LU84986A1 - HETEROCYCLIC HYDROCARBON COMPOUNDS BELONGING TO INDOLIC SERIES AND THEIR PHARMACOLOGICAL APPLICATION - Google Patents

Description

4

HETEROCYCLIC HYDROCARBON COMPOUNDS BELONGING

TO INDOLIC SERIES AND THEIR PHARMACOLOGICAL APPLICATION

The present invention relates to heterocyclic hydrocarbon compounds belonging to the indole series and having an amino substituent and relates to medicaments containing such compounds.

There is a very large bibliography relating to compounds of the 3- (aryloxy) -2-hydroxypropylamine series showing vaso-dilating properties and / or a blocking activity of beta-adrenergic receptors which are also useful for the treatment. cardiovascular disease. Most of this prior art relates to the class of beta-adrenergic blocking agents of these series of compounds.

The prototype of the compounds having this structure is propranolol which is chemically l- (isopropylamino) -3- (l-naphthyloxy) -2-propanol. Propranolol and certain naphthyloxy propanolamines which are related to them are the subject of United States patent No. 3,337,628 of August 22, 1967. Many subsequent patents have been issued relating to carbocyclic ethers in which other aromatic rings or 20 heterocyclic systems replace the naphthyloxy group of propranolol.

A number of patents have been issued to J. J. Baldwin relating to the use of the pyridinyloxy group in this way. These compounds and their salts are described and claimed as useful antihypertensive agents. These patents which are described below generally describe the following generic structure (I): r2 ‘

Vtl OR1 30! '-......

i “2 in which: R is an alkyl, phenalkyl or phenoxyalkyl radical; 0

II

R1 is H, C-L with L being an alkyl or aryl radical; R2 is H, CN, CF3s OH, C-L, Cl, NO2 "F, pyrrolyl, oxadiazolyl (L having the above meaning).

This set of Baldwin patents ceded to Merck & Co., Inc. includes the following patents: 4,000,282, December 28, 1976; 4,060,601, November 29, 1977; 4,091,104, May 23, 1978; 4,092,419, May 30, 1978; 4,144,343, March 13, 1979; 4,145,425, March 20, 1979; 4,151,284, April 24, 1979; 4,210,653, July 1, 1980; 4,259,327, March 31, 1981; 4,263,307, April 21, 1981; 4,279,913, July 21, 1981; and 4,329,351, May 11, 1982.

A compound preferably used in these series is 2- {3- (tert.-butylamino) -2-hydroxypropoxy} -3-dyanopyridine, also known by the name of MK-761; it has undergone considerable subsequent studies as described in particular in the following reviews and works: - Sweet, et al. The Journal of Pharmacology and Experimental Therapeutics, 211/1, 195-296 (1979; 20 - Sweet, et al. Clinical and Experimental Hypertension, 1 (4), 419-471 (1979); - and Vickers, et al., Drug Metabolism and Disposition, 8/3, 163-167 (1980).

Extensive human studies have been carried out, however, when MK-761 has been shown to have teratogenic properties in rabbits after chronic administration at high doses (cf. Journal of Medicinal Chemistry 25 22/11, 1284-1290 ( 1979)).

(Or ™ MK-761

n '/ ^ 0 / VjxX \ hC (CH3), -HCl OH

30

A number of indol-3-yl-tertio-butylaminopropanols (2,3) exhibiting hypertensive properties is described by Kreighbaum et al., In: - United States patent No. 4,234,595 issued on 18 November 35 1980; - United States patent No. 4,314,943 issued February 9, 1982; and - the journal Journal of Medicinal Chemistry, 23: 3, 285-289 (1980), Λ 3 s3 - ^)! - ° -Ar-Xn

l ^ kNAE2 OH

'‘<„ 10 r1 O)

A compound preferably used in this group is represented by the compound of structure (2), designated under the name of MO 13105, also known under the name of bucindolol and is currently undergoing a certain number of clinical evaluations as for its antihypertensive activity. .

CN

H

MJ 13105

A subject of the invention is a series of agents having vasodilating properties reflecting a certain range of beta-adrenergic blocking potency and having the general formula I and also relates to the acceptable acid addition salts of the point pharmaceutical view of these compounds of general formula I

B

35 (I) Λ 4

VS

In this structural formula: X is CHO, CH20H, CN, CF3, C0NRaRb or C02Rc with Ra and Rb being in-. depending on each other on hydrogen or Rc,

Rc being an arylalkyl, aryl or lower alkyl radical; 5 Y is a hydrogen or halogen atom or an acyloxy, alkoxy, aralkyloxy, aryloxy, or hydroxyl radical;

Q

R is a hydrogen atom or the group CL, L being chosen from alkyl * aryl *, ary substituted *, or arylalkyl *, · s R1, R2, A and B being independently of each other chosen from 10 the hydrogen atom or the alkyl radical; and C may be a halogen or hydrogen atony or a hydroxy, alkyl or alkoxy group.

The compounds preferably used are those in which X is in position 3 of the pyridine ring and the indolylalkylaminopropoxy side chain is linked in position 2 of the pyridine ring.

The invention covers the compounds having the above structural formula (I) as well as its acid addition salts. In the structural formula (I), X can be -CHO, -CN, -CF3, -C0NRaRb, or -C02RC.

Ra and Rb, independently of each other, are a hydrogen atom or a radical Rc which may be a lower C1-C6 alkyl radical, aryl or (lower alkyl-aryl, the aryl group preferably being a phenyl radical.

It is also preferred that X is linked in position 3 of the py-ridine nucleus.

Y represents a second substituent on the pyridine nucleus and can consist of a hydrogen or halogen atom or a lower C1-C * alkoxy radical, (lower alkoxy) aryl, hydroxy or 0

II

30 -C-O-alkyl in which the alkyl radical contains from 1 to 6 carbon atoms.

The entire pyridinyl group is associated with the indolylalkylaminopropoxy side chain in position 2 of the pyridine ring.

