CH661512A5 - 1-PYRIDYLOXY-3-INDOLYLALKYLAMINO-PROPANOLS SUBSTITUTED AND THEIR PREPARATION. - Google Patents

Description

The present invention relates to substituted 1-pyridyloxy-3-indolyl-alkylamino-2-propanols and their preparation and relates to medicaments containing such compounds.

There is a very large bibliography relating to compounds of the 3- (aryloxy) -2-hydroxypropylamine series showing vasodilatory properties and / or a beta-adrenergic receptor blocking activity which are also useful for the treatment of diseases. cardiovascular. 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, from the chemical point of view, l- (isopropylamino) -3- (l-naphthyloxy) -2-propanol. Propanolol 20 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 others aromatic rings or heterocyclic systems replace the naphthyloxy group of propanolol.

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):

2

nhr in which:

R is an alkyl, phenalkyl, phenoxyalkyl radical; R1 is H,

40 O

C-L

with L being an alkyl or aryl radical;

R2 is H, CN, CF3, OH,

O

II

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, 55 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-cyanopyridine, also known under 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);

65 - 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).

661,512

4

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 22/11, 1284-1290 (1979)].

MK-761

ftKC (CH3), HCl

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 November 18, 1980;

- United States patent No. 4,314,943 issued February 9, 1982; and

- the journal Journal of Medicinal Chemistry, 23: 3, 285-289 (1980).

3 <h

O-Ar-Xn

(2)

20

O-Ar-Het

(3)

30

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

CN

MJ 13105

40

The subject of the invention is the compounds of general formula I having vasodilator properties showing a certain range of beta-adrenergic blocking power and also relates to the addition salts of acids acceptable from the pharmaceutical point of view. of these compounds of general formula IX

(I) 50

In this structural formula:

X is -CHO, -CN, -CF3, —CONRaRb, or -C02Rc. Ra and Rb, independently of one another, are a hydrogen atom or a radical Rc, Rc being a lower alkyl radical in Cx to C4, aryl or (lower alkyl) aryl, the aryl group being preferably a phenyl radical.

It is also preferred that X is linked in position 3 of the pyridine nucleus.

Y represents a second substituent on the pyridine nucleus and consists of a hydrogen or halogen atom or a lower C1-C4 alkoxy radical, (lower alkoxy) aryl, hydroxy, or O II

- C — O — alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms.

The entire pyridinyl group is associated with the indolylalkylaminopropoxy side chain in position 2 or 4 of the pyridine ring.

R is a hydrogen atom or a group O

II

C-L _

in which L is chosen from the group comprising alkyl radicals comprising 1 to 10 carbon atoms, phenyls, substituted phenyls or phenylalkyls.

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

C represents a substituent in the benzene ring of the indole and is chosen from the group comprising hydrogen and halogen atoms, lower alkyl, lower alkoxy or hydroxy radicals, the indolyl system being linked by its position 2 or 3 .

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 man. 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 hydrohalogenic 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, that is to say mixtures of enantiomers, for example racemic modifications, as well as individual enantiomers. These individual enantiomers are commonly designated according to the optical rotation they produce by (+) 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 compound, it is the racemic modification.

Biological tests carried out with the compounds having the formula I on animals show that they have potent vasodilator 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 sought-after association of the abovementioned 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 can be shown on various types of animals and in particular the antagonism of isoproterenol in the anesthetized dog and treated by intravenous route (adrenergic beta-receptor action), the spontaneously hypertensive rat and the hypertensive rat by action of DOCA salt (antihypertensive action), the type of rat with lymph nodes kept blocked by angiotensin (vasodilating action) and on various other animals and laboratory models [cf. Deitchman et al., Journal Pharmacologi-cal 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 not effective toxic of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. By effective amount is meant the dose which exercises the desired pharmacological activity

5

661,512

such as that mentioned above without giving rise to undue toxic secondary actions, when administered to mammals in need of such treatment. The doses vary according to the subjects, the route of administration chosen in a planned field of 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 pro-panol having a suitable substituent W or intermediate of nascent pro-panol (II):

General hydrolysis process

(IIC)

In the above general process:

D is a hydrogen atom, or preferably a phenyl radical;

G is the radical

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- (heteraryloxy) -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 Ha 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 neutralization of the hydrolysis mixture and recovery of 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 into 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 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, can consist of benzene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are between 60 and 200 ° C.

The course of the process in a single step involves the reaction of IV 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 1.

