NOTES
Kovember, 1963 Experimental
-411 melting points are corrected. Elemental niicroanalyses were performed a t the microanalytical laboratory of the Sational Institutes of Health, Bethesda, Md., or a t Schwarzkopf Microanalytical Laboratory, Woodside 77, N. Y. i-Methyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboximide.To 90.5 g. (0.5 mole) of 7-oxabicyclo[2.2.1] heptane-2,3-dicarbosylic anhydride was added 150 ml. of a saturated aqueous solution of ammonia. After the vigorous reaction had subsided, the mixture was stirred and heated until homogeneous. The water was boiled off and the residue heated a t 160-180" for 2 hr. On cooling the mass solidified to give a quantitative yield of product melting a t 160-162". On recrystallization from chloroform-ligroin, it melted a t 161-162'.
805
fleeting hypotensive action for some of the compound^.^ These findings led directly to a related aiid orally effective adrenolytic agent, S,N'-bis [a-(2-pyrid yl) et hyl 1ethylenediamine (I). The pharmacologic properties of Q
c
H ( c H 3 ) N H c z H 4 m c H(CHI) I
this material were the subject of a recent report by Halliday, et al.4 Since compound I offered some promise, a structure-activity study mas undertaken to 4-Methyl-4,7-epoxyhexahydroisoindoline.-l-Methgl-7-oxadetermine the requirements for optimal activity. h bicyclo[2.2.l]heptane-2,3-dicarboximide(60 g., 0.3 mole) was few substituted alkylenediamines not closely related placed in a Soxhlet apparatus and extracted overnight into a to t,he compounds discussed here are reported by Schusstirred solution of 25 g. of lithium aluminum hydride in 1.5 1. teritz, et al.,s and Short, et ~ l . to , ~possess adrenolytic of absolute ether. The addition complex was decomposed by slow dropwise addition of water, and the mixture was stirred 4 or antihypertensive properties. hr. The inorganic precipitate was filtered, pressed tightly on the Compound I and most of the analogs reported here filter, and washed with two 100-ml. portions of ether. The were prepared by condensing 2 equiv. of a carbonyl et,here.d filtrate and washings were dried over anhydrous sodium compound with an alkyleiiediamiiie to afford symsulfate and filtered. The ether was stripped lind the residue was distilled to yield 26 g. (565;) of product, b.p. 123-125" ( 3 5 mni.), metrical Schiff bases. Catalytic reduction of the crude n Z 51.4926. ~ Schiff bases usually proceeded in good yield to the Anal. Calcd. for C9HIBXO:C, 70.53; H, 9.87; X, 9.14. expected products, which were isolated by distillation. Found: C, 70.26; H,9.73; S,8.98. A similar method was utilized by Lacoste' to prepare The hydrochloride was formed by bubbling anhydrous hydroT I (Table I) aiid by Szabo8 for the synthesis of relat'ed gen chloride gas through an ether solution of the base, m.p. 148.5-149.5'. On recrystallization from methanol-ether, it, alkylenediamines. All of the compounds listed in melted a t 150-151 '. Table I except IT7,YII, YIII, and XIII, were prepared Ana!. Calcd. for C4H1RC1SO: CI. 18.60. Found: C1. 18.81. in this manlier and converted to the indicated salts. 4-Methyl-4,7-epoxy-2-(2-cyanoethyl) hexahydroisoindo1ine.Compound IY was isolated and purified as a salt since 4-Methgl-4,7-eposyhexahydroisoindoline(19 g., 0.125 mole) was refluxed with a large excess of acrylonitrile (0.5 mole) for 2 hr. the base was thermally unstable. Compouiid VI1 was and the escess acrylonitrile was distilled. The residual oil was generated by addition of ethylenediamine to %vinyldistilled under redured pressure to give 24.5 g., 93yc,of the compyridine under acid cat'alysis. Compound VI11 repound, b.p. 158-160' (6 mm.). sulted from the catalytic reduction