Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-28
2002-07-23
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S314000, C514S326000, C514S397000, C514S398000, C544S031000, C546S152000, C546S245000, C548S315400, C548S327100
Reexamination Certificate
active
06423707
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to nitroimidazole ester analogues, such as metronidazole ester analogues, and more particularly relates to novel metronidazole ester analogues that have anti-microbial activity and therapeutic applications thereof.
2. Description of Related Art
Metronidazole and similar compounds such as tinidazole have long been known as anti-microbial compounds. For example, metronidazole is known to be useful for the treatment of various conditions, including amebiasis (acute amebic dysentery), trichomoniasis, bacterial vaginosis, and
Helicobacter pylori
infections associated with duodenal ulcer disease.
It has been estimated that a significant number of adults are infected with
H. pylon
. These persons, although infected, are typically not treated until and unless they develop painful symptoms such as associated with ulcers. However, this bacteria is implicated in two different cancers.
Only a few antibiotic agents are presently known that have any effect on
H. pylori
, and resistance to these is developing. Metronidazole is one of these.
U.S. Pat. No. 4,160,827, issued Jul. 10, 1979, inventors Cho et al., describes phosphates of metronidazole which are water soluble and said to be useful for treating those diseases for which metronidazole is known to be useful.
Cho et al.,
Journal of Pharmaceutical Sciences
, 74(8), pp. 883-885, 1985, disclose amino acid esters of metronidazole with improved solubility (phenylalanine ester and histidine ester). Cho et al.,
Journal of Pharmaceutical Sciences
, 71(4), pp. 410-414, 1982, describe water soluble metronidazole phosphate.
U.S. Pat. No. 4,482,722, issued November 13, 1984, inventors Thorbek et al. discloses the N,N-dimethylglycine ester of metronidazole, which has improved solubility and is said to be useful in the systemic treatment of anaerobic infection by parenteral administration.
Johansen and Larsen,
International Journal of Pharmaceutics
, 26, pp. 227-241, 1985, describe hydrolytic degradation rates of certain aliphatic and aromatic esters of metronidazole. These esters are described as prodrugs with increased water solubility (such as useful in preparing parenteral dosage forms) and said to have improved transport against different biological membranes. Johansen et al.,
Interniational Journial of Pharmaceutics
, 32, pp. 199-206, 1986, similarly describe permeation studies with a series of aliphatic ester prodrugs.
Cosar et al., “Nitro-imidazoles-Préparation et activité chimio-thérapeurique,” Arzeiniittel-Forsch, 16(1), 23-9 (Fr), 66:2512e, 1967, describe various esters of metronidazole and metronidazole analogs of which they report the most interesting are numbers 23 and 47 (of Tables 5 and 6). These are said to be active against
Trichomonas vaginalis
and others infectious agents. No. 47 is said to be distinguished by a weak toxicity and a good tolerance even upon prolonged administration.
Among formulations for various applications of metronidazole are those described by U.S. Pat. No. 5,840,744, issued Nov. 24, 1998, inventor Bordman, (describing a metronidazole composition that may be topically applied), and U.S. Pat. No. 6,017,516, issued Jan. 25, 2000, inventor Mody et al (describing a dental formulation including metronidazole benzoate and chlorhexydineglycanate).
Although metronidazole is one of the four antibiotics useful against bacteria, such as
H. pylori
, unfortunately some major problems have been encountered in the uses of metronidazole, such as in the treatment of
H. pylori
infections. Relapse is common and as earlier noted, various resistant strains are emerging. Accordingly, new compounds would be useful in the various therapeutic applications to which metronidazole may be put. Such new compounds could also provide efficacy against resistant strains of microbes, such as resistant
H. pylori
strains.
BRIEF SUMMARY OF THE INVENTION
In one aspect of the present invention, new nitroimidazole compounds are provided. Novel nitroimidazoles of the present invention typically have the structures generally illustrated by Formula A.
In Formula A, the R moiety has at least one aromatic ring. If the at least one aromatic ring is a single phenyl bonded directly to the carbonyl carbon of the ester linkage, then it is substituted with an amide substituent, or if not an amide substituent then with at least two different substituents. If the at least one aromatic ring is not bonded directly to the carbonyl carbon of the ester linkage, and is a single phenyl, then it is substituted with at least one substituent. Preferred substituents are nitro and halogen. When the substituent is amide, then it may be primary or secondary. The at least one aromatic ring may be or include a 5 or 6 membered heterocycle, or may be multiple rings formed from all carbon atoms or including one or more of the same or different heteroatoms. Heteroatoms, when present, may be oxygen, nitrogen and/or sulfur atoms.
Further in Formula A, the R′ moiety may be hydrogen, halogen, hydroxy, —SH, an alkoxy with 1-8 carbons or where one or more sulfur atoms replaces carbon, an alkyl with 1-8 carbons or where one or more sulfur atoms replaces carbon, and where n is an integer from 2 to 8.
Particularly preferred compounds are metronidazole ester analogs wherein R′ is hydrogen and n is 2, as illustrated by Formula B.
These inventive analogs preferably have anti-microbial properties. Some of the particularly preferred embodiments have remarkable toxicity against even resistant strains of microbes, such as resistant
H pylori
. Five particularly preferred embodiments, the structures of which are shown below, have demonstrated extraordinarily potent anti-bactericidal activity in an assay with
H pylori
that is predictive of efficacy in human treatment.
In the above-noted particularly preferred embodiments, Formula 3C is a di-ester where the at least one aromatic ring is a single phenyl bonded directly to the carbonyl carbon of the ester linkage, and is substituted with a nitro group as one substituent and with another substituent as a metronidazole ester moiety. The Formulas 1C and 2C embodiments illustrate respectively a six member heterocycle where the heteroatom is nitrogen and a five member heterocycle where the heteroatom is oxygen (and the ring is substituted with a nitro). The Formulas 4C and 5C embodiments illustrate multiple rings, where there is a phenyl substituent upon the nitrogen containing quinolyl for Formula 4C and both nitrogen and sulfur are present in the fused rings of Formula 5C.
Novel compounds of this invention are usefully formulated with pharmaceutically suitable carriers and administered for their biological activities, such as in anti-microbial applications.
DETAILED DESCRIPTION OF THE INVENTION
We have prepared a number of novel nitroimidazole compounds of the Formula A structure, shown below, and which have demonstrated anti-microbial activity. Preferred analogues of this invention have an enhanced anti-microbial activity as to at least one microbe, with respect to metronidazole. As will be hereinafter more fully described, many of the preferred embodiments have a Minimal Bactericidal Concentration (MBC) against at least one
H. pylori
strain that is less than about 25 mcg/mL and the particularly preferred five embodiments have a MBC value against a
H. pylori
resistant strain of between about 2-5 mcg/mL (by contrast to 89 mcg/mL for metronidazole). This means that these particularly preferred five embodiments are extremely potent and are about 45 times better at killing the resistant bacteria than metronidazole itself The assay demonstrating this potency is indicative of human anti-bacterial efficacy.
Novel nitroimidazole compounds of the present invention typically have the structure generally illustrated by Formula A.
In Formula A, the R moiety includes at least one aromatic ring. If the at least one aromatic ring is a single phenyl bonded directly to the carbonyl carbon of the ester linkage, then it is substituted with an a
Pan Xiandao
Wang Hui-Juan
Yang Li-Xi
California Pacific Medical Center
Cooley & Godward LLP
Shah Mukund J.
Truong Tamthom N.
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