CH656124A5 - 2-SUBSTITUTED-3-INDOLAMINES, METHOD FOR THE PRODUCTION AND USE THEREOF. - Google Patents

Description

The present invention relates to substituted indole amines, processes for their preparation, pharmaceutical compositions containing these substituted indole amines and their use for the preparation of agents for the treatment of diabetes.

In particular, the invention relates to compounds of the formula I.

R

worm

R.! represents hydrogen, fluorine, chlorine, alkyl (C14) or alkoxy (C ^ 4),

R2 and R3 independently of one another are alkyl (C, _4), or together with the adjacent nitrogen atom form a pyrrolidino, piperidino, hexamethyleneimino or morpholino ring and a) R for a group of the formula XX

XX

stands,

X is hydrogen and m is 2, 3 or 4 or b) R is biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of the formula XXa

-c-co-r4

c (nh2) r5

XXa stands

X is hydrogen or hydroxy and m is 1, 2, 3 or 4, where in the formulas XX and XXa R4 is hydrogen or alkyl (C] _4),

R5 represents hydrogen, alkyl (Ct 4), phenyl or phenyl substituted by halogen, alkyl (Cj_4) or alkoxy (C, _4) in the form of the free base or in the form of their acid addition salts.

The group

-c-co-ra

C (

Ï.'H-

u> 2

o can also be in the other tautomeric form r.

* \ s - Ì

C =

i r,

c (0h) r4

nh o

and because of the -C = C double bond are in the form of cis-trans isomers.

All tautomeric shapes and geometric isomers are within the scope of the present invention.

Compounds of the formula I in which X has a meaning other than hydrogen can occur in the form of optically active isomers which can be separated in a known manner. These isomeric forms are also encompassed within the scope of the invention, with the racemic form normally referred to unless otherwise stated.

The invention further relates to a process for the preparation of compounds according to claim 1 wherein R represents an io group of the formula XXa in the form of the free base or in the form of acid addition salts, characterized in that a compound of the formula Ip

X

/ R2

CH- (cH2) m-KR

IP

20th

y o, /

25 wherein Rj, R2, R3, R4, X and m are defined in connection with the formula I, reduced with hydrogen in the presence of a catalyst and the compounds of the formula I obtained in the form of the free base or in the form of an acid addition salt.

3o Also part of the invention is a process for the preparation of compounds according to claim 1 wherein R is biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of the formula XX in the form of the free base or in the form of acid addition salts, characterized thereby-35 that a compound of formula II

40

"'XX;

A

II

R '

H

45 wherein R ,, R2 and R3 are defined above, R 'for biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or one. Group of the formula XX stands for either Zi

0

50

-C- (CH2) mi or (CH2) m and Z2 is a direct bond or Z1 is a direct bond and Z2 is (CH2) m, in which m is defined above, reduced and the compounds of formula I obtained in Form of the free base or in the form of acid addition salts wins.

The reduction according to a) can expediently be carried out at 60 temperatures between 20 and 60 ° C., in particular 25 and 35 ° C. in an inert solvent, such as a lower alcohol, for example methanol or ethanol (preferably at room temperature) or, for example, dimethylformamide (preferably at higher temperatures) ) 65. The reduction is carried out under hydrogen using a suitable catalyst such as platinum oxide, Raney nickel, palladium-carbon, etc., with 10% palladium on carbon being preferred;

656 124

4th

at a pressure of, for example, 1.02 to 6.8 atm., preferably 2.72 to 4.08 atm.

The reduction according to b) is carried out under conditions which are customary for the reduction of a carbonyl group.

Suitable solvents are hydrocarbons such as hexane or benzene and ethers such as diethyl ether, dioxane or preferably tetrahydrofuran. The reducing agents include, for example, aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, di-borane or preferably lithium aluminum hydride. The reduction is expediently carried out in an inert gas atmosphere, for example under helium, argon or, in particular, nitrogen. It is pointed out that in all situations in which the position in the -Z1-CO-Z2-N (R2) - (R3) group which is adjacent to the indole ring is occupied by a carbonyl group, the reduction can only take place partially ( to give end products where X = OH) or complete (to give end products where X = H) and that the degree of reduction is affected by the reaction conditions used. Low temperatures are therefore preferred for partial reduction, for example those from -30 ° to +40 ° C

- 5 to + IO C if R 'has a different meaning than formula XX and 20 to 35' if R 'has the meaning of formula XX.

If a complete reduction is desired, temperatures of 40 to 150 °, preferably a reflux temperature of the reaction mixture should be used, if lower temperatures, for example 0 to 60, could be sufficient if Zj = (CH2) m. A partial reduction can of course be achieved by selecting a suitable weak reducing agent.

The various starting compounds can be prepared in a manner known per se.

For example, the starting compound for process a), which is partially covered by formula I, can be prepared analogously to process b) or, for example, as described in European Patent Application No. 81 810 131 (publication no. 38 298 A ) or in U.S. Patent No. 4,336,391.

