4-amino-2-(cyclic amino)-6-chloro-7-alkoxy-quinazoline derivatives,pharmaceutical compositions containing them and the corresponding 2-chlorointermediates therefor

4-Amino-2-(cyclic amino)-6-chloro-7-alkoxy-quinazoline derivatives, pharmaceutical compositions containing them and the corresponding Zychloro- intermediates therefor

PFIZER INC.

C:- 56282

Background of the Invention

Field of the Invention

This invention relates to certain 2,4-diaminoquinazolines. Particularly, the invention relates to certain 6-chloro-7alkoxy-4-amino-2-(cyclic amino)-quinazolines which are possibly further substituted by an 8-alkoxy group, their use as antihypertensive agents and pharmaceutical compositions thereof.

Description of the Prior Art

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-1yl]-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 6,7,8trialkoxy-2,4-diaminoquinazolines 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 ^nh2

<img file="IL61375A_D0001.tif" />

Trimazosin is also an active antihypertensive agent, see e.g._t Vlachikis et al., Current Therapeutic Research, 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 U.S. 4,044,135 disclose homopiperazinoquinazoline compounds as antihypertensive agents.

Several patents have issued, which disclose antihypertensive compounds of the general formula

NH, i ---^C1I) . ^CH3°^

U-S. 4,001,237 claims compounds wherein R^a is an oxazole, isoxazole, thiazole or isothiazole radical.

In U.S. 4,001,238, such compounds are disclosed wherein R is of the formula

N—N

Λ k /^S-alkyl

U.S. 3,780,040 discloses 3,4-dihydroquinazoline analogs of the above formula wherein R^a is 2-thienyl.

In U.S. 4,026,894 and U.S. 4,112,097, R^a is a 2rtetrahydrofuryl or 2**tetrahydropyranyl moiety. U.S. 4,060,615 claims compounds in which. R^a is cycloalkyl 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 R^a is

<img file="IL61375A_D0002.tif" />

and R is hydrogen, lower alkyl, NH_oor NHCO״R^c in י . c 2 2 which R is lower alkyl.

6,7-Dim.ethoxy-2- (4־-thiomorpholin-l-yl) . 4-aminoquinazolines and derivatives in which the 2-substituent 15 is is 0, 1 or 2

-N S(0)_d , d are disclosed as antihypertensive 4,115,565. .

British Patent No. 1,530,768 agents in U.S.

discloses prazosin 20 analogs in which the 2~amino group is of the formula / C0R^e where R 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 group substituted in the 3 or 4 position.

Summary of the Invention

The present invention discloses new 6-chloro-7-alkoxy 2-amino-4-(cyclic amino)-quinazoline compounds and processes for their production. The new quinazolines possess valuable pharmacological properties and other aspects of the invention relate tc 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 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 and other known quinazoline derivatives referred to above (cf. Example 19 herein). In addition, the invention compounds have improved water solubility when compared to prazosin. They can therefore be administered intravenously, particularly for emergency purposes and are uniformly absorbed by all patients. Examples 4 and 5 herein provide water-solubility data of 5 and 6 mg/ml. For comparison, the water solubility of prazosin hydrochloride is only 0.7 mg/ml.

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

The compounds of the invention fall within the broad generic disclosure of British Patent No. 1,390,014 (corresponding to Israel Patent No. 39369) but were not specifically mentioned therein. By virtue of their aforementioned advantages, which were entirely unexpected, the compounds of the invention constitute a selection in respect of the said British Patent.

The novel compounds disclosed are of the formula

<img file="IL61375A_D0003.tif" />

wherein Y is hydrogen or OR,. and the pharmaceutically acceptable acid addition salts thereof;

Ή is alkyl ־having froa one to three carbon atoms;

Z is chloro or where X is 0, NR³, NCOR⁴, NCOOR⁵, CHOR⁶ or CHR⁷, where m is 1, 2 or 3 and n is 2 or 3; provided that when m is 1, then X must be CHOR⁶ or CHR⁷;

R is alkenyl having from.3 to 5 carbon atoms, hydroxy substituted alkyl having from 2 to 5 carbon atoms, or -(^cH₂)qC₆H₄R⁸ where q is 0 or 1;

^⁴ hydrogen, cycloalkyl having from 4 to 6 carbon atoms, a radical of the formula where A is S or 0; or R is &lt;CH₂) C$H₄R⁸ where q is as defined above;

R is alkyl having from 1 to 6 carbon atoms or hydroxy substituted alkyl having from 2 to 5 carbon atoms;

R is lower alkoxyalkyl;

R is ־(CH₂)_gC₆H₄R where q is as defined above; and

R⁸ is H or CF.

•1

Formula (A) above includes the compounds of the general formula (I) wherein R and Y³ are as defined above and Z' is a group of the formula where m, n and X are as defined above.

Preferred compounds of the invention include the compounds of formula (A) wherein Z is

<img file="IL61375A_D0004.tif" />

where R is a member selected from the group consisting of

<img file="IL61375A_D0005.tif" />

<img file="IL61375A_D0006.tif" />

\ and cycloalkyl having from 4 to 6 carbon atoms and A is as previously defined. Also preferred are the compounds of formula (A) wherein Z is

<img file="IL61375A_D0007.tif" />

where R is hydroxy substituted alkyl having from 2 to 5 carbon atoms.

Particularly preferred compounds of the invention are:

2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6-chloro7-methoxyquinazoline,

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

7,8-dimethoxyquinazoline,

2-(4-(2-hydroxy-2-methy!prop-1-yloxycarbony1) piperazin-1-yl]-4-amino-6-chloro7־-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 compounds of formula (A) above in which Z is chloro are useful as intermediates in the preparation of the remaining compounds of formula (A), i.e. those of formula (1). These intermediates are of the formula (XII)

<img file="IL61375A_D0008.tif" />

where Y and R are as defined above.

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, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydrjtfiodic, 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 chloro substituent, at the 6-position of the invention compounds,. is 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 intraveneously.

- וו Detailed Description of the Invention The antihypertensive compounds of the invention are represented by the formula (I) above. They are prepared by synthetic methods described below.

Scheme I, below, outlines a preferred reaction sequence. In the first step a 4-alkoxy-5-chloro-anthranilic acid of formula (IX) containing the desired substituent Y³as 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., « 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 CONH₂, 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 recognized by one skilled in the art, they may also be represented as the corresponding tautomeric 2,4-dihydroxyquinazolines.

Scheme I

<img file="IL61375A_D0009.tif" />

where R, Z' and Y are as defined above.

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^eC. 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-dihaloquinazolines. The preferred embodiment, in which the above phosphorous chlorides are employed, is depicted in Scheme I to provide the intermediates of formula (XI) in which R and Y³ 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 iichloromethane, 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).

The key 2-chloro-4-aminoquinazoline intermediates of formula (XII) are provided by reacting equimolar amounts of ammonia and 2,4-dichloroquinazoline (XI) 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^eC. 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, dimethyl formamide or their mixtures with water.

