Process for preparing novel chloro- and alkoxy-substituted-2,4-diaminoquinazolines

PROCESS FOR PREPARATION OF NEW ODORO- AND ADCOXX-SUBSTITUTED-2,4-DIAMINOKINAZOLINS

<img file="PT72007B_D0001.tif" />

-2 stable; Carbon dams;

hydrogen, alkylalkyl having alkynyl each having on¹ is hydrogen or chlorine, | OR, R3 is hydrogen or OR so that when T is hydrogen, R is OR and when X is CH, is hydrogen or OR and its pharmaceutically acceptable salts an alkyl group having from one to three atoms.

Seen separately, R and R are each having from one to five carbon atoms, three to eight carbon atoms, alkenyl or one from three to five carbon atoms or hydroxy substituted hydroxy alkyl having from two to five t. carbon atoms, when taken together with the nitrogen atom to which they are attached, R and ά form a substituted or unsubstituted heterocyclic group, optionally containing an oxygen, sulfur or a second nitrogen atom as a ring component; They are used as antihypertensive agents in pharmaceutical compounds containing them and in intermediates for their production.

New substituted diaminoquinazolines-2--chloro and alkoxy

Related Patent Reference

This is in part a continuation of the patent with serial number 90,313 filed November 1, 1979.

BACKGROUND OF THE INVENTION

Pampo of the Invention

This invention relates to certain

2,4-diaminoquinazolines. In particular, the invention relates to certain 7-alkoxy-2,4-diaminoquinazolines which are

<img file="PT72007B_D0002.tif" />

After being replaced by a 6-chloro group and / or an S-alkoxy group, their use as antihypertensive agents, pharmaceutical compounds therefrom and intermediates for their production.

PREVIOUS TECHNIQUES

US patents NSs. 3,511,836; ·

3,635 · 979 θ 3,663.7 ° 6 reported 6,7-dimethoxy-2,4-diaminoquinazoles of the formula

<img file="PT72007B_D0003.tif" />

where Z is a nitrogen containing heterocyclic group. One of these with posts, 2- /^-4- (2-furoyl) piperazin-1-yl-7-4-amino-6,7-dimethoxyquinazoline is a clinically useful antihypertensive agent that has the trade name of Prazosin and whose pharmacology is discussed in Constantine et al., Hypertension. : Mechanisms and Management, edited by Onesti, Kin and Moyer, Grune and Stratton, 1973, PP · 429-44.

<img file="PT72007B_D0004.tif" />

X fe-i.

U.S. Patent Nos. 3,669,968 and 3,769,286 discloses 6,7,8, -trialkoxy-2,4-diaminoquinazolines in which the 2-amino group is substituted by some alkyl and hydroxy-substituted alkyl groups or is a heterocyclic such as piperidine or 4-substituted piperazine. One of these compounds is known under the generic name trimazosin and has the formula

<img file="PT72007B_D0005.tif" />

Triamazosin is also an active antihypertensive agent, see eg, Vlachikis et al Current Therapeutic Research, 17.564 (1975).

However, it is less potent than the deadlines. Althuis et al., J. Med. Chem., 20 146 (1977) have shown that the 6-0-demethyl derivative is an important metabolite of the termenin of considerably less hypotensive activity. The 7'0 “demethyl derivative is a less prevalent metabolite. U.S. Patent Nos. 3,920,636 and 4,044,135 disclose homopiperazine quinazoline compounds as antihypertensive agents.

Several patents have appeared that contain antihypertensive compounds of the general formula

<img file="PT72007B_D0006.tif" />

“Fll)

U.S. Patent 4,001,237 discloses compounds where R^The It is an oxazole, isoxazole, thiazole or isothiazole radical.

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

N — N

<img file="PT72007B_D0007.tif" />

S-methyl

U.S. Patent 3,780,040 discloses 3,4-dihydroquinazoline analogs of the above formula where R^The is

2-thienyl.

Μ

<img file="PT72007B_D0008.tif" />

.0'

In US Patents 4,026,894 and 4,112,097, R^The is a 2-tetrahydrofuryl or. a 2-tetrahydropyranyl moiety. U.S. Patent 4,060,615 discloses with stations in which R^The is cycloalkyl having from 3 to 8 carbon atoms and cycloalkenyl having from 4 to 8 carbon atoms. U.S. Patent 4,101,548 deals with 1,2,3-thiadiazole amides of the above formula wherein R^The is

<img file="PT72007B_D0009.tif" />

λ '# and R *³ is hydrogen, lower alkyl NEL, or NHCOgR⁰ wherein R ° is lower alkyl.

6,7-dimethoxy-2- (4-thiomorpholin-1-yl) 4-aniinoquinazolines and derivatives wherein the 2-substituent is R r are disclosed as antihypertensive agents in US Patent 4,115,565.

British patent NS. 1,530,768 discloses analogs of Prazosin in which the 2-amino group is of the formula

-N — CO0R^and where R^and is phenyl, substituted phenyl, furyl, thienyl or 5-alkylthio-1,3,4-oxadiazol-2-yl.

<img file="PT72007B_D0010.tif" />

-6French patent No. 2. 2,321,890 discloses Prazosin analogs in which the 2-amino substituent is a 3 or 4-substituted piperidine or piperazine group.

The compounds of the invention are highly potent antihypertensive agents with longer duration of action as they are not susceptible to metabolic demethylation at position 6 with loss resulting from activity as with Prazosin. In addition the compounds of the invention have better solubility in water as compared to Prazosin. They can therefore be administered intravenously and in particular in emergencies and are absorbed evenly by all patients.

SUMMARY OF THE INVENTION

This invention features novel compounds.

2,4-diaminoquinazoline and the processes for its production. The novel 2,4-diaminoquinazolines have 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 novel compounds and a pharmaceutically acceptable carrier. as well as a method for treating hypertension comprising oral or parenteral administration to mammals in need of such treatment of an effective antihypertensive amount of a compound of the invention.

The compounds of the invention are also useful for their vasodilatory properties, as anti-coma agents and in the treatment of congestive heart failure.

The new compounds presented are of the formula

<img file="PT72007B_D0011.tif" />

-ι / ο _ζ χ where Ί q is hydrogen or chlorine, is OS and r is hydrogen or OR so that when Ϊ¹ is hydrogen is OR and when is

7 , chlorine ·, and hydrogen or OR and salts derived from the addition of pharmaceutically acceptable acids:

R is alkyl having from one to three carbon atoms;

2

R and R are the same or different and when taken separately each is a member selected from the group consisting of hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkenyl having 3 to 5 carbon atoms, alkynyl having 3 to 5 carbon atoms, substituted hydroxy alkyl having 2 to 5 carbon atoms and when taken together with the nitrogen atom to which R and R are attached form

<img file="PT72007B_D0012.tif" />

-HX * ^ (cs₂)_no-&gt;

where X is a member selected from the group consisting of S (O), CHOR, and CHR 'and X is a member selected from the group consisting of X¹, 0, NB ?, NGOR? And NCOOR? Where m is 2 or 3 n is 2 or 3 p is 1 or 3, t is 0, 1, or 2;

z _zt

R is a member selected from the group consisting of hydrogen alkyl having from 1 to 6 carbon atoms, alkenyl from 3 to 5 carbon atoms, alkynyl having from 3 to 5 carbon atoms substituted hydroxy alkyl having from 2 to 5 carbon atoms,

Cycloalkyl having from 3 to 8 carbon atoms, - (CH 4) ΟθΗ ^ Ιτ and where q is 0 or 1;

Zl _z

R is a member selected from the group consisting of hydrogen, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to 5 carbon atoms, cycloalkyl and cycloalkylmethyl wherein said cycloalkyl has from 3 to 8 carbon atoms,

<img file="PT72007B_D0013.tif" />

<img file="PT72007B_D0014.tif" />

<img file="PT72007B_D0015.tif" />

<img file="PT72007B_D0016.tif" />

<img file="PT72007B_D0017.tif" />

I

H

R, GH_OR - e (CH_O) Ο, -Η ,, Η, where A and S or O, q as defined above and R is a member selected from the group consisting of

<img file="PT72007B_D0018.tif" />

<img file="PT72007B_D0019.tif" />

(CH-Jp zSfi, where r is 1 or 2;

is a member selected from the group consisting of alkyl having from 1 to 7 carbon atoms, alkenyl

<img file="PT72007B_D0020.tif" />

having from 3 to 5 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms, substituted hydroxy alkyl having from 2 to 5 carbon atoms,⁸, ΟΗ ^ Ο- ^ θΗ ^ Ε ^, OH ^ R¹⁰ and EC 4 O -pyridyl;

<img file="PT72007B_D0021.tif" />

Εθ is a member selected from the group conQ * 1 C consisting of hydrogen, ΟθΗ ^ Ε, - (ΟΗ ^^ ΖΒ.-²alkyl having from 6 carbon atoms and said alkyl substituted by a member selected from the group consisting of 01, F, Br, OH, CH 2 O, SO 4 OH 4 and NHSO 4 OH 4, where p and are as already defined. and Z is a member selected from the group consisting of 0, S, SO S0₂ and NR¹⁶;

z

E 'is a member selected from the group consisting of alkyl having from one to six carbon atoms, hydroxyalkyl having from one to five carbon atoms, - (GH_O) R20 and R40; and E ° is a member selected from the group consisting of δ, 01, Br, F, OH,, OH ^O, OF ^, OH, SO ^OH ^ and HHSOgOH ^;

Q,

AND^y and a member selected from the group consisting of H, C 1 H, OH 4, ^and

R3 is hydrogen or methylthio and

R · ^ is a member selected from the group consisting of H, alkyl having from one to four carbon atoms and NHOOgR¹⁴;

ft

R is alkyl having from one to four carbon atoms;

R is a member selected from the alkyl group having from one to four carbon atoms, and R is hydrogen or alkyl having from one to four carbon atoms.

<img file="PT72007B_D0022.tif" />

Preferred compounds of the invention include compounds of formula (I) wherein y² and Y ^ are like

T 2 z was defined above and BR E ê

-C / NCOR group consisting of where R is a selected member of the

<img file="PT72007B_D0023.tif" />

η η and cycloalkyl having from 3 to 8 carbon atoms and A, re R^XJ· Are as already defined. Also preferred are compounds of formula (I) where Y, Y and Y² are as defined above and HR¹]!² is

COCR⁵ where R2 is substituted hydroxy alkyl having from 2 to 5 carbon atoms.

Particularly preferred compounds of the invention are:

2- (4-2-furoyl) piperazin-1-yl-4-4-amino-7,8-dimethoxyquinoline, zoline,

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

<img file="PT72007B_D0024.tif" />

-112- / 4- (2-furoyl) piperazin-1-yl-7-4-amino-6-chloro-7,8dimethoxyquinazoline,

2“/”^Zl'' (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl-4-4-amino-7,8d.methoxyquinazoline

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

2- / 4- (2-h.hydroxy-2-methylprop-1-yloxycarboryl) piperazin;

-1-yl-4-4-amino-6-chloro-7,8-dimethoxyquinazoline and its hydrochloride salts.

The invention further provides some intermediates useful in the preparation of compounds of formula (I). Es. intermediates are of the formula

<img file="PT72007B_D0025.tif" />

3 * where Y, Y ^ and Y^? 'They are as already defined.

The term pharmaceutically acceptable term used herein to describe a salt derived from the acid addition of a compound of formula (I) refers to salts containing es. anionic species of a variety of relatively non-toxic inorganic or organic acids. The anion does not appreciably contribute to the toxicity of the salt or its pharmacological activity. Examples of such salts are those formed with acids such as acetic, lactic, succinic, malic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, iodidic, sulfamic, sulfonic, such as methanesulfonic, benzene -. sulfonic acid, p-toluenesulfonic acid and the like. The preparation of salts derived from the addition of mono acids may be processed in conventional manner by treating the solution or suspension of the

<img file="PT72007B_D0026.tif" />

The free base in an inert organic solvent is reacted with an acid chemical equivalent or if the salt derived from the addition of di-acid is desired, at least two chemical equivalents of the acid. Conventional concentration and crystallization techniques are employed to isolate the salts.

The compounds of formula (I) are especially useful as antihypertensive agents having significant advantages over those of the prior art. 0 substituent Ϊ¹at position 6 of the compounds of the invention is hydrogen or hydrogen. ro, groups that are not prone to metabolic attack. Accordingly the compounds of the invention are not subject to easy metabolic demethylation with the resulting loss of activity as demonstrated for Prazosin. Likewise the compounds of formula (I) have a longer duration of action than Prazin and other 6,7-dimethoxy- and 6,7,8-trimethoxyquinoline antihypertensive agents known in the art.

The compounds of the invention also have a significantly higher water solubility than Prazosin and as a result of their better solubility, are uniformly absorbed by all patients. In addition they may be administered in a slow release form as well as parenterally, even intravenously.

DETAILED DESCRIPTION OF THE INVENTION

The antihypertensive compounds of the invention

<img file="PT72007B_D0027.tif" />

(1)

<img file="PT72007B_D0028.tif" />

(III)

<img file="PT72007B_D0029.tif" />

-13where Y¹, Y², Y, R, R¹ and R² are like, already set. They are prepared by synthetic methods described below.

Scheme I below underlines a preferred reaction sequence. In the first step, a 4-alkoxyanthanilic acid of formula (IX) containing the 13 and Y substituents as defined above is cyclized to the corresponding 2,4-dioxoquinazoline of formula (X).

Cyclization is performed by reacting compound (IX) with sodium or potassium cyanate or urea according to the technique of Curd et al., Jour. Chem Soc. 777 (1947) for the corresponding 6,7-dimethoxyquinazolinates.

Of course, it will be apparent to one skilled in the art that the anthranilic acids of formula (IX) may be substituted in this reaction by the corresponding compounds in which half of the carboxylic acid is substituted by CONH 3, CN or a carboxylic ester group with results. satisfactory. The cyclized compounds of formula (X) are novel compounds, valued as intermediates for the preparation of the antihypertensive compounds of this invention. As will be recognized by one skilled in the art, they can also be represented by, »

the corresponding tautomeric 2,4-dihydroxyquinazolines.

• SCHEME I *

<img file="PT72007B_D0030.tif" />

(III) 'THERE--

<img file="PT72007B_D0031.tif" />

In the preparation of the intermediates of formula (X), the base material IX is suspended in a polar solvent in the presence of acid, preferably water-acetic acid, to which a 2-4 molar excess of the cyanoate salt is added. eg, potassium cyanate or urea. The resulting mixture is then heated to a temperature ranging from room temperature to the refluxing temperature of the solvent until the 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 is reheated to a temperature of about 70 to 100 ° C for 1 hour. 5 hrs ras. The resulting sodium salt of product (X) is then acidified and isolated by standard methods known to those skilled in the art.

The intermediate of formula (X) is then reacted with a mixture of phosphorous phosphorus pentachloride and phosphorous oxychloride, or the corresponding phosphorous bromides, to prepare the corresponding 2,4-dihaloquinazolines. The preferred embodiment in which the phosphorous salts cited above are employed is set forth in Scheme I to provide the intermediates of formula (XI) wherein R1 and T3 are. are as defined above. Typically, dione (X) and 2-4 molar excesses of phosphorous pentachloride and phosphorous oxychloride are heated at reflux temperature for 2 to 6 hours, residual phosphorous oxychloride evaporated and the residue mixed in an inert organic reaction solvent, for example chloroform or dichloromethane, and added to a water / ice mixture, insoluble material is removed and the product isolated from the organic layer by evaporation or precipitation by the addition of an insolvent, 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 an inert organic reaction solvent. Examples of suitable reaction inert solvents are ethyl ether,

<img file="PT72007B_D0032.tif" />

<img file="PT72007B_D0033.tif" />

- i-j-j

<img file="PT72007B_D0034.tif" />

<img file="PT72007B_D0035.tif" />

tetrahydrofuran, chloroform and benzene. A preferred solvent is tetrahydrofuran. In practice a preferred excess of one to ten moles ammonia may be used to divert the reaction to the end. The temperature at which this reaction may be carried out is about 25 to 200 ° C over a period of one to 48 hours. A preferred reaction temperature and time for this reaction will be 25 to 60 ° C for about five hours. After completion of the reaction the product is recovered by conventional means. For example, the solvent may be evaporated and the crude solid may 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 the like. their mixtures with water.

Conversion of the 2-chloroquine zoline intermediate of formula (XII) to the desired compound of formula (III) is accomplished by contacting intermediate (XII) with an equimolar amount of an amine of formula R 1 in the presence of an aqueous solvent or organic. Generally a small molar excess of amine is employed. Preferred organic solvents for this reaction include polar solvents, o, tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide, alcohols such as methanol, ethane and isoamyl alcohol and ketones such as methyl ethyl ketone and methyl isobutyl ketone. Particularly preferred solvents are isoamyl alcohol and methyl isobutyl ketone. The reaction mixture is preferably heated to a temperature of about 60 to 160 ° C for one to 65 hours. Particularly preferred reaction temperatures range from about 100 to 140 ° C. and temperatures in this zone are conveniently obtained by keeping the reaction mixture at the reflux temperature of the particularly preferred solvents. At this temperature the reaction is generally complete in about two hours to two days.

Other techniques may also be used in the preparation of the compounds of the invention with satisfactory results. For example the alternative methods presented in

<img file="PT72007B_D0036.tif" />

US Pat. No. 3,511,836 for the preparation of Prazosin and its analogs may also be used with appropriate base materials to provide the compounds of the invention of formula (I). These methods are enumerated and discussed briefly below.

1. 2-Amino-4-chloroquinazolines (XXIX) prepared by methods analogous to those described in US Patent 3,511,836 for the 6,7-dialkoxy correspondent compounds may be reacted with ammonia under the conditions described above for the conversion of compounds (XI). ) to (XII) with the resulting formation of the desired product of formula (I) where Y, Y, Y, R and R are as defined above.

<img file="PT72007B_D0037.tif" />

Di

NR R

NH.

* (X)

2. The quinazolinadione of formula (X) po. reacting with a reagent such as phosphorus pentasulfite or an analog to form the corresponding 2,4-quinazolinadithione which in turn reacts with an alkyl or benzyl halide to form the corresponding 2,4-dithioalkylquinazoline or 2,4-dithiobenzylquinazoline. It is then reacted with ammonia according to the technique already described for the reaction of 2,4-dichloroquinazolines (XI) to provide the corresponding 4-amino-2-thioalkyl or (thiobenzyl) quinazoline (XX). 0 The latter compound is then converted to the desired compound (1) using the compositions already described for the formation of compound (I) from the 2-chloro compounds.

