U.S. patent application number 12/144243 was filed with the patent office on 2008-10-23 for antibacterial agents.
This patent application is currently assigned to IDEXX Laboratories, Inc.. Invention is credited to Yerramilli V.S.N. MURTHY.
Application Number | 20080262083 12/144243 |
Document ID | / |
Family ID | 38049093 |
Filed Date | 2008-10-23 |
United States Patent
Application |
20080262083 |
Kind Code |
A1 |
MURTHY; Yerramilli V.S.N. |
October 23, 2008 |
ANTIBACTERIAL AGENTS
Abstract
D-(threo)-1-aryl-2-disubstitutedacylamido-3-fluoro-1-propanol
compounds compounds and analogues thereof ("Fenicol Compounds"),
compositions comprising an effective amount of a Fenicol Compound,
and methods for treating or preventing a bacterial infection in an
animal comprising administering to an animal in need thereof an
effective amount of a Fenicol Compound are disclosed.
Inventors: |
MURTHY; Yerramilli V.S.N.;
(Apex, NC) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER, EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
IDEXX Laboratories, Inc.
Westbrook
ME
|
Family ID: |
38049093 |
Appl. No.: |
12/144243 |
Filed: |
June 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11208889 |
Aug 23, 2005 |
7402697 |
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12144243 |
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60606513 |
Sep 2, 2004 |
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Current U.S.
Class: |
514/546 ;
514/625; 560/129; 564/192 |
Current CPC
Class: |
C07C 311/46 20130101;
C07C 317/32 20130101; C07C 311/37 20130101; C07C 235/08 20130101;
C07C 233/18 20130101; C07B 2200/07 20130101 |
Class at
Publication: |
514/546 ;
514/625; 564/192; 560/129 |
International
Class: |
A61K 31/222 20060101
A61K031/222; A61K 31/16 20060101 A61K031/16; C07C 233/01 20060101
C07C233/01; C07C 69/00 20060101 C07C069/00 |
Claims
1. A compound of formula (III): ##STR00026## or a pharmaceutically
acceptable salt thereof, wherein A is (R) --CH(CH.sub.3)(CF.sub.3)
substantially free of (S) --CH(CH.sub.3)(CF.sub.3), (R)
--CH(CH.sub.3)(halo) substantially free of (S)
--CH(CH.sub.3)(halo), (R) --CH(CF.sub.3)(halo) substantially free
of (S) --CH(CF.sub.3)(halo), (R)--CH(CF.sub.3)(OH) substantially
free of (S) --CH(CF.sub.3)(OH), (S) --CH(CH.sub.3)(CF.sub.3)
substantially free of (R) --CH(CH.sub.3)(CF.sub.3), (S)
--CH(CH.sub.3)(halo) substantially free of (R)
--CH(CH.sub.3)(halo), (S) --CH(CF.sub.3)(halo) substantially free
of (R) --CH(CF.sub.3)(halo), or (S)CH(CF.sub.3)(OH) substantially
free of (R) --CH(CF.sub.3)(OH); Z is hydrogen or an acyl group of
formula --C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH; Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halogen; -phenyl; or
-phenyl substituted with -halogen, --NO.sub.2, --SO.sub.2CH.sub.3,
-R.sub.1, or --OR.sub.1; halo is --Cl, --Br, --I, or --F; and
R.sub.1 is a C.sub.1 to C.sub.3 hydrocarbon group.
2. The compound of claim 1, wherein A is (R)
--CH(CH.sub.3)(CF.sub.3) substantially free of (S)
--CH(CH.sub.3)(CF.sub.3), (R) --CH(CH.sub.3)(halo) substantially
free of (S) --CH(CH.sub.3)(halo), (R) --CH(CF.sub.3)(halo)
substantially free of (S) --CH(CF.sub.3)(halo), or
(R)--CH(CF.sub.3)(OH) substantially free of (S)
--CH(CF.sub.3)(OH).
3. The compound of claim 2, wherein Z is hydrogen.
4. The compound of claim 1, wherein Z is hydrogen.
5. The compound of claim 3, wherein Y is --SO.sub.2CH.sub.3 and
Y.sub.1 is hydrogen.
6. The compound of claim 5, wherein A is (R)
--CH(CH.sub.3)(CF.sub.3) substantially free of (S)
--CH(CH.sub.3)(CF.sub.3).
7. The compound of claim 5, wherein A is (R) --CH(CH.sub.3)(halo)
substantially free of (S) --CH(CH.sub.3)(halo).
8. The compound of claim 7, wherein A is (R) --CH(CH.sub.3)(Cl)
substantially free of (S) --CH(CH.sub.3)(Cl).
9. The compound of claim 7, wherein A is (R) --CH(CH.sub.3)(F)
substantially free of (S) -CH(CH.sub.3)(F).
10. The compound of claim 7, wherein A is (R) --CH(CH.sub.3)(Br)
substantially free of (S) --CH(CH.sub.3)(Br).
11. The compound of claim 7, wherein A is (R) --CH(CH.sub.3)(I)
substantially free of (S) -CH(CH.sub.3)(I).
12. The compound of claim 5, wherein A is (R) --CH(CH.sub.3)(OH)
substantially free of (S) --CH(CH.sub.3)(OH).
13. The compound of claim 5, wherein A is (R) --CH(CF.sub.3)(halo)
substantially free of (S) --CH(CF.sub.3)(halo).
14. The compound of claim 13, wherein A is (R) --CH(CF.sub.3)(Cl)
substantially free of (S) --CH(CF.sub.3)(Cl).
15. The compound of claim 13, wherein A is (R) --CH(CF.sub.3)(F)
substantially free of (S) --CH(CF.sub.3)(F).
16. The compound of claim 13, wherein A is (R) --CH(CF.sub.3)(Br)
substantially free of (S) --CH(CF.sub.3)(Br).
17. The compound of claim 13, wherein A is (R) --CH(CF.sub.3)(I)
substantially free of (S) --CH(CF.sub.3)(I).
18. The compound of claim 5, wherein A is (R) --CH(CF.sub.3)(OH)
substantially free of (S) --CH(CF.sub.3)(OH).
19. A pharmaceutical composition comprising the compound of claim 1
and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 adapted for oral
administration.
21. The pharmaceutical composition of claim 19 adapted for
parenteral administration.
22. The pharmaceutical composition of claim 19 adapted for topical
administration.
23. A method of treating or preventing a bacterial infection in an
animal, comprising administering to an animal in need thereof the
compound of claim 1.
24. The method of claim 23, wherein the animal is a dog or cat.
25. The method of claim 23, wherein the compound of claim 1 is
administered at a dose ranging from about 0.1 mg/kg of body weight
to about 50 mg/kg of body weight.
26. The method of claim 23, wherein the compound of claim 1 is
administered daily until the bacterial infection is abated.
27. A method of treating a bacterial infection in an animal
comprising administering to an animal in need thereof a compound of
formula (III): ##STR00027## or a pharmaceutically acceptable salt
thereof, wherein A is a group of formula --CH(CH.sub.3)(CF.sub.3),
--CH(CH.sub.3)(halo), --CH(CF.sub.3)(halo), or --CH(CF.sub.3)(OH);
Z is hydrogen or an acyl group of formula --C(O)--R.sub.2, wherein
R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that may
optionally be substituted with a --NH.sub.2 or --COOH; Y and
Y.sup.1 is --H; --NO.sub.2; --SO.sub.2R.sub.1; --SOR.sub.1;
--SR.sub.1; --SONH.sub.2; --SO.sub.2NH.sub.2; --SONHR.sub.1;
--SO.sub.2NHR.sub.1; --COR.sub.2; --OR.sub.1; --R.sub.1; --CN,
-halogen; -phenyl; or -phenyl substituted with -halogen,
--NO.sub.2, --SO.sub.2CH.sub.3, -R.sub.1, or --OR.sub.1; halo is
--Cl, --Br, --I, or --F; and R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and wherein the group of formula A is in either
the (R) configuration substantially free of the (S) configuration
or the (S) configuration substantially free of the (R)
configuration and is the configuration that is cleared more slowly
when administered to an animal.
28. A method of selecting a compound for treating a condition in an
animal comprising: providing a first compound that has a first
carbon atom that is achiral and bonded to four first substituents;
modifying the first compound that has a first carbon atom that is
achiral by replacing a sufficient number of the first substituents
with second substituents to provide a second compound wherein the
first carbon atom has been changed to a chiral carbon atom, and
wherein the second compound exists as a mixture of the second
compound wherein the chiral carbon atom has the R stereochemical
configuration and the second compound wherein the chiral carbon has
the S stereochemical configuration; separating the second carbon
compound wherein the chiral carbon atom has the R stereochemical
configuration and the second carbon compound wherein the chiral
carbon atom has the S stereochemical configuration; testing the
second carbon compound that has the chiral carbon in the R
stereochemical configuration and the second carbon compound that
has the chiral carbon atom bonded in the S stereochemical
configuration for activity at treating the condition; selecting the
second carbon compound that has the higher activity for treating
the condition.
29. The method of claim 1, wherein the condition is a bacterial
infection.
30. The method of claim 1, wherein the second carbon compound that
has the higher activity for treating the condition is selected
based on its rate of clearance in the animal.
31. The method of claim 30, wherein the rate of clearance in the
animal of the second carbon compound that has the higher activity
for treating the condition is the second carbon compound that is
cleared more slowly.
32. A chemical compound selected using the method of claim 28.
Description
1. FIELD OF THE INVENTION
[0001] The present invention is related to
D-(threo)-1-aryl-2-disubstitutedacylamido-3-fluoro-1-propanol
compounds compounds and analogues thereof ("Fenicol Compounds")
that are useful as broad spectrum antibiotics, pharmaceutical
compositions comprising the Fenicol Compounds, and methods of
treating or preventing bacterial infections in an animal comprising
administering to an animal in need thereof an effective amount of a
Fenicol Compound. The invention further relates to methods for
preparing the Fenicol Compounds.
2. BACKGROUND OF THE INVENTION
[0002] Bacterial infections, especially bacterial infections of the
respiratory tract, are a major problem for production animals such
as cattle, pigs, sheep, and other livestock. Bacterial infections
are also a common problem with companion animals such as cats,
dogs, and horses. Bacterial infections are typically treated using
antibiotics.
[0003] A class of broad spectrum antibiotics classified as
D-(threo)-1-p-substituted
phenyl-2-halogenoacetylamido-1,3-propanediols are known in the art.
This class of antibiotics includes chloramphenicol
(D-(threo)-1-p-nitrophenyl-2-dichloroacetamido-1,3-propanediol),
thiamphenicol
(D-(threo)-1-p-methylsulfonylphenyl-2-dichloroacetamido-1,3-propanediol),
fluorthiamphenicol
(D-(threo)-1-p-methylsulfonylphenyl-2-difluoroacetamido-1,3-propanediol)
and tevenel
(D-(threo)-1-p-aminosulfonylphenyl-2-dichloroacetamido-1,3-propanediol)
(See, U.S. Pat. No. 4,235,892 to Nagabhushan). Replacing the
primary hydroxyl group at C-3 of chloramphenicol by chlorine or
bromine, however, destroys the biological activity thereof (F. E.
Hahn, Antibiotics, Ed. Gottlieb and Shaw, Springer-Verlag, New
York, (1967), p. 308; F. E. Hahn et al, Antibiotics and
Chemotherapy, 6, No. 9, 531 (1956); L. Cima and A. Ilecto, II
Farmaco, Ed. Sc. 12, No. 6, 535 (1957); S. Mitsuhasi et al, Jap. J.
Microbiol. 13, No. 2, 177-80 (1969); M. Kono et al, Jap. J.
Microbiology 15 (3), 219-27 (1971); and U.S. Pat. No. 4,235,892 to
Nagabhushan).
[0004] U.S. Pat. No.4,235,892 to Nagabhushan discloses
D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol compounds that are
allegedly useful as antibiotics. Florfenicol,
[(R-(R*,S*)]-2,2-dichloro-N-[1-fluoromethyl)-2-hydroxy-2-[4-(methylsulfon-
yl)phenyl]ethyl]acetamide or
D-threo-2,2-dichloro-N-[1-(fluoromethyl)-2-hydroxy-2-[4-methylsulfonyl)
phenyl]ethyl]-acetamide), commercially available from
Schering-Plough Animal Health, New Jersey as NUFLOR.RTM., is an
example of an antibiotic in this class of compounds.
[0005] United States published patent application no. US
2003/0216447 to Kohan et al. and United States published patent
application no. US 2003/0220302 also to Kohan et al. each disclose
compositions comprising flunixin and a florfenicol or
florfenicol-like compound that are allegedly useful for treating
microbial infections in animals.
[0006] International publication WO 03/077828 discloses
fluorfenicol-type antibiotics that allegedly exhibit antimicrobial
activity.
[0007] U.S. Pat. No. 5,556,829 to Camaggi et al. discloses N-alkyl
amides substituted on the alkyl group that are allegedly useful as
herbicides.
[0008] U.S. Pat. No. 5,883,115 to Santus et al. discloses the
transdermal delivery of the eutmer of a chiral drug when the
eutomer has greater clearance and pharmacodynamic activity than a
racemic mixture of the chiral drug.
[0009] Many of the known antibiotics, however, have side effects.
For example, chloramphenicol is known to cause anemia. Furthermore,
the known antibiotics can be ineffective in some animals, typically
because they are cleared too rapidly. Additionally, some of the
antibiotics are toxic to some animals. Accordingly, there is a need
in the art for improved antibiotics and, in particular, new
antibiotics that fall within the same general class as the
D-(threo)-1-p-substituted
phenyl-2-halogenoacetylamido-1,3-propanediols and the
D-(threo)-1-aryl-2-acylamido-3-fluoro-1-propanol compounds.
[0010] Citation of any reference in Section 2 of this application
is not to be construed that such reference is prior art to the
present application.
3. SUMMARY OF THE INVENTION
[0011] The invention is directed to compounds of formula (I):
##STR00001##
or a pharmaceutically acceptable salt thereof,
[0012] wherein [0013] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0014] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3; -halo, or --OH; [0015] Z is hydrogen or an acyl group
of formula --C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to
C.sub.18 hydrocarbon group that may optionally be substituted with
a --NH.sub.2 or --COOH; [0016] Y and Y.sup.1 is --H; --NO.sub.2;
--SOR.sub.1; --SR.sub.1; --SONH.sub.2; --SO.sub.2NH.sub.2;
--SONHR.sub.1; --SO.sub.2NHR.sub.1; --COR.sub.1; --OR.sub.1;
--R.sub.1; --CN, -halo; -phenyl; or -phenyl substituted with -halo,
--NO.sub.2, --SO.sub.2CH.sub.3, --R.sub.1, or --OR.sub.1; [0017]
R.sub.1 is a C.sub.1 to C.sub.3 hydrocarbon group; and [0018] halo
is --Cl, --Br, --I, or --F.
[0019] The invention further relates to compounds of formula
(Ia):
##STR00002##
and pharmaceutically acceptable salts thereof,
[0020] wherein [0021] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0022] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3; -halo, or --OH; [0023] R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH; [0024] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0025] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0026] halo is --Cl, --Br, --I, or --F.
[0027] The invention is further directed to compounds of formula
(II):
##STR00003##
or a pharmaceutically acceptable salt thereof,
[0028] wherein [0029] X.sub.1 is --CH.sub.3, --CF.sub.3; -halo, or
--OH; [0030] Z is hydrogen or an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH; [0031] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.1; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0032] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0033] halo is --Cl, --Br, --I, or --F.
[0034] The invention is further directed to compounds of formula
(III):
##STR00004##
or a pharmaceutically acceptable salt thereof,
[0035] wherein [0036] A is (R) --CH(CH.sub.3)(CF.sub.3)
substantially free of (S) --CH(CH.sub.3)(CF.sub.3), (R)
--CH(CH.sub.3)(halo) substantially free of (S)
--CH(CH.sub.3)(halo), (R) --CH(CF.sub.3)(halo) substantially free
of (S) --CH(CF.sub.3)(halo), (R)--CH(CF.sub.3)(OH) substantially
free of (S) --CH(CF.sub.3)(OH), (S) --CH(CH.sub.3)(CF.sub.3)
substantially free of (R) --CH(CH.sub.3)(CF.sub.3), (S)
--CH(CH.sub.3)(halo) substantially free of (R)
--CH(CH.sub.3)(halo), (S) --CH(CF.sub.3)(halo) substantially free
of (R) --CH(CF.sub.3)(halo), or (S)CH(CF.sub.3)(OH) substantially
free of (R) --CH(CF.sub.3)(OH); [0037] Z is hydrogen or an acyl
group of formula --C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to
C.sub.18 hydrocarbon group that may optionally be substituted with
a --NH.sub.2 or --COOH; [0038] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halogen; -phenyl; or
-phenyl substituted with -halogen, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0039] halo is --Cl, --Br, --I, or --F;
and [0040] R.sub.1 is a C.sub.1 to C.sub.3 hydrocarbon group.
[0041] A compound of formula (I), (Ia), (II), or (III) or a
pharmaceutically acceptable salt thereof is useful for treating or
preventing bacterial infections in animals.
[0042] The invention further relates to a method for treating or
preventing a bacterial infection in an animal comprising
administering to an animal in need thereof a compound of formula
(IV):
##STR00005##
or a pharmaceutically acceptable salt thereof,
[0043] wherein [0044] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0045] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3, -halo, or --OH; [0046] Z is hydrogen or an acyl group
of formula --C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to
C.sub.18 hydrocarbon group that may optionally be substituted with
a --NH.sub.2 or --COOH; [0047] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0048] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0049] halo is --Cl, --Br, --I, or --F.
[0050] Accordingly, the invention relates to a method of treating
or preventing a bacterial infection in an animal comprising
administering to an animal in need thereof a compound of formula
(I), (Ia), (II), (III), or (IV) or a pharmaceutically acceptable
salt thereof (a "Fenicol Compound").
[0051] The invention further relates to a method for treating a
bacterial infection in an animal comprising administering to the
animal in need thereof an effective amount of a Fenicol
Compound.
[0052] The invention further relates to a method for preventing a
bacterial infection in an animal comprising administering to the
animal in need thereof an effective amount of a Fenicol
Compound.
[0053] The invention further relates to compositions comprising an
effective amount of a Fenicol Compound and a pharmaceutically
acceptable excipient. The compositions are useful for treating or
preventing bacterial infections in animals.
[0054] The invention further relates to a method for preparing a
composition comprising the step of admixing a Fenicol Compound and
a pharmaceutically acceptable carrier or excipient.
[0055] The invention further relates to a kit comprising a
container containing an effective amount of a Fenicol Compound.
