5-hydroxy-{60 (substituted aminomethyl)-mu-xylene-{60 ,{60 -diols
United States Patent Schwender et al.  
 [ 1 5-HYDROXY-a(SUBSTlTUTED AMINOMETHYL)-MU-XYLENE-a,a-DIOLS [75] Inventors: Charles F. Schwender, Lebanon;  
 John Shavel, Jr., Mendham, both of NJ.  
 [73] Assignees Warner-Lambert Company, Morris Plains, NJ.  
 [22 Filed: Dec. 26, 1973 211 App]. No.: 428,557  
 Related US. Application Data [62] Division of Ser. No. 275,6l 1, July 27, I972.  
 [52] US. Cl 260/471 R; 260/519; 260/570.6;  
  424/309; 424/319; 424/330 [5]] Int. Cl. C070 101/42 [58] Field of Search 260/471 R, 519, 570.6  
 [56] References Cited UNITED STATES PATENTS 3,686,271 8/l972 Lefon 260/47l R Primary E.\-aminerLorraine A. Weinberger Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmAlbert H. Graddis; Frank S.  
 Chow  
 [ Apr. 22, 1975 57 ABSTRACT Compounds of the formula:  
  9 HOHCHZNHQ cu, R t  
 no cu 1cu 5 Claims, No Drawings 1 S-HYDROXY- a (SUBSTITUTED AMINOMETHYL)-MU-XYLENE-a,a-DIOLS This is a division, of application Ser. No. 275,611  
  Referring now to the above reaction scheme, the synthesis of the compounds of the invention:  
  on filed July 27, 1972. C 6 3 The present invention relates to novel compounds. 5 More particularly, the present invention relates to com- R1 pounds having the following structural formula:  
  CH3 no -on,0n ouoncumnd-cm-M I 1&#39; l involve the formation of the mono methyl ester of S-benzyloxyisophthalate (II). The intermediate H0 cmon benzyloxy-3-carboxy-a-(methylsulfinyl)-acetophenone (Ill) is obtained by treatment of II with dimethylsulfinyl wherem 1 and 2 are y g 1 1S methyl, anion. Aqueous acetic acid treatment of III causes a 2 is hydrogen P y Substituted the P Pummerer rearrangement of III and to give the methyl Position y y y alkoxy, &#39;p y or y thiomethyl acetal (IV) and subsequent hydrolysis to having carbon atoms branched or Stfalght chalnthe corresponding substituted phenylglyoxal product Among the Preferred Species those Compounds V. Reductive amination of IV or V with the appropriate wherein R1 and 2 are hydrogen; 2 15 y Pg and 1 amine and KBI-L, gives 3-benzyloxy-5-[2-(substituted i5 y and Where 1 is methyl and 2 15 p y amino)1-(hydroxy)ethyl]-benzoic acid, VI. Esterifi- I dd esters of the above compounds h s cation of VI with methanol and ethanesulfonic acid acetate, prop ate, benzoate, succinate, as ll as gives the ester VII, which is reduced with LiAlH, to azolidine derivatives, are also features of this invention. iv VIII, C l i reduction d b l VIII d The compounds of this invention also form salts with ives the desired product, IX. pharmaceutically acceptable acids or bases and these Th compound 1X i l th i d f di h l salts are also included within the scope of this inven- 5 h d i h h l (X) b reaction i h di h tion. sulfinyl anion giving the intermediate methyl 5- According to the present invention, the above comsh d 3[ th 1 ]fi 1) acetyubenzoate (XI), pounds are prepared by reactions which are illustrated A id- 1 d pummel-er rearrangement f X] by the following reaction scheme: gives the corresponding methylthiomethyl acetal (XII) (mocha (B sos Hno C O O CH: H5O nCHzO- C O 0 CH1 0 0 0 /SCH3 1-CHz CH: 91-03 OCH: 1150601110 COOH HsQflCHzO CO0H III I\&#39; 0 out ECHO CHOHCHzNHJfCHaRe l RI KBH, NHQC(CH3)R;CH2R2 HsC CHzO COOH HsCeCHgO COOH out no c moncmml donut: d&#39;HcHiNH 0 out) mount.  
 H5C5CH10- COQCH: H5C5CH1O CHnOI].  
