January, 1963
A L K Y L H Y D R A Z I N E S AS
Method B.-To a warm solution of 0.02 mole of an ethyl Nnrylsulfonylcarbamate in 75 ml. of toluene was added, dropwise, with stirring, a solution of 0.022 mole of the desired amine in 25 ml. of toluene. The mixture was refluxed for 3 hr. and cooled. If the product crystallized, it was isolated by filtration; otherwise, the toluene was removed under reduced pressure. The product was crystallized from dilute ethanol, with acidification a i t h 57, hydrochloric acid just prior t o cooling. Further purification was carried out as indicated in the tables. 4-Methylsulfinylbenzenesulfonamide.-To a solution of 12 g. (0.05 mole) of 4-methylmercaptobenzenesulfonamidein 200 ml. of acetic acid was added, portionwise, 5.7 g. (0.05 mole) of 30% hydrogen peroxide. After heating a t about 60" for 24 hr. the mixture was taken to dryness under reduced pressure and the residue was crystallized 3 times from dilute ethanol to give 8.3 g. ( i5c/;l) of product melting a t 177-179". Anal. Calcd. for C ~ H Q N O ~ S C,~ 38.34; : H, 4.15. Found: C, 38.10; H, 4.34. N-(4-Methylsulfinylphenylsulfonyl)urea.-Six grams (0.027 mole) of 4-methylsulfinylbenzenesulfonamide was converted to the sulfonylurea by Method A. Purification from dilute acetone gave 5 g. (54y0)of product melting a t 173-175" Snal. Calcd. for C I ~ H ~ ~ N Z OC,~ 48.82; S ~ : H, 5.85; N, 8.13. Found: C, 49.20; H, 5.93; N, 8.00. N- (4-Methylsulfonylphenylsulfonyl) -N'-cyclohexy1urea.-A mixture of 2 g. (0.006 mole) of N-(4-methylmercaptophenylsulfonyl)-N'-cyclohexylurea and 15 ml. of 30% hydrogen peroxide in 10 ml. of acetic acid was warmed for 30 min. on a steam bath. The crystalline material which separated on cooling weighed 1.7 g.. Crystallizations from dilute ethanol gave 1.3 g. (597,) of product melting a t 196-198". Anal. Calcd. for C14HL&20&: C, 46.65; H, 5.59; S , 7.77. Found: C, 46.96; H, 5.74; X, 7.35. N- [4(~Hydroxyethyl) phenylsulfonyl] -N'-cyclohexy1urea..4 solution of 20.0 g. (0.616 mole) of N-(4acetylphenylsulfonyl)-
MONAMINE OXIDASE I N H I B I T O R S
63
N'-cyclohexylurea, 100 ml. of absolute ethanol and 150 ml. of dioxane was reduced catalytically using initially 2.0 g. of 5% palladium on carbon under an initial hydrogen pressure of 2.8 kg./ cm.2 As the reaction proceeded the adsorption of hydrogen became quite slow. At this point an additional 2.0 g. of catalyst was added and the reaction then proceeded t o completion. The catalyst was removed by filtration and the filtrate evaporated to dryness in vacuo. The product, after three recrystallizations from dilute ethanol, melted a t 13&137", yield 14.7 g. (747c). Anal. Calcd. for CljH22S204S: C, 55.19; H, 6.79; X, 8.58. S, 9.86. Found: C, 55.16; H, 6.86; S , 8.09; S, 9.16. N- (4-Ethylphenylsulfonyl)-N'-n-hexy1urea.-Hydrogenation of 2 g. (0.006 mole) of &'-(4-acetylphenylsulfony1)-N'-n-hexylurea was carried out in 200 ml. of ethanol using 1 g. of 5% palladium on carbon as a catalyst with an initial hydrogen pressure of 2.8 kg./cm.*. Hydrogen uptake was complete in 15-20 min., and, after filtering, the ethanol was removed under reduced pressure. The residue crystallized on standing and two crystallixations from dilute acetone gave 5 g. (29%) of product melting at 107-109". An analytical sample melted a t 108-1 10". Infrared analysis did not show the presence of an OH and was consistent for an ethyl substituent. Anal. Calcd. for C1bH24S203S: C, 57.65; H, 7.75; X, 8.96; 0 , 15.35. Found: C, 57.64; H, 7.57; S , 9.04; 0,15.59.
Acknowledgment.-The authors are grateful to W.L. Brown, G. M. Maciak, H. L. Hunter, and R. M. Hughes for the microanalyses, to Dr. H. E. Boaz and D. 0. Woolf for physical-chemical data, and to Z. Frank, T. Lenahan, D. Caldwell, and P. Williams for their technical assistance in the biological testing of the compounds.
Monoamine Oxidase Inhibitors. The Synthesis and Evaluation of a Series of Substituted Alkylhydrazines D. J. DRAIN,J. G. B. HOWES, R. LAZARE, ANNhl. SALAMSS, R. SHADBOLT AND H. W. R. WILLIAMS Smith and Nephew Research Ltd., Hunsdon Laboratories, JVare, Hertfordshire, England Received June 8, 1968 A series of aryloxy-, arylthio-, and arylaminoalkylhydrazines has been prepared and evaluated as in vztro and in vivo inhibitors of monoamine oxidase. Many of the compounds are powerful inhibitors, the most active being (1-methyl-2-phenoxyethy1)hydrazine.
