NO812428L - Antibiotisk virksomme tiazolidinforbindelser. - Google Patents
Antibiotisk virksomme tiazolidinforbindelser.Info
- Publication number
- NO812428L NO812428L NO812428A NO812428A NO812428L NO 812428 L NO812428 L NO 812428L NO 812428 A NO812428 A NO 812428A NO 812428 A NO812428 A NO 812428A NO 812428 L NO812428 L NO 812428L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- group
- compounds
- substituted
- alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 25
- 230000003115 biocidal effect Effects 0.000 title description 2
- -1 acetoxymethyl Chemical group 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004472 Lysine Substances 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000001767 cationic compounds Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000001768 cations Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 2
- 150000002892 organic cations Chemical class 0.000 claims description 2
- 125000005633 phthalidyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 230000003213 activating effect Effects 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- 244000046052 Phaseolus vulgaris Species 0.000 description 3
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002960 penicillins Chemical class 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 241000588701 Pectobacterium carotovorum Species 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 206010039509 Scab Diseases 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000020971 citrus fruits Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000000590 phytopharmaceutical Substances 0.000 description 2
- 235000012015 potatoes Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 1
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 description 1
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 1
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 description 1
- VZDBJIBRLHHCHX-UHFFFAOYSA-N 1,3-thiazolidine-4-carbonyl chloride;hydrochloride Chemical compound Cl.ClC(=O)C1CSCN1 VZDBJIBRLHHCHX-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 1
- 244000291564 Allium cepa Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 241000919811 Collyria Species 0.000 description 1
- 241000990232 Curtobacterium flaccumfaciens pv. flaccumfaciens Species 0.000 description 1
- 244000000626 Daucus carota Species 0.000 description 1
- 235000002767 Daucus carota Nutrition 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000660443 Encyclops Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 241001508691 Martes zibellina Species 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 235000002725 Olea europaea Nutrition 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- 206010040047 Sepsis Diseases 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
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- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 235000004338 Syringa vulgaris Nutrition 0.000 description 1
- 240000004922 Vigna radiata Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 150000007513 acids Chemical class 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
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- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 229960004203 carnitine Drugs 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Foreliggende oppfinnelse vedrører nye 1,3-tiazolidin-4-yl-karboksylsyredérivater med den generelle formel I
hvor
R betyr hydrogen, (C^-C^)alkyl, aralkyl, fenyl, fenyl substituert med et halogenatom eller en metoksygruppe, formyl, acyl, trimetylsilyl;
R' betyr hydrogen, et farmasøytisk akseptabelt uorganisk eller organisk kation (C^-C^ )alkyl, 2 , 2 , 2-trikloretyl, acetonyl, benzyl, benzyl substituert med nitro eller metoksy, fenyl, nitrofenyl, benzhydryl eller trimetylsilyl;
R' kan også bety en rest som kan gi metabolisk aktivering in vivo valgt fra acetoksymetyl, pivaloyloksymetyl, ftalidyl, benzoyloksymetyl, 5-indanyl, en gruppe med formel
eller en gruppe med formel hvor R" står for (C^-C^ ) alkyl, (C^-Cg) cykloalkyl eller aryl; A betyr hydrogen, halogen, N^, OH, NF^j eller et kvartær-nært N-atom, spesielt
(og i dette tilfellet er R'
en negativ ladning); eller en O-CO-NI^ gruppe; eller en gruppe med formel OR"', 0-COR"', NH-CO-R"' eller SR"<1>, hvor R"' er (C-^-C^) alkyl, aryl, substituert aryl eller en heterocyklisk gruppe som kan være substituert med lavere alkylgrupper;
n kan være 0 eller 1.
Karakteristiske betydninger for resten R ved siden av de allerede ovenfor nevnte er metyl, etyl, isopropyl, benzyl, trityl, acetyl, propionyl, trifluoracetyl, benzoyl, benzoyl substituert med eri til tre hydroksy-, metyl-, metoksy-, halogen-, amino-og nitrogrupper, benzyloksykarbonyl, tert.-butoksyk-karbonyl eller en rest avledet fra en naturlig aminosyre.
Typiske, men ikke begrensende eksempler, på de uorganiske eller organiske kationer som er angitt med restene R<1>er natrium-, kalium-, kalsium-og magnesiumkationer; kationer avledet fra organiske baser som f.eks. dibenzylamin, N,N-diben-zyletylendiamin, glukamin, N-metylglukamin, heksametylen-tetramin, 2-amino-2-hydroksymetyl-l,3-propandiol, arginin, lysin, prolin, karnitin; eller aluminium, sink eller sølv-kationer.