over platinum of A n a l . Calcd. for ClrHI8S2O:C, 69.87; H, 8.79; S , 13.58. the commercially available azine ' in acetic acid followed Found: C,68.92; H, 8.54; ?;, 13.31. The methiodide was obtained as a tacky yellow material by by isolation aiid purification as the diacetate. Catarefluxing the base with a 10% escess of methyl iodide in ethyl lytic reduction of I over rhodium-on-alumina iii the acetate and diluting with ether. Vacuum drying for several presence of acid provided XITI. days a t room temperature gave a solid material, m.p. 156-157", Another group of allied materials is listed in Table 11. which on recrystallization from methanol-ether and methylene chloride-ether, melted a t 165-166'. Displacement reactions ,011 2-( a-bromoethyl)pyridiiie10 A n a l . Calcd. for C 1 3 H n I ~ 0I,: 36.45. Found: I, 36.56. with t-butylamine, piperidine, trimethylamine, ethyl4-Methy1-4,7-epoxy-Z-( 3-amidoximinopropyl)hexahydroisoenediamine, and 1-(o-methoxypheny1)piperaziiie gave indoline Dihydroch1oride.-To a solution of 14 g. of hydroxylXIV, XY, XVI, XYII, and X \ 111, respectively. The amine hydrochloride in 300 ml. of absolute ethanol was added 41.2 g. (0.2 mole) of 4-methyl-4,7-eposy-2-(2-cyanoethyl)hesa- possibility of dehydrobromiiiation of 2-( a-bromoethy1)hydroisoindoline. When a ,homogeneous solution was obtained, pyridine to 2-vinylpyridiiie followed by amine addition a solution of 4.6 g. (0.2 mole) of sodium in 150 nil. of absolute t o the corresponding 2-(P-amiiioethyl)pyridiiie was ethanol was added n-ith stirring. The misture was refluxed 3 hr. and let stand overnight. The nest day, the mixture w i ~ s investigated. Piperidine was condensed with 2-vinylpyridine to afford XIX which was not, ideiit'ical with filtered and gaseous hydrogen chloride bubbled in until precipitation was complete. After adding an equal volume of ether, XT'. Reductive aminations with 2-acetylpyridine and rnixing, and allowing tlie precipitate to settle, the producat was the appropriate amines were tried but fouiid less satisfiltered, washed with cold ethanol, and dried. It melted a t 162factory as a preparat'ive route to some of these materials 164' and on recrystallization from alcohol-ether a t 163-1 65'. A n a l . Calcd. for C12H23C12S302:C, 46.15; H, 7.37; C1, 22.71. Found: C, 45.88; H, 7.01; C1,23.32.
Mypotensives. V1.I Disubstituted Alkylenediamines and Related Compounds JERRY
E. ROBERTSOS,~ JOHX H. BIEL,THOMAS F. MITCHELL, JR., WALLACE K. HOYA,AND HELENA. LEISER
Chemical Research Ditiision, Lakeside Laboratories, Inc., Malwaukee 1, Wisconsin Receized J f a y 31, 1963
In an earlier report on studies of substituted alkylenediamines as diuretic agents we described a
(1) Paper T': J. E. Robertson, J. 11. Eiel, and F. DiPierro. J . X e d . Chem., 6, 381 (1963). ( 2 ) Central Research Laboratorim, Xinnesota hIining and Jlanufacturing Co., S t . Paul, XIinn. (3) J. H. Biel, I\-. K . Hoya, and H. A . Leiser, J . A m . Chem. Sur., 81, 2527 (1959). ( 4 ) R.. P. Halliday, W. J. Xinnard. and J. P. Buckley, Pharmarologist, 4, 148 (1962). ( 5 ) L. Pchusteritz, G. Stille, h l . W d t e r , and V. Wolf. Arzneimitlel-Forsch., 9, 628 (1939). (6) J. H. Short, W. L. Chan, >f. Freifelder. D. G. hlikolasek, .J. L. Echaidt, H. G. Schoepke, C. Shannon, and G. F.. Stone. Abstracts of Papers, 144th National Meeting. .-imerican Cheniical Society, Los .ingeles, California, April, 19G3, 11. 10-L. (7) P.. G . Lacoste, Ph.D. Thesis, Clark University, M-arcester. >lass., 1957. (8) J. L. Szabo, D. Hill, and W. F. Bruce, U. S. Patents 2,027,491, 2,739,981, and 2,870,236. (9) Aldrich Chemical Co., Xilwaukee, Wis, (10) B. H. Walker, J . O r g . Chem., 26, 1047 (1900).