’35 R is a hydrogen atom or a group], C-LJ, in which L is chosen from the group comprising alkyl radicals containing 1 to 10 carbon atoms, phenyl * phenylsubstituted or phenylalkyl.

R1, R2, A and B consist, independently of one another, of hydrogen 5 or a lower alkyl radical.

C represents a substiant in the benzo nucleus of indole and is. chosen from the group comprising hydrogen and halogen atoms, lower alkyl, lower alkoxy or hydroxy radicals.

5 The indole part itself is preferably associated with the main side chain by its position 3.

For medical application, the pharmaceutically acceptable acid addition salts are preferred in which the anion does not contribute significantly to increasing the toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained either by reaction of an organic base of structure I with an organic mineral acid, preferably by contact in solution or by any of the conventional methods known and available to humans. art. Examples of the most widely used organic acids are carboxylic acids such as maleic, acetic, tartaric, propionic, fumaric, isethionic, succinic, pamoic, cyclamic, pivalic and the like; as inorganic acids, mention may be made of hydrohalogenated acids such as HCl, HBr, HI, sulfuric acid, phosphoric acid and the like.

It should be noted that the compounds according to the present invention involve all forms of optical isomers, i.e. mixtures of enantiomers e.g. racemic modifications as well as individual enantiomers. These individual enantiomers are commonly designated according to the optical rotation they produce by 25 (+) and (-), (1) and (d), or combinations of these symbols. The symbols (L) and (D) and the symbols (S) and (R) which signify left and right respectively denote an absolute spatial configuration of the enantiomers. When no isomeric designation is given for a compound4 it is the racemic modification.

Biological tests carried out with the compounds having the formula I on animals show that they have potent vasodoplast properties at the same time as various degrees of adrenergic beta-receptor blocking properties and intrinsic sympathomimetic activity. Certain preferred compounds give rise to the particular combination sought * of the above actions and the secondary pharmacological effects.

or the lack of these effects make them particularly suitable for use in specific cardiovascular treatments, for example as antihypertensives. The usefulness of the compounds of formula I

6 can be shown on various types of animals and in particular the antagonism of isoproterenol in anesthetized dogs treated by intravenous route (adrenergic beta-receptor action), spontaneously hypertensive rats and hypertensive rats by action of DOCA salt (antihypertensive action ), rat type 5 with lymph nodes kept blocked by angiotensin (vasodilating action) and on various other animals and laboratory models (cf. Deitchman, et al., Journal Pharmacological Methods, 3, 311321, '(1980). It has been observed that no teratogenic or mutagenic action is associated with the compound of formula I.

For uses as antihypertensive agents, vasodilators, and / or beta-adrenergic blocking agents, the medicaments according to the present invention are administered systemically, both orally and parenterally, in an amount effective non-toxic of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. By effective amount is meant the dose which exerts the desired pharmacological activity such as that which is mentioned above without giving rise to undue toxic secondary actions, when it is administered to mammals in need of such treatment. The doses vary according to the subjects, the route of administration chosen in a field expected from approximately 0.1 mcg to 100 mg per kg of body weight of the compound of formula I or of one of its addition salts. pharmacologically acceptable acids generally producing the desired therapeutic action.

The compounds according to the present invention can be prepared by a large number of suitable general methods. This process involves the coupling of a Z-substituted pyridine (IV) with a propanol having a suitable W-substitute or intermediate of nascent propanol (II):

General procedure '30 W ^ T- | 30 Ο ^ Λ’-g / - "- * v / (ïia) hydrolysis 35 y w ^ V ^ -G (I) or

—— -P

(IV) V

\ W / ^ </ ° / H2NG

7

In the above-mentioned general process: D is a hydrogen atom, or preferably a phenyl radical; rl r> 2 - |

R} A X

G is the radical

B

Z is a hydroxyl group or a halogen, preferably chlorine; W is a halogen, preferably chlorine when Z is hydroxyl and is a hydroxyl radical when Z is halogen.

In general, the hydroxyl bearing reagent is initially converted to the oxide anion with a strong base prior to reaction with the halogen bearing intermediate.

This process employs methods known in the art for the preparation of 1- (substituted amino) -3- (hetaryloxy) -2-propanols as described in the patents and publications cited above. This process involves the reaction of a suitable substituted pyridine with either: 1) a {3- (indolylalkyl) oxazolidin-5-yl} methanol (or methyl halide) of formula IIA, or 2) an indolylalkyl-aminopropanediol (or halopropanol ) of formula IIB, or 3) a glycidol of formula IIC.

Reaction intermediate IV and 11a is converted to product I by hydrolysis under acidic conditions. This hydrolysis is accomplished in the presence of dilute mineral acid having a concentration of 0.1N at IN at temperatures between 20 and 100 ° C. The product of formula I can be recovered as a free base by neutralizing the hydrolysis mixture and recovering the precipitate. The acid addition salts can be obtained by evaporation of the hydrolysis mixture or by reaction of the free base with the acid. Purification is accomplished by conventional means such as recrystallization.

The conversion of the epoxide intermediate resulting from the reaction of IV with IIC to the product of formula I is carried out simply by heating the epoxy ether either as it is or in the presence of an organic solvent inert with respect to of the reaction with an amine of formula H2NG as indicated above. No catalyst or condensing agent is required. Suitable solvents may consist of 95% ethanol although other organic liquids inert to the reaction in which the reactants are soluble may be used. These, by way of nonlimiting examples, may consist of benzene, tetrahydro-furan, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene 8 glycol, etc. Suitable reaction temperatures are between 60 and 200 ° C.

. The course of the process in a single step involves the. IV reaction with IIB and this is the route preferably used for the synthesis of the products according to the present invention.

This process is illustrated by the following specific reaction equation which shows the method preferably used for the abovementioned synthesis as reaction I.

Reaction 1

10 R1 R2 A C

15 B '; (IV) (IIB) (I)

In the above scheme, X, Y, R, R1, R2, A, B and C are as defined in Formula I.

