IE45227B1 - Carbostyrils - Google Patents

Abstract

The invention relates to organic chemistry. It relates to compounds of the formula: [FR2355828A1]

Description

This invention relates to bicyclic and tricyclic carbostyril derivatives having antihypertensive activity anti to processes for preparation of such compounds.

Sheppard, M.A., J. Am. Chem. Soc., 87 (11), 2410 (1955) and Gilbert, E.E. et al., J. Org. Chem., 30, 1001 (1965) disclose a process for adding hexafluoroacetone to aniline derivatives to give α,a - bis(trifluoromsthyl) - p - aminobenzyl alcohols.

Allied Chemical Corporation, in British Patent 1,029,048, discloses hexahalohydroxyisopropyl aryl derivatives as intermediates in the pre10 paration of aromatic carboxylic acids.

Jones, E. S., in U.S. Patents 3,405,177 and 3,541,152, discloses hexahalohydroxyisopropyl aromatic amines useful as intermediates in the preparation of azo dyestuffs, polyesters, polyamides, insecticides, plasticizers, and pharmaceuticals.

Gilbert, Ε. E., in U.S. Patent 3,532,753, discloses aromatic amino derivatives of hexahaloacetona useful as insecticides.

German OS 2,552,393 discloses compounds containing a ureido or isoureido function which have utility as antihypertensive agents. ttyer, H., et al., in U.S. Patent 3,907,807, discloses benzoquinolizine 20 antihypertensive agents; the following compound is exemplary: Many current antihypertensive agents produce unwanted side effects because of their undesirable mechanism of action. For example, guanethidine is an adrenergic neurone blocker, mecamylamine is a ganglion blocker, phenoxybenzamine is an a - adrenergic receptor blocker, and reserpine is a catecholamine depletor. Each of these mechanisms of action is undesirable because of the serious side effects produced. The compounds of this invention appear to lower blood pressure by a desirable mechanism of action—direct aripheral vasodilation—and, therefore have a distinct advantage over the above undesirably acting antihypertensive agents.

Furthermore, these compounds do not appear to produce central nervous system effects such as those seen with clonidine and a - methyldopa administration.

Accord ing to this invention there are provided compounds of the following formula, processes for their manufacture, and pharmaceutical compositions containing cnem: R, where Ri = H or alkyl of 1—4 carbons; R2 = H or alkyl of 1—4 carbons; provided when Rj = alkyl, R2 = H, —CH3 or—CH2CH3; or - 3 . «ϋ337 Ri + R2, taken together, are: Rg Ry t i (a) —ε—c— fc fc where Rg — K or —CHg; Ry = H or ~CHj; Rg = H or alkyl of 7—4 carbons; Ro = H or alkyl of 1—4 carbons; or R8 f R9s taken together, are—(CH2)g—; provided i) at least one of fi6, R7, Rg, or Rg = H; and ii) the s®t of the carbons of Rg, R7, R8o and Rg is not more than 65 Rio B12 is) —CH-CH-CH— ! Rn where Rig - H, —CH32 or —SHgOHg, Ru = H, —CH3, or —CH2CH3; RJ2 ” H, —CHg, or—CH2CH3; or Rn, taken together with Ri0 or Rig, is —(CH2)i,—; provided at least one of Rias Rn, or Ri?. = li; or c) (ClhJif 5 R3 = H, CH3, F, Cl, Sr, R02, HH2, or OH; Rg = H, or alkyl of 1—4 carbons; and . 4 .

R5 = H, acyl, or alkyl of 1—6 carbons.

Within the above general formula are those compounds wherein Rj = H or alkyl of 1—4 carbon atoms; R2 = H or alkyl of 1—4 carbon atoms; provided that the sum of carbons in Rx + R2 is not more than , and when Ri = alkyl, R2 = H, —CH3 or —CH2CH3; or Rj + R2, taken together, are: R I (β) —CH2-—-CH2—-> --CH—CH2—, R i (b) —CHg—CH2—CHg j —CH—Ch2—CH2— R R R i 1 ί io “CHg—'CH’—CH2—, ~λ,·Η—CHg——CH—(c) —(CH2)i,—where R = —CH3 or i;H2Ui3; R3 = H, CH„ f, Cl, Br, N02, NH2, OH; Ru = H, or alkyl of 1—4 carbons; and R5 = H, alkanoyl, aroyi, or alkyl of 1—4 carbons.

Preferred for their high degree of activity are those compounds of formula I where Rj and R2, taken together, are: Re R9 or R) 0 Rj12 —CH—CH—CH— I R11 > 5 , rt Ο £. b £ w £ Also preferred are those compounds where, taken independently: a) R3 is hydrogen; or b) Ri, is methyl or ethyl; or c) Rs is hydrogen.

More preferred are those compounds where Rj and R2 taken together, are: Rg Rg and R6, R7, and Rg are hydrogen or |l0 &12 —CR—CH—CH— , Rn and R10 and Ru are hydrogen.

Still more preferred are those compounds where: a) Rj and R2, taken together are: Rs R? C—C— or R12 —CH—CH-CH— i Rn uo b) R3 is hydrogen; c) Ri, is methyl or ethyl; d) Rg, R7 and R8 are hydrogen or R10 and RX1 are hydrogen; and e) R5 is as defined and more preferably is hydrogen.

When Rs = alkyl, a preferred definition is alkyl of 1—4 carbons and more preferably 1—2 carbons. - 6 ¢5227 The following compounds are specifically preferred, 2,3 - dihydro 9 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 7 methyl - 1H5H - benzo{ij)quinolizin - 5 - 5 - one; 2,3 - di hydro - 3,7 dimethyl - 9 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - W,5H. - benzo{ij}guinolizin - 5 - one; 2,3 - dihydro - 7 - ethyl 9 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} 1H5H - benzo{ij}quiRolizin - 5 - cne; 1,2 - dihydro - 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 6 - methyl - 4H. pyrrolo{3,2,l - ij}quinolin - 4 - one; 1,2 - dihydro - 2,6 - dimethyl 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 4H pyrrolo{3,2,l - ijlquinolin - 4 - one; and 1,2 - dihydro - 6 - ethyl 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 4H pyrrolo{3,2,l - ijlquinolin - 4 - one.

Acyl derivatives of the hydroxy function of the compounds of this invention of formula I show excellent antihypertensive activity. The acyl derivatives (i.e., uhere R5 is not hydrogen or alkyl) are hydrolyzed easily to the parent hydroxy compound (R5 - H), and it is believed that their antihypertensive effect is due to a facile in vivo hydrolysis. Acylation can be used to give derivatives with a variety of different physical properties, but with little difference in biological properties from the parent hydroxy compound. It is concluded, therefore, that the range of acyl groups is practically unlimited and not critical for antihypertensive activity. Among the acyl groups that can be used are alkanoyl, alkenoyl, and aroyl.

