Novel 2-substituted-aminomethyl-1,4-benzodiazepines which have been found to be antagonists of the function of cholecystokinins (CCK), to the preparation of these compounds, and to the use of these compounds to antagonize the function of CCK, which antagonism is useful, e.g., for the treatment and prevention of disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals, especially of humans.

The present invention is directed to novel 
2-substituted-aminomethyl-1,4-benzodiazepines which have been found to be 
antagonists of the function of cholecystokinins (CCK), to the preparation 
of these compounds, and to the use of these compounds to antagonize the 
function of CCK, which antagonism is useful, e.g., for the treatment and 
prevention of disorders of the gastrointestinal, central nervous and 
appetite regulatory systems of mammals, especially of humans. 
BACKGROUND OF THE INVENTION 
Cholecystokinins (CCK) are neuropeptides (see, Mutt and Jorpes, Biochem. 
J., 125, 678 (1971)) which exist in both gastrointestinal tissue and the 
central nervous system (V. Mutt, Gastrointestinal Hormones, G. B. J. 
Glass, ed., Raven Press, N.Y., 1980, p. 169), and include e.g., CCK-33, a 
neuropeptide of thirty-three aminoacids and its carboxylterminal 
octapeptide, CCK-8. These molecules are believed to be physiological 
satiety hormones and, therefore, may play an important role in appetite 
regulation (G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. 
Stellar, Eds., Raven Press, New York, 1984, p. 67). 
In addition, CCK's stimulate colonic motility, gall bladder contraction, 
and pancreatic enzyme secretion, and inhibit gastric emptying. CCK's 
reportedly also co-exist with dopamine in certain mid-brain neurons, and 
thus may additionally play a role in the functioning of dopaminergic 
systems in the brain, as well as serve as neurotransmitters in their own 
right. See: A. J. Prange et al., "Peptides in the Central Nervous System", 
Ann. Repts. Med. Chem., 17, 31, 33 (1982), and references cited therein; 
J. A. Williams, Biomed. Res., 3, 107 (1982); and J. E. Morley, Life Sci., 
30, 479 (1982). 
Antagonists to CCK have been useful for preventing or treating CCK-related 
disorders of the gastrointestinal, central nervous and appetite regulatory 
systems of mammals, especially of humans. Three distinct chemical classes 
of CCK-receptor antagonists have been reported. The first class comprises 
derivatives of cyclic nucleotides, of which dibutyryl cyclic GMP has been 
shown to be the most potent by detailed structure-function studies (see, 
N. Barlos et al., Am. J. Physiol., 242, G161 (1982) and P. Robberecht et 
al., Mol. Pharmacol., 17, 268 (1980)). The second class comprises peptide 
antagonists which are C-terminal fragments and analogs of CCK, of which 
both shorter (Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2) and longer 
(Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) C-terminal fragments of 
CCK can function as CCK antagonists, according to recent 
structure-function studies (see, R. T. Jensen et al., Biochim. Biophys. 
Acta., 757, 250 (1983), and M. Spanarkel et al., J. Biol. Chem., 258, 6746 
(1983)). Then the third class of CCK receptor antagonists comprises the 
amino acid derivatives: proglumide, a derivative of glutaramic acid, and 
the N-acyl tryptophans, including para-chlorobenzoyl-L-tryptophan 
(benzotript), (see, W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 
6304 (1981) and R. T. Jensen et al., Biochim. Biophys. Acta., 761, 269 
(1983)). All of these compounds, however, are relatively weak antagonists 
of CCK (IC.sub.50 : generally 10.sup.-4 M, but down to 10.sup.-6 M in the 
case of the peptides) and the peptide CCK-antagonists have substantial 
stability and absorption problems. 
It was, therefore, an object of this invention to identify substances which 
more effectively antagonize the function of cholecystokinins in disease 
states in mammals, especially in humans. It was another object of this 
invention to prepare novel compounds which inhibit cholecystokinins and 
which display opiate agonism and analgesic activity. It was still another 
object of this invention to develop a method of preparing these novel 
cholecystokinin-antagonists. It was also an object of this invention to 
develop a method of antagonizing the function of cholecystokinins in 
disease states in mammals. It was still a further object of this invention 
to develop a method of preventing or treating disorders of the 
gastrointestinal, central nervous and appetite regulatory systems of 
mammals, especially of humans. 
