IE46285B1 - 6,7-dimethoxy-2-(4-thiomorpholinyl)-4-quinazolinamine,its oxides and salts - Google Patents

Abstract

Novel quinazoline derivatives of the formula: wherein n is 0, 1 or 2, are useful as hypotensive agents.

Description

The present invention is concerned with new quinazoline derivatives which have activity as hypotensive agents and is also concerned with the preparation thereof.

The quinazoline derivatives according to the present invention are compounds of the general formula :- wherein n is 0, 1 or 2; and the pharmaceutically acceptable acid-addition salts thereof.

Related compounds have been described in the literature. For example, the above compounds are pharmacologically related to prazosin, which is disclosed in U.S. Patent Specification No. 3,511,836 and has the formula: The compounds (I) in which n is 0 or 2 can be prepared by reacting chloroquinazoline, which has the formula :- with thiomorpholine or thiomorpholine, S,S-dioxide, respectively. The synthesis of chloroquinazoline has already been described by F.H.S. Curd (J. Chem. Soc., 1948, 1759).

The compound (I) in which n is 1 can be prepared by reacting the compound (I) in which n is 0 with one equivalent of an oxidising agent, such as m-chloroperbenzoic acid.

The pharmaceutically acceptable salts of the free bases of general formula (I) can be prepared by reaction with an eguivalent amount of an inorganic or organic acid. Examples of pharmaceutically acceptable salts include those of hydrochloric, hydrobromic, sulphuric, benzene-sulphonic, acetic, oxalic, malic and citric acids.

The compounds of general formula (I), as well as their 28 6 .-4i pharmaceutically acceptable inorganic and organic acid salts, may be administered enterally or parenterally in admixture with a liquid or solid pharmaceutical diluent or carrier.

Consequently, the present invention also provides a pharmaceutical composition comprising at least one of the compounds (I) according to the present invention, in admixture with a solid or liquid pharmaceutical diluent or carrier.

A particular aspect of the composition comprises at least one of the compounds (I) in an effective unit dose form, an effective unit dose being a predetermined amount sufficient to bring about the desired hypotensive reaction.

The present invention also provides a method of producing a hypotensive action in mammals, excluding man, which comprises administering an effective amount of a compound of general formula (I) and/or of a pharmaceutically acceptable salt thereof.

The dosage of the compounds of general formula (I) and of their pharmaceutically acceptable salts depends, of course, on the nature and severity of the excitability to be countered, as well as the route of administration. When tested in spontaneously hypertensive rats to determine hypotensive activity, the compound of Example 1 was active at a dose of 10 mg/kg and the compound of Example 3 was active at a dose of 30 mg/kg. The compounds (I) and their pharmaceutically acceptable salts are active as hypotensives in mammals when administered orally, parenterally or intravenously throughout a dose range of 1.0—100.0 mg/kg of mammalian body weight, preferably in the range of 5.0—50.0 mg/kg. In addition, these compounds appear to have less undesirable a-blocking activity than prazosin. - 5 The following Examples are given for the purpose of illustrating the present invention:Example 1. 6,7 - Dimethoxy - 2 - (4 - thiomorpholinyl) - 4 - quinazolin5 amine.

A mixture of 8.00 g. 2 - chloro - 6,7 - dimethoxy - 4quinazolinamine and 6.90 g. thiomorpholine in 80 ml. chlorobenzene was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected. There were obtained 8.00 g. (70.2% of theory) of white powder; m.p. 267—269°C. (dec.). The product was recrystallised from methanol to give an analytically pure sample of 6,7 - dimethoxy - 2 - (4 - thiomorpholinyl) - 4 - guinazolin15 amine hydrochloride; m.p. 270—271°C. (dec.).

Analysis: C 4H B^S . HCl calc.: C 49.05%; H 5.59%; Cl 10.34% N 16.34%; S 9.35% found: 48.91%; 5.59%; 10.53%; 16.18%; 9.51% Example 2. 6,7 - Dimethoxy - 2 - (4 - thiomorpholinyl) - 4 - quinazolinamine S - oxide.

To a solution of 1.00 g. 6,7 - dimethoxy - 2 - (4thiomorpholinyl) .-4- quinazolinamine in 100 ml. methylene chloride at 0°C. was added dropwise, over the course of 15 minutes, a solution of 0.66 g. 85% m-chloroperbenzoic acid in 25 ml. methylene chloride. After an additional 2 hours at 0°C., the reaction mixture was washed with a dilute aqueous sodium bicarbonate solution and with Water. The organic extracts were dried over anhydrous sodium sulphate and the solvent was evaporated. There remained 0.75 g. (71.4% of theory) of white powder; m.p. 278—280°C. (dec.). Recrystallisation from methylene chloride-isopropanol gave an analytically pure sample of 6,7 - dimethoxy - 2 - (4 - thiomotpholinyl) - 4 - quinazolinamine S - oxide; m.p. 283—285°C. (dec.).

