US3362954A

US3362954A - 4-tertiary amino-lower alkylamino-quinoline carboxamides and carboxylates

Info

Publication number: US3362954A
Application number: US571199A
Authority: US
Inventors: Alexander R Surrey
Original assignee: Sterling Drug Inc
Current assignee: STWB Inc
Priority date: 1965-08-12
Filing date: 1966-08-09
Publication date: 1968-01-09
Anticipated expiration: 1985-01-09

Description

United States Patent 3,362,954 4-TERTIARY AMINO-LOWER ALKYLAMINO- QUINOLINE CARBOXAMIDES AND CAR- BOXYLATES Alexander R. Surrey, Albany, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 9, 1966, Ser. No. 571,199 Claims priority, application Great Britain, Aug. 12, 1965, 34,644/ 65 21 Claims. (Cl. 260-247.2)

This invention relates to compositions of matter of the class of 4-tertiary-aminoalkylamino-quinolines.

This application is a continuation-in-part of my 00- pending application Ser. No. 392,642, filed Aug. 27, 1964, now abandoned.

The invention resides in the concept of a composition having a molecular structure in which the quinoline nucleus has attached thereto in the 4-position a lowertertiary-amino-(lower-alkyl) amino radical and in the 3- or 2-position a N-[(lower-tertiary-amino)(lower-alkyl)] carbamyl or lower-carbalkoxy radical.

Thus, there are provided the compounds of Formula I where Y and Y are each lower-alkylene having two to six carbon atoms and having its connecting linkages on diflerent carbon atoms, and, NB and NB are each lowertertiary-amino selected from the group consisting of di- (lower-alkyl) amino, N- (lower-alkyl) N- (lower-hydroxyalkyD-amino, piperidino, (lower-alkylated)-piperidino, pyrrolidino, (lower-alkylated)pyrrolidino and morpholino. 'Ihe CONH--Y' group is attached to either the 2- or 3-position of the quinoline ring. The benzenoid ring of Formula I can be substituted by low-molecular weight substituents, e.g., halo, lower-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkanoylamino, lower-alkylamino, nitro, amino, hydroxy, lower-alkanoyloxy, benzyloxy, tn'halomethyl, and the like, at any of the available positions, i.e., 5, 6, 7 or 8, and where more than one substituent is present, they can be the same or different and they can be in any of the various position combinations relative to each other. Such additions to the molecular structure of the inventive concept herein described are, therefore, equivalents of the subject matter sought to be patented.

The compounds of Formula I are useful because of their anti-inflammatory properties as established by known pharmacological test procedures, e.g., inhibition of granuloma pouch formation in rats, inhibition of dextraninduced local foot endema in rats, and inhibition of endotoxin-induced lung inflammation in mice.

The term halo, as used hereinabove, means c-hloro, bromo, iodo or fluoro.

Unles otherwise indicated, the adjective lower, as used herein, designates a group having from one to six carbon atoms, e.g., lower-alkyl means alkyl radicals having from one to six carbon atoms and is illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, n-amyl, isoamyl, n-hexyl, 3-hexyl, and the like.

The term lower-alkylene, as used herein and designated as Y and Y in Formula 1, means alkylene radicals having from two to six carbon atoms and having its two free valence bonds, i.e., connecting linkages, on difierent carbon atoms and is illustrated by CH CH 3;:62354 Patented Jan. 9, 1968 I CHzCHzCHCHa, CHzCHCHrCHaCH;

CHzJHCHaCHrOHaCHa --CH CH CH CH CH CH and the like. Also, the lower-alkylene radicals Y and Y of Formula I can be interrupted by O or S, e.g.,

CH CH OCH CH CH CH CH CH SCH CH CH etc., or substituted by hydroxy, e.g.,

CH CH (OH) CH etc.

The compounds of Formula I where Y and Y are NB=NB' are prepared by heating a lower-alkyl 4-chloroquinoline-3(or 2)-carboxylate (II) with at least two molar equivalents of the appropriate tertiary-aminoalkylamine III), illustrated structurally as follows:

C OOR HzNY-NB II III IIIH-Y-N B C O N H-Y-N B where R is lower-alkyl, preferably ethyl or methyl, and Y and NB have the meanings designated above. The reaction is run by heating the reactants in phenol at about C. for a heating period of about fifteen to twenty hours.

The compounds of Formula I Where Y and Y are different and/ or NB and NB are different are prepared by heating a lower alkyl 4 (tertiary aminoalkylamino)- quinoline-3 (or 2)-carboxylate (IV) with a molar equivalent of the appropriate tertiary-aminoalkylamine (Illa), illustrated as follows:

IV Illa where R is lower-alkyl, preferably ethyl or methyl, Y, Y, NB and NB have the meanings given above for Formula I. The reaction is run using the reaction conditions 3 given above for the preparation of the compound of Formula Ia.

The intermediates of Formula IV constitute another aspect of my invention. They are prepared as follows:

COOR

where X is halo, preferably chloro or iodo, and R, Y and NB have the meanings already given. The reaction conditions can be varied, as illustrated in the specific examples below.

Further to being useful as intermediates, compounds of Formula IV are useful because of their anti-inflammatory properties as established by known pharmacological test procedures illustrated hereinabove and, also, because of their wound healing properties as established by their ability on oral administration to accelerate the normal rate of skin wound healing and burn healing in rats. Particularly preferred embodiments because of their wound healing properties are the lower-alkyl 4-[5-.(lower-tertiary-amino) 2-pentylamino] 3-quinolinecarboxylates, e.g., ethyl 7-chloro-4-(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate, ethyl 7-chloro-4 [S-(N- ethyl-N-2-hydroxyethylamin0) 2-pentylamino1-3-quinolinecarboxylate, or salts thereof.

The compounds of Formulas I, Ia and IV are useful both in free base form and in acid-addition salt form and both forms are within the purview of the invention, and are considered to be one and the same invention. The acid-addition salts are simply a usually more convenient form for use; and, in practice, use of the salt form inherently amounts to use of the base form. The acids which can be used to prepare the acid-addition salts are preferably those which produce, when combined with the free base, pharmacodynamically acceptable salts, that is, salts wh se anions are relatively innocuous to the animal organism in pharmacodynamic doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions; in other words, the latter do not substantially affect the pharmacodynamic properties inherent in the cations. In practicing my invention, I found it convenient to employ the hydrochloride salt. However, other appropriate pharmacodynamically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrobromic acid,'hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, quinic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate, sulfa mate, sulfate, acetate, citrate, tartrate, lactate, methanesulfonate, ethanesulfonate and quinate, respectively.

The acid-addition salts are prepared preferably by reacting the free base and acid in an organic solvent, e.g., ethanol, in which case the salt separates directly or can be obtained by concentration of the solution.

Although pharmacodynamically acceptable salts are preferred, all acid-addition salts are within the scope of my invention. All acid-addition salts are useful as sources of the fi'ee base form even if the particular salt per se is not desired as the final product, as for example when the salt is formed for purposes of purification or identification, or when it is used as an intermediate in pretwo quaternary nitrogen atoms of the compounds of Formula IV, i.e., the nitrogen atoms of NB and/or the quinoline n'ng. These salts are useful for further identification of the aforesaid compounds. The quaternary ammonium salts are obtained by the addition of esters having a molecular weight less than about 200 to the free base form of the compounds. A preferred class of esters comprises lower-alkyl, lower-alkenyl having three to six carbon atoms or benzyl esters of inorganic acids or organic sulfonic acids of the formula Z-An' where Z is loweralkyl, lower-alkenyl having three to six carbon atoms or benzyl and An is defined as An above. Z when benzyl can be substituted in the benzene ring by from one to three substituents illustrated by, but not limited to loweralkyl, lower-alkoxy, halo, nitro, lower-alkylamino, lower alkylmercapto, and the like. Z-An is thus illustrated by, but not limited to methyl chloride, methyl bromide, methyl iodide, ethyl bromide, propyl chloride, 2-hydroxyethyl bromide, allyl chloride, allyl bromide, methyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate,

' benzyl chloride, benzyl bromide, p-chlorobenzyl chloride,

p-nitrobenzyl chloride, o-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, p-methoxybenzyl chloride, and the like. The quaternary ammonium salts are prepared by mixing the free base and the lower-alkyl, lower-alkenyl or benzyl esters in an organic solvent inert under the conditions of reaction, for example, ethanol, methanol, ether, acetonitrile and the like, or alternatively, in the absence of a solvent. Heating is preferably used to facilitate the reaction, although quaternary formation takes place at room temperature but a longer reaction time is needed. The quaternary ammonium salt separates directly or can be obtained by concentration of the solution.

