ISOXAZOLYL INDOLAMINES

Abstract: Isoxazolyl indolamines as hypoglycemic agents and agents for inhibiting or impeding post-prandial hypo­ glycemia. These compounds have the formula I wherein R₁ represents hydrogen, fluorine, chlorine, C₁₋₄alkyl or C₁₋₄alkoxy, R₂ represents hydrogen or hydroxyl, R₃ and R₄ represent, independently, C₁₋₄alkyl or together with the adjacent nitrogen atom wherein n is 1, 2 or 3, R₅ represents hydrogen or C₁₋₄alkyl and R₆ represents hydrogen, C₁₋₄alkyl, phenyl or phenyl mo­ no-substituted by fluorine, chlorine, C₁₋₄alkyl or C₁₋₄-­ alkoxy.

Description: ISOXAZOLYL INDOLAMINES This application relates to novel isoxazolyl indolamines, their acid addition and alkali metal salts, processes for their production and their use as pharmaceuticals in particular anti-diabetic agents. In particular the invention relates to compounds of formula I EMI1.1 wherein R1 represents hydrogen, fluorine, chlorine, Cl-C4alkyl or Cl-C4alkoxyX R2 represents hydrogen or hydroxyl, R3 and R4 represent, independently, Cl-C4alkyl or together with the adjacent nitrogen atom EMI1.2 or EMI1.3 wherein n is 1, 2 or 3, R5 represents hydrogen or Cl-C4alkyl and R6 represents hydrogen, C1-C4alkyl, phenyl or phenyl mono-substituted by fluorine, chlorine, Cl-C4alkyl or C1-C4alkoxy. The present invention further provides a process for the production of compounds of formula I which comprises reducing the corresponding compound of formula II EMI2.1 wherein R1, R3, R4, R5 and R6 are as defined above and Z signifies -CO- or -CH The reduction according to the process is suitably carried out under an inert atmosphere of, for example, helium, argon or preferably nitrogen and in an inert solvent such as an ether e.g. diethylether, dioxane or tetrahydrofuran. Examples of reducing catalysts which may be used when carrying out the process are those common for the reduction of carbonyl groups e.g. diborane and alkali metal hydride reducing agents e.g. sodium borohydride or, preferably, lithium aluminium hydride. It will be appreciated that when Z is -CO, depending on the conditions employed, reduction will be either partial (to give compounds of formula I wherein R2 represents hydroxyl) or complete (to give compounds of formula I wherein R2 represents hydrogen) and conditions will thus be chosen according to the desired final product. In cases where a final product is desired in which R2 represents hydroxyl, temperatures may thus be critical and a preferred range is from about lO0C to 300C, most preferably from about 200C to 250C. If complete reduction to final products wherein R2 represents hydrogen is desired, a temperature range of from about 6O0C to 15O0C is preferred but is not critical. It will be appreciated that partial reduction can also be achieved by selection of a suitably weak reducing agent. Alternatively, compounds of formula I in which R2 is H may be produced using compounds of formula II in which Z is -CH2-. The preferred temperatures in this case lie between 00 to 500C, most preferably between 200 and 300C. This embodiment represents the preferred method of producing compounds in which R6 is C1 4alkylO The compounds of formula II can be prepared by reacting a compound of formula III EMI4.1 with a compound of formula IV, EMI4.2 wherein X represents a leaving group such as chlorine or bromine and R1, R3, R4, R5 and R6 are as defined above. The reaction is carried out in the presence of an inert solvent. Examples of preferred solvents include water, an excess of a compound of the formula IV or an ether such as diethylether, dioxane or tetrahydrofuran, or an aromatic hydrocarbon such as benzene or toluene preferably the combination of water, diethvlether or tetrahydroduran and excess compound of formula IV. The preferred temperature is from about-lO0to 500C, most preferably from about 