CA1081228A - Oxazole, isoxazole, thiazole and isothiazole amides - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to compounds having the formula

Description

AZOLE ~IDES
(SY-1502-A) ~(38~22i~3 This invention relates to new nitrogenous containing heterocyclic carbonyl plperazinyl quinazolines which are potent antihypertensive drugs having generally less ~-adrener-gic blocking activlty than does 2-[4-(2-furoyl)-piperazin~
yl]-4-amino-6,7~dimethoxyquinazoline which is a known potent antihypertensive drug.

More particular~y, this invention relates to compounds having the formula ~ ;

CH30~;~N~~ C-Z
CH30 ~

~rherein Z is a substituted or unsubstituted oxazole, isoxazole, thiazole, isot~liazole or alkylthio substituted l,3,4-oxadiazole group, pharmaceutically acceptable acid addition salts thereof and to the processes ~or the preparation thereo~, ,, United States Patent Nos. 3,511,386; 3,635,979 and 3J663~706 disclose several 4-amino-6,7-dimethoxy-~-~L~-(hetero-cyclic-2-carbon~l)-piperazin-1-yl] quinazolines. One of these compoundsj i.e., 2-[4-(2-furoyl)-piperàzin-1-yl]-4-amino-6J7-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 established that the antihypertensive efficacy o~ prazosin results from a dual mechanism of action:
(i) a direct peripheral vasodilatation effect on vascular smooth muscle; and, (ii) a functional peripheral ~-adrenergic receptor blockade, ~ 2 ~ ~

H. Adrlaensen, The Practit~onerJ 21~, 268 (1975);
Mroczek, et al., Current Therapeutic Research, 16,769 (1974); ?
Scriabine, et al., ~xperientia, 2L~, 1150 (1968);
Gonstantine, et al., "~Iypertension: Mechanisms and Management", ed. by Onesti, Klm and Moyer, Grune and Stratton, 1973 pp. 429-44; and Zacest, Med. J, of AustraI. Special Supplement, 1,4 (1975)~
Although initial clinical a~sessments 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, _, 14l~ (1975). It is generally felt that this type of side effect results from the ~-blockade component of prazosin. IndeedJ it has been stated by Ro 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 hypo-tension',' United States Patents Nos. 3J 669~ 968 and 3,769,286 cover trialkoxyquinazolines~ such as those having the formula:

~2 C-R
~I30 CH30 ~

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. ThusJ it is stated that such compounds "have a more favorable pharmacolo-gical profile (e.g, 3 they are non-adrenolytic in dogs) and L2'~8 possess greatly improved solubility characteristics (particularly ln water) as contrasted to the corresponding 6,7-dialkoxy compounds reported in the prior artl'. One of the compounds disclosed in these patents is known by the generic name trimazosln and has the formula:

~1N N-C-O-CH2-~ CH3 CH30 C~30 ~

Trimazosin is reported to be active in humans as an antihy-pertensive agent, DeGuia, et al., Current Therapeutic Research, 15J 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. ~or trimazosin as compared to 1.5 to 15 mg. ~or prazosin. Trimazosin is there~ore 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 broncho-dilator and antihypertensive activity, e.g., a compound having the rormula~

~ N ~ ~ ~ R "

wherein A and B may each be alkoxy, etc~, R~ may be hydrogen or alkyl and R " may be hydrogen or a radical such as alkyl, -benzoyl, etc.

U. S. Patent No. 3,920,636 describes homopiperazino quinazolines as antihypertensive agents, e.g.~ the compound:

C~130 ~N~ CR~ ?

~H30 ~ ~I2~3 U. S. Patent No. 3~780,040 discloses compounds useful as antihypertensive agents such as the compound:

~ ~N ~ N ~ ~

Netherlands application 72 o6,06 (CA, 78, 72180s) .
describes a process ~or preparing aminoquinazolines, such as prazosin, by treating the corresponding o-aminobenzoni-trile in the presence of phenyl lithium according to the following mechanism: .

~ + PyNCN PhL1 >

wherein R2N may be the group 4-(2-furoyl)-l~piperazin~l.

The present invention provides compounds having the formula ~ :

~ N ~ N ~ 11 z CH30 ~ ;~

wherein Z is Rl Rl N ~ N ~ .-in which X is either oxygen or sulfur, Rl and R2 may be the same or different and are selected from the group consisting of hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, (lower)alkoxy ha~ng from 1 to 6 carbon atoms `.
and (lower)alkylthio having from 1 to 6 carbon atoms, and R3 is (lower?alkyl having from 1 to 6 carbon atoms and pharmaceutically acceptable acid addition salts thereof, possessing antihypertensive potency comparab.le to proazosin but having generally less of the peripheral ~-adrenergic blocking properties shown by prazosin. Embodiments of this invention are compounds having the formula:

