Hydroxamic acid derivatives of 4-phenyl 4-hydroxy, 4-phenyl 4-alkoxy and 4-phenyl 4-arylalkoxy butyric acid 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 4-phenyl-4-hydroxy-butyric 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
X is O or S;
R 1 is independently F, Cl, Br, I, alkyl of 1-3 carbons, or;
m is an integer having the value of 1 to 3;
R 2 is H or alkyl of 1 to 3 carbons,
R 3 is (CH 2 ) n NR 5 R 6 ;
n is an integer having the value of 1 to 6;
R 5 is H, alkyl of 1 to 6 carbons, phenyl where the phenyl is substituted with 0-3 R 1 groups, (CH 2 ) p phenyl where the phenyl is substituted with 0-3 R 1 groups,
or R 5 is (CH 2 ) p —N(C 1-3 alkyl)phenyl,
p is an integer having the values 1 to 4;
R 6 is H, alkyl of 1 to 6 carbons, phenyl optionally substituted with 0-3 R 1 groups or with an —OPh group, or (CH 2 ) p phenyl where the phenyl is substituted with 1-3 R 1 groups;
the asterisk indicates a carbon which is asymmetric or may be asymmetric, the wavy line represents a bond which can be of either R or S configuration, or
a pharmaceutically acceptable salt of said compound.
2. A compound in accordance with claim 1 where X is O.
3. A compound in accordance with claim 2 where R 1 is selected independently from the group consisting of F, Cl, and methyl.
4. A compound in accordance with claim 2 where m is an integer having the value of 1 or 2.
5. A compound in accordance with claim 1 where m is 1 and R 1 is F in the 4 (para) position to the side chain of the phenyl moiety.
6. A compound in accordance with claim 1 where m is 2, one R 1 group is in the 3 (meta) position on the phenyl ring relative to the side chain of the phenyl group, and the other R 1 group is in the 4 (para) position of the phenyl ring relative to the side chain of the phenyl group.
7. A compound in accordance with claim 2 where R 3 is (CH 2 ) n NHR 5 or (CH 2 ) n NR 5 R 6 .
8. A compound in accordance with claim 1 where X is S.
9. A compound of the formula
wherein R 1 is independently F, Cl, Br, I, alkyl of 1-3 carbons, or phenyl;
m is an integer having the value of 1 to 3;
R 5 is alkyl of 1 to 4 carbons, or phenyl substituted with 0 to 3 R 1 groups or R 5 is alkylphenyl where the alkyl group has 1 to 3 carbons and the phenyl group is substituted with 0 to 3 R 1 groups;
R 6 is alkyl of 1 to 4 carbons or alkylphenyl where the alkyl group has 1 to 4 carbons and the phenyl group is substituted with 1 to 3 R 1 groups;
the asterisk indicates a carbon which is asymmetric or may be asymmetric, the wavy line represents a bond which can be of either R or S configuration, or
a pharmaceutically acceptable salt of said compound.
10. A compound in accordance with claim 9 where the variable (R 1 ) m in the structural formula of the compound represents a fluoro atom in the 4 (para) position of the phenyl ring relative to its side chain.
11. A compound in accordance with claim 10 having the formula
or a pharmaceutically acceptable salt of said compound.
12. A compound of the formula
where R 1 is independently F, Cl, Br, I, alkyl of 1-3 carbons, or phenyl;
m is an integer having the value of 1 to 3;
R 5 is selected from the group consisting of
R 6 is hydrogen or alkyl of 1 to 3 carbons,
the asterisk indicates a carbon which is asymmetric or may be asymmetric, 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 the variable (R 1 ) m in the structural formula of the compound represents a fluoro atom in the 4 (para) position of the phenyl ring relative to its side chain.
14. A compound in accordance with claim 13 having the formula
or a pharmaceutically acceptable salt of said compound.
15. A compound of the formula
where R 1 is independently F, Cl, Br, I, alkyl of 1-3 carbons, or phenyl;
m is an integer having the value of 1 to 3;
the asterisk indicates a carbon which is asymmetric, the wavy line represents a bond which can be of either R or S configuration, or a pharmaceutically acceptable salt of said compound.
16. A pharmaceutical composition for the treatment of infection by bacillus anthraci in a mammal, including a human, adapted for systemic administration containing a pharmaceutically acceptable excipient and one or more compounds in accordance with claim 1 .
17. A method of treating infection of a mammal, including a human being, by bacillus anthraci by administering to said mammal a pharmaceutical composition containing a pharmaceutically acceptable excipient and one or more compounds in accordance with claim 1 .