2-Oxo-1-(aminocarbonylaminosulfonylaminocarbonyl)azetidines

Claim 2

A compound having the formula or a salt thereof, wherein R 1 is acyl; R 2 is hydrogen or methoxy; R 3 and R 4 are the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or a 5,6 or 7-membered heterocycle or one of R 3 and R 4 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH 2 X 1 , -S-X 2 , X 1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, arylsulfonyloxy,aryl, cyano, -S-X 2 or -O-X 2 ; X 2 is alkyl, substituted alkyl, aryl, arylalkyl, alkanoyl, substituted alkanoyl, arylcarbonyl or heteroarylcarbonyl; one of X 3 and X 4 is hydrogen and the other is hydrogen or alkyl, or X 3 and X 4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X 5 is formyl, alkanoyl, arylcarbonyl, arylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -CH 2 -CH=CH-, -(CH 2 )- m , -(CH 2 ) m ,-O-, -(CH 2 ) m ,-NH-, -(CH 2 ) m ,-S-CH 2 -, or -(CH 2 ) m -O-CH 2 -; m is 0, 1, 2 or 3; m' is 1 or 2; X 6 and X 7 are the same or different and each is hydrogen or alkyl, or X 6 is hydrogen and X 7 is amino, substituted amino, acylamino or alkoxy;. R 5 is hydrogen, alkyl or aryl; R 6 is hydrogen, alkyl, aryl, a 5,6 or 7-membered heterocycle, -NR 7 R 8 , or -(CH 2 ) n -X wherein n is 1,2,3 or 4 and X is halogen, aryl, alkoxy, aryloxy or -NR 9 R 10 ; R 7 and R 8 are the same or different and each is hydrogen, alkyl or aryl, or R 7 is hydrogen and R 8 is a 5,6 or 7-membered heterocycle or -(CH 2 ) n -Y wherein n is 1,2,3 or 4 and Y is alkoxy, amino, alkylthio or halogen; and R 9 and R 10 are the same or different and each is hydrogen or alkyl, or R 9 is hydrogen and R 10 is a 5,6 or 7-membered heterocycle.

Claim 3

A compound havinq the formula wherein R 2 , R 3 , R 4 , R 5 and R 6 are defined in claim 1 and A 1 -NH- is a protected amino group or A 1 - is hydrogen.

Claim 4

A compound in accordance with claims 1 and 2. wherein R 2 is hydrogen.

Claim 5

A compound in accordance with claims 1 and 2 wherein R 5 is hydrogen.

Claim 6

A compound in accordance with claims 1 and 2' wherein R 3 and R 4 are each hydrogen.

Claim 7

. A compound in accordance with claims 1 and 2 wherein R 2 , R3, R 4 and R 5 are each hydrogen.

Claim 8

A compound in accordance with claim 6: wherein R 6 is hydrogen.

Claim 9

A compound in accordance with claim 6 wherein R 6 is alkyl.

Claim 10

9 . A compound in accordance with claim 6 wherein R 6 is aryl.

Claim 11

A compound in accordance with claim 6 wherein R 6 is a.5,6 or 7-membered heterocycle.

Claim 12

A compound in accordance with claim 6 wherein R 6 is 4-alkyl-2,3-dioxo-1-piperazinyl.

Claim 13

A compound in accordance with claim 6 wherein R 6 is 2-oxo-1-imidazolidinyl.

Claim 14

A compound in accordance with claim 6 wherein R 6 is 3-alkyl-2-oxo-l-imidazolidinyl.

Claim 15

A compound in accordance with claim 6 wherein R 6 is 3-(substituted alkyl)-2-oxo-l-imidazolidinyl.

Claim 16

A compound in accordance with claim 14 wherein R 6 is 3-(2-aminoethyl)-2-oxo-l-imidazolidinyl.

Claim 17

A compound in accordance with claim 6 wherein R 1 is (Z)-2-amino-α-(alkoxyimino)-4-thiazoleacetyl.

Claim 18

A compound in accordance with claim 16 wherein R 1 is (Z)-2-amino-α-(methoxyimino)-4-thiazoleacetyl.

