Chloro- and alkoxy-substituted-2,4-diaminoquinazolines and pharmaceutical compositions containing them.

DK 153399 Β i

The invention relates to an analogous process for the preparation of novel 2,4-diaminoguinazoline compounds having the general formula (I) stated in the preamble of claim 1 or pharmaceutically acceptable acid addition salts thereof, which compounds are useful as antihypertensive agents. The invention further relates to novel devices

4-Aminoguinazoline compounds for use as a starting material in the process.

U.S. Patent Nos. 3,511,836, 3,635,979 and 3,663,706 disclose 6,7-dimethoxy-2,4-diaminoguinazolines of the formula:

CH

CH wherein Z is a nitrogen-containing heterocyclic group. One of these compounds, 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyguinazoline is a clinically useful antihypertensive agent and is marketed under the generic name prazosin. Its pharmacology is discussed in Constantine et al., Hypertension: Mechanisms and Management, edited by Onesti, Kin and Moyer, Grüne and Stratton, 1973, pages 429-444.

U.S. Patent Nos. 3,669,968 and 3,769,268 disclose 6,7,8-trialkoxy-2,4-diaminoguinazoline compounds in which

The 2-amino group is substituted with certain alkyl- and hydroxy-substituted alkyl groups, or it is a heterocyclic group such as piperidino or 4-substituted piperazino.

One of these compounds is well known by the generic name trimazosin and has the formula:

<img file="DK153399B_D0001.tif" />

Trimazosin is also an active antihypertensive agent, see e.g. Vlachikis et al., Current Therapeutic Research, 17, 564 (1975). However, it is less potent than prazosin. Althuis et al., J. Med. Chem., 20,

145 (1977) have shown that the 6-O-demethyl derivative is a predominant metabolite of prazosin with significantly lower blood pressure lowering effect. The 7-0 demethyl derivative is a less frequently occurring metabolite.

U.S. Patent Nos. 3,920,636 and 4,044,135 disclose homopiperazinoguinazoline compounds as being antihypertensive agents.

Several patents have been issued mentioning antihypertensive compounds of the general formula:

<img file="DK153399B_D0002.tif" />

(II)

U.S. Patent No. 4,001,237 discloses compounds in which R^a is an oxazole, isoxazole, thiazole or isothiazole group.

U.S. Patent No. 4,001,238 discloses such compounds wherein R has the formula:

Ν — N // \\ ^ Ao / ^ s-alkyl

U.S. Patent No. 3,780,040 discloses 3,4-dihydroguinazoline analogs of the above formula wherein R^a is 2-thienyl.

U.S. Patent Nos. 4,026,894 and 4,112,098 disclose compounds wherein R^a is a 2-tetrahydrofuryl or 2-tetrahydropyranyl moiety. In U.S. Pat.

060 615 discloses compounds in which R^a is (C₃-C 8) cycloalkyl and (C 1 -C 6) -cycloalkenyl. In U.S. Pat.

101 548 discloses 1,2,3-thiadiazolamides of the above formula wherein R^a is

R ~

<img file="DK153399B_D0003.tif" />

bc and R are hydrogen, lower alkyl, NH₂ or NHCO₂R, wherein R^c is lower alkyl.

6,7-Dimethoxy-2- (4-thiomorpholin-1-yl) -4-aminoquinazoline compounds and derivatives thereof in which the substituent in the 2-position is

-NS (O) wherein d is 0, 1 or 2 are listed as antihypertensive agents in U.S. Patent No. 4,115,565.

GB Patent Specification No. 1,530,768 discloses prazosin analogs in which the 2-amino group has the formula:

-N —COR^e wherein R^e is phenyl, substituted phenyl, furyl, thienyl or 5-alkylthio-1,3,4-oxadiazol-2-yl.

FR Patent Specification No. 2,321,890 discloses analogs of prazosin in which the 2-amino substituent is a piperidino or piperazino group substituted in 3- or

4-position.

The novel compounds of formula (I) are prepared by the process according to the invention, which is characterized by the characterizing part of claim 1.

The compounds of formula (I) prepared by the process of the invention are extremely potent antihypertensive agents and, due to their vasodilatory properties, they are also useful as antiglaucoma agents as well as for the treatment of heart failure by congestion.

The compounds have significant advantages over the prior art. The substituent in the 6-position of the present compounds is chlorine, which is not subject to metabolic attack. As a result, the present compounds are not subjected to a slight metabolic demethylation with consequent loss of activity, as has been demonstrated for prazosin. Accordingly, the present compounds of formula (I) have a longer duration of action than prazosin and other known 6,7dimethoxy and 6,7,8-trimethoxyguinazoline antihypertensive agents.

DK 153399Β

The present compounds also have significantly greater water solubility than prazosin. Thus, in the following Examples 1 and 2, water solubility data are given for some preferred compounds ranging from 5 mg / ml to 35 mg / ml. In comparison, the water solubility of prazosin hydrochloride is only 0.7 mg / ml.

As a result of their improved solubility, they are uniformly absorbed by all patients. They can be further administered in the form of time delay preparations as well as parenterally, including intravenously.

Those prepared by the process of the invention

2,4-Diaminoguinazoline compounds can be used in the form of pharmaceutical compositions for oral or parenteral administration to mammals and containing one or more of these novel compounds and a pharmaceutically acceptable carrier.

Preferred compounds are those of formula (I), wherein R and Y have the meaning given in claim 1, and

X is -COR where R is cyclopentyl, cyclohexyl, furyl, thienyl or 2-tetrahydrofuryl.

