Enteric coated compositions of 1,5-benzodiazepine derivatives having CCK antagonistic or agonistic activity

A pharmaceutical formulation in solid dosage form for oral administration which comprises a compound of the general Formula (I) ##STR1## or a physiologically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers wherein the formulation is encased in an enteric coating or capsule.

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; 
R.sup.1 is either Formula II or --NR.sup.4 R.sup.5 ; 
##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 
or 4-oxo-benzopyran may optionally be substituted in the benzo ring 
thereof by the group R.sup.9 as defined hereunder or 
(2) phenyl or phenyl mono- or disubstituted independently with halogen, 
hydroxy, cyano, carboxy, --O(C.sub.1-4 alkyl), --O(CH.sub.2 C.sub.6 
H.sub.5), --COO(C.sub.1-4 alkyl), amino, dimethylamino, --NHR.sup.10, 
1-pyrrolidinyl or tetrazolyl; or 
(3) pyridine or pyridinyl mono- or disubstituted independently with 
halogen, methyl, hydroxy, nitro, cyano, carboxy, --O(C.sub.1-4 alkyl), 
--O(CH.sub.2 C.sub.6 H.sub.5), --COO(C.sub.1-4 alkyl), amino or 
dimethylamino; or 
(4) --NHR.sup.11 where R.sup.11 is defined hereinunder or R.sup.11 is 
7-indazolyl containing a group R.sup.10 at the N-1 position; 
R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, phenyl or 
phenyl mono- or disubstituted independently with halogen; 
R.sup.4 is independently C.sub.3-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 
alkenyl, phenyl, --(CH.sub.2).sub.p CN or --(CH.sub.2).sub.p COO(C.sub.1-4 
alkyl) and R.sup.5 is independently C.sub.3-6 alkyl, C.sub.3-6 cycloalkyl, 
C.sub.3-6 alkenyl, benzyl, phenyl or phenyl mono- or disubstituted 
independently with C.sub.1-3 alkyl optionally substituted with 1 or more 
fluorine atoms, cyano, hydroxy, dimethylamino, --O(C.sub.1-4 alkyl), 
--O(CH.sub.2 C.sub.6 H.sub.5), --NH(C.sub.1-4 alkyl), --COO(C.sub.1-4 
alkyl), --N(C.sub.1-4 alkyl).sub.2 pyrrolidino, morpholino or halogen or 
R.sup.4 is C.sub.1-2 alkyl and R.sup.5 is phenyl substituted at the 2- or 
4-position with chloro, methyl, methoxy or methoxycarbonyl; 
R.sup.6 is hydrogen or methyl; 
R.sup.7 is hydrogen, hydroxy, fluoro, dimethylamino, --O(C.sub.1-4 alkyl) 
or --O(CH.sub.2 C.sub.6 H.sub.5); 
R.sup.8 is --(CH.sub.2).sub.b COOH; 
R.sup.9 is methyl, chloro, nitro, hydroxy, methoxy or --NHR.sup.10 ; 
R.sup.10 is hydrogen, acetyl, C.sub.1-4 alkyl, --S).sub.3 H, --SO.sub.2 
CH.sub.3, --SO.sub.2 CF.sub.3 or --SO.sub.2 C.sub.6 H.sub.5, C.sub.1-4 
alkoxycarbonyl; 
R.sup.11 is phenyl or phenyl mono- or disubstituted independently with 
fluorine, trifluoromethoxy, C.sub.1-4 alkylthio, --(CH.sub.2).sub.c COOH, 
--(CH.sub.2).sub.c COO(C.sub.1-4 alkyl), --(CH.sub.2).sub.c SCH.sub.3, 
--(CH.sub.2).sub.c SOCH.sub.3, --(CH.sub.2).sub.c SO.sub.2 CH.sub.3, 
--(CH.sub.2).sub.c CONH.sub.2, --SCH.sub.2 COOH, --CONH(SO.sub.2 
CH.sub.3), --CONH(SO.sub.2 CF.sub.3), --(CH.sub.2).sub.c N(C.sub.1-4 
alkyl).sub.2, --(CH.sub.2).sub.c NH(SO.sub.2 CF.sub.3), --(CH.sub.2).sub.c 
N(SO.sub.2 CF.sub.3)(C.sub.1-4 alkyl), --(CH.sub.2).sub.c SO.sub.2 
NHCO(C.sub.1-4 alkyl), --(CH.sub.2).sub.c SO.sub.2 N(C.sub.1-4 
alkyl)CO(C.sub.1-4 alkyl), --(CH.sub.2).sub.c CONHSO.sub.2 (C.sub.1-4 
alkyl), --(CH.sub.2).sub.c CON(C.sub.1-4 alkyl)SO.sub.2 (C.sub.14 alkyl), 
--(CH.sub.2).sub.c OR.sup.12 --(CH.sub.2).sub.c NHR.sup.10 or phenyl 