The molecular structures of the compounds of my invention are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses and by infrared (IR) spectral analyses.

The following examples will further illustrate the invention without, however, limiting it thereto.

EXAMPLE 1 N (2-diethylaminoethyl) 4 (2 diethylaminoethylamino)-3-quinolinecarboxamide-a mixture containing 54 g. of ethyl 4-chloro-3-quinolinecarboxylate, 54 g. of 2 diethylarm'noethylamine and 54 g. of phenol was heated with stirring at 130 C. for twenty hours and then poured into two liters of water. The resulting precipitate was solubilized by addition of concentrated hydrochloric acid. The resulting solution was extracted with chloroform to remove the phenol; the solution was then made weakly basic by addition of 35% aqueous sodium hydroxide solution and extracted with chloroform to remove any un: reacted ethyl 4-chloro-3-quinolinecarboxylate; the solution was then made strongly basic with 35% aqueous'sodium hydroxide solution and extracted first with chloroform and then with ethylene dichloride. The extracts of the strongly basic solution were combined, washed with water, dried over anhydrous potassium carbonate and;

. 113.8 C. (corn);

Analysis.-Calcd. for C22H35'N5O: c 68.61; H, 9.16.

Found: C, 68.36; H, 9 :18. v

EXAMPLE 2 N (2 diethylaminoethyl) 7 chloro 4 (2 diethylaminoethylamino)-2-quinolinecarboxamide was prepared following the procedure described in Example 1 using 14.5 g. of ethyl 4,7-dichloro-2-quinolinecarboxylate, 17.5 g. of Z-diethylaminoethylamine, 14.5 g. of phenol, a heating period of twenty-four hours at 130 C., and using ethylene dichloride as the extracting solvent. There was thus obtained 20 g. of the product, N-(Z-diethylaminoethyl) 7 chloro 4 (2 diethylaminoethylamino) 2- quinolinecarboxamide, which was taken up in 100 ml. of isopropyl alcohol. To the solution was added 25 ml. of 6 N solution of hydrogen chloride in ethanol, ether was added to near tubidity, and the solution allowed to stand. The solid that separated was collected, recrystallized from isopropyl alcohol, dried in a vacuum oven at 100 C. for three days to yield 4 g. of N-(2-diethylaminoethyl)-7- chloro 4 (2 diethylaminoethylamino) 2 quinolinecarboxamide as its trihydrochloride, M.P. 265.6267.2 C. (corn) with decomposition.

Analysis.Calcd. for C H ClN O-3HCl: Cl, 20.22; N, 13.20. Found: Cl", 19.76; N, 13.11.

EXAMPLE 3 N (2 diethylaminoethyl) 7 chloro 4 (2 diethylaminoethylamino)-3-quinolinecarboxamide was prepared following the procedure described in Example 1 using 8.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate, 7.0 g. of Z-diethylaminoethylamine, 8.0 g. of phenol and a heating period of twenty hours at 130 C. There was thus obtained 2.6 g. of N-(Z-diethylaminoethyl)-7-chloro- 4 (2 diethylaminoethylamino) 3 quinolinecarboxamide, M.P. 119.2121.8 C. (corn), after two recrystallizations from n-heptane.

Analysis.Calcd. for C H ClN O: Cl, 8.46; N, 16.67. Found: Cl, 8.17; N, 16.93.

N (2 dimethylaminoethyl)-7-chloro-4-(2-dimethylaminoethylamino) 3 quinolinecarboxamide was prepared following the procedure described in Example 1 using 8.5 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate, 5.4 g. of Z-dimethylaminoethylamine, 8.5 g. of phenol and a heating period of twenty hours at 130 C. There was thus obtained 2.0 g. of N-(2-dimethylaminoethyl) -7- chloro-4-(2 dirnet-hylaminoethylamino) 3 quinolinecarboxamide, M.P. 157.0-l58.4 C. (corr.), after two recrystallizations, once from benzene-n-hexane and once from benzene.

Analysis.Calcd. for C H ClN O: Cl, 9.76; N, 19.21. Found: Cl, 9.75; N, 19.09.

EXAMPLE 5 N (2 dimethylaminoethyl) 4 (2 dimethylaminoethylamino)-3quinolinecarboxamide was prepared following the procedure described in Example 1 using 10.0 g. of ethyl 4-chloro-3-quinolinecarboxylate, 7.4 g. of 2- dimethylaminoethylamine, 10.0 g. of phenol and a heating period of twenty hours at 130 C. There was thus obtained 2.7 g. of N-(2-dimethylaminoethyl) -4(2-d-imethylaminoethylarnino)-3-quinolinecarboxamide, M.P. 128.8- 129.6 C. (corr.), after recrystallization from benzene.

Analysis.Calcd. for C H N O: C, 65.63; H, 8.19; N, 21.26. Found: C, 65.72; H, 8.25; N, 21.04.

EXAMPLE 6 Quaternary ammonium salt derivatives of my compounds of Formula I are prepared by conventional means, as illustrated below.

(A) N-(Z-diethylaminoethyl) 4 (2 diethylaminoethylamino)-3-quinolinecarboxylate tris methiodide-A mixture containing 6.3 g. of N(2-diethylaminoethyl)-4- (Z-diethylaminoethylamino) 3 quinolinecarboxamide, 14.2 g. of methyl iodide and 50 m1. of anhydrous ethanol was allowed to stand at room temperature for about ten days whereupon an oil separated. The solvent was decanted, the oil dissolved in hot methanol, and the hot solution allowed to cool. The resulting precipitate was collected to yield 9 g. of N-(2-diethylaminoethyl)-4-(2- diethylaminoethylamino) 3 quinolinecarboxamide trismethiodide, M.P. 222.8-224.8 C. (corn), with decomposition.

Analysis.Calcd. for C H I N O: I", 46.96; N, 8.64. Found: 1, 46.90; N, 8.50.

Following the procedure described above in Example 6A but using molecular equivalent quantities of allyl bromide or benzyl chloride in place of methyl iodide, the corresponding tris-allobromide or tris-benzochloride, respectively, is obtained.

EXAMPLE 7 'The preparation of the intermediate lower-alkyl 4-halo- 3( or 2)-quinolinecarboxylates is illustrated in the following paragraphs:

(A) Ethyl 4 chloro 3 quinolinecarboxylate-A mixture containing 76 g. of ethyl 4-hydroxy-3-quinolinecarboxylate, 25 ml. of phosphorus oxychloride and 500 ml. of ethylene dichloride was heated on a steam bath for about five minutes to form a solution which was then refluxed with stirring for an additional thirty minutes. Dilute (6 N) aqueous ammonium hydroxide solution was added slowly with vigorous stirring at a rate to maintain reflux until the solution was slightly basic. The mixture was filtered and the ethylene dichloride layer was separated, washed successively with 1% aqueous sodium hydroxide solution and water, dried over anhydrous potas sium carbonate, and evaporated to yield an oily residue that solidified on cooling. This solid was recrystallized from n-pentane to yield ethyl 4-chloro-3-quinolinecarpoxylate, M.P. 45.547.0 C.

, Analysis.Calcd. for C H CINO Cl, 15 .04. Found: Cl, 15.04.

