Bartók, Mihály

Felföldi, K.

Kárpáti, E.

Laszlavik, M.

English

Felföldi K.

Laszlavik M.

Bartók Mihály

Kárpáti E.

University of Szeged

I CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXIII.* AMINOALKYL ESTERS OF XANTHENE-9-CARBOXYLIC ACID, II.** CHOLINOLYTIC AND BRÓNCHODILATOR ACTIVITY OF QUATERNARY SALTS OF NEW DIAMINOALKYL-XANTHENE-9-CARBOXYLATES By K. FELFÖLDI, M. LASZLAVIK, M. BARTÓK Department of Organic Chemistry, József Attila University, 6720 Szeged, Hungary and E. KÁRPÁTI Pharmacological Laboratory Chemical Works of Gedeon Richter Ltd., 1475 Budapest P.O.B. 27, Hungary (Received September 30, 1980) Quaternary salts of diaminoalkyl esters of xanthene-9-carboxylic acid were synthetized, and their cholinolytic and bronchodilator activities were examined as referred to atropine. The com-pounds were prepared by quaternization of the esters obtained from the appropriate diaminoalcohol and xanthene-9-carboxylic acid chloride. The connection was studied between the activity and the number of carbon atoms in the substituehts. An outstandingly good effect was observed for two compounds. The quaternary salts of aminoalkyl esters of xanthene-9-carboxylic acid are known to possess ganglion-blocking activity [1]. Some of them (Banthin, Probanthin) also display a strong cholinolytic effect [2]. It has further been reported [3] that the quaternary salts of certain esters of diaminoalcohols exhibit ganglion-blocking and hypotensive activity. Accordingly, we considered that the quaternary salts of diamino-alkyl-xanthene-9-carboxylates too migh well possess cholinolytic activity. The innervation of the respiratory tract is. known to be in part parasympathetic, and in part sympathetic. The parasympathetic innervation is ensured by the vagal nerve. The innervation of the vagus ensures the tonicity of the respiratory tract [4], and transection of the nerve or chemical blocking of the postganglionic efferent pathways results the dilation of the airways. Since the state of the airways is a deci-sive factor as regards the extent of pulmonary resistance [5], the possibility of in-fluencing the tonicity of the respiratory tract with pharmacons is of primary irppor-* Part XXII: M. Bartók, K. Felföldi, G. Bózóki—Bartók: Helv. Chim. Acta: 63, 2172 (1980) ** Part I: K. Felföldi, Á. Molnár, M. Bartók: Acta Chim. (Budapest) 91, 333 (1976). -164 K. FELFÛLDI, m. LASZLAVIK, M. BARTÔK and E. KÂRPÂT1 tance in respiratory diseases. In asthma, histamine brings about constriction of resp-iratory tracts directly, but nevertheless the main direction of the effect is a reflex one, and this arises via the mediation of the vagal nerve. This is proved by the fact that the asthmatic attacks of dogs can be reduced by cooling of the vagus or by administra-tion of atropine [6]. From the animal-experimental and clinical results it appears that acetylcholine or an enhanced parasympathetic activity plays a decisive role in the pathomechanism of chronic respiratory obstruction. In this case, cholinolytics are more effective than sympathomimetics, they have a longer duration of action, and they are free of side-effects [7]. In asthma, the sympathomimetics are the more effective, but combined administration of the two types of drug, with their different mechanisms of action, results in a greater and more lasting reaction than any one of them