FR2524881A1 - NEW INDOLE-ALKYLENE-AMINE SUBSTITUTES, THEIR PREPARATION AND THEIR USE AS MEDICINAL PRODUCTS - Google Patents

Abstract

THE INVENTION CONCERNS INDOLES-ALKYLENE-AMINES OF FORMULA I: (CF DRAWING IN BOPI) IN WHICH R IS A REMAINDER OF FORMULA: (CF DRAWING IN BOPI) OR A BIPHENYL, NAPHTYL, BENZYLPHENYL, INDANYL OR FLUORENYL, R IS H, F, C1 OR AN ALKYL OR ALCOXY GROUP, X IS H OR OH, M MEANS 1, 2, 3, 4 AND R AND R ARE ALKYL GROUPS OR FORM A REMAIN 1-PYRROLIDINYL, PIPERIDINO, HEXAMETHYLENEIMINO OR MORPHOLINO. THESE COMPOUNDS MAY BE USED AS ANTIDIABETICS.

Description

The present invention relates to new indole-alkyleneamines

  their preparation and their use in therapeutics,

  as active ingredients of drugs.

  The invention relates in particular to indole-alkyleneamines of formula I x

1 -R 2

R 1 CH- (CH 2) m -NsR (I

' "R

  Wherein R 1 represents hydrogen, fluorine, chlorine, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group, R 2 and R 3 each independently represent one of the groups other, a C 1 -C 4 alkyl group or together with the nitrogen atom to which they are attached a 1-pyrrolidinyl, piperidino, hexamethyleneimino or morpholino residue and a) R represents a group of formula XX R 4 (XX) R 5 X is hydrogen and m is 2, 3 or 4, or

  b) R represents a biphenyl, naphthyl, benzyl-

  phenyl, indanyl, fluorenyl or a group of formula X Xa

-C-CO-R

  C (NH 2) R 5 (X Xa) X is hydrogen or hydroxy and m is 1, 2, 3 or 4 in formulas XX and X Xa R 4 is hydrogen or C 1 -C 4 alkyl 1-C 4 and R 5 representing hydrogen or C 1 -C 4 alkyl, phenyl or phenyl substituted by halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; free base state or in the form of a L-residue-C 1 -I: 4 acid addition salt can also exist II C (NH in the tautomeric form - C = C (OH) R 4 C = Given the presence of a double bond in this residue, the compounds containing such a residue may also exist in the form of cis / trans isomers. All tautomeric forms and all

  geometric isomers are part of the present invention.

  tion. It should also be noted that

  compounds of formula I in which X has a meaning

  cation other than hydrogen, can exist in the form of optically active isomers which can be separated according to known methods. These isomeric forms are also part of the present invention. The invention also relates to a method

  for the preparation of the compounds of formula I

  In the process of the invention, to prepare the compounds of formula I a) when R is a group of formula X Xa, a compound of formula Ip X / HOH $ R 5 is reduced in Yaquelle R 1, R 2, R 3 , R 4, R 5, X and m have the meanings given for compounds of type b), with hydrogen in the presence of a catalyst, or

  b) when R is a biphenyl, naphthyl, benzyl-

  phenyl, indanyl, fluorenyl or a group of formula XX, a compound of formula II is reduced

0 R

* R 1 X 1 -C-Z 2, R

H

  in which R 1, R 2 and R 3 have the meanings

  previously, R 'represents a biph-

  nyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of formula XX and either Z 1 means O or (CH 2) 2 and Zo is a direct bond, -C- (CH 2) m-1 or Z 1 is a direct bond and Z 2 represents a group (CH 2) m in which my meaning is

previously given.

  The reduction according to process a) can advantageously be carried out at temperatures between 20 and 60, especially between 25 and 35, and / Y in an inert solvent such as a lower alcohol such as for example methanol or ethanol, in this case preferably at room temperature, or dimethylformamide, in this case preferably at higher temperatures. The reduction is carried out under hydrogen using a suitable catalyst such as, for example platinum, Raney nickel, palladium on charcoal and the like, preferably 10% palladium on charcoal, and at pressures of, for example, 1 to 6.6 atmospheres, preferably included.

between 2.6 and 4 atmospheres.

  The reduction according to method b) is carried out under conventional conditions for the reduction of carbonyl groups Suitable solvents include hydrocarbons such as hexane or benzene, and ethers such as diethyl ether,

  dioxane or preferably tetrahydrofuran.

  Reducing agents that may be mentioned include, for example, aluminum hydride, sodium hydride and bis (2-methoxyethoxy) aluminum, diborane or

  preferably lithium aluminum hydride.

  If appropriate, the reduction is carried out under an inert atmosphere, for example under an atmosphere of helium, argon or especially nitrogen It should be noted that in all cases where Z 1 means a direct bond, the reduction may be partial to give end products o X = OH, or complete to give end products o X = H the degree of reduction

  depending on the reaction conditions used.

  For a partial reduction, therefore, relatively low temperatures of between -30 and 40 ° C, for example between -5 and 10, are preferably used when R 'has a meaning other than the group of formula XX, and temperatures between 20 and 35 when R 'means a group

of formula XX.

