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US4501739A Expired / Lapsed US ⏱️ 0.0 years remaining

Thieno and furopyridinium-substituted cephalosporins

Assignee: Eli Lilly and Co
•
Filing: 1982-12-15
•
Granted: 1985-02-26
•
Expires: 2002-12-15
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Abstract

Abstract Cephalosporin compounds substituted in the 7-position by a 2-(5- or 6-membered heterocyclic)-2-oximinoacetylamino group and in the 3-position with a thienopyridinium methyl group or a furopyridinium methyl group are broad spectrum antibiotics highly effective in combating bacterial infections of gram-negative and gram-positive microorganisms. The cephalosporins are best prepared by reacting a silylated 7-[2-(heterocyclic)-2-oximinoacetylamino-3-iodomethyl-3-cephem-4-carboxylic acid with the thienopyridine or the furopyridine. Pharmaceutical formulations comprising a compound of the invention and a method for treating bacterial infections comprising their use are also provided.

Inventors

  • 👤 William H. W. Lunn
  • 👤 Robert T. Vasileff

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-01 06:54
CPC Classifications
C; C07; C07D; C07D491/00; C07D491/02; C07D491/04; C07D307/00; C07D307/02; C07D307/34; C07D307/38; C07D307/40; C07D307/46; C07D307/54; C07D495/00; C07D495/02; C07D495/04

