Claims
- 1. A chemical compound of the formula: ##STR5##or a pharmaceutically acceptable acid addition salt of said compound, wherein:
- R is hydrogen or methyl, with both R's not being methyl at the same time;
- R.sub.1 is branched chain lower alkyl of from 3 to 5 carbon atoms, cycloalkyl or cycloalkylmethyl, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##STR6##R.sub.2 and R.sub.3 are hydrogen, hydroxy, methoxy or, taken together in adjacent positions, methylenedioxy; and
- R.sub.4 is hydrogen or methyl.
- 2. The chemical compound according to claim 1 in which R is hydrogen.
- 3. A chemical compound according to claim 2 in which R.sub.1 is t-butyl, being the compound .alpha.-(t-butylaminomethyl)-3-(1,2-dihydroxyethyl)-4-hydroxy-benzyl alcohol.
- 4. The chemical compound according to claim 2 in which R.sub.1 is cyclopentyl, being the compound .alpha.-(cyclopentylaminomethyl)-3-(1,2-dihydroxyethyl)-4-hydroxy-benzyl alcohol.
- 5. The chemical compound according to claim 2 in which R.sub.1 is isopropyl, being the compound 3-(1,2-dihyroxyethyl)-4-hydroxy-.alpha.-isopropylaminomethyl-benzyl alcohol.
- 6. The chemical compound according to claim 2 in which R.sub.1 is 2-(3,4-methylenedioxyphenyl)-1-methylethyl, being the compound 3-(1,2-dihydroxyethyl)-4-hydroxy-.alpha.-[2-(3,4-methylenedioxyphenyl)-1-methylethylaminomethyl]-benzyl alcohol.
- 7. The chemical compound according to claim 2 in which R.sub.1 is 2-(4-hydroxyphenyl)-1,1-dimethylethyl, being the compound 3-(1,2-dihydroxyethyl)-4-hydroxy-.alpha.-[2-(4-hydroxyphenyl)-1,1-dimethylethylaminomethyl]-benzyl alcohol.
- 8. A chemical compound of the formula: ##STR7##wherein: R is hydrogen or methyl, with both R's not being methyl at the same time;
- R.sub.1 is branched chain lower alkyl of from 3 to 5 carbon atoms, cycloalkyl or cycloalkylmethyl, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##STR8##R.sub.2 and R.sub.3 are hydrogen, hydroxy, methoxy or, taken together in adjacent positions, methylenedioxy; and
- R.sub.4 is hydrogen or methyl.
- 9. The chemical compound according to claim 8 in which R is hydrogen.
- 10. A pharmaceutical composition having .beta.-adrenergic stimulant activity in dosage unit form comprising a pharmaceutical carrier and an effective amount of a chemical compound of the formula: ##STR9##or a pharmaceutically acceptable acid addition salt of said compound, wherein:
- R is hydrogen or methyl, with both R's not being methyl at the same time;
- R.sub.1 is branched chain lower alkyl of from 3 to 5 carbon atoms, cycloalkyl or cycloalkylmethyl, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##STR10##R.sub.2 and R.sub.3 are hydrogen, hydroxy, methoxy, or, taken together in adjacent positions, methylenedioxy; and
- R.sub.4 is hyrogen or methyl.
- 11. The pharmaceutical composition according to claim 10 in which R is hydrogen.
- 12. The pharmaceutical composition according to claim 11 in which R.sub.1 is t-butyl, the active ingredient being the compound .alpha.-(t-butylaminomethyl)-3-(1,2-dihydroxyethyl)-4-hydroxybenzyl alcohol.
- 13. A method of producing .beta.-adrenergic stimulant activity which comprises administering internally to animals in need thereof an amount sufficient to produce said activity of a chemical compound of the formula: ##STR11## or a pharmaceutically acceptable acid addition salt of said compound, wherein:
- R is hydrogen or methyl, with both R's not being methyl at the same time;
- R.sub.1 is branched chain lower alkyl of from 3 to 5 carbon atoms, cycloalkyl or cycloalkylmethyl, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##STR12##R.sub.2 and R.sub.3 are hydrogen, hydroxy, methoxy, or, taken together in adjacent position, methylenedioxy; and
- R.sub.4 is hydrogen or methyl.
