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Publication numberUS2891957 A
Publication typeGrant
Publication dateJun 23, 1959
Filing dateFeb 21, 1958
Priority dateFeb 21, 1958
Publication numberUS 2891957 A, US 2891957A, US-A-2891957, US2891957 A, US2891957A
InventorsRobert E Allen, William C Day, Vernon J Feil, Frank P Palopoli, Edward L Schumann
Original AssigneeWm S Merrell Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Amino alkoxy phenyl methanes
US 2891957 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent Ofiice 2,891,957 Patented June 23, 1959 AMINO ALKOXY PHENY L ME'IHANES Robert E. Allen, Wyoming, and Frank P. Palopoli, Cincinnati, Ohio, Edward L. Schumann, Kalamazoo, and William C. Day, Lansing, Mich., and Vernon J. Feil, Cincinnati, Ohio, assignors to The Wm. S. Merrell Company No Drawing. Application February 21, 1958 Serial No. 716,565

6 Claims. (Cl. 260-2945) Our invention relates to new chemical compounds which can be regarded as amino ethers of benzaland benzyl carboheterocycles. They are distinguished, in general, by their anti-estrogenic activity in the endocrine system, anti-inflammatory activity, anti-gonadotrophic activity, activity in decreasing blood cholesterol levels, activity in thyroid conditions, activity in the respiratory system and anti-fungal activity. Some of the compounds possess various combinations of these properties.

As estrogen antagonists, the compounds are useful in the treatment of hyperestrogenism and disorders related to this condition, e.g., ovarian hyperfunction, endometriosis, Kleinfelters syndrome, dysmenorrhea, amenorrhea, menopausal dysfunction, functional bleeding, sexual precocity and similar conditions. They are active both orally and parenterally and so can be administered by either route, though the oral route is preferred in most instances. Some of the compounds have a high degree of activity as estrogen antagonists and are also advantageously nonestrogenic. Some of the compounds with anti-estrogenic activity are also uterotrophic.

As anti-inflammatory agents, the compounds are useful in alleviating the symptoms of such collagen diseases as arthritis and rheumatism and in the topical treatment of inflammation. Some of the compounds possess the novel combination of anti-inflammatory and anti-estrogenic activities and are especially advantageous for this reason. They are useful topically, orally and parenterally for this purpose.

As blood cholesterol level depressants, the compounds are useful in the treatment of cardiovascular diseases such as atherosclerosis. They are useful orally for this purpose.

As gonadotrophic inhibition agents, the compounds are useful for the treatment of fertility and sterility problems and can be administered orally or parenterally for this purpose.

The compounds are also useful in treating respiratory diseases and are useful orally or intranasally for this purpose. Some of the respiratory infections that can be treated are common cold, influenza, sinusitis, whooping cough, adenovirus, and pneumonia of different etiologies.

The compounds are also useful in treating thyroid conditions as they exhibit activity in reducing thyroid weight. They are useful orally and parenterally for this purpose.

As anti-fungal agents, the compounds are useful in the topical treatment of fungus infections such as torulosis, ring worm, athletes foot, blastomycosis, histoplasmosis,

from 0.1 mg. to 5 grams daily, depending on the compound and condition under treatment. Parenterally, they can be used in doses ranging between 0.1 mg. and 1 gram daily depending on the compound and condition under treatment. Some irritation may be encountered. For topical use the compounds can be incorporated into creams, ointments or lotions in concentrations of up to 10 percent. Intranasally, e.g., in nose drops and atomizers, the concentration can be in the order of about 0.1 to 2 percent.

The compounds can be used as the free base. Some of the compounds can be isolated and used in the form of their salts with inorganic acids, e.g., hydrochloric or hydrobromic acids, or organic acids such as. citric acid, oxalic acid and the like. The compounds can also be isolated and used in the form of their N-oxides and their quaternary salts with quaternizing agents such as lower alkyl sulfates, e.g., methyl sulfates. Such salts are useful for special purposes.

The novel compounds of our invention are amino ethers of benzaland benzyl-carboheterocycles. They can be represented by the following formulas:

(a) The benzal compounds:

0 o .HMA (b) the benzyl compounds:

I l 0 C nHfl A and (c) the benzyl compounds:

(|)H O CnHzn The AC H O group is attached to the benzene ring in the meta or para position. A is amino, or alkylami'no in which the alkyl group contains from 1 to 4 carbon atoms, or dialkylamino in which the alkyl group contains from 1 to 4 carbon atoms, dibenzylamino, or an N- heterocycle such as morpholino, piperidino, or N-methylpiperazino and n is 2 or 3. Y is hydrogen or methyl. R is a fluorenylidene, indenylidene, tetrahydronaphthylidene, Xanthylidene or thioxanthylidene radical. R is a tinea capitis, and monila infections. They are also usefiuorenyl, indenyl, tetrahydronaphthyl, xanthyl, thioxanthyl or anthryl radical.

Expressed in another Way R and R are wherein B represents a bond in R (the benzal compounds), B is hydrogen in R (the benzyl compounds), and Z is oxygen or sulfur in R and oxygen, sulfur or methylene (CH in R.

In the benzyl compounds of Formulas b and c, the compounds in which R is fluorenyl are particularly preferred.

The novel benzal compounds can be prepared by four general methods, i.e.,

(1) By the reaction of a hydroxy-benzal compound, substituted with an R group, with a dihaloalkane, e.g., a bromochloro-alkane or a dibromoor dichloro-alkane, followed by reaction with a suitable amine, i.e.,

n=cn (Han man (2) By the reaction of the hydroxy-benzal compound of (1) with a haloalkylamino compound, e.g., a dialkylaminoalkyl halide or a haloalkylheterocyclic, i.e.,

O CnHg A (3) By the reaction of a benzaldehyde substituted with a AC H O group with the compound from which R is derived, e.g., fiuorene, in the presence of an alkaline catalyst, e.g., sodium methoxide or ethoxide, i.e.,

-CHO RH;

OGDH A AC H O o omiiQ RHLl (from an, BuLi) In the above methods R has the same meaning as in the novel benzal compounds of Formula a described above except that, in method 2, R is not indenylidene, and in method 4 R can be anthrylene. Also, the phenolic starting materials of methods 1 and 2 are preferably used in the form of their alkali metal salts, e.g., sodium, lithium or potassium.

