FR2543952A1 - HETEROCYCLIC HYDROCARBON COMPOUNDS BELONGING TO INDOLIC SERIES AND THEIR PHARMACOLOGICAL APPLICATION - Google Patents

Abstract

AS A NEW INDUSTRIAL PRODUCT, A COMPOUND PRESENTING THE FORMULA: (CF DRAWING IN BOPI) AS WELL AS ITS ACID ADDITIONAL SALTS IN WHICH: X IS CHOSEN FROM THE GROUP INCLUDING -CHO, -CN, -CF, -CONRR , OR -COR WITH R AND R INDEPENDENT OF ONE OF THE OTHER CONSISTING OF HYDROGEN OR R; R MAY BE A LOWER RADICAL ALKYL CONSISTING OF 1 TO 4 ATOMS OF CARBON, ARYL, OR (LOWER ALKYL) ARYL; Y IS A SECOND SUBSTITUTE FOR THIS PYRIDINE CORE AND CONSISTS OF AN ATOM OF HYDROGEN OR A RADICAL ALKYL OR HALOGURIA

Description

HETEROCYCLIC HYDROCARBON COMPOUNDS BELONGING

  INDOLIC SERIES AND THEIR PHARMACOLOGICAL APPLICATION

  The subject of the present invention is the hydrocarbon-based compounds

  terocyclics belonging to the indole series and having a substitute

  killing amino and refers to drugs containing such compounds.

  There is a very important bibliography on compounds

  3- (aryloxy) -2-hydroxypropylamine series showing vasomotor properties

  dilators and / or betaadrenergic receptor blocking activity.

  which are also useful for the treatment of cardio-

  vascular 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 a chemical point of view, 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol.

  Propranolol and certain naphthyloxypropanolamines which are

  United States Patent No. 3,337,628 of August 22, 1967 Many subsequent patents have been issued for carbocyclic ethers in which other aromatic rings or

  Heterocyclic systems replace the naphthyloxy group of propranolol.

  A number of patents have been issued to J J Baldwin

  This 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): ## STR2 ##

> O 4 HR

  Wherein R is alkyl, phenalkyl, phenoxyalkyl; R 1 is H, C-L with L being an alkyl or aryl radical; R 2 is H, CN, CF 3, OH, C-L, Cl, NO 2, F pyrrolyl, oxadiazolyl (L

having the meaning above).

  This set of Baldwin patents assigned 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-cyanopyridine, also known as

  denomination MK-761; it has undergone considerable subsequent studies and

  if it is described in particular in the following magazines and works: Sweet, et al The Journal of Pharmacology and Experimental Therapeutics,

211/1, 195-296 (1979;

  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).

  In-depth studies in humans have been performed, however, when MK-761 has been shown to have teratogenic properties in rabbits after chronic administration at high doses (see Journal of Medicinal Chemistry).

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

CN

MK-761

AN OH'C (CH 3) 3, HC 1

  A number of indol-3-yl-tert-butylaminopropanols (2,3) having hypertensive properties are described by Kreighbaum et al., In: U.S. Patent No. 4,234,595 issued Nov. 18

1980;

  U.S. Patent No. 4,314,943 issued February 9, 1982; and Journal of Medicinal Chemistry, 23: 3, 285-289 (1980), R 3 O 8 -Ar-Xn

YR 2 OH

R R

R 2

(2) R 3 O-Ar-Het X.

'' N "R 2 OH

R

  (3) A compound preferably employed in this group is represented by the compound of structure (2), designated under the name MJ 13105, also known as bucindolol, and sub-presently

  a number of clinical evaluations as to its anti-

hypertensive, i

N OH

H

MJ 13105

  The subject of the invention is a series of agents having vasodilating properties which reflect a certain range of beta-adrenergic blocking power and having the general formula I and also relates to the acid addition salts which are acceptable from the point of Pharmaceutical view of these compounds of general formula ## STR1 ## in this structural formula:

  X is CHO, CH 2 H, CN, CF 3, CON Ra Rb or C 02 R with R and R being

  c depending on each other of hydrogen or RC, where Rc is an arylalkyl, aryl or lower alkyl radical; Y is a hydrogen or halogen atom or an acyloxy, alkoxy, aralkyloxy, aryloxy or hydroxyl radical; Q R is a hydrogen atom or C-L group, L being selected from alkyl, aryl, arylsubstituted, or arylalkyl radicals; R 1, R 2, A and B being independently of each other selected from hydrogen atom or alkyl radical; and C may be a halogen atom or a hydrogen atom or a hydroxy group,

alkyl or alkoxy.

  The compounds preferably employed are those in which X is in a position

  3 pyridine ring and the indolylalkylaminopropoxy side chain

  is bound in position 2 of the pyridine ring.

  The invention covers compounds having the structural formula

  (I) above and its acid addition salts in the structural formula

turelle (I),

  X can be -CHO, -CN, -CF 3, -CON Ra Rb, or -C 02 Rc.

