US3375256A - 4-substituted-4'-tertiary aminoalkoxy biphenyls - Google Patents

Description

United States Patent 3,375,256 4-SUBSTlTUTED-4'-TERTIARY AMINOALKOXY BIPHENYLS Frederick Louis Bach, Montvale, N.J., and John Claire Barclay, New York, and Elliott Cohen, Pearl River, N .Y., assignors to American Cyanamid Company, Stamford, -Conn., a corporation of Maine No Drawing. Continuation-impart of application Ser. No. 427,094, Jan. 21, 1965. This application Nov. 18, 1966, Ser. No. 595,360

10 Claims. (Cl. 260--294.7)

ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 4-substituted- '-tertiary aminoalkoxy biphenyls useful as hypocholesteremic agents.

This application is a continuation-in-part of our copending application, Ser. No. 427,094, filed Jan. 21, 1965, now abandoned, which in turn is a continuation-in-part of our application Ser. No. 370,044, filed May 25, 1964, now abandoned.

This invention relates to certain novel 4-substituted-4- tertiary aminoalkoxy biphenyls and, more particularly, is concerned with novel compounds which may be represented by the following general formula:

wherein Z is nitro, lower alkanoyl, carboxy, lower carboalkoxy, trifluoromethyl, sulfonamido, methylsulfonyl or l-hydroxy-1-methyl-2-propynyl; R R R and R are each hydrogen, methyl or ethyl with the proviso that the total number of carbon atoms in the alkylene group is less than 7; R is lower alkyl; R is lower alkyl; and R and R taken together with the |N(itrogen) is pyrrolidino, piperidino or 4(lower alkyl)-1-piperazino. Lower alkyl and lower alkanoyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. and acetyl, propionyl, n-butyryl, etc. Suitable lower carboalkoxy groups are those having from 1 to 6 carbon atoms such as, for example, carbomethoxy, carbethoxy, etc.

Atherosclerosis is a form of arteriosclerosis where cholesterol and lipoid materials are deposited as plaques in the intima of large and medium sized arteries. Arteriosclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined. However, there is a statistical correlation between hypercholestcremia and the incidence of cardiovascular disease. For some time it has been considered desirable to lower high cholesterol and lipid levels as a possible preventive measure against atherosclerosis. In the past, attempts have been madeto lower the level of cholesterol in the blood by the oral feeding of various substances which have been generally referred to in the art as hypocholesteremic adjuvants. Typical of such substances are lecithin, cotton-seed oil, and corn oil.-

Our invention is based upon the discovery that our novel ,4-substituted-4-tertiary aminoalkoxy biphenyls exert a more powerful hypocholesteremic action than the adjuvants which have been used heretofore. It is not known how the novel compounds of the present invention operate to lower the cholesterol level in blood serum and no theory of why these compounds operate is advanced. It is not intended that the present invention should be limited to any theory as to mechanism.

The organic bases of this invention form non-toxic, acid-addition and quaternary ammonium salts with a I I I 3,375,256 Patented Mar. 26, 1968 variety of organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an acid, suitable in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids. Quaternary ammonium salts may be formed by reaction of the free bases with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. The organic reagents employed for quaternary ammonium salt formation are preferably lower alkyl halides. However, other organic reagents :are suitable for quaternary ammonium salt formation, and may be selected from among a diverse class of compounds including benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, allyl chloride, methallyl bromide and crotyl bromide. For purposes of this invention the free bases are equivalent to their non-toxic acid-addition and qua-ternary ammonium salts.

The novel compounds of the present invention are materials which may be purified by crystallization from common organic solvents such as ether, acetone, benzene and the like. They are generally insoluble in water, but relatively soluble in organic solvents such as lower alkanols, esters, ethers, ketones, benzene, toluene, chloroform, and the like. The acid-addition and quaternary ammonium salts of the organic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol, but relatively insoluble in non-polar organic solvents such as ether, benzene, toluene and the like.

