Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3700681 A
Publication typeGrant
Publication dateOct 24, 1972
Filing dateFeb 16, 1971
Priority dateFeb 16, 1971
Also published asCA978962A1, DE2204195A1, DE2204195C2, DE2265581C2, US3763173
Publication numberUS 3700681 A, US 3700681A, US-A-3700681, US3700681 A, US3700681A
InventorsWayne E Barth
Original AssigneePfizer
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines
US 3700681 A
Abstract
2-Hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)-pyridines and salts thereof, a novel class of beta -adrenergic agonist bronchodilators in mammals, and 2-hydroxymethyl-3-benzyloxy-6-pyridinecarboxaldehyde a valuable intermediate in the preparation of the subject compounds.
Images(14)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent Barth Oct. 24, 1972 [54] 2-HYDROXYMETHYL-3-HYDROXY-6- [56] References Cited (l-HYDROXY-2- A A S AMINOETHYUPYRIDINES UNITED ST TBS P TENT Inventor: W y E. New London, Nauta C n.

on Primary ExaminerAlan L. Rotman [73] Assignee: Pfizer Inc., New York, NY. u & Hum

[22] Filed: Feb. 16, 1971 ABSTRACT [21] Appl. No.: 115,878

2-Hydroxymethyl-3-hydroxy-6-( 1-hydroxy-2- aminoethyD-pyridines and salts thereof, a novel class [52] US CL "260/296 260/295 260/295 8! of B-adrenergic agonist bronchodilators in mammals,

260/296 260/296 260/297 and 2-hydroxymethyl-3-benzyloxy--pyridinecarboxal- 260/2943 424/263 424/266 dehyde a valuable intermediate in the preparation of [51] Int. Cl. ..C07d 31/42 the Subject compounds [58] Field of Search ..260/296 R, 296 AB 9 Claims, No Drawings 2-HYDROXYMETHYL-3-HYDROXY-6-( l HYDROXY- 2-AMINOETHYL)PYRIDINES BACKGROUND OF THE INVENTION Following the reported bronchodilator action of 5 epinephrine by Matthews, Brit. Med. J., l, 441 (1910) many research programs have been undertaken in an effort to uncover new, more effective, oral agents free of any other pharmacologic actions, the most detrimental of which are cardiovascular side effects.

Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924) reported the use of the alkaloid ephedrine as an oral efficacious bronchodilator with the same spectrum of activity as epinephrine. In 1940, Konzett,

Arch. Exp. Path. Pharmak., 197, 27 (1940), outlined claimed as bronchodilators in South African Patent 67/5591.

A series of l-(2-halopyridyl)-2-aminoethanol analogs has been disclosed in Belgian Pat. No. 724834 as therapeutic agents having cardiovascular activity with some members of the series possessing utility as bronchodilators.

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.

Also within the purview of the instant invention is 2- hydroxymethyl-3-benzyloxy-6-pyridinecarboxaldehyde, a valuable intermediate employed in the synthesis of the subject compounds.

SUMMARY OF THE INVENTION The bronchodilators of this invention are represented by the formula:

I /CE1 noonrli lin NnRl CH1O I HOCH N GHQ The scope of this invention is also meant to encompass congeners of I wherein R is substituted alkyl containing from three to five carbon atoms said substituent being selected from the group consisting of monoand di(lower)a1kyl-amino; phenyloxy and substituted phenyloxy said substituent being hydroxy or methoxy; cycloalkyl containing from three to seven carbon atoms; and heterocyclic ring said heterocyclic ring containing one or more heteroatoms selected from the group consisting of sulphur, oxygen or nitrogen. Also useful as bronchodilators are compounds related to those of formula I bearing an alkyl substituent on the carbon atom ato the amino group as follows:

wherein R is alkyl containing from one to three carbon atoms and R, is as previously indicated.

35 DETAILED DESCRIPTION OF THE INVENTION In accordance with the process employed for the preparation of compounds of the instant invention the following scheme is illustrative:

I OH 1.Naon,on,0 I 001124 M1102 \N 240313 noon \N onion 5 e011: I onanoi n,

noon \N 0110 K100 noon smog aldeh de #01120 or kGgJIIB noon \N on Nnl NEBHaCN CH2O H2 no noon on NHR noon on HR1 N g N A In the first reaction step of the aforementioned scheme 3-hydroxypyridine, a commercial reagent, is

condensed with at least two moles of formaldehyde, to generate in situ the corresponding 2,6-bis(hydroxymethyl)-3-hydroxypyridine. Said reaction is most conveniently carried out in an aqueous solvent containing sodium hydroxide and at elevated temperatures,

preferably 100 C., for 2-4 hours.

