FI57403B - PROCEDURE FOR THE FRAMSTATION OF THE BLODTRYCKSSAENKANDE 2-SUBSTITUERADE-4-AMINO-6,7,8-TRIALKOXIKINAZOLINER - Google Patents

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Patent and harbor patent An * 6kin uttafd och utUkrlftM publicand 30.0U. 80 (32) (33) (31) Requested «uoikws — Begird priority 21.05.70 USA (US) 395U1 (71) Pfizer Inc., 235 East U2nd Street, New York 17, NJ, USA (US) (72) Hans -Jiirgen Ernst Hess, Old Lyme, Connecticut, USA (US) (7U) Oy Roister Ab (5U) Method for the preparation of antihypertensive 2-substituted-U-amino-6,7,8-tri-alkoxyquinazolines - Förfarande för framställning av blodtryckssänkande This invention relates to a process for the preparation of novel antihypertensive 2-substituted-4-amino-6,7,8-trialkoxyquinazolines of the formula OR 'r' °-tY. V "zi R'0-» 2 and their acid addition salts, in which R 'is methyl or ethyl and Z is monoalkylamino or dialkylamino, each of which has up to three carbon atoms in the alkyl moiety, mono- (β-hydroxyethyl) amino, di- ( (i-hydroxyethyl) amino, pyrrolidino, piperidino, hemopiperidino or N-substituted piperazino of formula 2 57403 / \ °

-N N-C-R

wherein R is alkoxy of 1 to 6 carbon atoms, alkenyloxy of up to five carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, phenyl or furyl.

In the past, several attempts have been made in the field of medicinal chemistry to obtain new and useful antihypertensive agents. In the search for ever newer and better antihypertensive agents, companies have often not proved successful. Thus, e.g.

The 8-nonmethoxy, 6,7-methylenedioxy and 6,7-ethylenedioxy derivatives are all substantially ineffective.

According to the present invention, it has now surprisingly been found that the novel 6,7,8-trialkoxyquinazoline compounds are very useful as antihypertensive agents, despite previous experience, especially with regard to 8-monomethoxy derivatives.

However, it is known (U.S. Patent 3,511,836) that prazosin (a 6,7-dimethoxy derivative) with a close chemical structure has a good antihypertensive effect. The compounds of the invention have the advantage over prazosin in that they lower blood pressure directly by triggering vascular smooth muscle tension. Although with other substances such as prostaglandin A1 and guansydine φ. De Guia et al .: Gurrent Therapeutic Research, Vol. 15, p. 339 (1973)) is also a similar highly desirable mode of action, so that prostaglandin is disadvantaged by its short duration of action and is metabolically too unstable to be administered orally. Guansydine, on the other hand, is known to cause severe clinical side effects ^ A.W. Clark et al .: Annals of Internal Medicine, Vol. 76 pp. 579 (1972) J.

In addition, as the above-mentioned D. De Guia writing clearly shows, the well-known antihypertensive methyldqpa and guansydine are known to interfere with the adrenergic defense mechanism and thus cause adverse side effects.

Thus, the compounds of the invention, especially trimazosin (in the general formula R 'is methyl and Z is 2-methyl-2-hydroxypropyl-piperazinecarboxylate) represent a significant therapeutic advantage over known, widely used antihypertensive agents.

Typical and preferred compounds of the invention include 2- (N-monomethylamino) -4-amino-6,7,8-trimethoxyquinazoline, 2- (N, N-dimethylamino) -4-amino-6,7,8 -trimethoxyquinazoline, 2- (N, N, -dimethylamino) -4-amino-6,7,8-trimethoxyquinazoline, 2- (4- (2-furoyl) -1-piperazine) -4-amino-6, 7,8-3,5403 Trimethoxyquinazoline, isobutyl 4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) piperazine-1-carboxylate, 2-methylallyl- (4-amino-6,7 , 8-triethoxyquinazolin-2-yl) piperazine-1-carboxylate and 2-methyl-2-hydroxypropyl 4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) piperazine-1-carboxylate and their hydrochloric acid addition salts. All of these compounds have a significant antihypertensive effect. In addition, they have a more pharmacologically advantageous nature (e.g., they are non-adrenolytic for dogs) and have significantly better solubility properties (especially in water) in contrast to the corresponding 6,7-dialkoxy compounds mentioned above.

