IE44614B1 - 4-amino-6,7-dimethoxy-2-(4-(heterocyclylcarbonyl) piperazin-1-yl) quinazolines - Google Patents

Abstract

The compounds of the formula I are obtained by reacting compounds of the formula II with a reagent of the formula in which the substituents have the meaning given in Patent Claim 1. The products which are obtained exhibit an anti-hypertensive effect which is comparable with that of prazosin; however, the peripheral alpha -adrenergic blocking effect of the products is in general much smaller than that of prazosin.

Description

This invention relates to nitrogen containing heterocyclic carbonyl piperazinyl quinazolines which are potent antihypertensive drugs having generally less α-adrenergic blocking activity than does 2-/4-(2-furoyl)-piperazin-l-yl7-4-amino~6,7dimethoxyquinazoline which is a known potent antihypertensive drug.

More particularly, this invention relates to compounds having the formula wherein Z is 2 wherein X is either oxygen or sulfur, R and R may be the same or different and are selected from hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms and alkylthio having from 1 to 6 carbon atoms, and R is alkyl having from 1 to 6 carbon atoms; or pharmaceutically acceptable acid addition salts thereof.

The invention also includes processes for the preparation thereof.

United States Patent Nos. 3,511,386; 3,635,979 and 3,663,706 disclose several 4-amino-6,7-dimethoxy2-/4-(heterocyclic-2-carbonyl)-piperazin-l-yl7 quinazolines. One of these compounds, i.e. 2-£4-(2furoyl)-piperazin-l-yl/-4-amino-6,7-dimethoxyquinazoline described in Example LXXII of these Patents is a clinically useful antihypertensive agent and is marketed as such in many countries of the world under the generic name prazosin. It is well extablished that the antihypertensive efficacy of prazosin results from a dual mechanism of action: (i) a direct peripheral vasodilatation effect on vascular smooth muscle; and (ii) a functional peripheral a-adrenergic receptor blockade, II. Adriaensen, The Practitioner, 214, 268 (1,975); Mroczek, ei ql·, Current Therapeutic Research, 16, 769 (1974); Scriabine, et al., Experientia, 24, 1150 (1968); Constantine, et al., Hypertension: Mechanisms and Management, ed. by Onesti, Kim and Moyer; Grune and Stratton, 1973 pp. 429-44; and Zacest, Med. J-. of Austral. Special Supplement, 1, (1975).

Although initial clinical assessments on prazosin indicated an almost complete absence of side effects, recent reports have revealed severe adverse reactions of postural hypotension in some patients, Bendall, et al.. Brit. Med. J., 727 (June 28, 1975); Rees, Brit. Med. J., 593 (Sept. 6, 1975); Gabriel, et al_., The Lancet, 1095 (May 10, 1975); and, Bloom, et al., Current Therapeutic Research, 18, 144 (1975). It is generally felt that this type of side effect results from the a-blockade component of prazosin. Indeed, it has been stated by R. Zacest in the Med. J. of Austral. Special Supplement, 1, 4 (1975) that if the alpha adrenergic 'blocking* activity does prove to be significant with high doses it may lead to postural hypotension.

United States Patents Nos. 3,669,968 and 3,769,286 cover trialkoxyquinazolines, such as those having the formula: - 5 wherein R may be a number of different groups including furyl and thienyl. These patents claim to have certain advantages over the corresponding 6,7-dialkoxy compounds such as those disclosed in the patents previously discussed. Thus, it is stated that such compounds have a more favorable pharmacological profile (e.g., they are non-adrenolytic in dogs) and possess greatly improved solubility characteristics (particularly in water) as contrasted to the corres10 ponding 6,7-dialkoxy compounds reported in the prior art. One of the compounds disclosed in these patents is known by the generic name trimazosin and has the formula: Trimazosin is reported to be active in humans as an antihypertensive agent, DeGuia, et al., Current Therapeutic Research, 15, 339 (1973); Vlachakis, et al., Current Therapeutic Research, 17, 564 (1975). However, it is a much weaker drug than prazosin, the respective clinical daily dose ranges being approximately 150 to 500 mg. for trimazosin as compared to 1.5 to 15 mg. for prazosin. Trimazosin is therefore 100-fold weaker than prazosin at the lower end of the dosage range.

U.S. Patent Nos. 3,517,005; 3,594,480; and 3,812,127 describe certain piperazinyl quinazolines having both bronchodilator and antihypertensive activity, e.g., a compound having the formula: wherein A and B may each be alkoxy, etc., S' may be hydrogen or alkyl and R'1 may be hydrogen or a radical such as alkyl, benzoyl, etc.

U.S. Patent No. 3,920,636 describes homopipera zino quinazolines as antihypertensive agents, e.g., the compound: U.S. Patent NO. 3,780,040 discloses compounds useful as antihypertensive agents such as the compound: Netherlands Application 72 06,06 (CA, 78,, 72180s) describes a process for preparing aminoquinazolines, such as prazosin, by treating the corresponding o5 aminobenzonitrile in the presence of phenyl lithium according to the following mechanism: wherein RjN may be the group 4-(2-furoyl)-1-piperaziny 1.

