IE50366B1

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

Abstract

This record has no abstract on file.

IE50366B1, drawing sheet 1 — Sheet 1 of 30

Term

No projected expiry on record.

11 claims: 7 independent, 4 dependent

1
CLAIMS 1. A compound of the formula and the pharmaceutically acceptable acid addition salts thereof, wherein:R is alkyl having from one to three carbon atoms;1 2 2 R is hydrogen or chloro and R is hydrogen or OR, R being OR, when R 3 Is hydrogen, and hydrogen or OR when R 3 is chloro;X 1 is CHCH n C,H c , NR 3 , NCOR 4 or NCOOR 5 ;4 0 0 R is hydrogen, alkyl having from 1 to 6 carbon atoms, alkenyl from 3 to 5 carbon atoms, hydroxy-substituted alkyl having from 2 to 5 carbon atoms, phenyl, 3-trifluoromethyl-phenyl or benzyl;R 4 is hydrogen, alkyl having from 1 to 6 carbon atoms, cyclopentyl, phenyl, 2-furyl, 2-thienyl, 2-pyrrolidinyl, tetrahydro-2-furyl or l,4-benzodioxan-2-yl;R 3 is alkyl having from 1 to 7 carbon atoms, or hydroxy-substituted alkyl having from 2 to 5 carbon atoms;and n is 2 or 3, with the proviso that n is 2 when X 3 is when R 3 Is phenyl, 3-trifluoromethyl-phenyl or benzyl 4 and when R is cyclopentyl or phenyl. 1 4 4
4
2-(4-(2-Furoyl)-l-piperazinyl]-4-amino-6-chloro-7methoxy-quinazoliue.
5
2-[4-(2-Hydroxy-2-methylprop-l-yloxycarbonyl)piperazinl-yl]-4-amino-
6
6-chloro-7-methoxyquinazoline. 5 6. A pharmaceutical composition for oral or parenteral administration to a mammal comprising a pharmaceutically acceptable carrier and an antihypertensive effective amount of a compound according to any of claims 1 to 5.
8
A compound of the formula given and defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference 15 to Exanples 1-14 of the accompanying Exanples.
9
A process for the preparation of a conpound of the formula given and defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described and exemplified. 20
10
A conpcund of the formula given and defined in Claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by a process claimed in Claim 9.

Independent claims7

598 paragraphs in 44 sections, as filed

This invention relates to certain 2,4-diaminoquinazolines. Particularly, the invention relates to certain 7-alkoxy-2,4-diaminoquinazolines which are further substituted by a 6-chloro group and/or an 85 alkoxy group, these compounds for use as antihypertensive agents, and pharmaceutical compositions thereof.

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

where Z is a nitrogen-containing heterocyclic group. One of these compounds, 2-[4-(2-furoyl)piperazin-lyl]-4-amino-6,7-dimethoxyquinazoline, is a clinically useful antihypertensive agent and is marketed under the generic name prazosin, the pharmacology of which is discussed in Constantine et al., Hypertension: Mechanisms and Management, edited by Onesti, Kin and Moyer, Grune and Stratton, 1973, pp. 429-444.

U.S. 3,669,968 and U.S. 3,769,286 disclose 6,7,820 trialkoxy-2,4-diaminoguinazolines in which the 2-amino group is substituted by certain alkyl and hydroxy substituted alkyl groups or is a heterocyclic group such as piperidino or 4-substituted piperazino. One of these compounds is known by the generic name trimazosin and has the formula

Trimazosin is also an active antihypertensive agent, see e.g., Vlachikis et al., Current Therapeutic Research, 5 17 > 564 (1975). However, it is less potent than prazosin. Althuis et al., J. Med. Chem., 20, 146 (1977) have shown the 6-0-demethyl derivative is a major metabolite of prazosin of considerably lower blood pressure lowering activity. The 7-0-demethyl derivative is a less prevalent metabolite.

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

Several patents have issued which disclose anti15 hypertensive compounds of the general formula

U.S. 4,001,237 claims compounds wherein Ra is an oxazole, isoxazole, thiazole or isothiazole radical.

In U.S. 4,001,236, such compounds are disclosed wherein Ra is of the formula

N- N

S-alkyl

U.S. 3,780,040 discloses 3,4-dihvdroquinazoline analogs of the above formula wherein Ra is 2-thienyl.

Xn U.S. 4,026j894 and U.S. 4,112,027, Ra is a 2tetrahydrofuryl or 2-tetrahydropyranyl moiety. U.S.

4,060,615 claims compounds in which Ra is eyeloalkyl having 3 to 8 carbon atoms and cycloalkenyl having 4 to 8 carbon atoms. U.S. 4,101,548 is concerned with 1,2,3-thiadiazole amides of the above formula wherein

H c and R is hydrogen, lower alkyl, NHCC^R in which Rc is lower alkyl.

6,7-Dimethoxy-2- (4-thiomcrpholin-l-yl) · 4-aminoquinazolines and derivatives in which the 2-substituent is

-N S{O) . , d is 0, lor 2

W d are disclosed as antihypertensive agents in U.S. 4,115,565. .

Patent Specification No. 45051 discloses prazosin 2U analogs in which the 2-ajnino group is of the formula

-N —CORe where Re is phenyl, substituted phenyl, furyl, thienyl or 5-alkylthio-l,3,4-oxadiazol-2-yl.

French Patent No. 2,321,890 discloses analogs of 25 prazosin in which the 2-amino substituent is a piperidino or piperazino croup substituted in the 3 or 4 oositior..

The compounds of the invention are highly potent antihypertensive agents having improved duration of action since they are not susceptible to metabolic demethylation at the 6-position with resultant loss of activity as is the case with prazosin. In addition, the invention compounds have improved water solubility when compared to prazosin. They can therefore be administered intraveneously, particularly for emergency purposes and are uniformly absorbed by all patients.

The present invention discloses new 2,4-diaminoquinazoline compounds and processes for their production. The new 2,4-diaminoquinazolines possess valuable pharmacological properties and other aspects of the invention relate to pharmaceutical compositions for oral or parenteral administration to a mammal comprising one or more of said new compounds and a pharmaceutically acceptable carrier.

The compounds of the invention are also useful for their vasodilation properties, as antiglaucoma agents and in the treatment of congestive heart failure.

366

The novel compounds disclosed are of the formula:-

and the pharmaceutically acceptable acid addition salt thereof, wherein:

R is alkyl having frem one to three carbon atoms;

2 2 R is hydrogen or chloro and R is hydrogen or OR, R being OR, when R1 is hydrogen, and hydrogen or OR when is chloro;

X1 is CHCH2C6H5, NR3, NCOR4 or NCOOR5;

R3 is hydrogen, alkyl having from 1 to € carbon atoms, alkenyl from 3 to 5 carbon atoms, hydroxy-substitued alkyl having from 2 to S carbon atoms, phenyl, 3-trifluromethyl phenyl or benzyl;

R4 is hydrogen, alkyl having from 1 to 6 carbon atoms, cyclopentyl, phenyl, 2-furyl, 2-thienyl, 2-pyrrolidinyl, tetrahydro-2-furyl or 1,4-benzodioxan-2-yl;

R3 is alkyl having from 1 to 7 carbon atoms, or hydroxysubstituted alkyl having from 2 to 5 carbon atoms; and n is 2 or 3, with the proviso that n is 2 when X1 is CHCHjCgHg, when R3 is phenyl, 3-trifluoromethyl-phenyl or benzyl and when R is cyclopentyl or phenyl.

Preferred compounds of the invention are those in which

X1 is NCOR4 and R4 is 2-furyl and those in which X3 is

NCOOR and R is 2-methyl-2-hydroxypropyi in each case n being 2.

Particularly preferred compounds of the invention are:

2-(4-(2-furoyl)piperaz in-1 -yl ] -4-amino-7,8dimethoxyquinazoline,

2-(4-(2-furoyl)piperaz in-l-y1]-4-amino-6-chioro7-methoxyquinazoline,

2-[4-(2-furoyl)piperazin-l-yl]-4-amino-6-chloro7,8-dimethoxyquinazoline,

2-(4-(2-hydroxy-2-methylprop-l-yloxycarbonyl)10 piperazin-l-yl]-4-amino-7,8-dimethoxyquinazoline,

2-(4-(2-hydroxy-2-methylprop-l-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazo1ine and

2-[4-(2-hydroxy-2-methylprop-l-yloxycarbonyl) 15 piperazin-l-yl]-4-amino-6-chloro-7,8-dimethoxyguinazoline, and their hydrochloride salts.

