Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-12-29
2002-10-08
Gerstl, Robert (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C560S015000, C562S426000
Reexamination Certificate
active
06462081
ABSTRACT:
FIELD OF THE ART
The present invention relates to 5-thia-&ohgr;-substituted phenylprostaglandin E derivatives.
More particularly, it relates to 5-thia-&ohgr;-substituted phenylprostaglandin E derivatives of the formula (I)
(wherein, ail the symbols are as defined hereafter).
BACKGROUND OF THE ART
Prostaglandin E
2
(abbreviated as PGE
2
) has been known as a metabolite in the arachidonate cascade. It has been known that PGE
2
possesses cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on 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 physical role from each other. At present, four receptor subtypes are known and they are called EP
1
, EP
2
, EP
3
, EP
4
(Negishi M. et al, J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
The present inventors have studied to find the compound which can bind to each receptor specifically, have found that the compound of the present invention can bind to EP
4
subtype receptor strongly, and then have achieved the present invention.
It is thought that EP
4
subtype receptor relates to inhibition of producing TNF-&agr; and acceleration of producing IL-10. Therefore, the compounds of the present invention which can bind EP
4
subtype receptor strongly are expected to be useful for the prevention and/or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus etc., and rejection after organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, lung failure, liver damage, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, ambustion pain, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, and shock etc.
Further, it is thought that EP
4
subtype receptor relates to sleeping disorder and blood platelet aggregation, so the compounds of the present invention are expected to be useful for the prevention and/or treatment of such diseases.
The compounds of the present invention of the formula (I) bind weakly to the other subtype receptors and do not express other effects, so such compounds are expected to be an agent having less side effect.
On the other hand, a lot of prostaglandins in which carbon atom at 5th position in PG skeleton was replaced with sulfur atom and which carbon atom(s) in &ohgr;-chain was modified have been known. But among such prostaglandins, there has been no publication which disclosed prostaglandins possessing unsubstituted or substituted phenyl in the &ohgr;-chain of PG skeleton concretely.
For example, in Japanese Patent Application Kokai Sho 58-198466, it is disclosed that the following 5-thia-prostaglandin derivatives possess an activity of inhibition of blood plate aggregation. That is to say, it is disclosed that 5-thia-prostaglandins of the formula (A)
(wherein, R
1
is hydrogen or C1-10 alkyl,
R
2
is substituted or unsubstituted C1-10 alkyl or substituted or unsubstituted C5~6 cycloalkyl,
R
3
and R
4
are, same or differently, hydrogen or protecting group)
or non-toxic salts thereof when R
1
is hydrogen, possess an activity of inhibition of blood plate aggregation and a vasodilating activity, so they are useful as an agent for treatment or prevention of thrombosis and a hypertensive agent.
In this patent specification, the following &ohgr;-cyclopentyl-compound is shown in Example 3 as a concrete compound:
DISCLOSURE OF THE INVENTION
The present inventors have studied to find the stable compound which can bind to EP
4
receptor specifically and which can bind to neither the other EP subtype receptors nor the other prostanoid receptors.
From the results, they have found that 5-thiaprostaglandins modified by introducing substituted phenyl into&ohgr;-chain of the said prostaglandins meet these purposes, and then have achieved the present invention.
As mentioned later, they have found that the prostaglandin compounds in which 5th carbon atom of &agr;-chain of PG skeleton is replaced with sulfur atom and in which phenyl substituted with a particular functional group is introduced into &ohgr;-chain of PG skeleton can bind to EP
4
strongly, bind to the other prostanoid receptors including the other subtype receptors weakly and are stable. And then, they have achieved the present invention.
The present invention relates to
(1) a 5-thia-&ohgr;-substituted phenyl-prostaglandin E derivative of the formula (I)
(wherein, R
1
is hydroxy, C1-6 alkyloxy or NR
6
R
7
(in which R
6
and R
7
is, each independently, hydrogen or C1-4 alkyl),
R
2
is oxo, halogen or O—COR
8
(in which R
8
is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl)),
R
3
is hydrogen or hydroxy,
R
4a
and R
4b
is, each independently, hydrogen or C1-4 alkyl,
R
5
is phenyl substituted with the following substituent(s):
i) 1~3 of
C1-4 alkyloxy-C1-4 alkyl,
C2-4 alkenyloxy-C1-4 alkyl,
C2-4 alkynyloxy-C1-4 alkyl,
C3-7 cycloalkyloxy-C1-4 alkyl,
C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl, phenyloxy-C1-4 alkyl,
phenyl-C1-4 alkyloxy-C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl,
C2-4 alkenylthio-C1-4 alkyl,
C2-4 alkynylthio-C1-4 alkyl,
C3-7 cycloalkylthio-C1-4 alkyl,
C3-7 cycloalkyl (C1-4 alkylthio)-C1-4 alkyl,
phenylthio-C1-4 alkyl or
phenyl-C1-4 alkylthio-C1-4 alkyl,
ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,
C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkyloxy-C1-4 alkyl and hydroxy,
C1-4 alkyloxy-C1-4 alkyl and halogen,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,
C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,
C1-4 alkylthio-C1-4 alkyl and hydroxy or
C1-4 alkylthio-C1-4 alkyl and halogen,
iii) haloalkyl or hydroxy-C1-4 alkyl, or
iv) C1-4 alkyl and hydroxy;
{overscore (-----)} is single bond or double bond,
with the proviso that when R
2
is O—COR
8
, C8-C9 represents double bond) or a non-toxic salt thereof, or a cyclodextrin clathrate thereof,
(2) process for producing it, and
(3) a pharmaceutical composition comprising it as an active ingredient.
DETAILED EXPLANATION OF THE INVENTION
In the formula (I), C1-4 alkyl represented by R
4a
, R
4b
, R
6
, R
7
and R
8
and C1-4 alkyl in R
5
and R
8
means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-6 alkyl represented by R
1
means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), C2-4 alkenyl in R
5
means vinyl, propenyl, butenyl and isomers thereof.
In the formula (I), C2-4 alkynyl in R
5
means ethynyl, propynyl, butynyl and isomers thereof.
In the formula (I), C3-7 cycloalkyl in R
5
means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In the formula (I), halogen in R
2
and R
5
means fluoride, chloride, bromide and iodide.
In the present invention, the symbol
means single bond or double bond. Further, unless otherwise specified, in the present invention, the symbol
means that the substituent attached thereto is in front of the sheet, the symbol
means that the substituent attached thereto is behind the sheet and the symbol
or
means that there is a mixture of substituents in front of and behind the sheet or that the substituent attached thereto may be in front of or behind the sheet as would be clear to the person skilled in the art.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkylene group means straight-chain or branched-chain ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, &agr;-, &bgr;-isomer, enantiomer, diastereomer), optically active isomers (D-, L-, d-, I-isomer), polar compounds gener
Maruyama Toru
Ohuchida Shuichi
Gerstl Robert
Ono Pharmaceutical Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
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