CHOLECYSTOKININ ANTAGONISTS

Abstract: Compounds of formula (1) and pharmaceutically and veterinarily acceptable salts thereof, wherein each R¹ is, independently, alkyl, alkoxy, halogen, amino, hydroxy, nitro, cyano, carboxyl, trifluoromethyl, ethyl carboxylate, or hydrogen; m is 0, 1 or 2, inclusive; and A is either -(CH₂) n -C(O)R², where n is 1 to 5 and R² is hydroxy, alkoxy, araloxy, aralkyl, amino, alkyl, alkylamino, dialkyl­ amino, cycloalkylamino, or morpholino; or A is alkyl, hydroxy­ alkyl, alkoxyalkyl, aralkoxyalkyl, aryl, aralkyl, or cycloalkyl, are useful as cholecystokinin antagonists in the treatment of acute pancreatitis, gastric, peptic and duodenal ulcers and in 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 that 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 polysubstituted 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. In general, the invention features compounds having the formula: or a pharmaceutically or veterinarily acceptable salt thereof, wherein each R' 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, benzyloxy, 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 nitrogen-containing heterocyclic ring having 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, the tryptophan residue is of the L-configuration, the R¹,s are either both hydrogen, both chloro (at the 3 and 4 position of the ring), or one hydrogen and one chloro (at the 4 position). Preferred compounds of the invention include N-benzoyl-L-tryptyl-N¹-benzylglycine, N-benzoyl-L-tryptyl-N¹-benzylglycine ethylester, N-benzoyl-L-tryptyl-N¹-benzylglycineamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-(3, 4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-(3, 4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(3, 4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-benzoyl-L-tryptyl-N¹-benzyl-N¹-methylamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzyl-N¹-methylamide, N-(3, 4-dichlorobenzoyl)-N¹-benzyl-N¹-methylamide; or pharmaceutically acceptable salts thereof. In other preferred embodiments, a therapeutically effective amount of the therapeutic compound 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 intraperitonally; or an oral or a parenteral sustained release formulation. The compounds of the invention are effective cholecystokinin antagonists and as such are effective in preventing acute pancreatitis; in treating gastric, peptic, and duodenal ulcers; and in restoring appetite. They 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. Structure The compounds of the invention have the general formula recited in the summary of the invention above. Examples of preferred compounds within this formula are those referred to as preferred embodiments above. The compounds of the invention are N-substituted (D- or L-) tryptyl N¹-disubstituted glycine or N-substituted (D- or L-) tryptyl N¹-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, sulphuric, maleic, acetic, or fumaric acid; potassium, sodium, or aluminium hydroxide; or dicyclohexylamine. Synthesis The above compounds can be synthesized as follows. First, a compound of formula (2) , where X represents a hydroxyl or carboxylic acid activating group, e.g., a halogen such as chlorine, and R¹ is defined as above, is condensed with a secondary amino compound of formula (3) , where m and A are defined as before. Acids can be prepared from the corresponding 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 (2) and (3) are commercially available; alternatively they can be synthesized according to standard methods, e.g., as described in Greenstein, et al., Chemistry of the Amino Acids , Vols. 1-3, J. Wiley, New York (1961); J. Pharm. Sci. , 51 , 1058 (1962); Org. Reaction 5 , 301 (1949); J. Chem. Soc. (c), 2223 (1969); and J. Org. Chem. , 37 , 1673 (1972). The condensation reactions are preferably carried out in an inert organic