SUMMARY OF THE INVENTION 
The instant invention is directed to certain 
2-substituted-aminomethyl-1,4-benzodiazepines, which have been found to be 
antagonists of the function of cholecystokinins (CCK), to the preparation 
of these compounds, and to the use of these compounds in the treatment and 
prevention of disorders of the gastrointestinal, central nervous and 
appetite regulatory systems of mammals, especially of humans. 
DETAILED DESCRIPTION OF THE INVENTION 
The 2-substituted-aminomethyl-1,4-benzodiazepines of this invention are 
those of formula I: 
##STR1## 
wherein: X=one or two of the substituents: F, Cl or Br; C.sub.1 -C.sub.4 
-straight- or branched-chain alkyl, including methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, and t-butyl; C.sub.1 -C.sub.4 -alkoxy; C.sub.1 
-C.sub.4 -alkylthio; hydroxy; nitro; cyano; amino; or trifluoromethyl, and 
may be attached at either or both the 7- and/or 8-positions; 
Y=independently, the same as X, and may be attached at any of positions 2-6 
on the aromatic ring; 
R=H, C.sub.1 -C.sub.4 -alkyl, cyclo-C.sub.3 -C.sub.5 -alkyl, C.sub.1 
-C.sub.4 -alkenyl, or acetyl; 
R.sup.1 =H, C.sub.1 -C.sub.4 -alkyl or cyclo-C.sub.3 -C.sub.5 -alkyl; 
##STR2## 
or of the formula II: 
##STR3## 
wherein: X Y, R and R.sup.1 are as defined above; and R.sup.21 =R.sup.2 as 
defined above, including wherein R.sup.5, as defined above, also=pyridine, 
##STR4## 
where (CH.sub.2).sub.n is attached at the 2-, 3- or 4-position and n and 
X are as defined above; 
##STR5## 
where the point of attachment is at any position on the ring and n and X 
are as defined above; or 
##STR6## 
where the point of attachment is at the 2- or 3-position and W=H, 
straight or branched chain C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 
-alkoxy, nitro, F, Cl or Br, and Z is as defined above, 
the optical isomers of formula I, or pharmaceutically-acceptable salts of 
the compounds of formulae I or II. 
Preferred compounds of formula I according to the instant invention include 
those in which X is F or Cl; R is H or C.sub.1 -C.sub.4 -alkyl; R.sup.1 is 
H; R.sup.2 is 
##STR7## 
wherein R.sup.3 is -(CH.sub.2)-phenyl or (CH.sub.2)-2 or 3-indole, and 
R.sup.4 is C.sub.1 -C.sub.4 -alkyl; or R.sup.2 is 
##STR8## 
where R.sup.6 is (CH.sub.2)-2-indole or (CH.sub.2)-3-indole and R.sup.7 is 
H, COOR.sup.8, or 
##STR9## 
wherein R.sup.8 is C.sub.1 -C.sub.4 -alkyl; or R.sup.5 is 
##STR10## 
wherein Z is O, S or NR and X and R are as defined above; or R.sup.5 is 
##STR11## 
wherein Z is as defined above; or R.sup.5 is -CHOHC.sub.6 H.sub.5. 
