AU610328B2 - 2,4- diaminoquinazoline derivatives - Google Patents

Description

ANNOUNCEMENT OF THE LATER PUBLICATION OFAMENDED

PCT (AND, WHERE APPLICABLE, STATEMENT UNDER ARTICLE 19) 0 [I INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 05297 C07D 239/95, A61K 31/505 Al (43)ntern989 (15.06.89) C07D 401/04 (43) Intern a bli n D 5 J 1989 (15.06.89) C07D 401/04Fe (21) International Application Number: PCT/EP88/01127 (74) A G DI S, French Laboratories Ltd., Mundells, Welwyn Garden City, (22) International Filing Date: 2 December 1988 (02.12.88) Hertfordshire AL7 IEY (GB).

(31) Priority Application Numbers: 8728336 (81) Designated States: AU, DK, FI, HU, JP, KR, NO.

8820184.3 (32) Priority Dates: 3 December 1987 (03.12.87) Published August 1988 (25.08.88) With international search report With amended claims.

(33) Priority Country:

GB

Date of publication of the amended claims: 13 July 1989 (13.07.89) (71)Applicant: SMITHKLINE BECKMAN INTERC- REDIT B.V. [NL/NL]; 28-34 Blaak, P.O. Box 2, NL- 3000 DG Rotterdam (NL).

(72) Inventors: IFE, Robert, John 9 Edmonds Drive, Aston Brook, Stevenage, Hertfordshire BROWN, Thomas, Henry 17 Godfries Close, Tewin, Hertfordshire LEACH, Colin, Andrew 30 Wellington Road, Stevenage, Hertfordshire SG2 9HS This dt c s This document contains the amendments made under Section 49 and is correct for printing.

(54) Title: 9 Li'(lqzol/i-e ote1 tal6 /ves

R

4

NRR

6 3 R N (I) 2 N7 8

R

2 N- NR7R R1 (57) Abstract Compounds of structure in which RI to R 4 are the same or different and are each hydrogen, C 1 4alkyl, Ci4alkoxy, phenyl, C.4alkylthio, C 1 4 alkanoyl, amino, Ci.

6 alkylamino, diC 14 alkylamino, halogen or trifluoromethyl provided that at least two of R 1 to R 4 are hydrogen. R 5 and R 6 are the same, or different and are each hydrogen, C14alkyl,

(CH

2 )nAr in which n is 0 to 4 and Ar is an optionally substituted phenyl group, or R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; and R 7 and R 8 are the same or different A/ 1 d are each hydrogen, C 1 4alkyl, (CH2)nArl in which n is 0 to 4 and Ar 1 is an optionally substituted phenyl group, or R 7

R

8 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; and -A pi rmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them their use in therapy as inhibitors of gastric acid secretion.

Z

O-

iI i OPI DATE 05/07/89 AOJP DATE 27/07/89 APPLN. ID 28230 89

PCT

PCT NUMBER PCT/EP88/01127 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 05297 CO7D 239/95, A61K 31/505 Al C07D 239 6 3105 A l (43) International Publication Date: 15 June 1989 (15.06.89) C07D 401/04 (21) International Application Number: PCT/EP88/01127 174) Agent: GIDDINGS, Smith Kline French Laboratories Ltd., Mundells, Welwyn Garden City, (22) International Filing Date: 2 December 1988 (02.12.88) Hertfordshire AL7 1EY (GB).

(31) Priority Application Numbers: 8728336 (81) Designated States: AU, DK, FI, HU, JP, KR, NO.

8820184.3 (32) Priority Dates: 3 December 1987 (03.12.87) Published August 1988 (25.08.88) With international search report.

Before the expiration of the time limit for amending the (33) Priority Country: GB claims and to be republished in the event of the receipt of amendments.

(71) Applicant: SMITHKLINE BECKMAN INTERC- REDIT B.V. [NL/NL]; 28-34 Blaak, P.O. Box 2, NL- 3000 DG Rotterdam (NL).

(72) Inventors: IFE, Robert, John 9 Edmonds Drive, Aston Brook, Stevenage, Hertfordshire BROWN, Thomas, Henry 17 Godfries Close, Tewin, Hertfordshire LEACH, Colin, Andrew 30 Wellington Road, Stevenage, Hertfordshire SG2 9HS (GB).

(54)Title: COMPOUNDS 6

NR

7

R

8 (57) Abstract Compounds of structure in which RI to R 4 are the same or different and are each hydrogen, C.4alkyl, C 1 .4alkoxy, phenyl, Ct.4alkylthio, Ci-4alkanoyl, amino, C 16 alkylamino, diCl4alkylamino, halogen or trifluoromethyl provided that at least two of RI to R 4 are hydrogen. R 5 and R 6 are the same, or different and are each hydrogen, C 1 4 alkyl,

(CH

2 )nAr in which n is 0 to 4 and Ar is an optionally substituted phenyl group, or R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; and R 7 and R 8 are the same or different and are each hydrogen, C.4alkyl, (CH 2 )nAr' in which n is 0 to 4 and Ar 1 is an optionally substituted phenyl group, or R7 and R 8 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; and pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.

I /L lis~- 1 QUINAZOLINE DERIVATIVES The present invention relates to substituted quinazoline derivatives, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in therapy.

Accordingly the present invention provides, in a first aspect compounds of structure (I) in which, St R are the same or different and are each hydrogen, (1 N NR 8 in which R1 to R are the same or different and are each hydrogen.

C

1 4 alkyl, C 4 alkoxy, phenyl, C _4alkylthio, 1 Cl alkanoyl. amino. C 1 6 alkylamino, diCl 4 alkylamino.

halogen or trifluoromethyl provided that at least two '1 4 of R to R are hydrogen.

R and R are the same, or different and are each hydrogen.

C

1 4 alkyl. -(CH 2 Ar in which n is 0 to 4 and Ar is 5- n 6 6 an optionally substituted phenyl group, or R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; and:

R

7 and R are the same or different and are each hydrogen.

C 4 alkyl. (CH Ar in which n is O to 4 and Ar is 7 8 an optionally substituted phenyl group, or R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; RA^x 0 7\ t7

T

Ai WO 89/05297 PCT/EP88/01127 2 and pharmaceutically acceptable salts thereof.

Suitably at least two of R to R 4 are hydrogen and the others are the same or different and are each hydrogen, C _4alkyl, C _4alkoxy, phenyl, Cl_ 4 alkylthio, Cl_4alkanoyl, amino, C 4 alkylamino, diC 1 4alkylamino, halogen, 1 4 trifluoromethyl or nitro. More suitably, three of R to R are hydrogen and the other is hydrogen, C 4alkyl, C alkoxy, phenyl, C alkylthio, C alkanoyl, amino, 1-4 1-4 1-4 C alkylamino, diC alkylamino, halogen or 1-4 1-4 2 4 1 trifluoromethyl; preferably R to R are hydrogen and R is hydrogen, C1-4alkyl, C14alkoxy, phenyl, C 1 4 alkylthio, C -alkanoyl, amino, C alkylamino, diC alkylamino, 1-4 1-4 1-42 4 halogen or trifluoromethyl; more preferably R to R are hydrogen and R is hydrogen, C 4alkyl or C 4alkoxy; most 2 4 1 preferably R to R are hydrogen and R is hydrogen or C alkoxy, in particular methoxy.

1-4 Suitably R and R are the same or different and are each hydrogen or (CH 2 )nAr in which n is 0 to 4 and Ar is an optionally substituted phenyl group or R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring. More 5 6 suitably, one of R and R is hydrogen or C alkyl and 1-4 the other is hydrogen, C 4 alkyl or (CH 2 )nAr. Most 5 ib~ suitably one of R and R is hydrogen or C alkyl and the 1-4 other is (CH )nAr. Preferably one of R and R is C1_4alkyl and the other is (CH2)nAr; most preferably one 1-4 5 6 n of R and R is C 1 _4alkyl, in particular methyl and the other is (CH2) Ar in which n is O.

Suitably, Ar is unsubstituted or substituted by 1 to 3 substituents selected from hydrogen, C alkyl, C alkoxy, 1-4 1-4 C lalkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C14alkanoyl or trifluoromethyl. More suitably, Ar is unsubstituted or substituted by two substituents selected from hydrogen, C 14lkyl, C 4alkoxy, 1-4 1-4 WO 89/05297 PCT/EP88/01127 3 C alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, 1-4 carboxy, C 1 4 alkanoyl or trifluoromethyl. More preferably, Ar is unsubstituted or substituted by two substituents selected from C 4alkyl and C 1alkoxy. Most preferably, 1-4 1-1 Ar is unsubstituted or substituted by a single substituent selected from the above-noted groups, in particular C 4alkyl or C 4alkoxy.

Suitably, R 7 and R are the same or different and are each hydrogen, C_ 4 alkyl, (CH 2 )nAr in which n is 0 to 4 and Ar is an optionally substituted phenyl group, or R and R together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring.

7 8.

More suitably one of R and R is hydrogen or C 1 4 alkyl 1 and the other is hydrogen, C 14alkyl or (CH 2 )nAr or 7 8 R and.R together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic 7 8 ring. Most suitably, one of R and R is hydrogen or C alkyl and the other is hydrogen, C alkyl or 1-4 1-4 1 7 8

(CH

2 )nAr Preferably one of R and R is hydrogen or C 4alkyl and the other is (CH 2 )nAr more preferably one 7 8 1 of R and R is hydrogen and the other is (CH 2 )nAr most 7 8.

preferably, one of R and R is hydrogen and the other is 1 (CH2)nAr in which n is 0.

Suitably.. the group Arl is unsubstituted or optionally substituted by 1 to 3 substituents as hereinabove described o for the group Ar in R 5 Preferably the group Ar is unsubstituted or optionally substituted by two substituents as hereinabove described for Ar. Preferably.the group Ar is unsubstituted or substituted by two groups, which may be the same or different; more preferably the group Arl is unsubstituted or substituted by two groups which may be the same or different and selected from C alkyl and 1-4 C 14alkoxy. Most preferably the group Ar is unsubstituted or substituted by one or two groups, for example a WO 89/05297 PCT/EP88/01127 r 4 C 4alkyl group, in particular a methyl group or a halogen atom, in particular a fluorine atom; or a C 4alkyl group and a halogen atom in particular a methyl group and fluorine atom. Particularly preferably the group Ar is substituted by a methyl group in the 2-position of the ring and a fluorine atom in the 4-position of the ring.

