GB1583249A

GB1583249A - Carbostyrils

Info

Publication number: GB1583249A
Application number: GB26355/77A
Authority: GB
Original assignee: EI Du Pont de Nemours and Co
Current assignee: EIDP Inc
Priority date: 1976-06-24
Filing date: 1977-06-23
Publication date: 1981-01-21
Also published as: NL7707062A; AR224334A1; FR2372809A1; SE7707303L; IE45227L; IL52378A0; DK279777A; IL52378A; NO772230L; NZ184458A; FR2355828A1; JPS5323983A; IE45227B1; GR63361B; BE856024A; LU77609A1; FI771977A; ES460080A1; FR2372809B1; DE2728029A1

Description

(54) CARBOSTYRILS (71) We, E. I. DU PONT DE NEMOURS AND COMPANY, a corporation organised and existing under the laws of the State of Delaware, located at Wilmington, State of Delaware, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to bicyclic and tricyclic carbostyril derivatives having antihypertensive activity and to processes for preparation of such compounds.

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

Allied Chemical Corporation, in British Patent 1,029,048, discloses hexahalohydroxyisopropyl aryl derivatives as intermediates in the preparation 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, E. E., in U.S. Patent 3,532,753, discloses aromatic amino derivatives of hexahaloacetone useful as insecticides.

German OS 2,552,993 discloses compounds containing a ureido or isoureido function which have utility as antihypertensive agents.

Layer, H., et . al., in U.S. Patent 3,907,807, discloses benzoquinolizine 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 peripheral 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.

According to this invention there is provided compounds of the following formula, processes for their manufacture, and pharmaceutical compositions containing them:

where R,=H or alkyl of 1-4 carbons; R2=H or alkyl of 14 carbons; provided when Rl=alkyl, R2=H, -CM3 or -CH2CH3; or R,+R7, taken together, are:

where Rb=H or -CH3; R7=H or -CR3; R8=H or alkyl of 1-4 carbons; R9=H or alkyl of 1-4 carbons; or Ra+R9, taken together, are -(CM2)4-; provided i) at least one of R6, R7, R8, or Rg=H; and ii) the sum of the carbons of R6, R7, Ra, and R9 is not more than 6;

where R10=H, -CH3, or -CH2CH3; R11=H, -CH3, or -CH2CH3; R12=H, -CH3, or -CH2CH3; or R", taken together with R10 or R,2, is -(CR2)4-; provided at least one of R10, R11, or R12=H; or c) -(CM2)4-; R3=H, CH3, F, Cl, Br, NO2, NH2, or OH; R4=H, or alkyl of 14 carbons; and Rs=H, acyl, or alkyl of 1-6 carbons.

Within the above general formula are those compounds wherein R,=H or alkyl of 1-4 carbon atoms; R2=H or alkyl of 1-4 carbon atoms; provided that the sum of carbons in R,+R2 is not more than 5, and when R,=alkyl, R2=H, -CH3 or -CH2CH3; or R,+R2, taken together, are:

(c) -(CR2)4- where R=-CH3 or -CH2CH3; R3=H, CH3, F, Cl, Br, NO2, NH2, OH; R4=H, or alkyl of 1--4 carbons; and R5=H, alkanoyl, aroyl, or alkyl of 1-4 carbons.

Preferred for their high degree of activity are those compounds of formula I where R, and R2, taken together, are:

Also preferred are those compounds where, taken independently: a) R3 is hydrogen; or b) R4 is methyl or ethyl; or c) R5 is hydrogen.

More preferred are those compounds where R1 and R2 taken together, are:

and R6, R7, and R8 are hydrogen or

and R10 and R" are hydrogen.

Still more preferred are those compounds where: a) R, and R2, taken together are:

b) R3 is hydrogen; c) R4 is methyl or ethyl; d) R6, R7 and R8 are hydrogen or Rlo and R11 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.

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 - dihydro -3,7 dimethyl - 9 - [2,2,2 trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 1H, 5H benzo[iflquinolizin - 5 - one; 2,3 - dihydro - 7 - ethyl .9 - [2,2,2 - trifluoro - 1 hydroxy - 1 - (trifluoromethyl)ethyl] - 1H5H - benzo[ij]quinolizin - 5 - one; 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 - iliquinolin - 4 - one; and 1,2 - dihydro - 6 - ethyl - 8 - [2,2,2 trifluoro - 1 -- hydroxy - 1 - (trifluoromethyl)ethyl] - 4H - pyrrolo[3,2,1 is]quinolin - 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., where 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: When R1 and R2 are hydrogen or alkyl of 1--4 carbon atoms, the precursors are prepared as shown in the following reaction scheme:

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 completed. The product is triturated with chloroform and cooled; then filtered off and recrystallized.

