Hydroxamic acid derivatives of phenoxy-acetic acids and analogs useful as therapeutic agents for treating anthrax poisoning
View Patent ↗Compounds having the formula wherein the symbols have the meaning described in the specification are hydroxamic acid derivatives of phenoxy-acetic acids and analogs 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, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons, thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF 3 , OCF 3 , OH, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , COOH or COO(C 1 -C 6 alkyl);
m is an integer having the value of 1 to 3;
R 2 is alkyl of 2-6 carbons; C 1 -C 6 alkylphenyl where phenyl is substituted with 0-3 R 1 groups, C 2 -C 6 alkenylO(CH 2 ) n phenyl where alkenyl has 2 to 6 carbons and one double bond and phenyl is substituted with 0-3 R 1 groups, C 1 -C 6 alkylcyclohexyl, (CH 2 ) n OR 3 , (CH 2 ) n NHR 4 , NR 4 C 1 -C 6 alkyl, (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 ,
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, 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 heteroaryl 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 where the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatoms selected from O, S, 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 and designations of the variables R 1
where R 1 is 2-Me, 4-Me, 4-Br, 2-phenyl, 2-(3-propenyl), 4-O-n-Bu, 2-Me-4-Br, 2,4-diCl, 2,4-diBr, 2,5-diCl, 2,4,5-triCl, 2,5-diCl-4-Me, 2,4-diCl-4-Br, or 2-Me-4-Cl
and
where R 1 is 2-phenyl, 2-(3-propenyl), 2,3-dimethyl, or 2,4-diCl,
and
where R 1 is 2-Me, 2-Cl, 2-OMe, 3-Me, 3-Cl, 3-OMe, 3-CF 3 , 4-OMe, 4-SMe, 4-phenyl, 2-COOMe, 3-COOMe or 4-COOEt,
and
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 and methoxy.
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 of the formula
where
R 2 is H, alkyl of 1 to 6 carbons (CH 2 ) 2 OH, or (CH 2 ) 4 OH;
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, with the proviso that when R 2 is H then the carbon bearing the asterisk is not asymmetric.
6. A compound of the formula
where R 1 is H, or alkyl of 1 to 6 carbons;
R 2 is (CH 2 ) n NHR 4 , (CH 2 ) n OR 4 , CH 2 ) n N(CH 3 )R 4 ,
C 2-6 alkenylOCH 2 phenyl where alkenyl has one double bond and the phenyl group is substituted with 0 to 3 groups selected from methyl and fluoro;
n is an integer selected from 1 to 6;
R 4 is (CH 2 ) p phenyl, (CH 2 ) p thienyl, (CH 2 ) p furyl where the phenyl, thienyl and furyl groups are substituted with 0 to 3 groups selected from methyl and fluoro;
p is an integer selected from 1 to 3;
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 in accordance with claim 6 where p is one (1).
8. A compound in accordance with claim 6 where R 2 is (CH 2 ) n NHR 4 .
9. A compound in accordance with claim 6 where R 2 is (CH 2 ) n OR 4 .
10. A compound in accordance with claim 6 where R 2 is (CH 2 ) n N(CH 3 )R 4 .
11. A compound in accordance with claim 6 where R 2 is C 2-6 alkenylOCH 2 phenyl.
12. A compound in accordance with claim 6 where R 1 is H.
13. A compound of the formula
or a pharmaceutically acceptable salt of said compound.
14. A compound of the formula
or a pharmaceutically acceptable salt of said compound.
15. A method of treating infection of a mammal by bacillus anthraci by administering to said mammal a pharmaceutical composition containing a pharmaceutically acceptable excipient and one or more compounds defined by formula below
where
R 1 is F, Cl, Br, I, alkyl of 1-3 carbons, alkoxy of 1-3 carbons, thioalkoxy of 1-3 carbons, phenyl, O-phenyl, CN, CF 3 , OCF 3 , OH, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , COOH or COO(C 1 -C 6 alkyl);
m is an integer having the value of 1 to 3;
R 2 is alkyl of 1-6 carbons; C 1 -C 6 alkylphenyl where phenyl is substituted with 0-3 R 1 groups, C 2 -C 6 alkenylO(CH 2 ) n phenyl where alkenyl has 2 to 6 carbons and one double bond and phenyl is substituted with 0-3 R 1 groups, C 1 -C 6 alkylcyclohexyl, (CH 2 ) n OR 3 , (CH 2 ) n NHR 4 , NR 4 C 1 -C 6 alkyl, (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 (CH 2 ) n O(CH 2 ) n R 4 , (CH 2 ) n OR 4 ,
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, 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 heteroaryl 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 where the heteroaryl group is 5 or 6 membered and has 1 to 2 heteroatoms selected from O, S, 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.
16. A method of inhibiting the lethal factor enzyme released by bacillus anthraci in a mammal where such inhibition is needed, said method comprising contacting said enzyme with one or more compounds defined by formula in accordance with claim 15 .
17. A method in accordance with claim 16 where said mammal is a human being.