US3669968A - Trialkoxy quinazolines - Google Patents
Trialkoxy quinazolines Download PDFInfo
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- US3669968A US3669968A US39541A US3669968DA US3669968A US 3669968 A US3669968 A US 3669968A US 39541 A US39541 A US 39541A US 3669968D A US3669968D A US 3669968DA US 3669968 A US3669968 A US 3669968A
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- 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
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- 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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Abstract
A series of novel 2-substituted-4-amino-6,7,8trialkoxyquinazolines have been prepared, including their acid addition salts. These compounds are useful in therapy as potent antihypertensive agents. Methods for their preparation are described in detail, including various synthetic routes leading to the required novel intermediates.
Description
United States Patent Hess 1 June 13, 1972 [54] TRIALKOXY QUINAZOLINES Primary ExaminerAlex Mazel Assistant Examiner-R. J. Gallagher [72] Inventor. Hans Jurgen E. Hess, Old Lyme, Conn. Attorney connony and Hutz [73] Assignee: Pfizer Inc., New York, NY. 22 Filed: May 21, 1970 [57] ABSIRACT A series of novel 2-substituted-4-amino-6,7 8-trialkoxyquin- 4 [211 App! No 39 5 l azolmes have been prepared, including their acid addition salts. These compounds are useful in therapy as potent an- [52] US Cl- --2 /2 R, 2 /2 Q, 260/256-4 Q tihypertensive agents. Methods for their preparation are 424/200, 424/251 described in detail, including various synthetic routes leading [51 I Int- Cl. ..C07d to the required novel intermediates [58] Field of Search ..260/256.4 Q, 256.5 R
15 Claims, N0 Drawings BACKGROUND OF THE INVENTION 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.
In the past, various attempts have been made in the field of organic medicinal chemistry to obtain new and useful antihypertensive agents. For instance, in copending US. Pat. application, Ser. No. 690,101, filed Dec. 13, 1967, and now US. Pat. No. 3,511,836 issued May 12, 1970, there are disclosed various 2,4-diamino-6,7-dimethoxyquinazoline compounds useful for these purposes. However, in the search for still newer and better antihypertensive agents, other attempts have proven to be less successful, e.g., the 8-monomethoxy, 6,7- methylenedioxy and 6,7-ethylenedioxy derivatives in this series are all substantially inactive.
SUMMARY OF THE INVENTION In accordance with the present invention, it has now been rather surprisingly found that various 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:
and the acid addition salts thereof, wherein 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:
wherein 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. These novel compounds are all useful in reducing blood pressure of hypertensive subjects.
Of special interest in this connection are such typical and preferred member compounds of the invention as 2-(N- monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline, 2- (N,N-dimethylamino )-4-amino-6,7,S-trimethoxy-quinazoline, 2-[4-(2-furoyl)-l-piperazinyl]-4-amino-6,7,8-trimethoxyquinazoline, isobutyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2- yl)piperazine-l-carboxylate, 2-methyallyl 4-(4-amino-6,7,8- trimethoxyquinazolin-Zyl)piperazine-l-carboxylate and 2- methyl-Z-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylate, and their hydrochloride acid addition salts. All these compounds exhibit hypotensive activity to a significantly high degree. In addition, they have a more favorable pharmacological profile e.g., they are nonadrenolytic in dogs) and possess greatly improved solubility characteristics (particularly in water) as contrasted to the corresponding 6,7-dialkoxy compounds reported in the prior art.
DETAILED DESCRIPTION OF THE INVENTION In accordance with the process employed for preparing the novel compounds of this invention, a 2-halo-4-amino-6,7,8 5 trialkoxyquinazoline of the following structure:
where 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. In addition, 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. On the other hand, 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. or even a 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. In the case where a particular solvent is used and/or the boiling point of the amine is below the desired reaction temperature range, it is often customary in practice to employ a sealed pressure bottle as the proper vessel in which to conduct the reaction. Upon completion of same, recovery of the desired product is readily effected by any number of conventional means. For instance, the solvent is evaporated from the mixture and the crude concentrate or resulting solid residue is thereafter triturated with ethyl acetate or similar organic solvent, In this way, high yields of trialkoxy-quinazoline final product are obtained. It should 50 be noted in this connection that the amines (ZH) employed as reagent in this reaction are, for the most part, known compounds or else they can easily be prepared by those skilled in the art from readily available starting materials, using the standard procedures of organic chemistry.
