US3784606A - Novel 2-aryl-1,3-indandiones and 2-aryl-2,3-dihydrobenz(f)indene-1,3-diones - Google Patents

Abstract

NOVEL 2 - ARYL-1,3-INDANDIONES AND 2-ARYL-2,3-DIHYDROBENZ(F)INDENE-1,3-DIONES AND THEIR USE IN LOWERING THE BLOOD LIPID LEVEL IN MAMMALS.

Description

United States Patent 01 "mice 3,784,606 Patented Jan. 8, 1974 U.S. Cl. 260--590 3 Claims ABSTRACT OF THE DISCLOSURE Novel 2 aryl-1,3-indandiones and 2-aryl-2,3-dihydrobenz[f]indene-l,3-diones and their use in lowering the blood lipid level in mammals.

This application is a division of copending application Ser. No. 756,324, filed Aug. 29, 1968, now U.S. Pat. No. 3,622,632.

BACKGROUND OF THE INVENTION This invention relates to novel 2-aryl-l,3-indandiones and 2-aryl-2,3-dihybrobenz[f]indene-1,3-diones and their use in lowering the blood lipid level in mammals.

Atherosclerosis, a form of arteriosclerosis, is characterized by internal thickening of the major blood vessels due to localized accumulation of lipids, of which cholesterol and other p-lipoproteins such as the triglycerides comprise the major constituents. It has also been found that those suffering from the disease exhibit abnormally high blood cholesterol levels. While the etiology of the disease is not fully understood, it is believed that the fl-lipoproteins, in particular cholesterol, play an important role in the disease.

In the advanced stages of the disease, plaques, comprising cholesterol and other B-lipoproteins, accumulate in the aorta, coronary, cerebral, and peripheral arteries of the lower extremities. As these plaques increase in size, the danger of fibrin deposition, possibly resulting in thrombosis and occlusion, is enhanced.

While no established method has been found for preventing atherosclerosis, it has been recommended that dietary habits be observed that will ensure low p-lipoprotein levels. Besides stringent dietary management, various therapeutic agents such as estrogens, thyroxine analogs and sitosterol preparations have been used to lower the cholesterol levels of those afilicted with the condition.

It has now been found that various 2-aryl-1,3-indandiones and 2-aryl-2,3-dihydrobenz[f]indene-1,3-diones are eifective hypolipemic agents because of their ability to lower the blood lipid level of mammals. Consequently, these compounds can be expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases which are associated with elevated blood lipid levels.

We have also found that some of the compounds described herein also possess a high degree of anti-inflam matory activity in mammals and are eifective in preventing and inhibiting the formation of granulomatous tissue.

Consequently, these particular compounds are expected] to be of value in the treatment of those arthritic disorders that are responsive to the administration of anti-inflammatory agents.

Although some 2-aryl-1,3-indandiones have been reported in the prior art to exhibit anti-inflammatory activity, many of them also inhibit blood coagulation. Indeed, 2-aryl-1,3-indandiones have been used in man as anticoagulants, e.g., 2-phenyl-1,3-indandione. Nevertheless, the use of anti-coagulants is associated with a considerable amount of risk. Such compounds can cause fatal hemorrhaging even when average dosage levels are employed. In this respect, it should be noted that some of these compounds have even been used as pesticides, e.g., 2-pivalyl- 1,3-indandione (Pival) is used as a rodenticide. Accordingly, it would not be desirable to employ a 2-aryl-1,3- indandione for a therapeutic use if in addition it also inhibits the coagulation of blood, i.e., inhibits prothrombin synthesis.

The present invention describes a series of 2-ary1-1,3- indandiones and 2-aryl-2,3-dihydrobenz[f]indene 1,3- diones which lower the blood lipid level in mammals without exhibiting the objectionable property of inhibiting the coagulation of blood. Further, some of the novel compounds of the instant invention are also elfective antiinflammatory agents and have been described in J. Med. Chem., 11, 342 (1968).

SUMMARY OF THE INVENTION This invention comprises a series of novel 2-aryl-1,3- indandiones having the formulae:

where R1 is OH, '-NH2, OCH2C02H, (CH5)2NCH2CH20, -CF3, 0r SO2CF3; R and R? are CH O-, OH, SO Na, or (CH N50 provided that R and R are not both 0CH R is 'Br, NO CF or -NH,,; R is methoxyphenyl, bromophenyl, trifluoromethylphenyl, trifiuoromethyl-sulfonylphenyl, or Z-naphthyl; R is methoxyphenyl, 3-chlorophenyl, bromophenyl, trifluoromethylsulfouylphcnyl, or 2-naphthyl; R' is NO,, or CF and R is o-, m-, and p-tolyl This invention also comprises a series of 2-aryl-2,3- dihydrobenz[f]indene-1,3-diones having the formula:

where R is tolyl, bromophenyl, iodophenyl, trifluoro-, methylphenyl, methoxyphenyl, trifluoromethylsulfonylphenyl, or 2-naphthyl.

