CA1169062A - Quinazoline derivatives - Google Patents

Abstract

ABSTRACT

Quinazoline derivatives of formula (I) (I) wherein R? and R? are C2 - C7 alkoxycarbonyl, or R? and R? are linked together to form a group of the formula:

R2 and R3 are each hydrogen, C1 - C6 alkyl, halogen, nitro, amino, C1 - C6 alkoxy, phenoxy, C1 - C6 alkylthio, C1 - C6 alkylpiperazinyl, C1 - C18 alkanoylamino, di(C1 - C18)alkanoylamino, C3 - C9 alkoxalylamino, C4 - C8 cycloalkanecarbonylamino, C3 - C7 cycloalkyl (C1 - C6) alkanoylamino, benzamido, phenyl (C1 - C6) alkanoylamino, C1 - C6 alkanesulfonyl-amino or di(C1 - C6)alkylamino which may be substituted with hydroxy, and A1 is a group of the formula:

Description

? 0 ~ ~
This invention relates to new quinazoline derivative~. More particularly, it relates to new quinazoline derivatives, to processes for preparation thereof, to a pharmaceutical composi-tion comprising the same, and to a method of use of the same in the treatment of symptoms associated with allergic mani-festations, e~g. asthmatic conditions.
This application is a division of Canadian Patent Application S~. 365,968, filed December 2, 1~ 1980.
~ c~ordingly, the invention seeks to provide new quinazoline derivatives which are use-Eul as anti-allergic agent.
The invention also seeks to provide processes for preparing the quinazoline derivatives~
The invention also provides a pharmaceutical com~osition comprising the quinazoline derivatives.
In accordance with the invention, there is provided quinazoline derivatives of the formula (I):

Al- N

R2 ~H (I~
lR3 ~ .
.
wherein Rl and Rl are esterified carboxy, R2 and R3 are hydrogen,,alkyl, halogen, nitro, amino, alkoxy, aryloxy J alkylthio, alkylpiperazinyl, acylamino or - dialkylamino which may be substituted with hydroxy, ~5 A is a yroup of the formula~

- 2 ~ ~

~ RS

in whi¢h R is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, dialkylamino or 2,2-dialkoxycarbonyl-vinylamino, and R5 is alkyl or alkenyl, and their pharmaceutically acceptable salts.
The invention i~ more especially concerned with quinazoline derivatives of formula (I) wherein Ral and Rb are C2 - C7 alkoxycarbonyl, or Ral and Rb : are linked together to form a group of the formula:

_ COO \ / CH3 ~'C
~;COO CH3 R2 and R3 are each hydrogen, Cl - C6 alkyl, halogen, ; nitro, amino, Cl - C6 alkoxy, phenoxy, Cl - C6 alkylthio, Cl - C6 alkylpiperazinyl, Cl - Cl~ .
alkanoylamino, di(Cl - C18)alkanoylamino, C3 - Cg alkoxalylamino, C4 - C8 cycloalkanecarbonylamino, C3 - C7 cycloalkyl(Cl - C6)alkanoylamino, benzamido, phenyl(Cl - C6)alkanoylamino, Cl - C6 alkanesulfonyl-amino or di(Cl - C6~alkylamino which may be ~ub-stituted with hydroxy, and A is a group of the formula , .. . .

:' ~ 3 ~ ~90~

; 4 0 . N or 7 b in which R is hydrogen, Cl - C6 alkyl, hydroxy, Cl - C6 alkoxy, C2 - C6 alkenyloxy, di~l - C6jalkyl-amino or 2,2-di(C2 - C7)alkoxycar~Donylvinylamino, and R is Cl - C6 alkyl or C2 ~ ~6 alkenyl, The specification also describes pyrimido-quinazoline compounds of the formula (II):
,, O
~2_ ~ ~ Rl ~
I R2 ~ J (Il) ,. R

; wherein Rl is hydrogen, carboxy or ester~fied carboxy, q 10 A is a group of the formula-~, R4 5 ~ ~ or ¦ in which R4 is hydrogen, alkyl, hydroxy, alkoxy, :¦ alkenyIoxy or dialkylamino, R6 is carboxy or ester-1 ' ified carboxy and R5 is the same as defined above, and ~i 15 R2 and R3 are each as defined above.
:~¦ The pyrimidoquinazoline compounds of formula ~ (II) are the subject of the aforementioned Canadian ' :

- 4 ~ 0 6 2 Patent Application S.~. 365,968.
Particulars of the above definitions and suitable examples thexeof are explained as follows:
As to the term "lower" used in the specifi-cation and claims, it is to be understood that it means the one having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable esterified carboxy for Rl, Rl, Rb and R6 may be lower alkoxycarbonyl having 2 to 7 carbon atom(s) (e.g. methoxycarbonyl, ethoxycarbonyl, pro-poxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, iso-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl) and the~ like. Further, the esterified carboxy of Ral and Rb may be linked together to form a group of the formula:

/ \ ~ 3 Suitable alkyl Eor R , R , R , Ra and R
may be straight or branched lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl).
The halogen Eor R2 and R3 may be fluorine, - chlorine, bromine and iodine.
~' Suitable alkoxy for R , R3, R and Ra may , be straight or branched lower alkoxy (e.g. methoxy, ` 25 ethoxy, propoxy, isoprop~xy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy).

;

_ 5 _ 1 .7 ~

Suitable aryloxy for R and R may be phenoxy, naphthyloxy, tolyloxy or the like.
Suitable alkylthio for R and R may be straight or branched lower alkylthio (e.g. methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio, pentylthio, hexylthio).
Suitable dialkylamino for R , R3, R4 and Ra may be di(lower)alkylamino (e.g. dimethylamino, diethylamino, dipropylamino, diisopropylamino, di-butylamino), and the alkyl moiety of said dialkyi-amino group may be substituted with hydroxy to form bis(hydroxyalkyl)amino le.g. bis(hydroxyethyl)amino, etc~).
Suitable alkylpiperazinyl for R2 and R3 may be 4-lower alkyl piperazinyl (e.g. 4 methylpiper-azinyl, 4-ethylpiperazinyl, 4-propylpiperazinyl, 4-isopropylpiperazinyl, 4-t-butylpiperazinyl, 4-pentyl-piperazinyl, 4~hexylpiperazinyl).
The acylamino group for R and R includes both of monoacylamino group and diacylamino group.
Acyl moiety of the acylamino group may include the residue of organic carboxylic acid and organic sulfonic .~ acid. Suitable acyl may be alkanoyl including lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl, valeryl, isovaleryl, pivaloyl) and higher alkanoyl having 7 to lB carbon atoms~(e.g. heptanoyl, 2,3-dimethylpentanoyl, lauroyl, myristoyl, palmitoyl, stearoyl), lower alkox-alyl having 3 to 9 carbon atoms (e.g. methoxalyl, ~;

,.

- 5~ 9 ~ 6 2 ethoxalyl, propoxalyl), lower cycloalkanecarkonyl having ~ to 8 carbon atoms (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), lower (C3 - C7) cycloalkyl(lower)alkanoyl (e.g. 3-cyclo-pentylpropionyl), aroyl (e.g. benzoyl, naphthoyl,toluoyl, xyloyl, phthaloyl), ar(lower)alkanoyl (e.g.
phenylacetyl), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl).

Suitable alkenyloxy for R and Ra may be lower alkenyloxy having 2 to 6 carbon atoms (e.g.

vinyloxy, allyloxy, l-propenyloxy, 3-butenyloxy).
Suitable 2,2-dialkoxycarbonylvinylamino for R4 may be 2,2-di(lower)alkoxycarbonylvinylamino (e.g.
2,2-dimethoxycarbonylvinylamino, 2,2-diethoxycarbonyl-vinylamino).
Suitable alkenyl for R5 may be lower-alkenyl having 2 to 6 carbon atoms (e.g. vinyl, allyl, 2-propenyl, 3-butenyl, 3-pentenyl, 5-hexenyl, etc.~.
The general class of quinazoline derivatives, comprising compounds of formula (I~ and (II), can be pre-pared by various processes as illustrated below, Process 1 Substitution J ~ R ~ R

R3 R3 (I) .

:

.
Process 2 : Reduction 1 Rl R1 5 02N {J ~ Reduction ~,H2N~

~Ia~ ' (Ib) Process 3: Acylation _~ Ac~ I.t~en ~ 2 15(Ib) ~Ic) ~, : iP~ocess 4: Ring closu~e R2~ e~ ~ R~ 1 . , ~ I d) ( I I a) Process 5: Hydrolysis o 1 A2_N ~1~, COOH

R~ Ra EIydrolysis ~:: R3 (IIa) ~IIb) ' ~

,1 ~' ' - .

06~

wherein Rl, Rb, R2, R3, Al and A2 are each as defined above, R2 is acyl, and R7 is alkoxy.
The processes as illustrated above are explained in the following in more detail.
,~
Process 1: `
The object compound (I) can be prepared by reacting a compound (III) or its salt with a compound (IV).

Preferred examples of the alkoxy or R7 of the :-compound (IV) may be lower ones te.g. me~hoxy, ethoxy, propoxy, etc.~.

~¦ The salt of ~he compound ~III) may be a salt with an inorganic or organic acid such as hydrochloric acid, . hydrobromic acid, p-toluenesulfonic acid, etc.
The starting compounds (III) include known and novel ones. The known compoundsj e.~. 4-aminoquinaæoline, 2-chloro-4-aminoquinazoline, 2-hydroxy-4-aminoquinazoline.
and 2-methoxy-4-aminoquinazoline can be prepared by the method described in Journal of the Chemical Society (C) 1284 ~1969), ~hemical Abs~rac~s 54, 24778b and 9939C
:! : (1960)~ and the new compounds ~III) can be prepared in ~, the similar manner thereto. The method for preparing said new compound is to be referred to Preparation of starting compounds as described hereinafter.

The reaction of this process is usually conducted in a solvent such as N~N-dimethylformamide, ethanol, propanol, :~ isobutyl alcohol, ~e~rahydrofuran, diphenylether, .: 35 chloroform, toluene, xylene, or the like~ at a temperature ,:, . , ~
i , .
!
: l :~ 'I ' .

; :

~ 06 range from cooling to heating.

This reaction may be carrLed out in the presence of a base such as alkali metal hydride (e.g. sodium hydride), alkali metal amide (eOg. sodium amide) alkali metal alkoxide (e.g. potassium t-butoxide), diazabicyclo compound (e.g. 1,5-diazabicyclo~3,4,0]nonene-S, 1,5-diazabicyclo[5,4,0]undecene-5, etc.), or the like.
~' .
When this reaction is conducted at relatively high temperature, there may be occasionally pro`duced a ring closure compound, i.e. primidoquinazoline compound (II).
: ~t ~, Thus produced pyrimidoquinazoline compound can be trans-~ormed to quinazoline compound (I) by treating it with a strong base such as alkali metal alkoxide te.g. sodium ethoxide). This case is also included within the scope of this process.
.
Process 2:
The object compound (Ib) can be prepared by reducing a compound tIa).
., ~ The reduction can preferably be conducted by cataly-~- .
tic redu~tion.
The catalytic reduction is usually conducted at ambient temperature or under cooling in an inert solvent (e.g. N,N-dimethylformamide, ethanol, propanol, isobutyl ~' alcohol, tetrahydrofuran, chloroform, ethyl acetate, acetic acid, etc.) by using a conventibnal catalyst such ' as RaneY nickel, palladium on carbonJ or the like.

~ Process 3:
¦ The object compound (Ic) can be pTepared by reacting a compound (Ib) with an acylating agent~

~1 , .

~, - :

o ~ ~

The acylating agent to be used in this reaction includes an organic acid ~;.e. Ra OH, in ~h-ich R2 is a~ defined a~ove ) and it~ reactive derivative .
Suitable examples of the organic acids are to be referred to the descriptions of the suitable acyl moiety of the acylamino group for R2 ~f the compound (II).

The suitable reactive derivative may be a conven-. ~ .
tional ones such as an acid halide ~e.g. acid chloride, / ~- acid bromide, etc.), an acid azide, an acid anhydride, ; an actiYated amide, an activated ester, etc~
., When free acid is used as an acylating agent, the acylation reaction may preferably be conducted in the presence of a conventional condensing agent.
' ~ The reaction is usually conducted in a solvent i such as N,N-dimethylformamide; dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridlne or a mixture thereof.

i~ The reaction can also be conducted preferably in the presence of an organic or inorganic base such as alkali metal (e.g. sodium~, alkaline ea~th metal (e.g.
calcium), alkali or alk~line earth metal hydride ~e.g.
sodium hydride, calcium hydride, etc.)~ alXali or alkaline ear~h me~al hydroxide (e.g. sodium hydroxide, J potassium hydroxide, calcium hydroxide, etc.), alkali ~,~ 30 or alkaline earth metal carbonate or bicarbonate ~e.g.
sodium carbonate, potassium carbonate, sodium bicarbon-ate), alkali or al~aline earth mctal alkoxide (e.g.
1 sodium ethoxide, lithium methoxide, magnesium m~thoxi-le), ~, trialkylamine ~e.g. triethylamine), pyridine, bicyclodia7a ~:! 35 com~und ~e gO l s-diazabicyclo[3 4~o]nonene-5 i ~

, ~ .
.

~ ~ ~9~62 1,5-diazabicyclo[5,4,0]undecene-5, etc.) and the like.
-The reaction may preferably be conducted within the -range of cooling to ambient temperature.

When this acylation reaction is conducted with an excess amount of the acylating agent, there may occasion-ally be produced N,N-diacylated compound, and this case is also included within the scope of this process.
Process 4:
~; The object compound (IIa~ can be prepared by heating a compound tId).

This reaction is usually conducted undeT heating~
preferably at 160-270C in the presence or absence of a sol~ent such as N,N-dimethylformamide, diphenylether, biphenyl, paraffin or the li~e. ~he optimum reaction conditions can be selected from the above reaction condi-tions accordin~ to kinds of the s~arting compound.

p~ocess 5:
; The object compound (IIb~ can be prepared by sub-jecting a compound (IIa) to selective hydrolysis of the ester.

~i This reaction is usually conducted by heating a-compound (IIa~ in the presence of lithium iodide in an j inert solvent such as N,N-dimethylformamide, collidine, ~¦ 30 lutidine, ~yridine and the~like, and then treating th~
resultant compound with water.
i' .
I The object co~pound prepared by each process as mentioned above can be isolated and purified in a con-ventional manner.

, '~
., ~ , 1 ~ ~9~62 The object compound, quinazoline de~ivatives (I) and (II) possess strong antiallergic aetiYi~y and anti-inflammatory activity. Accordingly, the object compound o this inventisn is useful for the treatment of symptoms associated with allergic diseases such as allergic as~hma, allergic rhini~is, urticaria, pollenosis, alle~gic conjunctivi*is, atopic dermatitis, ulcerative colitis, alimentary allergy ~e.g. milk~allergy), bird fancier's disease, aphthous stomatitis and the like.
: lO For illustrating purpose, the antiallergic activity of some ~epresentative compoun~s of the object compounds ~I) - ~~ and (II) are shown in the following.
TEST ~ [Inhibi~ory effec~ on PCA tPassive Cu~aneous Anaphylaxis) reaction]
. _ (1) Test compound (a) Test compound of the formula:

( , . R3 1, ~ R2 _ _ ~ . .. . _ , _ Test compound R~ R3 R4 1 _ . H. H

2 CH3 _ _ ~ _ ~ . ........... _ f 3 CzH5- H H
, _ _. _ .. ~ _ :~ ~ 35 4CH3(CH2)2- H H

I

7 1 ~C~

, . ~ Test Compound R R3 R4 f lio. _ _~_ t~ ¦ 5CH3(CH2)3- H H
. .

, . ' _ .. _ . .

f 10 8 N02 H H
;' .. ,. . . ~ .
~ . 9 H CH30- H
~, . . _ .
~ O- H H
.l _ CH3 _ ~ -~ 11 CH3 ~ H H
~ _ _ ._ _ _ .

12 C~13-N ~ _ H H
.; . . . _ __ ~ . 13 CH3CONH- H H
':. __ _ . _ ,, ___ _ .
t 15 ~-C3H7CONH- H H
_ _ CH3 _ _ ~l 30 16 CH ,CHCCiNH- H H
~ 3 __ _ ~' 17 C2H50COCONH- H H
~'1 _ . _ ~
l 18 ~ CONH- H H
:'~ 35 _ . ~ _ , 19 ~ CONH- H H
: ! _ _ _ ~
:l 20 ~ H CH~O-., . .

: (b) Test Compound No. 21

3 X 3 ~ ~ \O

H

(c) Test Compo.und No. 22 ,~ .
CH 3 ~H 5 (d) Test compound of the formula:
~, 20 . R4 R Cooc~H5 ~25 ~ R3 2 ::~ R
,, . ~ . __ _ f: Test Compound R2 R3 Ra ,~:j ., _ ~ _ _ _ _ . . ~. ~ .

¦~ 35 24 ~H3- H H
_ _ ____ . . ._ j .
.

Tes t Compoun d ~ R2 R3 ¦ ~a _ _ .
2 6 ~ -C3H7 - H H
., . ~ _ 27 ~n -C4Hg ~ - H H

28 -- -- CH3- . H
. ~, , ~.... _ ~_ 2 9 Cl - - H H
~, __ . _ __ __I
' 15 3 0 H Cl - H
___ ___ _ _ _ _ . _ _ 31 N02 . H H
_ _ . _ _ _ . _ _ 3~ . CH30- H

~0 33 CH33~N- H H
; ~-" _. .
34 CH3 ~ H H
2 S _ ii 3 5 CH 3 CONH - - H H
__ , _ _ ~ ~
: ~ 30 37 C2H5-CONH- H ¦ H
.... _ _ _ _ . _ , . , _ 38 ~-C3H7CONH- H H
. -- -- ~ CH3 _ . __ 3 5 . _ _ cH3,CHCONH - 11 H

, ,,1 ' ', .

, : , .

,. .
, . -- ~,.. - ~.

Tes t Compound R2 ~ . _ (CH3) 3cCONH- H ~ ~

41 ~ C5HllCNH H ¦ H
_ . _ . _ . 10 , _ . .

4 3 C} CONH- H H
~`
44 ~CONH- H H
_ _ _ 4 S ~CH 2 CONH - H H
: _ . __ _ _ ___ _ 47 H .. H HO-' . _ . __ : .( . 4 8 H H CH30-, . . ._ _ 49 H H CHz-CHCH;20-, __ __ _ ~

5 0 C2:H5 - H HO-(e) Test Compound No. 51 O

~ . ' 1 3 ~ 2 (f) Test Compound No. 52 O
N~`N ~ COOCH3 ~ ~`N ~
~ .

(g) Test Compound No. 53 ~, O

.~ .
~h) Test Compound No. 54 2a CH3 ~ ~ COOC2H~

~

: (i~ Test Compound No. 55 ' ~ , : 30 :~ ~ O O
2-CHCH2 ~ N ~ N ~ COOC2H5 ~:

~! .
' ' .

`.. ~ . , ;~ ~' . ' . .

9~

(j ) Test Compound No . 56 COOC ~H5 ~H3 (k) Test Compo.und ND. 57 '"
COOC ~H5 ~ COOC 2H5 NHCOC(CH3)3 (2) Test method ~ (a) Preparation of antiserum : A solution of egg albumin ~2 mg) in B. pertussis-diphthe~ia-tetanus mixed vaccine (1 ml) was mixed with Freund incom~lete adjuvant ~1 ml) to give an emulsion.
The emulsion was giren subcutaneously in a single dose of 1 ml divided equally ~0.25 ml) to the four foot pads of male SD ~SpTague-Dawley~ s~rain rats aged 8 weeks, each weighing abou~ 300g.

10 days after the immunization, blood samples were collected from femoral artery of the rats and allowed tO
stand under ice-cooling for 5 hours. The separated supernatant was ce~trifuged at 4C (10,00~ r.p.m. x : 1 hour). The antisera thus obtained were stored a~
-80C prior to use.

1 ., !!

;
~ .

.

(b) Inhibitory effect on P.C.A.
Male SD-strain rats aged 8 weeks, weighing 290 to - 330 g, were used for PCA reaction wit~ the homologous reaginic antiserum as prepared above. Each 0.1 ml of 64 fold diluted antiserum weTe injected intradermally at separate sites on the back of rats clipped free of hair, and 48 houTs later, 1 ml of aqueous solution ontaining each 5 mg of ~he egg albumin and Evans blue was injected intravenously to evoke PCA ~eactiun.
Test compound was given to the animals orally 60 minutes or intravenously 5 minutes before the challenge with an~igen. Control group recei~ed vehicle. Each dose group consisted of 5 animals. One hour after the challenge with antigen, the animals were sacrificed and then skinned. Dye spots caused with antiserum were investigated for their size on the reversed side of the skin, respectively. The results were expressed by per cent inhibition values calcuated from averaged values of the longest and shoTtest diameters for each spot in comparison with those in con~rol group.

(3) Test results ( ~ Test results a~e shown in the following table.

_ _ Inhibitory efect (%) Test Com- _ d N Intravenous Oral administTa-poun o. administ~ation (lOmg/kg~ tion (100 mg/Xg) _ . ........... ~ ~ . . , .
i 1 100 ~

2 lOO

~ ,.,, ` ~ . . _ __ _ _ ~ ~ _ _ *

.
..

~ 7 ~9~J fi ~

. ~
. InhibitorY effect t%) Test Com- I ntTavenous oTal administra~
pound No. administration (lOmg/kg) ~ 0 ~g/1~1 34.8 *

. 6 100 , *
..... _ . _ __ _ _ 7 - 42.9 *
52.7 _ _ . . ._ 9 5~.3 *
_ _ -24 .4 *
. _ .
11 100 *
.

12 51 . 2 *
_ . .. ..,"., _ . _ 13 100 *
, "",.. _ _. ~_ . __ _ (, 14 * 77 .4 ' . ._ . .. _ _ _ -15 * 58 .1 : . __ . _ . _ .. ., . . .
16 100 -51 . 6 .' __ ' .. ._ 17 100 *
. . _ 18 100 *
. - _ _ 19 ~ * 73.7 __ _ 1 20 ~ :~7.6 .
.. . .

o s ~

- .
Inhibitory effec~ (%) Te s t Com - ~
~ ntravenous Oral administra-pound No. administratîon (lOmg/Xg) tion (100 mg/kg) . . . . .
21 75.~ *
... . _ . . . _ _ _ _ 22 100 '~ *
_ _ _ 23 100 *
. 1 0 . ,_ _ _ 24 100 _ . _._ . ~5 100 *
._ __ _ ' 15 26 100 -,~t ~.
._ _ _ 27 100 *
_ _ ' 28 100 *
2 0 _ . _ _ _ 29 100 *
~, ~ ~ _ _ 3 0 10 0 _ _ _ _ ~ I
1 2 5 3 1 6 4 . 9 *
. , _ _ _ _ . 32 67.5*
~j _ _ __ l 33 100 *
j 30 ~ ~
34 ~ 00 *
_ ~ _ .
~ ~ 72 .7 _ _ _ ~
:I 35 36 100 1 _ ' I

' -~

:
:

~ :~ 6~62 ~ . .... . ~
Inhibitorv effect r%~
Test Com-Intravenous oral admlnlstra-pound No. administration (lOmg/Xg) tion (100 mg/kg) __ . _ _ 37 * 74.2 _ 38 1 100 - ' 39 * 75.8 1 0 _ . .
r~ 40 100 . , _ . _ _ 41 * 100 . . .__., _ , _ ~2 1 100 *
_ _ _ _ _ _ 43 - lOO *
... . . ....
44 * 49.1 2 0 _ _y . ~ ~
~00 *
~, ~, .
46 76.3 *
~.~ _ 47 . 100 " _ ~ . . . _ 48 100 57.5.
_.. ~ ._ ,_ 49 83 . l *
: 30 _ ~ ' _ .
.39. 8 *
~ . . .
51 ~00 lOO
~ _ . - _ Y _ , ~ 35 52 lOO
__ ._ ,,,_ -' .

o ~ ~

, ~
I Inhibitory effect (~) Test Com- ~
ound No Intravenous oral administra-. administration (lOmg/kg) tion (100 mg/kg) ,_.__ ._ _ _ __ __ 53 85.0 *
_ . ._ .. __ .. . _ __ .54 48.4 . *
_ __ _ 91.0 *
..... _ _ _ .
56 100 24.2 .. _....... _ Note) *: Not tested.

TEST II [Inhibitory effect on PCA (Passive Cutaneous . Anaphylaxis) reaction]

(1) Test compound (a) Test compound No. 58 COOC2~15 COOC H
~ ~5 ~r ~1 2 5 N
H

NECOCH2C(CH~)3 .
., ' ~ .
.

~ 1 ~9062 (b) ~est com~ound of thc ~ormul.a.

.
o ~ ~ Rl S~l ' 'P

_ .
No. . ~1 R2 ~ ~ _ 59 -COOCH3 . -~COC(CH3)~
_ _ -COOH -~COC(CH ) ~ _ S ~
61 -500C~?H5 -NHCOCH2C ( C~

62 -C00~ -NHCOC112C~CH
_ __ _ 63 1 -COOH -NHCOCH (CH3) 2 ( ~ : . ,. ,~ _._ 69 : -COOH --NHCOCH (C2H5 ) 2 __ ~ . . , ~
~l 25 I

(2) Tes t method This test was carried out in substantially the same-;~ 30 manner as described in TEST I, excepting that 32 fold , : diluted antiserum was used in place of 64 fold diluted ? antiserum for passive sensitization.
;j (3) Test results ~ Test results are shown in the following table.
::j 35 ~!

