NOTES
Septerriber 1969
919
TABLE I1 Yield, Compd
%
hfp, O C
6 6 8
72 67 55
86 0-87.5 Two forms: 58-61, 81.5-83.0
L
Kugelrohr distn? O C (mm)
nD
("C)
110-120 1 5366 ( 2 0 ) (I x 10-3) 9 51 117 (7 X lo-') 1 3345 (23 5 ) Temperatwee given are those of the air bath, a t which the materials were collected.
same conditions. 4 small syrupy fraction was collected at' 140°, which solidified upon standing. It was recrystallized from C s H s petroleum ether (bp 30-60") as white, fine prismatic needle, mp 58-61', The second fraction was collected a t 155' and recrystallized twice from CeH6-petroleum ether as prismatic granules, mp 81.5-83.0'. The ir spectra of the two substances in solid state (Nujol mull) were markedly different, but were superimposable in solution (CHC1,): 2.9 (broad), 3.4, 5.95, 11.98 ,u. 3,3-Ethylenedioxytropane (15).--A mixture of tropinone hydrobromide (14, 30 g, 0.136 mol), ethylene glycol (17.5 g), and P h l I e (130 ml) was stirred and refluxed for 47 hr, while water phis the glycol (7 ml) was collected in a Barrett trap. After cooling, the organic layer was decanted, and the black KOH (100 ml) and contarry substance was dissolved in 2 tiiiiioiisly extracted with E t 2 0 (250 ml) for 6 hr. The Et20 extract and the PhMe layer were combined, dried, and evaporated in vacuo, giving the crude product as a dark liquid (31 g). Two kugelrohr distillations afforded the pure product as a colorless liquid, collected a t 43-50' (air-bath temperature) and 0.02 mm, n Z o1.4936. ~ Anal. ( C l , H l ~ S 0 2C, ) H, S. 3,3-Ethylenedioxynortropane(16).-To a mixture of 15 (9.2 g, 50 mmol), NaOH (20 g), and H20 (80 ml), which was cooled to -IO", was added a warm aqueous solution of K,Fe(CN), [98.8 g, 0.3 mol, in H,O (170 ml)] a t a rate to maintain the reaction rnixt'ure at' k3' with efficient stirring. The addition required 60 min. After stirring a t room temperature for 43 hr, the mixture was continuously extracted with Et20 (2.50 ml) for 72 hr. The EteO extract, was stirred with KOH pellets for 2 hr, filtered through Celite, and evaporated in vacuo. Kugelrohr distillation of t'he red liqliid residue (8 g ) gave the product (7 g, 837, yield), collect,ed a t 33-40' (0.002 mm). ,4n analytical sample was obt,ained by redistillation on kugelrohr, as a colorless liquid, collected a t 105-110" ( 5 mm), n19.8D 1.5033. Anal. (CgHibNO?) C, H, N.
Ana13 ses
C, H, N C, H, N C, H, N
Ci,H,,FKO?
C, H , S
TABLE I
Compda
Pemoline lh
AIin dose causing signif inc in spont motor act., mglkg IP Oral
hpprox LD,a, mg/kg IP Oral
10 300 .i00 30 300 300 100 7.50 IO0 Li 3a 200 > 1000 > l00U Adrniiiihtered as a 2(,i stispelision in 0.S';; trajacaiith.
10
. 0i .0i 100
--
Yield, so.
X p , OC"
c /o
la
188-1 93
1.i.0
b
21.5-220
16.2
C
220-225
16.0
d
248-233
21.3
e
262-266
31.2
f
"72-277
11.3
4!
24+232
30.7
h
278-28"
30,3
i
296-302
36.4
2(j-2G(j
2.5 , 8
k
318-321
27.8
1
"84-289
31 .-I
m
248-268
13.:3
Acknowledgments.-The authors are indebted t'o the Pharmacologx Department of the Bristol Research Laborat'ories, Syracuse, S. Y., for the biological tests.