~ ~ N ~ ~ G-~

in which R is (lower)alkyl having from 1 to 6 carbon atoms and pharmaceutlcally acceptable acid addition salts thereof.
m ese compounds posse~ss antihypertensive potency comparable to prazosin but have little or none of.the peripheral a -adrenergic blocking properties shown by prazosin. m ese compounds are potent antihypertensive agents which ha~e little or no potential for side effect as reflected by their lack of adrenolytic activity~
The most preferred compound of this invention is 4-amino-6,7-dimethyloxy-2-~4-(5-methylthio-1,3,4-oxidiazole-

2-carbonyl)piperazin-1-yl~-quinazoline having the formula:

Cii30 ~ N l N ~ N-C ~ ~I CH3 and acid addition salts -thereof, in particular~ the hydro-chloride salt.
m e term "pharmaceutically acceptable" used herein to describe an acid addition salt of a compound of Formula I
refers to those salts having anionic species of a variety of relatively non-toxic 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, benzoicJ
cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydro-bromic, hydroiodic, sulfamic, sul~inic acids such as methane-sulfonic, benzenesulfonic, ~-toluenesulfonic, and related 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 wi-th one chemical equivalent of the acid or, if the di-acid addi-tion 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 having the formula j - 6 -wherein Z is a substituted or unsubstituted oxazole, lsoxazole, thiazole, isothiazole or alkylthio substituted ?
l,3,4-oxadiazole group and non-toxic 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

CH30 ~ N~ ~ B II

in which substituent "A" is NH2 or NR'2, wherein R~2 is a conventional amine protecting group, and substituent "B"
is chlorine, piperaæino or OR" wherein R11 is the radical F3CC(o) ~, CH3SO2 -, F3CSO2 -, or alkyl SO2 - wlth a reactant of the group consisting of 9 and 8 ~ Y b z z C piperazine wherein "Y" is a carbonyl activating group of the type typically used in amidation reactions3 e.g., halo, azido, ethoxy, carbonyloxy, l-imidazo and the like; and æ is Rl Rl :`
N ~ N - N
~ ~ x2 , ~ ~ R Or ~ ~ S-R3 in which X is either oxygen or sulfur, Rl and R2 may be the same or different and are selected ~rom the group consisting of hydrogen, (lower)alkyl haying from`l to 6 carbon atoms, (lower)alkoxy having from l to 6 carbon atoms and (lower)alkylthio having from l to 6 carbon atoms, and R3 is (lower)alkyl having from l to 6 carbon atoms; when necessary, removing the amine protecting group R'2 by conventional means and, if desired, converting the product to a non-toxic, pharmaceutically acceptable acid addition salt by methods known, ~
The following reaction schemes of Equations 1-5 illustrate the various synthetic routes embodied in the preparation of the compounds of the instant invention according to the process discussed above.

Equation 1 30~ 2 \~ O
C 3 N J\ 2~ NH CH30/~ J~ ~_C_Z

, In a preferred embodiment of this process, Z is .
N N
SR where R is a (lower)alkyl group and the reaction O

is conducted in an ine~ solvent such as dioxane, chloroform, methylene chloride, glyme and the like at room temperature, and/or with heating at reflux to insure completion of the reaction.

In a more preerred embodiment, Y is chlorine, Z is N - N
~S-cH and the reaction is conducted in dioxane. .
O~ ;

Equation 2 CH~ + HN -C--Z ~ ~ O

N 7 N N/~ 1 - Z
CH30 Cl CH30 \J

Equation 3 ~ ~2N

CH30 Cl CH30 ~N + R 2NH ~
C~3O N'l Cl ¦ N~NH

CH30~ ~~ CH30~

C~30 N 1N,_~C Z 3 N~N-H

I~a) The amine protecting group R'2 may then be removed from compound I(a) by conventional means to provide the product compound I.

Equation 4 R' N--Cl CH30 ~ N 1 Cl CH30~1 + ~'2NH~ 1 HNOI-C-Z

R'2N

CH30 ~ 1~N-C-Z
I (a) 2~

As in the reaction of Equation 3, the amine protecting group R'2 may be removed from compound Ia by conventional means to provide the product compound I.
Equation 5 CH30 ~ N ::

CH30 ~ ~ R~ 0 (or R~Cl)--~ ~ N~l OR "

CH30 4N'l 0 / ~

:, , CH30 ~ N ~ ~ N~ z CH30 ~ N
CH3 0 N 1N~N-C-Z CH3 O 10R "

The compounds of the instant invention may also be prepared by the following reaction sequence~

CH30 ~02CH3 CH30 C2CH3 CH30 C02CH3 ~ ~ NaSCN ~ / CH3I \ ~
CH30 / ~ A~2 3 ~ ~k CH30 / C~35 ~H~HI
.
O ~. ~

N N-C-Z

O
CH30 ~ ~ ~ ~ ~ O 0 ~ ;

. ~ : . . . . .. . ~ . . . .

