US3700681A - 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines - Google Patents

2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines Download PDF

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US3700681A
US3700681A US115878A US3700681DA US3700681A US 3700681 A US3700681 A US 3700681A US 115878 A US115878 A US 115878A US 3700681D A US3700681D A US 3700681DA US 3700681 A US3700681 A US 3700681A
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hydroxy
hydroxymethyl
pyridine
benzyloxy
chloroform
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Wayne E Barth
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to 2-hydroxymethyl-3-hydroxy-6-( l-hydroxy-2-aminoethyl)pyridines, and more particularly to a series of substituted amino derivatives and salts thereof and to the use of said agents as bronchodilators in mammals. These agents are of particular interest because of their improved selectivity for pulmonary over cardiac tissue compared to similar agents in use today.
  • R is alkyl containing from one to three carbon atoms and R, is as previously indicated.
  • reaction is most conveniently carried out in an aqueous solvent containing sodium hydroxide and at elevated temperatures,
  • the sasfienninm is r t d w at least was 1 1 f a benzyl halide, e.g., benzyl bromide, and a water-miscible, unreactive solvent, generally ethanol, to assist in solublizing the halide.
  • a benzyl halide e.g., benzyl bromide
  • a water-miscible, unreactive solvent generally ethanol
  • Isolation of the desired product is conveniently carried out by first removing in vacuo the ethanol solvent followed by extraction of the product with a water-immiscible solvent, such as chloroform.
  • the product can be isolated by removal of the solvent.
  • the product can be converted to the hydrochloride salt by treatment of the dried chloroform layer with gaseous hydrogen chloride until a precipitate no longer forms.
  • nitroalkanes can be employed in said condensation and result in the corresponding 2-alkyl nitroalcohols. It is preferred that the nitroalkane be employed as the solvent, and is subsequently recovered at the completion of the reaction by removal from the product under reduced pressure.
  • Reduction of the nitro group of the above described nitroalcohol is effected using Raney nickel in a hydrogen atmosphere at an initial pressure of 50 p.s.i. and with cooling.
  • the solvent preferably methanol
  • the solvent is removed in vacuo and the product separated from non-basic by-products by partitioning I aminoalcohol with aldehydes or ketones is carried out with the reducing agent sodium cyanoborohydride in a reaction-inert solvent, e.g., lower alkanols.
  • a reaction-inert solvent e.g., lower alkanols.
  • Said reaction is 10 Y preferably effected using 5 percent palladium on charcoal and hydrogen gas.
  • the precursor in a methanol solvent is shaken in a hydrogen atmosphere at an initial pressure of 30-50 p.s.i.
  • the catalyst is filtered and the free base converted to the desired diacid salt by treatment with two equivalents of the requisite acid.
  • the first reaction of the above outlined route involves the reaction of the aforedescribed pyridinecarboxaldehyde derivatives with an isonitrile derived from a tert-amine.
  • a reaction-inert water-immiscible solvent e.g., chloroform or benzene, containing acetic acid are heated to the reflux temperature of the solvent.
  • ploying temperatures of 7080 C. requires a reaction time of 2 to 6 hours, with longer reaction periods for lower temperatures.
  • the acetic acid is removed by employing an aqueous sodium bicarbonate wash, and the non-aqueous layer over tion is effected in the presence of anhydrous hydrogen a suitable drying agent and the solvent removed in chloride at ambient temperature with a reaction time of l224 hours.
  • anhydrous hydrogen a suitable drying agent and the solvent removed in chloride at ambient temperature with a reaction time of l224 hours.
  • catalytic reductions employing hydrogen can also be employed.
  • the aqueous layer is subsequently made basic with aqueous sodium hydroxide and the product, as the free Reduction of the hydroxyacetamide derivative to the corresponding aminoalcohol is efiected in a reactioninert solvent, preferably tetrahydrofuran, using the reducing agent diborane.
  • a reactioninert solvent preferably tetrahydrofuran
  • the N-tertalkyl-2-( S-benzyloxy-6-hydroxymethyl-2-py1idyl)-2- hydroxyacetamide in tetrahydrofuran is added over a 30 to 40 minute period to diborane in the same solvent and cooled to C.
  • the benzyl blocking group of the key intermediate 2-hydroxymethyl-3-benzyloxy-6-pyridinecarboxaldehyde
  • the nuclear substituent can be any common organic radical and the asubstituent can be alkyl, phenyl or carbethoxy or a,adialkyl.