Typiske betydninger for R"' ved siden av de allerede ovenfor nevnte er metyl, etyl, propyl, butyl, isobutyl; fenyl eller benzyl; imidazol-2-yl, 1,2,3-triazol-5-yl, 1-metyl-l,2,3,4-tetrazol-5-yl, tiazol-2-yl, 1,3,4-tiadiazol-2-yl, 5-metyl-1,3,4-tiadiazol-2-yl, 1, 2 , 3,4-tiatriazol-5-yl, oksazol-5-yl, 3-metylisoksazol-5-yl, 1,2,4-oksadiazol-5-yl, pyrazinyl. Fordi et asymmetrisk C-atom foreligger i 4-stilling i tia-zolidinringen kan forbindelsene med formel I foreligge i D- og L-konfigurasjon eller som en racemisk forbindelse. Følgelig omfatter oppfinnelsen alle disse muligheter, selv om L-konfigurasjonen er den foretrukne.
En videre gjenstand for oppfinnelsen er også saltene av forbindelsene med formel I hvor nitrogenatornet i tiazolidinkjernen har basisk karakter med farmasøytisk akseptable syrer, f.eks. sitronsyre, askorbinsyre, maleinsyre, eddik-syre, saltsyre, salpetersyre, hydrogenbromid og svovelsyre.
En annen gjenstand for oppfinnelsen 'er de farmasøytiske blandinger for human- eller veterinærmedisinsk bruk, eller pesticide formuleringer for jordbruksformål som inneholder som aktiv bestanddel en eller fleire av forbindelsene med formel I ovenfor eller et farmasøytisk akseptabelt syreaddi-sjonssalt derav.
Det er nå overraskende funnet at forbindelsene med formel I ifølge oppfinnelsen er meget resistente mot penicillinaser når de prøves ifølge den metode som er beskrevet av GROVE et al., Assay methods of antibiotics, A Laboratory Manual, Med. Encyclop. Inc., 1955, 7, eller ifølge LORIAN V., Antibiotics and chemotherapeutic agents.in clinical and laboratory prac-tice, CC. Thomas Publ., 1966, 242. De har også vist seg virksomme mot forskjellige patogene organismer, f.eks. gram-positive og gram-negative, aerobe og anaerobe bakterier, innbefattet (3-laktamaseproduserende stammer.
Spesielt er forbindelsene med formel I aktive mot gram-positive bakterier så som f.eks. Staphylococcus aureus, Diplo-coccus'pneumoniae, Streptococcus pyogenes, Streptococcus faecalis, Bacillus subtilis og Sarcina lutea, samt gram-negative bakterier så som f.eks. Escherichia coli, Proteus mira-bilis, Shigella sonnei, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae og Salmonella typhimurium.
Forbindelsene med formel I utviser også en bemerkelsesverdig aktivitet mot forskjellige patogene organismer som gir infeksjoner hos planter, f.eks.: Pseudomonas syringae, som er ansvarlig for bacteriosis hos ..citrusfrukter og syriner; Pseudomonas phaseolicola (fettsyke på bønner); Pseudomonas aliicola (bakterielt angrep på løk); Pseudomonas savastandi (skabb på oliventrær).; Pseudomonas marginata (skabb på sabel-lilje);: Xantomonas phaseoli (bakteriell meldugg på bønner); Pectobacterium carotovorum (stump på poteter og bakterielle angrep på iris rhizomes); Erwinia amilovora (necrose på eple-grener); Erwinia carotovora (bakterielt angrep på gulerøtter); Corynebacterium flaccum-faciens (bakterielt angrep på bønner); Penicillum sp. (soppangrep på blomsterløk og knoller).
Som et representativt, men ikke begrensende eksempel, kan
det angis at 7-(1,3-tiazolidin-4-yl)karboksamido-7a-metoksy-3-karbamoyloksymetyl-3-cephem-4-karboksylsyre (formel I, hvori R = R' = H, A = O-CO-NI^ og n = 0), både som nåtrium-salt og som lysinsalt, er minst like aktiv som cephoxitin
mot gram-positive bakterier, og gir videre ikke resistens mot de undersøkte stammer.
