NZ203862A - 3-(omega-tertiaryaminoalkyl)-2-substitutedindoles and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £03862 Priority Date(s): /.>?.fy.. /P.-frS* Complete Specification Filed: Class: CO. 2£.3.0.2^. CO.?.0.0.Q.(.

■ C-^. ?.£.(< 1.3.J.. A6.1&$J. Jo-Q^nS, .RvS?. ^ Publication Date: .. ^ 1986 P-0. Journal, No: ...^^, (iy C\ w # aP&w83 * ■ .O 62 NEW ZEALAND No.: no PATENTS ACT, 1953 Dri f c: COMPLETE SPECIFICATION 2-SUBSTITUTED-3-INDOLAMINES K/We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate, hereby decl?.re the invention for which X./ we pray that a patent may be granted to rHS/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 -(followed by la) - la - 2-Substi tuted-3-i ndolami nes The present invention concerns substituted indolamines, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals, especially as anti-diabetics.

More particularly the invention concerns compounds of formula x r ri /^h"(ch?vn^ h r wherein R-j represents hydrogen, fluorine, chlorine, Chalky! or C-^alkoxy, R2 and R3 represent, independently, C^alkyl or, together with the adjacent nitrogen pyrrolidino, piperidino, hexamethylenimino or morpholino and a) R represents a group of formula XX x m b) R X m represents hydrogen and represents 2, 3 or 4; or represents biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of formula XXa -c-c°-r4 xxa c(nh2)r5 represents hydrogen or hydroxy and represents 1, 2, 3 or 4, whereby in-formulae XX and XXa 203862 - 2- - represents hydrogen or C-j ^alkyl, and R5 represents hydrogen, C^alkyl, phenyl or phenyl substituted by halogen, ^alkyl or C-j ^alkoxy in free base or acid addition salt form.

The group -C-CO-R^ can exist in the alternative tautomeric form double bond.

All tautomeric forms and geometric isomers are included within the scope of the invention.

It will also be appreciated that compounds of formula I wherein X is other than hydrogen may exist in the form of optically 15 active isomers which may be separated in conventional manner. These isomeric forms are included within the scope of this invention whereby reference is usually made to the racernic form unless other wise mentioned. a) when R is a group of formula XXa by reducing a compound of formula Ip -C=C(0H)R^ and in the form of cis/trans isomers about the C=C t The compounds of the invention may be prepared, R R Ip type b) wherein Rp Rg, R^ and Rg are as defined for formula I, X represents hydrogen and m represents 2, 3 or 4, with hydrogen in the presence of a catalyst or 203862 b) when R is biphenyl, naphthyl, benzylphenyl, indanylfluorenyl or a group of formula XX,' reducing a compound of formula II R,rvYi^VH^ H wherein Rj, R2 and R^ are as defined for Formula I> R' represents < biphenyl, naphthyl, benzylphenyl, indanyl, fiuorenyl or a group of • 5 formula XX and either Z-. represents £ -C-(CH2)m_i or (CH2^2 ancl Z2 ^ a direct bond or Z^ is a direct bond and Z2 represents (CH2)m wherein' m represents 1, 2, 3 or 4.

Reduction according to a) may be suitably carried out at temperatures of between 20° and 60°C, especially 25° to 35cC and in an inert 10 solvent such as a alcohol e.g. methanol or ethanol (preferred at room temperature) or e.g. dimethylformamide (preferred at higher temperatures). Reduction is carried out under hydrogen employing a suitable catalyst such as e.g. platinum oxide, raney nickel, palladium on carbon and the like, whereby 10% palladium on carbon 15 is preferred; and at pressures of e.g. 15 to 100, preferably 40 to 50 p.s.i.

Reduction according to b) is carried out under conditions conventional for the reduction of carbonyl groups.

Suitable solvents include hydrocarbons e.g. hexane or benzene 20 and ethers such as diethylether, dioxane or preferably tetrahydro-furan. Examples of reducing agents are aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, diborane or preferably lithium aluminium hydride. Where appropriate reduction is carried out under an inert atmosphere e.g. under helium, argon., or 25 especially nitrogen. It will be appreciated that in all situations 203862 where the position in the -Z-j-CO-Z^-N(R£)(R3) group adjacent to the indole ring is occupied by carbonyl reduction may be partial (to give end-products wherein X = OH) or complete (to give end-products wherein X = H) and that the degree of reduction will be influenced by 5 the reaction conditions employed. For partial reduction therefore lower temperatures are preferred such as -30° to 40°C e.g. -5 to 10°C when R' is other than XX and 20°.to 35° when R' = XX.

When complete reduction is desired temperatures of e.g. 40° to 150°C pteferably reflux temperature of the reaction mixture are 10 employed, whereby when Z-j = (CH^ lower temperatures e.g. 0° to 60° may also suffice. Partial reduction can, of course, also be achieved by selection of a suitably weak reducing agent.

The various starting materials may be prepared in a conventional manner.

Thus the starting materials for process a) which in part fall under formula I may be prepared analogously to process b) or e.g. as described e.g.-in New Zealand Patent Specification No. 196762.

The starting materials for process b) and their precursors are 20 either known or can be prepared analogously to known methods.

Examples of such methods are illustrated by the following reaction schemes: (i) 2 / 2 \ /VCY /Zi=-C-(CH~L •> \ XXX...

