Heterocyclic Amines with Antihistaminic Activity'

ROBERT E. LUTZ AND PHILIP S. BAILEY. Vol. 68. Acknowledgment.-The authors wish to ex- press their thanks to Mrs. Margaret Petroski for technical ...
0 downloads 0 Views 514KB Size
Oct., 184G

1999

HETEROCYCLIC AMINESWITH ANTIHISTAMINICACTIVITY

Summary 1. Procedures have been developed for the synthesis of 3,6-tliainino-2,4-dihydroxypyrimidine and 4-hydroxy-f ,S,C,-triaminopyrimidine bisulfite in appreciably better yields and involving fewer isolations of iiiterinediate products than previously r e p o r t d

2. These compounds have been condensed with several dicarbonyl compounds to yield pyrimido[4,5-b]pyrazines symmetrically substituted in the 6- and 7- positions. 3. Ultraviolet absorption spectra of alkaline solutions of the compounds have been measured Ti T r 1 c 4 , Y V

~ C O S T R I U I T I O N 1'I< IM THh IIEP l R 1 MESTS O F C H E M I S T R Y AND ~ f I C R O B I O L O G Y , CEUTICAL PRODUCTS, INC]

RECFIVED J U

RESEARCH DIVISION,CIBA

~ E7 ,

1946

PIIARMA-

Heterocyclic Amines with Antihistaminic Activity' BY

CHARLI:S

P.EIUTTRER,la

L.BE EARS,'^ RUDOLFL. ; I \ h Y C R SCHOLZ

C A R L D J E R A S S I , II'ARREN

Extensive work from Fourneau's Laboratory2 has indicated that some relatively simple aminoethers (type F929, F1379, F1464)3 and diamines :t\-pe Flt5il, FLG91, F1'709, R. P.2339, R. P. 2325)4 possesset. antihistaniinic activity. Since tertiary amines of this group containing heterocyclic radicals had so far not been studied, we have synthesized a number of asymmetricallysubstituted ethylenediarnines of the general type R"' I~'----CH:.---CH~--~'. ', in wliicli at least one, :tiid soinetinies two, substituents were of an heterocyclic natiire (pyridine or pyrinidine series). One member of this series, R. P. 2 i S G , N,N-dimethyl - K ' - ( p - methoxybenzyl) - N'-(a-pyridy1)cthylenediainine, has since been de~cribed.~" The work reported here was not published carlier pending estensive pharmacological and clinical investig:ition.5 In recent articles, IVhitiiiore atid ci)-workers6have described secondary amines of siniiliLrstructure as part of their work on antiinalarial+. [ I ) I'rerentmzd on the program { i f the Division of hledicinal Chemibtry a t the Atlantic C i t y meeting of the Binerican Chemical Society, .lpril 8 1 2 , 194ti l a ) Present addre..;: \I'arner Institute for 'I'hernpeiitic Research, 113 West 1 8 t h S t , New N. Y . Ib) I'rtic,imt a,ldtt-.s: H . 1'. ( h i d r i c h Coinpmy, Akron, Ohio. 12) 1;t)r I v c ri.fcreilu.\ a n i 1 pllxrinaculugical results, cf. Staub, f

I < , 1'. 2.{:3!1, N . S - ~ l i i i i e t l iI\ l"-bensyl-N'-ptir~iyl ethylenediamine; l i 1' :!.i2-t, X , N q l i i i i t , t l i \ I S ' ~ ~ t I ~ y l - P . : ' - p h r n y l c t l ~ y l r r i r i I i a m i i i r . I:,) l h 8 i i I I c ~ I ~ ~_It u r i tIi . \\,ilthrrt, ( ' o m p t r r i r i . 5 , ) ' / , i t , l , 138, O(/ I l ' i L l I L . 4 39,xu;IlII'~l4.5). lz, Sbieir;e, 102, Y 3 (19431; F d e i

