Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-04-14
1998-07-14
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3155
Patent
active
057804648
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn. 371 as a United States National Phase Application of International Application No. PCT/US95/12829, filed 13 Oct. 1995 which claims priority from GB 9420748.7, filed 14 Oct. 1994.
This invention relates to pharmaceutical compositions containing novel 1,5-benzodiazepine derivatives which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals.
Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxyl terminal octapeptide, CCK-8 (also a naturally occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH.sub.2 (CCK4) which is the common structural element shared by both CCK and gastrin.
CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body. There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system.
The CCK-A receptor, commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.
The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.
U.S. Pat. No. 4,988,692, to Gasc, et al. describes a group of 3-acylamino 1-alkyl-5-phenyl 1,5-benzodiazepine derivatives which behave as cholecystokinin antagonists to reverse or block the effects of the endogenous hormone at its receptors.
U.S. Pat. No. 4,490,304 and PTC applications No's W090/06937 and W091/19733 describe peptide derivatives that exhibit CCK-A agonist activity. Such compounds have been disclosed for appetite regulation as well as the treatment and/or prevention of gastrointestinal disorders or disorders of the central nervous in animals and, more particularly, humans.
We have now discovered that the bioavailability following oral administration of a novel group of 3-amino 1,5-benzodiazepine compounds which exhibit a agonist activity for the CCK-A receptor may be significantly increased if the compound is administered in a solid dosage form the outer layer of which is an enteric coating or shell.
The present invention thus provides a pharmaceutical formulation in solid dosage form for oral administration which comprises a compound of the general Formula (I) ##STR2## and physiologically salts and solvate thereof wherein: X is either hydrogen, trifluoromethyl, alkyl, C.sub.1-4 alkylthio, --O(C.sub.1-4 alkyl) or halogen; ##STR3## R.sup.2 is either: (1) a heterocycle linked at its 2- position and selected from pyrrole, tetrahydropyrrole, indole, benzofuran, thiophene, benzothiophene, indoline, quinoline or 4-oxobenzopyran and wherein said pyrrole, tetrahydropyrrole, indole or indoline may optionally be substituted on the ring nitrogen thereof by the group R.sup.8 as defined hereunder and said indole, indoline, quinoline, benzofuran, benzothiophene
REFERENCES:
patent: 5646140 (1997-07-01), Sugg et al.
Brink Robert H.
Glaxo Wellcome Inc.
Jarvis William R. A.
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