Claim 19

A compound in accordance with claim 16 wherein R 1 is (Z)-2-amino-α-[(1-carboxy-1-methylethoxy)imino]-4-thiazoleacetyl

Claim 20

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 21

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 22

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]-amino] sulfonyl]amino] carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 23

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(3-ethyl-2-oxo-1-imidazolidinyl)carbonyl]-amino] sulfonyl]amino] carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 24

. [3S(Z)]-2-[[[2-[[1-[[[[[[3-(2-aminoethyl)-2-oxo-1-imidazolidinyl]carbonyl] amino] sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1- . (2-amino-4-thiazolyl)-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 25

. [3S(Z)]-2-[[[2-[[1-[[[[[[3-(2-aminoethyl)-2-oxo-1-imidazolidinyl]carbonyl] amino] sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1- . (2-amino-4-thiazolyl)-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 26

[3S(Z)]-2-[[[2-[[1-[[[[[[3-(2-aminoethyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 27

[3S(Z)]-2-[[[2-[[1-[[[[[[3-(2-aminoethyl)-2-oxo-1-imidazolidinyl]carbonyl]amino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]-oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 28

[3S(Z)]-2-[[[2-[[1-[[[[[(3-methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methyl- propanoic acid, or a salt thereof.

Claim 29

[3S(Z)]-2-[[[2-[[1-[[[[[(3-methyl-2-oxo-1-imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methyl- propanoic acid, or a salt thereof.

Claim 30

[3S(Z)]-2-[[[2-[[1-[[[[[(3-methyl-2-oxo-1 imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 31

[3S(Z)]-2-[[[2-[[1-[[[[[(3-methyl-2-oxo-1 imidazolidinyl)carbonyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 32

[3S(Z)]-2-[[[2-[[1-[[[[[(2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3- azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2- . oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 33

[3S(Z)]-2-[[[2-[[1-[[[[[(2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3- azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2- . oxoethylidene]amino]oxy]-2-methylpropanoic acid, or a salt thereof.

Claim 34

[3S(Z)]-2-[[[2-[[1-[[[[[(2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3- azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 35

[3S(Z)]-2-[[[2-[[1-[[[[[(2-oxo-1-imidazolidinyl)-carbonyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3- azetidinyl]amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, dipotassium salt.

Claim 36

A compound in accordance with claims 1 to 26 for use in treating bacterial infections.

Claim 37

Pharmaceutical compositions comprising at least one compound in accordance with claim 1 and usual carriers, additives and adjuvants.

Claim 38

A process for preparing a compound having the formula or a salt thereof, wherein R 1 is acyl; R2 is hydrogen or methoxy; R 3 and R 4 are the same or different and . each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or a 5,6 or 7-membered heterocycle or one of R 3 and R 4 is hydrogen and the other is 'azido, halomethyl, dihalomethyl,. trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH 2 X 1 , -S-X 2 , X 1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, arylsulfonyloxy,aryl, cyano, -S-X 2 or -O-X 2 ; X 2 is alkyl, substituted alkyl, aryl, arylalkyl, alkanoyl, substituted alkanoyl, arylcarbonyl or heteroarylcarbonyl; one of X 3 and X 4 is hydrogen and the other is hydrogen-or alkyl, or X 3 and X 4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X 5 is formyl, alkanoyl, arylcarbonyl, arylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -CH 2 -CH = CH-, -(CH 2 )- m , -(CH 2 ) m -O-, -(CH 2 ) m ,-NH-, -(CH 2 ) m ,-S-CH 2 -, or -(CH 2 ) m -O-CH 2 -; m is 0, 1, 2 or 3; m' is 1 or 2; X 6 and X 7 are the same or different and each is hydrogen or alkyl, or X 6 is hydrogen and X 7 is amino, substituted amino, acylamino or alkoxy; R 5 is hydrogen, alkyl or aryl; R 6 is hydrogen, alkyl, aryl, a 5,6 or 7-membered heterocycle, -NR 7 R 8 , or -(CH 2 ) n -X wherein n is 1,2,3 or 4 and X is halogen, aryl, alkoxy, arylox y or -NR 9 R 10 ; R 7 and R 8 are the same or different and each is hydrogen, alkyl or aryl, or R 7 is hydrogen and R 8 is a 5,6 or 7-membered heterocycle or -(CH 2 ) n -Y wherein n is 1,2,3 or 4 and Y is alkoxy, amino, alkylthio or halogen; and R 9 and R 10 are the same or different and each is hydrogen or alkyl, or R 9 is hydrogen and R 10 is a 5,6 or 7-membered heterocycle, which comprises reacting a β-lactam having the formula wherein R 2 , R 3 and R 4 are as previously defined and Ri is acyl (R l ) as previously defined or the group R 1 -NH is a protected amino group with an isocyanate having the formula or sequential segments thereof wherein R 5 and R 6 are as previously defined, and where R 1 -NH- is a protected amino group removing said protecting group and acylating with the appropriate acylating group to form the desired product.