H XI \ / Ilia 20d862 (ii) Rt IV + (COY), Ilia (2X= -CO) XII (iii) R .COCH, sxcess para~ + NH(R2)(R3) formaldehyde n t7 (Z2-(CH2)2) (or as salt) XI (iv) R i..

IV + CH3C0Y' '• XIII \ 7" 11 lb (v) R (ch2)mc00h ~y Ilia (Z1 = (CH2)2) (vi) R /-C00R, mineral CHp-CH b ———> V (m = 2) ^COORg acid (vii) R1 . CH„ ^COOR, CH.N\ 6 + CH, fc ^ xru ^ COOR, XIV VI 1 E H r/zv 14 APR 1986^ J203862 - 6 (viii) R1 jCl + HN'CH3'2 ' > VII H R' + HCH0/H20 IV • 0 II 0 (ix) + HN(Rg) (R3n ^2^ =-C-(Cr^)jn_^ ; N' H " NXR. XI " = 2-3 or 4> IX 0 (x) RlV^i—r^-^^T"000^. > u N-H X (xi) RK^-\ .COOH T , + + ch3cn —> N R' H "-COOR IV XV In the above reaction schemes, Y represents chlorine or bromine, and • Y' represents, hydroxy, chlorine or bromine.

Each Rg represents, independently, ^alkyl and the remaining 5 substituents are as defined for formula I.

Reaction conditions are conventional for the type of reaction involved and are not usually critical, examples ara 1 2038 m (i) solvents (a), R' = other than XX, hydrocarbons e.g. hexane or benzene, halogenated hydrocarbons e.g. methylene chloride or chloroform, ether, e.g. diethyl-ether, dioxane or preferably tetrahydrofuran. 5 (b), R1 = XX, additionally v/ater or an excess of XI, preferably a combination of water, diethylether and excess XI. temperatures e.g. -20°to 50°C, especially -.5° to 10°C.

(RV XX) and 20° to 30°C (R*= XX) (ii) solvents as for (i) (a). temperatures e.g. -20° to 50°C especially 20° to 30°C.

It is also preferred that XII be added-at ca. -5° to 5°C. (iii) solvents e.g. Cj_,, alkanols such as methanol or preferably ethanol. temperatures e.'g. 60° to 150°C preferably at reflux of 15 reaction mixture. (iv) (a) (Y1 = OH) reacting IV in acetonitrile with acetic acid in the presence of phosphoric acid and tn'fluoroacetic anhydride. (b) (Y = CI or Br) reacting IV with silver trifluoromethane sulfonate and then with the desired acetylhalide solvents b) e.g. halogenated hydrocarbons such as chloroform or preferably methylene chloride temperatures e.g. a) 10° to S0°C preferably 20° to 40°C; b) 20° to 45°C preferably 25° to 35°C. (v) reacting V with a halogenating agent such as thionyl bromide, 25 phosphorous oxychloride or preferably thionyl chloride. solvents e.g. aromatic hydrocarbons such as benzene or toluene, ethers such as diethylether, dioxane or especially tetrahydrofuran. temperatures e.g. 0° to 60° preferably 20° to 30°C.

-J* - ::jinwiT77; (vi) Reacting VI with hydrobromic.acid or preferably with hydrochloric acid in water. temperatures e.g. 90° to 150°, preferably reflux. (vii) Reacting VII with XIV in the presence of lithium, potassium 5 or preferably sodium metal in excess (XIV). temperatures e.g. 100° to 200°, preferably 120° to 150°. 203862 (viii) reacting IV with XI in an aqueous formaldehyde solution and in the presence of acetic acid and an organic co-solvent co-solvent e.g. ether such- as diethylether, tetrahydrofuran or especially dioxane. (ix) IX first reacted with N-hydroxy succinimide and dicyclo-hexylcarbodiimide then with XI solvents as (i) (a) chlorinated hydrocarbons such as methylene chloride being preferred and for the second step additionally temperatures e.g.,10° to 50°C preferably 20° to 30°C. (x) conventional hydrolysis using e.g. NaQH, KOH, HC1. sol vents e.g. aqueous alcohols temperatures e.g. 15° to 80°C preferably 25° to 45°C 15 (xi) analogous to (iv) (a).

The final and intermediate products resulting from the above processes can be isolated and purified in conventional manner. Intermediate compounds can where appropriate be further reacted without isolation.

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. In this respect particular reference is made to New Zealand Patent Specification No. 196762 and US Patent Specification 4,336,391 where various;methods 25 for preparing IV, wherein R' is a group of formula XX are described.

The compounds of formula I may be recovered either in free base form or in acid addition salt form as required. The acid addition salt forms of the compounds of formula I also form part of the invention. temperatures e.g. -10° to 30°C especially 0° to 10°C. water. 203862 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, raaleic, 5 funiaric and the like.

The compounds of the formula I possess pharmacological activity. In particular they 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 10 groups of 5 which are fasted for 16 hours are given an initial dose t of from 5 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 15 body weight of sodium hexobarbital after which blood is collected via cardiac puncture. The blood samples are placed in an autoanalyzer cup containing 0.1 milliliters of heparin (1,000 units per milliters). 2) with an autoanalyzer. The blood sugar content is compared to the control group which receives 0.5 % carboxymethyl cellulose and an oral starch load and are run concurrently.

The compounds are thus indicated for use in the treatment of diabetes by inhibiting or impeding post-prandial hyperglycemia.