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-
dihalo-6,7,8-trialkoxyquinazolines of the formula:
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, on the other hand, 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.
As regards compounds of the invention where R of the N- substituted piperazine moiety is hydroxyalkoxy, as previously defined, 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. In this way, a compound such as 2- methylallyl 4-(4-amino-6,7,8-tri-methoxyquinazolin-2- yl)piperazine-l-carboxylate is converted to 2-methyl-2- hydroxypropyl 4-( 4-amin o-6,7 ,S-trimethoxyq uinazolin-2- yl)piperazine-l-carboxylate in a most facile manner, as is hereinafter described in more detail in the examples which follow.
Inasmuch as 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.
As previously indicated, 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. For instance, 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. after 2 hours subsequent to drug administration) when given by the oral route of administration at increasing dose levels ranging from 2.5-40 mg./kg., daily, for a period of up to four days. Additionally, these compounds are well absorbed in the body and none of them cause any substantial side effects to occur in the subject to whom they are administered, i.e., no problems of toxicity or of an untoward pharmacological nature, like postural hypotension, are ever encountered when said compounds are administered for the aforestated purpose in the manner described as indicated above.
In accordance with a method of treatment of the present invention, 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. In general, 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. However, 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. Nevertheless, it is still to be appreciated that other variations may also occur in this respect, depending upon the species of animal being treated and its individual response to said medicament, as well as on the particular type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, 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.
in connection with the use of the 2 substituted-4-amino- 6,7,8-trialkoxyquinazoline compounds of this invention for the treatment of hypertensive subjects, it is to be noted that they may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particu larly, 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. Moreover, such 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. In general, 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.
For purposes of oral administration, 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. When aqueous suspensions and/or elixirs are desired for oral administration, 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.
For purposes of parenteral administration, 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. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufiicient saline or glucose. These particular solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes.
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. (18.3 moles) of sodium hydroxide (pellets) thereto with aid of gentle external cooling to maintain the temperature below (or near) 40 C. The resulting suspension was thereafter stirred for 1 hour at room temperature C.) and finally, acidified with concentrated hydrochloric acid, with external cooling being required to keep the temperature below 25 C. The final mixture was stirred at this point for 1 hour and filtered, and the solid residue thus obtained (i.e., the filter cake) was subsequently washed with water and airdried before being ground to a fine powder. After drying the latter material to constant weight in vacuo over P 0 there was obtained a 135 g. (87 percent) yield of 6,7,8trimethoxy-2,4[1H, 3Hlquinazolindione in the form of a yellow crystalline powder, m.p. 259262 C. Recrystallization of the product from dimethylformamide-water then gave fine white plates, m.p. 266-269 C.
Anal. Calcd. forC H N o C, 52.38; H, 4.80;N, 11.11.
Found: C, 51.86; H, 4.78; N, 11.30.
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. In this particular case, 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
g. (91 percent) of 2,4-dichloro-6,7,8-trimethoxyquinazoline (m.p. l48-151C.) as a tan crystalline residue. Recrystallization of the latter material from ethanol then gave fine white needles, mp. 147-l50 C.
Anal. Calcd. for C H CI N Q; C, 45.99; H, 3.48; N, 9.68; C1, 24.52.
Found: C, 45.48; H, 3.14; N, 9.76; Cl, 24.60.
EXAMPLE II The procedure described in Example I is repeated except that 6,7,8-triethoxy-2,4[1H, 3H]-quinazolindione is the starting material employed and 2,4-dichloro-6,7,8-tri-ethoxyquinazoline is the corresponding final product thus obtained.
EXAMPLE III The procedure described in Example I is repeated except that phosphorus oxybromide is the actual reagent employed in lieu of phosphorus oxychloride and 2,4-dibromo-6,7,8- trimethoxyquinazoline is the corresponding final product thus obtained.
In like manner, 6,7,8-triethoxy-2,4[1H, 3H]-quinaz0lindione and phosphorus oxybromide react in accordance with this procedure to afford 2,4-dibromo-6,7,8-triethoxyquinazoline.