The starting compounds of process b) and their 20 precursors are either known or can be prepared using known methods. Examples of such processes are illustrated by the following reaction schemes:

0 ')

Z -, - C \ '

purple

+ H? I (R2} {R3)

XI

\ or (CK,) /

\ /

IV

(C0Y); XII

purple

(Iii)

GOCH-

KH (R2) (R

r>

O

Excess

(CHO)

(or as salt) XI

II (Z „= (CH?) R.)

Ù U (.

(iv) Rt o

H

IV

+ CH "C0Y XIII

nib

(v) ^ {CH ^ eooH

in

1) / N, p I

■ i <- -R '

H

Illa (Z1 =

5

656124

(vi)

^ ■ COQPsç Mineral-.chn-ch b v (ra - 2)

^ COORr acid

(vii) R,

(vili)

*1

.CR, ^ COOR,

xc! lkv 13 + ch, c

/ c ^ r ,,> 0

n jì ^

H VII

"A

H

IV

r '

cook-

0

VTW A * *

+ kn (ch3) 2

VI

VII

(ix)

l a 1

/ «V .. ^

^ N / XR '

/ - <CH2> ri = rC00H * (Zr-C- (CH2) ia „1)

xi

(x)

Ri

IX

0

! .. f

C - ^^ OORg

tx

(xi)

^ COOH a- fr'u \

^ COORj

XV

x

In the above reaction schemes, Y represents chlorine or bromine,

Y 'hydroxy, chlorine or bromine.

Every R <; independently means alkyl (CM) and the remaining substituents are defined in connection with formula I.

The reaction conditions are common to the reaction used and are usually not critical. examples are

(i) Solvent (a), R 'does not represent the formula XX, hydrocarbons, for example hexane or benzene, halogenated hydrocarbons, for example methylene chloride or chloroform, ether, for example diethyl ether, dioxane or preferably tetrahydrofuran.

55 (b), R 'stands for the formula XX, additionally water or an excess of XI, preferably a combination of water, diethyl ether and an excess of XI.

Temperatures for example - 20 to + 50 ° C, in particular - 5 to +10 ° C (R '* XX) and 20 to 30 ° C (R' = XX). so (ii) solvents as for (i) (a)

Temperatures, for example, -20 ° to + 50 ° C, in particular 20 'to 30 ° C.

It is preferred that XII is added at temperatures of about -5 ° to +5 ° C.

65 (iii) solvents, for example lower alkanols such as methanol or preferably ethanol.

Temperatures for example 60 to 150 ° C, preferably at the reflux temperature of the reaction mixture.

656 124

6

(iv) (a) (Y '= OH) reaction of IV in acetonitrile with acetic acid in the presence of phosphoric acid and trifluoroacetic anhydride.

(b) (Y = Cl or Br) reacting IV with silver trifluoromethanesulfonate and then with the desired acetyl halide.

Solvent b) for example halogenated hydrocarbons such as chloroform or preferably methylene chloride.

Temperatures for example a) 10 to 80 ° 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, phosphorus oxychloride or, preferably, thionyl chloride.

Solvents, for example aromatic hydrocarbons such as benzene or toluene, ethers such as diethyl ether, dioxane or in particular tetrahydrofuran.

Temperatures for example 0 to 60 °, preferably 20 to 30 ° C.

(VIII) reaction of IV with XI in an aqueous formaldehyde solution and in the presence of acetic acid and another organic solvent

Another solvent, for example ether such as diethyl ether, tetrahydrofuran or especially dioxane.

Temperatures for example —10 to +30 C, in particular 0 ° to 10 "C.

(IX) IX is first reacted with N-hydroxysuccinimide and di-cyclohexylcarbodiimide, then with XI.

Solvents such as (i) (a) chlorinated hydrocarbons such as methylene chloride are preferred and water for the second reaction stage.

Temperatures for example 10 to 50 C, preferably 20 to 30 ° C.

(X) Usual hydrolysis using, for example, sodium hydroxide, potassium hydroxide, HCl.

Solvents, for example aqueous alcohols

Temperatures for example 15 to 80 ° C, preferably 25 to 45 ° C.

(XI) Analogous to IV (a)

The end connections and the intermediate connections which are produced by means of the methods described above can be isolated and purified in a manner known per se. The intermediate connections can be implemented where appropriate without isolation.

If the production of other starting compounds is not described above, these are either known or can be prepared from known starting compounds in a manner known per se. In this context, the European Application No. 81 810 131 (Publication No. 38 298 A) and US Pat. No. 4,336,391, which describe various processes, for example for the preparation of IV, in which R 'is a group of the formula XX.

The compounds of the formula I can be isolated in a manner known per se either in the form of the free base or in the form of their acid addition salts. The acid addition salts of the compounds of formula I also form part of the present invention.

The free bases of the formula I can be converted into their acid addition salts in a manner known per se and vice versa.

Examples of suitable salt-forming acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, etc.

The compounds of the formula I have favorable pharmaceutical effects, in particular the compounds of the formula I inhibit those which occur after a meal

Hyperglycemia. This effect is shown by a decrease in blood sugar levels in male Wistar rats after oral starch feeding. In this test, male Wistar rats are left in groups of 5 for 16 hours without food and then with an initial dose of 50 to 200 mg / kg p. o. fed the test compound. One hour later, the rats are fed cooked starch in a proportion of 1 g per kg of animal body weight. 30 minutes after administration of the starch, the rats are anesthetized with io 120 mg per kg animal body weight sodium hexobarbital and blood is taken from them by cardiac puncture. The blood samples are placed in the container of an analyzer containing 0.1 ml of heparin (1000 units per ml).