We have found that compounds having the Formula I above and pharmaceutically acceptable acid addition salts thereof, possess antihypertensive potency comparable to prazosin but have generally less of the peripheral α-adrenergic blocking properties shown by prazosin. Preferred embodiments of this invention are compounds having the formula: 4 614 in Which R is (lower)alkyl having from 1 to 4 carbon atoms and pharmaceutically acceptable acid addition salts thereof. These compounds possess antihypertens5 ive potency comparable to prazosin but have little or none of the peripheral ct-adrenergic blocking properties shown by prazosin. These compounds are potent antihypertensive agents which have little or no potential for side effects as reflected by their lack of adrenoly tic activity.

The most preferred compound of this invention is 4-amino-6,7-dimethoxy-2-/%-(5-methylthio-l,3,4-oxidiazole-2-carbonyl)piperazin-l-y3/-quinazoiine having the formulas ch30 CHo0 4614 - 9 and acid addition salts thereof, in particular, the hydrochloride salt. Other preferred compounds are disclosed hereinafter in the Examples, two of which compounds are prepared in the form of the monohydrate thereof.

The term pharmaceutically acceptable1’ used herein to describe an acid addition salt of a compound of Formula I refers to those salts of relatively nontoxic inorganic or organic acids. The anion does not contribute appreciably to the toxicity of the salt or to its pharmacological activity. Illustrative of such salts are those formed with acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic and p-toluenesulfonic acids. Preparation of the mono-acid addition salts may be carried out in conventional manner by treating a solution or suspension of the free base in a reaction inert organic solvent with one chemical equivalent of the acid or, if the di-acid addition salt is desired, at least two chemical equivalents of the acid. Conventional concentration or crystallization techniques are employed in isolating the salts.

This invention also provides process for the preparation of compounds of the formula I and pharmaceutically acceptable acid addition salts thereof.

According to the present invention, compounds of Formula I are prepared by a process which comprises reacting a quinazoline derivative of Formula II B 4 61-1 in which substituent A is NH2 or NR'2, wherein R*2 is a conventional amine protecting group, and substituent B is chlorine, piperaz,inyl or OR' ’ wherein R'1 is the radical FjCC(0)-, CH3SO2-, F-jCSOj-, or alkyl S02~ II with a reactant selected from Y-C-Z when B is pipera0 II ainyl and Z-C-piperazine when B is other than piperazinyl, wherein Y ia a carbonyl activating group of the type typically used in amidation reactions, e.g. halo, azido,, ethoxy, carbonyloxy and 1-imidazo and Z is as defined above when necessary, removing the amine protecting group R'2 by conventional means and, if desired, converting the product to a, pharmaceutically acceptable acid addition salt by methods known per se.

The following reaction schemes of Equations 1-5 illustrate the various synthetic routes embodied in the preparation of the compounds of the present invention according to the process discussed above. 461 3 - 11 In a preferred embodiment of this process, Z is SR and the reaction is conducted in an inert solvent such as dioxane, chloroform, methylene chloride or glycol dimethyl ether at room temperature, and/or with heating at reflux to insure completion of the reaction.

In a more preferred embodiment, Y is chlorine, Z is conducted and the reaction is s-ch3 Equation 2 I In a preferred ^embodiment of this process t 4 614 - 13 The amine protecting group may then be removed from compound 1(a) by conventional means to provide the product compound I. 1(a) 448 1 4 As in the reaction of Equation 3, the amine protecting group R'j may be removed from compound la by conventional means to provide the product compound I. 4 6 11 - 15 The compounds of the present invention may also be prepared by the following reaction sequence: CII3O I 4611 ,-16The invention also includes pharmaceutical compositions in dosage unit form adapted for administration to a mammal comprising a compound of the formula I as defined above or a pharmaceutically acceptable acid addition salt thereof. The invention also includes pharmaceutical compositions comprising a compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof together with an inert pharmaceutical diluent or carrier.

The following Examples illustrate the invention.

Example 1 4-Amino-6,7-dimethoxy-2-/£-(5-methylthio-l,3,4-oxadiazole-2-carbonyl)-plperazin-l-yjj) -quinazoline hydrochloride , A solution of 5-methylthio-l,3,4-oxadiazole-2carbonyl chloride (0.601 g., 3.36 mmole) in dioxane (10 ml) was added to a solution of 4-amino-6,7-dimethoxy-2-(l-piperazinyl)quinazoline (0.972 g., 3.36 mmole) in dioxane (100 ml.). The resultant mixture was stirred at room temperature for 65 hours, then was heated at reflux for 30 minutes. Filtration gave the title compound (1.56 g.). Recrystallization from methanol gave a product having a M.P. of 280-285°C. with decomposition.

