DE19532235A1 - New antibacterial contg. osteotropic mol. fragments - Google Patents
New antibacterial contg. osteotropic mol. fragmentsInfo
- Publication number
- DE19532235A1 DE19532235A1 DE1995132235 DE19532235A DE19532235A1 DE 19532235 A1 DE19532235 A1 DE 19532235A1 DE 1995132235 DE1995132235 DE 1995132235 DE 19532235 A DE19532235 A DE 19532235A DE 19532235 A1 DE19532235 A1 DE 19532235A1
- Authority
- DE
- Germany
- Prior art keywords
- po3h2
- acid
- oxo
- dihydro
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000012634 fragment Substances 0.000 title claims abstract description 10
- 230000003642 osteotropic effect Effects 0.000 title claims abstract description 5
- 230000000844 anti-bacterial effect Effects 0.000 title abstract description 5
- -1 N-methylpiperazinyl Chemical group 0.000 claims abstract description 62
- 239000002253 acid Substances 0.000 claims abstract description 34
- 229910018828 PO3H2 Inorganic materials 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 12
- 229940124587 cephalosporin Drugs 0.000 claims abstract description 11
- 229930182555 Penicillin Natural products 0.000 claims abstract description 10
- 229930186147 Cephalosporin Natural products 0.000 claims abstract description 7
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 7
- 150000001780 cephalosporins Chemical class 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 6
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 6
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 5
- 239000002271 gyrase inhibitor Substances 0.000 claims abstract description 5
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 5
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims abstract description 4
- 208000015181 infectious disease Diseases 0.000 claims abstract description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 4
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- 239000002132 β-lactam antibiotic Substances 0.000 claims abstract description 4
- 229940124586 β-lactam antibiotics Drugs 0.000 claims abstract description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 3
- WSHJJCPTKWSMRR-RXMQYKEDSA-N penam Chemical compound S1CCN2C(=O)C[C@H]21 WSHJJCPTKWSMRR-RXMQYKEDSA-N 0.000 claims abstract description 3
- 150000007660 quinolones Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 150000002960 penicillins Chemical class 0.000 claims description 7
- LFKVROYJGKXUBJ-UHFFFAOYSA-N 4-[bis(diethoxyphosphoryl)methyl]aniline Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)C1=CC=C(N)C=C1 LFKVROYJGKXUBJ-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000003009 phosphonic acids Chemical class 0.000 claims description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical group OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 claims description 2
- 206010031252 Osteomyelitis Diseases 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001550 cephem group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- OGBVRMYSNSKIEF-UHFFFAOYSA-N Benzylphosphonic acid Chemical compound OP(O)(=O)CC1=CC=CC=C1 OGBVRMYSNSKIEF-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 8
- 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 abstract 3
- 125000001475 halogen functional group Chemical group 0.000 abstract 3
- 229940049954 penicillin Drugs 0.000 abstract 3
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 2
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 abstract 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 abstract 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- 150000001782 cephems Chemical class 0.000 abstract 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 1
- 125000001174 sulfone group Chemical group 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 238000000921 elemental analysis Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
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- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JCERWRSGUROEIE-UHFFFAOYSA-N 4-[bis(diethoxyphosphoryl)methyl]phenol Chemical compound CCOP(=O)(OCC)C(P(=O)(OCC)OCC)C1=CC=C(O)C=C1 JCERWRSGUROEIE-UHFFFAOYSA-N 0.000 description 2
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
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- 125000005600 alkyl phosphonate group Chemical group 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
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- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
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- 239000000312 peanut oil Substances 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
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- 229920000136 polysorbate Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- LZFIOSVZIQOVFW-UHFFFAOYSA-N propyl 2-hydroxybenzoate Chemical class CCCOC(=O)C1=CC=CC=C1O LZFIOSVZIQOVFW-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 238000004448 titration Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/4037—Esters of poly(thio)phosphonic acids containing halogen or nitro(so) substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/405—Esters of poly(thio)phosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- 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
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung bezieht sich auf antibakteriell wirkende Phosphonsäuren, besonders geminale und vicinale Bisphosphonsäuren und diese enthaltende Arzneimittel.The invention relates to antibacterial phosphonic acids, particularly geminal and vicinal bisphosphonic acids and medicaments containing them.
Synthetische Antibiotika, bzw. antibakteriell wirkende Präparate haben sich zur Bekämpfung unterschiedlichster Infektionen bewährt. Jedoch entziehen sich bestimmte Erreger, darunter auch die bestimmter Knochen-, Knochenhaut infektionen einer zufriedenstellenden Chemotherapie. Ursache hierfür ist, neben natürlicher oder erworbener Resistenz, v.a. im Bereich bakterieller Knocheninfektionen eine zu geringe Wirkortkonzentration.Synthetic antibiotics or antibacterial preparations have become Combating various infections has proven itself. However evade certain pathogens, including certain bone and periosteum infections of satisfactory chemotherapy. The reason for this is, besides natural or acquired resistance, especially in the field of bacterial Bone infections an insufficient concentration of the active site.
Es ist bekannt, daß Bisphosphonsäuren (Diphosphonsäuren) aufgrund ihres Komplexierungsvermögens gegenüber den Ca2+-ionen der Knochensubstanz Hydroxylapatit osteotrope Eigenschaften besitzen. Dies wird in der Therapie von z. B. Osteoporose, Morbus Paget, Hypercalzämie und Knochentumoren bereits medizinisch genutzt.It is known that bisphosphonic acids (diphosphonic acids) have osteotropic properties due to their ability to complex to the Ca 2+ ions of the bone substance hydroxyapatite. This is used in the therapy of e.g. B. osteoporosis, Paget's disease, hypercalcemia and bone tumors already used medically.
Es wurde nun gefunden, daß durch Funktionalisierung mit einer geminalen oder vicinalen Bisphosphonsäuregruppe die Wirkortkonzentration antibakteriell wirksamer Verbindungen am Knochen deutlich erhöht werden kann. Damit ist ein Haupthindernis zur Behandlung bakterieller Knochenerkrankungen überwunden.It has now been found that by functionalization with a geminal or vicinal bisphosphonic acid group the site concentration antibacterial effective connections on the bone can be increased significantly. So that's a Main obstacle to the treatment of bacterial bone diseases overcome.
Die Bisphosphonsäuregruppe kann dabei präparativ sowohl in eine bereits voll wirksame Verbindung eingeführt, als auch an geeigneter Stelle der üblichen Gesamtsynthese des Wirkstoffs eingebaut werden. Meist werden hierfür zunächst die entsprechenden Phosphonsäurealkylester verwendet, die am Ende des Syntheseweges hydrolytisch in die freien Phosphonsäuren umgewandelt werden. Wenn nötig können diese zur besseren Wasserlöslichkeit als Alkalimetall- oder Ammoniumsalze eingesetzt werden.The bisphosphonic acid group can be preparative both in an already full effective compound introduced, as well as in a suitable place of the usual Overall synthesis of the active ingredient are incorporated. Most of this will be done first the corresponding alkyl phosphonate used at the end of Syntheseges be converted hydrolytically into the free phosphonic acids. If necessary, these can be used for better water solubility than alkali metal or Ammonium salts are used.
Gegenstand der Erfindung sind antibakteriell wirksame Verbindungen, die als osteotropes Molekülfragment eine (oder mehrere) Phosphonsäuregruppe(n), insbesondere geminale oder vicinale Bisphosphonsäuregruppe(n) bzw. Bisphosphonsäurealkylestergruppe(n) enthalten und zur Prophylaxe und Therapie entzündlicher Erkrankungen im Bereich des Knochens eingesetzt werden können.The invention relates to antibacterially active compounds which as osteotropic molecular fragment one (or more) phosphonic acid group (s), in particular geminal or vicinal bisphosphonic acid group (s) or Bisphosphonic acid alkyl ester group (s) contain and for prophylaxis and therapy inflammatory diseases in the bone can be used.
Bevorzugt sind phosphonsäurefunktionalisierte Verbindungen, die sich von der Klasse der Gyrase-Hemmstoffe, β-Lactam-Antibiotika und Sulfonamide strukturell ableiten.Preferred are phosphonic acid functionalized compounds that differ from the Class of structural gyrase inhibitors, β-lactam antibiotics and sulfonamides deduce.
Die Wirkstoffe enthalten dabei Fragmente der Formel -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂, -C(NH₂)(PO₃H₂)₂ bzw. die entsprechenden Phosphonsäurealkyl ester oder entsprechenden Phosphonsäure-Alkalimetall- oder Ammoniumsalze. The active ingredients contain fragments of the formula -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂, -C (NH₂) (PO₃H₂) ₂ or the corresponding phosphonic acid alkyl ester or corresponding phosphonic acid alkali metal or ammonium salts.
Ein bevorzugter Gegenstand der Erfindung sind phosphonsäurefunktionalisierte Gyrase-Hemmstoffe (Chinolone) der allgemeinen Formel 1A preferred subject of the invention are phosphonic acid functionalized Gyrase inhibitors (quinolones) of the general formula 1
in der X, Y, Z = C, N sein kann und
R1 Alkyl (verzweigt oder geradkettig), Cycloalkyl, Aryl, Heteroaryl, die ihrerseits
mit Alkyl, Amino, Nitro, Halogen, Hydroxyl, Alkoxyl substituiert sein können,
besonders bevorzugt Ethyl, Cyclopropyl,
R2 (im Falle Z=N kein Rest) Wasserstoff, Alkyl (verzweigt oder geradkettig),
Cycloalkyl, Aryl, Heteroaryl, (die ihrerseits substituiert sein können, s. R1),
Halogen, Nitro, Cyano, Acetyl, Carboxyl, Alkoxyl,
besonders bevorzugt Fluor,
R3 Wasserstoff, Cycloalkyl, Aryl, Heteroaryl, Heterocycloalkyl, Alkoxyl,
besonders bevorzugt Fluor, Piperazinyl, N-Methylpiperazinyl,
R4 Wasserstoff
sein kann, wobei in jedem Falle mindestens einer der Reste R1, R2, R3, R4 mit u. a.