EXAMPLE IV A vigorously stirred solution of 2,4-dichloro-6,7,8- trimethoxyquinazoline (73.0 g., m.p. l48-15l C.) in tetrahydrofuran was treated with anhydrous ammonia by passing said gas through the solution for a period of 2 hours. The resulting reaction mixture was then stirred at room temperature 25 C.) for a period of 16 hours and finally, concentrated under reduced pressure to afford a solid residue. The latter material was subsequently triturated with car. 500 m1. of water and the resulting aqueous suspension thereafter filtered. The residual filter cake was then washed with water and partially air-dried, before being suspended in hot ethanol. The latter alcoholic suspension was then cooled and filtered to give, after drying to constant weight, 56.2 g. (75 percent) of 2- chloro-4-amino-6,7,8-trimethoxyquinazoline in the form of pure white crystals, m.p. 243-246 C. Recrystallization of the latter material from ethanol then raised the melting point to 244-246 C.
Anal. Calcd. for C,,H,,C1N,0,; C, 48.99; H, 4.49; N, 15.58; Cl, 13.15.
Found: C, 48.95; H, 4.53; N, 15.65; Cl, 13.09.
EXAMPLE V The procedure described in Example IV is repeated except that 2,4-dichloro-6,7,8-triethoxyquinazoline is the starting material employed and 2-chloro-4-amino-6,7,8-triethoxyquinazoline is the corresponding final product thus obtained.
EXAMPLE VI The procedure described in Example IV is repeated except that 2,4-dibromo-6,7,8-trimethoxyquinazoline is the starting material employed and 2-bromo-4-amino-6,7,8-trimethoxyquinazoline is the corresponding final product thus obtained.
In like manner, 2,4-dibromo-6,7,8-triethoxyquinazoline and anhydrous ammonia react in accordance with this procedure to afford 2-bromo-4-amino-6,7,8triethoxyquinazoline.
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. (93 percent) of 2-methylallyl 4-(4- amino-6,7 ,8-trimethoxyquinazolin-2 -yl )piperazinel -carboxylate as the pure hydrochloride salt, in the form of white crystals melting at 186188 C.(dec.). Recrystallization of the product from ethanolic hydrochloric acid did not raise the melting point.
Anal. Calcd. for c,.,H,,N,o,-Hc1= C, 52.92; H, 6.22; N, 15.43; Cl, 7.81.
Found: C, 52.83; H, 6.47; N, 15.45; Cl, 7.82.
Subsequent conversion of the above hydrochloride salt to the corresponding free organic base was then accomplished by dissolving 7.6 g. of said product in water-ethanol (9:1 by volume), followed by treatment with an excess of saturated aqueous sodium bicarbonate solution. The essentially pure free base compound was then separated from the resulting mixture by means of filtration, and washed with water and airdried to give 6.8 g. (97 percent) of 2-methylallyl 4-(4-amino- 6,7,8-trimethoxyquinazolin-Z-yl )-piperazinel -carboxylate in the form of pure white crystals, m.p. 170-l 73 C. Recrystallization of the latter material from chloroform-diisopropyl ether then raised the melting point to l72174 C.
Anal. Calcd. for C H N O C, 57.54; H, 6.52; N, 16.78.
Found: C, 57.06; H, 6.44; N, 16.43.
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. Recrystallization of this material from chloroform-diisopropyl ether then gave 5.0 g. (77 percent) of pure 2-methyl-2hydroxypropyl 4-(4-amino- 6,7,8-trimethoxyquinazolin-Z-yl)piperazine-l-carboxylate, as white crystals melting at l56-l59 C. A further recrystallization from the same solvent system then raised the melting point to 158-l59 C.
Anal. Calcd. for C H N O C, 55.16; H, 6.71; N, 16.08.
Found: C, 55.09; H, 6.62; N, 15.84.
Treatment of the above free organic base (4.5 g.) in ethanol with ethanolic hydrochloric acid in the cold (cooling being effected by means of an ice-water bath) then gave 3.24 g. (66 percent) of 2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8- trimethoxyquinazolin-Z-yl )piperazine- 1 -carboxylate hydrochloride, as white crystals melting at l66-l69 C. (dec.).
Anal. Calcd. for C H N O 'HCl-H O: C, 49.03; H, 6.58; N, 14.29; Cl, 7.24.
Found: C, 48.88; H, 6.63; N, 14.32; C], 7.36.
EXAMPLE IX The procedure described in Example VII was repeated to prepare the following 2-substituted-4-amino-6,7,8-trimethoxyquinazolines, reported as hydrochlorides, starting from 2- chloro-4-amino'6,7,8-triemthoxyquinazoline and the appropriate primary or secondary organic amine reagent in each case:
2-( N-monomethylamino )-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 22923 1 C.