Also preferred are compounds of formula (I) wherein R and Y are as previously defined and X 5 is -COOR, where R is hydroxy-substituted alkyl of 2-5 carbon atoms.

Particularly preferred compounds prepared by the process of the invention are:

2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6-chloro-7-methoxyguinazoline

2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6-chloro-7,8-dimethoxyguinazoline

2- (4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] -4-amino-6-chloro-7-methoxyquinazoline and

2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl) -4-amino-6-chloro-7,8-dimethoxyquinazoline and their hydrochloride salts.

The invention also comprises the 4-aminoquinazoline compounds of the formula given in claim 6 for use as starting material in the process of the invention, in particular the compounds of the formula:

<img file="DK153399B_D0004.tif" />

wherein R and Y have the meaning given in claim 1. Other novel compounds useful for use in preparing the starting materials have the formulas:

<img file="DK153399B_D0005.tif" />

<img file="DK153399B_D0006.tif" />

CN nh₂ wherein R and Y have the meaning given in claim 1.

The term pharmaceutically acceptable, as used herein to describe an acid addition salt of a compound of formula (I), refers to those salts which have anions derived from a variety of relatively non-toxic inorganic or organic acids. The anion does not contribute measurably to the toxicity of the salt or to its pharmacological effect. Examples of such salts are salts formed with acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, cinnamic acid, fumaric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfonic acid and sulfonic acid , p-toluenesulfonic acid and related acids. The preparation of addition salts of monobasic acids can be carried out in a conventional manner by treating a solution or suspension of the free base in a reaction-inert organic solvent with a chemical equivalent of the acid or, if an addition salt of a dibasic acid is desired, with at least two chemical equivalents of the acid. Conventional concentration and crystallization methods are used to isolate the salts.

The following Reaction Scheme I illustrates the preparation of the starting compounds and the process of the invention. In the first reaction step, a 4-alkoxyanthranilic acid of formula (IX) containing the desired substituents R and Y as defined above is cyclized to the corresponding 2,4-dioxo-guinazoline of formula (X). The cyclization is accomplished by reacting the compound (IX) with sodium or potassium cyanate or urea according to the procedure of Curd et al., Jour. Chem. Soc., 777 (1947) for the corresponding 6,7-dimethoxyquinazoline indions. As will be apparent to those skilled in the art, the anthranilic acids of formula (IX) in this reaction can be satisfactorily replaced by the corresponding compounds in which the carboxylic acid moiety is replaced by a group CONH 2, CN or the carboxylic acid ester. The cyclized compounds of formula (X) are novel compounds which are of value as intermediates in the preparation of the present compounds having antihypertensive action. As will be appreciated by those skilled in the art, they may also be depicted as the corresponding tautomeric 2,4-dihydroxyquinazolines.

DK 153399 Β

REACTION SCHEDULE I

<img file="DK153399B_D0007.tif" />

(XII)

<img file="DK153399B_D0008.tif" />

ΛΛ

Ν Ν-Χ

In the preparation of the intermediates of formula (X), the starting material (IX) is suspended in a polar solvent in the presence of an acid, preferably aqueous acetic acid, and a 2-4 molar excess of the cyanate salt,

eg. potassium cyanate or urea, is added. The mixture thus prepared is then heated to a temperature of from about room temperature to the reflux temperature of the solvent until the reaction is substantially complete. Typical reaction times are from approx. 1 to approx. 24 hours. The mixture is then cooled, made alkaline with sodium hydroxide or potassium hydroxide, and the alkaline mixture is reheated to a temperature of from about 70 to 100 ° C for 1-5 hours. The sodium salt of the reaction product (IX) thus prepared is then acidified and isolated by well-known standard methods.

The intermediate of formula (X) is then reacted with a mixture of phosphorus pentachloride and phosphorus oxychloride or the corresponding phosphorus bromides to produce the corresponding 2,4-dihaloquinazolines. The preferred embodiment in which the above phosphorus chlorides are used is depicted in Reaction Scheme I for the preparation of intermediates of formula (XI), wherein R and Y are as defined above. Typically, the ion (X) and a 2-4 molar excess of phosphorus pentachloride and phosphorus oxychloride, respectively, are heated to reflux for 2 to 6 hours, the excess phosphorus oxychloride is evaporated, and the evaporation residue is slurried in a reaction-inert organic solvent, e.g. chloroform or dichloromethane, and then poured into ice water. Insoluble material is removed and the reaction product is isolated from the organic layer by evaporation or precipitation by the addition of a non-solvent, e.g. hexane, to precipitate the dichloro compound of formula (XI).

The key intermediates, 2-chloro-4-aminoguinozalines of formula (XII), are prepared by reacting equimolar amounts of ammonia and 2,4-dichloroguinozalin (XI) in the presence of a reaction-inert organic solvent. Examples of suitable reaction-inert solvents are diethyl ether, tetrahydrofuran, chloroform and benzene. Tetrahydrofuran is a preferred solvent.

In normal practice, an excess of ammonia of 1 to 10 moles will preferably be used to force the reaction towards completion. The temperature at which this reaction can be carried out is from approx. 25 to approx. 200 ° C for a period of 1 - 48 hours. A preferred reaction temperature and time for this reaction will be from about 25 to approx. 60 ° C for approx. 5 hours. After completion of the reaction, the reaction product is recovered by conventional means. For example, the solvent may be evaporated and the crude solid reaction product may be triturated with water or precipitated from dilute aqueous acid in crystalline form with subsequent recrystallization from any number of organic solvents such as methanol, dimethylformamide or mixtures thereof with water.

