Imidazole antiproliferative agents

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S399000, C514S400000, C548S335100, C548S335500, C548S339500, C548S340100, C548S341100, C548S342500, C548S343100, C548S343500

Reexamination Certificate

active

06201001

ABSTRACT:

TECHNICAL FIELD
The present invention relates to compounds useful for treating pathological states which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
BACKGROUND OF THE INVENTION
Neoplastic diseases, characterized by the proliferation of cells which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs which disrupt microtubule synthesis are effective in inhibiting the proliferation of neoplastic cells.
Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The microtubule system of eucaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within noeplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
Because of the pivotal role played by cell proliferation, agents which inhibit microtubule polymerization have been the subject of active current research for their clinical potential. See, for example, Bioorg. Med. Chem. Lett. 8 (1998) 3153-3158 and JP 10081673. But there is still a need for tubulin polymerization-inhibiting compounds with modified or improved profiles of activity.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed tubulin polymerization-inhibiting compounds of formula I
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R
1
is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and iso-propyl; and
one of R
2
or R
3
is 3,4,5-trimethoxyphenyl, and the other is phenyl substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, halo, and —NR
4
R
5
, wherein R
4
and R
5
are independently selected from the group consisting of hydrogen and alkyl.
In another embodiment are disclosed compounds of formula I wherein R
2
is 3,4,5-trimethoxyphenyl.
In still another embodiment are disclosed compounds of formula I wherein R
2
is substituted phenyl.
In still yet another embodiment is disclosed a method of inhibiting tubulin polymerization in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of of formula I.
In still yet another embodiment is disclosed a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of of formula I.
In still yet another embodiment is disclosed a method of inhibiting tubulin polymerization in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of of formula I wherein R
2
is 3,4,5-trimethoxyphenyl.
In still yet another embodiment is disclosed a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of of formula I wherein R
2
is 3,4,5-trimethoxyphenyl.
In still yet another embodiment is disclosed a method of inhibiting tubulin polymerization in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of formula I wherein R
2
is substituted phenyl.
In still yet another embodiment is disclosed a method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically effective amount of formula I wherein R
2
is substituted phenyl.
In still yet another embodiment is disclosed a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier.
In still yet another embodiment is disclosed a a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I, wherein R
2
is 3,4,5-trimethoxyphenyl, in combination with a pharmaceutically acceptable carrier.
In still yet another embodiment is disclosed a a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula I, wherein R
2
is substituted phenyl, in combination with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
The term “C
1
-C
3
alcohol,” as used herein, refers to methanol, ethanol, propanol, and iso-propanol.
The term “C
1
-C
4
alkali metal alkoxide,” as used herein, refers to lithium, sodium, or potassium methoxide, ethoxide, propoxide, iso-propoxide, 2-methylpropoxide, 1-methylpropoxide, and tert-butoxide.
The term “alkoxy,” as used herein, refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term “alkyl,” as used herein, refers to a monovalent group of one to six carbon atoms derived from a straight or branched chain saturated hydrocarbon.
The term “halo,” as used herein, refers to —F, —Cl, —Br or —I.
The term “pharmaceutically acceptable salt,” as used herein, refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq, hereby incorporated by reference. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; and arylalkyl halides such as benzyl and phenethyl bromides. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium an

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