<img file="PT72007B_D0038.tif" />

2 r^Ther^znh (I)

<img file="PT72007B_D0039.tif" />

<img file="PT72007B_D0040.tif" />

Where Y ^, Υ ^, R ^ and R ^ are as already defined.

Ί O

3 Compounds of formula (I) where IffiTT forms a heterocyclic half of the formula

-Where! q NR ^, NCOR ^ or NCOOR ^ in, n, R ^,! and R ^ are as already defined but! cannot be hydrogen; may also be prepared from the compound where X is NH, e.g. 12 '

NR R is piperyl by acylation, alkylation and carbonyloxylation.

<img file="PT72007B_D0041.tif" />

&lt;(CH_?)_mN ^{2 m} NH λ n (XXI)

<img file="PT72007B_D0042.tif" />

N ² NW V, (CH₂)_no.

(XXII)

W * R³, COLOR⁴ or COOR⁵ compound (XXI) reacts with a compound of formula R 1 -X 2, R COX 3

5th Where R, R and R are as defined above and X is a free group preferably the halides, Cl or Br. When preferred halides are employed it is advantageous to use at least a slight · Molar excess to ensure complete reaction. Intermediate (XXI) and the reagent of the formula R ^X ^, R ^COX ^ or X ^COOR ^ are contacted in the presence of an inert organic reaction solvent, for example benzene, tetrahydrofuran,¹ methyl acetone ketone, methyl isobutyl ketone, 1,2-dimethoxyethane or diethylene glycol dimethylether. One such preferred solvent is methyl isobutyl ketone.

The reaction can be successfully performed at a wide range of temperatures. However, a tempe,

<img file="PT72007B_D0043.tif" />

The temperature range from about 0 ° C to the refluxing temperature of the solvent is preferred for reasons of effectiveness and convenience. At this preferred temperature, the reaction is generally complete within 30 minutes to six hours. The resulting solid product is then isolated either as hydrohalide or free base by conventional methods and purified, if desired, by crystallization, column chromatography or other similar techniques.

4 In this method the 2-aminobenzonitrile intermediate of formula (XIV) reacts with a guanidine of formula

L · · nh₂&lt;jnA²

NH

2 where R and R are as defined above. Benzonitrile (XIV) and an equivalent amount, but preferably a minor excess of guanidine are contacted in the presence of an inert organic reaction solvent, for example ethylene glycol diethylene glycol, dimethylformamide, dimethyl sulfoxide or diethyl enoglycol dimethylether, at a temperature of about 120-180 ° C for four to 15 hours. 0 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. _O The reaction is presented as follows:

<img file="PT72007B_D0044.tif" />

<img file="PT72007B_D0045.tif" />

Guanidine base materials are prepared by methods well known in the art. For example,

<img file="PT72007B_D0046.tif" />

<img file="PT72007B_D0047.tif" />

-19Ί ρ the amine of formula RR RH reacts with cyanogen bromide to form the corresponding R-cyano compound which in turn reacts with hydroxylamine, followed by catalytic hydrogenation using the methods and conditions of Carrington, Jour.Chem. Soc. London, 2527 (1955) for the conversion of anthranilonitrile to 2-aminobenzamidine.

Variations of the above method may also be employed using any of the following base materials in place of 2-aminobenzonitrile (XIV).

<img file="PT72007B_D0048.tif" />

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

5 D-substituted 2-chloro-4-alkoxy-7,8-quinazolines, which are prepared by methods described by

Ourd et al., Jour. Chem. Soc. 775 (1947) for the disubstituted 2-chloro-4-alkoxy-6,7-isomeric quinazolines which may be reacted with an amine, RR RH, to obtain the corresponding 2-aminoquinolines. The 4-alkoxy substituent is then substituted by HHg P^or reaction with ammonia as described above for the 4-chloro compounds of formula (XXIX). This reaction sequence is exemplified below for a 2-chloro-4-ethoxyquinazoline base material

<img file="PT72007B_D0049.tif" />

<img file="PT72007B_D0050.tif" />

(I)

I «»} »* '

<img file="PT72007B_D0051.tif" />

-20Υ ^, βΐ and are as already defined.

The 4-thioalkylquinazolines corresponding to the above 4-alkoxy compounds may also be employed as base materials in this sequence.

6 The compounds of the invention are also obtained by methods disclosed in U.S. Patent 3,935,213 for Prazosin, Trimazosin and their analogs as set forth below where Y, Y, Y, R and R are as defined above;

<img file="PT72007B_D0052.tif" />

A 2 is selected from the group consisting of CN and C (= NH) XR 4, where X is 0 or S and R 4 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 about 0.5 to 5 molar equivalents of a basic catalyst, eg sodium hydride, potassium ethoxide or triethylamine at a temperature between about 5 ° to 180 ° C. The products of formula (I) are isolated by well known methods, for example those described in US Patent 3,935,213. .

The compounds of formula (I) are also obtained by employing the appropriate base material of formula (XIV) in the process described in the Belgian patent No. 4,912. 861,821 and NS. 861,822 for the synthesis of deadlinesin. The method is outlined in scheme II. 0 o-aminobenzonitrile (XIV) where τ px

Y^x, Υ^ώ and Y² are as defined above react at least with an equimolar amount of thiophosgene in an organic solvent inherent to the reaction eg 1,2-dichloroethane.

<img file="PT72007B_D0053.tif" />

-21 A base is added to the mixture, eg calcium carbonate, water and

<img file="PT72007B_D0054.tif" />

<img file="PT72007B_D0055.tif" />

- '' Hl

<img file="PT72007B_D0056.tif" />

The mixture is typically stirred at about 0-5 ° C. It is then heated to about room temperature until the reaction is substantially complete. O - isothiocyanatobenzonitrile (XV) is produced and isolated in crude form for use in the next step. Intermediate (XV) dissolved in a

<img file="PT72007B_D0057.tif" />

The inert organic reaction substance, typically ethyl acetate, reacts with the amine of the formula RR NH, where R and R are as defined above at a temperature below 0 ° C, preferably between about -30 ° C and 5 ° C. ° C to give o.-thioureidobenzonitrile (XVI). This is then reacted with a methylating agent, for example methyl iodide or methyl bromide and the resulting S-methyl hydrohalide salt is treated with a weak base to obtain the S-methylthioformamidate of formula (XVII) which is. It is cyclized by reaction with anhydrous ammonia in the presence of a polar solvent and an alkali metal amide to give the desired compounds of formula (I). Preferred polar solvents for cyclization are formamide or N, N-dimethylformamide. Also preferred for the final step is the use of 1 to 3 equivalents of alkali metal amide, especially sodium amide and a temperature of about 100 to 150 ° C.

8 US Patent 4,138,561 discloses a novel process for preparing Prazosin and Trimazosin. This method is also suitable for the preparation of the compounds of the present invention as set forth below.

SCHEME III

<img file="PT72007B_D0058.tif" />

(XXXIII)

<img file="PT72007B_D0059.tif" />

<img file="PT72007B_D0060.tif" />

Y⁴x⁴,

<img file="PT72007B_D0061.tif" />

(XXXVI)

<img file="PT72007B_D0062.tif" />

Agent, ci.cl; tz.aa £ e (I) where Y

<img file="PT72007B_D0063.tif" />

-23The starting materials of formula (XXXIII)

3 ~ ,

Y and Y are as already defined are known compounds; see, for example, Gibson et al. Chem. Soc. 111: 79 (1917); Munavalli et al., Bull. Soo Ohim., France. 3311 (1966) Chem. Abstr., 66, 46303 (1967). 5, German. German patent 1,959,577; Ohem Abstr. 26: 63397d (1971). 0 base material (XXXIII) is converted to isothiocyanate (XXXIVj as described above for intermediate (XV)) and this reacts with an amine ER HH where R and R are as defined above to provide substituted atiourea (XXXV) by the method described. above for intermediate (XVI) .intermediate (XXXV),

4 In turn, it reacts with an alkylating agent, YX, to obtain an intermediate of formula (XXXVI) in which it is alkyl having from one to four carbon atoms or an aryl derivative containing electron scavenging groups, for example 2.4 -di4'nitrofemlo and X is a member selected from the group 01, Br, I-alkyl S0₄having from one to four carbon atoms, OgH ^ SO ^, F, OSO and FSO. An especially preferred alkylating agent_r 21 t do, YX, and methyl iodide. Alternatively, as disclosed in US Patent 4,138,561, fosgenie may be used in the first step of the reaction sequence set forth above in Scheme III, wherein each of intermediates (XXXIV) to (XXXVI) is the corresponding compound in which a oxygenium substitutes for the sulfur atom shown therein. 0 intermediate of formula (XXXVI) is then reacted with cyanamide to provide the corresponding intermediate carboxamidine of formula (XXXVII).

Alkylation of thiourea derivatives (XXXV) and subsequent reaction with cyanamide is usually carried out in an inert organic reaction solvent. Suitable solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide and alkanols having from one to five carbon atoms. These reactions are preferably processed at a temperature of about 25 to 100 ° C over a period of 0.5 to 24 hours. 0 intermediate of the formula '(XXXVII) may also be obtained by alternative methods described in US Patent 4,138,563,

<img file="PT72007B_D0064.tif" />

Conversion of the carboxamidine intermediates (XXXVII) to the desired quinazolines of formula (I) is effected by reaction with cyclizing agents such as triclo, phosphorus rectum or phosphorus pentachloride in a solvent amount of phosphorus oxychloride. Other phosphorus balls and phosphorus oxihaletes, such as tri. phosphorus bromide and phosphorus pentabromide in a solvent amount of phosphorus oxibromide.

Cyclization may also be effected by reacting intermediate (XXXVII) with acidic reagents such as aqueous hydrogen chloride, phosphorus oxide hydrogen chloride, trichloroacetic acid or Lewis acid catalysts such as ZnCl₂, PeO ^, AlCl,, AlBr ^ and the like.

With respect to the reaction process with phosphor halides, approximately equimolar amounts of carboxamidine (XXXVII) and phosphorus halides with a suitable amount of phosphorus oxyide relative to the amount of base material (XXXVII) are employed. The term solvent amount used herein refers to an amount of phosphorus oxychloride or phosphorus oxybromide sufficient to provide good mixing and handling characteristics with respect to reaction mixtures.

For this purpose, a ratio of about 2 to 15 ml of phosphorus oxyhalide is generally preferred for each gram of carboxamidine reagent of formula (XXXVII).

Temperatures generally used in the cyclization reaction process range from 25 to 125 ° C with a preferred temperature of 70 to 100 ° C. As will be appreciated by those skilled in the art, the reaction times and conditions required for the cyclization of intermediates (XXXVII) to form the desired products of formula (I) vary according to various factors, such as temperature and reaction time. For example, at lower temperatures, periods of

<img file="PT72007B_D0065.tif" />

- longer reactions, while at a higher temperature, the cyclization reaction is complete in a shorter period of time. Reaction periods of 0.5 to 24 hours may be used, however a period of 1 to 3 hours is preferred at the preferred reaction temperatures mentioned above.

The starting materials of formula (IX) required for the Scheme I technique above are obtained by the reaction sequences set forth in Schemes IV, V and VI below for the case where R is CH 2.

bw&gt; SCHEME IV

<img file="PT72007B_D0066.tif" />

(IXb, R = CH₃)

In the reaction schemes given above and below, for convenience, the letters below, b, and c are used after the roman numbers for the compounds shown.

<img file="PT72007B_D0067.tif" />

The. Y ^ = Ξ, Υ² where R is alkyl having from one to three carbon atoms.

B. Y¹ = 01, Y² = Y ^ = OR, R is as defined above

ç. Y ^ = 01, Y² = 0R as defined above Y ^ = H.

SCHEME V

1. HNO

O^nh2 2. cucn ^ Γ ^ γ^Ν_ at the₂ CH-ΟΑϊΟΑϊΟ, CH-Cf ^Ai;

(XVIII) ^MW2 ^w“3 '(XIX) (XX) • CN Cl ^^ - xCN

Ό —N

H₂CH₃O

NH.

ch₃O _Λ CH.

O l NO.

KMnO (XXIII) ch₃0 (XIVc,

R * .CIA)

I

IXγίίΧγΟΟΟΗ (IXc, x ^ \ zC00H x / ^ COOH R ”Ctí)&gt; jjj — ► o

CH., 0 NO ^{naked n} »

NOj CHjO

NH.

(XXI) (XXII)

<img file="PT72007B_D0068.tif" />

<img file="PT72007B_D0069.tif" />

▼ (IXa, R = CH₃) y / x-;

Following reactions of Scheme IV, vanillin is acetylated with, for example, acetic anhydride or estrus. Acetyl ester by well known methods and the acetylated intermediate is nitrated to give 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (V). The acetyl group is removed by hydrolysis, for example by treatment with a strong aqueous base, such as sodium hydroxide followed by acidification to afford the intermediate 4-hydroxy-3-methoxy-2-nitrobenzaldehyde of formula (VI). This intermediate is then alkylated with one of the well known alkylating agents generally employed for the conversion of phenolic groups to the corresponding alkyl ethers. Examples of such alkylating agents are dimethyl sulfate, diethyl sulfate, methyl bromide, n-propyl iodide and ethyl iodide. In the case shown in Scheme IV, a methylating agent is employed to obtain 3,4-dimethoxy-2-nitrobenzaldehyde.

'.'Λ',;.

<img file="PT72007B_D0070.tif" />

-28 (VII). Compounds in which the two ether groups are different are obtained by using for example diethyl sulfate or n-propyl iodide as alkylating agent. When folding ethyl vanillin or n-propyl vanillin in place of vanillin as the base material in this reaction sequence, the corresponding compounds are obtained in the same manner, where the corresponding alkoxy groups are 4,5-diethoxy, 4,5 -dipropoxy,

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

dialooxy intermediate of formula VII, eg is then oxidized to the corresponding carboxylic acid. Although a wide variety of oxidizing agents and conditions are known in the art for the oxidation of aromatic aldehydes to the corresponding carboxylic acids, the preferred oxidation conditions are those using potassium permanganate in aqueous acetone at reflux temperature. mixture. The benzoic 2-nitro-4,5-dialkoxyacid intermediate eg of the compound of formula (VIII) is isolated by known methods and reduced to the corresponding 2-amino acid, for example the compound of formula (IXa, R = CH ^) by well known methods, eg by catalytic hydrogenation employing a noble metal as a hydrogenation catalyst. A preferred catalyst is palladium.

The intermediate of formula (IXa) is useful as a base material in the reaction sequence shown in Scheme I above to provide the corresponding compounds of the invention with the corresponding formula (Ia) or (IIIa). Alternatively, as shown in Scheme IV, intermediates (IXa) serve as the base material for the corresponding 5-chloro intermediates of formula (IXb). The carboxylic acid is first esterified to form an alkyl ester eg the methyl or ethyl ester by well known means. The ester is then clear using for example chlorine or sulfuryl chloride and the latter reagent is preferred for reasons of efficiency and ease of handling. Typically, a slight

<img file="PT72007B_D0071.tif" />

-29% molar excess, eg a 20% molar excess of sulfuryl chloride to a cooled solution of the acid carboxylate ester. of the intermediate (IXa) in a chlorinated hydrocarbon solvent eg chloroform, methylene chloride or 1,2-d.chloroethane, the resulting mixture is warmed to room temperature and then to room temperature. It is then heated to reflux temperature until the reaction is substantially complete, eg for one to 24 hours. The crude 5-chloro ester is then hydrolyzed, eg by sodium hydroxide as described above to provide the corresponding 5-chloro acid of formula (iXb).

5-Chloro-5-alkoxy anthranilic acids of formula (IXc) are obtained as shown in Scheme V. 4-Methoxy-2-nitroaniline (XVIII) is treated with sodium nitrile in concentrated hydrochloric acid under conditions well known to those skilled in the art to form an intermediate diazonium salt to which an aqueous solution containing an equimolar amount of cuprous cyanide is then added. and a molar excess, typically a 5θ% excess, of potassium cyanide while heating the reaction mixture on a steam bath. The 4-cyano-3-nitroanisol product (XIX) is then isolated and then hydrolysed eg in the presence of aqueous sulfuric or hydrochloric acid of the formula (XXI). This in turn is hydrogenated as described above for the conversion of compound (VIII) to IXa) to provide 4-methoxy anthranilic acid (XXII) and the latter is chlorinated to provide the desired compound (IXc). R-CH 3) employing the conditions described above for the conversion of the compounds of formula (IXa) to 5-chloro (IXb) compounds.

As shown in Scheme V, other synthetic routes may be employed to obtain the desired base material of formula (IXc). In one of these alternation methods. v 4-cyano-3-nitroanisol (XIX) is hydrogenated as defined for the conversion of compound (VIII) to compound (IXa) pa. to provide the aminonitrile of formula (XX). This is chlorinated as described above for the conversion of compounds (IXa) to a (IXb) and the resulting 5-chloro nitrile (XIVc, R = CH3) θ

<img file="PT72007B_D0072.tif" />

-30 hydrolysate, as already described for the preparation of compound (XXI) from nitrile (XIX) to give the compound of (IXc, R = OH).

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

As will be apparent to those skilled in the art, when the methoxy group present in the base materials of formula (XVIII) and (XXIII) employed in Scheme V is replaced by an ethoxy or n-propoxy group, the corresponding compounds of the invention are obtained. formula (IXc) where R is 0₂^s5 ^or £^-θ3^Η7 'respectively.

Similarly, substituting one or both of the methoxy groups present in the base material of formula (XXV) employed in Scheme VI for ethoxy or n-propoxy provides the corresponding compounds of formula (iXa) and (iXb).

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

Many of the necessary amines of formula RR NH, where R and R are as already defined, are known compounds, see for example the references mentioned above in the prior art. Those that are new are prepared by methods that will be apparent to the technicians. For example, the amines of formula

EN 2H0R °

L · /

L ·

<img file="PT72007B_D0073.tif" />

Where a is 1, 2 or 5, n is 2 or 3 and θ is as defined above are obtained by reacting the appropriate appropriate N-protected amine where n is hydrogen with. for example, a compound of the formula (Εθ) - Hal where (S) has any of the as values, signaled above for ο βθ, except hydrogen and Hal is Cl, Br,

I or other known residual groups such as SO 4 CH 2. The reaction is typically carried out by employing an equimolar amount of metal hydride, for example sodium hydride and in the presence of an inert organic reaction solvent, eg 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, eg employing a palladium catalyst.

Alternatively, the above compounds where βθ contains half ether may be obtained in the reaction sequence, present the preparation of 4- (reactions shown below as xi-n-propoxy) piperidine.

OH

N

Ac (1) Ethanol, Hg (OAc).