Synthesis of Compounds with Potential Central Nervous System Stimulant Activity. I. 2-Amino-2-oxazolin-4-one-5-spirocycloalkanes and 2-Am ino-2-oxazolin-4-one-~-spiro(4'-piperidines) RI. R. €I.\RNDCS aiid R. 11. I ~ . - ~ s a ~ u s s e ~
j
D e p a d V Irnt, Research 1) iv is ion, . I Obott Laboratories, S o r t h Chicago, Illinois 6006.4 O q pII ic ('h enaist i
Formula
CiiH22FSO2 Ci7H22FNO2 CigH2aFrL'Oz
y
Received April 4, 1969
The known activity of many 2-amin0-2-oxazolines~~~ arid 2-amino-2-oxazoliii-4-ones3-~ as CNS stimulants (1) G . I. Poos, .J. R . Carson, J. D. Rosenau, A. P. Rosakowski, N . M . Kelley. and J. McC:owin. J . M e , / . Chem., 6 , 266 (1963). ( 2 ) 1.31). Daiinsr. Fwnrli Patent 1 ,426,OXO (1966). ( 3 ) L. Schmidt. A r z n e i m i l t e l - F o r . ~ c k 6 . . , 423 (1956). (4) H. Najer and R. Giudicelli, Bull. SOC.Chim. France, 1231 (1961). ( 5 ) C. F. Howell, E.Q. Quinones, and R . A. Hardy, Jr., J . O r g . Chem., 27, 1679 (1962).
a
All compounds melted with decomposition.
\
i~iidmorectic agents led ub to iyiitheiize a wrieb of 3+piro-substituted 2'-ainino-2-oxnzoliri-4-orles. With the exception of 2-amino-3,8-diazaspiro [4.51dcc-2-en-d-one (3g) which was obtained by hydrogenolysis of the S-benzyl derivative 3d, the spiro compouiidh were prepared by reaction of guanidine with thr c t h j 1 ester of the appropriate hydroxy acid.h l ' h 0 S C hydroxy acidy which were not commercially :tv:iil:ible were prepared from the corre~pondingketorie11) acid hydrolysis of the cyanohydrin5. Biological Data. - -Effwts on the g:itcd by obyervatiori of albino SI for g r o s chuiiges in behavior follon iiig administr:ttiori of test compounds. Evidence of CXS stimulation was see11 with compounds lh, lj, and 3a. In Table 1 thc potctiry :itid toxicit) of theae three compouiidh are cwnipared with +imilar data obtained for 2-amino-51Jtictq 1-2'-o.;:izolin-.l-ont. (pcrnoline). The rrmaining ~ ~ ~ i i i p o11uere r ~w l ~a k C'SS depressant3 m d generall? i ~ ) r i t o x i c:it closc>h helow 1 g / h g . S o n e of the coni~ ) o r i i i d shon s ( ~ significant 1 anorectic activit) in r a t a . Experimental Section .\I1 iiieltiiig points were determiried with a Thomas-Hoover c.:i~)iIlary apparatiis :md are rorrectetl. Elemental analyier t v t w perfortlied by AIr. I-.llauwliel a i d his associates iii thr :iii:ilytic:tl department of Abhott Laboratories. Where a n a l y w :II'C' it~dicntedonly I ,g symbols of the elements analytical remlt-: otit:iiiied f o r those elements were within +0.4(% of the theoretical yxliiw. 11...pectrn were determined by l l r . A . J . Kammer with b'. Trrtubertnd R . Ascher. Bar., 46, 20;; (1913). (71 11. Xiiljrr, I?. Giudicelli, E .Joannic-Voisinct, and AI. Joannic, UuIl so^. Chini. F w n c r , 1226 (1961). (iij
I'erkin-h;lmc!r 22 1 gratiiig hpect rotriot or. \Vhelc qLL;,, v:iliit+ are giveti for groups of compounds, the atworptions in the region 1600-1800 cm-1 for each compound within the group were withiii :k3 cm-l of the given value. At higher frequencies Y,,,,,~ for each compound was m-ithin i 2 0 cm-1 of the given value. 2-Amino-2-oxazolin-4-one-5-spiroalkanes ( la-m).-A solutioii of the appropriate 1-hydroxycycloalkanecarboxylic acid* (10.0 R ) and p-toluenesulfonic acid (0.03 g ) in EtOH (100 ml) was refluxed for 8 hr. The sohitioil was cooled and concentrated at reduced pi'essiire, and the residue was dissolved in ether (100 ml). T h r > b : t 2 0 snliition was xvashed [lor; aqiieoii. XayCO., ( 2 0 1n11 ) 1120 (two 20-nil portio~is)],dried (?;a2S;04),:iiid cvnrriLt rnted :I1. recliic,ed pieustire. The hydrosy esters were obtairied i n 70--!)0'; yield atid had Y , ~ : ,3520 ~ (OH) and 1720 iC-=0) ~ n i -17~ tioris in CHC1;j). loalkarie~:irbox?.lnte (0.1 nioie: Wits drochloride (9.56 g, 0.1 rriole), KO11 (.i.61 g, 0.1 mole), and EtOH (100 ml) for 1 hr. The mixtiwe mas cooled, diluted with H20(400 i d ) , and adjusted to pII i w i t h -1cOH. The white ct 1s xvhich deposited were collected, washed [IT.& (two 41)-rnl portioni'), l:t20 (three 40-rnl portions)], Ilized iI!~t,OII). Tllo 2-arni no-2-oxaxi ili n-4-ot i v :;LN, :;OX)( S I 1 I, I T20 !,.liaqi (T:tble 11) hat1 ii
