Hydroxamic acid derivatives of 3-phenyl propionic acids useful as therapeutic agents for treating anthrax poisoning
Compounds having the formula wherein the symbols have the meaning described in the specification are hydroxamic acid derivatives of 3-phenyl-propionic acid and capable of inhibiting the lethal effects of infection by anthrax bacteria and are useful in the treatment of poisoning by anthrax.
1. A compound of the formula
where
R 1 is F, Cl, alkyl of 1-3 carbons;
m is an integer having the value of 1 to 3;
R 2 is alkyl of 1-9 carbons; C 1 -C 6 alkylphenyl where phenyl is substituted with 0-3 R 1 groups, C 1 -C 6 alkylcyclohexyl, (CH 2 ) n OR 3 , (CH 2 ) n NHR 4 , (CH 2 ) n CF 3 , CH 2 OCH 2 phenyl; (CH 2 ) n NH(CH 2 ) n R 4 , (CH 2 ) n NR 6 R 4 , (CH 2 ) n NR 6 (CH 2 ) n R 4 , (CH 2 ) n O(CH 2 ) n R 4 , (CH 2 ) n OR 4 , CN, phenyl substituted with 0 to 3 R 1 groups, an alkenyl group having 2 to 9 carbons and one double bond,
n is an integer having the value of 1 to 8;
R 3 is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1 to 6 carbons and the phenyl is substituted with 0-3 R 1 groups;
R 4 is H, alkyl of 1 to 10 carbons, (CH 2 ) p cyclohexyl, C(O)alkyl of 1 to 4 carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and the phenyl is substituted with 0-3 R 1 groups or with a 5 to 6 membered heteroayl group having 1 to 2 heteroatoms selected from O, S, and N, or with a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S and N and condensed with a phenylgroup, said heteroaryl or condensed heteroaryl group itself substituted with 0-3 R 1 groups, or R 4 is C(O)(CH 2 ) p COOH, (CH 2 ) p phenyl where the phenyl is substituted with 0-3 R 1 groups or with a NO 2 group, or R 4 is C(O)OC 1 -C 6 alkyl, or R 4 is CH(CH 3 )phenyl where the phenyl is substituted with 0-3 R 1 groups, or R 4 is C(O)(CH 2 ) p phenyl where the phenyl is substituted with 0-3 R 1 groups, or R 4 is C(O)CH(Ph) 2 , C(O)—CH 2 -(3PhO—)Ph, or R 4 is a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S, and N, or a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S and N and condensed with a phenylgroup, said heteroaryl or condensed heteroaryl group itself substituted with 0-3 R 1 groups, or R 4 is CH 2 heteroaryl **CH 2 heteroaryl condensed with phenyl where the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatoms selected from O, S said heteroaryl group or condensed heteroaryl itself substituted with 0-3 R 1 groups, or R 4 is SO 2 -alkyl of 1 to 6 carbons, SO 2 -Ph where the phenyl is substituted with 0-3 R 1 groups or with NO 2 or with COOR 5 group, or R 4 is C(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkyl group has 1 to 4 carbons and where the phenyl is substituted with 0-3 R 1 groups;
p is an integer having the value of 0 to 4;
R 5 is alkyl of 1 to 6 carbons or phenyl substituted with 0-3 R 1 groups or with an OPh group;
R 6 is alkyl of 1 to 6 carbons;
the asterisk indicates an asymmetric carbon, the wavy line represents a bond that can be in the R or in the S configuration,
or a pharmaceutically acceptable salt of said compound,
with the proviso that compounds selected from the group consisting of compounds identified below with structural formulas
are not included in the claim.
2. A compound in accordance with claim 1 where R 1 is selected independently from the group consisting of F, Cl, methyl.
3. A compound in accordance with claim 2 where m is an integer having the value of 2 or 3.
4. A compound in accordance with claim 3 where m is 2, one R 1 group is methyl in the 3 (meta) position on the phenyl ring, and the other R 1 group is fluoro in the 4 (para) position of the phenyl ring.
5. A compound in accordance with claim 2 where m is 3, two R 1 groups are methyl in the 3,3 (meta, meta) positions on the phenyl ring and the third R 1 group is fluoro in the 4 (para) position of the phenyl ring.
6. A compound of the formula
where the asterisk represents that the adjacent carbon is asymmetric and the wavy line represents a bond which can be of either R or S configuration, or a pharmaceutically acceptable salt of said compound.
7. A compound of the formula
where
R 1 is H or alkyl of 1 to 6 carbons;
R 2 is H, CN, 4-Br-phenyl, alkyl of 1 to 8 carbons, alkenyl where the alkenyl group has 2 to 8 carbons and one double bond, (CH 2 ) 4 —O—CH 2 -3Me-4F-phenyl or (CH 2 ) 6-4 F-phenyl,
the asterisk represents that the adjacent carbon can be asymmetric and the wavy line represents a bond which can be of either R or S configuration,
or a pharmaceutically acceptable salt of said compound.
8. A compound in accordance with claim 7 where R 1 is H or methyl.
9. A compound in accordance with claim 8 where R 2 is H or methyl.
10. A compound in accordance with claim 8 where R 2 is 4-Br-phenyl, (CH 2 ) 4 —O—CH 2 -3Me-4F-phenyl or (CH 2 ) 6-4 F-phenyl.