H, NG

(I) b

In the above-mentioned scheme, X, Y, R, R1, R2, A, B and C are such as 40 defined in formula I.

This process essentially involves heating the substituted halopyri-dine chosen with the suitable indolylalkylaminopropanol (IIB) suitable 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 liquids can be chosen as 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 55-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 hydroxy group are prepared by cleavage of the corresponding methoxy precursor as shown in reaction 2.

60

Reaction 2

OMe

BBr.

ch2ci2 '

661,512

6

Other synthetic methods leading to conversion to hydroxylated 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 indicated in the technical literature. The preparation of the trisubstituted pyridines which are related to them is described in US Patent 4,329,351 issued May 11, 1982 to Baldwin et al. and the entire content of which is indicated here for reference.

Intermediate indolylalkylaminopropanols (IIB; R = H), preferred synthetically produced intermediates are suitably prepared by reacting an appropriate substituted indolylalkylamine (III) with 3-chloro-1,2-propanediol in alcohol at reflux containing sodium carbonate. This process is illustrated by reaction equation 3.

Reaction 3

HO

+ H2N

OH

(III)

B (HB)

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 for suitable acylation such as an 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

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 methods, of which the above bibliographical references are given, are applicable to the preparation of other indolylalkylamine 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 an additional 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 lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may not be coated or may be coated by known techniques so as to prevent their disintegration and absorption in the gastrointestinal transit and thus ensure sustained action for a long period of time.

Liquid preparations suitable for parenteral administration include solutions of suspensions or emulsions of the compounds of formula I. The aqueous suspensions of the pharmaceutical dosage forms of the compounds of formula I contain the active ingredient in admixture with one or more excipients pharmaceutically acceptable and non-toxic known to be used with advantage in the manufacture of aqueous suspensions. Such excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia. 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 mineral oil , for example liquid paraffin. The suspensions may contain a thickening agent such as beeswax, fine hard paraf-45 or cetyl alcohol. Sweetening and fragrance 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 in accordance with the present invention, their method of preparation and their biological activity will appear in more detail on analysis of the following examples and of the appended claims 55 which are given by way of illustration only and should in no way be considered as limiting the invention as to its scope or its value. In the examples which follow, used to illustrate the abovementioned synthesis process, the temperatures are expressed in degrees Celsius (° C), and the boiling points are given 60 without correction. The characteristics of the nuclear magnetic resonance (NMR) spectra refer to the chemical shifts [8 expressed as parts per million (ppm)], tetramethylsi-lane (TMS) being used as a reference. The relative zones indicated during the various displacements of the 65 NMR H 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) broad singlet, (s) singlet, (m) multiplet or '(d) doublet.

7

661,512

The abbreviations used are DMSO-d6: deuterodimethyl sulfoxide, CDC13: deuterochloroform and otherwise are conventional. Infrared (IR) spectrum descriptions include only the 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 summaries

A. Intermediaries of formula III.

Example 1:

\ 3- (2-Amino-2-methylpropyl) -6-methoxyindole | fÄ '= R2 = Me, A and B = H, C = 6-MeO)

To 15.2 ml of an aqueous solution cooled to 25% of dimethylamine are added, successively and with stirring and continuous cooling, the following products:

- 16.9 ml of acetic acid,

- 7.2 ml of formaldehyde at 37%,

- 27 ml of 95% ethanol.

The resulting stirred solution is kept at - 5-0 ° C using a cooling bath while adding, in parts, 10.0 g (0.07 mole) of 6-methoxyindole. The mixture is stirred and gradually heated to 30 ° C over a period of 30 minutes then kept 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 MgSO 4 and concentrated until an oily brown residue is obtained. (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 with a melting point of 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 are washed with water, dried over MgSO4 and concentrated in vacuo until a residue is obtained. Recrystallization of the residue from an isopropyl alcohol / water mixture leads to 7.6 g (80% yield) of 3- (2-methyl-2-nitropropyl) -6-methoxyindole in the form of '' a brown solid with a melting point of 98-100 ° C

The nitropropylindole compound and activated Raney nickel (4.2 g) are combined in 80 ml of 95% ethanol and heated to reflux temperature. The heating is stopped at the moment when one begins to add dropwise 85% hydrazine hydrate (7.8 g) in 8 ml of 95% ethanol. 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 which solidifies slowly and is recrystallized from the ethyl acetate / isopropyl ether mixture, which leads to 4.2 g of product. with a melting point of 125-128 ° C.

