US3330831A - Aminoalkoxy-diphenyl amines, ethers and thioethers - Google Patents

Aminoalkoxy-diphenyl amines, ethers and thioethers Download PDF

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US3330831A
US3330831A US597523A US59752366A US3330831A US 3330831 A US3330831 A US 3330831A US 597523 A US597523 A US 597523A US 59752366 A US59752366 A US 59752366A US 3330831 A US3330831 A US 3330831A
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hydrogen
ethers
diethylaminoethoxy
aminoalkoxy
thioethers
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English Jackson Pollard
Jr Frederick Louis Bach
Gordon Samuel
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority to US382383A priority Critical patent/US3321478A/en
Priority to FR987663A priority patent/FR1436566A/en
Priority to DE19641445452 priority patent/DE1445452A1/en
Priority to SE10910/64A priority patent/SE320086B/xx
Priority to CH1199764A priority patent/CH467751A/en
Priority to BE653274D priority patent/BE653274A/xx
Priority to NL6410914A priority patent/NL6410914A/xx
Priority to DK461364AA priority patent/DK117354B/en
Priority to FR997935A priority patent/FR4860M/fr
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US597523A priority patent/US3330831A/en
Priority to US597516A priority patent/US3330832A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention relates to certain novel disubstitutedaminoethoxyphenyl amines, ethers and sulfides and, more particularly, is concerned with novel compounds which may be represented by the following general formula:
  • 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;
  • R and R taken together with the N(itrogen) is pyrrolidino, piperidino or 4-lower alkyll-piperazino;
  • R is hydrogen, nitro or amino;
  • Z is imino, oxygen or sulfur.
  • Lower alkyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms.
  • the invention includes the novel disubstituted-aminoethoxyphenyl amines, ethers and sulfides and the method of lowering therewith the cholesterol level in blood serum.
  • Atherosclerosis is a form of arteriosclerosis where cholesterol and lipoid materials are deposited as plaques in the intirna of large and medium sized arteries.
  • Arteriosclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined.
  • hyperehloesteremia and incidence of cardiovascular disease.
  • Our invention is based upon the discovery that our novel disubstituted-aminoethoxyphenyl amines, ethers and sulfides 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 so operate is advanced. It is not intended that the present invention should be limited to any theory as to mechanism.
  • novel compounds of the present invention are limited to oral administration. 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 3 milligrams to 30 milligrams per kilogram of body weight per day. In terms of total weight, this is usually from about 0.2 gram to about 2.0 grams per daily dosage unit.
  • novel compounds of the present invention may be readily prepared by the interaction of a p-disubstitutedaminoethoxy aniline, phenol or mercaptobenzene with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
  • R R R R R R R and Z are as previously defined; X is halogen and R is hydrogen or an activating group such as carboxy (CO H) or sulfoxy (SO H) which may later be removed.
  • the reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, and the like, at temperatures ranging from about 20 C. to about 100 C. over a period of time ranging from about 1 hour to 15 hours or more.
  • the removal of the activating carboxy and sulfoxy groups may later be accomplished by procedures well known in the art.
  • ammonium polysulfide examples include ammonium polysulfide.
  • novel disubstituted-aminoethoxyphenyl ethers of the present invention may also be readily prepared by the interaction of p-hydroquinone with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
  • R and X are as previously defined.
  • the intermediate p-hydroxy-nitrodiphenyl ether so obtained is then treated with an appropriate disubstituted-aminoethyl halide whereupon the desired disubstituted-arninoethoxyphenyl ether is obtained.
  • the intermediate p-hydroxy-nitrodiphenyl ether is first converted to its alkali metal alkoxide in an inert solvent such as toluene before treatment with the disubstituted-aminoethyl halide.
  • novel disubstituted-aminoethoxyphenyl sulfides of i the present invention may also be readily prepared by the interaction of phenol with an appropriate substituted pnitrosulphenyl halide as set forth in the following reaction scheme:
  • the organic bases of this invention form non-toxic, acid-addition and quaternary ammonium salts with a variety of organic and inorganic salt-forming reagents.
  • acid-addition salts formed by admixture of the organic free base with an acid, suitably 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.
  • other organic reagents are suitable for 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.
  • the free bases are equivalent to their nontoxic acid-addition and quaternary ammonium salts.
  • novel compounds of the present invention are, in general, colored materials which may be purified by distillation under reduced pressure. 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.
  • 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.
  • EXAMPLE 3 4'-(Z-diethylaminoethoxy)2-amiiz0-4-nitrodiphenylamine
  • Alcoholic ammonium sulfide was added to a refluxing ethanolic solution of 4-(Z-diethylaminoethoxy)-2,4-dinitrodiphenylamine.
  • the cooled reaction mixture was treated with charcoal and filtered, and the filtrate was dried over anhydrous sodium carbonate. Passing dry hydrogen chloride gas through the dried filtrate precipitated the desired 4'-(2-diethylaminoethoxy)2-amino-4-nitrodiphenylamine dihydrochloride, M.P. l79-181 C.
  • EXAMPLE 4 4 -(2-dieth ylaminoethoxy 4-nilr0diphenyl ether A mixture of 3.3 g. of p-hydroquinone, 1.2 g. of sodium hydroxide and 4.2 g. of 4-nitrofluorobenzene was refluxed for 15 hours and then cooled to room tempera ture. On standing, the desired intermediate, 4-hydroxy-4- nitrodiphenyl ether, precipitated as a yellow granular solid. This intermediate was treated with 0.7 g. of sodium hydride in toluene followed by 4.1 g. of diethylaminoethyl chloride in toluene. Concentration of the reaction mixture gave a yellow oil which was purified by vacuum distillation. There was thus obtained the 4'-(2-diethylaminoethoxy)-4nitrodiphenyl ether, B.P. 170-175" C./ 0.2 mm.
  • EXAMPLE 5 4 (2-diethylaminoethoxy 4-nitr0diphenyl sulfide A solution of 11.2 g. of 4-nitrophenylsulphenyl chloride and 5.6 g. of phenol in 100 m1. of dry ether was allowed to stand overnight at room temperature. Concentration of the solution gave the desired intermediate, 4'hydroxy-4-nitrodiphenyl sulfide, as a yellow solid. A toluene solution of this intermediate was treated with sodium hydride and then refluxed for 3 hours.
  • R is lower alkyl;
  • R, is lower alkyl;
  • R and R taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and 4-lower alkyl-l-piperazino;
  • R is selected from the group consisting of hydrogen, nitro and amino;
  • Z is selected from the group consisting of NH, oxygen and sulfur; and the non-toxic acid-addition and quaternary ammonium salts thereof.
  • R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is NH.
  • R R R and R are each hydrogen; R and R are each ethyl;
  • v R is nitro; and Z is NH.
  • R R R and R are each hydrogen; R and R taken together with the N(itrogen) is 4-methyl-1-piperazino; R is nitro; and Z is NH.
  • R R R and R are each hydrogen; R and R are each ethyl; R is amino; and Z is NH.
  • R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is oxygen.
  • R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is sulfur.
  • R and R are each hydrogen; R R R and R are each methyl; R is hydrogen; and Z is NH.
  • R R R and R are each hydrogen; R and R taken together 5 methyl; R R and R are each hydrogen; R and R taken together With the N(itrogen) is piperidino; R is amino; and Z is sulfur.

