US3037983A - Piperazine derivatives - Google Patents

Description

PIPERAZINE DERIVATIVES Charles F. Geschiekter, Lorton, Va., Ebenezer E. Reid, Baltimore, Md., and John S. Pierce and Ying Ho Chen, Richmond, Va., assignors to The Geschickter Fund for Medical Research, Inc., Washington, D.C., a corporation of New York States Patent No Drawing. Filed Oct. 5, 1959, Ser. No. 844,172 6 Claims. (Cl. 260-268) This invention relates to derivatives of piperazine and this application is a continuation-in-part of our co-pending application, Serial No. 670,654, filed July 9, 1957, now abandoned. More specifically, this invention relates to compounds of the following structure, herein identiand their non-toxic acid addition salts, Where each of A and A is a member chosen from the group consisting of H and CH and each of B and B' is a member chosen from the group made up of pyrrolidino, piperidino, 2- methyl piperidino, 2,4-dimethy1-piperidino, morpholino and a dialkylamino radical of the structure where each of R and R is an alkyl radical containing from one to four carbons. In the individual compound C, A and A may be the same or may be dilierent; B and B may be the same or may be different; R and R may be the same or may be different.

The compounds of structure C are pharmacologically active and are useful in medicine. dilators and are useful in the control of asthma. They have relatively low toxicities.

They are bronchial Also, the compounds of structure C are useful intermediates for the formation of useful methiodies of the structure A (EH-CH2 B-CHzCHOHCHzN CHzCH NCHrCHOHCHrB-(CHsD These dimethiodides are relaxants of voluntary musculature and can be used to replace curare where muscular relaxation is important.

In the present invention, compounds of structure C were prepared by one of the following general reactions:

3,037,983 Patented June 5, 1962 equivalent. In reactions III and IV, B and B may be equivalent or may be different.

tion of compound C, given just above and it also includes the compound C, itself, within the definitions of A, A, B and B, preparation. 7 V

The following reactions were used in the preparation of some of the intermediates used in the present specification:

l /CHCH2 /O\ NaOH H-N NH+2ClCHzCHCH:

CHzCH CHI-CH2 CHzCH (IE-CH2 /O\ NaOH HCON N-H+CICH:CHCH2 A OHzCH Thisinvention includes the four methods of prepara-' given above, regardless of the method of CHrCH The intermediate formed in reaction 1 above is used in reaction II in the preparation of compound C. 'I'hefinal product in reaction 4 is used for the synthesis of C by the general reaction IV. It is noted'in this latter reaction that B and B maybe equivalent or they may be difierent. The final product in reaction 5 is used for the synthesis of C by reaction III. vAlso, in this case C may contain groups B and B which are equivalent or which are different; a 1

In the preparation of compounds of the structure 011-0112 B-CHCHOHCH2-N N-CH CHOHCH B omen as comprehended by above-identified structure C, the following distilled epihydrinamines were used:

orncnezNouzcnoui (cmomcmonomomorr-iorr,

Also, crude 3-pyrrolidino-l,Z-epoxypropane of the structure 7 indicate that in certain syntheses side reactions were decreased by carrying out the reaction of the epihydrinamine and secondary amine in the presence of a small amount of aqueous alkali.

In a typical reaction, to a solution of piperazine in ethanol was added slowly two molar quantities of epihydrinamine. The reaction mixture, after standing for seveial hours at room temperature, was heated for several hours to approximately C. (Note: All temperatures in this specification are on the centigrade scale.)

The preferred method for the synthesis of compounds 7 of the structure is illustrated by reaction IV. a The same epihydrinarnines which serve for reaction I also serve for reaction IV.

Usually, in the purification of a compound of structure C, the reaction product was dissolved in aqueous hydrochloric acid and the compound C was precipitated as an oil, with alkali. All of the compounds of this structure reported in this specification were purified by vacuum distillation. The boiling points given in the specification are for the purpose of identification only and are not intended to limit the claims.

including quaternization of one or both of the tertiary amino groups in D. The compounds of structure D usstructure in this specification, obtained by distillation, is ually were so reactive that they underwent self-condenlikely a mixture of diastereoisomers. Each of the comsation on standing for a short time at room temperature pounds of structure C reported in Table I, with a few or even in the refrigerator. Due to this activity, the bi exceptions, is a liquid, usually rather viscous, or a lowsepoxides of structure D usually were used for reaction melting solid. In general, the compounds of structure II, a bove, very soon after their preparation.

