CA1274830A - Intermediates useful for preparing substituted 3-(4- phenyl-1-piperazinyl)alkylquinazolin-2,4-(1h,3h) diones - Google Patents

Abstract

ABSTRACT
The compounds of 3-(2-hydroxyethyl)-5,6-dimethoxyquinazolin-2,4-(1H,3H)-dione and 3-(2-chloro-ethyl)-5,6-dimethoxyquinazolin-2,4-(1H,3H)-dione which are intermediates useful for preparing substituted 3-(4-phenyl-1-piperazinyl)alkylquinazolin-2,4-(1H,3H) diones.

Description

BACKGROUND OF THE INYENTION..

Field of the Invention This invention celates to certain substituted -3-(4-phenyl -l-pipecazinyl)alkylquinazolin -2,4-(lH,3H) diones. These compounds are antihypertensive and cardiovasrular agents and are therefore useful in male and ~emale mammals. Thi6 invention also relates to a process ~oe preparing these compounds, to composi~ions thereof and to methods of use.

Rgl--L~~

Several quinazolin-2~4-(~H,3H) diones having vasodilator, alpha~-blocking or antihypertensive activity have been reported in the literatu~e. Examples thereo~ are U.S.
Patent No. 3,879,393; European Patent No. 89065-A; U.S.
Pa~ent No. 3,91g,425 and J. Med. Chem. 8, 807 (1965);
German Patent No. 2,258,403 (June 7, 1973); and U.S.
Patent No. 4,405,623. None of the above reported quinazolinediones contain all of the specific substituents presently claimed.

Summary of the Inven~ion The substituted quinazolin-2,4-(lH,3H) diones which are - ~ the subject o this invention have the following yeneral formula:

,'~
~

33~31

- 2 -R ~ ~ CH2)n-N ~ R5 Z

R ~ N 0 H

wherein X is hydrogen, amino, nitro, acetamido or halo:

Rl and R3 are the same or diffeeent and are hydrogen, hydroxy or alkoxy:

R2 is hydroxy or alkoxy;

lS or when Rl and R2 or Rz and R3 are taken together they are lower alkylenedioxy;

n is an integer ~rom 2 to 6;

R4 and R5 are the same or different and are hydrogen, hydroxy, alkyl, alkoxy, halo, or tri~luoromethyl; or when R4 and R5 are taken together they are lowee alkylene-dioxy; or the pharmaceutically acceptable acid addition salts ~hereof.
~ Also included in this invention is a process for preparing - the compounds of foemula I Which comprises reacting a compound of the formula H-N ~ ~
~5 7~t~

with a compound o~ the-fsrmula ~, O
R~ N,CH2CH2CI
R3~1 ~0 X H IV

Rl, R2i R3, ~4, R5 and X are as defined above in connection with the produc~.

Also part of the present invention are cer~ain intermediates and the processe6 for the prepara~ion ~hereof.
., Preferred compounds of the present invention are:

3-{2-[4-(2-methoxyphenyl)-1-piperazinyl~ethyl}-5,6-dimethoxy-guinazolin-2,4(1H,3H)-dione;

8-chlo~o-3-12-[4-(2-methoxyphenyl)-1-piperazinyl~ethyl)-5,6-dimethoxyquinazolin-2,4-(lH,3H)-dione:

25 6,7-dimethoxy-3-l2-t4-t2-methoxyphenyl)-1-piperazinyl~
ethyl)-quinazolin-2,4-(lH,3H)dione;

5,6-dihydroxy-3-{2-~4 (2-methoxyphenyl)-1-piperazinyl3 ethyl}-quinazolin-2,4-(lH,3H~dione.
The compounds of this invention possess oral hypotensive activity in spontaneously hypertensive ~ats and peripheral - vasodilator activity in dogs th~ough, at least in part, an al-adrene~gic antagonist mechanis~. When compared to the pri.~r art, such as a representative compound o~ the ~.~7~

a~ove-mentioned European Paten~ No. 89065-A, (set forth in Table 1 herein~, the present compounds show less inhibition o~ the tilt ~e~lex r~sponse suggesting that the compounds will be be~ter tolerated in human~ due to a S lesser potential ~oe oethostatic hypotension. In addition, they show an unexpected ~uperior bioavailability profile o~er prior art when the oral/i.v. ratios are compared.

The compounds, compositions and methods for making the various aspects of the present invention noted above will become more readily apparent from the following descrip-tion.

