it is preferred that the linker chain contains four atoms. In this case, it is also preferred that R 3 and R 4 represent methylene groups
Zvlášť výhodné skupiny zlúčenín sú uvedené nižšie:Particularly preferred groups of compounds are listed below:
A-POj2’A-POj 2 '
IIIIII
VIIVII
VIIIVIII
A-POj2-A-POj 2 -
IXIX
/RS/ R S
XIXI
A-POj2’A-POj 2 '
XIIIXIII
a-po3 2·a-po 3 2 ·
ORjOR j
a-po3 2-a-po 3 2 -
a-po3 2-a-po 3 2 -
a-po3 2·a-po 3 2 ·
XXVIII Α-Ρ°32· (Α Ν ' %XXVIII Α - Ρ ° 3 2 · (Α Ν '%)
XXVIXXVI
XXIXXXIX
XXXXXX
XXXIXXXI
XXXVIXXXVI
XXXVIIXXXVII
a zodpovedajúce deriváty kyseliny fosfínovej a fosfinoyl-deriváty.and the corresponding phosphinic acid derivatives and phosphinoyl derivatives.
Špecifický popis vyššie uvedených výrazov a ich vhodné príklady sú uvedené nižšie'A specific description of the above terms and suitable examples thereof are given below.
Acyl znamená substituent odvodený od kyseliny, ako od organickej karboxylovej kyseliny, kyseliny uhličitej, kyseliny karbamidovej alebo tiokyseliny alebo imid-kyseliny zodpovedajúci vyššie uvedeným kyselinám, alebo od organickej sulfónovej kyseliny, kde uvedené kyseliny obsahujú v jednotlivých prípadoch v molekule alifatické, aromatické a/alebo heterocyklické skupiny a tiež karbamoylovú alebo karbamimidoylovú skupinuAcyl means a substituent derived from an acid such as an organic carboxylic acid, carbonic acid, carbamic acid or thioacid or an imide acid corresponding to the abovementioned acids, or from an organic sulfonic acid, wherein said acids contain in each case aliphatic, aromatic and / or heterocyclic groups as well as carbamoyl or carbamimidoyl
Vhodné príklady acylových skupín sú uvedené nasledovne. Alifatické acylové skupiny znamenajú acylové zvyšky odvodené od alifatickej kyseliny a zahrnujú nasledujúce skupiny:Suitable examples of acyl groups are given as follows. Aliphatic acyl groups mean acyl residues derived from an aliphatic acid and include the following groups:
alkanoyl (napríklad formyl, acetyl, propionyl, butyryl, izobutyryl, valeryl, izovaleryl, pivaloyl atď.); alkenoyl (napríklad akryloyl, metakryloyl, krotonoyl atď.); alkyltioalkanoyl (napr metyltioacetyl, etyltioacetyl atď.); alkánsulfonyl (napr. mesyl, etánsulfonyl, propánsulfonyl atď.); alkoxykarbonyl (napr. metoxykarbonyl, etoxykarbonyl, propoxykarbonyl, izopropoxykarbonyl, butoxykarbonyl, izobutoxykarbonyl atď.); alkylkarbamoyl (napr. metylkarbamoyl atď.); (N-alkyl)tiokarbamoyl (napr. (N-metyl)tiokarbamoyl atď.), alkylkarbamimidoyl (napr metylkarbamimidoyl atď ); oxalo; alkoxalyl (napr. metoxalyl, etoxalyl, propoxalyl atď.)alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.); alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.); alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl, etc.); alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl, etc.); alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.); alkylcarbamoyl (e.g., methylcarbamoyl, etc.); (N-alkyl) thiocarbamoyl (e.g., (N-methyl) thiocarbamoyl, etc.), alkylcarbamimidoyl (e.g., methylcarbamimidoyl, etc.); oxalo; alkoxalyl (e.g., methoxalyl, etoxalyl, propoxalyl, etc.)
Alifatická uhľovodíková časť vo vyššie uvedených príkladoch alifatických acylových skupín, predovšetkým v alkylových skupinách alebo alkánových zvyškoch, môže obsahovať jeden alebo viac substituentov znamenajúcich skupinu zo skupiny zahrnujúcej amino, halogén (napríklad fluór, chlór, bróm atď.), hydroxy, hydroxyimino, karboxy, alkoxy (napr. metoxy, etoxy, propoxy atď ), alkoxykarbonyl, acylamino (napr. benzyloxykarbonyiamino atď.), acyloxy (napr. acetoxy, benzyloxy atď ) a podobne; výhodné alifatické acylové zvyšky obsahujúce také substituenty zahrnujú napríklad alkanoylové skupiny • ·· ·· ·· ·· · ···· · · · · · · ·· • e · ···· · · · ·· ··· · · ··· · · ··· ···· · · · ··· ·· ·· ·· ·· ··· substituované skupinou ako je amino, karboxy, amino a karboxy, halogén, acylamino alebo podobne.The aliphatic hydrocarbon moiety in the above examples of aliphatic acyl groups, particularly alkyl or alkane radicals, may contain one or more substituents representing a group selected from amino, halogen (e.g., fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkoxycarbonyl, acylamino (e.g., benzyloxycarbonylamino, etc.), acyloxy (e.g., acetoxy, benzyloxy, etc.) and the like; Preferred aliphatic acyl radicals containing such substituents include, for example, alkanoyl groups. It is substituted with a group such as amino, carboxy, amino and carboxy, halogen, acylamino or the like.
Aromatické acylové zvyšky znamenajú acyiové zvyšky odvodené od kyseliny na substituovanej alebo nesubstituovanej arylovej skupine, kde arylová skupina môže znamenať fenyl, tolyl, xylyl, naftyl a podobne; vhodné príklady týchto skupín sú uvedené nižšie:Aromatic acyl radicals mean acyl radicals derived from an acid on a substituted or unsubstituted aryl group, wherein the aryl group may be phenyl, tolyl, xylyl, naphthyl and the like; suitable examples of these groups are given below:
aroyl (napr. benzoyl, toluoyl, xyloyl, naftoyl, ftaloyl atd’.); aralalkanoyl (napr fenylacetyl atd’.); aralalkenoyl (napr. cinnamoyl atd’.); aryloxyalkanoyl (napr. fenoxyacetyl atd’ ); aryltioalkanoyl (napr. fenyltioacetyl atd’ ); arylaminoalkanoyl (napr. N-fenylglycyl atd’.); arénsulfonyl (napr. benzénsulfonyl, tosyl alebo toluénsulfonyl, naftalénsulfonyl atd’.); aryloxykarbonyl (napr. fenoxykarbonyl, naftyloxykarbonyl atd’.), aralkoxykarbonyl (napr benzyloxykarbonyl atd’.); arylkarbamoyl (napr. fenylkarbamoyl, naftylkarbamoyl atd’.), arylglyoxyloyl (napr. fenylglyoxyloyl atd’ )aroyl (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.); aralalkanoyl (e.g. phenylacetyl, etc.); aralalkenoyl (e.g. cinnamoyl etc); aryloxyalkanoyl (e.g. phenoxyacetyl etc.); arylthioalkanoyl (e.g., phenylthioacetyl, etc.); arylaminoalkanoyl (e.g., N-phenylglycyl, etc.); arenesulfonyl (e.g. benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl, etc.); aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.), aralkoxycarbonyl (e.g., benzyloxycarbonyl, etc.); arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl, etc.), arylglyoxyloyl (e.g. phenylglyoxyloyl etc)
Vo vyššie uvedených skupinách, ako príkladoch aromatických acylových zvyškov, môže byť aromatická uhľovodíková skupina (predovšetkým arylový zvyšok) a/alebo alifatická uhľovodíková skupina (predovšetkým alkylový zvyšok) prípadne substituovaná jedným alebo viacerými substituentami zahrnujúcimi substituenty už uvedené vyššie ako substituenty vhodné pre alkylovú skupinu alebo pre alkánový zvyšok. Príklady výhodných aromatických acylových zvyškov obsahujúcich špecifické substituenty zahrnujú aroylovú skupinu substituovanú halogénom a hydroxyskupinou alebo halogénom a acyloxyskupinou, aralalkanoyl substituovaný skupinou zo skupiny zahrnujúcej hydroxy, hydroxyimino, dihalogénalkanoyloxyimino rovnako tak ako aryltiokarbamoyl (napr. fenyltiokarbamoyl atd’.); arylkarbamimidoyl (napr. fenylkarbamimidoyl atd’.).In the above groups, as examples of aromatic acyl radicals, the aromatic hydrocarbon group (especially the aryl radical) and / or the aliphatic hydrocarbon group (especially the alkyl radical) may be optionally substituted with one or more substituents already mentioned above as substituents suitable for an alkyl group or for the alkane residue. Examples of preferred aromatic acyl radicals containing specific substituents include aroyl substituted with halogen and hydroxy or halogen and acyloxy, aralalkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino as well as arylthiocarbamoyl (e.g. phenylthiocarbamoyl); arylcarbamimidoyl (e.g., phenylcarbamimidoyl, etc.).
Heterocyklický kyslý zvyšok znamená acylový zvyšok odvodený od kyseliny obsahujúcej heterocyklickú skupinu; uvedené zvyšky zahrnujú:Heterocyclic acidic residue means an acyl residue derived from an acid containing a heterocyclic group; said residues include:
heterocyklickú karbonylovú skupinu v ktorej heterocyklický zvyšok je aromatický alebo alifatický 5- až 6-členný heterocyklus obsahujúci najmenej jeden heteroatóm zo skupiny zahrnujúcej dusík, kyslík a síru (ako je napr tienyl, furoyl, pyrolkarbonyl, nikotinyl, atd’.), • ·· ·· ·· ·· ···· ···· ··· • · · ···· · · ·· ··· ·· ··· · • · · ···· ··a heterocyclic carbonyl group wherein the heterocyclic moiety is an aromatic or aliphatic 5- to 6-membered heterocycle containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur (such as thienyl, furoyl, pyrrolecarbonyl, nicotinyl, etc.); ···································································
I η ··· ·· ·· ·· ·· ·I η ··· ·· ·· ·· ·· ·
J heterocyklickú-alkanoylovú skupinu, v ktorej heterocyklický zvyšok je 5členný až 6-členný a obsahuje najmenej jeden heteroatóm zvolený zo skupiny zahrnujúcej dusík, kyslík a síru (napr. tiofenacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-tiazolyl)-2-metoxyiminoacetyl, atď.) a podobneJ is a heterocyclic-alkanoyl group in which the heterocyclic radical is 5- to 6-membered and contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4-) thiazolyl) -2-methoxyiminoacetyl, etc.) and the like
Heterocyklické a/alebo alifatické uhľovodíkové skupiny vo vyššie uvedených príkladoch heterocyklických kyslých zvyškov môžu prípadne obsahovať jeden alebo viac vhodných substituentov, ktoré znamenajú skupiny uvedené vyššie pre alkylové a alkánové skupiny.The heterocyclic and / or aliphatic hydrocarbon groups in the above examples of heterocyclic acid residues may optionally contain one or more suitable substituents, which are those mentioned above for alkyl and alkane groups.
Výraz alkyl znamená alkylový zvyšok s priamym alebo s rozvetveným reťazcom ako je skupina zo skupiny zahrnujúcej metyl, etyl, propyl, izopropyl, butyl, izobutyl, íerc-butyl, pentyl, hexyl a podobne.The term alkyl means a straight or branched chain alkyl radical such as a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
Výraz hydroxyalkyl znamená alkylový zvyšok s priamym alebo s rozvetveným reťazcom, ktorý obsahuje najmenej jednu hydroxyalkylovú skupinu, výhodne jednu alebo dve alkylové skupiny.The term hydroxyalkyl means a straight or branched chain alkyl radical containing at least one hydroxyalkyl group, preferably one or two alkyl groups.
Výraz alkenyl zahrnuje alkenylové skupiny s priamym alebo s rozvetveným reťazcom ako je napríklad vinyl, propenyl, (napr. 1-propenyl, 2propenyl), 1-metylpropenyl, 2-metylpropenyl, butenyl, 2-etylpropenyl, pentenyl, hexenyl.The term alkenyl includes straight or branched chain alkenyl groups such as vinyl, propenyl, (e.g., 1-propenyl, 2propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.
Výraz alkinyl zahrnuje alkinylové skupiny s priamym alebo s rozvetveným reťazcom.The term alkynyl includes straight or branched chain alkynyl groups.
Výraz cykloalkyl výhodne znamená prípadne substituovaný Cj. «cykloalkyl; prípadné substituenty môžu znamenať medzi iným skupinu zo skupiny zahrnujúcej alkyl, alkenyl, alkinyl, alkoxy (napr. metoxy, etoxy atď ), halogén (napr. fluór, chlór, bróm atď.), nitro a podobne.The term cycloalkyl preferably means optionally substituted C 1-6 alkyl. 'Cycloalkyl; optional substituents may include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy (e.g., methoxy, ethoxy, etc.), halogen (e.g., fluoro, chloro, bromo, etc.), nitro, and the like.
Aryl znamená aromatický uhľovodíkový zvyšok ako je fenyl, naftyl atď., ktorý môže prípadne obsahovať jeden alebo viac vhodných substituentov znamenajúcich skupiny ako je alkyl, alkenyl, alkinyl, alokoxy (napr metoxy, etoxy atď ), halogén (napr fluór, chlór, bróm atď.), nitro, a podobne • ·· ·· ·· ·· · ···· ···· · · ·· ······· · · · • · · · · ·· ··· · · ··· ···· · · · ··· ·· ·· ·· ·· ···Aryl means an aromatic hydrocarbon radical such as phenyl, naphthyl, etc., which may optionally contain one or more suitable substituents representing groups such as alkyl, alkenyl, alkynyl, alloxy (e.g. methoxy, ethoxy, etc.), halogen (e.g. fluorine, chlorine, bromine, etc.) .), nitro, and the like • ············································ · ··· ···· · · · ··· ·· ·· ·· ·· ···
Výraz aralkyl znamená skupiny zo skupiny zahrnujúcej mono-, di-, trifenylalkyly ako benzoyl, fenetyl, benzhydryl, trityl a podobne, kde aromatická skupina môže prípadne obsahovať jeden alebo viac vhodných substituentov zo skupiny zahrnujúcej alkoxy (napr. metoxy, etoxy atď), halogén (napr. fluór, chlór, bróm atď.), nitro a podobne.The term aralkyl means groups from the group consisting of mono-, di-, triphenylalkyls such as benzoyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic group may optionally contain one or more suitable substituents from the group consisting of alkoxy (e.g. methoxy, ethoxy, etc.), halogen (e.g., fluorine, chlorine, bromine, etc.), nitro and the like.
Zvyšky X3 a X4 sa výhodne volia tak, aby tvorili esterové skupiny s fosfínovou alebo fosfónovou skupinou. Vhodné príklady esterov podľa všeobecných vzorcov (I), (III) a (IV) zahrnujú mono- a diestery, a výhodné príklady týchto esterov zahrnujú alkylestery (napr hexadecylester, oktadecylester atď.), aralkylestery (benzylester, fenetylester, benzhydrylester, tritylester atď.); arylestery(napr. fenylester, tolylester, naftylester); aroylalkylester (napr. fenacylester atď ); a silylestery napr. trialkylhalogénsilyl, dialkylhalogénsi 1 y 1, alkyltrihalogénsilyl, dialkylarylhalogénsilyl, trialkoxyhalogénsilyl, dialkylaralkylhalogénsilyl, dialkoxydihalogénsilyl, trialkoxyhalogénsilyl atď.) a podobneThe radicals X 3 and X 4 are preferably chosen to form ester groups with a phosphine or phosphone group. Suitable examples of esters of formulas (I), (III) and (IV) include mono- and diesters, and preferred examples of such esters include alkyl esters (e.g., hexadecyl ester, octadecyl ester, etc.), aralkyl esters (benzyl ester, phenethyl ester, benzhydryl ester, trityl ester etc.). ); aryl esters (e.g., phenyl ester, tolyl ester, naphthyl ester); aroylalkyl ester (e.g., phenacylester, etc.); and silyl esters e.g. trialkyl halogensilyl, dialkyl halogensilyl, alkyltrihalogensilyl, dialkylarylhalogensilyl, trialkoxyhalogensilyl, dialkylaralkylhalogensilyl, dialkoxydihalogensilyl, trialkoxyhalogensilyl, etc.) and the like
Vo vyššie uvedených esteroch môžu alkánové a/alebo arénové skupiny prípadne obsahovať najmenej jeden vhodný substituent ako je halogén, hydroxyskupina, nitroskupina alebo podobne.In the above esters, the alkane and / or arene groups may optionally contain at least one suitable substituent such as halogen, hydroxy, nitro or the like.
Zlúčeniny vhodné podľa vynálezu podľa všeobecných vzorcov (I), (III) a (IV) môžu byť vo svojej protonizovanej forme ako vo forme amóniovej soli organickej alebo anorganickej kyseliny ako je kyselina chlorovodíková, bromovodíková, sírová, dusičná, metánsulfónová, p-toluénsulfónová, octová, mliečna, maleínová, fumarová, šťavelová, vínna, benzoová atďCompounds suitable according to the invention of formulas (I), (III) and (IV) may be in their protonated form as an ammonium salt of an organic or inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, methanesulfonic, p-toluenesulfonic, acetic, milk, maleic, fumaric, oxalic, wine, benzoic, etc.
Zlúčeniny vhodné podľa vynálezu všeobecných vzorcov (I), (III) a (IV) poskytujú napríklad v prípade, keď Ri, R3, R4, X3, X4 alebo A obsahujú dvojité väzby alebo sú to chirálne zlúčeniny, vznik priestorových izomérov. Použitie podľa vynálezu zahrnuje všetky priestorové izoméry či už ako jednotlivé čisté zlúčeniny tak ich zmesi.Compounds useful according to the invention of formulas (I), (III) and (IV), for example, when R 1, R 3 , R 4, X 3 , X 4 or A contain double bonds or are chiral compounds, give rise to the spatial isomers. The use according to the invention encompasses all the spatial isomers, both as individual pure compounds and as mixtures thereof.
Organické zlúčeniny fosforu sú vhodné na terapeutickú alebo profylaktickú liečbu infekcií ľudí a živočíchov vyvolaných vírusmi, baktériami, jednobunkovými a viacbunkovými parazitmi a hubami.Organic phosphorus compounds are useful for the therapeutic or prophylactic treatment of human and animal infections caused by viruses, bacteria, monocellular and multicellular parasites and fungi.
• ·· ·· ·· φφ ·· · · φ φ φ φ··· • · · ····· · • · φ φ φ ·· φ φ φ · ··· e · · ··· ··· ·· ·· ·· Φ· φ• · · · · · · φ · φ · e · · · · e · φ · e · · · e · · ·· ·· ·· Φ · φ
Vyššie uvedené zlúčeniny sú účinné voči jednobunkovým parazitom (Protozoa) predovšetkým voči pôvodcom malárie, spavej choroby a Chagasovej choroby, toxoplazmózy, amébovej dyzentérie, leishmaniózy, trichomoniázy, pneumocystózy, balantidiózy, kryptosporidiózy, sarkocytózy, akantoamebózy, neglerózy, kokcidiózy, giardiózy a lambliózy.The above compounds are effective against unicellular parasites (Protozoa) in particular against agents of malaria, somnolence and Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocytosis, acantoamebosis, lambiosis, gileriosis, lambiosis, lambiosis, gileriosis, lambiosis, lambiosis, lambiosis.
