DE1901519A1 - Quinazolinyl ureas - Google Patents

Description

LAWYERS

DR. JUR. DI. -1.-CF EM. WALTER BEIL ALFREO Ηθ: .νΓ: ίΞ! Ϊ

DR. JUR. DP ¹ ..- OiJ-AH-J. WOLFF DR. J "Uli. H ANS CiiR. BEIL

623 FRAMKFURTAM MAIN-HÖCHS7

ADELOK5IÜAS5E 58

13. J-n. ^ - 1

Hasere No. 15 282

Chas. Pfizer & Co., Inc, New York, ΪΓ.Υ., V.St.A.

Quinazolinyl ureas

The invention relates to new compounds in which it quinazolinyl ureas that correspond to the formulas

■ ir

NHCV HR, -t

it /

correspond. In these formulas, R ^ and Rp are hydrogen, Alkyl groups with 1 to 5 carbon atoms, Alkenylgruppeη with 3 to 5 carbon atoms, hydroxyalkyl groups with 2 to 5 carbon atoms, Phenyl, benzyl, phenylethyl, 2-furfuryl, 2,2,2-trifluoroethyl or cycloalkyl groups with 3 to 8 carbon

909835/1538

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Substance atoms, R_hydrogen or a. e alkyl group with 1 to 6 K ^ hlenstof fat omen, R, and R, - hydrogen or alkoxy groups with 1 to 3 carbon atoms (with at least one of the two groups R, and R, - being an alkoxy group) and Z is a morpholino radical, 1-asaeyelöheptyl radical, 1-azacyclooctyl radical, piperazino radical the formula

in which Y is hydrogen, alkyl with 1 to 5 carbon atoms, hydroxyalkyl, in which the alkyl part has 2 to 5 carbon atoms, acyl with 2 to 7 carbon atoms, allyl, propargyl, 2-methylallyl, phenyl, benzyl, benzoyl, halobenzoyl or halophenyl (where halogen is chlorine or bromine), trifluoromethylphenyl, methoxyphenyl, methylphenyl, methylbenzoyl, methoxybenzoyl, trifluoromethylbenzoyl, puroyl, benzofuroyl, thenoyl, pyridine carbonyl, 5,4,5-3! rimethoxybenzoyl, carboxylic acid alkyl ester (in which the alkyl part is 1 to 6 carbon atoms has) or carboxylic acid alkenyl ester (in which the alkenyl part has 3 to 6 carbon atoms) or piperidino of the formula _Ύ

in which X is hydrogen, alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy, hydroxyalkyl (in which the alkyl part has 2 to 5 carbon atoms), phenyl or benzyl, when X ^{1 is} hydrogen and in which X is alkyl carboxylate (in which the alkyl portion has 1 to 6 carbon atoms) when X. ^{1 is} phenyl.

These quinazolinyl ureas are potent hypotensive agents; they can be used as a free base or pharmaceutical for these purposes acceptable acid addition salts, either alone or in combination with a pharmaceutically acceptable carrier material will.

909835 / 153U

The compounds according to the invention, in which R, denotes alkyl, can be easily prepared from 4-amino quinazolines of the formulas produce:

In this. Formula «.R ^, Rgi R *» Rc and Z have the ones already given Meaning. The 4-amino quinazolines mentioned can be compared with the in the ÜSA patent application Serial No. 555,704 methods described be won.

If the 4-amino quinazolines mentioned are treated with an alkyl isocyanate R ~ -NCO, the desired compound of the formula I or II, in which R 1 is an alkyl group with up to 6 carbon atoms, is obtained. For best results it is necessary to use a substantial excess of the alkyl isocyanate. The reaction should preferably be carried out in a pressure vessel when the alkyl isocyanate has a low boiling point and consists, for example, of methyl isocyanate, in order to prevent loss of this reactant. With higher boiling isocyanates, the use of a pressure vessel is not so important; The use of such a vessel can be dispensed with entirely if the boiling point is sufficiently high. It is possible to use organic solvents which are customary under the reaction conditions, for example benzene, toluene, pyridine or triethylamine. However, since the reaction is best carried out in a basic environment, basic solvents such as pyridine or triethylamine are preferably used. Neither the reaction time nor the reaction temperature are critical. If you work in a pressure vessel, temperatures between room temperature and about 130 ⁰ O are sufficient; one works without a pressure vessel, i.e. with higher alkyl iso-

9Q983S / 153b

_ 4- -

eyanaten, temperatures between room temperature and reflux temperature are suitable. Reaction times up to about 24 hours are generally sufficient; of course, a higher reaction temperature allows shorter reaction times to be used without loss of end product. With methyl isocyanate can be achieved, for example, with reaction times of about 4 to 10 hours and a reaction temperature of about 100 ⁰ O satisfactory yields.