Preferred compounds of formula II according to the instant invention 
include those in which X is F or Cl; R is H or C.sub.1 -C.sub.4 -alkyl; 
R.sup.1 is H; R.sup.2 is 
##STR12## 
wherein R.sup.3 is -(CH.sub.2)-phenyl or (CH.sub.2)-2 or 3-indole, and 
R.sup.4 is C.sub.1 -C.sub.4 -alkyl; or R.sup.2 is 
##STR13## 
wherein R.sup.5 = 
##STR14## 
where R.sup.6 is (CH.sub.2)-2-indole or (CH.sub.2)-3-indole and R.sup.7 is 
H, COOR.sup.8, or 
##STR15## 
wherein R.sup.8 is C.sub.1 -C.sub.4 -alkyl; or R.sup.5 is 
##STR16## 
wherein Z is O, S or NR and X, R and n are as defined above; or R.sup.5 is 
##STR17## 
wherein Z is as defined above; or R.sup.5 is -CHOHC.sub.6 H.sub.5 ; or 
R.sup.5 is 
##STR18## 
wherein W and Z are as defined above; R.sup.5 is 
##STR19## 
wherein X is as defined above. 
Particularly preferred compounds of formula I include 
1-methyl-2-(2'-indolecarbonyl)aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro- 
1H-1,4-benzodiazepine, 
1-methyl-2-(4-thianaphthenemethylcarbonyl)aminomethyl-5-(2'-fluorophenyl)- 
2,3-dihydro-1H-1,4-benzodiazepine 
1-methyl-2-(2-L-hydroxy-2-phenylacetyl)aminomethyl-5-(2'-fluorophenyl)-2,3 
-dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-[1-(S)-1-methoxycarbonyl-2-phenylethylamino] 
methyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-(3'-trifluoromethylphenyl)aminomethyl-5-(2'-fluorophenyl)-2,3-d 
ihydro-1H-1,4-benzodiazepine, 
1-methyl-2-[2-((1,1-dimethylethoxy)carbonyl)amino-3-(1H-indol-3-yl)propano 
yl]aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-[(2-methylpropoxy)carbonyl]aminomethyl-5-(2'-fluorophenyl)-2,3- 
dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-[2-amino-3-(1H-indol-3-yl)propanoyl]aminomethyl-5-(2'-fluorophe 
nyl)-2,3-dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-(2-methoxy-2-trifluoromethyl-2-phenylacetyl)aminomethyl-5-(2'-f 
luorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine, 
1-methyl-2-[2-(S)-((1,1-dimethylethoxy)carbonyl)amino-3-acetamidomethylmer 
captopropanoyl]aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiaz 
epine, 
1-methyl-2-benzylsuccinoylaminomethyl-5-(2'-fluorophenyl)2,3-dihydro-1H-1, 
4-benzodiazepine, and 
1-methyl-2-(acetamidomethylmercaptoacetyl)aminomethyl-5-(2'-fluorophenyl)- 
2,3-dihydro-1H-1,4-benzodiazepine. 
Particularly preferred compounds of formula II include 
1-methyl-2-(2'-indolecarbonyl)aminomethyl-5-(2'-fluorophenyl)-2,3,4,5-tetr 
ahydro-1H-1,4-benzodiazepine, 
1-methyl-2-(4-thianaphthenemethylcarbonyl)aminomethyl-5-(2'-fluorophenyl)- 
2,3,4,5-tetrahydro-1H-1,4-benzodiazepine, 
1-methyl-2-(2-L-hydroxy-2-phenylacetyl)aminomethyl-5-(2'-fluorophenyl)-2,3 
,4,5-tetrahydro-1H-1,4-benzodiazepine, 
1-methyl-2-(1H-indol-3-yl)methylcarbonylaminomethyl-5-(2'-fluorophenyl)-2, 
3,4,5-tetrahydro-1H-1,4-benzodiazepine, 
1-methyl-2-(3-thiophenecarbonyl)aminomethyl-5-(2'-fluorophenyl)-2,3,4,5-te 
trahydro-1H-1,4-benzodiazepine, and 
1-methyl-2-p-chlorobenzoylaminomethyl-5-(2'-fluorophenyl)-2,3,4,5-tetrahyd 
ro-1H-1,4-benzodiazepine and 
1-methyl-2-o-fluorobenzoylaminomethyl-5-(2'-fluorophenyl)-2,3,4,5-tetrahyd 
ro-1H-1,4-benzodiazepine. 