An advantage offered by the novel compounds of the present invention is their oral activity. They may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets. It is an advantage of the present invention that our novel compounds may be orally administered in any convenient manner. The amount of a single dose or of a daily dose to be given will vary with the size of the individual to be treated, but should be such as to give a proportionate dosage of from one milligram to 30 milligrams per kilogram of body weight per day. In terms of total weight, this is usually from about 0.1 gram to about 1.0 gram per daily dosage unit.

The novel compounds of the present invention may be readily prepared by the interaction of the sodium or potassium salt of a 4-substituted 4'-hydroxybiphenyl with an appropriately substituted tertiary aminoalkyl halide as set forth in the following reaction scheme:

wherein M is sodium or potassium, X is halogen, and Z, R R R R R and R are as hereinabove defined. This reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, toluene, and the like, at temperatures ranging from about C. to

about C. over a period of time ranging from about as a condensing agent as set forth in the following reaction scheme:

4 1-methyl-2-chloroethylamine in 100 ml. of ethanol and 100 ml. of water was refluxed 15 hours. The ethanolwherein Z, R R R R R and R are as hereinabove defined. This reaction is preferably carried out by placing the reactants, without a solvent, in a sealed tube at a temperature of about 100 C. for a period of time ranging from about 15 hours to about 48 hours.

For therapeutic administration, the active compounds of this invention may be incorporated with excipients and used, for example, in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. Such compounds and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that a dosage unit form contains between about 10* and about 200 milligrams of active compound.

The tablets, troches, pills, capsules and the like may contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring. A syrup or elixir may contain the active compounds in the form of their non-toxic acid-addition salts, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.

Example 1 Example 2 Using the method and work-up described in Example 1, 5.0 g. of the potassiov derivative of 4-hydroxy-4-nitrobiphenyl and 3.3 g. of N,N-diisopropyl-2-chloroethylamine were refluxed in200 ml. of dry toluene and 75 ml. of n-amyl alcohol for approximately hours. The crude product yielded the desired 4-(2-diisopropylaminoethoxy) 4'-nitrobiphenyl' after two reerystallizations from etherpetroleum ether; melting point 5 0-5 1 C.

Example 3 A suspension consisting of 10.2 g. of the potassium salt of 4-hydroxy-4-nitrobiphenyl, 5.4 g. of N,N-dimethyl- R1 R2 R5 oHnNH) 200 water solution was removed using steam-cone temperature and reduced pressure leaving a semi-solid residue. The organic material was extracted with two -ml. portions of dry ether, and after decolorization using charcoal the ethereal extract was dried over anhydrous sodium sulfate and concentrated to a low-melting, yellow, solid residue. Partition chromatography (Celite; Methyl Cellosolve and n-heptane) afforded the desired 4-[(2-dimethylamino-Z-methyl)ethoxy] 4 nitrobiphenyl (melting point 62-64 C.) and 4-[(Z-dimethylamino-l-methyl) ethoxy]-4'-nitrobiphenyl in approximately equal amounts.

Example 4 Using the procedure outlined in Example 3, 10.2 g. of the potassium salt of 4-hydroxy-4-nitrobiphenyl, 5.4 g. of N,N-dimethyl-1,l-dimethyl-2-ehloroethylamine in 100 ml. of ethanol and 100 ml. of water was refluxed 15 hours. Using the same work-up as described previously an isomeric mixture consisting of 4-[(2-dimethylamino-2,2-dimethyl)ethoxy]-4-nitrobiphenyl and 4 [(2 dimethylamino-1,1-dirnethyl) ethoxy]-4-nitrobiphenyl (melting point 74-75 C.) was isolated.

Example 5 Using the method described in Example 1, 6.0 g. of 4-acetyl-4-hydroxybiphenyl, 1.2 g. of sodium hydride (54.7% active) and 3.8 g. of N,N-diethyl-2-chloroethylamine were refluxed in 60 ml. of toluene and 30 ml. of namyl alcohol for 16 hours. The crude product obtained in this manner was recrystallized from an ether-petroleum ether solution to give the desired 4-acetyla4-(2-diethylaminoethoxy)biphenyl (MP. 1l3-l14 C.)