An indicated suitable daily dosage is from about -50 to 2000 mg e.g. 75" .to 2000 (type a) wherein R represents a group of formula XX) or 50 to 1000 (type b) where R represents a group of formula XXa) preferably e.g. 2 to 4 times a day in divided dosages of about 12.5 to 100 mg. Administration preferably takes place at meal 30 times e.g. 3 times a day in dosages of about 20 to 700 mg particularly before a carbohydrate-rich meal.

The heparinized blood is used to determine the blood sugar level 2 038 62 D The compounds of formula I additionally exhibit fasting hypoglycemic activity as indicated by a lowering of serum glucose in 4 male cebus monkeys weighing 2 to 4 kilograms which are fasted for 16 to 18 hours before testing. At least a three-day interval 5 is allowed between experimental days. The compound to be tested is suspended in 0.5 % carboxymethyl cellulose (CMC) for oral dosing. Tv/o blood samples for basal serum glucose level are taken at minus 30 minutes and before administration of placebo (0.5 % CMC) or the compound at from 5 to 40 mg/kg of animal body weight. Blood samples 10 are thereafter taken hourly for 6 hours. Serum glucose levels were determined by the technicon auto-analyzer 2-glucose oxidase method, and these glucose levels are then compared with the glucose levels of the control group which received orally 0.5 % CMC and is run concurrently.

The compounds are additionally indicated for treating diabetes as hypoglycemic agents. An indicated daily dose for this indication is from about 25 to about 400 nig , preferably e.g. administered 2 to 4 times a day conveniently in unit dosage form containing from about 6 to about 200 mg., or in sustained release form. 203862 The invention therefore also concerns compounds of formula I suitable for use as pharmaceuticals e.g. as agents for inhibiting or impeding post-prandial hyperglycemia.

The compounds Of formula I may be administered in free base •\ < form or in the form of pharmaceutically acceptable acid addition salts e.g. as mentioned above which salt forms have the same order of activity as the free base forms.

The compounds of formula 1 or their pharmaceutically acceptable acid addition salts may be administered alone, or in admixture with a pharmaceutical ly acceptable diluent or carrier, and, optionally other excipients, and administered orally in such forms as tablets, elixirs, capsules or suspensions or parenteral^ in such 15 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 hard-filled or liquid-filled capsules.

A particular compound group comprises those of formula'I 20 wherein R represents the group XX wherein represents hydrogen or C^alkyl and Rg represents hydrogen, Chalky! or phenyl, X represents hydrogen and r,; 25 m represents 2, in free base or acid addition salt form.

Another group of compounds of formula I comprises those wherein R represents biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or.the group XXa as defined for formula I lh % ri4APRI986.pl // 2 038 6 13 X represents hydrogen or hydroxy and m represents 1 or 2, in free base or acid addition salt form.

Examples of alkyl are methyl 5 methoxy and ethoxy. ethyl and isopropyl and of alkoxy Particularly interesting substituent meanings are as follows: R = a) group of formula XX b) biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl, particularly naphthyl or biphenyl such as 2-naphthyl, o-biphenyl and p-biphenyl especially naphthyl such as 2-naphthyl group of formula XXa H R2'R3 R4'R5 fluorine or chlorine C1_4alkyl C-^alkoxy H, F» CH^ or OCHg, especially H independently Chalky! the same kj^alkyl each methyl pyrrolidino, piperidino, hexamethylenimino or morpholino, especially pyrrolidino independently C-j_^al kyl independently phenyl independently substituted phenyl as defined R4 = especially methyl or ethyl Rr = C, -a1kyl especially ethyl or methyl or phenyl 0 i "H R4 = R5 = C2H5 R4 -• CH3 R5 = phenyl JV ->r- wmp X = a) H b) OH m = a) 1, 2 or 3 b) 1 or 2.

Combinations of the above groups are especially preferred.

Particularly preferred individual compounds are 2-(3-ethy1-5-methyl-isoxazolyl)-3-(3-dimethyl aminopropyl)-indole; 2-(2-naphthyl)-3-[2-(N,N~dimethylamino)ethyl]-indole; 4-amino-3-[3-(3-dimethyl aminopropyl)-indol-2-yl]-3-hexen-2-one; and especially 4-anrino-3-[3-(2-dimethylamino-l-hydroxyethyl}-indol-2-yl]-3-hexen-2-one in free base or acid addition salt form.

The following examples illustrate the invention whereby temperatures are given in degrees centigrade. 1 2038S3 EXAMPLE' A ?;I5i!T§t!3^1:3;B!3§D^]:4:lsgxazo]y2j=3-{diraeth^1am2ngraeth^}}-2ndgle iG2!T22yD^_2f_f2r!i|yl5_yn} A mixture of 20.6 ml (0.24 mole) 37i£ aqueous formaldehyde, 18 ml (0.12 mole) 40* aqueous dimethylamine and 80 ml acetic acid is 5 cooled to 0° and treated by dropwise addition with 25.5 g (0.113 mole) 2-(5-methyl-3-phenyl-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% 10 potassium hydroxide and then extracted with methylene chloride. The methylene chloride is washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound, 88-S0°.

The preparation of the precursors of this compound and analogs 15 thereof is described in New Zealand Patent Specification No. 196762.