  When it is desired to carry out a complete reduction, one operates for example at temperatures

  between 40 and 150, preferably at the temperature

  the reflux ratio of the reaction mixture, the temperatures

  lower eratures for example between

  0 and 60 may also be sufficient when Z 1 = (CH 2) 2.

  Partial reduction can of course also be achieved by choosing a reducing agent

weak appropriate.

  The different starting products can

  be prepared according to the usual methods.

  Thus, the starting materials for process a), which form part of the compounds of formula 1, can be prepared analogously to process b) or for example as described in European Patent Application No. 81 810131 published under No. 38298 A

  or in U.S. Patent No. 4,336,391.

  The starting materials used in process b) and their precursors are known or can be prepared in a similar manner by known methods. Examples of such methods are illustrated in the following reaction schemes: ## STR2 ## (R 1) ## STR1 ## m-II I 2) (R 3) 1 or (Ci 12) 2 Y 1

+ (COI) 2

XII:> He Ia

(Z 1 = -CO-)

  + NH (R 2) (R 3) excess (CHO), (I under salt-melting) xi * CH 3 COY 'h XIII (y) RI <(Ci 12) COOH HI Ilb Illa (Z, ( CH A)> v

CGOOR 6

1 2 -COOR 6

  H VI) If - (vi) mineral acid v (m = 2) n 4 (vii) R 1 -C 3 CH 3 6

1 CH 2 N, + CH

2 C COOR 6

R '

H RXIV

VII (viii) R 1 o

H R

+ HN (CH 3) 2> VII

+ HCHO / H 20

  ## STR2 ## wherein R 1 is CH 2 OOH + HN (R 2) (R 3) II (Z = -5-C 2) e _ ú (1 -C (CH 2) m 1 NR 'XI m = 2.3 or 4) HI YJ O (x) 1 C 1 C- (CH)) m: T-COOR 6 x H f

R 1 9 R

H IV

COOH + CH 3 CN

+ (K_ 1 3

COOR 6

  In the above reaction schemes, Y is chlorine or bromine, Y is chlorine or bromine or hydroxy; each R 6 represents, independently of one another, a C 1 -C 4 alkyl group and

  other substituents are as defined above.

  The reaction conditions are those usually used for the type of reaction put

  and are not normally critical.

  VI> IX (xi) X - These reaction conditions are for example the following: (i) solvents (a) R 'is other than a group of formula XX, hydrocarbons such as for example hexane or benzene, hydrocarbons halogenated as for example methylene chloride or chloroform, ethers, for example diethyl ether,

  dioxane or preferably tetrahydrofuran.

  (b) RU means a group of formula XX, in addition to water or an excess of the compound of formula XI, preferably a combination of water, diethyl ether and an excess of the compound

of formula XI.

  Temperatures: for example between -20 and 50, special-

  between 5 and 1 O (R 'being different from

  group of formula XX) and between 20 and 30 (R 'means

trusting a group of formula XX).

(ii) Solvents as for (i) (a).

  Temperatures: for example between -20 and 50, especially between 20 and 30 The compound of

  formula XII is preferably added between

ron -5 and 5.0.

  (iii) Solvents: eg lower alkanols

  such as methanol or preferably ethanol.

  Temperatures: for example between 60 and 150,

  preferably at reflux of the reaction mixture.

  (iv) (a) (Y '= OH) The compound of formula IV in acetonitrile is reacted with acetic acid in the presence

  phosphoric acid and trifluoro-

  acetic. (b) (Y = Cl or Br) The compound of formula IV is reacted with silver trifluoromethanesulfonate

  and then with the appropriate acetyl halide

  prayed. Solvents (b) for example halogenated hydrocarbons such as chloroform or

  methylene chloride.

  Temperatures: for example (a) between 10 and 80, preferably between 20 and 400; (b) between 20 and 450,

preferably between 25 and 35.

  (v) The compound of formula V is reacted with an agent

  halogenation such as thionyl bromide, oxychloride

  phosphorus or preferably chloride

of thionyl.

  Solvents: eg aromatic hydrocarbons

  such as benzene or toluene, ethers such as diethyl ether,

  dioxane or especially tetrahydrofuran.

  Temperatures: for example between 0 and 60 *,

preferably between 20 and 30.

  (vi) The compound of formula VI is reacted with hydrobromic acid or preferably

  with hydrochloric acid in water.

  Temperatures: for example between 90 and 150,

preferably at reflux.

  (vii) The compound of formula VII is reacted with the compound of formula XIV in the presence of lithium, potassium or preferably sodium metal in an excess of the compound of

formula XIV.

  Temperatures: for example between 100 and 2000,

preferably between 120 and 150 '.

  (viii) The compound of formula IV is reacted

  with the compound of formula XI in a solution

  aqueous solution of formaldehyde and in the presence

  of acetic acid and an organic co-solvent.

  Co-solvent: for example an ether such as diethyl ether, tetrahydrofuran

or especially dioxane.

  Temperatures: for example between -10 and + 30

especially between 0 and 10.

  (ix) The compound of formula IX is first reacted with N-hydroxysuccinimide and dicyclohexylcarbodiimide and then with the compound of

formula XI.

