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US3105854A - Meta-substituted phenoxyethylamines - Google Patents

Meta-substituted phenoxyethylamines Download PDF

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US3105854A
US3105854A US841688A US84168859A US3105854A US 3105854 A US3105854 A US 3105854A US 841688 A US841688 A US 841688A US 84168859 A US84168859 A US 84168859A US 3105854 A US3105854 A US 3105854A
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Druey Jean
Schenker Karl
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BASF Corp
Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention relates to the manufacture of amines of the formula of theformula O-(CHh-N in which R to R have the meanings given above but contain together at least 5 carbon atoms, but preferably 7 to carbon atoms, and n is a number from 2 to 4, and salts thereof, and more particularly to compounds of the and their salts, in which R and R have the meanings given above and contain together at least 5 carbon atoms, but preferably 7 to 10 carbon atoms.
  • the hydrocarbon radical of aliphatic character, R with 3 to 7 carbon atoms is 'for example an alkyl group, such as propyl, isopropyl, butyl, secondary butyl, pentyl, isopentyl, hexyl or heptyl, a cycloalkyl radical such as cyclopentyl or cyclohexyl, or an unsaturated radical, such as allyl, cyclopentenyl or cyclohexenyl.
  • R is advantageously also of aliphatic character, more especially an aliphatic or cyc-loaliphatic hydrocarbon radical having 1 to 10 carbon atoms, and especially 3 to 6 carbon atoms, preferably a straight or branched lower alkyl or alkenyl radical, elg. methyl, ethyl, propyl, isopropyl, allyl, methallyl, butyl, secondary butyl, pentyl or hexyl, or also a cyclo alkyl radical, e.g. cyclopentyl or cyclohexyl.
  • R can have the same meanings, but advantageously stands for hydrogen. Together with the nitrogen atom R and R can represent for example a pyrrolidino or piperidino radical.
  • the new compounds are useful, local anaesthetics and are thus intended to be used as medicaments.
  • a preferred modification of this process consists in converting in compounds of the formula 0 R1 11 in which n has the meaning given above and X represents a radical convertible directly or in stages into the group X directly or in stages into the latter group.
  • the preferred form of the process consists in reacting a compound of the Formula II in which X represents a radical exchangeable [for an amino group, with an amine of the formula in which R has the meaning given above and Y represents a radical splittable by hydrolysis or hydrogenolysis, Y is split in the manner indicated.
  • Y is, for example, an acyl radical, eg.
  • lower alkanoyl, anoyl or aryl sulfonyl which can be split in the customary manner by hydrolysis, for example with a dilute alkali, or an arylmethyl or arylmethyloxyca-nbonyl radical, such as a carbobenzoxy radical which may be removed by hydrogen-olysis, for example by catalytically activated hydrogen in the presence of a palladium or platinum catalyst.
  • the tertiary amines of this invention can be prepared in such a way that in compounds of the formula wherein R has the meaning given above, the radical in which R has the meaning given above is introduced 3,1 3 directly in a customary manner erg. by reaction with a reactive ester of an alcohol of the itormula ITO-(CH2) n-N such as a corresponding halide.
  • the new compounds are obtained in the form of their bases or salts.
  • the tree amine bases can be obtained from the salts in a manner known per se. Again, from these amine ibases it is possible to obtain salts by reaction with acids which are suitable for forming therapeutically usable salts, such as, for instance salts of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid, propionic acid, oxalic acid, malonic acid, tartaric acid, succinic acid, malic acid, methane-sul fonic acid, ethane-sulfonic acid, hydroxyethane-sulfonic acid, lbenzeneor toluenesulfionic acid or of therapeutically, active acids.
  • acids which are suitable for forming therapeutically usable salts, such as, for instance salts of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic
  • the starting materials are known or can he produced by methods known per se. 7 n
  • the new compounds may be used as medicaments, for example in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, topical or parenteral admin-istnation.
  • a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, topical or parenteral admin-istnation.
  • the carrier there are used substances which do not react with the new compounds, such as, for example, water, gelatine, lactose, stanoh, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyal-kylene glycols, white petroleum jelly, chloesterol or other known carriers for medicaments.
  • the pharmaceutical preparations may be in the form, for example, of tablets, dragees or in liquid form as solutions, suspensions or emulsions.
  • auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or bufiers. They may also contain other therapeutically valuable substances. T'he preparations are produced by conventional methods.
  • Example 1 13.6 grams (0.05 mol) offi-(meta-mbutoxyphenoxy)- ethylbromide and 7.3 grams (0.1 mol) of n butylamine are heated for 1% hours at 120 C. After cooling, the reaction mixture is taken up in 100 cc. of chloroform and the solution is extracted with 25 cc. of 2 N-sodium hydroxide solution and then with water.
  • Example 2 11.0 grams (0.043 mol) of fi-(meta-n-propoxyphenoxy)- ethyl bromide and 11.8 grams (0.2 mol) of n-propylamine are refluxed for 12 hours in 20 cc. of ethanol, evaporated in a water-jet vacuum, treated with 50 cc. of N-sodium hydroxide solution and extracted with chloroform.
  • the 13-(meta-n-propoxyphenoxy)-ethyl bromide used as 1 starting material is prepared as follows:
  • Example 3 11.0 grams (0.043 mol) of B-(meta-n-propoxyphenoxy)- ethyl-bromide and 14.6 grams (0.2 mol) of isobutylamine yield by the process described in Example 2, the N-[fi- (meta-n-propoxyphenoxy)ethyl]N-isobutylarnine of the formula CH3CHaCHz( as a yellow oil which is then converted as described in Example 1 into its hydrochloride which on recrystallization from ethanol-ethyl acetate is obtained in colorless crystals melting at 139140 C.
