NO772230L - PROCEDURES FOR THE PREPARATION OF CARBOSTYRILES - Google Patents

Description

The present invention relates to antihypertensive hexafluorohydroxyisopropyl bicyclic and tricyclic carbostyrils and intermediates for the production of such compounds.

Sheppard, W. A., J. Am. Chem. Soc, 87 (11), 2410 (1965) and Gilbert, E. et al., J. Org. Chem., 30, 1001 (1965) describes a process for the addition of hexafluoroacetone to anilin derivatives to form α,α-bis(trifluoromethyl)-β-aminobenzyl alcohols.

Allied Chemical Corporation describes in British patent 1,029,048 hexahalogen hydroxyisopropylaryl derivatives as intermediates in the production of aromatic carboxylic acids.

E.. Jones describes in US patent specification 3,405,177 and

3,541,152 hexahalogen hydroxyisopropylaromatic amines which are

usable as intermediate products in the production of azo dyes, polyesters, polyamides, insecticides, plasticizers and pharmaceuticals.

E.E. Gilbert describes in US patent 3,532,753 aromatic amino derivatives of hexahalogenacetone which are useful as insecticides.

German OS 2 552 993 describes compounds containing

a ureido. or isoureido function which finds application as antihypertensive agents.

H. Myer et al. describes in US patent document 3,907,807 antihyperterisive benzoquinolizine agents, and whereby the following compound can be exemplified:

Many common antihypertensive agents cause unwanted side effects due to their unwanted mechanism of action. For example, guanthidine is an adrenergic neuron blocker, mecamylamine is a ganglion blocker, phenoxybenzamine is an α-adrenergic receptor blocker and reserpine is a catecholamine depressant. Each of these mechanisms of action is undesirable because of the serious side effects that are created. Compounds according to the invention appear to lower blood pressure by a desirable mechanism of action, direct peripheral vasodilation, and therefore exhibit a distinct advantage over for the above-mentioned antihypertensive agents with undesirable effects. Furthermore, these compounds do not appear to produce central nervous system effects such as those seen with clonidine and α-methyldopa administration. According to the invention, there are provided compounds of the following formula, methods for their production, pharmaceutical compositions containing them and methods of using them to treat hypertension in mammals.

where R1=.H or alkyl with 1-4 carbon atoms,

R2= H or alkyl with 1-4 carbon atoms,

provided that when R1= alkyl, R2= H, -CH3 or -CH2CH3,

or

Rl + R2^an together be

where Rg .= H or -CH3,7= H or -CH3, Rg = H or alkyl with 1-4 carbon atoms, Rg = H or alkyl with 1-4 carbon atoms, or Rg + Rg can together be -(CH^^ -, provided that i) , at least one of Rg, R^, Rg or Rg = H, and ii) the sum of the carbon atoms of Rg, R^, Rg and Rg is not more than 6,

where R1Q= H, -CH3 or -CH2CH3,

R1X= H, -CH3 or -CH2CH3,

R 12 =H'~CH 3 or -CH 2 CH 3 , or

R-^together with R^Qor R^2can be -(GH2)^-,

provided that at least one of R-^g/ R-^or-R-^ = H, or

c) -(CH2)4-,

R3= H, CH3, F, 1, r, NO2, NH2 or OH,

R^= H or alkyl with 1-4 carbon atoms, and

R^.= H, acyl or alkyl with 1-6 carbon atoms.

In addition, according to the invention, intermediate products of formula li and methods for their preparation are provided:

where R.^+ R.sub.2 together are defined according to (a), (b) and (c) in formula I.

Preferred connections

Preferred due to their high degree of activity are compounds of formula I where R-^ and R2 together are:

Also preferred are those compounds where independently:

a) R^ is hydrogen, or

b) R 1 is methyl or ethyl, or

c) R 1 is hydrogen.

More preferred are those compounds in which R 1 and R 2 together

is:

Rg, Ry and Rg are hydrogen or

R^O and R^^ are hydrogen.

Even more preferred are those compounds where:

a) R^ and R2 together are:

b) R^ is hydrogen,

c) R 1 is methyl. or ethyl,

d) Rg., R7 and Rg are hydrogen or R, Q and R are hydrogen, and e) R,- is as defined and preferably equal to hydrogen.

When R,. = alkyl is a preferred definition alkyl with 1-4 carbon atoms and preferably 1-2 carbon atoms.

The following compounds are particularly preferred: 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)-ethyl]-7-methyl-1H,5H-benzo[ij]quinolizine-5- 5-6n, 2,3-dihydro-3,7-dimethyl-9-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one , 2,3-dihydro-7-ethyl-9-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one, 1,2- dihydro-8-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3.2.1-ij]quinolin-4-one, 1,2-dihydro-2 ,6-di-methyl-8-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-4H-pyrrolo-[3.2.1-ij]quinolin-4-one, and 1,2- dihydro-6-ethyl-8-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-4H-pyrrolo [3 . 2 .1-i j] - quinolin-4-one.

Preferred intermediates of formula II for the preparation of antihypertensive compounds with a high degree of activity are those

compounds in which R 1 and R 2 together are

and

R 8 , R 8 and R 8 are hydrogen.

Also preferred are those compounds in which R, and R~ together

but is

and

Acyl derivatives

Acyl derivatives of the hydroxy function of compounds according to the invention of formula I exhibit excellent antihypertensive activity. easy in vivo hydrolysis. Acylation can be used to form derivatives with a myriad of different physical properties, but with little difference in biological properties from the parent hydroxy compound. It can therefore be concluded that the range of acyl groups is practically unlimited and not critical for the antihypertensive activity. Among acyl groups that can be used are alkanoyl, alkenoyl and aroyl.

Syntheses

The hexafluorohydroxyisopropylamine precursors are prepared on

the following way:

When R-^ and R2 are hydrogen or alkyl with 1-4 carbon atoms, the precursors are prepared as shown in the following reaction screen:

This reaction is described by Sheppard, W.A., J. Am.