15 The heparized blood is used to determine the blood sugar level in the analyzer. The blood sugar content is compared to that of a control group which has received 0.5% carboxymethyl cellulose and starch orally and is assessed at the same time.

According to the results obtained, the compounds of the present invention are suitable for treating diabetes by inhibiting post-meal hyperglycemia.

Suitable daily doses are from 50 to 2000 mg 25, for example 75 to 2000 (type a) or 50 to 1000 (type b), preferably for example 2 to 4 times a day in portions of 12.5 to 100 mg. Administration is preferably carried out with meals, for example 3 times a day in doses of 20 to 700 mg, in particular before 30 meals rich in carbohydrates.

Accordingly, the invention also relates to the use of compounds of the formula I for the preparation of agents for the treatment of diabetes.

The compounds of formula I can be administered in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts, for example as set out above, the therapeutic activity of the salts being of the same order of magnitude as that of the free bases.

The compounds of formula I or their pharmaceutically acceptable acid addition salts can be mixed alone or together with a pharmaceutically acceptable carrier and optionally further additives and administered orally in the form of tablets, elixirs, capsules or suspensions 45 or parenterally in the form of injection solutions or suspensions.

The preferred pharmaceutical composition from the standpoint of ease of manufacture and administration are solid compositions, particularly in the form of tablets and hard-filled or liquid-filled capsules.

A particularly preferred group of compounds of formula I is that in which

R represents the group of the formula XX, in which R4 represents 55 hydrogen or alkyl (C, _4) and R5 represents hydrogen, alkyl (Cm) or phenyl,

X is hydrogen and m is 2,

in the form of the free bases or the acid addition salts. Another preferred group of compounds of Formula I is that wherein

R represents biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or the group of the formula XXa as indicated in For-65 mei I,

X represents hydrogen or hydroxy and m represents 1 or 2,

in the form of the free bases or their acid addition salts.

Examples of the alkyl groups are methyl, ethyl and isopropyl and the alkoxy groups are methoxy and ethoxy.

The following are particularly interesting substituent meanings

R = a) group of formula XX

b) biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl, in particular naphthyl or biphenyl such as 2-naphthyl, o-biphenyl and p-biphenyl, in particular naphthyl such as 2-naphthyl c) group of the formula XXa R, = a) hydrogen b) fluorine or Chlorine c) alkyl (Cj-4)

d) alkoxy (Ci_4)

e) hydrogen, fluorine, methyl or methoxy, especially hydrogen

R ,, R, = a) independently of one another alkyl (Ci_4)

b) the same alkyl (Cj_4)

c) any methyl d) pyrrolidino, piperidino, hexamethyleneimino or morpholino, especially pyrrolidino

R4, R5 = a) independently alkyl (Q-J

b) independently phenyl c) independently substituted phenyl as defined above d) R4 = alkyl (Ci_4) in particular methyl or

ethyl

R5 = alkyl (Cj_4) especially ethyl or methyl or phenyl e) R4 = methyl R5 = ethyl f) R4 = methyl R5 = phenyl

X = a) hydrogen b) hydroxy m = a) 1,2 or 3 b) 1 or 2.

Combinations of the above groups are particularly preferred.

Very particularly preferred compounds are: 2- (3-ethyl-5-methyl-isoxazolyl) -3- (3-dimethylaminopropyl) indole;

2- (2-naphthyl) -3- [2- (N, N-dimethylamino) ethyl] indole; 4-amino-3- [3- (2-dimethylaminopropyl) indol-2-yl] -3-hexen

2-one;

and especially

4-amino-3- [3- (2-dimethylamino-1-hydroxyethyl) indole-2-

yl] -3-hexen-2-one in the form of the free base or an acid addition salt.

The following examples describe the invention, the temperatures being given in C.

Example A

2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (dimethylamino-methyl) indole (compound of the formula VII)

A mixture of 20.6 ml (0.24 mol) of 37% aqueous formaldehyde, 18 ml (0.12 mol) of 40% aqueous dimethylamine and 80 ml of acetic acid is cooled to 0 and added dropwise with a solution of 25. Treated 5 g (0.113 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) indole in 45 ml of acetic acid and 125 ml of dioxane. After the addition has ended, the mixture is stirred at room temperature for 1 hour and then poured into 500 ml of ice-water. The solution obtained is obtained by adding a

656 124

20% aqueous potassium hydroxide solution made alkaline and then extracted with methylene chloride. The methylene chloride solution is washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound, melting point 88-90.

The preparation of the precursors of this compound and their analogs is described in European patent application no. 81 810 131 (Publication No. 38 298 A).