[ C , If, N). Ethyl 4-Hydroxypiperidine-4-carboxylates (2a-f). The : I [ ) prupriately ,iit)stit,iited 4-piperidone (50.0 9 ) and acetont' vyaiiohydrin ( 2 0 0 nil) were allowed t o remain at, 25' for 2 days, dtiriiig which time white crystals of the piperidorre cyanohydrin were deposited. The crystals were rollected and dried a t 23" arid I (1 uIIIJY 3X(),:HIs? ( ( ) T I ? , : I I N I
refluxed with roiiceiit r [ i i d HCl (100ml) Cor 1 hr. The soliitioii was concentrated a t rediicwl pre.csure, the residiie was extracted with boiling i-PrC)FT (500 I n 1 ), :tiid the hot w h i t i o n \v;is filttwd. The filtrate WLS cocilrtl i i l l l l I.oiicwitratetl a t rtdtired preraiire to give the hydroxy acid 11) tlw(8) AI. R. IIarodrn, J . C'hrm. Soc., C, 960 (lY(i9)
KOTES
September 1969 chloride as a white solid, umaX 3320 (OH), 1720 (C=O) cm-’ (Nujol). The crude hydroxy acid hydrochloride was refluxed with ptoluenesulfonic acid (0.15 g) and EtOH (300 ml) for 16 hr. The solution was concentrated a t reduced pressure and the residue was treated with 10% aqueous NazC03 (200 ml). The HzO solution was extracted with CHCL (three 250-ml portions), the combined extracts were washed with HzO (100 ml), dried (Xa2S04), and concentrated a t reduced pressure to a clear liquid. The ethyl 4-hydroxypiperidine-4-carboxylates (Table 111) were purified by distillation and had vmsx 3520 (OH) and 1715 (C=O) cm-l ( 7 r & in CHC13), and analyzed correctly (C, HI N). 2-Amino-2-oxazolin-4-one-5-spiro( 4’-piperidines) ( 3a-f).--A solution of 1Ja (2.30 g, 0.1 g-atom) in EtOH (145 ml) was added to a solution of guanidine hydrochloride (9.56 g, 0.1 mole) in EtOH (45 ml). The precipitated NaC1 was removed by filtration and a solution of the ethyl 4-hydroxypiperidinecarboxylate (0.1 mole) in EtOH (50 ml) was added. The solution was refluxed for 1 hr and cooled. The white precipitate obtained was filtered, the filtrate was concentrated a t reduced pressure, and the residue was treated with EtOH (20 ml). A further quantity of white solid was obtained. This material was combined with the precipitate and recrystallized from EtOH to give the required product (Table IV). All of the compounds (3a-f) had vmax 3150 (NH), 1725 (sharp, C=N), and 1650 (C=O) cm-l (Nujol) and analyzed correctly (C, H, K). 2-Amino-3,S-diazaspiro 14.51 dec-2-en-4-one (3g).-2-Amino-8benzyl-3,8-diazaspiro[4.5] dec-2-en4-one (3d, 5.20 g, 0.02 mole) was dissolved in ethylene glycol monomethyl ether (100 ml) and hydrogenated over 57, Pd-C (1.0 g) a t 2 atm of pressure and 25’. Uptake of Ilz was complete after 0.25 hr but the reaction was continued for a further 0.5 hr. The catalyst was removed by filtration and the filtrate was concentrated a t reduced pressure to ca. 25 ml. The product was obtained as a white crystalline precipitate, collected, washed (EtzO, 25 ml), and dried; 3.30 g (97.27, yield); mp 313-317’ (from E t O H ) ; umaX 3260, 3125, (NH), 1715 (sharp, C=N), and 1625 (C=O) cm-l; analyzed correctly (C, H, N).
Acknowledgment.-We are grateful to Mrs. I. 31. Cole for the biological data and to Dr. C. 11. Lee and 31r. B. W. Horrom for helpful discussions.
