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US3321478A - Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine - Google Patents

Aminoethoxyphenyl amine, ether, and sulfide derivatives of pyrimidine Download PDF

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US3321478A
US3321478A US382383A US38238364A US3321478A US 3321478 A US3321478 A US 3321478A US 382383 A US382383 A US 382383A US 38238364 A US38238364 A US 38238364A US 3321478 A US3321478 A US 3321478A
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Prior art keywords
aniline
diethylaminoethoxy
ether
pyrimidyl
aminoethoxyphenyl
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US382383A
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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
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; and
  • R and R taken together with the N(itrogen) is pyrrolidino, piperidino, morpholino, thiomorpholino or 4-lower alkyl-l-piperazino;
  • Z is imino, oxygen or sulphur; and
  • R is 4-pyridyl, 3-nitro-2-pyridyl, S-nitro-Z-pyridyl, 5-halo-2-pyrimidyl, 2 benzothiazolyl, 2-ha1o-4-pyrimidyl, 2,6-dibalo-4-pyrimidyl or a p-nitrophenyl group of the following general formula:
  • R7 wherein R is hydrogen, nitro or amino.
  • Lower alkyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms. Halogen is exemplified by chlorine and bromine.
  • 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 intima of large and medium sized arteries. Arteriesclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined. However, there is a statistical correlation between hypercholesteremia and the incidence of cardiovascular disease. For some time it has been considered desirable to lower high cholesterol and lipid levels in man as a possible preventive measure against atherosclerosis.
  • 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 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 may be readily prepared by the interaction of an 0-, m-, or p-disubstituted aminoethoxy aniline, phenol, or mercaptobenzene with a 2,5-dihalopyrimidine, a 2-halobenzothiazole, a 2,4-dihalo-pyrimidine or a 2,4,6-trihalopyrimidine.
  • the reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, or the like, at temperatures ranging from about 50 C. to about C. over a period of time ranging from about 1 to 15 hours or more.
  • novel compounds of the present invention may be readily prepared by the interaction of an o, m-, or p-disubstituted-aminoethoxy aniline, phenol, or mercaptobenzene with an appropriately substituted pnitrohalobenzene 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.
  • R is hydrogen or an activating group such as carboxy (CO H) or sulfoxy (SO H) which may later be removed.
  • carboxy CO H
  • SO H sulfoxy
  • a pyridyl derivative it is only necessary in the above reaction scheme to substitute a 4-halopyridine, a 2-halo- 3-nitropyridine or a 2-halo-5-nitropyridine for the pnitrohalobenzene.
  • 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.
  • novel disubstituted-aminoethoxyphenyl ethers of the present invention may be readily prepared by the interaction of an oor p-hydroquinone with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
  • R and X are as previously defined.
  • a pyridyl derivative is desired, then a 4-halopyridine, or a 3) 2-halo-3-nitropyridine, or a Z-halo-S-nitropyridine is substituted for the p-nitrohalobenzene.
  • the intermediate 0- or p-hydroxynitrodiphenyl ether is then treated with an appropriate disubstituted-aminoethyl halide whereupon the desired disubstituted-aminoethoxyphenyl ether is obtained.
  • the intermediate 0- or phydroxynitrodiphenyl ether is first converted to its alkali metal alkoxide in an inert solvent such as toluene before treatment with the disubstituted-aminoethyl halide.
  • novel disubs'tituted-aminoethoxyphenyl sulphides of the present invention may be readily prepared by the interaction of phenol with an appropriate substituted p-nitrosulphenyl 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, aoetic, 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 non-toxic 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 1 4'- (Z-diethylaminoethoxy -4-rzitr0diphenylamine
  • the aqueous raffinate was acidified with dilute hydrochloric acid whereupon a precipitate formed which was removed by filtration and dried. There was thus obtained 2.1 g.
  • EXAMPLE 2 4'- (Z-diethylaminoethoxy)-2,4-dinitr0diphenylamina
  • a solution of 4.2 g. of p-(2-diethylaminoethoxy)- aniline and 2.8 g. of 2,4-dinitrofluorobenzene 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-(2-diethylaminoethoxy)-2,4-dinitrodiphenylamine, M.P. 7071 C.
