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WO1993012817A1 - Therapeutic combinations useful in the treatment of gastroesophageal reflux disease - Google Patents

Therapeutic combinations useful in the treatment of gastroesophageal reflux disease Download PDF

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Publication number
WO1993012817A1
WO1993012817A1 PCT/US1992/010692 US9210692W WO9312817A1 WO 1993012817 A1 WO1993012817 A1 WO 1993012817A1 US 9210692 W US9210692 W US 9210692W WO 9312817 A1 WO9312817 A1 WO 9312817A1
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Prior art keywords
amino
oxo
methyl
gastrin
cck
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PCT/US1992/010692
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French (fr)
Inventor
David Christopher Horwell
John Cureton Hunter
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Warner-Lambert Company
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • gastrin exerts many pharmacological effects throughout the gastrointestinal (GI) tract, it appears that its main physiological functions are stimulation of acid secretion in the stomach, and stimulation of mucosal growth in the stomach, small intestine, and colon.
  • GI gastrointestinal
  • the secretory activity of the gastrin-producing G-cell of the gastric antru depen s on the intragastric pH, on the presence c . absence of food in the stomach lumen, and on the activity of several epigastric endocrine, paracrine, or neuronal systems.
  • abolition of acid secretion, as in the achlorhydria of pernicious anemia is accompanied by a marked hypergastrinemia where gastrin levels may reach those seen in patients with gastrinoma, or with Zollinger Ellison syndrome (Yalow, R. S. and Berson, S. A., Radioimmunoassay of gastrin, Gastroenteroloqy 58:1-14 (1970); McGuigan, J. E.
  • Hyperfunction of the G-cell in achlorhydria of pernicious anemia or after vagotomy is associated with increases in G-cell number in the antral mucosa, but the hyperplasia of the G-cell is a consequence of achlorhydria itself, and is independent of the degree of hypergastrinemia.
  • gastric mucosal cells such as the acid-secreting parietal cell, or the histamine-for ing enterochromaffin-like cell (ECL-cel ) , where gastrin has a trophic function
  • the hyperplasia of achlorhydria will be dependent on hypergastrinemia (Becker, H. D., Arnold, R., B ⁇ rger, H.
  • the action of the former class of agent is by antagonism of the receptors for the histamine that has a dominant role in producing secretion of H + -ions by the parietal cell; the latter group inhibit acid secretion by a direct action at sulphydryl groups of the H + /K + -ATPase of the parietal cell membrane.
  • Treatment with either class of compound will produce achlorhydria, and a resulting hypergastrinemia; this in turn will affect the growth of GI mucosal cells.
  • the instant invention concerns pharmaceutical compositions containing a CCK-B/gastrin antagonist or a long-acting and potent H 2 antagonist and an ATP'ase proton pump inhibitor with or without a pharmaceutically acceptable carrier.
  • CCK B antagonists include but are not limited to: L-365-091 which is 1-( (3-( ( ( (4-chlorophenyl)- amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-l-yl)acetyl)-pyrrolidine; and (S)-5-[ (10,ll-dihydrodibenzo[a,d]cyclohepten- 5-yl)amino] -[ (lH-indol-2-yl)carbonyl]amino]-5-oxo- pentanoic acid.
  • L-365,260 which is (R)-N-(2,3-dihydro-l-methyl-2- oxo-5-phenyl-lH-l, -benzodiazepine-3-yl)-N'-(3- methyIpheny1)urea,
  • LY—262,690 which is fcrans-l-Pyrazolidinecarboxa- mide, 5-(2-chlorophenyl) -3-oxo-4-phenyl-N- [A-(tri- luoromethyl)pheny1]-,
  • LY-262,691 which is trans-5-(2-chlorophenyl)- 3-oxo-4-phenyl-N-[4-(bromo)phenyl]-1-pyrazolidine- carboxamide, and trans—l-pyrazolidinecarboxamide-N-(4- bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-.
  • R 1 is 2,3-dichloro, 3,4-(CH 2 ) 4 , 4-CF 3 , or 4-Br;
  • R 2 is hydrogen, 2-chloro, 2,3—dichloro, or CN; and R 3 is hydrogen -trans or -cis.
  • X 0 is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl
  • X j! is hydrogen, fluorine, chlorine, bromine, methyl ethyl isopropyl, methoxy, trifluoromethyl, propoxy, isopropoxy, cyclopentyloxyl, MeS, or NMe 2 ;
  • X p is hydrogen, methoxy, ethoxy, isopropoxy, isopropyl, MeS, or NMe 2 ; or X_, and X_ together are -OCH 2 0-; Y is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine; and
  • R is hydrogen or methyl
  • Proton pump inhibitors include but are not limited to: omeprazole, BY308, SK&F 95601 which is 2-[[ (3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]- 5-methoxy-(IH)-benzimidazole; and SK&F 96067 which is 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline.
  • the instant invention also includes a method of treating peptic disorders such as gastroesophageal reflux disease and ulcers.
  • the instant invention also includes a method of treating Zollinger-Ellison Syndrome.
  • compositions of the instant invention contain from 0.1 mg/kg to 10 mg/kg of a CCK-B antagonist and from 10 mg to 360 g of an ATP'ase proton pump inhibitor.
  • Figure I shows serum gastrin levels in venous blood from rats.
  • Figure II shows enterochromaffin-like cell (ECL) proliferation in the corpus of rat gastric mucosa.
  • Irreversible proton pump inhibitors such as omeprazole, BY308, and others are extremely effective in gastroesophageal reflux disease (GERD) , as indeed are the longer acting and potent H 2 antagonists, as well as in all other peptic disorders caused or aggravated by gastric acid.
  • GFD gastroesophageal reflux disease
  • a long-acting H 2 antagonist means dosing usually is once per day; that is once in 24 hours, usually nocturnally.
  • the compounds cause carcinoid tumors in animals because of the elevated levels of gastrin. This problem means that the duration of treatment with, for example, omeprazole in GERD is restricted.
  • Gerd is a chronic problem and the relief to sufferers provided by existing treatments renders them dependent on permanent therapy.
  • Proton pump inhibitors are also useful in the treatment of ulcers but the same problems pertain to the use of the drugs for ulcer treatment.
  • Proton pump inhibitors are also useful in the long-term treatment of Zollinger-Ellison syndrome.
  • the pharmaceutical compositions of the instant invention that contain combinations of an ATP'ase proton pump inhibitor and a CCK-B antagonist are useful for all of the above problems.
  • a CCK-B antagonist blocks the cellular hypertrophy of gastric mucosal cells.
  • Gastrin has been implicated as a growth factor in many areas of the gastrointestinal and respiratory tracts.