Analysis: Ci4Hi8N4°3S calc.: C 52.16%; H 5.63%; N 17.38%; S 9.95% found: 51.92%; 5.82%; 17.04%; 9.82% Example 3. 6,7 - Dimethoxy - 2 - (4 - thiomorpholinyl) - 4 - quinazolinamine S,S - dioxide.

\ S02 A mixture of 9.40 g. 2 - chloro - 6,7 - dimethoxy - 4quinazolinamine and 10.6 g. thiomorpholine S,S-dioxide in 200 ml. chlorobenzene was refluxed for 24 hours. The reaction mixture was cooled to ambient temperature and the precipitate was collected. There were obtained 9.10 g. (61.1% of theory) of white powder; m.p. 271—275°C. (dec.). Recrystallisation from aqueous ethanol gave pure 6,7 - dimethoxy - 2 - (4thiomorpholinyl) - 4 - quinazolinamine S,S - dioxide hydrochloride; m.p. 275—276°C. (dec.).

Analysis: C,.H,oN.0.S . HCl 18 4 4 calc.: C 44.86%; H 5.11%; Cl 9.46%; N 14.95%; S 8.55% found; 44.93%; 5.13%; 9.19%; 14.83%; 8.49% As stated above, the compounds of the present invention can be administered in oral dosage form, such as by tablet or capsule, by admixture with any oral pharmaceutically acceptable inert diluent, such as lactose, starch, dicalcium phosphate, calcium sulphate, kaolin, mannitol, powdered sugar, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids, such as stearic acid, and high molecular weight polymers, such as polyethylene glycols. In addition, when required, binders, lubricants and disintegrating, flavouring, sweetening, preserving, colouring, suspending, thickening anchor emulsifying agents can also be added. Typical binders include starch, gelatine, sugars, such as 46283 - 8 sucrose, molasses and lactose, natural and synthetic gums, such as acacia, sodium alginate, extract of Irish moss, carboxy-methyl cellulose, methyl-cellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes.

Examples of lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol. Examples of disintegrators include starch, methyl cellulose, agar agar, bentonite, cellulose and wood products, alginic acids, guar gum, citrus pulp, carboxymethyl-cellulose, and sodium lauryl sulphate.

If desired, pharmaceutically acceptable dyes, such as any of the standard PD a C dyes, may be incorporated into the dosage unit form.

As injection medium, it is preferred to use water which contains conventional pharmaceutical adjuvants for injection solutions, such as stabilising agents, solubilising agents and buffers, for example, ethanol, complex-forming agents, . such as ethylenediamine-tetraacetic acid, tartrate and citrate buffers and high molecular weight polymers, such as polyethylene oxide, for viscosity regulation.

Claims (10)

1. CLAIMS:1. Compounds of the general formula : - (0) wherein n is Ο, 1 or 2; and the pharmaceutically acceptable 5 acid-addition salts thereof.

2. 6,7 - Dimethoxy -2-(4- thiomorpholinyl) - 4quinazolinamine.

3. 6,7 - Dimethoxy - 2 - (

4. - thiomorpholinyl) - 4quinazolinamine S - oxide. 10 4. 6,7 - Dimethoxy - 2 - (4 - thiomorpholinyl) - 4quinazolinamine S,S - dioxide hydrochloride.

5. Process for the preparation of compounds of the general formula given in claim 1, wherein an appropriate 3chloroquinazoline is reacted with thiomorpholine or thio15 morpholine S,S-dioxide to give, respectively, a compound of the general formula given in claim 1, in which n is 0 or 2, whereafter, if desired, a compound of the general formula given in claim 1 in which n is 0 is reacted with one equivalent of an oxidising agent to give the corresponding compound 20 in which n. is 1.

6. Process according to claim 5, wherein the compound obtained is reacted with an equivalent amount of an inorganic or organic acid to give the corresponding pharmaceutically - 10 acceptable acid-addition salt.

7. Process for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified. 5

8. Compounds according to claim 1, whenever prepared by the process according to any of claims 5 to 7.

9. Pharmaceutical compositions, comprising at least one compound according to claim 1, in admixture with a solid or liquid pharmaceutical diluent or carrier.

10. 10. A method of producing a hypotensive action in mammals, excluding man, which comprises administering an effective amount of a compound according to claim 1. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.