ZA200007074B - Propenyl cephalosporin derivatives. - Google Patents
Propenyl cephalosporin derivatives. Download PDFInfo
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- ZA200007074B ZA200007074B ZA200007074A ZA200007074A ZA200007074B ZA 200007074 B ZA200007074 B ZA 200007074B ZA 200007074 A ZA200007074 A ZA 200007074A ZA 200007074 A ZA200007074 A ZA 200007074A ZA 200007074 B ZA200007074 B ZA 200007074B
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- South Africa
- Prior art keywords
- amino
- compounds
- compounds according
- formula
- optionally substituted
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- -1 Propenyl cephalosporin Chemical class 0.000 title claims description 141
- 229930186147 Cephalosporin Natural products 0.000 title claims description 4
- 229940124587 cephalosporin Drugs 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 110
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- 125000000623 heterocyclic group Chemical group 0.000 claims description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 39
- 150000002148 esters Chemical class 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 239000011593 sulfur Substances 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000004677 hydrates Chemical class 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000004946 alkenylalkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 208000035473 Communicable disease Diseases 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-O 1-methylpyrrolidin-1-ium Chemical compound C[NH+]1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-O 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 15
- 239000003814 drug Substances 0.000 claims 13
- 238000000034 method Methods 0.000 claims 13
- 238000011321 prophylaxis Methods 0.000 claims 12
- 239000000203 mixture Substances 0.000 claims 7
- 239000000126 substance Substances 0.000 claims 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 2
- BSIMZHVOQZIAOY-SCSAIBSYSA-N 1-carbapenem-3-carboxylic acid Chemical compound OC(=O)C1=CC[C@@H]2CC(=O)N12 BSIMZHVOQZIAOY-SCSAIBSYSA-N 0.000 claims 2
- 229940123930 Lactamase inhibitor Drugs 0.000 claims 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 2
- 239000004615 ingredient Substances 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-O 2-methylpyridin-1-ium Chemical compound CC1=CC=CC=[NH+]1 BSKHPKMHTQYZBB-UHFFFAOYSA-O 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
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- SJRJJKPEHAURKC-UHFFFAOYSA-O 4-methylmorpholin-4-ium Chemical compound C[NH+]1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-O 0.000 claims 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 1
- 239000002262 Schiff base Substances 0.000 claims 1
- 150000004753 Schiff bases Chemical class 0.000 claims 1
- 206010041925 Staphylococcal infections Diseases 0.000 claims 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 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 125000004423 acyloxy group Chemical group 0.000 claims 1
- 238000006136 alcoholysis reaction Methods 0.000 claims 1
- 125000005236 alkanoylamino group Chemical group 0.000 claims 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 1
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 230000000845 anti-microbial effect Effects 0.000 claims 1
- 239000004599 antimicrobial Substances 0.000 claims 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 claims 1
- 150000007942 carboxylates Chemical class 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- 125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 claims 1
- 125000005366 cycloalkylthio group Chemical group 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 229960002182 imipenem Drugs 0.000 claims 1
- GSOSVVULSKVSLQ-JJVRHELESA-N imipenem hydrate Chemical compound O.C1C(SCCNC=N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 GSOSVVULSKVSLQ-JJVRHELESA-N 0.000 claims 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 229940099678 norco Drugs 0.000 claims 1
- 239000012038 nucleophile Substances 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000000656 azaniumyl group Chemical group [H][N+]([H])([H])[*] 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 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 3
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 2
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
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- 125000001963 4 membered heterocyclic group Chemical group 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
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- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IBBLRJGOOANPTQ-JKVLGAQCSA-N quinapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 IBBLRJGOOANPTQ-JKVLGAQCSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Description
LN wovess PCT/EP99/04034
Propenyl Cephalosporin Derivatives
The present invention relates to cephalosporin derivatives of the general formula atthe 0 JB ——_—
COOH I wherein R is an organic residue with a molecular weight not exceeding 400 bonded to the adjacent sulphur atom via carbon and consisting of carbon, hydrogen, and optional oxygen, sulfur, nitrogen and/or halogen atoms; R' is hydrogen, lower alkyl or phenyl; and A is a secondary, tertiary or quaternary nitrogen atom bound directly to the propenyl group and being substituted by an organic residue with a molecular weight not exceeding 400 and consisting of carbon, hydrogen, and optional oxygen, sulfur, nitrogen and/or halogen atoms, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
The compounds of the present formula I are useful in the treatment of : infectious diseases in that they have potent and broad antibacterial activity; " especially against Gram-positive organisms, e.g. methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) staphylococci, enterococci and pneumococci.
In the above compounds of formula I the substituent in position 3 can be present in the E-form: [A ~
A or in the Z-form: / J
Compounds of formula I i.e. wherein the substituent in position 3 isin the E-form are generally preferred.
Compounds of formula I, in which R' is lower alkyl or phenyl, R'is attached at an asymmetric carbon atom which can have (R) or (S) configuration:
R10 = H
R) configuration: : A” (R) conte R— S$—CZ—CONH—
R oF (S) configuration: IR
R—S8—C-—CONH— 10 Generally, the S-form is preferred.
