Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-25
2001-10-30
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S524000
Reexamination Certificate
active
06310058
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to antibiotics. In particular it relates to compounds that inhibit the causative organism of tuberculosis,
Mycobacterium tuberculosis
, to pharmaceutical formulations comprising the compounds and to a method for the treatment of tuberculosis. The compounds provided are related to the siderophoric mycobactins which are key in the transport of iron into mycobacterium and the growth thereof.
2. Description of Related Art
The family of mycobactin compounds was first isolated by Snow; Snow, G. A.
Bacteriol. Rev.
1970, 34, 99. Structural work with the mycobactin factors was reported by Hu, Jingdan, Miller, Marvin J.
J. Am. Chem. Soc.
1997, 119, 3462-3468 and Xu, Yanping, Miller, Marvin J.
J. Org. Chem.
1998, 63, 4314-4322.
The latter publication describes analogs of mycobactins obtained via retrograde synthesis and the antimycobacterium activity obtained with the analogs.
SUMMARY OF THE INVENTION
The compounds provided by this invention are represented by the structural formula 1.
wherein R is a 2-phenyl oxazoline, thiazoline or imidazoline group represented by the formula (1a)
or a 2-phenyl oxazole, thiazole or imidazole group represented by the formula (1b)
R
1
is hydrogen or a substituent group e.g. lower alkyl, lower alkoxy, hydroxy, carboxy, amino or mono- or dialkylamino, aminocarbonyl, mono- or dialkylaminocarbonyl; or —C
1
-C
4
alkyl substituted by one or two phenyl groups; R
2
and R
3
independently are hydrogen or C
1
-C
3
alkyl; R
4
is a siderophoric group represented by the formula
—(CH
2
)
m
—N(OH)—C(O)—(CH
2
)
n
—(CH═CH)
o
—CH
3
;
X is O, S, or NH;
X
1
is O or NH;
Y is H or C
1
-C
4
alkyl;
Z is H, lower alkyl, mono or dialkylamino or N(R
5
)(R
5
′) when X
1
is NH and when X
1
is O, Z is mono or dialkyamino or N(R
5
)(R
5
′) wherein R
5
is hydrogen, lower alkyl, alkyloxycarbonyl, aryloxycarbonyl; aralkyloxycarbonyl, cycloalkoxycarbonyl, bicyloalkoxycarbonyl or lower alkanoyl; R
5
′ is hydrogen or lower alkyl;
m is an integer of from 2 to 6;
n is an integer of from 0 to 22;
o is an integer of from 0 to 4 provided that m+0 is no greater than 25;
p and q independently are 0, 1 or 2;
r is an integer of from 2 to 4;
and the pharmaceutically acceptable salts thereof.
The compounds of the invention are useful antimycobacterial agents useful in the treatment of tuberculosis according to the method provided herein. Pharmaceutical formulations also are provided.
DETAILED DESCRIPTION
The terms used in the formula 1 have the following meanings herein. Lower alkyl refers to straight or branched chain hydrocarbon radicals having from 1 to 6 carbon atoms such as e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, n-amyl, iso-amyl, n-hexyl, and the like. Lower alkoxy refers to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, and the like. Halogen refers to fluoro, chloro, and bromo. Mono- and dialkylamino refers to the amino group substituted by one or two of the same or different alkyl groups having from 1 to 4 carbon atoms such as e.g., methylamino, dimethylamino, ethylamino, methylethylamino, diethylamino, n-propylamino, iso-propylamino, t-butylamino, methyl-t-butylamino and the like. Mono- and dialkylaminocarbonyl refers to the aminocarbonyl group wherein the amino group is substituted as defined above for mono- and dialkylamino groups. C
1
-C
4
alkyl substituted by one or two phenyl groups refers to benzyl, diphenylmethyl, 2-phenylethyl, 1,2-diphenylethyl, 4-phenylbutyl, 1,3-diphenylpropyl and the like.