Conversion of the 2-chloroguinazoline intermediate of formula (XII) to the desired compound of formula (III) is carried out by contacting the intermediate (XII) with an equimolar amount of an amine of the indicated formula in the presence of an aqueous or organic solvent. A small molar excess of amine is usually used. Preferred organic solvents for this reaction include polar solvents such as tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide; alcohols such as methanol, ethanol and isoamyl alcohol, and ketones such as methyl ethyl ketone and methyl isobutyl ketone. Particularly preferred solvents are isoamyl alcohol and methyl isobutyl ketone. The reaction mixture is preferably heated to a temperature of from about 60 to approx. 160 ° C for 1 - 65 hours. Particularly preferred reaction temperatures are from approx. 100 to approx. 140 ° C, and temperatures are conveniently obtained in this range by keeping the reaction mixture at the reflux temperature of the particularly preferred solvents. At such temperatures the reaction is usually completed in from approx. 2 hours to approx. 2 days.

The starting materials of the formula (IX) required for the process of Reaction Scheme I, as previously described, are prepared by reaction sequences shown in the following Reaction Schemes II, III and IV, in the case where R is CH 2.

REACTION SCHEDULE II

<img file="DK153399B_D0009.tif" />

(IXb, R = CH₃)

In the above and the following reaction schemes, for convenience, lowercase letters, a, b and c, are used after the Roman numerals of the compounds shown to indicate the following:

a. R means alkyl having 1-3 carbon atoms, Y = OR, and the chlorine substituent in the 5-position is missing.

b. R has the meaning given above, and Y = OR.

c. R has the meaning given above, and Y = H.

DK 153399 Β

REACTION SCHEME III

<img file="DK153399B_D0010.tif" />

(XXIII) (XXI) (XXII)

REACTION SCHEDULE IV

<img file="DK153399B_D0011.tif" />

I ν

(XlVa, 3, j ÖH₃) i

(IXa, R = CK₃)

In the reaction sequence shown in Reaction Scheme II, vanillin is acetylated with, for example, acetic anhydride or acetyl chloride by well known methods, and the acetylated intermediate is nitrated to give 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (V). The acetyl group is removed by hydrolysis, e.g. by treatment with a strong base in aqueous solution such as sodium hydroxide, followed by acidification to give the 4-hydroxy-3-methoxy-2-nitrobenzaldehyde intermediate of formula (VI). This intermediate is then alkylated with one of the well-known alkylating agents commonly used to convert phenolic groups to the corresponding alkyl ethers. Examples of such alkylating agents are dimethyl sulfate, diethyl sulfate, methyl bromide, n-propyl iodide and ethyl iodide. In the case shown in Reaction Scheme II, a methylating agent is used to form 3,4-dimethoxy-2-nitrobenzaldehyde (VII). Compounds in which the two ether groups are different from each other are prepared using e.g. diethyl sulfate or n-propyl iodide as alkylating agent. Using ethylvanillin or n-propylvanillin instead of vanillin as a starting material in this reaction sequence gives the corresponding compounds in which the corresponding alkoxy groups are 4,5-diethoxy, 4,5-dipropoxy,

4-ethoxy-5-methoxy, 4-ethoxy-5-n-propoxy, 4-n-propoxy-5-methoxy and 4-n-propoxy-5-ethoxy,

The dialkoxy intermediate of formula (VII) is then oxidized e.g. to the corresponding carboxylic acid. Although a wide variety of oxidizing agents and oxidation conditions are known for carrying out oxidation of aromatic aldehydes to the corresponding carboxylic acids, the preferred oxidation conditions are those using potassium permanganate in aqueous acetone at the reflux temperature of the mixture. The 2-nitro-4,5-dialkoxybenzoic acid intermediate, e.g. the compound of formula (VIII), is isolated by well known methods and reduced to the corresponding 2-amino acid, e.g. compound of the formula (IXa,

R = CH 2) by well known means, e.g. by catalytic hydrogenation using a noble metal hydrogenation catalyst. A preferred catalyst is palladium.

The intermediates of formula (IXa) are useful as starting materials for the preparation of the corresponding 5chlor intermediates of formula (IXb) as shown in Reaction Scheme II. The carboxylic acid is first esterified to form an alkyl ester, e.g. the methyl ester or ethyl ester, by well known methods. The ester is then chlorinated using e.g. chlorine or sulfuryl chloride, and the latter reagent is preferred because of its efficiency and convenient handling. A small molar excess is typically added, e.g. a 20% molar excess, of sulfuryl chloride to the cooled solution of the carboxylate ester intermediate of the acid (IXa) in a chlorinated hydrocarbon solvent, e.g. chloroform, methylene chloride or 1,2-dichloroethane, and the mixture thus prepared is allowed to warm to room temperature and then heated to reflux until the reaction is substantially complete, e.g. for 1-24 hours. The raw

5-Chloroester is then hydrolyzed, e.g. by means of sodium hydroxide as described above, to give the corresponding 5-chloroacid of formula (IXb).

The 5-chloro-5-alkoxyanthranilic acids of formula (IXc) used as starting materials are prepared as shown in Reaction Scheme III. 4-Methoxy-2-nitroaniline (XVIII) is treated with sodium nitrite in concentrated hydrochloric acid under reaction conditions well known to those skilled in the art to form an intermediate in the form of diazonium salt, to which is added an aqueous solution containing an equimolar amount of cuprous cyanide and a typical % excess, of potassium cyanide while heating the reaction mixture on a steam bath. The reaction product 4-cyano-3-niDK 153399 Β troanisole (XIX) is then isolated, whereupon it is hydrolyzed e.g. in the presence of aqueous sulfuric acid or hydrochloric acid to form the carboxylic acid of formula (XXI). This is then hydrogenated as described above in connection with the conversion of the compound (VIII) to (IXa) to give 4-methoxyanthranilic acid (XXII), and the latter is chlorinated to give the desired compound (IXc,

R = CH 3), using the reaction conditions discussed above in the conversion of compounds of formula (IXa) to the 5-chloro compounds (IXb).