C 4alkyl groups (either alone or as part of another group) can be straight or branched.

It will be appreciated that compounds of structure (I) 1 8 in which one or more of R to R is a C 3 4 alkyl group (either alone or as part of another group) may contain an assymetric centre due to the presence of the C alkyl group. Such compounds will exist as two (or more) optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the present invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.

The compounds of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides in a further aspect a process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof which comprises reaction of a compound of structure (II)

R

4 NR5R 6 3 R (Ii) R2 N X 1 ~L 1 S. WO 89/05297 PCT/EP88/01127 6in which R to R are as described for structure except that where necessary they are in protected form, and X is a group displaceable by an amine, with an amine of structure R7R NH in which R 7 and R are as described for structure or reaction of a compound of structure (III)

R

4

X

R

R2 NR7R 8

(II)

R

1 in which R to R and R and R are as described for structure and X is a group displaceable by an amine, with an amine of structure R R NH in which R and

R

6 are as described for structure and optionally thereafter, 0 removing any protecting groups; S forming a pharmaceutically acceptable salt.

Suitable groups displaceable by an amine, X, will be apparent to those skilled in the art and include, for example, halogen, in particular chlorine, SC alkyl, 1-4 such as methylthio, hydroxy and phenoxy.

Reaction of a compound of structure (II) with an amine R R NH is suitably carried out in an inert solvent at elevated temperature. Preferably the reaction is carried out in the absence of a solvent in a sealed receptacle at 'levated temperature.

WO 89/05297 PCT/EP88/01127 c -6- Reaction of a compound of structure (III) with an amine R5R6NH is suitably carried out in the presence or absence of an inert solvent at elevated temperature.

Suitable solvents include, for example C1-4alkanols such as isopropanol or butanol, preferably isopropanol.

In particular, leaving groups X and X are halogen, preferably chlorine, and can be displaced by appropriate 56 78 amines R R NH and R R NH under the general conditions described above and in the specific examples.

Other conditions and reagents depending on the nature of the leaving groups will be apparent to those skilled in the art: for example compounds of structure in which 5 6 R and R are both hydrogen, can be prepared from the corresponding compounds of structure (III) in which X is hydroxy by reaction with phenylphosphordiamidate using the method described in J. Het. Chem (1972), 9, 1235.

Pharmaceutically acceptable acid addition salts of the compounds of structure can be prepared by standard procedures by, for example, reaction with suitable organic and inorganic acids the nature of which will be apparent to persons skilled in the art. For example, pharmaceutically acceptable salts can be formed by reaction with hydrochloric, sulphuric, or phosphoric acids; aliphatic, aromatic or heterocyclic sulphonic acids or carboxylic acids such as, for example, citric, maleic or fumaric acids.

The intermediate compounds of structure (II) and (III) can be prepared by procedures analogous to those known in the art. The amines of structure R5R NH and R R NH are available commercially or can be prepared by standard techniques well known to those skilled in the art of organic chemistry.

r- WO 89/05297 PCT/EP88/01127 7 For example compounds of structure (II) in which R 2 4 is OCH3' R to R are all hydrogen and X is chlorine can be prepared by the route outlined in Scheme I. It will be apparent to those skilled in the art that the reactions of Scheme 1 can also be carried out on compounds in which 1 4 R to R have different values to those indicated to produce further compounds of structure (II).

Scheme I CO2 H

NO

2

OCH

3

(A)

(i) (ii) N H

H

(C)

Cl C1 (iii) -N N Cl

OCH

3

(D)

(iv) 1111 i 1

N

Cl

(II)

OCH

3 (ii) (iii)

H

2 Pd/C 10%. EtOH KNCO, AcOH, NaOH POC1 3 PhNMe2'.

56 NaOAc THF/H0, R R NF NaOAc, THF/H O A.

(iv) WO 89/05297 PCT/EP88/01127 8 1 4 Compounds of structure (III) in which R to R are 7 8 all hydrogen and R and R are both hydrogen, C alkyl 1 or (CH 2 Ar or one is C 1-4alkyl and the other is

(CH

2 )nAr and X is chlorine can be prepared by the procedures outlined in Scheme II. Again, it will be apparent to those skilled in the art that the reactions of Scheme (II) can be carried out on compounds in which 1 4 R to R are other than all hydrogen to product further compounds of structure (III).

Scheme II NH2 OCH R7R N 2NH 3 2 (i)

(F)

(G)

(ii)

(III)

.7R NaOCH 3 nBuOH (ii) POC1 Alternatively, compounds of structure (III) can be prepared from compounds ol structure see Scheme I by the method used in J. Med. Chem., 1981, 24, 127-140.

WO 89/05297 PCT/EP88/01127 9 This alternative method is outlined in Scheme III.

Scheme III 3 (ii)

'N

N^ NR7R 8 (H;X Cl) (J)

(III)

(iii) 7R8 NaOH/H 2 0 (ii) R7R NH, solvent, A (iii) POCI 3 solvent. A The starting materials used to prepare compounds of structures (II) and (III) are available commercially or can be prepared by standard techniques. In addition it will be appreciated that further variations of the abovenoted schemes can be utilized, for example, in Scheme III, compounds of structure in which X 1 is Cl can be replaced by compounds of structure in which X is, for example methylthio and then converted to compounds of structure (III) as shown. Such compounds in which X '7,

A*

WO 89/05297 PCT/EP88/01127' WO 89/05297 10 is methylthio are prepared by standard techniques for example by treatment of the analogous thione precursor with methyl iodide in ethanol in the presence of sodium 1 4 hydroxide; or, for example, when RI to R are all H, are commercially available.

It is to be noted, and apparent to those skilled in the art that in the foregoing reactions, where necessary groups R to R 4 and groups on aromatic rings Ar and Ar 1 hydroxy or amino groups) will be in "protected" form.

For example, amino groups can be "protected" in the form of nitro groups and converted into amino groups as appropriate, and hydroxy groups can be protected using standard groups for example as described in "Greene, T.W., Protective Groups in Organic Chemistry" which also provides examples of further appropriate protective groups for other moities.

The compounds of structure and their pharmaceutically acceptable salts exert an anti-secretory effect by inhibition of the gastrointestinal HK +ATPase enzyme (Fellenius Berglindh Sachs Olke L., Elander Sjostrand and Wallmark 1981, Nature, 290, 159-61).

In a further aspect therefore the present invention provides compounds of structure and pharmaceutically acceptable salts thereof for use in therapy.

The compounds of structure and their pharmaceutically acceptable salts inhibit exogenously and endogenously stimulated gastric acid secretion and are useful in the treatment of gastrointestinal diseases in mammals, in particular humans. Such diseases include, for example, gastric and duodenal ulcers, and Zollinger-Ellison Syndrome. Further, the compounds of structure can be _I S- WO 89/05297 PCT/EP88/01127 11 used in the treatment of other disorders where an anti-secretory effect is desirable for example in patients with gastritis, NSAID induced gastritis, gastric ulcers, acute upper intestinal bleeding, in patients with a history of chronic and excessive alcohol consumption, and in patients with gastro oesophageal reflux disease (GERD).

In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of structure and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate. starch, lactose, sucrose and cellulose.

L I WO 89/05297 PCT/EP88/01127 12 A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

A typical suppository formulation comprises a compound of formula or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula oz a pharmaceutically acceptable salt thereof calculated as the free base.

The present invention also provides a method of inhibiting gastric acid secretion which comprises p~rrc il-? R- WO 89/05297 PCT/EP88/01127 13 administering to a mammal in need thereof an effective amount of a compound of structure or a pharmaceutically acceptable salt thereof; and a method of treatment of diseases of the stomach or intestine based on increased acid secretion which comprises administering to a mammal in need thereof an effective amount of a compound of structure or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable compounds of the invention will normally be administered to a subject for the treatment of gastrointestinal diseases and other conditions caused or exacerbated by gastric acidity. The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg. or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.

Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

In addition, the compounds of the present invention can be co-administered with further active ingredients, such as antacids (for example magnesium carbonate or hydroxide and aluminium hydroxide), non-steroidal antiflammatory drugs (for example indomethacin, aspirin or naproxen), steroids, or nitrite scavengers (for example j ascorbic acid or aminosulphonic acid), or other drugs used for treating gastric ulcers (for example pirenzipine, prostanoids for example 16.16 dimethyl PGE 2 or histamine h -antagonists (for example, cimetidine).

The following examples illustrate the invention.

Temperatures are recorded in degrees centigrade.

WO 89/05297 PCT/EP88/01127 WO 89/05297 14 Example 1 Preparation of 2-amino-8-methoxy-4-(2-methylphenylamino)quinazoline A. Preparation of 3-methoxyanthranilic acid 2-Nitro-3-methoxybenzoic acid (10 g, 0.051 mol) was suspended in ethanol with palladium/charcoal 10% (1 g).

The mixture was placed under hydrogen (50 psi) and shaken on a Parr until theoretical uptake had been achieved. The suspension was then flushed with nitrogen, the charcoal filtered off, and the filtrate evaporated in vacuo to give 3-methoxyanthranilic acid (7.76 g, 91%) m.p. 172-175 0

C.

B. Preparation of 8-methoxy-2,4-quinazolinedione 3-Methoxyanthranilic acid (6 g, 0.036 mol) was suspended in water (200 ml, 35 0 C) and glacial acetic acid (2.2 ml). A freshly prepared solution of potassium cyanate (3.7 g, 0.046 mol) in water (20 ml) was added dropwise to the stirred mixture. After 2 hours, sodium hydroxide (48.5 g 1.21 mol) was added in portions keeping the temperature below 40 0 C. A clear solution was obtained momentarily before precipitating the hydrated sodium salt.