Synthesis Hexafluorohydroxyisopropyl amine precursors are prepared in the following manner: - 7 When Rx and R2 are hydrogen or alkyl of 1—4 carbon atoms, the precursors are prepared as shown in the following reaction scheme: C This reaction is described by Sheppard, W.A., 2· Am. Chem. Soc., 87, 2410 (1965). A mixture of the appropriate aniline derivative, anhydrous aluminum chloride, and hexafluoroacetone is heated until the reaction is completed. The product is triturated with chloroform and cooled; then filtered off and recrystallized.

Precursors in which Rj and R2 are joined together are prepared as 10 shown, by way of example, in ths following reaction scheme: The reaction is conducted in a sealed pressure reactor at temperatures from 80—200°C; it can also be conducted in a refluxing solvent, such as ben2ene or toluene, in a flask with hexafluoroacetone monohydrate, sesqui- 8 a s 3 3 ? hydrate, cr trihydrate. Acidic catalysts such as A1C13, BF3, or £ to!uenesultonic acid can be used but are not necessary. Reaction time is usually 4—12 hours. A temperature of 100—120°C and use of 1—5 mole percent of A1C13 are preferred, based on the amine (A).

A modified method for preparing these precursors which produces higher yields for many of the compounds, especially the indolines, involves attaching a suitable protective group, such as benzyl or substituted benzyl, C' A2 - 9 where ¢5337 X = Cl or Br; R13 = H, F, Cl, Br, N0z, phenyl, or CH3; n = 2, 3 or 4.

Starting amine (A) is treated with a benzyl halide to give a tertiary N - benzylamine (A1). This is heated with hexafluoroacetone to give the adduct A2 which is then hydrogenated to remove the benzyl group to give the desired compound (C). Compounds (Cj and alkyl substituted derivatives thereof, as well as, their preparation are -described in British Patent. No. 1583258.

The hydrogenation step occasionally requires excess acid as a cocatalyst. Hydrogenolysis is attempted without addition of acid, and if little or no uptake Gf hydrogen is observed, acid is added (for example, concentrated hydrochloric acid), and the reaction is allowed to proceed.

The amine starting materials are either known in the art or easily prepared from those known in the art. flsthods of making the various ring systems, however, ars outlined as follows: Indolines sr9 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) p.l.

Tetrahydroqui noli nes See Elderfield, R.C Sons, Inc., New York, NY , Heterocyclic Compounds Vol. 4, John Wiley & (’-352) p.l.

Benzazepines + NH2OH-HC1--> In the reaction scheme outlines 3,4 - dihydro - 1 - (2H) - naphthalenone is contacted with hydroxylamine hydrochloride to give the corresponding oxime.

The oxime is rearranged by treatment with polyphosphoric acid to 5 give the lactam 1,3,4,5 - tetrahydro - Iji - 1 - benzazepin - 2 - one.

Reduction of the lactam with LiAlHif gives 2,3,4,5 - tetrahydro 1H - 1 - benzazepine.

The ketone starting materials for the parent systems discussed above are known in the art and are commercially available.

Intermediate amides (E) are prepared as shown in the following reaction: E where Rls R2 and Ri, are as previously defined except that R! and R2 are not both alkyl and Ri, is not hydrogen, R'3 is hydrogen or CHS, and R is an alkyl group of 1—5 carbons. - 12 Tiie amide (£) is prepared by heating equimolar amounts of amine (C) and 3 - ketoester (D) in an oil bath. The preferred temperature range is e.g. 180—220°C. Alternatively, the reactants can be refluxed together in a high-boiling solvent, for example, xylene.

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

When R 3 = H and Rk = CH3 the amides (E) are prepared more conveniently and in better yield using diketene instead of the 3 - ketoester (D).

An equimolar amount, of diketene >« added to amine (C) dissolved in an inert solvent (for example, anhydrous tetrahydrofuran or toluene) held 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 crude product is often satisfactory for cyclization in sulf·. k acid, but it can be purified by recrystallization and/or chromatography.

The final products are readily prepared as shown in the following cyclization reaction: - 13 Cyclization is accomplished by heating tha amide (E) in a condensing agent, such as sulfuric acid or polyphosphoric acid. Usually, heating in concentrated sulfuric acid on a steam bath for about 30— minutes completes 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 be conveniently checked by removing a small test sample, isolating the solids, and analyzing by thin layer chromatography. The product (r) is isolated by pouring the sulfuric acid solution into excess ice water, removing the precipitate by filtration, washing, and drying. Further purification, if necessary, can be done by recrystallization and/or chromatography.

When Rj and R2 are alkyl in Figure E, cyclization is not observed. Compounds described by Figure F where Rx and R2 are alkyl can be prepared by cyclization of the amide E where Rx is alkyl and R21S H. The product F has Rj = alkyl and R2 = H. When the product F is treated with R 5X, (R% = alkyl of 1—6 carbons or ___ where R13= H, F, Cl, Br, W02, phenyl, or CH3; X = halogen), an alkyl halide such as methyl iodide or aralkyl halide such as benzylbromide, in a solvent such as dimethylformamide with a base such as potassium carbonate, or sodium hydride, the oxygen-alkylated compound Fj is ¢5227 The compound Fi may then be alkylated on nitrogen by use of base such as sodium hydride or thallium ethoxide in a solvent such as DMF with an alkyl halide or sulfate, R2X, (R2 = —CH3 or—CH2CH3, X = halogen or sulfate) to give F2.

The alkyl or aralkyl group P.B or. compound F2 may be removed as necessary or desired by an appropriate reaction such as hydrolysis with aqueous hydrobromic acid or hydrogenolysis to give compound F3, where Rj and R2 are alkyl. The compounds wherein R5 is benzyl or substituted benzyl are valuable as intermediates and form another aspect of our invention. - 15 Compounds of formula I where R3 is other than hydrogen or methyl are preferably prepared from F (R3 = hydrogen) by well-known electrophilic substitution reactions, e.g.. chlorination, bromination, and nitration.

The fiO2 compound can be reduced to the FiHz compound, which is in turn useful.for preparing compounds where R3 = fluorine or OH.

To make compounds where Rtj is hydrogen the process is modified by using malonyl dichloride instead of ketoester (D). The resulting halfamide chloride of malonic acid (E, where Ri. = Cl) is then cyclized with a suitable condensing agent, for example, phosphorous oxychloride, to give G, which can be hydrogsnolytically cleaved to H.

C Hz Pd/C Alternatively, alkyl malonyl chloride can be used ester (D) to give the half-amide ester of malonic acid instead of keto(E, where l\= - 16 <ί 52 2 7 alkoxy e.g. OC2H5) which is cyclized with a condensing agent, for example, sulfuric acid, to give F where Ri, is OK. This is then treated with phosphorous pentachloride in phosphorous oxychloride solution to give G, which is converted to H as shown above.