(B) Ethyl 4,7 dichloro-3-quinolinecarboxylate, M.P. 81-82" C., was prepared following the procedure described in Example 7A using 21.0 g. of ethyl 7-chloro-4- hydroxy-3-quinolinecarboxylate, 7.6 ml. of phosphorous oxychloride, 200 ml. of ethylene dichloride, a refluxing period of two hours, and a recrystallizing medium of ethylene dichloride-n-pentane.

Analysis.-Calcd. for C H Cl NO N, 5.17. Found: N, 5.10.

(C) Ethyl 4,7 dichloro 2 quinolinecarboxylate, M.P. -81 C., was prepared following the procedure described in Example 7A using 84 g. of ethyl 7-chloro-4- hydroxy-2-quinolinecarboxylate, 30 ml. of phosphorus oxychloride, 400 ml. of ethylene dichloride, and a refluxing period of one hour.

(D) Ethyl 7 chloro 4 iodio 3 quinolinecarboxylate-To a refluxing solution containing 25.5 g. of sodium iodide in 250 ml. of acetone was added 23.4 g. of ethyl 4,7 dichloro 3 quinolinecarboxylate followed by 40 g. of ethyl iodide, and refluxing was continued for six hours. The reaction mixture was allowed to cool and then stand at room temperature. The solid that separated was filtered oif. The filtrate was evaporated to about one-third of its volume, treated with decolorizing charcoal, filtered and the filtrate cooled. The solid that separated was collected, triturated well with water, filtered and dried in a vacuum oven at 70 C. for four hours to yield 19 g. of ethyl 7- chloro-4-iodo-3-quinolinecarboxylate, M.P. 113 C.

Analysis.-Calcd. for C H ClINO I, 35.12; 0, 8.85. Found: I, 35.34; 0, 8.90.

(E) Ethyl 4-chloro 7 nitroquinoline 3 carboxylate-A mixture containing 43.5 g. of ethyl 4-hydroxy-7- nitro-3-quinolinecarboxylate and 250 ml. of phosphorus oxychloride was refluxed for five hours and then most of the excess phosphorus oxychloride was distilled off in vacuo. The concentrate was poured with stirring into a mixture containing about equal parts of an excess of 7 concentrated ammonium hydroxide and water along with ice. The solid that separated was collected and recrystallized twice from acetone to yield 5.5 g. of ethyl 4-chloro- 7-nitroquinoline-3-carboxylate, M.P. 164.6-167.2 C. (corn).

Analysis.Calcd. for C1zI'I9C1N204: Cl, 12.63 N, 9.98. Found: Cl, 12.39; N, 9.99.

Following the procedure described in Example 7A using molar equivalent quantities of the appropriate loweralkyl 4-hydroxy-3(or 2)-quinolinecarboxylate and phosphorus oxychloride, the following lower-alkyl 4-chloro-3 (or 2)-quinolinecarboxylates are prepared.

(F) Ethyl 4,5-dichloro-3-quinolinecarboxylate, using ethyl -chloro-4-hydroxy-3-quinolinecarboxylate.

(G) Isopropyl 4,7 dichloro-3-quinolinecarboxylate, using isopropyl 7-chloro 4 hydroxy 3 quinolinecarboxylate.

(H) Ethyl 4-chloro-8-ethoxy-3-quinolinecarboxylate, using ethyl 8-ethoxy-4-hydroxy-3-quinolinecarboxylate.

(1). Methyl 4-chloro-7-methyl-3-quinolinecarboxylate,. using methyl 4-hydroxy-7-methyl-3-quinolinecarboxylate.

(J) n-Propyl 4-chloro-2-quinolinecarboxylate, using n-propyl 4-hydroxy-2-quinolinecarboxylate.

(K) Ethyl 4-chloro-6,7-dimethoxy 3 -'quinolinecarboxylate, using ethyl 6,7-dimethoxy-4-hydroxy-3-quino linecarboxylate.

(L) n-Butyl 4-chloro-6-methoxy-3-quinolinecarboxylate, using n-butyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate.

(M) Methyl 4,7-dichloro 3 quinolinecarboxylate, using methyl 7-chloro-4-hydroxy-3-quinolinecarboxylate.

(N) Isobutyl 4,7-dichloro 3 quinolinecarboxylate, using isobutyl 7-chloro-4-hydroxy-3-quinolinecarboxylate.

(O) n-Hexyl 4,7-dichloro 2 quinolinecarboxylate, using n-hexyl 7-chloro-4-hydroxy-2-quinolinecarboxylate.

EXAMPLE 8 Ethyl 7-chloro-4-(Z-diethylaminoethylamino)-3-quinolinecarboxylateA mixture containing 7.2 g. of ethyl 7-chloro-4-iodo-3-quinolinecarboxylate, 4.6 g. of 2-diethylaminoethylamine and'50 ml. of ethanol was heated on a steam bath for about fifteen minutes until a solution resulted. The solution was then allowed to cool and stand at room temperature overnight. The solution was evaporated to dryness; the resulting solid was triturated in about 2% aqueous potassium hydroxide solution, filtered and recrystallized from cyclohexane to yield 5 g. of ethyl 7 chloro-4 -(Z-diethylaminoethylamino) 3 quinolinecarboxylate. The product was converted into its dihydrochloride salt by .dissolving it in hot isopropyl alcohol, adding 8 ml. of 6 N ethanolic hydrogen chloride, filtering the hot solution, and allowing the filtrate to cool to room temperature. The precipitate was collected, .washed with acetone and recrystallized from isopropyl alcohol to yield 4.0 gof ethyl 7-chloro-4-(2-diethylaminoethylamino) 3 quinolinecarboxylate dihydrochloride, M.P. 188.8190.4 .C. (corn), with decomposition.

Analysis.-Calcd. for C H C1N O -2HCl: Cl, 25.16; N, 9.94. Found: Cl, 24.85; N, 9.63.

EXAMPLE 9 and dilute hydrochloric acid, and the resulting solution extracted with chloroform to remove the phenol. It was then made .neutraLwith 35% aqueous sodium hydroxide solution and extracted with chloroform to remove any unreacted ethyl 4,7-dichloro-3-quinolinecarboxylate, and then made strongly basic with 35 aqueous sodium hydroxide solution and extracted with chloroform. The last chloroform extract was dried over anhydrous potassium carbonate and evaporated to yield 2.4 g. of oil. The first two chloroform extracts were combined, extracted with 0.1 N hydrochloric acid, the acidic extract made alkaline with 35% aqueous sodium hydroxide solution, and the alkaline solution extracted with chloroform. The chloroform extract was dried and evaporated to yield 10.7 g. of

oil which was combined with the above 2.4 g. of oil. The combined oil was dissolved in hot n-heptane, the hot solution treated with decolorizing charcoal and filtered, and the filtrate cooled to yield a solid material. This solid was collected and recrystallized successively from n-heptane, n-hexane and acetonitrile, each time using decolorizing charcoal. There was thus obtained 3.5 g. of ethyl 7- chloro-4-(Z-diethylaminoethylamino) 3 quinolinecarboxylate, M.P. 97.0100.6 c.

Analysis.Ca1cd. for C H ClN O Cl, 10.13; N, 12.01. Found: Cl, 10.17; N, 11.74.

EXAMPLE 10 Ethyl 4 (Z-diethylaminoethylamino)-3-quinolinecarboxylateA mixture containing 10.0 g. of ethyl 4-chloro- 3-quinolinecarboxylate, 4.9 g. of Z-diethylaminoethylamine and 10.0 g. of phenol was heated at 100 C. for twenty hours with stirring. The reaction mixture was poured into dilute hydrochloric acid. The acidic solution was extracted with chloroform, made strongly basic with 35% aqueous sodium hydroxide solution, and the alkaline solution extracted with chloroform. The second chloroform extract was washed with Water, dried over anhydrous potassium carbonate and evaporated to yield an oil which solidified. The solid was recrystallized once from n-hexane and once from n-pentane to yield 2.7 g. of ethyl 4-(Z-diethylaminoethylamino)-3-quinolinecarboxylate, M.P. 72.072.8 C. (corn).