Conversion of the 2-chloroquinazoline intermediate of formula (XU) to the desired compound of formula is accomplished by contacting the intermediate (XII) with an equimolar amount of a cyclic amine of the formula ΖΉ 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 tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide; alcohols such as methanol, ethanol and isoamyl alcohol

- לוand ketones such as methylethylketone and methyl isobutyl ketone. Particularly preferred solvents are isoamyl alcohol and methylisobutylketone. The reaction mixture is heated preferably at a temperature of from about 60 to 160’C. for from one to 65 hours. Particularly preferred reaction temperatures are from about 100 to 140®C. 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 compounds of formula (I). These methods are enumerated and discussed briefly below.

1. 2-Z'-4,6-dichloroquinazolines (XXIX) prepared by methods analogous to those described in U.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 resultant formation of the desired product of formula (I) where

Y , R and Z' are as defined above.

<img file="IL61375A_D0010.tif" />

XXIX

2, The quinazolinedione of formula (X) can be reacted with a reagent such as phosphorus pentasulfide or the like to form the corresponding 2,4-quinazolinedithione which are in turn reacted with an alkyl or benzyl halide to form the corresponding 2,4-bis(alkylthio).quinazoline or 2,4-bis(benzylthio)quinazoline. This is then reacted with ammonia by the procedure previously described for the reaction of the 2,4-dichlor^qv|ijnjazolines (XI) to provide the corresponding 4-amino-2 /thioalkyl (or benzylthio) quinazoline (XX). The latter compound is then converted to the desired compound (I) by employing conditions previously described for the formation of compound (I) from 2-chloro compounds of formula (XII).

<img file="IL61375A_D0011.tif" />

where Y , z' and R are as previously defined.

3. Compounds of formula (I) wherein in the heterocyclic moiety of the formula /-(CH ) -.

f z m ץ א- X ^-(¾) / ,

X is NR³, NCOR⁴ or NCOOR⁵ and m, n, R³, r⁴ and R⁵ are as previously defined, can also be prepared from the compound wherein X is NH, for example Z' is piperazino, by acylation, alkylation or alkoxycarbonylation.

<img file="IL61375A_D0012.tif" />

<img file="IL61375A_D0013.tif" />

(XXI) (XXII) 3 4 5

W«R , COR or COOR

The compound (XXI) is reacted with a compound of formula R³-X³, R⁴COX³ or X³COOR⁵, where R³, R⁴ and R⁵ are as defined above and X 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 3 5

X COOR are contacted in the presence of a reaction inert organic solvent, for example, benzene, tetrahydrofuran, acetone methylethyl ketone, methylisobutyl ketone, 1,2-dimethoxyethane 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 temperature in the range of about 0^eC. 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 formamidine of the formula

NHnCZ' * II

NH where Z' 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, diethylene glycol, dimethylformamide, dimethylsulfoxide or diethylene glycol dimethyl ether, at a temperature of from about 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:

RO !N + NH-C-Z * II

NH (XIV)

The formamidine starting materials are prepared by methods well known in the art. For example, the cyclic amine of formula Z’H 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 ®®terials in place of the 2-aminobenzonitrile (XIV)*

<img file="IL61375A_D0014.tif" />

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 11.223£ ׳ . Che®. Soc., 775 (1947) for the isomeric 2-chloro-4-alkoxy-6,7-disubstituted quinazolines, can be reacted with a cyclic amine, Z'H, to obtain the corresponding 2-Z'-quinazolines. The 4-alkoxy substituent is then replaced by NH₂ by reaction with ammonia as described above for the 4-chloro compounds of formula (XXIX). This reaction sequence is exemplified below for a 2-chloro-4ethoxyquinazoline starting material.

<img file="IL61375A_D0015.tif" />

* (I)

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

61375/:3

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 where Y³, 2' and R are as previously defined;

<img file="IL61375A_D0016.tif" />

<img file="IL61375A_D0017.tif" />

is selected from the group

C(*NH)XR₃ wherein X is 0 or S from one to six carbon atoms;

consisting of CN and and R₃ is alkyl having and Q is CN or -C(«NH)NH

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^eC. 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 (XIV) in the process described in Belgian Patent No. 861,821 and No, 861,822 for synthesis of prazosin. The method is outlined in Scheme II. The o-aminobenzonitrile (XIV) wherein r and Y³ 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

<img file="IL61375A_D0018.tif" />

CSC1₂

<img file="IL61375A_D0019.tif" />

(XV)

Ζ'Η

RO

<img file="IL61375A_D0020.tif" />

(xvi)

NH₃NaNH*

<img file="IL61375A_D0021.tif" />

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 concentrated with the cyclic amine of formula Z'H at a temperature below 0°C., preferably at about -30 to -5*C. to obtain the 0-Z¹-carbothiamidobenzonitrile (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-methylthioformamidate 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 N,Ndimethylformamide. 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 about 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.

... J

Scheme III

<img file="IL61375A_D0022.tif" />

(XXXIII) (XXXIV) (XXXV)

<img file="IL61375A_D0023.tif" />

(XXXVI) (XXXVII)

Cyclizing Agent (!)

The starting materials of formula (XXXIII) wherein R and Y are as previously defined are known compounds [see, for example, Gibson et al., J. Chem. Soc., 111, 79 (1917); Munavalli et al. 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 intermediate (XV) and this is reacted with a cyclic amine Z'H to provide the substituted Z'-carbothiamide (XXXV) by the method described above for intermediate (XVI). The intermediate (XXXV), in turn, is reacted with an alkylating agent, Y^X* to obtain an intermediate of formula (XXXVI) in which Y^ is alkyl having from one to four,carbon atoms or an aryl derivative containing electron withdrawing groups, for example, 2,4-dinitrophenyl, and X^ is a member selected from the group Cl, Br, I, alkyl-SO^ having from one to four carbon atoms, CgHgSOj, FjCSOj and FSO₃. An especially preferred alkylating agent, Y⁴X⁴, is methyl iodide. Alternatively, as disclosed in U.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 wtih cyanamide to provide the corresponding carboxamidine intermediate of formula (XXXVII).

Alkylation of Z'-carbothiamide 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 100*C. for a period of about 0.5 to 24 hours. The intermediate of formula (XXXVII) may also be obtained by alternate procedures described in U.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 phosphorous trichloride or phosphorus pentachloride in a solvent amount of phosphorus oxychloride. Other phosphorus halides and phosphorus oxyhalides such as phosphorous 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,, £ «κ

A1C1-, AlBr,, and the like.

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 tor each gram of carboxamidine 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 CH₃.

375/2 ן6

Scheme IV

<img file="IL61375A_D0024.tif" />

<img file="IL61375A_D0025.tif" />

<img file="IL61375A_D0026.tif" />

&lt;IXb', R ־ CH₃)

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. Y = OR where R is alkyl having from one to three carbon atoms, without the Cl substituent,

b. Y = OR, R is as defined above,

c. Y³ = H.