einer der folgenden phosphonsäuretragenden Reste (bzw. den entsprechenden
Phosphonsäurealkylestern oder Alkalimetall-, Ammoniumsalzen) versehen ist:
R1 Alkyl- (verzweigt und unverzweigt), Cycloalkyl-, Cycloheteroalkyl-, Aryl-,
und Heteroaryl-Rest, der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂,
-C(OH)(PO₃H₂)₂ oder -C(NH₂)(PO₃H₂)₂ enthält,
bevorzugt -CH(PO₃H₂)₂, -C(CH₃)₂CH₂CH(PO₃H₂)₂
-CHCH₂CH(PO₃H₂)₂, -CH[CH₂CH(PO₃H₂)₂]₂, -C₆H₄CH₂(PO₃H₂),
besonders bevorzugt -C₆H₄CH(PO₃H₂)₂, -CH₂CH₂CH(PO₃H₂)₂,
R2 bevorzugt -CH(PO₃H₂)₂, CH₂(PO₃H₂),
R3 über ein Stickstoffatom gebundener Alkyl- (verzweigt und unverzweigt),
Cycloalkyl-, Cycloheteroalkyl-, Aryl-, und Heteroaryl-Rest,
der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂
oder -C(NH₂)(PO₃H₂)₂ enthält,
bevorzugt -NHCH(PO₃H₂)₂, -NHCH₂CH₂CH(PO₃H₂)₂,
-NHC(CH₃)₂CH₂CH(PO₃H₂)₂,-NHCHCH₂CH(PO₃H₂)₂, -NHCH[CH₂CH(PO₃H₂)₂]₂
-NHC₆H₄CH(PO₃H₂)₂, -NHC₆H₄NHCH(PO₃H₂)₂, N(CH₂PO₃H₂)₂,
besonders bevorzugt Piperazinyl-Rest der am Stickstoff einen
-COCH₂CH₂CH(PO₃H₂)₂ oder -CH₂CH(PO₃H₂)₂ Rest trägt,
R4 über Amid- oder Esterbindung gebundener Alkyl (verzweigt und
unverzweigt), Cycloalkyl-, Cycloheteroalkyl-, Aryl-, und Heteroaryl-Rest,
der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂
oder -C(NH₂)(PO₃H₂)₂ enthält,
bevorzugt -NHCH(PO₃H₂)₂, -NHCH₂CH₂CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂,
-NHC(CH₃)₂CH₂CH(PO₃H₂)₂ ,-NHCHCH₂CH(PO₃H₂)₂, -NHCH[CH₂CH(PO₃H₂)₂]₂,
-NHC₆H₄CH(PO₃H₂)₂, -NHC₆H₄NHCH(PO₃H₂)₂, -OC₆H₄(PO₃H₂)₂.where X, Y, Z = C, N can be and
R1 alkyl (branched or straight-chain), cycloalkyl, aryl, heteroaryl, which in turn can be substituted by alkyl, amino, nitro, halogen, hydroxyl, alkoxyl, particularly preferably ethyl, cyclopropyl,
R2 (in the case of Z = N no residue) hydrogen, alkyl (branched or straight-chain), cycloalkyl, aryl, heteroaryl ((which in turn can be substituted, see R1), halogen, nitro, cyano, acetyl, carboxyl, alkoxyl, especially preferably fluorine,
R3 is hydrogen, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxyl, particularly preferably fluorine, piperazinyl, N-methylpiperazinyl,
R4 hydrogen
can be, in any case at least one of the radicals R1, R2, R3, R4 being provided, inter alia, with one of the following phosphonic acid-carrying radicals (or the corresponding phosphonic acid alkyl esters or alkali metal, ammonium salts):
R1 alkyl (branched and unbranched), cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical, which the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂ or Contains -C (NH₂) (PO₃H₂) ₂, preferably -CH (PO₃H₂) ₂, -C (CH₃) ₂CH₂CH (PO₃H₂) ₂ -CHCH₂CH (PO₃H₂) ₂, -CH [CH₂CH (PO₃H₂) ₂] ₂, -C₆H₄CH₂ ( PO₃H₂), particularly preferably -C₆H₄CH (PO₃H₂) ₂, -CH₂CH₂CH (PO₃H₂) ₂,
R2 preferably -CH (PO₃H₂) ₂, CH₂ (PO₃H₂),
R3 alkyl (branched and unbranched) bonded via a nitrogen atom, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical which contains the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) ( PO₃H₂) ₂ or -C (NH₂) (PO₃H₂) ₂ contains, preferably -NHCH (PO₃H₂) ₂, -NHCH₂CH₂CH (PO₃H₂) ₂, -NHC (CH₃) ₂CH₂CH (PO₃H₂) ₂, -NHCHCH₂CH (PO₃H₂) ₂, -NHCH [CH₂CH (PO₃H₂) ₂] ₂ -NHC₆H₄CH (PO₃H₂) ₂, -NHC₆H₄NHCH (PO₃H₂) ₂, N (CH₂PO₃H₂) ₂, particularly preferably piperazinyl radical which is a -COCH₂CH₂CH (PO₃H₂) ₂ or -CH₂CH (PO₃H₂) ₂ Radical carries, R4 via amide or ester bond-bound alkyl (branched and unbranched), cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical which has the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C Contains (OH) (PO₃H₂) ₂ or -C (NH₂) (PO₃H₂) ₂,
preferably -NHCH (PO₃H₂) ₂, -NHCH₂CH₂CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -NHC (CH₃) ₂CH₂CH (PO₃H₂) ₂, -NHCHCH₂CH (PO₃H₂) ₂, -NHCH [CH₂CH (PO₃H₂) , -NHC₆H₄CH (PO₃H₂) ₂, -NHC₆H₄NHCH (PO₃H₂) ₂, -OC₆H₄ (PO₃H₂) ₂.
Die Verbindungen der allgemeinen Formel 1 werden nach an sich bekannten Verfahren hergestellt. Die Synthese ist an geeigneter Stelle so modifiziert, daß eine (oder mehrere) Phosphonsäure- oder Phosphonsäurealkylestergruppierung(en) eingefügt werden kann. Im folgenden wird dies für die Einführung eines Restes R1, R2, R3 oder R4 (siehe obige Aufzählung) an der jeweiligen Position des Chinolongrundgerüstes (siehe Formel 1) skizziert, wobei die übrigen Reste oben genannter Art sind und entsprechend den üblichen Methoden eingeführt werden. Meist werden aus präparativen Gründen zunächst die Phosphonsäurealkylester synthetisiert. Deren Hydrolyse erfolgt am Ende des Syntheseweges besonders bevorzugt durch Umesterung zu Silylestern mittels Halogentrimethylsilanen und anschließender schonender Hydrolyse mit Alkoholen oder Wasser. Als pharmakologisch verträgliche Salze werden vor allem die Mono- bzw. Dialkali- oder Ammoniumsalze verwendet, die in üblicher Weise z. B. durch Titration der Verbindungen mit anorganischen oder organischen Basen wie Natrium- oder Kaliumhydrogencarbonat, Natronlauge, Kalilauge, wäßrigem Ammoniak oder diversen Aminen hergestellt werden können.The compounds of general formula 1 are known per se Process manufactured. The synthesis is modified at a suitable point so that a (or more) phosphonic acid or phosphonic acid alkyl ester grouping (s) can be inserted. In the following this is for the introduction of a residue R1, R2, R3 or R4 (see list above) at the respective position of the Quinolone skeleton (see Formula 1) outlined, the remaining residues above are of the type mentioned and are introduced in accordance with customary methods. Usually, for preparative reasons, the phosphonic acid alkyl esters synthesized. Their hydrolysis takes place particularly at the end of the synthetic route preferably by transesterification to silyl esters using halotrimethylsilanes and subsequent gentle hydrolysis with alcohols or water. As pharmacologically acceptable salts are especially the mono- or dialkali or Ammonium salts used in the usual manner, for. B. by titration of Compounds with inorganic or organic bases such as sodium or Potassium hydrogen carbonate, sodium hydroxide solution, potassium hydroxide solution, aqueous ammonia or various amines can be produced.
Einführung an Position 1 (R1):
Ausgehend von entsprechend substituierten o-Halogenbenzoylchloriden erhält man
durch Reaktion mit Malonsäurediethylester/Magnesiumethylat, partieller saurer
Verseifung und anschließender Reaktion mit Orthoameisensäuretriethylester die
3-Ethoxyacrylsäureester. Deren Reaktion mit primären Aminen mit Rest R1 führt zu
4-Chinolon-3-carbonsäureestern. Die Erfindung nicht näher einschränkend ist als
Verfahrensbeispiel die Synthese des 1-{4-[Bis-(diethoxyphosphoryl)-methyl
phenyl]-4-oxo-1,4-dihydro-chinolin-3-carbonsäuretetraethylesters aufgeführt (s. u.).
Nach Hydrolyse der Carbonsäureester und Phosphonsäurealkylester erhält man
den Wirkstoff, der wenn erwünscht in die entsprechenden Alkalimetall oder
Ammoniumsalze überführt werden kann.Introduction at position 1 (R1):
Starting from appropriately substituted o-halobenzoyl chlorides, the 3-ethoxyacrylic acid esters are obtained by reaction with diethyl malonate / magnesium ethylate, partial acid hydrolysis and subsequent reaction with triethyl orthoformate. Their reaction with primary amines with residue R1 leads to 4-quinolone-3-carboxylic acid esters. As a process example, the invention is not restricted in any more detail to the synthesis of 1- {4- [bis- (diethoxyphosphoryl) methylphenyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid tetraethyl ester (see below). After hydrolysis of the carboxylic acid esters and phosphonic acid alkyl esters, the active ingredient is obtained, which, if desired, can be converted into the corresponding alkali metal or ammonium salts.
Einführung an Position 6 (R2):
Der Addition von Ethoxymethylenmalonsäurediethylester an ein
Phosphonsäurealkylester tragendes Amin, besonders bevorzugt
H₂NC₆H₄CH(PO₃Et₂)₂ oder H₂NC₆H₄CH ₂(PO₃Et₂), folgt eine thermische Cyclisierung.
Nach Alkylierung des sekundären Stickstoff wird der Phosphonsäurealkylester
analog dem oben genannten Verfahren zur freien Phosphonsäure hydrolysiert.Introduction at position 6 (R2):
The addition of diethyl ethoxymethylene malonate to an amine carrying a phosphonic acid alkyl ester, particularly preferably H₂NC₆H₄CH (PO₃Et₂) ₂ or H₂NC₆H₄CH ₂ (PO₃Et₂), is followed by thermal cyclization. After alkylation of the secondary nitrogen, the phosphonic acid alkyl ester is hydrolyzed to the free phosphonic acid analogously to the process mentioned above.
Einführung an Position 7 (R3):
Die Einführung eines Phosphonsäure- bzw. Phosphonsäurealkylester tragenden
Restes, wie unter R3 aufgeführt, kann bevorzugt durch nukleophile Substitution
eines Halogenatoms in Position 7 des Chinolongrundgerüstes (siehe Formel 1) durch
ein entsprechend substituiertes Amin erfolgen.
Introduction at position 7 (R3):
The introduction of a radical carrying phosphonic acid or alkyl phosphonic acid, as listed under R3, can preferably be carried out by nucleophilic substitution of a halogen atom in position 7 of the quinolone backbone (see formula 1) by an appropriately substituted amine.