Analysis.Calcd. for C18H25N302I C, H, N, 13.32. Found: C, 68.71; H, 8.18; N, 13.26.

EXAMPLE 11 EXAMPLE 12 Ethyl 7-chloro-4-(S-diethylarnino 2 pentylamino)-3- quinolinecarboxylateA slurry containing 27.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate and 39.5 g. of 5-diethylamino-Z-pentylamine was stirred until an exothermic reaction resulted whereupon the temperature rose to about C. The reaction mixture was allowed to stand over- 7 night at room temperature, and then treated with 300 ml. of water and 25 ml. of 35 aqueous sodium hydroxide solution. The alkaline solution was extracted with chloroform; the chloroform extract was washed with water, dried over anhydrous potassium carbonate, and then evaporated under reduced pressure. The excess 5-diethylamino-2-pentylamine was removed by warming the mixture in a rotating evaporator at 0.2 mm; The residue was dissolved in 700 ml. of absolute ethanol, the ethanol solution warmed on a steam bath, and 168 ml. of 1 M phosphoric acid in absolute ethanol was added with stirring. Sufiicient water was added tomake the solution almost clear and it was 7 then allowed to cool overnight with stirring. The precipitate was collected, washed with absolute ethanol and dried at 55 C. and 25 mm. to yield 37.8 g. of ethyl 7-chloro- 4-(5-diethylamino 2 pentylamino)-3-quinolinecarboxylate as is diph-osphate. 20 g. of this product was recrystallized using 40 ml. of hot water and 600 m1. of hot absolute ethanol. The recrystallized product was collected and found to melt at 190.4-191.0 C. (corn), with decomposition.

Analysis.-Calcd. for C21H3QC1N3O2.2H3P04: N, Cl, 6.03. Found: N, 7.17; Cl, 6.20.

EXAMPLE l3 Ethyl 7 chloro-4-(3-dimethylaminopropylamino) 3- quinolinecarboxylate as its diphosphate was obtained following the procedure described in Example 12 using 27.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate and 25.3 g. of 3-dimethylaminopropylamine. There was thus obtained 45.3 g. of the product, M.P. 2l7.0217.8 C. (corr.), with decomposition.

Analysis.Calcd. for C17H2 ClN3.2H3PO4I Cl, 6.66; N, 7.90. Found: Cl, 6.76; N, 7.73.

EXAMPLE 14 Ethyl 7-chloro-4-(3-diethylamino 2 hydroxypropylamino)-3-quinolinecarhoxylate was prepared following the procedure described in Example 12 using 27.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate and 36.5 g. of 3-diethylarnino-2-hydroxypropylamine. The product was recrystallized once from isopropyl alcohol-acetonitrile and then purified further by placing it in a Soxhlet extractor and continuously extracting it with n-hexane. The first extract obtained after two hours and the second extract obtained after two additional hours were combined and evaporated in vacuo to yield 16.8 g. of the product, ethyl 7-chloro-4-(3-diethylamino 2 hydroXypropylamino)-3- quinolinecarboxylate, M.P. ll5.2-1l6.8 C. (corn).

Analysis.Calcd. for C H ClN O Cl, 9.33; N, 11.06. Found: Cl, 9.37;N, 11.34.

Ethyl 7-chloro-4-(3-diethylamino 2 hydroxypropylamino)-3-quinolinecarboxylate was converted into its diphosphate acid-addition salt as follows: To a solution containing 57 g. of ethyl 7-chloro-4-(3-diethylamino-2-hydroxypropylamino)-3-quinolinecarboxylate in 650 ml. of ethanol at 50 C. was added dropwise, with stirring over a period of twenty minutes, a solution containing 34.5 g. of 85% phosphoric acid dissolved in a mixture of 100 ml. of ethanol and 10 ml. of water, whereupon a crystalline precipitate resulted. The mixture was heated at reflux for fifteen minutes and cooled in an ice bath. The precipitate was collected, Washed successively with 100 ml. of ethanol and 100 ml. of n-hexane, and dried at 65 in vacuo for three hours to yield 86 g. of ethyl 7-chloro-4-(3-diethylamino-Z-hydroxypropylamino)-3-quinolinecarboxylate diphosphate, M.P. 217.0-2l8.0 C. (corn) with decomposition.

Analyis.Calcd. for C H ClN O 2H PO Base, 65.97%; N, 7.30; P, 10.77. Found: Base, 66%; N, 7.15; P, 11.02.

A 2 g. portion of the diphosphate was converted to l g. of the base, M.P. l13115 C.

Following the procedure described in Example 1 using corresponding molar equivalent quantities of the respective reactants and phenol, the compounds of Examples 1527 are prepared.

EXAMPLE 15 N-(Z-piperidinoethyl) 7 chloro-4-(2-piperidinoethylamino)-3-quinolinecarboxamide, using ethyl 4,7-dichloro- 3-quinolinecarboxylate and Z-piperidinoethylamine.

EXAMPLE 16 N-(Z-pyrrolidinoethyl) 5 chloro-4-(2-pyrrolidinoethylamino)-3-quinolinecarboxamide, using ethyl 4,5-dichloro-3-quinolinecarboxylate and 2 pyrrolidinoethylamine.

10 EXAMPLE 17 N-(2-morpholinoethyl) 6 methoxy-4-(2-morpholinoethylamino) 3 quinolinecarboxamide, using ethyl 4- chloro-6-methoxy 3 quinolinecarboxylate and Z-morpholinoethylamine.

EXAMPLE 18 N-[2-(4-ethylpiperidino)ethyl] 7 bromo-4-[2-(-4- ethylpiperidino)ethylamino] 2 quinolinecarboxamide, using ethyl 7-bromo-4-chloro-Z-quinolinecarboxylate and 2- (4-ethylpiperidino ethylamine.

EXAMPLE 19 N [2 (2,5 dimethylpyrrolidino)ethyl]-6,7-dimethoxy 4 [2 (2,5 dimethylpyrrolidino)ethylamino]- 3-quinolinecarboxamide, using ethyl 4-chloro-6,7-dimethoxy 3 quinolinecarboxylate and 2-(2,5-dimethy1pyrrolidino) -ethyl amine.

EXAMPLE 20 N [2 (N' ethyl-N-2-hydroxyethylamino)ethyl]-4- [2 (N ethyl-N-2-hydroxyethylamino)ethylamino]-7- methyl-3-quinolinecarboxamide, using ethyl 4-chloro-7- methyl 3 quinolinecarboxylate and 2-(N-ethyl-N-2-hydroxyethylamino)-ethylamine.

EXAMPLE 21 N-[5-(N-ethyl-N'-2-hydroxyethylamino) 2 pentyl]- 4-[5-(N ethyl-N'-2-hydroxyethylamino) 2 pentylamino]-3-quinolinecarboxamide, using ethyl 4-chlor0-3- quinolinecarboxylate and 5-(N-ethyl-N-2-hydroxyethylamino) -2-pentylamine.

EXAMPLE 22 N- (Z-di-n-butylaminoethyl) -4- (2-di-n-butylaminoethylamino)-3-quinolinecarboxaxmide, using ethyl 4-chloro-3- quinolinecarboxylate and 2-di-n butylaminoethylamine.

EXAMPLE 23 N-(Z-di-n-hexylaminoethyl)-4-(2-di-n-hexylaminoethylamino)-7-trifluoromethyl-2-quinolinecarboxamide, using ethyl 4 -'chloro 7 trifluoromethyl 2 quinolinecarboxylate and 2-n-hexylaminoethylamine.

EXAMPLE 24 N (6-dimethylaminohexyl) 7 chloro 4 (6-dimethylarninohexylamino) 3 quinolinecarboxarnide, using ethyl 4,7-dichloro-3quinolinecarboxylate and 6-dimethylaminohexylamine.