2-( N,N-dimethylamino )-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 237-239 C.
2-(N,N-diethylamino )-4-arnino-6,7,8-trimethoxyquinazoline hydrochoride, m.p. l86-l 88 C.
2-[ N,N-di-( n-propyl)amino]-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 20l-203 C.
2-[ N,N-di(fi-hydroxyethyl )amino -4-amino-6,7,8- trimethoxyquinazoline hydrochloride, m.p. 220222 C.
2-(N-pyrrolidino)-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 21 8220 C.
2-(N-piperidino)-4-amino-6,7,S-trimethoxyquinazoline hydrochloride, m.p. 219-221 C.
2-(N-homopiperidino)-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. l86-l89 C.
2-( 4-benzoyll -piperazinyl )-4-amino6,7 8-trimethoxyq ninazoline hydrochloride, m.p. 175 '1 77 C.
2-[4-( 2-furoyl l -piperazin yl]-4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 208209 C.
ethyl 4-( 4-amino-6,7,8-trimethoxyquinazolin-Z-yl piperazine-l-carbonylate hydrochloride, m.p. 228-230 C.
isobutyl 4-( 4-amino-6,7,8 trimethoxyq uinazolin-2-yl piperazine-l-carboxylate late hydrochloride, m.p. l90l 92 C.
Subsequent conversion of each of the above hydrochloride salts to the corresponding free organic base compound, in each case via saturated aqueous sodium bicarbonate solution in the manner of Example Vll,then affords the corresponding 2-substituted-4-amino-6,7,B-trimethoxyquinazoline in pure form as such.
EXAMPLE X The procedure described in Example VII is employed again to prepare the following 2-substituted-4-amin0-6,7,8-trialkox yquilazolines, starting from the corresponding 2-chloro-4- amino-6,7,8-trialkoxyquinazoline compound and the appropriate amine reagent in each instance:
The procedure described in the previous examples is employed once again to prepare the following 2-substituted-4- amino-6,7,8-trialkoxyquinazolines, starting from the corresponding 2-chloro-4-amino-6,7,8-t1ialkoxyquinazoline compound and the appropriate l-piperazinecarboxylate reagent in each instance:
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. In each and every case, the final product thus obtained (i.e., the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compound) is found to be identical with that reported previously for the corresponding reaction in the aforesaid examples. For instance, 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 XIII The other hydrohalide acid addition salts of the 2-substituted-4-amino-6,7,8-tria.lkoxyquinazoline base compounds of this invention reported previously, such as the corresponding hydrochloride, hydrobromide and hydriodide salts, are each individually prepared by first dissolving the respective organic base compound in absolute ether and then adding a saturated solution of the appropriate hydrohalide gas in ethyl acetate to the aforementioned ethereal solution, whereupon the desired acid addition salt soon precipitates from said solution. In this way, 2-methyl-2-hydroxypropyl 4-(4-amino-6,7,8- trimethoxyquinazolin-2-yl)piperazine-l-carboxylate (1.0 g.)
is converted via dry hydrogen bromide gas to the corresponding hydrobromide acid addition salt in almost quantitative yield.
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. In this manner, equimolar amounts of 2-(N,N-dimethylamino)-4-amino-6,7,8-trimethoxyquinazoline and concentrated sulfuric acid react to afford the corresponding sulfuric acid addition salt. In like manner, each of the other salts is also similarly prepared.
EXAMPLE XV A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
2-Methyl-2-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)piperazine-l-carboxylate hydrochloride 0 Sodium citrate 25 Alginic acid l0 Polyvinylpyrrolidone i l0 Magnesium stearate 5 After the dried mixture is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 50 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, l0 and 25 mg. of the active ingredient, respectively, by merely using the appropriate amount of the trialkoxy-quinazoline compound in each case.
EXAMPLE XVI A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
2-[4-( 2-Furoyl)-lpiperazinyl]-4-amino-6,7,8-trimethoxyquinazoline hydrochloride 50 Calcium carbonate 20 Polyethylene glycol, average molecular weight 4000 i 30 The dried solid mixture so prepared is then thoroughly agitated so as to obtain a powdered product that is completely uniform in every respect. Soft elastic and hard-filled gelatin capsules containing this pharmaceutical composition are then prepared, employing a sufficient quantity of material in each instance so as to provide each capsule with mg. of the active ingredient.
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.
