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

4-substituted-4'-tertiary aminoalkoxy biphenyls Download PDF

Info

Publication number
US3375256A
US3375256A US595360A US59536066A US3375256A US 3375256 A US3375256 A US 3375256A US 595360 A US595360 A US 595360A US 59536066 A US59536066 A US 59536066A US 3375256 A US3375256 A US 3375256A
Authority
US
United States
Prior art keywords
methyl
acid
hours
substituted
biphenyls
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US595360A
Other languages
English (en)
Inventor
Bach Frederick Louis
Barclay John Claire
Cohen Elliott
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GB17917/65A priority Critical patent/GB1063744A/en
Priority to FR1595509D priority patent/FR1595509A/fr
Priority to CH730665A priority patent/CH460041A/de
Priority to DE19651493426 priority patent/DE1493426A1/de
Priority to SE15192/65A priority patent/SE316190B/xx
Priority to NL6516582A priority patent/NL6516582A/xx
Priority to DK32366AA priority patent/DK123091B/da
Priority to BE675461D priority patent/BE675461A/xx
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US595360A priority patent/US3375256A/en
Application granted granted Critical
Publication of US3375256A publication Critical patent/US3375256A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group

Definitions

  • ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 4-substituted- '-tertiary aminoalkoxy biphenyls useful as hypocholesteremic agents.
  • This invention relates to certain novel 4-substituted-4- tertiary aminoalkoxy biphenyls and, more particularly, is concerned with novel compounds which may be represented by the following general formula:
  • Z is nitro, lower alkanoyl, carboxy, lower carboalkoxy, trifluoromethyl, sulfonamido, methylsulfonyl or l-hydroxy-1-methyl-2-propynyl;
  • R R R and R are each hydrogen, methyl or ethyl with the proviso that the total number of carbon atoms in the alkylene group is less than 7;
  • R is lower alkyl;
  • R is lower alkyl; and R and R taken together with the
  • Lower alkyl and lower alkanoyl groups contemplated by the present invention are those having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. and acetyl, propionyl, n-butyryl, etc.
  • Suitable lower carboalkoxy groups are those having from 1 to 6 carbon atoms such as, for example, carbomethoxy, carbethoxy, etc.
  • Atherosclerosis is a form of arteriosclerosis where cholesterol and lipoid materials are deposited as plaques in the intima of large and medium sized arteries.
  • Arteriosclerosis is associated with the degeneration of arterial walls by mechanisms not clearly defined.
  • hypercholestcremia and the incidence of cardiovascular disease.
  • Our invention is based upon the discovery that our novel ,4-substituted-4-tertiary aminoalkoxy biphenyls exert a more powerful hypocholesteremic action than the adjuvants which have been used heretofore. It is not known how the novel compounds of the present invention operate to lower the cholesterol level in blood serum and no theory of why these compounds operate is advanced. It is not intended that the present invention should be limited to any theory as to mechanism.
  • the organic bases of this invention form non-toxic, acid-addition and quaternary ammonium salts with a I I I 3,375,256 Patented Mar. 26, 1968 variety of organic and inorganic salt-forming reagents.
  • acid-addition salts formed by admixture of the organic free base with an acid, suitable in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids.
  • Quaternary ammonium salts may be formed by reaction of the free bases with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids.
  • the organic reagents employed for quaternary ammonium salt formation are preferably lower alkyl halides. However, other organic reagents :are suitable for quaternary ammonium salt formation, and may be selected from among a diverse class of compounds including benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, allyl chloride, methallyl bromide and crotyl bromide.
  • the free bases are equivalent to their non-toxic acid-addition and qua-ternary ammonium salts.
  • novel compounds of the present invention are materials which may be purified by crystallization from common organic solvents such as ether, acetone, benzene and the like. They are generally insoluble in water, but relatively soluble in organic solvents such as lower alkanols, esters, ethers, ketones, benzene, toluene, chloroform, and the like.
  • the acid-addition and quaternary ammonium salts of the organic bases of the present invention are, in general, crystalline solids, relatively soluble in water, methanol and ethanol, but relatively insoluble in non-polar organic solvents such as ether, benzene, toluene and the like.
  • novel compounds of the present invention are their oral activity. They may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets. It is an advantage of the present invention that our novel compounds may be orally administered in any convenient manner.
  • the amount of a single dose or of a daily dose to be given will vary with the size of the individual to be treated, but should be such as to give a proportionate dosage of from one milligram to 30 milligrams per kilogram of body weight per day. In terms of total weight, this is usually from about 0.1 gram to about 1.0 gram per daily dosage unit.