~!
.
... .

.
, ~J~49(~2 Inhibitory effect (%~
Test Com- _ _ , Intravenous Oral admi~istra-pound No. adminis~ration (l.mg/kg~ tion ~100 mg/kg) .

58 ~2.1 _ _ _ _ 59 100 I .O *
~ _ , _ _ ~. . 6~ 100 ~
1 0 _ ., . _ _ ~` 61 lQ~ . *

62 l IOO ~
. . _ .. .. . _ _ - _ .
63 loo *
1 5 , _ ., 64 100 * _ ¦ Note3 *: Not tested. ` ~ ~ ~ -~ ~
The quinazoline derivatives (I) and (II) of this invention can be used as an active antiallergic agent .( ~ either in f~ee form or in the form of the pharmaceutic-- ally acceptable salt such as a salt with inorganic or j - organic acid, a salt with inorganic or organic base and i a sal~ with an amino ac;d.

:i I . The object compound (I) and (II~ or i~s pharmaceutic-! ! ally acceptable salt can usually be administered $o mammals including human beings in the form of a conven-~ional pharmaceu~ical composition such as capsule,micro-, capsule~ tablet, granule, powder, troche, syrup, aerosol, ~i inhala~ion, solution, injection, suspension, emulsion, suppository, ointment, or the like.

~¦ The pharmaceutical composition of this invention 1 35 ! can con~ain various organic or inorganic carrier materials, 1 3 6~0 which are conventionally used for pharmaceutical purpose, such as excipien~ (e.g. sucrose, starrh, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropyl-pyrrolidone, gelatin, gum arabic, polyethyleneglyrol, sucrose, s~arch, etc.;, disintegrator (e.g. starch, carboxyme~hyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycole-starch, sodium bicarbonate, calcium phosphate, calcium ci~rate, etc.), lubricant (e.g. magnesium stearate, aerosil, talc, sodium laurylsulfate~ etc.) 9 flavoring agent (e.g. ci~ric acid, mentol, ammonium salt o grycyrlysine~ glycine, orange powders, etc.), preservative tsodium benzoate, sodium bisulite, methylparaben, propylparaben, etc.), stabilizer (citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g. methyl celluiose, polyvinylpyrrolidone, aluminum steara~e, etc.), dispersing agent [e.g. polysolbate 80, emal~en 408 (surface active agent), emasol (surface active agent), etc~], aqueous diluting agent (e.g. water) 9 base wax - (e~g. cacao butter, polyethyleneglycol, witepsol, white petrolatum, etc.).

A dosage of the present active ingredient is to be varied depending on various factors such as weigh~
and/or age of a patient and/or a stage of the allergic disease, and further the kind of administration route.
In general--,- an effecti~e dosage may be in a ~ange of ~- 30 about 20 - 2000 mg/day fo~ an oral rou~e, about 2.5 --~ 250 mg/day fOT an intramuscular or intravenous injec-tion, abou* 10 - 1000 mg/day for a subcu~ane~us injec-tion and about 120-mg - 2000 mg/day for a ~ectal route.
The total daily amount mentioned above may be division-ally given to the patient at the inter~al of 6 - 12 hours . per day. Preferable single dose of the present actiYe ; ingredient may be, for example, about 10 - 500 mg per tablet or capsule, about 1.25 - 250 mg per vial or ampoule, or about 60 - 500 mg per suppository, and so on, and further a pharmaceutical form for an external use may be, for e~ample, about l - 10% ointment solution or emulsion, etc.

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Starting compounds to be used in ~he p~eparation of the quinazoline derivatives of this invention can be specifically prepared in the following manneT.

Preparation 1 A mixture of o-aminobenzonitrile (~2.58 g~ and formamide (96 ml~ was refluxed for 2 hours ~t 220C.
Af~er the resultant mixture was cooled to ambient temperature~ precipitated crystals were separa~ed by C filtration, washed twice with a small ~olume of water and dried under ~educed pressure to give crystalline 4-aminoquinazoline (17.0 g~.
: lS mp: 265 - 268C
IR ~Nujol)*vmax : 3100, 1690, 1615~ 1585 cm^l , N.M.R. ~ppm (DMSO4-d6) : 7.4-8.0 ~5H, m), 8.30 r (lH, broad d, J=8.0Hz)~ 8.50 (lH, s3 The following compounds weTe prepared in substantially the same manner as that of the Preparation 1.

, . . .
4-Amino-6-chloroqui~azoline mp: ~270~C
IR (Nujol3*vmax : 3100l 1680, 15709 1548 cm 1 ~ .
~2~ 4-Amino 7-chloroquinazoline ' IR (Nujol)~vmax : 3275, 3100, 1685, 1605, 1575 cm 1 N.M.R. ~ppm (DMSO-d6~ : 7.52 (lH, dd, J~2.0 and . 30 8.0Hz), 7.70 ~lH, d, J=2.0Hz), 7.90 t2H, .broad s), 8.33 (lH, d, J=8.0Hz), 8.40 : tlH- S) , ~
(3) ~-~mino-6-methylquinazoline mp: 266-269C
* trade mark ~.
: i ,.
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90~

IR (Nujol) vmax : 3400-3100, 1680, 1580, 1555 cm l N.M.Ro ~ppm (DMSO-d6) : 2.44 (3H, s~, 7.56 (4H, m3, 8.05 ~lH, b~oad s), 8.30 (lH, broad s) (4~ 4-Amino-6-phenoxyquina~oline mp: 97 - 99~C
IR ~u~ol) ~max : 1664, 1642, 1590 cm 1 N.M.R. ~ppm (DMSO-d6) : 6.4-7.8 (7H, m), 7.93 . (lH, d, J-9.OHz~, 8.43 (lH, s), 10.4 (2H, s) ~l (5) 4-Amino-6-(N,N-dimethylamino)quinazoline , mp: ~270C
IR (Nujol) vmax : 3400-3000, 1662, 1612, 1565 cm~
N.M.R. ~ppm (DMSO-d6) : 2.96 (6H, s), 7.12 (lH, d, J=3.0Hz), 7.36 t4H, m), 8.12 (lH, s)

(6) 4-Amino-6-ethylthioquinazoline mp: 158 - 164C
. IR (Nujol) ~max : 3300, 3100, 1670, 1600 cm l ~: N.M.R. ~ppm tDMSO-d6) : 1.26 (3H, t, J-8.0Hz), ~
3~1 ~2H, quartet3 J~8.0Hz), 7.6-B.O ¦ -(4H, m)j 8~2 (lH, d, J~2.0Hz), 8.40 (lH, 5) : ~ (7) 4-Amino-7-methoxyquinazoline IR (Nujol) vmax : 3330, 3130, 1670, 1620, 1578 1560 cm 1 . N.M.R. ~ppm (DMSO-d6) : 3.86 (3H, s), 7.1 ~ t2H~, m), 7.56 (2H, broad s), 8.13 : (lH, d, J=lO.OHz), 8.30 (lH, s~

~, .
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~ ~ 69~6~

(8) 4-AminO-7-acetamidoquinazoline mp: ~300~C
IR tNujol) vmax : 16759 1628, 1570 cm 1 N.M.R. ~ppm (DMSO-d6) : 2.16 (3H, s), 7.6 (3H, broad s), 7.9-8.3 (2H, m), 8.36 (lH9 s), 10.23 ~lH, broad s) , (9) 4-Amino-5-ethylquinazoline i mp: 224 - 227C
IR (Nujol) vmax : 3300, 3100, 1665, 1575, i 1540 cm~l ~- NoM~R~ ~ppm (CDC13) : 1.30 (3H, t, J~7.0Hz~, ~~ 1.83 (2H, s3, 2,77 t2Hl qua~tet, J-7.0Hz~,

7.4 8.0 ~3H, m)~ 8.26 ~lH, s) ~10~ 4-Amino 6-butylquinazoline mp: 209 - 210C
IR (Nujol) vmax : 3050, 1680, 1570, 1540 cm 1 N.M.R. ~ppm (DMSO-d6~ : 0.7-1.8 (7H, m), 2.7 (2H, t, J-7~0Hz), 7.63 ~4H, broad s~

8.07 (lH, s), 8.37 (lH, s) ( ) tll) 4-Amino-8-methylquinazoline `
mp: 200 ~ 214DC
IR (Nujol) vmax : 3350, 3120, 1670, 1612, 1588 cm~l N.M.R. ~ppm (DMSO-d6) : 2.66 t3H, s~, 7.3-8.0 (4H~ m), 8.16 (lH, d, J-9.OHz), 8.56 (lH~ s) (12) 4-Amino-6-propyl~uinaz~line mp: 194 - 198C
IR (Nujol~ ~max 3320, 3~00, 1660~ 1570, 1550, 1500 cm 1 N.M.R. ~ppm ~DMSO-d6) : 0~93 (3H, t, J=7.0H2), . . .

: .' .
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. ' .

~ J ~ 2 1.3-2,1 (2H, m), 2.73 (2H, t, J=7.0HZ~, 7.70 (2H, S), 7.75 t2H, m), 8.13 (1H, S), 8.46 (1H~ S) (13) 4 AminO 6,7 dimethY1qUinaZO1ine mP: >360~C
IR (NUjO1) VmaX : 3270, 30709 1680, 16203 1560 Cm 1 (i4) 4 AminO 7 me~hY1qUinaZO1ine mP: 278 - 279C
. IR ~NUjO1) VmaX : 3330, 3150, 1670D 1620, ~00 790 Cm 1 N.M.R. ~PPm ~DMSO d6~ : 2.43 (3H9 S), 7O3 (1H, d, J-8.0HZ), 7.45 (1H, S) 7 7.6 ~2H, S), 8.1 (1H, d, J~8.0HZ3, .
.~ ~.33 (1H, S) ~ .
(15) 4 AminO 6 (4-methY1PiPe~aZinY1)qUinaZO1ine mP: 229 - 234~C
IR (NUjO1) VmaX : 3170, 3050, 1670, 1640, 1620 Cm 1 (~' N-M-R- ~PPm (DMSO d6) : 2-23 (3H, S), 2.5 (4H, m) ? 3.2~ ~4H, m), 3.45 (~H, S), : 25 7.3-?.6 t3H, m), 8.2 (1Hg S) : : :
; (16) 4 AminO 6,7 dimethOXYqUinaZO1ine mP: 204 - 206C
IR (NUjO1) VmaX : 3320, 1672, 1612, 1580 Cm 1 N.M.~. ~PPm (DMSO-d6~ : 3.90 ~6H, S), 7.1 H, S), 7.40 (2H, S), 7.6 (1H, 5), 8.27 (1H, S) ~17) 4 AminO 6 [biS(2 hYdrOXYethY1)aminO~qUinaZO1ine 3~ N.M,R, ~PPm (DMSO d6) : 3.53 (8H, m), 4.5 (2H3 ~), - 7.0-7.6 (5H, m), 8,1 (1H, S) IR (Nujol) vmax: 3380, 1660, 1618, 1575 cm l mp: ~27 - 231C

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.
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~: , ' ~ ' . ' ~ ' ~ ~ ~90~2 (18) 4-~mlno-7-pivalamidoquinazoline mp: 305 - 307C

Preparation 2 A mixture of 2-amino-5-nitrobenzonitTile (48.9 g), anh~drous po~assium carbonate (45.6 g~, formamide (240 ml) and N,N-dimethylformamide (~00 ml~ was stirred for 50 minutes at 150C and then cooled ~o ambient tempelature. To.the resultant mixture was added a small volume of water with stirring. Precipi~ated crystals were separat0d by filtration, washed three times with water and dried under reduced pressure to give crystalline 4-amino-6-nitroquinazoline (50.1 g).
lS mp: ~360C
IR ~Nujol) vmax : 3350, 3200, 1680, 1620 cm 1 N.M.R. ~ppm (DMS0-d6) : 7.76 (lH, d, J=9.OHz), 8.43 (lH, dd, J-3.0 ~nd 9.0Hz~, 9.26 (lH, d, J=3.0Hz), 8.30 (2H, m) Prepara~ion 3 ; ~a) A mixture of Z,4-quinazolinedione (20 g), tri-n-, propyla~ine (38 g) and phosphorus oxychloride (200 ml) was stirred for 40 minutes at 120C. The resultant mixture was concentrated under reduced pressure to give a solid residue, which was extracted twiGe with warm 2%
tri-n-propylamine-heptane solution (250 ml) and twice with 2% tri-n-propylamine-ether 501ution (250 ml).
To the combined extracts was added a small volume of benzene to dissolve precipitated c~ystals. The solution W25 washed with 0.5N sodium hydroxide ~queous solution, three ~imes with water and wi~h aqueous solu~ion satu-ra~ed with sodium ~hloride. The resultant solution was dried over anhydrous magnesium sulfate and concentrated 3~ under ~educed pressure to give crystalline-.

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~ J ~ 6 2 2,4-dichloroquinazoline (20 g). After the crystals were dissolved in dioxane ~140 ml), ammonia was passed through the resultant solution or 40 minutes and the resultant mixture was allowed to stand overnight.
Precipitates were separated by filtTation, washed twioe with water and dried under reduced pressure to give crystalline 2-chloro-4-aminoquinazoline (12.4 g).

(b) To the solution of sodium metal (0.7 g) in dried allylalcohol ~90 ml~ was added 4-amino-2-chloroquinazoline (3.5 g~ and the mixture was stirred for 5 hours at 100C.
After the resultant mixture was concentrated under reduced - pressure, to the residue was added a small volume of water, The aqueous mixture was ext~acted twice wi~h ethyl acetate. T~e organic layer was washed with wateT
and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentTated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to gi~e crystalline 2-allyloxy-4-aminoquinazoline t2.8 g).
mp: lOS - 110C
( , IR (Nujol) vmax : 3300, 3100, 1670, 1635, 1615 c~ 1 N.M.R. ~ppm (DMS0-d6) : 4.88 (2H, d, J=4.0Hz), 5.2-5.5 (2H, m), 6.1 (lH, m), 7.2-8.3 ~6H, m) .
Preparation, 4 .
(a) A mixture of l-methylquina~oline-2,4-dione t8.8 g), tri-n-propylamine (8.6 g) and phosphorus oxychlo~ide (80 ml3 was stirred for 1 hour at 110-120C. The resul-tant mixture was cooled to ambient temperature and con-centrated under re~uced pressure to give a resi~ue, which was dissolved in 2% tri-n-propylamine-chloroform solution.
The solu~ion was added dropwise to a mixture of 2N sodium

9~)6~
33 ~

hydroxide aqueous solution and ice at alkaline pH.
The aqueous layer was separated and extracted twice with chloroform. The combined chloroform layer was washed with water and with aqueous solution satu~ated with sodium chloride~ dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystalline 4-chloro-1-meth~l-lH~quinazoline-2-one.

(b~ A solution of 4-chloro-1-methyl-lH-quinazoline-2-one obtained above in methanol (50 ml) and dioxane (70 ml~ was ice-cooled. After ammonia was passed through the solution for 16 minutes, the resultant solution was allowed to stand overnight at ambient temperature. Insoluble materials were filtered off and washed with methanol. The combined filtrate and washings was concentrated under reduced pressure to give a residue, which was disso~ved in methanol.
To the solution was dropwise added ether to gi~e pre-cipitates, which was separated by fil~ration and washed with a mixture of methanol and ether to give crystalline 4-amino-1-methyl-lH-quinazoline-2-one (4.05 g).
- ( ~ The same crystalline compound (0.7 g) was recovered from the mother liquor in the same manner as mentioned above.
; 25 mp: 252 - 262C
IR (Nujol~ vmax : 3350~ 3160, 1708, 1652, 1590, 1530 cm 1 N.M.R. ~ppm (DMS0-d6) : 3.48 (3H, s), 3.50 (2H, broad s), 7.12-7.40 (2H, m), 7.72 tlH9 t~
J~3.0Hz), 8.16 (lH, d, J=8.0Hz) (a) A mixture of 2-bromo-4-ethylaniline ~29.2 g) and ; cuprous cyanide (14.4 g) in dry pyridine (25.4 g) was s~irred for 16 hours at 160.~C. After cooling ~o 60C, o ~ ~

the resultant mixture was poured into a mixture (250 ml) of conc. aqueous ammonia and water (1:1) wit~ stiTring.
To the resultant mixture was added ethyl acetate (300 ml) with stir~ing. Insoluble materialswere filtered off.
The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhyd~ous magnesium sulfa~e and concentrated under reduced pressure to give an oily~ residue, to which was added benzen~ and concentrated under reduced pressure These operationswere repeated twice to remove pyridine.
The resultant oily residue was subjected to a column chromatography using silica gel ~developing sol~ent:
a mixture of benzene and hexane (3:1)) to give 2^amino-4-ethylbenzonitrile (16.4 g).
IR (film) vmax : 3460, 3370, 3225, 2200, 1620 cm 1 N.M.R. ~ppm (CC14) : 1.16 ~3H, t, J=7.0Hz), 2.5 ~- (2H, quarte~, J=7.0Hz), 4 36 (2H7 S), 6.5 (lH, d, J=lO.OH~), 7-7.4 (2H, m) ~b) To a solution of 2-amino 4-ethylbenzonitTile (39.9 g) in acetic acid (200 ml) was added potassium cyanate (24.4 g) under ice-cooling in *he course of ( s 15 minutes and stirred o~ernight in water bath. To the resul~ant mixture was added water to give precipitates, which we~e separated by fil~ration, washed with water and dried at ambient tempe~ature. The resultant crude crystals were recrystallized f~om ethanol to gi~e crystalline (2-cyano-4-ethylphenyl)urea (29.0 g).
mp: ~360C
IR (Nujol) vmax : 3450, 3350, 3250, 3200, 2220, 1660, 1620 cm N.M.R, ~ppm (DMSO-d63 : 1~2 t3H, t, J 7.0Hz)1 2.6 (2~, qua~tet, J-7.0Hz), 6.40 (2H, broad s), 7.40-7.73 (2H9 m), 8.0 ~lE~, d, J~8.0H~), 8.50 (lH, broad s) I ~ ~9n~

(c) To a soluti~n of sodium metal tO.365 g) in dried methanol ~300 ml) was added (2-cyano-4-ethylphenyl)urea tlO g) and the reaction mixture was heated unde~ reflux oT S hours and a half. The resultant mixture W25 con-S centrated under reduced pressure to give a residue, to which was added water. The resultan~ crys~als were separated by fil~ration, washed with wa~e~ and dried under reduced pressure to give c~ystal~ine 4-amino-6-ethyl^2-hydroxyquinazoline (9.35 g).
mp: >350C
IR (Nujol) ~max : 3360, 3100, 16703 1635, 1600 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.2 (3H, t, J-8.DHz), 2.6 (2H, quartet, J~8.0Hz), 7.06 ~lH, d, J~8.0Hz) J
7.46 (lH, dd, J=2.0 and 8.0Hz), 7.6-8.0 (3H, m), 11.2 (lH, s) Prepara~ion 6 A mixture of 2-amino-5-ethylkenzoic acid (20.28 g) and ethyl chlorocarbonate ~53.5 g) was stiTred for 50 minutes at 100C and then cooled to 90C. To the mixture : was added dropwise ace~yl chloride (13.81 g) in the course of 15 minutes and ~he reaction mixtu~e was stirred C` for 2 hours at 100C. After the resulta~t mixture was cooled to ambient-temperature, to the mixture was added hexane and allowed to stand at ambient temperature to ~ive crystals, which were separated by filtration, washed with hexane and dried under ~educed pressure to give cTystalline 6-ethyl-~H-3,1-benzoxazine-2,4tlH)-dione (19 . 55 g) -mp: 178 - 181C
IR (Nu~ol) vmax : 3230, 1760, 1690, 1615, 1605 cm 1 N.M.R. ~ppm (CDC13) : 1.23 (3H, t3 J28.0Hz~, 2.7 2H, qu~rtet, J=8.0Hz), 7.0-8.0 ~3H, m), . 9.3 (lH, s) ` 1 30~2 (b3 A mixture of 6-ethyl-2H-3,1-benzoxazine-2,4~1H)-dione (19.55 g) and urea (6.1S g~ in dry N,N-dimethylformamide (98 ml) was heated under reflux for 3 hours and 40 minutes. After the reaction mixture was cooled to ambient temperature, to the mixture was added water w;th stirring to give crystals, which~ separated by filtra~ion, washed with water and dried under reduced pressure to gi~e crystalline 6-ethyl-1~,3H-quinazoline-2,4-dione (11.74 g).
10mp: Z71 - 274C
IR (Nujol) vmax : 3310, 3160, 3030, 1720, 1685, ~~" 1620 cm 1 N.M.R. ~ppm ~DMS0-d6) : 1.2 (3H, t, J=8.0Hz), 2.65 (2H, quartet7 J=8.0Hz), 7.1B (lH, d, Ja8.0Hz), 7.56 (lH, dd, J=2.0 and 8.0Hz~9 7.8 (lH, d, J=2.0Hz), 12.0 t2H, s) (c) A mixture of 6-ethyl-lH,3H-quinazol;ne-2,4-dione (3.78 g), ~ri-n-propylamine (5.7~ g) and phosphorus ~0 oxychloride (38 ml) was stirred or 40 minutes at 120C
and then cooled ~o ambient temperature. The reaction mixture was concentrated under reduced pressure to ~ive ( a residue, to which was added warm ~50-60C) 2% tri-n-propylamine-heptane solution (50 ml~ with s~iTring.
The supernatant was separated and the solid res;due was - treated three ~im~s in substantially same manner as mentioned above. To the combined heptane layer was added benzene. The resultant mixture was washed ~wice with 5% sodium hydroxide aqueous solution (50 ml), three times with water and with aqueous solution satura~ed with sodium chloride. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystallin~ 2,4-dichloro-6-ethylquina201ine ~4.07 g)-mp: ~0 - 83C

0 ~ 2 IR (Nujol) vmax : 1530, 1480, 1450, 1410, 1160, 1110 cm~l N.M.R. ~ppm (CDC13) : 1.4 (3Hj t, J~8.0Hz)~ 2.93 (2H, quartet~ J=8.0H~), 7.95 t2H, broad s), 8.1 (lH, s) (d) A solu~ion of 2,4-dichloro-6-ethylquinazoline (10.8 g) in me~hanol and chloroform (70 ml) was cooled with ice-water. Ammonia was passed through the reaction mixture for 20 minutes and the mixture was allowed to stand for 18 hours at ambient temperature. The resultant ~~ mixture was concentrated under reduced pressure to give a residue, to which was added water and hea~ed to 50 - 60C
with stirring. The precipitates was separated by filtra~ion, washed with hot water and recrystal~ed from dioxane to gi~e crystalline 4-amino^2-chloro-6-ethylquinazoline (8.3 ~). Crystals (0.7 g) of the same compound were obtained by treating the mother liquo~ in substantially ~he same manner as mentioned above.
2Q mp: 244 - 246C
IR ~Nujol) vmax : 3380, 3340, 31209 1660, 1570, 1540 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.3 ~3H, t, JY8.0HZ~, 2.8 ~2H, quartet, J-8.0Hz), 7.5-7.9 (2H, m~, 8.I6 (lH7 s), 8.3 (2H, broad s) ~e~ To a solution of sodium metal ~1.19 g) in methanol (270 ml)~was added 4-amino-2-chloro-6-ethylquinazolin~
(9.01 g?. The reaction mixture was heated under reflux for 7 hours and heated for 38 hours at 60C. The resul-~~ tant mixture was concentrated under reduced pressure to gi~e a residue, to which was added water undeT warming with stirring. The precipitates were separated by filt-ration and dried under reduced pressure to gi~e cTystall;ne 3S 4-amino-6-ethyl-2-methoxyquinazoline (6.77 g).

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~ 3 ~ 6 2 - ~8 mp: 168 - 170C
IR (~uj ol) OntaX : 3300, 1630, 1580 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.30 ~3H, t, J=7 . OHz), 2.76 (2H, quartet, J=7.0Hz), 4.06 (3H, s), 7.70 (2H, m), 8.36 (lH, broad s), 9.20 ~ 2H, m) Prepa~ation 7 A mixture of iron (113.9 g), conc. hydrochloric acid (57 ml~ and water (2.3 liters) was stirred at 9~C for 20 minutes. To the mixture was added during 10 minutes 4-amino-6-nitroquinazoline (114.1 g). ~he reaction mixture ~-^ was stirred at 95C for an hour and a half and then , ~ filtered. The filter cake was washed with hot water.
i The combined filtrate and washings were concentrated under lS reduced pressure to give a residue, to which was added ' `a small volume of ethanol to give precipitates. The '~ precipitates were separated by filtration and dried to give 4,6-diaminoquinazoline hydrochloride (94~8 g).
f' The same compound (4.3 g) WAS recovered from the mother liquor in *he same manner as mentioned above~
IR (Nujol) vmax : 3310, 1665, 1610, 1560 cm 1 Preparation 8 , A mixture of 4,6-diaminoquinazoline hydrochloride ~ 25 (1.97 g), sodium hydrogen carbonate ~Ç.72 g~ and pyridine l (20 ml) was stirred under ice-cooling. To the mixture was added dropwise during 30 minutes methanesulfonyl chloride (4.58 g) under ice-cooling. The reaction mixture was stirred for an hour under ice-cooling and 1 30 for 4 hours at amhient temperature~ To the mixture was ¦ added ice-water. The resultant mixture was stirred for - about ~ive minutes and concentrated under reduced pressurè.
f To ~h~ residue was added a mixture of chloroform and ~¦ methanol. The mixture was stirred under heating. In-1 35 soluble materials were removed by filtration and ~hen I the filtrate was concentrated under rèduced pressure to '~ give crude cry~tals, to which was added a mixture of ,, ~ . . , .. -:
.