N-hornopiperidino -20(2), -50 (4) 0-1 5( l0), 0-ll5(20) EXAMPLE XVIII The test procedure described in the previous example was repeated here to determine the hypotensive activity of the following 2-substituted-4-amino-6,7,S-trimethoxyquinazolirxe compounds, and the results obtained in this manner are re- What is claimed is:
l. A compound selected from the group consisting of 2-substituted-4-amino-6,7,8-trialkoxyquinazoline bases of the formula:
and the pharmaceutically acceptable acid addition salts thereof, wherein 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:
wherein 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.
2. A compound as claimed in claim 1 wherein Z is monoalkylamino.
3. A compound as claimed in claim 1 wherein Z is di-alkylamino.
4, 2-(N-Monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline.
5. 2-(N,N-Dimethylamino)-4-amino-6,7,S-trimethoxyquinazoline.
6. A compound as claimed in claim 1 wherein Z is N-substituted piperazino of the formula:
-1-{ N ll R v 7. A compound as claimed in claim 6 wherein R is furyl. 8. A compound as claimed in claim 6 wherein R is thienyl. 9. A compound as claimed in claim 6 wherein R is alkenyloxy having up to five carbon atoms.
10. A compound as claimed in claim 6 wherein R is alkoxy having from one to six carbon atoms.
11. A compound as claimed in claim 6 wherein R is hydroxyalkoxy having from two to six carbon atoms.
1 2. 2-[4-(2-Furoyl)-1-piperazinyl]-4-amino-6,7,8- trimethoxyq uinazoline.
l3. Z-Methallyl 4-(4-amino-6,7,S-trimethoxyquinazolin-Z- yl)- l -piperazinecarboxylate.
l4. lsobutyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)- l -piperazinecarboxylate,
15. Z-Methyl-Z-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazoline-Z-yl l -piperazinecarboxylate.
Claims (14)
- 2. A compound as claimed in claim 1 wherein Z is monoalkylamino.
- 3. A compound as claimed in claim 1 wherein Z is di-alkylamino.
- 4. 2-(N-Monomethylamino)-4-amino-6,7,8-trimethoxyquinazoline.
- 5. 2-(N,N-Dimethylamino)-4-amino-6,7,8-trimethoxyquinazoline.
- 6. A compound as claimed in claim 1 wherein Z is N-substituted piperazino of the formula:
- 7. A compound as claimed in claim 6 wherein R is furyl.
- 8. A compound as claimed in claim 6 wherein R is thienyl.
- 9. A compound as claimed in claim 6 wherein R is alkenyloxy having up to five carbon atoms.
- 10. A compound as claimed in claim 6 wherein R is alkoxy having from one to six carbon atoms.
- 11. A compound as claimed in claim 6 wherein R is hydroxyalkoxy having from two to six carbon atoms.
- 12. 2-(4-(2-Furoyl)-1-piperazinyl)-4-amino-6,7,8-trimethoxyquinazoline.
- 13. 2-Methallyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)-1-piperazinecarboxylate.
- 14. Isobutyl 4-(4-amino-6,7,8-trimethoxyquinazolin-2-yl)-1-piperazinecarboxylate.
- 15. 2-Methyl-2-hydroxypropyl 4-(4-amino-6,7,8-trimethoxyquinazoline-2-yl)-1-piperazinecarboxylate.
