Quaternary-tricyclic quinazolinones
United States Patent 1191 Hardtmann Apr. 1,1975  
 [ QUATERNARY-TRICYCLIC QUINAZOLINONES [22] Filed: Jan. 22, 1973 [2]] Appl. No: 325,946  
 [52] U.S. Cl 260/256.4 F. 424/251 [51] Int. Cl C07d 51/42 [58] Field of Search 260/2564 F [56] References Cited UNITED STATES PATENTS 3.257.401 6/1966 Wagner 260/2564 F 3.598.823 8/1971 Hardtmun 260/2564 F 3.621.025 11/1971 Jen 260/2564 F 3.790.573 2/1974 Blackburn ct a1 260/2564 F Primary lirumine&#34;Donald G. Daus Assistant Examiner-James H. Turnipseed Attorney. Agent, or Firm-Gerald D. Sharkin; Richard E. Vila [57] ABSTRACT The compounds are quaternary-tricyclic quinazolinones of the class of imidazol 2,1-b]quinazolin-5-ones, pyrimidol2,1-b]quinazolin-6-one and diazepinol2,lblquinazolin-7-ones, e.g., 1-methyl-2.3-dihydro-10- (4&#39;-fluorobenzy1)-imidazo[2.1-b]quinaz0lin-5(10H)- one iodide. useful. for examples, as bronchodilator agents. The compounds are prepared by quaternizing the corresponding tricyclic quinazolinone with an alkyl bromide or iodide. The compounds of the invention having anions other than the bromide 0r iodide are prepared from the bromide or iodide by well known anion exchange procedures.  
 34 Claims, N0 Drawings 1 QUATENARY TRlCYCLlC QUINAZOLINONES The present invention relates to tricyclic compounds which are quaternary quinazolinones, and to their preparation. The invention also relates to pharmaceutical methods and compositions for utilization of the compounds based on their biological activity.  
  The present invention provides compounds of the formula I:  
 wherein R is alkyl of l to 3 carbon atoms, preferably methyl,  
 Z is a pharmaceutically acceptable inorganic anion,  
 e.g. the iodide, bromide, chloride, hydroxide, sulfate and the like each of R, and R is, independently, hydrogen, halo of atomic weight not greater than 36 or lower alkyl of l to 3 carbon atoms, or both are lower alkoxy of l to 2 carbon atoms; or one is hydrogen and the other bromo, trifluoromethyl or lower alkoxy of l to 2 carbon atoms:  
 11 is to 2;  
 each of R and RC; is hydrogen or lower alkyl of l to 2 carbon atoms.  
 each of R and R&#39; is hydrogen or lower alkyl of l to 3 carbon atoms, provided that no more than three of R R;,. R, and R is lower alkyl;  
 R is lower alkyl of l to 6 carbon atoms, alkenyl of 3 to 8 carbon atoms,  
  X is a direct bond or (CH y is l to 3, m is 0 to 2, each of Y and Y is. independently, hydrogen. halo of atomic weight not greater than 36. i.e., fluoro or chloro. or lower alkyl of l to 3 carbon atoms, or both are lower alkoxy of l to 2 carbon atoms, or one is hydrogen and the other bromo, trifluoromethyl or lower alkoxy of l to 2 carbon atoms. The compounds of the formula I in which Z is iodine or bromine are preferably by subjecting the corresponding tricyclic quinazolinones of the formula A in which R, R,, R R;;, R&#39;;;. R R and n are as above defined, to reaction with a compound of the formula A-l:  
 v A I in which R, is as above defined and X, is bromo or iodo. The reaction may be carried out in a conventional manner at temperatures in the range of from 20 to 10- 0C. The reaction may be also carried out in inert organic solvents of conventional typebut it is generally preferred to use an excess of the bromide or iodide of the formula A-I as the sole solvent and conduct the reaction at the reflux temperature of the system. The iodide is generally preferred.  
  The compounds of the formula I in which Z is other thanthe iodide may be prepared from the iodide or bromide (other than the bromide) by subjecting the iodide or bromide to well known anion exchange procedures whereby the iodide or bromide is exchanged for the desired anion. Such exchanges are typically carried out at temperatures of from 20 to C. in an aqueous solvent system comprising water or water and a water miscible organic solvent of well known type such as diethyl ether and dioxane. The exchange may be carried out, for example, by employing the silver salt of the anion desired to be introduced and precipitating the resulting silver iodide or bromide.  
