CA1332411C - Benzodiazepine analogs - Google Patents
Benzodiazepine analogsInfo
- Publication number
- CA1332411C CA1332411C CA000561493A CA561493A CA1332411C CA 1332411 C CA1332411 C CA 1332411C CA 000561493 A CA000561493 A CA 000561493A CA 561493 A CA561493 A CA 561493A CA 1332411 C CA1332411 C CA 1332411C
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- Prior art keywords
- gastrin
- compound
- phenyl
- methyl
- cholecystokinin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- C07K5/06—Dipeptides
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Abstract
ABSTRACT OF THE DISCLOSURE
A benzodiazepine analog of the formula:
A benzodiazepine analog of the formula:
Description
1 3 3 2 4 ~
TITLE OF THE INVENTION
BENZODIAZEPINE ANALOGS
S .
~` 10 ". '''"''"'''''''''''''' ; 15 .:
BACKGROUND OF THE INVENTION
Cholecystokinins (CCK) and gastrin are .~.- ;
structurally-related neuropeptides ~hich exist in gastrointestinal tissue and in the the central nervous system~(see, V. Mutt, Gastrointestinal ! :' ','~'' Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., p. `i~
169 and G. Nisson, ibid, p. 127).
G ~
~
1 3~2~ 1 1 , . .
2848P/1023A - 2 - 17119IC ~
., ; . ~ .
Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (a naturally-occurring neuropeptide, also, and the minimum fully active sequence), and 39- and 12-amino acid forms, while gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal pentapeptide, Gly-Trp-Met-Asp-Phe-NH2, which is the common structural element shared by both CCK and ~;
gastrin.
CCK's are believed to be physiological satiety hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eatinq and Its Disorders, A. J. Stunkard and E.
Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as also stimulating colonic motility, gall bladder contraction, pancreatic enzyme secretion, and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of ; dopaminergic systems in the brain, in addition to serving 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])-The primary role of gastrin, on the other hand, appears to be stimulation of the secretion of water and electrolytes from the stomach, and, as such, it is involved in control of gastric acid and . .
C
1 3 ~ 2 4 1 ~
i pepsin secretion. Other physiological effects of gastrin then include increased mucosal blood flow and increased antral motility, with rat studies having shown that gastrin has a positive trophic effect on 5 the gastric mucosa, as evidenced by increased DNA, ;~
RNA and protein synthesis.
Antagonists to CCK and to gastrin have been useful for preventing and treating CCK-related and/or gastrin-related disorders of the gastrointestinal -(GI) and central nervous (CNS) systems of animals, especially of humans. Just as there is some overlap in the biological activities of CCK and gastrin, ;~
antagonists also tend to have affinity for both receptors. In a practical sense, however, there is ;~
enough selectivity to the different receptors that greater activity against specific CCK- or gàstrin-related disorders can often also be identified. ; ~
Selective CCK antagonists are themselves ~ ;
20 useful in treating CCK-related disorders of the ~ ~h~
appetite regulatory systems of animals as well as in potentiating and prolonging opiate-mediated analgesia, thus having utility in the treatment of pain ~see P. L. Faris et al., Science 226, 1215 (198g)], while selective gastrin antagonists are useful in the modulation of CNS behavior, as a I -~
palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, ~
30 such as peptic ulcers, Zollinger-Ellison syndrome, -antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic -value.
'' "' ';~ ~'''' G
1 3324 1 1 - :
Also, since CCK and gastrin also have trophic effects on certain tumors [K. Okyama, Hokkaido J. Med. Sci., 60, 206-216 (1985)], -~
antagonists of CCK and gastrin are useful in treating these tumors [see, R.D. Beauchamp et al., Ann. Surq., Z02,303 ~1985)].
Four 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, G 161 (1982) and P. Robberecht et al., Mol., Pharmacol., _, 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-NH2, Met-Asp-Phe-NH2), and longer (Cbz-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-NH2) C-terminal fragments of CCK can function as CCK
antagonists, according to recent structure-function studies (see, R. T. Jensen et al., Biochem. 8ioPhYs.
Acta., 757, 250 (1983), and M. Spanarkel et al., J.
Biol. Chem., 258, 6746 (1983)). The latter compound was recently reported to be a partial agonist [see, J. M. Howard et al., GastroenteroloqY 86(5) Part 2, 1118 (1984)].
Then, the third class of CCK-receptor -antagonists comprises the amino acid derivatives: -30 -proglumide, a derivative of glutaramic acid, ahd 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), R. T.
l, ~ .
, a ~ 3 3 2 4 1 ~
2848Pr'1023A - 5 - 17119IC ~
Jensen et al., Biochem. BioPhys. Acta., 761, 269 ;-(1983)]. All of these compounds, however, are relatively weak antagonists of CCK (IC50: generally 10 4M[although more potent analogs of proglumide have been recently reported in F. Makovec et al., Arzneim-Forsch Druq Res., 35 (II), 1048 (1985) and in German Patent Application DE 3522506A1 (Janua~y 2, 1986)], but down to 10 6M in the case o~ peptides), and the peptide CCX-antagonists have substantial stability and absorption problems.
In addition, a fourth class consists of improved CCK-antagonists comprising a nonpeptide of novel structure from fermentation sources [R. S. L.
Chang et al., Science, 230, 177-179 (1985)] and 3-substituted benzodiazepines based on this structure lEuropean Patent Applications 167 919 (lanuary 15, 1986), 167 920 :
(January 15, 1986) and 169 392 (Janua~y 29, 1986), B.E. Evans et aL, Pr~oc. Natl. 4~cad. Sci. U.S~.~ 83, p. 4918-4922 (1986) and R.S.L. Chang et al, ibid, p. 4923-4926] have also been reported.
No really effective receptor antagonists of the in vivo effects of gastrin have been reported (J. S. Morley, Gut PePt. Ulcer Proc., Hiroshima Symp. ~
2nd, 1983, p. 1), and very weak in vitro antagonists, ~ -such as proglumide and certain peptides have been described [(J. Martinez, J. Med. Chem. 2?, 1597 ~ -(1984)]. Recently, however, pseudopeptide analogs of tetragastrin have been reported to be more e~fective gastrin antagonists than previous agents [J. Martinez ;,,~
et al~., J. Med. Chem., 28, 1874-1879 (1985)].
The benzodiazepine (BZD) structure class, which has been widely exploited as therapeutic agents, especially as central nervous system (CNS) drugs, such as anxiolytics, and which exhibits strong ., ~
., , ,, -~ , ¢ '" ',', binding to "benzodiazepine receptors" ln vitro, has not in the past been reported to bind to CCK or gastrin receptors. Benzodiazepines have been shown to antagonize CCK-induced activation of rat hippocampal neurones but this effect is mediated by the benzo-diazepine receptor, not the CCK receptor [see J
Bradwejn et al., Nature, 312, 363 (1984)]. Of these reported BZD's, additionally, the large majority do not contain substituents attached to the 3-position of the seven membered ring, as it is well known in the art that 3-substituents result in decreasing anxiolytic activity, especially as these substituents increase in size.