Følgelig kan de nye forbindelser som er en av gjenstandene
for foreliggende oppfinnelse gis til varmblodige dyr, innbefattet mennesker ad oral, parenteral eller topisk veg for bekjempelse av septicaemiae, meningititt, endokardititt, infeksjoner i luftveis-, fordøyelses- og urinveiskanalen. og
på huden, øre-, nese-, halsinfeksjoner; infeksjoner i ben, endoabdominale og endopleurikale infeksjoner. De kan også anvendes for å gjøre huden aseptisk før injeksjoner eller, kirurgiske inngrep, samt for desinfeksjon av kirurgiske in-strumenter....
De farmasøytiske doseringsformer som egner seg for oral administrering kan f.eks. være tabletter, kapsler, piller, sukkerovertrukne tabletter, sirups, suspensjoner, dråper, eliksirer og granulater. Farmasøytiske doseringsformer som er egnet for topisk bruk er hovedsakelig salver, kremer, linimenter, collyria og lotions.
Alle de ovenfor nevnte farmasøytiske formuleringer fremstill-es på kjent måte og inneholder sammen med den aktive bestand-.del smøremiddel, fortynningsmiddel, eksipient og søtnings-midler samt de vanlig brukte farmasøytisk akseptable tilsetningsmidler.
På grunn av sine phytofarmasøytiske egenskaper kan forbindelsene brukes i forskjellige administreringsformer som f.eks. vandige løsninger som inneholder eller ikke inneholder ytter-ligere tilsetningsmidler så som f.eks. talkum eller leire; pulvere innbefattet atomiserte preparater; sprays, både flyt-ende og faste; suppositorier, innbefattet formuleringer med langsom avgivelse; granulater innbefattet formuleringer med langsom avgivelse; former absorbert på inerte materialer eller ionebytterharpikser, kapsler og mikro-innkapslede preparater. Alle disse administreringsformer er velkjente for en fagmann.
Følgelig kan forbindelsene også anvendes med fordel for pre-servering av næringsmidler så som f.eks. citrusfrukter eller poteter, ettersom de i motsetning til mange vanlig anvendte forbindelser, f.eks. bis-fenyl, er effektive antibiotiske midler med meget lav toksisitet. Forbindelsene kan frem-', stilles gjennom forskjellige fremgangsmåter. Således acyleres f.eks. aminogruppen i en forbindelse med formel II hvor R<1>, A og n er som ovenfor angitt, med et formålstjene-lig N-acylerende reagens avledet fra en syre med formel III
hvor R er som forut angitt. Beskyttelsesgruppene, hvis.
"slike foreligger, må.være lette å fjerne under milde betingelser. Typiske eksempler på en beskyttelsesgruppe er benzy-loksykarbonylresten. Slike acyleringsreaksjoner er velkjente på område penicilliner og cephalosporiner (se f.eks.
Flynn, Cephalosporins and penicyllins, Academic Press, 1972). Også utgangsmaterialene med formel II og III er velkjente for en fagmann. Valget av acyleringsmidler vil åpenbart avhenge av den kjemiske art av substituentene R og R' ifølge de vanlige teknikker og prinsipper.
N-acyleringsreaktantene som er avledet-fra forbindelsen med formel III ovenfor er f.eks. halogenidene eller sådanne som oppnås gjennom omsetning av III med karbodiimidet eller azidet; fortrinnsvis anvendes et anhydrid og, med fordel,
et blandet anhydrid blandet in situ ved omsetning med etyl-eller isobutylklorkarbonat eller pivaloylklorid.
Valget av løsningsmiddel og betingelser for reaksjonen,■
hvilke hovedsakelig avhenger av det valgte N-acylerings-middel, er en velkjent sak for fagmannen. Hvis, som et eksempel, acyleringsreagenset er et blandet anhydrid, kan reaksjonen utføres i et organisk løsningsmiddel valgt blant etylacetat, dimetylformamid., dietyleter, tetrahydrofuran, dioksan, metylenklorid eller analoge inerte løsningsmidler; temperaturen kan ligge mellom ca. -4 0°C og romtemperatur og, ligger fortrinnsvis mellom ca. -20 og -30°C.
En videre fordelaktig metode for fremstilling av forbindelsene med formel -I ovenfor er å omsette forbindelsen med. formel II og III ovenfor med silisiumtetraklorid ifølge italiensk patentansøkning nr. 29445 A/77. Forbindelsene kan isoleres ved hjelp av velkjente teknikker innenfor om-rådet penicilliner og cef alosporiner så som f . eks . krystalli-sering, lyofilisering eller spraytørking. En formålstjene-lig isoleringsmetode er absorpsjon på kjemisk.inert eller inaktivert materiale, som f.eks. ionebytterharpikser, og denne metode kan være spesielt anvendelig når det erholdte derivat må brukes som for for dyr eller phytofarmasøytika.