The products are isolated from the reaction mixtures in a customary manner known to the person skilled in the art, for example by precipitation, removal of the solvent, extraction, etc.

If compounds of the formulas I and II are to be prepared in which R ~ is alkyl, R ^ or R ₂ consists of hydrogen or R ₁ , R ₂ or Z contains a hydroxyl group, the above-described reaction with alkyl isocyanate is not favorable because the named substituents would likely react with the isocyanate. A useful synthesis for these compounds consists in the conversion of a 2-chloro-4-amino quinazolireB with alkyl isocyanate to 1- (2-chloro-4-quinazolinyl) -3-alkylurea, whereupon the 2-chloro group is replaced by the desired specific amino group ; this implementation takes place according to the following formula:

909835/1538

The various 2-chloro-4-aminochinazolines can be prepared according to the USA patent application Serial No. 555,704 methods described. The reaction with the alkyl isocyanate is carried out under the same time, temperature, pressure and quantity ratios as the treatment of the 4-amino quinazolines with alkyl isocyanate described above. The 1- (2-chloro-4-quinazolinyl) -3-alkylurea obtained can easily be converted into various 1- (2-amino-4-quinazolinyl) -3-alkylureas by mixing a solution or suspension of the chlorine compound with a suitable Amine heated; when heated with ethylamine, a 2-ethylamino quinazoline can be obtained. For suspending the chlorine compound is an ethanolic solution of the amine can be used easily, is carried out whereupon the reaction at temperatures between about 100 and 180 ⁰ C. Generally heating for about 24 hours is sufficient. The desired material can be easily isolated by evaporating the excess solvent and amine and recrystallizing the product.

The preparation of compounds of the formulas I and II, in which IU is hydrogen, is carried out by a 2-Amino-4- (unsubstituted amino) quinazoline with an inorganic Reacts cyanate and hydrochloric acid. Ammonium cyanate, Sodium cyanate and potassium cyanate are good for this purpose suitable. Preferably, at least equimolecular amounts, based on the quinazoline, of cyanate and hydrogen chloride are used acid; It is even better to have at least a 10big molar Use excess of the two remedies.

The reaction is carried out in a simple manner so that the Reagents to an aqueous suspension of the quinazoline are. Neither the reaction time nor the reaction temperature is critical; the reaction can be carried out between about room temperature and reflux temperature, with whichever is more satisfactory Yields necessary time depends on the temperature. It has been shown that if the

9 09835/1538

aqueous reaction mixture on a steam bath a satisfied Barking yield of the desired product gives which ε> can be subsequently isolated and cleaned; for the latter Common methods such as removal of the solvent, recrystallization, extraction, etc. can be used will.

Compounds of the formulas II and I in which IU is hydrogen, can also from the already mentioned 2-chloro-4-aminochinazolinen can be produced when the reactivity of a particular amino group in the 2-position is the desired Conversion could interfere; the implementation then runs according to the equation

The novel ohinazolinyl ureas according to the invention are effective hyphensive agents for animals and can be used to combat high blood pressure. The compounds are administered for this purpose in the conventional manner known to those skilled in the art. Particularly suitable agents are those in which R. and Rt are methoxy, especially 1 - //! - (43 / {2-furoyl τ -1-piperazinyl) -6,7-dimethoxy-4-quinazolinyl7-3-methylurea , 1- / 2- (Dimethylamino) -6,7-dimethoxy-4-quinazolinyl7-5-methylurea, 1 - ^ - (4 ~ Allyl-1-piperazinyl) -6 _? 7-dimethoxy-4-quinazolinyl 7-3-me thy! Urea and 1 - ^ 2- (4 ~ Ciarboi =! Obirtr:!:; \ · -1 -piperazinyl) -6,7-

808835 / H3i;

BATH ORIGINAL

dimethoxy ~ 4-quinazolinyl7-3-methylurea.

The compounds according to the invention can also be in the form of their pharmaceutically acceptable salts are administered. "Pharmaceutically acceptable salts" are understood as meaning those salts which have no significantly greater toxicity than free connection. Pharmaceutically acceptable acid addition salts are salts of mineral acids such as hydrogen chloride, hydrogen bromide, Hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids and salts of organic acids such as Tartaric acid, citric acid, maleic acid, glycolic acid, gluconic acid, gulonic acid, succinic acid, arylsulfonic acids, e.g. p-toluenesulfonic acid i.a.

