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United States Patent ?O?lice 3,063,984 Patented Nov. 13, 1962 1 the following formulas: 3 063,984 CYCLOPENTANOPHEIQANTHRENE COMPOUNDS? CH: AND PROCESS a John A. Zderic, Mexico City, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Dec. 15, 1960, Ser. No. 75,945 21 Claims. (Cl. 260-239) 2/ 6:0 HA5 The present invention relates to novel cyclopenta 10 nophenanthrene compounds and to a process for the pro duction thereof. In the above formulas Z indicates a double bond or a More particularly the present invention relates to 11a saturated linkage? between C-1 and C-2, R represents aza-C-homo progestational hormones and more speci? cally to 1la-aza-C-homo-A4-pregnene-3,207dione, to lla 15 hydrogen, an alkyl or an aralkyl group containing up to 12 carbon atoms and Ac represents the acylradical of aza~C-homo-Al-?i-pregnadiene-3,ZO-dione, and to N-acyl ated and N-alkylated derivatives thereof as well as to quaternary ammonium salts thereof. . t a hydrocarbon carboxylic acid of less than 12 carbons saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain or aromatic. The acyl radical is v, The novel compounds of the present invention which are progestational agents exhibiting anti-androgenic, anti preferably the acetyl or a lower alkanoyl radical.? ' ' ?The novel compounds of the present invention may be estrogenic, anti-gonadotrophic and anti-ovulato'ry activie ' 3'- prepared by a process illustrated by the following equa-I ties as well as hypotensive properties are represented by tion: I ' " ~ H53 l I 1 on, v agar/W5 . V VI 3,063,984 '4'. 3 1 l OH; 2:, /\ z. E?? ii VII In the above formulas Ac and Z have the same mean 20 by the following equation: ing as set forth above and R?- represents hydrogen or a OH hydrocarbon carboxylic acyl radical. In practicing the process outlined above,_ the starting compound, . \O 25 BLN 3ll-one (disclosed by Rothman and Wall in J. Am. Chem. Soc. 79, 3228 (1957)) with lithium aluminum hydride .1 to form 1l?,12?<dihydroxy-diosgenin, which, upon re action with lead tetra-acetate in an inert solvent such as benzene is converted into the ll,1'2-seco-22a-A5-spirosten B?-ol-l 1,12-dial (I). The dialdehyde is then reacted with ammonia in ethanol solution thereby yielding a Schi? base type intermediate which is then reacted with lithium 30 AC0v , tion, thus forming 3?-acyloxy-l1a~N-acetyl-C-homo-22a A5-spirostene (III) which may then be subjected to degra dation of the side chain to form the 11a-N-acetyl-C-horno? A5�-pregnadien-3,9-ol-20-one acylate (IV). i H0 EOE �0 X (?3H3 011. 0:0 (V:R'=acyl) which. is then preferentially saponi?ed at C-3 by treatment with methanolic hydrochloric acid to 1 i acylate 2 =0 R2?N/\i } R=?N/\ f l1a-N-acetyl-C-horno-A5-pregnen-318 - o1 - 20 - one (V:R?=hydrogen). The 3?-hydroxy-A5-group of the last H0 XI Selective 1la镹-acctyl-C-homo-A?-pregnen - 3B - ol-20-one MA 45 hydrogenation of the C-16,17-double bond of the latter compound over a palladium-charcoal catalyst results in 50 afford om 1 The degradation of the side chain may be preceded by acylation, preferably acetyla 1x (?3113 MAL 1 40 thus forming lla-N-ac?etyl-C-homo-AsJipregnadien-SB ol-ZO-one acetate (IV). i HO 4 aluminum hydride in tetrahydrofuran to form Ila-aza C-horno-22a-A5-spirosten-3?-ol (II). Degradation of the 35, spiroketal side chain is then effected by conventional pro cedure as by reaction with acetic anhydride at about 200�, oxidation of the resulting pseudo-compound to the di osone and alkaline hydrolysis and acetylation of the latter 0 0/ 1 . 11,12 - seco - 22 - A5 - spirosten-B??-ol-l1,12-dial (I) isjpre-pared by treating A5-22a-spirosten?3?,12?