The pharmaceutically-acceptable salts of the compounds of the instant 
invention include the conventional non-toxic salts or the quarternary 
ammonium salts of the compounds of this invention formed, for example, 
from non-toxic inorganic or organic acids. For example, such conventional 
non-toxic salts include those derived from inorganic acids, such as 
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the 
like; and the salts prepared from organic acids such as acetic, propionic, 
succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, 
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, 
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, theophylline, 
8-chlorotheophylline, p-aminobenzoic, p-acetamidobenzoic, methanesulfonic, 
ethane disulfonic, oxalic, isethionic, and the like. 
Certain 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine derivatives 
were disclosed in U.S. Pat. No. 4,325,957. However, those derivatives were 
suggested as simply possessing strong analgesic activities, in addition to 
psychopharmacological, diuretic and antiarrythmic properties. 
Additionally, the compound, where X=H, Y=2-F, R=CH.sub.3, R.sup.1 =H and 
R.sup.2 =thiophene-3-carbonyl, has been reported to be an opiate-agonist 
with selectivity for the kappa receptor (see, D. Roemer et al., Nature, 
298, 759 (1982)) and its (-)-enantiomer is preferred for high analgesic 
activity (see, H. Kley et al., Eur. J. Pharmacol., 87, 503 (1983)). This 
compound has also been shown to increase food intake in rats (See J. E. 
Morley et al., Eur. J. Pharmacol., 93, 265 (1983)). However, none of the 
compounds of the instant invention has been previously disclosed or 
suggested and it has not been previously suggested that even the 
previously-known, related compounds would antagonize the function, 
particularly the excessive function, of cholecystokinins in a disease 
state in mammals. 
Compounds according to formula (I) of the instant invention may be produced 
by either of two methods, viz: 
##STR20## 
wherein X.sup.1 =OH, Cl, 
##STR21## 
and X.sup.2 =Cl, Br, I, OSO.sub.2 C.sub.1 -C.sub.4 -alkyl, OSO.sub.2 
-phenyl or OSO.sub.2 -substituted phenyl; or 
##STR22## 
According to method MI, 2-substituted-aminomethyl-1,4-benzodiazepine 
derivatives of formula I may be prepared by acylating an amino compound of 
formula III, or an acid addition salt thereof, with a carbonic acid or a 
reactive carbonic acid derivative. (The preparation of 
2-aminomethyl-1,4-benzodiazepine derivatives of formula III which are used 
as starting materials in the present invention may be carried out in a 
known manner according to processes described in U.S. Pat. No. 4,325,957 
and German Offenlegungsschrift No. 2,221,558.) The acylation is carried 
out in an aprotic solvent at temperatures between -30.degree. C. and the 
boiling point of the solvent under normal atmospheric pressure. 
If a carbonic acid halogenate or a carbonic acid anhydride is used as the 
acylating agent, the reaction is preferably carried out in the presence of 
an acid-binding agent, such as a tertiary amine, for example, 
triethylamine, pyridine, 4-dimethylaminopyridine and the like, or an 
alkali metal hydroxide or alkali metal carbonate, for example, sodium 
hydroxide, potassium carbonate, and the like. Examples of suitable inert 
solvents include N,N-dimethylformamide, chloroform, methylene chloride, 
tetrahydrofuran, dioxane, toluene and chlorobenzene. 
The compounds of formula I may also be prepared by reacting a compound of 
formula III with a carbonic acid, R.sup.5 -CO.sub.2 H, in an inert solvent 
at temperatures of from -30.degree. C. to the boiling point of the 
solvent, preferably at room temperature, in the presence of a suitable 
coupling reagent, such as dicyclohexylcarbodiimide, 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 
carbonyldiimidazole, or the like. 
Compounds of formula I, wherein R.sup.1 represents hydrogen, may 
subsequently be converted into the corresponding N-alkyl compounds by 
alkylation in the conventional manner. For example, such alkylations may 
be effected by reacting compounds of formula I, wherein R.sup.1 is 
hydrogen, with a metallating agent, such as sodium or potassium hydride, 
or alkyl lithium reagent, in an inert solvent at temperatures of 
-78.degree. C. to the boiling point of the solvent. The metallated 
compound is then subsequently reacted with an alkyl halogenide, 
alkylsulfate or alkylsulfonic ester. 