Claims Analysis

Total Claims: 52
Claim 1
Independent Claim 282 words
The compound of the formula ##STR31## wherein R is an acyl group of the formula ##STR32## wherein R' is a 5- or 6-membered heterocyclic ring of the formulas ##STR33## R" is hydrogen, C 1 -C 4 alkyl, a carboxy-substituted alkyl or carboxy-substituted cycloalkyl group of the formula ##STR34## wherein n is 0-3; a and b when taken separately are independently hydrogen or C 1 -C 3 alkyl, and when taken together with the carbon to which they are bonded form a C 3 -C 7 carbocyclic ring; R'" is hydroxy, C 1 C 4 alkoxy, amino, or OR°, wherein R° is indanyl, phthalidyl, or an acyloxymethyl group of the formula --CH 2 --O--C(O)--R 2 wherein R 2 is C 1 -C 4 alkyl or phenyl; or R° is a carboxy-protecting group; or R" is an N-substituted carbamoyl group of the formula ##STR35## wherein R"" is C 1 -C 4 alkyl, phenyl or C 1 -C 3 alkyl substituted by phenyl; .sup.⊕ R 1 is a bicyclicpyridinium group selected from the group consisting of a thienopyridinium group of the formulas ##STR36## or a furopyridinium group of the formulas ##STR37## and said thienopyridinium and said furopyridinium wherein either or both of the hetero rings thereof is substituted by one or two C 1 -C 4 alkyl, halogen, carboxy, carbamoyl, C 1 -C 4 alkoxycarbonyl groups, --SO 3 H, hydroxy, C 1 -C 4 alkoxy, amino, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, C 2 -C 4 alkanoylamino, aminosulfonyl, cyano, formyl, trifluoromethyl, or a hydroxyamido group of the formula ##STR38## wherein R 3 and R 4 independently are hydrogen or C 1 -C 4 alkyl; and the pharmaceutically acceptable non-toxic salts thereof.
Claim 2
Dependent Claim 282 words
The compound of the formula ##STR31## wherein R is an acyl group of the formula ##STR32## wherein R' is a 5- or 6-membered heterocyclic ring of the formulas ##STR33## R" is hydrogen, C 1 -C 4 alkyl, a carboxy-substituted alkyl or carboxy-substituted cycloalkyl group of the formula ##STR34## wherein n is 0-3; a and b when taken separately are independently hydrogen or C 1 -C 3 alkyl, and when taken together with the carbon to which they are bonded form a C 3 -C 7 carbocyclic ring; R'" is hydroxy, C 1 C 4 alkoxy, amino, or OR°, wherein R° is indanyl, phthalidyl, or an acyloxymethyl group of the formula --CH 2 --O--C(O)--R 2 wherein R 2 is C 1 -C 4 alkyl or phenyl; or R° is a carboxy-protecting group; or R" is an N-substituted carbamoyl group of the formula ##STR35## wherein R"" is C 1 -C 4 alkyl, phenyl or C 1 -C 3 alkyl substituted by phenyl; .sup.⊕ R 1 is a bicyclicpyridinium group selected from the group consisting of a thienopyridinium group of the formulas ##STR36## or a furopyridinium group of the formulas ##STR37## and said thienopyridinium and said furopyridinium wherein either or both of the hetero rings thereof is substituted by one or two C 1 -C 4 alkyl, halogen, carboxy, carbamoyl, C 1 -C 4 alkoxycarbonyl groups, --SO 3 H, hydroxy, C 1 -C 4 alkoxy, amino, mono-(C 1 -C 4 alkyl)amino, di-(C 1 -C 4 alkyl)amino, C 2 -C 4 alkanoylamino, aminosulfonyl, cyano, formyl, trifluoromethyl, or a hydroxyamido group of the formula ##STR38## wherein R 3 and R 4 independently are hydrogen or C 1 -C 4 alkyl; and the pharmaceutically acceptable non-toxic salts thereof.
Claim 3
Dependent Claim 20 words
The compound of claim 1 wherein .sup.⊕ R 1 is an unsubstituted or substituted thieno[2,3-b]pyridinium-7-yl, thieno[3,2-b]pyridinium-4-yl, thieno[2,3-c]pyridinium-6-yl, or thieno[3,2-c]pyridinium-5-yl group.
Claim 4
Dependent Claim 12 words
The compound of claim 2 wherein R' is 2-aminopyrimidin-5-yl, 4-aminopyrimidin-2-yl, or 6-aminopyridin-2-yl.
Claim 5
Dependent Claim 11 words
The compound of claim 3 wherein R' is the 6-aminopyridin-6-yl group.
Claim 6
Dependent Claim 11 words
The compound of claim 2 wherein R' is 3-aminopyrazol-5-yl or pyrazol-5-yl.
Claim 7
Dependent Claim 12 words
The compound of claim 2 wherein R' is 2-aminothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, or 2-aminoisothiazol-4-yl.
Claim 8
Dependent Claim 11 words
The compound of claim 6 wherein R' is the 2-aminothiazol-4-yl group.
Claim 9
Dependent Claim 23 words
The compound of claim 7 wherein R" is carboxy-substituted alkyl or carboxy-substituted cycloalkyl and R'" is hydroxy or C 1 -C 4 alkoxy.
Claim 10
Dependent Claim 9 words
The compound of claim 8 wherein R" is 2-carboxyprop-2-yl.
Claim 11
Dependent Claim 18 words
The compound of claim 9 wherein .sup.⊕ R 1 is a substituted or unsubstituted thieno[2,3-c]pyridinium or thieno[3,2-c]pyridinium group.
Claim 12
Dependent Claim 13 words
The compound of claim 7 wherein R" is C 1 -C 4 alkyl.
Claim 13
Dependent Claim 9 words
The compound of claim 11 of the formula ##STR39##
Claim 14
Dependent Claim 9 words
The compound of claim 11 of the formula ##STR40##
Claim 15
Dependent Claim 9 words
The compound of claim 11 of the formula ##STR41##
Claim 16
Dependent Claim 9 words
The compound of claim 11 of the formula ##STR42##
Claim 17
Dependent Claim 23 words
The compound of claim 7 wherein the thienopyridinium group is substituted on the thieno ring by C 1 -C 4 alkyl or carboxy.
Claim 18
Dependent Claim 9 words
The compound of claim 16, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylthieno[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carobxylate.
Claim 19
Dependent Claim 9 words
The compound of claim 16, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-carboxythieno[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 20
Dependent Claim 9 words
The compound of claim 16, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-yl)oxyiminoacetamido]-3-(2-carboxythieno[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 21