  • Example 4 11.0 grams (0.043 mol) of B-(rneta-n-propoxyphenoxy)- ethyl-bromide and 17.4 grams (0.2 mol) of n-pentylarnine yield by the process described in Example 2 N-[B-(metan-propoxyphenoxy)-ethyl]-N-pentylamine of the formula 1 om-om-onho which is converted into its hydrochloride. The latter product is recrystallized from ethanol-ethyl acetate to form colorless crystals melting at 148-150 C.
  • Example 5 A mixture of 12.0 grams (0.044 mol) of B-(meta-nbutoxy-phenoxy)-ethylbromide and 9.0 grams (0.2 mol) of ethylamine is treated with 50 cc of ethanol and heated for 14 hours at 100 C. in a closed tube. Working up as described in Example 2 yields N-[fi-(meta-n-butoxyphenoxy) et-hylJ-N-ethylamine of the formula Its hydrochloride melts at 160-162 C. after having been recrystallized from ethanol-ethyl acetate.
  • Example 6 12.0 grams (0.044 mol) of B-(metam-butoxyphenoxy)- ethyl bromide and 11.8 grams (0.02 mol) of n-propylamine yield by the process described in Example 2 N- [B-(meta-n-butoxyphenoxy)ethyl] N-n propylamine of the formula 10.0 grams (0.037 mol) of fi-(mono-n-butoxyphenoxy)- ethyl-bromide and 14.6 grams (0.2 mol) of diethylamine are refluxed for 12 hours; working up in the manner described in Example 2 yields N-[p-(meta-n-butoxyphenoxy)-ethyl]NzN-diethylarnine of the formula CHaCHz-CH2CHz-( in the form of a colorless oil.
  • the hydrochloride prepared in the usual manner, yields on crystallization from ethyl acetate colorless flakes melting at 109'-110 C.
  • Example 8 12.0 grams (0.044 mol) of fi-(rneta-n-butoxyphenoxy)- ethyl-bromide and 14.2 grams (0.2 mol) of methallylamine yield by the process described in Example 2 N-[[3- (meta-n-butoxyphen-oxy) ethyl]N-methallylamine of the formula
  • Example 9 6.1 grams (0.022 mol) of B-(meta-n-butoxyphenoxy)- ethyl-bromide and 7.3 grams (0.1 mol) of isobutylamine are reacted as described in Example 2 to yield N-[fl- (meta-n-butoxyphenoxy)ethyl] N-isobutylarnine of the formula @o-ormoman-r-om-og as a brownish oil. From ethyl acetate the hydrochloride is obtained in colorless crystals melting at 137-138 C.
  • Example 10 8.0 grams (0.029 mol) of fi-(meta-n-butoxyphenoxy) ethyl-bromide and 14.6 grams (0.2 mol) of tertiary butylamine yield by the process described in Example 2, N- [,8-(meta-n-butoxyphenoxy)-ethyl]-N-tertiary butylamine of the formula CH3 CI-I3CHz-CH2OHzO as a pale-brown oil.
  • the hydrochloride prepared in the usual manner, melts at 108 C. after having been recrystallized from ethyl acetate-ether.
  • Example 11 8.0 grams (0.029 mol) of B-(meta-n-butoxyphenoxy)- ethyl-bromide and 17.4 grams 0.2 mol) of n-pentylamine yield by the process described in Example 2, N-[fi-(metan-butoxyphenoxy)-ethyl]-N-n-pentylamine of the forits hydrochloride melts at 142-144 C. after recrystallization from ethyl acetate.
  • Example 12 12.5 grams (0.046 mol) of ,B-(meta-isobutoxyphenoxy)- ethyl bromide and 11.8 grams (0.2 mol) of n-propylamine yield by the process described in Example 2, N-[fi- 7 (meta-isobutoxyphenoxy)-ethyl] -N-n-propylamine of the formula Its hydrochloride is obtained on recrystallization from ethyl acetate-ethanol in colorless needles melting at 138- The (meta-isobutoxyphenoxy)ethyl bromide used as starting material is prepared as follows:
  • Example 13 12.5' grams (0.046 mol) of B-(meta-isobutoxyphenoxy)-ethy1bromide and 20 cc. of diethylamine yield by the process described in Example 2, N-[,8(meta-isobutoxyphenoxy)-ethyl]-N:N-diethylarnine of the formula Its hydrochloride forms colorless crystals melting at 104- 106 C. after having been recrystallized from ethyl acetate.
  • Example 14 The reaction analogous to that described in Example 20f 12.5 grams (0.046 mol) of B-(meta-isobutoxyphenoxy)-ethyl-bromide with 20 cc. of n-butyl-amine yields N- [/8-(meta-isobutoxyphenoxy) ethyl] -N-n-buty1amine of the formula On recrystallization from ethyl acetate its hydrochloride melts at 136-138" C.
  • Example 15 12.5 grams (0.046 mol) of fl-(meta-isobutoxyphenoxy)- ethyl-bromide and cc. of isobutylamine yield by the process described in Example 2, N-[B-(meta-isobutoxyphenoxy)-et-hyl]-Nisobu-tylamine of the formula as a brownish oil. On recrystallization from ethyl ace tate its hydrochloride forms colorless needles melting at 140-442 C.