 VII VIII H0 cat (JHCHINHdJCHzRu R1 i CHIOH and subsequent hydrolysis to the corresponding substituted phenylglyoxal product, XIII. Reductive amination of XII or XIII with LiAll-I yields S-hydroxy-a- (substituted aminomethyl)m-xylene&#39;a-a&#39;diol (IX). Alternatively, reductive amination of XII or XIII-with KBl-I, and the appropriate amine gives ester intermediate XIV. Reduction of XIV with LiAll-I gives IX.  
 hydroxyisophthalate,&#39;171 g (1 mole) of benzylbromide and 138 g (1 mole) of K CO in 1 l. of acetone was refluxed for 18 hours. The reaction mixture was evaporated to a residue which was extracted with hot cyclohexane to give the crystalline product in a quantitative yield upon cooling. The analytical sample was obtained by recrystallization from cyclohexane, mp. 94-95.  
 C O OCH: O OCH:  
 DMS O H NaH IIO COOCHa lIO- -%3CH@SCH1 X XI  CH: C O OCH; 0 O OCH: CIIOHCHgNHCCI-IQRE OCH: LiAlHi II HO fi-Cg HO (&#34;L-CHO NH2C (CH3) R CH1R2 IIO CHaOlI 0 S OH:  
 XII XIII IX KBH ,NH2C (CHJ)R1GH21{2 LIAII&#39;I; ([JHOHCHzNHCWHURiCHaR:  
 HO- O 0 OCH:  
 XIV  
 The compounds of this invention have bronchodilator (B-sympathomimetic) activity useful in the treatment of bronchial asthma and related bronchial spasms. In animals such as dogs, a dose of about 0.1-5 mg/kg (i.p.) is effective to prevent an increase in pulmonary resistance due to bronchial spasms induced by the aerosol administration of 1 mg of histamine. Minimal car- EXAMPLE 2 Methyl 5-benzyloxyhydrogenisophthalate., A mixture of 91.0 g (0.304 mole) of dimethyl 5-benzyoxisophthalate and 13.4 g (0.334 moles) of NaOH in diac stimulant or heart rate increases are observed at 500 ml of MeOH was refluxed for 2.5 hrs. The mixture this dosage level. The compounds exhibit the same potency in the guinea pig against aerosolized histamine. Further, these compounds selectively exert their therapeutic effect in the lung following either oral or parenteral administration.  
  The compounds of this invention are indicated in the treatment or management of bronchial asthma. The dose required is within the above-described dosage range which, of course, can be varied depending upon the severity of the condition being treated and the age and sex of the patient, by methods well known to the clinical arts.  
 In order to use these compounds theyare combined with diluents such as lactose, dicalcium phosphate and compounded into dosage forms such as tablets by methods well known to the pharmacists art. They can also be formulated as an aerosol by suspending the selected compound in a vehicle such as normal saline and formulated by standard pharmaceutical procedures.  
  In order to enhance and broaden the therapeutic spectrum of these compounds other therapeutic agents such as steroids, typically those derived from the cortisone series, may also be included in these dosage forms.  
  In order to further illustrate the practice of this invention, the following examples are included:  
 EXAMPLE 1 Dimethyl S-benzyloxyisophthalate. A mixture of 156 g (0.743 mole) of dimethyl 5- was evaporated to a residual solid which was dissolved in EtOAc (l 1.) and washed with H O (2X500 ml). The aqueous phase was acidified with HCl and re-extracted with EtOAc (3X500 ml). After drying the EtOAc extract of acid phase with MgSO evaporation of the EtOAc gave a crude White solid which was recrystallized from MeOH-H O to give 70.1 g (80.5%) mp. l47-150. The analytical sample was obtained by recrystallization from MeOH-H O, mp. l54l55.  
  Anal. Calcd. for C H O C, 67.13, H, 4.93. Found: C, 67.02; H, 4.99.  
 EXAMPLE 3 3-Benzyloxy-5-carboxy-a-(methylsulfinyl)- acetophenone.  
 To a mixture of DMSO (210 ml) and benzene (420 ml) heated with NaI-I, 57 percent in oil (13.0 g, 0.31 mole) for 1 hr. at 75 a DMSO solution (270 ml) containing 27.0 g (94.7 mmoles) of methyl 5-benzyloxyhydrogenisophthalate was added. The mixture was stirred at room temperature for 2 hrs. and then added to 3 l.  
 i of Et O. The Na salt was collected and dissolved in H 0 (200 ml) which was then acidified to pH5 with HOAc. Cooling gave a yellow precipitate; yield 29.9 g (95.2%) mp. l28-134. Recrystallizations from 2- PrOI-I/hexane gave the analytical material, mp. l37-l40 dec.  