As shown in Reaction Scheme III, other synthetic routes can be used to prepare the desired starting material of formula (IX). In such an alternative process, the 4-cyano-3-nitroanisole (XIX) is hydrogenated as previously described by the conversion of the compound (VIII) into the compound (IXa) to give the aminonitrile of formula (XX). This is chlorinated as described above in the conversion of the compounds (IXa) to (IXb), and the 5-chloronitrile (XIVc, R = CH 2) thus prepared is hydrolyzed as described in the preparation of the compound (XXI) and the nitrile (XIX) to give the desired compound (IXc, R = CH 3).

Another synthetic route shown in Reaction Scheme III involves oxidation of the starting material 4-methyl-3-nitroanisole with potassium permanganate to give the intermediate (XIX) which is converted to the compound (IXc) as previously described.

As will be apparent to those skilled in the art, when the methoxy group present in the starting materials of formula (XVIII) and (XXIII) used in Reaction Scheme III is replaced by a methoxy or n-propoxy group, the corresponding compounds with the formula (IXc) wherein R is C₂H₃ respectively nC ^ Hy.

Similarly, replacement of each or both of the methoxy groups present in the starting material of formula (XXV) and used in Reaction Scheme IV with ethoxy or n-propoxy leads to the corresponding compounds of formula (IXa) or (IXb ).

Many of the necessary amines of the formula / \

HN NX in which X has the previously stated meaning are well known compounds, see e.g. the literature references mentioned in connection with the prior art. The novel ones are prepared by methods which will be readily understood by those skilled in the art.

The anti-hypertensive effect of the compounds prepared by the method of the invention is demonstrated by their ability to lower blood pressure in conscious, spontaneously hypertensive rats and in conscious renally hypertensive dogs when the compounds are administered orally at doses up to 30 mg / kg. .

For example, it has been found that 2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] -4-amino-6-chloro-7,8-dimethoxyquinazoline, which is a typical and preferred example of the present compounds, lowers blood pressure in renally hypertensive dogs to a statistically significant extent, e.g. when the compound of the compound was administered orally at dosages as low as 0.2 mg / kg, and this compound showed a decrease of 30 mmHg after 4 hours without any significant change in heart rate and without other side effects, similarly produced 2- [ 4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] -4-amino-6-chloro-7-methoxyguinazoline, which is a particularly preferred example of the present compounds, in the same dosage a reduction of 40 mmHg after 1 hour, which only increased by 20 mmHg 6 hours after administration; and another particularly preferred compound, 2- [4- (2-furoyl) -1-piperazinyl] -4-amino-6-chloro-7methoxyguinazoline, produced a 40 mmHg reduction in blood pressure which was increased by only 5 mmHg for 6 hours. after the oral dose of 0.2 mg / kg had been administered. Again in this case, with the latter two compounds, no significant change in heart rate or other unwanted side effects was found.

The compounds A, B and C prepared according to the invention were compared with the known antihypertensive agents prazosin and trimazosin for hypotensive activity in anesthetized renal hypertensive dogs by the procedure described by Prioli and Winbury, J. Applied Physiol, 15, 323 (1960). The compounds were administered as their hydrochloride salts by the oral route, and the blood pressure was determined just before the administration of the agent and at frequent intervals thereafter. At least two dogs were used for each experiment. The results are summarized in the following table.

<td colspan="4"> 18</td>

<td>Connection</td><td>Oral- dosage, mg / kg</td><td>Blood pressure fall, mmHg</td><td>Duration timer</td>

<td>A. Formula i, wherein:</td><td></td><td></td><td></td>

<td>R = CH₃, Y = AND₃, X = -CO₂CH (CH₃)₂OH</td><td> 0,2</td><td> 30</td><td> 4</td>

<td>B. Formula I, wherein:</td><td></td><td></td><td></td>

<td>R = CH₃, Y = H, x = -co₂ch (ch₃)₂OH</td><td> 0,2</td><td> 20-40</td><td> 6</td>

<td>C. Formula I, wherein:</td><td></td><td></td><td></td>

<td>R = CH-., Y = H, X = -cofl C)</td><td> 0,2</td><td> 35-40</td><td> 6</td>

<td>Prazosin</td><td> 0,625</td><td> 40</td><td> 6</td>

<td>Trimazosin</td><td> 2,5</td><td> 15-30</td><td> 6</td>

The compounds prepared by the method of the invention also show, in addition to their useful anti-hypertensive effect, efficacy in standard tests intended to show vasodilator activity, anti-glaucoma activity and utility in the treatment of congestive heart failure.

The present compounds may be administered alone, but they will usually be administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration as well as standard pharmaceutical practice. They may, for example, be administered orally in the form of tablets containing such excipients as starch or glucose, or in capsules, either alone or in admixture with

DK 153399Β excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, e.g. intramuscularly, intravenously or subcutaneously. They are best used for parenteral administration in the form of a sterile aqueous solution which may contain other solutes, e.g. sufficient salt or glucose to make the solution isotonic. For the treatment of glaucoma, they can be applied topically or they can be administered by any of the other modes of administration. For topical use, one of the present compounds is mixed under sterile conditions with a pharmaceutically acceptable liquid carrier or solvent such as water, a glycol or mixtures thereof, and toxicity control agents, preservatives and buffers are added as necessary. The solution or dispersion thus prepared is then sterile filtered and used for filling into sterile bottles.

