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3,022,308 i ; lyric‘ ‘Patented Feb. 20, 1962 1 2 hygroscopic than those containing the decahydroisoquino 3 022 308 . linium group. DECAHYDROBENZOI’WR’IDINE QUATERNARIES ' . The compounds of the present invention have been evaluated by standard pharmacological testing procedures and demonstrated to produce hypotensive activity in liv~ Chester John Cavallito and Allan Poe Gray, Decatur, 111., assignors to Irwin, Neisler and Co., Decatur, Ill, a corporation of Illinois ing animals. This hypotensive activity is not related to the No Drawing. Filed Dec. 3, 1957, Ser. No. 700,280 7 Claims. (Cl. 260—286) peripheral ganglionic blocking activity of the compounds and, as a result, this provides the advantage of eliminat This invention relates to unsymmetrical bis-(quaternary ing many of the undesirable side reactions associated withv the use of hypotensive agents which depend upon such ammonium)-subs‘tituted alkane salts, . and is more par ticularly concerned with such compounds wherein the two ganglionic blockade for their hypotensive eifect. As can ‘quaternary ammonium nitrogens are separated by 2 to 4 be seen from the representative pharmacological data presented infra the compounds of the present invention carbon atoms, inclusive, of the alkane portion of the are of relatively low order toxicity, high potency hypo< molecule, wherein the smaller quaternary ammonium group contains up to six carbon atoms and up to one-N-‘ 15 tensive activity with low order ganglionic blocking action heteromonocyclic group, and wherein the larger quater as compared with hypotensive activity. The compounds nary ammonium group is a N-lower-alkyldecahydrobenzo pyridinium radical. It is the concept of a composition of the present invention may be administered to- the ani ' mal organism orally, intravenously, intramuscularly, sub cutaneously, ‘and intracutaneously in solid form as in a of matter having a molecular structure wherein this par ticular larger quaternary ammonium group is separated 20 tablet or in liquid form in water or with any of‘the usual by 2-4 carbons from the smaller quaternary ammonium group that is the speci?c inventive feature. The compounds of the present invention can be made The, N - lower-alkyldecahydrobenzopyridinium radical ‘ by the reaction of a suitable haloalkyl quaternary’ am ‘includes N - lower-alkyldecahydroquinolinium and N monium halide (that which corresponds to all of the, de lower-alkyldecahydroisoquinolinium structures wherein 25 sired end molecule save the larger quaternary ammonium the lower-alkyl substituent contains up to about four car ,moiety) with the appropriate N-lower-alklydecahydro bons. ' ' * j benzopyridine- The reaction is carried out in- a suitable The smaller quaternary ammonium radical includes tri solvent'such as acetonitrile, dimethylformamide, alcohol, methylammonium, N-methylpiperidinium, N-methylmor ,dioxane-alcohol mixtures, et cetera. Reaction v'is pref pholinium, N - methylpyrrolidinium, dimethylethylam erably carried out at re?ux temperatures over prolonged premium and diethylmethylammonium with trimethylam time periods (1/2—4 days). Some of the starting omega haloalkyl quaternary ammonium halides are reported in monium and N-methylpyrrolidinium as preferred struc tures. ' 'J.A.(‘3.S. -77, 3648, (1955) and a type process whereby The two quaternary ammonium nitrogens may be' sep- ' such class of intermediates can be prepared,_for_ their arated by 2-4 carbon atoms of the alkane, with separa» 35 preparation is described in our copending application tion by 2, or 3 carbons being preferred. , The alkane Serial 406,053 ?led January 25, 1954; which issued De excipients. chain can be branched chain or straight chain and can contain up to about six carbon atoms. The quaternary ammonium nitrogens may be attached at the ends of the alkane chain or in any portion therein so long as they, are separated from each other by the proper number of carbon atoms. Those