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

Ethers are prepared from F by converting it to a salt by treating with a suitable base (for exsmp.'e, potassium tert.- butoxide), then 0 alkylating the salt by heating with a dialkyl sulfate or alkyl halide.

The following examples further illustrate the methods for synthesis 15 of the compounds of formulae I and II. All parts are by weight and all temperatures are in degrees centigrade unless otherwise indicated.

Part A—Prep·*: ation of Intermediate Compounds of Formula II Example 1 - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 5 - quinolinemethanol - 17 ! rj ¢5 cy rf λ « ’ Two hundred grams of 1,2,3,4 - tetrahydroquinoline and 2 g anhydrous aluminum chloride are added to a one liter stainless steel reactor.

The reactor is cooled and evacuated, 265 g (1.60 moles) hexafluoroacetone is added, and it is sealed and heated to 120°C with shaking for ten hours.

The reactor is then cooled to room temperature and vented. The contents are decanted to give a red semicrystalline solid, which is treated with 250 ml of methylene chloride and filtered. The filter cake is washed with three additional 250 ml portions of methylene chloride. The residual orange solid is treated with decolorizing carbon in hot 1 10 chlorobutane and filtered. From the filtrate is obtained 310 g (1.04 moles) α,a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol, as a pale yellow crystalline solid, m.p. 115—116°C.

Anal. Calcd. for Ci2HnF6M0r C, 48.17; H, 3.71; N, 4.68 Found: C, 48.46; H, 4.06; N, 4.93 Example 2 α,a - bis(trifluoromethyl) - 2,3 - dihydro - IH - indole - 5 methanol A. 1 - benzylindoline To a stirred refluxing mixture of 119 g (1 mole) of indoline, 800 ml of toluene (other solvents, e.g. isopropyl alcohol, are satisfactory), and 207 g (1.5 mole) of pulverized, anhydrous potassium carbonate is added dropwise 126.5 g (l.mole) of benzyl chloride. When addition is complete, refluxing is continued until evolution of gas ceases as evidenced by a gas meter (about three hours). The mixture is allowed to cool, and the solids kre removed by filtration. The filtrate is evaporated, - 18 45237 and the residue is distilled to give 153 g (73%) of 1 - benzylindoline, b.p. 162—155° (4.5 mm). Β. 1 - benzyl - α,λ - bis(trifluoromethyl) - 2,3 - dihydro - TH - indole 5 - methanol.

A stirred mixture of 83.6 g (0.4 mole) of 1 - benzylindoline, 250 mi of toluene, and 77.2 g (0.4 mole) of hexafluoroacetone sesquihydrate is refluxed for four hours. The mixture is then refluxed under Dean-Stark conditions until --'ll water is removed. The solution is evaporated.

The residue is dissolved in 590 ml of methyl cyclohexane (heating, if necessary) and allowed to crystallize under nitrogen atmosphere. The gummy crystals are filtered off, washed, and dried to give 116.3 g (77%) of 1 - benzyl - &,« - dis(trifluoromethyl) - 2,3 - dihydro - IH - indole 5 - methanol, m.p. 85—30°. Because solutions of these crystals oxidize readily, further purification by recrystallization entails needless loss; therefore, the crude crystals are used for the next step.

C. α,a - bis(trifluor A mixture of 55 g (0.15 mole) of 1 - benzyl - a,a - bis(trifluoromethyl) - 2,3 - dihydro - IH - indole - 5 - methanol, 200 ml of alcohol, ml of concentrated hydrochloric acid, and 2 g of 10% palladium on charcoal is shaken in a Parr apparatus at an initial pressure of three atmospheres until no further change of 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 - 19 £6227 the solution is cooled in an ice bath. The crystals are filtered off to give 33.3 g (80%) of α,α - bis(trifluorcmathyl) - 2,3 - dihydro - 1J4 indole - 5 - methanol, m.p. 161—152°.

Example 3 Example 2 is followed except £ - nitrobenzyl chloride is used in place of benzyl chloride. The first intermediate, 1 - £ - nitrobenzylindoline, m.p. S5—97° is obtained. This is then converted to the second intermediate. 1 - £- nitrobenzyl - a,a - bis (tri fluoromethyl) - 2,3 dihydro - IH - indole - 5 - methanol. This is inconvenient to purify because of reaction of its solutions v/ith air, so it is promptly hydrogenated to give α,α * bis (trifl uoromethyl) - 2,3 - dihydro - lii - indole 5 -methanol, m.p. 160—161°.

Examples 4—17 Using the procedure of Examples 1 or 2, the following compounds can be made from the appropriate starting material which is shown. 4, Starting Material H m.p. 163 - 164° Starting Material Η - 21 Starting Material Product Starting Material Product Part Β — Preparation of Compounds of Formula I Example 18 To a stirred solution of 32,9 g (0,11 mole) of α,a - bis(trifluoro- 23 ¢3337 methyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol in an inert solvent (e.g. dry toluene or tetrahydrofuran) is added 9.2 g (0.11 mole) of di ketene. The mixture is refluxed for 30—40 minutes, cooled and evaporated, The residue is triturated with 150 ml of dibutyl ether to give crystals. The crystals are separated by filtration to give 24.8 g (64%) of α,α - bis(trifluoromethyl) - 1 - (1,3 - dioxobutyl) - 1,2,3,4 tetrahydro - 6 - quinolinemethanol, m.p. 115—117°.

B. A stirred mixture of S.0g(0.02 mole) of α,a - bis(trifluoromethyl) 1,2,3,4 - tetrahydro - 6 - quinolinemathanol, 2.6 g (0.02 mole) of ethyl acetoacetate, and 100 ml of xylene is refluxed for 16 hours. The mixture is allowed to cool and is evaporated. The residue is triturated with a mixture of toluene, ethyl acetate, and hexane (60:10;30). The insoluble portion is filtered off, washed with ether, and dried to give 1.6 g (23% of α,a - bis(trifluoromethyl) - 1 - (1,3 - dioxobutyl) - 1,2,3,4 - tetra15 hydro - 5 - quinolinemathanol.

C. ‘ A solution of 10.5 g (0.027 mole) of a,a - bis(trifluoromethyl) - 1 (1,3 - dioxobutyl) - 1,2,3,4 = tetrahydro - 6 - quinolinemethanol in 30 ml of concentrated sulfuric acid is heated on a steam bath for 30—45 minutes, cooled to approximately 60°C, and poured onto ice. When the ice is melted, the precipitate is filtered off, washed with water, and dried. The solid is recrystallized 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 - benzoiij} - quinolizin 5 - one, m.p. 2S5—296°.