De følgende eksempler er gitt i illustrerende hensikt men skal ikke anses å være begrensende for oppfinnelsen.
EKSEMPEL 1
7- ( 1, 3- t iazol. idin- 4- yl) - karboksamido- 7a- metoksy- 3- karbamoyl-oksymetyl- 3- cephem- 4- karboksylsyre, natriumsalt (forbindelse ifølge formel I, hvor R = H; R' = Na; A = -0-CO-NH<*>2; n = null)
24,4 g 7-amino-7a-metoksy-3-karbamoyloksymetyl-3-c-ephem-4-karboksylsyre settes til 200 ml vannfritt Cr^Cl.,. Til den omrørte suspensjon hvori temperaturen holdes under -25°C tilsettes 13 g n-propylamin. Etter 30 min., ved denne temp-eratur tilsettes 26 g trimetylsilylklorid, og temperaturen stiger til -10°C. Blandingen røres 30 min. ved denne temp-eratur, og deretter tilsettes 18,5 g N,N-dimetylanilin og 88 g 1,3-tiazolidin-4-yl-karboksylsyreklorid-hydroklorid. Blandingen røres så 2 timer ved romtemperatur, deretter tilsettes 500 ml vann, røres ca. 30 min. til fullstendig spalt-ning av trimetylsilylgruppen, og til slutt nøytraliseres til pH 7-7,5 med fortynnet NaOH. Den organiske fasen skill-es fra og den vandige vaskes med 100 ml metylisobutylketon, deretter med 100 ml dietyleter. Den vandige fasen røres .15 min. med 3 g aktivt karbon og vakuumfUtreres på et sjikt "Dicalite 438". Fra den filtrerte løsning får man det ønsk-ede natriumsalt ved lyofilisering i form av et hvitt pulver hvis struktur bekreftes ved NMR-spektrum.
EKSEMPEL 2
7-(1,3-tiazolidin-4-yl)karboksamido-7a-metoksy-3-karbamoyl-oksymetyl-3-cephem-4-karboksylsyre, lysinsalt (forbindelse ifølge formel I hvori R = H; R<1>= lysinkation; A. = -0-C0-NH2;
n =. 0) .
Til en løsning av 0,1 mol lysin i 100 ml vann settes 0,1 mol 7-(l,3-tiazolidin-4-yl)-karboksamido-7a-metoksy-3-kar-bamoyloksymetyl-3-cephem-4-karboksylsyre (erholdt ved be-handling av natriumsaltet fra eksempel 1 med ionebyttere). Etter 1 time ved romtemperatur filtreres den vandige løs-ning på et sterilt, depyrogenereride filter, og doseres meka-nisk i glassflasker slik at man får flasker inneholdende lysinsalt tilsvarende 1 g av syren. Ved lyofilisering fås forbindelsen i en farmasøytisk form som kan gis intravenøst.
Claims (4)
- .1. Fremgangsmåte ved fremstilling av forbindelser med formel Ihvor R betyr hydrogen,(C] _-C4 )alkyl, aralkyl, fenyl, fenyl substituert med et halogenatom eller.en metoksygruppe, formyl, acyl, trimetylsilyl; R' betyr hydrogen, et farmasøytisk akseptabelt uorganisk eller organisk kation, (C-^-C^ ) alkyl, 2 , 2 , 2-trikloretyl, acetonyl, benzyl, benzyl substituert med nitro eller metok sy, fenyl, nitrofenyl, benzhydryl eller trimetylsilyl;R' kan også bety en rest som kan gi metabolsk aktivtering in vivo valgt fra acetoksymetyl, pivaloyloksymetyl, ftalidyl, benzoyloksymetyl, 5-indanyl, en gruppe med formeleller en gruppe med formelhvori R" står for (Cv-C )alkyl, (C-C,. )cykloalkyl eller aryl; 14 bo A betyr hydrogen, halogen, N , OH, NI^; eller et kvartær- nært N-atom, spesielt(og i dette tilfellet er R' en negativ ladning) ; eller en O-CO-NI-^ gruppe, eller en gruppe med formel OR" <*> , 0-COR" ' , NH-CO-R"' eller SR'", hvor R"' er (C^-C^)alkyl, aryl, substituert aryl eller en heterocyklisk gruppe som kan være substituert med lavere a1kylgrupper; n kan være 0 eller 1, det asymmetriske C-atom ( ) i tiazolidinkjernen har D- eller L-konfigurasjon eller foreligger i racemisk form, karakterisert ved at forbindelser med formelhvor R1, A og n er som ovenfor definert, acyleres på aminogruppen med forbindelser med formel IIIhvor R er som ovenfor angitt og Y er et halogenatom, en alkoksygruppe eller en rest av et homogent eller blandet anhydrid, eller en annen åpenbart aktiverende gruppe, og at når R = (CH^^Si hydrolyser.es denne gruppen etter acyler- ingsreaksjonen, og erstattes eventuelt av en annen R-gruppe som er forskjellig fra H og (CH^-jSi.