. . .
DescliPtion and Peeerred Embodiments Various ~erms used herein should be understood to signi~y the following.
. .
The ~erm "lower alkyl" r2~ers to a straight or branched chain substituent consisting solely o~ carbon and hydrogen with no unsaturation and con~aining ~rom 1 to 6 carbon atoms. The te~m "lower alkoxy~' reers to a lower alkyl chain as described above having no more than 4 carbons.
The term "halo" means ~luoro chloro, bromo and iodo.
?

The phease "pharmaceutically acceptable salts" denotes salts of the ~cee base which posses~ the desired pharmacological activity of the free base and which are neither biologically nor o~herwise undesirable. These salts may be derived from inorganic or organic acids.
Examples o~ inorganic acids are hydrochloric acid, nitric ~ acid, hydrobromic acid, sulfuric acid or phosphoric acid.
Examples o~ organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic ~cid, - ~7~

malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic aaid, methane sulfonic acid, ethane sulfonic acid, p-toluene sul~onic acid, ~alicylic acid and the like.

Pharmaceutical compo~ition~ containing a compsund of ~he presen~ invention as the active ingredient in intimate admixture wi~h a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of form~
depending on the form of preparation desired for administration, e.g., intravenous, oral or topical. In preparing ~he compositions in oral dosage ~orm, any of the usual pharmaceutical media may be employed, such as, for example, water, glycolsO oils, alcohols, ~lavoring agent~, preservativefi, coloring agents and the like in the case of oral liquid preparations such as, ~or example, suspensions, elixies and solutions; or carriers such as s~arches, sugars, diluent~, granulating agents, lubricants, binders, disintegrating agents and the lika in the ca~e or oral ~olid prepacations such as, for example, powders, capsules and tablets. Because of ~heir ease in admini~tration, ~ablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carrier~ are ob~iously e~ployed. I
desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually compeise sterile water, though other ingredients, ~or example, ~o aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which ca~e appropeiate liquid carriers, suspending agen~s and the like may be employed.
The pharmaceutical composition6 will generally contain per dosage u~it, e.g., tablet, capsule, powder, injection~

.. . ..

3~

tea~poonful and the like. from about 0.05 to about 100 mg~kg and pref erably f rom about 0.1 to abou~ 20 mg/kg of the active ingredient.

The novel quinazoline dione~ of the presen~ invention may be synthesized according to the following reaction scheme 1~ R2~ R3. R4, R~...R6, and X are as defined above and Q i6 a leaving group which is most preferably ethoxy.

m m ~ o Z; ~ '~
O =~ H =~
~X

P; ~ +

~Z~ ~

0~ ~ ~
~ L~t C~ P~
~;~ ~

,cl m O

1~ H r~ ;, H

~; Pi ~.~7~ 13 Compound II, in the reaction scheme above, may be initially prepared by reacting a cooled solution of an appropria~ely substituted ethyl 2-amino-benzoate with ethyl chloroformate and a suitable base such a6 triethyl-amine in a ~ hl ~ ~olvent such as tetrahydrofuran,dioxane oe no additional solvent.

The resultant appropriately substituted ethyl N-~2-carbe~oxy phenyl]carbamate i8 then reacted with ethanolamine a~ approximately 160 - 170C ~or between 30 minutes and 60 minutes.

The resultant product of ~ormula I r I is then treated with a suitable chlorinating agent such as thionyl chloside.
The chlorination reaction takes place in a suitable solvent such as chloroform or methylene chloride, preferably under re~lux ~or between 1 and 5 hours under nitrogan. The resultant compound IV is a novel compound, as is also compound III.
Compound IV is then reacted with compound ~ in order to produce compound I. The eeaction prefecably takes place in the presence of sodium iodide and potassium carbonate in a solYent such as dimethylfoemamide SDMF) or

4-methyl-2-pentanone at a temperature of between about and 85 C under nitrogen for about 1-36 hours.

In the instance wherein sub6tituents Rl, R2, and R3 are loweralkoxy, such substituents may be hydrolyzed to the corresponding hydroxyl groups by reacting the appropriately substituted compound of ormula I under reflux for about 24 hours in an acidic medium, pre~erably a mixture of hydcobromic acid and acetic acid. However, other acidic media such as HI, B~3r3, pyeidine bydro-chlocide or 47~ HBr, may also be used. When thi~

~2~
g procedure is carried out any lower alkoxy group onthe phenyl ring attached to the piperazine riny, remains unaffected.

The following specific preparations and examples are illustrative of -the present invention and should not be considered as limitative thereof in any manner.

Preparation 1 Ethyl N-[2-carbethoxy-4~5-dimethoxyphenyl]carbamate The following preparation illustrates the conversion of 2-amino-4,5-dimethoxybenzoate to compound II, in the instance wherein Q is ethoxy.