  Solvents: as for (i) (a), chlorinated hydrocarbons such as methylene chloride being preferred and for the second stage with water

more -

  Temperatures: for example between 10 and 50,

preferably between 20 and 300.

  (x) Typical hydrolysis for example by means of

of Na OH, KOH, HC 1.

  Solvents: for example aqueous alcohols.

  Temperatures: for example between 15 and 80,

preferably between 25 and 45.

(xi) Analogous to iv (a).

  End products and products

  mediated by the above processes, may

  be isolated and purified according to the usual methods.

  Intermediates may, where appropriate, be directly involved in the reaction

  following, without prior isolation.

  When the preparation of a particular starting material is not specifically described, it will be a known compound or one which can be prepared in known manner from known products. European patent application and the aforementioned US patent, there are described numerous methods for example for preparing compounds of formula IV wherein R 'is a group of formula XX. The compounds of formula I can be recovered in both the free base and the acid addition salt form. The free bases of formula I can be converted according to the known methods of addition salts. acids, and conversely as an example of suitable acids for

  formation of salt S, chlorhy-

  drique, hydrobromic, hydroiodic, phosphorous, sulfuric, acetic, maleic, fumaric, etc.

  The compounds of formula I possess

  Therefore, they inhibit or prevent postprandial hyperglycemia, as can be seen from the pharmacological properties and can therefore be used therapeutically as medicaments.

tests carried out in animals.

  In these tests, male Wistar rats are used. The animals are divided into groups of 5. The animals are allowed to fast for 16 hours and are administered orally an initial dose of 5 to 200 mg / kg of the test substance. later, 1 g / kg of cooked wheat starch is administered orally 30 minutes after the administration of

  starch, the rats are anesthetized by intra-

  peritoneal sodium hexobarbital (120 mg / kg) Blood is collected by cardiac puncture and placed in an auto-analyzer cup containing 0.1 ml heparin (10 Q00 units / ml) Blood is used heparinized to determine the level of sugar in

? 524881

  the blood by means of an auto-analyzer The blood glucose level is compared to that obtained in

  control animals given 0.5% of carboxy-

  methylcellulose and starch In these tests, the compounds of formula I cause a drop in

  of blood glucose in animals.

  Thanks to this property, the compounds of formula I can be used therapeutically for the treatment of diabetes, by inhibiting or preventing

posf-prandial hyperglycaemia.

  For their therapeutic use, the compounds of formula I will be prescribed at daily doses of between about 50 and 2000 mg, for example between 75 and 2000 mg for the compounds of formula I in which R is a group of formula XX or included between 50 and 1000 mg for the other compounds of formula I which will preferably be administered in divided doses 2 to 4 times per day in the form of unit doses each containing between

  approximately 12.5 and 100 mg of active substance.

  It will preferably be at the time of the meals, for example 3 times daily at doses of about 20 to 700 mg, especially before a high carbohydrate meal. The compounds of formula I also have a fasting hypoglycemic action as shown by the decrease in serum glucose in the tests carried out on 4 male Cebus monkeys weighing between 2 and 4 kg and which have been maintained in the diet for 16 to 18 hours. hours before the test An interval of at least 3 days is maintained between the days

  experience The compound to be tested is suspended

  in 0.5% carboxymethylcellulose for the administration of

  In order to determine the basal serum glucose level, two blood samples are taken.

  minutes before the test and then just before

  Placebo (0.5% carboxymethylcellulose) or the test compound administered at a dose of 5 to 40 mg / kg are then sampled.

  blood samples every hour for 6 hours.

  The glucose levels in the serum are determined by the autoanalyzer technicon according to the 2-glucose oxidase method, and the values obtained are then compared with those obtained with the control group.

  0.5% of carboxy-

  Methylcellules In this test, the compounds of formula I cause a decrease of glucose in the serum. Thanks to this property, the compounds of

  Formula I may also be used in therapeutic

  As a hypoglycemic agent for the treatment of diabetes, the daily dose to be administered for this indication is between about 25 and 400 mg, preferably administered in divided doses 2 to 4 times per day, advantageously in the form of a unit dose each containing between about 6 and about

  mg of active substance, or a form to liber-

delay -

  The invention therefore relates to

  compounds of formula I for use as a medicament

  for example as agents to inhibit or prevent

postprandial hyperglycemia.

  The compounds of formula I can be administered in the form of free bases or in the form of

  of pharmaceutically acceptable acid addition salts

  tables, for example those mentioned above.

  These salts have the same order of activity as the bases

corresponding free

I -

  The invention also relates to a medicament containing, as active principle, a compound of the formula I, in the free base state or in the form of a

pharmaceutically acceptable salt.

  As drugs, the compounds of

  formula I and their pharmaceutical acid addition salts

  The pharmaceutically acceptable compositions can be administered alone or in the form of pharmaceutical compositions containing the active substance in combination with a pharmaceutically acceptable diluent or carrier and, optionally, with other excipients. Such pharmaceutical compositions also form part of the invention. to be in the form of tablets, elixirs,

  capsules or suspensions intended for the administration

  orally, or in the form of injectable solutions or suspensions for administration

parenterally.

  Preferred pharmaceutical compositions from the point of view of ease of preparation and administration are solid compositions, particularly tablets and capsules containing

either a solid or a liquid.