Precursors in which R1 and R2 are joined together are prepared as shown, by way of example, in the 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 benzene or toluene, in a flask with hexafluoroacetone monohydrate, sesquihydrate, or trihydrate. Acidic catalysts such as AlCl2, BF3, or p - toluenesulfonic 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 AIC13 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, at the basic nitrogen atom of the amine starting material, then contacting this protected compound with hexafluoroacetone. The following diagram shows, in a general way, this reaction scheme:

where X=CI or Br; R,3=H, F, Cl, Br, NO2, phenyl, or CH3; n=2, 3 or 4.

Starting amine (A) is treated with a benzyl halide to give a tertiary N benzylamine (A'). 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 (C') and alkyl substituted derivatives thereof, as well as, their preparation are claimed in our copending Application No. 37619/79 (Serial No. 1,583,258).

The hydrogenation step occasionally requires excess acid as a co-catalyst.

Hydrogenolysis is attempted without addition of acid, and if little or no uptake of 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. Methods of making the various ring systems, however, are outlined as follows: Indolines

H6 H2 QR8 r+, R8 H2 N R9 H catalyst H H6 H6 Ei, H Rg tRk iH8 R9 H 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. 1.

Tetrahydroquinolines

10 H2 R10 H11 H, 0,Rll Catalyst XR or '/ R12 ol H R12 See Elderfield, R. C., Heterocyclic Compounds Vol. 4, John Wiley & Sons, Inc.

New York, NY (1952) p.l.

Benzazepines

Om1S + + Nii2OirUC1- > ketone oxim.e I polyphosphoric polyphosphoric acid WX L1Al;i4 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 give the lactam 1,3,4,5 - tetrahydro - lH - 1 - benzazepin - 2 - one.

Reduction of the lactam with LiAlR4 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:

where R1, R2 and R4 are as previously defined except that R1 and R2 are not both alkyl and R4 is not hydrogen, R2 is hydrogen or CH3, and R is an alkyl group of 15 carbons.

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 e.g. 180--2200C.

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 amide (E) is isolated by crystallization and/or chromatography.

Occasionally, purification is difficult and, therefore, cyclization of the crude amide is more convenient.

When R3=H and R4=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 is added to amine (C) dissolved in an inert solvent (for example, anhydrous tetrahydrofuran or toluene) held at OOC 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 sulfuric acid, but it can be purified by recrystallization and/or chromatograpyy.

The final products are readily prepared as shown in the following cyclization reaction:

Cyclization is accomplished 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 about 3060 minutes completes the reaction, but occasionally higher heating (up to 1200 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 (F) 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 R1 and R2 are alkyl in Figure E, cyclization is not observed. Compounds described by Figure F where Rl and R2 are alkyl can be prepared by cyclization of the amide E where R1 is alkyl and R2 is H. The product F has R1=alkyl and R2=H.

When the product F is treated with R5X, (alkyl of 1--6 carbons 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 benzylbromide, in a solvent such as dimethylformamide with a base such as potassium carbonate, or sodium hydride, the oxygen-alkylated compound Fl is obtained.

F3 R4 alkyl or CF3 R4 aralkyl HO h1id > R'5NR?a /1 I CF3 O DMF F3NH;\% I ?[ C K2C03 R1 R1 F F1 The compound Fl 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=-CR3 or -CH2CR3, X=halogen or sulfate) to give F3.

CF3 H4 R4 R'2X R5,O H base 1 H1 H' H1 H''2 F1 F2 The alkyl or aralkyl group R5 on 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 R1 and R2 are alkyl. The compounds wherein R; is benzyl or substituted benzyl are valuable as intermediates and form another aspect of our invention.

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 NO2 compound can be reduced to the NH2 compound, which is in turn useful for preparing compounds where R3=fluorine pr OH.

To make compounds where Ra is hydrogen the process is.modified by using malonyl dichloride instead of ketoester (D). The resulting half-amide chloride of malonic acid (E, where R4=CI) is then cyclized with a suitable condensing agent, for example, phosphorous oxychloride, to give G, which can be hydrogenolytically cleaved to H.

Alternatively, alkyl malonyl chloride can be used instead of ketoester (D) to give the half-amide ester of malonic acid (E, where R4=alkoxy e.g. OC2Hs) which is cyclized with a condensing agent, for example, sulfuric acid, to give F where R4 is OH. 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 the alcohol group, esterification is rather slow at room temperature but can 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 example, 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 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-Preparation of Intermediate Compounds of Formula II Example 1 a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol

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 1200C 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 - chlorobutane and filtered. From the filtrate is obtained 310 g (1.04 moles) a,a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol, as a pale yellow crystalline solid, m.p. 115--1160C.

Anal. Calcd. for C12H1'F6NO: 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 - lH - 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 (1 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 are removed by filtration. The filtrate is evaporated, and the residue is distilled to give 153 g (73%) of 1 - benzylindoline, b.p. 162165 (4.5 mm).

