US3218328A - Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof - Google Patents

Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof Download PDF

Info

Publication number
US3218328A
US3218328A US259460A US25946063A US3218328A US 3218328 A US3218328 A US 3218328A US 259460 A US259460 A US 259460A US 25946063 A US25946063 A US 25946063A US 3218328 A US3218328 A US 3218328A
Authority
US
United States
Prior art keywords
compounds
acid
salts
heterocyclic amino
acid addition
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
US259460A
Inventor
Florence M Shapiro
Freedman Louis
Soloway Harold
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.)
U S Vitamin & Pharmacentical C
Us Vitamin & Pharmacentical Corp
Original Assignee
U S Vitamin & Pharmacentical C
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
Application filed by U S Vitamin & Pharmacentical C filed Critical U S Vitamin & Pharmacentical C
Priority to US259460A priority Critical patent/US3218328A/en
Priority to US489774A priority patent/US3270024A/en
Priority to US489773A priority patent/US3270025A/en
Application granted granted Critical
Publication of US3218328A publication Critical patent/US3218328A/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
    • C07D295/096—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 separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms

Definitions

  • This invention relates to heterocyclic amino substituted phenoxyacetic acid compounds in which the heterocyclic amino group is attached to the phenyl ring through a ring nitrogen atom, and includes correlated improvements and discoveries whereby novel compounds having useful characteristics are provided.
  • a principal object of this invention is to provide novel heterocyclic amino substituted phenoxyacetic acid compounds, including the acids, esters, amides, salts, acid addition salts and quaternary ammonium salts.
  • Another object of the invention is to provide compositions which are particularly effective for reducing the cholesterol level of blood, containing heterocyclic amino substituted phenoxyacetic acid compounds, esters, amides and related compounds.
  • phenoxyacetic acid compounds having a heterocyclic amine group attached to the phenyl nucleus through a ring nitrogen atom are particularly effective as hypocholesteremic agents.
  • the heterocyclic amine group preferably contains at least about four carbon atoms and may also contain other heterocyclic substituents, such as nitrogen, oxygen and sulfur, either as part of the ring or attached to other atoms which are part of the ring.
  • the heterocyclic amine group has from four to ten atoms in the ring, of which from one to three, preferably one, should be heterocyclic atoms, the remainder being carbon atoms.
  • the heterocyclic amine group can be substituted in any position on the'phenyl nucleus, ortho, meta or para to the oxyacetic acid group.
  • the alpha carbon atom of the acetic acid group attached through an oxygen atom to the phenyl nucleus can be substituted or unsubstituted. If substituted, it is preferably substituted with a lower alkyl group having from 1 to 6 carbon atoms.
  • Suitable heterocyclic amino phenoxyacetic acid compounds of this invention are the phenoxyacetic acids and the esters and amides of the phenoxyacetic acids with lower alkyl alcohols, cycloalkyl alcohols, lower alkanolamines, ammonia and lower alkyl amines.
  • phenoxyacetic acid compounds of this invention can be defined by the following formula:
  • R can be hydrogen or a lower alkyl group having from 1 to 6 carbon atoms
  • R can be selected from the group consisting of hydroxy, lower alkoxy, cycloalkoxy preferably having from to 7 car- 3,218,328 Patented Nov. 16, 1965 bon atoms, hydrazino, monoand dilower alkyl-hydrazino, amino of the formula and lower oxyalkyl amino of the formula wherein R and R, can each be hydrogen, lower alkyl, monoand di-(lower alkyl)-amino-lower alkyl and aminolower alkyl [c.g.
  • C H NH in the above formula is a heterocyclic group, having from 4 to 10 atoms, preferably 5 to 7 atoms, in the ring, from one to three ring atoms thereof, preferably from one to two, being selected from the group consisting of nitrogen, oxygen and sulfur, at least one being nitrogen, the remaining ring atoms being carbon.
  • the total number of carbon atoms in the group preferably does not exceed about 15.
  • phenoxyacetic acid compounds of'the invention are acids when R is OH, esters when R is alkoxy or cycloalkoxy or oxyalkylene, and amides when R is amino;
  • acid compound is used generically herein to refer to all of these subgenera of the invention.
  • R R and R can each be, for example, hydrogen, methyl, ethyl, n-propyl, isopropl, n-butyl, iso-butyl, t-butyl and any of the pentyl and hexyl isomers.
  • R can, for example, be hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy and any of the isomeric pentoxy and hexoxy derivatives, cyclopentoxy, cyclohexoxy and cycloheptoxy, amino, monomethylamino, dimethylamino, monoethylamino, diethylainino, monoisopropylamino, diisopropylamino, mono-n-propylamino, di-n-propylamino, mono-n-butylamino, di-n-butylamino, mono-t-butylamino, di-t-butylamino, monopentylamino, dipentylamino, monohexylamino, dihexylamino, OCH CH -NH hydrazino, methyl hydrazyl, ethyl hydrazyl
  • N/ NH om-cg The following compounds are illustrative of compounds coming within the scope of the invention 7 1 o can be, for example oncHflulmocgH5 v /CH2-CH1 1 n N NY 0 O-CH C-NH:
  • the Q groups are alkylene groups containing 0 from one to about ten carbon atoms, n 1s zero or one and g 0-0112 --NHO,H5
  • the total number of ring atoms in the group a GHQ-CH2 N ⁇ / Q CHr-CH ranges from about four to about ten.
  • the compounds of this invention can be prepared by condensing a nitrophenol with an ethyl-alphahalo alkanoate, reducing the resultant nitrophenoxy acetate to the aminophenoxy acetate and cyclizing the amino group to form a heterocyclic group. Reduction and ring closure can take place either prior to or after esterification or amide formation.
  • An equation for this preparae tion is as follows:
  • the resultant compounds can be reacted with any pharmaceutically acceptable inorganic or organic acid to form non-toxic pharmacologi-cally acceptable acid addition salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, acetates, formates, tartrates, m-alates, theophyllinates, 8-chloroetheophyllinates, and the like.
  • non-toxic pharmacologi-cally acceptable acid addition salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, acetates, formates, tartrates, m-alates, theophyllinates, 8-chloroetheophyllinates, and the like.
  • quaternizing agents such as alkyl sulfates and alkyl halides, e.g., methyl iodide, ethyl bromide, methyl p-toluene-sulfonate, allyl bromide, ethyl bromoacetate, and the like, non-toxic pharmacologically acceptable quaternary salts of the novel compounds are readily prepared.
  • alkyl sulfates and alkyl halides e.g., methyl iodide, ethyl bromide, methyl p-toluene-sulfonate, allyl bromide, ethyl bromoacetate, and the like.
  • quaternary salts can be represented by the formula Br (I) wherein R is selected from the group consisting of hydrogen and an organic radical having from one to eight carbon atoms such as methyl, ethyl, propyl, butyl, octyl, a-llyl, pentyl, benzyl and carboethoxyalkyl such as carboethoxymethyl, and A is an inert' non-toxic pharmacologically acceptable anion, such as bromide, iodide, chloride and p-toluenesulfonate.
  • R is selected from the group consisting of hydrogen and an organic radical having from one to eight carbon atoms such as methyl, ethyl, propyl, butyl, octyl, a-llyl, pentyl, benzyl and carboethoxyalkyl such as carboethoxymethyl
  • A is an inert' non-toxic pharmacologically acceptable anion, such
  • the quaternary salt can be formed at that nitrogen atom or at both the R nitnogen atom and the heterocyclic nitrogen atom.
  • the quaternary ammonium salts can be prepared by conventional methods as by refluxing equivalent quantities of the appropriate amino substituted phenoxyacetic acid with an alkyl halide or an alkyl sulfate in an inert solvent such as ethanol or benzene.
  • the quaternary ammonium salts generally crystallize out on standing. Where crystallization does not occur, the solution can be cooled or an additional hydrocarbon solvent such as hexane can be added in accordance with conventional techniques. Where the double quaternary salt is desired, two equivalents of the alkyl halide or alkyl or alkyl sulfate can be added.
  • the acid addition salts are prepared by reacting equivalent quantities of the amino substituted phenoxyacetic acid and the desired acid in an inert solvent such as ethanol or benzene and recovering the acid addition salt by conventional means.
  • the compounds of this invention can be used to reduce the cholesterol level of blood either directly or preferably by incorporating into a hypocholesteremic composition.
  • hypocholesteremic compositions of the or parenterally Inaddition to the heterocyclic amino phenoxyacetic acid compound, the hypocholesteremic compositions of the or parenterally. By such methods these compositions have.
  • the ability to markedlyreduce the cholesterol level of blood in animals is quite low, and the active ingredient can be administered in dosages adequate to obtain a therapeutic effect without adverse side effects.
  • the concentration of the phenoxyacetic acid compound in these compositions is not in any way critical, but can be adjusted to meet the need. In general, the concentration for oral and parenteral administration will lie within about 1 to about 300 mg. per unit dosage, i.e., per cc. of solution or per tablet or capsule, depending upon the dosage regimen desired and the weight and hypocholesteremic state of the animal.
  • a composition having a low concentration of the active ingredient is administered several times daily, as compared to a single daily dose having a relatively high concentration of the active ingredient, to achieve the total daily dosage required.
  • the daily dosage is generally within the range of about 25 to about 300 mg. of acid compound.
  • the heterocyclic amino phenoxyacetic acid compound or mixture thereof in an appropriate amount to obtain a therapeutic effect is administered to the patient orally, parenterally or by any other appropriate method, and there results a hypocholesteremic response.
  • EXAMPLE VII A composition of matter for oral administration, comprising ethyl o-(l-pyrrolidinyl)phenoxy acetate acid as the active ingredient in combination with a suitable carrier, was prepared by thoroughly mixing together 1000 grams of the active compound and 3500 grams of betalactose (milk sugar), passing the blended mixture through a No. 40 screen and filling the mix into gelatin capsules, 450 mg. per capsule, each capsule to contain 100 mg. of active ingredient.
  • betalactose milk sugar
  • EXAMPLE VIII A composition of matter for oral administration, in tablet form, comprising cyclohexyl (m-l-pyrrolidinyl) phenoxy isopropionate as the active ingredient in combination with a suitable carrier, was prepared by compounding the following ingredients into a tablet mix:
  • the above mix was comphessed into tablets, weighing approximately 325 mg., each tablet containing 100 mg. of active ingredient.
  • Grams Active ingredient 25 Sodium hydroxide 5.74 Benzyl alcohol 5 under Examples V, VI and VII may be made by including other substances having therapeutic properties which enhance the total therapeutic value of the heterocyclic amino phenoxyacetic acid compound by their additive or by a synergistic effect; the effect, if synergistic, will enhance the therapeutic value of the heterocyclic amino phenoxyacetic compound without increase in dosage.
  • known therapeutic substances such as aspirin or equivalent salicylate compound
  • salicylate compound may be added for their analgesic and anti-rheumatic effect
  • butazolidin or antipyrine or related compounds for their anti-pyretic and anti-phlogistic effects
  • hydrocortisone or prednisolone or one of its equivalent corticosteroids for their anti-rheumatic, antiinflammatory and anti-phlogistic effects.