(2) NaflH₄, NaOH

CH₂-CH-CH₂Br

<img file="PT72007B_D0074.tif" />

Many of the necessary amines of the formula, &lt;&lt;^CB2&gt; a \,

HN CHR^f

- (XXXVIII)

<img file="PT72007B_D0075.tif" />

i

Where a, n, and R 'are as defined above, are known compounds. Those that are not known are prepared by well known methods. For example, the R? may be obtained by catalytic hydrogenation of the corresponding R?-substituted pyridines. Cyclic amines of the above formula where R 'is alkyl having from one to six carbon atoms are provided by reacting the appropriate N-protected aminoketone with a Grignard alkyl reagent, for example, as outlined below.

, ich₂&gt;

^Ç6^H5^CH2^N\ (CH „) ¹ 2'in

R MgBr — ► C_gH₅CH₂N, V ^k(here₂) n ^r7

Δ-catalyst

HH CHR⁷ % CH₂)_no-Z

Catalytic hydrogenolysis of the tertiary hydroxy group is often facilitated by prior acetylation.

The desired cyclic amines where R? hydroxyalkyl having from two to five carbon atoms are obtained, for example, by the methods set forth below;

IjCHjN. g&gt; CHHgBr ♦ CH₂-^CH-^Rlo '«^CT2&gt; n (Rjq H or C1 -C4 alkyl)

H.

,«“2&gt;.

IjCHjN. ^ CB-CB₂CH-R₁₀ Pd 'RN, _' ^ CHCHjCHR_1(|

OH ''

Wn

ÍCH₂)_no OH (CH-) ν&gt; ·

<img file="PT72007B_D0076.tif" />

- ^2nd\ ^Ç6^H5^CH2^N\ x-^{C = 0}&lt;^CH2&gt; n ^Ç6^H5^CH2^Nx&gt; &lt;^CH2&gt; a &lt;^CH2&gt; n

OH

HN&gt;^CH2&gt; a (ch₂,

-π + C_gH₅CH₂OÇH (ÇH-)_uMgBr ^R11^R12

R 4 and R 4 are each H or alkyl of 1 to 5 carbon atoms, ie 1 to 4.

{ch)_uochoch₂ç₆H₅^R12 ^R11 catalyst

CH (CH) CHOH I ^{1 R}12 ^Ril

Od compounds of formula (XXXVIII) where R? and hydroxymethyl are obtained eg by lithium aluminum hydride reduction of the corresponding carboxylic acid aldehydes or esters.

The compounds of formula (XXXVIII) where R?

Where Q is O or 1 and R is as already defined, may also be obtained by a Grignard reaction, as shown below, for example.

^ç6H_sCH₂1I_x ^ co ♦ E^sÇ₆H₄(CB₂) HgBr -.

(CH_{i) n} ^^H2 ^ q^Çg^H4^R^ 1 »Acetylation

2. H₂, Pd / C *, {CH₂)The _H^Ç6^H5^CH2^N\ ^{Here2&gt; n \ ^_whatw

CH «®2&gt; ^&gt; CH₂)_noNH

<img file="PT72007B_D0077.tif" />

<img file="PT72007B_D0078.tif" />

-34The starting materials of formula (XXXVIII)

8th where R 'is RΟθΟΗΟΟ can be obtained, for example, by Rriedel-Orafts acylation by an N-protected carboxylic acid halide as shown below.

(CH-CON)

x^(CB2'a_x

CHCOC1 ^(CH2&gt; n + R CgHg

A1C1.

CH-CON _χ ^ CHCOCg ^ R ^tCH2&gt; nh₂O

H * or OH “

HN CHCOC.H.RÔ

X yo 4

The piperidine derivatives of the latter formula are also obtained by employing the carboxylic acid halides p

corresponding pyridine and the compound of the formula R in the Rriedel-Crafts acylation, followed by hydrogenation in the pyridine moiety.

cyclic aminocarboxylic acid precursor to the N-protected cyclic amino acid halides referred to above are either readily available or can be obtained by the well-known Dieckmann reaction followed by hydrolysis and decarboxylation of the resulting alpha-keto ester to obtain an intermediate cyclic ketone which can be converted to the desired carboxylic acid by a variety of methods, eg

»13\

1. NaOCjHg 'tCB,) - ^CO2^Ç2^H5 ²* ^H2°' ^Na0H* ^R13\ ‘“2&lt;

[H]

1. HBr ^R13^N /^{, CH}2&gt; a \ Η ί · /^{| CB}2&gt; â_x ^ Xh ²· 9 ' _ZCHCOOH^(CR2&gt; n

3 CO.

«®2&gt;»

X^(CH2&gt; a \

HN CHCOOH

The sequence of reactions given above are as defined above and R3 is a suitable amino protecting group, eg benzyl or acetyl. As will be recognized by one of skill in the above reaction sequence, when R3 is benzyl the reduction step The ketone is preferably processed by a metal hydride, eg sodium borohydride or lithium aluminum hydride and removal of the benzyl group is carried out by hydrogenolysis.

use of a longer chain of protected R1-4 iminodicarboxylate esters in the Diekmann reaction above gives the corresponding R1 -protected amino ketones of the formula r₁₃no

OO which upon Wolff-Kishner reduction and deprotection provide base materials of the formula

Z

BR \

CCH-1 'a

KH₂l_no

KH.l &lt;ip where a, nep are as defined above

The antihypertensive activity of the compounds of the invention is demonstrated by their ability to reduce the blood pressure of spontaneously aware hypertensive rats and conscious hypertensive dogs due to conscious renal failure when administered orally at doses up to 30 mg / kg.

ιϊίΐ

<img file="PT72007B_D0079.tif" />

For example, 2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] -4- amino-6-chloro-7,8-dimethoxyquinoline, one. Typical and preferred compound of the invention lowers the blood pressure of hypertensive dogs because of renal failure to a statistically significant degree, and when this compound was administered orally at doses as low as 0.2 mg / kg. , caused a decrease of 30 mm Hg after 4 hours without significant changes in heart rate or other side effect. Similarly, at the same position, 2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] -4-amino-6-chloro-7-methoxyquinazoline, a particularly preferred compound of invention caused a 40 mm Hg reduction in blood pressure after one hour, which only increased 20 mm Hg 6 hours after administration; another particularly preferred composition is 2- [4- (2-furoyl) -1-piperazinyl]._&gt;7-4-amino-6-chloro-7-methoxyquinazoline caused a reduction in blood pressure of 40 mm Hg which only increased by 5 mm Hg six hours after the administration of an oral dose (0.2 mg / kg).

Again, no significant changes in heart rate or other undesirable side effects with the last two compounds were noted.

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

The compounds of the invention may be administered alone, but will generally be administered in a pharmaceutical carrier selected according to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of excipients containing starches such as starch or lactose or in capsules, either alone or with excipients or in the form of sweeteners or dyes containing elixirs or suspensions. Powder-

<img file="PT72007B_D0080.tif" />

-37 may 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 may contain other solutes, for example sufficient salt or glucose to make the solution isotonic. For the treatment of glaucoma, they may be administered either topically or by the routes of administration indicated above. For topical application, a compound of the invention is admixed aseptically with a pharmaceutically acceptable liquid carrier or a solvent such as water, a glycol or mixtures thereof, and added toxicity regulators, preservatives and buffers as needed. The resulting solution or dispersion is then aseptically filtered and presented in sterile vials.

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

The compounds of the invention may be administered to humans for the treatment of hypertension or congestive heart failure either orally or parenterally and may be administered orally at dosage levels ranging from approximately 1 to 500 mg / day to a disease. average adult (70 kg) administered in a single dose or up to three divided doses. Dosage levels for intravenous administration should be about half to one tenth of the daily oral dose. Thus, for an average adult patient, individual oral tablets or capsules will be approximately 0.5 to 250 mg of the active compound. Variations will necessarily occur depending on the weight and condition of the individual being treated and the route of administration will be chosen by the guardian.

The invention further provides a method for treating an animal, including a human, with

38, hypertension, which comprises administering to the animal an effective antihypertensive amount of a compound of formula (I) or the salt thereof by the addition of a pharmaceutically acceptable acid or one of the pharmaceutical formulas named above.

The following Examples exemplify the invention.

EXAMPLE 1

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

Acetic acid (177.4 mL) was added.

3.1 moles) to a vigorously stirred suspension of 3,4-dimethoxy anthranilic acid (436.5 g. 2.21 moles) in 10 liters of water. 2.24 L of 20% potassium cyanate (5.53 moles) was then added gradually and the mixture was stirred for one hour at 40 ° C. After cooling the reaction mixture to 20 ° C, 3.54 kg of sodium hydroxide pellets were added, keeping 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 pro was filtered off. The product was suspended in 6 liters of water, acidified with concentrated hydrochloric acid (37θ ml), cooled and filtered to yield 404 g (82%) of the product. Recrystallization from dimethylformamide gave colorless crystals, PE

314-6° 0.

Analysis, Percentage calculated for θιο ^ 1Ο ^ 2θ4^: θ '

Η 4.54; Ν 12.61

Found: 0. 53.96 ». 4.57? Ν 12.63

<img file="PT72007B_D0081.tif" />

EXAMPLE 2

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

A mixture of 7,8-dimethoxyquinazoline-2,4-dione (400 g, 1.80 mol), phosphorous pentachloride (75θ g ·

3.60 moles) and phosphorous oxychloride (4 liters) was refluxed under nitrogen for three hours. Phosphorous oxychloride (POO-1) was removed in vacuo and residual P0Cl-1 was removed as an azeotrope with toluene. The solid residue was slurried in eight liters of dichloromethane and was slowly added to ice-cold water. The suspension was stirred and the unresolved starter material (54.0 g) was filtered off. The organic layer was separated, dried over sodium sulfate and filtered. The solution was concentrated adi. then slowly adding 4 l of hexane. Upon cooling, a pale yellow product (346 g, 80.4%) was obtained by filtration and recrystallization from the toluene / ether mixture, PP -153-5 ° O.

Analysis, percentage calculated to 0_ηοΗρ01₉Ν₉0_?: 0. 46,35;

H. 3.11; N. 10.81

Found: 0: 46.14; Ξ 3.33? N. 10.60.

EXAMPLE 3

2-01oro-4-amino-7,8-dimethoxyquinazoline (Xlla)

Ammonia was passed through a solution of 2,4'-dichloro-7,8-dimethoxyquinazoline (287 g, 1.11 moles) in tetrahydrofuran (6 liters) for 5 hours at room temperature. The suspension was concentrated in vacuo to 2 liters and filtered. The solid part was suspended. NaHCO 3, filtered and washed with water and cold methanol. Recrystallization from dimethylformamide / water afforded 164 g (62%) of pure product, mp 300 ° C.

- X

<img file="PT72007B_D0082.tif" />

Analysis, percentage calculated for 0 ^ θΗ ^ θ01Ν ^ 0₂^: 0. 50,11}

H. 4.21} N. 17.53. ·

Found: 0. 50.07} H. 4.24j N. 17.58

Example 3A

When the suitable starting material selected from those set forth in Preparation I are used in place of 3,4-dimethoxy anthranilic acid in the technique of Example I and in all cases the resulting product is subjected to the techniques of Examples 2 and 3, the resulting product is obtained. the following compounds identically

<img file="PT72007B_D0083.tif" />

^CH3rd n °

W ac₃H₇oc₂B₅O

CH, 0 ^CH3°

W.

EXAMPLE 4

2-2 ”4- (2-Furoyl) piperazine-1-yl7-4-amino-7,8-dimethoxyquinazoline hydrochloride

A mixture of 2-chloro-4-amino-7,8-dimethoxyquinazoline (3.00 g. 12.5 moles and 1- (2-furoyl) piperazine

V

<img file="PT72007B_D0084.tif" />

-41 (2.71 g. 15.0 moles) 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 give 4.53 g (79%) of the final pure product, PP -251 ° C. Solubility in water was determined to be 20 mg / ml.

Analysis, percentage calculated for ^G19^H21^N5°4^{: HGl! σ}· 5 *, 55 H. 5.28; N. 16.68

Found: 0. 54.14; H. 5.21; N. 16.42.

EXAMPLE 5

A. 6-01oro-7,8-dimethoxyquinazoline-2,4-dione (Xb)

Acetic acid (10.5 g. 0.175 moles) was added to a vigorously stirred suspension of 5-chloro3,4-dimethoxyanthranilic acid (28.9 g · 0.125 moles) in 600 ml water. 506 ml of a 5% potassium cyanate solution (0.312 moles) was then gradually added and stirred for 1 hour at 40 ° C. After cooling the reaction mixture to 20 ° C, 175 g (4.37 moles) of sodium hydroxide pellets were added keeping the temperature below 40 ° C. The reaction mixture was heated to 90 ° C for 45 minutes. After cooling in an ice bath, the sodium salt of the product precipitated and was filtered, resuspended in 125 ml of water, acidified with concentrated hydrochloric acid, cooled and easy. yielded 25.8 g (80%) of pure, colorless product, PE-272-3 ° C.

Analysis, percentage calculated to 0_1θΞ₉01Ν₂0₄: 0, 46,79}

H. 3.53} '. 1.92.

Found: 0. 46.87} Η. 3.60; N. 10.90

<img file="PT72007B_D0085.tif" />

B. e-Oloro-4-methoxyquinazoline-4,4-dione (XVIII)

Similarly, 6-chloro-7-methoxyquinazoline-2,4-dione was prepared from 5-chloro-4-methoxyanthranilic acid in 83% yield, mp 356-8 ° C.

Analysis, Percentage calculated for ΟθΗΗΟΙΝΟΙΝΟΙΝΟ: O. 47.7 ° 5 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-dimethoxyquinazoline-2,4-dione (25.5 g · 0.099 moles), phosphorous pentachloride (41.4 g. 0.199 moles) and 300 ml phosphorous oxychloride was refluxed. under nitrogen for three hours. Phosphorous oxychloride was removed in vacuo and residual? 001 was removed.

- 3, - as an azeotrope with toluene. The reddish-red solid was dissolved in 200 ml of dichloromethane and the solution was added to ice-cold water. After stirring for 10 minutes, the organic layer was separated, washed with water and dried over sodium sulfate. The filtrate was concentrated and 150 mL of hexane was slowly added to precipitate the product as a pale yellow solid which was recrystallized from toluene / ether to give 18.0 g. (62% yield) PP 154-5 ° C.

Analysis, Percentage calculated for C_inEL01_xN_O0_O: 0. 40,91;

H. 2.40; H.₉,₅₅.

Found: 0.41.05; H. 2.48; No. 9.61.

<img file="PT72007B_D0086.tif" />

Β 2,4,6-Trichloro-7-methoxyquinazoline / XIX)

Refluxing 6-chloro-7-methoxyquinazoline-2,4-dione with PCl 3 in POCl 3 as described above. mp, 2,4,6-trichloro-7-methoxyjujazoline was obtained in 74% yield Mp -130-2 ° C.

Analysis, Percentage calculated for C C HH ^Cl ^N NO: C. 41.02; H. 1.91; N. 10.63.

Found: 0.40.90; H. 2.01; N. 10.54

EXAMPLE 7

A. 2,6-Dichloro-4-amino-7,8-dimethoxyquinazoline (X11b)

Ammonia was passed in a solution of 2.4,

6-trichloro-7,8-dimethoxyquinazoline (31.4 g, 0.10 µmol) in

650 ml dry tetrahydrofuran for one hour at room temperature. After stirring for another hour, the suspension was concentrated in vacuo and filtered. The solid was resuspended in water, filtered and washed with. water and methanol. Recrystallization from dimethylformamide / water afforded 23.7 (81%) of the desired product. MP-360 ° C.

Analysis, percentage calculated for ^g10^H9⁰¹2^N3°2^j θ ' ⁴⁵’⁸²’

H. 3.51; R. 15.53.

Found: C. 43.95; H. 3.53} R. 15.55 ·

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 in 58% yield. ; MP - 3θ0 ° 0 ·

<img file="PT72007B_D0087.tif" />

—H

II ¹¹

Analysis, Percentage calculated for C ^ HH ^ Gl GlgN ^O: 0. 44.28;

H. 2.89; N. 17.22.

Found: 0. 44.12; H. 3.16; N. 17.19

EXAMPLE 8

A. 2- [4- (2-Furoyl) piperazine-1-yl] -4-amino hydrochloride

-6-oloro-7,8-dimethoxyquinazoline (XIIIb)

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g, 5.47 mmol) and 1- (2-6 ml) was refluxed in 40 ml of isopropyl alcohol. furoyl) piperazine (1.08 g, 5.99 mmol) and then allowed to cool overnight. The resulting solid product was filtered and recrystallized from methanol / ether to give 1.83 S (74 of pure final product PP-208-9 ° C).

Analysis, Percentage calculated for O ^HgQOlN ^O ^ .HHOO / / / 2.H ^O: o. 49.25; Ξ 4.79; w. 15.17

Found: 0. 49.03; H. 4.61; N. 15.35 ·

Solubility in water: 8 mg / ml.

B. 2- [4- (2-furoyl) piperazine-1-yl] -4-amino-6-chloro-7-methoxyquinazoline hydrochloride

This compound was prepared similarly by refluxing 2,6-dichloro-4-amino-7-methoxyquinazoline and 1- (2-furoyl) piperazine in isoamyl alcohol, mp 229-31 ° C. 79% yield.

Analysis, calculated percentage for Ο ^ Ξ ^ ΟΙΝι-Ο ^ .ΗΟΙ.Η ^ Ο:

0 48.88; H. 4.79; N. 15.83.

Found: 0. 49.47; H. 4.70; N. 15.62.

Solubility in water: 5 mg / ml.

<img file="PT72007B_D0088.tif" />

EXAMPLE 9

A. 2-Methyl-2-hydroxypropyl-4- [4-amino-6-chloro-7,8-dimethoxyquinazoline-2-yl] piperazine-1-carboxylate hydrochloride

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g, 5.47 mmol) and 2-methyl-2-hydroxypropyl were refluxed in 30 ml of methyl isobutyl ether. -4-piperazine-1-carboxylate (1.22 g, 6.03 mmol). The yellowish solid formed was filtered off, resuspended in 40 ml of acetone and stirred for 15 minutes. The filtered solid was discolored with charcoal and recrystallized twice from ethanol ether to yield 1.47 g. (57%) of final product

PE 211-3 ° 0.

Analysis, Percentage calculated for C C SS ^ CCIN ^H ^,, HCl; C. 47.90% H. 5.50%; N. 14.70% '

Found: C. 47.70%; H. 5.74% »N. 14.36%

Solubility in water: 35 mg / ml.