The novel benzyl compounds of Formula c can be generally prepared by method 4.

The novel benzyl compounds of Formula 22 can be prepared by the hydrogenation, preferably in the presence of a catalyst, e.g., platinum or palladium on charcoal, of the corresponding benzal compounds, i.e.,

1" Y Q 5Q OC H A H oc,,H ,A The benzyl compounds (b) in which R is anthryl can be prepared by method 2 using a hydroxy-benzyl-anthracene starting material which can be prepared by method (c) below from anthrone. In method below when anthrone is used a hydroxy-benzyl-anthracene is obtained rather than a hydroxy-benzal-dihydroanthracene.

The novel benzyl compounds of Formula b or c in which A is amino can also be prepared by the hydrogenolysis of the corresponding benzal compound wherein A is dibenzyl amino.

The hydroxy-benzal intermediates used to prepare the new benzal compounds can be prepared by four general methods, i.e.z

(a) Reacting a compound from which R is derived, eg, fiuorene, with methoxy-benzaldehyde in the presence of a condensing agent such as sodium methoxide or ethoxide or piperidine to form the corresponding methoxy-benzal compound, and demethylating, e.g., with pyridine-HCl, hydrobromic acid or aluminum chloride, to produce the hydroxy-benzal compound, i.e.,

NaOMe RH; CHO

Me O

OMe OH (12) Reacting the R starting compound of (a) with m-hydroxybenzaldehyde, i.e.,

HO OH (0) Reacting a ketone containing R with a methoxybenzyl magnesium halide to form the corresponding methoxybenzal compound and demethylating as in meth- 0d (a), i.e.,

and

(d) Reacting the R starting compounds of (a) with the tetrahydropyranyl ether of hydroxybenzaldehyde, i.e.,

As noted above, an exception to method (0) is the behavior of anthrone (R anthrylene) which forms benzylmethoxy and benzyl-hydroxy intermediates rather than benzal intermediates, i.e.,

OMe

This benzyl intermediate can be used in method 2 above to produce the novel benzyl compounds wherein R is anthryl.

The novel compounds of our invention will be further illustrated by the following examples.

EXAMPLE 1 9- [p-( fi-ethylaminoethoxy) benzal] fluorene demethylate and A mixture of 735 g. of 9-anisalfluorene and 1070 g. of pyridine hydrochloride was refluxed for 30 minutes, cooled, and the mixture was shaken in water and ether. The ether solution was extracted twice with 10 percent sodium hydroxide solution, this alkaline solution was at room temperature for prolonged periods, crystals of 9-(phydroxybenzal)fluorene were obtained, melting at 110-112" C. This phenol was sufficiently pure for subsequent reactions to form others without the need for crystallization. The residue obtained by acidification of the above alkaline solution was either taken up in a known volume of ethanol or dry benzene and aliquot portions used.

A mixture of 82 g. of 9-(p-hydroxybenzal)fluorene and 18 g. of sodium methoxide in 300 ml. of ethanol was stirred for 30 minutes, 180 g. of l-bromo-Z-chloroethane was added and the mixture was refluxed 8 hours. The ethanol and bromoohloroethane were removed and a chloroform solution of the residue was washed with percent sodium hydroxide, water, then dried over anhydrous magnesium sulfate. The chloroform was removed and the oily residue, when taken up in ether, settled out as crystals of 9-[p-(B-chloroethoxy)benzal]fluorene, melting at 122-123" C.

A mixture of 89 g. of 9-[p-(fi-chloroethoxyybenzal]- fluorene and 60 g. of ethylamine in 240 ml. of ethanol was heated in a pressure bottle for 24 hours at 72 C. The excess ethylamine and ethanol were removed and the residue was acidified in ethanol with alcoholic hydrogen chloride. After removing the ethanol and washing the solid with anhydrous ether, the product was triturated three times with hot chloroform, then crystallized from ethanol to give 9- [p-( fi-ethylaminoethoxyfibenzel]fluorene hydrochloride, melting at 235-236 C.

Analysis.-Calcd. for C H NO-HCh C, 76.30; H, 6.40; CI, 9.38. Found: C, 76.01; H, 6.46; Cl, 9.25.

This compound exhibits the following activities: antiinflammatory; uterotrophic; produces mouse lung consolidation arrest; antifungal.

EXAMPLE 2 9- [p- (B-dimethylaminoethoxy) benzal] fluorene A mixture of 30 g. of 9-(p-hydroxybenzaDfluorene and 6.5 g. of sodium methoxide in 150 ml. of ethanol was stirred 30 minutes then was allowed to reflux with a solution of ,B-dimethylaminoethyl chloride (prepared from 21 g. of the hydrochloride salt) in 150 ml. of toluene for four hours. The solvent was removed,'the residue was taken up in ether and after washing twice with 10 percent sodium hydroxide solution and three times with water the ethereal solution was dried over anhydrous magnesium sulfate. After rendering this solution slightly acidic with alcoholic hydrogen chloride and removing the ether, the product was crystallized from methanolisopropanol to give 9-[p-(fi-dimethylaminoethoxy)benzal]fiuorene hydrochloride, melting at 217 C.

Analysis.-Calcd. for C H NO-HCl: C, 76.28; H, 6.40; N, 3.71. Found: C, 75.90; H, 6.41; N, 3.82.