alone [8]. For this reason, after determining the cholinolytic activities of our new compounds, we also examined them with regard to bronchodilator activity. A close correlation was found between the cholinolytic and bronchodilator activities of the new compounds: the two activities vary in parallel. Both effects depend to a large extent on the numbers of carbon atoms in the hydrocarbon chain and in the substituents on the nitrogen atoms (Table III), similarly as was observed for the quaternary salts of aminoalkyl-xanthene-9-carboxalates with simpler struc-tures [9]. In both respects, the highest activity is displayed by 21. The activity changes are correlated most strongly with the variation in m, the maximum occurring for m = 3 (see 20, 21, 23, 26, 27 and 28). The increase of n from two to three likewise raises the activities (see the pairs 18 and 20, and 19 and 21). With the increase of the number of carbon atoms in the substituents Rx and R2 (n=m=3), the activities vary according to a maximum curve (see 16, 17, 21 and 24). If Rv and R2 form a ring with the nitrogen, the activities decrease strongly (see 21 and 25). Increase of the number of carbon atoms in the substituent R3 or the quaterniz-ing alkyl group reduces the activity values (see 21 and 22, and 21 and 23). High activities are similarly to be observed for 29, which has a slightly different structure. The esters were prepared by the reaction of the appropriate diaminoalcohol and xanthene-9-carboxylic acid chloride in anhydrous acetone or benzene. After boiling for a short time, the base was obtained in the customary way from the pre-cipitating hydrochloride salt, and was quaternized in a mixture of acetone and methanol. Two methods were used to prepare the diaminoalcohols: reaction of the appropriate diamine with haloalcohol (Method A), or reaction of dialkylamino-alkyl chloride with alkylamino-alcohol (Method B). Different methods were employed to prepare two of the diaminoalcohols 9 and 14 (see Experimental section). The dialkylamino-alkyl chlorides were prepared by known methods [10, 11]. A new methods was used to prepare 3-methyl- and ethylamino-propanol-1. Experimental Pharmacology. The pupilla diameter in mice ( C F L P ) was determined by the method of P U L E W K A et al [12]. Various doses of the substances were administered subcutaneously to groups of 10 animals. The peak pupilla dilations were averaged and plotted against log dose. The relative potencies were calculated from dose-response curves. CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXIII 165: The antispasmodic effects were examined on isolated guinea-pig ileum by the method of MAGNUS [13]. Acetylcholine (ACh) was employed as agonist. The exami-nation materials were tested on 10 preparations per dose, and the relative potencies were calculated from the ED50 values [14]. Isolated, intact guines-pig trachea was prepared according to the method of FARMER and COLEMAN [15]. The trachea was stimulated by square-wave pulse of supramaximal voltage and 1 msec duration, repeated for 5 sec with a frequency of 20 Hz in each minute. Cumulative dose-response curves were plotted from the inhibition of the rise in intraluminal pressure. For each substance 10 preparations were used. The relative potencies were calculated from the pA2 values [16]. The bronchial resistance of guinea-pigs was