Example B

[[2- (5-methyl-3-phenyl-4-isoxazolyl) indol-3-yl] methyljpropanedicarboxylic acid diethyl ester (compound of the formula VI)

A mixture of 19.8 g (0.06 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (dimethylaminomethyl) indole and 30 g (0.185 mol) of diethyl malonate is made up to 120 ' heated and mixed with 100 mg of metallic sodium. The mixture is then heated to 120 'for 5 hours and a further 100 mg of metallic sodium are added. The temperature is then raised to 140 ° and this temperature is maintained for 18 hours. The mixture is then cooled and introduced into 150 ml of 10% hydrochloric acid and the mixture obtained is extracted several times with ether. The combined ether extracts are washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated to remove the ether and excess diethyl malonate and to give the title compound as an oil.

Example C

2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propionic acid (compound of the formula V)

A mixture of 22.8 g (0.05 mol) of [[2- (5-methyl-3-phenyl-4-isoxazolyl) indol-3-yl] methyl] pro-

Diethyl pandicarboxylic acid and 150 ml of a 12N hydrochloric acid is heated to boiling under reflux for 65 hours. The mixture is then cooled and extracted with ether. The ether extract is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The solid residue is decolorized with animal charcoal and recrystallized from a mixture of ether and hexane, the compound mentioned in the title having a melting point of 170 to 172 "being obtained.

Example D

2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole-propionyl-

chloride (compound of the formula purple) A mixture of 5.1 g (0.0147 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propionic acid and 7.0 g (0.059 mol) Thionyl chloride in 200 ml of tetrahydrofuran is stirred at room temperature for 18 hours. The solvent is then removed in vacuo, leaving the compound mentioned in the title.

Example E

N, N-dimethyl-2- (5-methyl-3-phenyl-4-isoxazolyl) -3-

indole propionamide (compound of formula II)

A suspension of 5.35 g (0.0147 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propionyl chloride in 100 ml of methylene chloride is added to 150 ml of a 40% aqueous dimethylamine solution, keeping the temperature between 0 and 10. The mixture is then stirred at room temperature for 2 hours and with methylene7

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

656 124

8th

chloride extracted several times. The combined organic layers are washed with water, dried over magnesium sulfate, filtered and evaporated. The solid residue is recrystallized from ethanol to give the compound mentioned in the title, melting point 174 to 177.

The following compounds can be prepared analogously or as described otherwise above.

Table I

(* as produced in Examples A to E)

Verb R '

r,

R4

rs

VII VI V Illa R2 R3

(R6 = C2H5) (Zi = (CH2) 2; Y = C1)

II

Z, = (CH2) 2

a * XX

h ch3

Phenyl

01 mp 170-172 ° ch3 ch3

Mp 174-7:

b

h ch3

c2hs ch3 ch3

c

h ch3

ch3

ch3 ch3

d

F

ch3

Phenyl ch3 ch3

e

h ch3

Phenyl

Morpholino

f

h ch3

Phenyl

Pyrrolidino

G

h ch3

Phenyl

Piperidino

H

h ch3

C2hs

Pyrrolidino

Example F

(Compounds 2- (3-ethyl-5-methyl-4-isoxazolyl) -3-acetylin-dol of the formula IHb)

To a mixture of 0.77 ml (13.45 m mol) of acetic acid and 0.17 g (1.47 m mol) of an 85% phosphoric acid in 10 ml of acetonitrile, 1.9 ml (13.45 m mol ) Trifluoroacetic anhydride added. The mixture is stirred for 15 minutes and then 1 g (4.42 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) indole in 10 ml of acetonitrile is added dropwise. The mixture obtained is stirred for 3 hours at room temperature and then poured into water. After multiple extraction with ether, the ether extracts are combined and dried over magnesium sulfate. It is then filtered off and evaporated in vacuo. The remaining oil is filtered through silica gel using a 10% methanol / methylene chloride mixture. The solvent is then evaporated and the oil obtained is dissolved in ether. The solution is washed with a 10% aqueous sodium bicarbonate solution, decolorized with animal charcoal, dried over magnesium sulfate and evaporated in vacuo. The remaining oil crystallizes after treatment with ether, the compound mentioned in the title being obtained from melting point 170 to 1711.

According to another method, 41.8 g (0.163 mol) of silver trifluoromethanesulfonate are added in portions to a solution of 33.5 g (0.148 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) indole in 450 ml of methylene chloride added. A solution of 12.8 g (0.163 mol) of acetyl chloride in 50 ml of methylene chloride is added dropwise to the suspension obtained. During the addition, the temperature rises to 35 °. After the addition has ended, the mixture is kept for 4

Stirred at room temperature for hours and then filtered. The filtrate is washed with 150 ml of a 2N aqueous sodium hydroxide solution, water and again with a 2N aqueous sodium hydroxide solution, then dried over anhydrous magnesium sulfate and finally evaporated in vacuo to give an oil. After the addition of ether, the oil crystallizes, the compound mentioned in the title having a melting point of 170 to 173 ° being obtained 30.