  • EXAMPLE 4 4-(Z-diethylaminoethoxy -2-amin0-4-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-(Z-diethylarninoeth-oxy)-2-amino-4- nitrodiphenylamine dihydrochloride, M.P. l79-181 C.
  • N-(4-pyl'idyl)-p-(Z-diethylaminoethoxy)aniline A solution of 9.6 g. of 4-bromopyridine hydrobromide and an excess of p-(Z-diethylaminoethoxy)aniline in 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-(Z-diethylaminoethoxy)aniline as grey-green platelets, M.P. 127 C.
  • EXAMPLE 7 4'- (Z-diethylaminoethoxy -4-nitr0aiphenyl 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 temperature. On standing, the desired intermediate, 4'-hydr-oxy-4-nitrodiphenyl ether, precipitated as a yellow granular solid. This intermediate was treated with 0.7 g. of sodium hy- A solution of 11.2 g. of 4-nitrophenylsulfenyl chloride and 5. 6 g. of phenol in 100 ml. of dry ether was allowed to stand overnight at room temperature.
  • N- (2-chloro-4-pyrimidyl) -p-(Z-dietlzylaminoethoxy) aniline A solution consisting of 6.2 g. of p-(Z-diethylaminoethoxy)aniline and 4.4 g. of 2,4-dichloropyrimidine in 75 ml. of ethanol is warmed to 70 C. and then allowed to stand overnight. After distilling off the volatile materials the remaining dark-brown oil is warmed with 250 ml. of Water and the aqueous layer is separated; extracted with two 50 ml. portions of ether, and then neutralized with dilute ammonium hydroxide. The desired N-(2- chloro 4-pyrimidyl) -p-(2-diethylaminoethoxy) aniline is obtained as a gray-white solid melting at 75-77 C.
  • N-(S-chloro-Z-pyrimidyl) -p- (2-dielhylamin0eth0xy) aniline A solution consisting of 3.7 g. of 2,5-dichloropyrimidine and 5.2 g. of p-(Z-diethylaminoethoxy) aniline in 25 ml. of ethanol is heated at 70 C. for three hours; cooled to room temperature and then worked up as described in Example 10.
  • the desired product, N-(-chloro-2- pyrimidyl)-p-(2-diethylaminoethoxy)aniline is recrystallized from ether-petroleum ether (3060 C.) M.P. 92-94" C.
  • EXAMPLE 13 2- p- (Z-diethylaminoethoxy) ani lino] benzothiazole
  • a solution consisting of 17.0 g. of 2-chlorobenzo- 6 thiazole and 20.8 g. of p-(2 diethylaminoethoxy)aniline in 200 ml. of ethanol is refluxed for 15 hours, and then concentrated to a semi-solid residue.
  • the residue is made basic with 10% potassium hydroxide solution, extracted with two ml. portions of ether, and the ethereal extracts are combined, decolorized with charcoal and dried over anhydrous sodium sulfate.
  • 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 (in vac.).
  • p-[(Z-diethyl-l-methyl)ethoxyJnitrobenzene 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-[(2-diethylamino-1-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 Florisil. After eluting the column with five 100-ml.
  • 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 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, morpholino, thiomorpholino and 4-lower alkyl-l-piperazino;
  • Z is selected from the group consisting of imino, oxygen and sulfur; and
  • R is selected from the group consisting of 5-halo-2-pyrimidyl, 2-halo-4-pyrirnidyl and 2,6-dihalo- 4-pyrimidyl; and the non-toxic acid-addition and quaternary ammonium salts thereof.