Z vyššie uvedeného vyplýva, že sú zvlášť vhodné na preventívnu liečbu malárie, spavej choroby a Chagasovej choroby, toxoplazmózy, amébovej dyzentérie, leishmaniózy, trichomoniázy, pneumocystózy, balantidiózy, kryptosporidiózy, sarkocytózy, akantoamebózy, neglerózy, kokcidiózy, giardiózy a lambliózyIt follows from the above that they are particularly suitable for the preventive treatment of malaria, sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcocytosis, acanthoameboses, neglerosis, coccidiosis, gicosis, gicosis
Účinné zlúčeniny podľa vynálezu možno použiť predovšetkým proti baktériám zahrnujúcim:In particular, the active compounds according to the invention can be used against bacteria comprising:
baktérie čeľade Propionibacteriaceae, predovšetkým rod Propionibacterium, zvlášť druhov Propionibacterium acnes, baktérie čeľade Actinimycetaceae, predovšetkým rod Actinomyces, baktérie rodu Corynebacterium, predovšetkým druhy Corynebacterium diphtheriae a Corynebacterium pseudotuberculosis, baktérie čeľade Mycobacetriaceae, rod Mycobacterium, predovšetkým druhy Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacetrium bovis a Mycobacterium avium, baktérie čeľade Chlamydiaceae, predovšetkým druhy Chlamydia trachomatis a Chlamydia psittaci, baktérie rodu Listeria, predovšetkým druhy Listeria monocytogenes, baktérie druhov Erysipelthrix rhusiopatiae, baktérie rodu Clostridium, baktérie rodu Yersinia, druhy Yersinia pestis, Yersinia pseudotubercolosis, Yersinia enterocolitica a Yersinia ruckeri, baktérie čeľade Mycoplasmataceae, rody Mycoplasma a Ureaplasma, predovšetkým druhy Mycoplasma pneumoniae, baktérie rodu Brucella, baktérie rodu Bordatella, baktérie čeľade Neisseriaceae, predovšetkým rody Neisseria a Moraxella, zvlášť druhy Neisseria meningitides, Neisseria gonorrhoeae a Moraxella bovis, baktérie čeľade Vibrionaceae, predovšetkým rody Vibrio, Aeromonas, Plesiomonas a Photobacterium, predovšetkým druhy Vibrio cholerae, Vibrio anguillarum a Aeromonas salmonicidas, baktérie rodu Campylobacter, predovšetkým druhy Campylobacter jejuni, Campylobacter coli a Campylobacter fetus, baktérie rodu Helicobacter, predovšetkým druhy Helicobacter pylori, baktérie čeľadí • ·· ·· ·· «e · ···· · · · · · c ·· ······· ··· • · · · · · · ··· · · • · · · · · · ·· e ··· ·· ·· ·· ·· ··· 16bacteria of the family Propionibacteriaceae, in particular the genus Propionibacterium, in particular of the species Propionibacterium acnes, bacteria of the family Actinimycetaceae, in particular the genus Actinomyces, bacteria of the genus Corynebacterium, in particular species Corynebacterium diphtheriae and Corynebacterium pseudotuberculc. and Mycobacterium avium, bacteria of the family Chlamydiaceae, in particular Chlamydia trachomatis and Chlamydia psittaci, Listeria, in particular Listeria monocytogenes, Erysipelthrix rhusiopatiae, Clostridium, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, Yersinia, , Mycoplasmataceae, Mycoplasma and Ureaplasma, in particular Mycoplasma pneumoniae, Brucella, Bordate IIa, bacteria of the family Neisseriaceae, in particular genera Neisseria and Moraxella, in particular species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis, bacteria of the family Vibrionaceae, in particular genera Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular Vibrio cholerailumum, Vibrio cholerailumum, Campylobacter, in particular Campylobacter jejuni, Campylobacter coli and Campylobacter fetus, Helicobacter spp., In particular Helicobacter pylori species, family of bacteria. ··· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·
Spirochaetaceae a Leptospiraceae, predovšetkým rody Treponema, Borrelia a Leptospira, predovšetkým druh Borrelia burgdorferi, baktérie rodu Actinobacillus, baktérie čeľade Legionellaceae, rod Legionella, baktérie čeľade Rickettsiaceae a čeľade Bartonellaceae, baktérie rodu Nocardia a Rhodococcus, baktérie rodu Dermatophilus, baktérie čeľade Pseudomonadaceae, predovšetkým rody Pseudomonas a Xanthomonas, baktérie čeľade Enterobacteriaceae, predovšetkým rody Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia a Shigella, baktérie čeľade Pasteurellaceae, predovšetkým rod Haemophillus, baktérie čeľade Micrococcaceae, predovšetkým rod Micrococcus a Staphylococcus, baktérie čeľade Streptococcaceae, predovšetkým rody Streptococcus a Enterococcus a baktérie čeľade Bacillaceae, predovšetkým rody Bacillus a Clostridium.Spirochaetaceae and Leptospiraceae, especially Treponema, Borrelia and Leptospira, especially Borrelia burgdorferi, Actinobacillus, Legionellaceae, Legionella, Rickettsiaceae, and Bartonellaceae bacterium, Bacteria, Bacteria, Bacteria, Bacteria, Bacteria Pseudomonas and Xanthomonas spp., Enterobacteriaceae, in particular Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella spp., Pasteurellaceae spp., in particular Haemophillus spp. and Enterococcus and bacteria of the family Bacillaceae, especially the genera Bacillus and Clostridium.
Organické zlúčeniny fosforu a ich deriváty sú preto vhodné na liečbu diftérie, akné vulgaris, listerióz, prasacej červienky zvierat, plynnej sneti ľudí a zvierat, maligného edému ľudí a zvierat, tuberkulózy ľudí a zvierat, lepry a ďalších mykobakteriálnych ochorení ľudí a zvierat, paratuberkulózy zvierat, mezenteriálnej lymfadenitídy a pseudotuberkulózy ľudí a zvierat, cholery, legionárskej choroby, boreliózy ľudí a zvierat, leptospiróz ľudí a zvierat, syfilídy, infekcii ľudí a zvierat vyvolaných Campylobacter enteritis, keratokonjuktivitídy a serozitídy zvierat, brucelózy zvierat a ľudí, antraxu u ľudí a zvierat, aktinomykóz ľudí a zvierat, streptotrichóz, psitakózy/ornitózy zvierat, horúčky Q, ehrlichiózy.Organic phosphorus compounds and derivatives thereof are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, swine, animal and animal gas, human and animal malignant edema, human and animal tuberculosis, leprosy and other mycobacterial human and animal diseases, paratuberculosis of animals , mesenterial lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires disease, human and animal borreliosis, human and animal leptospirosis, syphilis, human and animal infections caused by Campylobacter enteritis, keratoconjunctivitis and serositis of animals, animal and human brucellosis, anthrax in humans and animals, human and animal actinomycoses, streptotrichosis, psittacosis / ornithosis of animals, fever Q, ehrlichiosis.
Použitie uvedených zlúčenín je zvlášť výhodné na eradikáciu baktérií Helicobacter z vredov v gastrointestinálnom trakte.The use of said compounds is particularly advantageous for the eradication of Helicobacter bacteria from ulcers in the gastrointestinal tract.
Na liečbu vyššie uvedených chorôb je tiež možné použiť kombinácie s ďalšími antibiotikami. Na liečbu tuberkulózy sú zvlášť vhodné kombinované prípravky obsahujúce izoniazid, rifampicin, pyrazínamid, streptomycín, protiónamid a dapson s ďalšími protiinfekčnými prostriedkami fCombinations with other antibiotics may also be used to treat the above diseases. Combination formulations containing isoniazide, rifampicin, pyrazinamide, streptomycin, protonamide and dapson with other anti-infective agents are particularly suitable for the treatment of tuberculosis.
Účinné zlúčeniny podľa vynálezu sú predovšetkým ďalej vhodné na použitie pri infekciách vyvolaných nasledujúcimi vírusmi.In particular, the active compounds of the invention are further suitable for use in infections caused by the following viruses.
·· ·· • ·· ·· ·· ·· · · ···· · · • · · ···· · · ·· · · · ·· ··· · · • · · ···· 9 9 9 jy ..............··························· 9 9 9 jy ..............
Parvoviridae: parvovírusy, dependovírusy, densovírusy; Adenoviridae adenovírusy, mastadenovírusy, aviadenovírusy;Parvoviridae: parvoviruses, dependoviruses, densoviruses; Adenoviridae adenoviruses, mastadenoviruses, aviadenoviruses;
Papovaviridae' papovavírusy, predovšetkým papilomavírusy (takzvané vírusy bradavíc), polyomavírusy, predovšetkým JC vírus, BK vírus a miopapovavírusy,Papovaviridae 'papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus and miopapovaviruses,
Herpesviridae: všetky herpetické vírusy , predovšetkým vírusy herpes simplex, varicella-zooster, ľudský cytomegalovírus, vírusy Epstein-Barr, všetky ľudské herpetické vírusy, ľudský herpesvírus 6, ľudský herpesvírus 7, ľudský herpesvírus 8; Poxviridae: poxvírusy, ortopoxvírusy, parapoxvírusy, molluscum contagiosum vírus, avivírusy, caprivírusy, leporipoxvírusy, všetky primárne hepatotropné vírusy, vírusy hepatitídy, vírusy hepatitídy A, vírusy hepatitídy B, vírusy hepatitídy C, vírusy hepatitídy D, vírusy hepatitídy E, vírusy hepatitídy F, vírusy hepatitídy G; Hepadnavírusy: všetky hepatitídové vírusy, vírus hepatitídy B, vírusy hepatitídy D; Picornaviridae: pikornavírusy, všetky enterovírusy, všetky poliovírusy, všetky Coxsackie vírusy, všetky echovírusy, všetky rinovírusy, vírus hepatitídy A, aftovírusy; Calciviridae' vírusy hepatitídy E; Reoviridae· reovírusy, orbivírusy, rotavírusy; Togaviridae: togavírusy, alfavírusy, rubivírusy, pestivírusy, rubeolla vírus, Flaviviridae: flavivírusy, FSME vírus, vírus hepetitídy C; Orthomyxoviridae: všetky chrípkové vírusy, Paramyxoviridae paramyxovírusy, morbilli vírus, pneumovírus, vírus osýpok a príušníc; Rhabdoviridae: rhabdovírusy, rabies vírus, iyssavírus, vírus vaskulárnej stomatitídy; Coronaviridae: coronavírusy, Bunyaviridae: Bunyavírusy, nairovírus, phlebovírus, uukuvírus, hantavírus, Hantaan vírus, Arenaviridae: arenavírusy, vírus lymfocytárnej choriomeningitídy, Retroviridae: retrovírusy, všetky HTLV vírusy, vírus ľudskej T-lymfocytárnej leukémie, onkornavírusy, spumavírusy, lentivírusy a všetky HIV; Filoviridae: vírusy Marburg a Ebola, pomaly pôsobiace vírusy, prióny, onkovírusy a vírusy leukémie.Herpesviridae: all herpes viruses, in particular herpes simplex viruses, varicella-zooster, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpesvirus 6, human herpesvirus 7, human herpesvirus 8; Poxviridae: poxviruses, orthopoxviruses, parapoxviruses, molluscum contagiosum virus, aviviruses, capriviruses, leporipoxviruses, all primary hepatotropic viruses, hepatitis viruses, hepatitis A viruses, hepatitis D viruses, hepatitis D viruses, C virus hepatitis viruses, hepatitis G viruses; Hepadnaviruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses; Picornaviridae: picornaviruses, all enteroviruses, all polioviruses, all Coxsackie viruses, all echoviruses, all rhinoviruses, hepatitis A virus, aftoviruses; Calciviridae 'hepatitis E viruses; Reoviridae · reoviruses, orbiviruses, rotaviruses; Togaviridae: togaviruses, alphaviruses, rubiviruses, pestiviruses, rubella virus, Flaviviridae: flaviviruses, FSME virus, hepetitis C virus; Orthomyxoviridae: all influenza viruses, Paramyxoviridae paramyxoviruses, morbilli virus, pneumovirus, measles and mumps virus; Rhabdoviridae: rhabdoviruses, rabies virus, iyssavirus, vascular stomatitis virus; Coronaviridae: coronaviruses, Bunyaviridae: Bunyaviruses, nairovirus, phlebovirus, uucvirus, hantavirus, Hantaan virus, Arenaviridae: arenaviruses, lymphocytic choriomeningitis virus, Retroviridae: retroviruses, human lymphocytic virus, all HTLVirus viruses ; Filoviridae: Marburg and Ebola viruses, slow-acting viruses, prions, oncoviruses and leukemia viruses.
Organické zlúčeniny fosforu použité podľa vynálezu sú preto vhodné na potlačovanie nasledujúcich vírusových infekcií.The organic phosphorus compounds used according to the invention are therefore suitable for controlling the following viral infections.
Na eradikáciu papilomavírusov na prevenciu vzniku tumorov, predovšetkým tumorov v pohlavných orgánoch, spôsobených papilomavírusmi u ľudí, na • ·· ·· ·· ·· · · · · · · • · · · · ·· ·· ··· ·· · • · · · · · · ··· ·· ·· ·· ·· ·· ··· eradikáciu JC vírusov a BK vírusov, na eradikáciu herpesvírusov, na eradikáciu ľudských herpesvírusov 8 pri liečbe Kaposiho sarkómu, na eradikáciu cytomegalovírusov pred transplantáciami, na eradikáciu vírusov Epsteina-Barrovej pred transplantáciami a na prevenciu tvorby tumorov spojovaných s vírusmi Epsteina-Barrovej, na eradikáciu vírusov hepatitídy pri liečbe chronických ochorení pečene a na prevenciu vzniku tumorov pečene a cirhózy pečene, na eradikáciu Coxsackie vírusov u pacientov s kardiomyopatiou, na eradikáciu Coxsackie vírusov u pacientov s diabetes mellitus, na eradikáciu vírusov oslabujúcich imunitný systém ľudí a zvierat, na liečbu sekundárnych infekcií pacientov trpiacich AIDS, na liečbu zápalov vírusového pôvodu respiračného traktu (larynx papillomas, hyperlázie, rhinitis, faringitida, bronchitída, pneumónia), zmyslových orgánov (keratokonjunktivitída), nervového systému (poliomyelitída, meningoencefalitída, encefalitída, subakútna sklerotizujúca panencefalitída (SSPE), progresívna viacložisková leukoencefalopatia, lymfocytárna choriomeningitida), gastrointestinálneho traktu (stomatitída, gingivostomatitída, ezofagitída, gastritída, gastroenteritída, choroby prejavujúce sa hnačkou), pečene a žlčníka (hepatitída, cholangitída, hepatocelulárny karcinóm), lymfatických tkanív (mononukleóza, lymfadenitída), hemopoetického systému, pohlavných orgánov (orchitida pri príušniciach), kože (bradavice, dermatitída, herpes labialis, potničky, herpes zoster, pásový opar), mukóznych slizníc (papilómy, papilómy spojivky, hyperplázia, dysplázia), kardiovaskulárneho systému (arteriitída, myokarditída, endokarditída, perikarditída), obličiek/močového systému, pohlavných orgánov (anogenitálne lézie, bradavice, genitálne bradavice, akútne kondylómy, dysplázie, papilómy, dysplázie cervixu, condyloma accuminatum, epidermodysplasia verruciformis), pohybových orgánov (myozitída, myalgia), na liečbu ochorení tlamy a kopýt párnokopytníkov, Koloradskej kliešťovej horúčky, dengue syndrómu, hemoragickej horúčky, skorej letnej meningoencefalitídy (FSME) a žltej horúčky.For the eradication of papillomaviruses to prevent the onset of tumors, particularly tumors in the genital organs, caused by papillomaviruses in humans, to: · · · · · · · · · · · · · · · · · · · · · · · · Eradication of JC and BK viruses, for the eradication of herpesviruses, for the eradication of human herpesviruses 8 in the treatment of Kaposi's sarcoma, for the eradication of cytomegaloviruses prior to transplantation, for the eradication of Epsteine-Barr viruses prior to transplantation and for the prevention of Epstein-Barr-associated tumors, for the eradication of hepatitis viruses in the treatment of chronic liver diseases and for the prevention of liver and liver cirrhosis, for the eradication of Coxsackie viruses in cardiomyopathy patients Coxsackie viruses in patients with diabetes mellitus, for eradication of viruses that weaken the immune system of humans and animals, for the treatment of secondary infections of patients suffering from AIDS, for the treatment of inflammations of viral origin of the respiratory tract (larynx papillomas, hyperlasia, rhinitis, faringitis, bronchitis, pneumonia), sensory organs (keratoconjunctivitis), nervous system (poliomyelitis, SS, meningoencephalitis, paningoencephalitis, paningoencephalitis) progressive multi-focus leukoencephalopathy, lymphocytic choriomeningitis), gastrointestinal tract (stomatitis, gingivostomatitis, esophagitis, gastritis, gastroenteritis, diarrhea manifestations, lymphoma, lymphoma, hepatitis), hepatitis, genital organs (mumps orchitis), skin (warts, dermatitis, herpes labialis, sweats, herpes zoster, shingles), mucosal mucosa (papillomas, conjunctival papillomas, hyperplasia, dysplasia), cardiovascular system in (arteriitis, myocarditis, endocarditis, pericarditis), kidney / urinary system, genital organs (anogenital lesions, warts, genital warts, acute condylomas, dysplasia, papillomas, dysplasia of the cervixodus, myocardial epithelium, condyloma accuminitis, condyloma accuminitis) ), for the treatment of diseases of the muzzle and hoofed biungulates, Colorado tick fever, dengue syndrome, hemorrhagic fever, early summer meningoencephalitis (FSME), and yellow fever.
Opísané zlúčeniny, t.j. organické zlúčeniny fosforu všeobecných vzorcov (I), (III) a (IV) a ich estery a amidy s fosfínovou skupinou a ich soli, majú významnú cytotoxickú účinnosť voči jednobunkovým a viacbunkovým parazitom, predovšetkým voči patogénnym pôvodcom malárie a spavej choroby. Uvedené zlúčeniny podľa vynálezu môžu teda liečiť infekčné choroby vyvolané vi19 rusmi, parazitmi a hubami u ľudí a zvierat. Uvedené zlúčeniny sú tiež vhodné na prevenciu pred chorobami vyvolanými vírusmi, parazitmi a hubami, predovšetkým môžu byť použité ako profylaktické prostriedky voči malárii a spavej chorobe.The disclosed compounds, i. the organic phosphorus compounds of the general formulas (I), (III) and (IV) and their phosphine group esters and amides and their salts have significant cytotoxic activity against monocell and multicellular parasites, in particular against pathogenic agents of malaria and sleeping sickness. Thus, the compounds of the invention can treat infectious diseases caused by Russian, parasite and fungi in humans and animals. Said compounds are also suitable for the prevention of diseases caused by viruses, parasites and fungi, in particular they can be used as prophylactic agents against malaria and sleeping sickness.
Organické zlúčeniny fosforu vhodné na použitie podľa vynálezu, ktoré všeobecne zahrnujú farmaceutický prijateľné soli, amidy, estery, a soli týchto • esterov alebo ďalšie zlúčeniny, ktoré pri aplikácii poskytujú zlúčeniny vhodné na použitie podľa vynálezu vo forme metabolických produktov alebo rozkladných produktov, nazývané tiež ako proliečivá, možno pre podanie spracovať podobne ako iné známe antiinfekčné prostriedky ktorýmkoľvek vhodným spôsobom (zmiešaním s netoxickou farmaceutický prijateľnou prísadou).Organic phosphorus compounds suitable for use in the present invention, which generally include pharmaceutically acceptable salts, amides, esters, and salts of these esters, or other compounds which upon application provide compounds suitable for use in the form of metabolic products or decomposition products, also referred to as prodrugs may be formulated for administration, similar to other known anti-infective agents, by any suitable means (by mixing with a non-toxic pharmaceutically acceptable excipient).
Farmaceutický prijateľné soli uvedených zlúčenín zahrnujú soli, ktoré tvoria zlúčeniny podľa vynálezu všeobecných vzorcov (I), (III) a (IV) v ich protonizovanej forme ako amóniových solí anorganických alebo organických kyselín ako je kyselina chlorovodíková, kyselina sírová, kyselina citrónová, kyselina maleínová, kyselina fumarová, kyselina vínna, kyselina ptoluénsulfónová.Pharmaceutically acceptable salts of said compounds include salts which form the compounds of the formulas (I), (III) and (IV) in their protonated form as ammonium salts of inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid , fumaric acid, tartaric acid, ptoluenesulfonic acid.
Farmaceutický zvlášť vhodné sú soli pripravené vhodným výberom X3 a X4, ako je sodná soľ, draselná soľ, vápenatá soľ, amónna soľ, etanolamínová soľ, trietylamínová soľ, dicyklohexylamínová soľ a soli s aminokyselinou ako je soľ s kyselinou arginínovou, asparagínovou, a glutámovou.Pharmaceutically particularly suitable are salts prepared by a suitable selection of X 3 and X 4 , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt, and amino acid salts such as arginic acid, asparagine, and glutamic acid.
Aktivitu uvedených zlúčenín je možné určiť v skúšobnom systéme Tento systém je založený na in vitro stanovení inhibicie rastu parazitov, vírusov húb • alebo rastlín. Na tento účel sa používajú skúšobné systémy, z ktorých niektoré sú pracovníkom v odbore všeobecne známe.The activity of the compounds can be determined in an assay system. This system is based on an in vitro assay for inhibiting the growth of parasites, fungal viruses or plants. Test systems are used for this purpose, some of which are well known to those skilled in the art.
Napríklad pre stanovenie antimalarickej účinnosti sa stanovuje inhibícia rastu parazitárnych pôvodcov malárie v krvných kultúrach.For example, the growth inhibition of parasitic malaria agents in blood cultures is determined to determine antimalarial activity.
Stanovenie antibakteriálnej účinnosti je založené na stanovení inhibicie rastu baktérií v živnej pôde alebo pri kultivácii v tekutých kultúrachThe determination of antibacterial activity is based on the determination of the inhibition of bacterial growth in the culture medium or in cultivation in liquid cultures.
Stanovenie antivírusovej účinnosti je založené na inhibícii tvorby vírusových elementov v bunkových kultúrach.Determination of antiviral activity is based on inhibition of viral element formation in cell cultures.
Stanovenie fungicídnej účinnosti je založené na inhibícii rastu húb v živnej pôde a v tekutých kultúrach.The determination of fungicidal activity is based on the inhibition of fungal growth in the culture medium and in liquid cultures.
Niektoré mikroorganizmy, ktoré je žiaduce hodnotiť, je možné hodnotiť iba na zvieracích modeloch. V tom prípade sa používajú zodpovedajúce modelyCertain microorganisms that are desirable to be evaluated can only be evaluated in animal models. In this case, the corresponding models are used
Zlúčeniny u ktorých bola preukázaná účinnosť v in vitro pokusoch sa potom ďalej hodnotia v pokusoch in vivo Antiparazitická, antivirusová, fungicídna alebo antibakteriálna účinnosť sa ďalej hodnotí na príslušných modeloch v pokusoch na zvieratách.Compounds which have been shown to be potent in in vitro assays are then further evaluated in in vivo assays. The anti-parasitic, antiviral, fungicidal or antibacterial activity is further evaluated in appropriate animal model models.
Skríning herbicídnej účinnosti sa uskutočňuje v systémoch s použitím rias meraním emisií izoprénu z rastlín za štandardných podmienok.Herbicidal efficacy screening is performed in algae systems by measuring isoprene emissions from plants under standard conditions.
Farmaceutický účinné prostriedky je možné pripraviť ako farmaceutické prípravky obsahujúce dávkové jednotky. To znamená, že prípravok je vo forme individuálnych častíc, napríklad tabliet, dražé, toboliek, piluliek, čapíkov a ampúl, v ktorých obsah účinnej zložky zodpovedá frakcii alebo násobku jednotlivej dávky, napríklad zodpovedá 1, 2, 3 alebo 4 jednotlivým dávkam alebo 1/2, 1/3 alebo 1/4 jednotlivej dávky. Jednotlivá dávka výhodne obsahuje množstvo účinnej zložky, ktoré sa podáva jeden krát denne a obvykle zodpovedá celej, polovičnej, tretinovej alebo štvrtinovej dennej dávke.Pharmaceutically active compositions can be prepared as pharmaceutical compositions containing dosage units. This means that the preparation is in the form of individual particles, for example tablets, dragees, capsules, pills, suppositories and ampoules, in which the content of the active ingredient corresponds to a fraction or multiple of a single dose, for example 1, 2, 3 or 4 single doses or 2, 1/3 or 1/4 of a single dose. A single dose preferably contains an amount of active ingredient that is administered once a day and usually corresponds to an entire, half, one-third, or quarterly daily dose.
