Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-25
2002-12-17
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S333000, C514S348000, C546S261000, C546S280400, C546S283400, C546S296000
Reexamination Certificate
active
06495571
ABSTRACT:
TECHNICAL FIELD
The present invention relates to certain novel pyridine compounds. The compounds of the present invention are especially useful for producing new acyl derivatives of 4-demethylpenclomedine (also referred to herein as DM PEN). The acyl derivatives, in turn, exhibit anticancer activity, and are the subject of U.S. patent application Ser. No. 60/116,675 filed Jan. 21, 1999 and entitled “Acyl Derivatives of 4-Demethylpenclomedine, Use and Preparation Thereof”, the entire disclosure of which is incorporated herein by reference. Certain of the pyridine compounds of the present invention also exhibit anticancer activity. Accordingly, the present invention also relates to pharmaceutical compositions comprising those particular pyridine compounds, as well as a method of using them in treating cancer in a mammal. The present invention also relates to a method for producing the compounds of the present invention and to a method for producing the acyl derivatives of 4-demethylpenclomedine from the pyridine compounds of the present invention.
BACKGROUND OF INVENTION
Even though significant advances have occurred in treatment of cancer, it still remains a major health concern. It has been reported that cancer is the cause of death of up to one of every four Americans.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, TAXOL®, nitrogen mustard, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient. For example, U.S. Pat. No. 4,717,726 reportedly discloses a compound suitable for inhibiting the growth of certain types of malignant neoplasms in mammals. See also Plowman et al.,
Cancer Res.,
49 (1989), 1909-1915. The disclosed compound, 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine, also known as penclomedine, is not satisfactory as a chemotherapeutic, however, because it is known to produce certain undesirable side effects especially in the central nervous system.
For example, neurological and hematological toxicities of penclomedine have been reported in preclinical and early clinical studies. Dose related neurotoxicity, consisting of muscle tremors, incoordination, convulsions and reduced activity, has been observed in rats. Neurotoxicity appears to be related to peak plasma drug concentrations, as it developed during or immediately after infusion and could be ameliorated by decreasing the rate of drug administration. In dogs, severe emesis and seizures have been associated with plasma penclomedine levels above 30 &mgr;M. Neurotoxicity, consisting of dysmetria, ataxia, and vertigo, was also the principal dose limiting toxicity of penclomedine administered as a one hour infusion for 5 consecutive days in patients with advanced solid tumors. The presence of these toxicities, at much lower peak plasma concentrations compared to those reported in preclinical studies, may preclude the administration of higher doses of penclomedine and the achievement of concentrations associated with optimal antitumor activity. Berlin et al.,
Proc. Amer. Assoc. Cancer Res.,
36, 238 (1005); O'Reilly et al.,
Proc. Amer. Soc. Clin. Oncol.,
14, 471 (1995).
Some relevant background art can be found in O'Reilley et al.,
Clinical Cancer Research,
2 (March 1996), 541-548. This reference describes a study to assess the distribution of
14
C-penclomedine in the tissues and tumors of tumor-bearing rats. The study found that the predominant radioactive species in the brain was penclomedine, which may explain the observed neurotoxicity of the drug.
More recently, 3,5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine or 4-demethylpenclomedine has been suggested as a compound for treating cancer. See WO 97/46531 to Hartman et al.
Notwithstanding the advances in cancer treatment that have been made, there still remains room for improved drugs that are effective in treating cancer, while at the same time exhibit reduced adverse side effects.
SUMMARY OF INVENTION
The present invention relates to new pyridine compounds that find especial utility as precursors for producing certain acyl derivatives of 4-demethylpenclomedine which, in turn, possess anticancer activity as will be discussed hereinbelow.
The compounds of the present invention are represented by the following formulae:
wherein
each R
1
is independently an alkyl group provided that at least one R
1
is an alkyl group containing at least two carbon atoms; and
each R
2
is independently H, acyl or an alkyl group having at least two carbon atoms or R
2
can be methyl in position 4 provided that R
2
is acyl in position 6.
The present invention also relates to a process for preparing compounds of formula I by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base to produce the corresponding 3,5-dichloro-4,6-dialkoxy-2-(trichloromethyl)pyridine of formula I.
The compound according to formula II wherein both R
2
are H can be prepared by reacting the compound of formula I with a dealkylating agent such as anhydrous aluminum chloride to produce didemethylpenclomedine.
The compounds according to formula II wherein at least one of R
2
is acyl can be prepared by reacting didemethylpenclomedine with an acylating agent to form a corresponding acyl compound of formula II.
The acyl compound of formula II can then be reacted with an alkylating agent such as (trimethylsilyl)diazomethane or diazomethane to produce the acyl derivatives of 4-demethylpenclomedine.
These novel acyl derivatives of 4-demethylpenclomedine compounds are represented by the formula:
Pharmaceutically acceptable salts thereof can also be provided.
The present invention also relates to compounds represented by the formula
wherein one of R
3
or R
4
is Cl and the other of R
3
or R
4
is O-alkyl.
A further aspect of the present invention is concerned with producing compounds of formula IV. The compounds of formula IV can be produced by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base and separating the desired compound from the reaction mixture.
Another aspect of the present invention relates to an alternative method for producing a compound of formula I above by reacting a compound of the formula IV
wherein one of R
3
or R
4
is Cl and the other of R
3
or R
4
is O-alkyl with an alcohol in the presence of a base.
In addition, compounds of formula I above can be produced by reacting a compound of the formula
wherein R
1
is an alkyl group having at least two carbon atoms with an alkylating agent.
A still further aspect of the present invention is directed to producing a compound of formula II above wherein R
2
in position 4 is H and R
2
in position 6 is an alkyl which comprises reacting a compound represented by the formula I
wherein each R
1
is independently an alkyl group with R
1
in position 4 having at least two carbon atoms with a dealkylating agent to selectively dealkylate said compound in position 4.
Compounds of the present invention wherein the R
1
group located at position 4 is ethyl show anticancer activity. Accordingly, the present invention also relates to pharmaceutical compositions containing these compounds wherein the R
1
group located at position 4 is ethyl, and to methods of using such compounds in treating cancer in a mammal.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
BEST AND VARIOUS MODES FOR CARRYING OUT INVENTION
The present inventio
Blatter Herbert M.
Struck Robert F.
Tiwari Anita
Connolly Bove Lodge & Hutz
Coppins Janet L
Rotman Alan L.
Southern Research Institute
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