  • G-cell mass in the gastric mucosa.
  • ECL enterochromaffin-like cells
  • gastric carcinoid tumors formed from ECL cell hyperplasia in omeprazole-treated rats are related to the achlorhydria and secondary hypergastrinemia produced by the drug. If this is the case then treatment with gastrin antagonists should- inhibit this omeprazole—induced phenomeno .
  • gastrin-dependent tumors include a human small cell carcinoma of the lung, which was recently reported to contain CCK-B/gastrin receptors, and a mouse carcinoid tumor of the colon.
  • CCK-B/gastrin antagonist compounds of the instant invention are able to block acid secretion in the rat in response to stimulation by pentagastrin
  • Proton pump inhibitors such as omeprazole, 5-methoxy-2-[ [ (4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfinyl]-IH-benzimidazole, which are described and claimed in United States Patent 4,255,431, are useful in the instant invention.
  • the patent is hereby incorporated by reference.
  • proton pump inhibitors include but are not limited to: [[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl]- methyl]sulfenamide;
  • Figure I concerns serum gastrin levels. It shows levels of gastrin-like immunoreactivity in venous blood from rats, before and after 1, 4, 7, or 14 days of treatment with vehicles (veh/veh: isotonic saline 3 subcutaneous injections at 8-hour intervals, methocel orally at 8:00 a.m.)
  • Compound 1 which is [R-[R*,S*-(E) ] ] ] -A-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.l 3,7 ]dec-2-yloxy)- carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4- oxo-2-butenoic acid, 18 mg/kg thrice daily (veh/1189) , BY 308 40 mg/kg orally in methocel (308/veh) or BY 30
  • Figure II concerns ECL-cell proliferation in the corpus. It shows the uptake of 3 H-thymidine into enterochromaffin-like cells (ECL-cell) of rat gastric mucosa after 14 days of treatments (as Figure 1) ; and labelled ECL-cells as a percentage of total ECL-cell count in the field ("labelling index") .
  • I ⁇ M is Methocel/NaCl; &22Z229 i- s Methocel/compound 1; is BY308/NaCl; and ⁇ g is BY308/compound 1.
  • Fe ale Sprague-Dawley rats were used with free access to lab diet and water. Groups of 10 animals were treated three times daily with 18 mg/kg of compound 1 for 14 days as follows:
  • Blood was drawn from the retro-orbital venous plexus before treatment on Days 0, 1, 4, 7, and 14 for assay of serum gastrin and CCK levels.
  • H-thymidine was infused into a tail vein (1 ⁇ ci/g body weight as a bolus injection, followed by continuous infusion for 8 hours of 0.25 ⁇ Ci/g/h) , for subsequent measurement of ECL-cel labeling index by autoradiography.
  • Optimal tissue preservation was achieved by perfusion fixation in Bouin's fixative for 8 minutes, and by fixation for 24 hours of excised tissue blocks in Bouin's solution, with embedding in paraffin wax.
  • 5 ⁇ m sections were cut; 2 ⁇ m for autoradiography (Eissele, R., Rosskopf, B., Koop, H., Adler, G., and Arnold, R.,
  • Antral G-cells were visualized after removal of the paraffin wax by immunostaining for gastrin using the avidin-biotin-peroxidase complex technique (Hsu, S. M., Raine, L., and Fanger, H., Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques; a comparison between ABC and unlabeled antibody (PAP) procedures, J Histochem Cvtochem 29:577-780 (1981)) .
  • avidin-biotin-peroxidase complex technique Hsu, S. M., Raine, L., and Fanger, H., Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques; a comparison between ABC and unlabeled antibody (PAP) procedures, J Histochem Cvtochem 29:577-780 (1981)
  • ECL-cell density was evaluated in sections of oxyntic mucosa by the silver impregnation method or by immunostaining for chromogranin for autoradiographic studies (Grimelius, L., A silver nitrate stain for A 2 cells of human pancreatic islets, Acta Soc Med Ups 73:271-294 (1968) ) .
  • Gastrin levels in unfixed sections of antrum and somatostatin in the fundus were measured by radioimmunoassay. Unfixed samples of pancreas were taken to assay for enzyme and DNA levels by standard methods. .
  • Antral mucosal G-cells were increased from 56/mm (saline + methocel), or 60 ⁇ mm ( ( [R-[R*,S*-(E) ] ]-4-[ [2- [[3-(lH-indol-3-yl)-2-methyl-l-oxo-2-[ [ (tricyclo- [3.3.1.1 3 ' 7 ]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]amino]-4-oxo-2-butenoic acid, + methocel) to 75/mm and 88/mm in the corresponding groups given BY 308.
  • the increases by BY 308 were statistically significant at the 2% level. That is, the increase in G-cell number is attributable to the achlorhydria, and is obtained in either group treated with BY 308.
  • CCK B /gastrin antagonists are expected to have clinical utility in the periphery, in the management of gastrin-dependent hyperplasias.
  • compositions or combinations of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides pharmaceutical compositions comprising a compound which is a CCK-B/gastrin antagonist (or a long-acting and potent H 2 antagonist) or a pharmaceutically acceptable salt thereof and a proton pump inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, if desired.
  • composition can be given orally formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules, and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound of pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, nonaqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, nonaqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose, and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates, or oils, and the dispersion or suspension, then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil.
  • a typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins, or cocoa butter or other low melting vegetable or synthetic waxes or fats.
  • composition is in unit dose form such as a tablet or capsule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains pre erably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the pharmaceutically acceptable compositions of the invention will normally be administered to a subject for the treatment of peptic disorders and other conditions caused or exacerbated by gastric acidity.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example, for a week or more.
  • composition of the present invention can be coadministered with further active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminum hydroxide) , nonsteroidal antiinflammatory drugs (for example, indomethacin, aspirin, or naproxen) , steroids, or nitrite scavengers (for example, ascorbic acid or aminosulphonic acid) , or other drugs used for treating gastric ulcers (for example, pirenzepine, prostanoids, for example, 16, 16-dimethyl PGE 2 , or histamine H 2 -antagonists (for example, cimetidine, ranitidine, famotidine, and mareatidine) .
  • active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminum hydroxide) , nonsteroidal antiinflammatory drugs (for example, indomethacin, aspirin, or naproxen) , steroids, or nitrite scavengers (for example, as
  • a syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
  • Flavoring agent 0.1 g
  • Phenylacetic acid (54.46 g, 0.4 M) was dissolved in acetic anhydride (80 mL) .
  • O-chlorobenzaldehyde (56.23 g, 0.4 M) was added slowly, with stirring. This was followed by the slow addition of triethylamine (40 mL) .