- 14. The method according to claim 13 in which R is hydrogen.
- 15. The method according to claim 14 in which R.sub.1 is t-butyl, the active ingredient being the compound .alpha.-(t-butylaminomethyl)-3-(1,2-dihydroxyethyl)-4-hydroxybenzyl alcohol.
- 16. The chemical compound according to claim 1 in which one of the R's is hydrogen and the other is methyl.
- 17. The chemical compound according to claim 16 in which R.sub.1 is t-butyl.
- 18. The chemical compound according to claim 17 being the compound .alpha.-(t-butylaminomethyl)-4-hydroxy-3-(2-hydroxy-1-methoxyethyl)-benzyl alcohol.
- 19. The chemical compound according to claim 17 being the compound .alpha.-(t-butylaminomethyl)-4-hydroxy-3-(1-hydroxy-2-methoxyethyl)-benzyl alcohol.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 18669/75 |
May 1975 |
UK |
|
FORMULA I
This application is a continuation-in-part of application Ser. No. 475,675 filed June 3, 1974, now abandoned.
This invention relates to novel .alpha.-aminoalkyl-3-(1,2-dihydroxyethyl)-4-hydroxy-benzyl alcohols which have useful pharmacodynamic activity. More specifically, the compounds of this invention have utility as .beta.-adrenergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle. Therefore these compounds have direct bronchodilator action with minimal cardiac stimulation as demonstrated in standard pharmacological test procedures.
Two in vitro test systems used for determining selective .beta.-stimulant activity are: (1) effect on spontaneous tone of guinea pig tracheal chain preparations as a measure of .beta.-stimulant (direct relaxant) effect on airway smooth muscle, and (2) effect on rate of spontaneously beating right atria of the guinea pig as a measure of .beta.-stimulant effect on cardiac muscle. The compounds of this invention have selective bronchodilating properties since they are active in (1) above at a dose lower than is required in (2) above resulting in a positive separation ratio.
The compounds of this invention are represented by the following general structural formula: ##STR1##
R represents hydrogen or methyl, with both R's not being methyl at the same time;
R.sub.1 represents a branched chain lower alkyl group of from 3 to 5 carbon atoms, a cycloalkyl or cycloalkyl methyl group, the cycloalkyl moiety having from 3 to 6 carbon atoms, or ##STR2##
R.sub.2 and R.sub.3 represent hydrogen, hydroxy, methoxy, or taken together in adjacent positions, methylenedioxy; and
R.sub.4 represents hydrogen or methyl.
Preferred compounds of this invention are represented by formula I above when R is hydrogen and R.sub.1 is isopropyl, t-butyl, cyclopropyl, cyclopentyl, 4-hydroxyphenylisopropyl, 3,4-methylenedioxyphenylisopropyl or 3,4-dimethoxyphenylisopropyl.
The compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art, are formed with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, glyconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl sulfamic, phosphoric and nitric acids.
Further the compounds of this invention contain two asymmetric carbon atoms and may be present as diastereoisomers, each of which may be resolved as d and l-optical isomers. Unless otherwise specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mixtures thereof.
A preferred compound of this invention is .alpha.-(t-butylaminomethyl)-3-(1,2-dihydroxyethyl)-4-hydroxy-benzyl alcohol which relaxes the spontaneous tone of guinea pig tracheal ring preparation at an ED.sub.50 of 0.018 mcg/ml while increasing the rate of contraction of guinea pig right atria at an ED.sub.25 of 1.9 mcg/ml. These activities give an absolute separation ratio of 105 which is a 210 fold improvement when compared to the corresponding activity of d, 1-isoproterenol (absolute separation ratio = 0.5) in similar in vitro preparations.
