Nova Patents
EP0127902A2

Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents.

Abstract

Novel aminomethyl oxooxazolidinyl benzene derivatives, including the sulfides, sulfoxides, sulfones and sulfonamides, such as (I)-N-[3-[4- (methylsulfonyl) phenyl] -2- oxooxazolidin -5- ylmethyl] carbamic acid, methyl ester possess useful antibacterial activity.

EP0127902A2, drawing sheet 1
Sheet 1 of 89

Term

Term ended

Projected expiry passed 5 June 2004, 22.3 years ago.

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10 claims: 5 independent, 5 dependent

  1. 1
    A compound of the formula wherein, for the ℓ, and mixtures of the d and ℓ stereoisomers of the compound. A is -NO 2 , -S(O) n R 1 , -S(O) 2 -N=S(O) p R 2 R 3 . - S H. -COR 5 , -CONR 5 R 6 , -CN, -OR 5 , -NR 5 R 6 . alkyl of 1 to 5 carbons, optionally substituted with one or more halogen atoms, alkenyl of 2-5 carbons or cycloalkyl of 3-8 carbons:R 1 is C 1 -C 4 alkyl, optionally substituted with one or more halogen atoms. CN. NR 5 R 6 or CO 2 R 8 ;C 2 -C 4 alkenyl;-NR 9 R 10 ;- N 3 : - N X 2 -: NR 9 x - - NXZ + : R 2 and R 3 are independently C 1 -C 2 alkyl or, taken together, are -(CH 2 ) q -: R 4 is alkyl of 1-4 carbons, optionally substituted with one or more halogens: R 5 and R 6 are independently H, alkyl of 1- 4 carbons or cycloalkyl of 3-8 carbons: R 7 is -NR 5 R 6 or -OR 5 : R 8 is H or alkyl of 1-4 carbons: R 9 is H. C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl: R 10 is H. C 1 -C 4 alkyl. C 2 -C 4 alkenyl. C 3 -C 4 cycloalkyl. -OR 8 or -NR 11 R. 11a R 11 and B 11a are independently H or C 1 -C 4 alkyl, or taken together, are -(CH 2 ) r -: X is Cl. Br or I: Y is H. F, Cl. Br or NO 2 . or A and Y taken together can be -O(CH 2 ) t O-: Z is a physiologically acceptable cation: n is 0, 1 or 2: p is 0 or 1: q is 3. 4 or 5: r is 4 or 5: t is 1, 2 or 3: B is -NH 2 , or N 3 ;R 12 is H. C 1 -C 10 alkyl or C 3 -C 8 cycloalkyl;R 13 is H;C 1 -C 4 alkyl optionally substituted with one or more halogen atoms: C 2 -C 4 alkenyl: C 3 -C 4 cycloalkyl: phenyl: -CH 2 OR 15 : -CH(OR 16 )OR 17 : -CH 2 S(O) v R 14 ;-OR 18 ;-SR 14 : -CH 2 N 3 ;the aminoalkyl groups derived from α-amino acids such as glycine, L-alanine. L-cysteine, L-proline, and O-alanine: -NR 19 R 20 : or C(NH 2 )R 21 R 22: R 14 is C 1 -C 4 alkyl, optionally substituted with one or more halogen atoms: R 15 is H or C 1 -C 4 alkyl, optionally substituted with one or more halogen atoms: R 16 and R 17 are independently C 1 -C 4 alkyl or, taken together, are -(CH 2 ) m -;R 18 is C 1 -C 4 alkyl or C 7 -C 11 aralkyl: R 19 and R 20 are independently H or C 1 -C 4 alkyl: R 21 and R 22 are independently H. C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl or, taken together, are -(CH 2 ) s -;u is 1 or 2: v is 0, 1 or 2: and m is 2 or 3: s is 2. 3. 4 or 5: or a pharmaceutically suitable salt thereof: provided that: 1) when A is CH 3 S-, then B is not 2) when A is CH 3 SO 2 -, then B is not 3) when A is H 2 NSO 2 - and B is then R 12 is H;4 ) when A is -CN. B is not -N 3 ;5) when A is (CH 3 ) 2 CH. B is not NHCOCH 2 Cl.
  2. 2
    A compound of Claim 1 wherein, for the ℓ. and mixtures of the d and ℓ stereoisomers of the compound. Y is H:A, substituted in the para position is -NO 2 , -S(O) n R 1 or -S(O) 2 -N=S(O) p R 2 R 3 : R 1 is C 1 -C 4 alkyl optionally substituted with one or more halogen atoms. C 2 -C 4 alkenyl. -NR 9 R 10 , -N 3 , -NX 2 . -NR 9 X or - - NXZ + ;R 2 and R 3 are independently C 1 -C 2 alkyl or. taken together, are -(CH 2 ) q -;R 9 is H, C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl: R 10 is H . C 1 -C 4 alkyl. C 2 -C 4 alkenyl. C 3 -C 4 cycloalkyl. -OR 8 or -NR 11 R 11a X is Cl. Br or I: Z is a physiologically acceptable cation: R 8 is H or C 1 -C 4 alkyl: R 11 and R 11a are independently H or C 1 -C 4 alkyl. or, taken together, are -(CH 2 ) r -;n is 0, 1 or 2: p is 0 or 1: q is 3. 