-diol TH: a (?i=0 55 named compound is converted to the A4-_-3,-,keto moiety by oxidizing under Oppenauer conditions or with chromic ,__. O; XIII HO XII acid in acetone solution followed by treatment with acid to thus form 1la-N-acetyl-C-homo-M-pregnene-B?,20 dione (VI). Upon reaction with methanolic potassium 60 ? ta hydroxide, the acetyl group is removed and there is 0=o formed lla-aza-C-homo-A?i-pregnene-3,20-dione (VIII: Z=saturated linkage). RaX_. \+/\ For introduction of a double bond at C-l,2, the Ila-N 65 acetyl-C-horno-A4-pregnene-3,20-dione (VI) is re?uxed R??N Z with selenium dioxide in a solvent such as t-butanol in the presence of catalytic amounts of pyridine to form the corresponding l-dehydro compound, lla-N-acetyl-C homo-A1�pregnadiene-3,2Q-dione (VII). Upon reaction with methanolic potassium hydroxide, the lla-aza-C homo-ul-?t-pregnadiene- 3,20-dione bond) is obtained. ' (VIII: Z=?double 0= 70 - XIV In the above formulas, R2 represents an alkyl or aralkyl group containing up to 12 carbon atoms; R3 represents a lower alkyl' group; X represents a halogen such as iodine, The novel lla-N-alkylated-Ohorno compounds of the bromine or chlorine and Z and Ac have the same mean. present invention may be prepared by a process illustrated 75 ing as previously set forth. 3,063,984 . . . . . 6 5 In practicing the process outlined above lla-N-acyl-C decomposed by careful addition ?of acetone, then a small horno-A5I16-pregnadien-3lfi-ol-20-one acylate, preferably 11a-N-acetyl-C-homo-A5,ls-pregnadien-3,8-01-20-0ne acyl amount of saturated aqueous sodium sulfate solution and ?nally solid anhydrous sodium sulfate were added. The solid was collected by ?ltration and the ?ltrate evaporated ate (IV) is re?uxed with lithium aluminum hydride in tetrahydrofuran for 5 hours to form lla-N-ethyl-C homoA5,16-pregnadiene-3B,20-diol (XI) which upon re to dryness under reduced pressure. Crystallization from aqueous ethanol yielded 11a-aza-C-homo-22a-A5-spi rosten-3B-ol. action with manganese dioxide in chloroform at room temperature affords 11a-N-ethyl-C-homo-Ail?-pregna Example II dien-3B-ol-20-one (X). The latter compound can also be formed by ?rst protecting the keto group of lla-N-acetyl 10 C-homo-A5J6-pregnadien-3?-ol-ZO-one acylate (IV) by formation of the cyclic ethylene ketal thereof by conven tional methods, followed by reduction with lithium alu? minum hydride to produce the cyclic ethylene ketal of 11a-N-ethyl-C-homo-A5-16-pregnadien-35-ol-20-one (IX) ml. of 80% acetic acid; after stirring for three hours at room temperature, the mixture was diluted with water, which is then hydrolyzed with acid to form lla-N-ethyl C-homo-A5'16-pregnadien-3?-ol-ZO-one (X). The latter extracted with ether and the extract was washed with water, dried over anhydrous sodium sulfate and the ether was evaporated. The residue was mixed with 200 ml. of compound is converted to lla-N-ethyl-C-homo-A5-preg nen-3/8-ol-20~one (XII) by hydrogenation in the presence 60% acetone containing 2 g. of potassium hydroxide and refluxed for 5 hours, then concentrated to a small volume, cooled, diluted with water and extracted with ether. The of a hydrogenation catalyst such as palladium, and, upon oxidation under Oppenauer conditions there is formed 11a - N - ethyl - C - homo-A4-pregnene-3,20-dione 4 g. of the latter compound was heated with 20 ml. of acetic anhydride in a sealed tube at 200� C. for 55 min utes; it was then cooled, the excess of anhydride was hy drolyzed by the addition of 8 ml. of water and the mix ture was treated with 2 g. of chromium trioxide in 25 (XIII: Z=saturated linkage). A double bond may then be in troduced at C-1,2 by reaction with selenium dioxide to extract was washed several times with water, dried over afford the l-dehydro compound (XIII: Z=double bond). Upon conventional acetylation, followed by recrystalliza The quaternary ammonium salt of the latter compound is prepared by conventional methods, as for example, tion from acetone-hexane, there was obtained 3,8-acetoxy anhydrous sodium sulfate and evaporated to dryness. 