  • other protecting techniques can be employed including phenacyl, cyanomethyl and formation of an acetonide.
  • the starting reagents for the aforedescribed reaction schemes are either commercially available or can be prepared by one skilled in the art according to procedures outlined in the chemical literature.
  • the requisite aldehydes and ketones can be synthesized according to the synthetic methods reported by Patai, Chemistry of the Carbonyl Group, Interscience Publishers, 1966, New York, N.Y., chapters 4, 5 and 6; and Camduff, Quart. Rev., 20, (1966).
  • the isonitriles are prepared from the corresponding N-formyl amines according to the procedure of Ugi, et al., Chem. Ber., 94, 2814 (1961).
  • the N-formyl amines are available via the Ritter reaction, outlined in Organic Reactions, John Wiley & Sons, Inc., 1969, New York, N.Y., chapter 3, page 213.
  • compounds of the instant invention can form acid addition salts.
  • Basic compounds of the present invention are converted to the acid addition salts by interaction of the base with an acid either in an aqueous or non-aqueous medium.
  • treatment of the acid addition salts with an aqueous base solution e.g., alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or with a metal cation which forms an insoluble precipitate with the acid anion, results in a regeneration of the free base form.
  • Such conversions are best carried out as rapidly as possible and under temperature conditions and method dictated by the stability of said basic products.
  • the bases thus regenerated may be reconverted to the same or a different acid addition salt.
  • the utilization of the chemotherapeutic activity of those compounds of the present invention which form salts it is preferred, of course, to use pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts water-insolubility, high toxicity, or lack of crystalline nature may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the waterinsoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt as described above, or alternately they can be converted to any desired pharmaceutically acceptable acid-addition salt.
  • acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, and gluconic.
  • compounds of the instant invention contain an asymmetric carbon atom at the site of the carbinol carbon atom on the amine bearing side chain.
  • a pair of enantiomorphs which are exactly the same in their chemical and physical properties, but which differ in the direction they will rotate the plane of polarized light.
  • Resolution of the pair into optically active isomers can be carried out by methods familiar to those skilled in the art and which are reviewed by Gilman, Organic Chemistry An Advanced Treatise, John Wiley & Sons, Inc., New York, N.Y., 1953, Vol. 1, chapter 4, page 214.
  • 2-hydroxymethyl-3-hydroxy-6-(l-hydroxy-2-aminoethyl)pyridines of the present invention are all readily adapted to therapeutic use as smooth muscle relaxants and in particular as bronchodilators.
  • Compounds notable for this therapeutic use with a high specificity for pulmonary as opposed to cardiac tissue include 2-hydroxymethyl-3-hydroxy-6 l-hydroxy-2-isopropylaminoethyl)pyridine, 2- hydroxymethyl-3-hydroxy-6-( l-hydroxy-Z-tert-butylaminoethyl)pyridine, 2-hydroxymethyl-3-hydroxy-6- 1-hydroxy-2- ⁇ 3-(p-methoxyphenyl)- 1 -methylpropylamino ⁇ ethyl]pyri dine, 2-hydroxymethyl-3- hydroxy-6-[ 1-hydroxy-2- ⁇ Z-(p-hydroxyphenyl )-1- 7 methylethylamino ⁇ ethyl]pyridine, 2-hydroxymethyl-3- hydroxy-6,-[ l-hydroxy-2- ⁇ Z-
  • the pyridylethanolamines and the pharmaceutically acceptable salts thereof, which are useful bronchodilators in mammals, may be administered either as individual therapeutic agents or as mixtures of therapeutic agents. They may be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents, or filters, sterile aqueous media and various nontoxic organic solvents. Moreover, the oral pharmaceutical compositions of this invention may be suitably sweetened and flavored by means of various agents of the type commonly used for this purpose.
  • the particular carrier selected and the proportion of active ingredient to carrier are influenced by the soluginic acids, and certain complex silicates, together with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, may also be used in producing tablets for the oral administration of these compounds.
  • lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc
  • lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers.
  • aqueous suspensions are to be used for oral administration, the compounds of this invention may be combined with emulsifying or suspending agents. Diluents such as ethanol, propylene glycol, glycerine and their combinations may be employed as well as other materials.
  • solutions or suspensions of the instant compounds in sesame or peanut oil or in aqueous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the soluble acid addition salts described hereinafter.
  • These particular solutions are especially suited for intramuscular and subcutaneous injection purposes.
  • the aqueous solutions including those of the acid addition salts dissolved in pure distilled water, are also useful for intravenous injection purposes provided that their pH is properly adjusted beforehand.
