Classifications

• • 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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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1969
  • 1969-11-17 SE SE15762/69A patent/SE368197B/xx unknown
  • 1969-11-17 DE DE1957706A patent/DE1957706C3/de not_active Expired
  • 1969-11-17 CA CA067,618A patent/CA957364A/en not_active Expired
  • 1969-11-17 BE BE741762D patent/BE741762A/xx not_active IP Right Cessation
  • 1969-11-17 ES ES373606A patent/ES373606A1/es not_active Expired
  • 1969-11-18 CH CH1716569A patent/CH522588A/fr not_active IP Right Cessation
  • 1969-11-18 FR FR6939589A patent/FR2023556B1/fr not_active Expired
  • 1969-11-18 JP JP44091872A patent/JPS501012B1/ja active Pending
• 1970
  • 1970-05-11 US US00036461A patent/US3723524A/en not_active Expired - Lifetime

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