US2003207859A1PendingUtilityA1
Novel substituted succinic acid metallo-beta-lactamase inhibitors and their use in treating bacterial infections
Priority: Oct 28, 1999Filed: Jan 9, 2003Published: Nov 6, 2003
Est. expiryOct 28, 2019(expired)· nominal 20-yr term from priority
C07D 405/06A61P 31/04C07C 59/64C07C 57/38C07D 249/08C07C 57/58C07D 409/06C07D 333/20C07D 307/91A61P 43/00C07C 69/734C07D 231/12C07C 69/612C07D 233/56
46
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Claims
Abstract
This invention relates to novel substituted succinic acid metallo-β-lactamase inhibitors which are useful potentiators of β-lactam antibiotics. Accordingly, the present invention provides a method of treating bacterial infections in animals or humans which comprises administering, together with a b-lactam antibiotic, a therapeutically effective amount of a compound of formula I: including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by formula I:
including pharmaceutically acceptable salts, prodrugs, anhydrides, and solvates thereof, wherein:
M 1 and M 2 are independently selected from:
(a) Hydrogen,
(e) Pharmaceutically acceptable cation,
(e) Pharmaceutically acceptable esterifying group; and
(g) A negative charge;
R 1 and R 2 are independently selected from the following:
(d) Hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;
(e) a C 1 to C 16 straight, branched or unsaturated alkyl group substituted with 0 to 2 R q groups and substituted with 0 to 3 R x groups and optionally interrupted by one of the following O, S, SO 2 , —C(O)—,
(f) —C(O)—NR a —, —CO 2 —;
(c) a group of the formula:
wherein
—A— represents a single bond, C 1 to C 8 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x groups and optionally interrupted by one of the following O, S, SO 2 , —C(O)—, —C(O)—NR a —, —CO 2 —;
represents:
(1) a C 6 to C 14 aryl group;
(2) a C 3 to C 10 alicyclic group;
(3) a C 3 to C 14 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C 3 to C 10 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur; or
(d) a group of the formula:
wherein:
—A— is as defined above;
A′ is a single bond, O, S, or a C 1 to C 6 straight, branched or unsaturated alkyl group optionally substituted with 1-2 R x groups and optionally interrupted by one of the following groups O, S, SO 2 , —C(O)—, —C(O)—NR a —, —CO 2 —;
are independently selected from:
(1) a C 6 to C 10 aryl group;
(2) a C 3 to C 8 alicyclic group;
(3) a C 2 to C 9 heteroaryl group, which contains 1 to 3 heteroatoms, 0 to 3 of which heteroatoms are nitrogen and 0 to 1 of which are oxygen or sulfur;
(4) a C 3 to C 8 heterocyclic group, which contains 1 to 2 heteroatoms, 0 to 1 of which heteroatoms are nitrogen, and 0 to 2 of which are oxygen or sulfur;
provided that at least one R q group is present in R 1 or R 2 and that when more than one R q is present the total number of cationic nitrogen atoms does not exceed 8; the total number of cationic nitrogen atoms can be charged balanced by M 1 and/or M 2 or by M 1 and/or M 2 in combination with an appropriate number of Y − ;
wherein:
R q is —E—Q + Y − ;
Y − is a pharmaceutically acceptable anionic group;
E is —(CH 2 ) m —X—(CH 2 ) n —;
m is 0 to 6;
n is 0 to 6 (but when E is attached to an aromatic ring n is 1-6);
X is a bond, O, S, SO 2 , —C(O)—, —C(O)—N(R a )—, —C(O)O—, —CH═CH— or —C≡C—, provided that when X is O, S, —C(O)—N(R a )— or —C(O)O—, then n is 2 to 6
and Q + , attached to the (CH 2 ) n terminus of E is:
(1) a cationic group selected from the following:
wherein:
R u and R v are independently hydrogen or C 1-6 alkyl optionally substituted with 1 to 2 R y ;
R w is hydrogen or C 1-6 alkyl optionally substituted with 1 to 2 R x ;
R u and R v when bonded to the same nitrogen atom may together be a C 3-6 alkyl radical, which when taken together with the intervening atoms form a ring;
Two R u groups on separate nitrogen atoms may together comprise a C 2-5 alkyl radical, which when taken together with the intervening atoms form a ring;