B. I - benzyl - a,- bis(trifluoromethyl) - 2,3 - dihydro - lH - indole - 5 - methanol A stirred mixture of 83.6 g (0.4 mole) of 1 - benzylindoline, 250 ml 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 all water is removed. The solution is evaporated. The residue is dissolved in 500 ml of methylcyclohexane (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 /n) of 1 - benzyl - a,a - bis(trifluoromethyl) - 2,3 - dihydro - lH - indole - 5 methanol, m.p. 8590 . 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. a,a - bis(trifluoromethyl) - 2,3 - dihydro - lH - indole - 5 - methanol A mixture of 55 g (0.15 mole) of 1 - benzyl - X - 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 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 the solution is cooled in an ice bath. The crystals are filtered off to give 33.3 g (80%) of a,a bis(trifluoromethyl) - 2,3 - dihydro - lH - indole - 5 - methanol, m.p. 161162 .

Example 3 Example 2 is followed except p - nitrobenzyl chloride is used in place of benzyl chloride. The first intermediate, 1 - p - nitrobenzylindoline, m.p. 95-97 is obtained. This is then converted to the second intermediate, 1 - p - nitrobenzyl a,a - bis(trifluoromethyl) - 2,3 - dihydro - 1H - indole - 5 - methanol. This is inconvenient to purify because of reaction of its solutions with air, so it is promptly.

hydrogenated to give a,a - bis(trifluoromethyl) - 2,3 - dihydro - 1H - indole - 5 methanol, m.p. 16-161".

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.

Starting material Product

HO CF3 4. < < H H m.p. 159-160 HO CF3 CH3 HO CF3 CH3 3 'N 5. 1 CF3;i H H rn.p. 163-164 CH3 HO CF3 CH3 z CF < J H H m.p. 158-159' CH3 HO CF3 7,MN ceCF3 H HO HO CF3 < \CH C X CH3 N CH HN CH3 H13 rti.p. 93-94' C2H5 5 9. ) F%ycr3 C2H5 CF3 H H Starting Material Product

Part B-Preparation of Compounds of Formula I Example 18

A. To a stirred solution of 32.9 g (0.11 mole) of X - bis(trifluoromethyl) 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 diketene. The mixture is refluxed for 340 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 a,a - bis(trifluoromethyl) - 1 - (1,3 - dioxobutyl) - 1,2,3,4 - tetrahydro 6 - quinolinemethanol, m.p. 115117 .

B. A stirred mixture of 6.0 (0.02 mole) of a,a - bis(trifluoromethyl) - 1,2,3,4 tetrahydro - 6 - quinolinemethanol, 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 a,a - bis(trifluoromethyl) - 1 - (1,3 - dioxobutyl) 1,2,3,4 - tetrahydro - 6 - quinolinemethanol.

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 3045 minutes, cooled to approximately 600 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 - I hydroxy - I - (trifluoromethyl)ethyl] - 7 - methyl - lH,5H - benzo[ji]- quinolizin - 5 - one, m.p. 295296 .

Anal. for C,6H,3F6NO2: Calcd.: C, 52.62; H, 3.59; N, 3.84 Found: C, 52.58; H, 3.78; N, 3.85 Example 19

A stirred mixture of 23.5 g (0.075 mole) of a,a - bis(trifluoromethyl) - 1,2,3,4 tetrahydro - 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,a - bis(trifluoromethyl) - 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 from toluene and ethyl acetate mixture (9:1) gives 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 - benzolU]quinolizin - 5 - one, m.p. 195198 .

Examples 2024 The appropriate tetrahydroquinoline can be used in place of a,a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 2 - methyl - 6 - quinolinemethanol of Example 19 for conversion to the corresponding benzoquinolizinone as shown in the following chart: Example Tetrahydroquinoline Product

OF OH H 303 3 20 0311N CF H 3 m.p. 158159o HO CF CF3 m.p. 174-177 CH3 CIHI /CB CH3 N a 'N 21 OF3 'N OP3 H HO 0113 3 CF C CH2CH3 22 1M0 OF3 NOHOH O3 H23 HO CE3 OP3 3 OH3 CH 3 23 H 0 '3 OP 3'NHOH OF 3 010113 HO CF3 HO c$I N 0 3NH CF3 CH3 Example 25

A mixture of 15.0 g (0.05 mole) of a,a - bis(trifluoromethyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol and 7.2 g (0.05 mole) of ethyl propionylacetate is heated with stirring in an open flask in an oil bath at 200220 . When the internal temperature rises to 18(200o, the mixture is then allowed to cool. The crude product is chromatographed on silica gel successively with the following eluents: (1) toluene-hexane (60:40), (2) toluene - ethyl acetate - hexane 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 a,a - bis(trifluoromethyl) 1 - (1,3 - dioxopentyl) - 1,2,3,4 - tetrahydro - 6 - quinolinemethanol. The 5.3 g of oil is dissolved in 50 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)ethyl] - 1H,5H - benzo[iI]quinolizin - 5 - one, m.p. 209210 .