EXAMPLE B' I£22(5-methvl-3-ghenyl ;;4-isoxazolyl i ndoV^yl ]methyl Jprogarie--^i2i£_§?l^A_^i§£by!§§£§r (Cc-rngoynd_of"_T2rQ?yl5_VI} A mixture of 19.8 g (0.06 mole) of 2-(5-tnethyl~3-phenyl-4-iso-xazolyl)-3-(dimethylaminomethyl)-indole and 30 g (0.185 mole) of 20 diethylmalonate is heated to 120°.and 100 mg of metallic sodium is added. The mixture is then heated for five hours at 120°C and an additional 100 mg of metallic sodium is added. The temperature is increased to 140° and maintained for 18 hours. The mixture is cooled and poured into 150 ml 10% hydrochloric acid and extracted with 25 ether. The ether.extracts are washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the ether and excess diethylamalonate to give the title compound as an oil. /> EXAMPLE C 2-£5-meth^2-3-ghenyl-4-lsoxazoj^l3-lodole_gro2ionic acid (C_o_mp_o_uii_d _o_f _fo_rm_u_l_aM_V)_ A mixture of 22.8 g (0.05 mole) of [[2-(5-methyl-3-phenyl-4~ isoxazolyI) indol-3-yl ]rnethyl ]propanedioic acid, diethyl ester and 150 ml of 12 N hydrochloric acid is refluxed for 65 hours. The mixture is cooled and extracted with ether. The ether is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The solid residue is then decolorized with charcoal and recrystallized from ether hexane to give the title compound m.p. 170° to 172°.

EXAMPLE D 23£53meth^2-3~ghen^/l-4-i soxazo2yl ^33-indol e^rogi onYl_ch lori de IQ20P2yo^_2f_f2r!ryls_inaj A mixture of 5.1 g (0.0147 mole) of 2-(5-methyl-3-phenyl-4-iso-xazolyl)-3-indole propionic acid and 7.0 g (0.059 mole) of thionyl chloride in 200 ml tetrahydrofuran is stirred for 18 hours at room temperature. The solvent is then removed in vacuo to give the title compound.

EXAMPLE E ^i^l^iO-'s^bylliiiSrlPr^ylz^iEhenyl-^isoxazolyl );3-indole^groDignamide (Q20B2yOd_2Lformula_n] A suspension of 5.35 g (0.0147 mole) of 2-(5-methyl-3-phenyl-4-isoxazolyl)-3~indole propionyl chloride in 100 ml methylene chloride is added to 150 ml 40% aqueous dimethyl amine while maintaining temperatures at 0° to 10°. The mixture is then stirred for two hours at room temperature and then extracted v/ith methylene chloride. The combined organic layers are washed with water, dried over magnesium } ? - - 1.1, l sulfate, filtered and evaporated. The solid residue is recrystallized from ethanol to give the title compound, m.p. 174° to 177°.

The following compounds may be prepared analogously or as otherwise hereinbefore described. (* as prepared.in Examples A to.E) Cmpd.

R' R1 R4 R5 ci* XX H CH3 phenyl b H CH, sJ C2H5 c H CH3 ch3 d F CH3 phenyl e H CH, phenyl f H CH3 phenyl 9 H CH0 phenyl h \ H CH3 C2H5 ) ' TABLE' I Ilia (Z1=(CH2)2;Y=C1) II z1=(CH2)2 m.p.170-172° CHc ch- ch: ch! CH, ch, CH, CH' 3 m.p.174-7' morpholino pyrrolidino pi peridino pyrrolidino k it EXAMPLE F 2:^3~ethyl-5~met!2^!-£-i soxazol^l^^S-acet^l^indol e (Comgourid_of_forniu]a_IIIb} To a mixture of 0.77 milliliters (13.45 m mole) of acetic acid arid 0.17 grams (1.47 m mole) of 85$ phosphoric acid in 10 milliliters 5 of acetonitrile is added, at room temperature, 1.9 milliliters (13.45 m rncle) of tn'fluoroacetic acid anhydride. The mixture is stirred for 15 minutes and then treated by dropwise addition with 1.0 grains (4.42 m mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in 10 milliliters acetonitrile. The mixture is stirred for 3^2 hours at room temperature 10 and then poured onto water and extracted with ether. The ether extracts are dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is filtered through silica gel using 10% methanol/methylene chloride. The solvent is evaporated, and the oil obtained is dissolved in ether. The solution is washed with 10%.sodium 15bicarbonate solution, decolorized with charcoal, dried over magnesium sulfate and evaporated in vacuo. The resulting oil crystallizes upon treatment with ether to give the title compound, m.p. 170-171°.