Example 2:

2- (2-Amino-2-methylpropyl) indole (R '= R2 = Me, A, B and C = H)

A solution comprising 10.0 g (0.06 mole) of indole-2-carboxylic 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. 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 Et20. The solution

ethereal 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 concentrated filtrate 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.

3.0 g (0.01 mole) of the crude quaternary salt are combined with 2.0 g (0.05 mole) 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 the order of about 6, then subjected to extraction using Et 2 O. The ethereal extracts are combined, washed with water, dried over MgSO4 and concentrated until a dark residue is obtained which is chromatographed on a silica column, the eluent consisting of methylene chloride. 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-nitro-propyl) indole under 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 in accordance with the process used in example 1 above leads to the desired indolalkylamine 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.

Table I

r ~

b

Example

R1

R2

AT

B

VS

3

Me

H

3-H

Me

H

4

Me

Me

2-Me

H

H

5

Me

Me

2-H

H

5-Br

6

Me

Me

2-H

H

5-OMe

7

H

Me

2-H

H

H

8

H

Me

2-Me

Me

5-OPr

9

H

Me

3-Me

Me

5-Br

10

Me

Me

2-H

H

6-OMe

11

Me

H

2-And

H

4-C1

12

Me

H

2-H

H

7-OMe

B. Intermediaries of formula II.

Example 13:

Hydrate of 3 - {[2- (3-indolyl) -1,1-dimethylethyl] amino} -1,2-propanediol (IIB)

A mixture of 10.0 g (0.05 mole) of a, ct-dimethyl-P- (3-indolyl) -ethanamine, of 11.3 g (0.11 mole) of Na, C03, of 7, 0 g (0.06 mole) of 3-chloro-1,2-propanediol and 250 ml of EtOH is stirred overnight during reflux temperature. After cooling.

5

10

15

20

25

30

35

40

45

50

55

60

65

661,512

8

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; 7.7 g (55% yield) are thus obtained of a product whose 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 or a similar method, a variety of intermediates of formula IIB are readily obtained.

Product summaries Example 14:

2- {2-Hydroxy-3 - {[2- (1H-indol-3-y) -1, 1-dimethyl-ethyl-Jaminopropoxy} -3-pyridinecarbonitrile hydrochloride

(Y = H, X = CN, R = H, R 'and R2 = Me, A, B and C = H)

47.3 g (0.18 mole) of 3 - {[2- (3-indolyl) -1,1-dimethylethyl] amino} -1,2-propanediol and 7.6 g of a 57% dispersion in the oil (0.18 mole) of sodium hydride is 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 (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 and then the washing product is combined with the original EtOAc layer. The mixtures in EtOAc are dried over MgS04 and concentrated while hot to about half their volume. After cooling, they precipitate a solid which is isolated by filtration; about 41 g (62% yield) of the crude base product are thus obtained.

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 with a melting point of 181-183 ° C.

On analysis, for the product with the formula:

c21h24n4o2, hci we obtain the following result:

Calculated: C 62.92 H 6.29 N 13.98%

Found: C 62.85 H 6.29 N "14.04%

NMR (DMSO-d6): 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); 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 treating the crude base which has been synthesized above (2 g of crude base) with cyclami-que 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 from the methanol-acetonitrile mixture leads to the production of 2 g of a white solid whose melting point is 172-174 ° C.

On analysis, for the product with the formula:

c21h24n4o2, c6h13no3s we obtain the following result:

Calculated: C 59.65 H 6.87 N 12.89%

Found: C 59.74 H 6.77 N 12.82%

Example 15:

4- {2-Hydroxy-3- {[2- (1H-indol-3-yl) -1,1-dimethylethyl] amino} -propoxy} -3-pyridinecarbonitrile

Using the method of Example 14, using 10.4 g (0.04 mole) 5 of 3 - {[2- (3-indolyl) -1, 1-dimethylethyl] amino} -1,2 -propanediol, 1.7 g (0.04 mole) of sodium hydride, 550 ml of toluene, 5.5 g (0.04 mole) of 4-chloro-3-cyanopyridine [cf. Wieland and Biener, Chem. Berichte, 96, 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 an eraser. This gum is subjected to column chromatography on silica, eluted with methylene chloride (90 parts), methanol (10 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. The recrystallization of this material from ethyl acetate leads to 4.2 g of a white solid, the melting point is 126-128 ° C.

On analysis, for the product with the formula:

20

c21h24n4o2

we get the following result:

Calculated: C 69.21 H 6.64 N 15.38%

25 Found: C 69.41 H 6.75 N 15.65%

NMR (DMSO-d6): 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).