200 to 30 C. The compounds of formula III in which Z is -COcan be prepared by reacting a compound of formula V EMI5.1 with a compound of formula VI (COX)2 VI wherein R1, R5, R6 and X are as defined above. The reaction is carried out in the presence of an inert solvent. Examples of preferred solvents include an ether such as diethylether, dioxane or tetrahydrofuran or an aromatic hydrocarbon such as benzene or toluene,preferably diethylether. The preferred temperature is from about-100to 50 C, most preferably from about 200 to 300C. The compounds of formula V can be prepared by cyclising a compound of formula VII EMI5.2 wherein R1, R5 and R6 are as defined above. The cyclisation is preferably carried out in the presence of an acid such as acetic acid, p-toluenesulphonic acid or, preferably, polyphosphoric acid, and in the presence of-an inert solvent such as an aromatic hydrocarbon e.g. benzene or toluene or preferably an excess of said acid. Preferred temperatures are of from about 700 to 150 C, most preferably 105-1200C. The compounds of formula VII can be prepared by reacting a compound of formula VIII EMI6.1 with a compound of formula IX EMI6.2 wherein R1, R5 and R6 are as defined above. The reaction is preferably carried out in the presence of an acid such as sulphuric acid, a polyphosphoric acid or preferably p-toluene sulphonic acid and in the presence of an inert solvent. Examples of preferred solvents are aromatic hydrocarbons such as benzene or toluene or a lower alkanol such as methanol and most preferably ethanol. Preferred temperatures are of from about 00-1000C, most preferably 200 to 350C. The compounds of formula III in which Z is -CH2-can be prepared by introducing the X group into a compound of formula Xa. EMI7.1 wherein R1, R5 and R6 are as defined above. When X is halogen, for example a suitable agent for its introduction is e.g. thionyl chloride or bromide or phosphorous oxychloride. The remaining reaction conditions are similar to those described for the reaction of compounds of formula V and formula VIS The compounds of formula Xa can be prepared by reacting a compound of formula XI EMI8.1 wherein R1 and R3 to R6 are as defined above, with an alkali metal cyanide such as sodium or potassium cyanide. The reaction is effected in the presence of an aqueous alcoholic solvent. Suitable alcohols are e.g. lower alkanols such as methanol and preferably ethanol. Preferred reaction temperatures are from 800 to 1500C. This reaction leads to a mixture of the compound of formula'Xa and the corresponding amide of formula Xb EMI8.2 which can be converted to the compound of formula Xa by conventional hydrolysis techniques. The compounds of formula XI can be prepared by reacting a compound of formula V with a compound of formula IV both as defined above in the presence of formaldehyde, an acid catalyst such as acetic acid and an organic co-solvent. Examples of suitable solvents are ethers such as diethylether, tetrahydrofuran and particularly dioxane. Preferred temperatures are from about -100 to +300C, most preferably Oo to 100C. The products resulting from the above processes can be isolated and purified in conventional manner. Intermediate compounds can where appropriate be further reacted without isolation. The compounds of formulae II, III, V, VII, Xa, Xb and XI are new and also form part of the invention. Insofar as the production of other starting materials is not described above, these are either known or can be prepared in conventional manner from known starting materials. Depending on the conditions employed the compounds of formula I may be obtained either in free base form or in acid addition salt form. The acid addition salt forms of the compounds of formula I also form part of the invention. Free base forms of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Examples