Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
  • C07D239/96—Two oxygen atoms

Definitions

• This invention relates to various new and useful trialkoxyquinazoline compounds, and to their chemical method of preparation. More particularly, it is concerned with a novel series of 2-substituted-4-amino-6,7,8-trialkoxyquinazolines and their pharmaceutically acceptable acid addition salts, which are of especial value in medicine in view of their unique chemotherapeutic properties.
• novel 6,7,8-trialkoxyquinazoline compounds are extremely useful as antihypertensive agents, despite the aforesaid teaching indicated above, particularly regarding the 8-monomethoxy derivatives. More specifically, the novel compounds of this invention are all 2- substituted-4-amino-6,7,8-trialkoxyquinazolines of the formula:
• R is chosen from the group consisting of methyl and ethyl; and Z is a member selected from the group consisting of monoalkylamino and dialkylamino each having up to three carbon atoms in the alkyl moiety, mono(/3-hydroxyethyl)amino and di(B-hydroxyethyl)-amino, pyrrolidino, piperidino, homopiperidino and N-substituted piperazino ofthe formula:
• R is chosen from the group consisting of alkoxy having from one to six carbon atoms, alkenyloxy having up to five carbon atoms and hydroxyalkoxy having from two to six carbon atoms, alkyl having from one to six carbon atoms, phenyl, naphthyl, fury] and thienyl.
• R is defined as aforesaid and X is a halogen atom selected from the group consisting of chlorine and bromine, is treated with an appropriate amine base of the formula ZH, where Z is as previously defined, to form the desired 2-substituted-4-amino-6,7,8-trialkoxyquinazoline final product.
• This particular reaction is normally carried out by using an excess of the amine base with respect to the required equimolar ratio, since this serves to shift the reaction equilibrium to the product side of the equation.
• the excess amine can also function as a solvent for the reaction, with a preferred excess for these purposes being from about two to about ten moles of amine per one mole of 2-halo-4-amino-6,7,8-trialkoxyquinazoline.
• a reaction-inert polar organic solvent may also be used for the reaction and this would ordinarily entail employment of a cyclic ether such as dioxane and tetrahydrofuran, or a lower dialkylsulfoxide such as 3 dimethyl and diethlsulfoxide, or a lower alkanol solvent like methanol, ethanol or isoamyl alcohol, etc.
• N,N-dialkyl lower alkanoamide such as N,N-dimethylformamide, N,N- dimethylacetamide, N,N-diethylformamide and the like.
• the temperature at which the reaction can be conducted varies widely within the range of from about 50 C. up to about 200 C. for a period of about I to about 12 hours.
• a preferred reaction time and temperature for the process at hand would be about l-l50 C. for about 2-4 hours.
• a sealed pressure bottle as the proper vessel in which to conduct the reaction.
• pounds used as starting materials in the herein described process of this invention such as 2-chloro and 2-bromo-4- amino-6,7,S-trimethoxyquinazoline, are themselves new compounds which are prepared by treating the corresponding 2,4-
• the 2-halo-4-amino-6,7,8-trialkoxyquinazoline base com- I of the desired intermediate is readily accomplished using conventional means, such as, for example, partial evaporation of the solvent from the reaction mixture until incipient crystallization takes place, followed by trituration of the resulting residue with water or by reprecipitation of said residue from dilute aqueous acid.
• the 2,4dihalo-6,7,B-trialkoxyquinazolines are all new compounds obtained by essentially known methods, starting from the corresponding known 2-amino-3,4,5-trialkoxybenzoic acid and reacting the latter type compound with either sodium or potassium cyanate in an aqueous acidic medium, followed by cyclization with aqueous base to form the intermediate 6,7,8-trialkoxy- 2,4[1H,3H ⁇ -quinazolindione ring compound, which, in turn, then yields the correspond-mg novel 2,4-dihalo-6,7,8-trialkoxyquinoline on treatment with either phosphorus oxychloride or phosphorus oxybromide in accordance with the general procedure of F.H.S. Curd et al., as described in the Journal of the Chemical Society (London), 1948, p. 1759.
• a preferred and alternate method of preparation simply involves treating the corresponding compounds where R is alkenyloxy, as obtained by the principal process of this invention, with water in the presence of at least a catalytic amount of concentrated sulfuric acid to form the desired secondary or tertiary alcohol, as the case may be, in accordance with the standard methods of organic chemistry.