Anal, for C16H13F6N02: Calcd.: C, 52.62; H, 3.59; N, 3.84 Found: C, 52.58; H, 3.78; N, 3.85 - 24 4 & 3 2 7 A stirred mixture of 23.5 g (0.075 mole) of a,a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydra - 2 - methyl - 6 - quinolinemethanol, 100 ml of dry toluene, and 8.3 g (0.099 mole) of diketene is refluxed for 16 hours under dry nitrogen. The toluene is evaporated. The residue, which is crude «,a - bis (tri fluoromethyl) -1-(1,3- dioxobutyl) 1,2,3,4 - tetrahydro - 2 - methyl - 6 - quinolinemethanol, is dissolved in 100 ml of concentrated sulfuric acid and is heated on a steam bath for one hour. The solution is poured into ice water. When the ice is melted, the insoluble material is extracted with ether. The ether solution is dried and evaporated to give 26.8 g of residue. Trituration of the residue with a mixture of toluene, hexane, and ethyl acetate (60:30:10) induces crystals to separate. The crystals are filtered off, and two recrystallizations frcm toluene arid ethyl acetate mixture (9:1) gives .0 g (35%) of crystals of 2,3 - dihydro - 3,7 - dimethyl - 9 - {2,2,2 trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 1H,5H - benzoiij}- 25 ί, 5 3 3 7 quinolizin - 5 - one, m.p. 195—198°.

Examples 20—24 The appropriate tetrahydroquinoline can be used in place of α,αbis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 2 - methyl - 6 - quinolinemethanol of Example 19 for conversion to the corresponding benzoquinolizi none as shown in the following chart: Example Tetre-iydroqui nol i ne Product - 26 Example Tetrahydroqui no!i ne Product Example 25 - 27 A mixture of 15.0 g (0.05 mole) of o,e - bis(trifluoromethy!) 1,2,3,4 - tetrahydro - 6 - quino!inemethanol and 7.2 g (0.05 mole) of ethyl propionylacetate is heated with stirring in an open flask in an oil bath at 200—220°. When the internal temperature rises to 180— 200°, the mixture is then allowed to cool. The crude product is chromatographed on silica gel successively with the following eluents: (!) toluene-hexane (50:40), (2) toluene - ethyl acetate - hexane (60:10:30), and (3) toluene = ethyl acetate - hexane (60:20:20). Later fractions yield 5.3 g (26%) of a red oil, which is identified by nmr spectroscopy as α,a - bis(trifluoromethyl) -1-(1,3- dioxopentyl) - 1,2,3,4 tetrahydro - 6 - quino!inemethanol. The 5.3 g of oil is dissolved in ml of concentrated sulfuric acid and heated on 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 recrystallization from dibutyl ether, gives 0.7 g (14%) of 2,3 - dihydro - 7 ethyl - 9 - (2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyll lHD5jf - benzoiijlquinolizin - 5 - one, m.p. 209—210°.

Example 26 To a stirred suspension of 7.3 g (0.02 mole) of 6,7 - dihydro - 9 {2,2,2 - trifluoro - 1 - hydroxy -1-(1- tri fluoromethyl)ethyl} - 1 methyl - 3H.5H - benzoijjiquinolizin - 3 - one in 100 ml of concentrated hydrochloric acid is gradually added 1.95 g (0.01 mole) of calcium hypo5 chlorite (73.2%) by means of a powder addition funnel. The mixture is stirred for 5 hours at room temperature. The mixture is poured into 400 ml of cold wat-'r. The white solid is filtered off, washed with water, and dried re give 6.0 g of solid. A portion is purified by dissolving 4.2 g in 25 ml of trifluoroacetic acid and adding water, a little at a time, to incipient precipitation. The mixture is allowed to cool and crystallize to give 1.1 g of 6 - chloro - 2,3 - dihydro - 9 - {2,2,2 tri fluoro - 1 - hydrcxy - 1 - (trifluoromethyl)ethyl} - 7 - methyl 1H.5H - benzoiijlquinolizin - 5 - one, m.p. 266—268°.

Example 27 Br To a stirred suspension of 7.3 g (0.02 mole) of 6,7 - dihydro - 9 (2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl) - 1 - 29 68331? methyl - 3J{,5j{ - benzol ij} - ouinolizin - 3 - one in 100 ml of warm concentrated hydrochloric acid is added dropwise 3.2 g (0.02 mole) of bromine. The mixture is allowed to stir for IS hours, and then the precipitate is filtered off, washed with water, and dried. The solid is recrystallized from alcohol and dried in an oven at 409° to give 6.3 g (71%) of white crystalline 5 - bromo - 2,3 - dihydro - 9 - {2,2,2 trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 7 - methyl 1H,5H - benzo - {ijlquinolizin - 3 ~ one, m.p. 265—266° Example 28 To a stirred solution of 343 g (1.26 mole) ef «,o - bis(trifluoromethyl) - 2,3 - dihydro - 1J{ - indole - 5 - methanol in 1880 ml of dry tetrahydrofuran cooled in an ice bath is added dropwise 106 g (1.26 mole) of diketene. The solution is allowed to warm to room temperature for 16 hours and then is refluxed for 30 minutes. The solvent is evaporated to give 463 g (100%) af crude «,« - bis (tri fluoromethyl) -1-(1,3dioxobutyl) - 2,3 - dihydro - IH - indole - 5 - methanol, m.p. 150—151°.

The product is added with stirring to 1450 ml af concentrated sulfuric acid, and the solution is heated on a steam bath for 45 minutes. The mixture is cooled to approximately 60° and is poured into ice water. The - 30 4 3327 solid is filtered off, washed with water, and dried to give 315 g of crude solid. The solid is recrystallized from dimethylformamide to give 273 g (62%) of 1,2 - dihydro - 8 - {2,2,2 - trifluoro - 1 - hydroxy 1 - (trif!uoromethy!)ethyl} - 6 - methyl - 4H - pyrrolo{3,2,l - ijjquinolin 4 - one, m.p. 337—338°.

Example 29 To a stirred mixture of 7.0 g (0.02 mole) of 1,2 - dihydro - 8 {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyi)ethyl} - 6 10 methyl - 4H - pyrrolo{3,2,l - jjlquinolin - 4 - one and 70 ml of trifluoroacetic acia is added 4.2 g (0.042 mole) of potassium nitrate.

The mixture is stirred for 16 hours at room temperature and then is refluxed for 30 minutes. The mixture is poured into 300 ml of water.

The solid 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 - (trifluoromethyi)ethyl} - 6 methyl - 5 - nitro - 4H - pyrrolo{3,2,l - ijjquinolin - 4 - one, m.p. 289— 290° (dec).

