Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-04-29
2001-02-27
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007400
Reexamination Certificate
active
06194387
ABSTRACT:
DESCRIPTION
1. Technical Field of the Invention
The present invention relates to erythromycin derivatives. More particularly, the present invention pertains to 6-O-alkyl derivatives of 9-oxime erythromycin B, a process for making those compounds and the use of the compounds as antibiotics.
2. Background of the Invention
Erythromycin B is a known macrolide antibiotic (C,E.G., U.S. Pat. No. 5,141,926) it is a fermentaion product produced by the gram-positive bacterium
saccharopolyspora erythraea.
Erythromycin B can be methylated at the 6-hydroxyl position to produce 6-O-methyl erythromycin B, the structure of which is shown below. There are no known reports, however, erythromycin Bor 6-O-methyl of erythromycin B derivatives where in the keto group at position 9 has been replaced with alternative functional group.
BRIEF SUMMARY OF THE INVENTION
The present invention provides 6-O-alkyl derivatives of 9-oxime erythromycin B and methods of synthesizing those compounds. A 6-O-alkyl derivative of 9-oxime erythromycin B compound of the present invention has the structure 1, below:
where R
1
is alkyl, R
2
and R
4
are each independently hydrogen or a conventional O-protecting group, and R
3
is —NR
5
(CH
3
)
2
, where R
5
is methyl (CH
3
) or a conventional N-protecting group or —N
+
(CH
3
)
2
R
6
X
−
, where R
6
is 2-alkenyl, benzyl or substituted benzyl, and X is a halogen. In a preferred embodiment, R
1
is methyl, R
2
and R
4
are both hydrogen and R
3
is dimethylamine.
The synthetic process for making a 6-O-alkyl derivative of 9-oxime erythromycin B starts with conversion of erythromycin B (a fermentation product) to 2′-acetyl erythromycin B. That conversion is accomplished by reacting erythromycin B with an acetylating reagent such as acetic anhydride. 2′-Acetyl erythromycin B is then alkylated at the 6-hydroxyl to provide a 2′-acetyl-6-O-alkyl erythromycin B. Alkylation of the 6-hydroxyl group is accomplished using an alkylating reagent such as an alkyl halide or an alkyl sulfate. The 2′-acetyl-6-O-alkyl erythromycin B is then oximated and deacetylated to form 6-O-alkyl-9-oxime erythromycin B.
In another aspect, the present invention provides a pharmaceutical composition containing a 6-O-alkyl-9 derivative of oxime erythromycin B and a non-toxic pharmaceutically acceptable carrier. Still further, the present invention provides a method of treating a bacterial infection in a patient including the step of administering to the patient a therapeutically effective amount of a 6-O-alkyl derivative of 9-oxime erythromycin B. The compound of the invention is a useful intermediate in the synthesis of 6-O-methyl erythronolide B, disclosed in U.S. patent application Ser. No. 08/980,919 filed Dec. 1, 1997, now U.S. Pat. No. 5,919,916.
DETAILED DESCRIPTION OF THE INVENTION
A number of defined terms are used herein to designate particular elements of the present invention. When so used, the following meanings are intended:
The term “alkyl” refers to saturated, straight or branched-chain hydrocarbon radicals containing between one and ten carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl. More preferably, the alkyl is limited to 1-4 carbons.
The term “alkylating agent” refers to a reagent capable of placing an alkyl group onto a nucleophilic site, including, but not limited to, alkyl halides such as methyl bromide, ethyl bromide, n-propyl bromide, methyl iodide, ethyl iodide; and n-propyl bromide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate; and di-n-propyl sulfate; and alkyl or aryl sulfonates such as methyl-p-toluenesulfonate, ethyl methanesulfonate, n-propyl methanesulfonate, and the like.
The term “aryl(lower alkyl)” refers to a lower alkyl radical having appended thereto 1-3 aromatic hydrocarbon groups, as for example benzyl, diphenylbenzyl, trityl and phenylethyl.
The term “aryloxy” refers to an aromatic hydrocarbon radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom), as for example phenoxy.
The term “cycloalkyl” refers to a saturated monocyclic hydrocarbon radical having from three to eight carbon atoms in the ring and optionally substituted with between one and three additional radicals selected from among lower alkyl, halo(lower alkyl), lower alkoxy, and halogen. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-fluoro-cyclopropyl, and 2-fluorocyclopropyl.
The term “lower alkenyl” refers to a straight or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon-carbon double bond. Examples of lower alkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-, 4- or 5-hexenyl and isomeric forms thereof.
The term “lower alkoxy” refers to a lower alkyl radical which is joined to the rest of the molecule via an ether linkage (i.e., through an oxygen atom). Examples of lower alkoxy radicals include, but are not limited to, methoxy and ethoxy.
The term “lower alkyl” refers to an alkyl radical containing one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
The term “polar aprotic solvent” refers to polar organic solvents lacking an easily removable proton, including, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile or ethyl acetate, and the like.
The term “strong alkali metal base” refers to an alkali metal base having a weak conjugate acid, including, but not limited to, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium t-butoxide, and the like.
The term “substituted aryl(lower alkyl)” refers to an aryl(lower alkyl) residue as defined above having between one and three non-hydrogen ring substituents, each independently selected from among halogen, lower alkoxy, lower alkyl, hydroxy-substituted lower alkyl, and (lower alkyl)amino. Examples of substituted aryl(lower alkyl) radicals include 2-fluorophenylmethyl, 4-fluorophenylethyl and 2,4-difluorophenylpropyl.
The term “weak organic amine base” refers to an organic amine base having a strong conjugate acid, including, but not limited to trimethylamine, triethylamine, tripropylamine, pyridine, 2-methoxypyridine, 1-methylpyrrolidine, 1-methylpiperidine, and 1-ethylpiperidine, and the like.
I. 6-O-Alkyl Derivatives of 9-Oxime Erythromycin B
A 6-O-alkyl derivative of 9-oxime erythromycin B has the structure I, below.
where R
1
is alkyl, R
2
and R
4
are each independently hydrogen or a conventional O-protecting group and R
3
is —NR
5
CH
3
, where R
5
is methyl (CH
3
) or a conventional N-protecting group or —N
+
(CH
3
)
2
R
6
X
−
, where R
6
is 2-alkenyl, benzyl or substituted benzyl, and X is a halogen. In a preferred embodiment, R
1
is methyl, R
2
is hydrogen or acetyl, R
3
is dimethylamine and R
4
is hydrogen.
The compound of structure I is shown without spatial bond orientation. Structure I thus defines all combinations of bond orientation and is intended to cover all possible stereo-configurations (e.g., epimers). In a preferred embodiment, the bond orientations of Structure I are the same as shown above for 6-O-methyl erythromycin B.
In structure I, the 2′- and/or 4″hydroxyl groups can contain conventional O-protecting groups that are well known in the art and include silyl, acyl, lower alkyl monocarbonyl, lower alkenyl monocarbonyl, alkoxycarbonyl, alkylcarbonyl, lower alkoxycarbonylalkylcarbonyl, and arylcarbonyl groups (See, e.g., Greene and Wuts'
Protective Groups in Organic Synthesis,
2d. Ed. John Wiley & Sons, Inc., New York, 1991., the disclosure of which is incorporated herein by reference). Such a substituted erythromycin B oxime derivative results in a compound of structure I, where R
2
and R
4
are each independently silyl, carbonyl, acyl, alkox
Liu Jih-Hua
Montgomery Stephen H.
Abbott Laboratories
Peselev Elli
Sickert Dugal S.
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