of suitable salt forming acids are hydrochloric, hydrobromic,hydroiodic, phosphorous, sulphuric, acetic, maleic, fumaric and the like. The compounds of formula I may also be isolated in the form of salts with bases, e.g. alkali metal salts such as sodium or potassium salts. Such salt forms also form part of the invention. It will be understood that compounds of formula I wherein R2 = OH may exist in racemic form or in the form of optically active isomers which can be produced or separated and isolated from the racemate in conventional manner. The invention extends to such isomeric forms as well as racemic forms. The compounds of the formula I possess pharmacological acticity. In particular, they possess hypoglycemic activity as indicated by the lowering of blood glucose in 6 to 8 week old male Royal Hart mice weighing 30 to 35 gram which are fasted in groups of 5 for 16 hours and thenare given an initial dose of 50 to 200 milligrams per kilogram of animal body weight of the compound orally. Two hours after the test compound is administered the mice are anesthetized with 85 milligrams per kilogram of animal body weight of sodium hexobarbital and five minutes later blood is collected via cardiac puncture. The blood samples are placed in an autoanalyser cup containing 0.025 millilitres of heparin (1.000 units per millilitres); and the samples are capped, shaken and stored in ice. The glucose level is determined by the auto analyser potassium ferric cyanide N-2b method and these glucose levels are then compared with the glucose levels of the control group which receives orally 0.5 % carboxymethyl cellulose and is run concurrently. To validate this experiment, a known hypoglycemic standard is included each time the test is run. The compounds are thus indicated for use as in the treatment of diabetes as hypoglycemic agents. The compounds of formula I also inhibit or impede post-prandial hyperglycemia as indicated by a lowering of the blood sugar levels in male Wistar rats after an oral starch load. In this test male Wistar rats in groups of 5 which are fasted for 16 hours are given an initial dose of from 25 to 200 mg/kg p.o. of the test compound. One hour later the rats are given 1.0 grams per kilogram of animal body weight of cooked starch load. Thirty minutes after administration of the starch, the rats are anesthetized with 120 milligrams per kilogram of animal body weight of sodium hexobarbital after which blood is collected via cardiac puncture. The blood samples are placed in an autoanalyser cup containing 0.1 millilitres of heparin (1.000 units per millilitres). The heparinized blood is used to determine the blood sugar level with an autoanalyser. The blood sugar content is compared to the control group which receives 0.58 carboxymethyl cellulose and an oral starch load and are run concurrently. The compounds are thus also indicated for use in the treatment of diabetes by inhibiting or impeding postprandial hyperglycemia. An indicated suitable daily dosage in the treatment of diabetes as hypoglycemic agents is from about 50 to 2000 mg suitably administered in divided dose of 12.5 to 1000 mg, two to four times daily or in retard form. An indicated suitable daily dosage for inhibiting or impeding post-prandial hyperglycemia in the treatment of diabetes is from about 25 to 1000 mg preferably administered at mealtimes e.g. three times a day in divided dosages of from about 10 to 400 mg The invention therefore also concerns a method of treating diabetes by lowering blood sugar levels or inhibiting or impeding post-prandial z bypergi by administration of a compound of formula I, and also to compounds of formula I for use as pharmaceuticals e.g. as hypoglycemic agents or as agents for inhibiting or impeding post-prandial hyperglycemia or for use in the treatment