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US3723524A - Polar-substituted propanolamines as anti-angina and anti-hypertensive agents - Google Patents

Polar-substituted propanolamines as anti-angina and anti-hypertensive agents Download PDF

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US3723524A
US3723524A US00036461A US3723524DA US3723524A US 3723524 A US3723524 A US 3723524A US 00036461 A US00036461 A US 00036461A US 3723524D A US3723524D A US 3723524DA US 3723524 A US3723524 A US 3723524A
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methylphenoxy
propan
carbamoyl
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J Augstein
A Ham
P Leeming
M Snarey
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Pfizer Corp Belgium
Pfizer Inc
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • 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 novel propanolamine derivatives, which have useful therapeutic properties in the field of medicinal chemistry, and is particularly concerned with 3-phenoxy-l-phenoxyalkylamino-Z- propanols, in which the phenyl group of the l-substituent carries an electron-withdrawing polar substituent, and analagous compounds in which one or other of the phenyl groups is replaced by a naphthyl group. More particularly the compounds of the invention are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension.
  • Angina pectoris and cardiac arrhythmias are due to interference with the blood supply to the heart muscle.
  • drugs have been sought which would improve the blood supply and most work has concentrated on attempts to dilate the coronary arteries. More recently, efforts have been made to find drugs which will block the B-adrenergic receptors in heart muscle and thus prevent over stimulation of the heart.
  • The'heart muscle is directly influenced by nervous system stimuli substances or catecholamines (e.g. adrenaline, non-adrenaline, and isoprenaline) which affect body organs such as the heart by attaching themselves to receptors which are specialized areas of the cell membranes.
  • catecholamines e.g. adrenaline, non-adrenaline, and isoprenaline
  • the fl-adrenergic receptors are concerned in the stimulation of heart muscle, and the compounds of this invention exhibit a tendency to block B-adrenergic receptors and reduce the effect of the nervous system catecholamines on the heart.
  • R and R are each hydrogen, lower alkyl, or phenyl, or taken together with the nitrogen atom to which they are attached complete a heterocyclic group, e.g. a pyrrolidino, piperidino, piperazino, or morpholino group;
  • R and R each represent hydrogen or a lower alkyl group
  • R represents hydrogen or a lower alkyl, lower alkanoyl or benzyl group
  • rings A and B may each be phenyl or naphthyl
  • X represents oxygen or sulfur
  • Y represents oxygen, sulfur, or a sulfinyl, sulfonyl, or
  • R represents hydrogen or lower alkyl
  • m is 0 or I
  • n is 1,2, or3 when m is l
  • n isO, 1,2, 3,01'4 when m is 0.
  • K is0,1,or2; the carboxylic acid esters and aldehyde condensation products of such compounds, and their pharmaceutically acceptable acid addition salts.
  • novel compounds of the invention are useful as anti-angina and anti-hypertensive agents in mammals.
  • Particularly effective compounds are those belonging to the class of 3-phenoxy-I-phenoxyalkylamino-Z- propanols. Even more particularly effective are the compounds of the class previously mentioned in which the polar substituent is a carbamoyl group.
  • halogen comprises fluorine, chlorine, bromine and iodine; and the term lower, used to qualify an alkyl (R), alkoxy (OR), or alkanoyl (RCO) group, indicates that within such group R con tains up to 4 carbon atoms.
  • aldehyde condensation products of the compounds of the invention are oxazolidines, having the formula:
  • CHDKRS which are formed by condensation of compounds of the invention in which R.is hydrogen'with an aldehyde of the formula R CI-IO, where R is hydrogen or a lower alkyl group.
  • the compounds of the invention which includes optically-active isomers, have the property of blocking the B-adrenergic receptors and are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension.
  • Particularly effective compounds of the invention are those of the class of 3- phenoxy-l-phenoxyalkylamino-2-propanols.
  • the polar substituent is a carbamoyl group such as, l-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2-ol; I-[2- (4-carbamoylphenoxy)ethylamino]-3-(Z-methoxyphenoxy)propan-2ol; l-[2-(2-carbamoyl-4- methylphenoxy)ethylaminoI-3-(Z-methylphenoxy) propan-2-ol; 1-[2-(2-carbamoyl-4-methylphenoxy)-lmethyl-ethylamino]-3-(2-methylphenoxy)propan-Z-ol;
  • Electron-withdrawing polar substituents are those which contain a polar group with its electropositive atom either adjacent to the phenyl or naphthyl ring or separated from the phenyl or naphthyl ring by a methylene or ethylene group.
  • Such polar groups include carbonyl, sulfonyl, sulfinyl, cyano, azido, nitro, trihalomethyl groups.
  • R in the above formula may be carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, substituted carbamoyl, N-amino-carbamoyl, sulfo, sulfino, alkoxysulfonyl, alkoxysulfinyl, substituted sulfamoyl, N- amino-sulfamoyl, cyano, azido, nitro, or trifluoromethyl group.
  • This does not exclude other electron-withdrawing polar substituents which are contemplated by this invention.
  • Substituted carbamoyl and sulfamoyl groups and their N-amino derivatives are those having the formulas CO. NR R -SO NR R9, CO.NHNRR, and -SO NHNR R respectively, where R and R are each hydrogen or a lower alkyl or a phenyl group, or together with the nitrogen atom to which they are attached complete a hetero-cyclic group, e.g. a pyrrolidino, piperidino, piperazino or morpholino group.
  • the compounds of the invention may be prepared in a number of ways: (I A compound of the formula where Z is halogen or any other suitable leaving group, e.g. a sulfonyloxy group such as C H .SO .O or pCl-l .CH .SO .0-, may be reacted with an amine of the formula mula where R is hydrogen, lower alkyl, or benzyl, may be reacted with a compound of the formula and the product recovered, the conditions for reaction and recovery being similar to those given for method (1).
  • Z halogen or any other suitable leaving group
  • a sulfonyloxy group such as C H .SO .O or pCl-l .CH .SO .0-
  • R is hydrogen, lower alkyl, or benzyl
  • An epoxy compound of the formula may be reacted with an amine of the formula where R is hydrogen, lower alkyl, or benzyl, in equimolar proportions at ambient temperature, and the product recovered as in methods (1) and (2).
  • An amine of the formula may be reacted with an aldehyde or ketone of the formula to give the corresponding Schiffs base, which is reduced in the presence of a catalyst, e.g. platinum, to a compound of the invention in which R and R are each hydrogen. This method is preferred where R is lower alkyl.
  • the aldehyde condensation products of the compounds of the invention may be prepared by reacting a compound of the invention in which R is hydrogen with an aldehyde of the formula RCHO, where R is lower alkyl, in a diluent or solvent, e.g.v ethanol, preferably in the presence of an acid catalyst, e.g. hydrochloric or acetic acid, and preferably at an elevated temperature.
  • a diluent or solvent e.g.v ethanol
  • an acid catalyst e.g. hydrochloric or acetic acid
  • the water formed in the reaction may be removed by azeotropic distillation by means of an entraining solvent, e.g. benzene, or by a dehydrating agent such as anhydrous potassium carbonate.
  • Esters of compounds of the invention, and com- "pounds in which R is lower alkanoyl, may be formed by acylation of the free hydroxyl group or the secondary amino group, respectively, in a conventional manner with a carboxylic acid chloride or anhydride derived from a saturated or unsaturated aliphatic acid or from an aromatic acid (e.g. acetic anhydride or benzoyl chloride) for the esters, or with a lower alkanoic acid chloride or anhydride for introduction of R.
  • a carboxylic acid chloride or anhydride derived from a saturated or unsaturated aliphatic acid or from an aromatic acid (e.g. acetic anhydride or benzoyl chloride) for the esters, or with a lower alkanoic acid chloride or anhydride for introduction of R.
  • the compounds of the invention exist in D- and L- opticallyactive isomeric forms and the invention includes these forms as well as the racemic mixtures.
  • Methods of preparation (1), (2) and (4) described previously may be used to prepare opticallyactive isomers by using the appropriate substituted 2- propanol enantiomer as starting material, whereas method (3) will result in the production of racemic mixtures.
  • the racemic product of any of the above methods may be resolved by well known techniques, e.g. by fractional crystallization of an addition salt formed with an optically active acid.
  • Acids from which pharmaceutically acceptable addition salts of the compounds of the invention can be prepared are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulfonate salts.
  • pharmaceutically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulfonate salts.
  • the compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the. intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the. intended route of administration and standard pharmaceutical practice.
  • they may be administered orally, preferentially in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • They may be injected parenterally, for example, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous-solution which may contain other solutes,-for example, enough salts or glucose to make the solution isotonic.
  • the starting materials necessary for the above reaction methods leading to the desired compounds are either all known compounds or else they can easily be prepared by those skilled in the art in accordance with standard organic procedures.
  • R is hydrogen or a methyl group
  • R is hydrogen
  • Y is oxygen
  • n is 1.