Chem. Soc., 87, 2410 (1965). A mixture of the appropriate aniline derivative, anhydrous aluminum chloride and hexafluoroacetone is heated until the reaction is complete. rt. The product is triturated with chloroform and cooled, then filtered off and recrystallized.

Precursors in which R, and R are bound together are produced 1 2

as shown in the following reaction core:

The reaction is carried out in a sealed pressure reactor at a temperature from 80 to 200° C. It can also be carried out in a refluxing solvent such as benzene or toluene, in a flask with hexafluoroacetone monohydrate, sesquihydrate or trihydrate. Acid catalysts such as AlC13, BF3 or p-toluenesulfonic acid can be used but are not necessary. The reaction time is usually 4-12 hours. A temperature of 100 - 120° C and the use of 1-5 mol% AlCl 2 is preferred.

A modified method for the preparation of these precursors which gives higher yields for many of the compounds, especially indolines, involves attachment of a suitable protecting group such as benzyl or substituted benzyl, at the main nitrogen atom of the amine starting material, after which this 'protected' compound is contacted with hexafluoroacetone. The following diagram generally shows this reaction:

where X = Cl or Br,

R13= H, F, Cl, Br, NO2, phenyl or CH3,

n = 2, 3 or 4.

The starting amine (A) is treated with a benzyl halide to form a tertiary N-benzylamine (A1). This is heated with hexafluoroacetone to form the adduct A 2 , which is then hydrogenated to remove the benzyl group to form the desired compound (C).

The hydrogenation step occasionally requires an excess of acid as a cocatalyst. The hydrogenolysis is attempted without addition, acid is added (eg concentrated hydrochloric acid) and the reaction is allowed to proceed.

The Arain starting materials are either known in the art or can be easily prepared from those known in the art. However, methods for producing the various ring systems are indicated as follows:

Indoles

Tin and hydrochloric acid or zinc and hydrochloric acid can also be used as reducing agents.

See Elderfield, R.C., Heterocyclic Compounds Vol. 3, John Wiley&Sons, Inc., New York, N.Y. (1952). s.l.

Tetrahydroquinolines

See Elderfield, R.C., Heterocyclic Compounds Vol. 4, John Wiley & Sons, Inc. New York, NY (1952), p.

Benzazepines

In the specified reaction core, 3,4-dihydro-1-(2H)-naphthalenone is brought into contact with hydroxylamine hydrochloride to form the corresponding oxime.

Oximet. is rearranged by treatment with polyphosphoric acid to form the lactam 1,3,4,5-tetrahydro-1Hr-1-benzazepin-2-one.

The reduction of the lactam with LiAlH^ gives 2,3,4,5-tetrahydro-1H-1-benzazepine.

The ketone starting material for the main system indicated above is known in the art and is commercially available.

The intermediate amides (E) are prepared as shown in the following reaction core:

where P^, R2 and R4 are as previously stated, R<1>3 is hydrogen or CH^ and R is an alkyl group with 1-5 carbon atoms.

The amide (E) is prepared by heating equimolar amounts of amine (C) and 3-ketoester (D) in an oil bath. The preferred temperature range is 180 - 220° C. Alternatively, the reactants can be boiled together under reflux in a high-boiling solvent, e.g. xylene.

The reaction can conveniently be followed by periodically removing a test amount and performing thin-layer chromatography. When no further reaction is observed, the amide (E) is isolated by crystallization and/or chromatography. Sometimes purification is difficult and therefore cyclization of the crude amide is more appropriate.

When R'3 = H and R^ = CH3, the amides (E) are prepared more conveniently and in better yield using the aV diketene instead of the 3-ketoester (D). An equimolar amount of the diketene is added to amine (C) dissolved in an inert solvent (e.g. anhydrous tetrahydrofuran or toluene) kept at 0° C. or room temperature. If the reaction is slow (as indicated by thin layer chromatography) the mixture is heated until no further reaction is observed. The impure product is often satisfactory for cyclization in sulfuric acid, but can be purified by recrystallization and/or chromatography.

The end products are easily prepared as shown in the following cyclization reaction:

The cyclization is carried out by heating the amide (E) in a condensing agent, such as sulfuric acid or polyphosphoric acid. Usually, heating in concentrated sulfuric acid on a steam bath for 30 - 60 minutes will complete the reaction, but occasionally higher heating (up to 120° C) for a longer time (up to 24 hours) is necessary. Completion of the reaction can conveniently be checked by removing a small test sample, isolating the solid materials and analyzing by thin-layer chromatography. The product (F) is isolated by pouring the sulfuric acid solution into an excess of ice water, removing the precipitate by filtration, washing and drying. Further purification, if necessary, can be carried out by recrystallization and/or chromatography.

When and R2 is alkyl in formula E, no cyclization is observed. Compounds described by formula F in which R-1 and R2 are alkyl can be prepared by cyclization of the amide E where R-1 is alkyl and R2H. The product F has = alkyl and R2 = H. When the product F is treated with R'5X, (R'5= alkyl with 1-6 carbon atoms or where R13= H, F,. Cl, Br, NO2, phenyl or CH3 , X = halogen), an alkyl halide such as methyl iodide or aralkyl halide such as benzyl bromide, in a solvent such as dimethylformamide with a base such as potassium carbonate, or sodium hydride, the oxygen-alkylated compound F-, is obtained. : —

The compound F-^ can then be alkylated on nitrogen using, of base such as sodium hydride or thallium ethoxide in a solvent such as DMF with an alkyl halide or sulfate, R'2X/(R'2=~CH3 or -CH2CH3, X = halogen or sulfate) during formation of F^.

The alkyl or aralkyl group R'5 on compound F2 can be removed by a suitable reaction such as hydrolysis with aqueous hydrobromic acid or hydrogenolysis to form compound F3, where R1 and R1 2 are alkyl.

Compounds of formula I where R3 is different from hydrogen or methyl are preferably prepared from F (R<1>3= hydrogen) by well-known electrophilic substitution reactions, e.g. chlorination, bromination and nitration. The N02 compound can be reduced to the NH2 compound which in turn is. applicable for the preparation of compounds where R^= fluorine or OH.

