US 5,801,242 A · Process for making quinolonyl lactam antimicrobials and novel intermediate compounds

Abstract

The present invention provides processes for making compounds of the structure (Q--L.sup.1)--L--(L.sup.2 --B) wherein (I) Q is a quinolone moiety; (II) B is a lactam moiety; and (III) L, L.sup.1, and L.sup.2 together comprise a linking moiety; comprising the steps of: (1) coupling a compound of Formula (III) with a lactam-containing compound to form an intermediate compound; and (2) cyclizing the intermediate by reaction with an organosilicon compound to give a compound of the formula (Q--L.sup.1)--L--(L.sup.2 --B). Preferably, the process additionally comprises a step prior to the coupling step, wherein protected forms of the compound of Formula (III) and the lactam compound are formed; and deprotection steps after the cyclization step, wherein the protecting groups are removed. Preferred antimicrobial compounds made by these processes are those where the beta-lactam moiety is a penem, a carbapenem, a cephem, or a carbacephem. Also preferred are those compounds where L.sup.1, L, and L.sup.2 form a carbamate moiety, or a secondary or tertiary amine moiety. The present invention also provides novel intermediate compounds of the formula (M--L.sup.1)--L--(L.sup.2 --B), where (I) M has a structure according to formula (IV) ##STR1## (II) B is a lactam moiety; and (III) L, L.sup.1, and L.sup.2 together comprise a linking moiety.