EXAMPLE 25 N [2 (2 diethylaminoethylmercapto)ethyl] 7- chloro 4 [2 (2 diethylaminoethylmercapto)ethylamino] -3-quinolinecarboxamide, using ethyl 4,7-dichlor0- S-qninolinccarboxylate and 2-(2-diethylaminoethylmercapto)ethylamine.

' EXAMPLE 26 N [3 (2 dimethylaminoethoxy)propyl] 4 [3 (2- dimethylaminoethoxy)propylamino] 3 quinolinecarboxamide, using ethyl 4-chloro-3-quinolinecarboxylate and 3-(Z-dimethylaminoethoxy)propylamine.

EXAMPLE 27 N (2 diethylaminoethyl) 4 (2 diethylaminoethylamino)-7-nit.ro-3-quinolinecarboxamide, using ethyl 4- chloro-7-nitro-3-quinolinecarboxylate and 2- diethylaminoethylamine.

Following the procedure described in Example 12 using corresponding molar equivalent quantities of the respective reactants, the compounds of Examples 28-39 are prepared.

EXAMPLE 28 Ethyl 5-chloro-4-(2-piperidinoethylamino)-3-quinolinecar-boxylate, using ethyl 4,5-dichloro-3quinolinecarboxylate and 2-piperidinoethylamine.

1 1 EXAMPLE 29 Isopropyl 7-chloro-4-(2-pyrrolidinoethylamino)-3-quinolinecarboxylate, using isopropyl 4,7-dichloro-3-quinolinecanboxylate and 2-pyrrolidinoethylamine.

EXAMPLE 3O Ethyl 8 ethxy-4-(2-morpholinoethylamino)-3-quinolinecarboxylate, using ethyl 4-chloro-8-ethoxy-3-quinolinecarboxylate and 2-morpholinoethylamine.

EXAMPLE 31 Methyl 4 [2-4-ethylpiperidino)ethylamino] 7 methyl-3-quinolinecarboxylate, using methyl 4-chlor0-7-methyl-3-quinolinecarboxylate and 2-(4-ethylpiperidino)-ethylamine.

EXAMPLE 32 Ethyl 7 chloro-4-[3-(Z-dimethylaminoethoxy)propylamino]-3-quinolinecarboxylate, using ethyl 4,7-dichloro- S-quinolinecarboxylate and 3-(2-dimethylaminoethoxy) propylamine.

EXAMPLE 38 Ethyl 4 [2 (2 diethylaminoethylmercapto)ethylamino] -3-quinolinecarboxylate, using ethyl 4-chloro-3- quinolinecarboxylate and 2 (2 diethylaminoethylmercapto)ethylamine.

EXAMPLE 39 Ethyl 4 (2 diethylaminoethylamino) 7 nitro 3- quinolinecarboxylate, using ethyl 4-chloro-7-nitro-3-quino- 'linecarboxylate and 2-diethylaminoethylamine.

Following the procedure described in Example 1 using equimolar quantities of the appropriate lower-alkyl 4- (tertiary-aminoalkylamino)-3-quinolinecarboxylate (Formula IV) and (lower-tertiary-amino)-lower-all ylamine (Formula Illa), the compounds of Examples 40-47 are prepared. 7

EXAMPLE 4O 4 (2 diethylaminoethylamino) 7 chloro N (2- piperidinoethyl)-3-quinolinecarboxamide, using ethyl 7- chloro-4-( Z-diethylaminoethylamino) -3-quinolinecarb0xylate and 2-piperidinoethylamine.

EXAMPLE 41 4 (2 diethylaminoethylamino) N [2-N-ethyl-N'- 2-hydr0xyethyl amino ethyl] -3-quinolinecarboxamide, using ethyl 4-(Z-diethylaminoethylamino)-3-quinoline-car- 12 boxylate and 2-(N-ethyl-N-Z-hydroxyethylamino)ethylamine.

EXAMPLE .42

4 (3 diethylaminopropylamino) N (2 dimethylaminoethyl)-3-quinolinecarboxamide, using ethyl 4-(3- diethylaminopropylamino)-3-quin0linecarboxylate and 2- dimethylaminoethylamine.

EXAMPLE 43 7-chloro-N-(Z-diethylaminoethyl) 4-(5-diethylamin0- Z-pentylamino)-3-quinolinecarboxamide, using ethyl 7- chloro 4 (S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate and Z-diethylaminoethylamine.

EXAMPLE 44 p 7 chloro 4-(3-dimethylaminopropylamino)-N-(2- pyrrolidinoethyl)-3-quinolinecarboxamide, using ethyl 7- chloro 4 (3-dimethylaminopropylamino)-3-quinolinecarboxylate and 2-pyrrolidinoethylamine.

EXAMPLE 45 7 chloro 4-(3-diethylamino-2-hydroxypropylamino)- N (6-dimethylaminohexyl) 3-quinolinecarboxarnide, using ethyl 7-ch1or0-4-(3-diethylamino-2-hydroxypropylamino 3-quinolinecarboxylate and 6 dimethylaminohexylamine.

' EXAMPLE 46 5 chloro N-(3-diethylamino-2-hydroxypropyl)-4- (Z-piperidinoethylamino) 3-quinolinecarboxamide, using ethyl 5-chl0ro-4-(2-piperidin0ethylamino) -3-q-uinolinecarboxylate and 3-diethylamino-2-hydroxypropylamine.

EXAMPLE 47 7 chloro 4 (2 diethylaminoethylamino)-N-(3- dimethylaminopropyl) 2 quinolinecarboxamide, using ethyl 7-chloro-4-(2-diethylaminoethylamino)-'3-quino1inecarboxylate and 3-dimethylaminopropylamine.

EXAMPLE 4s n-Propyl 4-[2-(2,5-dimethylpyrrolidino)ethyl-amino]- 2-quinolinecarboxylate is prepared following the procedure described in Example 10 using corresponding molar equivalent quantities of n-propyl 4-chl'or o-2-quinolinecar-.

boxylate and 2-(2,5-dimethylpyrrolidino)ethylamine.

EXAMPLE 49 n-Hexyl 7 chloro- 4- (Z-diethylaminoethylamino)-2- quinolinecarboxylate is prepared following the procedure described in Example 10 using corresponding molar equivalent quantities of n-hexyl 4,7-dichloro-2-quinolinecarboxylate and Z-diethylaminoethylamine.

EXAMPLE 50 Ethyl 7 chloro-4-(Z-diethylaminoethylamino)-2-quinolinecarboxylate is prepared following the procedure described in Example 10 using corresponding molar equivalent quantities of ethyl 4,7-dichloro-2-quinolinecarboxylate and Z-diethylaminoethylamine.

EXAMPLE 51 Ethyl 7 chloro 4-(3-diethylaminopropylamino)-3- quinolinecarboxylate-To 54 g. of ethyl 4,7-dichl0ro-3- quinolinecarboxylate was added 65 g. of 3-diethylaminopropylamine and the resulting mixture was stirred overnight at room temperature. The reaction mixture was taken up in about'SOO ml. of n-hexane and 200 ml. of 10% aqueous sodium hydroxide solution. A creamy white precipitate settled out in the hexane phase. The two phases were separated and the aqueous phase was extracted twice with ml. portions of n-hexane. The hexane extracts were combined with the hexane phase and the resulting mixture was filtered to remove some White crystalline product Which was air-dried to yield 435 g, of ethyl 7- chloro 4 (3 diethylaminopropylamino)-3-quinolinecarboxylate, M.P. 63.565.0 C. The hexane filtrate yielded more crystalline precipitate on standing; to this mixture was added sufficient ether to dissolve the precipitate and the resulting solution was washed with three 100 ml. portions of water, dried over anhydrous sodium sulfate, and then cooled to yield more of the white crystalline product. This additional portion of the product was washed with cold n-hexane and dried overnight in vacuo at 45 C. to yield 37.1 g. of ethyl 7-chloro-4-(3- diethylaminopropylamino) 3-quinolinecarboxylate, M.P. 71.8-73.6 C .(corr.).