The compounds of this invention where R is hydrogen are prepared as shown in the following sequence of reactions: ##STR3## in which Ac is acetyl and R.sub.1 is as defined in formula I. Thus, as shown above, an appropriately protected acetophenone is treated with bromine or pyrrolidone hydrotribromide to give the .alpha.-bromoacetophenone. The latter is reacted with an N-benzylamine and the resultant .alpha.-benzylaminoacetophenone is treated with sodium borohydride to give the corresponding benzyl alcohol intermediate. This compound is hydrogenated catalytically, preferably with palladium-on-carbon, to give the debenzylated dihydroxyethyl benzyl alcohol product.
Similarly, to prepare the compounds of this invention where R is methyl, the analogous 1-methoxy-2-acetoxy or 1-acetoxy-2-methoxy acetophenone is used as the starting material in the above sequence of reactions.
It will be appreciated that the benzylated derivatives of the following formula: ##STR4## in which R and R.sub.1 are as defined in formula I, are useful intermediates in the preparation of the products of this invention and as such form a part of the invention.
The protected acetophenones used as starting materials herein are prepared by methods known in the art. For example, methyl salicylate is treated with acetyl chloride under Friedel-Crafts reaction conditions to yield methyl 5-acetylsalicylate which is reacted with benzyl chloride in the presence of potassium hydroxide or potassium carbonate to give the corresponding benzyl ether. The latter is treated with ethylene glycol and p-toluenesulfonic acid, followed by reduction of the resultant 1,3-dioxolane, with lithium aluminum hydride to the salicyl alcohol. This derivative is oxidized to a benzaldehyde using manganese dioxide which is then treated with trimethylsulfonium iodide and sodium hydride in dimethylsulfoxide to convert the aldehyde group to an epoxide. Treatment of the epoxide with perchloric acid in dioxane yields 4-benzyloxy-3-(1,2-dihydroxyethyl)-acetophenone; acid catalyzed methanolysis of the epoxide gives the 3-(2-hydroxy-1-methoxyethyl)acetophenone; and treatment of the epoxide with sodium methoxide-methanol gives a mixture of primary and secondary alcohols which is separated to give the 3-(1-hydroxy-2-methoxyethyl)acetophenone. Subsequent acetylation in pyridine furnishes the required acetylated acetophenones.
U.S. Pat. No. 3,644,353 describes .alpha.-aminoalkyl-4-hydroxy-3-(hydroxyalkyl)-benzyl alcohols, however, there is no disclosure of the 3-(1,2-dihydroxyethyl)benzyl alcohols of this invention. In addition to structural features, the compounds of this invention are further distinguished by having marked separation between bronchodilator action and cardiac stimulation.
The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables, aerosols, or the like, by incorporating the appropriate dose of a compound of formula I with carriers according to accepted pharmaceutical practices.
Preferably a compound or an acid addition salt thereof is administered orally to an animal organism in a tablet or capsule comprising an amount sufficient to produce .beta.-adrenergic stimulant activity. Each dosage until will contain the active ingredient in an amount of about 10 mg. to about 500 mg., preferably from about 20 mg. to about 300 mg. Advantageously equal doses will be administered 2 to 4 times daily with the daily dosage regimen being about 20 mg. to about 2000 mg., preferably from about 40 mg. to about 1200 mg.
The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule, or an aqueous or nonaqueous liquid suspension.
Of particular applicability is an aerosol dispensing system wherein the active medicament is incorporated with Freon (fluorohydrocarbon) or other inert propellant in an aerosol container. Such an aerosol system will deliver a metered dose of about 100 mcg. to about 1000 mcg. administered once or twice at a time as needed.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
|
3705233 |
Lunts et al. |
Dec 1972 |
|
|
3732300 |
Lunts et al. |
May 1973 |
|
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
475675 |
Jun 1974 |
|
Patent Grant
4012528