Anal. Calcd for ClgH21N7O4S.HCl: C, 46.20; H, 4.74; Cl, 7.58; N, 20.96; S, 6.85 C, 46.34; H, 4.89; Cl, 7.59; N, 20.38; S, 6.58.

Found: 4 614 - 17 Example 2 4-Amino-6,7-dimethoxy-2-/4-(5-ethylthio-l,3,4-oxadiazole-2-carbonyl)-piperazin-l-yl7_quinazoline hydrochloride Pound: The title compound was prepared from 5-ethylthiol,3,4-oxadiazole-2-carbonyl chloride (0.79 g., 4.1 mmole) and 4-amino-6,7-dimethoxy-2-(l-piperazinyl)“ quinazoline (1.19 q., 4.1 mmole) following the procedure described in Example 1. The product had a M.P. of 246248.5°C.

Anal. Calcd. for C19H23N7O4S.HC1: C, 47.34; H, 5.02; N, 20.34; S, 6.65 Found: C, 47.37; H, 4.76; N, 20.15; S, 6.71. (corrected for 4.11% Il20) Example 3 4-Amino-6,7-dimethoxy-2-/3-(5-isopropylthio-l,3,4oxadiazole-2-carbonyl)-piperazin-l-yl7~quinazoline hydrochloride The title compound was prepared from 5-isopropylthio-l,3,4-oxadiazole-2-carbonyl chloride (1.54 g., 7.5 mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.1 g., 7.5 mmole) following the procedure of Example 1. The product has a M.P. of 26O-263°C. with decomposition.

Anal. Calcd. for C2OH25N7°4S‘HC1: C, 48.43; H, 5.28; N, 19.77 C, 48.05; H, 5.20; N, 19.61. 4 614 - 18 Example 4 4-Amino-67-dimethoxy-2-/T- (5-n-propylthio-l, 3,4-oxadiazole-2-carbonyl)-piperazin-l-yiy-quinazoline hydrochloride The title compound was prepared from 5-n-propylthio-1,3,4-oxadiazole-2-carbonyl chloride (1.68 g., 8.16 mmole) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (2.36 g., 8.16 mmole) following the procedure of Example 1. The product had a M.P. of 23O-245°C. with decomposition.

Anal. Calcd. for C2OH25N7°4®‘HC''': C, 48.43? H, 5.25; N, 19.77 Found: C, 48.11; H, 5.35; N, 19.65.

Example 5 4-Amino-6,7-dimethoxy-2~23“(5-jj-butylthio-l,3,4-oxadiazole-2-carbonyl)-piperazin-l-yl7-quinazoline hydrochloride .

The title compound was prepared from 5-n-butylthio l,3,4-oxadiazole-2-carbonyl chloride and 4-amino-6,720 dimethoxy-2-(1-piperazinyl) quinazoline following the procedure of Example 1.

Example 6 4-Amino-6',7“dimethoxy-2-ZJ- (isoxazole-5-carbonyl) piperazin-l-yl7qulnazoline hydrochloride A solution of isoxazole-5-carbonyl chloride (1.33 g., 0.01 mole) in dioxane was added to a solution at 30°C. of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)•1 u 6 1 .j - 19 quinazoline (2.94 g.r 0.01 mole) in dioxane. The mixture was stirred at reflux for three minutes, then at room temperature for 16 hours. Filtration gave the title compound (4.02 g., 94% yield). Recrystallizat- ion from aqueous methanol gave a product having a : of 27O°C. with decomposition. Anal. Calcd. c,£or C18H2ON6°4HC;L: 51.37; H, 5.03; Cl, 8.42; N, 19.97 Found: c, 50.86; H, 4.65; H, 4.65; Cl, 8.52; N, 19.81 (corrected for 4.30%H2°) Example 7 4-Amino-6,7-dimethoxy-2-/4- (isoxazole-3-carbonyl) piperazin-l-yjj'quinazoline hydrochloride A solution of isoxazole-3-carbonyl chloride (0. 753 g., 0.0057 mole) in dioxane (20 ml.) was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.66 g., 0.0057 mole) in dioxane (60 ml.). The mixture was stirred at reflux for 30 minutes, then at room temperature for 64 hours. Filtration gave the title compound which was recrystallized from methanol (1.81 g., 75% yield). The product had a m.p. of 268273°C. with decomposition.

Anal. Calcd. for C^gHgQNgO^HCl: C, 51.37; R, 5.03; Cl, 8.42; N, 19.97 Found: C, 50.04; H, 4.86; Cl, 8.66; N, 19.57 (corrected for 3.11%H2°) . -20Example 8 4-Amino-6,7-dimethoxy-2-/£-(isoxazole-4-carbonyl)pipera2in-l-yl7quinazoline hydrochloride A solution of isoxazole-4-carbonyl chloride 5 (1.06 g., 8.08 mole) in dioxane (8 ml.) was added to a solution of 4-amino“6,7-dimethoxy-2-(l-piperazinyl)quinazoline (2.34 g., 8.08 mmole) in dioxane (200 ml.). The mixture was stirred, at room temperature for 20 hours. Filtration gave the title compound, which, after recrystallization from methanol, had a m.p. of 255-26O°C. with decomposition.