This process essentially involves heating the selected substituted halopyridine with the suitable indolylalkylaminopropanol (IIB) in the presence of a base, in a reaction medium comprising an inert organic liquid under mild conditions. Conventional strong bases such as potassium t-butoxide, potassium hydroxide, sodium hydride can be used although sodium hydride is preferably used. Likewise, any inert organic liquid can be chosen as the reaction medium or else cyanopyridine and indolylalkylaminopropanol can be reacted as such in the presence of the base. By way of nonlimiting examples of suitable solvents, mention may be made of benzene, toluene, tetrahydrofuran, dibutyl ether, dimethoxyethane, etc. Suitable reaction temperatures are between 20 and 80 ° C. The addition of a suitable crown ether, for example 18-crown-6 ether, helps to carry out the reaction.

The products of formula I in which Y and / or C are a hydroxyl group, are prepared by cleavage of the corresponding methoxy precursor as shown in reaction 2.

9 Reaction 2 x 1 2

GOLD

B!

B

Other synthetic methods leading to conversion to hy-droxylated products, such as the hydrogenolysis of benzyloxy precursors are well known to those skilled in the art and can also be applied in this case.

The halopyridines suitable for carrying out this reaction are commercially available or can be prepared using conventional methods such as those which are indicated in the technical literature. The preparation of the tri-substituted pyridines which are related to them is described in U.S. Patent 4,329,351 issued May 11, 1982 to Baldwin, et al. and the entire content of which is indicated here for reference.

The preferred intermediate synthesized indolylalkylaminopropanols (I IB; R = H) are suitably prepared by reaction of an appropriate substituted indolylalkylamine (III) with 3-chloro-1,2-propanediol in alcohol. reflux containing sodium carbonate. This process is illustrated by reaction equation 3.

25 Reaction 3 Η0 · χε1 + B b (III) (IIB), 35 In this reaction scheme 3, the groups R1, R2, A, B and C are as defined in formula I.

The products of formula I according to the present invention in which R is other than a hydrogen atom, are suitably prepared by treatment of the corresponding product of formula I in which R is a hydrogen atom with an agent. suitable acylation such as acyl halide among others undecanoyl chloride, pivaloyl chloride, benzoyl chloride, para-methoxybenzoyl chloride or anhydrides such as acetic anhydride and the like. The reaction is illustrated by the following reaction scheme indicated as reaction 4: Reaction 4 R1 R2 c ^ 1 10 Y “fQj V k Λ R" C ~ C1 x R R2

0H I (R-C) —O 'H

B ff 2 OR

0 B

Indolylalkylamines (III) are described in the patents and articles of Kreighbaum, et al. cited above, the full description of which is given here for reference as well as the content of the references therein. Although these processes, the bibliographic references of which are given above, are applicable to the preparation of other indolyl-20 alkylamines intermediates not specifically described but which are suitable as intermediates for the present invention, the synthesis of the compounds is given below. of formula III as a further example.

The compounds according to the present invention can be put into formulas suitable for conventional pharmaceutical uses to lead to obtaining pharmaceutical compositions and in particular in the form of unit doses comprising for example pills, capsules, powders, granules, emulsions, suspensions and the like. The solid preparations contain the active ingredient in admixture with pharmaceutically acceptable and non-toxic excipients such as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as for example corn, starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricants, for example. 35 magnesium stearate, stearic acid or talc. The tablets may not be coated or may be coated by known techniques so as to avoid their disintegration and absorption in the gastrointestinal transit and thus ensure sustained action for a long period of time.

11

Liquid preparations suitable for parenteral administration include solutions of suspensions or emulsions of the compounds of formula .1. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of formula I contain the active ingredient in admixture with one or more pharmaceutically acceptable and non-toxic excipients known to be used with advantage in the manufacture of aqueous suspensions. Such excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and acacia gum. Suitable moistening or release agents are naturally occurring phosphatides such as, for example, lecithin, polyoxyethylene stearate.

Non-aqueous suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example olive oil, sesame oil, or coconut oil, or in an oil mineral, for example liquid paraffin. The suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents, generally used in pharmaceutical compositions, can also be included such as saccharin, sodium cyclamate, sugar and caramel to lead to the production of tasty oral preparations. The compositions may also contain other absorbents, stabilizers, wetting agents and buffers.

The compounds according to the present invention, their method of preparation and their biological activity will appear in more detail on analysis of the following examples and the appended claims which are given for illustrative purposes only and should not in any way be taken as limiting the invention as to its scope or its value. In the. The following examples are used to illustrate the aforementioned synthesis process, the temperatures are expressed in degrees Celsius (°), and the boiling points are given without correction. The characteristics of the nuclear magnetic resonance (NMR) spectra refer to the chemical shifts (δ expressed as parts per million (ppm)}, tetramethylsilene (TMS) being used as a reference. The zones, 35 relative indicated during different displacements of the H NMR spectrum data correspond to the number of hydrogen atoms of a particular functional type in the molecule The nature of the displacements with regard to their multiplicity is indicated in the form (bs) singlet »12 large, (s) singlet, (m) multiplet, or (d) doublet.

The abbreviations used are DMS0-d6: deuterodimethylsulfoxide, CDC13: deuterochloroform and otherwise are conventional. Infrared (IR) spectra descriptions include only absorption wave numbers (cm-1) having the functional group identification values.

The infrared determinations are carried out on a medium in which the diluent is potassium bromide (KBr). The elementary analyzes are indicated as a percentage by weight.

Intermediate synthesis 10 A.- Intermediaries of formula III.

EXAMPLE 1 3- (2-friend no-2-methylpropyl) -6-methoxyindole (R1 = R2 = Me, A and B = H, C = 6-Me0) To 15.2 ml of an aqueous solution cooled to 25¾ of dimethylamine 15 are added, successively and with stirring and continuous cooling, the following products:. 16.9 ml, acetic acid,. 7.2 ml of 37% formaldehyde,. 27 ml of 95% ethanol.