The term pharmaceutically acceptable used herein to describe an acid addition salt of a compound of formula (I) refers to those salts having anionic species of a variety of relatively non-toxic inorganic or organic acids. The anion does not contribute appreciably to the toxicity of the salt or to its pharmacological activity. Illustrative of such salts are those formed with acetic, lactic, succinic, maleic,

S0366 tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, and related acids. Preparation of the mono-acid addition salts may be carried out in conventional manner by treating a solution or suspension of the free base in a reaction inert organic solvent with one chemical equivalent of the acid or if the di-acid addition salt is desired, at least two chemical equivalents of the acid. Conventional concentration or crystallization techniques are employed in isolating the salts.

The compounds of formula (I) are especially useful as antihypertensive agents having significant advantages over the prior art. The Y^ substituent, at the 6-position of the invention compounds, is either hydrogen or chloro, groups which are not prone to metabolic attack. Consequently, the invention compounds are not subject to facile metabolic demethylation with resultant loss of activity, as has been shown for prazosin. Accordingly, the compounds of formula (I) have greater duration of action than prazosin and other 6,7-dimethoxy- and

6,7,8-trimethoxyquinazoline antihypertensive agents known in the art.

The invention compounds also have significantly greater water solubility than prazosin and as a result of their improved solubility, are uniformly absorbed by all patients. Furthermore, they can be administered in time release form, as well as parenterally, including intravenously.

The antihypertensive compounds of the invention are prepared by synthetic methods described below.

Scheme 1, below, outlines a preferred reaction seguence. In the first step a 4-alkoxyanthranilic acid of formula (IX) containing the desired substituents R* and R as defined above is cyclized to the corresponding

2,4-dioxoquinazoline of formula (X). The cyclization is brought about 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-dimethoxyquinazolinediones. Of course, as will be apparent to one skilled in the art, the anthranilic acids of formula (IX) may be replaced in this reaction by the corresponding compounds in which the carboxylic acid moiety is replaced by a CONHj, CN, or carboxylic ester group with satisfactory results. The cyclized compounds of formula (X) are novel compounds, of value as intermediates for preparing the antihypertensive compounds of the invention. As will be recognised by one skilled in the art, they may also be represented as the corresponding tautomeric 2,4-dihydroquinazolines.

In preparing the intermediates of formula (X), the starting material (IX) is suspended in a polar solvent in the presence of acid, preferably wateracetic acid, and a 2-4 molar excess of the cyanate salt, e.g., potassium cyanate or urea added. The resulting mixture is then heated at a temperature of from about room temperature up to the reflux temperature of the solvent until reaction is substantially complete. Typical reaction times are from about 1 to 24 hours. The mixture is then cooled, made alkaline with sodium hydroxide or potassium hydroxide and the alkaline mixture heated again at a temperature of from about 70 to 100*C. for 1 to 5 hours. The resulting sodium salt of the product (X) is then acidified and isolated by standard methods known in the art.

The intermediate of formula (X) is then reacted with a mixture of phosphorus pentachloride and phosphorus oxychloride or the corresponding phosphorus bromides to prepare the corresponding 2,4-dihaloouinazolines. The preferred embodiment, in which the above phosphorus chlorides are employed, is depicted in

Scheme I to provide the intermediates of formula -(XI)

2 in which R, R and R are as defined above. Typically the dione (X) and a 2 to 4 molar excess each of phosphorus pentachloride and phosphorus oxychloride are heated at reflux for 2 to 6 hours, the residual phosphorus oxychloride evaporated and the residue slurried in a reaction inert organic solvent, for example, chloroform or dichloromethane, and poured into ice-water. Insoluble material is removed and the product isolated from the organic layer by evaporation or precipitation by addition of a non-solvent, for example, hexane, to precipitate the dichloro compound of formula (XI).

366

The key 2-chloro-4-aminoquinazoline intermediates of formula (XII) are provided by reacting equimolar amounts of ammonia and 2,4-dichloroquinazoline (XX) in the presence of a reaction inert organic solvent.

Examples of suitable reaction inert solvents are ethyl ether, tetrahydrofuran, chloroform and benzene. A preferred solvent is tetrahydrofuran. In ordinary practice a preferred excess of ammonia of from one to ten moles would be used in order to shift the reaction toward completion. The temperature at which this reaction can be carried out is from about 25 to 200°C. for a period of from one to 48 hours. A preferred reaction temperature and time for this reaction would be about 25 to 60°C. for about five hours. Upon completion of the reaction the product is recovered by conventional means. For instance, the solvent can be evaporated and the crude solid can be triturated with water or precipitated from dilute aqueous acid in crystalline form and subsequently recrystallized from any number of organic solvents such as methanol, dimethylformamide or their mixtures with water.

Conversion of the 2-chloroquinazoline intermediate of formula (XII) to the desired compound of formula (I) is accomplished by contacting the intermediate (XII) with an equimolar amount of a cyclic amine of formula (III) in the presence of an aqueous or an organic solvent. A small molar excess of amine is generally employed. Preferred organic solvents for this reaction include polar solvents like tetrahydro30 furan, dioxane, dimethylacetamide, dimethylformamide; alcohols such as methanol, ethanol and isoamyl alcohol and ketones such as methylethylketone and methylisobutylketone. Particularly preferred solvents are isoamyl alcohol and methylisobutylketone. The reaction mixture is heated preferably at a temperature of from 60 to 160*C. for from one to 65 hours. Particularly preferred reaction temperatures are from about 100 to 140eC. and temperatures in this range are conveniently obtained by maintaining the reaction mixture at the reflux temperature of the particularly preferred solvents. At such temperature the reaction is ordinarily complete in from about two hours to two days.

Alternate procedures for preparing the compounds of the invention may also be used with satisfactory results. For example, the alternate methods disclosed in D.S. 3,511,836 for preparation of prazosin and its analogs can also be used with the appropriate starting materials to provide the invention oompounds of formula (I). These methods are enumerated and discussed briefly below.

1. 2-Amino-4-chloroguinazolines (XXIX) prepared by methods analogous to those described in D.S. 3,511,836 for the corresponding 6,7-dialkoxy- compounds may be reacted with ammonia under conditions described above for the conversion of compounds (XI) to (XII) with re25 sultant formation of the desired product of formula (I), (I)

are as defined above.

NH,

2. The quinazolinedione of formula (X) can be reacted with a reagent such as phosphorus pentasulfide to form the corresponding 2,4-quinazolinedithione which are in turn reacted with an alkyl or benzyl halide to form the corresponding 2,4-dithioalkylguinazoline or 2,4-dithiobenzylguinazoline. This is then reacted with ammonia by the procedure previously described for the reaction of the 2,4-dichloroguina2olines (XI) to provide the corresponding 4-amino-2-thioalkyl (or thiobenzyl) guinazoline (XX). The latter compound is then converted to the desired compound (I) by employing conditions previously described for the formation of conpound (I) from 2-chloro compounds of formula (XII).

1 where R, R , R end X are as previously defined.

3. Compounds of formula (I, other than those in which X3 ' 1 is NH, can also be prepared from the compound wherein X is 2o NH by acylation, alkylation or carbonyloxylation:

The compound (XXI) is reacted with a compound of formula R3-X3, R4COX3 or X3COOR5, where R3, R4 and RS are as defined above and X3 is a leaving group, preferably the halides, Cl or Br. When the preferred halides are employed it is advantageous to use at least a slight molar excess to ensure complete reaction. The intermediate (XXI) and reagent of formula R3X3, R4COX3 or X3COOR3 are contacted in the presence of a reaction inert organic solvent, for example, benzene, tetra10 hydrofuran, acetone methylethyl ketone, methylisobutyl ketone, 1,2-diaethoxyethane or diethyleneglycol dimethylether. A preferred such solvent is methylisobutyl ketone. The reaction may be carried out successfully over a wide range of temperatures. However, a tempera15 ture in the range of about O’C. up to the reflux temperature of the solvent is preferred for reasons of efficiency and convenience. At such a preferred temperature the reaction is ordinarily complete in from about 30 minutes to six hours. The resulting solid product is then isolated as either the hydrohalide or the free base by conventional methods and purified, if desired, by crystallization, column chromatography or the like.