Example G

3-Dimethylamino-1 - [2- (3-ethyl-5-methyl-4-isoxazolyl) indol-3-yl] -l-propanone (compound of formula II) 35 A mixture of 12 g (0.045 mol) 2 - (3-Ethyl-5-methyl-4-isoxazolyl) -3-acetylindole, 4 g (0.049 mol) of dimethylamine hydrochloride and 0.5 mg of concentrated hydrochloric acid in 70 ml of ethanol are heated to boiling under reflux and in portions with 14 g (0.47 mol) of paraformalde-40 hyd were added over 5 hours. The mixture obtained is heated to boiling for a further 24 hours, then cooled and evaporated in vacuo. The residue is dissolved in 300 ml of methylene chloride and the solution is washed with 200 ml of 2N hydrochloric acid. The aqueous solution is cooled and made alkaline by adding a 2N aqueous sodium hydroxide solution and then extracted with methylene chloride. The organic layer is dried over anhydrous magnesium sulfate, filtered off and evaporated in vacuo. The residue is umkri-50 installed from ether, the compound mentioned in the title of melting point 146 to 148 ° is obtained.

The following compounds can be prepared analogously or in another way as described above.

Tables (* as produced in the examples F + G)

Verb.R'R, R4 R5 IHb R2 R3 II

Z2 = (CH2) 2

i) *

xx h

ch3

c2H5

Mp 170-173 °

ch3 ch3

j)

H

ch3

Phenyl

ch3 ch3

k)

h ch3

ch3

ch3 ch3

1)

h ch3

c2hs

Pyrrolidino m)

f ch3

Phenyl

ch3 ch3

n)

2-

Naphthyl h

-

-

ch3 ch3

O)

O-

Diphenyl h

-

-

ch3 ch3

9

Example H

N, N-dimethyl-2- (2-naphthyl-3-indole) glyoxamide (compound of the formula II)

A solution of 11 ml (0.123 mol) of oxalyl chloride in 150 ml of tetrahydrofuran is made up to 5; cooled and then 5 added dropwise with a solution of 27 g (0.111 mol) of 2- (2-naphthyl) indole in 150 ml of tetrahydrofuran, the temperature being kept between 0 and 10. The mixture is then stirred at room temperature for 2 hours, then cooled to 10: and quickly mixed with 100 ml of a 40% aqueous dimethylamine solution.

656 124

puts. The mixture is stirred at room temperature for one hour and the phases are separated. The tetrahydrofuran phase is washed with aqueous salt solution and the aqueous phase is washed with methylene chloride. The organic phases are then combined, dried over magnesium sulfate, filtered off and the filtrate evaporated. The remaining solid residue is mixed with ether, whereby the compound mentioned in the title of melting point 208 to 210 ° is obtained.

The following compounds can be prepared analogously or else differently as described above.

Table III * as prepared in Example H

Verb.

R

Ri

R,

R,

Ri

R,

II ° 11 n

(Z, = - C-)

p) *

2-naphthyl h

ch3 ch3

q)

o-biphenyl h

- '' '

•

• -

- ■

r)

p-biphenyl h

s)

o-benzylphenyl h

t)

2-fluorenyl h

u)

5-indanyl h

v)

Naphthyl

F

w)

Naphthyl ch3

X)

Naphthyl ch3o

y)

XX

H

ch3 phenyl z)

Naphthyl h

Pyrrolidino

aa)

Naphthyl h

Piperidino

from)

Naphthyl h

Morpholino

M.p. 208-210 °

Example I

2- (3-ethyl-5-methyl-4-isoxazolyl) y-oxo-indole-3-butyric acid methyl ester (compound of the formula X)

A solution of 59.4 g (0.45 mol) of monomethyl succinate in 300 ml of acetonitrile is added dropwise with 5.5 g of an 85% phosphoric acid, then 63.5 ml (0.45 mol) of trifluoroacetic anhydride are added dropwise. The mixture is stirred for 15 minutes at room temperature and then a solution of 33.9 g (0.15 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) indole in 300 ml of acetonitrile is added dropwise. The mixture is stirred at room temperature overnight and then mixed with 1.5 liters of water and 1 liter of ether. The layers are separated, the ether layer washed with water and made alkaline by adding solid sodium carbonate and water. The mixture is stirred at room temperature for 1 hour, the layers are separated, the ether layer is washed with water, dried over magnesium sulfate, filtered off and evaporated to give the compound mentioned in the title.

Example J

2- (3-ethyl-5-methyl-4-isoxazolyl) y-oxo-indole-3-butyric acid (compound of the formula IX)

A solution of methyl 2- (3-ethyl-5-methyl-4-isoxazolyl) -y-oxo-indole-3-butyrate in 250 ml of methanol is mixed with 250 ml of a 2N aqueous solution of sodium hydroxide and the resulting mixture is brought to 40 over 15 minutes heated to 45 ° and then stirred at room temperature for 1 hour. Thereafter, ether and water are added to the mixture and the layers obtained are separated. The organic layer is washed with water and the combined aqueous layers are washed with ether, then treated with animal charcoal and filtered through Celite. The aqueous alkaline solution is carefully

The addition of concentrated hydrochloric acid makes it acidic. The aqueous acidic solution is washed several times with ether and the ether wash solutions are combined. The combined ether wash solutions are washed with water and with aqueous salt solution, dried over magnesium sulfate, filtered off and evaporated. The remaining foam crystallizes out, the title compound of melting point 98 to 110 ° being obtained.

