Phosphorus-containing beta-lactams

Claim 2

A 0-lactam having a ~P substituent 6 . in the 1-position and an amino substituent or an acylamino substituent in the 3-position, or a salt thereof; wherein R^ is hydrogen, alkyl, substituted alkyl, phenyl, or substituted phenyl; and Rg is hydroxy, alkoxy, (substituted alkyl)oxy, phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, amino, substituted amino, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl) thio, 1-(ethoxycarbonyloxy))ethoxy, 1,3- 0 M dihydro-3-oxo-l-isobenzofuranyloxy, R"-C-0-CH-0-, 0 R' II R"-C-0-CHo-CH„-0-, or R'" -C=C-CH-0-, 22 11 'iv 0 0 R \ / C II o wherein R' is hydrogen or alkyl, R" is alkyl or phenyl, R"' is hydrogen, methyl or phenyl, and R1V is hydrogen or together with R"1 is -(CI^)^-or -(CH2)5~.

Claim 3

A g-lactam in accordance with claim 1 „ . °/°E5 having a -P^ substituent in.the 1-position, an amino , 6 substituent or acylamino substituent in the 3-position, and a methoxy substituent in the 3-position, or a salt thereof. -125- 200155

Claim 4

A 0-lactam in accordance with, claim 1 II ^ having a -P. substituent/ wherein R- is methyl or ethyl, OH 3 in the 1-position and an amino substituent or acylamino substituent in the 3-position, or a salt thereof.

Claim 5

A $-lactam in accordance with claim 1 having the formula s2 h R, -NH-C C-R, 1 I I s/~ N-P 0 6 or a salt thereof, wherein R1 is acyl; R2 is hydrogen or methoxy; R_ and R. are the same or different and 3 4 each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R^ and R^ is hydrogen and the other is alkoxycarbonyl, alken-l-yl, alkyn-l-yl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CHjX^ (wherein X^ is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, halogen, benzylthio, (substituted phenyl)methylthio, triphenylmethylthio, cyano or mercapto), -S-X2 or ~0-X2 (wherein X2 is alkyl, phenyl, substituted phenyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl), X, X- I 3 | 3 or -S-C-X. or -O-C-X. (wherein one of X-, and X„ I 4 | 4 3 4 Xc X„ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with the carbon atom to which, they are attached form a cycloalkyl group; and X^ is forrnyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)- carbonyl, or cyano; R5 is hydrogen, alkyl, substituted alkyl, phenyl, or substituted phenyl; and Rg is hydroxy, alkoxy, (substituted alkyl)- oxY/ phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, amino, substituted amino, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl)thio, 1-(ethoxycarbonyloxy)ethoxy, 1,3- 0 II dihydro-3-oxo-l-isobenzofuranyloxy, R"-C-0-CH-0-, 0 R1 R"-C-0-CHo-CH_-0- , or R"'—C=C-CH-0- , 22 1 1 1 iv 0 0 R \ / C II o wherein R' is hydrogen or alkyl, R" is alkyl or phenyl, R'" is hydrogen, methyl or phenyl, and iv R is hydrogen or together with R"' is -(CH2)3-or -(CH2)5-. GC171a -127- 0,01-5 5. X

Claim 6

A 8-lactam in accordance with claim 4 wherein anc^ ^4 are ^e same or different and each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl,

Claim 7

A 8-lactam in accordance with claim 4 wherein one of R^ and is hydrogen and the other is methyl.

Claim 8

A 8-lactam in accordance with claim 4 wherein R^ is (Z)-TC2-amino-4-thiazolyl)(methoxyimino) acetyl] .

Claim 9

A 8-lactam in accordance with claim 4 wherein R^ is (Z)-C(2-amino-4-thiazolyl)] (1-carboxy-l-methylethoxy)imino]acetyl].

Claim 10

A 8-lactam in accordance with claim 4 having the formula 14 R, -NH-CH C-R-, 1 I I g>R5 C N-P^ O OH , or a salt thereof, wherein R^ is methyl or ethyl.

Claim 11

A 8-lactam in accordance with claim 9 wherein R-. and R. are the same or different and 3 4 each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl.

Claim 12

A 8-lactam in accordance with claim 9 wherein R^ and R^ each is hydrogen.

