Process of preparing benzodiazepine compounds useful as antagoni

Details Process of preparing benzodiazepine compounds useful as antagoni Process of preparing benzodiazepine compounds useful as antagoni

1996-05-02

1998-03-17

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540480, 514183, 514212, 514221, C07D24324, C07D40302, A61K 3133, A61K 3155

Patent

active

057288291

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/01859, filed Aug. 25, 1994, published as WO95/06040 Mar. 2, 1995.
This invention relates to benzodiazepine derivatives which are useful as drugs exhibiting antagonism at the gastrin and/or CCK-B receptor, and to their production.
Many benzodiazepine derivatives have been described in the course of development of psychotropic drugs which act as agonists at the "benzodiazepine receptor" in the central nervous system. More recently benzodiazepine derivatives have been described which act as antagonists at the CCK-A (cholecystokinin-A) and CCK-B receptors. It was further reported that those compounds which were selective antagonists for the CCK-B receptor were able to reduce the secretion of gastric acid in response to the administration of pentagasuin (V J Lotti & R S L Chang, Eur J Pharmacol 1989, 162, 273-280). Examples of benzodiazepine derivatives which act as antagonists at the CCK-B receptor are disclosed in, for example, U.S. Pat. No. 4,820,834.
Most of the compounds of the present invention are novel. They differ from the compounds described in U.S. Pat. No. 4,820,834, particularly in the nature of the substituents at positions 1 and 5 of the benzodiazepine nucleus. The present invention includes compounds of superior pharmacological characteristics than those described in U.S. Pat. No. 4,820,834; preferred compounds of the invention have a higher affinity for the CCK-B receptor and/or discriminate more selectively between the CCK-B and CCK-A receptors than the previously described compounds.
The present invention provides a benzodiazepine derivative of formula X, or a pharmaceutically acceptable salt thereof: ##STR3## wherein: (a) R.sup.4 is an alkyl, cycloalkyl or aryl group; CH.sub.3, OCH.sub.3, NO.sub.2, NHCHO, CO.sub.2 H, CN and NR.sup.11 R.sup.12, where R.sup.11 and R.sup.12 are independently selected from H and alkyl (C.sub.1 -C.sub.5) or together with the N they form a cyclic structure XI, ##STR4## and wherein a is 1-6. heterocycle containing at least two heteroatoms of which at least one is nitrogen.
Herein all `alkyl` and `cycloalkyl` groups are preferably of up to 8 carbon atoms. When R.sup.4 is an aromatic residue it may be mono or disubstituted, and it is preferably monocyclic.
Preferably the substituent R.sup.10 is at the meta position of the phenyl ring.
Preferably R.sup.2 is an unsubstituted or monosubstituted heterocycle containing two heteroatoms of which at least one is nitrogen.
Most preferably R.sup.4 is tert-butyl or 2-, 3- or 4-methylphenyl.
Most preferably R.sup.2 is selected from 2-pyrimidine, 4-pyrimidine, 2-pyrazine, 6-pyridazine, 2-thiazole, 4-thiazole, 2-oxazole, 4-oxazole, 3-pyrazole, 5-pyrazole, 3-isoxazole, 3-isothiazole, 2-imidazole, 4-imidazole, 5-imictazole, 2-(N-methyl)imidazole, 4-(N-methyl)imidazole and 5-(N-methyl)imidazole.
The compounds of this invention all have at least one stereogenic centre and so can exist as optical isomers. It should be understood that these isomers, either separately or as mixtures, are included within the scope of this invention. In preferred compounds according to the invention, the absolute configuration at the 3-position of the benzodiazepine ring is R (as shown in XII). ##STR5##
Amongst preferred compounds according to the invention are those listed below and salts thereof. Some of the compounds are exemplified hereinafter as indicated against the individual compounds concerned.


LIST A
1H- 1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl) area (Example 3); 1H- 1,4-benzodiazepin-3-yl)-N'-(3-dimethylaminophenyl)urea(Example 4); utylcarbonylmethyl-2,3-dihydro-5-(2-(1-methyl)imldazolyl)-2-oxo-1H-1,4-ben zodiazepin-3-yl)-N'-(3-methylphenyl)urea(Example 1 ); 1-tert-Butylcarbonylmethyl-2,3-dihydro-5-(2-(1-methyl)imidazolyl)-2-oxo-1H -1,4-benzodiazepin-3-yl)-N'-(3-dimethytaminophenyl)urea(Example 2); 1-tert-Butylcarbonylmethyl-2,3-dihydro-5-(2-imidazolyl)-2-oxo-1H-1,4-benzo diazepin-3-yl)-N'-(3-methylphenyl)urea(Example 7); N-((3RS)-1-tert-Butylcarbonylmethyl-2,3-dihydro-5-(2-imidazolyl)-2-oxo-1H- 1,4-ben

REFERENCES:
patent: 4820834 (1989-04-01), Evans et al.
Fryer et al., "The Chemistry of Heterocyclic Compounds", vol. 50, Chapter VII, (1991) pp. 631-642.
Lotti et al., "A New Potent and Selective Non-Peptide Gastrin Antagonist and Brain Cholecystokinin Receptor (CCK-B) Lingand: L-365,260", E. Jour. Pharmacology, vol. 162, (1989) pp. 273-280.

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