4. In this method the 2-aminobenzonitrile intermediate of formula (XIV) is reacted with a cyclic guanidine of the formula h x12 2Λ / (CH )

2 n where X is as defined above. The benzonitrile (XIV) and an equivalent amount, but preferably a molar excess, of the guanidine are contacted in the presence of a reaction inert organic solvent, for example, ethylene glycol, diethyleneglycol, dimethylformamide, dimethylsulfoxide or diethyleneglycol dimethylether, at a temperature of from 120-180°C. for from about four to 15 hours. The desired product of formula (I) is then isolated by well known'methods, for example, the solvent is evaporated, the residue contacted with water and the precipitated product is filtered, recrystallized and dried. The reaction is illustrated as follows:

The guanidine starting materials are prepared by methods well known in the art. For example, the cyclic amine of formula (III) is reacted with cyanogen bromide to form the corresponding N-cyano-compound which, in turn, is reacted with hydroxylamine, followed by catalytic hydrogenation using the methods and conditions of Carrington, Jour. Chem. Soc., London, 2527 (1955) for the conversion of anthranilonitrile into 2-aminobenzamidine.

Variations of the above method can also be carried out employing either of the following starting materials in place of the 2-aminobenzonitrile (XTV).

The 2-chlorobenzonitriles are obtained, for example, by diazotization of (XIV) in the presence of cuprous chloride. The 2-aminobenzamidines are obtained, for example, by the method of Carrington, above.

5. 2-Chloro-4-alkoxy-7,8-disubstituted quinazolines, which are prepared by methods described by Curd et al.,

Jour. Chem. Soc., 775 (1947) for the isomeric 2-chloro4-alkoxy-6,7-disubstituted quinazolines, can be reacted with cyclic amine (III)to obtain the corresponding

2-aminoquinazolines. The 4-alkoxysubstituent is then 15 replaced by NH^ by reaction with ammonia as described above for the 4-chloro compounds of formula (XXIX). This is exemplified below for a 2-chloro-4starting material.

reaction sequence ethoxyqu ina zoline

R , R and X are as previously defined. The 4-thioalkylquinazolines corresponding to the above 4-alkoxy compounds can also be employed as starting materials in this sequence.

6. The compounds of the invention are also provided by methods disclosed in U.S. 3,935,213 for prazosin, trimazosin and analogs thereof as set forth below 12 1 where R, R , R and X are as previously defined;

NH,

ΛΆ / \ 1 + A—N X

1 iCB2>n

A1 is selected from the group consisting of CN and C(=NH)XR3 wherein X is 0 or S and R^ is alkyl having from one to six carbon atoms; and Q is CN or -C(=NH)NH2· Preferably the reaction is carried out in the presence of from about 0.5 to 5 molar equivalents of a basic catalyst, e.g., sodium hydride, potassium ethoxide or triethylamine, and at a temperature in the range of from about 50 to 180°C. The products of formula (I) are isolated by well known methods, for example, those described in U.S.

3,935,213.

7. Compounds of formula (I) are also obtained by employing the appropriate starting material of formula (XXV) in the process described in Belgian Patent No. 861,821 and No. 861,822 for synthesis of prazosin. The method is outlined in Scheme 1 2 ii. The o-aminobenzonitrile (XIV) wherein R, R and R are as defined above is reacted with at least an equimolar amount of thiophosgene in a reaction inert organic solvent, e.g.,

1,2-dichloroethane. To the mixture is added a base, e.g., calcium carbonate, water and

Scheme II

20 the mixture stirred typically at about 0-5°C., then warmed to about room temperature until reaction is substantially complete. The o-isothiocyanatobenzonitrile (XV) produced is isolated in crude form for use in the next step. The intermediate (XV), dissolved in a reaction inert organic solvent, typically ethyl acetate, is contacted amine of formula (IXI) at a below O°C., preferably at with the cyclic temperature about -30 to -5’C. to obtain the o-thioureidobenzonitrile (XVI). This is then contacted with a methylating agent, for example methyl iodide or methyl bromide, and the resulting S-methyl hydrohalide salt treated with a mild base to obtain the S-methyl thioformamidate of formula (XVII) which is cyclized by reaction with anhydrous ammonia in the presence of a polar solvent and an alkali metal amide to provide the desired compounds of formula (I). Preferred polar solvents for the cyclization are formamide or Ν,Νdimethylformamide. Also preferred for the final step are use of from 1 to 3 equivalents of alkali metal amide, especially sodium amide and a temperature of from 100 to 150°C.

8. In U.S. 4,138,561 a novel process for preparing prazosin and trimazosin is disclosed. This method is also suitable for preparation of the compounds of the present invention as shown below.

(XXXIII)

Scheme III

Cyclizing Agent

The starting materials of formula (XXXIII) wherein R, R and R are as previously defined are known compounds (see, for example, Gibson et al.,

J. Chem. Soc., 111, 79 (1917); Munavalli et al., 5 Bull· Soc. Chim., France, 3311 (1966); Chem. Abstr., 66, 46303s (1967); and German Offenlegungsschrift 1,959,577; Chem. Abstr., 75, 63397d (1971)]. The starting material (XXXIII) is converted to the isothiocyanate (XXXIV) as described above.for inter10 mediate (XV) and this is reacted with the cyclic amine (III) to provide the substituted thiourea (XXXV) by the method described above for intermediate (XVI). The intermediate (XXXV), in turn, is reacted with an alkylating agent, Y4X4 to obtain an intermediate of

A formula (XXXVI) in which X* is alkyl having from one to four.carbon atoms -or an aryl derivative containing electron withdrawing groups, for example,

A

2,4-dinitrophenyl, and X is a member selected from the group Cl, Br, I, alkyl-SO4 having from one to four carbon atoms, CgEgSO^, F^CSOj and FSO^. An especially preferred alkylating agent, Y4X4, is methyl iodide. Alternatively, as disclosed in O.S. 4,138,561, phosgene may be used in the first step in the above reaction sequence of Scheme III, wherein each of the intermediates (XXXIV) to (XXXVI) is the corresponding compound in which an atom of oxygen replaces the sulfur atom shown therein. The intermediate of formula (XXXVI) is then reacted with cyanamide to provide the corresponding carboxamidine intermediate of formula (XXXVII).

Alkylation of thiourea derivatives (XXXV) and subsequent reaction with cyanamide is normally carried out in a reaction inert organic solvent.

Suitable solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide, and the alkanols having from one to five carbon atoms. These reactions are preferably carried out at a temperature of from about 25 to 100aC. for a period of about 0.5 to 24 hours. The intermediate of formula (XXXVII) may also be obtained by alternate procedures described in D.S. 4,138,561.

The conversion of carboxamidine intermediates (XXXVII) to the desired quinazolines of formula (I) is carried out by reaction with cyclizing reagents such as phosphorus trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride.

Other phosphorus halides and phosphorus oxyhalides such as phosphorus tribromide and phosphorus pentabromide in a solvent amount of phosphorus oxybromide may be employed. The ring closure may also be carried out by reacting the intermediate (XXXVII) with acidic reagents such as aqueous hydrogen chloride, hydrogen chloride in phosphorus oxychloride, trichloroacetic acid or Lewis .acid catalysts such as ZnCl^, FeCl^,

AlCl^ or AlBr^.

with respect to carrying out the reaction with phosphorus halides, approximately equimolar amounts of the carboxamidine (XXXVII) and phosphorus halides are employed with a convenient amount of phosphorus oxyhalide relative to the amount of starting material (XXXVII). The term solvent amount as used herein refers to a quantity of phosphorus oxychloride or phosphorus oxybromide sufficient to provide good mixing and handling characteristics with respect to the reaction mixtures. For this purpose a ratio of from about 2 to 15 ml. of the phosphorus oxyhalide

0366 tor each gram of carboxaroidine reactant of formula (XXXVII) is generally preferred.

Commonly used temperatures for carrying out the cyclization reaction range from about 25 to 125*C. with a preferred temperature of from about 70 to 100°C. As will be appreciated by those skilled in. the art, reaction times and conditions required for cyclization of intermediates (XXXVII) to form the desired products of formula (I) vary according to several factors such as temperature and reaction time. For example, at lower temperatures, longer reaction periods are needed, while at higher temperatures, the cyclization reaction is completed in a shorter time. Reaction periods of from about 0.5 to 24 hours can be used, however a period of from about 1 to 3 hours is preferred at the above mentioned preferred reaction temperatures.

The required starting materials of formula (IX) for the procedure of Scheme I, above are obtained by the reaction sequences illustrated in Schemes IV, V and VI below, for the case where R is CH^.

Scheme IV

In the reaction schemes above and below, for the sake of convenience, the lower case letters a, b and c are used after the Roman numerals for the compounds shown to denote the following:

a. R1 = H, R2 = OR where R is alkyl having from one to three carbon atoms.

b. R^ = Cl, R2 = OR, R is as defined above.

R1 = Cl, R2 = H.