The resulting stirred solution is kept at-5-0 ° C using a cooling bath while 10.0 g (0.07 mole) of 6-methoxyindole is added in portions. The mixture is stirred and gradually heated to 30 ° over a period of 30 minutes, then maintained at 30 ° C with stirring for an additional 3 hours. The reaction mixture is then cooled to 10-15 ° C and acidified by the addition of 170 ml of 2N hydrochloric acid.

The acid mixture is discolored (Darco G-60), filtered and the filtrate is made basic with 245 ml of 20% NaOH while being cooled and stirred.

An oily brown precipitate is obtained which is subjected to extraction with ether, then the extracts are washed with water, dried over MgSOz, and concentrated until a residue is obtained. oily brown (14 g). The residue is recrystallized from isopropyl ether and hexane and 9 g (65% yield) of 6-methoxygramine are thus obtained in the form of a brown solid, the melting point of which is 88 ° -90 ° C.

A mixture of 7.7 g (0.04 mole) of 6-methoxygramine, 26.5 g, (0.03 mole) of 2-nitropropane and 1.7 g (0.04 mole) of NaOH pellets, is maintained at reflux under a nitrogen atmosphere for 3 to 5 hours. The reaction mixture is cooled to room temperature, acidified by addition of 10% acetic acid and extracted with ether. The ethereal extracts 13 are washed with water, dried over MgSO ** and concentrated in vacuo until a residue is obtained. Recrystallization of the residue from the isopropyl alcohol / water mixture leads to 7.6 g (80¾ yield) of 3- (2-methyl-2-metropyl) -6-methoxyindole in the form of a solid. brown with a melting point of 98-100 ° C.

The nitropropylindole compound and activated Raney nickel (4.2 g) are combined in 80 ml of 95¾ ethanol and heated to reflux temperature. The heating is stopped when Ton starts to add. dropwise hydrazine hydrate at 85¾ (7.8 g) in 8 ml of ethanol 10 at 95¾. The reaction mixture is then heated at reflux temperature for 2 hours, then cooled to room temperature and then filtered. The filtrate is concentrated until a residual oil is obtained which slowly solidifies and is recrystallized from the ethyl acetate / etherisopropyl mixture, which leads to 4.2 g of product. with a melting point of 125-128 ° C.

EXAMPLE 2 1 2- (2-amino-2-methylpropyl) indole (Ri = R2 = Me, A, B, and C = H)

A solution comprising 10.0 g (0.06 mole) of indole-2-carbo-xylic acid and 20.0 g (0.17 mole) of thionyl chloride in 130 ml of dry Et 2 O is stirred for 12 to 18 hours at room temperature and under a nitrogen atmosphere. The reaction mixture is filtered then the filtrate is concentrated until an oily residue is obtained which is taken up in 150 ml of dry Et 2 O. The ethereal solution is treated with 80 ml of dimethylamine in 90 ml of Et20. The ethereal reaction mixture is concentrated to dryness and the residue crystallized from isopropyl alcohol. The solid is isolated by filtration, 4.0 g (34% yield) of 2-indolylamide is thus obtained, the melting point of which is 181-183 ° C.

The amide is dissolved in 100 ml of THF and the solution is added dropwise to a stirred suspension comprising 3 g of lithium aluminum hydride in 50 ml of THF under a nitrogen atmosphere. After heating to reflux temperature for 2 hours, the reaction mixture is cooled and decomposed by a small amount of water and a dilute NaOH solution.

The mixture is filtered, then the filtrate concentrated until an oily residue is obtained which is taken up in absolute ethanol and treated with a slight excess of dimethyl sulfate. The resulting alcoholic solution is stirred at room temperature for 4 hours, then concentrated to dry vacuum; the quaternary trimethylamine salt is thus obtained as a residue.

14 3.0 g (0.01 mol) of the crude quaternary salt are combined with 2.0 g (0.05 mol) of NaOH pellets and 15 ml of 2-nitropropane, then the mixture is heated to reflux temperature under an atmosphere of 'nitrogen-for one hour. The resulting dark thick mixture is cooled, diluted by addition, acidified with acetic acid to a pH of about 6, then extracted with Eta0. The ethereal extracts are combined, washed with water, dried over Mg $ 04 and concentrated until a dark residue is obtained which is chromatographed on a column of silica, the eluent consisting of chloride of methylene. The elimination of methylene chloride and the recrystallization of the raw material in the isopropyl alcohol / water mixture leads to the production of 0.4 g of 2- (2-methyl-2-nitropropyl) indole in the form of '' a creamy colored solid with a melting point of 102-103 ° C.

The reduction of this nitrated product using Raney nickel and hydrazine according to the method used in Example 1 above, leads to the desired indoalkylamine in the form of a white solid with a melting point of 130- 133 ° C.

Additional examples of indolalkylamine are available and are given in Table I.

20 Table I

Indol al kyl friend born 2 a c

h2n I

25 B

(III)

Example R1 R2 A B _C_

3 Me H 3-H Me H

4 Me Me 2-Me H H

30 5 Me Me 2-H H 5-Br 6 Me Me 2-H H 5-OMe

7:00 a.m. 2:00 a.m.

8 H Me 2-Me Me 5-OPr 9 H 'Me 3-Me Me 5-Br ”35 10 Me Me 2-HH 6-OMe 11 Me H 2-And H 4-C1 12 Me H 2-HH 7- OMe 15 B.- Intermediaries of formula II.