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Description

United States Patent 3,321,478 AMINOETHOXYPHENYL Am, ETHER, AND SULFIDE DERIVATIVES F PYRIMIDINE 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. Filed July 13, 1964, Ser. No. 382,383 7 Claims. (Cl. 260-256.4)
This application is a continuation-in-part of our copending application Ser. No. 310,466, filed Sept. 20, 1963, now abandoned, which in turn is a continuation-in-part of our copending 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; and R and R taken together with the N(itrogen) is pyrrolidino, piperidino, morpholino, thiomorpholino or 4-lower alkyl-l-piperazino; Z is imino, oxygen or sulphur; and R is 4-pyridyl, 3-nitro-2-pyridyl, S-nitro-Z-pyridyl, 5-halo-2-pyrimidyl, 2 benzothiazolyl, 2-ha1o-4-pyrimidyl, 2,6-dibalo-4-pyrimidyl or a p-nitrophenyl group of the following general formula:
R7 wherein R is hydrogen, nitro or amino. Lower alkyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms. Halogen is exemplified by chlorine and bromine. 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 intima of large and medium sized arteries. Arteriesclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined. However, there is a statistical correlation between hypercholesteremia and the incidence of cardiovascular disease. For some time it has been considered desirable to lower high cholesterol and lipid levels in man 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 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.
3,321,478 Patented May 23, 1967 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.
Certain of the novel compounds of the present invention may be readily prepared by the interaction of an 0-, m-, or p-disubstituted aminoethoxy aniline, phenol, or mercaptobenzene with a 2,5-dihalopyrimidine, a 2-halobenzothiazole, a 2,4-dihalo-pyrimidine or a 2,4,6-trihalopyrimidine. The reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, or the like, at temperatures ranging from about 50 C. to about C. over a period of time ranging from about 1 to 15 hours or more.
Certain of the novel compounds of the present invention may be readily prepared by the interaction of an o, m-, or p-disubstituted-aminoethoxy aniline, phenol, or mercaptobenzene with an appropriately substituted pnitrohalobenzene 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. Where a pyridyl derivative is desired, it is only necessary in the above reaction scheme to substitute a 4-halopyridine, a 2-halo- 3-nitropyridine or a 2-halo-5-nitropyridine for the pnitrohalobenzene. 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 polysulphide;
Certain of the novel disubstituted-aminoethoxyphenyl ethers of the present invention may be readily prepared by the interaction of an oor p-hydroquinone with an appropriately substituted p-nitrohalobenzene as set forth in the following reaction scheme:
wherein R and X are as previously defined. Where a pyridyl derivative is desired, then a 4-halopyridine, or a 3) 2-halo-3-nitropyridine, or a Z-halo-S-nitropyridine is substituted for the p-nitrohalobenzene. The intermediate 0- or p-hydroxynitrodiphenyl ether is then treated with an appropriate disubstituted-aminoethyl halide whereupon the desired disubstituted-aminoethoxyphenyl ether is obtained. Advantageously, the intermediate 0- or phydroxynitrodiphenyl ether is first converted to its alkali metal alkoxide in an inert solvent such as toluene before treatment with the disubstituted-aminoethyl halide.
Certain of the novel disubs'tituted-aminoethoxyphenyl sulphides of the present invention may be readily prepared by the interaction of phenol with an appropriate substituted p-nitrosulphenyl halide as set forth in the following reaction scheme:
wherein R and X are as previously defined. The intermediate 4-hydoxy-4'-nitrodiphenyl sulphide so obtained is then treated with an appropriate disubstituted-aminoethyl halide whereby the desired disubstituted-aminoethoxyphenyl sulphide is obtained. Again, it is preferred to convert the intermediate 4-hydroxy-4-nitrodiphenyl sulphide 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, aoetic, 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 non-toxic 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-rzitr0diphenylamine A solution of 4.2 g. of p-(2-diethylaminoethoxy)- aniline and 3.6 g. of potassium 2-ehloro-S-nitrobenzoate in 50 ml. of water and 50 ml. of ethanol was refluxed for 15 hours and then extracted with two 100-ml. portions of chloroform. The aqueous raffinate 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-(Z-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 etfervescing at 180 C. (0.1 mm.). When decar-boxylation 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' (2 diethylaminoethoxy) 4-nitrodiphenylamine, M.P. 8688 C.