Claim 13

A 8-lactam in accordance with claim 9 wherein one of R^ and R^ is hydrogen and the other is methyl. 128 - 200155

Claim 14

A 0-lactam in accordance with claim 4 having the formula or a salt thereof, wherein R,. is R^-C-O-CH-O- . ' . R<

Claim 15

The 0-lactam in accordance with claim 4, £3S (Z) ]-f3-L[ (2-amino-4-th.iazolyl)(methoxyimino)-acetyl]amino]-2-oxo-l-azetidinyl]phosphonic acid, methyl ester.

Claim 16

The 0-lactam in accordance with claim 4, a salt of £3SCZ)]-£3-[I(2-amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-oxo-l-azetidinyl]-phosphonic acid, methyl ester.

Claim 17

The 0-lactam in accordance with claim 4, a salt of f3S (Z) ]-2-C £tl-^2-aunino-4-rthiazolyl)-2- l[1-(hydroxymethoxyphosphinyl)-2-oxo-3-azetidinyl]-amino]-2-oxoethyiidene] amino]oxy]-2-methyl propanoic acid.

Claim 18

The 0-lactam in accordance with claim 4, C3S-[3a (Z) ,4 0] J -2-rtIl"" (2-amino-4-thiazolyl) -2- [[4-methyl-2-oxo-l-(hydroxymethoxyphosphinyl)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid.

Claim 19

The 0-lactam in accordance with claim 4, a salt of £3S-£3a(Z),40]]-2-[([1-(2-amino-4-thiazolyl)-2-£[1-(hydroxyethoxyphosphinyl)-4-. methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]-2-methylpropanoic acid. G 0 II -129-

Claim 20

The g-lactam in accordance with claim 4, £3S-[3a(Z),4 8]]-2-[[£1-(2-amino-4-thiazolyl)-2- [C1— ££(2,2-dimethyl-l-oxopropoxy)methoxy]methoxy-phosphinyl]-2-methyl-4-oxo-3-azetidinyl]amino]-2-oxoethylidene] amihoj oxy]-2-methylpropanoic acid.

Claim 21

The 8-lactam in accordance with claim 4, £3S (Z)3-[£3-££(2-amino-4-thiazolyl) (methoxyimino)-acetyl]amino]-2-oxo-l-azetidinyl]phosphonic acid, (2,2-dimethyl-l-oxopropoxy)methyl ester, methyl ester.

Claim 22

The 8-lactam in accordance with claim 4, a salt of [3S(Z)]-2-[££l-(2-amino-4-thiazolyl)-2-C[l-(ethoxyhydroxyphosphinyl)-2-oxo-3-azetidinyl]- amino]-2-oxoethylidene]amino]oxy] -2-methyl- propanoic acid.

Claim 23

A g-lactam in accordance with claim 1 having the formula wherein R2 is hydrogen or methoxy; and R^ are the same or different and each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R^ and R^ is hydrogen and the other is alkoxycarbonyl, alken-l-yl, alkyn-l-yl, 2-phenylethenyl, 2-phenylethynyl, halogen, carboxyl, -CI^X^ (wherein X^ is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, halogen, benzylthio, NH -130- (substituted phenyl)methylthio, triphenylmethylthio, cyano or mercapto), -S-X2 or -0-X2 (wherein X2 is alkyl, phenyl, substituted phenyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, X_ X, I 3 I 3 or heteroarylcarbonyl), or -S-C-X^ or -O-C-X^ X5 X5 (wherein one of X^ and X^ is hydrogen and the other is hydrogen or alkyl, or X^ and X^ when taken together with, the carbon atom to which they are attached form a cycloalkyl group; and X,. is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; R,. is hydrogen, alkyl, substituted alkyl, phenyl, or substituted phenyl; and Rg is hydroxy, alkoxy, (substituted alkyl)- oxy, phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, amino, substituted amino, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl)thio, 1-(ehtoxycarbonyloxy)ethoxy, 1,3- O U dihydro-3-oxo-l-isobenzofuranyloxy, R"-C-0-CH-0- O R' II R"-C-0-CH--CH„-0- , or R"' -C=C—CH-0- 00 III 19 R1V C II I 1 r gel 7 la •• -131- wherein R1 is hydrogen or alkyl, R" is alkyl or phenyl, R'" is hydrogen, methyl or phenyl, and R1V is hydrogen or together with R'" is -(CH^^-or -CCH2)5- .

Claim 24

A 8-lactam in accordance with claim 22 wherein R2 is hydrogen.