  • the combination of a heterocyclic amino phenoxyacetic acid compound with one or more of the above additive substances also serves the purpose of an additive effect.
  • composition of matter may be added to the composition of matter in adequate dosage to exert their individual activity for therapeutic uses they are known to have.
  • other substances such as ascorbic acid, vitamin K, thiamine, etc., may be added to the composition of matter in adequate dosage to exert their individual activity for therapeutic uses they are known to have.
  • hypocholesteremic compositions can be sterilized and can contain auxiliary substances such as buffering lagents, stabilizing agents, wetting agents and emulsifying agents.
  • the hypocholsteremic response is indicated in Table III.
  • the compound is identified by its number in the list above.
  • the LD indicates the minimum dose which is lethal to mice when the compound is administered subcutaneously and is expressed in mg./kg.
  • the dose is the dosage of the drug administered subcutaneously expressed mg./kg. under the schedule described above and the effect of the compound in reducing cholesterol is indicated by the percent reduction from the cholesterol level noted for the animal at the initiation of the experiment (percent 'hypocholesteremia).
  • the noted cholesterol level was 80 mg. percent and at a subsequent interval, the noted cholesterol level was 60 mg. percent, this would be shown as 25% hypocholesteremia.
  • the compounds of this invention in addition to their hypocholesteremic activity are also useful intermediates in the production of other compounds and also have utility as muscle relaxants and anti-inflammatory agents.
  • R is selected from the group consisting of hydrogen and lower alkyl
  • X-pyrrolidino is selected from the group consisting of X-pyrrolidino, X- piperidino, X-hexamethyleneimino, X-morpholino, X-
  • X is selected from the group consisting of hydrogen, lower alkyl, hydroxy and acetyl; and the non-toxic acid addition salts and quaternary ammonium salts thereof.
  • NICHOLAS S. RIZZO Primary Examiner.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent 3,218,328 HETEROCYCLIC AMINO PI-IENOXYACETIC ACIDS, ACID ADDITION SALTS AND QUA- TERNARY AMMONIUM SALTS THEREOF Seymour L. Shapiro, deceased, late of Hastings on Hudson, N.Y., by Florence M. Shapiro, executrix, Hastings on Hudson,- N.Y., Louis Freedman, Bronxville, and Harold Soloway, New Rochelle, N.Y., assiguors to US. Vitamin & Pharmaceutical Corporation, New York, N.Y., a corporation of New York No Drawing. Filed Feb. 18, 1963, Ser. No. 259,460 3 Claims. (Cl. 260-294) This application is a continuation in part of application S.N. 818,548 filed June 8, 1959, now abandoned.
This invention relates to heterocyclic amino substituted phenoxyacetic acid compounds in which the heterocyclic amino group is attached to the phenyl ring through a ring nitrogen atom, and includes correlated improvements and discoveries whereby novel compounds having useful characteristics are provided.
A principal object of this invention is to provide novel heterocyclic amino substituted phenoxyacetic acid compounds, including the acids, esters, amides, salts, acid addition salts and quaternary ammonium salts.
Another object of the invention is to provide compositions which are particularly effective for reducing the cholesterol level of blood, containing heterocyclic amino substituted phenoxyacetic acid compounds, esters, amides and related compounds.
In accordance with this invention, it has been determined that phenoxyacetic acid compounds having a heterocyclic amine group attached to the phenyl nucleus through a ring nitrogen atom are particularly effective as hypocholesteremic agents. The heterocyclic amine group preferably contains at least about four carbon atoms and may also contain other heterocyclic substituents, such as nitrogen, oxygen and sulfur, either as part of the ring or attached to other atoms which are part of the ring. Preferably the heterocyclic amine group has from four to ten atoms in the ring, of which from one to three, preferably one, should be heterocyclic atoms, the remainder being carbon atoms. The heterocyclic amine group can be substituted in any position on the'phenyl nucleus, ortho, meta or para to the oxyacetic acid group.
The alpha carbon atom of the acetic acid group attached through an oxygen atom to the phenyl nucleus can be substituted or unsubstituted. If substituted, it is preferably substituted with a lower alkyl group having from 1 to 6 carbon atoms.
Suitable heterocyclic amino phenoxyacetic acid compounds of this invention are the phenoxyacetic acids and the esters and amides of the phenoxyacetic acids with lower alkyl alcohols, cycloalkyl alcohols, lower alkanolamines, ammonia and lower alkyl amines.
The phenoxyacetic acid compounds of this invention can be defined by the following formula:
In the above formula, R can be hydrogen or a lower alkyl group having from 1 to 6 carbon atoms, R can be selected from the group consisting of hydroxy, lower alkoxy, cycloalkoxy preferably having from to 7 car- 3,218,328 Patented Nov. 16, 1965 bon atoms, hydrazino, monoand dilower alkyl-hydrazino, amino of the formula and lower oxyalkyl amino of the formula wherein R and R, can each be hydrogen, lower alkyl, monoand di-(lower alkyl)-amino-lower alkyl and aminolower alkyl [c.g. C H NH in the above formula is a heterocyclic group, having from 4 to 10 atoms, preferably 5 to 7 atoms, in the ring, from one to three ring atoms thereof, preferably from one to two, being selected from the group consisting of nitrogen, oxygen and sulfur, at least one being nitrogen, the remaining ring atoms being carbon. The ring atoms can be unsubstituted or substituted with inert groups such as lower alkyl, hydroxy and carbonyl or keto oxygen, =0. The total number of carbon atoms in the group preferably does not exceed about 15.
It will be evident from the foregoing that the phenoxyacetic acid compounds of'the invention are acids when R is OH, esters when R is alkoxy or cycloalkoxy or oxyalkylene, and amides when R is amino; The term acid compound is used generically herein to refer to all of these subgenera of the invention.