Without isolation of the bis( hydroxymethyl)adduct 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. As much as a -20 percent excess of benzyl halide can be employed without altering the course of the reaction which leads to the corresponding 3-benzyloxy-2,6-bis(hydroxymethyl)pyridine. Reaction temperatures are not critical, longer reaction times being required for lower temperatures.

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. Altemately, 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.

Addition of the 3-benzyloxy-2,6-bis(hydroxymethyl)pyridine to a heated suspension of activated manganese dioxide in a reaction-inert solvent results in the oxidation of the 6-hydroxymethyl substituent to a carboxaldehyde. A suitable solvent for said oxidation is refluxing benzene, in which case the reaction time required for completion is 5-10 minutes.

Filtration of the hot suspension followed by removal of the solvent results in isolation of the crude product,

which can be further purified by chromatographing' over silica gel.

Condensation of the above aldehyde with nitromethane in the presence of a catalytic amount of potassium carbonate leads to the synthesis of 2-hydroxymethyl-3-benzyloxy-6( l-hydroxy-Z- nitroethyl)pyridine. Other 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. When the up-take of hydrogen ceases, generally 1-2 hours, the solvent, preferably methanol, 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. Said reducdescribed 2-hydroxymethyl-3-benzyloxy-6-(1-hydroxy 'Z-substituted aminoethyl)pyridine. Said reaction is 10 Y preferably effected using 5 percent palladium on charcoal and hydrogen gas. Experimentally, the precursor in a methanol solvent is shaken in a hydrogen atmosphere at an initial pressure of 30-50 p.s.i. When hydrogen uptake is complete the catalyst is filtered and the free base converted to the desired diacid salt by treatment with two equivalents of the requisite acid.

The aforedescribed scheme is especially applicable to the preparation of compounds wherein the alkyl-carbon substituted on the amino moiety is primary or secondary. Products of the present invention wherein said alkyl-carbon is tertiary, however, cannot be synthesized by the described scheme. Preparation of these analogs, as well as those wherein the amine is primary of secondary, is carried out by a modified route starting with 2-hydroxymethyl3-benzyloxy-6- pyridinecarboxaldehyde and a tertiary-alkyl isonitrile, t-R NC, as

follows:

HOOK N CH0 2. sq. HOl

acme

l 0 B2B] HOCH \N CH-llNH-t-Ri The first reaction of the above outlined route involves the reaction of the aforedescribed pyridinecarboxaldehyde derivatives with an isonitrile derived from a tert-amine. In practice, the aldehyde and isonitrile in a reaction-inert water-immiscible solvent, e.g., chloroform or benzene, containing acetic acid are heated to the reflux temperature of the solvent. Em

. ploying temperatures of 7080 C. requires a reaction time of 2 to 6 hours, with longer reaction periods for lower temperatures. On completion of the reaction 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. Altemately, catalytic reductions employing hydrogen can also be employed.

Removal of the solvent followed by partition of the product between chloroform and water containing 12N hydrochloric acid removes any non-basic byproducts.

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. Experimentally, 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. After allowing the reaction mixture to stir for several hours at room temperature it is heated to reflux for 30 to 60 minutes, cooled, and treated with sufficient ethanolic hydrogen chloride to form the insoluble hydrochloride salt. Liberation of the free base is carried out by treatment of an aqueous solution of the salt with sufficient sodium hydroxide solution to provide a solution of pH 11. The basic product is subsequently extracted with a suitable waterimmiscible solvent.

Debenzylation of the protecting group, the final step in the above described scheme, is effected in a manner as previously described wherein R is derived from a primary or secondary alkyl group.

In both aforedescribed reaction schemes the benzyl blocking group of the key intermediate, 2-hydroxymethyl-3-benzyloxy-6-pyridinecarboxaldehyde, can be substituted by a wide variety of protecting groups familiar to those skilled in the art and include simple substituted benzyl moieties wherein the nuclear substituent can be any common organic radical and the asubstituent can be alkyl, phenyl or carbethoxy or a,adialkyl. Further, 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). In turn, 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.