This invention seeks to identify substances which more effectively antagonize the function of cholecystokinins and gastrin in disease states in animals, preferably mammals, especially in humans.
This invention also seeks to prepare novel compounds which more selectively inhibit chole-cystokinins or inhibit gastrin.
This invention still further seeks to develop a method of antagonizing the functions of cholecystokinin and gastrin in disease states in mammals.
Furthermore, this invention seeks to develop -a method of preventing or treating disorders of the gastrointestinal, central nervous and appetite regula-tory systems of mammals, especially of humans, or of increasing food intake of animals.
.
~' ' :
- 7 - ~ ~
1 332~
SUMMARY OF THE INVENTION
In accordance with one aspect of the inven~
tion there is provided a compound of formula 3 O O ~ 3 N ~ r N/ (I) . ~ ' ' ~'' or a pharmaceutically acceptable salt thereof.
In accordance with another aspect of the invention there is provided a pharmaceutical composi-tion comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in associa-tion with a pharmaceutically acceptable carrier.
It has now been found that the compound of formula (I) and pharmaceutically acceptable salts thereof are antagonists of gastrin and cholecystokinin ' ~,~
(CCK) and bind to the gastrin and CCK receptors. The -~
compound and salts are useful in the treatment and , prevention of CCK-related disorders of the gastro-intestinal, central nervous and appetite regulatory systems of animals, preferably mammals and especially , ;~
humans. They are also useful in the treatment and prevention of gastrin related disorders, gastro-intes~
; 30 tinal ulcers, Zollinger-Ellison syndrome, antral!G
cell hyperplasia, and other conditions in which . .
~ reduced gastrin activity is of therapeutic value.
DETAILED DESCRIPTION OF THE INVENTION ~ ;
The compound of formula (I) and its pharma-ceutically acceptable salts are useful in antagonizing the binding of cholecystokinins to cholecystokinin receptors or antagonizing the binding of gastrin to gastrin receptors which comprises contacting the cholecystokinin receptors or the gastrin receptors, respectively, with the compound of formula (I), as defined hereinbefore, or a pharmaceutically acceptable salt thereof.
In the compound of formula (I), the preferred stereochemistry for CCK antagonism relates to D-tryptophan, where c2 and N4 of formula (I) corre-spond to the carbonyl carbon and ~-amino N of D-tryptophan and the 3-methylphenyl urea chain occupies the position of the indolylmethyl side chain.
In the compound of formula (I), the stereo-chemistry for gastrin antagonism can be either D or L, ;`
the preferred stereochemistry corresponds to L-tryptophan.
The pharmaceutically acceptable salts of the compound of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compound of formula (I) formed, e.g., from non-toxic inorganic or organic acids. For example, such conven-tional 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 30 acetic, propionic, succinic, glycolic, stearic, j `~`
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, mathanesulfonic, ethane ~-disulfonic, oxalic, isethionic, and the like.
~ . .
. ~ ~... ~
~_ 9 _ t33241 1 The pharmaceutically acceptable salts of the ~ ~ :
present invention can be synthesized from the compound of formula (I), which contains a basic moiety, by con~
ventional chemical methods~ Generally, the salts are ::.
prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. .;:
The ability of the compound of formula (I) ~:
10 and its pharmaceutically acceptable salts to antago- `
nize CCK and gastrin makes this compound useful as a :~
pharmaceutical agent for mammals, especially for humans, for the treatment and prevention of disorders :~
wherein CCK and/or gastrin may be involved. Examples ~
15 of such disease states include gastrointestinal dis- ~ ~;
orders, especially such as irritable bowel syndrome, gastroesophageal reflux disease or ulcers, excess pan- :: :;
creatic or gastric secretion, acute pancreatitis, or ...
motility disorders; 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;
disorders of appetite regulatory systems; Zollinger- `-:
Ellison syndrome, antral G cell hyperplasia, or pain ~
25 (potentiation of opiate analgesia); as well as certain :
tumors of the lower esophagus, stomach, intestines and ::
colon.
The compound of formula (I), or pharmaceuti- -~ cally acceptable salts thereof, may be administered to :
! 130 a human subject either alone or, preferably, in combi-nation with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as ~
alum, in a pharmaceutical composition, according to ~`:
standard pharmaceutical practice. The compounds can be administered orally or parenterally, including ,: .
~ 3324 ~ 1 . -- 10 --intravenous, intramuscular, intraperitoneal, sub-cutaneous and topical administration.
For oral use of an antagonist of CCK, according to this invention, the compound (I), or pharmaceutically acceptable salts thereof, 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 emul-sifying and suspending agents. If desired, certainsweetening 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 the compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally -varying 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 50 mg/kg of body weight, and preferably, of from 0.5 mg/kg to about 20 mg/kg of body weight, administered in single or divided doses.
In some cases, however, it may be necessary to use dosages outside these limits.
'- - 11 - 13324~
In the treatment of irritable bowel ~ -syndrome, for instance, 0.1 to 10 mg/kg of a CCK
antagonist might be administered orally (p.o.), ;
divided into two doses per day (b.i.d.). In treating delayed gastric emptying, the dosage range would probably be the same, although the drug might be ;~
administered either intravenously (I.V.) or orally, with the I.V. dose probably tending to be slightly lower due to better availability. Acute pancreatitis 10 might be treated preferentially in an I.V. form, ~ -whereas spasm and/or reflex esophageal, chronic pan-creatitis, post vagotomy diarrhea, anorexia or pain -associated with biliary dyskinesia might indicate p.o. -form administration.
In the use of a gastrin antagonist as a ~ ;~
tumor palliative for gastrointestinal neoplasms with gastrin receptors, as a modulator of central nervous system activity, treatment of Zollinger-Ellison syndrome, or in the treatment of peptic ulcer disease, 20 a dosage of 0.1 to 10 mg/kg administered one-to-four - ~
times daily might be indicated. -Because the compound antagonizes the func-tion of CCK in animals, it may also be used as a feed ~
additive to increase the food intake of animals in -daily dosage of approximately 0.05 to 50 mg/kg of body weight.
In accordance with another aspect of the invention there is provided a process for the prepara-tion of the compound of formula (I) which process com-30 prises reacting an amine of formula (II): I
'~ :
' ;
.
C ~ .
. ' . ,, - t ~
CH
3~ N~ \)3 ~N H (II) with an isocyanate of formula (III):
~ N - C O (III) The reaction is suitably carried out in an ether, for example, tetrahydrofuran.
