Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-12
2003-06-10
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S231000
Reexamination Certificate
active
06576785
ABSTRACT:
FIELD OF INVENTION
This invention is related to &ohgr;-cycloalkyl-prostaglandin E
2
derivatives. More particularly, this invention is related to:
(1) &ohgr;-cycloalkyl-prostaglandin E
2
derivatives of the formula (I)
wherein all the symbols are the same meaning as hereafter defined, non-toxic salt thereof, prodrug thereof and cyclodextrin clathrate thereof.
BACKGROUND
Prostaglandin E
2
(abbreviated as PGE
2
hereafter) has been known as metabolite in the arachidonate 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 a recent study, it was found that PGE
2
receptor was divided into some subtype which possess different physiological roles from each other. At present four receptor subtypes are known and they are called as EP
1
, EP
2
, EP
3
and EP
4
(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, we found that the compounds of the present invention could bind strongly on EP
2
subtype receptor and achieved the present invention.
The compounds of the formula (I) of the present invention possess a binding activity for EP
2
subtype receptor strongly. Therefore, they are useful for prevention and/or treatment of immunologic diseases (autoimmune diseases, organ transplantation, etc.), asthma, abnormal bone formation, neuronal cell death, liver damage, abortion, premature birth or retina neuropathy of glaucoma etc.
Among the compounds of the present invention of the formula (I), compounds which bind weakly on receptor subtypes except for EP
2
and another arachidonic acid metabolism receptor (thromboxane receptor, PGI
2
receptor, etc.) do not exhibit other effects and therefore, it is thought that such compounds will be useful as 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 U.S. Pat. No. 4,132,738, a compound of the formula (A)
wherein
R
1A
and R
2A
is hydrogen atom;
R
3A
is hydrogen atom, or together with R
4A
is a methylene chain of 4 carbon atoms such that a cycloalkyl of 6 carbon atoms inclusive is formed, or together
with R
4A
is a bicycloalkenyl or bicycloalkyl moiety having the formula
(in which 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 or bicycloalkyl or bicycloalkenyl as defined above, or together with R
5A
is a methylene chain of 3 carbon atoms such that a cycloalkyl of 4 carbon atoms inclusive is formed;
R
5A
is hydrogen atom, or together with R
4A
forms a cycloalkyl as defined above; and
R
6A
is hydrogen atom or straight-chain alkyl having from 1 to 8 carbon atoms; are disclosed as having an inhibitory activity on prostaglandin like.
DISCLOSURE OF THE INVENTION
The present invention is related to
(1) &ohgr;-cycloalkyl-prostaglandin E
2
derivatives of the formula (I)
wherein
R is carboxy or hydroxymethyl;
R
1
is oxo, methylene or halogen atom;
R
2
is hydrogen atom, hydroxy or C1-4 alkoxy;
R
3
is (i) hydrogen atom, (ii) C1-8 alkyl, (iii) C2-8 alkenyl, (iv) C2-8 alkynyl or (v) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, each substituted by 1-3 substituents, being same or different, selected from (1)-(5);
(1) halogen atom,
(2) C1-4 alkoxy,
(3) C3-7 cycloalkyl,
(4) phenyl, or
(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;
is double bond or triple bond;
is single bond, double bond or triple bond;
with the proviso that,
1) when 5-6 position is triple bond, 13-14 position is not triple bond,
2) when 13-14 position is double bond represent E or Z form; non-toxic salt thereof, prodrug thereof and cyclodextrin clathrate thereof,
(2) processes for the preparation thereof, and
(3) pharmaceutical agents containing such a derivative as an active ingredient.
In the present invention, prodrug means
1) for compounds of formula (I) of the present invention, those in which R represent COOR
10
(in which R
10
is C1-6 alkyl), i.e., the compounds of formula (IA)
wherein all symbols are the same meaning as hereinbefore defined
2) for compounds of formula (I) of the present invention, those in which R represent CONR
2
R
13
(in which R
12
and R
13
each, independently, is hydrogen atom or C1-6 alkyl), i.e., the compounds of formula (IB)
wherein all symbols are the same meaning as hereinbefore defined, or
3) for compounds of formula (I) of the present invention, those in which R represent COOR
10
(in which R
10
is the same meaning as hereinbefore defined), R
1
represent R
11
—COO (in which R
11
is C1-4 alkyl, C1-4 alkoxy, phenyl, phenyl-C1-4 alkyl, R
14
—OOC—C1-4 alkyl or R
14
—OOC—C2-4 alkenyl (in which R
14
is hydrogen atom or C1-4 alkyl) 8-9 position is double bond), i.e., the compounds of formula (IC)
wherein all symbols are the same meaning as hereinbefore defined.
In formula (I) or (IC), C1-4 alkyl represented by R
3
, R
11
, and R
14
means methyl, ethyl, propyl, butyl and isomers thereof.
In formula (I), (IA) or (IB), C1-6 alkyl represented by R
10
, R
12
and R
13
means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In formula (I), C1-8 alkyl represented by R
3
means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In formula (I), C2-4 alkenyl represented by R
11
means vinyl, propenyl, butenyl 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 alknyl represented by R
3
means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomers thereof.
In formula (I), or (IC), C1-4 alkoxy represented by R
2
, R
11
and R
3
means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In formula (I), C3-7 cycloalkyl represented by R
3
means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
In formula (I), a halogen atom represented by R
1
and R
3
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 is a mixture of in front of and behind the sheet or may be in front of or 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 include E, Z and EZ mixture ones. Isomers generated by the existence of asymmetric carbon atom(s) e.g. in are included in branched-chain alkyl are included in the present invention.
Preferred compounds of the present invention of the formula (I) are listed in examples, Table 1-14 or prodrug thereof.
TABLE 1
(Ia)
No.
n
R
3
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
(Ib)
No.
n
R
3
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
(Ic)
No.
n
R
3
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 4
(Id)
No.
n
R
3
1
0
2
0
3
0
4
0
5
0
6
0
7
0
8
0
9
0
10
0
11
1
12
1
Ohuchida Shuichi
Tani Kousuke
Gerstl Robert
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
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