measured on the basis of the method of KONZETT and ROSSLER [17, 18]. The inhibition of the bronchostriction induced with intravenous ACh injections was plotted against log dose. The relative potencies. Table I Physical constants of R i \ I R / Compd. RI R2 R3 tl m Formula B. p. °C (Hgmm) n20 D Yield Method 1» CH3 CH3 CH3 2 2 C7H18N2O 85—88 (30) 1.4555 44 A 2 CH3 CH3 CH3 3 3 C9H22N2O 88—97 (7) 1.4612 43 A 3 C2H6 CH3 CH3 3 3 C10H24N2O 118—120 (25) 1.4585 38 A 4 b C2H6 C2H6 CH3 2 2 C9H22N2O 136—138 (30) 1.4585 84 A 5 c 2 H 5 C2H5 CH3 2 3 C10H24N2O 142—144 (30) — 72 A 6 ^ H S c 2 H 5 CH3 3 2 C10H21N2O 124—126 (8) — 77 B 7 C2H5 C2H5 CH3 3 3 CUH26N20 145—146 (15) 1.4608 74 B 8 C2H6 c 2 H 5 c2H5 3 3 C12H28N2O 118—120 (6) 1.4636 48 A 9 c 2 H 5 C 2 H 5 CH3 3 4 C12H28N2O 123—125 (4) 1.4614 42 — 10 C2H5 c2H6 CH3 3 5 C13H30N2O 125—127 (3) 1.4645 68 B 11 C 3 H 7 C 3 H 7 CH3 3 3 C13H30N2O 111—112 (3) 1.4696 75 A 1 12 —(CH2)4— CH3 3 2 ' C10H22N2O 147—150 (30) — 62 A 13 — ( C H 2 ) 4 - CH3 3 3 ChH 2 4 N 2 0 157—160 (30) — 42 A 14 x ° CH3 CH3 3 3 CnH2gN202 150—154 (2) . 1.4793 51 — • Lit. [20] b.p. 52 °C (1 Hgmm), n%\ 1.4550 b Lit. [20] b.p. 96 °C (7 Hgmm), n™: 1.4580 • X: 3-hydroxypropyl-1 -166 K. FELFÛLDI, m. LASZLAVIK, M. BARTÔK and E. KÂRPÂT1 Table II Physical constants of dimethoiodide quaternary salt of s ?3 P % s O Compd. Ri Ri , R 3 n m Formula Melting point, °C 15 CH3 CH3 CH3 2 2 C23H32I2N2O3 2 1 7 — 2 1 8 16 CH, CH3 CH3 3 3 C26H36I2N2O3 1 9 3 — 1 9 5 17 CH3 C2H6 CH3 3 3 C26H38I2N8O3 1 7 6 — 1 7 8 18 C2H5 C2H5 CH3 2 2 C25H36I2N2O3 1 9 9 — 2 0 0 19 C2H5 c2H5 CH3 2 3 C2SH38I2N203 1 8 6 — 1 8 8 20 C2H5 c2H5 CH3 3 2 C26H38I2N2O3 1 8 9 — 1 9 0 21 C2H5 c2H5 CH3 3 3 CS,H40I2N2O3 1 5 6 — 1 5 7 22 Q H S c2H5 c2H5 3 3 C28H42I2N2O3 1 5 4 — 1 5 6 23" caH5 c2H5 CH3 3 3 C29H44I2N2O3 1 4 2 — 1 4 3 24 C3H, C 3 H 7 CH3 3 3 C29H44I2N203 1 7 5 — 1 7 6 25 —(CH2)4— CH3 3 3 C27H38I2N2O3 1 8 0 — 1 8 1 26 —(CH2)4— CH3 3 2 C26H36I2N2O3 2 1 8 — 2 1 9 2 7 Q H 5 C2H6 CH3 3 4 C28H42I2N2O3 1 4 9 — 1 5 1 28 c2H5 c2H5 CH3 3 5 C29H44I„N2O3 1 4 3 — 1 4 5 29 xb CH3 CH3 3 3 C4IH48T2N2OC 1 9 4 — 1 9 5 Diethoiodide X: 3-(xanthene-9-carbonyloxy)-propyl-l werecalculated from dose-response curves. For each substance and each dose, >6—9 experiments were performed. The substances were administered intravenously. Guinea-pigs were placed individually in plexi-glass boxes exposed to an aerosol of a 1 % aqueous ACh solution. The time elapsed between the beginning of the aerosol exposure and severe dyspnea in individual animals was recorded as the prostration time, a prolongation of which was considered indicative of bronchodilator activity. The substances were administered subcutaneously, and the maximum enhancement of the prostration time was evaluated as percentage inhibition compared to the •control group. The relative potency was calculated from the dose-response curves. .A total of 12 animals were used per dose. CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXIII 167: Table 111 Pharmacological properties of quaternary salts Cholinolytic activity® Bronchodilator activity a Compd. Pupil size ACh-induced contraction of ileum Isolated trachea Bronchia! resistance ACh-induced prostration 15 0.52 0.04 0.05 . 