The 3-amino-5-phenyl-1-methyl benzodi-azepines (II) are prepared as described in the prior art. Alternatively, 9 (R3=NH2) are prepared as shown in the following scheme:
/ NCH~//O C1l3/ O
1. KOtBu ~ ~ NO~I Ni(R) 2. iAmONO ~ ~32 ~ ~
`.."',:
Treatment of the 3-unsubstituted compound - with a suitable base, preferably potassium t-butoxide, following by a nitrosating agent, preferably isoamyl nitrite, provides the 3-oxime. Reduction, preferably -- 13 - 1~ 3 2 4 1 1 : -with Raney nickel, gives the 3-amino compound (II).
Alternatively compound (II~ is prepared by the method disclosed in U.S. Patent 4,628,084.
The 3-amino-5-phenyl-1-methyl benzodi-5 azepines (II) are reacted with isocyanates (III) to -~
produce the corresponding urea (I).
Where the starting materials are optically active, the chirality at C3 is controlled by the synthesis. When racemic starting materials are 10 employed, racemic products are obtained. The enan- -~
tiomers may be separated by resolution.
In Vitro ActivitY of Compound of Formula (I) The biological activity of the compound of formula (I) has been evaluated using l.)an 125I-CCK
receptor binding assay and in vitro isolated tissue preparations and 2.) 125I-gastrin and 3H-pentagastrin binding assays.
Materials and Methods 1. CCK Rece~tor Bindinq (PancreasL
CCK-33 was radiolabeled with 125I-Bolton Hunter reagent (2000 Ci/mmole) as described by Sankara et al. (J. Biol. Chem. 254: 9349-9351, 1979). Recep-tor 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, phenylmethane sulfonyl fluoride and o-phenanthroline. The latter two compounds have no effect on the 125I-CCK receptor binding assay.
Male Sprague-Dawley rats (200-350g) were sacrificed by decapitation. The whole pancreas was dissected free of fat tissue and was homogenized in 20 volumes of ice-cold 50 mM, Tris HCl (pH 7.7 at 20C) with a Brinkmann Polytron PT lOTM. The homogenates were centrifuged at 48,000 g for 10 min. Pellets were resuspended in Tris Buffer, centrifuged as above and C
`` - 14 - I 3324 ~ I
resuspended in 200 volumes of binding assay buffer (50 mM Tris HCl, pH 7.7 at 25C, 5mM dithiothrietol, 0.1 mM bacitracin, 1.2 mM phenylmethane sulfonyl fluoride and 0.5 mM 0-phenanthroline). For the binding assay, 25 ~1 of buffer (for total binding) or unlabeled CCK-8 sulfate to give a final concentration of l~M (for non-specific binding) or the compound of formula (I) (for determination of inhibition of 125I-CCK binding) and 25 ~1 of 125I-CCK-33 (30,000-40,000 cpm) were added to 450 ~1 of the membrane suspensions in microfuge tubes.
All assays were run in duplicate or triplicate. The reaction mixtures were incubated at 37C for 30 minutes and centrifuged in a Beckman MicrofugeTM (4 minutes) immediately after adding 1 ml of ice-cold ~;
incubation buffer. The supernatant was aspirated and discarded, pellets were counted with a Beckman gamma 5000. For Scatchard analysis (Ann. N~Y. Acad. Sci.
51: 660, 1949), 125I-CCK-33 was progressively diluted with increasing concentrations of CCK-33.
2. CCK Rece~tor Bindinq (Brain) CCK-33 was radiolabeled and the binding was performed according to the description for the pan-creas method with modifications according to Saito al., J. Neurochem. 37: 483-490, 1981.
Male Hartley guinea pigs (300-500g) were sacrificed by decapitation and the brains were removed and placed in ice-cold 50 mM, Tris HCl plus 7.58 g/l Trizma-7.4 (pH 7.4 at 25C). Cerebral cortex was dissected and used as a receptor source. Each gram of ;~
30 fresh guinea pig brain tissue was homogenized inilO ml ;~
of Tris/Trizma buffer with a Brinkmann polytron PT-10. ~-The homogenates were centrifugéd at 42,000 g for 15 minutes. Pellets were resuspended in Tris buffer, centrifuged as above and resuspended in 200 volumes of binding assay buffer (10 mM N-2-hydroxyethyl-piperazine-n'-2-ethane sulfonic acid (HEPES), 5 mM
' l~ ~ :. .
- 15 - 133~411 MgC12, 0.25 mg/ml bacitracin, 1 mM ethylene glycol-bis-(~-aminoethylether-N,N'-tetraacetic acid) (EGTA), and 0.4% bovine serum albumin (BSA)). For the binding assay, 25 ~1 of buffer (for total binding) or unlabeled CCK-8 sulfate to give a final concentration of 1 ~m (for nonspecific binding) or the compound of formula (I) (for determination of inhibition of 125I-CCK binding) and 25 ~1 of 125I-CCK-33 (30,000-40,000 cpm) were added to 450 ~1 of the membrane suspensions 10 in microfuge tubes. All assays were run in duplicate ;
or triplicate. The reaction mixtures were incubated at 25C for 2 hours and centrifuged in a Beckman Microfuge (4 minutes) immediately after adding 1 ml of ice-cold incubation buffer. The supernatant was aspirated and discarded, pellets were counted with a Beckman gamma 5000.
The compound of formula (I) can be deter-mined to be a competitive antagonist of CCK according to the following assays.
TITLE OF THE INVENTION
BENZODIAZEPINE ANALOGS
S .
~` 10 ". '''"''"'''''''''''''' ; 15 .:
BACKGROUND OF THE INVENTION
Cholecystokinins (CCK) and gastrin are .~.- ;
structurally-related neuropeptides ~hich exist in gastrointestinal tissue and in the the central nervous system~(see, V. Mutt, Gastrointestinal ! :' ','~'' Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., p. `i~
169 and G. Nisson, ibid, p. 127).
G ~
~
1 3~2~ 1 1 , . .
2848P/1023A - 2 - 17119IC ~
., ; . ~ .
Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (a naturally-occurring neuropeptide, also, and the minimum fully active sequence), and 39- and 12-amino acid forms, while gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal pentapeptide, Gly-Trp-Met-Asp-Phe-NH2, which is the common structural element shared by both CCK and ~;
gastrin.
CCK's are believed to be physiological satiety hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eatinq and Its Disorders, A. J. Stunkard and E.
Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as also stimulating colonic motility, gall bladder contraction, pancreatic enzyme secretion, and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of ; dopaminergic systems in the brain, in addition to serving 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])-The primary role of gastrin, on the other hand, appears to be stimulation of the secretion of water and electrolytes from the stomach, and, as such, it is involved in control of gastric acid and . .
C
1 3 ~ 2 4 1 ~
i pepsin secretion. Other physiological effects of gastrin then include increased mucosal blood flow and increased antral motility, with rat studies having shown that gastrin has a positive trophic effect on 5 the gastric mucosa, as evidenced by increased DNA, ;~
RNA and protein synthesis.