EXAMPLES

Example 1 J

4-Amino-6l7-dimethoxy-2-l4-~5-methylthio-l~3~ oxadiazole-2-car bonyl)-piperazin-l-yl]-quinazoline hyd ochloride - ~ solution of 5-methylthio-1,3,4-oxadiazole-2-carbonyl chloride (0.601 9.,

3.36 mmole) in dioxane (10 ml.) was added to a solution of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)~uinazoline (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 re-flu~ for 30 minutesO Eiltration gave the title compound (1.56 g.).
Recrystallization from methanol gave a product having a M.P. of 280-285C. with decomposition.
Anal. Calcd ~or C H N O S-HCl: C, 46.20; H, 4.74; Cl, 7.58;
--- 18 21 7 ~
N; 20.96; S, 6.85 Found: C, 46.34; ~I, 4.89; Cl, 7.59;
N, 20.38; S, 6.58.

Example 2

4--Amino-6,7-dimethoxy-2-[4-(5-ethylthio-1,3,4-oxadiazole-2-car-bonyl)-piperazin-I-ylI-quinazoline hydrochloride - The title compound was prepared from 5-ethylthio-1,3,4-oxadiazole-2-car-bonyl chloride (0.79 g., 4.1 mmole) and 4-amino-6,7-dimethoxy-2-~1-piperazinyl)quinazoline (1.19 g~, 4.1 mmole) following the procedure described in Example 1. The product had a M.P.
o~ 2~6-248.5C.

Anal. Calcd for C H N O S.~ICl: C, 47.34; ~I, 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% H2O) ~L~8~

Example 3 ~-~mino-6,7-dilTI~t~loxy-2-~4-(5-isopropylthio-l~3~4-oy~a(liazo~c-2 carbonyl)-piperazin-l_yl]-qUlna7oline hyc~rochlori(le - The title compound was prepared from 5-isopropylthio-l~3~4-oxadiazole-2-car bonyl chloride (1.54 g., 705 mmole) and 4-amino-6,7-dimethoxy-2 piperazinyl)quinazoline (2.1 9., 7.5 mmole) follo~ing the procedure of Example 1. The product had a M.P. of 260-263C. with decomposi-tion.

20H25N7Q4S HCI: C, 48.43; H, 5 28; N 19 77 ~ound: C, 48.05; ~I, 5.~0; N, 19.61.

Example 4 4-Amino-6,7-dimethoxy-2-E4-(5-n-propylthio-1,3,4-oxadiazole-2-.

carbonyl)-piperazin-l-yl]-quinazoline hydrochloride - The title compound was prepared from 5-n-propylthio-1,3,4-oxadiazole-2-car-bonyl 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 lo The product had a Pl.P. of 230-245C.
with decomposition~

Anal. Calcd for C H N 0 S~HCl: C, 48.43; H, 5.25; N, 19.77 20 25 7 4Found: C, 48.11; Il, 5.35; N, 19.65.
j`.:, Example 5 4-Amino~6~7-dimethoxy-2~[4~(5~n~butylthio-1,3,4-oxadiazole-2~
carbonyl)-piperazin-l-yl]-quinazoli'ne hydrochloride - The title compound was prepared from 5-n-butylthio-1,3,4-oxadiazole-2-carbonyl chloride and 4-amino-6,7-dimethoxy-2-(l-piperazinyl) quinazoline following the procedure o~ Example 1.

22~

Example 6 ~ ?

4-~rnino-6,7-dirn~thyo~y-2-[~-(iso~:a201e-5-carbonyl)-piperazin-l-yl~quinazoline llyclrochloride - A solution oE isoxazDle-5-carbonyl chloride (1.33 9., 0.0l molc) in dioxane was added to a solu-tion at 30C. of ~-alnino-6,7-dimethoxy-2-~1-piperazinyl]quin-azoline (2.94 9., 0.01 mole) in dioxane. The mixture was stirred at reflux for three minutes, then at room temperatULe for 16 hours. Filtration qave the title compound ~.02 ~., 94% ~ield). Recrystallization ~rom aqueous methanol gave a product having a m.p. of 270C. with decomposition.
H2o~l6o~llcl: C 51 37; ~I, 5.03; Cl 8 42;

Found: C, 50.86; 11, 4.65; Cl, 8.52;
N, 19.~1 (corrected for 4.30~ ~l20) Example 7 . ~
4-~mino-6,7-dimethoxy-2-[4-(isoxazole-3-carbonyl)-piperazin-1-... . . .
ylJquinazoline llydrochloride ~ A solution of isoxazole-3-carbonyl chloride (0.753 9., 0.0057 mole~ in dioxane (20 ml.) was added to a solution of 4-amino-6,~-diimethoxy~2-(l-pipera2inyl)quin-azoline (1.66 g., 0.0057 mole~ in dioxane (60 ml.). The mix-ture was stirred at reflux for 30 minutes, t~en at room tempera-ture for 6q hours. Filtration gave the title compound whic~h was recrystallized from methanol (-1.81 g., 75~ yield). Tl~ product had a m.p. o~ 26~-273C. with decomposition.
C18~120N60~1Cl: C, 51 37; ~, 5.03; Cl 8 42;