  One method for preparation of compounds of formula A involves reacting in a Step A a compound of the formula II:  
 wherein R R; and R are as defined, with a compound of formula lll:  
 wherein n. R R&#39;;;, R and R are as defined and R is lower alkyl or benzyl.  
  The preparation of compounds A by Step A can be carried out at temperatures in the range of 20 to 160C. more usually 20C. to 140C, preferably 80 to C. The reaction is conveniently carried out in an organic solvent of conventional type providing an inert medium. The aromatic solvents and cyclic ethers suitable for use at reflux temperatures represent the pre- H RC-(I: (ca -on in which R, R R R;,, R&#39;;,, R R&#39; and n are as abovedefined, with a cyclizing agent, and treating the reaction product with an acid binding agent.  
  The preparation of compounds A from compounds IV involves a cyclization of known type carried out by treating a compound IV with a reagent suitable for such type of cyclization, for example, a phosphorus halide or thionyl halide in which the halide has an atomic weight of from 35 to 80, i.e., the chloride or bromide, more preferably the chloride. The preferred reagent is thionyl chloride. The reaction with the cyclizing reagent may be carried out in absence of a solvent or in the presence of inert solvents of known type, e.g., the halogen-containing hydrocarbons such as methylene chloride and chloroform, and the aromatic solvents such as benzene and pyridine. An excess of the cyclizing agent may, however, where appropriate, be employed to provide a solvent. The treatment with an acid-binding agent, e.g., an inorganic base or tertiary amine, is preferably effected after removal of the remaining cyclizing reagent. The reaction product of formula A may be isolated from the reaction mixture by working up by established procedures.  
  The compounds of the formulae II and III employed as starting materials in the reaction of Step A are either known or may be prepared from known materials by established procedures.  
  The compounds of formula IV may be prepared by reacting a compound of the formula V:  
 wherein R, R, R and R are as defined, with a compound of formula VI:  
 H n-c p -(CH -OH VI I R3 a wherein :1, R R&#39;;,, R and R, are as defined.  
  The preparation of the compounds IV from compounds V and VI is suitably carried out at temperature in the range of from 0 to 120C, preferably to 80C. An excess of compound VI is preferably employed. The reaction may be carried out in the absence ofa solvent but is preferably conducted in the presence of an inert organic solvent which may be any of several of the well known types, preferably a chlorinecontaining hydrocarbon such as chloroform and methylene chloride. The reaction product of formula IV may be isolated from the reaction mixture for use in preparation of compounds A by working up by established procedures.  
  The compounds of formula V may be prepared by reacting a compound of formula VII:  
 VII  
 wherein R, R, and R are as defined, with an iodo compound of formula VIII:  
 wherein R is as defined.  
  The preparation of compounds V by reacting of compounds VI and VIII is suitably carried out at temperatures in the range of from 0 to C., preferably l5 to 60C. The reaction is desirably effected in the presence of an inert organic solvent which may be any of several well known types, preferably a lower alcohol of l to 5 carbon atoms or an ether, e.g., ethanol and dioxane, preferably ethanol. The reaction product of formula V may be isolated from the reaction mixture for use in preparation of compounds IV by working up by established procedures.  
  The compounds of the formulae VI. VII and VIII are either known or may be prepared from known materials by established procedures.  
  The compounds of formula I of the invention are useful because they possess biological activity. In particular, the compounds of the formula I in which R is alkyl, alkenyl, or a phenyl or substituted phenyl ring separated from the ring nitrogen by an alkylene moiety, i.e., the compounds ofthe following formulae Ia, lb and It:  
  Z R&#39; a 1 3 R1 I N r Ia 2 a e (C x R P @l 3 R N N\&#39; RI l I] i Ib 2 mm nse R CH3-(IIH N N 1 Nf 3 R which R R Y. R. R R&#39;;;. R R&#39; R,. Z, and n are as defined and p is l or 2 and R is alkyl of l to 5 carbon atoms or alkenyl of 3 to 8 carbon atoms are useful as bronchodilator agents as indicated by measuring bronchial resistance on intravenous administration (0.1-5 mgs./kgs.) in the anesthetized guinea pig and according to the test of Knozett and Rossler. Arch. Exp. Path. and Pharmak. 195:7] (1940); and by observing the respiratory status on oral administration (0.5-100 mgs./kgs.) to the unanesthetized guinea pig exposed to aerosolized histamine dihydrochloride according to a modification of the method of Van Arman et al.. J. Pharm. pharmacol. Exptl. Therap. 133:90-97, 1961; and in vitro by observing the effect (0.1- micrograms/ml.) on strips ofguinea pig trachea according to the method of Constantine. J. Pharm. Pharmacol. 17: 384-385. 1960. For such use and depending upon known variables satisfactory results are obtained in general on the daily admin istration of from 0.5 to 100 milligrams per kilogram of body weight. preferably given in divided doses two to four times a day. or in sustained release form. For most mammals the administration of from 30 to 3.000 milliforms suitable for internal administration comprise 8 to 1.500 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.  