80ti
\
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>] ?I
?I 41 ?I ^ I ?1 ?I ?1 41
7
._
B
01. 0
SOTES
Kovember, 1963 except in the case of 2-(octahydro-l-azocinyl)ethylamine which gave XX. A preliminary report by Halliday and co-workers on structure-activity relatioilships for the compounds described here has already appeared." These materials n-ere evaluated for hypotensive action in the normotensive anesthetized dog aiid rat and for adrenolytic effectiveness in the dog. In addition to the two reports mentioned,4 other aiid more detailed descriptions of biological activities can lie found elsewhere.12 Furthermore, a summary publication on structure-activity relationships aiid mechanism of actioii of the more potent compounds will appe~1r.l~These studies reveal that a s y m - S ,S '-bis( 2-pyridylalkyl) et hyleiiediamiiie skeleton is necessary for maximum adrenolytic potency. That is, all of the compounds listed in Table I1 in addition to 11, 111, I\-,IT,YIII, IX, and XIII, are substantially less adrenolytic than I a t comparable doses. Compounds I, TI,aiid IT1 are of similar adrenolytic potency in that 10 mg. kg. (calculated as amount of base administered intravenously) usually reversed the pressor response to 2 y 'kg. of epinephrine in the normotensive anesthetized dog. Branching the ethylenediamine chain markedly increased adrenolytic potency. Compared to I, the branched compounds X aiid XI are roughly 2 and 10 times, respectively, more potent adrenolytic agents. Presently available data indicate that branching caused no changes in the quality of biological activity. ExperimentalI4 Pi,N'-Bis[ ~-(2-pyridyl)ethyl] ethylenediamine (I).--ii mixture of 121 g. (1.0 mole) 2-acetylpyridine and 37 g. (0.E0 mole) of 817c aqueous ethylenediamine in 400 ml. of benzene TTas heated a t reflux for 5 hr. n-hile 23 nil. of water was collected in a Eean-Stark apparatus. After cooling to room temperature, the precipitate \vas collected, washed n-ith benzene, and dried. A mixture of this niaterial and 0.4 g. of Pt,02in 200 nil. of ethanol \vas reduced under 3 atin. (3.0'3 kg./cm.*) of hydrogen. The ciitalj-st was removed bl- fi1tr:ition and the filtrate concentrnted i n L'aczio t o a sirup. 1~istill:rtionprorided120g. (895;) of product. 1,2-Bis(2-pyrrolylcarboxaldim.ino'ethane.-To a solution uf 28 g. (0.29 mole) of pyrrole-2-c.arb[)saldeh!.de in 100 nil. of benzene was added 12 nil. of 725; aqueous ethylenediamine. After heati n g a t reflux n-ith &ring for S hr., the mixture a-as cooled. The precipitate n-as collected, washed with benzene, and dried to afford 26.8 g. (8741) of product, ni.p. 175-179". =l,ml. Calcd. for C I HI, ~ S,:S,26.15. Found; S,26.18. N,N'-Bis( 2-pyrro1ylmethyl)ethylenediamine Dihydrochloride (VI).--4 mixture c)f26.1) g. (0.125 mole) of the Schiff base and 0.3 g. I I E P t 0 2 in 200 nil. of ethanol was reduced under 3 atm. (3.09 k g . / ( * ~ i i .of ~ ) Iiydrogen. Tlie c s t a l y t was removed by filtration : m i excess ethereal hydrogen rliloride was added to the cooled filtrate. The prec7ipit:ite was collected and recrystallized from nietlianol t o provide 6.7 g. (19yc)of product. N,N'-Bis[a-( 2-pyridy1)ethyl ]ethylenediaminelj (I'II).-A solution of 21 g. (0.20 mole) of 2-vinylpyridine, 6.1 g. (0.090 mole) aqueous ethylenediamine, and 12 g. (0.20 mole) of glacial acetic acid in 100 ml. of ethanol x a s heated a t reflux for 6 hr. The reaction niisture was concentrated i n z'ucuo and the resi-
807
due was treated with excess aqueous sodium hydroxide. This niixture was extracted twice with tetrahydrofuran, and the combined and dried organic layers were distilled t o afford 10.8 g. (467,) of product. N,N'-Bispicolylhydrazine Diacetate (VIII).-A mixture of 21 g. (0.10 mole) of 2-pyridinealdazine,g 24 g. (0.40 mole) of glacial acetic acid, and 0.5 g. of PtOz in 200 nil. ethanol was reduced under 3 atm. of hydrogen. The catalyst was separated by filtration, and t,he filtrate was concentrat,ed to dryness. Trituration of the residue v-ith ether folloxed by recrystallization from acetonitrile afforded 4.9 g. (155%)of product. N,N'-Bis [a-(2-piperidyl )ethyl] ethylenediamine (XIII).