monosubstituted with --(CH.sub.2).sub.c (tetrazolyl), --(CH.sub.2).sub.c 
(carboxamidotetrazolyl) or --(CH.sub.2).sub.c (pyrrolidinyl) or R.sup.11 
is selected from pyridine or pyridinyl mono- or disubstituted 
independently with halogen, methyl, hydroxy, nitro, cyano, carboxy, 
--O(C.sub.1-4 alkyl), amino, dimethylamino, --NHR.sup.10 ; 
R.sup.12 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, --CH.sub.2 
C.sub.6 H.sub.5, --CH.sub.2 COOH, --CH.sub.2 CONH.sub.2, --CH.sub.2 
CONH(C.sub.1-4 alkyl), --CH.sub.2 CON(C.sub.1-4 alkyl).sub.2 or 
##STR4## 
z is 1 or 2; 
n is 1 or 2; 
p is an integer from 1-4; 
b is an integer from 0-3; and 
c is 0 or 1. 
together with one or more pharmaceutically acceptable carriers, wherein the 
formulation is encased in an enteric coating or capsule. 
Conveniently the formulation according to the invention is in the form of a 
tablet coated with a conventional enteric coating. Alternatively the 
formulation according to the invention may be presented in the form of a 
capsule the shell of which is made from enteric material or is coated with 
an enteric material. 
In the context of this application it will be understood that the term 
enteric coating or material refers to a coating or material that will pass 
through the stomach essentially intact but will rapidly disintegrate in 
the small intestine to release the active drug substance. 
The tablets and capsules for oral administration may contain conventional 
excipients such as binding agents, (for example, syrup, acacia, gelatin, 
sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers 
(for example, lactose, sugar, microcrystalline cellulose, maize-starch, 
calcium phosphate or sorbitol), lubricants (for example, magnesium 
stearate, stearic acid, talc polyethylene glycol or silica), disintegrants 
(for example, potato starch or sodium starch glycollate) or wetting 
agents, such as sodium lauryl sulphate. The enteric coatings may be 
applied to the tablets and/or capsules according to methods well-known in 
the art. 
Suitable enteric coatings for use in the invention will be these coatings 
known to those skilled in the art. Such coatings include cellulose acetate 
phthalate, polyvinyl acetate phthalate, shellac, styrene maleic acid 
copolymers, methyacrylic acid copolymers and hydroxypropyl methyl 
cellulose phthalate. The said coatings may also contain a plasticizer and 
or a dye. 
In the compounds of formula (I) when R.sup.1 represents the group of 
Formula (II), examples of such a group include those wherein R.sup.6 is 
hydrogen or more examples of such a group include those wherein R.sup.6 is 
hydrogen or more particularly methyl, R.sup.7 is hydrogen, hydroxyl, 
methoxy, or fluorine, and n is 1. 
When R.sup.1 represents the group NR.sup.4 R.sup.5, examples of suitable 
groups include those wherein R.sup.4 represent C.sub.3-6 alkyl, such as 
propyl or isopropyl, cyclohexyl or phenyl and R.sup.5 represents C.sub.3-6 
alkyl, benzyl or phenyl optionally substituted in the para- position by 
hydroxy, dimethylamino methoxy, trifluoromethyl, fluorine, pyrrolidino or 
morpholino. Within this group, particularly useful R.sup.1 groups include 
those wherein R.sup.4 is propyl and, more particularly, isopropyl and 
R.sup.5 represents phenyl or phenyl substituted in the para-position by 
groups selected from hydroxy, methoxy dimethylamino, fluorine, or 
morpholino. 