compounds within the scope of the present invention which are alpha, omega-bis-(quater I ' ' i cember 24, 1957 as“U.S. Patent 2,817,664. ' ' » , The use of a cis— ‘or a trans-decahydrobenzopyridine 40 starting base will yield a bis-quaternary ammonium salt product with,lrespectively, a cis- or a trans-fused deca J hydrobenzopyridine nucleus. N-alkyl-cis-decahydroquin olines (for example) react more rapidly than do the cor responding trans-isomers, but if the quaternization of a cis-trans mixture of isomeric decahydroquinolines is car nary ammonium)-substituted alkane salts are a preferred 45 ried essentially to completion the product will likewise class. The two anions can be any of the pharmaceutically ac be a mixture of isomers. ‘ If, however, two equivalents ceptable anions, and may be the same or different. Thus, the compounds of the present invention may be described as bis-(quaternary-ammonium)-substituted al kane salts, wherein the two quaternary nitrogen atoms are separated by from 2 to 4 carbon atoms, inclusive, of the alkane portion of the molecule; wherein one quater nary ammonium group contains up to 6 carbon atoms, - inclusive, and up to one N-teteromonocyclic group; where in the other quaternary ammonium group is a N-lower of a cis-trans mixture of the secondary decahydroquino line bases are alkylated with one equivalent of an alkyl halide, there is' obtained one equivalent each of trans decahydroquinoline hydrohalide and of an N-alkyl-cis decahydroquinoline. The latter will then yield a bis quaternary ammonium salt product with a cis-fused deca hydroquinoline nucleus. ’ V I > Another method of preparingthe compounds of the 55 present invention which sometimes may be used is to bis alkyldecahydrobenzopyridine radical and, wherein the quaternize the free diamine base corresponding to the anions are non-toxic acid residues. desired end molecule. The compounds of the present invention are generally ' solids, which can exist in the cis or trans form or as The following examples will more particularly illustrate the compounds of the present invention and the pro mixtures thereof and any and all forms of the compound are intended when not otherwise speci?ed. The isom be construed aslimiting. erism is in the juncture of the two rings of the decahydro benzopyridine system. Those compounds ‘which contain "the decahydroquinolinium structure‘ ‘are generall-ymore = cedures whereby they may be prepared, but are not to . I Example 1 . > . - An acetonitrile solution of 5.4 grams (0.035 mole) of 8,022,308 3 4 anol-ethyl acetate, yielding 9 grams ('72 percent of theory) .1-methyldecahydroquinoline (cis-trans mixture) and 9.1 grams (0.035 mole) of 3-bromopropyltrimethylammo of ethylene - 1 - (1-methyldecahydroquinolinium)-2-(tri- . methylammonium) dibromide as a hygroscopic solid, nium bromide was refluxed on the steamhath for 15 hours. The cooled solution was diluted with ether to yield 12.8 melting at 142 degrees centigrade With decomposition. Analysis-Calculated: C, 45.00; H, 8.06; Br, 39.93. Found: C, 44.75; H, 7.78; Br, 39.91. grams (88 percent of theory) of trimethylene-l-(l-methyl decahydroquinolinium)-3 - (trimethylammonium) dibro mide as a ‘hygroscopic solid, melting with gas evolution Example 6 A soluble of 10.0 grams (0.06 mole) of 2umethyldeca Analysis.—-Calculated: C, 46.38; H, 8.29; Br, 38.58. hydroisoquinoline and 17.0 grams (0.06 mole) of 3 10 Found: C, 46.11; H, 8.10; Br, 38.15. ' bromopropyltrimethylammonium bromide in 50 milliliters at 108-110 degrees ccntigrade. _ Example 2 of acetonitrile was re?uxed on the steam-bath for 7 hours. The precipitate, which formed on cooling, was A-s'olution of 8:0‘gr'ams (0.05 mole) of Lmethyl-trans decahydroquinoline and 13.6 grams (0.05 mole) of 3 recrystallized from isopropyl alcohol to give 15.5 grams brornopropyltrimethyl-ammonium bromide in isopropyl 15 (57 vpercent yield) of trimethylene-1-(2-methyldecahydro alcohol was re?uxed on the steam-bath for 24 hours. isoquinolinium) - 3 - (tri-methylammonium)dibromide as vAddition of ether to ‘the cooled ‘solution precipitated an colorless crystals, melting vat 228-230 degrees centigrade. oil which was'diss'olved in ethanol and reprecipitated with Analysis-Calculated: C, 46.40; H, 8.27; Br, 38.58. ether. ‘Drying the oil over P205 in ‘vacuo afforded 11.0 Found: C, 45.72; H, 8.58; Br, 38.65. ‘grams (51 percent of the theoretical yield) ‘of trimethyl 20 ‘Example 7 ene-1-( l-methyl-tran's - decahydr'oquinolinium)-‘3 - (tri Following the general procedure described in Example methylarnmonium) dibrornide as an extremely hygro scopic solid, melting from 130 to 136 degrees centigrade. Analysis-,Calculated: C, 46.38; H, 8.29; Br, 38.58. ‘Found: c, 45.56; H, 3.27; Br, 38.33. _ 6, Z-methyldecahydroisoquinoline was reacted with 3 bromopropyl-l-methylpyrrolidinium bromide to a?ord colorless crystals of trimethylene-l-(Z-methyldecahydro - ‘Example 3 isoquinolinium) - 3 - (l-methylpyrrolidinium) dibromide, melting‘ point 218-220 degrees centigrade, after several Following the procedure of Example 2, l-ethyldecahy recrystallizations from isopropyl alcohol. droquinoline (from -a mixture of cis and trans-decahy 7 ‘ Analysis---~Calculated: C, 49.09; H, 8.24; Br, 36.30. droquinoline) was reacted with 3-bromopropyltrimethyl- ~ ammonium bromide to yield 65 percent of the theoretical 30 Found: C, 49.45; H, 8.64; Br, 36.22. From the isopropyl alcohol mother liquors there was obtained a smaller amount of crystalline material, which methylammonium) dibromide, an extremely hygroscopic melted at 196-499 degrees centigrade ‘after recrystalli material. It is'probable that the product is almost en— zation from isopropyl alcohol and was apparently "a , Analysis.—-Calculated: Br, 37.32. Found: Br, 37.23. of trimethy_lene-1-( 1-ethyldecahydroquinolinium) ~3-(tri tirely derivedlfrom cis-decahydroquinoline. stereoisomeric trimethylene-1-(2-methyldectahydroisoquin 35 olinium) -3-( l-methylpyrrolidinium) dibromide. Analysis.—Calculated: C, 49.09; H, 8.24; Br, 36.30. Found: C, 49.32; H,"8.2.9; Br, 36.48. Example 4 Essentially as described in Example 1, reaction of >1 methyl-trans-decahydroquinoline with 3-bromopropyl-N Example 8 methylpyrrolidinium bromide a?orded 52 percent of the 40 theoretical ‘yield of trimethylene-'1‘-‘( l-methyl-tr'ans-deca hydroquinoliniu'm) -3-( lémethylpyrrolidinium) dibromide Following‘ the procedure of Example 1, l-butyldecahy vdroquinoline (cis-trans mixture) was reacted with 4 ‘chlorobutyltrimethyl-ammonium chloride to produce tet ‘as a hygroscopic ‘solid melting at 87-88 degrees centi "grade. "ramethylehe-l-(1-burtyldeoahydroquinolinium) '- 4 ~ (tri A?alysis.-‘—éCalculated: c, 49.09; H, 3.24; Br, 36.30. Found: 0, 43.50; a, 8.08; Br, 3572. , 45 Example 5 methylamrnonium) dichloride as a hygroscopic solid. Example 9 Following the‘ procedure of Example ‘2,, l-ethyl-trans A. To 30 grams (0.22'mole) of decahydroquinoline (c-is-trans mixture) was added, dropwise with stirring, ‘decahydroquinoline was reacted with 3-iodopropyldiethyl vmethylamrnonium iodide to produce trimethylene-l-(‘l a solution of_11."6 grams (0.11 mole) of ‘dimethylamino 50 ethyl-trams-decahydroquinolinium) - 3-(diethylmethylam ethyl chloride in 75 milliliters of benzene. The reaction mixture was re?uxed on the steam-bath for 80 hours. moniurn) diiodide as an extremely hygroscopic solid. Filtering off the precipitate of decahydroquinoline hy drochloride land distilling the residue yielded 9.0 ‘grams (40 percent of theory) of 1-(dimethylaminoethyl)-dec ahyd'roquinoline, boiling'point 104—106 degrees centigrade Example 10 Following the procedure of Example l,‘1-propyldecahy 55 droquinoline was reacted with 3-bromopropyl-N-methyl morpholinium bromide to product trimethylene - 1-(1 propyldecahydroquinolinium)43 - (methylmorpholinium) dibromide ‘as a hygroscopic solid. ‘at 1.5 millimeters, r1925 1.4862. ‘Since the decahydroquin oline’hyd'rochloride obtained was‘shown to be almost pure trans '(melting'point of the base), it