EXAMPLE 13

Hydrate of 3- {¢ 2- (3-indolyl) -1,1-dimethylethyl amino} -1,2-propanediol (ΠΒ) 5 A mixture of 10.0 g (0.05 mole) of a, a- dimethyl - (? - (3-indolyl) ethanamine, 11.3 g (0.11 mole) of Na2CO3, 7.0 g (0.06 mole) of 3-chloro-1,2-propanediol and 250 ml of EtOH is stirred overnight at reflux temperature After cooling, the mixture is filtered and then concentrated in vacuo The residue is dissolved in EtOAc, discolored using Darco G-60 , then evaporated to a volume of 100 ml. The solution gives rise to a deposit consisting of a white solid which is recrystallized from EtOAc, thus obtaining 7.7 g (yield 55¾) of a product whose point melting point is 112-114 ° C. This material crystallizes with a fifth of a mole of water.

By using other intermediates of formula III, in this process or in a similar process, a variety of intermediates of formula 11B are readily obtained.

Product Syntheses EXAMPLE 14 20 2- {2-Hydroxy-3 - {[2- (1H-indol-3-yl) 1,1-dimethylethyl1] ami no} propoxy} -3-pyri di necarboni tri 1e ( Y = H, X = CN, R = H, Ri and R2 = Me, A, B, and C = H) 47.3 g (0.18 mole) of 3- {j; 2- (3-indolyl) -1,1-dimethyl aminoj -1,2-propanediol and 7.6 g of a 57¾ dispersion in oil (i.e. 0.18 mole) of sodium hydride are stirred in 2.5 liters of toluene and heated at 70 ° C for 3 hours under a nitrogen atmosphere. The mixture is then left to cool to ambient temperature while being stirred and 0.5 g of 18-crown-6 ether, 62.1 g of anhydrous powdery K2CO3 in powder form (0.45 mole) are successively added thereto and 25.0 g 30 (0.18 mole) of 2-chloro-3-cyanopyridine, then the whole is stirred for an additional 42 hours. The dry concentration leads to a residue which is separated between a hot water phase and EtOAc. After cooling to room temperature, the aqueous layer is separated, washed with additional EtOAc, then the washing product is combined with the original EtOAc coating. The mixtures in EtOAc are dried over MgS0 <* and concentrated hot to about half their volume. After cooling, they precipitate a solid which is isolated by filtration; about 41 g are thus obtained (yield 62¾) of the crude base product.

16

The conversion of the base to the hydrochloride is carried out by treatment of a solution in isopropyl alcohol of the base with ethanolic HCl. The recrystallization of the crude hydrochloride from absolute ethanol leads to the production of a white solid, the melting point of which is 181-183 ° C.

On analysis, for the product having the formula: C2iN24Nîi.02, HCl, the following result is obtained:

C H N

10 - calculated: 62.92 6.29 13.98 - found: 62.85 6.29 14.04 NMR (DMSO-de): 1.30 (6, s); 3.20 (4, m); 3.99 (3, m); 6.02 (1, d {4.0 Hz}); 7.30 (6, m); 8.31 (1, dd {2.0, 7.6 Hz}); 8.51 (1, dd {2.0, 5.6 Hz}); 8.82 (1, bs); 9.32 (1, bs); 15 11.27 (1, bs).

IR (Kbr): 750, 1110, 1310, 1440, 1460, 1580, 1588, 2230, 2790, 2980, and 3400 cm-1.

Cyclamate preparation

Cyclamate can be prepared by treatment of the crude base 20 'which has been synthesized above (2 g of crude base) with cyclamic acid (1 g) in 50 ml of methanol. The methanolic solution is heated, filtered and then the filtrate concentrated under vacuum; a residue is thus obtained which is crystallized from 10 ml of acetonitrile. The recrystallization of the crude salt in the methanol-acetonitrile mixture leads to the production of 25 g of a white solid with a melting point of 172-174 ° C.

On analysis, for the product having the formula: C2iH2i * N * 02, C6H13N03S, the following result is obtained:

C H N

30 - calculated: 59.65 6.87 12.89 - found: 59.74 6.77 12.82 EXAMPLE 15 4- (2-hydroxy-3 -) {2- (1H-i ndol-3-yl) -1,1-dimethylethyl} ami no) propoxy} -3-pyri di necarboni tri 1e - 35 Using the method of Example 14, using 10.4 g (0.04 mole) of 3- { C2- (3-indolyl) -1, 1-dimethylethyl) amino} -1,2-propanediol, 1.7 g (0.04 mole) sodium hydride, 550 ml toluene, 5.5 g (0 , 04 mole) of 4-chloro-3-cyanopyridine (cf. Wieland and Biener, Chem. Berichte, 96, 17 pages 268-274, (1963) ·); 0.11 g of 18-crown-6 ether and 13.7 g (0.1 mole) of powdery anhydrous K2CO3, 15 g of a material having the appearance of a gum are obtained. This gum is subjected to chromatography on a column of silica, eluted using methylene chloride (90 parts), methanol (10 by 5 parts) and ammonium hydroxide (1 part) to produce two fractions.

The second fraction to be eluted contains 6.8 g of a gum which is recrystallized from ethyl acetate; 5 g of a solid are thus obtained, the melting point of which is 124-126 ° C. Recrystallization of this material from ethyl acetate leads to 4.2 g of a white solid, the melting point of which is 126 ° -128 ° C.

On analysis, for the product with the formula; ^ 2ΐΗ2 ^ Ν ^ θ2 we obtain the following result:

C H N

15 - calculated: 69.21 6.64 15.38 - found: 69.42 6.75 15.65 NMR (DMSO-de): 1.00 (6, s); 1.55 (1, bs); 2.75 (4, m); 3.90 (1, m); 4.27 (2, m); 5.10 (1, bs); 7.25 (6, m); 8.64 (1, d {6.0 Hz}); 8.78 (1, s); 10.82 (1, bs).