In order to prepare compounds where R is hydrogen, the process is modified by using malonyl dichloride instead of ketoester (D). The resulting hemi-amide chloride of malonic acid.e

(E, where R^= Cl) is then cyclized with a suitable condensing agent, e.g. phosphorus oxychloride, forming G, which can be hydrogenolytically split to H.

Alternatively, ethylmalonyl chloride can be used instead of ketoester (D) to form the half-amide ester of malonic acid

(E, where R. = OC2Hj) which is cyclized with a condensing agent, e.g. sulfuric acid, forming E where Rr= OH. It is then treated with phosphorus pentachloride in phosphorus oxychloride solution to form G which is converted to H as shown above.

Esters are produced from F by reaction with acid chlorides or anhydrides with or without solvents. Because of the tertiary nature and high acidity. of the alcohol group, the esterification is relatively slow at room temperature but can be greatly accelerated by the use of high-boiling solvents (with or without the addition of a base) or by the use of refluxing pyridine as a solvent and base.

Ethers are prepared from F by conversion to a salt by treatment with a suitable base (eg potassium tert-butoxide), after which the salt is O-alkylated by heating with a dialkyl sulfate or alkyl halide.

The following examples illustrate the synthesis of the compound of formula I and II. All parts are by weight and all temperatures in degrees Celsius unless otherwise stated.

Part A - Preparation of Intermediates of Formula II

Example 1

a, a- bis-(trifluoromethyl)- 1, 2, 3, 4- tetrahydro- 6- quinolinemethanol

200 g of 1,2,3,4-tetrahydroquinoline and 2 g of anhydrous aluminum chloride are added to a 1 liter stainless steel reactor. The reactor is cooled and evacuated, 265 g (1.60 mol) of hexafluoroacetone is added, and the reactor is sealed and heated to 120° C. with shaking for 10 hours. The reactor is then cooled to room temperature and vented. The contents are decanted from below forming a red semi-crystalline solid which is treated with 250 ml

methylene chloride and filtered. The filter cake is washed with three 250 ml portions of methylene chloride. The orange colored solid residue is treated with decolorizing carbon in hot chlorobutane and filtered. From the filtrate, 310 g (1.04 mol) of 2,2-bis-(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol are obtained as a pale yellow crystalline solid with a melting point of 115 - 115°C.

Analysis calculated for C^H^FgNO: C 48.17, H 3.71, N 4.68

Found: C 48.46, H 4.06, N 4.93.

Example 2

a, a- bis-( trifluoromethyl)- 2, 3- dihydro- 1H- indole- 5- methahol A. 1- benzylindolin - To a stirred refluxing mixture of 119 g (1 mol) indoline, 800 ml toluene (other solvents, e.g. isopropyl alcohol is satisfactory), and 207 g (1.5

moi) of powdered, anhydrous potassium carbonate is added dropwise to 126.5 g (1 mol) of benzyl chloride. When the addition is complete, the reflux is continued until the evolution of gas decreases as determined by a gas meter (approx. 3 hours). The mixture is allowed to cool and the solid material is removed by filtration. The filtrate is evaporated and the residue is distilled to give 153 g (73%) of 1-benzylindoline, b.p. 162 - 165°C (4.5mm).

B. 1-benzyl-q,q-bis-(trifluoromethyl)-2,3-dihydro-1H-indole^-5-methanol

A stirred mixture of 83.6 g (0.4 mol) of 1-benzylindoline,. 250 ml of toluene and 77.2 g (0.4 mol) of hexafluoroacetone sesquihydrate are boiled under reflux for 4 hours. The mixture is then refluxed under Dean-Stark conditions until all water is removed. The solution evaporates. The residue is dissolved in 500 ml of methylcyclohexane (heating if necessary) and allowed to crystallize under a nitrogen atmosphere. The gummy crystals are filtered off, washed and dried to give 116.3 g (77%) of 1-benzyl-2,2-bis-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol, sm. p. 85 -90° C.

Because solutions of these crystals oxidize quickly, purification by recrystallization entails unnecessary loss, which is why the impure crystals are used in the next step.

C.; g,g-bis-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol

A mixture of 55 g (0.15 mol) 1-benzyl-<g>,<g->bis-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol, 200 ml of alcohol, 32 ml of concentrated hydrochloric acid and 2 g of 10% palladium on charcoal are shaken in a Parr apparatus at an initial pressure of 3 atm. until no further change in pressure is observed. The catalyst is filtered off and the filtrate is evaporated. The residue is distributed between ether and 8N ammonium hydroxide. The ether layer is separated, washed (saturated sodium chloride solution), dried (magnesium sulfate) and evaporated. Dibutyl ether is added to the residue and the solution is cooled in an ice bath. The crystals are filtered off to give 33.3 g (80%)<g>,<g->bis-(trifluoromethyl)-2,3-dlhydro-1H-indole-5-methanol, m.p. 161 - 162° C.

Example 3

Example 2 is followed with the exception that p-nitrobenzyl chloride is used instead of benzyl chloride. The first intermediate: 1-p-nitrobenzylindoline with m.p. 95 - 97° C is obtained. This is then converted to the second intermediate, 1-p-nitrobenzyl-<g>,<g->bis-(trifluoromethyl)-2,3-dihydro-1H-indole-5-methanol. This is inappropriate to purify because of the reaction between solutions of this and air, so that this is quickly hydrogenated to form <g>,<g->bis-(trifluoromethyl)-2,3-dihydro-1H-indole-5- methanol,

sm.p. 160 - 161° C.

Example 4- 17

Using the procedure described in examples 1 and 2, the following compounds can be prepared from suitable starting materials as shown below:

Part B - Preparation of compounds of formula I Example, 18 ' -

A. To a stirred solution of 32.9 g (0.11 mol).α,α-bis-(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol in an inert solvent ( e.g. dry toluene or tetrahydrofuran) is added to 9.2 g (0.11 mol) of the diketene. The mixture is boiled under reflux for 30 - 40 minutes, cooled and evaporated. The residue is triturated with 150 ml of dibutyl ether to form crystals. The crystals are separated by filtration to form 24.8 g

(64%) α,α-bis-(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, m.p. 115 - 117° C.