28Scheme V

1. HNO

<img file="IL61375A_D0027.tif" />

<img file="IL61375A_D0028.tif" />

(XVIII) (XIX) (XX) (XIVc,

R = CH ) I *

<img file="IL61375A_D0029.tif" />

(XXIII) (XXI) (XXII)

<img file="IL61375A_D0030.tif" />

Scheme VI

<img file="IL61375A_D0031.tif" />

<img file="IL61375A_D0032.tif" />

(XlVa, R = CH₃) (IXa, R = CH₃)

In the reaction sequence of Scheme IV vanillin is acetylated with, for example acetic anhydride or acetyl chloride by well known methods and the acetylated intermediate nitrated to obtain 4-acetoxy5 3-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 4-hydroxy3-methoxy-2-nitrobenzaldehyde intermediate of formula 10 (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 15 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-proproxy-

5-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 = CH^), 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 compounds of formula (la). 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 = CHp 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 (IXa). 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 = CH₃) is hydrolyzed as described for the preparation of compound (XXI) from nitrile (XIX), to provide the desired compound (IXc, R = CH₃).

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 C₂H₅ or n-c₃H₇, 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 amines of formula Z'H wherein 2 '״' i_S as previously defined 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. For example, the amines of formula . , ' 2'n where a is 1, 2, or 3, π is 2, or 3 and R⁶ is as defined above are obtained by reacting the appropriate corresponding N-protected amine wherein R⁶ is hydrogen with, for example, a compound of the formula (R )'Hal where (R )' has any of the values assigned above for R except hydrogen and Hal is Cl, Br, I or other known leaving groups such as SO₃CH_r The reaction is typically carried out employing an equimolar amount of a metal hydride, for example sodium hydride and in the presence of a reaction inert organic solvent, e.g. dimethylformamide. The N-protecting group is then removed to provide the desired amine of the above formula. Typically, protecting groups such as acetyl or benzyl are employed. The former being removed by hydrolysis and the latter by catalytic hydrogenation, e.g., employing a palladium catalyst.

Alternatively, the above compounds wherein R⁶ contains an ether moiety can be obtained by the reaction sequence below which illustrates the preparation of 4-(ethoxy-n-propoxy)piperidine.

* CH₂«CH-CH₂Br ^,N' Ac

OCH₂CH־CH₂

N^xAc (2) NaBH₄, NaOH Γ I 3

Many of the requisite amines of formula

CHR⁷ (XXXVIII) wherein a, n and R⁷ are as defined above are known compounds. Those that are not known are prepared by well known methods. For example, the *⁷-substituted piperidines may be obtained by catalytic hydrogenation of the corresponding *⁷-substituted pyridines.

_gthe compounds of formula (XXXVIII) wherein R⁷⁸ ® ^C6^B4^(CB2’&lt;j ^whe«in 9 is 0 or 1 and R⁸ is as

Piously defined may also be obtained via a Grignard reaction as shown below, for example.

>^C32'a_x /C־o . R⁸C₆H₄(CH₂) MgBr -----(CBj)_n י _{p n r} >^CT2’ax ״H ^{6 5 2}\m . ------ ^tCB2>q^C6^B4^B’ 1. Acetylation ~=₂, Pd/C »

CH ^iCH2^^>CH₂)_n

H

The starting materials of formula (XXXVII1) wherein R is R CjH₄CO may be obtained, for example, by Friedel-Crafts acylation of R⁸c.H, by an Nprotected carboxylic acid halide as illustrated below.

׳*׳ Al Cl (CH-)\

CH-CON CHCOC1 + R⁸c מ ^XCI3 ' ² A _ ''(ch 1 ^{6 5}----- ⁰®' .-'׳'“נ*«V ^{20 (CB}2’n ס-------► H or OH“

J^CB2’a

HN icSCOC.H.R’ ^(CB2>n .

The piperidine derivatives of the latter formula are also obtained by employing the corresponding pyridine carboxylic acid halides and compound of formula * C₆H₅ in the Friedel-Crafts acylation followed by hydrogenation of the pyridine moiety.

The cyclic aminocarboxylic acid precursors of the above N-protected cyclic aminoacid halides are either readily available or may be obtained by the well known Dieckmann reaction followed by hydrolysis and decarboxylation of the resulting alpha-ketoester to provide a cyclic ketone intermediate which can be converted to the desired carboxylic acid by a variety of methods, e.g.

JC^h2)s 1. n»oc2h5 r13h ^aj.o ^(CB2*n* ^CO2^C2^H5 ². ^h2°&lt; NaOH* n

<img file="IL61375A_D0033.tif" />

¹- HBr^/^2^

2. Mg, r^n CHCOOH->

³- ^C02<®2’ζ /^(CS2>a\ ®ז CHCOOH

JCH *An

In the above reaction sequence a and n are as defined above and R₁₃ is a suitable amino protecting group, e.g. benzyl or acetyl. As will be recognized by one skilled in the art, in the above reaction sequence when R₁₃ is benzyl the ketone reduction step is preferably carried out by a metal hydride, e.g. sodium borohydride or lithium aluminum hydride, and removal of the benzyl group is accomplished by hydrogenolysis.

The antihypertensive activity of the compounds of formula (I) 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-lyloxycarbonyl)piperazin-l-yl]-4-amino-6-chloro-7,8dimethoxyquinazoline, 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. £., 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-C2-hydroxy-2-methylprop-lyloxycarbonyl)piperazin-l-yl]-4-amino-6-chloro-7methoxyquinazoline, 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-C2-furoyll־rl-piperazinyl]-4-amino6-־chlor0’-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./hg.) 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 ac— tivity, 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 approximately 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.

EXAMPLE 1 *’ ^³¹¹”⁰־»'⁷־«»ethiavouihatoHne.־^(Ih,3H)-dign. _(מ>) . ^{AC־ti־ acid} <¹⁰.⁵ 9- «.״δ mole) was added to I-----vigorously stirred suspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g0.125 ״ mole) in 600 ml.

*star. Then 506 ml. 5% potassium cyanate (0.312 *“ ^sradually added and stirred 1 hour ־* --. After cooling the reaction mixture to

J. (4.37 moles) of sodium hydroxide pellets while maintaining the temperature below

The reaction mixture was heated to 9O*C. for Opon cooling in an ice bath, the sodium at 40’C. ; 20^eC., 175 g were added 40®C. Γ 45 minutes.

salt of the product precipitated, was filtered off'“ resuspended In 15־ ml. water, acidified with concentrated ---- _□ yield 25.8 , pureproduct, M.P. 272-3^eC.

C, 46.79;

hydrochloric acid, cooled and filtered to 9» (80%) of colorless, ---- Analysis, Percent Calcd. for C,״H״C1N 0 . _L 3-53 ׳־; N, 10.92. ^{10 5 2 4}־

Pound: C, 46.87; H, 3.60,- H, 10.90.

^B* ^¹⁰”¹^¹¹⁰*⁸־⁷־”«wliM-Z^llH^HI-dione (χοτττ: Similarly, 6-chloro-7-methoxyquina־oline-2,4(lH,3H)dione was prepared from 5-־hloro-4-methoxy_anthranilic acid in 83% yield, M.P. 356-8^eC.