The process according to the invention for the preparation of these new compounds is characterized by the administration of 2 halo-4-amino-6,7,8-trialkoxyquinazolines of the formula OR '

R '° —y \\ η-X

R '0 - NH 2 wherein R' is as defined above and X is chlorine or bromo, react with an amine of formula ZH wherein Z is as defined above and, if necessary, then hydrogenating the resulting compound of formula I wherein R is alkenyloxy, to form a compound of formula I wherein R is hydroxyalkoxy, and optionally converting the resulting compound to an acid addition salt. The reaction is normally carried out using an excess of amine base to the required equimolar ratio, as this helps to shift the equilibrium of the reaction to the reaction product side in the equation, with a suitable excess of about two to ten moles of amine per mole of 2-halo-4-amino-6,7,8-trialkoxyquinazoline. . On the other hand, a polar organic solvent which is ineffective with the reaction can also be used, most commonly using a cyclic ether such as dioxane or tetrahydrofuran, or a lower dialkyl sulfoxide such as dimethyl and diethyl sulfoxide, or a lower alkanol solvent such as methanol, ethanol or isoalcohol; -dialkyl derivatives such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide, Ν, Ν-diethylformamide and the like. The temperature at which the reaction can be carried out varies widely between 50 ° C and 200 ° C and from one hour to twelve hours. The most suitable reaction time and temperature is about 120-150 ° C for about 2-4 hours. In the case where a special solvent is used and / or the boiling point of the amine is below the desired reaction temperature range of 4,570,33, it is often practical to use a closed pressure vessel as a suitable vessel for carrying out the reaction. After the reaction, the reaction product can be easily recovered by any conventional method. For example, the solvent is evaporated from the mixture and the crude concentrate or solid residue obtained is triturated with ethyl acetate or a similar organic solvent. In this way, large amounts of the final product of trialkoxyquinazoline are obtained. The amines (ZH) used as reagents in this reaction are for the most part known compounds or can otherwise be readily prepared from readily available starting materials using standard methods in organic chemistry.

The 2-halo-4-amino-6,7,8-trialkoxyquinazoline base compounds used as starting materials in the process described herein, such as 2-chloro and 2-bromo-4-amino-6,7,8-trimethoxyquinazoline, are themselves new compounds prepared by treating the corresponding 2,4-dihalo-6,7,8-trialkoxyquinazolines of the formula

OR

X. N v

R'0 - ^ _ X

R '° -

X

wherein R 'and X are as defined above, with at least an equimolar amount of ammonia and preferably using one to ten moles in a reaction-ineffective organic solvent of the same type as used in the final step described above. The temperature of this reaction ranges from about 15-75 ° C over a period of about 1-24 hours. After the reaction, recovery of the desired intermediate is readily accomplished by conventional means, e.g., partial evaporation of the solvent from the reaction mixture until gradual crystallization occurs, followed by trituration of the resulting residue with water or remixing of said residue with a mild aqueous acid solution. 2,4-Dihalo-6,7,8-trialkoxyquinazolines are all novel compounds obtained mainly by known methods starting from the corresponding known 2-amino-3,4,5-trialoxybenzoic acid and reacting it with either sodium or potassium cyanate in a medium which contains an acid-water solution, followed by cyclization with an aqueous base solution, to give the intermediate, 6,7,8-trialkoxy-5 57403 2,4-^ H, 3t ^ -quinazolinedione, which is a ring compound which gives the corresponding new 2,4- dihalo-6,7,8-trialkoxyquinazoline by treatment with either phosphorus oxychloride or phosphorus oxybranide according to the general method of FHSCurd et al., described on page 1759, Journal of the Chemical Society (London), 1948.

With respect to those compounds in which R of the N-substituted piperazine moiety is hydroxyalkoxy as defined above, a more preferred alternative method of preparation is to treat the corresponding compounds wherein R a is alkenyloxy such as obtained according to the main process of the invention with water having at least a catalytic amount of concentrated sulfuric acid to form the desired secondary or tertiary alcohol. The preferred temperature range for this reaction is 0-20 ° C. In this way, a compound such as 2-methylallyl-4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) -piperazine-1-carboxylate is readily converted to 2-methyl-2-hydroxypropyl-4- ( 4-amino-6,7,8-trimethoxyquinazolin-2-yl) piperazine-1-carboxylate, as described in more detail in the examples.

When the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compounds are basic compounds, they are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable in order to be used as a medicament, it is often desirable to first isolate the 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compound from the reaction mixture as a pharmaceutically unsuitable salt and then convert the latter back to free. by treatment with an alkaline reagent and then subsequently converting the free base into a pharmaceutically acceptable acid addition salt.