S.2 _ 39_ chloroform and methanol (4:1) 7 The mixture was stirred under heating to give crystals, which were separated by filtration to give crystalline 4-amino-6-methanesul~on-amidoquinazoline (1.45 g).
mp: 287 - 290C
~R (Nujol3 vmax : 3350, 3150, 1660, 1615 cm 1 N.M.R. ~ppm (DMSO-d6) : 3.3 (3H, s~, 7.7-8.33 (4H, m~, 8.83 (lH, s), 9.8 (2H, s) .
Preparation 9 To a mixture of 4,6-diaminoquinazoline hydrochloride (10.0 g), tripropylamine tl7.61 g) and dry pyridine (100 ml) was added dropwise during 35 minutes 3,3-dimethylbutyryl chloride (10~34 g) under ice-cooling.
The reaction mixture was stirred for 2 hours at the same temperature. To the resultant mixture was added ice-water. The mixture was stirred for 5 minutes and then concentrated under reduced pressure. To the residue was added water and sodium hydrogen carbonate (13.0 g) little by little to give precipitates, which were separated by filtration, washed with water and dried. Thus obtained ( -~ crude cr~stals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was conc~ntrated under reduced pressure to give a residue, which was suspended in 5% methano~chloroform solution (70 ml3.
After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(3,3-dime~hylbutyramido)-quinazoline (8.5 g).
mp: 273 - 274 DC
IR (Nujol) vmax : 3330, 3220, 1685, 16SO cm 1 N.M.R. ~ppm (D~O~d6) : 1.05 (9H, s), 2.26 (2H, s) t ;~ 7.6 (2H, s), 7.63 (lH, d, J=8.0Hz), 7.83 ~lH, dd7 J=2.0 and 8.0Hz), 8.4 (lH, s), 8.4 (lH, d, J=2.0Hz), 10~03 (lH,s) ~ .

~ 1 6~0~2 . ~ 40 .
Preparation 10 The following o~ounds were prepared in substantially the same mannex as that of Preparation ~.

(1) 4-Amino-6-~ivalamidoquinazoline mp: 269 - 273C
IR (Nujol) vmax : 3325, 3175, 1670, 1580, 1560, 1525 cm 1 N.M.R. ~ppm (DMSO~d6) : 1.23 (9H, s), 7.5 (2H, s), 7.56 (lH, d, J=9.0Hz), 7,80 (lH, dd, J-2.0 and 9.0Hz), 8.3 (lH, s), 8.35 ~~~ (lH~ s), 9.4 (lH, s) .

(2) 4-Amino-6-(2~3-dimethylpentanamido)quinazoline mp: 240 - 243C

.

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: 30 , ~,, .

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~ ~ ~90~
~1 To a mixture of 4 ,6-diaminoquinazoline hydrochloride tl. 97 g), tripropylamine (2 , 60 g) and dry py~idine (20 ml) in an ice-bath was added dropwise during 10 minutes 2^ethylbutyryl chloride ~1.75 g~, The mix~ure was stirred for 3 hours at the same temperature. Crushed ice was added to the reaction mixture.'~ The mixture was stirred for 5 minutes and concentrated under reduced pressure. After the addition of water (50 ~ sodium hydrogen carbonate (3.36 g~ was added in small portions to the residue to give precipitates which were separated by filt~ation, washed with wate~ and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in e~hyl acetate. After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(2-ethylbutyramido)quinazoline (1.20 g).
mp. 248-250C.
; IR ~Nujol) vmax : 33209 3100, 1660, 1570, 1535 cm 1 N.M.R. ~ppm (DMSO-d6) : 9.2 ~6H, t, J=6.0Hz) 3 - 1.34-1.88 (4H, m), 2.08-2.44 (lH9 m), - 7,2 (2H, s), 7.6 (lH, d, J~lO.OHz3, 7.8 (lH, dd, J=3.0, lO.OHz~, 8.34 (lH, s), 8.38 ~lH, d~ J-3.0Hz~, 10.02 ~lH, s) . ~
A mixture of 4,6-diaminoquinazoline hydrochloride tlO g) and tripropylamine (17.6 g) in dry pyridine ~100 ml~ was stirred in an ice-bath for 1 hour.
To the mixture was added dropwise during 40 minutes isobutyric anhydride (8.85 ~). The mixture was stiTred for l hour at 5C. Crushed ice was added to the reaction ; mixture. The mixture was stirred for 5 minutes and con-centrated under reduced pressure to give a residue which .

.

I fia(3 - ~2 -was dissolved in water. After insoluble materials were removed by filtration~ the filtTate was adjusted to pH 8-9 with aqueous sodium bicarbonate solution and concentrated under reduced pressure to give a residue S which was dissolved in a mixture of chloroform and methanol. The solution was filtered and concentrated under reduced pressure to give a cryst~line residue which was suspended in ethyl acetate~ The suspension -was filtered to give 4-amino-6-(2-methylpropionamido)-quinazoline (S,O5 g).
mp. 2~0-283C
IR tNujol) vmax : 3260, 3120, 1655, 1575, 1510 cm l N.M.R. ~ppm (DMSO-d6) : 1.12 (6H~ d, J#7.0Hz), 2.5-2,8 (lH, m), 7.5 (2H, s), 7.5 (lH~ d7 J=9.OHz), 7.85 (lH, ddD J=2.0, 9.0Hz), 8.3 ~lH, s), 8.4 (lH~ d, J-2.0Hz), 10.03 (lH, s) Pre~aration 13 A mixture of 4,6-diaminoquinazoline hydrochloride (12 g~ and tripropylamine (31.7 g) in dry pyridine (120 ml~ was stirr~d in an ~ce-bath for l hour.
~-- Cyclohexanecarbonyl chloride (12.1 g) was added dropwise during 4 hours and 20 minu~es to the mixture at 70Cr The mixture was stirred for additional 1 hour at 5C.
Crushed ice was added to the reaction mixture.
The mixture was stirred for 1 hour and concentrated under reduced pressure. After addition of water, the mixture was adjusted to pH 8 with sodium hydrogen ;`~ carbonate to give precipitates ~hich were separa~ed 3Q by filtration, washed with water and dried~
The precipitates were dissolved in a mixture of chloro~orm and methanol under heating. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give crystalline 4-amino-6-cyclohexanecarboxamidoquina~oline (9,25 ~).
,.~

mp. 301-303C
IR (Nujol) vmax : 3700-31009 1650, 1585) 1560, 1510 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.0-2.0 (lOH, m), ~.4-2.8 ~lH, m), 7.53 (2H, s~ 7,6 (lH, dg J=8.0Hz), 7,78 (lH, dd, J=2.0~
8.0H2), 8.3 (lH7 s), 8.43 (lH, d, J-2.0Hz~, Preparation_l4 ~ 10.0 (lH, s) A mix~ur~ o~ 4,6-diaminoquinazoline hyd~ochloride (10 g3 and tripropylamine (26. 4 g~ in dry pyridine ~100 ml~ was stirred in an ice-bath for 20 minu~es.
To the mixture was added dropwise during 1.5 hours 3-cyclopentylpropionyl chloride tl2,2 g). The mixture was stirTed in an ice-bath fo~ 1.5 hours. Crushed ice was added to the reaction mixture. The mixture was stir~ed for 5 minutes and concentrated under reduced p~essure. After addition of wa~er, sodium hydrogen carbonate was added in small por~ions to the mixture to give precipitates which were separated by filtration, washed with water and dried. The crude~crystals were dissolved in a mixture of chloroform and methanol under heating. After the filtration of insoluble materials, the filtrate was treated with activated charcoal and concentrated under reduced pressure to give a residue.
2S The residue was suspended in ethyl acetate. The sus-pension was stirred for 1 hour under heating and filtered to give crystalline 4-amino-6-(3-cyclopentylpropionamido~-~uinazoline (7.2 g).
mp. 279-283C
IR (~ujol) vmax : 3280, 3120, 1660, 1565, 1510 cm 1 N,M.R. ~ppm (DMSO-d6) : 0.7-2.16 ~llH, m), 2.46 (2H, t, J=6.0Hz), 7.6 (2H, m), 7.66 ~lH, d, J=9.0Hz), 7.93 tlH, d, J=9.OHz), 8.33 ~lH, s), 8.50 (lH, s), 10.40 (lH, s~

.

.
.~ . . .

. ~ , . .

7 ~
- 4~ -The ollowing Examples are giYen for the purpose of illustrating this invention.

A mixture of 4-aminoquinazoline (11.6 g) and diethyl S ethoxymethylenepropanedioate (19.0 g) in N,N-dimethylfo~mamide (40 ml) was s~irred for l hour and 20 minutes at 160C and then cooled to 0C to precipirate crys~als. To the mixture was added small volume of water with stirring. The crystalswere separated by filtration, washe~ with water, dried overnight under reduced pressu~e and dissolved in ethyl acetate.
. The resultant solution was dried over anhydrous magnesium sulfate and recrys~alli~ed from a mixture of ethyl acetate and hexane to give crystalline diethyl[(4-lS quinazolinylamino)methylene]propanedioate (22.7 g).
mp: 115 - 117C
IR (Nujol~ vmax : 1735, 1660, 1628 cm l N.M.R. ~ppm (CDC13) : 1.36 ~3H, t, J=7.0Hz), 1.40 (3H, t, J=7.0Hz), 4.36 (4H3 m), 7.5-8.2 ~4H, m), 8.96 (lH, s), 9O40 (lH, d, J-12.0Hz), 12.3 (lH, broad d, J~12Hz3 Example 2 The following compounds were prepared in substant-ially the same manner as that of Example 1.
(1) Diethyl [(6-phenoxy-4-quinazolinylamino)methylene]-prcpanedioate.

.

.

m~. 121 - lZ3C (recrystallized from ~ mixture of chloroform, ethyl acetate and hexane) IR (Nujol) vmax : 17209 1625, 1G17, 1608, ` 1580 cm 1 S N.M.R. ~ppm (CDC13) : 1.40 (6H, t, 3-8.0Hz), 4.33 t2H, quartet, J=8.0Hz) 9 4.37 (2H, : quartet~ J=8.0Hz), 7.0-~7.6 t7H, m), 8.06 (lH, d, J=9.OHz), ~.90 (lH, s~, 9.33 (1~, d, J=12.0Hz), 12.16 (lH, d, J=.l~ OHz) ~~ (2) Diethyl [(6-dimethylamino-4-quinazolinylamino)-methylene]propanedioate mp: 156 - 158C trecrystallized from a mixture of chloroform and hexane) IR tNujol) ~max : 1720, 1652, 1628, 1600 cm 1 .N.M.R. ~ppm ~CDC13) : 1.36 (6H, m), 3.04 (6H, s), 4.34 (4H, m), 6.50 (lH, d, J-3.0Hz), 7.34 (lH, dd, J=3.0 and 9.0Hz), 7.72 (lH, d, J=9.OHz), 8.50 (lH, s), g.24 tlH~ d, J-ll.OHz), 11.90 (lH, d, J=ll.OHz~

, . .
(3) Diethyl [(6-ethylthio-4-quinazolinylamino)methylene]-propanedioate mp: 103 - 106C trecTys~allized from a mixture of ethyl acetate and hexane) IR ~Nujol) vmax : 1722, 1650, 1624, 1600 cm 1 N.M.R. ~ppm tCDC13~ : 1.3-1.8 ~9H, m), 3.14 .
: : (2H, quartet, J~8.0Hz), 4.2-4.7 ~4H, m)~
7.7-8,1 (3H, m), 8.90 (lH, s), 9.3 ; ; (lH, d, J=12.0Hz)) 12.4 ~lH, d, J~12.0Hz) (4) Die~hyl [~7^m~thoxy-4-quinazolinylamino)~et~ylen~]-propanedioate . 35 mp: 134 - 138C (recrystallized from a mixture -., .

-:
. .

:
: , ': - ~ . - ' ~: ~

i 3 ~9~)6 - ~6 -of ethyl acetate and hexane) IR ~Nujol) vmax : 1736, 1630, 1572 cm 1 N.M.R. ~ppm (CDC13) : 1.40 (3H, t, 7.0Hz~, 1.43 (3H, t, Jz7.0Hz), 3.96 (3H~ s), 4.36 (4H7 m), 7.1-7.4 (2H~ m), 7.83 (lH9 d, J-9.OHz), 8.87 (lH, s~ 9.30 (lH, d, J=12.0Hz3, 12.2 ~lH, d, J-12.0Hz) (5~ Diethyl [(7-acetamido-4-quinazol;nylamino)-methylene~propanedioate IR (Nujol) vmax 3420, 1720, 1695J 1655, ~; 1630, 1585 cm 1 N.M R. ~ppm (CDC13-DMSO-d6) : 1.36 (3H, t, J=7.0Hz), 1.43 (3H, t, J=7.0Hz), 2.23 ~3H~ s), 4.30 (4H, m), 7.93 (2H, m), 8.34 (lH, m), 8.gO (lH, s), 9.30 (lH, d, J-12Hz), 10.27 (lH, 5~, 12.2 (lH, d, J=12Hz) 20 (6) Diethyl [(2-hydroxy-4-quinazolinylamino)methylene]-propanedioate mp: 265 - 26~C (recrystallized from a mixture ( . of N,N-dimethylformamide and wate~) IR (Nujol) vmax : 1702, 1660, 1630~ 15859 ~ 75 cm 1 N.M.R. ~p~m (CDC13) : 1.40 (6H, m), 4.40 (4H, m)~ 7.3-B.a (4HJ m), 9.24 (lH, d - J=ll.OHz), 12.3 (lH, d, J~ll.OHz~, -~ 12.90 ~1H1 s) (7) Diethyl [~2-methoxy-4-quinazolinylamino)methylene]-?: propanedioate mp: 129 - ~35C (~ecrys~allized f~om a mixt~se of ethyl acetate and hexane) ~ 35 IR (Nujol~ ~max : 1692, 1645, 1630, 160B~ 1568 cm l .;
-.1 6 ~ 2 N.M~R. ~ppm (CDC13) : 1.40 (3H, t, J~7.0Hz), 1.46 ~3H, t, J=7.0Hz), 4.16 ~3H, s), 4.32 (4H, m), 7.3-8.0 ~4H, m), 9.30 (lH, d, J~ll.OHz~, 12.3 (lH, d, J311.0~z~

(8) Diethyl [(2-allyloxy-4-quinazolinylamino)methylene3-.propanedioate mp: 117 - 119C (~ecrystallized fr~m a mixtu~e of ethyl acetate and hexane~
IR (Nujol) ~max : 1672, 1640, 1620, 1560 cm 1 N.M.R. ~ppm (CDC13) : 1.40 (3H, t, J~7.0Hz), c 1.45 (3H, t, J~7.0Hz), 4.40 (4H, m~, 5.0-6.5 (5H, m~, 7.3-8.0 (4H, m~, 9.30 (lH, d, J=12.0Hz), 12.3 (lH, d, J~12~0Hz) (9) Diethyl [(2-methyl-4-quinazolinylamino)methylene~-propanedioate : I~ (Nuj-ol) vmax : 16809 1640, 1620, 1600, 1550 cm~l N.M.R. ~ppm tCDC13) : 1.40 t6H, m) 3 2.76 (3H~ ~), 4.33 t4H, m), 7.44-8.0 ~4H, m~, 9.34 (lH, d, J=12.0Hz), 12.14 (lH, d, J-12.0H~) .

(10) Diethy~ [(Z-dimethylamin~-4-quinazo~inylamino)-methylene3propanedioate mp: lZ6 - 128C (recrystallized from e~hanol) IR (Nujol) vmax : 3250, ~695, 1640, 1610, 1565 cm~
: 30 N.M.R. ~ppm (CDC13) : 1.40 (6H, ~)~ 3.26 (6H, s)~ 4.37 (4H, m), 7.0-7077 ~4H~ m), 9027 (lH, d, J-12Hz), 11.90 (lH, d, J=12H~)

(11) Diethyl [ (2-hydroxy-6-ethyl-4-quina~olynylamino) -: 3 5 methyl ene ~ prop aned i oat e .
' ' :
:
:

mp: 267 - 270C (recrystallized from a mixture of chloroform and methanol) IR (Nujol) vmax : 17Z0, 1665, 1615~ 1588 cm l N.M.~. ~ppm (CDC13) : 1.16-1.76 (9H, m~, 2.83 (2H~ quartet~ J~8.0Hz), 4.30 ~4H~ m~, 7.56 (3H,broads)~ 9.26 (lH, d~ J=11.5Hz3,

12.26 (lH, d, J~ll.SHz), 12.90 (lH, s) (12) Diethyl ~t2-methoxy-6-ethyl-4-quinazolinylamino)-methylene~prppanedioate mp: 149 - 152~C (recrystallized f~om ethyl ~` acetate) IR ~Nujol) vmax : 1730, 1652, 1635, 1622, 1575 cm~l N.M.R. ~ppm (CDC13) : 1.20-1.67 t9H, m), 2.86 (2H, quartet! J-8.0Hz)p 4.17 t3H, s3, 4.36 (4H, m)~ 7,63 (3H, m), 9.23 (lH, Z, J=11.5Hz~, 12.16 (lH~ d, J=11.5Hz) Exam~0 3 A mix~ure of 4-amino-6-ethylquinazoline (S.35 g) and diethyl ethoxymethylenepropanedioate ~9.5~ g) in ~;. N,N-dimethyl~ormamide (25 ml) was stirred fo~ 3 hours at llO~C and then cooled to ambient temperature.
A small volume. o water was added to the resultant ` : mixture.to precipitate crystals, which were separated : by filtration and washed with water. The crystals were dissolved in chloroform, washed with an aqueous solution saturated with sodium chloride, dried over anhydrous . 30 magnesium sulfate and concen~rated undeT ~edu~ed pressure to give a cTystalline residue, which was recrystallized from a mixtu~e of ethyl acetate and hexane to gi~e ~: crystalline diethy~ [(6-ethyl-4-quinazolinylamino)-methylene]propanedioate~8.40 g). Further, crys~als (Z.75 g~ of the same compound wcre recovered from the ~.

mother liquor in the same manner as mentioned ab~ve.
mp: io4 - 106DC
IR (N~jol) vmax : 3?50, 1700~ 164'5~ 1610, 1560 cm 1 N.M.R. ~ppm (CDC13): 1.2-l.S (9H, m), 2,g6 (2H, quartet, J~7.0Hz), 4.1-4.7 ~4H, m), 7.7-8.1 (3H, m), 8.95 (lH, s~, 9.4 (lH, d, J=12.0Hz), 12.3 (lH, d, J=12.0Hz) le 4 -The ~ollowin~ compounds were prepa~ed in substant-ially the same manne~ as that of Example 3, ~ (1) Diethyl ~(6-me~hyl-4-quinazolinyl~mino)methylene~-: propanedioate mp: 137 - 139C (recrystallized from a mixture of chloroform and hexane) IR (Nujol) vmax : 1735, 1655, 1630, 1615 cm 1 N.M.R. ~ppm (CDC13) : 1.40 (3H, t, J=8.0Hz);
1.46 (3H, t, J=8.0~z), 2.63 (3H, s), 4.33 (2H, quartet, J=8.0Hz), 4.46 (2H, quartet, J=8.0Hz~, 7.8-8~1 (3H, m), 8,93 (lH, s), 9.4 ~lH9 d, J=12.0Hz), l 12.16 (lH, d, J=12.0Hz) (2) Diethyl [(6-butyl-4-quinazslinylamino)methylene]-propanedioate mp: 83 - 85C (rec~ystallized fr~m a mix~ure `~ - of ethyl acetate and hexane) IR (Nujol) ~max : 3220, 1730~ 1650, 1630, 1610, 1560 cm~l N.M.R. ~ppm (CC14) : 0.7-Z.1 (13H, m), 2.86 (2H, t, J~7.0Hz), 4.26 (2H, quartet, J=7.0Hz), 4.36 (2H, quartet, J=7.0Hz)~
j~ 7.6-~.0 (3H, m), 8.76 (lH, s~, 9.23 ~lH, d, J=12.0Hz), 12.2 (lH, d, J~12.0Hz) ~2 (3) Diethyl [(8-methyl-4-quinazolinylamino)methylene]-p~op~nedioate mp: 121 - 123C (recrystallized fr~m a mixture of ethyl acetate and hexane) IR ~Nujol) ~max 1705, 1650, 1618, 160S, 1580 cm 1 N.M.R. ~ppm ~CDC13) : 1.40 (3H, t, J~7.0Hz)~
1.43 (3H, t, J=7.0Hz), 2.73 (3H, s), 4.37 (4H, m), 7.4-7.9 (3H, m~, 8.97 ~lH, s), 9.33 (lH, d, J~12.0Hz), 12.26 (lH, d, J~12.0Hz) (4) D~ethyl. [~6-propyl-4-quinazolinylamino)methylene]--propanedioate lS . mp: 96 - 99~C ~recry-stallized from a ~ixtu~e of ethyl acetate and hexane) IR ~Nujol) vmax : 3200, 1690, 1640~ 1630, 1600, 1550 cm l : N.M.R. ~ppm (CC14) : 0.8-2.2(11H, m~, 2.9.
~: 20 (2H, t, J-8.0Hz), 4.0-4.7 t4H~ m), 7,5-8.0 ~3H, m), 8.8 ~lH, s), 9.23 (lH, d, J=12Hz), 12.23 ~lH, d, J=12.0Hz) .
(5) Diethyl [(7-methyl-4-quinazolinylamino)methylenel-propanedioate ; mp: 118 - 120C trecrys*allized from a mix~ure of chlorofoTm and hexane) IR ~Nujol) vmax : 3250, 1685, 1640, 1620, 1605, 1560 cm~l N.M.R. ~ppm (DMSO-d6) : 1.2 (3H, ~, J=7.0Hz), : ~ : 1.26 (3H., t~ J=7.OHz~, 3.2 (3H, s), : 4.15 t2H, quartet; J~7.0Hz), 4.26 ~2H, ~` quartet, J~7.0Hz), 7.4-8.0 (3H, m), 8.8 (lH, s), 9.06 (lH, d, J-12.0Hz), 11.53 (lH, d, J~l~.OHz) .

.~ ~. -, . .

, , ' ~ ~ 6~0~2 (6) Diethyl [(6-{bis(2-hydroxyethyl)amino~ 4-quin~zolinylamino]methylene]propanedioate mp: 194 - 195C (recrystallized from chloroform) I~ (Nujol) vmax : 3300, 1720, 1648, 1630, 1605 cm ~
N.M.R. ~ppm (DMSO-d6) : 1030 ~3H, t, J~7.0Hz~, 1.33 (3H, t3 J=7.0Hz), 3.6U (8H, m), 4.26 (4H, m~, 4.80 t2H,!m), 6.73 (lH, broad s)~ 7.7 (2H, m), 8.63 (lH, s), 9.16 (lH, d; J=12.0Hz), 11.56 (lH, d, J~12.0Hz) ~'`'` , .
. A mixture of 4 amino-6-(4-methylpiperazinyl)-quinazoline (2.19 g) and diethyl ethoxyme~hylene-propanedioate (2.13 g) in isobutylalcohol (9 ml~ was stirred for 2 hours and 25 minutes a~ lOO~C and ~hen cooled to ambient temperature. The resultant mixture was concentrated under reduced pressure to give a residue, which was recrys~allized from ethanol to g;Ye crystalline diethyl [{6-(4-methylpiperazinyl)-4-quinazolinylamino}methylene]propanedioate (1.58 g).
~~ mp- 154 ~ 159C
IR (Nujol~ ~max : 3300, 1760, 1740, 1690, 1650, 163D, 1600 cm 1 : N.M.R. ~ppm (CDC13) : 1.40 ~3H, t, ~=7.OHz), :~ 1.43.(3H, t, J=7.0Hz), 2~40 (3H, s), 2.63 :~ (4H, m), 3.43 (4H, m), 4~33 (4H, m), 7.0: ~lH, d, J=3.0Hz), 7.56 (lH, dd~ J=3.0 and 9.0Hz), 7.86 tlH, d, J-9.OHz), 8.76 tlH3 s), 9.30 (lH, d, J=12.0Hz) Example 6 The following compoùnd was prepared by substantially the same manner as that of Example 5.

~ ` .