11a-N-acetyl-C-homo-Ati,16-pregnadien-20-one. the N-ethyl compound (XIII) is reacted with an alkyl or an aralkyl halide in a solvent such as notroalkane to thus form the quaternary ammonium halide (XIV). derivative 30 Example III 2 g. of 1?1a-aza-C-homo-22a-spirosten-3B-ol (described in Example I) was treated with 2 ml. of acetic anhydride in 10 ml. of pyridine at room temperature. The mixture was allowed to stand overnight and was then diluted with Other N-acylated and N-alkylated compounds are pre-? pared by substituting for the N-acetyl group other acyl groups of the type mentioned previously. Thus there are water, the solid was collected by ?ltration, washed with obtained N-acylated and N-alkylated compounds con 35 water, dried and recrystallized from acetone~hexane thus taining up to 12 carbon atoms such at N-propionyl, N aifording 3?-acetoxy-l1a-N-acetyl-C-homo-22a-A5-spiro benzoyl, N-butyryl and the corresponding N-propyl, N sten. The latter compound was then treated with acetic benzyl and N-butyl derivatives. anhydride at 200�, the resulting pseudo-sapogenin was The following examples serve to illustrate but are not intended to limit the scope of the invention: oxidized to the ?diosone and was then treated with potas 40 sium hydroxide followed by reesteri?cation as described in Example II to thus yield 3;8-acetoxy-1la-N-acetyl-C homo-A5,l?-pregnadien-ZO-one, identical with the com Example I pound obtained in Example H. A solution of 10 g?. of A5-22a-spirosten-3?,12/3-diol-l1 one-diacetate (Rothman and Wall, J. Am. Chem. Soc. Example IV 79, 3228 (1957)) in 300 ml. of anhydrous tetrahydro 45 furan was added dropwise to a suspension of 10 g. of lithium aluminum hydride in 1 liter of anhydrous tetra hydrofuran while stirring and the resulting mixture was re?uxed for 30 minutes. =Acetone was added cautiously to decompose the excess of the hydride, then treated with saturated aqueous sodium sulfate, ?nally with anhydrous sodium sulfate, the solid was ?ltered and the ?ltrate evap orated to dryness. The residue was triturated with hexane yielding 1 1B, IZ?-dihydroxy-diosgenin. A solution of 1.25 g. of 3/3-acetoxy-lla-N-acetyl-C homo-A5?le-pregnadien-ZO-one in 50 cc. of ethyl acetate was hydrogenated at room temperature and atmospheric pressure using 200 mg. of prereduced 10% palladium on charcoal catalyst, until 1 molar equivalent of hydrogen was absorbed, the catalyst was ?ltered and the ?ltrate evaporated to a small volume. Addition of methanol gave the crystalline S/S-acetoxy-I1a-N-acety1-C-homo-A5 pregnen-ZO-one. 1 To a mixture of 8.1 g. of 1l?,IZ?-dihydroxy-diosgenin, 55 A solution of 11 g. of the above compound in 25 cc. 140 ml. of glacial acetic acid and 210 ml. of thiophene of 2.5% methanolic solution of perchloric acid was kept free benzene, 12.1 g. of lead tetraacetate were added and at room temperature for 18 hours, it was then diluted the mixture was stirred at room temperature for 5 min with water, the formed precipitate collected by ?ltration, utes. 200 ml. of water containing 100 g. of sodium ace washed with water, dried and recrystallized from ace tate and 4 g. of sodium iodide were added, the color was 60 tone-hexane, thus giving 11a-N-acetyl-C-homo-A5-preg discharged by the addition of 80 ml. of saturated aqueous nen-3;8_ol-20-one. ? sodium thiosulfate solution and the product extracted 1 g. of the latter compound was dissolved in 10 cc. of twice, using each time 200 ml. of ethyl acetate. The acetone, cooled to 0� C., flushed with nitrogen and pooled extracts were washed with aqueous sodium bi treated under stirring with 8 N chromic acid solution carbonate and water, dried over anhydrous sodium sul 65 added in a thin stream, at 0� C., until the red color of fate and evaporated to dryness. The residue was crystal chromium trioxide persisted in the mixture. (The 8 N lized from a mixture of 60 ml. of methanol and 12.5 ml. solution of chromic acid was prepared by dissolving 26.7 of water to a?ord l1,12-seco-22a-A5-spirosten-3,8-01-1l, g. of chromium trioxide in 23 cc. of