A subgroup of the compounds of the invention consists of compounds of the general formula
SOREN
0 LS
COOH I wherein
R° is lower alkyl or lower alkenyl, these groups being optionally substituted by one or more substituent(s) R’ represented by: halogen lower cycloalkyl naphthyl optionally substituted phenyl or heterocyclyl optionally substituted acyl optionally etherified or acylated hydroxy
“ \ NM] :
YT wo 9967255 ) -3- PCT/EP99/04034 optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy " etherified mercapto, lower alkylsulfinyl, phenylsulfinyl lower alkylsulfonyl, phenylsulfonyl cyano amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino; or
R° is phenyl, naphthyl or heterocyclyl, these groups being optionally substituted by one or more substituents R’® represented by: halogen optionally substituted lower alkyl, lower alkenyl or lower cycloalkyl optionally substituted phenyl or heterocyclyl optionally substituted acyl optionally etherified or acylated hydroxy optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy etherified mercapto, lower alkylsulfinyl, phenylsulfonyl optionally amidated sulfonyl lower alkylsulfonyl, phenylsulfonyl ‘cyano;
A° is a quaternary nitrogen residue of the general formula
R2 + — \ —R3
Re III wherein R?, B® and R* may be the same or different and each are alkyl cycloalkyl, alkenylalkyl or saturated heterocyclyl; or R? and R® together with the N atom represent a saturated or partly unsaturated 5 to 8 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, R* being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring represented by R’ and R’; : or R?, R® and R' together with the N atom represent an aromatic 5 or 6 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen; or
A° is a secondary or tertiary nitrogen residue of the general formula
JRS
AR
Na
Re Iv wherein R® and R® may be the same or different and each are alkyl, cycloalkyl, alkenylalkyl or heterocyclyl or R’ is hydrogen; or R® and R°® together with the N atom represent a saturated or partly unsaturated or aromatic 5 or 6 membered optionally fused heterocyclic ring which may contain additional hetero atoms : selected from oxygen, sulfur and nitrogen, and wherein, where R%, BR’, RY, R’ and/or R® represent alkyl, this group is optionally substituted by carbamoyloxy or ene or more substituents
R’, wherein R has the above meaning; and where R?, R® and R* and R® and R’ represent heterocyclyl or together form part of a heterocyclic ring as defined above, this heterocyclyl group/heterocyclic ring is optionally substituted by one or more substituents R®, wherein R® has the above meaning, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable 90 salts of said compounds and hydrates of the compounds of formula II and of their esters and salts.
Subgroups of the compounds of formula II are as follows:
Compounds of the general formulas ve il
Nz + 0 Porat — R30
COOH
Rao IIA wherein R® and R' are as defined above and R”, R* and R* may be the same or different and each are alkyl (optionally substituted by
R’ as for R?, R® and R* above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R’ as for R? R® and R' above);
4 a WO 99/67255 -5- PCT/EP99/04034
FS CHRON 9 i + 0 {conan Q
COOH
IIB wherein R° and R' are as defined above, Q' is a saturated or partly unsaturated 5 to 8 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen (optionally substituted by R’ as for R* and R’® above) and R" is alkyl (optionally substituted by R’ as for R* above), cycloalkyl, alkenylalkyl or saturated heterocyclyl or may represent a 1-2-, 1-3- or 1-4-alkylene or a vinylene bridge to the heterocyclic ring;
I vy
NZ + 0 [ooetiR) : COOH
IIC wherein R° and R' are as defined above and Q” is an aromatic 5 or 6 ‘membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen (optionally substituted by R® as for R’, R’ and R' above); : HD vg / Rso 0 NP
Reo
COOH IID
: wherein R® and R' are as defined above and R* and R® may be the same or different and each are alkyl (optionally substituted by R’ as for R® and
R® above), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R® as for R® and R® above) or R” is hydrogen;
Re-S-CHR! PN : 0 Phonon 3) 0 coon IIE wherein R° and R' are as defined in above and Q’ is a saturated or partly unsaturated or aromatic 5 or 6 membered optionally fused heterocyclic ring which may contain additional hetero atoms :
selected from oxygen, sulfur and nitrogen (optionally substituted by
R? as for R® and R® above), as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formulas ITA-IIE and of their esters and salts.
The term "halogen" or "halo" used herein refers to all four forms, that 18 chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine. or fluoro, unless specified otherwise.
As used herein, the terms "alkyl" and “lower alkyl" refer to both straight and branched chain saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, t- butyl and the like.
By the term “substituted lower alkyl" is meant a "lower alkyl" moiety as defined above substituted by, for example, halogen, amine, lower alkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, cyano, carboxy, carbamoyl etc., such as carboxymethyl, carbamoylmethyl, trifluoromethyl, 2,2 2-trifluoroethyl, 2-chloroethyl, 2-hydroxyethyl, methoxymethyl, methylaminomethyl, dimethylaminoethyl and the like.
As used herein, the term "lower alkoxy" refers to a straight or branched 90 chain hydrocarbonoxy group wherein the "alkyl" portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy and the like.
The "alkyl" portion may be substituted as defined above.
As used herein, "alkenyl" and "lower alkenyl" refer to unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, 95 preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl, 2-propenyl, 9-butenyl, 3-butenyl, 2-methyl-2-propenyl.
The expressions “alkenylalkyl” and "lower alkenylalkyl" are employed to indicate that the double bonds of said radicals are not connected with the first carbon atom (such as in vinyl and 1-propenyl), but that these radicals are limited to groups having their unsaturation in 2-, 3- and further positions. Itis understood that "lower alkenylalkyl" refers to groups containing up to and including 8 carbon atoms, e.g. 9-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2- propenyl.
By the term “substituted lower alkenyl” is meant a lower alkenyl moiety as defined above, preferably vinyl, substituted as for “substituted lower alkyl” but preferably substituted by cyano or by carboxy which may be amidated by amino, lower alkylamino, (di-lower alkyl)-amino or by the amino group of a natural a-amino acid such as glycine, alanine or phenylalanine.
By the term "cycloalkyl" or "lower cycloalkyl" is meant a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclohexyl, etc.
By the term "substituted lower cycloalkyl” is meant a lower cycloalkyl moiety as defined above substituted by, for example, lower alkyl, halogen, amino, lower alkylamino, di-(lower alkyl)amino, hydroxy, lower alkoxy, cyano, carboxy etc., such as 3-hydroxy-cyclobutyl, 4-methyl-cyclohexyl or 3,4- : dimethoxy-cyclopentyl. "Acyl" alone or in combination with other groups such as in "acylamino”, is preferably derived from a carboxylic acid and is thus e.g. lower alkanoyl, e.g. formyl, acetyl, propionyl, isobutyryl, pivaloyl; lower cycloalkanoyl, e.g. cyclopropylcarbonyl; benzoyl “By the term "aryl" is meant a radical derived from an aromatic hydro- carbon by the elimination of one atom of hydrogen and can be substituted or unsubstituted. The aromatic hydrocarbon can be mononuclear or polynuclear.