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Description

tates tent 3,330,831 AMINOALKOXY-DIPHENYL AMINES, ETHERS AND THIOETHERS Jackson Pollard English, Princeton, and Frederick Louis Bach, Jr., Montvale, N.J., and Samuel Gordon, Pearl River, N.Y., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Original application July 13, 1964, Ser. No. 382,383. Divided and this application Nov. 29, 1966, Ser. No. 597,523
Claims. (Cl. 260-268) This application is a division of our copending application Ser. No. 382,383, filed July 13, 1964, which in turn is a continuation-in-part of our application Ser. No. 310,466, filed Sept. 20, 1963, now abandoned, which in turn is a continuation-in-part of our application Ser. No. 218,135, filed Aug. 20, 1962, now abandoned.
This invention relates to certain novel disubstitutedaminoethoxyphenyl amines, ethers and sulfides and, more particularly, is concerned with novel compounds which may be represented by the following general formula:
wherein 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; R and R taken together with the N(itrogen) is pyrrolidino, piperidino or 4-lower alkyll-piperazino; R is hydrogen, nitro or amino; and Z is imino, oxygen or sulfur. Lower alkyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms. The invention includes the novel disubstituted-aminoethoxyphenyl amines, ethers and sulfides and the method of lowering therewith the cholesterol level in blood serum.
Atherosclerosis is a form of arteriosclerosis where cholesterol and lipoid materials are deposited as plaques in the intirna 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 hyperehloesteremia and 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 made to 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, cottonseed oil and corn oil.
Our invention is based upon the discovery that our novel disubstituted-aminoethoxyphenyl amines, ethers and sulfides 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 so operate is advanced. It is not intended that the present invention should be limited to any theory as to mechanism.
The method of administering the novel compounds of the present invention is limited to oral administration. 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 3 milligrams to 30 milligrams per kilogram of body weight per day. In terms of total weight, this is usually from about 0.2 gram to about 2.0 grams per daily dosage unit.
- The novel compounds of the present invention may be readily prepared by the interaction of a p-disubstitutedaminoethoxy aniline, phenol or mercaptobenzene with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
wherein R R R R R R R and Z are as previously defined; X is halogen and R is hydrogen or an activating group such as carboxy (CO H) or sulfoxy (SO H) which may later be removed. The reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, and the like, at temperatures ranging from about 20 C. to about 100 C. over a period of time ranging from about 1 hour to 15 hours or more. The removal of the activating carboxy and sulfoxy groups may later be accomplished by procedures well known in the art. When R is nitro,
this may later be reduced to an amino group with, for
example, ammonium polysulfide.
The novel disubstituted-aminoethoxyphenyl ethers of the present invention may also be readily prepared by the interaction of p-hydroquinone with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
wherein R and X are as previously defined. The intermediate p-hydroxy-nitrodiphenyl ether so obtained is then treated with an appropriate disubstituted-aminoethyl halide whereupon the desired disubstituted-arninoethoxyphenyl ether is obtained. Advantageously, the intermediate p-hydroxy-nitrodiphenyl ether is first converted to its alkali metal alkoxide in an inert solvent such as toluene before treatment with the disubstituted-aminoethyl halide.
The novel disubstituted-aminoethoxyphenyl sulfides of i the present invention may also be readily prepared by the interaction of phenol with an appropriate substituted pnitrosulphenyl halide as set forth in the following reaction scheme:
wherein R and X are as previously defined. The intermediate 4-hydroxy-4-nitrodiphenyl sulfide so obtained is Q then treated with an appropriate disubstituted-aminoethyl halide whereby the desired disubstituted-aminoethoxyphenyl sulfide is obtained. Again, it is preferred to convert the intermediate 4-hydroxy-4'-nitrodiphenyl sulfide to its alkali metal alkoxide in an inert solvent such as toluene prior to reaction with the disubstituted-aminoethyl halide.
The organic bases of this invention form non-toxic, acid-addition and quaternary ammonium salts with a variety of organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an acid, suitably 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 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 nontoxic acid-addition and quaternary ammonium salts.