Found: C, 50.04; ~, ~.86; Cl, 8.66;
N, 19.57 (corrected for 3.11~ H20) Example 8 4-~mino-6,7-dimethox~-2-[~-(lsoxazole-4~ iperazin-l-yl]quin~zoline ~yd~ochlotide - ~ solution of isoxazole-~-carbonyl chloride ~1~06 g., 8.08 mmole)~ in dioxane (8 ml.) was adcled to a solution of 4-amino-6,7-dimethoxy-2-(1-pipelazinyl)~uinazoline (2.34 9., 8.08 mmole) in dioxane (200 ml.). The mixture was stirred at room tempeLature for 20 hours. Piltration gave the title compound, which, after recrystallization ~rom methanol, had a m.p. of 255-260C. with decomposition.

Anal. Calcd. for C18H~0~6O4~1Cl: C, Sl.37; H, 5.03; Cl, 8.42;
N, 19.97 Found: C, 51.37; H, 4.95; Cl, 8.34;
N, 19.95 ~corrected for 1.63% ~12) Example 9 . .

4-Amino-h,7-dimethoxy-2-14-~S-methyliso~zole-3-carbonyl)piper-, azin-l-yll~uinazoline HydrochloLide - A solu~ion of 5-methyliso-xazole-3-carbon~l chloride ~0.41 ~., 2.83 ~mole) in dioxane was addecl to a solution of 4-amino-~,7-dimethoxy-2-~1-piperaæinyl) quinazoline ~0.82 g., 2.83 mmole) in dioxane. ~he mixture was treated as described in the previous éxample to give the title compound havin~ a m.p. of 271-273C. with decomposition.
~nal Calcd- for C19H22N64HC1 ~12 ~1 0, 3.92 Found: C, 50.58; H, 5.4Q; N, 18.86;
~l2' 3.72 2~3 Exa~ple 10 J

~5-Amino-6~7-dirncthoxy-2-~ (3-methylisoxazole-~-c~rbonyl)piDer ~zin-l-ylJ~uinazoline llyclrochloride - ~ solution oE 3-methyl-____ .
isoxazole-4-calbonyl chloride (1.01 g., 6.9 mmole) in dio~ane and 4-amino-6,7-dimethoxy-2-(1-pipera~inyl)quinazoline (2.00 g., 6.9 mmole) in dioxane was stirred under reflux or 15 hours, then worked up as described in Example 6. The titlc compound after recrystallization from methanol had a m.p. of 300-301C.
with decomposition.

Anal. Calcd. for C19E~22N604~3Cl: C, 52.47; El, 5.3~; N, 19.3~
Found~ C, 52.62; El, 5031; N, 19.12 (corrected for 1~13~o ~2) Fxample 11 4-Amino-6,7-dimethoxy-2-i~-(3-methylisoxazole-5-carbonyl)piper-_ _ _ azin-l-yl~uinazoline Hydrochloride - ~ solution of 3-methyl-isoxazole-5-carbonyl chloride (0.73 g., 5.02 m~ole) in dioxane was added to a solution of 4-amino-6,~-dimethoxy-2-~1-piper~zinyl~
quinazoline (1.45 g., 5.02 mmole) in dioxane. The mixture was heated briefly, then was stirred at %0C. for 2.5 hours. ~ork-up as in Example 6 gave the title compound having a m.p. of 263-264C. with decomposition.

Anal. Calcd. for ClgEI22N6C~EICl: C, 52.47; ~1, 5.33; Cl, 8.15;
N, 19.33 Found: C, 51.82; ~1, 5.04; Cl, 8.36;
N, 19.46 (corrected for 4.82~ ~l2) Example 12 .

4-Amino-6,7-dimethox~-2-~4-(oxazole-4-carbonyl)plperazin-1-yl]
quinazoline Hydrochloride - A solution of oxazole-4-carbonyl chloride (O.73 g., 5,53 mmole) in dioxane was added to a solu-tion o~ 4-amino-6,7-dimethoxy-2-(l-plpera~inyl)quinazoline (1.60 g,, 5.53 mmole) in dioxane. m e misture wa~ heated at reflux ~or O.5 hour, ~hen was stirred at 20C ~or:64 hours.
Filtration g~ve the title compound having a m.p. o~ 291-294C, with decomposition a~ter rec~y~tallization from aqueous ethanol. ..
18 20N64HCl ~l2 Ci 49 26 tl, 5.28;
Found: C, 48.92; tl, ~.83;
Cl, 8.33; N, 18.94 Example 13 .

