CCK antagonists

Abstract: Cholecystokinin (CCK) antagonists are described of the formula: or a pharmaceutically acceptable salt thereof, wherein each R¹ is, independently, an alkyl group having 1-5, inclusive, carbon atoms, an alkoxy group having 1-5, inclusive, carbon atoms, a halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoreomethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive,; and A is either -(CH₂) n - -R², where n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, an alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group, independently having 1-5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4-6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxyalkyl group having 1-5, inclusive, carbon atoms, an alkoxyalkyl group having 2-8, inclusive, carbon atoms, an aralkoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, and a cycloalkyl group having 3-12, inclusive, carbon atoms. CCK antagonists are also described of the formula: or pharmaceutically acceptable salt thereof, wherein m is an integer between 0 and 2, inclusive; A is either -(CH₂) n - -R², wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, an alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group having 1-5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4-6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxalkyl group having 1-5, inclusive, carbon atoms, an alkoxyalkyl group group having 2-8, inclusive, carbon atoms, an aralkoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, or a cycloalkyl group having 3-12, inclusive, carbon atoms. Use is described of these antagonists for the treatment of disorders such as gastric, peptic or duodenal ulcers, or acute pancreatitis and for the suppression of appetite.

Description: This invention relates to cholecystokinin (CCK) antagonists. Chang et al., 230 Science 177 (1985), describes CCK as "a hormonal regulator of pancreatic and gastric secretion, contraction of the gallbladder, and gut motility," and states that "CCK also exists in the brain and may have an equally important role as a central nervous system transmitter." Chang et al. further mentions the CCK antagonists have "potential therapeutic utilities" and describes the compound asperlicin, which has the structure , as a CCK antagonist. Rovati et al., U.S. Pat. 4,000,297, discloses compounds of the structure in which R includes mono and poly substituted phenyl groups, and R¹ includes hydroxyl, an aniline group substituted at the para position with a carboxylic acid or ester thereof, an amino group substituted with phenylacetic acid or ester derivative thereof, or an alkoxy group terminating with an amino group. The compounds are described as having an antispastic effect on the smoother muscle of the gastroenteric tract, as regulating gastric secretion, and as being protective of gastroenteric mucosa. EP-A-0230151 describes compounds having the formula: or a pharmaceutically acceptable salt thereof, wherein each R¹ is, independently, an alkyl group having 1 to 5, inclusive, carbon atoms, an alkoxy group having 1 to 5, inclusive, carbon atoms, a halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive; and A is either where n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1 to 5, inclusive, carbon atoms, aralkoxy (e.g., benzyloxy), aralkyl (e.g., benzyl), amino, an alkyl group having 1 to 5, inclusive, carbon atoms, an alkylamino group having 1 to 5, inclusive, carbon atoms, a dialkylamino group with each alkyl group, independently having 1 to 5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4 to 6, inclusive, carbon atoms (e.g., pyrrolidino, piperidino. N-methylpiperazino), or morpholino; or A is an alkyl group having 1 to 5, inclusive, carbon atoms, a hydroxyalkyl group having 1 to 5, inclusive, carbon atoms, an alkoxyalkyl group having 2 to 8, inclusive, carbon atoms, an aralkoxyalkyl group having 8 to 14, inclusive, carbon atoms, an aryl group (e.g., phenyl, toluyl) having 6 to 14, inclusive, carbon atoms, an aralkyl group (e.g., benzyl, phenylethyl) having 6 to 14, inclusive, carbon atoms, and a cycloalkyl group having 3 to 12, inclusive, carbon atoms, and the synthesis of such compounds. In one aspect, the invention features compounds having the formula: or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2, inclusive; and A is either where n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1 to 5, inclusive, carbon atoms, aralkoxy (e.g., benzyloxy), aralkyl (e.g., benzyl), amino, an alkyl group having 1 to 5, inclusive, carbon atoms, an alkylamino group having 1 to 5, inclusive, carbon atoms, a dialkylamino group with each alkyl group, independently, having 1 to 5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4 to 6, inclusive, carbon atoms (e.g.. pyrrolidino, piperidino, N-methylpiperazino), or morpholino; or A is an alkyl group having 1 to 5, inclusive, carbon atoms, a hydroxyalkyl group having 1 to 5, inclusive, carbon atoms, an alkoxyalkyl group having 2 to 8, inclusive, carbon atoms, an aralkoxyalkyl group having 8 to 14, inclusive, carbon atoms, an aryl group (e.g., phenyl, toluyl) having 6 to 14, inclusive, carbon atoms, an aralkyl group (e.g., benzyl, phenylethyl) having 6 to 14, inclusive, carbon atoms, or a cycloalkyl group having 3 to 12, inclusive, carbon atoms. In preferred embodiments of the invention of formula (2), the tryptophan residue is of the L-configuration, m is 2, and R² is an alkoxy group or