The pharmaceutically unacceptable salts which are unsuitable for therapy are valuable for isolation and purification of the compounds according to the invention. They can also be used for the preparation of therapeutically valuable pharmaceutically acceptable substances Salts are used. Typical salts of this group include the salts with hydrofluoric acid and Perchloric acid. The hydrofluorides are special for manufacture pharmaceutically acceptable salts suitable. The hydrochlorides can be prepared, for example, by one solution of the hydrofluoride in hydrochloric acid and the resulting hydrochloride crystallizes out.

The active substance must be present in the pharmaceutical preparation in an amount sufficient for the intended dosage form are present. It is possible to administer different dosage forms at the same time. Although in itself it is possible to use preparations to be administered that is less than 0.005 percent by weight of the containing active material, preparations containing not less than 0.005 # of the active substance should preferably be used contain. Otherwise the amount of extender or carrier material will be too large. Activity increases with concentration of the active ingredient. The preparation can be 10, 50, 75,

909835 / Ib-Jb

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BATH ORIGINAL

95 percent by weight or an even greater amount by weight of the active substance.

The level of the dose which is "most suitable" in the individual case must depend on the age, habit and reaction of the patient in question, as well as on the nature and extent of the symptoms and the pharmacological properties of the particular patient applied agent can be determined. in general, initial small doses will be administered, which are then gradually increased to the extent, has been to the optimum amount determined. it is frequently found that, when orally administered products larger amounts but achieve the same concentration is supplied in the body In the latter case, smaller amounts are sufficient To lower blood pressure in an effective way. In individual cases it may of course be desirable, even larger ones or to use smaller amounts, which is entirely possible.

The following examples serve to further illustrate the invention.

example 1

1 - / * 2-Dimethylamino) -6, T-dimethoxy ^ -quinazolinyl / ^ - methylurea

To a solution of Z-dimethylamino- ^ amino-ejT-dimethoxyhinazoline (4.84 g; 0.0195 mol) in 150 ml of pyridine was added methyl isocyanate (20.6 gj 0.36 mol). The mixture was heated in a pressure vessel at 80 ^° C. for 4 hours and then cooled in an ice bath. The crystalline material obtained in this way was filtered off, washed with Xther and dried; in this way to give the desired product in an amount of 4.76 g (80 $) with i. ^1: 260-263 ⁰ C.

909835/1536

Analysis:

■ Calculated for O ₁₄ H ₁₉ N ₅ O ₃ : 0.55, 7ϊ Η, 6.27; N, 22.94;

found O, 55.39; H, 6.07; II, 22.95.

Example 2

1 - ^ - (4- ^ pFaroyl7-1-piperazinyl) -6,7-aimeth.oxy-4-ch.ina2iolinyl / -3-methylurea

Methyl isocyanate (20.6 g; 0.36 mol) was added to a solution of 2-A- (2-S ¹ UTOyI) piperazin-1-yl7-4-amino-6,7-d imethoxyquinazoline (7.67 g, 0.0195 mol) in 150 ml of pyridine. The mixture was heated in a pressure vessel at 100 ^° C. for 7 hours and then cooled in an ice bath. The resulting crystalline material was filtered off, washed with ether and dried. The desired product was in an amount of 5.6 g (635ε) with]:. 240-243 ⁰ C before.
Analysis:

Calcd for O ₂₁ H ₂₄ H ₆ O ₅ : C, 57.26; H, 5.49; IT, 19.08; found C, 56.88; H, 5.59; N, 19.00.

Example 3

Alkyl isocyanates were made with 2-dimethylamino-4-amino-6,7 * dimethoxychinaζölin and 2- / 4- (2-furoyl) piperazin-1-yl7-4-amino-6,7-dimethoxyquinazoline implemented according to the method described in Examples 1 and 2; the following products were obtained:

1 -JjL- (Whore thylamino) -6,7-d ime thoxy-4-quinazolinyl7-3-ethylurea

1- / 2- (Dimethylamine) -6,7-dimethoxy-4-quinazolinyl7-3 ~ isopropylurea

1- ^ 5- (Dimethylamino) -6,7-dimethoxy-4-quinazoliny ^ 7-3-n-hexyl urea

1 -0- (4-Furoy 1 / ^ - 1 -piperazinyl) -6 ^ -di
ethylurea

1- / 5- (4- £ ^l uroyl £ -1 -piperazinyl) -6,7-d imethoxy-4-quinazoliny l7-3-isopropylurea

- ^ - (4 - / ^ - I ¹ UrOyIj-I -piperazinyl) -6,7-d imethoxy-4-quinazoliny l7 3hlhtff

-3-n-hexylurea.