Thus, in the foregoing formula, R R and R can each be, for example, hydrogen, methyl, ethyl, n-propyl, isopropl, n-butyl, iso-butyl, t-butyl and any of the pentyl and hexyl isomers. R can, for example, be hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy and any of the isomeric pentoxy and hexoxy derivatives, cyclopentoxy, cyclohexoxy and cycloheptoxy, amino, monomethylamino, dimethylamino, monoethylamino, diethylainino, monoisopropylamino, diisopropylamino, mono-n-propylamino, di-n-propylamino, mono-n-butylamino, di-n-butylamino, mono-t-butylamino, di-t-butylamino, monopentylamino, dipentylamino, monohexylamino, dihexylamino, OCH CH -NH hydrazino, methyl hydrazyl, ethyl hydrazyl, propyl hydrazyl,
, 3 4 and GHQ-CH1 /-CH3 N/ NH(CH;) 'N fl,
- 5 GIL-0H, Thus N/ NH om-cg The following compounds are illustrative of compounds coming within the scope of the invention 7 1 o can be, for example oncHflulmocgH5 v /CH2-CH1 1 n N NY 0 O-CH C-NH:
, /CHr-CH3 2% g a /N I CHI-CH:
in which the Q groups are alkylene groups containing 0 from one to about ten carbon atoms, n 1s zero or one and g 0-0112 --NHO,H5
the total number of ring atoms in the group a GHQ-CH2 N\/ Q CHr-CH: ranges from about four to about ten. Representative (4) f 0CHzONH(CHz)3N(CH GET-OH; 40" N/ 1 OHg-CH;
groups include GET-CH1 (5) I Fame-0 01115 CHz-CH, v
I CHPCHQ CHr-CE; CH 2 r t CH2- H:
Gin-0H: on CH CH (6) 1? N/ 2 OCH;C-OCH CHgN 5 01115 a CH -01; OH
2 2" I I CH3 a I v I I N /CH H H V UHF H: N
\OH H (7) o o-oHni-NH, 011,-011, I N QHf-CH,
GH-CH, 5
0235 7 CHF H2 CH:CHg-CH1 I H noxy acetates which can then be converted to any desired esters or amides, in accordance-with conventional procedures. Equations for the foregoing preparations are as follows, with X being halogen The acetate ester thus obtained can be hydrolyzed to form the acid, can be transesterified with an alcohol of the formula R OH' to form the appropriate ester, can be reacted to form amides with ammonia and with primary or secondary amines, and with hydrazines. In an alternative procedure, the compounds of this invention can be prepared by condensing a nitrophenol with an ethyl-alphahalo alkanoate, reducing the resultant nitrophenoxy acetate to the aminophenoxy acetate and cyclizing the amino group to form a heterocyclic group. Reduction and ring closure can take place either prior to or after esterification or amide formation. An equation for this preparae tion is as follows:
(8) I R1 (l l) OH w OH-OOCgHg NO:+X-CHCOOC3H3 (b) R1 R! (I) odH-iiocm, ohm-doom,
. [H] N03 NH;
with further procedure as Preparation I.
An alternative method of preparing the heteroaminophenols which can be used in Preparation I consists of 12 ring closure with ortho, meta or para anisidine followed by cleavage of the ether with hydriodic acid. This procedure can be illustrated as follows:
(a) con: I 0on3 NH; XZ--X N (b) O CH:
N HI N The resultant compounds can be reacted with any pharmaceutically acceptable inorganic or organic acid to form non-toxic pharmacologi-cally acceptable acid addition salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, acetates, formates, tartrates, m-alates, theophyllinates, 8-chloroetheophyllinates, and the like. Similarly, through the use of selected quaternizing agents, such as alkyl sulfates and alkyl halides, e.g., methyl iodide, ethyl bromide, methyl p-toluene-sulfonate, allyl bromide, ethyl bromoacetate, and the like, non-toxic pharmacologically acceptable quaternary salts of the novel compounds are readily prepared.
These quaternary salts can be represented by the formula Br (I) wherein R is selected from the group consisting of hydrogen and an organic radical having from one to eight carbon atoms such as methyl, ethyl, propyl, butyl, octyl, a-llyl, pentyl, benzyl and carboethoxyalkyl such as carboethoxymethyl, and A is an inert' non-toxic pharmacologically acceptable anion, such as bromide, iodide, chloride and p-toluenesulfonate.
When R contains a nitrogen atom, the quaternary salt can be formed at that nitrogen atom or at both the R nitnogen atom and the heterocyclic nitrogen atom.
The quaternary ammonium salts can be prepared by conventional methods as by refluxing equivalent quantities of the appropriate amino substituted phenoxyacetic acid with an alkyl halide or an alkyl sulfate in an inert solvent such as ethanol or benzene. The quaternary ammonium salts generally crystallize out on standing. Where crystallization does not occur, the solution can be cooled or an additional hydrocarbon solvent such as hexane can be added in accordance with conventional techniques. Where the double quaternary salt is desired, two equivalents of the alkyl halide or alkyl or alkyl sulfate can be added.
The acid addition salts are prepared by reacting equivalent quantities of the amino substituted phenoxyacetic acid and the desired acid in an inert solvent such as ethanol or benzene and recovering the acid addition salt by conventional means.
The following working examples illustrate the best modes of preparing the compounds of this invention.
EXAMPLE I A mixture of 102 g. (0.84 mole) of o-anisidine, g. (0.84 mole) of 1,4-dibromobutane, 172 g. (1.12 mole) of sodium carbonate and 900 mls of aoetonitrile were refluxed with stirring for 34 hours. After filtering off the salts, the solution was evaporated down and the residue taken up in dilute hydrochloric acid. The solution was 13 washed with ether, then made basic with dilute sodium hydroxide and the resulting oil extracted into three portions of ether. These were combined, dried over anhydrous magnesium sulfate, then filtered, the solvent evaporated off and the residue distilled to give 103 g. of o-(lpyrrolidinyl)anisole, boiling at 127-130 at mm. gm. of the o-(1-pyrrolidinyl)anisole so prepared and 50 ml. of constant boiling hydriodic acid were refluxed together for 28 hours, permitting methyl iodide to distill out as formed. At the end of this time, the hydriodic acid was removed at. diminished pressure leaving a clear, thick oil. This was dissolved in water, the solution rnade basic with a saturated, aqueous solution of sodium bicarbonate and the resulting precipitate filtered off to yield o-(lpyrrolidinyl)phenol, melting at 109-111". 21.2 g. (0.13 mole) of this o-(l-pyrrolidinyl)phenol, 21.8 g. (0.13 mole) of ethyl bromoacetate, 18.5 g. (0.13 mole) of potassium carbonate and 200 ml. of acetone were refluxed with stirring for 40 hours. The solids were then filtered off, the filtrate evaporated down to a thick oil and this oil dissolved in benzene. This solution was extracted with several portions of dilute hydrochloric acid, and the resulting aqueous solution made basic again with 40% aqueous sodium hydroxide to yield an oil which was taken up in ether. The ethereal solution was then dried over anhydrous magnesium sulfate, the drying agent filtered off, the ether removed and the residue distilled to give 26 g. of ethyl-a-[o-(1-pyrrolidinyl)phenoxy] acetate, boiling at 136-l39 C. at 0.25 mm. n =1.5465.
