CH668593A5 - HETEROCYCLIC COMPOUNDS BELONGING TO INDOLIC SERIES AND THEIR PREPARATION. - Google Patents

Description

DESCRIPTION

The subject of the invention is starting compounds according to the definitions in claims 1, 2 and 5, for the preparation of the compounds of general formula I:

GOLD

having vasodilator properties showing a certain range of beta-adrenergic blocking power and also relates to the processes for their preparation according to the definitions in claims 3, 4 and 6. In the general formula I:

Xest -CHO, -CN, -CF3, - CONRaRb or -C02Rc. Ra and Rb, independently of each other, are a hydrogen atom or an Rc radical, Rc being a C1-C4 lower alkyl, aryl or (lower alkyl) aryl radical, the aryl group preferably being 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 C 1-4 alkoxy radical (lower alkoxy) aryl, hydroxy or

O

II

—C — O — alkyl in which the alkyl radical contains from 1 to 6 carbon atoms. The entire pyridinyl group is associated with the in-dolylalkylaminopropoxy side chain in position 2 or 4 of the pyridine ring.

R is a hydrogen atom or a group

~ 0

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 of 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.

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

General process

'-G

(IIA)

N-G

Hydrolysis

GOLD

(IIB)

h2ng

(IV)

(IIC) ^%

In the above general process:

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

B

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

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

W is a halogen, preferably chlorine when Z is a 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 halogen bearing intermediate.

This process employs methods known in the art for the preparation of 1- (amnosubstitutes) -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 indolylalkylaminepropanediol (or halopropanol) of formula IIB, or

3. a glycidol of formula IIC.

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668593

4

Reaction intermediate IV and 11a is converted to product I by hydrolysis under acidic conditions. This hydrolysis is carried out in the presence of dilute mineral acid having a concentration of 0.1 to IN at temperatures between 20 and 100 ° C. The product of formula I can be recovered as free base by neutralization of the mixture of hydrolysis and recovery of 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 epoxyether 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, may consist of benzene, tetrahydrofuran, dibutyl ether,

butanol, hexanol, methanol, dimethoxyethane, ethylene, glycol, etc. Suitable reaction temperatures are between 60 and 200 ° C.

The flow 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. 25

This process is illustrated by the following specific reaction equation which shows the method preferably used for the abovementioned synthesis as reaction 1.

Reaction 1 30

Reaction 2

CTfe

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 Pat. No. 4,329,351 issued May 11, 1982 to Baldwion et al. and the entire content of which is indicated here for reference.

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

Reaction 3

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 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 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, assists in carrying 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.

In this reaction scheme 3, the groups R1, R2, A, B and C are as defined in formula I.

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 which are given for illustrative purposes only and should in no way be taken 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 (°), and the boiling points are given without correction. The characteristics of the nuclear magnetic resonance (NMR) spectra refer to the chemical shifts [8 expressed as parts per million (ppm)], tetramethylsilane 65 (TMS) being used as a reference. The relative zones indicated during the various 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 trips

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668,593

for their multiplicity is indicated in the form (bs) broad singlet, (s) singlet, (m) multiplet, or (d) doublet.

The abbreviations used - DMSO-d6: deuterodimethylsulfoxide, 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 synthesis A. Compound of formula III

Method 1

3- (2-amino-2-methylpropyl) -6-methoxyindole (R1 = 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 continuous stirring and 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 ° 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 ° over a period of 30 minutes, then maintained at 30 ° with stirring for an additional 3 hours. The reaction mixture is then cooled to 10-15 ° and acidified by adding 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 °.

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 the 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. whose melting point is 98-100 °.

The compound of nitropropylindole and activated Raney nickel (4.2 g) is combined in 80 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 °.

Method 2

2- (2-amino-2-methylpropyl) indole (R1 = R? = 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 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 °.

The amide is dissolved in 100 ml of THF and the solution is added dropwise to a stirred suspension comprising 3 g of aluminum lithium 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; there is thus obtained, as residue, the quaternary salt of trimethylamine.

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 nitrogen atmosphere 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 lead 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 °.

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 °.

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

Table I

1

R

H.

2

Process

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

Example 1

Hydrate of 3 - [(2- (3-indolyl) -1, 1-dimethylethyl) amino] -1,2-propane-diol (IIB)

A mixture of 10.0 g (0.05 mole) of a, a-dimethyl-p- (3-indolyl) -ethanamine, of 11.3 g (0.11 mole) of Na2CO3, of 7.0 g (0.06 mole) of 3-chloro-1,2-propanediol and 250 ml of EtOH is stirred overnight over 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 substantial deposit

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668 593 6

into a white solid which is recrystallized from EtOAc; Thus, using other intermediates of formula III,

7.7 g (55% yield) of a product whose melting point is a process or in a similar process, an easily obtained

112-114 °. This material crystallizes with a fifth of a mole of water. variety of intermediaries of formula IIB.

R

Claims (10)

668593 1 „2 "c m GOLD B 1 —C — O — alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms, and the oxazolylmethyloxy side chain of the formula: - ^ Vi Y N-G Y D being associated with pyridine in position 2 or 4; D is a hydrogen atom or a phenyl radical, and G is a radical: wherein R1, R2, A and B, independently of each other, consist of hydrogen or a lower alkyl radical; 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. 1. A compound having the formula: »VM (v) and its acid addition salts, in which: X is chosen from the group comprising —CHO, —CN, —CF3, —CONRaRb or —COzRc 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 nucleus and consists of a hydrogen or halogen atom or a lower C1-C4 alkoxy or (lower alkoxy) aryl, or hydroxy, or O II —C — O — alkyl in which the alkyl radical comprises from 1 to 6 carbon atoms, and the 2,3-epoxypropoxy side chain being associated with pyridine in position 2 or 4. 2. A compound with the formula: - & V, 0M Y N-G Y D and 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 aryl lower alkyl; Y is a second substituent of this pyridine ring and consists of a hydrogen or halogen atom or a lower Ct to C4 alkoxy radical, or lower aryl or hydroxy alkoxy, or 0 2 claims 3 668,593 in which: 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 a hydrogen atom 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 hydroxy groups. 3. Compound according to claim 2, characterized in that D is a phenyl radical. 4. A process for the preparation of the compound according to claim 1, said process comprising the coupling of a pyridine having a substituent Z of formula IV: .X (IV) Wherein X and Y are as defined in claim 1, and wherein Z is hydroxy or halogen with a propanol having a substituent W or nascent propanol intermediate, of formula IIA: Y N-G (IIA) in which: D is a hydrogen atom or a phenyl radical and G is the radical: (VI) 30 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 in which W is a halogen atom when Z is a hydroxyl 40 and W is a hydroxyl when Z is a halogen. 5. Method according to claim 4, characterized in that D is a phenyl radical. 6. A process for the preparation of the compound according to claim 2, said process comprising the coupling of a pyridine having a 45 substituting Z of formula IV: , X (IV) wherein X and Y are as defined in claim 2, and wherein Z is a hydroxy group or a halogen atom with a propanol having a substituent W or an incipient nascent propanol of formula IIC: 55 „^ o (IIC) in which W is a halogen atom when Z is a hydroxyl and in which W is a hydroxyl when Z is a halogen. 60 7. Method according to claim 4 or 6, characterized in that W is a chlorine atom. 8. A compound having the formula IIB: 9. A process for the preparation of a component having the formula IIB, indicated in claim 5, characterized in that a compound of formula III is reacted: 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. 10. Method according to claim 9, characterized in that the base consists of sodium carbonate.