Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-06-23
2001-07-17
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S053000, C560S065000, C560S066000, C562S432000, C562S463000, C562S473000, C562S474000
Reexamination Certificate
active
06262293
ABSTRACT:
TECHNICAL FIELD
This invention relates to &ohgr;-cycloalkyl-prostaglandin E
2
derivatives, a process for the preparation thereof, and a pharmaceutical agent containing it as an active ingredient. More particularly, this invention relates to
(1) &ohgr;-cycloalkyl-prostaglandin E
2
derivatives of formula
(wherein all symbols are as defined hereinafter)
or non-toxic salts thereof, or prodrugs thereof or cyclodextrin clathrates thereof,
(2) processes for the preparation thereof, and
(3) a pharmaceutical agent containing it as an active ingredient.
BACKGROUND ART
Prostaglandin E
2
(abbreviated as PGE
2
hereinafter) has been known as a metabolite in the arachidonic acid cascade. It has been known that PGE
2
has cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect of digestive peristalsis, an awakening effect, a suppressive effect of gastric acid secretion, hypotensive activity and diuretic activity etc.
In the recent study, it was found that PGE
2
receptor was divided into some subtypes which possess different physiological roles each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors investigated to find new compounds which bind on each receptor specifically, so that we found that the compounds of the present invention could bind strongly on EP2 subtype receptor and achieved the present invention.
The compounds of the present invention of formula (I), possess a strong binding activity on EP2 subtype receptor. Therefore, they are useful for prevention and/or treatment of immunological diseases (autoimmune diseases, organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, hepatopathy, abortion, premature birth or retina neuropathy of glaucoma etc.
Among the compounds of the present invention of formula (I), compounds which bind weakly on receptor subtypes except EP2 receptor and on other receptors for arachidonic acid cascade metabolites (thromboxane receptor, PGI
2
receptor etc.) do not express other effects and therefore, it is probable that these compounds will be medical agents which have less side-effects.
On the other hand, many patent applications of PG derivatives are known. The following application is mentioned for example.
In the specification of JP54-115351 (i.e. U.S. Pat. No. 4,275,224), a compound of formula (A)
[wherein R
1A
and R
2A
are hydrogen; R
3A
is hydrogen or is taken together with R
4A
to form a methylene chain of 4 carbon atoms wherein a cycloalkyl of 6 carbon atoms inclusive is formed, or is taken together with R
4A
to form a bicycloalkenyl or bicycloalkyl moiety having the formula
(wherein pA is an integer having a value of from 0 to 1 and qA is an integer having a value of from 2 to 3 and wherein the double bond of such bicycloalkenyl is in the qA bridge); R
4A
together with R
3A
forms a cycloalkyl, bicycloalkyl or bicycloalkenyl as defined above, or together with R
5A
forms a methylene chain of 3 carbon atoms wherein a cycloalkyl of 4 carbon atoms inclusive is formed; R
5A
is hydrogen, or is taken together with R to form a cycloalkyl as defined above; and R
6A
is hydrogen or straight-chain alkyl having 8 carbon atoms.]
are disclosed as having prostaglandin-like activity.
DISCLOSURE OF THE INVENTION
The present invention relates to
(1) an &ohgr;-cycloalkyl-prostaglandin E
2
derivative of formula
(wherein A is benzene, thiophene or furan ring;
R
1
is hydroxy, C1-6 alkoxy or a group of formula
NR
10
R
11
(wherein R
10
and R
11
are each independently, hydrogen atom or C1-4 alkyl);
R
2
is C1-4 alkylene, C2-4 alkenylene, —S—C1-4 alkylene, —S—C2-4 alkenylene or C1-4 alkylene-S—;
R
3
is oxo, methylene, halogen atom or a group of formula
R
32
—COO—
(wherein R
32
is C1-4 alkyl, C1-4 alkoxy, phenyl, phenyl-C1-4 alkyl,
R
33
—OOC—C1-4 alkyl or R
33
—OOC—C2-4 alkenyl (wherein R
33
is hydrogen atom or C1-4 alkyl);
R
4
is hydrogen atom, hydroxy or C1-4 alkoxy;
R
5
is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-3 substituents selected from (1)-(5) below:
(1) halogen atom,
(2) C1-4 alkoxy,
(3) C3-7 cycloalkyl,
(4) phenyl,
(5) phenyl substituted by 1-3 substituents selected from halogen atom, C1-4 alkyl, C1-4 alkoxy, nitro or trifluoromethyl;
n is 0-4;
is single bond or double bond;
with the proviso that when the C8-9 position is double bond, R
3
is R
32
—COO—, and R
1
is C1-6 alkoxy),
a non-toxic salt thereof, a prodrug thereof or a cyclodextrin clathrate thereof,
(2) a process for the preparation thereof, and
(3) a pharmaceutical agent containing it as an active ingredient.
In formula (I), C1-4 alkyl in the definitions of R
11
, R
12
, R
32
, R
33
and R
5
means methyl, ethyl, propyl, butyl and isomers thereof.
In formula (I), C1-8 alkyl in the definitions of Rs means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In formula (I), C1-4 alkoxy represented by R
32
, R
4
and Rs means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In formula (I), C1-6 alkoxy representedby R′ means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isomers thereof.
In formula (I), C2-4 alkenylin the definitions of R
32
means vinyl, propenyl, butenyl and isomers thereof.
In formula (I), C1-4 alkylene represented by R
2
is methylene, dimethylene, trimethylene, tetramethylene and isomers thereof.
In formula (I), C2-4 alkylenerepresentedby R
2
is vinylene, propenylene, butenylene and isomers thereof.
In formula (I), C2-8 alkenyl represented by R
3
means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomers thereof.
In formula (I), C2-8 alkynyl representedby R5 means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.
In formula (I), C3-7 cycloalkyl in the definitions of R
5
means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In formula (I), halogen atom in the definitions of R
3
and R
5
means fluorine, chlorine, bromine and iodine.
In the present invention, it may be easily understood by those skilled in the art, unless otherwise specified, the symbol:
indicates that the substituent attached thereto is in front of the sheet, unless otherwise specified, the symbol:
indicates that the substituent attached thereto is behind the sheet,
unless otherwise specified, the symbol:
or
indicates that the substituent attached thereto may be in front of or behind the sheet or may be a mixture of isomers in front of and behind the sheet.
Unless otherwise specified, all isomers are included in the present invention. For example, the alkyl, alkenyl and alkynyl groups include straight-chain and also branched-chain ones. The double bond in alkenyl group includes E, Z and EZ mixed isomers. Isomers resulting from the presence of asymmetric carbon atom(s) e.g. in branched-chain alkyl are included in the present invention.
In the present invention, in the case of a compound wherein the C7 position is sulfur, the configuration of C8 position of the compounds of the present invention are shown as 8&agr;, but as is known in the art, these 8&agr;-compounds are in the equilibrium state with 8&bgr;-compounds (8-epi compound). Therefore the compounds of formula (I) mean mixtures of 8&agr;-compound and isomeric 8&bgr;-compound.
Preferred compounds of the present invention include compounds of the formula (I) listed in the examples or in Tables 1-20 below.
TABLE 1
No.
n
R
5
1
0
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
10
0
11
1
12
1
13
1
14
1
15
1
16
1
17
1
18
1
19
1
20
1
TABLE 2
No.
n
R
5
1
0
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
10
0
11
1
12
1
13
1
14
1
15
1
16
1
17
1
18
1
19
1
20
1
TABLE 3
No.
n
R
5
1
0
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
10
0
1
Ohuchida Shuichi
Tani Kousuke
Gerstl Robert
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
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