Example 6 4-(2-diethylaminoethoxy)biphenyl magnesium bromide (prepared from 7.6 g. of 4.-bromo-4'-(Z-diethylaminoethoxy)-biphenyl and 0.5 g. of magnesium in 20 ml. of ether and 10 ml. of tetrahydrofuran) was poured on 200 g. of solid carbon dioxide. The semi-solid material obtained in this manner was hydrolyzed with cold, dilute hydrochloric acid. The aqueous layer was made basic, extracted with two 100 ml. portions of ether, decolorized using charcoal and then adjusted to a pH 67 by portionwise addition of dilute hydrochloric acid. On standing a crystalline substance deposited; this material was collected by filtration, dissolved in anhydrous methanol and acidified using anhydrous hydrogen chloride. The desired monohydrochloride of 4-carboxy-4'-(2-diethylaminoethoxy)biphenyl separated as colorless granules; M.P. 261-262" C.

Example 7 4-acetyl-4-(2-diethylaminoethoxy)biphenyl (4.9 g.) was added to a solution of lithium acetylide in liquid ammonia at 70 C. (the lithium acetylide was formed from 0.3 g. of lithium, 50 ml. of liquid ammonia and an excess of dry acetylene) and the suspension was shaken in a rocking-autoclave for 18 hours at room temperature. The crude reaction mixture was then removed from the autoclave and the excess ammonia evaporated-in a stream of dry nitrogen. Approximately 3.0 g. of ammonium chloride was added to the residue and the crude product was extracted using two 200-ml. portions of ether. The ethereal extracts were combined and washed with two 100-ml. portions of dilute sulfuric acid. The acidic washes were aminoethoxy)biphenyl, M.P. 116l18 C.

' Example 8 -Using the method and work-up desc-ribed in Example 1 18.97 g. of the potassio derivative of 4-hydroxy-4-nitrobiphenyl and 12.8 g. of N-(2-chloroethyl)pyrrolidine was refluxed in 200 ml. of toluene and 200 ml. of n-amylalcohol fQnapproximately 68 hours. The crude reaction mixture yielded the desired 4-nitro-4 (Z-pyrrolidinoethoxy)'biphenyl which was recrystallized twice from an ether-petroleum ether solution; M.P. 71-72 C.

Example 9 A mixture consisting of 89.9 g. of p-iodo'benzotrifluoride, 152.5 g. of. p-iodoanisole and 322.7 g. of copper powder was heated with stirring for approximately 5 days. After cooling, the solid reaction product was ground, placed in a Soxhlet extractor and extracted with 1.0 liter of n-hept'ane for 2 days. On cooling to room temperature 4,4'-dimethoxybiphenyl separated as a white, crystalline mass. The mother liquor was concentrated to yield the crude 4-methoxy-4'-trifluoromethylbiphenyl. After four recrystallizations from petroleum-ether (30-60 C.) the desired product was isolated in a pure state; 21.7 g. (26% yield) melting at 125-1 26 C.

Twenty-two grams of 4-methoxy-4'-trifluoromethylbiphenyl was dissolved in 850 ml. of glacial acetic acid and 175 ml. of 48% hydrobromic acid and refluxed under nitrogen for approximately 24 hours. The solution was then concentrated to a crude solid which was washed with water and then air-dried. The crude material was recrystallized from an ether-petroleum ether (3060 C.) solution to yield 11.8 g. of 4-hydroxy-4-trifluoromethylbiphenyl; M.P. 147148 C.

4-hydroxy-2'-trifluoromethylbiphenyl (14.5 g.) was dissolved in 100 ml. of dry dimethylformamide and treated with 2.7 g. of sodium hydride dispersed in mineral oil (54.7% active). N-(2-chloroethyl)pyrrolidine (8.0 g.) was added to the sodio derivative and the suspension was refluxed 18 hours. The suspension was then cooled, filtered and the clear, mother liquor concentrated to a brown, solid residue. The crude product was recrystallized from acetone and the first batch of material melting at 105- 110 C. was recrystallized from methanol-Water to afford 9.8 g. (49%) of the desired 4-(2-pyrrolidinoethoxy)-4'- trifluoromethylbiphenyl; M.P. 108-110 C.

