MC511A1 - New heterocyclic compounds and their preparation - Google Patents

Description

HAS

©

Av fX'

CASE: 1915

SPj (f/j) o 2. S-$-

New heterocyclic compounds and their preparation.

-O-O-O-O-O-O-O-O-O-O-O-O-

The present invention relates to new heterocyclic compounds

corresponding to the general formula I

1

8

r2-

9bXV

NX /'5a -V

7Y N

6 5"| 4

i iL

N-R<

/<4a 3

(I)

in which

R.| represents a hydrogen atom, a lower alkyl or hydroxyalkyl group, or the benzyl group; R2 represents a hydrogen or halogen atom or a lower alkyl group; and

represents a phenyl group, possibly bearing a chlorine atom or a methyl group. Other possible combinations include: methylthiol group, benzyl group, pyridyl group, pyridylmethyl group, thienyl group,

as well as the salts that these compounds form with acids.

The invention also relates to a method for preparing these new compounds, a method in which a 1,2,3,4,4a,9b-hexahydro-5H-indeno/~1,2-c_7"pyridine-(5)-one corresponding to the general formula II is reacted

v \ / »

^ ~VJ\ 's/

1

(II)

11

0

in which

R2 has the meaning indicated above and

R'.| represents a lower alkyl group or the benzyl group, with an organometallic compound corresponding to the general formula III

Sea-

(III)

in which Rg has the meaning given above and Me represents the lithium atom or a halogen-magnesium remnant, the reaction product is hydrolyzed to obtain 1.2.3.4.4a.9b-hexahydro-5H-indeno/~"l ,1-cJJ-pyridine-(5)-ol corresponding to the general formula IV,

/v

N-R»

1

(IV)

HO

R,

- 3 -

Then

15

a) When we want to obtain a compound of formula I in which there is a lower alkyl group or the benzyl group, we dehydrate the compound of formula IV,

b) when R'^ is the methyl group and we want to obtain a compound of formula I in which R1 is hydrogen, we treat the compound of formula IV with an alkyl chloroformate, we remove by hydrolysis the alkoxy-carbonyl group thus created in position 2 and we dehydrate the secondary amine formed corresponding to the general formula V,

b') if desired, the secondary amine of formula V obtained above is reacted with a hydroxyalkylating agent or with a benzyl halide, so as to obtain a compound of formula I in which is a lower hydroxy-alkyl group or the benzyl group,

and we may transform the compounds obtained under a), b) and b') into their acid addition salts.

(V)

HO

R

'3

The present process can advantageously be carried out as described below.

A solution of a compound of formula II in an anhydrous organic solvent is added drop by drop to a solution of the compound of formula III in the same solvent or in another anhydrous solvent, and

To complete the reaction, the reaction mixture is stirred for approximately 1 hour at 0-20°C or boiled for a period of time. After hydrolyzing the reaction product at room temperature with an aqueous ammonium chloride solution, it is extracted with an organic solvent, then isolated and purified in the usual manner. The water removal reaction is then carried out, for example by heating with a mineral acid, such as concentrated hydrochloric acid, or with a strong organic acid, such as acetic anhydride, thionyl chloride, or phosphorus oxychloride, thus yielding a final product corresponding to formula I, in which the lower alkyl group or the benzyl group is represented.

To obtain final products of formula I, in which R is a hydrogen atom, one starts with compounds of formula IV, in which R' is the methyl group: for example, 2-methyl-5-phenyl-1,2,3,4,4a,9b-hexahydro-5H indeno-1,2-c-7pyridine-(5)-ol is reacted under heat in an inert organic solvent, such as benzene or toluene, with an alkyl chloroformate, and the isolated 2-alkoxycarbonyl compound, possibly purified by crystallization, is then removed by heating in a solution

basic alcoholic, preferably in a n-butanolic solution of potassium hydroxide.

The compounds of formula V thus obtained, which contain a secondary amino group, can be subjected to the water removal reaction, as already mentioned above. This yields final products of formula I, in which hydrogen is present.

But they can also be reacted with an alkylene oxide, for example with ethylene oxide or propylene oxide, or heated with chloropropanol or a benzyl halide in the presence of an alkali carbonate, a tertiary amine, or a second mole of the compound, for example in absolute ethanol. One mole of water is removed from the 2-(hydroxyalkyl)- or 2-benzyl-1,2,3-15 4,4a,9b-hexahydro-5H-indeno/1,2-c-7"pyridine-(5)-ol obtained by heating it with a strong acid, preferably methanolic hydrochloric acid, and a final product of formula I is thus obtained, in which R represents a lower hydroxyalkyl group or the benzyl group.