  The compounds of the formula 1 in which R is phenyl or substituted phenyl or cycloalkyl or cycloalkylalkyl, i.e.. the compound of the following formulae 1d and 1e:  
  ZG 1 R, R I 3 N N\, R. Ri l l 3 Id R2 (c1t h l cs (CH -CH t R \CH2 I 29 N (9 N 3 I e 1 R2 a.  
 wherein R R Y. Y. X. R R&#39;;,, R R R,. Z. In and n are as defined are also useful as hypotensive/antihypertensive agents as indicated by a lowering of blood pressure on intravenous administration to the anesthetized dog. For such use and depending upon known variables satisfactory results are obtained in general on daily administration of from 0.1 to milligrams per kilogram of body weight. For most mammals the administration of from 40 to 1,500 milligrams per day provides satisfactory results and dosage forms for internal administration comprise from 10 to 750 milligrams in combination with a suitable carrier. The preferred compounds for effecting a lowering of blood pressure are those in which R is cycloalkylalkyl, n is O and R and R are hydrogen, more preferably R is cyclopr&#39;opylmethyl.  
  The preferred compounds of the invention from the standpoint of bronchodilator activity, e.g.. in the histamine aerosol assay. are those in which R is benzyl including substituted benzyl, particularly unsubstituted benzyl and more particularly those which have a 4-halo substituted-benzyl. and the more preferred such compounds are those in which each of R and R is hydrogen. and those in which n is O.  
  For the uses indicated above. the compounds may be combined with a pharmaceutically acceptable carrier. and such other conventional adjuvants as may be necessary, and administered orally or parenterally. For most uses oral administration with carriers is preferred and may take place in such conventional forms as tablets. dispersible powders granules. capsules. suspensions. syrups and elixirs. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents. flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients. e.g.. inert diluents such as calcium carbonate. sodium carbonate, lactose and talc, granulating and disintegrating agents. e.g., starch and alginic acid, binding agents, e.g.. starch. gelatin and acacia, and lubricating agents, e.g., magnesium stearate. stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents(methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin. polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservatives (ethyl-p-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g.. calcium carbonate. calcium phosphate and kaolin. The preferred pharmaceutical compositions from the standpoint of preparation and ease of oral administration are solid compositions, particularly hard-filled capsules and tablets. Parenteral administration may be in such&#39;conventional forms as injectionable solutions and suspensions.  
  A representative formulation is a tablet for oral administration two to four times a day for effecting a reduction in blood pressure and prepared by conventional tabletting techniques to contain the following ingredients:  
  A representative formulation is also a capsule for oral administration two to four times a day for effecting a reduction in blood pressure and prepared by conventional capsulating techniques to contain the following ingredients:  
 Capsule Ingredients Weight (Mg) lO-cyclopropylmetltyl-ZJ-dihy&#39;drol-methyl-imitlazol 2.l&#39;b]quina1.olin- 5( IUH l-one iodide 25 Lactose 316 Stcrotcx K(a triglycerol ester lubricant) It) A representative formulation is a tablet for oral administration two to four times a day for prophylatic treatment of bronchial asthma and prepared by conventional tabletting techniques to contain the following ingredients:  
 Ingredients Weight tmg.)  
 dihydro-imidazol 2. l -b]quina7.olin- 5( lOH )-one iodide 25 Tragacanth I Lactose 222.5 Corn Starch 25 Talcum l Magnesium Stearatc 2.5  
 imidazol Z. l -b Iquinazolin-5( 10H )-one iodide 0.4-1? Ethyl alcohol Ill-% Ascorbic Acid l-l(l/i Freon l I 10-30); Freon l l4 10-30% Freon II 30-60% Buffer System pH control q.s.  
 Flavor q.s.  
  The following examples show representative compounds encompassed within the scope of this invention and the manner in which such compounds are prepared. However, it is to be understood that the examples are for purposes of illustration only.  
