Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-09
2003-12-09
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S244000, C544S265000, C544S276000
Reexamination Certificate
active
06660745
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel purine derivative dihydrate with a phosphodiesterase IV inhibitory effect, to drugs containing the dihydrate as an active ingredient and to a method of using the drugs. The invention further relates to a compound useful as an intermediate in the production of the purine derivative dihydrate.
BACKGROUND ART
Cyclic AMP (cAMP) is an important second messenger which is involved in relaxation of respiratory tract smooth muscles and control of inflammatory cells, and the messenger is decomposed by phosphodiesterase (hereinafter abbreviated as “PDE”in the specification) to be converted into inactive 5′-AMP. Therefore, it is believed that suppression of the decomposition of cAMP by PDE may increase the concentration of cAMP, thereby bronchodilatation and anti-inflammatory action can be achieved. For this reason, PDE inhibitors having inhibitory action against the decomposition of cAMP have been focused as medicaments for the treatment of asthma, chronic obstructive pulmonary disease (hereinafter abbreviated as “COPD” in the specification) and/or other inflammatory diseases. In addition, five PDE isozymes (PDE I, II, III, IV and V) have recently been isolated, and their specific tissue distributions have been revealed (Adv. Second Messenger Phosphoprotein Res., 22, 1 (1988): Trends Pharm., Sci., 11,150 (1990)).
Among inhibitors for these isozymes, in particular, inhibitors specific for PDE IV have been suggested to be possibly useful for the treatment of asthma, COPD and/or other inflammatory diseases (Thorax 46, 512 (1991) etc.). Herein, chronic articular rheumatism, atopic dermatitis, psoriasis, etc., are listed as concrete examples of the inflammatory disease. As a compound having specific inhibitory activity against PDE IV, for example, the compound disclosed in Japanese Patent Unexamined Publication (Kokai) No. 50-157360/1975 (Rolipram) has been known.
Although various compounds have been known as PDE IV inhibitors (for example, compounds disclosed in Japanese Patent Unexamined Publication (Kokai) No. 4-253945/1992, International Patent Publication in Japanese (Kohyo) Nos. 6-504782/1994, 7-504442/1995, 8-501318/1996and9-500376/1997 and so forth), they have not been used clinically so far, and development of novel compounds having PDE IV inhibitory activity has been desired.
DISCLOSURE OF THE INVENTION
As a result of diligent research directed toward providing a novel compound which has a specific inhibitory effect against PDE IV and is useful for asthma, COPD and/or other inflammatory diseases, the present inventors have found that specific purine derivatives have an excellent inhibitory effect against PDE IV (WO99/24432). Upon continued investigation, the present inventors discovered a specific purine derivative dihydrate with excellent stability as well as an intermediate useful for its production, and the present invention has thus been completed.
In other words, the present invention provides a dihydrate of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide and a process for its production.
According to another aspect, the invention provides drugs containing the dihydrate as an active ingredient thereof. Such drugs are preferably provided as pharmaceutical compositions containing the dihydrate and formulating additives, and may be used, for example, as preventives and/or remedies for asthma, COPD and/or other inflammatory diseases. According to yet another aspect, the invention provides the use of the aforementioned dihydrate for production of the aforementioned drugs; therapeutic treatment, that is, a remedy and/or preventive for asthma, COPD and/or other inflammatory diseases which comprises a step of administering an effective dose of the dihydrate to a mammalian animal including human; a PDE IV inhibitor containing the dihydrate; and a process for producing the dihydrate by treating anhydride crystals of 4-[[9-[(3-cyclopentyloxy-4-methoxy) benzyl]-6,8-dimethyipurin]-2-yl-3-oxypropyl] pyridine N-oxide under anhydrous conditions.
According to still another aspect, the invention provides a compound represented by the following general formula (I)
where X is a halogen atom or a group represented by —S—(CH
2
)
n
—A, —SO—(CH
2
)
m
—B, —SO
2
—(CH
2
)
m
—B, —OSO
2
—(CH
2
)
m
—B, —OCO—(CH
2
)
m
—B or —OPO(OR)—(CH
2
)
m
—B (wherein n represents an integer of 0-4, A represents an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, m represents an integer of 0-4, B represents an optionally substituted alkyl group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, and R represents an optionally substituted alkyl group), which is useful as an intermediate in the production of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide.
The invention further provides a compound represented by the following general formula (II):
where X is as defined above. This compound is also useful as an intermediate in the production of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide.
BEST MODE FOR CARRYING OUT THE INVENTION
The dihydrate of the invention can be produced by treatment under hydrous conditions of anhydride crystals obtained by the process described in Example 5 of WO99/24432, for example. The hydrous conditions are not particularly restricted, and as an example, the production may be carried out by a process of dissolving the anhydride crystals in a hydrous organic solvent (such as hydrous isopropyl alcohol, for example) with warming and then cooling to room temperature for crystallization; a process of allowing the anhydride to stand for several weeks at room temperature under conditions with a relative humidity of 75% or greater; or a process of adding water to the anhydride and heating with warming (for example, about 12 hours at 70° C.) and then cooling to room temperature. The dihydrate production process of the invention is of course not limited to treatment under these hydrous conditions.
The dihydrate of the invention has a specific inhibitory effect against PDE IV, and is useful as an active ingredient in drugs for asthma, COPD and/or other inflammatory diseases. In particular, the dihydrate of the invention is stable and has excellent physicochemical properties as an active ingredient for drugs. When the dihydrate of the invention is used as an active ingredient in a drug, the dihydrate itself may be administered directly or as a pharmaceutical composition prepared using pharmacologically acceptable formulating additives. The composition and form of the pharmaceutical composition is determined based on the route of administration, the administration plan, etc. For example, it may be prepared in the form of granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions or the like for oral administration or in the form of an injection for intravenous administration, intramuscular administration or subcutaneous administration. It may also be in the form of powders for injection and prepared at the time of use. Alternatively, it may be a composition for parenteral administration, such as a transdermal agent or transmucosal agent.
For the manufacturer of pharmaceutical compositions suitable for oral, enteral, parenteral, or topical administration, organic or inorganic pharmaceutical additives can be used. These additives may be a solid or liquid, and examples include carriers and diluents for pharmaceutical formulations and the like. As excipients used for the manufacture of solid pharmaceutical compositions, for example, lactose, sucrose, starch, talc, cellulose, dextrin and the like can be used. For the manufacturer of liquid pharmaceutical compositions for oral administration such as emulsions, syrups, suspensions and solutions,
Ohshima Masahiro
Sekiya Kouichi
Takemiya Akihiro
Berch Mark L
Greenblum & Bernstein P.L.C.
Mitsubishi Chemical Corporation
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