The new compounds corresponding to formula I are basic substances which, with mineral or organic acids, form stable and crystalline salts at room temperature. For the formation of salts, examples of mineral acids include hydrochloric acid, hydrobromic acid and sulfuric acid, and examples of organic acids include malonic acid, fumaric acid, maleic acid, tartaric acid, malic acid, naphthalene-1,5-disulfonic acid, cyclohexanecarboxylic acid, benzenesulfonic acid and p-toluenesulfonic acid.

Compounds of formula I possess valuable pharmacodynamic properties, and that is why

- 6 -

They can constitute active substances in medications. Thus, they exhibit sedative and neuroleptic properties, while having only low toxicity. For example, they potentiate nar-5s and inhibit conditioned responses and

emotional as well as motor activity. These properties are very pronounced, particularly in the case of 2-methyl-5-phenyl-1,3,4,9β-tetrahydro-2H-indeno-1,2-c-7pyridine. The compounds of the invention also have adrenolytic properties. They are preferably administered in the form of their water-soluble salts, which are physiologically tolerated.

For use as medicinal products, new compounds may be presented either as is or in suitable drug forms for enteral or parenteral administration. To prepare such forms, the active compounds are processed with pharmacologically inert mineral or organic excipients. Examples of excipients used include:

For tablets and coated tablets: lactose, starch,

talc, stearic acid, etc...

For injectable preparations: water, alcohols, glycerol, vegetable oils, etc...

The preparations may also contain appropriate preservatives, stabilizers, wetting agents, dissolving aids, sweeteners, colorings, flavoring products, etc.

It is understood that the present invention does not relate to the bodies described when used in therapy.

The starting bodies of formula II are new and they can be prepared as described in the following paragraph.

An alkyl ester of 1-alkyl- or 1-benzyl-β-isonipecotinic acid corresponding to formula VI is reacted

/Ntf-R'

R400cix J ('VI')

^ 'V/

in which R'^ has the meaning indicated above and R4 denotes a lower alkyl group, with a Grignard compound corresponding to formula VII

,■<^1 -Mg-Br l !

(VII)

in which R2 has the meaning indicated above, the reaction product is hydrolyzed and the alkyl ester of isonipecotinic acid formed corresponding to formula VIII is cyclized

\ /\]-R'

R4OOC

-f IN-I* 1

J (VIII)

either by passing through the free acid and the acid chloride with the help of aluminium chloride, or directly by means of polyphosphoric acid, cyclization which produces a compound corresponding to formula II.

The following examples illustrate the present invention without in any way limiting its scope.

The temperatures given are uncorrected.

EXAMPLE 1 s

2-methyl-5-phenyl-1.3,4.9b-tetrahydro-2H~ indeno^ 1.2-cJ7pyridine.

a) 2-methyl-5-phenyl~1.2.3.4.4a.9b-hexahydro-5H-indeno/"" 1.2-c_7pyridine-(5)«-ol.

To a phenyl-magnesium bromide solution, prepared from 1.46 g of magnesium turnings and 9.4 g of bromobenzene in 25 ml of absolute ether, a solution of 5.04 g of 2-methyl-

/in 40 ml

1.2.3.4 «4a. 9b-hexahydro-5H-indeno/ 1 «2-c_7'pyridine-(5)-on^ of absolute tetrahydrofuran. After which, the whole is boiled for 2 hours at reflux temperature, then cooled and the reaction mixture is poured into 100 ml of a 10% ammonium chloride solution. Extracted with methylene chloride, the organic phase is dried over magnesium sulfate, the solution is evaporated, and the residue is recrystallized from ethanol. The compound obtained melts at 190-191°.

b) 2-methyl-5-phenyl-1.3.4.9b-tetrahydro-2H-indeno/"~1.2-c__7pyridine.

Four to six grams of the compound obtained in step a) are boiled under reflux for 1 hour with a mixture of 40 mL of concentrated hydrochloric acid and 20 mL of water. The mixture is then evaporated under reduced pressure, and the residue is recrystallized in ethanol. The resulting hydrochloride melts at 211–212°C (with decomposition). The base prepared from the hydrochloride melts, after crystallization in isopropanol, at 113–114°C.

The 2-methyl-1.2.3.4.4a.9b-hexahydro-5H-indeno/""! .2-c_7pyridine-(5)-one used as the starting material is prepared in the following manner.

- 9 -

To a solution of phenyl-magnesium bromide, prepared from 21.8 g of magnesium turnings, 140 g of bromo-benzene and 500 ml of ether, add drop by drop, while stirring at a temperature

5. Temperature between -15 and -10°C, a solution of 69.5 g

/ 3

1-methyl ester of 1-methyl-1/2-isonipecotinic acid is mixed in 150 ml of ether. The mixture is then stirred for another 30 minutes at -10°C, and the mixture is poured into 1 liter of a 20% ammonium chloride solution. The etheric layer is separated and extracted with 1 liter of cold 5% hydrochloric acid. While cooling thoroughly, the aqueous extract is alkalized with potassium carbonate, and then extracted again with ether. After drying over magnesium sulfate, the ether is removed by distillation, and the residue is distilled under high vacuum.