• a preferred temperature range for this reaction would normally be from about -20 C.
• the 2-substituted-4-amino-6,7,8-tria.lkoxyquinazoline compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must first be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compound from the reaction mixture as a pharmaceuticaliy unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and thereafter, subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds of this invention are readily prepared by treating the base compound with an equivalent amount of the chosen acid in an aqueous solution or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.
• the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluene-sulfonate and pamoate [i.e., 1,1- methylene-bis( 2-hydroxy-3-naphthoate)]salts.
• non-toxic acid addition salts
• the 2-substituted-4-amino-6,7,8- trialkoxyquinazoline compounds of the present invention are all readily adapted to therapeutic use as antihypertensive agents, particularly in view of their ability to lower the blood pressure of hypertensive subjects to a statistically significant degree.
• 2-methyl-2-hydroxypropyl 4-(4-amino- 6,7,8-trimethoxyquinazolin-2-yl)piperazinel -carboxylate a typical and preferred agent of the present invention, has been found to lower the blood pressure of conscious hypertensive dogs to a statistically significant degree e.g., up to 42 mm. Hg.
• the herein described 2-substituted4-amino-6,7,8-trialkoxyquinazoline anti-hypertensive agents can be administered to a hypertensive subject via either the oral or parenteral routes of administration.
• these compounds are most desirably administered in doses ranging from about 10 mg. up to about 600 mg. per day, although variations will still necessarily occur depe.iding upon the weight of the subject being treated.
• a dosage level that is in the range of from about 0.16 mg. to about 9.6 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results, with a preferred oral range in man being about 2.5-5.0 mg./kg.
• dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side effects to occur provided that such higher dose levels are first divided into several smaller doses that are to be administered throughout the day.
• the novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
• Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
• oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose.
• the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5 percent to about percent by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
• tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
• Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules; preferred materials in the connection would also include lactose or milk sugar, as well as high molecular weight polyethylene glycols.
• the essential active ingredient therein may be combined with various sweetneing or flavoring agents, coloring matters or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
• solutions of these particular 2-substituted-4-amino6,7,8-trialkoxyquinazolines in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble, non-toxic mineral and organic acid addition salts previously enumerated.
• aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufiicient saline or glucose.
• PREPARATION A A solution consisting of 65.3 g. (0.805 mole) of potassium cyanate dissolved in 200 ml. of water was added with stirring, during the course of a -minute period, to a suspension of 112 g. (0.535mole) of 2-amino-3,4,5-trimethoxybenzoic acid [obtained by saponification, with 1N NaOH in methanolwater (4:1 by volume), of the corresponding known methyl ester] in 2.6 liters of water containing 46 ml. of glacial acetic acid, while maintaining the temperature of the mixture at ca. 30 C. throughout the course of the addition. The resulting reaction mixture was then stirred at this same temperature for 2 hours, followed by the subsequent addition of 746 mg.
• PREPARATION B The procedure described in Preparation A is repeated except that 2-amino-3,4,5-triethoxybenzoic acid is the starting material employed in place of the corresponding trimethoxy acid.
• the corresponding final product obtained is 6,7,8-triethoxy-2,4[1H, 3H]quinazolindione.
• EXAMPLE I A mixture consisting of 70.0 g. (0.278 mole) of 6,7,8- trimethoxy-2,4-[ 1H, 3H]-quinazolindione (m.p. 259-262 C.) and 1,100 m1. of phosphorus oxychloride was heated to reflux with stirring for a period of 2 hours. At the end of this time, the resulting clear solution was concentrated under reduced pressure and the residue thus obtained was dissolved in ca. 750 ml. of chloroform. The chloroform solution was slowly poured, with stirring, into an excess of saturated aqueous sodium bicarbonate and the resulting mixture vigorously stirred until evolution of carbon dioxide gas virtually ceased.
• the chloroform layer was then separated from the mixture and combined with two subsequent chloroform extracts (750 ml.) of the aqueous phase.
• the combined chloroform extracts were then washed with water, dried over anhydrous sodium sulfate and filtered to give a dry organic filtrate that was subsequently concentrated under reduced pressure to yield 73.0
• EXAMPLE VII A mixture consisting of 8.08 g. (0.030 mole) of 2-chloro-4- amino-6,7,S-triemthoxyquinazoline (m.p. 243-246 C.) and 5.88 g. (0.033 mole) of 2-methylallyl l-piperazinecarboxylate in 200 m1. of isoamyl alcohol was heated to reflux for a period of 75 minutes. The resulting mixture was then cooled and concentrated under reduced pressure to afford an amorphous residue, which was subsequently triturated with ethyl acetate. The residue thus obtained was recovered by means of filtration and washed with ethyl acetate to give, after air drying to constant weight, 12.6 g.