Example K

2- (3-ethyl-5-methyl-4-isoxazolyl) -N, N-dimethyl-y-oxo-45 indole-3-butanamide (compound of the formula II)

A solution of 978 mg (0.003 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) y-oxo-indole-3-butyric acid in 15 ml of methylene chloride is mixed with 345 mg (0.003 mol) of N-hydroxy- succinimide was added and then a solution of 615 mg (0.003 mol) of dicyclohexylcarbodiimide in 10 ml of methylene chloride was added dropwise. The mixture obtained is stirred for 5 hours at room temperature. It is then filtered off, the filter residue is washed with methylene chloride and the combined methylene chloride solutions are added dropwise to 20 ml of a 40% aqueous dimethylamine solution and 20 ml of methylene chloride. The mixture thus obtained is stirred overnight, then water is added and the layers formed are separated. The methylene chloride layer is washed with water and with aqueous 6o salt solution, dried over magnesium sulfate, filtered off and evaporated. The residue crystallizes out, the title compound of melting point 144.5 to 148 ° being obtained.

65 Example 1

4-Amino-3- [3- (2-dimethylamino-1-hydroxyethyl) indol-2-yl]] - 3-hexen-2-one (Compound No. 1) A mixture of 3.1 g (0, 01 mole)

656124

10th

a-Dimethylaminimethyl-2- (3-ethyl-5-methyl-4-isoxazolyl) -

indole-3-methanol and 0.31 g of a 5% palladium-carbon catalyst is dissolved in 70 ml of ethanol at a hydrogen pressure of 3.4 atm. and a temperature of 25 ° until the starting material is no longer recognizable using thin layer chromatography (3 days). The mixture is then filtered through Celite and the Celite washed with ethanol. The combined ethanol filtrates are evaporated in vacuo and the remaining oil crystallizes after the addition of ether. The title compound s obtained melts at 90 to 104 :.

The following connections can be made analogously. (R = XXa)

Verb.

m

X

R.

R2

r3

r4

Rs

l (ii)

1

oh h

ch3

ch3

ch3

Phenyl

l (iii)

1

Oh

F

ch3

ch3

ch3

c2h5

l (iv)

1

oh ch3

ch3

ch3

ch3

C2Hs

1 (V)

1

oh ch3o ch3

ch3

ch3

c2h5

l (vi)

1

oh h

Morpholino ch3

c2h5

1 (vii)

1

oh h

Pyrrolidino ch3

c2h5

Mp 177-179 °

l (viii)

1

oh h

Piperidino ch3

c2h5

l (ix)

1

oh h

ch3

ch3

c2h5

ch3

Mp 184-185 °

Example 2

4-amino-3- [3- (3-dimethylaminopropyl) indol-2-yl] -

4-phenyl-3-buten-2-one (Compound No. 2 (i)) A mixture of 3.6 g (0.01 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3 - (Dimethylaminopropyl) -lH-indole and 0.75 g of Raney nickel is in 75 ml of methanol at a hydrogen pressure of 3.4 atm. and hydrogenated 25 ° until the thin layer chromatography no presence of

Starting material shows more (18 hours). Then the mixture is filtered through Celite and the Celite is washed with methanol. The combined methanol filtrates are evaporated in a vacuum and the remaining oil crystallizes after the addition of ethanol. The compound obtained in the title melts at 268 to 269 °.

The following compounds can be prepared analogously (R = XXa).

Verb.

m

X

ri rz r3

r *

Rs

2 (ii)

1

h h

ch3

ch3

ch3

c2h5

2 (iii)

1

h h

ch3

ch3

ch3

Phenyl

Mp 222-224 °

2 (iv)

1

H

F

ch3

ch3

ch3

Phenyl

2 (v)

1

h ch3

ch3

ch3

ch3

Phenyl

2 (vi)

1

h ch3o ch3

ch3

ch3

Phenyl

2 (vii)

1

h h

Morpholino ch3

Phenyl

2 (viii)

1

h h

Piperidino ch3

Phenyl

2 (ix)

2nd

h h

ch3

ch3

ch3

c2hs

158-159.5 °

Example 3

2- (5-methyl-3-phenyl-4-isoxazolyI) -3- (3-dimethylaminopropyl) indole A solution of 2 g (0.0054 mol) of N, N-dimethyl-2- (5-methyl -3-phenyl-4-isoxazolyl) -3-indole propionamide in 80 ml of tetrahydrofuran is added dropwise to a suspension of 0.82 g (0.0216 mol) of lithium aluminum hydride in 40 ml of tetrahydrofuran, the temperature being kept between 20 and 25 ° . After the addition has ended, the mixture is stirred at room temperature for 2 hours, then cooled and mixed with a mixture of 2 ml of water and 20 ml of tetrahydrofuran. The mixture thus obtained is dried over magnesium sulfate, filtered and evaporated. The solid residue is recrystallized from ethanol, the title compound of melting point 156 to 157 ° being obtained.