is probable that "the product "is essentially derived from cis-decahydroquin— Example 1 1 60 oline. Following the'procedure of Example 7, Z-methyldec chloride, prepared by the addition of etherealihydrogen ahydroisoquin‘oline was reacted vwith '4-chlo'rohutyltri 'methylammonium chloride ‘to produce tetramethylene-l chloride to an ether solution of the base and recrystallized (2-methyldecahydroisoquinolinium) - 4 - (trimethylam 1-(dimethylaminoethyl)-decahydroquinoline dihydro ‘from ethanol, melted ‘at ‘272 degrees centigrade with de 65 moniu'm) dichloride. composition. _ . . "Example 12 _ Analysis-Calculated: C, 55.10; H, 9.96; Cl, 25.03. Found: c, 55.24; H, 10.21; or, 24.48. _ Following the procedure of Example ‘3, 2-‘ethyldecahy B. ‘Into a methanol solution of 6.5 grams (0.03 mole) 70 droisoquinoline was reacted with 3-bromopropyltrimethyl ammonium bromide to produce trimethylene-1-(2-ethyl of l-(dimethylaminoethyl)fdecahydroquinoline was intro duced ‘8.8 grams (0.09 mole) of methyl bromide. After being heated in a pressure bottle‘at 75 degrees centigrade for 24 hours, the cooled'solution was diluted with ethyl acetate. The precipitated oil was crystallized from eth 75 decahydroisoquinolinium)~3 - (trirnethylarnmonium) di h'romide. _ . V. Example 13 7 Following the procedure of Example 7, 2-ethyldecahy 3,022,308 E a droisoquinoline was reacted with 2-br'omoe‘thylriiethyl pyrrolidinium bromide to produce ethylene-‘1-2(-ethyl II. Hypo'tensive ‘activity: Effects on the blood pressure‘ of anesthetized dogs: decahydroisoquinolinium - 2 - (methylpyrrolidinium) di bromide. Compound of Example Example 14 LV. dose, mgjkg. Percent Duration , 13.1’. fall hours Following the procedure of Example 7, 2-butyldecahy 1 _________________________________ __ droisoquinoline was reacted with B-bromopropyl-N-meth ylmorpholinium bromide to produce trimethylene-l (2 - butyldecahydroisoquinolinium) - 3 - (methylmorphm linium) dibromide. . 0.025 2 _________________________________ __ Essentially as described in our paper J. Am. Chem. Soc., __________________ __ " 0.1 15 5 _________________________________ __ 0.1 6 _________________________________ _- 0.01 20 7 (high-melting material) ......... .. 0.01 0. 025 7 (low melting material) __________ _. >4 >4 60 >4 20 35 65 0. 25 1.0 >1. 0 0.6 2 >3 __________________ __ 5 ........ __ 0. 5 0.1 1~(4-bromo-2 - pentyl) - l - methylpyrrolidinium bromide. 50 60 __________________ __ 0.05 0.1 In a similar manner to Example 15, N-methylpyrroli dine was reacted with 2,4-dibromopentane to provide >2 >2 10 30' 50 0.025 0.05 0.1 methylene-1 - (1 - methyldecahydroquinolinium) - 3 - (tri >4 __________________ __ 0. 25 0. 5 1. 0 hydroquinoline (cis-trans mixture) to yield Z-ethyltri 45 60 50 __________________ __ 0.01 0. 05 cedure of Example 1, this was reacted with 1—methyldeca 45 65-70 ' >2 >3 40 >3 55-60 >3 III. Sympathetic ganglionic blockade on anesthetized cats by superior cervical ganglion-nictitating membrane preparation-—electrical stimulation: Then, following the procedure of Example 7, this was reacted with 2-methyldecahydroisoquinoline to yield 1,3-dimethyltrimethylene-l - (Z-methyldecahydroisoquino linium)-3-(l-methylpyrrolidinium) dibromide. Example 17 Compound of Example LV. dose, mgJkg. Degree of block (0—4~|where 4+ is complete Duration, hours blockade) In a similar manner to Example 15, trimethylamine was reacted with 1,4-dibromo~2-methylpehtane to provide 1 ___________________ _. 4-bromo-2-methyl-l-pentyltrimethylammonium 'bromide. Then, following the procedure of Example 6, this was reacted with Z-methyldecahydroisoquinoline to yield 1,3 0. 05 __________ _ _ 0. 1 0.25 0. 4 1. 0 >1. 0 0. 5 v0. 125 -dimethyltetramethylene - 1 - (Z-methyldecahydroisoquinm linium)~4-(trimethylammonium) dibromide. Example 18 Two equivalents of decahydroquinoliue (cis-trans mix . >1.5 0.005 77, 3648 (1955), trimethylamine was reacted with l-bro methyl-ammonium) dibromide. Example 16 >1. 0 55 0. 0250. 05 0.1 0. 5 4 _________________________________ -_ 0. 