  • R is hydrogen, methyl, methoxy (R being hydrogen or methoxy when R is methoxy) or chloro
  • R is an unsubstituted carbamoyl group
  • K is or 1.
  • the unsubstituted carbamoyl group is attached to a phenyl ring in the 2- position or the 4-position, and when it is in the 2-position then preferably R is methyl or methoxy in the 4-, or 6-position.
  • the second crop (10.3 g.) was recrystallized from isopropanol to give DL-l-[3-( 2-carbamoyl-phenoxy)propylamino1-3-(2-methylphenoxy)propan-2-ol as a white crystalline solid (8 g.) m.p. 1 17-l 18C.
  • EXAMPLE IV 1-(4-Dimethylsulfamoylphenoxy)-2-bromethane (6 g.), DL-3-(2-methylphenoxy)-1-aminopropan-2-ol g.) and 1 sodium bicarbonate (1.6 g.) were refluxed together in absolute ethanol (100 ml.) for 16 hours. After cooling the mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in ether and converted to the oxalate by treatment with ethereal oxalic acid solution.
  • the oxalate was recrystallized from water and DL-1-[2-(4-dimethylsulfamoylphenoxy)ethylamino]-3-(2-methy1phenoxy)propan-2-ol oxalate wasobtained as a white crystalline solid (1.6 g.) m.p. 182183.5C.
  • This compound was prepared by'the method of Example Xl from 4-carbamoylphenoxyacetone and DL-lamino-3-( l-naphthoxy) propan-2-ol and isolated as the free base, m.p. l43l44.
  • the amount synthesized in each case by the enzyme is measured as its tritium to carbon-l4 ratio.
  • test (a) force and rate of contraction, and flow rate through the coronary vessels, are measured.
  • the response to standard doses of one or more .catecholamines are obtained, and the test compound is 30 then administered.
  • the catecholamines and test compounds are in all cases injected directly into the perfusing fluid immediately before entering the coronary vessels.
  • the catecholamine doses are repeated and the extent of inhibition of the responses by the test compound is measured.
  • test (b) groups of five urethane-anaesthetized rats are dosed with the test compound (2 mg./kg.) subcutaneously. Heart rates are recorded before dosing and for thirty minutes after and the rats are then given a subcutaneous challenge of isoprenaline (0.1 ,g/kg.). The degree of isoprenaline-induced tachycardia is recorded at fifteen minute intervals. Similarly, chloralosed cats are dosed with the test compound (0.1 to 1.0 mg./kg.) intravenously, and the effect of an isoprenaline challenge on heart rate is measured.
  • test (0) homogenized rat heart in a standardized medium is incubated with adenosine-S'-triphosphoric acid (ATP) labelled with tritium, with and without isoprenaline, and the test compound is added at various concentrations to the homogenate with the isoprenaline.
  • ATP adenosine-S'-triphosphoric acid
  • cyclic-AMP containing a known proportion of carbon-l4 labelled material, is added and synthesis of cyclic-AMP by the adenyl cyclase enzyme is stopped by raising the temperature. Cyclic-AMP is separated and purified, and
  • carbamoyl-methyl (K is l for (CI-I R -substituent), methoxycarbonyl or cyano group in the 2- or 4-position on a phenyl group, R is hydrogen or a methyl group, R and R are each hydrogen, Y is oxygen and n is 1.
  • EXAMPLE Ll Similarly, other carboxylic acid esters are prepared
  • the aldehyde condensation product of each of the by this same procedure corresponding to formyl compounds of Examples I-XLVIII is prepared by reactchloride, propionyl chloride, butyrylchloride, iso-buing the compound as a free base, in which R is tyrylchloride, benzoyl chloride, acetic anhydride,
  • propionic anhydride butyric anhydride, isobutyric anhydrid'e, benzoic anhydride, crotonic chloride and crotonic anhydride.
  • The-dosage levels at which compounds of the invention should be administered will depend on the purpose for which they are administered, i.e. the treatment of the cardiac conditions already mentioned or the treatment of hypertension, and also on the route of administration, i.e. oral or parenteral, e.g. intravenous. They will also depend on the age, body-weight and idiosyncrasies of the individual patient, the physician in any event determining the appropriate dosage which is most suitable for a patient. Broadly, however, oral dosage levels for the treatment of cardiac conditions will be in the range from 0.5 to 4 mg/Kg/day, and for the treatment of hypertension will be in the range from 2m mg/Kg/day, these amounts being given in up to 4 divided doses per day.
  • Dosage levels for intravenous administration will be about one-tenth of these in a single dose.
  • individual oral doses in tablet or capsule form will be in the'range from 10 to 50 mg. of active compound, and intravenous doses will be in the range from 1 to 20 mg. of active compound.
  • R is selected from the group consisting of hydrogen and lower alkyl
  • R is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, phenyl, and phenyl-substituted lower alkyl
  • R and R" are each selected from the group consisting of hydrogen, halo en, lower alkyl, and lower alkoxy
  • R is an electron-wt hdrawmg polar substltuent selected from the group consisting of CONR"R and CONHNIUR where R and R" are each hydrogen or lower alkyl
  • R, R and R are each selected from the group consisting of hydrogen and lower alkyl; andn is 1,2,or 3.
  • R is hydrogen, chlorine, methyl, or methoxy.
  • R is CONH in the 2- or 4-ring position, provided that so t i i i UNITED STATES PATENT omcr CERTIFICATE OF CORRECTION Patent No. 3'723'524 Dated 27, 1973 Joachim Aligstein, Allan, L. Ham, Peter R. Leeming and Michael Snarey Inve-ntor(s) It is certified that .error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel propanolamine derivatives, especially 3-phenoxy-1phenoxyalkylamino-2-propanols, useful in the treatment of hypertension and cardiac conditions, such as angina pectoris and cardiac arrhythmias.

Description

Uite tates Patent Augstein et a1,
1ULAR-SU$'11'E'1J'1ED PROPANQLAMKNES AS AN'i'K-ANGHNA AND ANTK-HYPERTENSHVE AGENTS inventors: Joachim Augsteln, Linford; Allan L. Ham, Leeming; Peter R. Learning; Michael Snarey, both of Kent, all of England Assignee: Pfizer 11110., New York, NY.
Filed: May 11, 1970 Appl. No: 36,461
Related U.S.. Application Data Continuation-in-part of Ser. No. 877,006, Nov. 14', 1969, abandoned.
Foreign Application Priority Data Nov. 18, 1968 Great Britain ..54534/68 June 5, 1969 Great Britain ..28492/69 U.S. Cl ..260/559 S, 260/559 A,
[ 5] Mar. 27, 1973 S, 260/326.3, 260/326.5 SF, 2450/3265 E,
, 2 0/562 P [51 H1111. C1 ..C07C 103/28 [58] Flfiid 0f Search260/559 S, 559A, 559 1'1, 307 F [56] References Cited UNITED STATES PATENTS 3,408,387 10/1968 Howe et al. ..260/307 F 3,538,150 11/1970 Gilman (it 8.1... ....260/307 F 3,634,511 1/1972 Howe et a1. ..260/307 F 3,644,353 2/1972 Lunts et a1 ..260/559 S 3,663,607 5/1972 Barrett et al ..260/559 A OTHER PUBLICATIONS Levy: Proc. Soc. Exp'tl. B 105M661. V0]. "177357 8 (1966). Somani: C.A. Vol. 70: 66535e (April 1969).
Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. Winters AttorneyC0nno1ly and l-lutz [57] ABSTRACT Novel propanolamine derivatives, especially 3- phenoxy-l-phenoxya1kylamino-2-propanols, useful in the treatment of hypertension and cardiac conditions, such as angina pectoris and cardiac arrhythmias.
12 Claims, N0 Drawings POLAR-SUBSTITUTED PROPANOLAMINES AS ANTI-ANGINA AND ANTI-HYPERTENSIVE AGENTS CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part application of US. Ser. Number 877,006, filed on Nov. 14, 1969 under Group 126, and now abandoned.
BACKGROUND OF THE INVENTION This invention relates to novel propanolamine derivatives, which have useful therapeutic properties in the field of medicinal chemistry, and is particularly concerned with 3-phenoxy-l-phenoxyalkylamino-Z- propanols, in which the phenyl group of the l-substituent carries an electron-withdrawing polar substituent, and analagous compounds in which one or other of the phenyl groups is replaced by a naphthyl group. More particularly the compounds of the invention are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension. Angina pectoris and cardiac arrhythmias (irregular heart beat) are due to interference with the blood supply to the heart muscle. In the past, drugs have been sought which would improve the blood supply and most work has concentrated on attempts to dilate the coronary arteries. More recently, efforts have been made to find drugs which will block the B-adrenergic receptors in heart muscle and thus prevent over stimulation of the heart.