Analysis, Percent Calcd. for C.H.C1N.0,־ c, 47 70.

B, 3.11, N, 12.36. ³

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

A.

4nn ^{iXtUre Of 6}“^chloro-7,8-dimethoxyquinazoline2,4 (1h,3H)-dione (25.5 a., n 099 ו^וחוזז _u chloride (41 4 ο 0 14, , . ׳ ^Ph°^Sphorus ui * ⁹*' ^{0,199 mole) and 300} ®ג. phosphorous oxychloride «a־ refluxed under nitrogen for three

P0Cl^{־PhOrUS 0Xy־hl0ride was} i־ vacuo and re.H _ ^{3 rem0Ved as the} azeotrope with toluene. The ddish-orange solid was dissolved in 200 »1. dichloro»ethane and the solution was slowly added to ice-cold ־״tex. After stirring for 10 ninutes the organic layer was separated, washed with water, and dried ל'־־1^עב w^S“^lfate. ”⁶־^£Utrate ״^{a־ concen}trated and 150 ml. hexane was added the product as a pale yellow from toluene/ether to afford M.P., 154-5^eC.

Analysis, Percent Calcd. for

B, 2.40; N, 9.55.

slowly to precipitate solid which was recyrstallized 18.0 g. (62% yield), ^C10^H7^C13^N2°2^{: c}40.91 ׳;

Found־ c, 41.05, H, 2.48, _S, ₉.₆!.

^B’ 2z.⁴f6-Tr1chloro-7-methoxyquinazoline (mi

Refluxing 6-chloro-7-_methoxyquinazoline-2,4(l_H 3H) dione with PC1_ in Pnn _ae _____ . . ׳ ^; afforded yield.

כ---3* aoove ,4,6־trichloro-7-methoxyquinazoline in 74% M.P., 150-2®C.

Analysis, Percent Cald. for C^CIno: c, 41.02

B, 1.91־ N, 10.63. ^{3 2}

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

EXAMPLE

A. 2,6-Dichloro-4-amino-7^:, 8-dimethoxyquinazoline (XTIb) Ammonia was passed into a solution of 2,4,6-tri- chloro-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., 360°C.

Analysis, Percent Calcd. for C^qH^C^^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-methoxyquinazoline (XX) Reaction of 2,4,6-trichloro-7-methoxyquinazoline with ammonia as described above afforded 2,6-dichloro-

4-amino-7-methoxyquinazoline as a white solid, M.P., 300°C. in 58% yield.

Analysis, Percent Calcd. for CgH^CljN^O: C, 44.28; H, 2.89; N, 17.22.

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

EXAMPLE 4

A. 2-[4-(2-Furoyl)piperazin^-l-yl]-4-amino-6chloro-7,8-dimethoxyquinazoline hydrochloride (XHIb) A mixture of 2,6-dichloro-4-amino-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.

-I4&lt;Analysis, Percent Calcd. for C^H^CiN ° nd 1/2.H,O:

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* -²2 )-4) ־-Furoyl)piperaz in^-l-yl]-4־amino6־chloro-7-methoxyquinazoline hydrochloride

The title compound was prepared similarly by refluxing 2,6־*dichloro-4-amino-7-methoxyquinazoline and I”(2-furoyl)piperazine in isoamyl alcohol, M.P. 229-31’C., 79% yield.

Analysis, Percent Calcd. for C H C1N 0,.HCl.H,0:

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 5 ^A2_ ־-Methyl-2-hydroxypropyl 4-[4-amino-6-chloro7,8-dimethoxyguinazolin-2-yl] hydrochioride

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyguinazoline (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. methylisobutylketone for two days. The yellowish solid was filtere&lt;y,^ffresuspended 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.

־ 44 ־

Analysis Percent Calcd. for C._QH_9&lt;;C1N_EO-.HC1: a-l כ ב C, 47.90%; ff, 5.50%,. N, 14.70%,

Found: C, 47.70%; H, 5.74%; N, 14.36%,

Water Solubility: 35 mg./ml.

B:---2-ethyl-2-hydroxypropyl 4~ [4-amino-6*»chloro7־~ ngthoxyquinazolin-2-yl]pipera2ine-l-carboxylate hydrochloride [XXI, R¹ + r²_c ^COOCH_?C(pH). CCHnJ^I

The title compound was prepared similarly by refluxing 2,6-dichloro-4-amino-7-methoxy quinazoline and 2-methyl-

2-hydroxypropyl-4-piperazine-l-carboxylate in methyl isobutyl ketone for 4 days, M.P, 243-5’C,, 69% yield. Analysis Percent Calcd. for C_1ftH,.ClN_E0.HCl.H,0

Λ0 x4 2 4 כ

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-fl, 4-Benzodioxan-2-carbonyl)piperazln-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-7methoxyquinazoline and N-Cl, 4-benzodioxan-2-carbonyl)piperazine in methylisobutylketone, M.P. 194-196’C.

EXAMPLE 6

2-(4-(2-Tetrahydrofuroyl)piperazin-l-yl]-4-amino---------S-chloro-7,8-diroethoxyquinazoline________ To 35 ml. of isoamyl alcohol were added 1.50 g.

(5.47 mmole) of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g. (6.02 ״״ole) _pf 1-₍₂__tetra_ hydrofuroyl)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. Th. 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, B.p. 192-193®C.

Analysis, Percent Calc’d. for ^gH^O^Cl: 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 1.

Employing the procedures of Examples _s 4 ;; and '5׳; the following compounds are similarly prepared from the appropriate starting materials.

RO V

Y³

RO ^CH3° ^C2^H5° n-C3H7O ch3o ^CH3° ^c2^H5° ch3o ^CH3° ch₃o ^CH3° ch₃o

H η-Ο₃ΗγΟ

H ch₃o

H

H ch₃o

H

H

CH₂C(CH₃)=ch₂

CH₂C(CH₃)=chch₃

CH₂CH₂OH

CH₂CH(OH)CH₃

CH(CH₃)CH(CH₃)CH₂OH

C(CH₃)₂C(OH)CH₃

CHO cyclopropylcarbonyl

3-thenoyl

<img file="IL61375A_D0034.tif" />

<td> CH₃O</td><td> H</td><td> CH₃OCO</td>

<td> CH₃O</td><td> H</td><td> (CH₃)₂C(OH)CH₂CH₂OCO</td>

<td> C_oH.0 כ 2</td><td> C₀H_cO z כ</td><td> CH₃CH(OH)CH₂OCO</td>

EXAMPLE 8 ^A3 ־_zChloro4־-methoxy-6-isothiocyanatobenzonitrile

To a solution of 27.4 g. (0.15 mole) of 6-amino-

3-chloro-4-methoxybenzonitrile in 150 ml. of 1,2dichloro-ethane at 0-5.C. is added with stirring a mixture of 23 g. (0.2 mole) thiophosgene, 100 ml. 1,2dichloroethane, 20 g. (0.2 mole) calcium carbonate and 200 ml. of water. After the addition the mixture is stirred for one hour at 0-5°C., warmed to 20°C. and stirred for 6 hours at this temperature and finally at 35’C. for an hour. The reaction mixture is filtered and the organic layer separated, washed with dilute hydrochloric acid, water and dried (MgSO₄). The solvent is removed by evaporation and the residue used without purification in the next step.