Darüberhinaus kann eine Derivatisierung an einem Stickstoff enthaltenden Heterocyclus in Position 7, bevorzugt einem Piperazinyl-Rest vorgenommen werden. Dies kann bevorzugt durch Michael analoge Addition von Ethenylidenbisphosphonsäurealkylester an die sekundäre Aminogruppe geschehen. Besonders bevorzugt kann die sekundäre Aminogruppe des Piperazinyl-Substituenten, insbesondere bei Gyrase-Hemmern wie Pipemidsäure oder den Fluorchinolonen, wie Norfloxacin, Enoxacin, Ciprofloxacin, mit einem Phosphonsäure-, bzw. Phosphonsäurealkylester tragenden Säurechlorid zur Reaktion gebracht werden. Neben gegebenenfalls in situ erzeugten Säurechloriden besonders Carbonsäurechloriden, können auch Anhydride oder Carbonsäuren mit Kondensationsmitteln bzw. Katalysatoren eingesetzt werden. Als Verfahrensbeispiel, das die Erfindung nicht einschränkt, ist die Synthese von 7-{4-(4,4-Bis-(diethoxyphosphoryl)-butyryl]-piperazin-1yl}-1-ethyl-6-fluor-4-oxo-1,4- dihydro-chinolin-3-carbonsäuretetraethylester aufgeführt (s. u.).In addition, a derivatization to a nitrogen containing Heterocycle in position 7, preferably a piperazinyl radical will. This can preferably be done by Michael adding analog Ethenylidenebisphosphonsäurealkylester happen to the secondary amino group. The secondary amino group of the Piperazinyl substituents, especially in gyrase inhibitors such as pipemidic acid or the fluoroquinolones, such as norfloxacin, enoxacin, ciprofloxacin, with a Acid chloride bearing phosphonic acid or alkyl phosphonic acid Response. In addition to acid chlorides which may be generated in situ especially carboxylic acid chlorides, can also include anhydrides or carboxylic acids Condensing agents or catalysts are used. As Process example, which does not limit the invention, is the synthesis of 7- {4- (4,4-bis- (diethoxyphosphoryl) butyryl] piperazin-1yl} -1-ethyl-6-fluoro-4-oxo-1,4- dihydro-quinoline-3-carboxylic acid tetraethyl ester listed (see below).
Einführung an Position 3 (R4):
Ein Rest R4 kann nach Aktivierung der Carbonsäurefunktion in Position 3 durch
Reaktion mit einem entsprechend substituierten Amin oder Alkohol eingeführt
werden. Die Reaktion kann durch Kondensationsmittel bzw. Katalysatoren
unterstützt werden. Bevorzugt ist die vorherige Herstellung des
Carbonsäurechlorids des Chinolons. Besonders bevorzugt kann dieses in situ durch
Reaktion mit Chlorameisensäurealkylestern erzeugt werden.Introduction at position 3 (R4):
A residue R4 can be introduced after activation of the carboxylic acid function in position 3 by reaction with an appropriately substituted amine or alcohol. The reaction can be supported by condensing agents or catalysts. Preference is given to the prior preparation of the quinolone carboxylic acid chloride. This can particularly preferably be generated in situ by reaction with chloroformic acid alkyl esters.
Die Erfindung nicht näher einschränkend ist als Verfahrensbeispiel die Synthese von {4-[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphtyridin-3-carbonyl)--amino phenyl}-phosphono-methyl-phosphonsäure aufgeführt (s. u.).The invention is not restrictive as a process example, the synthesis of {4 - [(1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carbonyl) amino phenyl} -phosphono-methyl-phosphonic acid listed (see below).
Ein weiterer bevorzugter Gegenstand der Erfindung sind phosphonsäure funktionalisierte Sulfonamide der allgemeinen Formel 2Another preferred subject of the invention are phosphonic acid Functionalized sulfonamides of the general formula 2
in der
A ein Aryl-, Heteroaryl- (seinerseits mit Resten,wie Alkyl, Alkoxy, Nitro, Amino,
Halogen, Hydroxy, u. a.) Rest sein kann, der eine geminale oder vicinale
Bisphosphonsäure-, bzw. Bisphosphonsäurealkylester-Gruppierung,
besonders Fragmente der Formel -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂,
-C(OH)(PO₃H₂)₂, -C(NH₂)(PO₃H₂)₂ trägt,
A besonders bevorzugt -C₆H₄CH(PO₃H₂)₂, -C₆H₄NHCH(PO₃H₂)₂ sein kann.in the
A can be an aryl, heteroaryl (in turn with residues such as alkyl, alkoxy, nitro, amino, halogen, hydroxy, etc.) residue, which is a geminal or vicinal bisphosphonic or bisphosphonic acid group, especially fragments of the formula - CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂, -C (NH₂) (PO₃H₂) ₂,
A can particularly preferably be -C₆H₄CH (PO₃H₂) ₂, -C₆H₄NHCH (PO₃H₂) ₂.
Zur Synthese der Verbindungen der allgemeinen Formel 2 wird bevorzugt ein entsprechend mit Phosphonsäurealkylestergruppen substituiertes primäres Amin z. B. in Pyridin als Losemittel und Saurefanger, mit 4-Acetylamino benzolsulfonylchlorid umgesetzt. Die Phosphonsäurealkylestergruppen des so entstandenen Sulfonamids werden mit der oben erwähnten Hydrolyse-Methode der Umesterung zu Silylestern verseift.A is preferably used to synthesize the compounds of the general formula 2 primary amine correspondingly substituted with alkyl phosphonate groups e.g. B. in pyridine as a solvent and acid trap, with 4-acetylamino benzenesulfonyl chloride implemented. The phosphonic acid alkyl ester groups of the so The resulting sulfonamides are produced using the hydrolysis method mentioned above Transesterification saponified to silylesters.
Als Verfahrensbeispiel ist, die Erfindung nicht näher einschränkend die Synthese von [4-(4-Amino-benzolsulfonylamino)-phenyl]-phosphono-methyl-phosphonsä-ure aufgeführt (s. u.).As a process example, the invention is not restrictive of the synthesis of [4- (4-amino-benzenesulfonylamino) -phenyl] -phosphono-methyl-phosphonic acid listed (see below).
Ein weiterer bevorzugter Gegenstand der Erfindung sind phosphonsäurefunktionalisierte β-Lactam-Antibiotika.Another preferred subject of the invention are Phosphonic acid functionalized β-lactam antibiotics.
Hierbei werden solche der Penam-Gruppe, bevorzugt Penicilline, Oxymethyl-Penicilline und Sulfonpenicilline, der Carbapenem-Gruppe, bevorzugt Thienamycine, der Cephem-Gruppe, bevorzugt Cephalosporine und Oxymethyl-Cephalosporine, sowie Oxa-Cephalosporine mit geminalen oder vicinalen Bisphosphonsäure- bzw. Bisphosphonsäurealkylester-Gruppen versehen.Here, those of the Penam group, preferably penicillins, Oxymethyl penicillins and sulfonpenicillins, the carbapenem group, are preferred Thienamycine, the cephem group, preferably cephalosporins and Oxymethyl-cephalosporins, as well as oxa-cephalosporins with geminal or vicinal bisphosphonic acid or bisphosphonic acid alkyl ester groups.
In Formel 3 und 4 ist dies am Beispiel der Penicilline und der Cephalosporine verdeutlicht.In formulas 3 and 4, this is the example of penicillins and cephalosporins clarifies.
Hier ist
B Aryl, Heteroacryl, Cyclo(Hetero)alkyl mit diversen Substituenten, darunter vor
allem Fragmente der Formel -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂
und -C(NH₂)(PO₃H₂)₂.Here is
B aryl, heteroacrylic, cyclo (hetero) alkyl with various substituents, including in particular fragments of the formula -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂ and -C (NH₂) ( PO₃H₂) ₂.
Die Phosphonsäuren tragenden Reste werden dabei bevorzugt über Amid-Bindung an der Aminogruppe der β-Lactam-Grundstruktur fixiert. Im Falle der Penicilline wird beispielsweise die 6-Aminopenicillansäure mit einer aktivierten Carbonsäure, die Phosphonsäure(ester)gruppen trägt an der Aminofunktion derivatisiert, analog den üblichen Synthesen der verschiedenen Penicilline. (Analog bei den Cephalosporinen die 7-Aminocephalosporansäure, usw.)The residues carrying phosphonic acids are preferred via amide bonding fixed to the amino group of the β-lactam basic structure. In the case of penicillins for example 6-aminopenicillanic acid with an activated carboxylic acid, the Phosphonic acid (ester) groups derivatized to the amino function, analogous to usual syntheses of the various penicillins. (Analogously with the Cephalosporins the 7-aminocephalosporanic acid, etc.)
Ein weiterer Gegenstand der Erfindung sind Phosphonsäurealkylester, die im Sinne der Erfindung als wichtige Synthesebausteine Verwendung finden.Another object of the invention are phosphonic acid alkyl esters in the sense find the invention as important synthesis building blocks.
Bevorzugt sind dies:
3-Nitro-pentan-1,1,5,5-tetrakisphosphonsäureoktaethylester,
3-Amino-pentan-1,1,5,5-tetrakisphosphonsäureoktaethylester,
3-Nitro-3-methyl-butan-1,1-bisphosphonsäuretetraethylester,
3-Amino-3-methyl-butan-1,1-bisphosphonsäuretetraethylester,
4-Hydroxyphenyl-diethoxyphosphoryl-methyl-phosphonsäurediethylester,-
4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonsäurediethylester.These are preferably:
3-nitro-pentane-1,1,5,5-tetrakisphosphonic acid ocethylester,
3-amino-pentane-1,1,5,5-tetrakisphosphonic acid ocethylester,
3-nitro-3-methyl-butane-1,1-bisphosphonic acid tetraethyl ester,
3-amino-3-methyl-butane-1,1-bisphosphonic acid tetraethyl ester,
4-hydroxyphenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester,
4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester.
Ihre Synthese ist unter dem Punkt Verfahrensbeispiele aufgeführt.Their synthesis is listed under process examples.
Gegenstand der Erfindung ist auch die Herstellung von Arzneimitteln mit antibakteriell wirksamen phosphonsäuregekoppelten Verbindungen, wie sie oben beschrieben wurden. The invention also relates to the production of pharmaceuticals antibacterially active phosphonic acid-coupled compounds as described above have been described.
Die erfindungsgemäßen Arzneimittel werden vor allem intravenös, aber auch intraperitoneal, subkutan, rektal oder peroral verabreicht. Auch eine äußerliche Applikation ist möglich. Bevorzugt ist die Verabreichung durch intravenöse Injektion oder intravenöse Infusion.The pharmaceuticals according to the invention are primarily intravenous, but also administered intraperitoneally, subcutaneously, rectally or orally. Also an external one Application is possible. Administration by intravenous injection is preferred or intravenous infusion.