  Anal. Calcd. for C I-1, 0 5: C, 61.43; H, 4.85; S, 9.65. Found: C, 61.13; H, 4.86; S, 9.57.  
 EXAMPLE 4 3-Benzyloxy-5-carboxyphenylglyoxal and 3- benzyloxy-S-carboxyphenylglyoxal methylthio-methyl acetal. A mixture of 40.0 g (120 mmoles) of 3-benzyloxy-5- carboxy-a-(methylsulfinyl)acetophenone, 1.6 1. of 50 percent aqueous HOAc and 0.8 1. MeOH was refluxed for 68 hrs. The mixture was extracted with CHCl 1X3 1.). The CHCl phase was dried with MgSO, and evaporated to give a quantitative yield of a light yellow solid, mp. l65168 which was purified by recrystallization from benzene-hexane, mp. 167-169 dec.  
 EXAMPLE 5 3-Benzyloxy-5-[2-(isopropylamino)- l -hydroxye thyl]-benzoic acid. The 3-benzyloxy-5-carboxyphenylglyoxal (120 moles) was dissolved in MeOH (l l.) and cooled to lsopropylamine (200 ml) was added at 0 and the resulting mixture was stirred at 0 for 1 hr. before KBH, (12.2 g, 228 moles) was added over a period of 2 hrs., portionwise. The resultant mixture was allowed to stir at room temperature overnight before it was evaporated to a residual glass. The residue was acidified with 6N HCl (1 1.) and extracted with CHCl (l 1.). The solid HCl precipitated from the CHCl extract upon standing; yield 21.9 g which gave 20.0 g (50 percent) mp. 290-292 dec. of the free base upon stirring in aqueous NH OH and collecting by filtration.  
  Anal. Calcd. for C I-l NO C, 69.28; H, 7.04; N, 4.05. Found C, 68.74; H, 7.07, N, 4.01.  
 EXAMPLE 6 Methyl 3-benzyloxy-5-[2(isopropylamino)-l hydroxyethyl]-benzoate. A mixture of 19.0 g (57.8mmoles) of 3-benzyloxy-5-[2- (isopropylamino)l-hydroxyethyl]-benzoic acid and 7.7 g (70.0mmoles) of ethanesulfonic acid was refluxed for 20 hrs. The mixture was then evaporated in vacuo and the residue obtained was dissolved in CHCl (500 ml). After washing the CHCl solution with percent NaH- CO l 250 ml) and drying with MgSO the crude ester was obtained by evaporation of the CHCl yield 17.5 g (88.3%). The analytical sample was obtained as the HCl salt from Z-PrOH/Et O, mp. 164-165.  
  Anal. Calcd. for C H NO &#39;HCl: C, 63.24; H, 6.90; N, 3.69; Cl, 9.33. Found: C, 63.07; H, 6.99; N, 3.89; Cl, 9.15.  
 EXAMPLE 7 5-Benzyloxy-a-[ (isopropylamino )methyl l-m-xylenea,a&#39;-diol. To a suspension of LiAlH, (4.57 g, 120 moles) in anhydrous Et O (0.5 1.) was added an ethereal solution (0.5 l.) of the methyl 3-benzyloxy-5-[2-(isopropylamino)- l-hydroxyethyl1-benzoate (17.5 g, 50.9mmoles) slowly at room temperature. The resultant mixture was heated at reflux for 4 hrs. The LiAlH, and complex was hydrolyzed by the slow addition of 40 ml of H 0. The granular precipitate which formed was removed by filtration and an oily product was obtained from the either filtrate after evaporation; yield 15.2 g. (94.3%). The crude product was crystallized from Et O-hexane; yield 9.24 g (57.4%) mp. 84-89. The analytical sample was obtained from EtOAc-hexane, mp. 9093.  
  Anal. Calcd. for C H NO C, 72.35; H, 7.99; N, 4.44. Found C, 72.21; H, 8.17; N, 4.18.  