Anal.-Calc. for C H NO C, 67.4; H, 7.7; N, 5.6. Found: C, 67.2; H, 7.6; N, 5.3.
EXAMPLE II 3-dimethylaminopropylamine (7.5 g., 0.075 mole), 3.8 g. (0.015 mole) of ethyl-a-[-o-(1-pyrrolidinyl)phenoxy] acetate and 10 drops of 25% methanolic sodium methylate were heated in an oil bath at 140 C. for a total of 17 hours. From time to time, the bath was raised to 160 C. to distill out the ethanol formed. After cooling, pentane was added to the reaction mixture and a small quantity of insoluble material filtered off. The pentane filtrate was then evaporated down with the excess 3-dimethylaminopropylamine being distilled 011. The product remaining which boiled at 178182 C. at 0.005 mm. (n =1.5474), was identified as a-[o-(1-pyrrolidinyl)phenoxy]-N-(3-dimethylaminopropyl) acetamide.
EXAMPLE III A solution of 33.4 g. (0.2 m.) of ethyl bromoacetate in 50 mls. of acetone was slowly added to a stirred mixture of 27.4 g. (0.2 m.) of m-nitrophenol, 27.6 g. anhydrous potassium carbonate and 150 mls. of acetone. After refluxing and stirring for 7 hours, the solid was filtered 01f, solvent evaporated off from the filtrate and the residue distilled to give 41.9 g. (93%) of ethyI-Z-(m-nitrophenoxy)acetate. A solution of 41.9 g. (0.19 m.) of the ethyl 2 (m-nitrophenoxy)acetate in 208 mls. of ethanol with 0.3 g. of platinum oxide was hydrogenated in a Parr hydrogenator at an initial pressure of 3 atmospheres. Hy.- drogen uptake was complete (105%) after 70 minutes of shaking. After removal from the hydrogenator and filtration, the solvent was removed at diminished pressure, the residue taken up in dry ether and treated with .dry hydrogen chloride. Filtration yielded 38 g. melting at 1 25 135. Recrystallization from acetonitrile gave 33 g. of ethyl Z-(m-aminophenoxy) acetate hydrochloride. A mixture of 8.0 g. (0.034 m.) of the ethyl Z-(m-aminophenoxy) acetate hydrochloride and 5.4 g. (0.051 in.) of anhydrous sodium carbonate and 30 mls. of acetonitrile was added while a solution of 7.4 g. (0.034 m.) of 1,4-dibromo1 butane in 20 mls. of acetonitrile was slowly added. Stirring was continued while refluxing for 27 hours. tion, removal of solvent and distillation. gave 5.9 g. (70%) of product, boiling at 150-154 at 0.2 mm. The distillate solidified slowly on cooling to give a low melting Filtra- 14 solid identified as ethyl 2-(m-pyrrolidinylphenoxy) acetate. Anal.Calc. for C H NO N, 5.6. Found: N, 5.4.
EXAMPLE IV By following the procedure set forth in Example III, but using 1,5-dibromopentane in place of 1,4-dibromobutane, the corresponding piperidiny-l derivative, ethyl 2- (m-piperidinylphenoxy)acetate, was obt-ained.
EXAMPLE V Additional compounds were prepared in accordance with the procedure of Examples I and II. The melting points of representative compounds are listed in Table I:
Table I Compound No. (as listed above) Recrystallization Melting Solvent Point C.) 1
2 Acetonitrile 133-134 3 Hexane 61- 62 7 Ethanol 156 8 Hexane 96- 99 12 Isopropmol 134-137 13 do 109-111 17 ..(10 148-150 18 Hexane 101-102 19 do 113-116 20 do 78- 81 22 Ethanol 57- 58 23 Methanol 211 24 Ethanol 175 25 Hexane 97- 98 28 Ethanol 164 29 Heptane 33 Ethanol 161 4 34 Heptane 144 37 Hexane 88- 89 41 do 88- 89 42 do 63- 64 points and/or refractive indices of representative compounds are listed in Table II.
Table 11 Compound No. (as listed above) Boiling Pressure, o
Point, C. mm.
The compounds of this invention can be used to reduce the cholesterol level of blood either directly or preferably by incorporating into a hypocholesteremic composition.
Inaddition to the heterocyclic amino phenoxyacetic acid compound, the hypocholesteremic compositions of the or parenterally. By such methods these compositions have.
the ability to markedlyreduce the cholesterol level of blood in animals. The toxicity of these compounds is quite low, and the active ingredient can be administered in dosages adequate to obtain a therapeutic effect without adverse side effects. The concentration of the phenoxyacetic acid compound in these compositions is not in any way critical, but can be adjusted to meet the need. In general, the concentration for oral and parenteral administration will lie within about 1 to about 300 mg. per unit dosage, i.e., per cc. of solution or per tablet or capsule, depending upon the dosage regimen desired and the weight and hypocholesteremic state of the animal. Ordinarily, it is preferable to administer a composition having a low concentration of the active ingredient several times daily, as compared to a single daily dose having a relatively high concentration of the active ingredient, to achieve the total daily dosage required. The daily dosage is generally within the range of about 25 to about 300 mg. of acid compound.
In the process of the invention, the heterocyclic amino phenoxyacetic acid compound or mixture thereof in an appropriate amount to obtain a therapeutic effect is administered to the patient orally, parenterally or by any other appropriate method, and there results a hypocholesteremic response.
The examples illustrate various types of compositions coming within the invention for a variety of administration techniques.