B. A stirred mixture of 6.0 g (0.02 mol) α,α-bis-(tri-fluoromethyl)-1,2,3,4-6-quinolinemethanol, 2.6 g (0.02 mol) ethyl acetoacetate and 100 ml of xylene are boiled under reflux for 16 hours. The mixture is allowed to cool and evaporate. The residue is triturated with a mixture of toluene, ethyl acetate and hexane (6:10:30). The insoluble part is filtered off, washed with ether and dried to give 1.6 g (23%) of a,a-bis-(trifluomiethyl)-1-(1,3-dioxobutyl)-1,2,3,4- tetrahydro-6-quinolinemethanol.

C. A solution of 10.5 g (0.027 mol) of α,α-bis-(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3 N,4-tetrahydro-6-quinolinemethanol in 30 ml of concentrated sulfuric acid is heated on a steam bath for 30 - 45 minutes, cooled to approx. 60° C and then poured over ice. When

the ice is melted, the precipitate is filtered off, washed with water and dried. The solid material is crystallized from 2-ethoxyethanol to give 7.2 g (74%) of 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7- methyl-1H,5H-benzo[ij]quinolizin-5-one,

sm.p. 295 - 296° C.

Analysis for C,,H.oF,N0o:

J161362

Calculated: C 52.62, H 3.59, N 3.94

Found: C 52.58, H 3.78, N 3.85

Example 19 —

A stirred mixture of 23.5 g (0.075 mol) α,α-bis-(tri-fluoromethyl)-1,2,3,4-tetrahydro-2-methyl-6-quinolinemethanol, 100 ml of dry toluene and 8.3 g (0.099 mol) of the diketene is refluxed for 16 hours under dry nitrogen. The toluene evaporates. The residue, which is impure α,α-bis-(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-2-methyo-6-quinol.inmethanol, is dissolved in 100 ml of concentrated sulfuric acid and heated on a steam bath for 1 hour. The solution is poured over ice water. When the ice has melted, the insoluble material is extracted with ether. The ether solution is dried and evaporated to form 26.8 g of residue. Trituration of the residue with a mixture of toluene, hexane and ethyl acetate (60:30:10) causes the crystals to separate. The crystals are filtered off and two recrystallizations from toluene and ethylene acetate mixture (9:1) give 10.0 g (35%) of crystals of 2,3-dihydro-3,7-dimethyl-9-[2.2.2-trifluoro-1- hydroxy-1-(trifluoromethyl)-ethyl]-1H,5H-benzo- .

[ij]quinolizin-5-one, m.p. 195 - 198° C.

Example 20 - 24

The suitable tetrahydroquinoline can be used instead of α,α-bis-(trifluoromethyl)-1,2,3,4-tetrahydro-2-methyl-6-quinolinemethanol according to example 19 for conversion to the corresponding benzo-quinolizinone as shown in the following :

A mixture of 15.0 g (0.05 mol) α,α-bis-(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol and 7.2 g (0.05 mol) ethylpropionyl acetate is heated with stirring in an open flask in an oil bath at 200 - 220° C. When the internal temperature rises to 180 - 200° C the mixture is allowed to cool. The impure product is chromatographed on silica gel successively with the following eluents: (1) toluene-hexane (60:40), (2) toluene-ethyl acetate-hexane (60:20:20) and (3) toluene- ethyl acetate-hexane (60:20:20). Subsequent fractions yield 5.3 g (26%) of a red oil identified by nmr spectroscopy as α,α-bis-(trifluoromethyl)-1,3-(1,3-dioxo-pentyl)-1,2, 3,4-tetrahydro-6-quinolinemethanol. 5.3 g of the oil are dissolved in 50 ml of concentrated sulfuric acid and heated in a steam bath for 45 minutes. The solution is poured into 300 ml of ice water. The precipitate is filtered off, washed with water and dried. Chromatography on silica gel with toluene-ethyl acetate (60:40), followed by ay recrystallization from dibutyl ether, gives 0.7 g (14%) of 2,3-dihydro-7-ethyl-9-[2.2.2-trifluoro-l- hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo-[ij]quinolizin-5-one, m.p. 209 - 210° C. Example 26

To a stirred suspension of 7.3 g (0.02 mol). 6,7-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(1-trifluoromethyl)-ethyl]-1-methyl-3H,5H-benzo[ij]quinolizin-3-one i 100 ml of concentrated hydrochloric acid is gradually added with 1.95 g (0.01 mol) of calcium hypochloride (73>2%) using a powder addition funnel. The mixture is stirred for 5 hours at room temperature. The mixture is poured into 400 ml of cold water. The white solid material is filtered off, washed with water and dried to form 6.0 g of solid material. A portion is purified by dissolving 4.2 g in 25 ml of trifluoroacetic acid and by adding water, a little at a time, to start the precipitation. The mixture is allowed to cool and crystallize to give 1.1 g of 6-chloro-2,3-dihydro-9-[2. 2.2-4:trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-7-methyl-1H,5H-benzo[ij]quinolizin-5-one, m.p. 266 - 268° C.

Example 27

To a stirred suspension of 7.3 g (9.92 mol) 6,7-dihydro-9-[2.2.2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-1-methyl-3H,5H -benzo[ijYquinolizin-3-one in 100 ml of hot concentrated hydrochloric acid is added dropwise 3.2 g (0.02 mol) bromine. The mixture is allowed to stir for 16 hours, after which the precipitate is filtered off, washed with water and dried. The solid material is recrystallized from alcohol and dried in an oven at 400° C to give 6.3 g (71%) of white crystalline 6-bromo-2,3-dihydro-9-[2,2,2-trifluoro -1-hydroxy-1-(trifluoromethyl)-ethyl]-7-methyl-1H,5H-benzo[ij]quinolizin-3-one, m.p. 265 - 266° C.