 EXAMPLE 8 5-Hydroxy-a-[(isopropylamino)methyl]-m-xylenea,a&#39;-diol hemifumarate. An ethanol solution (200 ml) containing 9.34 g (29.6mmoles) of crystalline S-benzyloxy-a- [(isopropylamino)methyl]-m-xylene-a,oz&#39;-diol was hydrogenated over 4.0 g of 10 percent Pd-C catalyst until hydrogen uptake had ceased (1 hr.). The catalyst was removed by filtration through a celite pad and the filtrate was evaporated to give an oily residual product. A crystalline fumarate salt was obtained; yield 6.71 g (8.20%) mp. 230245 dec. The analytical sample was obtained from MeOH-Et O; yield 6.13 g (73.2%) mp. 246-248 dec.  
  Anal. Calcd. for C H NO l/2C.,H,O C, 59.35; H, 7.47; N, 4.94. Found: C, 59.28; H, 7.45; N, 4.80.  
 EXAMPLE 9 3 -Benzyloxy-5 -[2-(tert-butylamino)-1-hydroxyethyl]-benzoic acid. A solution of 3-benzyloxy-5-carboxyphenylglyoxal (l20mmoles) in MeOH (1 l.) was stirred at 0 for 1 hr. KBH (12.2 g, 228mmoles) was added at 0 in aliquots over a period of 3 hrs. and the resulting mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue obtained was acidified with 3N HCl (400 ml). The aqueous mixture was extracted with CHCl (3X500 ml). The CHCl extracts were combined and ether was added after cooling. A white precipitate was collected; yield 23.6 g (51.8%) mp. 222-225 dec of the product HCl salt. The analytical sample was obtained from 2- PrOH/Et- O, mp. 228-230 dec. The free base was obtained by stirring the salt in NH OH. Filtration gave 15.2 g (36.9%) mp. 270-272 dec.  
  Anal. Calcd. for C H NO HCl: C, 63.24; H, 6.90; N, 3.69; Cl, 9.33. Found: C, 63.02; H, 7.04; N, 3.45; Cl, 9.36.  
 EXAMPLE 10 Methyl 3-benzyloxy-5-[2-(t-butylamino)-1- hydroxyethyl]-benzoate. A mixture of 15.2 g (44.3mmoles) of 3-benzyloxy-5-[2- (t-butylamino)-l-hydroxyethyl]-benzoic acid and 5.5 g (SOmmoles) of ethanesulfonic acid was heated at reflux for 20 hrs. in 300 ml of MeOH. The reaction mixture was evaporated in vacuo to give a crude oily residue which was partitioned between CHCl (500 ml) and 5% NaHCO (200 ml). The CHCl phase was dried with MgSQ, and evaporated to give a solid residue in a quantitative yield. A crystalline HCl salt was obtained from Z-PrOH/Et O, mp. l92-l95.  
 EXAMPLE 1 l 5-Benzyloxy-a-[(t-butylamino)methyl]-m-xylenea,a-diol fumarate.  
 To a suspension of LiAlH, (3.42 g, mmoles) in 300 ml of dry THF was added a THF solution (500 ml) of the methyl 3-benzyloxy-5-[ 2( t-butylamino l hydroxyethyl1benzoate (14.8 g, 41.3 mmoles). The reaction mixture was refluxed for 4 hrs. The LiAlH, and complex was hydrolyzed by the addition of 40 ml of H 0, slowly. The granular precipitate which formed was removed by filtration and the THF filtrate was evaporated to give 13.1 g (95.3%) of crude product as an oil. A crystalline fumarate salt was obtained from MeOH-Et O; yield 10.7 g (66.8%) mp. 195200 dec. Anal. Calcd. for C20H27N03-l/2 (L l I404: C, H, 7.54; N, 3.61. Found: C, 67.79; H, 7.68; N, 3.40.  
 EXAMPLE l2 a-[(t-butylamino)methyl]-5-hydroxy-m-xylene-a,a&#39;- diol hemifumarate. An ethanolic solution (200 ml) containing S-benzyloxy-a-[(t-butylamino) methyl]-mxylene-a,a&#39;-diol EXAMPLE 15 (8.25 g, 25.1mmoles) was hydrogenated over 4.0 g of 10 y &#39;p y y 1&#39; 10% Pd-C catalyst until hydrogen uptake had ceased (1 hr.). The catalyst was removed by filtration through a celite pad and the EtOl-l filtrate was evaporated to give an oily residual product; yield 5.75 g (95.9%). A crystalline hemifumarate salt was obtained from MeOH- Et O; yield 5.06 g (67.9%) mp. 24925 1 dec. The analytical sample was obtained by recrystallization from MeOH-Et O; yield 3.33 g (44.7%) mp. 263-265 dec. Anal. Calcd. for C H NO &#39;l/2C H O C, 60.59; H, 7.80; N, 4.71. Found: C, 60.79; H, 7.88; N, 4.56.  