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US3920636A (en) * | 1972-10-30 | 1975-11-18 | Eisai Co Ltd | Quinazoline compounds |
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US4060615A (en) * | 1976-02-18 | 1977-11-29 | Mead Johnson & Company | 2-Piperazinyl-6,7-dimethoxyquinazolines |
DE2725019A1 (en) | 1976-06-15 | 1977-12-22 | Pfizer | PROCESS FOR THE PREPARATION OF SUBSTITUTED AMINOCHINAZOLINE DERIVATIVES AND INTERMEDIATE PRODUCTS THEREFORE |
US4098788A (en) * | 1977-06-20 | 1978-07-04 | Bristol-Myers Company | Process for preparing quinazolines |
US4101548A (en) * | 1977-02-22 | 1978-07-18 | Bristol-Myers Company | 1,2,3-Thiadiazole amides |
US4171363A (en) * | 1977-02-22 | 1979-10-16 | Bristol-Myers Company | 1,2,3-Thiadiazole process |
US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
US4287341A (en) * | 1979-11-01 | 1981-09-01 | Pfizer Inc. | Alkoxy-substituted-6-chloro-quinazoline-2,4-diones |
US4351940A (en) * | 1980-03-03 | 1982-09-28 | Pfizer Inc. | Chloro- and alkoxy-substituted-2-chloro-4-aminodquinazolines |
US4377581A (en) * | 1980-03-03 | 1983-03-22 | Pfizer Inc. | Chloro- and alkoxy-substituted-2,4-diaminoquinazolines |
US4435401A (en) | 1980-12-29 | 1984-03-06 | Pfizer Inc. | 4-Amino-6,7-dimethoxy-2-(4-heteroaryl-piperazino)quinazoline antihypertensives |
US4582832A (en) * | 1984-10-09 | 1986-04-15 | Pfizer Inc. | Trimazosin as an anti-atherosclerosis agent |
US5064833A (en) * | 1989-05-10 | 1991-11-12 | Smithkline Beecham Intercredit B.V. | Substituted quinazoline derivatives for use in gastrointestinal diseases |
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US20060247272A1 (en) * | 2004-09-23 | 2006-11-02 | Pfizer Inc | 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds |
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WO2007062314A2 (en) | 2005-11-23 | 2007-05-31 | Bristol-Myers Squibb Company | Heterocyclic cetp inhibitors |
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US20070238716A1 (en) * | 2006-03-14 | 2007-10-11 | Murthy Ayanampudi S R | Statin stabilizing dosage formulations |
WO2008070496A2 (en) | 2006-12-01 | 2008-06-12 | Bristol-Myers Squibb Company | N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases |
US20080153896A1 (en) * | 2006-07-14 | 2008-06-26 | Gyan Chand Yadav | Polymorphic Forms of an HMG-CoA Reductase Inhibitor and Uses Thereof |
US20080248035A1 (en) * | 2005-11-08 | 2008-10-09 | Ranbaxy Laboratories | Pharmaceutical Combination |
US20100056602A1 (en) * | 2003-05-30 | 2010-03-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors |
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WO2014170786A1 (en) | 2013-04-17 | 2014-10-23 | Pfizer Inc. | N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases |
WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
WO2020150473A2 (en) | 2019-01-18 | 2020-07-23 | Dogma Therapeutics, Inc. | Pcsk9 inhibitors and methods of use thereof |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1383409A (en) * | 1972-09-09 | 1974-02-12 | Pfizer Ltd | Derivatives of 2-amino- and 4-amino-quinazoline and pharmaceutical compositions containing them |
US4026894A (en) * | 1975-10-14 | 1977-05-31 | Abbott Laboratories | Antihypertensive agents |
DK140695C (en) | 1976-05-07 | 1980-05-12 | Synthelabo | ANALOGY PROCEDURE FOR PREPARING 2,4-DIAMINO-6,7-DIMETHOXYQUINAZOLINE DERIVATIVES OR ACID ADDITION SALTS |
US4102885A (en) * | 1977-06-20 | 1978-07-25 | Bristol-Myers Company | Process for preparing 2,4-dihaloquinazolines |
US4130647A (en) * | 1977-07-08 | 1978-12-19 | Pfizer Inc. | Methods for treating congestive heart failure and ischemic heart disease |
DK154082C (en) * | 1977-11-05 | 1989-02-27 | Pfizer | METHOD OF ANALOGUE FOR THE PREPARATION OF 4-AMINO-6,7-DIMETHOXY-2- (PIPERAZIN-1-YL OR HOMOPIPERAZIN-1-YL) -QUINAZOLINE COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE ACID ADDITIONAL SALTS |