Netoxickými, inertnými, farmaceutický vhodnými prísadami sa rozumejú tuhé, polotuhé, alebo tekuté riedidlá, plnivá a pomocné prostriedky rôznych druhov.Non-toxic, inert, pharmaceutically acceptable additives are solid, semi-solid or liquid diluents, fillers and auxiliaries of various kinds.
Ako vhodné farmaceutické prípravky možno uviesť tablety, obalené tablety, tobolky, pilulky, granuly, čapíky, roztoky, suspenzie a emulzie, pasty, masti, gély, krémy, omývadlá, prášky a spreje. Tablety, obalené tablety, tobolky, pilulky a granuly môžu obsahovať okrem účinnej zložky alebo účinných zložiek obvykle prísady ako (a) plnivá a riedidlá, napríklad škroby, laktózu, • ·· ·· ·· ·· ···· ···· ··· ··· · · ·· · · • · ··· ·· ··· · • · · · · · · · · ··· ·· ·· ·· ·· · trstinový cukor, glukózu, manitol a oxid kremičitý, (b) spojivá, napríklad karboxymetylcelulózu, algináty, želatínu, polyvinylpyrolidón, (c) zvlhčovacie prostriedky napríklad glycerol, (d) suspendačné prostriedky napríklad agar, uhličitan vápenatý a uhličitan sodný, (e) retardéry rozpustnosti, napríklad parafín a (f) urýchľovače rezorpcie, napríklad kvartérne amóniové zlúčeniny, (g) zmáčacie prostriedky, napríklad cetyialkohol, glycerolmonostearát, (h) adsorpčné prostriedky, napríklad kaolín a bentonit a (i) klzné prostriedky, napríklad mastenec, stearan vápenatý a stearan horečnatý a tuhé polyetylénglykoly, alebo zmes zložiek uvedených v položkách (a) až (i).Suitable pharmaceutical preparations include tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays. Tablets, coated tablets, capsules, pills, and granules may contain, in addition to the active ingredient (s), usually additives such as (a) fillers and diluents, for example starches, lactose, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · and silica, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, (c) wetting agents such as glycerol, (d) suspending agents such as agar, calcium carbonate and sodium carbonate, (e) solubility retarders such as paraffin and ( f) resorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and bentonite, and (i) glidants such as talc, calcium stearate and magnesium stearate and here or polyethylene glycols, or a mixture of the components specified in (a) to (i).
Tablety, obalené tablety, tobolky, pilulky a granuláty môžu byť vybavené obvyklými poťahmi a obalmi prípadne s obsahom prostriedkov brániacich prístupu svetla, ale je tiež možné spracovať ich do foriem, u ktorých dochádza k uvoľňovaniu aktívnej zložky alebo aktívnych zložiek iba s oddialením uvoľnenia alebo výhodne v špecifickej časti intestinálneho traktu, kde ako matricové zlúčeniny sa používajú napríklad polymérne substancie a vosky.Tablets, coated tablets, capsules, pills and granules may be provided with conventional coatings and coatings, optionally containing light-blocking agents, but may also be formulated to release the active ingredient or active ingredients only with delayed release or preferably in a specific part of the intestinal tract where, for example, polymeric substances and waxes are used as matrix compounds.
Účinná zložka alebo účinné zložky môžu tiež byť spracované do mikrozapuzdrenej formy s jednou alebo s viacerými z vyššie uvedených prísadThe active ingredient (s) may also be formulated in a microencapsulated form with one or more of the above ingredients.
Čapíky môžu okrem účinnej zložky alebo účinných zložiek tiež obsahovať obvyklé vo vode rozpustné alebo vo vode nerozpustné prísady, ako sú napríklad polyetylénglykoly, tuky, napríklad kakaové maslo a vyššie estery (napríklad ester Cu-alkoholu s Cie-mastnou kyselinou), alebo zmesi vyššie uvedených zložiek.The suppositories may also contain, in addition to the active ingredient (s), customary water-soluble or water-insoluble ingredients such as polyethylene glycols, fats, for example cocoa butter and higher esters (for example C12-C12-fatty acid ester), or mixtures of the above. components.
Masti, pasty, krémy a gély môžu okrem účinnej zložky alebo účinných zložiek obsahovať obvykle používané prísady ako napríklad živočíšne a rastlinné tuky, vosky, parafíny, škroby, tragant, deriváty celulózy, polyetylénglykoly, silikóny, bentonity, oxid kremičitý, mastenec, a oxid zinočnatý, alebo zmesi vyššie uvedených prísad.Ointments, pastes, creams and gels may contain, in addition to the active ingredient (s), commonly used ingredients such as animal and vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc, and zinc oxide or mixtures of the above additives.
Prášky a spreje môžu obsahovať okrem účinnej zložky alebo účinných zložiek obvyklé prísady, napríklad laktózu, mastenec, oxid kremičitý, hydroxid hlinitý, kremičitan vápenatý a polyamidový prášok alebo zmesi vyššie uvede22 • ·· · · B · · · · ···· ···· · · ·· ··· B · ·· · · · ·· ··· · · ··· · · ··« · · · · ·· · ··· ·· ·· ·· ·· ··· ných prísad. Spreje môžu okrem toho obsahovať obvyklé hnacie prostriedky, napríklad chiórfluóruhľovodíky.The powders and sprays may contain, in addition to the active ingredient (s), conventional additives such as lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of the foregoing. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ingredients. Sprays may additionally contain conventional propellants, for example chlorofluorocarbons.
Roztoky a emulzie môžu okrem účinnej zložky alebo účinných zložiek obsahovať obvykle používané prísady ako sú rozpúšťadlá, solubilizátory a emulgátory, napríklad voda, etylalkohol, izopropylalkohol, etylkarbonát, etylacetát, benzylalkohol, benzylbenzoát, propylénglykol, 1,3-butylénglykol, dimetylformamid, oleje, predovšetkým olej z bavlníkových semien, podzemnicový olej, kukuričný olej, olivový olej, ricínový olej, a sezamový olej, glycerol, glycerol-formal, tetrahydrofurfurylalkohol, polyetylénglykoly a estery sorbitanu s mastnými kyselinami, alebo zmesi týchto prísad.The solutions and emulsions may contain, in addition to the active ingredient (s), customary additives such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil, and sesame oil, glycerol, glycerol-formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, or mixtures of these additives.
Roztoky a emulzie môžu byť spracované do sterilných, s krvou izotonických foriem, vhodných pre parenterálnu aplikáciu.Solutions and emulsions can be formulated in sterile, blood-isotonic forms suitable for parenteral administration.
Suspenzie môžu okrem účinnej zložky alebo účinných zložiek obsahovať obvyklé piísady ako sú tekuté riedidlá, napríklad voda, etylalkohol, propylénglykol, suspendačné prostriedky, napríklad etoxylované izostearylalkoholy, polyoxyetylénsorbitol a estery sorbitanu, mikrokryštalická celulóza, metahydroxid hlinitý, bentonit, agar, a tragant alebo zmesi vyššie uvedených zložiek.The suspensions may contain, in addition to the active ingredient (s), conventional ingredients such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide or bentonite, agar of the above ingredients.
Vyššie uvedené prípravky môžu tiež obsahovať farbivá, konzervačné prostriedky a prostriedky korigujúce vôňu a chuť ako je napríklad matový olej a eukalyptový olej a sladidlá, napríklad sacharínThe above compositions may also contain coloring agents, preservatives and flavoring agents, such as, for example, frosted oil and eucalyptus oil, and sweeteners, for example saccharin.
Obsah zlúčenín všeobecného vzorca (I), (III) a (IV) vo vyššie uvedených farmaceutických prípravkoch by sa mal výhodne pohybovať v koncentráciách asi 0,1 až 99,5 % hmotn , výhodne v rozmedzí koncentrácii približne 0,5 až 95 % hmotn., vztiahnutých na celkovú hmotnosť zmesiThe content of the compounds of formula (I), (III) and (IV) in the aforementioned pharmaceutical preparations should preferably be in a concentration of about 0.1 to 99.5% by weight, preferably in a concentration range of about 0.5 to 95% by weight. %, based on the total weight of the mixture
Okrem zlúčenín všeobecného vzorca (I), (III) a (IV) môžu uvedené farmaceutické prípravky obsahovať tiež ďalšie farmaceutický účinné prostriedky.In addition to the compounds of formula (I), (III) and (IV), said pharmaceutical preparations may also contain other pharmaceutical active agents.
Zlúčeniny vyššie uvedených všeobecných vzorcov možno podávať s doposiaľ opísanými substanciami majúcimi antibakteriálne, antivírusové, fungicídne a antiparazitické vlastnosti Do tejto skupiny patria zlúčeniny ktoré sa už pri liečbe použili, alebo sa stále používajú. Zvlášť vhodné pre vyššie uvedený účel sú substancie uvedené v Red List alebo v Simon/Stille, Antibiotika-Therapie in Kliník und Praxis, 9.vydanie 1998, Schattauer Verlag alebo na Internete pod adresou http /www.customs.treas.gv/imp-exp/rulings/harmoniz/hr m I29.html. Predovšetkým je možné ich použiť s prostriedkami zahrnujúcimi penicilíny, benzylpenicilín (Penicilín G), fenoxypenicilíny, izoxazolylpenicilíny, aminopenicilíny, ampicilín, amoxicilín, bacampicilín, karboxypenicilín, tikarcilín, temocilín, acylaminopenicilíny, azlocilín, mezlocilín, piperacilín, apaicilín, mecilinam, cefalosporíny cefazolínovej skupiny, cefuroxímovej skupiny, cefoxitínovej skupiny, cefoxitín, cefotetán, cefmetazol, latamoxef, flomoxef, cefotaxímové skupiny, cefozidim, ceftazidimové skupiny, ceftazidim, cefpirom, cefepim, obvyklé cefalosporíny, cefsulodin, cefaperazon, orálne cefalosporíny cefalexínovej skupiny, loracarbef, cefprozil, nové orálne cefalosporíny s rozšíreným spektrom , cefixim, cefpodoxim-proxetil, cefuroxim-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, ďalšie β-laktámové antibiotiká, karbapenem, imipenem/cilastatín, meropenem, biapenem, aztreonam, inhibítory β-laktamázy, kyselinu klavulánovú/amoxicilín, kyselinu klavulánovú/tikarcilín, sulbaktam/ampicilín, tazobaktam/piperacilín, tetracyklíny, oxytetracyklín, rolitetracyklín, doxycyklín, minocyklín, chloramfenikol, aminoglykozidy, gentamycín, tobramycín, netilmycín, amikacin, spektinomyxín, makrolidy, erytromycín, klaritromycín, roxitromycín, azitromycín, diritromycín, spiramycin, josamycín, linkosamidy, klindamycín, kyselinu fusidovú, glykopeptidové antibiotiká, vankomycín, tekoplanin, prostinamycínové deriváty, fosfomycín, antimikrobiálne pôsobiace antagonisty kyseliny listovej, sulfónamidy, kotrimoxazol, trimetoprim, ďalšie kombinácie diaminopyrimidín-sulfónamid, nitrofurány, nitrofurantoin, nitrofurazon, inhibitory gyrázy (chinolóny), norfloxacín, ciprofloxacín, ofloxacín, sparfloxacín, enoxacín, fleroxacín, pefloxacín, lomefloxacín, Bay Y3118, nitroimidazoly, antimykobakteriálne prostriedky, izoniazid, rifampicín, rifabutin, etambutol, pyrazínamid, streptomycín, kapreomycín, protiónamid, terizidín, dapson, klofazimín, antibiotiká na topické podanie, bacitracín, tyrotricín, polymyxíny, neomycín, kanamycín, paromomycín, mupirocín, antivírusové prostriedky, aciklovir, ganciklovir, azidotymidín, didanozín, zalcitabín, tiacy24The compounds of the above formulas may be administered with the substances described to date having antibacterial, antiviral, fungicidal and antiparasitic properties. This group includes compounds that have been used or are still in use. Particularly suitable for the above purpose are the substances listed in the Red List or in Simon / Stille, Antibiotics-Therapy in Klinik und Praxis, 9th edition 1998, Schattauer Verlag or on the Internet under http /www.customs.treas.gv/imp- exp / rulings / harmonize / hr m I29.html. In particular, they can be used with formulations including penicillins, benzylpenicillin (Penicillin G), phenoxypenicillins, isoxazolylpenicillins, aminopenicillins, ampicillin, amoxicillin, bacampicillin, carboxypenicillin, ticarcillin, temocillin, cililinilcillin, acylaminopillin, cefuroxime group, cefoxitin group, cefoxitin, cefotetane, cefmetazole, latamoxef, flomoxef, cefotaxime groups, cefozidime, ceftazidime groups, ceftazidime, cefpirom, cefepime, cefalosporins, cefsuphorins, cefsulphorin, cefsulphorin extended spectrum, cefixime, cefpodoxime-proxetil, cefuroxime-axetil, cefetamet, cefotiam-hexetil, cefdinir, ceftibuten, other β-lactam antibiotics, carbapenem, imipenem / cilastatin, meropenem, ectopulamine, lactamine, lactamine, lactamine, lactamine, lactamine, lactamine, lactamine New / amoxicillin, clavulanic acid / ticarcillin, sulbactam / ampicillin, tazobactam / piperacillin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, minocycline, chloramphenicol, aminoglycosides, gentamicin, tobramycin, netilmicin, amikacin, spektinomyxín, macrolides, erythromycin, clarithromycin, roxithromycin, azithromycin , dirithromycin, spiramycin, josamycin, lincosamides, clindamycin, fusidic acid, glycopeptide antibiotics, vancomycin, tecoplanin, prostinamycin derivatives, fosfomycin, antimicrobially acting folic acid antagonists, sulfonamides, nitrrofurinide, nitrimeuronide, trimetoprimtoxide, trimetoprimide, gyrase inhibitors (quinolones), norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, enoxacin, fleroxacin, pefloxacin, lomefloxacin, Bay Y3118, nitroimidazoles, antimycobacterial agents, isoniazide, rifabutin, rifabutin, rifabutin, rifabutin n, capreomycin, protonamide, terizidine, dapson, clofazimine, antibiotics for topical administration, bacitracin, tyrotricin, polymyxins, neomycin, kanamycin, paromomycin, mupirocin, antiviral agents, aciclovir, gancicloval, dididitabine, azidotymidine, azidotymidine, azidotymidine, azidotymidine, azidotymidine, azidotymidine24
tidín, stavudín, ribavirín, idoxuridín, trifluridín, foskarnet, amantidín, interferóny, tibolové deriváty, inhibítory proteinázy, fungicídne prostriedky, polyény, amfotericín B, nystatín, natamycín, azoly, azoly pre septickú liečbu, mikonazol, ketokonazol, itrakonazol, flukonazol, UK-109,496, azoly pre topické podanie, klotrimazol, ekonazol, izokonazol, oxikonazol, bifonazol, flucytozín, grizeofulvín, ciklopiroxolamín, tolnaftát, naftifín, terbinafin, amorolfin, antrachinóny, kyselinu betulínovú, semiantrachinóny, xantóny, naftochinóny, arylaminoalkoholy, chinín, chinidíny, meflochín, halofantrín, chlorochín, amodiachín, akridín, benzonaftyridín, mepakrín, pyronaridín, dapson, sulfónamidy, sulfadoxín, sulfalény, trimetoprim, proguanil, chlórproguanil, diaminopyrimidíny, pyrimetamín, primachín, aminochinolóny, WR 238,605, tetracyklín, doxycyklin, klindamycín, norfloxacín, ciprofloxacín, ofloxacín, artemizinín, dihydroartemizinín, 10b artemether, arteether, artesunat, atovaquon, suramín, melarsoprol, nifurtimox, sodnú soľ stiboglukonátu, pentamidín, amfotericín B, metronidazol, kliochinol, mebendazol, niklozamid, praziquantel, pyrantel, tiabendazol, dietylkarbamizín, ivermektín, bitíonol, oxamnichín, metrifonát, piperazín, embonátthidine, stavudine, ribavirin, idoxuridine, trifluridine, foscarnet, amantidine, interferons, tibol derivatives, proteinase inhibitors, fungicidal agents, polyenes, amphotericin B, nystatin, natamycin, azoles, azoles for septic therapy, miconazole, ketoconazole, itraconazole, itraconazole, itraconazole, itraconazole -109,496, azoles for topical administration, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, flucytosine, grizeofulvin, ciclopiroxolamine, tolnaphthate, naphthifine, terbinafine, amorolfine, anthraquinones, betulinic acid, quinoleaquinone, quinoleaquinone quinone, quinoleaquinone quinone, quinoline quinone, quinoline quinine , halofantrine, chloroquine, amodiaquine, acridine, benzonaphthyridine, mepacrine, pyronaridine, dapson, sulfonamides, sulfadoxin, sulfalenes, trimethoprim, proguanil, chloroproguanil, diaminopyrimidines, pyrimethamine, primachine, clinocinone, tinacin, quinoline, aminoquinoline, ofloxacin, artemizinin, dihydroartemizinin, 10 b artemether, arteether, artesunate, atovaquone, suramine, melarsoprole, nifurtimox, stibogluconate sodium, pentamidine, amphotericin B, metronidazole, clioquinol, mebendazole, niclozamide, praziquantel, pyrantel, piperazine, tiabendinone, diethylcarbone, diethylcarbone, diethylcarbone pamoate
Uvedené organické zlúčeniny fosforu môžu byť obsiahnuté vo farmaceutických prípravkoch v kombinácii so substanciou zo skupiny zahrnujúcej sulfónamid, sulfadoxín, artemizinín, atovaquon, chinín, chlorochín, hydroxychlorochín, meflochín, halofantrín, pyrimetamín, armezín, tetracyklíny, doxycyklin, proguanil, metronidazol, praziquantel, niklozamid, mebendazol, pyrantel, tiabendazol, dietylkarbamazín, piperazín, pyrivinum, metrifonát, oxamnichín, bitionol a suramín, alebo s dvoma alebo s viacerými substanciami z tejto skupiny.Said organic phosphorus compounds may be contained in pharmaceutical preparations in combination with a substance selected from the group consisting of sulfonamide, sulfadoxin, artemizinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, armesine, tetracycline amide, doxycycline, proxycycline, doxycycline, doxycycline, , mebendazole, pyrantel, thiabendazole, diethylcarbamazine, piperazine, pyrivinum, metrifonate, oxamnichine, bitionol and suramine, or with two or more of this group.
Vyššie uvedené farmaceutické prípravky sa pripravia známymi spôsobmi s použitím známych postupov, napríklad zmiešaním účinnej zložky alebo účinných zložiek s prísadou alebo s prísadami.The above pharmaceutical preparations are prepared by known methods using known methods, for example by mixing the active ingredient or active ingredients with the additive or additives.
Vyššie uvedené prípravky možno podávať ľuďom a zvieratám orálne, rektálne, parenterálne (intravenózne, intramuskulárne, subkutánne), intracisternálne, intravaginálne, intraperitoneálne, topicky (vo forme prášku, masti, kvapiek) a na liečbu infekcií v kavernách a v telesných dutinách. Vhodné príprav• ·· ·· ·· ·· ···· ···· · ······· · · · ·· ··· · · ··· · · ··· ···· ·· · ··· ·· ·· ·· ·· ··· 25 ky zahrnujú injekčné roztoky, roztoky a suspenzie na orálne podanie, gély, infúzne prípravky, emulzie, masti alebo kvapky Na topickú liečbu je tiež možné použiť oftalmologické a dermatologické prípravky s obsahom solí striebra a ďalších solí, ušné kvapky, očné masti, prášky alebo roztoky Podanie zvieratám je možné realizovať vo vhodnej forme s potravou alebo s vodou. U ľudí a zvierat je tiež možná aplikácia vo forme gélov, prípravkov tvoriacich prášky, práškov, tabliet, tabliet s riadeným uvoľňovaním, premixov, koncentrátov, granúl, peliet, tabliet, ako bolus, toboliek, aerosólov, sprejov, prípravkov na inhaláciu. Zlúčeniny podľa vynálezu možno okrem toho včleniť do ďalších nosných prostriedkov, ako sú napríklad prostriedky z plastických hmôt (plastové prostriedky pre topickú liečbu), kolagén alebo kostný cement.The above formulations can be administered to humans and animals orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, topically (in the form of powder, ointment, drops) and for treating cavity and body cavity infections. Appropriate preparation ·········································· These include injectable solutions, solutions and suspensions for oral administration, gels, infusion preparations, emulsions, ointments or drops. Ophthalmological and dermatological preparations may also be used for topical treatment. containing silver salts and other salts, ear drops, eye ointments, powders or solutions The animals may be administered in a suitable form with food or water. Application in the form of gels, powders, powders, tablets, controlled release tablets, premixes, concentrates, granules, pellets, tablets such as bolus, capsules, aerosols, sprays, inhalation preparations is also possible in humans and animals. In addition, the compounds of the invention may be incorporated into other carriers, such as, for example, plastic (topical treatment), collagen or bone cement.