0.02 0.09 16 42 3.1 11 35 42 17 95 7.2 17 57 61 18 0.31 0.05 0.01 0.03 0.08 19 2.9 0.31 0.12 0.21 6.2 20 3.7 0.29 0.21 0.17 7.1 21 311 25 60 270 " 214 22 45 2.9 9.6 17 44 23 101 6.2 12.3 65 63 24 15 1.5 5.7 19 11 25 89 5.6 15 34 57 26 4.2 0.36 0.17 0.09 7.3 27 27 1.8 0.97 22 15 28 0.62 0.07 0.05 0.05 ' 0.08 1 29 305 107 50 157 131 * Atropine = 100 . Chemistry. Constants relating to the diaminoalcohols and quaternary salts prepared are listed in Tables I and II. The melting and boiling point .values are not corrected. The tic examinations were made on Kieselgel HF (Merck) plates, with ethanol-diethylamine (96:4, v/v) as solvent mixture, and the Draggendorf reagent as developer. The quaternary salts were recrystallized from aqueous ethanol, the yield being in general 40—60%. The G, H and N analyses were within 0.4% of the theoretical for all compounds. 3-Methylamino-propanol-l A solution of 3-chloro-propanol-l (71 g, 0.75 mole) and methylamine (62 g, 2 mole) in EtOH (400 ml) was shaken for 15 hr at 130 °C in an autoclave. After cooling, the EtOH was distilled off and the residue was dissolved in concentrated aqueous KOH solution. The organic phase was separated, dried and distilled. Yield -168 K . FELFÛLDI, m. LASZLAVIK, M. BARTÔK and E. KÂRPÂT1 37 g (55%), b.p. 95—100 °C (30 Hgmm), «»: 1.4450; lit. [19] b.p. 175—177 °C (750 Hgmm), «1°: 1.4479. 3-Ethylamino-propanol-l was prepared in an analogous manner. Yield 48%, b.p. 96—98 °C (30 Hgmm), wf,0: 1.4452; lit. [19] b.p. 184—187 °C (750 Hgmm), n%2: 1.4475. Method A. 3-[N-Methyl-N-(3-dipi;opylamino-propyl)]-amino-propanol-l (11) 3-Methylamino-propanol-l (17 g, 0.19 mole), 3-dipropylamino-propyl-chloride (34.4 g, 0.2 mole) and anhydrous K2C03 (35 g) were stirred in EtOH (150 ml) during boiling for 15 hr. After filtration of the cooled reaction mixture, the filtrate was evaporated and the residue was distilled. Yield 35 g (75%). Method B. 3-[N-Methyl-N-(3-diethylamino-propyl)]-amino-propanol-l (7) N,Af-Diethyl-A'/-methyl-propane-1,3-diamine (Fluka) (16.6 g, 0.115 mole), 3-chloropropanol-l (11 g, 0.116 mole) and anhydrous K2C03 (15 g) were stirred in EtOH (75 ml) during boiling for 15 hr. The mixture was worked up as in Method A. Yield 17.2 g (74%). N,N'-Dimethyl-N,N'-bis(3-hydroxypropyl)-propane-l,3-diamine (14) A solution of 3-methylaminopropanol-l (8.9 g, 0.1 mole) in EtOH (40 ml) was added dropwise with stirring to a mixture of 1,3-dibromopropane (10.1 g, 0.05 mole) and anhydrous K2C03 (15 g) in EtOH (75 ml), and the reaction mixture was then boiled for 15 hr. After filtration, the filtrate was evaporated and the residue was distilled., Yield 5.5 g (51%), m.p. of dihydrochloride 144—146 °C. 4-[N-Methyl-N-(3-diethylamino-propyl)]-aminobutanol-l (9) A mixture of jV,./V-diethyl-,/V'-methylpropane-7)J-diarnine (20.2 g, 0.14 mole) and butyrolactone (12 g) was heated at 100° for 24 hr. The reaction product was dissolved in abs. Et20 (100 ml), the solution was added with stirring and cooling to a solution of Li[AlH4] (4.7 g, 0.12 mole) in Et20 (100 ml), and the reaction mixture was then boiled for 6 hr. With cooling and stirring, 9 ml water and then 9 ml 65% NaOH solution were added dropwise to the reaction mixture. The EtaO solution was evapo-rated and the residue was distilled. Yield 12.6 g (42%). 