The novel compounds of the present invention are, in general, colored materials which may be purified by distillation under reduced pressure. 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.
The invention will be described in greater detail in conjunction with the following specific examples.
EXAMPLE 1 4'-(Z-diethylaminoethoxy)4-nit1'0diphenylamine A solution of 4.2 g. of p-(Z-diethylaminoethoxy)aniline and 3.6 g. of potassium 2chloro-5-nitrobenzoate in 50 ml. of water and 50 ml. of ethanol was refluxed for hours and then extracted with two 100-ml. portions of chloroform. The aqueous raflinate was acidified with dilute hydrochloric acid whereupon a precipitate formed which was removed by filtration and dried. There was thus obtained 2.1 g. of crude 4-(2-diethylaminoethoxy)- 2-carboxy-4-nitrodiphenylamine which was placed in a distillation flask packed with glass beads and heated under reduced pressure. The solid mass melted and began effervescing at 180 C. (0.1 mm.). When decarboxylation was complete, the reaction mixture was cooled and triturated with sodium hydroxide solution. This crude solid was recrystallized from ethanol whereby there was obtained 4-(Z-diethylaminoethoxy)4 nitrodiphenylamine, M.P. 8688 C.
EXAMPLE 2 4'-(Z-diethylaminoethoxy )-2,4-a'initr0diphenylamine A solution of 4.2 g. of p-(2-diethylaminoethoxy)-aniline and 2.8 g. of 2,4-dinitrofiuorobenzene in 100 ml. of ethanol was refluxed for 3 hours. The reaction mixture was then poured onto crushed ice, the insoluble red solid which separated was collected by filtration, and this crude material was recrystallized from ethanol whereby there was obtained 4'-(Z-diethylaminoethoxy)-2,4-dinitrodiphenylamine, M.P. 7071 C.
EXAMPLE 3 4'-(Z-diethylaminoethoxy)2-amiiz0-4-nitrodiphenylamine Alcoholic ammonium sulfide was added to a refluxing ethanolic solution of 4-(Z-diethylaminoethoxy)-2,4-dinitrodiphenylamine. The cooled reaction mixture was treated with charcoal and filtered, and the filtrate was dried over anhydrous sodium carbonate. Passing dry hydrogen chloride gas through the dried filtrate precipitated the desired 4'-(2-diethylaminoethoxy)2-amino-4-nitrodiphenylamine dihydrochloride, M.P. l79-181 C.
EXAMPLE 4 4 -(2-dieth ylaminoethoxy 4-nilr0diphenyl ether A mixture of 3.3 g. of p-hydroquinone, 1.2 g. of sodium hydroxide and 4.2 g. of 4-nitrofluorobenzene was refluxed for 15 hours and then cooled to room tempera ture. On standing, the desired intermediate, 4-hydroxy-4- nitrodiphenyl ether, precipitated as a yellow granular solid. This intermediate was treated with 0.7 g. of sodium hydride in toluene followed by 4.1 g. of diethylaminoethyl chloride in toluene. Concentration of the reaction mixture gave a yellow oil which was purified by vacuum distillation. There was thus obtained the 4'-(2-diethylaminoethoxy)-4nitrodiphenyl ether, B.P. 170-175" C./ 0.2 mm.
EXAMPLE 5 4 (2-diethylaminoethoxy 4-nitr0diphenyl sulfide A solution of 11.2 g. of 4-nitrophenylsulphenyl chloride and 5.6 g. of phenol in 100 m1. of dry ether was allowed to stand overnight at room temperature. Concentration of the solution gave the desired intermediate, 4'hydroxy-4-nitrodiphenyl sulfide, as a yellow solid. A toluene solution of this intermediate was treated with sodium hydride and then refluxed for 3 hours. The red brown suspension thus obtained was refluxed an additional 3 hours with diethylaminoethyl chloride whereby the desired 4'-(Z-diethylaminoethoxy)-4-nitrodiphenyl sulfide was obtained as a yellow oil.
What is claimed is:
1. A member of the class consisting of compounds of the formula:
F group consisting of hydrogen, methyl and ethyl with the proviso that the sum of the carbon atoms of is less than 5; R is lower alkyl; R, is lower alkyl; R and R taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and 4-lower alkyl-l-piperazino; R is selected from the group consisting of hydrogen, nitro and amino; and Z is selected from the group consisting of NH, oxygen and sulfur; and the non-toxic acid-addition and quaternary ammonium salts thereof.
2. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is NH.
3. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R are each ethyl;
v R is nitro; and Z is NH.
4. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R taken together with the N(itrogen) is 4-methyl-1-piperazino; R is nitro; and Z is NH.
5. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R are each ethyl; R is amino; and Z is NH.
6. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is oxygen.
7. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R are each ethyl; R is hydrogen; and Z is sulfur.
5 8. A compound according to claim 1 wherein R and R are each hydrogen; R R R and R are each methyl; R is hydrogen; and Z is NH.
9. A compound according to claim 1 wherein R R R and R are each hydrogen; R and R taken together 5 methyl; R R and R are each hydrogen; R and R taken together With the N(itrogen) is piperidino; R is amino; and Z is sulfur.
No references cited.
ALEX MAZEL, Primary Examiner.
HENRY R. JILES, Examiner.