The novel compounds of the present invention eflectively lower the blood lipid level in mammals and are expected to be useful in the treatment of atherosclerosis and related cardiovascular diseases which are associatedwith also exhibit anti-inflammatory activity and are expected to be of value in the treatmentfof those arthritic disorders that are responsive to the administration of anti-inflame matory agents. i

' Furthermore, unlikernany of the known compou d's'jin the 2-aryl-1,3-indandione series, the compounds of the. present invention do not have the objectionable property of inhibiting prothrombimsyn'thesis. DETAILED DESCRIPTION. OF THE INVENTION:

The novel compounds of'the present inventiod'canbef prepared by three previously described procedures. Of the" greatest utility for preparing analogs with no substit ijents in the indane ring is the method of S. L. Shapiriif Kff Geiger, I. Youlus andL. Freedman, J. Org. Chem, 26, 3580 (1961), which isoutlined in Chart I. i

In this synthetic scheme, a solution of sodium methoxide in methanol is added to a mixture of benzaldehyde and phthalide contained in anhydrous ethyl propionate. The resultant mixture is stirred at about 55 C. for 2 hours, cooled and the solvent removed. The residue is dissolved in water and the resultant solution extracted with ether. Acidification of the aqueous phase provides the 2-aryl-l,3- indandione, which is separated and recrystallized from an appropriate solvent.

Since substituted phthalic acids are more readily accessi'ble than substituted phthalides, a second preparative method was used which involves the condensation of an arylacetic acid with a substituted phthalic anhydride fol-" lowed by rearrangement of the condensationproduct in sodium methoxide solution. The synthetic scheme outlined below in Chart II. 1 i

" CHART 1r X==Br, CP and CH In this procedure the approp anhydride and arylacetic acid are heated together-under nitrogen with anhydrous sodiurntacetate at 270-275? riately substituted phtliahc:

l .b I h I k i I "'fo'r'several hours. The crude condensation produc s rema r m than lson ai sodium o ideth reaction mixture evaporated to dryness, and the residue dissolved in water and the resultant solution extracted several times with ether. The aqueous phase is acidified and the 2-aryl-1,3-indandionethat separates is collected and recrystallized from anappropriate solvent. This procedure is also u'se d to prepare the 2-aryl-2,3-dihydrobenz[ f]in-' dene-1,3-dione's. I With the 3 and ,4-nitrophthalic anhydrides, the milder procedure of V. Oskaja and G. Vanays reported inLatvijas PSR Zinatmi Akad. Vestis, No.' 6,57 (1961); Chem.

Abstr., 56, 58 95 1962); ibid., No. 1, 81 (1962); Chem. Abstr., 59, 7439 (l9 63 )r, which is outlined in Chart III,

i5 is used. A

' CHART III I A020 N0 0 ArCHgCOrH EtIN 11+ NO I A mixture of the nitrophthalic anhydride, phenylacetic acid, acetic anhydride, and triethylamine is warmed on a steam bath, cooled and poured onto a mixture of ice and concentrated hydrochloric acid. The product is separated, dissolved-in-aqueous sodium hydroxide, and the resultant solution washed with ether. The aqueous phase is acidifiedand'the 2-aryl-'l;3-indandi01ie'i's separated and recrystallized from an appropriatesolvent. "Most of the phthalic anhydrides, arylacetic acids, and tion of the novel compounds of the present invention have either been reported in the prior art, or are readily synthesized by conventional procedures well known to those a. skilledin the art.

Almost all of the indandiones are isolated as their enol form, as evidenced by their deep red-violet colon-Followingrecrystallization from polar solvents suchas ethanol, the IR spectra (KBr) of most of these compounds exhibits'a.single carbonylabsorption band near 61011. and the dicative of the diketo form.

While the compounds of the present invention are named and depicted as 1*,3-diones, it is to be understood 3;,that'the corresponding enols and keto-enol equilibrium"; mixtures'are embraced within theclassifica'tion scheme usedhereim v I As previously mentioned, the novel compounds of the present invention are effective hypolipem'ic agents, i.e.,

. they lower the blood'lipid level of mammals. This propeach comprising 4*;animals, of normal Sprague-Dawley (Charles River) male rats weighing from -220 g. are

benzaldehydes used as starting materials in the prepara- UV spectra determined in methanol or methanol-sodium bonyl absorption bands at 5.73 (m) and 5.81 s (s), in-

erty has been dramatically demonstrated in rats. Groups,

fed rat chow containing' 0.25% of the compounds described hereinfor two overnightfeeding periods. On the morning of the third day the animals are anesthetized and f bled from the abdominal aorta. The total plasma cholesterol is then determined by the method of J. J. Carr and I. I. Drekter reported in Clin. Chem., 2, 353 (1956). The plasma cholesterol level of the treated animals is found to be significantly reduced, when compared to animals not receiving the test compound.