- 2. Fremgangsmåte ifølge krav 1 ved fremstilling av forbindelser .med formel I hvor R = H, R <1> = H, A = 0-CO-NH2 , n=0, karakterisert ved at man velger tilsvarende substituert
- 3. Fremgangsmåte ifølge krav 1 ved fremstilling av forbindelser med formel I- hvor R H, R' = Na, A = 0-CO-NH , n = 0, , karakterisert ved at man velger tilsvarende substituerte utgangsmaterialer.
- 4. Fremgangsmåte ifølge krav 1 ved fremstilling av forbindelser med formel I hvor R = H, R' = kation av lysin, A = 0-CO-NH2 , n = 0, karakterisert ved at man velger tilsvarende substituerte utgangsmaterialer.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT23455/80A IT1148888B (it) | 1980-07-15 | 1980-07-15 | Composti antibiotici |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO812428L true NO812428L (no) | 1982-01-18 |
Family
ID=11207252
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO812426A NO812426L (no) | 1980-07-15 | 1981-07-14 | Antibiotisk virksomme forbindelser. |
| NO812427A NO812427L (no) | 1980-07-15 | 1981-07-14 | Antibiotisk virksomme cephalosporinforbindelser. |
| NO812428A NO812428L (no) | 1980-07-15 | 1981-07-14 | Antibiotisk virksomme tiazolidinforbindelser. |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO812426A NO812426L (no) | 1980-07-15 | 1981-07-14 | Antibiotisk virksomme forbindelser. |
| NO812427A NO812427L (no) | 1980-07-15 | 1981-07-14 | Antibiotisk virksomme cephalosporinforbindelser. |
Country Status (17)
| Country | Link |
|---|---|
| US (3) | US4405618A (no) |
| JP (3) | JPS5740490A (no) |
| AR (3) | AR227926A1 (no) |
| AU (3) | AU7256781A (no) |
| BE (3) | BE889630A (no) |
| CA (1) | CA1173435A (no) |
| DE (3) | DE3127489A1 (no) |
| DK (3) | DK314881A (no) |
| ES (3) | ES8203905A1 (no) |
| FR (3) | FR2486944A1 (no) |
| GB (3) | GB2086375B (no) |
| IT (1) | IT1148888B (no) |
| NL (3) | NL8103345A (no) |
| NO (3) | NO812426L (no) |
| PH (2) | PH16897A (no) |
| SE (3) | SE8104309L (no) |
| ZA (3) | ZA814582B (no) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3239365A1 (de) * | 1982-10-23 | 1984-04-26 | Bayer Ag, 5090 Leverkusen | Neue cephalosporine und verfahren zu ihrer herstellung |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4071529A (en) * | 1971-06-02 | 1978-01-31 | Merck & Co., Inc. | Derivatives of 6-aminopenicillanic acid |
| FR2100769B1 (no) * | 1971-06-16 | 1974-09-27 | Merck & Co Inc | |
| JPS4947385A (no) * | 1972-03-09 | 1974-05-08 | ||
| DE2353584A1 (de) * | 1973-10-25 | 1975-05-07 | Bayer Ag | Penicilline, ein verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittal |
| NZ176206A (en) * | 1973-12-25 | 1978-03-06 | Takeda Chemical Industries Ltd | Cephalosporins |
| US3907787A (en) * | 1974-02-22 | 1975-09-23 | American Home Prod | 7-(2-Thioxo-4-thiazolidinecarboxamido)cephalosporanic acids and the corresponding S-ethers |
| JPS5119765A (en) * | 1974-08-09 | 1976-02-17 | Takeda Chemical Industries Ltd | Aminochiazoorujudotaino seizoho |
| US3971776A (en) * | 1975-02-19 | 1976-07-27 | E. R. Squibb & Sons, Inc. | Thio-β-lactam penicillins |
| JPS5946237B2 (ja) * | 1976-04-02 | 1984-11-10 | 武田薬品工業株式会社 | セフアロスポリン誘導体およびその製造法 |
| US4322347A (en) * | 1978-04-03 | 1982-03-30 | Bristol-Myers Company | 2-Carbamoyloxymethyl-penicillin derivatives |