  Ra and Rb Ra and Rb independently of one another are a hydrogen atom or a radical Rc which may be a lower alkyl radical at

  C 4, aryl or (lower alkyl) aryl, the aryl group being preferably

preferably a phenyl radical.

  It is also preferred that X be bound at position 3 of the pyelone

ridine.

  Y represents a second substituent on the pyridine ring and may consist of a hydrogen or halogen atom or a lower (C 1 -C 4) alkoxy, (lower) alkoxy aryl, hydroxy or oC-C-Oalkyl radical in which the alkyl radical comprises from 1 to 6 atoms

of carbon.

  The entire pyridinyl group is associated with the side chain

  indolylalkylaminopropoxy at the 2-position of the pyridine ring.

  R 1 is a hydrogen atom or a groupC-LJ, wherein L is selected from the group consisting of alkyl radicals comprising 1 to 10

  carbon atoms, phenyl phenylsubstituted or phenalkyl 5.

  R 1, R 2, A and B consist, independently of one another, in hydrogen

or a lower alkyl radical.

  C represents a substituent in the benzo ring of indole and is selected from the group consisting of hydrogen and halon atoms

  gene, lower alkyl radicals, lower alkoxy or hydroxy.

  The indole part itself is preferably associated with the chain

  main side by its position 3.

  For the medical application, acid addition salts are preferred

  pharmaceutically acceptable in which the anion does not contribute

  not significantly increase the toxicity or phar-

  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

  conventional methods known and available to those skilled in the art.

  The most commonly 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 HC 1, H Br, HI, sulfuric acid, phosphoric acid and the like.

  lar. It should be noted that the compounds according to the present invention

  involve all Tormes of optical isomers, that is, mixtures of

  Examples of enantiomers are racemic modifications as well as individual enantiomers These individual enantiomers are commonly referred to according to the optical rotation they produce by (+) and (-), (1) and (d), or combinations thereof. 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 isomer designation is given for a compound

of racemic modification.

  Biological tests carried out with compounds having the

  mule I on animals show that they possess vasodilitic properties.

  powerful tutors at the same time as various degrees of blocking properties.

  beta-adrenergic receptors and intrinsic sympathomimetic activity

  Some preferred compounds give rise to the particular combination of

  The above-mentioned actions have been sought 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 utility of the compounds of formula I

2543952.

  can be shown on various types of animals including antagonism of isoproterenol in anesthetized and intravenously treated dogs (adrenergic beta-receptor action), spontaneously hypertensive rat and hypertensive action rat DOCA (antihypertensive action) the rat type with ganglions maintained blocked by angiotensin (vasodilator action) and on various other animals and laboratory models (see Deitchman, et al., Journal Pharmacological Methods, 3, 311321, (1980). no teratogenic or mutagenic action is associated with the compound of Formula I.

  For uses as antihypertensive agents, vasodilator

  and / or beta-adrenergic blockade, the drugs according to

  The present invention is administered systemically, both orally and parenterally, in an effective non-toxic amount.

  of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof

  The term "effective amount" means the dose which exerts the desired pharmacological activity such as that mentioned above without giving rise to undue toxic secondary actions.

  when administered to mammals requiring such treatment.

  The doses vary according to the subjects, the route of administration chosen in

  an expected range of about 0.1 mcg to 100 mg per kg body weight of

  Formula I or a pharmacologically acceptable acid addition salt thereof generally producing the desired therapeutic action. The compounds according to the present invention can be prepared by a large number of suitable general methods.

  coupling of a Z-substituted pyridine (IV) with a propanol having a sub-

  Proporbant (II) suitable or intermediate w: General process w 10 e

O

(IIA) \ hydrolysis / x'X

y w (-

<(I)

GOLD

(IV) (IIB)

  ## EQU1 ## (Ti C) In the above general process: D is an atom of hydrogen, or preferably a phenyl radical; 1 R 2 G is the radical

1 _

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

  and is a hydroxyl radical when Z is a halogen.

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

  with the intermediary carrying the halogen.

  This process employs methods known from the prepa-

  of substituted 1- (substituted amino) -3- (hetaryloxy) -2-propanols as

  in the above-mentioned patents and publications This process involves

  that 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-aninopropanediol (or halopropanol) of formula IIB, or

3) a glycidol of formula IIC.

  The reaction intermediate IV and Ia are converted to product I by hydrolysis under acidic conditions. This hydrolysis is performed in the presence of dilute mineral acid having a concentration of 0.1 N at 1 N at temperatures between 20 and 100. 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 hydrolysis mixture.

  free base with acid Purification is accomplished by the standard 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 such or in the presence of an organic solvent which is inert to the the reaction with an amine of the formula H 2 NG as indicated above No catalyst or condensing agent is required Suitable solvents may consist of 95% ethanol although other inert organic liquids the reaction in which the reagents are soluble can be used.

  non-limiting examples may be benzene, tetrahydro-

  furan, dibutyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are between

and 200 C.

  The one-step process involves the reaction of IV with IIB and this is the preferred route 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 above synthesis as reaction I. Reaction 1

R RA C

  Embedded image In the above scheme, X, Y, R, R 1, R 2, A, B and C are as defined in Formula I.