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 - (I - trifluoromethyl)ethyl] - I - methyl - 3H,5H benzo[ij]quinolizin - 3 - one in 100 ml of concentrated hydrochloric acid is gradually added 1.95 g (0.01 mole) of calcium hypochlorite (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 water. The white solid is filtered off, washed with water, and dried to 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 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 7 - methyl - 1H,5H - benzo[ij]quinolizin - 5 - one, m.p.

266268 .

Example 27

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 - methyl - 3H,5H benzo[ij] - quinolizin - 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 16 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 400O to give 6.3 g (71%) of white crystalline 6 - bromo - 2,3 - dihydro - 9 - [2,2,2 - trifluoro - I hydroxy - 1 - (trifluoromethyl)ethyli - 7 - methyl - 1H,5H - benzo [ij]quinolizin - 3 - one, m.p. 265266o.

Example 28

To a stirred solution of 343 g (1.25 mole) of a,a - bis(trifluoromethyl) - 2,3 dihydro - lH - 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%) of crude a,a - bis(trifluoromethyl) - 1 (1,3 - dioxobutyl) - 2,3 - dihydro - lH - indole - 5 - methanol, m.p. 150-151 .

The product is added with 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 approximately 60O and is poured into ice water. The 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 - (trifluoromethyl)ethyl] - 6 - methyl - 4H - pyrrolo[3,2,1 - 4]quinolin - 4 - one, m.p. 337338o.

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 - (trifluoromethyl)ethyl] - 6 - methyl - 4H pyrrolo[3,2,1 - ij]quinolin - 4 - one and 70 ml of trifluoroacetic acid 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 - (trifluoromethyl)ethyl] - 6 - methyl - 5 - nitro - 4H pyrrolo[3,2,1 - ii]quinolin - 4 - one, m.p. 289290 (dec).

Anal. for C,5H,oF6N204: Calcd.: C, 45.46; H, 2.54; N, 7.07 Found: C, 45.64; H, 2.79; N, 6.82 Example 30

A mixture of 3.0 g (0.0075 mole) of 1,2 - dihydro - 8 - [2,2,2 - trifluoro - 1 hydroxy - 1 - (trifluoromethyl)ethyl] - 6 - methyl - 5 - nitro - 4H pyrrolo[32,l - ij]quinolin - 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 dihydro - 8 - [2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 5 amino - 6 - methyl - 4H - pyrrolo[3,2,1 - ]quinolin - 4 - one, m.p. 292293o.

Example 31

a) To a stirred solution of 6.0 g (0.02 mole) of a,a - bis(trifluoromethyl) - 2,3 dihydro - 2 - methyl - 1H - indole - 5 - methanol in 50 ml of anhydrous tetrahydrofuran is added 1.9 g (0.022 mole) of diketene. 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 - 1H 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 - pyrrolo[3,2,1 - ij]quinolin - 4 - one, m.p. 232310.

Examples 32-38 The appropriate indoline used in place of a,a - bis(trifluoromethyl) - 2,3 dihydro - 2 - methyl - 1H - indole - 5 - methanol of Example 31 can be converted to the corresponding heterocyclic ring-substituted derivative as shown in the following chart: Example Neo. Indoline Product

32 < 3 OH3 op3 H 0F3 cF3 F3 m.p. 163-lv m.p. 282-283? OH OH : H2CH3 r CH2CH3 33 cX 2 3 HS m.p. 89-90 m.p. 164-165 Example No. Indoline Product

OF3 HO H CH C = 3'i HN/ < ' .-ix \PF OF H3 HO FH3 35 H OH3 CH3 HO OF3 OH3 CH3 OF 36 C X Cut13 CH3 CF3 CH3 OH OH OP 3i3 3 0 OH3 37 HO 30H NO f33OF.0;1 OF3OH HO GF3 CH3 HO 0F3 38 38 c H m.p. 120-1210 OF3 CH3 Example 39

A. A stirred mixture of 13.7 g (0.05 mole) of a,a - bis(trifluoromethyl) - 2,3 dihydro - 1H - indole - 5- methanol and 7.2 g (0.05 mole) of ethyl propionylacetate is heated at 2000 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 toluene - ethyl acetate (60:40). A fraction is obtained, which can be recrystallized from I - chlorobutane to give 3.0 g (16%) of crystals, m.p. 118-119 . a,a bis(trifluoromethyl) - 1 - (1,3 - dioxopentyl) - 2,3 - dihydro - 1H - indole - 5 methanol.

