Prostaglandin E analogues

Details Prostaglandin E analogues Prostaglandin E analogues

2002-03-04

2002-11-19

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C564S443000

Reexamination Certificate

active

06482990

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an excellent pharmaceutical preparation for prevention or treatment of the restenosis after percutaneous transluminal coronary angioplasty (PTCA) which comprises as an effective ingredient a prostaglandin analog, a pharmaceutically acceptable salt thereof or a hydrate thereof.
BACKGROUND ART
Since PG (hereinafter PG represents prostaglandin) exhibits various important physiological actions, the syntheses of a great number of the derivatives and the biological activities have been investigated and have been reported in many literatures, for example, Japanese Patent Kokai No. 52-100446 and U.S. Pat. No. 4,131,738.
PG and the derivatives thereof have biological actions such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action or a lowering action of intraocular pressure, and are useful for treatment or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension or duodenal ulcer, and further useful for labor induction, artificial termination of pregnancy, etc.
On the other hand, PTCA has low invasiveness to the patient as a therapeutic modality of ischemic heart diseases and has an excellent initial treatment effect, therefore, it is a plasty which recently has rapidly been developed. However, there has been an unsolved drawback of causing restenosis of coronary artery at a frequency of 30-40% within a few months after PTCA.
The compounds which can control not only the migration from intima to mesothelium of vascular smooth muscle cells deeply associating with the onset of restenosis but also their growth in the mesothelium are greatly expected as drugs for prevention of the restenosis. However, no clinically available drugs have been found.
An object of the present invention is to provide a pharmaceutical preparation for prevention or treatment of the restenosis after PTCA which exhibits an inhibiting action on the growth of vascular smooth muscle.
DISCLOSURE OF THE INVENTION
As a result of the continued extensive studies, the present inventors have found that a prostaglandin analog represented by the following Formula (I) exhibits a characteristic inhibiting action on the growth of vascular smooth muscle, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin analog represented by Formula (I):
[wherein A is an ethylene group, a vinylene group or an ethynylene group, Y
1
and Y
2
are the same or different, and each a hydrogen atom, a halogen atom, a cyano group, a C
1-3
aminoalkyl group, a C
1-6
hydroxyalkyl group, NR
5
R
6
(wherein R
5
and R
6
are the same or different, and each a hydrogen atom or a C
1-6
alkyl group), a hydroxyl group, a C
1-6
alkoxy group, a C
1-9
alkyl group, a C
1-6
alkyl group substituted with halogen(s) or a C
1-5
acyl group, R
1
and R
2
are the same or different, and each a hydrogen atom, a halogen atom, a C
1-9
alkyl group or a C
1-6
alkyl group substituted with halogen(s), m is an integer of 0 to 6, and n is an integer of 0 to 3], a pharmaceutically acceptable salt thereof or a hydrate thereof.
MODE FOR CARRYING OUT THE INVENTION
In the present invention, the vinylene group means a cis- or trans-vinylene group.
The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
The C
1-3
aminoalkyl group means a straight or branched aminoalkyl group having 1 to 3 carbon atoms, examples of which are an aminomethyl group, an aminoethyl group and an aminopropyl group, and preferably an aminomethyl group.
Examples of the C
4-8
cyclic amine are pyrrolidine, piperidine and morpholine, and preferably piperidine.
The C
1-6
hydroxyalkyl group means a straight or branched hydroxyalkyl group having 1 to 6 carbon atoms, examples of which are a hydroxymethyl group, a dimethylhydoxymethyl group and a dihydroxymethyl group.
The C
1-6
alkoxy group means a straight or branched alkoxy group having 1 to 6 carbon atoms, examples of which are a methoxy group, an ethoxy group and a propoxy group.
The C
1-6
alkyl group substituted with halogen(s) means a straight or branched alkyl group having 1 to 6 carbon atoms which is substituted with fluorine atom(s), chlorine atom(s), bromine atom(s) or iodine(s), and is preferably a perfluoroalkyl group, and more preferably a trifluoromethyl group.
The C
1-6
alkyl group means a straight or branched alkyl group having 1 to 6 carbon atoms, and examples of which are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a 2-ethylpropyl group, a hexyl group, an isohexyl group and a 1-ethylbutyl group.
The C
1-9
alkyl group means the above-mentioned C
1-6
alkyl group and a straight or branched C
7-9
alkyl group means, example of which are a heptyl group, an octyl group and a nonyl group.
The C
1-5
acyl group means a straight or branched alkanoyl, alkenoyl or alkynoyl group having 1 to 5 carbon atoms, examples of which are an acetyl group, a propionyl group, a crotonoyl group and a propioloyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metals (e.g., sodium or potassium), alkali earth metals (e.g., calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammonium or tris(hydroxymethyl)aminomethane.
When Y
1
or Y
2
is NR
5
R
6
, R
5
and R
6
are preferably each a methyl group.
The compounds of Formula (I) of the present invention can be specifically prepared, for example, by the methods summarized by the following reaction scheme.
In the reaction scheme, TBS is a tert-butyldimethylsilyl group, A′ is an ethylene group or a vinylene group, Et is an ethyl group, A, Y
1
, Y
2
, R
1
, R
2
, m and n are as defined above.
The above-mentioned reaction scheme is illustrated as follows:
(1) At first, a known compound of Formula (II) is reacted with 0.8 to 2.0 equivalents of a compound represented by Formula (III) or (IV) in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride or n-hexane) at −78 to 30° C. according to the method of Sato et al. (
Journal of Organic Chemistry,
vol. 53, page 5590 (1988)) to stereospecifically give a compound of Formula (V). Herein, the compound wherein A is an ethylene group or a vinylene group (i.e., the compound wherein A is A′) can be obtained by a reaction using a compound of Formula (III) at −78 to 0° C., and the compound wherein A is an ethynylene group can be obtained by a reaction using a compound of Formula (IV) at 0 to 30° C.
The organic copper compound of Formula (III) used as a material can be prepared, for example, according to a method shown by the following reaction scheme.
In the reaction scheme, A′, R
1
, R
2
and TBS are as defined above.
That is, an aldehyde compound represented by Formula (VIII) is reacted with methyl (triphenylphosphoranilidene)acetate in an inert solvent (e.g., methylene chloride, benzene, toluene or xylene) at 0° C. to a reflux temperature of the solvent, followed by a reaction using a reductant such as diisobutylaluminum hydride to give a compound of Formula (IX).
Subsequently, the compound of Formula (IX) is subjected to a stereoselective oxidation reaction using diisopropyl L-(+)-tartrate and titanium tetraisopropoxide in tert-butyl hydroperoxide and methylene chloride at −20° C. to give an epoxy compound. The resulting epoxy compound is subjected to methanesulfonylation and substitution with lithium chloride, successively, to give a compound of Formula (X).
The compound of Formula (X) is reacted with n-butyl lithium in tetrahydrofuran at −70° C. to give an acetylene derivative, the hydroxyl group of which is then protected. in an ordinary manner, th

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