 EXAMPLE 13 Methyl 3-benzyloxy-5-[2-(1,l dimethyl-2- phenylethylamino 1 -hydroxyethyl -benzo ate.  
 The 3-benzyloxy-S-carboxyphenylglyoxal 120 mmoles) was dissolved in MeOH (1 1.) and cooled to&#39; l,1-Dimethyl-2-phenylethylamine (100 g, 0.67 moles) was added at 0 and the resulting mixture was stirred at 0 for 1 hr. before addition of KBH, (12.2 g, 228 mmoles) over a period of 2 hrs. portionwise. The resultant mixture was allowed to react at room temperature for 18 hours before it was evaporated to.a residual glass. The residue was acidified with 6N l-lCl (1 l.) and extracted with CHCl;, (1 1.). Addition of ether to the CHCl extract gave the l,1-dimethyl-2&#39; phenylethylamine HCl as a white precipitate which was removed by filtration. The CHCl filtrate was evaporated to give the crude 3-benzyloxy-5-[2-(1,1dimethyl- 2-pheny1ethylamino)-1-hydroxyethyl]benzoic acid HCl. The base was obtained by treating the crude salt with conc. NH OH, extracting with CHCl and drying with MgSO before evaporation to give the crude oily base.  
  A mixture of 3-benzyloxy-5-[2-(1,1-dimethyl-2- phenylethyl)-2-hydroxyethyl]-benzoic acid (120 mmoles) and 17.7 g (160 mmoles) of ethanesulfonic acid was heated at reflux for 18 hours in 500 ml of MeOH. The reaction mixture was evaporated to a residual oil which was dissolved in Cl-lCl (200 ml) and washed with 5% Nal-lCO (2X200 ml). The CHCl phase was dried (MgSO and evaporated to give the crude, oily methyl 3-benzyloxy-5-[(1,1-dimethyl-2- phenylethylamino)-2-hydroxyethyl]-benzoate which was converted to a crystalline hemifumarate salt; yield 14.7 g. (24.8%) mp. 173175 dec.  
  Anal. Calcd. f0! C27H31NO4&#39;l/2C4H404: C, H, 6.77;, N, 2.85. Found: C, 70.90; H, 6.89; N, 2.73.  
 EXAMPLE 14 hydroxy-m-xylene-a,a&#39;-diol hemifumarate.  
 An ethanolic solution (200 ml) of the benzyloxy intermediate 8.73 g (21.4mmoles) was hydrogenated over 4.0 g of Pd-C catalyst until hydrogen uptake had 15 ceased (1 hr.). The mixture was filtered through celite and the filtrate was evaporated and gave an quantitative yield of the free base product as a clear oil. A white cyrstalline hemifumarate salt was obtained; yield 6.62 g (82.3%) mp. 209-212 dec. The analytical sample was obtained by recrystallization from MeOH-Et O;  
 yield 5.69 g (70.8%) mp. 214215.5 dec.  
  Anal. Calcd. for C H NO -1/2C H O C, 67.54; H, 7.29; N, 3.75. Found: C, 67.45; H, 7.53; N, 3.67.  
 25 EXAMPLE l6 Methyl benzoate. To a cold suspension of NaH (105 mmole) in 71 ml of DMSO and 71 ml of benzene was added slowly 10.0 g  
  (47.6 mmoles) of dimethyl S-hydroxyisophthalate dissolved in 25 ml of DMSO and 25 ml of benzene. The resulting mixture was then heated at reflux for 1.5 hrs; cooled and acidified with 100 ml of 40 percent HOAc. The aqueous phase was separated and extracted with CHC13 (3X250 ml). The combined organics were dried (MgSO and distilled off under vacuum giving a gummy residue. The crude gum was washed with hexane (2X20 m1) and triturated with EtOAc (10 ml) with heat. Cooling gave 4.20 g (35%) of a yellow solid, mp.  
  144-150. Recrystallizations from EtOAc-hexane gave the analytical sample, mp. 153l55.  
  Anal. Calcd. for C I-1, 0 5: C, 51.55; H, 4.72;, S, 12.51. Found: C, 51.84; H, 4.90; S, 12.64.  
