Cyclic ketone derivatives and their medical applications

Details Cyclic ketone derivatives and their medical applications Cyclic ketone derivatives and their medical applications

1999-05-25

2001-02-06

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...

C514S438000, C514S432000, C514S449000, C514S675000, C549S292000, C549S028000, C549S060000, C549S418000

Reexamination Certificate

active

06184245

ABSTRACT:

TECHNICAL FIELD
The present invention relates to drugs and in particular to haemopoietic agents in which a cyclic ketone derivative or pharmacologically acceptable salt thereof is an effective component.
TECHNICAL BACKGROUND
Cyclic ketone derivatives include lactones and lactams.
The lactones are known in the form of natural materials such as carolic acid and carolinic acid, and as synthetic materials such as the compounds described in
J. Chem. Soc. Perkin Trans. I,
14, 1485-1491 (1976) and
Synth. Comm.,
22(6), 809-816 (1992). As lactams, there are known, for example, the compounds disclosed in Japanese Unexamined Patent Publication (Kokai) Nos 2-279691, 4-49289, 2-48591 and 1-313488,
Chem. Pharm. Bull.,
32(10), 4197-4204 (1984),
Pharmazie,
43(7), 473-474 (1988),
Monatsh. Chem.,
123(1-2), 93-98 (1992),
J. Inorg. Biochem.,
24(3), 167-181 (1985),
J. Am. Chem. Soc.,
107(18), 5219-5224 (1985),
J. Org. Chem.,
50(8), 1344-1346 (1985) and
Chem. Rev.,
95, 1981-2001 (1995).
With regard to the applications of the lactones, the compounds described for example in Japanese Unexamined Patent Publication (Kokai) No. 5-43568 and EP 0508690 are known as anti-inflammatory agents with phospholipase A
2
inhibitory activity; the compounds described in
Archive des Pharmazie
(Weinhelm, Ger.) (1983), 316(2), 115-120 are known as anticoagulants; and the compounds described in
J. Anitbiot.,
(1994), 47(2), 143-7 are known as an anti-AIDS drug with HIV-protease inhibitory activity. With regard to the applications of the lactams, the compounds described in for example
Chem. Pharm. Bull.,
32(10), 4197-4204 (1984) are known as drugs with antimicrobial activity and the compounds described in
Antibiot.,
33(2), 173-181 (1980) are known as anaerobic antibiotics.
However, cyclic ketone derivatives with a haemopoietic action are totally unknown. The present invention has the objective of offering cyclic ketone derivatives with an outstanding haemopoietic action.
DISCLOSURE OF THE INVENTION
The aforesaid objective is realized by the present invention as described below.
Specifically, the present invention relates to ketone derivatives represented by the following general formula (I)
(where R
1
to R
8
represent a hydrogen atom or a substituent group,
X represents O, S, CH
2
or NH, and
Y represents O or S) and pharmacologically acceptable salts thereof, and to drugs, in particular haemopoietic agents, containing a ketone represented by general formula (I) or pharmacologically acceptable salt thereof.
In particular, in general formula (I), R
1
, R
2
and R
3
are independently a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
10
alkyl group, C
1
to C
10
alkenyl group, C
1
to C
10
alkynyl group, C
6
to C
12
aryl group, C
6
to C
12
arylalkyl group, C
6
to C
12
alkylaryl group, C
6
to C
12
arylalkenyl group, or —(CH
2
)
p
Z (where p represents an integer in the range 0 to 3, and Z represents a cyano group, carboxyl group, methylthio group, phenylthio group, trifluoromethyl group, methylthiomethyl group or nitro group), or R
1
and R
2
may together form —CH═CH—CH═CH— or —(CH
2
)
n
— (where n represents an integer in the range 2 to 5), or R
2
and R
3
may together form —(CH
2
)
m
− (where m represents an integer in the range 2 to 5) (but excluding the case where R
1
, R
2
and R
3
are all substituents selected from the hydrogen atom, fluorine atom, chlorine atom and bromine atom),
R
4
and R
5