Acid addition salts of 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds can be readily prepared by treating the base compound with an equivalent amount of the selected acid in aqueous solution or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, a solid salt is obtained.

The acids used in the preparation of the pharmaceutically acceptable acid addition salts of the above-mentioned 2-substituted-4-amino-6,7,8-trialkoxyquinazoline base compounds form non-toxic acid addition salts, i. salts containing pharmaceutically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, fumarate methanesulfonate, ethanesulfonate, benzenesulfonate, 6 57403 p-toluenesulfonate and pamoate. 1,1'-methylene-bis (2-hydroxy-3-naphtho-benzoate) ^.

The novel 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compounds are all suitable for therapeutic use as antihypertensive agents, especially when they lower the blood pressure to a statistically significant degree in hypertensive individuals. For example, 2-methyl-2-hydroxy-propyl-4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) -piperazine-1-carboxylate, a typical and preferred compound, has been found to lower blood pressure in a conscious manner. over-excited dogs at statistically high levels (e.g., up to 42 nm Hg 2 hours after dosing) when administered orally at increasing doses totaling 2.5-40 mg / kg / day for approximately four days. In addition, these substances are well absorbed into the body and none of them cause significant side effects in the individual to whom they are administered, i. no toxicity or other pharmacologically harmful aspect, such as excessive hypotension due to posture, has ever been observed.

The novel 2-substituted-4-amino-6,7,8-trialkoxyquinazolines can be administered to a hypertensive patient either orally or parenterally. In general, these compounds are preferably administered in doses ranging from 10 to 600 mg per day depending on the weight of the patient. However, it is preferable to use a dosage range ranging from 0.16 to 9.6 mg per kilogram of body weight per day to be effective, with the preferred oral dose for humans being about 2.5 to 5 mg / kg.

When using the novel 2-substituted-4-amino-6,7,8-trialkoxyquinazoline compounds for the treatment of hypertensive patients, it should be noted that they can be administered as a medicament either alone or with pharmaceutically acceptable carriers in either of the above ways and that they can be administered either as simple or in multiple doses. The new compounds can be administered in a wide variety of forms; thus, they may be combined with pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, powders, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or excipients, sterile aqueous solutions and various non-toxic organic solvents.

57403

Such oral pharmaceutical preparations can be suitably sweetened and / or flavored with various substances / which are generally used for this purpose. In general, the concentration of these therapeutically active compounds in such dosage forms will range from 0.5 to 90% of the total weight of the preparation, i. in amounts sufficient to provide the desired dosage unit.

For oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate, disintegrants such as starch, preferably potato or tapioca starch, alginic acid or silicates together with a binder such as polyvinyl jarosinone, binder such as polyvinyl pyrrolidone, are used. Lubricants such as magnesium stearate, sodium lauryl or talc may also be used in the manufacture of tablets. When aqueous suspensions and / or elixirs are desired for oral use, sweetening or flavoring and coloring agents and, if desired, emulsifying and / or suspending agents may be added to the active ingredients together with a diluent such as water, ethanol, propylene glycol, glycerol or combinations thereof.

Solutions of these 2-substituted-4-amino-6,7,8-trialkoxyquinazolines in either sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, can be used parenterally. Such aqueous solutions should be buffered, if necessary, by first rendering the liquid diluent isotonic with sufficient saline or glucose. These solutions are suitable for intravenous, intramuscular and subcutaneous injection purposes.

Method of preparation A

A solution of 65.3 g (0.805 mol) of potassium cyanate dissolved in 200 ml of water was added with stirring over 15 minutes to a suspension of 112 g (0.535 mol) of 2-amino-3,4,5-trimethoxybenzoic acid. by saponification with 1N aqueous methanol of NaOH (4: 1 by volume) from the corresponding known methyl ester in 2,62.6 liters of water containing 46 ml of glacial acetic acid, keeping the temperature of the mixture at about 30 ° C throughout the addition. The resulting reaction mixture was then stirred at this same temperature 8 57403 for two hours, after which 746 mg of 18.3 moles of sodium hydroxide (in spheres) was added and the temperature was maintained below (or near) 40 ° C by gentle external cooling. The resulting suspension was then stirred for 1 hour at room temperature (25 ° C) and finally acidified with concentrated hydrochloric acid, with external cooling necessary to keep the temperature below 25 ° C. The final mixture was stirred at this point for one hour and filtered, and the solid residue thus obtained (i.e. the cake remaining on the filter) was then washed with water and air-dried before being ground to a fine powder. The latter was further dried in vacuo over P 2 O 3 to constant weight to give 133 £ (87 #) of 6.7,8-trimethoxy-2,4- [1H, 3H] quinazolinedione as a yellow crystalline powder, m.p. 259-262 ° C. Recrystallization of the product from an aqueous solution of dimethylformamide gave five white plates, m.p. 266-269 ° C.