Anal, for C15HleF6N204: Calcd.: C, 45.46; H, 2.54; N, 7.07 Found: C, 45.64; H, 2.79; N, 6.82. - 31 4 S 2 3 7 Example 30 A mixture of 3.0 g (0.0075 mole) of 1,2 “ dihydro - 8 - {2,2,2 trifluoro - 1 - hydroxy - 1 - (trif1uoromethyl)ethyl} - 6 - methyl - 5 5 nitro - - pyrrolo{3,2,l - ijlquinolin - 4 - one, 150 ml of alcohol, and 0.5 g of 10% palladium on charcoal is hydrogenated at an initial pressure of 3 atmospheres in a Parr shaker apparatus until uptake 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 10 dihydro - 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} 5 - amino - 6 - methy! - 4H - pyrrolo{3,2,l - ijlquinolin - 4 - one, m.p. 292—293°. - 32 a) To a stirred solution of 6.0 g (0.02 mole) of α,α - bis(trifluoromethyl) - 2,3 - dihydro - 2 - methyl - Ijj - indole - 5 - methanol in ml of anhydrous tetrahydrofuran is added 1.9 g (0.022 mole) of di ketene. After 16 hours at room temperature, the solution is refluxed for one hour. The solvent is evaporated, and the residue is recrystallized from dibutyl ether to give 5.7 g (74%) of a,a - bis(trifluoromethyl) - 1 (1,3 - dioxobutyl) - 2,3 - dihydro - 2 - methyl - IH - indole - 5 methanol, m.p. 118—119°. b) A solution of 2.8 g (0.0073 mole) of the product in 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. Recrystallization 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 15 pyrrolo{3,2,l - ij}quinolin - 4 - one, m.p. 230—231°.

Examples 32—38 The appropriate indoline used in place of α,α - bis(trifluoromethyl) 2,3 - dihydro - 2 - methyl - Ijl - indole - 5 - methanol of Example 31 can be converted to the corresponding heterocyclic ring-substituted derivative as shown in the following chart; Example No. Indoline Product - 33 Example No.

Moline Product - 34 Example No.

Indoline !S2a, Product - 35 <3-5 2 2 7 Example 33 A. A stirred mixture of 13.7 g (0.05 mole) of «,c - bis(trifluoromethyl) 2,3 - dihydro - Ijj - indole - 5 - methanol and 7.2 g (0.05 mole) of ethyl propionylacetate is heated at 200° in an oil bath for 3 hours. The mixture is allowed to cool and is triturated with ether. The mixture is filtered, and the filtrate is evaporated. The residue is chromatographed on silica gel with a mixture of to’uene - ethyl acetate (60:40). A fraction is obtained, which can be recrystallized from 1 - chlorobutane to give 3.0 g (16%) of crystals, m.p. 118—119°, - bis(trifluoromethy!) -1-(1,3- dioxopentyl) - 2,3 - dihydro - IH - indole - 5 methanol.

B. A stirred mixture of 2.9 g of α,α - bis (tri fluoromethyl) -1-(1,3dioxopentyl) - 2,3 - dihydro - Ijj - 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 - (tri'fluoromethyl)ethyl} - 4jj - pyrrol{3,2,l jj}quinolin - 4 - one, m.p. 251—252°. - 36 Example 40 Use of ethyl valerylacetate in place of ethyl pripionylacetate of Example 39 gives 1,2 - dihydro - 6 - £ - butyl - 8 - {2,2,2 - trifluoro 5 1 - hydroxy - 1 - (trifluoromethyl) - ethyl} - 4H - pyrrolo - {3,2,1 ijlquinolin - 4 - one.

Example 41 By the method shown in Example 31, α,a - bis(trifluoromethyl) 10 2,3,4,5 - tetrahydro - 1H - 1 - benzazepine - 7 - methanol is converted to α,a - bis(trifluoromethyl) - 1 -(1,3- dioxobutyl) - 2,3,4,5 - tetrahydro IH - 1 - benzazepine - 7 - methanol, m.p. 159—171°, which is cyclized by heating in sulfuric acid (in this instance at 120° for 24 hours) to give - 37 5,6,7,8 - tetrahydro - 10 - {2,2,2 - trifiuoro - 1 - hydroxy - 1 - (trifl uoromethyl) ethyl} - 1 - methyl - 3H - azepinoi3,2,1 - ijjquinolin - 3 one, m.p. 197—198°.

Example 42 ί, 5 3 3 7 A mixture of 63.2 g (0.68 mole) of aniline, 2 g of anhydrous aluminum chloride, and 135 g (0.81 mole) of hexafluoroacetone is heated at 140° in an autoclave for 16 hours. The product is triturated with 800 ml of chloroform and cooled to 0°. The solid is filtered off and recry10 stallized from methyl cyclohexane - dibutyl ether (50:50) to give 104 g (59%) of a,a - bis(trifluoromethyl) - 4 - aminobenzenecarbinol, m.p. 145—150° {W. A. Sheppard, J. An. Chem. Soc. 87, 2410 (1965), reports m.p. 150—151.5°}.

By the method shown in Example 31, the a,cs - (trifluoromethy!) - 4 15 amino - benzenecarbinol is converted to κ,α - bis(trifluoromethyl) - 4 (1,3 - dioxobutylamino)benzenecarbinol, which is cyclized uy heating in sulfuric acid to give 6 - (2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifl uoromethyl )ethyl) - 4 - methy! - 2 - (IH) - quinolinone, m.p. 157—158°. - 38 fip o «ί ? Examples 43—48 By the procedure of Example 31b, the following compounds can be made from the appropriate starting materials which are shown.

Starting Materials Products A mixture of 82.0 g (0.68 mole) of N - ethylaniline, 2 g of anhydrous aluminum chloride, and 135 g of hexafluoroacetone is heated at 140° in - 40 '833 3 an autoclave for 16 hours. The crude product is chromatographed on 700 g of silica gei with chloroform as eluent. The initial fractions are recrystallized from methyleyclohexane to give 73 g (37%) of α,a bis (tri fluoromethyl) - 4 - (ethylamino) - benzenecarbinol, m.p. 90—92°.

By the method shown in Example 31, the α,a - bis(trifluoromethyl) 4 - (ethylamino) - benzenecarbinol is converted to α,a - bis(trifluoromethyl) - 4 - {N - (1,3 - dioxobutyl) - N - ethylaminolbenzenecarbinol, m.p, 91—92°, wi.'h is cyclized by heating in sulfuric acid to give 1 ethyl - 6 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} 4 - methyl - 2 - (IH) - quinolinone, m.p. 185—187° (in this instance purified by trituration of the product with ether). 3y the procedure of Example 31, the following compounds can be made from the appropriate starting materials which are shown.

Starting Materials Products QH3 - 41 4 53 3 7 Starting Materials Products To a solution of β - {2,2,2 - trifluoro 1 - hydroxy - 1 - (tri5 fluoromethyl)ethyl} - 4,8 - dimethyl - 2 - (Iji) - quinoline in dimethylformamide is added potassium carbonate end benzyl bromide. The solution - 42 $ 822 ? is heated with stirring at reflux under nitrogen.