  This process essentially involves heating the halopyridine

  selected with the intermediate 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

  dium can be used even though sodium hydride is used

  In the same way, any inert organic liquids can

  may be selected as a reaction medium or cyanopyridine and indolylalkylaminopropanol may be reacted

  in the presence of the base As non-limiting examples of solvents con-

  Suitable benzene, toluene, tetrahydrofuran, dibutyl ether, dimethoxyethane, etc. The suitable reaction temperatures are between 20 and 80 ° C. The addition of a suitable crown ether, for example

  Example 18-crown-6 ether assists in carrying out the reaction.

  The products of formula I in which Y and / or C are hydroxy are prepared by cleavage of the corresponding methoxy precursor.

  as shown in reaction 2.

Reaction 2 Pl 2 e B Br y R 1 2

OR 2 OR

B O

B

  Other methods of synthesis leading to conversion into hy-

  Suitable hydroxyloxides, such as the hydrogenolysis of benzyloxy precursors, are well known to those skilled in the art and may also be applied in this case. Halopyridines suitable for carrying out this reaction are commercially available or can be prepared using the

  classical methods such as those indicated in the literature.

  The preparation of the corresponding trisubstituted pyridines is described in United States Patent 4,329,351, issued May 11, 1982 to Baldwin, et al., the entire contents of which are hereby incorporated by reference.

  is shown here for reference.

  Intermediate indolylalkylaminopropanols (IIB, R = H),

  Preferred synthetic products are prepared in a suitable manner.

  by reaction of a substituted indolylalkylamine (III) appropriate with

  3-chloro-1,2-propanediol in refluxing alcohol containing carbon

  sodium nate This process is illustrated by reaction equation 3.

Reaction 3

R 1 R 2

  C Base Ho A% <N Cl + H 2 N HO / C 1 + H 2 A Alcohol ,, OH

B B

(III) (IIB)

  In this reaction scheme 3, the groups R 1, R 2, 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 wherein R is a hydrogen atom with a suitable acylating agent such as acyl halide, inter alia undecanoyl chloride, pivaloyl chloride,

  benzoyl chloride, para-methoxybenzoyl chloride or anhy-

  such as acetic anhydride and the like The reaction is illustrated by the following reaction scheme indicated as reaction 4: Reaction 4

R R 2 C

Y <C e Y R-c-cl R 2 R 1 + or

OH, (R-C) O

  B t OR B Indolylalkylamines (If I) are described in patents and articles

  Kreighbaum, et al., the entire description of which is indi-

  here as a reference as well as the contents of the references that

  Although these methods are given bibliographic references, they are

  graphs above are applicable to the preparation of other indolyl-

  Intermediate alkylamines not specifically described but which are suitable

  as intermediates for the present invention, reference is made hereinafter

  below the synthesis of compounds of formula III as an additional example

  mentary. The compounds according to the present invention can be formulated into formulas suitable for conventional pharmaceutical uses to lead to

  obtaining pharmaceutical compositions and in particular in the form of

  unitsincluding, for example, pills, capsules, powders, granules, emulsions, suspensions and the like

  the active ingredient in admixture with pharmaceutically acceptable excipients

  non-toxic and non-toxic such as inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegrating agents such as, for example, starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents for example magnesium stearate, stearic acid or talc Tablets may not

  not be coated or coated with known techniques of

  avoid their disintegration and absorption in the transit

  trointestinal and thus ensure sustained action for a long time

period of time.

  Liquid preparations suitable for parenteral administration

  include suspension solutions or emulsions of

  The aqueous suspensions of 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 of advantage in the manufacture of aqueous suspensions. such excipients are, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone,

  gum tragacanth and gum acacia Agents for humidifying or degenerating

  are naturally occurring phosphates such as

  as for example lecithin, polyoxyethylene stearate.

  The 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 a mineral oil. for example liquid paraffin The suspensions may contain a thickening agent such as beeswax, hard paraffin or

  acrylic alcohol Sweetening and fragrance agents, generally

  in the pharmaceutical compositions, may also be

  taken such as saccharin, sodium cyclamate, sugar and caramel for

  lead to obtaining tasteful oral preparations.

  may also contain other absorption agents,

  stabilization, humidifying agents and buffers.

  The compounds according to the present invention, their method of

  preparation and their biological activity will appear in more detail

  analysis of the following examples and the attached claims which

  are given for illustrative purposes only and should in no way be considered as limiting the scope or value of the invention. In the examples which follow, used to illustrate the aforementioned synthesis process, the temperatures are expressed in degrees Celsius ( ),

  and the boiling points are given without correction The characteristics

  Nuclear magnetic resonance (NMR) spectra refer to chemical shifts <6 expressed as parts per million (ppm 4, with tetramethylsilene (TMS) being used as a reference. The relative areas indicated during the various data displacements of

  H NMR spectrum correspond to the number of hydrogen atoms of a functional type.

  The nature of displacements with respect to their multiplicity is indicated as (bs) singlet

  broad, (s) singlet, (m) multiplet, or (d) doublet.

