Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-01-04
2002-09-24
Killos, Paul J. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C560S121000, C182S069400
Reexamination Certificate
active
06455584
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
BACKGROUND ART
Since prostaglandin (hereinafter referred to as “PG”) exhibits various important physiological actions in a trace amount, the syntheses of a large number of derivatives from natural PGs and the biological activities have been investigated with the intention of a practical use as medicines 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 therapy or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension, labor induction, etc.
On the other hand, percutaneous transluminal coronary angioplasty (PTCA) has low invasiveness to the patient as a therapeutic modality of ischemic heart diseases and has an excellent initial therapy 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 to be usable as drugs for prevention of the restenosis caused after PTCA. However, no clinically available drugs have been found.
An object of the present invention is to provide novel PG derivatives which exhibit excellent action in inhibiting the growth of vascular smooth muscle and are useful as a drug for prevention of restenosis after PTCA.
DISCLOSURE OF THE INVENTION
As a result of the continued extensive studies, the present inventors have found that the prostaglandin derivatives having a triple bond between the 13- and 14-positions and a hydroxyalkylthio group at the 11-position attain the above-mentioned object, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by the following Formula (I):
wherein A is an ethylene group, a vinylene group, an ethynylene group, O(CH
2
)
q
or S(O)
r
(CH
2
)
q
, R
1
is a C
3-10
cycloalkyl group, a C
1-4
alkyl-C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-4
alkyl group, a C
1-10
alkyl group, a C
1-10
alkyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s), a C
2-10
alkenyl group, a C
2-10
alkenyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s), a C
2-10
alkynyl group, a C
2-10
alkynyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s) or a bridged cyclic hydrocarbon group, R
2
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group, m is an integer of 1 to 5, n is an integer of 1 to 4, p is 0, 1 or 2, q is an integer of 1 to 5 and r is 0, 1 or 2; a pharmaceutically acceptable salt thereof or a hydrate thereof.
Preferred compounds of the present invention are those of Formula (I) wherein R
1
is a C
5-10
alkyl group, a C
5-10
alkyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s), a C
5-10
alkenyl group, a C
5-10
alkenyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s), a C
5-10
alkynyl group, or a C
5-10
alkynyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s), and q is 1 or 2, and specially preferred compounds are those of Formula (I) wherein m is an integer of 2 to 4, and n is 2 or 3.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective ingredient a compound represented by Formula (I), a pharmaceutically acceptable salt thereof or a hydrate thereof.
The terms used in the present invention are defined as follows:
The vinylene group refers to a cis- or trans-vinylene group.
The C
3-10
cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C
1-4
alkyl-C
3-10
cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms substituted with a straight or branched alkyl group having 1 to 4 carbon atoms, and examples thereof are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C
3-10
cycloalkyl-C
1-4
alkyl group means a straight or branched alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof are a cyclopropylmethyl group, cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The C
1-10
alkyl group means a straight or branched alkyl group having 1 to 10 carbon atoms, and examples thereof are a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopropyl group, a hexyl group, a heptyl group, an octyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 2,4-dimethylpentyl group, a 2-ethylpentyl group, a 2-methylheptyl group, a 2-ethylhexyl group, a 2-propylpentyl group, a 2-propylhexyl group, a 2,6-dimethylheptyl group, a nonyl group and a decyl group.
The C
1-10
alkyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s) means a straight or branched alkyl group having 1 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 5-hydroxy-2-methylpentyl group, a 4,5-dihydroxypentyl group, a 5-methoxy-2-methylpentyl group, a 4-ethoxybutyl group or a 4-allyloxybutyl group.
The C
2-10
alkenyl group means a straight or branched alkenyl group having 2 to 10 carbon atoms, and examples thereof are a vinyl group, an allyl group, a 2-propenyl group, a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethyl-3-pentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C
2-10
alkenyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s) means a straight or branched alkenyl group having 2 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 6-hydroxy-2-methyl-3-hexenyl group and a 6-methoxy-3-hexenyl group.
The C
2-10
alkynyl group means a straight or branched alkynyl group having 2 to 10 carbon atoms, and examples thereof are an ethynyl group, a 2-propynyl group, a 3-pentynyl group, a 3-hexynyl group, a 4-hexynyl group, a 1-methylpent-3-ynyl group, a 2-methylpent-3-ynyl group, a 1-methylhex-3-ynyl group and a 2-methylhex-3-ynyl group.
The C
2-10
alkynyl group substituted with hydroxyl group(s) or C
1-4
alkoxy group(s) means a straight or branched alkynyl group having 2 to 10 carbon atoms substituted with hydroxyl group(s) or straight or branched alkoxy group(s) having 1 to 4 carbon atoms, and examples thereof are a 5-hydroxy-1-methylpent-3-ynyl group and a 6-methoxy-3-hexynyl group.
Examples of the bridged cyclic hydrocarbon group are a bornyl group, a norbornyl group, an adamantyl group, a pinanyl group, a thujyl group, caryl group and a camphanyl group.
Examples of the pharmaceutically acceptable salt are salts with alkali metal (e.g. sodium or potassium), alkali earth metal (e.g. calcium or magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethyl-monoethanolamine, tromethamine, lysine, a tetraalkyl ammonium and tris(hydroxymethyl)aminomethane.
The compounds of Formula (I) can be prepared, for example, by the methods su
Hirano Hitomi
Ono Naoya
Sato Fumie
Tanaka Hideo
Tanami Tohru
Killos Paul J.
Lorusso & Loud
Taisho Pharmaceutical Co. Ltd.
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