  • novel compounds of the present invention may be readily prepared by the interaction of the sodium or potassium salt of a 4-substituted 4'-hydroxybiphenyl with an appropriately substituted tertiary aminoalkyl halide as set forth in the following reaction scheme:
  • M is sodium or potassium
  • X is halogen
  • Z, R R R R R and R are as hereinabove defined.
  • This reaction is preferably carried out in a solvent such as a lower alkanol, dioxane, tetrahydrofuran, toluene, and the like, at temperatures ranging from about C. to
  • the active compounds of this invention may be incorporated with excipients and used, for example, in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like.
  • Such compounds and preparations should contain at least 0.1% of active compound.
  • the percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that a dosage unit form contains between about 10* and about 200 milligrams of active compound.
  • the tablets, troches, pills, capsules and the like may contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring.
  • a syrup or elixir may contain the active compounds in the form of their non-toxic acid-addition salts, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Example 1 Example 2 Using the method and work-up described in Example 1, 5.0 g. of the potassiov derivative of 4-hydroxy-4-nitrobiphenyl and 3.3 g. of N,N-diisopropyl-2-chloroethylamine were refluxed in200 ml. of dry toluene and 75 ml. of n-amyl alcohol for approximately hours. The crude product yielded the desired 4-(2-diisopropylaminoethoxy) 4'-nitrobiphenyl' after two reerystallizations from etherpetroleum ether; melting point 5 0-5 1 C.
  • Example 3 A suspension consisting of 10.2 g. of the potassium salt of 4-hydroxy-4-nitrobiphenyl, 5.4 g. of N,N-dimethyl- R1 R2 R5 oHnNH) 200 water solution was removed using steam-cone temperature and reduced pressure leaving a semi-solid residue. The organic material was extracted with two -ml. portions of dry ether, and after decolorization using charcoal the ethereal extract was dried over anhydrous sodium sulfate and concentrated to a low-melting, yellow, solid residue.
  • Example 4 Using the procedure outlined in Example 3, 10.2 g. of the potassium salt of 4-hydroxy-4-nitrobiphenyl, 5.4 g. of N,N-dimethyl-1,l-dimethyl-2-ehloroethylamine in 100 ml. of ethanol and 100 ml. of water was refluxed 15 hours. Using the same work-up as described previously an isomeric mixture consisting of 4-[(2-dimethylamino-2,2-dimethyl)ethoxy]-4-nitrobiphenyl and 4 [(2 dimethylamino-1,1-dirnethyl) ethoxy]-4-nitrobiphenyl (melting point 74-75 C.) was isolated.
  • Example 5 Using the method described in Example 1, 6.0 g. of 4-acetyl-4-hydroxybiphenyl, 1.2 g. of sodium hydride (54.7% active) and 3.8 g. of N,N-diethyl-2-chloroethylamine were refluxed in 60 ml. of toluene and 30 ml. of namyl alcohol for 16 hours. The crude product obtained in this manner was recrystallized from an ether-petroleum ether solution to give the desired 4-acetyla4-(2-diethylaminoethoxy)biphenyl (MP. 1l3-l14 C.)
  • Example 6 4-(2-diethylaminoethoxy)biphenyl magnesium bromide (prepared from 7.6 g. of 4.-bromo-4'-(Z-diethylaminoethoxy)-biphenyl and 0.5 g. of magnesium in 20 ml. of ether and 10 ml. of tetrahydrofuran) was poured on 200 g. of solid carbon dioxide. The semi-solid material obtained in this manner was hydrolyzed with cold, dilute hydrochloric acid. The aqueous layer was made basic, extracted with two 100 ml. portions of ether, decolorized using charcoal and then adjusted to a pH 67 by portionwise addition of dilute hydrochloric acid.
  • Example 7 4-acetyl-4-(2-diethylaminoethoxy)biphenyl (4.9 g.) was added to a solution of lithium acetylide in liquid ammonia at 70 C. (the lithium acetylide was formed from 0.3 g. of lithium, 50 ml. of liquid ammonia and an excess of dry acetylene) and the suspension was shaken in a rocking-autoclave for 18 hours at room temperature. The crude reaction mixture was then removed from the autoclave and the excess ammonia evaporated-in a stream of dry nitrogen. Approximately 3.0 g. of ammonium chloride was added to the residue and the crude product was extracted using two 200-ml. portions of ether. The ethereal extracts were combined and washed with two 100-ml. portions of dilute sulfuric acid. The acidic washes were aminoethoxy)biphenyl, M.P. 116l18 C.
  • Example 8 using the method and work-up desc-ribed in Example 1 18.97 g. of the potassio derivative of 4-hydroxy-4-nitrobiphenyl and 12.8 g. of N-(2-chloroethyl)pyrrolidine was refluxed in 200 ml. of toluene and 200 ml. of n-amylalcohol fQnapproximately 68 hours. The crude reaction mixture yielded the desired 4-nitro-4 (Z-pyrrolidinoethoxy)'biphenyl which was recrystallized twice from an ether-petroleum ether solution; M.P. 71-72 C.
  • Example 9 A mixture consisting of 89.9 g. of p-iodo'benzotrifluoride, 152.5 g. of. p-iodoanisole and 322.7 g. of copper powder was heated with stirring for approximately 5 days. After cooling, the solid reaction product was ground, placed in a Soxhlet extractor and extracted with 1.0 liter of n-hept'ane for 2 days. On cooling to room temperature 4,4'-dimethoxybiphenyl separated as a white, crystalline mass. The mother liquor was concentrated to yield the crude 4-methoxy-4'-trifluoromethylbiphenyl. After four recrystallizations from petroleum-ether (30-60 C.) the desired product was isolated in a pure state; 21.7 g. (26% yield) melting at 125-1 26 C.