  The abbreviations employed are DMSO-d 6: deuterodimethylsulfoxide, CD C 13:

  deuterochloroformnia and otherwise are classic descriptions of

  Infrared (IR) spectra include only the absorbing wave numbers

  tion (cm- ') having the functional group identification values. The infrared determinations are carried out on a medium in which the diluent is potassium bromide (K Br) Elemental analyzes

  are given as percentage by weight.

Intermediate syntheses

Intermediates of formula III.

EXAMPLE 1

  3- (2-amino-2-methylpropyl) -6-methoxyindole | (Ri = R 2 = Me, A and B = H, C = 6-Me O) To 15.2 ml of an aqueous solution cooled to 25% of dimethylamine are added, successively and with stirring and continuous cooling, the 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 ° C. with a cooling bath while 10.0 g (0.07 mole) of 6-methoxyindole is added in portions. The mixture is stirred and heated. gradually to 30 over a period of 30 minutes, then maintained at 30 C with stirring for 3 additional hours The reaction mixture is then cooled to 10-15 C and acidified by adding 170 ml of 2N hydrochloric acid. The acid mixture is discolored (Darco G-60), filtered and the filtrate is rendered

  with 245 ml of 20% NaOH while cooling and stirring.

  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 to a residue. oily brown (14 g) The residue is recrystallized from isopropyl ether and hexane to give 9 g (65% yield) of 6-methoxygramine as a brown solid.

  whose melting point 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 The reaction mixture is refluxed 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 MgSO 4 and concentrated under vacuum until a residue is obtained. Recrystallization of the residue from the isopropyl alcohol / water mixture gives 7.6 g (yield 80%) of 3- (2-methyl-2-nitropropyl) -6-methoxyindole as a brown solid having a melting point of 98-100 C. The compound of nitropropylindole and activated Raney nickel (4 2 g) are combined in 80 ml of 95% ethanol and heated to reflux temperature. The heating is stopped when hydrazine hydrate is started to be added dropwise. at 85% (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 to obtain a residual oil that slowly solidifies and is recrystallized from the acetate mixture

  of ethyl / etherisopropyl, which leads to the production of 4.2 g of

  duit having a melting point of 125-128 C.

EXAMPLE 2

  12- (2-amino-2-methylpropyl) indole (R1 = R 2 = Me, A, B, and C = H)

  A solution comprising 10.0 g (0.06 mole) of indole-2-carboxylic acid

  xyl and 20.0 g (0.17 mol) of thionyl chloride in 130 ml of Et 2 O.

  Dry is stirred for 12 to 18 hours at room temperature and under atmospheric pressure.

  The reaction mixture is filtered and the filtrate is then filtered.

  The ethereal solution is treated with 80 ml of dimethylamine in 90 ml of Et 2. The ethereal reaction mixture is concentrated to dryness and the residue is concentrated to dryness. crystallized residue in isopropyl alcohol The solid is isolated by filtration, thus obtaining 4.0 g (yield 34%) of 2-indolylamide

  whose melting point 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 aluminum hydride.

  lithium in 50 ml of THF under a nitrogen atmosphere.

  Refluxed for 2 hours, the reaction mixture was cooled and decomposed with a small amount of water and a dilute NaOH solution. The mixture was filtered and the filtrate concentrated until an oily residue was obtained. is taken up in absolute ethanol and treated with a slight excess of dimethyl sulphate. The resulting alcoholic solution is stirred at ambient temperature for 4 hours and then concentrated under vacuum to dryness; the quaternary salt of trimethylamine is thus obtained as a residue. 3.0 g (0.01 mol) of the crude quaternary salt are combined with 2.0 g (0.05 mol) of pellets of NaOH and 15 ml of 2-nitropropane, and the mixture is then heated at reflux temperature under an atmosphere of Nitrogen

  hour The resulting dark thick mixture is cooled, diluted by

  acidified to about pH 6, then extracted with Et 2

  are combined, washed with water, dried over MgSO 4 and concentrated

* that to obtain a dark residue that is chromatographed on a

  column of silica, the eluent consisting of methylene chloride

  methylene chloride and the recrystallization of the raw material from the isopropyl alcohol / water mixture gives 0.4 g of 2- (2-methyl-2-nitropropyl) indole in the form of a colored solid.

  creamy with a melting point of 102-103 C.

  The reduction of this nitrated product with Raney nickel and hydrazine according to the process used in the above Example 1, leads to the desired indoalkylamine in the form of a white solid of

melting point 130-133C.