of the human or animal body by therapy. The compounds of formula I may be administered in free base form or in the form of pharmaceutically acceptable acid addition or alkali metal salts1 which salt forms have the same order of activity as the free forms. The compounds of formula I or their pharmaceutically acceptable acid addition or alkali metal salts may be administered alone, or in admixture with a pharmaceutically acceptable diluent or carrier, and, optionally other excipients, and administered orally in such forms as tablets, elixirs, capsules or suspensions or parenterally in such forms as injectable solutions or suspensions. The preferred pharmaceutical compositions from the stand-point of ease of preparation and administration are solid compositions, particularly tablets and hardfilled or liquid-filled capsules. Such compositions also form part of the invention. The following examples, in which all temperatures are in OC and room temperatures is 20-3O0C,illustrate the invention. EXAMPLE 1 : 1-(3-Ethyl-5-methyl-4-isoxazolyl)-1- ethanone phenyl hydrazone (Compound of formula VII) A mixture of 61.1 g (0.4 mol) of 4-acetyl-3-ethyl5-methyl-isoxazole, 39.4 ml (0.4 mol) of phenyl hydrazine and 500 mg toluenesulphonic acid in 400 ml ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1(3-ethyl- 5-methyl- 4-isoxazolyl) -1-ethanone phenyl hydrazone; m.p. 720 to 750. EXAMPLE 2: 2-(3-Ethyl-5-methyl-4-isoxazolyl)-indole (Compound of formula V) To 1350 grams of polyphosphoric acid at 1000 to 1100 there is added portionwise 74.5 g (0.307 mol) of 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethannone -phenyl hydrazonewhile maintaining the temperature between 1050 and 1150. After addition is complete, the -mixture is stirred at 1000 to 1100 for 3 hours. The mixture is then poured onto ice and water and the resulting gum extracted into methylene chloride. The methylene chloride is decolorized, dried over anhydrous magnesium sulphate filtered and evaporated in vacuo to give 2- (3-ethyl-S- methyl-4-isoxazolyl)-indole. EXAMPLE 3: 2-(3-Ethyl-5-methvl-4-isoxazolyl)-3-indole glyoxyl chloride (Compound of formula III) A mixture of 163 g (0.72 mol) of 2-(3-ethyl-5methyl-4-isoxazolyl)-indole and 3 litres of ether are cooled to Oo to 100 and 61.6 ml (0.72 mol) of oxalyl chloride in 450 ml of ether is added dropwise, maintaining the temperature at Oc to 10 during the addition. The cooling bath is removed and the mixture allowed to warm to room temperature. After 11/2 hours, some starting material is still present and 3.1 ml (0.0362 mol) of oxalyl chloride is added and the mixture stirred for an additional 11/2 hours. Total stirring at room temperature is 3 hours. The solvent is evaporated in vacuo to give a solid residue. The residue is suspended in ether and evaporated twice more to give 2-(3-ethyl 5-methyl-4-isoxazolyl)-3-indole-lyoxyl chloride. EXAMPLE 4 : N, N-dimethyl-2-(3-ethyl-5-methyl-4-isoxa- zolyl-3-indole-glvoEyl amide (Compound of formula II) 79.0 g (0.250 mol) of 2-(3-ethyl-5-methyl-4-is6xa- zolyl)-3-indole-glyoxyl chloride is added portion-wise to a 0 to 100 cooled mixture of 1200 ml of 40% aqueous dimethylamine and 1000 ml of ether. The resulting mixture is stirred for 1 hour without an ice bath and then filtered. The solid is then washed well with water and with three portions of cold ether to give N,N-dimethyl 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyOxylamide; m.p. 2120 to 2150. The following compounds of formulae II, III, V and VII may be prepared analogously to Examples 1 to 4 or by any other method as hereinbefore described. TABLE I (* = cmpds. of Examples 1 to 4) EMI18.1 Cmpd. <SEP> R4 <SEP> R5 <SEP> R6 <SEP> III <SEP> V <SEP> VII <SEP> R3 <SEP> R4 <SEP> II <tb> No. <tb> a* <SEP> H <SEP> CH3 <SEP> C2H5 <SEP> m.p. <SEP> 72-75 <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 221-223 <tb> b <SEP> H <SEP> C2H5 <SEP> m.p. <SEP> 211-212 <tb> c <SEP> C2H5 <SEP> C2H5 <SEP> m.p. <SEP> 218-219 <tb> d <SEP> i-C3H7 <SEP> C2H5 <tb> e <SEP> t-C4H9 <SEP> C2H5 <tb> f <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 211-214 <tb> g <SEP> CH3 <SEP> H <tb> h <SEP> CH3 <SEP> n-C3H7 <SEP> m.p. <SEP> 153-154 <tb> i <SEP> CH3 <SEP> t-C4H9 <SEP> m.p. <SEP> 270 <SEP> (dec.) <tb> j <SEP> C2H5 <SEP> CH3 <SEP> m.p. <SEP> 155-156 <tb> k <SEP> CH3 <SEP> i-C3H7 <SEP> m.p. <SEP> 231-233 <tb> l <SEP> F <SEP> C2H5 <tb> m <SEP> CH3 <tb> n <SEP> OCH3 <tb> o <SEP> H <SEP> C2H5 <SEP> C2H5 <SEP> m.p. <SEP> 2-1-213 <tb> p <SEP> H <SEP> # <tb> q <SEP> H <SEP> # <SEP> m.p. <SEP> 194-197 <tb> TABLE I (cont'd) EMI19.1 Cmpd. <SEP> R4 <SEP> R5 <SEP> R6 <SEP> III <SEP> V <SEP> VII <SEP> R3 <SEP> R4 <SEP> II <tb> No. <tb> r <SEP> H <SEP> CH3 <SEP> C2H5 <SEP> # <SEP> m.p. <SEP> 199-203 <tb> s <SEP> F <SEP> C2H5 <SEP> # <tb> t <SEP> H <SEP> phenyl <SEP> m.p.145-146 <SEP> m.p.129-133 <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 259-261 <tb> u <SEP> F <SEP> CH3 <SEP> CH3 <tb> v <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> w <SEP> OCH3 <SEP> CH3 <SEP> CH3 <tb> x <SEP> H <SEP> # <SEP> m.p. <SEP> 210-221 <tb> y <SEP> H <SEP> # <SEP> m.p. <SEP> 193-195 <tb> z <SEP> H <SEP> # <tb> aa <SEP> F <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 220-222 <tb> ab <SEP> F <SEP> C2H5 <SEP> CH3 <SEP> CH3 <SEP> CH3 <tb> ac <SEP> F <SEP> CH3 <SEP> CH3 <SEP> # <tb> ad <SEP> F <SEP> CH3 <SEP> CH3 <SEP> # <tb> ae <SEP> H <SEP> CH3 <SEP> phenyl <SEP> C2H5 <SEP> C2H5 <tb> EXAMPLE 5 : a-(Dimethylaminomethyl)-2-(3-ethyl-5- methyl-4-1soxazolyl)-lH-indole-3-methanol (Compound of formula I in which R2 represents hydroxyl) To a suspension of 9.9 g (0.26 mol) of lithium aluminium hydride and 950 ml tetrahydrofuran under nitrogen there is added 21.0 g (0.065 mol) of N,N-di methyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyOxyl- amide in 735 ml of tetrahydrofuran, while maintaining the temperature between 200 to 250. After addition is complete, the mixture is stirred at room temperature for 5 hours then cooled to Oo and quenched by the addition dropwise of 20 ml of water in 180 ml of tetrahydrofuran. The resulting solids are filtered and the tetrahydrofuran dried over anhydrous magnesium sulphate, filtered and evaporated. The residue is recrystallized from ethanol to give a- (dimethylaminomethyl) -2- (3-ethyl-S-methyl- 4-isoxazolyl) - lH-indole-3-methanol; m.p. 1780 to 1800. EXAMPLE 6 : 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-(dimethyl- aminoethyll-indole (Compound of formula I in which R2 represents hydrogen) To a refluxing suspension of 22.8 g (0.60 mol) of lithium aluminium hydride in 1100 ml of tetrahydrofuran under nitrogen, there is added dropwise over approximately 1 to 1V2 hours a warm solution of 48.7 g (0.15 mol) of N,N-dimethyl-2- (3-ethyl-5-methyl-4-isoxazolyl) -3 indole-glyoxyl anide in2250 ml of tetrahydroduran. The mixture is ref fluxed for 3 hours after addition is completed. The resulting suspension is cooled to -100 to +5 and a solution of 270 ml of tetrahydrofuran and 90 ml of water is added dropwise with the temperature maintained between -100 and +5 . The suspension is stirred for approximately 1 hour without a cooling bath and then allowed to stand overnight without stirring. The mixture is filtered, the filtrate evaporated in vacuo and the residue is dissolved in methylene chloride. The methylene chloride is washed with water, dried and evaporated in vacuo. The residue is crystallized from ether to give 2-(3 ethyl- 5-methy 1- 4-isoxazolyl) - 3-dimethylaminoethyl) - indole; m.p. 1180 to 1200. EXAMPLE 7 : 2-(3-Ethyl-5-methyl-4-isoxazolyl)-3-(di- methylamino ethyll-indole (Compound of formula I wherein R2 is hydrogen Step