The methyl ester of 1-methyl-3-phenylisonipecotinic acid (mixture of stereoisomers) distills at 135-

99

136° under 0.5 mm of mercury, n = 1.5235. We heat

D

For 2 hours, 60 g of the preceding compound is reacted with 325 mL of 20% hydrochloric acid. 125 mL of liquid is then slowly distilled off. The residue is then evaporated under reduced pressure and thoroughly dried. Afterward, the residue is covered with 150 mL of thionyl chloride and the solution is stirred for 2 hours at room temperature. The excess thionyl chloride is then removed under reduced pressure, the residue is dissolved in 350 mL of tetrachloroethane, 100 mL is removed by distillation under reduced pressure to completely eliminate the thionyl chloride, and 67 g of 40% aluminum chloride is added and the mixture is stirred for 1 hour. The reaction mixture is poured onto 1 liter of approximately normal hydrochloric acid. The solution is extracted twice with ether, and the

- 10 -

The mixture is extracted with ether, then alkalized with a 50% caustic potassium hydroxide solution and extracted three times with ether. After drying over magnesium sulfate and evaporation of the ether, the crystallized residue is recrystallized in hexane. The resulting 2-methyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/2-cj__7'pyridine-(5)-one melts at 94-96°C.

EXAMPLE 2 • .

2-methyl-5-benzyl~1.3.4.9b-tetrahydro-2H-indeno-1 .2-c__7pyridine.

10 A solution of benzyl chloride-

Magnesium, prepared from 7.3 g of magnesium turnings, 38 g of benzyl chloride, and 150 mL of ether, is combined with a solution of 12.08 g of 2-methyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/~1,2-c-7pyridine-(5)-one in 150 mL of anisol. The ether is then removed by distillation, the mixture is boiled under reflux for 16 hours, the reaction mixture is cooled, and it is poured into 500 mL of a 10% ammonium chloride solution and extracted with ether. The ether solution is extracted three times, each time with 50 mL of dinormal hydrochloric acid. To this extract, 100 mL of concentrated hydrochloric acid is added, and the mixture is boiled under reflux for 1 hour. Next, the mixture is cooled, the precipitated hydrochloride is separated by filtration, dried, and recrystallized in methylethanol. The hydrochloride of 2-methyl-5-benzyl-1,3,4,9β-tetrahydro-2H-indeno/7μl 2-c-7pyridine melts at 238°C (with decomposition). The citrate melts at 135-137°C (with decomposition).

EXAMPLE 3:

30 2-methyl~5-/_ pyridyl-(2)-methyl_7-1.3.4.9b-

tetrahydro-2H-indeno/~ 1.2-c_7pyridine.

a) 2-methyl-5-/pyridyl-(2)-methyl_7*-1.2,3.4.4a.9b-hexahydro-5H-indeno/~1.2-c_/pyridine-(5)-ol.

û

To a phenyl-lithium solution, prepared from 1.4 g of lithium, 15.7 g of bromo-benzene and 75 ml of ether, 9.5 g of 2-methyl-pyridine is added drop by drop, at room temperature. The mixture is heated under reflux for 30 minutes, then cooled, and a solution of 10.06 g of 2-methyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/~" 1,2-cJ-pyridine-(5)-one in 40 mL of absolute tetrahydrofuran is added dropwise. The mixture is boiled under reflux again for 1 hour, cooled once more, and poured into 250 mL of dinormal hydrochloric acid. The solution is extracted with ether, the ether extract is discarded, then alkalized with sodium hydroxide solution and extracted with methylene chloride. After drying over potassium carbonate and evaporation of the solvent, the residue is chromatographed on 750 g of Broclmann's alumina, with elution carried out using methylene chloride. The first 600 mL still contain the starting compound; the next 3.5 liters contain the 2-methyl-5-/~pyridyl-(2)-methyl_7~1.2.3.4.4a.9b-hexahydro-5H-indenoJ/ 1.2-c_7"-pyridine-(5)-ol oily. 9.6 g of this oil are dissolved in 25 ml of methanol. Then 9.3 g of naphthalene-1,5-disulfonic acid are added and complete dissolution is achieved by heating. Upon cooling, the naphthalene-1,5-disulfonic acid crystallizes immediately; recrystallized in water, it melts at 245-250°C (with decomposition).

b) 2-methyl-5-/~pyridyl-(2 )-methyl_J7'-1 .3.4.9b-tetrahydro-2H-indeno/~ 1 .2-c_7pyridine.