solvent, e.g., dimethylformamide, dichloromethane, tetrahydrofuran, benzene, or acetonitrile, using a suitable mild condensing agent, e.g., thionylchloride, oxalylchloride, or dicyclohexylcarbodiimide (DDC), and optionally a catalyst, e.g., 1-hydroxybenzotriazole (HOBT). The reaction temperature is preferably maintained below room temperature (-15°C to room temperature) in order to minimize side reactions. Typical condensation procedures are described in Schroeder et al., The Peptides , Vols. 1-2 (1965, 1966) and Gross et al., The Peptides , Vols, 1-3 (1979, 1980, 1981). The intermediate and final products may be isolated and purified by standard methods e.g., column chromatography or crystallization. Purity is determinable using chromatographic, spectroscopic, and chemical analysis. The following examples illustrate the invention. EXAMPLE 1 N-Benzoyl-L-tryptyl-N¹-benzylglycine ethylester The first step is the preparation of N-benzoyl-L-tryptophan, as follows. 10ml benzoyl chloride and 45ml 2N NaOH are added, in several and alternate portions, to a vigorously stirred and ice-cooled solution of 17g L-tryptophan in 41ml 2N NaOH. The solution is maintained at an alkaline pH by the addition of extra base when necessary. Upon completion of the addition of reagents, the mixture is stirred at room temperature for 1 hour, after which it is acidified to pH 1-2 with HCl. The crude product is dried and then triturated with cold ether to give 20g of the product as a colourless solid. TLC: (silica gel; CHCl₃/MeOH/HOAC = 6:1:0.25) Rf = 0.53. A cold solution of 1.44g dicyclohexylcarbodiimide in 4ml dimethylformamide is added to a stirred ice-cooled solution of 2.0g N-benzoyl-L-tryptophan and 1.26g N-benzylglycine ethylester in 8ml dry dimethlformamide. The resulting mixture is stirred at 0° for 1 hour and then at room temperature overnight. It is then filtered and the solvent is evaporated to dryness in vacuo . The residue is partitioned between chloroform and water. The chloroform layer is washed with 5% aqueous NaHCO₃ and water, and then dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (250g) using chloroform/acetone (19:1). Appropriate fractions are pooled and the solvent removed in vacuo to yield 1.55g of the product as a foam. TLC: (silica gel; CHCl₃/acetone = 9:1) Rf = 0.35. EXAMPLE 2 N-Benzoyl-L-tryptyl-N ¹ -benzylglycineamide 490mg N-benzoyl-L-tryptyl-N¹-benzylglycine ethylester is dissolved in 10ml saturated methanolic ammonia, and the solution is kept at room temperature in a pressure bottle overnight. Excess ammonia and solvent are then removed in vacuo , and the residue is recrystallized from ethanol to yield 286mg of the crystaline product. m.p. 203-204°; TLC: (silica gel; CHCl₃/MeOH = 9:1) Rf = 0.47. EXAMPLE 3 N-Benzoyl-L-tryptyl-N ¹ -benzylglycine 500mg N-benzoyl-L-tryptyl-N¹-benzylglycine ethylester is dissolved in 5ml ethanol and treated with 1ml 2N NaOH. After stirring at room temperature for 1 hour, the solution is diluted with water, acidified to pH 1-2 with 2N HCl, and extracted with ethylacetate (3 X 50ml). The combined extracts are dried over anhydrous MgSO₄, and solvent is removed in vacuo to yield 440mg of the product as a foam. TLC: (silica gel; CHCl₃/MeOH/HOAC = 6:1:0.25) Rf = 0.6. EXAMPLE 4 N-(3, 4-Dichlorobenzoyl)-L-tryptyl-N ¹ -benzylglycine ethylester The first step is the preparation of N-(3, 4-dichlorobenzoyl)-L-tryptophan in an analogous manner to the preparation of N-benzoyl-L-tryptophan except substituting 3, 4-dichlorobenzoyl chloride (dissolved in either dioxane, tetrahydrofuran, or acetone) for benzoyl chloride. A cold solution of 1.74g dicyclohexylcarbodiimide in 2ml dimethlformamide is added to a stirred ice-cooled solution of 3.0g N-(3, 4-dichlorobenzoyl)-L-tryptophan, 1.55g N-benzylglycine ethylester, and 2.16g 1-hydroxybenzotriazole in 10ml dimethylformamide. The mixture is stirred at 0°C for 1 hour and then at room