Examples of particularly suitable R.sup.1 groups include those wherein 
R.sup.1 is the group of Formula (II) wherein R.sub.6 is methyl, n is 1 and 
R.sup.7 is hydrogen, hydroxy, fluorine or methoxy or R.sup.1 is the group 
NR.sup.4 R.sup.5 wherein R.sup.4 is propyl or isopropyl and R.sup.5 is 
phenyl optionally substituted in the para position by a group selected 
from hydroxy, methoxy, fluoro, dimethylamino, pyrrolidino or morpholino. 
When R.sup.2 represents a group selected from indole, indoline, benzofuran, 
benzothiophene, quinoline or 4-oxobenzopyran, the optional substituent 
R.sup.9 is conveniently a group selected from hydrogen, methyl, methoxy, 
hydroxy, nitro or amino and, where appropriate, the optional substituent 
on nitrogen, (R.sup.8), is --CH.sub.2 CO.sub.2 H. 
When R.sup.2 is an optionally substituted phenyl group, this is 
conveniently phenyl or phenyl substituted by one or two groups, which may 
be the same or different and selected from chlorine, fluorine, amino, 
hydroxy or carboxyl. 
When R.sup.2 represents the group NHR.sup.11, R.sup.11 is conveniently 
phenyl (optionally substituted by fluoro, hydroxy, amino, dimethylamino, 
trifluoromethylsulphonylamino, C.sub.1-4 alkoxycarbonyl, carboxy, 
1H-tetrazol-5-yl, acetylamino or OR.sup.12 wherein R.sup.12 represents 
hydrogen, methyl, benzyl, CH.sub.2 CO.sub.2 H, CH.sub.2 CONH.sub.2, 
CH.sub.2 CONHCH.sub.3, CH.sub.2 CON(CH.sub.3).sub.2 
##STR5## 
or a 7-indazolyl group wherein the N-1 substituent, (R.sup.10), is 
hydrogen. 
When R.sup.11 is a mono substituted phenyl group, the substituted is 
conveniently in the meta- position. 
Examples of particularly suitable R.sup.2 groups includes indole, 
benzofuran, thiophene, benzothiophene, indoline, quinoline, 
4-oxobenzopyran, an optionally substituted phenyl group or the group 
NHR.sup.11. Conveniently, R.sup.2 is selected from the group indole, 
indoline or benzofuran, an optionally substituted phenyl group or the 
group NHR.sup.11. More particularly, R.sup.2 represents an indole, an 
optionally substituted phenyl or NHR.sup.11. 
When R.sup.3 represents C.sub.1-6 alkyl, examples of suitable groups 
include methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isoamyl. 
When R.sup.3 represents C.sub.3-6 cycloalkyl, examples of suitable groups 
include cyclopropyl, cyclopentyl or cyclohexyl. 
When R.sup.3 represents phenyl, mono or disubstituted by independently with 
halogen, examples of suitable groups include those wherein the halogen 
substituent is fluorine e.g., 2-fluorophenyl or 4 fluorophenyl. 
Examples of particularly suitable R.sup.3 groups include hydrogen, methyl, 
cyclohexyl, 2-fluorophenyl or phenyl, and more particularly, phenyl. 