When the reaction is complete as indicated by thin layer chromatography, the solvent is removed at reduced pressure and the residual c material is treated with water and extracted into ether. The ethereal solution is dried with anhydrous magnesium sulfate and filtered. The ether is evaporated at reduced pressure. The residual material is chromatographed on silicic acid to give 6 - {2,2,2 - trifluoro - 1 benzyloxy - 1 - (trifluoromethyl)ethyl} - 4,8 - dimethyl - 2 - (IH) quinolinone, m.p. 162—164°.

To a solution of 6 - {2,2,2 - trifluoro - 1 - benzyloxy - 1 (trifluoromethyl)ethyl} - 4,8 - dimethyl - 2 - (IH) - quinolinone in dimethylformamide is added an equivalent of thallium ethoxide. The solution is stirred under nitrogen. To the solution is added methyl iodide, and the solution is stirred and heated to 50° until thin layer chromatography indicates ths 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 residual material is extracted with hexane and the filtered solution is evaporated at reduced pressure. The residual material is heated to 250° in a nitrogen atmosphere for 4 hours. At the end of this period, the residual material is chromatographed on silicic acid to give 6 - {2,2,2 - trifluoro - 1 - benzyloxy - 1 - (trifluoromethyl)ethyll - 1,4,8 - trimethyl 2 - (IH) - quinolinone.

To a solution of 6 - {2,2,2 - trifluoro - 1 - benzyloxy - 1 - (trifl uoromethyl )ethyl) - 1,4,8 - trimethyl - 2 - (1JH) - quinolinone in - 43 55227 ethanol is added 10% palladium on carbon catalyst. The solution is arranged on a Parr hydrogenation apparatus and shaken with 50 pounds of hydrogen pressure. Shaking is continued until no further hydrogen uptake is noted. The solution is filtered and evaporated to give 6 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl! 1,4,8 - trimethyl - 2 - (IH) - quinolinone, m.p. 241—243°.

Examples 55—53 By a procedure similar to Example 54, the following compounds can be made from the appropriate starting materials.

Starting Materials Products - 44 8 3 2 7 Starting Materials Products - 45 To a stirred solution of 15.0 g (0.05 mole) of b,q - bis (trifluoromethyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemsthanoi in 50 ral of anhydrous toluene at reflux is added dropwise 7.1 g (0.05 mole) of malonyl dichloride. Reflux is continued until evolution of hydrogen chloride is complete, Tha toluene is then removed by evaporation, and the residue is refluxed with 120 ml of phosphorus oxychloride for two hours. The solution is poured into ice water with stirring. When the excess phosphorus oxychloride is 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 frora a minimum of alcohol to give 7 - chloro - 2,3 - dihydro - 9 - {2,2,2 - trifluoro 1 - hydroxy - 1 - (trifluoromethyi)ethyl} - '!H35H - benzo{ij}quinolizin 5 - one, m.p. 283—284°.

A mixture of 0.7 g of 7 - ehk···-? - 2,3 - dihydro - 9 - {2,2,2 trifluoro - 1 - hydroxy - 1 - (tr;i'luoro3iethyl)ethyl} - 1)4,51(- benzo{ij}quinolizin - 5 - one, 150 g»' of glacial acetic acid, 5 g of sodium acetate trihydrate, and 0.5 g of 10% palladium on charcoal is hydrogenated in a Parr shaker apparatus for 4 hours at an initial pressure of 3 atm. The catalyst is removed by filtration, solvent is removed by evaporation, and the residue is triturated with water. The insoluble material is filtered off, dried and recrystallized to give 2,3 - dihydro - 9 {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 1H,5H benzoiijlquinolizin - 5 - one, m.p. 295—296°. - 46 ζ, η σ ο t*, tt J »<* M ( Example 61 A stirred suspension of 3.5 g (0.01 mole) of 1,2 - dihydro - 8 {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyll - 6 5 methyl - 4H - pyrrolo{3,2,l - jjlquinolin - 4 - one and 50 ml of propionic anhydride is refluxed for four hours. Then 50 ml of water is added cautiously to the refluxing mixture. The mixture is stirred with a mixture of 200 ml of ether ani 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 sulfate, and evaporated.

The residue is recrystallized to give 2,45 g (60%) of 1,2 - dihydro 8 - {2,2,2 - trifluoro - 1 - hydroxy - I - (trifluoromethyl)ethyl} 6 - methyl - 4H - pyrrolo{3,2,l - jjlquinolin - 4 - one propanoate, m.p. 136—137°.

Example 62 Substituting acetic anhydride for the propionic anhydride in Example 61 gives 1,2 - dihydro - S - {2,2,2 - trifluoro - 1 - hydroxy 1 - (trifluoromethyl)ethyl} - 6 - methyl - 4H ~ pyrrolo{3,2,l - ij}quin- Example 63 A stirred mixture of 3.5 g (0.01 mole) of 1,2 - dihydro - 8 {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl} - 6 methyl - 4H - pyrrolo{3,2,l - jjjquinolin - 4 - one, 4 ml of anhydrous pyridine, and 2.8 g (0.012 mole) of lauroyl chloride is heated at reflux until homogeneous. The mixture is cooled and poured into excess 2N HCl. The mixture is extracted with ether. The ether extract is washed with cold 2N NaOH and then with saturated sodium. chloride solution; it is then dried (KgSOi.) 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,l ijjquinolin - 4 - one laurate, m.p. 72—73°. - 48 ••g I't ·> O t*» ii «I fi ti C Anal, for C21|H33FqN03ϊ Calcd.: C, 60.78; H, 6.23; N, 2.63 Found: C, 61.00; H, 6.37; N, 2.76 Examples 64—67 Following the procedure of Example 63 and using the appropriate chloride in place of lauroyl chloride, one can make the following products: Example No. Ac:i Chloride Product isovaleryl chloride - 49 § 3 3 3 7 Example No.

Acid Chloride Product Example 58 To a stirred mixture of 3.8 g of 1,2 - diiydro - 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl Jethyl} - 6 - methyl - 4H ·· pyrroloi3,2,l -,ijJguinolin - 4 - one and 20 ml of dry dimethylformamide is added 1.3 g (0.012 mole) of potassium tert - butoxide in a dry nitrogen atmosphere. The mixture is heated gently to 100° and is allowed to cool. Than 1 ml (1.3S g, 0.011 mole) of dimethylsulfate is added, and the mixture is warmed gently to 100°. The mixture is allowed to cool to room temperature and is poured into 100—200 ml of water. The precipitate is filtered off and then is triturated with 10% sodium hydroxide solution. The insoluble material is filtered off, washed with water, - 50 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 - 4Ji - pyrro1o{3,2,l - ijlquinolin - 4 - one, m.p. 242—243°.

Example 69 By using diethyl sulfate in place of the dimethyl sulfate in Example 68 one obtains 1,2, - dihydro - 8 - {2,2,2 - trifluoro - 1 - ethoxy 1 - (trifluoromethyllethyl} ~ 6 - methyl - 4H - pyrrolo{3,2,l - ijlquin10 olin - 4 - one, m.p. 189—190°.

