Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-08-02
2001-09-11
Geist, Gary (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S503000
Reexamination Certificate
active
06288119
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 11,15-O-dialkyl prostaglandin E derivatives. More particularly, this invention relates to
(1) 11,15-O-dialkyl prostaglandin E derivatives of formula (I)
(wherein all symbols are as defined hereinafter), non-toxic salts thereof and cyclodextrin clathrates thereof,
(2) processes for the preparation thereof and
(3) pharmaceutical compositions containing them as active ingredient.
BACKGROUND
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 on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity etc.
In the recent studies, it was found that the PGE
2
receptor was divided into some subtypes which possess different roles from each other. At present, four main receptor subtypes are known and they are called EP
1
, EP
2
, EP
3
and EP
4
, respectively (Negishi M. et al., J. Lipid Mediators Cell Signaling 12, 379-391 (1995)).
PGE
2
has various kinds of physiological activities, and so it has the disadvantage that its undesired effect leads to a side effect. Research to overcome this disadvantage has been carried on by investigating the roles of each subtype and obtaining those compounds which are effective only on the subtype.
Accordingly, the present inventors investigated to find those compounds which bind on EP
3
subtype receptor specifically, so that we found that 11,15-O-dialkyl prostaglandin E derivatives of formula (I) could bind specifically on EP
3
receptor and hardly on other subtype receptors, and we achieved the present invention.
As to the compounds whose structures are similar to those of the compounds of the present invention of formula (I), the following techniques are known.
In JP55-115836, processes for the preparation of methyl ether derivatives are disclosed, wherein 11,15-O-dimethyl-prosta-5Z,13E-dienoic acid methyl ester is synthesized from prostaglandin E
2
, but nothing is described about the utility of the compounds obtained.
In JP47-42647, it is described that 15-O-alkyl ether prostaglandin E derivatives have PG-like activity. More particularly, 15-O-methyl-PGE
2
is described.
DISCLOSURE OF THE INVENTION
The present invention relates to
1) 11,15-O-dialkyl prostaglandin E derivatives of formula (I)
(wherein R is oxo or halogen atom,
R
1
and R
2
are each independently C1-4 alkyl,
R
3
is C1-10 alkyl, C2-10 alkenylene, C2-10 alkynylene, or C1-10 alkyl, C2-10 alkenyl or C2-10 akkeynyl substituted by phenyl, phenoxy, C3-7 cycloalkyl or C3-7 cycloalkyloxy, wherein phenyl and cycloalkyl may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, trihalomethyl or nitro, and
is bond or double-bond), or non-toxic salts thereof or cyclodextrin clathrates thereof,
2) processes for the preparation thereof and
3) pharmaceutical compositions containing them as active ingredient.
DESCRIPTION
In formula (I), C1-4 alkyl in the definitions of R
1
, R
2
and R
3
means methyl, ethyl, propyl, butyl and isomers thereof.
In formula (I), C1-4 alkoxy in the definition of R
3
means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In formula (I), C1-10 alkyl in the definition of R
3
or represented by R
3
means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof.
In formula (I), C2-10 alkenyl in the definition of R
3
or represented by R
3
means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and isomers thereof.
In formula (I), C2-10 alkynyl in the definition of R
3
or represented by R
3
means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and isomers thereof.
In formula (I), C3-7 cycloalkyl in the definition of R
3
or represented by R
3
means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
In formula (I), halogen in the definition of R
3
or represented by R means fluorine, chlorine, bromine and iodine.
In the present specification, as 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, all isomers are included in the present invention. For example, alkyl, alkenyl and alkynyl groups include straight-chain and also branched-chain ones. Double-bond in alkenylene 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.
Preferred compounds among the present invention of formula (I) include compounds listed in the examples and the following.
