Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-20
2001-05-22
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S349000, C514S646000, C514S658000, C544S162000, C546S297000, C564S431000, C564S433000
Reexamination Certificate
active
06235736
ABSTRACT:
This application is a 371 of PCT/JP97/04857 filed Dec. 25, 1997.
TECHNICAL FIELD
The present invention relates to a novel 3-anilino-2-cycloalkenone derivative having a phosphodiesterase (PDE) IV inhibitory activity.
BACKGROUND ART
The intracellular second messenger CAMP is involved in relaxation of airway smooth muscles and regulation of the functions of inflammatory cells. CAMP is broken down by phosphodiesterase (PDE) and becomes inactive 5′-AMP. It is considered that an increase in concentration of cAMP due to suppression of cAMP metabolism by PDE would give bronchodilating and anti-inflammatory actions and would exhibit a therapeutic effect on inflammatory diseases such as asthma [
Eur. Respir. J
., 7, 579 (1994)]. Up to now, PDE has been classified into five types of isozymes (i.e., types I to V PDE). Their distributions differ among tissues [
Trends Pharmacol. Sci
., 12, 19 (1991)]. This suggests a possibility that selective inhibitors of PDE isozymes would result in tissue specific increase of intracellular CAMP concentration.
It is reported that a specific inhibitor of type IV PDE isozyme suppresses inflammatory cells functions [
Thorax
, 46, 512 (1991)] and is useful for inflammatory diseases such as asthma [
J. Pharmacol. Exp. Ther
., 266, 306 (1993)] and dermatitis [
Br. J. Pharmacol
., 112, 332 (1994)] and autoimmune diseases such as multiple sclerosis [
Nature Medicine
, 1, 244 (1994)] and rheumatoid arthritis [
Clin. Exp. Immunol
., 100, 126 (1995)]. In addition, it is thought that cardiovascular side effect caused by non-selective PDE inhibitors such as theophylline could be reduced by using selective type IV PDE inhibitor. Rolipram of the following formula (Japanese Unexamined Patent Publication (Kokai) No. 50-157360) is known as a compound having a specific inhibitory activity against type IV PDE.
Other compounds having a specific inhibitory activity against type IV PDE are known (W094/10118, W094/12461, Japanese Unexamined Patent Publication (Kokai) No. 5-117239, Japanese Unexamined Patent Publication (Kokai) No. 7-101861, WO95/03794, WO95/08534, etc.), but they have not been clinically applied up to now. Development of more useful compounds is desirable.
A compound having the formula (IV):
wherein R represents a hydrogen atom or a methyl group has been known [
Tetrahedron Letter
5, 25, 5023(1984)], but there is no description regarding the physiological activity of this compound. Japanese Unexamined Patent Publication (Kokai) No. 49-85050 describes that the compound having formula (V):
has a pharmacological action against an analgesic, sedative, antipyretic, ataractic, anticonvulsive, and other pharmacological actions against the central never system and a hypoglycemic, but does not describe a PDE IV inhibitory activity.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide a novel compound having a type IV PDE inhibitory activity.