US4510307A (en) * | 1980-08-20 | 1985-04-09 | Asahi Kasei Kogyo Kabushiki Kaisha | 6-Quinazolinesulfonyl derivatives and process for preparation thereof |
US4704284A (en) * | 1982-08-12 | 1987-11-03 | Pfizer Inc. | Long-acting matrix tablet formulations |
EP0724480B1 (en) * | 1993-10-18 | 1997-11-19 | Imperial Chemical Industries Plc | Catalytic process |
US7759336B2 (en) * | 2002-12-10 | 2010-07-20 | Ono Pharmaceutical Co., Ltd. | Nitrogen-containing heterocyclic compounds and medicinal use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1156973A (en) * | 1965-07-06 | 1969-07-02 | Quinazoline Derivatives |
-
1970
- 1970-05-21 US US39541A patent/US3669968A/en not_active Expired - Lifetime
- 1970-09-09 GB GB4323070A patent/GB1309835A/en not_active Expired
-
1971
- 1971-04-27 DE DE2120495A patent/DE2120495C2/en not_active Expired
- 1971-04-27 DE DE2167157A patent/DE2167157C2/en not_active Expired
- 1971-04-28 FR FR7115185A patent/FR2092154B1/fr not_active Expired
- 1971-04-29 SE SE7105610A patent/SE384211B/en unknown
- 1971-04-29 CH CH634571A patent/CH521353A/en not_active IP Right Cessation
- 1971-04-29 BE BE766444A patent/BE766444A/en not_active IP Right Cessation
- 1971-04-30 AT AT374771A patent/AT308120B/en not_active IP Right Cessation
- 1971-05-03 NL NLAANVRAGE7106029,A patent/NL178594C/en not_active IP Right Cessation
-
1972
- 1972-04-03 US US00240865A patent/US3769286A/en not_active Expired - Lifetime
-
1973
- 1973-10-29 SE SE7314685A patent/SE400280B/en unknown
-
1976
- 1976-09-27 JP JP51115730A patent/JPS5268191A/en active Granted
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US3980650A (en) * | 1972-05-05 | 1976-09-14 | N.V. Koninklijke Pharmaceutische Fabrieken V/H Brocades-Stheeman En Pharmacia | 4-Amino-pyrimidine derivatives |
US3920636A (en) * | 1972-10-30 | 1975-11-18 | Eisai Co Ltd | Quinazoline compounds |
US4060615A (en) * | 1976-02-18 | 1977-11-29 | Mead Johnson & Company | 2-Piperazinyl-6,7-dimethoxyquinazolines |
DE2725019A1 (en) | 1976-06-15 | 1977-12-22 | Pfizer | PROCESS FOR THE PREPARATION OF SUBSTITUTED AMINOCHINAZOLINE DERIVATIVES AND INTERMEDIATE PRODUCTS THEREFORE |
US4101548A (en) * | 1977-02-22 | 1978-07-18 | Bristol-Myers Company | 1,2,3-Thiadiazole amides |
US4171363A (en) * | 1977-02-22 | 1979-10-16 | Bristol-Myers Company | 1,2,3-Thiadiazole process |
US4098788A (en) * | 1977-06-20 | 1978-07-04 | Bristol-Myers Company | Process for preparing quinazolines |
US4188390A (en) * | 1977-11-05 | 1980-02-12 | Pfizer Inc. | Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines |
US4287341A (en) * | 1979-11-01 | 1981-09-01 | Pfizer Inc. | Alkoxy-substituted-6-chloro-quinazoline-2,4-diones |
US4351940A (en) * | 1980-03-03 | 1982-09-28 | Pfizer Inc. | Chloro- and alkoxy-substituted-2-chloro-4-aminodquinazolines |
US4377581A (en) * | 1980-03-03 | 1983-03-22 | Pfizer Inc. | Chloro- and alkoxy-substituted-2,4-diaminoquinazolines |
US4435401A (en) | 1980-12-29 | 1984-03-06 | Pfizer Inc. | 4-Amino-6,7-dimethoxy-2-(4-heteroaryl-piperazino)quinazoline antihypertensives |
US4582832A (en) * | 1984-10-09 | 1986-04-15 | Pfizer Inc. | Trimazosin as an anti-atherosclerosis agent |
US5064833A (en) * | 1989-05-10 | 1991-11-12 | Smithkline Beecham Intercredit B.V. | Substituted quinazoline derivatives for use in gastrointestinal diseases |
US5576322A (en) * | 1991-09-30 | 1996-11-19 | Eisai Co., Ltd. | Anti-ischemic 2,4-diaminoquinazolines |
US7547702B2 (en) * | 2000-09-20 | 2009-06-16 | Ortho-Mcneil Pharmaceutical, Inc. | 4-amino-quinazolines |
US20060019974A1 (en) * | 2000-09-20 | 2006-01-26 | Werner Mederski | 4-Amino-quinazolines |
WO2004017964A1 (en) | 2002-08-19 | 2004-03-04 | Pfizer Products Inc. | Combination therapy for hyperproliferative diseases |