After cooling, the precipitate was filtered off, dissolved in hot water which was acidified to pH 5, causing precipitation of 8-methoxy-2,4-quinazolinedione (4.6 g, 58%) m.p. 255-257 0

C.

C. Preparation of 8-methoxy-2.4-dichloroquinazoline A suspension of 8-methoxy-2.4-quinazolinedione (4 g, 0.019 mol) suspended in phosphoryl chloride (10 ml 0.108 mol) and N,N-dimethylaniline (1.6 ml, 0.0125 mol) was heated under reflux for 5 hours. The reaction WO 89/05297 PCT/EP88/01127 15 mixture was poured onto ice and the precipitate washed and dried to give 8-methoxy-2,4-dichloroquinazoline (3.79 g, 87%) m.p. 155-1570C.

D. Preparation of 8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline 8-Methoxy-2,4-dichloroquinazoline (3.7 g, 0.016 mol) was stirred in a mixture of water (85 ml), tetrahydrofuran (125 ml), o-toluidine (1.7 g, 0.016 mol) and sodium acetate (2.2 g, 0.027 mol) for a total of 4 days with heating to for a total of 32 hours and the addition of a total of ml 0.01 mol NaOH dropwise over this period maintaining the pH at 7. The reaction mixture was evaporated in vacuo and crystallized from ethanol/water to give 8-methoxy-4-(2methylphenylamino)-2-chloroquinazoline (2.89 g, 60%) m.p.

218-220 0

C.

E. Preparation of 2-amino-4-(2-methylphenylamino)-8methoxyquinazoline 8-Methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (1.8 g, 0.006 mol) was dissolved in ethanolic ammonia and heated in a sealed vessel at 120°C for 3 hours. After cooling, removal of excess solvent and chromatography (silica gel, 2% methanolic ammonia in chloroform) the 2-amino-4-(2-methylphenylamino)-8-methoxyquinazoline was isolated as crystals (0.52 g, 31%) from ethanol, m.p.

218-220 0

C.

C H N 0 0.37EtOH 16 16 4 Found C 67.61, H 6.26, N 18.81 Requires C 67.61, H 6.17, N 18.84 4 L:U UY LWU bU U b L.IL UeLI Lb selected from hydrogen, C 14 alkyl. C alkoxy, WO 89/05297 PCT/EP88/01127 Example 2 Preparation of 2-amino-8-methoxy-4-benzvlaminoguinazolime A. Preparation of 2-chloro--8-methoxy-4-benzylaminoquinazoline Substituting benzylaminpe (1.4 g) for o-toluidine and using corresponding molar proportions in Example 1D gave, 2-chloro-8-methoxy--4-benzylaminoquinazoline (3.2 g. 82%) m.p. 253-254 0

C.

B. Preparation of 2-amino-8-methoxy-4-benzylaminoquinazoline Substituting 2-chloro-8--methoxy-4-benzylaminoquinazoline (2 g. 0.0067 mol) for 2-chloro-8-methoxy-4- (2-methylphenylamino)quinazoline and using corresponding molar proportions of the other reagents in Example 1E, gave 2-amino-8-methoxy-4-benzylaminoquinazoline (0.29 g, from ethanol, m.p. 243-245 0

C.

C H NO0 16 16 4 Found C 68.77, H 5.52, N 20.16 Requires C 68.55. H 5.75, N 19.99 Example 3 f. Preparation of 2-amino-8-methoXv7-4-(2-methyl-4methoxyphenylamino)quinazoline A. Preparation of 2-chloro-B-methoxy.-4-(2-methyN4methoxyphenylamino)quinazoline Substituting 4-methoxy-o-toluidine (1.6 g, 0.0122 mol) for o-toluidine and using corresponding molar proportions I L zUUtUL.LuLeG Dy one or two groups, for example a WO 89/05297PcE8/012 17 of the other reagents in Example 1D, gave 2-chloro-8methoxy-4-(4-methoxy-2-methylpheny'Lamino)quinazolile (2.02 g. 51%) m.p. 230-232 0

C.

B. Preparation of 2-amino-8-methoxy-4-(2-methyl- 4.-me thoxyphenylamino )quinazo line Substituting 2-chloro-8-methoxy-4-(2--methyl-4methoxyphenylaiuino)quinazoline (2.0 g, 0.006 mol) for 2-chloro-8-methoxy-4-(2-me~ttiylphenylamino)q'iinazoline and using corresponding molar proportions of the other reagents in the Example IE. gave 2-amino-8-methoxy- 4-(2-methyl-4-methoxyphenylamino)quinazoline (0.25 g, 13%) from ethanol/water. m.p. 185-187 0

C.

C H N 0 0.5 H- 0 17 18 42 2 iiFound C 63.95, H 5.77. N 17.52 Requires C 63.93. H 5.99, N 17.54 Example 4 Preparation of 2-amino-8-methoxy-4-(2-methylbenzylamino)quinazoline A. Preparation of 2-chloro-8-methoxy-4-(2-methylbenzylamino )quinazo line Substituting 2-ehlezlmn o gavludi e (1.41 g. 0.0117 mol) and using corresponding molar proportions of the ohreantinthe xmpeIgv (3.36 g. 89%) m.p. 279-281 OC.

B. Preparation of 2-amino-8-methoxy-4-(2-methiylbenzylamino)quinazoline L- WO 89/05297 PCT/EP88/01127 -18 Substituting 2-chloro-8-methoxy-4-(2-methylbenzylamino)quinazoline (2.3 g, 0.0073 mol) for 2-chloro-8methoxy-4-(2-methylphenylamino)quinazoline in Example 1E, gave 2-amino--8-methoxy-4--(2-methylbenzylamiflo)quinazoline (0.4 g. 18.5%) from acetonitrile, m.p. 274-275 0

C.

Found Requires C 17H 18N 40 0.67H 20 0.36CH 3CN C 68.78, H 6.20. N, 19.07 C 69.03. N 6.19, N, 19.03 Example Preparation of 2-dimet-hv.amino-8-methoxy-4-(2-methylphenylamino )cuinazoline A. Preparation of 2-dimethylamino-8-methoxy-4-(2methyiphenylamino) quinazo line Substituting ethanolic dimethylamine for ethanolic ammonia and using corresponding molar proportions of the other reagents in the Example 1E, gave 2-dimethylamino-8methoxy-4-(2-methylphenylamino)quinazoline (0.73 g, 59%) from acetonitrile. m.p. 141-143 0

C.

Found Requires C El N 0 0. 2H 0 18 20 4. 2 C 69.37. H 6.34, N 18.01 C 69.30. H 6.59, N 17.96 Example 6 Preparation of 2-amino-8-methy1-4-(2-rnethvlphenvlamino)guinazoline A. Preparation of 8-methyl-2.4-quinazolone WO 8905297PCT/EP88/01 127 19 Substituting 3-methylanthranilic acid (5 g, 0.033 mol) for 3-methoxyanthrarlilic acid and using corresponding molar proportions of the other reagents in Example lB gave 8-methyl-2,4-quiflazolinedione (4.18 g, m.p. 285-287 0

C.

B. Preparation of 2,4-dichloro-C--methylquinazoline Substituting 8-methyl--2,4-quinazolinedione (4.0 g, 0.023 mol) for 8-methoxy-2,4-quinazolinedione and using corresponding molar proportions of the other reagents in Example 1C, gave 2.4-dichloro-8-methylqiilnazoline (4.12 g, m.p. 180-230 0 C which !-as used without further purification.

C. Preparation of 2-ctloro-8-methyl-4-(2-methylphenylamino) quinazoline Substituting 2.4-dichloro-8-methyl-4-C2-methylphenylamino)quinazoline (3.7 g. 0.018 mol) for 2.4-dichloro-8methoxyquinazoline and using corresponding molar proportions of the other reagents in Example ID, gave 2-chloro-8-methyl- 4-(2-methylphenylamino)quinazoline (3.96 g, m.p.

125-126 0

C.

D. Preparation of 2-amino-8-methyl-4-(2--methylphenylamino) quinazo line Substituting 2-chloro-8-methyl-4-(2-methylphenylamino)quinazoline (2.0 g, 0.007 mol) for 2-chloro-8methoxy-4-(2-methylphenylamino)quinazoline and using corresponding molar proportions of the other reagents in Example IE. gave 2-amino-8-methyl-4-(2-methylphenylamino)quinazoline (0.27 g, 15.3%) from acetonitrile/water, m.p. 118-120 0

C.

WO 89/05297 PCT/EP88/01127 WO 89/05297 16 16 4 Found C 72.59, H 6.21, N 21.17 Requires C 72.70, H 6.10, N 21.20 Example 7 Preparation of 2-amino-4-(2-methylphenylamino)quinazoline A. Preparation of 2-amino-4-(3H)-quinazolone Guanidine hydrochloride (47.77 g, 0.5 mol) was added portionwise to a stirred suspension of sodium methoxide (32.42 g. 0.60 mol) in n-butanol (450 ml) at ambient temperature over 0.5 hour. After a further 0.5 hour a solution of methyl anthranilate (15 g, 0.10 mol) in n-butanol (150 ml) was added dropwise and then slowly brought to reflux. After distilling off ca. 100 ml of solvent the reaction mixture was heated under reflux at 116 0 C for 117 hours. The cooled suspension was filtered, excess solvent removed and the residue dissolved in water, acidified to pH 5 and extracted with diethyl ether. The aqueous suspension was reacidified to pH 5, filtered off, washed with water and dried. The solid was then triturated in methanol, filtered, washed with ether and dried to give 2-amino-4-(3H)-quinazolone (3.0 g, 19%) m.p. >300 0

C.

B. Preparation of 2-amino-4-chloroquinazoline 2-Amino-4-(3H)-quinazolone (2.0 g, 0.0124 mol) was heated under reflux in phosphoryl chloride (19.02 g, 0.0124 mol) for 2.5 hours. The reaction mixture was partitioned between chloroform, ice and NaOH solution (pH 9) and the organic phase dried, filtered, excess solvent removed and the residue triturated with chloroform to give 2-amino-4-chloroquinazoline (0.42 g. 19%) m.p. 275-278 0

C.

