Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-25
2002-06-11
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S385000, C514S924000
Reexamination Certificate
active
06403623
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of Invention
This invention relates to the treatment of infectious diseases, certain heterocyclic compounds useful as therapeutic agents therein and, to pharmaceutical formulations containing said therapeutic agents. In particular this invention relates to a method for treating
Mycobacterium tuberculosis
infections in man, certain carboxy substituted 2-aryloxazoline, 2-arylthiazoline, 2-arylimidazoline compounds and similarly substituted related unsaturated heterocyclic compounds e.g. oxazole, thiazole and imidazole compounds, and to pharmaceutical formulations comprising said heterocyclic compounds.
Among bacterial infections, tuberculosis is usually a respiratory infection, although it can cause damage to virtually any organ in the human body. It is estimated that about 40% of the world's population is infected with the tuberculosis bacterium. Early in this decade, the incidence of tuberculosis began rising after a 33-year downward trend. Streptomycin, the first antibiotic capable of killing the tuberculosis organism, was discovered in 1944. Other antituberculosis agents were subsequently developed. (Lemke, T. L. In
Principles of Medicinal Chemistry,
4th ed.; Foye, W. O., Lemke, T. L. Williams & Wilkins: Baltimore, 1995; pp 747-758.) However, the recent emergence of drug resistant strains of tuberculosis has raised serious concern. Between 1989 and 1992 drug resistant strains had appeared in 17 states. (Tuberculosis and HIV Public Health Policy: A Dual Challenge. Washington: AIDS Action Foundation, March 1992). Recently, studies on the application of siderophore substituted mycobactins and analogs thereof were reported (Xu, Yanping, and Miller, Marvin J.
J. Org. Chem.,
1998,63, 4314). It was found that structural variations of the natural mycobactins produced by the mycobacterium were effective inhibitors of the mycobacterium. The retrograde synthesis work on the mycobactins carried out in this study has led to the discovery of the antituberculosis therapeutic agents of this invention.
SUMMARY OF THE INVENTION
The compounds provided by this invention are useful in the method described herein for the treatment of tuberculosis and are represented by the following formula 1.
wherein X is O, S, or NH,
Y represents fragments
Y
1
is OR
4
, wherein R
4
is hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, diphenylmethyl, or a biologically-labile ester, —NHR
4
′, or —NHNHR
4
′ wherein R
4
′ is hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, diphenylmethyl, or a 5- or 6-membered saturated or unsaturated heterocycle containing from 1 to 3 of the same or different nitrogen, oxygen or sulfur hetero atoms, and wherein said phenyl, benzyl, diphenylmethyl and R
4
′ groups can be substituted by R as defined herein;
R is hydrogen or a substituent group e.g. lower alkyl, halogen, alkoxy, amino, substituted amino, hydroxy, carboxy or aminocarbonyl;
R
1
is hydrogen, alkyl, 5- to 7- membered cycloalkyl, alkyl substituted by phenyl or diphenyl, e.g. benzyl or diphenylmethyl, or a t-vinyl or ethinyl group represented by the formulas —C(C
1
-C
3
)
2
—CH═CH
2
, —C(C
1
-C
3
)
2
—C≡CH;
R
2
is hydrogen or C
1
-C
3
alkyl; and
R
3
is hydrogen or lower alkyl;
The compounds represented by the formula 1 inhibit the growth of
Mycobacterium tuberculosis
and are useful in the treatment of tuberculosis in man when administered in an effective non toxic amount. Pharmaceutical formulations comprising a compound of the formula 1 or a pharmaceutically acceptable salt thereof and a suitable carrier are useful in the method for treating tuberculosis.