B. A stirred mixture of 2.9 g of a,- 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 - I - hydroxy - 1 - (trifluoromethyliethyl] - 4H pyrrolo[3,2,1 - ij]quinolin - 4 - one, m.p. 251-252 .

Example 40

Use of ethyl valerylacetate in place of ethyl pripionylacetate of Example 39 gives 1,2 - dihydro - 6 - n - butyl - 8 - [2,2,2 - trifluoro - 1 - hydroxy - I (trifluoromethyl) - ethyl] - 4H - pyrrolo - [3,2,1 - ij]quinolin - 4 - one.

Example 41

By the method shown in Example 31, a,a - bis(trifluoromethyl) - 2,3,4,5 tetrahydro - lH - 1 - benzazepine - 7 - methanol is converted to a,a bis(trifluoromethyl) - 1 - (1,3 - dioxobutyl) - 2,3,4,5 - tetrahydro - 1H - I benzazepine - 7 - methanol, m.p. 169-171 , which is cyclized by heating in sulfuric acid (in this instance at 1200 for 24 hours) to give 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--1980.

Example 42

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 1400 in an autoclave for 16 hours. The product is triturated with 800 ml of chloroform and cooled to 00. The solid is filtered off and recrystallized from methylcyclohexane - dibutyl ether (50:50) to give 104 g (59 /n) of a,a - bis(trifluoromethyl) - 4 - aminobenzenecarbinol, m.p. 145-150 [W. A. Sheppard, J. Am. Chem. Soc. 87, 2410 (1965), reports m.p. 1515l.50j.

By the method shown in Example 31, the a,a - (trifluoromethyl) - 4 - amino benzenecarbinol is converted to a, - bis(trifluoromethyl) - 4 - (1,3 - dioxobutylamino)benzenecarbinol, which is cyclized by heating in sulfuric acid to give 6 - (2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl) - 4 - methyl 2 - (1H) - quinolinone, m.p. 157-158 .

Examples 43-48 By the procedure of Example 3 lb, the following compounds can be made from the appropriate starting materials which are shown.

Starting Materials Products

CH3 OH CF3 '""1"5 -C-OH '43 Io" 2 3 OF3%/ HO HO HO \ HO OF3 OF OH3 m.p. 282-284 CH2CH3 H2CH3 OH OH 0F3 NO,,0UO,,OH3 0 0 "\"3CH3 HO OF3 Or3 o 3 44 HO CF3 CH3 m.p. 250-251 (CH2) 2CH3 CH3 (CII2 OF3 NH--CX2'j"CH3 HN//O '45 HO OF3 HO CF CH3 CH(CH3)2 46 H -NH-Ji-CH2'I"C93 3 2 < 0 0 0F3 OH (OH 3 . 23 (CH))3CH3 H N OF. XNH ,C, 2 3 "," 0 C HO HO CT3 OF3 CF3 CH3 Starting Materials Products

Example 49

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 1400 in an autoclave for 16 hours. The crude product is chromatographed on 700 g of silica gel with chloroform as eluent. The initial fractions are recrystallized from methylcyclohexane to give 73 g (37%) of a,a - bis(trifluoromethyl) - 4 (ethylamino) - benzenecarbinol, m.p. 992o.

By the method shown in Example 31, the a,a - bis(trifluoromethyl) - 4 (ethylamino) - benzenecarbinol is converted to a,a - bis(trifluoromethyl) - 4 [N - (1,3 - dioxobutyl) - N - ethylamino]benzenecarbinol, m.p. 91---920, which is cyclized by heating in sulfuric acid to give 1 - ethyl - 6 - [2,2,2 - trifluoro - 1 hydroxy - 1 - (trifluoromethyl)ethyl] - 4 - methyl - 2 - (lH) - quinolinone, m.p.

185---187" (in this instance purified by trituration of the product with ether).

By the procedure of Example 31, the following compounds can be made from the appropriate starting materials which are shown.

Starting Materials Products

CH, C\F3 Hj 1 50 0" 0 HO W HO CH3 OH3 m.p. 275-2760 CH CH CH O,H20H2 OH3 I' - N---CH2. CH3 ELF Hd OF 3 OF3 Starting Materials Products

(CH2) CH3 (CIH2)3CH3 2 0 F3'N 1 52 F3 -N-OH- CH3 HO OF OH3 m.p. 138i39.50 CH,C(CH3)2 CF3/f' 3N czar --N-O- 3N1 53 9C OH2O0:1H3 HO OF3 HO OF3 OH3 Example 54

To a solution of 6 - [2,2,2 - trifluoro - 1 - hydroxy - 1 (trifluoromethyl)ethyl] - 4,8 - dimethyl - 2 - (1H) - quinolinone in dimethylformamide is added potassium carbonate and benzyl bromide. The solution 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 material is treated with water and extracted into ether. The etheral 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 - (1H) - quinolinone, m.p. 162164 .