C derived from trans-2,5-dimethylpiperazine melt higher Of the four bisepoxides of structure D, only one, namely than the corresponding compounds derived from pipera- Since each of the compounds of structure C contains at least two asymmetric carbons, each product of this zine, 2-methyl piperazine or cis-2,5-dimethylpiperazine.

A partial separation of diastereoisomers of one of the 0 OH-CH2 0 compounds of structure C is here described. A sample L of distilled 1,4-bis[3-(di-n-butylamino)-2-hydroxypropyl] t H H piperazine of the structure Tans 0 8 CHZCH: (CHHCHQCHZCHZ)2NCH2CHOHCHPN N CH2CHOHOH2N(GHEOHBCHZCH3)? CHgCH which gave an excellent analysis for nitrogen, remained an oil until it was seeded with a crystalline product of tained-as gums or viscous oils.

the same compound from another run. After standing The following examples are given to illustrate specific for a few hours the mass became semi-solid. After methods which have been used in the synthesis of comstanding for about a month the sample was subjected pounds of the present invention but are not meant to limit to suction filtration. the scope thereof.

The residue in the Buchner funnel was placed on a clay plate to remove as much as possible of the liquid diastereoisomer. After standing on the clay plate for about three days the white solid melted at 5455. The

was isolated as a solid. The other bisepoxides were ob- EXAMPLE 1 1,4Bis[3- (Di-n-Propylamino)-2-Hydroxypropyl] Cis-ZJ-Dim'ethylpiperazine CH3 HEP-CH2 N-CH2CHOHCH2N(CH2CH2CH3)2 (E) as.

(CH3CHsCH2)zNCHgCHOHCHzcis filtrate in the suction flask became quite viscous when cooled to about -10 but did not become a solid.

The original distillate, the solid and the filtrate gave nitrogen analyses as follows:

Calculated for C H N O Nitrogen, 12.27%.

Nitrogen found, percent To 190 g. (1.20 mole) of 3-di-n-propylamino)-1,2- epoxypropane was added slowly over a period of one hour 68 g. (0.60 mole) of cis-2,idi-methylpiperazine dissolved in 100 ml. of ethanol, the temperature being kept below 15 The reaction mixture was allowed to stand over night at room temperature and was heated on a gently boiling water bath for about 15 hours.

Original distillate 12.27 The mixture was cooled and was treated with 1.5 1. of Solid (M.P. 54-55") 12. 1 N hydrochloric acid and with 500 ml. of ether. After Filtrate 12.09 separation, the aqueous layer was made strongly basic. An oil came to the surface. The oil and a ueous la e Typical compounds of structure C of the present 1nq y r vention were converted into acid addition salts which were extracied Wlth 500 i l one Pomon the such acids as hydrobromic acid, sulfuric acid, phosphoric elher solutlqn on evaporatlqn m an open .contamer acid, acetic acid, lactic acid, citric acid and thiodisalicy- 55 Welded a f l Y i the lie acid. Each of the first six acids listed above was found elher and Yacuum d'lstluimon of the resldue yleided i' to form a soluble salt with about twenty-five of the amino bls [3 d1 f Pr OP ylammo)'2"hydroxyp mp Y1] a1 01S of Structure C methylprperazrne, 199-202 at 0.20 mm.

In the preparation of a typical compound of the fol- At tunes It flmnd l products j l lowing structure herein identified ture C whrch were semi-solrds originally, on distillation yielded liquids which tended to remain in the liquid state,

some remaining in this form for several months or longer. 0 CHOHc v Some samples, on being seeded, readily deposited crys- CE/ITLCHOHPN tals, some becoming solid in'appearance.

Compound E has been used efiectrvely clrmcally, 1n the CH2 |3H control of asthma, in over one hundred cases. The dosage usually is 50 mg. This compound is given orally, as the free base, dissolved in sesame oil and in a capsule or as the hydrochloride, dissolved in water. Also, it is given epichlorohydrin was caused to react with the piperazine,

H-CH; by intramuscular injection as the hydrochloride, in sterile aqueous solution.

\ The acute toxicity of the compounds of structure C of 23 the present specification, when tested in the rat, usually is between LD 50:100 m g./kg. and LD50==300 mg./kg. and the reaction product was treated with alkali. Us The acute toxicity of compound E in the rat is LD ually, the yields were low, likely due to side reactions, 50:400 mg./kg.

x to the surface.