, This compound exhibits the following activities: antiinflammatorry; antifungal.

EXAMPLE 3 When the fi-dimethylaminoethyl chloride was replaced with ,B-diethylaminoethyl chloride in the procedure of Example 2, the hydrochloride salt of 9-[p-(fi-diethylaminoethoxy)benzal1fluorene was obtained (from chloroform-ethyl acetate), melting at 196197 C.

Analysis.Calcd. for C H NO-HCl: C, 76.93; H, 6.95; N, 3.45. Found: C, 76.71; H, 7.29; N, 3.38.

This compound can also be prepared by the following procedure:

To 175 ml. of refluxing dihydropyran, containing four drops of concentrated hydrochloric acid, was added 36.6 g. of 'p-hydrox'ybenzaldehyde. After refluxing an hour,

the excess dihydropyran was removed by distillation at 25 mm. of pressure. One-half of the residue was dissolved in ml. of ethanol and added to a mixture of 16.6 g. of fluorene and 16.6- g. of sodium methoxide in 200ml. of ethanol. The mixture was refluxed an hour,

the solvent was removed and the residue taken up in ether. After washing the ether solution with water, then with saturated aqueous solution of sodium bisulfite, and again with water, 100 ml. of 10 percent hydrochloric acid was added and the ether was allowed to evaporate by heating on a steam bath. An ether extract of the organic layer was extracted with 10 percent sodium hydroxide, the aqueous layer was acidified with 10 percent hydrochloric acid and the precipitated oil was dissolved in ether, washed with water, dried over magnesium sulfate, and the solvent was removed. The residue was 9(p-hydroxybenzal)fluorene which, when allowed to react (as the sodium salt) with B-diethylaminoethyl chloride, gave 9-[p-(B-diethylaminoethoxy)benzal]-fluorene, whose hydrochloride salt was identical with the above.

This compound exhibits the following activities: antiinflammatory; produces mouse lung consolidation arrest; antifungal.

EXAMPLE 4 9- [m- (p-diezhylam inoethoxy) benzal] fluorene A mixture of 41.5 g. of fluorene and 54 g. of sodium methoxide in 450 ml. of ethanol was warmed to 65 C. and 30.6 g. of m-hydroxybenzaldehyde in 300 ml. of ethanol was added with stirring. After standing at room temperature for 16 hours and then refluxing for 6 hours, the mixture was diluted with an excess of 10 percent hydrochloric acid and extracted with benzene. The organic layer was extracted with 10 percent sodium hydroxide solution, the aqueous layer was acidified and extracted with benzene and the benzene solution was dried over anhydrous magnesium sulfate. The solution was distilled to give 9-(m-hyd'roxybenzal)-fluorene, boiling at 232 at 0.2 mm.

Following the procedure of Example 3, the 9-(mhydroxybenzaDfluorene (as the sodium salt) was treated with ediethylarninoethyl chloride to give 9-[m-(B-diethylaminoethoxy)benzal]fluorene Whose hydrochloride salt melted at 193-195 C. (from isopropanol).

Analysis.-Calcd. for c, H, N0-Hc1: C, 76.93; H, 6.95; N, 3.45. Found: C, 76.70; H, 7.17; N, 3.44.

This compound exhibits the following activities: antiinflammatory; decreases thyroid weight; antifungal; phospholipogenic.

EXAMPLE 5 9- [p- ('y-dim'ethylaminopropoocy) benzaflflu'orene EXAMPLE 6 9- [p- 'y-diethylwmtin0pr0p0oty) benzal] fluore ne A mixture of 20 g. of 9-(p-hydroxybenzal)fluorene and 4 g. of sodium methoxide in ml. of dry benzene was refluxed two hours, a solution of y-diethylarninopropyl chloride (prepared from 22.3 g. of its hydrochloride salt) in 150ml. of toluene was added and the mixture was stirred and refluxed 16 hours. Following the Work-up de scribed in Example 2, the hydrochloride salt of 9[p'-('y diethylarninopropoxy) benzalJfiuorene was obtained (from isopropanol), melting ati203'-204 C.

7 Analysis.-Calcd. for CgqHggNOHClI C, 77.22; H, 7.20; N, 3.34. Found: C, 76.84; H, 7.13; N, 3.55.

This compound exhibits the following activities: antiinflammatory; antifungal.

EXAMPLE 7 9- [p-(y-dibutylaminoethoxy) benzal] fiuorene When fi-di-n-butylaminoethyl chloride replaced the dimethylaminoethyl chloride in the procedure of Example 2, the hydrochloride salt of 9-[p-(B-dibutylaminoethoxy)- benzallfluorene was obtained (from isopropanol), melting at 170171 C.

Analysis.Calcd. for C H NO-HCl: C, 78.00; H, 7.86; N, 3.03. Found: C, 77.88; H, 8.07; N, 2.97.

This compound exhibits the following activities: antiinflammatory; produces mouse lung consolidation arrest.

EXAMPLE 8 9- p- ,B-a' i b enzy laminoeth oxy benzal fiuorene A mixture of 33 g. of 9-[p-(fi-chloroethoxy)benzal]- fiuorene and 40 g. of dibenzylamine was heated at 160- 190 C. for 34 hours, the mixture was triturated several times with benzene and the benzene was removed. The residual oil was triturated with 40-60 petroleum ether three times, the residue was acidified with alcoholic hydrogen chloride and after crystallizing twice from ethanol, the hydrochloride salt of 9-[p-(fi-dibenzylaminoethoxy)- benzallfluorene was obtained, melting at 180-182" C.

Analysis.-Calcd. for C H NO-HCl: C, 81.56; H, 6.09; N, 2.64. Found: C, 81.92; H, 5.93; N, 2.64.

This compound exhibits the following activities: uterotrophic.