In accordance with the present invention, there are provided a 3-anilino-2-cycloalkenone derivative having the formula (I):
wherein R
1
represents a C
1
to C
8
alkyl group which may have a substituent, a C
3
to C
7
cycloalkyl group, a C
6
to C
10
bicycloalkyl group, a 3-tetrahydrofuryl group, or an indanyl group, R
2
represents a C
1
to C
4
alkyl group, R
3
represents a hydrogen atom, a C
3
to C
7
alkyl group which may have a substituent, a C
3
to C
7
cycloalkyl group, or an acyl group, R
4
represents a hydrogen atom, a C
1
to C
5
alkyl group which may have a substituent, a halogen atom, a group having the formula (II):
wherein R
9
and R
10
independently represent a C
1
to C
5
alkyl group, or a group having the formula (III):
wherein, m represents an integer of 2 to 6, provided that one CH
2
group may be substituted with one hetero atom selected from the group consisting of oxygen, nitrogen, and sulfur, R
5
, R
6
, R
7
, and R
8
independently represent a hydrogen atom, a C
1
to C
5
alkyl group which may have a substituent, or a phenyl group which may have a substituent, X represents —(CR
11
R
12
)
n
— wherein R
11
and R
12
independently represent a hydrogen atom, a C
1
to C
5
alkyl group which may have a substituent, or a phenyl group which may have a substituent, and n represents an integer of 0 to 2 provided that, when n is 0, X in the formula (I) is absent and the carbon atoms bonded to X in the formula (I) are bonded together to form a 5-membered ring, or —NR
13
— wherein R
13
represents a hydrogen atom or a C
1
to C
5
alkyl group which may have a substituent, and its optical isomers or a pharmaceutically acceptable salt thereof or a hydrate thereof or a solvate thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors conducted a search for a novel is compound having a type IV PDE inhibitory activity and, as a result found that the above 3-anilino-2-cycloalkenone derivative had a strong type IV PDE inhibitory activity and had a bronchodilator and anti-inflammatory effects, whereby the present invention was completed.
The present invention will now be explained in detail below.
As the R
1
in the above general formula (I), a C
1
to C
8
linear or branched alkyl group (for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 1,1-dimethylbutyl, n-heptyl, n-octyl) may be mentioned. These may have a substituent group (for example, a halogen atom; a hydroxyl group; a nitro group; a cyano group; an amino group; a carboxyl group; a cycloalkyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group; an aryl group which may include at least one hetero atom selected from the group consisting of oxygen, nitrogen, and sulfur, etc.).
As the substituted C
1
to C
8
alkyl group, for example, cyclopropylmethyl, (1-phenylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 2-indanylmethyl, 2-(2-indanyl)ethyl, etc. may be mentioned. Here, an unsubstituted methyl group is excluded from R
1
. Further, as R
1
, a C
3
to C
7
cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), a C
6
to C
10
bicycloalkyl group [(1RS,2RS,4SR)bicyclo[2.2.1]hept-2-yl group, etc.], 3-tetrahydrofuryl, or indanyl may be mentioned. As R
1
, preferably a C
4
to C
6
alkyl group, a C
4
to C
7
cycloalkyl group, a C
6
to C
8
bicycloalkyl group, a C
1
to C
5
alkyl group having, as a substituent group, a phenyl group, a naphthyl group, an indanyl group, or a C
3
to C
7
cycloalkyl group which may have a substituent, a 3-tetrahydrofuryl group, or an indanyl group may be mentioned. More preferably cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, 2-(2-indanyl)ethyl, (1RS,2RS,4SR)bicyclo[2.2.1]hept-2-yl, or 2-indanyl may be mentioned.
As R
2
, a C
1
to C
4
linear or branched alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, etc.) may be mentioned. Preferably, methyl or ethyl, more preferably methyl may be mentioned.
As R
3
, a C
1
to C
5
linear or branched alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, etc.) may be mentioned. These may have a substituent group (for example, a halogen atom; a hydroxyl group; a nitro group; a cyano group; an amino group; a carboxyl group; a cycloalkyl group; a haloalkyl group; a carbamoyl group; an alkoxy group; an alkylcarbonyl group; an aryl group which may include at least one hetero atom selected from the group consisting of oxygen, nitrogen, and sulfur, etc.). As the substituted C
1
to C
5
alkyl group, for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, furylmethyl, thiazo
Akiyama Toshihiko
Ina Shinji
Noda Kyoji
Takahama Akane
Yamana Kenjirou
Christie Parker & Hale LLP
Lambkin Deborah C.
Nikken Chemicals Co., Ltd.
Wright Sonya N.
LandOfFree
3-anilino-2-cycloalkenone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3-anilino-2-cycloalkenone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3-anilino-2-cycloalkenone derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2507453