As has been previously noted, 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. In a similar manner, 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. 7

1n 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. Although 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.

Examples of acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, or sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, and gluconic.

As is obvious to one skilled in the art, compounds of the instant invention contain an asymmetric carbon atom at the site of the carbinol carbon atom on the amine bearing side chain. Thus, for each structure there is 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.

As previously indicated, 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-(p-methoxyphenyD- l methyIethyLamino}ethyllpyridine, and 2-hydroxymethyl-3-hydroxy-6-[ 1-hydroxy-2- 3-(p-hydroxyphenyl)-l-methylpropylamino ethyl]pyridine.

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. For oral administration in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically acceptable carriers. Where 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.

For purposes of parenteral administration and in halation, 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. When administered by means of a spray formulated as a 1% solution in an aqueous or nonaqueous solvent, e.g., freons, utilization several times a day is preferred.

It is necessary that the active ingredient form a proportion of the composition such that a suitable dosage form will be obtained. Obviously, several dosage unit forms may be administered at about the same time. Although 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.

Although the use of the present invention is directed toward the treatment of mammals in general, the 60 preferred subject is humans. In determining an efficacious dose for human therapy, results of animal testing are frequently extrapolated and a correlation is assumed between animal test behavior and proposed human dosage. When a commercially employed standard is available, the dose level of the clinical candidate in humans is frequently determined by comparison of its performance with the standard in an animal test. For

example, 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.

Obviously, 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.

Having full regard for the foregoing factors it is considered that 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 following examples are provided solely for the purpose of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I 2-Hydroxymethyl-3-hydroxy-6-( l-hydroxy-Z- isopropylaminoethyl)pyridine dihydrochloride A. 3-Benzyloxy-2,6-bis(hydroxymethyl)pyridine hydrochloride.

To a solution of 252 g. of sodium hydroxide in 1.2 l. of water is added 600 g. of 3-hydroxypyridine and 1.26 l. of 35 percent aqueous formaldehyde and the mixture heated on a steam bath for 2 hours and subsequently cooled to room temperature. A solution of 750 ml. of benzyl bromide in 4.5 l. of ethanol is then added dropwise over a period of minutes. After allowing the reaction mixture to stir for 16 hours, an additional 200 ml. of water containing 50 g. of sodium hydroxide and 150 ml. of benzyl bromide are added and the mixture heated at C. for 2 hours.

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.,

I l25-l28C.

A small sample is recrystallized for analysis, l28-l30 C.

Anal. Calcd. for C,,H,,CINO,:

C, 59.7; Found: C, 59.

H, 5.7; N, 5.0 8; H, 5.9; N, 4.6.

B. 2-l-lydroxymethyl-3-benzyloxy-6-pyridinecarboxaldehyde.

To a refluxing suspension of 190 g. of activated manganese dioxide in 3.5 l. of benzene is added 95 g. of 3- benzyloxy-2,6-bis(hydroxymethyDpyi-idine and refluxing continued for an additional 5 minutes. The suspension is filtered while warm and the filtrate concentrated in vacuo to an oil, 87.3 g.

The oil in chloroform is chromatographed through a silica gel column and eluted with chloroform in 500 ml. fractions. Fractions containing the desired material are combined, concentrated to dryness and the residual product recrystallized from ether, 19.05 g., m.p. 67-70 C. (Starting material was recovered from the column by elution with chloroform-methanol.) A 1 gram sample of the product is recrystallized further for analysis, m.p. 75.576 C.

Anal. Calcd. for u z a C, 69.1; H, 5.4; N, 5.8. Found: C, 69.0; H, 5.4; N, 5.6.

C. 2-Hydroxymethyl-3-benzyloxy-6-( l-hydroxy-2- nitroethyl)pyridine.

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.