R u , R v and R w when bonded to the same nitrogen atom may together form a C 6-10 tertiary alkyl radical, which with N + forms a bicyclic ring;
(2) A dicationic group:
wherein:
E 1 is —(CH 2 ) p —Z—(CH 2 ) r —;
p and r are independently 1 to 4;
Z is a bond, O, S, SO 2 , —C(O)—, —C(O)O—**, —CH═CH—, —C≡C—, or
Provided that when Z is O or S, p is 2 to 4 and r is 2 to 4 and when Z is
or —C(O)O—**, r is 2 to 4;
wherein ** denotes the atom which is bonded to the —(CH 2 ) r — moiety of E 1 above;
Q 1 is selected from the following:
Q 2 is selected from the following:
R u , R v and R w are independently selected and defined as above,
And in addition, in the case where two R u groups on separate nitrogen atoms are joined to form a ring as defined above, two R v groups on the same two separate nitrogen atoms may also comprise a C 1-5 alkyl radical to form together with the intervening atoms a bicyclic ring; an example of such is:
(5) A tricationic group selected from the following:
wherein:
Each E 1 is as defined above, but selected independently;
Each Q 1 is as defined above, but selected independently;
Each Q 2 is as defined above, but selected independently;
R u , R v and R w are defined as in the definition of Q + item (2) above and selected independently; or
(6) A tetracationic group selected from the following:
wherein:
Each E 1 is as defined above, but selected independently;
Each Q 1 is as defined above, but selected independently;
Each Q 2 is as defined above, but selected independently;
R u , R v and R w are defined as in the definition of Q + item (2) above and selected independently;
where each R x is independently selected from the group consisting of:
(f) F, Cl, Br, I,
(g) CF 3 ,
(h) OR b ,
(i) CN,
(j) —C(O)—R c ,
(f) —S(O 2 )—R f ,
(g) —C(O)—OR a
(h) —O—C(O)—R c ,
(i) —S—R b ,
(j) —N(R a )—C(O)—R c ,
(q) —N(R a )—C(O)—OR f ,
(r) —S(O)—R f ,
(s) —N(R a )—S(O 2 )—R f ,
(t) NO 2 , and
(u) C 1 to C 8 straight, branched or unsaturated alkyl optionally substituted with one of the substituents (a) through (t) above;
(v) —CH 2 -aryl wherein the aryl is optionally substituted with one of the substituents (a) through (t) above;
or two adjacent R x groups on an aromatic ring may consist of the following divalent moiety, —O—CH 2 —O—;
wherein:
R a is H, C 1 to C 6 alkyl optionally substituted with R y ;
R b is H, C 1 to C 6 alkyl optionally substituted with R y , CH 2 -aryl, or aryl, said aryls optionally substituted with 1-2 R y groups;
R c is H, C 1 to C 6 alkyl optionally substituted with R y , CF 3 , or aryl, said aryl optionally substituted with 1-2 R y groups;
R d and R e are independently hydrogen, C 1 to C 4 alkyl optionally substituted with R y , or R d and R e taken together may represent a 3 to 5-membered alkyl radical to form a ring, or R d and R e taken together may represent a 2 to 4-membered alkyl radical interrupted by O, S, SO or SO 2 to form a ring;
R f is C 1 to C 6 alkyl optionally substituted with R y , or aryl, said aryl optionally substituted with 1-2 R y groups; and
R y is —OH, —OCH 3 , OCONH 2 , OCOCH 3 , CHO, COCH 3 , CO 2 CH 3 , CONH 2 , CN, SOCH 3 , SO 2 CH 3 , SO 2 NH 2 , F, Cl, Br, I or CF 3 .
2 . A compound in accordance with claim 1 wherein M 1 and M 2 are independently hydrogen or a negative charge and all other variables are as defined above.
3 . A compound in accordance with claim 1 wherein R 1 and/or R 2 represents a C 1 to C 16 straight, branched or unsaturated alkyl group substituted with 0 to 2 R q , and substituted with 0 to 3 R x groups, provided that at least one of R 1 or R 2 contains an R q and all other variables are defined as above.
4 . A compound in accordance to claim 1 where R 1 and/or R 2 represents
wherein at least one R q group is present on R 1 or R 2 and all other variables are defined as above.
5 . A compound in accordance to claim 1 where R 1 and/or R 2 represents (d)
wherein at least one R q group is present on R 1 or R 2 and all other variables are defined as above.