[0056] The present invention can be understood more fully by
reference to the following detailed description and illustrative
examples, which are intended to exemplify non-limiting embodiments
of the invention.
4. BRIEF DESCRIPTION OF THE DRAWINGS
[0057] FIG. 1 is a plot of the serum concentration of NUFLOR.RTM.
and the serum concentration of an illustrative Fenicol Compound
(Fenicol Compound Al) as a function of time following subcutaneous
administration of Nuflor and Fenicol Compound A1 to dogs at a dose
of 40 mg/kg. NUFLOR.RTM. was commercially available from
Schering-Plough Animal Health, New Jersey. Fenicol Compound A1 was
formulated as a solution containing 3 g of Fenicol Compound A1, 9 g
N-methyl pyrrolidone, 2.25 g propylene glycol, QS to 20 mL with
polyethylene glycol. .tangle-solidup. represents data for Fenicol
Compound A1 and .box-solid. represents data for NUFLOR.RTM..
[0058] FIG. 2 is a plot of the serum concentration of an
illustrative Fenicol Compound (Fenicol Compound A2) as a function
of time following subcutaneous administration of Nuflor and Fenicol
Compound A2 to dogs at a dose of 40 mg/kg. NUFLOR.RTM. was
commercially available from Schering-Plough Animal Health, New
Jersey. Fenicol Compound A2 was formulated as a solution containing
925 mg of Fenicol Compound A2, 2 mL N-methyl pyrrolidone, 0.5 mL
propylene glycol, QS to 5 mL with polyethylene glycol.
[0059] FIG. 3 is a plot of the serum concentration Fenicol Compound
A2 wherein the acylamido group is in the (R) stereochemical
configuration and the serum concentration of Fenicol Compound A2
wherein the acylamido group is in the the (S) stereochemical
configuration as a function of time following subcutaneous
administration to dogs of Fenicol Compound A2 wherein the acylamido
group is present as an equimolar mixture of the (R) stereochemical
configuration and the (S) stereochemical configuration at a dose of
40 mg/kg. Fenicol Compound A2 wherein the acylamido group is
present as an equimolar mixture of the (R) stereochemical
configuration and the (S) stereochemical configuration was
administered as a solution containing 925 mg of Fenicol Compound A2
wherein the acylamido group is present as an equimolar mixture of
the (R) stereochemical configuration and the (S) stereochemical
configuration, 2 mL N-methyl pyrrolidone, 0.5 mL propylene glycol,
QS to 5 mL with polyethylene glycol.
5. DETAILED DESCRIPTION OF THE INVENTION
5.1 Fenicol Compounds of Formula (I)
[0060] As stated above, the present invention encompasses Fenicol
Compounds of formula (I):
##STR00006##
and pharmaceutically acceptable salts thereof,
[0061] wherein [0062] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0063] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3, -halo, or --OH; [0064] Y and Y.sup.1 is --H;
--NO.sub.2; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN; -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0065] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0066] halo is --Cl, --Br, --I, or --F.
[0067] In one embodiment, Y.sub.1 is hydrogen.
[0068] In one embodiment, Y.sub.1 is hydrogen and Y is
hydrogen.
[0069] In one embodiment, Y.sub.1 is hydrogen and Y is
--NO.sub.2.
[0070] In one embodiment, Y.sub.1 is hydrogen and Y is
--SOR.sub.1.
[0071] In one embodiment, Y.sub.1 is hydrogen and Y is
--SR.sub.1.
[0072] In one embodiment, Y.sub.1 is hydrogen and Y is
SONH.sub.2.
[0073] In one embodiment, Y.sub.1 is hydrogen and Y is
SO.sub.2NH.sub.2.
[0074] In one embodiment, Y.sub.1 is hydrogen and Y is
--SONHR.sub.1.
[0075] In one embodiment, Y.sub.1 is hydrogen and Y is
--SO.sub.2NHR.sub.1.
[0076] In one embodiment, Y.sub.1 is hydrogen and Y is
--COR.sub.1.
[0077] In one embodiment, Y.sub.1 is hydrogen and Y is
--OR.sub.1.
[0078] In one embodiment, Y.sub.1 is hydrogen and Y is
--R.sub.1.
[0079] In one embodiment, Y.sub.1 is hydrogen and Y is --CN.
[0080] In one embodiment, Y.sub.1 is hydrogen and Y is -halo.
[0081] In one embodiment, Y.sub.1 is hydrogen and Y is -phenyl
optionally substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1.
[0082] In one embodiment, X is --CH.sub.3 and X.sub.1 is
--CH.sub.3.
[0083] In one embodiment, X is --CH.sub.3 and X.sub.1 is
--CF.sub.3.
[0084] In one embodiment, X is --CH.sub.3 and X.sub.1 is --OH.
[0085] In one embodiment, X is --CF.sub.3 and X.sub.1 is
--CF.sub.3.
[0086] In one embodiment, X is --CF.sub.3 and X.sub.1 is -halo.
[0087] In one embodiment, X is --CF.sub.3 and X.sub.1 is --Cl.
[0088] In one embodiment, X is --CF.sub.3 and X.sub.1 is --Br.
[0089] In one embodiment, X is --CF.sub.3 and X.sub.1 is --I.
[0090] In one embodiment, X is --CF.sub.3 and X.sub.1 is --F.
[0091] In one embodiment, X is --CF.sub.3 and X.sub.1 is --OH.
[0092] In one embodiment, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0093] In one embodiment, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0094] In one embodiment, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0095] In one embodiment, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0096] In one embodiment, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0097] In one embodiment, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0098] In one embodiment, X is --CF.sub.3, X.sub.1 is -halo,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0099] In one embodiment, X is --CF.sub.3, X.sub.1 is -halo,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2
[0100] In one embodiment, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0101] In one embodiment, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0102] In one embodiment, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0103] In one embodiment, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0104] In one embodiment, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0105] In one embodiment, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0106] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0107] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0108] In one embodiment, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0109] In one embodiment, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0110] In one embodiment, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0111] In one embodiment, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0112] The present invention also encompasses Fenicol Compounds of
formula (Ia):
##STR00007##
and pharmaceutically acceptable salts thereof,
[0113] wherein [0114] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0115] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3; -halo, or --OH; [0116] R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH; [0117] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0118] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0119] halo is --Cl, --Br, --I, or --F.
[0120] In one embodiment, R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group substituted with a --NH.sub.2 or --COOH.
[0121] In one embodiment, R.sub.2 is an unsubstituted C.sub.1 to
C.sub.18 hydrocarbon group.
[0122] In one embodiment, Z is acetyl.
[0123] In one embodiment, Z is butanoyl.
[0124] In one embodiment, Z is hexanoyl.
[0125] In one embodiment, Y.sub.1 is hydrogen.
[0126] In one embodiment, Y.sub.1 is hydrogen and Y is
hydrogen.
[0127] In one embodiment, Y.sub.1 is hydrogen and Y is
--NO.sub.2.
[0128] In one embodiment, Y.sub.1 is hydrogen and Y is
--SO.sub.2R.sub.1.
[0129] In one embodiment, Y.sub.1 is hydrogen and Y is
--SOR.sub.1.
[0130] In one embodiment, Y.sub.1 is hydrogen and Y is
--SR.sub.1.
[0131] In one embodiment, Y.sub.1 is hydrogen and Y is
SONH.sub.2.
[0132] In one embodiment, Y.sub.1 is hydrogen and Y is
SO.sub.2NH.sub.2.
[0133] In one embodiment, Y.sub.1 is hydrogen and Y is
--SONHR.sub.1.
[0134] In one embodiment, Y.sub.1 is hydrogen and Y is
--SO.sub.2NHR.sub.1.
[0135] In one embodiment, Y.sub.1 is hydrogen and Y is
--COR.sub.1.
[0136] In one embodiment, Y.sub.1 is hydrogen and Y is
--OR.sub.1.
[0137] In one embodiment, Y.sub.1 is hydrogen and Y is
--R.sub.1.
[0138] In one embodiment, Y.sub.1 is hydrogen and Y is --CN.
[0139] In one embodiment, Y.sub.1 is hydrogen and Y is -halo.
[0140] In one embodiment, Y.sub.1 is hydrogen and Y is -phenyl
optionally substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1.
[0141] In one embodiment, Y.sub.1 is hydrogen and Y
--SO.sub.2CH.sub.3.
[0142] In one embodiment, X is --CH.sub.3 and X.sub.1 is
--CH.sub.3.
[0143] In one embodiment, X is --CH.sub.3 and X.sub.1 is
--CF.sub.3.
[0144] In one embodiment, X is --CH.sub.3 and X.sub.1 is --OH.
[0145] In one embodiment, X is --CF.sub.3 and X.sub.1 is
--CF.sub.3.
[0146] In one embodiment, X is --CF.sub.3 and X.sub.1 is -halo.
[0147] In one embodiment, X is --CF.sub.3 and X.sub.1 is --Cl.
[0148] In one embodiment, X is --CF.sub.3 and X.sub.1 is --Br.
[0149] In one embodiment, X is --CF.sub.3 and X.sub.1 is --I.
[0150] In one embodiment, X is --CF.sub.3 and X.sub.1 is --F.
[0151] In one embodiment, X is --CF.sub.3 and X.sub.1 is --OH.
[0152] In one embodiment, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0153] In one embodiment, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0154] In one embodiment, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0155] In one embodiment, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0156] In one embodiment, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0157] In one embodiment, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0158] In one embodiment, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0159] In one embodiment, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0160] In one embodiment, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0161] In one embodiment, X is --CF.sub.3, X.sub.1 is -halo,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0162] In one embodiment, X is --CF.sub.3, X.sub.1 is -halo,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0163] In one embodiment, X is --CF.sub.3, X.sub.1 is -halo,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0164] In one embodiment, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0165] In one embodiment, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0166] In one embodiment, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0167] In one embodiment, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0168] In one embodiment, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0169] In one embodiment, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0170] In one embodiment, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0171] In one embodiment, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0172] In one embodiment, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0173] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0174] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0175] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0176] In one embodiment, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0177] In one embodiment, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0178] In one embodiment, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0179] In one embodiment, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0180] In one embodiment, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0181] In one embodiment, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
5.2 Fenicol Compounds of Formula (II)
[0182] The present invention also relates to compounds of formula
(II):
##STR00008##
or a pharmaceutically acceptable salt thereof,
[0183] wherein [0184] X.sub.1 is --CH.sub.3, --CF.sub.3; -halo, or
--OH; [0185] Z is hydrogen or an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH; [0186] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.1; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0187] R.sub.1 is a C.sub.1 to C.sub.3
hydrocarbon group; and [0188] halo is --Cl, --Br, --I, or --F.
[0189] In one embodiment, Z is --H.
[0190] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH.
[0191] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is an unsubstituted C.sub.1 to
C.sub.18 hydrocarbon group.
[0192] In one embodiment, Z is acetyl.
[0193] In one embodiment, Z is butanoyl.
[0194] In one embodiment, Z is hexanoyl.
[0195] In one embodiment, Y.sub.1 is hydrogen.
[0196] In one embodiment, Y.sub.1 is hydrogen and Y is
hydrogen.
[0197] In one embodiment, Y.sub.1 is hydrogen and Y is
--NO.sub.2.
[0198] In one embodiment, Y.sub.1 is hydrogen and Y is
--SO.sub.2R.
[0199] In one embodiment, Y.sub.1 is hydrogen and Y is
--SOR.sub.1.
[0200] In one embodiment, Y.sub.1 is hydrogen and Y is
--SR.sub.1.
[0201] In one embodiment, Y.sub.1 is hydrogen and Y is
SONH.sub.2.
[0202] In one embodiment, Y.sub.1 is hydrogen and Y is
SO.sub.2NH.sub.2.
[0203] In one embodiment, Y.sub.1 is hydrogen and Y is
--SONHR.sub.1.
[0204] In one embodiment, Y.sub.1 is hydrogen and Y is
--SO.sub.2NHR.sub.1.
[0205] In one embodiment, Y.sub.1 is hydrogen and Y is
--COR.sub.1.
[0206] In one embodiment, Y.sub.1 is hydrogen and Y is
--OR.sub.1.
[0207] In one embodiment, Y.sub.1 is hydrogen and Y is
--R.sub.1.
[0208] In one embodiment, Y.sub.1 is hydrogen and Y is --CN.
[0209] In one embodiment, Y.sub.1 is hydrogen and Y is -halo.
[0210] In one embodiment, Y.sub.1 is hydrogen and Y is -phenyl
optionally substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR,
[0211] In one embodiment, Y.sub.1 is hydrogen and Y
--SO.sub.2CH.sub.3.
[0212] In one embodiment, Z is hydrogen and X.sub.1 is
--CH.sub.3.
[0213] In one embodiment, Z is hydrogen and X.sub.1 is
--CF.sub.3.
[0214] In one embodiment, Z is hydrogen and X.sub.1 is -halo.
[0215] In one embodiment, Z is hydrogen and X.sub.1 is --Cl.
[0216] In one embodiment, Z is hydrogen and X.sub.1 is --Br.
[0217] In one embodiment, Z is hydrogen and X.sub.1 is --I.
[0218] In one embodiment, Z is hydrogen and X.sub.1 is --F.
[0219] In one embodiment, Z is hydrogen, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0220] In one embodiment, Z is hydrogen, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0221] In one embodiment, Z is hydrogen, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0222] In one embodiment, Z is hydrogen, X.sub.1 is -halo, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0223] In one embodiment, Z is hydrogen, X.sub.1 is -halo, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0224] In one embodiment, Z is hydrogen, X.sub.1 is -halo, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0225] In one embodiment, Z is hydrogen, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0226] In one embodiment, Z is hydrogen, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0227] In one embodiment, Z is hydrogen, X.sub.1 is --Cl, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0228] In one embodiment, Z is hydrogen, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0229] In one embodiment, Z is hydrogen, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0230] In one embodiment, Z is hydrogen, X.sub.1 is --Br, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0231] In one embodiment, Z is hydrogen, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0232] In one embodiment, Z is hydrogen, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0233] In one embodiment, Z is hydrogen, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0234] In one embodiment, Z is hydrogen, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0235] In one embodiment, Z is hydrogen, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0236] In one embodiment, Z is hydrogen, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0237] In one embodiment, Z is hydrogen, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0238] In one embodiment, Z is hydrogen, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --NO.sub.2.
[0239] In one embodiment, Z is hydrogen, X.sub.1 is --OH, Y.sub.1
is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0240] In one embodiment, Z is hydrogen, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0241] In one embodiment, Z is hydrogen, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0242] In one embodiment, Z is hydrogen, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0243] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2,
--SO.sub.2CH.sub.3, or --SONH.sub.2.
[0244] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0245] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0246] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen and Y is
--SO.sub.2NH.sub.2.
[0247] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --CH.sub.3.
[0248] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --CF.sub.3.
[0249] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is -halo.
[0250] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --Cl.
[0251] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --Br.
[0252] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --I.
[0253] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --F.
[0254] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and X.sub.1 is --OH.
[0255] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CH.sub.3, Y.sub.1 is hydrogen,
and Y is --SO.sub.2CH.sub.3.
[0256] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CH.sub.3, Y.sub.1 is hydrogen,
and Y is --NO.sub.2.
[0257] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CH.sub.3, Y.sub.1 is hydrogen,
and Y is --SO.sub.2NH.sub.2.
[0258] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is -halo, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0259] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is -halo, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0260] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is -halo, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0261] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Cl, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0262] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Cl, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0263] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Cl, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0264] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Br, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0265] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Br, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0266] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --Br, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0267] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --I, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0268] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --I, Y.sub.1 is hydrogen, and Y is
--NO.sub.2.
[0269] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --I, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0270] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --F, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0271] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --F, Y.sub.1 is hydrogen, and Y is
--NO.sub.2.
[0272] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --F, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0273] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --OH, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0274] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --OH, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0275] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --OH, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0276] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CF.sub.3, Y.sub.1 is hydrogen,
and Y is --SO.sub.2CH.sub.3.
[0277] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CF.sub.3, Y.sub.1 is hydrogen,
and Y is --NO.sub.2.
[0278] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X.sub.1 is --CF.sub.3, Y.sub.1 is hydrogen,
and Y is --SO.sub.2NH.sub.2.
5.3 Fenicol Compounds of Formula (III)
[0279] The present invention also relates to compounds of formula
(III)
##STR00009##
and pharmaceutically acceptable salts thereof,
[0280] wherein [0281] A is (R) --CH(CH.sub.3)(CF.sub.3)
substantially free of (S) --CH(CH.sub.3)(CF.sub.3), (R)
--CH(CH.sub.3)(halo) substantially free of (S)
--CH(CH.sub.3)(halo), (R) --CH(CF.sub.3)(halo) substantially free
of (S) --CH(CF.sub.3)(halo), (R) --CH(CF.sub.3)(OH) substantially
free of (S) --CH(CF.sub.3)(OH), (S) --CH(CH.sub.3)(CF.sub.3)
substantially free of (R) --CH(CH.sub.3)(CF.sub.3), (S)
--CH(CH.sub.3)(halo) substantially free of (R)
--CH(CH.sub.3)(halo), (S) --CH(CF.sub.3)(halo) substantially free
of (R) --CH(CF.sub.3)(halo), or (S) --CH(CF.sub.3)(OH)
substantially free of (R) --CH(CF.sub.3)(OH); [0282] Z is hydrogen
or an acyl group of formula --C(O)--R.sub.2, wherein R.sub.2 is a
C.sub.1 to C.sub.18 hydrocarbon group that may optionally be
substituted with a --NH.sub.2 or --COOH; [0283] Y and Y.sup.1 is
--H; --NO.sub.2; --SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1;
--SONH.sub.2; --SO.sub.2NH.sub.2; --SONHR.sub.1;
--SO.sub.2NHR.sub.1; --COR.sub.2; --OR.sub.1; --R.sub.1; --CN,
-halogen; -phenyl; or -phenyl substituted with -halogen,
--NO.sub.2, --SO.sub.2CH.sub.3, --R.sub.1, or --OR.sub.1; [0284]
halo is --Cl, --Br, --I, or --F; and [0285] R.sub.1 is a C.sub.1 to
C.sub.3 hydrocarbon group.
[0286] In one embodiment, Z is hydrogen.
[0287] In one embodiment, Y.sub.1 is hydrogen.
[0288] In one embodiment, Z is an acyl hydrocarbon of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18 group
that may optionally be substituted with a --NH.sub.2 or --COOH.
[0289] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is an unsubstituted C.sub.1 to
C.sub.18 hydrocarbon group.
[0290] In one embodiment, A has the (R)-configuration.
[0291] In one embodiment, A has the (S)-configuration.
[0292] In one embodiment, A is (R) --CH(CH.sub.3)(CF.sub.3).