N-Aminonormorphinela ALI ~ I O D I R JOSEPH I, G. CANNON,^^ Division of Medicinal Chemistry, College of Pharmacy AND
s. Y . YEH
Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa 66140 Received M a y 9, 1969
I n the course of a study of centrally acting emetics, a sample of N-aminonormorphine (1) was required; a search of the literature did not reveal that this compound has been reported. Attempts to utilize a Raschig hydrazine synthesis2 between chloramine and normorphine or norcodeine were unsuccessful. Schopf and coworkers3had reduced N-nitrosopiperidine derivatives to N-amino systems with LAH, and Xeurath and Duenger4had used this reagent to convert N-nitrosonor tobacco alkaloids to the hydrazine derivatives. How(1) (a) This investigation was supported in part b y Grant NB-04349, National Institute of Neurological Diseases and Blindness. (bj T o whom all rorrespondence should be addressed. ( 2 ) L. F. Audrieth and L. H. Diamond, J . Amer. Chem. Soc., 76, 4869 (1954): L. H. Diamond and L. F. Audrieth, ibid., 77, 3131 (1955). (3) V. C. SchGpf, H. Arm, and H. Koop, Justus Liebios Ann. Chem., 712, 168 (1968). (4) G. Iieurath and M. Duenger. Be&. Tabakforsch., 3, 339 (1966).
92 1
ever, treatment of N-nitrosonormorphine (2) and N-ni troso-0,0’-diacetylnormorphine (3) with LAH did not result in identifiable materials. Similar reduction of S-nitrosonorcodeine ( 5 ) gave a low yield of impure N-aminonorcodeine (6) which could be characterized
fpJR’’ RO
OR’
1,R = R = H,R” = NH2 2. R = R‘ = H;R”= NO
3 , R = R = Ac; R” = NO 4, R = R = Ac;R”= NH, 5, R = Me;R’ = H R ” =KO 6, R = Me;R’ = H; R”= NH2 7,R=Me;R‘=H;R‘=N=(CHJ2
only as its acetone adduct 7. Pure Y-aminonorcodeine was prepared by a literature method :j Zn-AcOH reduction of N-nitrosonorcodeine ( 5 ) . This method also permitted conversion of S-nitroso-0,O’-diacetylnormorphine (3) to its K-amino derivative (4). Zn-AcOH treatment of N-nitrosonormorphine (2) gave a complex mixture of unidentifiable products; however, acid-catalyzed hydrolysis of the ester links of N-amino-0,O’-diacetylnormorphine (4) permitted isolation of 1 in good yield. It appears that these K-aminomorphine derivatives undergo deep-seated decomposition in the presence of base. Pharmacology.-N-Amino-0,O ’-diacetylnormorphine (4), N-aminonormorphine hydrochloride (1) and N-aminonorcodeine hydrochloride (6) were dissolved in water and administered subcutaneously to SwissWebster male mice, weighing 17-20 or 30-35 g, and analgetic activity was tested by the hot plate method of Eddy and Leimbach.6 Ten mice were used for each group and tested just prior to giving the drug and after 30 and/or 60 min. The reaction times of animals given the test drugs were compared with reaction times of mice given morphine sulfate, 7.5 mg/lO ml per kg. Mice injected with 4 (28.4 mg/lO ml per kg, 60 mg/15 ml per kg, and 90 mg/20 ml per kg) showed prolongation of reaction times as compared with the control reaction times. The analgetic potency of 4 was estimated to be 0.1-0.067 times that of morphine. The miceinjected with either 1 (15 mg/lO ml per kg, 30 mg/lO ml per kg, and 45 mg/lO ml per kg) or 6 (4.43 mg/1.65 ml per kg and 26.5 mg/lO ml per kg) showed no significant differences in reaction times between the control and the “after drug” periods. ~
Experimental Section7 N-Aminonorcodeine (6) was prepared in 40% yield by the method of von Braun,s mp 172.5-174”, lit.6 mp 174’. Acetone N-Aminonorcodeinyl Hydrazone (7)-Compound 6 (1.7 g, 0.0056 mole) was refluxed with 10 ml of RIe2C0 for 0.25 Ber., 49, 761 (1916). (6) N. B. Eddy and D. Leimbach. J. Pharmacol. E x p . Ther., 107, 385 ( 5 ) J. von Braun,
(19 53).
( 7 ) Melting points were determined on a Thomas-Hoover apparatus in open capillaries and are corrected. Elemental analyses were performed b y Galbraith Laboratories, Knoxville, Tenn. Where analyses are indicated by the symbols of the elements, the analytical results obtained for those elements were within &0.4% of the theoretical values.
