Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-24
2001-07-10
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S007400
Reexamination Certificate
active
06258785
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates crystalline 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyloxy)6-O-methyl-12,11 -(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1-yl)propyl)hydrazono))-3-oxoerythromycin wherein said crystalline compound is the free base of said compound (including the hemihydrate of said free base) or the mesylate (methanesulfonic acid) salt of said compound. The crystalline compound of this invention is useful as an antibiotic agent in mammals, including man, as well as in fish and birds. The compound of the present invention is a broad-spectrum macrolide antibiotic that is effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
A non-crystalline, amorphous form of 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyloxy)-6-O-methyl-12,11 -(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1-yl)propyl)hydrazono))-3-oxoerythromycin is referred to in PCT international patent application number PCT/IB98/00741, filed May 15, 1998, which is incorporated herein by reference in its entirety. The crystalline compound of the present invention is believed to be more stable than the amorphous compound referred to in the foregoing PCT application, which facilitates the manufacture of precise dosage forms of the compound for pharmaceutical use and improves the shelf-life of the compound. The crystallization of the amorphous compound significantly improves the purity of the compound which further facilitates the preparation of precise and safe dosage forms of the compound for pharmaceutical use. Further, the crystalline hemihydrate form of the free base is non-hygroscopic which is advantageous in the manufacture of accurate dosages.
SUMMARY OF THE INVENTION
The present invention relates to crystalline 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyloxy)-6-O-methyl- 2,11 -(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1 -yl)propyl)hydrazono))-3-oxoerythromycin wherein said crystalline compound is either the free base of said compound (including the hemihydrate of said free base) or the methane sulfonic acid salt of said compound.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of the crystalline compound referred to above and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of the crystalline compound referred to above.
The present invention also relates to the preparation of crystalline 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-0-methyl-&agr;-L-ribohexopyranosyioxy)-6-0-methyl-12,11 -(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1 -yl)propyl)hydrazono))-3-oxoerythromycin (including the hemihydrate of said compound) which comprises introducing amorphous 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyloxy)+O-methyl-12,11 -(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1 -yl)propyl)hydrazono))-3-oxoerythromycin into a solvent comprising (C
1
-C
6
alkyl)
2
O
1
such as isopropyl ether or methyl tert-butyl ether, containing ethanol, heating the composition to approximately 60° C., and then cooling the composition to a temperature within the range of about 20° C. to 25° C.
The present invention also relates to the preparation of crystalline 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl&agr;-L-ribohexopyranosyloxy)-6-O-methyl-12,11-(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1 -yl)propyl)hydrazono))-3-oxoerythromycin methanesulfonate which comprises treating a composition of amorphous 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-&agr;-L-ribohexopyranosyloxy)-6-O-methyl-12,11 iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1-yl)propyl)hydrazono))-3-oxoerythromycin in a polar organic solvent such as CH
2
Cl
2
, methanol, or ethanol, or a mixture of the foregoing solvents, preferably CH
2
Cl
2
, with methanesulfonic acid, evaporating the composition to provide a residue containing 9-E-(O-methyl)oxime of 11,12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-0-methyl-&agr;-L-(ibohexopyranosyloxy)-6-O-methyl-12,11-(iminocarbonyl-(2-(3-(4-(3-pyridinyl)-1H-imidazol-1-yl)propyl)hydrazono))-3-oxoerythromycin methanesulfonate, dissolving the residue in ethyl acetate, introducing isopropyl ether into the ethyl acetate composition, and then concentrating the resulting composition.
The term “treatment”, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention, including curing, reducing the symptoms of or slowing the progress of said infection. The terms “treat” and “treating” are defined in accord the foregoing term “treatment”.
As used herein, unless otherwise indicated, the term “bacterial infection(s)” or “protozoa infection” includes bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections and disorders related to such infections include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus
,or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by
Streptococcus pyogenes,
Groups C and G
streptococci, Clostridium diptheriae,
or
Actinobacillus haemolyticum;
respiratory tract infections related to infection by
Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae,
or
Chlamydia pneumoniae;
uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by
Staphylococcus aureus
, coagulase-positive staphylococci (i.e.,
S. epidermidis, S. hemolyticus,
etc.),
Streptococcus pyogenes , Streptococcus agalactiae
, Streptococcal groups C-F (minute- colony streptococci), viridans streptococci,
Corynebacterium minutissimum
, Clostridium spp., or
Bartonella henselae;
uncomplicated acute urinary tract infections related to infection by
Staphylococcus saprophyticus
or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by
Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum,
or
Neisernia gonordieae;
toxin diseases related to infection by
S. aureus
(food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by
Helicobacter pylori;
systemic febrile syndromes related to infection by
Borrelia recurrentis;
Lyme disease related to infection by
Borrelia burgdorferi;
conjunctivitis, keratitis, and dacrocystitis related to infection by
Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae,
or Listeria spp.; disseminated
Mycobacterium avium
complex (MAC) disease related to infection by
Mycobacterium avium,
or
Mycobacterium intracellulare;
gastroenteritis related to infection by
Campylobacter jejuni;
intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by
Bordetella pertussis:
gas gangrene related to infection by
Clostridium perfringens
or Bacteroides spp.; and atherosclerosis re
Durkin Daniel J.
Kaneko Takushi
Smyth Kathleen T.
Su Wei-guo
Wu Yong-Jin
Ginsburg Paul H.
Peselev Elli
Pfizer Inc.
Richardson Peter C.
Zielinski Bryan C.
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