[0293] In one embodiment, A is (R) --CH(CH.sub.3)(halo).
[0294] In one embodiment, A is (R) --CH(CH.sub.3)(Cl).
[0295] In one embodiment, A is (R) --CH(CH.sub.3)(Br).
[0296] In one embodiment, A is (R) --CH(CH.sub.3)(I).
[0297] In one embodiment, A is (R) --CH(CH.sub.3)(F).
[0298] In one embodiment, A is (R) --CH(CH.sub.3)(OH).
[0299] In one embodiment, A is (R) --CH(CF.sub.3)(halo).
[0300] In one embodiment, A is (R) --CH(CF.sub.3)(Cl).
[0301] In one embodiment, A is (R) --CH(CF.sub.3)(Br).
[0302] In one embodiment, A is (R) --CH(CF.sub.3)(I).
[0303] In one embodiment, A is (R) --CH(CF.sub.3)(F).
[0304] In one embodiment, A is (R) --CH(CF.sub.3)(OH).
[0305] In one embodiment, A is (S) --CH(CH.sub.3)(CF.sub.3).
[0306] In one embodiment, A is (S) --CH(CH.sub.3)(halo).
[0307] In one embodiment, A is (S) --CH(CH.sub.3)(Cl).
[0308] In one embodiment, A is (S) --CH(CH.sub.3)(Br).
[0309] In one embodiment, A is (S) --CH(CH.sub.3)(I).
[0310] In one embodiment, A is (S) --CH(CH.sub.3)(F).
[0311] In one embodiment, A is (S) --CH(CH.sub.3)(OH).
[0312] In one embodiment, A is (S) --CH(CF.sub.3)(halo).
[0313] In one embodiment, A is (S) --CH(CF.sub.3)(Cl).
[0314] In one embodiment, A is (S) --CH(CF.sub.3)(Br).
[0315] In one embodiment, A is (S) --CH(CF.sub.3)(I).
[0316] In one embodiment, A is (S) --CH(CF.sub.3)(F).
[0317] In one embodiment, A is (S) --CH(CF.sub.3)(OH).
[0318] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --NO.sub.2, --SO.sub.2CH.sub.3, or --SO.sub.2NH.sub.2.
[0319] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0320] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0321] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0322] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(CF.sub.3).
[0323] In one embodiment, Z is hydrogen, A is (R)
--CH(CH.sub.3)(halo).
[0324] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(Cl).
[0325] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(Br).
[0326] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(I).
[0327] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(F).
[0328] In one embodiment, Z is hydrogen and A is (R)
--CH(CH.sub.3)(OH).
[0329] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(halo).
[0330] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(Cl).
[0331] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(Br).
[0332] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(I).
[0333] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(F).
[0334] In one embodiment, Z is hydrogen and A is (R)
--CH(CF.sub.3)(OH).
[0335] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(CF.sub.3).
[0336] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(halo).
[0337] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(Cl).
[0338] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(Br).
[0339] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(I).
[0340] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(F).
[0341] In one embodiment, Z is hydrogen and A is (S)
--CH(CH.sub.3)(OH).
[0342] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(halo).
[0343] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(Cl).
[0344] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(Br).
[0345] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(I).
[0346] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(F).
[0347] In one embodiment, Z is hydrogen and A is (S)
--CH(CF.sub.3)(OH).
[0348] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) --H(CH.sub.3)(CF.sub.3).
[0349] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) --CH(CH.sub.3)(halo).
[0350] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) --CH(CH.sub.3)(Cl).
[0351] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) --CH(CH.sub.3)(Br).
[0352] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) 13 CH(CH.sub.3)(I).
[0353] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) 13 CH(CH.sub.3)(F).
[0354] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) 13 CH(CH.sub.3)(OH).
[0355] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R)--CH(CF.sub.3)(halo).
[0356] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R)--CH(CF.sub.3)(Cl).
[0357] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R)--CH(CF.sub.3)(Br).
[0358] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R)--CH(CF.sub.3)(I).
[0359] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R)--CH(CF.sub.3)(F).
[0360] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (R) --CH(CF.sub.3)(OH).
[0361] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0362] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(halo).
[0363] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(Cl).
[0364] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(Br).
[0365] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(I).
[0366] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(F).
[0367] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CH.sub.3)(OH).
[0368] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(halo).
[0369] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(Cl).
[0370] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(Br).
[0371] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(I).
[0372] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(F).
[0373] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2CH.sub.3, and A is (S) --CH(CF.sub.3)(OH).
[0374] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(CF.sub.3).
[0375] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(halo).
[0376] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(Cl).
[0377] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(Br).
[0378] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(I).
[0379] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(F).
[0380] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CH.sub.3)(OH).
[0381] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(halo).
[0382] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(Cl).
[0383] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(Br).
[0384] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(I).
[0385] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(F).
[0386] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (R) --CH(CF.sub.3)(OH).
[0387] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0388] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(halo).
[0389] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(Cl).
[0390] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(Br).
[0391] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(I).
[0392] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(F).
[0393] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CH.sub.3)(OH).
[0394] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(halo).
[0395] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(Cl).
[0396] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(Br).
[0397] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(I).
[0398] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(F).
[0399] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--NO.sub.2, and A is (S) --CH(CF.sub.3)(OH).
[0400] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(CF.sub.3).
[0401] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(halo).
[0402] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(Cl).
[0403] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(Br).
[0404] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(I).
[0405] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(F).
[0406] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R) --CH(CH.sub.3)(OH).
[0407] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(halo).
[0408] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(Cl).
[0409] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(Br).
[0410] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(I).
[0411] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(F).
[0412] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (R)--CH(CF.sub.3)(OH).
[0413] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0414] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(halo).
[0415] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(Cl).
[0416] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(Br).
[0417] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(I).
[0418] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(F).
[0419] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CH.sub.3)(OH).
[0420] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(halo).
[0421] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(Cl).
[0422] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(Br).
[0423] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(I).
[0424] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(F). In one
embodiment, Z is hydrogen, Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(OH).
[0425] In one embodiment, Z is an acyl hydrocarbon of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2,
--SO.sub.2CH.sub.3, or --SO.sub.2NH.sub.2.
[0426] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0427] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0428] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0429] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(halo).
[0430] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(Cl).
[0431] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(Br).
[0432] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(I).
[0433] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(F)
[0434] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(OH).
[0435] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(halo).
[0436] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(Cl).
[0437] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(Br).
[0438] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(I).
[0439] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(F).
[0440] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CF.sub.3)(OH).
[0441] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (R) --CH(CH.sub.3)(CF.sub.3).
[0442] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(halo).
[0443] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(Cl).
[0444] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to Cl.sub.8
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(Br).
[0445] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(I).
[0446] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(F).
[0447] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(OH).
[0448] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(halo).
[0449] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(Cl).
[0450] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(Br).
[0451] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(I).
[0452] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(F).
[0453] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CF.sub.3)(OH).
[0454] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0455] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(CF.sub.3).
[0456] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(halo).
[0457] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(Cl).
[0458] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(Br).
[0459] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18 group
that may optionally be substituted with a --NH.sub.2 or --COOH,
Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3, and A is (R)
--CH(CH.sub.3)(I).
[0460] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(F).
[0461] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CH.sub.3)(OH).
[0462] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(halo).
[0463] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(Cl).
[0464] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(Br).
[0465] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(I).
[0466] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(F).
[0467] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (R) --CH(CF.sub.3)(OH).
[0468] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0469] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(halo).
[0470] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(Cl).
[0471] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(Br).
[0472] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(I).
[0473] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(F).
[0474] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CH.sub.3)(OH).
[0475] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(halo).
[0476] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(Cl).
[0477] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(Br).
[0478] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(I).
[0479] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(F).
[0480] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2CH.sub.3,
and A is (S) --CH(CF.sub.3)(OH).
[0481] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(CF.sub.3).
[0482] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(halo).
[0483] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(Cl).
[0484] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(Br).
[0485] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(I).
[0486] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18 group
that may optionally be substituted with a --NH.sub.2 or --COOH,
Y.sub.1 is hydrogen, Y is --NO.sub.2, and A is (R)
--CH(CH.sub.3)(F).
[0487] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CH.sub.3)(OH).
[0488] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(halo).
[0489] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(Cl).
[0490] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(Br).
[0491] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(I).
[0492] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(F).
[0493] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (R) --CH(CF.sub.3)(OH).
[0494] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CH.sub.3)(CF.sub.3).
[0495] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CH.sub.3)(halo).
[0496] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sup.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CH.sub.3)(Cl).
[0497] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18 group
that may optionally be substituted with a --NH.sub.2 or --COOH,
Y.sub.1 is hydrogen, Y is --NO.sub.2, and A is (S)
--CH(CH.sub.3)(Br).
[0498] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18 group
that may optionally be substituted with a --NH.sub.2 or --COOH,
Y.sub.1 is hydrogen, Y is --NO.sub.2, and A is (S)
--CH(CH.sub.3)(I).
[0499] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CH.sub.3)(F).
[0500] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CH.sub.3)(OH).
[0501] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(halo).
[0502] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(Cl).
[0503] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(Br).
[0504] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(I).
[0505] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(F).
[0506] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --NO.sub.2, and A
is (S) --CH(CF.sub.3)(OH).
[0507] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(CF.sub.3).
[0508] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(halo).
[0509] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Yi is hydrogen, Y is --SO.sub.2NH.sub.2, and
A is (R) --CH(CH.sub.3)(Cl).
[0510] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(Br).
[0511] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(I).
[0512] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(F).
[0513] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CH.sub.3)(OH).
[0514] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CF.sub.3)(halo).
[0515] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CF.sub.3)(Cl).
[0516] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CF.sub.3)(Br).
[0517] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Yi is hydrogen, Y is --SO.sub.2NH.sub.2, and
A is (R) --CH(CF.sub.3)(I).
[0518] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CF.sub.3)(F).
[0519] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (R) --CH(CF.sub.3)(OH).
[0520] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(CF.sub.3).
[0521] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(halo).
[0522] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(Cl).
[0523] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(Br).
[0524] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(I).
[0525] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(F).
[0526] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CH.sub.3)(OH).
[0527] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CF.sub.3)(halo).
[0528] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CF.sub.3)(Cl).
[0529] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CF.sub.3)(Br).
[0530] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CF.sub.3)(I).
[0531] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 Y.sub.1 is hydrogen, Y is
--SO.sub.2NH.sub.2, and A is (S) --CH(CF.sub.3)(F).
[0532] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, Y is --SO.sub.2NH.sub.2,
and A is (S) --CH(CF.sub.3)(OH).
5.4 Illustrative Fenicol Compounds
[0533] Illustrative Fenicol Compounds useful in the compositions
and methods of the invention are listed below in Tables A-L.
TABLE-US-00001 TABLE A ##STR00010## Compound Y X.sub.1 X A1
--SO.sub.2CH.sub.3 --CH.sub.3 --CH.sub.3 A2 --SO.sub.2CH.sub.3
--CH.sub.3 --CF.sub.3 A3 --SO.sub.2CH.sub.3 --CF.sub.3 --CF.sub.3
A4 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl A5 --SO.sub.2CH.sub.3
--CF.sub.3 --Br A6 --SO.sub.2CH.sub.3 --CF.sub.3 --I A7
--SO.sub.2CH.sub.3 --CF.sub.3 --F A8 --SO.sub.2CH.sub.3 --CH.sub.3
--OH A9 --SO.sub.2CH.sub.3 --CF.sub.3 --OH A10 --NO.sub.2
--CH.sub.3 --CH.sub.3 A11 --NO.sub.2 --CH.sub.3 --CF.sub.3 A12
--NO.sub.2 --CF.sub.3 --CF.sub.3 A13 --NO.sub.2 --CF.sub.3 --Cl A14
--NO.sub.2 --CF.sub.3 --Br A15 --NO.sub.2 --CF.sub.3 --I A16
--NO.sub.2 --CH.sub.3 --F A17 --NO.sub.2 --CH.sub.3 --OH A18
--NO.sub.2 --CF.sub.3 --OH A19 --SO.sub.2NH.sub.2 --CF.sub.3
--CH.sub.3 A20 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 A21
--SO.sub.2NH.sub.2 --CF.sub.3 --CF.sub.3 A22 --SO.sub.2NH.sub.2
--CF.sub.3 --Cl A23 --SO.sub.2NH.sub.2 --CF.sub.3 --Br A24
--SO.sub.2NH.sub.2 --CF.sub.3 --I A25 --SO.sub.2NH.sub.2 --CF.sub.3
--F A26 --SO.sub.2NH.sub.2 --CH.sub.3 --OH A27 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00002 TABLE B ##STR00011## Compound Y X.sub.1 X B1
--SO.sub.2CH.sub.3 --CH.sub.3 --CH.sub.3 B2 --SO.sub.2CH.sub.3
--CH.sub.3 --CF.sub.3 B3 --SO.sub.2CH.sub.3 --CF.sub.3 --CF.sub.3
B4 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl B5 --SO.sub.2CH.sub.3
--CF.sub.3 --Br B6 --SO.sub.2CH.sub.3 --CF.sub.3 --I B7
--SO.sub.2CH.sub.3 --CF.sub.3 --F B8 --SO.sub.2CH.sub.3 --CH.sub.3
--OH B9 --SO.sub.2CH.sub.3 --CF.sub.3 --OH B10 --NO.sub.2
--CH.sub.3 --CH.sub.3 B11 --NO.sub.2 --CH.sub.3 --CF.sub.3 B12
--NO.sub.2 --CF.sub.3 --CF.sub.3 B13 --NO.sub.2 --CF.sub.3 --Cl B14
--NO.sub.2 --CF.sub.3 --Br B15 --NO.sub.2 --CF.sub.3 --I B16
--NO.sub.2 --CF.sub.3 --F B17 NO.sub.2 --CH.sub.3 --OH B18 NO.sub.2
--CF.sub.3 --OH B19 --SO.sub.2NH.sub.2 --CH.sub.3 --CH.sub.3 B20
--SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 B21 --SO.sub.2NH.sub.2
--CF.sub.3 --CF.sub.3 B22 --SO.sub.2NH.sub.2 --CF.sub.3 --Cl B23
--SO.sub.2NH.sub.2 --CF.sub.3 --Br B24 --SO.sub.2NH.sub.2
--CF.sub.3 --I B25 --SO.sub.2NH.sub.2 --CF.sub.3 --F B26
--SO.sub.2NH.sub.2 --CH.sub.3 --OH B27 --SO.sub.2NH.sub.2
--Cf.sub.3 --OH
TABLE-US-00003 TABLE C ##STR00012## Compound Y X.sub.1 X C1
--SO.sub.2CH.sub.3 --CH.sub.3 --CH.sub.3 C2 --SO.sub.2CH.sub.3
--CH.sub.3 --CF.sub.3 C3 --SO.sub.2CH.sub.3 --CF.sub.3 --CF.sub.3
C4 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl C5 --SO.sub.2CH.sub.3
--CF.sub.3 --Br C6 --SO.sub.2CH.sub.3 --CF.sub.3 --I C7
--SO.sub.2CH.sub.3 --CF.sub.3 --F C8 --SO.sub.2CH.sub.3 --CH.sub.3
--OH C9 --SO.sub.2CH.sub.3 --CF.sub.3 --OH C10 --NO.sub.2
--CH.sub.3 --CH.sub.3 C11 --NO.sub.2 --CH.sub.3 --CF.sub.3 C12
--NO.sub.2 --CF.sub.3 --CF.sub.3 C13 --NO.sub.2 --CF.sub.3 --Cl C14
--NO.sub.2 --CF.sub.3 --Br C15 --NO.sub.2 --CF.sub.3 --I C16
--NO.sub.2 --CF.sub.3 --F C17 --NO.sub.2 --CH.sub.3 --OH C18