In the alternative procedure , 41.8 grams (0.163 mole) of silver trifluoromethanesulfonate is added portionwise to a solution of 33.5 20 grams (0.148 mole) of 2-(3-ethyl-5-inethyl-4-isoxazolyl )-indole in 450 milliliters of methylene chloride. The resulting suspension is then treated by dropwise addition with 12.8 grams (0.163 mole) of acetyl chloride in 50 milliliters of methylene chloride. The temperature rises to 35°.during the addition. After the addition is 25 complete the mixture is stirred at room temperature for 4 hours and then filtered. The filtrate is washed with 150 milliliters of 2N sodium hydroxide, water and 2N sodium hydroxide, then dried over anhydrous magnesium sulfate and finally evaporated in vacuo to yield an oil. The oil is crystallized from ether to give the title 30 compound, m.p. 170-173°. zio EXAMPLE G no-1 = £2-_(3-e th^/1-5-methY2~4-i so^azol^l i ndol-3-y23z2~ P!2P0§D2!]§ 1^2lP22yD^_2f..f2Di?yI?_IIJ A mixture of 12 g (0.045 mole) of 2-(3-ethyl-5-methyl-4-isoxa-zolyl )-3-acet.yl indole, 4 g (0,049 mole) of dimethyl amine hydro-5 chloride, and 0.5 ml concentrated hydrochloric acid in 70 ml of ethanol is heated to reflux and treated by portionwise addition with 14 g (0.470 mole) of paraformaldehyde over 5 hours. The resulting mixture is refluxed an additional .24 hours, cooled and evaporated in vacuo. The residue is then dissolved in 300 ml methylene 10 chloride and washed with 200 ml 2N hydrochloric acid. The aqueous acid is cooled and made basic with 2N sodium hydroxide and extracted with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give the title compound, m.p. 146-148°, The following compounds may be prepared analogously or as otherwise hereinbefore described.

TABLE II (* as prepared in Examples F + G) Cmpd.

R' R1 «4 R5 11 lb r2.

R3 ii Z2=(CH2)2 1)* J IX H CH^ c2h5 m.p.170-173° ch3 ch3 in. p. 146-148° j) H CH3 phenyl ch3 CH3 k) H ch3 ch0 ch3 ch3 1) H cm o c2h5 pyrrolidino in) N / r CH3 phenyl ch3 ch3 n) 2-naphthyl H - - ch3 ch3 o) o-biphenyl H - - ch3 1 ch3 203862 EXAMPLE' H jfCom90und_of_f"ormuJa_ 11J A solution of 11.0 milliliters (0.123 mole) of oxalyl chloride in 150 milliliters tetrahydrofuran is cooled to 5° and then treated by dropwise addition with 27.0 grams (0.111 mole) of 2-(2-naphthyl)-5 indole in 150 milliliters of tetrahydrofuran, while maintaining the temperature between 0° arid 10°. The mixture is allowed to stir at room temperature for 2 hours and then cooled to 10° and treated by rapid addition with 100 milliliters of 40£ aqueous dimethylamine. The mixture is stirred at room temperature for 1 hour and the phases 10 separated. The tetrahydrofuran layer is washed with brine and the aqueous layer with methylene chloride. The organic layers are combined and dried over magnesium sulphate, filtered and evaporated. The resulting solid is triturated with ether to give the title compound, m.p. 208-210°.

The following compounds may be prepared analogously or as otherwise hereinbefore described. table-iii Cmpd.

R .

R1 ..

R2 R 3 h R5 ii 9 (z-i=--c-). p)* 2-naphthyl H Sh /N h > m.p.208-210° q) o-bi phenyl H • r) ■ p-biphenyl H s) o-benzylphenyl H t) 2-fluorenyl h -indanyl H V 2-naphthyl F w) II ch, sJ >0 II ch30 y r y) XX h ' 1 > ch3 phenyl 2) 2-naphthyl H pyrrolidino - - aa) II H pi peri di no i - •- ab) II h morpholino I - - E N 2 038 6 j#2" EXAMPLE I =l(^I§£bYll!?l!U§£t}Yll!hl§2^29lYl)ir-ox03indole-3-butanoic_acid, 1^2!DR9yo^_2f_f2ir!?y^a x) A solution of 59.4 g (0.45 mole) mono-methyl succinate in 300 ml acetonitrile is treated by dropwise addition of 5.5 g 85% phosphoric 5 acid and then by the dropwise addition of 53.5 ml (0.45 mole) tn'fluoroacetic acid anhydride. The mixture is stirred 15 minutes at room temperature and then treated by dropwise addition of 33.9 g (0.15 mole) 2-(3-ethyl-5-methyl-4-isoxazoy'ly)-indole in 300 ml acetonitrile. The mixture is stirred at room temperature overnight 10 followed by the addition of 1.5 liters of water and 1 liter of ether. The layers are separated and the ether washed with water and made basic by the addition of solid sodium carbonate and water. The mixture is stirred 1 hour at room temperature, the layers are separated, the ether washed with water, dried over MgSO^, filtered 15 and evaporated to give the title compound.

EXAMPLE 0 2-^3-eth^l ^S-mathY]lz^ri§2^§^2-ZlYiz^~' 2*2llD^2l§l3:byt§Q2l2_§2ld iQ2!D22yQ!L2f_f2!!™]a_IX] A solution of 2-(3-ethyl-5-methyl-4-isoxazolyl)-y-oxo-indole- 3-butanoic acid, methyl ester in 250 ml methanol is treated 20 with 250 ml 2N sodium hydroxide solution and the mixture heated 15 minutes to 40-45° and then stirred at room temperature for 1 hour. Ether and water are added to the mixture and the layers separated, the ether washed v/ith water and the combined aqueous layers washed with ether, treated with charcoal and filtered through 25 celite. The aqueous basic solution is made acidic by careful addition of concentrated HC1 and extracted with ether. The aqueous 203862 acidic solution is washed with water, brine, dried over KgSO^, filtered and evaporated. The resulting foam is"crystallized to give the title compound, m.p. 98-110°.