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- ' ~9~)~2 5~

Diethyl [(6,7-dimethoxy-4-quinazolinylamino)-methylene] propanedioate mp: 226 - 229C (recrystallized from a mixture of chloroform and hexane) IR (Nujol) vmax : 1675, 1636, 16209 160B, 1550 cm l N~M.R. ~ppm (CDCl3) : 1.37 (3H, t, J~7.0Hz), 1.40 (3H, t, J=7.0Hz~, 4.03 t3H, s), 4.06 ~3H, s), 4.33 (4~, m), 7.03 ~lH, s), 7.23 (lH, s), 8.76 (lH, s), 9.30 ~lH, d, J=12.0Hz), 12.0 ~lH, d, J=12.0Hz) --~ Bxample 7 A mixture of 4-amino-l-methyl-lH-quinazoline-2-one (4.20 g) and diethyl ethoxymethylenepropanedioate (5.7 g) in N,N-dimethylformamide ~0 ml) was stirred for 3 hours at 150~C and then cooled to ambien~ tempera~ure.
Precipitated crystalswere sepa~ated by filtration, washed ;~ with water and dried under reduced pressu~e ~o give crude :~ 20 crystals, which were recrystallized rom a mixture of : chloroform, ethyl acetate and hexane ~o gi~e crystalline diethyl [(l-methyl-lH-2-oxo-4-quinazolinylamino)methylene~-. propanedioate (4.0 g).
mp: 182 - 185C
IR (Nujol) vmax : i725, lioo? 1675, 1635, 1610, - 1588 cm 1 . N.M.R. ~ppm ~CDC13~ : 1.30 t3H, t, J=7.0H~), 1.40 (3H, t, J=7.0Hz), 3.66 (3H, s), 4.33 ~4H, m), 7.2-7.5 (2H, m), 7.6-8.0 (2H9 m), 9.16 (lH, d, J=12.0Hz), 12.23 ~lH, d~ J~12.0Hz) :
Exa ~
A mix~ure of 2~4-diaminoquinazoline t3 g)3 die~hyl ethoxymethylenepropanedioate (8.5 g) in N,N-35 dimethylformamide ~15 ml) was sti~red for 2 hours and .
, ,, ;~
. .
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~ ~ B 9 0 6 2 45 minutes at 150~C and then cooled to ambient tempe-rature, To the resultant mixture was added a small volume of wa~er to giYe crystals, whIch WeTe separated by filtration~ washed with water and dried under reduced pressure. The resultant crude crystals were subjected to a column chromatography using silica gel (developing solvent: a mixture of chlsroform and ethyl acetate) to give crystall.ine tetraethyl 2,2-[2,4-q~inazolin~diylbis-~iminomethylidyne)]bispropanedioate (1.8 g).
mp: 146 - 14.8C
IR (Nujol) vmax : 3250, 1700, 1680, 1650, 1640, 1630, 1600, 1545 cm 1 N.M.R. ~ppm (C~C13) : 1.43 (12H, m), 4.40 (~H, m), 7.33-8.00 (4H, m), 9.23 (lH~ d, J=12.0Hz), 9.25 (lH, d, J=13.0Hz), 11.0 (lH, d, J-13.0Hz)~
12.30 (lH, d, J=12.0Hz) ; ~ .
A mixture of 4-aminoquinazoline ~2.9 g) and 2,2-dimethyl-S-ethsxymethylene-1,3-dioxane-4,6-dione (4.46 g) in N,N-dimethylformamide (20 ml) was stirred for 1 hour and 10 minutes at 110C. The resultant mixture was cooled ( to ambien~ temperature and allowed to stand overnight to give crystals, which ~ere separated by fil~ration and washed with a mixture of ethyl aceta~e and hexane to give ~ c~ystalline 2,2-dimethyl-5-[(4-quinazolinyl)amino]-I methylen~-l 9 3-dioxane-4,6-dione ~4,1 g).
I mp: 191 - 193C
', IR (Nujol) vmax : 1732, 1680, 1620 D 1608 cm 1 N.M.R. ~ppm (CDC13) : 1.80 (6H, s), 7.60-8.17 ~4H; m), 9.03 (lH, s), 9.67 ~lH~ d, J=12.2Hz), 11.43 ~lH, broad d, J=12.2Hz) A mixture oz 4-amino-6-nitroquinazoline (57.0 ~) .

~ `

and diethyl ethoxymethylenepropanedioate (130 g~ in anhydrous N,N-dimethylformamide (570 ml) was cooled at 5C. To the reaction mixture was added sodium hydride (65.5% in mineral oil)tl3.2 g) in the couTse ; 5 of 30 minutes and the mixture was stirrçd ~or 1 hour and 40 minutes under ice-cooling. After ammonium chloride (47.2 g) was added to the reaction mixture and stirred for 20 minutes, ice-water ~1 liter) was added to the resultant mixture with stirring and allowed to stand to give crystals, whichwere separated by filt-ration, washed with water and dried overnight at ambient ~~~ temperature. The resultant crude crystals were dissol~ed in chloroform (1.5 li~ers) under heating. Insoluble materials were filtered off and the filtra~e was con centrated under reduced pressure to give orystals, which were dissolved in methanol t-300 ml) under heating and allowed to stand at ambien~ temperature. The resultant ~ crys*als were separated by filtrat;on, washed with i methanol and dried under reduced pressure to give yellowish crystalline diethyl [(6-nitro 4-quinazolinyl-amino)methylene~propanedioate t64.9 g).
; mp: 228 - 230CC
3 ~ IR tNujol) vmax : 1715, 1640, 1618 cm 1 ~ N.M.R. ~ppm (CDC13) : 1.40 ~3H, t, J~7~0Hz), 1.46 f 25 (~H, t, J=7.0Hz), 4.33 (2H, ~, J=7.0Hz) 9 4.46 (2H, q, J=7.0Hz~, 8.18 (lH, d, Js9.0Hz), 8.7 (lH, dd, J=2.0 and 9.0H~), 8.98 (lH, d, J=2.0Hz), 9.06 (lH, s), 9.3 (lH, d, J-12.0Hz), 12.55 ~lH~ d, J=12.0Hz) . 30 A mixtu~e of 4-amino-6-chloroquinazoline (807 g~
and diethyl ethoxy~ethylenepropanedioate (11.53 g) in N,N-dimethylformamide (25 ml~ was s~ir~ed for 2 hours and 40 minutes at 150C. After the reaction mixture ~1 .

~6 was cooled ~o ambient temperature, to the mixture was added water with stirring to give crys~als~ which were washed with wa~er, dried under reduced pressure and dissolved in ethyl acetate under heating. Insoluble materials were filtered off. To the filtrate was added hexane and allowed to stand at ambient temperature to give crystals~ which were separated by ,filtration and washed with a mixture of ethyl acetate~and hexane to ~give a mixture (13.48 g) of crystalline diethyl ~(6-chloro-4-quinazolinylamino~methylene]propanedioate and ethyl 10-chloro-4-oxo-4H-pyrimido[1,2-c]quina201ine-3-carboxylate.
. .
(a) Diethyl ~(6-chloro-4-~uinazolinylamino)methylene]-propanedioate N.M.R. ~ppm (CDC13) : 1.3-1.6 (6H, m), 4.2-4.6 (4H, m), 7.7-8.2 (3H, m), 8.9 (lH3 s), 9.26 ~lH, d, J-ll.OHz), 12.16 (lH, broad d, J=ll.OHz) 2~
(b) Ethyl 10-chloro-4-oxo-4H-pyrimido[1,2-c]-quinazoline-3-carboxylate ( ~ N.M.R. ~ppm (CDC13) : 1.43 (3H, t, J~7.0Hz)~
4.40 (2H, q, J=7.0Hz), 7.88 (2H, b~oad s), 8.70 ~lH, m), 8.93 (lH, s~, 9.54 tlH, s) A mixture of 4-amino-7-chloroquinazoline ~1.3 g) and diethyl ethoxymethylenepropanedioate ~1.72 g) in N~N-dimethylformamide (6 ml) was stirred for 2 hou~s at 150C. The resultant mixture was cooled to ambient tempera~ure and po~red into ice-wa~er to gi~e crys~als, which were separated by filtration9 washed with water and recrys~allized from ethanol to gi~e a mixture ~1.65 g) .

~ :~ fi9()~

of di~ethyl [(7-chloro-4-quinazolinylamino)methylene]-propanedioate and ethyl 9-chloro-4-oxo-4H-pyrimido-[1,2-c]quinazoline-3-carboxylate. The mixture was subjected to a column chromatography using silica gel (developing sol~ent: a mixture of benzene znd ethyl acetate (10:1)) to give purified crys~als.

(a) Diethyl [(7-chloro-4-quinazolinyl^amino)methylene]-propanedioate N.M.R. ~ppm tCDC13) : 1.42 (6H, m), 4.35 (4H, m), 7.56 (lH, dd, J=2.0 and 8.0Hz~, C- 7,90 (lH, d, J=8.0Hz), 7.97 (lH, broad s), 8.90 (lH, s), 9.27 (lH, d, J=12.0Hz), 12.26 (lH, d, J=12.0Hz) (b) Ethyl 9-chloro 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate N.M.R. ~ppm (CDC13) : 1.43 (3H, t, J=7.5Hz), 4.46 (2H, q, J=7.5Hz), 7.72 (lH, dd, J=2.0 and 9.0Hz~, 8.02 (lH~ d, J-~Hz), 8.80 ~lH, d, J~9.OHz), 9.03 (lH, s~, ; 9.66 (lH, s) Example 13 A mixture of 4-aminoquinazoline (7.27 g) and dimethyl methoxymethylenepropanedioate (9.6 g) in N,N-dimethylformamide ~35 ml) was stirr`ed for 2 hours at 150C. The reaction mixture was cooled ~o ambien~ tem-: perature and poured into ice-water to give c~ystals, whichwere separated by filtration, washed with water and dried at ambient temperature to give a mixture (13.3 g) of dimethyl [(4-quinazolinylamino)methylene]propanedioate and methyl 4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.
~5 .~

.

~ :~ 6~0~
~ 5i ~a) Dimethyl ~4-~uinazolinylamino)methylene]-propanedioate N.M.R. ~ppm (CDC13) : 3.87 (6H, s), 7.5-8.2 (4H, m~, 9.07 (lH9 s), 9.37 (lH, d~
J=12.0Hz), 12.3 (lH, d, J=12.0Hz) (b) Methyl 4-oxo-4H-pyrimido~1,2-c]quinazoline-3-carboxylate N.M.R. ~ppm (CDC13) : 4.03 (3H, s) 7 7 6-8.12 (3H, m), 8.88 (lH, d, J=8.0Hz), 9.10 (lH, s)~ 9.73 (lH, s) i, .
(a) A mixture of 4-amino-6,7-dimethylquinazoline (11.3 g) and diethyl ethoxymethyleneproparledioate (15.55 g) in N,N-dimethylformamide (45 ml) was stir~ed for 4 hours at 110C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water to give crystals, which ~e~e separated by filtration, washed with water and dried under reduced pressure to give crude crystals (18.5 g). The crude crustals were dis-solved in 1% methanol-chloroform solution (500 ml) and conce~trated under reduced pressure after insoluble materials were removed by filtration. The residue was recrystallized from chloroform to give crystalli~e ethyl 9,10-dimethyl-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (3.57 g~. -mp: 221 - Z23C
IR ~Nujol) vmax : 1710, 1690, 1610, 810 cm 1 NDM.R. ~ppm (CDC13) : 1.4 (3H, t~ J=7.0Hz)g 2.5 (6H, s), 4.34 (2H, quartet, J=7.0Hz), 7.8 ~lH, s), 8.6 tlH, s), 9.7 (lH, s), 11 35 (lH, s~

tb) A mixture of ethyl 9,10-dimethyl-4-oxo-4H-p~imido-[1,2-c~quinazoline-3-carboxylate (4.46 g) and anhydrous dimethylsulfoxide (17 ml) was stirred at ambient tempe-rature. To the mixture was dropwise IN sodium-ethoxide-ethanol solution (20 ml) and the reaction mixture was stirred for 3 hours at ambient tempera~ure. To the resul~ant mixture was added ammonium chloride (2.4$ g) and the mixture was stirred for S minu~es. To the mixture was added water and extracted ~wice with chlors-orm. After washing three times with water and with a~ueous solution.saturated wi~h sodium chloride, the combined chloroform layer was treated with activated charcoal, dried over magnesium sulfate and concentrated under reduced pressure to gi~e a residue, which was dissolved in a mixture of chloroform and ethyl acetate.
Insoluble materials were removed by fil~ration.
The filtrate was concentrated under reduced pressure and recrystallized twice from ethyl acetate and from a mixture of chloroform and hexane to give diethyl [(6,7-; dimethyl-4-quinazolinylamino)methylene]propanedioate (2-01 g).
mp: 146 - 148~C
IR (Nujol) vmax : 3160, 1730, 16~0, 1655, 1625, ~ . 1615 cm~l i N.M.R. ~ppm ~CDC13) : 1.32 (3H, t, J=7.0Hz), 1.4 (3H, t, J=7.0Hz), 2.5 (6H, s~, 4.3 (2H, q, J=7.0Hz3, 4.43 (2H, q, J=7.0H~), 7.66 ~lH, s), 7.76 (lH~ s), 8.9 (lH, s~, 9.36 ~lH, d, J-12.0Hz), 11.56 (lH9 d~ Jal2~0Hz) A suspension of diethyl ~(fi-nitro-4-~ quinazolinylamino)methylene]propanedioate (2.8 g) in I N,N^dimethylformam~de (152 ml) was shaken with 10%
¦ palladium on carbon (0.93 g) in hydrogen atmosphere at ¦ 35 ambient ~emperature for an hour. Ater *he reaction was !

.
.
, - ;

~ 75~9Q~2 completed, the catalyst was removed by filtration and washed with chloroform. The combined filtrate and washing was concentrated under reduced pressure to give a residue, to which was added toluene and con-centrated under reduced pressure. This operation was repeated ~o give crystalline diethyl [(6-amino-4-quinazollnylamino)methylene]propanedioate (2.50 g).
IR (Nujol) vmax : 3260, 1690, 1640, 1630, 1600 cm~l N.M.R. ~ppm (DMSO-d6) : 1.3 (3~1, t, J~7.0Hz), 1.35 (3H, t, J=7Hz), 4.23 (2H, quartet, J=7.0Hz) 3 4.39 (ZH, quartet, J=7.0Hz), 7.2 (lH, d, J=2.0Hz), 7.4 ~lH, dd, J=Z
and lOHz), 7.83 (lH, d, J=lO.OHz), 9.36 (lH, s), 9.5-10 (3H, m), 12.3 (lH, d, J=14.OHz) Example 16 A mixture of diethyl [(5-amino-4-quinazolinylamino)-methylene~p~opanedioate (2.5 g), pyridine ~1.2 g) and dichloromethane (55 ml) was stirred undeT ice-cooling.
To ~he reac~ion mixture was added dropwise isobutyryl ( ; chloride (1.06 g). The reaction mixture was stirred under ice-cooling for 30 minutes and at ambient tempe-rature for 20 minutes. After ice-water was added to the reaction mixture~ the resultant mixture was s~irred and extracted wi~h chloroform. Insoluble materials were removed by fil~ration from the ex~racts~ The extracts were washed th~ee times with water and with aqueous solution saturated with sodium chloride, d~ied over magnesium sulfate and concentrated under reduced pressure.
1 The resultant residue was purified by a column chromato-I graphy using silic~ gel tde~eloping solvent: chloroform) I and crystallized from a mixture of chloroform and hexane ¦ 35 to give crystalline diethyl [~6-isobutyramido-4-I
i ` .

I ~ 6~Q62 ~ 60 quinazolinylamino)methylene]propanedioate (1.28 g).
Crystals (0.67 g) of the same compoundwere recovered from the mother-liquor by substantiall~ the same - crystallization as mentioned above.
mp: 190 ^ 193C
IR (Nujol) vmax : 3530, 1775, 1710, 1700, 1678, 1660, 1615 cm 1 N.M.R. ~ppm (CDC13) : 1.2-1.5 ~12~, m), 2,2-2.8 .
(lH, m), 4.25 t2H, quartet, J=6Hz), 4.39 i 10 (2H, quartet, J-6Hz), 7.4-8.2 (4H, m3, 8.8 (lH, s), 9.15 (lH, d, J=12Hz), 12.06 ' C (lH, d, J=12Hz) '. Example 17 The ~ollowing compounds were p~epared in substant-~ ially the same manner as that of Example 16.
¦ (1) Diethyl [(6-acetamido-4-quinazolinylaminD)methylene]-propanedioate mp: 178 - 180C (recrystallized from a mixtuTe of tet~ahydrofuran and hexane) IR ~Nujol) ~max : 3380, 1695, 1660~ 1630, ; 1610 cm s ( N.M.R. ~ppm (CDC13) : 1.32 (3H, t, J-6Hz), 1.36 3H, t~ J~6Hz), 2.08 (3H, s), 4.3 (4H, i 25 qua~tet, J=6Hz), 7.7-8.1 ~2H, m~, 8.44 (lH, s), 8.83 (lH, s), 9.2B ~lH, s), 9.28 (lH, d~ 3=l~Hz), 11.98 (lH, d~ J=12Hz) ~ .
:~ (2~ Diethyl [(6-propionamido-4-quinazolinylamino~-methylene]propanedioate ! mp 190 - 193~C (recrystallized from a mixture :! of ethyl acetate and hexane) IR ~Nujol) ~max : 3340, 1736, 1670, 1660~ 1635, , 1572 cm~l .
N.M.R. ~ppm ~CDC13) : 1.2-1.6 (9H, m~, 2.50 'I . .
, .
- , ~ 3~

(2H, quartet, J=7.0Hz), 4.34 (2H~
quartet, J=7.0Hz), 4.40 ~2H, quartet~
J=7.0Hz~, 8.0 (2H, m), 8.40 (lH, broad s), 8.56 (lH, s), 8.90 (lH9 s), 9.36 (lH, d, J=12Hz~, 12.1 (lH, d, J=12Hz) (3) Diethyl [(6-butyramido-4-quinazolinylamino)~
: methylene]propanedioate mp: 187 - 190C (recrystallized from methanol) . IR (Nujol.) vmax : 3380, 1748~ 16B0, 1625, 1580 9 1554 cm~
N.M.R.-~ppm (CDC13) : 0.98 (3H, t, J=7.0Hz~, 1,27 ~3H, t, J=6.8Hz), 1.33 (3H, t, ~
J~6.8Hz), 1.80 (2H, m), 2.43 (2H, ts J=7Hz), 4.33 (4H, m), B.0 ~2H, m), 8.43 (lH, broad s), 8.90 (2H, s), 9.40 ~lH, d, J=12Hz), 12.1 (lH, d, J=12Hz) i (4) Diethyl [(6-hexanamido-4-quinazolinylamino)-i 20 methylene]propanedioate ~ mp: 157 - 162C (recrystallized from chloroform, I ethylacetate and hexane) I ( IR ~Nujol) vmax : 1686, 16409 1620, 1600, i 1550 cm N.M.R. ~ppm (CDC13) : 0.6-1.2 (3H, m), 1.2-2.2 (12H, m), 2.80 (2H, broad t, J37.0Hz), 4.36 (4H, m), 7.83 (lH, d3 J-g~OHz), . : 8 tl-8 . 5 ~2H, m~, 8.76 tlH, s), 9.16 : ~ (lH, d, J~12Hz), 10.2 (lH, s~, 12.3 ; : 30 ~lH, d, J=12Hz) . ~
t5) Diethyl ~6-ethoxalamido-4-quinazolinylamino~^
~ methylene3pro~anedioate : : mp: l91 - 192C (recrystallized ~rom chloroform, ~ ~ 35 ethylacetate and hexane) .~

:: : :
''l ' .
~,1 , ., , -:

~: , ; . ~ ' . , ' ' :
', 9~6~

IR tNujol) vmax : 3300, 1720, 1685, 1650, 1630, 16~0 cm~l N.M.R. ~ppm (CDC13) : 1.27-1.6~ (9H, m), 4.17-4.66 (6H, m~, 7.9-8.27 (2H9 m), 8.50 (lH, broad s)~ 8.93 (lH, s~, 9.33 (lH, d, J=12.0Hz)l 9.43 (lH, s), 12.23 (lHg d5 J~12.0Hz~

(6~ Die~hyl [(6-cyclohexanamido-4-quinazolinylamino) j 10 methylene~pr~panedioate ; mp: 202 - 208C (recrys~allized rom a mixture C of chloroform and methanol) IR (Nujol~ ~max : 3340, 1728, 1660, 1634, 1615, 1570 cm 1 lS N.M.R.~ ppm (CDC13) : 1.37 (6H, t, J~7.0Hz), 1.0-2.6 (llH, m)~ 4.37 (4Hg m), 7.8-8.2 (3H, m), 8.33 (lH, broad s), 8.90 (lH, s), 9.37 (lH, d, J=12.0Hz), 12.1 (lH, d J=12.OHz) (7) Diethyl [(6-benzamido-4-quinazolinylamino)-methylene]propanedioate ( mp: 164 - 165C (recrystallized from a mixture of ehloroform and hexane) IR (Nujol) vmax : 3400, 1715, 1710, 1660, 1640, 1610 cm~l .M.R.~ ppm (CDC13~ : 1.33 (6H, t, J~8.0Hz), 4.30 ~2H, quartet, J~8.0Hz), 4.33 ~2H, quartet, J-B.OHz), 7.4-8.3 (7H, m) 9 8.46 (lH, s)~ 8.7 (lH, s), 8.90 ~lH, s~5 9.33 (lH, d, J~12Hz), 12.1 (lH, d, J-12Hz) .
~8) Diethyl [~6-p~enylacetamido-4-quinazolinylamino3-methylene~propanedioate mp: 113 - 117C (r~crystallized from a mix~ure .
, :, `: : :
, : , - - -} ~ ~9~)~2 of ether and hexane) IR (Nujol) Vmax : 3600, 1748, 1710, 1690, 1660, 1632, i620 cm 1 N.M.R. ~ppm (CDC13) : 1.33 (3H, t9 J=7.0Hz), 1.37 (3H, t~ J=7.0Hz), 3.80 (2H, s), 4.33 (4H, m), 7.33 (5H, s), 7.83 (2H~
broad s), 8.43 (2H, broad s), 8.83 (lH, s), 9.33 (lH~ d, J=12Hz), 12.0 (lH, d, J~12Hz) (9) Diethyl [(6-pivalamido-4-quinazolinylamino~-methylene]propanedioate mp: 141 - 142C (recrystalli2ed from a mixture of ethe~ and ethyl acetate IR (Nujol) vmax : 3380, 1720, 1672~ 1652, 1628, 1610 cm 1 N.M.R. ~ppm ~CDC13) : 1.2-1.7 tl5H, m), 4.2-4.7 (4H, m), 7.7-8.16 (3H, m), 8.33 (lH, s), 8.83 (lH, s), 9.3~
(lH, d, J=12Hz), 12.0 (lH, d, J-12Hz) Example 18 A mixture of diethyl [~6-amino-4-quinazolinyl~mino)-methylene~propanedioate ~3.03 g), pyridine (3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture was added acetic anhydride (1.88 g). The reaction mixture was stirred for 30 minutes unde~ ice-cooling and then ~or 2 hours and 15 minutes at ambien~ tempera~ure.
;: Ice water was added to the mixture. The resultant mix-ture was extracted wi~h chloroform. The organic layer was washed ~hree times with wateT and with ~queous solution sa~urated wi~h sodium chloride, dried over anhyd~ous magnesium sulfate and concentrated under reduced pressure to~give a residue, which was purified by a column chromatography on silica gel (developing solYent: chloroorm~ and recrystallized from chloroform, : .
'' 7 ~ ~062 - 64 ^

ethyl acetate and hexane to give crystalline diethyl ~(6-acetamido-4-quinazol;nylamino)methylene]-propanedioate (2.2 g).
N.M.R. ~ppm (CDC13) : 1.32 ~3H, t, J~6Hz), 1,36 S (3H~ t, J~6Hz), 2.08 (3H/ s), 4.3 (4H, quartet, J=6Hz) 3 7.7-8.1 (2H, m), 8.44 (lH, s), 8.83 (lH, s), 9.28 (lH, s), 9.28 (lH, ds J=12Hz), 11.98 (lH,~d, J=12Hz) Example 19 A suspension of diethyl [(6-nitro-4-quinazolinyl-amino)methylene]propanedioate (0.7 g) in NgN-dimethylformamide (56 ml) was shaken with 10% palladium on carbon (60 mg) in hydrogen atmosphere at ambient temperature until hydrogen gas (160 ml) was absorbed.
The catalyst was removed by filtration and washed with a small volume of chloroform. To the combined filtrate and washings was added a mixture of acetic anhydride ~15 ml) and pyridine (15 ml) and the reaction mix~ure ' 20 was al~owed at ambien~ ~emperature for 1 day. The reaction mixture was concent~ated under reduced pressure to give a Tesidue, to which was added ~oluene and the m~xture was concen~rated under reduced pressure. This operation was repeated twice to remove N,N-dimethylformamide and acetic anhydride. The result~nt residue was subjected ~o frartionation on silica gel column ~developing sol~en~: ethyl acetate and chloroform3 to give crude crystals of diethyl [t6 N,N-diacetylamino-4-quinazolinylamino~methylene]-propanedioate (0.24 g3. The crude crystals were Tecrystallized f~om a mixture of ethyl acetate and hexane to give purified c~ystals of the same compound.
mp: 148 - 151C
I IR (Nujol) ~max : 1800, 1700, 1645, 1608 cm 1 1 35 N.M.R. ~ppm (CDC13) : 1.24-1.52 (6H, m~, i ` , .

~90 Z.24 (3H, s)~ ~.40 (3H, s), 4.22-4.55 (4H, m), 7.92 (lH~ d, J=2.0Hz)~ 7.98 t~H, d, J=9.OHz), 8.16 '(lH, dd, J-2.D
and ~.OHz), 8.92 (lH, s), 9.3 (lH, d, J=12.DHz), 12.24 ~lH, broad d, J=12.0Hz) ~ . .
A suspension of diethyl [(6-nitro-4-quinazolinyl-~mino~methylene]propanedio,ate (10.8 g) in N,N-10 dimetnylformamide (380 ml) was shaken with 10% palladium on carbon ~3.6 g) in hydrogen atmosphere at ambient tem-~'' perature until hydrogen gas (2030 ml) was absorbed.
The catalyst was removed by filtration and washed wi~h a small volume of N,N-dimethylformamide. To the combined filtrate and washings was added pyridine ~17 ml) and the mixture was cooled o~er an ice-bathO To the solution was added dropwise pi~alic chl,oride (6.33 g) for 20 minutes and then the reaction mixture was stirred for 2 hours and 40 minutes at ambient-tempera~ur~O To ~he resul$ant mixture was added ice-water under stirring an~ then the mix~ure was concentTated under reduced pressure. To the ~esi~ue was added chlorofo~m and then the mixture was washed with an aqueous solution sa~urated wi~h sodium bicarbonate and with water. :Insoluble materials were.
~, 25 removed by il~ration from the chloroform layer.
The filtra~e was washed with aqueous solution saturated : with sodium chloride, d~ied over anhydrous magnesium ~ sulfate and concentrated under reduced pressure.
:~ The Tesultant oil was subjected to a chromatography ~' ~ , 30 using silica gel (developing solvent: dichlorome~hane) - to give the firs.t Fraction~ and the second Fraction B.
The Fraction A was concentrated under reduced pressure : to give crystallin~ diethyl [(6-pivalamido-4-: quina~olinylamino)methylene]propanedioate ~4.6 g), Further, ~raction B was concentra~ed under reduced ~. ~ ...