concentrated sul 12-diol. furic acid and diluting with water to 100 cc.) The reac A mixture of 5 g. of the dialdehyde and 250 ml. of tion mixture was stirred for 5 minutes further, diluted ammonia-saturated ethanol was re?uxed during 10 hours. with water and the product collected by ?ltration, washed Upon evaporation of the solvent, a crystalline residue was with water and dried under vacuum. obtained which was re?uxed with 2.5 g. of lithium alu The crude product was dissolved in 40 cc. of methanol minum hydride in mixture with 250 ml. of tetrahydro and treated at room temperature with a solution of 0.1 furan during 20 hours. The excess of hydride was then 75 g. of oxalic acid in 1 cc. of water. The mixture was kept 7 standing for 3 hours, then diluted with water and the 8 by following the method of Example IV, gave 1?-1a-N= product was collected by ?ltration, washed with water to neutral and dried. There was thus obtained Ila-N ethyl-C-hom'o-A1'4-pregnadiene-3,20-diotie. acetyliC-homosA4-pregnene-3,ZO-dione. ? A stirred mixture of 500 mg. of the above compound, 25 .cc. of t-butanol, 200 mg. of selenium dioxide and 0.15 cc. of pyridine was re?uxed for 48 hours under an at Example VII A mixture of 2 g. of 3B-acetoxy-lla-N-acetyl-C-homoa A5Y1G-pregnadien-?ZO-Qne, 20 cc. of dry benzene, 16 cc. of ethylene glycol and 300 mg. of p-toluenesulfonic?acid monohydrate was re?uxed for 8 hours, using a Dean6 Stark water separator. The cooled reaction solution was ?ltrate was evaporated to dryness under reduced pres washed with 5% aqueous sodium bicarbonate and water sure. The residue was dissolved in acetone, treated with 10 to neutral, dried over anhydrous sodium sulfate and the mosphere of nitrogen, ?ltered through celite, and the decolorizing charcoal, re?uxed for 1 hour, ?ltered and the acetone was evaporated. The residue was puri?ed by chromatography on neutral alumina and the solid eluates were crystallized from acetone-hexane, thus giving 11a N-acetyLC-homo-AL?Lpregnadiene-3,20-dione. Example V 1 g. of 11a-N-acetyl-C-homo-A4-pregnene-3,20-dione, obtained as described in the preceding example was re ?uxed for 48 hours under an atmosphere of nitrogen with 50 cc. of 4% methanolic potassium hydroxide solution and then neutralized with acetic acid. Part of the solvent was removed under reduced pressure, water added and solvent was evaporated. Crystallization of the residue from acetone-ether afforded ZO-ethylenedioxy-lla-N acetyl-C-homo-A5?16-pregnadien-3B-ol-acetate. By following the reduction method of the preceding ex ample, the above compound was reduced with lithium aluminum hydride in tetrahydrofuran, thus giving 20 ethylenedioxy-lla-N-ethyl - C - homo - A546 - pregnadien 35-01. A solution of 1 g. of the latter compound in 50 cc. of acetone was treated with 20 mg. of p-toluenesulfonic acid monohydrate and the mixture kept at room tem perature for 16 hours, poured into dilute sodium car bonate solution and the solid collected by ?ltration. then extracted with methylene chloride, the organic ex Crystallization from acetone-hexane gave lla-N-ethyl tract washed to neutral, dried over anhydrous sodium 25 C-homO-AE'JG-pregnadien-S?-ol-ZO-one, identical with the sulfate and evaporated to dryness. Chromatography of the residue gave the pure 1la~aza-C-homo-A4-pregnene intermediate of Example VI. Example VIII 3,20-dione. . In a similar manner, lla-N-acetyl-C-homo-nl-?i-preg A solution of 200 mg. of l1a-N-ethyl-C-homo-M-preg nadiene-3,20-dione was converted into lla-aza-C-homo 30 nene-3,20-dione in 20 cc. of nitromethane was treated with A1�pregna-diene-3,2O-dione. 