--NO.sub.2 --CF.sub.3 --OH C19 --SO.sub.2NH.sub.2 --CH.sub.3
--CH.sub.3 C20 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 C21
--SO.sub.2NH.sub.2 --CF.sub.3 --CF.sub.3 C22 --SO.sub.2NH.sub.2
--CF.sub.3 --Cl C23 --SO.sub.2NH.sub.2 --CF.sub.3 --Br C24
--SO.sub.2NH.sub.2 --CF.sub.3 --I C25 --SO.sub.2NH.sub.2 --CF.sub.3
--F C26 --SO.sub.2NH.sub.2 --CF.sub.3 --OH C27 --SO.sub.2NH.sub.2
--CH.sub.3 --OH
TABLE-US-00004 TABLE D ##STR00013## Compound Y X.sub.1 X D1
--SO.sub.2CH.sub.3 --CH.sub.3 --CH.sub.3 D2 --SO.sub.2CH.sub.3
--CH.sub.3 --CF.sub.3 D3 --SO.sub.2CH.sub.3 --CF.sub.3 --CF.sub.3
D4 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl D5 --SO.sub.2CH.sub.3
--CF.sub.3 --Br D6 --SO.sub.2CH.sub.3 --CF.sub.3 --I D7
--SO.sub.2CH.sub.3 --CF.sub.3 --F D8 --SO.sub.2CH.sub.3 --CH.sub.3
--OH D9 --SO.sub.2CH.sub.3 --CF.sub.3 --OH D10 --NO.sub.2
--CH.sub.3 --CH.sub.3 D11 --NO.sub.2 --CH.sub.3 --CF.sub.3 D12
--NO.sub.2 --CF.sub.3 --CF.sub.3 D13 --NO.sub.2 --CF.sub.3 --Cl D14
--NO.sub.2 --CF.sub.3 --Br D15 --NO.sub.2 --CF.sub.3 --I D16
--NO.sub.2 --CF.sub.3 --F D17 --NO.sub.2 --CH.sub.3 --F D18
--NO.sub.2 --CF.sub.3 --OH D19 --SO.sub.2NH.sub.2 --CH.sub.3
--CH.sub.3 D20 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 D21
--SO.sub.2NH.sub.2 --CF.sub.3 --CF.sub.3 D22 --SO.sub.2NH.sub.2
--CF.sub.3 --Cl D23 --SO.sub.2NH.sub.2 --CF.sub.3 --Br D24
--SO.sub.2NH.sub.2 --CF.sub.3 --I D25 --SO.sub.2NH.sub.2 --CF.sub.3
--F D26 --SO.sub.2NH.sub.2 --CH.sub.3 --OH D27 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00005 TABLE E ##STR00014## Compound Y X.sub.1 X E1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 E2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl E3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br E4
--SO.sub.2CH.sub.3 --CH.sub.3 --I E5 --SO.sub.2CH.sub.3 --CH.sub.3
--F E6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl E7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br E8 --SO.sub.2CH.sub.3 --CF.sub.3 --I E9
--SO.sub.2CH.sub.3 --CF.sub.3 --F E10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH E11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH E12 --NO.sub.2
--CH.sub.3 --CF.sub.3 E13 --NO.sub.2 --CH.sub.3 --Cl E14 --NO.sub.2
--CH.sub.3 --Br E15 --NO.sub.2 --CH.sub.3 --I E16 --NO.sub.2
--CH.sub.3 --F E17 --NO.sub.2 --CF.sub.3 --Cl E18 --NO.sub.2
--CF.sub.3 --Br E19 --NO.sub.2 --CF.sub.3 --I E20 --NO.sub.2
--CF.sub.3 --F E21 --NO.sub.2 --CH.sub.3 --OH E22 --NO.sub.2
--CF.sub.3 --OH E23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 E24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl E25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br E26 --SO.sub.2NH.sub.2 --CH.sub.3 --I E27
--SO.sub.2NH.sub.2 --CH.sub.3 --F E28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl E29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br E30 --SO.sub.2NH.sub.2
--CF.sub.3 --I E31 --SO.sub.2NH.sub.2 --CF.sub.3 --F E32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH
TABLE-US-00006 TABLE F ##STR00015## Compound Y X.sub.1 X F1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 F2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl F3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br F4
--SO.sub.2CH.sub.3 --CH.sub.3 --I F5 --SO.sub.2CH.sub.3 --CH.sub.3
--F F6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl F7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br F8 --SO.sub.2CH.sub.3 --CF.sub.3 --I F9
--SO.sub.2CH.sub.3 --CF.sub.3 --F F10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH F11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH F12 --NO.sub.2
--CH.sub.3 --CF.sub.3 F13 --NO.sub.2 --CH.sub.3 --Cl F14 --NO.sub.2
--CH.sub.3 --Br F15 --NO.sub.2 --CH.sub.3 --I F16 --NO.sub.2
--CH.sub.3 --F F17 --NO.sub.2 --CF.sub.3 --Cl F18 --NO.sub.2
--CF.sub.3 --Br F19 --NO.sub.2 --CF.sub.3 --I F20 --NO.sub.2
--CF.sub.3 --F F21 --NO.sub.2 --CH.sub.3 --OH F22 --NO.sub.2
--CF.sub.3 --OH F23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 F24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl F25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br F26 --SO.sub.2NH.sub.2 --CH.sub.3 --I F27
--SO.sub.2NH.sub.2 --CH.sub.3 --F F28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl F29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br F30 --SO.sub.2NH.sub.2
--CF.sub.3 --I F31 --SO.sub.2NH.sub.2 --CF.sub.3 --F F32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH F33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00007 TABLE G ##STR00016## Compound Y X.sub.1 X G1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 G2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl G3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br G4
--SO.sub.2CH.sub.3 --CH.sub.3 --I G5 --SO.sub.2CH.sub.3 --CH.sub.3
--F G6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl G7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br G8 --SO.sub.2CH.sub.3 --CF.sub.3 --I G9
--SO.sub.2CH.sub.3 --CF.sub.3 --F G10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH G11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH G12 --NO.sub.2
--CH.sub.3 --CF.sub.3 G13 --NO.sub.2 --CH.sub.3 --Cl G14 --NO.sub.2
--CH.sub.3 --Br G15 --NO.sub.2 --CH.sub.3 --I G16 --NO.sub.2
--CH.sub.3 --F G17 --NO.sub.2 --CF.sub.3 --Cl G18 --NO.sub.2
--CF.sub.3 --Br G19 --NO.sub.2 --CF.sub.3 --I G20 --NO.sub.2
--CF.sub.3 --F G21 --NO.sub.2 --CH.sub.3 --OH G22 --NO.sub.2
--CF.sub.3 --OH G23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 G24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl G25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br G26 --SO.sub.2NH.sub.2 --CH.sub.3 --I G27
--SO.sub.2NH.sub.2 --CH.sub.3 --F G28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl G29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br G30 --SO.sub.2NH.sub.2
--CF.sub.3 --I G31 --SO.sub.2NH.sub.2 --CF.sub.3 --F G32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH G33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00008 TABLE H ##STR00017## Compound Y X.sub.1 X H1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 H2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl H3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br H4
--SO.sub.2CH.sub.3 --CH.sub.3 --I H5 --SO.sub.2CH.sub.3 --CH.sub.3
--F H6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl H7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br H8 --SO.sub.2CH.sub.3 --CF.sub.3 --I H9
--SO.sub.2CH.sub.3 --CF.sub.3 --F H10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH H11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH H12 --NO.sub.2
--CH.sub.3 --CF.sub.3 H13 --NO.sub.2 --CH.sub.3 --Cl H14 --NO.sub.2
--CH.sub.3 --Br H15 --NO.sub.2 --CH.sub.3 --I H16 --NO.sub.2
--CH.sub.3 --F H17 --NO.sub.2 --CF.sub.3 --Cl H18 --NO.sub.2
--CF.sub.3 --Br H19 --NO.sub.2 --CF.sub.3 --I H20 --NO.sub.2
--CF.sub.3 --F H21 --NO.sub.2 --CH.sub.3 --OH H22 --NO.sub.2
--CF.sub.3 --OH H23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 H24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl H25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br H26 --SO.sub.2NH.sub.2 --CH.sub.3 --I H27
--SO.sub.2NH.sub.2 --CH.sub.3 --F H28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl H29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br H30 --SO.sub.2NH.sub.2
--CF.sub.3 --I H31 --SO.sub.2NH.sub.2 --CF.sub.3 --F H32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH H33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00009 TABLE I ##STR00018## Compound Y X.sub.1 X I1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 I2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl I3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br I4
--SO.sub.2CH.sub.3 --CH.sub.3 --I I5 --SO.sub.2CH.sub.3 --CH.sub.3
--F I6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl I7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br I8 --SO.sub.2CH.sub.3 --CF.sub.3 --I I9
--SO.sub.2CH.sub.3 --CF.sub.3 --F I10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH I11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH I12 --NO.sub.2
--CH.sub.3 --CF.sub.3 I13 --NO.sub.2 --CH.sub.3 --Cl I14 --NO.sub.2
--CH.sub.3 --Br I15 --NO.sub.2 --CH.sub.3 --I I16 --NO.sub.2
--CH.sub.3 --F I17 --NO.sub.2 --CF.sub.3 --Cl I18 --NO.sub.2
--CF.sub.3 --Br I19 --NO.sub.2 --CF.sub.3 --I I20 --NO.sub.2
--CF.sub.3 --F I21 --NO.sub.2 --CH.sub.3 --OH I22 --NO.sub.2
--CF.sub.3 --OH I23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 I24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl I25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br I26 --SO.sub.2NH.sub.2 --CH.sub.3 --I I27
--SO.sub.2NH.sub.2 --CH.sub.3 --F I28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl I29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br I30 --SO.sub.2NH.sub.2
--CF.sub.3 --I I31 --SO.sub.2NH.sub.2 --CF.sub.3 --F I32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH I33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00010 TABLE J ##STR00019## Compound Y X.sub.1 X J1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 J2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl J3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br J4
--SO.sub.2CH.sub.3 --CH.sub.3 --I J5 --SO.sub.2CH.sub.3 --CH.sub.3
--F J6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl J7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br J8 --SO.sub.2CH.sub.3 --CF.sub.3 --I J9
--SO.sub.2CH.sub.3 --CF.sub.3 --F J10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH J11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH J12 --NO.sub.2
--CH.sub.3 --CF.sub.3 J13 --NO.sub.2 --CH.sub.3 --Cl J14 --NO.sub.2
--CH.sub.3 --Br J15 --NO.sub.2 --CH.sub.3 --I J16 --NO.sub.2
--CH.sub.3 --F J17 --NO.sub.2 --CF.sub.3 --Cl J18 --NO.sub.2
--CF.sub.3 --Br J19 --NO.sub.2 --CF.sub.3 --I J20 --NO.sub.2
--CF.sub.3 --F J21 --NO.sub.2 --CH.sub.3 --OH J22 --NO.sub.2
--CF.sub.3 --OH J23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 J24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl J25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br J26 --SO.sub.2NH.sub.2 --CH.sub.3 --I J27
--SO.sub.2NH.sub.2 --CH.sub.3 --F J28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl J29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br J30 --SO.sub.2NH.sub.2
--CF.sub.3 --I J31 --SO.sub.2NH.sub.2 --CF.sub.3 --F J32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH J33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00011 TABLE K ##STR00020## Compound Y X.sub.1 X K1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 K2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl K3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br K4
--SO.sub.2CH.sub.3 --CH.sub.3 --I K5 --SO.sub.2CH.sub.3 --CH.sub.3
--F K6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl K7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br K8 --SO.sub.2CH.sub.3 --CF.sub.3 --I K9
--SO.sub.2CH.sub.3 --CF.sub.3 --F K10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH K11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH K12 --NO.sub.2
--CH.sub.3 --CF.sub.3 K13 --NO.sub.2 --CH.sub.3 --Cl K14 --NO.sub.2
--CH.sub.3 --Br K15 --NO.sub.2 --CH.sub.3 --I K16 --NO.sub.2
--CH.sub.3 --F K17 --NO.sub.2 --CF.sub.3 --Cl K18 --NO.sub.2
--CF.sub.3 --Br K19 --NO.sub.2 --CF.sub.3 --I K20 --NO.sub.2
--CF.sub.3 --F K21 --NO.sub.2 --CH.sub.3 --OH K22 --NO.sub.2
--CF.sub.3 --OH K23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 K24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl K25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br K26 --SO.sub.2NH.sub.2 --CH.sub.3 --I K27
--SO.sub.2NH.sub.2 --CH.sub.3 --F K28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl K29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br K30 --SO.sub.2NH.sub.2
--CF.sub.3 --I K31 --SO.sub.2NH.sub.2 --CF.sub.3 --F K32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH K33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
TABLE-US-00012 TABLE L ##STR00021## Compound Y X.sub.1 X L1
--SO.sub.2CH.sub.3 --CH.sub.3 --CF.sub.3 L2 --SO.sub.2CH.sub.3
--CH.sub.3 --Cl L3 --SO.sub.2CH.sub.3 --CH.sub.3 --Br L4
--SO.sub.2CH.sub.3 --CH.sub.3 --I L5 --SO.sub.2CH.sub.3 --CH.sub.3
--F L6 --SO.sub.2CH.sub.3 --CF.sub.3 --Cl L7 --SO.sub.2CH.sub.3
--CF.sub.3 --Br L8 --SO.sub.2CH.sub.3 --CF.sub.3 --I L9
--SO.sub.2CH.sub.3 --CF.sub.3 --F L10 --SO.sub.2CH.sub.3 --CH.sub.3
--OH L11 --SO.sub.2CH.sub.3 --CF.sub.3 --OH L12 --NO.sub.2
--CH.sub.3 --CF.sub.3 L13 --NO.sub.2 --CH.sub.3 --Cl L14 --NO.sub.2
--CH.sub.3 --Br L15 --NO.sub.2 --CH.sub.3 --I L16 --NO.sub.2
--CH.sub.3 --F L17 --NO.sub.2 --CF.sub.3 --Cl L18 --NO.sub.2
--CF.sub.3 --Br L19 --NO.sub.2 --CF.sub.3 --I L20 --NO.sub.2
--CF.sub.3 --F L21 --NO.sub.2 --CH.sub.3 --OH L22 --NO.sub.2
--CF.sub.3 --OH L23 --SO.sub.2NH.sub.2 --CH.sub.3 --CF.sub.3 L24
--SO.sub.2NH.sub.2 --CH.sub.3 --Cl L25 --SO.sub.2NH.sub.2
--CH.sub.3 --Br L26 --SO.sub.2NH.sub.2 --CH.sub.3 --I L27
--SO.sub.2NH.sub.2 --CH.sub.3 --F L28 --SO.sub.2NH.sub.2 --CF.sub.3
--Cl L29 --SO.sub.2NH.sub.2 --CF.sub.3 --Br L30 --SO.sub.2NH.sub.2
--CF.sub.3 --I L31 --SO.sub.2NH.sub.2 --CF.sub.3 --F L32
--SO.sub.2NH.sub.2 --CH.sub.3 --OH L33 --SO.sub.2NH.sub.2
--CF.sub.3 --OH
5.5 Definitions
[0534] As used herein, the following terms have the following
meaning:
[0535] "C.sub.1 to C.sub.3 hydrocarbon group" means a straight or
branched, saturated or unsaturated, non-cyclic hydrocarbon having
from 1 to 3 carbon atoms. Representative C.sub.1-C.sub.3
hydrocarbon groups include, but are not limited to, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3, and
--CH.sub.2CH.dbd.CH.sub.2.
[0536] "C.sub.1-C.sub.18 hydrocarbon group" means a straight or
branched, saturated or unsaturated, cyclic or non-cyclic, aromatic
or non-aromatic hydrocarbon having from 1 to 18 carbon atoms.
Accordingly, the phrase "an acyl group of formula --C(O)--R.sub.2,
wherein R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that may
optionally be substituted with a --NH.sub.2 or --COOH" means
R.sub.2 of the acyl group of formula --C(O)--R.sub.2 is a straight
or branched, saturated or unsaturated, cyclic or non-cyclic,
aromatic or non-aromatic hydrocarbon having from 1 to 18 carbon
atoms that may optionally be substituted with a --NH.sub.2 or
--COOH. Representative acyl group of formula --C(O)--R.sub.2,
wherein R.sub.2 is an unsubstituted C.sub.1 to C.sub.18 hydrocarbon
group include, but are not limited to, acetyl, propionyl, butanoyl,
hexanoyl, caproyl, laurolyl, myristoyl, palmitoyl, stearoyl,
palmioleoyl, oleoyl, linoleoyl, linolenoyl, and benzoyl.
Representative acyl groups of formula --C(O)--R.sub.2, wherein
R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that is
substituted with a --COOH, include but are not limited to, oxaloyl,
malonoyl, succinoyl, glutamoyl, adipoyl, and pimeloyl.
Representative acyl groups of formula --C(O)--R.sub.2, wherein
R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that is
substituted with a --NH.sub.2, include but are not limited to, acyl
groups derived from amino acids such as tyrosine, alanine,
threonine, serine, hydroxyproline, proline, phenylalanine, leucine,
valine, and glycine.
[0537] The term "animal" includes, but is not limited to, cow,
horse, sheep, pig, ungulate, chimpanzee, monkey, baboon, chicken,
turkey, mouse, rabbit, rat, guinea pig, and human.
[0538] The term "halo" or "halogen" means --Cl, --Br, --I, or
--F.
[0539] The phrase "effective amount" when used in connection with a
Fenicol Compound means an amount for treating or preventing a
bacterial infection.
[0540] The phrase "effective amount" when used in connection with
another therapeutic agent means an amount for providing the
therapeutic effect of the therapeutic agent.
[0541] The phrase "treating," "treatment of," and the like includes
the ameleration or cessation of a specified condition, typically a
bacterial infection.
[0542] The phrase "preventing," "prevention of," and the like
include the avoidance of the onset of a condition, typically a
bacterial infection.
[0543] The phrase "substantially free of the enantiomeric
stereochemical configuration," means a functional group having a
chiral center, and therefore capable of existing in either of two
stereochemical configurations, is present in predominately one
desired stereochemical configuration, i.e., either the the (R)
configuration or the (S) configuration, and greater than 50 percent
of the functional groups have the desired stereochemical
configuration, preferably at least 75 percent of the functional
groups have the desired stereochemical configuration, more
preferably at least 90 percent of the functional groups have the
desired stereochemical configuration, even more preferably at least
95 percent of the functional groups have the desired stereochemical
configuration, and most preferably at least 99 percent of the
functional groups have the desired stereochemical configuration.
For example the phrase "the (R) stereochemical configuration
substantially free of the enantiomeric stereochemical
configuration" or the phrase "the (R) stereochemical configuration
substantially free of the (S) stereochemical configuration" means a
chiral functional group that is predominately present in the (R)
stereochemical configuration and that greater than 50 percent of
the functional groups have the (R) stereochemical configuration,
preferably at least 75 percent of the functional groups have the
(R) stereochemical configuration, more preferably at least 90
percent of the functional groups have the (R) stereochemical
configuration, even more preferably at least 95 percent of the
functional groups have the (R) stereochemical configuration, and
most preferably at least 99 percent of the functional groups have
the (R) stereochemical configuration.
[0544] The phrase "pharmaceutically acceptable salt," as used
herein, is a salt formed from an acid and a basic nitrogen group of
one of the Fenicol Compounds. Illustrative salts include, but are
not limited, to sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term
"pharmaceutically acceptable salt" also refers to a salt prepared
from a Fenicol Compound having an acidic functional group, such as
a carboxylic acid functional group, and a pharmaceutically
acceptable inorganic or organic base. Suitable bases include, but
are not limited to, hydroxides of alkali metals such as sodium,
potassium, and lithium; hydroxides of alkaline earth metal such as
calcium and magnesium; hydroxides of other metals, such as aluminum
and zinc; ammonia, and organic amines, such as unsubstituted or
hydroxy-substituted mono-, di-, or trialkylamines;
dicyclohexylamine; tributyl amine; pyridine; N-methyl,
N-ethylamine; diethylamine; triethylamine; mono-, bis-, or
tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like.
[0545] The phrase "THF," as used herein means tetrahydrofuran.
[0546] The phrase "DCM," as used herein means dichloromethane.
[0547] The phrase "DMF," as used herein means
dimethylformamide.
[0548] The phrase "EDC" as used herein means ethyl
diisopropylcarbodimide.
[0549] The phrase "HOBT" as used herein means
hydroxybenzotriazole.
[0550] The phrase "BOP" as used herein means butyloxyphosphine.
[0551] The phrase "DCC" as used herein means
dicyclohexylcarbodimide.
5.6 Methods for Making the Fenicol Compounds
5.6.1 Fenicol Compounds of Formula (I), (Ia) and (II)
[0552] The Fenicol Compounds of formula (I), (Ia), and (II) can be
obtained by the following illustrative method shown below in Scheme
1:
##STR00022##
[0553] A N-hydroxysuccinimide ester of a carboxylic acid, B, is
prepared by methods well known to those of ordinary skill in the
art. For example, N-hydroxysuccinimide esters of a carboxylic acid
can be obtained by dissolving about 1 eq. of carboxylic acid and 1
eq. of N-hydroxysuccinimide in about 200 mL of an organic solvent,
and cooling the resulting solution to about 0.degree. C. About 1
eq. of DCC in 50 mL of the same organic solvent is then added
dropwise to the cooled solution of carboxylic acid and
N-hydroxysuccinimide. The resulting mixture is allowed to stir for
about 30 min. to provide an organic solution of the
N-hydroxysuccinimide ester of a carboxylic acid, B. The
N-hydroxysuccinimide ester of a carboxylic acid, B, can be
recovered by removing the organic solvent under reduced pressure.