The'heart muscle is directly influenced by nervous system stimuli substances or catecholamines (e.g. adrenaline, non-adrenaline, and isoprenaline) which affect body organs such as the heart by attaching themselves to receptors which are specialized areas of the cell membranes. Particularly, the fl-adrenergic receptors are concerned in the stimulation of heart muscle, and the compounds of this invention exhibit a tendency to block B-adrenergic receptors and reduce the effect of the nervous system catecholamines on the heart.
SUMMARY OF THE INVENTION The compounds of the invention are those having the general formula:
ora
trifluoromethyl, CONRR, SO NR R, CONI-INRR and SO NI-INRR, where R and R are each hydrogen, lower alkyl, or phenyl, or taken together with the nitrogen atom to which they are attached complete a heterocyclic group, e.g. a pyrrolidino, piperidino, piperazino, or morpholino group;
R and R each represent hydrogen or a lower alkyl group;
R represents hydrogen or a lower alkyl, lower alkanoyl or benzyl group;
rings A and B may each be phenyl or naphthyl;
X represents oxygen or sulfur;
Y represents oxygen, sulfur, or a sulfinyl, sulfonyl, or
N(R) wherein R represents hydrogen or lower alkyl; m is 0 or I; n is 1,2, or3 when m is l;n isO, 1,2, 3,01'4 when m is 0.; andKis0,1,or2; the carboxylic acid esters and aldehyde condensation products of such compounds, and their pharmaceutically acceptable acid addition salts.
The novel compounds of the invention are useful as anti-angina and anti-hypertensive agents in mammals. Particularly effective compounds are those belonging to the class of 3-phenoxy-I-phenoxyalkylamino-Z- propanols. Even more particularly effective are the compounds of the class previously mentioned in which the polar substituent is a carbamoyl group.
DETAILED DESCRIPTION OF THE INVENTION In this specification halogen" comprises fluorine, chlorine, bromine and iodine; and the term lower, used to qualify an alkyl (R), alkoxy (OR), or alkanoyl (RCO) group, indicates that within such group R con tains up to 4 carbon atoms.
The aldehyde condensation products of the compounds of the invention are oxazolidines, having the formula:
(CHDKRS which are formed by condensation of compounds of the invention in which R.is hydrogen'with an aldehyde of the formula R CI-IO, where R is hydrogen or a lower alkyl group. p
The compounds of the invention, which includes optically-active isomers, have the property of blocking the B-adrenergic receptors and are useful in the curative or prophylactic treatment of cardiac conditions, such as angina pectoris and cardiac arrhythmias, and in the treatment of hypertension. Particularly effective compounds of the invention are those of the class of 3- phenoxy-l-phenoxyalkylamino-2-propanols. More particularly are those in which the polar substituent is a carbamoyl group such as, l-[2-(4-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2-ol; I-[2- (4-carbamoylphenoxy)ethylamino]-3-(Z-methoxyphenoxy)propan-2ol; l-[2-(2-carbamoyl-4- methylphenoxy)ethylaminoI-3-(Z-methylphenoxy) propan-2-ol; 1-[2-(2-carbamoyl-4-methylphenoxy)-lmethyl-ethylamino]-3-(2-methylphenoxy)propan-Z-ol;
l-[ 2-( Z-carbamoyl-4-methoxyphenoxy )-l -methylethylamino1-3-(2-methylphenoxy)propan-2-ol; (2-carbamoylo-methylphenoxy)-l-methylethylamino1-3-(2-methylphenoxy)propan-Z-ol; l-[2- (4-carbamoylphenoxy)-l-methylethylamino]-3-(2- phenylphenoxy)propan-Z-ol; and l-[2-(4-methoxycarbonyl-2,o-dimethylphenoxy)-l-rnethyl-ethylamino]-3- (2-methylphenoxy)propan-Z-ol.
Electron-withdrawing polar substituents are those which contain a polar group with its electropositive atom either adjacent to the phenyl or naphthyl ring or separated from the phenyl or naphthyl ring by a methylene or ethylene group. Such polar groups include carbonyl, sulfonyl, sulfinyl, cyano, azido, nitro, trihalomethyl groups.
Thus R in the above formula may be carboxy, lower alkoxycarbonyl, formyl, lower alkanoyl, substituted carbamoyl, N-amino-carbamoyl, sulfo, sulfino, alkoxysulfonyl, alkoxysulfinyl, substituted sulfamoyl, N- amino-sulfamoyl, cyano, azido, nitro, or trifluoromethyl group. This, of course, does not exclude other electron-withdrawing polar substituents which are contemplated by this invention.
Substituted carbamoyl and sulfamoyl groups and their N-amino derivatives are those having the formulas CO. NR R -SO NR R9, CO.NHNRR, and -SO NHNR R respectively, where R and R are each hydrogen or a lower alkyl or a phenyl group, or together with the nitrogen atom to which they are attached complete a hetero-cyclic group, e.g. a pyrrolidino, piperidino, piperazino or morpholino group.
The compounds of the invention may be prepared in a number of ways: (I A compound of the formula where Z is halogen or any other suitable leaving group, e.g. a sulfonyloxy group such as C H .SO .O or pCl-l .CH .SO .0-, may be reacted with an amine of the formula mula where R is hydrogen, lower alkyl, or benzyl, may be reacted with a compound of the formula and the product recovered, the conditions for reaction and recovery being similar to those given for method (1). (3) An epoxy compound of the formula may be reacted with an amine of the formula where R is hydrogen, lower alkyl, or benzyl, in equimolar proportions at ambient temperature, and the product recovered as in methods (1) and (2). (4) An amine of the formula may be reacted with an aldehyde or ketone of the formula to give the corresponding Schiffs base, which is reduced in the presence of a catalyst, e.g. platinum, to a compound of the invention in which R and R are each hydrogen. This method is preferred where R is lower alkyl.
The aldehyde condensation products of the compounds of the invention may be prepared by reacting a compound of the invention in which R is hydrogen with an aldehyde of the formula RCHO, where R is lower alkyl, in a diluent or solvent, e.g.v ethanol, preferably in the presence of an acid catalyst, e.g. hydrochloric or acetic acid, and preferably at an elevated temperature. The water formed in the reaction may be removed by azeotropic distillation by means of an entraining solvent, e.g. benzene, or by a dehydrating agent such as anhydrous potassium carbonate.
Esters of compounds of the invention, and com- "pounds in which R is lower alkanoyl, may be formed by acylation of the free hydroxyl group or the secondary amino group, respectively, in a conventional manner with a carboxylic acid chloride or anhydride derived from a saturated or unsaturated aliphatic acid or from an aromatic acid (e.g. acetic anhydride or benzoyl chloride) for the esters, or with a lower alkanoic acid chloride or anhydride for introduction of R.
The compounds of the invention exist in D- and L- opticallyactive isomeric forms and the invention includes these forms as well as the racemic mixtures.
Methods of preparation (1), (2) and (4) described previously may be used to prepare opticallyactive isomers by using the appropriate substituted 2- propanol enantiomer as starting material, whereas method (3) will result in the production of racemic mixtures. Alternatively, the racemic product of any of the above methods may be resolved by well known techniques, e.g. by fractional crystallization of an addition salt formed with an optically active acid.
Compounds of the invention in which R is not the same as R have two asymmetric centers and exist as two racemic. pairs of diastereoisomers. In general, the products of each of the methods (1) to (4) described above, when R is not the same as R will be a mixture of the two pairs of steroisomers, and these pairs may usually be separated from each other by physical methods, e.g. by fractional crystallization or chromatography of the free bases or suitable salts, as shown in Examples XIII and XLVlI The invention includes the separated pairs, as well as mixtures thereof, as racemic mixtures or as separated D- and L- forms.
Acids from which pharmaceutically acceptable addition salts of the compounds of the invention can be prepared are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulfonate salts.
The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the. intended route of administration and standard pharmaceutical practice. For example, they may be administered orally, preferentially in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous-solution which may contain other solutes,-for example, enough salts or glucose to make the solution isotonic.
The starting materials necessary for the above reaction methods leading to the desired compounds are either all known compounds or else they can easily be prepared by those skilled in the art in accordance with standard organic procedures.
Among these compounds, a preferred class of compounds has been found to be those in which R is hydrogen or a methyl group, R is hydrogen, Y is oxygen and n is 1. More particularly, there are preferred those compounds in which R is hydrogen, methyl, methoxy (R being hydrogen or methoxy when R is methoxy) or chloro, R is an unsubstituted carbamoyl group, and K is or 1. Preferably, the unsubstituted carbamoyl group is attached to a phenyl ring in the 2- position or the 4-position, and when it is in the 2-position then preferably R is methyl or methoxy in the 4-, or 6-position.