The ability of the herein described compounds to lower the blood triglyceride level is illustrated by administering the compounds to dogs. A dosage level of 50 mg./kg. of the compound, in gelled capsules, is administered to dogs twice a-gday. This treatment is continued over a period of 2 weeks andon every second day, the cholesterol and triglyceride blood levels are determined. The cholesterol level is determined by the methodgiven above, and the triglyceride level is measured by the method of E. Van

Handel and Dr B. Zilversmith, reported in J. Lab. & Clin.: 1

Med., 50, 152 (1957). s;

Comparison of the blood triglyceride levels of dogs receiving the test compounds shows a significant reduction as compared to the triglyceride levels of untreated animals.

For oral administration in capsule form, the preferred excipients are lactose and high'molecular weight polyethylene glycols. When aqueous suspensions are desired, the essential active ingredients are combined with emulsifying ingredients and/or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and various combinations of diluents are employed.

A typical human dosage form for oral administration is as follows:

Mg. 2-aryl-1,3-indandione 250 Corn starch, dry 17.50 Lactose 163.50 Magnesium stearate 17.10 Sodium lauryl sulfate 1.90

The compounds described herein can be administered parenterally as well as orally. For parenteral administration, solutions of the active ingredients in combination with other solutes such as glucose or saline are used. Such aqueous solutions should be suitably buffered, if necessary, to render then isotonic.

The dosage required to lower the blood lipid level will be determined by the nature and the extent of the symptoms. Generally, small dosages will be administered initially with a gradual increase in dosage until the optimum level is determined. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a smaller quantity administered parenterally. In general, from about 50 to 500 mg. of active ingredient per kilogram of body weight administered in single or multiple dosage units significantlylowers the blood lipid level. In generaL-when administered.

the lastIdose;-.blood samples were drawn into oxalatd' syringes from ,the descending aorta' ,.while the animals were maintained" under light pentobarbital anesthesia. Plasma was separated by centrifugation, :and prothrombin time was determined automatically with a Model 2-02-Clot Timer (Mechrolab Inc.) using thromboplastin extract (Simplastin, Warner-Chilcott, Morris Plains, NJ.) as directed by the manufacturer.

In Table I are listed some of the data obtained with known compounds in the series as well as data obtained for some of the novel compounds of the present invention.

TABLE I Prothrombin time Compound: in rats 1 (l) 2-phenyl-l,3-indandione (2) 2-(1'-naphthyl)-1,3-indandione (3) 2-(4-methoxyphenyl)-1,3-indandione (4) 2-(3'-chlorophenyl)-l,3-indandione (5) 2-(4'-nitrophenyl)-1,3-indandione (6) 2-phenyl-5-bromo-1,3 indandione (7) 2-phenyl-5-nitro-l,3-indandione (8)' 2-(3'-nitrophenyl)-1,3 indandione (9) 2-(2rhydroxyphenyl)-1,3-indandione (l0) 2 (4-acetamidophenyl) 1,3-indandione (l1) 2-(4'-hydroxyphenyl)-l,3-indandione (12) 2-(3' methoxyphenyl)-5-methyl1,3-indandione (13) 2 (2' naphthyl)-5-bromo-1,3-indandione (14) 2 (3' trifluoromethylphenyl)-4-nitro- 1,3-indandione (l5) 2-(2'-naphthyl) 5 trifluoromethyl-LS- indandione 1 prolongation of prothrombin time 1'6 hours after administration of nine oral doses, 8 hours apart (100 mg./kg. p0) prolongation of prothrombin time 16 hours after administration of two oral doses, 8 hours apart (100 mg./ kg. p0) no prolongation of prothrombin time after nine oral doses (100 mg./kg. p0).

Compounds (1)-(7) listed in Table I have been previously described in the prior art and all of them have the undesirable property of inhibiting prothrombin synthesis. On the other hand, compounds (8)-(15), now described for the first time, do not inhibit prothrombin synthesis 0 o l CH; R HQ H and where R is methoxyphenyl, 3-chlorophenyl, bromophenyl, tricfluorom'ethylsulfonylphenyl or 2-naphthyl;

R is 0-, m-, and p-tolyl; and v Z is CF or CF SO 2-(3'-nitropheny1)-1,3-indandione 2-(3-methoxyphenyl)-5-methyl-1,3-indandione 2-(2-naphthyl)-5-bromo-l,3-indandione 2-(3'-methylphenyl)-5-trifiuoromethyl-1,3-indandione 2-(2'-naphthyl)-5-trifiuoromethyl-1,3-indandione.

