Prostaglandin derivatives

Details Prostaglandin derivatives Prostaglandin derivatives

2002-03-11

2003-09-02

Gerstl, Robert (Department: 1624)

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

Organic compounds

Carboxylic acid esters

C560S118000, C562S500000, C514S059000

Reexamination Certificate

active

06613932

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts thereof and hydrates thereof.
BACKGROUND ART
Since prostaglandin (PG) exhibits various important physiological actions in a trace amount, the biological activities of a great number of natural PGs and synthesized PG derivatives 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. Natural PGs and PG derivatives 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, percutaneous transluminal coronary angioplasty (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 caused after PTCA. However, no clinically available drugs have been found.
An object of the present invention is to provide novel PG derivatives which have an excellent action in inhibiting the growth of vascular smooth muscle and are greatly expected as drugs for prevention or treatment of the restenosis after PTCA.
DISCLOSURE OF THE INVENTION
As a result of the continued extensive studies, the present inventors have found that novel prostaglandin derivatives having an alkylthio group, an arylthio group or the like at the 11-position represented by the following Formula (I) achieve the above-objects, and thereby the present invention has been accomplished.
That is, the present invention is directed to a prostaglandin derivative represented by Formula (I):
[wherein X is CH
2
, O or a group represented by the formula: S(O)
q1
(wherein q1 is an integer of 0 to 2),
Y is an ethylene group, a vinylene group, an ethynylene group or a group represented by the formula: O(CH
2
)
t1
or S(O)
q2
(CH
2
)
t1
(wherein q2 is an integer of 0 to 2, and t1 is an integer of 1 to 3),
Z is an ethylene group, a vinylene group or an ethynylene group,
R
1
is a hydrogen atom, a C
1-10
alkyl group or a C
3-10
cycloalkyl group,
R
2
is a C
1-10
alkyl group, a C
2-10
alkenyl group, a C
2-10
alkynyl group, a C
3-10
cycloalkyl group, a C
1-5
alkyl-C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-5
alkyl group, a hydroxy-C
1-5
alkyl group, a halogeno-C
1-5
alkyl group, a C
1-5
alkoxy-C
1-5
alkyl group, a C
2-4
alkoxycarbonyl-C
1-5
alkyl group, a carboxyl-C
1-5
alkyl group, a cyano-C
1-5
alkyl group, a C
1-5
alkyl group substituted with a group represented by the formula: —NR
7
R
8
(wherein R
7
and R
8
are the same or different, and each a hydrogen atom or a C
1-5
alkyl group, or R
7
and R
8
together with the nitrogen atom to which they are attached form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group or a thiomorpholino group), an acyl group, a group represented by the formula: —(CH
2
)t
2
CH(NH
2
)COOR
9
(wherein R
9
is a hydrogen atom or a C
1-5
alkyl group, t2 is 1 or 2) or a group represented by the formula:
(wherein R
4
and R
5
are the same or different, and each a hydrogen atom, a hydroxyl group, a halogen atom, a C
1-10
alkyl group, a C
1-10
alkoxy group, a C
2-10
alkenyl group, a C
2-10
alkynyl group, a hydroxy-C
1-5
alkyl group, a halogeno-C
1-5
alkyl group, a C
1-5
alkoxy-C
1-5
alkyl group, a C
2-4
alkoxycarbonyl group, a carboxyl group, an acyl group, a nitro group, an amino group or an amino group which is mono- or di-substituted with C
1-5
alkyl group(s), and r is an integer of 0 to 3),
R
3
is a hydrogen atom, a C
1-10
alkyl group, a C
3-10
cycloalkyl group, a C
1-5
alkyl-C
3-10
cycloalkyl group, a C
3-10
cycloalkyl-C
1-5
alkyl group, a C
2-10
alkenyl group or a C
2-10
alkynyl group,
m is an integer of 0 to 3, n is an integer of 1 to 3, p is an integer of 0 to 5 and q is an integer of 0 to 2], a pharmaceutically acceptable salt thereof or a hydrate thereof.
Furthermore, the present invention is directed to a pharmaceutical preparation which comprises as an effective ingredient the compound represented by formula (I), the pharmaceutically acceptable salt thereof or the hydrate thereof.
In the present invention, the vinylene group refers to a cis- or a trans-vinylene group. The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C
1-10
alkyl group means a straight or branched alkyl group having 1 to 10 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, a 2-ethylpropyl group, a hexyl group, an octyl group and a decanyl group.
The C
1-10
alkoxy group means a straight or branched alkoxy group having 1 to 10 carbon atoms, and examples of which are a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group a tert-butoxy group, a pentyloxy group and an octyloxy group.
The C
2-10
alkenyl group means a straight or branched alkenyl group having 2 to 10 carbon atoms, and examples of which are a vinyl group, an allyl group, a 3-pentenyl group, a 4-hexenyl group, a 5-heptenyl group, a 4-methyl-3-pentenyl group, a 2,4-dimethylpentenyl group, a 6-methyl-5-heptenyl group and a 2,6-dimethyl-5-heptenyl group.
The C
2-10
alkynyl group means a straight or branched alkynyl group having 2 to 10 carbon atoms, examples of which are an ethynyl group, a propargyl group, a 3-pentynyl group, a 4-hexynyl group, a 5-heptynyl group, a 4-methyl-3-pentynyl group, a 2,4-dimethylpentynyl group, a 6-methyl-5-heptynyl group and a 2,6-dimethyl-5-heptynyl group.
The C
3-10
cycloalkyl group means a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
The C
1-5
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 5 carbon atoms, examples of which are a methylcyclopropyl group, a methylcyclohexyl group and an ethylcyclohexyl group.
The C
3-10
cycloalkyl-C
1-5
alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl group having 3 to 10 carbon atoms, examples of which are a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclohexylmethyl group, a cyclohexylethyl group and a cycloheptylmethyl group.
The hydroxy-C
1-5
alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with a hydroxyl group, examples of which are a hydroxymethyl group, a hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group and a 5-hydroxypentyl group.
The halogeno-C
1-5
alkyl group means a straight or branched alkyl group having 1 to 5 carbon atoms substituted with at least one of a fluorine atom, a chlorine atom and a bromine atom, examples of which are a chloroethyl group, a 2-bromopropyl group, a 3-chloropropyl group, a 4-fluorobutyl group, a 5-chloropentyl group and a trifluoromethyl group.
The C
1-5
alkoxy-C
1-5
alkyl groupmeans a straight or branched alkyl gr

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