*I

<s r L% 11 L I VdCt .JktU -1 riv t-i 2 U A WO 89O~297PCT/EP88/O1 127 -21- C. Preparation of 2-amino-4-(2-methylphenylamino)quinazolime 2-Amino-4-chloroquinazoline (0.64 g, 0.0036 mol) was heated to 170 0 C in o-toluidine (I ml, 0.008 mol) for 1 hour. The reaction mixture was dissolved in ethanol, stripped and partitioned between chloroform and NaOH solution (pH The organic solution was dried, filtered and excess solvent removed to give an oil which afforded crystals of 2-amino.-4-(2-methylphenylamino)quinazoline (0.55 g. 62%) m.p. 273-275 0 C (from ethanol).

C isH 14N 40.2CHC1 3 Found C 71.08. H 5.42, N 22.04 Requires C 71.36. H 5.59, N 22.16 Example 8 Preparation of 2-Rvrrolidino--4-(2-methylphenylamino)guinazoline A. Preparation of 2-chloro-4-(2-.methylphenylamino)quinazolime Substituting 2.4-dichloroquinazoline (9.95 g, 0.05 mol) for 8-methoxy--2.4-dichloroquinazoline and using corresponding molar proportions of the other reagents in Example ID. gave 2-chloro-4-(2-methylphenylamino)quinazoline (10.19 g. 76%) m.p.192-194 0

C.

B. Preparation of 2-pyrrolidino--4-(2-methylphenylamino) quinazolime 2-chloro-4-(2-methylphenylamino)quinazoline (5 g, 0.0185 mol) and pyrrolidine (6.59 g, 0.093 mol) were dissolved in ethanol (65 ml) placed in a sealed vessel by the method used in J. Med. Chem., 1981. 24, 127-140.

tII WO 89/05297 PCT/EP88/01127 -22 and heated to 135 0 C for 5 hours. After cooling, the reaction mixture was dissolved in ethanol and then evaporated in vacuo. The oily residue afforded crystals of 2-pyrrolidino-4-(2-methylphenylamino)quinazoline (3.67 g, 65%) from ethanol/water, m.p. 152-154 0

C.

C19 H20 N4 Found C 74.58, H 6.60, N 18.49 Requires C 74.97, H 6.62. N 18.41 Example 9 Preparation of 2-ethylamino-4-(2-methylphenylamino)cguinazoline 2-.Chloro-4-(C2-methylphenylaminomethyl )quinazoline (5.00 g. 0.0185 mol) and ethylamine in ethanol (33%, ml) were dissolved in ethanol (35 ml) placed in a sealed vessel and heated for 5 hours at 130 0 C. After cooling and removal of excess solvent in vacuo the r.esidue afforded crystals of 2-ethylamino-4-.(2-methylphenylamino)quinazoline (1.7 g, 33%) from ethanol/water, m.p.

127-129 0

C.

C H N 17 18 4 Found C 73.09, H 6.43, N 20.06 Requires C 73.35, H 6.52, N 20.13 Example Preparation of 2-benzylamino-4-(2-methylphenylamino)quinazoline 2-Chloro-4-(2-methylphenylamino)qui.nazoline (2.7 g, 0.01 mol) and benzylamine (2.4 g, 0.022 mol) were dissolved in n-butanol (20 ml) and heated under reflux for 5 hours.

WO o89/05297 PCT/EP88/01127 -23 The solution was cooled, excess solvent removed in vacuc and the residue treated with water, filtered and crystallised from ethanol/water. The compound was then chromatographed (silica gel, 0.5% methanolic ammonia! chloroform) to afford an oil, which on trituration with ether gave crystals of 2-benzylamino-4-(2--methylphenylamino)quinazoline (1.88 g, m.p. 127-1?O 0

C.

C22 H20 N4 Found C 77.50, H 6.00. N 16.45 Requires C 77.62, H 5.92, N 16.46 Example 11 Preparation of 2-amino-4-(2--methylphenylamino)-6-ethylguinazoline A. Preparation of 6-ethyl-2,4--quinazoline dione Substituting 6-ethylanthranilic acid for 1; 3-methoxyanthranilic acid and using corresponding molar proportions of the other reagents in Example lB. gave 6-ethyl-2.4-quinazoline dione (20.15 g, 90%) m.p, 325 0

C.

B. Preparation of 6-ethyl-2.4-dichloroquinazoline Substituting 6-ethyl-2.4-quinazolinedione (20 g, 0.105 mol) for 8-methoxy-2.4-quinazolinedione and using corresponding molar proportions of the other reagents in Example IC. gave 6-ethyl-2.4-dichloroquinazoline (19.57 g.

82%) m.p. 90-92 0

C.

C. Preparation of 2-chloro-4-(2-meth-ylphenylamino)- 6-ethylquinazoline WO 89/05297 PCT/EP88/01127 -24 Substituting 6-ethyl-2,4-dichloroquinazoline (10.0 g, 0.044 mol) for 8-methoxy-2,4-dichloroquiazolie and using corresponding molar proportions of the other reagents in Example 1D. gave &--chloro-4-(2-methylphenylamino)-6ethyiquinazoline (7.23 g. 56%) m.p. 177-179 0

C.

D. Preparation of 2-amino-4-(2-methylphenylamino)-6ethyiquinazoline Substituting 2-chloro-4-(2-methylphenylamino)-6ethyiquinazoline (2.98 g. 0.01 mol) for 8-methoxy-2chloro-4-(2-methylphenylamino)quinazoline and using corresponding molar proportions of the other reagents in Example IE. gave 2-amino-4-(2-methylphenylamino)-6ethylquinazoline (0.76 g. 27%) from ether. m.p. 263-265-C.

C H N 1.5% w/w CHC1 3 17 18 43 Found C 72.18, H 6.4 9. N 19.76 Requires C 72.40. H 6.43. N 19.83 Example 12 Preparation of 8-methoxx'-2,4-bis(2-methvlphenylamino)ciuinazoline 8-methoxy-4-(2-methylphenylamino) -2-chloroquinazo line (1.00 g. 0.0033 mol) was dissolved in ethanol (15 ml) with o-toluidine (1.06 g. 0.C0099 mol) and heated in a sealed vessel at 150 0 C for 5 hours. After cooling and removal of excess solvent in vacuo the solid was chromatographed (silica gel. chloroform). 8-Methoxy-2.4-bis(2-methylphenylamino)quinazoline was isolated as crystals (0.93 g, 76%) from ethanol/water. m.p. 185-187 0

C.

C23 H22 Found C 74.48, H 6.00. N 14.92 Requires C 74.57. H 5.99. N 15.12 1. ,WO 89/ 05297 PCT/EP88/01 127 Example 13 Preparation of 2-methylamino-8-methoxy-4-(2-methvlphenylamino )cuinazo line Substituting ethanolic methylamine for ethanolic ammonia and using corresponding molar proportions of the other reagents in the Example 1E, gave 2-methylamino-8methoxy-4-(2-methylphenylamino)quinazoline (0.3 g, from ethanol/water, m.p. 190-192 0

C.

C17 H18 Found C 69.24, H 6.07. N 18.81 Requires C 69.37. H 6.16. N 19.04 Example 14 Preparation of 2-benzvlamino-8-methoxy-4-(2-methylphenylamino) cuinazoline Substituting benzylamine (0.53 g 0.00495 mol) for o-toluidine and using corresponding molar proportions of the other reagents in Example 12 gave 2-benzylamino-8methoxy-4-(2-methylphenylamino)quinazoline hydrochloride (0.62 g, 46%) from ethanolic HCl. m.p. 237-238 0

C.

C H N O.HCl 0.5H 2 0O 23 22 4 Found C 65.65. H 5.69, N 13.41, Cl 8.3 Requires C 67.42, H 5.81, N 13.47, Cl 8.52 Example Preparation of 2-pyrrolidino-8-methoxy-4- (2-methylphenyl amino )cuinazoline Substituting pyrrolidine (2.1 g, 0.03 mol) for o-toluidine and using corresponding molar proportions of inhibiting gastric acid secreti on which comprises WO 89/05297 PCT/EP88/01127 26the other reagents in Example 12 gave 2-pyrrolidino-8methoxy~4-(2-methylpheflylamiflo)quinazolile (1.71 g, 77%) from ethanol. m.p. 181-183 0

C.

Found Requires H22 C 71.55, H 6.75. N 16.60 C 71.83, H 6.63, N 16.75 Example 16 Preparation of 2-phenylethylamino-4-(2-methylphenylamino)quinazoline Substituting phenylethylamine (3.64 g. 0.03 mol) for benzylamine and using corresponding molar proportions of the other reagents in Example 10 and using ethanol as the solvent gave 2-phenylethylamino-4-(2-methylphenylamino)quinazolinb (1.45 g, 58%) from ether, m.p. 95-96 0

C.

Found Requires C 23H 22N 40.15H C 77.39. H 6.24. N 15.71 C 77.34, H 6.29, N 15.68 Example 17 Preparation of 8-methyl-4-(2-methylphenylamino)-2- (2-phenylethylamino)cquinazoline hydrochloride 8-Methyl-4-(2-methylphenylamino) -2--chloroquinazo line (0.71 g. 0.0025 mol) was dissolved in ethanol (20 ml) with 2-phenylethylamine (0.61 g. 0.005 mol) and heated in a sealed vessel at 140 0 C for 4 hours. After cooling and removal of excess solvent in vacuo the glass was dissolved in a small amount of methanol and 2N HCl added to form the hydrochloride salt which was recrystallized from ethanol/ether to give 8-methyl-4-(2-methylphenylamino)- Temperatures are recorded in degrees centigrade.

01 89059 PCT/EP88/01127 27- 2-(2-phenylethylamino)quinazoline hydrochloride (0.5 g.

m-p. >250 0

C.