B. 2-Ethyl-2-hydroxypropyl 4 - [4-amino-6-chloro-7-yl] azazolin-2-yl] piperazine-1-carboxylate hydrochloride / XXI, -OOOCH_?G (OH) (OH)_?7

This compound was similarly prepared by refluxing 2,6-dichloro-4-amino-7-niethoxyquinazoline and 2-methyl-2-hydroxypropyl-4-piperazine-1-earboxylate in methyl iso. butyl ketone for 4 days, PE 243-5 ° C, 69% yield.

Analysis, percentage calculated for c₁₈H₂₄huh₅O₄, HCl, h₂0.46.55%; H. 5.36% N. 14.08%

Found: 0. 46.89%; H. 5.6% N. 15.22%

Solubility in water: 6 mg / ml

<img file="PT72007B_D0089.tif" />

<img file="PT72007B_D0090.tif" />

O, 2- [4- (1,4-Benzodioxan-2-carbonyl) piperazin-1-yl 7-4-amino-6-chloro-7-methoxy quinazoline hydrochloride

This compound was prepared by the technique of part A, above, by refluxing 2,6-dichloro-4-amino-7-methoxyquinoline and N- (1,4-benzodioxan-2-carbonyl) piperazine into methylbutyl ketone, PP 194 -196 ° C.

EXAMPLE 10

When employing the appropriate N-substituted piperazine in the technique of Example 4 in place of 1- (2-furoyl) piperazine, the analogous products in the table below are obtained as hydrochloride salts unless otherwise indicated.

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<img file="PT72007B_D0091.tif" />

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<td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>rd</td>

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Example 10 (continued)

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<td>• laughs</td><td>s</td>

<td>rH</td><td>M)</td>

<td>•H</td><td rowspan="2">The</td>

<td></td>

<td>pl</td><td>&lt;D</td>

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<td> 03</td><td>d</td>

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Pd g

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<td colspan="6">rd</td>

<td>L0</td><td>frog</td><td>frog</td><td>s</td><td>THE</td><td>L0</td>

<td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td>

<td>frog THE</td><td>THE O</td><td> &amp;</td><td>THE frog</td><td>frog rd</td><td>THE co</td>

<td>rd</td><td>Hello</td><td>rH</td><td>rd</td><td>Hello</td><td>rd</td>

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<img file="PT72007B_D0099.tif" />

<img file="PT72007B_D0100.tif" />

u, ·

EXAMPLE 11

2- [4- (2-Euroylhomopiperazine-1-yl] -4-amino-7,8-dimethoxyquinazoline hydrochloride

A. N- (2-Euroyl) homopiperazine

Homopiperazine (70 g, 0.70 moles) was treated in 160 ml water with 6N hydrochloric acid to adjust to pH 5.5.

At the same time, furoyl chloride was added; (79.5 g, 0.60 mole) and 25% aqueous sodium hydroxide solution (w / w to maintain a pH of 4.5-5.5 · Additional sodium hydroxide was then added to bring the mixture to pH 9.5 The solution was extracted with chloroform, dried over anhydrous potassium carbonate and distilled to yield 63 g of product, PE 124-130 ° C at 10 mm.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (1.76 g, 7.3 moles) N- (2-furoyl) homopiperazine (1.50 g, 7.7 moles) and 40 ml isoamyl alcohol were combined and the mixture was heated to reflux temperature under a nitrogen atmosphere for

1.5 hours. After cooling to room temperature, the mixture was stirred for one hour, filtered and the precipitated product washed with ether and recrystallized from methanol / ether to yield 2.15 g of this compound, PE 182-183 °. 0

Analysis, Percentage calculated for σ_2θΞ₂₃Ν₅^θ4.01 0.5 H₂0:

0.54.23, H. 5.69; N.15.81.

Determined; 0. 53.84; H. 5.40; N. 15.49

Solubility in water was 30 mg / ml.

<img file="PT72007B_D0101.tif" />

. 'i.

<img file="PT72007B_D0102.tif" />

EXAMPLE 12

2- [4- (2-Tetrahydrofuroyl) homopiperazine-1-yl] -4-amino-7,8-dimethoxyquinazoline hydrochloride

A. R- (2-tetrahydrofuroyl) homopiperazine

A. R- (2-Puroyl) homopiperazine (33.0 g) was hydrogenated in 200 ml ethanol over a 5% rhodium on carbon catalyst at a pressure of three atmospheres. The catalyst was removed by filtration and the product distilled to yield the product of, desired, 135 mm O at 1 mm.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.10 g, 8.75 mole), N- (2-tetrahydrofuroyl) homopiperazine (1.9 g, 9.58 mole) and 50 ml of isoamyl alcohol were mixed and heated at reflux temperature 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 charcoal and diatomaceous earth. 0 The filtrate was adjusted to alkaline pH by the addition of sodium bicarbonate solution, extracted four times with 50 ml portions of ethyl acetate and the extracts extracted over sodium sulfate. The solvent was evaporated and the residue chromatographed on 30 g of silica gel, eluting with chloroform / ethanol. Fractions containing the desired product (free base) were combined and evaporated to yield the free base as a foam, 1.0 g. The free base was dissolved in ether, saturated with hydrogen chloride and filtered to obtain this compound, PP 130 ° C.

Analysis, Percentage calculated for ^σ20^Η27^Ν5^θ4’ ^H01’ °’⁵° ^H2°

0 53.74; H. 6.54; R. 15.67.

Found 0. 53.56; H. 6.68; N. 15.44

Solubility in water: 120 mg / ml.

A. 2- (4-Benzylpiperidin-1-yl) -4-amino-7,8 hydrochloride

-dimethoxyquinazoline

<img file="PT72007B_D0103.tif" />

4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.40 g. 10 mmol), 4-benzylpiperidine (1.93 g. 11 moles) and 50 ml isoamyl alcohol were heated to re temperature. flow under a nitrogen atmosphere for two hours and cooled to room temperature. Diethyl ether (50 ml) was added and the mixture was refrigerated for two days. The solid precipitate was collected by filtration and recrystallized from ethane / diethyl ether to yield 2.50 g (60%) of this PP compound. 216-217 ° 0 ·

Analysis, percentage calculated for ^ 22 ^ 26 ^ 2¾ • 0.63.68; Ξ 6.56; N. 13.50

Found: C. 63.78; Ξ 6.67; 13.89 Solubility in water: 6 mg / ml.

EXAMPLE 14

Employing suitably substituted 2-chloro- (or 2-bromo) 4-amino quinazoline and amine of the formula

Hn

2^zn in the process of Example 13 the following products are obtained

<img file="PT72007B_D0104.tif" />

54ΝΗ_ I ²

<td>Where</td><td>a is 1 or me</td><td>O- &lt; men are</td><td>Cch₂) Cch₂i 2 or</td><td> /-^The?no 3</td>

<td>Y¹</td><td>Y²</td><td>Y³</td><td>The</td><td>no</td>

<td></td><td></td><td></td><td></td><td></td>

<td>H .</td><td>ch₃O</td><td>CB₃°</td><td> 1</td><td> 2</td>

<td>Cl</td><td>ch₃O</td><td>H</td><td> 1</td><td> 2</td>

<td>Cl.</td><td>ch₃O</td><td>CH₃O</td><td> 1</td><td> 2</td>

<td>H</td><td>ç₂H₅°</td><td>θ2 ^ 5θ</td><td> 1</td><td> 2</td>

<td>Cl</td><td>ç₂H₅O</td><td>B</td><td> 1</td><td> 2</td>

<td>Cl</td><td>^Ç2^H5°</td><td>^Ç2^H5°</td><td> 1</td><td> 2</td>

<td>H</td><td>nC₃H_?O</td><td>CH₃O</td><td> 1</td><td> 3</td>

<td>Cl</td><td>no₃B₇O</td><td>B</td><td> 1</td><td> 3</td>

<td>Cl</td><td>nC₃^H7°</td><td>nC₃H_?O</td><td> 1</td><td> 3</td>

<td>H</td><td>here₃0</td><td>B</td><td> 1</td><td> . 3</td>

<td>Cl '</td><td>ch₃O</td><td>ch₃O</td><td> 2'</td><td> 2</td>

<td>Cl</td><td>ch₃O</td><td>ch₃O</td><td> 2</td><td> 2</td>

<td>B</td><td>ch₃O</td><td>CB₃O</td><td> 2</td><td> 2 .</td>

<td>Cl</td><td>ch₃O</td><td>H</td><td> 2</td><td> 3</td>

<td>Cl</td><td>CH₃O</td><td>CHjO</td><td> 2</td><td> 3</td>

<td>B</td><td>^Ç2^H5°</td><td>H</td><td> 2</td><td> 3</td>

<td>Cl *</td><td>ch₃O</td><td>ch₃O</td><td> 2</td><td> 3</td>

<td>Cl</td><td>ch₃0</td><td>CH₃O</td><td> 2</td><td> 3</td>

<td>H</td><td>ch₃O</td><td>nC₃H₇O</td><td> 3</td><td> 3</td>

<td>Cl</td><td>nC₃B₇O</td><td>B</td><td> 3</td><td> 3</td>

<td>Cl</td><td>CB₃O</td><td>B</td><td> 3</td><td> 3</td>

<td>H</td><td>ch₃°</td><td>ch₃O</td><td> 3</td><td> 3</td>

<td>Cl</td><td>CH-jO</td><td>ch₃O</td><td> 1 .</td><td> 3</td>

<td>Cl</td><td>• CH₃O</td><td>B</td><td> 1</td><td> 3</td>

<td>H</td><td>ch₃O</td><td>ch₃O</td><td> 1</td><td> 2</td>

<td>Cl</td><td>ch₃0</td><td>B</td><td> 1</td><td> 2</td>

<td>Cl</td><td>ch₃0</td><td>ch₃O</td><td> 2</td><td> 2</td>

<td>B</td><td>cb₃0</td><td>CH₃O</td><td> 2</td><td> 3</td>

<td>Cl</td><td>cb₃O</td><td>H</td><td> 3</td><td> 3</td>

<td>Cl</td><td>ch₃O</td><td>B</td><td> 1</td><td> 3</td>

<td>B</td><td>• ch₃O</td><td>ch₃O</td><td> 1</td><td> 2</td>

CH₃

CH₃(CH₂)_s (CH₃)₂CHCH₂^Ç6^H5 ^Ç6^H5^CH2

3- CH₃Ç₆^H4 (CH3) 2CH · ch3 (c^H2)₄³“^FC6^H4

4- CH₃OC_gH₄CH₂4-HOC₆H₄

3- CH₃ONLY₂Ç₆H₄2-ch₃only₂nhc₆H₄ch₂^CH3^CH2

4- CH, SO.NHC, .H.

2 6 4 ch₃(ch₂)₃4-CF₃Ç₆H₄^çH₂4-FC₆H₄ch₃^Ç6^H5 ^Ç6^H5^CH2

4 ~ CH₃Ç₆^H4 ·

2- ClCgH₄CO CgHgCO 4-BrCgH₄CO 4-HOCgH₄CO 4-CF₃CgH₄CO

4-FC.H.CO

4

3- CH ^ SO „C_çHCO *

2 6 4

CgHgCO HOCH „

<img file="PT72007B_D0105.tif" />

<td>y¹</td><td>Y²</td><td>Y³</td><td>The</td><td>no</td><td>R⁷</td>

<td>Cl</td><td>CH₃O</td><td>CH₃O</td><td> 1</td><td> 2</td><td>HOCH₂CH₂</td>

<td>Cl</td><td>ch₃O</td><td>H</td><td> 1</td><td> 2</td><td>(CH3) -C (OH) CH3</td>

<td>H .</td><td>CH₃O</td><td>ch₃O</td><td> 1</td><td> 3</td><td>(CH₃)₂CHCH (OR) CH₂</td>

<td>Cl</td><td>ch₃0</td><td>ch₃what</td><td> 1</td><td> 3</td><td>(CH₃)₂C (OH) CH₂CH₂</td>

<td>Cl</td><td>ch₃O</td><td>H</td><td> 1</td><td> 3</td><td>(CH₃)₂C (OH)</td>

<td>H</td><td>CH₃O</td><td>ch₃O</td><td> 2</td><td> 2</td><td>CH₂OH</td>

<td>Cl</td><td>ch₃0</td><td>ch₃O</td><td> 2</td><td> 2</td><td>CH₂CH₂OH</td>

<td>Cl</td><td>ch₃0</td><td>H</td><td> 2</td><td> 2</td><td>CH₃CH (OH)</td>

<td>H</td><td>ç₂H₅O</td><td>ç₂H₅O</td><td> 3</td><td> 3</td><td>CH₂OH</td>

<td>Cl</td><td>CH₃O</td><td>ch₃O</td><td> 3</td><td> 3</td><td>(CH₃)₂C (OH)</td>

<td>Cl</td><td>CFL₃</td><td>H</td><td> 3</td><td> 3</td><td>(CH₃CH₂)₂C (OH)</td>

EXAMPLE 15

2- [4- (2-Tetrahydrofuroyl) piperazine-1-yl]^,-4-amino-6-chloro-7,8-dimethoxyquinazoline

To 35 ml of isoamyl alcohol was added 1.50 g (5.47 mmol) of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g (6.02 mmol) of 1- ( 2-Tetrahydrofuroyl) piperazine and the mixture was heated at reflux temperature under a nitrogen atmosphere for 1.5 hours. The mixture was cooled, 20 ml of ethyl ether was added and the resulting mixture was stirred at room temperature overnight. It was then cooled on ice and the solid precipitate was collected by filtration. 0 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, under stirring, the precipitated brownish solid was filtered off, discolored with activated charcoal and recrystallized from isopropanol / ethyl ether to 0.38 g of yellow solid, PE 192-193 ° C ·

<img file="PT72007B_D0106.tif" />

-56:¹ τ 'uwi »

Analysis, Percentage calculated for ^ aAV¹0.54.09; H. 5.73! H. 16.60

Given 0.83.83? H. 5.73? N. 16.58

Mass spectrum peaks (Μ⁺/ θ)? 421 (molecular ion), 406, 392, 378, 350, 321, 293, 280 and 266.

Example 16

Employing the processes of Examples 8, θ 10 the following compounds are prepared similarly from the appropriate base materials.

<img file="PT72007B_D0107.tif" />

<img file="PT72007B_D0108.tif" />

<td>yl</td><td>y2</td><td></td><td>W</td>

<td></td><td> **</td><td></td><td></td>

<td>H</td><td>σ₂Η₅ο</td><td>W</td><td>cyclopropyl</td>

<td>Cl</td><td>n-CjH ^ O</td><td>no ^ O</td><td>cyclopentilo</td>

<td>H</td><td>nC ^ O</td><td>nC ^ O</td><td>cyclohexyl</td>

<td>Cl</td><td>ch₃O</td><td>H</td><td>cyclooctyl</td>

<td>H</td><td>CH-, 0 3</td><td>CH-, 0 y</td><td>4-C10₆H₄</td>

<td>Cl</td><td>CH-, 0 3</td><td>H</td><td>2-FC₆H₄</td>

<td>H</td><td>CH, 0 y</td><td>ch₃O</td><td>4-CH₃0C₆H₄CH₂</td>

<td> 01</td><td>CH_x0 y</td><td>Ξ</td><td>3-cf₅ç₆H₄gh₂</td>

<td>H</td><td>0Ξ-0 y</td><td>CH, 0 y</td><td>4-H0C₆H₄</td>

<td>H</td><td>CH-, 0 y</td><td>CH-, 0 3</td><td>2-CH₅S0₂Ç₆H₄</td>

<td>Cl</td><td>CH-, 0 y</td><td>CH-, 0 y</td><td>4-CH-, SO_NHC₍-H. yd 0 4-</td>

<td>Cl</td><td>ç₂H₅O</td><td>H</td><td>4-ch₅only₂hhc₆H₄ch₂</td>

<td>Cl</td><td>W</td><td>ç₂H₅O</td><td>4-CH₃S0₂'Ç₆H₄CH₂</td>

<td>Cl</td><td> °2^H5°</td><td>H</td><td>4-BrC₆H₄CH₂</td>

<td> 01</td><td>W</td><td>ç₂H₅°</td><td>2-CH₅Ç₆H₄CH₂</td>

<td>Cl</td><td>ç₂H₅O</td><td>H</td><td>3-fc₆H₄ch₂</td>

<td>Cl</td><td rowspan="4">CH ^ O CH-, 0 y^CH5th CH_ZO y</td><td>H</td><td>2-fluoro-1-naphthyl</td>

<td>Ξ</td><td>ch₅O</td><td>4-brom.o-2-E.aphthyl</td>

<td>H</td><td rowspan="2">^CH5th CH-, 0 3</td><td>4-methyl-1-naphthyl</td>

<td>H</td><td>3-trifluoromethyl- -naphthyl</td>

<td>Cl</td><td rowspan="2">^CH5th ch₅O</td><td rowspan="2">^σΞ5th CH 0</td><td>2-h.hydroxy-E.Faphthyl</td>

<td>H</td><td>4-hydroxy-1-naphthylmethyl</td>

<td>Cl</td><td>ch₅O</td><td>«Z Η</td><td>4-methoxy-2-naphthylmethyl</td>

<td>Cl</td><td>ch₅O</td><td>ch₅O</td><td>3-fluoro-1-naphthylmethyl</td>

<td>H</td><td>CH-, 0 y</td><td>CH-, 0 y</td><td>6-methylsulfonylamino-1- naphthylmethyl</td>

<td>H</td><td>CH-, 0 y</td><td>CH. 0 y</td><td>4-methylsulfonyl-1-naphthyl tilo</td>

<td>H</td><td>ch₅O</td><td>CH ^ O</td><td>ch₂c = ch</td>

<td>Cl</td><td>0H, 0 3</td><td>CH-, 0 y</td><td>ch₂= cch₃</td>

<td>Cl</td><td rowspan="2">^θΗ5^θCH. 0 y</td><td rowspan="2">^CH5th CH-, 0 y</td><td rowspan="2">CHgCãCCHgCH ^ CH₂(0H₂)₂here</td>