The anti-inflammatory activity of these compounds is determined by the inhibition of edema formation in the 7 hind paw of rats (Charles River strain; average weight 170 g.) in response to a sub-plantar injection of carrageenin (rat-foot edema test). The experimental procedures followed are those of Winter et al., as reported.

Statham Pressure Transducer. The output from the transducer is fed through a control unit to a microvoltameter. The volume of mercury displaced by the immersed. paw is read. Drugs are given by gavage. One hour after drug administration, edema is induced by injection of 0.05 ml. of 1% solution of carrageenin into the plantar tissue of the marked paws. Immediately thereafter, the volume of the injected foot is measured. The increase in foot volume 3 hours after the injection of carrageenin constitutes the individual response. The increase in volume of the feet of drug-treated animals are compared with those just receiving vehicle alone.

The results obtained for some of the compounds of the present invention are tabulated in Table II.

TABLE II Rat foot edema test Inhibition of edma formation as compared with 1 Anti-inflammatory activity is reported as a mean inhibition of edema in the treated animals within the range of 0.5-1.5 times that of the mean inhibition of concurrently treated animals receiving aspirin (100 mg./kg. p) drug given at 100 mg./kg.; drug given at 33 mg./kg.; drug given I: mg./kg. po.

As can be seen by examination of Table H, some of the novel compounds of the present invention are effective anti-inflammatory agents and, as previously mentioned,

have the further pharmacological advantage of not in- 65 hibiting prothrombin synthesis. These compounds are expected to be useful in alleviating the swelling and inflammation exhibited by arthritic and rheumatic subjects. They can be administered either alone or in com binations with pharmaceutically-acceptable carriers. The proportion of active ingredient to carrier is determined by the solubility and chemical nature of the compound,

chosen route of administration and standard pharmaceutical practice. For oral administration in capsule form, preferred excipients are lactose and high molecular weight polyethylene glycols. When aqueous suspensions arein Table HI are also prepared according to the above desired, the essential active ingredients are combined with emulsifying and/or suspending agents. Diluents such as; ethanol, propylene glycol, glycerine and variouscombina: tions of diluents are employed. For parenteral administra-,' tion, solutions of the active ingredients incombination with other solutes such as glucose or saline are used. Such aqueous solutions should be'suitably buffered, if necessary, torender them isotonic. v

The dosage required to reduce inflammation and swelling in arthriticand rheumatic subjects will be determined by the nature and the extent of the symptoms. Generally, small dosages will be administered initially with a gradual increase in dosage until the optimum level isdetermined. It will generally be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally. In general, from about 1 to 100 mg. of active ingredient per kilogram offbody weight administered in single or multiple dosage units effectively reduces inflammation and swelling in; arthritic and rheumatic subjects.

The following examples are provided to more fully illustrate the present invention, but are not to be construed as limiting .the scope thereof in any way.

EXAMPLE I To a mixture of 1 mole of 3-nitrobenzaldehyde, 1 mole of phthalide, and 480 ml. of dry ethylpropionate is rapidly added 3 moles of sodium methoxide in 700 ml. of methanol..The reaction mixture is stirred at C. for 2 hours, cooled, and the solvent removed under reduced pressure. The residue is dissolved in 5.5 liters" of water and the mixture extracted with ether and filtered. The filtrate is acidified to a pH of about 2 and the2-(3'-nitrophenyl)-l,3- indandione is filtered and recrystallized from methyl ethyl ketone. The yield is 49%; M.P. 224226 C.

Analysis.Calcd for C H NO (percent): C, 67.40; H, 3.39; N, 5.24. Found (percent): C, 67.58; H, 3.64; N,' 5.19.

Using the appropriate starting materials, the compounds procedure. 7

TABLE III Crystalliza- Yield,

2-aryl-1,3-indand1one tion solvent percent M.P., C.

Z-(earboxymethoxyphenyl) -1,3- Ethanol- 64 198. 53-200. 5 aii a fn i ih 1 mi th (1 78 I me ya me oxy- 0...": 230-232 phenyl)-1,3-indandione. 2-(4-acetamidophenyl)-1,3-indo 54 239-241 dandione. j I 2(4-methoxy-3-sodiun1 sulfodo 9 286-288 pheny1)-1,3-indandione. 2-(4-methoxy-3-dimethylsulamyldo 15 185.5-1815.

phenyl)-1,3-indandione.

1 Decomposed.

EXAMPLE It (A) 2-(2'-methoxyphenyl)-l,3-indandione is prepared accordingto the procedure of Example I from the appropriate starting materials. Yield: 71%; crystals from HBr acid for 3 /2 hours. After cooling, the dark red solids are filtered and recrystallized froma small amount of ethanol to yield 2-(2-hydroxyphenyl)-l,3-indandione. Yield: 0.34 g. (39%); M.P.,218'-223 C.