Všeobecne je ako v humánnej tak vo veterinárnej medicíne výhodné podávať na dosiahnutie požadovaných výsledkov účinnú zložku alebo účinné zložky všeobecných vzorcov (I), (III) a (IV) v celkových množstvách asi 0,05 až asi 600, výhodne 0,5 až 200 mg/kg telesnej hmotnosti každých 24 hodín, prípadne rozdelených do dvoch alebo viacerých jednotlivých dávok Jednotlivá dávka výhodne obsahuje aktívnu zložku alebo aktívne zložky v množstve od asi 1 do asi 200, predovšetkým 1 až 60 mg/kg telesnej hmotnosti. Môže však byť výhodné podávať množstvo odlišné od dávok uvedených vyššie, a to v závislosti od typu pacienta a jeho telesnej hmotnosti, od podstaty a závažnosti choroby, druhu prípravku a spôsobu podávania farmaceutického prípravku a tiež od doby podávania prípravku.In general, both in human and veterinary medicine, it is advantageous to administer the active ingredient (s) of formulas (I), (III) and (IV) in total amounts of about 0.05 to about 600, preferably 0.5 to 200, to achieve the desired results. mg / kg of body weight every 24 hours, optionally divided into two or more individual doses The single dose preferably contains the active ingredient (s) in an amount of about 1 to about 200, in particular 1 to 60 mg / kg of body weight. However, it may be advantageous to administer an amount different from the above dosages, depending on the patient's type and body weight, the nature and severity of the disease, the type of formulation and the route of administration of the pharmaceutical formulation, as well as the time of administration.
V niektorých prípadoch teda môže postačovať podávať dávky účinnej zložky menšie než sú uvedené vyššie, zatiaľ čo v iných prípadoch je potrebné vyššie uvedené dávky účinnej zložky prekročiť. Pracovník v odbore bude iste schopný na základe svojich skúseností určiť v každom jednotlivom prípade optimálnu dávku a spôsob aplikácie účinnej zložkyThus, in some cases it may be sufficient to administer doses of the active ingredient less than those mentioned above, while in other cases the above-mentioned doses of the active ingredient need to be exceeded. The person skilled in the art will certainly be able to determine, on the basis of his / her experience, the optimum dose and method of administration of the active ingredient in each case.
Zlúčeniny podľa vynálezu sa podávajú zvieratám v obvyklých koncentráciách a prípravky na veterinárne použitie sa podávajú s potravou alebo v prípravkoch spracovaných do formy krmiva, alebo s vodou na napájanie zvierat.The compounds of the invention are administered to the animals in the usual concentrations, and the preparations for veterinary use are administered with food or in feed formulations, or with water to feed the animals.
Zlúčeniny podľa vynálezu majú okrem toho veľmi výhodné uplatnenie ako baktericídne, fungicídne a herbicídne prostriedky pri ošetrovaní rastlín.In addition, the compounds according to the invention have a very advantageous application as bactericidal, fungicidal and herbicidal agents in the treatment of plants.
Ak je štruktúra zlúčeniny známa, pracovník v odbore je obvykle schopný navrhnúť na základe analógie so známymi zlúčeninami spôsob prípravy. Spôsoby prípravy niektorých zlúčenín podľa vynálezu sú uvedené formou príkladov nižšie.If the structure of the compound is known, one of ordinary skill in the art will be able to design a method of preparation based on analogy with known compounds. Methods for preparing some of the compounds of the invention are exemplified below.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
5-[2-(fosfóno)etyl]-N-hydroxypyrolidin-2-ón (1)5- [2- (Phosphono) ethyl] -N-hydroxypyrrolidin-2-one (1)
N-fluorenyímetoxykarbonyl-pyrolidin-2-yl-metanol (la)N-fluorenylmethoxycarbonyl-pyrrolidin-2-yl-methanol (1a)
Roztok 476 g (1,85 mol) l-(9-fluorenylmetyl)esteru kyseliny chlórmravčej (F-MOC) v 1 1 dioxánu sa pridá pomaly, za chladenia ľadom, k roztoku 182 g (1,8 mol) pyrolidin-2-yl-metanolu v 1200 ml dioxánu a 1800 ml 10% roztoku uhličitanu sodného. Pripravená zmes sa mieša 4 hodiny pri uvedenej teplote a potom 8 hodín pri teplote miestnosti, potom sa vleje do 1,5 ľadovo chladnej vody a extrahuje sa dietyléterom. Ľadom chladená vodná fáza sa potom mierne okyslí zriedenou HCI, nechá sa cez noc pri 0 °C a potom sa odfiltruje s vyhovujúcim výťažkom a čistotou produkt (la).A solution of 476 g (1.85 mol) of 1- (9-fluorenylmethyl) chloroformic acid ester (F-MOC) in 1 L of dioxane was added slowly, with ice-cooling, to a solution of 182 g (1.8 mol) of pyrrolidine-2- of methanol in 1200 ml dioxane and 1800 ml 10% sodium carbonate solution. The resulting mixture was stirred at this temperature for 4 hours and then at room temperature for 8 hours, then poured into 1.5 ice-cold water and extracted with diethyl ether. The ice-cooled aqueous phase is then slightly acidified with dilute HCl, left overnight at 0 ° C and then filtered with a suitable yield and purity of product (1a).
O-(metánsulfonylmetyl)-N-fluorenylmetoxykarbonyl-pyrolidín (1 b)O- (methanesulfonylmethyl) -N-fluorenylmethoxycarbonyl-pyrrolidine (1 b)
470 g (1,4 mol) zlúčeniny (la) sa znovu rozpusti v 300 ml absolútneho pyridínu a spojí sa so 400 g (3,5 mol) metánsulfonylchloridu. Táto zmes sa mieša v atmosfére argónu najprv 16 hodín pri 0 °C a potom ďalšie 3 hodiny pri teplote miestnosti. Potom sa zmes vleje do ľadovej zmesi a ihneď sa opakovane extrahuje dietyléterom, organická fáza sa postupne premyje ľadovo chladnou ·· ·· ·· ·· · ··· · · ·· · · ··· ······· · · · ·· ··· ·· · · · · · ··· ···· ·· · ··· ·· ·· ·· ·· ··· 27 zriedenou HC1, NaHCO3 a vodou. Po vysušení MgSO4 sa odparením získa produkt (lb), ktorý je možné prekryštalizovať z acetónu/petroléteru.470 g (1.4 mol) of compound (Ia) are redissolved in 300 ml of absolute pyridine and combined with 400 g (3.5 mol) of methanesulfonyl chloride. The mixture was stirred under argon for 16 hours at 0 ° C and then for an additional 3 hours at room temperature. The mixture is then poured into an ice mixture and immediately extracted repeatedly with diethyl ether, the organic phase is washed successively with ice-cold. Dilute with HCl, NaHCO 3, and water. Dried MgSO 4, evaporated gave the product (Ib), which can be recrystallised from acetone / petroleum ether.
2-(jódmetyl)-N-fluorenylmetoxykarbonyl-pyrolidín (1c)2- (iodomethyl) -N-fluorenylmethoxycarbonyl-pyrrolidine (1c)
K roztoku 331 g (0,8 mol) zlúčeniny (lb) v acetóne sa pridajú 3 ekvivalenty (359,7 g) Nal. Reakčná zmes sa mieša 12 hodín pri teplote miestnosti, potom sa prefiltruje, filtrát sa pridá k 800 ml vody ku ktorej bol pridaný tiosiran sodný. Zmes sa opakovane extrahuje dietyléterom, extrakty sa spoja, premyjú sa vodou, vysušia sa MgSO4 a odparia sa za zníženého tlaku. Zmes sa ponechá pri zníženej teplote, pri ktorej sa najprv získa olej, ktorý je možné rekryštalizovať z petroléteru.To a solution of 331 g (0.8 mol) of compound (1b) in acetone was added 3 equivalents (359.7 g) of NaI. The reaction mixture is stirred at room temperature for 12 hours, then filtered, the filtrate is added to 800 ml of water to which sodium thiosulfate is added. The mixture was repeatedly extracted with diethyl ether, the extracts were combined, washed with water, dried over MgSO 4 and evaporated under reduced pressure. The mixture is kept at a reduced temperature at which an oil is obtained which can be recrystallized from petroleum ether.
2-[2-(dimetylfosfóno)etyl)-pyrolidín (1 d)2- [2- (dimethylphosphono) ethyl] -pyrrolidine (1 d)
K 37,2 g (0,3 mol) dimetylesteru kyseliny metánfosfónovej v 900 ml suchého THF sa pridá pri -78 °C v atmosfére argónu po kvapkách 190 ml 1,6 M roztoku butyllítia v hexáne (zodpovedajúcich 0,30 mol). Zmes sa mieša ďalších 15 minút pri uvedenej teplote aby sa umožnilo dokončenie tvorby karbaniónu. K tomuto roztoku sa za miešania pri teplote -78 °C pridá po kvapkách 133,9 g (0,3 mol) zlúčeniny (lc) v 300 ml suchého THF. Len čo teplota dosiahne teplotu miestnosti, v miešaní sa pokračuje ďalšie 4 hodiny. Potom sa pridá 85,15 g (1 mol) piperidínu a zmes sa mieša cez noc. Potom sa zmes prefiltruje, filtrát sa vleje do 2 1 vody, organická fáza sa oddelí a vodná fáza sa 4-krát extrahuje 100 ml podielmi dichlórmetánu. Spojené organické fázy sa vysušia MgSO4, rozpúšťadlo sa odstráni a zvyšok sa spracuje frakčnou destiláciou vo vákuu. 2[2-(dimetylfosfóno)etyl)-pyrolidín (ld) sa získa vo forme bezfarebného oleja s výťažkom 3 0-40 %.To 37.2 g (0.3 mol) of methanephosphonic acid dimethyl ester in 900 ml of dry THF was added dropwise at -78 ° C under argon, 190 ml of a 1.6 M solution of butyllithium in hexane (corresponding to 0.30 mol). The mixture was stirred for an additional 15 minutes at this temperature to allow completion of carbanione formation. To this solution 133.9 g (0.3 mol) of compound (1c) in 300 ml dry THF was added dropwise with stirring at -78 ° C. Once the temperature reached room temperature, stirring was continued for an additional 4 hours. Then 85.15 g (1 mol) of piperidine is added and the mixture is stirred overnight. The mixture is filtered, the filtrate is poured into 2 l of water, the organic phase is separated and the aqueous phase is extracted 4 times with 100 ml portions of dichloromethane. The combined organic phases were dried over MgSO 4 , the solvent was removed and the residue was worked up by fractional distillation in vacuo. 2- [2- (dimethylphosphono) ethyl] -pyrrolidine (1d) was obtained as a colorless oil in a yield of 30-40%.
• ·· ·· ·· ·· · ···· · · · · · · ·· ······· e e · ·· · · 9 · · ··· · · ··· ···· ·· 9• ······················································ m available 9 ·· 9
999 99 99 99 99 999999 99 99 99 99 999
5-[2-(dimetylfosfóno)etyl]-pyrolidinón (le)5- [2- (dimethylphosphono) ethyl] -pyrrolidinone (le)
K roztoku 3,32 g (15 mmol) zlúčeniny (ld) v 50 ml suchého acetónu, ochladenému na 0 °C sa pridá po kvapkách roztok 60 mmol dimetyldioxiránu v 120 ml suchého acetónu Zmes sa mieša 30 minút pri 0 °C a potom sa rozpúšťadlo odparí vo vákuu Získaný surový produkt sa rekryštalizuje z izopropanolu. 5-[2-(dimetylfosfóno)etyl)-pyrolidinón (le) sa získa v strednom výťažku vo forme bezfarebných kryštálov.To a solution of 3.32 g (15 mmol) of compound (1d) in 50 mL of dry acetone cooled to 0 ° C was added dropwise a solution of 60 mmol of dimethyldioxirane in 120 mL of dry acetone. The mixture was stirred at 0 ° C for 30 min. the solvent was evaporated in vacuo. The crude product obtained was recrystallized from isopropanol. 5- [2- (Dimethylphosphono) ethyl) -pyrrolidinone (1e) was obtained in the medium yield as colorless crystals.
Dimetyldioxirán sa pripraví spôsobom podľa Org. Syntheses IX, 288.Dimethyldioxiran was prepared according to the method of Org. Syntheses IX, 288.
5-[2-(fosfóno)etyl]-N-hydroxy-pyrolidin-2-ón (lf)5- [2- (phosphono) ethyl] -N-hydroxy-pyrrolidin-2-one (1f)
K roztoku 1,19 g (5 mmol) zlúčeniny (le) v 50 ml suchého acetonitrilu ochladeného na 0 °C sa pridá po kvapkách roztok 3,06 g (20 mmol) trimetylbrómsilánu. Táto zmes sa mieša 3 hodiny pri teplote miestnosti, potom sa rozpúšťadlo odstráni vo vákuu, zvyšok sa znovu rozpustí v 20 ml ľadovej vody, zmes sa mieša 1 hodinu pri teplote miestnosti, dvakrát sa extrahuje 20 ml podielom éteru, hodnota pH sa upraví na 4,5 pomocou 2 M NaOH a voda sa potom odstráni v rotačnom odparovači Rotavapor najviac pri teplote 50 °C. Pevný zvyšok sa potom nechá kryštalizovať z metanolu/etylacetátu. 5-[2(fosfóno)etyl]-N-hydroxy-pyrolidin-2-ón (lf) sa získa vo vyhovujúcom výťažku vo forme žltkastých mikrokryštálov.To a solution of 1.19 g (5 mmol) of compound (1e) in 50 mL of dry acetonitrile cooled to 0 ° C was added dropwise a solution of 3.06 g (20 mmol) of trimethyl bromosilane. The mixture was stirred at room temperature for 3 hours, then the solvent was removed in vacuo, the residue was redissolved in 20 ml of ice water, stirred for 1 hour at room temperature, extracted twice with 20 ml portions of ether, adjusted to pH 4 1.5 with 2 M NaOH and water is then removed in a Rotavapor at no more than 50 ° C. The solid residue was then crystallized from methanol / ethyl acetate. 5- [2 (Phosphono) ethyl] -N-hydroxy-pyrrolidin-2-one (1f) was obtained in a suitable yield as yellowish microcrystals.
Príklad 2Example 2
3-(fosfónometyl)-N-hydroxy-pyrolidin-2-ón (2)3- (phosphonomethyl) -N-hydroxy-pyrrolidin-2-one (2)
3-metyl-N-(2-trimetylsilyletoxy)-pyrolidin-2-ón (2a)3-Methyl-N- (2-trimethylsilylethoxy) -pyrrolidin-2-one (2a)
Roztok 120 mmol etanolátu sodného v 50 ml absolútneho etanolu sa za vylúčenia vlhkosti pridá pri 0 °C k roztoku 20,37 g (120 mmol) O-(2trimetylsilyletyl)hydroxylamín-hydrochloridu v 100 ml absolútneho etanolu • ·· ···· ·· · · · ·· • · · · ··· • · · · · ·· • · · · ·· · ··· ·· ····A solution of 120 mmol of sodium ethanolate in 50 ml of absolute ethanol is added to a solution of 20.37 g (120 mmol) of O- (2-trimethylsilylethyl) hydroxylamine hydrochloride in 100 ml of absolute ethanol at 0 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·
Všetok vyzrážaný NaCI sa odfiltruje s pomocou argónu cez filter zo sintrovaného skla. Potom sa etanol z filtrátu odstráni za zníženého tlaku a len čo argón prejde zvyškom, tak sa zvyšok znovu rozpustí v absolútnom toluéne. Potom sa pridá pri 0 °C 1 mol % RhChJH^O, 5 mol % DMAP a po kvapkách 5,01 g (50 mmol) 2-metylbutyrolaktónu Zmes sa ponechá aby sa uviedla do tekutého stavu a mieša sa cez noc za refluxovania v aparatúre so separátorom vody. Po ochladení sa prchavé zložky odstránia vo vákuu pri 50 °C na rotačnom odpaľovači Rotavapor, pričom sa získa slabožlto sfarbený olej. Opätovným rozpustením oleja v 50 ml éteru, filtráciou cez krátku kolónu S1O2 a odstránením rozpúšťadla sa získa 3-metyl-N-(2-trimetylsilyletoxy)-pyrolidin-2-ón (2a) v strednom výťažku vo forme prakticky bezfarebného oleja s vyhovujúcou čistotou.All precipitated NaCl was filtered with argon through a sintered glass filter. Then, the ethanol was removed from the filtrate under reduced pressure, and as soon as the argon passed through the residue, the residue was redissolved in absolute toluene. Then, at 0 ° C, 1 mol% RhCl 3 · H 2 O, 5 mol% DMAP was added and 5.01 g (50 mmol) of 2-methylbutyrolactone was added dropwise and the mixture was allowed to flow and stirred overnight at reflux in the apparatus. with water separator. After cooling, the volatiles were removed in vacuo at 50 ° C on a Rotavapor rotary launcher to yield a pale yellow oil. Dissolution of the oil in 50 mL of ether, filtration through a short S102 column and removal of the solvent gave 3-methyl-N- (2-trimethylsilylethoxy) -pyrrolidin-2-one (2a) in medium yield as a virtually colorless oil of satisfactory purity.
3-brómmetyl-N-(2-trimetylsilyletoxy)-pyrolidin-2-ón (2b) mmol zlúčeniny (2a) rozpustených v 30 ml absolútneho tetrachlórmetánu sa spojí s 1,2 ekvivalentmi N-brómsukcínimidu a reakčná zmes sa zahrieva pri teplote spätného toku 12 hodín. V hodinových intervaloch sa pridáva po malých množstvách azobisizobutyronitril (AIBN). Po ochladení sa produkt odfiltruje od sukcínimidu, ten sa premyje CC14 a spojené podiely CC14 sa odparia za zníženého tlaku. Získaný olej sa potom spracuje chromatografiou na SiO2 a získa sa zlúčenina (2b) v nízkom výťažku.3-Bromomethyl-N- (2-trimethylsilylethoxy) -pyrrolidin-2-one (2b) mmol of compound (2a) dissolved in 30 ml of absolute carbon tetrachloride was combined with 1.2 equivalents of N-bromosuccinimide and the reaction mixture was heated to reflux. 12 hours. Small amounts of azobisisobutyronitrile (AIBN) are added in hourly intervals. After cooling, the product is filtered from succinimide, the latter is washed with CC1 4, and the combined fractions CC1 4 were evaporated under reduced pressure. The oil obtained is then chromatographed on SiO 2 to give compound (2b) in low yield.
3-(dietylfosfónometyl)-N-(2-trimetylsilyletoxy)-pyrolidin-2-ón (2c)3- (Diethylphosphonomethyl) -N- (2-trimethylsilylethoxy) -pyrrolidin-2-one (2c)
100 mmol (17,3 ml) trietylfosfitu sa spojí so 100 mmol zlúčeniny (2b) a reakčná zmes sa zahrieva 0,5 h bez rozpúšťadla pri 150 °C. Po ochladení sa zmes odparí za zníženého tlaku a žltkastý hnedý olej sa spracuje chromatografiou na S1O2 s použitím chloroformu/metanolu v pomere 25 1 Po odstránení prchavých zložiek sa vo forme žltého oleja a v strednom výťažku získa zlúčenina (2c) • ·· ·· ·· ·· · ···· · · · · ···· ······· · · · ·· · · · · · ··· · · ··· · · · · · · · ··· ·· ·· ·· ·· ···100 mmol (17.3 mL) of triethyl phosphite are combined with 100 mmol of compound (2b) and the reaction mixture is heated at 150 ° C without solvent for 0.5 h. After cooling, the mixture was evaporated under reduced pressure and the yellowish brown oil was chromatographed over SiO2 using chloroform / methanol (25 L). After removal of the volatiles, compound (2c) was obtained as a yellow oil in medium yield. ···························································· ·· ·· ·· ·· ···
3-(fo sfó no mety l)-N-(2-trimety Isi 1 y letoxy )-py rol i d i η-2-όη (2d)3- (Phosphonomethyl) -N- (2-trimethylethoxy) -pyrrolidin-2-yl (2d)
K 30 mmol zlúčeniny (2c) v 50 ml absolútneho acetonitrilu sa pridajú po kvapkách za chladenia ľadom 4 ekvivalenty (120 mmol, 15,4 ml) trimetylbrómsilánu a zmes sa mieša 15 minút pri vyššie uvedenej teplote a potom 2 h pri teplote miestnosti, a odparením za zníženého tlaku sa potom získa žltkastý olej, ktorý sa znovu rozpustí v 100 ml vody a hydrolyzuje sa 1 h pri teplote miestnosti (pri pH pod 1). Získaný roztok sa dvakrát extrahuje CHCI3, reextrahuje sa vodou a spojené vodné fázy sa odparia za zníženého tlaku pri 45 °C. Získaný žlto-hnedý olej sa potom rozpustí vo vode a pH sa upraví na 4,4 až 5,0. Po premytí ľadovou vodou sa získa prakticky bezfarebná sodná soľ zlúčeniny (2d) vo výťažku 50 %.To 30 mmol of compound (2c) in 50 mL of absolute acetonitrile was added dropwise, while cooling with ice, 4 equivalents (120 mmol, 15.4 mL) of trimethyl bromosilane, and the mixture was stirred at the above temperature for 15 minutes and then at room temperature for 2 h. evaporation under reduced pressure then gave a yellowish oil which was redissolved in 100 ml of water and hydrolyzed for 1 h at room temperature (below pH 1). The resulting solution was extracted twice with CHCl 3, re-extracted with water, and the combined aqueous phases were evaporated under reduced pressure at 45 ° C. The yellow-brown oil obtained is then dissolved in water and the pH adjusted to 4.4-5.0. After washing with ice water, the practically colorless sodium salt of compound (2d) is obtained in a yield of 50%.