2 g. of methyl iodide and heated in a sealed tube at 100� C. for 3 hours concentrated almost to dryness, diluted Example VI with a little cold ether and the precipitate was collected A solution of 5 g. of 3f3-acetoxy-1la-N-acetyl-C-homo 35 by ?ltration, thus giving the methoiodide of lla-N-ethyl A5'16~pregnadien-2O-one, obtained as described in Ex C-homo-A4-pregnene-3,ZO-dione. ample II, in 150 cc. of anhydrous tetrahydrofuran was In a similar manner, 11a-N-ethyl-C-homo-N-4~preg added dropwise to a suspension of 5 g. of lithium alumi nadiene-3,20-dione was converted into the methoiodide num hydride in 300 cc. of anhydrous tetrahydrofuran and the mixture re?uxed for 30 hours with stirring. 40 Acetone was added cautiously to decompose the excess of hydride, then saturated aqueous sodium sulfate solution and ?nally solid anhydrous sodium sulfate were added. The solid was ?ltered and washed well with hot ethyl acetate, and the ?ltrate and washings were evaporated to dryness under reduced pressure. Crystallization of 45 the residue from acetone-hexane gave llla-N-ethyl-C homo-A5?15-pregnadiene-3;8,20-diol. A solution of 3? g. of the above compound in 300 cc. of chloroform, distilled over calcium chloride was stirred for 18} hours at room, temperature with 30 g. of freshly precipitated manganese dioxide. The inorganic material was ?ltered, washed with hot chloroform and the solu tion evaporated; the residue crystallized on trituration with hexane. Recrystallization from acetone-hexane gave 11a~N-ethyl-C-homo-A5JS-pregnadien-313-ol-20-one. A solution of 2 g. of the above compound in 80 cc. of ethyl acetate was hydrogenated at room temperature of 11a-N-ethyl-C-homo-Al-4-pregnadiene-3,ZO-dione. I claim: 1. A compound of the following formula: . Med or wherein Z is selected from the group consisting of a double bond between C-1 and C-2 and a saturated link age between C-1 and C-2. 2. 11a-aza-C-homo-M-pregnen-B,20-dione. 3. 'l1a-aza-C-homo-A1I4-pregnadiene-3,20-dione. 4. A compound of the following formula: and atmospheric pressure using 400 mg. of 10% pal ladium- on charcoal catalyst, in accordance with the meth od' of Example IV. There was thus obtained lla-N ethyl-C-homo-A5-pregnen-3?-ol-20-one. A solution of 1 g. of the latter compound in 80 cc. of toluene and 20 cc. of cyclohexanone was dried by dis tilling oil, 10 cc. of solvent. A solution of 1 g. of alumi . IQ num isopropoxide dissolved in 7 cc. of anhydrous 65 toluene was then added and the mixture was re?uxed for 45?minutes; 4 cc. of acetic acid were added and the sol vents removed by steam distillation. The product was wherein R2 is selected from the group consisting of alkyl extracted several times with ethyl acetate and the organic extracts washed with 5% hydrochloric acid solution, 70 and aralkyl containing up to 12 carbon atoms and Z is selected from the group consisting of a double bond be water, 10% sodium carbonate solution and water until tween C-1 and 0-2 and a saturated linkage between C-1 neutral, dried over anhydrous sodium sulfate and evapo and C-2. rated until crystallization started. There was thus ob tained l1a-N-ethyl-C-homo-A4-pregnene-3,ZO-dione. Selenium dioxide oxidation of the above compound, 75 5. 1la-N-ethyl-C-homo-A4-pregnene-3,ZO-dione. 6. 1 1 a-N-ethyl-C-homo-A1e-pregnadiene-iZO-dione. 8,068,984 9 10 7. The lower alkyl quaternary ammonium salts of a compound of the following formula: from the group consisting of a double bond between 0-1 and 0-2 and a saturated linkage between 0-1 and C-2. 1 1. 1 la-N-acetyl-C-homo-M-pregnene-3,20-dione. CH8 12. lla-N-acetyl-C-homo - A1�- pregnadiene - 3,20 4}_ 5 dione. ?0 13. A compound of the following formula: BLN/\ 0H, 2 =0 1? wherein R2 is selected from the group consisting of alkyl 15 and aralkyl containing up to 12 carbon atoms and Z is RIO selected from the group consisting of a double bond be- - . neg� ' ? . . _ _ ggggolodlde of ll'a'N'ethyl'c hOmO'N Preg' ' '. group of less than 12 carbon atoms; and R' is selected 20 from the group consisting of hydrogen and a hydrocar bon carboxylic acyl group of less than 12 carbon atoms. . 14. nag?iegg 525312811051? of 11a'N'ethyl'c'homo'Al'Lpreg' acetate. 25 OH: (5:0 z 11a-N-acetyl-C-homo-A5-pregnen-3p-ol-2O-one. 15. lla-N-acetyl-C-homo - A5 - pregnen-3?