6 . A compound in accordance with claim 1 wherein the relative and absolute stereochemistry is:
7 . A compound in accordance with claim 6 wherein R 1 and/or R 2 represents C 4-12 straight, branched or unsaturated alkyl group optionally substituted with 1 to 2 R x and optionally substituted with 1 to 2 R q groups provided that at least one of R 1 or R 2 contains an R q and all other variables are as described above.
8 . A compound in accordance with claim 6 wherein R 1 and/or R 2 represents a group of the formula:
wherein A is (CH 2 ) 1-5 and
is phenyl, naphthyl, cyclohexyl or dibenzofuranyl, provided that at least one of R 1 or R 2 contains an R q and all other variables are as originally defined.
9 . A compound in accordance with claim 6 wherein where R 1 or R 2 represents a group of the formula:
wherein
A is (CH 2 ) 1-3 , A′ is a single bond, —O— or (CH 2 ) 1-2 and
independently represent phenyl, thienyl, pyridyl, furanyl or cyclohexyl.
10 . A compound in accordance with claim 6 where one of R 1 or R 2 is C 4-8 straight, branched or unsaturated alkyl optionally substituted with 1 to 2 R x or a group of the formula:
where A is (CH 2 ) 1-2 and
is phenyl, cyclopentyl or cyclohexyl and the other of R 1 or R 2 is:
i) a C 7-12 alkyl group substituted with R q ,
ii) a group of the formula:
where A is (CH 2 ) 1-2 , A′ is a single bond,
is phenyl, thienyl or cyclohexyl and is phenyl, thienyl or pyridyl, or
iii) a group of the formula:
where A is (CH 2 ) 1-3 ,
is phenyl or thienyl and R q is —(CH 2 ) 2-6 —Q + Y Q ; and all other variables are as originally defined.
11 . A compound according to claim 6 wherein R 1 is C 5-7 alkyl substituted with 0 to 2 R x goups,
R 2 is C 7-10 alkyl substituted with 1 R q groups and 0 to 2 R x groups,
and all other variables are as originally defined.
12 . A compound according to claim 11 wherein
R 1 is:
R 2 is:
and all other variables are as originally defined.
13 . A compound according to claim 1 wherein 1 or 2 R q groups are present containing a total number of 2 to 6 cationic nitrogen atoms.
14 . A compound according to claim 1 wherein a single R q substituent is present containing a tricationic or tetracationic Q + group.
15 . A compound according to claim 14 wherein R q is —E—Q + Y − wherein E is (CH 2 ) 0-6 or —C(O)—N(R a )—(CH 2 ) 2-4 — and Q + is a tricationic or tetracationic group and Y − and R a are as originally defined.
16 . A compound according to claim 14 wherein the tricationic Q + group is selected from the group consisting of:
wherein E 1 is (CH 2 ) 2-4 or —(CH 2 )—C(O)—N(R a )—(CH 2 ) 2-4 — and R a , Q 1 and Q 2 are as previously defined.
17 . A compound according to claim 16 wherein the tricationic Q + group is selected from:
wherein R u , R v , and R w are as defined above.
18 . A compound according to claim 14 wherein the tetracationic Q + group is selected from the group consisting of:
wherein E 1 is (CH 2 ) 2-4 or —(CH 2 )—C(O)—N(R a )—(CH 2 ) 2-4 — and R a , Q 1 , Q 2 , and R w are as defined above.
19 . A compound according to claim 18 wherein the tetracationic Q + group is selected from:
wherein R a , R u , R v , and R w are as described above.
20 . A compound of the structural formula:
21 . A compound represented by Tables 3-7:
TABLE 3
Example No.
Q ⊕
Y ⊖
5
3 Cl ⊖
6
3 Cl ⊖
7
3 Cl ⊖
8
4 Cl ⊖
9
4 Cl ⊖
10
3 Cl ⊖
11
3 Cl ⊖
12
3 Cl ⊖
13
3 Cl ⊖
14
3 Cl ⊖
TABLE 4
Example No.
Q ⊕
Y ⊖
15
CF 3 CO 2 ⊖
16
CF 3 CO 2 ⊖
17
2 Cl ⊖
18
2 CF 3 CO 2 ⊖
19
3 CF 3 CO 2 ⊖
20
3 CF 3 CO 2 ⊖
TABLE 5
Example No.