^B* 3rChloro-4-methoxy-6-(homomorpholin-4-yl) thiocarbamidobenzonitrile

To 11.3 g. (0.05 mole) of the above residue dissolved in 65 ml. of ethyl acetate is slowly added with stirring at 0°C., a solution of 5.1 g. (0.05 mole) of homomorpholine in an equal volume of the same solvent. The resulting mixture is cooled to -25^ec. and allowed to stand overnight. The precipitate is collected by filtration, washed with cold ethyl acetate and dried to obtain the desired product.

^C* EL(³־Methoxy-4-chloro-6-cyanophenyl)-(homomorpholin_4-yl )-methylthioformamidate

In 200 ml. of diglyme (diethylene glycol dimethylether) is dissolved 16.3 g. (0.05 mole) of 3-chloro-4methoxy-6-(homomorpholin-4-yl)-thiocarbamidobenzonitrile and 14.2 g. (0.1 mole) of methyl iodide and the mixture heated at reflux (60°C.) for eight hours then cooled to room temperature. The resulting mixture is filtered, the solid product washed with ether and dried to obtain the hydr^iodide salt of the title compound.

־ 48 The hyd^iodide salt is dissolved in 150 ml. of methanol and 90 ml. of 25% ammonium hydroxide is added with stirring. The resulting mixture is stirred for two hours at 0®C., filtered and washed with ether to obtain the title compound as the free base.

^D* ²*־&lt;Homomorpholin-4-yl)-4-amino-6-chloro-7־methoxyguinazoline

To a solution of 3.4 g. (0.01 mole) of the free, base obtained in Part C, above, in 75 ml. of formamide is added 1.3 g. of sodium amide and the resulting solution is cooled to 0*C. and saturated with ammonia gas; The cold solution is warmed slowly over 2-3 hours to 120״C., then maintained at this temperature for 4 hours. The reaction mixture is then cooled to room temperature, 100 ml. of ice-water added, the mixture extracted with chloroform, the extracts washed with water, dried and evaporated to dryness. The crude residual product is purified by crystallization.

EXAMPLE 9 ^A. _2-[4-(2-Ethoxyethoxy)piperidin-l-yl] -4-amino-6chloro-7₁8-dimethoxyquinazoline hydrochioride

4-Amino-2,6-dichloro-7,8-dimethoxyquinazoline (4.9 g.), 4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) in n-butanol (400 ml.) are heated at reflux overnight under an atmosphere of nitrogen. The mixture is then cooled, evaporated in vacuo, and the residue basified (aqueous Na₂c0j) and extracted 3 times with chloroform. The combined chloroform extracts are evaporated and the residue chromatographed on neutral alumina to give the crude product which is converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol to afford the title compound.

3. By the above procedures the following compounds are similarly provided from the appropriate starting materials in each case.

־ 50 -

ר

RO 1 2! CH₃O η ch₃o η ch₃o ch₃o

JCHj)^

IT CHO(CH₂) ₃OCH₃^Χ(<:Η2>Γ _X^(CH2\

N CHOCH₂OCH₃ >^CH2\

N CHOCH-CH(CH-),CH״

S' / 2 ג ג (CH₂)₃ och₃

EXAMPLE 10

2-(Morpholin-4-yl)-4-amino-7,8dim.thoxyquinaroline hydrochloride (Reference Exm.nl.)

To 500 ml. of methylethylketone is added 0.1 mole of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 0.12 mole of morpholine and the mixture is refluxed overnight. After cooling in ice־water the solid precipitated is collected by filtration, washed with ether and air dried to obtain the title compound.

When the appropriate starting materials are employed in each case in the above procedure or the procedure of Example 8, the following compounds are likewise obtained.

<img file="IL61375A_D0035.tif" />

CH₃O H 2 2

CH3O H 23 ^ct₃0 CH-0 23 ^C2^a5° ^c2^H5° ³³

־

EXAMPLE (Reference Example)

<img file="IL61375A_D0036.tif" />

<img file="IL61375A_D0037.tif" />

To a stirred solution of 1.78 g. (0.01 mole) 3,4-dimethoxy-2-aminobenzonitrile in 30 ml. of N,Ndimethylformamide is added 2.88 g. (0.01 mole) ethyl 4-(2-furoyl)piperazin-l-ylformimidate hydrochloride followed by 855 mg. (0.02 mole) of a 56.1% dispersion of sodium hydride in mineral oil. The reaction mixture is stirred at ambient temperature for 30 minutes, and then it is heated to ca. 100^eC. and maintained at that temperature for 12 hours. The reaction mixture is cooled to ambient temperature, diluted with an excess of water, and then extracted with chloroform. The chloroform extract is washed several times with water, dried using anhydrous magnesium sulfate, and then evaporated to dryness in vacuo. This affords crude 7,8-dimethoxy-4-amino-2-[4(2-furoyl)piperazin-l-yl]quinazoline, which is purified further by recrystallization from aqueous ethanol.

־

B. The procedure of Part A is repeated, except that the 3,4-dimethoxy-2-aminobenzonitrile used therein is replaced by an equimolar amount of:

5-chloro-3,4-dimethoxy-2-aminobenzonitrile, 5-chloro-3,4-diethoxy-2-aminobenzonitrile, 5-chloro-4-methoxy-2-aminobenzonitri1e, or 5-chloro-4-isopropoxy-2-aminobenzonitrile, to provide the following compounds, respectively.

<img file="IL61375A_D0038.tif" />

ch₃o H (ch₃)₂cho H

EXAMPLE ¹²

5-Chloro-4-methoxy-2-aminobenzamidine hydrochloride prepared by the procedure of U.S. 3,935,213 for analogous compounds (0.01 mole) and an equimolar 5 amount of l-cyano-4-ethoxycarbonylpiperazine also provided in the same reference, are dissolved in 50 ml. of anhydrous ethanol and stirred overnight at ainbient temperature. A 5 ml. aliquot of triethylamine is added and the mixture is heated at reflux for 12 hours. The solvent is evaporated to provide 4-amino-

6-chloro-7-methoxy-2-[4-ethoxycarbonylpiperazin-1yl]quinazoline as the hydrochloride salt.

EXAMPLE 3T 13 stirred solution of 24 ml. of concentrated sulfuric acid dissolved in an equal volume of water was cooled to 10-12’C. and 0.015 mole of methallyl 4(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-l-carboxylate is added in small portions with stirring. The addition is carried out at a rate 20 sufficient to keep the reaction temperature below

20*C. The resulting mixture is stirred for 15 minutes ^at 15-20^eC., then for two hours at 10-15°C. The reaction mixture is diluted with 150 ml. of ice-water and adjusted to pH 10 with sodium hydroxide while maintaining the temperature below 12°C. After extraction with chloroform, the combined extracts are washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo and the residue recrystallized to afford 2-methyl-2-hydroxypropyl 4-(4-amino-630 chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1carboxylate.

