Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-12-04
2003-10-14
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S121000, C560S128000, C560S190000
Reexamination Certificate
active
06632958
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing a purified prostaglandin derivative.
BACKGROUND ART
Since six structures of prostaglandins (hereinafter prostaglandin will be referred to as PG) PGE
1
, PGE
2
, PGE
3
, PGF
1
&agr;
, PGF
2
&agr;
and PGF
3
&agr;
had been determined in 1960, PG analogues have been found one after another, and their biological activities have also been clarified one after another. Specifically, their various biological activities become known such as a platelet aggregation inhibitory action, a diastolic blood pressure lowering action, a gastric-acid secretion inhibitory action, a smooth muscle contraction action, a cell protection action and a diuresis action. Further, it is also known that PGs are a class of compounds which are effective for treatment or prevention of e.g. myocardial infarction, angina pectoris, arterial sclerosis, hypertension, duodenal ulcer, induction of labor and artificial termination of pregnancy.
Meanwhile, according to literature, pharmaceuticals comprising such PGs are expected to have an important role in future. PGs are typical local hormones, which are produced locally as the case requires and act locally. Accordingly, it is proposed that a drug delivery system taking properties as an autacoid and chemical properties into consideration is necessary for such PGs-related pharmaceuticals. The drug delivery system is a system to improve the value of a pharmaceutical having such a drawback that it has a weak effect when administered systemically and will cause strong systemic side effects. As one example of the drug delivery system of the PGs, lipid microspheres (hereinafter referred to as LMs) as carriers, are mentioned. The LMs are considered as emulsified fine particles of PG-containing lipid practically, and referred to also as a fat emulsion. The fat emulsion-PG as mentioned hereinafter means an emulsified lipid containing a PG.
Conventionally, a target therapeutic agent comprising fat emulsion-PGE
1
having PGE
1
contained in LMs with a diameter of 2 &mgr;m has been reported to have high stability in the body and to show higher vasodilator action and platelet aggregation inhibitory action as compared with PGE
1
alone (Sim, A.K., et al., Arzneim-Forsch/Drug Res., 1206-1209, 1986).
However, if the fat emulsion-PGE
1
is administered to the body, a large amount of PGE
1
will be released from the LMs. Accordingly, a study has been made to suppress the release amount by employing fat emulsion-PGE
1
ester (Igarashi et al, Ensho (Inflamation), 8,243-246, 1988). Specifically, it was confirmed that a PGE
1
ester had no activity and that the PGE
1
ester was cut at the ester linkage by an esterase in the body to form PGE
1
and to exhibit activity (such a PGE
1
ester is called prodrug of PGE
1
) firstly, and then the stability of the fat emulsion-PGE
1
ester in blood was studied.
In said study, as the PGE
1
ester, a methyl ester, an ethyl ester, a butyl ester or an octyl ester was used. As the index indicating the activity of the PGE
1
ester, a platelet aggregation inhibitory action was employed. Further, the stability as the fat emulsion in blood was evaluated by measuring the release of the PGE
1
ester from LMs when incubated in an isotonic salt solution. As a result, the storage stability and effectiveness of LM preparations of PGE
1
esters were confirmed.
Here, in production of the fat emulsion, it is necessary to finely disperse the fat emulsion-PGE
1
in a dispersion medium so as to increase sustained release of the fat emulsion-PGE
1
. In such a case, the PGE
1
and the other materials are dissolved under heating, followed by homogenization in water at a high temperature of a level of from 80 to 90° C. However, a conventional PGE
1
quickly decompose under such a high temperature. Further, a conventional PGE
1
quickly decompose also in commercial distribution channel since it has a low storage stability. Accordingly, it has been proposed to develop PGE
1
analogues having a good stability even when prepared at a high temperature, and having an improved storage stability also in distribution channel. For example, a PGE
1
analogue having a carbonyl group at the 9-position modified with an enol ester has been reported (Japanese Pat. No. 2,602,964).
As a method of synthesizing such a PG derivative, a method of using an organic copper reagent is mentioned. Further, a method of adding e.g. an organic phosphorus compound or an organic sulfur compound to coordinate such a compound with the organic copper reagent, with a purpose of increasing the solubility of said organic copper reagent in a reaction solvent, may be mentioned. In a case where a PG derivative is synthesized by said method, compounds used for the reaction and by-products derived from said compounds are present in the PG derivative. If it is attempted to remove them by a conventional after-treatment such as extraction operation, it is difficult to completely remove them. Further, if it is attempted to remove such compounds by a purification method such as column chromatography, the number of steps will increase, such being inefficient, and the yield may decrease in the after-treatment process.
DISCLOSURE OF THE INVENTION
Namely, the present invention has been made to overcome the problems mentioned above, and provides a process for producing a purified prostaglandin derivative, which comprises adding an alkene represented by the following formula (1) to cyclopentenone represented by the following formula (2) under the action of an alkyllithium and an organic copper reagent to form an adduct, reacting said adduct with a carboxylic halide represented by the following formula (3), a carboxylic anhydride represented by the following formula (4) or a mixed carboxylic anhydride represented by the following formula (5) to obtain a reaction product containing a prostaglandin derivative represented by the following formula (6), and then treating said reaction product with a nitrogen-containing compound:
provided that symbols in the formulas represent the following meanings:
R
1
is an alkanoyl group or an alkanoyl group containing a hetero atom in the alkyl group moiety,
R
2
is an alkyl group or an alkyl group containing a hetero atom,
each of R
3
and R
4
which are independent of each other, is a protecting group for a hydroxyl group or a hydrogen atom,
R
5
is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkenyl group or an alkynyl group,
R
6
is an alkanoyl group or an alkanoyl group containing a hetero atom in the alkyl group moiety, and is different from R
1
.
Q is an ethylene group or a vinylene group,
X
1
is an iodine atom or a trialkyltin group, and
X
2
is a halogen atom.
X
1
in the alkene represented by the formula (1) (hereinafter referred to as alkene (1), the same applies to the other compounds) is an iodine atom or a trialkyltin group, and as the trialkyltin group, a tributyltin group is preferred. X
1
is preferably an iodine atom.
R
4
in the alkene (1) is a protecting group for a hydroxyl group or a hydrogen atom. As the protecting group for a hydroxyl group, protecting groups as described in literature by Greene et al (Protective Groups in Organic Synthesis, John Wiley & Sons, 1981) may be used. Among them, preferred as the protecting group for a hydroxyl group, are an acyl group (such as an alkanoyl group containing a lower alkyl group, preferably an acetyl group etc., or an acryl group containing an aromatic ring, preferably a benzoyl group, a p-methylbenzoyl group or a p-phenylbenzoyl group etc.), a trialkylsilyl group (such as a trimethylsilyl group or a t-butyldimethylsilyl group), a triarylsilyl group, an alkyldiarylsilyl group, an aryldialkylsilyl group, an aralkyl group (such as a benzyl group), a tetrahydropyranyl group and the like.
R
5
in the alkene (1) is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkenyl group or an alkynyl group.
In a case where R
5
is an alkyl group, preferred is a linear or
Morizawa Yoshitomi
Urushihara Masahiro
Forohar Farhad
Geist Gary
Mitsubishi Pharma Corporation
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