EXAMPLE K ^il^ethyl-5-methyl-4; isoxazglyl)-N2N-di methyl-$-gxo-i ndol e-3- butanamide iCompound_of_formula_IIJ A solution of 978 mg (0.003 mole) 2-(3-ethyl-5-methyl-4-iso~ xazolyT)-^'-oxo-indole~3-butanoic acid in 15 ml methylene chloride is treated with 345 mg (0.003 mole) M-hydroxy-succinimide followed by the dropwise addition of 615 mg (0.003 mole) dicyclohexyl-10 carbodiimide in 10 ml Ch^C^. The resulting mixture is stirred 5 hours at room temperature. The mixture is filtered, the filter cake washed with CH^Cl^ and the combined layers added dropwise to 20 ml 40% aqueous dimethyl amine and 20 ml CH^Cl. The mixture is stirred overnight, water is added, the layers separated, the 15 CHgC^ washed with water, brine, dried over MgSO^, filtered and evaporated. The residue is crystallized to give the title compound, m.p. 144.5 - 148°.

EXAMPLE 1. 2-dimethyl ami no-lrhydroxyethyl}-i ndol-2^13-3- l£2!D22un$LN°' "U A mixture of 3.1 grams (0.01 mole) of a-dimethylaminomethyl-2- (3-ethyl-5-methyl-4-isoxazolyl)-indole-3-methanol and 0.31 grams of 5% Pd/C in 70 milliliters of ethanol is hydrogenated. at 50 psi and 25° until thin layer chromatography shows no starting material (3 days). The mixture is filtered through celite and the celite 25 washed with ethanol. The combined ethanol' filtrates are evaporated in vacuo, and the resulting oil is crystallized from ether to give the title compound, m.p. 90-104° . 8 1 4 APR I986 203862 24 The following may be obtained analogously (R = XXa) Cmpd. m X R1 R? R3 R4 l(ii) 1 oh h ch3 ch3 ch, phenyl Kiii) 1 oh F ch3 ch3 ch^ C2H5 l(iv) 1 oh ch3 ch3 ch3 ch3 C2H5 1 (v) 1 oh CH3° ch3 ch3 ch3 C2H5 l(vi) 1 oh h morpholino CH, C?H5 l(vii).. 1 oh h pyrrol idino CH, c„hr c 5 m.p.177-179° l(vIII) 1 oh H pi peri dino CH, C2H5 l(ix) 1 oh H ch, ch3 C2H5 ch3 m.p.184-185° EXAMPLE 2 4-ami no-3^ [3-(3-dimethyl ami nogrogylj^i ndol-2-vl]-4-phenyl-^buten; ?~20§ A mixutre of 3.6 grams (0.01 mole) of 2-(5-methyl-3~phenyl-4~ isoxazolyl)-3-(3-dimethylamino propyl)-lH-indole and 0.75 grams of Raney nickel in 75 milliliters of methanol is hydrogenated at 50 psi and 25° until thin layer chromatography shows no remaining starting material (IS hours). The mixture is filtered through celite and the celite washed with methanol. The combined methanol filtrates are evaporated in vacuo, and the resulting oil is crystallized from ethanol to give the title compound, m.p. 268-269°.

-J& - The following may be obtained analogously. R = XXa Cmpd. m x R1 R? Rv R4 R5 1 2(ii) 1 H h ch3 ch3 ch3 C2H5 2(iii) 1 H h CH3 CH3 CH3 phenyl m.p.222-224° 2(iv) 1 H F CH3 ch, ch, phenyl 2(v) 1 H CH3 ch, CH3 ch, phenyl 2(vi) 1 H CH,0 CH, CH3 ch, phenyl 2 (v i i) 1 h h morpholino ch, phenyl 2 (v i i i) 1 h h piperidino ch, phenyl 2(ix) 2 h h ch3 ch3 ch3 c2h5 m.p.158-159.5° EXAMPLE 3 ^{§:niet.hyl23-ghenyl-4-isoxazolyl J-3;f 3-dimeth^laniinoprop^l}-indo}e A solution of 2.0 g (Q.0054 mole) of NjN-dimethyl-2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionamide in 80 ml tetrahydrofuran is added to a suspension of 0.82 g (0.0216 mole) of lithium aluminum hydride in 40 ml tetrahydrofuran dropwise, maintaining the temperature between 20° and 25°. After the addition is complete the mixture is stirred at room temperature for two hours, cooled and quenched by the addition of 2 ml of water in 20 ml tetrahydrofuran. The resulting mixture is dried over magnesium sulfate, filtered and evaporated. The solid residue is recrystallized from ethanol to give 2-(5-methyl-3-phe-nyl-4-isoxazolyl)-3-(3-dimethyl--5 aminopropyl )-indole m.p. 156° to 157°.

EXAMPLE 4 2~ {3-e thyl-5-methYl-4-i soxazol^l J-3-^ 3-dimeth,v/l5rainogrggYl_)-i nd°l e A mixture of 5.0 grams (0.015 mole) of 3-dimethyl-amino-1-[2-(3-ethyl-5-methyl-4-isoxazolyl)-—indol-3~y]]-l-propanone in 120 milliliters of tetrahydrofuran is added dropwise to a refluxing 10 mixture of 2.0 grams of lithium aluminum hydride (0.053 mole) and 200 milliliters of tetrahydrofuran. The combined mixture is refluxed for one hours, cooled in an ice bath and quenched by the cautious addition of 7 milliliters of water. The mixture is then filtered through celite and the solvent evaporated in vacuo to yield an oil, 15 which slowly crystallized. The crystals are triturated with ether to gi ve 2- (3-ethyl -5-methyl-4-isoxazolo)-3- (3-dimethylaminopropyl )-indole, m.p. 131-133°.