IR (KBr): 745,1010,1190,1290,1315,1455,1495,1520,1590, 30 2225, 2970 and 3400 cm "1.

Example 16:

2- {2-Hydroxy-3 - {[2- (1H-indol-3-yl) -1, 1-dimethylethyl] amino} -propoxy} -3-pyridinecarboxamide 35 Using a process similar to that which is indicated in Example 4 above, 10.5 g (0.04 mole) of 3 - {[2- (3-indolyl) -1, 1-dimethylethyl] amino} -1,2-propanediol, 1.7 g (0.04 mol) of sodium hydride, 400 ml of toluene, 5.6 g (0.04 mol) of 2-chloronicotin-amide, 0.11 g of 18-crown-6 ether and 13.8 g (0.1 mole) of powdered anhydrous K2CO3 40 are brought to react, which leads to the production of 17 g of a residual gum. This gum is chromatographed on a column of silica, 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 from 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 the drying in a vacuum oven lead to 4 g of a white solid with a melting point of 50 131-133 ° C.

On analysis, for the product with the formula:

c21h26n4o3

the following results are obtained:

55

Calculated: C 65.95 H 6.86 N 14.65%

Found: C 65.80 H 6.85 N 14.31%

NMR (DMS0-d6): 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). 60 IR (KBr): 740, 780,1100,1235,1430,1460,1585,1670,2970, 3330 and 3470 cm-1.

Example 17:

65 Conversion of methoxy derivatives to hydroxy derivatives - general procedures

The methoxy derivative is dissolved in methylene chloride and stirred under a nitrogen atmosphere, while maintaining the mixture

9

661,512

chilled using an ice bath. 3 equivalents of boron tribromide in a solution of methylene chloride are added dropwise. 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 charcoal, filtered and the cooled filtrate is made basic by adding ammonium dioxide until a pH of about 8 is obtained. The precipitate the resulting product is filtered, washed with water, dried and subsequently purified by chromatography on a column of silica gel and elution using 90 parts of CHCl 3, 10 parts of methanol and 1 part of NH4OH. 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 indolylalkylamine, it is possible to synthesize additional examples of the compounds of formula I, operating according to substantially the same procedures as those described above. Certain additional products, of formula I, capable of being synthesized are listed in Table II.

G in these formulas represents the group:

which is obviously a function of the intermediary III chosen (cf. examples 1 to 12).

Table II

Biological determination tests

These biological tests are used to determine the car-

dio-vascular of a number of compounds of formula I both in their vasodilator activity and in their beta-adrenergic blocking activity.

661,512

10

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, then 5 24 h 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 anesthetized rats 30 minutes after intravenous dosing 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 indications "active" and "inactive"

are values greater or less than this range of values.

Example 33: 25

The diastolic blood pressure and the responses of the heart rhythm to a fixed fixed dose of isoproterenol used as a control are determined before and then 15 minutes after administration of graduated doses of the test compound, the administration being administered intravenously over an interval. from 3 minutes to 30

anesthetized dogs. Part of a femoral artery and a vein are cauterized 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 the dogs ventilated mechanically (using the Hervard ventilator) using ambient air at a flow rate of 201 / minute and a volume jerk 20 ml / kg. The heart rate is monitored using a heart rate monitor 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 (micrograms / kg) causing a 50% inhibition of the result of isoproterenol.

The following abbreviations used in the present description and in the claims to which they give rise have the following meanings:

- Ph = phenyl group;

- Pr = propyl group;

- Me = methyl group;

- Et = ethyl group.

A convention generally used in modern chemistry and organic was used in this description. For structures of the alkyl type, the number of carbon and hydrogen groups has been indicated in short form. Thus, for example, formula I can be put in the following form:

R

Claims (22)