<td>H</td>

<img file="PT72007B_D0109.tif" />

<td> •^1</td><td>Ϊ²</td><td rowspan="2">I⁵</td><td>W</td>

<td> —</td><td>«M</td><td></td>

<td>Cl</td><td>ch₅O</td><td>H</td><td>CHO</td>

<td>Cl</td><td>ch₅O</td><td>H</td><td>coch₃</td>

<td>H</td><td>iso-0, H „0</td><td>iso-C ^HnO</td><td>coch (oh₃)₂</td>

<td>H</td><td>g₂H₅O</td><td>ç₂H₅O</td><td>C0-CH₂(CH₂)₄CH₃</td>

<td>Cl</td><td>OH.O 2</td><td>CH-, 0 2</td><td>COCH₂(CH₂)₂CH (CH₃)₂</td>

<td>Cl</td><td>ch₅O</td><td>H</td><td>C0CH₂CH = CH₂</td>

<td>H</td><td>nC-, Η ^ Ο 2 /</td><td>nC ^ O</td><td>COCH₂C (CH₃) = CH₂</td>

<td>Cl</td><td>ch₅O</td><td>ch₃O</td><td>COCH₂C (CH₃) = CHCH₃</td>

<td>Cl</td><td>OH₅O</td><td>H</td><td>C0CH₂C = CH</td>

<td>H</td><td>CH-, 0 2</td><td>CH-, 0 2</td><td>.COCHC₂^ CGH₃</td>

<td>Ξ</td><td>ch₃O</td><td>ch₅O</td><td>coc »cch_Pch₂ch.</td>

<td>Cl</td><td>ch₅O</td><td>ch₃O</td><td>cyclopropylcarbonyl</td>

<td>H</td><td>ch₅O</td><td rowspan="2">CH ^ O ç₂H₅°</td><td>cyclobnylcarbonyl</td>

<td>H</td><td>ç₂H₅°</td><td>cycloheptylcarbonyl</td>

<td>H</td><td>ch₅O</td><td>ch₅O</td><td>cyclooctylcarbonyl</td>

<td>H</td><td>ch₃O</td><td>CH_O P</td><td>cyclopropylmethylcarbonyl</td>

<td>Cl</td><td>oh₅O</td><td>H</td><td>cyclooctyl methylcarbonyl</td>

<td>Cl</td><td>ch₅O</td><td>Ξ</td><td>3-thenoyl</td>

<td>H</td><td>ch₅O</td><td>ch₅O</td><td>5-chloro-2-thenoyl</td>

<td>H</td><td rowspan="2">CH ^ O ch₅O</td><td rowspan="2">^θΗ3rd ch₃O</td><td>4-methyl-3-thenoyl</td>

<td>Cl</td><td>5-phenyl-2-thenoyl</td>

<td>H</td><td>ch₅O</td><td>ch₃O</td><td>5-ethyl-3-furoyl</td>

<td>H</td><td>ch₃O</td><td>ch₃O</td><td>5-phenyl-2-uroyl</td>

<td>H</td><td>ch₃O</td><td>ch₃O</td><td>2-pyridylcarbonyl.</td>

<td>H</td><td>ch₅O</td><td>ch₃O</td><td>2-chloro-4-pyridylcarbonyl</td>

<td>Cl</td><td>ch₃O</td><td>Η</td><td>g-methyl-pyrimidinylcarb. Nile</td>

<td>H</td><td>CH-, 0 2</td><td>CH-, 0 2</td><td>2-fen1-4-p irimidini1carbo Nile</td>

<td>Ξ</td><td>CH-, 0</td><td>CH, 0</td><td></td>

<img file="PT72007B_D0110.tif" />

<td>I¹</td><td>Y²</td><td>Y³</td><td>ϋ Cj - ^ - co</td>

<td>Cl</td><td>CH-jO</td><td>ch₃O</td><td></td>

<td>Cl</td><td>CH-, 0</td><td>H</td><td></td>

<td></td><td>J</td><td></td><td></td>

<td>H</td><td>CH-jO</td><td>ch₃O</td><td>'Qo</td>

<td>H</td><td>CH-jO</td><td>ch₃O</td><td>Coconut</td>

<td>Cl</td><td>CH-, 0</td><td>H</td><td></td>

<td></td><td></td><td></td><td>Oç ^ -co</td>

<td>Cl</td><td>CH₃O</td><td>CH-.0</td><td></td>

<td></td><td></td><td></td><td>^ Ο'-ο ^ οο</td>

<td>Cl</td><td>CH₃O</td><td>CH₃O</td><td>^ O'CH CO</td>

<td>H</td><td>ch₃0</td><td>ch₃0</td><td>THE</td>

<td></td><td></td><td></td><td>och₂co</td>

<td>H</td><td>CH-, 0</td><td>CH-, 0</td><td></td>

<td></td><td> 3</td><td> 3</td><td>ÇL _no</td>

<td></td><td></td><td></td><td>0 CH₂CO</td>

<td>Cl</td><td>CH, 0</td><td>H</td><td></td>

<td></td><td>O</td><td></td><td>0CH₂CO</td>

<td>Cl ·</td><td>CH₃O</td><td>H</td><td>l * -hydrox: xri-2-naphthoyl ·</td>

<td>H</td><td>ch₃0</td><td>ch₃O</td><td>4rr-dloro-1-naphthylmethyl</td>

carbon.yl

<img file="PT72007B_D0111.tif" />

hey hey

H

H

CH₃The tea₃0 ch₃0

I³

H π

CH ^ O ^ CO ch₃0 ch₃0 ch₃the CH₃0

Cl CH₃Oh h₃the tea₃O

Cl CH₃0 ch₃O

Cl CH₃0 h η CH₃0 CH₃O

Cl CH₃0 H

H CH₃The CH₃0

N—, ^ 'CO ca ^^ s ^ co

N—

yc

N_

CttjS- ^ O ^ '* co

NN LI LI ch₃s^mo ^ co NN

CH-S- ^ S ^ CO ςλ

s ^co^Nvs"^THE'co

<img file="PT72007B_D0112.tif" />

<img file="PT72007B_D0113.tif" />

<td>Y ·¹</td><td>Y²</td><td>I⁵</td>

<td></td><td>MM</td><td></td>

<td> 01</td><td>oh₅O</td><td>Ξ</td>

<td>Ξ</td><td>oh₅O</td><td>oh₃O</td>

<td> 01</td><td>oh₅O</td><td>oh₅O</td>

<td>H</td><td>oh₃O</td><td>0H 0</td>

<td> 01</td><td> . ^GH5°</td><td>«Z H</td>

<td> 01</td><td>ΟΗ, Ο</td><td>ΟΗ, Ο</td>

<td></td><td> 3</td><td> 3</td>

<td>H * '</td><td>ΟΗ, Ο 5th</td><td>ΟΗ, Ο 3</td>

<td>H '</td><td>ch₃O</td><td>OH ^ O</td>

<td>Cl</td><td>CH, 0 5th</td><td>ΟΗ, Ο 3</td>

<td> 01</td><td>OH ^ O</td><td>Η</td>

<td> 01</td><td>O₂H₅°</td><td>Η</td>

<td>ci;</td><td>no ^ H ^ O</td><td>Ξ '</td>

<td>H.</td><td>n-0, H „0</td><td>η-Ο, Η, -, Ο</td>

<td></td><td> 3 7</td><td> - 3 7</td>

<td> 01</td><td>oh₅O</td><td>οξ₃°</td>

<td> 01 .</td><td>•O₂H₅O</td><td>ο₂η_?ο</td>

<td>H '</td><td>O₂H₅°</td><td>ο₂η₅ο.</td>

<td> 01. · ·</td><td>oh₅O</td><td>OHjO</td>

<td> 01</td><td>oh₃O</td><td>OHiO</td>

<td>Cl</td><td>oh₃O</td><td>✓ · Ξ </td>

<td> 01</td><td>• oh₅O</td><td> ' ^Ξ</td>

<td>H , • 1</td><td>'ΟΗ, Ο,'. 3 -</td><td>• ΟΗ, Ο 5th</td>

<td>H</td><td>CH ^ O '</td><td>ΟΞ 0</td>

<td> 01</td><td>^!ch₃°·</td><td>«Ζ . Η '</td>

<td> 01 · .'</td><td>ΟΗ, Ο '3</td><td>ΟΗ, Ο. · 5</td>

<td> 01</td><td>• oh₃O</td><td>ΟΗ, Ο • 3 '</td>

<td>H</td><td>ch₃O .</td><td>• οη₃ο</td>

<td> 01</td><td>• CH, 0 7 5</td><td>• ζ 'Η ·</td>

<td>Cl</td><td>ch₃0</td><td>Η^- '</td>

<td>C1</td><td>ch₃O</td><td>ch₃O</td>

<td>Η</td><td> CH₃O</td><td>CH₃O</td>

<td>C1</td><td>ch₃O</td><td>ΟΗ₃Ο_ζ</td>

oh ^ ooo oh₅(oh₂)₅oh₂ooo oiclohexil OCO hooh₂gh₂ooo (ch₅)₂c (oh) ch₂ch₂hollow. 4-Br0₆H₄0H₂0G0

1-hydroxy-2-naphthylmethyl-OGO oh₂= gh-oh₂ogo gh₂= g (gh₅) gh₂ogo CH₃GEL = (GH₃) GH₂OGO cyclopropyl-000 cyclohexyl-OCB cyclooctyl-000 cyclooctyl-OCO GH₅GH (OH) GH₂0C0 '

2- GH₅G₆H₄GH₂0G0.

3- GF₅G₆H₄GH₂000

4- GH₅OG₆H₄GH₂OGO 4-H00₆H₄CH₂0C0 '

3- GH₅S0₂G₅H₄GH₂0GO

4- GHjS0₂NHG₆H₄CH₂0G0 • 47-chloro-1-naphthylmethyl-OCO 1-fluoro-2-naphthylmethyl-0'0-3-hydroxy-2- n.aphthylmethyl-2'-2'methyll-naphthylmethyl-000'-methoxy-2-naphthylmethyl-0'0 4-trifluoromethyl -1-naphthylmethyl-000

<img file="PT72007B_D0114.tif" />

Ç | —oçh₂hollow q ^ och₂hollow gBCT — ιγ, Μ'.ιιμ ·· ^ ts'

<td>Y¹</td><td>y²i,; ·</td><td>Y³</td><td>w</td>

<td>H</td><td>ch₃0 '</td><td>CH₃O</td><td>Ç ^ -ch₂hollow</td>

<td rowspan="2">Cl</td><td>CH, 0</td><td rowspan="2">ch₃0</td><td></td>

<td> 3</td><td>I'm_OCO</td>

<td rowspan="2">Cl</td><td>CH.O</td><td rowspan="2">H</td><td> 0</td>

<td> 3</td><td>% ^ CH₂HOLLOW</td>

<td>Cl</td><td>CH₃O</td><td>H</td><td>O ^ ch₂hollow</td>

<td>H</td><td>^Ç2^H5°</td><td>ç₂H₅O</td><td>Ç ^ ch₂hollow</td>

<td>Cl</td><td>CH₃O</td><td>H %</td><td>^ 4 ^ 'O' ^ CH₂0C0</td>

<td>Cl</td><td>w</td><td>H .</td><td>^ Ç ^ CHjOCO</td>

<td>Cl</td><td>CH.O</td><td></td><td></td>

<td></td><td> 3 ·</td><td>CH₃O</td><td> . ^^sS'^S,CH₂HOLLOW</td>

<td>H</td><td>ch₃O</td><td>ch₃O</td><td>Oto</td>

<td>Cl</td><td>ch₃O</td><td>ch₃O</td><td>stump ·</td>

<td>Cl '</td><td>CH, 0 • j</td><td>H</td><td>I'm co</td>

<td>H</td><td>t CH₃O</td><td>- ch₃O</td><td>Gxr ^ CHjCO</td>

<td>Cl.</td><td>CH₃O</td><td>ch₃O</td><td>OsP ^ CH₂CO</td>

<td>Cl</td><td>CH₃O</td><td>H</td><td>G ^ PCH₂HOLLOW</td>

<td>H</td><td> CH₃O</td><td>CH₃O'</td><td>^ xz ^ ce ^ co</td>

<img file="PT72007B_D0115.tif" />

Example 17

A. 5-Chloro-4-methoxy-6-isothiocyanatobenzonitrile

To a solution of 27.46 (0.15 mol) of 6-amino-3-chloro-4-methoxybenzonitrile in 150 ml of 0-dichloroethane at 0-5 ° C is added with stirring a mixture of 23 g (0.2 moles) thiophosgene, 100 ml 1,2-dicloethane, 20 g (0.2 moles) calcium carbonate and 200 ml water. After 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 one 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. 5-01oro-4-methoxy-6- (homomorpholin-4-yl) thiocarbamidobenzortitrile

To 11.3 g (0.05 mol) of the residue obtained above dissolved in 65 ml of ethyl acetate is slowly added with stirring at 0 ° C a solution of 5.1 g (θ, θ5 mol). homomorpholine in an equal volume of the same solvent. The resulting mixture is cooled to -25 ° C and allowed to stand overnight. The precipitate is collected by filtration, washed with cold ethyl acetate and dried to give the desired product.

0 N- (3-Methoxy-4-chloro-6-cyanophenyl) - (homomorpholin-4-yl) methylthioformamidate

Dissolve 16.3 g (0.05 mol) of 3-chloro-4-methoxy-6- (homomorpholin-4-yl) -thiocarbamidobenzonitrile in 200 ml of diglyme (diethylene glycol dimethyl ether) and 14.2 g (0 1 mole) of methyl iodide and the mixture is heated to room temperature.

<img file="PT72007B_D0116.tif" />

64 ° C (60 ° C) for eight hours and then cooled to room temperature. The resulting mixture is filtered, the pro. solid duct washed with ether and dried to give the hydroiodide salt of the above compound.

The hydroiodide 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 above compound as free base.

ί). '2- (Ηοιιιθ] ΐΐΌΓίο1ΐη-4-ίΐ) -4-5ύΐιΐηο-6-ο1θΓθ-7-ιη ^ οχίαη1-η &amp; ζο1ΐηη

To a solution of 3.4 g (0.01 moles) of the free base obtained in part 0 above in 75&gt; 1 of formamide is added 1.3 g of sodium starch and the resulting solution is cooled to 0 ° C and saturated with ammonia gas. The cold solution is slowly heated for 2-3 hours to 120 ° C, and then kept at this temperature for 4 hours. The reaction mixture is then cooled to room temperature, 100 ml of ice water is added, the mixture is extracted with chloroform, the extracts washed with water, dried and evaporated to dryness.

Crude material is purified by crystallization.

EXAMPLE 18

Employing one of the processes of Examples 4, 8, θ 17, the following compounds are prepared from suitable starting materials.

<img file="PT72007B_D0117.tif" />

/%..

ίϊ

S?

VL .

L · α '.

’··:·

<img file="PT72007B_D0118.tif" />

<td>ϊ¹</td><td>y2</td><td>ϊ⁵</td><td>Ε¹</td><td>AND²</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>Η</td><td>H</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>Η</td><td>oh₃</td>

<td> 01</td><td>οη₃ο</td><td>ΟΗ, Ο 2</td><td>Η</td><td>(0H₃)₂0H</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>Ξ</td><td>Η</td><td>(0H₃)₂CHCH (OH)</td>

<td> 01</td><td>ο₂η₅ο</td><td>Η</td><td>ΟΗ 2</td><td>oh₃</td>

<td>Ξ</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>ch₃(0H₂)₃huh₂</td><td>OH₃OH₂</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>οη₃(οη₂)₃οη₂</td><td>0H₃(0H₂)₃0H₂</td>

<td> 01</td><td>οη₃ο</td><td>0Η₃0</td><td>Η</td><td>oiclopropyl</td>

<td> 01</td><td>οη₅ο</td><td>Η</td><td>ΟΗ 2</td><td>cyclopenjbyl</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>Η</td><td>cyclooctyl</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>oiclopropyl</td><td>oiclopropyl</td>

<td> 01</td><td>ch₃O</td><td>ΟΗ, Ο 2</td><td>cyclohexyl</td><td>cyclohexyl</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>Η</td><td>Hiclohexil</td><td>cyclooctyl</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>Η</td><td>0H₂= CH-0H₂</td><td>oh₂= ohoh₂</td>

<td>Η</td><td>η.-0, Η_π0 ~ 2 7</td><td>η-0 ^ 0</td><td>GH₂= CH (0H₂)₃</td><td>oh₂= oh (oh₂)₃</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>Η</td><td>OH₂= O (OH₃) OH₂</td><td>OH₂= O (0H₃) OH,</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>oh₃</td><td>0H₂= 0H0H₂</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>οξ₃ο</td><td>H</td><td>0H₂= 0H0H₂</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>H</td><td>(oh₃)₂g = ghoh₂</td>

<td>Η</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>H</td><td>0HCCH₂</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>Ξ</td><td>0H = 0 (0H₂)₃</td>

<td> 01</td><td>οη₃ο</td><td>Η</td><td>οη₃οξ₂οη₂</td><td>0H = 00H₂</td>

<td> 01</td><td>ΟΗ, Ο 2</td><td>ΟΗ, Ο 2</td><td>oiclopropyl</td><td>0H₃0 = 00H₂</td>

<td> 01</td><td>ch₃O</td><td>οη₃ο</td><td>cyclohexyl</td><td>oh = ooh₂</td>

<td>Η</td><td>οη₃ο</td><td>οξ₃ο</td><td>ch₂= ohoh₂</td><td>OHsOOHg</td>

<td>Ξ</td><td>οη₃ο</td><td>οη₃ο</td><td>oh₃(oh₂)₄oh₂</td><td>0H₂= 0H0H₂</td>

<img file="PT72007B_D0119.tif" />

-66Σ¹ ϊ² ϊ⁵ β¹ β²¹ 1

<td> 01</td><td>CH-, 0 5th</td><td>CH. 0 5th</td><td>cyclooctyl</td><td>i'oh₃oh = ohoh₂</td>

<td> 01</td><td>CH, 0 5th</td><td>H</td><td>oh₃(oh₂)₃oh₂</td><td>(ch₃)₂c = choh₂</td>

<td> 01</td><td>oh₅O</td><td>H</td><td>hoch₂ch₂</td><td>hooh₂oh₂</td>

<td>H</td><td>oh₅O</td><td>oh₃O</td><td>H</td><td>HO (OH₂)₃</td>

<td> 01</td><td>0H, 0 3</td><td>CH-, 0 5th</td><td>Η</td><td>H00H₂0H₂</td>

<td> 01</td><td>0H, 0 5th</td><td>H</td><td>ho (oh₂)₅</td><td>ho (oh₂)₅</td>

<td> 01</td><td>CH-, 0 5th</td><td>Ξ</td><td>oh₃ ...</td><td>H00H₂0H₂0H₂</td>

<td>H</td><td>CH, 0 5th</td><td>oh₃O</td><td>(0H₃)₂0H0H₂0H₂</td><td>H00H₂0H₂</td>

<td> 01</td><td>CH-, 0 5th</td><td>ch₃O</td><td>cyclohexyl</td><td>OH₅OH OH OH₂</td>

<td> 01</td><td>CH-, 0 5th</td><td>H</td><td>ch₂= ohoh₂</td><td>(GH₃)₂O (OH) OH,</td>

<td>H</td><td>CH-, 0 5th</td><td>CH-, 0 5th</td><td>oh = ooh₂</td><td>h ° (oh₂)5</td>

<td>H</td><td>0Ξ_χ0</td><td>0Η_χ0</td><td>cyclopropyl</td><td>H00H_O</td>

Example 19

Α 2- (5-Thiazolidinyl) -4-amino-7,8-dimethoxyquinazoline hydrochloride

A mixture of 4.8 g (0.02 mol) of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 4.5 g (0.05 mol) of thia zolidine in 50 ml chlorobenzene is heated to room temperature. reflux for 18 hours, cooled to room temperature and precipitate collected by filtration to give the above compound which was purified by recrystallization.