Preferably, however, the organic solution of the
N-hydroxysuccinimide ester of a carboxylic acid, B, is combined
directly with the D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol of
formula A, as described below. The organic solution of the
N-hydroxysuccinimide ester can be stored overnight at refrigerator
temperature. Useful solvents for obtaining the N-hydroxysuccinimide
ester of a carboxylic acid, B, include, but are not limited to THF,
DCM, carbon tetrachloride, chloroform, dioxane, and DMF.
[0554] The D-(threo)-1-aryl-2-amino-3-fluoro-1-propanols of formula
A are commercially available or can be obtained as described in
U.S. Pat. Nos. 4,235,892; 4,311,857; 4,582,918; 4,973,750;
4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673;
5,352,832; 5,663,361; and WO 03/077828, the contents of which are
expressly incorporated herein. For example,
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol can be
easily obtained by hydrolyzing fluorfenicol under acidic
conditions.
[0555] A D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, (1 eq.)
is then reacted with an N-hydroxysuccinimide ester of a carboxylic
acid, B, according to methods well known to those skilled in the
art to provide the Fenicol Compound of formula (I), (Ia), or (II).
Typically, the D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, (1
eq.) is dissolved in about 110 mL of an organic solvent, cooled to
about 0.degree. C. and about 1 eq. of the N-hydroxysuccinimide
ester of a carboxylic acid, B, dissolved in about 250 mL of the
same organic solvent (obtained as described above) is added
dropwise and the resulting solution allowed to stir for about 4 h.
To the resulting solution is then added about 50 mL of water and
the organic solvent removed under reduced pressure. The resulting
aqueous mixture is then extracted with an organic solvent,
typically DCM. The DCM is washed with aq. 5% sodium carbonate,
brine, and water; dried (Na.sub.2SO.sub.4); and the solvent removed
under reduced pressure to provide the Fenicol Compound of formula
(I), (Ia), or (II), which can be purified by recrystallization.
Suitable organic solvents for obtaining the Fenicol Compound of
formula (I), (Ia), and (II) include, but are not limited to THF,
DCM, carbon tetrachloride, chloroform, dioxane, and DMF.
[0556] The Fenicol Compounds of formula (I), (Ia), and (II) can
also be obtained by reacting a
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, (1 eq.) with an
acid anhydride. For example, a
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, (0.1 mmol, 1 eq.)
is dissolved in 2.5 mL of an organic solvent and the acid anhydride
(at least 1 eq., preferably at least 2 eq., more preferably about 5
eq.) is added dropwise with stirring to provide a mixture,
optionally the acid anhydride can be added as a solution in the
same organic solvent (about 1 to 1.5 mL). Additional, organic
solvent (about 1.5 mL) is added and the resulting mixture allowed
to stir for about 30 min. Additional organic solvent (about 25 mL)
is added followed by water (about 20 mL) and the organic layer is
separated. The organic layer is then washed 5% sodium carbonate,
brine, and water; dried (Na.sub.2SO.sub.4); and the solvent removed
under reduced pressure to provide the Fenicol Compound of formula
(I), (Ia), or (II), which can be purified by recrystallization.
Suitable organic solvents for obtaining the Fenicol Compound of
formula (I), (Ia), and (II) include, but are not limited to THF,
DCM, carbon tetrachloride, chloroform, dioxane, and DMF. Acid
anhydrides are commercially available or can be obtained by methods
well known to those of ordinary skill in the art.
[0557] Progress for each reaction can be monitored using any method
well known to those skilled in the art including, but not limited
to, high pressure liquid chromatography (HPLC), gas chromatography
(GC), thin-layer chromatography (TLC), and nuclear magnetic
resonance spectroscopy (NMR).
[0558] The Fenicol Compounds of formula (I) and (Ia) wherein Z is
an acyl group of formula --C(O)--R.sub.2, wherein R.sub.2 is a
C.sub.1 to C.sub.18 hydrocarbon group that may optionally be
substituted with a --NH.sub.2 or --COOH can be obtained by
acylating the alcohol group of a Fenicol Compound of Formula (I),
(Ia), or (II) wherein Z is hydrogen using an acid halide of formula
T--C(O)--R.sub.2, wherein T is a halide, preferably chloride, and
R.sub.2 is as defined above, using methods well known to those
skilled in the art. The Fenicol Compounds of formula (I) and (Ia)
wherein Z is an acyl group of formula --C(O)--R.sub.2, wherein
R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that may
optionally be substituted with a --NH.sub.2 or --COOH, can also be
obtained by acylating the alcohol group of a Fenicol Compound of
Formula (I), (Ia), or (II) wherein Z is hydrogen with an acid
anhydride using methods well known to those of ordinary skill in
the art.
[0559] Acid halides can be obtained using methods well known to
those skilled in the art such as those described in J. March,
Advanced Organic Chemistry, Reaction Mechanisms and Structure,
4.sup.th ed. John Wiley & Sons, NY, 1992, pp. 437-8. For
example, acid halides can be prepared by reacting a carboxylic acid
with thionyl chloride, bromide, or iodide. Acid chlorides and
bromides can also be prepared by reacting a carboxylic acid with
phosphorous trichloride or phosphorous tribromide, respectively.
Acid chlorides can also be prepared by reacting a carboxylic acid
with Ph.sub.3P in carbon tetrachloride. Acid fluorides can be
prepared by reacting a carboxylic acid with cyanuric fluoride. Acid
anhydrides can also be obtained using methods well known to those
skilled in the art such as those described in J. March, Advanced
Organic Chemistry, Reaction Mechanisms and Structure, 4.sup.th ed.
John Wiley & Sons, NY, 1992, pp. 400-402.
5.7.2 Fenicol Compounds of Formula (III)
[0560] Method 1: The Fenicol Compounds of formula (III) can be
obtained by same procedure as described above for obtaining the
Fenicol Compounds of formula (I), (Ia), and (II) except that the
N-hydroxysuccinimide ester of a carboxylic acid, B, is obtained
from an optically active carboxylic acid. Optically active
carboxylic acids are commercially available or can be obtained by
methods well known to those skilled in the art including, but not
limited to resolving a racemic mixture of the carboxylic acid using
an optically active amine to provide a pair of diasteriomeric salts
that can be separated or by esterifying the optically active acid
with an optically active alcohol to provide a pair of
diasteriomeric esters that can be separated (See, e.g., Advanced
Organic Chemistry, Reactions, Mechanisms, and Structure, 4.sup.th
ed, J. March, Wiley-Interscience, NY (1992), 120-125).
[0561] Optically active 2-chloropropionic acid and 2-bromopropionic
acid are commercially available from Sigma-Aldrich, St. Louis, Mo.
(www.sigma-aldrich.com).
[0562] Optically active 2-fluororopropionic acid is commercially
available from Metrix Corporation of India.
[0563] Optically active 2-iodopropionic acid can be obtained by
reacting optically active 2-bromopropionic acid with excess iodide
ion. Without wishing to be bound by theory it is believed that the
iodide ion replaces the bromide of the optically active
2-bromopropionic acid by an SN.sub.2 mechanism to provide the
optically active 2-iodopropionic acid of inverted
configuration.
[0564] Optically active 2-chloro-3,3,3,-trifluoropropionic acid can
be obtained by reacting optically active 3,3,3-trifluoro lactic
acid (commercially available from Sigma-Aldrich, St. Louis, Mo.
(www.sigma-aldrich.com)) with thionly chloride using methods well
known to those of ordinary skill in the art. For example, about 7
mmol of 3,3,3-trifluoro lactic acid is dissolved in a mixture of
about 15 mL DCM and 3 mL THF. The resultant solution is cooled to
about 0.degree. C., 7 mmol of thionyl chloride is added with
stirring, and the resulting solution is stirred for about 30 min.
The solution is allowed to warm to room temperature and about 7
mmol of thionyl chloride is added with stirring and the resulting
solution stirred for about 2 h. The resulting optically active acid
chloride of 2-chloro-3,3,3,-trifluoropropionic acid can then be
used to acylate the D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol of
formula A or can be hydrolyzed, using methods well known to those
skilled in the art, to provide optically active
2-chloro-3,3,3,-trifluoropropionic acid.
[0565] Optically active 2-bromo-3,3,3,-trifluoropropionic acid can
be obtained by the same method used to obtain
2-chloro-3,3,3,-trifluoropropionic acid except that optically
active 3,3,3-trifluoro lactic acid is reacted with thionyl bromide
instead of thionyl chloride.
[0566] Optically active 2-iodo-3,3,3,-trifluoropropionic acid can
be obtained by the same method used to obtain
2-chloro-3,3,3,-trifluoropropionic acid except that optically
active 3,3,3-trifluoro lactic acid is reacted with thionyl iodide
instead of thionyl chloride.
[0567] Optically active 2-fluoro-3,3,3,-trifluoropropionic acid is
commercially available from Metric Scientific of India.
[0568] Optically active 3,3,3-trifluoro-2-methyl propionic acid can
be obtained by resolving racemic 3,3,3-trifluoro-2-methyl propionic
acid using methods well known to those skilled in the art.
3,3,3-Trifluoro-2-methyl propionic acid can be obtained by
hydrogenating 1-trifluoromethyl acrylic acid (commercially
available from Sigma-Aldrich, St. Louis, Mo.
(www.sigma-aldrich.com)). For example, 14.2 mmol of
1-trifluoromethyl acrylic acid is dissolved in about 25 mL of
methanol and about 0.3 g of Pd/C is added to the solution. The
resulting solution is then placed under a hydrogen atmosphere for
about 19 h. The catalyst is then removed by filtration and the
solvent removed under reduced pressure to provide
3,3,3-trifluoro-2-methyl propionic acid.
[0569] Optically active 2-hydroxy-propionic acid is commercially
available from Sigma-Aldrich, St. Louis, Mo.
(www.sigma-aldrich.com).
[0570] Optically active 2-hydroxy-3,3,3,-trifluoropropionic acid is
commercially available from Sigma-Aldrich, St. Louis, Mo.
(www.sigma-aldrich.com).
[0571] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of (R)
2-chloropropionic acid.
[0572] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of (R)
2-bromopropionic acid.
[0573] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-iodopropionic acid.
[0574] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-fluoropropionic acid.
[0575] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester
(R)-2-hydroxypropionic acid.
[0576] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-chloro-3,3,3,-trifluoropropionic acid.
[0577] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-bromo-3,3,3,-trifluoropropionic acid.
[0578] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-iodo-3,3,3,-trifluoropropionic acid.
[0579] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-fluoro-3,3,3,-trifluoropropionic acid.
[0580] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(R)-2-hydroxy-3,3,3,-trifluoropropionic acid.
[0581] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of (S)
2-chloropropionic acid.
[0582] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of (S)
2-bromopropionic acid.
[0583] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-iodopropionic acid.
[0584] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-fluoropropionic acid.
[0585] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester
(S)-2-hydroxypropionic acid.
[0586] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-chloro-3,3,3,-trifluoropropionic acid.
[0587] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-bromo-3,3,3,-trifluoropropionic acid.
[0588] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-iodo-3,3,3,-trifluoropropionic acid.
[0589] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-fluoro-3,3,3,-trifluoropropionic acid.
[0590] In one embodiment, the N-hydroxysuccinimide ester of a
carboxylic acid is a N-hydroxysuccinimide ester of
(S)-2-hydroxy-3,3,3,-trifluoropropionic acid.
[0591] Method II: The Fenicol Compounds of formula (III) wherein
the acylamido group has the (R) stereochemical configuration
substantially free of the (S) stereochemical configuration can also
be obtained by reacting a
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, with at least
about 2 eq., preferably at least about about 3 eq., and more
preferably about 3 eq. of a racemic mixture of an
N-hydroxysuccinimide ester of a carboxylic acid, B. Unexpectedly,
the product is a Fenicol Compounds of formula (III) wherein the
acylamido group has the (R) stereochemical configuration
substantially free of the (S) stereochemical configuration. Without
wishing to be bound by theory, it is believed that the
(R)-N-hydroxysuccinimide ester of a carboxylic acid, B, reacts more
quickly with D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol than the
(S)-N-hydroxysuccinimide ester of a carboxylic acid.
[0592] Accordingly, the invention further relates to a method of
preparing a Fenicol Compound of formula (III) wherein the acylamido
group has the (R) stereochemical configuration substantially free
of the (S) stereochemical configuration. The method involves
combining a D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, with
at least about 2 eq., preferably at least about about 3 eq., and
more preferably about 3 eq. of a racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, for sufficient
time to acylate substantially all of the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, and recovering the
Fenicol Compound of formula (III) wherein the acylamido group has
the (R) stereochemical configuration substantially free of the (S)
stereochemical configuration.
[0593] Typical reaction conditions are the same as those described
above for reacting a N-hydroxysuccinimide ester of a carboxylic
acid, B, with a D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol to
provide a Fenicol Compound of formula (I), (Ia), or (II).
[0594] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is combined with
about 3 eq. of the racemic mixture of the N-hydroxysuccinimide
ester of a carboxylic acid.
[0595] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol.
[0596] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol.
[0597] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 2-chloropropionic acid.
[0598] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 2-bromopropionic acid.
[0599] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 2-iodopropionic acid.
[0600] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 2-fluoropropionic acid.
[0601] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 2-hydroxypropionic acid.
[0602] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-chloro-3,3,3,-trifluoropropionic acid.
[0603] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-bromo-3,3,3,-trifluoropropionic acid.
[0604] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-iodo-3,3,3,-trifluoropropionic acid.
[0605] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-fluoro-3,3,3,-trifluoropropionic acid.
[0606] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-hydroxy-3,3,3,-trifluoropropionic acid.
[0607] In one embodiment, the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic 3,3,3-trifluoro-2-methyl
propionic acid.
[0608] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-chloropropionic acid.
[0609] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinmide ester of racemic 2-bromopropionic
acid.
[0610] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-hydroxypropionic acid.
[0611] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-chloro-3,3,3,-trifluoropropionic acid.
[0612] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-bromo-3,3,3,-trifluoropropionic acid diment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic 2-iodopropionic
acid.
[0613] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-fluoropropionic acid.
[0614] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-iodo-3,3,3,-trifluoropropionic acid.
[0615] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-fluoro-3,3,3,-trifluoropropionic acid.
[0616] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
2-hydroxy-3,3,3,-trifluoropropionic acid.
[0617] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol and the
racemic mixture of a N-hydroxysuccinimide ester of a carboxylic
acid, B, is a N-hydroxysuccinimide ester of racemic
3,3,3-trifluoro-2-methyl propionic acid.
[0618] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 2-chloropropionic acid.
[0619] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 2-bromopropionic acid.
[0620] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 2-iodopropionic acid.
[0621] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 2-fluoropropionic acid.
[0622] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 2-hydroxypropionic
acid.
[0623] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is D-(threo)-1-p
nitro-2-amino-3-fluoro-1-propanol and the racemic mixture of a
N-hydroxysuccinimide ester of a carboxylic acid, B, is a
N-hydroxysuccinimide ester of racemic
2-chloro-3,3,3,-trifluoropropionic acid.
[0624] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic
2-bromo-3,3,3,-trifluoropropionic acid.
[0625] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic
2-iodo-3,3,3,-trifluoropropionic acid.
[0626] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic
2-fluoro-3,3,3,-trifluoropropionic acid.
[0627] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic
2-hydroxy-3,3,3,-trifluoropropionic acid.
[0628] In one embodiment, the
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, is
D-(threo)-1-p-nitro-2-amino-3-fluoro-1-propanol and the racemic
mixture of a N-hydroxysuccinimide ester of a carboxylic acid, B, is
a N-hydroxysuccinimide ester of racemic 3,3,3-trifluoro-2-methyl
propionic acid.
[0629] Method III: The Fenicol Compounds of formula (III) wherein
the acylamido group has the (R) stereochemical configuration
substantially free of the (S) stereochemical configuration can also
be obtained by reacting a
D-(threo)-1-aryl-2-amino-3-fluoro-1-propanol, A, with about 1 eq.
of a racemic mixture of an N-hydroxysuccinimide ester, B, to
provide Fenicol Compounds of formula (III) wherein the acylamido
group is present in both the (R) configuration and the (S)
configuration, i.e., the mixture is not substantially free of the
Fenicol Compounds of formula (III) wherein the acylamido group is
present in the (S) configuration. Fenicol Compound of formula (III)
wherein the acylamido group is present in both the (R)
configuration and the (S) configuration is then contacted with
silica gel. Unexpectedly, the Fenicol Compound of formula (III)
wherein the acylamido group is present in the (S) configuration is
isomerized to the Fenicol Compound of formula (III) wherein the
acylamido group has (R) stereochemical configuration to provide a
Fenicol Compound of formula (III) wherein the acylamido group has
(R) stereochemical configuration substantially free of the (S)
stereochemical configuration. Without wishing to be bound by
theory, it is believed that the silica gel catalyzes the
isomerization of Fenicol Compound of formula (III) wherein the
acylamido group has the (S) configuration to the Fenicol Compound
of formula (III) wherein the acylamido group has the (R)
stereochemical configuration substantially free of the (S)
stereochemical configuration.
[0630] Accordingly, the invention further relates to a method of
converting a Fenicol Compound of formula (III) wherein the
acylamido group has the (S) stereochemical configuration to a
Fenicol Compound of formula (III) wherein the acylamido group has
the (R) stereochemical configuration. The method involves
contacting the Fenicol Compounds of formula (III) wherein the
acylamido group has the (S) configuration with silica gel for a
sufficient time to convert the Fenicol Compounds of formula (III)
wherein the acylamido group has the (S) configuration to a Fenicol
Compounds of formula (III) wherein the acylamido group has the (R)
stereochemical configuration. In one embodiment, the method
converts Fenicol Compound of formula (III) wherein the acylamido
group is present in both the (R) stereochemical configuration and
the (S) stereochemical configuration to a Fenicol Compound of
formula (II) wherein the acylamido group has the (R) stereochemical
configuration substantially free of the (S) stereochemical
configuration. In one embodiment, the Fenicol Compounds of formula
(III) wherein the acylamido group has the (S) configuration is
present as part of an equimolar mixture of Fenicol Compounds of
formula (III) wherein the acylamido group has the (S) configuration
and Fenicol Compounds of formula (III) wherein the acylamido group
has the (R) configuration.