Analysis.Calcd. for C19H2C1N302I Cl, N, 11.95, Found: Cl, 9.79; N, 11.44.

EXAMPLE 52 Ethyl 7 chloro 4 (2 morpholinoethylamino)-3- quinolinecarboxylateTo 27.0 g. of ethyl 4,7-dichloro- 3-quinolinecarboxylate was added 32.5 g. of 2-morpholinoethylamine; considerable heat evolved and a precipitate began to separate before the addition of the morpholinoethylamine had been completed. After allowing the reaction mixture to stand overnight at room temperature, the precipitate was collected, taken up in about 250 ml. of hot chloroform and about 100 ml. of 10% aqueous sodium hydroxide solution, and shaken well. The two phases were separated and the alkaline aqueous phase was extracted with 100 ml. of chloroform; this chloroform extract was combined with the chloroform phase. The resulting chloroform solution was washed twice with about 100 ml. of water, dried over anhydrous sodium sulfate and evaporated by heating in vacuo on a steam bath to yield a solid which was recrystallized from benzene to yield 29.8 g. of the product, ethyl 7-chloro-4-(2-morpholinoethylamino) 3 quinolinecarboxylate, M.P 151.0- 154.0 C. (corr.).

Anaylsis.Calcd. for CmHgzClNgOgI 11.56. Found: Cl, 10.00; N, 11.64,

EXAMPLE 5 3 Ethyl 7-benzyloxy-4-(5-diethylamino-2-penty1amino)- 3-quinolinecarboxylate-A mixture containing 23.9 g. of ethyl 7-benzyloxy-4-chloro-3 quinolinecarboxylate and 27.8 g. of 5-diethylamino-2-pentylamine was stirred and then allowed to stand for three days. The reaction mixture was then stirred on a steam bath for about two hours, cooled and taken up with a mixture of 250 ml. of chloroform and 100 ml. of 10% aqueous sodium hydroxide solution. The mixture was shaken well and the layers separated. The aqueous layer was washed with about 100 ml. of chloroform and the chloroform washing was added to the original chloroform layer. The combined chloroform solution was washed successively with 100 ml. of 10% aqueous sodium bicarbonate solution and twice with 100 ml. portions of water. The chloroform solution was then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo on a steam bath to yield a dark liquid. The liquid was distilled in vacuo to remove the excess starting alkylenediamine and the remaining oil was taken up in 50 ml. of hot absolute ethanol. The hot ethanol solution Was added to 68 ml. of hot ethanolic 1 M phosphoric acid solution, whereupon a red gummy material separated. A small quantity of methanol plus ml. of water and more absolute ethanol was added and the resulting mixture was triturated on the steam bath for about ten minutes and then allowed to cool and stand at room temperature overnight. The resulting crystalline precipitate was collected, washed with absolute ethanol and dried in vacuo at 55 C. overnight to yield 21.1 g. of ethyl 7-benzyloxy 4-(S-diethylamino-2-pentylamino)-3- quinolinecarboxylate diphosphate. A 5.0 g. sample was recrystallized by dissolving it in 30 ml. of hot water, adding decolorizing charcoal, filtering the mixture through infusorial earth (Super-Cel), adding 300 ml. of hot absolute ethanol to the hot filtrate and allowing the mixture to cool. The white crystalline product was collected,

Cl, 9.75; N,

washed with small portions of the mother liquor and dried in vacuo at 55 C. overnight to yield 3.4 g. of said diphosphate, M.P. 161.5-1635" C.

Anwlysis.Calcd for C21H31H3032H3PO4I N, P, 9.39. Found: N, 6.55; P, 9.79.

The above intermediate ethyl 7-benzyloxy-4-chloro-3- quinolinecarboxylate was prepared in two steps as folliows: A mixture containing 138.2 g. of 3-benzyloxyaniline and 165.2 g. of diethyl ethoxymethylenemalonate was heated on a steam bath for one hour and then allowed to cool to room temperature. The resulting crystalline diethyl N-(B-benzyloxyanilino)-methylenemalonate was dissolved in 700 ml. of Dowtherm A (eutectic mixture of diphenyl and diphenyl ether) and the solution heated with stirring to 250 C. and maintained at this temperature for fifteen minutes, while distilling olf ethanol formed by the reaction (51 ml. of ethanol collected). The reaction mixture was cooled and allowed to stand at room temper-ature overnight. The resulting solid was collected by filtration, washed with n-hexane, tritu-rated in about 800 ml. of hot methanol, collected again by filtration, and then dried in vacuo at 55 C. overnight to yield 75.1 g. of ethyl 7 benzyloxy-4-hydroxy-3-quinolinecarboxylate, M.P. 281 C. A mixture containing 25.0 g. of ethyl 7- benzyloxy-4-hydroxy-3-quinolinecarboxylate, 13.4 g. of phosphorus oxychloride and 220 ml. of ethylene dichloride was refluxed with stirring on a steam bath for two hours. The reaction mixture was then cooled and kept below 25 C. while adding dropwise to it 60 ml. of water. The phases were separated and allowed to stand at room temperature overnight. To the ethylene dichloride phase containing a small quantity of separated solid was added 150 ml. of 35% aqueous sodium hydroxide solution and the mixture shaken well. The ethylene dichloride phase was separated, washed twice with 250 ml. portions of water, dried over anhydrous sodium sulfate overnight and filtered through anhydrous sodium sulfate. The filtrate was concentrated in vacuo on a steam bath to yield 23.9 g. of crystalline ethyl 7-benzyloxy-4-chloro3-quinolinecarboxylate.

EXAMPLE 54 Ethyl 4- (S-diethylamino-2-pentylamino -7-hydroxy-3- quinolinecarboxylate was prepared by catalytic hydro genation of the corresponding 7-benzyloxy compound or Example 53, as follows: A 6.6 g. portion of ethyl 7- benzyloxy-4-(5-diethylamino-2-pentylamino) 3 qlllllulinecarboxylate diphosphate in 100 ml. of aqueous ethanol was hydrogenated at atmospheric pressure (753 mm.) and room temperature (31 C.) in the presence or 0.5 g. of 10% palladium-on-charcoal. The theoretical volume of hydrogen was taken up in forty minutes. The catalyst was filtered off and the filtrate evaporated to cloudiness and allowed to stand at room temperature whereupon the crystalline product separated. Isopropyl alcohol was added to the mixture in small portions until no further product separated. The solid product was collected, washed with isopropyl alcohol, dried overnight at 50 C. and 20 mm., recrystallized from ethanol-water and dried for eighteen hours at 50 C. and 20 mm. to yield 4.8 g. of ethyl 4-(5-diethylamino-Z-pentylamino)-7- hydroxy-3-quinolinecarboxylate diphosphate, M.P. 203.0- 205.0 C. (corr.) with decomposition.

Analysis.Calcd. for C21H31N3032H3P04Z N, P, 10.88. Found: N, 7.56; P, 10.95.

EXAMPLE 55 n Propyl 7 chloro 4 (5 diethylamino 2 pentylamino)-3-quinolinecarboxylateA mixture containing 12.75 g. of ethyl 7-chloro-4-(S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate in 50 ml. of benzene and a solution containing 0.5 g. of sodium dissolved in n-propanel was refluxed on a steam bath for three days. The reaction mixture was taken up in 500 ml. of benzene and washed twice with 200 m1. portions of hot water, dried over anhydrous sodium sulfate, and filtered through anhydrous sodium sulfate. The filtrate was concentrated by heating it in vacuo to yield a dark liquid residue. The liquid residue was taken up in 50 ml. of hot absolute ethanol and the resulting hot solution was added to 51 ml. of hot ethanolic 1 M phosphoric acid solution to yield an amber oil. Small amounts of methanol and water were added whereupon some of the oil dissolved. The mixture was triturated while allowing to cool, whereupon a gummy precipitate became crystalline. The crystalline product was collected, washed with small portions of the mother liquor and dried in vacuo at 55 C. for three days. The product was recrystallized by dissolving it in 20 ml. of hot water, filtering the solution, adding to the filtrate 600 m1. of absolute ethanol and 200 ml. of absolute ether, and cooling the solution overnight. The resulting crystalline product was collected, washed with absolute ether and dried in vacuo at 55 C. overnight to yield 3.2 g. of n-propyl 7-chloro-4- -diethylamino-2-pentylamino -3-quinolinecarboxylate diphosphate, M.P. 154.5158.5 C.