A) 2-(3-Ethyl-5-methyl-4-isoxazoly)-3-(dimethyl aminomethyl)-indole (Compound of formula XI) A mixture of 20.6 ml (0.24 mol) 37% aqueous formaldehyde, 18 ml (0.12 mol) 40% aqueous dimethylamine and 80 ml acetic acid is cooled to 0 and treated by the dropwise addition of 25.5 g (0.113 mol) 2- (3-ethyl-5-methyl-4-isoxazolyl) -indole in a solution of 45 ml acetic acid and 125 ml dioxane. After addition is complete the mixture is stirred for 1 hour at room temperature and poured onto 500 ml ice-water. The resulting solution is made basic with 20% potassium hydroxide and then extracted with methylene chloride. The methylene chloride is washed with water, brine, dried over anhydrous magnesium sulphate, filtered and evaporated to give a gum that crystallizes to give 2- (3-ethyl- 5-methyl- 4-isoxazolyl) - 3- (dimethylaminomethyl)-indole; m.p. 880 to 900. Step B) 2-(3-Ethyl-5-methyl-4-isoxazolyl)-3-indole acetic acid (Compound of formula Xa) A mixture of 24.8 g (0.088 mol) of 2-(3-ethyl-5methyl-4-isoxazolyl)-3-(dimethylaminomethyl)-indole and 23 g (0.47 mol) of sodium cyanide in 175 ml ethanol and 50 ml water are refluxed for 80 hours. The mixture is then cooled and poured onto water, stirred for 1 hour and filtered to yield 2-(3-ethyl5-methyl-4-isoxazolyl)-3-indole acetamide; m.p. 1940 to 1950. The filtrate, which contains the sodium salt of 2- (3-ethyl-5-methyl-4-isoxazolyl) -3-indole acetic acid is evaporated to remove ethanol and acidified with cold 12N hydrochloric acid and the precipitate filtered to give 2- (3-ethyl-5-methyl-4-isoxazolvl) -3- indole acetic acid; m.p. 194"to 1970. Step C) 2-(3-Ethyl-5-methyl-A-isoxazoly)-3-indole acetyl chloride (Compound of formula III) A mixture of 10.3 g (0.036 mol) 2-(3-ethyl-5-methyl4-isoazolyl)-3-indole acetic acid and 22.0 g (0.185 mol) thionyl chloride in 106 ml toluene is stirred at room temperature for 18 hours. The toluene is removed in vacuo to give 2- (3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetyl chloride. Step D) N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)- 3-indoleacetamide (Compound of formula II) A mixture of 11.2 g (0.036 mol) of 2-(3-ethyl-5methyl-4-isoxazolyl)-3-indole acetyl chloride in 100 ml of tetrahydrofuran is added to a vigorously stirred solution of dimethylamine in water (25 ml 40% dimethylamine in water) at 0 to 100. The resulting mixture is allowed to warm to room temperature and poured into ether-water. The organic layer is separated, dried over anhydrous magnesium sulphate, filtered and evaporated to give N,N-dimethyl-2-( 3-ethyl-5-methyl-4-isoxazolyl) -3- indole acetamide; m.p. 1760 to 1780. Step E) 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-dimethyl aminoethyl)-indole A solution of 4.7 g (0.015 mol) of N,N-dimethyl-2 (3-ethyl-5-methyl-4-isoxazolyl)-3-indoleacetamide in 47 ml of tetrahydroduran under nitrogen is added dropwise to a suspension of 2.28 g (0.06 mol) lithium aluminium hydride in 50 ml tetrahydrofuran, while maintaining the reaction at room temperature. The mixture is stirred for 1V2 hours at room temperature, cooled in ice and quenched with 5 ml water in 50 ml tetrahydrofuran. The resulting solids are filtered and the filtrate dried over anhydrous magnesium sulphate, filtered and evaporated and the-residue crystallized from ether to give 2-(3-ethyl S-methyl)-4-isoxazolyl) -3- (dimethylaminoethyl)-indole; m.p. 118 to 1200. The following compounds of formula I can be prepared analogously to the appropriate Examples 5 to 7 or according to any other method as hereinbefore described. TABLE 2 EMI25.1 Cmpd. <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Physical <tb> No. <SEP> data <tb> 1 <SEP> (Ex. <SEP> 5) <SEP> H <SEP> OH <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> C2H5 <SEP> m.p. <SEP> 178-180 <tb> <SEP> 2 <SEP> H <SEP> C2H5 <SEP> m.p. <SEP> 