[0631] In one embodiment, the Fenicol Compound of formula (III)
wherein the acylamido group has the (S) configuration is contacted
with silica gel for a sufficient time to convert the Fenicol
Compound of formula (III) wherein the acylamido group has the (S)
configuration to a Fenicol Compound of formula (III) wherein the
acylamido group has the (R) stereochemical configuration by
dissolving the Fenicol Compound of formula (III) wherein the
acylamido group has the (S) configuration in a solvent, adding
silica gel, and allowing the resulting mixture to stir for
sufficient time to convert the Fenicol Compound of formula (III)
wherein the acylamido group has the (S) stereochemical
configuration to a Fenicol Compound of formula (III) wherein the
acylamido group has the (R) stereochemical configuration.
[0632] Typically, the reaction is conducted at a temperature of
ranging from about about 25.degree. C. to 100.degree. C.
Preferably, the reaction is conducted at the reflux temperature of
the solvent.
[0633] Suitable solvents include, but are not limited to THF,
dioxane, methanol, ethanol, DCM, and chloroform.
[0634] Typically, the Fenicol Compound of formula (III) wherein the
acylamido group has the (S) configuration is present in an amount
of about 0.05 to 1 g per 10 mL of solvent, preferably about 0.1 to
0.5 g per 10 mL of solvent, and more preferably about 0.15 to about
0.3 g per 10 mL of solvent.
[0635] Typically, the ratio of silica to Fenicol Compound of
formula (III) ranges from about 0.1:1 to 10: 1, preferably about
0.5:1 to 2: 1, more preferably about 0.3:1 to about 3: 1, and most
preferably about 0.25:1.
[0636] Typically, the mixture is allowed to stir for a time period
ranging from about 2 to 24 h and preferably about 3 to 12 h.
[0637] In another embodiment, the Fenicol Compound of formula (III)
wherein the acylamido group has the (S) configuration is contacted
with silica gel by simply placing the Fenicol Compound of formula
(III) wherein the acylamido group has the (S) configuration on a
silica column and eluting the column with a solvent.
[0638] Suitable solvents for eluting the silica column include, but
are not limited to THF, dioxane, methanol, ethanol, DCM, and
chloroform.
[0639] Typically, the amount of the silica used in the column is at
least about 10 fold, preferably at least about 20 fold, more
preferably at least about 30 fold, and most preferably at least
about 40 fold greater than the amount of the Fenicol Compound of
formula (III) wherein the acylamido group has the (S) configuration
that is applied to the column.
[0640] Typically, the silica column is eluted at a rate of about 1
mL/min. or less.
5.7.3 Fenicol Compounds of Formula (IV)
[0641] The Fenicol Compounds of formula (IV) can be obtained by
same procedure as described above for obtaining the Fenicol
Compounds of formula (I), (Ia), and (II).
5.8 Therapeutic Uses of the Fenicol Compounds
[0642] In accordance with the invention, the Fenicol Compounds are
administered to an animal in need of treatment or prevention of a
bacterial infection. The Fenicol Compounds are a broad spectrum
antibacterial useful to treat bacterial infections caused by both
gram negative and gram positive bacteria.
[0643] Accordingly, the invention further relates to a method of
treating a bacterial infection in an animal comprising
administering to an animal in need thereof an effective amount of a
compound of formula (IV):
##STR00023##
or a pharmaceutically acceptable salt thereof,
[0644] wherein [0645] X is --CH.sub.3 and X.sub.1 is --CH.sub.3,
--CF.sub.3, or --OH or [0646] X is --CF.sub.3 and X.sub.1 is
--CF.sub.3; -halo, or --OH; [0647] Z is hydrogen or an acyl group
of formula --C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to
C.sub.18 hydrocarbon group that may optionally be substituted with
a --NH.sub.2 or --COOH; [0648] Y and Y.sup.1 is --H; --NO.sub.2;
--SO.sub.2R.sub.1; --SOR.sub.1; --SR.sub.1; --SONH.sub.2;
--SO.sub.2NH.sub.2; --SONHR.sub.1; --SO.sub.2NHR.sub.1;
--COR.sub.2; --OR.sub.1; --R.sub.1; --CN, -halo; -phenyl; or
-phenyl substituted with -halo, --NO.sub.2, --SO.sub.2CH.sub.3,
--R.sub.1, or --OR.sub.1; [0649] R.sub.1is a C.sub.1 to C.sub.3
hydrocarbon group; and [0650] halo is --Cl, --Br, --I, or --F.
[0651] In one embodiment, Z is --H.
[0652] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH.
[0653] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is an unsubstituted C.sub.1 to
C.sub.18 hydrocarbon group.
[0654] In one embodiment, Z is acetyl.
[0655] In one embodiment, Z is butanoyl.
[0656] In one embodiment, Z is hexanoyl.
[0657] In one embodiment, Y.sub.1 is hydrogen.
[0658] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen and Y
is --NO.sub.2, --SO.sub.2CH.sub.3, or --SONH.sub.2.
[0659] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --NO.sub.2.
[0660] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --SO.sub.2CH.sub.3.
[0661] In one embodiment, Z is hydrogen, Y.sub.1 is hydrogen, and Y
is --SO.sub.2NH.sub.2.
[0662] In one embodiment, Z is hydrogen, X is --CH.sub.3, and
X.sub.1 is --CH.sub.3.
[0663] In one embodiment, Z is hydrogen, X is --CH.sub.3, and
X.sub.1 is --CF.sub.3.
[0664] In one embodiment, Z is hydrogen, X is --CH.sub.3, and
X.sub.1 is --OH.
[0665] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --CF.sub.3.
[0666] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is -halo.
[0667] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --Cl.
[0668] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --Br.
[0669] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --I.
[0670] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --F.
[0671] In one embodiment, Z is hydrogen, X is --CF.sub.3, and
X.sub.1 is --OH.
[0672] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CH.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0673] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CH.sub.3, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0674] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CH.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0675] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0676] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0677] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0678] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0679] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0680] In one embodiment, Z is hydrogen, X is --CH.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0681] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is -halo, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0682] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is -halo, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0683] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is -halo, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0684] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Cl, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0685] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Cl, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0686] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Cl, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0687] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Br, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0688] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Br, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0689] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --Br, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0690] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --I, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0691] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --I, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0692] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --I, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0693] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --F, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0694] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --F, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0695] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --F, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0696] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0697] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0698] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --OH, Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0699] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0700] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0701] In one embodiment, Z is hydrogen, X is --CF.sub.3, X.sub.1
is --CF.sub.3, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0702] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2,
--SO.sub.2CH.sub.3, or --SONH.sub.2.
[0703] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0704] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is
--SO.sub.2CH.sub.3.
[0705] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, Y.sub.1 is hydrogen, and Y is
--SO.sub.2NH.sub.2.
[0706] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, and X.sub.1 is
--CH.sub.3.
[0707] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, and X.sub.1 is
--CF.sub.3.
[0708] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, and X.sub.1 is --OH.
[0709] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is
--CF.sub.3.
[0710] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is -halo.
[0711] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is -halo.
[0712] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is --Cl.
[0713] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is --Br.
[0714] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is --I.
[0715] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is --F.
[0716] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, and X.sub.1 is --OH.
[0717] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0718] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0719] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CH.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0720] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0721] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0722] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0723] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0724] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0725] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CH.sub.3, X.sub.1 is --CF.sub.3, Yi is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0726] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is halo, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0727] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is halo, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0728] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is halo, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0729] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0730] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0731] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Cl, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0732] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0733] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0734] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --Br, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0735] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0736] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0737] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --I, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0738] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0739] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0740] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --F, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0741] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --SO.sub.2CH.sub.3.
[0742] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --NO.sub.2.
[0743] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --OH, Y.sub.1 is
hydrogen, and Y is --SO.sub.2NH.sub.2.
[0744] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2CH.sub.3.
[0745] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --NO.sub.2.
[0746] In one embodiment, Z is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH, X is --CF.sub.3, X.sub.1 is --CF.sub.3,
Y.sub.1 is hydrogen, and Y is --SO.sub.2NH.sub.2.
[0747] The invention further relates to a method of treating a
bacterial infection in an animal comprising administering to an
animal in need thereof an effective amount of a compound of formula
(I).
[0748] The invention further relates to a method of treating a
bacterial infection in an animal comprising administering to an
animal in need thereof an effective amount of a compound of formula
(Ia).
[0749] The invention further relates to a method of treating a
bacterial infection in an animal comprising administering to an
animal in need thereof an effective amount of a compound of formula
(II).
[0750] The invention further relates to a method of treating a
bacterial infection in an animal comprising administering to an
animal in need thereof an effective amount of a compound of formula
(III).
[0751] Representative bacterial infections that can be treated
using the Fenicol Compounds of the invention include, but are not
limited to, bacterial infections caused by bacteria of the genus
Pasteurella, Haemophilus, Fusobacterium, Moraxella, Bacteroides,
Aeromonas, Escherichia, Enterobacter, Klebsiella, Salmonella,
Shigella, Serratia, Ureaplasma, Chlamydia, Actinobacillus,
Streptococcus, Edwardsiella, Staphylococcus, Enterococcus,
Bordetella, Proteus, Mycoplasma, or Mannheimia.
[0752] Representative bacterial infections that can be treated
using the Fenicol Compounds of the invention include, but are not
limited to, bacterial infections caused by Pasteurella haemolytica,
Pasteurella multocida, Pasteurella haemolytica, Haemophilus somnus,
Actinobacillus pleuropneumoniae, Actinomyces pyogenes, Pseudomonas
aeruginosa, Klebsiella pneumonia, Klebsiella oxytoca, Escherichia
faecalis, Escherichia coli, Staphylococcus aureaus, Staphylococcus
intermedius, Enterococcus faecalis, Enterococcus faecium,
Streptococcus pyogenes, Bacillus subtilis, Peptococcus indolicus,
Mycoplasma bovis, Mycoplasma dispar, Mycoplasma hyopneumoniae,
Mycoplasma hyorhinis, Mycoplasma gallisepticum, Mycoplasma
mycoides, Mycoplasma ovipneumonia, Haemophilus influenzae,
Klebsiella salmonella, Shigella, Proteus enterobacter, Enterobacter
cloacae, Mannhemia haemolytica, Haemophilus somnus, Fusobacterium
necrophorum, Bacterioides melaninogenicus, Proteus mirabillis,
Streptococcus suis, Salmonella cholerasuis, Edwardsiella ictaluri,
Aeromonas salmonicidia, Actinobaccilus pleuropneumoniae, and
Bordetella bronchoseptica.
[0753] In one embodiment, the bacteria is Pasteurella haemolytica,
Pasteurella multocida, or Haemophilus somnus
[0754] In one embodiment, the animal is a human.
[0755] In one embodiment, the animal is a dog.
[0756] In one embodiment, the animal is a cat.
[0757] In one embodiment, the animal is a cow.
[0758] In one embodiment, the animal is a pig.
[0759] In one embodiment, the animal is a horse.
[0760] Typically, the minimum inhibitory concentration of the
Fenicol Compound against a specific bacteria is less than 10
.mu.g/mL, preferably less than 5 .mu.g/mL, more preferably less
than 1 .mu.g/mL, and most preferably less than 0.5 .mu.g/mL.
[0761] The activity of a Fenicol Compound against a bacteria is
determined using standard dilution tests. For example, the minimum
inhibitory concentrations can be determined using the disk
diffusion susceptibility testing method described in Clinical
Microbiology Procedures Handbook, volume 1, edited by Henry D.
Isenberg, American Society for Microbiology, 1992, section 5.1 or
the well known method of Bauer et al. "Antibiotic Susceptibility
Testing by a Standardized Single Disc Method," Amer. J. Clin.
Pathol., 45, p. 493-496.
[0762] Table I provides the minimum inhibitory concentration (MIC)
for illustrative Fenicol Compounds against various bacteria.
TABLE-US-00013 TABLE I Fenicol Minimum Inhibitory Concentration
(.mu.g/mL).sup.a Compound K. pneumoniae E. faecalis E. coli S.
aureaus S. pyogenes B. subtilis B. bronchoseptica Fluorfenicol 3 3
1 1 1 1 1 A1 5 3 5 2 A2 5 7 7 5 5 E2 + I2 5 3 2 0.5 3 (Racemic
Mixture) E2 5 >5 3 3 >5 1 >5 I2 3 2 0.5 5 3 5 5 E5 + I5 5
3 5 5 5 1 >10 (Racemic Mixture) D-threo-2-chloro-N-[1- 5 3 2 0.5
3 (fluoromethyl)-2- hydroxy-2-[4- methylsulfonyl)
phenyl]ethyl]-acetamide .sup.aMinimum Inhibitory Concentrations
were determined using the disk diffusion susceptibility testing
method described in Clinical Microbiology Procedures Handbook,
volume 1, edited by Henry D. Isenberg, American Society for
Microbiology, 1992, section 5.1.
[0763] The results reported in Table I show that the Fenicol
Compounds are effective antibiotics and therefore are useful for
treating or preventing bacterial infections in animals.
[0764] The Fenicol Compounds have lower clearance rates than
conventional antibiotics, such as fluorfenicol (commercially
available as NUFLOR.RTM.). Conventional antibiotics, such as
fenicol, are ineffective in many animals because the clearance rate
of the antibiotic is so rapid that it is excreted by the animal
before it can exert its antibacterial effect. For example,
fluorfenicol (commercially available as NUFLOR.RTM.), when
subcutaneously administered to dogs is cleared too rapidly to be
effective. Accordingly, the Fenicol Compounds are particularly
useful for treating bacterial infections in animals where these
conventional antibiotics are ineffective because of rapid
clearance.
[0765] FIG. 1 shows the serum plasma levels for NUFLOR.RTM. and
Fenicol Compound A1 administered subcutaneously to dogs at a dose
of 40 mg/kg as a function of time. NUFLOR.RTM. was commercially
available from Schering-Plough Animal Health, New Jersey. Fenicol
Compound A1 was formulated as a solution containing 3 mg of Fenicol
Compound A1, 9 g N-methyl pyrrolidone, 2.25 g propylene glycol, QS
to 20 mL with polyethylene glycol. FIG. 1 clearly shows that the
clearance rate for NUFLOR.RTM. in dogs is rapid. Indeed, the
clearance rate of NUFLOR.RTM. in dogs is so rapid that NUFLOR.RTM.
only attains a maximum serum concentration of less than 0.8
.mu.g/mL. As a result of this rapid clearance, NUFLOR.RTM. is
ineffective as an antibiotic in dogs. In contrast, Fenicol Compound
A1 is cleared much more slowly in dogs such that Fenicol Compound
A1 achieves a maximum serum level of almost 7 .mu.g/mL.
Accordingly, Fenicol Compound A1 can be more effective at treating
or preventing bacterial infections in dogs than NUFLOR.RTM..
[0766] Similarly, the clearance rate of Fenicol compound A2 in dogs
is much slower than the clearance rate of NUFLOR.RTM.. Therefore,
administering Fenicol Compound A2 to dogs results in higher serum
concentrations of the antibiotic than are obtainable when
NUFLOR.RTM. is administered to dogs. FIG. 2 shows the serum
concentration of Fenicol Compound A2 when Fenicol Compound A2 was
administered to dogs as a 40 mg/kg subcutaneous injection of a
formulation containing 925 mg of Fenicol Compound A2, 2 mL N-methyl
pyrrolidone, 0.5 mL propylene glycol, QS to 5 mL with polyethylene
glycol. FIG. 2 clearly shows that Fenicol Compound A2, when
administered to dogs, achieves a maximum serum concentration of
almost 5 .mu.g/mL. Accordingly, Fenicol Compound A2 can be more
effective at treating or preventing bacterial infections in dogs
than NUFLOR.RTM..
[0767] Similarly, it was observed that a Fenicol Compound of
formula (V)
##STR00024##
wherein Z is a hydrogen or an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and R.sub.2 is defined above is also cleared
more slowly from dogs than fluorfenicol. Accordingly, the invention
further relates to a method of treating a bacterial infection in a
dog comprising administering to a dog in need thereof a Fenicol
Compound of formula (V). In one embodiment, Z in the Fenicol
Compound of formula (V) is hydrogen. In one embodiment Z in the
Fenicol Compound of formula (V) is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that may optionally be substituted with a
--NH.sub.2 or --COOH and R.sub.2 is defined. In one embodiment, Z
in the Fenicol Compound of formula (V) is an acyl group of formula
--C(O)--R.sub.2, wherein R.sub.2 is a C.sub.1 to C.sub.18
hydrocarbon group that is unsubstituted. In one embodiment, Z in
the Fenicol Compound of formula (V) is an acetyl group. In one
embodiment, Z in the Fenicol Compound of formula (V) is a butanoyl
group. In one embodiment, Z in the Fenicol Compound of formula (V)
is a hexanoyl group.
[0768] It has also unexpectedly been discovered that the clearance
rate of Fenicol compounds wherein the acylamido group is in the (R)
stereochemical configuration differs from the clearance rate of
Fenicol Compounds wherein the acylamido group is in the (S)
stereochemical configuration. Typically, the Fenicol Compound
wherein the acylamido group is in the (R) stereochemical
configuration has a slower clearance rate. Accordingly,
administering a Fenicol Compound wherein the acylamido group is
present as a single stereochemical configuration substantially free
of the other stereochemical configuration, preferably the (R)
stereochemical configuration substantially free of the (S)
stereochemical configuration, can provide higher serum
concentrations of the Fenicol Compound, a better therapeutic
profile, and a more effective treatment for bacterial infections
than administering a Fenicol Compound wherein the acylamido group
is an equimolar mixture of the (R) stereochemical configuration and
the (S) stereochemical configuration.
[0769] FIG. 3 depicts the serum concentration of Fenicol Compound
A2 wherein the acylamido group is present in the (R) stereochemical
configuration and the serum concentration of Fenicol Compound A2
wherein the acylamido group is present in the (S) stereochemical
configuration as a function of time when Fenicol Compound A2
wherein the acylamido group is present as an equimolar mixture of
the (R) stereochemical configuration and the (S) stereochemical
configuration was administered to dogs subcutaneously at a dose of
40 mg/kg as a formulation containing 925 g of Fenicol Compound A2
wherein the acylamido group is present as an equimolar mixture of
the (R) stereochemical configuration and the (S) stereochemical
configuration, 2 mL N-methyl pyrrolidone, 0.5 mL propylene glycol,
QS to 5 mL with polyethylene glycol. Serum concentrations of
Fenicol Compound A2 wherein the acylamido group is present in the
(R) stereochemical configuration and Fenicol Compound A2 wherein
the acylamido group is present in the (S) stereochemical
configuration were measured as a function of time using high
pressure liquid chromatography ("HPLC") and the maximum serum level
was determined for each isomer (C.sub.maxR, and C.sub.maxS,
respectively). The percent of the Fenicol compound wherein the
acylamido group has the (R) stereochemical configuration was then
determined at each time point by dividing the serum concentration
of Fenicol compound wherein acylamido group has the (R)
stereochemical configuration by C.sub.maxR. Similarly, the percent
of the Fenicol Compound wherein the acylamido group has the (S)
stereochemical configuration was determined at each time point by
dividing the serum concentration of Fenicol Compound wherein the
acylamido group has the (S) stereochemical configuration by
C.sub.maxS. FIG. 3 graphically depicts the percent of the Fenicol
Compound wherein the acylamido group has the (R) stereochemical
configuration and the percent of Fenicol Compound wherein the
acylamido group has the (S) stereochemical configuration as a
function of time. FIG. 3 shows that Fenicol Compound A2 wherein the
acylamido group has the (R) stereochemical configuration is cleared
more slowly than Fenicol Compound A2 wherein the acylamido group
has the (S) stereochemical configuration.