The present compounds can be administered to humans by the treatment of hypertension or congestive heart failure by either the oral or the parenteral route, and they can be administered orally in dosage levels ranging from about 1 to about 50 mg / day for an average adult patient (70 kg). ), which can be administered in a single dose or up to three sub-doses. Intravenous dosage levels are expected to be approximately one-half to one-tenth of the daily oral dosage. For the average adult patient, individual oral dosage in tablet or capsule form will range from about 0.5 to about 250 mg of active ingredient. There will necessarily be variations, depending on the weight and condition of the patient being treated and the particular method of administration chosen, as will be known to those skilled in the art.

The process according to the invention is further illustrated by the following examples. The following preparations illustrate the preparation of starting materials.

EXAMPLE 1

A. 2- [4H, furoyl, EiEerazin-1, Yllzizamino, chloELZiS5 (xmb)

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g, 5.47 mmol) and 1- (2-furoyl) -piperazine (1.08 g, 5.99 mmol) was kept at reflux in 40 ml of isoamyl alcohol for 2 hours and then cooled overnight. The solid thus prepared was collected by filtration and recrystallized from methanol / ether to give 1.83 g (74%) of pure final product, mp 208 209 ° C.

Analysis, percent for C_igH₂₍₎ClN₅ISLAND₄, HCl, 1/2 H₂ISLAND:

Calculated: C 49.25 - H 4.79 - N 15.17

Found: C 49.03 - H 4.61 - N 15.35.

Water solubility: 8 mg / ml.

^B · 2₌J4₌_ (2-furoylXpigerazine₌l_zylX₌4-amino₌6₌chlor₌ 75} 2i ^ 22y92ii} 222ii2i_hydrochloride

The title compound was prepared analogously to reflux of 2,6-dichloro-4-amino-7-methoxyquinazoline and 1- (2-furoyl) piperazine in isoamyl alcohol, m.p. 224-231 ° C, 79% yield.

Analysis, percent for ^c18^H18^clN5^ISLAND3, HCl, H₂ISLAND:

Calculated: C 48.88 - H 4.79 - N 15.83

Found: C 49.47 - H 4.70 - N 15.62.

Water solubility: 5 mg / ml.

EXAMPLE 2

A. å ^ methyl ^ S ^ hydroxypropyl ^^ J ^ - ^ ino- ^ chlor ^^ SåiS2iik22X2Hi2É22li5zål ^ ilEiE £ Eå £ i-3 ~ 2 -.-- 2 £ Zi ^ i:&gt;

hydrochloride

A mixture of 2,6-dichloro-4-amino = 7,8-dimethoxyquinazoline (1.50 g, 5.47 mmol) and 2-methyl-2-hydroxypropyl-4-piperazine-1-carboxylate (1.22 g, 6 .03 mmol) was kept at reflux in 30 ml of methyl isobutyl ketone for two days. The yellowish solid was filtered off, resuspended in 40 ml of acetone and stirred for 15 minutes. The filtered solid was decolorized with charcoal and recrystallized twice from ethanol / ether to give 1.47 g (57%) of the final product, mp 211-213 ° C.

Analysis, percent for C

Calculated: C 47.90 - H 5.50 - N 14.70

Found: C 47.70 - H 5.74 - N 14.36.

Water solubility: 35 mg / ml.

B-ethyl-hydroxyprogyl-1-amino-β-chloro-T-methoxy22i2222ii2z23yl] -piperazine-122-carboxylate_x_hydrochloride

The title compound was similarly prepared by refluxing 2,6-dichloro-4-amino7-methoxyquinazoline and 2-methyl-2-hydroxypropyl-4-piperazine-1-carboxylate in methyl isobutyl ketone for 4 days, m.p. 243-245 ° C, 69% yield.

Analysis, percent for C₁₈H₂₄C1N₅ISLAND₄, HCl, H₂ISLAND:

Calculated: C 46.55 - H 5.86 - N 14.08

Found: C 46.89 - H 5.67 - N 15.22

Water solubility: 6 mg / ml.

C. 2 ^ _ [IzJ-benzodioxane ^^ carbonyljjjigerazin ^ l ^ Y ilz ^^ai? iB2ZÉZ £ klor272niethoxy2uinazolin_in_hydrochloride

The title compound was prepared by the same procedure as indicated under point A by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and N (1,4-benzodioxane-2-carbonyl) piperazine in methyl isobutyl ketone, m.p. - 196 ° C.

EXAMPLE 3 TetrahydrofuroylXpiperazin-11β-tetrahydrofuroyl

2i} i ° iz2zå2Éin? ® £ koxyguinazolin

To 35 ml of isoamyl alcohol was added 1.50 g (5.47 mmol)

4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g (6.02 mmol) of 1- (2-tetrahydrofuroyl) piperazine, and the mixture thus formed was heated under reflux and under a nitrogen atmosphere for 1 ,5 hours. The mixture was cooled, 2.6 ml of ethyl ether was added and the mixture thus prepared was stirred at room temperature overnight. It was then cooled in ice and the precipitated solid was collected by filtration. The crude material was recrystallized once from a mixture of isopropanol, methanol and ethyl ether. The recrystallized material was dissolved in water made strongly alkaline with sodium hydroxide solution with stirring, and the precipitated brownish solid was collected by filtration, dried, decolorized with activated carbon and recrystallized from isopropanol / ethyl ether to give 0.38 g of a yellow solid, mp 192 - 193 ° C.