Claim 25

A 8-lactam having the formula R, -NH ?2 §4 C-R, I I c n-P 3 0 CI wherein R^ is acyl; R2 is hydrogen or methoxy; R_ and R. are the same or different and 3 4 each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R^ and R4 is hydrogen and the other is alkoxycarbonyl, alken-l-yl, alkyn-l-yl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X^ (wherein X^ is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, halogen, benzylthio, (substituted phenyl)methylthio triphenylmethylthio, cyano or mercapto), -S-X2 or -0-X2 (wherein X2 is alkyl, phenyl, substituted phenyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl), or X. X 3 13 -S-C-X^ or -O-C-Xj (wherein one of X^ and X^ *5 *5 is hydrogen and the other is hydrogen or alkyl, -132- GC171Q- 200155 or X^ and when taken together with the carbon atom to which they are attached form a cycloalkyl group; and X^ is formyl, alkanoyl/ phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)-carbonyl, or cyano; and R is alkoxy, (substituted alkyl)oxy, ct phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl)thio or O II R"-C-0-CH-CH-0-. SCI 7 la- -133- 155

Claim 26

A 8-lactam having the formula R, -NH ?2 §4 C-R, I I c n-P 3 0 CI wherein R^ is acyl; R2 is hydrogen or methoxy; R_ and R. are the same or different and 3 4 each is hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R^ and R4 is hydrogen and the other is alkoxycarbonyl, alken-l-yl, alkyn-l-yl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2X^ (wherein X^ is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, halogen, benzylthio, (substituted phenyl)methylthio triphenylmethylthio, cyano or mercapto), -S-X2 or -0-X2 (wherein X2 is alkyl, phenyl, substituted phenyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl), or X. X 3 13 -S-C-X^ or -O-C-Xj (wherein one of X^ and X^ *5 *5 is hydrogen and the other is hydrogen or alkyl, -132- GC171Q- 200155 or X^ and when taken together with the carbon atom to which they are attached form a cycloalkyl group; and X^ is formyl, alkanoyl/ phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)-carbonyl, or cyano; and R is alkoxy, (substituted alkyl)oxy, ct phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl)thio or O II R"-C-0-CH-CH-0-. SCI 7 la- -133- 155

Claim 27

A process for preparing a 0 it ^ R5 8-lactam having a -P^R substituent in the 1-position and an amino substituent or an acylamino substituent in the 3-position, or a salt thereof; wherein R^ is hydrogen, alkyl, substituted alkyl, phenyl, or substituted phenyl; and Rg is hydroxy, alkoxy, (substituted alkyl)oxy, phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, amino, substituted amino, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl) thio, 1-(ethoxycarbonyloxy))ethoxy, 1,3- 0 II dihydro-3-oxo-l-isobenzofuranyloxy, R"-C-O-CH-O-, 0 r' II R"-C-0-CHo-CH„~0-, or R,M -C=C-CH—0-, ' ' 'iv 0 O R \ / c II o wherein R' is hydrogen or alkyl, R" is alkyl or phenyl, RIM is hydrogen, methyl or phenyl, and Rlv is hydrogen or together with R,M is -(CI^)^-or -(CH2)5- characterized by phosphorylating a corresponding 3-lactam having a hydrogen atom in the 1-position with a group. "P\ OR^: , 29 SiAft 3982 '

Claim 28

A process for preparing a 0 it ^ R5 8-lactam having a -P^R substituent in the 1-position and an amino substituent or an acylamino substituent in the 3-position, or a salt thereof; wherein R^ is hydrogen, alkyl, substituted alkyl, phenyl, or substituted phenyl; and Rg is hydroxy, alkoxy, (substituted alkyl)oxy, phenyloxy, (substituted phenyl)oxy, alkyl, substituted alkyl, phenyl, substituted phenyl, heteroaryl, amino, substituted amino, alkylthio, (substituted alkyl)thio, phenylthio, (substituted phenyl) thio, 1-(ethoxycarbonyloxy))ethoxy, 1,3- 0 II dihydro-3-oxo-l-isobenzofuranyloxy, R"-C-O-CH-O-, 0 r' II R"-C-0-CHo-CH„~0-, or R,M -C=C-CH—0-, ' ' 'iv 0 O R \ / c II o wherein R' is hydrogen or alkyl, R" is alkyl or phenyl, RIM is hydrogen, methyl or phenyl, and Rlv is hydrogen or together with R,M is -(CI^)^-or -(CH2)5- characterized by phosphorylating a corresponding 3-lactam having a hydrogen atom in the 1-position with a group. "P\ OR^: , 29 SiAft 3982 '