Example 28

To a stirred solution of 343 g (1.25 mol) α,α-bis-(tri-fluoromethyl)-2,3-dihydro-1H-indole-5-methanol in 1880 ml of dry tetrahydrofuran cooled in an ice bath is added dropwise 106 g (1.26 mol) diketene. The solution is allowed to warm to room temperature for 16 hours and is then boiled under reflux for 30 minutes. The solvent is evaporated to give 463 g (100%) of impure α,α-bis-(trifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, m.p. 150-151°C.

The product is added while stirring to 1450 ml of concentrated sulfuric acid, and the solution is heated on a steam bath for 45 minutes. The mixture is cooled to approx. 60° C and poured into ice water. The solid material is filtered off, washed with water and dried to form 315 g of impure solid material. The solid material is recrystallized from dimethylformamide to give 273 g (62%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoro-methyl)-ethyl]-6-methyl -4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 337 - 338° C.

Example 29

To a stirred mixture of 7.0 g (0.02 mol) 1,2-dihydro-. 8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 70 ml of trifluoroacetic acid are added 4.2 g (0.042 mol) of potassium nitrate. The mixture is stirred for 16 hours at room temperature and then boiled under reflux for 30 minutes. The mixture is poured into 300 ml of water. The solid material is filtered off, washed with water and dried. Recrystallization from 250 ml of acetonitrile gives 3.3 g (42%) of 1,2-dihydro-8-[2,2,2-trifluoro-^1-hydroxy-1-(trifluoromethyl)-ethyl]-6^methyl -5-nitro-4H-pyrrolo[3,2,1-ij]quinoliri-4-one, m.p. 289 - 290° C cleavage).

Analysis for ci5<H>^Q<F>6<N>2°4<:>

Calculated: C 45.46, H 2.54, N 7.07

Found: C 45.64, H 2.79, N 6.82

Example 3 0

A mixture of 3.0 g (0.00 75 mol) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl- 5-nitro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, 150 ml of alcohol and 0.5 g of 10% palladium on bone charcoal are hydrogenated at an initial pressure of 3 atmospheres in a Parr- shakes the device until the recording is complete. The catalyst is filtered off and the filtrate is evaporated. Recrystallization of the residue from alcohol gives 1.7 g (62%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-5-amino-6- methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, smd. 292 - 292°C..

Example 31.

a) To a stirred solution of 6.0 g (0.02 mol) α,α-bis-.(trifluoromethyl)-2,3-dihydro-2-methyl-1H-indole-5-methanol in 50 ml of anhydrous tetrahydrofuran 1.9 g (0.022 mol) diketene is added. After 16 hours at room temperature, the solution is boiled under reflux for 1 hour. The solvent is evaporated and the residue is recrystallized from dibutyl ether to form 5.7 g (74%) of α,α-bis-(trifluoromethyl)-1-(1,3-dioxobutyl)-2,2-dihydro-2-methyl-1H- indole-5-methano, m.p. 118 - 119° C. . b) A solution of 2.8 g (0.0073 mol) of the product in 10 10 ml of concentrated sulfuric acid is heated on a steam bath for 45 minutes. The solution is poured into ice water and the precipitate is filtered off, washed with water and dried to give 1.8 g of solid material, mcrystallization from dibutyl ether gives 1.4 g (52%) of crystalline 1,2-dihydro-2,6-dimethyl-8-[2,2, 2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 230 - 231°C.

Examples 32 - 38

The appropriate indoline used instead of α,α-bis-(trifluoromethyl)-2,3-dihydro-2-methyl-1H-indole-5-methanol according to Example 31 can be converted into the corresponding heterocyclic ring-substituted derivative which shown in the following:

A. E stirred mixture of 13.7 g (0.05 mol) α,α-bis-(tri-fluoromethyl)-2,3-dihydro-1H-indole-5-methanol and 7.2 g.(0, 05 mol) of ethyl propionyl acetate is heated at 200° C in an oil bath for 3 hours. The mixture is allowed to cool and triturated with ether. The mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel with a mixture of toluene-ethyl acetate (60:40). A fraction is obtained which can be recrystallized from 1-chlorobutane to form 3.0 g (16%) of crystals with melting point 118 - 119° C, α,α-bis-(trifluoromethyl)-1-(1,3-dioxopentyl) -2,3-dihydro-1H-indole-5-methanol.

B. A stirred mixture of 2.9 g of α,α-bis-(trifluoromethyl)-1-(1,3-dioxopentyl)-2,3-dihydro-1H-indole-5-methanol and 10 ml of concentrated sulfuric acid is heated on a steam bath for 45 minutes. The solution is poured into 100 ml of ice water. The precipitate is filtered off, washed with water and dried. Recrystallization from dibutyl ether gives 0.6 g (22%) of 1,2-dihydro-6-ethyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-4H- pyr.rolo [3, 2 ,1-i j ] quinolin-4-one, m.p. 251 - 252° C.

Example 40

Use of ethyl valeryl acetate instead of ethyl propionyl acetate as described in example 3.9 gives 1,2-dihydro-6-n-butyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-4H- pyrrolo-[3,2,1-ij]quinolin-4-one.

Example 41

In the method shown in example 31, α,α-bis-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol is converted to α,α-bis-(trifluoromethyl)- 1-(1,3-dioxobutyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol, m.p. 169 - 171° C, which is cyclized by heating in sulfuric acid (in this case at 120° C 24 hours) to form 5,6,7,8-tetrahydro-10-[2,2,2-trifluoro-1-hydroxy -1-(trifluoromethyl)-ethyl]-1-methyl-3H-azepino-[3,2,1-ij]quinolin-3-one, m.p. 197 - 198° C.

Example 42

A mixture of 63.2 g (0.68 mol) aniline, 2 g anhydrous aluminum chloride and 135 g (0.81 mol)•hexafluoroacetone is heated to 140° C. in an autoclave for 16 hours. The product is triturated with 800 ml of chloroform and cooled to 0° C. The solid material is filtered off and recrystallized from methylcyclohexane-dibutyl ether (50:50) to form 104 g (59%) of a,a-bis-(trifluoromethyl)-4- aminobenzenecarbinol, m.p. 145 - 150° C [W.A. Sheppard, J. Am. Chem. Soc. 87, 2410 (1965) states a sm.p. 150 - 151.5° C].