  • Such solutions should also be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the compounds may be administered to subjects suffering from bronchoconstriction by means of inhalators or-other devices which permit the active compounds to come into direct contact with the constricted areas of the tissues of the subject.
  • inhalators or-other devices which permit the active compounds to come into direct contact with the constricted areas of the tissues of the subject.
  • a spray formulated as a 1% solution in an aqueous or nonaqueous solvent, e.g., freons utilization several times a day is preferred.
  • compositions with less than 0.005 percent by weight of active ingredient might be used in certain instances, it is preferred to use compositions containing not less than 0.005 percent of the active ingredient; otherwise the amount of carrier becomes excessively large.
  • Activity increases with the concentration of the active ingredient.
  • the composition may contain 10, 50, 75, 95 or an even higher percentage by weight of the active ingredient.
  • the use of the present invention is directed toward the treatment of mammals in general, the 60 preferred subject is humans.
  • results of animal testing are frequently extrapolated and a correlation is assumed between animal test behavior and proposed human dosage.
  • the dose level of the clinical candidate in humans is frequently determined by comparison of its performance with the standard in an animal test.
  • theophylline is employed as a standard bronchodilator and is administered to humans at the rate of 150 to 300 mg. every 4 hours. It is assumed, then, that if compounds of the present invention have activity comparable to theophylline in the test assay, that similar doses will provide comparable responses in humans.
  • the physician will ultimately determine the dosage which will be most suitable for a particular individual, and it will vary with the age, weight and response of the particular patient as well as with the nature and extent of the symptoms and the pharmacodynamic characteristics of the particular agent to be administered. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. It will often be found that when the composition is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quantity administered parenterally.
  • an effective daily dosage of the compounds of the present invention in humans of approximately 1 to 20 mg..per day, witha preferred range of about5 to 20 mg. per day in single or divided doses, or at about 0.07 to 0.28 mg./kg. of body weight will effectively al- I leviate bronchoconstriction in human subjects.
  • These values are illustrative, and there may, of course, be individual cases where higher or lower dose ranges are merited.
  • the reaction mixture is cooled, concentrated in vacuo and the residual oil extracted in 6 l. of chloroform.
  • the chloroform layer is washed with water, 5 percent sodium hydroxide solution and dried over sodium sulfate. Gaseous hydrogen chloride is bubbled into the chloroform layer until a precipitate of the product as the hydrochloride salt ceases to form. Filtration and drying provides the crude product, 943.6 g.,
  • a suspension of 30 g. of 2-hydroxymethyl-3- benzyloxy-6-pyridine-carboxaldehyde and 3.0 g. of potassium carbonate in 150 ml. of nitromethane is heated to reflux and maintained at that temperature for 10 minutes.
  • the dark solution is filtered while hot and the filtrate concentrated in vacuo to an oil, 45 g., which is subsequently used without further purification.
  • the reaction mixture consisting of 38 g. of N-tertbutyl-2-( 5-benzyloxy-6-hydroxymethyl-2-pyridy)-2- acetoxyacetamide, 500 ml. of water and ml. of l2N hydrochloric acid solution is heated on a steam bath for 1.5 hours. The hot solution is decanted from an insoluble dark oil and the decant cooled overnight in a refrigerator. The precipitated monohydrochloride salt, which forms on standing, is filtered, g. A small sample is recrystallized from ethanol, m.p., 195 dec. The remainder is treated with an aqueous sodium hydroxide solution and the resulting free base extracted into chloroform.
  • the chloroform layer is separated, dried over sodium sulfate and concentrated under reduced pressure to dryness, 22 g., m.p. l28-130 C.
  • a small sample is recrystallized from isopropyl ether, m.p. 128129.5 C.
  • EXAMPLEV Z-Hydroxymethyl-3-hydroxy-6-[- l -hydroxy-2- ⁇ 3-(pmethoxyphenyl 1 -methylpropylarnino ⁇ ethyl pyridine dihydrochloride extracted (2 X 100 ml.) with additional chloroform. The organic layers are combined, dried over sodium sulfate and concentrated under reduced pressure to an oil. The residual product is converted to the dihydrochloride salt by addition of 30 ml. of ethanol and 10 ml. of 3.2 N hydrogen chloride in the same solvent. The crude salt of the desired product, 3.8 g., m.p.