  A particular group of compounds include those of formula I wherein R is the group of formula XX where R is hydrogen

  or a C 1 -C 4 alkyl group and R 5 signifies hydro-

  gene, a C 1 -C 4 alkyl group or a phenyl group, X is hydrogen and m is 2, in the form of

  of alkaline bases or in the form of an acid addition salt.

  Another group of compounds includes those

  of formula I in which R represents a biphenyl group

  nyl, naphthyl, benzylphenyl, indanyl, fluorenyl or the group of formula X Xa as defined above, X represents hydrogen or a hydroxyl group and m represents 1 or 2, in the form of a free base or a

form of an acid addition salt.

  Examples of alkyl groups include methyl, ethyl and isopropyl. Examples of alkoxy groups include methoxy and

ethoxy group.

  Meanings of particular substituents

  Of particular interest are: R = a) a group of formula XX b) a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group, in particular naphthyl or biphenyl such as 2-naphthyl, obiphenyl and p-biphenyl, especially naphthyl such as 2-naphthyl c) a group of formula X Xa R 2, R 1 = R 3 =

R 4, R 5 =

  a) H b) fluorine or chlorine c) C 1 -C 4 alkyl d) C 1 -C 4 alkoxy e) H, F CH 3 or OCH 3, especially H a) independently one of the other, a C 1 -C 4 alkyl group b) the same C 1 -C 4 alkyl group c) each a methyl group

  d) 1-pyrrolidinyl, piperidino, hexamethyl

  leneimino or morpholino, especially 1-pyrrolidinyl a) independently of one another a C 1 -C 4 alkyl group b) independently of one another a phenyl group c) independently one of the other a substituted phenyl group as defined above d) R 4 = C 1 -C 4 alkyl, especially methyl or ethyl R 5 = C 1 -C 4 alkyl, especially ethyl or methyl or phenyl e) R 4 = CH 3

R 5 = C 2 H 5

  O f) R 4 CH 3 R 5 = phenyl X = a) H b) OH = a) 1, 2 or 3

(b) 1 or 2.

  The combinations of the groups above are

especially preferred.

  Particularly preferred compounds are

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

  propyl) -indole, 2- (2-naphthyl) -3-1- (N, N-dimethylamino) -

  Ethyllindole, 4-amino-3-1-3 (3-dimethylaminopropyl) -indole-2-

  yll-3-hexen-2-one, and especially 4-amino-3-E 3-

  (2-dimethylamino-1-hydroxyethyl) indoe-2-yl-3-hexene

  2-one, as a free base or as a salt

acid addition.

  The following examples illustrate this

  invention without in any way limiting its scope.

  Temperatures are all in degrees Celsius.

Example A

  2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (dimethylaminino)

  methyl) -indole (compound of formula VII) A mixture of 6 ml (0.24 moles) of 27% aqueous formaldehyde, 18 ml, was cooled to 0.degree.

n -r- -

  I (0.12 moles) 40% aqueous dimethylamine and 80 ml acetic acid and treated by dropwise addition.

  dropwise 25.5 g (0.113 mnol) of 2- (5-methyl-3-

  phenyl-4-isoxazolyl) -indole in solution in 45 ml of acetic acid and 125 ml of dioxane The addition is complete, the mixture is stirred for 1 hour at room temperature and poured into 500 ml of a mixture of Water and ice The resulting solution is made alkaline with 20% potassium hydroxide solution and extracted with methylene chloride. The methylene chloride phase is washed with water and then with a sodium chloride solution. sodium, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound.

  title; it melts at 88-90 The preparation of

  sliders of this compound and their analogues is described in European Patent Application No. 81 810131

(Publication No. 38298 A).

Example B

  diethyl ester of {E 2- (5-methyl-3-phenyl) -4-

  isoxazolyl) -indole-3-ylmethylpropanedio Yque (compound of formula VI) A mixture of 19.8 g

  (0.06 moles) 2- (5-methyl-3-phenyl-4-isoxazolyl) -3-

  (dimethylaminomethyl) -indole and 30 g (0.185 mol) of diethyl malonate and 100 mg of sodium metal is added. The mixture is then heated for hours at 120 and again 100 mg of sodium metal is added. The mixture is heated to 140 ° C. and

  it is kept at this temperature for 18 hours.

  The mixture is cooled and poured into 150 ml.

  10% hydrochloric acid and extracted with ether.

  The ethereal extracts are combined, the overall solution is washed with a saturated solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the ether and the excess diethyl malonate. The title compound is thus obtained in the form of an oil.

Example C

  2- (5-methyl-3-phenyl-4-isoxazolyl) -indole-3-propionic acid

  (compound of formula VI) A mixture of 22.8 g (0.95 mole) of diethyl ester is heated for 65 hours under reflux.

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

  3-methylmethyl} propanedio Yque and 150 ml of 12 N hydrochloric acid. The mixture is then cooled and extracted with ether. The ethereal solution is washed.

  with water, it is dried over anhydrous magnesium sulphate.

  It is then filtered and evaporated. The solid residue is then decolorized with charcoal and recrystallized from a mixture of ether and hexane to give the mixture.

  composed of the title melting at 170-172.