, . .

.

' 6 2 pressure to give a solid (3.6 g), which was suspended in methanol. Insoluble materialswere separated by filtration and recrys~allized from ethyl acetate to give crystalline diethyl [(6-formamido-4-quinazolinylamino)methylene]propanedioate (0.58 g~.mp: 182 - 185C
, Example 21 To diethyl [(4-quinazolinylamino)methylene]-propanedioate tl6,0 g) was added diphenylether (70 ml) which had been heated at 250C in advance. The ~eaction ~- mixture was stirred at 250-260C for 20 minutss and -~ cooled to ambient temperature. To the resultant mixture was added hexane. The mixture was stirred to gi~e crystals~ which was washed with hexane and dried.
The crude crystals were dissolved in ethyl acetate under heating. After insoluble materials were removed by filtration, the filtrate was concentrated unde~
reduced pressure to a volume of 200 mlO To the concen-trate was added hexane and the mixtu~e was allowed to stand at ambient ~emperature to precipitate crystals, which were s~parated by filtTation, washed with a ~` mixture Gf ethyl acetate and hexane and dried to gi~e crys~alline ethyl 4-oxo-4H-py~imido[1,2-c]quinazoline-3-carboxylate (12.4 g).
mp: 171 - 172C
IR (Nu~ol) vmax : 1725, 1702, 1620 cm 1 N.M.R. ~ppm (CDC13) : 1.43 (3H, t, J-7.0Hz), 4.40 (2H, quartet, J=7.0Hz), 7.6-8.2 (3H~ m), 8.84 (lHJ brsad d, J=7~0Hz), 9.03 tlH, s), 9.66 (lH, s) _ .
The following compounds were prepa~ed in substant-ially the same manner as that of Example 21.
. .

~ ~ ~i90~2 (1~ Methyl 4-oxo-4H-pyrimido[1,2-c]quina~oline-3-ca~boxylate mp: 203 - 205C (recrystalliz~d from chloroform) N.M.R. ~ppm (CDC13) : 4.03 ~3H, s), 7.6-8.12 (3H, m), 8.88 (lH, d, J-8.0Hz) 9 9.10 (lH, s~, 9.73 (lH, s) (2) Ethyl 4-oxo-10-chloro-4H-pyrimidoEl,2-c~quinazoline-3-carboxylate mp: 161 -. 163C (recrystallized fro~ a mixture of chloroform and hexane) IR (Nujol) vmax : 1752, 17007 1621, 1584 cm l N.M.R. ~ppm (CDCl3) : 1.43 (3H? t, J~7.0Hz)~
4.40 (2H, quartet, J=7.0Hz3, 7.88 (2H, broad s),-8-.70 (lH, m), 8.93 (lH, s), 9 5~ , s) .~ . .
(3) Ethyl 4-oxo-9-chloro-4H-pyrimido[1,2-c3quinazoline-3-carboxylate mp: 192.5 - 193.5C (recrystallized from a mix~ure ~ : of diphenyl ether and hexane) : IR (Nujol) vmax : 1755, 1710, 1610, 1603, 1580 cm 1 ~ ~ .N.M.R. ~ppm (CDC13) ; 1.43 (3H, ~ J=~.5Hz), 4 46 : (2H, quartet, J=7.5Hz), 7.72 (lH, dd, J=2.0 and 9.0Hz), 8.02 (lH, d, J=2Hz~, ~ ~ . 8.80 (lH, d, J~9.OHz), 9.03 ~lH, s), :~ ~ 9.66 (lH, s) (4) Ethyl 4-oxo-lO-methyl-4H-pyrimido[1,2-c]quinazoline-30 : 3-carboxylate : mp: 182 - 183C (recrystallized from a mixtu~e o~
: chloroform, ethyl acetate and hexane~
IR ~Nujol~vmax : 1752, 1690, 1614 cm l N~M~Ro ~ppm (CDCl3) : 1.42 (3H, t, J~7.8Hz), 2.56 .~ 35 (3H, s), 4.40 (2H, quarte~, J~7.8Hz), ~,`
~ .

, .

.~ .
, ~9Q~2 7 76 (2H, m), 8.52 (lH, broad s), 8 92 (lH9 S) ~ 9.50 (lH, s) (S~ Ethyl 4-oxo-10-nitro-4H-pyrimido[1,2-c]quinazoline-3-carboxylate mp: 171 - 174C (recrystallized from a mixture of chloroform and hexane) IR (Nujol) vmax : 1720, 1700, 1625, 1585 cm 1 N.M.R. ~ppm (CDC13) : 1.43 (3H, t, J=6.0Hz), 4.36 (2H, quar~et, J~6.0Hz), 8.16 (lH, d, J-9.OHz), 8.73 tlH, dd, J=3.0 and 9.0Hz), 9.03 ~lH, 5)9 9.56 (lH, d, J~3.0Hz), _ 9 73 tl~, s) t6) Ethyl 4-oxo-10-phenoxy-4H-pyrimido[1,2-c]quinazoline-3-ca~boxylate mp: 210 - 213C (recrystallized from a mixture of chloroform, ethyl aceta~ and hexane~
IR ~Nujol) vmax : 1750, 1680, 1618~ 1~93 cm 1 N.M.R. ~ppm (CDC13~ : 1.43 (3H, t ~J~7.0Hz), 4.43 ~2H, d, J-7.0Hz), 7.0-8.4 (7H, m), 8.0 (lH, d, J=8.0Hz), 9.0 (lH, s), (~l . g.63 (lH, s) Z5 (~) Ethyl 4-oxo-10-~dimethylamino)-4H-pyrimido~ -c]-quinazoline-3-carboxylate mp: 240 - 24~C (recrystallized f~om tçtrahydro-furan) IR (Nu~ol) vmax : 1745, 1685, 161~, 1595 cm 1 NoM~R~ ~ppm (CDCl~ : 1.44 (3H, t, J=7.5Hz~, 3.16 t6H, s), 4.44 (2H, quartet, J=735Hz), 7.3-7.5 (2H, m), 7.80 (lH, m~, 8.98 ~lH~ s), 9344 (lH, s) ;~ .
~ 35 (8~ Ethyl 4-oxo-10-ethylthio-4H-pyrimido~lp2-c~-:; ' .. ..
.
.

:
:
:

~ 1 6~0~2 quinazoline-3-carboxylate mp: 168 - 170C (recrystallized from a mixture of chloroform and hexane) IR (Nujol) vmax : 1750, 1695~ 1610l 1495 cm 1 N.M.R. ~ppm (CDC13) : 1.45 (6H, , J~8.0Hz), 3.16 (2H, quar~et, J~8.0Hz)~ 4.47 (2H, quartet, J~.OHz), 7.8-8.0 (2H, m~, 8.6 (lH, m), 9.03 (lH~ s)~ g.60 (lH, s) .
(9) ~thyl 4-oxo-9-methoxy-4H-pyrimidol1,2-c]quinazoline-3-ca~boxylate ~^ mp: 202 --206C (recrystallized from a mix~ure of chloroform and hexane) IR (Nujol) vmax : 1740, 1680, 1615, 15~5 cm 1 : 15 N.M.R. ~ppm (CDC13`) : 1.43 t3H, t, J~7.0Hz), 4.00 (3~, s), 4.43 (2H, quarte~, J-7~0Hz), 7.40 (2H, m), 8.77 (lH, d, J=lO.OHz), 9.00 (lH, s), 9.67 (lH, s) (10) Ethyl 4-oxo-10-acetamido-4H-pyrimido[1,2-c]-; quina7.01ine-3-carboxylate mp: 294 - 295C ~recrystallized from N,N--~ ( dimethylformamide) -IR ~Nujol) vmax : 3360, 1740, 1720~ 1675, 1615 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.3 (3H, t, JG6.0HZ), 2.1 ~3H, s), 4.30 (2H, quar~et, J~6.0Hz) D
~ 7.83 (lH, d, J39.0Hz), 8.1 (JH, dd, J~2.0 - and 9.0Hz), 8.87 (lH, s), 9.03 (lH~ d, J=2.0Hz), 9.36 (lH, s), 1~.46 ~lH, s~
.
: tl1) Ethy 4-oxo-9-acetamido-4H-pyrimido~1,2-c]quinazoline-3-carboxylate~
mp: 281 - 285C ~recrystallized from a mixture Of N~N-dimethY1fOrmamide and Uater) ~ .
:~ .
, ~ .

I ~ 6 ~

IR (Nujol) vmax : 3560, 3400, 1742, 1616, 1588 cm~

(12) Ethyl 4-oxo-10-propionamido-4H-pyrimido[1,2-c]-quinazoline-3-carboxylate mp: 274 - 276C (recrystallized from a mixture of chlorofoTm and methanol~
IR (Nujol) ~max : 3360, 1740, I720, 1670, 1618 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.13 (3H, t, J=7.0Hz), 1.30 (3H, t, J=7..0Hz), 2.43 ~2H, quartet~
~; J=7.OHz), 4.30 (2H, quartet, J~7.0Hz), . 7.90 (lH, d, J=lO.OHz), 8.16 (lH, dd, : J~2.0 and lO.OHz), 8.90 (lH, s), 9.10 (lH, d, J~2.0Hz), 9.40 ~lH, s)~ 10.43 (lH, s~

(13) Ethyl 4-oxo-10-butyramido-4H-pyrimido[1,2-c]-quinazQline-3-carboxylate mp: 278 - 282C (recrystallized from a mixture --of chlorofo~m and methanol) ~: IR (Nujol) vmax : 3410, 1745, 1712, 1680, 1615 cm 1 ( N.M.R. ~ppm (CDC13~ : 1.03 (3H, t9 J=7.0Hz~, 1.43 (3H, t, J-7.OHz), 1.76 (2H, m), 2~46 : 25 (2H, t, J=7.0Hz~, 4.46 (2H, quar~et, J=7.0Hz), 8.0 ~lH9 d9 J-9.OH~), 8~43 (lH, dd, J=2.0 and 9.0Hz), 8.97 (lH, d, J-2.0Hz), 9.05 (lH, s), 9.63 (lH, s)

(14) Ethyl 4-oxo-10-isobutyramido-4H-pyrimido[1,2-c]-quinazoline.-3-carboxylate mp: 245 - 247C (recrystallized from a mixture of chlo~oform and hexane) IR (Nujol) vmax : 3400, 1730, 1710, 1690, 1625, 1410 cm~~
.
, ' .
, ~'.. , ' ` , ,:

N.M.R. ~ppm ~DMSO-d6) : 1.2-1.8 (9H7 m), 2.3-2.9 (lH, m), 4.46 (2H, quaTtet, J=7.0Hz), 7.8-8.1 (2H9 m), 8.43 (lH, dd, J=2 and lOHz), 8.92 tlH9 d, J=2Hz), 9.05 tlHJ s), 9,63 (lHt s) (l5) Ethyl 4-oxo-10-hexanamido-4H-pyrimido[1~2-c]-quinazoline-3-carboxylate mp: 231 - 234C (recrystallized from a mixture . . 10 of c~lo~oform and methannl) IR ~Nujol) vmax : 3400, 3100, 1745, 1720, 1680, C - 1610 cm~
; ~ N.M.R. ~ppm (DMS04-d6) : 0.6-2.0 ~lOH, m)j - 2.1-2.6 (4H, m), 4.30 (2H, quartetp J~7.0Hz~, 7.9 (lH, d, J~9.0Hz~, 8.16 (lH, dd, J=2.0 and 9.0Hz), 8.90 (lH~ s)~
9.13 (lH, d, J=2.0Hz), 9.40 (lH, s), : ~0.55 (lH, s) (16) Ethyl 4-oxo-10-ethoxalamido-4H-pyrimido[1,2-c]-quinazoline-3-c~rbo~late mp: 263 - 264C (recrys*allized from a mixture : ~ of chloroform and methanol) : IR~ (Nujol) vmax : 3400, 1745, 1725, 1610 cm 1 ~' 25 N.M.R. ~ppm (DMSO-d~) : 1.26 t3H, t~ J=6Hz), 1.30 (3H, t, J=6Hz), 4.3 t2H, quartet, J=6Hz), 4.36 (~Hg quartet, J-6Hz), 7.96 lH, d, J-9.OHz), 8.33 (lH, dd, J22 and 9Hz), 8.Y ~lH, s)p 9.27 (lH, d, J=2Hz3, : 9.43 ~lH, s), 11.4 (lH~ s) j : (17) Ethyl 4-oxo-10-cyclohexaneca~boxamido-4H-pyrimido-j ~1,2-c]quinazQliné-3-carboxyla~e : ~ mp: 262 - 266C (~ecrystallized from a mixture of chloroform and hexane) I
:~

.

. ~ .

0 6 ~
~ 72 IR (Nujol~ vmax : 3400, 3100, 1730, 1692, 1672, 1612 cm 1 N.M.R. ~ppm (CDC13) : 1.40 (3H, ~, J~7.OHz) 9 1.0-2.6 (llH~ m), 4~46 (2H, quartet, J~7.0Hz), 7.90 ~lH, s~, 8.0 (lH, d, J-9.OHz), 8.43 (lHt dd, J~3.0 and 9.0Hz) D
8.93 (lH, d, J~3.0Hz), 9.1 tlH, s), 9.66 (lHI s~ ~

(18) Ethyl 4-oxo-lO-benzamido-4H-pyrimido[1,2-c~- .
quinazoline-3-carboxylate ~-~ mp: 237 - 239C (recrystallized from a mixture - of chlorofo~m and methanol) IR ~Nujol~ vmax : 3400, 1730, 1680, 1620 cm 1 NoM~R~ ~ppm (DMSO-d6) : 1.40 (3H, ~, J=7.0Hz), 4.40 (2H, quartet, J=7.0Hz~, 7.5-8.3 : (6H, m), 8.55 (lH, dd, J=2.0 and lO.OHz), 9.0 (lH, s)~ 9.40 (lH, d~ J-2.0Hz), 9.53 (lH, s), 10.86 (lH, s~
: 20 (19) Bthyl 4-oxo-10-phenylacetamido-4H-pyrimid~[1,2-c]-. quinazoline-3-carboxyla~
. .
mp: 230 - 235~C (recrystallized from a mix*ure of methanol and chloroform) IR ~Nujol) vmax : 3370, 1735, 1720, 1670, 1618 cm~l N.M.R. ~ppm (~MSO-d6) : 1.3 ~3H, t, J~7.0Hz~, 3.75 (2H, s), 4.33 (2H, ~ua~et, J~7.0Hz), . 7.33 (5H, s), 7.8-8.3 ~2H, m), ~.90 ; ~ 30 (lH, s)~ 9.12 (lH, d, J=2Hz)~ 9.40 (lH, s), 10.76 (lH, s) ~, .
(20) Ethyl 4-oxo-lQ-ethyl-pyrimido[1,2-c~quinazoline-3-carboxyla~e 3~ mp: 168 - 170C (~ecrystallized rom a mixture ;

of ethyl acetate and hexane) I~ (Nujol~ vmax : 1720~ 1700, 1620, 1500 cm 1 N.M.R. ~ppm (CDC13) : 1.4 (3Hj t, J~8.0H~), 1.46 (3H, t9 J-8.0Hz), 2.95 (2H, quartet, J=8.0H2), 4.46 (2H, quartet, J~8.0Hz), 7.9-8.1 (2H9 m), 8.7 (1H, s), 9.06 (lH, s), 9.66 (lH, s) (21) Ethyl 4-oxo-10-butyl-pyrimido[1,2~c]quinazoline-3-carboxylate mp: 151 - 154C (recrystallized from a mixture of ethyl acetate and hexane) IR (Nujol~ vmax : 1720~ 1690, i610, 1490, ~' 800 cm 1 N.M.R. ~ppm (CC14) : 0.8-2.1 (lOH, m), 2.9 (2H, t, J=8.0H~), 4.43 (~H, quartet, J-7.0Hz), 7.7-8.0 ~2H, m), 8.63 (lH, s~, 8.9 ~lH~ s), 9.53 (lH, s) (22) Ethyl 4-oxo-8-methyl-4H-pyrimido{1,2-c]quinazoline-3-carboxylate mp: 166 - 172C (recrystallized from a mixture of chlororform, ethyl acetate and hexane7 IR (Nujol~ vmax : 1750, 1692, 1622, 1600 cm 1 N.M.R. ~ppm (CDC13) : 1.46 (3H, t, J~7.0Hz), : 25 2.73 (3H, s3, 4.46 (2H, quartet, J~7.0Hz), 7.4-7.9 (~H, m), 8.60 (lH, broad d, ~ ~ J-8.0H~, 8.93 (lH, s)~ 9.56 (lH, s3 : (23) Ethyl 4-oxo-10-propyl-4H-pyrimido~1,2-c]quinazoline-3-ca~boxylate mp: 161 - 163C ~rec~ystallized rom.benzene) IR (Nujol) vmax : 1700, 1620, 1610, 1500, ~ llSO cm 1 N.M.R. ~ppm (CDC13) : 1.0 (3H, t, J-7.OHæ), 1.3-2.2 (SH, m), 2.9 (2H, t~ J37.0H~), ;
~ .
.~ . .

. . .

4.43 (2H, quartet, J=7.0Hz)~ 7.8-8.1 (2H~ m3, 8.63 (lHD s~, 9.0 (lH, s~, 9.6 (lH, s) S t24) E~hyl 4-oxo-9-methyl-4H-pyrimido~1,2-c]quinazoline-3-carboxylate mp: 186 - 188C (recrystallized from ~etra-- hydrofuran) IR tNujol) vmax : 1705, 1680, 1490, 1300, 800 cm 1 N.M.R. ~ppm (CDC13) : 1.4 (3H, t, J~8.0Hz), 2.6 (3H, s), 4.33 ~2H, quar~et, J=8.0Hz) 9 7.56 (lH, d, J=8.0Hz), 7.76 ~lH, s3, 8.7 (lH, d~ J=8.0Hz), 9.0 (lH, s)~
9.63 (lH, s) ~25) Ethyl 4-oxo-10 (4-methylpiperazinyl)-4H-pyrimido-[1,2-c~quinazoline-3-carboxylate mp: 203 - 206C (recrystall~zed from a mixture of ethanol and chloroform) IR ~Nujol) ~max : 1740p 16BO, 1608 cm 1 N.M.R. ~ppm (CDC13) : 1.43 (3H, t, Jz7.0H~), ~ 2.36 (3H, 5)3 2.60 (4H, m), 3.46 ~4H, m), - 4 43 (2H, quartet9 J-7.0Hz), 7.50 (lH, 2S dd, J=3.0 and 8.5Hz), 7.80 (lH, d7 ~=8.5Hz), .
8.03 (lH, d, J=3.0Hz), 8.96 (lH, s), 9.4S
:; ' (1~, s) ' (26) Ethyl 4-oxo-9910-dime~hoxy-4H-py~imido[1,2-c~-3u quinazoline-3-carboxylate mp: 262 - 264C (recrystallized from chloroform) ; IR (Nujol) vmax : 1705, 1675, 1i95 cm l ; N.M.R. ~ppm (CDC13) : 1.43 (3H, t, J-7.0Hz), ~ 4.13 (6H, s3, 4.46 (2H, quarte~, J-7.0Hz)~
;~ 35 7.40 (lH, 5)9 8.16 (lH~ s)~ 9.05 (lHJ s)~

`' ' . ' 0 ~ 2 9.67 (lH, s) (27) Ethyl 4-oxo-10-pivalamido-4H-pyrimido[1,2-c]^
quinazoline-3-carboxylate S mp: 247 - 250C (recrystallized from a mixture of chlorofoTm and methanol) Nujol) ~max : 3370, 1712, 1672, 1610 cm 1 N.M.R. ~ppm (CDC13) : 1.45 (3H,o t, J=7.0Hz)~
1.37 (9H, s), 4.46 (2H, quartet9 J-7.0Hz), 7.96 (lH, d7 J~9.SHz), 8.41 (1~, dd, J~3 and 9.5Hz), 9.13 ~2H, broad s)~ 9.63 (lH, s), 12.1 tlH, s) , (28) Ethyl 4-oxo-6-hydroxy-4H-pyrimido[1,2-c]quinazoline-lS 3-carboxyla~e mp. >270C (recrystallized from a mixture of chlo~oform and meth~nol) IR (Nujol) vmax : 1770, 1742, 1705, 1638, 1615, 1602 cm~l N.M.R. ~ppm (DMSO-d6~ : 1.32 (3H, t, JY6.0HZ), 4.30 (2H, quartet, J=6.OHz), 7.2^7.6 (2H, m), 7.74 (lH, t, J-8.0Hz), 8.26 ~ tlH, d, J=8.0Hz), 8.92 (lH, s), 12.5 ~lH,..broad s) :~ 25 (29) Ethyl 4-oxo-6-methyl 4H-py~imido[1,2-c]quinazoline-3-carboxylat~
mp: 167 - 168C (recrystalliz~d from benzene) IR ~Nujol) ~max : 1735, 1700, 1615, 1590 cm 1 N.M.R. ~ppm tCDC13) : 1.43 ~3H, t, J~.OHz) 9 3.20 (3~, s~, 4.47 ~2H, quartet, J~7.0Hz), 7.6-8.0 (3H, m), 8.73-8.93 ~lH~ m), 8~93 ~lH~ s) (30) Ethyl 4-oxo-6-hydrcxy-10-ethyl-4H-pyrimido[1,2-c]-' .:
' 9 (~ ~ 2 quinazoline-3-carboxylate mp: 315 - 318C (recrystallized from a mixtu~e of chloroform and methanol) IR (Nujol) vmax : 1748, 1630, 1595 cm 1 Example 23 . A mixture of diethyl [(2-allyloxy-4-quinazolinyl-amino)methylene]propanedioate (6.0 g) ~n diphenyl e~er ~14 ml) was ~tirred for l5 minutes at 260C and then cooling to ambient temperature. Hexane was added to the resultant mixture to give precipitates, which separated by filtration and washed with hexane to give ~ crude crystals. The crude crystals were subjected to a column chromatography using silica gel (developing lS solvent: chloroform) to give the first Fraction A and th~ second Fraction Bo The fraction A was concentrated unde~ reduced pressure to give crys~als, which were recrystallized from a mixture o chloroorm, ethyl acetate and hexane to give crystalline ethyl 4-oxo-6-allyloxy-4H-pyrimido-~1,2-c]quinazoline-3-carboxylate (1.~ g).
mp. 1~1 - 195C
IR (Nujol) vmax : 1775, 1725, 1690, 16D8 cm 1 ~ N.M,R. ~ppm (CDC133 : 1.40 ~3H, t, J~7.0Hz), 4.43 (2H3 quartet, J-7.0Hz)~ 4.90 (2H, m), 5.40 (2H, m~, 6.0 (lH9 m), 7.30 (2H, m), l ~: 7.80 (lH, t, J=7.0Hz3, 8.56 (lH, d, J~7.0H~3, 8.66 (lH, s) ~ .
: On the other hand, the Fraction B was concentTated under reduced pressure to give crystals, which were recrystallized from a mixture of ethyl acetate and hexane to gi~e crystalline ethyl 4,6-diox~^7-allyl-4H-6,7-: 35 dihydropyrimido~l,2~c]quinazoline 3-carboxyla~e ~l.S g).

' . ' .

o ~ ~

mp: 163 - 166C
IR (Nujol) ~max : 1740, 1710, 1682, 16451 1615, 1600 cm~l N.M.R. ~ppm (CDC13) : 1.40 (3H, t, J=7.0Hz), 4.40 (2H, quartet 9 J-7.0Hz), 4.88 (2H, m), 5.24 (2H, m), 6.92 (lH, m), 7.34 t2H~ m), . 7.74 (lH, t, J=8.0Hz), 8.60 (lH, d~
; J=7.OHz), 9.14 (lH, s) Example 24 A mixture of diethyl [(2-methoxy-4-quinazolinylamino3-.~ methylene~propanedioate (8.0 g) in diphenylether (30 ml)`
- was stirred for 32 minutes at 260C. The reac~ion mixture was allowed to s~and overnight at ambient temperature to give crystals, which were separated by fil~ration and washed with hexane to give crude crystals (A). Fur~her, a large volume of hexane was added to the filtrate and the mixture was allowed to stand overnight at ambient temperatuTe to give crystals, which were recrystalli ed 20 from a mixture of ethyl acetate and hexane to gi~e crude crystals (B) and mother liquor (A~. -The crude crystals (A) and (B) were combined and subjected : ~ to a column chromatography using silica gel ~developing solvent: a mixture of ethyl acetate and chloroformGl:9~.
One of t~e f~actions was concentTated under reduced : pressure to give crystals, which were recrystallized : from a mixture of chloroform and hexane ~o gi~e crys~alline e*hyl 496-dioxo-7-methyl-4H,6H-6,7-dihydropyrimido~1,2-c~-quinazoline-3-carboxylate (0.7 g).
mp: ~65 - 271C
~! ` IR (Nujol) vmax : 1732, 1642, 1610 cm 1 :i N.M.R. ~ppm (CDC13) : 1.40 ~3H, t, J=7.8Hz), 3.80 3H~ s2, 4.45 (2H, quartet, J~7.8~z)~
i 7~30~8.00 ~3H, m), 8.73 (lH, d~ J~8.0Hz3, 9.~2 (1~, s) : ~:

:, ' :
, Further, mother liquo~ (A) was concentrated under r~duced pressure and subjected to a column chromatography using silica gel (developing solvent: chloroform).
The eluate was concentrated under reduced pressure to give crystals, which were recrystallized from a mixture ' of chloroform and hexane to gi~e crystalline e~hyl 4-oxo-6 : methoxy-4H-pyrimido[l ,2-c]quinazoline-3-carboxylate (0.45 g)-mp: 180 - 183C
IR (Nujol) vmax: 1765, 170~ 1625, 1610~ .
1590 cm-l s` ~~ N.M.R. ~ppm (CDC13) : 1.46 (3H, t, J-7.0Hz), 4.33 (3H, s), 4.46 (2HJ quartet, J=7.0HZ), ~: 7.3-8.0 (3H, m), 8.70 (lH, d, Jn7.0Hz), 8.86 (lH, s) !