11. A compound in accordance with claim 8 where R 2 is alkenyl.
12. A compound of the formula
where
R 1 is H or alkyl of 1 to 6 carbons;
R 2 is (CH 2 ) n NR 6 (CH 2 ) p -phenyl, (CH 2 ) n NH(CH 2 ) p phenyl said phenyl groups being substituted with 0 to 3 groups selected from the group F, Cl and methyl, (CH 2 ) n NH(CH 2 ) p cyclohexyl, (CH 2 ) n NH(CH 2 ) p furanyl, (CH 2 ) n NH(CH 2 ) p pyrazinyl, (CH 2 ) n NH(CH 2 ) p -2-benzo[b]thienyl said furanyl, pyrazinyl and 2-benzo[b]thienyl rings being substituted with 0 to 3 R 1 groups
n is an integer having the value of 1 to 6,
p is an integer having the value of 0 to 4,
R 6 is alkyl of 1 to 3 carbons,
the asterisk represents that the adjacent carbon can be asymmetric and the wavy line represents a bond which can be of either R or S configuration,
or a pharmaceutically acceptable salt of said compound.
13. A compound in accordance with claim 12 where R 1 is H or methyl.
14. A compound in accordance with claim 13 where n is 4 and p is 1.
15. A compound in accordance with claim 13 where n is 4 and R 6 is methyl.
16. A compound selected from the group of compounds consisting of
or a pharmaceutically acceptable salt of said compound.
17. A compound of the formula
or a pharmaceutically acceptable salt of said compound.
18. A compound of the formula
or a pharmaceutically acceptable salt of said compound.
19. A pharmaceutical composition containing a pharmaceutically acceptable excipient and one or more compounds of the formula
where
R 1 is F, Cl, alkyl of 1-3 carbons;
m is an integer having the value of 1 to 3;
R 2 is alkyl of 1-9 carbons; C 1 -C 6 alkylphenyl where phenyl is substituted with 0-3 R 1 groups, C 1 -C 6 alkylcyclohexyl, (CH 2 ) n OR 3 , (CH 2 ) n NHR 4 , (CH 2 ) n CF 3 , CH 2 OCH 2 phenyl; (CH 2 ) n NH(CH 2 ) n R 4 , (CH 2 ) n NR 6 R 4 , (CH 2 ) n NR 6 (CH 2 ) n R 4 , (CH 2 ) n O(CH 2 ) n R 4 , (CH 2 ) n OR 4 , CN, phenyl substituted with 0 to 3 R 1 groups, an alkenyl group having 2 to 9 carbons and one double bond,
n is an integer having the value of 1 to 8;
R 3 is H, alkyl of 1 to 6 carbons, alkylphenyl where the alkylgroup has 1 to 6 carbons and the phenyl is substituted with 0-3 R 1 groups;
R 4 is H, alkyl of 1 to 10 carbons, (CH 2 ) p cyclohexyl, C(O)alkyl of 1 to 4 carbons, C(O)alkylphenyl where the alkylgroup has 1 to 4 carbons and the phenyl is substituted with 0-3 R 1 groups or with a 5 to 6 membered heteroayl group having 1 to 2 heteroatoms selected from O, S, and N, or with a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S and N and condensed with a phenylgroup, said heteroaryl or condensed heteroaryl group itself substituted with 0-3 R 1 groups, or R 4 is C(O)(CH 2 ) p COOH, (CH 2 ) p phenyl where the phenyl is substituted with 0-3 R 1 groups or with a NO 2 group, or R 4 is C(O)OC 1 -C 6 alkyl, or R 4 is CH(CH 3 )phenyl where the phenyl is substituted with 0-3 R 1 groups, or R 4 is C(O)(CH 2 ) p phenyl where the phenyl is substituted with 0-3 R 1 groups, or R 4 is C(O)CH(Ph) 2 , C(O)—CH 2 -(3PhO—)Ph, or R 4 is a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S, and N, or a 5 to 6 membered heteroaryl group having 1 to 2 heteroatoms selected from O, S and N and condensed with a phenylgroup, said heteroaryl or condensed heteroaryl group itself substituted with 0-3 R 1 groups, or R 4 is CH 2 heteroaryl **CH 2 heteroaryl condensed with phenyl where the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatoms selected from O, S said heteroaryl group or condensed heteroaryl itself substituted with 0-3 R 1 groups, or R 4 is SO 2 -alkyl of 1 to 6 carbons, SO 2 -Ph where the phenyl is substituted with 0-3 R 1 groups or with NO 2 or with COOR 5 group, or R 4 is C(O)NH-alkylphenyl, or C(O)NH-phenyl where the alkyl group has 1 to 4 carbons and where the phenyl is substituted with 0-3 R 1 groups;
p is an integer having the value of 0 to 4;
R 5 is alkyl of 1 to 6 carbons or phenyl substituted with 0-3 R 1 groups or with an OPh group;
R 6 is alkyl of 1 to 6 carbons;
the asterisk indicates an asymmetric carbon, the wavy line represents a bond that can be in the R or in the S configuration,
or a pharmaceutically acceptable salt of said compound.