temperature for 2 hours. It is then filtered, and the solvent is evaporated in vacuo to dryness. The residue is dissolved in chloroform, washed with 5% aqueous NaHCO₃ and water, and dried over anhydrous MgSO₄. Solvent is evaporated in vacuo to dryness and 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 (260g) using CHCl₃/acetone (40:1) as the eluent. Appropriate fractions are pooled and the solvent removed in vacuo to yield 2.4g of the product as a colorless solid. m.p. 190-192°; TLC: (silica gel: CHCl₃/acetone = 9:1) Rf = 0.42. EXAMPLE 5 N-Benzoyl-L-tryptyl-N ¹ -benzyl-N ¹ -methylamide A cold solution of 0.5g dicyclohexylcarbodiimide in 2 ml dichloromethane is added to a stirred ice-cooled solution of 0.6g N-benzoyl-L-tryptophan and 0.3g N-benzylmethylamine in dichloromethane dimethylformide (2:1, 20 ml.). The mixture is stirred at 0°C for 1 hour and then at room temperature overnight. It is then filtered and the solvent evaporated in vacuo to dryness. The residue is partitioned between chloroform and water. The chloroform layer is washed with 5% NaHCO₃ and water, and then dried over anhydrous MgSO₄. After evaporation of solvent, the residue is chromatographed on silica gel (35g) using chloroform/acetone (19:1). Appropriate fractions are pooled and the solvent removed in vacuo to yield 0.57g of the product as colourless solid. m.p. 65-68°; TLC: (silica gel; CHCl₃/acetone = 4:0) Rf = 0.45. Use When administered to a patient (e.g., orally, intravenously, parenterally, nasally, or by suppository), the compounds are effective in preventing gastric, peptic, and duodenal ulcers; in preventing acute pancreatitis; and in restoring 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 : BE, FR, DE, NL, LU, IT, SE, CH, LI and GB A compound having the formula (1) or pharmaceutically or veterinarily 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, trifluoromethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive; A is either wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1 to 5, inclusive, carbon atoms, benzyloxy, 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 having 1 to 5, inclusive, carbon atoms, a nitrogen-containing heterocyclic ring having 4 to 6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1 to 5, inclusive, carbon atoms, a hydroxalkyl group having 1 to 5, inclusive, carbon atoms, an alkoxyalkyl group group having 2 to 8, inclusive, carbon atoms, an aralkoxyalkyl having 8 to 14, inclusive, carbon atoms, an aryl group having 6 to 14, inclusive, carbon atoms, an aralkyl group having 6 to 14, inclusive, carbon atoms, or a cycloalkyl group having 3-12, inclusive, carbon atoms. A compound as claimed in claim 1, wherein the tryptophan residue is of the L-configuration. A compound as claimed in claim 1 or 2, wherein (R¹)₂ represents two hydrogen atoms, or a hydrogen atom at the 3 position and a chlorine atom at the 4 position, or two chlorine atoms at the 3 and 4 positions. N-benzoyl-L-tryptyl-N¹-benzylglycine, N-benzoyl-L-tryptyl-N¹-benzyglycine ethylester, N-benzoyl-L-tryptyl-N¹-benzylglycineamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycine, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-benzoyl-L-tryptyl-N¹-benzyl-N¹-methylamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-methylamide, or N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzyl-N¹-methylamide or a pharmaceutically or veterinarily acceptable salt thereof. A compound as claimed in claim any of claims 1 to 4 for use in medicine. A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 4 and a pharmaceutically or veterinarily acceptable carrier therefor. The use of a compound as claimed in any one of claims 1 to 4 in the preparation of a cholecystokinin antagonist. A process for the preparation of a compound as claimed in any one of claims 1 to 4 the process comprising: (a) condensing a compound of formula (2): where X represents