EXAMPLE 2 4'- (Z-diethylaminoethoxy)-2,4-dinitr0diphenylamina A solution of 4.2 g. of p-(2-diethylaminoethoxy)- aniline and 2.8 g. of 2,4-dinitrofluorobenzene 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-(2-diethylaminoethoxy)-2,4-dinitrodiphenylamine, M.P. 7071 C.
EXAMPLE 3 2-(2 diethylaminoethoxy)-2,4-dirzitrodiphenylamine A solution of 4.2 g. of o-(2-diethylaminoethoxy) aniline and 2.8 g. of 2,4-dinitrofluorobenzene in 100 ml. of ethanol was refluxed for 4 hours. The reaction mixture was then worked up as described in Example 2 to yield 2' (2 diethylaminoethoxy) 2,4-dinitrodiphenylamine, M.P. 909l C.
EXAMPLE 4 4-(Z-diethylaminoethoxy -2-amin0-4-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-(Z-diethylarninoeth-oxy)-2-amino-4- nitrodiphenylamine dihydrochloride, M.P. l79-181 C.
EXAMPLE 5 N-(4-pyl'idyl)-p-(Z-diethylaminoethoxy)aniline A solution of 9.6 g. of 4-bromopyridine hydrobromide and an excess of p-(Z-diethylaminoethoxy)aniline in 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-(Z-diethylaminoethoxy)aniline as grey-green platelets, M.P. 127 C.
EXAMPLE 6 N- (3-nitr0-2-pyridyl) -p-(Z-diethylaminoethoxy 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 ether-petroleum ether gave N-(3-nitro-2-pyridyl)-p- (Z-diethylaminoethoxy)aniline, M.P. 47-48" C.
EXAMPLE 7 4'- (Z-diethylaminoethoxy -4-nitr0aiphenyl 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 temperature. On standing, the desired intermediate, 4'-hydr-oxy-4-nitrodiphenyl ether, precipitated as a yellow granular solid. This intermediate was treated with 0.7 g. of sodium hy- A solution of 11.2 g. of 4-nitrophenylsulfenyl chloride and 5. 6 g. of phenol in 100 ml. 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 yell-ow 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'-(2-diethylaminoethoxy) -4-nitrodiphenyl sulfide was obtained as a yellow oil.
EXAMPLE '9 N-(2,6-dichJr0-4-pyrimidyl) -p- (Z-diethylaminoethoxy) aniline- 2,4,-6-trichloropyrirnidine (5.1 g.) and 6.2 g. of p-(2- diet-hylaminoethoxy)aniline are added to 15 g. of phenol and warmed at 75-80 for 3 hours. The phenolic solution is then poured on crushed ice and worked up as described above. The desired N-(2,6-dichloro-4-pyrimidyl)-p-(Z-diethylaminoethoxy)aniline is obtained by two recrystallizations from a benzene solution; M.P. 104- 106 C.
EXAMPLE 10 N- (2-chloro-4-pyrimidyl) -p-(Z-dietlzylaminoethoxy) aniline A solution consisting of 6.2 g. of p-(Z-diethylaminoethoxy)aniline and 4.4 g. of 2,4-dichloropyrimidine in 75 ml. of ethanol is warmed to 70 C. and then allowed to stand overnight. After distilling off the volatile materials the remaining dark-brown oil is warmed with 250 ml. of Water and the aqueous layer is separated; extracted with two 50 ml. portions of ether, and then neutralized with dilute ammonium hydroxide. The desired N-(2- chloro 4-pyrimidyl) -p-(2-diethylaminoethoxy) aniline is obtained as a gray-white solid melting at 75-77 C.
EXAMPLE 11 N-(S-chloro-Z-pyrimidyl) -p- (2-dielhylamin0eth0xy) aniline A solution consisting of 3.7 g. of 2,5-dichloropyrimidine and 5.2 g. of p-(Z-diethylaminoethoxy) aniline in 25 ml. of ethanol is heated at 70 C. for three hours; cooled to room temperature and then worked up as described in Example 10. The desired product, N-(-chloro-2- pyrimidyl)-p-(2-diethylaminoethoxy)aniline is recrystallized from ether-petroleum ether (3060 C.) M.P. 92-94" C.