Example D

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

  3-propionyl (compound of formula I Ita) A mixture of 5.1 g (0.0147 mol) is stirred for 18 hours at room temperature. 2- (5-methyl-3-phenyl-4-isoxazolyl) -indoacid 11-3-propionic and 7.0 g (0.059 mol) of thionyl chloride in 200 ml of tetrahydrofuran. The solvent is then removed in vacuo to give the title compound. Example E

  N, N-dimethyl-2- (5-1-methyl-3-phenyl-4-isoxazolyl) -indole-3-

  propionamide (compound of formula II) To 150 ml of 40% aqueous dimethylamine, MwM is added a suspension of 5.35 g (0.0147 mole)

  2- (5-methyl-3-phenyl-4-isoxazolyl) chloride

  Indole-3-propionyl in 100 ml of methylene chloride while maintaining the temperature between 0 and 10 The mixture is then stirred for 2 hours at room temperature and extracted with methylene chloride. the overall phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The solid residue is recrystallized from

  ethanol to give the title compound.

Mp 174-177.

  The following compounds can be prepared

  analogously or as previously described.

  (Table I see next page) / i to I-I it he pr ~ 'pard as described in Examples A to E) JI l> Co r- M r. C r%) CD l ln P%) Co Co -à

Example F

  2- (3-ethyl-5-methyl-4-isoxazolyl) -3-acetylindole (compound of formula II Ib) to a mixture of 0.77 ml (13.45 mmol) of acetic acid and 0, 17 g (1.47 m mole) of 85% phosphoric acid in 10 ml of acetonitrile are added at room temperature 1.9 ml (13.45 m moles) of trifluoroacetic anhydride. The mixture is stirred for 15 minutes. minutes and then add-on drop by drop

  1.0 g (4.42 m moles) of 2- (3-ethyl-5-methyl-4-isoxazolyl) -

  indole in 10 ml of acetonitrile. The mixture is stirred

  After standing at room temperature for 3.5 hours, it is poured into water and extracted with ether. The ethereal extracts are combined, the whole solution is dried over magnesium sulphate, filtered and filtered. Evaporated under vacuum The resulting oil is filtered through silica gel using methylene chloride at 10% methanol. The solvent is evaporated and the resulting oil is dissolved in ether. The solution is washed with a 10% solution. % sodium bicarbonate, decolorized with charcoal, dried over magnesium sulfate and evaporated in vacuo The oil

  obtained crystallizes by treatment with ether.

  The title compound is thus obtained; F = 170-171.

  In another process, 41.8 g (0.163 mol) of silver trifluoromethanesulphonate are added portionwise to a solution of 33 g (0.148 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl). In the suspension thus obtained, 12.8 g (0.163 mol) of toluene are added dropwise to the mixture.

  acetyl chloride in 50 ml of methylene chloride.

  During the addition, the temperature of the mixture rises to 35 ° C. The addition is complete, the mixture is stirred at room temperature for 4 hours and the filtrate is washed with 150 ml of 2 N sodium hydroxide. , water and 2N sodium hydroxide, dried over anhydrous magnesium sulfate and evaporated in vacuo The resulting oil is crystallized from ether to give the title compound;

F = 170-173.

Example G

  3-dimethylamino-1- [2- (3-ethyl-5-rithyl-4-isoxazolyl) -indol-3-yl] -1-propionene (compound of formula II).

mixture of 12 g

  (0.045 mole) 2- (3-ethyl-5-methyl-4-isoxazolyl) -3-

  acetyl-indole, 4 g (0.049 mol) of dimethylamine hydrochloride and 0.5 ml of concentrated hydrochloric acid in 70 ml of ethanol and 14 g (0.470 mole) of paraformaldehyde are added in portions over The mixture is refluxed for a further 24 hours, cooled and evaporated under vacuum. The residue is dissolved in 300 ml of methylene chloride and washed with 200 ml of 2N hydrochloric acid. The aqueous solution is acidified, basified with 2N sodium hydroxide and extracted with methylene chloride. The organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. residue in ether, the title compound is obtained;

F = 146-148.

  The following compounds can be prepared

  analogously or as previously described.

(Table II see next page)

WATER TAB II

  prepared as described in Examples F + G) ## STR2 ## CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 2 CH 3 CH 3 CH 3 CH 3 CH 3 n) 2 Example HN, N-dimethyl-2- (2-naphthyl-3-indole) glyoxamide (compound of formula II) is cooled to a solution of 11 ml. (0.123 mol) of oxalyl chloride in 150 ml of tetrahydrofuran and 27.0 g (0.116 mol) of 2- (2-naphthyl) -indole in 50 ml of tetrahydrofuran are added dropwise, while maintaining the temperature The mixture is stirred for 2 hours at room temperature, cooled to 10 and 100 ml of 40% aqueous dimethylamine are rapidly added. The mixture is stirred at room temperature for 1 hour and then the phases are separated. The tetrahydrofuran phase is washed with a solution of chlorine The organic phase is pooled with sodium chloride and the aqueous phase with methylene chloride. The combined solution is dried over magnesium sulfate, filtered and evaporated. The resulting solid product is triturated in ether. give the compound

of the title; F = 208-210.

  The following compounds can be

  prepared in a similar manner or as previously described

ously.