The acute toxicities in the rat of a few compounds very closely related in structure to E are given below:

8 amino-Z-hydroxypropyl] cis-2,5-dimethylpiperazine, B.P. 184186 at 0.55 mm.

CH3 LL 50 OlEl-CH2 MgJKg.

(CH3CHzCH2)zNCHzCHOHCHzN N-CH2CHOHCHzN(CHzCHzGHs)2 250 trans CHQOH CH3 CHCH2 (CHaCHzGHzhNCHzCHOHCHzN N-CH2CHOHCHzN(CHzCHzCHa)2 300 CH CH CH3 OHGH2 (CH3OH2CH2CH2)2NCH2CHOHCH2N TOHZCHOHCH2N CH2CH2OH2OH3 Z 200 (is CE2C-H CH3 CHI-CH;

(cnaornonlcrmmomononoum C 2CE2 Each of the four compounds above, as well as compound E, has been used to relax muscle spasm in arthritics, in sprained backs and for muscular spasm in the gastronongouononzmonzougcmcnm 275 EXAMPLE 3 1 ,4-Bis [3- (2,4-Dzmethylpiperidino) -2-Hydr0xypropyl] T runs-2,5 -Dimethylpiperazine intestinal tract. The results were good. Each of these four compounds proved effective in relieving asthma.

EXAMPLE 2 1,4-Bis [3-(Diethylamino)-2-Hydr0xypr0pyl] Cis-2,5- Dimethylpiperazine CH: DH-CH2 (GH3CH2)2NCH2CH OHGHzN V CHaCH CH3 cis A mixture of 25.8 g. (0.20 mole) of 3-diethylamino-' 1,2-epoirypropane. 12.8 g. (0.10 mole) of cis-ZJ-Gimethylpiperazine in 20 ml. of ethanol and '8 drops of waterwas allowed to stand over night at room temperature and was heated to 50 for 7 hours, On treatment-with 500 m1. of water the "reaction mixture tended 'to stay in solution.

On addition of 50 g. of potassium carbonate an oil came vacuum evaporated. Onsecond distillation the residue The oil was extracted 150 m1. of 1 ether. The ether layer was filtered and theether was t A mixture of 20.3 g. of 3-( 2,4-dimethylpiperidino) -1,2-

' epoxypropane, 8.0 g. of trans-2,5-dimethyl-piperazine in 30 ml. of ethanol and 4 drops of Water was allowed to stand at room temperature for two days. The reaction mixture was warmed on the water bath for about 20 hours.

On treatment of the reaction mixture with 1 liter of water, an oil, mixed with solid, rose to the surface. The p 60 lower aqueous layer was discarded. The upper layer was treated' with 400 ml. of ether and 1 liter of water. The aqueous layer was discarded. The upper ether layer and some undissolved solid was vacuum-evaporated to remove the ether and the residue was vacuum-distilled. The

. yield of 1,'4-bis [3-(2,4-dimethylpipe1idino)-2-hydroxypropyl] trans-2,5- dimethylpiperazine, B.P. 212-213 at .10 0 mm was 11 g EXAMPLE4 1,4-Bis [3-,(Di-n-Butylamino)-2-Hydr0xypr0pyl] Piperazine 9 A mixture of 38.8 g. (0.20 mole) of piperazine hexaand epihydrinamiues of the structure hydrate in ml. of alcohol and 74.4 g. (0.40 mole) of 3-(di-n-butylamino)-l,2-epoxypropane, after standing for several hours, was heated to 60 for 7 hours. The re- BOH2OHOH:

action mixture was treated with 1.5 l. of water and 500 ml. of ether. The ether solution was washed with 1 l. in ethanol solution and in the presence of a small amount of water. Since much of the ether was lost, at this point of aqueous sodium hydroxide solution, were allowed to 200 ml. of ether was added. The ether solution was stand at room temperature, usually over night, and then; evaporated and the residue was vacuum-distilled. On the were heated gently for about four to six hours, sometimes second distillation the yield of 1,4-bis [3-(di-n-butyl 10 longer.

amino)-2-hydroxypropyl] piperazine, B.P. 225228 at The reaction mixture was treated with water or water 0.50 mm. was 32 g. (35% of theory). and alkali and the oil which came to the surface was separated, frequently by ether-extraction. The oil was EXAMPLE 5 subjected to fractional distillation in a vacuum. 1,4-Bis [3-(Ethylbutylamino)-2-Hydr0xypr0pyl]-2- 15 In some runs a slight excess of substituted piperazine Methylpiperazine was used; in some runs the reverse was true.