Ethyl chloroformate (10.4 g, 0.096 mole) was added to a cooled solution containing 6.5 g (0.028 mole) of ethyl 2-amino-4, 5-dimethoxybenzoate, 6.6 g (0.065 mole) of triethylamine and 90 ml of tetrahydrofuran.
The resultant reaction mixture was allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was filtered and the filtrate was evaporated to give a yellow gum which was crystalliz-20 ed from hexane giving 4.0 g (46.6~) of desired product, mp 59 -61 C.

3-(2-Hydroxyethyl)5,6-dimethoxyquinazolin-2,4-(lH,3H) dione This example illustrates the preparation of compounds of formula III.

A mixture of ethyl N-[2-carbethoxy-3,4 dimethoxy-phenyl)-carbamate (2.2 g, 0.006 mole) and ethanol-amine (0.8 g, '~

~ ~7~

0.013 mole) was heated at 160-170C in an oil bath ~or 0.5 hours. The semisolid which formed was triturated wi~h 2-propanol and ~he insolubie solid was collected to give Che dPsired product, mp 2Z2-224~C.

EX~MPLE 2 3-t2-chloroethyl)-5~6-dlmethox~fquinazolin-2.4-(lH~3H)~dione This example illustrates the preparation oE compounds o~
formula IV.

A mixture of 3-(2-hydroxyethyl)-5, 6-dimethoxyquina-zolin-2,4- (1~,3H)dione (2.0 g, 0.0075 mole) and thionyl 15 chloride (1.24 g, 0.010 mole) in 20 ml of chloroform was heated at reflux for 4 hours ~nder nitrogen. The solid which formed was washed with chloroform and collected to give ~he crude product which was recrystallized from methanol to give 1.3B g ~64.5~ yield) o~ the desired 20 product, mp 110-113C.

3-{2-[4-(2-Methoxyphenyl)-l-piperazinyl]ethyl} -5,6-dimethoxyquinazolin-2,4-(lH 3H)dione monohYdrobromide A mixture of 3-~Z-chloroethyl)-5,6-dimethoxyquinazolin-2,4-(lH,3H)dione 15.0 y, 0.018 mole), 1-(2-methoxyphenyl) piperazine (3.4 g, 0.018 mole), sodium iodide (2.64 9, 30 0.018 mole) and potassium carbonate (1.23 g, 0.009 mole) in 28 ml of dry DMF (dimethylformamide) was heated at 80 - 85C under nitrogen for 23 hours. Ice-water (75 ml) was then added to the solution and the resultant mixture extracted with chloroform (400 ml). The organics were dried with magnesium sulfate and evaporated in vacuo ~7f~

to give a yellow-brown gummy residue which yielded 4.979 of an off-white solid upon tritura~ion with ether.
Treatment o~ the crude product with one equivalen~ of hyd~og~n bromide in teSrahydro~uran gave the monohydro-bromide salt which was puri~ied by washing with hot 2-propanol to give a white solid; yield, 3.72 g, ~40~) mp 168-lil . Treatmen~ of the free base with excess hydrogen bromide ga~e the dihydrobromide salt, mp 184-189C.

5,6-Dihydroxy-3-~2-~4-(2-methoxyphenyl~-l-piperazinyl~ethy l}-quinazolin-2,4(1H,3H)-dione monohydrobromide monohYdrate.

This example illustrates the hydrolysis of the 5,6~dimethoxy substituted compound to the corresponding 5,6-dihydroxy substituted compound.
A solu~ion of 3-{2-t4-(2-methoxyphenyl)-l-piperazinyl ethyl)-5,6-dimethoxyquinazolin-2,4-(lH,3~)dione (1.6 g, 2.66 M) in hydrobromic acid (4~% aqueous, 9.6 ml) and glacial acetic acid (26.2 ml) was heated at reflux for 18 hours. The reaction mixture was cooled and the resulting solid wa ~iltered, washed with ether (30 ml), hexane (30 ml) and dried under high vacuum at 62C overnight to give a crude product as a white ~olid. The crude p~oduct was recrystallized from methanol (75 ml). The product was dried under high vaauum at 6ZC for 2 days to afford 5,6-dihydroxy-3-2-t~-(2-methoxyphenyl)- l-piperazinyl~
ethyl quinazolin-2, 4(1H,3H)-dione (dihydrobromide) as a ~ white solid~ (A); 0.72 g (yield 47.~%) mp,283-286C.
A second crop precipitated out of the filtrate. I~ was 8~