-
1980
- 1980-07-15 IT IT23455/80A patent/IT1148888B/it active
-
1981
- 1981-07-01 US US06/279,454 patent/US4405618A/en not_active Expired - Fee Related
- 1981-07-01 US US06/279,425 patent/US4389407A/en not_active Expired - Fee Related
- 1981-07-01 US US06/279,456 patent/US4387096A/en not_active Expired - Fee Related
- 1981-07-02 PH PH25857A patent/PH16897A/en unknown
- 1981-07-02 PH PH25858A patent/PH16969A/en unknown
- 1981-07-03 GB GB8120695A patent/GB2086375B/en not_active Expired
- 1981-07-03 AU AU72567/81A patent/AU7256781A/en not_active Abandoned
- 1981-07-03 AU AU72568/81A patent/AU7256881A/en not_active Abandoned
- 1981-07-03 GB GB8120694A patent/GB2086374B/en not_active Expired
- 1981-07-03 GB GB8120693A patent/GB2086883B/en not_active Expired
- 1981-07-03 AU AU72569/81A patent/AU7256981A/en not_active Abandoned
- 1981-07-07 ZA ZA814582A patent/ZA814582B/xx unknown
- 1981-07-07 ZA ZA814584A patent/ZA814584B/xx unknown
- 1981-07-07 ZA ZA814586A patent/ZA814586B/xx unknown
- 1981-07-09 CA CA000381453A patent/CA1173435A/en not_active Expired
- 1981-07-10 SE SE8104309A patent/SE8104309L/xx not_active Application Discontinuation
- 1981-07-10 AR AR286036A patent/AR227926A1/es active
- 1981-07-10 FR FR8113696A patent/FR2486944A1/fr active Granted
- 1981-07-10 SE SE8104308A patent/SE8104308L/xx not_active Application Discontinuation
- 1981-07-10 SE SE8104310A patent/SE8104310L/xx not_active Application Discontinuation
- 1981-07-10 FR FR8113697A patent/FR2486945A1/fr active Granted
- 1981-07-10 AR AR286035A patent/AR230641A1/es active
- 1981-07-10 FR FR8113695A patent/FR2486943B1/fr not_active Expired
- 1981-07-10 AR AR286034A patent/AR229589A1/es active
- 1981-07-11 DE DE19813127489 patent/DE3127489A1/de not_active Withdrawn
- 1981-07-11 DE DE19813127488 patent/DE3127488A1/de not_active Withdrawn
- 1981-07-11 DE DE19813127555 patent/DE3127555A1/de not_active Withdrawn
- 1981-07-13 JP JP56109909A patent/JPS5740490A/ja active Pending
- 1981-07-13 JP JP56109910A patent/JPS5740491A/ja active Pending
- 1981-07-13 JP JP56109908A patent/JPS5740489A/ja active Pending
- 1981-07-14 NL NL8103345A patent/NL8103345A/nl not_active Application Discontinuation
- 1981-07-14 ES ES503931A patent/ES8203905A1/es not_active Expired
- 1981-07-14 NL NL8103346A patent/NL8103346A/nl not_active Application Discontinuation
- 1981-07-14 NO NO812426A patent/NO812426L/no unknown
- 1981-07-14 NL NL8103350A patent/NL8103350A/nl not_active Application Discontinuation
- 1981-07-14 ES ES503932A patent/ES503932A0/es active Granted
- 1981-07-14 NO NO812427A patent/NO812427L/no unknown
- 1981-07-14 NO NO812428A patent/NO812428L/no unknown
- 1981-07-14 ES ES503933A patent/ES8300336A1/es not_active Expired
- 1981-07-15 BE BE2/59263A patent/BE889630A/nl not_active IP Right Cessation
- 1981-07-15 DK DK314881A patent/DK314881A/da not_active Application Discontinuation
- 1981-07-15 DK DK314981A patent/DK314981A/da not_active Application Discontinuation
- 1981-07-15 BE BE2/59262A patent/BE889629A/nl not_active IP Right Cessation
- 1981-07-15 DK DK314781A patent/DK314781A/da not_active Application Discontinuation
- 1981-07-15 BE BE2/59261A patent/BE889628A/nl not_active IP Right Cessation
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