Scheme V

(XXIII) (XXI) (XXII)

Scheme VI

(IXa, R « CS3)

In the reaction sequence of Scheme IV vanillin is acetylated with, for example acetic anhydride cr acetyl chloride by well known methods and the acetylated intermediate nitrated bo obtain 4-aceroxy3-methoxy-2-nitrobenzaldehyde (V). The acetyl group is removed by hydrolysis, for example by treatment with an aqueous strong base such as sodium hydroxide, followed by acidification to provide the A-hydroxy10 3-methoxy-2-nitrobenzaldehyde intermediate of formula {VI). This intermediate is then alkylated with one of the well known alkylating agents commonly employed for the conversion of phenolic groups to the corresponding alkyl ethers. Examples of such alkylating agents are dimethylsulfate, diethyl sulfate, methyl bromide, n-propyl iodide and ethyl iodide. In the case illustrated in Scheme IV a methylating agent is employed to provide 3,4-dimethoxy-2-nitrobenzaldehyde, (VII). Compounds in which the two ether groups are different are obtained by use of, for example, diethyl sulfate or n-propyl iodide as the alkylating agent. When ethyl vanillin or n-propyl vanillin are employed in place of vanillin as starting material in this reaction sequence the corresponding compounds are likewise obtained wherein the corresponding alkoxy groups are 4,5-diethoxy, 4,5-dipropoxy, 4ethoxy-5-methoxy, 4-ethoxy-5-n-propoxy, 4-n-proproxy5-methoxy and 4-n-propoxy-5-ethoxy.

The dialkoxy intermediate of formula VII, e.g., is then oxidized to the corresponding carboxylic acid. While a wide variety of oxidizing agents and conditions are known in the art to bring about oxidation of aromatic aldehydes to the corresponding carboxylic acids, preferred oxidizing conditions are those employing potassium permanganate in aqueous acetone at the reflux temperature of the mixture.

The 2-nitro-4,5-dialkoxy-benzoic acid intermediate, e.g. the compound of formula (VIII) is isolated by known means and reduced to the corresponding 2-amino acid, for example, the compound of formula (IXa, R =

CH3), by well known means, e.g. by catalytic hydrogenation employing a noble metal hydrogenation catalyst. A preferred catalyst is palladium.

The intermediate of formula (IXa) is useful as a starting material in the reaction sequence shown in Scheme I, above, to provide the corresponding invention compounds of formula (Xa).

Alternatively, as shown in Scheme IV, the intermediates (IXa) serve as a starting material for the corresponding

5-chloro intermediates of formula (IXb). The carboxylic acid is first esterified to form an alkyl ester, e.g. the methyl or ethyl ester, by well known means.

The ester is then chlorinated employing, for example chlorine or sulfuryl chloride and the latter reagent is preferred for reasons of efficiency and ease of handling. Typically a slight molar excess, e.g. a 20% molar excess, of sulfuryl chloride is added to a cooled solution of the intermediate carboxylate ester of the acid (IXa) in a chlorinated hydrocarbon solvent, e.g. chloroform, methylene chloride or 1,2dichloroethane, the resulting mixture is allowed to warm to room temperature, then heated at reflux until reaction is substantially complete, e.g. from one hour to 24 hours. The crude 5-chloro ester is then hydrolyzed, e.g. by means of sodium hydroxide as described above to provide the corresponding 5chloro acid of formula (IXb).

The starting 5-chloro-5-alkoxyanthranilic acids of formula (IXc) are obtained as shown in Scheme V. 4-Methoxy-2-nitroaniline (XVIII) is treated with sodium nitrite in concentrated hydrochloric acid under conditions well known to those skilled in the art, to form an intermediate diazonium salt to which is then added an aqueous solution containing an equimolar amount of cuprous cyanide and a molar excess, typically a 50% excess, of potassium cyanide while warming the reaction mixture on a steam bath.

The product 4-cyano-3-nitroanisole (XIX) is then isolated and then hydrolyzed, e.g. in the presence of aqueous sulfuric or hydrochloric acid to obtain the carboxylic acid of formula (XXI). This, in turn, is hydrogenated as described above for the conversion of compound (VIII) to (IXa) to provide 4methoxy anthranilic acid (XXII) and the latter chlorinated to provide the desired compound (IXc,

R = CH3) employing the conditions described above for the conversion of compounds of formula (IXa) to

5-chloro compounds (IXb).

As shown in Scheme V, other synthetic routes may be employed to provide the desired starting material of formula (IXc). In one such alternate method the 4-cyano-3-nitroanisole (XIX) is hydrogenated as previously defined for conversion of compound (VIII) to compound (IXa) to provide the aminonitrile of formula (XX). This is chlorinated as described above for the conversion of compounds (IXa) to (IXb) and the resulting 5-chloro nitrile (XIVc, R = CH^J is hydrolyzed as described for the preparation of compound (XXI) from nitrile (XIX), to provide the desired compound (IXc, R = CH^).

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

As will be obvious to those skilled in the art when the methoxy group present in the starting materials of formula (XVIII) and (XXIII) employed in Scheme V is replaced by an ethoxy or n-propoxy group, the corresponding compounds of formula (IXc) are obtained wherein R is CjHg or n-C^H?, respectively.

Similarly, replacement of either one or both of the methoxy groups present in the starting material of formula (XXV, employed in Scheme VI by ethoxy or n-propoxy provides the corresponding compounds of formula (IXa, or (IXb).

The starting materials of formula (XIV) employed in the reaction sequence illustrated in Scheme II for the preparation of the compounds of the invention, are prepared as shown in Scheme V for compounds (XIVc) and in Scheme VI for compounds (XlVa) and (XlVb), and as described above.

Many of the requisite cyclic amines of formula (III) are known compounds, see for example, the references mentioned above as prior art. Those that are new are prepared by methods which will be apparent to those skilled in the art.

The antihypertensive activity of the compounds of the invention is shown by their ability to lower the blood pressure of conscious spontaneously hypertensive rats and conscious renally hypertensive dogs, when administered orally at doses of up to 30 mg./kg.

For instance, 2-/4-(2-hydroxy-2-methylprop-l-yloxycarbonyl)piperazin-l-yl/-4-amino-6-chloro-7,8-dimethoxyquinazoline, a typical and preferred compound of the invention, has been found to lower blood pressure in renally hypertensive dogs to a statistically significant degree, e.g., when this compound is administered orally at doses as low as 0.2 mg./kg., it effected a decrease of 30 mm. Hg after 4 hours with no significant change in heart rate or other side effect. Similarly, at the same dosage 2-/4-(2-hydroxy-2methylprop-l-yloxycarbonyl)piperazin-l-yl/-4-amino-6-chloro7-methoxyquinazoline, a particularly preferred compound of the invention, caused a reduction of 40mm. Hg after one hour which increased only by 20 mm. Hg 6 hours after administration; and another particularly preferred compound: 2-/4-(2-furoyl)-l-piperazinyl/ -4-amino-6chloro-7-methoxyquinazoline effected a reduction in blood pressure of 40 mm. Hg which increased by only mm. Hg six hours after the oral dose (0.2 mg./kg.) had been administered. Again, no significant heart rate change or other unwanted side effect was noted with the latter two compounds.

In addition to their useful antihypertensive activity, the compounds of the invention also demonstrate activity in standard tests designed to show vasodilator activity, antiglaucoma activity and utility in the treatment of congestive heart failure.

The compounds of the invention can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic. For treatment of glaucoma, they can be administered topically as well as by the above mentioned routes of administration. For topical application, a compound of the invention is admixed under sterile conditions with a pharmaceutically-acceptable liquid carrier or solvent such as water, a glycol or mixtures thereof, and toxicity adjustors, preservatives and buffers added as required. The resulting solution or dispersion is then sterilely filtered and used to fill sterile bottles.

The Invention also provides a pharmaceutical composition comprising an antihypertensive effective amount of a compound of the formula (I) or pharmaceutically acceptable acid addition salts thereof together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for the treatment of hypertension or congestive heart failure by either the oral or parenteral routes, and may be administered orally at dosage levels approxi10 mately within the range 1 to 500 mg./day for an average adult patient (70 kg.), given in a single dose or up to 3 divided doses. Intravenous dosage levels would be expected to be about one-half to one-tenth of the daily oral dose. Thus for an average adult patient, individual oral doses in the tablet or capsule form will be approximately in the range from 0.5 to 250 mg. of the active compound. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.

The following Examples illustrate the invention.

366

EXAMPLE 1

7,8-Dimethoxyquinazoline-2,4-dione (Xa)

Acetic acid (177.4 ml., 3.1 moles) was added to a vigorously stirred suspension of 3,4-dimethoxyanthranilic acid (436.5 g., 2.21 moles) in 10 liters of water. Then 2.24 liters of 20% potassium cyanate (5.53 moles) solution was gradually added and the mixture was stirred for one hour at 40°C. After cooling the reaction mixture to 20°C., 3.54 kg. sodium hydroxide pellets were added maintaining the temperature below 40°C. The reaction mixture was heated to 90°C. for 45 minutes and then slowly cooled in an ice bath.