TABLE III

as described in Example H)

Example I

  Methyl 2- (3-ethyl-5-methyl-4-isoxazolyl) -1'-oxoindole-3-butanate (compound of formula X) To a solution of 59.4 g (0.45 mole) ) of monomethyl succinate in 300 ml of acetonitrile is added dropwise 5.5 g of 85% phosphoric acid and then dropwise 63.5 ml (0, 45 mole) of trifluoroacetic anhydride The mixture is stirred for 15 minutes at room temperature and then 33.9 g (0.15 mole) of 2- (3-ethyl-5-methyl-4-isoxazolyl) -indole are added dropwise in 300 ml of acetonitrile. The mixture is heated at room temperature overnight and then 1.5 liters of water and 1 liter of ether are added. The phases are separated, the ethereal phase is washed with water and rendered alkaline.

  by addition of solid sodium carbonate and water.

  The mixture is stirred for one hour at room temperature, the phases are separated, the ethereal phase is washed with water, dried over magnesium sulphate, filtered and evaporated to give the title compound.

of the title.

Example J

  2- (3-ethyl-5-methyl-4-isoxazolyl) y-oxoindole-

  3-Butanofus (compound of formula IX)

  A solution of 2- (3-ethyl-5-

  methyl methyl-4-isoiazolyl) oxo-indole-3-butanoate in 250 ml of methanol per 250 ml of a 2N solution of sodium hydroxide, the mixture is heated for minutes at 40 -45 and It is stirred at room temperature for 1 hour. Ether and water are added to the mixture, the phases are separated, the ether phase is washed with water and the combined aqueous phases with ether, treated. The basic aqueous solution is acidified with care by the addition of concentrated hydrochloric acid and extracted with ether. The ether solution is washed with water and with sodium chloride solution. It is dried over magnesium sulfate, filtered and evaporated. The resulting foam is recrystallized to give the title compound;

F = 98-110.

Example K

  2- (3-ethyl-5-methyl-4-isoxazolyl) -N, N-dimethyloxo

  indole-3-butanamide (compound of formula II) A solution of 978 mg (0.003 mol) is treated

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

  3-butanoic acid in 15 ml of methylene chloride with 345 mg (0.003 mol) of N-hydroxy-succinimide and then 615 mg (0.003 mol) of dicyclohexylcarbodiimide in 10 ml of methylene chloride are added dropwise. The mixture thus obtained for hours at ambient temperature is then filtered, the filter cake is washed with methylene chloride and the methylene chloride phases, combined with 20 ml of 40% aqueous dimethylamine, are added dropwise. 20 ml of methylene chloride The mixture is stirred overnight, water is added, the phases are separated, the methylene chloride phase is washed with water and then with sodium chloride solution, and dried

  on magnesium sulfate, it is filtered and evaporated.

  After crystallization of the residue, the compound is obtained

of the title; F = 144.5-148.

Example 1

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

yll-3 hexen-2-one (compound 1)

  A mixture of 3.1 g (0.01 mole) of α-dimethyl-

  aminomethyl-2- (3-ethyl-5-methyl-4-isoxazolyl) -indole-3-

  methanol and 0.31 g of 5% Pd / C in 70 ml of ethanol is hydrogenated at 3.3 atmospheres and at 25, until thin layer chromatography reveals no more starting material (3 The mixture is filtered through celite and the celite is washed with ethanol. The ethanolic filtrates are combined and evaporated in vacuo to give an oil. After crystallization of the oil in ether, we obtain

the name of the title; F = 90-104.

  The following compounds of formula I wherein R is a group of formula X Xa can

be obtained in a similar way.

Example 2

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

  phenyl-3-butene-2-one (compound 2 (i))

  A mixture of 3.5 g (O, Olmol) of 2- (5-

  methyl-3-phenyl-4-isoxazolyl) -3- (3-dimethylaminopropyl) -

  1 H-indole and 0.75 g of Raney nickel in 75 ml of methanol are hydrogenated at 3.3 atmospheres and until thin layer chromatography is obtained.

  no longer reveals starting material (18 hours).

  The mixture is filtered through celite and the celite is washed with methanol. The methanolic filtrates are combined, evaporated in vacuo and the oil obtained is recrystallized from ethanol.

of the title; Mp 268-269.

  The following compounds of formula I wherein R is a group of formula X Xa may

be obtained in a similar way.

  R 1 R 2 R, RR p.oss _ __2 l (ii) 1 OH CH 3 CH 3 CH 3 phenyl l (iii) 1 OH F CH 3 CH 3 CH 3 C 2 H 5 1 (iv) 1 OH ## STR1 ## H pyrrolidino CH 3 C 2 H 5 F = 77-179 il (v III) 1 OH CH 3 CH 5 1 (ix) 1 IOH CH 3 CH 3 C 2 H 5 CH 3 F 184-

Example 3

  2- (5-methyl-3-phenyl-4-ioxazolyl) -3- (3-dimethylamino)

  propyl) -indole To a suspension of 0.82 g (0.0216 mol) of aluminum hydride and lithium in 40 ml of tetrahydrofuran is added dropwise a

  solution of 2.0 g (0.0054 mole) of N, N-dimethyl-2-

  (5-methyl-3-phenyl-4-isoxazolyl) -indole-3-propionamide in 80 ml of tetrahydrofuran, while maintaining the temperature between 20 and 25. The addition is complete, the mixture is stirred at room temperature for 2 hours. it is cooled and the reaction is stopped

  by adding 2 ml of water in 20 ml of tetrahydro-

  The mixture is dried over magnesium sulphate, filtered and evaporated. After crystallization of the solid residue in ethanol, the following is obtained:

composed of the title; F = 156-1570.