3- (fosfónometyl)-N-hydroxy-pyrolidin-2-ón (2e)3- (phosphonomethyl) -N-hydroxy-pyrrolidin-2-one (2e)
5,3 mmol BF3-eterátu sa pridá k roztoku 2,65 mmol zlúčeniny (2d) v absolútnom acetonitrilu a reakčná zmes sa mieša 0,5 h pri teplote miestnosti Po odparení roztoku za zníženého tlaku sa zvyšok znovu rozpustí v 40 ml etylacetátu, premyje sa 3% soľným roztokom, vysuší sa MgSC>4, prefiltruje sa cez membránový filter a rozpúšťadlo sa odstráni za zníženého tlaku. Čistá forma produktu sa získa rekryštalizáciou z MeOH/EtOH v dobrom výťažku5.3 mmol of BF3-etherate is added to a solution of 2.65 mmol of compound (2d) in absolute acetonitrile and the reaction mixture is stirred for 0.5 h at room temperature. After evaporating the solution under reduced pressure, the residue is redissolved in 40 ml of ethyl acetate, washed with 3% brine, dried over MgSO 4, filtered through a membrane filter, and the solvent was removed under reduced pressure. The pure form of the product is obtained by recrystallization from MeOH / EtOH in good yield
Príklad 3Example 3
4-(fosfónometyl)-N-hydroxy-pyrolidin-2-ón (3)4- (phosphonomethyl) -N-hydroxy-pyrrolidin-2-one (3)
4- metyl-2[5H]-furanón (3a) g monoetylesteru kyseliny 3-metylglutárovej a 31 g octanu olovičitého sa rozpustí v 400 ml absolútneho CCI4 a reakčná zmes sa zahrieva pri teplote varu v atmosfére argónu. Potom sa zmes ožaruje 10 minút viditeľným svetlom volfrámovej lampy, počas 45 minút pokračujúceho ožarovania sa pridá • ·· ·· ·· ·· ···· ···· ··· • · · e > · · · · • · · ···· ·· · ··· ·· ·· ·· ·· ···4-Methyl-2 [5H] -furanone (3a) g of 3-methylglutaric acid monoethyl ester and 31 g of lead acetate are dissolved in 400 ml of absolute CCl 4 and the reaction mixture is heated to boiling under an argon atmosphere. The mixture is then irradiated with visible tungsten lamp light for 10 minutes, and added for 45 minutes of continued irradiation. ·····················································
23,1 g jódu. Po ochladení sa zmes prefiltruje, filtrát sa premyje vodným roztokom tiosíranu sodného, roztokom sódy a vodou, vysuší sa MgSO4 a odparí sa za zníženého tlaku. Vo forme oleja sa získa gama-jód-ester (3a'), ktorý sa priamo použije v ďalšej reakcii bez čistenia. 18,4 g čerstvo vyzrážaného octanu strieborného a 24 g anhydridu kyseliny octovej sa zahrieva pri 120 °C 1 hodinu v 82 ml ľadovej kyseliny octovej a potom sa pridá 19,1 g gama-jód-esteru 3a' a zmes sa zahrieva pri teplote spätného toku ďalšie 2 hodiny. Táto zmes sa potom udržuje 15 h pri teplote miestnosti, potom sa spojí s 300 ml éteru a prefiltruje sa. Filtrát sa premyje vodou potom vodným roztokom sódy, vodná fáza sa znovu extrahuje éterom, spojené organické extrakty sa vysušia MgSO4 a odparia sa za zníženého tlaku. Získaný olej sa potom znovu rozpustí v 70 ml 2 N NaOH, 10 ml EtOH a 50 ml vody, zmes sa opakovane extrahuje éterom a éterové podiely sa kvantitatívne odstránia. Vodná fáza sa okyslí 150 ml 6 N HCI, extrahuje sa éterom a po vysušení MgSO4 a destiláciou za zníženého tlaku (102-105 °C pri 34 torr [34.133,2 Pa]) sa získa 4,4 g 4-metyl-2[5H]-furanónu (3a) Zostávajúce stupne prípravy zlúčeniny (3) sa uskutočnia sledom reakcií opísaných v príklade 2 zahrnujúcimi použitie O-(2-trimetylsilyletyl)-hydroxylamínhydrochloridu, NBS, trietylfosfitu a hydrolýzu esterov kyseliny fosfónovej trimetylbrómsilánom a uvoľnenie cyklickej hydroxámovej kyseliny pomocou BF3eterátu. Uvedený sled reakcií je opísaný v práci Sakamoto T., Kikugawa Y., J.Org.Chem., 1994, 59, 929-931.23.1 g of iodine. After cooling, the mixture was filtered, the filtrate was washed with aqueous sodium thiosulfate solution, soda solution and water, dried over MgSO 4 and evaporated under reduced pressure. The γ-iodo-ester (3a ') is obtained as an oil which is used directly in the next reaction without purification. 18.4 g of freshly precipitated silver acetate and 24 g of acetic anhydride are heated at 120 ° C for 1 hour in 82 ml of glacial acetic acid, and then 19.1 g of gamma-iodo-ester 3a 'is added and the mixture is heated to reflux. flow for another 2 hours. The mixture was then kept at room temperature for 15 h, then combined with 300 mL of ether and filtered. The filtrate was washed with water then aqueous sodium carbonate solution, the aqueous phase was re-extracted with ether, the combined extracts were dried over MgSO4 and evaporated under reduced pressure. The oil obtained is then redissolved in 70 ml of 2 N NaOH, 10 ml of EtOH and 50 ml of water, the mixture is repeatedly extracted with ether and the ether fractions are removed quantitatively. The aqueous phase is acidified with 150 ml of 6 N HCl, extracted with ether and dried over MgSO 4 and distilled under reduced pressure (102-105 ° C at 34 torr) to give 4.4 g of 4-methyl-2. [5H] -furanone (3a) The remaining steps in the preparation of compound (3) are carried out by the sequence of reactions described in Example 2 involving the use of O- (2-trimethylsilylethyl) -hydroxylamine hydrochloride, NBS, triethylphosphite and hydrolysis of phosphonic acid esters with trimethyl bromosilane and BF 3 etherate. The sequence of reactions is described in Sakamoto T., Kikugawa Y., J. Org. Chem., 1994, 59, 929-931.
Príklad 4Example 4
N-hydroxy-3-amino-4-(fosfónometyl)-pyrolidin-2-ón (4)N-hydroxy-3-amino-4- (phosphonomethyl) pyrrolidin-2-one (4)
2-fenyl-4-(2-acetoxy-l-acetoxymetyl-etylidén)-2-oxazolin-5-ón (4a)2-Phenyl-4- (2-acetoxy-1-acetoxymethyl-ethylidene) -2-oxazolin-5-one (4a)
Do 500 ml THF sa vnesie 0,2 mol kyseliny hipurovej, 0,6 mol anhydridu kyseliny octovej, 0,24 mol 1,3-diacetoxyacetónu a 0,1 mol octanu olovnatého a reakčná zmes sa zahrieva 16 hodín v atmosfére argónu. Po ochladení na teplotu miestnosti sa anorganické soli odfiltrujú, zmes sa odparí za zníženého tlaku.To 500 ml of THF was added 0.2 mol of hippuric acid, 0.6 mol of acetic anhydride, 0.24 mol of 1,3-diacetoxyacetone and 0.1 mol of lead acetate, and the reaction mixture was heated under argon for 16 hours. After cooling to room temperature, the inorganic salts are filtered off, and the mixture is evaporated under reduced pressure.
·· ·· zvyšok sa rozpustí v 500 ml toluénu a zavádza sa plynný sírovodík tak dlho pokým sa zráža PbS, potom sa zmes prefiltruje a filtrát sa odparí. Chromatografiou na S1O2 s použitím zmesi rozpúšťadiel hexán/chloroform sa v 73% výťažku získa zlúčenina (4b)The residue is dissolved in 500 ml of toluene and hydrogen sulfide gas is introduced as long as PbS precipitates, then the mixture is filtered and the filtrate is evaporated. Chromatography on S1O2 using a hexane / chloroform solvent mixture yielded compound (4b) in 73% yield.
Diacetoxyacetón sa pripraví spôsobom podľa práce Fischer A.O.L , Mildbrand H., Ber.Dt chem Ges., 57,707, 1924.Diacetoxyacetone was prepared according to the method of Fischer A.O.L, Mildbrand H., Ber.Dt chem Ges., 57,707, 1924.
Kyselina 2-amino-3-metoxy-butánová (4b)2-Amino-3-methoxy-butanoic acid (4b)
Roztok 31,8 mol zlúčeniny (4a) v 150 ml dioxánu sa spojí s 1 g Pd/C a uskutoční sa hydrogenácia za štandardného tlaku až sa absorbuje 10 mol vodíka (4-6 h). Potom sa katalyzátor odfiltruje, zmes sa odparí do sucha, potom sa znovu rozpustí v 40 ml vody a 60 ml koncentrovanej HCI, zahrieva sa 4 hodiny pri teplote spätného toku a nechá sa cez noc v chladničke. Prefiltrovaný roztok sa potom odparí, znovu sa odparí v 50 ml vody prečistí sa na meniči iónov Amberlite IR 120, H+ s použitím 300 ml vodného roztoku amoniaku ako elučného prostriedku. Získaná zmes sa varí až do okamihu, keď amoniak nie je možné detegovať, znovu sa odparí za zníženého tlaku a produkt sa rekryštalizuje.A solution of 31.8 mol of compound (4a) in 150 ml of dioxane was combined with 1 g of Pd / C and hydrogenated under standard pressure until 10 mol of hydrogen was absorbed (4-6 h). The catalyst is filtered off, the mixture is evaporated to dryness, then redissolved in 40 ml of water and 60 ml of concentrated HCl, heated at reflux for 4 hours and left in the refrigerator overnight. The filtered solution is then evaporated, re-evaporated in 50 ml of water and purified on an Amberlite IR 120, H + ion exchanger using 300 ml of aqueous ammonia solution as eluent. The mixture is boiled until no ammonia can be detected, re-evaporated under reduced pressure and the product recrystallized.
Alfa-amino-beta-metoxy-gama-butyrolaktón (4c) mmol zlúčeniny (4b) sa mieša 15 minút pri teplote miestnosti v 20 ml 2,5% HCI. Získaný roztok sa odparí do sucha a extrahuje sa cez noc v Soxhletovom extrakčnom zariadení Odstránením rozpúšťadla za zníženého tlaku sa v prakticky kvantitatívnom výťažku získa laktón (4c).The alpha-amino-beta-methoxy-gamma-butyrolactone (4c) mmol of compound (4b) was stirred for 15 minutes at room temperature in 20 mL of 2.5% HCl. The solution obtained is evaporated to dryness and extracted overnight in a Soxhlet extraction apparatus. Removal of the solvent under reduced pressure yields the lactone (4c) in virtually quantitative yield.
Ν,Ν-dibenzylamino-beta-metoxy-gama-butyrolaktón (4d)Ν, Ν-dibenzylamino-beta-methoxy-gamma-butyrolactone (4d)
0,2 mol zlúčeniny (4c), 72 g K2CO3 a 300 mg tetrabutylamóniumjodidu a 500 mg korunkového éteru 18-crown-6 sa suspendujú v 100 ml etanolu a suspenzia sa zahreje na 40 °C Po kvapkách sa počas 15 minút pridá 0,65 mol ben ······· ··· ·· ··· ·· · · · · · ··· · · · · ·· ·0.2 mol of compound (4c), 72 g of K 2 CO 3 and 300 mg of tetrabutylammonium iodide and 500 mg of 18-crown-6 crown ether are suspended in 100 ml of ethanol and the suspension is heated to 40 ° C. 0.65 mol ben ·······························
............................
zylbromidu, zmes sa mieša 12 hodín pri teplote miestnosti, fázy sa oddelia, vodná fáza sa dvakrát premyje 75 ml podielmi éteru, organické fázy sa spoja, premyjú sa nasýteným roztokom NaCI a vysušia sa MgSO4 Po odparení za zníženého tlaku sa zmes spracuje chromatografiou na krátkej silikagélovej kolónezylbromidu, the mixture was stirred for 12 hours at room temperature, the phases were separated, the aqueous phase was washed twice with 75 ml portions of ether, the organic phases are combined, washed with saturated NaCl and dried over MgSO 4 Evaporation in vacuo the mixture is chromatographed on short silica gel column
N,N-dibenzylamino-beta-(brómmetyl)-butyrolaktón (4e)N, N-dibenzylamino-beta- (bromomethyl) -butyrolactone (4e)
K zmesi 4,12 mmol zlúčeniny (4d), 6,18 mmol PPh3 a 20 ml absolútneho acetonitrilu sa pridá 2,23 g (6,18 mmol) CBr4. Získaná zmes sa mieša 20 hodín pri teplote miestnosti, potom sa rozpúšťadlo odstráni za zníženého tlaku a chromatografiou na silikagéli s použitím etylacetátu/hexánu ako rozpúšťadla sa získa v premenlivom výťažku zlúčenina (4e) vo forme žltkastého oleja.To a mixture of 4.12 mmol of 4d, 6.18 mmol of PPh 3 and 20 mL of absolute acetonitrile was added 2.23 g (6.18 mmol) of CBr 4 . The resulting mixture was stirred at room temperature for 20 hours, then the solvent was removed under reduced pressure and chromatography on silica gel using ethyl acetate / hexane as solvent gave the variable compound (4e) as a yellowish oil in variable yield.
N,N-dibenzylamino-beta-(dimetylfosfónometyl)-butyrolaktón (4f) mmol zlúčeniny (4e) a 1 ekvivalent trimetylfosfitu v toluéne sa zahrievajú 0,5 až 1 hodinu pri teplote spätného toku. Po ochladení sa zmes odparí za zníženého tlaku a zvyšok vo forme oleja sa spracuje chromatografiou na S1O2 s použitím chloroformu/metanolu ako mobilnej fázy. Po odstránení prchavých zložiek sa v strednom výťažku získa zlúčenina (4f).N, N-dibenzylamino-beta- (dimethylphosphonomethyl) -butyrolactone (4f) mmol of compound (4e) and 1 equivalent of trimethylphosphite in toluene are heated at reflux for 0.5 to 1 hour. After cooling, the mixture was evaporated under reduced pressure and the residue as an oil was chromatographed on SiO 2 using chloroform / methanol as the mobile phase. After removal of the volatiles, compound (4f) is obtained in medium yield.
N,N-dibenzylamino-beta-(dimetylfosfónometyl)-butyrolaktám (4g)N, N-dibenzylamino-beta- (dimethylphosphonomethyl) butyrolactam (4g)
K roztoku 120 mmol O-benzylhydroxylamín-hydrochloridu v 100 ml absolútneho etanolu sa pridá pri 0 °C po kvapkách za vylúčenia vlhkosti 100 ml etanolátu sodného v 50 ml absolútneho etanolu. Všetok vyzrážaný NaCI sa odfiltruje cez filter zo sintrovaného skla s pomocou argónu. Z filtrátu sa odstráni etanol za zníženého tlaku, zvyškom sa nechá prejsť argón a potom sa rozpustí v absolútnom toluéne. Potom sa pridá pri 0 °C 1 % mol RhCl3.3H2O, 5 % mol DMAP a po k vapkách 50 ml zlúčeniny (4f) Zmes sa nechá zmäknúť do tekutého stavu a mieša sa cez noc za refluxovania s odlučovačom vody. Po ochladení ·· · · ···· ··· • · · ···· · e • · · ···· ·· · ··· ·· ·· ·· ·· ··· sa prchavé zložky odstránia vo vákuu pri 50 °C na rotačnom odpaľovači Rotavator čím sa získa zvyšok vo forme oleja. Ten sa znovu rozpustí v 40 ml etylacetátu, prefiltruje sa cez krátku kolónu SiO2 a odstránením rozpúšťadla sa získa stredný výťažok zlúčeniny (4g) vo forme žltého oleja vyhovujúcej čistoty.To a solution of 120 mmol of O-benzylhydroxylamine hydrochloride in 100 mL of absolute ethanol is added dropwise at 0 ° C with exclusion of moisture, 100 mL of sodium ethanolate in 50 mL of absolute ethanol. All precipitated NaCl was filtered through a sintered glass filter with argon. Ethanol was removed from the filtrate under reduced pressure, argon was passed through the residue, and then dissolved in absolute toluene. Then, at 0 ° C, 1 mol% of RhCl 3 .3H 2 O, 5 mol% of DMAP is added and 50 ml of compound (4f) are added dropwise. The mixture is allowed to soften and stirred overnight under reflux with a water trap. After cooling, the volatile constituents are removed after cooling. under vacuum at 50 ° C on a Rotavator to give an oil residue. This was re-dissolved in 40 mL of ethyl acetate, filtered through a short column of SiO 2 and removal of the solvent gave a medium yield of compound (4g) as a yellow oil of satisfactory purity.
N-hydroxy-3-amino-4-(dimetylfosfónometyl)-pyrolidin-2-ón (4h) mmol zlúčeniny (4g) v 60 ml metanolu a 10 ml kyseliny mravčej sa hydrogenuje s 5 % mol Pd/C (10-20 %) za štandardného tlaku 13 hodín pri teplote miestnosti. Potom sa katalyzátor odfiltruje, zmes sa odparí za zníženého tlaku a použije sa v ďalšej reakcii bez ďalšieho čistenia.Compound (4g) N-hydroxy-3-amino-4- (dimethylphosphonomethyl) -pyrrolidin-2-one (4h) mmol in 60 mL of methanol and 10 mL of formic acid was hydrogenated with 5 mol% Pd / C (10-20%). ) at standard pressure for 13 hours at room temperature. The catalyst is then filtered off, the mixture is evaporated under reduced pressure and used in the next reaction without further purification.
N-hydroxy-3-amino-4-(fosfónometyl)-pyrolidin-2-ón (4i)N-hydroxy-3-amino-4- (phosphonomethyl) pyrrolidin-2-one (4i)
K 10 mmol zlúčeniny (4h) v 20 ml absolútneho acetonitrilu sa za chladenia ľadom pridá po kvapkách 35 mmol trimetylbrómsilánu a zmes sa mieša pri uvedenej teplote 15 minút, potom 2 hodiny pri teplote miestnosti, potom sa odparí za zníženého tlaku až na žltkastý olej, ktorý sa potom znovu rozpustí v 100 ml vody a podrobí sa hydrolýze počas 1 hodiny pri teplote miestnosti. Získaný roztok sa dvakrát extrahuje CHCI3, potom sa uskutoční reextrakcia vodou a spojené vodné fázy sa odparia za zníženého tlaku pri 45 °C. Získaný tmavý olej sa znovu rozpustí vo vode a pH sa upraví na 6,0. Vyzrážaná zlúčenina (4i) sa odfiltruje a premyje sa ľadovou vodou. Zlúčenina (4i) sa získa ako sodná soľ vo forme béžových kryštálov s výťažkom 35-40 %.To 10 mmol of compound (4h) in 20 ml of absolute acetonitrile is added dropwise 35 mmol of trimethyl bromosilane under ice-cooling, and the mixture is stirred at this temperature for 15 minutes, then for 2 hours at room temperature, then evaporated under reduced pressure to a yellowish oil. which is then redissolved in 100 ml of water and subjected to hydrolysis for 1 hour at room temperature. The solution obtained is extracted twice with CHCl 3, then reextracted with water and the combined aqueous phases are evaporated under reduced pressure at 45 ° C. The dark oil obtained was redissolved in water and the pH adjusted to 6.0. The precipitated compound (4i) is filtered off and washed with ice water. Compound (4i) is obtained as the sodium salt in the form of beige crystals in a yield of 35-40%.
Príklad 5Example 5
N,2-dihydroxy-5-(2-fosfónoetyl)-pyrol (5) ·· ··N, 2-dihydroxy-5- (2-phosphonoethyl) -pyrrole (5) ·· ··
N-benzyloxy-5-[2-(dimetylfosfóno)etyl]pyrolidin-2-ón (5a) mmol 5-[2-(dimetylfosfóno)etyl]pyrolidinónu (le) sa mieša cez noc sThe N-benzyloxy-5- [2- (dimethylphosphono) ethyl] pyrrolidin-2-one (5a) mmol of 5- [2- (dimethylphosphono) ethyl] pyrrolidinone (1e) is stirred overnight with
1,2 ekvivalentami benzylbromidu, 10 mg tetrabutylamóniumjodidu a 1,3 ekvivalentami trietylamínu v 30 ml THF a potom sa vleje do ľadovej vody, zmes sa opakovane extrahuje malými podielmi éteru, dietyléterová fáza sa premyje chladnou zriedenou HC1 a nasýteným soľným roztokom, vysuší MgSO4, odparí sa a chromatografiou surového produktu na silikagéli s použitím chloroformu/metanolu 25:1 sa získa v dobrom výťažku zlúčenina (5a).1.2 equivalents of benzyl bromide, 10 mg of tetrabutylammonium iodide and 1.3 equivalents of triethylamine in 30 ml of THF and then poured into ice water, extracted repeatedly with small portions of ether, washed with cold dilute HCl and saturated brine, dried over MgSO4, Evaporate and chromatograph the crude product on silica gel using chloroform / methanol 25: 1 to give compound (5a) in good yield.
N-benzyloxy-3-fenylseleno-5-[2-(dimetylfosfóno)etyl]pyrolidin-2-ón (5b)N-Benzyloxy-3-phenylseleno-5- [2- (dimethylphosphono) ethyl] pyrrolidin-2-one (5b)
2,0 mmol zlúčeniny (5a), sa rozpustí v 1 ml absolútneho THF a mieša sa 20 minút pri -78 °C a potom sa roztok pridá pri rovnakej teplote k 2,4 mmol diizopropylamidu v 3 ml THF (LDA sa pripraví z 0,35 ml diizopropylämínu aCompound (5a) (2.0 mmol) was dissolved in absolute THF (1 mL) and stirred at -78 ° C for 20 min and then added at the same temperature to diisopropylamide (2.4 mmol) in THF (3 mL) at 0 [deg.] C. , 35 ml of diisopropyl amine and
1,6 ml 1,65 M BuLi v hexáne v atmosfére argónu pri -78 °C). K enolátu (5a) sa pridá pri -78 °C 2,4 mmol difenyldiselenidu rozpusteného ml THF a 1,2 mmol HMPT. Reakčná zmes sa mieša 40 minút pri -78 °C a 1,5 hodiny pri -40 °C Reakcia sa ukončí prídavkom 0,1 N HC1 a následnou opakovanou extrakciou éterom a po chromatografii na silikagéli sa získa žltkastý olej (5b) ktorý má charakteristický zápach.1.6 mL of 1.65 M BuLi in hexane under argon at -78 ° C). 2.4 mmol of diphenyldiselenide dissolved in 1 ml of THF and 1.2 mmol of HMPT are added to the enolate (5a) at -78 ° C. The reaction mixture was stirred at -78 ° C for 40 minutes and at -40 ° C for 1.5 hours. The reaction was quenched by the addition of 0.1 N HCl followed by repeated extraction with ether to give a yellowish oil (5b) after chromatography on silica gel. odor.