Analysis: Calculated for C 11 H 20 N 2 O 2 C 52.30, H 4.80, N 11.11 Found: C 51.86, H 4.78, N 11.30.

Method of preparation B

The procedure described in Preparation A is repeated except that the starting material used is 2-amino-3,4,5-triethoxybenzoic acid instead of the corresponding trimetholic acid. In this case, the corresponding end product is 6,7,8-triethoxy-2,4- [1H, 3H] -quinazolinedione.

Example 1

A mixture of 70.0 g (0.278 mol) of 6,7,8-trimethoxy-2,4- [1H, 3H] -quinazolinedione (m.p. 259-262 ° C) and 1100 ml of phosphorus oxychloride was heated using a condenser and stirred for two hours. for an hour. After this time, the resulting clear solution was concentrated under reduced pressure, and the residue thus obtained was dissolved in about 750 ml of chloroform. The chloroform solution was slowly poured, with stirring, into excess saturated aqueous sodium bicarbonate solution, and the resulting mixture was stirred vigorously until the evolution of carbon dioxide gas was virtually complete. The chloroform layer was then separated from the mixture and combined with the following two chloroform extracts from the aqueous phase (750 ml). The combined chloroform extracts were then washed with water, dried over anhydrous sodium sulfate and filtered to give a dry organic filtrate, which was then concentrated under reduced pressure to give a final yield of 75.0 g ($ 91) of 2,4-dichloro-6,7,8-trimethoxyquinazoline (m.p. 148-151 ° C), a tan crystalline substance. Recrystallization from ethanol gave white needles, m.p. 147-150 ° C.

Analysis calculated for C 11 H 10 Cl 2 N 2 O 5: C 45.99, H 3.48, N 9.68, Cl 24.52 Found: C 45.48, S 3.14, N 9.76, Cl 24.60.

57403

Example II

The procedure described in Example I was repeated except that 6,7,8-triethoxy-2,4- [1H, 3H] -quinazolinedione is the starting material and 2,4-dichloro-6,7,8-triethoxyquinazoline is the final product.

Example III

The procedure described in Example I was repeated except that phosphorus oxybromide was used instead of phosphorus oxychloride as the reagent and 2,4-dibromo-6,7,8-trimethoxyquinazoline is thus obtained.

Similarly, 6,7,8-triethoxy-2,4- [1H, 3H] -quinazolinedione and phosphorus oxybromide react according to this method to give 2,4-dibromo-6.7.8-triethoxyquinazoline.

Example IV

A vigorously stirred solution of 2,4-dichloro-6,7,8-trimethoxyquinazoline (73.0 g, mp 148-151 ° C) in tetrahydrofuran was treated with anhydrous ammonia by allowing said gas to flow through the solution for about two hours. The resulting reaction mixture was then stirred at room temperature (25 ° C) for 16 hours and finally concentrated under reduced pressure to give a solid residue. It was triturated with about 300 ml of water and the resulting aqueous suspension was then filtered. The cake remaining on the filter was washed with water and partially air dried before being suspended in hot ethanol. This alcohol suspension was cooled and filtered and, after drying to constant weight, gave 56.2 g (75 ° Pi, 2-chloro-4-amino-6,7,8-trimethoxyquinazoline) as pure white crystals, m.p.

243-246 ° C. Recrystallization from ethanol raised the melting point of the material to 244-246 ° C.

Analysis calculated for 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 used and 2-chloro-4-amino-6,7,8-triethoxyquinazoline is the corresponding end 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 used and 2-Bromo-4-amino-6,7,8-trimethoxyquinazoline is the final product thus obtained.

Similarly, 2,4-dibromo-6,7,8-triethoxyquinazoline and anhydrous ammonia reacted according to this method to give 2-Bromo-4-amino-6.7.8-triethoxyquinazoline.