  • the reaction mixture was stirred at reflux for 5 hours.
  • the reaction mixture was steam distilled until the distillate was no longer cloudy.
  • the distillate was discarded.
  • the aqueous residue was cooled.
  • the solution was decanted from the gummy solid. This solid was dissolved in a 10% K 2 C0 3 solution.
  • the basic solution was charcoaled then filtered through a pooled Super cell.
  • the filtrate was made acidic (pH 1) with 10% HC1, cooled, and the solid filtered.
  • the product was recrystallized from 50% ethanol/H 2 0 to yield 52.14 g of white solid, mp 158
  • Step 2 Preparation of c-phenyl-2-chlorocinnamic acid methyl ester oPhenyl-2-chlorocinnamic acid (26.29 g (0.102 M) was dissolved in ethanol (300 cc) . Anhydrous HC1 was bubbled through the reaction mixture with stirring for 15 minutes. The reaction mixture was refluxed for 2 hours, then HC1 was bubbled through the reaction mixture for another 15 minutes. The reaction was stirred at reflux overnight. The methanol was removed in vacuo and the residue taken up in ether. The ether solution was washed with H 2 0, saturated NaHC0 3 solution, and brine. It was then dried over MgS0 4 . The ether solution was concentrated in vacuo to yield an oil that quickly solidified to yield 27.13 g of product, mp 67-69°C.

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Abstract

The invention concerns combinations of proton pump inhibitors and CCK-B/gastrin antagonists in pharmaceutical compositions that are useful in the treatment of peptic disorders such as ulcers and gastroesophageal reflux disease and in the treatment of Zollinger-Ellison Syndrome.

Description

THERAPEUTIC COMBINATIONS USEFUL IN THE TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE
BACKGROUND OF THE INVENTION
Although gastrin exerts many pharmacological effects throughout the gastrointestinal (GI) tract, it appears that its main physiological functions are stimulation of acid secretion in the stomach, and stimulation of mucosal growth in the stomach, small intestine, and colon.
The secretory activity of the gastrin-producing G-cell of the gastric antru depen s on the intragastric pH, on the presence c . absence of food in the stomach lumen, and on the activity of several epigastric endocrine, paracrine, or neuronal systems. Thus, abolition of acid secretion, as in the achlorhydria of pernicious anemia, is accompanied by a marked hypergastrinemia where gastrin levels may reach those seen in patients with gastrinoma, or with Zollinger Ellison syndrome (Yalow, R. S. and Berson, S. A., Radioimmunoassay of gastrin, Gastroenteroloqy 58:1-14 (1970); McGuigan, J. E. and Trudeau, W. L., Serum gastrin concentrations in pernicious anemia, New Engl J Med 282:358-61 (1970); Creutzfeld, ., Arnold, R. , Creutzfeld, C, Feurle, G., and Ketterer, H., Gastrin and G-cells in the antral mucosa of patients with pernicious anemia, acromegaly and hyperthyroidism and in a Zollinger- Ellison tumor of the pancreas, Eur J Clin Invest 1:461-79 (1971); Ganguli, P. C, Cullen, D. R. , and Irvine, . J., Radioimmunoassay of plasma gastrin in pernicious anaemia, achlorhydria without pernicious anaemia, hypochlorhydria, and in controls, Lancet i:155-58 (1971)) .
Hyperfunction of the G-cell in achlorhydria of pernicious anemia or after vagotomy is associated with increases in G-cell number in the antral mucosa, but the hyperplasia of the G-cell is a consequence of achlorhydria itself, and is independent of the degree of hypergastrinemia. However, in other gastric mucosal cells such as the acid-secreting parietal cell, or the histamine-for ing enterochromaffin-like cell (ECL-cel ) , where gastrin has a trophic function, the hyperplasia of achlorhydria will be dependent on hypergastrinemia (Becker, H. D., Arnold, R., Bδrger, H. W., Creutzfeld, C, Schafmayer, A., and Creutzfeld, W., Influence of truncal vagotomy on serum and antral gastrin and G-cells, Gastrpenterology 72:811 (1977); Delince, P., Williams, G., and de Graef, J., Antral gastrin cell proliferation after vagotomy in rats, Dicrestion 18:27-34 (1978); Arnold, R., von Hύlst, M., Neuhof, C, Schwarting, H., Becker, H. D., and Creutzfeld, W., Antral gastrin-producing G-cells and somatostatin-producing D-cells in different states of acid secretion. Gut 23:285-91 (1982); Larsson, H., Carlsson, E., Hakabnson, R., Mattsson, M., Nilsson, G.,
Seensalu, R., Wallmark, B., and Sundler, F., Time course of development and reversal of gastric endocrine cell hyperplasia after inhibition of acid secretion. Studies with omeprazole and ranitidine in intact and adrenalectomized rats. Gastroenteroloqy 95:1477-86 (1988); Hakanson, R., Oscarson, J. , and Sundler, F., Gastrin and the trophic control of gastric mucosa, Scand J Gastroenterol 21(suppl. 118) :18-30 (1986)). The most powerful pharmacological agents for blocking acid secretion, clinically or experimentally, are the H2-ant gonists and the benzimidazole proton-pump inhibitors. The action of the former class of agent is by antagonism of the receptors for the histamine that has a dominant role in producing secretion of H+-ions by the parietal cell; the latter group inhibit acid secretion by a direct action at sulphydryl groups of the H+/K+-ATPase of the parietal cell membrane. Treatment with either class of compound will produce achlorhydria, and a resulting hypergastrinemia; this in turn will affect the growth of GI mucosal cells. This effect has been most thoroughly investigated with omeprazole, or related compounds, in the rat stomach, but it is reported that treatment with the H2-antagonist ranitidine is equally effective in producing hyperplasia of ECL—cells, and that toxicological studies in rats with omeprazole, or H2-antagonists have revealed that chronic treatments were associated with increased incidence of carcinoid tumors. (Creutzfeld, W., Stockman, F., Conlon, J. M., Fδlsch, U. R. , Bonatz, G. , and Wulfrath, M., Effect of short and long-term feeding of omeprazole on rat gastric endocrine cells, Digestion 35(suppl. 1):84-97 (1986); Allen, J. M., Bishop, A. E., Daley, M. J., Larsson, H., Carlsson, E., Polack, J. M., and Bloom, S. R., Effect of inhibition of acid secretion on the regulatory peptides in the rat stomach, Gastroenteroloqy 90:970-077 (1986); Larsson, H., Carlsson, E., Mattsson, H., Lundell, L., Sundler, F., Sundell, G., Wallmark, B., Watanabe, T., and Hakonson, R., Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation. Studies with omeprazole and ranitidine in intact and adrenalectomized rats, Gastroenteroloqy 90:391-399 (1986); Koop, H. , Wille er, S., Steinbach, F., Eiselle, R., Tuch, K., and Arnold, R., Influence of chronic drug-induced achlorhydria by substituted benzimidazoles on the endocrine stomach in rats, Gastroenteroloqy 92:406-13 (1987); Ryberg, B., Bishop, A. E., Bloom, S. R., Carlsson, E., Hakonson, R., Larsson, H., Mattsson, H., Polack, J. M., and Sundler, F., Omeprazole and ranitidine, antisecretagogues with different modes of action, are equally effective in causing hyperplasia of enterochromaffin-like cells in the rat stomach, Regul Pept 25:235-246 (1989); Betton, G.s R., Dormer, C. S., Wells, J., Pert, P., Price, C. A., and Buckley, P., Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SKF 93479 and oxmetidine and omeprazole, Toxicol Pathol 16:288-98 (1988)).