  • Example 16 12.0 grams (0.043 mol) of B-(meta-n-pentyloxyphenoxy)-ethylbromide and 11.8 grams (0.2 mol) of n-propyb amine yield by the process described in Example 2, N-
  • Example 17 The reaction analogous to that described in Example 2 of 12.0 grams (0.043 mol) of B-(meta-n-pcntyloxyphem oxy)ethylbromide with 20 ccof diethylamine yields N- [B (meta n pentyloxyphenoxy)-ethyl]-N:N-diethy1a-- mine of the formula v OHQCH;
  • Example 19 12.0 grams (0.043 mol) of fi-( meta-napentyloxyphenoxy)-cthylbromide and 14.6 grams (0.2 mol) of isobutylamine yield by the process described in Example 2, N [f3 (meta-n-pentyloxyphenoxy)-ethyl]-N-isobutyl amine of the formula V o-om-om-Nn-om-ofi V CH3(CH2)4O V 7 Its hydrochloride forms on recrystallization from ethanolethyl acetate colorless crystals melting at 135-136" C.
  • Example 20 p 20.0 grams (0.065 mol) of N-[B-(meta-n-butoxyphen oxy)ethyl]-N-acetyl-N-butylamine boiling at 132-134 C. under 0.04 mm. of pressure which can be obtained; for example, by reacting the sodium salt of resorcinol monobutyl ether with N-(fl-chloro-ethyl)-N-acetyl-butylamine in absolute benzene, are boiled under reflux overnight with 30 cc. of methanol and 30 cc. of'2 N-sodium hydroxide solution. After cooling, the mixture is acidified with cc.
  • N-[fi- (meta-n-butoxyphenoxy)-ethy1] -N-butylamine of the formula is a colorless oil boiling at 123-126" C. under 0.05 mm. of :pressure. Its hydrochloride crystallizes from a mixture of ethanol and ether in the form of colorless crystals melting at 157-158 C. It is identical in every respect with the hydrochloride described in Example 1.
  • Example 21 27.2 grams (0.10 mol) of [3-(meta-n-butoxyphenox-y)- ethyl bromide are dissolved in 30 cc. of ethanol; 12.0 grams (0.10 mol) of N-methyl-benzylamine are added and the whole is heated under reflux for 12 hours. After cooling, 150 cc. of Water are added, extraction is carried out with methylene chloride after adding 50 cc. of 2 N- sodium hydroxide solution, and the extracts are washed neutral with water.
  • N-[fi- (meta n butoxy-phenoxy)-ethyl]-N-methyl-N-benzylamine of the formula CH3 CHr-(CHQa-O remains as a yellow, highly viscous oil which is debenzylated catalytically.
  • the base is dissolved in 200 cc. of ethyl acetate and the solution agitated in the presence of 0.5 gram of palladium charcoal Pd) in a hydrogen atmosphere. After 2.1 liters of hydrogen have been taken up, the absorption of hydrogen ceases. The catalyst is filetered off and the solvent evaporated. The residue is distilled in a high vacuum.
  • N-[B-(metan-butoxyphenoxy)-ethyl]-N-methylamine of the formula OHs(CHz)3-O is a colorless oil boiling at 110-112 C. under 0.08 mm. of :pressure.
  • the hydrochloride fonrns colorless crystals melting at 138-139 C.
  • Example 22 From 16.0 grams (0.062 mol) of B-(meta-allyoxyphenoxy)-ethyl bromide and 30 cc. of n-butylamine there is obtained by the method described in Example 2 N-[B- (meta-allyloxyphenoxy)-ethyl]-N-n-butylamine of the a s0 is a yellowish liquid boiling at 102-110 C. under 0.08 mrn. of pressure.
  • Example 24 83 grams (0.50 mol) of meta-n-butoxyphenol, 110 grams (0.59 mol) of N-(y-chloropropyl)-diethylamine hydrochloride and 208 grams (1.50 mols) of anhydrous potassium carbonate are heated under reflux in 800 cc. of acetone for 15 hours with vigorous stirring. After cooling, the inorganic constituents are filtered off, the filtrate evaporated and the residue dissolved in chloroform. in order to remove the starting phenol the reaction solution is extracted several times wi-th dilute sodium hydroxide solution. The chloroform solution is finally washed neutral with water, dried over sodium sulfate and the solvent evaporated.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

United States Patent 3,105,854 META-SUBSTITUTED HENGXYETHYLAMINES Jean Druey, Riehen, and Karl Schenlrer, Basel, Switzerland, assignors to Cilia Corporation, a corporation of Delaware No Drawing. Filed Sept. 23, 1159, Ser. No. 841,688
Claims priority, application Switzerland Nov. 6, 1958 21 Claims. (Ci. zen-570.7)
The present invention relates to the manufacture of amines of the formula of theformula O-(CHh-N in which R to R have the meanings given above but contain together at least 5 carbon atoms, but preferably 7 to carbon atoms, and n is a number from 2 to 4, and salts thereof, and more particularly to compounds of the and their salts, in which R and R have the meanings given above and contain together at least 5 carbon atoms, but preferably 7 to 10 carbon atoms.
The hydrocarbon radical of aliphatic character, R with 3 to 7 carbon atoms is 'for example an alkyl group, such as propyl, isopropyl, butyl, secondary butyl, pentyl, isopentyl, hexyl or heptyl, a cycloalkyl radical such as cyclopentyl or cyclohexyl, or an unsaturated radical, such as allyl, cyclopentenyl or cyclohexenyl. R is advantageously also of aliphatic character, more especially an aliphatic or cyc-loaliphatic hydrocarbon radical having 1 to 10 carbon atoms, and especially 3 to 6 carbon atoms, preferably a straight or branched lower alkyl or alkenyl radical, elg. methyl, ethyl, propyl, isopropyl, allyl, methallyl, butyl, secondary butyl, pentyl or hexyl, or also a cyclo alkyl radical, e.g. cyclopentyl or cyclohexyl. R can have the same meanings, but advantageously stands for hydrogen. Together with the nitrogen atom R and R can represent for example a pyrrolidino or piperidino radical.