Analysis.'-Calcd for C H O (percent): C, 75.62; H, .4123. Found; (percent): C, 75.5 8; H, 4.42. I L

EXAMPLE III (A) 2 (4' methoxyphenyl)-1,3-indandione is prepared according to the procedure of Example I from the appropriate starting materials. M.P. 154155.5 C.

(B) 2 (4' hydroxyphenyl) 1,3-indandione is prepared from 2-(4'-methoxyphenyl)-1,3-indandione according to the procedure of Example II(B). Yield 64%; crystals from methanol, M.P. 259-260" C.

Analysis.-Calcd for C H O (percent): C, 75.62; H, 4.23. Found (percent): C; 75.93; H, 4.28.

EXAMPLE IV (A) 2 (3,4' dimethoxyphenyl)-1,3-indandione is prepared according to the method of Example I from the appropriate starting materials. Yield: 65%; crystals from ethanol, M.P. 190.5-192.5 C.

Similarly, using the appropriate starting materials the following compounds are also prepared:

2- (3 -carboxymethoxyphenyl) 1, 3 -indandione 2- 3 '19-dimethylaminoethoxyphenyl)-1,3-indandione 2-(2'-acetamidopheny1-1,3-indandione 2-(3-acetamidophenyl)-1,3-indandione 2-(3-trifluoromethylphenyl)-1,3-indandione 2-(4'-trifluoromethylphenyl)-1,3-inclandione 2- (3 '-trifluoromethylsulfonylphenyl) 1, S-indandione 2- (4'-trifiuoromethylsulfonylphenyl)-1,3-indandione 2- (4'-hydroxy-3-s0dium sulfophenyl)-1,3-indandione 2-(3'-hydroxy-4'-dimethylsulfamylphenyl)-1,3-

indandione 2-(3',4-di-sodium sulfophenyl)-1,3-indandione 2- 3-dimethylsulfamyl-4-sodium sulfophenyl)-1,3-

indandione 2- (3 ',4'-di-dimethylsulfamylphenyl) -1,3-indandione 2-(3'-methoxy-4'-sodium sulfophenyl)-1,3-indandione 2- (3 '-methoxy-4-dimethylsulfamylphenyl 1, 3-

indandione.

(B) 2 (3',4 dihydroxyphenyl)-1,3-indandione is prepared from 2-(3',4-dimethoxypheny1)-1,3-indandione according to the procedure of Example II(B). Yield: 11%; crystals from acetic acid-Water, M.P. 252-254 dec.

Analysis.-Calcd for C H O (percent): C, 70.97; H, 3.96. Found (percent): C, 70.97; H, 4.14.

EXAMPLE V A suspension of 2.8 g. (0.010 mole) of 2-(4'-acetamidophenyl)-1,3-indandione is refluxed in 100 ml. of 6 N HCl for 4 hours. After filtration, the collected solids are dissolved in aqueous sodium hydroxide and the red solution is acidified with acetic acid to a pH of 6. The red precipitate is filtered and recrystallized from ethanol to give 0.76 g. (28%) of 2-(4-aminophenyl)-1,3-indandione; M.P. 227-229 C.

Ainulysis.-Calcd for C H NO (percent): C, 75.93; H, 4.67. Found (percent): C, 76.20; H, 4.80.

EXAMPLE VI 0.10 mole of 2-(3',4'-dihydroxyphenyl)-1,3-indandione is dissolved in about 300 ml. of a 1 molar sodium hydroxide solution and 0.10 mole of dimethyl sulfate is slow- 1y added \m'th stirring. The solution is stirred at about 50 C. for /2 hour, cooled, filtered and acidified to a pH of about 2 with hydrochloric acid. The mixture of 2-(3'- hydroxy 4' methoxyphenyl) 1,3-indandione and 2 (3' methoxy 4 hydroxyphenyl) 1,3 indandione is separated and purified by column chromatography on silica gel or alumina.

EXAMPLE VII 4-bromophthalic anhydride is prepared by refluxing a solution of 3.7 g. (0.015 mole) of 4-bromophthalic acid for 2 hours in 50 ml. of acetic anhydride containing 1 drop of sulfuric acid, followed by evaporation of the mixture to dryness. To the crude anhydride is added 2.8 g. (0.015 mole) of Z-naphthylacetic acid and 50 mg. of anhydrous sodium acetate. The solid mixture is heated under nitrogen at 275 C. for 2 hours. Upon cooling, a brown solid is obtained which is triturated with 10% sodium bicarbonate and dried under vacuum. The dried crude solid is rearranged in 100 ml. of refluxing methanol containing 2.1 g. (0.039 mole) of sodium methoxide. After 1 hour, the reaction mixture is evaporated to dryness and the residue dissolved in water. The aqueous solution is extracted several times with ether and the aqueous layer is acidified with 6 N HCl acid. The crude red precipitate of 2 (2' naphthyl)-5-bromo-l,3-indandione is recrystallized from ethanol to yield 2.5 g. of product (47%); M.P. 180.5-181-5 C.