D. 2-Hydroxymethyl-3-benzyloxy-6-( l-hydroxy- 2aminoethyl)pyridine.

The above crude 2-hydroxymethyl-3-benzyloxy-6- (1-hydroxy-2-nitroethyl)-pyridine, 45 g., in 500 ml. of methanol containing sealed cubes of ice, is hydrogenated over 45 g. of Raney nickel in an atmosphere of hydrogen at an initial pressure of 50 p.s.i. After 1.3 hours hydrogen up-take ceases, the catalyst is filtered, and the filtrate concentrated under reduced pressure to an oil. The residual oil is partitioned between 400 ml. of chloroform and 100 ml. of water containing 6.5 ml. 12N hydrochloric acid. The aqueous layer is separated, basified with sodium hydroxide solution to pH 11 and extracted with chloroform. The chloroform layer is separated, dried over sodium sulfate and concentrated in vacuo to an oil. The intermediate is employed in the next reaction without further purification.

E. 2-Hydroxymethyl-3-benzyloxy-6-( l-hydroxy-2- isopropylaminoethyl)pyridine.

A mixture of 18.8 g. of 2-hydroxymethyl-3-benzyloxy-6-(l-hydroxy-2-aminoethyl)pyridine, and 6.9 g. of sodium cyanoborohydride in 380 ml. of methanol containing 60 ml. of acetone and 30 ml. of 1.7N ethanolic hydrogen chloride is allowed to stir at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the residue partitioned between 250 ml. of chloroform and 75 ml. of water. The water layer is separated, basified with sodium hydroxide the product extracted into chloroform. The chloroform layer is dried over sodium sulfate and concentrated in vacuo to a dark oil which is extracted with 2 X 250 ml. of ether. The ether extracts are combined and concentrated in volume and cooled.

The solid product, which crystallizes, is filtered and dried, 7.0 g., m.p. 83-85 C.

Anal. Calcd. for lB ll 3 C, 68.3; H, 7.8; N, 9.0. Found: C 68.4; H, 7.7; N, 8.8.

sure provides the crude base as an oil, which is dissolved in ethanol and treated with 2 equivalents of ethanolic hydrogen chloride. To the resulting hazy solution is added 30 ml. of isopropyl ether. After cooling overnight in a refrigerator, the product is filtered, 4.69 g., m.p. 186 C. dec.

Anal. Calcd. for C,,H, Cl,N,O C, 44.2; H, 6 8; N, 9.4. Found: C, 44.2: H, 6 7; N, 9.4.

EXAMPLE II Starting with 2-hydroxymethyl-3-benzyloxy-6-(lhydroxy-2-aminoethyl)-pyridine prepared in Example I--D and the requisite ketone or aldehyde and repeating the procedures of Example I-E and F, the following compounds are preparedz 5 E0011. N 0Q NHRI 2-Hydroxymethyl-3-hydroxy-( l-hydroxy-2-tertbutylaminoethyl)pyridine dihydrochloride A. N-tert-Butyl-2-(5-benzyloxy-6-hydroxymethyl-2- pyridyl)-2-acetoxyacetamide.

A solution of 200 ml. of chloroform containing 30.0 g. of 2-hydroxy-methyl-3-benzyloxy-6-pyridinecarboxaldehyde, ml. of glacial acetic acid and 12.5 g. of tbutyl isonitrile is heated to reflux for 4 hours. The reaction is cooled and the chloroform extracted several times with aqueous sodium bicarbonate in order to remove the acetic acid present. The non-aqueous layer is separated, dried over sodium sulfate and concentrated in vacuo to viscous oil, 38 g., which is not further purified.

B. N-tert-Butyl-2-( 5-benzyloxy-6-hydroxymethyl-2- pyridyl)-2-hydroxyacetamide hydrochloride.

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.

Anal. Calcd. for lb u a a Found:

, 59. H, 6.4; N, 7.6. 59. H, 6.6; N, 7.2.

C. 2-Hydroxymethyl-3-benzyloxy-( l-hydroxy-2-tertbutylaminoethyl)pyridine.

To 78 ml. of a 1M solution of diborane in tetrahydrofuran under nitrogen and cooled to 0 C. is added dropwise over a period of minutes 13.5 g. of N-tert-buty1-2-(5-benzyloxy-6-hydroxymethyl-2- pyridyl)-2-hydroxy-acetamide in 250 ml. of the same solvent. the reaction mixture is allowed to stir at room temperature for 3.5 hours, and is then heated to reflux for 30 minutes and cooled to room temperature. Hydrogen chloride (70 ml. 1.34N) in ethanol is added dropwise, followed by the addition of 300 ml. of ether. The mixture is allowed to stir for 1 hour and is then filtered, l 1.0 g., mp. 202C., dec. The hydrochloride dissolved in water is treated with a sodium hydroxide solution to pH 1 1 and is extracted into chloroform (2 X 250 ml.). The chloroform layer is dried over sodium sulfate, concentrated to dryness in vacuo, and the residue recrystallized from isopropyl ether, 3.78 g., m.p. 8l83.5C. D. 2-Hydroxymethyl-3-hydroxy-(1-hydroxy-2-tert-bu tylarninoethyl)pyridine dihydrochloride.