US20100056602A1 (en) * | 2003-05-30 | 2010-03-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors |
US20110190369A1 (en) * | 2003-05-30 | 2011-08-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors |
US20110190296A1 (en) * | 2003-05-30 | 2011-08-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors |
US7923467B2 (en) | 2003-05-30 | 2011-04-12 | Ranbaxy Laboratories, Inc. | Substituted pyrrole derivatives and their use as HMG-CO inhibitors |
US20050037063A1 (en) * | 2003-07-21 | 2005-02-17 | Bolton Anthony E. | Combined therapies |
US20060025406A1 (en) * | 2004-07-06 | 2006-02-02 | Angion Biomedica Corporation | Modulators of hepatocyte growth factor/c- Met activity |
US20060247272A1 (en) * | 2004-09-23 | 2006-11-02 | Pfizer Inc | 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds |
WO2007024945A1 (en) | 2005-08-25 | 2007-03-01 | Novartis Ag | Condensed imidazolo derivatives for the inhibition of aldosterone synthase and aromatase |
EP2270011A1 (en) | 2005-08-25 | 2011-01-05 | Novartis AG | Condensed imidazolo derivatives for the inhibition of aromatase |
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US7956198B2 (en) | 2005-11-08 | 2011-06-07 | Ranbaxy Laboratories, Limited | Pharmaceutical compositions |
US20090118520A1 (en) * | 2005-11-08 | 2009-05-07 | Ranbaxy Laboratories Limited | Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
US20080287690A1 (en) * | 2005-11-08 | 2008-11-20 | Ranbaxy Laboratories Limited | Process For (3R, 5R)-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4- [(4-Hydroxy Methyl Phenyl Amino) Carbonyl]-Pyrrol-1-Yl]-3,5-Dihydroxy-Heptanoic Acid Hemi Calcium Salt |
US7671216B2 (en) | 2005-11-08 | 2010-03-02 | Ranbaxy Laboratories Limited | Process for preparation of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
US20080248035A1 (en) * | 2005-11-08 | 2008-10-09 | Ranbaxy Laboratories | Pharmaceutical Combination |
US8026377B2 (en) | 2005-11-08 | 2011-09-27 | Ranbaxy Laboratories, Limited | Process for (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
WO2007062314A2 (en) | 2005-11-23 | 2007-05-31 | Bristol-Myers Squibb Company | Heterocyclic cetp inhibitors |
US20080058312A1 (en) * | 2006-01-11 | 2008-03-06 | Angion Biomedica Corporation | Modulators of hepatocyte growth factor/c-Met activity |
US20070213319A1 (en) * | 2006-01-11 | 2007-09-13 | Angion Biomedica Corporation | Modulators of hepatocyte growth factor/c-Met activity |
WO2007105050A1 (en) | 2006-03-10 | 2007-09-20 | Pfizer Products Inc. | Dibenzyl amine compounds and derivatives |
US20070238716A1 (en) * | 2006-03-14 | 2007-10-11 | Murthy Ayanampudi S R | Statin stabilizing dosage formulations |
US20080153896A1 (en) * | 2006-07-14 | 2008-06-26 | Gyan Chand Yadav | Polymorphic Forms of an HMG-CoA Reductase Inhibitor and Uses Thereof |
WO2008070496A2 (en) | 2006-12-01 | 2008-06-12 | Bristol-Myers Squibb Company | N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases |
WO2014170786A1 (en) | 2013-04-17 | 2014-10-23 | Pfizer Inc. | N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases |
WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
WO2020150473A2 (en) | 2019-01-18 | 2020-07-23 | Dogma Therapeutics, Inc. | Pcsk9 inhibitors and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
NL7106029A (en) | 1971-11-23 |
CH521353A (en) | 1972-04-15 |
SE384211B (en) | 1976-04-26 |
BE766444A (en) | 1971-10-29 |
GB1309835A (en) | 1973-03-14 |
DE2120495C2 (en) | 1982-06-03 |
NL178594B (en) | 1985-11-18 |
FR2092154B1 (en) | 1975-01-17 |
NL178594C (en) | 1986-04-16 |
SE400280B (en) | 1978-03-20 |
JPS5268191A (en) | 1977-06-06 |
DE2120495A1 (en) | 1971-12-02 |
FR2092154A1 (en) | 1972-01-21 |
JPS5439386B2 (en) | 1979-11-27 |
DE2167157C2 (en) | 1982-06-09 |
AT308120B (en) | 1973-06-25 |
US3769286A (en) | 1973-10-30 |
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