EXAMPLE 9 Alpha- [p-(fl-diethylaminoethoxy)phenyl] -alpha- (9-flu0renyl) ethanol A solution of butyl lithium (from 2.5 g. of lithium wire and 24.7 g. butyl bromide in 150 ml. dry ether) was added to a solution of 25 g. of fiuorene in 150 ml. of dry ether and after stirring 30 minutes, a solution of 35.2 g. of p-(B-diethylaminoethoxy)-acetophenone in 100 ml. of dry ether was added slowly with stirring. The mixture was decomposed with cold water, the ethereal solution was washed repeatedly with water, was dried over anhydrous magnesium sulfate and the solvent was replaced with isopropanol. Crystals of alpha[p-(Bdiethylarninoethoxy)phenyl] alpha (9 fiuorenyl)ethanol were obtained, melting at 104 C.

Analysis.-Calcd. for 14 810 C, 80.76; H, 7.78; N, 3.49. Found: C, 80.86; H, 7.85; N, 3.47.

This compound exhibits the following activities: antiinfiammatory; estrogen antagonist; cholesterol depressant and phospholipogenic; antifungal.

Alpha [p (,8 diethylaminopropoxy)phenyl] alpha- (l-indenyl)methanol was prepared by the procedure of Example 9 utilizing indene and 4 (a diethylaminopropoxy)benzaldehyde (prepared from p-hydroxybenzaldehyde and a-diethylaminopropyl chloride), which had a boiling point of 142l44 C. (0.5 mm.) The product formed a dihydrogen citrate monohydrate melting at 94 C. with decomposition.

Analysis.-Calcd. for C H NO -C I-I O -H O: C, 62.00; H, 7.00; N, 2.50. Found: C, 61.76; H, 6.86; N, 3.02.

EXAMPLE l0 9-[alpha-methyl-p- (fi-diethylaminoethoxy) benzal] fiuorene The ethanol of Example 9 was dehydrated by refluxing in alcohol containing an excess of hydrogen chloride for six hours. Upon cooling, a crystalline product settled out which was recrystallized from ethanol, then dried at 160 C. at 0.5 mm. to give the hydrochloride salt of 9- [alpha methyl p (B diethylaminoethoxy)benzal]- fluorene, melting at 22l223 C.

8 Analysis.Calcd. for C H NO-HCl: C, 77.20; H, 7.20; N, 3.34. Found: C, 77.18; H, 7.44; N, 3.36.

This compound exhibits the following activities: antiinflammatory; uterotrophic.

EXAMPLE 1 1 9- p- B-piperidinoethoxy) benzal] fiuorene When the fl-dirnethylaminoethyl chloride was replaced with N-fl-chloroethylpiperidine in the procedure of Example 2, the hydrochloride salt of 9-[p-(B-piperidinoethoxy)'oenzallfluorene was obtained (for methanolchloroform) which, after drying at 150 C. at 0.5 mm., melted at 2l52l6 C.

Analysis.-Calcd. for CzqHzqNO'HCll C, 77.57; H, 6.75; N, 3.35. Found: C, 77.99; H, 6.27; N, 3.09.

This compound exhibits the following activities: uterotrophic; gonadotrophic inhibitor; produces mouse lung consolidation arrest; antifungal.

EXAMPLE 12 9- p- ,B-morpholinoethoxy) benzal] fiuorene When the fi-dimethylaminoethyl chloride was replaced with N-[i-chloroethylmorpholine in the procedure of Example 2, the hydrochloride salt of 9-[p-(fi-morpholinoethoxy)benzallfluorene was obtained (from ethanol), melting at 208-2l0 C.

Analysis.-Calcd. for CZGHZ5NOZ'HCIZ C, 74.36; 6.24; N, 3.34. Found: C, 74.24; H, 6.31; N, 3.57.

This compound exhibits the following activities: antiinflammatory (dextran edema test).

EXAMPLE l3 9- p- B-4-methylpiperazinoethoxy benzal1fluorene A mixture of 50 g. of p-hydroxybenzaldehyde and 22.4 g. of sodium methoxide in 150 m1. of methanol and 300 ml. of xylene was heated until all the methanol had been removed. A solution of [3-4-methylpiperazinoethyl chloride (prepared from 122 g. of the dihydrochloride salt, 69 g. KOH and approximately 75 ml. water) in xylene was added while the sodium salt was being stirred and refluxed. After 16 hours of refluxing, the xylene solution was washed with 10 percent sodium hydroxide, then water and distilled to give 4-(,B-4-methylpiperazinoethoxy)benzaldehyde, boiling at 168 C. at 0.2 mm.

A mixture of 12.7 g. of fiuorene and 12.9 g. of sodium methoxide in ml. of ethanol was heated with stirring for 30 minutes. A solution of 19 g. of the above benzaldehyde in 100 ml. of ethanol was added and the mixture stood overnight at room temperature. After refluxing an hour, the ethanol was removed, the residue was dissolved in ether and washed with water. The ether solution was then extracted with 10 percent hydrochloric acid, the aqueous layer was rendered basic with 10 percent sodium hydroxide and the oily precipitate was taken up in ether, dried over anhydrous magnesium sulfate and acidified with alcoholic hydrogen chloride. The yellow solid was boiled in ethanol and filtered while hot from the insoluble portion. The filtrate was cooled and the yellow crystals obtained were dried in vacuo at 100. The dihydrochloride of 9-[p-(B-4-methylpiperazinoethoxy)benzal]fluorene melted at 261-264 C.

Analysis.Calcd. for C H N O-2HCl: C, 69.08; H, 6.44; N, 5.97. Found: C, 69.13; H, 6.81; N, 5.70.

EXAMPLE 14 9-[p-( -piperidinopropoxy) benzallfluorene When -piperidinopropyl chloride replaced the fi-dimethylaminoethyl chloride in the procedure of Example 2, the hydrochloride salt of 9-p-(' -piperidinopropoxy)- benzal fiuorene was obtained, melting at 246248 C.