Analysis.Calcd for C H BrO (percent): C, 64.97; H, 3.16. Found (percent): C, 64.63; H, 3.26.

Using the above procedure and the appropriate starting materials, 2 (3 trifluoromethylphenyl)-5-bromo-1,3- indandione is similarly prepared in 27% yield; M.P. 154- 155.5 C. (ethanol).

Analysis.-Calcd for C H BrF O (percent): C, 52.06; H, 2.18. Found (percent): C, 51.86; H, 2.17.

Similarly, the following compounds are prepared from the appropriate starting materials:

2- 4'-methoxyphenyl)-5-bromo-1,3-indandione 2- (3 '-methoxyphenyl)-5-bromo-1,3-indandione 2- (2'-bromophenyl) -5-bromo-1, B-indandione 2-(4'-trifluoromethylsulfonylphenyl) -5-bromo-1,3-

indandione 2- (3 '-trifiuoromethylsulfonylphenyl) -5-bromo-1,3

indandione.

3-bromophthalic anhydride is prepared from 3-bromophthalic acid by the above procedure and used to prepare the compounds below:

2-(2'-naphthyl)-4-bromo-1,3-indandione 2-(3-trifluoromethylphenyl)-4-bromo-1,3-indandione 2- 4'-methoxyphenyl) -4-bromo- 1, 3 -indandione 2- 3 '-methoxyphenyl) -4-bromo- 1, 3-indandione 2- 2'-bromophenyl) -4-bromo- 1,3-indandione 2- (4'-trifluoromethylsulfonylphenyl) -4-bromo-1,3-

indandione 2- (3 -trifluoromethylsulfonylphenyl) -4-bromo-1 ,3-

indandione.

EXAMPLE VIII A solution of 0.05 mole of 3-nitrophthalic anhydride, 0.05 mole of 3-trifluoromethylphenyl acetic acid, 1.8 moles of acetic anhydride, and 0.15 mole of triethylamine is warmed on a steam bath for 15 minutes. After cooling, the reaction mixture is poured onto a mixture of ice and concentrated hydrochloric acid. The resultant gummy solid is separated, dissolved in aqueous sodium hydroxide, and the resultant solution washed with ether. The cooled aqueous layer is acidified with 6 N hydrochloric acid and stirred at 0 C. to provide crude 2-(3'-trifluoromethylphenyl) 4 nitro 1,3-indandione in 19% yield; M.P. 174-176.5 C. (ethanol).

Analysis.-Calcd for C H F NO (percent): C, 57.20; H, 2.40. Found (percent): C, 57.50; H, 2.77.

Using the appropriate starting materials, the following compounds are similarly prepared.

2-(3'-methoxyphenyl)-4-nitro-1,3-indandione 2-(4'-methoxypheny1)-4-nitro-1,3-indandione 2- (2'-b romophenyl) -4-nitro- 1,3 -indandione 2-(4'-bromophenyl)-4-nitro-1,3-indandione 2- (3 '-trifluoromethylsulfonylphenyl) -4-nitro-1,3-

indandione 2- 2'-naphthyl) -4-nitro-1 ,3-indandi0ne 2- (3 '-methylphenyl) -4-nitro-1,3-indandione 2- (4'-methylphenyl) -4-nitro- 1,3 -indandione.

Using S-nitrophthalic anhydride in the above reaction instead of 4-nitrophthalic anhydride, the compounds in Table IV are prepared from the appropriately substituted phenylacetic acids:

indandione. 2-(2'-naphthyl)-5-nitro-1,3-indandione.

Likewise, the following compounds are also prepared:

2- (4'-methoxyphenyl)-5-nitro-l,3-indandione 2-(3'-bromophenyl)-5-nitro-1,3-indandione 2- 4-trifluoromethylsulfonylphenyl) --nitro- 1,3-

indandione.

EXAMPLE 1X Dry nitrogen is bubbled into a solution of 0.01 mole of 2 (3'-trifluoromethylphenyl)-4-nitro-1,3-indandione in 150 ml. of absolute ethanol. After the addition of 0.045 mole of hydrazine hydrate, a small portion of fresh Raney nickel catalyst is added. After stirring the reaction mixture for about 20 minutes at room temperature, a second portion of catalyst is added. After an additional hour, excess catalyst is added and the mixture is heated to boiling and filtered while hot. Acidification of the filtrate with 6 N hydrochloric acid and addition of water provides crude 2 (3' trifluoromethylphenyl)-4-amino-l,3-indandione, which is crystallized from ethanol.