Anal. Calcd. for C-^B^NgO^HCl: C, 51.37; H, 5.03; Cl, 8.42; N, 19.97 Found: C, 51.37; H, 4.95; Cl, 8.34; N, 19.95 15 (corrected for 1.63% h2o) Example 9 4-Amino-6,7-dimethoxy-2-/4-(5-methylisoxazole-3carbonyl)piperazin-l-yl7quinazoline hydrochloride hydrate ' A solution of 5-methylisoxazole-3-carbonyl chloride (0.41 g., 2.83 mmole) in dioxane was added to . a solution of 4-amino-6,7-dimethoxy-2-(l-piperazinyl) quinazoline (0.82 g., 2.83 mmole) in dioxane. The mixture was treated as described in the previous example to give the title compound having a m.p. of 271-273°C. with decomposition.

Anal. Calod. for C-^H^NgO^HCl HjO: C, 50.38; H, 5.56; N, 18.56; H20, 3.92 4 61.1 - 21 Found: C, 50.58; H, 5.40; N, 18.86; H20, 3.72 Example 10 4-Amino-6,7-dimethoxy-2-/?·-(3-methylisoxazole-4carbonyl)plperazin-l-yl7qulnazoline hydrochloride A solution of 3-methylisoxazole-4-carbonyl chloride (1.01 g., 6.9 mmole) in dioxane and 4-amino6,7-dimethoxy-2-(l-piperazinyl)quinazoline (2.00 g., 6.9 mmole) in dioxane was stirred under reflux for 15 hours, then worked up as described in Example 6. The title compound after recrystallization from methanol had a m.p. of 300“301°C. with decomposition.

Anal. Calcd. for CigH22 nco:hci 6 4 c. 52.47; H, 5.33; N, 19.33 Found : C, 52.62; H, 5.31; N, 19.12 (corrected for 1.13% 1^0) Example 11 4-Amino-6,7~dimethoxy-2-/J-(3-methylisoxazole-5carbonyl)pipera2 in-l-y!7quinazoline hydrochloride A solution of 3-methylisaxazole-5-carbonyl chloride (0.73 g., 5.02 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl) quinazoline (1.45 g., 5.02 mmole) in dioxane. The mixture was heated briefly, then was stirred at 20°C. for 2.5 hours. Workup as in Example 6 gave the title compound having a m.p. of 263-264°C. with decomposition. Anal. Calcd. for C^gH^NgO^HCl: - 22 C,. 52.47? fi, 5.33; Cl, 8.15? N, 19.33 Found; C, 51.82? H, 5.04? Cl, 8.36? N, 19.46 (corrected for 4.82% H20) Example 12 4-Amino-6,7-dimethoxv-2--/T- (oxazole-4-carbonyl)piperazin-l-yi7guinazoline 'hydrochloride hydrate A solution of oxazole-4-carbonyl chloride (0.73 g., 5.53 mmole) in dioxane was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.60 g., 5.53 mmole) in dioxane. The mixture was heated at reflux for 0.5 hour, then was stirred at 20°C for 64 hours. Filtration gave the title compound having a m.p. of 291-294°C. with decomposition after recrystallization from aqueous ethanol.

Anal. Calcd. c, for C18H2ON6O*HC1-H2O: 49.26; H, 5.28; Cl, 8.08; N, 19.15 Found: C, 48.92; H, 4.83; Cl, 8.33; N, 18.94 Example 13 4-Amino-6,7-dimethoxy-2-^T-(2-methyloxazole-4-carbonyl)piperazin-l-yJ7quinagollbe hydrochloride A solution of 2-methyloxazole-4-carbonyl chloride (l.ol g., 6.9 mmole) in dioxane was added to a solution Of 4-amino-6,7~dimethoxy-2-(1-piperazinyl)quinzoline (2.00 g., 6.9 mmole) in dioxane. The mixture was heated at reflux for 2 hours. Filtration gave the title compound having a m.p. of 278-28O°C. with decomposition after recrystallization from methanol. 16 1 -J - 23 Anal. Calcd. for ClgH NgO^HCl: C, 52.47; H, 5.33; N, 19.33 Found: C, 52.08; H, 5.43; N, 18.89 (corrected for moisture) Example 14 4-&nino-6,7-dimethoxy-2-/T-(4-methyloxazole-5-carbonyl)piperazin-l-yl~7guinazoline hydrochloride The title compound was prepared from 4-methyloxazole-5-carbonyl chloride (0.85 g.) and 4-amino-6,7dimethoxy-2-(1-piperazinyl) quinazoline (1.68 g.) following the procedure of Example 6. The product had a m.p. of 283.5-288°C. with decomposition.