C 24H 24N 4.OHCl Found C 71.28, H 6.35, N 13.82. Cl 8.77 Requires C 71.18. H 6.22, N 13.84, C1 8.76 Example 18 Preparation of 2-amino-8-methoxy-4-(2-methoxyphenylaminojcuinazoline A. Preparation of 2-chloro-8-methoxy-4-(2-iuethoxyphenylamino)quinazoline Substituting o-anisidine (2.94 g) for o-toluidine and using corresponding molar proportions of the other reagents in Example 1D gave, 2-chloro-8-methoXy-4-(2-methoxyphenylamino)quinazoline (6.74 g, 98%) m.p. 194-196 0

C.

B. Preparation of 2-amino.-8-methoxy-4--(2-methoxyphenylamino )quinazo line Substituting 2-chloro-8-methoxy-4-(2-methoxyphenylamino)quinazoline (4.0 g) for 2-chloro--8-methoxy-4-(2methylphenylamino )quinazoline and using corresponding molar proportions of the other reagents in Example lE gave, after recrystallisation from ethanol/water 2-amino-8-methoxy-4- (2-methoxyphenylamino)quinazo line (0.16 g, m.p. 243-244 0

C.

C16 H16 N4 02 0.8H20 Found C 63.88. H 5.38. N 18.87 Requires C 64.14. H 5.50, N 18.70.

WO 89/05297 PCT/EP88/01127 28- Example 19 Preparation of 2-.4-Bis-(N-methylphenvlamino)-8-methoxquinazoline 8-Methoxy-2,4-dichloroquinazoline (1.5 g, 0.007 mol) was heated under reflux in a solution of N-methyl aniline (1.43 ml, 0.014 mol) in tetrahydrofuran (50 ml) for 16 hours precipitating a solid, which was collected and crystallised from ethanol/water to give 2,4-bis-(Nmethylphenylamino)-8-methoxyquinazoline (0.37 g, m.p. 169-170 0

C.

C23 H22 Found C 74.32. H 5.85. N 15.04.

Requires C 74.57, H 5.99, N 15.12.

Example Preparation of 2.4-Bis-(N-methylphenylamino)cquinazoline hydrochloride Substituting 2.4-dichloroquinazoline (4.5 g, 0.0226 mol) for 8-methoxy-2,4-dichloroquinazoline and using corresponding molar proportions of the other reagents in Example 20, gave after crystallisation from ethanolic hydrogen chloride 2.4-bis--(N-methylphenylamino)quinazoline hydrochloride (2.2 g, M.p. 243-244 0

C.

C 22H 20N 1 IOHCl Found C 69.79. H 5.56, N 14.72, Cl 9.02 Requires C 69.89. H 5.70, N 14.68. Cl 9.29 1,WO 89/05297 PTE8/12 PCT/EP88/01127 29 Example 21 Preparation of 2-(N-methylphenylamino)-4-(2-methylphenylamino)-B-methoxciuinazolime substituting N-methylaniline (1.4 g. 0.013 mol) for o-toluidine and using the corresponding molar proportions of the other reagents in Example 12 gave after crystallisation from ethanol 2-CN-methylphenylamino)-4- (2-methylphenylamino)quinazoline (0.45 g, m.p.

145-147 0

C.

Found Requires C23 H22 C 74.89. H 6.10, N 15.34.

C 74.57, H 5.99, N 15.12.

Example 22 Preparation of 2-(N-methylphenylamino)..4-(2-methyl.

Phenylamino)cquinazoline hydrochloride Substituting N-methylaniline (2.39 g, 0.022 mol) for benzylamine and usinq corresponding molar proportions of the other reagents in Example 10 and using ethanol as the solvent gave after crystallisation from ethanolic hydrogen chloride 2 -(N-methylphenylamino)-4-(2-.methylphenylamino)quinazoline hydrochloride (1.64 g, m.p. 284-286 0

C.

Found Requires C 22H 20N 4.OHCl C 70.06. H 5.73, N 14.83, Cl 9.17 C 70.11, H 5.62, N 14.87, Cl 9.41 WO 89/05 297 PCT/EP88/01127" Example 23 Preparation of 2-phenethvlamino-4-(2-methylphenylamino)- 8-methoxyguinazoline hydrochloride Substituting phenylethylamine (1.2 ml, 0.009 mol) for o-toluidine and using corresponding molar proportions of the other reagents in Example 12, gave after crystallisation from ethanolic hydrogen chloride/ether 2-phenethylamino-4-(2--methylphenylamino)-8-methoxyquinazolinehydrochloride (0.38 g, m.p. 263-265 0

C.

C 24 2 N 40 1.OEICl Found C 68.62. H 6.06, N 13.64. Cl 8.22 Requires C 68.48. H 5.99. N 13.31. Cl 8.42 Example 24 Preparation of 4-(N-methylphenvlamino)-2-(2-methyl- Phenylamino)-8-methoxyguinazoline A. Preparation of 8-methoxy-4-(N-methylphenylamino) -2-chloroquinazoline Substituting N-rnethylaniline (3.85 g, 0.036 mol) for o-toluidine and using corresponding molar proportions of the other reagents in Example 1D, gave after crystallisation from ethanol/water 8-methoxy-4.-(N-methylphenylamino)-2-chloroquinazoline (6.19 g. m.p.

115-117 0

C.

B. Preparation of 8-methoxy-4-(N-methylphenylamino)- 2-(2-methylphenylamino)quinazoline hydrochloride WO 89/05297 PCT/EP88/O1 127 31- Substituting 8-methoxy-4-(N-methylphenylamino)-2chloroquinazoline (1.5 g, 0.005 mol) for 8-methoxy-4- (2-methylphenylamino)-2-chloroquilazolile and using corresponding molar proportions of the other reagents in Example 12. gave after crystallisation from ethanolic hydrogen chloride/ether 4-(N-methylphenylamino)-2-(2methylphenylamino)-8-methoxyquinazoline hydrochloride (0.99 g, m.p. 232-234 0

C.

C 2 3

H

2 2

N

4 0 1.OHCl Found C 67.74. H 5.63, N 13.76, Cl 8.39 Requires C 67.89, H 5.70. H 13.77, Cl. 8.71 Example Preparation of 2-amino-4-(2-methvlbenzylamino)cruinazoline A. Preparation of 2-chloro-4-C2--methylbenzylamino)quinazoline 2.4-Dichloroquinazoline (3.Og 0.015 mol) was stirred in a mixture of water (60 ml), tetrahydrofuran (100 ml), o-methylbenzylamine (1.83 g, 0.015 mol) and sodium acetate (1.38 g. 0.017 mol) for a total of 16 hours. The reaction mixture was evaporated under reduced pressure and crystallized from ethanol to give 2-chloro-4-(2 -,,ethylbenzylamino)quinazoline (1.44 g, 30%) m.p. 2,15-217 0

C.

B. Preparation of 2-amino--4-(2-methylbenzylamino)quinazoline hydrochloride Substituting 2-chloro-4- (2-methylbenzylamino) quinazoline (1.3 g. 0.004 mol) for 2-chloro-4-(2-methylphenylamino)-8--methoxyquinazoline and using corresponding molar proportions off the other reagents in the Example lE WO 89/05297 PCT/EP88/01127 -32 gave after crystallisation from ethanolic hydrogen chloride/ether 2-amino-4-(2--methylbenzylamilo)quiflazoline hydrochloride (0.5 g, m.p. 258-260 0

C.

C 16H 16N 41.OHCl 0.1H Found C 63.41, H 5.69, N 18.54, Cl 11.90 Requires C 63.51. H 5.73, N 18.51. Cl 11.71 Example 26 Preparation of 2-(2-methylphenylamino)-4-(N-methylphensrlamino)guinazoline hydrochloride A. Preparation of 2-chloro-4-(N-methylphenylamino)cqytnazoline Substituting N-methylphenylamine (9.9 g, 0.092 mol) for 27methyl-benzylamine and using corresponding molar proportions of the other reagents in Example 25A, gave after crystallisation from ethanol/water 2-chloro-4-(Nmethylphenylamino)quinazoline hydrochloride (24.47 g, m.p. >300 0

C.

B. Preparation of 2-C2-methylphenylamino)-4-(Nmethylphenylamino)quinazoline hydrochloride Substituting 2-chloro-4-(N-methylphenylanino)quinazoline (2.0 g. 0.007 mol) for 2-chloro-8-methoxy-4- (2-methylphienylamino )quinazoline and us ing corresponding molar proportions of the other reagents in Example 12, gave after crystallisation from ethanolic hydrogen chloride 2-(2-methylphenylamino)-4-(N-methylphenylamino).

quinazoline hydrochloride (1.36 g. m.p. 255-257 0

C.

C 22H 2ON 41.OHCl Found C 69.95. H 5.58, N 14.89, Cl 9.38 Requires C 70.11, H 5.62, N 14.87, Cl 9.41 WO 8/59 PC/EP88/Ot 127 33 Example 27 Preparation of 2-phenylamino-4-(N-methylphenylamino)puinazoline hydrochloride 2-Chloro-4-(N-methylphenylamino)quinazoline (2.0 g, 0.007 mol) was dissolved in ethanol (20 ml) with aniline (1.37 g. 0.15 mol) and heated in a sealed vessel at 150O?C for 5 hours. After cooling and removal of excess Fsolvent in vacuo pressure the solid was treated with ethzanolic hydrogen chloride to form the hydrochloride which was recrystallized from ethanol to give 2-phenylamino-4-(Nmethylphenylamino)quinazoline hydrochloride (1.99 g, 74%), m.p. 265-267 0

C.

C 21H 18N 41OHCl Found C 69.28, H 5.17. N 15.35, Cl 9.78 Requires C 69.51, H 5.28, N 15.44, Cl 9.77 Example 28 Preparation of 2-amino-4-(N-methylphenylamino)ciuinazoline Substituting N-methylaniline (1.95 g, 0.0183 mol) for 0-toluidine and using corresponding molar proportions of the other reagents in Example 7C, gave after crystallisation from ethanolic hydrogen chloride 2-amino- 4-(N-methylphenylamino)quinazoline hydrochloride (0.27 g.

m.p. 190-192 0

C.