(1) 11&agr;,15&agr;-dipropyloxy-9-oxoprosta-5Z,13E-dienoic acid,
(2) 11&agr;,15&agr;-dibutyloxy-9-oxoprosta-5Z,13E-dienoic acid,
(3) 11&agr;-methoxy-15&agr;-ethoxy-9-oxoprosta-5Z,13E-dienoic acid,
(4) 11&agr;-methoxy-15&agr;-propyloxy-9-oxoprosta-5Z,13E-dienoic acid,
(5) 11&agr;-methoxy-15&agr;-butyloxy-9-oxoprosta-5Z,13E-dienoic acid,
(6) 11&agr;-ethoxy-15&agr;-methoxy-9-oxoprosta-5Z,13E-dienoic acid,
(7) 11&agr;-ethoxy-15&agr;-propyloxy-9-oxoprosta-5Z,13E-dienoic acid,
(8) 11&agr;-ethoxy-15&agr;-butoxy-9-oxoprosta-5Z,13E-dienoic acid,
(9) 11&agr;-propyloxy-15&agr;-methoxy-9-oxoprosta-5Z,13E-dienoic acid,
(10) 11&agr;-propyloxy-15&agr;-ethoxy-9-oxoprosta-5Z,13E-dienoic acid,
(11) 11&agr;-propyloxy-15&agr;-butoxy-9-oxoprosta-5Z,13E-dienoic acid,
(12) 11&agr;-butoxy-15&agr;-methoxy-9-oxoprosta-5Z,13E-dienoic acid,
(13) 11&agr;-butoxy-15&agr;-ethoxy-9-oxoprosta-5Z,13E-dienoic acid,
(14) 11&agr;-butoxy-15&agr;-propyloxy-9-oxoprosta-5Z,13E-dienoic acid.
Salts
The compounds of the present invention of formula (I) may be converted into the corresponding salts by a conventional method. Non-toxic and water-soluble salts are preferable. Appropriate salts are described hereinafter; salts of alkali metals (e.g. potassium, sodium), salts of alkaline-earth metals (e.g. calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine etc.).
Cyclodextrin Clathrates
11,15-O-Dialkyl prostaglandin E derivatives of formula (I) may be converted into cyclodextrin clathrates using &agr;-, &bgr;- or &ggr;-cyclodextrin or their mixture, by the methods described in the specification of Japanese Kokoku No. 50-3362, Japanese Kokoku No.52-31404 or Japanese Kokoku No.61-52146. Conversion into their cyclodextrin clathrates serves to increase the stability and solubility in water of the compounds, and therefore it is convenient in the use for pharmaceuticals.
Processes for the Preparation of the Compounds of the Present Invention
(1) A compound of the present invention of formula (I) may be prepared by subjecting to hydrolysis using an enzyme a compound of formula (II)
(wherein R, R
1
, R
2
, R
3
and
are as defined hereinbefore).
Hydrolysis using an enzyme is known. For example, hydrolysis using an enzyme may be carried out in a mixture of a water-miscible organic solvent (ethanol, dimethylsulfoxide or mixed solvent thereof etc.) and water, in the presence or absence of buffer, using an ester cleaving enzyme (esterase, lipase etc.) at a temperature of from 0° C. to 50° C.
A compound of formula (II) may be prepared by subjecting to O-alkylation a compound of formula (III)
(wherein all symbols are as defined hereinbefore) and a compound of formula (IV)
R
2
X (IV)
(wherein X is halogen atom, and R
2
is as defined hereinbefore).
O-alkylation is known. For example, O-alkylation may be carried out in an inert organic solvent (acetonitrile, tetrahydrofuran (THF), methylene chlorid
Maruyama Takayuki
Ohuchida Shuichi
Geist Gary
Maier Leigh C.
Ono Pharmaceuticals Co. Ltd.
Stevens Davis Miller & Mosher L.L.P.
LandOfFree
11,15-O-dialkylprostaglandin E derivatives, process for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 11,15-O-dialkylprostaglandin E derivatives, process for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 11,15-O-dialkylprostaglandin E derivatives, process for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2519284