20 IR (KBr): 745, 1010, 1190, 1290, 1315, 1455, 1495, 1520, 1590, 2225, 2970, and 3400 cm- '.

EXAMPLE 16 | 2- (2-hydroxy-3 - {{2- (1H-indol-3-yl) -1,1- j dimethylethyl} ami no} propoxy} -3-pyri di necarboxami of 25 Using a process similar to that indicated in Example 4 above, 10.5 g (0.04 mole) of 3- {£ 2- (3-indoly1) -1,1-dimethylethyl} amino} -1 , 2-propanediol, 1.7 g (0.04 mole) sodium hydride, 400 ml toluene, 5.6 g (0.04 mole) 2-chloronicotinamide, 0.11 g 18-crown- 6-ether and 13.8 g (0.1 mole) of anhydrous K2CO3 powder are brought to react, which leads to the production of 17 g of a residual gum. This gum is chromatographed on a silica column, the eluent consisting of 90 parts of methylene chloride, 10 parts of methanol and 1 part of ammonium hydroxide The fractions containing the product are combined, concentrated until a residue is obtained which is crystallized in ethyl acetate; 5.2 g of a material are thus obtained, the melting point of which is 68-72 ° C. and the recrystallization from ethyl acetate and drying hage in a vacuum oven leads to the production of 4 g of a white solid with a melting point of 131-133 ° C.

V

18 On analysis, for the product having the formula: C21H26N4O3, the following result is obtained:

C H N

5 - calculated: 65.95 6.86 14.65 - found: 65.80 6.85 14.31 NMR (DMSO-de): 1.03 (6, s); 2.77 (4, m); 3.95 (1, m); 4.46 (2, m); 7.20 (6, m); 7.81 (2, bs); 8.30 (2, d {6.1 Hz}); 10.85 (1, bs).

10 IR (KBr): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, 2970, 3330 and 3470 cm “1.

. EXAMPLE 17

Conversion of methoxy derivatives to hydroxy derivatives - general methods The methoxy derivative is dissolved in methylene chloride and stirred under a nitrogen atmosphere, while keeping the mixture cooled using an ice bath. 3 equivalents of boron tribro-mure are added dropwise in a methylene chloride solution. After this addition, the ice bath is removed and the stirring of the reaction mixture is continued at room temperature for 6 to 8 hours. The reaction mixture is again cooled using an ice bath, then the excess reagent is decomposed by adding an excess of H2O drop by drop, which causes the production of a gummy material which precipitate. The supernatant phase is separated by decantation of the gummy material which is rinsed with two parts of water. The gum is dissolved in hot water, treated with Darco activated carbon, filtered and the cooled filtrate is made basic by adding ammonium dioxide until a pH of about 8 is obtained. The resulting precipitate is filtered, washed with water, dried and subsequently purified by chromatography on a column of silica gel 30 and elution using 90 parts of CHCl 3, 10 parts of metha-nol and 1 part of ΝΗ ^ ΟΗ . The concentration of the fractions containing the product leads to the production of a residue which is recrystallized from an ethanol-water mixture; the pure hydroxy derivative is thus obtained.

Starting from suitable pyridine and indolglalkylamine, it is possible to synthesize additional examples of compounds of formula I by operating in substantially the same procedures as those described above. Certain additional products, of formula I, capable of being synthesized are listed in Table 2.

19 G in these formulas represents the group: ‘<R2 A cl —X-ç @ B - 5 which is obviously a function of the intermediary III chosen (cf. examples there 12), TABLE 2

Example Formula Example Formula

Bike ^ KG26

OH 0K

HQv ^ S> CN Cl. CN

20 IÖT 27

KG KG

20 OH OCCH

»I J

KÎ ^ V ^ C ° XH2 O

21 Uvy ^ 28 Mto-v-.KG

OH '

OH

25 CH0 N ^ VCHO

”TX ^. ”® - r- OCCH3 oh - oc. ¢ ¢ ^ ..

DH 'OCEt <r> CF3 ‘0

• ^ 24 (oT

\ Ο ng OCPh Π

O

* 20

Biological determination tests

These biological tests are used to determine the cardiovascular profile of a certain number of compounds of formula I both in their vasodilator activity and in their beta-adrenergic blocking activity.

EXAMPLE 31 The efficacy of antihypertensive agents, other than beta-adrenergic receptor blocking agents, is generally determined in spontaneously hypertensive rats. The blood pressure values are determined on the animals tested beforehand and then 24 hours after administration of the oral doses of 50 mg / kg of test compounds. The percentage of variation observed in the heart rate is also noted. A drop in blood pressure of the order of 19 to 24 mm of mercury is considered "questionable". The indications "active" and "inactive" correspond to decreases greater or less than this range of values.

EXAMPLE 32

Angiotensin blocked lymph nodes are used in tests to determine the vasodilator activity of the compounds. Percentage changes in blood pressure in the 20 anesthetized rats 30 minutes after the intravenous doses are determined. The doses administered intravenously contain the test compound at the rate of 3 mg / kg of body weight. Limit activity is defined as 15 to 20% drop in blood pressure measured 30 minutes after administration. The "active" and "inactive" indications are values above or below this value range.

EXAMPLE 33

The diastolic blood pressure and the responses of the heart rhythm to a fixed fixed dose <Jisoproterenol used as controls, 30 are determined before then 15 minutes after administration of graduated doses of the test compound "the administration being done intravenously over an interval 3 minutes to anesthetized dogs. Part of a femoral artery and a vein are caterized to determine blood pressure and to administer drugs dissolved in saline. The vagina is sectioned bilaterally in the mid-cervical region of the neck and dogs ventilated by mechanical route (using the Hervard respirator) using ambient air at a flow rate of 20 / minute and a sudden volume of 20 ml / kg. The heart rate is monitored using a cardiotachometer set by the pressure pulse. All measurements are recorded on a Beckman R-612 type recorder. The effect of the drug is expressed in terms of cumulative doses (microgram / kg) causing a 50% inhibition of the result of iso-5-protenol.

The following abbreviations used in the present description and in the claims to which they give rise have the following meanings:. Ph = phenyl group; 10. Pr = propyl group; . Me = methyl group; . Et = ethyl group.

A convention generally used in modern chemistry and organic was used in this description. For alkyl type structures, the number of carbon and hydrogen groups has been indicated in shorthand. Thus, for example, formula I can be put in the following form: 20 R1 R2 / ° v (Yrnf

U CH 'N CH „--- \\ - J

L H.