N-benzyloxy-2-hydroxy-4-[2-(dimetylfosfóno)etyl]pyrol (5c)N-benzyloxy-2-hydroxy-4- [2- (dimethylphosphono) ethyl] pyrrole (5c)
0,2 mmol fenylselénovej zlúčeniny (5b) rozpustenej v 1 ml THF sa spojí s 30 μΐ ľadovej kyseliny octovej, a potom sa pridá za chladenia ľadom po kvapkách 140 μΐ Perhydrolu (30% peroxid vodíka) a zmes sa mieša 30 minút pri vyššie uvedenej teplote Potom sa roztok vleje do chladného nasýteného vodného roztoku hydrogénuhličitanu sodného, zmes sa extrahuje éterom, vysuší sa MgSC>4, odparí sa za zníženého tlaku a chromatografiou surového produktu0.2 mmol of phenylselene compound (5b) dissolved in 1 ml of THF is combined with 30 μľad glacial acetic acid and then 140 μΐ Perhydrol (30% hydrogen peroxide) is added dropwise under ice-cooling and the mixture is stirred for 30 minutes at the above The solution was then poured into cold saturated aqueous sodium bicarbonate, extracted with ether, dried over MgSO 4, evaporated under reduced pressure and chromatographed on the crude product.
na silikagéli sa vo forme žltkastého oleja získa v dobrom výťažku zlúčenina (5c)on silica gel, compound (5c) is obtained in good yield as a yellowish oil.
N,2-dihydroxy-4-[2-(dimetylfosfóno)etyl]pyrol (5d)N, 2-dihydroxy-4- [2- (dimethylphosphono) ethyl] pyrrole (5d)
Do 50 ml absolútneho EtOH sa vnesie 0,15 mmol zlúčeniny (5c) a množstvo na špičke špachtle 10% Pd na aktívnom uhli a zmes sa hydrogenuje 1 hodinu v štandardnej tlakovej hydrogenačnej aparatúre za intenzívneho miešania. Potom sa katalyzátor odfiltruje a surový produkt sa použije v ďalšom stupni bez čistenia.0.15 mmol of compound (5c) and a spatula tip of 10% Pd on charcoal are added to 50 ml of absolute EtOH and the mixture is hydrogenated for 1 hour in a standard pressure hydrogenation apparatus with vigorous stirring. The catalyst is then filtered off and the crude product is used in the next step without purification.
N,2-dihydroxy-5-(2-fosfónoetyl)-pyrol (5e)N, 2-dihydroxy-5- (2-phosphonoethyl) -pyrrole (5e)
K 15 mmol zlúčeniny (5d) v absolútnom acetonitrile sa za chladenia ľadom pridajú 4 ekvivalenty (60 mmol, 8 ml) trimetylbrómsilánu a zmes sa mieša 15 minút pri vyššie uvedenej teplote a potom 2 hodiny pri teplote miestnosti, potom sa odparí za zníženého tlaku až na žltkastý olej, ten sa znovu rozpusti v 80 ml vody a podrobí sa hydrolýze počas 1 hodiny pri teplote miestnosti (pH < 1) Získaný roztok sa dvakrát extrahuje CHCI3, spätne sa extrahuje vodou a spojené vodné fázy sa odparia do sucha za zníženého tlaku pri teplote najviac 45 °C. Získaný olej sa znovu rozpustí vo vode a hodnota pH sa upraví pomocou NaHCCh na 4,5 až 5,0. Zlúčenina (5e) sa potom získa odfiltrovaním pomocou odsávania a premytím ľadovou vodou, vo forme prakticky bezfarebnej sodnej soli s výťažkom 40 %.To 15 mmol of compound (5d) in absolute acetonitrile was added 4 equivalents (60 mmol, 8 mL) of trimethyl bromosilane under ice-cooling, and the mixture was stirred at the above temperature for 15 minutes and then at room temperature for 2 hours, then evaporated under reduced pressure to to a yellowish oil which is redissolved in 80 ml of water and subjected to hydrolysis for 1 hour at room temperature (pH <1). The solution obtained is extracted twice with CHCl3, back-extracted with water and the combined aqueous phases are evaporated to dryness under reduced pressure temperature not exceeding 45 ° C. The oil obtained is redissolved in water and the pH is adjusted to 4.5-5.0 with NaHCO3. Compound (5e) is then obtained by filtration by suction and washing with ice water, in the form of a virtually colorless sodium salt in a yield of 40%.
Príklad 6Example 6
N-hydroxy-3-[2-(fosfóno)etyl]-lH-pyridón (6)N-hydroxy-3- [2- (phosphono) ethyl] -1H-pyridone (6)
2-bróm-3-(brómmetyl)pyridín (6a) ·· ·· • ·· ·· ·· · · ···· ···· ··· · · ·· ··· • · · · · · · ··· · · • · · ···· ·· ·2-Bromo-3- (bromomethyl) pyridine (6a) ··· ············ · ··· · · · · · · ·
............................
g (58,1 mmol) 2-bróm-3-metylpyridínu a 11,4 g (64 mmol) [sic] sa zahrieva pri teplote spätného toku 24 hodín v 250 ml CCI4. Sukcinimid sa oddelí filtráciou a organická fáza sa dvakrát premyje vodou. Po odparení za zníženého tlaku sa zlúčenina (6a) získa frakčnou kryštalizáciou vo forme bezfarebnej tekutiny (t v.: 90 °C, 1 torr (133,32 Pa)).g (58.1 mmol) of 2-bromo-3-methylpyridine and 11.4 g (64 mmol) of [sic] are heated at reflux for 24 hours in 250 ml of CCl4. The succinimide is separated by filtration and the organic phase is washed twice with water. After evaporation under reduced pressure, compound (6a) is obtained by fractional crystallization as a colorless liquid (b.p .: 90 ° C, 1 torr).
2-bróm-3-[2-(dimetylfosfóno)etyl]pyridín (6b)2-Bromo-3- [2- (dimethylphosphono) ethyl] pyridine (6b)
K 100 ml absolútneho THF sa pridá po kvapkách 0,21 mol MeLi v éteri a potom sa pridá po kvapkách počas 15 minút 0,1 mol trimetylfosfitu rozpusteného v 50 ml THF tak, aby teplota zmesi postupne dosiahla 0 °C. Potom sa pridá po kvapkách pri teplote -78 °C 0,107 mol zlúčeniny (6a) v 20 ml THF a v miešaní sa pokračuje ďalších 30 minút pri vyššie uvedenej teplote, potom sa zmes uvedie do tekutého stavu a reakcia sa preruší pri teplote 0 °C prídavkom 80 ml 3 M HCI pridávaných po kvapkách. Organická fáza sa oddelí a vodná fáza sa trikrát extrahuje 40 ml podielmi dichlórmetánu a potom po vysušení MgSC>4 sa spojené organické podiely odparia. Žltý surový produkt je možné prečistiť na krátkej kolóne SÍO2.To 100 mL of absolute THF was added dropwise 0.21 mol of MeLi in ether, and then 0.1 mol of trimethyl phosphite dissolved in 50 mL of THF was added dropwise over 15 minutes so that the temperature of the mixture gradually reached 0 ° C. 0.107 mol of compound (6a) in 20 ml THF is added dropwise at -78 ° C and stirring is continued for 30 minutes at the above temperature, then the mixture is brought to a liquid state and the reaction is stopped at 0 ° C by addition. 80 ml of 3 M HCl added dropwise. The organic phase is separated and the aqueous phase is extracted three times with 40 ml portions of dichloromethane and then, after drying over MgSO4, the combined organics are evaporated. The yellow crude product can be purified on a short SiO2 column.
2-bróm-3-[2-(dimetylfosfóno)etyl]pyridín-N-oxid (6c)2-Bromo-3- [2- (dimethylphosphono) ethyl] pyridine-N-oxide (6c)
100 mmol zlúčeniny (6b) v 60 ml ľadovej kyseliny octovej sa spojí s 2 ekvivalentami kyseliny peroctovej v 40% roztoku, pričom teplota by nemala prevýšiť 50 °C. Po 5 hodinách zahrievania pri 50 °C a 12 hodinách zahrievania pri 70 °C sa roztok odparí na polovicu svojho objemu za zníženého tlaku, vleje sa do ľadovej zmesi a zalkalizuje sa 40% vodným KOH. Reakčná zmes sa potom trikrát extrahuje chloroformom, vysuší sa K2CO3, odparí sa za zníženého tlaku a získa sa tak vo forme oleja N-oxid (6c), ktorý sa použije v ďalších reakciách bez ďalšieho čistenia100 mmol of compound (6b) in 60 ml of glacial acetic acid is combined with 2 equivalents of peracetic acid in a 40% solution, the temperature should not exceed 50 ° C. After 5 hours of heating at 50 ° C and 12 hours of heating at 70 ° C, the solution is evaporated to half its volume under reduced pressure, poured into an ice mixture and basified with 40% aqueous KOH. The reaction mixture was then extracted three times with chloroform, dried over K 2 CO 3, evaporated under reduced pressure to give an oil, N-oxide (6c), which was used in subsequent reactions without further purification.
N-hydroxy-3-[2-(dimetylfosfóno)etyl]-lH-pyridón (6d)N-hydroxy-3- [2- (dimethylphosphono) ethyl] -1H-pyridone (6d)
Zlúčenina (6c) sa zahrieva 3 hodiny pri 120 °C v absolútnom metanole spoločne s v trecej miske roztretým hydroxidom draselným, uhličitanom draselným a tris(3,6-dioxaheptyl)amínom Po ochladení sa reakčná zmes vleje do vody, hodnota pH sa upraví na 6, zmes sa odparí vo vákuu a prídavkom etanolu sa získa surový produkt, ktorý možno rekryštalizovať zo zmesi etanol/toluén za stredného výťažku.Compound (6c) was heated for 3 hours at 120 ° C in absolute methanol together with a scattering dish with ground potassium hydroxide, potassium carbonate and tris (3,6-dioxaheptyl) amine. After cooling, the reaction mixture was poured into water, adjusted to pH 6 The mixture was evaporated in vacuo and the addition of ethanol gave a crude product which could be recrystallized from ethanol / toluene in medium yield.
N-hydroxy-3-[2-(fosfóno)etylj- lH-pyridón (6e)N-hydroxy-3- [2- (phosphono) ethyl] -1H-pyridone (6e)
K ľadom chladeným 10 mmol zlúčeniny (6d) v 30 ml absolútneho acetonitrilu sa pridá po kvapkách 40 mmol trimetylbrómsilánu, zmes sa mieša 15 minút pri vyššie uvedenej teplote, potom 2 hodiny pri teplote miestnosti, potom sa odparí za zníženého tlaku až na olejový zvyšok, ktorý sa znovu rozpustí v 20 ml vody a hydrolyzuje sa 1 hodinu pri teplote miestnosti (pri kyslom pH). Tento roztok sa dvakrát extrahuje CHCI3, uskutoční sa reextrakcia vodou a spojené vodné podiely sa odparia za zníženého tlaku pri 45 °C. Získaný hnedý olej sa znovu rozpustí vo vode, dvakrát sa premieša s aktívnym uhlím, odfiltruje sa od nej, a pH sa upraví na 5 Zlúčenina (6e) ktorá sa vyzráža, sa odfiltruje, premyje sa ľadovou vodou a je možné ju rekryštalizovať z MeOH/EtOH.To ice-cooled 10 mmol of compound (6d) in 30 mL of absolute acetonitrile was added dropwise 40 mmol of trimethyl bromosilane, stirred for 15 minutes at the above temperature, then 2 hours at room temperature, then evaporated under reduced pressure to an oily residue. which was redissolved in 20 ml of water and hydrolyzed at room temperature (acidic pH) for 1 hour. This solution is extracted twice with CHCl 3, reextracted with water and the combined aqueous fractions are evaporated under reduced pressure at 45 ° C. The brown oil obtained is redissolved in water, stirred twice with activated carbon, filtered off, and the pH is adjusted to 5. The compound (6e) which precipitates, is filtered off, washed with ice water and can be recrystallized from MeOH / EtOH.
Príklad 7Example 7
N-hydroxy-6-[2-(fosfóno)etyl)-l H-pyridón (7)N-hydroxy-6- [2- (phosphono) ethyl] -1H-pyridone (7)
2-bróm-6-brómmetylpyridín (7a)2-Bromo-6-bromomethylpyridine (7a)
10,1 g (58,7 mmol) 2-bróm-6-metylpyridínu, 11,1 (62,4 mmol) Nbrómsukcínimidu (NBS) a 0,1 g (0,6 mmol) AIBN sa zahrieva 6 hodín v atmosfére argónu pri 110 °C v 150 ml toluénu, pričom zmes sa súčasne oža• ·· ·· ·· ·· · ···· ···· ···· • · · ···· ··· • · · · · ·· ··· · · • · · ···· ·· · ··· ·· ·· ·· ·· ··· 39 ruje viditeľným svetlom volfrámovej lampy (150 W, >320 nm). Po ochladení sa sukcínimid odfiltruje a roztok sa odparí za zníženého tlaku. Chromatografiou na silikagéli (mobilná fáza hexán/dichlórmetán) sa najprv získa 2-bróm-6dibrómmetylpyridín, a následnou elúciou sa vo výťažku až 45 % získa zlúčenina (7a) (t.t. 138 °C).10.1 g (58.7 mmol) of 2-bromo-6-methylpyridine, 11.1 (62.4 mmol) of N-bromosuccinimide (NBS) and 0.1 g (0.6 mmol) of AIBN are heated under argon for 6 hours at 110 [deg.] C. in 150 ml of toluene, at the same time the mixture being annealed. 39 visible light of the tungsten lamp (150 W,> 320 nm). After cooling, the succinimide is filtered off and the solution is evaporated under reduced pressure. Silica gel chromatography (hexane / dichloromethane) eluted first gave 2-bromo-6-dibromomethylpyridine, followed by elution to give compound (7a) (mp 138 ° C).
2-bróm-6-[2-(dimetylfosfóno)etyl]pyridín (7b)2-Bromo-6- [2- (dimethylphosphono) ethyl] pyridine (7b)
K 100 ml absolútneho THF sa pridá po kvapkách 0,21 mol MeLi v éteri, a potom sa pridá po kvapkách 0,1 mol trimetylfosfitu rozpusteného v 50 ml THF spôsobom, aby vnútorná teplota pomaly dosiahla 0 °C. Potom sa pridá po kvapkách pri -78 °C 0,107 mol zlúčeniny (7a) v 15 ml THF a zmes sa mieša pri rovnakej teplote ďalších 30 minút, potom sa nechá ohriať do tekutého stavu a reakcia sa preruší pri 0 °C prídavkom 80 ml 3 M HCI pridávanej po kvapkách Organická fáza sa oddelí a vodná fáza sa opakovane extrahuje 40 ml podielmi dichlórmetánu a po vysušení MgSO4 sa spojené organické podiely odparia. Surový žltý produkt možno prečistiť chromatografiou na SiO2 a zlúčenina (7b) sa získa vo výťažku 47 %.To 100 mL of absolute THF was added dropwise 0.21 mol of MeLi in ether, and then 0.1 mol of trimethyl phosphite dissolved in 50 mL of THF was added dropwise in such a way that the internal temperature slowly reached 0 ° C. 0.107 mol of compound (7a) in 15 ml THF is added dropwise at -78 ° C and the mixture is stirred at the same temperature for a further 30 minutes, then allowed to warm to liquid and quenched at 0 ° C by addition of 80 ml 3. M HCl added dropwise The organic phase is separated and the aqueous phase is repeatedly extracted with 40 ml portions of dichloromethane and, after drying over MgSO 4 , the combined organic portions are evaporated. The crude yellow product can be purified by SiO 2 chromatography and compound (7b) is obtained in a yield of 47%.
2-bróm-6-[2-(dimetylfosfóno)etyI]pyridín-N-oxid (7c) mmol zlúčeniny (7b) v ľadovej kyseline octovej sa spojí s 2 ekvivalentami kyseliny peroctovej v 40% roztoku pri teplote v rozmedzí 25 až 45 °C. Po 5 hodinách zahrievania pri 50 °C a 12 hodinách zahrievania pri 70 °C sa roztok vleje do ľadovej zmesi a zalkalizuje sa 40% vodným KOH. Po trojnásobnej extrakcii chloroformom, vysušení K2CO3 a odparení za zníženého tlaku sa získa N-oxid (7c) vo forme oleja, ktorý je možné rekryštalizovať z éteru/etanolu.2-Bromo-6- [2- (dimethylphosphono) ethyl] pyridine-N-oxide (7c) mmol of compound (7b) in glacial acetic acid was combined with 2 equivalents of peracetic acid in a 40% solution at 25-45 ° C C. After heating at 50 ° C for 5 hours and heating at 70 ° C for 12 hours, the solution was poured into ice and basified with 40% aqueous KOH. Extraction with chloroform three times, drying of K 2 CO 3 and evaporation under reduced pressure gave the N-oxide (7c) as an oil which can be recrystallized from ether / ethanol.
N-hydroxy-6-[2-(dimetylfosfóno)etyl]-1 H-pyridón (7d) • ·· ·· ·· ·· ···· ···· · • · · ···· ·e ·· ··· ·· ···· • · · ···· ··N-Hydroxy-6- [2- (dimethylphosphono) ethyl] -1H-pyridone (7d) • · · · · · · · · · ··· ·· ···· · · · ···· ··
4θ ..... ·· ···· ·4θ ..... ·· ···· ·
Zlúčenina (7c) spoločne s hydroxidom draselným spráškovaným v miske, uhličitanom draselným a tris(3,6-dioxaheptyl)amínom sa zahrieva v sklenenom autokláve 2,5 hodiny pri 100 °C v absolútnom MeOH. Po ochladení sa reakčná zmes vleje do vody a hodnota pH sa upraví na 6, zmes sa odparí vo vákuu a po prídavku etanolu sa získa surový produkt, ktorý podobne ako zlúčeninu (6d) možno za dosiahnutia stredného výťažku rekryštalizovať.Compound (7c) along with potassium hydroxide powdered in a bowl, potassium carbonate and tris (3,6-dioxaheptyl) amine was heated in a glass autoclave at 100 ° C in absolute MeOH for 2.5 hours. After cooling, the reaction mixture is poured into water and the pH is adjusted to 6, the mixture is evaporated in vacuo and ethanol is added to give a crude product which, like compound (6d), can be recrystallized to obtain a medium yield.
N-hydroxy-6-[2-(fosfóno)etyl]- ΙΗ-pyridón (7e)N-hydroxy-6- [2- (phosphono) ethyl] -4-pyridone (7e)
K ľadom chladeným 10 mmol zlúčeniny (7d) v 25 ml absolútneho acetonitrilu sa pridá po kvapkách 40 mmol trimetylbrómsilánu, zmes sa mieša 10 minút pri vyššie uvedenej teplote, potom 2 hodiny pri teplote miestnosti, potom sa odparí za zníženého tlaku až na olejový zvyšok, ktorý sa znovu rozpustí v 20 ml vody a hydrolyzuje sa 1 hodinu pri teplote miestnosti Tento roztok sa dvakrát extrahuje CHCI3, uskutoční sa reextrakcia vodou a spojené vodné podiely sa odparia za zníženého tlaku pri 45 °C Získaný tmavý olej sa znovu rozpustí vo vode a hodnota pH sa upraví na 4,8. Zlúčenina (7e) sa tak vyzráža vo forme sodnej soli. Surový produkt (7e) sa získa po filtrácii a premytí ľadovou vodou a je možné ho rekryštalizovať z MeOH/toluénu.To the ice-cooled 10 mmol of compound (7d) in 25 ml of absolute acetonitrile is added dropwise 40 mmol of trimethyl bromosilane, stirred for 10 minutes at the above temperature, then for 2 hours at room temperature, then evaporated under reduced pressure to an oily residue. This solution is extracted twice with CHCl 3, reextracted with water and the combined aqueous fractions are evaporated under reduced pressure at 45 ° C. The dark oil obtained is redissolved in water and The pH is adjusted to 4.8. Compound (7e) thus precipitates in the form of the sodium salt. The crude product (7e) is obtained after filtration and washing with ice water and can be recrystallized from MeOH / toluene.