B. 2- (3-Thiazolidinyl) -4-amino-7,8-dimethoxyquinazoline-S-oxide product obtained in part A. 1.0 g. It is converted to the free base by partition between aqueous sodium hydroxide and methylene chloride.

------ The organic extracts are dried and concentrated in vacuo to 100 ml. Add dropwise to the free base methylene chloride solution at 0 ° C. for 15 minutes, a solution of 0,60 g of m-chloroperbenzoic acid in 25 ml of the same solvent. After stirring for 2 hours at 0 ° C. The reaction mixture is washed with dilute sodium bicarbonate and water. The organic extracts are dried (NaSO4) and evaporated to dryness in vacuo to give the above indicated S-oxide which will be purified by recrystallization, if desired the above compound can also be obtained by the process of¹ part A, above, when using thiazolidine S-oxa. as a base material in place of thiazolidine.

0 2- (5-thiazolylidinyl) -4-amino-7,8-dimethoxyquinazoline-S, S-oxide

A mixture of 9.6 g (0.04 mol) of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 10.0 g of thiazolidine-S, S-dioxide in 200 ml of chlorobenzene is heated to room temperature. reflux for 24 hours, cooled to room temperature and the product collected by filtration. The crude compound is obtained which is purified if desired by recrystallization.

D. Using the above processes or those of Examples 4,8 or 17 the following compounds are obtained in the same manner from suitable starting materials.

<img file="PT72007B_D0120.tif" />

brV —68

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

<img file="PT72007B_D0121.tif" />

NI ^ R² í²'Y³

CHgO CH₃O /^ÍCH2^}2_x

N J5

CH₃H

CH₃The CH₃O

CH₃The CH₃O

CHjO _ B

CH₃The tea₃O ^Ç2^H5° ^Ç2^H5 ° nC₃H₇The nC₃H₇The tea₃the ca₃the tea₃the tea₃ here₃the CA₃oa (ca₂)₂ &gt;^CH2&gt;2\

N SO (CH₂)₂ ^ jch₂)₂.

N.

ICH₂)₂CH „.

X ²\

NS

X (CH₂) f CH 2.

X ² \

N - SO, 'ÍCH₂)₃

-&lt;^CH2&gt;2^

X (ch₂)₃

B SO \ cHjX / &lt;^CH2&gt;3_x

BS \ | ch₂)/

N S0₉ \here₂)₃/

N _/ÇH₂ O

\here₂)₂^ X^ÍCH2⁾2 \ ^ (CH₉)₉

2'2 &gt;^CH2&gt;₃ (ch₂)₃

<img file="PT72007B_D0122.tif" />

-69EXAMPLE 20

A. 2- (5-Hydroxypyrrolidin-1-yl) -4-amino-6-chloro-7,8-dimethoxyquinazoline hydrochloride

A mixture of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline (5.48 g. 0.020 moles) and 3-pyrrolidinol (2.18 g. 0.25 moles) in 15θ ml isoamyl alcohol is heated at reflux temperature for five hours and then cooled on ice. The precipitated product is collected by filtration and purified by recrystallization to obtain the compound.

B. 2 - [4- (2-Ethoxyethoxy) piperidin-1-yl] 7-4-amino-6-chloro-7,8-dimethoxyquinazoline-7,8-dimethoquinazoline hydrochloride

I

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 a nitrogen atmosphere. The mixture is then cooled, evaporated in vacuo and the residue basified (aqueous Na2 O4) and extracted 3 times with chloroform. The combined chloroform extracts are evaporated and the residue chromatographed on neutral alumina to provide crude product which is transformed into the hydrochloride salt by treatment with hydrogen chloride in ethanol to obtain the above compound.

0 By the processes indicated above, the following compounds are also provided from suitable base materials for each case.

<img file="PT72007B_D0123.tif" />

4.

-70ch₃O

<img file="PT72007B_D0124.tif" />

Cl CH₃0 ch₃the ^^CH2^

N CHOCH, \ X ³ (CH₂)3

Cl ch₃the tea₃O

-^(CH2⁵ 3 ^ / hoch₂ (ch₂) ₄ch₃

Cl

Cl

Cl

Cl

CH₃0 ch₃0 '(CH₂) Ç ch₃the tea₃O

CH₃0 / CH₃0

CH₃O

CH₃O

CH₃0 ch₃O

CHOC_gH₅^X(CH2) ζ /^(CH2&gt; 2x

N CHO (4-ClC, .H₄). · \ ⁶⁴(CH₂)₃^CH2

CHO (2-BrCz-H) \ ⁶⁴Wf

CHICH₂)3 .(^ch2) 2 ^ N '^^shohO^-^;

CH0 (CH₂)₃0CH₃ &gt; ch₂)/₂

N CHOCH, OCH, \ -X ^{2 3} (CH₂) £; ch₂)₂

CHOCH₂CH₂S (CH₂)₃CH.

(CH₂)₂

X

<img file="PT72007B_D0125.tif" />

you

<img file="PT72007B_D0126.tif" />

ci ci

Cl

CH₃O

CH₃The tea₃the tea₃the tea₃O

<img file="PT72007B_D0127.tif" />

ch₃0

Cl ch₃O

Cl

Cl

Cl

Cl

CH₃O

CH₃The tea₃the tea₃O

<img file="PT72007B_D0128.tif" />

CH Ν '(CH

2^;₂ '(CH₂)₃

2 NR R

ΟΗΟΟΗ-ΟΗ-ΞΟ, -Η, s 2 2 6 5 (ch₂)₂

H tj 'tHOCH-CH-SO-V S / 2 2 2 ich₂)₂

CH₃ONLY₂ , (ch₂)₂ '' (CH -,) /

CH-jO N 'CHOCH₂CH₂NHCH₃ ; ch₂)₂· '^X,(CH₂) 2 ^ .CH ~ 'CHOCH₂NHCH₂ (ch₂) ₂ch₃

CH-, 0 N 'CH0CH_OCH₉N (CH 2)_O \ si ii (CH₂)₂ ch₃the ch₃the N

CHOCH₂Ck₂CH₂N (CH₃)_ch (CH₂⁾2 &gt;^ch2 \ ch₃the N

CHOCH₂CH₂Br (CH₂)

CH „(ch₂)₂. (ch₂)₂ (ch₂)₃ (CH

2' 2

CHOCH-CHCH, 2 | 3

OH

CHOCH₂CH (CH 2), CHOCH.

j: hoch₂ch₂only₂ch₃ (CH₂)₂^ (CH₂) ₂^

N 2 CHOCH-CHCH-CH 2/2 3 (ch₂)₂ no₂ch₃

NR ^ R² ch₃O

CB₃O n _χ choch₂och₂ch (ch₃)₂ (ch₂)£

Cl

CH₃O&gt; CB₂), \ CHOCH₂CH₂N (CH₃) ch₂- / ~ \ ch (ch₂)^ \—&lt; ^J

Cl, ch₃0 &gt; ch₂)

CH, I 3 _x CHOCH₂CH-NH (CH₂)₃CH₃(CH₂)₂

EXAMPLE 21

A. 2- (O-Tetamethyleneimin-1-yl) -4-amino-7,8-dimethoxyquinazoline hydrochloride

23.9 g (0.10 mol) of 4-amino-2-chloro-7.8 dimethoxyquinazoline and 14.0 g (0.11 mol) of octamethyleneimine are added to 5θΟ ml of isoamyl alcohol and the mixture is heated at reflux temperature for 3.5 hours. After cooling, the solid precipitate is collected, washed with ether and dried to obtain the compound.

B. Employing the above process with the appropriate starting materials for each case, the following compounds are provided in the same manner.

<img file="PT72007B_D0129.tif" />

• where pn

<img file="PT72007B_D0130.tif" />

esaRW '* ·⁵’”⁰

1-3

2,3

-73H

Cl

H

Cl '

H

Cl

Cl

Cl

Cl

H ch₃the tea₃O ^Ç2^H5°

CjHgO nC₃H₇Iso-CjH ^ Q ch₃the tea₃the tea₃the tea₃O

CH, 0 ch₃O ^Ç2^H5 ° = A ° nC₃H₇O

H

H

H ^CH3rd ch₃the p + n

9

EXAMPLE22

2- (5-Methylpiperidin-1-yl) -4-amino-7,8-dimethoxyquinazoline

Equimolar amounts (0.10 moles) of

7,8-dimethoxy-2,4- (1H, 3 ') quinazolinadione and oxychloride fos. Phosphate products are stirred at room temperature overnight and the volatiles evaporated in vacuo to give a 2-chloro-7,8-dimethoxy-4 (3H) -quinazolinone residue which is purified by washing with aqueous sodium bicarbonate, chloroform extraction and solvent evaporation. To the residue is added a 0.10 mole solution of 3-methylpiperidine in 300 ml of isoamyl alcohol and the mixture is heated at reflux for three hours, the solvent is then evaporated in vacuo to give 2- (3- Methylpiperidin-1-yl) -7,8-dimethoxy-4 (3H) -quinazolinone. To this is added ΙβΟ ml of oxy. phosphorus chloride and the resulting mixture is heated to reflux for two hours. The liquids are evaporated to yield a 2- (3-methylpiperidin-1-yl) 4-chloro-7,8-dimethoxyquinazoline hydrochloride residue. The product is dissolved in dilute aqueous sodium bicarbonate, extracted with chloroform,

<img file="PT72007B_D0131.tif" />

desiccated (Na2 SO4) and the solvent evaporated.

The above product is dissolved in 35θ ml of tetrahydrofuran and an anhydrous ammonia solution (5.3 g) in the same solvent is added. The mixture is stirred at room temperature for 24 hours, the precipitate collected by filtration and purified by recrystallization to give the compound.

EXAMPLE 23

2- (3-n-Hexylpyrnolidin-1-yl) -4-amino-6-chloro-7,8-dimethoxyquinazoline

To 12 grams of 6-chloro-7,8-dimethoxy-2,4- (1H, 3H) -quinazolinadione in 200 ml of pyridine is added 30 g of phosphorus pentasulfide and the mixture is refluxed for 5 hours. with continuous agitation. Evaporate the solvent in vacuo and decompose the residue with hot water. The solid substance is filtered off to give 6-chloro-7,8-dimethoxy-2,4- (1H, 3H) -quinazolinadithione.

Add slowly and with stirring to 0.1 mol of 6-chloro-7,8-dimethoxy-2,4- (1H, 3H) -quinazolinadithine in 220 ml 1 N potassium hydroxide solution and 100 ml methanol 0.22 mol of methyl iodide. The mixture is heated on a steam bath for 2 hours, cooled and the resulting precipitate is filtered off. The product obtained is

6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline.

To 0.1 mol of 6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline in 200 ml of tetrahydrofuran is added a solution of 0.1 mol of anhydrous ammonia in tetrahydrofuran.

Stir the mixture at room temperature for 18 hours, collect the precipitate formed, recrystallize from dimethyl formamide / water to yield 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline . A mixture of 0.1 mole of 2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline and 0.12 mole of 3-n-hexylpyrrolidine in isoamyl alcohol is heated at reflux for 16 hours, cooled, washed with water and the organic phase and concentrated in vacuo. Hexane is slowly added to the residue and the above solid compound is collected which is purified, if desired, by silica gel column chromatography.

EXAMPLE 24

2- [4- (2,5-Dihydro-4H-benzopyran-2carbonyl) -piperazin-1-yl] -4-amino-6-chloro-7-methoxyquinazoline hydrochloride

To 0.10 mol of 2- (piperazin-1-yl) -4-amino-6-chloro-7-methoxyquinazoline in 300 ml of methanol is added with vigorous stirring, 0.10 mol of 2,3-hydrochloride. dihydro-4H-benzopyran-2-carboxylic acid. After complete addition, the mixture is stirred for three hours at room temperature and the precipitated compound indicated by filtration.

EXAMPLE 25

2-Diethylamino-4-amino-6-chloro-7-methoxyquinazoline

To 0.1 mol of 2,5-dichloro-4-methoxybenzonitrile in dimethylformamide (3θθ ml) is added 0.5 moles of β, β-diethylguanidine and the mixture is heated at 150 ° C for 12 hours. The solution is concentrated in vacuo to a small volume and poured into ice water. The solid precipitate is collected by filtration and the crude product is purified by

<img file="PT72007B_D0132.tif" />

Column chromatography with silica gel.

When 2-amino-5-chloro-4-methoxybenzonitrile or 2-amidino-5-chloro-4-methoxyaniline is used in the above reaction instead of 2,5-dichloro-4-methoxybenzonitrile, the same is obtained. compound.

EXAMPLE 26

2- (N-methyl-N-cyclohexylamino) -4-amino-6-chloro-7,8-dimethoxyquinazoline

A. To 5 liters of ethanol containing 0.2 moles of sodium ethoxide is slowly added with stirring 0.1 moles, respectively, of phenol and 2,4,6-trichloro-7,8-dimethoxyquinazoline. The mixture is heated to boiling and then allowed to stand at room temperature overnight, poured into ice water, stirred 15 minutes and the precipitate collected by filtration. 0 The cake is washed with water, then cold ethanol, dried and re-crystallized from ethanol / hexane to give 2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline.

B. A mixture of 0.1 mol of the above product and 0.11 mol of N-methylcyclohexylamine in 350 ^m1 of ethanol, is heated at reflux temperature for three hours, cooled and poured into a dilute aqueous sodium carbonate solution. 0 pro The precipitated product is extracted with chloroform and the extracts evaporated to dryness to give 2- (N-methyl-N-cyclohexylamino) -4-ethoxy-7,8-dimethoxyquinazoline suitable for use in the following step.

0 At 0.1 moles of the Part B product in 300 ml of tetrahydrofuran, anhydrous ammonia is passed until the mixture has absorbed 0.11 moles. The mixture is then stirred for 24 hours.

<img file="PT72007B_D0133.tif" />

^:í * &amp;

<img file="PT72007B_D0134.tif" />

. · hours at room temperature and then heated to reflux temperature for two hours and cooled in ice. The precipitate solution is collected by filtration to provide the above compound which may be purified, if desired, by recrystallization or chromatography.

ν ~ D. When 2,6-dichloro-7,8-dimethoxy-4-methylthioquinazoline (prepared from the corresponding compound 2,4,6-trichloro and methylmercaptan in the presence of sodium ethoxide by the process of Curd et al., J. Chem. Soc, 775-783 (1947) for 2-chloro-4-methylthioquinazoline) is used in place of 2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline in part B, above, and the resulting conserved product subjected to the above processes, the similarly named compound is obtained.

EXAMPLE 27

2- (Morpholin-4-yl) -4-amino-7Î ± 8-dimethoxyquinazoline hydrochloride /

&lt;&gt; · L

To ml of methyl ethyl ketone is added 0.1 mole of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 0.12 mole of morpholine and the mixture is heated at reflux temperature overnight. After cooling in ice water, the precipitated solid is collected by filtration, washed with ether and air dried to obtain the compound.

When the appropriate base materials are employed for each case in the above process or any of the processes of Examples 17, or 22-26 the following compounds are similarly obtained.

<img file="PT72007B_D0135.tif" />

<img file="PT72007B_D0136.tif" />

<td>X¹</td><td>I²</td><td>y³</td><td>m</td><td>no</td>

<td>H</td><td>- ch₃0</td><td>ch₃0</td><td> 2</td><td> 3</td>

<td>Cl</td><td>ç₂H₅O</td><td>ch₃O</td><td> 2</td><td> 2</td>

<td>Cl</td><td>nC ^ H ^ O</td><td>H</td><td> 3</td><td> 3</td>

<td>Cl</td><td>ch₃0</td><td>H</td><td> 2</td><td> 2</td>

<td>Cl</td><td>CH₃O</td><td>H</td><td> 2</td><td> 3</td>

<td>Cl</td><td>ch₃O</td><td>ch₃O</td><td> 2</td><td> 3</td>

<td>H</td><td>ch₃0</td><td>ch₃0</td><td> 3</td><td> 3</td>

<td>Cl</td><td>ç₂H₅0</td><td>ç₂H₅O</td><td> 3</td><td> 3</td>

<img file="PT72007B_D0137.tif" />

<img file="PT72007B_D0138.tif" />

To a stirred solution of 1.78 g (0.01 mol) of 3,4-dimethoxy-2-aminobenzonitrile in 30 ml of β, dimethylformamide is added 2.88 g (0.01 mol) of hydrochloride. 4- (2-furoyl) piperazin-1-ylformimidate ethyl acetate and then 855 mg (0.02 mol) of a 56.1% hydride dispersion alone. in mineral oil. The reaction mixture is stirred at room temperature. at room temperature for 30 minutes and then is warmed to a temperature of about 100 ° C and maintained at that temperature for 12 hours. The reaction mixture is cooled to room temperature, diluted with excess 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 produces

7,8-dimethoxy-4-amino-2- [4- (2-furoyl) piperazin-1-yl] quinazo.

crude blade which is then purified by recrystallization from aqueous ethanol.

B. The above process is repeated except that the 4- (2-furoyl) piperazin-1-ylformimidate ethyl hydrochloride used herein is replaced by an equimolar amount of;

methyl 4-allylpiperazin-1-ylformimidate methanesulfate methyl 4-benzoylpiperazin-1-ylformimidate isopropyl hydrochloride 4- ($ - furoyl) piperazin-1-yl-formimidate methyl 4- (allyloxycarbonyl) piperazin-1-ylthiomorphide hydrochloride 4- (2-methylprop-2-enyloxycarbonyl) piperazin-1-ylthioformimidate and ethyl-4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) -piperaziua-1-ylthioformimidate hydrobromide, respectively .