Analysis, percent for ^C19^H24°4^N5^C1:

Calculated: C 54.09 - H 5.73 - N 16.60

Found: C 53.83 - H 5.73 - N 16.58.

Mass spectrum peaks (M⁺/ e); 421 (molecular ion),

406, 392, 378, 350, 321, 293, 280 and 266.

PREPARATION A

4-acetoxy-3-methoxybenz aldehyde (IV)

To a solution of vanillin (2.0Q kg, 13.15 mol) and acetic anhydride (2.6 liters, 27.5 mol) in methylene chloride (11.3 liters) was added drop by drop triethylamine (2.8 liters, 20 , 1 mol), keeping the temperature below 25 ° C. After adding 4-dimethylaminopyridine (20 g), the solution was kept under stirring at room temperature for 30 minutes. The reaction mixture was washed twice with water followed by 20% (w / w) hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane U15 liters) was added slowly while removing residual methylene chloride. After cooling, 2.45 kg (96% yield) of reaction product were filtered off. Recrystallization of a small sample from anhydrous ether gave the acetate as fine yellow needles, mp 76-78 ° C.

PREPARATION B

4-Acetoxy-32-methoxy-2-nitrobenzaldehyde (V)

Over a period of 1.5 hours, 4-acetoxy-3-methoxybenzaldehyde (1120 g, 5.77 mol) was added in small portions to 4 liters of red fuming nitric acid cooled to 0 ° C. After stirring for 1 hour below 5 ° C, the reaction mixture was added to a large amount of ice water and kept under stirring for a further 1 hour. The resulting yellow reaction product (1130 g, 82% yield) was filtered off and washed three times with water, and it was sufficiently pure for direct use in the next synthesis step. Recrystallization from ether / cyclohexane gave the pure nitroaldehyde, m.p. 84-86 ° C.

DK 153399 Β

PREPARATION C Hydroxy-32methoxy-2-nitrobenzaldehyde (VI)

4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (1120 g, 4.72 mol) was added in portions to a freshly prepared 33% (w / w) NaOH solution (4.5 liters). The slurry thus prepared was heated on a steam bath at 75 ° C for 10 minutes, after which it was diluted with 5 liters of water. The reaction mixture was acidified with 6.4 liters of 6 N hydrochloric acid while cooling, and the resulting product (794 g, 85% yield) was filtered off and washed with water. Recrystallization from ether / cyclohexane gave the desired reaction product as a pale yellow solid, mp 136-137 ° C.

PREPARATION D

i. 3,4-Dimethoxy-2-nitrpbenzaldehyde (VII)

Anhydrous sodium carbonate (956 g, 9, Q3 mol), toluene (5 liters), 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (1424 g, 7.22 mol) and dimethyl sulfate (810 ml, 8.67 mol) were kept under reflux for 4 hours. Toluene was removed in vacuo and the residual solid was dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was separated, washed with 2 liters of 1 N NaOH and 6 liters of brine, decolorized with charcoal, dried over magnesium sulfate and filtered. Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527 g of reaction product are obtained by filtration. The crude material was recrystallized from ethanol to give 1187 g (78%) of the title compound as a light yellow solid, mp 60-62 ° C.

ii. Using diethyl sulphate instead of dimethyl sulphate in the process described above 1549999Β, 4-ethoxy-3-methoxy-2 nitrobenzaldehyde was similarly obtained.

iii. When n-propyl bromide is used as the alkylating agent, the corresponding 4-n-propyloxy compound is obtained.

PREPARATION E

.4-dimethoxy-2-nitrobenzoic acid (VIII)

A solution of 823 g of potassium permanganate in about 8.5 liters of H₂0 was gradually added a refluxing solution of 3,4-dimethoxy-2-nitrobenzaldehyde (550 g, 2.60 mol) in 5.6 liters of acetone. The reaction mixture was kept under reflux for a further 4 hours and then filtered through diatomaceous earth while hot and the filter cake was washed with hot water. The acetone was removed in vacuo and a small amount of unreacted solid was filtered off. The aqueous solution was acidified with 2 N hydrochloric acid (1.8 liters) to give 505 g (85%) of the substantially pure compound described in the title. Recrystallization from water led to colorless crystals, m.p. 200-202 ° C.

PREPARATION F

3,4-Dimethoxyanthranyl acid (IXa, R = CH₃)

A solution of 3,4-dimethoxy-2-nitrobenzoic acid (1011 g, 4.45 mol) in 14 liters of 1.3 N ammonium hydroxide was reduced at a pressure of 60 psi (4 atmospheres) in the presence of 60 g of palladium-on-barium carbonate. . heard after 4 hours, filtered through diatomaceous earth

Uptake of hydrogen The reaction mixture was acidified with glacial acetic acid (1.2 liters) to give 685 g (78%) of the anthrailic acid, m.p. 183-184 ° C.

DK 153399 Β

PREPARATION G (^χχιΐ)

i. 4-cyano-3-nitroanisole (XIX)

To a cooled solution of 4-methoxy-2-nitroaniline (68.0 g, 0.404 mol) in 300 ml of water and 94 ml of concentrated hydrochloric acid was added dropwise a saturated solution of sodium nitrite (33.5 g, 0.485 mol). keeping the temperature at 0 ° C and the pH at 6 by adding sodium carbonate.

The cold solution of diazonium salt was carefully added through a jacketed pouring funnel to a hot solution of cuprous cyanide (36.2 g, 0.404 mol) and potassium cyanide (42.1 g, 0.646 mol) in 500 ml of water with vigorous stirring and intermittent heating. on a steam bath. The stirring yellow suspension was further heated for 15 minutes. The solid was filtered off, dried and dissolved in ethyl acetate, discarding the undissolved inorganic salts. After decolorization with charcoal, concentration of the ethyl acetate solution to 95.1 g (71%) of clear yellow-orange crystals, m.p.