A mixture of tetraethyl 2,2'-[2,4-quinazolinediylbis-(iminomethylidyne)]bispropanedioate ~2.2 g~ in diphenyl-~0 ether (11 ml) was stirred for 35 minutes 8~ 260C and ~ ~hen cooled to ambient temperature. To the ~eaction -; mixtu~e was added hexane to give crystals, which were i ~ ~ separated by filtration and dried to give crude crystals (1.3 g)~ which were recrystalli~ed from ethanol to give di~thyl 4,9-dioxo-4H,9H-pyrimido[l J 2-c]pyrimido[l,?-a]-. quinazoline-3,8-dicarboxylate (0.9 g).
mp: 193 - 195C
IR tNUjol) ~max : 1760, 1720, 1680, 1640, 1600 cm 1 ~: 30 N.M.R. ~ppm (CDC13) : 1.43 (6H, t, J~8.0Hz), 4 . 40 t4H, qua~tet 9 J~8.OHz)> 7.5-8.0 (2H, m~, 8.67 (lH, s3, 8.67-9.16 (2HJ m), ~ 9.73 (~H, s) i ~' 35 .J ~ 2 . 79 A mixture of 2J2-dime~hyl-5-~(4-quinazolinyl)-. : amino]methylene-1,3-dioxane-4,6-dione (3.5 g) in dlphenylether (15 ml~ was stirred for 10 minutes at 250-260C and then cooled ~o ambient temperature.
To the reaction mixture was added hexane ~nd allowed to to stand at ambient temperature to gi~e crystals which were separated by filtration and washed with hexane t~ give crude crystals ~3 g). The crude crystals were subjected to a column chromatography using silica gel ~developing solvent: a mixture of ethyl acetate and hexane (3:7~). The eluate was con-C.- centrated under reduced pressure to give crystals, which were recrystallized from chloroform and hexane to give 4H-pyrimido~1,2-c]quinazoline-4-one (1.6 g).
mp. 181 - 183C
IR tNujol~ vmax : 1700, 1625, 1610, 1582 cm 1 N.M~R. ~ppm (CDC13~ : 6.57 (lH, d, 3~7.0Hz~, .7.86 (3H, m~, 8.27 (1~, d, J-7.0H2), 0 8.76 (lH, br~ad d, J~8.~Hz), 9.53 ~lH, s) ; ' E~ , . A mixture of methyl 4-oxo-4H-pyrimido~ -c3-: quin~zoline-3-carboxylate (6.3 ~ and lithium iodide 25 (15.8 g) in N,N-dimethyl~ormamide tlnO ml) was stirred for 2 h~urs and a hal at 150C and then cooled to ambient temperature. To the reaction mixture was added water separated by filtration, washed with water (600 ml~ and dried to gi~e crystalline 4-oxo-4H-pyrimido[1,2-c~-quinazoline-3-carboxylic acid (0.9 g) mp: ~270C
: IR (Nujol) vmax : 1720, 1620 cm 1 N.M.R. ~ppm (~P3COO~) : 8.10-8.66 (3H, m), 8.~-9.2 (lH, m~, 9.53 (lH, 5), 10.16 (lH, s~

~ , I
;: ~ '~ .

-906~

Example 2.8 mixture of 4-amino-6-(3,3-dimethylbutyramido)~
quinazoline (8.5 g), dimethyl methox~nethylenepropanedioate ~12.75 g) and N,N-dimethylformamide (34 g) was stirred : 5 for an hour at 100C. After cooling to ambient ~emperature, to the resultant mixture was added water to give precipitates, which were separated by filtration, washed with water and dried to gi~e crystalline dimethyl ~{6-(3,3-dimethyl~
butyr~lmido)-4-quinazolinylamino}methylene]propanedioate 10 ~10 . 9 g) .
~ mp: 196 - 198C
.p ~ IR (Nujol) vmax : 3540, 3350, 3250, 1705, 1680, . 1660, 1650, 1610 cm N.~l.R. ~ppm (CDC13) : 1.10 (9H, s), 2.3 (2H, s), 4.83 (3H, s), 4.9 (3H, s), 7.93 (2H, s), ~` 8.3 (2H, m), 8.8 51H, s~, 9.3 (lH~ d, J=12.0~Iz~, 11.~ (lH, d, J-12.0Hz) ;

Example 29 A mixture of 4-amino-6-(3,3-dimethylbutyramido~-quinazoli~e (12.2 g), diethyl ethoxymethylenepropandioa~e :
( -. 25 , , f .. . .

I ~ 6 ~
~1 (15.3 g) and N,N-dimethylformamide (50 ml) was stirred at 150C for 2 hours. The reaction mixture was cooled to ambient temperature. After adding water, the resultant mixture was extracted with chloroform.
The chloroform layer was washed twice with water and once with saturated a~ueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated unde~ reduced pressure to give a residue, to which was added ethyl acetate.
: Inso~uble materials were sepaxated by filtration and dried to give ethyl 4-oxo-10-(3,3~dimethylbutanamido)-4H-pyrimido[l,2-c]quinazoline-3-carboxylate (4.7 g) melting ~ at 253 - 254C. Further, the ~iltrate was concentrated under reduced pressure to give a residue, which was recrystallized rom a mixture of ethyl acetate and hexane to give crystalline diethyl [{6-t3,3-dimethylbutyramido)-4~quinazolinylamino}methylene]propanedioate (10.1 g).
mp: 133 - 135C
IR (Nujol) vmax : 3350, 1695, 1640, 1625, 1610 cm 1 N~M.R. ~ppm (CDC13) : 1.15 (9H, s), 1.38 (3~, t, J=6.0Hz), 1.40 (3~, t, J=6.0Hz), 2.35 (2H, s), 4.33 (2H, q, J=6.0~z), 4.43 . (2H, q, J=6.0Hz~, 7.80 (lH, s), . 7.9-8.1 (2H, m), 8.20 (lH, s), 8.86 (lH, s), 9.33 (lH, d, ~=12.0Hz), ~ 25 12.0 (lH, d,~J=12.0Hz) j Anal- calcd- ~or C22H28N495 ~ ~ 61.66;
H 6.54; N 13.08 Found : C 61.51; ~ 6.49;
N 13.19 J E~
A mixture of 4-~amino-6-pivalamidoquinazoline (2.44 g),.dimethyl methoxymethylenepropanedioate (2.61 g) and N,N-dimethyl formamide (10 ml) was stirred at 100C
for an hour. After cooling to ambient ~emperature, to ;

.

o ~ ~
~ 82-the mixture was added water. The mixture was stirred togive crystals, which was filtered of~ and purified by a column chromatography on silicagel [developing solven~:
a mixture of e~hyl acetate ~nd chloroform tl:2)] to give crystals (3.48 g), whichwere-dissol~ed in chloroform.
To the solution was added activated charcoal. The mixture was filtered and the ~iltrate was concentrated under reduced pressure to give crystals, which were recrystallized from ethyl acetate to give crystalline dimethyl [{6-pivalamido - 4-quinaæolinylamino}methylene]propanedioate - ~2~3 g).
- mp: 18~ - 190C
IR (Nujol) vmax : 3400, 3350, 1750, 1690, 1630, 1615 cm 1 f N.M.R. ~ppm (CDC13) : 1.4 (9H, s), 3.8 (3H, s), ,' lS 3~93 (3H, s), 7.85 (lH, s), 8.00 (2H, m~, ~ 8.45 (lH, s), 8.9 (lH, s), 9.4 (lH, d, i ~-12.0HZ) Anal. Calcd. for C~g~2N4O5 : C 59.06;
5.74; N 14.50 Cound : C 58.99; ~ 5.53;
14.21 (.
Ex-m-ple 31 A mixture of 4~amino-6-methanesulfonamidoquinazoline , 25 (2.0 g), diethyl ethoxymethylenepropanedioate (3.15 g) and N,N-dimethylformamide (16 ml) was stirred at 140DC for an hour and a half. To the reaction mixture was added '~ diethyl ethoxymethylenepropanedioate (1.57 g). The reaction mixture was stirred for an hour and cooled to ambient temperatur~. To the mixture was added water to five crystals, which were filtered off and dissolved in a mixture of chloroform and methanGl. The solution was dried over anhydrous magnesium sulfate and concentrated ii under reduced pressure to give a residue, to which was 3~ added chlorof~rm. The mixture was heated and insoluble I ~ &na~2 materials ~ere filtered off to give crystalline ethyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]~uinazoline 3-carboxylate (0.12 g) melting at 310-312C. Furthex, the fil~rate was concentrated under reduced pressure and allowed to stand at ambient temperature to give crystals (1.63 g)~ which were purified by a column chromatography on silica gel (60 g) (developing solven~ : 3% methanol-chloroform solution). The crystals were dissolved in 10~ methanol-chloroform solution. The solution was treated with activated charcoal and concentra~ed under reduced pressure. Th~ residue was recrystallized from chloroform to give crystalline diekhyl ~{6-methanesulfon-amido-4-quinazolinylamino}methylene]propanedioate (1.45 g).
p: 200 - 202C
IR (Nujol) vmax : 3500, 3210, 1720, 1690, 1675, 1640, 1625, 1600 cm 1 N~M.R. ~ppm (D~lSO-d6) : 1.3 (3H, t, J=7.0Hz), i 1.35 (3H, t, J=7.0Hz), 3.16 (3H, s~, -. 4.25 (2H, q, J=7.0Hz), 4.38 (2H, q, ;~ 20 J=7.0Hz), 7.8-8.1 (3H, m), 8.9 (1~, s), g.2 (lH, d, J=12.0Hz), 10.53 (lH, s~, 11.55 (lH, d, ~-12.0Hz~

~`~ 25 A mixture of 4-amino-6-methanesulfonamidoquinazoline j (6.89 g) 9 diethyl ethoxymethylenepropanediate (15.5 g) ¦ --and N,N-dimethylformamide (55 ml) was stirred at 155C
for 2.5 hours. The reaction mixture was cooled to ambient ~ temperature. To the mixture was added water to give :~' 30 precipitates~ which were separated by filtration and ., washed with water. To the crystals was added a mixture :, of methanol and chloroform ~1:43 (400 ml). After s~irring under heating, insoluble materials (6.~5 g) were filt~red off and recrystallized from N,N-dimethylformamide to give crystalline ethyl ~-oxo-10-methanesulfonamido-4H-pyrimido . , ' .
'.

.: , ' . .

1 :1 6 ~
~ g4 [1/2-c]quina~oline-3-carboxylate ~5.76 g).
mp: 310 - 312 C
IR (Nujol) ~1max : 3200, 3050, 1725, 1665, 1610 s::m 1 N.M.R. ~ppm (DMSO-d6) : 1.3 (3H, t~ J-7.0Hz), 3.1 (3H~ s), 4.3 ~2H, q, ;J=7.0Hz), 7.7-8.1 (2H, m), . 8.56 (lH, d, J=2.0Hz), 8.9 (lH, s), 9.4 (lH, ~), 10.5 (lH, m) Anal. Calcd. for C15H14N405S
H 3.89; N 15.46; S 8.85 . Found: C 49.88; H 3.96 N 15 . 52; S 8 . 71 , , , Example33 A mixture of 4-amino-6 methanesulfonamidoqui~azoline t6.68 g), dimethyl methoxymethylenepropanedioate (6.35 g) and N,N-dimethylformamide (27 ml) was stirred at 100C
for an hour. The reaction mixture was cooled to ~mbient temperature. To the mixture was added water to gi~e crystals, which were ~iltered off and recrystallized from NtN-dimethylformamide to gibe crystalline dimethyl [{6-methanesulfonamido-4-quinazolinylamino]methylene~
( : propanedioate (7.20 g).
mp: 284 - 287C
IR (Nujol) vmax : 3230, 3130, 1730, 1690, 1650, 1625, 1600 cm 1 N-M-R. ~ppm (DMS04-d6) : 3.12 (3H, s), 3.76 (3H, 3.90 (3H, s), 7.7-8.1 (4H, m), 8.86 (lH, s), 9.26 (lH, mj xample ~4 (1) A solution of diethyl [(6~nitro-4-quinazolinylamino)-methylene]propanediQ~te (10.8 g) i~ N,N-dimethylformamide ~325 ml) was shaken with 10~ palladium on carbon (306 q) in hydrogen atmosphere at ambient temperature. ~fter the ab~orption of hydrogen was finished, the catalyst wa-C

.
-. .

, 1 ~ ~9V~;2 remov~d by filtra~ion. The filtrate was concentrated under reduced pressure to give a resid~e, to which was added ~enzene. The mixture was concentrated under reduced pres~ure to give crude crystals of diethyl ~(6-amino-4-quinazolinylamino)methylen2~pxopanedioate.

(2~ A mixture of diethyl [(6-amino~-4-quinazolinyl-amino)m~thylene]propanedioate as obtainad above, pyridine (3.32 g) and dry methylene chloride 1200 ml~ was stirred under ice-cooling. To the mixture was added dropwise ~~ a solution of 3,3-dimethyl~utyryl chloride (4.B g) in ., methylene chloride (10 ml) during 50 minutes und~r ice cooling. The reaction mixture was stirred under ire-cooling for 3 hours and 10 minutes. To the mixture was added ice-water. After stirring, the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concen~rated under reduced pressUre to give a residue, which was subjected to a column chromatography on slica qel ~200 g) (Developing solvent: methylene chloride~
to gi~e fraction A and fraction B. The fraction ~ was concentrated under reduced pressure to gi~e crystals (4.28 g), which were dissolved in ethyl acetate, treated with activated charcoal and recrystallized to give crystalline diethyl [{6-~3,3-dimethylbutyramido) 4-quinazolinylamino}methylene]propanedioate (2.29 g).
mp: 133 - 135C
IR ~ujol) vmax : 3350, 1695, 1640, 1625, 1610 cm 1 N.M.R. ~ppm (CDC13) : 1.15 (9H, s), 1.38 (3H, t, J-6.0Hæ~, 1.40 (3H, t, J=6.0Hz), 2.35 (2H, s) r 4.33 (2H~ ql J=6.0H2) 4.43 (2H, q, Js6.0Hz), 7.80 (lH, s), 7.9-8.1 (2H, m~, 8.2 (lH, s), 8.86 (lH, s), 9.33 (lH, d, J=12.0Hz), - .
. ' : .
:, :

,', ' 9 ~ ~; 2 ~ ,6 12.0 (lH, d, J=12.0Hz) Anal. Calcd. for C22H2BN4O5 C 61.66;
H 6.54; ~ 13.08 Found ~ C 61.51;
H 6.49; N 13.19 ~urther, the fra~tion B wa~ concentratPd under reduced pressure to give crystals (2.6 g), which were dissolved in hexane, treated with activated charcoal and recrystallized to give crystals ~1.48 g~. A.part (1.25 g) of the crystals was purified by a column .
chromatography on silica gel (20 g) and recrystallized from hexane to give diethyl [[6-{bi~(3,3-dimethylbut~ryl )~
amino}-4-quinazolinylamino]methylene~propanedioatP (O.g g).
mp: 100 - 102C
IR (Nujol) vm~x : 3200, 1775 r 1730 ~ 1710, 1645, 1625, 1610, 1560 cm 1 N.M.R. ~ppm (CDC13) : 1.03 (9~, s~, 1.06 (9H, s~, 1.33 (3H, t, J=7.0Hz), 1.40 (3~, t, J=7.0Hz), 2030 ~2H, ~), 2.45 (2~, s), 4.3 (2H, q, J=7.0Hz), 4.4 (2H, q, J=7.0Hz), 7.9-8.15 (3H, m), 9n25 ( (lH, s), 9.8 (lH, d, J=12.0Hz) Anal. Calcd~ for C~8H3~N406 H20 . C 61.74; H 7.40; N 10.60 ~ 25 Found C 61.81; H 7.19; ~ 10.29 :~ Example 35 A mixture o~ dimethyl [{6-pivalamido - 4-quinazolinyl-amino}methylene]propanedioate (24.5 g) and diphenyl ether 30 (150 ml) was heated at 260C fox 20 minutes and cooled to ambient temperature. To the reaction mixture was ~, added hexane to give crystals, which were filtered off, washed with hexane and dissolved in chloroform (400 ml~
under heating. Insolu~le material~ were removed by ~iltration. The filtrate was conce~trated under reduced . .~, . . :
. .
-:

.
'~
.

~ ~ 690~2 - &7 pressure to 200 ml and allowed to stand under cooling.
The precipitated crystals were filtered off and washed with chlor~form to give crystalline methyl 4 sxo-10-pivalamido - 4H pyrimido~l~2-c~quinazoline-3-carboxylate (18.29 g). The mother liqour was concentrated under reduced pressure to give crystals, which were purified by a column chromatography on silica gel (50 g) (Developing solvent: 5~ methanol-chloroform solution) and recrystallized ~rom chloroform to give the same object compound ~3.2 g).
mp: 239 - 240C
IR (Nujol) vmax : 3380, 171~, 1685, 1610 cm 1 _.
N~M.R. ~ppm (CDC13) : 1.4 (9H, s), 3.96 (3H, s), 7.85 (lH, s), 8.0 (lH, d, J=9.0~z), 8.4 (lH, dd, J=3.0 and 9.0Hz), 8.9 (lH, d, J-3.0Hz), 9.05 (lH, s7, 9.63 (lH, s) Exam~le 36 mixture of dimethyl [(6-methanesulfonamido-4-quinazolinylamino)methylene]propanedioate (7.2 q~ and i diphenyl ether (4~ ml) was stirred at 250C for 15 minutes t ~ '~ and then.cooled to ambient temperature to give crystals, which were filtered off and washed with a mixture of chlorofonm and methanol to give crystalline methyl 25 4-oxo-10-methanesulfonamido 4H-pyrimido[1,2-c]quinazoline~
3-carboxylate (4.72 g).
mp: 293 - 296~C
IR (Nujol) vmax : 3220, 1725, 1670, 1608 cm 1 .
Exam~le 37 A mixture of diethyl [{6-(3~3-dimethylbutyramido-4-quinazolinylamino~methylene]propandioate 113.1 g) and ~¦ diphenyl ether (79 ml) was stirred at 250C for 15 minutes and cooled o ambient temperature. To the mixture was added hexa~e. The resulran- mixture was stirred to give -, " , :

o ~ ~

_ 88-precipitates, which were separated by filtratio~ and dissolved in a mixture of chloroform ~nd methanol. To the mixture was added charcoal and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure to give crys~als, which were recxystallized from a mixture of chloroform and hexane to give crystalline ethyl 4-oxo-10-(3,3~dimethylbut~ramido~-4H-pyrimido[1,2-c]quina~oline-3-carboxylate ~9.15 g).
mp: 253 - 254C
10IR (Nujol) vmax : 3350, 1715, 1680, 1615, 1585, 1565, 1505 cm 1 NoM~R~ ~ppm (DMSO -d6) : 1.1 (9H, s), 1.3 (3~, t, J=8.0Hz), 2.26 (2H, s), 4.3 (2~, q, J=8.0Hæ), 7.9 (lH, d, J=9oOHZ) ~
8.16 (lH, dd, J=2.0 and 9.0Xz), 8~9 tlH, s~, 9.15 (lH, d, J=2.0Hz), 9.4 (lH, s), 10.36 ~lH, s) Anal- Calcd for C20~22N44 C 62-81;
H 5.80; N 14.65 . -.
Found : C 62.69; H 5.77: N 14.67 Example 38 A ~ixture of dimethyl [{6-(3,3-dimethylbu~yramido)-4-quinazolinylamino}methylene]propanedioate (7.30 g~ and diphenylether (44 ml) was stirred at 260C for 10 minutes and then cooled to ambient temperature. To the mixture was added hexane to give crystals, which were filtered off and washed with hexane to give crystalline methyl 4-oxo-10-(3,3,dimethylbutyramido~-4H-pyrimido[1,2-c]quinazoline-3-carboxylate ~6.28 g).
mp: 247 - 249C
IR ~Nujol) vma~ : 3350, 1740, 1720, 1685, 1610 cm 1 N.M.R. ~ppm (DMSO-d6) : 1Y 1 (9H, s), 2,33 (2~, s), 3.9 ~3H, 8), 7.96 (lH, d, Jz9.0Hz), 8.23 (1~, dd, J=2.0 and 9.0~z), 9.00 .

~ 3 6~2 (lH, s), 9.22 (lH, s), 9.46 ~lH, s), 10.~3 (1~1, ~) .

A mixture of methyl 4-oxo-10-pivalamido - 4H-pyrimido[l,2-c~quinazoline 3-carboxylate ~ 7 g), anhydrous lithium iodide (3.18 g) and d~y pyridine (13 ml) was stirred at 120C for 3 hours and then concentrated under reduced pressure to give a residue, which was dissolved in water. Insoluble materiais were removed by fi'tration. The filtrate was adjusted to ~-' pH 1 with conc. hydrochloric acid to give crystals, which wen~ filtered off and washed with water. To the crude crystals was added methanol. The mixture was stirred and filter~d to give crystals (1.0 g), which were washed with a mixtuxe of chloroform and methanol to give crystalline 4-oxo-10- pivalamido - ;4H-pyrimido[1,2-c]
quinazoline-3-carboxylic acid ~0.65 g).
mp. 330 - 332C
IR ~Nujol3 vmax : 3340, 1720, 1680, 1660, 1610 cm 1 N.McR. ~ppm (DMSO-d6) : 1.25 (9H, s), 7.9 ~lH, d, C~ Jc9.0~z), 8.3~ (lH, dd, J=2.0 and g.OHz), '~ 8.93 (lH, s~, 9.13 (lH, d, J=2.bHz), 9.4 (lH, s), 9.75 (lH, s) ~nal. Calcd. for C17H16N4O4 :
H 4.74; N 16.46 Found : C 59.49; H 4.S0;
16.39 ~1 30 ~ 0 .~ A mixtuxe of methyl 4-oxo-10-methanesulfonamido-4H-pyrimido~l,2-c]quinazoline~3-carboxylate (4.32 g), ~j anhydrous lithium iodide (10.8 g) and dry pyxidine (43 ml) :¦ was stirred at 120C ~or 2 hours. The reaction mixture ~, 35 was concentrated under reduced pressure to give a residue, : ~

1 ~ ~9~2 which was dissolved in water (900 ml). Insoluble materials were removed by ~iltrationO The aqueous layer was adjusted to pH 5 with conc. hydrochloric acid to give crystals, which were filtered off, suspended i~ a mixture of chloroform and methanol, stirred and filtered to give crystals, which were dried to give crystalline 4-oxo-10-me~hanesulfon~mido-4H-pyrimido~1,2-c~quinazoline-3-carboxylic acid (2.8 g).
mp: 319 - 322.C
IR (Nujol) vmax : 3550, 3450, 1695, 1680, 1605 cm 1 ~ N.M.R. ~ppm (DMSO-d6) : 3.20 (3H, s), 7.8-8.2 (2H, m), - 8.65 (lH, d, J=2.0Hz), 9.0 (lH, s3, 9.5 (lH, s), 10.56 (lH, s) Example 41 A mixture of methyl 4-oxo-10-(3,3-dimethylbutyramido)-4H-pyrimido[1,2-c~quinazoline-3-carboxylate 16.0 g), anhydrous lithium i~dide (15.0 g) and dry pyridine (60 ml) was stirred at 120C for 2 hours. The reaction mixture - 20 was concentrated under reduced pressure to give a residue, to which was added water. The mixture was filterPd ~o ( . give crystals, which were suspended in water (100 ml) and adjusted to pH 1-2 with con. hydrochloric acid to give crystals, which were separated by filtration and dried to give crys~alline 4-oxo-10-~3,3-dimethylbutyramido)-4H-pyrimido[1,2-c]quinazoline-3 carboxylic acid ~2.5 g).
j mp: 304 - 305~C
I IR (Nujol) vmax : 3330, 1730, 1690, 1660, 1610 cm 1 NoM~R~ ~ppm (DMSO-d6) : 1.00 (9H, s~, 2.26 (2H, s), 7.93 (lH, d, J=9.OHz), 8.16 (lHg dd, ~ J=2.0 and 9~0Hz), 8.96 (1~, s~, 9~20 i (lH~ d, J=2.0Hz), 9.43 (lH, s), , 10.40 ~lH, s) i l 35 .1 ~ ~ ~9~i2 Example 42 A mixture of 4-amino-6-~2-ethylbutyramido)-quinazol~ne (5.58 g) 9 dimethyl methoxymethylene-propanedioate t5.62 g) and N,N-dimethylformamide (22 ml) was stirred at 100C for 1.5 hours.
After cooling to ambient temperature, water (90 ml~
was added ~o the reaction mixture. The resulting solid was.separated by filtration, washed with water and dried to give dimethyl ~[6-(2-ethylbutyram~do)-4-quinazolinylamino]methylene]propanedioate (4.85 g).
m.p. 221-225C
IR (Nujol), vmax : 3280, 1725, 1660, 1630, 1610, 1570, 1525 cm 1 : N~M.R. 8ppm (DMSO-d6) : 0.92 (6H, t, J=7.0Hz~, 1.3-1.8 (4H, m), 2.0-2.5 (lH, m), 3.76 (3~l, s), 3.92 ~3H, s~, 7.9 tlH, d, J=lO.OHz), 8.2 (lH, dd, J=2.0, lO.OHz), 8.56 (lH, d, J=2.0Hz), 8.83 (lH, s~, 9,23 (lH, d, J=12.0Hz)~ 10~5 (lH, s), 11.52 (lH, d, J=12,0Hz~