Dependent Claim 16 words
The compound of claim 1 wherein .sup.⊕ R 1 is a substituted or unsubstituted furopyridinium group.
Claim 22
Dependent Claim 12 words
The compound of claim 20 wherein R' is 2-aminopyrimidin-5-yl, 4-aminopyrimidin-2-yl, or 6-aminopyrimidin-2-yl.
Claim 23
Dependent Claim 11 words
The compound of claim 20 wherein R' is 3-aminopyrazol-5-yl or pyrazol-5-yl.
Claim 24
Dependent Claim 12 words
The compound of claim 20 wherein R' is 2-aminothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, or 2-aminoisothiazol-4-yl.
Claim 25
Dependent Claim 9 words
The compound of claim 23 wherein R' is 2-aminothiazol-4-yl.
Claim 26
Dependent Claim 15 words
The compound of claim 24 wherein R" is a carboxy-substituted alkyl or carboxy-substituted cycloalkyl group.
Claim 27
Dependent Claim 9 words
The compound of claim 25 wherein R" is 2-carboxyprop-2-yl.
Claim 28
Dependent Claim 13 words
The compound of claim 24 wherein R" is C 1 -C 4 alkyl.
Claim 29
Dependent Claim 9 words
The compound of claim 27 of the formula ##STR43##
Claim 30
Dependent Claim 9 words
The compound of claim 27 of the formula ##STR44##
Claim 31
Dependent Claim 9 words
The compound of claim 27 of the formula ##STR45##
Claim 32
Dependent Claim 9 words
The compound of claim 27 of the formula ##STR46##
Claim 33
Dependent Claim 20 words
The compound of claim 24 wherein the furopyridinium is substituted on the furo ring by C 1 -C 4 alkyl.
Claim 34
Dependent Claim 9 words
The compound of claim 32, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[3,2-b]pyridinium-4-ylmethyl)-3-cephem-4-carboxylate.
Claim 35
Dependent Claim 9 words
The compound of claim 32, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[2,3-c]pyridinium-6-ylmethyl)-3-cephem-4-carboxylate.
Claim 36
Dependent Claim 16 words
The compound of claim 24 wherein the furopyridinium is substituted on the furo ring by carboxy.
Claim 37
Dependent Claim 25 words
A pharmaceutical composition comprising an effective amount of an antibiotic compound of claim 1 wherein R is an acyl group and a pharmaceutically acceptable carrier.
Claim 38
Dependent Claim 11 words
The composition of claim 36 wherein R' is the 2-aminothiazol-4-yl group.
Claim 39
Dependent Claim 34 words
The composition of claim 37 wherein the thienopyridinium or furopyridinium group is substituted on the thieno or furo ring by carboxy or C 1 -C 4 alkyl and wherein R" is 2-carboxyprop-2-yl or methyl.
Claim 40
Dependent Claim 11 words
The composition of claim 38 wherein the antibiotic compound is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-carboxythieno[3,2-c]-pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 41
Dependent Claim 11 words
The composition of claim 38 wherein the antibiotic compound is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 42
Dependent Claim 11 words
The composition of claim 38 wherein the antibiotic compound is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-carboxyfuro[2,3-c]pyridinium-6-ylmethyl)-3-cephem-4-carboxylate.
Claim 43
Dependent Claim 48 words
A method for treating bacterial infections in a mammal which comprises administering to said mammal in an effective dose of between about 100 mg. and about 2 g. of an antibiotic compound of claim 1 wherein R is an acyl group or a pharmaceutically acceptable non-toxic salt thereof.
Claim 44
Dependent Claim 10 words
The method of claim 42 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(thieno[3,2-c]pyridinium-7-ylmethyl)-3-cephem-4-carboxylate.
Claim 45
Dependent Claim 10 words
The method of claim 42 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(furo[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 46
Dependent Claim 10 words
The method of claim 42 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(furo[2,3-c]pyridinium)-3-cephem-4-carboxylate.
Claim 47
Dependent Claim 33 words
The method of claim 42 wherein the thienopyridinium or furopyridinium is substituted on the thieno or furo ring by carboxy or C 1 -C 4 alkyl and wherein R" is 2-carboxyprop-2-yl or methyl.
Claim 48
Dependent Claim 10 words
The method of claim 46 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-carboxythieno[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 49
Dependent Claim 10 words
The method of claim 46 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-methylfuro[2,3-c]pyridinium-6-ylmethyl)-3-cephem-4-carboxylate.
Claim 50
Dependent Claim 10 words
The method of claim 46 wherein the antibiotic is syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-carboxyfuro[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.
Claim 51
Dependent Claim 50 words
An acid salt of the compound of claim 1 of the formula ##STR47## wherein R 7 is hydrogen, indanyl, phthalidyl, or an acyloxymethyl group of the formula ##STR48## wherein R 2 is C 1 -C 4 alkyl or phenyl; and A is a chloride, bromide, iodide, sulfate, or phosphate anion.
Claim 52
Dependent Claim 9 words
The compound of claim 11, said compound being syn-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(2-aminothieno[3,2-c]pyridinium-5-ylmethyl)-3-cephem-4-carboxylate.

References Cited (Backward Citations)

US4278671A Cited
US4278793A Cited
US4267176A Cited
US4258041A Cited
GB2098216A Cited
US4406898A Cited
US4430499A Cited

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1988-02-26 1988-08-27 1989-02-26 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1992-02-26 1992-08-27 1993-02-26 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 1996-02-26 1996-08-27 1997-02-26 $7700.00 Window Closed / Lapsed

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