Example 4-acetamido-4-chlorosulfonylbiphenyl (6.2 g.) was added to a solution of sodium sulfite (10.0 g.) in 200 ml. of water and stirred for 20 hours at room temperature; portions of 50% sodium hydroxide solution were added periodically to maintain a basic solution during the reduction. The aqueous suspension was diluted to 1.0 liter, filtered and acidified using concentrated sulfuric acid. A White solid precipitated and this material was collected by filtration and combined with a second crop obtained by concentrating the filtrate (5.5 g. total yield).

4-acetamido-4'-biphenylsulfinic acid (5.5 g.) was suspended in 100 ml. of water and potassium carbonate was added until a clear solution was obtained (pH 8-9). Methyl iodide (4.3 g.) in 300 ml. of ethanol was added and the reaction refluxed for 64 hours with stir-ring. After cooling the precipitate was collected by filtration and the mother liquor concentrated to yield a second crop of material; the combined, crude yields were triturated with two 100-ml. portions of water before recrystallization from methanol (3.1 g.). An analytically pure sample of 4- acetamido-4'-methylsulfonylbiphenyl was obtained from hot, glacial acetic acid; M.P. 267-268 C.

' A suspension consisting of 4-acetamido-4'-methylsulfonylbiphenyl (1.9 g.) in 100 ml. of 20% hydrochloric acid was refluxed 20 hours, filtered hot and then made strongly basic using sodium hydroxide pellets. The crude product isolated in this manner was recrystallized from hot methanol to yield 1.42 g. of the desired 4-amino-4'- methylsulfonylbiphenyl (M.P. 203-205 C.).

The diazotization of 4-amino-4-methylsulfonylbiphenyl was carried out by adding 2.3 g. of the amine to 14 ml. of glacial acetic acid and 14 ml. of 40% sulfuric acid. The suspension was cooled to 5 C. and treated with 1.6 g. of sodium nitrite dissolved in approximately 4.0 ml. of water over a period of 20 minutes. After addition was complete urea was added at 0 C. to decompose excess nitrous acid. The diazonium solution was added slowly to 5.3 ml. of refluxing 40% sulfuric acid; a gummy solid separated which solidified on cooling. The crude product was taken up in 1 N sodium hydroxide solution, filtered and acidified affording 1.7 g. of the desired 4-hydroxy-4'-methylsulfonylbiphenyl (M.P. l89190 C.).

4-hydroxy-4'-methylsulfonylbiphenyl (1.7 g.) was dissolved in approximately 90 ml. of dry dimethylformamide and treated with 0.2 g. of sodium hydride dispersed in mineral oil (54.7% active). After hydrogen evolution ceased the suspension was refluxed until the sodio derivative dissolved. Alkylation was carried out by adding 1.2 g. of N-(2-chloroethyl)py'rrolidine in 10 ml. of dry toluene to the cooled suspension and then reheating the reaction mixture for an additional 68 hours. After cooling,

the dark-brown solution was decolorized using charcoal, filtered and the clear filtrate concentrated to a solid residue. The residual material was taken up in approximately 300 ml. of benzene, dried over anhydrous sodium car- 'bonate, filtered and the clear filtrate was treated with an excess of hydrogen chloride. The gummy, yellow hydrochloride salt was dissolved in water ml.) and made strongly basic with sodium hydroxide; the basic solution was extracted with two 75 ml. portions of benzene and the combined extracts were dried and concentrated to afiord 1.0 g. of the desired 4-(2-pyrrolidinoethoxy)-4'- methylsulfonyl'biphenyl; M.P. 153154 C.

