Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfur containing
Reexamination Certificate
2002-07-03
2003-10-28
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfur containing
C568S045000, C514S706000
Reexamination Certificate
active
06639111
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a 5-thia-&ohgr;-substituted phenyl-prostaglandin E alcohol.
More detail, it relates to a 5-thia-&ohgr;-substituted phenyl-prostaglandin E alcohol of the formula (I)
(wherein, all the symbols are the same meaning as defined hereinafter), a process for producing it and a pharmaceutical composition it as an active ingredient.
BACKGROUND
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.
A recent study has proved existence of various PGE
2
subtype receptors possessing a 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)).
It is thought that EP
4
subtype receptor relates to inhibition of producing TNF-&agr; and acceleration of producing IL-10. Therefore, the compounds which can bind on 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, 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 such compounds are expected to be useful for the prevention and/or treatment of these diseases.
The present inventors et al. have found out that 5-thia-prostaglandin derivatives of the following formula (A) are useful as a compound which satisfies these purposes and have filed a patent application relates to such compounds (WO00/03980). These compounds can bind on EP
4
subtype receptor selectively and binds on the other subtype receptors weakly, so they show no any other activities. Therefore they are expected to be drugs possessing less side effects. 5-Thia-&ohgr;-substituted phenyl-prostaglandin E derivatives of the following formula (A):
(wherein, R
1A
is hydroxy, C1-6 alkyloxy, or the formula: NR
6
AR
7A
(in which, R
6A
and
R
7A
are, independently, hydrogen or C1-4 alkyl),
R
2
is oxo, halogen or the formula: O—COR
8A
(in which, R
8A
is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl)),
R
3A
is hydrogen or hydroxy,
R
4Aa
and R
4Ab
are, independently, hydrogen or C1-4 alkyl,
R
5A
is phenyl substituted with the following group:
i) 1-3 of substituent(s) selected from the group consisting 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(Cl-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;
is a single bond or a double bond,
with the proviso that when R
2A
is the formula: O—COR
8A
, bond of C8-C9 is a double bond) and cyclodextrin clathrate thereof are described in the specification of WO00/03980.
DISCLOSURE OF THE INVENTION
The present inventors et al. have studied to find out the stable compounds which can bind on EP
4
subtype receptor specifically, and do not bind on any other EP subtype receptors nor any other prostanoid receptors. The present inventors have found out 5-thiaprostaglandin wherein a substituted phenyl is introduced into &ohgr;-chain have achieved this object, and then filed the said patent application (WO00/03980).
The present inventors et al. have confirmed that converting carboxy group of the compounds described in the said patent application into hydroxy group (alcohol) improved an absorption of the compounds into the living body and then, have completed the present invention. The compounds of the formula (I) of the present invention may be converted into carboxylic acid which is an active compound by oxidation in the living body. The said active carboxylic acid possesses an activity to bind on EP
4
subtype receptor strongly and bind on the other prostanoid receptors including the other subtype receptors weakly, and a sufficient stability as a drug.
That is to say, the present invention relates to
(1) a 5-thia-&ohgr;-substituted phenyl-prostaglandin E alcohol of the formula (I)
(wherein, —A— is absent or —A— is methylene or ethylene,
R
1
is hydrogen, C1-6 alkyl, phenyl-C1-6 alkyl, C2-6 alkanoyl, or phenyl-C2-6 alkanoyl,
R
2
is oxo or halogen,
R
3
is hydrogen or hydroxy,
R
4a
and R
4b
are, independently, hydrogen or C1-4 alkyl,
R
5
is phenyl substituted with the following group:
i) 1-3 of group selected from the group consisting 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, and
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;
is a single bond or a double bond) or cyclodextrin clathrate thereof,
(2) a process for producing it and
(3) a pharmaceutical composition comprising it as an active ingredient.
In the formula (I), C1-4 alkyl in R
4a
, R
4b
and R
5
means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), C1-6 alkyl in R
1
means methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), C2-6 alkyl in R
1
means ethyl, propyl, butyl, pentyl, hexyl and isomers thereof.
In the formula (I), C2-6 alkanoyl in R
1
means acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl 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, cycloheptyl.
In the formula (I), halogen in R
2
and R
5
means fluorine, chlorine, bromine and iodine.
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
means that there is a mixture of substituents in front of and behin
Kobayashi Kaoru
Maruyama Toru
Ono Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
Vollano Jean F.
LandOfFree
5-thia-&ohgr;-(substituted phenyl)-prostaglandin E alcohols,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 5-thia-&ohgr;-(substituted phenyl)-prostaglandin E alcohols,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-thia-&ohgr;-(substituted phenyl)-prostaglandin E alcohols,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3134041