EXAMPLE 5 3:dirnethylamino-];[2-_(3:ethy];5-methyl-4-isoxazolYl);indol-3^1 ]: 1-groganol A suspension of 816 mg (0.022 mole) of lithium aluminum hydride in 125 ml tetrahydrofuran under nitrogen is cooled to 5° and treated by dropwise addition with 3.5 g (0.011 mole) of 3-~dimethylamino-1- [2-(3-ethyl-5-methyl-4-isoxazolyl) indol-3-yU-l-propanone in 125 ml tetrahydrofuran while maintaining the teiiperature between 5° 25 to 3°. The resulting mixture is then stirred for 4 hours at 0° to 5°, then cooled to -50° and quenched by the addition of 10 ml saturated magnesium sulfate solution. The mixture is warmed to room tempera 203S62 ture and filtered and the filtrate is evaporated in vacuo. The resulting residue is dissolved in methylene chloride, washed v/ith water, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is crystallized from ether to give 3-dimethyl- amino-l-[2-(3-ethyl -5-niethyl-4-isoxazolyl)- indo-3-yl]-l- propanol, m.p. 166-169°.

EXAMPLE 6 ?:I3;ethyl-5-methyl-42isoxazolyl}^^(4-dimethyl aminobutyl}-indole A solution of 5.3 g (0.015 mole) 2-(3~ethyl-5-methyl-4-isoxar. zolyl )-N,N-dir(iethyl-j^oxo-indolr3-butan3mide in 25 ml dry THF is 10 added dropwise to a refluxing suspension of 1.71 g (0.045 mole) LiAlH^- and 50 ml THF. The mixture is refluxed 2 hours after addition and then cooled and quenched by the addition of ethyl-acetate, 2N sodium hydroxide and water. The mixture is filtered and the THF evaporated. The residue is dissolved in CF^Clg, washed 15 with water, dried over MgSO^, filtered and evaporated. The residue is dissolved in ether and converted to the hydrochloride salt v/ith gaseous HC1 giving the title compound as hydrochloride, m.p. 155.5-157.5°.

EXAMPLE 7 ^lI^lQSBhtt'Yljl^-C^-^N^N-dimethylaminojethyl]-indole A suspension of 4.5 grams (0.119 mole) of lithium aluminum hydride and 800 ml of tetrahydrofuran under nitrogen is heated at 55° and treated by portionwise addition with 10.0 grams (0.029 mole) of N,N~dimethyl-2-(2-naphthyl )-3-indole glyoxainide over ten minutes. The mixture is heated at reflux for 2 hours ar.d then cooled 25 to -60° and quenched by the careful addition of 150 milliliters of saturated magnesium sulfate solution. The mixture is warmed to room temperature and filtered through celite arid the celite washed with methylene chloride. The layers in the filtrate are separated 2$ and the aqueous layer is washed with methylene chloride. The organic layers are then combined, dried over magnesium sulfate, filtered and evaporated. The residue is triturated with ether and the resulting solid recrystal1ized from ethanol to give the title compound 5 m.p. 185-186°. example 8 A suspension of 4.5 grams (0.119 mole) of lithium aluminum hydride in 800 ml of tetrahydrofuran under nitrogen is cooled to 4° and treated by portionwise addition with 10.0 grams (0.029 mole) of 10 N,N-dimethyl-2-(2-naphthyl)-3-indole glyoxamide over 5 minutes, keeping the temperature below 10°. The mixture is stirred for 2 hours at 5°.and then cooled to -60° and quenched by the careful addition of 150 milliliters of saturated magnesium sulfate solution. The mixture is warmed to room temperature and filtered through 15 celite and the celite washed with methylene chloride. The layers in the filtrate are separated and the aqueous layer is washed with methylene chloride. The organic layers are then combined, dried over magnesium sulfate, filtered and evaporated. The residue is triturated with ether and the resulting solid chromatographed on silica gel 20 to give 2-(2-naphthyl)-3-[l-hydroxy-2-(N,Nrdimethyl ami no)ethyl]-indole, m.p. 172-174°.

The following compounds Jtiay be prepared analogously to Examples 3 to 5 aboye. ...

Cmpd. m X R Rl..