[0770] Accordingly, the invention further relates to a method of
treating a bacterial infection in an animal comprising
administering to an animal in need thereof a compound of formula
(III):
##STR00025##
or a pharmaceutically acceptable salt thereof,
[0771] wherein A is a group of formula --CH(CH.sub.3)(CF.sub.3),
--CH(CH.sub.3)(halo), --CH(CF.sub.3)(halo), --CH(CF.sub.3)(OH);
[0772] Z is hydrogen or an acyl group of formula --C(O)--R.sub.2,
wherein R.sub.2 is a C.sub.1 to C.sub.18 hydrocarbon group that may
optionally be substituted with a --NH.sub.2 or --COOH;
[0773] Y and Y.sup.1 is --H; --NO.sub.2; --SO.sub.2R.sub.1;
--SOR.sub.1; --SR.sub.1; --SONH.sub.2; --SO.sub.2NH.sub.2;
--SONHR.sub.1; --SO.sub.2NHR.sub.1; --COR.sub.2; --OR.sub.1;
--R.sub.1; --CN, -halogen; -phenyl; or -phenyl substituted with
-halogen, --NO.sub.2, --SO.sub.2CH.sub.3, -R.sub.1, or
--OR.sub.1;
[0774] halo is --Cl, --Br, --I, or --F; and
[0775] R.sub.1 is a C.sub.1 to C.sub.3 hydrocarbon group;
[0776] wherein the group of formula A is in either the (R)
configuration substantially free of the (S) configuration or the
(S) configuration substantially free of the (R) configuration and
the configuration of the group of formula A is the configuration
that provides the compound of formula (III) that is cleared more
slowly when administered to an animal.
[0777] The invention further relates to a method of selecting a
compound for treating a condition in an animal comprising: [0778]
(i) providing a first compound that has a first carbon atom that is
achiral and bonded to four first substituents; [0779] (ii)
modifying the first compound that has a first carbon atom that is
achiral by replacing a sufficient number of the first substituents
with second substituents to provide a second compound wherein the
first carbon atom has been changed to a chiral carbon atom, and
wherein the second compound exists as a mixture of the second
compound wherein the chiral carbon atom has the R stereochemical
configuration and the second compound wherein the chiral carbon has
the S stereochemical configuration; [0780] (iii) separating the
second carbon compound wherein the chiral carbon atom has the R
stereochemical configuration and the second carbon compound wherein
the chiral carbon atom has the S stereochemical configuration;
[0781] (iv) testing the second carbon compound that has the chiral
carbon in the R stereochemical configuration and the second carbon
compound that has the chiral carbon atom bonded in the S
stereochemical configuration for activity at treating the
condition; [0782] (v)selecting the second carbon compound that has
the higher activity for treating the condition.
[0783] In one embodiment, the condition is a bacterial
infection.
[0784] In one embodiment, the second carbon compound that has the
higher activity for treating the condition is selected based on its
rate of clearance in the animal.
[0785] In one embodiment, the rate of clearance in the animal of
the second carbon compound that has the higher activity for
treating the condition is the second carbon compound that is
cleared more slowly.
[0786] The invention further relates to a chemical compound
selected using the method of selecting a compound for treating a
condition in an animal.
5.8 Therapeutic/Prophylactic Administration and Compositions of the
Invention
5.8.1 Therapeutic/Prophylactic Administration
[0787] Due to their activity, the Fenicol Compounds are
advantageously useful in veterinary and human medicine. As
described above, the Fenicol Compounds are useful for treating or
preventing a bacterial infection in an animal in need thereof.
[0788] When administered to an animal, the Fenicol Compounds are
administered as a component of a composition that comprises a
pharmaceutically acceptable carrier or excipient. The Fenicol
Compounds of the invention can be administered by any convenient
route, for example, orally, by infusion or bolus injection, by
absorption through epithelial or mucocutaneous linings (e.g., oral,
rectal, and intestinal mucosa, etc.) and can be administered
together with another therapeutically active agent. Administration
can be systemic or local. Various delivery systems are known, e.g.,
encapsulation in liposomes, microparticles, microcapsules,
capsules, tablets, etc., and can be used to administer the Fenicol
Compounds.
[0789] Methods of administration include, but are not limited to,
intradermal; intramuscular; intraperitoneal; intravenous;
subcutaneous; intranasal; epidural; oral; sublingual;
intracerebral; intravaginal; transdermal; rectal; by inhalation; or
topical, particularly to the ears, nose, eyes, or skin. The mode of
administration is left to the discretion of the practitioner. In
most instances, administration will result in the release of the
Fenicol Compound into the bloodstream.
[0790] In one embodiment, the Fenicol Compound is administered
orally.
[0791] In one embodiment, the Fenicol Compound is administered as a
subcutaneous injection.
[0792] In one embodiment, the Fenicol Compound is administered as
an intramuscular injection.
[0793] In one embodiment, the Fenicol Compound is administered
intravenously.
[0794] In one embodiment, the Fenicol Compounds are delivered
topically.
[0795] In one embodiment, the Fenicol Compounds are administered by
simply mixing the Fenicol Compound with the animal's feed.
[0796] In yet another embodiment, the Fenicol Compounds can be
delivered in a controlled-release system or sustained-release
system (see, e.g., Goodson, in Medical Applications of Controlled
Release, supra, vol. 2, pp. 115-138 (1984)). Controlled- or
sustained-release systems such as those discussed in the review by
Langer, Science 249:1527-1533 (1990) can be used. In one
embodiment, a pump can be used (Langer, Science 249:1527-1533
(1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald
et al., Surgery 88:507 (1980); and Saudek et al., N. Engl. J. Med.
321:574 (1989)). In another embodiment, polymeric materials can be
used (see Medical Applications of Controlled Release (Langer and
Wise eds., 1974); Controlled Drug Bioavailability, Drug Product
Design and Performance (Smolen and Ball eds., 1984); Ranger and
Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy
et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351
(1989); and Howard et al., J. Neurosurg. 71:105 (1989)). In yet
another embodiment, a controlled- or sustained-release system can
be placed in proximity of a target of the Fenicol Compounds, thus
requiring only a fraction of the systemic dose.
[0797] In specific embodiments, it can be desirable to administer
the Fenicol Compounds locally. This can be achieved, for example,
and not by way of limitation, by local infusion during surgery,
topical application, e.g., in conjunction with a wound dressing
after surgery, by injection, or by means of an implant, said
implant being of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes or fibers.
[0798] The amount of the Fenicol Compound that is effective in the
treatment or prevention of a bacterial infection can be determined
by standard clinical techniques. In addition, in vitro or in vivo
assays can optionally be employed to help identify optimal dosage
ranges. The precise dose to be employed will also depend on the
route of administration, the seriousness or severity of the
bacterial infection, the susceptibility of the infecting organism
to the Fenicol Compound, and the characteristics of the animal
being treated and can be decided according to the judgment of a
practitioner and/or each animal's circumstances. Suitable effective
dosage amounts, however, typically range from about 0.1 mg/kg of
body weight to about 50 mg/kg of body weight, preferably about 0.5
mg/kg of body weight to about 25 mg/kg of body weight, more
preferably 0.75 mg/kg of body weight to about 20 mg/kg of body
weight, and most preferably 1 mg/kg of body weight to about 15
mg/kg of body weight. The effective dosage amounts described herein
refer to total amounts administered; that is, if more than one
Fenicol Compound is administered, the effective dosage amounts
correspond to the total amount administered.
[0799] In one embodiment, an effective dosage amount is
administered about every 7 days until the bacterial infection is
abated.
[0800] In one embodiment, an effective dosage amount is
administered about every 7 days for 4 weeks.
[0801] In one embodiment, an effective dosage amount is
administered about every 7 days for 2 weeks.
[0802] In one embodiment, a single effective dosage amount is
administered.
[0803] In one embodiment, 2 effective dosage amount are
administered 24 hours apart.
[0804] In one embodiment, 2 effective dosage amount are
administered 48 hours apart.
[0805] In one embodiment, an effective dosage amount is
administered about every 24 h until the bacterial infection is
abated.
[0806] In one embodiment, an effective dosage amount is
administered about every 12 h until the bacterial infection is
abated.
[0807] In one embodiment, an effective dosage amount is
administered about every 24 h for about 4 weeks.
[0808] In one embodiment, an effective dosage amount is
administered about every 12 h for about 4 weeks.
[0809] In one embodiment, an effective dosage amount is
administered about every 24 h for about 2 weeks.
[0810] In one embodiment, an effective dosage amount is
administered about every 12 h for about 2 weeks.
[0811] In one embodiment, an effective dosage amount is
administered about every 24 h for about 1 week.
[0812] In one embodiment, an effective dosage amount is
administered about every 12 h for about 1 week.
[0813] In one embodiment, an effective dosage amount is
administered daily until the bacterial infection is abated. The
daily dose may be divided into about 2 to 4 individual doses.
[0814] Typically, topical compositions are applied from about 1 to
5 times each day until the bacterial infection is abated. In one
embodiment, the topical compositions are applied once each day. In
one embodiment, the topical compositions are applied twice each
day. In one embodiment, the topical compositions are applied three
times each day. In one embodiment, the topical compositions are
applied four times each day. In one embodiment, the topical
applications are applied for 4 weeks. In one embodiment, the
topical applications are applied for 3 weeks. In one embodiment,
the topical applications are applied for 2 weeks. In one
embodiment, the topical applications are applied for 1 week.
[0815] The present methods for treating or preventing a bacterial
infection in an animal in need thereof can further comprise
administering another therapeutic agent to the animal being
administered a Fenicol Compound. In one embodiment, the other
therapeutic agent is administered in an effective amount.
[0816] The other therapeutic agent include, but are not limited to,
other antibiotics, antifungal agents, antiviral agents,
antiparasitic agents, and anti-inflammatory agents.
[0817] Examples of useful antibiotics include, but are not limited
to, amoxicillin; ampicillin; ceftiofor; erythromycin;
oxytetracycline; procaine penicillin G; sulfonamides; tylosin;
tilmicosin; cephalosporins; chloramphenicol; aminoglycosides such
as kanamycin and gentamycin; metronidazole; clindamycin; and
tetracycline (See, e.g., Bradford P. Smith, Large Animal Internal
Medicine, 2.sup.nd ed. Mosby, St. Louis, 1996 p. 644 and S.
Birchard and R. Sherding, Saunders Manual of Small Animal Practice,
W.B. Saunders Company, Philadelphia, 1994 p. 739).
[0818] Examples of useful antifungal agents include, but are not
limited to amphotericin B, ketaconazole, miconazole,
5-fluorocytosine, enilconazole, itraconazole, thiabendazole, and
iodides (See, e.g., Bradford P. Smith, Large Animal Internal
Medicine, 2.sup.nd ed. Mosby, St. Louis, 1996 p. 576 and S.
Birchard and R. Sherding, Saunders Manual of Small Animal Practice,
W.B. Saunders Company, Philadelphia, 1994 p. 576).
[0819] Examples of useful antiviral agents include, but are not
limited to, interferon (See, e.g., Bradford P. Smith, Large Animal
Internal Medicine, 2.sup.nd ed. Mosby, St. Louis, 1996 p. 646).
[0820] Examples of useful antiparasitic agents include, but are not
limited to, benzimidazoles, such as thiabendazole, fenbendazole,
mebendazole, oxfendazole, oxibendazole, albendazole, parbendazole,
and febantel; tetrahydropyridines such as morantel
tartrate/pyrantel pamoate; levamisole, organophosphates such as
haloxon, coumaphos, trichlorfon, and dichlorvos; piperazine salts;
ivermectin; and phenothiazine (See, e.g., Bradford P. Smith, Large
Animal Internal Medicine, 2.sup.nd ed. Mosby, St. Louis, 1996 p.
1688).
[0821] Examples of useful antiinflammatory agents include, but are
not limited to, corticosteroids such as dexamethasone;
antihistamines, and non-steroidal antiinflammatory drugs such as
aspirin, flunixin meglumine, phenylbutazone, and ibuprofin (See,
e.g., Bradford P. Smith, Large Animal Internal Medicine, 2.sup.nd
ed. Mosby, St. Louis, 1996 p. 645).
[0822] Effective amounts of the other therapeutic agents are known
to those skilled in the art. It is well within the skilled
artisan's purview to determine the other therapeutic agent's
optimal effective-amount range. In one embodiment of the invention,
where another therapeutic agent is administered to an animal, the
effective amount of the Fenicol Compound is less than its effective
amount would be were the other therapeutic agent not administered.
In this case, without being bound by theory, it is believed that
the Fenicol Compound and the other therapeutic agent act
synergistically to treat or prevent a bacterial infection.
[0823] The Fenicol Compound and the other therapeutic agent can act
additively or, in one embodiment, synergistically. In one
embodiment, a Fenicol Compound is administered concurrently with
another therapeutic agent; for example, a composition comprising an
effective amount of a Fenicol Compound and an effective amount of
another therapeutic agent can be administered. Alternatively, a
composition comprising an effective amount of a Fenicol Compound
and a different composition comprising an effective amount of
another therapeutic agent can be concurrently administered. In
another embodiment, an effective amount of a Fenicol Compound is
administered prior or subsequent to administration of an effective
amount of another therapeutic agent. In this embodiment, the
Fenicol Compound is administered while the other therapeutic agent
exerts its therapeutic effect, or the other therapeutic agent is
administered while the Fenicol Compound exerts its therapeutic
effect for treating or preventing a bacterial infection.
[0824] In one embodiment, a mixture of two Fenicol Compounds of the
invention are administered simultaneously. For example, a
composition comprising both a Fenicol Compound wherein the
acylamido group of Fenicol Compound is in both the (R)
stereochemical configuration and a Fenicol Compound wherein the
acylamido group of Fenicol Compound is in the (S) stereochemical
configuration is administered to an animal. In one embodiment, the
ratio of the Fenicol Compound with the acylamido groups in the (R)
stereochemical configuration and the Fenicol Compound with the
acylamido groups of Fenicol Compounds (S) stereochemical
configuration is not 1:1. Administering such compositions to an
animal allows the serum concentration of total Fenicol Compounds as
a function of time to be controlled.
[0825] FIG. 3 shows that Fenicol Compound A2 wherein the acylamido
group is present in the (S) stereochemical configuration, when
administered to dogs, provides a rapid increase in the serum
concentration of Fenicol Compound A2 that then decreases rapidly.
In contrast, Fenicol Compound A2 wherein the acylamido group is
present in the (R) stereochemical configuration, when administered
to dogs, provides a rapid increase in the serum concentration of
Fenicol Compound A2 that then decreases much more slowly than
Fenicol Compound A2 wherein the acylamido group is in the (S)
stereochemical configuration. Accordingly, by varying the ratio of
Fenicol Compound A2 wherein the acylamido groups is in the (R)
stereochemical configuration to Fenicol Compound A2 wherein the
acylamido group is in the (S) stereochemical configuration in a
pharmaceutical composition it is possible to control the serum
concentration of the Fenicol Compound so as to maximize the
therapeutic effect. For example, a pharmaceutical composition
having Fenicol Compound A2 wherein the acylamido group is in the
(S) stereochemical configuration will provide a serum level of
Fenicol Compound that increases and then rapidly decreases. In
contrast, a pharmaceutical composition having Fenicol Compound A2
wherein the acylamido group is in the (R) stereochemical
configuration will provide a serum level of Fenicol Compound that
increases and then decreases more slowly.
5.8.2 Pharmaceutical Compositions Comprising Fenicol Compounds
[0826] Compositions comprising a Fenicol Compound can take the form
of solutions, suspensions, emulsions, tablets, pills, pellets,
capsules, capsules containing liquids, powders, sustained-release
formulations, suppositories, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the composition is
in the form of a tablet or capsule (See e.g., U.S. Pat. No.
5,698,155).
[0827] In one embodiment, the Fenicol Compounds are formulated in
accordance with routine procedures as a composition adapted for
oral administration. Compositions for oral delivery can be in the
form of tablets, lozenges, aqueous or oily suspensions, granules,
powders, emulsions, capsules, syrups, or elixirs, for example.
Tablet and pill form are the preferred form for oral delivery.
Moreover, where in tablet or pill form, the compositions can be
coated to delay disintegration and absorption in the
gastrointestinal tract thereby providing a sustained action over an
extended period of time. Selectively permeable membranes
surrounding an osmotically active driving compound are also
suitable for orally administered compositions. In these latter
platforms, fluid from the environment surrounding the capsule is
imbibed by the driving compound, which swells to displace the agent
or agent composition through an aperture. These delivery platforms
can provide an essentially zero order delivery profile as opposed
to the spiked profiles of immediate release formulations. A
time-delay material such as glycerol monostearate or glycerol
stearate can also be used. Oral compositions are preferred for
bacterial infections of the gastrointestinal tract that can cause
diarrhea.
[0828] In one embodiment, the Fenicol Compounds are formulated for
subcutaneous injection, intramuscular injection, or intravenous
administration. Typically, compositions for subcutaneous injection,
intramuscular injection, or intravenous administration comprise
sterile isotonic aqueous buffer. Where necessary, the compositions
can also include a solubilizing agent. Non-aqueous compositions can
also be used. Compositions for intravenous administration can
optionally include a local anesthetic such as lidocaine to lessen
pain at the site of the injection. Generally, the ingredients are
supplied either separately or mixed together in unit dosage form,
for example, as a dry lyophilized powder or water free concentrate
in a hermetically sealed container such as an ampule or sachette
indicating the quantity of active agent. Where the Fenicol
Compounds are to be administered by infusion, they can be
dispensed, for example, with an infusion bottle containing sterile
pharmaceutical grade water or saline. Where the Fenicol Compounds
are administered by injection, an ampule of sterile water for
injection or saline can be provided so that the ingredients can be
mixed prior to administration.