4 or 5: r is 4 or 5: B is -NH 2 . or N 3 ;R 12 is H. C 1 -C 10 alkyl or C 3 -C 8 cycloalkyl: R 13 is H: C 1 -C 4 alkyl optionally substituted with one or more halogen atoms: C 2 -C 4 alkenyl: C 3 -C 4 cycloalkyl: phenyl: -CH 2 OR1 5 ;-CH(OR 13 )OR 14 ;-CH 2 S(O) v R 14 ;-OR 18 ;-SR 14 : the aminoalkyl groups derived from a-amino acids such as glycine. L-alanine, L-cysteine, L-proline, and D-alanine: or -NR 19 R 20 ;R 14 is C 1 -C 4 alkyl. optionally substituted with one or more halogen atoms: R 15 is H or C 1 -C 4 alkyl optionally substituted with one or more halogen atoms: R 16 and R 17 are independently C 1- C 4 alkyl or, taken together, are -(CH 2 ) m -: R 18 is C 1 -C 4 alkyl or C 7 -C 11 aralkyl: R 19 is H or C 1 -C 4 alkyl: R 20 is H or C 1 -C 4 alkyl: u is 1 or 2: v is 0. 1 or 2: and m is 2 or 3: or a pharmaceutically suitable salt thereof: provided that: 1) when A is CH 3 S-, then B is not 2) when A is CH 3 SO 2 -, then B is not 3) when A is H 2 NSO 2 - and B is then R 12 is H. 3. A compound of Claim 1 wherein Y is H: A, substituted in the para position, is -S(O) n R 1 , N0 2 . or -CH(CH 3 ) 2 ;R 1 is C 1 -C 2 alkyl optionally substituted with one or more halogen atoms or NR 5 R 6 ;R 5 is H or CH 3 : R 6 is H or CH3: n is 0, 1 or 2 when R 1 is alkyl or substituted alkyl: n is 2 when R 1 is NR 5 R 6 .
  3. 3
    4. A compound of Claim 1 wherein B is R 13 is H, CH 3 , OR 18 , CHCl 2 , CH 2 Cl or CH 2 OR 15 ; R 15 is H or C 1 -C 4 alkyl:and R 18 is C 1 -C 4 alkyl.
  4. 4
    5. A compound of Claim 1 with the stereochemical configuration wherein A is -S(O)CH 3 . -S-CH 3 , -S(O)2CH3. SO 2 NH 2 , -COCH 3 or -CH(CH 3 ) 2 .
  5. 5
    6 . A compound of Claim 1 with the stereochemical formula wherein B is
  6. 6
    7. A compound of Claim 5 wherein B is or -
  7. 7
    8. A compound of Claim selected from (ℓ)-N-[3- [4-(methylsulfonyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-carbamic acid, methyl esters (ℓ)-N-[3-[4-(methylthio)phenyl]-2-oxooxazalidin-5-ylmethyl]carbamic acid, methyl ester, (ℓ)-N-[3-[4-(methylsulfonyl)phenyl]-2-oxoaxazolidin-5-ylmethyl]-formamide, (ℓ)-N-[3-[4-(methylsulfonyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-acetamide, (ℓ)-N-[3-[4-(methylthio)phenyl]-2-oxooxazolidin-5-yimethyl]acetamide, (ℓ)-N-[3-[4-(aminosulfonyl)phenyl]-2-oxooxazolidin-5-ylmethyl]-acetamide, (ℓ)-N-[3-[4-(methylsulfinyl)phenyl]-2-oxaoxazolidin-5-ylmethyl]-acetamide, (ℓ)-2,2-dichloro-N-[3-[9-(methylsulfonyl)phenyl]-2-oxooxazoli- din-5-ylmethyl]acetamide, (ℓ)-N-[3-(4-isopropylphenyl)-2-oxooxazolidin-5-ylmethyl]-acetamide, and (ℓ)-N-[3-(4-acetylphenyl)-2-axooxazolidin-5-ylmethyl]-acetamide.
  8. 8
    9 . A compound having the formula:wherein, for the ℓ, and mixtures of the d and ℓ stereoisomers of the compound, R 12 is H, C 1 -C 10 alkyl or C 3 -C 8 cycloalkyl.
  9. 9
    10. A compound of the formula wherein, for the ℓ, and mixtures of the d and ℓ stereoisomers of the compound, R12 is H , C 1 -C 10 alkyl or C 3 -C a cycloalkyl:R 13 is H: C 1 -C 4 alkyl optionally substituted with one or more halogen atoms: C 2 -C 4 alkenyl: C 3 -C 4 cycloalkyl: phenyl: -CH 2 OR 15 ;-CH(OR 16 )OR 17 ;-CH 2 S(O) v R 14 ;-OR 18 ;-SR 14 ;the aminoalkyl groups derived from a-amino acids such as glycine, L-alanine, L-cysteine. L-proline, and D-alanine: -NR 19 R 20 ;or C(NH 2 )R 21 R 22 ;R 14 is C 1 -C 4 alkyl, optionally substituted with one or more halogen atoms: R 15 is H or C 1 -C 4 alkyl. optionally substituted with one or more halogen atoms: R 16 and R 17 are independently C 1 -C 4 alkyl or, taken together. are -(CH 2 ) m -;R 18 is C 1 -C 4 alkyl or C 7 -C 11 aralkyl: R 19 and R 20 are independently H or C 1 -C 4 alkyl: R 21 and R 22 are independently H. C 1 -C 4 alkyl. C 3 -C 6 cycloalkyl phenyl or, taken together, are -(CH 2 ) s -;m is 2 or 3: v is 0. 1 or 2. s is 2. 3. 4 or 5.
  10. 10
    11. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an antibacterially effective amount of at least one comoound of claims 1 to 8.
Independent claims10