In 1952, Zeller and eo-workers1 found iproniazid to be a powerful and specific inhibitor of the enzyme monoamine oxidase and much suggestive evidence has been subsequently presented to support the thesis that the pharmacological and clinical effects of this drug may be explained in terms of monoamine oxidase inhibition. An exhaustive study by Zeller's group of the structural features necessary for monoamine oxidase inhibition led to the discovery that simple alkylhydrazines were considerably more potent than iproniazid.2 This, together with the reported high activity of a-methylphenethylhydra~ine~ led us t o examine some related aryloxyalkylhydrazines as potential inhibitors of monoamine oxidase. 2-Phenoxyethylhydrazine and 3-phenoxypropylhydrazine were first prepared by Gabriel in 1914 by reaction of the appropriate phenoxyalkyl bromide with (1) E. A . Zeller, .J. Barsky, J. R . Fonts, W.F. Kirchheimer and L. S. Van Ordern, Esperienlia, 8, 349 (1952). (2) E. A . Zeller, J. Barsky, J. R. Fouts and J. C. Lazanas, Biochem. J.,60,
hydrazine.4 2-Phenoxyethylhydrazine was examined and found to be a potent inhibitor of monoamine oxidase whereas 3-phenoxypropylhydrazine was much less active. It was thus of interest to investigate the relationship between structure and activity in this class of compound, and this paper describes the synthesis and evaluation as monoamine oxidase inhibitors of a series of substituted hydrazines of general formula ArX(CH,).CH(Y)SHNH,, in which variations are made in the aryl group, the alkyl chain ( n and T varied) and the linking group X. Experimental Chemistry.-The substituted hydrazines were prepared by the method of Gabriel4 from the corresponding bromide by reaction with hydrazine in boiling ethanol. In most instances they were colorless liquids which, on a small scale, could be distilled under reduced pressure in a nitrogen atmosphere with only slight decomposition. Occasionally, however, complete decomposition occurred during distillation, a hazard which appeared to be somewhat dependent upon batch size. The bases were rather
I'
(1935). ( 3 ) J. H. Biel, .\. E. Drukkor, P. A. Shore, S. Spector and B. B. Brodie, J. A m . Chem. Soc., 80, 1519 (1938).
(4) S. Gabriel, Be?., 47, 3029 (1914).
uiistable in the presence of air, even a t room temperature slowly evolving nitrogen on standing. The salts, however, appeared to be stable under normal laboratory storage conditions. The intermediate bromides, many of which have been previously described were prepared by one of four general methods: (E) froin a phenol and excess 1,2-dibromoethane; (F) from the appropriate alcohol with phosphorus tribromide (no solvent); (ti) from the appropriate alcohol with phosphorus tribroniide in chloroform; (H) from the appropriate alcohol n-ith thionyl bromide. 1-Anilino-2-bromopropane was prepared as the hydrobromide salt by method I. Intermediate alcohols were prepared by one of these general methods: (A) from phenoxyacetaldehyde and a Grignard reagent; ( U ) from a phenol and propylene oxide; (C) from a thiophenol and propylene oxide; (U) from a phenol or thiophenol iind 2-chloroethanol. Iletails of some typical preparations are given below. (i) Synthesis of Alcohols, ArX(CHP).CH(Y)OH.-Physical constants and analytical data for compounds not hitherto reported are given in Table I. All melting points are uncorrected. A. I-Phenoxy-2-pentanol.-To a solution of n-propylmagriesium bromide prepared from n-propyl bromide (86.5 g., 0.705 niole) and magnesium turnings (17.25 g., 0.72 at.) in dry ether (500 nil.) was added a solution of phenoxyacetaldehyde5 (34 g., 0.25 mole) in dry ether (30 ml.) slovly over 90 min. The mixture ivas kept overnight at room temperature and finally boiled under reflux for 3 hr. After cooling, the complex was deconiposed by cautious addition of iced water (500 ml.) and 2 N hydrochloric acid until acidic. The ethereal layer was separated and the aqueous layer extracted with ether (4 X 150 ml.). The combined extracts were dried (NazSO4) and distilled to yield a colorless oil, b.p. 143-147" (18 mm.). B. 1-(o-Methoxyphenoxy)-2-propanol.