Die Arzneimittel werden nach an sich bekannten Verfahren hergestellt, wobei die erfindungsgemäßen Substanzen als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Trägerstoffen eingesetzt werden. Enthalten die neuen pharmazeutischen Zubereitungen neben dem Wirkstoff pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt der Mischungen 0.1 bis 99.5, vorzugsweise 0.5 bis 95 Gewichtsprozent der Gesamtmischung.The pharmaceuticals are produced by methods known per se, the Substances according to the invention as such or, if appropriate, in combination with suitable pharmaceutical carriers are used. Contain the new pharmaceutical preparations in addition to the active ingredient pharmaceutical Carriers, the active ingredient content of the mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.
Die pharmazeutischen Zubereitungen gemäß der Erfindung können, wenn sie in Einheitsdosen vorliegen und für die Applikation z. B. am Menschen bestimmt sind, etwa 0.1 bis 500 mg, vorteilhafterweise 10 bis 200 mg und insbesondere 50 bis 150 mg Wirkstoff enthalten.The pharmaceutical preparations according to the invention, when in Unit doses are available and for application z. B. are intended for humans, about 0.1 to 500 mg, advantageously 10 to 200 mg and in particular 50 to 150 mg contain active ingredient.
Im allgemeinen erweist es sich in der Humanmedizin als vorteilhaft, den oder die Wirkstoffe bei parenteraler Gabe in einer Tagesdosis von etwa 0.1 bis 5, vorzugsweise 1 bis 3 Einzelgaben zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder die Wirkstoffe in Mengen von etwa 0.1 bis etwa 5, vorzugsweise 1 bis 3 mg/kg Körpergewicht. Bei einer oralen Anwendung können ähnliche Dosierungen zur Anwendung kommen.In general, it proves to be advantageous in human medicine Active ingredients when administered parenterally in a daily dose of about 0.1 to 5, preferably 1 to 3 single doses to achieve the desired results administer. A single dose contains the active ingredient (s) in amounts of approximately 0.1 to about 5, preferably 1 to 3 mg / kg body weight. With an oral Similar dosages can be used.
Wie bei der internistischen Therapie üblich, kann zur Reduzierung des Nebenwirkungsrisikos die Behandlung mit den erfindungsgemäßen Arzneimitteln mit der Verabreichung anderer Therapeutika mit unterschiedlichen Wirkungs spektren kombiniert werden.As is usual with internal therapy, can reduce the Side effects risk treatment with the medicaments according to the invention with the administration of other therapeutic agents with different effects spectra can be combined.
Die Festlegung der jeweils erforderlichen optimalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.The determination of the optimal dosage and type of application required The active ingredients can easily be used by any specialist on the basis of their specialist knowledge respectively.
Die pharmazeutischen Zubereitungen bestehen in der Regel aus den erfindungsgemäßen Verbindungen und nichttoxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel in fester, halbfester oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beutels oder eines anderen Behältnisses, für den therapeutisch aktiven Bestandteil zur Anwendung kommen. Ein Trägerstoff kann z. B. als Vermittler für die Arzneimittelaufnahme durch den Körper, als Formulierungshilfsmittel, als Süßungsmittel, als Geschmackskorrigens, als Farbstoff oder als Konservierungsmittel dienen.The pharmaceutical preparations usually consist of the Compounds according to the invention and non-toxic, pharmaceutical compatible drug carriers used as an admixture or diluent in solid, semi-solid or liquid form or as a coating agent, for example in In the form of a capsule, pill cover, sachet or other Container for which the therapeutically active component are used. A carrier can e.g. B. as an intermediary for the drug intake by the Body, as formulation aid, as sweetener, as taste corrector, serve as a dye or as a preservative.
Wäßrige Suspensionen können Suspendiermittel, z. B. Natriumcarboxymethylcellu lose, Methylcellulose, Hydroxypropylcellulose, Natriumalginat, Polyvinylpyrrolidon, Traganthgummi oder Akaziengummi, Dispergier- und Benetzungsmittel, z. B. Po lyoxyethylenstearat, Heptadecaethylenoxycetanol, Polyoxyethylensorbitanfettsäure ester, wie z. B. Polyoxyethylensorbitanmonooleat sowie Lecithin, Konservierungs mittel, z. B. Methyl oder Propylhydroxybenzoate, Geschmacksmittel und/oder Süßungsmittel, z. B. Saccharose, Lactose, Natriumcyclamat, Dextrose, Invert zuckersirup enthalten.Aqueous suspensions can include suspending agents, e.g. B. Sodium carboxymethyl cellu loose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, Tragacanth or acacia, dispersing and wetting agents, e.g. B. Po lyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitan fatty acid esters such as B. polyoxyethylene sorbitan monooleate and lecithin, preservatives medium, e.g. As methyl or propyl hydroxybenzoates, flavoring agents and / or Sweeteners, e.g. B. sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup included.
Emulsionen können z. B. Oliven , Erdnuß oder Paraffinöl neben Emulgiermitteln wie z. B. Traganthgummi oder Akaziengummi, Phosphatiden, Sorbitanmonooleat, Polyoxyethylensorbitanmonooleat und Süßungs- und Geschmacksmittel enthalten.Emulsions can e.g. B. olives, peanut or paraffin oil in addition to emulsifiers such as e.g. B. tragacanth or acacia, phosphatides, sorbitan monooleate, Contain polyoxyethylene sorbitan monooleate and sweetening and flavoring agents.
Zur parenteralen Anwendung der Arzneistoffe dienen steril injizierbare wäßrige Suspensionen, Liposomen, isotonische Salzlösungen oder sonstige Lösungen, die Dispergier- oder Benetzungsmittel und/oder pharmakologisch verträgliche Verdün nungsmittel, z. B. Propylen- oder Butylglykol, und/oder Lösungsvermittler, z. B. Tween, Cremophor oder Polyvinylpyrrolidon, enthalten.Sterile injectable aqueous solutions are used for parenteral use of the drugs Suspensions, liposomes, isotonic saline solutions or other solutions that Dispersing or wetting agents and / or pharmacologically acceptable diluents agent, e.g. B. propylene or butyl glycol, and / or solubilizers, for. B. Tween, cremophor or polyvinylpyrrolidone.
Die Wirkstoffe können gegebenenfalls mit einem oder mehreren der angegebenen Träger- oder Zusatzstoffe auch in mikroverkapselter Form formuliert werden.The active ingredients can optionally with one or more of the specified Carriers or additives can also be formulated in microencapsulated form.
Die folgenden Beispiele erläutern die Erfindung näher, ohne sie einzuschränken.The following examples illustrate the invention without restricting it.
2-Nitropropan (0.9 g, 10 m mol) wird mit trockenem Tetrahydrofuran (25 ml), Di-(isopropyl)amin (1.1 g, 11 mmol) und Ethenylidenbisphosphonsäuretetraethylester (3 g, 10 mmol) gemischt. Die Lösung wird unter Rühren 2 Tage zum Rückfluß erhitzt und nach Abkühlung auf Raumtemperatur mit 0.5 n Salzsäure neutralisiert. Nach Einengen auf 15-20 ml wird 4mal mit 20 ml Chloroform extrahiert. Die vereinigten organischen Phasen werden über Natriumsulfat getrocknet und anschließend am Rotationsverdampfer eingeengt. Das verbleibende gelbe Öl wird einer säulenchromatographischen Trennung (Säulenmaterial: Kieselgel, Laufmittel: Essigester/Ethanol 3 : 1) unterzogen. Man erhält 3-Nitro-3-methyl-butan- 1,1-bisphosphonsäuretetraetylester als farbloses viskoses Öl.2-nitropropane (0.9 g, 10 m mol) is mixed with dry tetrahydrofuran (25 ml), Di (isopropyl) amine (1.1 g, 11 mmol) and tetraethyl ethenylidenebisphosphonate (3 g, 10 mmol) mixed. The solution is refluxed with stirring for 2 days and after cooling to room temperature neutralized with 0.5 N hydrochloric acid. After Concentrate to 15-20 ml is extracted 4 times with 20 ml of chloroform. The United organic phases are dried over sodium sulfate and then on Rotary evaporator concentrated. The remaining yellow oil becomes one separation by column chromatography (column material: silica gel, mobile phase: Ethyl acetate / ethanol 3: 1) subjected. 3-Nitro-3-methyl-butane is obtained. 1,1-bisphosphonic acid tetraetylester as a colorless viscous oil.
Dieses wird in Methanol gelöst und mit 20% Palladium/Aktivkohle (enthaltend 51%
H₂O, DEGUSSA) versetzt. Bei atmosphärischem Druck und Raumtemperatur wird
nun unter kräftigem Rühren Wasserstoff eingeleitet. Nach beendeter
Wasserstoffaufnahme wird der Katalysator abfiltriert und die verbleibende Lösung
am Rotationsverdampfer eingeengt. Das leicht gelbliche Öl wird dann
säulenchromatographisch gereinigt (Säulenmaterial: Al₂O₃ , basisch). Eine
Essigester/Ethanol-Mischung, zunächst im Verhältnis 3 : 1, dann 1 : 1 wird als
Laufmittel benutzt um Verunreinigungen abzutrennen. Das Produkt wird dann mit
Ethanol eluiert.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse:
ber.: C 43.45 H 8.70 N 3.90 P 17.24%
gef.: C 43.17 H 8.62 N 3.81 P 17.21%.This is dissolved in methanol and mixed with 20% palladium / activated carbon (containing 51% H₂O, DEGUSSA). At atmospheric pressure and room temperature, hydrogen is then introduced with vigorous stirring. When the uptake of hydrogen has ended, the catalyst is filtered off and the remaining solution is concentrated on a rotary evaporator. The slightly yellowish oil is then purified by column chromatography (column material: Al₂O₃, basic). An ethyl acetate / ethanol mixture, first in a ratio of 3: 1, then 1: 1, is used as the eluent to remove impurities. The product is then eluted with ethanol.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis:
calc .: C 43.45 H 8.70 N 3.90 P 17.24%
found: C 43.17 H 8.62 N 3.81 P 17.21%.