Using the appropriate starting materials the following compounds are similarly prepared:

2-( 3 -methoxyphenyl) -4-amino-1,3-indandione 2- (4'-methoxyphenyl) -4-amino-1, 3 -indandione 2- 2'-bromophenyl) -4-aminol ,3 -indandione 2-(4-bromophenyl)-4-amino-1,3-indandione 2- 3 '-trifluoromethylsulfonylphenyl) -4-amino-1,3-

indandione 2-(2'-naphthyl)-4-amino-1, 3-indandione 2-( 3 '-methylphenyl) -4-aminol ,3-indandione 2-(4-methylphenyl)-4-amino-1,3-indandione 2- (3 '-trifluoromethylphenyl) -5-amino- 1 ,3-indandione 2- 3 '-methylphenyl) -5-amino-1,3-indandione 2- (2'-naphthyl)-5-amino-1,3-indandione 2-(4 '-methoxyphenyl)-5-amino-1,3-indandione 2- 3 -bromophenyl)-5-amino-1,3-indandione 2- (4'-trifluoromethylsulfonylphenyl) -5-amino-1,3-

indandione.

EXAMPLE X 4-trifluormethylphthalic anhydride is prepared by refluxing 4.7 g. (0.02 mole) of 4-trifiuoromethylphthalic acid in 50 ml. of acetic anhydride containing 1 drop of concentrated sulfuric acid for 4 hours. Evaporation to dryness under reduced pressure alfords the crude anhydride as a dark solid; To the crude anhydride is added 8.2 g. (0.040 mole) of 3-trifluoromethylphenylacetic acid and 400 mg. of anhydrous sodium acetate. The mixture is heated at 275C. for 2 hours, under nitrogen, and the residue subjected to high vacuum for approximately 15 minutes. The resdue is then combined with 25 ml. of methanol and a solution of 8.7 g. (0.16 mole) of sodium methoxide and 100 ml. of methanol. After refluxing for three quarters of an hour, and evaporation to dryness, the residue is dissolved in 300 ml. of water and extracted three times with 200-ml. portions of ether. Owing to the influence of the two lypophilic trifluoromethyl substituents, the sodium salt of the 1,3-indandione is exn'acted into the ether. Evaporation of the ether extracts affords the crude sodium salt, which is then dissolved in water and the resultant solution acidified. The red 2-(3'-trifluoromethylphenyl)-5-trifluoromethyl 1,3 indandione which separates from solution is filtered. Yield: 7.1 g. (50%); M.P. 129-131 C.

12 Analysis.Calcd for C H F O (percent): C, 56.99; H, 2.25. Found (percent): C, 57.12; H, 2.59.

EXAMPLE XI A thorough mixture of 0.020 mole of 4-trifluoromethylphthalic anhydride, 0.020 mole of Z-naphthylacetic acid, and 200 mg. of anhydrous sodium acetate, is heated under nitrogen at 270 C. for about 3 hours. After cooling, the residue is subjected to high vacuum for approximately 15 minutes and dissolved in 50 ml. of methanol. To this solution is then added 4.3 g. (0.080 mole) of sodium methoxide in 30 ml. of methanol. The resulting dark red solution is refluxed 1 hour, cooled, and evaporated to dryness. The residue is dissolved in 150 ml. of water, and the resultant solution is acidified with 6 N HCl to afford crude 2-(2'-naphthyl)-5-trifluoromethyl- 1,3-indandione. Yield: 27%; M.P. 189.5191 C. (ethanol).

Analysis.-Calcd for C H F O (percent): C, 70.58; H, 3.26. Found (percent): C, 70.64; H, 3.60.

Using the above procedure, the compounds in Table V are prepared from the appropriate starting materials.

TABLE V Crystalllza- Yield,

2-aryl-1,3-indandlone tion solvent percent M.P., C;

2-(3 -methylphenyl)-5-trifluoro- Ethanol- 38 126-128 methyl-1,3-indandlone. water. 2-(3-methoxyphenyl)-5-trlfluoro- Isopropanol- 33 166. 5-168 methyl-1,3-indandlone. water. 2-(3-bromophenyl)-5-trifluoro- Ethanol- 19 172. 5-174 methyl-1,3-indandione. water.

Similarly, the following compounds are also prepared: 2-(4-trifluoromethylsulfonylphenyl)-5-trifluoromethyl- 1,3-indandione 2-(3'-trifluoromethylsulfonylphenyl)-5-trifluoromethyl- 1,3-indandione 2-(4-methylphenyl)-5-trifluoromethyl-l,B-indandione 2- (2-methoxyphenyl) -5-trifluoromethyl-1,3-indandione 2- (4'-bromomethyl) -5-trifluoromethyl-l ,3-indandione.

EXAMPLE XII 2-(3'-trifluoromethylphenyl) 4 trifiuoromethyl-l,3- indandione is prepared from 3-trifluoromethylphthalic anhydride and 3-trifluoromethylphenylacetic acid according to the procedure of Example X.

