US3330832A - N-pyridyl-4-aminoalkoxy anilines - Google Patents

N-pyridyl-4-aminoalkoxy anilines Download PDF

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US3330832A
US3330832A US597516A US59751666A US3330832A US 3330832 A US3330832 A US 3330832A US 597516 A US597516 A US 597516A US 59751666 A US59751666 A US 59751666A US 3330832 A US3330832 A US 3330832A
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pyridyl
aniline
nitro
hydrogen
methyl
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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 DE19641445452 priority patent/DE1445452A1/en
Priority to FR987663A priority patent/FR1436566A/en
Priority to SE10910/64A priority patent/SE320086B/xx
Priority to CH1199764A priority patent/CH467751A/en
Priority to NL6410914A priority patent/NL6410914A/xx
Priority to BE653274D priority patent/BE653274A/xx
Priority to DK461364AA priority patent/DK117354B/en
Priority to FR997935A priority patent/FR4860M/fr
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Priority to US597516A priority patent/US3330832A/en
Priority to US597523A priority patent/US3330831A/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
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    • 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 disubstitutedamino-ethoxyphenyl amines 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 alkyl-1- piperazino;
  • R is 4-pyridyl, 3-nitro-2-pyridyl or S-nitro- 2-pyridyl.
  • 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 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 intima of large and medium sized arteries.
  • Arteriosclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined.
  • hypercholesteremia and the incidence of cardiovascular disease.
  • Our invention is based upon the discovery that our novel disubstituted-aminoethoxyphenyl amines 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 ice 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 with a 4-halopyridine, a 2-halo-3- nitropyridine or a 2-halo-5-nitropyridine as set forth in the following reaction scheme:
  • 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 C. over a period of time ranging from about 1 hour to 15 hours or more.
  • a solvent such as a lower alkanol, dioxane, tetrahydrofuran, and the like
  • 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, hydrochlon'c, 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 rela tively insoluble in nonpolar organic solvents such as ether, benzene, toluene and the like.
  • Example 1.N-(4-pyridyl)-p-(Z-diethylaminoethoxy) aniline A solution of 9.6 g. of 4-bromopyridine hydrobromide and an excess of p-(Z-diethylaminoethoxy)aniline in 100 ml. of ethanol was warmed for a short time and then concentrated to a semi-solid residue. This crude material was triturated with two 100-ml. portions of water, dissolved in ether and precipitated by the addition of petroleum ether. There was thus obtained the N-(4-pyridyl)-p-(2- diethylaminoethoxy)aniline as grey-green platelets, M.P. -127 C.
  • Example 2.N-(3-m'tro-2-pyridyl) -p-(2-diethylamin0- eth0xy)aniline An ethanolic solution of 6.3 g. of 2-chloro-3-nitropyridine and 8.3 g. of p-(2-diethylaminoethoxy)aniline was heated on a steam bath for one hour. After removing the solvent and treating the semi-solid residue with an excess of aqueous sodium hydroxide, recrystallization from etherpetroleum ether gave N-(3-nitro-2-pyridyl)-p-(2-diethylaminoethoxy)aniline, M.P. 47-48 C.
  • Example 3 -N-(5-rzitr0-2-pyridyl -p-(2-diethylamin0- ethxy)aniline 2-chloro-5-nitropyridine (7.9 g.) is added to 10.4 g. of p-(Z-diethylaminoethoxy)aniline in 75 ml. of ethanol to form a deep-red solution. After standing 3 hours the ethanol is removed and the semi-solid red residue is treated with an excess of dilute ammonium hydroxide.
  • the yellow granular precipitate is recrystallized from benzenepetroleum ether (30-60 C.) to yield the desired N-(S- nitro-2-pyridyl)-p-(2 diethylaminoethoxy)aniline; M.P. 143-145 C. (sintering at 136 C.).
  • Sodium hydride (7.2 g.) is added to 131 g. of l-diethylamino-Z-propanol cooled to 0-10 C.
  • After hydrogen evolution ceases 72.3 g. of 1-fiuoro-4-nitrobenzene is added portionwise with stirring.
  • the cold reaction mixture is then allowed to warm to room temperature with stirring, filtered and concentrated to a heavy, brown oil.
  • the organic material is taken up in ether, treated with anhydrous hydrogen chloride gas and the granular monohydrochloride collected on a sintered glass filter.
  • the hydrochloride is then dissolved in a minimum amount of water (approximately 100 ml.), decolorized with charcoal and neutralized with dilute sodium hydroxide solution.
  • the basic, organic material is extracted with ether and the ether extract subjected to a fractional distillation.
  • p-[(2- diethylamino-l-methyl)ethoxy]nitrobenzene is obtained as a yellow oil boiling at 130-135" C. (0.3-0.4 mm.).
  • the product obtained in this manner is used in the next step without further purification.
  • 2-chloro-5-nitropyridine (3.8 g.) is added to 5.6 g. of p-[(Z-diethylarnino-l-methyl)ethoxy]aniline in 75 ml. of ethanol and the clear red solution is warmed at 70 C. for two hours; cooled to room temperature and allowed to stand 48 hours. Removal of the volatile materials leaves a red-brown oil which is dissolved in benzene (25 ml.) and placed on a 2.5-cm. x 50-cm. column packed with Florasil. After eluting the column with five 100-ml.
  • R is selected from the group consisting of 4- pyridyl, 3-nitro-2-pyridyl and 5-nitro-2-pyridyl;
  • 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;
  • R and R taken together with the N(itrogen) is selected from the group consisting of pyrrolidino, piperidino and 4-lower alkyl-lpiperazino; and the non-toxic acid-addition and quaternary ammonium salts thereof.
  • R is 4- pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
  • R is 3- nitro-Z-pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
  • R is 5- nitro-2-pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
  • R is 5- nitro-2-pyridyl; R is methyl; R R and R are each hydrogen; and R and R are each ethyl.
  • R is 4- pyridyl; R and R are each hydrogen; and R R R and R are each methyl.
  • R is 4- pyridyl; R is methyl; R R and R are each hydrogen; and R and R are each ethyl.
  • R is 3- nitro-Z-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is pyrrolidino.
  • R is 3- nitro-2-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is piperidino.
  • R is 5-nitro-2-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is 4-methyl-1-piperazino.