Zu einer Mischung aus Nitromethan (0.31 g, 5 mmol) und Di-(isopropyl)amin (0.56 g, 5.5 mmol) in 20 ml trockenem Tetrahydrofuran wird Ethenyliden bisphosphonsäuretetraethylester (3 g, 10 mmol) zugeben. Nach zweistündigem Rühren bei Raumtemperatur werden flüchtige Bestandteile am Rotationsverdampfer abgezogen. Säulenchromatographische Reinigung des Rohprodukts (Säulenmaterial: Kieselgel, Laufmittel, Essigsäureethylester/Ethanol 3 : 1) liefert 3-Nitro-pentan-1,1,5,5-tetrakisphosphonsäureoctaethylester als blaßgelbes viskoses Öl. To a mixture of nitromethane (0.31 g, 5 mmol) and di (isopropyl) amine (0.56 g, 5.5 mmol) in 20 ml of dry tetrahydrofuran becomes ethenylidene Add bisphosphonic acid tetraethyl ester (3 g, 10 mmol). After two hours Stirring at room temperature becomes volatile components on a rotary evaporator deducted. Column chromatographic purification of the raw product (Column material: silica gel, eluent, ethyl acetate / ethanol 3: 1) provides 3-nitro-pentane-1,1,5,5-tetrakisphosphonic acid octaethyl as pale yellow viscous oil.
Dieses wird in Methanol gelöst und mit 20% Palladium/Aktivkohle (enthaltend 51%
H₂O, DEGUSSA) versetzt. Bei atmosphärischem Druck und Raumtemperatur wird
nun unter kräftigem Rühren Wasserstoff eingeleitet. Nach beendeter
Wasserstoffaufnahme wird der Katalysator abfiltriert und die verbleibende Lösung
am Rotationsverdampfer eingeengt. Das leicht gelbliche Öl wird dann
säulenchromatographisch gereinigt (Säulenmaterial: Al₂O₃ , basisch). Eine
Essigester/Ethanol-Mischung, zunächst im Verhältnis 3 : 1, dann 1 : 1 wird als
Laufmittel benutzt um Verunreinigungen abzutrennen. Das Produkt wird dann mit
Ethanol eluiert. Durch Aufnahme des erhaltenen Öls in Methanol und abziehen des
Lösungsmittels erhält man das Produkt als Monohydrat.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₂₁H₄₉NO₁₂P₄ × 1 H₂O
ber.: C 38.83 H 7.91 N 2.16 P 19.08%
gef.: C 38.86 H 7.86 N 1.97 P 19.12%.This is dissolved in methanol and mixed with 20% palladium / activated carbon (containing 51% H₂O, DEGUSSA). At atmospheric pressure and room temperature, hydrogen is then introduced with vigorous stirring. When the uptake of hydrogen has ended, the catalyst is filtered off and the remaining solution is concentrated on a rotary evaporator. The slightly yellowish oil is then purified by column chromatography (column material: Al₂O₃, basic). An ethyl acetate / ethanol mixture, first in a ratio of 3: 1, then 1: 1, is used as the eluent to remove impurities. The product is then eluted with ethanol. By taking up the oil obtained in methanol and removing the solvent, the product is obtained as a monohydrate.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₂₁H₄₉NO₁₂P₄ × 1 H₂O
calc .: C 38.83 H 7.91 N 2.16 P 19.08%
found: C 38.86 H 7.86 N 1.97 P 19.12%.
3 g (0.009 mol) 4-(2,2,2-Trifluor-Acetylamino)-benzyl-phosphonsäure-diethylester
(herhalten durch Trifluoracetylierung des Amins mit Trifluoracetanhydrid) werden in
60 ml absolutem CCl₄ gelöst und 1.76 g (0,009 mol) N-Bromsuccinimid zugegeben.
Die Mischung wird in einem vorgeheizten Ölbad zum Sieden erhitzt und mit einer
UV-Lampe bestrahlt. Die radikalische Bromierungsreaktion springt sofort an. Nach 3
Stunden wird von entstandenem spezifisch leichteren Succinimid heiß abfiltriert.
Das Filtrat wird auf etwa das halbe Volumen eingeengt. Es bildet sich ein
Niederschlag, der abgesaugt wird. Der Feststoff besteht aus Brom-[4-(2,2,2-trifluor
acetylamino)-phenyl]-methyl-phosphonsäurediethylester und zu etwa einem Viertel
Edukt (laut ¹H NMR). Dieses Rohprodukt (3 g) wird in 20 ml absolutem
Tetrahydrofuran gelöst, mit 1.2 g (0,007 mol) Triethylphosphit versetzt und 4
Stunden unter Rühren zum Rückfluß erhitzt. Man befreit die Reaktionsmischung am
Rotationsverdampfer vom Lösemittel und kocht den verbleibenden Feststoff mit
Ether aus. Es verbleiben 1.9 g (0.004 mol) eines weißen, feinkristallinen Feststoffs
(Schmelzpunkt 165°C). Dieser wird zur Abspaltung der Trifluoracetylgruppe mit
einem Überschuß an 0.1 n NaOH versetzt und unter Erwärmung 5 Stunden gerührt.
Nach Abkühlung wird mit CH₂Cl₂ mehrmals extrahiert, mit Natriumsulfat getrocknet
und zur Trockne einrotiert. Man erhält 1.3 g (0.0035 mol) des gewünschten Produkts
als Feststoff, der sich beim Stehenlassen mit der Zeit leicht gelb färbt.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₁₅H ₂₇NO₆P₂
ber.: C 47.50 H 7.17 N 3.69 P 16.33 O 25.31%
gef.: C 47.47 H 7.16 N 3.62 P 16.17%.3 g (0.009 mol) of diethyl 4- (2,2,2-trifluoroacetylamino) benzylphosphonate (obtained by trifluoroacetylation of the amine with trifluoroacetic anhydride) are dissolved in 60 ml of absolute CCl₄ and 1.76 g (0.009 mol) of N- Bromosuccinimide added. The mixture is heated to boiling in a preheated oil bath and irradiated with a UV lamp. The radical bromination reaction starts immediately. After 3 hours, the lighter succinimide obtained is filtered off hot. The filtrate is concentrated to about half the volume. A precipitate forms, which is suctioned off. The solid consists of bromo- [4- (2,2,2-trifluoroacetylamino) phenyl] methylphosphonic acid diethyl ester and about a quarter of the starting material (according to 1 H NMR). This crude product (3 g) is dissolved in 20 ml of absolute tetrahydrofuran, 1.2 g (0.007 mol) of triethyl phosphite are added and the mixture is heated to reflux with stirring for 4 hours. The reaction mixture is freed from the solvent on a rotary evaporator and the remaining solid is boiled out with ether. 1.9 g (0.004 mol) of a white, finely crystalline solid (melting point 165 ° C.) remain. To split off the trifluoroacetyl group, an excess of 0.1N NaOH is added and the mixture is stirred with heating for 5 hours. After cooling, it is extracted several times with CH₂Cl₂, dried with sodium sulfate and evaporated to dryness. 1.3 g (0.0035 mol) of the desired product are obtained as a solid which, when left to stand, turns slightly yellow over time.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₁₅H ₂₇NO₆P₂
calc .: C 47.50 H 7.17 N 3.69 P 16.33 O 25.31%
found: C 47.47 H 7.16 N 3.62 P 16.17%.
1 g (0.0026 mol) 4 Aminophenyl-diethoxyphosphoryl-methyl-phosphonsäure
diethylester wird in 2.3 ml halbkonzentrierter Salzsäure gelost. Nach Abkühlung auf
-10°C (Eis/Kochsalz) wird während 10 Minuten 0.18 g (0.0026 mol) Natriumnitrit in 1
ml Wasser zugegeben (Temperaturkontrolle!). Nach Erwärmenlassen auf
Raumtemperatur wird die Diazoniumsalzlösung mit H₂O auf das doppelte Volumen
verdünnt und erhitzt. Es tritt bald N₂-Entwicklung auf. Die entstehende goldgelbe
Lösung wird 2 Stunden bei 100°C erhitzt und nach Abkühlung auf Raumtemperatur
mehrmals mit CH₂Cl₂ extrahiert, mit Wasser gewaschen, mit Magnesiumsulfat
getrocknet und einrotiert. Das verbleibende Öl kristallisiert langsam durch.
Umkristallisation aus Ether ergibt 0.5 g eines schwach gelben Feststoffs.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₁₅ H₂₆O₇P₂
ber.: C 47.37 H 6.89 P 16.29 O 29.45%
gef.: C 47.24 H 6.93 P 16.04%.1 g (0.0026 mol) of 4 aminophenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester is dissolved in 2.3 ml of semi-concentrated hydrochloric acid. After cooling to -10 ° C (ice / common salt) 0.18 g (0.0026 mol) sodium nitrite in 1 ml water is added over 10 minutes (temperature control!). After warming to room temperature, the diazonium salt solution is diluted to twice the volume with H₂O and heated. There will soon be N₂ development. The resulting golden yellow solution is heated at 100 ° C for 2 hours and extracted several times with CH₂Cl₂ after cooling to room temperature, washed with water, dried with magnesium sulfate and evaporated. The remaining oil slowly crystallizes. Recrystallization from ether gives 0.5 g of a pale yellow solid.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₁₅ H₂₆O₇P₂
calc .: C 47.37 H 6.89 P 16.29 O 29.45%
found: C 47.24 H 6.93 P 16.04%.
0.45 g, (0.001 2 mol) 4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonsäure
diethylester wird in 2 ml absolutem Pyridin gelöst und während einer halben Stunde
0.28 g (0.001 2 mol) 4-Acetylamino-benzolsulfonylchlorid portionsweise eingetragen.
