US3655676A - 4-hydroxy-3-hydroxymethylphenyl-2-piperidinylcarbinols - Google Patents
4-hydroxy-3-hydroxymethylphenyl-2-piperidinylcarbinols Download PDFInfo
- Publication number
- US3655676A US3655676A US91222A US3655676DA US3655676A US 3655676 A US3655676 A US 3655676A US 91222 A US91222 A US 91222A US 3655676D A US3655676D A US 3655676DA US 3655676 A US3655676 A US 3655676A
- Authority
- US
- United States
- Prior art keywords
- hydroxy
- hydroxymethylphenyl
- compounds
- erythro
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
Definitions
- This invention relates to 4-hydroxy-3-hydroxymethylphenyl-2-piperidinylearbinols which have useful pharmacodynamic activity. More specifically the compounds of this invention have utility as 'fi-adren'ergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle. Therefore these compounds have direct brorichodilato'r action with minimal cardiac stimulation as demonstrated in standard pharmacological test procedures.
- Two in vitro test systems used for determining selective fl-stimulant activity are: (1) eifect on spontaneous tone of guinea pig tracheal chain preparations as a measure of ,B -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 B-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 may be present as diastereoisomers and are designated as erythroand theroisomers which may be resolved as d, 1 optical isomers. Unless otherwise specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mixtures thereof.
- the compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utlity of the free base.
- Such salts are formed with both inorganic or organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic methanesulfonic, ethanedisulfonic, acetic, oxalic, propionie, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl, sulfamic, phosphoric and nitric acids.
- a preferred compound of this invention is erythro-4- hydroxy 3 hydroxymethylphenyl 2 piperidinylcarbinol which relaxes the spontaneous tone of guinea pig tracheal ring preparation at an ED of 0.125 mcg./ ml. while increasing the rate of contraction of guinea pig right atria less than 25% at a dose of 15 mcg./ml.
- the compounds of this invention are prepared from a sequence of reactions illustrated by the following preparation of 4-hydroxy-3-hydroxymethylphenyl-Z-piperdinylcarbinol:
- a lower alkyl ether derivative of an appropriately substituted methylbenzaldehyde is condensed with a 2-halopyridine, preferably bromo, in the presence of an organometal derivative, preferably butyl lithium, and in an organic nonreactive solvent such as tetrahydrofuran or ether to give a substituted phenyl 2- pyridylcarbinol.
- a 2-halopyridine preferably bromo
- an organometal derivative preferably butyl lithium
- organic nonreactive solvent such as tetrahydrofuran or ether
- the ketone is demethylated with 48% hydrobromic acid and then reduced with for example platinum oxide and hydrogen to give the 3- carboxy 4 hydroxyphenyl 2 piperidihylcarbinol. This results in a mixture of erythro-threo isomers present in about a 4:1 ratio.
- the acid is then reduced to the desired hydroxymethylphenyl derivative by reacting it with a suitable reducing agent such as borane in a nonreactive organic solvent.
- a benzyl ether derivative of an appropriately substituted hydroxybenzaldehyde is condensed as above with a 2-halopyridine to give a substituted phenyl-2- pyridylcarbinol.
- the ketone is reduced with platinum oxide and hydrogen to give the corresponding 2-piperidinylcarbinol which is debenzylated with palladium-on-carbon and hydrogen to yield the hydroxyphenyl-2-piperidinylcarbinol.
- a further modification of the preparation of the compounds of this invention is the condensation of the Grignard reagent derived from a methyl ether derivative of an appropriately substituted hydroxy halobenzene, preferably bromobenzene, with 2-cyanopyridine.
- the resulting ketone is oxidized, demethylated, and reduced as described above to give the product.
- the erythro and threo diastereoisomers of the compounds of Formula I may be separated, for example, by fractional crystallization of the product, preferably as an acid addition salt.
- the compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of Formula I, with carriers according to accepte pharmaceutical practices.
- a compound or an acid addition salt thereof is administered orally to an animal organism in tablet or capsule comprising an amount sufficient to produce fl-adrenergic stimulant activity.
- Each dosage unit will contain the active medicament in an amount of about 25 mg. to about 50 mg.
- Advantageously equal doses will be administered 3 to 4 times daily with the daily dosage regimen being about 75 mg. to about 200 mg.
- the pharmaceutical carrier employed may be, for example, either a solid or liquid.
- solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- liquid carriers are syrup, peanut oil, olive oil, water and the like.
- 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.
- a solid carrier 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.
- a liquid carrier 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.
- an aerosol dispensing system wherein the active medicament is incorporated with Freon or other inert propellant is an aerosol container.
- Such an aerosol system will deliver a metered dose of about 250 mcg. to about 500 mcg., administered once or twice at a time as needed.
- a liquid formulation in a plastic squeeze bottle is also useful for this purpose.
- a stirred suspension of 30.0 g. (0.131 m.) of the above carbinol in 250 ml. of water is heated to 70 C. and 72.0 g. (0.45 m.) of potassium permanganate is added in portions.
- the mixture is stirred and heated on a steam bath for 30 minutes and an additional 12.0 g. (0.08 m.) of potassium permanganate is added.
- the mixture is heated at 90 C. for 30 minutes more and then filtered through Super-Cel.
- the filtrate is concentrated in vacuo to approximately 60 ml. and acidified with acetic acid to yield 4 3-carboxy-4-methoxyphenyl 2 pyridyl ketone with an M.P. of 250 C.
- a mixture fo 3.0 g. of platinum oxide and a solution of 12.0 g. of 3-carboxy-4hydroxyphenyl-2-pyridy1 ketone hydrobromide in 200 ml. of methane is hydrogenated on the Parr apparatus using an initial hydrogen pressure of 50 p.s.i. at room temperature.
- the reaction mixture is filtered, the filtrate concentrated in vacuo and the residue triturated with acetone and filtered to give erythro-3-carb0xy-4-hydroxyphenyl 2 piperidinylcarbinol hydrobromide, M.P. 219 C. (decomp.).
- the acetone filtrate is concentrated to yield threo-3-craboxy-4-hydroxyphenyl- 2-piperidylcarbinol.
Abstract
4-HYDROXY - 3 - HYDROXYMETHLPHENYL -2 - PIPERIDINYLCARBNOLS PREPARED BY THE CONDESSATION OF AN APPROPRIATELY SUBSTITUTED ETHER DERIVATIVE OF A METHYLBENZALDEHYDE WITH 2-PYRIDYL LITHIUM FOLLOWED BY OXIDATION OF THE METHYL GROUP, REMOVAL OF THE ETHER GROUP, AND REDUCTION OF THE CARBOXY PYRIDINE HAVE B-ADRENERGIC STIMULANT ACTIVITY. ERYTHRO AND THERO DIASTEREOISOMERS MAY BE CONVENIENTLY SEPARATED.
Description
United States Patent ABSTRACT OF THE DISCLOSURE 4 hydroxy 3 hydroxymethylphenyl 2 piperidinylcarbinols prepared by the condensation of an appropriately substituted ether, derivative of.a methylbenzaldehyde with 2-py1fidyl lithium followed by oxidation of the methyl group, removal of the ether group, and reduction of the carboxy pyridine'have fl-adrenergie stimulant activity. Erythro and thero diaste'reoisomers may be conveniently separated."
This invention relates to 4-hydroxy-3-hydroxymethylphenyl-2-piperidinylearbinols which have useful pharmacodynamic activity. More specifically the compounds of this invention have utility as 'fi-adren'ergic stimulants with relatively greater activity on respiratory smooth muscle than on cardiac muscle. Therefore these compounds have direct brorichodilato'r action with minimal cardiac stimulation as demonstrated in standard pharmacological test procedures.
Two in vitro test systems used for determining selective fl-stimulant activity are: (1) eifect on spontaneous tone of guinea pig tracheal chain preparations as a measure of ,B -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 B-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:
Hoca H FORMULA I The compounds of this invention may be present as diastereoisomers and are designated as erythroand theroisomers which may be resolved as d, 1 optical isomers. Unless otherwise specified in the description and accompanying claims, it is intended to include all isomers, whether separated or mixtures thereof.
The compounds of this invention may be used in the form of a pharmaceutically acceptable acid addition salt having the utlity 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, bismethylenesalicyclic methanesulfonic, ethanedisulfonic, acetic, oxalic, propionie, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexyl, sulfamic, phosphoric and nitric acids.
A preferred compound of this invention is erythro-4- hydroxy 3 hydroxymethylphenyl 2 piperidinylcarbinol which relaxes the spontaneous tone of guinea pig tracheal ring preparation at an ED of 0.125 mcg./ ml. while increasing the rate of contraction of guinea pig right atria less than 25% at a dose of 15 mcg./ml. These data demonstrate significant potential bronchodilating activity without concomitant cardiac stimulation.