Dosage Forms The antihypertensive agents of formula I can be administered to treat hypertension by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical - 51 4 3 3 3 5 practice.

The dosage administered will, of course, vary depending upon known factors such as the phansacodynaniic characteristics of the particular agent, and its mode and route of adainistration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be e.g. 0.91 to 50 milligrams per kilogram of body weight. Ordinarily 0.05 to ¢0, end preferably 0.2 to 20, milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release forai is effective to obtain desired results For the more potent compounds the daily dosage ranges are 0.01 to 10 milligrams per kilogram, preferably 0.0? to W milligrams per kilogram, and more preferably 0.05 to 5 mi 111.,.¾¾ ?sw kilogram.

Dosage forms (composicions) suitable for internal administration contain e.g. from 1.0 milligrams fc 100 mi1ligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily ba present 'x en amount of e.g. 0.5—95% by weight based on the total weight of the composition.

The active ingredient can be administrered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally, in sterile liquid dosage forms Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate and stearic acid. Similar diluents can be used to - 52 4333? make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

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

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 5 milligrams of powdered active ingredient, 150 mi‘iigrams of lactose, 32 milligrams of talc, and 8 milligrams magnesium stearate.

Capsules A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 2 milligrams of the active ingredient.

The capsules are washed in petroleum ether and dried.

Tablets A large number of tablets are prepared by conventional procedures - 53 so that the dosage unit is 15 mill'/grams of active ingredient, 7 milligrams of ethyl cellulose, 0.2 milligrams of colloidal silicon dioxide, milligrams of magnesium stearate, 11 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 93.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension An aqueous suspension ‘is prepared for oral administration so that each 5 milliliters contain 10 milligrams of finely divided active ingredient, 500 milligrams of acacia, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., 5 milligrams cf sodium saccharin, and 0.025 milliliters of vanilla rinctor-·.

Utility The antihypertensive activity of the compounds of formula I is detected with a procedure using KC3 hypertensive rats, which has been shown te be a good predictor of human efficacy.

Rats are made hypertensive by subcutaneous implantation of pellets of desoxycorticostarone acetate (DOCA) and by giving saline solution to drink essentially according to the method described by Sturtevant {Annals of Internal Medicine, 49, 1281 (1358)}. Graded dose levels of each compound are administered orally to groups of 8 hypertensive rats. The compound is prepared in an aqueous polyvinyl alcohol/acscia vehicle and administered at a volume to body weight ratio of 5.0 ml/kg. Sixteen hypertensive rats receiving ths aqueous vehicle by the same route serve as controls for each test. At various intervals of time after treatment, - 54 5 ‘-5237 usually 90 minutes, the systolic arterial blood pressure of each rat is determined by a modification of the microphone-manometer technique {Friedman, M. and Freed, S.C., Proc. Soc. Exp. Biol., and Med., 70, 670 (1949)]. That dose of compound which produces a 30 mm mercury (mmHg) reduction in blood pressure when compared to the mean systolic arterial blood pressure of the control animals is then determined (Effective Dose 30).

When testin'; oy this procedure, the following ED30 dosages were determined.

Antihypertensive Carbostyrils Compound Rs ED30 mg/kg Ri Rz Rs R, —CH2—CH2—CH2— H CH3 H 1.0 CH, j J —CH2-—CH,—CH-— H ch3 H 0.66 CH, —ch-ch2—ch2~ H ch3 H 3.5 —ch2—ch2~ch2— H —CH^CH 3 H 0.27 - 55 CcSpaUtid R, R2 •*3 D( ‘-s £D30 Hi!/kg Cl CK3 ri . 1.5 -ch2-sh2-ch2— sif Cri3 π 9.0 ——CHgT^Vn-?—r- Uu2 Cri. Li l.s *CM —c8* CH- H 5.4 ~ch2—ch,— i! r! 0.13 ru γ“3 I —“Vi'(2—blj—·“ H Ck5 H 0.047 ch3 ~CH-€H2—· H (¾ ri 0.50 —SH2—Cti2— 3 K 0.11 —:k2-ck?-^H2-ch2 F ri 1.3 ck3 ri Η -¾ ri 3.7 C2Hs H !-! pij ’-‘*3 K 1.3 ' H ri H CH:. ri 4,1 H cj >i Cris- Π 0.4 H —ch2ch3 H es H 1.2 H —CCHghCHj H ts’il H 5.2 ri H H -3—9 —ch2—ch2— H Cri3 propionate 0.22 —CH2—CH2— ri '••‘3 . acetate 0.20 —ch2—ch2— ri Ch3 laurate 0.12 CK2—-CH2— H Cri, benzoate 0.25 ——^Hg—CK2—«- ;j ch3 ch3 0.35 —-CH2—CH2 H Cri3 CH3CH2 0.50 WHAT WE CLAIM IS:-

Claims (10)

1. A compound of the formula: where R x = H or alkyl of 1—4 carbons; R 2 = H or alkyl of 1—4 ca. ; provided when R, - alkyl, R z = H, —CH 3 or —CH 2 CH 3 ; or Rj + R 2 , taken together, are: R 6 «9 where R 3 = H or CH 3 ; R 7 = H or --CH ji R B = K or alkyl of 1—4 carbons; Rr, = H or alkyl of 1—4 carbons; or Ro + Rg, taken together, are —(CH 2 )i*—; provided i) at least one of Rg, R 7 , Rg, or Rg = H; and ii) the sum of the carbons of R6, R 7 , Re, and Rg is not more than 6; - 57 - · Λ· i “Π bj where Κτ 3 “Η, -CH 3 , Or —-CrigCHgJ Rtj - H. —CfLfs Or —-CH^chj j

2. fl. compound of Claim i where is hydrogen. 3. ?.. A modification of the process of Claim 30 wherein (a) said compound-of the general formula (C) is reacted with malonyl dichlorode; (b) the resulting amide from (a) is cyclized with a condensing agent to 10 yield a derivative of general fos-asila (’} wherein is replaced by chlorine; and (¢)- said compound is re ^-ced to ε compound of general formula (I) wherein R«» is hydrogen. 33. A modification of the.;-; csss of Claim 30 wherein (a) said compound of the general το. ®’-, (C) is reacted with an alkyl malonyl 15 chloride: (b) the resulting amide fr-c?. (5) is cyclized with a condensing agent to yield a derivative of general formula (I) wherein Ru is replaced by hydroxyl; and (c) said hydroxyl is repletsd by hydrogen via halogenation and reduction. 34. A process for preparing a compound of the formula: CF·» - 62 where R x = alkyl of 1—4 carbons; R 2 = —CH 3 or —CH £ CH 3 ; R 3 = H or Crf 3 ;