10 5 7403

Example VII

A mixture of 8.08 g (0.050 mol) of 2-chloro-4-amino-6,7,8-trimethoxy-quinazoline (m.p. 243-246 ° C) and 5.88 g (0.033 mol) of 2-methylallyl -1-piperazinecarboxylate in 200 ml of isoamyl alcohol, heated under reflux for 75 minutes. The resulting mixture was cooled and concentrated under reduced pressure, and the resulting amorphous residue was triturated with ethyl acetate. The residue thus obtained was collected by filtration and washed with ethyl acetate, acknowledged by air drying to constant weight to give 12.6 g ($ 93) of 2-methylallyl-4- (4-amino-6,7,8-trimethoxy-quinazolin-2-yl). ) piperazine-1-carboxylate as the pure hydrochloride salt, in the form of white crystals melting at 186-188 ° C (decomposes). Recrystallization of the product from ethanolic hydrochloric acid solution did not increase the melting point.

Analysis calculated for C 12 H 12 N 2 O 2 .ClCl: 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.

Conversion of the above hydrochloride salt to the corresponding free organic base was carried out by dissolving 7.6 g of said product in a water-ethanol solution (9 * 1 by volume), followed by treatment with an excess of saturated sodium bicarbonate stock solution. Substantially pure free base compound was then separated from the mixture by filtration, washed with water and air dried to give 6.8 g (97 ° / °) of 2-methylallyl-4- (4-amino-6,7,8-trimethoxyquinazoline). 2-yl) -piperazine-1-carboxylate, in the form of white pure crystals, m.p. 170-173 ° C. Recrystallization from chloroform-diisopropyl ether solution increased the melting point to 172-174 ° C.

Analysis calculated for C 57 H 24 N 2 O 2: 0 57.54, H 6.52, N 16.78 Found: C 57.06, H 6.44, N 16.43.

Example VIII

A stirred solution of 24 ml of concentrated sulfuric acid dissolved in an equal volume of water was cooled to about 12 ° C and treated with 2-methylallyl-4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) piperazine-1 carboxylate, which was added in small portions of 6.25 g (0.015 mol), continuing to stir throughout the addition at such a rate that the temperature of the reaction mixture always remained below 20 ° C. Stirring was continued for a further 15 minutes, at which time the temperature dropped to 18 ° C, at which time the solution was clear, stirring was then continued for a further two hours at a temperature of 10-15 ° C. The resulting aqueous solution was diluted to 150 ml without ice and its pH was adjusted to approximately 10-50% aqueous sodium hydroxide while maintaining the temperature below 12 ° C. throughout this phase. The resulting alkaline mixture was next extracted with four 150 ml portions of chloroform, the chloroform extracts were combined, washed with water and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the organic solvent was evaporated under reduced pressure to give a white crystalline solid. The amount of product rose to 6.0 g and melted at 151-159 ° C. Recrystallization from chloroform-diisopropyl ether solution gave 5.0 g (77%) of pure 2-methyl-2-hydroxypropyl-4- (4-amino-6,7,8-trimethoxyquinazolin-2-yl) piperazine-1. carboxylate as white crystals, melting at 150-159 ° C. A second recrystallization from the same solvent raised the melting point to 158-159 ° C.

Analysis calculated for c20H29N5O6; 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 a cold solution of hydrochloric acid in ethanol (cooling with an ice-water bath) gave 5.24 g (66 u / o) of 2-methyl-2-hydroxypropyl-4- (4-amino-6, 7,8-Trimethoxy-quinazolin-2-yl) -piperazine-1-carboxylate hydrochloride as white crystals, melting at 166-169 ° C (decomposes).

Analysis calculated for C 18 H 18 N 2 O 2 .HCl.H 2 O 5; C 49.05, H 6.58, N 14.29,

Cl, 7.24 Found: C 48.88, H 6.63, N, 14.52, Cl 7.56.

Example IX

The procedure described in Example VII was repeated to prepare the following 2-substituted-4-amino-6,7,8-trimethoxyquinazolines, expressed as hydrochlorides, starting from 2-chloro-4-amino-6,7,8-tri- methoxyquinazoline and a suitable primary or secondary organic amine reagent in each case.

2- (N-monomethylamino) -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 229-231 ° C.

2- (N, N-dimethylamino) -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 237-259 ° C.

2- (N, N-diethylamino) -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 186-188 ° C.

2- [N, N-di- (n-propyl) amino] -4-amino-6,7,8-trimethoxyquinates soline hydrochloride, m.p. 201-205 ° C.

2- [N, N-di (p-hydroxyethyl) amino] -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 220-222 ° C.

2- (N-pyrrolidine) -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 218-220 ° C.

2- (N-piperidine) -4-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 219-221 ° C.

12 57403 2- (N-homopiperidine) - * + - amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 186-189 ° C, 2- (4-benzoyl-1-piperazine) -1H-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 175-177 ° C.