To a solution of 6- [2,2,2 - trifluoro - 1 - benzyloxy - 1 - (trifluoromethyl)ethyl] - 4,8 - dimethyl - 2 - (1H) - 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 500 until thin layer chromatography indicates 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 residual material is extracted with hexane and the filtered solution is evaporated at reduced pressure.

The residual material is heated to 2500 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)ethyl] - 1,4,8 trimethyl - 2 - (IH) - quinolinone.

To a solution of 6 - [2,2,2 - trifluoro - 1 - benzyloxy - 1 (trifluoromethyl)ethyl] - 1,4,8 - trimethyl - 2 - (1H) - quinolinone in 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 - (1H) - quinolinone, m.p. 241243o.

Examples 55-59 By a procedure similar to Example 54, the following compounds can be made from the appropriate starting materials.

Starting Materials Products

Example n

To a stirred solution of 15.0 g (0.05 mole) of a,a - bis(trifluoromethyl) 1,2,3,4 - tetrahydro - 6 - quinolinemethanol in 50 ml 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. The 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 from a minimum of alcohol to give 7 - chloro - 2,3 dihydro - 9 - [2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] 1H,5H - benzo[ij]quinolizin - 5 - one, m.p. 283284 .

A mixture of 0.7 g of 7 - chloro - 2,3 - dihydro - 9 - [2,2,2 - trifluoro - I hydroxy - I - (trifluoromethyl)ethyl] - IH,5H- benzo[iflquinolizin - 5 - one, 150 ml 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 I - hydroxy - 1 - (trifluoromethyl)ethyl] - lH,5H - benzo[ij]quinolizin - 5 - one, m.p. 295-296 .

Example 61

A stirred suspension of 3.5 g (0.01 mole) of 1,2 - dihydro - 8 - [2,2,2 trifluoro - hydroxy - 1 - (trifluoromethyl)ethyl] - 6 - methyl - 4H pyrrolo[3,2,1 - ij]quinolin - 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 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 sulfate, and evaporated.

The residue is recrystallized to give 2.45 g (60 /n) 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--1370.

Example 62

Substituting acetic anhydride for the propionic anhydride in Example 61 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 .

Example 63

A stirred mixture of 3.5R(0.01 mole) of 1,2 - dihydro - 8 - [2,2,2 - trifluoro 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 6 - methyl - 4H - pyrrolo[3,2,1 ijiquinofin - 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 HCI. The immure is extracted with ether. The ether extract is washed with cold 2N NaOH and then with saturated sodium chloride solution; it is then dried (MgSO4) and evaporated. Recrystallization from methylcyclohexane gives waxy crystals of 1,2 - dihydro - 8 - [2,2,2 - trifluoro - I - hydroxy - 1 (trifluoromethyl)ethyl] - 6 - methyl - 4H - pyrrolo[3,2,1 - iliquinolin - 4 - one laurate, m.p. 7273o.

Anal. for C24H33FeNO3: Calcd.: C, 60.78; H, 6.23; N, 2.63 Found: C, 61.00; H, 6.37; N, 2.76 Examples 6467 Following the procedure of Example 63 and using the appropriate chloride in place of lauroyl chloride, one can make the following products: Example No. Acid Chloride Product

64 benzoyl chloride X , > 0 65 crotonyl chloride d Cur'3 0113 66 isovaleryl chloride C < (CH3)2CHCH2-c-o CP3 i3 67 phenylacetyl chloride 0ca$i O CH2 cA 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 - iI]quinolin - 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. Then 1 ml (1.35 g, 0.011 mole) of dimethyl sulfate is added, and the mixture is warmed gently to 100 . The mixture is allowed to cool to room temperature and is poured into 100200 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, 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. 2422430.

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 - (trifluoromethyl)ethyl] - 6 - methyl - 4H - pyrrolo[3,2,1 - ij]quinolin - 4 - one, m.p. 189190 .

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 administred with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; 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. 0.01 to 50 milligrams per kilogram of body weight. Ordinarily 0.05 to 40, and preferably 0.2 to 20, milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results. For the more potent compounds the daily dosage ranges are 0.01 to 10 milligrams per kilogram, preferably 0.05 to 10 milligrams per kilogram, and more preferably 0.05 to 5 milligrams per kilogram.