90983 5 / 153b

19C-J519

Example 4

The following 1- (2-amino-4-ehinazolinyl) ureas have been found in prepared in the same manner as indicated in Examples 1 to 3 by mixing the appropriate 4-amino-quinazoline with isocyanate implemented:

909835 / 153ö

I. IU 35/1 (ΛΧΧ ^ Γ * Χ3 * ft_
UIl ₃ - OJl ₃ U- bab ^R 5 R ₁ WCNHR ₃
C. ^G 6 ^H 5 ~ CH ₅ - CH ₃ O- CH ₃ O- CgH ₅ CH ₂ - CH ₃ - CH ₃ O- CH ₃ O- 0, -Hp-CH ₀ - CH ₂ = CH-CH ₂ - CH ₃ - CH ₃ O- CH ₃ O- CHp = CH — CHp— CH ₂ = CH- (CH _{2) 5} CH ₃ - CH ₃ O- CH ₃ O- CH ₂ = CH- (CH ₂ J ₅ - Ό ι? CH ₃ - CH ₃ O- CH ₃ O- ° 6 ^H 5 "" ^CH 2 ~ D 5 ₃ ) ₂ CH-CH ₂ - CH ₃ O- H- 2-HO-C ₆ H ₄ - C ₆ H ₅ - (CH CH ₅ - CH ₃ O- H- 4-Cl-C ₆ H ₄ - / "ITT
V / JlX * t ^ " ■ x / pCH — CHp- H— CH ₃ O- (2-C ₄ H ₃ O) -CH ₂ - C ₆ H ₅ - (CH CH ₃ - CH ₃ O- CH ₃ O 2-CH, 0-C, -H, -
3 64 ° 6 ^H 5- CH ₃ - C ₂ H ₅ O- H- CgH ₅ - C ₆ H ₅ -CH ₂ - plTT μ (Λ TT f
\ jSl'z ^mm O. ~ w -zlliyv, C ₂ H ₅ O- ^C 6 ^H 5 " ^GH 2" 3-Br-C ₆ H ₄ - ΛΙΤΤ Γ \ TT (\
OJl ₅ - O ₂ U ₅ U- ) - QC ₃ H ₇ O- 3-Br-CgH ₄ - 3-CH ₃ OC ₆ H ₄ - Γ 2 5 " C ₂ H ₅ O- 3-CH ₅ O-CgH ₄ - 4-C ₆ H ₁₃ OC ₆ H ₄ CgH ₅ - CH ₅ - CH ₃ O- CH ₃ O- 4-CgH ₁₃ 0-CgH ₄ - 5- 2,4- (C ₆ H ₁₃ ) ₂ - CH ₃ - C ₂ H ₅ O- C ₂ H ₅ O- 2,4- (CgH ₁₅ ) ₂ -CgH. 2,4-Br ₂ -CgH ₃ - CH ₅ - H- CH ₃ O- 2,4-Br ₂ -CgH ₅ - 3-CH ₃ -CgH ₄ - ft TT _ TT_
wpllp ™ Xl "~ CH ₃ O- 3-CH ₅ -C ₆ H ₄ - 3-Cl-C ₆ H ₄ C ₂ H ₅ - CH ₅ O- C ₃ H ₇ O- 3-Cl-C ₆ H ₄ 3-PC ₆ H ₄ - C ₂ H ₅ - CH ₃ O- CH ₃ O- 3-PC ₆ H ₄ - C ₆ H ₅ -C ₂ H ₄ - H- C ₆ H ₅ -C ₂ H ₄ - 9098

- 12 -

Example 5

1- / 2- (4-Methyl-1-piperazinyl) -6,7-aimetliozy-4-chiaazolinyl7-3-methylurea

Methyl isocyanate (20.6 g; 0.56 mol) is added to a solution of 2- (4-methyl-1-piperazinyl) -4-amino-6,7-aimethoxyquinazoline (6.11 g; 0.0195 mol) in Given 150 ml of pyridine. The mixture is heated in a pressure vessel at 100 ⁰ O for 7 hours and then cooled in an ice bath. The resulting precipitate is filtered off, washed with ether and dried; then the desired product is available.