148-150 <tb> <SEP> 3 <SEP> C2H5 <SEP> C2H5 <SEP> m.p. <SEP> 148-149 <tb> <SEP> 4 <SEP> i-C3H7 <SEP> C2H5 <tb> <SEP> 5 <SEP> t-C4H9 <SEP> C2H5 <tb> <SEP> 6 <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 188-189 <tb> <SEP> 7 <SEP> CH3 <SEP> H <tb> <SEP> 8 <SEP> CH3 <SEP> n-C3H7 <SEP> m.p. <SEP> 176-178 <tb> <SEP> 9 <SEP> CH3 <SEP> t-C4H9 <SEP> m.p. <SEP> 205-206 <tb> <SEP> 10 <SEP> C2H5 <SEP> CH3 <SEP> m.p. <SEP> 153-155 <tb> <SEP> 11 <SEP> CH3 <SEP> i-C3H7 <SEP> m.p. <SEP> 186-188 <tb> <SEP> 12 <SEP> F <SEP> C2H5 <SEP> m.p. <SEP> 125-127 <tb> <SEP> 13 <SEP> CH3 <tb> <SEP> 14 <SEP> OCH3 <tb> TABLE 2 (cont'd) EMI26.1 Cmpd. <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Physical <tb> No. <SEP> data <tb> <SEP> 15 <SEP> H <SEP> OH <SEP> C2H5 <SEP> C2H5 <SEP> CH3 <SEP> C2H5 <SEP> m.p. <SEP> 153-154 <tb> <SEP> 16 <SEP> H <SEP> # <SEP> m.p. <SEP> 169-171 <tb> <SEP> 17 <SEP> H <SEP> # <SEP> m.p. <SEP> 166-168 <tb> <SEP> 18 <SEP> H <SEP> # <SEP> m.p. <SEP> 166-167 <tb> <SEP> 19 <SEP> F <SEP> # <SEP> m.p. <SEP> 159-160 <tb> <SEP> 20 <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 118-120 <tb> <SEP> 21 <SEP> H <tb> <SEP> 22 <SEP> C2H5 <tb> <SEP> 23 <SEP> i-C3H7 <tb> <SEP> 24 <SEP> t-C4H9 <tb> <SEP> 25 <SEP> CH3 <SEP> CH3 <tb> <SEP> 26 <SEP> CH3 <SEP> H <tb> <SEP> 27 <SEP> CH3 <SEP> n-C3H7 <tb> TABLE 2 (cont'd) EMI27.1 Cmpd. <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Physical <tb> No. <SEP> data <tb> <SEP> 28 <SEP> H <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> t-C4H9 <tb> <SEP> 29 <SEP> F <SEP> C2H5 <tb> <SEP> 30 <SEP> CH3 <tb> <SEP> 31 <SEP> OCH3 <tb> <SEP> 32 <SEP> H <SEP> C2H5 <SEP> C2H5 <tb> <SEP> 33 <SEP> # <tb> <SEP> 34 <SEP> # <tb> <SEP> 35 <SEP> # <tb> <SEP> 36 <SEP> CH3 <SEP> CH3 <SEP> phenyl <SEP> m.p. <SEP> 141-143.5 <tb> <SEP> 37 <SEP> F <SEP> m.p. <SEP> 152-154 <tb> <SEP> 38 <SEP> CH3 <tb> <SEP> 39 <SEP> OCH3 <tb> TABLE 2 (cont'd) EMI28.1 Cmpd. <SEP> RÚ <SEP> Rê <SEP> R <SEP> R4 <SEP> R5 <SEP> R6 <SEP> Physical <tb> No. <SEP> data <tb> <SEP> 40 <SEP> H <SEP> H <SEP> # <SEP> CH3 <SEP> phenyl <SEP> m.p. <SEP> 104-105 <tb> <SEP> 41 <SEP> H <SEP> H <SEP> # <SEP> CH3 <SEP> phenyl <SEP> m.p. <SEP> 150-151 <tb> <SEP> 42 <SEP> H <SEP> H <SEP> # <SEP> CH3 <SEP> phenyl <tb> <SEP> 43 <SEP> F <SEP> OH <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> CH3 <SEP> m.p. <SEP> 175-178 <tb> <SEP> 44 <SEP> F <SEP> OH <SEP> CH3 <SEP> CH3 <SEP> C2H5 <SEP> CH3 <SEP> m.p. <SEP> 79-80 <tb> <SEP> 45 <SEP> F <SEP> OH <SEP> # <SEP> CH3 <SEP> C2H5 <SEP> m.p. <SEP> 168-169 <tb> <SEP> 46 <SEP> F <SEP> OH <SEP> # <SEP> CH3 <SEP> CH3 <tb> <SEP> 47 <SEP> H <SEP> H <SEP> C2H5 <SEP> C2H5 <SEP> CH3 <SEP> phenyl <SEP> m.p. <SEP> 110-112 <tb> Examples of preferred compound groups are for example those wherein a) Re and R4 represent, independetly, C1-C4alkyl or together with the adjacent nitrogen atom EMI29.1 or EMI29.2 R5 and R6 represent, independently, hydrogen or Cl-C4alkyl and R1, R2 and n are as defined above. Within this group compounds wherein R2 represents hydroxyl are especially preferred. b) R2 represents hydrogen R3 and R4, independently, represent Cl-C4alkyl or together with the adjacent nitrogen atom EMI29.3 or EMI29.4 R5 represents methyl, R6 represents phenyl or phenyl mono-substituted by fluorine, chlorine, C1 4alkyl or C1 4alkoxy and R1 is as defined above. Within these groups and generally for compounds of formula I the following meanings for the individual substituents or combinations thereof are preferred. R1 = a) H, F, CH3, OCH3; b) H R3 = R4 = CH3; EMI30.1 R5 and R6, independently, a) H, C1 4alkyl b) C1-2alkyl or c) R5 = CH3 R6 = phenyl d) R5 = CH3 R6 = C1-4alkyl e) R5 = C1-4alkyl R6=C2H5 f) R5 = CH3 R6 = C2H5 A particularly preferred compound is &alpha;-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4- isoxazolyl)-1H-indole-3-methanol.