Compounds of the invention may be prepared in a number of ways as described previously, but the' preferred method for preparation of compounds in which R is lower alkyl and R is hydrogen is that in which an amine of the formula Y is reacted with a ketone of the formula EXAMPLE I 2-(2-Bromoethoxy)benzamide (l2.2g.), DL-lamino-3-(2-methylphenoxy )propan-Z-ol (9 g.), sodium bicarbonate (4.2 g.) and ethanol ml.) were refluxed together for 16 hr. The mixture was cooled, filtered and evaporated in vacuo to give a semi-solid residue. The residue was stirred with benzene (60 ml.) and the insoluble material was removed by filtration. Evaporation of the benzene liquors gave a gum which was redissolved in ethanol and converted to an oxalate by treatment with ethereal oxalic acid solution. The oxalate was recrystallized from aqueous ethanol as white needles m.p. 121C. Basification of the oxalate gave the free base of DL-l-[2-(2-carbamoylphenoxy)ethylamino]-3-(2-methylphenoxy)propan-Z-ol (2 g.) as a white solid, m.p. 105.5l06C.
Analysis found: C, 66.4; H, 6.9; N, 8.0%
Calcd for: C, H N O C, 66.25; H, 7.0; N, 8.1%
EXAMPLE ll 2-(3-Chloropropoxy)benzamide (19.4 g.), DL-lamino-3-(2-methylphenoxy)propan-Z-ol (16.4 g.), sodium bicarbonate (11.4 g.) and ethanol (200'ml.) were refluxed together for 16 hr. The mixture was cooled and filtered to remove inorganic material. The ethanolic liquors were evaporated in. vacuo to give the crude product as a sticky solid (35.5 g.). Recrystallization from ethanol gave two crops which differed in physical properties. The second crop (10.3 g.) was recrystallized from isopropanol to give DL-l-[3-( 2-carbamoyl-phenoxy)propylamino1-3-(2-methylphenoxy)propan-2-ol as a white crystalline solid (8 g.) m.p. 1 17-l 18C.
Analysis found: C, 66.95; H, 7.5; N,'7.7%
Calccl for C T-1 N 0 C, 67.0; H, 7.3; N, 7.8%
EXAMPLE in A mixture of 2-carbamoyl-phenoxy-acetone (19 g.) DL-l-amino-3-(Z-methylphenoxy)propan-2-ol (18.1g.) and ethanol (250 ml.) was treated with Tplatinum oxide (100 mg.) and hydrogenated at a pressureof 60 p.s.i. and.50C. for 12 hours. The catalyst was removed by filtration followed by evaporation to dryness in vacuo. The oily residue was converted to the oxalate and dissolved in a boiling mixture of ethanol and water. On cooling, the oxalate of unchanged start- 8 Analysis found: C, 52.3 H, 5.9; N, 5.75; S, 6.5% Calc'd for C,,H N,O S: C, 53.0; H, 6.1; N, 5.6; S,
The following compounds'were prepared by the methods of Examples 1 or 11, from the appropriate .(halo-alkoxy) benzene derivative and DL-l-amino-3- phenoxy-propan-Z-ol derivative, as indicated:
R I H R Example R R R n (1 [alo-alkoxy) benzene II 2-NO? 1 1-(2-hr0m0et1l0xy)-2-nitr0benzene. H 4-CONH'; 1 4-(2-bi'omoethoxy)-benzamide. 4-011 .Z-CONlh 1 2-(2-bromoethoxy)-5-n1ethylbenZamide. 3-0011; 4-CONI'I2 1 4-(2-bromoethoxy)-2-metl1oxybenZamidu. 2-011; 4-CON1I: 1 4-(2-bromoetl1oxy)-3-methylbenzamido. lI 4-C1I2C0 N 11: l 1-(2-bron1oet11oxy)phenylacetmnide. 4-0 O 11 2-00 N H z 1 2-(2-br0m0etl10xy) -1-methoxybenzamide. 3-CII 4-CONH9 l 1-(2-br0m0etlloxy)-3-methylbenzamide. II 4-C0NH2 1 4-(2-br0n100t110xy) benzamide. II 4-CONIIPh 1 4-(2-bromoethoxy)-N-pheny1benzamide. II 4-CONH2 2 4-(3-ch10r0pr0p0xy)benzamide. lI 3-CONH: 1 3- -brm0eth0xy)benzamide. 2,6-(1i-0C11; 4-CONH2 1 4- ..-brom0et1i0Xy)-2,6-dlmetl\oxy-llelllamido. 11 Z-CONIICI-Ia 1 2-(2-brom0ethoxy)-N-methyllmnZamidu. I1 4-CON(Cl'Ia)2 1 4-(2-bromoethoxy)-N,N-dimetliylhenzmnide. 11 4-CON1IC1I 1 4-(2-br0moetli0xy)-N-methylbenzamidu.
"NOTE.FOI Example X(I), R and R are 2-0011; and 6-0C1I3, respectively.
ing material was deposited and removed by filtration. The ethanolic liquors were evaporated to dryness and basified with sodium carbonate to give DL-1-[2-(2-carbamoy1phenoxy)-1-rnethyl-ethy1amino]-3-(2- methylphenoxy)propan2-ol as the free base, whichafter extraction into chloroform, followed by drying and evaporation, was obtained as an oily solid. Recrystallization-from ethyl acetate gave the product as a white solid (2 g.) m.p. 131-4C.
Analysis found: C, 67.4; H, 7.55; N, 7.6%
Calcd for C,,,H,,N 0 C, 67.0;1-1, 7.3; N, 7.8%
EXAMPLE IV EXAMPLE V 1-(4-Dimethylsulfamoylphenoxy)-2-bromethane (6 g.), DL-3-(2-methylphenoxy)-1-aminopropan-2-ol g.) and 1 sodium bicarbonate (1.6 g.) were refluxed together in absolute ethanol (100 ml.) for 16 hours. After cooling the mixture was filtered and evaporated to dryness in vacuo. The residue was dissolved in ether and converted to the oxalate by treatment with ethereal oxalic acid solution. The oxalate was recrystallized from water and DL-1-[2-(4-dimethylsulfamoylphenoxy)ethylamino]-3-(2-methy1phenoxy)propan-2-ol oxalate wasobtained as a white crystalline solid (1.6 g.) m.p. 182183.5C.
The products, isolated as the free base in each case Analysis Example m.pt. C H N (62.41 6.46 8.09) Vll 157-159" 66.2 7.0 7.8 (66.25 7.0 8.1) V111 103-104" 66.7 7.3 7.8 (67.0 7.3 7.8) 1X 187-190 57.1 6.3 6.2 (oxalate) (56.9 6.1 6.0) X(A) 178-181 58.9 6.6 6.5 (oxalate) (58.9 6.3 6.3) X(B) 129-130 66.7 7.4 7.7 (67.0 7.3 7.8) X(C) 108-110 64.0 6.6 7.4 (64.2 7.0 7.5) X(D) -118 66.9 7.1 7.9 (67.0 7.3 7.8) X(E) 234-238 54.2 5.6 7.1 (hydrochloride) (53.9 5.5 7.0) X(F) 138-9 71.1 6.7 6.5 (71.4 6.7 6.7) X(G) 118-119 66.7 7.2 7.6 (67.0 7.3 7.8) X(H) 191-195" 59.8 6.4 6.9 (hydrochloride) (59.9 6.6 7.4) X(l) -156 62.0 6.9 6.6 g (62.4 7.0 6.9) X(J) 96-98 67.1 7.4 7.7 67.0 7.3 7.8) X(K) 124-127 59.9 6.7 5.11 (oxalate) (59.7 6.5 6.1) X(L) 181-184 58.3 6.4 6.1 (oxalate) (58.9 6.3 6.3)
EXAMPLE X1 l-[2-(2-Carbamoy1-4-methylphenoxy)-1-methy1- ethylamino]-3-(Z-methylphenoxy)propan-2-ol 2-Carbamoyl-4-methylphenoxyacetone (5 g.) and DL-l-amino-3-(Z-methylphenoxy)propan-Z-ol (4 g.) were refluxed in ethanol for 1 hour. The ethanol was removed in vacuo and replaced with methanol (50 ml.)