This produces:

7.8-dimethoxy-4-amino-2- (4-allylpiperazin-1-yl) quinazoline

718-dimethoxy-4-amino-2- (4-b enz oilpiperazin-1-yl) quinazoline

7.8-dimethoxy-4-amino-2- [4- (3-furoyl) piperazin-1-yl_&gt;_7 quinazoline,

7.8-dimethoxy-4-amino-2- [4- (allyloxycarbonyl) piperazin-1-yl] quinazoline

7.8-dimethoxy-4-amino-2- [4- (2-methylprop-2-enyloxycarbonyl) piperazin-1-yl] quinazoline and

7.8-dimethoxy-4-amino-2- [4- (hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] quinazoline, respectively

C. The process of Part A is repeated except that the 3,4-dimethoxy-2-aminobenzonitrile used therein is replaced by a quant. equimolar capacity of:

<img file="PT72007B_D0139.tif" />

5-chloro-3,4-dimethoxy-2-aminobenzonitrile,

5-chloro-3,4-diethoxy-2-aminobenzonitrile,

5-chloro-4-methoxy-2-aminobenzonitrile or

5-chloro-4-isopropoxy-2-aminobenzonitrile to provide the following compounds respectively,

<img file="PT72007B_D0140.tif" />

CH₃O

<img file="PT72007B_D0141.tif" />

ch₃0 (CH₃)₂CHO

EXAMPLE 29

5-Chloro-4-methoxy-2-a minobenzamidine hydrochloride prepared by the process described in US patent

3.935 * 213 for analogous compounds (0.01 moles) and an equimolar amount of 1-cyano-4-ethoxycarbonylpiperazine also described in the same reference, are dissolved in 50 ml of anhydrous ethanol and stirred overnight at room temperature. A 5 ml aliquot portion of triethylamine is added and a. The mixture is heated at reflux temperature for 12. hours.

The solvent is evaporated to afford 4-amino-6-chloro-7-methoxy-2- [4-ethoxycarbonylpiperazin-1-yl] quinazoline as the hydrochloride salt.

Example 30

A 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 moles of 4- (4-amino-6-chloro-7,8-dimethoxyquinazoline-2-yl) methylene. piperazine-1-carboxylate are

<img file="PT72007B_D0142.tif" />

added in small portions with stirring. The addition is processed at a rate sufficient to maintain the reaction temperature below 20 ° C. The resulting mixture is stirred for 15 minutes at 15-20 ° C and 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 standing. the temperature below 12 ° 0. 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-hydrox;₁propyl 4- (4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl) piperazine-1-carboxylate.

EXAMPLE 51

2- [4- (3-Hydroxypropyl) homopiperazine-1-yl] -4-amino-7,8-dimethoxy quinazoline hydrochloride

A. 2-Chloro-4-amino-7,8-dimethoxyquinazoline, 17 g and R-formylomopiperazine, 18.2 g. 170 ml of n-butanol are added and the mixture is refluxed for three hours, cooled and the collected solid precipitate collected by filtration.

The precipitate is washed with a small amount of ethanol and air dried. A mixture of 13 g of this solid and 80 ml of 9% (by weight) hydrochloric acid is heated at reflux for 60 minutes, then cooled and the 2-homopiperazine-4-amino-7,8 precipitate. dimethoxyquinazoline is collected and purified, if desired, by recrystallization.

B. A mixture of 4 g triethylamine, 3.0 g 2-homopiperazine-4-amino-7,8-dimethoxyquinazoline, 4.5 g 3-bromo-1-propanol and 5θ ml diethylneglycol dimethylether is heated. at 100 -20 ° C with stirring for 16 hours. The reaction mixture is concentrated in vacuo and the residue made alkaline by addition

<img file="PT72007B_D0143.tif" />

of sodium hydroxide solution. The mixture is extracted with chloroform, the water washed extracts are dried over potassium carbonate and filtered. The filtrate is concentrated, the residue taken up in isopropanol and a solution of hydrogen chloride in isopropanol is added until precipitation is complete. The compound is collected by filtration and dried.

0 When an equivalent amount of 1,3-propandiol monotosylate or 1,3-propandiol monomethylsulfonate is used in place of 3-bromo-1-propanol in Part B, above, substantially the same results are obtained.

Example 32

Employing the appropriate starting materials in each case the following compounds are prepared by the same processes as in Examples 31 according to equation.

<img file="PT72007B_D0144.tif" />

NR ~

Where a is 1 or m; men are 2 or 3 and Q is a radical available as Br, 01, jo-toluene sulfonyloxy or methanesulfonyloxy.

ORTUG4

<img file="PT72007B_D0145.tif" />

<td>I¹</td><td>I²</td><td>I⁵</td><td>The.</td><td>no</td><td>R⁵</td>

<td>Cl</td><td>ch₅O</td><td>H</td><td> 1</td><td> 2</td><td>ch₃</td>

<td>Cl</td><td>CH-, 0 2</td><td>CH. 0 2</td><td> 1</td><td> 3</td><td>ch₃(ch₂)₅</td>

<td>H</td><td>ç₂H₅O</td><td>_ç₂H₅°. ·</td><td> 2</td><td> 2</td><td>(ch₃)₂ch (ch₂)₅</td>

<td>Cl</td><td>ç₂H₅O</td><td>Ξ</td><td> 2</td><td> 2</td><td>CH₃(CH₂)₅</td>

<td>Cl</td><td>nC ^ H ^ O</td><td>nC-JI-O ~ 2 t</td><td> 2</td><td> 2</td><td>CH₂= CHCH₂</td>

<td>H</td><td>i-OjHyO</td><td>iC ^ O</td><td> 3</td><td> 2</td><td>OH₅CH = CHCH₂</td>

<td>Cl</td><td>CH-, 0 2</td><td>H</td><td> 3</td><td> 2</td><td>(ch₃)₂c = chgh₉</td>

<td>Cl</td><td>ch₅O</td><td>ch₅O</td><td> 3</td><td> 3</td><td>HC ^ C-CH₂</td>

<td>H</td><td>ch₅O</td><td>CH. 0 2</td><td> 3</td><td> 3</td><td>CH₃CSCCH₂</td>

<td>Cl</td><td>ch₃O</td><td>CH₃O</td><td> 1</td><td> 2</td><td>HOOH₂OH₂</td>

<td>Cl</td><td>ch₅O</td><td>go H</td><td> 2</td><td> 2</td><td>(ch₅)₂c (oh) ch₂</td>

<td>H</td><td>ch₃O</td><td>CH₃O</td><td> 1</td><td> 2</td><td>(CH₃)₂0 (0H) 0H₂0H,</td>

<td>Cl</td><td>ch₅O</td><td>Ξ</td><td> 2</td><td> 2</td><td>cyclopropyl</td>

<td>Cl</td><td>ch₃O</td><td>ch₃0</td><td> 2</td><td> 3</td><td>cyclopentyl</td>

<td>H</td><td>ch₅O</td><td>ch₃O</td><td> 3</td><td> 3</td><td>cyclohexyl</td>

<td>Cl</td><td>CH-, 0 9th</td><td>Ξ</td><td> 2</td><td> 2</td><td>cycloheptyl</td>

<td>Cl</td><td>ch₅O</td><td>oh₃O</td><td> 2</td><td> 2</td><td>cyclooctyl</td>

<td>H</td><td>ch₅O</td><td>ch₃O</td><td> 2</td><td> 3</td><td>1-naphthyl</td>

<td>H</td><td>ch₃O</td><td>ch₃O</td><td> 2</td><td> 2</td><td>2-naphthylmethyl</td>

<td>H</td><td>ch₅O</td><td>CH-, 0 3</td><td> 2</td><td> 2</td><td> '^MOC6^H5</td>

<td>H</td><td>ch₃O</td><td>CH₃O</td><td> 2</td><td> 2</td><td>4-BrC₆H₄CH₂</td>

<td>H</td><td>ch₅O</td><td>CH-, 0 2</td><td> 1</td><td> 2</td><td>3-CH₃Ç₆H₄CH₂</td>

<td>Cl</td><td>CH₃O</td><td>ch₃O</td><td> 1</td><td> 3</td><td>(l</td>

NHSO₂CH₃

CH₃The tea₃O

ΓΗ

<img file="PT72007B_D0146.tif" />

L · ·

CH₃The tea₃O

OH

H.

ch₃the tea₃O

CP, -CO /^CH2

<img file="PT72007B_D0147.tif" />

-84EXAMPLE 55

A. 2,3-Dimethoxyaniline, obtained by the method of Gibson et al.

J. Chem. Soc., 111, 79 (1917) ® converted to 2,3-dimethoxy isothiocyanate according to the procedure of Dyson et al., J. Chem. Soc. 436 (1927) for analogous compounds.

A solution of 2,3-dimethoxy isothiocyanate (32.1 g. 0.164 moles) in 100 ml absolute ethanol is added to a solution of 1- (2-furoyl) piperazine (29.6 g. 0.164 moles) prepared by method of Desai et al., Org. Prep. Proed Int 8.85 (1976) in 35 ml of absolute ethanol and the mixture heated at reflux for 2.5 hours. A 4- (2-furoil) pipe. Crude razin-1- (N-2,3-dimethoxyphenyl) carbothioamide is isolated by evaporation of the solvent in vacuo and purified by recrystallization.

Β To a suspension of 22.0 g (0.0586 mol) of the product obtained in Part A above in 400 ml of methanol is added 8.32 g of methyl iodide (0.0586 mol). The mixture is stirred at reflux for 2.5 hours cooled to 20 ° C and 18.7 g of cyanamide (0.445 moles) is added and the resulting mixture is heated at reflux temperature for a further 16 hours. The solvent is evaporated in vacuo and the residue made strongly basic with 4.0 sódio sodium hydroxide. The alkaline mixture is extracted with chloroform, the extracts washed first with water and then with strongly saturated salt water are dried over anhydrous magnesium sulfate. The dried extract is concentrated to dryness under reduced pressure and the residue crystallized to yield 4- (2-furoyl) piperazine-1 H-N-cyanoalkyl.ⁱ'- (2,3-dimethoxyphenyl carboxamidine).

0 Following the process of Part A above but employing an equimolar amount of 2,3-dimethoxyphenyl isocyanate instead of 2,3-dimethoxyphenyl isothiocyanate gives N- (2,3-dimethoxyphenyl) -4- (2-furoyl) -1-piperazinecarboxamide. The reaction of this carboxamide with methyl fluorosulfonate and then with cyanamide,

<img file="PT72007B_D0148.tif" />

-85 according to the procedure in Part B, above provides the same product as in Part B.

D. Employing other amines of the formula R7RTJH, where R and Rr are as set forth in Examples 18 and 19 or form together.

Z ~ \ together / NW as in Examples 10 and 16 or N

X^(0H2⁾The_x „ \ ?'^AND Example 14, in the processes of Parts A and B or Part 0, above, are provided in the same manner compounds of the following formula:

<img file="PT72007B_D0149.tif" />

NHCN^{A &lt;}N = C-NR¹R²

3

Y, Y, Y have the values ​​given in Examples 10, 14, 16 and 19.

L · - ··

... $ 4

4-Amino-7,8-dimethoxy-2- {4- (2-furoyl) · piperazin-1-ylquinazoline hydrochloride

A. To 10 ml of phosphorus oxychloride is added with stirring 0.31 g. of phosphorus pentachloride (1.48 mmol) followed by 0.54 g (1.48 mol) of 4- (2-furoyl) piperazine-1 H-N-cyano N '- (2,3-dimethoxyphenyl) carboxamidine of the Example 33, Part B.

The reaction mixture is heated at 95 DEG-98 DEG C. for 2.5 hours, cooled to 3 DEG-0 DEG C. and excess phosphorous oxychloride is evaporated in vacuo and the residue triturated with ice water. The aqueous solution is filtered and the filtrate concentrated in vacuo to strength. provide the crude product which is purified by crystallization or column chromatography.

V ·:

<img file="PT72007B_D0150.tif" />

B. When ο phosphorus pentachloride used above is replaced by an equimolar amount of phosphorus pentabromide hydrogen chloride gas, trifluoroacetic acid, ZnCl_?, FeCl 3, AlCl 3 or Al Br 3, and the reaction is run at 70-100 ° C for one to three hours, the results are substantially identical to those in Part A.

EXAMPLE 35

A tablet base is prepared by mixing the following ingredients in the proportion indicated by weight.

Sucrose, USP .......... 80.3

Tapioca Starch ........ 15,2

Magnesium Stearate ... 6.5

2- / 4- (2-furoyl) -1-piperazinyl-7-4-amino-6-chloro-7-methoxyquinazoline hydrochloride is sufficiently mixed to provide tablets containing 0.5, -4.0 , 10, ΙθΟ and 250 mg of active ingredient.

EXAMPLE 56

Capsules

A mixture containing the following ingredients is prepared:

Calcium carbonate, USP ..... 17.6

Dicalcium phosphate 18.8

Magnesium Trisilicate, USP 5.2

Lactose, USP ................. 5.2

Potato Starch ................. 5.2

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

Magnesium stearate B ........ 0.55

<img file="PT72007B_D0151.tif" />

To this mixture is added 2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazine-1-yl] -4-amino-6-chloro-7-methoxyquinazoline to provide formulations containing 0, 5, 1.0 5, 10, 100, 250 β 500 mg of active ingredient and the formulations are enclosed in appropriately sized hard gelatin capsules.

SSEMPLO 57

2- [4- (2-furoyl-1-piperazinyl] -4- amino-6,7-dimethoxyquinazoline hydrochloride is intimately mixed and triturated with 2500 g of sodium ascorbate. sterilized with ethylene oxide which are then aseptically capped.For intravenous administration water is added to the vials in sufficient quantity to form a solution containing 10 mg of the active ingredient per milliliter.

EXAMPLE 58

A solution of 2- [4- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazin-1-yl] 4-4-amino-6-chloro-7,8-di_iMethoxyquinazoline or a pharmaceutically acceptable salt thereof is prepared with the following composition:

<img file="PT72007B_D0152.tif" />

Active 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 5θ mg / ml and is suitable for parenteral, especially intramuscular administration.

<img file="PT72007B_D0153.tif" />

PREPARATION

4-Acetoxy-3-methoxybenzaldehyde (IV)

Triethylamine (2.8 liters, 20.1 moles) was added dropwise to a solution of vanillin (2.00 kg, 13.15 moles) and acetic anhydride (2.6 liters, 27.5 moles) in chloride. of methylene (11.3 liters) keeping the temperature below 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, then with cesium acid. 20% (w / w) and high salt water. The organic layer was dried over sodium sulfate and concentrated in vacuo to 8 liters. Hexane (15 liters) was added slowly while removing the remaining methylene chloride. After cooling, the product was filtered to give 2.45 (96% yield). Recrystallization of a small sample from anhydrous ether provided the acetate as thin yellow needles,

PE 76-78 ° C.

PREPARATION B

4-Ac et oxy-3-methoxy-2-nitrob aldehyde enz (V)

Over a period of 1.5 hours 4-acetoxy-3-methoxybenzaldehyde (1120 g. 5.77 moles) was added portionwise to 4 liters of red gas nitric acid cooled at 0 ° C. After being stirred for one hour below 5 ° C, the reaction mixture was added to a large amount of ice water and stirred for another hour. 0 The resulting yellow product (1130 g · 82% yield) was filtered, filtered and washed three times with water and was sufficiently pale to be used directly in the next step. Recrystallization from ether / cyclohexane provided pure nitroaldehyde, PE 84-86 ° C.

<img file="PT72007B_D0154.tif" />

<img file="PT72007B_D0155.tif" />

PREPARATION

4-hydroxy-3-methoxy-2-nitrobenzaldehyde (VI)

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

i .. 5,4-Dimethoxy-2-nitrobenzaldehyde (VII) · '

Anhydrous sodium carbonate (957 6 · 9, θ3 mo.

les), toluene (5 liters), 4-hydroxy-3-methoxy-2-nitrobenzaldehyde. (1424 g, 7.22 moles) and dimethyl sulfate (810 ml, 8.6 moles) were refluxed for 4 hours. Toluene was removed, clear in vacuo and the residual solid dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was gone. The solution was then washed with 2 liters of 1 N NaOH and 6 liters of water discolored with charcoal-colored salt, dried over magnesium sulfate and filtered. Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527 g of product were obtained by filtration. The crude material was recris. It was crystallized from ethanol to yield 1187 g (78%) of the compound as a pale yellow solid PR 60-62 ° C.

ii. By employing diethyl sulfate instead of dimethyl sulfate in the above process, 4-etcm.-3-m is similarly obtained.

<img file="PT72007B_D0156.tif" />

toxi-2-nitrobenzaldehyde.

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

PREPARATION AND

3,4-Dimethoxy-2-nitro-benzoic acid (VIII)

A solution of 823 g. powder permanganate. NaCl in about 8.5 liters of H2 O was gradually added to a refluxing solution of 3Z-dimethoxy-2-nitrobenzaldehyde (55 ° g · 2.60 moles) in 5.6 liters of acetone. The reaction mixture was refluxed for a further 4 hours, and then easy. through diatomaceous earth while hot and the filter residue washed with hot water. Acetone was removed in vacuo and a small amount of unreacted solid was removed by filtration. The aqueous solution was acidified with 2N hydrochloric acid (1.8 liters) to yield 505 g (85%) of essentially pure compound. Recrystallization from water yielded colorless crystals, PP 200-202 ° C.

PREPARATION P

3,4-Bimethoxyanthranilic Acid (IXa, RsGH ^)

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

<img file="PT72007B_D0157.tif" />

-91PREPARATION G

4-Methoxyantranilic Acid (XXII)

<img file="PT72007B_D0158.tif" />

i. 4-Oiano-3-nitroanisol (IX)

A saturated solution of sodium uitrite (33.5 g. 0.485 moles) was added dropwise to a cooled solution of 4-methoxy-2-nitroaniline (68.0 g. 0.404 moles) in 300 ml of water and 94 ml. of concentrated hydrochloric acid while maintaining the temperature at 0 ° C and pH at 6 by the addition of sodium carbonate.

The cold diazonium salt solution was added. Carefully swim through a dripping mango funnel into a warm solution of cuprous cyanide (36.2 g. 0.404 moles) and potassium cyanide (42.1 g. 0.646 moles) in 5 ° ml of water with vigorous stirring and heating. flashing on a steam bath. The stirred yellow suspension was heated for a further fifteen minutes. The solid was filtered, dried and dissolved in ethyl acetate by separating undissolved inorganic salts. After discoloration with charcoal, concentration of the ethyl acetate solution afforded 55.1 g (71%) of bright yellow-orange crystals, PE 135-7 ° C.