Claims: What is Claimed is 1. Compounds of formula I EMI31.1 wherein R1 represents hydrogen, fluorine, chlorine, C1-4alkyl or C1-4alkoxy, R2 represents hydrogen or hydroxyl, R3 and R4 represent, independently, Cl 4- alkyl or together with the adjacent nitrogen atom EMI31.2 or EMI31.3 wherein n is 1, 2 or 3, R5 represents hydrogen or C1-4 alkyl and R6 represents hydrogen, C1 4alkyl, phenyl or phenyl mono-substituted by fluorine, chlorine, C1 4alkyl or C1 4alkoxy. 2. A compound as Claimed in Claim 1 wherein a) R3 and R4 represent independently C1-4alkyl or together with the adjacent nitrogen atom EMI32.1 and R5 and R6 represent independently hydrogen or C14 alkyl, b) R3 and R4 represent independently C1 4alkyl or together with the adjacent nitrogen atom EMI32.2 and R2 represents hydroxyl or c) R2 represent hydrogen, R3 and R4 independently represent C1 4alkyl or together with the adjacent nitrogen atom EMI32.3 R5 represents methyl and R6 represents phenyl or phenyl mono-substituted by fluorine, chlorine, C1 4alkyl or C1 4alkoxy. 3. A compound as claimed in Claim 1 or 2 wherein R1 represents hydrogen, fluorine, methyl or methoxy preferably hydrogen. 4. A compound as claimed in any one of Claims 1 to 3 wherein R3 and R4 represent methyl or together with the adjacent nitrogen atom EMI33.1 5. A compound as claimed in any one of Claims 1 to 4 wherein a) R5 and R6 represent independently hydrogen or C1 4- alkyl, preferably C12alkyl, b) R5 represents methyl and R6 represents phenyl, c) R5 represents methyl and R6 represents C1 4alkyl, preferably ethyl or d) R5 represent C1 4alkyl and R6 represents ethyl. 6. -(Dimethylaminomethyl)-2-(3-ethyl-5-methyl-4- isoxazolyl) -lH-indole-3-methanol. 7. A compound as claimed in any one of Claims 1 to 6 in free base form or in the form of an acid addition or alkali-metal salt thereof. 8. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 6 in free base form or in the form of a pharmaceutically acceptable acid addition or alkali metal salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. 9. A compound as claimed in any one of Claims 1 to 6 for use as a pharmaceutical in particular as a hypoglycemic agent and/or an agent for inhibiting or impeding post-prandial hyperglycemia and for use in the treatment of the human or animal body by therapy. 10. A process for the production of compounds of formula I which comprises reducing the corresponding compound of formula II EMI34.1 wherein R1, R3, R4, R5 and R6 are as defined in in Claim 1, Z signifies -CO- or -CH2-. 11. A compound selected from those of formula II, III, V, VII, Xa, Xb or XI as hereinbefore defined.

Inventors: BRAND, LEONARD JAY, NADELSON, JEFFREY
Applicants: SANDOZ AG
Application year: 1981
Main classification: C07D413
IPC codes: C07D413, C07D261