It is clear that with long-term therapy utilizing powerful blockers of acid secretion where hypergastrinemia is apparent, there may be consequences for either the growth, or turnover rate of GI mucosal cells, with the hypersecretion of gastrin a causal factor. It is also clear that if any of the effects of the hypergastrinemia of iatrogenic achlorhydria may be of serious clinical consequences, and they are to be avoided, there will be a clinical role for any agent that is a selective blocker of the release of gastrin, or a selective blocker of the action of gastrin at its receptor. Although antagonists of gastrin-releasing peptide
("bombesin antagonists") are known, no agent has been available that will produce a powerful and selective block of the release of gastrin. SUMMARY OF THE INVENTION
The instant invention concerns pharmaceutical compositions containing a CCK-B/gastrin antagonist or a long-acting and potent H2 antagonist and an ATP'ase proton pump inhibitor with or without a pharmaceutically acceptable carrier.
CCKB antagonists (gastrin antagonists) include but are not limited to: L-365-091 which is 1-( (3-( ( ( (4-chlorophenyl)- amino)carbonyl)amino)-2,3-dihydro-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-l-yl)acetyl)-pyrrolidine; and (S)-5-[ (10,ll-dihydrodibenzo[a,d]cyclohepten- 5-yl)amino] -[ (lH-indol-2-yl)carbonyl]amino]-5-oxo- pentanoic acid.
Other compounds useful in the compositions and methods of the instant invention are:
L-365,260 which is (R)-N-(2,3-dihydro-l-methyl-2- oxo-5-phenyl-lH-l, -benzodiazepine-3-yl)-N'-(3- methyIpheny1)urea,
Butanoic acid, 4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ [ (1,7,7-trimethylbicyclo[2.2.l]hept- 2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]- amino]-4-oxo-, [lS-[lα,2β[S* (S*) ] ,4β]]-, [R-[R*,S*-(E) ]]-4-[ [2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.13' ]dec-2-yloxy)- carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4- oxo-2-butenoic acid,
[R-(R*,R*) ]-4-[ [2-[ [3-(lH-indol-3-yl)^-methyl-I¬ oxo-2-[[ (tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- amino]propyl]amino-1-phenylethyl]amino]-4-oxo-butanoic acid,
[R-[R*,R*-(E) ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.13'7]dec-2-yloxy)- carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4- oxo-2-butenoic acid,
LY—262,690 which is fcrans-l-Pyrazolidinecarboxa- mide, 5-(2-chlorophenyl) -3-oxo-4-phenyl-N- [A-(tri- luoromethyl)pheny1]-,
LY-262,691 which is trans-5-(2-chlorophenyl)- 3-oxo-4-phenyl-N-[4-(bromo)phenyl]-1-pyrazolidine- carboxamide, and trans—l-pyrazolidinecarboxamide-N-(4- bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-.
Other compounds useful in the instant invention are pyrazolidinones of formula
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof wherein R1 is 2,3-dichloro, 3,4-(CH2)4, 4-CF3, or 4-Br;
R2 is hydrogen, 2-chloro, 2,3—dichloro, or CN; and R3 is hydrogen -trans or -cis.
These are disclosed in Drugs of the Future 16(7) :631-740 (1991) . The compounds are made as described in Synthetic Examples 1 and 2 below.
Other compounds useful in the compositions and methods of treatment of the instant invention and quinazolinones disclosed in J. Med. Chem. 34:1505-1508 (1991) of formula
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof wherein X0 is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl; Xj! is hydrogen, fluorine, chlorine, bromine, methyl ethyl isopropyl, methoxy, trifluoromethyl, propoxy, isopropoxy, cyclopentyloxyl, MeS, or NMe2;
Xp is hydrogen, methoxy, ethoxy, isopropoxy, isopropyl, MeS, or NMe2; or X_, and X_ together are -OCH20-; Y is hydrogen, methyl, methoxy, fluorine, chlorine, or bromine; and
R is hydrogen or methyl.
Although several synthetic routes are available for preparing the above series, the compounds are also made as described in Synthetic Example 3 below. Proton pump inhibitors include but are not limited to: omeprazole, BY308, SK&F 95601 which is 2-[[ (3-chloro-4-morpholino-2-pyridyl)methyl]sulfinyl]- 5-methoxy-(IH)-benzimidazole; and SK&F 96067 which is 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline. The instant invention also includes a method of treating peptic disorders such as gastroesophageal reflux disease and ulcers.
The instant invention also includes a method of treating Zollinger-Ellison Syndrome.
The compositions of the instant invention contain from 0.1 mg/kg to 10 mg/kg of a CCK-B antagonist and from 10 mg to 360 g of an ATP'ase proton pump inhibitor. Especially preferred is a composition of
[R-(R*,R*) ] -A- i[2-[[3-(lH-indol-3-yl)-2-methyl-l-oxo- 2-[[ (tricyclot3.3.1.13'7]dec-2-yloxy)carbonyl]- amino] ropyl]amino-1-phenylethyl]amino]-4—oxo-butanoic acid and omeprazole.
BRIEF DESCRIPTION OF DRAWINGS
Figure I shows serum gastrin levels in venous blood from rats. Figure II shows enterochromaffin-like cell (ECL) proliferation in the corpus of rat gastric mucosa.
DETAILED DESCRIPTION
Irreversible proton pump inhibitors such as omeprazole, BY308, and others are extremely effective in gastroesophageal reflux disease (GERD) , as indeed are the longer acting and potent H2 antagonists, as well as in all other peptic disorders caused or aggravated by gastric acid. A long-acting H2 antagonist means dosing usually is once per day; that is once in 24 hours, usually nocturnally. Unfortunately, the compounds cause carcinoid tumors in animals because of the elevated levels of gastrin. This problem means that the duration of treatment with, for example, omeprazole in GERD is restricted.