55 ־

EXAMPLE 14

2-(4-(3-hydroxypropyl)homopiperazin-l-yl]-4amino-7,8-dimethoxyquinazoline hydrochloride (Reference Example)

A mixture of 4 g. of triethylamine, 3,0 g, of 2homopiperazino-4-amino-7,8-dimethoxyquinazoline_t 4.5 g. of 3-bromo-l-propanol and 50 ml. of diethyleneglycol dimethyl^ether is heated at 100-120*C. with stirring for 16 hours. The reaction mixture is concentrated' in vacuo and the residue made alkaline by addition of sodium hydroxide solution. The mixture is extracted with chloroform, the extracts washed with water, dried with potassium carbonate and filtered. The filtrate is concentrated, the residue taken up in isopropanol and a solution of hydrogen chloride in isopropanol added until precipitation is complete. The title compound is collected by filtration and dried.

When an equivalent amount of 1,3-propaipiiol mono tosyl ate or 1,3-proparjtiiol monomethyl sulfonate are employed in place of 3-bromo-l-propanol in the above procedure, the results are substantially the same.

EXAMPLE 15

Employing the appropriate starting materials in each case the following compounds are prepared by the procedure of

Example 14 according to the equation

<img file="IL61375A_D0039.tif" />

Where a is 1 or m; m and n are

<img file="IL61375A_D0040.tif" />

or 3 and Q is a leaving group such as Br, Cl, p-toluenesulfonyloxy or methanesulfonyloxy.

<td> RO</td><td></td><td> a</td><td> n</td><td> R^</td>

<td> n-C₃H₇O</td><td> n-C₃H₇O</td><td> 2</td><td> 2</td><td> ch₂=chch₂</td>

<td> ch₃o</td><td> H</td><td> 3</td><td> 2</td><td> (CH₃)₂C=CHCH₂</td>

<td> ch₃o</td><td> ch₃o</td><td> ו</td><td> 2</td><td> HOCH₂CH₂</td>

<td>^CH3°</td><td> H</td><td> 2</td><td> 2</td><td> (CH₃)₂C(OH)CH₂</td>

EXAMPLE

Tablets

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

Sucrose, u.S.P

Tapioca starch13.2

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

Into this base is blended sufficient 2-[4-(2-f uroyl} _r1-piperazinyl] -4-amino-6-chloro-7-methoxyquinazoline© hydrochloride to provide tablets containing 0.5, 1.0, 10, 100 and 250 mg. of active ingredient.

EXAMPLE

Capsules

A blend, is prepared containing the following ingredients:

Calcium carbonate, U.S.P!7.6

Dicalcium phosphate 18.8

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

Lactose, U.S.P... 5.2

Potato starch5,2

Magnesium stearate A,0.8

Magnesium stearate B,0.35

To this blend is added sufficient 2-[4י- Q2 !-hydroxy-2methylprop-l-yloxycarbonyl [piperazin-l-yl] -43-amino!-6!chloro-7-methoxyquinazoline to provide formulations containing 0.5, 1.0, 5, IQ, 10Q, 250 and 500 mg. of active ingredient, and the formulations are filled into hard gelatin capsules of a suitable size.

EXAMPLE

Injectable Preparation

2-[4-(2-furoyl-1-piperazinyl]-4-amino-6-chloro-7-methoxyquinazoline hydrochloride is intimately mixed and ground with 25 QQ 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

Solution

Ά solution of 2-[4- (2-hydroxy-2-methyIprop-1yloxycarbonyllpiperazin-l-yl]-4-amino-6-chloro-7,8dimethoxyquinazoline or a pharmaceutically acceptable salt thereof is prepared with the following composition:

- Effective ingredient 30.22g.

Magnesium chloride hexahydrate 12.36g.

Monoethanolamine 8.85ml.

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.

־ 58 ־

EXAMPLE 20

Biological Test Results

Compounds A, B and C of the invention, as well as control antihypertensive agents prazosin and trimazosin, were compared for hypotensive activity in conscious renal hypertensive dogs by the procedure of Prioli and Winbury, J. Applied Physiol, 1!5, 323 (1960). The compounds were administered as their hydrochloride salts by the oral route and. blood pressure was determined just prior to administration of drug and at frequent intervals thereafter. At least two dogs were used for each experiment. Results are summarized in the table.

Blood

Oral Dose Pressure Duration, Compound mg/kg Decrease Hours

A. Formula I where:

R־CH- ־= OCH, י___4 >Z־׳ N^NCO₂CH(CH₃)₂ 0.2 30 mmHg 4

OH

B. Formula I where;

¾= _.CH₃, y³ = h, ־^{Z =} __NCO₂CH(CH₃)₂ - 0.2 20-40 mmHg 6

OH

C. Formula I where:

R= CH₃ Y³ = h,

<td> Z'= N NCO-A^</td><td> 0.2</td><td> 35-40</td><td> mmHg</td><td> 6</td>

<td> Prazosin</td><td> 0.625</td><td> 40</td><td> mmHg</td><td> 6</td>

<td> Trimazosin</td><td> 2.5</td><td> 15-30</td><td> mmHg</td><td> 6</td>

PREPARATION 4^Acetoxy-‘3^methoxybenzaldehyde QV1 Triethylamine (2.8 liters, 20.,1 molesL was added dropwise to a solution of vanillin (2.Q0 kg., 13.15 moles! and acetic anhydride (2.6 liters, 27.5 moles[ in methylene chloride QI«3 liters! maintaining temperature below⁴ 25 *C. After adding 4-dimethylaminopyridine (20 g.! the solution was stirred at room temperature for 30 minutes. The reaction mixture was washed twice with water, followed by 20% Cw/wJ. hydrochloric acid and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane Q5 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. 7678°€-י.

PREPARATION

4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (V) Over a period of 1.5 hours 4-acetoxy-3-methoxybenzaldehyde Q120 g., 5.77 moles) was added in small portions to 4 liters of red fuming nitric acid cooled to 0^eC. After stirring for one hour below 5°C., the reaction mixture was added to large amount of ice-water and stirred an additional hour. The resulting yellow product Q130 g., 82% yield! was filtered off 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

4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (y!) 4~Acetoxy-3-methoxy-2-nitrobenzaldehyde Q.12 Q 9., 4.72 moles1 was added portionwise to a freshly prepared 33% (w/w! NaOH solution C4.5 liters!. The resulting slurry was heated on 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 6N hydrochloric acid while cooling, IQ and the resulting product C794 g., 85% yield) was filtered off and washed with water. Recrystallization from ether/cyclohexane gave the desired product as light yellow solid, M.P. 136-137®c.

PREPARATION ¹⁵-Dimethoxy-2-nitrobenzaldehvde (VI! ן

Anhydrous sodium carbonate □57 g., 9,03 ®oles), toluene (5 liters), 4-hydroxy-3-methoxy-2nitrobenzaldehyde C1424 g., 7.22 moles! and dimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4 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 activated charcoal, dried over magnesium sulfate and filtered. Hexane C7.6 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-3^ ®ethoxy-2-nitrobenzaldehyde is similarly obtained.

iii. When n^propyl bromide is employed as the alkylating agent the corresponding 4-n-propyloxy 35 compound is provided.