 EXAMPLE A 10-( 4 &#39;-fluorobenzyl -2,3-dihydro-imidazol 2. l blquinazolin-5( lOH )-one Step A: Preparation of N-(p-fluorobenzyl)isatoic anhydride.  
 To a solution of 3.2 kgs. isatoic anhydride in IS kgs.  
 dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 880 gms. of a 57 percent dispersion in mineral oil. while maintaining the temperature below 25C. The resulting mixture is heated to about 60C. and held at about -60C. for l hour. The reaction mixture is then cooled to 20-30C. and to it is added 3.0 kgs. p-fluorobenzyl chloride. The mixture is then reheated to about C. and held there for about 4 hours. It is then cooled again to 20C. and to it is added 17.4 kgs. of ice and then 24 kgs. water. The mixture is stirred for IS minutes, the solids collected by filtration. washed with several 2 kg. portions of water and then three times with 0.7 kg. dicthylether. The washed solids are dried to obtain N-(p-fluorobenzyl)isatoic anhydride, m.p. 140l43C. Step B: Preparation of l-(4-fluorobenzyl)-2.3- dihydroimidazo [2,1-b]quinazolin-(1OH)-one.  
  a charge of 26 kgs. toluene, 2.5 kgs. 2-methylmercaptoimidazoline hydroiodide, 2.4 kgs. N-(pfluorobenzyl)isatoic anhydride and 1.55 kgs. powdered anhydrous sodium carbonate is refluxed for 18-20 hours in a reaction vessel which is vented to a caustic gas washing tower. Any water formed during the reaction is collected in a Dean-Stark separator. The reaction is cooled to 20C. and kgs. water added. The mixture is stirred for about 30 minutes and the solids collected, washed several times with 2 kg. portions of water. and three times with 0.8 kg. toluene. The solids are then dried at reduced pressure (about 55C.) to obtain a crude product, m.p. 196198C. The crude is dissolved at 50C. in a solution of 14 kgs. chloroform and 4 kgs. ethanol and treated in solution with 0.1 kg. decoloring charcoal for about 10 minutes. The charcoal is removed by filtration through a celite bed and solids reprecipitated by concentrating the filtrate to a volume of about 8 liters. This concentrate is cooled to 05C., the solids collected by filtration, washed with cold ethanol and then diethyl ether, and dried at reduced pressure to obtain 10-(4-fluorobenzyl)-2,3- dihydro-imidazo[2,l-b]quinazolin-5(1OH)-one, m.p. 197-198C.  
 EXAMPLE 1 1-methyl-2,3-dihydro-10-(4-fluorobenzyl)- imidazo[2.l-b]quinazolin-5( lOH)-one iodide EXAMPLE 2 Following the procedure of Example 1, the following compounds of the invention are prepared:  
 A. 1,1 l-trimethyl-8-chloro-2,3,4,1 ltetrahyd ropyrimidol 2 1-b]quinazolin-6-one iodide.  
 B. l-methyl-2,3-dihydro-10-benzyl-imidazo[2,l-  
 b]quinazolin-5( 10l-l)-one idoide.  
 . 1-methyl-2,3-dihydro-10-(4-f1uorobenzyl)- imidazol2.1b}quinazolin-5( 1OH)-one bromide.  
 D. l-methyl-2,3-dihydro-10-benzyl-imidazol2.l-  
 b]quinazolin-5( lOH l-one bromide.  
 benzyU-imidazolZ, l-b]quinazolin-5( lOH)-one iodide.  
 F. 10-(a-methyl-benzyl)-2,3-dihydro-1-methylimidazo[2,1-b]quinazolin-5(1OH)-one iodide.  
 G. l0-(4&#39;-fluorobenzyl)-2,3-dihydro l ,2-dimethylimidazol2,l b]quinazolin-5( 10H )-one iodide.  
 H. 1l-(4&#39;-fluorobenzyl)-2,3.4,1 l-tetrahydro-3- ethyl- 1 ,3-dimethylpyrimidol2, 1-b]quinazolin- 6-one iodide.  
 l. l ,2,8,lO-tetramethyl-2,3-dihydro-imidazo[2,1-  
 b]quinazolin-5( 10H )-0ne iodide.  
 .l. 10-(4-fluorobenzyl)-2,3-dihydro-7,8-dimethoxyl-methyl-imidazo[2,l-b]quinaz0lin-5( lOl-l)-one iodide.  
 . l0-(4-fluorobenzyl)-1,2,2-trimethyl-2,3- dihydro-imidazolZ,1-b]quinazo1in-5(1OH)-one iodide. L. lO-cyclopropylmethyl-1-methy1-2,3-  
 dihydroimidazo[2,1-b]quinazolin-5(lOH)-one iodide.  