Example 4

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

  propyl) -indole has a mixture maintained at reflux and constitutes Com m X R R R R

R 3 R 4 R

  poss 2 3 4 5 2 (ii) 1 H H CH 3 CH 3? | C 2 H 5 2 (iii) 1 HH CH 3 CH 3 H ephenylF = 222-224 2 (iv) 1 HF CH 3 CH 3 CH phenyl 2 (v) 1 H CH 3 CH CH 4 H 3 phenyl 2 (vi) ## STR2 ## wherein R 1 is HH 2 (3H) 2H (3H) 2H (1HH) piperidino Cl '3ph: enyl 2 (ix) 2HH CH 3 CH 3 C 2, FI 5F = 158-159.5% of 2 g (0.053 mol) of lithium aluminum hydride and 200 ml of tetrahydrofuran are added dropwise to

  a mixture of 5 g (0.015 mole) of 3-dimethyl-

  amino-1- [2- (3-ethyl-5-methyl-4-isoxazolyl) -indole-3-

  yll-1-propanone in 120 ml of tetrahydrofuran. The mixture is then refluxed for one hour, cooled in an ice bath and the reaction is stopped by cautious addition of 7 ml of water. The mixture is then filtered through Celite and the solvent is evaporated in vacuo. gives an oil which crystallizes slowly The crystals are triturated in ether to give the title compound;

F = 131-133 '

Example 5

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

  Indole-3-yl 11-propandl A suspension of 816 mg (0.022 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran is cooled to 5 ° under a nitrogen atmosphere and 3.5 is added dropwise. g (0.011 mol) of

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

  indole-3-ylel-1-propanone in 125 ml of tetrahydro-

  furanne, while keeping the temperature between 5 and 8.

  The mixture is then stirred for 4 hours at a temperature of between 0 and 5, cooled to -50 and the reaction is stopped by the addition of 10 ml of saturated magnesium sulfate solution. The mixture is warmed to room temperature. The residue obtained is dissolved in methylene chloride and the organic solution is washed with water, dried over magnesium sulphate, filtered and evaporated under vacuum. After crystallization of the residue in water, the residue is dissolved in methylene chloride. ether, f

  the title compound is obtained; F = 166-169.

Example 6

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

  Butyl) -indole To a suspension maintained at reflux and consisting of 1.71 g (0.045 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran, a solution of 5.3 g is added dropwise.

  (0.015 mole) 2- (3-ethyl-5-methyl-4-isoxazolyl) -N,

  dimethyl - / - oxoindole-3-butanamide in 25 ml of anhydrous tetrahydrofuran The mixture is then heated under reflux for 2 hours, cooled and the reaction is stopped by the addition of ethyl acetate and sodium hydroxide. 2 N and water On filter

  then the mixture and the tetrahydrofuran is evaporated.

  The evaporation residue is dissolved in CH 2 Cl 2, the solution is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is dissolved in ether and converts the product into its hydrochloride by means of gaseous hydrochloric acid. The hydrochloride of the compound is thus obtained.

of the title; it melts at 155.5-157.5.

Example 7

  2- (2-Naphthyl) -3-1- (N, N-dimethylamino) ethyl-indole A suspension of 4.5 g (0.119 mol) of lithium hydride is heated under nitrogen at 55 ° C. and aluminum and 300 ml of tetrahydrofuran and added portionwise over a period of 10 minutes,

  g (0.029 mol) of N, N-dimethyl-2- (2-naphthyl) -indole-

  3-Glyoxamide The mixture is then heated under reflux for 2 hours, cooled to -60 and the reaction is stopped by carefully adding 150 ml of a saturated solution of magnesium sulphate. The mixture is warmed to room temperature. It is filtered on celite and the celite is washed with methylene chloride. The phases of the filtrate are separated and the aqueous phase is washed with methylene chloride. The organic phases are combined, the overall solution is dried over magnesium sulphate. It is filtered and evaporated. The evaporation residue is triturated in ether and the solid product thus obtained is recrystallized from ethanol.

  thus obtains the title compound; he melts at 185-186.

Example 8

  2- (2-Naphthyl) -3-1-hydroxy-2- (N, R-dimethylamino) ethyl-

  Indole To a suspension of 4.5 g (0.119 mol) of lithium aluminum hydride in 800 ml of tetrahydrofuran maintained under nitrogen and cooled to 4 was added in portions (0.029 mol). ) of N, N-dimethyl-2- (2-naphthyl) -indole-3-glyoxamide in the course of 5 minutes, keeping the temperature below 10 ° C. The mixture is stirred for 2 hours at 5 ° C. cooled to -60 and quenched by carefully adding 150 ml of saturated magnesium sulfate solution The mixture was warmed to room temperature, filtered through

  celite and the celite is washed with methyl chloride

  The phases of the filtrate are separated and the aqueous phase is washed with methylene chloride. The organic phases are combined, the overall solution is dried over magnesium sulphate, filtered and evaporated. The residue is triturated in water. ether and the solid product thus obtained is chromatographed on silica gel to give the title compound;

he melts at 172-174.