A process for making a compound of the formula

(Q--L.sup.1)--L--(L.sup.2 --B)
the method comprising the steps of:
(1) coupling a compound having a structure according to Formula (III) ##STR34## wherein (A)
(1) A.sup.1, A.sub.2 or A.sub.3 is N C(R.sup.7), C(R.sup.2), or C(R.sup.5);
where
(a) R.sup.5 is hydrogen
(b) R.sup.2 is R.sup.5 or halogen
(c) R.sup.7 is R.sup.2, hydroxy, alkoxy, nitro, cyano, alkyl, or --N(R.sup.8)(R.sup.9), and
(d) R.sup.8 and R.sup.9 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring;
or R.sup.8 and R.sup.9 together form a heterocyclic ring including the nitrogen to which they are bonded;
(2) R.sup.1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or --N(R.sup.8)(R.sup.9);
(3) R.sup.3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring;
(4) R.sup.4 is hydroxy;
(5) R.sup.6 is hydrogen, halogen, nitro or --N(R.sup.8)(R.sup.9);
and
(6) X is a leaving group
(B) and
(1) when A.sup.2 is C(R.sup.2), R.sup.2 and R.sup.3 may together form --O--(CH.sub.2).sub.n --O--, where n is from 1 to 4;
(2) when A.sup.3 is C(R.sup.5), R.sup.4 and R.sup.5 may together form a heterocyclic ring;
and
(3) when A.sup.1 is C(R.sup.7), R.sup.7 and R.sup.3 may together form a heterocyclic ring including A.sup.1 and the carbon atom to which R.sup.3 is bonded;
or a protected form, salt, ester, or solvate thereof;
with a lactam-containing compound having a structure according to Formula (II), to form an intermediate compound;
and
(2) cyclizing the intermediate compound by reaction with an organosilicon compound to give a compound of the formula (Q--L.sup.1)--L--(L.sup.2 --B);
wherein
(I) Q has a structure according to Formula (I) ##STR35## wherein (A)
(1) A.sup.1, A.sup.2 or A.sup.3 is N or C(R.sup.7) C(R.sup.2) or C(R.sup.5);
where
(a) R5 is hydrogen,
(b) R2 is R5 or halogen,
(c) R.sup.7 is, R2 or, hydroxy, alkoxy, nitro, cyano, alkyl, or --N(R.sup.8)(R.sup.9), and
(d) R.sup.8 and R.sup.9 are, independently, R.sup.8a where R.sup.8a is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring;
or R.sup.8 and R.sup.9 together form a heterocyclic ring including the nitrogen to which they are bonded;
(2) R.sup.1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or --N(R.sup.8)(R.sup.9);
(3) R.sup.3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring;
(4) R.sup.4 is hydroxy;
and
(5) R.sup.6 is hydrogen, halogen, nitro or --N(R.sup.8)(R.sup.9);
(B) and
(1) when A.sup.2 is C(R.sup.2), R.sup.2 and R.sup.3 may together form --O--(CH.sub.2).sub.n --O--, where n is from 1 to 4;
(2) when A.sup.3 is C(R.sup.5), R.sup.4 and R.sup.5 may together form a heterocyclic ring;
and
(3) when A.sup.1 is C(R.sup.7), R.sup.7 and R.sup.3 may together form a heterocyclic ring including A.sup.1 and the carbon atom to which R.sup.3 is bonded;
(C) and provided that one of R.sup.1, R.sup.3, or R.sup.6 is a covalent bond to L.sup.1 ;
(II) B has a structure according to Formula (II):
##STR36## wherein (A) R.sup.10 is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, R.sup.8 --O--, R.sup.8 CH.dbd.N--, (R.sup.8)(R.sup.9)N--, R.sup.17 --C(.dbd.CHR.sup.20)--C(.dbd.O)NH--, R.sup.17 --C(.dbd.NO--R.sup.19)--C(.dbd.O)NH--, or R.sup.18 --(CH.sub.2).sub.m --C(.dbd.O)NH--;
where
(1) m is an integer from 0 to 9;
(2) R.sup.17 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring;
(3) R.sup.18 is R.sup.17, --Y.sup.1, or --CH(Y.sup.2)(R.sup.17);