A solution of 1.7 g. of 2-hydroxymethyl-3-benzyloxy- 6O (l-hydroxy-2-tert-butylaminoethyl)pyridine in 30 ml. of methanol containing 1.2 ml. of water is shaken with 700 mg. of 5 percent palladium-on-charcoal in an atmosphere of hydrogen at atmospheric pressure. In 17 minutes the theoretical amount of hydrogen has been consumed and the catalyst is filtered. Concentration of the filtrate under reduced pressure provides 1.4 g. of

12 the crude product as an oil. Ethanol (5ml.) is added to the residual oil followed by 6 ml. of 1.75N ethanolic hydrogen chloride solution and, finally, by 5 ml. of isopropyl ether. The precipitated product is filtered and washed with isopropyl ether containing 20 percent ethanol, 1.35 g., m.p. 182 C. dec.

Anal. Calcd. r6:

1 0 c,,H,,cl,N,o,= c, 46.0; H, 7.1; N, Found: C, 45.5; H, 7.1; N,

EXAMPLE IV The procedures of Example IH-A D are repeated, I 15 starting with 2-hydroxymethyl 3-benzyloxy-6- pyridinecarboxaldehyde andthe requisite isonitrile, to synthesize the following congeners:

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. 188 C., dec., is converted to the free base by treatment l1 and the organic layer is separated and the aqueous B. 2-Hydroxymethyl-3-hydroxy-6-[ l-hydroxy-2- {3-( pmethoxyphenyl)- l -methylpropylamino} ethyl]pyridine dihydrochloride.

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 VI Starting with 2-hydroxymethyl-3-benzyloxy-6-(1- hydroxy-Z-aminoethyl)-pyridine and the appropriate aldehyde or ketone, which are either commercial materials or reported in the chemical literature, and repeating the procedures of Example V, the following analogs synthesized: sythesized:

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. At

14 the end of one minute of exposure, the respiratorystatus, which is a reflection of bronchoconstriction, is evaluated. 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/

*Interval between dosing with drug and challenging with histamine EEQSQL. 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.

Employing the above-described procedure three agents are compared, salbutamol, isoproterenol and 2- hydroxymethyl-3-hydroxy-6-( l-hydroxy-2-t-butylaminoethyl)pyridine dihydrochloride.

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.

CONCINTIATIDN ace/ML.

Iig. 1

' A Ilopretntenol o Sllbutuol x 2-hydroxylethyl3-hydroxy6(l-hydroxy-Z- g-hucyluinoechynpyridinn hydrochloride T stand. error EXAMPLE IX Starting with 2-hydroxymethyl-3-benzyloxy-6-(1- hydroxy-2-aminoethyl)-pyridineprepared in Example 1-D and the requisite ketone or aldehyde and repeating the procedures of Example I-E and F the following congeners are prepared:

2-H0C|H40CH(CHa)OH:- Z-pyr'ldyl-(CHfldfH- CH3 2pyrldy1-(CH:):- 4-pyrldyl-(CH:);(|JH- 5 CH:

3-p rldyl-(CH 2-thienyl-(CH 2-f1ryl-(GH:)a 2-thlenyl-(CH;): 2-pyr1dyl-(CH;)4-- mum- 0H,

EXAMPLE X 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:

Sucrose, U.S.P. 80.3 Tapioca starch l 3.2 Magnesium stearate 6.5

17 Into this tablet base there is blended sufficient 2- hydroxymethyl-3-hydroxy-6-( l-hydroxy-Ztert-butylaminoethyl)pyridine to provide tablets containing 20, 100 and 250 mg. of active ingredient per tablet.

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.

The compositions are each compressed into tablets, 5

each weighing 360 mg., by conventional means.

EXAMPLE Xll Capsules A blend is prepared containing the following ingredients:

Calcium carbonate, U.S.P. Dicalcium phosphate Magnesium trisilicate, U.S.P. Lactose, U.S.P.