The new compounds, more especially those of the forin which R stands for a butyl or pentyl radical and R for methyl or ethyl or, more preferred for a propyl or bu'tyl radical, as well as their salts are useful, local anaesthetics and are thus intended to be used as medicaments. Special mention deserve in this connection N-[B-(meta-npentyloxy-phenoxy) -ethyl] -N-met.hyl amine, N- 8- (metan-pentyloxyphenoxy)-ethyl]-N-isobutylarnine and N [fl- (meta-n butoxyphenoxy)-ethyl]-N-n butylamine as well as their salts.
3,ld5,854 Patented Get. 1, 1963 The new amines are obtained by customary methods. It is of advantage to proceed in such a way that in phenol ethers of the formula )34 (I) in which n and R have the meanings given above and X stands for a radical convertible into the group in which R and R have the meanings given above, X is converted into the latter group.
A preferred modification of this process consists in converting in compounds of the formula 0 R1 11 in which n has the meaning given above and X represents a radical convertible directly or in stages into the group X directly or in stages into the latter group.
The preferred form of the process consists in reacting a compound of the Formula II in which X represents a radical exchangeable [for an amino group, with an amine of the formula in which R has the meaning given above and Y represents a radical splittable by hydrolysis or hydrogenolysis, Y is split in the manner indicated. Y is, for example, an acyl radical, eg. lower alkanoyl, anoyl or aryl sulfonyl which can be split in the customary manner by hydrolysis, for example with a dilute alkali, or an arylmethyl or arylmethyloxyca-nbonyl radical, such as a carbobenzoxy radical which may be removed by hydrogen-olysis, for example by catalytically activated hydrogen in the presence of a palladium or platinum catalyst.
Finally, the tertiary amines of this invention can be prepared in such a way that in compounds of the formula wherein R has the meaning given above, the radical in which R has the meaning given above is introduced 3,1 3 directly in a customary manner erg. by reaction with a reactive ester of an alcohol of the itormula ITO-(CH2) n-N such as a corresponding halide.
The above reactions are carried out in the usual manner, in the presence or absence of a diluent and/or condensing agent, at a low, ordinary or raised temperature, under atmospheric or superatmospheric pressure.
Depending on the method of working, the new compounds are obtained in the form of their bases or salts. The tree amine bases can be obtained from the salts in a manner known per se. Again, from these amine ibases it is possible to obtain salts by reaction with acids which are suitable for forming therapeutically usable salts, such as, for instance salts of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic acid, propionic acid, oxalic acid, malonic acid, tartaric acid, succinic acid, malic acid, methane-sul fonic acid, ethane-sulfonic acid, hydroxyethane-sulfonic acid, lbenzeneor toluenesulfionic acid or of therapeutically, active acids.
The starting materials are known or can he produced by methods known per se. 7 n
The new compounds may be used as medicaments, for example in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, topical or parenteral admin-istnation. For making the carrier there are used substances which do not react with the new compounds, such as, for example, water, gelatine, lactose, stanoh, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyal-kylene glycols, white petroleum jelly, chloesterol or other known carriers for medicaments. The pharmaceutical preparations may be in the form, for example, of tablets, dragees or in liquid form as solutions, suspensions or emulsions. If desired, they are sterilized and/or contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or bufiers. They may also contain other therapeutically valuable substances. T'he preparations are produced by conventional methods.
The following examples illustrate the invention:
Example 1 13.6 grams (0.05 mol) offi-(meta-mbutoxyphenoxy)- ethylbromide and 7.3 grams (0.1 mol) of n butylamine are heated for 1% hours at 120 C. After cooling, the reaction mixture is taken up in 100 cc. of chloroform and the solution is extracted with 25 cc. of 2 N-sodium hydroxide solution and then with water. solution is dried over anhydrous sodium sulfate and then evaporated in a water-jet vacuum, leaving N-[B-(meta-nhutoxy-phenoxy)-ethyl]-N-n-butylaimine as a yellow oil which is neutralized with a 2 N-solutio-n of hydrogen chloride in ethyl acetate. The solution is evaporated and the resulting hydrochloride is twice recrystallized from ethanol-ether. The product is obtained in colorless crystals melting at 157-15 8 C.; it corresponds to the formula The j3-(meta-n butoxyphenoxy)ethyl bromide used as starting material can :be prepared as follows:
A solution of 83 grams (0.5 mol) of meta-butoxyphenol in 100 cc. of absolute ethanol is run into a solution of 11.5 grams (0.5 mol) of sodium in 250 cc. of absolute ethanol. The mixture is cooled to C. and mixed with 282 grams 1.5 mob) of ethylene bromide. The content of the flask is refluxed with vigorous stirring until it gives a neutral reaction (2-3 hours), then cooled and the so: dium bromide formed is filtered off and the filtrate is The chlorofonmic sulfate. V tilled in a high vacuum, ,9-(meta-n-propoxyphenoxy)- evaporated in a water-jet vacuum. The residue is taken up in 200 cc. of chloroform, extracted twice with 50 cc.
of 2 N-sodium hydroxide solution on each occasion, and
QHa- I)a-O in the form of a pale-yellow oil which boils at 157460 C. under 12 mm. Hg pressure. 7
Example 2 11.0 grams (0.043 mol) of fi-(meta-n-propoxyphenoxy)- ethyl bromide and 11.8 grams (0.2 mol) of n-propylamine are refluxed for 12 hours in 20 cc. of ethanol, evaporated in a water-jet vacuum, treated with 50 cc. of N-sodium hydroxide solution and extracted with chloroform.
Evaporation of the chloroformic extracts yields N-[fi- -(meta-n-propoxyphenoxy)-ethyl]-N-n-propyl-amine of the formula Qo-cmcnrun-om-om-om OHa-CHz-CH'ras a yellowish oil which'is directly converted into the hydrochloride by neutralization with hydrochloric acid in ethyl acetate. On recrystallization from ethanol-ethyl acetate it forms colorless crystals melting at 148l50 C.