Anal. Calcd. for ^19^22^60^^3-1 C, 52.48; H, 5.33; Cl, 8.15; N, 19.33 Found: C, 52.19; H, 4.94; Cl, 8.13; N, 19.05 (corrected for 1.59% H20) Example 15 4-Amino-6,7-dimethoxy-2-/J-(isothiazole-4-carbonyl)piperazin-l-yl7quinazoline hydrochloride The title compound was prepared from isothiazole4-carbonyl chloride (1.01 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.99 g.) following previously described procedures. The product had a m.p. of 286-287°C. with decomposition.

Anal. Calcd. for C^gHjQNgOjS’HCl: C, 49.48; H, 4.84; Cl, 8.11; N, 19.23; - 24 4 4614 S, 7.34 Found: C, 49.20; H, 4.81; Cl, 8.19; N, 19.27; S, 7.23 (corrected for 0.93% H20) Example 16 4-Amino-6,7-dimethoxy-2-/J-(thiazole-2-carbonyl)piperazin-l-yl7quinazoline hydrochloride,' The title compound was prepared from thiazole2-carbonyl chloride ¢0.79 g.) and 4-amino-6,710 dimethoxy-2-(1-piperazinyl)quinazoline (1.54 g.) following previously described procedures. The product had a m.p. of 273-276°C. with decomposition.

Anal. Calcd. for C18H2ON6O3S.HC1: c, 49.48; H, 4.84; N, 19.23 15 Found: c, 48.68; H, 4.62; N, 18.87 (corrected for 4.19% H.,0) Example 17 4-Amino-6,7-dimethoxy-2-yT- (thiazole-4-carbonyl)piperazin-l-vC7quinazollne hydrochloride 20 The title compound was prepared from thiazole4-oarbonyl chloride (1.02 g.) and 4-amino-6,7dimethoxy-2-(1-piperazinyl)quinazoline (2,00 g.) following previously described procedures. The product had a m.p. of 274-277°C with decomposition.

Anal. Calcd. for ci8H2O^6°3S'HCL: C, 49.48; H, 4.84; N, 19.24; 4461 - 25 Found: C, 49.11; H, 4.69; N, 19.31 (corrected for 4.47% H20) Example 18 4-Amino-6,7-dimethoxy-2-Z3-(2-methylthiazole-4-carbonyl)piperazin-l-yl7guinazoline hydrochloride The title compound was prepared from 2-methylthiazole-4-carbonyl chloride (0.49 g.) and 4-amino-6,7 dimethoxy-2-(1-piperazinyl)quinazoline (0.87 g.) following previously described procedures. The product has a m.p. of 26O-263°C. with decomposition.

Anal. Calcd. for C19H22NgO3S’HCl: C, 50.60; H, 5.14; N, 18.64 Found: C, 50.88; H, 4.96; N, 18.67 (corrected for 2.88% H20) Example 19 4-Amino-6,7-dimethoxy-2-/3-(thiazole-5-carbonyl)pipera zin-l-yl/quinazoline hydrochloride The title compound was prepared from thiazole-5carbonyl chloride (0.77 g.) and 4-amino-6,7-dimethoxy2-(1-piperazinyl)quinazoline (1.51 g.) following previously described procedures. The product had a m.p. of 28O-281°C. with decomposition.

Anal. Calcd. for C18H2oNgO3S«HCl: C, 49.48; H, 4.84; Cl, 8.11; N, 19.23; S, 7.34 Found: C, 49.22; H, 5.19; Cl, 8.31; N, 19.49; S, 6. 79 4 614 - 26 (corrected for 2.63% H20) Example 20 4-2Smino-6,7-dimethoxy-2-/T-(2-methylthiazole-5-carbonyl)piperazin-l-yl7guinazoline hydrochloride The title compound was prepared from 2-methylthiazole-5-carbonyl chloride (0.42g.) and 4-amino6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.75 g.) following previously described procedures. The product had a m.p. of 294-297°C. with decomposition.

Anal. Calcd. for ci9H22N6°3SHCli C, 50.60; H, 5.14; N, 18.64 Found: C, 50.60; H, 4.95; N, 18.50 (Corrected for 1.96% H20) Example 21 4-Amino-6,7-dimethoxy-2-/J-(4-methylthiazole-5-oarbonyl)piperazin-l-yl^ quinazoline hydrochloride The title compound was prepared from 4-methylthiazole-5-carbonyl chloride (1.1 g.) and 4-amino-6,7dimethoxy-2-(1-piperazinyl)quinazoline (2.0 g.) following previously described procedures. The product had a m.p. of 293-295°C. with decomposition.

Anal. Calcd. for C H„oNc0oS*HCl: 3,9 zz o 4 C, 50.60; H, 5.14; N, 18.64 Found: C, 50. 47; H, 4.78; N, 18.43 (corrected for 4.72% H20) -3461α -27Το determine the efficacy of the compounds of this invention as antihypertensive agents, tests were conducted comparing these products to prazosin.