Analysis.Calcd. for C H ClN O -2H PO N, 6.98; P, 10.29. Found: N, 6.91; P, 10.24.

EXAMPLE 5'6 Methyl 7 chloro 4 (5 diethylamino 2 pentylamino)-3-quinolinecarboxylateA mixture containing 12.75 g. of ethyl 7-chloro-4-(5-diethylamino-2-pentylamino)-3-quinolinecarboxylate in 50 ml. of benzene and 1.0 g. of sodium methoxide in 100 ml. of methanol was refluxed on a steam bath for three days. The reaction mixture was taken up in 500 ml. of benzene and washed twice with 250 m1. portions of warm water, dried over anhydrous sodium sulfate and filtered through anhydrous sodium sulfate. The filtrate was concentrated by heating it in vacuo on a steam bath to yield a liquid which was taken up in 50 ml. of hot absolute ethanol. The hot solution was added to 66 ml. of hot 1 M ethanolic phosphoric acid solution. A yellow gum separated. Small amounts of methanol and water were added to the mixture which was heated on a steam bath whereupon partial dissolution of the gum resulted. The mixture was allowed to cool and the gummy material was triturated. The resulting mixture was allowed to stand overnight whereupon some crystals formed along with the gummy material. The mixture was triturated whereupon all of the gummy material became crystalline. The crystalline product was then collected, washed with small portions of the mother liquor and dried in vacuo at 55 C. overnight. The product was recrystallized by dissolving it in 25 ml. of hot water, filtering the solution and adding to the filtrate 450 ml. of absolute ethanol to cloudiness and allowing the mixture to cool and stand overnight. The resulting crystalline product was collected, washed with small portions of the mother liquor and dried in vacuo at 55 C. overnight to yield 13.8 g. of methyl 7-chloro-4-(5-diethylamino-2 pentylamino)-3- quinolinecarboxylate diphosphate, M.P. 182-183 C.

Analysis.Calcd. for C2QHZ8CIN3O2'ZH3PO4Z N, P, 10.80. Found: N, 7.33; P, 10.64.

EXAMPLE 57 Ethyl 4-(S-diethylamino-Z-pentylamino)-7-methoxy-3- quinolinecarboxylate-A mixture containing 18.3 g. of ethyl 4-chloro-7-methoxy-3-quinolinecarboxylate and 27.4 g. of 5-diethylamino-2-pentylarnine was stirred for five hours and then with continued stirring, was heated on a steam bath for one hour and cooled. The reaction mixture was taken up in 250 ml. of chloroform and then extracted with 100 ml. of 10% aqueous sodium hydroxide solution.

The remaining chloroform solution was washed successively with 100 ml. of 10% aqueous sodium bicarbonate solution and twice with 150 ml. portions of water, dried over anhydrous sodium sulfate and filtered through anhydrous sodium sulfate. The filtrate was distilled in vacuo to remove the excess S-diethylamino-2-pentylamine. The remaining 25.3 g. of residue was taken up in 100 ml. of

hot absolute ethanol and added to 131 ml. of hot 1 M ethanolic phosphoric acid solution whereupon a gummy precipitate resulted. Small amounts of methanol and water were added, and to the resulting stirred mixture at about 50 C. was added isopropyl alcohol until cloudiness resulted. The mixture was allowed to cool to room temperature and was stirred overnight. The crystals which had formed were collected, washed with small portions of the mother liquor, dried in vacuo at 55 C. overnight and then recrystallized by dissolving them in 50 ml. of hot water, treating the solution with decolorizing charcoal, filtering the mixture through infuson'al earth, and adding 300 ml. of isopropanol to the filtrate. There separated a semi-crystalline oily material which crystallized completely when cooled and allowed to stand overnight. There was thus obtained 13.2 g. of ethyl 4-(5-diethylamino-2- pentylarnino)-7-methoxy-3-quinolinecarboxylate diphosphate, M.P. -1125 C.

AHQIYSiSr-CfllCd. for C22H33N303'2H3PO41 N, P, 10.62. Found: N, 7.30; P, 10.70.

EXAMPLE 5 8 Ethyl 7 chloro-4-[5-(N ethyl-N-Z-hydroxyethylamino)-2-pentylamino] 3-quinolinecarboxylate-54.0 g. of ethyl 4,7-dichloro-3-quinolinecarboxylate and 87.0 g. of 5 (N-ethyl-N-Z-hydroxyethylamino) 2 pentylamine were mixed with stirring whereupon there was considerable evolution of heat. The resulting mixture was allowed to cool to room temperature and was stirred at this temperature overnight. The reaction mixture was taken up in about 500 ml. of chloroform and 200 ml. of 10% aqueous sodium hydroxide solution. The resulting mixture was shaken well and the chloroform phase was separated, washed with 100 ml. of water, dried over anhydrous sodium sulfate and then concentrated in vacuo to remove the starting alkylenediamine and to yield in crude free base form the product, ethyl 7-chloro-4-[5-(N-ethyl- N-Z-hydroxyethylamino) 2 pentylamino] 3 quinolinecarboxylate. A portion of the base was converted into its dihydrochloride salt as follows: 19.8 g. of said base was dissolved in ml. of hot isopropyl alcohol and the solution treated with 10 ml. of concentrated hydrochloric acid. When no precipitate separated, the solvent was removed by distilling in vacuo. The residue was triturated with isopropyl alcohol and ethyl acetate, and the mixture cooled at 3 C. for three days. The resulting semi-crystalline gummy material was separated and triturated with absolute ether, and the mixture cooled. The resulting crystalline product was collected, washed with small portions of absolute ether and dried in vacuo at 55 C. overnight. This product was further purified by dissolving it in 70 ml. of hot absolute ethanol, treating the solution with decolorizing charcoal, filtering the mixture through infusorial earth, cooling the filtrate, separating the resulting gummy material, triturating the gummy material with 340 ml. of absolute ether, cooling the mixture, separating the resulting crystalline product, washing it with absolute ether and drying it in vacuo at 55 C. overnight to yield 16.8 g. of ethyl 7-chloro-4-[5-(N- ethyl-N-2 hydroxyethylamino) 2 pentylamino]-3- quinolinecarboxylate dihydrochloride, M.P. 1-69.'0170.0' C. (corn) with decomposition.

' Analysis.Calcd. for C H ClN O -2HCl: Cl, 22.12; N, 8.74. Found: Cl, 21.88; N, 8.70.

EXAMPLE 59 Ethyl 4 (5 diethylamino 2 pentylamino)-3-quinolinecarboxylate47.14 g. of ethyl 4-chloro-3-quinolinecarboxylate was mixed while stirring with 79.2 g. of 5- diethylamino-Z-pentylamine whereupon an exothermic reaction resulted. The reaction mixture was stirred overnight and then taken up with a mixture of 200 ml. of 10% aqueous sodium hydroxide solution and 500 ml. of n-hexane-benzene (4:1 ratio). The phases were separated and the alkaline phase was extracted twice with 100 ml.

portions of 4:1 n-hexane-benzene and the extracts were combined with the n-hexane-benzene phase. The resulting n-hexane-benzene solution was washed twenty times with 100 ml. portions of water, dried over anhydrous sodium sulfate and heated on a steam bath in vacuo using a water aspirator to yield 66.9 g. of the crude oily product in free base form. A 31.5 g. portion of the crude free base form was dissolved in 150 ml. of isopropyl alcohol and the solution treated with 18 ml. of concentrated hydrochloric acid. When no precipitate separated, the alcohol was removed by distilling in vacuo. The semi-crystalline product was recrystallized once from absolute ethanol (175 ml.)-absolute ether (1600 ml.) and once from isopropyl alcohol (100 ml.)-absolute ether (375 ml), using a decolorizing charcoal treatment on the hot isopropyl alcohol solution, to yield 32.0 g. of ethyl 4-(5 diethylamino 2 pentylamino) 3 quino linecarboxylate dihydrochloride, M.P. 176.0176.5 C. (corn) with decomposition, after drying in vacuo at 55 C. for three days.