CH3 CHaCHz /CH-CH2 CHzCHa NCH2CHOHCHz-N NCHzCHOHCH2-N 11-43-1119 CHzOH: 11-04119) I A mixture of 10 g. (0.10 mole) of Z-methylpiperazine EXAMPLE 7 in ml. of ethanol and 32 g. (0.20 mole) of 3-(ethyl butylamino)-l,2-epoxypropane, after standing for a short P y yp py Y time, was heated to 60 for 4 hours. The product was amin0)-2-Hydr0xypr0pyl] Cz's-Z,S-Dimethylpiperazine (3H3 OH GH- V (JR-0H2 O N-CHzCHOHCH -N N-OHZOHOHCHZN(CH2OH2CH2CH3)B CH2CH2 ClS CHZCH treated with 400 ml. of water. An oily upper layer was To a solution of 7.5 g. (0.04 mole) of 3-(di-n-butylformed when 50 g. of potassium carbonate was added. amino) -1,2-epoxypropane in 10 ml. of ethanol was added The oily layer was separated, dissolved in ether and the 40 2 drops of 6 N sodium hydroxide solution and 10 g. ether solution was filtered. On vacuum-evaporation of (0.04 mole) of 1-(3-morpho1ino-2-hydroxypropyl)cis-2,5 the ether and vacuum-distillation of the residue, the yield dimethylpiperazine in 10 ml. of ethanol. The mixture of 1,4-bis [3-(ethylbutylamino)-2-hydroxypropyl]-2- was allowed to stand for 2 days and was heated just below methylpiperazine, B.P. l99202 at 0.30 mm., was 21.1 boiling for about 4 hours. g. (51% of theory). To the reaction mixture was added 125 ml. of water. Some oil separated. The amount of oil was increased EXAMPLE 6 by treatment with 125 ml. of 6 N sodium hydroxide solution. The oil was extracted with 100 ml. of ether. The General Merhod for Preparation of Compounds of the ether was evaporated and the residue was vacuum-dis- Structure tilled. The yield of 1-[3-(morpholino)-2-hydroxypropyl]- 4-[3-(dibutylamino)-2-hydroxypropyl1cis 2,5 dimethyl- 7 piperazine, B.P. 2l3-214 at 0.09 mm., was 7.0 g. (39 OHOH2 per-cent of theory). B-crnorroHomN N-CHzCHOHCHrB' EXAMPLE 8 2? 1 -(3 -Piperidino-Hyd'roxypropyl -4 (3 -D iethylamino-Z- Hydroxypropyl)-2-Methylpiperazine 0H3 onion. (EH-CH2 CH2 N-CH2OHOHCH2 N NCH2CH0HCHzN(O2Hs)n OI-TECH; CHZCEz Approximately equimolar quantities of substituted pi- To a solution of 2.58 g. (0.020 mole) of 3-diethy1- perazines of the Stru t e amino-1,2-epoxypropane in 25 ml. of ethanol was added 4 5 ml. of 6 N sodium hydroxide solution and 6.2 g. 0.027 mole) of 1-(3-piperidino-Z-hydroxypropyl)-2-methylpi- B-CHqCHOHCHz-N NH perazine in 25 ml. of ethanol. After standing for a few OHQCH days at room temperature the reaction mixture was heated just below boiling for about 6 hours.

11 .01: treatment of the reaction mixture with 300 m1. of 6 N sodium hydroxide solution an oil separated. This oil was extracted with 100 of ether. The ether layer,

on vacuum-evaporation and vacuum distillation of the residue, yielded 2.4 g. (32% of theory) of 1-(3-piperidino 2 hydroxypropyl) 4 (3 diethylamino 2 hydroxypropyl) -4-( 3 -diethylamino-Z-hydroxypropyl-2-methylpiperazine, B.P. l90l91 at 0.15 mm.

Note: Likely some isomeric 1-(3-diethylamino-2-hydroxypropyl) -4- 3 -piperid ino-2-hydroxypropyl) -2-methy1- 1 piperazine was present, also.

