Hygromycin A prodrugs

Details Hygromycin A prodrugs Hygromycin A prodrugs

2000-10-27

2002-12-10

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S025000, C536S016800, C536S017900, C536S018100

Reexamination Certificate

active

06492342

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel hygromycin A prodrugs that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment. The hygromycin prodrugs of this invention possess an advantage over the parent drugs in terms of efficacy, formulation, solubility, side effects or stability.
Hygromycin A is a fermentation-derived natural product first isolated from
Streptomyces hygroscopicus
in 1953. As an antibiotic, hygromycin A possesses activity against human pathogens and is reported to possess potent in vitro activity against
Serpulina
(
Treponema
)
hyodysenteriae
which causes swine dysentery. Several references refer to semisynthetic modifications of hygromycin A, including the following: derivatization of the 5″ ketone of hygromycin A to the 2,4-dinitrophenylhydrazone is referred to in K. Isono et al.,
J. Antibiotics
1957, 10, 21, and R. L. Mann and D. O. Woolf,
J. Amer Chem. Soc
. 1957, 79, 120. K. Isono et al., ibid., also refer to the thiosemicarbazone at 5″; reduction of the 5″ ketone of hygromycin A to the 5″ alcohol is referred to in R. L. Mann and D. O. Woolf, ibid., as well as in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1992, 2, 533 and S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1993, 3, 295; furanose analogues are referred to in B. H. Jaynes et al.,
Bioorg. Med. Chem. Lett
. 1993, 3, 1531, and B. H. Jaynes et al.,
J. Antibiot
. 1992, 45, 1705; aromatic ring analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1993, 3, 289, and C. B. Cooper et al.,
Bioorg. Med. Chem. Lett
. 1997, 7, 1747; enamide analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1992, 2, 533; aminocyclitol analogues are referred to in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1992, 2, 1015, and in S. J. Hecker et al.,
Bioorg. Med. Chem. Lett
. 1992, 2, 1043. The hygromycin A derivatives of the present invention possess activity against both gram-negative and gram-positive bacteria and protozoa.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
or the pharmaceutically acceptable salts thereof; wherein
a is 0 or 1;
b is 0, 1, 2 or 3;
R
1
is hydrogen or hydroxy;
R
2
is methyl;
R
3
is (C
6
-C
10
)aryl optionally substituted by one to three groups independently selected from hydrogen, halo, (C
1
-C
6
)alkoxy, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, nitro, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkoxyC(O), (C
1
-C
6
)alkylaminoC(O), (C
6
-C
10
)aryl, (C
2
-C
9
)heterocycloalkyl, (C
2
-C
9
)heteroaryl or (C
1
-C
6
)alkyl optionally substituted by one to three fluoro;
X is (R
4
O)
2
P(O)—, (R
4
O)S(O)
n
—, (C
6
-C
10
)arylC(O), (C
2
-C
9
)heteroarylC(O), (C
2
-C
9
)heterocycloalkylC(O), (R
7
)
2
N(CHR
5
)C(O)—, R
6
pyridinium(C
1
-C
6
)acyl, (R
8
)
3
N
+
(C
1
-C
1
-C
6
)acyl, (C
1
-C
6
)acyl, (C
6
-C
10
)aryl(C
1
-C
3
)acyl, (C
2
-C
9
)heteroaryl(C
1
-C
3
)acyl and (C
2
-C
9
)heterocycloalkyl(C
1
-C
3
)acyl;
wherein n is 1 or 2;
R
4
is hydrogen, (C
1
-C
5
)alkyl, (C
6
-C
10
)aryl or an alkaline metal;
R
5
is hydrogen, (C
1
-C
6
)alkyl optionally substituted by hydroxy, aminoC(O)—, thio, methylthio, carboxy or amino; (C
6
-C
10
)aryl optionally substituted by hydroxy; or (C
2
-C
9
)heteroaryl;
R
6
is hydrogen, halo, nitro, amino, (C
1
-C
6
)alkylamino, ((C
1
-C
6
)alkyl)
2
amino, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkyoxyC(O) or (C
1
-C
6
)alkylaminoC(O);
R
7
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl or (C
6
-C
10
)aryl(C
1
-C
6
)alkyl;
R
8
is hydrogen or (C
1
-C
6
)alkyl;
Y is CH or N, wherein the wavy bond symbol linking Y and (CH
2
)
a
designates a single bond in either the “Z” or “E” configuration relative to the furanyl ring;
Z is oxygen or NR
12
wherein R
12
is hydrogen, (C
1
-C
6
)alkyl or (C
6
-C
10
)aryl;
with the proviso that when Y is CH, a is 1; and
with the proviso that when Y is nitrogen, a is zero.
The term “halo”, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Said alkyl group may include one or two double or triple bonds. It is understood that for said alkyl group to include a carbon—carbon double or triple bond at least two carbon atoms are required in said alkyl group.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, and also benzyl.
(C
2
-C
9
)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C
2
-C
9
)heterocycloalkyl rings is through a carbon or a sp
3
hybridized nitrogen heteroatom.
(C
2
-C
9
)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C
2
-C
9
)heterocycloalkyl rings is through a carbon atom or a sp
3
hybridized nitrogen heteroatom.
The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Preferred compounds of formula I include those wherein Y

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