(4) R.sup.19 is R.sup.17, arylalkyl, heteroarylalkyl, --C(R.sup.22)(R.sup.23)--COOH, --C(.dbd.O)O--R.sup.17, or --C(.dbd.O)NH--R.sup.17, where R.sup.22 and R.sup.23 are, independently, R.sup.17 or together form a carbocyclic ring or a heterocyclic ring including the carbon atom to which R.sup.22 and R.sup.23 are bonded;
(5) R.sup.20 is R.sup.19, halogen, --Y.sup.1, or --CH(Y.sup.2)(R.sup.17);
(6) Y.sup.1 is --C(.dbd.O)OR.sup.21, --C(.dbd.O)R.sup.21, --N(R.sup.24)R.sup.21, --S(O).sub.p R.sup.29, or --OR.sup.29 ;
and Y.sup.2 is Y.sup.1 or --OH, --SH, or --SO.sub.3 H;
(a) p is an integer from 0 to 2;
(b) R.sup.24 is hydrogen;
alkyl;
alkenyl;
heteroalkyl;
heteroalkenyl;
a carbocyclic ring;
a heterocyclic ring;
--SO.sub.3 H;
--C(.dbd.O)R.sup.25 ;
or, when R.sup.18 is --CH(N(R.sup.24)R.sup.21)(R.sup.17), R.sup.24 may form a moiety bonded to R.sup.21 to form a heterocyclic ring;
and
(c) R.sup.25 is R.sup.17, NH(R.sup.17), N(R.sup.17)(R.sup.26), O(R.sup.26), or S(R.sup.26);
where R.sup.26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R.sup.25 is --N(R.sup.17)(R.sup.26), R.sup.26 may be a moiety bonded to R.sup.17 to form a heterocyclic ring;
and
(7) R.sup.21 is R.sup.29 or hydrogen;
where R.sup.29 is alkyl;
alkenyl;
arylalkyl;
heteroalkyl;
heteroalkenyl;
heteroarylalkyl;
a carbocyclic ring;
a heterocyclic ring;
or, when Y.sup.1 or Y.sup.2 is --N(R.sup.24)R.sup.21 and R.sup.21 is R.sup.29, R.sup.21 and R.sup.24 may together form a heterocyclic ring including the nitrogen atom to which R.sup.24 is bonded;
(B) R.sup.11 is hydrogen, halogen, alkoxy, or R.sup.27 C(.dbd.O)NH--, where R.sup.27 is hydrogen or alkyl;
(C) bond "a" is a single bond or is nil;
and bond "b" is a single bond, a double bond, or is nil;
except bond "a" and bond "b" are not both nil;
(D) R.sup.12 is --C(R.sup.8)--, or --CH.sub.2 --R.sup.28 --;
where R.sup.28 is --C(R.sup.8), --O--, or --N--, and R.sup.28 is directly bonded to N" in Formula (II) to form a 5-membered ring;
except, if bond "a" is nil, then R.sup.12 is
(1) --C(R.sup.8)(X.sup.1)--, where
(a) X.sup.1 is --R.sup.21 ;
--OR.sup.30 ;
--S(O).sub.r R.sup.30, where r is an integer from 0 to 2;
--OC(.dbd.O)R.sup.30 ;
or --N(R.sup.30)R.sup.31 ;
and
(b) R.sup.30 and R.sup.31 are, independently, alkyl, alkenyl, a carbocyclic ring or a heterocyclic ring;
or R.sup.30 and R.sup.31 together form a heterocyclic ring including the nitrogen atom to which R.sup.30 and R.sup.31 are bonded;
or
(2) --CH.sub.2 --R.sup.32 --;
where R.sup.32 is --C(R.sup.8)(R.sup.21), --O--, or --NR.sup.8, and R.sup.32 is directly bonded to N" in Formula (II) to form a 5-membered ring;
(E)
(1) if bond "b" is a single bond, R.sup.13 is --CH(R.sup.33);
or, --C(O)NHSO.sub.2 --, if bond "a" is nil;
or --C*(R.sup.33)-- if R.sup.14 contains a R.sup.36 moiety;
where R.sup.33 is hydrogen or COOR.sup.46 where R.sup.46 is hydrogen, alkyl or alkenyl, and C* is linked to R.sup.36 to form a 3-membered ring;
(2) if bond "b" is a double bond, R.sup.13 is --C(R.sup.33).dbd.;
or
(3) if bond "b" is nil, R.sup.13 is hydrogen, --SO.sub.3 H, --PO(OR.sup.34)OH, --C(O)NHSO.sub.2 N(R.sup.34)(R.sup.35), --OSO.sub.3 H, --CH(R.sup.35)COOH, or --OCH(R.sup.34)--COOH;
where R.sup.34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring;
and R.sup.35 is hydrogen, alkyl, alkenyl, or --NHR.sup.8 ;
or, if R.sup.13 is --C(O)NH--SO.sub.2 N--(R.sup.34)(R.sup.35), R.sup.34 and R.sup.35 may together comprise a heterocyclic ring including the nitrogen to which R.sup.34 and R.sup.35 are bonded;
and
(F)