C 15H 14N 40.3H 20 O7L5HC1 Found C 68.43. H 5.48, N 21.59. Cl 2.17 Requires C 68.81. H 5.70. N 21.40. C1 2.04 PCT/EP88/01127 WO 89/05297 34 Example 29 Preparation of 2-amino-4-(N-methylphenylamino)-8-methoxyguinazoline hydrochloride Substituting 2-amino-4-chloro-8-methoxyquinazoline for 2-amino-4-chloroquinazoline and using corresponding molar proportions of the other reagents in Example 28.

gave after crystallisation from ethanolic hydrogen chloride 2-amino-4-(N-methylphenylamino)--8-methoxyquinazoline hydrochloride (0.27 g. m.p. 282-284 0

C.

Found Requires C 16H 16N 40 HCl C 60.34. H 5.60. N 17.67, Cl 10.98 C 60.66. H 5.38. N 17.69. Cl 11.19 Example Preparation of 2-r(4-hvdroxy-2-methylphenyl)amino]-4- (N-methylphenylamino) ciuinazoline hydrochloride Substituting 4-hydroxy-2--methylaniline (1.8 g 0.0148 mol) for aniline and using corresponding molar proportions of the other reagents in Example 27, gave after crystallisation from ethanolic hydrogen chloride C4-hydroxy-2-methylphenyl)aminojquinazoline hydrochloride (0.72 g. m.p. 274-276 0

C.

C 22H 20N 40 1OHCl Found C 66.91. H 5.33. N 14.06. Cl 8.97 Requires C 6- 1.25. H 5.39. N 14.26. C1 9.02 Example 31 Preparation of 2-(2-methylbenzlamino)4.(N methylphenylamino)cjuinazoline hydrochloride dissolved in ethanol (65 ml) placed i~n a sealed vessel WO 89/05297 PCT/EP88/01127 Substituting 2-methylbenzylamine (1.79 g, 0.0148 mol) for aniline and using corresponding molar proportions of the other reagents in Example 27, gave after crystallisation from ethanolic hydrogen chloride 2- (2-methylbenzylamino)--4--N-methylphenylamino)quinazoline hydrochloride (0.61 g, m.p. 226-228 0

C.

C 23H 22N 4.OHCl Found C 70.44, H 5.90. N 14.36, Cl 9.08 Requires C70.67. H 5.93, N 14.33, Cl 9.07 Example 32 Preparation of (2-methyl--4-fluorophenvl)aminol- 4-(N-methylphenylamino)quinazoline hydrochloride Substituting 2-methyl-4-fluoroaniline (1.85 g, 0.0148 mol) for aniline and using corresponding molar proportions of the other reagents in Example 27, gave after crystallisation from ethanolic hydrogen chloride 4 C2-methyl-4-fluorophenyl)amino]-4-(N-methylphenylamino)quinazoline hydrochloride (0.6 g, m.p. 243-245 0

C.

C

22

H

1 N F 1.OHCl Found C 66.50. H 5.24. N 14.17, Cl 8.93 Requires C 66.92. H 5.11, N 14.19. Cl 8.98 Example 33 Preparation of 2-C 2-methylphenylamino) -4-phenylaminoguinazolime hyrdrochlor ide A. Preparation of 2-(2-methylphenylamino)-4quinazolone -1 L-j~-ctLU tu mi) and rieated under reflux for 5 hours.

WO 89/05297 PCT/EP88/01127 -36 2-Methylthio-4-quinazolone (10.0 g, 0.052 mol) was fused with o-toluidine (8.35 g, 0.078 mol) at 160 0

C.

After 4 hours, the solid was treated with ethanol, and filtered to give 2-methylphenylamino)-4-.quinazolone (10.7 g, 82%) m.p. 278-280 0

C.

B. Preparation of 4-chloro-2-(2--methylphenylamino)quinazoline 2-(2-Methylphenylamino)-4-quinazol-one (5.0 g, 0.0198 mol) was dissolved in phosphoryl chloride (20 ml, 0.216 mol) and N.N-dimethylaniline (3.5 ml, 0.025 mol) and refluxed for 3/4 hours. The reaction mixture was poured onto ice/N NaoH (100 ml) and the precipitate washed and dried to give 4-chloro-2-C(2--methylphenylamino)qui.nazoline hydrochloride (5.79 g. used without purification.

C. Preparation of 2-(2-methylphenylamino)-4phenylaminoguinazoline hydrochloride 4-Chloro-2--(2-methylphenylamino)quinazoline (1.5 g, 0.0048 mol) was dissolved in aniline (1.5 ml, 0.016 mol) and heated at 170 0 C for 1 hour. After cooling and evaporation of excess solvent the residue was crystallised from ethanolic hydrogen chloride to give 2-(2-methylphenylamino)-4--phenylaminoquinazoline hydrochlor"Ide (0.30 g. 17%) m.p. 239-240 0

C.

C H N 1.OHCl 0.19H 0 0.O2EtOH 21 18 4 2 Found C 68.96. H 5.31. N 15.42. Cl 9.59 Requires C 68.71. H 5.37. N 15.22. Cl 9.63 WO 89/05297 PC/EP88/01127 37 Example 34 Preparation of 2-(2-methylphenylamino)-4-methylaminoguinazoline hydrochloride 2-(2-methylphenylamino)-4-chloroquinazoline (2 g, 0.0065,mol) and methylamine in ethanol 30 ml) were placed in a pressure vessel and heated for 4 hours at 140 0 C. After cooling, the reaction mixture was evaporated to dryness. The residue afforded crystals of 2-(2-methylphenylamino)-4--methylaminoquinazoline hydrochloride (0.29 g, from ethanolic hydrogen chloride, m.p. 275-279 0

C.

Found Requires C 16H 16N 4HC C 63.70, H 5.56, N 18.58, Cl 11.76 C 63.89, H 5.70, N 18.63, Cl 11.79 Example Preparation of 2-(2-methylphenylamino)-4-propylaminoqulnazoline hyd ochloride Substituting n-propylamine (1.77 g, 0.03 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation 2-(2-methylphenylamino)-4-propylaminoquinazoline hydrochloride (0.67 g, 20.5%) from ethanolic hydrogen chloride, m.p. 215-217 0

C.

Found Requires C 17H 18N 4HCl C 65.12, H 6.20, N 17.83, Cl 11.20 C 64.86, H 6.08, N 17.80, Cl 11.26 WO 8905297PCT/EP88/01127 38 Example 36 Preparation of 2- (2-methyl phenylamino)-4-(n-pentylamino)guinazoline hydrochlioride Substituting amylamine (1.13 g .0.013 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation 2-(2-methylphenylamino)--4-(n-pentylamino)quinazoline hydrochloride (0.24 g. 10.3%) from ethanolic hydrogen chloride/ether. m.p. 129-130 0

C.

C 20H 24N 4HC Found C 67.37, H 7.19. N 15.46. Cl 9.86 Requires C 67.31. H 7.06. N 15.70, Cl 9.93 Example 37 Preparation of 2-(2-methylphenylam'ino)-4-(2-methoxybenzylamino)ciuinazoline hydrochloride Substituting 2-methioxybenzylamine (1.78 g.

0.0147 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation 2-(2-methylphenylamino)-4-(2methoxybenzylamino)quinazoline hydrochloride (1.52 g, 57.5%) from ethanolic hydrogen chloride, m.p. 218-220 0

C.

C23 H22 N40 C "WO 89/05297 PCTIEP88/01 127 39 Example 38 Prenaration of 2-(2-methvlphenvlamino)-4-N-Diperidinoauinazoline hydrochloride Substituting piperidine (1.25 g. 0.0147 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation 2-(2-methylphenylamino)-4-N--piperidinoquinazoline hydrochloride (0.25 g, 10%) from ethanolic hydrogen chloride/ether, m.p. 218-220 0

C.

Found Requires C 20H 22N 4HC C 67.48, H 6.51. N 15.63. Cl 9.94 C 67.69. H 6.53, N 15.79, Cl 9.99 Example 39 Preparation of 2-(2-methylphenylaminoj-4-N-morpholinocuinazoline hydrochloride Substituting morpholine (1.28 g, 0.0147 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave -fter crystallisation 2-(2-methylphenylam, N-morpholinoquinazoline hydrochloride (0.26 g from ethanolic hydrogen chloride/ether, m.p. 244-246 0

C.

Found Requires C 19H 20N 40 HC1 C 64.04. H 6.03, N 15.80, Cl 10.04 C 63.95. H 5.93, N 15.70, Cl 9.94 WO 9/0297PCT/EP88/01127 Example Preparation of 2-(2-methylphenylamino)-4--dimethylaminoguinazoline hydrochloride Substituting dimethylamine (30 ml) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation 2-(2-methylphenylamino)-4-dimethylamiiioquinazoline hydrochloride (0.29 g, m.p. 277-282'C decomp.

C 17H 18N 4HC Found C 65.10. H 6.20. N 17.83. C1 11.20 Requires C 64.86, H 6.08, N 17.80, Cl 11.26 Example 41 Preparation of 2-(2-methyl-4-fluorophenylamino)-4-(Nmethy phenylamino)-8-methoxyguinazoline hydrochloride 2-Chloro-4-N-methylphenylamino-8-methoxyquinazolime (0.8 g, 0.0026 mol) and 4-fluoro-2-methylaniline (0.66 g, 0.0053 mol) were dissolved in ethanol (20 ml) placed in a pressure vessel and heated for 4 hours at 150 0 C. After cooling the reaction mixture was evaporated to drynesgs.

The residue afforded crystals of 2-(2--methyl-4-fluorophenylamino)-4-(N-methylphenylamino)-8-methoxyquinazoline ~z~f hydrochloride (0.25 g, 22%) from ethanolic hydrogen chloride, m.p. 218-220 0

C.

C 23H 21N 4FO HCl Found C 64.87, H 5.19. N 13.05, Cl 8.16 Requires C 65.01, H 5.22. N 13.19, Cl 8.34 WO 8905297PCT/EP88/01 127 41.