  Additional examples of indolalkylamine are obtainable and are given in Table I. Table I Indolalkylamines 2 A C R H 2 N 1 R 2

B

  (III) EXAMPLE RR 2 ABC 3 Me H 3 -H Me H 4 Me Me 2-Me HH 5 Me Me 2 -HH 5-Br 6 Me Me 2 -HH 5 -O-M Me 7 H Me 2 -HHH 8 H Me 2-Me Me 5-O Me 9 Me Me 2 -HH 6 Me Me 2 Me H 2 -H 2 HH-HH 7 -O-Me

B. Intermediates of formula II.

EXAMPLE 13

  3- {1- (2- (3-Indolyl) -1,1-dimethylethylamino) -1,2-propanediol hydrate (IIB) A mixture of 10.0 g (0.05 mole) of a, a- dimethyl-B- (3-indolyl) ethanol

  11.3 g (0.11 mol) of Na 2 C 03, 7.0 g (0.06 mol) of 3-chloro

  1,2-propanediol and 250 ml of EtOH is stirred for one night at reflux temperature. After cooling, the mixture is filtered and then concentrated in vacuo. The residue is dissolved in EtOAc, decolourized at room temperature. 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; This gives 7.7 g (55% yield) of a product whose melting point is 112-114 C. This material crystallizes with a fifth

of mole of water.

  By using other intermediates of formula III, in this

  assigned or in a similar process, a variety of

intermediates of formula IIB.

Product overviews

EXAMPLE 14

  2- {2-Hydroxy-3- {1- (1H-indol-3-yl) -1,1-dimethylethyl) propoxy} -3-pyridinecarbonitrile hydrochloride (Y = HX = CN, R = H, RI and R); 2 = Me, A, B, and C = H) 47.3 g (0.18 mol) of 3- {1- (3indolyl) -1,1-dimethylethyllamino) -1,2-propanediol and 7.6 57% of the dispersion in oil (0.18 mol) 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 allowed to cool to room temperature while being stirred and successively added 0.5 g of 18-crown-6 ether, 62.1 g of anhydrous K 2 C0 3 powder in powder form (0.45 mole) and 25.0 g (0.18 mol) of 2-chloro-3-cyanopyridine, then the whole is stirred for an additional 42 hours. The concentration in dryness leads to a residue.

  that separates between a phase of hot water and Et O Ac After cooling

  at room temperature, the aqueous layer is separated, washed with water,

  of Et O Ac additional then the product of the wash is combined with the cou-

  The original Et O Ac mixtures in Et O Ac are dried on Mg SO 4

  and concentrated hot to about half of their volume After cooling

  they precipitate a solid which is isolated by filtration; we obtain

  thus about 41 g (62% yield) of the crude base product.

  The conversion of the base to the hydrochloride is carried out by

  solution in isopropyl alcohol of the base with HCl

  ethanolic Recrystallization of the crude hydrochloride in absolute ethanol leads to the production of a white solid whose melting point is 181 ° -183 ° C. For analysis, for the product having the formula:

C 21 H 4 N 402, HC 1

we obtain the following result:

C H N

  calculated: 62.92 6.29 13.98 found: 62.85 6.29 14.04 NMR (DMSO-d 6): 1.30 (6, s); 3.20 (4, mn); 3.99 (3, m); 6.02 '(1, d (4.0 Hz)); 7.30 (6, mn); 8.31 (1, dd (2.0, 7.6 Hz)); 8.51 (1, ddt 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.

  Preparation of Cyclamate The cyclamate can be prepared by treating the crude base 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 filtered. filtrate concentrated under vacuum; a residue is thus obtained which is crystallized in 10 ml of acetonitrile. The recrystallization of the crude salt in the methanol-acetonitrile mixture leads to obtaining

  2 g of a white solid whose melting point is 172-174 ° C.

  In the analysis, for the product having the formula: C 2 H 24 N 402, C 6 H 13 N 0 35, the following result is obtained:

C H N

  calculated: 59.65 6.87 12.89 found: 59.74 6.77 12.82

EXAMPLE 15

  4- {2-hydroxy-3-1-l- (1H-indol-3-yl) -1,1-

  1-dimethylethyl) aminolpropoxy} -3-pyridinecarbonitrile Using the method of Example 14, using 10.4 g (0.04 mole) of 3-tl 2- (3-indolyl) 1,1-dimethylethylamino. 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, Wieland, and Biener, Chem Berichte, 96, pp. 268-274, (1963)); 0.11 g of 18-crown-6 ether and 13.7 g (0.1 mole) of anhydrous K 2 C0 3 powder give 15 g of a substance having the appearance of an eraser. silica column chromatography,

  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

  whose melting point is 124-126 ° C. The recrystallization of this material

  in ethyl acetate leads to 4.2 g of a solid

  white with a melting point of 126-128 C.

  On analysis, for the product having the formula:

C 21 H 24 N 402

we obtain the following result:

C H N

  calculated: 69.21 6.64 15.38 found: 69.42 6.75 15.65 NMR (DMSO-d 6): 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 (K Br): 745, 1010, 1190, 1290, 1315, 1455, 1495, 1520, 1590, 2225,

2970, and 3400 cm-1.