A mixture of 4-amino-6-~2-methylpropionamido)-~' quinazoline (6~2 g) and dimethyl methoxymethylene-p~opanedioate (7.01 g) in N,N-dimethylfo~mamide (25 ml) was stirred at 100C for lo 5 hours and cooled to room temperature, Water was added to the reaction mixture.
The resulting solid was sep~rated by filtration, washed with water and dried ~o give dimethyl [[6-~2-methyl-propionamido)-4-quinazolinylamino]methylene]propanedioate 3a (8.9 g). Recrystallization from ethyl acetate gave pure ` crystals mel~ing a~ 212-214C.
IR (Nujol), vmax: 3270, 1710, 1660, 1630, 1610, 1560, 1530 cm 1 N.M.R. ~ppm (D~ISO-d6) : 1020 ~6H, d, J=7.0~1z), 2.40-2,66 (1ll, m), 3.76 ~3ll, s), 3~90 (3H, s)~ 7.93 (lH, d, J~9.OHz), 8.08 (lH, dS J39.OHz), 8.4 (lH, s~; 8.73 (lH, s)~ 9.13 (lH, d, J~12.0Hz), 10.4 (lHg s), 11.13 ~lH, d, J.~12.0Hz), s Anal. Calcd. for C18H2~N405 : C, 58.06; H, 5-41;
N, 15~03 Found : Cg 58 14; H, 5.39;
N, 15.19.
Example 44 A mixture of 4-amino-6-cyclohexanecarboxamido-~uinazoline (8 85 g) and dimethyl me~hoxymethylene-prop~nedioate (8.55 g) in N,N-dimethylformamide (35 ml3 was s~irTed a~ 100C for 1 hour. After cooling So ~: (. ambient temperature, water was added to the reaction ~ixture. The resulting-solid was collected by filtra-tion, washed with water.and dried. The solid was chromatographed on silica gel with 1% methanol-chloroform and recrystallized from ch~oroform to give a crystalline solid (6.13 g). The solid is a mixture of dimethyl ~[6-cyclohexanecarboxamido-4-quinazolinyl-amino]methylene]propanedioate and methyl 4-oxo-lO-cyclohexanecarbo~amido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate in the ratio of about 2:1.
{ ~ mp. 210-212C
.~ - 25 IR (Nujol) ~max : 3330, 1735, 1710, 1682, 1662, : ` 1625, 1608 cm~l A:mixture of 4-amino-6-(3-cyolopentylpropionamido)-I : ~ quinazoline ~7.05 g) and dimethyl methoxymethylene-I : 30 propanedioate (6.48 g) in N~N-dimethylformamide t28 ml) ;was stirred a~ 100C for 1 hour and 10 minutes.
: After cooling to ambient temperature~ water was added ' ~ to:the rea`ction mixture. The resulting solid l~as separated by filtration, washed with water, and dried.
3~5:~ :The c~ude crystals were dissolved in a mix~ure of . : ~

;:
.. . . .
' : ~
. ~ ' ' .

_ chloroform and methanol9 treated wi~h activated charcoal, and evaporated under reduced pressure until crystallization began. Aft~r cooling, the Tesulting solid was collected, washed with methanol and with dichlorome~hane, and dried. There was obtained crystalline methyl 4-oxo-10-(3-cyclopentyl-p~opionamido)-4H-pyrimido[1,2- C]quinaz~line - 3-carboxylate (2 . lS g) . The filtra~e was evaporated unde~ reduced pressure to give a residue which was chromato~raphed on silica gel with 1% methanol-dichloromethane, The firs~ frac~ions contalned methyl ; ~ 4-ox~-10-(3-cyclo~en~ylpropionamido) 4H-py~imido[1,2-C]-quinazoline-3-carboxylate (1.9 g). Th~ second fractions contained dimethyl [[6-(3-cyclopentylpropionamido~-4-. 15 quinazolinylamino~methylene~propanedioate (5~16 g~.
: mp. 193-197C
IR (Nujol) vmax : 3340, 1745, 1708, 1690, 1660, 1630, 1620 cm 1 N.M.R. ~ppm (DMSO-d6) : 0,8-2.1 (llH, m), 2.23 (2H, t, J=7,0Hz), 3.75 (3H, s), 3.90 (3H, s), 7.78 (lH, d, J=9.OHz), 8.05 (lH3 d, J=9.OHz)~ 8.36 (lH, s), 8.73 (lH, s), 9.11 (lH, d, J=12.0Hz), 10.40 (lH, s), 11.40 (lH, d, J=12.0Hz) ~5 I

;I 30 -! .
.

3~2 ~ 94 -A mixture of dimethyl[[6^(2-e~hylbutyramido)-4-quinazolinylamino]methylene]propanedioate (5.3 g) and diphenyl ether t32 ml) was heated at 255C for 15 S minutes and cooled to ambient temperature. Hexane was added ~o the reaction mixture. The resulting crystals were filtered off, washed with hexane and dried.
The crude crystals were dissolved in a mixtur~ of chloroform and methanol (10:1) under hea~ing.
Insolubl~ materials we~e remo~ed by filtration.
The filtrate was concentrated under reduced pressure to give crystals, which were recrystallized from a mixture of chloroform and hexane to give methyl 4-oxo-10 - t 2 - e thylbutyrami do) - 4H -pyrimi do [ 1, 2 - C ] quinazoline-3-carboxylate (3.81 g).
mp. 239-240C.
IR (Nujol) vmax : 3350, 1730, 1690, 1665, 1610, 1490 cm~l N.~.R. ~ppm (D~S0-d6) : 0.92 (6H, t, J-8.0Hz), 1.24-1.84 (4H, m), 2.12-2.42 (lH, m), 3.84 (3H, s), 7.92 (lH, d, J~8.0Hz), ~ 8.18 (lH, dd, J=2.0, 8,0Hz), 8.88 (lH, s), `~ C` 9.12 (lH, d, J=2.0Hz), 9.38 (lH, s), 10.4 (lH~ s) :~ 25 Anal. Calcd. for ClgH20N4O4 : C, 61.94; H, 5.47;
N, 15. 21 Found : C, 61.71; H, 5.55;
N, 15.38 ~ 7 A mixture of dimethyl [[6-(2-methylpropionamido)-4-quinazolinylamino]me~hylene3propanedioate (8.4 g) in diphenyl ether ~42 ml) was s~cirred at 255C for 15 minutes. The reaction mixture was ~ooled to ambient temperature to give crystals which were fil~ered off, 3, washed with hexane and dried, There were obtained ~9 ~ 95 -6,9 8 of the crude crystalsO The crude crystals were dissolved in a mixture of chloroform and methanol (4:1) under heating. Insoluble materials were remo~ed by filtration. The filtrate was concentrated un~er reduced pressure to abou~ lS0 ml. After cooling, there was obtained crystalline methyl 4-oxo-10-(2-methyl-propionamido)-4H-pyrimido[l,~-C]quinazoline-3-carboxylate (5.85 g).
mp. 275-277C
IR (Nujol) vmax : 3345, 1700, 16709 1610, 1580, 1560 cm 1 N.M.R. ~ppm (DMSO-d6) : 1.16 (6H, d, J=7Hz), 2,4-2.8 (lH~ m), 3,86 (3H, s), 7.93 (1~IJ d~ J=9Hz), 8.22 (1~, dd, J-2, 9Hz), 8,93 (lH, s), 9.2 (lH, d, J=2Hz), 9.43 tlH, s), 10.43 (lH, s) : m Anal. Calcd. for C17H16N4O4 : C, 59.99; H, 4-74;
N, 16.46 Found : C, 59~73; H~ 4.58;
Nl 16.37 Example 48 A mixture of dimethyl ~[6-cyclohexanecarboxamido-: ~ 4-quinazolinylamino3methylene]propanedioate (4 g~ and : diphenyl ether (31 ml~ was stirred at 260C for lS
minutes . After cooling to ambient temperature~ the resulting solid was collected by filtration, washed - with hexane and d-~ied, There was obtained met~yl 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1~2-C]-: quinazoline- 3-carboxylate (3.6 g).
mp. 250-251C
:~ N.M.R. ~ppm ~DMSO-d6) : 1.1-2.1 tlH, m)~
2,2-2.8 (lH, m), 3.86 (3H, s), 7.9 (111~ tl~ J=9.0Hz) a 8,18 (111~ dd, J32.0 9.0Hz) ~ 8.9 (111~ s) ~ 9.13 (lH~ d~
J-2, 011z) ~ 9. 4 ~ s) ~ 10 . 36 ~111, ~) 69(~6 Anal. Calcd. for C20HzoN404 : C7 63.15; ~, 5,30;
N, 14,73 Found : C, 63.12; H, 5.24;
N, 14.78 ~
A mix~ure o~ dimethyl [~6-(3-cyclopentylpropionamido3-4-quinazolinylamino]methylene]propaned~ioate (6.9 g) in diphenyl ether tS3 ml~ was s~irred at 255C for 15 minu~es and cooled to ambien~ temperature. The resulting solid was collected, washed with hexane and dried. There was obtained m~thyl 4-oxo-10-(3-cyclopentylpropîonam;do)-4H-pyrimido[l,2-C]quinazoline-3-carboxylate (4.5 g).
mp. 244-247C
. IR (Nujol) vmax : 3350~ 1712, 1682, ~612 cm 1 N.M.R. ~ppm ~DMS0-d6) : 1.0-2.0 (llH, m), 2.3 (2H, m), 3.85 (3H, s), 7.8-8.2 ~2H~ m), 8.93 ~lH, s), 9.20 ~lH, s), 9.43 (lH, s), 10.50 ~lH, s) C
:;

J
' ' .
, .

:

,:

I 1 ~ 9 ~

A mixture of methy.l 4-oxo-10- (2-ethylbutyramido~-4H-~yrimido~1,2-C]quinazoline-3-carboxylate (3.2 g), anhydrous li~hium iodide (8.0 g) and dry pyridine S (32 ml) was stirred at 120C for 1.5 hours. The reac-tion mixture was concentrated under reduced pressure ~o g~Ye a residue, which was dissolved in water.
Insoluble ma~erials were removed by fil~ration.
The aqueous layer was adjusted to pH 1-2 with conc.
hydrochloric acid.to gi~e crystals, which were separated by filtration and dried. The crude crystals were washed with methanol three times and recrystallized from -' acetonitrile to gi~e 4-oxo-10- ~2-ethylbutyramido~-4H-pyrimido [1, 2 - C] quinazoline - 3- carboxylic acid (û ~ 7 g) .
mp. 295-298C
N.M.R. ôppm (DMSO-d6) : 0.96 (6H, t" J-7,0Hz), 03-l-9 (4H, m) ~ 2.0-2.6 (lH, m), 8.0 (lH, d, J=9.OHz), 8,26 (lH, dd, J=2.û, 9.0Hz~, 9.0 (lH, s), 9.26 (lH, d, J=2.0Hz), 9. 5 (lH, s), 10. 5 (lH, s) Exam~ le 51 A mixture of methyl 4-oxo-10-(2-methylpropionamido)-~; 4H-pyrimido[1,2-C~quinazoline-3-carboxylate ~5.42 g) and anhydrous li~hium iodide (13.55 g) in dry pyridine :~ ~S ~54 ml) was stirred at 100C for 1.5 hours. The reaction . mixture was cooled to give crystals which we~e collected ; by filtration and washed w;th pyridine. The crystals were suspende~ in water (200 ml). The suspension was ad~usted to pH 2.5-3,0 with conc. hydrochloric acid ~o giv~ yellow crystals, which were separated by filtrstionO washed with : ` water and dried. The crude crys~als were washed with a ~: mixtu~e of chloroform and methanol (1~ wo times and dried. There was obtained crystalline 4-oxo-10-(2-methylpropionamido) -4~l-pyrimido ll, 2-Clquin~zoline-3-carboxylic acid (3. 80 g), .

~ ~ ~9 mp . 312 - 314C
IR (Nu~ol) ~'max : 3350, 1730, 1698, 1655, 1620 cm 1 N,M.R. ~ppm (DMS0-d6) : 1.15 (6H, d, J~7.0Uz), 2.4-2.8 (lH, m3, 7.9 tlH, d~ J~9.0Hz), 8,2 (lH, dd, J~2.0, 9.0Hz), 8,93 ~lH, s) 9 9.15 (lH, d, J~2,0Hz), 9.36 ~lH, s), 10.4 tlH, s) Allal. Calcd- for C16H14N4~4 C, 58- 89; H~4. 32 ~, 17.17 Found : C, 58. 73; H-,4. 36 N, 17. 22 ~'',' ~ .
~ A mixture of methyl 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido[1~2-C]quinazoline-3-carboxylate ~4.7 g) and anhydrous lithium iodide (11. 75 g~ in dry pyridine (47 ml) was stirred a'~ 100C for 1 hour and 20 minutes and cooled to ambient tempe~ature. The resul~ing solid was collected by filtration and washed wi~h ethanol.
: The solid was suspended in water (100 ml). The sus-pension was adjusted ~o pH 1-2 wi~h conc. hydrochloric acid to gi~e yellow crystals which were separated by filtration, washed with water and dried. The crude crystals were washed with a mixture of chloroform and . methanol and dried. TheTe was obtained 4-oxo-10-cyclohexanecarboxamido-4H-pyrimido~1~2-C~quinazoline-~: 3-carbo.xylic acid (2,75 g).
; mpO 311-314C
IR ~Nujol) vmax : 3330, 30209 1740, 1710, 1660, 1610, 1580 cm~l ~:~ 30 N.M,R. ~ppm (D~IS0-d6) : 1.0-2.2 (lOH, m), 2,23-2.8 (1ll, m), 7.93 (1}l, d, J=9.0l-lz), ~ 8.2 ~lH, dd, J=9.0, 2.01~z), 8.96 (lH, s), ; 9,2 ~H, d, J~2.0Hz3, 9.45 (lHD S), 10.4 (lH, s) ~nal. Calcd~ for cl9lll8N4o4 , .: ' ."

_ 99 ~

N, lS.Z9 Found : C, 61.59; H, 4,91;
N 3 15.20 _ample 53 S A mixtur~ of methyl 4-oxo-10-t3-cyclopentyl-propionamido~-4H-pyrimido[192-Clquinazoline-3-carboxyl~te ~5.7Z g) and anhydrous lithium iodide tl4.3 K) in dry pyridine (59 ml) was stirred at 120C for 1.5 hours.
The reaction mixture was concentra~ed under reduced pTesstlre to give a crystalline residue, which was sus-pended in water (100 ml). The suspension was adjusted to pH 1,7 with conc. hydrochloric acid t~ yield yellow crystals, which were sepa~ated by filtration, washed with water and dried. Recrystallization from N,N-dimethylformamide gave crystalline 4-oxo-10-(3-cyclopentylpropionamido~-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (4,4 g), mp. ~79-283~C
IR (Nujol) vmax : 3350, 1730, 1690, 1668, 1610 1600, 1580 cm~l N.M.R. ~ppm tDMSO-d6~ : 0.7-2.1 (llH, m3, 2.4 (2H, m), 7.90 ~2H, d, J=8Hz), 8.16 (lH, dd, J=8.0, 2.0Hz)~ 8.93 (lH, s), 9.13 (lH, d, J-2~0Hz), 9.23 tlH, s3, 10.41 (lH; s) : 30 ' ~.

I

o ~

Example 54 A mixture of 4-amino-6-(2-ethylbutyramido)-quinazoline ~0O9 g) and diethyl ethoxymethylene~
propanedioate tO.95 g~ in N9N-dimethylformamide (4 ml) was stirred a~ 100C for 2 hours and 40 minutes.
Water was added to the reac~ion mixture.
The resulting crystals were collected,~washed with water and dried. The crude crystals were chromato-graphed on silica gel with 20% ethyl acetate-chloroform and recrystallized from a mixture of ethyl acetate, ~- chloroform and hexane to give crystalline diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]-propanedioate (1.1 g).
mp: 191 - 194C
IR (Nujol) vmax : 3280, 1720, 1658, 1628, 1610, lS70 cm 1 NMR ~ppm (DMSO-d6) : 0.92 (6H, t, J=7Hz), 1.28 (31~, t, J=7Hz), 1.32 (3H, t, J=7Hz)~ 1.56 (4H, m), 2.36 (lH, m), 4.2 (2H, q, J=7Hz), 4.36 (21-1, q, J=7Hz), 7.88 (lH, d, J=91lz), 8.16 (11~, d, J=9Hz)~ 8.48 (lH, s), 8.8 (lH, s), 9~16 (lH, d, J=1211z), 10.44 (lH, s), 11.4 (lH~ d, J=12Hz) Example 55 A mixture of diethyl [[6-(2-ethylbutyramido)-4-quina~olinylamino]methylene]propanedioate (0.6 g3 in diphenyl ether (3 ml~ was stirTed at 250C for 15 minutes and cooled to ambient temperature.
The resulting crystals were filtered, washed with ethyl acetate and dried. There was obtained ethyl 4-oxo-10-(2-ethylbutyramido)-~l-pyrimido[1,2-C]-quina~oline-3-carboxylate (0.5 g).
mp: 220 - 222C
IR (Nujol) ~max : 334(), 1715, 1700, 1668 cm 1 ~ J ~i90~

NMR ~ppm (DMS0-d6) : 0.88 (6H, t, J=7Hz), 1~32 (3H, t, J=7Hz), 1.56 (4H, m), 2.35 (lH~ m), 4.3 (21~, q, J=7Hz), 7.92 (lH, d, J=9Hz), 8.16 (lH, d, J=9Hz), 8.88 (lH, s), 9.16 (lH, broad d), 9.38 (lH, s), 10.4 (1ll, s) Example 56 A mix~ure of 4-amino-6- (3-cyclopen~ylpTopionamido)-quinazoline (4.4 g) and diethyl ethoxymethylenepropane-dioate (5,5 g) in N,N-dimethylformamide (20 ml) was stirred at 100C for 3 hours. To the reaction mixture was added water. The resulting crystals were collected by fil*ration j washed with water, and suspended in dichloromethane under heating. After the suspension was cooled to ambient temperature, the resulting crystals were collected by filtration and washed with dichloromethane, There was obtained ethyl 4-oxo-10-~3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]-quinazoline-3-carboxylate (2.4 g). The filtrate was concentrated to 1/4 of its original volume and cooled to 0 to yield an additional 0.37 g of the same product, The cryde substance (2.77 g) ob~ained above - was chTomatographed on silica gel with 2% methanol-dichloromethane-. The product was recrystallized from a mixture of methanol and dichloromethane to give ; crystalline pure product (2,45 g).
mp: 241 - 246C
IR tNujol) vmax : 3350, 1725, 1655, 1672, 1615, 1582, 1560 cm The mother liquor was chromatograplled on silica gel with 1,~ methanol-chloroform to give an oil l (~,15 g), which was crystallized from a mixture of : t ethyl~ acetate and ~exane, There was ol)~ained dicthyl [ 16- (3-cyclopentylpropionami do) -4-quinazolinylam;no] -methylene]propanodioato (0.82 g).
I

:
~ ` .

~ : :
:- .

~ ~ ~90~ 2 mp: lSS - 158C
IR (Nujol) vmax : 3280, 1730, 1660, 1615, 1608, 1568, 1540 cm 1 NMR ~ppm (DMSO-d6) : 1.30 (3H, t, J=7Hz), 1.32 (31-l; t, J=711z), 0.9-2.0 (11l-1, m), 2.36 (2H, m), 4 20 (2~1, q, J=71~z~, 4.33 (21-l, q, J=7~z), 7.80 (lH, d, J=9Hz), 8.06 (lH, d, ~=9Hz), 8.36 (lH, br s), 8.73 (lH, s), 9.10 (lH, d, J=12Hz) 9 10.36 (lH, s), 11.5 (lH, d, J=12Hz) ~e~
A mixture of 4-amino-6-(2,3-dim~thylpentanamido)-quinazoline (6.75 g) and-dimethyl methoxymethylene-pr~panedioate (6.48 g) in N,N-dimethylformamide (20 ml) was stirred at 100C for 1 hour and cooled ~o ambient t~mperature. Water was added to the reaction mixture.
The resulting solid was separated by filtration, washed with water, and dried. There was obtained dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]-methylene]propanedioate (6.58 g) A portion of the crude product was chromatographed on silica gel with chloroform and ethyl acetate (3:1) and recrystallized ~-~ from e~hyl acetate to give analytical]y ~ure d;methyl [[6-~2,3-dimethylpentanamido)-4-quinazolinyla~ino]-methylene]propanedioate (0.45 g).
mp: 216 - 217C
IR (Nujol) ~max : 3270, 1725, 1660, 1630, 1610, 1565, 1540, 1500 cm 1 NMR ~ppm (DMSO-d6) : 0.7-2.0 (12}-l, m), 2,2-2.8 (lH~ m), 3.8 (3H, s), 3.93 (3TI, s), 7.93 (1ll, d, J=9Hz)f 8.2 (lH, dd, J=2,9Hz), 8.55 ~1ll, d, J=2Hz), 8.85 (lH, s), 9.23 (lH, d, J=12llz), 10,43 (1l~, s), 11.6 (1ll, ~ J=121-1z), Anal- Calc~ ~or C2]l~26N45 C, 60.85; Il, 6.32;
N, l3.52 .

- --:
: ~
- -- " - ~ ~

:

v ~ ~

Pound : C, 61.16; H, 6.15;
N, 13.56 A mixture of dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]methylene]propanedioate (5.75 g) in diphenyl ether (28 ml) was stirred at ~55C for 15 minutes and cooled to ambient temperature. The result-ing solid was collected by filtration, washed with hexane, and dried The crude crystals were chromato-graphed on silica gel with 4% methanol-chloroform.
The product was recrystallized from a mixture of methanol and chloroform. There was obtained methyl 4-oxo-lO-(2,3-dimethylpentanamido)-4H-pyrimido~1,2-C]-quinazoline-3-carboxylate (0.4 g). Concentration of the mother liquor gave a crystalline residue, which was recrystallized from a mixtu~e of chloroform and hexane to give additional 4.25 g of the same product.
mp: 220 - 221C
IR ~Nujol) vmax : 3350, 1715, 1690, 1620, 1585, 1565, 1510 cm 1 NMR ~ppm (~MSO-d6) : 0.7-2.0 ~12H, m)g 2 2-2.7 (lH, m), 3.83 (3H, s), 7.9 (lH, d, J=911z), 8.2 (111, dd, J=2, 9Hz3, 8 9 (lH, s), 9.33 ~lHg d, J=2Hz), ~.4 (lH, s), 10.36 (I~l, s) A~ Calcd. for C20H2zN4O4 : C, 62-81; l~, 5.~0;
N, 14t65 Found : C, 62.80; 1l, 5.55;
N, 14.66 Exam~le 59 A mixture of methyl 4-oxo-10-(2,3-dimethyl-pentanamido)-4ll-pyrimido~1,2-C]quinazoline-3-carboxylate (3.4 g) an~ anllydrou.~ lithium iodidc (8.5 g) in dry ~yridinc (3~ ml) wa~ stirre~ at ]nO~

.

, J 1 ~9~

for 1 hour and 20 minutes. The reaction mixture was concentrated under reduced pressure. Wa~er was added to the residue to give precipita~es, which were col-lected by filtration and washed with water.
The resulting crystals were suspended in water.
The suspension was adjusted to pl~ 1-2 with conc.
hydrochloric acid ~o give yellow crystals, whicn were separated by filtration, washed with water, and dried, The crude crystals (3.85 g) were dissolved in a mixture of chloroform and methanol under heating The solution was filtered to remove insoluble materials.
The filtrate was concentrated under reduced pressure to 40 ml and cooled in an ice bath. The resulting crystal~
were çollectedby filtration and suspended in a mixture of chloroform and methanol under heating. After the suspension was cooled to ambient temperature, the crystals were filtered and dried. There was obtained 4-oxo-10- (2, 3-dimethylpentanamido)-4}l-pyrimido[l ,2-C] -quinazoline 3-carboxylic acid (1.0 g).
mp: 286 - 288C
IR (Nujol) vmax : 3330, 1740, 1700, 1660, 1610;
1580, 1520 cm~l NMR ~ppm (DMS0-d6) : 0.7-1.9 (12H, m), 2,2-2.7 (lH, m), 7.9 (lH, d, J=9Hz), 8.18 (lH, dd, J=2, 9Hz), 8.93 (1l~, s), 9.16 (lH, d, J=2Hz), i 9.4 (111, s)~ 10.33 (lH, s), 12.3-13.1 (1ll, broad S~
:~

A mixture of 4-amino-7-pivalamidoquina7oline (10.5 g) and dimethyl methoxymethylenepropanedioate i (10.9 g) in N jN-dimethylformamide (32 ml) was s~irred at lOO~C for 1 hou~ and 25 minu~es. After th~ reaction j mixture was cooled to ambient temperature, water was ~ 35 added. ~`he resulting so}id was separsted by filtration, ~ - .