Chess, Hays, Mathieson, Mayer

.IXD CIIES.IR

I10y CisHi9NnHCI HCl 13.15 13.10 >5y CieHziNsHCl HCI 15.52 15.51 0.027 CirHzsNaO.HC1 HCI 11.35 11.32 0.02~ CieHi9N10.HCl HCl CirHlaNa.HC1 HC1 CirHnNrHCl He1 CibHiaN1.2HCl HCl CwHiaNu2HCI HC1 CisHioNa~2HCI HCI CIIHZ~N~.HCIHC1 CiiHaaNa.2HC1 HC1 CirHaNa.HC1 HC1 CisHmN4,HCI HC1 HC1 CirHzaNa.HC1 CisHzsNa.2HCl HC1 CirHasNa.HC1 HC1 CisHnN4.2HCI HC1 . CisHnsNrHCl HCI CidHasNs.HC1 HC1 CigHreNs.HC1 HC1 CiaHuN~0.2HC1HCI ~~

~

11.95 11.95 14.99 23.18 23.18 23.25 11.95 21.34 11.95 12.48 11.95 20.50 13.44 21.28 11.43 13.54 11.01 19.73

11.97 12.10 14.86 23.20 23.30 23.15 11.81 21.44 11.94 12.40 12.2 19.98 13.65 21.43 11.77 13.56 11.01 19.67

>57 >1Oy >10y >1Oy >10y ly

2y 0.27 >5y

>lor >5y >10y >lor >lo, >2y

a The activity is expressed in y of compound per ml. of bath liquid, capable of neutralizing the contraction of an isolated guinea pig gut:, caused by l y per ml. of histamine diphosphate ( c j . ref. 5 ) . Bovet, et aE.," reported some of the pharmacological but none of the chemical properties of this compound. Pharmacological results not yet available.

Oct., 1946

HETEROCYCLIC AMINESWITH ANTIHISTAMINIC ACTIVITY

The antihistarninic activity of these compounds is listed in Table 11. Several of the tertiary amines reported here exhibited a specific protective action against histamine and anaphylactic shock.5 One of the compounds, N,Ndimethyl - N'- benzyl - N' - (CY - pyridyl) - ethylenediamine (Pyriber zamine), is now under clinical investigation, reports of which have appeared in another j o u r ~ i a l . ~ ~ :

ExperimentallOJ1 Alkyl Halides.-These were obtained in good yield (7898%) as their hydrogen halide salts according to methods described in the 1iti:rature. The melting points agreed with those previously reported, with the exception of that of dimethylaminoeth.yl bromide hydrobromide, which was found to be 189°.12 Procedure A. 2-( 8-Dimethylaminoethyl)-aminopyridine.'a-Method I of Whitmore. et al..& was emdoved with the following modifications :' S o d a k d e could ieadily be replaced by lithium amide, and since the hydrobromide12 or hydrochloride saltj14of the aminohalides were employed, double quantities OF the condensing agents were used. The reaction time was increased to twenty-two hours. Using this method, we obtained a 67% yield of the secondary amine, b. p. 100-106" a t 0.1 mm., or 150-157" at 25 mm., n26~1.5418-1.Ei428.15 The dihydrochloride was prepared by adding 86.5 cc. of 7.4 N methanolic hydrogen chloride solution to 48 g. of the base, concentrating in a current of air and chilling; m. p. 220-222". After two recrystallizations from ethyl acetate-methanol, the analytical sample was obttined as colorless dimorphic crystals, m. p. 224 or 229 Both forms gave a correct analysis. Anal. Calcd. for C S H I ~ N ~ . ~ H C C,I :45.38; H , 7.14; HCl,'o 30.67. Found: C, 45.37; H, 7.38; HCI, 30.70 (compound of m. p. 229'), 30.61 (compound of m. p. 224 ") . Procedure B.-This procedure was adapted from Method I1 of Whitrnore and co-workersoa using 2-bromopyridine and unsymmetrical dimethylethylenediamine; 2-(8-Dimethylaminoethyl)-aminopyridine,b. p. 93-106 a t 0.08 mm., fiZ51) 1.5424, was obtained in 507, yield. The corresponding diethyl derivative, b. p. 110-115" at 0.05 mm., +SD 1.5301-1.5303,16 was obtained in 85% yield. Procedure C. N,N-Dimethyl-"-benzyl-"-( a-pyridy1)-ethylenediamine.-A stirred suspension of 12 g. (0.31 mole) of dry, pulverized sodamide and 46 g. (0.28 mole) of 2-(p-dimethylaminoethyl)-aminopyridine was refluxed for two hours, the mixture cooled to about 50" and 57.2 g. (0.53 mole) of benzyl bromide was added dropwise. At the end of the addition, the orange colored solution was cooled to room temperature" and worked up as in procedure A. The tertiary amine (51 g., 72% yield) thus obtained was a yellow oil, b. p. 138-142' at 0.01 mm., %*)D 1.5759-1.5765. The amine was converted into the mono-