a hydroxyl or carboxylic acid activating group and R¹ is as defined in claim 1 for formula (1), with a secondary amino compound of formula (3): where m and A are as defined in claim 1 for formula (1); and (b) optionally converting a compound or salt of formula (1) so formed into another compound or salt of formula (1). Claims for the following Contracting States : AT, ES, GR A process for the preparation of a compound having the formula (1) or pharmaceutically or veterinarily 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, trifluoromethyl, ethyl carboxylate, or a hydrogen; m is an integer between 0 and 2, inclusive; A is either wherein n is an integer between 1 and 5, inclusive, and R² is hydroxy, an alkoxy group having 1 to 5, inclusive, carbon atoms, benzyloxy, 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 having 1 to 5, inclusive, carbon atoms, a nitrogen-containing heterocyclic ring having 4 to 6, inclusive, carbon atoms, or morpholino; or A is an alkyl group having 1 to 5, inclusive, carbon atoms, a hydroxalkyl group having 1 to 5, inclusive, carbon atoms, an alkoxyalkyl group group having 2 to 8, inclusive, carbon atoms, an aralkoxyalkyl having 8 to 14, inclusive, carbon atoms, an aryl group having 6 to 14, inclusive, carbon atoms, an aralkyl group having 6 to 14, inclusive, carbon atoms, or a cycloalkyl group having 3-12, inclusive, carbon atoms, the process comprising: (a) condensing a compound of formula (2): where X represents a hydroxyl or carboxylic acid activating group and R¹ is as defined above for formula (1), with a secondary amino compound of formula (3): where m and A are as defined above for formula (1); and (b) optionally converting a compound or salt of formula (1) so formed into another compound or salt of formula (1). A process as claimed in claim 1, wherein the tryptophan residue is of the L-configuration. A process as claimed in claim 1 or 2, wherein (R¹)₂ represents two hydrogen atoms, or a hydrogen atom at the 3 position and a chlorine atom at the 4-position, or two chlorine atoms at the 3 and 4 positions. A process as claimed in claim 1, 2 or 3 for the preparation of N-benzoyl-L-tryptyl-N¹-benzylglycine, N-benzoyl-L-tryptyl-N¹-benzyglycine ethylester, N-benzoyl-L-tryptyl-N¹-benzylglycineamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(4-chlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycine, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycine ethylester, N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzylglycineamide, N-benzoyl-L-tryptyl-N¹-benzyl-N¹-methylamide, N-(4-chlorobenzoyl)-L-tryptyl-N¹-methylamide, or N-(3,4-dichlorobenzoyl)-L-tryptyl-N¹-benzyl-N¹-methylamide or a pharmaceutically or veterinarily acceptable salt thereof. A process as claimed in claim 1, 2, 3 or 4 wherein step (b) involves ester hydrolysis or ammonolysis. A process as claimed in any one of steps 1 to 5 wherein step (b) involves the formation of a salt. A process for the preparation of a pharmaceutical or veterinary composition comprising a compound having the formula (1) or pharmaceutically or veterinarily acceptable salt thereof, wherein each R¹, m and A are as defined in claim 1 and a pharmaceutically or veterinarily acceptable carrier therefor, the process comprising admixing the compound or salt of formula (1) with the carrier. A process as claimed in claim 7, wherein the compound of formula (1) is as defined for claim 2, 3 or 4. The use of a compound having the formula (1) or pharmaceutically or veterinarily acceptable salt thereof, wherein each R¹, m and A are as defined in claim 1 in the preparation of a cholecystokinin antagonist. The use as claimed in claim 9, wherein the compound of formula (1) is as defined for claim 2, 3 or 4.

Inventors: KIM, SUN HYUK
Applicants: BIOMEASURE INC.
Application year: 1986
Main classification: C07K5
IPC codes: C07D209, A61P1, A61K31, C07K5, A61P5, A61K38