By the method shown in example 31, α,α-(trifluoromethyl)-4-aminobenzenecarbinol is converted to α,α-bis-(trifluoromethyl)-4-(1,3-dioxobutylamino)-benzenecarbinol, which is cyclized by heating in sulfuric acid to form 6-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl)-4-methyl-2(1H)-quinoline, m.p.

157 - 158° C.

Examples 43 - 48

By the method shown in example 31b, the following compounds can be prepared from the suitable starting materials as shown in the following:

Example 49

A mixture of 82.0 g (0.68 mol) of N-ethylaniline, 2 g of anhydrous aluminum chloride and 135 g of hexafluoroacetone is heated to 140° C. in an autoclave for 16 hours. The impure product chromatographed. on 700 g of silica gel with chloroform as eluent. The starting fractions are recrystallized from methylcyclohexane to form 73 g (37%) of α,2-bis-(trifluoromethyl)-4-(ethylamino)-benzenecarbinol, m.p. 90 - 92° C.

By the method shown in example 31, α,α-bis-(trifluoromethyl)-4-(ethylamino)-benzenecarbinbl is converted to α,α-bis-(trifluoromethyl)-4-[N-(1,3-dioxobutyl) -N-ethylamino]-benzenecarbinol, m.p. 91 - 92° C, which is cyclized by heating in sulfuric acid to form l-ethyl-6-[2,2,2-trifluoro-l-hydroxy-1-(trifluoromethyl)-ethyl]-4-methyl-2(1H )-quinolinone, m.p. 185 - 187° C (in this case purified by trituration of the product with ether).

Using the method according to Example 31, the following compounds can be prepared from suitable starting materials as shown below:

Example 54

Potassium carbonate and benzyl bromide are added to a solution of 6-[2,2,2-trifluoro-1-hydroxy-1-(tri-fluoromethyl)-ethyl]-4,8-dimethyl-2(1H)-quinolinone in dimethylformamide. The solution is heated with stirring to reflux under nitrogen.

When the reaction is complete as indicated by thin layer chromatography, the solvent is removed under reduced pressure and the residue is treated with water and extracted into ether. The ether solution is dried with anhydrous magnesium sulfate and filtered. The ether is evaporated at reduced pressure. The residue is chromatographed on silica gel to form 6-[2,2,2-trifluoro-1-benzyloxy-^1-(trifluoromethyl)-ethyl]-4,8-dimethyl-2(1H)-quinolinone, m.p. . 162 - 164° C.

To a solution of 6-[2,2,2-trifluoro-1-benzyloxy-1-(tri-fluoromethyl)-ethyl]-4,8-dimethyl-2(1H)-quinlinone in dimethylformamide is added one equivalent of thallium methoxyd. The solution is stirred under nitrogen. Methyl iodide is added to the solution, and the solution is stirred and heated to 50° C until thin-layer chromatography indicates that the reaction is complete. The solution is cooled and treated with 5 ml of methanol. The cooled solution is filtered and evaporated at reduced pressure. The residue is extracted with hexane and the filtered solution is evaporated under reduced pressure. The residue is heated to 250° C in a nitrogen atmosphere for 4 hours. At the end of this period, chromatograph on silica gel with the formation of 6-

[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)-ethyl]-1,4,8-trimethyl-2(1H)-quinolinone.

To a solution of 6-[2,2,2-trifluoro-1-benzyloxy-1-(tri-fluoromethyl)-ethyl]-1,4,8-trimethyl-2(1H)-quinolinone in ethanol is added to 10% palladium on carbon catalyst. The solution is placed in a Parr hydrogenation apparatus and shaken with 3.5 kg/cm<2> hydrogen pressure.

The shaking is continued until no more hydrogen uptake is observed. The solution is filtered and evaporated to form 6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-1,4,8-tri-methyl-2 (1H)-quinolinone, m.p. 241 243°C.

Examples 55 - 59

When using the method according to example 34

the following compounds can be prepared from suitable starting materials:

To a stirred solution of 15.0 g (0.05 mol.) 2,2-bis-(trifluoromethyl)-1,2,3,4-tetrahydro-.6-quinolinemethanol in 50 ml of anhydrous toluene at reflux conditions, add dropwise 7.1 g

(0.05 mole) of malonyl dichloride. Boiling under reflux is continued until evolution of hydrogen chloride is complete. The toluene is then removed by evaporation and the residue is boiled under reflux with 120 ml of phosphorus oxychloride for 2 hours. The solution is poured into ice water while stirring. When excess phosphorus oxychloride has been decomposed, the remaining tarry, insoluble material is filtered off, washed and dried. The tarry material is chromatographed on silica gel with a mixture of toluene and ethyl acetate (60:40) to give a solid which is recrystallized from a minimal amount of alcohol to give 7-chloro-2,S-dihydro-^[2,2, 2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-1H,5H-benzo[ij]quinolizine-5-dn, m.p. 283 284°C.

A mixture of 0.7 g of 7-chloro-2,3-dihydro-9-[2,2,2-tri-fluoro-1-hydroxy-1-(trifluoromethyl)-ethyl)-1H,5H-benzo[ij ]quinolizin-5-one, 150 ml of glacial acetic acid, 5 g of sodium acetate trihydrate and 0.5 g of 10% palladium on bone charcoal are hydrogenated in a Parr shaker apparatus for 4 hours at an initial pressure of 3 atm. The catalyst is removed by filtration, the solvent is removed by evaporation and the residue is triturated with water. The insoluble material is filtered off, dried and recrystallized to form 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-1H,5H-benzo[ ij]-quinolizin-5-one, m.p. 295 - 296° C.