Examples of aryl include phenyl, naphthyl, anthryl, phenanthryl and the like.
The aryl group can have at least one substituent selected from, as for example, halogen, hydroxy, cyano, carboxy, nitro, amino, dimethylamino, lower alkyl, lower alkoxy, carbamoyl, such as in tolyl, xylyl, mesityl, cumenyl, 2,4- difluorophenyl, 4-carboxyphenyl, 4-nitrophenyl, 4-dimethyl-aminophenyl, 4- 95 methoxyphenyl, 2,4,5-trichlorophenyl and 6-carboxy-2-naphthyl.
As used herein, the term "lower alkylamino and di-lower alkylamino" : refers to mono and dialkylamino residues wherein lower alkyl is as defined above, for example methylamino, 2-ethylamino, N-methylamino, N-ethyl- amino, N,N-dimethylamino, N,N-diethylamino and the like. The terms (lower alkyl)amidino, (di-lower alkyl)amidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino are defined in analogous manner.
As used herein "heterocyclyl" or "heterocyclic ring" refers to an unsaturated or saturated, unsubstituted or substituted 4-, 5-, 6-, or 7- membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen, or sulfur. Exemplary heterocyclic rings include, but are not limited to, for example, the following groups: azetidinyl, pyridyl, pyrazinyl, piperidyl, morpholinyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3- thiadiazolyl, 1,2 4-thiadiazolyl, 1,2 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyi; furyl, 1H-azepinyi, thiophenyl. isoxazolyl, isothiazolyl, oxazolidinyl, etc. Substituents for the heterocyclic ring include, for example, optionally hydroxy substituted lower alkyls such as methyl, ethyl, propyl, hydroxypropyl, etc., lower alkoxys such as methoxy, ethoxy, etc., halogens such as fluorine, chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxyl groups. A further substituent is oxo, such as in 2-0x0-oxazolidin-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl.
Further examples of substituted heterocycles are 6-methoxy-pyridin-3-yl, 5- methyl-isoxazol-3-yl, 2-methylpyridinyl, 3-hydroxypyridinyl, 4-[4-(3-hydroxy- propyl)]-pyridinyl, 1-methylpyrrolidinyl, 4-methyl-morpholinyl and 4- ethoxycarbonyl-5-methyl-thiazolyl.
The terms “heterocyclyl” or “heterocyclic ring” may also mean a “fused heterocyclic ring”. By the expression "fused heterocyclic ring" utilized hereinabove is meant a heterocyclic system fused e.g. to a second carbocylic or heterocyclic 5- or 6-membered saturated or unsaturated ring forming a bicyclic saturated, partly unsaturated or aromatic ring system containing at least 1 heteroatom selected from oxygen, nitrogen and sulfur. Exemplary of fused heterocyclic rings include, but are not limited to, for example the following groups: 1-quinolinyl, 2-quinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 1-quinuclidinyl (1-azonia-bicyclo[2,2,2]oct-1-y1), 3-hydroxy- quinuclidinyl, dehydroquinuclidinyl, 1,5-diazabicyclo{3.3.0]octanyl, 1,4- diazabicyclo[2.2.2] octanyl (4-aza-bicyclo(2,2,2]oct-1-y1), 4-aza-1-azonia-bicyclo- [2,2,2]oct-1-y1, 1-aza-5-methyl-4,6-dioxabicyclo (3.3.1]nonanyl, 2,3,4,6,7,8,9,10- octahydro-pyrimido[1,2-a}azepin-1-yl and the like. The heterocyclic rings falling under Q' and Q’ in formulas IIB and IIC above are quaternary, i.e. the above examples for heterocyclic rings apply also to their quaternary forms, e.g. 1-methyl-pyrrolidin-1-ium (in formula IIB), pyridin-1-ium (in formula 110).
By the term "substituted phenyl" is meant phenyl mono, di- or tri- substituted by halogen, optionally substituted lower alkyl, optionally protected hydroxy, cyano, hydroxy or carbamoyl.
As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group(s) of which (for
0 LR 9. PCT/EP99/04034 example the 2-carboxy group) is/are present in the form of readily hydrolyzable ester groups. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e.g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e.g., the methoxycarbonyl- oxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e.g., the methoxymethyl ester) and the lower alkanoylaminomethyl esters (e.g., the acetamidomethyl ester). Other esters (e.g., the benzyl and cyanomethyl esters) can also be used. Other examples of such esters are the following: (2,2-dimethyl-1-oxopropoxy)methyl ester; 2-[(2- methylpropoxy)carbonyl]-2-pentenyl ester; 1-[[(1-methylethoxy)carbonyl]oxy] ethyl ester; (5-methyl-2-0x0-1,3-dioxol-4-yl) methyl ester; 1- [[(cyclohexyloxy)carbonylloxy] ethyl ester; and 3,3-dimethyl-2-oxobutyl ester.
It will be appreciated by those of ordinary skill in the art that the readily : hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound. ‘As used herein pharmaceutically acceptable salts useful in this invention include base addition salts derived from metals, the ammonio salt or quaternary ammonio salts derived from organic bases or, preferably, acid addition salts derived from inorganic or organic acids. Examples of preferred metal salts are those derived from the alkali metals, for example, sodium.
Examples of quaternary ammonio salts derived from organic bases include tetramethylammonio, tetraethylammonio and the like. These salts derived 95 from amines include salts with N-ethylpiperidine, procaine, dibenzylamine,
N,N’-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine. Especially preferred are hydrochlorides, chlorides, sulfates, phosphates, lactates, mesylates and the inner salts.