The compounds of this invention are prepared from a sequence of reactions illustrated by the following preparation of 4-hydroxy-3-hydroxymethylphenyl-Z-piperdinylcarbinol:
CH3 CH0 Z-bromopyridine CHEO BEL).
S KMnO,
onao E H000 1 1i 2 P o onao t 2. 2
on J; on
n Hooo- B2B noon.
HO THF HO n Thus, as shown above, a lower alkyl ether derivative of an appropriately substituted methylbenzaldehyde is condensed with a 2-halopyridine, preferably bromo, in the presence of an organometal derivative, preferably butyl lithium, and in an organic nonreactive solvent such as tetrahydrofuran or ether to give a substituted phenyl 2- pyridylcarbinol. The latter is oxidized for example with excess potassium permanganate to yield 3-carboxy-4- methoxyphenyl-Z-pyridyl ketone. The ketone is demethylated with 48% hydrobromic acid and then reduced with for example platinum oxide and hydrogen to give the 3- carboxy 4 hydroxyphenyl 2 piperidihylcarbinol. This results in a mixture of erythro-threo isomers present in about a 4:1 ratio. The acid is then reduced to the desired hydroxymethylphenyl derivative by reacting it with a suitable reducing agent such as borane in a nonreactive organic solvent.
Alternatively a benzyl ether derivative of an appropriately substituted hydroxybenzaldehyde is condensed as above with a 2-halopyridine to give a substituted phenyl-2- pyridylcarbinol. Following oxidation of the methyl group, the ketone is reduced with platinum oxide and hydrogen to give the corresponding 2-piperidinylcarbinol which is debenzylated with palladium-on-carbon and hydrogen to yield the hydroxyphenyl-2-piperidinylcarbinol.
A further modification of the preparation of the compounds of this invention is the condensation of the Grignard reagent derived from a methyl ether derivative of an appropriately substituted hydroxy halobenzene, preferably bromobenzene, with 2-cyanopyridine. The resulting ketone is oxidized, demethylated, and reduced as described above to give the product.
If desired the erythro and threo diastereoisomers of the compounds of Formula I may be separated, for example, by fractional crystallization of the product, preferably as an acid addition salt.
The compounds of this invention may be administered orally or parenterally in conventional dosage unit forms such as tablets, capsules, injectables or the like, by incorporating the appropriate dose of a compound of Formula I, with carriers according to accepte pharmaceutical practices. Preferably a compound or an acid addition salt thereof is administered orally to an animal organism in tablet or capsule comprising an amount sufficient to produce fl-adrenergic stimulant activity. Each dosage unit will contain the active medicament in an amount of about 25 mg. to about 50 mg. Advantageously equal doses will be administered 3 to 4 times daily with the daily dosage regimen being about 75 mg. to about 200 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 for intranasal administration is an aerosol dispensing system wherein the active medicament is incorporated with Freon or other inert propellant is an aerosol container. Such an aerosol system will deliver a metered dose of about 250 mcg. to about 500 mcg., administered once or twice at a time as needed. Also useful for this purpose is a liquid formulation in a plastic squeeze bottle.
The foregoing is a general description of how to prepare the compounds of this invention. The following example illustrates the preparation of specific compounds having fl-adrenergic stimulant activity and shouldd not be construed as a limitation of the invention.
EXAMPLE A stirred solution of 187.5 ml. of 1.6 M solution of butyl lithium in hexane is cooled to -40 C. under nitrogen and 39.5 g. (0.25 m.) of 2-bromopyridine in 100 ml. of ether is added dropwise. The mixture is stirred 15 minutes at 40 C. and a solution of 41.5 g. (0.25 m.) of 3-methyl-4-methoxybenzaldehyde in 200 ml. of ether is added. After stirring at 15 C. for 45 minutes, the mixture is poured into 500 g. ice/ 100 ml. concentrated hydrochloric acid. The separated aqueous layer is made alkaline with concentrated ammonium hydroxide, extracted with ether and the dried extract concentrated. The residual oil is crystallized to give 3-methyl-4-methoxyphenyl- 2-pyridylcarbinol.