-Guaiaco1 (80 g., 0.645 mole), propylene oxide (41.2 g., 0.i1 mole), and 50% sodium hydroxide solution (0.8 nil.) were placed in an autoclave and heated to 150' for 4 h r . Fractional distillation of the residue yielded 78.1 I . of a colorless oil, b.p. 96" (0.15 mm.). C. l-(p-Methoxyphenylthi0)-2-propanol.-To a stirred suspension of sodium hydride (0.2 g.) in p-methoxythiophenol6 (40 g., 0.286 mole), propylene oxide (18.2 g., 0.315 mole) was :dded dropwise. Reaction was initiated by gentle warming and the vigorous reaction R-as moderated by external cooling. i ~ i i i d l ythe mixture was heated a t 100" for 30 min., cooled and poured into water. The oil 'ivas extracted with ether (3 x 200 nil.) and the combined extracts ivere washed with dilute sodium hydroxide and water. The dried (?;aaS04)extract was distilled to yield 41.6 g. (80yo)of colorless oil, b.p. 06-100" (0.02 mm.). D. 2-(p-Methoxyphenylthio)ethanol.-2-Chloroethanol (28 g.) \\asadded to a solution of p-niethoxythiophenol (35 g., 0.25 mole) in nclueous sodium hydroxide (13.1 g. in 175 nil.). The solution x i s boiled under reflux for 1 hr., cooled and extracted with ether. 1)istill:ttion of the dried (Na2S04)extract yielded :33.3 g. (72%) of ;I I):& yellow solid which was recrystallized from light petroleum to give colorless plates m.p. 42-13". (ii) Synthesis of Bromides, ArS(CHz),lCH(YjBr.-Physical constants and microanalytical data for new compounds are given in Table 11. E. 2-(3,4-Dimethylphenoxy)ethylBromide.-To a stirred, refluxing mixture of 3,4-xylenol (150 g.), 1,2-dibromoethane (132 ml. j and water (180 ml.), was added a solution of sodium hydroxide ( 5 3 9.) in water (100 ml.) slowly over 1 hr. After a further 6 hr. boiling the mixture was cooled and the lower organic liiyer separated. The aqueous laj-c,r vas extracted with chloroforiii and the combined organic layers w r e washed with dilute sotliiiin hydroxide solution, then Tvater. Distillation yielded 128 g. (.4Gcx) of a colorless oil, h.p. 136-140" ( IO mm.) which solidified :mil d t e r recrystallization from nieth:rnol formed needles, m.p. 4.5--47".
F. I-Methyl-2-phenoxyethyl Bromide.-Phosphorus trihroniitie (100 g., 0.38 mole) was added dropwise with stirring over 1 lir. to 1-phenoxy-2-propanol7 (101.4 g., 0.67 mole) cooled to 0". ,litcar a further hour the mixture W ~ Bheated on a steam bath for 30 min., cooled, and poured onto ice (200 g.). The oil was extracted into ether and the ether extract washed with 10% sodium hydroxide solution, followed by nater. Distillation of the dried (Xa2SOd) extract yielded a fraction of b.p. 120-130" M. R o t b a r t , A n n . Clcim.. [ I l l 1, 439 (1934). 11. Ruter a n d H. L. Hansen. J . Am. Chem. Soc.. 54, 4100 (1932). ( 7 ) A. 11. Sexton and 12. C . Britton, J . Am. Chem. Sac., 7 0 , 3606 (1948). Li)
( e ) C.
(15 nun.), (87.3 g., 60',,j. After redistillation the b.1). i 1 - i ~ ~ l19.5-122° (13.5 mni.). G. 2-(3,4-DichlorophenyIthio)ethyl Bromide.-I'husphorus tribromide (87 g.? 0.137 mole) was added dropivisc with stirring over 1 lir. to :I solution of 2-(3,4-diclilor.ophe1iyltliio)etlinriol~ (60.1 g., 0.25s iiiolej iii dry chloroforni (125 nil. j cool(:tl to 0 The mixture irits allon.ed to attain rooin tenipc finally boiled under reflux for 1 hr. .lfter cooliiig it, \v:ts poured into iced \vntcr (300 inl.) and tliu chioroforin l a j w scy~ar:ttctl. The q u e o u s layer iras extracted with ether, aut1 the i w ~ i l i i n t ~ ~ l u \\-aslied \\-ell x i t h lo[,C socliuiii carl,oiiiitt~ The dried (Na2d04)extract I\ :LS distillccl to of a colorless liquid, b.p. 110-112" (0.0:)nitii. j . H. 2-Bromo- 1 -phenoxypentane. -1 -Phenoxy-2-peiit aiiol (20.3 g.) and pyridine (14.2 g.) in chloroform (100 m1.j \\-ere cooled to -30". Tliioiiyl bromide (37.4 g , j i r i chloroforin ( 4 0 i d . ) \v:is added dropwise over 1 Iir. n i t h st.irriiig aiid cooling. Thc i i i i i ture \\-as : ~ l l o \ r dto :ttt:tiii rooin temp"rturc~ and fin:Llly Ijoihvl unclcr refiux for 13 i i i i i i . After coolirig, it \vas poiird iiito ;Ltcbr and tlie cliloroforiii la~.orseparated m(1r\-ashcd with water, tliliitchydrochloric arid, dilute sodium hq-tlrosicleaiid fiiially iritli wattir. Distillation of the c h i d (Na1S04)wtract yieltloti 3 . 5 g. (51' I of :t colorless liquid, 1j.p. i4-78" (0.08 iuni. I . I. I-Anilino-2-bromopropane Hydrobromide.-€~ytlrobr~riiic acid (ti g. of Ai'