The 13-(meta-n-propoxyphenoxy)-ethyl bromide used as 1 starting material is prepared as follows:
83.8 grams (0.55 mol) of resorcmol-mono-n-propyl' ether are added to a solution of 12.8 grams (0.56 mol) of sodium in 400 cc. of ethanol. the boil and 310 grams (1.65 mols) of ethylene bromide are run in with vigorous stirring. The contents of the flask are then refluxed until it gives a neutral reaction (2-3 hours),.cooled to 0 C., the precipitated sodium bromide is filtered oil, and the filtrate is evaporated in'a water-jet vacuum. The residue is taken up in 200 cc. of chloroform, extracted twice with 50 cc. of 2 N-sodium hydroxide solution on each occasion, washed with water until it is neutral and then dried over anhydrous sodium The solvent is removed and the residue is disethylbromide or the formula OOH2CH2Br is an almost colorless oil boiling at 75-83 C. under a pressure of 0.02 mm. Hg.
The new resorcinol ethers used as starting material in this example and in the following examples are obtained in the following manner:
A solution of grams (1 mol) of resorcinol in 300 cc. of ethanol'is run into a solution of 23 grams (1 mol) of sodium in 400 cc. of ethanol. The mixture is stirred for 30 minutes, 200 grams (1.18 mols) of n-propyl iodide are added, and the whole is refluxed with stirring for 3 hours. The solvent is evaporated, and the darkcolored residue is taken up in chloroform, the chloroformic solution is extracted with dilute hydrochloric acid mol) of sodium and 110 grams (1.0 mol) of resorcinol The whole is heated to and carrying out the reaction in 400 cc. of ethanol, yield by reaction with 165 grams (1.2 rnols) of isobutylbromide the meta-isobutoxyphenol as a colorless liquid boiling at 8087 C. under a pressure of 0.06 mm. Hg.
When 110 grams (1.0 mol) of resorcinol are added to a solution of 23 grams (1.0 mol) of sodium in 400 cc. of ethanol, and the reaction described above is performed with 180 grams (1.0 mol) of n-amylbromide, metapentyl-oxyphenol is obtained; it boils at 100-105 C. under a pressure of 0.05 mm. Hg.
Finally, in the same manner by reacting 110 grams (1.0 mol) of resorcinol with 23 grams (1.0 mol) of sodium and then with 145 grams (1.20 mols) of allyl bromide there is obtained meta-allyloxyphenol boiling at 145150 under a pressure of 12 mm. Hg.
Example 3 11.0 grams (0.043 mol) of B-(meta-n-propoxyphenoxy)- ethyl-bromide and 14.6 grams (0.2 mol) of isobutylamine yield by the process described in Example 2, the N-[fi- (meta-n-propoxyphenoxy)ethyl]N-isobutylarnine of the formula CH3CHaCHz( as a yellow oil which is then converted as described in Example 1 into its hydrochloride which on recrystallization from ethanol-ethyl acetate is obtained in colorless crystals melting at 139140 C.
Example 4 11.0 grams (0.043 mol) of B-(rneta-n-propoxyphenoxy)- ethyl-bromide and 17.4 grams (0.2 mol) of n-pentylarnine yield by the process described in Example 2 N-[B-(metan-propoxyphenoxy)-ethyl]-N-pentylamine of the formula 1 om-om-onho which is converted into its hydrochloride. The latter product is recrystallized from ethanol-ethyl acetate to form colorless crystals melting at 148-150 C.
Example 5 A mixture of 12.0 grams (0.044 mol) of B-(meta-nbutoxy-phenoxy)-ethylbromide and 9.0 grams (0.2 mol) of ethylamine is treated with 50 cc of ethanol and heated for 14 hours at 100 C. in a closed tube. Working up as described in Example 2 yields N-[fi-(meta-n-butoxyphenoxy) et-hylJ-N-ethylamine of the formula Its hydrochloride melts at 160-162 C. after having been recrystallized from ethanol-ethyl acetate.
Example 6 12.0 grams (0.044 mol) of B-(metam-butoxyphenoxy)- ethyl bromide and 11.8 grams (0.02 mol) of n-propylamine yield by the process described in Example 2 N- [B-(meta-n-butoxyphenoxy)ethyl] N-n propylamine of the formula 10.0 grams (0.037 mol) of fi-(mono-n-butoxyphenoxy)- ethyl-bromide and 14.6 grams (0.2 mol) of diethylamine are refluxed for 12 hours; working up in the manner described in Example 2 yields N-[p-(meta-n-butoxyphenoxy)-ethyl]NzN-diethylarnine of the formula CHaCHz-CH2CHz-( in the form of a colorless oil. The hydrochloride, prepared in the usual manner, yields on crystallization from ethyl acetate colorless flakes melting at 109'-110 C.
CHz-CH;
Example 8 12.0 grams (0.044 mol) of fi-(rneta-n-butoxyphenoxy)- ethyl-bromide and 14.2 grams (0.2 mol) of methallylamine yield by the process described in Example 2 N-[[3- (meta-n-butoxyphen-oxy) ethyl]N-methallylamine of the formula Example 9 6.1 grams (0.022 mol) of B-(meta-n-butoxyphenoxy)- ethyl-bromide and 7.3 grams (0.1 mol) of isobutylamine are reacted as described in Example 2 to yield N-[fl- (meta-n-butoxyphenoxy)ethyl] N-isobutylarnine of the formula @o-ormoman-r-om-og as a brownish oil. From ethyl acetate the hydrochloride is obtained in colorless crystals melting at 137-138 C.