661,512 1. Compound presenting the formula Y GOLD B as well as its acid addition salts in which: X is chosen from the group comprising - CHO, - CN, - CF3, --CONRaRb, or - C02Rc with Ra and Rb independently of one another consisting of hydrogen or Rc; Rc being 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 C 1 -C 4 alkoxy radical (lower alkoxy) aryl, hydroxy, or O II C-O-alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms; the indolylalkylaminopropoxy side chain being associated with pyridine in position 2 or 4; R is a hydrogen atom or a radical O L consisting of an alkyl radical comprising from 1 to 10 carbon atoms, phenyl, substituted phenyl, or phenylalkyl; 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 indolyl ring is linked by its position 3. 4. A compound according to claim 2 or 3, wherein; X is a cyano or amido radical; Y is a hydrogen atom; 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-indol-3-yl) -1, l-dimethylethyl] amino} propoxy} -3-pyridine-carbonitrile or one of its pharmaceutically acceptable acid addition salts. 6. The cyclamic acid addition salt of the compound according to claim 5. 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- (1 H-indol-3-yl) -1,1-dimethylethyl] amino} propoxy} -3-pyridine- carbonitrile or one of its pharmaceutically acceptable acid addition salts. 9. A compound according to claim 1, consisting of 2- {2-hydroxy-3 - {[2- (1H-indol-3-yl) -1, 1-dimethylethyl] amino} propoxy} -3-pyridine-carboxamide or one of its pharmaceutically acceptable acid addition salts. 10. A compound according to one of claims 1 to 9 as a vasodilator. 11. Compounds according to one of claims 1 to 9 as agents for treating hypertension. 12. Pharmaceutical composition in the form of unit doses suitable for systemic administration to a mammal, characterized in that it comprises a pharmaceutically inert support and an amount of a compound of formula I according to one of claims 1 to 9. 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) -1, l-dimethylethyl] amino } propoxy} -3-pyridine-carbonitrile or a pharmaceutically acceptable acid addition salt thereof. 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, l-dimethylethyl] amino } propoxy} -3-pyridine-carbonitrile or a pharmaceutically acceptable acid addition salt thereof. 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-pyridine-carboxamide or a pharmaceutically acceptable acid addition salt thereof. 16. A method of preparing a compound of formula I according to claim 1, said method comprising (a) coupling a pyridine having a substituent Z of formula in which X and Y are as defined in claim 1 and Z is a hydroxyl group or a halogen, with a compound of formula 1 not Y wherein D is a hydrogen atom or a phenyl group, and R1, R2, A, B and C are as defined in claim 1, and wherein W is a halogen atom when Z is a hydroxyl group and W is a hydroxyl when Z is a halogen; and (b) converting the resulting product by hydrolysis under acidic conditions. 17. A method of preparing a compound of formula I according to claim 1, said method comprising coupling a pyridine having a substituent Z of formula IV indicated in claim 16, in which X and Y are as defined in claim 1 and Z is a hydroxyl group or a halogen, with a compound of formula (IIB) or wherein R1, R2, A, B and C are as defined in claim 1, and wherein W is a halogen atom when Z is a hydroxyl group and W is a hydroxyl when Z is a halogen. 18. A method of preparing a compound of formula I according to claim 1, said method comprising (a) coupling a pyridine having a substituent Z of formula IV indicated in claim 16, in which X and Y are such that 2 5 10 15 20 25 30 35 40 45 50 55 60 65 3 661,512 defined above and Z is a hydroxyl group or a halogen, with a compound of formula (IIC) in which W is a halogen atom, when Z is a hydroxyl group and W is a hydroxyl when Z is a halogen, and (b) heating the epoxyether obtained either as it is or in the presence of an organic solvent inert with respect to the reaction with an amide of formula hydroxy as a means for carrying out the process according to claim 17 . wherein R1, R2, A, B and C are defined in claim 1. 19. A process according to claim 17, in which W is a hydroxyl group, when Z is a halogen and said coupling comprises the heating of compounds IV with a compound IIB in the presence of a base, the reaction being carried out under conditions sweet in an inert organic liquid. 20. A method according to claim 16, wherein said hydrolysis under acidic conditions uses a dilute mineral acid whose concentration is between 0.1N and IN and at temperatures between 20 and 100 ° C, said method also including a recovery stage either (a) of the product of formula I as a free base for neutralizing the mixture of hydrolysis and recovering the precipitate, or (b) the acid addition salts which result therefrom by evaporation of the hydrolysis mixture or by reaction of the free base with an acid. 21. A process for the preparation of a compound according to claim 1, in which Y and / or C are a hydroxy group, characterized in that a compound of formula I is prepared according to the process for claim 17, in which Y and / or C are a methoxy group, and the methoxy compound obtained by the reaction is cleaved according to the following scheme 22. A compound having the formula IIB indicated in claim 17, wherein W is a halogen atom or a hydroxyl group; R is a hydrogen atom or a group O II C-L L being chosen from the group comprising the alkyl radical having from 1 to 10 carbon atoms, phenyl, substituted phenyl or phenylalkyl, and in which R1, R2, A and B independently of one another consist of an atom of hydrogen or a lower 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 the group