respectively independently represent a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
6
alkyl group, hydroxy group, C
1
to C
6
alkoxy group, carboxy group or C
2
to C
10
alkoxycarbonyl group,
R
6
represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
10
alkyl group, C
6
to C
12
aryl group, C
6
to C
12
arylalkyl group, C
6
to C
12
alkylaryl group, C
6
to C
12
arylalkenyl group, or —(CH
2
)
q
G (where q represents an integer in the range 1 to 3, and G represents a hydroxy group or C
2
to C
10
alkoxycarbonyl group),
R
7
represents a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
10
alkyl group, C
6
to C
12
aryl group, carboxy group or C
2
to C
10
alkoxycarbonyl group, or R
6
and R
7
together represent —CH═CH—CH═CH— or —(CH
2
)
l
— (where l represents an integer in the range 2 to 5), and
R
8
represents a hydrogen atom or C
1
to C
10
alkyl group and, more preferably,
R
1
to R
5
are independently a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
10
alkyl group, or substituted or unsubstituted phenyl group, R
6
and R
7
are independently a hydrogen atom, fluorine atom, chlorine atom, bromine atom, C
1
to C
10
alkyl group, or substituted or unsubstituted phenyl group or R
6
and R
7
together form —CH═CH—CH═CH— or —(CH
2
)
l
— (where l represents an integer in the range 2 to 5), and R
8
is a hydrogen atom or C
1
to C
10
alkyl group.
Optimum Mode for Practising the Invention
The C
1
to C
10
alkyl groups in general formula (I) may be straight-chain, branched or cyclic, and examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like. The C
1
to C
10
alkenyl groups may be straight-chain or branched, and include isomers pertaining to the double bond (E or Z isomers). Examples are ethenyl, 2-propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,3-hexadienyl, 1,4-pentadienyl, 1,4-hexadienyl, 1,4-heptadienyl, 1,3,5-hexatrienyl and the like. The C
1
to C
10
alkynyl groups may be straight-chain or branched, and examples are propynyl, butynyl, pentynyl, hexylnyl, heptynyl, octynyl and the like.
The aryl group in the C
6
to C
12
aryl groups, C
6
to C
12
arylalkyl groups, C
6
to C
12
alkylaryl groups and C
6
to C
12
arylalkenyl groups may be substituted with one, or more than one, halogen atom such as a chlorine atom, bromine atom or fluorine atom, hydroxy group, nitro group, methoxy, ethoxy or other such alkoxy group, carboxyl group, carbomethoxy, carboethoxy group or other such carboalkoxy group, cyano group, trifluoromethyl group, methylthio or other such alkylthio group, or phenylthio group.
Examples of the C
6
to C
12
aryl groups are phenyl, naphthyl, biphenyl and the like, and also aryl groups mono-substituted with a chlorine atom, bromine atom, fluorine atom, hydroxy group, nitro group, methoxy group, ethoxy group, carboxyl group, carbomethoxy group, carboethoxy group, cyano group, trifluoromethyl group, methylthio group, phenylthio group or the like, such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carbomethoxyphenyl, 3-carbomethoxyphenyl, 4-carbomethoxyphenyl and the like; or disubstituted with the aforesaid groups, such as 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-chloro-3-bromophenyl, 2-chloro-3-hydroxyphenyl, 2-chloro-3-cyanophenyl, 2-chloro-3-methoxyphenyl, 2-hydroxy-3-chlorophenyl, 2-methoxy-3-chlorophenyl and the like; or trisubstituted with the aforesaid groups, such as 2,3,4-trichlorophenyl, 2,3,4-tribromophenyl, 2,3,4-trifluorophenyl, 2-chloro-3-hydroxy-4-methoxyphenyl, 2-hydroxy-3-hydroxy-4-methoxyphenyl and the like.
Examples of the C
6
to C
12
alkylaryl groups are 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl and the like, or these mono-substituted with a chlorine atom, bromine atom, fluorine atom, hydroxy group, nitro group, methoxy group, ethoxy group, carboxyl group, carboethoxy group, carbomethoxy

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