2- (2- (2-iuroyl) -1-piperazine) -N-amino-6,7,8-trimethoxyquinazoline hydrochloride, m.p. 208-209 ° C.

Ethyl * - (* ♦ -amino-6,7,8-trimethoxyquinazolin-2-yl) -piperazine-1-carboxylate hydrochloride, m.p. 228-230 ° C.

isobutyl 4- (U-amino-6,7,8-triraethoxyquinazolin-2-yl) piperidine-1-carboxylate hydrochloride, m.p. 190-192 ° C.

Conversion of each of the above hydrochloride salts to the corresponding free organic base compound, in each case with saturated aqueous sodium bicarbonate, as in Example VII, gives the corresponding 2-substituted-4-amino-6,7,8-trimethoxyquinazoline in pure form as such.

Therapeutic experiments

The antihypertensive effect of the following 2-substituted-4-amino-6,7,8-trimethoxyquinazolines was tested against consciously over-stressed dogs using the method of Priol and Winbury, described in Journal of Applied Physiology, 15 (1960), p. 323, and were found to be effective at the reported concentrations given both orally and intravenously. Compounds were administered as hydrochloride salts and blood pressure determinations were performed just prior to drug administration and several times thereafter (e.g., two, four, and 2 * »hours thereafter) using at least two or more dogs to evaluate each compound. Activity has therefore been reported as a range of blood pressure (mm Hg) reductions observed in two or more dogs, while concentrations are reported in mg / kg per dose.

) CH3 JL .H.

HjCO- ^ - Z

nh2 13 57403

Activity a) vascular b) oral administration Z AP mm Hg (mg / kg / day) «AP mm Hg (mg / kg / day) NHCH3 25-42 (10), 25-30 (20) N (ch3> 2 12-20 (1), 30-60 (4) 7-45 (10), 12-32 (20) N (C2H5) 2 0-15 (1), 10-20 (4) 20 (5), 0 -25 (10) N (n-C3H2) 2 0-15 (4), 0-70 (8) ..............- N (CH2CH2OH) 2 .... ...... 0-30 (10) ------- N-pyrrolidino 10-15 (1), 10-22 (4) -------- ------- N-piperidino 10-30 (1), 15-40 (2) 0-8 (10), 0-20 (20) N-homopiperidine 0-20 (2), 10-50 (4) 0-15 (10) ), 0-15 (20)

Values in parentheses refer to dose levels in mg / kg / day. The reduction in blood pressure (AP mm Hg) represents the maximum values obtained regardless of time in each individual case. The reported blood pressure ranges indicate degradation between different dogs.

The above test procedure was repeated to determine the antihypertensive activity of the following 2-substituted-4-amino-6,7,8-trimethoxyquinazoline compounds, and the results obtained were as follows:

H3C0 - \ / '® · R

h3co —'- NH2 “57403

Activity a) vascular b) oral R R mm mm Hg (mg / kg / day) AP nun Hg (mg / kg / day) phenyl 0-10 (4), 0-15 (8) ------ - 2-furyl 15-25 (3.2), 20-40 (6.4) 8-35 (10), 35-42 (20) OC ^ Hgi iso) 15-24 (4), 18-40 (10) 35 -40 (10), 18-35 (20) 0CH2C (CH3) = CH2 20 (4), 15-25 (8) 15-20 (10), 15-20 (20) OCH2C (OH) (CH3) 2 10-26 (1), 6-24 (4) 15-30 (2.5), 30-42 (10)

Claims (1)

A process for the preparation of antihypertensive 2-substituted-* - - amino-6,7,8-trialkoxyquinazolines of the formula OR 'R' ° -—z 1 R, ° - nh2 and their acid addition salts, wherein R ' is methyl or ethyl and Z is monoalkylamino or dialkylamino each having up to three carbon atoms in the alkyl moiety, mono- (N-hydroxyethyl) amino, di - (N-hydroxyethyl) amino, pyrrolidino, piperidino, homopiperidino or N-substituted piperazino having is wherein R is alkoxy of 1 to 6 carbon atoms, alkenyloxy of up to five carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, phenyl or furyl, characterized in that 2-halo-4 -amino-6,7,8-trialkoxyquinazoline of the formula OR 'R'0-1 (| formula ZH, where Z has the same meaning as above, and that, if necessary, hydrogenation is subsequently obtained a compound of formula I wherein R is alkenyloxy to form a compound of formula I wherein R is hydroxyalkoxy, and optionally converting the resulting compound to an acid addition salt.