The sodium salt of the product was filtered, resuspended in 6 liters of water, acidified with concentrated hydrochloric acid (370 ml.), cooled and filtered to yield 404 grams (82%) of the product. Recrystallization from dimethylformamide gave colorless crystals,

M.P. 314-6eC.

Analysis, Percent Calcd. for cjqH2qN2°4: c'

H, 4.54; N, 12.61.

Found: C, 53.96; H, 4.57; N, 12.63.

EXAMPLE 2

2,4-Dichloro-7,8-dimethoxyquinazoline (XIa)

A mixture of 7,8-dimethoxyquinazoline-2,4-dione (400 g., 1.80 moles), phosphorus pentachloride (750 g., 3.60 moles) and phosphorus oxychloride (4 liters) was refluxed under nitrogen for three hours. Phosphorus oxychloride (POCl^) was removed in vacuo and residual POClj was removed as an azeotrope with toluene. The solid residue was slurried in eight liters of dichloromethane and the slurry slowly added to ice-cold HjO.

The suspension was stirred and unreacted starting material (54.0 g.) was filtered off. The organic layer was separated, dried over sodium sulfate and filtered. The solution was concentrated and then 4 liters of hexane was slowly added. Upon cooling, a pale yellow product (346 g., 80.4%) was collected by filtration and recrystallized front toluene/ether,

M.P. 153-5’C.

Analysis, Percent Calcd. for cioHgc82N2°2: C, 46.35; 5 H, 3.11; N, 10.81.

Found; C, 46.14; H, 3.33; N, 10.60.

' EXAMPLE 3

2-Chloro-4-amino-7,8-dimethoxyguinazoline (Xlla)

Ammonia was passed into a solution of 2,410 dichloro-7,8-dimethoxyquinazoline (287 g., 1.11 moles) in tetrahydrofuran (6 liters) for five hours at room temperature. After stirring an additional hour the suspension was concentrated in vacuo to 2 liters and filtered. The solid was suspended in 2 liters of water, filtered, washed with water and cold methanol. Recrystallization from dimethylformamide/ water yielded 164 g. (62%) of pure product, M.P.

300’. (dec.).

Analysis, Percent Calcd. for C^qH^qCINjOj5 C, 50.11; B, 4.21; N, 17.53.

Found; C, 50.07; H, 4.24; N, 17.58.

503SS

EXAMPLE 4

2-/4-(2-Furoyl)piperazine-l-yl/-4-ainino7,8-dimethoxyquinazoline hydrochloride

A mixture of 2-chloro-4-amino-7,8-dimethoxy5 quinazoline (3.00 g., 12.5 mmoles) and 1-(2-furoyl)piperazine (2.71 g., 15.0 mmoles) was refluxed in 80 ml. isoamyl alcohol for two hours and then cooled in an ice-bath. The resulting white product was collected by filtration and recrystallized from methanol/ether to yield 4.53 g. (79%) of pure final product, M.P.

251°C. The water solubility was found to be 20 mg./ml.

Analysis, Percent Calcd. for Ο-^ί^Ν,-Ο^ΗΟΙ: C,

54.35; H, 5.28; N, 16.68.

Found: C, 54.14; H, 5,21; N, 16.42.

EXAMPLE 5

A. 6-Chloro-7,8-dimethoxyquinazoline-2,4-dione (Xb)

Acetic acid (10.5 g., 0.175 mole) was added to a vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g., 0.125 mole) in 600 ml. water. Then 506 ml. 5% potassium cyanate (0.312 mole) solution was gradually added and stirred 1 hour at 40 *C. After cooling the reaction mixture to 20*C., 175 g. (4.37 moles) of sodium hydroxide pellets were added while maintaining the temperature below 40*C. . The reaction mixture was heated to 90eC. for 45 minutes. Upon cooling in an ice bath, the sodium salt of the product precipitated, was filtered, resuspended in 125 ml. water, acidified with concentrated hydrochloric acid, cooled and filtered to yield 25.8 g. {80%) of colorless, pure-product, M.P. 272-3’C. Analysis, Percent Calcd. for CinH.ClN.O,: C, 46.79?

H, 3.53? N, 10.92.

Found: C, 46.87? H, 3.60? N, 10.90.

B. 6-Chloro-7-methoxyquinazoline-2,4-dione (XVIII)

Similarly, 6-chloro-7-oethoxyquinazoline-2,4dione was prepared from 5-chloro-4-methoxyanthranilic acid in 83% yield, M.P. 356-8eC.

Analysis, Percent Calcd. for CgH^ClNjOj: C, 47.70;

H, 3.11? N, 12.36.

Found: C, 47.72; H, 3.44; N, 12.27.

EXAMPLE 6

A. 2,4,6-Trichloro-7,8-dimethoxyquinazoline (Xlb)

A mixture of 6-chloro-7,8-dimethoxyquinazoline2,4-dione (25.5 g. , 0.099 mole), phosphorus- penta5 chloride (41.4 g., 0.199 mole) and 300 ml. phosphorus oxychloride was refluxed under nitrogen for three hours. Phosphorus oxychloride was removed in vacuo and residual POCl^ was azeotroped with toluene. The reddish-orange solid was dissolved in 200 ml. dichloro10 methane 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. hexane was added slowly to precipitate the product as a pale yellow solid which was recrystallized from toluene/ether to afford 18.0 g. (62% yield),

M.P., 154-5°C.

Analysis, Percent Calcd. for CiqRjCIjNjOjJ C, 40.91;

H, 2.40; N, 9.55.

Found: C, 41.05; H, 2.48; N, 9.61.

B. 2,4,6-Trichloro-7-methoxyquinazoline (XIX)

Refluxing 6-chloro-7-methoxyquinazoline-2,4dione with PCl^ in POCl^ as described above afforded

2,4,6-trichloro-7-methoxyquinazoline in 74% yield,

M.P., 150-2°C.

Analysis, Percent Cald. for CgH^Cl^NjO: C, 41.02;

H, 1.91; N, 10.63.

Found: C, 40.90; H, 2.01; N, 10.54.

EXAMPLE 7

A. 2,6-Dichloro-4-amino-7,8-dimethoxyquinazoline (Xllb)

Ammonia was passed into a solution of 2,4,6-trichloro-7,8-dimethoxyquinazoline (31.4 g., 0.107 mole) in 650 ml. dry tetrahydrofuran for one hour at room temperature. After stirring for an additional hour, the suspension was concentrated in vacuo and filtered.

The solid was resuspended in water, filtered, washed with water and methanol. Recrystallization from dimethylformamide/water yielded 23.7 g. (81%) of the desired product, M.P., 360eC.

Analysis, Percent Calcd. for C^qH^CIjN^Oj: C, 43.82;

H, 3.31; N, 15.33.

Pound: C, 43.95; H, 3.53; N, 15.35.

B. 2,6-Dichloro-4-amino-7-methoxyquinazoline (XX)

Reaction of 2,4,6-trichloro-7-methoxyquinazoline with ammonia as described above afforded 2,6-dichloro4-amino-7-methoxyquinazoline as a white solid, M.P.,

300°C. in 58% yield.

Analysis, Percent Calcd. for CgH^C^NjO: C, 44.28;

H, 2.89; N, 17.22.

Found: C, 44.12; H, 3.16; N, 17.19.

EXAMPLE 8

A. 2-[4-(2-Furoyl)piperazine-l-yl)-4-amino-6chloro-7,8-dimethoxyquinazoline hydrochloride (XHIb)

A mixture of 2,6-dichloro-4-aroino-7,8-dimethoxyquinazoline (1.50 g., 5.47 mmole) and l-(2-furoyl)piperazine (1.08 g., 5.99 mmole) was refluxed in 40 ml. isoamyl alcohol for 2 hours and then cooled overnight. The resulting solid was filtered and recrystallized from methanol/ether to yield 1.83 g.

(74%) of pure final product, M.P., 208-9°C.

Analysis, Percent Calcd. for cigH20C1N5°4.HCl 1/2.HjO: 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-[4-(2-Furoyl)piperazine-l-yl]-4-amino-6chloro-7-methoxyquinazoline hydrochloride

The title compound was prepared similarly by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and 1-(2-furoyl)piperazine in isoamyl alcohol, M.P.

229-31°C., 79% yield.