Potato starch Magnesium stearate A Magnesium stearate B To this blend is added sufficient 2-hydroxymethyl-3- hydroxy-6-[ l-hydroxy-Z- {3-( p-methoxyphenyl)- l methylpropylamino} ethyl]pyridine to provide capsules containing 5, l0 and 25 mg. of active ingredient per capsule. The compositions are filled into conventional hard gelatin capsules in the amount of 350 mg. per capsule.

EXAMPLE XIII Injectable Preparation EXAMPLE XIV Solution A solution of 2-hydroxymethyl-3-hydroxy-6-(lhydroxy-2-tert-butyl-aminoethyl)pyridine dihydrochloride is prepared with the following composition:

Effective ingredient 6.04 grams Magnesium chloride hexahydrate 12.36 grams Monoethanolamine 8.85 ml. Propylene glycol 376.00 grams Water, distilled 94.00 ml.

The resultant solution has a concentration of eflective ingredient of 10 mg./rnl. and is suitable for parenteral and especially for intramuscular administration.

EXAMPLE XV Suspension A suspension of Z-hydroxymethyl-3-hydroxy-6-[1- h ydroxy-2- 2-(p-hydroxyphenl)- l -methylethylarnino} ethyl]pyridine dihydrochloride is prepared with the following composition:

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.

propyl)pyridine dihydrochloride A. 2-Phenyl-3-oxo-2,3-dihydro-7-( l-hydroxypropyl)-5 H-[ l ,4]-dioxepino[6,5-b]-pyridine.

To an aqueous solution of 16.0 g. (0.4 mole) of sodium hydroxide in 160 ml. of water is added 32.3 g. (0.2

mole) of 3-hydroxy-2-hydroxymethyl-pyridine hydrochloride and the resulting solution warmed to 90 C. A solution of 13.9 g. (0.24 mole) of propionaldehyde in 40 ml. of ethanol is added dropwise over a period of one hour while the temperature of the reaction mixture is maintained at C. After 16 hours of continuous heating, 53.5 g. (0.22 mole) of ethyl abromophenylacetate in 60 ml. of ethanol is added and heating at 90 C. maintained for an additional 6 hours.

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.

Twenty grams of I Z-phenyl-3-oxo-2,3-dihydro-7- lhydroxypropyl)-5H-[ l,4]-dioxepino[6,5 b]pyridine are combined with 40 g. of activated manganese dioxide in 600 ml. of benzene and the resulting mixture heated to reflux for four hours during which time water is removed from the reaction with a Dean Stark trap. The mixture is filtered hot, the filtered solids washed with benzene and the combined washings and filtrate concentrated in vacuo. The residual, semicrystalline product is purified by recrystallization from ether. C. 2-Phenyl-3-oxo-2,3-dihydro-7-(a-bromopropionyD- 5l-l-[ 1,4] -dioxepino[6,5-b]-pyridine.

A solution of 14.9 g. (0.05 mole) of the above oxidation product, Z-phenyl-3-oxo-2,3-dihydro-7-propionyl- 51-1-[l,4]-dioxepino[6,5-b]pyridine, in 150 m1. of glacial acetic acid is warmed to 75 C. and treated with 8.0 g. (0.05 mole) of bromine in 60 ml. of the same solvent. Heating and stirring are maintained for 1 hour, after which the reaction mixture is cooled and the precipitated hydrobromide salt of the product is filtered. The filtered cake is suspended in 200 ml. of chloroform and sufficient 2 percent sodium hydroxide solution added to neutralize the hydrobromide salt. The chloroform layer is separated, dried over sodium sulfate and concentrated in vacuo. The resulting product is used directly in subsequent reactions without further purification. D. 2-Phenyl-3-oxo-2,3-dihydro-7-( l-hydroxy-2- bromopropyl)-5H-[ l ,4]-dioxepino-[ 6,5-b]pyridine.

To 11.3 g. (0.03 mole) of the above bromo ketone, 2-phenyl-3-oxo-2,3-dihydro-7-(a-bromopropionyD-S H-[l,4]-dioxepino[6,5-b]pyridine, in 200 ml. of

methanol is added 1.52 g. (0.04 mole) of sodium borohydride in ml. of water. The reaction mixture is allowed to stir at room temperature, after which it is concentrated in vacuo to 50 ml. The concentrate is treated with 50 ml. of water and 100 ml. of chloroform,

and the organic layer subsequently separated, dried over sodium sulfate and concentrated under reduced pressure. The oily residue is used without further purification.