methylphenoxy)propan-2-ol and Analysis: Found C, 67.23; H, 7.36; N, 6.99% I C, 66.65; H, 7.16; N, 7.21% Calcd for: C H N O C, 67.72; H, 7.58; N, 7.52%
The following compounds were prepared by the method of Example XI from DL-1-amino-3-(2- the appropriate ketone, as indicated:
10 EXAMPLE XIII 1-[2-(2-carbamoyl-4-chlorophenoxy )-1 -methy1- ethylamino1-3-(2-methylphenoxy)-propan-2-ol Isolated as two racemic pairs of diastereoisomers,
m.p. 132l 34 1 and 1 1 9l21 (2), respectively Analysis: I
isomer (1) found: C, 61.21; H, 6.50; N, 6.84; CI,
9.82% i isomer (2) found: C, 61.05 H, 6.33; N, 6.85; CI,
9.23% v A I Caltt'd f01' CzoHzsNzOqClI C, H, N, Cl, 9.03%
EXAMPLE XIV 1-[2-(4-carbamoylphenoxy)-1-methyl'-ethylamino]-3- (2-methylphenoxy)propan12-ol m.p.113114.5 Analysis: Found C, 66.44; H, 7.1 I; N, 7.49
ethy1amino]-3-(2-methylphenoxy)propan2-ol 65 R2 OCHZCHCHQNHCHCHQO 2o Calc dforc,,n,,N,o, C,67.02,H, 7.31,N, 7.82%
H 4 EXAMPLE XV CH3 7 I Ra 1-[2-(2-carbamoy1-5-methylphenoxy)-l-methyl- Example R R R ketone XII 5-CH 3-CONH2 CH 3-carbamoyl-5-methylphenoxyacetone XIII 4-Cl Z-CONI-I; CH3 2-carbamoyl-4-chlorophenoxyacetone XIV H 4-CONH CH 4-carbamoylphenoxyacetone XV S-CH: Z-CONH: CH Z-carbamoyl-5-methylphenoxyacetone XVI H 3-.CONH CH S-carbamoylphenoxyacetone XVII H 3-C0N(CI-I CH 3-dimethylcarbamoylphenoxyacetone XVIII H Z-CONH; C211 1-(2-carbarnoy1phenoxy)butan-2-one XIX H 4-NO CH 4-nitrophenoxyacetone XX H 4-COOCH CH 4-methoxycarbonylphenoxyacetone XXI 1-1 4-CN CH 4-cyanophenoxyacetone XXII H 3-CF CH 3-trifluoromethylphenoxyacetone XXIII H 4-CHzCONH2 CH 4-carbamoylmethylphenoxyacetone XXIV H Z-CH CONH CH 2-carbamoylmethylphenoxyacetone X'XV H 2-CONHCflH5 CH 2-(N-phenylcarbamoyl)phenoxyacetone XXVI Z-OCH S-CONH CH 5-carbamoyl-2-methoxyphenoxyacetone XXVIII 4-CH 2-CON(CH CH 2-(N,N-dimethylcarbamoyl)-4-methylacetone XXIX 3-CH 4-CONH2 CH 4-carbamoyl-3-methylphenoxyacetone I XXX H 4-S0NH2 CH 4-sulfamoyl-phenoxyacetone XXXI 2-OCH3 4-CONH CH 4-carbamoyl-2-methoxyphenoxyacetone XXXII 4-OCH Z-CONH CH 2-carbamoyl-4-methoxyphenoxyacetone XXXIII Z-CI-I 4-CONH CH 4-carbamoy1-Z-methylphenoxyacetone XXXIV B-CI-I 4-NO2 CH 3-methyl-4-nitrophenoxyacetone XXXVI 2-CH S-CONH CH 5-carbamoyl-Z-methylphenoxyacetone XXXVII 6-CH; Z-CONH; CH 2-carbamoyl-6-methylphenoxyacetone *XXXVIII 2,6-di-CH, 4-COOCH CH 4-metlioxycarbonyl-2,6-dimenthylphenoxyacetone XXXIX 3-OCH 4-CONH CH, 4-carbamoyl-3-methoxyphenoxyacetone *XL 2,6-di-OCH 4-CONI-I CH 4-carbamoyl-2,6-di-meth0xyphenoxyacetone *NOTE: For Example XXXVII], R and'R are Z-CH and G-CI-I respectively.
For Example XL, R and R are 2-OCH and 55 ethylamino]-3-(2-methy1phenoxy) propan-2-0l 6-OCI-I respectively. m.p. 138 I v The products, isolated as the free base in each case, Analysis: Found 4 C, 67 .88; H, 7 .08; N, 6.80% unless otherwise stated, were characterized as Calcd'for C,,I-1', N O,-C, 67.72; H, 7.58; N, 7.52%
folloes. 6o EXAMPLE XVI l-[2-(3-carbamoylphenoxy)-1-methyl-ethylamino]-3- (Z-methylphenoxy )propan-2-ol m.p. 116117 Analysis: Found -'C, 65.74; H, 7.52;'N, 7.22% Calcd for c,.,H,,N,0,- c, 65.74; H, 7.54; N, 7.48%
+ kCI-I OH EXAMPLE XII 1-[2-(3 -carbamoyl-5 -methylphenoxy)- 1 -methyl- Oil, identified by spectroscopic evidence. 7
EXAMPLE XXXV --OCH-1CHCH-;NHCH2CH2O- l-[2-(4-N-aminocarbamoyl-phenoxy)-1-methyl- R1 5 ethylamino1-3-(2-methylphenoiry)propan-Z-ol CONHg This compound was prepared from the product of Example XX by heating with hydrazme hydrate 1n bxampke m p C H N ethanol.
m.p. 129 I XL"! 2 C H I24 125 70 7 66 7 Analysis: Found C, 64.2; H, 7.1; N, 11.2% g g (70:9 C810 d for C20H27N3O4 113% 10 xuv 3-011, l24l26 66.1 7.2 8.4
' (66.3 7.0- 8.1) EXAMPLE XXXVI XLV z-ocu, 108-1 12 63.2 6.9 1.9 (63.3 6.7 7.8)
1-[2-( 5-carbamoyl- 2-methylphenoxy)- 1 -methylethylamino]-3-(2-methylphenoxy) propan-2-ol Analysis: Found C, 67.2; H, 7.1; N, 7.1% I EXAMPLE XLVI .Calmd for C l-1 N 0 C, 67.7; H,.7.6; N, 7.5% 1 [2 (4 carbamoylphenoxy)ethylamino];3
naphthoxy)propan -2-ol EXAMPLE XXXVI! This compound was prepared by the method of Exy y p y)- 1 y ample W, from H 1-naphthoxy)-2:3-epoxypropane and ethyl-amino]-3-(2-methylphenoxy) propan-Z-ol 4-(2-aminoethoxy) benzamide, and isolated as the free isolated as the oxalate, m.p. 170-17l .5 base, m.p. l22-1 23.
Analysis: Found C, 63.3; H, 7.0; N, 7.0% A ai 'i Found C, Calc'd for C23H30N2OB C H! N1 25 calcd for CzgI'ImNzOq- C, 69.5; H, N, EXAMPLE XXXVIII I EXAMPLE XLVII l -[2-(4-methoxycarbonyl-2,6-dimethylphenoxy)-1- 1' [N.BenzylQ-(2-carbariioyl-4-methylphenoxy)- 1- methyl-ethylamino]-3-(2-methylphenoxy )propan-Z-ol ethyl-ethylamino]-3-(2-methylphenoxy)propan-2-ol isolated as the hydrochloride, m.p. l28.l 30 30 l-( 2-Methylphen0Xy)-2,3-epoxypropane (13.8g.), 1-
An ly i F n 31% (2-carbamoyl-4-methylphenoxy)-2-(benzylamino)- CalCd for C H E 32% propane (25 g.), ethanol (250 ml.) and water (50 ml.) were heated together under reflux for 6 hours. The
I EXAMPLE xxxlx reaction mixture was evaporated and dried in vacuo to 1-[2-(4-carbamoyl-3-methoxyphenoxy)-l-methyl- 35 give the free base of the desired productas a clear oil ethylamino]-3-(2-methylphenoxy)propan-2-ol (39g.). This oil was then dissolved in the minimum hydrochloride, identified by spectroscopic evidence. quantity of chloroform and chromatographed on a column (80X3cm) packed with silicagel, using chloroform as the eluting solvent. The first 500 ml. of EXAMPLE XL eluate was collected and the solvent removed in vacuo 40 1- 2 4 2 1- to give an ml which solidified after standing for two ethylamino]-3-(2-methylphenoxy)propan-Z-ol weeks. Repeated fractional recrystallization of the solid hydrochloride, identified by spectroscopic evidence. 'Q ethyl acetate gave Solid Products A and -P- 1 1 15 and 132, respectively, which were the two racemic pairs of diastereoisomers of the product.
EXAMPLE XLI Analysis:
. Found for Product A: C, 72.29; H, 7.35; N, 6.20%. l-[2-(4-carbamoyl-phenoxy)-1-methyl-ethylammo]-3- for Product B: C 72-31; H 7.21; N 6.06%
(l-naphthoxy) propan-2-ol.
This compound was prepared by'the method of Example Xl from 4-carbamoylphenoxyacetone and DL-lamino-3-( l-naphthoxy) propan-2-ol and isolated as the free base, m.p. l43l44.