hydroxy. Preferred compounds include α-N-(2-indolylcarbonyl)-L-tryptyl-N'-phenylethylglycine and α-N-(2-indolylcarbonyl)-L-tryptyl- N'-phenyl- ethylglycineethylester; or a pharmaceutically acceptable salt thereof. In other preferred embodiments, a therapeutically effective amount of the therapeutic compounds and a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate or lactose, form a therapeutic composition, e.g., a pill, tablet, capsule, or liquid, for oral administration to a patient; a liquid or an ointment capable of being administered transdermally, nasally, rectally, or sublingualy; a liquid capable of being adminstered intravenously, parenterally, subcutaneously, or intraperitoneally; or an oral or a parenteral sustained release formulation. The compounds of the invention are effective cholecystokinin antagonists and as such are effective in treating acute pancreatitis; in treating gastric, peptic, and duodenal ulcers; and in suppressing appetite. They are also effective, alone or in combination with other chemotherapeutic agents, in the treatment of pancreatic cancers; this activity is believed to occur because of antagonism to the action of cholecystokinin in inducing pancreatic hyperplasia in the presence of known carcinogens, e.g., nitrosamine. The compounds are stable, inexpensive to make, and non-toxic. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. We now describe the structure, synthesis, and use of preferred embodiments of the invention. The compounds of the invention have the general formulae (2) recited above. Examples of preferred compounds within these formulae are those referred to as preferred embodiments above. The compounds of the invention are N-substituted (D- or L-) tryptyl N'-disubstituted glycine or N-substituted (D- or L-) tryptyl N'-disubstituted amide derivatives. The compounds can also be provided in the form of pharmaceutically acceptable salts. Examples of suitable salts include those formed with hydrochloric, hydrobromic, sulfuric, maleic, acetic, or fumaric acid; potassium, sodium, or aluminum hydroxide; or dicyclohexylamine. Compounds of formula (2) above can be synthesized as follows. First, a compound of formula (5) , where X represents a hydroxyl or carboxylic acid activating group, e.g., a halogen such as chlorine, is condensed with a secondary amino compound of formula (6) where m and A are defined as before. The corresponding acids are then prepared from these esters by hydrolyzing the esters with aqueous base. Amides can be prepared by treating the corresponding esters with ammonia or an amine. Compounds within formulae (5) and (6) are commercially available; alternatively they can be synthesized according to standard methods, e.g., as described in Greenstein, et al., 1961, supra ; 1962, supra ; 1949, supra ; 1969, supra ; and 1972, supra . The condensation reactions are preferably carried out as described above for compounds synthesized from formulae (3) and (4). The intermediate and final products are isolated and purified by standard methods e.g., column chromatography or crystallization. Purity is determined using chromatographic, spectroscopic, and chemical analysis. Specific compounds within forumula (2) are made as follows. α-N-(2-Indolylcarbonyl)-L-tryptyl-N′-phenylethylglycineethylester The first step is the preparation of α-N-(2-indolylcarbonyl)-L-tryptophan, as follows. To an ice-cooled solution of L-tryptophan methylester HCl (1.0g), indole-2-carboxylic acid (0.63g), diethylcyanophosphonate (0.71g) in 10ml dimethylformide is added dropwise 1.65ml triethylamine, and the reaction mixture is stirred at 0.5°C for 1 hour and then at room temperature overnight. Volatile substances are removed in vacuo , and the residue is partitioned between chloroform and water. Precipitate (1.2g) is collected by filtration, washed with chloroform, and then dried. TLC: (silica gel; CHCl₃/MeOH = 9:1). Rf = 0.71. To a suspension of α-N-(2-indolylcarbonyl)-L-tryptophan methylester (1g) in 20ml ethanol is added 3ml 1N NaOH, and after 1 hour stirring at room temperature, solvent is removed in vacuo to a small volume (∼5ml). The resulting solution is diluted with water and acidified with dilute HCl to pH 2-3. Pale pink solid (950mg) is collected by filtration; washed with water, and then dried. TLC: (silica gel; CHCl₃/MeOH/HOAC = 9:1:0.1). Rf = 0.32. The acid is then condensed with the N′-phenylethyl substituted ethyl ester of glycine, as follows. To an ice-cooled solution of α-N-(2-indolylcarbonyl)-L-tryptophan (0.8g), 1-hydroxybenzotriazole (0.65g) and N-phenylethylglycine ethylester (0.51g) in dimethylformide-dichloromethane (1:1, 20ml) is added a cold solution of dicyclohexylcarbodiimide (0.55g) im 1ml dichloromethane. The mixture is stirred at 0.5°C for 1 hour and then at room temperature overnight. The mixture is then filtered, and solvents are evaporated in vacuo to dryness. The residue is dissolved in chloroform, washed with 5% aqueous NaHCO₃ and water, and dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (45g) using chloroform-acetone (9:1) as eluant. Appropriate fractions are pooled and the solvent removed in vacuo to dryness. The pale yellow solid is recrystallized from ethanol to form a colorless solid. 