Omeprazole is indicated for short-term treatment
(4-8 weeks) . rPhvsicians' Desk Reference (1991) ] . Reversible inhibitors of the gastric (H+ and K+)-ATP'ase, such as SK&F 96067 are also included in the instant invention.
Gerd is a chronic problem and the relief to sufferers provided by existing treatments renders them dependent on permanent therapy. Proton pump inhibitors are also useful in the treatment of ulcers but the same problems pertain to the use of the drugs for ulcer treatment.
Proton pump inhibitors are also useful in the long-term treatment of Zollinger-Ellison syndrome. The pharmaceutical compositions of the instant invention that contain combinations of an ATP'ase proton pump inhibitor and a CCK-B antagonist are useful for all of the above problems.
At high doses of omeprazole, for example, which totally suppress gastric acid secretion and raise gastrin blood levels very significantly, a CCK-B antagonist blocks the cellular hypertrophy of gastric mucosal cells.
Gastrin antagonists coadministered with proton pump inhibitors offer great therapeutic advantage over
H2 antagonists. Gastrin has been implicated as a growth factor in many areas of the gastrointestinal and respiratory tracts.
Studies have shown that achlorhydria. causes a marked hypergastrinemia due to hypertrophy, hyperplasia, and hyperfunction of the gastrin-cell
(G-cell) mass in the gastric mucosa. This increased gastrin secretion, in turn, has been suggested to be the underlying cause of a proliferation of the number, size, and activity of the enterochromaffin-like (ECL) cells in the gastric or duodenal mucosa in achlorhydric animals. Thus, it appears that gastric carcinoid tumors formed from ECL cell hyperplasia in omeprazole-treated rats are related to the achlorhydria and secondary hypergastrinemia produced by the drug. If this is the case then treatment with gastrin antagonists should- inhibit this omeprazole—induced phenomeno .
Other gastrin-dependent tumors include a human small cell carcinoma of the lung, which was recently reported to contain CCK-B/gastrin receptors, and a mouse carcinoid tumor of the colon.
CCK-B/gastrin antagonist compounds of the instant invention are able to block acid secretion in the rat in response to stimulation by pentagastrin
(Hayward, N. J., Harding, M., Lloyd, S. A. C, McKnight, A. T., Hughes, J., and Woodruff, G. N., The effect of CCKB gastrin antagonists on stimulated gastric acid secretion in the anesthetized rat, Br J Pharmacol, 104: 973-977 (1991).
Some of the compounds that are CCK-B antagonists and useful in the instant invention are fully described in European Application Publication Number 0405537 (United States Serial Number 07/545,222, filed June 28, 1990), United States Serial Numbers 07/726,656, 07/726655, 07/726,654, 07/726,653, 07/726,652, and 07/726,651, all filed on July 12, 1991 by Horwell, et al. All of the above United States applications are hereby incorporated by reference.
Other compounds which are CCK-B/gastrin antagonists and useful in the instant invention are fully described in United States Patent 4,820,834, which is hereby incorporated by reference. Proton pump inhibitors such as BY 308, 5-trifluoromethyl-2-[4-methoxy-3-methyl-2-pyridyl- methyl]-thio-[lH]-benzimidazole, which are described and claimed in United States Patent 4,472,409, are useful in the instant invention. The patent is hereby incorporated by reference.
Proton pump inhibitors such as omeprazole, 5-methoxy-2-[ [ (4-methoxy-3,5-dimethyl-2-pyridinyl)- methyl]sulfinyl]-IH-benzimidazole, which are described and claimed in United States Patent 4,255,431, are useful in the instant invention. The patent is hereby incorporated by reference.
Other useful proton pump inhibitors include but are not limited to: [[4-(2,2,2-trifluoroethoxy)-3-methyl-2-pyridyl]- methyl]sulfenamide;
(Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4- piperidinopyridine HC1;
2-(4-cyclohexyloxy-5-methylpyridin-2-yl)-3-(1- naphthyl)-l-propanol; methyl 2-σyano-3-(ethylthio)-3-(methylthio)-2- propenoate;
2-( (4-methoxy-2-pyridyl) ethylsulphinyl)-5- (1,1,2,2-tetrafluoroethoxy)-IH-benzimidazole sodium; 5-(difluoromethoxy)-2-[ [ (3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-IH-benzimidazole;
2-[ [4-(3-methoxypropoxy)-3-methylpyridin-2- yl]methylsulfinyl]-IH-benzimidazole, sodium;
2-[[ [4-(2,2,3,3,4,4,4-heptafluorobutoxy)-2- pyridyl] ethyl]sulfinyl]-lH-thieno[3,4-d]imidazole;
2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2- pyridy1] ethyl]sulfinyl]-IH-benzimidazole;
2-[[[4-(2,2,2-trifluoroethoxy)-3-methyl-2- pyridyl]methyl]sulfinyl]-IH-benzimidazole; 2-methyl-8-(phenylmethoxy)-imidazo(1,2-A)- pyridine-3-acetonitrile;
(2-((2-dimethylaminobenzyl)sulfinyl)— benzimidazole) ; 4-(N-allyl-N-methylamino)-l-ethyl-8-( (5-fluoro-6- methoxy-2—benzimidazolyl)sulfinylmethyl)-1-ethyl- 1,2,3,4-tetrahydroquinolone;
2-[[(2-dimethylaminophenyl) ethyl]sulfinyl]-4,7- dimethoxy-lH-benzimidazole; 2-[(2-(2-pyridyl)phenyl)sul inyl)-IH- benzimidazole;
(2-[ (2-amino-4-methylbenzyl)sulfinyl]-5- methoxybenzo[d]imidazole;
(4-(2-methylpyrrol-3-yl)-2-guanidisothiazole) ; 4—(4—(3—(imidazole)propoxy)phenyl)—2- phenylthiazole;
(E)-2-(2-(4-(3-(dipropylamino)butoxy)phenyl)- ethenyl)benzoxazole;
(E)-2-(2-(4-(3-(dipropylamino)propoxy)phenyl)- ethenyl)-benzothiazole;
Benzeneamine, 2-[[ (5-methoxy-lH-benzimidazol-2- yl)sul inyl]methyl]-4-methyl-; Pumilacidin A;
2,3-dihydro-2-methoxycarbonylamino-l,2- benzisothiazol-3-one;
2—(2-ethylaminophenylmethylsulfinyl)-5,6- dimethoxybenzimidazole;
2-methyl—8-(phenylmethoxy)imidazo[1,2-a] yridine- 3—acetonitrile; 3—amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]- pyrazine HC1;
2-[[(3-chloro-4-morpholino-2-pyridyl)methyl]- sul inyl]—5-methoxy-(IH)-benzimidazole;
[3—butyryl-4—(2-methylphenylamino)-8-methoxy- quinoline] ; 2-indanyl 2-(2-pyridyl)-2-thiocarbamoylacetate HC1;
2,3-dihydro-2-(2-pyridinyl)-thiazolo(3,2-a)- benzimidazole; 3-cyanomethyl-2-methyl-8-(3-methyl-2-butenyloxy)-
(1,2-a)imidazopyridine; Zinc L-carnosine.