The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.
The term "amino protecting groups" refers to protecting groups conventionally used to replace an acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic
Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218-287, herein incorporated by reference. These examples include carbamates, c.g fluorenylmethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilanyl)ethyl, t-butyl, allyl, benzyl. Further protecting groups are 3,5-dimethoxybenzyl, p- nitro-benzyl, diphenylmethyl, triphenylmethyl, benzyl, formyl, acetyl, phenylacetyl, trifluoroacetyl, chloro-acetyl, the cyclic imides of N-phthaloyi, N- trimethylsilanyl, N-benzenesulfonyl, N-toluenesulfonyl, N-p-methylbenzyi- sulfonyl. Preferred is BOC [t-butoxycarbonyl, other name (1,1-dimethyi- ethoxy)carbonyl], benzyloxycarbonyl and allyloxycarbonyl.
The term "carboxylic acid protecting group" refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. Examples of such groups are described in Greene, T., Protective Groups in Organic
Synthesis, Chapter 5, pp. 152-192 (John Wiley and Sons, Inc. 1981), incorporated herein by reference. Preferably these examples include methoxy- methyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2- (trimethylsilanyl)ethyl, t-butyl, allyl, benzyl, triphenylmethy! (trityl, henzhydryl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilanyl, triethylsilanyi, t-butyldimethylsilanyl, i-propyl-dimethylsilanyl. Preferred are benzhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.
The term "hydroxy protecting group” refers to protecting groups as conventionally used in the art such as trimethylsilanyl, t-butyl- dimethylsilanyl, dimethylphenylsilanyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl or t- butyloxycarbonyl.
More specific embodiments of R’ and R’ in Formulas II and IIA-IIE are as follows:
R® when substituted lower alkyl, lower alkenyl or lower cycloalkyl is substituted by hydroxy, lower alkoxy, cyano, carboxy, amino, lower alkyl- amino, di-(ower alkyl)amine, carbamoyl, carbamoyloxy or 1-3 halogens.
Substituted lower alkenyl is preferably vinyl and is preferably substituted by cyano or by carboxy which may be amidated by amino, lower alkylamino, (di- lower alkyl)-amino or by the amino group of a natural a-amino acid such as glycine, alanine or phenylalanine.
The carboxy group optionally present on lower alkyl, lower alkenyl or lower cycloalkyl values R’ can be esterified or amidated quite in the same way as indicated below for esterified and amidated carboxy values R' or Rr’.
Claims (76)
1. Cephalosporin derivatives of the general formula OES 0 NI COOH I wherein R is an organic residue with a molecular weight not exceeding 400 bonded to the adjacent sulphur atom via carbon and consisting of carbon, hydrogen, and optional oxygen, sulfur, nitrogen and/or halogen atoms; R' is hydrogen, lower alkyl or phenyl; and A is a secondary, tertiary or quaternary nitrogen atom bound directly to the propenyl group and being substituted by an organic residue with a molecular weight not exceeding 400 and consisting of carbon, hydrogen, and optional oxygen, sulfur, nitrogen and/or halogen atoms, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.
2. Compounds according to claim 1 with the 3-substituent in the E-form viz. having the formula FO CHRT CONS ’ : N A 0 Ps COOH la wherein R, R' and A are as in claim 1, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula Ia and of their esters and salts.
3. Compounds according to claim 1 or 2 having the formula
R® R TSTCTOONRN_ oS Ib <S> AN o I "CH=CH-CH_,-A 2 COOH wherein R and A are as in claim 1 and R* is lower alkyl or phenyl, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula Ib and of their esters and salts.
4. Compounds according to any one of claims 1-3 having the formula OH OOS 0 SN COOH — Li wherein R® is lower alkyl or lower alkenyl, these groups being optionally substituted by one or more substituent(s) R’ represented by: halogen lower cycloalkyl naphthyl optionally substituted phenyl or heterocyclyl optionally substituted acyl optionally etherified or acylated hydroxy optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy etherified mercapto, lower alkylsulfinyl, phenylsulfinyl lower alkylsulfonyl, phenylsulfonyl cyano amidino, (lower alkyl)amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino; or
©." WO 99/67255 .83- PCT/EP99/04034 R’ is phenyl, naphthyl or heterocyclyl, these groups being optionally substituted by one or more substituents R® represented by: halogen optionally substituted lower alkyl, lower alkenyl or lower cycloalkyl optionally substituted phenyl or heterocyclyl optionally substituted acyl optionally etherified or acylated hydroxy optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy etherified mercapto, lower alkylsulfinyl, phenylsulfinyl optionally amidated sulfonyl : lower alkylsulfonyl, phenylsulfonyl cyano; A° is a quaternary nitrogen residue of the general formula
R2 . +] BE RY III i | wherein R?, R® and R* may be the same or different and each are alkyl, : cycloalkyl, alkenylalkyl or saturated heterocyclyl; or R? and R’ together with the N atom represent a saturated or partly unsaturated 5 to 8 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, R’ being as above or may represent a 1-2-, 1-3- or 1-4-alkylene or vinylene bridge to the heterocyclic ring represented by R’ and R’; or R?, R® and R' together with the N atom represent an aromatic 5 or 6 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen; or A° isa secondary or tertiary nitrogen residue of the general formula 5 a See Iv wherein R’ and R® may be the same or different and each are alkyl, cycloalkyl, alkenylalkyl or heterocyclyl or R® is hydrogen;
or BR’ and R® together with the N atom represent a saturated or partly unsaturated or aromatic 5 or 6 membered optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen, and wherein, where R?, R”, RY, R® and/or R’ represent alkyl, this group is optionally substituted hy carbamovloxy or one or more substituents R’, wherein R’ has the above meaning; and where R’, R’ and R* and R’ and R’ represent heterocyclyl or together form part of a heterocyclic ring as defined above, this heterocyclyl group/heterocyclic ring is optionally substituted by one or more substituents R’, wherein R® has the above meaning, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula II and of their esters and salts.