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Description

United States Patent 3,330,832 N-PYRIDYL- l-AMINOALKOXY ANILINES Jackson Pollard English, Princeton, and Frederick Louis Bach, .l'r., 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. 597,516
10 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 disubstitutedamino-ethoxyphenyl amines 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 alkyl-1- piperazino; and R is 4-pyridyl, 3-nitro-2-pyridyl or S-nitro- 2-pyridyl. 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 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 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 correlaton between hypercholesteremia and the incidence of cardiovascular disease. For some time it has been considered desirableto 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 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 ice 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 with a 4-halopyridine, a 2-halo-3- nitropyridine or a 2-halo-5-nitropyridine as set forth in the following reaction scheme:
wherein R, R R R R R and R are as previously defined and X is halogen. 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 C. over a period of time ranging from about 1 hour to 15 hours or more.
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, hydrochlon'c, 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 rela tively insoluble in nonpolar 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.N-(4-pyridyl)-p-(Z-diethylaminoethoxy) aniline A solution of 9.6 g. of 4-bromopyridine hydrobromide and an excess of p-(Z-diethylaminoethoxy)aniline in 100 ml. of ethanol was warmed for a short time and then concentrated to a semi-solid residue. This crude material Was triturated with two 100-ml. portions of water, dissolved in ether and precipitated by the addition of petroleum ether. There was thus obtained the N-(4-pyridyl)-p-(2- diethylaminoethoxy)aniline as grey-green platelets, M.P. -127 C.
Example 2.N-(3-m'tro-2-pyridyl) -p-(2-diethylamin0- eth0xy)aniline An ethanolic solution of 6.3 g. of 2-chloro-3-nitropyridine and 8.3 g. of p-(2-diethylaminoethoxy)aniline was heated on a steam bath for one hour. After removing the solvent and treating the semi-solid residue with an excess of aqueous sodium hydroxide, recrystallization from etherpetroleum ether gave N-(3-nitro-2-pyridyl)-p-(2-diethylaminoethoxy)aniline, M.P. 47-48 C.
Example 3 .-N-(5-rzitr0-2-pyridyl -p-(2-diethylamin0- ethxy)aniline 2-chloro-5-nitropyridine (7.9 g.) is added to 10.4 g. of p-(Z-diethylaminoethoxy)aniline in 75 ml. of ethanol to form a deep-red solution. After standing 3 hours the ethanol is removed and the semi-solid red residue is treated with an excess of dilute ammonium hydroxide. The yellow granular precipitate is recrystallized from benzenepetroleum ether (30-60 C.) to yield the desired N-(S- nitro-2-pyridyl)-p-(2 diethylaminoethoxy)aniline; M.P. 143-145 C. (sintering at 136 C.).
Example 4.N- (S-nitro-Z-pyridyl) -p- (Z-diethylamino- 1-methyl)eth0xy]zmiline Sodium hydride (7.2 g.) is added to 131 g. of l-diethylamino-Z-propanol cooled to 0-10 C. After hydrogen evolution ceases 72.3 g. of 1-fiuoro-4-nitrobenzene is added portionwise with stirring. The cold reaction mixture is then allowed to warm to room temperature with stirring, filtered and concentrated to a heavy, brown oil. The organic material is taken up in ether, treated with anhydrous hydrogen chloride gas and the granular monohydrochloride collected on a sintered glass filter. The hydrochloride is then dissolved in a minimum amount of water (approximately 100 ml.), decolorized with charcoal and neutralized with dilute sodium hydroxide solution. The basic, organic material is extracted with ether and the ether extract subjected to a fractional distillation. p-[(2- diethylamino-l-methyl)ethoxy]nitrobenzene is obtained as a yellow oil boiling at 130-135" C. (0.3-0.4 mm.). The product obtained in this manner is used in the next step without further purification.
Twelve grams of p-[ (Z-diethylamino-l-methyl)ethoxy]- nitrobenzene is dissolved in ethanol and reduced at room temperature and 35 p.s.i. of hydrogen using 5% palladiumon-charcoal catalyst. The desired p-[(2-diethylamino-1- methyl)-ethoxy]aniline is obtained as a yellowish oil boiling at approximately 147-149 C. (1.0 mm.). The aniline derivative obtained in this manner is used in the next step without further purification.