Example 6

The following 1- (2-amino-4-ehinazolinyl) ureas can be used in the in Example 5 can be prepared in the manner described by reacting the corresponding 4-amino quinazoline with isocyanate:

909835 / 153ö

Morpholino

4-allyl-1-piperaziriyl 2,6-dipentylmorpholino

Morpholino

Piperidino

4-benzyl-1-piperazinyl 1-azacyclooctyl 4-phenyl-1-piperazinyl 4-methyl-1-piperazinyl 4-Pentyl-1-piperazinyl Gyclopropylamino Cyclohepty! Amino Cyclohexylamine 4-Acetyl-1-piperazinyl 4-n-Valeryl-1-piperazinyl 4-Benzoyl-1-piperazinyl 2,6-dimethylmorpholino 2,6-dipentylmorpholino 1-azacycloheptyl 1-azacyclooctyl

Piperazin-1-yl-4-carboxylic acid rice butyl ester

90983b / S ₄ .

CH -

- CH ₃ O-

CH ₃ - 1-C ₃ H ₇ O- 1-C ₃ H ₇ O QO ₄ H ₉ - CH ₃ O- CH ₃ O- HC ₄ H ₉ - CH ₃ O- H- HC ₄ H ₉ - H- nC ₃ H ₇ O HC ₄ H ₉ - H- 1-C ₃ H ₇ O nC ₄ H ₉ - C ₂ H ₅ O- H- HC ₄ H ₉ - C ₂ H ₅ O- H- C ₂ H ₅ - H- nC ₃ H ₇ O C ₂ H ₅ - CH ₃ O- CH ₃ O- CH- CH ^ O- CH, 0- C. Z> C ₂ H ₅ - CH ₃ O- CH ₃ O- C ₂ H ₅ - H- CH ₃ O- C ₂ H ₅ - nC ₃ H ₇ O- H- CH ₃ - OH ₃ O- nC ₃ H ₇ O CH ₃ - H- C ₂ H ₅ O- / Trj
\ JJLX * Z C ₂ H ₅ O- CH ₃ O- ft DD C ₂ H ₅ O- CH ₃ O- OH ₃ O- CH ₃ O-

CH ₅ - H- ΟΗ, Ο- CH ₅ - H- . PH ₅ O- OH,-
j Η— CH ₅ O- OH ₅ - OH ₅ O- CH ₅ O-

Piperazin-i-yl ^ -carboxylic acid-methyl- CH, - ΟΗ, Ο- CH, O-ester 7 ο ρ

Piperazia-1-yl-4-carljorisaure-n.-h.exyl- OH-- CH ^ O- CH ^ O-ester ο ο ο

4- (2-methylallyl) -1-piperazinyl OH ₅ - OH ₅ O- GH ₅ O-piperazin-i-yl-4-carboxylic acid allyl ester CH ₅ - CH ₅ O- CH ₅ O-

4-Benzyl-1-piperidino 4-n-Propyl-1-piperidino 4-n.-heptanoyl-1-piperazinyl 4-methyl-1-piperidino

4-n-pentyl-1-piperidino CH ₅ - CH ₅ O- CH ₅ O-

4-n-Butoxy- ¹ -piperidino CH ₅ - CH ₅ O- CH ₅ O-

4- (o-Methy! Phenyl) -1-piperazinyl CH ₅ - CH ₅ O- CH ₅ O-

4- (o-Trifluoromethylbenzoyl) -1-piperazinyl CH ₅ - CH ₅ O- CH ₅ O-4-methoxy-1-piperidino C ₂ H ^ - CH ₅ O- CH ₅ O-

4-phenyl-1-piperidino 4-o-chlorophenyl-1-piperidino 4-thenoyl-1-piperazinyl 4- (p-methoxyphenyl) -4-piperazinyl 4- (o-methoxybenzoyl) -1-piperazinyl

4- (m-Methylbenzoyl) -i-piperazinyl 25 3 3

4- (o-Methoxybenzoyl) -i-piperazinyl ° 2 ^H 5 " ^GH 3 ° ~ CH ₅ O-4- (3,4,5-trimethoxybenzoyl) -1-pipera-C ₀ H ₁ --CH ^ O- CH ^ O-zinyl ^{ά 5} * ■>

C ₂ H ₅ - H- CH ₅ O- C ₂ H ₅ - H- CH ₅ O- O ₂ H ₅ - H- CH ₅ O- C ₂ H ₅ - H- CH ₅ O-

4- (o-Chloropb.enyl) -1-piperazinyl ^σ 2 ^ΙΪ 5 ~ ^GH 3 ° ""