  • a suspension of 700 mg. of 5% palladium on charcoal in 50 ml. of methanol containing 1.48 g. of 2- hydroxymethyl-3-benzyloxy-6-[ l -hydroxy-2- ⁇ 3-(p methoxyphenyl l -methylpropylamino ⁇ ethyl ]pyridine and 1 ml. of water is shaken in a hydrogen atmosphere at an initial pressure of 50 psi. for 90 minutes.
  • the catalyst is filtered and the oil which remains, after the solvent is removed in vacuo, is treated with 8 ml. of ethanol and 3 ml. of 3.2N hydrogen chloride in ethanol. Addition of 8 ml. of isopropyl ether followed by heating on a steam bath for a few minutes results in a solution from which precipitates the desired salt.
  • the product is finally filtered and dried, 560 mg., mp. 172 C., dec.
  • EXAMPLE VII Bronchodilator Activity Conscious female guinea pigs, which have been fasted for 12 hours, receive oral or parenteral dosages of the compound which is to be tested for effectiveness. Control animals receive doses of saline solution which do not contain the compound which is under test. Subsequent to this administration, each animal is chal-i 1 lenged with histamine aerosol.
  • the challenge procedure consists of spraying a 0.4 percent aqueous solution of histamine, at a pressure of 5 lb./in. into an 8 X 8 X 12 inch plastic container for l minute. lmmediately after the container is subjected to the histamine spray the animal is placed within it.
  • the respiratorystatus which is a reflection of bronchoconstriction
  • Evaluation levels are designated and scored as normal breathing (0), slightly deepened breathing (I), labored breathing (2), severely labored breathing and ataxis (3) and unconsciousness (4).
  • Each group of animals contains 8 to 10 individuals and a control group containing the same approximate number is used.
  • the scores for the control group and the group which has been treated with the compound under test are compared and the difference is expressed as per- HOCHg- N Percent protection Time* Dose, a/
  • Salbutamol l5 EXAMPLE VIII Isolated Guinea Pig Atria As previously indicated compounds of the present invention displayed a specificity for pulmonary as opposed to cardiac tissue compared to other bronchodilators.
  • the positive chronotropic activities of the tested drug are measured using the atria of female Reed-Willett guinea pigs (600--1,000 g.). The animals are sacrificed by a blow on the back of the head. The atria are quickly removed and dissected free of extraneous tissue in at 37 C. Tyrodes solution is constantly oxygenated with a 0 5% CO mixture. The atria .are suspended under 2 g. tension in 10 ml. jacketed baths containing the same media. The beats were recorded via a statham face displacement transducer model FT .03 on a Grass Polygraph. Cumulative dose responses are obtained, adding drug aliquots every 5 minutes, the interval necessary for development of maximal chronotropic effects. Tissues were repeatedly washed in the 1-2 hour interval between determinations to restore rates to normal level.
  • Concentration vs. response curves comparing percent maximum rate increase in the isolated guinea pig right atria with concentrationof drug in mcgJrnl. is illustrated in FIG. 1.
  • Example IIl-A-D The procedures of Example IIl-A-D are repeated, starting with the requisite isonitrile and 2-hydrox- Tablets
  • a tablet base is prepared by blending the following 65 ingredients in the proportion by weight indicated:
  • Glycerine U.S.P. 185.35 g. Gum acacia (10% solution) 100.00- ml. Polyvinylpyrrolidonc 0.50 g. Distilled Water Sufficient to make I liter.
  • compositions are each compressed into tablets, 5
  • the resultant solution has a concentration of eflective ingredient of 10 mg./rnl. and is suitable for parenteral and especially for intramuscular administration.
  • Effective ingredient m M QP FWPFWL To this suspension, various sweeteners and flavorants are added to improve the palatability of the suspension.
  • the suspension contains approximately mg. of effective agent per milliliter.
  • the reaction mixture is cooled, the majority of the ethanol removed in vacuo and 500 ml. of chloroform added.
  • the organic phase is washed with 2 percent sodium hydroxide solution and the product extracted from the chloroform with 100 ml. of percent hydrochloric acid solution.
  • the aqueous acid solution is back-washed with chloroform and finally neutralized with 5 percent sodium hydroxide solution.
  • the product is extracted (2 X 100 ml.) into chloroform and the organic phase separated, dried over sodium sulfate and concentrated under reduced pressure to provide the desired product as a viscous oil.
  • the product is further purified by chromatographing on a silica-gel column.
  • B 2-Phenyl-3-oxo-2,3-dihydro-7-propiony1-5H-[ 1,4]- dioxepino[6,5-b]pyridine.