Analysis.Calcd. for C H NO-HCl: C, 77.84; H, 7.00; N, 3.24. Found: C, 78.04; H, 7.30; N, 3.21.

This compound exhibits the following activities: antiinflammatory; antifungal.

A mixture of 13 g. of indcne and 6.1 t. of sodium methoxide in 100 ml. of ethanol was refluxed an hour then a solution of 22 g. of 4-(p-diethylaminoethoxy)- benzaldehyde in 100 ml. ethanol was added and refluxing was continued for two hours. The alcohol was removed, the residue was taken up in either, extracted with percent hydrochloric acid, the aqueous layer was rendered basic and extracted with ether. The dried ether solution was acidified with'alcoholic hydrogen chloride and the precipitated oil was crystallized from methylene chloride-benzene to give the hydrochloride salt of l-[p- (fi-diethylaminoethoxy)benzallindene, melting at 197- 198 C.

AnalysinfiCalcd. for C H NO-HCl: C, 74.25; H, 7.36; N, 3.94. Found: C, 73.89; H, 7.22; N, 4.07.

This compound exhibits the following activities: antiinflammatory; gonadotrophic inhibitor or androgen antagonist; decreases thyroid weight; increases adrenal weight; cholesterol depressant.

EXAMPLE 16 1 [pp-d 'ethylaminoethoxy ),be nzal1 tetrahydroriaphthaler e The Grignard reagent from 102 g. of p-methoxybenzyl chloride in 1400 ml. of ether was added to a solution of 100 g. of alpha-tetralone in 300 m1. of ether and refluxed three hours. After decomposing the' mixture with dilute hydrochloric acid, the ether solution was evaporated and the residue was refluxed in alcoholic hydrogen chloride three hours. Crystals of l-anisaltetrahydronaphthalene separated upon cooling, melting at 86-88 C.

Analysia-Calcd. for C Hi O: C, 86.38; H, 7.25. Found: C, 86.09; H, 7.32.

A mixture of 90 g. of the anisaltetrahydronaphthalene and 168 g. of pyridine hydrochloride was heated at 200 C. for 6 hours. The mixture was taken up in water and ether, the ether layer was extracted with 10 percent sodium hydroxide, the acidified alkaline solution was extracted with ether and the ether was replaced with ethanol-water. Crystals of 1-(p-hydroxybenzal)tetrahydronaphthalene were obtained, melting at 133-135 C.

An'alysis.-Calcd. for C H O: C, 86.40; H, 6.82. Found: C, 86.34; H, 6.89.

When the 9-(p -hydroxybenzal)fluorene was replaced with 1-(p-hydroxybenzal)tetrahydronaphthalene in the procedure of Example 3, 1-[p-(,B-diethylaminoethoxy)- benzalltetrahydronaphthalene was obtained as the hydrochloride (from ethanol), melting at 219-221 C.

Analysis.-Calcd. for C H No'HCl: C, 74.28; H, 8.13; N, 3.77. Found: C, 74.42;.H, 8.25; N, 3.76.

This compound exhibits thefollowing activities: estro gen antagonist.

EXAMPLE 17 9- [p- (fl-diethylaminoethoxy) benzal] xanihene When the alpha-tetralone was replaced with xanthone in the procedure of Example 16, the following intermediates and final product were obtained:

9 (p ni'ethoxybenzahxanthene (from ethanol ethyl acetate), meltingat 104107 C.

9 (p hydroxybenzal)xanthene (from ethanol ethylacetate), melting at 18:1-182 C.

The hydrochloride salt of 9 [p (B diethylamin'oethoxy)-benzal]xanthene (from methanol-isopropanol), melting-at 196-197 C.

Analysis.--Calcd.' for C H NO -I-ICl: C, 74.00; H, 6.69; N, 3.32; Found: C, 73.45; H, 6.78; N, 3.55.

This compound exhibits the following activities: antiinflammatory.

EXAMPLE 18 9- [p- (p-diethylwminoeth oxy) benzal] thioxanthene Wlltlll i116 iillill-ltlaione Was replaced with thioxanthone in the procedin'e of Example 16, the following intermediates and final product were obtained:

9-(p-methoxybenzal)thioxanthene (from ethyl acetatemethanol), melting at 134-136 C.

9-(p-hydroxybenzal)thioxanthene (from ether-petroleum ether), melting at 176-177 'C. 1

The hydrochloride salt of 9-[p-(fl-diethyl 'oethoxy)benzal] thioxanthene (from methanol-isopropanol), melting at 205 C.

Analysis.Calcd. for C H NOS'HCl: C, 71.28; H, 3.4;; N, 3.20. Found: C. 71.06; H, 6.62; N, 3.15; S, 7.32,

This compound exhibits thefollowing activities: antiinflammatory: lowers cholesterol/phospholipid ratio; uterotrophic estrogen antagonist.

EXAMPLE 19 9- [p-(/E-diethylaminoethoxy)benzyllanthracene EXAMPLE 20 e 9- [p- (fi-aminoethoxy benzyl] fluorene A mixture of the free base derived from 22 g. of the hydrochloride of 9- [p- (fl-dibenzylaminoethoxy) betnzal fluoren'e (Example 8) and 2 g. of 10 percent palladium on charcoal in 200 ml. of ethanol was hydrogenated under 3 atmospheres of hydrogen until the theoretical three molar equivalents of hydrogen had been consumed. After removing the catalyst and acidifying the ethanol solution with hydrogen chloride, the product obtained was recrystallized from chloroform-isopropanol to give the hydrochloride salt of 9- [p-(p-aminoethoxy)benzyUflnorene, melting at 199 C. (after drying at at 0.5 mm).