Claims (1)

1. A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS OF THE FORMULA
US597523A 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers Expired - Lifetime US3330831A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US382383A US3321478A (en) 1963-09-20 1964-07-13 Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine
FR987663A FR1436566A (en) 1963-09-20 1964-09-10 Process for the preparation of (nu-disubstituted amino) ethoxyphenyl-amines, -ethers and-thioethers
DE19641445452 DE1445452A1 (en) 1963-09-20 1964-09-10 New Aminoaethoxyphenylamines and Processes for Their Preparation
SE10910/64A SE320086B (en) 1963-09-20 1964-09-11
CH1199764A CH467751A (en) 1963-09-20 1964-09-15 Process for the preparation of new disubstituted aminoethoxyphenyl derivatives
NL6410914A NL6410914A (en) 1963-09-20 1964-09-18
BE653274D BE653274A (en) 1963-09-20 1964-09-18
DK461364AA DK117354B (en) 1963-09-20 1964-09-19 Process for the preparation of disubstituted aminoethoxyphenylamines or acid addition salts or quaternary ammonium salts thereof.
FR997935A FR4860M (en) 1963-09-20 1964-12-09
US597523A US3330831A (en) 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers
US597516A US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US31046663A 1963-09-20 1963-09-20
US382383A US3321478A (en) 1963-09-20 1964-07-13 Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine
US597523A US3330831A (en) 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers
US597516A US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines

Publications (1)

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US3330831A true US3330831A (en) 1967-07-11

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US382383A Expired - Lifetime US3321478A (en) 1963-09-20 1964-07-13 Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine
US597516A Expired - Lifetime US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines
US597523A Expired - Lifetime US3330831A (en) 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers

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US382383A Expired - Lifetime US3321478A (en) 1963-09-20 1964-07-13 Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine
US597516A Expired - Lifetime US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines

Country Status (8)

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US (3) US3321478A (en)
BE (1) BE653274A (en)
CH (1) CH467751A (en)
DE (1) DE1445452A1 (en)
DK (1) DK117354B (en)
FR (2) FR1436566A (en)
NL (1) NL6410914A (en)
SE (1) SE320086B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3471504A (en) * 1964-12-23 1969-10-07 Warner Lambert Pharmaceutical Benzyl-(ortho tertiary amino alkoxy)-benzyl ethers
US3904628A (en) * 1971-03-05 1975-09-09 Egyt Gyogyszervegyeszeti Gyar Novel cycloalkanol fumarate ethers and a process for the preparation thereof
US3960886A (en) * 1968-07-03 1976-06-01 Sterling Drug Inc. Substituted N-arylanilines
EP0302792A2 (en) * 1987-08-07 1989-02-08 Sanofi Alkylaminoalkoxyphenyl derivatives, process of preparation and compositions containing the same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4025514A (en) * 1973-09-20 1977-05-24 Delalande S.A. Arylamino pyrimidinic derivatives
CH593266A5 (en) * 1973-09-20 1977-11-30 Delalande Sa
JPS57203072A (en) * 1981-06-05 1982-12-13 Sankyo Co Ltd 4-anilinopyrimidine derivative, its preparation, antidepressant comprising it as active ingredient
IT1211096B (en) * 1981-08-20 1989-09-29 Lpb Ist Farm PYRIMIDINES AND S.TRIAZINICS HYPOLIPIDEMIZING ADAPTITY.
FR2830862A1 (en) * 2001-10-16 2003-04-18 Lipha New nitroso diphenylamine derivatives are nitrogen monoxide generating agents, useful for treating pathologies characterized by an oxidative stress condition

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2899434A (en) * 1959-08-11 Z-phenylamino-l
US2087131A (en) * 1933-03-03 1937-07-13 Alba Pharmaceutical Company In Quaternary ammonium compounds
US2657206A (en) * 1951-07-30 1953-10-27 Burroughs Wellcome Co 2, 4-diamino-5-aryloxy-pyrimidines
US2937117A (en) * 1953-06-19 1960-05-17 Chimie Atomistique Process for lowering high blood cholesterol levels
US3033870A (en) * 1958-03-24 1962-05-08 Ciba Pharm Prod Inc Certain derivatives of 4-(aminophenylmercapto)-pyridine
US2978381A (en) * 1958-06-20 1961-04-04 Freedman Louis Process and composition for lowering blood serum cholesterol and chylomicron levels
NL270720A (en) * 1960-10-28
US3149115A (en) * 1962-11-02 1964-09-15 American Cyanamid Co Pyrazolinones and method of preparing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3471504A (en) * 1964-12-23 1969-10-07 Warner Lambert Pharmaceutical Benzyl-(ortho tertiary amino alkoxy)-benzyl ethers
US3960886A (en) * 1968-07-03 1976-06-01 Sterling Drug Inc. Substituted N-arylanilines
US3904628A (en) * 1971-03-05 1975-09-09 Egyt Gyogyszervegyeszeti Gyar Novel cycloalkanol fumarate ethers and a process for the preparation thereof
EP0302792A2 (en) * 1987-08-07 1989-02-08 Sanofi Alkylaminoalkoxyphenyl derivatives, process of preparation and compositions containing the same
EP0302792A3 (en) * 1987-08-07 1990-11-28 Sanofi Alkylaminoalkoxyphenyl derivatives, process of preparation and compositions containing the same

Also Published As

Publication number Publication date
SE320086B (en) 1970-02-02
US3330832A (en) 1967-07-11
DK117354B (en) 1970-04-20
FR4860M (en) 1967-02-27
DE1445452A1 (en) 1968-12-19
CH467751A (en) 1969-01-31
FR1436566A (en) 1966-04-29
NL6410914A (en) 1964-11-25
US3321478A (en) 1967-05-23
BE653274A (en) 1965-03-18

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