The groups represented in the formula [1] wherein Z is N(R
5
R
5
′) include for example where R
5
′ is a C
1
-C
6
alkoxycarbonyl group such as e.g., methoxycarbonyl, ethoxycarbonyl, iso-propoxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl (t-Boc), iso-amyloxycarbonyl, and straight and branched hexyloxycarbonyl groups; the cycloalkoxycarbonyl groups having from 3 to 7 ring carbon atoms such as e.g., cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl; the aryloxycarbonyl groups wherein aryl is phenyl or naphthyl such as e.g., phenyloxycarbonyl, 2,6-dimethylphenyloxycarbonyl and 1- or 2-naphthyloxycarbonyl; the aralkyloxycarbonyl groups such as e.g., benzyloxycarbonyl, 2,6-dimethylbenzyloxycarbonyl, 2-phenyl-2-propyloxycarbonyl, and 2,6-dichlorobenzyloxycarbonyl; bicycloalkoxycarbonyl groups such as e.g., bicycloheptyloxycarbonyl, adamantyloxycarbonyl, bicyclohexyloxycarbonyl, and the like. The mono or dialkylamino groups represented by Z include, for example, sec-butylamino, t-butylamino, diethylamino, iso-propylamino, di-n-propylamino, pentylamino, hexylamino, dihexylamino, and like mono or di-(C
1
-C
6
alkyl) amino groups.
In the formula (1) where, in R
4
o is greater than 1, the ethylene groups can be conjugated or non-conjugated. For example, m+o can represent (CH
2
)
2
CH═CHCH═CH(CH
2
)
9
CH
3
, (CH
2
)
2
CH═CH(CH
2
)
2
CH═CH(CH
2
)
9
CH
3
and the like. When o is greater than 0, the double bonds can be epoxidized or converted to diols by standard procedures.
The cyclic-hydroxyamino groups represented when r of —(CH
2
)r— is 2 to 4 are N-hydroxypyrrolidin-2-one, N-hydroxypiperidin-2-one and N-hydroxyazepin-2-one.
The compounds represented by the formula 1 are obtained by the methods described by Xu, Yanping, and Miller, Marvin J.
J. Org. Chem.
1998, 63, 4314-4322, employing a retrograde synthesis approach. The process for preparing the compounds of the invention is a multi-step process. Solely for purposes of ease of description herein, the compounds of the formula 1 are referred to in two portions. The portion shown to the left of formula 1 as drawn above and represented by the partial formula R—NH—CH(R
4
)—C(O)— is referred to as the “mycobactic acid” portion. For example, as represented by the formula [4] below as the free acid or as an ester thereof. The portion to the right in formula 1 beginning with X
1
as shown is referred to as the “cobactin” portion. For example as represented by the formula [7] below. The coupling of the mycobactic acid portion with the cobactin portion provides the compound of the invention.
Initially the compound represented by the formula 2
is coupled with an &ohgr;-(N-acyl-N-protected or unprotected hydroxyamino) amino acid ester [3] represented by the formula CH
3
—(CH
2
)
n
—C(O)—N—(OH)—(CH
2
)
m
—CH—(NH
2
)COOCH
3
wherein the N-hydroxy group may be protected with a silyl protecting group, preferably [2-(trimethylsilyl)ethoxy] methyl group. The coupling reaction is carried out in an inert solvent with a diimide e.g. 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide in the presence of 1-hydroxy-7-azabenzotriazole and 4-(dimethylamino)pyridine providing the coupling product referred to herein as an ester of a mycobactin acid and represented by the following formula [4], wherein X is O, having the siderophore hydroxyamino acyl group.
A like coupling product is obtained under the same conditions with the heterocyclic acid represented by the formula [5], e.g. an oxazole-2-carboxylic acid.
The &ohgr;-(N-acyl-N-protected hydroxyamino)-&agr;-protected-amino acid [3], is obtained by the oxidation of the &ohgr;-amino-&agr;-protected amino acid with dimethyldioxirane (DMD) (Hu, J.; Miller, M. J.
J.Org. Chem.
1994, 59, 4858). After oxidation, the N-hydroxyamino group is acylated on the amino group with the acid CH
3
—(CH
2
)
n
—COOH. The acylation is carried out with an acyl halide or active ester of the acid. For example, stearyl chloride is reacted in an inert solvent with the amine in the presence of a base such as sodium bicarbonate. Acids which are used include capric acid, lauric acid, myristic acid, palmitic acid, hebenic acid, and like fatty acids. The N—(OH) group is protected prior to use in the coupling reaction. Useful in protecting the hydroxy group are the silyl protecting groups suc
Miller Marvin J.
Xu Yanping
Kifle Bruck
Scanlon William B.
University of Notre Dame du Lac
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