Claim 39

A process for preparing a compound having the formula or a salt thereof, wherein R 1 is acyl; R2 is hydrogen or methoxy; R 3 and R 4 are the same or different and . each is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or a 5,6 or 7-membered heterocycle or one of R 3 and R 4 is hydrogen and the other is 'azido, halomethyl, dihalomethyl,. trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH 2 X 1 , -S-X 2 , X 1 is azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, arylsulfonyloxy,aryl, cyano, -S-X 2 or -O-X 2 ; X 2 is alkyl, substituted alkyl, aryl, arylalkyl, alkanoyl, substituted alkanoyl, arylcarbonyl or heteroarylcarbonyl; one of X 3 and X 4 is hydrogen and the other is hydrogen-or alkyl, or X 3 and X 4 when taken together with the carbon atom to which they are attached form a cycloalkyl group; X 5 is formyl, alkanoyl, arylcarbonyl, arylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl, or cyano; A is -CH=CH-, -CH 2 -CH = CH-, -(CH 2 )- m , -(CH 2 ) m -O-, -(CH 2 ) m ,-NH-, -(CH 2 ) m ,-S-CH 2 -, or -(CH 2 ) m -O-CH 2 -; m is 0, 1, 2 or 3; m' is 1 or 2; X 6 and X 7 are the same or different and each is hydrogen or alkyl, or X 6 is hydrogen and X 7 is amino, substituted amino, acylamino or alkoxy; R 5 is hydrogen, alkyl or aryl; R 6 is hydrogen, alkyl, aryl, a 5,6 or 7-membered heterocycle, -NR 7 R 8 , or -(CH 2 ) n -X wherein n is 1,2,3 or 4 and X is halogen, aryl, alkoxy, arylox y or -NR 9 R 10 ; R 7 and R 8 are the same or different and each is hydrogen, alkyl or aryl, or R 7 is hydrogen and R 8 is a 5,6 or 7-membered heterocycle or -(CH 2 ) n -Y wherein n is 1,2,3 or 4 and Y is alkoxy, amino, alkylthio or halogen; and R 9 and R 10 are the same or different and each is hydrogen or alkyl, or R 9 is hydrogen and R 10 is a 5,6 or 7-membered heterocycle, which comprises reacting a β-lactam having the formula wherein R 2 , R 3 and R 4 are as previously defined and Ri is acyl (R l ) as previously defined or the group R 1 -NH is a protected amino group with an isocyanate having the formula or sequential segments thereof wherein R 5 and R 6 are as previously defined, and where R 1 -NH- is a protected amino group removing said protecting group and acylating with the appropriate acylating group to form the desired product.

Claim 40

A process for preparing a compound of the formula wherein R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1 and A 1 -NH- is a protected amino group or A 1 - is hydrogen characterized by reacting a compound of the formula wherein the group A 1 -NH- is a protected amino group with an isocyanate having the formula or sequential segments thereof to form a product wherein A 1 -NH- is a protected amino group and removing said protecting group to form a product wherein A l - is hydrogen.