[0829] Compositions for oral, subcutaneous injection, intramuscular
injection, or intravenous administration typically contain the
Fenicol Compound in an amount ranging from about 1 percent to 80
percent by weight of the pharmaceutical compositions. In one
embodiment, the compositions contain the Fenicol Compound in an
amount ranging from about 5 percent to 75 percent by weight of the
pharmaceutical compositions. In one embodiment, the compositions
contain the Fenicol Compound in an amount ranging from about 10
percent to 70 percent by weight of the pharmaceutical compositions.
In one embodiment, the compositions contain the Fenicol Compound in
an amount ranging from about 15 percent to 65 percent by weight of
the pharmaceutical compositions. In one embodiment, the
compositions contain the Fenicol Compound in an amount ranging from
about 20 percent to 55 percent by weight of the pharmaceutical
compositions.
[0830] In another embodiment, the Fenicol Compounds are formulated
for topical administration. Compositions for topical administration
can be in the form of a salve, gel, lotion, cream, or ointment.
Compositions for topical administration can be either hydrophillic
or hydrophobic and can be aqueous or non-aqueous. Compositions for
topical administration can be in the form of an emulsion.
[0831] For topical administration, the compositions typically
contain the Fenicol Compound in an amount ranging from about 0.05
to 10 weight percent of the topical formulation, preferably about
0.05 to 5 weight percent of the topical formulation, more
preferably about 0.07 to 4 weight percent of the topical
formulation, and most preferably about 0.1 to 3 weight percent of
the topical formulation.
[0832] The present compositions can optionally comprise a suitable
amount of a pharmaceutically acceptable excipient so as to provide
the form for proper administration to the animal. Such
pharmaceutical excipients can be liquids, such as water and oils,
including those of petroleum, animal, vegetable, or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil,
and the like. Pharmaceutically acceptable excipients include, but
are not limited to, binding agents, filling agents, lubricating
agents, suspending agents, sweeteners, flavoring agents,
preservatives, buffers, wetting agents, disintegrants, effervescent
agents, coloring agents, pH buffering agents, and other excipients
depending upon the route of administration and the dosage form
desired. Such excipients are known in the art. Examples of suitable
pharmaceutical excipients are described in Remington's
Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed.
1995), the contents of which are incorporated herein by
reference.
[0833] Examples of filling agents are lactose monohydrate, lactose
anhydrous, and various starches; examples of binding agents are
various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose, such as Avicel.RTM. PH101 and
Avicel.RTM. PH102, microcrystalline cellulose, and silicified
microcrystalline cellulose (ProSolv SMCC.TM.).
[0834] Suitable lubricants, including agents that act on the
flowability of the powder to be compressed, are colloidal silicon
dioxide, such as Aerosile.RTM. 200, talc, stearic acid, magnesium
stearate, calcium stearate, and silica gel.
[0835] Examples of sweeteners are any natural or artificial
sweetener, such as fructose, sucrose, xylitol, sodium saccharin,
cyclamate, aspartame, and acsulfame. Examples of flavoring agents
are Magnasweet.RTM. (trademark of MAFCO); oil of wintergreen;
bubble gum flavor; peppermint flavor; spearmint flavor; fruit
flavors such as cherry, grape, and orange; and the like. Sweetners
and flavoring agents are particularly useful in orally administered
dosage forms to provide a pharmaceutically palatable
preparation.
[0836] Examples of preservatives are potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or quarternary compounds such as benzalkonium chloride.
[0837] Suitable diluents include pharmaceutically acceptable inert
fillers, such as microcrystalline cellulose, lactose, dibasic
calcium phosphate, saccharides, and/or mixtures of any of the
foregoing. Examples of diluents include microcrystalline cellulose,
such as Avicel.RTM. PH101 and Avicel.RTM. PH102; lactose such as
lactose monohydrate, lactose anhydrous, and Pharmatose.RTM. DCL21;
dibasic calcium phosphate such as Emcompress.RTM.; mannitol;
starch; sorbitol; sucrose; and glucose.
[0838] Suitable disintegrants include lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch, and modified
starches, croscarmellose sodium, cross-povidone, sodium starch
glycolate, and mixtures thereof.
[0839] Examples of effervescent agents are effervescent couples
such as an organic acid and a carbonate or bicarbonate. Suitable
organic acids include, for example, citric, tartaric, malic,
fumaric, adipic, succinic, and alginic acids and anhydrides and
acid salts. Suitable carbonates and bicarbonates include, for
example, sodium carbonate, sodium bicarbonate, potassium carbonate,
potassium bicarbonate, magnesium carbonate, sodium glycine
carbonate, L-lysine carbonate, and arginine carbonate.
Alternatively, only the sodium bicarbonate component of the
effervescent couple may be present.
[0840] In one embodiment, the pharmaceutically acceptable
excipients are sterile when administered to an animal. Water, and
in one embodiment physiological saline, is a particularly useful
excipient when the Fenicol Compound is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions can
also be employed as liquid excipients, particularly for injectable
solutions. In one embodiment, the liquid excipient is a non-aqueous
solvent such as N-methyl-2-pyrollidone; a mixture of
N-methyl-2-pyrollidone, polyethylene glycol, and propylene glycol;
or the solvents described in U.S. Pat. No. 5,082,863 to Apelian,
the contents of which are expressly incorporated herein by
reference.
[0841] The composition of the invention are prepared by a method
comprising admixing a Fenicol Compound and a pharmaceutically
acceptable carrier or excipient. Admixing can be accomplished using
methods well known for admixing a compound and a pharmaceutically
acceptable carrier or excipient.
5.9 Kits
[0842] The invention encompasses kits that can simplify the
administration of a Fenicol Compound to an animal. A typical kit of
the invention comprises a unit dosage form of a Fenicol Compound.
In one embodiment, the unit dosage form is a container, which can
be sterile, containing an effective amount of a Fenicol Compound
and a pharmaceutically acceptable carrier or excipient. The kit can
further comprise a label or printed instructions instructing the
use of the Fenicol Compound to treat a bacterial infection. The kit
can also further comprise a unit dosage form of another therapeutic
agent, for example, a second container containing an effective
amount of the other therapeutic agent and a pharmaceutically
acceptable carrier or excipient. In another embodiment, the kit
comprises a container containing an effective amount of a Fenicol
Compound, an effective amount of another therapeutic agent and a
pharmaceutically acceptable carrier or excipient. Examples of other
therapeutic agents include, but are not limited to, those listed
above.
[0843] Kits of the invention can further comprise a device that is
useful for administering the unit dosage forms. Examples of such a
devices include, but are not limited to, a syringe, a drip bag, a
dropper, and a patch.
[0844] The following examples are set forth to assist in
understanding the invention and should not be construed as
specifically limiting the invention described and claimed herein.
Such variations of the invention, including the substitution of all
equivalents now known or later developed, which would be within the
purview of those skilled in the art, and changes in formulation or
minor changes in experimental design, are to be considered to fall
within the scope of the invention incorporated herein.
6. EXAMPLES
[0845] Examples 1 to 7 relate to the synthesis of illustrative
Fenicol Compounds of the invention.
6.1 Synthesis of Fenicol Compound A1
[0846] To a suspension of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (0.111 g,
0.45 mmol, 1 eq.) in 2.5 mL of DCM was added isobutyric anhydride
with stirring to provide a thick mixture. After 5 min., 1.5 mL of
DCM was added to the thick mixture and the resulting solution was
allowed to stir for 30 min. An additional 25 mL of DCM was then
added to the mixture and the resulting DCM mixture extracted with
water (20 mL) followed by 5% NaHCO.sub.3 (20 mL). The organic
extract was dried (Na.sub.2SO.sub.4) and the solvent removed under
reduced pressure to provide Fenicol Compound A1 that can be
purified using silica gel column chromatography eluted with 70%
ethyl acetate in hexane.
6.2 Synthesis of Fenicol Compound A2
[0847] To a solution of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (2.89 g,
11.69 mmol, 1 eq.) in 50 mL of DCM was added
3,3,3-trifluoro-2-methyl propionic acid (1 eq.) followed by an
additional 50 mL of DCM. To the resulting solution was then added
EDC (1 eq.) and HOBT (1 eq.) with stirring. The resulting mixture
was allowed to stir for about 12 h. and was then washed with water
(2.times.100 mL), dried (Na.sub.2SO.sub.4), and the solvent removed
under reduced pressure to provide Fenicol Compound A2 that can be
purified using silica gel column chromatography eluted with 5%
methanol in chloroform.
6.3 Synthesis of Fenicol Compound I2
[0848] To a solution of (S)-2-chloropropionic acid (5 g, 46.08
mmol, 1 eq.) and N-hydroxysuccinimide (1 eq.) in THF (50 mL) at
about 0.degree. C. was added a solution of dicyclohexylcarbodiimide
(1 eq.) in 20 mL of THF at about 0.degree. C. and the resulting
solution allowed to stir for about 2 h. at about 0.degree. C. and
then maintained at about 4.degree. C. for about 12 h to provide a
solution of the N-hydroxysuccinimide ester of (S)-2-chloropropionic
acid.
[0849] Separately a solution of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (7.4 g, 30
mmol) in 150 mL of THF was added dropwise the 70 mL solution of the
N-hydroxysuccinimide ester of (S)-2-chloropropionic acid (1.5 eq.)
prepared above at 0.degree. C. and the resulting solution allowed
to stir for about 3 h. The resulting solution was then quenched
with water, the THF removed under reduced pressure, and the
resulting aqueous mixture extracted with DCM (150 mL). The DCM
solution was dried (Na.sub.2SO.sub.4), and the solvent removed
under reduced pressure to provide Fenicol Compound I2 that can be
purified by recrystallization from ethanol.
6.4 Synthesis of Fenicol Compound A7
[0850] To a solution of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (0.5 g,
2.0 mmol, 1 eq.) in DMF (6 mL) was added
2,3,3,3-tetrafluoropropionic acid (1.2 eq.) followed by BOP (1.2.
eq.) and HOBT (1.2 eq.) and the resulting solution was allowed to
stir for about 48 h. DCM (150 mL) was added to the solution and the
resulting solution extracted with 5% NaHCO.sub.3, brine, and water;
dried (Na.sub.2SO.sub.4); and the solvent removed under reduced
pressure to provide Fenicol Compound A7 that can be purified by
recrystallization.
6.5 Synthesis of Fenicol Compound I9
[0851] To a solution of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (0.5 g,
2.0 mmol, 1 eq.) in DMF (5 mL) was added (S)-3, 3,
3-trifluoro-2-hydroxy propionic acid (1.2 eq.) followed by EDC
(1.2. eq.) and HOBT (1.2 eq.) and the resulting solution allowed to
stir for about 40 h. DCM (150 mL) was added to the solution and the
resulting solution extracted with 5% NaHCO.sub.3, brine, and water;
dried (Na.sub.2SO.sub.4); and the solvent removed under reduced
pressure to provide Fenicol Compound 19 that can be purified by
recrystallization from ethanol.
6.6 Synthesis of Fenicol Compound E2
[0852] To a solution of (R)-2-chloropropionic acid (16.3 g, 150
mmol, 1 eq.) and N-hydroxysuccinimide (1 eq.) in THF (150 mL) at
about 0.degree. C. was added a solution of DCC (1 eq.) in 50 mL of
THF at about 0.degree. C. and the resulting solution allowed to
stir for about 30 min. at about 0.degree. C. and then maintained at
about 4.degree. C. for about 12 h to provide a solution of the
N-hydroxysuccinimide ester of (R)-2-chloropropionic acid.
[0853] Separately a solution of
D-(threo)-1-p-methylsulfonyl-2-amino-3-fluoro-1-propanol (7.4 g, 30
mmol) in 150 mL of THF was added dropwise to the 60 mL of a
solution of the N-hydroxysuccinimide ester of (R)-2-chloropropionic
acid (1.5 eq.) prepared above at 0.degree. C. and the resulting
solution allowed to stir for about 3 hr. The resulting solution was
then quenched with water, the THF removed under reduced pressure,
and the resulting aqueous mixture extracted with DCM (150 mL). The
DCM solution was dried (Na.sub.2SO.sub.4), and the solvent removed
under reduced pressure to provide Fenicol Compound E2 that can be
purified by recrystallization from ethanol.
6.7 Administration of of Fenicol Compound A1 to Dogs
[0854] Fenicol Compound Al was formulated as a pharmaceutical
composition containing 150 mg of Fenicol Compound Al, 25 mL
N-methyl pyrrolidone, 25 mL propylene glycol, QS to 100 mL with
polyethylene glycol. The pharmaceutical composition was then
administered to dogs at a dose of 40 mg/kg. Blood samples were
taken from the dog at various time points and serum separated using
standard methods well known to those skilled in the art. The serum
was then analyzed using HPLC according to the following
procedure:
[0855] A C.sub.18 Sep-Pak Plus.RTM. cartridge (Sep-Pak)
(commercially available from Waters of Milford, Mass.) was rinsed
with 5 mL of methanol followed by 5 mL of water and loaded with 1
mL of serum. After loading, the Sep-Pak was washed with 2 mL of
water, 2 mL of 15% aqueous acetonitrile, and 3 mL of hexane. The
Sep-Pak was then eluted with 4 mL of acetonitrile and the eluant
collected. The acetonitrile was evaporated using a stream of
nitrogen to provide a residue and the resulting residue was
reconstituted with 1 mL of 25% aqueous acetonitrile to provide an
assay solution. 50 .mu.L of the assay solution was then analyzed by
HPCL using high pressure liquid chromatography equipped with a
Beckman Coulter Ultraphere C-18 5 .mu.M.times.4.6 mm.times.250 mm
analytical column eluted at a flow of 1.2 mL/min. using a gradient
of water and acetonitrile according to the following profile:
TABLE-US-00014 Time (min.) Percent Water Percent Acetonitrile 0 75
25 4 75 25 10 40 60 20 40 60 25 75 25 42 75 25
The HPLC system was interfaced to a UV detector operated at 223 nm.
The serum concentration of Fenicol Compound A1 was then determined
by comparing the area under the curve for the HPLC peak
corresponding to Fenicol Compound A1 to a standard curve of peak
areas v. known concentrations of Fenicol Compound A1 in cat serum.
The standard curve was prepared using the following concentrations
of Fenicol Compound A1 in cat serum 0.1, 0.3, 1, 2, 3, 5, 7, and 10
.mu.g/mL.
[0856] FIG. 1 is a plot of the serum concentration of Fenicol
Compound A1 as a function of time following subcutaneous
administration of Fenicol Compound A1 to dogs at a dose of 40 mg/kg
as a pharmaceutical composition containing 3 g of Fenicol Compound
A1, 9 g N-methyl pyrrolidone, 2.25 g propylene glycol, QS to 20 mL
with polyethylene glycol. FIG. 1 also shows the serum concentration
when NUFLOR.RTM. (commercially available from Schering-Plough
Animal Health, New Jersey) was administered to dogs at a dose of 40
mg/kg. FIG. 1 shows that Fenicol Compound A1, when administered to
dogs, acheives a higher serum concentration than NUFLOR.RTM. and is
cleared more slowly than NUFLOR.RTM.. Therefore administering
Fenicol Compound Al to dogs results in a higher serum concentration
of the antibiotic than is obtainable when NUFLOR.RTM. is
administered to dogs. Accordingly, Fenicol Compound A1 can be more
effective than NUFLOR.RTM. at treating or preventing a bacterial
infection in dogs and other small animals.
6.8 Administration of Fenicol Compound A2 to Dogs
[0857] Fenicol Compound A2 was formulated as a pharmaceutical
composition containing 925 mg of Fenicol Compound A2, 2 mL N-methyl
pyrrolidone, 0.5 mL propylene glycol, QS to 5 mL with polyethylene
glycol. The pharmaceutical composition was then administered to
dogs subcutaneously at a a dose of 40 mg/kg. Blood samples were
taken from the dogs at various time points and the blood samples
treated as described above. The serum was then analyzed using the
HPLC procedure described above.
[0858] FIG. 2 is a plot of the serum concentration of Fenicol
Compound A2 as a function of time following the subcutaneous
administration. FIG. 2 shows that Fenicol Compound A2, when
administered to dogs, achieves a much higher serum concentration
and is cleared more slowly than is NUFLOR.RTM.. Therefore,
administering Fenicol Compound A2 to dogs results in a higher serum
concentration of the antibiotic than is obtainable when NUFLOR.RTM.
is administered to dogs. Accordingly, Fenicol Compound A2 can be
more effective than NUFLOR.RTM. at treating or preventing a
bacterial infection in dogs and other small animals.
6.9 Administration of Fenicol Compound A2 to Dogs
[0859] Fenicol Compound A2, i.e., wherein the acylamido group is
present as an equimolar mixture of the (R) stereochemical
configuration and the (S) stereochemical configuration, was
formulated as a pharmaceutical composition containing 925 mg of
Fenicol Compound A2, 2 mL N-methyl pyrrolidone, 0.5 mL propylene
glycol, QS to 5 mL with polyethylene glycol The pharmaceutical
composition was then administered to dogs subcutaneously at a a
dose of 40 mg/kg. Blood samples were taken from the dogs at various
time points and the blood samples treated as described above. The
serum was then analyzed using the HPLC procedure described above.
The HPLC method is capable of separating Fenicol Compound A2
wherein the acylamido group is in the (R) configuration (i.e.,
Fenicol Compound II) and Fenicol Compound A2 wherein the acylamido
group is in the (S) configuration (i.e., Fenicol Compound E1). The
maximum serum level was determined for each isomer (C.sub.maxR and
C.sub.maxS, respectively). The percent of Fenicol Compound A2
wherein the acylamido group has the (R) stereochemical
configuration was then determined at each time point by dividing
the serum concentration of the Fenicol Compound A2 wherein the
acylamido group has the (R) stereochemical configuration at that
time point by C.sub.maxR. Similarly, the percent of Fenicol
Compound A2 wherein the acylamido group has the (S) stereochemical
configuration was then determined at each time point by dividing
the serum concentration of the Fenicol Compound A2 wherein the
acylamido group has the (S) stereochemical configuration at that
time point by C.sub.maxS.
[0860] FIG. 3 graphically depicts the percent of Fenicol Compound
A2 wherein the acylamido group has the (R) stereochemical
configuration and the percent of Fenicol Compound A2 wherein the
acylamido group has the (S) stereochemical configuration as a
function of time. FIG. 3 shows that Fenicol Compound A2 wherein the
acylamido group has the (R) stereochemical configuration is cleared
more slowly than Fenicol Compound A2 wherein the acylamido group
has the (S) stereochemical configuration.
[0861] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
[0862] A number of references have been cited, the entire
disclosure of which are incorporated herein by reference.
* * * * *