Analysis, Percentage calculated for ΟθΗ ^ Ν ^ Ο ^, C. 53.93;

Ξ 3,395 N. 15.73

Found: C. 53.92; H. 3.47} N. 15.85 ii. 4-Methoxy-2-nitrobenzoic acid (XXI)

4-Oano-3-nitroanisole (52.3 g. 0.294 moles) was slowly added to a cooled solution of 53 ml of acetic acid, water and sulfuric acid respectively. The solution was refluxed for 5 hours and then diluted with 160 ml of water. After cooling, the resulting solid was filtered and dissolved in 10% sodium hydroxide solution. After discoloration with charcoal

<img file="PT72007B_D0159.tif" />

The solution was acidified with cooled 6N HCl and the yellow product (51.0 g, 88% yield) was filtered. An analytical sample was recrystallized from methanol / PE ether.

196-7°0.

Analysis Percentage calculated for OgH ^NO ^; 0. 48.74; H.3,585

N. 7.11

Found: C. 48.37, H. 3.57; No. 7, θ3 iii. 4-Methoxy anthranilic acid

A solution of 4-methoxy-2-nitrobenzoic acid (19.3, 97.9 mmol) in 200 mL of 1N NH4 OH was reduced overnight in the presence of 5% Pd / BaCO3. The reaction was filtered and acidified to give 15.8 g (96%) of anthranilic acid, PE 186-188 ° C.

iv. Employing 4-ethoxy-2-nitroaniline or the corresponding 4-n-propoxy or 4-isopropoxy compounds as a base material in the above processes yields the following similarly similar compounds.

<img file="PT72007B_D0160.tif" />

^sNH_

COOH where Y² is ethoxy, n-propoxy or isopropoxy.

PREPARATION Ξ i ,. Methyl-3,4-dimethoxyantranylate

Hydrogen chloride was passed in a solution of 3,4-dimethoxy anthranilic acid (100 g. 0.51 moles) in

1.5 liters of methanol for 40 minutes. The reaction mixture was refluxed for 4 days while intermittently introducing hydrogen chloride gas. The solvent was removed in vacuo and the residual white solid was dissolved in 5 θ ml of water, cooled and reached to pH 10 with sol. sodium hydroxide solution. After cooling for an additional hour, the cream colored product (87.0 g 82% yield) was filtered. Recrystallization from methanol gave the pure product, mp 66-67 ° C.

Analysis, Percentage calculated for ^G10^H13^N04^{s C}» 56,86;

H 6.20; N. 6.63

Found: 0. 56.56; H. 6.15; R. 6.66 ii. Methyl-4-methoxyantranylate

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

PREPARATION 1 i 5-Chloro-5,4-dimethoxyanthranilic acid (IXb, R 1 GH 2)

Sulfur chloride (19.3 ml, 0.24 moles) was added dropwise to a cooled solution of methyl 3,4-dimethoxyantranylate (42.2 g. 0.20 moles) in 400 ml of chloroform a. 0 ° C (The sulfur dioxide produced was siphoned). After stirring for 30 minutes at room temperature, the solution was refluxed for two hours. ras. The black solution was treated with charcoal and the solvent was evaporated. The H-NMR nuclear magnetic resistance spectrum indicated that the black oily residue was largely the desired intermediate ester. The crude methyl ester was saponified with 400 ml of 5% (w / v) sodium hydroxide on a steam bath for one hour. After cooling, the suspen

<img file="PT72007B_D0161.tif" />

Basic acid was acidified with acetic acid to precipitate a brown solid which was filtered and recrystallized from carbon tetrachloride to yield a light brown crystalline product (29.0 g. 63.1% yield). Mp 140-2 ° C / mp 142-3 ° C. J.Ohem. Soc. 4310-4, 1964_7

Analysis, calculated percentage for Ο ^ Ξ ^ θΟίΝΟ ^: 0. 46.66;

H. 4.355 N. 6.05

Found: 0.46.45; H. 4.45; U. 5.90 ii. 5-Chloro-4-methoxyantranylic acid (1Xc. R = OH) Treatment of methyl-4-methoxyantranylate with sulfuryl chloride as described above yielded methyl-4-methoxy-5-chloroanthanilate, mp 197-200 ° C. with a yield of 90%.

Saponification of methyl-4-methoxy-5-chloro anthranilate afforded 5-chloro-4-methoxyanthranilic acid in 64% yield Mp 213-3 ° C.

Analysis, Percentage calculated for ΟθΗθΟΙΝΟ ^; 0.47.66;

Ξ 4.00; N. 6.95

Found: 0. 48.00; Ξ 4.11; N. 6.94.

When methyl 4-ethoxyantranylate or methyl-4-n-propyloxyantranylate is subjected to the above process, 5-chloro-4-ethoxyantranyl acid and 5-chloro-4-n-propyloxyantranilic acid are obtained in the same manner.

PREPARATION J

When ethyl vanillin (3-ethoxy-4-hydroxybenzaldehyde) or propyl vanillin, (4-hydroxy-3n-propyloxybenzaldehyde) are used as the base material in the process of

<img file="PT72007B_D0162.tif" />

-Parison is in place of vanillin and in turn the resulting products subjected to the processes of Preparation BF and with heat. optional by the processes of Preparations Hei, the corresponding compounds of the following formula are obtained similarly.

· Ν?^?’.

<img file="PT72007B_D0163.tif" />

<img file="PT72007B_D0164.tif" />

Y¹ Y² y³_yl

<td>ç₂H₅°</td><td>ç₂H₅O</td><td>Cl</td>

<td>nC₃H_?0</td><td>nyC₃H₇O</td><td>Cl</td>

<td>ch₃0</td><td>ç₂H₅O</td><td>Cl</td>

<td>nC₃H₇O</td><td>ch₃0</td><td>ci</td>

<td> ?₂^H5°</td><td>CH₃O</td><td>Cl</td>

<td></td><td>^Ç2^H5°</td><td>Cl</td>

Y² y³

Ç₂HgO nC ^ H ^ O nC₃H₇The tea₃oc₂H₅oc₂H₅the tea₃O

HT^Ç3H₇the CH₃the nC₃^H7 ° c₂H₅O

PREPARATION K

5- (m-Trifluoromethylphenyl) piperidine

i. N-Benzyl-5-hydroxy-5- (m-trifluoromethylphenyl) piperidine

Under anhydrous conditions, an iodine crystal is added to a mixture of 11 g of magnesium in 15 ml of ethyl ether followed by the addition of a solution of 100 mg of m-bromotrifluoromethylbenzene in 50θ ml of ether over a period of two hours. hours The resulting mixture is stirred for two hours at room temperature and then cooled to 5 ° C. A solution of 70 g of N-benzyl-3-piperidone in 300 ml of ether is added at this temperature for one hour.

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Stirring for 15 minutes at 5 ° θ θ 1 hour at 20-25 ° 0, the reaction mixture was poured into 800 ml of ice water with stirring. The mixture was filtered, the organic layer extracted with 4 x 100 ml of 1N hydrochloric acid and once with saturated water. turbid salt. The aqueous phase is made alkaline by the addition of cold triethylamine and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and evaporated to dryness. 0 The crude product is purified by chromatography on silica gel eluting with cyclohexane / chloroform / triethylamine ((85: 10: 5, by volume)) to give the desired product as an orange solid.

ii. N-Benzyl-3-Aethoxy-3-H-trifluoromethylphenyl) piperidine Hydrochloride

A mixture of 37 g of N-benzyl-3-hydroxy-3- (m-trifluoromethylphenyl) piperidine 220 ml of acetic anhydrous and 0.3 ml of concentrated sulfuric acid is heated at 110 ° C for one hour. After cooling, it is poured into ice water, the resulting mixture stirred for 15 minutes and made alkaline by the addition of sodium hydroxide solution.

The mixture is extracted with ethyl acetate, the extracts washed with brine and dried (MgSO4) and evaporated to dryness to give 39 g of free base. This is^: dissol. life in 600 ml of ice-cooled ethyl acetate and 100 ml of hydrogen chloride-saturated ethanol is added.

The solvent is removed by evaporation in vacuo. The residue is triturated with 200 ml of ethyl acetate and then 200 ml of ethyl ether is added and the mixture is allowed to stand overnight. The crystalline compounds are collected by filtration washed with ether and dried to give 36 g, iii. The product obtained in Part II is dissolved in 7 ml of ethanol. Palladium on carbon catalyst (40 g) is added and the mixture is hydrogenated at room temperature. When hydrogen uptake ceases, the catalyst is filtered off and the solvent evaporated in vacuo. 0 solid

<img file="PT72007B_D0166.tif" />

The remainder is washed with ether and dried to give 21 g of estrus. 5- (m-trifluoromethylphenyl) piperidine hydrate as colorless crystals mp 200 ° C.

IV. Employing the appropriate cyclic amino ketones, select. N-benzyl-3-pyrrolidone, N-benzyl-3-piperidine, N-benzyl-4-piperidone, N-benzyl-4-oxoazacycloheptane and N-benzyl-4-oxo-azacyclooctane, to the appropriate R'Hos (where Hal is Cl, Br or I) in the above process, the following compounds are obtained in a similar manner f chr 'a

1 2 2 *

ch₃ ch₃(ch₂)₅ (CH₃)₂CH-CH₂^Ç6^H5 ^ç6am₄ch₂^4_C1C6^H4^CH2 ^3_CH3^Ç6^H4 &lt;ch₃)₂ch ch₃(ch₂)₄

3- FC₆B₄

4- CH₃OCgH₄CH₂4-HOC₆H₄

3- CH₃ONLY₂CgH₄

2- CH₃ONLY₂NHC_gH₄CH₂^CH3^CH2

4- CH₃ONLY₂NHCgH₄CH₃(CH₂)₃^4-CF3^Ç6^B4^CH2

4-PC₆H₄

CB, ^Ç6^H5

CjHjCBj

4-CH₃Ç₆B₄

3- ch₃oc₆H₄

<img file="PT72007B_D0167.tif" />

PREPARATION L · · Benzoyl piperidine hydrochloride

The method is as described in U.S. Patent 3,576,810. To 500 ml of thionyl chloride was added 85.6 g (0.5 mol) of 1-acetylnipecotic acid. The stirred mixture was heated at about 60 ° C for two hours and then the solvent was evaporated under reduced pressure. The crude acid chloride was taken up with 200 ml dry benzene and the resulting solution was slowly added to a mixture of 133 g (1.0 mol) aluminum chloride in 400 ml dry benzene. After the addition was complete the mixture was refluxed for one hour and then poured onto crushed ice. The organic layer was separated and the aqueous layer was extracted with benzene. The combined extracts were dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residual oil which did not crystallize on cooling was decylated under reduced pressure and the boiling fraction collected at 160-170 ° C / 0.5 mm. The crude product weighed 50 g. A mixture of crude 5θ g cLe 1-acetyl-3-benzoylpyrrolidine and 200 ml of 6N hydrochloric acid was refluxed for 12 hours, cooled and extracted with benzene. The combined extracts were washed with water, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residual oil weighed 15.1 g (16% yield). A portion (2.5 g of the free base) was dissolved in 50 ml of isopropanol and treated with ethereal hydrogen chloride. 0 white crystalline salt which formed weighed 2.4 g and melted at 193-195 ° C.

ii. By employing the appropriate N-acetylamino acid in place of the N-acetylnipecotic acid and benzene or the appropriately substituted benzene in each case, the following compounds are obtained.

Q with the previous process. When R is OH the base material is the corresponding acetate and the final product is obtained after hydrolysis if desired.

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<td>The</td><td>no</td><td>R⁸</td><td>.The</td><td>no</td><td>r⁸</td>

<td> 1</td><td> 2</td><td>H</td><td> 2</td><td> 2</td><td>4-CF₃</td>

<td> 1</td><td> 2</td><td>4-Br</td><td> 2</td><td> 2</td><td>2-CH, 0</td>

<td> 1</td><td> 2</td><td>4-OH</td><td> 2</td><td> 3</td><td>4-F</td>

<td> 1</td><td> 3</td><td>Η</td><td> 2</td><td> 3</td><td>3-CH, S0</td>

<td> 1</td><td> 3</td><td>2-C1</td><td> 3</td><td> 3</td><td>4-OH</td>

<td> 1 ·=</td><td> 3</td><td>4-C1</td><td> 3</td><td> 3</td><td>4-F</td>

PREPARATION Μ

N- (1,4-Benzodioxan-2-carbonyl) piperazine

1,4-Benzodioxan-2-carboxylic acid prepared by the oxidation of 2-hydroxymethyl-1,4-benzodioxan with potassium permanganate in aqueous potassium hydroxide at 5-15 ° θ was converted to the acid by reaction with thionyl chloride in the standard way.

A suspension of piperazine (11.88 g) and a. sodium acetate (20.30 g) in a mixture of water (70 ml) and acetone (95 ml) was stirred at 10-15 ° C, then concentrated hydrochloric acid (about 35 ml) was added until pH of so. 1.5 benzodioxan-2-earbonyl chloride (31.0 g) and sodium hydroxide (5N, about 45 ml) were added fractionally while maintaining the temperature at 10-15Â ° C. keeping the pH of sodium hydroxide at 1.7-2.2. In

<img file="PT72007B_D0169.tif" />

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 was obtained, acetone was removed in vacuo and the aqueous phase was alkalized to a pH of 8-9 with water. sodium oxide (5N), reextracted with chloroform (3 x 200 ml) and the extracts washed with water, dried (MgSO4) and evaporated in vacuo. 0 Oily residue was dissolved in ethyl acetate, treated with ethereal hydrogen chloride, evaporated in vacuo and the solid residue was triturated with ether, followed by recrystallization from methanol to give N (1,4-benzodioxan-2-carbonyl hydrochloride ) piperazine (4.85 g) mp 265-267 ° C

PREPARATION N

N-Acetyl-4-allyloxypiperidine

A solution of N-acetyl-4-hydroxypiperidyl. NaCl (100 g) in dimethylformamide (250 ml) was added dropwise sodium hydride (38 g. 5θ% dispersion in mineral oil) under a nitrogen atmosphere. The mixture was stirred for 2 hours and then allyl bromide (93 g) was slowly added while maintaining the reaction temperature at 25 ° C 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. Soy beverage. The residue was provided by N-acetyl-4-allyloxypiperidine (108.8 g.) PE 128 ° C / 2 mm, spectroscopically identified.

PREPARATION 0

4- (2-Methoxy-n-propoxy) piperidine

A solution of N-acetyl-4-allyloxypiperidine (6.4 g) in dry methanol (10 ml) is added dropwise.

y. λΣ? '.

<img file="PT72007B_D0170.tif" />

-101a a stirred suspension of mercury acetate (11.5 g) in methanol (50 ml) at room temperature. After 20 minutes, the mercury acetate is dissolved and the mixture is stirred for a further 40 minutes, cooled in ice water and then sodium hydroxide (20 ml, 5U) is added. A yellow precipitate forms during the addition. A solution of sodium borohydride (1.3 g) in sodium hydroxide (20 ml, 5U) is then added, the mixture is stirred for 10 minutes and acetic acid is added to bring the pH to 6. The mixture is It is filtered from the precipitated mercury, the ethanol is evaporated in vacuo and the resulting aqueous phase extracted with chloroform.

The organic extracts are dried (NagSQ evaporated in vacuo and the resulting crude residue taken up with methanol (50 mL) and heated under reflux overnight with sodium hydroxide (20 mL 5U) and water (20 mL). The aqueous phase extracted with ether, the desiccated extracts (NagSQ ^) are evaporated to leave a residue, the residue is treated with hydrochloric acid (20 ml. 2N) and heated in a water bath. steam for 10 hours. The mixture is then washed with ether, the alkalized aqueous phase (Na₂C0j) extracted with ether and the dried organic extract (Ua₂S0₂. and evaporated to leave a residue. Distillation of the residue under reduced pressure yields the title compound.

PREPARATION P

4- (2-hydroxy-n-propoxy) piperidine

N-Acetyl-4-allyloxypiperidine (18 g) in tetrahydrofuran (30 ml) was added dropwise to a stirred yellow suspension of mercury acetate (34 g) in a mixture of water (120 ml) and tetrahydrofuran ( 120 ml). The suspension is dissolved during the addition and the resulting clear solution was stirred at room temperature for 20 minutes.

-102-

<img file="PT72007B_D0171.tif" />

and then sodium hydroxide (7θ ml, 5N) was added accompanied by cooling with water / ice. The intermediate thus obtained was then reduced by the addition of sodium borohydride (2g) in sodium hydroxide (40 ml, 5N) and the excess hydride was destroyed 10 minutes later with glacial acetic acid.

The liquid phase was decanted, saturated with sodium chloride, the organic phase was separated and the remaining aqueous layer extracted four times with chloroform. The combined organic phases were dried (Na2 SO4) and evaporated in vacuo to leave a colorless oil (23 g).

This oil was stirred with 5N sodium hydroxide at room temperature for 16 hours and then at 100 ° C for 2 hours. The solution was then extracted with chloroform (four times), the combined desiccated extracts (Na2 SO4) evaporated in vacuo to leave a crude crystalline product (16.1 g. This was taken up in methylene chloride, filtered, evaporated and the residue taken. triturated with petroleum ether (PE, 40% 60 ° C) to yield 4- (2-hydroxy-n-propoxy) piperidine (11.0 g) mp 55-57 ° θ · θ oxalate salt thus obtained was prepared by combining ethereal solutions of the two reagents and recrystallized from isopropanol Mp 104-105 ° C.

PBEPARAQÃO Q,

4- (3-Methoxypropoxy) piperidine

A solution of N-acetyl-4-hydroxypiperidyl. NaCl (30.5 g) in dimethylformamide (200 ml) was added dropwise to a stirred suspension of sodium hydride (11.26 g. 5θ% dispersion in mineral oil) in dimethylformamide (300 ml) under an atmosphere. of nitrogen. The reaction temperature is maintained below 30 ° C by external cooling and, after addition of es. After stirring is continued for a further 1 1/4 hours. A solution of 1-bromo-3-methoxypropane (35.2 g) in dimethylformamide (100 ml) is then added dropwise with cooling.

<img file="PT72007B_D0172.tif" />

-103 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 dried organic extracts (Na2 SO4) and evaporated to leave a crude residue. The above aqueous phase is saturated with sodium chloride, then extracted with chloroform and the organic phase is dried (NagSO4) and evaporated to leave another residue. This residue is combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 ml, 2N). The reaction mixture is extracted with chloroform to remove residual mineral oil, concentrated aqueous phase, made alkaline with sodium hydroxide (pH 12) and then extracted with chloroform. The organic extracts are washed with brine (NagSO4) and evaporated to yield the desired product.