EXAMPLE 12 N-(5-nitro-2-pyridyl)-p-(Z-diethylaminoethoxy)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 benzene-petroleum ether (30-60 C.) to yield the desired N (5-nitro-2-pyridyl)-p-(Z-diethylaminoethoxy)aniline; M.P. 143-145 C. (sintering at 136 C.).
EXAMPLE 13 2- p- (Z-diethylaminoethoxy) ani lino] benzothiazole A solution consisting of 17.0 g. of 2-chlorobenzo- 6 thiazole and 20.8 g. of p-(2 diethylaminoethoxy)aniline in 200 ml. of ethanol is refluxed for 15 hours, and then concentrated to a semi-solid residue. The residue is made basic with 10% potassium hydroxide solution, extracted with two ml. portions of ether, and the ethereal extracts are combined, decolorized with charcoal and dried over anhydrous sodium sulfate. After removing the lowboiling materials the residual oil is distilled in vacuo until no more p-(Z-diethylaminoethoxy)aniline distills over. The pot-residue is recrystallized from an. etherpetroleum ether (30-60 C.) solution to give 2-[p-(2- diethylaminoethoxy)anilihoJbenzothiazole; M.P. 92- 94 C.
EXAMPLE 14 N (5 -nitro-2-pyridyl -p-[ (Z-dz'ethylamino-I -methyl ethoxylaniline Sodium hydride (7.2 g.) is added to 131 g. of l-diethylamino-Z-propanol cooled to 010 C. After hydrogen evolution ceases 72.3 g. of l-fluoro-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 (in vac.). p-[(Z-diethyl-l-methyl)ethoxyJnitrobenzene 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; 35 p.s.i. of hydrogen using 5% palladiumon-charcoal catalyst. The desired p-[(2-diethylamino-1- methyl)ethoxy]nitrobenzene 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 distillation.
2-chloro-5-nitropyridine (3.8 g.) is added to 5.6 g. of p-[(2-diethylamino-1-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 Florisil. After eluting the column with five 100-ml. portions of benzene-petroleum ether (3060 C.) 40:60 the desired N- 5 -nitro-2-pyridyl -p- 2-diethylamino-1 methyl)ethoxy1aniline is eluted from the column with ethyl acetate, and recrystallized from ether-petroleum ether (30-60 C.); M.P. 59-61 C.
EXAMPLE 15 N 5 -ch l0r0-2-pyrimidyl -p- Z-dim et/zylamin0-2,2- dimethyl) ethoxy] aniline A Pyrex tube was charged with 6.3 g. of p-[(2-dimethylamino-2,2-dimethyl)ethoxy]aniline and 3.9 g. of 2,5-dichloropyrimidine, flushed with dry argon and sealed. After heating the mixture for 15 hours the semi-solid residue was dissolved in water, decolorized using charcoal, and made basic with dilute sodium hydroxide solution. The insoluble material was collected, dissolved in benzene and chromatographed on Florisil which was eluted with benzene-petroleum ether (30-60") 8:2. The benzene-petroleum ether eluates were combined and concentrated to a residue which was recrystallized from a benzene-petroleum ether (30-60") solution to give the desired product N (5 chloro 2-pyrimidyl)-p-[ (2-dimethylamino 2,2 dimethyl)ethoxy] aniline; M.P. 121 C.
7 EXAMPLE 16 N-(5-chl0r0-2-pyrimidyl) -p-(Z-pyrrolidinaethoxy)aniline Using the procedure described in Example 15, 8.3 g. of p-(2-pyrrolidinoethoxy)aniline and 6.0 g. of 2,5-dichloropyrimidine were heated in a sealed tube under argon for 15 hours. The desired product N-(S-chloro-Z- pyrimidyl)-p-(2-pyrrolidinoethoxy)aniline was isolated by passing a benzene solution of the crude reaction mixture through a Florisil column.