Table 1 below sets forth the comparison of the 5 product of Example 1 to prazosin. As shown in Table 1, the product obtained in Example 1, above (hereinafter referred to as BL-5111) is of comparable antihypertensive potency to prazosin, but has little or none of the peripheral α-adrenergic blocking properties shown by prazosin. io Tnis compound thus represents a significant and unexpected advance in the continuing quest for potent antihypertensive drugs which have little or no potential for side effects as reflected by their lack of α-adrenergic blocking activity.

In Table 1, antihypertensive activity was determined by oral administration to spontaneous hypertensive rats, and the in vitro and in vivo α-adrenergic receptor blocking effect was determined by tests described following Table 1. In the in vitro test, the inhibition by BL-5111 Of norepinephrine induced contractions of rat seminal vesicles was measured; and in the in vivo test, the inhibition by BL-5111 of norepinephrine induced pressor responses in anesthetized dogs was measured. The in vivo tests were conducted using intravenous administration, each compound being assayed in 4 dogs with 2 dose response results in each dog. -28Table o o in Q > H P 0 •P +1 ft □ Φ φ 0 M-l Φ M Ρί W □ σ Ή β ΰ\Ή Ρ 44 Φ ο β Ο Φ Η Μ CQ Ό S Cn λ: \ tn β Ο >ι > +> •rl *r| Ο > >·Η •H +J β +> Λ Η Ο « - < Ο ·Η·Η Ο £υ« < >1 •Ρ •rl· > Ο •Η «Η Ρ Ρ □ Φ Η kO 1*3 Ο «Η ο ί—j Γ* ιη μ· Ο Ο σ r-I σ> Ο £ •Η > •Η Ρ ϋ < Φ V) β φ Ρ Μ Φ ft •Η Ρ β < Cn mX Q 2* φ ρ β φ rd wO cr ο οΐββ Ο Φ Φ Η Ρ§Λ iQfteo όΡ m fM μ< ω ch Μ* Γ4 Η III ο fO Η Η Ο cn Η γΗ «Η «Η m η I 4 614 -29ISOLATED RAT SEMINAL VESICLE ASSAY Dangan al, Int. J. Neuropharmacol., 4:219 (1965) have shown that the seminal vesicle of the rat is a tissue which is notably responsive to compounds which activate a-receptors but is relatively insensitive to compounds which activate β-receptors. Lietch et al, Brit. J. Pharmacol., 9:236 (1954) have employed the isolated rat seminal vesicle in the comparative assay of α-receptor blocking drugs and the present studies were carried out using a modification of their procedure.

Male Long Evans rats weighing approximately 300 g. were sacrificed by a sharp blow on the head. Seminal vesicles were removed and transfered to a shallow dish containing modified Tyrode's solution. The vesicles were emptied of their contents by squeezing them gently with a pair of forceps. Silk thread (4-0) was attached to both ends of the vesicle and it was suspended in a 20 ml. muscle chamber containing modified oxygenated Tyrode's solution (g./liter: NaCl 8, KC1 0.2, CaCl2 0.26, NaHCOj l,Na2HPO4 0.0575, glucose 0.5 and MgCl2 0.02). The bathing fluid was maintained at 37°C. with a thermostatically controlled isolated organ tissue bath. Contractions were recorded isometrically by means of a force displacement transduced and recordings were made with a Beckman RP Dynograph. (Beckman is a 4 614 -30Registered Trade Mark) Norepinephrine (NE) was added to the muscle chamber ih volumes ranging from 0.1 to 0.4 ml with a one ml. syringe attached to a 3 inch 20 gauge needle.

NE and test compounds were dissolved in deionized water.

NE dose response curves were obtained alone and in the presence of test compounds. NE was allowed to remain in contact with the strip until a maximal contraction was obtained. The strip was then washed with the perfusion fluid for 15'—30 seconds and the preparation was allowed to return to base line before a subsequent dose of NE was given. Increasing amounts of NE were injected into the bath in the same manner until a complete dose response was obtained.

The seminal vesicles used to obtain the control NE dose response were discarded and new preparations were placed in the tissue bath for evaluation of the test compound. The test compound was added directly to the perfusion fluid (10 nanograms/ml.) and the strips were allowed to remain in contact with the bathing media for at least 10 minutes before the NE dose response was determined.

ED50 values for NE were obtained by regression analysis as described by Finney, Frobit. Analysis, 2d Ed., Cambridge (1964). A minimum of 4 strips and at least 4 doses were employed to calculate the regression lines. The ED50 value is defined as the concentration of NE which produces a contraction equal to 50% of the maximal contraction. 34614 -31The ratio of the α-adrenergic blocking activity of BL-5111 relative to that of prazosin was calculated as follows: % Change from NE =ED50 NE + Drug - ED50 NE Alone x 100 ED50 NE Alone 5 The value obtained for BL-5111 was then expressed as a ratio of the value obtained for prazosin.