Figure I concerns serum gastrin levels. It shows levels of gastrin-like immunoreactivity in venous blood from rats, before and after 1, 4, 7, or 14 days of treatment with vehicles (veh/veh: isotonic saline 3 subcutaneous injections at 8-hour intervals, methocel orally at 8:00 a.m.) Compound 1 which is [R-[R*,S*-(E) ] ] -A-[ [2-[ [3-(lH-indol-3-yl)-2-methyl-l- oxo-2-[ [ (tricyclo[3.3.1.l3,7]dec-2-yloxy)- carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4- oxo-2-butenoic acid, 18 mg/kg thrice daily (veh/1189) , BY 308 40 mg/kg orally in methocel (308/veh) or BY 308 and Compound 1. Days of treatment are along the X-axis and serum gastrin (pg/md) on the Y-axis.
is veh/veh; jis veh/compound 1;
Figure imgf000015_0001
is 308/veh; and B88ȣ 308/compound 1
Figure II concerns ECL-cell proliferation in the corpus. It shows the uptake of 3H-thymidine into enterochromaffin-like cells (ECL-cell) of rat gastric mucosa after 14 days of treatments (as Figure 1) ; and labelled ECL-cells as a percentage of total ECL-cell count in the field ("labelling index") . I^M is Methocel/NaCl; &22Z229 i-s Methocel/compound 1; is BY308/NaCl; and βg is BY308/compound 1. Fe ale Sprague-Dawley rats were used with free access to lab diet and water. Groups of 10 animals were treated three times daily with 18 mg/kg of compound 1 for 14 days as follows:
S.C. saline (x3) + oral Methocel (8 am)
S.C. saline (x3) + BY 308 40 mg/kg in methocel (8 am)
S.C. Compound 1 in saline + oral methocel
S.C. Compound 1 in saline + BY 308 40 mg/kg
Two animals were used from the Compound 1 groups, for preparation with gastric fistulae, to confirm that the acid secretory response to pentagastrin remained blocked after long-term treatment with the gastrin antagonis .
Blood was drawn from the retro-orbital venous plexus before treatment on Days 0, 1, 4, 7, and 14 for assay of serum gastrin and CCK levels.
Three days before sacrifice 3H-thymidine was infused into a tail vein (1 μci/g body weight as a bolus injection, followed by continuous infusion for 8 hours of 0.25 μCi/g/h) , for subsequent measurement of ECL-cel labeling index by autoradiography.
Optimal tissue preservation was achieved by perfusion fixation in Bouin's fixative for 8 minutes, and by fixation for 24 hours of excised tissue blocks in Bouin's solution, with embedding in paraffin wax. For estimation of cell density, 5 μm sections were cut; 2 μm for autoradiography (Eissele, R., Rosskopf, B., Koop, H., Adler, G., and Arnold, R.,
Proliferation of endocrine cells in rat stomach caused by drug-induced achlorhydria, Gastroenteroloqy, in press (1991) ) .
Antral G-cells were visualized after removal of the paraffin wax by immunostaining for gastrin using the avidin-biotin-peroxidase complex technique (Hsu, S. M., Raine, L., and Fanger, H., Use of avidin- biotin-peroxidase complex (ABC) in immunoperoxidase techniques; a comparison between ABC and unlabeled antibody (PAP) procedures, J Histochem Cvtochem 29:577-780 (1981)) .
ECL-cell density was evaluated in sections of oxyntic mucosa by the silver impregnation method or by immunostaining for chromogranin for autoradiographic studies (Grimelius, L., A silver nitrate stain for A2 cells of human pancreatic islets, Acta Soc Med Ups 73:271-294 (1968) ) .
Gastrin levels in unfixed sections of antrum and somatostatin in the fundus were measured by radioimmunoassay. Unfixed samples of pancreas were taken to assay for enzyme and DNA levels by standard methods. .
Treatment with the proton-pump inhibitor BY 308 (Koop, H., Schubert, B., Schwarting, H., Schikierka, D., Eissele, R. , Willemer, S., and Arnold, R., Increased visualization of antral gastrin-producing G-cells after acute stimulation of gastrin release in the rat, Eur J Clin Invest 17:111-16 (1987)) produced the expected rise in serum gastrin levels, irrespective of the presence or absence of co-treatment with Compound 1. The compound had no effect by itself on gastrin levels (Figure 1) . Levels of gastrin in antral sections were also increased in the groups treated with BY 308, but somatostatin in the fundus was not affected by any treatment.
Antral mucosal G-cells were increased from 56/mm (saline + methocel), or 60\mm ( ( [R-[R*,S*-(E) ] ]-4-[ [2- [[3-(lH-indol-3-yl)-2-methyl-l-oxo-2-[ [ (tricyclo- [3.3.1.13'7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3- phenylpropyl]amino]-4-oxo-2-butenoic acid, + methocel) to 75/mm and 88/mm in the corresponding groups given BY 308. The increases by BY 308 were statistically significant at the 2% level. That is, the increase in G-cell number is attributable to the achlorhydria, and is obtained in either group treated with BY 308.
In keeping with previous data from this group that ECL-cell density is not much affected until exposure to BY 308 extends beyond the third week of treatment, in the present 2-week study ECL-cell number was not significantly affected by any treatment (density around 200/mm) . As in the earlier study by this group, however, the 3H-thymidine labeling index, as an indicator of cell turnover, was increased from between 0.3% and 0»5% of cells in vehicle-treated controls to between 3% and 4% in the group treated for 14 days with the proton-pump inhibitor. This increase was abolished in the group also given Compound 1 for the 14—day period; by itself the compound had no effect on ECL-cell labeling index (Figure 2) .
The above experiments show that in the female rat in achlorhydria with chronic treatment with the proton pump inhibitor BY 308, the resultant hypergastrinemia is unaffected by cotreatment with a dose of Compound 1 high enough to guarantee complete blockade of the gastrin receptor on the parietal cell. The 14-day treatment with the high dose of Compound I did not affect gastrin levels.