EXAMPLE XIII The following compounds are prepared from 3-tri-, fluoromethylphthalic anhydride and the appropriately substituted arylacetic acids according to the method of Example XI:

EXAMPLE XIV A thorough mixture of 0.030 mole of 4-methylphthalic anhydride, 0.030 mole of 3-methoxyphenylacetic acid, and mg. of anhydrous sodium acetate is heated under nitrogen at 290 C. for 3 hours. The resultant product is triturated with. 75 ml. of 10% sodium bicarbonate and filtered, and the filtered material is dried under vacuum over phosphorous pentoxide. Combination of the resulting dry solid with 15 ml. of methanol and 2.2 g. (0.045 mole) of sodium methoxide in 50 ml. of methanol produces a red solution which is refluxed for hour and TABLE VI Crystallization Yield, M.P., 2-ary1-1,3-1ndandlone solvent percent 0.

2-(2'-bromophenyl)-5-methyl-1,3- Ethano1 40 131-133 indandione. 2-(3-chlorophenyl)-6-methy1-1,3 :-.---.do 72 123425 indandione.

The compounds below are also prepared according to the above procedure from the appropriately substituted starting materials:

2- (3 '-trifluoromethylsulfonyl) --methyl-1,3-indandione 2-(2-naphthyl)-5-methyl- 1,3-indandione 2- (4'-bromophenyl) -5-methyl-1, 3-ind andione 2- (4'-chlorophenyl) -5-methyl-1,3 -indandione 2-(2-methoxyphenyl)-5-methy1-1,3 -indandione 2- 3 '-methoxyphenyl -4-methyll ,3-indandione 2- (3 '-trifiuoromethylsulfonyl) -4-methyl-1,3 -indandione 2- (2-naphthyl) -4-methyll 3-indandione 2-(4'-bromophenyl)-4-methyl-1,3-indandione 2-(4-chlorophenyl) -4-methyl-1,3-indandione 2-(2'-methoxyphenyl) -4-methyl-1,3-indandione.

EXAMPLE XV 2,3-naphth'alene dicarboxylic acid anhydride is prepared by refluxing 4.3 g. (0.02 mole) of 2,3-naphthalenedicarboxylic acid in 50 ml. of acetic anhydride containing 2 drops of concentrated sulfuric acid for 2 hours. The mixture is evaporated to dryness and the resulting anhydride is thoroughly mixed with 3.0 g. (0.02 mole) of m-tolylacetic acid and 100 mg. of sodium acetate. The mixture is heated under nitrogen at 270 C. for 3 hours and cooled. To the resultant solid is added 20 ml. of methanol and a solution of 3.3 g. (0.06 mole) of sodium methoxide in 50 ml. of methanol. After refluxing 1 hour and evaporating to dryness, the residue is dissolved in 250 ml. of Water and the solution extracted with ether. The aqueous phase is acidified with 6 N hydrochloric acid, and the orange solid which separates from solution is recrystallized from 1 liter of boiling acetone to give in several crops 2.2 g. (39%) of 2-(3-methylphenyl)-2,3-dihydrobenz[f]indene-1,3-dione. M.P. 258-260 C.

Analysis.-Calcd for C H O (percent): C, 83.39; H, 4.94. Found (percent): C, 83.72; H, 4.95.

Using the above procedure, the compounds in Table VII are prepared from the appropriate starting materials:

14 The compounds below are also prepared according to the above procedure from the appropriate starting materials: 2- (3 '-bromophenyl -2,3-dihydrobenz [f indene- 1 ,3-dione 2-(4'-iodophenyl)-2,3-dihydrobenz[f]indene-1,3-dione 2- (2'-methoxyphenyl) -2,3-dihydrobenz [f indene- 1 ,3-

dione 2- 3 -trifiuoromethylsulfonylphenyl) -2,3-dihydro'benz- [f]indene-1,3-dione.

What is claimed is:

1. A compound selected from the group consisting of those having the formula:

where R and R are selected from the group consisting of CH 0- and 0H; provided that R and R are not both OCH;,.

2. A compound selected from the group consisting of those having the formula:

where R is selected from the group consisting of methoxyphenyl and trifluoromethylsulfonylphenyl.

3. A compound selected from the group consisting of those having the formula:

where R is selected from the group consisting of tolyl, bromophenyl, iodophenyl, trifiuoromethylphenyl, methoxyphenyl, trifluoromethylsulfonylphenyl, and 2-naphthyl.

References Cited UNITED STATES PATENTS 2,938,925 5/1960 Molho 260590 3,413,353 11/1968 Nauta 260-590 OTHER REFERENCES Horton et al.: Chemical Abstracts, 54, 21002 (1960).

DANIEL D. HORWITZ, Primary Examiner