A'nalysz's.Calcd. tfor c ,H,,No-Ho1; C, 75.12; H, 6.31,; N, 3.98; Found: C, 75.02; H, 6.61; N, 3.95.

This compound exhibits the following activities: orally active anti-inflammatory; estrogen antagonist; gonadotrophic inhibitor or androgen antagonist; decreases thyroid weight; phospholipogenic.

EXAMPLE 21 9- [pfl-ethylaminoethoxy benzyl] fluorene vA mixture of 24 g. of the hydrochloride, salt of the compound of Example 1 and 3 g. of 10 percent palladium on charcoal in 250 ml. of ethanol was hydrogenated under 3 atmospheres of hydrogen'until the uptake of hydrogen ceased. More ethanol was added and the mixture was warmed on a steam bath to dissolve the precipitated amine salt in order to remove the catalyst. After concentrating and cooling the ethanol solution, the hydrochloride salt of 9-[p-(,B-ethylaminoethoxy)benzyl]fluorene was obtained, melting at 217-219 C.

Analysis.-Ca=lcd. for C H NO-HCl: C, 75.90; H, 6.90; N, 3.69. Found: C, 75.64; H, 6.80; N, 3.84.

This compound exhibits the following activities: antiinflammatory; uterotrophic; gonadotrophic inhibitor; cho-v lesterol depressant.

EXAMPLE 22 9- [p-( fl-dimethylaminoeth oxy) benzyl] fluorene When the hydrochloride of 9-[p-(fi-dimethylarninoethoxy)benzal]fluorene replaced the substituted fluorene in the procedure of Example 21, the hydrochloride salt of 9 [p-(B-dimethylaminoethoxy)-benzyl]fluorene was obtained, melting at 209211 C.

Analysis.Ca.lcd. for C H NO-HCl: C, 75.90; H, 6.90; N, 3.69. Found: 0, 75.48; H, 6.95; N, 4.03.

This compound exhibits the following activities: antiinfiammatory; uterotrophic; gonadotrophic inhibitor or androgen antagonist; phospholipogenic.

EXAMPLE 23 9- [p-( fl-diethylaminoethoxy) benzyll fluorene When the hydrochloride of 9 [p-(fi-diethylaminoethoxy)benzallfluorene replaced the substituted fluorene in the procedure of Example 21, the hydrochloride salt of 9-[p-(fi-diethylaminoethoxy)benzyl]fluorene was obtained (from isopropanol), melting at 176-178" C. (after drying at 125 C. at 0.5 mm.).

Analysis-Called. for C H NO-HCl: C, 76.52; H, 7.41; N, 3.43. Found: C, 76.41; H, 7.60; N, 3.54.

This compound exhibits the following activities: antiinfiammatory; uterotrophic; antifungal.

EXAMPLE 24 9- [p-( l8-dibutylaminoethoxy) benzyl] fluorene When the hydrochloride of 9-[p-(fi-dibutylaminoethoxy)benzal]fluorene replaced the substituted fluorene in the procedure of Example 21, the hydrochloride salt of 9-[p-(l3-dibutylaminoethoxy)-benzyl]fiuorene was obtained (from isopropanol), melting at 156 C.

Analysis.-Calcd. for C H NO-HCI: C, 77.65; H, 8.25; N, 3.02. Found: C, 77.90; H, 8.31; N, 3.11.

This compound exhibits the following activities: antiinflammatory; uterotrophic.

EXAMPLE 25 9- [p-( -dimeIhyZaminO rOpOxy) benzyl] fluorene When the hydrochloride of 9-[p-('y-dimethylaminopropoxy)benzal]fluorene replaced the substituted fluorene in the procedure of Example 21, the hydrochloride salt of 9 [pOy-dimethylaminopropoxy)benzyllfluorene was obtained (from isopropanol), melting at 2162l7 C.

Analysis.-Calcd. for C H NO-HCh C, 76.20; H, 7.16; N, 3.56. Found: C, 75.55; H, 6.99; N, 3.59.

This compound exhibits the following activities: antiinfiammatory; estrogen antagonist; gonadotrophic inhibitor or androgen antagonist; decreases thyroid weight.

EXAMPLE 26 9-[p-(fi-pip ridinoethoxy)benzyllfluorene When the hydrochloride of 9-[p-(fi-piperidinoethoxy)- bcnzallfluorene replaced the substituted fluorene in the procedure of Example 21, the hydrochloride salt of 9- [p (5 piperidinoethoxy)benzyllfiuorene was obtained (from chloroform-isopropanol), melting at 228-230" C.

Analysis.-Calcd. for C H NO'HCl: C, 77.21; H, 7.20; N, 3.34. Found: C, 76.64; H, 7.17; N, 3.56.

This compound exhibits the following activities: antiinflammatory; weak uterotrophic.

. EXAMPLE 27 9- [p-( fi-diethylaminoethoxy benzal] fluorene N -oxide The free base obtained by neutralizing 12 g. of the hydrochloride salt of Example 3 was allowed to react in 200 ml. of methanol with 3.5 ml. of 30 percent hydrogen peroxide for three days. The mixture was stirred with 0.2 g. platinum oxide until oxygen evolution ceased, the catalyst was removed and the solution was concentrated under vacuum below 30 C. Ether was added to the 12 gummy residue whereupon crystals of 9-[p-(fi-diethylaminoethoxy)benzallfluorene N-oxide, existing as a hydrate, were obtained, decomposing at 111 C.

Anal.-Calcd. for c H No -H o; C, 77.40; H, 7.25; N, 3.46. Found: C, 77.35; H, 7.42; N, 3.51.