Príklad 8Example 8
N-hydroxy-5-[(2-fosfóno-2-hydroxy)etyl]pyrolidin-2-ón(8)N-hydroxy-5 - [(2-phosphono-2-hydroxy) ethyl] pyrrolidin-2-one (8)
N-benzy 1-2-(l,3-ditioylmetyl)-pyrolidín (8a)N-benzy 1-2- (1,3-dithioylmethyl) -pyrrolidine (8a)
V atmosfére ochranného plynu sa odváži 100 mmol (12,0 g) 1,3-ditiánu, pridá sa 250 ml absolútneho THF a potom po kvapkách v priebehu 3-5 minút pri -40 °C 5% prebytok BuLi v hexáne. Táto zmes sa mieša 2 hodiny pri -25 až -15 °C, potom sa teplota zníži na -60 °C až -78 °C v atmosfére ochranného plynu sa pridá 100 mmol 2-jódmetyl-N-benzyloxy-pyrolidínu. Po 5-6 hodinách ·· ·· ·· ·· • · · · ·· e · • · · · ·· ·· • · · · ·· ···· • · ···· ·· • ·· ·· ·· ·· miešania pri -20 až -10 °C sa teplota zvýši na 0 °C a reakčná zmes sa umiestni na tri dni do chladničky. Potom sa zmes odparí na objem asi 20 ml, vleje sa do trojnásobného objemu vody, extrahuje sa päťkrát chloroformom, organické podiely sa spoja, premyjú sa postupne vodou, 6% KOH a opäť vodou a chloroformový podiel sa vysuší K2CO3. Získaný zvyšok sa použije v ďalších reakciách bez ČisteniaUnder a shielding gas atmosphere, 100 mmol (12.0 g) of 1,3-dithiane are weighed, 250 ml of absolute THF are added, and then a 5% excess of BuLi in hexane is added dropwise over 3-5 minutes at -40 ° C. The mixture was stirred at -25 to -15 ° C for 2 hours, then the temperature was lowered to -60 ° to -78 ° C under a protective gas atmosphere and 100 mmol of 2-iodomethyl-N-benzyloxy-pyrrolidine was added. After 5-6 hours · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · With stirring at -20 to -10 ° C, the temperature is raised to 0 ° C and the reaction mixture is placed in a refrigerator for three days. The mixture was then evaporated to a volume of about 20 ml, poured into three times the volume of water, extracted five times with chloroform, the organics were combined, washed successively with water, 6% KOH and again with water and dried over K 2 CO 3. The obtained residue was used in further reactions without purification
N-benzyl-2-(formylmetyl)-pyrolidín (8b)N-Benzyl-2- (formylmethyl) -pyrrolidine (8b)
K roztoku 9 mmol zlúčeniny (8a) v 30 ml THF a 6 ml vody sa pridá 1,1 g CaCO3 a 2,5 ml 4 M vodného roztoku Hg(C104)2, zmes sa premiešava ďalších 5 až 10 minút, potom sa pridá 150 ml éteru a anorganické soli sa odfiltrujú. Odparením roztoku za zníženého tlaku sa získa farebný surový produkt, ktorý sa prečistí rýchlou chromatografiouTo a solution of 9 mmol of compound (8a) in 30 mL of THF and 6 mL of water was added 1.1 g of CaCO3 and 2.5 mL of a 4 M aqueous solution of Hg (C104) 2 , stirred for an additional 5-10 minutes, then added. 150 ml of ether and inorganic salts were filtered off. Evaporation of the solution under reduced pressure gave a colored crude product which was purified by flash chromatography
N-benzyl-2-[2-(dietylfosfóno)-2-hydroxy]pyrolidín (8c) g (145 mmol) dietylfosfonátu a 140 mmol zlúčeniny (8b) sa zahrieva v atmosfére argónu 8 hodín pri 80 až 85 °C. Po ochladení sa zmes odparí za zníženého tlaku a produkt (8c) sa prečistí chromatografiou na silikagéli.N-benzyl-2- [2- (diethylphosphono) -2-hydroxy] pyrrolidine (8c) g (145 mmol) diethylphosphonate and 140 mmol of compound (8b) was heated under argon at 80-85 ° C for 8 hours. After cooling, the mixture was evaporated under reduced pressure and the product (8c) was purified by silica gel chromatography.
N-benzyl-2-[2-(dietylfosfóno)-2-acetoxy]pyrolidín (8d)N-benzyl-2- [2- (diethylphosphono) -2-acetoxy] pyrrolidine (8d)
Zmes 50 mmol esteru kyseliny 1-hydroxyfosfónovej (8c), 75 mmol trietylamínu, 75 mmol anhydridu kyseliny octovej a 4 mmol dimetylaminopyridínu (DMAP) sa ponechá 14 hodín pri teplote miestnosti, potom sa pridá 100 ml éteru a 2 N HCI, éterová fáza sa premyje nasýteným vodným roztokom NaHCCh, vysuší sa MgSO4 a prečistí sa na krátkej kolóne ALOX.A mixture of 50 mmol of 1-hydroxyphosphonic ester (8c), 75 mmol of triethylamine, 75 mmol of acetic anhydride and 4 mmol of dimethylaminopyridine (DMAP) is left at room temperature for 14 hours, then 100 ml of ether and 2N HCl are added. Wash with saturated aqueous NaHCO 3, dry over MgSO 4 and purify on a short ALOX column.
2-[2-(dietylfosfóno)-2-acetoxy]pyrolidín (8e) ·· ·· •· •· •· •· ·· ·· ···2- [2- (diethylphosphono) -2-acetoxy] pyrrolidine (8e) ··· ··· ···
K roztoku 40 mmol zlúčeniny (8d) v 3 ml ľadovej kyseliny octovej sa pridá 400 mg PtC>2 a zmes sa hydrogenuje 6 hodín pri 70 °C a štandardnom tlaku. Katalyzátor sa odfiltruje a zmes sa opakovane extrahuje éterom v silne alkalickom prostredí, spojené éterové podiely sa vysušia MgSO4, odparia sa a získa sa tak v dobrom výťažku produkt (8e) ktorý sa použije priamo v ďalšej reakcii bez čistenia.To a solution of compound (8d) (40 mmol) in glacial acetic acid (3 mL) was added PtCl 2 (400 mg) and hydrogenated at 70 ° C and standard pressure for 6 h. The catalyst is filtered off and the mixture is repeatedly extracted with ether in strongly alkaline medium, the combined ether portions are dried over MgSO 4 , evaporated to give the product (8e) in good yield which is used directly in the next reaction without purification.
N-hydroxy-5-[(2-dietylfosfóno-2-acetoxy)etyl]pyrolidin-2-ón (8f)N-hydroxy-5 - [(2-diethylphosphono-2-acetoxy) ethyl] pyrrolidin-2-one (8f)
K roztoku 20 mmol zlúčeniny (8e) v 50 ml suchého acetónu ochladeného na 0 °C sa pridá po kvapkách roztok 70 mmol dimetyldioxiránu v 110 ml suchého acetónu Získaná zmes sa potom mieša 30 minút pri 0 °C a potom sa rozpúšťadlo odstráni vo vákuu. Získa sa žltý olej, ktorý možno prečistiť na silikagéli s použitím chloroformu/metanolu ako mobilnej fázy.To a solution of 20 mmol of compound (8e) in 50 mL of dry acetone cooled to 0 ° C was added dropwise a solution of 70 mmol of dimethyldioxirane in 110 mL of dry acetone. The resulting mixture was then stirred at 0 ° C for 30 minutes and then the solvent was removed in vacuo. A yellow oil is obtained which can be purified on silica gel using chloroform / methanol as the mobile phase.
N-hydroxy-5-[(2-dietylfosfóno-2-hydroxy)etyl]pyrolidin-2-ón (8g)N-hydroxy-5 - [(2-diethylphosphono-2-hydroxy) ethyl] pyrrolidin-2-one (8g)
Žltý olej (8f) sa mieša cez noc s 5 M vodným KOH v MeOH pri teplote miestnosti, potom sa zmes zneutralizuje, MeOH sa odstráni za zníženého tlaku a zmes sa extrahuje éterom. Spojené organické podiely sa vysušia MgSO4 a odparia sa do sucha. Získaný produkt (8g) sa použije v ďalších reakciách bez ďalšieho prečistenia.The yellow oil (8f) was stirred overnight with 5 M aqueous KOH in MeOH at room temperature, then the mixture was neutralized, the MeOH was removed under reduced pressure, and the mixture was extracted with ether. The combined organics were dried over MgSO 4 and evaporated to dryness. The obtained product (8g) was used in subsequent reactions without further purification.
N-hydroxy-5-[(2-fosfóno-2-hydroxy)etyl]pyrolidin-2-ón (8h)N-hydroxy-5 - [(2-phosphon-2-hydroxy) ethyl] pyrrolidin-2-one (8h)
K roztoku 20 mmol zlúčeniny (8g) v 50 ml suchého acetonitrilu ochladeného na 0 °C sa pridá po kvapkách 80 mmol trimetylbrómsilánu. Získaná zmes sa mieša 3 hodiny pri teplote miestnosti, potom sa rozpúšťadlo odstráni vo vákuu, zvyšok sa znovu rozpustí v 60 ml ľadovo chladnej vody, zmes sa mieša 1 hodinu pri teplote miestnosti, extrahuje sa trikrát 60 ml podielmi éteru, hodnota pH sa upraví pomocou 2 M NaOH na 5,5 až 6,0 a potom sa voda odstrániTo a solution of 20 mmol of compound (8g) in 50 mL of dry acetonitrile cooled to 0 ° C was added dropwise 80 mmol of trimethyl bromosilane. The resulting mixture was stirred at room temperature for 3 hours, then the solvent was removed in vacuo, the residue was redissolved in 60 ml of ice-cold water, stirred at room temperature for 1 hour, extracted three times with 60 ml portions of ether, adjusted to pH 2 M NaOH to 5.5-6.0 and then water is removed
• . . · • · · · ·· · · • ··· ·· ··· · • · ···· ·· ·· ·· ·· ·· ·· ··· na rotačnom odparovači Rotavapor najviac pri teplote 45 °C. Pevný zvyšok sa nechá kryštalizovať z metanolu/etylacetátu. N-hydroxy-5-[(2-fosfóno-2hydroxy)etyl]pyrolidin-2-ón (8h) sa získa vo forme žltkastých bielych mikrokryštálov v dobrom výťažku.•. . On a Rotavapor rotary evaporator at a temperature of not more than 45 ° C . The solid residue was crystallized from methanol / ethyl acetate. N-hydroxy-5 - [(2-phosphono-2-hydroxy) ethyl] pyrrolidin-2-one (8h) was obtained as yellowish white microcrystals in good yield.
Príklad 9Example 9
3-(metylfosfóno)-N-hydroxy-sukcínimid (9)3- (methylphosphono) -N-hydroxy-succinimide (9)
Anhydrid kyseliny 3-brómmetyljantárovej (9a) mmol anhydridu kyseliny 2-metyljantárovej rozpustené v 30 ml absolútneho tetrachlórmetánu sa nechá reagovať s 1,2 ekvivalentami N-brómsukcínimidu za refluxovania počas 12 hodín podobným spôsobom aký je uvedený pre prípravu N-(2-ti imetylsilyletoxy)-pyrolidin-2-ónu (2b). V hodinových intervaloch sa pridávajú malé množstvá azobisizobutyronitrilu (A1BN). Po ochladení sa produkt oddelí od sukcínimidu, ten sa premyje CCI4 a spojené CCI4 fázy sa potom odparia za zníženého tlaku. Získaný olej je možné prečistiť chromatografiou na SiO2 za nízkeho výťažku zlúčeniny (9a).3-Bromomethylsuccinic anhydride (9a) mmol of 2-methylsuccinic anhydride dissolved in 30 ml of absolute carbon tetrachloride is reacted with 1.2 equivalents of N-bromosuccinimide under reflux for 12 hours in a manner similar to that for the preparation of N- (2-imethylsilylethoxy) 1-Pyrrolidin-2-one (2b). Small amounts of azobisisobutyronitrile (A1BN) are added at hourly intervals. After cooling, the product is separated from succinimide, which is washed with CCl4 and the combined CCl4 phases are then evaporated under reduced pressure. The oil obtained can be purified by chromatography on SiO 2 in low yield of compound (9a).
Anhydrid kyseliny 3-[2-(dimetylfosfóno)etyl]-jantárovej (9b) mmol zlúčeniny (9a) sa zahrieva pri teplote spätného toku 0,5 až 1 hodinu s 1 ekvivalentom trimetylfosfitu v toluéne. Po ochladení sa zmes odparí za zníženého tlaku a žltkastý olej sa spracuje chromatografiou na S1O2 Odstránením prchavých zložiek sa získa v nízkom výťažku zlúčenina (9b).3- [2- (dimethylphosphono) ethyl] succinic anhydride (9b) mmol of compound (9a) was heated at reflux for 0.5 to 1 hour with 1 equivalent of trimethylphosphite in toluene. After cooling, the mixture was evaporated under reduced pressure and the yellowish oil was subjected to SiO 2 chromatography. Removal of the volatiles yielded compound (9b) in low yield.
3-[2-(dimetylfosfóno)metyl]-N-benzyloxy-sukcínimid (9c) • ·· ·· ·· ·· ·· · · ···· ··· ··· ···· ·· • · · · · · · · · ··· ·· ·· ·· ·· ·3- [2- (dimethylphosphono) methyl] -N-benzyloxy-succinimide (9c) · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·
1,0 g benzyloxyamínu sa zahrieva v sklenenom autokláve 30 minút pri 180 °C s 1,0 ekvivalentom zlúčeniny (9b). Po ochladení sa olej odparí za zníženého tlaku za zisku surového produktu v nízkom výťažku a získaná zlúčenina (9c) sa použije v ďalších reakciách bez čistenia.1.0 g of benzyloxyamine was heated in a glass autoclave at 180 ° C for 30 minutes with 1.0 equivalent of compound (9b). After cooling, the oil was evaporated under reduced pressure to give the crude product in low yield and the obtained compound (9c) was used in further reactions without purification.
3-[2-dimetylfosfbno)metyl]-N-hydroxy-sukcínimid (9d)3- [2-Dimethylphosphonyl) methyl] -N-hydroxy-succinimide (9d)
9,28 mmol benzyloxy-zlúčeniny (9c) sa rozpustí v 60 ml etanolu a spojí sa so 700 mg Pd/C a zmes sa hydrogenuje za štandardného tlaku 4 hodiny pri teplote miestnosti. Len čo ustane absorpcia vodíka, tak sa katalyzátor odfiltruje, zmes sa odparí za zníženého tlaku a rekryštalizáciou z etylacetátu/hexánu sa získa v dobrom výťažku zlúčenina (9d).The benzyloxy compound (9c) (9.28 mmol) was dissolved in ethanol (60 ml) and combined with Pd / C (700 mg) and the mixture was hydrogenated under standard pressure at room temperature for 4 hours. Once hydrogen uptake ceased, the catalyst was filtered off, the mixture was evaporated under reduced pressure and recrystallized from ethyl acetate / hexane to give compound (9d) in good yield.
3-[2-fosfónometyl]-N-hydroxy-sukcínimid (9e)3- [2-phosphonomethyl] -N-hydroxy-succinimide (9e)
K roztoku 30 mmol zlúčeniny (9g) v 70 ml suchého acetonitrilu ochladenému na 0 °C sa pridá po kvapkách 110 mmol trimetylbrómsilánu. Získaná zmes sa mieša 3 hodiny pri teplote miestnosti, potom sa rozpúšťadlo odstráni vo vákuu a zvyšok sa znovu rozpustí v 80 ml ľadovo chladnej vody a zmes sa mieša 1 hodinu pri teplote miestnosti, trikrát sa extrahuje 50 ml podielmi éteru, hodnota pH sa upraví na 5,5 až 6,0 pomocou NaHCO3 a potom sa voda odstráni na rotačnom odparovači Rotavapor najviac pri teplote 45 °C Pevný zvyšok sa nechá kryštalizovať zo zmesi metanol/acetón. Zlúčenina (9e) sa získa vo forme béžových kryštálov v dobrom výťažku.To a solution of 30 mmol of compound (9g) in dry acetonitrile (70 mL) cooled to 0 ° C was added trimethyl bromosilane (110 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 hours, then the solvent was removed in vacuo and the residue was redissolved in 80 ml of ice-cold water and stirred for 1 hour at room temperature, extracted three times with 50 ml portions of ether. 5.5-6.0 with NaHCO 3 and then water is removed on a Rotavapor at a maximum of 45 ° C. The solid residue is crystallized from methanol / acetone. Compound (9e) is obtained in the form of beige crystals in good yield.
Príklad 10Example 10
-N-(2-fosfónoetyl)-3-hydroxy-7-metyl-xantín (10)-N- (2-Phosphonoethyl) -3-hydroxy-7-methyl-xanthine (10)
-N-(2-dimetylfosfóno-etyl)-7-metylxantín (10a) • ·· ·· ·· ·· · ···· ···· ···· ······· · · · ·· ··· ·· ··· · · ··· ···· ·· · ··· ·· ·· ·· ·· ···-N- (2-Dimethylphosphono-ethyl) -7-methylxanthine (10a) ··· ··············· · ··· ············································································
K 50 g 7-metylxantínu (2,6-dihydroxy-7-metylpurín) rozpustených v 1 1 vriaceho etanolu sa pridá 38 g 50% roztoku hydroxidu draselného. Zmes sa ochladí na 15 až 20 °C pričom sa vyzráža draselná soľ 7-metylxantínu, tá sa odfiltruje a preleje sa vrúcim acetónom a vrúcim absolútnym etanolom.To 50 g of 7-methylxanthine (2,6-dihydroxy-7-methylpurine) dissolved in 1 l of boiling ethanol is added 38 g of 50% potassium hydroxide solution. The mixture was cooled to 15-20 ° C, whereupon the 7-methylxanthine potassium salt precipitated, which was filtered and washed with boiling acetone and boiling absolute ethanol.
K 25 mmol draselnej soli 7-metylxantínu sa pridá roztok obsahujúci 20 mmol dimetylesteru kyseliny 2-brómmetylfosfónovej a 2 mmol hexadecyltributylfosfónium-bromidu v 10 ml toluénu a zmes sa zahrieva 2 hodiny pri 100 °C Potom sa reakčná zmes ochladí, nerozpustené podiely sa odfiltrujú a zvyšok po odparení organickej fázy sa spracuje chromatografiou na silikagéli s použitím éteru/chloroformu ako mobilnej fázy. Opísaným spôsobom sa získa ako požadovaný l-N-(2-dimetylfosfóno-etyl)-7-metylxantín (10a) tak aj v menšom výťažku 3-N-(2-dimetylfosfóno-etyl)-7-metylxantín (10a').To 25 mmol of 7-methylxanthine potassium salt is added a solution containing 20 mmol of 2-bromomethylphosphonic acid dimethyl ester and 2 mmol of hexadecyltributylphosphonium bromide in 10 ml of toluene and the mixture is heated at 100 ° C for 2 hours. The evaporation residue of the organic phase is chromatographed on silica gel using ether / chloroform as the mobile phase. As described above, the desired 1-N- (2-dimethylphosphono-ethyl) -7-methylxanthine (10a ') was obtained as well as a smaller yield of 3-N- (2-dimethylphosphono-ethyl) -7-methylxanthine (10a').
-N-(2-dimetylfosfóno-etyl)-3-hydroxy-7-metylxantín (10b)-N- (2-Dimethylphosphonoethyl) -3-hydroxy-7-methylxanthine (10b)
K roztoku 25 mmol zlúčeniny (10a) v 50 ml suchého acetónu ochladeného na 0 °C sa pridá po kvapkách roztok 60 mmol dimetyidioxiránu vo 120 ml suchého acetónu Zmes sa mieša 30 minút pri 0 °C a potom sa rozpúšťadlo odstráni za zníženého tlaku. Získaný surový produkt sa spracuje chromatografiou na silikagéli a získa sa tak l-N-(2-dimetylfosfóno-etyl)-3-hydroxy-7metylxantín (10b) s nízkym výťažkom.To a solution of 25 mmol of compound (10a) in 50 mL of dry acetone cooled to 0 ° C was added dropwise a solution of 60 mmol of dimethyidioxirane in 120 mL of dry acetone. The mixture was stirred at 0 ° C for 30 minutes and then the solvent was removed under reduced pressure. The obtained crude product was chromatographed on silica gel to give 1-N- (2-dimethylphosphonoethyl) -3-hydroxy-7-methylxanthine (10b) in low yield.
Podobným spôsobom sa 3-N-(2-dimetylfosfóno-etyl)-7-metylxantín (10a') prevedie na 3-N-(2-dimetylfosfóno-etyl)-l-hydroxy-7-metylxantín (10b').In a similar manner, 3-N- (2-dimethylphosphono-ethyl) -7-methylxanthine (10a ') is converted to 3-N- (2-dimethylphosphono-ethyl) -1-hydroxy-7-methylxanthine (10b').
-N-(2-fosfóno-etyl)-3-hydroxy-7-metylxantín (10c)-N- (2-Phosphonoethyl) -3-hydroxy-7-methylxanthine (10c)
K 25 mmol zlúčeniny (10b) v 50 ml absolútneho acetonitrilu sa za chladenia ľadom pridajú 4 ekvivalenty (100 mmol) trimetylbrómsilánu a zmes sa mieša 15 minút pri vyššie uvedenej teplote, potom 2 hodiny pri teplote miestnosti, potom sa odparí za zníženého tlaku až na olej, ktorý sa potom znovu roz• ·· ·· ·· ·· ···· ···· · · · • «e ···· · · ·· ··· ·· ··· · pustí v 100 ml vody a hydrolyzuje sa 1 hodinu pri teplote miestnosti. Kvôli odstráneniu hexametyldisiloxánu sa roztok dvakrát extrahuje CHClj, uskutočni sa reextrakcia vodou a spojené vodné fázy sa odparia za zníženého tlaku pri teplote neprevyšujúcej 45 °C. Získaný béžový olej sa potom znovu rozpustí vo vode a hodnota pH sa upraví na 6,5 až 7,0. Premytím ľadovo chladnou vodou sa získa prakticky bezfarebná sodná soľ zlúčeniny (10c) s výťažkom 55 %.To 25 mmol of compound (10b) in 50 mL of absolute acetonitrile was added 4 equivalents (100 mmol) of trimethyl bromosilane under ice-cooling, and the mixture was stirred at the above temperature for 15 minutes, then at room temperature for 2 hours, then evaporated under reduced pressure to the oil, which is then redistributed in 100 ml of water and hydrolyzed for 1 hour at room temperature. To remove hexamethyldisiloxane, the solution is extracted twice with CHCl 3, reextracted with water, and the combined aqueous phases are evaporated under reduced pressure at a temperature not exceeding 45 ° C. The beige oil obtained is then redissolved in water and the pH adjusted to 6.5-7.0. Washing with ice-cold water gave the practically colorless sodium salt of compound (10c) in a yield of 55%.
Podobným spôsobom sa nechá reagovať 3-N-(2-dimetylfosfóno-etyl)-lhydroxy-7-metylxantín (10b') s trimetylbrómsilánom a získa sa tak 3-N-(2fosfóno-etyl)-l -hydroxy-7-metylxantín (10c’).In a similar manner, 3-N- (2-dimethylphosphono-ethyl) -1-hydroxy-7-methylxanthine (10b ') is reacted with trimethyl bromosilane to give 3-N- (2-phosphono-ethyl) -1-hydroxy-7-methylxanthine ( 10c ').