Example 10 8.0 grams (0.029 mol) of fi-(meta-n-butoxyphenoxy) ethyl-bromide and 14.6 grams (0.2 mol) of tertiary butylamine yield by the process described in Example 2, N- [,8-(meta-n-butoxyphenoxy)-ethyl]-N-tertiary butylamine of the formula CH3 CI-I3CHz-CH2OHzO as a pale-brown oil. The hydrochloride, prepared in the usual manner, melts at 108 C. after having been recrystallized from ethyl acetate-ether.
Example 11 8.0 grams (0.029 mol) of B-(meta-n-butoxyphenoxy)- ethyl-bromide and 17.4 grams 0.2 mol) of n-pentylamine yield by the process described in Example 2, N-[fi-(metan-butoxyphenoxy)-ethyl]-N-n-pentylamine of the forits hydrochloride melts at 142-144 C. after recrystallization from ethyl acetate.
Example 12 12.5 grams (0.046 mol) of ,B-(meta-isobutoxyphenoxy)- ethyl bromide and 11.8 grams (0.2 mol) of n-propylamine yield by the process described in Example 2, N-[fi- 7 (meta-isobutoxyphenoxy)-ethyl] -N-n-propylamine of the formula Its hydrochloride is obtained on recrystallization from ethyl acetate-ethanol in colorless needles melting at 138- The (meta-isobutoxyphenoxy)ethyl bromide used as starting material is prepared as follows:
'75 .0 grams (0.45 mol) of meta-isobutoxyphenol are treated with a solution of 10.4 grams (0.45 mol) of sodium in 400 cc. of ethanol for conversion into the sodium salt which is then converted with 255 grams (1.35 mols) of ethylene bromide, as described in Example 2, into the {3-(meta-isobutoxypheuoxy)-ethyl-br0mide of the formula G a which is obtained in the form of a pale-yellow oil boiling at 82-90 C. under a pressure of 0.06 mm. Hg.
Example 13 12.5' grams (0.046 mol) of B-(meta-isobutoxyphenoxy)-ethy1bromide and 20 cc. of diethylamine yield by the process described in Example 2, N-[,8(meta-isobutoxyphenoxy)-ethyl]-N:N-diethylarnine of the formula Its hydrochloride forms colorless crystals melting at 104- 106 C. after having been recrystallized from ethyl acetate.
Example 14 The reaction analogous to that described in Example 20f 12.5 grams (0.046 mol) of B-(meta-isobutoxyphenoxy)-ethyl-bromide with 20 cc. of n-butyl-amine yields N- [/8-(meta-isobutoxyphenoxy) ethyl] -N-n-buty1amine of the formula On recrystallization from ethyl acetate its hydrochloride melts at 136-138" C.
Example 15 12.5 grams (0.046 mol) of fl-(meta-isobutoxyphenoxy)- ethyl-bromide and cc. of isobutylamine yield by the process described in Example 2, N-[B-(meta-isobutoxyphenoxy)-et-hyl]-Nisobu-tylamine of the formula as a brownish oil. On recrystallization from ethyl ace tate its hydrochloride forms colorless needles melting at 140-442 C.
Example 16 12.0 grams (0.043 mol) of B-(meta-n-pentyloxyphenoxy)-ethylbromide and 11.8 grams (0.2 mol) of n-propyb amine yield by the process described in Example 2, N-
[(3-(meta-n-pentyloxyphenoxy) -ethyl]-N-n propylaminc of the formula forms a colorless oil boiling at 102-112 C. under a pressure of 0.08 mm. Hg.
Example 17 The reaction analogous to that described in Example 2 of 12.0 grams (0.043 mol) of B-(meta-n-pcntyloxyphem oxy)ethylbromide with 20 ccof diethylamine yields N- [B (meta n pentyloxyphenoxy)-ethyl]-N:N-diethy1a-- mine of the formula v OHQCH;
OCH2CHr-N Its hydrochloride forms on recrystallization from ethanolethyl acetate colorless hydroscopic crystals melting at Example 18 10.0 grams (0.035 mol) of B-(meta-n-pentyloxyphenoxy)-ethylbromide and 14.5 grams (0.2 mol) of nbutylamine yield by the process described in Example 2, N [B-(meta-n pentyloxyphenoxy)-ethyl]-N-n-butylamine of the formula -OC HrUHa-NH-Ciir-OfirCHrCHa (inhalant- 7 Its hydrochloride melts at 151153 C. after recrystallization from methanol-ethyl acetate.
Example 19 12.0 grams (0.043 mol) of fi-( meta-napentyloxyphenoxy)-cthylbromide and 14.6 grams (0.2 mol) of isobutylamine yield by the process described in Example 2, N [f3 (meta-n-pentyloxyphenoxy)-ethyl]-N-isobutyl amine of the formula V o-om-om-Nn-om-ofi V CH3(CH2)4O V 7 Its hydrochloride forms on recrystallization from ethanolethyl acetate colorless crystals melting at 135-136" C.
Example 20 p 20.0 grams (0.065 mol) of N-[B-(meta-n-butoxyphen oxy)ethyl]-N-acetyl-N-butylamine boiling at 132-134 C. under 0.04 mm. of pressure which can be obtained; for example, by reacting the sodium salt of resorcinol monobutyl ether with N-(fl-chloro-ethyl)-N-acetyl-butylamine in absolute benzene, are boiled under reflux overnight with 30 cc. of methanol and 30 cc. of'2 N-sodium hydroxide solution. After cooling, the mixture is acidified with cc. of 2 N-hydrochloric acid and the neutral products are removed by extraction with ether. The aqueous phase is agitated with active charcoal and, after filtering, rendered alkaline with concentrated ammonia. The precipitating base is taken up in chloroform and, after distilling off the solvent, is distilled in a high vacuum. N-[fi- (meta-n-butoxyphenoxy)-ethy1] -N-butylamine of the formula is a colorless oil boiling at 123-126" C. under 0.05 mm. of :pressure. Its hydrochloride crystallizes from a mixture of ethanol and ether in the form of colorless crystals melting at 157-158 C. It is identical in every respect with the hydrochloride described in Example 1.