EXAMPLE 9 1 [3 -M orpholino-Z-Hy'droxypropyl -4 [3-( 2,4 -Dimethyl-.

piperia'ino) -2-Hyd'roxypropyl1Piperazin e 1 2 EXAMPLE 10 1 -(3-Dimethylamino-2-Hydroxypropyl)-4 (3-M0rpholin0- Z-Hydroxypropy-l C z's-2,5 -Dimethylpiperazine CH H-CHQ OHzCHa (CHalnNCHzGHOHOHz-N CH2CHOHCH2N O cis omen onion,

To 5.16 ml. (0.06 mole) of epichlorohydrin in ml. of ethanol was added 1 ml. of 2 N sodium hydroxide solution. To this mixture was added slowly with stirring over a period of 1.5 hours a solution of 12.9 g. (0.053 mole) of 1-(3-morpholino-2-hydroxy-propyl)cis-2,5-dimethylpi' perazine, the temperature being kept below After 3 hours of stirringthe reaction mixture was treated with a V OHs CHzCH: CHzCHa EH-CH O N-CHQGHOHCH2N. N-CH2CHOHCH2N CHCHs CHQG a CHgCHz CHzCHz 1 was allowed to stand for about two days and was heated just below boiling for about 4 hours.

The reaction mixture was treated 250 ml. of 3 N sodium hydroxide solution. The oil, which separated, was dissolved in ether and was filtered. On vacuumevaporation of the ether and vacuum-distillation of the residue there was obtained 4.5 g. (40% of theory) of I-(B-morpholino 2 hydroxypropyl)-4-[3-(2.4dirnethylpiperidino) -2 -'hydroxypropyl]piperazine, B.P. ZZZ-223 at 0.10mm.

solution.

solution of 4 g. of sodium hydroxide dissolved in 60 ml. of water. After 1 hour of stirring the mixture was extracted with 150 ml. of ether. To the ether solution was added 0.10 mole of dimethylamine in 25 percent aqueous The mixture was allowed to stand over night. The ether was vacuum-evaporated and the residue remaining was heated gently on a sand bath for about 4 hours.

The reaction mixture was treated with 125 ml. of 6 N sodium hydroxide solution. An oily layer was formed.

On addition of 125 ml. of'water much of this oil dissolved. The amount of oily layer was increased by the addition of another 125 ml. portion of 6 N sodium hydroxide solution. The oil was extracted with 125 ml. of ether. On vacuum-evaporation of the ether and vacuum- 40 distillation,of the residue there was obtained 1.8 g. (10

propyl) 4 (3 morpholino 2-hydroxypropyl)cis-2,5-dipercent of theory) of V 1-(B-dimethylamino-Z-hydroxyj methylpiperazine, B.P. 194-196? at 0.09 mm. pressure.

In Table I are given representative compounds of struc- The example given just below illustrates reactions 5 C in which A, A" B and are varied.

and III. 1

Q TABLE I V V CH-OH= BCH1OHOHCHN N-CHzCHOHCHr-B omo A A B B B.P.O. Press Molecular Nitrogen, Percent (uncon) mm. formula caled. found H rr ormgN wort 21m. -150 0.15 oinmlNioi' 15.01 15.01

H p N N V. 198-204 V 0.07 cliHnNloi 16.48 10.40

, V 7 V w V 1 n N V V 210-215 V 0.30 o omuNioa 15.20 15.00

grrj H ,N (nC4H0)z- 7 211-214 0.10 021111501101 13.01 15.70

H s L wreat 220-221 0.15 011731101103 13.52 13. 52 1 e 1; H N: oH= 220-223- 0.10 C11H11N10= 14.08 13.03

; VCH:

H 'H 220-221 0.50 CuHhNiOa 1115 13.03

A A B B B.P. 0. Press. Molecular Nitrogen, Percent (uncon) mm. formula calcd. found (6h CH3 CH3 CH3 H d N .0 Hz 227-234 0. 150. 20 CzaHszNtOa 12.28 12.00

CH3 CH3 (n-C 3H7) 2N N (nCsH?) 2 198-202 0. 20 C24H52N402 13. 04 13.

CH3 CH9, H3O N N(DC4Hu)z 223-229 0. 07 C27H55N40fl 11. 98 12.