  • Example 4-acetamido-4-chlorosulfonylbiphenyl (6.2 g.) was added to a solution of sodium sulfite (10.0 g.) in 200 ml. of water and stirred for 20 hours at room temperature; portions of 50% sodium hydroxide solution were added periodically to maintain a basic solution during the reduction.
  • the aqueous suspension was diluted to 1.0 liter, filtered and acidified using concentrated sulfuric acid. A White solid precipitated and this material was collected by filtration and combined with a second crop obtained by concentrating the filtrate (5.5 g. total yield).
  • the diazotization of 4-amino-4-methylsulfonylbiphenyl was carried out by adding 2.3 g. of the amine to 14 ml. of glacial acetic acid and 14 ml. of 40% sulfuric acid. The suspension was cooled to 5 C. and treated with 1.6 g. of sodium nitrite dissolved in approximately 4.0 ml. of water over a period of 20 minutes. After addition was complete urea was added at 0 C. to decompose excess nitrous acid. The diazonium solution was added slowly to 5.3 ml. of refluxing 40% sulfuric acid; a gummy solid separated which solidified on cooling. The crude product was taken up in 1 N sodium hydroxide solution, filtered and acidified affording 1.7 g. of the desired 4-hydroxy-4'-methylsulfonylbiphenyl (M.P. l89190 C.).
  • 4-hydroxy-4'-methylsulfonylbiphenyl (1.7 g.) was dissolved in approximately 90 ml. of dry dimethylformamide and treated with 0.2 g. of sodium hydride dispersed in mineral oil (54.7% active). After hydrogen evolution ceased the suspension was refluxed until the sodio derivative dissolved. Alkylation was carried out by adding 1.2 g. of N-(2-chloroethyl)py'rrolidine in 10 ml. of dry toluene to the cooled suspension and then reheating the reaction mixture for an additional 68 hours. After cooling,
  • the dark-brown solution was decolorized using charcoal, filtered and the clear filtrate concentrated to a solid residue.
  • the residual material was taken up in approximately 300 ml. of benzene, dried over anhydrous sodium car- 'bonate, filtered and the clear filtrate was treated with an excess of hydrogen chloride.
  • the gummy, yellow hydrochloride salt was dissolved in water ml.) and made strongly basic with sodium hydroxide; the basic solution was extracted with two 75 ml. portions of benzene and the combined extracts were dried and concentrated to afiord 1.0 g. of the desired 4-(2-pyrrolidinoethoxy)-4'- methylsulfonyl'biphenyl; M.P. 153154 C.
  • Example 1 4 hydroxy-4'-sulfonamidobiphenyl (8.0 g.) dissolved in 200 ml. of toluene and ml. of n-amyl alcohol was treated with 0.8 g. of sodium hydride dispersed in mineral oil (54.7% active). The sodio derivative thus obtained was refluxed for approximately 70 hours with 4.0 g. of N-(2-chloroethyl)pyrrolidine. On cooling the reaction mixture was filtered and concentrated to a semi-solid residue. The crude reaction product was dissolved in benzene, decolorized with charcoal and dried over anhydrous sodium carbonate. Dry hydrogen chloride was passed through the clear benzene solution and the insoluble material was collected and dissolved in 100 ml. of water. The acidic solution was treated with an excess of sodium hydroxide to yield the desired 4-(2-pyrrolidinoethoxy)-4-sulfonamidobiphenyl.
  • Example 12 Following the procedure outlined in Example 1, 9.2 g. of 2-piperidin0ethyl chloride monohydrdchloride was neutralized, extracted into 50 ml. of toluene and added to a suspension consisting of 12.6 g. of the potassium salt of 4-hydroxy-4'-nitrophenyl in 100 ml. of toluene and 100 ml. of n-amyl alcohol. After a 30 hour reflux period the suspension was filtered hot and the clear filtrate was worked up as previously described. The crude, basic material was taken up in ether, decolorized with charcoal, dried over anhydrous sodium sulfate, filtered and saturated with dry hydrogen chloride. The monohydrochloride of 4-(2-piperidinoethoxy)-4'-nitrobiphenyl obtained in this manner melted at 227-230" C.
  • a compound according to claim 1 wherein Z is acetyl; R R R and R are each hydrogen; and R and R are each ethyl. 7. A compound" according to claim 1 wherein Z is nitro; R R R3 and R are'each hydrogen; and R and R taken together with the N(it'rogen) is pyrrolidino.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US595360A 1964-05-25 1966-11-18 4-substituted-4'-tertiary aminoalkoxy biphenyls Expired - Lifetime US3375256A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
GB17917/65A GB1063744A (en) 1964-05-25 1965-04-28 4-substituted-4'-tertiary aminoalkoxy biphenyls
FR1595509D FR1595509A (de) 1964-05-25 1965-05-20
CH730665A CH460041A (de) 1964-05-25 1965-05-25 Verfahren zur Herstellung von 4-substituierten 4'-tert.-Aminoalkoxyphenylen
DE19651493426 DE1493426A1 (de) 1964-05-25 1965-05-25 In 4-Stellung substituierte 4'-tert.-Aminoalkoxy-biphenyle
SE15192/65A SE316190B (de) 1964-05-25 1965-11-24
NL6516582A NL6516582A (de) 1964-05-25 1965-12-20
DK32366AA DK123091B (da) 1964-05-25 1966-01-20 Analogifremgangsmåde til fremstilling af 4-substituerede 4'-tert. aminoalkoxy-biphenyler eller disse forbindelsers syreadditionssalte.
BE675461D BE675461A (de) 1964-05-25 1966-01-21
US595360A US3375256A (en) 1964-05-25 1966-11-18 4-substituted-4'-tertiary aminoalkoxy biphenyls