PREPARATION

3,4-Dimethcxy-2-nitro-benzoic acid (yup

A solution of 823 g. potassium permanganate in about 8,5 liters of HjO was gradually added to a refluxing solution of 3,4T־d±methoxy^2-nitrobenzaldehyde (.550. g., 2,60 molesl in 5.5 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. 200-202°C,

PREPARATION F

3,4-Dimethoxyanthranilic acid

ClXa, R־CH_1 _________ **

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.

(XXII1 nitrite to a cooled

C68.0 g., 0.4Q4 concentrated hydro« ^J temperature at

3Q

0.404

9. t 0.646 mole) in and intermittent

PREPARATION Wiethoxy anthranilic acid ^rQfano—3-nitroanisole (Xrxy , ^A saturated solution of sodium ’ . ⁹0,485 ׳״ moleJ was added dropwise solution of 4«methoxy-2-nitroanxline ®ole) in 300 ml. water and 54 ml _cchloric acid, while maintaining the °‘^C- “^{d PH at 5} * .“**״» Of sodium carbonate added 7“ ““ “¹*¹⁰י־ °^{f dia־Oni}™ ״־־ Z dded carefully through a jacketed d™ a hot solution ^roPP!ng funnel to ^solution of cuprous cyanide (36.2 ®ole) and potassium cyanide (42.1 g. ־ 500 al. water, vigorous heating on a steambahl.! י , was heated an *mu___ן _fift ? ?«¹low suspension ״as filtered off a a ״“״^tes. ^The «¹¹־d . . ׳-“־ ^{dr1ed a}^d dissolved in ethyl acetate discarding the ״״dissolved inorganic salts After ^conc«ntration of tnyi acetate solution yielded 55.1 _g. _{c7״) of}>״״rht yellow^range crystals, «.p. _13S-V_CAnalysis, Percent Calc’d. for c w μ n

3.39; N, 15.73 ^fOrW₂°353.93 ,־> ־, _B, Found: c, 53.92; _H״._{3 ׳}, _{H< 15>85}. ii. ±:MethoxY-2-_nitrobenzoic acid gpm

4-Cyano-3-nitroanisole (52 3 σ n 0 0>t slowly added to a cooled solution «531! e h‘ acetic acid, water and sulfuric acL. _T^₈7 ^f°^{r 5} ״d then diluted 1״T 0 rntXTf/‘״ °^OOlin9׳ ^{toe resultin? 01־id} ־»״ xiltered off and dissolved in ו na

After decolorization with activated ־^־o“־“:״־ ⁶ ש ה ה^{N bc1}°°°¹ ׳^ed “^d «>־ x ^wasCSl.Og., ״־ yield) was filtered off. An analytics!

sample was recrystallized from methanol/water, M.P. 196-7°C.

Analysis, Percent Calc*d, for CgH^NOg; C, 48,74; H, 3.58; N, 7,11

Found: C, 48.37; H, 3,57; 7,03.

iii. 4-Methoxy anthranilic acid (XXII),

A solution of 4-methoxy-2-nitrobenzoic acid (19.3 g., 97.9 mmoleJ in 200 ml. IN NH_AOH was reduced

ר overnight in presence of 5% Pd/BaCO^. The reaction 10 mixture was filtered and acidified with acetic acid to yield 15.8 g. (96%) of the anthranilic acid, M.P. 186-188°C.

iv. Employing 4-ethoxy-2-nitroaniline or the corresponding 4-n-propoxy- or 4-isopropoxy- compounds 15 as starting material in the above procedures the following products are similarly obtained.

<img file="IL61375A_D0041.tif" />

where Y is ethoxy, n-propoxy or isopropoxy.

PREPARATION

i. Methyl/3,4-dimethoxyanthranilate

Hydrogen chloride was passed into a solution of 3,4-dimethoxyanthranilic acid QOQ g_t, 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 to pH 10 with sodium hydroxide solution. After cooling for an additional hour, the cream color off product C87.0 g., 82% yield) was filtered/ Recrystallization from methanol furnished pure product, M.P.

66-67®C.

Analysis, Percent Calc’d. for C_1QH₁₃NO₄; 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-methoxy anthranilic acid as described above afforded methyl/4-methoxyanthranilate, M.P. 77-79°C., in 77% yield.

PREPARATION

1. S-Chloro-3,4v»dimethoxyanthranilic acid (IXb, R ° CHJ

Sulfuryl chloride GL9.«3 ml«, 0.,24 mole) was added dropwise to a cooled solution of methyl 3,4dimethoxyanthranilate 02.2 g,, Q.2Q mole! in 40.0 ml. chloroform at Q״C, (The sulfur dioxide produced was passed through a water trapl. After stirring 3a minutes at ambient temperature the solution was refluxed for 2 hours. The black solution was treated with activated charcoal and the solvent was evaporated. The

H-NMR spectrum indicated that the black, oily residue was largely the desired intermediate ester. The crude methyl ester was saponified with 400. ml. 5% 15 Cw/v) sodium hydroxide on a steam bath for one hour.

After cooling, the basic suspension was acidified with acetic acid to precipitate a brown solid which was filtered off and recrystallized from carbon tetrachloride to afford light-brown crystalline product (29.0 g., 63.1% yield), M.P. 140-2^eC. {Reported M.P.

142-3^eC., J. Chem. Soc., 4310-4, 1964].

Analysis, Percent Calc’d. for C_gH_1QClNO₄: 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, Treatment of methyl 4-methoxyanthranilate

R=CHJ J* 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-methcxyanthranilic acid in 64% yield, M.P«, 21Q-3°C, Analysis, Percent CalcM for C_fiH״ClNQ; C. 47,66,- H,

4.QQ,״ N, 6.S5

Found; C, 48.00; ff, 4.11; N, 6,a4,

When methyl 4-ethoxyanthranilate or methyl

4- n-propyloxyanthranilate are carried through the above procedure 5-chloro-4-ethoxyanthranilic acid and

5- chloro-4-nT־propyloxyanthranilic acid are obtained in like manner.

. .

W^־

PREPARATION J

3.- Qn-Txifluoromethy Ip henyl )!piperidine

i. N-B.enzyl-3-hydroxy-3- Gnrtr if luoromethy!phenyl.!piperidine' ־־ ----------5 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-bromotrifluoromethy !benzene in 300 ml. of ether over a two hour period. The resulting mixture is stirred for two hours at ambient temperature then cooled to 5®C. 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 5nto 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 ' . 20 the resulting mixture extracted with ethyl acetate.