Example 1] 4 hydroxy-4'-sulfonamidobiphenyl (8.0 g.) dissolved in 200 ml. of toluene and ml. of n-amyl alcohol was treated with 0.8 g. of sodium hydride dispersed in mineral oil (54.7% active). The sodio derivative thus obtained was refluxed for approximately 70 hours with 4.0 g. of N-(2-chloroethyl)pyrrolidine. On cooling the reaction mixture was filtered and concentrated to a semi-solid residue. The crude reaction product was dissolved in benzene, decolorized with charcoal and dried over anhydrous sodium carbonate. Dry hydrogen chloride was passed through the clear benzene solution and the insoluble material was collected and dissolved in 100 ml. of water. The acidic solution was treated with an excess of sodium hydroxide to yield the desired 4-(2-pyrrolidinoethoxy)-4-sulfonamidobiphenyl.

Example 12 Following the procedure outlined in Example 1, 9.2 g. of 2-piperidin0ethyl chloride monohydrdchloride was neutralized, extracted into 50 ml. of toluene and added to a suspension consisting of 12.6 g. of the potassium salt of 4-hydroxy-4'-nitrophenyl in 100 ml. of toluene and 100 ml. of n-amyl alcohol. After a 30 hour reflux period the suspension was filtered hot and the clear filtrate was worked up as previously described. The crude, basic material was taken up in ether, decolorized with charcoal, dried over anhydrous sodium sulfate, filtered and saturated with dry hydrogen chloride. The monohydrochloride of 4-(2-piperidinoethoxy)-4'-nitrobiphenyl obtained in this manner melted at 227-230" C.

7 What is claimed is: 1. A member of the class consisting of compounds of the formula:

R1 R3 R5 Q Q Z OO -N 1 33 I i; Ru' wherein Z is selected from the group consisting of nitro, lower alkanoyl, carboxy, lower carboalkoxy, trifluoromethyl, sulfonamido, methylsulfonyl and l-hydroxy-lmethyI-Z-propynyl; R R R and R are each selected from the group consisting of hydrogen, methyl and ethyl with the proviso that the sum of the carbon atoms of R +R +R +R is less than 5; R is lower alkyl; R is lower alkyl; and R and R taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and 4-(lower alkyl)-1-piperazino; and the non-toxic acid-addition and quaternary ammonium salts thereof.

2.. A compound according to claim 1 wherein Z is nitro; R R R and R are each hydrogen; and R and R are each ethyl.

'3. A compound according to claim 1 wherein Z is nitro; R is methyl; R R and R are each hydrogen; and R and R are each methyl.

4. A compound according to claim 1 wherein Z is nitro; R and R are each hydrogen; R and R are each methyl; and R and R are each methyl.

5. A compound according to claim 1 wherein Z is nitro; R and R are each methyl; R and R are each hydrogen; and R and R are each methyl.

6. A compound according to claim 1 wherein Z is acetyl; R R R and R are each hydrogen; and R and R are each ethyl. 7. A compound" according to claim 1 wherein Z is nitro; R R R3 and R are'each hydrogen; and R and R taken together with the N(it'rogen) is pyrrolidino.

81A compound according to claim '1 wherein Z is trifiuorome'thyl; R R R and R are eachhydrogen; and R and R taken together with the N(itrogen) is pyrrolidino.

9. A. compound according to claim 1 wherein Z is methylsulfonyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is pyrrolidino.

10. A compound according to claim 1 wherein Z is nitro; R R R ar1d R are each hydrogen; and R and R taken together with the N(itr'ogen) is piperidino.

References Cited UNITED STATES PATENTS 2,495,772 1/1950 Rieveschl et a1. 260570.7 2,748,116 5/1956v Cusic et al 260326.5 2,935,439 5/1960 Wright et a1. 260294.7 2,966,518 12/1960 Johnson 260-294.7 3,135,745 6/1964 Palopoli' et al. 260294.7 3,196,159 7/1965 Bencze 260294.7 3,077,472 2/1965 Burckhalter 260-2947 JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

A. D. SPEVACK, Assistant Examiner.