According to method MII, the compounds of formula I may alternatively be 
prepared by reacting a 2-halomethyl-1,4-benzodiazepine derivative of 
formula IV (prepared according to procedures in Eur. J. Med. Chem., 11, 
501 (1976) and U.S. Pat. No. 4,325,957) with an amine of the formula, 
HNR.sup.2 R.sup.1, in an inert solvent at temperatures of 0.degree. C. to 
the boiling point of the solvent, or without solvent, at temperatures of 
0.degree. C. to the boiling point of the amine, HNR.sup.2 R.sup.1, in the 
presence of an acid-binding agent, such as an alkali metal hydroxide or 
alkali metal carbonate, as defined above. 
Compounds according to formula II of the instant invention may be produced 
according to method MIII: 
##STR23## 
According to method MIII, 2-substituted-aminomethyl-1,4-benzodiazepine 
derivatives of formula II may be prepared by dissolving a compound of 
formula V (prepared analogously to the preparation of compounds of formula 
III) in a suitable solvent, such as glacial acetic acid, methanol or 
ethanol, and the solution is cooled to -30.degree. to +15.degree. C. and 
treated with a suitable reducing agent, such as sodium cyanoborohydride, 
sodium borohydride, or lithium borohydride. The reaction mixture is 
stirred until completion of the reaction (approximately 5 minutes to 5 
hours) and poured into water. The resulting reaction mixture is extracted 
with an organic solvent, such as ethyl acetate, chloroform or methylene 
chloride, and the combined organic extracts are washed with sodium 
bicarbonate solution and brine. Concentration affords the crude product 
which may be further purified by chromatography or recrystallization. 
The pharmaceutically-acceptable salts of the present invention may be 
synthesized from the compounds according to the instant invention which 
contain a basic or acidic moiety by conventional chemical methods. 
Generally, the salts are prepared by reacting the free base or free acid 
with stoichiometric amounts of or with an excess of the desired 
salt-forming inorganic or organic acid or base in a suitable solvent or in 
various combinations of solvents. The pharmaceutically-acceptable salts of 
the acids according to this invention are also readily prepared by 
conventional procedures such as treating an acid of this invention with an 
appropriate amount of a base, such as an alkali or alkaline earth metal 
hydroxide, e.g., sodium, potassium, lithium, calcium, or magnesium, or an 
organic base such as an amine, e.g., dibenzylethylenediamine, 
triethylamine, piperidine, pyrrolidine, benzylamine, and the like. 
In addition to the racemic forms of the compounds of formulae I and II 
produced according to the foregoing preparation methods, the present 
invention also includes the optically-active forms of these compounds 
which may be obtained from the racemic mixtures in a conventional manner 
by formation of the salts using suitable optically-active acids, such as 
tartaric acid, O,O'-dibenzoyl tartaric acid, mandelic acid or 
di-O-isopropylidene-2-oxo-L-gulonic acid, and fractionated crystallization 
of the optically active antipodes of the resulting salts (see, S. W. 
Willen et al., Tetrahedron, 33, 2725-2736 (1977)). The salts may be 
transformed into free bases which may be further transformed into the 
pharmacologically-acceptable salts, and the racemic mixtures, 
optically-active isomers and acid-addition salts may be purified by 
recrystallization from solvents, such as lower alkyl alcohols or ethers. 
The preferred stereochemical configuration of the 2-position of all 
compounds according to the instant invention for CCK-antagonism is that 
designated (S) when R.sup.1 =H. 
Screening of the novel compounds according to the present invention to 
determine biological activity and obtain an IC.sub.50 value for them, in 
order to identify significant CCK-antagonism, may be accomplished using an 
.sup.125 I-CCK receptor binding assay and in vitro isolated tissue 
preparations. These tests involve the following: 
CCK receptor binding (pancreas) method 
CCK-33 was radiolabeled with .sup.125 I-Bolton Hunter reagent (2000 
Ci/mmole), as described by Sankara et al. (J. Biol. Chem., 254, 9349-9351, 
1979). Receptor binding was performed according to Innis and Snyder (Proc. 