Activity Ratio = % Change for NE - BL-5111 % Change from NE - Prazosin The results obtained with NE, prazosin and BL-5111 are summarized in Table II.

Table II Effect of Prazosin and BL-5111 on NE Response in Isolated Rat Seminal Vesicles NE Activity ED50 with 95% Ratio Treatment No. of Strips Conf. Limits Percent Change Relative (ug/ml) From control Prazosin Control 32 0.89 (0.84-0.94) - - Prazosin, 10 nano/ml. 8 6.03 (5.30-6.81) 578 1.0 BL-5111 10 nano/ml. 7 0.93 (0.80-1.08) 4.5 0.008 These data indicate rather clearly that at a concentration of 10 nanograms/ml., prazosin caused nearly a six fold decrease in the sensitivity of isolated rat seminal vesicles to the stimulant activity of NE while 14 -32BL-5111 was essentially inactive in this respect. It was concluded that BL-5111 possesses less than one percent of the α-adrenergic blocking activity of prazosin.

ANESTHETIZED DOG ASSAY FOR a-ANDRENERGIC BLOCKING AGENTS Nash, C.B., Pharmacological Research Communications, 4:423, (1969) and Maxwell, R.A., Drill's Pharmacology in Medicine, (1971) p. 683 have shown that in anesthetized dogs α-adrenergic blocking agents antagonize the blood pressure elevating effects of intravenous norepinephrine. Thus, blood pressure responses to norepinephrine (NE) in anesthetized dogs was used as a comparative assay for aadrenergic receptor blocking properties of drugs .. -Experiments were done on mongrel dogs anesthetized with sodium pentobarbital, 30 mg./kg. iv. The left femoral artery was cannulated to record aortic blood pressure and a femoral vein was cannulated for administration of drugs.

All animals underwent a bilateral vagotomy. A norepinephrine dose-response curve was obtained by administering increasing doses of iv. norepinephrine (0.01 - 1 ug/kg).

The test drug (prazosin, BL-5111) was then administered iv. at 3 mg/kg. Approximately 30 minutes later a dose-response curve was again established for iv. norepinephrine (0.0110 ug/kg). The dose of norepinephrine (with 95% confidence limits) that increased blood pressure by 50 mm of HG was obtained from dose-response curve analysis before and after 4 614 -33prazosin and BL-5111. The ratio of the a-adrenergic blocking activity of BL-5111 relative to that of prazosin was obtained as follows; ED5O mm HG ED5O mm Hg Activity Ratio = BL-5111 _NE_ ED50 mm Hg - ED50 mm Hg Prazosin NE The results obtained with norepinephrine, prazosin and BL-5111 are summarized in Table III. The results indicate that BL-5111 was approximately 30 times less active than prazosin in causing α-adrenergic blockade at 3 mg/kg iv.

Table III Effect, of Prazosin and BL-5111 on the Blood Pressure Response to Intravenous Norepinephrine Treatment N Control 20 Prazosin, 4 mg/kg BL-5111 4 NE ED50 mm Hg W/95% Conf. Limits 0.23 (0.19-0.28) 6.90 (4.80-10.7) 0.47(0.40-0.55) Activity Ratio Relative to Prazosin 1.00 0.036 Table IV below sets forth the comparison test data for the products of Examples 6-21 and prazosin. As shown in this table, the products obtained in the foregoing Examples 6-21 are of comparable antihypertensive potency to prazosin, but have generally less of the peripheral aadrenergic blocking properties shown by prazosin. These compounds thus represent a significant and unexpected advance in the continuing quest for potent antihypertensive drugs. -34Antihypertensive Activity ct-A3renergic Receptor Blocking Effect TABLE IV Example Dose . ng/kg. % Blood Pressure Change In Vitro Activity Ratio Prazosin ΓΟ -42 1.0 (Reference 3 -29 Drug) 1 -14 6 10 -35 0.11 3 -26 1 -15 7 10 -32 3 -26 1 -12 8 10 -35 0.S2 3 -23 1 -13 9 10 -41 0 3 -18 1 -14 10 10 -33 0.30 3 -29 1 -17 11 10 -37 0.25 3 -21 1 -18 12 10 -45 0.6 3 -29 1 -15 13 10 -35 0.17 3 -31 1 -13 14 10 -41 0.19 3 -26 1 -14 15 10 -25 3 -23 1 -14 16 10 -33 3 -27 1 -14 m Vivo Activity Ratio 1.0 0.18 0.24 0.18 1.22 4 614 -35TABLE IV (Cont'd) Antihypertensive Activity a-Andrenergic Receptor Blocking Effect Example 17 Dose % Blood Pressure In Vitro In Vivo irgAg__Change Activity Ratio Activity Ratio -32 0.12 -24 -20 -28 -28 -19 -33 -22 -12 -37 -25 -20 -28 -22 -4 0.02 0.10 0.19 0.09 0.35 4 614

Claims (28)

1. CLAIMS:1. Compounds having the formula in which Z is *\X N O J-' Al· 2 X J- s 1 2 wherein X is either oxygen or sulfur, R and R may be the same or different and are selected from hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms and alkylthio having from 1 to 6 carbon atoms, 10 and R is alkyl having from 1 to 6 carbon atoms; or pharmaceutically acceptable acid addition salts thereof.