4-Amino-6,7-dimetho~y-2-~ (2-methylo~:azole-4-ca~bonyl)~ peL~
azin-l-yl~quinazoline tlydrochlo~ide - A sol~tion of 2-methyl-oxazole-4-carbonyl chloride (1.01 g., 6,9 ~ole) in dioxane was added to a solution of 4-amino-6~7-dime~hoxy-2-(l-pipera~ `
zinyl)quinazoline (2.00 g., 6.9 mmole) in d~oxane. The mix- .
tule was heated at reflux for 2 hours. Fil~ra~ion ~ave the title compound having a m.p. of 278-280C. ~ith decomposition after recrystallization from methanol.
~al. Calcd. for C19~122N6O~HCl: C, 52.47; H, 5.33; N, 19.33 ~ound: C, 52.08; ~, 5.~3; N, 18.89 ~
~correcte~ for moisture) .
,.
~.

.-J

z~

Example 14 ?

4-~mino-6,-7-clillleth_xy~2-~4-(4~ et}lyloxazo.lc-5-caL~onyl)pipec-azin-l-yl~quinazoline llydrochloride - The title compound was prepar~d frorn ~-rnethyloxazolc-5~carbonyl chloride (0.85 ~.) and 4-amino-6,7-dimethoxy-2-~1-piPerazinyl)q-linazoline (1.68 g.) followin~ the procedure of Example 6. Tlie produc~
had a m.p. of 283.5-288C. with decomposition.
H22N6O4HCl: C 52 48; H,. 5.33; Cl 8 i5 Found: C, 52.~9; H, 4.94; Cl" 8.13;
N, 19.05 ~corrected for 1.59~ H2O) Example 15 4-Amino-6,7-dimethoxy-2-[4-~isothiazole-~-carbonyl)pipcrazin-:
l-yl~auinazoline ~ydrochloridc - The title compound was pre- -.

pared from isothiazole-4-carbonyl chloride ~1.01 ~.) and 4-amino-6,7-dimethoxy-2-(1-pipeLazinyl)qulnazoline (1.99 g.) ~o~lowing previously clescribed proc~dures. The product had a m.p. of 286-287C. with decomposition.

1 Calcd for C18~l20N6O3S N 19 23, S, 7 34 Found: C, 49.20; ~I, 4.81; Cl, 8.19;
N, 19.27; S, 7.23 (corrected for 0.93 % H2O) Example 16 ~-~mil-o-fi,7 dil_etho_y-2~ ( tt)~ zol-e-2-cclLbonyl)pi~erazin-t-yl]quirla~olln~ _yclrochloride - The title compouncl was prepaLed from thia%ole 2-c~Lbonyl clllolide (0.79 cJ.) and 4-amino-6,7-dimethoY.y-2-(1-pipeLa~inyl)quinazoline (1.5~ g.) ollowing previously described proceclures. The product had a m.p. of 273-276C. with decomposition.

nal. Calcd. for C18~120N6O3S HCl: C, 49.~8; ~I, 4.84; N, 19.23 Found: C, 48.6~; ~1, 4.62; N, 18.87 ~corrected foc 4.19 ~ ~12O) Example 17 4-Amino-6,7-dimethoxy-?-[4-(thiazole-4-carb3nyl)piper~z n-l-yl~quinazoline ~!ydrochloride - The title compound was prepared from thiazole-4~carbonyl chloride (1~02 ~.) and 4-amino--6,7-dimethoxy-2-~1-piper~%inyl)quinazoline (2.00 g.) following previously described procedures. The product had a m.p. of 274-277C. with decomposition.

C18~12o~6O3S ~ICl: C, 49.48; E3, 4.84; N 19 24 Found: C, 49.11; H, 4.69; N, 19.31 ~corrected for 4.47% H2O) Example 18 4-~mino-6,7~dimethoxy-2-[4-(2-methylthiazole 4-calbonyl)piper-azin~l-yl~quinazoline 33ydrochloride - The title compound was , pre~ared rom 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 had a m.p. of 260-263C. with decomposltion ~nal- Calcd. for C19~122N6O3S ~ICl: C, S0.60; ~1, 5.1~; N, 1~ 6~
Found: C, S0.88; Il, 4.96; N, 18.67 ~corrected for 2.88 ~ H2O) Example 19 ~I-Amino-6~7~ rle~llO:~y-~ 14--(thia~ole-s-carL)onyl)piperazi~
yl]quinazoline l_ydrochlori(1e - The title com~oun~ was p~epared from thiazole-5-carbonyl chloride (0.77 g.) and 4-arnino-6,7-dimethoxy-2-~1-piperazinyl)q-linazoline ~1.51 9.) following previously desc~ib~d proc~dur~s. The product had ~ m.p. of 280-281C. with decomposition.
Anal. Calcd. for C H N O S IICl: C, 49.48; ~1, 4.84; Cl, 8.11 18 20 6 3 N, 19.23; S, 7.34 Found: C, 49.22; H, 5.19; Cl, 8,31;
N~ 19.49; S, 6.79 (corrected for 2.63~ H2O) Example 20 ... .
4-Amino-6,7-dimethoxy-2-[4-(2-m_ hylthiazole-5-carbonyl)piper-azin-l-yl]quinazoline Hydrochlorlde - The title compound ~las prepared from 2-methylthiazole-5-carbonyl chloride (0.42 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (0.75 g.) following previously described procedures. The product had a .p. of 294-297C. with decomposition.