Antagonists to CCK and to gastrin have been useful for preventing and treating CCK-related and/or gastrin-related disorders of the gastrointestinal -(GI) and central nervous (CNS) systems of animals, especially of humans. Just as there is some overlap in the biological activities of CCK and gastrin, ;~
antagonists also tend to have affinity for both receptors. In a practical sense, however, there is ;~
enough selectivity to the different receptors that greater activity against specific CCK- or gàstrin-related disorders can often also be identified. ; ~
Selective CCK antagonists are themselves ~ ;
20 useful in treating CCK-related disorders of the ~ ~h~
appetite regulatory systems of animals as well as in potentiating and prolonging opiate-mediated analgesia, thus having utility in the treatment of pain ~see P. L. Faris et al., Science 226, 1215 (198g)], while selective gastrin antagonists are useful in the modulation of CNS behavior, as a I -~
palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, ~
30 such as peptic ulcers, Zollinger-Ellison syndrome, -antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic -value.
'' "' ';~ ~'''' G
1 3324 1 1 - :
Also, since CCK and gastrin also have trophic effects on certain tumors [K. Okyama, Hokkaido J. Med. Sci., 60, 206-216 (1985)], -~
antagonists of CCK and gastrin are useful in treating these tumors [see, R.D. Beauchamp et al., Ann. Surq., Z02,303 ~1985)].
Four 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, G 161 (1982) and P. Robberecht et al., Mol., Pharmacol., _, 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-NH2, Met-Asp-Phe-NH2), and longer (Cbz-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-NH2) C-terminal fragments of CCK can function as CCK
antagonists, according to recent structure-function studies (see, R. T. Jensen et al., Biochem. 8ioPhYs.
Acta., 757, 250 (1983), and M. Spanarkel et al., J.
Biol. Chem., 258, 6746 (1983)). The latter compound was recently reported to be a partial agonist [see, J. M. Howard et al., GastroenteroloqY 86(5) Part 2, 1118 (1984)].
Then, the third class of CCK-receptor -antagonists comprises the amino acid derivatives: -30 -proglumide, a derivative of glutaramic acid, ahd 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), R. T.
l, ~ .
, a ~ 3 3 2 4 1 ~
2848Pr'1023A - 5 - 17119IC ~
Jensen et al., Biochem. BioPhys. Acta., 761, 269 ;-(1983)]. All of these compounds, however, are relatively weak antagonists of CCK (IC50: generally 10 4M[although more potent analogs of proglumide have been recently reported in F. Makovec et al., Arzneim-Forsch Druq Res., 35 (II), 1048 (1985) and in German Patent Application DE 3522506A1 (Janua~y 2, 1986)], but down to 10 6M in the case o~ peptides), and the peptide CCX-antagonists have substantial stability and absorption problems.
In addition, a fourth class consists of improved CCK-antagonists comprising a nonpeptide of novel structure from fermentation sources [R. S. L.
Chang et al., Science, 230, 177-179 (1985)] and 3-substituted benzodiazepines based on this structure lEuropean Patent Applications 167 919 (lanuary 15, 1986), 167 920 :
(January 15, 1986) and 169 392 (Janua~y 29, 1986), B.E. Evans et aL, Pr~oc. Natl. 4~cad. Sci. U.S~.~ 83, p. 4918-4922 (1986) and R.S.L. Chang et al, ibid, p. 4923-4926] have also been reported.
No really effective receptor antagonists of the in vivo effects of gastrin have been reported (J. S. Morley, Gut PePt. Ulcer Proc., Hiroshima Symp. ~
2nd, 1983, p. 1), and very weak in vitro antagonists, ~ -such as proglumide and certain peptides have been described [(J. Martinez, J. Med. Chem. 2?, 1597 ~ -(1984)]. Recently, however, pseudopeptide analogs of tetragastrin have been reported to be more e~fective gastrin antagonists than previous agents [J. Martinez ;,,~
et al~., J. Med. Chem., 28, 1874-1879 (1985)].
The benzodiazepine (BZD) structure class, which has been widely exploited as therapeutic agents, especially as central nervous system (CNS) drugs, such as anxiolytics, and which exhibits strong ., ~
., , ,, -~ , ¢ '" ',', binding to "benzodiazepine receptors" ln vitro, has not in the past been reported to bind to CCK or gastrin receptors. Benzodiazepines have been shown to antagonize CCK-induced activation of rat hippocampal neurones but this effect is mediated by the benzo-diazepine receptor, not the CCK receptor [see J
Bradwejn et al., Nature, 312, 363 (1984)]. Of these reported BZD's, additionally, the large majority do not contain substituents attached to the 3-position of the seven membered ring, as it is well known in the art that 3-substituents result in decreasing anxiolytic activity, especially as these substituents increase in size.
This invention seeks to identify substances which more effectively antagonize the function of cholecystokinins and gastrin in disease states in animals, preferably mammals, especially in humans.
This invention also seeks to prepare novel compounds which more selectively inhibit chole-cystokinins or inhibit gastrin.
This invention still further seeks to develop a method of antagonizing the functions of cholecystokinin and gastrin in disease states in mammals.
Furthermore, this invention seeks to develop -a method of preventing or treating disorders of the gastrointestinal, central nervous and appetite regula-tory systems of mammals, especially of humans, or of increasing food intake of animals.
.
~' ' :
- 7 - ~ ~
1 332~
SUMMARY OF THE INVENTION
In accordance with one aspect of the inven~
tion there is provided a compound of formula 3 O O ~ 3 N ~ r N/ (I) . ~ ' ' ~'' or a pharmaceutically acceptable salt thereof.
In accordance with another aspect of the invention there is provided a pharmaceutical composi-tion comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in associa-tion with a pharmaceutically acceptable carrier.
It has now been found that the compound of formula (I) and pharmaceutically acceptable salts thereof are antagonists of gastrin and cholecystokinin ' ~,~
(CCK) and bind to the gastrin and CCK receptors. The -~
compound and salts are useful in the treatment and , prevention of CCK-related disorders of the gastro-intestinal, central nervous and appetite regulatory systems of animals, preferably mammals and especially , ;~
humans. They are also useful in the treatment and prevention of gastrin related disorders, gastro-intes~
; 30 tinal ulcers, Zollinger-Ellison syndrome, antral!G
cell hyperplasia, and other conditions in which . .
~ reduced gastrin activity is of therapeutic value.
DETAILED DESCRIPTION OF THE INVENTION ~ ;
The compound of formula (I) and its pharma-ceutically acceptable salts are useful in antagonizing the binding of cholecystokinins to cholecystokinin receptors or antagonizing the binding of gastrin to gastrin receptors which comprises contacting the cholecystokinin receptors or the gastrin receptors, respectively, with the compound of formula (I), as defined hereinbefore, or a pharmaceutically acceptable salt thereof.