EXAMPLE 16

  2- {2-hydroxy-3 - ({2- (1H-indol-3-yl) -1,1-

  dimethylethylamino} propoxy} -3-pyridinecarboxamide

  Using a procedure similar to that indicated in the Ex-

  above 4, 10.5 g (0.04 mol) of 3 - {{2- (3-indolyl) -1,1-dimethylethylamino} -1,2-propanediol, 1.7 g (0.04 mol) ) sodium hydride, 400 ml of

  toluene, 5.6 g (0.04 mol) of 2-chloronicotinamide, 0.11 g of

  6-ether and 13.8 g (0.1 mole) of anhydrous K 2 C0 3 powder are reacted, 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 crystallized in the a-

  ethyl acetate; 5.2 g of a material whose melting point is 68-72 ° C. and whose recrystallization in ethyl acetate is thus obtained.

  and drying in a vacuum oven leads to 4 g of a solution.

  white lide with a melting point of 131-133 C.

  On analysis, for the product having the formula:

C 21 H 26 N 403

we obtain the following result:

C H

  calculated: 65.95 6.86 14.65 found: 65.80 6.85 14.31 NMR (DMSO-d 6): 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));

, 85 (1, bs).

  IR (K Br): 740, 780, 1100, 1235, 1430, 1460, 1585, 1670, 2970, 3330

and 3470 cm-1.

EXAMPLE 17

  Conversion of Methoxy Derivatives to Hydroxy Compounds General Processes The methoxy derivative is dissolved in methylene chloride and stirred under a nitrogen atmosphere, while maintaining the mixture cooled using

  An ice bath is added dropwise 3 equivalents of trihydro-

  boron in a solution of methylene chloride.

  tion, the ice bath is removed and the reaction mixture

  at room temperature for 6-8 hours Cooled again

  the reaction mixture with an ice bath and then decomposing the

  reagent by adding an excess of H dropwise, which

  the production of a gummy material that precipitates the

  nageante 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 off, washed with water, dried and further purified by chromatography on a gel column.

  of silica and elution with 90 parts of CHCl 3, 10 parts of methacrylate

  and 1 part of NH 40 H The concentration of the fractions containing the

  duit leads to the production of a residue which is recrystallised in a

  ethanol-water mixture; the pure hydroxy derivative is thus obtained.

  Starting from the appropriate pyridine and indolylalkylamine, it is

  possible to produce, by synthesis, additional examples of

  Formula 1, practicing substantially the same procedures as described above Certain additional products, of formula I, which can be prepared synthetically are reported

in Table 2.

  G in these formulas represents the 9 roup: which is obviously a function of the intermediate III chosen (see examples 1 to 12).

TABLE 2

Exemplary Formula Exeniple Formula

F O> -NC

t, 3 o o # I F CNH Me I OH

CONH 2

OH CHO

-N O- '"1 NN

OH

F CN

N ON HO

CONH 2

OCCU i 3 O NG OH CF 3 OC Ph Ie O OH

N -CHO

11 (: :) NG

  OH CO OCE t i, O 19 23 Biological determination tests

  These biological tests are used to determine the cardio-

  of a number of compounds of formula I both in their

  vasodilator activity only in their beta-adrenergic blocking activity.

cal.

EXAMPLE 31

  The efficacy of antihypertensive agents, other than beta-adrenergic receptor blocking agents, is generally determined in

  the spontaneously hypertensive rat The blood pressure values are de-

  completed on animals previously tested and then 24 hours after oral doses of 50 mg / kg of test compounds The percentage of variation

  observed in the heart rhythm is also noted A fall of the pres-

  blood pressure in the range of 19 to 24 mm of mercury is considered "questionable". The "active" and "inactive"

  decreases greater or less than this value range.

EXAMPLE 32

  Ganglion rats maintained blocked by angiotensin are used.

  In percentile blood pressure tests in anesthetized rats 30 minutes after dosing with

  Intravenous routes are determined. The doses administered intravenously

  Venous contain the tested compound at a rate of 3 mg / kg body weight Limit activity is defined as 15 to 20% fall of the

  measured blood pressure 30 minutes after administration.

  "active" and "inactive" are higher or lower values

to this area of value.

EXAMPLE 33

  Diastolic blood pressure and cardiac rhythm responses at a fixed fixed dose of isoproterenol used as controls,

  are determined before and after 15 minutes after

  of the test compound, the administration being carried out intra-

  vein over a 3-minute interval to anesthetized dogs.

  Femoral artery and vein are cerebralized to determine blood pressure and to administer dissolved drugs in a solutional solution. Vaginulas are sectioned bilaterally in the mid-cervical region of the neck and mechanically ventilated dogs (at the same time). (using the Hervard respirator) using ambient air at a rate of / minute and a volume per spurt of 20 ml / kg. The heart rate is

  monitored with a cardiotachometer controlled by the pressure pulse.

  All measurements are recorded on a Beckman R612 recorder The effect of the drug is expressed in terms of cumulative doses

  (microgram / kg) causing a 50% inhibition of the result of the iso-

protérénol.

  The following abbreviations used in this description

  and the claims to which they give rise, have the

  following conditions: Ph = phenyl group; Pr = propyl group; Me = methyl group;

Et = ethyl group.