15 g of the salt obtained according to example 3 a) is boiled under reflux for 1 hour with 150 ml of 20% hydrochloric acid. Then it is cooled, alkalized with a 40% sodium hydroxide solution, and the sodium nanhtalene-1.5-disulfonate is separated.

The base is sparingly soluble and extracted with methylene chloride. After drying over sodium sulfate and evaporation of the solvent, the oily base is dissolved in 10 mL of ethanol, and the amount of hydrochloric acid calculated for the formation of the monohydrochloride is added to the solution (e.g., 6.7 g of the base, 12.1 mL of dinormal hydrochloric acid). The solution is then evaporated to dryness under reduced pressure, and the residue is recrystallized from ethanol. The hydrochloride of 2-methyl-5-pyridyl-(2)-methyl-1,3,4,9β-tetrahydro-2H-indeno/1,2-c/pyridine melts at 205°C (with decomposition).

Acid fumarate, recrystallized in ethanol, melts at 181-182° (with decomposition).

EXAMPLE 4:

2-methyl-5-p-chlorophenyl~1.3.4.9b-tetrahydro-2H-indeno1 .2-cJ/pyridine.

a) 2-methyl-5-p-chlorophenyl-1.2,3.4,4a.9b-hexahydro-5H-indeno/~ 1 .2-c_7pyridine-(5)-ol.

A small grain of iodine and 5 mL of a solution of 65 g of p-chlorobromobenzene in 100 mL of absolute tetrahydrofuran are added to a suspension of 8.C2 g of magnesium in 25 mL. The mixture is heated until the reaction begins, then the heating bath is removed and the remainder of the solution is added rapidly enough to maintain a constant boiling point. The mixture is then heated under reflux until all the magnesium is dissolved (approximately 1 hour), cooled to room temperature, 50 mL of methylene chloride is added, and the mixture is cooled to -50°C. At this temperature, a solution of 20.1 g of 2-methyl-1.2.3,4.4a.9b-hexahydro-5H-indeno/~1.2-c_Jpyri-dine-(5)-one in 50 ml of methylene chloride is added dropwise, with thorough stirring, and

Continue stirring for another hour at 0-20°C. Then pour the reaction mixture into a solution of 80 g of ammonium chloride in 300 ml of water and 200 g of ice. After three extractions with methylene chloride, dry the combined extracts over potassium carbonate and evaporate the solvent. Recrystallize the residue in acetone. The resulting compound melts at 162-164°C.

b) 2~methyl-5-p~chlorophenyl-1.3.4,9b-tetrahydro~ 2H-indeno/~ 1.2-cJ/pyridine.

Five grams of the compound obtained in step a) are heated under reflux for 1 hour with 25 mL of 2.5-n methanolic hydrochloric acid. The mixture is evaporated under reduced pressure, and the residue is recrystallized twice in ethanol. The hydrochloride melts at 224–230°C (with decomposition). The base prepared from the hydrochloride melts at 106–107°C after being recrystallized in hexane.

EXAMPLE 5:

2-metnyl-5-m-chlorophenyl-1.3,4.9b-tetrahydro-2H-indeno/~1»2-c_7pyridine.

a) 2-methyl-5-m-chlorophenyl-1.2.3,4.4a.9b-hexahydro-

5H-indeno/~" 1.2-c_7pyridine-(5)-ol.

This compound is prepared like the compound in Example 4 a); instead of p-chlorobromobenzene, m-chlorobromobenzene is used. Its melting point, after recrystallization in ethanol, is 185-187°.

b) 2-methyl-5-m-chlorophenyl-1,3,4,9b-tetrahydro-

2H-indeno/]~ 1 ^-cJTpyridine.

Five grams of the compound obtained in step a) are heated under reflux for 1 hour with 25 mL of 2.5-n methanolic hydrochloric acid. After evaporation under reduced pressure, the residue is dissolved in water, the solution is alkalinized with caustic soda, and it is extracted with methylene chloride. After drying the extract

After evaporation of the solvent over potassium carbonate, the residue is distilled under high vacuum. The thick oil, which passes through 0.05 mm of mercury at 150-200°C (bath temperature), is dissolved in ethanol, and the calculated amount of maleic acid is added to the solution. Upon cooling, the acidic maleate crystallizes; when recrystallized in ethanol, it melts at 147-148°C.

EXAMPLE 6:

2-methyl-5-o-tolyl-1.3.4.9b-tetrahydro-2H-indeno/-1.2-c_7"pyridine.

a) 2-methyl-5-o-toly1-1.2,3.4.4a.9b-hexahydro-5H-

indeno/"1 .2-c_7pyridine~(5)-ol.

This compound is prepared like the compound described in Example 4 a), but starting from o-bromo-toluene. Recrystallized in ethyl acetate it melts at 171-172°.

b) 2-methyl-5-o-tolyl-1,3,4,9b-tetrahydro-2H-

indeno/" 1 .2-c_7pyridine.