filtered and dried under high vacuum at 62C for 6 days to afford additional 5,6-dihydroxy-3- 2-t4-~2-methoxy-phanyl)-l-piperazinyl] ethyl quinazolin-Z,~(lH,3~I)-dione (monohydrobromide monohydrate) as a white solid; (B) 0.54 S g, yield 39.7~, mp , 223-227C. The total yield o~
product was 86.~%.
. .
The compounds set forth in Table l are prepared by ~he procedures of Examples l through 4 using appropriately substituted starting comp~unds. The last column of Table l indicates the speci~ic example, the procadure o~ which is utilized to prepare the indicated compound. In Table l, the final compounds are designated as A through E
respectively.
The prior art compound Z set forth at the bottom o Table l is that disclosed in the Chugai European Patent No. 89065-A.
. , z x ~1 ~ ~ O 1 r ~ r ~ N ~ 0 o\o ~r ~1 ~1 ~) ^ O Ll') O O ^
N ~1 1-- ~ CO 5~ 0 C:) N ~ ~, ~, ~ m N ~ ~I N V N N N
o I I I m I ~ I I I I :c I I I
N O a~ o . ~ t~
N ~ ~ ~ D 00 Ll~
N ~1 ~-- r~ N ~ l N ~I N N N
N
N

0 ~X~

O V I O V I O V

X X ::C X V V U ~ ~ ::C
~
:C ~
Vo V

:C ~ ~ X ~ X
N V V V V V U V U V
P~ O O O O O O O O O

~; ~ ~ 5~ ~ 5 '~
V V V U V ") O O O O O O

o ~ ~ m v o v r~

~7~
--13a-o z X r~

.,1 O O ~D
~ co ~r ~
o\o ,-- ~
~r ~ co t~ l l l O O rl o ~ ~ ~ 00 ,_ r~ :C
~ Co) O ~ ~ xro zl) (j X ;~

~; ~ ~ x K O O O

~1 ~ ~C O
O O O :C
~ ra o n ~ ~ o ~ o 1, ~
O h Ll 0 O ~ ~

~7~

The compounds of the pEeSent invention were evaluated f OL
their biological properties. The biological data indicate that certain of the compounds desceibed herein are potent an~ effective antihypertensivs agen~s. In addition, the data 5UppOL ~ cept o~ unexpected ~indings regarding side ef~ect liability. For example, Compound ~
demonstrate6 ~ignificantly 1~8 (p 0.05) inhibitio~ of the tilt reflex recovery respon e than the prior art Chugai compound Z (Compound A: 37% ~ 12 vs. Chugai compound Z: 83~ ~ a). Furthermore, a direct comparison in autonomic tests between Compound A and the Chugai compound Z shows that Compound A possesses almost no antihistaminic or anticholinergic effect, suggesting less sids effects such as dryness of mouth, drowsiness or sedation. In contrast, Compound Z inhibits histamine and acetylcholine blood pressure Lesponses in dogs indicating antihistamine and anticholinergic properties . ~hese ~indings taken together support the contention that Compound A possesses an orally efEective antihypertensive pro~ile with the unexpected finding6 of a mor6 tolerable ~ide ef~ect profile. In addition, the biological data also support Che finding of unexpected superior bioavailability, as with compound A when compared with the prior art compound Z, by means of the oral~i.v. ratio (Table 3).
The tilt reElex recovery response i6 determined as ~ollows:

Adult mongrel dogs of either sex are anesthetized with pentobarbital sodium, secured Co a tilt table and surgically prepared for measurement o~ blood pressure and heart rate. Animals are tilted and the percent recovery of the tilt response in the blood pressure is quantitated.

- 15 ~

The percent recovery i~ calculated by dividing the maximum decrease in mean arterial blood pres6ure (mm ~g) caused by tilt into the amoun~ o~ eise in blood pre~su~e at 15 seconds after initia~ing tilt. The antihypectensive as well as the alpnal-aarenergic blocking propeLties of the no~el guinazolinedione piperazines were evaluated and set ~orth in Tabl~ 2.

The antihypertensive evaluation followed the following procedure:

Adult male spontaneously hypertensive rats (SHR) were placed in restrainers in a chamber warmed tO 32C. A
s~andard indirect method employing a pneumatic pulse lS transducer and inflatable tail cuf was used to measure systolic blood pressuee (SBP) in the conscious state.
After baseline SBP were recorded, groups o~ 4 SHR received a single oral dose of drug or vehicle (0.5% methylcellu-lose) administered with a gavage tube. SBP's were obtained at 1/2, 1, 2, 3 and 4 hours post treatment.
Changes in SBP ' 5 were stat~stically compared to ~he vehicle effec~ usin~ Students t test. at p c.05.