Analysis, Percent Calcd. for C2gH^gClNgO3.HCl.H2O:

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 9

A. 2-Methyl-2-hydroxypropyl 4-[4-amino-6-chloro7,8-dimethoxyguinazolin-2-yl]piperazine-1-carboxylate hydrochloride

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxy20 quinazoline (1.50 g., 5.47 mmole) and 2-methyl-2hydroxypropyl-4-piperazine-l-carboxylate (1.22 g.,

6.03 mmole) was refluxed in 30 ml. roethylisobutylketone for two days. The yellowish solid was filtered, resuspended in 40 ml. acetone and stirred for 15 minutes. The filtered solid was decolorized with charcoal and recrystallized twice from ethanol/ether to yield 1.47 g. (57%) of final product, M.P.,

211-3°C.

Analysis Percent Calcd, for C^jHjgClNgOj.HCl:

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· 2-methyl-2-hydroxypropyl 4-[4-aroino-6-chloro-7methoxyquinazolin-2-yl]piperazine-1-carboxylate hydrochloride (XXI, R1 + R2 = -COOCH^C(OH)(CH^)

The title compound was prepared similarly by refluxing

2,6-dichloro-4-amino-7-methoxy guinazoline and 2-methy110 2-hydroxypropyl-4-piperazine-l-carboxylate in methyl isobutyl ketone for 4 days, M.P. 243-5°C., 69% yield. Analysis Percent Calcd. for C18H24C1N5O4-HC1-H2°

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-[4-(1,4-Benzodioxan-2-carbonyl)piperazin-l-yl)4-amino-6-chloro-7-methoxyquinazoline hydrochloride

The title compound was prepared by the procedure of Part A, above, by refluxing 2,6-dichloro-4-amino-720 methoxyquinazoline and N-(l,4-benzodioxan-2-carbonyUpiperazine in methylisobutylketone, M.P. .194-196eC.

EXAMPLE 10

When the appropriate N-substituted piperazine is employed in the procedure of Example 4 in place of 12S (2-furoyl)piperazine, the analogous products tabulated below are obtained as the hydrochloride salts except as otherwise noted.

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X «σ φ

C

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X

Ο ϋ

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φ «

Φ Ο Φ -Η rH Μ 3

Ο, Β ε ο Μ Sm

4J . •Η pH η ε *4 \ Λ 2 ρ ςτ η ε ο ca υ

Ο ιη

X to

Ο pH

Ο ή* ο ο ΟΙ in X Ζ η w

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Example 10 (continued)

*ϋ φ

C

4J

C ο

α ct ε

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'47

EXAMPLE 11

2-[4-(2-Furoyl-homopiperazine-l-yl]-4-amino-7,8_dimethoxyquinazoline hydrochloride_

A. N-(2-Furoyl)homopiperazine

Homopiperazine (70 g., 0.70 mole) in 160 ml. water was treated with 6N hydrochloric acid to adjust to pH 5.5 Furoyl chloride (79.5 g., 0.60 mole) and 25% (w/w) aqueous sodium hydroxide solution were added simultaneously to maintain a pH of 4.5-5.5. Then additional sodium hydroxide was added to bring the mixture to pH 9.5. The solution was extracted with chloroform, dried over anhydrous potassium carbonate and distilled to afford 63 g. of product, B.P. 124-130’ C. at 10 am.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (1.76 g.,

7.3 mole), N-(2-furoyl)homopiperazine (1.50 g., 7.7 mole) and 40 ml. of isoamyl alcohol were combined and the mixture heated at reflux under a nitrogen atmosphere for 1.5 hours. After cooling to room temperature, the mixture was stirred for one hour, filtered and the pre20 cipitated product washed with ether and recrystallized from methanol/ether to afford 2.15 g. of the title compound, M.P. 182-183’ C.

Analysis, Percent Calcd. for Cjo623Ng04.HC1.0.5 HgO:

C, 54,23; H, 5.69; N, 15.81.

Found: C, 53.84; H, 5.40; N, 15.49.

The solubility in water was found to be 30 mg./ml.

0 3 6 6

EXAMPLE 12

2-[4-(2-Tetrahydrofuroyl)homopiperazin-l-yl]-4-amino·

7,8-dimethoxyquinazoline hydrochloride

A. N-(2-Tetrahydrofuroyl)homopiperazine

N-(2-Furoyl)homopiperazine (33.0 g.) in 200 ml. of ethanol was hydrogenated over 5% rhodium-on-carbon catalyst at three atmospheres pressure. The catalyst was removed by filtration and the product distilled to give the desired product, B.P. 135° at 1 mm.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.10 g., 8.75 mmole), N-(2-tetrahydrofuroyl)homopiperazine (1.9 g. 9.58 mmole) and 50 ml. of isoamyl alcohol were mixed and heated at reflux under nitrogen for 2.5 hours. The solvent was removed by evaporation in vacuo, the residue dissolved in water and filtered through a mixture of activated carbon and diatomaceous earth. The filtrate was adjusted to an alkaline pH by addition of sodium bicarbonate solution, extracted four times with 50 ml. portions of ethyl acetate and the extracts dried over sodium sulfate. The solvent was evaporated and the residue chromatographed on 30 g. of silica gel, eluting with chloroform/ethanol. The fractions containing the desired product (free base) were combined and evaporated to afford the free base as a foam, 1.0 g. The free base was dissolved in ether, saturated hydrogen chloride and filtered to obtain the title compound, M.P. 130° (dec.). Analysis, Percent Calcd. for CjQHj^NgO^.HCl.0.50 HjO:

C, 53.74; H, 6.54; N, 15.67.

Found: C, 53.56; H, 6.68; N, 15.44.

Water Solubility: 120 mg./ml.

EXAMPLE 13

A. 2-(4-Benzylplperidin-l-yl)-4-amino-7,8-dimethoxyquinazoline hydrochloride

4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.40

g., 10 mmole), 4-benzylpiperidine (1.93 g., 11 mmole) and 50 ml. of isoamyl alcohol were heated at reflux under a nitrogen atmosphere for two hours and cooled to room temperature. Diethyl ether (50 ml.) was added and the mixture allowed to stand in the refrigerator for two days. The precipitated solid was collected by filtration and recrystallized from ethanol/diethyl ether to afford 2.50 g. (60%) of the title compound, M.P. 216-217eC.

Analysis, Percent Calc'd. for C22H26°2N4,HC3:

C, 63.68; H, 6.56; N, 13.50

Found: C, 63.78; H, 6.67; N, 13.89.

Water Solubility: 6 mg./ml.

EXAMPLE 14

2-[4-(2-Tetrahydrofuroyl}piperazin-l-ylJ-4-amino___6-chloro-7,8-dimethoxyquinazoline_

To 35 ml. of isoamyl alcohol were added 1.50 g.

(5.47 mmole) of 4-amino-2,6-dichloro-7,8-dimethoxyguinazol ine and 1.11 g. (6.02 mmole) of 1-(2-tetrahydrofuroyl )piperazine and the mixture was heated at reflux under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, 20 ml. of ethyl ether was added and the resulting mixture stirred at room temperature overnight. It was then cooled in ice and the precipitated, solid 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 while stirring, the precipitated brownish solid collected by filtration, dried, decolorized with activated carbon and recrystallized from isopropanol/ ethyl ether to obtain 0.38 g. of yellow solid, M.P.

192-193’C.

Analysis, Percent Calc’d. for CigH24O4N5Cl:

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.

EXAMPLE 15 Tablets

A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:

Sucrose, U.S.P. ..........80,3

Tapioca starch...........13.2

Magnesium stearate. ........ 6,5

Into this base is blended sufficient 2-I4-C2-furoyllr1-piperazinyl]-4-aTn-ino-fi-chloro-7-methoxy<piinazoline hydrochloride to provide tablets containing 0.5, 1.0, 10, 100 and 250 mg. of active ingredient.

EXAMPLE 16

Capsules

A blend.is prepared containing the following ingredients:

Calcium carbonate, U.S.P......17.6

Dicalcium phosphate........18.8

Magnesium trisilicate, U.S.P. ... 5.2

Lactose, U.S.P...........5.2

Potato starch...........5.2

Magnesium stearate A, ....... 0.8

Magnesium stearate B........ 0.35

To this, blend is added sufficient 2-[4-C2rhydroxy-2eethylprop-l-yloxycarbonylipiperasin-l-yl] -4-amino-625 chloro-7-methoxyquinazoline to provide formulations containing 0.5, 1.0, 5, IQ, 100, 250 and 500 mg. of active ingredient, and the formulations are filled into hard gelatin capsules of a suitable size.