E. .2-Hydroxymethyl-3-(a-[N-tert-butylcarbamyl]benzyloxy)-6-( 1-hydroxy-2-tert-butylaminopropyl)pyridine.

Eleven grams (0.15 mole) of tert-butylamine is added to 150 ml. of ethanol containing 11 g. (0.03 mole) of 2-phenyl-3 oxo-2,3-dihydro-7-( l-hydr0xy-2- bromopropyl)-5H-[ 1,4]-dioxepino[6,5-b]pyridine.

The resulting solution is heated to reflux for 2 hours, and is then cooled and the solvent removed in vacuo. The residue is extracted with chloroform which, in turn, is washed with water and dried over sodium sulfate. Removal of the solvent under reducedpres sure provides the crude product, which is used without further purification.

F. 2-Hydroxymethyl-3-hydroxy-6-(l-hydroxy-2-tertbutylaminopropyl)pyridine Dihydrochloride.

Five grams of 2-hydroxymethyl-3-(a-[N-tert-butylcarbamyl]benzyloxy-6-(1-hydroxy-2-tert-butylaminopropyl)pyridine and 1 g. of 10 percent palladiurn on charcoal in ml. of methanol containing 1 ml. of water is shaken in a hydrogen atmosphere at an initial pressure of 14 p.s.i. After one equivalent of hydrogen has been taken up, the catalyst is filtered and the filtrate concentrated to a small volume. The residue is treated with 20 ml. of 1N hydrochloric acid solution, washed with chloroform and 500 ml. of ethanol added to the aqueous acid solution. The aqueous-ethanol solution is concentrated in vacuo to remove excess water and the residual concentrate treated with ether to precipitate the hydrochloride salt of the desired product. Further purification is effected by recrystallization from ethanol-ether.

' EXAMPLE XVIII Starting with 3-hydroxy-2-hydroxymethylpyridine,

the appropriate aldehyde and the requisite amine, and

following the procedures of Example XVII-A-F, the following congeners are prepared:

The following isonitriles (isocyanides), not previously reported in the chemical literature, are prepared R NC PREPARATION B N-Formylamines What is claimed is: 1 A compound selected from those of the formula:

I CH2 HO CHz C NHR1 and the pharmaceutically acceptable acid addition salts thereof, wherein:

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. The compound of claim 1 wherein R is alkyl con taining from one to five carbon atoms.

3. The compound of claim 2 wherein R is iso-propyl. 4. The compound of claim 2 wherein R, is tert-butyl. 5. The compound of claim 1 wherein R is substituted phenylalkyl wherein said alkyl contains from three to five carbon atoms.

6. The' compound of claim 5 wherein R is 3-(4'- methoxyphenyl)- l-methylpropyl of the formula:

omO-Q-cInCmEH- 7. The compound of claim 5 wherein R, is 3- (4'- hydroxyphenyly 1 -methylpropyl of the formula:

lie-Germaniu- 8. The compound of claim 5 wherein R is 2-(4- methoxyphenyl) l-methylethyl of the formula:

CHzO-CH2CH 9. The compound of claim 5 wherein R is 2-(4- hydroxyphenyl)-1-methylethyl of the formula:

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,700,681 Page 1 of 2 DATED OCTOBER 24, 1972 |NVENTOR(S) WAYNE E. BARTH It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected asshown below:

Col. 6, line 47, "1-methylpropylamino ethyl]" should read 1-methylpropylamino3 ethyl] Col 7, line 56, "ingredient. the" should read ingredient. The

Col. 13, line 28, "analogs synthesized: synthesized" should read analogs are synthesized:

Col. 15, graph, "PERCENT MAXIMUM RAT INCREASE" should read PERCENT MAXIMUM RATE INCREASE Col. 15, second R column, last line, "2-pyridylCH CH-" n-C3H should read 2-pyridyl-CH CH- Col. 17, line 64, "p-hydroxyphenl)" should read p-hydroxyphenyl) Col. 18, fifth line from end of R column, "3,4-(CH2O) C H3(CH2)3-" should read 3,4-(CH202)C H3 (CH2)3- UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3,700, 81

DATED OCTOBER 24, 1972 INV WAYNE E. BARTH It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected asshown below:

Page 2 of 2 C01 20, 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.