EXAMPLE 28 9- i p- ,fi diethylaminoethoxy) benzal] fluorene methosulfate The free base from 25 g. of the hydrochloride salt of Example 3 in 200 ml. of dry ether was allowed to react with 8 g. of freshly distilled dimethylsulfate. After standing for three days, the ether was decanted and the residual yellow oil was triturated repeatedly with dry ether. The viscous gum was dissolved in about ml. of methylene chloride and this solution wis diluted with 400 ml. of dry ether. The gummy precipitate was allowed to stand under dry ether for two days whereupon solidification of the entire mass finally was elfected. The solid was dissolved in a minimum of ethanol and this solution was diluted with butanone and a little dry ether. Crystals of the methosulfate of 9-[p-(l8-diethylaminoethoxy)benzal]fluorene were obtained, melting at 179- 180 C.

AnaL-Calcd. for C2eH27NO'(CH3)2SO4Z C, 67.86; H, 6.71. Found: C, 67.34; H, 6.70, N, 2.83, N, 2.89.

The compounds of the above examples exhibited the activities described for each (except anti-fungal activity and blood cholesterol and phospholipogenic activity) when administered parenterally (subcutaneously). Also, the compound of Example 20 exhibited anti-inflammatory activity and the compounds of Examples 3, 7 and 11 produced mouse lung consolidation arrest when administered orally. The compounds of Examples 4, 9, 15, 18, 20, 21 and 22 exhibited blood cholesterol or phospholipogenic activity when administered orally. The tests were carried out on mice and rats. Anti-fungal activity was determined in vitro with the fungi described above.

The following examples illustrate suitable pharmaceutical preparations containing the new compounds. In these examples, the quantities are given for single units, it being understood that in actual practice, the dosage forms will be prepared in suitable quantities, and the amounts of materials used adjusted accordingly.

EXAMPLE 29 25 MG. TABLETS Twenty-five mg. of the hydrochloride of 9-[p-(fl-diethylaminoethoxy)benzallfluorene (Example 3). 48 mg. of powdered sugar, and 32 mg. of corn starch are mixed and granulated with 10 percent gelatin solution. The granulation is dried and ground to fine granules for tableting. About 1 percent magnesium stearate is added as a lubricant, together with suflicient corn starch to give a weight of 2.5 grains per tablet. The product is compressed on a single punch or rotary machine using a inch punch.

EXAMPLE 30 500 MG. TABLETS Five hundred mg. of the hydrochloride of 9-[p-(fl-diethylaminoethoxy)benzallfluorene (Example 3) in finely powdered form is admixed with 60 mg. of corn starch and 100 mg. of powdered sugar and then granulated with 10 percent gelatin solution. The granulation is dried and ground to size suitable for tableting. About 1 percent magnesium stearate is added as a lubricant, together with sufficient corn starch to give a weight of 700 mg. per tablet. The product is compressed on a single punch or rotary machine using a A inch punch.

The tablets of Example 29 and Example 30 may be suitably coated if desired, as, for example, with sugar.-

3 .3 EXAMPLE 3.1 CAPSULE Twenty-five of the hydrochloride of I-[p-(fl-dieth- 14 EXAMPLE 39 ISOTONIC SOLUTION, 0.25%

A mixture of 0.25 g. of the hydrqchloiide of MP- V/lIHIiIMfiOXJ/ibtllZt/ililtitflt (Example ii) is admired 5 (,6 rliitlzylamiiioetlbry)benzallfiuorene (Example 3).

with corn starch in quantity required to provide suflicient bulk for the desired size capsule, and the mixture is encapsulated.

EXAMPLE 32 CAPSULE Five hundred mg. of the hydrochloride of 9-[p-(paminoethoxy)-benzyllfluorene (Example 20) is admixed with sufiicient corn starch to give the proper bulk for the desired size capsule, and the mixture is encapsulated.

EXAMPLE 33 INJECTABLE SUSPENSION, 100 MG. PER ML.

The following ingredients are sterilized separately: 100 mg. of the hydrochloride of 9-[p-(B-diethylaminoethoxy)benzal]fluorene (Example 3), 0.1 mg. of Tween 80 and q.s. corn oil to make a final volume of 1 ml. These ingredients are admixed aseptically. Particle size may be achieved by use of micronized material or by use of a ball mill, maintaining aseptic conditions. The above suspension may be administered subcutaneously and intramuscularly.

EXAMPLE 34 LIQUID (SYRUP) 25 MG. PER TEASPOON Twenty-five mg. of the hydrochloride of 1-[p( 8-diethylaminoethoxy)benzal]indene (Example 15) is dissolved in 1 ml. of water. Five mg. of sodium benzoate, 3.5 ml. of liquid sugar, 5 mg. of citric acid, and 0.375 mg. of butoben are added and stirred until dissolved, using gentle heat if necessary. Flavor, as desired, and water q.s. are then added.

EXAMPLE 35 LIQUID (SYRUP) 500 MG. PER TABLESPOON Five hundred mg. of the hydrochloride of 9-[p-(18-diethylaminoethoxy)benzallfiuorene (Example 3) and 4.5 mg. of sugar are dissolved in suflicient water so that after the addition of 2.25 ml. of alcohol USP and flavor, as desired, the volume is 15 ml.

EXAMPLE 36 INJECTABLE SOLUTION 100 MG. PER ML.

One hundred mg. of the hydrochloride of 9-[p-(fl-diethylaminoethoxy)benzyl]fluorene (Example 3) and water for injection q.s. 1 ml. are mixed and warmed gently till solution is accomplished. The solution is filtered through fine sintered glass, filled into sterile 1 ml. ampuls, and sterilized at 250 F. for 30 minutes.

EXAMPLE 37 1% OINTMENT To a melt of 1.5 lbs. of propylene glycol 6.68 lbs. of polyethylene glycol 400 USP and 6.68 lbs. of carbowax 4000 USP is added 0.15 lb. of micropulverized hydrochloride of 9-[p-(B-aminoethoxy)benzyllfluorene (Example 20). The product is stirred until almost solid and milled if necessary to a smooth ointment. Fill in suitable containers.

