Benzodiazepine derivatives useful as CCK-receptor antagonists

Details Benzodiazepine derivatives useful as CCK-receptor antagonists Benzodiazepine derivatives useful as CCK-receptor antagonists

1994-09-14

1997-11-18

Bond, Robert T.

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

Organic compounds

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

514 221, C07D24334, A61K 3155

Patent

active

056889437

DESCRIPTION:

BRIEF SUMMARY
This application is the U.S. National stage of International Application PCT/GB93/00404, filed 26 Feb. 1993.
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 pentagastrin (V. J. Lotti & R. S. L. Chang, Eur. J. Pharmacol. 162, 273-280, 1989). 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.
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 substituent at position 1 of the benzodiazepine nucleus. The present invention includes compounds of better 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 derivate of formula I, or a pharmaceutically acceptable salt thereof: ##STR1## wherein (a) R.sup.1 is --CH.sub.2 CHOH(CH.sub.2).sub.a R.sup.4 or a ketone group --CH.sub.2 CO(CH.sub.2).sub.a R.sup.5 in which a is 0 or 1 and R.sup.4 and R.sup.5 are selected from alkyl and cycloalkyl groups and saturated heterocyclic groups optionally substituted at a hetero-atom; and heterocyclic residues; and halogen and hydrogen atoms.
Herein all "alkyl", "cycloalkyl", "acyl" and "alkoxy" groups are preferably of up to 8 carbon atoms, and "halogen" may for example be fluorine, chlorine, bromine or iodine. The aromatic residues herein (R.sup.2, R.sup.3) may be substituted; they are preferably monocyclic, usually of 5 or 6 ring atoms; when heterocyclic they may for example have 1, 2 or 3 hetero ring atoms. Preferably at least one of R.sup.2 and R.sup.3 is unsubstituted, monosubstituted or disubstituted phenyl or unsubstituted, monosubstituted or disubstituted 2-, 3-, or 4-pyridyl. Preferably one (most preferably each) of W and X is a hydrogen atom.
Preferably R.sup.4 is alkyl (e.g. C.sub.4 -C.sub.7, linear or branched); or is cyclo- or polycycloalkyl (which may be unsubstituted or substituted with one or more alkyl groups) and contains e.g. from 3 to 8 carbon atoms; or is of formula II or III: ##STR2## in which R.sup.6 is H, alkyl (e.g. C.sub.1 -C.sub.3) or --CO-alkyl (where the alkyl is e.g. C.sub.1 -C.sub.3) and b is 1 or 2. Preferably R.sup.5 is alkyl (e.g. C.sub.1 -C.sub.3) or as defined for R.sup.4.
Examples of alkyl and cycloalkyl groups include tert-butyl, cyclopentyl and cyclohexanemethyl.
Examples of saturated heterocyclic groups include pyrrolidyl and tetrahydropyranyl. Examples of substituents at the heteroatom include simple alkyl and acyl groups (e.g. of up to 3,4,5 or 6 carbon atoms, such as formyl, acetyl, etc).
Examples of substituents on the aromatic residues (R.sup.2, R.sup.3) include halogen atoms (e.g. fluorine, chlorine, etc); hydroxyamino, nitro, carboxylic acid and cyano groups; and alkyl, alkoxy, alkylamino and dialkylamino groups in which the or each alkyl component is preferably of up to 6 (e.g. up to 3) carbon atoms (methyl; ethyl etc.); for substituted R.sup.2, meta-substitution is preferred.
Most preferably R.sup.2 is unsubstituted phenyl; phenyl having a meta substituent chosen from F, Cl, Br, OH, OCH.sub.3, NH.sub.2, NMe.sub.2, NO.sub.2, Me, --(CH.sub.2).sub.c --CO.sub.2 H, CN, NHMe, NMeEt, NEt.sub.2, CH.sub.2 NMe.sub.2, NHCHO and --(CH.sub.2).sub.c --SO.sub.3 H where c is 0-2; or 2-, 3- or 4-pyridyl optionally with a substituent selected from F, Cl, CH.sub.3 and CO.sub.2 H.
Most p

REFERENCES:
patent: 4820834 (1989-04-01), Evans et al.
Lotti et al. "A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin . . . ", European Jnl. of Pharm., 162:273-280, 1989.
Bock, et al. "Development of 1,4-Benzodiazepine Cholecystokinin Type B Antagonists", Jnl. Med. Chem., 36:4276-4292, 1993.
Bock, et al. "Benzodiazepine Gastrin and Brain Cholecystokinin Receptor Ligands: L-356,260", Jnl. Med. Chem., 32:13-16, 1989.

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