25 B

Claims (29)

1. As a new industrial product, a compound having the formula: 'OR | (I) B 10 as well as its acid addition salts in which: ci b X is chosen from the group comprising -CHO, -CN, -CF3> -C0NR R, or -C02Rc with Ra and independently one the other consisting of hydrogen or Rc; Rc may be a lower alkyl radical comprising 1 to 4 carbon atoms, aryl, or (lower alkyl) aryl; 15 Y is a second substituent of this pyridine ring and consists of a hydrogen or halogen atom or a lower C1 to U alkoxy radical, (lower alkoxy! Aryl, hydroxy, or O II CO-alkyl in which the radical alkyl contains from 1 to 6 carbon atoms; the indolylalkylaminopropoxy side chain being associated with pyridine in position 2 or 4; 0 II R is a hydrogen atom or a radical -CL, L consisting of an alkyl radical comprising of 1 with 10 carbon atoms, phenyl, 25 or phenalkyl; R1, R2, A and B independently of one another consist of a hydrogen atom or a lower alkyl radical; C is a substituent on the benzene ring of the indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxy radical, the indolyl system being linked by its position 2 or 3. 2. A compound according to claim 1 in which the indolylalkylaminopropoxy-side chain is linked to pyridine in position 2. 3. A compound according to claim 1 in which the in-dolyl ring is linked by its position 3. 4. A compound according to claim 2 or 3, in which: X is a cyano or a do-do radical. Y is a hydrogen atom; 23 R is a hydrogen atom; R1 and R2 are lower alkyl radicals; A · and B are a hydrogen atom; C is a halogen, hydrogen atom, or a hydroxy, alkyl or alkoxy group. 5. A compound according to claim 1, consisting of 2- {2-hydroxy- 3- {{2- (1H-i ndol-3-yl) -1,1-dimethylethyl} ami no} propoxy} -3-pyridi ne-carbonitrile or a pharmaceutically acceptable acid addition salt thereof. 6. The cyclamic acid addition salt of the compound according to claim 10. 7. The hydrochloric acid addition salt of the compound according to claim 5. 8. A compound according to claim 1, consisting of 4- {2-hydroxy- 3- {£ 2- (1H-indol -3-yl) -1, 1-dimethylethyl} amino} propoxy} -3-pyridine-carbo - 5 nitrile or a pharmaceutically acceptable acid addition salt thereof. 9. A compound according to claim 1 consisting of 2- {2-hydroxy- 3- {{2- (1H-i ndol-3-yl) -1,1-dimethylethyl} ami no} propoxy} -3-pyridi ne -carboxa-mide or a pharmaceutically acceptable acid addition salt thereof. 10. As a medicament exerting a vasodilating action in a mammal, composition containing a compound according to any one of claims 1 to 9. 11, - As medicament for treating hypersion, any composition containing one or more of the compounds according to any of claims 1 to 9. 12. A pharmaceutical composition in the form of unit doses suitable for systemic administration to a mammal, said composition comprising a pharmaceutically inert carrier and an amount of a compound of formula I according to any of claims 1 to 9, said unit form containing a non-toxic dose of the order of 0.1 mcg to 100 mg / kg body weight of said mammal. 13. Pharmaceutical composition according to claim 12, characterized in that the compound of formula I is 2- (2-hydroxy-3 - {{2- (1H-indol-3-yl-l, 1-dimethyl ethyl}) ami no} propoxy} -3-pyridinecarbonitri or a pharmaceutically acceptable acid addition salt thereof. "35 14.- Pharmaceutical composition according to claim 12, characterized in that the compound of formula I is 4- {2-hydroxy-3 - {(2- (1H-indol -3-yl-1,1-dimethyl tethyl} ami no} propoxy} -3-pyridinecarbonitri or one of its pharmaceutically acceptable acid addition salts .24 15.- Pharmaceutical composition according to claim 12, characterized in that the compound of formula I is 2- {2-hydroxy-3 - {{2- (1H-indol-3-yl) -1, l-dimethylethyl} amino} propoxy} -3-pyridinecarboxamide or one of its pharmaceutically acceptable acid addition salts. 16. Process for the preparation of a compound having the formula: OR, (I) B and of its acid addition salts in which s: * 15 X is chosen from the group comprising -CHO, -CN, -CF3 , -C0NRaR ^, or -C02RC with Ra and R * 3 independently of each other consisting of hydrogen or Rc; Rc may be a lower alkyl radical comprising 1 to 4 carbon atoms, aryl, or {lower alkyl) aryl; Y is a second substituent of this pyridine ring and consists of a hydrogen or halogen atom or a lower C1-U alkoxy (lower alkoxy) aryl, hydroxy, or O 11 CO-alkyl radical in which the radical alkyl comprises from 1 to 6 carbon atoms; The indolylalkylaminopropoxy side chain being associated with pyridine in position 2 or 4; 0 II R is a hydrogen atom or a -C-L, L radical consisting of an alkyl radical comprising from 1 to 10 carbon atoms, phenyl, or phenalkyl; R1, R2, A and B independently of one another consist of a hydrogen atom or a lower alkyl radical; C is a substituent on the benzene ring of the indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxy radical; and the indolyl system being linked by its position 2 or 3, said method consisting in: (a) coupling a pyridine having a substituent Z of formula IV: in which X and Y are as defined above and Z is a hydroxyl group or a halogen, with a propanol having a substituent W or a nascent propanol intermediate II chosen from group 10 comprising the compound IIA, IIB and IIC: Ό — i IJ IIA C> NG 15 S / Q i ^ W N — G IIB OR O W ^ <1 ne in which D is a hydrogen atom, a phenyl group and preferably a phenyl group; and G is the radical 30 Γ O1 T, 2 R., R A; ’35 B \ * 26 in which: R1, R2, A, B, and C are as defined above; and where W is a halogen atom and preferably a chlorine atom when Z is a hydroxyl group and W is a hydroxyl when Z is a halogen; and (b) i) when compound IIA reacts with compound IV to convert the resulting product by hydrolysis under acidic conditions of said compound I; ii) when compound IIC reacts with compound IV this forms an epoxy ether, the process then comprising an additional step of heating said epoxy ether either as it is or in the presence of an organic solvent inert to the reaction with an amide of formula H2NG in which G is as defined above so as to form said compound I. 17. A process according to claim 16, in which said compound IIB is used, in which W is a hydroxyl group, when Z is a halogen and said coupling of step (a) comprises heating the compounds IV with a compound IIB in the presence of a base, the reaction being carried out under mild conditions in an inert organic liquid. 