Analysis.-Calcd. for C21H31N302.2HC11 C, H, 7.73; Cl, 16.48; N, 9.76. Found: C, 58.59; H, 8.00; Cl, 16.54; N, 9.86.

I claim:

I. A compound of the formula where Y and Y are each lower-alkylene having from two to six carbon atoms and having its conecting linkages on different carbon atoms, NB and NB are each tertiaryamino selected from the group consisting of di- (lower-alkyl)amino, N-(lower-alkyl) N (lower-hydroxyalkyhamino, piperidino, (lower-alkyl) piperidino, pyrrolidino, (lower-alkyl) pyrrolidino and morpholino.

2. A compound according to claim 1 in which --CONHYNB is attached at the 3-position of the quinoline nucleus, and NB and NB are each N(lower alky1) 3. N-(2 diethylaminoethyl) 4 (2 diethylaminoethylamino) 3 quinolinecarboxamide according to claim 2 in which Y and Y are each CH CH and loweralkyl in each instance is C 11 4. N (2 diethylaminoethyl) 7 chloro 4 (2- diethylaminoethylamino) 3 quinolinecarboxamide according to claim 2 in which Y and Y are each CH CH lower-alkyl in each instance is C H and the quinoline nucleus is substituted at its 7-position by chloro.

5. N (2 dimethylaminoethyl) 7 chloro 4 (2- dimethylaminoethylamino) 3 quinolinecarboxamide according to claim 2 in which Y and Y are each CH CH lower-alkyl in each instance is CH and the quinoline nucleus is substituted at its 7-position by chloro.

6. N-(Z-dimethylaminoethyl) 4 (2 dimethylaminoethylamino)-3-quinolinecarboxamide according to claim 2 in which Y and Y are each CH CH and lower-alkyl in each instance is CH 7. N-(2-diethylaminoethyl) 7 chloro 4 -(2-diethylaminoethylamino)-2-quinolinecarboxamide according to claim 1 in which CONH--Y'NB' is attached at the 2-position of the quinoline nucleus, Y and Y are each CH CH NB and NB are each N(C H and the quinoline nucleus is substituted at its 7-position by chloro.

8. A compound of the formula C O O-(lower-alkyl) and Y is lower-alkylene having from two to six carbon atoms and having its connecting linkages on different carbon atoms and NB is tertiary-amino selected from the group consisting of di-(lower-alkyDarnino, N-(loweralkyl)-N-(lower-hydroxya1kyl)amino, piperidino, (loweralkyl)-piperidino, pyrrolidino, (lower-alkyl)-pyrrolidino and morpholino.

9. A compound according to claim 8 in which COO-(loWer-alkyl) is attached at the 3-position of the quinoline nucleus and NB is N(lower-alkyl) 10. Ethyl 4-(3-diethylaminopropylamino)-3-quin0linecarboxylate according to claim 9 in which Y is CH CH CH and lower-alkyl in each instance is C H 11. Ethyl 4- (2-diethylaminoethylamino)-3-quinolinecarboxylate according to claim 9 in which Y is CH CH and lower-alkyl in each instance is C H 12. Ethyl 7-chloro-4-(2 diethylaminoethylamino)-3- quinolinecarboxylate according to claim 9 in which Y is CH CH lower-alkyl in each instance is C H and the quinoline nucleus is substituted at its 7-position by chloro.

13. Ethyl 7-chloro-4-(5-diethylamino-2-pentylamino)- 3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH )CH CH CH N (C H -COOC H is attached at the 3-position of the quinoline nucleus, and the quinoline nucleus is substituted at its 7-position by chloro.

14. Ethyl 7-chloro-4-(3 dimethylaminopropylamino) 3-quinolinecarboxylate according to claim 9 in which YNB is CH CH CH N (CH lower-alkyl is C H and the quinoline nucleus is substituted at its 7-position by chloro.

15. Ethyl 7-chloro-4-(3-diethylamino-2-hydroxypropylamino)3-quinolinecarboxylate according to claim 9 in which YNB is CH CH(OH)CH TN(C H loweralkyl is ethyl, and the quinoline nucleus is substituted at its 7-position by chloro.

16. Ethyl 7-chloro-4-(3 diethylaminopropylamino)-3- quinolinecarboxylate according to claim 9 in which YNB is CH CH CH N(C H lower-alkyl is ethyl, and the quinoline nucleus is substituted at its 7-position by chloro.

17. Ethyl 7 chloro 4 (2-morpholinoethylarnino)-3- quinolinecarboxylate according to claim 8 in which Y is CH CH NB is morpholino, -COOC H is attached at the 3-position of the quinoline nucleus, and, the quinoline nucleus is substituted at its 7-position by chloro.

18. n-Propyl 7 chloro 4 (S-diethylamino-Z-pentylamino)-3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH )CH CH CH N(C H COOCH CH CH is attached at the 3-position of the quinoline nucleus, and the quinoline nucleus is substituted at its 7-position by chloro.

19. Methyl 7-chloro-4-(S-diethylamino-2-pentylamino) 3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH )CH CH CH N(C H -COOCH is attached at the 3-position of the quinoline nucleus, and the quinoline nucleus is substituted at its 7-position by chloro.

20. Ethyl 7-chloro 4 [5-(N-ethyl-N-Z-hydroxyethylamino)-2-pentylamino] -3-quinolinecarboxylate according to claim 8 in which YNB is CH(CH CH CH CH N (C H (CH CH OH) OOOC H is attached at the 3-position of the quinoline nucleus, and the quinoline nucleus is substituted at its 7-position by chloro.

21. Ethyl 4-(5-'diethylamino-2-pentylamino) -3-quinolinecarboxylate according to claim 8 in which Y--NB is and is attached at the 3-position of the quinoline nucleus.

No references cited.

ALEX MAZEL, Primary Examiner.

I. TOVAR, Assistant Examiner.

UNITED STATES PATENT O FFICE CERTIFICATE OF CORRECTION Patent No. 3,362,954 January 9, 1968 Alexander R. Surrey It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2 line 24 "Y and Y are" should read Y=Y and line 25, "NB=NB"' should read NB NB Column 4, line 72, "3quinolinecarboxyamide should read 3- quinolinecarboxamide Column 5, line 14, "tubidity" should read turbidity line 72, "-3-quinolinecarboxy1ate" should read -3-quinolinecarboxamide Column 6, lines 35 and 36, "-3-quinolinecarpoxylate" should read -3-quinolinecarboxylate Column 11, line 12, "[2-4-ethylpiperidino)ethylamino]" should read [2-(4ethy1piperidino]ethylamino] line 73, [2N-ethyl-N"' should read [2- (N -ethyl-N Column 14, line 4, "C H31H3O3" and "7.38" ShOLlld read C28H37N203 and 6.37 respectively. Column 17, line 34, "conecting" should read connecting Signed and sealed this 13th day of January 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents

Claims

1. A COMPOUND OF THE FORMULA

8. A COMPOUND OF THE FORMULA

17. ETHYL 7 - CHLORO - 4 - (2-MORPHOLINOETHYLAMINO)-3QUINOLINECARBOXYLATE ACCORDING TO CLAIM 8 IN WHICH Y IS CH2CH2, NB IS MORPHOLINO, -COOC2H5 IS ATTACHED AT THE 3-POSITION OF THE QUINOLINE NUCLEUS, AND, THE QUINOLINE NUCLEUS IS SUBSTITUTED AT ITS 7-POSITION BY CHLORO.