Example 4

2- (3-ethyl-5-methyl-4-isoxazolyl) -3- (3-dimethylamino-

propyl) indole A mixture of 5 g (0.015 mol) of 3-dimethylamino-l- [2- (3-ethyl-5-methyl-4-isoxazolyl) -

indol-3-yl] -1-propanone and 120 ml of tetrahydrofuran is added dropwise to a mixture of 2 g of lithium aluminum hydride (0.053 mol) and 200 ml of tetrahydrofuran boiling in the reflux condenser. The combined mixture is refluxed for 1 hour, then cooled in an ice bath and carefully mixed with 7 ml of water. The mixture is then filtered through Celite and the solvent evaporated in vacuo, leaving an oil which slowly crystallizes. The crystals are treated with ether, giving the compound mentioned in the title of melting point 131 to 133 °.

Example 5

55 3-Dimethylamino-1 - [2- (3-ethyl-5-methyl-4-isoxazolyl) indol-3-yl] -l-propanol A suspension of 816 mg (0.022 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran is added Nitrogen cooled to 5 ° and then added dropwise with a solution 60 of 3.5 g (0.011 mol)

3-dimethylamino-1 - [2- (3-ethyl-5-methyl-4-isoxazolyl) -in-

dol-3-yl] -l-propanone in 125 ml of tetrahydrofuran, the temperature being kept between 5 and 8 '. The resulting mixture 65 is then stirred at 0 to 5: for 4 hours, then cooled to −50 and mixed with 10 ml of saturated, aqueous magnesium sulfate solution. The mixture is warmed to room temperature, filtered off and the filter

11

656 î24

evaporated in vacuo. The residue is dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over magnesium sulfate, filtered off and evaporated in vacuo. The residue crystallizes after the addition of ether, giving the compound mentioned in the title of melting point 166 to 169c.

Example 6

2- (3-ethyl-5-methyl-4-isoxazolyl) -3- (4-dimethylamino-

butyl) indole A solution of 5.3 g (0.015 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) -N, N-dimethyl-y-oxo-

Indole-3-butanamide in 25 ml of dry tetrahydrofuran is added dropwise to a refluxing suspension of 1.71 g (0.045 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture is then heated to boiling for a further 2 hours on a reflux condenser, then cooled and mixed with ethyl acetate, an aqueous 2N sodium hydroxide solution and water. The mixture obtained is filtered off and the tetrahydrofuran is evaporated. The residue obtained is dissolved in methylene chloride, the methylene chloride solution is washed with water, dried over magnesium sulfate, filtered off and evaporated. The residue is dissolved in ether and converted into the hydrochloride by introducing hydrogen chloride gas. The hydrochloride of the compound mentioned in the title melts at 155.5 to 157.5 °.

Example 7

2- (2-Naphthyl) -3- [2- (N, N-dimethylamino) ethyl] -indole A suspension of 4.5 g (0.119 mol) of lithium aluminum hydride in 800 ml of tetrahydrofuran is heated to 55 ° under nitrogen and then during 10 g (0.029 mol) of N, N-dimethyl-2- (2-naphthyl) -3-indolglyoxamide were added in portions over 10 minutes. The mixture is heated to boiling on the reflux condenser for 2 hours and then cooled to —60 ° and carefully with

150 ml of a saturated, aqueous magnesium sulfate solution were added. The mixture obtained is warmed to room temperature and filtered through Celite and the Celite is then 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 off and evaporated. The residue is treated with ether and the solid obtained is recrystallized from ethanol. This compound obtained in the title melts at 185 to 186 \

Example 8

2- (2-Naphthyl) -3- [l-hydroxy-2- (N, N-dimethylamino) -i5 ethyl] indole

A suspension of 4.5 g (0.119 mol) of lithium aluminum hydride in 800 ml of tetrahydrofuran is added under nitrogen. cooled to 4 ° and then mixed in portions with 10 g (0.029 mol) of N, N-dimethyl-2- (2-20 naphthyl) -3-indolglyoxamide in the course of 5 minutes, the temperature being kept below 10. The resulting mixture is then stirred at 5 ° for 2 hours and then cooled to -60 ° and 150 ml of a saturated aqueous magnesium sulfate solution are carefully added. The mixture is then warmed to room temperature and filtered through Celite and the Celite is then 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 off and evaporated. The residue is treated with ether and the solid obtained is chromatographed on silica gel. The compound obtained in the title mentioned melts at 172 to 174 °.

35 The following compounds can be prepared using the procedures described in Examples 3 to 6.

Verb.

m

X

R

r.