-ol-20-one 10. A compound of the following formula: Ae__N/\? - wherein Ac represents a hydrocarbon carboxylic acyl Zigzag g4 and C_?2 and a saturated linkage between 0-1 " ' Tom - 16. 11a-N~acety1-C-homo - A5116 - pregnadien-3p-ol-20 one acetate. 17. lla-N-ethyl-C-homo - A5,? - pregnadien-3p-ol-20 one. 18. 1 1a-N-ethyl-C-homo-A5-pregnen-3B-ol-20-one. 30 20. 19. 11,12-seco-22a-A5-spirosten-3?-ol-11,12-dial. 1 1a-aza-C-homo-22a-A5-spirosten-3p-ol. 21. 11a-N-acetyl-C-homo-22a - A5 - spirosten - 3B - ol acetate. 0_ 35 References Cited in the ?le of this patent UNITED STATES PATENTS wherein Ac represents a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and Z is selected 2,806,028 2,806,029 Mazur ______________ __ Sept. 10, 1957 Mazur ______________ _._ Sept. 10, 1957 UNITED STATES PATENT OFFICE Certi?cate of Correction Patent No. 3,063,984 November 13, 1962 John A. Zderie It?is hereby certified that error appears in the above numbered patent requiring correct-1011 and that the said Letters Patent should read as corrected below. _ Column 2, lines 2 to 12, the formulas should appear as shown below instead of as 111 the patent: columns 1 and 2, Formulas II, III, IV, V and VI should appear as shown below instead of as in the patent: J O ?Al/J m H m M05 w Mom MQEY CH| CH1 = =0 columns 3 and. 4, Formulas VIII and VII should appear as shown below instead of as in the patent: OH: OH: z i 0Q VIII 0 Q v11 3,063,984 column 4, Formulas IV, IX, XI, X, XIII, XII and XIV should appear as shown below instead of as in the patent: CH1 OH: e=o M15 Ac 0s . "<31 mm 110C IV on, om HOH =0 R'-?N/\ /� 110 m-nAi? Cb? :10 x1 3:; O5 x ii; Mm 0Q 11: 3% xm HCPC 1:11 on. x? 2 =0 ? 0Q xxv colungn 8,l lines 41 to 52, the formula should appear as shown below instead of as in the patent : OH: m m column 8, lines 58 to 68, the formula; should appear as shown below instead of as in the patent: 3,063,984 column 9, lines 5 to 14, the formula should appear as shown below instead of as in the patent: CHI 6:0 Z Iii-NA, of; column 9, lines 26 ?to 36, the formula. should appear as shown below instead of as in the patent: 0H: column 10, lines 7 to 17, the formul paten1;: 2� should appear as shown below instead of as in the Ara-NA? Signed and sealed this 6th day of August 1963. [SEAL] Attest: ERNEST W. SWIDER, Attestz'ng U?icer. DAVID L. LADD, Oomndssz'mer of Patents. UNITED STATES PATENT OFFICE Certi?cate of Correction Patent No. 3,063,98I November 13, 1062 John A. Zderio It, is hereby certiliecllhnl error appears in the above numbered patent requiring correction and that the srud Letters Patent should read as corrected below. _ Column 2, lines 2 Lo 12, the formulas should appear as shown below instead of as m the patent: W50 Mo (1/ no? columns 1 and 2, Formulas II, III, IV, V and VI should appear as shown below inslead of as in the patent: O UNA?: ? / I no n We we Rob v o5 w columns 3 and 4, Formulas VIII and VII should appear as shown below instead of as in the patent; 2% o5 Mu 0o 3,063,984 column 4:, Formulas IV, IX, XI, X, XIII, XII and XIV should appear as shown below instead of as in the patent: TH? OH; /0 =0 癨0] m w M005 RG3? MW Rm H003 H005 rv 1x 0H; 0 E: HOE :0 x1 Z I: OH: OH: = 5:0 nI-NAi R1-N/\\ 4 0Q XIII 1104C x11 CH] x? =0 Egon m m oohun閘 8, lines 41 to 52, the formula, should appear as shown below instead. of as in the pat/en? : Z III-NA of) O column 8, lines 58 to 68, the formula, shoulzl appear as shown below instead of as in the patent : nI-NA 3,083,984 column 9, lines 5 to 14, the formula should appear as shown below instead of as in the patent: m o? column 9, lines 26 ?to 36, the formula should appear as shown below instead of as in the patent: Q ol ooltl閙n 10, lines 7 to 17, the formula should appear as shown below instead of as in the pa. nt: mm ?1115 Signed and sealed this 6th day of August 1963. [SEAL] Attest: ERNEST W. SWIDER, Attestz'ng Oy?cer. DAVID L. LADD, Oomwnissz'amr of Patents.