In the compound of formula (I), the preferred stereochemistry for CCK antagonism relates to D-tryptophan, where c2 and N4 of formula (I) corre-spond to the carbonyl carbon and ~-amino N of D-tryptophan and the 3-methylphenyl urea chain occupies the position of the indolylmethyl side chain.
In the compound of formula (I), the stereo-chemistry for gastrin antagonism can be either D or L, ;`
the preferred stereochemistry corresponds to L-tryptophan.
The pharmaceutically acceptable salts of the compound of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compound of formula (I) formed, e.g., from non-toxic inorganic or organic acids. For example, such conven-tional 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 30 acetic, propionic, succinic, glycolic, stearic, j `~`
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, mathanesulfonic, ethane ~-disulfonic, oxalic, isethionic, and the like.
~ . .
. ~ ~... ~
~_ 9 _ t33241 1 The pharmaceutically acceptable salts of the ~ ~ :
present invention can be synthesized from the compound of formula (I), which contains a basic moiety, by con~
ventional chemical methods~ Generally, the salts are ::.
prepared by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. .;:
The ability of the compound of formula (I) ~:
10 and its pharmaceutically acceptable salts to antago- `
nize CCK and gastrin makes this compound useful as a :~
pharmaceutical agent for mammals, especially for humans, for the treatment and prevention of disorders :~
wherein CCK and/or gastrin may be involved. Examples ~
15 of such disease states include gastrointestinal dis- ~ ~;
orders, especially such as irritable bowel syndrome, gastroesophageal reflux disease or ulcers, excess pan- :: :;
creatic or gastric secretion, acute pancreatitis, or ...
motility disorders; 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;
disorders of appetite regulatory systems; Zollinger- `-:
Ellison syndrome, antral G cell hyperplasia, or pain ~
25 (potentiation of opiate analgesia); as well as certain :
tumors of the lower esophagus, stomach, intestines and ::
colon.
The compound of formula (I), or pharmaceuti- -~ cally acceptable salts thereof, may be administered to :
! 130 a human subject either alone or, preferably, in combi-nation with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as ~
alum, in a pharmaceutical composition, according to ~`:
standard pharmaceutical practice. The compounds can be administered orally or parenterally, including ,: .
~ 3324 ~ 1 . -- 10 --intravenous, intramuscular, intraperitoneal, sub-cutaneous and topical administration.
For oral use of an antagonist of CCK, according to this invention, the compound (I), or pharmaceutically acceptable salts thereof, 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 emul-sifying and suspending agents. If desired, certainsweetening 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 the compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally -varying 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 50 mg/kg of body weight, and preferably, of from 0.5 mg/kg to about 20 mg/kg of body weight, administered in single or divided doses.
In some cases, however, it may be necessary to use dosages outside these limits.
'- - 11 - 13324~
In the treatment of irritable bowel ~ -syndrome, for instance, 0.1 to 10 mg/kg of a CCK
antagonist might be administered orally (p.o.), ;
divided into two doses per day (b.i.d.). In treating delayed gastric emptying, the dosage range would probably be the same, although the drug might be ;~
administered either intravenously (I.V.) or orally, with the I.V. dose probably tending to be slightly lower due to better availability. Acute pancreatitis 10 might be treated preferentially in an I.V. form, ~ -whereas spasm and/or reflex esophageal, chronic pan-creatitis, post vagotomy diarrhea, anorexia or pain -associated with biliary dyskinesia might indicate p.o. -form administration.
In the use of a gastrin antagonist as a ~ ;~
tumor palliative for gastrointestinal neoplasms with gastrin receptors, as a modulator of central nervous system activity, treatment of Zollinger-Ellison syndrome, or in the treatment of peptic ulcer disease, 20 a dosage of 0.1 to 10 mg/kg administered one-to-four - ~
times daily might be indicated. -Because the compound antagonizes the func-tion of CCK in animals, it may also be used as a feed ~
additive to increase the food intake of animals in -daily dosage of approximately 0.05 to 50 mg/kg of body weight.
In accordance with another aspect of the invention there is provided a process for the prepara-tion of the compound of formula (I) which process com-30 prises reacting an amine of formula (II): I
'~ :
' ;
.
C ~ .
. ' . ,, - t ~
CH
3~ N~ \)3 ~N H (II) with an isocyanate of formula (III):
~ N - C O (III) The reaction is suitably carried out in an ether, for example, tetrahydrofuran.
The 3-amino-5-phenyl-1-methyl benzodi-azepines (II) are prepared as described in the prior art. Alternatively, 9 (R3=NH2) are prepared as shown in the following scheme:
/ NCH~//O C1l3/ O
1. KOtBu ~ ~ NO~I Ni(R) 2. iAmONO ~ ~32 ~ ~
`.."',:
Treatment of the 3-unsubstituted compound - with a suitable base, preferably potassium t-butoxide, following by a nitrosating agent, preferably isoamyl nitrite, provides the 3-oxime. Reduction, preferably -- 13 - 1~ 3 2 4 1 1 : -with Raney nickel, gives the 3-amino compound (II).
Alternatively compound (II~ is prepared by the method disclosed in U.S. Patent 4,628,084.
The 3-amino-5-phenyl-1-methyl benzodi-5 azepines (II) are reacted with isocyanates (III) to -~
produce the corresponding urea (I).
Where the starting materials are optically active, the chirality at C3 is controlled by the synthesis. When racemic starting materials are 10 employed, racemic products are obtained. The enan- -~
tiomers may be separated by resolution.
In Vitro ActivitY of Compound of Formula (I) The biological activity of the compound of formula (I) has been evaluated using l.)an 125I-CCK
receptor binding assay and in vitro isolated tissue preparations and 2.) 125I-gastrin and 3H-pentagastrin binding assays.
Materials and Methods 1. CCK Rece~tor Bindinq (PancreasL
CCK-33 was radiolabeled with 125I-Bolton Hunter reagent (2000 Ci/mmole) as described by Sankara et al. (J. Biol. Chem. 254: 9349-9351, 1979). Recep-tor 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, phenylmethane sulfonyl fluoride and o-phenanthroline. The latter two compounds have no effect on the 125I-CCK receptor binding assay.