.

200 1

hydrochloride by the above method and crystallized from ethzl acetate-methanol as colorless prisms, m. p. 192193 . Anal. Calcd. for CI~HZ&.HCI: C, 65.87; H, 7.54; N, 14.41; HCl, 15.52. Found: C, 65.91; H, 7.50; A;, 14.23; HC1, 15.51. Procedure D. N,N-Diethyl-N',N'-bis-(a-pyridy1)-ethyleneditmine.-This method is similar to Eisleb's8 alkylation of secondary cyclic amines. A suspension of 1.12 g. (0.03 mole) of sodamide and 5 g. (0.026 mole) of %(&diethylaminoethy1)-aminopyridine in 100 cc. of dry toluene was refluxed with stirring for two hours, 4.93 g. (0.031 mole) of a-bromopyridine was then added dropwise and the mixture refluxed for twenty-two hours. Four and one-half grams (66%) of the tertiary base was collected as a yellow oil boiling at 13&140Dand 0.04 mm. The crude dihydrochloride was very hygroscopic. After recrystallization from methyl ethyl ketone, the analytical sample melted at 189-192 "and was fairlystable. Anal. Calcd. for C I B H Z Z N ~ , ~ HC, C I 55.98: : H, 6.99 ; HCl, 21.28. Found: C, 55.95; H , 6.84: HCl. 21.43. N,N-Dimethyl-"-phenyl-"-( 8-pyridy1)-ethylenediamine.-A mixture of 5 g. (0.032 mole) of redistilled 3bromopyridine, 1.2 g. (0.032 mole) of sodamide, 5.2 g. (0.032 mole) of N,N-dimethyl-Nf-phenylethylenediamine18 and 40 cc. of dry toluene was refluxed for four hours. After working up as before, the yield of dark yellow oil, b. p. 161-165" a t 0.08 mm., was 3 g. (39%). The dihydrochloride melted at 202-204" after recrystallization from methanol-methyl ethyl ketone. Anal. Calcd. for C15HlsNa.ZHCl: C, 57.32; H , 6.69; HC1, 23.25. Found: C, 57.22; H, 6.64; HCl, 23.15. Procedure E.Ig N,N-Dimethyl-N'-(p-methoxybenzy1)N'-(a-pyridy1)-ethylenediamine.-To a stirred suspension of 13.8 g. (0.6 mole) of lithium amide and 107 g. (0.5 mole) of p-methoxybenzylaminopyridinezo in 750 cc. of benzene, which had been kept under reflux for t*vo hours, was added a solution of 64.5 g. (0.6 mole) of diinethylaminoethyl chloride in 125 cc. of benzene and the mixture refluxed for six and one-half hours. The mixture was cooled, filtered and the filtrate fractionated under reduced pressure. The tertiary amine2I was obtained as a light yellow oil, b. p. 165-173" a t 0.07 mm., nZ6D 1.5750, yield, 115.3 g. (81%). The monohydrochloride melted a t 143143.5'. Anal. Calcd. for C,~H~~ON&!l: C, 63.45; H, 7.47; N, 13.06; HC1, 11.35. Found: C, 63.54; H, 7.26; IC, 12.81; HC1, 11.36.