A stirred suspension of 30.0 g. (0.131 m.) of the above carbinol in 250 ml. of water is heated to 70 C. and 72.0 g. (0.45 m.) of potassium permanganate is added in portions. The mixture is stirred and heated on a steam bath for 30 minutes and an additional 12.0 g. (0.08 m.) of potassium permanganate is added. The mixture is heated at 90 C. for 30 minutes more and then filtered through Super-Cel. The filtrate is concentrated in vacuo to approximately 60 ml. and acidified with acetic acid to yield 4 3-carboxy-4-methoxyphenyl 2 pyridyl ketone with an M.P. of 250 C.
A solution of 49.0 g. of the above ketone in 500 ml. of 48% hydrobromic acid is refluxed for two hours and then concentrated in vacuo. The residue is dissolved in ethanol, toluene is added, the solution concentrated and the residue stripped with toluene to yield 3-carboxy-4- hydroxyphenyl-Z-pyridyl ketone hydrobromide.
A mixture fo 3.0 g. of platinum oxide and a solution of 12.0 g. of 3-carboxy-4hydroxyphenyl-2-pyridy1 ketone hydrobromide in 200 ml. of methane is hydrogenated on the Parr apparatus using an initial hydrogen pressure of 50 p.s.i. at room temperature. The reaction mixture is filtered, the filtrate concentrated in vacuo and the residue triturated with acetone and filtered to give erythro-3-carb0xy-4-hydroxyphenyl 2 piperidinylcarbinol hydrobromide, M.P. 219 C. (decomp.). The acetone filtrate is concentrated to yield threo-3-craboxy-4-hydroxyphenyl- 2-piperidylcarbinol.
Treatment of the above hydrobromide with equeous sodium bicarbonate yields the free base of the carbinol, M.P. 250 C. 0.91 g. (.0036 m.) of the erythro amino acid is added to an ice cold solution of 40 cc. of 1 M borane in tetrahydrofuran (0.04 M) while stirring un der nitrogen. The temperature is kept at 0 C. for 20 hours. The solution is then refluxed one hour under nitrogen and concentrated in vacuo. Three portions of methyl alcohol are added, the solution is concentrated and the residue is dissolved in ethanol and filtered. Sulfuric acid is added to a pH of 2.0 and the filtered product is recrystallized from ethanol-water yielding erythro-4-hydroxy- 3 hydroxymethylphenyl-2-piperidinyl-carbinol sulfate as white crystals having a melting point of 400 C.
The threo 3 carboxy-4-hydroxyphenyl-2-piperidinylcarbinol is reduced with borane in the same fashion to yield threo 4 hydroxy 3 hydroxymethylphenyl 2- piperidinylcarbinol. I
What is claimed is:
1. A chemical compound of the formula:
in a uoca 11 HN I or a pharmaceutically acceptable acid addition salt of said compound.
2. The erythro diastereoisomer of the compound according to claim 1.
3. The threo diastereoisomer of the compound according to claim 1.
References Cited UNITED STATES PATENTS 2,976,291 3/1961 Jacob et al. 424267
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9122270A | 1970-11-19 | 1970-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3655676A true US3655676A (en) | 1972-04-11 |
Family
ID=22226674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US91222A Expired - Lifetime US3655676A (en) | 1970-11-19 | 1970-11-19 | 4-hydroxy-3-hydroxymethylphenyl-2-piperidinylcarbinols |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3655676A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3985887A (en) * | 1973-10-19 | 1976-10-12 | Smithkline Corporation | 3-Substituted-4-hydroxyphenyl-2-piperidylcarbinols as β-adrenergic stimulants |
| WO1991018602A1 (en) * | 1990-06-01 | 1991-12-12 | Merrell Dow Pharmaceuticals Inc. | (+)-α-(2,3-DIMETHOXYPHENYL)-1-[2-(4-FLUOROPHENYL)ETHYL]-4-PIPERIDINEMETHANOL |
| US6004980A (en) * | 1990-06-01 | 1999-12-21 | Merrell Pharmaceuticals, Inc. | (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol |
| US6028083A (en) * | 1997-07-25 | 2000-02-22 | Hoechst Marion Roussel, Inc. | Esters of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol |
-
1970
- 1970-11-19 US US91222A patent/US3655676A/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3985887A (en) * | 1973-10-19 | 1976-10-12 | Smithkline Corporation | 3-Substituted-4-hydroxyphenyl-2-piperidylcarbinols as β-adrenergic stimulants |
| WO1991018602A1 (en) * | 1990-06-01 | 1991-12-12 | Merrell Dow Pharmaceuticals Inc. | (+)-α-(2,3-DIMETHOXYPHENYL)-1-[2-(4-FLUOROPHENYL)ETHYL]-4-PIPERIDINEMETHANOL |
| US5134149A (en) * | 1990-06-01 | 1992-07-28 | Merrell Dow Pharmaceuticals Inc. | (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol |
| US5700812A (en) * | 1990-06-01 | 1997-12-23 | Merrell Pharmaceuticals Inc. | (+)-α-(2,3-dimethoxyphenyl)-1- 2-(4-fluorophenyl)ethyl!-4-piperidinemethanol |
| US5700813A (en) * | 1990-06-01 | 1997-12-23 | Merrell Pharmaceuticals Inc. | (+)-α-(2,3-dimethoxyphenyl)-1- 2-(4-fluorophenyl)ethyl!-4-piperidinemethanol |
| US5874445A (en) * | 1990-06-01 | 1999-02-23 | Merrell Pharmaceutical, Inc. | (+) -α- (2,3-dimethoxyphenyl)-1-(2-(4-fluorephenyl) ethyl)-4-piepridinemethanol |
| US6004980A (en) * | 1990-06-01 | 1999-12-21 | Merrell Pharmaceuticals, Inc. | (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol |
| US6028083A (en) * | 1997-07-25 | 2000-02-22 | Hoechst Marion Roussel, Inc. | Esters of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol |
| US6063793A (en) * | 1997-07-25 | 2000-05-16 | Hoechst Marion Roussel, Inc. | Esters of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidi nemethanol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3661917A (en) | 3-sulfonamido-4-hydroxyphenyl-2-piperidylcarbinols | |
| US3743737A (en) | 3-sulfonamido-4-hydroxyphenyl-2-piperindinylcarbinol compositions | |
| US3952101A (en) | α-Amino methyl-5-hydroxy-2-pyridinemethanols | |
| US3538104A (en) | Pyridyl-2-imidazolones | |
| US4514414A (en) | N-Substituted pyrrolidineacetic acids and their esters | |
| US3655676A (en) | 4-hydroxy-3-hydroxymethylphenyl-2-piperidinylcarbinols | |
| US3711545A (en) | Alpha-aminoalkyl-4-hydroxy-3-sulfamoylaminobenzyl alcohols | |
| US3917704A (en) | Alpha-aminoalkyl-4-hydroxy-3-alkylsulfonylmethylbenzyl alcohols | |
| US3705169A (en) | Hydroxyphenyl-2-piperidinylcarbinols | |
| US3910934A (en) | Process for the preparation of {60 -(hydroxy and alkoxy substituted)phenyl-{60 -(2-piperidinyl)-methanols | |
| US2966493A (en) | Certificate of correction | |
| US3851059A (en) | Method for the stimulation of appetite in patients | |
| US3795677A (en) | Aryl 4-piperidyl ketone derivatives | |
| US3408396A (en) | alpha-cyclohexyl-3, 4-disubstituted-phenyl acetamides | |
| US3598829A (en) | Certain isoxazolylpyridines and isothiazolylpyridines | |
| US3879557A (en) | Compositions for producing {62 -adrenergic stimulant with 4-hydroxy-3-hydroxymethylphenpyl-2-piperidinylcarbinols | |
| US3843794A (en) | Pharmaceutical compositions comprising hydroxyphenyl-2-piperidinylcarbinols | |
| US3985887A (en) | 3-Substituted-4-hydroxyphenyl-2-piperidylcarbinols as β-adrenergic stimulants | |
| US3910933A (en) | 3-Substituted-4-hydroxyphenyl-2-piperidylcarbinols | |
| US3637712A (en) | Piperidylpropanol compounds | |
| US3691172A (en) | Hydroxyphenyl-2-decahydroquinolylcarbinols | |
| US4004028A (en) | Phenoxypropanolamines | |
| US3773954A (en) | Hydroxyphenyl-2-decahydroquinolyl-carbinols in producing beta-adrenergic stimulant activity | |
| US2997478A (en) | Oxygenated piperidines and processes for their manufacture | |
| US3966770A (en) | 4-Hydroxy-α-[(3,4-methylenedioxyphenyl)isopropylaminoethyl]-3-(methylsulfonylmethyl)benzyl alcohol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 Owner name: SMITHKLINE BECKMAN CORPORATION Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 |