5. Compounds according to claim 4, wherein R’ is selected from halogen lower cycloalkyl naphthyl Zz0 optionally substituted phenyl! or heterocyclyl optionally substituted acyl optionally etherified or acylated hydroxy optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy etherified mercapto, lower alkylsulfinyl, phenylsulfinyl lower alkylsulfonyl, phenylsulfonyl cyano and R’ is selected from halogen optionally substituted lower alkyl or lower cycloalkyl optionally substituted phenyl optionally substituted acyl optionally etherified or acylated hydroxy optionally acylated amino (lower alkyl)amino, (di-lower alkyl)amino, lower cycloalkylamino optionally esterified or amidated carboxy
2 «WO 99/67255 -85- PCT/EP99/04034 etherified mercapto, lower alkylsulfinyl, phenylsulfinyl optionally amidated sulfonyl lower alkylsulfonyl, phenylsulfonyl cyano.
6. Compounds of claim 4 or 5 having the formula R’-S-CHR'-CONH ws il + 0 LN R3 COOH | “0 R IIA wherein R® and R' are as defined in claim 4 and and R®, R® and R® may be the same or different and each are alkyl (optionally substituted by R’ as for R’, R’ and R’ in claim 4 or 5), cycloalkyl, alkenylalkyl or saturated heterocyclyl (optionally substituted by R® as for R’, R’ and R'in claim 4 or 5), as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula IIA and of their esters and salts. y 15
7. Compounds of claim 4 or 5 having the formula Re-S-CH ROOMS il 0 ON Vo) COOH IIB wherein R° and R' are as defined in claim 4, Q' is a saturated or partly unsaturated 5 to 8 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen (optionally substituted by R® as for R® and R® in claim 4 or 5) and R" is alkyl (optionally substituted by R’ as for R' in claim 4 or 5), cycloalkyl, alkenylalkyl or saturated heterocyclyl or may represent a 1-2-, 1-3- or 1-4-alkylene or a ~ vinylene bridge to the heterocyclic ring, as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula IIB and of their esters and salts.
8. Compounds of claim 4 or 5 having the formula
RO-S-CHR'-CONHN,__S — N DEO NZ COOH 7) IIC wherein R° and R' are as defined in claim 4 and Q® is an aromatic 5 or 6 membered, optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen (optionally substituied by R" as for R’, KR’ and RK’ 1n claim 4 or 5), as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula IIC and of their esters and salts.
9. Compounds of claim 4 or 5 having the formula R?-S-CHR'-CON Deg Ree 0 A Reo COOH IID wherein R° and R' are as defined in claim 4 and R* and R* may be the same or different and each are alkyl (optionally substituted by R' 26 fr B® and B® in claim 4 or 85), cycloalkyl, alkenylaikyi or saturated heterocyclyl (optionally substituted by R® as for R® and R® in claim 4 or 5) or R” is hydrogen; as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula IID and of their esters and salts.
10. Compounds of claim 4 or 5 having the formula RI-S-CHR'-CONH 4 N J 0” NY roy) COOH IIE wherein R° and R' are as defined in claim 4 and Q’ is a saturated or partly unsaturated or aromatic 5 or 6 membered optionally fused heterocyclic ring which may contain additional hetero atoms selected from oxygen, sulfur and nitrogen (optionally substituted by R’ as for R® and R’® in claim 4 or 5),
as well as readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula IIE and of their esters and salts. BEETS Compounds according to any one of claims 4-10 wherein R® when substituted lower alkyl, lower alkenyl or lower cycloalkyl is substituted by hydroxy, lower alkoxy, cyano, carboxy, amino, lower alkylamino, di-(lower alkyl)amino, carbamoyl, carbamoyloxy or 1-3 halogens.
12. Compounds according to claim 11, wherein R’ is vinyl substituted by cyano or by carboxy which may be amidated by amino, lower alkylamino, (di- lower alkylamino or by the amino group of a natural o-amino acid.
13. Compounds according to claim 12, wherein R® is 2-carboxy-vinyl or 2- (carboxymethyl-carbamoyl)-vinyl.
14. Compounds according to claim 11, wherein R’ is carbamoylmethyl.
15. Compounds according to claim 14, wherein R’ is hydroxyethyl- carbamoylmethyl or hydroxyethoxyethylcarbamoylmethyl.
16. Compounds according to any one of claims 4-10 wherein R’ or R® when’ 3 substituted phenyl are substituted by 1-3 halogens, lower alkoxy, cyano, hydroxy or carbamoyl.
17. Compounds according to any one of claims 4-10 wherein R’ when optionally substituted heterocyclyl is a saturated or unsaturated 5 to 6 membered heterocyclic ring which may contain additional heteroatoms selected from oxygen, sulfur and nitrogen and is optionally substituted by hydroxy, halogen, lower alkoxy, carboxy, amino, lower alkylamino, di-(lower alkyDamino, cyano or oxo.
18. Compounds according to any one of claims 4-10 wherein R® when optionally substituted heterocyclyl is a saturated or unsaturated 5 to 6 membered heterocyclic ring which may contain additional heteroatoms selected from oxygen, sulfur and nitrogen and is optionally substituted by hydroxy, halogen, lower alkoxy, carboxy, amino, lower alkylamino, di-(lower alkyl)amino, cyano or oxo.
19. Compounds according to any one of claims 4-10 wherein R’ or R’ when optionally substituted acyl is lower alkanoyl, lower cycloalkanoyl or benzoyl optionally substituted by 1-3 halogens, hydroxy, lower alkoxy, amino, lower alkylamino, di-(lower alkyl)amino, carbamoyl, carbamoyloxy, cyano or phenyl.