3. A compound of Claim 1 cr : whore Rh is methyl or ethyl.

4. A compound of any of Claims 1—3 where Sg is hydrogen. 15 5. A compound of Cla«s ί where Rs. and R 2 , taken together, are 5. Where R = —CH 3 or —CH 2 CH 3 ; R 3 = H, CH 3 , F, Cl, Br, NO Z , NH 2 , OH; Ri, = H, or alkyl of 1—4 carbons; and Rg = H, alkanoyl, aroyl, or alkyl of 1—4 carbons. 5 R u = H or alkyl of 1—4 carbons; and R 5 = H, alkyl of 1—6 carbons; comprising (a) reacting a compound of the formula: r. where 10 Ri, Rg and Ri, aro as defined above and R5 is as R 5 defined above or where R i3 = H, F, Cl, Br, N0 2 , phenyl or CH 3 , with an alkylating agent, 15 R 2 X, where R 2 is as defined above and X is halogen or sulfate, in the presence of a base; and (b) hydrolyzing or tiydrogenolyzino to rsmovt a isnzyl or substituted benzyl group at Rg or optional Ij hydrolysing er fcydrcgeswlyzing to remove an alkyl group at P.5. 35. A process for preparing a coapeiri ef Claim 1 wherein R3 is 5 other titan hydrogen or methyl which romro-ies introducing a desired R 3 substituent into a compound of general formula (Ij wherein Rs is hydrogen by methods known jter se. 35. A process for 7..-eparing a compov'd c- claim I wherein R s is acyl or alkyl of 1—3. carbon atoms ccmprises acylating or C A _ 6 “ 10 alkylating a corresponding compound ••/nerein R5 is hydrogen. 37. A process according to any of Claims 3C—23, substantially as illustrated in any cf Example >&~Sy heroin. 38. A compound of Claim 1 of the formula where Ri = !1 or alkyl of 1—4 carbon atoms; Rj = H or alkyl of 1—4 carbon trass; provided that the sue of carbons in Ri + Rj is not more than 5; and when Rj = alkyl, R z ·- H, —CH 3 or—CH2CH3; or R, + R 2 > taken together, are: - 54 R I (fl) —CH?·——CHg— 9 —-CH—CHg—9 R I (b) —CHg“-CHg‘—CH 2 > —CH-—CHg—CHg— R R R . I II —CH 2 —CH—CH 2 —, —CH—CH 2 —CH— (t) — (CH,) U —

5 . (fc: (seating tiie »-2$„«sing d.n.-.·: f·an (5) in a condensing agent. 31. Step (b) of Claim 30. 5 is where Rj- is H, F, Cl. Br, K0 2? ahsay 1 or CH, 21. A pharmaceutical composition comprising ?. pharmaceutically suitable carrier and an effective anti hyp;-. '-t-snsive amount of a compound 10 of any of Claims i—11, 18 or IS. 22. A pharmaceutical «.«position casprtsing a pharmaceutically suitable carrier and an effective anti hypertensive amount of the compound of Claim 12. 23. A.pharmaceutical composition comprising a pharmaceutically 15 suitable carrier and an st'Fec;;ve antihypertensive amount of the compound of Claim 13. 24. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 14. 20 25. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 15. 25. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound - CO 4ΰ!22γ of Claim 16. 27. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 17. 5 28. A composition of any of Claim 21—27 in unit dosage form, each dosage unit comprising 1—100 rag of said compound. 29. A composition or Claim il substantially as illustrated herein. 30. A process for preparing a compound of the formula: 10 where Ri = H or alkyl of :—4 carbons; R 2 - H or alkyl of 1—-4 carbons; provided at least one of Ri and R 2 = H; or Rj + R 2 , taken together, can be (a), (b) or (c) as defined in Claim 1 15 R3 = H or CH ; and Ri, = alkyl of 1—4 carbons; comprising (a) reacting a compound of the formula: where Ri and R 2 are defined as ab^ve, with either o—T H>C—J_J where k) end R, ; are es defined ?bove 9 and R is allyl of 1—5 carbons; and 5 Hjg H, —CHgj or—ULC.·^; *?= ·. taken 't-jgecaer with R i(i or r :2; -is —{wMi,—5 provided at least one of s'. ig , R ;1 , or ft iz = H; or c) — (CH 2 }, ( —; R s = Hj CH 3 , Fj Cl, Sr, NO,. KH 2 j 0, )«> 10 Rif '» H or alkyl of ϊ ; —4 eer&Gi.j: ard R 5 = H, acyl, or alkyl of 1—0 carbons.

6. , A compound of Claim 5 where Rj and R 2 , taken together, are n s n 7 and R 6 , R?, and R 8 are hydrogen. - 58 jt t*' ΰ £> η <4 γ

7. A compound of Claim 5 where Ri and R 2 , taken together, are: —CH—CH—CH— ! R n and R 10 and R n are hydrogen.

8. A canpound of Claim 6 where R 3 is hydrogen and Rt, is methyl or £ ethyl.

9. A compcui'.- of Claim 7 where R 3 is hydrogen and Rl, is methyl or ethyl. 10. A compound of Claim 8 where R 5 is hydrogen. 11. A compound of Claim 9 where R 5 is hydrogen. 10 12. 2,3 - dihydro - 9 {2,2,2 - trifluoro - 1 - hydroxy - 1 (trifluoromethyl)ethy1} - 7 - n.stnyl - 1H.5H - benzoijjlquinolizin - 5 one. 13. 2,3 - dihydro - 3,/ - dimethyl - 9 - {2,2,2 - trifluoro - 1 hydroxy - 1 - (trifluoromethyilethyl} - 1H,5H - benzoiijjquinolizin - 5 15 one. 14. 2,3 - dihydro - 7 - ethyl - 9 - {2,2,2 - trifluoro - 1 - hydroxy 1 - (trifluoromethyi)ethyl} - 1H,5H - benzo{ij}quinolizin - 5 - one. 15. 1,2 - dihydro - 8 - {2,2,2 - trifluoro - 1 - hydroxy - 1 (trifluoromethyi )ethyU - 5 - methyl - 4H - pyrroloi3,2,l - ijlquinolin 20 4 - one. IS. 1,2 - dihydro - 2,6 - dimethyl - 8 - {2,2,2 - trifluoro - 1 hydroxy - 1 - (trifluoromethyl)ethyl} - 4H - pyrrolo{3,2,l - ijjquinolin 4 - one. 17. 1,2 - dihydro - 6 - ethyl - 8 - {2,2,2 - trifluoro - 1 - hydroxy 25 1 - (trifluoromethyl)ethyl} - 4H - pyrrolo{3,2,l - ijlquinolin -4- one. - 59 18. A compound of Claim 1, subotantielly so hereinbefore described, 19. A compound of Claim 1 as hereir^-jf.-re csclf’cally disclosed excepting ths compounds of Claims 12—17. 20. A compound as defined in Claim 1 -ith the modification that R s

10. 39. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of a compound of Claim 38.