EXAMPLE 17

Injectable Preparation

2-(4- C2-£ uroyl-l-piperazinylj -4-amino-7,8-dimethaxyquinazoline hydrochloride is intimately mixed and ground with. 25QQ g, of sodium ascorbate. The ground dry mixture is filled into vials, sterilized with ethylene oxide and the vials sterile stoppered. For intravenous administration sufficient water is added to the vials to form a solution containing 10 mg. of active ingredient per milliliter.

EXAMPLE 18

Solution'

A solution of 2-(4-C2-hydroxy-2-methylprop-lyloxycarbonyl 1 piperazin-l-yl] -4-amino-6-chloro-7,815 dimethoxycpvinazoline or a pharmaceutically acceptable salt thereof is prepared with the following caiposition:

Effective ingredient 30.22 g.

Magnesium chloride hexahydrate 12.36 g.

Monoethanolamine 8.85 ml.

Propylene glycol 376 g.

Water 94 ml.

The solution has a concentration of 50 mg./ml. and is suitable for parenteral and especially for intramuscular administration.

PREPARATION A

4-Acetoxy-3-methoxybenzaldehyde (TV! Triethylamine (2,8 liters, 20,1 molesL was added dropwise to a solution of vanillin (2.Q0 kg., 13.15 5 moles1 and acetic anhydride (2.6 liters, 27,5 moles!

in methylene chloride 0.1,3 liters! maintaining temperature Below 25’C. After adding 4-dimethylaminopyridine (2Q g-1 the solution was stirred 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 sodi,ma sulfate and concentrated in vacuo to 8 liters.

Hexane O.5 liters} was added slowly while removing remaining methylene chloride. After cooling, 2.45 kg. (96% yield) product was filtered off. Recrystallization of a small sample from anhydrous ether gave the acetate as fine yellow needles, M.P. 76-78°C.

PREPARATION B

4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (V)

Over a period of 1.5 hours 4-acetoxy-3-methoxybenzaldehyde (1120 g., 5.77 moles! was added in small portions to 4 liters of red fuming nitric acid cooled to O’C. After allowing to stir for one hour below S’C., the reaction mixture was added to large amount of ice-water and stirred an additional hour. The resulting yellow product (1130 g., 82% yield! was filtered and washed three times with water, and was sufficiently pure for use directly in the next step. Recrystallization from ether/cyclohexane furnished the pure nitroaldehyde, M.P. 84-86’C.

PREPARATION C

4-Hydroxy-3-mefchoxy-2-n itrobenzaldehyde _ (yi).

4-Acetoxy-3-methoxy—2-n±trobenzaldehyde CL12Q. g., 4.72 moles I was added portionwise to a freshly prepared 33% Cw/w] NaOH solution 0,5 liters!, The resulting slurry was heated on steam hath, 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 6N hydrochloric acid while cooling,

IQ and the resulting product (794 g., 85% yield] was filtered and washed with water. Recrystallization from ether/cyclohexane gave the desired product as light yellow solid, M.P. 136-137eC.

PREPARATION D i_. 3,4-Dimethoxy-2-aitrobeazaldefayde (VII)

Anhydrous sodium carbonate (557 g., 9.03 moles), toluene (5 liters), 4-hydroxy-3-roethoxy-2nitrobenzaldehyde <1424 g., 7.22 moles] and dimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4

2o hours. Toluene was removed in vacuo and the residual solid dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was separated, washed with 2 liters of IN 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. product was obtained by filtration. The crude material was recrystallized from ethanol to yield 1187 g. <78%] of the title compound as a pale yellow solid, 60-62’C,

3q ii. By employing diethyl sulfate in place of dimethyl sulfate in the above procedure, 4-ethoxy-3methoxy-2-nitrobenzaldehyde is similarly obtained.

iii. When n-propyl bromide is employed as the alkylating agent the corresponding 4-n-propyloxy compound is provided.

PREPARATION Ε

3,4-Dlmathoxy-2-nitro-benzoic acid (yill). λ solution of 823 g. potassium permanganate in about 8,5 liters of HjO was gradually added to a refluxing solution of 3,4i-dime.thoxy-2-nitrobenzaldehyde (550 g,, 2,60 moles! in 5.6 liters of acetone. The reaction mixture was refluxed for four more hours, then filtered through, diatomaceous earth while hot and the filter cake 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. 2N hydrochloric acid (1.8 liters! to yield 505 g. (85%) of the essentially pure title compound. Recrystallization from water afforded colorless crystals, M.P. 200-2Q2’C.

PREPARATION F

3,4-Dimethoxyanthranilic acid (IXa, R-CR^l

A solution of 3,4-dimethoxy-2-nitro benzoic acid (1011 g., 4.45 moles) in 14 liters of 1.3N ammonium hydroxide was reduced at 60 psi in presence of 60 grams of palladium on barium carbonate. Hydrogen uptake ceased after four hours. The reaction mixture was filtered through diatomaceous earth and acidified with glacial acetic acid (1.2 liters) to yield 685 grams (78%) of the anthranilic acid, M.P. 183-184°C.

PREPARATION G

4-Methoxy anthranilic acid (XXII1 i„ 4°Cyano-3nitroanisola (XIXT.

A saturated solution of sodium nitrite 5 (33.5 g., 0,485 molel was added dropwise to a cooled solution of 4-methoxy-2-nitroan±line (68.0 g., 0..40,4 mole! in 300 ml. water and 14 ml, concentrated hydrochloric acid, while maintaining the temperature at O’C. and the pH at 6 by addition of sodium carbonate10 The cold solution of diazonium salt was added carefully through a jacketed dropping funnel to a hot solution of cuprous cyanide (36.2 g., 0.404 mole) and potassium cyanide (42.1 g., 0.646 molel in 500 ml. water, with vigorous stirring and intermittent heating on a steambath. The stirred yellow suspension was heated an additional fifteen minutes. The solid was filtered, dried and dissolved in ethyl acetate, discarding the undissolved inorganic salts. After decolorization with charcoal, concentration of the ethyl acetate solution yielded 55.1 g. (71%) of bright yellow-orange crystals, M.P. 135-7°C.

Analysis, Percent Calc'd. for CgHgNjO^: C, 53.93; H,

3.39; N, 15.73

Pound: C, 53.92; H, 3.47; N, 15.85.

ii. 4-Methoxy-2-nitrobenzoic acid (XXI)

4-Cyano-3-nitroanisole (52.3 g., 0.294 molel was slowly added to a cooled solution of 53 ml. each of acetic acid, water and sulfuric acid. The solution was refluxed for 5 hours, and then diluted with 160 ml. water. After cooling, the resulting solid was filtered and dissolved in 10% sodium hydroxide solution After decolorization with charcoal the solution was acidified with 6N HCl, cooled and the yellow product (51.0 g., 88% yield) was filtered. An analytical sample was recrystallized from methanol/water, M.P. 196-7*C.

Analysis, Percent Calc'd, for CgH^NOgj C, 48,74; B, 3.58; N, 7,11

Found; C, 48.37; H, 3,57; Nf 7.Q3. ill. 4-Methoxy anthranilic acid QgII).

A solution of 4-methoxy-2-nitrobenzoic acid (19.3 g., 97.9 mmole] in 200 ml. IN NH^OH was reduced overnight in presence of 5% Pd/BaCO^. The reaction mixture was filtered and acidified with acetic acid to yield 15.8 g. (96%1 of the anthranilic acid, M.P. 136-188eC.

PREPARATION Η

i. Methyl-3,4-dimethoxyanthranilate

Hydrogen chloride was passed into a solution of 3,4-dimethoxyanthranilic acid Q.00 g,, Q,51 mole!

in 1.5 liters methanol for 40. minutes. The reaction mixture was refluxed for 4 days while introducing hydrogen chloride gas intermittently. The solvent was removed in vacuo, and the residual white solid was dissolved in 500 ml. water, cooled and basified

IQ to pH 10 with sodium hydroxide solution. After cooling for an additional hour, the cream color product <87.0 g., 82% yield] was filtered. Recrystallization from methanol furnished pure product, M.P.

66-67°C.

Analysis, Percent Calc'd. for ciqhi3NO4s C, 56.86;

H, 6.20; H, 6.63

Pound: C, 56.56; H, 6.15; N, 6.66.

ii. Methyl-4-methoxyanthranilate

Esterification of 4-methoxy anthranilic acid as described above afforded methyl-4-methoxyanthranilate, M.P. 77-79°C., in 77% yield.

PREPARATION I

i. 5-Chloro-3,4-dimethoxyanthranili-c acid (IXb, R - C&p

Sulfuryl chloride 0.2.,3 ml,, 0.,24 moleL was 5 added dropwise to a cooled solution of methyl 3,4v dimethoxyanthranilate (42,2 g,, 0.20. moleL in 40.0 ml. chloroform at O’C, Q?he sulfur dioxide produced was passed through a water trapl, After stirring 30. minutes at ambient temperature the solution was

IQ refluxed for 2 hours. The black solution was treated with charcoal and the solvent was evaporated. The

NMR spectrum indicated that the black, oily residue was largely the desired intermediate ester.