 M. IO-phenyl-1-methyl-2,3-dihydro-imidazo[2,1-  
 b]quinazolin-5( lOl-l)-one iodide.  
 N. 10-cyclopropylmethyl-7,S-dimethoxy-l-methyl 2,3-dihydro-imidazol 2,l-b]quinazolin-5( lOH)- one iodide.  
 O. l-methyl-7-methoxy-10-phenyl-im&#39;idazd[2,1-  
 b]quinazo1in-5( 10H )-one iodide.  
 P. l-methyll 2-benzyl-2,3,4,5-tetrahydro-( 12H diazepinol2,1-b]quinazolin-7-one iodide.  
 Q. lO-cyclopropylmethyl-1,2,2-trimethyl-2.3-  
 dihydro-imidazo[2,l-b]quinazolin-5(1OH)-one iodide.  
 R. 10-(4&#39;-bromobenzyl)-1-methy1-2,3-  
 dihydroimidazo[2,1-b]quinazolin-5(1OH)-one iodide.  
 S. l0-(3&#39;,4-difluorobenzyl)-1-methyl-2,3-dihydroimidazo[2,l-b]quinazolin-5(10l-1)-one iodide.  
 T. 7-bromolO-ethyl-1-methyl-2,3-dihydroimidazo[2,l-b]quinazolin-5( 10H )-one iodide.  
 U. 10-(2-methylbenzy1)-l-methyl-2,3- dihydroimidazolZ,l-b]quinazolin-5(lOH)-one iodide.  
 V. ll-(3, 4&#39;-dimethoxybenzyl)-l-methyl-2,3,4,1ltetrahydro-pyrimido[2,1-b]quinazolin-6-one iodide.  
 What is claimed is:  
 l. A compound of the formula:  
 wherern R, is alkyl of 1 to 3 carbon atoms, Z is a pharmaceutically acceptable inorganic anion,  
 each of R and R is. independently. hydrogen, halo of atomic weight no greater than 36 or alkyl of l to 3 carbon atoms, or both are alkoxy of l to 2 carbon atoms; or one is ,hydrogen and the other bromo. trifluoromethyl or alkoxy of I to 2 carbon atoms:  
 11 is to 2.  
 each of R and R is hydrogen or alkyl of l to 2 carbon atoms.  
 each of R and R; is hydrogen or alkyl of l to 3 carbon atoms, provided that no more than three of R;,, R&#39;;,. R and R; is alkyl,  
 R is alkyl of l to 6 carbon atoms. alkenyl of 3 to 8 carbon atoms X is a direct bond or (CH- y is l to 3,  
 m isO to 2.  
 each of Y and Y&#39; is. independently. hydrogen. halo of atomic weight not greater than 36 or alkyl of l to 3 carbon atoms, or both are alkoxy of l to 2 carbon atoms; or one is hydrogen and the other bromo. trifluoromethyl or alkoxy of l or 2 carbon atoms.  
 2. A compound of claim 1 in which each of R R;,.  
 R and R&#39; is hydrogen.  
 3. A compound of claim 2 in which R is n cit ar.  
 14. A compound of claim 13 in which each of R and 7 R is hydrogen.  
  15. A compound of claim 9 in which R;,, R R and R are each hydrogen.  
  16. A compound ofclaim 14 in which R R R and R are each hydrogen.  
 17. A compound of claim 1 in which R is F QN 22. A compound of claim 18 in which Y and Y are selected from the group consisting of hydrogen and fluoro.  
  23. A compound of claim 22 in which Y is hydrogen and Y is fluoro.  
  24. A compound of claim 2 in which R is cycloalkyl or cycloalkylalkyl.  
  25. A compound of claim 24 in which R is cycloalkylalkyl.  
  26. A compound of claim 25 in which R is cyclopropylmethyl.  
  27. A compound of claim 2 in which R is phenyl or substituted phenyl.  
  28. A compound of claim I in which R is alkyl or alkenyl.  
 29. A compound of claim 28 in which R is alkyl.  
  30. A compound of claim 28in which each of R R;,, R and R is hydrogen.  
 3]. A compound of claim 1 in which R is methyl.  
 32. A compound of claim 3 in which R, is methyl.  
  33. A compound of claim 1 in which 2 is iodine or bromine.  
 34. A compound of claim 33 in which z is iodine. =l