Natl. Acad. Sci., 77, 6917-6921, 1980), with the minor modification of 
adding the additional protease inhibitors, phenyl-methane sulfonyl 
fluoride and o-phenanthroline, which have no effect on the .sup.125 I-CCK 
receptor binding assay. 
The whole pancreas of a male Sprague-Dawley rat (200-350 g), which had been 
sacrificed by decapitation, was dissected free of fat tissue and 
homogenized in 20 volumes of ice-cold 50 mM Tris HCl (pH 7.7 at 25.degree. 
C.) with a Brinkmann Polytron PT-10. The homogenates were centrifuged at 
48,000 g for 10 minutes, then the resulting pellets were resuspended in 
Tris Buffer, centrifuged as above, and resuspended in 200 volumes of 
binding assay buffer (50 mM Tris HCl, pH 7.7 at 25.degree. C., 5 mM 
dithiothreitol, 0.1 mM bacitracin, 1.2 mM phenylmethane sulfonyl fluoride 
and 0.5 mM o-phenanthroline). 
For the binding assay, 25 .mu.l of buffer (for total binding), or unlabeled 
CCK-8 sulfate sufficient to give a final concentration of 1 .mu.M of CCK-8 
(for nonspecific binding), or the compounds of the formula of the 
compounds according to the instant invention (for determination of 
antagonism to .sup.125 I-CCK binding) and 25 .mu.l of .sup.125 I-CCK-33 
(30,000-40,000 cpm), were added to 450 .mu.l of the membrane suspensions 
in microfuge tubes. All assays were run in duplicate or triplicate, and 
the reaction mixtures were incubated at 37.degree. C. for 30 minutes and 
centrifuged in a Beckman Microfuge (4 minutes) immediately after adding 1 
ml of ice-cold incubation buffer. The supernatant was aspirated and 
discarded, and the pellets were counted with a Beckman Gamma 5000. For 
Scatchard analysis to determine the mechanism of inhibition of .sup.125 
I-CCK binding by the most potent compounds (Ann. N.Y. Acad. Sci., 51, 660, 
1949), .sup.125 I-CCK-33 was progressively diluted with increasing 
concentrations of CCK-33. 
CCK receptor binding (brain) method 
CCK-33 was radiolabeled and the binding was performed according to the 
description for the pancreas method, with modifications according to Saito 
et al., J. Neurochem., 37, 483-490, 1981. 
Male Hartley guinea pigs (300-500 g) were sacrificed by decapitation, and 
the brains were removed and placed in ice-cold 50 mM Tris HCl (Trizma-7.4) 
[pH 7.4 at 25.degree. C.]. The cerebral cortex was dissected and used as a 
receptor source and each gram of fresh guinea pig brain tissue was 
homogenized in 10 ml of Tris/Trizma buffer with a Brinkman polytron PT-10. 
The homogenates were centrifuged at 42,000 g for 15 minutes, then the 
resulting pellets were resuspended in 80 volumes of binding assay buffer 
(10 mM N-2-hydroxy-ethyl-piperazine-N'-2-ethanesulfonic acid (HEPES), 5 mM 
MgCl.sub.2, 1 mM ethylene 
glycol-bis-(.beta.-amino-ethyl-ether-N,N'-tetraacetic acid (EGTA), 0.4% 
BSA and 0.25 mg/ml bacitracin, pH 6.5). 
The remainder of the binding assay method was as described for the pancreas 
method, except that the reaction mixtures were incubated at 25.degree. C. 
for 2 hours before centrifugation. 
In vitro effect of the compounds according to this invention on .sup.125 
I-CCK-33 receptor binding 
The compounds of the instant invention inhibited specific .sup.125 I-CCK-33 
binding in a concentration-dependent manner, generally with an IC.sub.50 
less than or equal to 100 .mu.M. 