  • R is selected from the group consisting of hydrogen, alkyl containing from one to five carbon atoms and 22 phenylalkyl and substituted phenylalkyl wherein said alkyl group contains from three to five carbon atoms and said substituent is selected from the group consisting of hydroxy, methoxy, 3 ,4-dimethoxy and 5 2.
  • R is alkyl con taining from one to five carbon atoms.
  • R is iso-propyl. 4.
  • R is tert-butyl. 5.
  • R is substituted phenylalkyl wherein said alkyl contains from three to five carbon atoms.
  • Page 2 of 2 C01 9, ninth line in R1 column "4-HOC H4 (CH )2C(CH3) should read 4-HOC H4(CH2)2C(CH3)2 C01. 22, line 4, "3 ,4-dimethoxy and” should read and 3,4-dimethoxy.

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US115878A 1971-02-16 1971-02-16 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines Expired - Lifetime US3700681A (en)

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Cited By (29)

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US3948919A (en) * 1973-12-26 1976-04-06 Pfizer Inc. 2-Hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-t-butylaminoethyl)pyridine preparation and intermediate compounds
US3952101A (en) * 1975-04-14 1976-04-20 Smithkline Corporation α-Amino methyl-5-hydroxy-2-pyridinemethanols
JPS5246081A (en) * 1975-10-03 1977-04-12 Pfizer 22hydroxymethyll33hydroxyy66 *11hydroxyy22ttbuthylaminoethyl* pyridine and intermediate product preparation method thereof
JPS5329935A (en) * 1976-08-26 1978-03-20 Pfizer Lung function promoting medical composition
US4175128A (en) * 1979-01-03 1979-11-20 Pfizer Inc. Method for treating congestive heart failure
EP0058070A3 (en) * 1981-02-09 1982-08-25 Pfizer Inc. Process for preparing pirbuterol
US4601897A (en) * 1985-11-06 1986-07-22 Pfizer Inc. Prazosin-pirbuterol combination for bronchodilation
US4632992A (en) * 1981-02-09 1986-12-30 Pfizer Inc. Intermediates for preparing pirbuterol and analogs
WO1993000091A1 (en) * 1991-06-26 1993-01-07 Sepracor, Inc. Methods and compositions for treating pulmonary and cardiac disorders using optically pure (-)pirbuterol
WO1993000090A1 (en) * 1991-06-26 1993-01-07 Sepracor, Inc. Methods and compositions for treating pulmonary and cardiac disorders using optically pure (+) pirbuterol
US20050075383A1 (en) * 2003-08-29 2005-04-07 Palle Venkata P. Inhibitors of phophodiesterase type-IV
WO2005092860A1 (en) * 2004-03-23 2005-10-06 Pfizer Limited Compounds for the treatment of diseases
US7101534B1 (en) 1991-12-18 2006-09-05 3M Innovative Properties Company Suspension aerosol formulations
US7105152B1 (en) 1991-12-18 2006-09-12 3M Innovative Properties Company Suspension aerosol formulations
WO2007045979A1 (en) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Pharmaceutical compositions of muscarinic receptor antagonists
US20070259874A1 (en) * 2003-11-26 2007-11-08 Palle Venkata P Phosphodiesterase Inhibitors
EP1958947A1 (en) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type 4
WO2008111010A1 (en) 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Pyrazolo (3, 4-b) pyridine derivatives as phosphodiesterase inhibitors
US20090054382A1 (en) * 2005-10-19 2009-02-26 Abhijit Ray Compositions of phosphodiesterase type iv inhibitors
EP2111861A1 (en) 2008-04-21 2009-10-28 Ranbaxy Laboratories Limited Compositions of phosphodiesterase type IV inhibitors
US20100029728A1 (en) * 2006-09-22 2010-02-04 Ranbaxy Laboratories Limited Phosphodiesterase inhibitors
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AT315842B (de) 1974-06-10
NL7201471A (enExample) 1972-08-18
CH541560A (fr) 1973-10-31
GB1367669A (en) 1974-09-18
DE2204195C2 (de) 1981-11-19
US3763173A (en) 1973-10-02
NL174349C (nl) 1984-06-01
DE2265581C2 (de) 1982-07-01
GB1367668A (en) 1974-09-18
DE2204195A1 (de) 1972-08-17
NL174349B (nl) 1984-01-02
FR2125309B1 (enExample) 1976-05-14
FR2125309A1 (enExample) 1972-09-29
BE778771A (fr) 1972-08-01

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