EXAMPLE VII A composition of matter for oral administration, comprising ethyl o-(l-pyrrolidinyl)phenoxy acetate acid as the active ingredient in combination with a suitable carrier, was prepared by thoroughly mixing together 1000 grams of the active compound and 3500 grams of betalactose (milk sugar), passing the blended mixture through a No. 40 screen and filling the mix into gelatin capsules, 450 mg. per capsule, each capsule to contain 100 mg. of active ingredient.
EXAMPLE VIII A composition of matter for oral administration, in tablet form, comprising cyclohexyl (m-l-pyrrolidinyl) phenoxy isopropionate as the active ingredient in combination with a suitable carrier, was prepared by compounding the following ingredients into a tablet mix:
Grams Active ingredient 308 Sugar 308 Lactose 177 Starch 98 Dextrin 50 Talcum l Stearic acid 10 Starch paste q.s. to make 1000.
The above mix was comphessed into tablets, weighing approximately 325 mg., each tablet containing 100 mg. of active ingredient.
EXAMPLE IX A composition of matter for parenteral administration comprising m-(l-pyrrolidinyl) phenoxy methylacetamide as the active ingredient in combination with a liquid carrier having the following formula was prepared:
Grams Active ingredient 25 Sodium hydroxide 5.74 Benzyl alcohol 5 under Examples V, VI and VII may be made by including other substances having therapeutic properties which enhance the total therapeutic value of the heterocyclic amino phenoxyacetic acid compound by their additive or by a synergistic effect; the effect, if synergistic, will enhance the therapeutic value of the heterocyclic amino phenoxyacetic compound without increase in dosage. Thus, known therapeutic substances, such as aspirin or equivalent salicylate compound, may be added for their analgesic and anti-rheumatic effect, butazolidin or antipyrine or related compounds for their anti-pyretic and anti-phlogistic effects, hydrocortisone or prednisolone or one of its equivalent corticosteroids for their anti-rheumatic, antiinflammatory and anti-phlogistic effects. The combination of a heterocyclic amino phenoxyacetic acid compound with one or more of the above additive substances also serves the purpose of an additive effect.
If desired, other substances, such as ascorbic acid, vitamin K, thiamine, etc., may be added to the composition of matter in adequate dosage to exert their individual activity for therapeutic uses they are known to have.
If desired, the hypocholesteremic compositions can be sterilized and can contain auxiliary substances such as buffering lagents, stabilizing agents, wetting agents and emulsifying agents.
To illustrate the therapeutic utility of the compounds of this invention in reducing the cholesterol level of blood, normal adult guinea pigs were given subcutaneous doses corresponding to 30 mg./ kg. of the test compound at the beginning of the experiment, 24 hours later and finally, 40 hours later.
Blood samples Were drawn for the determination of serum cholesterol levels at the initiation of the experiment and at 48, and 72 hours thereafter.
The hypocholsteremic response is indicated in Table III.
In this table, the compound is identified by its number in the list above. The LD indicates the minimum dose which is lethal to mice when the compound is administered subcutaneously and is expressed in mg./kg. The dose is the dosage of the drug administered subcutaneously expressed mg./kg. under the schedule described above and the effect of the compound in reducing cholesterol is indicated by the percent reduction from the cholesterol level noted for the animal at the initiation of the experiment (percent 'hypocholesteremia).
Thus, if at the initiation of the experiment the noted cholesterol level was 80 mg. percent and at a subsequent interval, the noted cholesterol level was 60 mg. percent, this would be shown as 25% hypocholesteremia.
Table III HYPOCHOLESTEREMIC EFFECT OF REPRESENTATIVE COMPO UNDS Percent Hypoeho- L mM lesteremia Compound No. mg./kg.s.c.
48 hrs. 72 hrs.
'rapid and sustained overall hypocholesteremic response.
It is evident from Table III that the compounds of this invention show substantial hypocholesteremic activity at dosage levels substantially below the minimum lethal doses. Aconsiderable reduction of cholesterol levels is 17 obtained at substantially of the LD for many of the compounds.
Under clinical conditions the rapidity of the depression of cholesterol levels obtained in the tests reported above would not be required so that even smaller doses could be used, thereby increasing the margin of safety.
The compounds of this invention in addition to their hypocholesteremic activity are also useful intermediates in the production of other compounds and also have utility as muscle relaxants and anti-inflammatory agents.
We claim:
1. A compound selected from the group consisting of those having the formula wherein R is selected from the group consisting of hydrogen and lower alkyl, and
is selected from the group consisting of X-pyrrolidino, X- piperidino, X-hexamethyleneimino, X-morpholino, X-
'thiomorpholino, and X-oct-amethyleneimino, wherein X is selected from the group consisting of hydrogen, lower alkyl, hydroxy and acetyl; and the non-toxic acid addition salts and quaternary ammonium salts thereof.
2. A compound in accordance with claim 1 wherein is pyrrolidino.
3. A compound in accordance with claim 1 wherein References Cited by the Examiner UNITED STATES PATENTS is piperidino.
NICHOLAS S. RIZZO, Primary Examiner.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,218,328 November 16, 1965 Seymour L. Shapiro, deceased, by Florence M. Shapiro, as executrix, et a1.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 4, lines 44 to 50, formula (5) should appear as shown below instead of as in the patent:
O-CH C-OC H CH -CH column 7, lines 44 to 54, formula (30] should appear as shown below instead of as in the patent:
3 H 3 CH NHCH2CH2-CH2N /CH2- H2 I\\ column 10, lines 35 to 43, formula (52) should appear as shown below instead of as in the patent:
same column 10, lines 55 to 62, formula (54) should appear as shown below instead of as in the patent:
H -CH N CH H column 15, line 52, for "comphessed" read compressed Signed and sealed this 27th day of September 1966.
(SEAL) Attest:
ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents

Claims (2)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULA
3. A COMPOUND IN ACCORDANCE WITH CLAIM 1 WHEREIN
US259460A 1963-02-18 1963-02-18 Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof Expired - Lifetime US3218328A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US259460A US3218328A (en) 1963-02-18 1963-02-18 Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof
US489774A US3270024A (en) 1963-02-18 1965-07-23 Heterocyclic amino phenoxyacetic acid amides, acid addition salts, and quaternary ammonium salts thereof
US489773A US3270025A (en) 1963-02-18 1965-07-23 Heterocyclic amino phenoxyacetic esters; acid addition salts, and quaternary ammonium salts thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US259460A US3218328A (en) 1963-02-18 1963-02-18 Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof

Publications (1)

Publication Number Publication Date
US3218328A true US3218328A (en) 1965-11-16

Family

ID=22985045

Family Applications (1)

Application Number Title Priority Date Filing Date
US259460A Expired - Lifetime US3218328A (en) 1963-02-18 1963-02-18 Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof

Country Status (1)

Country Link
US (1) US3218328A (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4511714A (en) * 1982-03-02 1985-04-16 Nitrokemia Ipartelepek Herbicidal antidote compositions
US20050020481A1 (en) * 1998-04-01 2005-01-27 Bain Allan I. Ion channel modulating compounds and uses thereof
US20050026993A1 (en) * 2003-05-02 2005-02-03 Beatch Gregory N. Uses of ion channel modulating compounds
US20050070552A1 (en) * 2003-08-07 2005-03-31 Cardiome Pharma Corp. Ion channel modulating activity I
US20050209307A1 (en) * 2000-10-06 2005-09-22 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20060247300A1 (en) * 2003-10-31 2006-11-02 Cardiome Pharma Corp Aminocyclohexyl ether compounds and uses thereof
US20070099983A1 (en) * 2003-05-02 2007-05-03 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US20080004333A1 (en) * 2000-10-06 2008-01-03 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20080171785A1 (en) * 2004-11-08 2008-07-17 Cardiome Pharma Corp. Dosing Regimens For Ion Channel Modulating Compounds
US20090041841A1 (en) * 2003-05-02 2009-02-12 Cardiome Pharma Corp. Controlled release tablet formulations for the prevention of arrhythmias
US7507545B2 (en) 1999-03-31 2009-03-24 Cardiome Pharma Corp. Ion channel modulating activity method
US20090088464A1 (en) * 2004-04-01 2009-04-02 Cardiome Pharma Corp. Merged ion channel modulating compounds and Uses Thereof
US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2520673A (en) * 1949-03-22 1950-08-29 Polaroid Corp Acid salts of an n-acetyl-10-trimethylammoniumdihydrohomomeroquinene ethyl ester and their production
US2884426A (en) * 1954-08-05 1959-04-28 Thomae Gmbh Dr K Basic esters of mandelic acid and a process of making same
US2980585A (en) * 1958-09-11 1961-04-18 Stambul Rae Controlling the blood cholesterol level by administration of diiodotyrosine polypeptide
US3057777A (en) * 1957-10-28 1962-10-09 Lilly Co Eli Method of reducing cholesterol level of the blood

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2520673A (en) * 1949-03-22 1950-08-29 Polaroid Corp Acid salts of an n-acetyl-10-trimethylammoniumdihydrohomomeroquinene ethyl ester and their production
US2884426A (en) * 1954-08-05 1959-04-28 Thomae Gmbh Dr K Basic esters of mandelic acid and a process of making same
US3057777A (en) * 1957-10-28 1962-10-09 Lilly Co Eli Method of reducing cholesterol level of the blood
US2980585A (en) * 1958-09-11 1961-04-18 Stambul Rae Controlling the blood cholesterol level by administration of diiodotyrosine polypeptide