(18) This compound was prepared in 72-77% yield by refluxing an alcoholic solution of aniline and dimethylaminoethyl bromide hydrobromide for three and one-half hours in the presence of anhydrous potassium carbonate; b. p. 103-107O a t 0.2 mm., 1 ~ 2 1.5380. The monopicrate was obtained as orange prlsms from ethanol, m. P. 120.5-121.5°. Anal. Calcd. for Ci6HiaOTNs: C, 48.83; H, 4.87; N, 17.82. Found: C,48.57; H, 4.78; N , 17.91. The dipicrate Crystallized as yellow needles from ethanol, m. p. 176-177'. (10) All melting points are corrected. Anal. Calcd. for CnHxOlcNs: C, 42.43; H, 3.56; N, 18.01. (11) Microanalyses b r Dr. G. Oppenheimer. California Institute of Found: C,42.40; H, 3.54; N, 17.93. Technology, Pasadena, and Dr. W.Saschek, Columbia Presbyterian The dihydrochloride melted at 176-177'. Medical Center, New York City. Anal. Calcd. for C I O H M N P ~ H CHCI, ~ : 30.80. Found: HCI, (12) Gabriel, Ber., 50, 826 (1917); 172.5-173.5'; Cortese, THIS 30.79. JOURNAL, 68, 191 (1936;~; 174-175O. The corresponding diethyl compound was prepared by a similar (13) The synthesis of this compound was completed before we method, using diethylaminoethyl chloride hydrochloride, aniline and became acquainted with Goldsmith's thesisob reporting a 51% yield. sodium carbonate and refluxing for twenty-two hours in toluene solu(14) Slotta and Behnisch, Bey., 68, 754 (1938). tion. A 73% yield of N,N-diethyl-N'-phenylethylenediamineboil(15) Cf.Table I, notes a and b. ing a t 154-158' and 17 mm. was obtained. Schulemann, Schoen(16) The hydrogen chloride determinations were carried out achoefer and Wingler (U. S. Patent 1,752,617; C. A , , 24, 2469 (1930)) cording t o the method of Dubsky and Trtilek, Mikrochcmie, 12, 315 reported b. p. 121-122' at 5 mm. (1Y33), using standardized mercuric nitrate and symmetrical di(19) Preliminary experiments were carried out by Dr. E. Urech phenylcarbazone. of the Ciba laboratories. (17) T o obtain similar yields with benzyl chloride, i t was necessary (20) Tschitschibabin and Knunjanz, Be?., 64, 2839 11931). to reflux for a n additional two hours after all the halide had been (21) Cf.Table 11, note b. added.

6 ~

ROBERT E. LUTZAND PHILIPS. BAILEY

2002

Acknowledgment.-The authors wish to express their thanks t o Mrs. Margaret Petroski for technical assistance.

Summary 2-.2minopyridine a n d 2-atninopyrimidine and several of I heir methyl deriya tives were alkylated with alkyl halides using wtlamide or lithiuni ainide as the condeiisirig agent. Ftirtlicr JLJSI:L-

Vol. 68

tion of the secondary amines with alkyl or aralkyl halides led to the corresponding tertiary amines, which could be obtained also by condensing halogenated heterocyclic compounds with the corresponding asymmetrically tri-substituted ethylenediamines. Several of these compound c, posse^ strong antihistaminic activity. bTlMMII, \ I LL JI I < \ L l

RI

C I I \ I I ) 1’1 IIRITAR\

[ CONTRLBUTION FROM THE COBB CHEMICAL LABORATORY O F THE UNIVERSITY O F

13. 194fi

\-IRGINIA]

The Use of the Bromo- and Chloromethylation Reactions in the Synthesis of Some Dialkylaminomethyl-2,5-diphenylfurans BY ROBERT E. LUTZAND PHILIPs. BAILEY~