 EXAMPLE 17 components gave the crude 3-carboxym thy1-5-hydroxyphenylglyoxal in a quantitative yield.  
  A methanolic&#39;solution (100 ml) containing the crude substituted phenylglyoxal was cooled to 0 and 20 ml of t-butylamine was added. After stirring the mixture at 0 for 1 hr., KBl-l 1.78 g, 33 mmoles) was added in 4 aliquots over a 2 hr. period. The mixture was allowed to reach room temperature and stir overnight.  
  The reaction mixture was evaporated in vacuo and the residue obtained was suspended in 6N HC] (100 m1) and washed with CHCl (2X50 ml). The acidic phase was basified with NH OH and extracted with EtOAc (3x200 ml). The EtOAc extracts were dried (MgSO and evaporated to give the crude product as an oil; yield 1.35 g (31%). The product was purified as a hemifumarate salt from MeOH/Et O, mp. 261-262.5 dec.  
  Anal Calcd. C H NO &#39;l/2C H O C, 59.07; H, 7.13; N, 4.31. Found: C, 59.16; H, 7.19; N, 4.17.  
 EXAMPLE 18 To illustrate the in vivo effects, compounds wherein R is methyl and R is hydrogen; R is methyl and R is phenyl; and R and R are hydrogen are tested in dogs which are challenged by the aerosol administration of 1 mg of histamine. These compounds are identified as W9803A, W989OA, and 9640A respectively in the following table:  
  on. RFCHPJJNHCHICH -o cm Ha OH wherein R is COOH or COOCH and wherein R is phenyl or hydrogen, with the proviso that R is hydrogen only when R, is COOH and R is phenyl only when R, is COOCH benzoic acid.  
  2. A compound according to claim 1 which is 3- benzyloxy-S-[2-(tert-butylamino)-1-hydroxyethyl]- Note: Doses chosen for salbutanol and Thl 165a still demonstrated a dose-response relationship and were not on the upper right flat portion of the dose-responsive curve for the dilation vs, dose. A Hr./Min. change in heart rate per minute.  
  While salbutamol and Th1165a are more potent bronchodilators than the compounds of this invention, these known compounds also exhibit the undesirable cardiac stimulatory effects. Consequently, the compounds of this invention possess unique therapeutic properties over these known bronchodilators in that they do not produce significant heart stimulatory actions.  
 Reference compound structures:  
  (FHOHCHQNHCHCHS CHOHCHaNHC(CH;)3 IHe H O OH CHzOH l HO HO salbutainel Thllfifia We claim:  
 1. A compound of the formula:  
 VIII  
 wherein R and R are hydrogen. 5. A compound of the formula:  
 CHaOH I I Page l of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3&#34;&#39;879 44 2 Dated April 22 1225 vlnventofls) Charles F, Schwender,et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 . 0n the cover sheet item (54) should read -5-Hyd roxya (Substituted Aminomethyl)Meta-Xylenea;  
  Diols Column 9, in the Table, &#34;salbutanol&#34; should read salbutamol Column 4-, and claim 4, the formulas should read as shown on the-attached sheet.  
 - Page 2 of 2 e Patent No. -5,879, +2  
 Column CHOHCH NHQCMR R1 7 LiA).H  
 Q NH2C(CH3)R4CH2R2 HO (ll-[ 0,  
 Claim 4 A Conmmmd of the formula 2 wzwuctcua-micn scacn io&#34; c ow G vnu Q v l v Signed andifi&#39;caled this I Twenty-fourth Day f n 1916&#34; sum I I I Arrest:  
  c. MARSHALL mum v Commissioner oj&#39;larems and Trademarks &#39;aq m &#39;c. MASON Anestr&#39;ng Officer UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5879Lm2 Dated April 1975 O lnventofls) Charles F. Schwender et al.  
  It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 Column 9, in the Table, &#34;salbutanol&#34; should read salbutamol Claim 1, delete &#34;benzoic acid&#34; Claim 2, after &#34;hydroxyethyl]-&#34; insert benzoic acid.  
 &#39; Signed and flcalcd this second Day of Dawn [SEAL] Attest:  
 RUTH C. MASON C. MARSHALL DAMN A nesting Officer Commissioner oflntenls and Trademarks FORM PO-1050 (10- USCOMM-DC 60376-1 69 U.S. GOVERNMENT PRINTING OFFICE: 869. 93 o