18. A process according to claim 16, in which said hydrolysis under acidic conditions makes use of a dilute mineral acid whose concentration is between 0.1N and IN and at temperatures between 20 and 100 ° C, said process also including a recovery stage either: (a) of the product of formula I as a free base for neutralizing the mixture of hydrolysis and recovery of the precipitate, or (b) the acid addition salts which result by evaporation of the hydrolysis mixture or by reaction of the free base with an acid. 19. A method according to claim 16, wherein Y and / or C in said products of formula I are a hydroxy group, said method comprising the method according to claim 16 wherein said compound IIB is used and also including a step of cleavage of the corresponding methoxy precursor by the reaction according to the following reaction II scheme: '* ^ B, B * 27' 20. A compound having the formula: - {§Π and its acid addition salts, in which: X is chosen from the group comprising -CH0, -CN, -CF3, -C0NRaRb, or 10 -C02Rc with Ra and Rb independently of each other consisting of hydrogen or Rc; RC can be a lower alkyl radical comprising 1 to 4 carbon atoms, aryl, or (lower alkyl) aryl; Y is a second substituent of this pyridine ring and consists of a hydrogen or halogen atom or a lower alkoxy radical in C-, C1-, or (lower alkoxy) aryl, or hydroxy, or O II C-0-alkyTe wherein the alkyl radical comprises from 1 to 6 carbon atoms; and the indolylalkylaminopropoxy side chain being associated with pyridine 20 in position 2 or 4. 21. A compound having the formula: << ΓΊ O NG v · D 30 and its acid addition salts in which: X is chosen from the group comprising -CH0, -CN, -CF3, -C0NRaRb, or - C02RC with Ra and Rb independently of each other consisting of hydrogen or RC; Rc may be a lower alkyl radical com-. ”35 taking 1 to 4 carbon atoms, aryl, or lower alkyl aryl; Y is a second substituent of this pyridine nucleus and consists of a hydrogen or halogen atom or a lower C 1 -C 4 alkoxy radical, or lower aryl or hydroxy alkoxy, or 28 Ο U CO-alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms; and the indolylalkylaminopropoxy side chain being associated with pyridine 5 in position 2 or 4; D is a hydrogen atom or a phenyl radical, and preferably is a phenyl radical: G is a Γ R1 R2 A radical; "/ - B 15 in which R1, R2, A and B independently of one another consist of a hydrogen or a lower alkyl radical; C is a substituent on the benzene nucleus of the indole and consists of a d atom hydrogen or halogen or a lower alkyl, lower alkoxy or hydroxy group, and the indolyl system is linked in position 2 or 3. 22. A process for the preparation of the compound according to claim 20, said process comprising the coupling of a pyridine having a substituent Z of formula IV * “f§Î s (IV) in which X and Y are as defined in claim 20, and 30 wherein Z is hydroxy or halogen with a propanol having a substituent W or nascent propanol intermediate, of formula IIA ^ l O NG IIA D - · 35 * 29 wherein: D is an atom d hydrogen or a phenyl radical and preferably a phenyl radical; and G is the radical L β ίο in which R1, R2, A and B independently of one another consist of a - - hydrogen or a lower alkyl radical; C · is a substituent on the benzene ring of the indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxy group; and wherein W is a halogen and preferably chlorine atom when Z is a hydroxyl and W is a hydroxyl when Z is a halogen. 23. A process for preparing the compound according to claim 21, said process comprising coupling a pyridine having a substituent Z of formula IV 20 (IV) in which X and Y are as defined in claim 21, and in which Z is a hydroxy group or a halogen atom with a pro-panol having a substituent W or an incipient propanol intermediate of formula IIC HC in which W is a halogen atom preferably chlorine when Z is a hydroxyl and in which W is a hydroxyl when Z is a ha-. ’35 house. 24. A compound having the formula IIB OR IIB V 30 ♦ ♦ in which: W is a halogen atony or a hydroxyl group; 0 11 R is a hydrogen atom or a C-L group, L being chosen from the group comprising the alkyl radical having from 1 to 10 carbon atoms, phenyl, substituted phenyl or phenalkyl; and in which G is the radical of formula Γ JL _2 A / c :: B in which R1, R2, A and B independently of one another consist of a hydrogen atom or an alkyl radical, and C is a substituent on the benzene ring of the indole which is chosen from the group comprising hydrogen and halogen atoms and lower alkyl, lower alkoxy, or hydroxy groups. 25.- A process for the preparation of a component having the formula IIB: w N-G OR 25 wherein: W is a halogen or a hydroxyl group; and II R is a halogen atom or a C-L group, L being selected from the group consisting of Ο -, - Ο-, ο alkyl, phenyl, substituted phenyl or phenalkyl; and in which G is the radical of formula B r- 31 in which R1, R2, A and B independently of one another consist of a hydrogen atom or a lower alkyl radical, and C is a substituent on the benzene nucleus of the indole selected from the group comprising hydrogen and halogen atoms and lower alkyl, lower alkoxy or hydroxy groups, said process consisting in reacting a compound of formula III io L in which A, B, R1, R2, and C are as defined above, with a 3-chloro-1,2-propanediol in alcohol at reflux temperature and a base which preferably consists of carbonate sodium.