Example 61

A stirred suspension of 3.5 g (0.01 mol) of 1,α-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H- pyrrolo[3,2,1-ij]quinolin-4-one and 50 ml of propionic anhydride are boiled under reflux for 4 hours. Then 50 ml of water is carefully added to the refluxing mixture. The mixture is stirred with a mixture of 200 ml of ether and a solution of 50 g of potassium bicarbonate in 300 ml of water. The ether layer is separated, washed with saturated sodium chloride solution, dried with magnesium sulphate and evaporated. The residue is recrystallized to form 2.45 g (60%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo [3,2,1-ij]quinolin-4-one propanoate, m.p. 136 - 137° C.

Example 62

Use of acetic anhydride instead of propionic anhydride as described in Example 43 gives 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl],-6-methyl- 4H-pyrrolo-[3,2,1-ij]-quinolin-4-one acetate, m.p. 221.5 - 223° C.

Example 6 3

A stirred mixture of 3.5 g (0.01 mol) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H- pyrrolo[3,2,1-ij]quinolin-4-one, 4 ml of anhydrous pyridine and 2.8 g.

(0.012 mole) of lauroyl chloride is heated under reflux until the mixture is homogeneous. The mixture is cooled and poured into an excess of 2N HCl. The mixture is extracted with ether* The ether extract is washed with cold 2N NaOH and then with saturated sodium chloride solution and dried over MgSO^ and evaporated. Recrystallization from methylcyclohexane gives waxy crystals of 1,2-dihydro-

8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl ].-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one laurate, sm .p. 72 - 73° C.

Analysis for <C>24H33FgN03: Calculated: C 60.78, H 6.23, N 2.63

Found: C 61.00, H 6.37, N 2.76

Examples 64 - 67

By following the procedure described in example 63 and using suitable chloride instead of lauroyl chloride, the following products can be prepared: Example 68

To a stirred mixture of 3.5 g of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo-[3, 2,1-ij]quinolin-4-one and 20 ml of dry dimethylformamide are added to 1.3 g (0.012 mol) of potassium tert.-butoxide in a dry nitrogen atmosphere. The mixture is gently heated to 100°C and allowed to cool. Then added.! ml (1.35 g, 0.011 mol) of dimethyl sulfate and the mixture is heated carefully to 100° C. The mixture is allowed to cool to room temperature and poured into 100 - 200 ml of water. The precipitate is filtered off and then triturated with 10% sodium hydroxide solution. The insoluble material is filtered off, washed with water and dried. Recrystallization from alcohol gives 1.8 g (49%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H- pyrrolo[3,2,1-ij]quinolin-4-one, m.p.

242 - 243° C.

Example 69

By using diethyl sulfate instead of dimethyl sulfate as described in example 68, 1,2-dihydro-8-[2,2,2-trifluoro-1-ethoxy-1-(trifluoromethyl)ethyl]-6-methyl- 4H-pyrrolo-[3,2/1-ij]quinolin-4-one, m.p. 189 - 190d C.

Dosage forms ..

The antihypertensive agents of formula I can be administered to treat hypertension by any means that provides contact between the active agent and the agent's site of action in the mammalian body. They may be administered by any conventional means available in conjunction with pharmaceutical agents, either as individual therapeutic agents or in combination with therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the method of administration and standard pharmaceutical practice used.

The dose administered will of course vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, its mode of action and method of administration, age, health and weight of the recipient, the nature and degree of symptoms, the type of accompanying treatment, frequency of treatment and the desired effect.

Generally, a daily dose of active ingredient can carry 0.01 - 50 mg per kg body weight. Usually 0.05 - 40, and preferably from 0.2 to 20, mg per kg body weight given in divided doses of 2 to 4 times a day or in the form of a dose with prolonged effect be effective, to achieve a desired result. For the more powerful compounds, the daily dose varies from 0.01 to 10' mg per kg, preferably from 0.05 to 10 mg per kg and preferably from 0.05 to 5 mg per kg.

Dosage forms suitable for intravenous administration contain from 1.0 mg to 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will usually be present in an amount of from 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions, and it can also be administered parenterally in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, suerose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured as extended-release products to provide continuous release of drug over a period of several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or coated for selective degradation in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain flavoring agents and coloring agents to increase the patient's acceptability.

Suitable pharmaceutic carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a standard reference in this field.

Usable pharmaceutical dosage forms for administering the compounds according to the invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standard two-part hard gelatin capsules, each with 5 mg of powdered active ingredient, 150 mg of lactose, 32 mg of talc and 8 mg of magnesium stearate.

Capsules

A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin, forming soft gelatin capsules containing 2 mg of active ingredient. The capsules are washed in petroleum ether and dried.

Pills

A large number of tablets are prepared by conventional methods such that the dosage unit is 15 mg of active ingredient, 7 mg of ethyl cellulose, 0.2 mg of colloidal silicon dioxide, 7 mg of magnesium stearate, 11 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of lactose. Suitable coatings can also be applied to improve taste or delay absorption.

Suspension

An aqueous suspension is prepared for oral administration ingredient, 500 mg acacia, 5 mg sodium benzoate, 1.0 g sorbitol solution, USP, 5 ml sodium saccharin and 0.025 ml vanilla tincture.

Application

The antihypertensive activity of the compounds of formula I is determined by a procedure using DOCA hypertensive rats, which has been shown to be a good predictor of human efficacy.

Rats are made hypertensive by subcutaneous implantation of pellets of deoxycorticosterone acetate (DOCA) and by being given physiological saline as drinking water essentially in accordance with the method described by Sturtevant [Annals of Internal Medicine, 49, 1281 (1958)]. Graded dose levels for

each compound is administered orally to groups of 8 hypertensive rats. The compound is prepared in an aqueous polyvinyl alcohol/acacia carrier and administered at a. volume body weight ratio on

5.0 ml/kg. Sixteen hypertensive rats receiving the aqueous vehicle by the same route of administration serve as controls for each test. At various time intervals after treatment, usually 90 minutes, the systolic arterial blood pressure of each rat is determined by a modification of the microphone-manometer method [Friedman, M. and Freed, S.C., Proe. Soc. Exp. Biol, and Med., 70, 670 (1949)] . The dose of compound which induces a 30 mm Hg compared to the mean systolic arterial blood pressure of control animals is then determined (effective dose 30).