20. Compounds according to any one of claims 4-10 wherein R’ or R® when etherified hydroxy is lower alkoxy, lower cycloalkoxy or phenoxy, each optionally substituted by 1-3 halogen atoms, amino, hydroxy, methoxy, carbamoyloxy, carboxy or carbamoyl.
21. Compounds according to any enc of claims 4-10 wherein R' or B® when acylated hydroxy is lower alkanoyloxy, benzoyloxy, heterocyclyl-carbonyloxy or lower alkoxycarbonyloxy; each optionally substituted by amino, (lower 16 alkyl)amino, {(di-lower alkyl)amino, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
22. Compounds according to any one of claims 4-10 wherein R’ or R® when acylated amino is lower alkanoylamino, lower cycloalkylamine, benzoylamino, heterocyclyl-carbonylamino or lower alkoxycarbonylamino, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
23. Compounds according to any one of claims 4-10 wherein R’ or R® when esterified carboxy is lower alkoxycarbonyl, cycloalkoxycarbonyl, phenoxycarbonyl, phenyl-lower alkoxycarbonyl, each optionally substituted by amino, (lower alkyl)amino, (di-lower alkyl)aminc, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
24. Compounds according to any one of claims 4-10 wherein R’ or R® when amidated carboxy is carbamoyl, lower alkylcarbamoyl, (di-lower alkyl) carbamoyl or lower cycloalkylcarbamoyl, each optionally substituted by amino, (lower alkyl)amino, (di-lower-alkyl)amino, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms.
25. Compounds according to any one of claims 4-10 wherein R® when substituted lower alkylcarbamoyl or lower cycloalkylcarbamoyl is substituted by hydroxy, lower alkoxy, hydroxy-lower alkoxy, amidino, (lower alkyl)- amidino, (di-lower alkyl)amidino, guanidino, (lower alkyl)guanidino, (di-lower alkyl)guanidino or heterocyclyl.
26. Compounds according to any one of claims 4-10 wherein R’ or R® when etherified mercapto is lower alkylthio, lower cycloalkylthio or phenylthio, each optionally substituted by methoxy or 1-3 halogen atoms amino, (lower t 4 WO 99/67255 -89 - PCT/EP99/04034 alkyl)amino, (di-lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1-3 halogen atoms. :
27. Compounds according to any one of claims 4-10 wherein R’ or R® when amidated sulfonyl is lower alkyl-aminosulfonyl, or lower cycloalkyl- aminosulfonyl, each optionally substituted by amino, (lower alkyl)amino, (di- lower alkyl)amino, hydroxy, methoxy, carboxy, carbamoyl, carbamoyloxy or 1- 3 halogen atoms.
28. Compounds according to any one of claims 1-27, wherein R and R® are optionally substituted phenyl.
29. Compounds according to claim 28, wherein R and R° are phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl or 4-hydroxy- methylphenyl.
30. Compounds according to claim 28, wherein R and R° are 3,5- dimethylphenyl.
31. Compounds according to any one of claims 1-27, wherein R and R° are optionally substituted naphthyl. a
32. Compounds according to claim 31 wherein R and R° are 2-naphthyl or 6-carboxy-2-naphthyl.
33. Compounds according to any one of claims 1-27, wherein R and R® are optionally substituted heterocyclyl.
34. Compounds according to claim 33, wherein R and R° are 2-benzo- oxazolyl, 2-benzothiazolyl or 4-pyridinyl. :
35. Compounds according to any one of claims 1-34, wherein A and A° are a group of formula R20 +] Re Rf 111A wherein R®, R¥ and R" are as defined in claim 6.
36. Compounds according to claim 35, wherein A and A° are trimethyl- ammonio or carbamoylmethyl-dimethyl-ammonio.
37. Compounds according to claim 35, wherein A and A® are dimethyl-(2- hydroxyethyl)-ammonio, (2-hydroxy-1-hydroxymethyl-ethyl)-trimethyl- ammonio, bis-(2-hydroxy-ethyl)-methyl-ammonio or (Ex. 112).
38. Compounds according to any one of claims 1-34, wherein A and A®° are a group of formula Re —N CON \O IIIB wherein Q' and R" are as defined in claim 7.
39. Compounds according to claim 38 wherein A and A° are 1-methyl- pyrrolidin-1-ium or 4-methyl-morpholin-4-ium.
40. Compounds according to claim 38 wherein A and A° are 4-aza-1- azonia-bicyclo[2,2,2]oct-1-yl or 1-azonia-bicyclo[2,2,2]oct-1-yl.
41. Compounds according to any cone of claims 1-34, wherein A and A°® are a group of formula + =z IIIC wherein Q° is as defined in claim 8.
42. Compounds according to claim 41 wherein A and A° are pyridin-1- ium, 2-methyl-pyridin-1-ium, 4-carbamoyl-pyridin-1-ium or quinolin-1-ium.
43. Compounds according to any one of claims 1-34, wherein A and A°® are a group of formula RS / —N HID Ng wherein R” and R” are as defined in claim 9.
44. Compounds according to claim 43 wherein A and A’ are dimethyl- amino or methylcyclopropylamino.
: 5 WO 99/67255 | -91- PCT/EP99/04034
45. Compounds according to any one of claims 1-34, wherein A and A°® are a group of formula : _ 3 {@) IE wherein Q’ is as defined in claim 10.
46. Compounds according to claim 45 wherein A and A’ are benzo- imidazol-1-yl, pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl.