The preparation of this substance is carried out as in example 4b). Its hydrochloride, recrystallized in ethanol, melts at 233-237°C (with decomposition). EXAMPLE 7:

2-methyl-5-p-methoxy-phenyl-1,3,4,9b-tetrahydro~ 2H~indenoJ/ 1 .2-c_7pyridine.

a) 2-methyl-5-p-methoxy-phenyl-1,2,3,4,4a,9b-

hexahydro-5H-indeno/1.2-c_J7pyridine-(5)-ol.

The procedure is as described in example 4 a), but using p-bromo-anisol. Recrystallized in ethyl acetate, the resulting compound melts at 172-174°.

b) 2-methyl-5-p-methoxy-phenyl-1,3,4,9b-tetrahydro-

2H-indeno/1.2-c_7pyridine •

This compound is prepared as described in Example 4 b). Its hydrochloride, recrystallized in a 9:1 mixture of isopropanol and water, melts at 198-204°

- 15 -

(with decomposition).

EXAMPLE 8:

2-methyl-5-p~methylthio-phenyl-1.3.4.9b-tetrahydro-2H-indenoi/f"1 .2~c_7pyridine.

5 a) 2-methyl-5-p-methylthio-phenyl-1.2.3.4.4a.9b-hexahydro-5H-indeno/~" 1 ,2-cJ/rpyridine-(5)-ol.

This compound is prepared by operating as described in Example 4 a), but using p-bromo-

Thio-anisol. Recrystallized in ethyl acetate,

10 it melts at 174-176°.

b) 2-methyl-5-p-methylthio-phenyl-1.3,4.9b-1-tetrahydro-2H-indeno/~ 1,2-c__7pyridine.

For the preparation of this substance, the procedure is as described in example 4 b). The hydrochloride melts at 15,189-191° (with decomposition) after being recrystallized in isopropanol.

EXAMPLE 9

2-methyl-5-pyridyl-(2)-1,3,4.9b-tetrahydro-

2H-indeno/f"1 .2~cJ7pyridine.

20 a) 2-methyl-5-pvridyl-(2)-1 .2 .3 .4^a^b-hexahydro-SH-indeno/ 1.2-c_7pyridine~(5)-ol.

To a suspension of 0.98 g of lithium wire cut into small sections in 50 ml of absolute ether, a solution of 8.9 g of n-butyl bromide in 20 ml of ether is added dropwise at -10°C, while stirring well for 25 minutes under a nitrogen atmosphere, and the mixture is stirred until the lithium is dissolved. After cooling to -50°C, a solution of 8.7 g of 2-bromopyridine in 10 ml of ether is added dropwise over 15 minutes, followed by a solution of 10.1 g of 2-methyl-1,2,3,4,4a.9b-hexahydro-5H-indeno/1,2-cI-7pyridine-(5)-one in 40 ml of absolute tetrahydrofuran. After stirring for 2 hours at -40°C, the temperature is allowed to rise to 20°C, and the reaction mixture is poured onto 200 ml of a

- 16 -

A 10% ammonium chloride solution is used, and the reaction mixture is extracted several times with ether. After drying the combined extracts on magnesium sulfate and evaporating the solvent, the residue is recrystallized first in acetone, then twice in hexane. The melting point of the resulting compound is 119-120°C.

b) 2~methyl-5-pyridyl-(2)-1.3,4.9b-tetrahydro-2H-indeno/~ 1.2-c_7pyridine.

2.9 g of the compound obtained in step a) is heated at 120°C for 1 hour with 15 g of benzenesulfonic acid. Then, 50 mL of water is added to the reaction mixture, undissolved flakes are removed by filtration, the solution is alkalinized with 40% sodium hydroxide, and it is extracted several times with methylene chloride. After drying the combined extracts over magnesium sulfate and evaporation of the solvent, the residue is distilled under high vacuum. The thick oil, which passes through 0.02 mm of mercury at 135-160°C (bath temperature), is dissolved in acetone, and the solution is adjusted with the amount of maleic acid calculated to form acid maleate. The maleate crystallizes upon cooling. It is recrystallized first in acetone, then in ethanol. It crystallizes with half a molecule of water of crystallization. This hemihydrate of maleate 25 melts at 135-137°C (with decomposition); sintering occurs from 133°C.

EXAMPLE 10:

2-methyl-5-thienyl-1.3.4.9b-tetrahydro-2H-indeno/'"'1 .2-c_7*pyridine.

30 a) 2-methyl-5-thienyl-1,2,3,4,4a,9b-hexahydro-

5H-indeno/~1 .2-c_/pyridine-(5)-ol.

This compound is prepared as described in example 4a), but using α-bromo-thiophene.

