Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-10-19
1997-08-19
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 72, 536 73, 536 74, A61K 3170, C07M 1708
Patent
active
056588887
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to erythromycin derivatives and their salts which act to stimulate the contractile motility of alimentary canals of mammals, and are thus useful as stimulants for the contractile mobility of alimentary canals.
DESCRIPTION OF THE PRIOR ART
On the basis of differences in their mechanisms, prokinetic agents are roughly classified into 4 groups: direct cholinergic drugs such as aclatonium napadisilate; indirect cholinergic drugs such as cisapride; dopamine blockers such as domperidone; and opiate agonists such as trimebutine maleate, and are widely used as therapeutic agents for dysfunction of enterokinesis, particularly for symptoms of digestive organs such as, for example, gastrointestinal complaints due to hypokinesia. However, these drugs have adverse effects such as extrapyramidal 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 fluor, 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 of 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, and EM-523, one of the derivatives, is being developed as a prokinetic agent (Japanese Patent Application Disclosure SHO No. 60-218321, Japanese Patent Application Disclosure SHO No. 61-87625, Japanese Patent Application Disclosure SHO No. 63-99016, Japanese Patent Application Disclosure SHO No. 63-99092 and The Journal of Pharmacology and Experimental Therapeutics, vol. 251, No. 2, pp. 707-712, 1989).
EM-523 is, however, unstable in the presence of an acid, and therefore it is supposed that its action diminishes due to the decomposition thereof by gastric acid when used via oral administration. In view of these facts, we the present inventors have conducted research in order to find erythromycin derivatives which are acid resistant and capable of being administered orally, and as a result, we have found that the non-documented novel erythromycin derivatives described hereunder have such properties and action as mentioned above, thus eventually completing the present invention based on this finding.
DISCLOSURE OF THE INVENTION
That is, the present invention relates to the compounds represented by the following formula (I): ##STR2##
wherein R.sub.1 is a hydrogen atom or an acyl group;
R.sub.2 and R.sub.3 may be the same or different, and each represents a hydrogen atom, hydroxyl group, acyloxy group or amino group, or, in combination, they represent .dbd.O or .dbd.NOR.sub.10, where R.sub.10 represents a hydrogen atom or lower alkyl group;
R.sub.4 represents a hydrogen atom or lower alkyl group; and
Y represents --NR.sub.5 R.sub.6 or --N.sup.+ R.sub.7 R.sub.8 R.sub.9 X.sup.-, where R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 may be the same or different, and each represents a hydrogen atom or an unsubstituted or substituted lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group or 3-7-membered heterocyclic group comprising an oxygen atom, nitrogen atom or sulphur atom as an heteroatom, and X represents an anion, where R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8 may form an azacycloalkyl group together with the neighboring nitrogen atom, respectively, and salts thereof.
Throughout the specification and the claims, the acyl group means formyl group, acetyl group, propionyl group, butyryl grou
REFERENCES:
patent: 4677097 (1987-06-01), Omura et al.
Omura et al., "Macrolides with Gastrointestinal Motor Stimulating Activity", Journal of Medicinal Chemistry, vol. 30, No. 11, pp. 1941-1943, Nov. 1987.
Therapeutic Research, vol. 11, No. 11, pp. 58(3548)-69(3559), 1990.
Sunazuka et al, Mortilides, Macrolides with Gastrointestinal Motor Stimulating Activity. II. Quaternary N-Substituted Derivatives of 8,9-Anhydroerythromycin A 6,9-Hemiacetal and 9,9-Dihydroerythromycin A 6,9-Epoxide, Chem. Phar. Bull., vol. 37 No. 10, pp. 2701-2709, 1989.
Tsuzuki et al, Motilides, Macrolides with Gastrointestinal Motor Stimulating Activity. I.O-Substituted and Tertiary N-Substituted Derivatives of 8,9-Anhydroerythromycin A 6,9-Hemiacetal, Chem. Pharm. Bull., vol. 37, No. 10, pp. 2687-2700, Oct. 1989.
Koga Hiroshi
Sato Tsutomu
Takanashi Hisanori
Chugai Seiyaku Kabushiki Kaisha
Peselev Elli
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