Anal~ Calcd. for C19H22N6O3S HCl: C, 50.6~; H, 5 l4; N, 18.64 ~ound; C, 50.60; ~1, 4.95; N, 18.50 ~corrected for 1.96 ~ ~12O) ~.

Example 21 4-Amino-6,7-dimethoxy-2-[4-(4-nlethylthiazole-5-c~bonyl)piper-azin-l-yl]quinazoline Hydrochloride - The title co~pound was prepared from 4-methylthiazole-5-carbonyl chloride (1.1 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline ~2.0 g.) following previously described procedures. The product had a m.p~ of 293-295C. with decomposition.

~ound: C, 50.47; H, 4.78; N, 18.43 tcorrected for 4.72~ H2O) 8~22~

To 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 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 o~ comparable antihypertensive potency to prazosin, but has little or none of the peripheral ~-adrenergic blocking properties shown by prazosin. This compound thus represents a significant and unexpected advance in the continuin~ quest for potent antihypertensive drugs which have little or no potential ~or side effects as re~lected by their lack o~ a-adrenergic blocking activity, In Table 1, antihypertensive activity was determined by oral administration to spontaneous hypertensive rats, and the in vitro and in vivo ~-adrenergic receptor blocking e~ect was determined by tests described following Table 1. ln the in itro test, the inhibition by BL-5111 o~
norepinephrine induced contractions of rat seminal vesicles was measured; and in the in vivo test, the inhibition by BL-5111 o~ norepinephrine induced pressor responses in anesthetized dogs was measured. The in vivo tests were conducted using intra-venous administration, each compound bèing assayed in 4 dogs with 2 dose response results in each dog.

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ISOLI\T~:D l~/~T SEMII`~I\L VESICI.E I~SSI~Y J

Dangan ct al, Int. J. Ncuropl)~rmacol., 4:219 (1965) have shown th~t the seminal vesicle of the rat is a tissue which is notably responsive to compounds which activate a-re-ceptors but is relatively insensitive to compounds which activate ~-receptors. Lietch et al, Brit. J~ Pharmacol., 9:236 ~1954), have employed the isolated rat seminal vesicle in the comparative assay of a-receptor blocking drugs and the present studies were carried out using a modification of their procedure.
Male l,ong 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 cantents by squeezing them gently with a pair of Eorceps. Silk thread (4-0) was attached to both ends of the vesicle and it was sus-pended in a 20 ml. muscle chamber containing modi~ied oxygenated .
Tyrode's solution (g./liter: ~aCl 8, KCl 0.2, CaC12 0.26, NaHCO~
ll Ma2HP0~ 0.0575, glucose 0.5 and MgC12 0.02). The bathing fluid was maintained at 37C. with a thermostatically controlled iso-lated organ tiss~e bath. Contractions were recorded isometrically by means of a force displacement transd~cer and recordings were made with a Beckman RP Dynograph. Norepinephrine ~NE) was added to the muscle chamber in 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.

2'~8 NE dose resporlse curves were obtained alone and in the preserlce of test compoullds. Nl~ was allowed to remain in contact with the strip until a maximal contraction was obtaincd~ 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 sub-sequent dose of NE was given. Increasing amounts of ME were in-jected into the bath in the same manner until a co~nplete dose response was obtainedO
The seminal vesicles used to obtain the control NE dose response were discarded and new preparations were placed in the tissue bath for evalllation of the test compound. The test com-pound 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 1~ minutes before the NE dose response was determined.
ED50 values for NE were obtained by regression analysis as described by Finneyl Probit. Analysis, 2d Ed., Cambridge (1964).
A minimum of ~ strips and at least 4 doses were employed to cal-culate the regression lines. The ED50 value is defined as the concentration oE NE which produces a contraction equal to 50% of the ~aximal contraction.
The ratio of the a-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 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 o~tainecl ~ith NE, prazosin and BL 511~ are summarized in Table II.

Table _I

Effect of Prazosin and BL-5111 on NE Response in Isolated Rat Seminal Vesicles NE Activity ED50 with 95~ - Ratio No. of Conf. Li~its Percent Change Relative to Treatment Strips (,ug/ml)From Control Prazosin Control 32 0.89 (0.84-0.94) - -Prazosin, ~ 6.03 ~5.30-6.81)578 1.0 10 nano/ml.