CH3 CH3 (ll-43411 N N (ll-C4110): 221-222 0. 45 C28H6BN40fl 11. 56 11. 54

- Trans. b cis.

kanolamines of structure C with three molar quantities V of methyl iodide at room temperature for approximately three weeks. Details are given below for the formation and isolation of a typical dimethiodide.

. EXAMPLE 11 Reaction of 1,4-Bis[3-(2-Methylpiperidin0)-2-Hydr0xypropyl]Cis-2,5-Dimethylpiperazine with Methyl Iodide A solution of 4.3 g. (0.01 mole) of the title alkanolamine and 4.26 g. (0.03 mole) of methyl iodide in ap proximately 25 ml. of ethanol was allowed to stand for about three weeks in a stoppered flask. On the addition of anhydrous ether a gum was formed. After trituration of the gum with ether it was dissolved in absolute ethanol. Again the gum was precipitated by [the addition of anhydrous ether. On trituration with ether the gum solidified. The solid was filtered and dried in a vacuum desiccator. The quaternary salt thus obtained was a high melting solid, very soluble in water but not appreciably hygroscopic. Calculated for (C H N O (CH I) I, 36.0%. Found, 36.1%.

By the same general procedure, dimethiodides were obtained 'by the reaction of methyl iodide on l,4-'bis(3-din-propylarnino-Z-hydroxypropyl)cis-2,5 dimethylpiperazine, 1,4 bis [3 Z-methylpiperidino) -2-hydroxypropyl] 2-methylpiperazine and 1,4 bis [3-(2,4-dimethylpiperidino)-2=hydroxypropyl]cis-2,5-dimethylpiperazine. of these products had high melting points and were very (CHsCHzCHr) zNCHgCHOHCHr-N (GHzOHzOHQ NCHzOHOHOHzN cis eis

trans soluble in water. being hygroscopic.

The dimethiodides of compounds of structure C are curare-like substances which have proved capable of complete relaxation of skeletal musculature without the production of respiratory paralysis. These compounds have the advantage over many curare-like products that they are potent but transient in action.

We claim:

1. A compound selected from the group consisting of They were on the border line as to CHa (DH-CH2 NCH:CHOHCH2N(CHgCH CHa):

.CHzCH 3. A compound of the formula CH: )HCH2 V N-GHzGHOHCHzN(CH CHzCHs):

' CHQCH H: '4. A compound of the formula (IJHCH2 N-OI-IQQHofloHtNwHrcnzomom CHrCH- 5. A compound of the formula CH3 )HCHn (OHgCHgCHqCHahNCHzCHOHCH N N-OHaCHOHCfl NwHzOHqCHaCHm 01530 1 6. A compound of the formula CH3CH2 N0H20HoHcmmomcmomom)1 CHQCHZ No references cited.

(CHsCHzCHgCHz) NOHQCHOHCHZN UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,037,983 June 5, 1962 Charles F. Geschickter et a1.

It in hereby certified that error eppeere in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column l line 46, for "methiodies" read methiodides column 2, line 3, for

CH2CHCH read CH CHCH same column 2, line 69 and column 3, lines 4, l0, l7, and 24, for I A if cu-cu H-CH Hco' t y read. HCON i y cH cH CH CH column 3, line 4, for

CH C EH readv CH CQ EH line 24, strike out line 37, for

ClCH O CH read ClCH CHCH column 5 line 60,strike out the period and insert instead a comma; column 6, line l2, for

N-CHQ CH read NCH CHCH column 6, line 41, for "3-di-n-propy1amino) read Patent No. 3,037,983

3 (din-propy1amino) column 8, line 6, for "LL 50" read LD 50 column 11, line 7, strike out "-4-(3- diethylamino-2-hydroxypropy1"; column 12, line 41, strike out "propy1)-4(3-morpholino2hydroxypropyl)cis-2,5di" and insert the same after "hydroxy-" in line 42, same column 12; column 13, TABLE 1, line 1, for

H read 1-1 same line 1, for

H CH

read

column 13, line 9, for

6 read i both occurrences; same column 13, line 12, for

5 read H column 15, line 1, for

CH H

read

Patent No. 3,037,983

;ame line I for H read H :ame column 15, line 3, for

3 read 3 (SEAL) kttest: ERNEST W. SWIDER attesting Officer DAVID L. LADD Commissioner of Patents

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FROMULA