An additional method of confirming competitive antagonism of CCK which may 
be used is the following: 
Isolated guinea pig gall bladder method 
The two halves of the gall bladders, free of adjacent tissue, of male 
Hartley guinea pigs (400-600 g), which had been sacrificed by 
decapitation, are suspended under 1 g tension along the axis of the bile 
duct in 5 ml organ bath, containing a Kreb's bicarbonate solution of 118 
mM NaCl, 4.75 mM KCl, 2.54 CaCl.sub.2, 1.19 mM KH.sub.2 PO.sub.4, 1.2 mM 
MgSO.sub.4, 25 mM NaHCO.sub.3 and 11 mM dextrose, which is maintained at 
32.degree. C. and bubbled with a mixture of 95% O.sub.2 and 5% CO.sub.2. 
The tissues are washed every 10 minutes for 1 hour to obtain equilibrium 
prior to the beginning of the study and the isometric contractions of the 
strips are recorded using Statham (60 g:0.12 mm) strain gauges and a 
Hewlett-Packard 77588 recorder. 
CCK-8 is added cumulatively to the baths and EC.sub.50 's are determined 
using regression analysis. After washout (every 10 minutes for 1 hour), 
the compound to be tested is added at least 5 minutes before the addition 
of CCK-8 and the EC.sub.50 of CCK-8 in the presence of compound to be 
tested is similarly determined. 
A shift to the right of the CCK dose response curve without reduction of 
the maximal centractile response, indicates competitive antagonism of CCK 
from this method. 
The ability of the compounds of the instant invention to antagonize CCK 
makes these compounds useful as pharmaceutical agents for mammals, 
especially for humans, for the treatment and prevention of disorders 
wherein CCK may be involved. Examples of such disease states include 
gastrointestinal disorders, especially such as irritable bowel syndrome or 
ulcers excess pancreatic or gastric secretion, acute pancreatis, or 
motility disorder; central nervous system disorders, caused by CCK 
interactions with dopamine, such as neuroleptic disorders, tardive 
dyskinesia, Parkinson's disease, psychosis or Gilles de la Tourette 
Syndrome; and disorders of appetite regulatory systems. 
The compounds of the instant invention or pharmaceutically-acceptable salts 
thereof, may be administered to a human subject either alone or, 
preferably, in combination with pharmaceutically-acceptable carriers or 
diluents, in a pharmaceutical composition, according to standard 
pharmaceutical practice. The compounds can be administered orally or 
parenterally, including intravenous, intramuscular, intraperitoneal, 
subcutaneous and topical administration. 
For oral use of an antagonist of CCK, according to this invention, the 
selected compounds may be administered, for example, in the form of 
tablets or capsules, or as an aqueous solution or suspension. In the case 
of tablets for oral use, carriers which are commonly used include lactose 
and corn starch, and lubricating agents, such as magnesium stearate, are 
commonly added. For oral administration in capsule form, useful diluents 
include lactose and dried corn starch. When aqueous suspensions are 
required for oral use, the active ingredient is combined with emulsifying 
and suspending agents. If desired, certain sweetening and/or flavoring 
agents may be added. For intramuscular, intraperitoneal, subcutaneous and 
intravenous use, sterile solutions of the active ingredient are usually 
prepared, and the pH of the solutions should be suitably adjusted and 
buffered. For intravenous use, the total concentration of solutes should 
be controlled in order to render the preparation isotonic. 
When a compound according to the instant invention, or a salt thereof, is 
used as an antagonist of CCK in a human subject, the daily dosage will 
normally be determined by the prescribing physician. Moreover, the dosage 
will vary according to the age, weight, and response of the individual 
patient, as well as the severity of the patient's symptoms. However, in 
most instances, an effective daily dosage will be in the range of from 
about 0.05 mg/kg to about 100 mg/kg, and preferably, of from 0.5 mg/kg to 
about 20 mg/kg, administered in single or divided doses. In some cases, 
however, it may be necessary to use dosages outside these limits. 
The invention is further defined by reference to the following example 
which is intended to be illustrative and not limiting.