Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-12
2002-12-10
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S318000, C514S326000, C514S327000, C546S194000, C546S207000, C546S216000, C546S223000
Reexamination Certificate
active
06492392
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition comprising as an active ingredient a 2-piperidone compound which has antitumor activity and is useful as a medicament such as an antitumor agent.
BACKGROUND ART
Although studies have been widely made on antitumor agents efficacious on solid tumors, there are only few antitumor agents having low toxicity. The present inventors investigated antitumor agents efficacious on solid tumors and, as a result, found that certain 2-piperidone compounds are efficacious on solid tumors while showing low toxicity, thus completing the present invention.
4,6-Diphenyl-5-nitro-2-piperidone has been known as an intermediate for the synthesis of 3-aminopiperidine derivatives (U.S. Pat. No. 5,232,929). However, no pharmacological activity of this compound has been known. Also, 5-nitro-6-phenyl-1-(2-phenylethyl)-2-piperidone has been known (
Synthesis,
615-616 (1976)) but its pharmacological activity is also unknown.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide 2-piperidone compounds which have an activity of inhibiting the proliferation of solid tumor cells and are useful as excellent antitumor agents.
The present invention relates to a 2-piperidone compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R
1
represents —(CH
2
)
n
R
1a
{wherein n is an integer of from 0 to 5, and R
1a
represents amino, lower alkylamino, di(lower alkyl)amino, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group}, and
R
2
and R
3
independently represent lower alkyl which may be substituted by lower alkoxycarboyl; lower alkenyl, aralkyl or lower alkynyl which may be substituted by substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; substituted or unsubstituted aryl; or a substituted or unsubstituted heterocyclic group. Among the compounds of the formula (I), the compounds wherein R
1a
represents a substituted or unsubstituted heterocyclic group and R
2
and R
3
independently represent substituted or unsubstituted aryl or pharmaceutically acceptable salts thereof are preferable, and the compounds wherein R
1a
represents a heterocyclic group, and R
2
and R
3
independently represent substituted aryl or pharmaceutically acceptable salts thereof are further preferable. The present invention also relates to a pharmaceutical composition which comprises as an active ingredient the aforementioned 2-piperidone compound or a pharmaceutically acceptable salt thereof. The present invention further relates to an antitumor agent which comprises as an active ingredient the aforementioned 2-piperidone compound or a pharmaceutically acceptable salt thereof.
The present invention further relates to a pharmaceutical composition which comprises the 2-piperidone compound of the formula (I) or a pharmaceutically acceptable salt thereof; an antitumor agent which comprises the 2-piperidone compound of the formula (I) or a pharmaceutically acceptable salt thereof; a method for preventing or treating a patient having tumor, which comprises administering to the patient an effective amount of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof; and use of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition which is effective in preventing or treating a patient having tumor; use of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a patient having tumor; and a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable dosage form.
Hereinafter, the compounds represented by the above formula (I) will be referred to as Compounds (I), and the same will apply to compounds represented by other formula numbers.
In the definition of each group given in the formula (I), the term “aryl” stands for a mono- to tricycle of 3- to 7-membered carbon rings wherein at least one of the rings is an aromatic ring. Examples thereof include phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl and phenanthrenyl.
Examples of the heterocyclic group include azepinyl, benzimidazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxazolyl, 1,4-benzodioxanyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, furyl, imidazolidinyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, isochromanyl, isoindolyl, 1,3-dioxolanyl, 1,3-dithiolanyl, isoxazolyl, isoquinolyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrazolinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl and pyridonyl.
Examples of the aralkyl include C
7-20
aralkyl such as benzyl, phenethyl, benzhydryl, naphthylmethyl and trityl.
The lower alkyl and the lower alkyl moieties in the lower alkylamino, di(lower alkyl)amino and lower alkoxycarbonyl include linear, branched or cyclic C
1-10
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl.
The lower alkenyl includes linear, branched or cyclic C
2-10
alkenyl such as vinyl, allyl, crotyl, 1-propenyl, prenyl, isopropenyl, 2-methyl-2-butenyl, pentenyl, hexenyl, heptenyl, 2,6-dimethyl-5-heptenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The lower alkynyl includes linear or branched C
2-10
alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and octynyl.
Substituents on the aryl or heterocyclic group may be the same or different 1 to 3 substituents, and examples thereof include hydroxy; halogen; nitro; amino; carboxy; lower alkyl optionally substituted by 1 to 3 halogen, lower alkoxycarbonyl or hydroxy; lower alkoxy optionally substituted by 1 to 3 halogen or lower alkoxy; lower alkoxycarbonyl; lower alkylthio; lower alkenyl optionally substituted by 1 to 3 lower alkoxy, lower alkoxycarbonyl or a heterocyclic group; lower alkynyl; aryl optionally substituted by 1 to 3 halogen atoms; aryloxy; aryloxy(lower alkyl); aroyloxy; lower alkylamino optionally substituted by a heterocyclic group; hydroxyamino; formyl; lower alkanoyl; lower alkanoyloxy; amino substituted by lower alkanoyloxy or lower alkanoyl; di(lower alkyl)amino; di(lower alkyl)aminocarbonyloxy; lower alkanoylamino; lower alkylsulfonylamino; lower alkoxycarbonylamino; aralkylamino; sulfamylamino (aminosulfonylamino); ureido (carbamoylamino); cyano; aralkyl; aralkyloxy; arylsulfonyl; a heterocyclic group; a heterocyclic group-carbonyloxy; camphanoyloxy; methylenedioxy; ethylenedioxy; B(OH)
2
and SO
3
H. The term “halogen” stands for fluorine, chlorine, bromine and iodine atoms. The aralkyl and the aralkyl moieties in the aralkylamino and the aralkyloxy are each as defined above. The lower alkyl and the lower alkyl moieties in the lower alkoxy, lower alkoxycarbonyl, aryloxy(lower alkyl), lower alkanoyl, lower alkylthio, lower alkylamino, lower alkanoyloxy, di(lower alkyl)amino, di(lower alkyl)aminocarbonyloxy, lower alkanoylamino, lower alkylsulfonylamino and lower alkoxycarbonylamino are each as defined above. The aryl and the aryl moieties in the aryloxy, aryloxy(lower alkyl), arylsulfonyl and aroyloxy are each as defined above. The heterocyclic group and the heterocyclic group moi
Akinaga Shiro
Ashizawa Tadashi
Eishima Jun
Hara Mitsunobu
Kanda Yutaka
Covington Raymond
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Rotman Alan L.
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