What is claimed is:
1. N (2,6-dich1oro-4-pyrimidyl)-p-(2-diethylaminoethoxy) aniline.
2. N (2 chloro 4 pyrimidyl) p-(Z-diethylaminoethoxy) aniline.
3. N (5 chloro 2 pyrimidyl) p-(2-diethy1aminoethoxy) aniline.
4. N (5-chloro-2-pyrimidyl)-p-[(2-dimethylamino-2,2- dimethyl) ethoxy] aniline.
5. N (S-chloro-Z-pyrimidyl)-p-(2-pyrrolidinoethoxy) aniline.
6. A member of the class consisting of compounds of the formula:
wherein 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 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, morpholino, thiomorpholino and 4-lower alkyl-l-piperazino; Z is selected from the group consisting of imino, oxygen and sulfur; and R is selected from the group consisting of 5-halo-2-pyrimidyl, 2-halo-4-pyrirnidyl and 2,6-dihalo- 4-pyrimidyl; and the non-toxic acid-addition and quaternary ammonium salts thereof.
7. N (5-chloro-2-pyrimidyl)-p-(2-piperidinoethoxy) aniline.
References Cited by the Examiner UNITED STATES PATENTS 2,087,131 7/1937 Taub et al 260-570.7 2,657,206 10/1953 Hitchings et a1. 260256.4 2,899,434 8/1959 Bloom 260-256.4 2,937,117 5/1960 Cottet et al. 167-65 2,978,381 4/1961 Freedman 16765 3,033,870 5/1962 Druey et a1 260294.8 3,165,516 1/1965 Altermatt 260-249 ALEX MAZEL, Primary Examiner.
HENRY R. JILES, Examiner. MARY U. OBRIEN, Assistant Examiner.

Claims (2)

1. N - (2,6 - DICHLORO-4-PYRIMIDYL)-P-(2-DIETHYLAMINOETHOXY)ANILINE.
6. A MEMBER OF THE CLASS CONSISTING OF COMPOUNDS OR OF THE FORMULA:
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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
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US597523A US3330831A (en) 1963-09-20 1966-11-29 Aminoalkoxy-diphenyl amines, ethers and thioethers
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US4025514A (en) * 1973-09-20 1977-05-24 Delalande S.A. Arylamino pyrimidinic derivatives
US4450162A (en) * 1981-06-05 1984-05-22 Sankyo Company, Limited Pyrimidine derivatives and a pharmaceutical composition containing them
US4559345A (en) * 1981-08-20 1985-12-17 Lbp Istituto Faraceutico S.P.A. Pyrimidine and s-triazine derivatives with antilipidemic activity
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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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
IL87181A (en) * 1987-08-07 1993-08-18 Sanofi Sa Aminoalkoxyphenyl derivatives, their preparation and pharmaceutical and veterinary compositions containing them

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US2978381A (en) * 1958-06-20 1961-04-04 Freedman Louis Process and composition for lowering blood serum cholesterol and chylomicron levels
US3033870A (en) * 1958-03-24 1962-05-08 Ciba Pharm Prod Inc Certain derivatives of 4-(aminophenylmercapto)-pyridine
US3165516A (en) * 1960-10-28 1965-01-12 Ciba Ltd 5-sulfo and carboxyphenyl-1-(2'-chloro-4'-amino-1':3':5'-triazinylamino) monoanthraquinones

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US2937117A (en) * 1953-06-19 1960-05-17 Chimie Atomistique Process for lowering high blood cholesterol levels
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US3978055A (en) * 1973-09-20 1976-08-31 Delalande S.A. Arylamino pyrimidinic derivatives
US4025514A (en) * 1973-09-20 1977-05-24 Delalande S.A. Arylamino pyrimidinic derivatives
US4450162A (en) * 1981-06-05 1984-05-22 Sankyo Company, Limited Pyrimidine derivatives and a pharmaceutical composition containing them
US4559345A (en) * 1981-08-20 1985-12-17 Lbp Istituto Faraceutico S.P.A. Pyrimidine and s-triazine derivatives with antilipidemic activity
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
WO2003033467A1 (en) * 2001-10-16 2003-04-24 Merck Patent Gmbh Nitroso diphenylamine derivatives as nitrogen monoxide generating agents

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