EXAMPLE 38 OINTMENT To a melt of 1.5 lbs. of propylene glycol, 6 lbs. of polyethylene glycol 400 USP and 6 lbs. carbowax 4000 USP is added 1.5 lbs. of micropulverized hydrochloride of 1-[p-(fl-aminoethoxy)benzyl]fluorene (Example 20). The product is stirred until almost solid and milled if necessary to a smooth ointment. Fill in suitable containers.

0.026 g. of methylparaben, 0.014 g. of propylparaben, 0.875 g. of sodium chloride, and ml. of distilled Water is stirred until a clear solution is obtained. Distilled water is added to make a final volume of ml. The solution is put in suitable containers for dispensing as nose drops, for atomizing, or for use in aerosol sprays.

EXAMPLE 40 ISOTONIC SOLUTION, 2%

A mixture of 2.0 g. of the hydrochloride of 9-[alpha- (B-diethylaminoethoxy)benzallfluorene (Example 3), 0.026 g. of methylparaben, 0.014 g. of propylparaben, 0.613 g. of sodium chloride, and 90 ml. of distilled Water is stirred until a clear solution is obtained. Distilled water is added to bring the final volume to 100 ml. The solution is put in suitable containers for dispensing as nose drops, for atomizing, or for use in aerosol sprays.

EXAMPLE 41 AEROSOL SPRAY, AQUEOUS Solutions from Examples 39 or 40 may be placed into a pressurized container, pressurized with nitrogen, helium or a mixture of both, so that the initial head pressure is in the range of 65-75 pounds per square inch, and atomized through micro-mist valves (available from Precision Valve Company).

Such a solution may also be metered through a number of different aerosol valves to give a solution weight of from 25 mg. to 250 mg. per charge. (Such metered valves are available from Risdon Valve Company or Aerosol Techniques, Inc.). Container size may be selected from any of the many available containers commercially available, varying in size from 10 ml. to 8 ounces and made from glass, nylon, aluminum or coated tin plate.

EXAMPLE 42 FREON PROPELLED AEROSOL Twenty grams of the hydrochloride of 9-[p-(B-aminoethoxy)benzyllfluorene (Example 20) is dissolved in water, and 100 ml. 5 percent sodium hydroxide solution is added. The water insoluble oily base is extracted with ether; the ether extract is dried over anhydrous magnesium sulfate and evaporated on the steam bath and finally in a vacuum desiccator. One gram of the residual oily free base is dissolved in a mixture of 80 g. of Freon 114 and 20 g. of Freon 12 in. the cold (20 C. or lower). The solution is cold filled into an appropriate pressure container. Such a container may have a gauge pressure of 18-25 pounds per square inch at normal room temperature and can be dispensed from a metered valve.

We claim:

1. Compounds of the formula selected from the group consisting of O O Hg A Y was from the group consisting of amino, alkylamino in which and 15 316 the alkyl group contains from 1 to 4 carbon atoms, difiuorenyl, indenyl, tetrahydronaphthyl, xanthyl, thioalkylamino in which the alkyl group contains from 1 to xanthyl and anthryl radicals.

4 carbon atoms, dibenzylarnino, morpholino, piperidino, 2. 9-[p-(B-diethylaminoethoxy)benzalJfluorene. and N-methylpiperazino groups; n is an integer of 2 to 3. 9-[m-(fi-diethylaminoethoxy)benzal1fluorene. 3; Y is selected from the group consisting of hydrogen 5 4. 9-[p-(fi-piperidinoethoxy)benzaflfluorene. and methyl; wherein R is selected from the group con- 5. 1-[p-(,B-diethylaminoethoxy)benza11indene. sisting of fluorenylidene, indenylidene, tetrahydronaph- 6. 9-[p-(5-aminoethoxy)benzyflfiuorene.

thylidene, xanthylidene and thioxanthylidene radicals N r f r s ited. and wherein R is selected from the group consisting of o e 6 61166 c

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3162637 *Mar 14, 1960Dec 22, 1964Colgate Palmolive CoPiperazinoalkyl esters of 9-hydroxyfluorene-9-carboxylic acid
US3177209 *Sep 7, 1961Apr 6, 1965Kefalas AsDihydroanthracene compounds
US3178420 *Jun 25, 1959Apr 13, 1965Richardson Merrell IncAmino-2-hydroxy-1-propoxy benzal derivatives of fluorene and xanthene
US3196159 *Sep 29, 1959Jul 20, 1965Ciba Geigy Corp(aminoalkyleneoxy)-phenyl alcohols
US3494961 *Jun 27, 1967Feb 10, 1970Hoffmann La Roche1,4-bis-(p-(dialkylaminoalkoxy)aryl)-1,4-bis-(aryl)-2-b-1,4-diols
US4323707 *May 12, 1980Apr 6, 1982Eli Lilly And CompanyAntifertility compounds
US7482344Dec 15, 2004Jan 27, 2009Eli Lilly And CompanyTricyclic steroid hormone nuclear receptor modulators
US20070088016 *Dec 15, 2004Apr 19, 2007Coghlan Michael JTricyclic steroid hormone nuclear receptor modulators
WO2005066153A1 *Dec 15, 2004Jul 21, 2005Eli Lilly And CompanyTricyclic steroid hormone nuclear receptor modulators
Classifications
U.S. Classification546/203, 544/145, 544/396, 544/397, 544/375, 544/155, 549/26, 564/324, 544/380, 544/174, 250/396.00R, 549/388, 546/196, 544/154, 546/205, 546/202
International ClassificationC07D295/092, C07D311/82
Cooperative ClassificationC07D311/82, C07C2103/18, C07D295/088
European ClassificationC07D311/82, C07D295/088