3-[N-Methyl-N-(3-diethylamino-propyl)]-amino-propyl-xanthene-9-carboxylate di-hydrochloride and dimethoiodide (21) A solution of diaminoalcohol 7 (5.2 g, 0.025 mole) in Me2CO (20 ml) was added dropwise with stirring and cooling to a solution of xanthene-9-carboxylic acid chloride (6.4 g, 0.026 mole) in Me2CO (40 ml), and the reaction mixture was CHEMISTRY OF 1,3-BIFUNCTIONAL COMPOUNDS, XXIII 169: then boiled for 20 min. An EtOH—HC1 solution was added to the still hot mixture, and after cooling the precipitated dihydrochloride salt was filtered off and recrys-taUized from EtOH. Yield 9.6 g (80%), m.p. of dihydrochloride salt 195—196 °C. The dihydrochloride salt (4.8 g, 0.01 mole) was dissolved in cold NaOH solu-tion. After EtsO extraction, the Et ,0 solution was dried and evaporated. The residue was dissolved in Me2CO (40 ml), Mel (3 g) was added, and the mixture was boiled for 20 min and then cooled. The dimethoiodide (21) which separated out was fil-tered off and recrystallized from EtOH. Yield 5 g (72%). References [1] Cusic, J. W., R. A. Robinson: J. Org. Chem. 16, 1921 (1951). [2] Johnson, E. A., D. R. Wood: Brit. J. Pharmacol. 9, 218 (1954). [3] Adamson, D. W., J. W. Billinghurit: Nature 177, 523 (1956). [4] Nadel, J. A., J. G. Widdicombe: Ann. N.Y. Acad. Sei. 109, 712 (1963). [5] Macklem, P. T„ J. Mead: J. Appl. Physiol. 22, 395 (1967). [6] Gold, W. M„ P.Y.C.Yv.: J. Appl. Physiol. 33, 719 (1972). [7] Poppius, H„ Y. Salorinne: Brit. med. J. 4, 134 (1973). [8] Pel lie, G. R., K. N. V. Palmer: Brit. med. J. 1, 430 (1969). [9] Nádor, K.: Progress in Drug Research (Birkhäuser Verlag), 2, 323 (1960). [10] Oilman, H„ D. A. Shirley: i. Am. Chem. Soc. 66, 1889 (1944). [11] Leonard, F., L. Simet: J. Am. Chem. Soc. 77, 2857 (1955). [12] Pulewka, P.: Arch. exp. Path. Pharmak. 168, 307 (1932). [13] Magnus, R.: Pfüler's Arch. 102, 123 (1904). [14] Litchfield, J. T., F. Wilcoxon: J. Pharmacol, exp. Therap. 96, 99 (1949). [15] Farmer, J. B., R. A. Coleman: J. Phar. Pharmac. 22, 461 (1970). [16] Anmlakshama, O., H. O. Schild: Brit. J. Pharmac. Chemother. 14, 48 (1959). [17] Komett, H., R. Rössler: Arch. exp. Path. Pharmak., 195, 71 (1940). [18] Gardner, D. G.: Brit. J. Pharmac. Chemother. 41, 128 (1971). [19] Schlögl, K., R. Schlögl: Monatsh. 95, 922 (1964). [20] Korsunov, M. A., P. H. Bodnaryuk: Zh. Org. Khim. 5, 1947 (1969). ХИМИЯ 1,3-БИФУНКЦИОНАЛЬНЫХ СОЕДИНЕНИЙ, XXIII. АМИНОАЛКИЛЬНЫЕ ЭФИРЫ КСАНТЕНО-9-КАРБОКСИЛЬНЫХ КИСЛОТ, И. ХОЛИНОЛИТИЧЕСКАЯ И БРОНХОДИЛАТОРНАЯ АКТИВНОСЬ ЧЕТВЕРТИЧНЫХ СОЛЕЙ НОВЫХ ДИАМИНОАЛКИЛ-КСАНТЕНО-9-КАРБОКСИЛАТОВ К. Фелфе.чди, М. Лаславик, М. Барток и Э. Карпаты Синтезированы четвертичные соли диаминоалкильных эфиров ксантено-9-карбоксиль-ных кислот и изучены их холинолитическая и бронходилаторная активность в сравнении с атропином. Соединения были синтезированы при кватернизации эфиров, полученных из соответствующих диаминоспиртов и хлорангидридов ксантено-9-карбоксильных' кислот. Изучена связь между активностью действия и числом углеродных атомов в заместителях. Исключительно хороший эффект найден для двух соединений. 

Chemistry of 1,3-bifunctional compounds 3. : Aminoalkyl esters of xanthene-9-carboxylic acid 2. : Cholinolytic and bronchodilator activity of quaternary salts of new diaminoalkyl-xanthene-9-carboxylates

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Chemistry of 1,3-bifunctional compounds 3. : Aminoalkyl esters of xanthene-9-carboxylic acid 2. : Cholinolytic and bronchodilator activity of quaternary salts of new diaminoalkyl-xanthene-9-carboxylates

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