4- (p-bromophenyl) -i-piperazinyl ^C 2 ^H 5 ~ ^GH 3 ° "OH ₅ O-

4- (o-Chlorobenzyl) -i-piperazinyl ^C 2 ^H 5 " ^0H 3 ° ~ OH ₅ O

4- (o-Brombenzy3) -1 -piperazinyl C ₂ H ^ - CH ₅ O- CH ₅ O-

4- (trifluoromethyl) -1-piperazinyl ° 2 ^H 5 ~ OH ₅ O-

909835/1 hSH

Example 7

The following 1- (6,7-dimethoxy-4-ehinazolinyl) -3-methylureas can also be prepared in the manner described in Example 5:

N-Y

1- (6,7-Dimethoxy-4-quinaaiinyl) -3-methy! Urea can also be used in can be made in this way:

Example 8

1- / 2- (4-AlIyI-I-piperazinyl) -6,7-dimethoxy-4-quinazoliny17-3-methylurea

The procedure was again as indicated in Example 5, using an equivalent amount of Z - ^ - allyl-i-piperazinylJ ^ -amino-e ^ - dimethoxyquinazoline. The reaction was ^{carried out at 100 °} C. in 4 hours; the desired product was obtained in 78.5 $ igsr yield with F .: 248-250 ⁰ C.

90983b / I

ψψψΐ ■■

Analysis:

for C ₁₉ H ₂₆ FgO ₃ : C, 59.05; H, 6.78; N, 21.75.

found O, 59.03; H, 6.62; N, 21.78.

Example 9

1 - / "2- (4-carisobutoxy-1-piperazinyl) -6,7-aimethoxy-4-quinazolinyl 7 -3-methylurea

The procedure was as indicated in Example 5, but an equivalent amount of 2- (4-carbisobutoxy-1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline was used. The reaction was carried out at 100 ⁰ C in 4 hours and gave the desired product ^ in 48 # iger yield with P .: 241-243 ⁰ C.

Analysis:

for C ₂₁ H ₅₀ NgO ₅ : C, 56.49; H, 6.77; U, 18.82

found C, 56.39; H, 6.70; N ", 18.83.

Example 10

(2-Dimethylamino-6,7-d-imethoxy-4-quinazolinyl) urea

To a suspension of 7.44 g (0.3 mol) of 4-amino-2-dimethylamino-6,7-dimethoxyquinazoline in 30 ml of warm water were added 2.75 ml (0.33 mol) of concentrated hydrochloric acid (12N) with stirring. The solution obtained in this way was placed in a porcelain evaporation dish, and 1.98 g (0.33 mol) of ammonium cyanate were added. The mixture was then heated on a steam bath for one hour. The mixture was then allowed to cool and a Hour at room temperature aside. It was then slowly evaporated to dryness in the course of 2-3 hours. The crystalline one The residue was finely comminuted and treated with 30 ml of water, whereupon the mixture was evaporated again. That as Residual powder was finally heated on a steam bath for 4-5 hours.

The resulting mixture of crude product and ammonium chloride was finely powdered and suspended in 30 ml of water. The mixture

909835 / Ί 53b

was slowly heated with mechanical stirring to 70 G, then cooled to 35 ⁰ C and the product filtered off with suction on a Pilter.

Example 11

The procedure given in Example 10 was repeated, wherein an equivalent amount of the corresponding quinazoline was used to obtain the following products:

Cf ₅ CH ₂

CH ₂ = CH-OH ₂ -

Cj? .7 OHp-

CH, O-

C ₂ H ₅ O CH, O-

Example 12

1- (2-Ethylamino-6,7-d-imethoxy-4-quinazolinyl) -3-methylurest off

Methyl isocyanate (6.84 g; 0.12 mol) and catalytic amounts are added to a solution of 2-chloro-4-amino-6,7-dimethoxyquinazoline (6.2 g; 0.03 mol) in 120 ml of toluene .an pyridine. The mixture is heated in a pressure vessel to 120 ^° C. for 12 hours and the 1- (2-chloro-6,7-dimethoxy-4-quinazolinyl) -3-methylurea formed is filtered off and recrystallized from ethanol.

A suspension of 1- (2-chloro-6,7 ~ dimethoxy-4-quinazolinyl) -3-methyl-urea (5 g) in 90 ml of 25 $ strength by weight ethanolic Äthylaminlösung is heated for 16 hours at 160 ⁰ C. The solution and excess ethylamine are then evaporated and the residue recrystallized from methanol / water to give the desired product.