25 30 0.1 0.01 10 ‘Example 15 mo-2-bromornethylbutane to provide Z-bromomethylbutyl trimethylammonium bromide. Then, following the pro , 10 0. 05 __________ _ _ 0.25 0.75 0.05 0.1 0 0.75 0.25 4-0 5 ___________________ ._ 1.0 0.5 _________ _. 0.25 _________ __ 0. 5 0.75 1.0 ture) was reacted with 1 equivalent of 1,3-dichloro— butane in benzene solution, in a manner similar to that >2 IV. Effect on the pupils of unanesthetized male cats: described in Example 5A, to provide 1-(3-chlorobutyl) cis-decahydroquinoline. This, reacted with pyrrolidine in essentially the same manner, yielded l-(3-pyrrolidino» Compound LP. dose of Example rug/kg. Pupil Dilation Reaction to Light butyl)-cis-decahydroquinoline, which was then treated with excess methyl iodide to yield l-methyltrimethylene 4 _________ __ pyrrolidinium) diiodide. Example 19 0.05 None ______ __ 01 3 - ( l - methyl-cis-decahydroquinolinium) - 1 - (l-methyl 0.15 Complete. Complete _. None (duration about 2 hours). ___..do _____ __ None. 50 V. Effect when the compound of Example 4 was ad ministered intravenously to an unaesthetized male monkey ‘In a completely analogous manner to Example 18, in a dosage of 0.75 milligrams per kilogram of body piperidine was reacted with 2,3-dichlorobutane to provide weight was: No immediate etfects. The animal became l-(3-chloro-2-butyl)-pipetridine. Reaction of this with somewhat quieter and there was possibly some dilation of decahydroisoquinoline yielded 2-(3-piperidino-2-butyl) the pupils. The monkey showed no evidence of dry decahydroisoquinoline, which was then treated with excess mouth or postural hypotension. methyl iodide thereby affording 1,2-dimethylethylene~l Various modi?cations which will be obvious to those (Z-methyldecahydroisoquinolinium) - 2 - (l-methylpiper skilled in the art may be made in the present invention 60 idinium) diiodide. without departing from the spirit or scope thereof, and The following illustrates typical pharmacological test it is to be understood that we intend to limit ourselves results obtained for the compounds of the present inven only by the scope of the appended claims. tion: We claim: I. Acute toxicity (LD50) by intravenous injection in mice—-dosage in terms of milligrams per kilogram of body weight: wherein one quaternary ammonium group is selected Compound of Example: I.V. toxicity 1 __ 2 __ 4 _ 5 1. Bis - (quaternary ammonium) - substituted alkane salts; wherein the alkane portion is selected from the group consisting of alkanes having 2-6 carbon atoms; 67.5 73.5 63.0 from the group consisting of trimethylammonium, di 70 methylethylarnmonium, methylpiperidinium, diethylmethylammonium, N-methylmorpholinium and N N methylpyrrolidinium; wherein the other quaternary am 31.5 monium group is N-lower-alkyldecahydrobenzopyridin 7 (high melting) _______________________ __ 60.5 7 (low melting) _______________________ __ 62.0 ium; wherein the two quaternary nitrogen atoms are sep 75 arated by from 2 to 4 carbon atoms, inclusive, of the 3,022,308 7 8 alkane poytion of the, molecule; andrwherein the two 7. Trirnvethylene - 1 - (2 - methyldeeahyroisoquinof 1inium)-3-‘(1-n1ethy1pyrro1ic1inium) dibromide. anions are each non-toxic acid residues. 2. Trimethylene- 1, - (1 - methyidecahydroquinohni References Cited in the ?le of this patent UNITED STATES PATENTS um)-3-(trimethylammonium) dihromide. 3. Trimethylene - 1 - (1 - methyl - trans - decahydi'o quinoliniun1)—3 ~ ( trimethy] ammonium) dibromide. 2,834,779 4.. Trimethylene - 1 - (1 - methy1- trans - decahydro FOREIGN PATENTS quinoliniurn) -3-( 1-methy1pyn'olidinium) dibromide. 5. Ethylene - 1 (1 - methyldec'ahydroquinolinum) - 2 (trimethylammcnium) dibromidc. 6. Trimethylene - 1 - (2 - methyldecahydroisoquino linium)-3-(trimethyiamrnoniurn) dibromide. ' Biel et a1 _____________ __ May 13, 1959 1,108,117 10 France ______________ __ Aug. 24, 1955 OTHER REFERENCES Rice: J.A_C.S., vol. 75 (page 4911) (1953). Gray et' 31.: J.A.C.S., v01. 77 (1955) p. 3536.