- 17 -

Recrystallized in ethyl acetate, it melts at 188-190°.

b) 2-methyl-5-thienyl-1.3.4.9b-tetra'nydro-2H-indeno;/~V'.2-c__7pyridine.

5 g of the compound obtained under a) is heated under reflux for 1 hour in 30 ml of isopropanol with 4 g of benzenesulfonic acid. After cooling, the crystallized benzenesulfonate is separated by filtration and recrystallized in ethanol. Benzenesulfonate melts at 158-160°C. 10 The base prepared from benzene-

sulfonate melts at 72-73° after being recrystallized in pentane.

EXAMPLE 11:

2-(2-hydroxyethyl)-5-phenyl-1.3,4.9b-15 tetrahydro-2H-indeno/~1 .2-c_7pyridine.

a) 2-ethoxy-carbonyl-5-phenyl-1.2.3.4.4a.9b-

hexahydro-SH-indeno/-1.2-c_7pyridine-(5)-ol.

A hot solution of 21.6 g of 2-methyl-5-phenyl-1,2,3,4,4a,9b-hexahydro-5H-indeno-20 £~\ .2-c_7pyridine-(5)-ol (prepared according to example 1)

A solution of 26 g of ethyl chloroformate in 100 ml of benzene is added dropwise to 400 ml of benzene, and the reaction mixture is heated under reflux for 2.5 hours. After cooling, a small amount of the precipitated hydrochloride is separated by filtration, and the filtrate is evaporated under 15 mm of mercury. The residue is recrystallized in acetone. The melting point is 148–149°C.

b) 5-phenyl-1,2,3,4,4a,9b-hexahydro-5H-indeno-30,2-cM7pyridine-(5)-°l,

The heating process is carried out under reflux for 9 hours.

Under a nitrogen atmosphere, 21.3 g of the compound obtained under a) with 210 mL of n-butanol and 17.7 g of potassium hydroxide. After allowing the mixture to stand for

- 18 -

At night, at room temperature, the crystallized compound is separated by filtration, washed thoroughly with water, dried, and recrystallized in ethanol. Its melting point is 190-191°C. From the butanolic mother liquor, an additional quantity of the same substance can be obtained: c) 2-(2-hydroxyethyl)-5-phenyl-1,3,4,9β-tetrahydro-

2H-indenoj/71.2-c_7pyridine.

To a 5.3 g solution of the compound obtained (b) in 100 mL of absolute ethanol, 20 mL of a 6.7% absolute ethanolic solution of ethylene oxide is added, and the mixture is heated to 85°C in an autoclave for 3 hours. The reaction mixture is then evaporated under 15 mm of mercury, and the residue is heated for 1 hour under reflux with 2,5-n methanolic hydrochloric acid. After evaporation of the solvent, the residue is dissolved in acetone, and the hydrochloride crystallizes. It is recrystallized twice in ethanol. It is obtained as fine, felt-like needles that melt at approximately 175–182°C (with decomposition). Neutral naphthalene-1,5-disulfonate melts at 227–228°C.

after having been recrystallized in methanol.

EXAMPLE 12:

5-phenyl-1.3.4.9b-tetrahydro-2H-indeno/_ 1.2-c_7~ 25 pyridine.

A mixture of 5 g of 5-phenyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/~1,2-c-7'-pyridine-(5)-ol (prepared according to Example 11b) and 50 mL of 2,5-n methanolic hydrochloride is heated under reflux for 15 minutes. After cooling the reaction mixture, the precipitate formed is separated by filtration and recrystallized twice in 95% ethanol. The hydrochloride of 5-phenyl-1,3,4,9b-tetrahydro-2H-indeno/~1,2-c-7'-pyridine

- 19 -

It crystallizes with 1/4 of a molecule of water of crystallization. Its melting point is 175-178° (with decomposition).

EXAMPLE 13:

5 7-chloro-2-methyl-5-phenyl-1.3,4.9b-tetrahydro-

2H-i ndeno/~ 1.2à-c_7pyridine.

a) 7-chloro-2-methyl-5-phenyl-1.2,3 ,4.4a.9b-hexahydro~ 5H-indeno/~"I »2-c_7pyridine-(5)-ol.

To a suspension of 8.02 g of magnesium 10 in 25 mL of absolute tetrahydrofuran, a small grain of iodine and 5 mL of a solution of 53.4 g of bromobenzene in 50 mL of absolute tetrahydrofuran are added. The mixture is heated until the reaction begins, then the heating bath is removed and the remainder of the solution is added at a rate high enough to keep the reaction mixture constantly boiling. The mixture is then heated under reflux until all the magnesium is dissolved (approximately 1 hour), then cooled to room temperature, 50 mL of methylene chloride is added, and the mixture is cooled to -50°C. At this temperature, a solution of 23.6 g of 7-chloro-2-methyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/~1,2,c_J7"pyridine-(5)-one in 50 ml of methylene chloride is added dropwise, with thorough stirring, and the mixture is stirred for another hour at 0-20°C. Afterward, the reaction mixture is poured into a solution of 80 g of ammonium chloride in 300 ml of water and 200 g of ice. After three extractions with methylene chloride, the combined extracts are dried over potassium carbonate, and the solvent is evaporated. The residue is crystallized in methanol. The resulting compound melts at 210-214°C (with decomposition).