Male Sprague-Dawley rats (200-350g) were sacrificed by decapitation. The whole pancreas was dissected free of fat tissue and was homogenized in 20 volumes of ice-cold 50 mM, Tris HCl (pH 7.7 at 20C) with a Brinkmann Polytron PT lOTM. The homogenates were centrifuged at 48,000 g for 10 min. Pellets were resuspended in Tris Buffer, centrifuged as above and C
`` - 14 - I 3324 ~ I
resuspended in 200 volumes of binding assay buffer (50 mM Tris HCl, pH 7.7 at 25C, 5mM dithiothrietol, 0.1 mM bacitracin, 1.2 mM phenylmethane sulfonyl fluoride and 0.5 mM 0-phenanthroline). For the binding assay, 25 ~1 of buffer (for total binding) or unlabeled CCK-8 sulfate to give a final concentration of l~M (for non-specific binding) or the compound of formula (I) (for determination of inhibition of 125I-CCK binding) and 25 ~1 of 125I-CCK-33 (30,000-40,000 cpm) were added to 450 ~1 of the membrane suspensions in microfuge tubes.
All assays were run in duplicate or triplicate. The reaction mixtures were incubated at 37C for 30 minutes and centrifuged in a Beckman MicrofugeTM (4 minutes) immediately after adding 1 ml of ice-cold ~;
incubation buffer. The supernatant was aspirated and discarded, pellets were counted with a Beckman gamma 5000. For Scatchard analysis (Ann. N~Y. Acad. Sci.
51: 660, 1949), 125I-CCK-33 was progressively diluted with increasing concentrations of CCK-33.
2. CCK Rece~tor Bindinq (Brain) CCK-33 was radiolabeled and the binding was performed according to the description for the pan-creas method with modifications according to Saito al., J. Neurochem. 37: 483-490, 1981.
Male Hartley guinea pigs (300-500g) were sacrificed by decapitation and the brains were removed and placed in ice-cold 50 mM, Tris HCl plus 7.58 g/l Trizma-7.4 (pH 7.4 at 25C). Cerebral cortex was dissected and used as a receptor source. Each gram of ;~
30 fresh guinea pig brain tissue was homogenized inilO ml ;~
of Tris/Trizma buffer with a Brinkmann polytron PT-10. ~-The homogenates were centrifugéd at 42,000 g for 15 minutes. Pellets were resuspended in Tris buffer, centrifuged as above and resuspended in 200 volumes of binding assay buffer (10 mM N-2-hydroxyethyl-piperazine-n'-2-ethane sulfonic acid (HEPES), 5 mM
' l~ ~ :. .
- 15 - 133~411 MgC12, 0.25 mg/ml bacitracin, 1 mM ethylene glycol-bis-(~-aminoethylether-N,N'-tetraacetic acid) (EGTA), and 0.4% bovine serum albumin (BSA)). For the binding assay, 25 ~1 of buffer (for total binding) or unlabeled CCK-8 sulfate to give a final concentration of 1 ~m (for nonspecific binding) or the compound of formula (I) (for determination of inhibition of 125I-CCK binding) and 25 ~1 of 125I-CCK-33 (30,000-40,000 cpm) were added to 450 ~1 of the membrane suspensions 10 in microfuge tubes. All assays were run in duplicate ;
or triplicate. The reaction mixtures were incubated at 25C for 2 hours and centrifuged in a Beckman Microfuge (4 minutes) immediately after adding 1 ml of ice-cold incubation buffer. The supernatant was aspirated and discarded, pellets were counted with a Beckman gamma 5000.
The compound of formula (I) can be deter-mined to be a competitive antagonist of CCK according to the following assays.
3. Isolated Guinea Piq Gall Bladder Male Hartley guinea pigs (400-600 g) are sacrificed by decapitation. The whole gall bladder is dissected free from adjacent tissues and cut into two equal halves. The gall bladder strips are suspended 25 along the axis of the bile duct in a 5 ml organ bath `
under 1 g tension. The organ bath contains a Kreb's bicarbonate solution (NaCl 118 mM, KCl 4.75 mM, CaCl `~
2.54 mM, KH2P~4 1.19 mM, mg SO4 1.2 mM, NaHC03 25 mM
and dextrose 11 mM) maintained at 32C and bubbled with 95% 2 and 5% CO2. Isometric contractions are recorded using Statham (60 g; 0.12 mm) strain gauges and a Hewlett-Packard (77588) recorder. The tissues are washed every 10 minutes for 1 hour to obtain equi-librium prior to the beginning of the study. CCK-8 is added cumulatively to the baths and ECsO'$ determined using regression analysis. After washout (every 10 ~: , ~ 3324 ~ I
.
::
minutes for 1 hour), the compound of formula (I) is added at least 5 minutes before the addition of CCK-8 and ECso of CCK-8 in the presence of the compound of , formula (I) similarly determined.
under 1 g tension. The organ bath contains a Kreb's bicarbonate solution (NaCl 118 mM, KCl 4.75 mM, CaCl `~
2.54 mM, KH2P~4 1.19 mM, mg SO4 1.2 mM, NaHC03 25 mM
and dextrose 11 mM) maintained at 32C and bubbled with 95% 2 and 5% CO2. Isometric contractions are recorded using Statham (60 g; 0.12 mm) strain gauges and a Hewlett-Packard (77588) recorder. The tissues are washed every 10 minutes for 1 hour to obtain equi-librium prior to the beginning of the study. CCK-8 is added cumulatively to the baths and ECsO'$ determined using regression analysis. After washout (every 10 ~: , ~ 3324 ~ I
.
::
minutes for 1 hour), the compound of formula (I) is added at least 5 minutes before the addition of CCK-8 and ECso of CCK-8 in the presence of the compound of , formula (I) similarly determined.
4. Isolated longitudinal muscle of quinea ~ , ~iq ileum Longitudinal muscle strips with attached nerve plexus are prepared as described in Brit. J. ~,~
Pharmac. 23: 356-363, 1964; J. Phvsiol. 194: 13-33, -10 1969. Male Hartley guinea pigs are decapitated and -~ ' the ileum removed (10 cm of the terminal ileum is dis- ~ , carded and the adjacent 20 cm piece used). A piece , (10 cm) of the ileum is stretched on a glass pipette.
Using a cctton applicator to stroke tangentially,away ' ~' from the mesentery attachment at one end, the longitu-dinal muscle is separated from the underlying circular ,'~
muscle. The longitudinal muscle is then tied to a thread and by gently pulling, stripped away from the entire muscle. A piece of approximately 2 cm is sus- ~' 20 pended in 5 ml organ bath containing Krebs solution ~, and bubbled with 95% 2 and 5% CO2 at 37G under 0.5 g `
tension. CCK-8 is added cumulatively to the baths and ';
ECso values in the presence and absence of the com~
pound of formula (I) determined as described in the ~,"''' , 25 gall bladder protocol (above). ' Gastrin Antaqonism Gastrin antagonist activity of the compound of formula (I) is determined using the following 'I assay. i ~ ;` ' ' 30 Gastrin Receptor Bindinq in Guinea Pi Gastric Glands ,~ ;
,Preparation of Guinea Piq Gastric Mucosal Glands Guinea pig gastric mucosal glands were pre- ,, pared by the procedure of Berglingh and Obrink Acta Physiol. Scand. 96: 150 (1976~ with a slight modifica-; ` ~'':
' ~ ` :
~ . :
-- - 17 - ~ 3~24 1 1 tion according to Praissman et al. C.J. Receptor Res.