A particularly useful group of compounds for use in the formulations 
according to the invention include those wherein R.sup.1 represents the 
group of Formula (II) wherein R.sup.6 is methyl, n is 1 and R.sup.7 is 
hydrogen, fluorine, hydroxy or methoxy, or more particularly NR.sup.4 
R.sup.5 wherein R.sup.4 is propyl or isopropyl and R.sup.5 is phenyl 
optionally substituted in the para position by a group selected from 
hydroxy, methoxy, fluoro, dimethylamino or monopholino; R.sup.2 represents 
phenyl (optionally substituted independently by one or two groups selected 
from chlorine, fluorine, hydroxy, amine or carboxy), NHR.sup.11 wherein 
R.sup.11 represents phenyl (optionally substituted by amino, 
dimethylamino, trifluoromethyl- sulphonylamino, carboxy, 1H-tetrazol-5-yl, 
acetylamino or OR.sup.12 wherein R.sup.12 represents hydrogen, methyl, 
benzyl, CH.sub.2 CO.sub.2 H, CH.sub.2 CONH.sub.2, CH.sub.2 CONHCH.sub.3, 
CH.sub.2 CON(CH.sub.3).sub.2, 
##STR6## 
wherein the substituent is preferably in the meta- position) or an indole 
wherein the nitrogen atom is optionally subtituted by the group --CH.sub.2 
CO.sub.2 H and the benzo ring is optionally substituted by chlorine, 
methyl, methoxy, nitro, hydroxy or amino; R.sup.3 represents hydrogen, 
methyl, cyclohexyl, 2-fluorophenyl or phenyl or, more particularly, 2 
fluorophenyl or phenyl; and X represents fluorine and z is 1 or, more 
particularly, X is hydrogen; 
A particularly interesting class of compounds for use in the formulation 
according to the present invention because they exhibit a very high and 
selective affinity for the CCK-A receptor as well as exceptional efficacy 
are those wherein R.sup.2 is an indole group. A preferred group of 
compounds within this class are those wherein the indole group is 
substituted on the nitrogen atom by the group --CH.sub.2 CO.sub.2 H or, 
more preferably, the nitrogen atom is unsubstituted, and benzo ring of the 
indole group is optionally substituted by a group selected from chlorine, 
methyl, methoxy, nitro, hydroxy or amino. 
A particularly preferred compound for use in the formulation according to 
the invention is: 
1 H-lndole-2-carboxylic acid 
{1-lsopropyl-(4-methoxyphenyl)carbamoyl-methyl!-2,4-dioxo-5-phenyl-2,3,4, 
5-tetrahydro-1H-benzob!1 ,4!diazepin-3-yl}-amide and enantiomers thereof. 
As provided herein, the term alkyl is generally intended to mean both 
straight chain and branched chain aliphatic isomers of the corresponding 
alkyl. For example, C.sub.1-6 alkyl is intended to include methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl, etc. 
The term cycloalkyl, as provided herein, is intended to mean all alicyclic 
isomers of the corresponding alkyl. For example, the term C.sub.3-6 alkyl, 
as provided herein, is intended to include such groups as cyclopropyl, 
cyclopentyl and cyclohexyl. 
The term halogen is intended to mean F, Cl, Br or I. 
The term tetrazole as a group or part of a group refers to the (1 
H)-tetrazol-5-yl grouping and tautomers thereof. 
Those skilled in the art will recognize that stereocenters exist in 
compounds of Formula (I). Accordingly, the present invention includes all 
possible stereoisomers and geometric isomers of Formula (I) and includes 
not only racemic compounds but also the optically active isomers as well. 
When a compound of Formula (I) is desired as a single enantiomer, it may 
be obtained either by resolution of the final product or by stereospecific 
synthesis from either isomerically pure starting material or any 
convenient intermediate. Resolution of the final product, an intermediate 
or a starting material may be effected by any suitable method known in the 
art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel 
(Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. 
Additionally, in situations where tautomers of the compounds of Formula 
(I) are possible, the present invention is intended to include all 
tautomeric forms of the compounds. 
It will also be appreciated by those skilled in the art that the compounds 
of the present invention may also be utilized in the form of a 
pharmaceutically acceptable salt or solvate thereof. The physiologically 
acceptable salts of the compounds of Formula (I) include conventional 
salts formed from pharmaceutically acceptable inorganic or organic acids 
as well as quaternary ammonium acid addition salts. More specific examples 
of suitable salts include hydrochloric, hydrobromic, sulphuric, 
phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, 
glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, 
hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, 
toluenesulphonic, methanesulphonic, naphthalene-2-sulphonic, 
benzenesulphonic and the like. Other acids such as oxalic, while not in 
themselves pharmaceutically acceptable, may be useful in the preparation 
of salts useful as intermediates in obtaining the compounds of the 
invention and their pharmaceutically acceptable salts. References 
hereinafter to a compound for use in the invention include both compounds 
of Formula (I) and their pharmaceutically acceptable salts and solvates. 