Example 42 Preparation of 2-[(4-methoxv--2-methylphenyl)aminol-4-(Nmethylphen lamino)guinazoline hydrochloride A. Preparation of 2-[(4-methoxy-2-methylphenyl)amino] quinazolin-4-one Substituting 4-methoxy-2-methylaniline (5.48 g) for o-.toluidine and using corresponding molar proportions of other reagents in Example 33A gave 2-[(4-methoxy-2-methylphenyl)aminojquinazolin-4-one (4.35 g, 77%) crystallised from methanol, m.p. 270-272 0

C.

Preparation of 4-chloro.-2-[(4-methoxy-2-methylphenyl )amino ]quinazo line Substituting 2-[(4-methoxy-2-methylphenyl)amino]quinazolin-4-one (3.6 g) for 2-(2-methylphenylamino)quinazolin-4-one and using corresponding molar proportions of other reagents in Example 33B gave 4-chloro-2-[(4methoxy-2-mec~hylphenyl)aminojquinazoline (3.8 g) which was used without purification.

C. Preparation of 2-[(4-methoxy-2-methylphenyl)amino]-4-(N-methylphenylamino)quinazoline hydrochloride Substituting 4-chloro-2-[(4-methoxy-2-methylphenyl)amino]quinazoline (3.8 g) for 4-chloro--2-[(2-methylphenyl)aminojquinazoline and N-methylaniline for aniline in Example 33C gave the title compound (2.0 g, 38% 2 steps) which was recrystallised from ethanol/diethyl ether as yellow needles, m.p. 248-250 0

C.

C 23

H

22

N

4 0.HCl.0.25 H2 0 Found C 67.01, H 5.72, N 13.52, Cl 8.33 Requires C 67.14, FH 5.76, N 13.62, Cl 8.62 PCT/EP88/01127 WO 89/05297 42 Example 43 Preparation of 4-(N-methylphenylamino)-2-(2-methylphenylamino)-6-methoxyquinazoline hydrochloride A. 2,4-Dihydroxy-6-methoxyquinazoline A mixture of 5-methoxy anthranilic acid (40 g, 0.24 acetic acid (18.0 g, 0.3 M) and 1 litre warm water (35 0 C) was stirred and allowed to cool. A solution of potassium cyanate (24.3 g, 0.3 M) in water (100 ml) was added over 15 minutes and then stirred for a further minutes. Sodium hydroxide (320 g, 8.0 M) solid was added portionwise and the reaction was then heated at 90 0 C for 30 minutes and allowed to cool overnight. The solid was filtered off and dissolved in hot water (500 ml) and then acidified with dilute sulphuric acid to precipitate the product. The solid was filtered off and washed free of acid with water and then dried at 100 0 C/vacuum to yield the title compound (37.7 g) m.p. >290 0

C.

B. 2,4-Dichloro-6-methoxyquinazoline 2,4-Dihydroxy-6-methoxyquinazoline (37 g, 0.19 M), phosphoryl chloride (95 ml) and dimethylaniline (40 ml) were heated under reflux for 3 hours. After cooling the reaction mixture was poured onto ice and the precipitated solid was filtered off, washed with water and air dried.

The product was used immediately in the next stage.

C. 2-Chloro-4-(N-methylphenylamino)-6-methoxyquinazoline A mixture of 2,4-dichloro-6-methoxyquinazoline, (38.3 g, 0.19 M assuming 100% yield from previous step), N-methylaniline (19.26 g, 0.18 sodium acetate (16.4 g, i: WO 89/05297 CT/EP88/01127 WO 89/05297 43 0.2 M) in tetrahydrofuran (2 litres) and water (1 litre) was stirred at room temperature for 8 days. Reaction was then concentrated to low volume (about 500 ml) and an oil separated out which solidified. The solid was filtered off and extracted with dichloromethane. Silica gel column chromatography followed by evaporation to dryness gave a residue which was washed with 40-60 0 C petroleum ether (to remove trace impurity) to yield title compound (31.25 g) m.p. 133-4 0

C.

D. Preparation of 4-(N-methylphenylamino)-2-(2methylphenylamino)-6-methoxyguinazoline hydrochloride A mixture of 2-chloro-4-(N-methylphenylamino)-6methoxyquinazoline (5.4 g, 0.027 o-toluidine (4.28 g.

0.04 M) in ethanol (50 ml) was heated in a Berchof pressure vessel at 140 0 C for 5 hours (maximum pressure psi). After cooling, ethanol/HCL was added and the solid which crystallised out was filtered off and recrystallised from isopropanol/ether to yield the title compound (4.23 g, m.p. 258-260 0

C).

Example 44 4-(N-Methylphenylamino)-2-(2-methyl-4-fluorophenylamino)-6methoxyguinazoline 2-Chloro-4-(N-methylphenylamino)-6-methoxyquinazoline (5.4 g, 0.02 M) and 4-fluoro-2-methylaniline (4.96 g, 0.04 M) were dissolved in ethanol (50 ml) and heated at 140 0 C for 5 hours in a Berghof pressure reactor. The mixture was cooled and ethereal/HCl added. The precipitated solid was filtered off and recrystallised (isopropanol/ether followed by isopropanol) to yield the title compound (3.8 g) m.p. 248-250 0

C.

WO 89/05297 PCT/EP88/01127 44 Example Preparation of 2-(2-methylphenvlamino)-4-(N-methyl-4methoxyphenylamino)ciuinazoline hydrochloride Substituting N-methyl--p-anisidine (3.18 g, 0.023 mol) for methylamine and using corresponding molar proportions of the other reagents in Example 34, gave after crystallisation,2- (2-methylphenylamino)-4- (N-methyl-4methoxyphenylamino)quinazoline hydrochloride (2.45 g, 33%), from ethanolic hydrogen chloride, m.p. 224-226 0

C.

Example 46 Preparation of 2-(2-methylphenylamino)-4-(N-methyl-4hydroxyplhenylamino)quinazoline hydrochloride, 2- C2-Methylphenylamino)-4- (N-methyl--4-methoxyphenylamino)quinazoline hydrochloride (1.6 g, 0.0043 mol) was stirred in dry dichloromethane (50 ml) at 0-5 0 C under nitrogeti. To this solution was added boron tribromide ml, 0.0216 mol) dropwise at 0-5 0 C over 10 minutes.

The mixture was stirred for 3 hours at 0-5 0 C and then allowed to reach room temperature over 16 hours. After pouring onto ice. basifying and neutralising the aqueous phase was extracted with dichloromethane, the organic extracts which dried and evaporated to dryness. The residue afforded crystals of 2-(2--methylphenylamino)-4- (n-methyl-4-hydroxyphenylamino)quinazoline hydrochloride (0.4 g, 23.7%) from ethanolic hydrogen chloride m.p.

317-3 19 0

C.

WO 89/05297 PCT/EP88/01 127 Example 47 Preparation of 2-F (4-chloro-2-methylphenyl)aminol-4- (N-methylphenvlamino)quinazolile hydrochloride.

A. Preparation of 2-Ii(4-chloro-2--methylphenyl)amino] -4-(N-methylphenylamino)quinazo lone.

Substituting 2-methyl-4--chloroaniline (2.6 g) for o-toluidine and using corresponding molar proportions of the other reagents in Example 33A gave the title compound (2.73 m.p. >270 0 C (dec).

B. Preparation of 4-chloro-2--[(4-chloro-2-methylphenyl)aminojquinazoline.

Substituting 2-[(4-chloro-2-methylphenyl)amino]-4quinazolone (2.5 g) for 2-[(2-methylphenyl)amino]-4quinazolone and using corresponding molar proportions of the other reagents in Example 33B gave the title compound g) which was used without purification.

C. Preparation of 2-[(4-chloro-2-methylphenyl)amino]-4-(N-methylphenylamino)quinazoline hydrochloride Substituting 4-chloro-2-[(4-chloro-2-methylphenyl)aminolquinazoline (1.0 g) and N-methylaniline (1.0 g) for the reagents in Example 33C and using analogous conditions and work-up gave the title compound (0.17 m.p.

263-265 0 C, after two recrystallisations from ethanol! diethyl ether.

*A~-2.tatt 7.9±.

WO 89/ 05297 PCT/EP88/01 127 -46 Example 48 Preparation of 2-(2-methylphenylamino)-4-(N-methylphenylamino)-8-fluoroquinazolile hydrochloride In a procedure analogous to that of Example 41 2-chloro-4-(N-methylphenylaminio)-8-fluoroquinazoline and o-toluidine are reacted together to give the title compound. The starting 2-chloro-4-(N-methylphenylamino)- 8-fluoroquinazoline is prepared via procedures analogous to those of Example 1.

Example 49 Preparation of 2-(2-methyl-4-fluorophenylamino)-4- (N-methylph nylamino )-8--fluoroguinazolime In a procedure analogous to that of Example 41 2-chloro-4-(N-methylphenylamino)-8-flu.oroquinazoline and 2-methyl-4-fluoroaniline are reacted together to give the title compound.

Preparation of 2-2mtypeyaio--Nehlhnl amino)ciuinazoline hydrochloride A. Preparation of 4-(N--ethylphenylamino)-2chloroquinazoline.

N-ethylaniline for N-methylphenylamine and using corresponding molar proportions of other reagents in Example 26A, gives the title compound.

IL

WO 89105297 PCT/EP88/01 127 47 B. Preparation of 2-(2-methylphenylamino)-4- (N-ethylphenylamino)quinazoline hydrochloride.

Substituting 4-CN-ethylphenylamino)-2-chloroquinazoline for 4-(N-methylphenylamino)-2-chloroquinazoline and using molar proportions of the other reagents in Example 26B gives the title compound.

iu it L P LLIt I Y L dC1ILLIL Lq ulna z o i ine flYdrochloride WO 89/05297 PCT/EP88/01127 48 Biological Data.

H K ATPase Activity.

The effects of a single high concentration (100 iM) of a compound of structure on K-stimulated ATPase activity in lyophilised gastric vesicles was determined.

Preferred compounds of structure were also tested over a range of concentrations to determine IC 50 values.

Preparation of lyophilised gastric vesicles (H/K-ATPase).