3: (1983). Gastric mucosa from guinea pigs (300-500 g body weight, male Hartley) were washed thoroughly and minced with fine scissors in standard buffer consist-ing of the following: 130 mM NcCl, 12 mM NaHCO3, 3 mMNaH2PO4, 3 mM Na2HPO4, 3 mM K2HPO4, 2 mM MgSo4, 1 mM
CaC12, 5 mM glucose and 4 mM L-glutamine, 25 mM HEPES
at pH 7.4. The minced tissues were washed and then incubated in a 37C shaker bath for 40 minutes with the buffer containing 0.1% collagenase and 0.1% BSA
and bubbled with 95% 2 and 5% CO2. The tissues were passed twice through a 5 ml glass syringes to liberate the gastric glands, and then filtered through 200 mesh nylon. The filtered glands were centrifuged at 270 g for 5 minutes and washed twice by resuspension and centrifugation.
Bindinq Studies The washed guinea pig gastric glands pre-pared as above were resuspended in 25 ml of standard buffer containing 0.25 mg/ml of bacitracin. For bind-ing studies, to 220 ~1 of gastric glands in triplicate tubes, 10 ~1 of buffer (for total binding) or gastrin (1 ~M final concentration for nonspecific binding) or test compound and 10 ~1 of 125I-gastrin (NEN, 2200 Ci/mmole, 25 pM final) or 3H-pentagastrin (NEN 22 Ci/mmole, 1 nM final) were added. The tubes were aerated with 95% 2 and 5% CO2 and capped. The reac-tion mixtures after incubation at 25C for 30 minutes were filtered under reduced pressure on glass G/F B
filters (Whatman) and immediately washed further with 4 x 4 ml of standard buffer containing 0.1% BSA. The ~-radioactivity on the filters was measured using a Beckman gamma 5500 for 125I-gastrin or liquid scintil-lation counting for 3H-pentagastrin.
- ~
- 18 - 133241 1 :. :
In Vitro Results l. Effect of the ComPound of Formula (I) on 5I-CCK-33 Receptor Bindinq ;
, The compound of formula (I) inhibits ;~
specific l25I-CCK-33 binding in a concentration dependent manner.
Scatchard analysis of specific l25I-CCK-33 receptor binding in the absence and presence of the compound of formula (I) indicated the compound of -~
formula (I) competitively inhibited specific 125I-CCK-33 receptor binding since it increased the KD -~
(dissociation constant) without affecting the BmaX -(maximum receptor number). A Ki value (dissociation ~ ;
constant of inhibitor) of the compound of formula (I) 15 was estimated. ;~
The data in Table l were obtained for the compound of formula (I).
TABLE I
CCK Receptor Bindinq Results ~ -I
Compound of 125I-CCK ~25I_CCK l25I-Gastrin ~
ExamPle Pancreas Brain Gastxic Glands ~ ;
25 l 1.4 0.003 0.00066 The invention is further defined by refer~
ence to the following preparation and example which is intended to be illustrative and not limiting.
All temperatures are in degrees Celsius.
EXAMPLE l (R)-N-(2,3-Dihydro-l-methyl-2-oxo-5-phenyl-lH-1,4-benzodiaze~in-3-Yl)-N'-(3-methYlPhenYl)-urea Equimolar amounts of 3(R)-amino-1,3-dihydro- ~;~
35 l-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction : '~ ,; ,' : :.
~ . ~
~ - 19 1 3324 1 1 mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2Os to give , the analytical product: m.p. 208-210C.
Pharmac. 23: 356-363, 1964; J. Phvsiol. 194: 13-33, -10 1969. Male Hartley guinea pigs are decapitated and -~ ' the ileum removed (10 cm of the terminal ileum is dis- ~ , carded and the adjacent 20 cm piece used). A piece , (10 cm) of the ileum is stretched on a glass pipette.
Using a cctton applicator to stroke tangentially,away ' ~' from the mesentery attachment at one end, the longitu-dinal muscle is separated from the underlying circular ,'~
muscle. The longitudinal muscle is then tied to a thread and by gently pulling, stripped away from the entire muscle. A piece of approximately 2 cm is sus- ~' 20 pended in 5 ml organ bath containing Krebs solution ~, and bubbled with 95% 2 and 5% CO2 at 37G under 0.5 g `
tension. CCK-8 is added cumulatively to the baths and ';
ECso values in the presence and absence of the com~
pound of formula (I) determined as described in the ~,"''' , 25 gall bladder protocol (above). ' Gastrin Antaqonism Gastrin antagonist activity of the compound of formula (I) is determined using the following 'I assay. i ~ ;` ' ' 30 Gastrin Receptor Bindinq in Guinea Pi Gastric Glands ,~ ;
,Preparation of Guinea Piq Gastric Mucosal Glands Guinea pig gastric mucosal glands were pre- ,, pared by the procedure of Berglingh and Obrink Acta Physiol. Scand. 96: 150 (1976~ with a slight modifica-; ` ~'':
' ~ ` :
~ . :
-- - 17 - ~ 3~24 1 1 tion according to Praissman et al. C.J. Receptor Res.
3: (1983). Gastric mucosa from guinea pigs (300-500 g body weight, male Hartley) were washed thoroughly and minced with fine scissors in standard buffer consist-ing of the following: 130 mM NcCl, 12 mM NaHCO3, 3 mMNaH2PO4, 3 mM Na2HPO4, 3 mM K2HPO4, 2 mM MgSo4, 1 mM
CaC12, 5 mM glucose and 4 mM L-glutamine, 25 mM HEPES
at pH 7.4. The minced tissues were washed and then incubated in a 37C shaker bath for 40 minutes with the buffer containing 0.1% collagenase and 0.1% BSA
and bubbled with 95% 2 and 5% CO2. The tissues were passed twice through a 5 ml glass syringes to liberate the gastric glands, and then filtered through 200 mesh nylon. The filtered glands were centrifuged at 270 g for 5 minutes and washed twice by resuspension and centrifugation.
Bindinq Studies The washed guinea pig gastric glands pre-pared as above were resuspended in 25 ml of standard buffer containing 0.25 mg/ml of bacitracin. For bind-ing studies, to 220 ~1 of gastric glands in triplicate tubes, 10 ~1 of buffer (for total binding) or gastrin (1 ~M final concentration for nonspecific binding) or test compound and 10 ~1 of 125I-gastrin (NEN, 2200 Ci/mmole, 25 pM final) or 3H-pentagastrin (NEN 22 Ci/mmole, 1 nM final) were added. The tubes were aerated with 95% 2 and 5% CO2 and capped. The reac-tion mixtures after incubation at 25C for 30 minutes were filtered under reduced pressure on glass G/F B
filters (Whatman) and immediately washed further with 4 x 4 ml of standard buffer containing 0.1% BSA. The ~-radioactivity on the filters was measured using a Beckman gamma 5500 for 125I-gastrin or liquid scintil-lation counting for 3H-pentagastrin.