The al-adrenergic blockade: inhibition of phenyl-ephrine-induced increases in diastolic blood pressure in the anesthetized dog was determined according to the method set ~orth in the following literature reference:

Arunlakshana, 0. and Schild, HØ (1959). Same Quantitative Uses of Drug Antagonists. ~r. J. Pharmac.
Chemothee., 14:48-58.

The procedure is as follows:

Dogs are anesthetized and bilaterally vagotomized.

"

~ ~74~

~emoral artery and vein.are cannulated for detection of diastolic blood pressure and drug admini6~ration, respecti~ely. Percent inhibition o~ alpha adrenergic recep~or ancagoni~m 18 quan~lta~ed by det~rmining the dose-re6ponse (increase in diastolic pressure) relationship of phenylephrine be~ore and a~ter variou doses o~ the antagonist. Statistical analysis of percent inhibition is calculated by use o~ the variance component estimation test. In addition, the Dose Ratio (DR20) may be calculated for potency compari60ns an~ is deined as the dose of antagonist required to produce an agonist dose ratio o~ 20.

The biological activity as determin~d by the above tests, is set forth in Table 2. The ~ested compounds were the same as those described in detail in Table 1 and referred to as compounds A through E, respectively. The prior art compound set forth at the bottom of ~able 2 i6 that disclosed in the Chugai Eueopean Patent No. 89065-A.
The bioavailability comparison was determined in conscious direct cannulated spontaneously hypertensive ~ats.
Brie~ly, the SH~s were anesthetized with ether and a carotid arterial cat~eter was inserted foe measurement of Z5 arterial blood pressure while a jugular catheter was inserted ~or i.v. drug administration. Por oral dosing, a catheter was also passed via the e60phagus into the stomach. All caSheters were exteriorized at the nape of the neck and animals were placed in restrainers and allowed to recover from surgery. Blood pres6ure was continuou&ly recorded. Drugs were dissolved in 5%
dextrose in water and administered as a bolus at time - zero. Bioavailability results are presented in Table 3.

~7~ 3 -V
O ~ aJ
.,~
-1-) H ~
-rl I O
O 0~' Q ~: ~
~ ~ ~ o o o r~ ~ oo m a ~ ~ ~; O ~ ~O
~1 H Q. ~1 ,_1 d ~ ~

rn h ,~ h ~ a .~
s~ _~ ^o O H ~
h Q
P~ ., _, ~ ~ ~7 ~ U~ O~ O O O
Y ~ Q ~ O 0 1~1 ~1 0 0 0 O N ~_ O O O OO _I O
1 ~ 'a) a) ~ ~ ~
O ,~ ~ X ~~ X X 5 X
X ~ ~
E~ ~ ~ ~ a~ o o o . a) >
ro P~ U~
~ N
~ 0 rl O ~;
O _, O
~1 ~ ~4 11 .~~ ~ ~ ,~ o ~ ~ ~, X O O OO O O O O
.~, ,, . Q ~ ,~ ~
r:l ~ ~;
.,, ~n .~, ~
~ o m ~ o ~ o~ ~ 's~ o ~: m ~ Q

.~ , .
. :

.. . .

~-~7~

'- -- 1~ --Table_3 Bioavailabilitv COmDari60n of Quinazoline dione Piperazines in SPontaneo-u6ly H~Pertensive Rats I.V. . P.O. Ratio CompoundE.D.-lO~_(a) E.D -10% tb~(P.o./I.V. (cl (mg/kg) (mg~kg) A 1.8 70 38.9 Z ~prior art) 0.5 370 740 (a) I.V. bolus dose that lowers MABP in conscious SHR by 10%.

(b~ Oral gavage dose that lowers ~ABP in conscious cannulated SHR by 10%.

(c) Bioavailability ratio with small numbers (close to unity) indicating good bioavailability.

THIS APPLICATION IS A DIVISION OF
Application No. 519,319 filed on September 29, 1986

Claims (3)

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

1. A compound selected from the group consisting of 3-(2-hydroxyethyl)-5,6-dimethoxy-quinazolin-2,4 (1H,3H)- dione and 3-(2-chloroethyl)-5,6-dimethoxyquinazolin-2,4-(1H,3H)-dione.

2. The compound 3-(2-hydroxyethyl)-5,6-dimethoxyquinazolin-2,4-(1H,3H)-dione.

3. The compound 3-(2-chloroethyl)-5,6-dimethoxyquinazolin-2,4-(1H,3H)-dione.