Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1999-05-25
2000-08-08
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 72, 536 74, A61K 3170, C07H 1708
Patent
active
061002399
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a 13-membered ring macrolide compound or a salt thereof which acts to stimulate the contractile motility of alimentary canals of mammals and is thus useful as a stimulant for the contractile motility of alimentary canals.
BACKGROUND ART
On the basis of differences in their mechanisms, prokinetic agents are roughly classified into 4 groups: direct cholinergic drugs (aclatonium napadisilate); indirect cholinergic drugs (cisapride); dopamine blockers (domperidone); and opiate agonists (trimebutine maleate), and are widely used as therapeutic agents for dysfunction of enterokinesis, particularly for symptoms of digestive organs such as gastrointestinal complaints due to hypokinesia. However, these drugs have adverse effects such as extra-pyramidal symptoms or stimulation of prolactin release caused by the dopamine blocking action. In addition, it is known that the action of these drugs, which is different from that of a spontaneous, physiological movement propagating from the upper gastrointestinal tract to the lower gastrointestinal tract, often leads to the onset of adverse effects such as diarrhea, emesis or the like.
On the other hand, motilin is known as a gastrointestinal hormone which stimulates the contractile motility of alimentary canals, but its supply by extraction from natural sources or by chemical synthesis has not been satisfactory, and thus a large supply thereof has been difficult to secure. Further, motilin is a peptide consisting of 22 amino acids, so the development of an oral preparation comprising it has been difficult.
In recent years, erythromycin and its derivatives have been found to have a powerful stimulating activity with respect to the contractile motility of alimentary canals, of which activity is similar to that of motilin (see Japanese Patent Application Disclosures SHO No. 60-218321, SHO No. 61-87625, SHO No. 63-99016, SHO No. 63-99092, HEI No. 6-56873, and The Journal of Pharmacology and Experimental Therapeutics, vol. 251, No. 2, pp. 707-712, 1989). However, each of these compounds is a 14-membered ring macrolide compound, and a 13-membered ring macrolide compound has never been known.
The present inventors have intensively studied to provide a substance which is capable of stimulating the contractile motility of alimentary canals and of being supplied with a large amount. As a result, they have succeeded in synthesizing a novel 13-membered ring macrolide compound using antibiotic erythromycin A as a starting material. They have investigated the pharmacological activity of the compound, and have found that the novel 13-membered ring macrolide has a powerful stimulating activity with respect to the contractile motility of alimentary canals.
Accordingly, an object of the present invention is to provide a novel 13-membered ring macrolide which is capable of stimulating the contractile motility of alimentary canals and of being supplied with a large amount.
DISCLOSURE OF THE INVENTION
The present invention relates to a compound represented by the formula (I): ##STR2## wherein R.sub.1 represents a hydrogen atom or an acyl group; R.sub.2 and R3 may be the same or different, and each represents a hydrogen atom, a hydroxyl group, an acyloxy group or an amino group, or R.sub.2 and R.sub.3 in combination represent .dbd.O or .dbd.NOR.sub.1 ; where R.sub.11 represents a hydrogen atom or a lower alkyl group; R.sub.4 and R.sub.5 may be the same or different, and each represents a hydrogen atom or a hydroxyl group, or R.sub.4 and R.sub.5 in combination represent .dbd.O or .dbd.NOR.sub.11 ; Y represents --N(R.sub.6) (R.sub.7) or --N.sup.+ (R.sub.8) (R.sub.9) (R.sub.10)X.sup.- ; where R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 may be the same or different, and each represents a hydrogen atom, an acyl group, an unsubstituted or substituted lower alkyl group, an unsubstituted or substituted lower alkenyl group, an unsubstituted or substituted lower alkynyl group, an unsubstituted or substituted cycloalkyl group, or a monocyclic, saturated,
REFERENCES:
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C. Burnell-Curty et al, "A Novel . . . Contraction", J. Org. Chem., vol. 61, No. 15, (1996) pp. 5153-5154.
Ataka Kikuo
Miyata Hiroyuki
Takama Akira
Chugai Seiyaku Kabushiki Kaisha
Lambkin Deborah C.
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