BL-5111 7 n~s3 (0.80-1008)4.5 0.008 10 nano/ml.

These data indicate rather clearly that at a concentra-tion of 10 nanograms/ml., prazosin caused nearly a six fold de-crease in the sensitivity of isolated rat seminal vesicles to the stimulant activity of NE while BL--5111 was essentially in-active in this respect. It was concludéd that BL-Slll possesses less than one percent of the a-adrenergic ~locking activity of prazosin.

., ~' ' ANESTHETIZED DOG ASSAY FOR a-ADRENERGIC BLOCKIMG ~GENTS

Nashl 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 a-adrenergic blocking agents antagonize the blood pressure elevating effects of intravenous norepinephr-ine. Thus, blood pressure responses to norepinephrine (~E) in anesthetized dogs was used ~s a com-parative assay for a-adrenergic receptor blocking properties of drugs.

3~3~ Z8 Experim~nts ~ler~ done on mongrel ~lo~Js anes~hetized with sodium pentoharbital, 30 mcJ./kg. iv. The le[t femoral artery was ?
cannulat~d to recoL-d aortic bloo(l pressure ancl a femoral vein was cannul~ted foc cldministration of drugs. All anim~ls underwent a bilat~ral vagotorny. A norepinephrin~ dose-respons~ curve was ob-tained by administeriny increasin~ doses of iv. norepinephrine (0.01 - 1 ,ug/kg). The test drug (prazosin, BL-5111) was then ad-ministered iv. at 3 mg/kg. Approximately 30 minutes later a dose-response curve was again established for iv. norepinephrine (0.01-10 ~g/kg). The dose of norepinephrine (with 95% confidence limits) that increased blood pressure by 50 mm of Hg was obtained from dose-re,sponse curve analysis before and after vrazosin and BL-5111~
The ratio of the a-adrenergic blocking activity of BL-Slll rela- ~`
tive to that of prazosin was obtained as follows:

EDS0 mm llg ED50 mm Elg ~ctivity R~tio = BL-5111 - NE
ED50 mm ~g ~D5Q mm E~g Prazosin NE

The results obtained with norepinephrine, prazosin and BL-5111 are summarized in Table III. The results indicate that BL-Slll was approximately 30 times less active than prazosin in causing ~-adrenergic blockade at 3 mg/kg iv. !', Table III

Effect of Prazosin and BL-5111 on the Blood Pressure Response to Intravenous ~orepinephrine NE ED50 mm Elg Activity Ratio Treatment Nw/ 95% Conf. Limits Rela~ive to Prazosin .
Control 200.23 (0.19-Q.28) Prazosin, ~ 6.90 (4.R0-lQ.7) 1.00 3 mg/kg BL-5111 ~ 0.47~0.40-0.55) 0.036 Table IV below sets forth -the comparison test data for the products of Examples 6-21 and prazosin. As ? -shown in thls table, the products obtained in the foregoing Examples 6-21 are of comparable antihypertensive potency to prazosin, but have generally less o~ the peripheral ~--adrenergic blocking properties shown by prazosin. These compounds thus represent a significant and unexpected advance in the continuing quest ~or potent antihypertensive drugs.

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TABLE IY

Antihypertensive Activlty ~-Adrenergic Recéptor Blocking Effect Dose % Blood Pressure In Vitro In Vivo Examplemg/kg ChangeActlvity Ratio: Activity Ratio Prazosin 10 -42 1.0 1.0 (Reference 3 -29 Drug) 1 -14 6 lO -35 0.11 0.18 3 -26 ::

8 10 -35 0.92 9 10 -41 0 0.24 -33 0.30 0.18 11 10 -37 0.25 3 -21 ~ `

12 10 -45 0.6 1.22 1 -15 `
13 10 -35 0.17 14 10 -41 0.19 -:

1 -14 -~
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TABLE IV ~Cont'd.) Antihypertensive Activity ~ -Adrenergic Receptor Blocking Effect Dose % Blood Pressure In Vitro In Vivo :
Example mg/kg Change Activity Ratio Activity Ratio 17 10 -32 0.12 3 -24 .
l -20 18 10 -28 0.02 19 10 -33 0.10 l -12 -37 0.19 0.09 21 10 -28 0.35 3 -22 : :
1 ~4 -. , :

