Perfume compositions – Perfume compositions – Ring containing active ingredient
Patent
1996-11-04
1998-03-31
Bond, Robert T.
Perfume compositions
Perfume compositions
Ring containing active ingredient
540518, C07D24312, A61K 3155
Patent
active
057338671
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 94/02352, filed Jul. 18, 1994, which claims priority of British Application 9315018.3 filed 26 Jul. 1993.
This invention relates to novel 1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
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 to thirty-three amino acids in its originally isolated forms, its carboxy terminal octapeptide sulphate, 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 (CCK-4), which is the common structual 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. CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal and central nervous systems of animals, and more particularly humans.
U.S. Pat. No. 4,988,692 describes a group of 3-acylamino 1-alkyl-5-phenyl 1,5-benzodiazepine derivatives as cholecystokinin antagonists. Further the specification teaches that the compounds have a significantly greater affinity for the CCK-A receptor over the CCK-B receptor.
We have now found a novel group of 3-substituted 1,5-benzodiazepine compounds which are potent and specific antagonists of gastrin and/or CCK and in particular antagonists of gastrin and/or CCK at the CCK-B receptor which exhibit a particularly advantageous profile of activity.
Thus, the invention provides compounds of general formula (I) ##STR2## wherein R.sup.1 represents a phenyl, C.sub.3-7 cycloalkyl, C.sub.7-11 bridgedcycloalkyl or C.sub.1-6 alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C.sub.1-6 alkoxycarbonyl, C.sub.3-7 cycloalkyl, or C.sub.3-7 bridgedcycloalkyl group; R.sup.5, O(CH.sub.2).sub.p R.sup.6, or (CH.sub.2).sub.n CO.sub.2 R.sup.11 ; hydroxy; carboxyl and/or amino groups or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C.sub.1-4 alkyl or hydroxy groups. R.sup.9 ; ester group; by one or more hydroxy, carboxyl and/or amino groups or R.sup.8 and R.sup.9 together with the nitrogen atom heterocylic group examples of suitable groups include morpholino, to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C.sub.1-4 alkyl or hydroxy groups; metabolically labile ester group; m is zero, 1 or 2; pharmaceutically acceptable salts thereof.
It will be appreciated that compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 3-position of the diazepine ring) and the compounds of the invention thus include all stereoisomers and mixtures thereof including the racemates.
In the compounds of formula (I) `alkyl` when used as a substituent or part of a substituent group means that the group may be straight or branched. Thus, C.sub.1-6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl.
For the group R.sup.1 the term C.sub.3-7 cycloalkyl as a group or part of a group refers to a monocyclic alkyl group such as cycl
Curotto Giovanni
Pellegatti Mario
Polinelli Stefano
Bond Robert T.
Glaxo Wellcome SpA
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