Analysis: Found C, 69.8; H, 6.7; N, 6.8%
Calc'd for C H N O C, 72.70; H, 7.41; N, 6.06% Hydrogenation of each of the products A and B of this example, using a palladium-on-carbon catalyst, removes the N-benzyl group and yields one of the racemic pairs of-diastereoisomers of the product of Ex- Calcd for c,,u,,N,o,- c, 70.0; H, 6.6; N, 7.1% ample EXAMPLE EXAMPLE XLVlll 'F Y P Y)' y The following propanolamine derivatives are Y -(Z- y p y)p p prepared according to the procedures described in Excompound. was P p y the method of 0 amples I, IV, V, and XI from the appropriate starting ample from 3'carbamoyl'2'naphthoxyacetone f compounds, those in which R is lower alkanoyl being y p z y)pg p and prepared by conventional acylation procedures from lated as the free base -P- 106 corresponding compounds in which R is H:
Analysis: Found C, 70.21; H, 7.0; N, 6.6% "I calcd for C H N O --C, 70.56; H, 6.9; N, 6.7% 5 m V mi The following compounds were prepared by the method of Example IV, from the appropriately sub- A X QCmOHwH? MR6) i (CHM (Yb B 1 stituted l-phenoxy-2:3-epoxypropane and 2-(4-car- R5 bamoylphenoxy)-ethylamine, and isolated as the free base in each case. (0 0x11 Rings A and B are each l-naphthyl in the following table:
the amount synthesized in each case by the enzyme is measured as its tritium to carbon-l4 ratio. The concen- X Y R 11 R R R R 11 K R Z-Cl -1-Cz115 21711 050; (11 C11 C11 1 2 30 S 11 5450003117 3-Nx 11 11 (311 ((1 1 11 (l 4 S-(l 11-0011 N-C NH: 2115 11 (43115.(113 L. .3 1'llSl)(1(';;117 (1 24'111; l-(llzt 7-( 119N)NS()2 11:; 11 11 3 U 11 (1 (1 2-(11 11 -1-11C411DUSU 11;; 1&(3117' 11 .Z (1 2 02115 (1 2-(11: 11 3-( 4119UC0 (1113 11 11 1 11 11 O 0 2 011:; 11 4-CON112 1'1 11 150C3117CO 3 U 11 O U 4-Cl 11 4-CON112 11 11 C113 2 O 11 O 841113 11 Z-CONl-lz 11 II 11 1 0 1-01 0 O 11 3432115 2'C'ON1I2 .11 1103117 11 1 0 H O 3-0113 11 Z'C1I3OSO C113 11 C113 1 0 11 S 0 2-01 11 3'11C4HBOSO2 C113 H CH3 1. O 11 U 0 5-1 11 4-CONH2 11 11 1'1 1 0 H S 0 20113 11 4-CON1'12 11 1'1 11 1 0 11 O 0 l-C113 H 4- 0 ON H z 11 H 11 1 O 11 The activity of compounds of the invention as B- adrenergic blocking agents has been shown by their effectiveness in one or more of the following tests: (a) blocking the action of injected catecholamines on the isolated, perfused guinea-pig heart; (b) suppressing the tachycardia induced by isoprenaline in the anaesthetized rat or cat; (c) blocking the stimulating action of isoprenaline on the adenyl cyclase enzyme present in rate heart muscle.
In test (a), force and rate of contraction, and flow rate through the coronary vessels, are measured. The response to standard doses of one or more .catecholamines are obtained, and the test compound is 30 then administered. The catecholamines and test compounds are in all cases injected directly into the perfusing fluid immediately before entering the coronary vessels. The catecholamine doses are repeated and the extent of inhibition of the responses by the test compound is measured.
In test (b), groups of five urethane-anaesthetized rats are dosed with the test compound (2 mg./kg.) subcutaneously. Heart rates are recorded before dosing and for thirty minutes after and the rats are then given a subcutaneous challenge of isoprenaline (0.1 ,g/kg.). The degree of isoprenaline-induced tachycardia is recorded at fifteen minute intervals. Similarly, chloralosed cats are dosed with the test compound (0.1 to 1.0 mg./kg.) intravenously, and the effect of an isoprenaline challenge on heart rate is measured.
In test (0), homogenized rat heart in a standardized medium is incubated with adenosine-S'-triphosphoric acid (ATP) labelled with tritium, with and without isoprenaline, and the test compound is added at various concentrations to the homogenate with the isoprenaline. After incubation at 30 C., cyclic-3', 5'- adenosinemonophosphoric acid (cyclic-AMP), containing a known proportion of carbon-l4 labelled material, is added and synthesis of cyclic-AMP by the adenyl cyclase enzyme is stopped by raising the temperature. Cyclic-AMP is separated and purified, and
tration of test compound which gives a 50 percent inhibition of the stimulating effect of isoprenaline on cyclic-AMP synthesis is taken as a measure of its activi- By these criteria, the more active compounds have been found to be those in which R is a carbamoyl (including N-substituted-and N-amino-carbamoyl', as
hereinbefore described), carbamoyl-methyl (K is l for (CI-I R -substituent), methoxycarbonyl or cyano group in the 2- or 4-position on a phenyl group, R is hydrogen or a methyl group, R and R are each hydrogen, Y is oxygen and n is 1.
Further evaluation of these more active compounds has been carried out by assessing their activity in suppressing isoprenaline-induced tachycardia in dogs, the compound being administered intraveneously and orally to conscious dogs at dose levels of 0.125 and 0.25 mg/Kg (intravenous) and 0.5 to 4mg/Kg (orally).
These tests have shown that, of these compounds, the most active when administered orally are those in which R is a methyl, methoxy or phenyl group in the 2- position on a phenyl group and R is an unsubstituted carbamoyl group or a methoxycarbonyl group, provided that, when R is in the 2-position on the phenyl group, then R is a methyl or methoxy groupin the 4-, 5- or 6-position. Intravenous test results in dogs confirmed relative activities found in test (b) in rats or cats, in or test (c).
The activity of compounds of the invention as antihypertensive agents has been shown by their effectiveness in lowering the blood pressure of conscious hypertensive rats or dogs, using a subcutaneous dose of IOmgJKg. in the rat and an oral dose of 20 mg/Kg. in the dog. Compounds having most activity in these tests are those in which R is a carbamoyl or nitro group, R is hydrogen or a methyl group, R and R are each hydrogen and n is l or 2.
The following example shows the therapeutic activity of many of the compounds whose preparations are illustrated in the previous examples.
"" QMTEBTXMPLE XLIX Anti-hypertensive B-Blocking activity ctivity Test (b): inhibition of isoprenaline tachycardia Dog dose Test (0): Ghloral- 60 mgJkg denylosed cat (orally) cyclase, Rat dose: Dog dose: dose: Rat dose: or
11) 0 nun/kg. 0.5-4 mg./ 0.1-1 mm] 10 mgJkg. 5 nag/kg. (MX10) (5.0.) kg. (orally) kg. (i.v.) (5.0.) (i.v.)
1.4 NR 1.0 N It C) N It N R (1. U N It N It N R 1 as: u its EXAMPLE XLIX Continued Anti-hypertensive B-Blocking activity Activity Test (b): inhibition of isoprenalino Dog dose: 20 mgJkg. (orally) or tachycardia Test (0): Adenyl- Dog v(lose: dose: Rat dose: 0.5-4 mlgJ 0.1-1 mg./ 10 mgJkg. 5 1nu., kg. kg. (cm ly) kg. (i.v.) (s c (LV.)
eyclasc. Rat dose:
ID fimgJkg. (MXIO (5.0.)
RR RRRRRRRRR NN+NNNNNNNNN+++++++o00oo ttxultiltisruttn lllllllll ll Rt. R a ERR... RRRRRRRR MN N" n u NNN" NNNNNNNNNNNNNNNNNNNNN a nun nunnnnnnuanann a t a i N. NNN. t NNNNNNNNNNNNNh.
4 3642 8002101 74Z 1 121416 0 l l RRRRR NNNNN Similarly, the other aldehyde condensation products are prepared by this same procedure corresponding to acetaldehyde, propionaldehyde, butyraldehyde, and isobutyraldehyde.
RRR NNNNN Good, approx. equiaetive with propranolol. Good, but less active than propanolol. Moderate. Poor. 0 nil N R No result available. ++=good.
+=modcrato. O=nil; l'.v. intravenously. S.c.=subcutnneously.
I h dro en with formaldeh de in ethanol and an acid EXAMPLEL y g 1 catalyst such as hydrochloric or acetic, at an elevated The hydrochloride salt of each of the compounds of temperature, and the product is then recovered after Examples l-XLVIII is prepared by dissolving the comremoval of the excess water by azeotropic distillation pound as a free base in an aqueous solution containing 55 or by means of an entraining solvent such as benzene.
.Similarly,-other acid addition salts are prepared by this same procedure corresponding to hydrobromide,
an equivalent amount of hydrochloric acid and evaporating the resultant solution.
hydroiodide, sulfate or bisulphate, phosphate or acid 450 phosphate, acetate, maleate, fumarate, lactate, tar- EXAMPLE LII The carboxylic acid ester of each of the-compounds of Examples I-XLVIII is prepared by acylating in the trate, citrate, gluconate, saccharate, and p-toluene sulfonate by employing the appropriate acid.