Príklad 1 1Example 1 1
N-hydroxy-l,2,3,4-tetrahydro-l-oxo-3-[2-fosfónoetyl)]izochinolín (11)N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3- [2-phosphonoethyl]] isoquinoline (11)
3-fenyl-2-aminopropanol (11a) mol LiAlH4 sa suspendujú s 900 ml bezvodého furánu v trojhrdlej banke tepelne vysušenej a preplachovanej argónom, vybavenej miešadlom KPG, a potom sa pridá po častiach za chladenia ľadom 1,5 mol fenylalanínu Táto zmes sa zahrieva 6 hodín pri teplote spätného toku, potom sa nechá vychladnúť a hydrolyzuje sa rozdrveným ľadom Zmes sa potom prefiltruje a rozpúšťadlo sa odstráni vo vákuu. Filtrát sa potom znovu rozpustí v CH2CI2, premyje sa nasýteným roztokom NaCI a vysuší sa Na2SO4. Ďalšie spracovanie sa uskutoční vákuovou destiláciou 3-fenyl-2-aminopropanol (1 la) sa získa s výťažkom 76 % l-fenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropán (1 lb)3-Phenyl-2-aminopropanol (11a) mol LiAlH 4 is suspended with 900 ml of anhydrous furan in a three-necked, argon purged flask equipped with a KPG stirrer, and then 1.5 mol of phenylalanine is added in portions with ice cooling. The mixture was then refluxed for 6 hours, allowed to cool and hydrolyzed with crushed ice. The mixture was then filtered and the solvent was removed in vacuo. The filtrate was then redissolved in CH 2 Cl 2, washed with saturated NaCl solution and dried over Na 2 SO 4 . Further work-up was carried out by vacuum distillation of 3-phenyl-2-aminopropanol (11a) to obtain 76% yield of 1-phenyl-3- (tetrahydro-2-pyranyloxy) -2-aminopropane (11b).
K 1,4 mol 3-fenyl-2-aminopropanolu (11a) sa pridá 2,5 mol dihydropyránu a 5,3 g kyseliny p-toluénsulfónovej a zmes sa mieša 20 hodín pri teplote miestnosti Potom sa prebytok dihydropyránu odstráni vo vákuu, zvyšok sa znovu rozpustí v 700 ml etylacetátu a premyje 300 ml podielmi nasýtenéhoTo 1.4 mol of 3-phenyl-2-aminopropanol (11a) was added 2.5 mol of dihydropyran and 5.3 g of p-toluenesulfonic acid, and the mixture was stirred at room temperature for 20 hours. Excess dihydropyran was then removed in vacuo. redissolved in 700 mL of ethyl acetate and washed with 300 mL portions of saturated
roztoku NaHCCh a nasýteného roztoku NaCl. Potom sa zmes vysuší MgSO4, prefiltruje sa a odstránením rozpúšťadla vo vákuu sa získa l-fenyl-3(tetrahydro-2-pyranyloxy)-2-aminopropán (11b) vo výťažku 63 %.NaHCO 3 solution and saturated NaCl solution. The mixture was dried over MgSO 4 , filtered and the solvent removed in vacuo to give 1-phenyl-3- (tetrahydro-2-pyranyloxy) -2-aminopropane (11b) in 63% yield.
l-fenyl-3-(tetrahydro-2-pyranyloxy)-2-izokyanopropán (1 lc)1-Phenyl-3- (tetrahydro-2-pyranyloxy) -2-isocyanopropane (11c)
0,88 mol 1 -fenyl-3-(tetrahydro-2-pyranyloxy)-2-aminopropánu (11b) sa pridá po kvapkách k roztoku 3,52 mol fosgénu v 1,5 1 toluénu a zmes sa varí 3 hodiny pri 80 °C. Potom sa rozpúšťadlo odstráni vo vákuu. Požadovaný produkt, l-fenyl-3-(tetrahydro-2-pyranyloxy)-2-izokyanopropán (11c) sa získa vo výťažku 83 %. Produkt sa použije bez ďalšieho prečistenia.0.88 mol of 1-phenyl-3- (tetrahydro-2-pyranyloxy) -2-aminopropane (11b) is added dropwise to a solution of 3.52 mol of phosgene in 1.5 l of toluene and the mixture is boiled at 80 ° for 3 hours. C. The solvent is then removed in vacuo. The desired product, 1-phenyl-3- (tetrahydro-2-pyranyloxy) -2-isocyanopropane (11c) was obtained in a yield of 83%. The product was used without further purification.
1.2.3.4- tetrahydro-l-oxo-3-hydroxymetyl-izochinolín (11 d)1,2.3.4-tetrahydro-1-oxo-3-hydroxymethyl-isoquinoline (11 d)
Roztok 0,72 mol 1-fenyl-3-(tetrahydro-2-pyranyloxy)-2-izokyanopropánu (11c) v 80 ml bezvodého acetónu sa pomaly po kvapkách pridá k 100 ml ľadom chladenej kyseliny fosforečnej a mieša sa 3 hodiny pri teplote miestnosti Potom sa pridá ľadovo chladná voda a zmes sa mieša 0,5 hodiny a potom sa extrahuje CH2CI2. Organická fáza sa potom premyje vodou, nasýteným roztokom Na2CO3, opäť vodou a nasýteným roztokom NaCl a potom sa vysuší MgSO4. Potom sa zmes prefiltruje a rozpúšťadlo sa odstráni vo vákuu a rekryštalizáciou zvyšku z hexánu/benzénu sa získa vo výťažku 28 % 1,2,3,4-tetrahydro-1-oxo3-hydroxymetyl-izochino!ín (1 ld).A solution of 0.72 mol of 1-phenyl-3- (tetrahydro-2-pyranyloxy) -2-isocyanopropane (11c) in 80 ml of anhydrous acetone is slowly added dropwise to 100 ml of ice-cold phosphoric acid and stirred for 3 hours at room temperature. Ice-cold water was then added and the mixture was stirred for 0.5 hours and then extracted with CH 2 Cl 2. The organic phase is washed with water, saturated Na 2 CO 3, again with water and brine and dried MgSO4. Then the mixture was filtered and the solvent was removed in vacuo and recrystallization of the residue from hexane / benzene gave 1,2,3,4-tetrahydro-1-oxo-3-hydroxymethyl-isoquinoline (1d) in 28% yield.
1.2.3.4- tetrahydro-l-oxo-3-brómmetyl-izochinolín (Íle)1,2.3.4-Tetrahydro-1-oxo-3-bromomethyl-isoquinoline (Ile)
K roztoku 150 mmol l,2,3,4-tetrahydro-l-oxo-3-hydroxymetylizochinolínu (1 ld) a 210 mmol CBr4 v 150 ml CH2CI2 sa pridá roztok 180 mmol PPh3 v 120 ml CH2CI2 a spojené roztoky sa miešajú 20 hodín pri teplote miestnosti Potom sa rozpúšťadlo odstráni vo vákuu a zvyšok sa opakovane ne·· ·· ·· ·· • · ···· ··· • · · · ·· · · chá kryštalizovať z benzénu. Produkt, l,2,3,4-tetrahydro-l-oxo-3-brómmetylizochinolín (Íle) sa získa vo výťažku 3 1 %.To a solution of 150 mmol of 1,2,3,4-tetrahydro-1-oxo-3-hydroxymethyl-isoquinoline (1d) and 210 mmol of CBr 4 in 150 mL of CH 2 Cl 2 is added a solution of 180 mmol of PPh 3 in 120 mL of CH 2 Cl 2 and combined The solutions were stirred at room temperature for 20 hours. The solvent was then removed in vacuo and the residue repeatedly crystallized from benzene. The product, 1,2,3,4-tetrahydro-1-oxo-3-bromomethylisoquinoline (IIIe) was obtained in a yield of 31%.
• ·· ·· ·· ·· ·• ·· ·· ·· ·· ·
1,2,3,4-tetrahydro-1 -oxo-3-(2-dietylfosfónoetyl)-izochinolín (11 f)1,2,3,4-tetrahydro-1-oxo-3- (2-diethylphosphonoethyl) -isoquinoline (11 f)
K roztoku 75 mmol dimetylmetylfosfonátu v 120 ml absolútneho THF v atmosfére argónu sa pridá po kvapkách pri -78 °C 66,2 mmol roztoku butyllítia (1,15 M) v hexáne a zmes sa mieša 1,5 hodiny pri vyššie uvedenej teplote K tomuto roztoku sa potom pri -78 °C pridá po kvapkách 46,5 mmol 1,2,3,4tetrahydro-l-oxo-3-brómmetyl-izochinolínu (Íle) v 50 ml absolútneho THF a zmes sa pri -78 °C mieša ďalšiu 1 hodinu a potom sa nechá cez noc ohriať na teplotu miestnosti. Potom sa pridá 100 ml vody, vodná fáza sa oddelí a trikrát sa extrahuje 50 ml podielmi etylacetátu. Spojené organické podiely sa vysušia MgSO4, prefiltrujú sa a rozpúšťadlo sa odstráni vo vákuu. Prečistením zvyšku chromatografiou (silikagél, hexán/etylacetát 5:1) sa získa 1,2,3,4-tetrahydro-loxo-3-(2-dietylfosfónoetyl)-izochinolín (11 f) v 24% výťažku.To a solution of 75 mmol of dimethyl methyl phosphonate in 120 mL of absolute THF under an argon atmosphere was added dropwise at -78 ° C a solution of butyllithium (1.15 M) in hexane dropwise at -78 ° C and stirred for 1.5 hours at the above temperature. of solution was then added dropwise at -78 ° C to 46.5 mmol of 1,2,3,4-tetrahydro-1-oxo-3-bromomethyl-isoquinoline (IIIe) in 50 mL of absolute THF, and the mixture was stirred at -78 ° C for another 1 hour and then allowed to warm to room temperature overnight. 100 ml of water are then added, the aqueous phase is separated and extracted three times with 50 ml portions of ethyl acetate. The combined organics were dried over MgSO 4 , filtered, and the solvent was removed in vacuo. Purification of the residue by chromatography (silica gel, hexane / ethyl acetate 5: 1) afforded 1,2,3,4-tetrahydro-oxo-3- (2-diethylphosphonoethyl) -isoquinoline (11f) in 24% yield.
N-hydroxy-1,2,3,4-tetrahydro-l -oxo-3-(2-dietylfosfóno-etyl)-izochinolín (Hg)N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3- (2-diethylphosphono-ethyl) -isoquinoline (Hg)
5,36 mmol l,2,3,4-tetrahydro-l-oxo-3-(2-dietylfosfóno-etyl)izochinolínu (6) sa rozpustí v 30 ml absolútneho acetónu a roztok sa ochladí na 0 °C Potom sa po kvapkách pridá roztok 17,15 mmol dimetyldioxiránu a zmes sa mieša 30 minút pri 0 °C. Potom sa rozpúšťadlo odstráni vo vákuu a prečistením zvyšku chromatografiou (silikagél, hexán/etylacetát 4:1) sa získa N-hydroxy-1,2,3,4tetrahydro-1-oxo-3-(2-dietylfosfóno-etyl)-izochinolín (1 lg) v 33% výťažku.Dissolve 5.36 mmol of 1,2,3,4-tetrahydro-1-oxo-3- (2-diethylphosphono-ethyl) isoquinoline (6) in 30 ml of absolute acetone and cool the solution to 0 ° C. dimethyldioxirane solution (17.15 mmol) was added and the mixture was stirred at 0 ° C for 30 min. Then the solvent is removed in vacuo and purification of the residue by chromatography (silica gel, hexane / ethyl acetate 4: 1) affords N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3- (2-diethylphosphonoethyl) isoquinoline ( 1 g) in 33% yield.
N-hydroxy-1,2,3,4-tetrahydro-1 -oxo-3-(2-fosfónoetyl)-izochinolín (11 h)N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3- (2-phosphonoethyl) isoquinoline (11 h)
1,77 mmol N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3-(2-dietylfosfónoetyI)izochinolínu (I lg) sa rozpustí v 15 ml absolútneho CH2C12 v atmosfére argónu • ·· ·· ·· · ···· ···· ··· ··· t··· · · • · · · · ·· ··· · • ·· · · · · ·· ··· ·· ·· ·· ·· · a roztok sa ochladí na 0 °C. Potom sa po kvapkách z injekčnej striekačky pridá 10 mmol trimetylbrómsilánu a zmes sa mieša ďalšiu 1 hodinu pri 0 °C a potom cez noc pri teplote miestnosti. Potom sa rozpúšťadlo odstráni vo vákuu a zvyšok sa znovu rozpustí v 20 ml vody a mieša sa I hodinu pri teplote miestnosti. Potom sa pridá 15 ml CHCh a organická fáza sa oddelí. Vodná fáza sa ešte dvakrát extrahuje 10 ml podielmi CHCI3 a zmes sa odparí do sucha Zvyšok sa prečistí chromatografiou (silikagél, H2O/metanol 1:1). Požadovaný produkt sa získa s výťažkom 54 %.1.77 mmol of N-hydroxy-1,2,3,4-tetrahydro-1-oxo-3- (2-diethylphosphonoethyl) isoquinoline (11g) is dissolved in 15 ml of absolute CH 2 Cl 2 under an argon atmosphere. ···························································································· Cool the solution to 0 ° C. Then, 10 mmol of trimethyl bromosilane was added dropwise from the syringe and the mixture was stirred for an additional 1 hour at 0 ° C and then overnight at room temperature. The solvent was then removed in vacuo and the residue redissolved in 20 ml of water and stirred at room temperature for 1 hour. Then 15 ml of CHCl 3 are added and the organic phase is separated. The aqueous phase is extracted twice more with 10 ml portions of CHCl 3 and the mixture is evaporated to dryness. The residue is purified by chromatography (silica gel, H 2 O / methanol 1: 1). The desired product is obtained in a yield of 54%.
Príklad 12 fExample 12 f
Účinnosť zlúčenín uvedených v tabuľke I proti malárii bola stanovená spôsobom na in vivo kultúrach organizmu spôsobujúceho maláriu, Plasmodium falciparum. Rímske číslice označujú zvlášť výhodné zlúčeniny opísané na príslušných stránkach opisu. Do každej z jamiek 96-jamkovej mikrotitračnej doštičky sa vnesie po 200 μΐ asynchrónnej kultúry Plasmodium falciparum s koncentráciou 0,4 % parazitov v krvi a hematokritom 2 % Použijú sa tri postupné riedenia hodnotených zlúčenín v rozmedzí koncentrácií 100 až 1 μπιοΙ ľ1. Doštičky sa inkubujú 48 hodín pri 37 ’C s 5 % O2. Potom sa do každej jamky pridá 30 μΙ média s obsahom 27 μ(3ί.m!’1 [3H]-hypoxantínu. Po 24 hodinách sa podiel obsahujúci parazity odfiltruje filtrom zo sklenených vlákien a vo filtráte sa zisti rádioaktivita. Inhibicia rastu parazitov sa stanoví percentom inhibície včlenenia trícia vzhľadom ku kontrolnému pokusu bez hodnotenej zlúčeniny. Výsledky pre tri rôzne koncentrácie sú uvedené v tabuľke I.Malaria activity of the compounds listed in Table I was determined by a method of in vivo cultures of a malaria-causing organism, Plasmodium falciparum. The Roman numerals denote particularly preferred compounds described on the respective pages of the specification. To each well of 96-well microtiter plate was added with 200 μΐ of an asynchronous culture of Plasmodium falciparum at a concentration of 0.4% of the parasites in the blood and hematocrit of 2% using three successive dilutions of test compounds in a concentration range 100-1 μπιοΙ apos first Plates are incubated for 48 hours at 37 ° C with 5% O 2 . Subsequently, 30 μΙ of medium containing 27 μ (3 µmol -1 [ 3 H] -hypoxanthin) is added to each well. After 24 hours, the parasite-containing fraction is filtered through a glass fiber filter and radioactivity is detected in the filtrate. determined by the percentage inhibition of tritium incorporation relative to the control without the test compound The results for three different concentrations are shown in Table I.
Tabuľka ITable I
Príklad 13Example 13
Bola tiež stanovená antibakteriálna účinnosť zlúčenín s výsledkami uvedenými v tabuľke II Rímske číslice označujú zvlášť výhodné zlúčeniny uvedené na stranách 5 až 8. Postup bol uskutočnený nasledovne. Do piatich mikroskúmaviek pre kultiváciu sa vnesú jednotlivé zlúčeniny v sérii riedení s koncentráciami 500, 100, 50 a 10 μπιοΙ.Ι'1 v LB médiu objemu 0,5 ml. Každá mikroskúmavka sa inokuluje 10 μΙ kultúry E.coli a pretrepáva sa cez noc pri 37 °C. Rast baktérií sa hodnotí stanovením turbidity média Určí sa minimálna koncentrácia vyvolávajúca inhibíciu rastu baktérií (minimálna inhibičná koncen·· ·· ·· ·· • · ···· ··· • · · ♦ ·· ♦ · trácia MIC). Rovnakým spôsobom sa stanoví antibakteriálna účinnosť vočiThe antibacterial activity of the compounds was also determined with the results shown in Table II. The Roman numerals indicate the particularly preferred compounds shown on pages 5 to 8. The procedure was carried out as follows. Five compound microtubes for culture were loaded with individual compounds in a series of dilutions of 500, 100, 50 and 10 μπιοΙ.Ι -1 in 0.5 ml LB medium. Each microtube is inoculated with 10 μΙ of E. coli culture and shaken overnight at 37 ° C. Bacterial growth is assessed by determining the turbidity of the medium. The minimum concentration inducing bacterial growth inhibition is determined (minimum inhibitory concentration). In the same way, antibacterial activity against
P.aeruginosa. Výsledky sú uvedené v tabuľke II.P. aeruginosa. The results are shown in Table II.
• ·· ·· ·· ·· ·• ·· ·· ·· ·· ·
Tabuľka IITable II
7/ • ·· 99 99 997 / • 99 99 99
9 9 9 9 9 9 9 9 99 9 9 9 9
9 9 9 9 99 9 99 9 9 9 99
9 9 9 9 9 9 9 99 9 9 9 9
999 99 99 99 99 9999 99 99 99 99
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CN101646664B (en) | 2006-10-06 | 2013-12-04 | 拜欧希格诺有限公司 | Furanone compounds |
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1998
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1999
- 1999-12-22 TR TR2001/01832T patent/TR200101832T2/en unknown
- 1999-12-22 IL IL14347099A patent/IL143470A0/en unknown
- 1999-12-22 BR BR9916466-3A patent/BR9916466A/en not_active IP Right Cessation
- 1999-12-22 EP EP99968365A patent/EP1140952B1/en not_active Expired - Lifetime
- 1999-12-22 DE DE59906907T patent/DE59906907D1/en not_active Expired - Fee Related
- 1999-12-22 WO PCT/EP1999/010274 patent/WO2000037477A1/en not_active Application Discontinuation
- 1999-12-22 MX MXPA01006456A patent/MXPA01006456A/en unknown
- 1999-12-22 JP JP2000589547A patent/JP2002533350A/en active Pending
- 1999-12-22 AT AT99968365T patent/ATE248846T1/en not_active IP Right Cessation
- 1999-12-22 CZ CZ20012284A patent/CZ20012284A3/en unknown
- 1999-12-22 AP APAP/P/2001/002168A patent/AP2001002168A0/en unknown
- 1999-12-22 OA OA00100153A patent/OA11730A/en unknown
- 1999-12-22 CA CA002356289A patent/CA2356289A1/en not_active Abandoned
- 1999-12-22 KR KR1020017007908A patent/KR20010089670A/en not_active Application Discontinuation
- 1999-12-22 PT PT99968365T patent/PT1140952E/en unknown
- 1999-12-22 HU HU0104866A patent/HUP0104866A3/en unknown
- 1999-12-22 PL PL99349045A patent/PL349045A1/en not_active Application Discontinuation
- 1999-12-22 CN CN99814915A patent/CN1331695A/en active Pending
- 1999-12-22 DK DK99968365T patent/DK1140952T3/en active
- 1999-12-22 AU AU25385/00A patent/AU2538500A/en not_active Abandoned
- 1999-12-22 ES ES99968365T patent/ES2204189T3/en not_active Expired - Lifetime
- 1999-12-22 EA EA200100689A patent/EA200100689A1/en unknown
- 1999-12-22 SK SK889-2001A patent/SK8892001A3/en unknown
-
2001
- 2001-05-30 ZA ZA200104443A patent/ZA200104443B/en unknown
- 2001-06-21 NO NO20013085A patent/NO20013085L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
EP1140952A1 (en) | 2001-10-10 |
AU2538500A (en) | 2000-07-12 |
MXPA01006456A (en) | 2002-04-24 |
DE59906907D1 (en) | 2003-10-09 |
OA11730A (en) | 2005-05-12 |
BR9916466A (en) | 2001-09-25 |
DK1140952T3 (en) | 2004-01-12 |
PL349045A1 (en) | 2002-07-01 |
ZA200104443B (en) | 2002-01-14 |
JP2002533350A (en) | 2002-10-08 |
CN1331695A (en) | 2002-01-16 |
ES2204189T3 (en) | 2004-04-16 |
KR20010089670A (en) | 2001-10-08 |
EA200100689A1 (en) | 2001-12-24 |
DE19859426A1 (en) | 2000-07-06 |
HUP0104866A2 (en) | 2002-06-29 |
CA2356289A1 (en) | 2000-06-29 |
AP2001002168A0 (en) | 2001-06-30 |
EP1140952B1 (en) | 2003-09-03 |
CZ20012284A3 (en) | 2001-10-17 |
TR200101832T2 (en) | 2001-12-21 |
NO20013085L (en) | 2001-08-22 |
ATE248846T1 (en) | 2003-09-15 |
WO2000037477A1 (en) | 2000-06-29 |
NO20013085D0 (en) | 2001-06-21 |
PT1140952E (en) | 2004-02-27 |
HUP0104866A3 (en) | 2002-08-28 |
IL143470A0 (en) | 2002-04-21 |
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