-A mixture of 27 g. (0.10 mole) of I, 66 ml. of 6 hydrochloric acid, and 5 g. of 57, rhodium-on-alumina in 150 inl. of ethanol \vas reduced under 3 atni. of hydrogen. The catalyst was removed by filtration and the filtrate concentrated to a sirup Lt-hich was treated n-ith excess aqueous sodium hydroxide. This mixture vias extracted with ether, then tetrahydrofuran, and the combined organic layers n-ere dried over potassium carbonate. Distillation provided 20.1 g. (7142) of product. N-t-Butyl-N-[a-(2-pyridyl)ethyl]amine (XIV;.-t-Butylaniine (53 g., 0.72 mole) and 14 g. (0.075 mole) of 2-(~bromoethyljpyridinel0 in 100 ml. of ethanol were heated in a citrate bottle for 0.5 hr. a t 100". After cooling and removal of solvent by distillation, 4.2 g. (0.075 mole) of potassiuni hydroside dissolved in 75 mi.ethanol was added, and the mixture was filtered to remove inorganic salt. The filtrate was concentrated and the residue u-as distilled to provide 4.5 g. (347;) of crude product. N-[a-(2-Pyridyl)ethyl]piperidine(XI').-To a boiling sdution of 34 g. (0.40 mole) of piperidine in benzene was added a solution of 8.8 g. (0.047 mole) of 2-(~~-bromoethyl)pyridine in benzene over 0.5 hr. Heating a t reflux was cuntinued for an additional 3 hr. After cooling, the mixture was fltered m d the filtrate was distilled to afford 7.3 g. (81%) of product. [~(2-Pyridyl)ethyl]trimethylammonium Bromide (XVI1.-A solution of 47 g. (0.80 mole) of trimethylamine and 15 g. (0.080 mole) of 2-( a-bromoethy1)pyridine in 100 ml. ethanol was heated in a pressure bottle for 3 hr. a t 100". The solvent was evaporated and the residue Tvas recrystallized from acetonitrile to provide 11.3 g. (E8Y0)of material. N- [@-(2-Pyridyl)ethyl]piperidine(XIX).-A solution of 21 g. (0.20 mole) of 2-vin~-lpyridine,12 g. (0.20 mole) of glacial acetic acid, and 17 g. (0.20 mile) of piperidine in 85 nil. of ethanol was heated a t reflux for 8 hr. The solvent was removed by evaporation and the residue \\-as treated n-ith exi'ess aqueous potassium hydroxide. This mixture n-as extracted three times n-ith ether. The combined and dried organic layers Tvere concentrated and the residue was dist,illed to yield 29.5 g. (777,) of XIX. N- [a-(l-Pyridyl)ethyl]-p-(octahydro-1-azociny1)ethylamine (XX).-A solution of 15 g. (0.12 mole) of 2-acetylpyridine in 50 ml. of ethanol was added to a stirred solution of 19.5 g. (0.12 mole) in 100 nil. of ethanol of 2-(octahydro-l-azccinyl)ethylaniine~~ during 10 min. An exothermic reaction ensued. After stirring for an additional 0.5 hr., 0.5 g. of PtOZn-as added, and the mixture was reduced under 3 atm. of hydrogen. The exothermic reduction n-as completed in 0.5 hr. The catalyst \\-as removed by filtration, and the filtrate was concentrated in I ~ U C U Oto a residue n-hich \vas distilled to give 16.2 g. (52%,) of product. ~~
(10) R . P. ~ 1 ~ 111. 1 , E. Egbert, and 31. R . Dapero, 1953 (1960).
J. O r g . Chen.,
26,
3,6-Disubstituted Pyridazines' DOVGLAS I. RELYEI, J. A. RIDDELL, A \ L ) PLINY 0. T A w S E Y
Research Center, Unzted States Rubber C'ompany, Ti-ayne, AY.J . (11) R. 1'. Halliday. TV. .T. Kinnard, and .I. P. Buckle,,
.Ihstracts of Papers. .iiiierican Pharmaceutical Association Annual lIeeting, Miami Beach, Florida, May 12-17, 1963. (12) (a) R. P. Halliday, 11.9,Thesis, Unirersity of Pittsburgh, 1YfiO; (h) It. P. Halliday, P1i.D. Thesis, University of Pittsburah, 1962. (13) .J. P.Iluckley, personal comniunication. (14) l l e l t i n e Iioints are corrected. Boiling points a r e uncorrected. 3Iost analyses were performed under the direction of I I r . E . Kluchesky in the .inaiytical a n d Control Department, Lakeside Laboratories, Inc. (1.5) .i recent report suggests t h a t this reaction affords t h e unsymmetrical i7roduct: 11. Profft a n d S. Lojack, Rri,. Chim. Roumnine. 7, 405 (1963). 1 n d f . r Chemiiris. 9 , 2!3185 (1963).
Recezced February 12, 1963
Since maleic hydrazide was first shown to regulate plant growth2 there has been much interest in deriva(1) Contribution No. 2 2 8 from Research Center, Unlted States Rnhber Company. ( 2 ) D. L. Schoene and 0. I,. Hoffinann, Science, 109, 588 ( 1 9 4 9 ) . (3) 0. L . Hoffmann and D. L. Schoene ( t o E. d. Ruhber ConiIiany), U. 9. Patent 2,614,916 (Oct. 2 1 , 1RfiZ).
