Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-27
2002-06-18
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S520000
Reexamination Certificate
active
06407087
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel UCF116 derivatives or salts thereof which have antitumor and antibacterial activities and are useful as antitumor agents. Also, the present invention relates to a pharmaceutical composition which comprises the UCF116 derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
BACKGROUND ART
Compounds which are represented by the following structural formulae, namely UCF116-B and UCF116-D (WO 96/15114), mycotrienin II and mycotrienin I [
Journal of Antibiotics
, 35:1460, 1467, 1474 (1982),
Tetrahedron Letters
, 32:841 (1991)], T-23-VIII and T-23-IX (U.S. Pat. No. 4,587,237), ansatrienin A2 and ansatrienin A3
[Journal of Antibiotics
, 36:187 (1983)], ansatrienin A4
[Journal of Natural Products
, 50:108 (1987)] and hexadehydromycotrienin II [
The Journal of Biological Chemistry
, 270:25949 (1995) are known. It has been reported that these compounds have antibacterial activities and antitumor activities.
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 UCF116 derivatives are efficacious on solid tumors while showing low toxicity, thus completing the present invention.
DISCLOSURE OF THE INVENTION
The present invention relates to UCF116 derivatives represented by formula (I):
wherein
Q represents
and
R represents
hydrogen,
C(═O)R
1a
(wherein
R
1a
represents
methyl,
ethyl,
propyl,
isopropyl,
2,2-dimethylpropyl,
pentyl,
alkyl having 6 to 10 carbon atoms,
1-propenyl,
isopropenyl,
2-methyl-1-propenyl,
substituted or unsubstituted alicyclic alkyl having 3 to 5 carbon atoms,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl,
a substituted or unsubstituted heterocyclic group,
substituted or unsubstituted aralkyloxy,
or
substituted lower alkyl),
C(═X)NHR
1b
(wherein
X represents
an oxygen or sulfur atom, and
R
1b
represents
substituted or unsubstituted lower alkyl,
substituted or unsubstituted alicyclic alkyl,
substituted or unsubstituted lower alkoxycarbonyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, or
a substituted or unsubstituted heterocyclic group), or
SO
2
R
1c
(wherein
R
1c
represents
substituted or unsubstituted lower alkyl,
substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl,
a substituted or unsubstituted heterocyclic group, or
substituted or unsubstituted lower alkenyl),
with the proviso that, when Q is
R is not benzoyl,
salts thereof, isomers thereof, hydrates thereof, or solvates thereof.
Furthermore, the present invention relates to a pharmaceutical composition, which comprises the above-described derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof, and a pharmaceutically acceptable carrier.
Moreover, the present invention relates to an antitumor agent or antibacterial agent, which comprises as an active ingredient the above-described derivative, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the compound represented by formula (I) is referred to as Compound (I). The same shall apply to compounds of other formula numbers.
In the definition of each group in formula (I), examples of the lower alkyl include straight- or branched-chain alkyls having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, and decyl.
Examples of the alkyl having 6 to 10 carbon atoms include those having 6 to 10 carbon atoms among the above-described lower alkyls.
Examples of the alicyclic alkyl include those having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
Examples of the alicyclic alkyl having 3 to 5 carbon atoms include those having 3 to 5 carbon atoms among the above-described alicyclic alkyls.
A lower alkyl moiety contained in the lower alkoxycarbonyl has the same meaning as the above-described lower alkyl.
Examples of the lower alkenyl include straight- or branched-chain or cyclic alkenyls having 2 to 8 carbon atoms, such as vinyl, allyl, crotyl, 1-propenyl, prenyl, isopropenyl, 2-methyl-2-butenyl, pentenyl, hexenyl, heptenyl, octenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The aryl is a mono- to tricyclic carbon ring composed of three- to seven-membered rings in which at least one ring is an aromatic ring. Examples include phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl, and phenanthrenyl.
Examples of the aralkyl include those having 7 to 15 carbon atoms, such as benzyl, phenetyl, benzhydryl, naphthylmethyl, and fluorenylmethyl.
An aralkyl moiety contained in the aralkyloxy has the same meaning as the above-described aralkyl.
The heterocyclic group means a mono- to tricyclic ring composed of three- to eight-membered rings having 1 to 7 carbon atoms and contains at least one of nitrogen, oxygen and sulfur atoms. Examples include heterocyclic groups, such as azepinyl, benzimidazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, furyl, imidazolidinyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, isochromanyl, isoindolyl, isoxazolyl, isoquinolyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopyrrolinyl, 2-oxopyrrolidinyl, piperidinyl, piparazinyl, pyridyl, pyrrazinyl, pyrazolinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, imidazothiazolyl and triazolyl.
A substituent on the lower alkyl, alicyclic alkyl, alicyclic alkyl having 3 to 5 carbon atoms, lower alkenyl, lower alkoxycarbonyl, aryl, aralkyl, aralkyloxy or heterocyclic group is 1 to 3 substituents which are the same or different, such as hydroxy, halogen, nitro, amino, carboxy, cyano, lower alkyl, alicyclic alkyl, lower alkenyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, aryl, aryloxy, aryloxy(lower alkyl), lower alkylamino, di(lower alkyl)amino, lower alkanoylamino, aralkyl, aralkyloxy, arylamino, arylsulfonyl, and a heterocyclic group. In the definition of the substituents, the halogen means a fluorine, chlorine, bromine or iodine atom, and the lower alkyl, alicyclic alkyl, lower alkenyl, lower alkoxycarbonyl, aryl, aralkyl, aralkyloxy and heterocyclic group have the same meanings as defined above. Also, the lower alkyl moiety contained in the lower alkoxy, lower alkanoyl, lower alkylthio, lower alkylamino, di(lower alkyl)amino, lower alkanoylamino or aryloxy(lower alkyl) has the same meaning as the above-described lower alkyl. The aryl moiety in the aryloxy, aryloxy (lower alkyl), arylamino and arylsulfonyl has the same meaning as the above-described aryl. Additionally, the substituent may be further substituted with a similar substituent. For example, the alkyl and aryl moieties of the above-described substituent may be substituted with 1 to 3 halogen atoms and the heterocyclic group may be substituted with 1 to 3 substituents such as lower alkyl and trifluoromethyl.
Compound (I) may form a salt, and examples of the salt and pharmaceutically acceptable salt of Compound (I) include an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt and an amino acid addition salt. Examples of the acid addition salt include an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, nitrate) and an organic acid addition salt (e.g., forma
Akinaga Shiro
Hara Mitsunobu
Johnson David A.
Kanda Yutaka
Powers Timothy S.
Kifle Bruck
Kyowa Hakko Kogyo Co. Ltd.
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