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US37004464A 1964-05-25 1964-05-25
US42709465A 1965-01-21 1965-01-21
US595360A US3375256A (en) 1964-05-25 1966-11-18 4-substituted-4'-tertiary aminoalkoxy biphenyls

Publications (1)

Publication Number Publication Date
US3375256A true US3375256A (en) 1968-03-26

Family

ID=27408945

Family Applications (1)

Application Number Title Priority Date Filing Date
US595360A Expired - Lifetime US3375256A (en) 1964-05-25 1966-11-18 4-substituted-4'-tertiary aminoalkoxy biphenyls

Country Status (9)

Country Link
US (1) US3375256A (de)
BE (1) BE675461A (de)
CH (1) CH460041A (de)
DE (1) DE1493426A1 (de)
DK (1) DK123091B (de)
FR (1) FR1595509A (de)
GB (1) GB1063744A (de)
NL (1) NL6516582A (de)
SE (1) SE316190B (de)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4067904A (en) * 1975-12-19 1978-01-10 Mead Johnson & Company Alkylsulfonylphenoxypropanolamine derivatives
US4119729A (en) * 1975-12-19 1978-10-10 Mead Johnson & Company Alkylsulfonylphenoxypropanolamine therapeutic process
US4220603A (en) * 1977-10-07 1980-09-02 Mitsubishi Chemical Industries, Limited Pharmaceutically active (omega-aminoalkoxy)bibenzyls
US4732896A (en) * 1981-12-24 1988-03-22 Delalande S.A. Aromatic derivatives comprising an aminoalkoxy chain, the salts thereof, the process for preparing these derivatives and salts and the application thereof in therapeutics
US5234946A (en) * 1987-11-27 1993-08-10 Banyu Pharmaceutical Co., Ltd. Substituted alkylamine derivatives
WO2002040461A3 (en) * 2000-11-17 2002-08-01 Abbott Lab Aminoalkoxybiphenyl carboxamides as histamine-3 receptor ligands and their therapeutic applications
US20030105095A1 (en) * 2001-10-10 2003-06-05 Cheil Jedang Corporation 4'-Methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor
US20060178399A1 (en) * 2003-03-14 2006-08-10 Rena Nishizawa Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
EP1790637A1 (de) 2004-09-13 2007-05-30 Ono Pharmaceutical Co., Ltd. Stickstoffhaltiges heterocyclisches derivat und dieses als wirkstoff enthaltendes medikament
US20090131403A1 (en) * 2006-03-10 2009-05-21 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative , and pharmaceutical agent comprising the derivative as active ingredient