The combined extracts are washed with brine, dried (MgSO₄) and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with cyclohexane/chloroform/triethylamine (85:1055 25 by volume) to obtain the desired product as an orange colored solid.

ii. N’־'Benzyl-3-acetoxy-3T- Cmvtr if luor omethylpheny 1).piperidine hydrochloride ~~———————

A mixture of 37 g, of Menzyl-3^hydroxy-3(m^trifluoromethylphenyl[piperidine, 220. ml. of acetic anhydride and 0.3 ml. of concentrated sulfuric acid is heated to HO’C. for one hour, After cooling it is poured pnto 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 (MgSO₄I and evaporated to dryness to obtain 39. 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 C40 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&lt;-trifluoromethyIpheny 1) piperidine hydrochloride as colorless crystals, M.P. 200^eC.

iv. Employing the appropriate cyclic aminoketone, selected from (״N> feenayl 3 pyrrolidonoy N’-benzyl-3־' piperidine, Nr-benzyl^4-piperidone, N-benzyl-4-oxo azacycloheptane and N-benzyl-4-oxo-azacyclooctane, and the appropriate R⁷Hal (where Hal is Cl, Br or I) in the above procedure the following compounds are obtained in similar manner.

<img file="IL61375A_D0042.tif" />

a

ו ^{2 C}6^H5 ^{2 C}6^H4^CH2

4-CF_QC,H.CH_O^{3 C}6^H5

C.H.CH, כס Z

PREPARATION K

Ql, 4«-Benzodioxan-2-carbonyllpiperazine l,4-Benzodioxan-2-carboxyl±c 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 CH« 88 g.) and sodium acetate (.20.30 g.) in a mixture of water C70 ml.) and IQ acetone C95 ml.) was stirred at 10^erl5°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 C31.0 g.) and sodium hydroxide (5N, about 45 ml.) were then added portionwise while maintaining the temperature at 10^e°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 aqueous phase was basified to pH 8-9 with sodium hydroxide (5N), re-extracted with chloroform C3 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 in vacuo and the solid residue triturated with ether, followed by recrystallization from methanol to give N1-(l,4-benzodioxan-2-carbonyl)׳.

piperazine hydrochloride Q4.85 g.[, M.P. 265⁰&lt;-267°C.

PREPARATION L

N׳-Acetyl-4-allyloxypiperidine

A solution of N-acetyl-4-hydroxypiperidine C100 g.) in dimethylformamide C250 ml.l was added dropwise to sodium hydride C38 g., 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours then allyl bromide (93 g.) was added slowly whilst maintaining the reaction temperature at 25^eC. by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20. ml.), and ether (500 ml.!, filtered, and evaporated in vacuo, Distillation of the residue gave N&lt;-acetyl-4-allyloxypiperidine (108.8 g.I, B.P. 128^eC./2 mm., identified spectroscopically.

PREPARATION M 4- (2-Methoxy-n-propoxy) piperidine A solution of N’-acetyl-4-allyloxypiperidine (6.4 g.) in dry methanol (10 ml.) is added dropwise to a stirred suspension of mercuric acetate (11.5 g.) in methanol (50 ml.) at room temperature. After 20 minutes the mercuric acetate is dissolved and the mixture is stirred for a further 40 minutes, cooled in ice-water, and sodium hydroxide (20 ml., 5N) is then added. A yellow precipitate formed during the addition. A solution of sodium borohydride CL.3 g.) in sodium hydroxide (20 ml., 5N) is then added, the mixture stirred for 10 minutes, and acetic acid added to bring the pH to 6. The mixture is filtered from precipitated mercury, the ethanol evaporated in vacuo, and the resulting aqueous phase extracted with chloroform.

The organic extracts are dried (Na^SO^, evaporated in vacuo, and the resulting crude residue taken up in methanol (50 ml.) and heated under reflux overnight with sodium hydroxide (20 ml., 5N) and water C2Q ml.).

Most of the alcohol is then removed in vacuo, the aqueous layer extracted with ether, the extracts dried (Na₂SO₄) and evaporated to leave a residue.

The residue is treated with hydrochloric acid C20 ml., 2N) and heated on a steam bath for IQ hours. The mixture is then washed with ether, the aqueous phase basified (Na₂CO₃), extracted with ether and the organic extract dried 0ia₂SO₄) and evaporated to IQ leave a resiude. Distillation of the residue at reduced pressure affords the title compound.

PREPARATION _N4-(2-Hydroxy-n-propoxy)piperidine

N-Acetyl-4-allyloxypiperidine (18 g.) in tetrahydro15 furan (30 ml.) was added dropwise to a stirred yellow suspension of mercuric acetate (34 g.) in a mixture of water (120 ml.) and tetrahydrofuran (120 ml.). The suspension dissolved during the addition and the resulting clear solution was stirred at room temperature 20 for 20 minutes, then sodium hydroxide C70 ml., 5N) was added, accompanied by ice/water cooling. The intermediate thus obtained was then reduced by the addition of sodium borohydride (2g.) in sodium hydroxide (40 ml., 5N), the excess hydride being 25 destroyed after 10 minutes with glacial acetic acid.

The liquid phase was then decanted off, saturated with sodium chloride, the organic phase separated, and the remaining aqueous layer extracted four H1m»a with chloroform. The combined organic phases were 30 dried {Na₂SO₄), and evaporated in vacuo to leave a colorless oil Q23 g.).

This oil was stirred with. 5N sodium hydroxide at room temperature for 16 hours, then at 10.0°C_t for 2 hours. The solution was then extracted with chloroform (four times1, the combined extracts dried (Na 230^), 5 and evaporated in vacuo to leave a crude crystalline product (16.1 g.!_f This was taken up in methylene chloride, filtered, evaporated, and the. residue, triturated with petroleum ether (B.p. 4Q^e/60^eC.l to yield 4- C2-hydroxy-n-propoxy!piperidine (!1,0 g.), 10 M.P. 55-57°C. The oxalate salt thereof was prepared by combining ethereal solutions of the two reactants and recrystallized from isopropanol. M.P. 104-105°C.

PREPARATION 0

4- (3-Methoxypropoxy) piperidine

A solution of N-acetyl-4-hydroxypiperidine (30.5 g.) in dimethylformamide (200 ml.) is added d^opwise to a stirred suspension of sodium hydride (11.26 g., 50% dispersion in mineral oil) in dimethylformamide (300 ml.) under an atmosphere of nitrogen.

The reaction temperature is kept below 30’C. by external cooling and, after the addition is complete, stirring is continued for a further 1 1/4 hours. A solution of l-bromo-3-methoxypropane (35.2 g.)_ in dimethylformamide (100 ml.) is then added dropwise with external cooling, and the resulting clear solution is stirred at room temperature overnight. The reaction mixture is then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (NajSO^) and evaporated to leave a

3Q crude residue. The above aqueous phase is saturated with sodium chloride, further extracted with chloroform, and the organic phase is dried (Na2SO^!, and evaporated to leave a further residue. This residue is combined with the original residue and heated on a steam bath 35 overnight with hydrochloric acid (243 ml., 2N). The reaction mixture is extracted with chloroform to remove the residual mineral oil, the aqueous phase concentrated, has if led with, sodium hydroxide (pa 12), then reextracted with, chloroform« The. organic extracts are washed with. Brine, dried (Na₂SO₄L and evaporated to afford the desired product.