DETAILED DESCRIPTION
The terms used in the above formula 1 have the following meanings herein
R is hydrogen, C
1
-C
4
alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl; C
1
-C
4
alkoxy such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy and the like; C
1
-C
4
alkoxy substituted by phenyl, diphenyl such as benzyloxy diphenylmethoxy, 2-phenylethoxy, 1,2-diphenylethoxy, 3-phenylpropoxy, 2,2-diphenylethoxy, and the like; halogen such as fluoro, chloro, or bromo; hydroxy; carboxy; cyano; aminocarbonyl; amino, mono- or di-C
1
-C
4
alkyl)aminocarbonyl such as dimethylaminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, iso-propylaminocarbonyl, n-propylaminocarbonyl, t-butylaminocarbonyl, and the like; amino and mono- or di-C
1
-C
4
alkyl)amino such as methylamino, ethylamino, t-butylamino, dimethylamino, diethylamino, methylethylamino, n-propylamino, and the like;
R
1
is hydrogen, C
1
-C
4
alkyl as exemplified for the term R above; 5- to 7-membered cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl and the like; a di-C
1
-C
3
alkyl) carbinyl ethinyl or vinyl-t-carbinyl group of the formula —C(C
1
-C
3
)
2
CH═CH
2
or —C(C
1
-C
3
)
2
—CH═CH
2
such as dimethylethinylcarbinyl, dimethylvinylcarbinyl, methylethylethinylcarbinyl, diethylethinylcarbinyl and the like; C
1
-C
4
alkyl substituted by phenyl or diphenyl such as benzyl, diphenylmethyl, 2-phenylethyl, 2,2-diphenylethyl, 1,3-diphenylpropyl and, wherein said phenyl and diphenyl groups can be substituted by a group R as defined herein above;
R
2
is hydrogen or C
1
-C
3
alkyl;
R
3
is hydrogen or C
1
-C
4
alkyl;
R
4
is hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, diphenylmethyl or a biologically-labile ester;
R
4
′ hydrogen, C
1
-C
4
alkyl, phenyl, benzyl, diphenylmethyl, or a 5- or 6-membered saturated or unsaturated heterocyclic ring containing from 1 to 3 of the same or different nitrogen, oxygen, or sulfur hetero atoms such as for example, pyridyl, piperidyl, pyrrolidyl, pyrrolidinyl, pyrimidyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, thiazinyl or tetrazolyl, and wherein said phenyl, benzyl, diphenylmethyl and heterocyclic ring groups can be substituted by R substituents having the same meanings as defined herein above.
When R
4
is a biologically-labile ester, R
4
represents an acyloxymethyl group, —CH
2
—C(O)-alk, a acyloxyalkyl group, alk-C(O)O—CH-alk or alk-OC(O)O—CH-alk, a alkoxyethyl ether group, alk-O-(CH
2
)
2
—O—CH
2
—, where in the foregoing alk is C
1
-C
4
alkyl, or is R
4
phthalidyl, indanyl, or a 2-oxo-1,3-dioxolene group represented by the formula.
Examples of such labile ester groups are acetoxymethyl, propionoxymethyl, pivaloyloxymethyl, 2-(methoxy)ethoxymethyl, 2-(ethoxy)ethoxymethyl, and 2-(t-butoxy)ethoxymethyl, and like labile ester moieties.
The compounds represented by the formula 1 having basic or acidic groups form salts with mineral acids and organic acids and inorganic and organic bases respectively. For example, when an R substituent is a basic group such as an amino or substituted amino group or when R
4
is a basic heterocyclic group such as piperidyl or pyridyl, salts can be formed with mineral acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids. Organic acids which can be used are e.g. the sulfonic acids such as methanesulfonic, benzenesulfonic, toluenesulfonic, or naphthalenesulfonic; benzoic, chlorobenzoic, salicylic, malonic, maleic and succinic acids. Acidic groups e.g., when R is a carboxy group, form salts with basis such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium or potassium bicarbonate and ammonia. Also such acidic groups form salts with organic bases such as alkylamines e.g., methylamine, t-butylamine, diethylamine, cyclohexylamine, dicyclohexylamine, abietylamine, diethanolamine, and ethanolamine. Such salts are useful in the isolation and purification of formula 1 compounds and in the preparation of pharmaceutical formulations for administration in the therapeutic method provided herein.
Preferred compounds of the invention are represented by the formula 1 wherein Y is the fragment (1a) or (1b) and X is O or S. In particular, of the preferred compounds are those wherein R
1
is benzyl or diphenylmethyl and Y
1
is OR
4
wherein R
4
is benzyl or diphenylmethyl are preferred. Among this preferred group, the compound (S
Hu Jingdan
Miller Marvin J.
Scanlon William B.
Unuversity of Notre Dame du Lac
Weddington Kevin E.
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