9 0 9 8 3 b / 1 5 J b

1 90- *! 19th

Example 13

The procedure of Example 12 is repeated using of the corresponding quinazoline and isocyanate to give the following compounds:

ι O C ^ XX f "\ ι fiTT ^^
ι £ ^, '" ^Λ \ ja xjL *? * · ^ y ¹ ^ v / ΧΙλ ^^
r J? ί- C. Ro 90 983 5 ΚΗΠ ^X X _{R. E.} ^C 6 ^H 5 H- _R. 3 CH ₅ O- CH ₅ O- I. 4-Gl-C ₆ H ₄ - H- OH ^ " H- CH ₅ O- 3,4-Cl ₂ C ₆ H ₅ - H- CH ₅ - G ₂ H ₅ O- H- 2-HO-C ₆ H ₄ - H- CH ₅ - nC ₅ H _? 0- nG ₅ H ₇ O- HO- (GH ₂ ) ₅ - H- GH ₅ - 1-G ₅ H ₇ O- H- 2-GH ₅ OG ₆ H ₄ - HO- (CH ₂ ) ₅ - CH ₅ - H- 1-C ₅ H ₇ O- OT ₃ OHg- H- GH ₅ - CH ₅ O- CH ₅ O- CF ₅ CH ₂ -
2,4- (CH ₅ ) 2-G ₆ H ₅ - H- GH ₅ - H- nC ₅ H ₇ O- ² " ^C 6 ^H 13" ° 6 ^H 4 " H-
H- GH ₅ - CH ₅ O-
C ₂ H ₅ O- GH ₅ O-
GH ₅ O- 2-CH ₅ -C ₆ H ₄ H- GH ₅ - C ₂ H ₅ O- CH ₅ O- I. 2-HO-C ₆ H ₄ - H-
H- CH ₅ - H-
- CH ₅ O- C ₂ H ₅ O-
G ₂ H ₅ O- 3-FG ₆ H ₄
H- H- GH ₅
C ₂ H ₅ - H- G ₅ H ₁₁ O- GH ₅ - H-
H- C ₂ H ₅₁ - CH ₅ O-
- CH ₅ O- GH ₅ O-
CH ₅ O- HC ₅ H ₁₁ - H- G ₂ H ₅ - CH ₅ O- H- H- C ₂ H ₅ . - CH ₅ O- H- C ₂ H ₅ '' ■ b

iL S ¹⁵ S Rjji Rc

1-PipeAinyl CH ₅ - CH ₅ O- CH ₅ O-

4-hydroxyethyl-1-piperazinyl OH ₅ - OH ₅ O- GH ₅ O-

4-hydroxypentyl-1-piperazinyl nC ₄ Hg- CH ₅ O- H-

4-ß-hydroxyethyl-1-piperidino OH ₅ - H- CH ₅ O-

4-Hydroxy-1-piperidino CH, - CH ₅ O- OH ₅ O-

2-ß-hydroxyethyl-1-piperidino CH ₅ - GH ₅ O- CH ₅ O-

4- (4-Hydroxybutyl) -1-piperidino C ₃ H ₅ - H- CH ₅ O-

Example 14

(2-Ethylamino-6,7-dimethoxy-4-quinazolinyl) urea

2.75 ml (0.33 mol) of concentrated hydrochloric acid ( 12 n). The solution obtained is placed on a porcelain evaporation dish, 1.98 g (0.33 mol) ammonium cyanate are added and the mixture is heated on a steam bath for one hour. The liquid is allowed to cool, it is left at room temperature for one hour and allowed to slowly evaporate to dryness over a period of 2-3 hours. The crystalline material is finely crushed, treated with 30 ml of water, whereupon the mixture is slowly evaporated. The remaining powder is heated on a steam bath for 4-5 hours, after which it is in a finely powdered form and is again suspended in 30 ml of water. The mixture is slowly heated ^{to 70 ° C. with stirring.} Then allowed to cool to 35 ⁰ C. The (2-chloro-6,7-dimethoxy-

4-china;> olin) harastoff is filtered off.

9 0 9 8 3 5/15 3b

A suspension of 5 g (2-chloro-6,7-äimethoxy-4-quinazolinyl) urea in ethanolic ithylaminlösung is heated for 16 hours at 160 ⁰ C. The solvent and excess ethylamine are then evaporated; the residue is recrystallized from methanol / water, whereby the desired product is obtained.

Example 15

One works again as described in Example 14, whereby one corresponding quinazolines are used, which lead to the following compounds:

HOOH ₂ CH ₂ -H-.

HIGH ₂ CH ₂ H-

CH ₃ O-

C ₂ H ₅ O CH ₃ O-CH ₃ O-

Example 16

Pharmaceutically acceptable salts

They add salts of the products according to hydrochloric acid Examples 1 to 12 are prepared by each an alcoholic solution of a product is mixed with dilute hydrochloric acid and the resulting solution is dried evaporates.