- 20 -

b) 7-chloro-2-methyl-5-phenyl-1.3,4.9b-tetrahydro-2H-indeno/"~ 1.2~c_7pyridine.

Five grams of the compound obtained in step a) are heated under reflux for 1 hour with 25 mL of 2.5-n methanolic hydrochloric acid. The mixture is evaporated under reduced pressure and the residue is recrystallized twice in isopropanol. The hydrochloride melts at 217–222°C (with decomposition).

The base prepared from the hydrochloride and recrystallized in ethyl acetate melts at 120-123°.

The 7-chloro-2-methyl-1.2.3.4.4a.9b-hexahydro-5H-indeno/~" 1.2-c_y*pyridine-(5)-one used as the starting material is prepared as described below.

Methyl ester of 1-methyl-3-p-chlorophenyl-isonipecotinic acid (mixture of stereoisomers).

To a suspension of 51 g of magnesium in 200 mL of absolute tetrahydrofuran, one grain of iodine and 25 mL of a solution of 0.421 g of p-chlorobromobenzene in 600 mL of toluene and 200 mL of absolute tetrahydrofuran are added. The mixture is heated until the reaction begins, then the heating bath is removed and the remaining solution is added quickly enough to maintain a constant boil (approximately 1 hour), with the temperature rising from 70 to 110°C. The reaction mixture is then heated under reflux for another hour while stirring.

After cooling the Grignard solution to -15°C, a solution of 155 g of methyl ester of 1-methyl-1/2-isonipecotinic acid in 200 ml of toluene is introduced dropwise over 2 hours, below its surface, with thorough stirring.

21

After stirring for another hour at -15°C, the reaction mixture is poured into a solution of 300 g of ammonium chloride in 1000 ml of water and 1000 g of ice. After adding 1000 ml of ether and filtering through highly purified infusoria earth, the organic phase is separated, and the aqueous phase is extracted twice more with ether. The organic extracts are then extracted with 2000 ml of normal hydrochloric acid, and then three times with 1000 ml of water each time. The aqueous extracts are then alkalized with sodium hydroxide while being thoroughly cooled, and this aqueous phase is extracted three times with a total of 2500 ml of methylene chloride. After drying the entire extract over magnesium sulfate and removing the solvent by evaporation, the residue is distilled. The fraction that passes through

at 135-150°C under 0.1 mmHg is then distilled once more in a Vigreux flask. The mixture of stereoisomers passes at 118-125°C under 0.02 mmHg, in the form of a slightly yellow oil. Its index of

20 refraction n is equal to 1.5329.

D

7-chloro-2-methyl-1.2.3.4.4a.9b-hexahydro-5H-indeno/7"1.2-cJTpyridine-(5)-one.

40 g of the methyl ester obtained with 400 g of poly-25 phosphoric acid is heated at 180°C for 4 hours. The reaction mixture is then poured into 1000 ml of water and, while adding ice, the pH of the solution is brought to 8 with a 40% caustic potassium hydroxide solution. Afterward, the reaction mixture is extracted three times with ether, the entire etheric extract is dried on potassium carbonate, and

The solvent evaporates. The residue is distilled in a nitrogen atmosphere: the desired compound passes through 120-128°

under 0.02 mm of mercury in the form of a yellow oil

- 22 -

which crystallizes when cold. Recrystallized in hexane, it melts at 82-84°C. The compound oxidizes rapidly in solution. The hydrochloride, recrystallized in ethanol,

background at 220-223° (with decomposition).

5 EXAMPLE 14;

2.7-dimethyl-5-phenyl-1.3.4.9b-tetrahydro-2H~indeno/7'1 »2-c_/pyridine.

a) 2#7-dimethyl-5-phenyl-1.2.3.4,4a.9b-hexahydro-5H-indeno/""1,2-c_7pyridine-(5)-ol.

10 This preparation is carried out according to example 13 a), but using 21.5 g of 2,7-dimethyl-

1.2.3,4.4a.9b-hexahydro-5H-indeno/~1.2-cJ7pyridine-(5)-on€

Recrystallized in ethyl acetate, the compound melts

at 189-191°.

15 b) 2.7-dimethyl~5-phenyl-1.3.4.9b-tetrahydro-2H-indeno/7*1 «2-c_7pyridine.

We proceed as described in example 13 b).