47. The compounds according to claim 1, - (E)-(6R,7R)- 8-Oxo0-7-(2-phenylsulfanyl-acetylamino)- 3-(3-pyridin-1-ium-1- yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]Joct-2-ene-2-carboxylate - (E)-(6R,7R)-7-[2-(5-Ethoxycarbonyl-4-methyl-thiazol-2-ylsulfanyl)- acetylamino]-8-oxo-3-(3-pyridin-1-ium-1-yl-propenyl)-5-thia-1-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylate - - (E)-(6R,7R)-3-[3-(2-Methyl-pyridin-1-ium-1-y})-propenyl]-7-[2-(naphthalen- 2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylate - (E)-(6R,7R)- 3-[3-(2-methyl-pyridin-1-ium-1-yl)-propenyl}- 8-0xo0-7-(2- phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0}oct-2-ene-2- carboxylate - (E)-(6R,7R)- 3-[3-(3-Hydroxy-pyridin-1-ium-1-yl)-propenyl]- 8-oxo-7-(2- ‘phenylsulfanyl-acetylamino)- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- : carboxylate - (E)-(6R,7R)- 8-Oxo-7-[2-phenylsulfanyl)-acetylamino]-3-(3-quinolin-1-ium-1- yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate - (E)-(6R,7R)- 3-[3-(1-Methyl-pyrrolidin-1-ium-1-yl)-propenyl]-8-oxo-7-(2- phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylate and - (E)-(6R,7R)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-ox0-3-(3- trimethylammonio-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylate.
48. The compounds according to claim 1, - (E)-(6R,TR)-7-{2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-8-0x0-3-(3-pyridin- 1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate - (E}{6R,7R)-8-Ox0-3-(3-pyridin-1-um-1-yl-propenyl)-7-12-(2,4,5- trichlorophenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylate - (E)-(6R,TR)-3-[3-(3-Hydroxy-pyridin-1-ium-1-yl)-propenyl]-7-[2-(naphthalen- 2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclof4.2.0]oct-2-ene-2- carboxylate - (E)-(6R,7R)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-ox0-3-(3- quinolin-1-ium-1-yl-propenyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2- carboxylate - (E)-(6R,7R)- 3-[3-(1-Methyl-pyrrolidin-1-ium-1-yl)-propenyl]-7-[2- (naphtalen-2-ylsulfanyl)-acetylamino]-8-cxc-5-thia-1-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylate - (E)<(6R,7R)- 3-[3-(Carbamoylmethyl-dimethyl-ammonio)-propenyl]-7-{2- (naghthalen-2-ylsulfanyl)-acetylamineg]-8-cxc-5-thia 1-aza bicycic(4.2.0 uct 2-ene-2-carboxylate and - (E)-(6R,7TR)-7-[2-(Naphthalen-2-ylsulfanyl)-acetylamino]-8-0xc-3-[3-pyridin- 1-ium-1-yl-propenyl]-5-thia-1-aza-bicyclo|4.2.0]oct-2-ene-2-carboxylate.
49. The compounds according to claim 1, - (E)-(6R,7R)-3-[3-[Dimethyl-(2-hydroxy-ethyl)-ammonio]-propenyl]-7-[2- (benzothiazol-2-ylsulfanyl)-acetylaminc]-8-cxo-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylate - (E)-(6R,7R)-3-[3-(4-Aza-1-azonia-bicyclo[2,2,2]octan-1-yl)-propenyl]-7-{2- (naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylate - (E)-(6R,7R)-3-[3-[(3-Hydroxy-propyl)-dimethyl-ammonio}-propenyl]-7-{2- (naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylate
A © WO99/67255 93. PCT/EP99/04034 ¢ . - (E)-(6R;7R)-3-[3-[(2-Hydroxy-1-hydroxymethyl-ethyl)-dimethyl-ammonio}- : propenyl]-2-[2-(naphthalen-2-ylsulfanyl)-acetylamino}-8-oxo-5-thia-1-aza- " bicyclo[4.2.0]Joct-2-ene-2-carboxylate . (E)-(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino)-8-oxo0-3-[3-[(2- hydroxy-1-hydroxymethyl-ethyl)-dimethyl-ammonio]-propenyl]-5-thia-1-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylate - (E)-(6R,7R)-3-[3-[Bis-(2-hydroxy-ethyl)-dimethyl-ammonio]-propenyl]-7-[2- (3,5-dimethyl-phenylsulfanyl)-acetylamino}-8-oxo-5-thia-1-aza-bicyclo-
(4.2.0]oct-2-ene-2-carboxylate - (E)-(6R,7R)-3-[3-Carbamoylmethyl-dimethyl-ammonio]}-propenyl}-7-[2-(6- carboxy-naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo-
[4.2.0]oct-2-ene-2-carboxylate - (E)<(6R,7R)-7-[2-(Benzothiazol-2-ylsulfanyl)-acetylamino]-8-oxo-3-[3-(1- carboxylatomethyl)-1,4-diazonia-bicyclo[2.2.2]octan-4-yl)-propenyl]-5-thia-1- aza-bicyclo[4.2.0Joct-2-ene-2-carboxylate.
50. Compounds of the general formula : | HR CONN 0 SN : 3 : COOH (or COO) VII in which R' and A are as defined in claim 1 and Hal is halogen, and esters and salts thereof. : 20
51. Compounds of the general formula R-S-CHR'-CONH hry 0 ASN COOR® VIII in which R and R' are as defined in claim 1 and R’ is a carboxy protecting group.
52. Compounds of the general formula
. PCT/EP99/04034 Rk-S-CHR'-CONH Drs 0 i A crcrcrar COOR® X in which R' is as defined in claim 1, R* is hydrogen or a carboxy protecting group, R* is as R in claim 1 and A" is as A above with the proviso that at least one of the following provisions is fulfilled: i) R* is a carboxylic acid protecting group, (ii) R* is a residue defined under R having protected amino, protected hydroxy and/or protected carboxylic group(s); (ili) ~~ A~ is a residue defined under A having protected amino, protected hydroxy - and/or protected carboxylic group(s); and salts thereof. : 53. Compounds as in any one of claims 1-49 for use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases.