Further acid addition salts of the products can be found in the corresponding Way from aqueous solutions of the following acids instead

9098 3 5/153 8

produced by hydrochloric acid: hydrobromic, Hydrogen iodic, nitric, sulfuric, citric, phosphoric, maleic, tartaric and lactic acids.

Example 17

Antihypertensive activity

Hypotensive activity was measured in hypertensive dogs with systolic blood pressure of at least 150 mm Hg. The letterpress was evoked according to the Goldblatt ~; ef a ?, ^e J. Exp. Med. 59, 347 (1934).

Systolic blood pressure was measured on the coccyx artery by the method of Prioli and Wynbury, J. Appl. Physiol. 15, 323 (1960) measured before the drug was administered and 2.6 and 24 hours afterwards. The medicine was given to the dogs orally in the form supplied by capsules except where otherwise indicated.

The following hypotensive effects have been noted:

Dimethylamine
4- (2-furoyl) -1-piperazinyl 4-allyl-1-piperazinyl 4-carbisobutoxy-1-piperazinyl *

Dose (mm / kg)
10
30th
40
40

Decrease in blood pressure (mm. Hg. )

33 20 30 30

* aqueous suspension

909835/16 3

Claims (6)

Claims 1) 1- (2-Amino-4-quinazolinyl) ureas of the formula T A in which R, hydrogen or an alkyl group having 1 to 6 carbon atoms means, R ^ and Er can be the same or different and are hydrogen or represent alkoxy groups having 1 to 3 carbon atoms, at least one of the two groups R. and Rr must mean alkoxy, and R.J and Rp can be the same or different and are hydrogen, Alkyl groups with 1 to 5 carbon atoms, alkenyl groups with 3 to 5 carbon atoms, hydroxyalkyl groups with 2 to 5 carbon atoms, phenyl, benzyl, phenylethyl, 2-furfuryl, 2,2,2-trifluoroethyl or cycloalkyl groups with 3 to 8 carbon atoms or together with the nitrogen atom, to which they are bound, a morpholino radical, 1-azacycloheptyl radical, 1-azacyclooctyl radical, Piperazine residue of the sormel F-Y in which Hydrogen, alkyl with 1 to 5 carbon atoms, hydroxyalkyl (in which the outer alkyl part is 2 has up to 5 carbon atoms), acyl with 2 to 7 carbon atoms, allyl, propargyl, 2-methylallyl, Phenyl, benzyl, benzoyl, halobenzoyl, halophenyl (in which halogen OhlcB? 909835 / 153Ö or bromine), trifluoromethy! phenyl, Methoxyphenyl, methylphenyl, methylbenzoyl, methoxybenzoyl, trifluoromethylbenzoyl, furoyl, Benzofuroyl, Ihenoyl, Pyridincarbonyl, 3,4 »5-Irimethoxybenzoyl, Carboxylic acid alkyl esters (at in which the alkyl part contains 1 to 6 carbon atoms), carboxylic acid alkenyl ester (in which the alkenyl portion has 3 to 6 carbon atoms having), or piperidine radical of the formula in which X ^{1 is} hydrogen or phenyl and X is hydrogen, alkyl with 1 to 5 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxyl, hydroxyalkyl (where the alkyl part has 2 to 5 carbon atoms), phenyl or benzyl when X ^{f is} hydrogen, or Carboxylic acid alkyl ester (in which the alkyl part has 1 to 6 carbon atoms) when X ^{1 is} phenyl, form,
including the acid addition salts thereof. 2) Compounds according to Claim.1, in which R. and R, - both Mean methoxy. 3) A compound of the formula IA according to claim 1, in which R ₁ , R «and R, in each case methyl and R, and Re both denote methoxy. 4) Compound of formula IA according to claim 1, in which R ^ and Rp together with the nitrogen atom to which it is attached are, a piperazino radical of the formula 9 O 9 8 3 b / 1 b Ii b in which Y is 2-furoyl, R _{5 is} methyl and R _{1 and R 5 are} both methoxy. 5) Compound of formula IA according to claim 1, in which R ^ and R ₂ together with the nitrogen atom to which they are attached, a piperazino radical of the formula -N N-Y in which Y is allyl, R, methyl and R. and R _{5 are} both methoxy, form. 6) Compound of formula IA according to claim 1, in which R .. and R ₂ together with the nitrogen atom to which they are attached, a piperazino radical of the formula - N N-Y in which Y is garbisobutoxy, R, methyl and R. and R, - both ^ Methoxy mean, form. For Chas. Pfizer & Co., Inc. New / Tork, N.Y., V.St.A. Lawyer 909835 / 153b