Nach zweistündigem Rühren gießt man zur kräftig rot gefärbten Lösung zunächst
Wasser und dann CH₂Cl₂ zur Ausfällung zu. Der erhaltene Feststoff wird mit
Aktivkohle aus Ethanol und daraufhin mit Petrolether/Essigester (1 : 1)
umkristallisiert. Die so erhaltenen 0.6 g (0.001 mol) [4-(4-Acetylamino
benzolsulfonylamino)-phenyl]-diethoxyphosphoryl-methyl-phosphonsäure-diethyl
ester (Schmelzpunkt 192°C, charakterisiert mittels Elementaranalyse, ¹H, ¹³C, ³¹P
NMR) werden in 200 ml absolutem Acetonitril gelöst. Nach Zugabe von 1,5 g
(0.01 mol) Bromtrimethylsilan wird 4 Stunden bei 50°C gerührt. Anschließend wird
eingeengt. Der schmierige Feststoff wird in Wasser aufgenommen und eine Stunde
zum Rückfluß erhitzt und dann einrotiert. Die erhaltene freie Phosphonsäure wird
zur Abspaltung der Acetyl-Schutzgruppe in 2n-Salzsäure aufgeschlämmt und fünf
Stunden bei 100°C gerührt. Anschließend wird zur Trockne einrotiert, in Methanol
aufgenommen und mit Anilin als Aniliniumsalz gefällt. Das Aniliniumsalz kann nach
lösen in Wasser auf eine Kationenaustauschersäule gegeben werden. Nach
Abrotieren des Wassers verbleibt ein glasiger Feststoff der im Hochvakuum
getrocknet wird.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₁₃ H₁₆ N₂O₈P₂S
ber.: C 36.98 H 3.82 N 6.63%
gef.: C 36.58 H 3.92 N 6.57%.0.45 g of (0.001 2 mol) 4-aminophenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester is dissolved in 2 ml of absolute pyridine and 0.28 g (0.001 2 mol) of 4-acetylamino-benzenesulfonyl chloride is added in portions over a period of half an hour. After stirring for two hours, water is poured into the bright red solution and then CH₂Cl₂ for precipitation. The solid obtained is recrystallized with activated carbon from ethanol and then with petroleum ether / ethyl acetate (1: 1). The 0.6 g (0.001 mol) thus obtained [4- (4-acetylamino benzenesulfonylamino) phenyl] diethoxyphosphoryl-methyl-phosphonic acid diethyl ester (melting point 192 ° C., characterized by elemental analysis, 1 H, 13 C, 31 P NMR) are in 200 ml of absolute acetonitrile dissolved. After adding 1.5 g (0.01 mol) of bromotrimethylsilane, the mixture is stirred at 50 ° C. for 4 hours. It is then concentrated. The greasy solid is taken up in water and heated to reflux for one hour and then evaporated. The free phosphonic acid obtained is slurried in 2N hydrochloric acid to split off the acetyl protective group and stirred at 100 ° C. for five hours. It is then evaporated to dryness, taken up in methanol and precipitated with aniline as the anilinium salt. After dissolving in water, the anilinium salt can be added to a cation exchange column. After the water has been spun off, a vitreous solid remains which is dried under high vacuum.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₁₃ H₁₆ N₂O₈P₂S
calc .: C 36.98 H 3.82 N 6.63%
found: C 36.58 H 3.92 N 6.57%.
Zu einer Suspension von 0.46 g (0.0021 mol) Nalidixinsäure, 0.4 ml Triethylamin und
40 ml Aceton/Dioxan (1.3) werden bei 0°C 0.19 ml (0.0021 mol)
Chlorameisensäureethylester unter Rühren zugegeben. Nach halbstündigem
Rühren bei Raumtemperatur werden in Aceton gelöster 0.8 g (0.0021 mol)
4-Aminophenyldiethoxyphosphoryl-methyl-phosphonsäurediethylester und 0.4 ml
Triethylamin zugegeben und nach halbstündigem Rühren bei Raumtemperatur 2
Stunden zum Rückfluß erhitzt. Nach dem Abkuhlen wird vom Niederschlag abfiltriert
und das Filtrat auf etwa ein Drittel eingeengt. Der entstehende Niederschlag wird
abgesaugt. Umkristallisation aus Methanol/Essigester liefert als farblose kleine
Nadeln (Schmelzpunkt 176°C) den {4-[(1-ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]
naphtyridin-3-carbonyl)-amino]-phenyl)-diethoxyphosphoryl-methyl-pho-sphos
säurediethylester.
(Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₂₇H₃₇N₃O₈P₂
ber.: C 54.64 H 6.28 N 7.08 P 10.44 O 21.56%
gef.: C 54.73 H 6.46 N 7.24 P 10.16%)0.19 ml (0.0021 mol) of ethyl chloroformate are added to a suspension of 0.46 g (0.0021 mol) of nalidixic acid, 0.4 ml of triethylamine and 40 ml of acetone / dioxane (1.3) with stirring. After stirring for half an hour at room temperature, 0.8 g (0.0021 mol) of 4-aminophenyldiethoxyphosphoryl-methyl-phosphonic acid diethyl ester and 0.4 ml of triethylamine are added and, after stirring for half an hour at room temperature, the mixture is heated under reflux for 2 hours. After cooling, the precipitate is filtered off and the filtrate is concentrated to about a third. The resulting precipitate is suctioned off. Recrystallization from methanol / ethyl acetate gives the {4 - [(1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carbonyl) as colorless small needles (melting point 176 ° C.) ) -amino] -phenyl) -diethoxyphosphoryl-methyl-phophosphosic acid diethyl ester.
(Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₂₇H₃₇N₃O₈P₂
calc .: C 54.64 H 6.28 N 7.08 P 10.44 O 21.56%
found: C 54.73 H 6.46 N 7.24 P 10.16%)
0.5 g (0.00084 mol) dieses Phosphonsäurealkylesters werden in 10 ml absolutem Chloroform gelöst und mit 0.7 g Bromtrimethylsilan versetzt. Es wird 5 Stunden bei Raumtemperatur gerührt. Bei Zugabe von Wasser fällt als weißer Niederschlag die freie Phosphonsäure aus.0.5 g (0.00084 mol) of this phosphonic acid alkyl ester are dissolved in 10 ml of absolute Chloroform dissolved and mixed with 0.7 g of bromotrimethylsilane. It will be at 5 hours Room temperature stirred. When water is added, the precipitate falls as white free phosphonic acid.
Zur besseren Wasserlöslichkeit wird die {4-[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-
[1,8]naphtyridin-3-carbonyl)-amino-phenyl}-phosphono-methyl-phosphonsäure in
Wasser suspendiert und mit 0.1 n NaOH zum Di-Natrium-Salz titriert, das durch
Umfällung gereinigt werden kann und als Trihydrat charakterisiert wurde.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₁₉H₁₉N₃Na₂O₈P₂ × 3 H₂O
ber.: C 39.39 H 4.35 N 7.25 P 10.69 O 30.38%
gef.: C 39.47 H 4.28 N 7.23 P 10.49%.The {4 - [(1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carbonyl) -amino-phenyl} -phosphono-methyl-phosphonic acid suspended in water and titrated with 0.1N NaOH to the disodium salt, which can be purified by reprecipitation and has been characterized as a trihydrate.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₁₉H₁₉N₃Na₂O₈P₂ × 3 H₂O
calc .: C 39.39 H 4.35 N 7.25 P 10.69 O 30.38%
found: C 39.47 H 4.28 N 7.23 P 10.49%.
Zu einer Lösung von 6,6 g (0.025 mol) 2-(2-Fluor)-benzoyl-3-ethoxy-acryl
säureethylester in absolutem Ethanol wird eine Lösung von 10 g (0.026 mol)
4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonsäurediethylester in 100 ml
absolutem Ethanol unter Eiskühlung während 10 min zugetropft. Nach einstündigem
Rühren bei Raumtemperatur wird Wasser zugegossen. Die untere Phase wird
abgetrennt und die wäßrige Phase noch zweimal mit CH₂Cl₂ extrahiert. Die
vereinigten organischen Phasen werden mit Natriumsulfat getrocknet und vom
Lösemittel befreit. Es verbleiben 12,5 g 3-{4-[Bis-diethoxyphosphoryl)-methyl]-
phenylamino}-2(2-Fluorbenzoyl)-acrylsäureethylester als gelbes Öl, das in 45 ml
Dimethylformamid gelöst und mit 9.9 g Natriumfluorid 2 Stunden bei 145°C gerührt
wird. Anschließend wird heiß filtriert und auf Eis gegossen. Es wird mit Ether
extrahiert und eine säulenchromatographische Reinigung (Säulenmaterial.
Kieselgel, Laufmittel: zunächst Aceton, dann Aceton/Ethanol) liefert den
1-{4-[Bis-(diethoxyphosphoryl)-methyl-phenyl]-4-oxo-1,4-dihydro-chinoli-n-
3-carbonsäuretetraethylester dessen Phosphonsäure- und Carbonsäure-Gruppen
dann verseift werden können.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₂₇H₃₅NO₉P₂
ber.: C 55.96 H 6.09 N 2.42 P 10.69 O 24.85%
gef.: C 55.58 H 6.19 N 2.33 P 10.52%.
A solution of 10 g (0.026 mol) of 4-aminophenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester is added to a solution of 6.6 g (0.025 mol) of ethyl 2- (2-fluoro) -benzoyl-3-ethoxyacrylate in absolute ethanol added dropwise in 100 ml of absolute ethanol with ice cooling for 10 min. After stirring for one hour at room temperature, water is poured in. The lower phase is separated and the aqueous phase extracted twice more with CH₂Cl₂. The combined organic phases are dried with sodium sulfate and freed from the solvent. 12.5 g of 3- {4- [bis-diethoxyphosphoryl) methyl] phenylamino} -2 (2-fluorobenzoyl) acrylic acid ethyl ester remain as a yellow oil, which is dissolved in 45 ml of dimethylformamide and with 9.9 g of sodium fluoride at 145 for 2 hours ° C is stirred. It is then filtered hot and poured onto ice. It is extracted with ether and purification by column chromatography (column material. Silica gel, mobile phase: first acetone, then acetone / ethanol) yields 1- {4- [bis- (diethoxyphosphoryl) methylphenyl] -4-oxo-1,4 dihydro-quinoli-n-3-carboxylic acid tetraethyl ester whose phosphonic acid and carboxylic acid groups can then be saponified.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₂₇H₃₅NO₉P₂
calc .: C 55.96 H 6.09 N 2.42 P 10.69 O 24.85%
found: C 55.58 H 6.19 N 2.33 P 10.52%.
Zu einer Lösung von 2 g (0.0056 mol) 4,4-Bis-(diethoxyphosphoryl)-butansäure und
2 ml n-Tributylamin in 20 ml Chloroform wird 1-Methyl-2-Chlor-pyridiniumiodid
gegeben. Es wird eine halbe Stunde am Rückfluß gekocht, dann eine Mischung von
1,76 g (0,0056 mol) Norfloxacin, 2 ml n-Tributylamin und 150 ml Chloroform
zugegeben. Nach 2 Stunden wird heiß abfiltriert und das Lösemittel abgezogen.
Reinigung kann durch Kieselgel-Säulentrennung und Umkristallisation aus Toluol
erfolgen. Der erhaltene Phosphonsäureester kann mittels Umsilylierung
(Bromtrimethylsilan in absolutem Chloroform) und anschließender Zugabe von
Methanol hydrolysiert werden.
Charakterisierung mittels ¹H, ¹³C, ³¹P NMR
Elementaranalyse: berechnet für C₂₈H₄₂FN₃O₁₀P
ber.: C 50.83 H 6.40 N 6.35 P 9.36 F 2.87 O 24.18%
gef.: C 50.61 H 6.58 N 6.36 P 8.86%.1-Methyl-2-chloropyridinium iodide is added to a solution of 2 g (0.0056 mol) of 4,4-bis (diethoxyphosphoryl) butanoic acid and 2 ml of n-tributylamine in 20 ml of chloroform. The mixture is refluxed for half an hour, then a mixture of 1.76 g (0.0056 mol) of norfloxacin, 2 ml of n-tributylamine and 150 ml of chloroform is added. After 2 hours, the mixture is filtered hot and the solvent is stripped off. Purification can be done by silica gel column separation and recrystallization from toluene. The phosphonic acid ester obtained can be hydrolyzed by means of resilylation (bromotrimethylsilane in absolute chloroform) and subsequent addition of methanol.