0.44g TLC: (silica gel; CHCl₃/acetone = 9:1). Rf = 0.34. α-N-(2-Indolylcarbonyl)-L-tryptyl-N′-phenylethylglycine To a suspension of α-N-(2-indolylcarbonyl)-L-tryptyl-N′-phenylethylglycine ethylester (200mg) in 2ml ethanol is added 1ml 2N NaOH. After 1 hour stirring at room temperature, most of the ethanol is removed in vacuo . The solution is then acidified with dilute HCl to pH 2-3. Colorless solid (130mg) is collected by filtration, washed with water, and then dried. TLC: (silica gel); CHCl₃/MeOH/HOAC = 9:1:0.1). Rf = 0.55. When administered to a patient (e.g., orally, intravenously, parenterally, nasally, or by suppository), the compounds are effective in the treatment of gastric, peptic, and duodenal ulcers; in the treatment of acute pancreatitis; and in suppressing appetite. The compounds can be administered to a human patient in a dosage of 0.1 - 50mg/kg/day, preferably about 0.1mg/kg/day when administered parenterally and about 50mg/kg/day when administered orally.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound having the formula or pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 inclusive; A is either wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, an alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group having 1-5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4-6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxalkyl group having 1-5, inclusive, carbon atoms, an alkoxyalkyl group group having 2-8, inclusive, carbon atoms, an aralyoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, or a cycloalkyl group having 3-12, inclusive, carbon atoms. The compound of claim 1, wherein the tryptophan residue is of the the L-configuration, m is 2, and A is said compound having the name α-N-(2-indolylcarbonyl)-L-tryptyl-N'-phenylethylglycine; or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the tryptophan residue is of the L-configuration, m is 2, and A is said compound having the name α-N-(2-indolylcarbonyl)-L-tryptyl-N'-phenylethylglycineethylester; or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein m is 2, The compound of claim 1, wherein A is wherein R² is hydroxy or an alkoxy group having 1-5, inclusive, carbon atoms. The compound of claim 1, wherein m is 1. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any preceding claim together with a pharmaceutically acceptable carrier or diluent. A compound as defined in any of Claims 1 to 6 for use in therapy or to suppress appetite. A compound as defined in any of Claims 1 to 6 for use in the treatment of disorders, such as gastric, peptic or duodenal ulcers or acute pancreatitis, associated with excessive cholecystokinin. Use of a compound as defined in any of Claims 1 to 6 for the manufacture of a medicament for use in the treatment of disorders, such as gastric, peptic or duodenal ulcers or acute pancreatitis, associated with excessive cholecystokinin, or for the suppression of appetite. A method of synthesizing a compound as defined in Claim 1, comprising the step of condensing a compound of formula (5) where X represents a hydroxyl or carboxylic acid activating group, with a secondary amino compound of formula (6) where m and A are defined as in Claim 1. Claims for the following Contracting States : ES, GR A method of producing a pharmaceutical composition comprises mixing a compound having the formula: or pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 inclusive; A is either wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1-5, inclusive, carbon atoms, aralkoxy, aralkyl, amino, an alkyl group having 1-5, inclusive, carbon atoms, an alkylamino group having 1-5, inclusive, carbon atoms, a dialkylamino group with each alkyl group having 1-5, inclusive, carbon atoms, a cycloalkylamino group wherein the ring has 4-6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1-5, inclusive, carbon atoms, a hydroxalkyl group having 1-5 inclusive, carbon atoms, an alkoxyalkyl group having 2-8, inclusive, carbon atoms, an aralkoxyalkyl having 8-14, inclusive, carbon atoms, an aryl group having 6-14, inclusive, carbon atoms, an aralkyl group having 6-14, inclusive, carbon atoms, or a cycloalkyl group having 3-12, inclusive, carbon atoms, with a pharmaceutically acceptable carrier or diluent. The method of Claim 1, wherein the tryptophan residue is of the L-configuration, m is 2, and A is said compound having the name α-N-(2-indolylcarbonyl)-L-tryptyl-N'-phenylethylglycine; or a pharmaceutically acceptable salt thereof. The method of Claim 1, wherein the tryptophan residue is of the L-configuration, m is 2, and A is said compound having the name α-N-(2-indolylcarbonyl)-L-tryptypl-N'-phenylethylglycineethylester; or a pharmaceutically acceptable salt thereof. The method of Claim 1, wherein m is 2. The method of Claim 1, wherein A is wherein R² is hydroxy or an alkoxy group having 1-5, inclusive, carbon atoms. The method of Claim 1, wherein m is 1. Use of a composition produced by the method of any of Claims 1 to 6 for the manufacture of a medicament for use in the treatment of disorders, such as gastric, peptic or duodenal ulcers or acute pancreatitis, associated with excessive cholecystokinin, or for the suppression of appetite. A method of synthesizing a compound of the formula as defined in Claim 1, comprising the step of condensing a compound of formula (5) where X represents a hydroxyl or carboxylic acid activating group, with a secondary amino compound of formula (6) where m and A are defined as in Claim 1.

Inventors: KIM SUN HYUK, KIM, SUN HYUK
Applicants: BIOMEASURE INC, BIOMEASURE INC.
Application year: 1989
Main classification: C07K5
IPC codes: A61K31, A61P1, A61K38, C07D209, C07K5