A compound of Claim 1, in which Z is the radical Λ7Λ2. -37'3461 1 and R 3 is alkyl of 1 to 4 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.

3. A compound according to Claim 2, or a pharmaceutically acceptable acid addition salt thereof, wherein R is methyl. 5

4. The compound of Claim 1, in which Z is the radical 1 2 in which X, R and R are as defined in Claim 1.

5. A compound of Claim 4 in which X is oxygen.

6. A compound of Claim 4 in which X is sulfur. 10

7. A compound of Claim 1, in which Z is the radical. 1 2 in which X, R and R are as defined in Claim 1. -384 46 1-1

8. A compound of Claim 7 in which X is oxygen.

9. A compound of Claim 7 in which X is sulfur.

10. 4-Amino-6,7-dimethoxy-2- [4-(oxazole-4-carbonyl) piperazin-l-yl]-quinazoline hydrochloride, optionally as its 5 monohydrate.

11. 4-Amino-6,7-dimethoxy-2-β-(isothiazole-4-carbonyl) piper az in-l-ylj-quinazoline hydrochloride.

12. 4-Amino-6,7-dimethcxy-2-]4-(2-methylthiazole-4carbonyl)piperazin-l-y_l]-quinazoline hydrochloride. 10

13. 4-Amino-6,7-dimethoxy-2-[4-(2-methylthiazole-5carbonyl)piperazin-l-yfj-quinazoline hydrochloride.

14. 4-Amino-6,7-dimethoxy-2-0-(5-methylisoxazole-3carbonyl)piperazin-l-ylj-quinazoline hydrochloride, optionally as its monohydrate.

15 15. 4-Amino-6,7-dimethoxy-2-[4-(5-methylthio-l,3,4oxadiazole-2-carbonyl)-piperazin-l-ylj-quinazoline hydrochloride.

16. A process for the preparation of a compound havihg the formula I as defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof; which process -39comprises reacting a quinazoline derivative of the formula in which substituent A is -NH 2 or -NR' 2 , wherein R' 2 is a conventional amine protecting group, and substituent B is 5 chlorine, piperazinyl or OR 1 ', wherein R'' is the radical F 3 CC(O)-, CI1 3 SO 2 -, F 3 CSO 2 -, or alkyl S0 2 — with a reactant selected from Υ-ϋ-Ζ when B is piperazinyl and from Z-l-piperazine when B is other than piperazinyl, wherein Y is a carbonyl activating group of the type typically used j_ 0 in amidation reactions, and Z is as defined in Claim 1, when necessary, removing the amine protecting group R' 2 by conventional means and, if desired, converting the product to a pharmaceutically acceptable acid addition salt by methods known, per se . 35 17. The process of Claim 16, wherein

A is -NH 2 and B is piperazinyl in said compound of formula II and said reactant is tl Y - C - z 2. O wherein Y and Z are as defined in Claim 16. 5 4 614

-4018. The process of Claim 17 wherein Z is -A >— S-R 3 wherein R 3 is as defined in Claim 1,

19. The process of Claim 17 of 18 wherein said process 5 is conducted in the presence of an inert solvent selected from dioxane, chloroform, methylene chloride and glycol dimethyl ether.

20. The process of Claim 19 wherein R is methyl, Y is chlorine and the reaction is conducted in dioxane. 10

21. The process of Claim 16 wherein A is NHg and B is -Cl in said compound of formula II and said reactant is Z - c - piperazine wherein Z is as defined in Claim 1. The process of Claim 21 wherein Z is

22. 3. 4 4 6 11 wherein R is as defined in Claim 1.

23. The process of Claim 22 wherein R is methyl.

24. A pharmaceutical composition in dosage unit form 5 adapted for administration to a mammal comprising a quinazoline compound according to any one of Claims 1 to 15 or a quinazoline compound of formula I prepared by the process of any one of Claims 16 to 23.

25. Quinazoline compounds according to Claim 1 sub10 stantially as hereinbefore described in the Examples.

26. A process for the preparation of quinazoline compounds according to Claim 1 substantially as hereinbefore described in any one of the Examples.

27. Quinazoline compounds of formula I whenever pro15 duced by the process of any one of Claims 16 to 23 or Claim 26.

28. A pharmaceutical composition comprising a compound in accordance with any one of Claims 1 to 15, Claim 25 b'\- or Claim 27, or a pharmaceutically acceptable acid addition salt thereof, and an inert pharmaceutical diluent or carrier.