  By proceeding in a manner analogous to that described in Examples 3 to G above, it is possible to prepare

Com x R R R R - -1 -

1 1 3 1 4

  The following compounds of the formula I CH 3 phenyl phenyl phenyl phenyl are preferably used.

C 2.45

phenyl

C 2 H 5

1 -

CH 3 CH 3

CH 3 CH 3

  1HHHHHHFH 3 HH HH HH CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 HHHHHHHFH CH 3 1 3 ## STR1 ## wherein L-naphthylb-biphenyl-2-naphthyl-o-biphenyl-o-biphenyl-p-biphenyl-benzylphosphonyl-1-yl indanyl 2-naphthyl-2-naphthyl-2-naphthyl-2-naphthyl-2-naphthyl-2-naphthyl-o-biphenyl-p-biphenyl-benzyl-p-nyl-2-uorenyl-indanyl-2-naphthyl-1-naphthyl-1

F = -159-10610

F = 166-167 '

F = 166-16B '

O R R R

2 3 5

) dared 0 CH

39 3 3 'H 3 "43' 2 '5

  1 CH 2 -thiazolylpyrrolidino 41 1 04 2-itaphthyl H pi peroxide

  42 1 O Li 12-naphthli ,,, H ruorpho 1 i no -

He-

Claims (7)

REVENDI CATI ONS   1. Indole-alkyleneaminires of formula I X 1, (R 2 R C (CH (2) 1 N ()   HR in which is hydrogen, fluorine, chlorine, a C 1 -C alkyl group or a C 1 -C 4 alkoxy group, R 2 and R 3 are each independently of one another , a C 1 -C 4 alkyl group or together with the nitrogen atom to which they are attached a 1-pyrrolidinyl, piperidino, hexamethyleneimino or morpholino residue and a) R represents a group of formula XX R 4 (XX)   R 1 is hydrogen and m is 2, 3 or 4, or   b) R represents a biphenyl, naphthyl, benzyl-   phenyl, indanyl, fluorenyl or a group of formula X Xa -C-CO-R 4   C (NH 2) R 5 (X Xa) X is hydrogen or hydroxy and m is 1, 2, 3 or 4, in formulas XX and X Xa where R 4 is hydrogen or an alkyl group C 1 -C 4 and R 5 being hydrogen or C 1 -C 4 alkyl, phenyl or phenyl substituted by halogen, C 1 -C 4 alkyl or C 1 -C alkoxy 4, in the form of free bases or in the form of a salt acid addition.   2. An indole-alkyleneamine, characterized   in that it is selected from 2- (3-ethyl-5-ethyl-4-   isoxazolyl) -3- (3-dimethylaminopropyl) indole; 2- (2-naphthyl) -3-1- (N, N-dimethylamino) ethyl-indole;   4-amino-3- [3- (3-dimethylaminopropyl) indole-2-yl]   3-hexene-2-one; and 4-amino-3-1 3- (2-dimethylamino)   1-hydroxyethyl) -indole-2-yl-3-hexen-2-one, in the state   free base or as an acid addition salt.   3. A process for the preparation of an indole-   Alkyleneamine according to Claim 1, in the free base state or in the form of an acid addition salt, characterized in that a) when R is a group of formula X Xa, a compound of formula Ip X NR I I R   In which R 1 R 2 R 3, RR 5 X and m have the meanings given in claim 1 for the compounds of type b), with the; iydrog; èee in the presence of a catalyst, or   b) when R is a biphenyl, naphthyl, benzyl-   phenyl, indanyl, fluorenyl or a group of formula XX, a compound of formula II is reduced 1 1 -C-Z 2-N 2 R "'R 3   (II) H in which R1, R2 and R3 have the meanings   data in claim 1, R 'represents a biph-   nyl, naphthyl, benzylphenyl, indanyl, fluorenyl or a group of formula XX and either Z 1 is O or (CH 2) 2 and Z 2 is a direct link C- (CH)   either Z 1 is a direct bond and Z 2 represents a group (CH 2) m in which m has the meaning given in claim 1, and the compound of formula I thus obtained is recovered,   in the free base state or in the form of an additive salt acid.   4 indole-alkylene amines according to claim 1 or 2, in the form of free bases or in the form of a pharmaceutically acid addition salt   acceptable, for use as a medicine.   5. The indole-alkylene amines according to claim 1 or 2, in the form of free bases or in the form of a pharmaceutically acid addition salt.   acceptable, for use as an antidiabetic.   6. A medicine, characterized in that   contains, as active principle, an indole-alkylene-   amine according to claim 1 or 2, in the basic form   free form or in the form of a pharmaceutical acid addition salt ceutically acceptable.   7. A pharmaceutical composition, characterized   in that it contains as active substance an indolealkyleneamine according to claim 1 or 2, in a free base state or in the form of a pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable diluent or vehicle acceptable.