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds having the formula in which Z is , or in which X is either oxygen or sulfur, R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, (lower)alkoxy having from 1 to 6 carbon atoms and (lower)alkylthio having from 1 to 6 carbon atoms, and R3 is (lower)alkyl having from 1 to 6 carbon atoms; or a non-toxic pharmaceutically acceptable acid addition salt thereof; which process comprises reacting a quinazoline derivative of the formula II

in which substituent "A" is -NH2 or -NR'2, wherein R'2 is a conventional amlne protecting group, and substituent "B"
is chlorine, piperazino or OR ", wherein R " is the radical F3CC(o)--, CH3SO2--, F3CSO2-- , or alkyl SO2--with a reactant selected from the group consisting of Y - ? - Z and Z - ? - piperazine wherein Y is a carbonyl activating group of the type typically used in amidation reactions, and Z is , or in which X is either oxygen or sulfur, R1 and R2 may be the same or diferent and are selected from the group consisting of hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, (lower)alkoxy having from 1 to 6 carbon atoms and (lower)alkylthio having from 1 to 6 carbon atoms, and R3 is (lower)alkyl having from 1 to 6 carbon atoms; when necessary, removing the amine protecting group R'2 by conventional means and, if desired, converting the product to a non-toxic, pharmaceutically acceptable acid addition salt by methods known, per se.

2. The process of Claim 1, wherein A is NH2 and B is piperazino in said compound of formula II and said reactant is

3. The process of Claim 2, wherein Z is and R3 is (lower)alkyl of 1 to 4 carbon atoms.

4. The process of Claim 3, wherein R3 is methyl.

5. The process of Claim 2, 3 or 4, wherein said process is conducted in the presence of an inert solvent selected from the group consisting of dioxane, chloroform, methylene chloride and glyme.

6. The process of Claim 1, wherein A is -NH2 and B is -C1 in said compound of formula II and said reactant is Z - ? - piperazine.

7. The process of Claim 6, wherein Z is and R3 is (lower) alkyl of 1 to 4 carbon atoms.

8. The process of Claim 7, wherein R3 is methyl.

9, Compounds having the formula in which Z is , or wherein X is either oxygen or sulfur, R1 and R1 may be the same or different and are selected from the group consisting of hydrogen, (lower)alkyl having from 1 to 6 carbon atoms, (lower)alkoxy having from 1 to 6 carbon atoms and (lower)alkylthio having from 1 to 6 carbon atoms, and R3 is (lower)alkyl having from 1 to 6 carbon atoms; or pharmaceutically acceptable acid addition salts thereof, whenever prepared or produced by the process of Claim 1 or by an obvious chemical equivalent thereof.

10. A compound of Claim 1, in which Z is the radical and R3 is (lower)alkyl of 1 to 4 carbon atoms, whenever prepared or produced by the process of Claim 3 or by an obvious chemical equivalent thereof.

11. A compound of Claim 1, in which Z is the radical and R3 is methyl, whenever prepared or produced by the process of Claim 4 or by an obvious chemical equivalent thereof.

12. A compound of Claim 1, in which Z is the radical and R3 is (lower)alkyl of 1 to 4 carbon atoms, whenever prepared or produced by the process of Claim 7 or by an obvious chemical equivalent thereof.

13. A compound of Claim 1, in which Z is the radical and R3 is methyl, whenever prepared or produced by the process of Claim 8 or by an obvious chemical equivalent thereof.

14. The process of Claim 1, wherein Z is and R3 is (lower) alkyl of 1 to 4 carbon atoms.

15. The process of Claim 14, wherein R3 is methyl.

16. The process of Claim 14 or 15, wherein said process is conducted in the presence of an inert solvent selected from the group consisting of dioxane, chloroform, methylene chloride and glyme.

17. A process for the preparation of compounds having the formula I

or a non-toxic, pharmaceutically acceptable organic acid addition salt thereof; which process comprises reacting a quinazoline derivative of the formula II

in which substituent "A" is -NH2 or -NR'2, wherein R'2 is a conventional amine protecting group, and substituent "B" is chlorine, piperazino or OR'', wherein R'' is the radical F3CC(o)__ , CH3SO2__, F3CSO2__, or alkyl SO2__ with a reactant selected from the group consisting of Y - ? - Z and Z - ? - piperazine wherein Y is a carbonyl activating group of the type typically used in amidation reactions, and Z is when necessary, removing the amine protecting group R'2 by conventional means and, if desired, converting the product to a non-toxic, pharmaceutically acceptable acid addition salt by methods known, per se.

18. A process as in claim 17 wherein the salt is produced.

19. A process of claim 17 wherein said process is conducted in the presence of an inert solvent selected from the group consisting of dioxane, chloroform, methylene chloride and glyme.

20. A process of claim 18 wherein said process is conducted in the presence of an inert solvent selected from the group consisting of dioxane, chloroform, methylene chloride and glyme.

21. The compound 4-amino-6, 7-dimethoxy-2-[4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl]quinazo-line or a non-toxic, pharmaceutically acceptable organic acid addition salt thereof; whenever prepared or produced by the process of claim 17 or 19,or by an obvious chemical equivalent thereof.

22. A non-toxic, pharmaceutically acceptable organic acid addition salt,of 4-amino-6,- 7-dimethoxy-2-[4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-piperazin-1-yl]-quinazoline, whenever prepared or produced by the process of claim 18 or 20, or by an obvious chemical equivalent thereof.