The hydrochloride of the compound sought, recrystallized in ethanol, melts at 220-230° (with decomposition).

20 2.7-dimethyl-1.2,3.4.4a.9b-hexahydro-

5H-indeno/_~"l »2-c_7pyridine-(5)-one used as the starting material is prepared by the same process as 7-chloro-2-methyl-1.2 .3.4.4a.9b-hexahydro-5H-indeno/~ 1.2-c J-pyridine-(5)-one (see example 13).

25 Methyl ester of 1-methyl-3-p-tolyl-

isonipecotinic (mixture of stereoisomers).

From 376 g of p-bromo-toluene

>3

and 155 g of the methyl ester of 1-methyl- acid

isonipecotinic. Boiling point below 0.08 mm of

22

30 mercury: 125-130°, n = 1.5215.

D

- 23 -

2.7-dimethyl-1.2.3,4.4a.9b-hexahydro-5H-indeno/~1.2-c__7pyridine-(5)-one.

When recrystallized in ethyl acetate this compound melts at 90-91°.

EXAMPLE 15:

2-benzyl-5-phenyl-1,3,4,9β-tetrahydro-2H

indeno/]"^ .2-cJ7pyridine.

a) 2-benzyl~5-phenyl-1.2.3 ^^a^b-hexahydro-SH-

indeno/""* 1 .2-c_7pyridine-(5)-ol.

A mixture of 5 g of 5-phenyl-1,2,3,4,4a,9b-hexahydro-5H-indeno/1,2-c-7pyridine-(5)-ol (see Example 11b), 2.8 g of benzyl chloride, 3 mL of triethylamine, and 100 mL of ethanol is heated under reflux for 4 hours. The solution is then evaporated under reduced pressure, and the residue is diluted with dilute caustic soda and methylene chloride. The methylene chloride extract is washed with water, dried over sodium sulfate, and evaporated. The residue is then recrystallized several times in isopropanol. The resulting compound melts at 139–141°C.

b) 2-benzyl-5-phsnyl-1.3,4.9b-tetrahydro-2H-

indeno^ol .2-c__7pyridine,

4.5 g of the compound obtained in step a) is heated under reflux for 15 minutes with 25 ml of 2.5-n methanolic hydrochloric acid. Upon cooling, the hydrochloride crystallizes. Recrystallized twice in ethanol, it melts at 212-214°C (with decomposition).

Claims (1)

- 24 - SUMMARY The present invention includes, in particular: 1°) As novel industrial products, heterocyclic compounds corresponding to the general formula I \I-R, (I) in which R^ represents a hydrogen atom, a lower alkyl or hydroxyalkyl group, or the benzyl group; R2 represents a hydrogen or halogen atom or a lower alkyl group; and R3 represents a phenyl group possibly bearing a chlorine atom or a methyl, metho-xy, or methylthio group, or the benzyl, pyridyl, pyridylmethyleouthienyl group. as well as the salts that these compounds form with acids. 2°) A process for preparing new heferocyclic compounds: specified under 1°, a process in which a 1,2,3,4,4a,9b-hexahydro-5H-indeno/""l .2-c7"pyridine-(5)-one corresponding to the general formula II is reacted /X I ' R2"l\>; .HAS- / 11 0 N-R'. (II) - 25 - in which has the meaning indicated under 1° and R'.j represents a lower alkyl group or the benzyl group, with an organometallic compound corresponding to the general formula III Me - R3 (III) in which R^ has the meaning given under 1° and Me represents the lithium atom or a halogen-magnesium remnant, the reaction product is hydrolyzed so as to obtain a 1.2.3,4.4a.9b-hexahydro~5H-indeno-,2-cJ7pyridine-(5)-ol corresponding to the general formula IV;. y v H° ' then a) when we want to obtain a compound of formula I in which R^ is a lower alkyl group or the benzyl group, we dehydrate the alcoholic compound of formula IV, b) when we want to obtain a compound of formula I in which R^ is hydrogen and in the compound of formula IV, R'^ represents the methyl group, we treat the latter with a chlorofor- alkyl miate, the alkoxy-carbonyl group present in the 2-alkoxy-carbonyl derivative formed is eliminated by hydrolysis and the secondary amine formed corresponding to the general formula V is then dehydrated, - 26 - *2" "NH (V) HO " R3 b') when one wants to obtain a compound of formula I 5 in which represents a hydroxy- group lower alkyl or benzyl group, the secondary amine obtained, corresponding to formula V, is reacted with a hydroxyalkylating agent or with a benzyl halide, then the resulting compound is dehydrated, and we may transform the compounds obtained according to a), b) and b') into their acid addition salts. ORIG! ^ A L in , . , - • C0T . , . ■ , ....W.ov nu, José CURAU Industrial Property Consultant By own*/** é@ frfWDùZ £,■}