The 14-day treatment with BY 308 showed there was a substantial increase in the incorporation of thymidine into the ECL—cells of the fundic mucosa, indicating an increased rate of cell division. The increased thymidine labeling index was completely blocked by Compound 1, indicating that the effect is truly a consequence of the hypergastrinemia of achlorhydria.
These results show CCKB/gastrin antagonists are expected to have clinical utility in the periphery, in the management of gastrin-dependent hyperplasias.
The compositions or combinations of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides pharmaceutical compositions comprising a compound which is a CCK-B/gastrin antagonist (or a long-acting and potent H2 antagonist) or a pharmaceutically acceptable salt thereof and a proton pump inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, if desired.
The composition can be given orally formulated as liquids, for example, syrups, suspensions or emulsions, tablets, capsules, and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound of pharmaceutically acceptable salt in a suitable liquid carrier(s), for example, ethanol, glycerine, nonaqueous solvent, for example, polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates, or oils, and the dispersion or suspension, then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins, or cocoa butter or other low melting vegetable or synthetic waxes or fats.
Preferably the composition is in unit dose form such as a tablet or capsule.
Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains pre erably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base. The pharmaceutically acceptable compositions of the invention will normally be administered to a subject for the treatment of peptic disorders and other conditions caused or exacerbated by gastric acidity. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example, for a week or more.
The dosing regimen will be within the skill or a skilled physician. In addition, the composition of the present invention can be coadministered with further active ingredients such as antacids (for example, magnesium carbonate or hydroxide and aluminum hydroxide) , nonsteroidal antiinflammatory drugs (for example, indomethacin, aspirin, or naproxen) , steroids, or nitrite scavengers (for example, ascorbic acid or aminosulphonic acid) , or other drugs used for treating gastric ulcers (for example, pirenzepine, prostanoids, for example, 16, 16-dimethyl PGE2, or histamine H2-antagonists (for example, cimetidine, ranitidine, famotidine, and nazatidine) .
EXAMPLE 1
Tablet
(1) Compound 1 30 mg
(2) Corn starch 20 mg
(3) Lactose 85.2 mg
(4) Micro crystalline cellulose 60 mg (5) Light anhydrous silicic acid 1.8 mg
(6) Magnesium stearate 3.0 mg
(7) Magnesium hydroxide 30 mg
(8) L-Cysteine 20 mg
250 mg (One Tablet) EXAMPLE 2
Capsule
Figure imgf000022_0001
A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
Omeprazole 2.0 g Saccharin 0.6 g
Sugar 30.0 g
Glycerin 5.0 g
Flavoring agent 0.1 g
Ethanol 96% 10.0 mL
Distilled water (sufficient to obtain a final volume of 100 mL) , sugar, saccharin, and the acid addition salt were dissolved in 60 g of warm water.
After cooling, glycerin and a solution of flavoring agents dissolved in ethanol were added. Water was added to the mixture to obtain a final volume of 100 mL.
The above given active sustance may be replaced with other pharmaceutically acceptable acid addition salts. SYNTHETIC EXAMPLE 1 Trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4- (bromophenyll-l-pyrazolidinecarboxamide Step 1. Preparation of αphenyl-2-chlorocinnamic acid Method used: Pro. Svn. Coll. IV:777 (1963) .
Phenylacetic acid (54.46 g, 0.4 M) was dissolved in acetic anhydride (80 mL) . O-chlorobenzaldehyde (56.23 g, 0.4 M) was added slowly, with stirring. This was followed by the slow addition of triethylamine (40 mL) . The reaction mixture was stirred at reflux for 5 hours. The reaction mixture was steam distilled until the distillate was no longer cloudy. The distillate was discarded. The aqueous residue was cooled. The solution was decanted from the gummy solid. This solid was dissolved in a 10% K2C03 solution. The basic solution was charcoaled then filtered through a pooled Super cell. The filtrate was made acidic (pH 1) with 10% HC1, cooled, and the solid filtered. The product was recrystallized from 50% ethanol/H20 to yield 52.14 g of white solid, mp 158-161°C. •
Step 2. Preparation of c-phenyl-2-chlorocinnamic acid methyl ester oPhenyl-2-chlorocinnamic acid (26.29 g (0.102 M) was dissolved in ethanol (300 cc) . Anhydrous HC1 was bubbled through the reaction mixture with stirring for 15 minutes. The reaction mixture was refluxed for 2 hours, then HC1 was bubbled through the reaction mixture for another 15 minutes. The reaction was stirred at reflux overnight. The methanol was removed in vacuo and the residue taken up in ether. The ether solution was washed with H20, saturated NaHC03 solution, and brine. It was then dried over MgS04. The ether solution was concentrated in vacuo to yield an oil that quickly solidified to yield 27.13 g of product, mp 67-69°C.
Step 3. Preparation of 4-(O'-chlorophenyl)-5-phenyl- 3-pyrazolidine
The ester from Step 2 (27.05 g, 0.0993 M) was dissolved in ethanol (75 cc) . Eighty-five percent hydrazine hydrate (5.76 g, 0.0993 M) was added. The reaction mixture was stirred at reflux for 24 hours, then cooled. H20 was added slowly with stirring. The product oiled out. The ethanol water was decanted from the oil. The oil was taken up in ether. The ether solution was washed with cold water, then dried over MgS04. The ether solution was concentrated in vacuo. A small amount of ether was added to the residue. The white solid was filtered and dried in vacuo to yield 9.56 g of product, mp 123-124°C.
Step 4. Preparation of trans-5-(2-chlorophenγl)-3- oxo—4-phenyl-N— \A-(bromophenyll-1-pyrazolidine- carboxamide
The pyrazolidone obtained in Step 3 (2.73 g, 0.01 M) was dissolved in THF (100 mL) . p-Bromophenyl isocyanate (1.98 g, 0.01 M) was added. The reaction mixture was stirred overnight at room temperature.
The clear solution was concentrated in vacuo to yield 4.73 g of a white solid. The solid was boiled in isopropyl ether. The insoluble solid was filtered from the warm ether and dried to yield 3.71 g of the product, mp 189-190°C.
Analysis for C22H17BrClN302 (MW 470.762) :
Calcd. : C, 56.13; H, 3.64; N, 8.91.
Found: C, 56.43; H, 3.87; N, 8.71.
IR NMR and MS consistent for the desired product. SYNTHETIC EXAMPLE 2 Trans-5-(2-chlorophenyl)-3-oxo-4-phenyl-N-T4- (trifluoromethyl)phenyl]-l-pyrazolidinecarboxamide Substituting αααtrifluoro-p-tolyl isocyanate (1.87 g, 0.01 M) for p-bromophenyl isocyanate in Step 4, one obtains 3.6 g of the product, mp 193-194°C.