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4511714A (en) * 1982-03-02 1985-04-16 Nitrokemia Ipartelepek Herbicidal antidote compositions
US7101877B2 (en) 1998-04-01 2006-09-05 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7534790B2 (en) 1998-04-01 2009-05-19 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7875611B2 (en) 1998-04-01 2011-01-25 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20050192208A2 (en) * 1998-04-01 2005-09-01 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20050020481A1 (en) * 1998-04-01 2005-01-27 Bain Allan I. Ion channel modulating compounds and uses thereof
US20100029639A1 (en) * 1998-04-01 2010-02-04 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20070004718A1 (en) * 1998-04-01 2007-01-04 Cardiome Phama Corp. Ion channel modulating compounds and uses thereof
US7507545B2 (en) 1999-03-31 2009-03-24 Cardiome Pharma Corp. Ion channel modulating activity method
US8008342B2 (en) 2000-10-06 2011-08-30 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7057053B2 (en) 2000-10-06 2006-06-06 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20050209307A1 (en) * 2000-10-06 2005-09-22 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20100056603A1 (en) * 2000-10-06 2010-03-04 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20070190156A1 (en) * 2000-10-06 2007-08-16 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7259184B2 (en) 2000-10-06 2007-08-21 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US7524879B2 (en) 2000-10-06 2009-04-28 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20080004333A1 (en) * 2000-10-06 2008-01-03 Cardiome Pharma Corp. Ion channel modulating compounds and uses thereof
US20090041841A1 (en) * 2003-05-02 2009-02-12 Cardiome Pharma Corp. Controlled release tablet formulations for the prevention of arrhythmias
US20110118329A1 (en) * 2003-05-02 2011-05-19 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US20080188547A1 (en) * 2003-05-02 2008-08-07 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US8188140B2 (en) 2003-05-02 2012-05-29 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US7345086B2 (en) 2003-05-02 2008-03-18 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US8163938B2 (en) 2003-05-02 2012-04-24 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US20070254945A1 (en) * 2003-05-02 2007-11-01 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US20070099983A1 (en) * 2003-05-02 2007-05-03 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US20050026993A1 (en) * 2003-05-02 2005-02-03 Beatch Gregory N. Uses of ion channel modulating compounds
US20110004006A1 (en) * 2003-05-02 2011-01-06 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7820712B2 (en) 2003-05-02 2010-10-26 Cardiome Pharma Corp. Uses of ion channel modulating compounds
US7767830B2 (en) 2003-05-02 2010-08-03 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US20100120890A1 (en) * 2003-08-07 2010-05-13 Cardiome Pharma Corp. Ion channel modulating activity i
US7674820B2 (en) 2003-08-07 2010-03-09 Cardiome Pharma Corp. Ion channel modulating activity I
US20060135536A9 (en) * 2003-08-07 2006-06-22 Cardiome Pharma Corp. Ion channel modulating activity I
US20050070552A1 (en) * 2003-08-07 2005-03-31 Cardiome Pharma Corp. Ion channel modulating activity I
US8207219B2 (en) 2003-08-07 2012-06-26 Cardiome Pharma Corp. Ion channel modulating activity I
US20060247300A1 (en) * 2003-10-31 2006-11-02 Cardiome Pharma Corp Aminocyclohexyl ether compounds and uses thereof
US7345087B2 (en) 2003-10-31 2008-03-18 Cardiome Pharma Corp. Aminocyclohexyl ether compounds and uses thereof
US7977373B2 (en) 2004-04-01 2011-07-12 Cardiome Pharma Corp. Prodrugs of ion channel modulating compounds and uses thereof
US8058304B2 (en) 2004-04-01 2011-11-15 Cardiome Pharma Corp. Merged ion channel modulating compounds and uses thereof
US20090088464A1 (en) * 2004-04-01 2009-04-02 Cardiome Pharma Corp. Merged ion channel modulating compounds and Uses Thereof
US20080171785A1 (en) * 2004-11-08 2008-07-17 Cardiome Pharma Corp. Dosing Regimens For Ion Channel Modulating Compounds
US8263638B2 (en) 2004-11-08 2012-09-11 Cardiome Pharma Corp. Dosing regimens for ion channel modulating compounds

Similar Documents

Publication Publication Date Title
US3218328A (en) Heterocyclic amino phenoxyacetic acids, acid addition salts and quaternary ammonium salts thereof
US4093734A (en) Amino-benzoic acid amides
CH626611A5 (en)
CH630359A5 (en) METHOD FOR PRODUCING NEW AMINOALKYLHETEROCYCLES AND THEIR ACID ADDITION SALTS.
US3954872A (en) 1-(2',6'-Dimethyl-phenoxy)-2-amino-alkanes and salts thereof
US3950393A (en) Aminobenzyl-amides and salts thereof
CH633249A5 (en) METHOD FOR PRODUCING NEW POLYPRENYL DERIVATIVES.
US3852455A (en) 4-{8 4({60 hydroxybenzyl)piperidino{9 -4-fluorobutyrophenone derivatives as tranquilizers
US3772308A (en) Cyclopentanecetamides and cyclopentaneacetonitriles
US3272827A (en) Alpha-phenyl-beta-(2-furyl propionitrile compounds and a process of making same
US4395413A (en) Oxime ethers and pharmaceutical compositions containing the same
US3270024A (en) Heterocyclic amino phenoxyacetic acid amides, acid addition salts, and quaternary ammonium salts thereof
US2918407A (en) Anti-spasmodics specific for upper gastrointestinal pain and spasm
US4096259A (en) Non-amphetaminic psychostimulating compositions of 1,4-disubstituted piperazines
US3081302A (en) Certain-p-acetaminophenoxyacetamido derivatives
US3166562A (en) Novel nicotinic acid phenyl-ethylamides and process for preparing them
US3054794A (en) Process for preparing 3-(aminoalkyl)-oxazolidine-2, 4-diones
US3882174A (en) Amides of 4-(4{40 -biphenylyl)-butyric acid and its 4-hydroxy and 4-oxo derivatives
US4139621A (en) N-(4-substituted-3,5-dichloro-phenyl)-piperazines
US3860581A (en) Preparation of 1,4-benzodiazepines
DE1568929A1 (en) Amino-substituted indanes and tetralins and processes for their preparation
US4101671A (en) Aminobenzyl-amines and salts thereof
US4031244A (en) Pharmaceutical compositions containing a 1-(2,6-dimethyl-phenoxy)-2-amino-alkane and method of use
US4117122A (en) 11-aminoalkylmorphanthridin-11-ols
US3056792A (en) Unsymmetrical 1, 3-diamino-2-propanols