• EXAMPLE VIII A stirred solution consisting of 24 ml. of concentrated sulfuric acid dissolved in an equal volume of water was cooled to ca. l2 C. and treated with 6.25 g. (0.015 mole) of 2-methylallyl 4-(4-amino-6,7,8-trimethoxyquinazolin-Z-yl)piperazine-1- carboxylate added in small portions, with stirring being maintained throughout the course of the addition at such a rate as to always keep the temperature of the reaction mixture below 20 C. The resulting mixture was then further stirred for 15 minutes,while at 18 C., to give a clear solution, which was subsequently stirred for an additional two hours at lO-15 C.
• the aqueous solution thus obtained was then diluted with 150 ml. of ice-water and adjusted to a pH of ca. with 50 percent aqueous sodium hydroxide, while maintaining the temperature below 12 C. throughout this step.
• the resulting alkaline mixture was next extracted with four 150 ml. portions of chloroform, and the chloroform extracts were combined, washed with water and then dried over anhydrous sodium sulfate. After removal of the drying agent by means of filtration and the organic solvent by means of evaporation under reduced pressure, there was ultimately obtained a white crystalline solid as residue.
• the yield of product amounted to 6.0 g. and it melted at 15 l-l 15 C.
• Example VII The procedure described in Example VII is employed once again to prepare the final products of Examples VII and IX-XI by merely using the appropriate 2-bromo-4-amino-6,7,8-trialkoxyquinazoline compound, in place of the corresponding 2- chloro compound, as proper starting material for the reaction.
• the final product thus obtained i.e., the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compound
• the final product thus obtained is found to be identical with that reported previously for the corresponding reaction in the aforesaid examples.
• 2-bromo-4-amino-6,7,8-trimethoxyquinazoline and 2-methallyl l-piperazinecarboxylate react in this manner to afford 2-methallyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2- yl)piperazine-l-carboxylate, identical in every respect with the product of Example VII.
• EXAMPLE XIV The nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and parnoate [i.e., 1,1 -methylene-bis(2-hydroxy-3- naphthoate)]salts of each of the aforementioned 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds reported previously are each prepared by dissolving the proper molar amounts of the respective acid and base in separate portions of ethanol and then mixing the two solutions together, followed by the addition of diethyl ether to the resultant solution in order to effect precipitation of the desired acid addition salt therefrom.
• EXAMPLE XV A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
• a dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
• EXAMPLE XVII The following 2-substituted-4-amino-6,7,8-trimethoxyquinazolines were tested for hypotensive activity in conscious hypertensive dogs by the procedure of Prioli and Winbury, as described in the Journal of Applied Physiology, Vol. 15, p. 323 (1960) and found to be effective at the indicated concentration levels by both the oral and intravenous routes.
• the compounds were administered in the form of their hydrochloride salts and the blood pressure determinations were made just prior to and at frequent intervals after drug administration (e.g., at 2, 4 and 24 hours thereafter), using at least two or more dogs for the evaluation of each compound.
• the activity is therefore expressed in terms of the observed range in reduction of blood pressure in mm. Hg in two or more dogs, while the concentration levels are reported as mgjkg. per dose.
• R is chosen from the group consisting of methyl and ethyl; and Z is a member selected form the group consisting of monoalkylamino and dialkylamino each having up to three carbon atoms in the alkyl moiety, monoUS-hydroxyethyl)amino and di(fl-hydroxyethyl)amino, pyrrolidino, piperidino, homopiperidino and N-substituted piperazino of the formula:
• R is chosen from the group consisting of alkoxy having from one to six carbon atoms, alkenyloxy having up to five carbon atoms and hydroxyalkoxy having from two to six carbon atoms, alkyl having from one to six carbon atoms, phenyl, naphthyl, furyl and thienyl.
• R is furyl.
• R is thienyl.
• R is alkenyloxy having up to five carbon atoms.
• R is alkoxy having from one to six carbon atoms.
• R is hydroxyalkoxy having from two to six carbon atoms.

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• 1970
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