(1) if bond "a" or bond "b" is nil, then R.sup.14 is a covalent bond;
(2) if bond "a" and "b" are single bonds, R.sup.14 is --W--C'".dbd.C(R.sup.8)--R.sup.37 --, or --W--C'"(R.sup.36)--R.sup.37 --;
or
(3) if bond "a" is a single bond and bond "b" is a double bond, R.sup.14 is --C(R.sup.8)(R.sup.38)--W--C'"--R.sup.37 --;
--W--C(R.sup.8)--(R.sup.38)--C'"--R.sup.37 --;
or --W--C'"--R.sup.37 --;
(4) where
(a) W is O;
S(O).sub.s, where s is an integer from 0 to 2;
or C(R.sup.38), where R.sup.38 is hydrogen, alkyl or alkoxy;
(b) R.sup.36 is hydrogen;
alkyl;
alkenyl;
--COOH;
or, if R.sup.13 is --C*(R.sup.33), R.sup.36 may be linked to C* to form a 3-membered carbocyclic ring;
(c) R.sup.37 is covalent bond, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring;
and
(d) C'" is directly bonded to R.sup.13 to form a 5- or 6-membered ring;
and
(III)
(A) L is --C(.dbd.Z)--;
--S(O).sub.v --;
--N(R.sup.44)--;
--N.sup.+ (R.sup.44)(R.sup.45)--;
--N(R.sup.44)--N(R.sup.44)--;
--O--;
.dbd.N--;
or a covalent bond;
and L is bonded to L.sup.3 and L.sup.4 ;
where
(1) Z is O, S, or .sup.+ N(H).sub.2 ;
(2) v is 0, 1 or 2;
(3) R.sup.44 is hydrogen, substituted or unsubstituted lower alkyl, aryl, acyl, hydroxy, alkoxy, aryloxy, or acyloxy;
and
(4) R.sup.45 is hydrogen, unsubstituted or substituted lower alkyl, or substituted or unsubstituted aryl;
(B) L.sup.1 is L.sup.3 or R.sup.15 L.sup.3 ;
where
(1) when L is --C(.dbd.Z)--, L.sup.3 is a covalent bond, oxygen, sulfur, or nitrogen;
and when L is other than --C(.dbd.Z)--, L.sup.3 is a covalent bond;
(2) R.sup.15 is alkyl, alkenyl, heteroalkyl, a heterocyclic ring, a carbocyclic ring, or R.sup.15 together with L.sup.3 is a heteroalkyl or a heterocyclic ring;
and
(3) L.sup.1 is bonded to Q at the point of attachment of R.sup.1, R.sup.3 or R.sup.6, whichever is a covalent bond;
(C) L.sup.2 is L.sup.4, --X.sup.2.sub.t --R.sup.39 --L.sup.4, or --X.sup.3.sub.t --R.sup.39 --L.sup.4 ;
where
(1) when L is --C(.dbd.Z)--, L.sup.4 is a covalent bond, oxygen, sulfur, or nitrogen;
and when L is other than --C(.dbd.Z)--, L.sup.4 is a covalent bond;
(2) X.sup.2 is oxygen, or S(O).sub.v, where v is 0, 1, or 2;
(3) X.sup.3 is nitrogen;
--N(R.sup.40)--;
--N.sup.+ (R.sup.41)(R.sup.42)--;
or R.sup.43 --N(R.sup.41);
and is linked to R.sup.14 by a single or double bond;
or, if R.sup.14 is covalent bond, X.sup.3 is linked to B by a single or double bond;
where
(a) R.sup.40 is R.sup.8 ;
--OR.sup.8 ;
or --C(.dbd.O)R.sup.8 ;
(b) R.sup.41 and R.sup.42 are, independently, hydrogen;
alkyl;
alkenyl;
carbocyclic rings;
heterocyclic rings;
or, if R.sup.6 is R.sup.16 X, then R.sup.41 and R.sup.42 together with "Q" may form a heterocyclic ring as R.sup.16 ;
(c) R.sup.43 is N(R.sup.41), oxygen or sulfur;
(4) t is 0 or 1;
(5) R.sup.39 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring;
and
(6)
(a) if bond "a" or bond "b" is nil, then L.sup.2 is bonded directly to R.sup.12 or R.sup.13 ;
or
(b) if bond "a" and bond "b" are not nil, then L.sup.2 is bonded to R.sup.14 ;
(D) provided that if L.sup.1, L.sup.2 and R.sup.37 are each a covalent bond, then L cannot be a covalent bond;
or a protected form, salt, pharmaceutically-acceptable salt, biohydrolyzable ester, or solvate thereof.

182 more elements

Process for making quinolonyl lactam antimicrobials and novel intermediate compounds

Life of this patent

Process for making quinolonyl lactam antimicrobials and novel intermediate compounds

Life of this patent

Abstract

Claims24