Q ⊕
Y ⊖
21
Cl ⊖
22
2 Cl ⊖
23
3 Cl ⊖
24
3 Cl ⊖
TABLE 6
Example No.
Q ⊕
Y ⊖
25
Cl ⊖
26
2 Cl ⊖
27
3 Cl ⊖
28
3 Cl ⊖
TABLE 7
Example No.
Q ⊕
Y ⊖
29
Cl ⊖
22 . A compound represented by Tables 8-18:
TABLE 8
Example No.
Q ⊕
Y ⊖
30
3 Cl ⊖
31
3 CH 3 CO 2
32
3 Cl ⊖
33
3 Cl ⊖
34
3 Cl ⊖
35
3 Cl ⊖
36
4 Cl ⊖
37
4 CH 3 CO 2 ⊖
38
4 Cl ⊖
39
4 Cl ⊖
40
4 Cl ⊖
41
4 Cl ⊖
42
Cl ⊖
43
Cl ⊖
44
3 Cl ⊖
45
3 Cl ⊖
46
4 Cl ⊖
47
3 Cl ⊖
TABLE 9
Example No.
Q ⊕
Y ⊖
48
Cl ⊖
49
2 Cl ⊖
50
3 Cl ⊖
51
3 Cl ⊖
52
3 Cl ⊖
53
3 Cl ⊖
TABLE 10
Example No.
Q ⊕
Y ⊖
54
Cl ⊖
55
2 Cl ⊖
56
3 Cl ⊖
57
3 Cl ⊖
58
3 Cl ⊖
59
4 Cl ⊖
Example No.
Q ⊕
Y ⊖
60
Cl ⊖
61
2 Cl ⊖
62
3 Cl ⊖
63
3 Cl ⊖
64
3 Cl ⊖
65
4 Cl ⊖
TABLE 2
Example No.
Q ⊕
Y ⊖
66
Cl ⊖
67
2 Cl ⊖
68
3 Cl ⊖
69
3 Cl ⊖
70
3 Cl ⊖
71
4 Cl ⊖
TABLE 13
Example No.
Q ⊕
Y ⊖
72
Cl ⊖
73
2 Cl ⊖
74
3 Cl ⊖
75
3 Cl ⊖
76
3 Cl ⊖
77
4 Cl ⊖
TABLE 14
Example No.
Q ⊕
Y ⊖
78
Cl ⊖
79
2 Cl ⊖
80
3 Cl ⊖
81
3 Cl ⊖
82
3 Cl ⊖
83
4 Cl ⊖
TABLE 15
Example No.
Q ⊕
Y ⊖
84
Cl ⊖
85
2 Cl ⊖
86
3 Cl ⊖
87
3 Cl ⊖
88
3 Cl ⊖
89
4 Cl ⊖
TABLE 16
Example No.
Q ⊕
Y ⊖
90
Cl ⊖
91
2 Cl ⊖
92
3 Cl ⊖
93
3 Cl ⊖
94
3 Cl ⊖
95
4 Cl ⊖
TABLE 17
Example No.
Q ⊕
Y ⊖
96
Cl ⊖
97
2 Cl ⊖
98
3 Cl ⊖
99
3 Cl ⊖
100
3 Cl ⊖
101
4 Cl ⊖
TABLE 18
Example No.
102
103
104
23 . A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
24 . A pharmaceutical composition in accordance with claim 23 used in the manufacture of a medicament for the treatment of bacterial infections.
25 . A pharmaceutical composition in accordance with claim 23 further comprising a β-lactam antibiotic.
26 . A pharmaceutical composition in accordance with claim 25 wherein the β-lactam is a carbapenem antibiotic.
27 . A composition according to claim 25 which further contains a serine β-lactamase inhibitor.
28 . A composition according to claim 26 which further contains a DHP inhibitor.
29 . A method of treating a bacterial infection comprising administering to a mammalian patient in need of such treatment a metallo-β-lactamase inhibitor compound as defined in claim 1 in combination with a pharmaceutically acceptable β-lactam antibiotic in an amount which is effective for treating a bacterial infection.
30 . A method according to claim 29 wherein the β-lactam is a carbapenem antibiotic.
31 . A method according to claim 30 , which further contains a DHP inhibitor.
32 . A method according to claim 31 wherein the DHP inhibitor is cilastatin.
33 . A method according to claim 29 which further contains a serine β-lactamase inhibitor.Join the waitlist — get patent alerts
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