The compounds of formula (I) exhibit CCK-A agonist activity and can be 
considered full or partial cholecystokinin agonists in that they bind to 
CCK-A receptors and either fully or partially stimulate gallbladder 
contraction and/or reduce feeding in animal paradigms. 
As agonists of CCK-A receptors, the compounds of formula (I) are useful 
anorectic agents advantageous in the treatment of obesity as well as 
related pathologies, such as diabetes or hypertension. Moreover, the 
compounds disclosed herein provide for new approaches for inducing 
satiety, providing for appetite regulation and modifying food intake in 
mammals, especially humans, to regulate appetite, treat obesity and 
maintain weight loss. 
Additionally, certain compounds of formula (I) may also exhibit some 
antagonist activity at particular site-specific CCK-B and gastrin 
receptors as demonstrated by their inhibition of CCK-4 stimulated 
contraction of isolated guinea-pig ileum longitudinal muscle-myenteric 
plexus and pentagastrin-stimulated acid secretion in rat isolated gastric 
mucosa using the procedures described by M. Patel and C. F. Spraggs in Br. 
J. Pharmac., (1992), 106, 275-282 and by J. J. Reeves and R. Stables in 
Br. J. Pharmac., (1985), 86, 677-684. 
The relative affinities of compounds of formula (I) for the CCK-A and CCK-B 
receptors may be determined using known conventional procedures such as 
described by Fornos et al J. Pharmacol Exp. Ther., 1992 261,1056-1063. 
The ability of compouds of formula (I) to inhibit gastric acid secretion, 
such as pentagastrin stimulated acid secretion may be determined in the 
conscrious gastric fistula rat using methods described by Hedges and 
Parsons Journal of Physiology 1977, 267 191-194. 
According to a further aspect of the present invention, there is provided 
herein a method for the treatment of a mammal, including man, in 
particular in the treatment conditions where modification of the effects 
of CCK and/or gastrin is of therapeutic benefit, the method comprising 
administering to the patient an enterically coated tablet or capsule 
containing a therapeutically effective amount of a compound of Formula (I) 
or a pharmaceutically acceptable salt or solvate thereof. 
It will be appreciated by those skilled in the art that reference herein to 
treatment extends to prophylaxis as well as the treatment of established 
diseases or symptoms. Moreover, it will be appreciated that the amount of 
a compound of the invention required for use in treatment will vary with 
the nature of the condition being treated and the age and the condition of 
the patient and will be ultimately at the discretion of the attendant 
physician or veterinarian. In general, however, doses employed for adult 
human treatment will typically be in the range of 0.02-5000 mg per day, 
e.g., 1-1500 mg per day. The desired dose may conveniently be presented in 
a single dose or as divided doses administered at appropriate intervals, 
for example as two, three, four or more sub-doses per day. 
Compounds of general Formula (I), methods for their preparation and their 
activity as CCK-A agonists are described in W09424149.

EXAMPLE 
The following example illustrates the invention but should not be construed 
as a limitation thereto. 
Tablet 
______________________________________ 
Active Ingredient 50 mg 
Lactose anhydrous USP 163 mg 
Microcystalline Cellulose NF 
69 mg 
Pregelatinized starch Ph. Eur. 
15 mg 
Magnesium stearate USP 3 mg 
Compression weight 300 mg 
______________________________________ 
The active ingredient, microcrystalline cellulose, lactose and 
pregletinized starch are sieved through a 500 micron sieve and blended in 
a suitable mixer. The magnesium starate is sieved through a 250 micron 
sieve and blended with the active blend. The blend is compressed into 
tablets using suitable punches, then coated with cellulose acetate 
phthalate in a conventional manner.