- ~
- 18 - 133241 1 :. :
In Vitro Results l. Effect of the ComPound of Formula (I) on 5I-CCK-33 Receptor Bindinq ;
, The compound of formula (I) inhibits ;~
specific l25I-CCK-33 binding in a concentration dependent manner.
Scatchard analysis of specific l25I-CCK-33 receptor binding in the absence and presence of the compound of formula (I) indicated the compound of -~
formula (I) competitively inhibited specific 125I-CCK-33 receptor binding since it increased the KD -~
(dissociation constant) without affecting the BmaX -(maximum receptor number). A Ki value (dissociation ~ ;
constant of inhibitor) of the compound of formula (I) 15 was estimated. ;~
The data in Table l were obtained for the compound of formula (I).
TABLE I
CCK Receptor Bindinq Results ~ -I
Compound of 125I-CCK ~25I_CCK l25I-Gastrin ~
ExamPle Pancreas Brain Gastxic Glands ~ ;
25 l 1.4 0.003 0.00066 The invention is further defined by refer~
ence to the following preparation and example which is intended to be illustrative and not limiting.
All temperatures are in degrees Celsius.
EXAMPLE l (R)-N-(2,3-Dihydro-l-methyl-2-oxo-5-phenyl-lH-1,4-benzodiaze~in-3-Yl)-N'-(3-methYlPhenYl)-urea Equimolar amounts of 3(R)-amino-1,3-dihydro- ~;~
35 l-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction : '~ ,; ,' : :.
~ . ~
~ - 19 1 3324 1 1 mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2Os to give , the analytical product: m.p. 208-210C.
5 NMR: Confirms structure assignment of product. -~
HPLC: Greater than 99% pure.
MS: Molecular ion at m/e=399 (FAB).
Anal. Cald'd for C24H22N402:
C, 72.34; H, 5.56; N, 14.06 Found: C, 72.12; H, 5.84; N, 14.04 C :' - .
~ ' ' .
HPLC: Greater than 99% pure.
MS: Molecular ion at m/e=399 (FAB).
Anal. Cald'd for C24H22N402:
C, 72.34; H, 5.56; N, 14.06 Found: C, 72.12; H, 5.84; N, 14.04 C :' - .
~ ' ' .
Claims (23)
1. A compound of formula (I) (I) and pharmaceutically acceptable salts thereof.
2. (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea.
3. A pharmaceutically acceptable salt of (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodi-azepin-3-yl)-N'-(3-methylphenyl)urea.
4. A salt according to claim 3 of an inorganic acid selected from the group consisting of hydro-chloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric.
5. A salt according to claim 3 of an organic acid selected from the group consisting of acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxy-maleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluene-sulfonic, methanesulfonic, ethane disulfonic, oxalic and isethionic.
6. A pharmaceutical composition comprising a compound or salt as claimed in claim 1, 3, 4 or 5 and a pharmaceutically acceptable carrier therefor.
7. A pharmaceutical composition comprising the urea of claim 2 in association with a pharmaceutically acceptable carrier therefor.
8. A cholecystokinin antagonist pharmaceutical composition comprising an acceptable cholecystokinin antagonistic amount of a compound or salt of claim 1, 3, 4 or 5 in association with a pharmaceutically acceptable carrier therefor.
9. A cholecystokinin antagonist pharmaceutical composition comprising an acceptable cholecystokinin antagonistic amount of (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methyl-phenyl)urea, in association with a pharmaceutically acceptable carrier.
10. A gastrin antagonist pharmaceutical composi-tion comprising an acceptable gastrin antagonistic amount of a compound or salt of claim 1, 3, 4 or 5 in association with a pharmaceutically acceptable carrier.
11. A gastrin antagonist pharmaceutical composi-tion comprising an acceptable gastrin antagonistic amount of (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea, in association with a pharmaceutically acceptable carrier.
12. A cholecystokinin and gastrin antagonist pharmaceutical composition comprising an acceptable cholecystokinin and gastrin antagonistic amount of a compound or salt of claim 1, 3, 4 or 5, in association with a pharmaceutically acceptable carrier.
13. A cholecystokinin and gastrin antagonist pharmaceutical composition comprising an acceptable cholecystokinin and gastrin antagonistic amount of (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea, in asso-ciation with a pharmaceutically acceptable carrier.
14. A compound of formula (I) or pharmaceuti-cally acceptable salt thereof as defined in claim 1, 3, 4 or 5 for use in antagonizing the binding of cholecystokinins to cholecystokinin receptors.
15. A compound of formula (I) or pharmaceuti-cally acceptable salt thereof as defined in claim 1, 3, 4 or 5 for use in antagonizing the binding of gastrin to gastrin receptors.
16. (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea for use in antagonizing the binding of cholecystokinins to cholecystokinin receptors.
17. (R)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea for use in antagonizing the binding of gastrin to gastrin receptors.
18. The use of a compound of formula (I) or salt as claimed in claim 1, 3, 4 or 5 for the manufacture of a medicament for antagonizing the binding of cholecystokinins to cholecystokinin receptors or antagonizing the binding of gastrin to gastrin receptors.
19. The use of (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methyl-phenyl)urea in the manufacture of a medicament for antagonizing the binding of cholecystokinins to cholecystokinin receptors or antagonizing the binding of gastrin to gastrin receptors.
20. A process for the preparation of a compound of formula (I):
(I) which process comprises reacting an amine of formula (II):
(II) with an isocyanate of formula (III):
(III)
(I) which process comprises reacting an amine of formula (II):
(II) with an isocyanate of formula (III):
(III)
21. A process for the preparation of (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea comprising reacting 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzo-diazepin-2-one with 3-methylphenyl isocyanate.
22. The process as claimed in claim 20 or 21 carried out in an ether.
23. The process as claimed in claim 22 wherein the ether is tetrahydrofuran.
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US026,420 | 1987-03-16 |
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ZA881866B (en) | 1988-09-06 |
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US4820834A (en) | 1989-04-11 |
JP3039783B2 (en) | 2000-05-08 |
IL85668A (en) | 1995-03-30 |
DK139588A (en) | 1989-01-06 |
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KR880011126A (en) | 1988-10-26 |
PT86980A (en) | 1988-04-01 |
CY1948A (en) | 1988-03-11 |
AU1313388A (en) | 1988-09-15 |
DE3889756T2 (en) | 1994-12-08 |
KR960012197B1 (en) | 1996-09-16 |
IL85668A0 (en) | 1988-08-31 |
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