Signed and Scaled this Eighteenth Day of March 1986 [SEAL] Arrest:

DONALD J. QUIGG Arresting Officer Commissioner ofhmm Ild Trudeau-ks

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3433796 *Aug 23, 1965Mar 18, 1969Koninklijke Pharma Fab NvEthers of alpha-(2-pyridyl) benzyl alcohols
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3948919 *Oct 9, 1974Apr 6, 1976Pfizer Inc.Adrenergic, bronchodilators
US3952101 *Apr 14, 1975Apr 20, 1976Smithkline CorporationBeta adrenergic stimulant
US4175128 *Jan 3, 1979Nov 20, 1979Pfizer Inc.Method for treating congestive heart failure
US4601897 *Nov 6, 1985Jul 22, 1986Pfizer Inc.Prazosin-pirbuterol combination for bronchodilation
US4632992 *Aug 16, 1984Dec 30, 1986Pfizer Inc.Bronchodilators; treatment of congestive heart failure
US7101534May 31, 1995Sep 5, 20063M Innovative Properties CompanySuspension aerosol formulations
US7105152May 31, 1995Sep 12, 20063M Innovative Properties CompanySuspension aerosol formulations
US7825147Aug 30, 2004Nov 2, 2010Ranbaxy Laboratories LimitedEnzyme inhibitors of phosphodiesterases for treatment of AIDS, asthma, arthritis, bronchitis and other disorders
US7915286Sep 11, 2006Mar 29, 2011Ranbaxy Laboratories LimitedSubstituted pyrazolo [3,4-b] pyridines as phosphodiesterase inhibitors
US8420666Mar 14, 2008Apr 16, 2013Ranbaxy Laboratories LimitedPyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors
US8507670Aug 21, 2007Aug 13, 2013Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
US8816073Jul 8, 2013Aug 26, 2014Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
US8846910Jul 8, 2013Sep 30, 2014Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
EP0058070A2 *Feb 8, 1982Aug 18, 1982Pfizer Inc.Process for preparing pirbuterol
EP1958947A1Feb 15, 2008Aug 20, 2008Ranbaxy Laboratories LimitedInhibitors of phosphodiesterase type 4
EP2111861A1Apr 21, 2008Oct 28, 2009Ranbaxy Laboratories LimitedCompositions of phosphodiesterase type IV inhibitors
EP2322507A1Aug 21, 2007May 18, 2011Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
EP2474531A2Aug 21, 2007Jul 11, 2012Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
WO1993000090A1 *Jun 25, 1992Jan 7, 1993Sepracor IncMethods and compositions for treating pulmonary and cardiac disorders using optically pure (+) pirbuterol
WO1993000091A1 *Jun 25, 1992Jan 7, 1993Sepracor IncMethods and compositions for treating pulmonary and cardiac disorders using optically pure (-)pirbuterol
WO2005092860A1 *Mar 11, 2005Oct 6, 2005Alan Daniel BrownCompounds for the treatment of diseases
WO2007045979A1Oct 19, 2006Apr 26, 2007Ranbaxy Lab LtdPharmaceutical compositions of muscarinic receptor antagonists
WO2008111010A1Mar 14, 2008Sep 18, 2008Ranbaxy Lab LtdPyrazolo (3, 4-b) pyridine derivatives as phosphodiesterase inhibitors
WO2012014114A1Jul 14, 2011Feb 2, 2012Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
WO2012038942A1Sep 26, 2011Mar 29, 2012Ranbaxy Laboratories LimitedMatrix metalloproteinase inhibitors
WO2014087298A1Nov 25, 2013Jun 12, 2014Pfizer Inc.Novel selective androgen receptor modulators
Classifications
U.S. Classification546/300, 546/301, 514/826
International ClassificationC07D491/04, C07D317/58, C07D213/65
Cooperative ClassificationC07D317/58, C07D491/04, C07D213/65, C07C251/00, Y10S514/826
European ClassificationC07C251/00, C07D317/58, C07D213/65, C07D491/04
Legal Events
DateCodeEventDescription
Mar 18, 1986CCCertificate of correction