2-chloro-5-nitropyridine (3.8 g.) is added to 5.6 g. of p-[(Z-diethylarnino-l-methyl)ethoxy]aniline in 75 ml. of ethanol and the clear red solution is warmed at 70 C. for two hours; cooled to room temperature and allowed to stand 48 hours. Removal of the volatile materials leaves a red-brown oil which is dissolved in benzene (25 ml.) and placed on a 2.5-cm. x 50-cm. column packed with Florasil. After eluting the column with five 100-ml. portions of benzene-petroleum ether (30-60 C.) 40:60 the desired 5 N-(5-nitro-2-pyridyl)-p-[(Z-diethylamino 1 methyl) ethoxy] aniline is eluted from the column with ethyl ace- 4 tate, and recrystallized from ether-petroleum ether (30- C.); M.P. 59-61 C.
What is claimed is: 1. A member of the class consisting of compounds of the formula:
wherein R is selected from the group consisting of 4- pyridyl, 3-nitro-2-pyridyl and 5-nitro-2-pyridyl; 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-lpiperazino; and the non-toxic acid-addition and quaternary ammonium salts thereof.
2. A compound according to claim 1 wherein R is 4- pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
3. A compound according to claim 1 wherein R is 3- nitro-Z-pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
4. A compound according to claim 1 wherein R is 5- nitro-2-pyridyl; R R R and R are each hydrogen; and R and R are each ethyl.
5. A compound according to claim 1 wherein R is 5- nitro-2-pyridyl; R is methyl; R R and R are each hydrogen; and R and R are each ethyl.
6. A compound according to claim 1 wherein R is 4- pyridyl; R and R are each hydrogen; and R R R and R are each methyl.
7. A compound according to claim 1 wherein R is 4- pyridyl; R is methyl; R R and R are each hydrogen; and R and R are each ethyl.
8. A compound according to claim 1 wherein R is 3- nitro-Z-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is pyrrolidino.
9. A compound according to claim 1 wherein R is 3- nitro-2-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is piperidino.
10. A compound according to claim 1 wherein R is 5-nitro-2-pyridyl; R R R and R are each hydrogen; and R and R taken together with the N(itrogen) is 4-methyl-1-piperazino.
References Cited UNITED STATES PATENTS 3,149,115 9/1964 Brabender et a1. 260268 ALEX MAZEL, Primary Examiner.
H. JILES, Assistant Examiner.

Claims (1)

1. A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS OF THE FORMULA
US597516A 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines Expired - Lifetime US3330832A (en)

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US382383A US3321478A (en) 1963-09-20 1964-07-13 Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine
DE19641445452 DE1445452A1 (en) 1963-09-20 1964-09-10 New Aminoaethoxyphenylamines and Processes for Their Preparation
FR987663A FR1436566A (en) 1963-09-20 1964-09-10 Process for the preparation of (nu-disubstituted amino) ethoxyphenyl-amines, -ethers and-thioethers
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
BE653274D BE653274A (en) 1963-09-20 1964-09-18
NL6410914A NL6410914A (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
US597516A US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines
US597523A US3330831A (en) 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers

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US597516A US3330832A (en) 1963-09-20 1966-11-29 N-pyridyl-4-aminoalkoxy anilines
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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
US4025514A (en) * 1973-09-20 1977-05-24 Delalande S.A. Arylamino pyrimidinic derivatives
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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.
IL87181A (en) * 1987-08-07 1993-08-18 Sanofi Sa Aminoalkoxyphenyl derivatives, their preparation and pharmaceutical and veterinary compositions containing them
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

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US3149115A (en) * 1962-11-02 1964-09-15 American Cyanamid Co Pyrazolinones and method of preparing the same

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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
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