r2

ra r *

r5

9

2nd

H

XX

h ch3

ch3

ch3

ch3

10th

2nd

H

F

ch3

ch3

ch3

Phenyl

11

2nd

H

H

Morpholino ch3

Phenyl

12

2nd

H

H

Pyrrolidino ch3

Phenyl

13

2nd

H

H

Piperidino ch3

Phenyl

14

2nd

H

H

Pyrrolidino ch3

c2h5

15

2nd

Oh

h ch3

ch3

ch3

Phenyl

16

2nd

Oh

F

ch3

ch3

ch3

c2h5

17th

2nd

H

2-

Naphthyl h

ch3

ch3

-

18th

2nd

H

0

■ Biphenyl h

ch3

ch3

-

-

19th

2nd

Oh

2-naphthyl h

ch3

ch3

-

-

20th

2nd

Oh

0

-Biphenyl h

ch3

ch3

-

-

21st

1

H

0

-Biphenyl h

ch3

ch3

-

-

22

1

h p-biphenyl h

ch3

ch3

-

-

23

1

h o-benzylphenyl h

ch3

ch3

-

-

24th

1

H

2-fluorenyl h

ch3

ch3

-

-

25th

1

H

5-indanyl h

ch3

ch3

-

-

26

1

H

2-naphthyl

F

ch3

ch3

-

-

27th

1

H

2-naphthyl ch3

ch3

ch3

-

-

28

1

H

2-naphthyl ch3o ch3

ch3

-

-

29

1

H

2-naphthyl h

Pyrrolidino

-

-

30th

1

H

2-naphthyl h

Piperidino

-

-

31

1

H

2-naphthyl h

Morpholino

-

-

32

1

oh o-biphenyl h

ch3

ch3

-

-

33

1

oh p-biphenyl h

ch3

ch3

-

-

34

1

Oh

0

-Benzylphenyl h

ch3

ch3

-

-

M.p. 159-161 m.p. 166-167

M.p. 166-168

656 124

(Continuation)

12

Verb.

m X

R

R,

r 2

R3 R4

r5

35

1 oh

2-fluorenyl h

ch3

ch3 -

-

36

1 oh

5-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 ch3o ch3

ch3 -

-

40

1 oh

2-naphthyl h

Pyrrolidino -

-

41

1 oh

2-naphthyl h

Piperidino -

-

42

1 oh

2-naphthyl h

Morpholino -

-

15

20th

25th

30th

35

40

45

50

55

60

S

Claims (3)

656124 2- (2-naphthyl) -3- [2- (N, N-dimethylamino) ethyl] indole; 4-amino-3- [3- (2-dimethylaminopropyl) indol-2-yl] -3-hexen-2-one and 35 40 II wherein Rj, R2 and R3 are defined above, R 'is biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of formula XX and either Zj is 0 - £ - (CH2) m., 50 or (CH2) m and Z2 is a direct bond or Zj is a direct bond and Z2 is (CH2) m, in which m is defined above, reduced and the compounds of formula I obtained in the form of the free base or in the form of acid addition salts wins. 10. A pharmaceutical composition containing a compound according to claims 1 to 7 in the form of the free bases or in the form of acid addition salts, together with pharmaceutically acceptable diluents or carriers. 11. Use of compounds according to claims 1 to 7 for the preparation of agents for treatment 65 of diabetes. 60 2- (3-ethyl-5-methyl-isoxazolyl) -3- (3-dimethylaminopropyl) indole; 2. A compound according to claim 1, wherein R is a group of formula XXa in the form of the free base or in the form of acid addition salts. 3. A compound according to claim 2, wherein R4 is methyl and R5 is ethyl or phenyl in the form of the free base or in the form of acid addition salts. 4. A compound according to claim 1, wherein R is naphthyl in the form of the free base or in the form of acid addition salts. 5. A compound according to any one of claims 2 to 4, wherein m is 1 in the form of the free base or in the form of acid addition salts. 6. A compound according to any one of claims 1 to 5, wherein Rj is hydrogen. 7. A compound according to claim 1 selected from the following: 2'm NN * 3 15 20th 4th XX stands, X is hydrogen and m is 2, 3 or 4 or b) R is biphenyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of the formula XXa -C-C0-R4 C (NH2) R5 wherein Rj, R2, R3, R4, X and m are defined in connection with the formula I, reduced with hydrogen in the presence of a catalyst and the compounds of the formula I obtained in the form of the free base or in the form of an acid addition salt. 9. A process for the preparation of compounds according to claim 1 wherein R is biphenyl, naphthyl, benzylphenyl, 30 indanyl, fluorenyl or a group of the formula XX in the form of the free base or in the form of acid addition salts, characterized in that a compound of the formula II XXa stands X is hydrogen or hydroxy and m is 1, 2, 3 or 4, where in the formulas XX and XXa R4 is hydrogen or alkyl (C] _4), Rs is hydrogen, alkyl (C, _4), phenyl or phenyl substituted by halogen, alkyl (C | _4) or alkoxy (C14) in the form of the free base or in the form of their acid addition salts. 2nd PATENT CLAIMS 1. Compounds of Formula I X R CII- (CH2) m-1 <R23 wherein Rj represents hydrogen, fluorine, chlorine, alkyl (CM) or alkoxy (CM), R2 and R3 independently of one another are alkyl (C [_4), or together with the adjacent nitrogen atom form a pyrrolidino, piperidino, hexamethyleneimino or morpholino ring and a) R for a group of the formula XX 4-amino-3- [3- (2-dimethylamino-1-hydroxyethyl) indole-2- yl] -3-hexen-2-one in the form of the free base or in the form of acid addition salts. 8. A process for the preparation of compounds according to claim 1 wherein R represents a group of the formula XXa in the form of the free base or in the form of acid addition salts, characterized in that a compound of the formula Ip X R 3rd 656124