Example 21 27.2 grams (0.10 mol) of [3-(meta-n-butoxyphenox-y)- ethyl bromide are dissolved in 30 cc. of ethanol; 12.0 grams (0.10 mol) of N-methyl-benzylamine are added and the whole is heated under reflux for 12 hours. After cooling, 150 cc. of Water are added, extraction is carried out with methylene chloride after adding 50 cc. of 2 N- sodium hydroxide solution, and the extracts are washed neutral with water. After evaporating the solvent, N-[fi- (meta n butoxy-phenoxy)-ethyl]-N-methyl-N-benzylamine of the formula CH3 CHr-(CHQa-O remains as a yellow, highly viscous oil which is debenzylated catalytically. For this purpose the base is dissolved in 200 cc. of ethyl acetate and the solution agitated in the presence of 0.5 gram of palladium charcoal Pd) in a hydrogen atmosphere. After 2.1 liters of hydrogen have been taken up, the absorption of hydrogen ceases. The catalyst is filetered off and the solvent evaporated. The residue is distilled in a high vacuum. N-[B-(metan-butoxyphenoxy)-ethyl]-N-methylamine of the formula OHs(CHz)3-O is a colorless oil boiling at 110-112 C. under 0.08 mm. of :pressure. When recrystallized from a mixture of ethanol and ethyl acetate the hydrochloride fonrns colorless crystals melting at 138-139 C.
Example 22 From 16.0 grams (0.062 mol) of B-(meta-allyoxyphenoxy)-ethyl bromide and 30 cc. of n-butylamine there is obtained by the method described in Example 2 N-[B- (meta-allyloxyphenoxy)-ethyl]-N-n-butylamine of the a s0 is a yellowish liquid boiling at 102-110 C. under 0.08 mrn. of pressure.
Example 23 33.2 grams (0.20 mol) of meta-n-butoxyphenol, 41.3
grams (0.24 mol) of fi-chloroethyl-diethylamine hydrochloride and 83 grams (0.6 mol) of potassium carbonate are heated at the boil in 400 cc. of acetone for 12 hours with vigorous stirring. The reaction mixture is cooled, the inorganic salts are suction filtered and the filtrate evaporated nearly to dryness. The residue is taken up in chloroform and liberated from the starting phenol by being extracted several times with dilute sodium hydroxide solution. The chloroform solution is then washed several times with water and dried over anhydrous sodium sulfate. After evaporattion the solvent, a dark residue remains which on distillation yields N-[B-(rneta-n-butoxyphenoxy)-ethyl]-N:N-diethylarnine of the formula in the form of a pale yellow liquid boiling at 126-134 C. under 0.03 mm. of pressure. Hydrochloride: colorless flakes from ethyl acetate melting at 109-110 C. The hydrochloride is identical with the hydrochloride having the same melting point and described in Example 7.
Example 24 83 grams (0.50 mol) of meta-n-butoxyphenol, 110 grams (0.59 mol) of N-(y-chloropropyl)-diethylamine hydrochloride and 208 grams (1.50 mols) of anhydrous potassium carbonate are heated under reflux in 800 cc. of acetone for 15 hours with vigorous stirring. After cooling, the inorganic constituents are filtered off, the filtrate evaporated and the residue dissolved in chloroform. in order to remove the starting phenol the reaction solution is extracted several times wi-th dilute sodium hydroxide solution. The chloroform solution is finally washed neutral with water, dried over sodium sulfate and the solvent evaporated. On distillation the residue yields N- [y (meta-n-butoxyphenoxy)-propyl]-N:N-diethyl amine of the formula -o-orn-om-on=-N in the form of a yellow oil boiling at 116-120" C. under 0.08 mm. of pressure.
The citrate crystallized from a mixture of ethanol and ethyl acetate in the form of very fine crystals melting at 87-88 C.
What is claimed is:
1. A member of the group consisting of amines of the formula Ra -0-(CH2)n-N in which R stands for alkyl containing from 3 to 7 car- 11 bon atoms, R represents alkyl containing from 3 to 6 carbon atoms, and n represents a Whole number from 2 to 4.
3. Addition salts of the compounds in claim 2 with therapeutically usable acids.
4. Secondary amines of the formula @o-om-orn-mr-a in which R stands for alkyl containing from 3 to 6 carbon atoms, and R represents alkyl containing from 3 to 7 carbon atoms.
5. Addition salts of the compounds in claim 4 with therapeutically usable acids.
6. N {p (meta n pentyloxyphenoxy) ethyl] N- isobutylamine.
7. Addition salts of the compound in claim 6 with therapeutically usable acids.
8. N 3 (meta n butoxyphenoxy) ethyl] N nbutylamine.
9. Addition salts of the compound in claim 8 with therapueutically usable acids] 10. N [18 (meta n butoxyphenoxy) ethyl] l 2 ethylamine.
11. Addition salts of the compound in claim 10 with therapeutically usable acids. 7
12. N [13 (meta n butoxyphenoxy) ethyl] N- n-propylamine.
13. Addition. salts of the compound in claim 12 with therapeutically usable acids. I
14. .N [B (meta n butoxyphenoxy) ethyl] N- methallylamine.
15. Addition salts of the compound in claim 14 therapeutically usable acids.
16. N [B (meta n bu-toxyphenoxy) ethyl] N- I.
isobutylamine.