- conventional manner the compound as the free base 65 with acetyl chloride and recovering the ester.
EXAMPLE Ll Similarly, other carboxylic acid esters are prepared The aldehyde condensation product of each of the by this same procedure corresponding to formyl compounds of Examples I-XLVIII is prepared by reactchloride, propionyl chloride, butyrylchloride, iso-buing the compound as a free base, in which R is tyrylchloride, benzoyl chloride, acetic anhydride,
propionic anhydride, butyric anhydride, isobutyric anhydrid'e, benzoic anhydride, crotonic chloride and crotonic anhydride.
The-dosage levels at which compounds of the invention should be administered will depend on the purpose for which they are administered, i.e. the treatment of the cardiac conditions already mentioned or the treatment of hypertension, and also on the route of administration, i.e. oral or parenteral, e.g. intravenous. They will also depend on the age, body-weight and idiosyncrasies of the individual patient, the physician in any event determining the appropriate dosage which is most suitable for a patient. Broadly, however, oral dosage levels for the treatment of cardiac conditions will be in the range from 0.5 to 4 mg/Kg/day, and for the treatment of hypertension will be in the range from 2m mg/Kg/day, these amounts being given in up to 4 divided doses per day. Dosage levels for intravenous administration will be about one-tenth of these in a single dose. Thus, for an average (70Kg) adult patient, individual oral doses in tablet or capsule form will be in the'range from 10 to 50 mg. of active compound, and intravenous doses will be in the range from 1 to 20 mg. of active compound.
What is claimed is:
l. A compound selected from the group of propanolamines consisting of those of the formula:
the 'pharmaceutically-acceptable acid addition salts thereof; the carboxylic acid esters of the formulai 'wherein R is'selected from the group consisting of formyl, lower alkanoyl, lower alkenoyl, and benzoyl', and
the aldehyde condensation-products of the formula:
wherein R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, phenyl, and phenyl-substituted lower alkyl; R and R" are each selected from the group consisting of hydrogen, halo en, lower alkyl, and lower alkoxy; R is an electron-wt hdrawmg polar substltuent selected from the group consisting of CONR"R and CONHNIUR where R and R" are each hydrogen or lower alkyl;
R, R and R are each selected from the group consisting of hydrogen and lower alkyl; andn is 1,2,or 3.
2. A compound as claimed in claim I in which R is I hydrogen or a methyl group, R ishydrogen, and n is l.
3. A compound as claimed in claim 2 in which R is hydrogen, chlorine, methyl, or methoxy.
4. A compound as claimed in claim 2, in which R is in the 2- or 4-ring position.
5. A compound as claimed in claim 4, in which R is methyl, methoxy, or phenyl on the 2-ring position, and
R is CONH in the 2- or 4-ring position, provided that so t i i i UNITED STATES PATENT omcr CERTIFICATE OF CORRECTION Patent No. 3'723'524 Dated 27, 1973 Joachim Aligstein, Allan, L. Ham, Peter R. Leeming and Michael Snarey Inve-ntor(s) It is certified that .error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Page 1, first column (in the designation of inventors) Line 6 change "Linford" to Leicestershire Line 7 delete "Leeming" 7 v Line 8 change "both" to each These addresses, as corrected above, of the inventors are given in the Declaration, Power of Attorney and Petition, as well as in the Assignment, all of record.
Signed and sealed this 20th day of Novemoer 1973.
Attest:
EDWARD VLFLETUMER, JH. RENE 1 TIDUTI-VIEYER Attesting; Officer r Acting; Commissioner of Patent:

Claims (11)

  1. 2. A compound as claimed in claim 1 in which R4 is hydrogen or a methyl group, R5 is hydrogen, and n is 1.
  2. 3. A compound as claimed in claim 2 in which R2 is hydrogen, chlorine, methyl, or methoxy.
  3. 4. A compound as claimed in claim 2, in which R3 is in the 2- or 4-ring position.
  4. 5. A compound as claimed in claim 4, in which R1 is methyl, methoxy, or phenyl on the 2-ring position, and R3 is CONH2 in the 2- or 4-ring position, provided that when R3 is in the 2-position then R2 is methyl or methoxy in the 4-, 5- or 6-ring position.
  5. 6. 1-(2-(4-carbamoylphenoxy)ethylamino)-3-(2-methyl-phenoxy)propan-2-ol.
  6. 7. 1-(2-(4-carbamoylphenoxy)ethylamino)-3-(2-methoxy-phenoxy)propan-2-ol.
  7. 8. 1-(2-(2-carbamoyl-4-methylphenoxy)ethylamino)-3-(2-methylphenoxy)propan-2 -ol.
  8. 9. 1-(2-(2-carbamoyl-4-methylphenoxy)-1-methyl-ethylamino)-3-(2 -methylphenoxy)propan-2-ol.
  9. 10. 1(2-(2-carbamoyl-4-methoxyphenoxy)-1-methyl-ethyl-amino)-3-(2 -methylphenoxy)propan-2-ol.
  10. 11. 1-(2-(2-carbamoyl-6-methylphenoxy)-1-methyl-ethyl-amino)-3-(2 -methylphenoxy)propan-2-ol.
  11. 12. 1-(2-(4-carbamoylphenoxy)-1-methyl-ethylamino)-3-(2-phenylphenoxy)propan-2 -ol.
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US3911007A (en) * 1974-08-08 1975-10-07 Searle & Co N-substituted N-benzyloxy-2-methyl-2-(4-halophenoxy)propionamides
US3911008A (en) * 1973-08-18 1975-10-07 Pfizer Polar-substituted propanolamines as anti-angina and anti-hypertensive agents
US3968218A (en) * 1972-09-29 1976-07-06 L'oreal Cosmetic composition containing a hydroxylated amino thioether for application to the hair and skin
US4041074A (en) * 1973-07-19 1977-08-09 Imperial Chemical Industries Limited 1-Hydroxyaryl-2-amidoalkylaminoethanol derivatives
US4041075A (en) * 1973-12-12 1977-08-09 Imperial Chemical Industries Limited Phenoxy-alkanolamine derivatives
US4065584A (en) * 1974-09-30 1977-12-27 Victor Lafon Sulphur containing arylamine derivatives
US4086272A (en) * 1970-07-18 1978-04-25 Pfizer Inc. Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US4145443A (en) * 1977-10-31 1979-03-20 Syntex (U.S.A.) Inc. Bicyclo 3.1.0!hexylethylaminocarbonyl-substituted naphthyloxy cardiovascular agents
US4151297A (en) * 1977-10-31 1979-04-24 Syntex (U.S.A.) Inc. Bicyclo [3.1.0] hexyl-substituted ethylamino carbonyl phenoxy cardiovascular agents
US4152446A (en) * 1974-11-16 1979-05-01 Boehringer Mannheim Gmbh Aminopropanol compounds and compositions for the treatment of cardiac and circulatory diseases
US4163053A (en) * 1977-12-27 1979-07-31 Schering Corporation Anti-hypertensive 5-[2-(substituted anilinoalkylamino)-1-hydroxyalkyl]salicylamides
US4165384A (en) * 1974-11-01 1979-08-21 Aktiebolaget Hassle Amide substituted phenoxy propanol amines
US4288452A (en) * 1978-02-09 1981-09-08 Merck Patent Gesellschaft Mit Beschrankter Haftung 1-Aryloxy-3-nitratoalkylamino-2-propanols and use as β-receptor blocker
EP0043736A1 (en) * 1980-07-09 1982-01-13 Reckitt And Colman Products Limited Propanolamine derivatives, their salts, processes for preparation and pharmaceutical compositions
US4329358A (en) * 1979-10-25 1982-05-11 Beecham Group Limited 3-Chlorophenyl anti-obesity agents
US4373106A (en) * 1980-02-08 1983-02-08 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives and process of producing them
US4385066A (en) * 1980-05-22 1983-05-24 Beecham Group Limited Arylethanolamine derivatives, their preparation and use in pharmaceutical compositions
US4391826A (en) * 1978-07-03 1983-07-05 Eli Lilly And Company Phenethanolamines, compositions containing the same, and method for effecting weight control
US4497813A (en) * 1979-03-01 1985-02-05 Ciba-Geigy Corporation Derivatives of 3-aminopropane-1,2-diol
US4532239A (en) * 1980-12-22 1985-07-30 Cassella Aktiengesellschaft N-phenoxypropanol-N'-pyridazinyl ethylendiamines as β-receptor blockers
US4554282A (en) * 1981-02-26 1985-11-19 Warner-Lambert Company Substituted 2,2-dimethyl-5-phenoxypentanoic acid benzamides as anti-arteriosclerotic agents and method