54. Process for the manufacture of compounds according to any one of claims 1- 49, which process comprises (a) treating a compound having the formula NT 0 Norco COOH (or COO7) v in which A is as defined in claim 1 and R is hydrogen or a silanyl protecting group; or an ester or salt thereof with a carboxylic acid of the general formula } R-S-CHR-COOH VI in which R and R' are as defined in claim 1, or a reactive derivative thereof; or (b) treating a compound having the general formula AMENDED SHEET
PCT/EP99/04034
EEN 0 SS . COQH (or COO) VII in which R! and A are as defined in claim 1 and Hal is halogen, or an ester or salt thereof with a thiol of formula R-SH or a salt thereof in the presence of a base; or (c) treating a compound having the formula R-S-CHR'-CONH Dr 0 {Norio COORe VIII in which R and R! are as defined in claim 1 and R® is a carboxy protecting group, with a nitrogen nucleophile yielding the group A wherein A has the above meaning and splitting off the carboxy protecting group RS; or (d) for the manufacture of compounds of formula I, in which A is a group of the formula NH-RS, treating a compound having the formula VIII with a Schiff base on the general formula Z-CH=N-R® IX : in which RS is as in claim 3 and Z is the residue or an aldehyde ZCHO, in which Z is alkyl, aryl or heterocyclyl, preferably phenyl, and subjecting the reaction product to hydrolysis or alcoholysis; or (e) for the manufacture of a compound of formula I in which R and/or A may contain free amino, hydroxy or carboxylic group(s) cleaving off the amino, hydroxy and/or carboxy protecting group(s) in a compound having the formula oS CHRLCONAN 0 NA crcrcrar COOR" X in which R! is as defined.in claim 1, R? is hydrogen or a carboxy protecting group, RE is as R above and A™ is as A in claims 1 with the proviso that at least one of the following provisions is fulfilled: REPLACEMENT SHEET
’ PCT/EP99/04034 -96- B 3) R* is a carboxylic acid protecting group, (ii) R* is a residue defined under R having protected amino, protected hydroxy and/or protected carboxylic group(s) (ili) A" is a residue defined under A having protected amino, protected hydroxy and/or protected carboxylic group(s), or a salt thereof, or ® for the manufacture of a readily hydrolyzable ester of a compound of formula I subjecting a carboxylic acid of formula I to a corresponding esterification, or 6) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts converting a compound of formula I into a salt or hydrate or into a hydrate of said salts.
55. A medicament containing a compound according to any one of claims 1-49.
56. A medicament for the treatment and prophylaxis of infectious diseases containing a compound according to any one of claims 1-49.
57. The use of the compounds according to any one of claims 1-49 for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases.
58. A medicament according to claim 55 or 56 additionally containing a carbapenem or a (-lactamase inhibitor.
59. A medicament according to claim 58, wherein the carbapenem antibiotic is imipenem.
60. A medicament according to claim 58, wherein the ($-lactamase inhibitor is (Z)- (2S,3S,5R)-3-(2-cyanoethenyl)-3-methyl-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0.]Jheptane-2- carboxylic acid.
61. A medicament according to any one claims 58-60, wherein the ratio by weight of the first ingredient to the second ingredient is about 1:20 to about 20:1.
62. A medicament as in any one of claims 58-60 for the treatment and prophylaxis of infectious diseases, including MRSA infections.
63. A medicament containing an antimicrobial composition according to any one of claims 58-60 and a therapeutically inert carrier, particularly for the treatment and prophylaxis of infectious diseases, including MRSA. AMENDED SHEET
. PCT/EP99/04034
64. Compounds according to any one of claims 1-49, whenever prepared according to the process claimed in claim 54 or by an obvious chemical equivalent thereof.
65. A substance or composition for use in a method of treatment or prophylaxis of infectious diseases, said substance or composition comprising a compound as defined in any one of the claims 1 to 49, and said method comprising administering an effective amount of said substance or composition.
66. Use of the compounds according to any one of claims 1 to 49 for the treatment and prophylaxis of infectious diseases.
67. A compound as claimed in any one of claims 1,50,51,52 or 64 substantially as herein described and illustrated.
68. A compound for use in a method of treatment or prophylaxis as claimed in claim 53, substantially as herein described and illustrated.
69. A process as claimed in claim 54, substantially as herein described and illustrated.
70. A medicament as claimed in claim 55, substantially as herein described and illustrated.
71. A medicament for use in a method of treatment or prophylaxis as claimed in claim 56 or claim 62 or claim 63, substantially as herein described and illustrated.
72. Use as claimed in claim 57, substantially as herein described and illustrated.
73. Use as claimed in claim 66, substantially as herein described and illustrated.
74. A substance or composition for use in a method of treatment or prophylaxis as claimed in claim 65, substantially as herein described and illustrated.
75. A new medicament; a medicament for a new use in a method of treatment or prophylaxis; a new use of a compound according to any one of claims 1 to 49, a readily hydrolyzable ester thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof; or a substance or composition for a new use in a method of treatment or prophylaxis, substantially as herein described.
76. The novel compounds, formulations, processes and methods substantially as described herein. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP98111415 | 1998-06-22 |
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ZA200007074B true ZA200007074B (en) | 2002-05-30 |
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ID=27675828
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Application Number | Title | Priority Date | Filing Date |
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ZA200007074A ZA200007074B (en) | 1998-06-22 | 2000-11-30 | Propenyl cephalosporin derivatives. |
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AR (1) | AR018905A1 (en) |
CO (1) | CO5080796A1 (en) |
PE (1) | PE20000706A1 (en) |
ZA (1) | ZA200007074B (en) |
-
1999
- 1999-06-18 CO CO99038283A patent/CO5080796A1/en unknown
- 1999-06-22 AR ARP990102970 patent/AR018905A1/en not_active Application Discontinuation
- 1999-06-22 PE PE1999000556A patent/PE20000706A1/en not_active Application Discontinuation
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PE20000706A1 (en) | 2000-08-22 |
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