The bromomethylation and chloromethylation rated diketone (V), whereas the free base analyzed reactions3have been carried out successfully with unmistakably for the furan. The molecule of 2,5-diphenylfuran(I), 2,5-diphenyl-3-(morpholino-water was not removed by heating a t 140’ under 1 methyl)-furan (VI) and 3-chloro-2,5-diphenyl- mm. pressure. This compound is to be contrasted furan (X), and the resulting halogenomethyl with the salts of the other three of the type, IVb-d, compounds have been condensed with a nurnber of secondary amines t o give H-c-c-H CHZO+ HCI C~CHr--C---C---CH~CI I/ iI 1; !I 3-dialkylaniinomethyl and 3,4-di-(di- C~H~-C,,, -4cOH CsHs-C ,C--CsH, alkylaminomethyl)-2,5-diphenylfurans. OI’C-c6HK 0 Many of the products were made as a H L Pt rr I 7part of an exploratory program in the search for new types of antimalarial CH3-cpc-cH3 RLS CH2-C-C-CHzNRz drugs. The work was carried t o the ll I! I! /I extent herein reported because of indi- CCHK---C\ ,c-c~H, CaHa-C C-CsHh cation of activity in some of the first 0 ‘0 members weDared.4 I11 IV (a) R I S = morpholino (b) RzN = piperidino Chlorome~hylationof 2,5-diphenyl(c) RzN = N(CzHs)* furan (I) yielded only the disubstitu(d) R L N = X(CH8)z tion product, 3,4di-(chloromethyl)2,5-diphenylfuran (11). ,%ttempts to obtain the which analyzed correctlv for the furans. It is a mono- (chloromethyl) product failed. The struc- possibility that hydrolysis of the one of these ture of the di-(chloromethyl) compound was furans (IVa) to the saturated diketone (V) occurs proved by catalytic hydrogenolysis which yielded during the formation of the salt under the conthe known 3,4-dimethyl-2,5-diphenylfuran (III).6 ditions employed, namely, precipitation from aceThereactions between 3,4-di-(chloromethyl)-2,5- tone by means of ethereal hydrogen chloride, and diphenylfuran (11) and secondary amines proHCI HC1 ceeded smoothly to yield the corresponding 3,4I ! di- (dialkylaminomethyl)-2,5-diphenylfurans (IV) . OCiHsNCHz CH2XCdHxO The amines used were morpholine, piperidine, ! I C~H~COCH-CHCOCRH~ diethylamine, and dimethylamine. It is interesting to note that analyses of the div hydrochloride of the di- (morpholinomethy1)-furan (IVa) indicated it t o be either a monohydrate of that spontaneous furanization occurs upon liberaextraordinary stability or the open chain satu- tion of the free base by treatment with aqueous sodium carbonate; however, this would be sur(1) The greater part of this work was done under a contract, recprising because the conditions involved would ommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of not be expected to bring about facile furan ring Virginia. The Survey Number, designated SN, identifies a drug in cleavage and closure and do not (10 so in the other the records of the Survey of Antimalarial Drugs. The antimalarial analogous cases in hand. activities of those compounds to which Survey Numbers have been The relationship between the previously preassigned will be tabulated in a forthcoming monograph. (2) Present address: The University of Texas, Austin, Texas. pared 2,5-diphenyl-3-(morpholinoniethyl)-furan4 (3) Fuson an83 NcKeever in Adams, “Organic Reactions,” John (VI) and 3,4-di-(morpholinomethyl)-2,5-diphenylWiley & Sons, Inc., Xew Tork, N. Y.,Vol. I, 1942, p. 63. furan (IVa) was established by conversion of the (4) L u t z and Bailey, THISJOURNAL, 67, 2229 (1945). one into the other (VI to IVa) in tn-0 steps, ( 5 ) Lutz and Taylor, ibid., 56, 1593 (1933). _____f

+

+