Characterization using 1 H, 13 C, 31 P NMR
Elemental analysis: calculated for C₂₈H₄₂FN₃O₁₀P
calc .: C 50.83 H 6.40 N 6.35 P 9.36 F 2.87 O 24.18%
found: C 50.61 H 6.58 N 6.36 P 8.86%.
Claims (8)
R1 Alkyl (verzweigt oder geradkettig), Cycloalkyl, Aryl, Heteroaryl, die ihrerseits mit Alkyl, Amino, Nitro, Halogen, Hydroxyl, Alkoxyl subtituiert sein können, besonders bevorzugt Ethyl, Cyclopropyl,
R2 (im Falle Z=N kein Rest) Wasserstoff, Alkyl (verzweigt oder geradkettig), Cycloalkyl, Aryl, Heteroaryl, (die ihrerseits substituiert sein können, s.R1), Halogen, Nitro, Cyano, Acetyl, Carboxyl, Alkoxyl, besonders bevorzugt Fluor,
R3 Wasserstoff, Cycloalkyl , Aryl, Heteroaryl, Heterocycloalkyl, Alkoxyl, besonders bevorzugt Fluor, Piperazinyl, N-Methylpiperazinyl,
R4 Wasserstoff
sein kann, wobei in jedem Falle mindestens einer der Reste R1, R2, R3, R4 mit u. a. einer der folgenden phosphonsäuretragenden Reste (bzw. den entsprechenden Phosphonsäurealkylestern oder Alkalimetall-, Ammoniumsalzen) versehen ist:
R1 Alkyl- (verzweigt und unverzweigt), Cycloalkyl-, Cycloheteroalkyl-, Aryl-, und Heteroaryl-Rest, der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂ oder -C(NH₂)(PO₃H₂)₂ enthält, bevorzugt -CH(PO₃H₂)₂, -C(CH₃)₂CH₂CH(PO₃H₂)₂, -CHCH₂CH(PO₃H₂)₂, -CH[CH₂CH(PO₃H₂)₂]₂, -C₆H₄CH₂(PO₃H₂), besonders bevorzugt -C₆H₄CH(PO₃H₂)₂, -CH₂CH₂CH(PO₃H₂)₂,
R2 bevorzugt -CH(PO₃H₂)₂, CH₂(PO₃H₂),
R3 über ein Stickstoffatom gebundener Alkyl- (verzweigt und unverzweigt), Cycloalkyl-, Cycloheteroalkyl-, Aryl-, und Heteroaryl-Rest, der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂ oder -C(NH₂)(PO₃H₂)₂ enthält, bevorzugt -NHCH(PO₃H₂)₂, -NHCH₂CH₂CH(PO₃H₂)₂₁, -NHC(CH₃)₂CH₂CH(PO₃H₂)₂, -NHCHCH₂CH(PO₃H₂)₂, -NHCH[CH₂CH(PO₃H₂)₂]₂ -NHC₆H₄CH(PO₃H₂)₂, -NHC₆H₄NHCH(PO₃H₂)₂), -N(CH₂PO₃H₂)₂, besonders bevorzugt Piperazinyl-Rest der am Stickstoff einen -COCH₂CH₂CH(PO₃H₂)₂ oder -CH₂CH(PO₃H₂)₂ Rest trägt
R4 über Amid- oder Esterbindung gebundener Alkyl- (verzweigt und unverzweigt), Cycloalkyl-, Cycloheteroalkyl-, Aryl-, und Heteroaryl-Rest, der die Gruppierung -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂ oder -C(NH₂)(PO₃H₂)₂ enthält, bevorzugt -NHCH(PO₃H₂)₂, -NHCH₂CH₂CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -NHC(CH₃)₂CH₂CH(PO₃H₂)₂, -NHCHCH₂CH(PO₃H₂)₂, -NHCH[CH₂CH(PO₃H₂)₂]₂ -NHC₆H₄CH(PO₃H₂)₂, -NHC₆H₄NHCH(PO₃H₂)₂, -OC₆H₄(PO₃H₂)₂
sein kann.2. gyrase inhibitors (quinolones) of the general formula 1, n which can be X, Y, Z = C, N and
R1 alkyl (branched or straight-chain), cycloalkyl, aryl, heteroaryl, which in turn can be substituted by alkyl, amino, nitro, halogen, hydroxyl, alkoxyl, particularly preferably ethyl, cyclopropyl,
R2 (in the case of Z = N no residue) hydrogen, alkyl (branched or straight-chain), cycloalkyl, aryl, heteroaryl ((which in turn can be substituted, see R1), halogen, nitro, cyano, acetyl, carboxyl, alkoxyl, especially preferably fluorine,
R3 is hydrogen, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, alkoxyl, particularly preferably fluorine, piperazinyl, N-methylpiperazinyl,
R4 hydrogen
can be, in any case at least one of the radicals R1, R2, R3, R4 being provided, inter alia, with one of the following phosphonic acid-carrying radicals (or the corresponding phosphonic acid alkyl esters or alkali metal, ammonium salts):
R1 alkyl (branched and unbranched), cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical, which the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂ or -C (NH₂) (PO₃H₂) ₂ contains, preferably -CH (PO₃H₂) ₂, -C (CH₃) ₂CH₂CH (PO₃H₂) ₂, -CHCH₂CH (PO₃H₂) ₂, -CH [CH₂CH (PO₃H₂) ₂] ₂, -C₆H₄CH₂ (PO₃H₂), particularly preferably -C₆H₄CH (PO₃H₂) ₂, -CH₂CH₂CH (PO₃H₂) ₂,
R2 preferably -CH (PO₃H₂) ₂, CH₂ (PO₃H₂),
R3 alkyl (branched and unbranched) bonded via a nitrogen atom, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical which contains the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) ( PO₃H₂) ₂ or -C (NH₂) (PO₃H₂) ₂ contains, preferably -NHCH (PO₃H₂) ₂, -NHCH₂CH₂CH (PO₃H₂) ₂₁, -NHC (CH₃) ₂CH₂CH (PO₃H₂) ₂, -NHCHCH₂CH (PO₃H₂) ₂, -NHCH [CH₂CH (PO₃H₂) ₂] ₂ -NHC₆H₄CH (PO₃H₂) ₂, -NHC₆H₄NHCH (PO₃H₂) ₂), -N (CH₂PO₃H₂) ₂, particularly preferably piperazinyl radical which is nitrogen -COCH₂CH₂CH (PO₃H₂) ₂ or -CH₂CH ) ₂ rest carries
R4 via amide or ester bond-bonded alkyl (branched and unbranched), cycloalkyl, cycloheteroalkyl, aryl and heteroaryl radical, which has the grouping -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH ) (PO₃H₂) ₂ or -C (NH₂) (PO₃H₂) ₂, preferably -NHCH (PO₃H₂) ₂, -NHCH₂CH₂CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -NHC (CH₃) ₂CH₂CH (PO₃H₂) ₂, -NHCHCH₂CH (PO₃H₂) ₂, -NHCH [CH₂CH (PO₃H₂) ₂] ₂ -NHC₆H₄CH (PO₃H₂) ₂, -NHC₆H₄NHCH (PO₃H₂) ₂, -OC₆H₄ (PO₃H₂) ₂
can be.
A ein Aryl-, Heteroaryl- (seinerseits mit Resten,wie Alkyl, Alkoxy, Nitro, Amino, Halogen, Hydroxy,u. a.) Rest sein kann, der eine geminale oder vicinale Bisphosphonsäure-, bzw. Bisphosphonsäurealkylester-Gruppierung, besonders Fragmente der Formel -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂, -C(NH₂)(PO₃H₂)₂ trägt,
A besonders bevorzugt -C₆H₄CH(PO₃H₂)₂, -C₆H₄NHCH(PO₃H₂)₂ sein kann.3. Sulfonamides of the general formula 2 in the
A can be an aryl, heteroaryl (in turn with residues such as alkyl, alkoxy, nitro, amino, halogen, hydroxy, etc.) residue, which is a geminal or vicinal bisphosphonic or bisphosphonic acid group, especially fragments of the formula - CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂, -C (NH₂) (PO₃H₂) ₂,
A can particularly preferably be -C₆H₄CH (PO₃H₂) ₂, -C₆H₄NHCH (PO₃H₂) ₂.
Hierunter solche der Penam-Gruppe, bevorzugt Penicilline, Oxymethyl-Penicilline und Sulfonpenicilline, der Carbapenem-Gruppe, bevorzugt Thienamycine, der Cephem-Gruppe, bevorzugt Cephalosporine und Oxymethyl-Cephalosporine, sowie Oxa-Cephalosporine mit geminalen oder vicinalen Bisphosphonsäure- bzw. Bisphosphonsäurealkylester-Gruppen.
In Formel 3 und 4 ist dies am Beispiel der Penicilline und der Cephalosporine verdeutlicht. Hier ist
B Aryl, Heteroaryl, Cyclo(Hetero)alkyl mit diversen Substituenten, darunter vor allem Fragmente der Formel -CH(PO₃H₂)₂, -N(CH₂PO₃H₂)₂, -C(OH)(PO₃H₂)₂ und -C(NH₂)(PO₃H₂)₂.4. β-lactam antibiotics.
These include those from the Penam group, preferably penicillins, oxymethyl-penicillins and sulfonpenicillins, the carbapenem group, preferably thienamycins, the cephem group, preferably cephalosporins and oxymethyl-cephalosporins, and oxa-cephalosporins with geminal or vicinal bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or biskyphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid or bisphosphonic acid. Groups.
This is illustrated in formula 3 and 4 using the example of penicillins and cephalosporins. Here is
B aryl, heteroaryl, cyclo (hetero) alkyl with various substituents, including in particular fragments of the formula -CH (PO₃H₂) ₂, -N (CH₂PO₃H₂) ₂, -C (OH) (PO₃H₂) ₂ and -C (NH₂) ( PO₃H₂) ₂.