In tests following this procedure, the following ED^Q doses were determined.

Claims (12)

1. Procedure for the preparation of a compound of the formula where R-^ = H or alkyl with 1-4 carbon atoms, R2 = H or alkyl with 1-4 carbon atoms, provided that one of and R2 = H, or Rl + R2 together ^an be: where Rg = H or ~ CH3 , R7 = H or -CH3, RoQ = H or alkyl with 1-4 carbon atoms, Rg = H or alkyl with 1-4 carbon atoms, or Rg + Rg together can be -('CH^ )^ -, provided that i) at least one of Rg, R^ , Rg or Rg = H, and ii) the sum of the carbon atoms of Rg, R^ , Rg and Rg is not more than 6, where <R>10 = H, -CH3 or -CH2 CH3 , Rll = H'~ CH3 or _CH2 CH3 R12 = H'~ CH3 or~ CH2 CH3 , or Rll' together with <^ Rio eHer Ri2 ^an be ~ (CH2^ 4~' provided that at least <:> one of R^ Q, R^^ or R^ 2 = H/ or c) -(CH2 )4 -, R<1>3 = H or CH3 and R4 = alkyl with 1-4 carbon atoms, characterized by that a) a compound of the formula: . ' <R>l R 2 NH : <C\>(QJ HO'<CF>3 where R-^ and R2 are as indicated above, is either reacted with ii ii °—r° o o H CJ orR 4 -C-CH-C-OR R,3 where R'3 and R4 are as defined above, and R is alkyl with 1-5 carbon atoms, and b) that the resulting amide from (a) is heated in a condensing agent. 2. Process according to claim 1 in the preparation of 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-7-methyl-1H,5H-benzo[ij ]quinolizin-5-one. 3. Process according to claim 1 in the preparation of 2,3-dihydro-3,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoro-methyl)-ethyl]-1H, 5H -benzo[ij]quinolizin-5-one. 4. Process according to claim 1 in the preparation of 2,3-dihydro-7-ethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-1H,5H-benzo[ij ]quinolizin-5-one. 5. Process according to claim -1 in the preparation of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3, 2,1-ij]quinolin-4-one. 6. Process according to claim 1 in the preparation of 1,2-dihydro-2,6-dimethyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoro-methyl)ethyl]-4H-pyrrolo[ 3,2,1-ij]quinolin-4-one. 7. Process according to claim 1 in the preparation of 1,2-dihydro-6-ethyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-4H-pyrrolo[3,2 ,1-ij]quinolin-4-one. , 8. Procedure for the preparation of a compound of the formula: <R> l <R> 2 R'5 0 <CF> 3 <R>4 where R1 = alkyl with 1-4 carbon atoms, <R>2 = -CH3 or -CH2 CH3 , R'3 = H or CH3, R^ = H or alkyl with 1-4 carbon atoms and R*[j = H, alkyl with 1-6 carbon atoms or -CH 2_// Æ when R13 = H, F, Cl, Br, N02 , phenyl or CH3 , characterized in that a) a compound of the formula: .Rl H cHoT T ( R' 0 ^ \ J . 3 5 CP3 R4 where R 1 , R 3 , R 4 and R 5 are as indicated above, reacted with an alkylating agent, R 2 X, where R 2 is as indicated above and X is halogen or sulfate, in the presence of a base, and b) possible hydrolysis or hydrogenolysis. 9.': Connection of the formula: HO / <CF> 3 )WRi CF3 L 1 N-R-, H where R^ + R2 together can be <R>6<R>7 a) -C C- <R>8<R>9 where Rg = H or -CH3, R? = H or -CH3 , Rg = H or alkyl with 1-4 carbon atoms, Rg = H or alkyl with 1 - 4 carbon atoms, or Rg + Rg together can be -(CH^ )^ -, provided that i) at least one of Rg, R^ , Rg. or Rg. = H, and ii) the sum of the carbon atoms of Rg, Ry, Rg and Rg is not more than 6, <b> ) <R> 10 <R> 12 ■ ■ ■ -CH-CH-CH- 1 <R> 11 where R10 = H, -CH3 or -CH2 CH3 , R1;L = H, -CH3 or -CH2 C <H>3 , R12 = H'~ CH3 or~ CH2 CH3 or Rll' together with <^ Rio eHer R 12 ^an be ~ (CH2 ^4~'' provided that at least one of R-^ø' R-^ or R^2 = H, or c) -(CH 2 ) 4 -. 10. Compound according to claim 9, characterized in that R^ and R2 together are R6 R7 -C C- and <R> g <R> g and Rg, Ry and Rg are hydrogen. 11, Compound according to claim 9, characterized in that and R2 together are <R> 10 <R> 12 -CH-CH-CH- and <R> 11 R-j^q and R^ are hydrogen. 12. Process for producing the compound according to claim 9, characterized in that a compound of the following formula is reacted with hexafluoroacetone and heated: ,0^ where R^ + R2 together are <R> 6 <R> 7 a) -C C- <i> i <.> / Rg Rg where Rg = H or -CH3, R? = H or -CH3 ., Rg = H or alkyl with 1-4 carbon atoms, R9 = H or alkyl with 1-4 carbon atoms, or Rg + Rg together can be -(CH2 )4 -, provided that i) at least one of R&/R7 , Rg or Rg = H, and ii) the sum of the carbon atoms of Rg, R7, Rg and Rg are not more than 6, <R> 10 <R> 12 b) -CH-CH-CH- ■ <R>11 where R10 = H, -CH3 or.-CH2 CH3 , R1X = H, -CH3 or -CH2 CH3 , R12 = H'~ CH3 or -CH2CH3 or R11' the saitun with Rio or Ri2 can ffiBe~ (CH2 ^4~' provided that at least one of R1Q/ R-^ eHer Ri2 = H' or .. c) -(CH2)4-, and in R 4 = H or; -CH 2-^ / where R13 = H, F, Cl, Br, N02 , phenyl or C <H>3 ' <.>