Classifications

• • 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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• 1964
  • 1964-07-13 US US382383A patent/US3321478A/en not_active Expired - Lifetime
  • 1964-09-10 DE DE19641445452 patent/DE1445452A1/de active Pending
  • 1964-09-10 FR FR987663A patent/FR1436566A/fr not_active Expired
  • 1964-09-11 SE SE10910/64A patent/SE320086B/xx unknown
  • 1964-09-15 CH CH1199764A patent/CH467751A/de unknown
  • 1964-09-18 NL NL6410914A patent/NL6410914A/xx unknown
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  • 1964-09-19 DK DK461364AA patent/DK117354B/da unknown
  • 1964-12-09 FR FR997935A patent/FR4860M/fr not_active Expired
• 1966
  • 1966-11-29 US US597516A patent/US3330832A/en not_active Expired - Lifetime
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