Derivatives of phenyl 4-aminosalicylate and method of making...

Details Derivatives of phenyl 4-aminosalicylate and method of making... Derivatives of phenyl 4-aminosalicylate and method of making...

2000-10-23

2003-07-29

Killos, Paul J. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S023000

Reexamination Certificate

active

06600063

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel antimycobacterial compounds or pharmaceutically acceptable derivatives thereof, and methods for making the same. More specifically, this invention relates to novel derivatives of phenyl 4-aminosalicylate or pharmaceutically acceptable derivatives thereof, and methods for making the same. The compounds and pharmaceutical compositions of this invention may be advantageously used as agents against mycobacterial infections.
2. Description of the Related Art
The designation of tuberculosis as a global public health crisis by the World Health Organization in the mid-1990's has underscored the stern challenges facing the research community. The occurrence of some three million new cases of tuberculosis per year world-wide and the emergence of new strains of
Mycobacterium tuberculosis
characterized by drug resistance or increased virulence have made clear the pressing need for the evolution of newer and more powerful drugs. Moreover, several other mycobacterial diseases have begun to emerge, caused by nontuberculous mycobacteria. These include diseases caused by
Mycobacterium avium, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium kansasii
and
Mycobacterium haemophilum.
It is has been known in the art that phenyl 4-aminosalicylate has value as an antituberculosis compound. Tests have suggested that phenyl 4-aminosalicylate destroys the virulent strain of
M.tuberculosis
(H37Rv) even better than 4-aminosalicylic acid, a standard widely-used antituberculosis drug to which it is structurally related. (U.S. Pat. No. 2,604,488 (to Soc. Usines Chim. Rhone-Poulenc); Chemical Abstracts, vol. 48, 12807 c (1954).) The present invention provides useful, novel antimycobacterial compounds, namely derivatives of phenyl 4-aminosalicylate, which are effective against a number of species of mycobacteria.
In addition to the need for the evolution of newer and more powerful antimycobacterial drugs, the biological evaluation of compounds suspected to be active against mycobacteria requires that the compounds be readily available in pure form on quantity scale, generally understood to be gram or multi-gram scale, as opposed to milligram scale. Gram scale quantities are necessary for the large numbers of biological tests which must be performed and replicated for the evaluation of a new drug candidate.
Products of synthetic reactions are most desirable when they can be easily and cheaply obtained as dry and free-flowing solids. In the long run, dry and free-flowing solids permit better formulations of drugs as tablets, capsules or syrups. The invention disclosed herein provides a novel method of phenyl 4-aminosalicylate derivative synthesis which yields products directly as dry free-flowing solids in analytically pure form. The products of the prior art syntheses are obtained as intractable oils which are difficult and labor-intensive to purify or bring into dry free-flowing form. The present invention overcomes these drawbacks and provides methods of phenyl 4-aminosalicylate derivative synthesis which yield products that are suitable for biological evaluation or for further chemical transformation to other derivatives of phenyl 4-aminosalicylate.
BRIEF SUMMARY OF THE INVENTION