US4558156A (en) * 1980-02-08 1985-12-10 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives
US4599333A (en) * 1982-06-14 1986-07-08 Teikoku Hormone Mfg. Co., Ltd. Hydrazinopyridazine compound, process for production thereof, and use thereof as medicament
US4603138A (en) * 1982-06-10 1986-07-29 Beecham Wuelfing Gmbh & Co. Kg Amine derivatives
US4772631A (en) * 1985-07-30 1988-09-20 Imperial Chemical Industries Plc Phenyl ethers
US4845127A (en) * 1978-07-03 1989-07-04 Eli Lilly And Company Phenethanolamines, compositions containing the same and method for effecting weight control
US4892886A (en) * 1987-07-21 1990-01-09 Hoffman-La Roche Inc. Phenoxypropanolamines
US4931474A (en) * 1986-08-06 1990-06-05 Nippon Kayaku Kabushiki Kaisha Ether derivative and an acaricidal or insecticidal composition comprising said derivative
US5064863A (en) * 1983-10-19 1991-11-12 Hoffmann-La Roche Inc. Phenoxypropanolamines and pharmaceutical use
US5166218A (en) * 1983-10-19 1992-11-24 Hoffmann-La Roche Inc. Phenoxypropanolamines and pharmaceutical compositions thereof
US5187190A (en) * 1989-11-06 1993-02-16 Imperial Chemical Industries Plc Phenoxypropanolamine compounds
US5491134A (en) * 1994-09-16 1996-02-13 Bristol-Myers Squibb Company Sulfonic, phosphonic or phosphiniic acid β3 agonist derivatives

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DE2309887C2 (en) * 1973-02-28 1983-11-10 C.H. Boehringer Sohn, 6507 Ingelheim 1-aryloxy-2-hydroxy-3-alkynylaminopropane derivatives and their physiologically acceptable acid addition salts, pharmaceutical preparations and manufacturing processes for the compounds
HU169464B (en) * 1974-02-20 1976-11-28
DD146749A3 (en) 1977-12-01 1981-03-04 Dieter Lehmann PROCESS FOR THE PREPARATION OF PHENOXYALKANOLAMINE DERIVATIVES
DE3125870C2 (en) * 1980-07-09 1994-09-15 William John Louis 3-aminopropoxyphenyl derivatives, their preparation and medicaments containing them
US4556668A (en) * 1983-07-15 1985-12-03 American Hospital Supply Corporation Ethylenediamine derivatives of aryloxypropanolamine aryl esters having various medicinal properties
JPS60158153A (en) * 1984-01-12 1985-08-19 イーライ・リリー・アンド・カンパニー Modifier
DE3428525A1 (en) * 1984-08-02 1986-02-13 Boehringer Mannheim Gmbh, 6800 Mannheim USE OF ALKYLENEDIAMINE DERIVATIVES FOR THE TREATMENT OF CIRCULATORY DISEASES AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4086272A (en) * 1970-07-18 1978-04-25 Pfizer Inc. Phenyl-alkanolamine, alkylamine and alpha-aminoalkyl ketone derivatives as heart stimulants
US3968218A (en) * 1972-09-29 1976-07-06 L'oreal Cosmetic composition containing a hydroxylated amino thioether for application to the hair and skin
US4041074A (en) * 1973-07-19 1977-08-09 Imperial Chemical Industries Limited 1-Hydroxyaryl-2-amidoalkylaminoethanol derivatives
US3911008A (en) * 1973-08-18 1975-10-07 Pfizer Polar-substituted propanolamines as anti-angina and anti-hypertensive agents
US4041075A (en) * 1973-12-12 1977-08-09 Imperial Chemical Industries Limited Phenoxy-alkanolamine derivatives
US3911007A (en) * 1974-08-08 1975-10-07 Searle & Co N-substituted N-benzyloxy-2-methyl-2-(4-halophenoxy)propionamides
US4065584A (en) * 1974-09-30 1977-12-27 Victor Lafon Sulphur containing arylamine derivatives
US4165384A (en) * 1974-11-01 1979-08-21 Aktiebolaget Hassle Amide substituted phenoxy propanol amines
US4152446A (en) * 1974-11-16 1979-05-01 Boehringer Mannheim Gmbh Aminopropanol compounds and compositions for the treatment of cardiac and circulatory diseases
US4151297A (en) * 1977-10-31 1979-04-24 Syntex (U.S.A.) Inc. Bicyclo [3.1.0] hexyl-substituted ethylamino carbonyl phenoxy cardiovascular agents
US4145443A (en) * 1977-10-31 1979-03-20 Syntex (U.S.A.) Inc. Bicyclo 3.1.0!hexylethylaminocarbonyl-substituted naphthyloxy cardiovascular agents
US4163053A (en) * 1977-12-27 1979-07-31 Schering Corporation Anti-hypertensive 5-[2-(substituted anilinoalkylamino)-1-hydroxyalkyl]salicylamides
US4288452A (en) * 1978-02-09 1981-09-08 Merck Patent Gesellschaft Mit Beschrankter Haftung 1-Aryloxy-3-nitratoalkylamino-2-propanols and use as β-receptor blocker
US4845127A (en) * 1978-07-03 1989-07-04 Eli Lilly And Company Phenethanolamines, compositions containing the same and method for effecting weight control
US4391826A (en) * 1978-07-03 1983-07-05 Eli Lilly And Company Phenethanolamines, compositions containing the same, and method for effecting weight control
US4497813A (en) * 1979-03-01 1985-02-05 Ciba-Geigy Corporation Derivatives of 3-aminopropane-1,2-diol
US4636511A (en) * 1979-03-01 1987-01-13 Ciba-Geigy Ag Derivatives of 3-aminopropane-1,2-diol
US4329358A (en) * 1979-10-25 1982-05-11 Beecham Group Limited 3-Chlorophenyl anti-obesity agents
US4731478A (en) * 1980-02-08 1988-03-15 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives, their preparation, and pharmaceutical compositions, containing them
US4868216A (en) * 1980-02-08 1989-09-19 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives and process of producing them
US4761500A (en) * 1980-02-08 1988-08-02 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives, their preparation, and pharmaceutical compositions, containing them
US4373106A (en) * 1980-02-08 1983-02-08 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives and process of producing them
US4558156A (en) * 1980-02-08 1985-12-10 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl-substituted phenethylamine derivatives
US4703063A (en) * 1980-02-08 1987-10-27 Yamanouchi Pharmaceutical Co., Ltd. Sulfamoyl substituted phenethylamine derivatives and process of producing them
US4385066A (en) * 1980-05-22 1983-05-24 Beecham Group Limited Arylethanolamine derivatives, their preparation and use in pharmaceutical compositions
US4410548A (en) * 1980-07-09 1983-10-18 Reckitt & Colman Products Limited Propanolamine derivatives
EP0043736A1 (en) * 1980-07-09 1982-01-13 Reckitt And Colman Products Limited Propanolamine derivatives, their salts, processes for preparation and pharmaceutical compositions
US4532239A (en) * 1980-12-22 1985-07-30 Cassella Aktiengesellschaft N-phenoxypropanol-N'-pyridazinyl ethylendiamines as β-receptor blockers
US4554282A (en) * 1981-02-26 1985-11-19 Warner-Lambert Company Substituted 2,2-dimethyl-5-phenoxypentanoic acid benzamides as anti-arteriosclerotic agents and method
US4603138A (en) * 1982-06-10 1986-07-29 Beecham Wuelfing Gmbh & Co. Kg Amine derivatives
US4599333A (en) * 1982-06-14 1986-07-08 Teikoku Hormone Mfg. Co., Ltd. Hydrazinopyridazine compound, process for production thereof, and use thereof as medicament
US5064863A (en) * 1983-10-19 1991-11-12 Hoffmann-La Roche Inc. Phenoxypropanolamines and pharmaceutical use
US5166218A (en) * 1983-10-19 1992-11-24 Hoffmann-La Roche Inc. Phenoxypropanolamines and pharmaceutical compositions thereof
US4772631A (en) * 1985-07-30 1988-09-20 Imperial Chemical Industries Plc Phenyl ethers
US4931474A (en) * 1986-08-06 1990-06-05 Nippon Kayaku Kabushiki Kaisha Ether derivative and an acaricidal or insecticidal composition comprising said derivative
US4892886A (en) * 1987-07-21 1990-01-09 Hoffman-La Roche Inc. Phenoxypropanolamines
US5187190A (en) * 1989-11-06 1993-02-16 Imperial Chemical Industries Plc Phenoxypropanolamine compounds
US5491134A (en) * 1994-09-16 1996-02-13 Bristol-Myers Squibb Company Sulfonic, phosphonic or phosphiniic acid β3 agonist derivatives

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BE741762A (en) 1970-05-19
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DE1957706A1 (en) 1970-05-27
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FR2023556B1 (en) 1974-05-24
CH522588A (en) 1972-06-30

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