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1265978A (de) * 1968-04-29 1972-03-08
GB1266170A (de) * 1968-09-27 1972-03-08

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2495772A (en) * 1947-02-07 1950-01-31 Parke Davis & Co Beta-(2-biphenyloxy) ethyl beta-haloalkyl amines
US2748116A (en) * 1951-12-20 1956-05-29 Searle & Co Arylcycloalkyloxyalkylamine derivatives and methods for their preparation
US2935439A (en) * 1957-11-25 1960-05-03 Abbott Lab Method of inhibiting growth of fungi
US2966518A (en) * 1957-07-22 1960-12-27 Bristol Myers Co Process of producing nitrtogen-containing chemical compounds
US3077472A (en) * 1961-03-21 1963-02-12 Univ Kansas Res Foundation 3-[4-(aminoalkoxy)-phenyl]-4-(4-oxyphenyl)-alkanes and alkenes
US3135745A (en) * 1961-10-17 1964-06-02 Frank P Palopoli Heterocyclic derivatives of diarylethanes and diarylethylenes ii
US3196159A (en) * 1959-09-29 1965-07-20 Ciba Geigy Corp (aminoalkyleneoxy)-phenyl alcohols

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2495772A (en) * 1947-02-07 1950-01-31 Parke Davis & Co Beta-(2-biphenyloxy) ethyl beta-haloalkyl amines
US2748116A (en) * 1951-12-20 1956-05-29 Searle & Co Arylcycloalkyloxyalkylamine derivatives and methods for their preparation
US2966518A (en) * 1957-07-22 1960-12-27 Bristol Myers Co Process of producing nitrtogen-containing chemical compounds
US2935439A (en) * 1957-11-25 1960-05-03 Abbott Lab Method of inhibiting growth of fungi
US3196159A (en) * 1959-09-29 1965-07-20 Ciba Geigy Corp (aminoalkyleneoxy)-phenyl alcohols
US3077472A (en) * 1961-03-21 1963-02-12 Univ Kansas Res Foundation 3-[4-(aminoalkoxy)-phenyl]-4-(4-oxyphenyl)-alkanes and alkenes
US3135745A (en) * 1961-10-17 1964-06-02 Frank P Palopoli Heterocyclic derivatives of diarylethanes and diarylethylenes ii