[4-(4-Amino-benzolsulfonylamino)-phenylamino]-phosphono-methyl-phosp-honsäure
4-Oxo-1-(4-phosphonomethyl-phenyl)-1,4-dihydro-chinolin-3-carbonsäur-e
7-Fluor-4-oxo-1-(4-phosphono-methyl-phenyl)-1,4-dihydro-chinolin-3-c-arbonsäure
6-Fluor-4-oxo-1-(4-phosphono-methyl-phenyl)-1,4-dihydro-chinolin-3-c-arbonsäure
6,7-Difluor-4-oxo-1-(4-phosphono-methyl-phenyl)-1,4-dihydro-chinolin--3-carbonsäure
1-[4-(Bis-phosphono-methyl)-phenyl]-4-oxo-1,4-dihydro-chinolin-3-car-bonsäure
1-[4-(Bis-phosphono-methyl)-phenyl]-7-fluor-4-oxo-1,4-dihydro-chinol-in-3-carbonsäure
1-[4-(Bis-phosphono-methyl)-phenyl]-6-fluor-4-oxo-1,4-dihydro-chinol-in-3-carbonsäure
1-[4-(Bis-phosphono-methyl)-phenyl]-6,7-difluor-4-oxo-1,4-dihydro-ch-inolin-3-carbonsäure
1-(3,3-Bis-phosphono-propyl)-4-oxo-1,4-dihydro-chinolin-3-carbonsäur-e
1-(3,3-Bis-phosphono-propyl)-7-fluor-4-oxo-1,4-dihydro-chinolin-3-ca-rbonsäure
1-(3,3-Bis-phosphono -propyl)-6-fluor-4-oxo-1,4-dihydro-chinolin-3-carbonsäure
1-(3,3-Bis-phosphono-propyl)-6,7-difluor-4-oxo-1,4-dihydro-chinolin--3-carbonsäure
4-Oxo-1-(4-phosphono-methyl-phenyl)-7-pipernzin-1yl-1,4-dihydro-chin-olin-3-carbonsäure
1-[4-Bis-phosphono-methyl)-phenyl]-4-oxo-7-piperazin-1yl-1,4-dihydro--chinolin-3- carbonsäure
1-[4-Bis-phosphono-methyl)-phenyl]-6-fluor-4-oxo-7-piperazin-1yl-1,4--dihydro-chinolin-3- carbonsäure
1-(3,3-Bis-phosphono-propyl)-4-oxo-7-piperazin-1yl-1,4-dihydro-chino-lin-3-carbonsäure
1-(3,3-Bis-phosphono-propyl)-6-fluor-4-oxo-7-piperazin-1yl-1,4-dihyd-ro-chinolin-3- carbonsäure
4-[(5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]chinolin-7-carbonyl-)-amino]-benzyl- phosphonsäure
{4-[(5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]chinolin-7-carbonyl-)-amino]-phenyl}- phosphono-methyl-phosphonsäure
7-(3,3-Bis-phosphono-propylamino)-1-ethyl-4-oxo-1,4-dihydro-chinolin--3-carbonsäure
7-(3,3-Bis-phosphono-propylamino)-1-ethyl-6-fluor-4-oxo-1,4-dihydro--chinolin-3- carbonsäure
7-[4-(Bis-phosphono-methyl)-phenylamino]-1-ethyl-4-oxo-1,4-dihydro-c-hinolin-3- carbonsäure
7-[4-(Bis-pho sphono-methyl)-phenylamino]-1-ethyl-6-fluor-4-oxo-1,4-dihydro-chinol-in-3- carbonsäure
4-[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphtyridin-3-carbonyl)--amino]-benzyl- phosphonsäure
{4-[(1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphtyridin -3-carbonyl)-amino-phenyl}- phosphono-methyl-phosphonsäure
7-[4-(4,4-Bis-phosphono-butyryl]-piperazin-1yl]-1-ethyl-6-fluor-4-ox-o-1,4-dihydro-chinolin- 3-carbonsäure
2-[4-(4,4-Bis-phosphono-butyryl)-piperaziny-1yl]-8-ethyl-5-oxo-5,8-d-ihydro-pyrido[2,3-d] pyrimidin-6-carbonsäure
7-[4-(4,4-Bis-phosphono-butyryl)-piperazin-1yl]-1-ethyl-6-fluor-4-ox-o-1,4-dihydro- [1,8]naphtyridin-3-carbonsäure
7-[4-(4,4-Bis-phosphono-butyryl)-piperazin-1yl]-1-cyclopropyl-6-flu-or-4-oxo-1,4-dihydro- chinolin-3-carbonsäure. 5. [4- (4-Amino-benzenesulfonylamino) -phenyl] -phosphono-methyl-phosphonic acid
[4- (4-Amino-benzenesulfonylamino) phenylamino] phosphonomethylphosphonic acid
4-oxo-1- (4-phosphonomethyl-phenyl) -1,4-dihydro-quinoline-3-carboxylic acid e
7-fluoro-4-oxo-1- (4-phosphonomethylphenyl) -1,4-dihydroquinoline-3-c-arbonic acid
6-fluoro-4-oxo-1- (4-phosphonomethylphenyl) -1,4-dihydroquinoline-3-c-arbonic acid
6,7-difluoro-4-oxo-1- (4-phosphonomethylphenyl) -1,4-dihydroquinoline - 3-carboxylic acid
1- [4- (bis-phosphonomethyl) phenyl] -4-oxo-1,4-dihydroquinoline-3-car-bonic acid
1- [4- (bis-phosphonomethyl) phenyl] -7-fluoro-4-oxo-1,4-dihydro-quinol-in-3-carboxylic acid
1- [4- (bis-phosphonomethyl) phenyl] -6-fluoro-4-oxo-1,4-dihydro-quinol-in-3-carboxylic acid
1- [4- (bis-phosphonomethyl) phenyl] -6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
1- (3,3-bis-phosphono-propyl) -4-oxo-1,4-dihydro-quinoline-3-carboxylic acid e
1- (3,3-bis-phosphono-propyl) -7-fluoro-4-oxo-1,4-dihydro-quinoline-3-ca-rbonic acid
1- (3,3-bis-phosphono-propyl) -6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
1- (3,3-bis-phosphonopropyl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline - 3-carboxylic acid
4-Oxo-1- (4-phosphono-methyl-phenyl) -7-pipernzin-1yl-1,4-dihydro-quinoline-3-carboxylic acid
1- [4-bis-phosphonomethyl) phenyl] -4-oxo-7-piperazin-1yl-1,4-dihydro-quinoline-3-carboxylic acid
1- [4-bis-phosphonomethyl) phenyl] -6-fluoro-4-oxo-7-piperazin-1yl-1,4-dihydroquinoline-3-carboxylic acid
1- (3,3-bis-phosphonopropyl) -4-oxo-7-piperazin-1yl-1,4-dihydro-quino-lin-3-carboxylic acid
1- (3,3-bis-phosphonopropyl) -6-fluoro-4-oxo-7-piperazin-1yl-1,4-dihydro-quinoline-3-carboxylic acid
4 - [(5-Ethyl-8-oxo-5,8-dihydro- [1,3] dioxolo [4,5-g] quinoline-7-carbonyl -) amino] benzylphosphonic acid
{4 - [(5-ethyl-8-oxo-5,8-dihydro- [1,3] dioxolo [4,5-g] quinoline-7-carbonyl -) - amino] -phenyl} - phosphono-methyl- phosphonic acid
7- (3,3-bis-phosphono-propylamino) -1-ethyl-4-oxo-1,4-dihydro-quinoline - 3-carboxylic acid
7- (3,3-bis-phosphono-propylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid
7- [4- (bis-phosphonomethyl) phenylamino] -1-ethyl-4-oxo-1,4-dihydro-c-hinoline-3-carboxylic acid
7- [4- (bis-phosphonomethyl) phenylamino] -1-ethyl-6-fluoro-4-oxo-1,4-dihydro-quinol-in-3-carboxylic acid
4 - [(1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carbonyl) amino] benzylphosphonic acid
{4 - [(1-ethyl-7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine -3-carbonyl) amino-phenyl} - phosphono-methyl-phosphonic acid
7- [4- (4,4-bis-phosphonobutyryl] piperazin-1yl] -1-ethyl-6-fluoro-4-ox-o-1,4-dihydro-quinoline-3-carboxylic acid
2- [4- (4,4-bis-phosphonobutyryl) piperaziny-1yl] -8-ethyl-5-oxo-5,8-d-ihydro-pyrido [2,3-d] pyrimidine-6- carboxylic acid
7- [4- (4,4-bis-phosphonobutyryl) piperazin-1yl] -1-ethyl-6-fluoro-4-ox-o-1,4-dihydro- [1,8] naphthyridine-3 -carboxylic acid
7- [4- (4,4-bis-phosphonobutyryl) piperazin-1yl] -1-cyclopropyl-6-fluoro-or-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
3-Nitro-pentan-1,1,5,5-tetrakisphosphonsäureoktaethylester
3-Amino-pentan-1,1,5,5-tetrakisphosphonsäureoktaethylester
3-Nitro-3-methyl-butan-1,1-bisphosphonsäuretetraethylester
3-Amino-3-methyl-butan-1,1-bisphosphon säuretetraethylester
4-Hydroxyphenyl-diethoxyphosphoryl-methyl-phosphonsäurediethylester
4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonsäurediethylester.6. As synthesis building blocks important for the preparation of phosphonic acid-functionalized compounds in the sense of the present invention, especially the following phosphonic acid alkyl esters:
3-nitro-pentane-1,1,5,5-tetrakisphosphonic acid ocethylester
3-Amino-pentane-1,1,5,5-tetrakisphosphonic acid ocethylester
3-Nitro-3-methylbutane-1,1-bisphosphonic acid tetraethyl ester
3-Amino-3-methyl-butane-1,1-bisphosphonic acid tetraethyl ester
4-Hydroxyphenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester
4-Aminophenyl-diethoxyphosphoryl-methyl-phosphonic acid diethyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995132235 DE19532235A1 (en) | 1995-08-31 | 1995-08-31 | New antibacterial contg. osteotropic mol. fragments |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1995132235 DE19532235A1 (en) | 1995-08-31 | 1995-08-31 | New antibacterial contg. osteotropic mol. fragments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19532235A1 true DE19532235A1 (en) | 1997-03-06 |
Family
ID=7770969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1995132235 Withdrawn DE19532235A1 (en) | 1995-08-31 | 1995-08-31 | New antibacterial contg. osteotropic mol. fragments |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE19532235A1 (en) |
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| WO2000044358A3 (en) * | 1999-01-26 | 2001-03-15 | Hassan Jomaa | Use of phosphororganic compounds for the prophylactic and therapeutical treatment of infections |
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| WO2007017762A3 (en) * | 2005-04-21 | 2007-07-26 | Targanta Therapeutics Inc | Phosphonated fluoroquinolones, antibacterial analogs thereof, and methods for the prevention and treatment of bone and joint infections |
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-
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- 1995-08-31 DE DE1995132235 patent/DE19532235A1/en not_active Withdrawn
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