  A convention generally used in chemistry and organic

  modern has been used in this description for the structures of

  alkyl type, it is indicated by short, the number of carbon and hydrogen groups Thus, for example, the formula I can be put in the following form:

Y R R 2

CH CH 2 C

0 CHN 1 _ C

OR H 2

B

Claims (25)

  1. As a new industrial product, a compound having the formula: Y R C R 1 R 2 A GOLD (1) B   as well as its acid addition salts wherein: ab X is selected from the group consisting of -CHO, -CN, -CF 3, -CON Ra Rb, or -CO 2 RC with Ra and R independently one of the other consisting of   hydrogen or RC; Rc may be a lower alkyl radical   1-4 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 (1-4C) alkoxy, lower (lower) alkoxy, hydroxy, or (II) alkyl radical in which the alkyl radical comprises 1 to 6 carbon atoms, the indolylalkylaminopropoxy side chain being associated with pyridine at the 2- or 4-position: R is a hydrogen atom or a radical -CL, L consisting of an alkyl radical comprising from 1 to 10 atoms of carbon, phenyl, or phenalkyl, R 1, R 2, A and B independently of one another are hydrogen or lower alkyl, C is a substituent of the benzene ring of indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxy radical;   the indolyl system being bound by its position 2 or 3.   2. A compound according to claim 1 wherein the side chain   Indolylalkylaminopropoxy is bound to pyridine at the 2-position.   3. A compound according to claim 1 wherein the nucleus Dolly is bound by its position 3.   4. A compound according to claim 2 or 3 wherein: X is cyano or amido; Y is a hydrogen atom; R is a hydrogen atom; RI and R 2 are lower alkyl radicals; A and B are a hydrogen atom; C is a halogen atom, hydrogen atom, or a hydroxy, alkyl or alkoxy group.   5. A compound according to claim 1, consisting of 2- {2-hydroxy-   3 - {{2- (1 H -indol-3-yl) -1,1-dimethylethyl} amino} propoxy} -3-pyridinecarbonyl   trile or a pharmaceutically acceptable acid addition salt thereof.   6. The cyclamic acid addition salt of the compound according to sales 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-carbohydrate   nitrile or a pharmaceutically acceptable acid addition salt thereof.   9. A compound according to claim 1 consisting of 2- {2-hydroxy-   {{2- (1 H -indol-3-yl) -1,1-dimethylethyl} amino} propoxy} -3-pyridinecarboxa   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 a medicine to treat hypersion, any composition   containing one or more of the compounds according to any of the claims cations 1 to 9.   12 Pharmaceutical composition in the form of unit dosesconve-   systemic administration to a mammal, said composition   comprising a pharmaceutically inert carrier and a non-toxic amount   than a compound of formula I according to any one of the 1 to 9.   Pharmaceutical composition according to claim 12, characterized   in that the compound of formula I is 2- {2-hydroxy-3 - "{2- (1   3-yl-1, 1-dimethylethyl) amino} propoxy} -3-pyridinecarbonitrile or one of   its pharmaceutically acceptable acid addition salts.   Pharmaceutical composition according to claim 12, characterized   in that the compound of formula I is 4- {2-hydroxy-3 - {{2- (1-Hindol-3-yl-1,1-dimethylethyl} amino} propoxy} -3-pyridinecarbonitrile or one of   its pharmaceutically acceptable acid addition salts.   15. The pharmaceutical composition according to claim 12, characterized   in that the compound of formula I is 2- {2-hydroxy-3-fl {{2- (1H-   indol-3-yl) -1,1-dimethylethyl-amino-propoxy-3-pyridinecarboxamide or a   of its pharmaceutically acceptable acid addition salts.   Process for the preparation of a compound having the formula: x y RI 2 A C, OR MI) B   and its acid addition salts wherein X is selected from the group consisting of -CHO, -CN, -CF 3, -CON Ra Rb or -C 02 Rc with Ra and Rb independently of one of other consisting of   hydrogen or RC; Rc may be a lower alkyl radical   taking 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, (lower) alkoxy aryl, hydroxy, or C 1 -C alkyl radical in wherein the alkyl radical comprises from 1 to 6 carbon atoms; the indolylalkylaminopropoxy side chain being associated with pyridine in position 2 or 4; O R is a hydrogen atom or a -C-L radical, L being an alkyl radical having 1 to 10 carbon atoms, phenyl, or phenalkyl; R 1, R 2, A and B independently of one another are hydrogen or lower alkyl; C is a substituent of the benzene ring of indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkyl or hydroxy radical; and   the indolyl system being bound by its position 2 or 3, said process   (a) coupling a pyridine having a substituent Z of formula IV: y (IV) wherein 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 selected from the group consisting of the compound IIA, IIB and IIC: w IIA H W W N-G IIB: OR O W IIC   in which D is a hydrogen atom, a phenyl group and preferably   phenyl group; and G is the radical L R 1 R B   wherein: R 1, R 2, A, B, and C are as defined above; and 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 reacted with compound IV this forms an epoxy ether, the process then comprising an additional step of heating said epoxy ether as such, or in the presence of an organic solvent inert to the reaction with a amide of formula H 2 NG wherein G is as defined above so as to form said compound I. 17. A process according to claim 16 wherein said compound IIB, wherein W is a hydroxyl group, when Z is halogen and said coupling of step (a) comprises heating the   compounds IV with a compound IIB in the presence of a base, the reaction   under mild conditions in an inert organic liquid.   