135 137 ° C.

Analysis, percent for ΟθΗ ^ Ν₂Ο₃:

Calculated: C 53.93 - H 3.39 - N 15.73

Found: C 53.92 - H 3.47 - N 15.85.

ii. 4-methoxy-2-nitrophenoic acid (XXI)

4-Cyano-3-nitroanisole (52.3 g, 0.294 mol) was slowly added to a cooled solution of 53 ml of each of acetic acid, water and sulfuric acid. The solution was kept under reflux for 5 hours and then diluted with 160 ml of water. After cooling, the solid thus prepared was filtered and dissolved in 10% sodium hydroxide solution. After decolorization with charcoal, the solution was acidified. 6 N HCl, cooled and the yellow reaction product (51.0 g, 88% yield) were filtered off. A sample for analytical purposes was recrystallized from methanol / water, m.p. 196-197 ° C.

Analysis, percent for C

Calculated: C 48.74 - H 3.58 - N 7.11

Found: C 48.37 - H 3.57 - N 7.03.

iii. 4-methoxyanthranilic acid (XXII)

A solution of 4-methoxy-2-nitrobenzoic acid (19.3 g, 97.9 mmol) in 200 ml of 1 N NH 4 OH was reduced overnight in the presence of 5% Pd / BaCO 3. The reaction mixture was filtered and acidified with acetic acid to give 15.8 g (96%) of the anthranilic acid, m.p. 186-188 ° C.

iv. In a similar manner, using 4ethoxy-2-nitroaniline or the corresponding 4-n-propoxy or 4-isopropoxy compounds as starting material, the following products were obtained by the methods described above:

COOH

NH, '2

<img file="DK153399B_D0012.tif" />

PREPARATION H

i. Methyl 3,4-dimethoxyanthranylate

Through a solution of 3,4-dimethoxyanthranilic acid (100 g, 0.51 mol) in 1.5 liters of methanol, hydrogen chloride was bubbled through for 40 minutes. The reaction medium was kept under reflux for 4 days, adding hydrogen chloride in gaseous form from time to time. The solvent was removed in vacuo and the remaining white solid was dissolved in 500 ml of water, cooled and basified to pH 10 with sodium hydroxide solution. After cooling for a further 1 hour, the cream crude product (87.0 g, 82% yield) was filtered off. Recrystallization from methanol gave the pure reaction product, m.p. 66 DEG-67 DEG.

Analysis, percent for ^C20^Hi3^NO4^:

Calculated: C 56.86 - H 6.20 - N 6.63

Found: C 56.56 - H 6.15 - N 6.66.

ii. Methyl 4-methoxyanthranilate

Esterification of 4-methoxyanthranilic acid as described above led to methyl 4-methoxyanthranilate, m.p. 77-79 ° C, with a yield of 77%.

PREPARATION I

i. 5-Chloro-3,4-dimethoxyanthranilic acid (Xlb, R = CH 3)

To a cooled solution of methyl 3,4-dimethoxyanthranilate (42.2 g, 0.20 mol) in 400 mL of chloroform at 0 ° C was added drop by drop sulfuryl chloride (19.3 mL, 0.24 mol). The sulfur dioxide formed was discharged through a water trap. After stirring for 30 minutes at room temperature, the solution was kept under reflux for 2 hours. The black solution was treated with charcoal and the solvent was evaporated. 1 H NMR spectrum indicated that the black, oily evaporation residue consisted largely of the desired intermediate ester. The crude methyl ester was saponified with 400 ml of 5% (w / v) sodium hydroxide on a steam bath for 1 hour. After cooling, the basic suspension was acidified with acetic acid to precipitate a brown

Solids which were filtered off and recrystallized from carbon tetrachloride to give a light brown crystalline reaction product (29.0 g, 63.1% yield), m.p. 140-142 ° C. [Reported melting point 142 - 143 ° C,

J. Chem. Soc., 4310-14, 1964].

Analysis, percent for C

Calculated: C 46.66 - H 4.35 - N 6.05

Found: C 46.45 - H 4.45 - N 5.90.

ii. 5-chloro-4-methoxyanthranilic acid (IXc, R = CHg)

Treatment of methyl 4-methoxyanthranilate with sulfuryl chloride as described above gave methyl 4-methoxy-5-chloroanthranilate, m.p. 197 DEG-200 DEG C., in 90% yield.

Saponification of methyl 4-methoxy-5-chloroanthranilate gave 5-chloro-4-methoxyanthranilic acid in 64% yield, m.p. 210 DEG-213 DEG.

Analysis, percent for C 9 H 9 ClNO 2:

Calculated: C 47.66 - H 4.00 - N 6.95

Found: C 48 O 50 - H 4.11 - N 6.94.

In a similar manner, using methyl 4-ethoxyanthranilate or methyl 1-4-n-propyloxyanthranilate, they were obtained by the procedure described above.

S-chloro-1-ethoxyanthranilic acid and 5-chloro-4-n-propyloxyanthranilic acid.

PREPARATION J

Nzllii ^ benzodioxane 32-carbonylXpiperazine 1,4-benzodioxane-2-carboxylic acid prepared by oxidation of 2-hydroxymethyl-1,4-benzodioxane with potassium permanganate in aqueous potassium hydroxide at 5-15 ° C was converted to the acid chloride by reaction with thionyl chloride as standard.