17. Addition salts of the compound in claim 16 with therapeutically usable acids.
18. N [B (meta isobutoxyphenoxy) ethyl] N- References Cited in the file of this patent UNITED STATES PATENTS 2,765,338 Suter et al. Oct. 2, 1956 2,967,201 Soper Jan. 3, 1961 FOREIGN PATENTS Great Britain Nov. 19, 1928 OTHER REFERENCES Bovet et al.: Archflntern. Pharmaccdynamie, vol-' ume 56, pages 33 to 37 (1937).

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF AMINES OF THE FORMULA
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Cited By (10)

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US3203992A (en) * 1962-02-14 1965-08-31 Sanol Arznei Schwarz Gmbh Derivatives of 1-(o-bromophenoxy)-2-hydroxy-3-aminopropane
US3205136A (en) * 1962-12-24 1965-09-07 Smith Kline French Lab Antidepressant phenyloxyalkylamines
US3988475A (en) * 1974-02-05 1976-10-26 Istituto Luso Farmaco D'italia S.R.L. Phenoxyalkylamines
WO1997015548A1 (en) * 1995-10-27 1997-05-01 Astra Aktiebolag New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics
WO1999032431A1 (en) * 1997-12-22 1999-07-01 Astrazeneca Ab A NOVEL PHOSPHATE SALT OF ISOPROPYL-METHYL-[2-(3-n-PROPOXYPHENOXY)ETHYL]AMINE
WO1999032103A1 (en) * 1997-12-19 1999-07-01 Astrazeneca Ab New use of local anaesthetics against vascular headaches
US6432986B2 (en) 1997-07-21 2002-08-13 Bruce H. Levin Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
US20150239825A1 (en) * 2007-10-05 2015-08-27 Acucela Inc. Alkoxy compounds for disease treatment
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators

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GB300695A (en) * 1927-08-18 1928-11-19 Ig Farbenindustrie Ag Process for the manufacture of basic ethers of resorcinol
US2765338A (en) * 1952-06-08 1956-10-02 Cilag Ltd New aliphatic acid amide derivatives and processes for the production thereof
US2967201A (en) * 1958-06-02 1961-01-03 Lilly Co Eli Alkylaminoalkyl ethers of phenols

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB300695A (en) * 1927-08-18 1928-11-19 Ig Farbenindustrie Ag Process for the manufacture of basic ethers of resorcinol
US2765338A (en) * 1952-06-08 1956-10-02 Cilag Ltd New aliphatic acid amide derivatives and processes for the production thereof
US2967201A (en) * 1958-06-02 1961-01-03 Lilly Co Eli Alkylaminoalkyl ethers of phenols

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3203992A (en) * 1962-02-14 1965-08-31 Sanol Arznei Schwarz Gmbh Derivatives of 1-(o-bromophenoxy)-2-hydroxy-3-aminopropane
US3205136A (en) * 1962-12-24 1965-09-07 Smith Kline French Lab Antidepressant phenyloxyalkylamines
US3988475A (en) * 1974-02-05 1976-10-26 Istituto Luso Farmaco D'italia S.R.L. Phenoxyalkylamines
KR100460652B1 (en) * 1995-10-27 2005-04-14 아스트라제네카 악티에볼라그 New [(3-Alkoxy-Phenoxy)-Ethyl]-Dialkylamine Derivatives and Their Use as Local Anaesthetics
WO1997015548A1 (en) * 1995-10-27 1997-05-01 Astra Aktiebolag New [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics
AU704635B2 (en) * 1995-10-27 1999-04-29 Astra Aktiebolag New {(3-alkoxy-phenoxy)-ethyl}-dialkylamine derivatives and their use as local anaesthetics
US6310252B1 (en) 1995-10-27 2001-10-30 Astrazeneca Ab [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives and their use as local anaesthetics
CN1113856C (en) * 1995-10-27 2003-07-09 阿斯特拉公司 New (3-alkoxy-phenoxy)-ethyl] dialkylamine derivatives and their use as local anaesthetics
US7799337B2 (en) 1997-07-21 2010-09-21 Levin Bruce H Method for directed intranasal administration of a composition
US6432986B2 (en) 1997-07-21 2002-08-13 Bruce H. Levin Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches
WO1999032103A1 (en) * 1997-12-19 1999-07-01 Astrazeneca Ab New use of local anaesthetics against vascular headaches
WO1999032431A1 (en) * 1997-12-22 1999-07-01 Astrazeneca Ab A NOVEL PHOSPHATE SALT OF ISOPROPYL-METHYL-[2-(3-n-PROPOXYPHENOXY)ETHYL]AMINE
US6235792B1 (en) 1997-12-22 2001-05-22 Astra Ab Phosphate salt of isopropyl-methyl- [2-(3-n-propoxyphenoxy)ethyl]amine
US20150239825A1 (en) * 2007-10-05 2015-08-27 Acucela Inc. Alkoxy compounds for disease treatment
US9458088B2 (en) * 2007-10-05 2016-10-04 Acucela Inc. Alkoxy compounds for disease treatment
US9737496B2 (en) 2007-10-05 2017-08-22 Acucela Inc. Alkoxy compounds for disease treatment
US10188615B2 (en) 2007-10-05 2019-01-29 Acucela Inc. Alkoxy compounds for disease treatment
US10639286B2 (en) 2007-10-05 2020-05-05 Acucela Inc. Alkoxy compounds for disease treatment
US11446261B2 (en) 2007-10-05 2022-09-20 Acucela Inc. Alkoxy compounds for disease treatment
US12029708B2 (en) 2007-10-05 2024-07-09 Acucela Inc. Alkoxy compounds for disease treatment
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators

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