Broadly, the invention comprises novel derivatives of phenyl 4-aminosalicylate or pharmaceutically acceptable derivatives thereof, and methods for making the same. This invention further comprises methods for their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them. More particularly, this invention comprises methods of yielding novel derivatives of phenyl 4-aminosalicylate which have improved antimycobacterial activity and are comprised of structural elements which change the reaction chemistry and physical properties at the conjugation sites of phenyl 4-aminosalicylate during xenobiotic transformation. This invention further provides a method of yielding novel derivatives of phenyl 4-aminosalicylate having enhanced lipophilicity with respect to 4-aminosalicylic acid itself, signifying better permeation of the mycobacterial cell wall lipid domain and better drug action, on a multi-gram scale and in high purity for subsequent biological evaluation in drug discovery.
In one aspect, the invention comprises an antimycobacterial compound which comprises the formula:
where R
1
=H; and
where R
2
-R
3
=CHR
4
where R
4
=C
l
to C
14
alkyl, C
1
to C
14
substituted alkyl, C
2
to C
10
alkenyl, C
2
-C
10
substituted alkenyl, C
2
to C
9
substituted dialkenyl, C
3
to C
7
cycloalkyl, C
3
to C
7
substituted cycloalkyl, phenyl, substituted phenyl, C
7
to C
16
phenylalkyl, C
7
to C
16
substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle; or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another aspect of the invention comprises an antimycobacterial compound which comprises the formula:
where R
1
=H, COR
5
where R
5
=C
1
to C
14
alkyl, C
1
to C
14
substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C
1
to C
10
alkoxy, C
1
to C
10
substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C
2
-C
20
substituted alkenyloxy, C
2
to C
10
alkenyl, C
2
-C
10
substituted alkenyl, C
2
to C
9
substituted dialkenyl, C
3
to C
7
cycloalkyl, C
3
to C
7
substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C
7
to C
16
phenylalkyl, C
7
to C
16
substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle;
where R
2
=H; and
where R
3
=COR
6
where R
6
=C
1
to C
14
alkyl, C
1
to C
14
substituted alkyl, trifluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trideuteriomethyl, iodomethyl, C
1
to C
10
alkoxy, C
1
to C
10
substituted alkoxy, benzyloxy, substituted benzyloxy, steroidal, propenyloxy, difluorochloromethyl, pentafluoroethyl, perfluoropropyl, C
2
-C
20
substituted alkenyloxy, C
2
to C
10
alkenyl, C
2
-C
10
substituted alkenyl, C
2
to C
9
substituted dialkenyl, C
3
to C
7
cycloalkyl, C
3
to C
7
substituted cycloalkyl, phenyl, substituted phenyl, aminoalkyl, substituted aminoalkyl, C
7
to C
16
phenylalkyl, C
7
to C
16
substituted phenylalkyl, benzyl, substituted benzyl, naphthyl, substituted naphthyl, heterocycle, or substituted heterocycle;
or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another aspect of the invention comprises an antimycobacterial compound of the formula:
where R
1
=H, COCH
3
, COCH
2
CH
3
;
where R
2
=H; and
where R
3
=COCH
3
, COCH
2
CH
3
, CSNHC
6
H
5
, CSNH-4-C
6
H
4
Br, CSNH-4-C
6
H
4
CH
3
, CSNH-4-C
6
H
4
Cl, CSNHCH
2
CH
3
, CSNHCH(CH
3
)
2
, CSNHC(CH
3
)
3
, CSNH-3-pyridyl, CSNH-2,3,4-C
6
H
2
F
3
, CSNH-4-C
6
H
4
F, CSNH-3,5-C
6
H
3
F
2
, CSNH-2,6-C
6
H
3
F
2
, CSNH-2-Cl-4-NO
2
C
6
H
3
, CSNH-2-F-4-BrC
6
H
3
, CSNH-4-C
6
H
4
NO
2
, CSNH-3-CF
3
-4-Cl—C
6
H
3
, CSNH-2-F-5-CF
3
-C
6
H
3
, CSNH-2-CF
3
-4-F—C
6
H
3
, CSNH-3-CF
3
-4-F—C
6
H
3
, CSNH-2-C
6
H
4
OCF
3
, CSNH-4-C
6
H
4
OCF
3
, CSNH-4-C
6
H
4
CF
3
, CSNH-2-C
6
H
4
SCF
3
, CSNH-3-C
6
H
4
CN, CSNH-4-C
6
H
4
CN, CSNH-2-C
6
H
4
OCHF
2
, CSNH-4-C
6
H
4
OCHF
2
, CSNH-4- C
6
H
4
OCH
3
, CSNH-3-C
6
H
4
CH
3
, CSNH-2-OCH
3
-4-NO
2
C
6
H
4
, CSNH-4-C
6
H
4
SCH
3
, CSNH-3,5-(CF
3
)
2
-C
6
H
4
, CSNH-3,4,5-(CH
3
)
3
C
6
H
2
, CSNH-1-naphthyl and CSNH-2-naphthyl; or a pharmaceutically acceptable salt thereof; or a pharmaceutical isomer thereof; or a combination of the same.
Another embodiment of the invention comprises an antimycobacterial compound of the formula:
where R
1
=H, COCH
3
, COCH
2
CH
3
; and
where R
2
=H; and
where R
3
=C

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