18. A method according to claim 16, wherein said   drolysis under acidic conditions employs a dilute mineral acid having a concentration of between 0.1 N and 1 N and at temperatures between 20 and 1000 C, said process also including a recovery step of: (a) product of formula I as a free base for neutralization of the mixture of hydrolysis and recovery of the precipitate, or   (b) the resulting acid addition salts by evaporation of the   hydrolysis mixture or by reaction of the free base with an acid.   19. A process according to claim 16, wherein Y and / or C in said products of formula I are hydroxy, said process comprising the process of claim 16 wherein said IIB compound is used and also including a cleavage step corresponding methoxy precursor by the reaction according to the following reaction scheme II: R 3 Y -C 2 c 2 OH tees OR B B   20. An intermediate compound of the preparation of the compound according to a   conque of claims 1 to 19 characterized in that it presents the formula y é x N O   and its acid addition salts, wherein X is selected from the group consisting of -CHO, -CN, -CF 3, -CON Ra Rb, or -C 02 Rc with Ra and Rb independently one of the other consisting of   hydrogen or RC; Rc may be a lower alkyl radical   taking 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 of C 1 to C 4, or (lower alkoxy) aryl, or hydroxy, or o O II C-0 alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms; and the indolylalkylaminopropoxy side chain being associated with pyridine in position 2 or 4.   21. An intermediate compound in the preparation of the compound according to any   conque claims claims 19 characterized in that it has the formula: y- O N-G   D and its acid addition salts wherein: X is selected from the group consisting of -CHO, -CN, -CF 3, -CON Ra Rb, or -C 02 Rc with Ra and Rb independently of one of other consisting of   hydrogen or RC; Rc may be a lower alkyl radical   taking 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 group of C 1 to C 4, or lower alkoxy aryl, or hydroxy, or o C -C 0 alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms; and the indolylalkylaminopropoxy side chain being associated with pyridine at position 2 or 4; D is a hydrogen atom or a phenyl radical, and is preferably a phenyl radical: G is a radical R 1 2 A C   Wherein R 1, R 2, A and B independently of each other are hydrogen or lower alkyl; C is a substituent on the benzene ring of indole and consists of a hydrogen or halogen atom 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 coupling a pyridine having a substituent Z of formula IV X X Bu (Iv) wherein X and Y are as defined in claim 20, and wherein Z is hydroxy or halogen with propanol having a substituent W or intermediate nascent propanol of formula IIA O 'N-G IIA   Wherein: D is a hydrogen atom or a phenyl radical and preferably a phenyl radical; and G is the radical R B   wherein R 1, R 2, A and B independently of one another are hydrogen or lower alkyl; C is a substituent on the benzene ring of indole and consists of a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxy group; and wherein W is a halogen atom and preferably chlorine when   Z is hydroxyl and W is hydroxyl when Z is halogen.   A process for preparing the compound of claim 21, which process comprises coupling a pyridine having a Z substituent of formula IV X   Y-S (IV) wherein X and Y are as defined in claim 21, and   wherein Z is a hydroxy group or a halogen atom with a   panol having a substituent W or an intermediate nascent propanol of formula IIC XK lic W IIC   in which W is a halogen atom, preferably chlorine, when Z   is hydroxyl and wherein W is hydroxyl when Z is a logéne.   24. An intermediate compound of the preparation of the compound according to   shell claims 11 to 9 caratérisé in that itpresent formula IIB   Wherein W is a halogen atom or a hydroxyl group; R is a hydrogen atom or a C-L group, L being selected from the group consisting of alkyl of 1 to 10 carbon atoms, phenyl, substituted phenyl or phenalkyl; and wherein G is the radical of formula R R 2 A c 1 I   B in which R 1, R 2, A and B independently of each other consist of a hydrogen atom or an alkyl radical, and C is a substituent on the benzene ring of the indole chosen in the group consisting of hydrogen and halogen atoms and   lower alkyl, lower alkoxy, or hydroxy group.   25. A process for preparing a compound according to claim 24 having the formula IIB: H W \ N-G   Wherein: W is a halogen or a hydroxyl group; and R is a halogen atom or a C-L group, L being selected from the group consisting of C 1 -C 10 alkyl, phenyl, substituted phenyl or phenalkyl; and wherein G is the radical of the formula R 1, R 2, R 2, R 2, A and B independently of one another are hydrogen or lower alkyl, and C is a substituent on the benzene nucleus of the indole chosen in the   group consisting of hydrogen and halogen atoms and radi-   lower alkyl, lower alkoxy, or hydroxy group, said process comprising reacting a compound of formula III A wherein A, B, R ', R 2, and C are as defined above, with a chlorine, 1,2-propanediol in alcohol at reflux temperature   and a base which is preferably sodium carbonate.