Analysis for C23H17C1F3N302 (MW 459.859): Calcd. : C, 60.07; H, 3.73; N, 9.14. Found: C, 60.16; H, 3.81; N, 9.09.
IR, NMR and MS consistent for the desired product.
SYNTHETIC EXAMPLE 3 3-nitrophenol (50.0 g, 360 mmol), isopropyl iodide (76.19 g, 450 mmol), and K2C03 (60 g) were. combined and heated at reflux under N2 overnight in acetone (400 mL) . After solvent removal in vacuo, the residue was partitioned between EtOAc and H20. The separated organic layer was washed with 1 N NaOH, brine, dried over Na2S04, and concentrated in vacuo to provide 56 g (86%) of 3-isopropoxynitrobenzene as a clear yellow oil.
A mixture of the above product (8.5 g, 50 mmol), Pt02 (0.3 g) , and EtOH (200 mL) was hydrogenated (40 psi H2) at room temperature for 1.5 hours in a
Paar shaker. The mixture was filtered through Celite and concentrated in vacuo to furnish 7.08 g of the desired aniline. This material was combined with isatoic anhydride (7.35 g, 45 mmol) and heated at 90°C for 2 hours. Upon cooling and addition of hexanes, the product crystallized to give 10.19 g (83%) of 2-amino—N-(3-isopropoxyphenyl)benzamide as a white solid. An analytical sample was obtained by recrystallization from 20% EtOAc/hexanes, mp 79-86°C; XH NMR (CDC13) δ 1.36 (6H, d, J-6.1 Hz), 4.59 (IH, h, J=6.1 Hz), 5.2 (2H, bs) , 6.6-6.8 (3H, m) , 7.0-7.1 (IH, m), 7.2-7.4 (3H, m) , 7.47 (IH, d, J=7.7 Hz), 7.80 (IH, bs); IR (CHC13) 1664, 1611, 1524, 1490 cm"1; MS (FD) 270 (M+) . Anal. (C16H18N202) C, H, N. A solution of 3-[(2,2-dimethyl-4,6-dioxo-l,3- dioxan-5-yl)methyl]-5-bromoindole (4.12 g, 12 mmol) prepared according to the method of Farlow, et al (Farlow, D. S.; Flaugh, M. E.; Horvath, S. D.; Lavignino, E. R.; Pranc, P. Two Efficient Syntheses of Indole-3-Proρionic Esters and Acids. Further
Applications of Meldrum's Acid. Org. Prep. Proced. Int. 13:39-48 (1981), the above benzamide (3.48 g, 13 mmol) and pyridinium p-toluenesulfonate (1.64 g, 6.5 mmol) in 50 mL of pyridine was heated at reflux for 3.5 days. The reaction mixture was concentrated in vacuo, chromatographed (Si02, 30% EtOAc/hexanes) , and crystallized to give 2.13 g (36%) of compound 22, mp 179-181°C; K NMR (CDC13) δ 1.31 (3H, d, J=6.0 Hz), 1.34 (3H, d, J=6.1 Hz), 2.8 (2H, m) , 3.2 (2H, m) , 4.53 (IH, h, J=6.0 Hz), 6.7-7.6 (9H, m) , 7.8 (2H, m) ,
8 .2-8 .4 (2H, m) ; IR (KBr) 1671 cm"1; MS (FAB) 502, 504 (M+ + H) . Anal. (C27H24N302Br) C, H, N .

Claims

1. A pharmaceutical composition containing a CCK-B/ gastrin antagonist and an ATP'ase proton pump inhibitor with or without a pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to Claim 1 wherein the CCK-B antagonist is one or more selected from
[R-(R*,R*) ]-4-[ [2-[ [3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.l3' ]dec-2- yloxy) carbonyl]amino]propyl]amino-1- phenylethyl]amino]-4-oxo-butanoic acid,
[R-[R*,R*-(E)]-4-[[2-[[3-(lH-indol-3-yl)-2- methyl-l-oxo-2-[ [ (tricyclo[3.3.1.l3,7]dec-2- yloxy) carbonyl]amino]propyl]amino]-1- phenylethyl]amino]-4-oxo-2-butenoic acid,
Butanoic acid, 4-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ [ (1,7,7-trimethylbicyclo- [2.2.l]hept-2-yl) oxy]carbonyl]amino]propyl]- amino]-1-phenylethyl] mino]-4-oxo-,
[lS-[lα,2β[S*(S*) ] ,4β]]-, and
[R-[R*, S*-(E) ] ]-4-[ [2-[ [3- (lH-indol-3-yl) -2- methyl-l-oxo-2-[ [ (tricyclo [3.3.1.l3,7]dec-2- yloxy) carbonyl] amino]propyl] amino]-3-phenyl- propyl]amino] —A—oxo-2-butenoic acid.
3. A pharmaceutical composition according to Claim 1 wherein the CCK-B antagonist is (R)-N-(2,3- dihydro-l-methyl-2-oxo-5-phenyl-lH-l,4- benzodiazepine-3-yl) -N'- (3—methylphenyl)urea.
4. A pharmaceutical composition according to Claim 1 wherein the CCK-B antagonist is trans-1- pyrazolidinecarboxamide, 5-(2-chlorophenyl)-3- oxo-4-phenyl-N—[4-(trifluoromethyl)phenyl]-.
5. A pharmaceutical composition according to Claim 1 wherein the ATP'ase proton pump inhibitor is one or more selected from: BY308,- omeprazole,
SK&F 95601 and SK&F 96067.
6. A pharmaceutical composition according to Claim 1 wherein the CCK-B antagonist is [R-(R*,R*) ]-4-
[[2-[[3-(lH-indol-3-yl)-2-methyl-l-oxo-2- [t(tricyclo[3.3.1.13'7]dec-2-yloxy)carbonyl]- : amino]propyl]amino-1-phenylethyl]amino]-4-oxo- butanoic acid and the proton pump inhibitor is omeprazole.
7. A method for treating peptic disorders in a patient suffering therefrom which comprises administering a composition according to Claim 1.
8. A method according to Claim 7 wherein the peptic disorder is gastroesophageal reflux.
9. A method according to Claim 7 wherein the peptic disorder is ulcer.
10. A method for treating Zollinger-Ellison Syndrome in a patient suffering therefrom which comprises administering a composition according to Claim 1.
11. A pharmaceutical composition according to Claim 1 containing from 0.1 mg/kg to 10 mg/kg of a CCK-B antagonist and from 10 mg to 360 mg of an ATP'ase proton pump inhibitor.
PCT/US1992/010692 1991-12-20 1992-12-11 Therapeutic combinations useful in the treatment of gastroesophageal reflux disease WO1993012817A1 (en)

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