The crude methyl ester was saponified with 400. ml. S% (w/v) sodium hydroxide on a steam bath for one hour.

After cooling, the basic suspension was acidified with acetic aeid to precipitate a brown solid which was filtered and recrystallised from carbon tetrachloride to afford light-brown crystalline product (29.0 g., 63.1% yield), M.P. 140-2’C. (Reported M.P.

142-3’C., J. Chem. Soc., 4310-4, 1964].

Analysis, Percent Calc'd. for CgH1QClNO4: 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

Treatment of methyl-4-methoxyanthranilate with sulfuryl chloride as described above afforded methyl-4-methoxy-5-chloroanthranilate, M.P., 197-200’C. in 90% yield.

Saponification of methyl-4-methoxy-5-chloro anthranilate yielded 5-chloro-4-methoxyanthranilic acid in 64% yield, M.P., 210-3°C.

Analysis, Percent Calc'd for CgHgClNOg: C, 47.66; H,

4.00; N, 6.95

Found: C, 48.00; H, 4.11; N, 6.94.

PREPARATION J

3.- (m-Trxfluoromethylphsnylipiperidine.

N^Senxyl-3-hydroxy-3- (jm-trifluoromethylphaiyl) piperidine

Under anhydrous conditions, to a mixture of g, of magnesium in 15 ml. of ethyl ether an iodine crystal is added followed By the addition of a solution of 100 g, of m-Bromotrifluoromathylbenzene in 300 ml, of ether over a two hour period. The resulting mixture is stirred for two hours at ambient temperature then cooled to 5HC. A solution of 70 g. of N<-benzyl3-piperidone in 300 ml. of ether is added at this temperature over one hour. After stirring for 15 minutes at 5°C. and one hour at 20-25°C., the reaction mixture was poured onto 800 ml. of ice-water with •stirring. The mixture is filtered, the organic layer extracted with 4 x 100 ml. of IN hydrochloric acid and once with brine. The aqueous phase is made alkaline by addition of triethylamine in the cold and the resulting mixture extracted with ethyl acetate.

The combined extracts are washed with brine, dried (I-lgSO^) and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with cyclohexane/chloroform/triethylamine (85:10:5 by volume) to obtain the desired product as an orange colored solid.

ii. N-Benzyl-3-acetoxy-3- fgvtrifluoro methylphenyl)piperidine hydrochloride

A mixture of 37 g, of Nt-Benzyl-3-hydroxy-3(m-trifluoromethylphenyl{piperidine, 220. al, of acetic anhydride and Q.3 ml, of concentrated sulfuric acid is heated to 110’C, for one hour, After cooling it is poured onto ice-water, the resulting mixture agitated for 15 minutes and made alkaline by addition of sodium hydroxide solution. The mixture is extracted with ethyl acetate,, the extracts washed with brine, dried QigSO^l and evaporated to dryness to obtain 31 g. of the free base. This is dissolved in 600 ml. of ethyl acetate, cooled in ice, and 100 ml. of ethanol saturated with hydrogen chloride is added. The solvent is removed by evaporation in vacuo and the residue triturated with 200 ml. of ethyl acetate then 200 ml. of ethyl ether is added and the mixture allowed to stand overnight. The crystalline title compounds is collected by filtration, washed with ether and dried to obtain 36 g., M.P. 206-207’C.

iii. The product obtained in Part ii is dissolved in 700 ml. of ethanol. Palladium-on-carbon catalyst £40 g.) is added and the mixture hydrogenated at room temperature. When hydrogen uptake ceases the catalyst is removed by filtration and solvent evaporated in vacuo. The resulting solid is washed with ether and dried to obtain 21 g. of 3-(m-trifluoromethylphenyllpiperidine hydrochloride as colorless crystals, M.P. 200’C.

PREPARATION K

Q., 4^-Benzodioxan--2-ear£>onylLptpera2ine

1,4-Benzodioxan-2?-car&oxylic acid, prepared by oxidation of 2-hydroxymethyl-l,4-benzodioxan with 5 potassium permanganate in aqueous potassium hydroxide at 5-15°C., was converted to the acid chloride by reaction with thionyl chloride in the standard manner.

A suspension of piperazine ¢11.38 g.) and sodium acetate <20.30 g.) in a mixture of water <70 ml.) and acetone <95 ml.) was stirred at 10e-15°C., then concentrated hydrochloric acid was added <about 35 ml.) until the pH of the solution reached 1.5.

l,4-Benzodioxan-2-carbonyl chloride <31.0 g.) and sodium hydroxide (5N, about 45 ml.) were then added portionwise while maintaining the temperature at

10°-15°C., the sodium hydroxide maintaining the pH 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 stirred for a further 30 minutes.

Water was then added until a homogeneous solution resulted, the acetone removed in vacuo, and the agueous phase was basified to pH 8-9 with sodium hydroxide (5N), re-extracted with chloroform <3 x 200 ml.) and the extracts washed with water, dried <MgSO4) and evaporated in vacuo. The oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated ia vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N«-{l,4-ben2odioxan-2-carbonyl)>30 piperazine hydrochloride <4.85 g.I, M.P. 265e-267°C.

Contents44

50 members in 19 offices

This recordMember, by publication datePriority claim9 more offices are in the list below

Priority claims8

Priority claims
Document	Office	Kind	Date
9031379	United States of America	A	1979-11-01
9031379	United States of America	A	1979-11-01
12683880	United States of America	A	1980-03-03
12683880	United States of America	A	1980-03-03
126838	–	–	–
90313	–	–	–
US19790090313	–	–	–
US19800126838	–	–	–

Members50

Family members, oldest first
Document	Office	Kind
PT72007A	Portugal	A	1980-11-01
IL61375A0	Israel	A0	1980-12-31
IE802258L	Ireland	L	1981-05-01
DK462380A	Denmark	A	1981-05-02
FI803397L	Finland	L	1981-05-02
AU6389680A	Australia	A	1981-05-07
EP0028473A1	European Patent Office (EPO)	A1	1981-05-13
JPS5679676A	Japan	A	1981-06-30
PT72007B	Portugal	B	1981-08-31
US4287341A	United States of America	A	1981-09-01
ES496442A0	Spain	A0	1982-01-16
ES8202334A1	Spain	A1	1982-01-16
AU520344B2	Australia	B2	1982-01-28
ES507042A0	Spain	A0	1982-08-16
ES8206491A1	Spain	A1	1982-08-16
US4351940A	United States of America	A	1982-09-28
ES507043A0	Spain	A0	1982-10-01
ES8207520A1	Spain	A1	1982-10-01
AR227650A1	Argentina	A1	1982-11-30
GR70728B	Greece	B	1983-01-24
ES507041A0	Spain	A0	1983-02-01
ES8303360A1	Spain	A1	1983-02-01
US4377581A	United States of America	A	1983-03-22
CA1146546A	Canada	A	1983-05-17
YU277580A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1983-06-30
KR830004265A	Republic of Korea	A	1983-07-09
ES516286A0	Spain	A0	1983-10-16
ES8400415A1	Spain	A1	1983-10-16
KR840001095B1	Republic of Korea	B1	1984-08-01
PH17552A	Philippines	A	1984-09-20
EP0028473B1	European Patent Office (EPO)	B1	1985-01-09
DE3069944D1	Germany	D1	1985-02-21
PH18321A	Philippines	A	1985-05-29
IE50366B1This record	Ireland	B1	1986-04-02
PH20061A	Philippines	A	1986-09-18
IL61375A	Israel	A	1986-09-30
JPS6243996B2	Japan	B2	1987-09-17
YU41745B	Yugoslavia, later Serbia and Montenegro (until 2006)	B	1987-12-31
DK153399B	Denmark	B	1988-07-11
FI77455B	Finland	B	1988-11-30
DK153399C	Denmark	C	1988-12-19
FI77455C	Finland	C	1989-03-10
US2011167455A1	United States of America	A1	2011-07-07
WO2011085246A1	World Intellectual Property Organization (WIPO)	A1	2011-07-14
CN102696246A	China	A	2012-09-26
EP2522163A1	European Patent Office (EPO)	A1	2012-11-14
JP2013516922A	Japan	A	2013-05-13
JP5529292B2	Japan	B2	2014-06-25
US8863192B2	United States of America	B2	2014-10-14
EP2522163B1	European Patent Office (EPO)	B1	2015-03-04