Dosage forms (compositions) suitable for internal administration contain e.g.

from 1.0 milligrams to 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of e.g. 0.595% 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; 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 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 follo

Antihypertensive Carbostyrils

Compound R1 R2 R3 R4 R5 ED30 milks -CR2-CR2-CH2- H CH3 H 1.0 sCH3 -CH2-CR3-CR- H CH3 H 0.66 CH3 I -CH-CR2-CR2- H CH3 H 3.6 -CR2-CH2-CH2- H --CH,CH, H 0.27 -CR2-CH2-CR2- Cl CH3 H 1.6 -CH2-CR2-CR3- Br CH3 H 9.0 -CR2-CR2- NO2 CH3 H 1.5 CRrnCM3- NH2 CH3 H 5.4 -CII2-CH2- H CH3 H 0.13 CH3 -CR2-CM- H CH3 H 0.047 CH3 -CR-CM2- H CH3 H 0.60 -CH2-CM3- H -CR2CH3 H 0.11 -CH2-CM2-CH3-CR2 H CH3 H 1.3 CH3 H H CH3 H 3.7 C3H5 H H CH3 H 1.3 H H H CH3 H 4.1 H CH3 H CH3 H 0.4 H -CM3CH3 H CH3 H 1.2 H -(CH3)3CM3 H CH3 H 5.2 -CM2-CH2-CH3- H H H 3-9 -CH2-CR3- H CH3 propionate 0.22 -CM2-CH3- H CH3 acetate 0.20 -CM2-CH2- H CH3 laurate 0.12 -CH2-CH3- H CH3 benzoate 0.25 -CH2-CH2- H CH3 CH3 0.35 -CH2-CR2 H CH3 CH3CR3- 0.50 WHAT WE CLAIM IS:- 1. A compound of the formula:

where R,=H or alkyl of 1-4 carbons;

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Antihypertensive Carbostyrils

Compound R1 R2 R3 R4 R5 ED30 milks -CR2-CR2-CH2- H CH3 H 1.0 sCH3 -CH2-CR3-CR- H CH3 H 0.66 CH3 I -CH-CR2-CR2- H CH3 H 3.6 -CR2-CH2-CH2- H --CH,CH, H 0.27 -CR2-CH2-CR2- Cl CH3 H 1.6 -CH2-CR2-CR3- Br CH3 H 9.0 -CR2-CR2- NO2 CH3 H 1.5 CRrnCM3- NH2 CH3 H 5.4 -CII2-CH2- H CH3 H 0.13 CH3 -CR2-CM- H CH3 H 0.047 CH3 -CR-CM2- H CH3 H 0.60 -CH2-CM3- H -CR2CH3 H 0.11 -CH2-CM2-CH3-CR2 H CH3 H 1.3 CH3 H H CH3 H 3.7 C3H5 H H CH3 H 1.3 H H H CH3 H 4.1 H CH3 H CH3 H 0.4 H -CM3CH3 H CH3 H 1.2 H -(CH3)3CM3 H CH3 H 5.2 -CM2-CH2-CH3- H H H 3-9 -CH2-CR3- H CH3 propionate 0.22 -CM2-CH3- H CH3 acetate 0.20 -CM2-CH2- H CH3 laurate 0.12 -CH2-CH3- H CH3 benzoate 0.25 -CH2-CH2- H CH3 CH3 0.35 -CH2-CR2 H CH3 CH3CR3- 0.50 WHAT WE CLAIM IS:- 1. A compound of the formula:

where R,=H or alkyl of 1-4 carbons;

R2=H or alkyl of 1-4 carbons; provided when R1=alkyl, R2=M, -CR3 or -CH2CR3; or R1+R2, taken together, are:

where R6=H or -CR3; R7=H or -CR3; R8=H or alkyl of 1-4 carbons; R9=H or alkyl of 1-4 carbons; or R8+Rg, taken together, are -(CH2)4-; provided i) at least one of R6, R7, R8, or R9=H; and

ii) the sum of the carbons of R6, R7, R8, and R9 is not more than 6;

where R10=H, -CH3, or -CR2 CR3; R11=H, -CH3, or -CH2CH3; R12=H, -CH3, or -CM2CH3; or R11, taken together with R10 or R12, is -(CR2)4-; provided at least one of R10, R11, or R12=H; or

c) -(CR2)4-; R3=H, CH3, F, Cl, Br, NO2, NH2, or OH; R4=H or alkyl of 1-4 carbons; and Rs=H, acyl, or alkyl of 1-6 carbons.
2. A compound of Claim 1 where R2 is hydrogen.
3. A compound of Claim 1 or 2 where R4 is methyl or ethyl.
4. A compound of any of Claims 1-3 where Ra is hydrogen.
5. A compound of Claim 1 where R1 and R2, taken together, are:
6. A compound of Claim 5 where R1 and R2, taken together, are:

and R6, R7, and Ra are hydrogen.
7. A compound of Claim 5 where R1 and R2, taken together, are:

and R10 and R11 are hydrogen.
8. A compound of Claim 6 where R3 is hydrogen and R4 is methyl or ethyl.
9. A compound of Claim 7 where R3 is hydrogen and R4 is methyl or ethyl.
10. A compound of Claim 8 where Ra is hydrogen.
11. A compound of Claim 9 where R5 is hydrogen.
12. 2,3 - dihydro - 9 - [2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 7 - methyl - 1H,5H - benzo[ij]quinolizin - 5 - one.
13. 2,3 - dihydro - 3,7 - dimethyl - 9 - [2,2,2 - trifluoro - 1 - hydroxy - I - (trifluoromethyl)ethyl] - 1H,5H - benzo[lilquinolizin - 5 - one.
14. 2,3 - dihydro - 7 - ethyl - 9 - [2,2,2 - trifluoro - 1 - hydroxy - 1 (trifluoromethyl)ethyl] - 1H,5H - benzo[ii]quinolizin - 5 - one.
15. 1,2 - dihydro - 8 - [2,2,2 - trifluoro - 1 - hydroxy - 1 (trifluoromethyl)ethyl] - 6 - methyl - 4H - pyrrolo[3,2,1 - ij]quinolin - 4 - one.
16. 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.
17. 1,2 - dihydro - 6 - ethyl - 8 - [2,2,2 - trifluoro - 1 - hydroxy - 1 - (trifluoromethyl)ethyl] - 4H - pyrrolo[3,2,1 - ij]quinolin - 4 - one.
18. A compound of Claim 1, substantially as hereinbefore described.
19. A compound of Claim 1 as hereinbefore specifically disclosed excepting the compounds of Claims 12-17.
20. A compound as defined in Claim 1 with the modification that R5 is

where R,3 is H, F, Cl, Br, NO3, phenyl or CH3.
21. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of a compound of any of Claims 11, 18 or 19.
22. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 12.
23. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective 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.
25. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 15.
26. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 16.
27. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of the compound of Claim 17.
28. A composition of any of Claim 21-27 in unit dosage form, each dosage unit comprising 1-100 mg of said compound.
29. A composition of Claim 21 substantially as illustrated herein.
30. A process for preparing a compound of the formula:

where R,=H or alkyl of 1-4 carbons; R2=H or alkyl of 1-4 carbons; provided at least one of R; and R2=H; or R,+R2, taken together, can be (a), (b) or (c) as defined in Claim 1; R3=H or CH3; and Alkyl of 1--4 carbons; comprising (a) reacting a compound of the formula:

where R, and R3 are defined as above, with either

where R3 and R4 are as defined above, and R is alkyl of 1--5 carbons; and (b) heating the resulting amide from (a) in a condensing agent.
31. Step (b) of Claim 30.
32. 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 yield a derivative of general formula (I) wherein R4 is replaced by chlorine; and (c) said compound is reduced to a compound of general formula (I) wherein R4 is hydrogen.
33. A modification of the process of Claim 30 wherein (a) said compound of the general formula (C) is reacted with an alkyl malonyl chloride; (b) the resulting amide from (a) is cyclized with a condensing agent to yield a derivative of general formula (I) wherein R4 is replaced by hydroxyl; and (c) said hydroxyl is replaced by hydrogen via halogenation and reduction.
34. A process for preparing a compound of the formula:

where R1=alkyl of 1---4 carbons; R2=-CH3 or -CH3CR3; R3=H or CH3 R4=H or alkyl of 1-4 carbons; and Rs=H, alkyl of 1--6 carbons; comprising (a) reacting a compound of the formula:

where R1, R3 and R4 are as defined above and Rs is as R5 defined above or

where R13=H, F, Cl, Br, NO3, phenyl or CH3, with an alkylating agent, R2X, where R2 is as defined above and X is halogen or sulfate, in the presence of a base; and (b) hydrolyzing or hydrogenolyzing to remove a benzyl or substituted benzyl group at Ra or optionally hydrolyzing or hydrogenolyzing to remove an alkyl group at Ra.
35. A process for preparing a compound of Claim 1 wherein R3 is other than hydrogen or methyl which comprises introducing a desired R3 substituent into a compound of general formula (I) wherein R3 is hydrogen by methods known per se.
36. A process for preparing a compound of Claim 1 wherein Ra is acyl or alkyl of 1-6 carbon atoms which comprises acylating or C1-6-alkylating a corresponding compound wherein Ra is hydrogen.
37. A process according to any of Claims 3036, substantially as illustrated in any of Example 18-69 herein.
38. A compound of Claim 1 of the formula

where R,=H or alkyl of 1-4 carbon atoms; R2=H or alkyl of 1-4 carbon atoms; provided that the sum of carbons in R,+R2 is not more than 5; and when R1=alkyl, R2=H, -CR3 or -CH2CH3; or R1+R2, taken together, are:

(c) -(CR3)4- where R=-CR3 or -CH2CR3; R3=H, CH3, F, Cl, Br, NO3, NH2, OH; R4=H, or alkyl of 1-4 carbons; and Ra=H, alkanoyl, aroyl, or alkyl of 1-4 carbons.
39. A pharmaceutical composition comprising a pharmaceutically suitable carrier and an effective antihypertensive amount of a compound of Claim 38.