Lyophilised gastric vesicles were prepared from pig fundic mucosa after the method of Keeling et. al. (Biochem.

Pharmacol., 34, 2967, 1985).

(ii) K -stimulated ATPase -activity.

K -stimulated ATPase activity was determined at 37 0

C

in the presence of the following 10 mM Pipes/Tris buffer pH 7.0, 2 mM MgSO 4 1 mM KC1, 2 mM Na ATP and 3-6 lg protein/ml lyophilised gastric vesicles. After incubation for 30 minutes, the inorganic phosphate hydrolysed from ATP was determined by the method of Yoda and Hokin (Biochem.

Biophys. Res. Commun. 40, 880, 1970).

Compounds of structure were dissolved in dimethylsulphoxide which up to the highest concentration used had no effect on K+-stimulated ATPase activity.

The effect of the highest concentration of each compound of structure on the recovery of a standard amount of inorganic phosphate was also determined.

(iii) Results.

The compounds of the examples had IC5 values in the range of from 0.02 to 30 uM.

1 W O 89/05297 PCT/EP88/01127 49 B. Rat: Lumen perfused stomach (pentaqastrin stimulated gastric acid secretion).

Using a modification of the procedure described by Ghosh and Schild (Br. J. Pharmacology, 13, 54, 1958), the compounds of the following Examples were found on i.v.

administration at a concentration of lOimble/kg to cause an inhibition of pentagastrin stimulated gastric acid secretion as indicated in the following Table.

Compound Rat G.S.

inhibition lOpmole/kg PCT/EP88/01127 '11 WO 89/05297 50 Example A A tablet for oral administration is prepared by combining'" Mg/Tablet Compound of structure (I) lactose Starch crospovidone microcrystalline cellulose magnesium stearate into a 9 mm tablet.

100 153 33 12 2 330 mg Example B An injection for parenteral administration was prepared from the following %w:w Compound of Example 20 1M citric acid sodium hydroxide (qs) water for injection EP 0,50% (W:v) 30% (v:v) to pH 3.2 to 100 ml The compound of Example 20 was dissolved in the citric acid and the pH slowly adjusted to pH 3.2 with the sodium hydroxide solution. The solution was then made up to 100 ml with water, sterilised by filtration and sealed into appropriately sized ampoules and vials.

1

Claims (2)

1. A compound of structure (1) R 4 NR R 6 in which I *1 I R 1 to R 4 are the same or different and are each hydrogen. C 4alkyl. C 4alkoxy, phenyl. C14alkylthio. C1_4alkanoyl. amino. C -6alkylamino. diC 1 -4alkylamino. halogen or trifluoromethyl provided that at least two of R 1 to R 4 are hydrogen. S I I. R 5 and R 6 hydrogen, R 7 and R 8 hydrogen, are the same, or different and are each Cl_4alkyl, -(CH2)nAr in which n is 0 to 4 and Ar is a phenyl group optionally substituted by 1 to 3 substituents selected from Cl_4alkyl, C 1 4 alkoxy, C 1 _4alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C 1 4 alkanoyl, or trifluoromethyl or R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring, and: are the same or different and are each Cl_ 4 alkyl, (CH 2 )nArl in which n is 0 to 4 and Arl is a phenyl group optionally substituted by 1 to 3 substituents selected from C 1 _4alkyl, Cl_ 4 alkoxy, Cl_4alkylthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C 1 4 alkanoyl, or trifluoromethyl or R 7 and R 8 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; or a pharmaceutically acceptable salt thereof, provided that I I 0 R 5 R 6 R 7 and R 8 are not, at the same time, all hydrogen; at least one of R 5 R 6 R 7 and R 8 is a (CH2)nAr or (CH2)nAr' group as appropriate; and o when R 1 and R 4 are both hydrogen and one of R 2 and R 3 is Cl-. 4 alkoxy, the other is not hydrogen or C 1 4 alkoxy. S. S S S 45 Se S. S S S. S S S 55 S *OSO

55.. S S S. S 555555 S I ~i 2. A compound according to claim 1 in whichR2 to R 4are hydrogen and R 1is hydrogen or C 14alkoxy. 3. A compound according to claim 2 in which one of R 5 and R6is (CH 2 )nAr in which n is 0 to 4 and Ar is a phenyl group optionally substituted as defined in claim 1 and the other is Cl.. 4 alkyl. poe*4. A compound according to claim 3 in which n isO0. S. A compound according to claim 4 in which one of 0 .R 7 and R 8 is hydrogen and the other is -(CH 2 )nArl in :which n is 0 to 4 and Ar 1 is a phenyl group optionally substituted as defined in claim 1. 6. A compound according to claim 1 which is S. S 2-amino-6-methoxy-4-(2-methylphenylamino)quinazoline 2.4-Bis-(N-methylphenylamino)quinazoline 4-(N-methylphenylamino)-2-(2-methylphenamn-8-nethoxy 0: quinazoline 2-C( 2-methylhe-fylamio)-4- )am ]--(N-methylphenylaninmuiaoine quinazoline 2- (2-methyiphenylamino) -4-phenylaminoquinazoline or a Pharmaceutically acceptable salt thereof, 7. A pharmaceutical composition comprising a compound according to any one of claims I to 6 and a Pharmaceutical carrier. ~A E§YM. iou o~ oornpo~rid oC ~gu~u~i~ I CCC0 0 0 0 0 00 00 000 0 0 0 00.0 ooo 0 00 SG a 3 I 0 0 I I x I*1 a II in which RI to R6 are as described for structure except that where necessary they are in protected form, and X is a group displaceable by an amine. with an amine of structure R, M-IinUhoich R?7 a a a R<are as dc scril gor Structurc reaction of a coxnpolnd of structure (111) I> 00 00 0 0 0000 00 00 00 0 0 0 0 0 0 00 ov 0 0 0 0.000 0 0 0 0 0 in wl in w], disp: K 0 2 C> 00 C) fl (2000 0~ 0 0 9 (Vili) PYL~N. 000009 S 54 4~*e zrp" q 0 0 00 990 00 0 c 0 0 ga st:cl t~inal aIA iki viich 00(0 0 0 0 00 0 0,000 0 0 0 0 0 00 0 0 00 0 0 0 00 C, 0 01 0 RI to R 4 are the same or Li C 1 4 alkyl, C 1 4 alkoxy, phL' C~j-dllanoyl, amino, Cj-. 6 al j trifluoromethyl 1 arehdrgn Cl,-071 '11~ 2 lAr in *vj a phenyl group optionalLY L claim 1 or R and R 6 to which they are attached tc,- unsaturated carbocyclic ring, 2,nre:~~ !n o nd Air. DAT! 0000 0 00 0 0000 *90 00 0 0 00 OC C215EJHSPL 0 9 4 ese. a a 0. 0 00a 0 S .00. 5-7 R 7 and R8are the same or different and are each .hydrogen.- Cl.. 4 alkyl, (CH 2 )nArl in which n is 0 to 4 and Ar 1 is a phenyl group optionally substituted as defined in claim 1, or R 7 and R 8 together with the nitrogen atom to which they are attached form a saturated or unsaturated carbocyclic ring; or a pharmaceutically acceptable salt thereof. 12. The method according to claim 11 wherein the mammal is a human. DATED this 15th day of February, 1991 SMITHKLINE BECKMAN INTERCREDIT, B.V. By Its Patent Attorneys DAVIES COLLISON CLAIMS: 9102 15,EJHSPE.013,28230.spe,61 S 055505 S 5005 OS *5 0 S 55 S 00 S. S 005( S S 00 S @5 1L 1/_1 V. 1 INTERNATIONAL SEARCH REPORT International Application No PCT/EP 88/01127 1 I. CLASSIFICATION OF SUBJECT MATTER (it several classification symools aoply, indicate all) According to International Patent Classification (IPC) or to both National Classification and IPC IPC 4 C 07 D 239/95; A 61 K 31/505; C 07 D 401/04 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System I Classification Symbols IPC C 07 D 239/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched III. DOCUMENTS CONSIDERED TO BE RELEVANT I Category Citation of Document, with Indication, where approorlate, of the relevant passages 12 Relevant to Claim No, 1 X DE, C, 958197 SKRAUP) 1 14 February 1957 see pages 1,2 X GB, A, 806772 (WELLCOME) 1,7,8 31 December 1958 see pages 1,2 X FR, A, 1310457 (WELLCOME) 1,7,8 22 October 1962 see pages 1-3 X US, A, 3635979 HESS) 1,7-11 18 January 1972 see columns 1-26 X CH, A, 457460 (PARKE, DAVIS) 1 August 1968 see columns 1-6 X US, A, 4098788 CRENSHAW) 4 July 1978 see columns 6-10 Special categories of cited documents: 10 later document published after the international filing date document defining the general state of the art which is not or priority date and not in conflict with the plication but considered to be of particular relevance cited to understand the principle or theory underlying the invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the climed invention citation or other special reason (as specified) document of particular relevance;' the claimed invention citation o other special reason (as specified) cannot be considered to involve an inventive steo when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means ments, such combination being obvioug to a person skilled document published prior to the International filing date but in the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 3rd April 1989 0 3. 05. 89 International Searching Authority Signature of Authorized Oflic EUROPEAN PATENT OFFICE "I VAN MOL Form PCT/ISA/210 (second sheet) (January 1985) Initenational Aoollcation No. PCT/EP 88/01127 III, DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) category' Citation of Docujment. witfl indr-stlef, wtwe aopfopfiats, of the relevant P~assages Relevant to Claim No x x US, A, 3956495 LACEFIELD) 11 May 1976 see columns 1-3,7-18 EP, A, 0028473 (PFIZER) 13 May 1981 see pages 5,11-15,42,43,68-78; claims GB, A, 1390014 KONINKLIJKE PHARMACEUTISCHE FABRIEKEN V/H BROCADES-STHEEMAN PHARMACIA) 9 April 1975 see pages 1,2,4-9 1,7,8,10 1,7-11 1,7,8 Form PCT ISA'210 (extra shoot) January 1985)