R? V R4 r5. i 9 2 h H ch3 ch3 ch3 ch3 2 h F ch3 ch. ch3 phenyl 11 2 h * H morphol ino CIL phenyl ■x- 2 03862 y Cmpd. m x r h: r2 r3 V r. 0 , 12 2 h h pyrrolidino ch3 phenyl 13 2 h h piperidino ch3 phenyl 14 2 h h pyrrolidino ch3 C2H5 2 OH h ch3 ch3 ch3 phenyl 2 OH \ t f ch3 ch3 ch3 17 2 h 2-naphthyl h ch3 ch3. - - 18 2 h o-biphenyl h ch3 ch3 - - 19 2 oh 2-naphthyl h ch3 -ch3 - - 2 oh o-biphenyl h ch3 ch3 - - 21 1 h o-biphenyl h ch3 ch3 - - m.p.159-161° 22 1 H p-biphenyl h ch0 o ch3 - - m.p.165-167° 23 1 h o-benzylphenyl h ch3 ch3 - - 24 1 H 2-fluorenyl h ch3 ch3 - - 1 H -indanyl h CH, ch3 - - 26 1 h 2-naphthyl f ch3 ch3 - - 27 1 h 2-naphthyl ch3 ch3 ch3 - - 28 1 h 2-naphthyl ch3° CH, ch3 - - 29 1 h 2-naphthyl h pyrroli dino - - 1 h 2-naphthyl h piperidino - - 31 1 h 2-naphthyl h morpholi no - - 32 1 oh o-biphenyl h ch3 ch3 - - m.p.166-168° 33 .1 oh p-biphenyl h ch3 ch3 - - 34 1 oh o-benzylphenyl h ch3 ch3 - - 1 oh 2-fluorenyl h ch3 ch3 - - 1 oh -indanyl h ch3 ch3 37 1 oh 2-naphthyl f ch3 ch3 - - 38 1 oh 2-naphthyl ch3 ch3 ch3 - - 39 1 oh 2-naphthyl ch3° ch3 ch3 - - 40 1 oh 2-naphthyl h pyrrolidino - - 41 1 oh 2-naphthyl h piperidino - - 42 1 oh 2-naphthyl h morpholino — 203863

Claims (13)

WHAT WE CLAIM IS:

1. Compounds of formula I X R vi ch-<c!|2Vn-R: •R wherein R-j represents hydrogen, fluorine, chlorine, C-j ^alkyl or C-j_^al koxy, R"2 and represent, independently, Cj .alkyl or, together with the adjacent nitrogen pyrrolidino, piperidino, hexatriethylenimino or morpholinc and R represents a group of formula XX a) R- ^ t al R- b 5-U >r \ 1 XX X represents hydrogen and "10 m represents 2, 3 or 4; or b) R represents biphenylj naphthyl, benzylphenyl, indeny], fluorenyl or a group of formula XXa i-C0~R4 XXa C(KH2)R5 X represents hydrogen or hydroxy and m represents 1,2, 3 or 4, 15 whereby in formulae XX and XXa represents hydrogen or C-j ^alky"), and Rc- represents hydrogen, Chalky!, phenyl or phenyl substituted by halogen, C._^alkyl or C-j- ^alkoxy in free base or acid addition salt form. y >TE^\ O \\ f\- -o 14APRJ986 203882 - 31 -

2. A compound according to Claim 1, wherein R represents a group of formula XX wherein represents hydrogen or C^_^ alkyl and Rg represents hydrogen, C-^ alkyl or phenyl, X represents hydrogen and m represents 2, in free base or acid addition salt form.

3. A compound according to Claim 1, wherein R represents bi phenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of formula XXa, X represents hydrogen or hydroxy and m represents 1 or 2, in free base or acid addition salt form.

4. A compound according to Claim 1, wherein R represents a group of formula .XXa in free base or acid addition salt form.

5. A compound according to Claim 4,wherein R^ represents methyl and R,- represents ethyl or phenyl in free base or acid addition salt form.

6. A compound according to Claim'1. wherein R represents naphthyl in free base or acid addition salt form.

7. A compound according to any one of Claims 3 to 6 wherein m represents 1 in free base or acid addition salt form.

8. A compound according to any one of Claims 1 to 7 wherein R-j represents hydrogen.

9. A compound selected from 2-(3-ethyl-5-methyl-isoxazolyl)-3-(3-dimethyl ami nopropyl)-indole; 2-(2-naphthyl)-3-[2-(N,N-dimethylamino)ethyl]-indole; 4-ami no-3- [3- (3-dimethyl ami nopropyl )-indol-2-yl ]-3-hexen-2-one; and 4-amino-3-[3-(2-dimethy 1 amino-l-hydroxyethyl)-indol-2-yl]-3-hexen-2-or.e in free base or acid addition salt form. 20386$ 32 -

19. A process for preparing a compound according to Claim 1 in free base or acid addition salt form which comprises 20 a) when R is a group of formula XXa by reducing a compound of formula Ip R, X R .CH-{CHz)B-NCg2 h ip type b) wherein Rp Rg, R3# R^ and Rg are as defined in Claim 1, X represents hydrogen and m represents 2, 3 or 4, with hydrogen in the presence of a catalyst or b) when R is bi phenyl ,■ naphthyl, benzylphenyl. indanyl/ fluorenyl or a group of formula XX, reducing a compound of formula II X ^-C-Zg-N: •R' II wherein R^, R2 and R are as defined iri Claim 1, R1 represents biphenyl, naphthyl> benzylphenyl, indanyl, fluorenyl or a group of formula XX and either Z, represents 2 or (CH9}„ and Z., is. a direct "C"(CH2Vl bond or Z^ is a direct bond and Z2 represents (CH2)m wherein m represents 1, 2, 3 or 4 and recovering the compound thus obtained in free base o>.vacid addition salt form.

11. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 9 in free base or pharmaceutically acceptable acid addition salt form together with a pharmaceutically acceptable diluent or carrier. - 33 - 203&62

12. A compound according to any one of Claims 1 to 9 in free base or pharmaceutically acceptable acid addition salt form suitable for use as a pharmaceutical.

13. A compound according to any one of Claims 1 to 9 in free base or pharmaceutically acceptable acid addition salt form suitable for use as an anti-diabetic. *;Dated this 14 April 1986 A J PARK & SON;Agents for the Applicants;14 APR 1986 m)*