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4119729A (en) * 1975-12-19 1978-10-10 Mead Johnson & Company Alkylsulfonylphenoxypropanolamine therapeutic process
US4067904A (en) * 1975-12-19 1978-01-10 Mead Johnson & Company Alkylsulfonylphenoxypropanolamine derivatives
US4220603A (en) * 1977-10-07 1980-09-02 Mitsubishi Chemical Industries, Limited Pharmaceutically active (omega-aminoalkoxy)bibenzyls
US4323568A (en) * 1977-10-07 1982-04-06 Mitsubishi Chemical Industries Limited Pharmaceutically active (omega-aminoalkoxy)bibenzyls
US4732896A (en) * 1981-12-24 1988-03-22 Delalande S.A. Aromatic derivatives comprising an aminoalkoxy chain, the salts thereof, the process for preparing these derivatives and salts and the application thereof in therapeutics
US5234946A (en) * 1987-11-27 1993-08-10 Banyu Pharmaceutical Co., Ltd. Substituted alkylamine derivatives
WO2002040461A3 (en) * 2000-11-17 2002-08-01 Abbott Lab Aminoalkoxybiphenyl carboxamides as histamine-3 receptor ligands and their therapeutic applications
US20030105095A1 (en) * 2001-10-10 2003-06-05 Cheil Jedang Corporation 4'-Methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor
US6583321B1 (en) * 2001-10-10 2003-06-24 Cheil Jedang Corporation 4′-methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor
US7910741B2 (en) 2003-03-14 2011-03-22 Ono Pharmaceutical Co., Ltd. Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
US20060178399A1 (en) * 2003-03-14 2006-08-10 Rena Nishizawa Nitrogen-containing heterocyclic derivatives and drugs containing the same as the active ingredient
EP1790637A1 (de) 2004-09-13 2007-05-30 Ono Pharmaceutical Co., Ltd. Stickstoffhaltiges heterocyclisches derivat und dieses als wirkstoff enthaltendes medikament
EP1790637A4 (de) * 2004-09-13 2010-03-24 Ono Pharmaceutical Co Stickstoffhaltiges heterocyclisches derivat und dieses als wirkstoff enthaltendes medikament
US20080057074A1 (en) * 2004-09-13 2008-03-06 Yoshikazu Takaoka Nitrogenous Heterocylic Derivative and Medicine Containing the Same as an Active Ingredient
US20110152520A1 (en) * 2004-09-13 2011-06-23 Ono Pharmaceutical Co., Ltd. Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient
US8143404B2 (en) 2004-09-13 2012-03-27 Ono Pharmaceutical Co., Ltd Nitrogenous heterocylic derivative and medicine containing the same as an active ingredient
EP2546234A1 (de) * 2004-09-13 2013-01-16 Ono Pharmaceutical Co., Ltd. Stickstoffhaltige heterocyclische Derivate und Medizin damit als ein Wirkstoff
US8410276B2 (en) 2004-09-13 2013-04-02 Ono Pharmaceutical Co., Ltd. Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient
US8604207B2 (en) 2004-09-13 2013-12-10 Ono Pharmaceutical Co., Ltd. Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient
US20090131403A1 (en) * 2006-03-10 2009-05-21 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative , and pharmaceutical agent comprising the derivative as active ingredient
US8003642B2 (en) 2006-03-10 2011-08-23 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient

Also Published As

Publication number Publication date
BE675461A (de) 1966-07-22
GB1063744A (en) 1967-03-30
DK123091B (da) 1972-05-15
FR1595509A (de) 1970-06-15
SE316190B (de) 1969-10-20
CH460041A (de) 1968-07-31
NL6516582A (de) 1966-07-22
DE1493426A1 (de) 1969-04-24

Similar Documents

Publication Publication Date Title
US4289772A (en) 1-Piperidinophthalazines as cardiac stimulants
US3375256A (en) 4-substituted-4'-tertiary aminoalkoxy biphenyls
US3816516A (en) Phenyl-alkanolamine,alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US3963729A (en) Pharmacologically active pyridine derivatives
US3992441A (en) Sulfamylbenzoic acids
US4514414A (en) N-Substituted pyrrolidineacetic acids and their esters
US3510560A (en) Method of producing anti-adrenal activity with diarylalkylamines
US3456060A (en) Therapeutic compositions containing piperidine derivatives and methods of treating cough and pain therewith
US4086272A (en) Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US3330832A (en) N-pyridyl-4-aminoalkoxy anilines
US4442102A (en) 1,5-Diphenylpyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing same
US4971985A (en) Pyridylketoxime ether compound and pharmaceutical composition containing it
US3663608A (en) 1-phenyl-3-aminoalkyl-1,2,3,4-tetrahydronaphthalenes and the salts thereof
US3213138A (en) N, n-disubstituted-n'-phenylalkyl hydrazines
DE3012123C2 (de)
US3372162A (en) 1-(2-thienyl)-1-oxo-2-amino propanes
US4138399A (en) Sulfamylbenzoic acid
DE2456947A1 (de) Neue alkensulfonamide, deren herstellung und diese enthaltende arzneimittel
US3998965A (en) 4-Aminoalkyl-4-cyano-4-phenyl-butanoic acid esters
US2828314A (en) p-(n-lower alkyl-n-dilower alkyl aminoethyl) aminobenzaldehyde isonicotinoyl hydrazone
US4377521A (en) Sulfamylbenzoic acids
US2762812A (en) Arylcycloalkenyl-tertiary-aminoalkyl acetonitriles
US3959261A (en) Biphenyl compounds
JP3683180B2 (ja) ヒドラジン誘導体
US3652590A (en) 4-bromo and chloro-4'-tertiary aminoalkoxy biphenyls