9 ~

washed with water and dried.
The crustals were recrystallized rom a mixture of ethyl acetate and ethanol to give crystalline dimetnyl [[7-pivalamido-4-quinazolinylamino]methylene]propane-dioate (13.7 g).
mp: 183 - 184C
IR (Nujol) vmax : 3470, 3250, 1705, 1680, 1650, 1620, 1540 cm 1 NMR ~ppm (DMSO-d6) : 1.32 (9~1, s), 3.72 (3H, s), 3.82 (3i~, s), 7.72 (lH, d, J=lOHz), 7.92 (lH, dd, J=2,10Hz), 7.35 (lH, d, J=2Hz), . ~
~- 8.72 (lH, s), 9.02 (lH, d, J=12Hz), 9.66 (lH, s), 11.36 (lH, d, J=12Hz) ;

Exam~le_61 a mixture of dimethyl [[7-pivalamido-4-quinazo-i linylamino~methylene]propanedioate (11.7 g) in diphenyl r ether ~58 ml) was stirred at 250C for 15 minutes and cooled to ambient temperature. Hexane was added to the reac~ion mixture. The resulting crystals were collected r by filtration, washed with-hexane, and dried.
The crystals were dissolved in a mixture of chloroform - and ethanol under heating. The solu~ion was f;ltered to remove insoluble materials. The filtrate was con-centrated under reduced pressure until crystallization ~ began. After the solution was cooled to ambient tem-! perature~ the resulting crystals were collected by filtration to give methyl 4-oxo-9-pivalamido-4l1-pirimido[l,2-C]quinazoline-3-carboxylate ~5.1 ~).
Concentra~ion of the mother liquor gave additional crystals of the same compound (3~4 g).
mp: 260 - 262C
IR (Nujol) vm~x : 3340, 1725, 1680, 16109 1580 1560, 1525 cm 1 NMR ~ppm (I)MSO-d6) : 1.3 (9l1, s), ~.8 (3l~, ~s), ' ~ :
:`
:, .
: ~ ' ~;
.
:" ' ': " `,`:'` ' ~ 3 ~0~

8,06 (lH, d, J=9Hz), 8.36 ~lH, s), 8.64 (lH, d3 J=9Hz), 8.84 (lH~ s), 9.42 (lH~ s), 9.80 (1ll~ s) Example 62 A mixture of methyl 4-oxo-9-pivalamido-4H-pyrimido[l,2-C]quinazoline-3-carboxylate (6.5 g~ and anhydrous lithium iodide (16.25 g) in dry pyridine (65 ml) was stirred at 100C for 1 hour and 30 minutes and at 120C for addi~ional 30 minutes. The reaction mixture was concentrated under reduced pressure to give ~- an oily residue, which was dissolved in water.
The resulting solution was adjusted to pH 1 with conc.
hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water, and dried.
The crude crystals were dissolved in a mixture of chloroform and methanol under hea~ing. The solution was ~iltered to remove insoluble materials.
The solution was concentrated under reduced pressure until crystallization began and cooled. The resulting crystals were collected by filtration and dried.
There was obtained 4-oxo-9-pivalamido-4H-pyrimido-[lDz-c]quinazoline-3-carboxylic acid (2.9 g).
mp: 252 - 256~C
i 25 IR ~Nujol) vmax : 3370, 3250, 1735, 1690, 1650 S 1615, 1550 Cm 1 ~f NMR ~ppm tDMSO-d6) : 1.30 (9H, s~, 8.08 (1ll, dd, ~ J=2, 9 Hz), 8.38 ~1ll, d, JY2HZ), 8.64 (lH, d, S~ :: J=9HZ), 8.86 (1ll, s), 9.44 (lH, s), 9.82 (lH, s) his~peci~i~ation the expres~o~ "such n3"
means "for example" an~ i~ not intended to b~ con~trued a~ limiting the ~ nvenStion.
~:
` 35 ' ~ s ' ' ' ," ' :: ~ . . :
~ ' , ., ' , ~ ' .

Claims (136)

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

1. A process for preparing a quinazoline compound of the formula:

wherein R? and R? are C2 - C7 alkoxycarbonyl, or R? and R? are linked together to form a group of the formula:

R2 and R3 are each hydrogen, C1 - C6 alkyl, halogen, nitro, amino, C1 - C6 alkoxy, phenoxy, C1 - C6 alkylthio, C1 - C6 alkylpiperazinyl, C1 - C18 alkanoylamino, di(C1 - C18)alkanoylamino, C3 - C9 alkoxalylamino, C4 - C8 cycloalkane-carbonylamino, C3 - C7 cycloalkyl(C1 - C6) alkanoyl-amino, benzamido, phenyl(C1 - C6)alkanoylamino, C1 - C6 alkanesulfonylamino or di(C1 - C6)alkyl-amino which may be substituted with hydroxy, and A1 is a group of the formula:

or in which R4 is hydrogen, C1 - C6 alkyl, hydxoxy, C1 - C6 alkoxy, C2 - C6 alkenyloxy, di(C1 - C6)alkyl-amino or 2,2-di(C2 - C7)alkoxycarbonylvinylamino, and R5 is C1 - C6 alkyl or C2 - C6 alkenyl, and pharmaceutically acceptable salt thereof, which comprises, reacting a compound of the formula:

wherein R2, R3 and A1 are each as defined above, with a compound of the formula:

wherein R? and R? are each as defined above, and R7 is C1 - C6 alkoxy, to give a compound of the formula:

wherein R? , R?, R2, R3 and A1 are each as defined above, or reducing a compound of the formula:

wherein R?,R? and A1 are each as defined above, to give a compound of the formula:

wherein R? , R? and A are each as defined above, or reacting a compound of the formula:

wherein R?, R? and A1 are each as defined above, with a compound of the formula:

wherein R? is acyl selected from the group of C1 - C18 alkanoyl, C3 - C9 alkoxalyl, C4 - C8 cycloalkanecarbonyl, C3 - C7cycloalkyl(C1 - C6)alkanoyl, benzoyl, phenyl-(C1 - C6)alkanoyl and C1 - C6 alkanesulfonyl; or its reactive derivative, to give a compound of the formula:

wherein R? , R? , R? and A1 are each as defined above, and when desired converting a quinazoline product thus obtained, to a corresponding pharmaceutically acceptable salt thereof.

2. A process for preparing a quinazoline compound of the formula:

wherein R? and R? are C2 - C7 alkoxycarbonyl, or R? and R? are linked together to form a group of the formula:

R2 and R3 are each hydrogen, C1 - C6 alkyl, halogen, nitro, amino, C1 - C6 alkoxy, phenoxy, C1 - C6 alkylthio, C1 - C6 alkylpiperazinyl, C1 - C18 alkanoylamino, di(C1 - C18)alkanoylamino, C3 - C9 alkoxalylamino, C4 - C8 cycloalkane-carbonylamino, C3 - C7 cycloalkyl(C1 - C6)alkanoyl-amino, benzamido, phenyl(C1 - C6)alkanoylamino, C1 - C6 alkanesulfonylamino or di(C1 - C6)alkyl-amino which may be substituted with hydroxy,and A1 is a group of the formula:

or in which R4 is hydrogen, C1 - C6 alkyl, hydroxy, C1 - C6 alkoxy, C2 - C6 alkenyloxy, di(C1 - C6)alkyl-amino or 2,2-di(C2 - C7)alkoxycarbonylvinylamino, and R5 is C1 - C6 alkyl or C2 - C6-alkenyl, and pharmaceutically acceptable salt thereof, which comprises, reacting a compound of the formula:

wherein R2, R3 and A1 are each as defined above, with a compound or the formula:

wherein R? and R? are each as defined above, and R7 is C1 - C6 alkoxy, and when desired converting a quinazoline product thus obtained, to a corresponding pharmaceutically acceptable salt thereof.

3. A process according to claim 2, in which R?,R?, R2, R3 and R7 are each as defined in claim 2 and A1 is a group of the formula:

in which R4 is the same as defined in claim 2.

4. A process according to claim 3, in which R? and R? are methoxycarbonyl or ethoxycarbonyl, or R? and R? are liked together to form a group of the formula:

R2 is hydrogen, 6-methyl, 7-methyl, 8 methyl, 6-ethyl, 6-propyl, 6-butyl, 6-chlorine, 7-chlorine, 6-nitro, 6-amino, 6-methoxy, 7-methoxy, phenoxy 6-methylthio, 6-(4-methylpiperazinyl), 7-acetamido, 6-isobutyramido, 6-pivalamido, 7-pivalamido, 6-(3,3-dimethylbutyramido), 6-(2-ethylbutyramido), 6-(2,3-dimethylpentanamido), 6-[bis(3,3-dimethylbutyryl)amino], 6-cyclohexane-carboxamido, 6-(3-cyclopentylpropionamido), 6-methanesulfonamido, 6-dimethylamino or 6-[bis(2-hydroxyethyl)amino], R3 is hydrogen, 7-methyl or 7-methoxy, R4 is hydrogen, methyl, hydroxy, methoxy, allyloxy, dimethylamino or 2,2-diethoxycarbonylvinylamino,and R7 is methoxy or ethoxy.

5. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2, R3 and R4 are each hydrogen, and R7 is ethoxy.

6. A process according to claim 4, in which R1 and R? are each ethoxycarbonyl, R2 is 6-phenoxy, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

7. A process according to claim 4, in which R? and R? are each ethoxycarbonyl R2 is 6-dimethylamino, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

8. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6- ethylthio, R3 is hydrogen, R4 is hydrogen and R7 is ethoxy.

9. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 7-methoxy, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

10. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 7-acetamido, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

11 . A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen, R4 is hydroxy , and R7 is ethoxy.

12. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen R4 is methoxy , and R7 is ethoxy.

13. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen R4 is allyloxy , and R7 is ethoxy.

14. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen, R4 is methyl , and R7 is ethoxy.

15. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen, R4 is dimethylamino , and R7 is ethoxy,

16. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-ethyl, R3 is hydrogen, R4 is hydroxy , and R7 is ethoxy.

17. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-ethyl, R3 is hydrogen, R4 is methoxy , and R7 is ethoxy.

18. A procsss according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-ethyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

19. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-methyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

20. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-butyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

21. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 8-methyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

22. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-propyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

23. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 7-methyl, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

24 . A process aecording to claim 4, in which R? and R? are each ethoxycarhonyl, R2 is 6-[bis(2-hydroxyethyl)amino], R3 is hydrogen, R4 is hydrogen and R7 is ethoxy.

25. A process according to laim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-(4-methylpiperazinyl), R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

26. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-methoxy, R3 is 7-methoxy, R4 is hydrogen , and R7 is ethoxy,

27. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is hydrogen, R3 is hydrogen, R4 is 2,2-diethoxy carbonylvinylamino, and R7 is ethoxy.

28 . A process according to claim 4, in which R? and R? are linked together to form a group of the formula: R2 is hydrogen, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy

29 . A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-nitro, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

30. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-chlorine, R3 is hydrogen, R4 is hydrogen, , and R7 is ethoxy.

31 . A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 7-chlorine, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

32. A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

33. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6 methyl, R3 is 7-methyl, R4 is hydrogen , and R7 is ethoxy.

34. A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 6-(3,3-dimethylbutyramido), R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

35. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-(3,3-dimethylbutyramido), R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

36. A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 6-pivalamido, R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

37. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-methanesulfonamido, R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

38. A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 6-methanesulfonamido, R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

39. A process according to claim 4, in which R? and R? are each ethoxycarbonyl, R2 is 6-[bis(3,3-dimethylbutyryl)amino], R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

40 . A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 6-(2-ethylbutyramido), R3 is hydrogen, R4 is hydrogen , and .
R7 is methoxy.

41. A process according to claim 4, in which Ra1 and Rb1 are each methoxycarbonyl, R2 is 6-isobutyramido, R3 is hydrogen R4 is hydrogen , and R7 is methoxy.

42. A process according to claim 4, in which Ra1 and Rb1 are each methoxycarbonyl, R2 is 6-cyclohexanecarboxamido, R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

43. A process according to claim 4, in which Ra1 and Rb1 are each methoxycarbonyl, R2 is 6-(3-cyclopentylpropionamido), R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

44 . A process according to claim 4, in which Ra1 and Rb1 are each ethoxycarbonyl, R2 is 6-(2-ethylbutyramido) -R3 is hydrogen, R4 is hydrogen, , and R7 is ethoxy.

45. A process according to claim 4, in which Ra1 and Rb1 are each ethoxycarbonyl, R2 is 6-(3-cyclopentylpropionamido), R3 is hydrogen, R4 is hydrogen , and R7 is ethoxy.

46 . A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 6-(2,3-dimethylpentanamido), R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

47 . A process according to claim 4, in which R? and R? are each methoxycarbonyl, R2 is 7-pivalamido, R3 is hydrogen, R4 is hydrogen , and R7 is methoxy.

48. A process according to claim 2, in which R?, R?, R2 and R3 are each as defined in claim 2, and A1 is a group of the formula:

in which R5 is the same as defined in claim 2.

49. A process according to claim 48, in which R? and R? are each ethoxycarbonyl, R2 and R3 are each hydrogen, and R5 is methyl,

50. A process for preparing a quinazoline compound of the formula:

wherein R? are R? are C2 - C7 alkoxycarbonyl, or R? and R? are linked together to form a group of the formula:

and A1 is a group of the formula:

or in which R is hydrogen, C1 - C6 alkyl, hydroxy, C1 - C6 alkoxy, C2 - C6 alkenyloxy, di (C1 - C6) alkyl-amino or 2, 2-di (C2 - C7) alkoxycarbonylvinylamino, and R5 is C1 - C6 alkyl or C2 - C6 alkenyl, and pharmaceutically acceptable salt thereof , which comprises, reducing a compound of the formula:

wherein R?, R? and A1 are each as defined above, and when desired converting a quinazoline product thus obtained, to a corresponding pharmaceutically acceptable salt thereof.

51. A process according to claim 50, in which R? and R? are each C2 - C7 alkoxycarbonyl and A1 is a group of the formula:

52. A process according to claim 51, in which R? and R? are each ethoxycarbonyl.

53. A process for preparing a quinazoline compound of formula:

wherein Ra1 and Rb1 are C2 - C7 alkoxycarbonyl, or Ra1 and Rb1 are linked together to form a group of the formula:

Ra2 is acyl selected from the group of C1 - C18 alkanoyl, C3 - C9 alkoxalyl, C4 - C8 cycloalkanecarbonyl, C3 - C7 cycloalkcyl(C1 - C6)alkanoyl, benzoyl, phenyl-(C1 - C6)alkanoyl and C1 - C6 alkanesulfonyl, and A1 is a group of the formula:

or in which R4 is hydrogen, C1 -C6 alkyl, hydroxy, C1 - C6 alkoxy, C2 - C6 alkenyloxy, di(C1 - C6)alkyl-amino or 2,2-di(C2 - C7)alkoxycarbonylvinylamino, and R5 is C1 - C6 alkyl or C2 - C6 alkenyl, and pharmaceutically acceptable salt thereof, which comprises, reacting a compound of the formula:

wherein R?, R? and A1 are each as defined above:
with a compound of the formula:

R? OH

wherein R? is the same as defined above, or its reactive derivative, and when desired converting a quinazoline product thus obtained, to a corresponding pharmaceutically acceptable salt thereof.

54. A process according to claim 53, in which R? and R? are C2 - C7 alkoxycarbonyl, R2 is acyl selected from the group of C1-C18 alkanoyl, C3 - C9 alkoxalyl, C4 - C8 cycloalkanecarbonyl, benzoyl and phenyl (C1 - C6) alkanoyl, and A1 is a group of the formula:

55. A process according to claim 54, in which the object compound is a quinazoline compound of the formula:

wherein R? and R? are each ethoxycarbonyl and R2 is formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, 3,3-dimethylbutyryl,hexanoyl, ethoxycarbonyl, cyclohexanecarbonyl, benzoyl and phenylacetyl, and the starting compound is a compound of the formula:

R?OH

wherein R? and R? are the same as defined above, and a compound of the formula:
R?OH
wherein R2 is the same as defined above or its reactive derivative.

56. A process according to claim 55, in which R2 is formyl.

57. A process according to claim 55, in which R? is acetyl.

58. A process according to claim 55, in which R? is propionyl.

59. A process according to claim 55, in which R? is butyryl.

60. A process according to claim 55, in which R? is isobutyryl.

61. A process a according to claim 55, in which R? is pivaloyl.

62. A process according to claim 55, in which R? is 3,3-dimethylbutyryl.

63. A process according to claim 55, in which R? is hexanoyl.

64. A process according to claim 55, in which R? is ethoxycarbonyl.

65. A process according to claim 55, in which R? is cyclohexanecarbonyl.

66. A process according to claim 55, in which R? is benzoyl.

67. A process according to claim 55, in which R? is phenylacetyl.

68. A compound of the formula:

wherein R?, R?, R2, R3 and A1 are each as defined in claim 1, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

69. A compound of the formula:

wherein R?, R?, R2, R3 and A1 are each as defined.
in claim 2, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

70. A compound of the formula:

wherein R?, R?, R2, R3 and R4 are each as defined in claim 3, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

71. A compound of the formula:

wherein R?, R?, R2, R3 and R4 are each as defined in claim 4, or a pharmaceutically acceptable salt thereof whenever prepared by the precess of claim 4 or by an obvious chemical equivalent thereof.

72.Diethyl [(4- quinazolinylamino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

73. Diethyl [(6-phenoxy-4-quinazolinylamino)methylene]
propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

74. Diethyl [(6-dimethylamino-4-quinazolinylamino)-metylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

75. Diethyl [(6-ethylthio-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.

76. Diethyl [(7-methoxy-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

77. Diethyl [(7-acetamido.-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.

78. Diethyl [(2-hydroxy-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.

79. Diethyl [2-methoxy-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

80.Diethyl [(2-allyloxy-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

81. Diethyl [(2-methyl-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

82. Diethyl [(2-dimethylamino-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

83. Diethyl [(2-hydroxy-6-ethyl-4-quinazolynylamino) methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

84 Diethyl 1(2-methoxy-6-ethyl-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

85. Diethyl [(6-ethyl-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.

86. Diethyl [(6-methyl-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

87.Diethyl [(6 butyl-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 20 or by an obvious chemical equivalent thereof.

88. Diethyl [(8-methyl-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

89.Diethyl [(6-propyl 4-quinazolinylamino)methrlene]
propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.

90. Diethyl [(7-methyl-4-quinazolinylamino)methylene]-propanedioateor a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

91. Diethyl [(6- {bis (2 -hydroxyethyl)amino}-4-quinazolinylamino]methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.

92.Diethyl [{6-(4-methylpiperaziny1)-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

93. Diethyl[(6,7-dimethoxy-4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process or claim 26 or by an obvious chemical equivalent thereof.

94. Tetraethyl 2,2-[2,4-quinazolinediylbis-(iminomethylidyne)]bispropanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.

95. 2,2-Dimethyl-5-[(4-quinazolinyl)aminolmethylene-1,3-dioxane-4,6-dione or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 28 or by an obvious chemical equivalent thereof.

96. Diethyl [(6-nitro-4-quinazolinyl-amino)methylene]propanedioate or a pharmaceuticaiiy acceptable salt thereof whenever prepared by the process of claim 29 or by an obvious chemical equivalent thereof.

97 Diethyl [(6-chloro-4-quinazolinylamino)methylene]
propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.

98. Diethyl [(7-chloro-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 31 or by an obvious chemical equivalent thereof.

99.Dimethyl [(4-quinazolinylamino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 32 or by an obvious chemical equivalent thereof.

100. DiethyL [(6,7-dimethyl-4-quinazolinylamino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 33 or by an obvious chemical equivalent thereof.

101. Dimethyl[{6-(3,3-dimethyl-butyramido)-4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 34 or by an obvious chemical equivalent thereof.

102. Diethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 35 or by an obvious chemical equivalent thereof.

103. Dimethyl [{6-pivalamido - 4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 36 or by an obvious chemical equivalent thereof.

104. Diethyl [{6-methanesulfon-amido-4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 37 or by an obvious chemical equivalent thereof.

105. Dimethyl [{6-methanesulfonamido-4-quinazolinylamino]methylene]-propanedioate or a pharmaceutically acceptable salt,thereof whenever prepared by the process of claim 38 or by an obvious chemical equivalent thereof.

106. Diethyl [[6-{bis(3,3-dimethylbutyryl )-amino}-4-quinazolinylamino]methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 39 or by an obvious chemical equivalent thereof.

107. Dimethyl[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 40 or by an obvious chemical equivalent thereof.

108. Dimethyl [[6-isobutyramido-4-quinazolinylamino]methylene]propanedioate or a pharmaceutical]y acceptable salt thereof whenever prepared by the process of claim 41 or by an obvious chemical equivalent thereof.

109. Dimethyl [[6-cyclohexanecarboxamido-4-quinazolinyl-amino]methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 42 or by an obvious chemical equivalent thereof.

110. Dimethyl [[6-(3-cyclopentylpropionamido) quinazolinylamino]methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 43 or by an obvious chemical equivalent thereof.

111. Diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 44 or by an obvious chemical equivalent thereof.

112. Diethyl [[6-(3-cyclopentylpropionamido)-4-quinazolinylamino]-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 45 or by an obvious chemical equivalent thereof.

113. Dimethyl [[6-(2,3-dimethylpentanamido)-4-quinazolinylamino]-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 46 or by an obvious chemical equivalent thereof.

114. Diethyl [[7-pivalamido-4-quinazolinylamino]methylene]propane-dioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 47 or by an obvious chemical equivalent thereof.

115. A compound of the formula:

wherein R?, R?, R2, R3 and R5 are each as defined in claim 48, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 48 or by an obvious chemical equivalent thereof.

116.Diethyl[(1-methyl-1H-2-oxo-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 49 or by an obvious chemical equivalent thereof.

117. A compound of the formula:

wherein R?, R? and A1 are each as defined in claim 50, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 50 or by an obvious chemical equivalent thereof.

118. A compound of the formula:

wherein R? and R? are each as defined in claim 51, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 51 or by an obvious chemical equivalent thereof.

119. Diethyl[(6-amino-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 52 or by an obvious chemical equivalent thereof.

120. A compound of the formula:

wherein R? , R? and R?, and A1 are each as defiend in claim 53, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 53 or by an obvious chemical equivalent thereof.

121. A compound of the formula:

wherein R? , R? , R? and A1 are each as defined in claim 54, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 54 or by an obvious chemical equivalent thereof.

122. A compound of the formula:

wherein R?, R? and R? are each as defined in claim 55, or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 55 or by an obvious chemical equivalent thereof.

123. Diethyl [(6-form amido-4-, quinazolinylamino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 56 or by an obvious chemical equivalent thereof.

124 Diethyl [(6-acetamido-4-quinazolinylamino)methylene]-propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 57 or by an obvious chemical equivalent thereof.

125. Diethyl [(6-propionamido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 58 or by an obvious chemical equivalent thereof.

126. Diethyl [(6-butyramido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 59 or by an obvious chemical equivalent thereof.

127. Diethyl [(6-isobutyramido-4-quinazolinylamino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 60 or by an obvious chemical equivalent thereof.

128. Diethyl [(6-pivalamido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 61 or by an obvious chemical equivalent thereof.

129. Dimethyl[{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 62 or by an obvious chemical equivalent thereof.

130.Diethyl [(6-hexanamido-4-quinazolinylamino) methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 63 or by an obvious chemical equivalent thereof.

131.Diethyl [(6-ethoxalamido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 64 or by an obvious chemical equivalent thereof.

132 Diethyl [(6-cyclohexanecarboxamido-4-quinazolinyl-amino)methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 65 or by an obvious chemical equivalent thereof.

133 Diethyl [(6-benzamido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable salt thereof whenever prepared by the process of claim 66 or by an obvious chemical equivalent thereof.

134. Diethyl [(6 phenylacetamido-4-quinazolinylamino)-methylene]propanedioate or a pharmaceutically acceptable sait thereof whenever prepared by the process of claim 67 or by-an obvious chemical equivalent thereof.

135. A process for preparing quinazoline compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R? and R? are esterified carboxy, R2 and R3 are hydrogen, alkyl, halogen, nitro, amino, alkoxy, aryloxy, alkylthio, alkylpiperazinyl, acylamino or dialkylamino which may be substituted with hydroxy, A1 is a group of the formula:

OR

in which R4 is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, dialkylamino or 2,2-dialkoxycarbonyl-vinylamino, and R5 is alkyl of alkenyl, and a pharmaceutically acceptable salt thereof, which comprises, reacting a compound of the formula:

wherein R2, R3 and A1 are each as defined above, with a compound of the formula:

wherein R? and R? are each as defined above, and R7 is alkoxy, to give a compound of the formula:

(I) wherein R?, R?, R2, R3 and A1 are each as defined above, or reducing a compound of the formula:

wherein R?, R? and A1 are each as defined above, to give a compound of the formula:

wherein R?, R? and A1 are each as defined above, or reacting a compound of the formula:
with a compound of the formula:

R? OH
wherein R? is acyl, or its reactive derivative, to give a compound of the formula:
wherein R?, R?, R2 and A1 are each as defined above, and when desired converting the compound (I) obtained to a corresponding pharmaceutically acceptable salt thereof.

136. A quinazoline compound of formula (I), as defined in claim 135, whenever prepared by the process of claim 135 or by an obvious chemical equivalent.