A suspension of piperazine (11.88 g) and sodium acetate (20.3 g) in a mixture of water (70 ml) and acetone (95 ml) was kept under stirring at 10-15 ° C. Then concentrated hydrochloric acid (ca. 35 ml) was added until the pH of the solution reached 1.5. Then 1,4-benzodioxane-2-carbonyl chloride (31.0 g) and sodium hydroxide (5 N, about 45 ml) were added in portions, maintaining the temperature at 10-15 ° C, maintaining the sodium hydroxide at 1.7 2. 2. After the addition was complete, the pH was adjusted to 2.0 by the addition of sodium hydroxide, the suspension was kept under stirring for another 30 minutes. Then water was added until a homogeneous solution was obtained, the acetone was removed in vacuo and the aqueous phase was basified to pH 8-9 with sodium hydroxide (5 Ν), it was again extracted with chloroform (3 x 200 ml). and the extracts were washed with water, dried (MgSO 4) and evaporated in vacuo. The evaporation residue in the form of an oil was dissolved in ethyl acetate, treated with hydrogen chloride in ether, evaporated in vacuo and the solid evaporation residue was triturated with ether, followed by recrystallization from methanol to give N- (1,4-benzodioxane-2- carbonyl) piperazine, hydrochloride (4.85 g), m.p. 265 ° 267 ° C.

PREPARATION K

A. G ^ chloro ^ x ß ^ dimethoxyguinazoline ^^^ dione (Xb)

To a vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g, 0.125 mol) in 600 ml of water was added acetic acid (10.5 g, 0.175 mol).

Then 506 ml of 5% potassium cyanate solution (0.312 mol) were gradually added and stirred for 1 hour at 40 ° C. After cooling the reaction mixture to 20 ° C, 75 g (4.37 mol) of sodium hydroxide in pellet form were added, keeping the temperature below 40 ° C. The reaction mixture was heated to 90 ° C for 45 minutes. Upon cooling in an ice bath, the sodium salt of the reaction product precipitated, it was filtered off, resuspended in 125 ml of water, acidified with concentrated hydrochloric acid, cooled and filtered to give 25.8 g (80%) of a colorless,. pure product, melting point 272 - 273 ° C.

Analysis, percent for Ο ^ θΗ ^ ΌΐΝ₂Ο₄:

Calculated: C 46.79 - H 3.53 - N 10.92

Found: C 46.87 - H 3.60 - N 10.90.

B. Él2 ^ i2HlZl5) 2i ^ 25y22iS222iiSlBxålåi2S (Xc)

In a similar manner, 6-chloro-7-methoxyquinazoline-2,4-dione was prepared from 5-chloro-4-methoxuanthranilic acid in 83% yield, m.p. 356-358 ° C.

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Analysis, percent for C₂ISLAND₃:

Calculated: C 47.70 - H 3.11 - N 12.36

Found: C 47.72 - H 3.44 - N 12.27.

PREPARATION L

Α. 2_Λ4,6₌trichlor27_z8₌dimethoxyguinazoline (Xlb)

A mixture of 6-chloro-7,8-dimethoxyguinazoline-2,4-dione (25.5 g, 0.099 mol), phosphorus pentachloride (41.4 g, 0.199 mol) and 300 ml of phosphorus oxychloride was kept under reflux under a nitrogen atmosphere for 3 hours. timer. Phosphorus oxychloride was removed in vacuo and the remaining POCl 3 was azeotroped with toluene.

The reddish orange solid was dissolved in 200 ml of dichloromethane and the solution was slowly added to ice-cold water. After stirring for 10 minutes, the organic layer was separated, washed with water and dried over sodium sulfate. The filtrate was concentrated and 150 ml of hexane was slowly added to precipitate the reaction product as a pale yellow solid which was recrystallized from toluene / ether to give 18.0 g (62% yield), m.p. 154-155 ° C.

Analysis, percent for

Calculated: C 40.91 - H 2.40 - N 9.55

Found: C 41.05 - H 2.48 - N 9.61.

B · 2_X4_x62trichloro2Z2 methoxyguinazoline (XIc)

Refluxing of 6-chloro-7-methoxyquinazoline-2,4-dione with PCI.- in POCl- as described above led to 2,4,6 □ o trichloro-7-methoxyquinazoline in 74% yield, m.p. 150-152 ° C.

Analysis, percent for C

Calculated: C 41.02 - H 1.91 - N 10.63

Found: C 40.90 - H 2.01 - N 10.54.

PREPARATION M

A. ²&gt; 6-Dichloro-4-amino-7,8-dimethoxyquulnazole (XIIb)

Ammonia was bubbled through a solution of 2,4,6-trichloro-7,8-dimethoxyquinazoline (31.4 g, 0.107 mol) in 650 ml of dry tetrahydrofuran for 1 hour at room temperature. After stirring for an additional 1 hour, the suspension was concentrated under vacuum and filtered. The solid was resuspended in water, filtered and washed with water and methanol. Recrystallization from dimethylformamide / water gave 23.7 g (81%) of the desired reaction product, m.p. 360 ° C.

Analysis, percent for C 10 H₉C1₂N₃°_2!

Calculated: C 43.82 - H 3.31 - N 15.33

Found: C 43.95 - H 3.53 - N 15.35.

B. 2,6-Dichloro-4-amino-7-methoxyguinazoline (XIIc)

Reaction between 2,4,6-trichloro-7-methoxyquinazoline and ammonia as described above gave 2,6-dichloro-4amino-7-methoxyquinazoline as a white solid, m.p. 300 ° C and 58% yield .

Analysis, percent for C

Calculated: C 44.28 - H 2.89 - N 17.22

Found: C 44.12 - H 1.36 - N 17.19.