IE45257B1 - 11-oxo-pyrido 2,1-b quinazoline-2-carboxylic acid and esters and salts thereof - Google Patents

Description

ll-oxo-llH-pyrido [2,l-b]quinazoline-2-carboxylic acid and esters and salts thereof This invention relates to novel derivatives of quinazoline having interesting pharmacologicical properties.

According to one feature, this invention relates to the novel compound ll-oxo-llH“pyrido[2,l-b]quinazOline-2-carboxylic acid of the formula COOH (I) its Cj - ¢4 alkyl esters and the salts thereof.

The compounds according to the invention and the physiologically acceptable salts thereof possess interesting pharmacological properties. In particular they show an anti-allergic effect and also a muscle-relaxing (e.g. bronchcdilating) and vasodilatory activity. The anti-allergic properties of the compounds according to the invention make them suitable for the prophylaxis and treatment of allergic diseases such as, for example, asthma, hay-fever, conjunctivitis, urticaria, eczema and atopic dermatitis. Tests which we have con15 ducted have shown that in the prophylaxis of asthma the compounds of the invention and physiologically acceptable salts thereof subjected to testing have a longer duration of action compared to the known compound cromoglycinic acid and also exhibit an activity when admin. istared orally. - 2 4S3S7 In compounds of the invention which are (4 - C4 esters of the compounds of formula I, the alkyl groups preferably contain up to 2 carbon atoms.

It will be appreciated that the salts of compounds of the invention 5 for use in medicine should be physiologically acceptable. Other salts however may be useful in the preparation of the compounds according to the invention or the physiologically acceptable salts thereof.

The compound of the formula I may be prepared by the following methods: a) Reacting a compound of the formula (ID wherein X represents a halogen atom preferably fluorine, chlorine or bromine with a compound of the formula wherein Rj represents an alkyl group containing from 1 to 4 carbon atoms.

The reaction is preferably effected at an elevated temperature, and advantageously at a temperature of from 120 to 160‘C. If desired it may be effected without a solvent or in a high boiling solvent, for example dimethylformamide, or sulfolane. It is useful to add an acidacceptor, for example an excess of the compound of formula III. - 3 45257 The starting materials used for this process are known and may be obtained by conventional processes. b) Oxidizing' a compound of the formula COOH (IV) Acyl and subsequently acidifying the compound thereby formed.

The oxidation is generally effected at an elevated temperature with for example, potassium permanganate in an aqueous solution buffered with magnesium sulfate. The acidification may if desired be effected with mineral acids, for example hydrochloric acid, or with organic acids, for example acetic acid.

The starting compounds of the formula IV may be produced by conventional methods. The carboxyl substituent in formula IV can also be formed in situ from the corresponding methyl-substituted compound or from other correspondingly substituted compoundsunder the reaction conditions. c) Converting the substituent Rg in a compound of the formula wherein fig represents a group readily convertible to carboxyl, into carboxyl. - 4 45257 The conversion car) be effected by conventional methods. For example, by saponification of a corresponding ester or amide, or also by oxidation of the corresponding methyl-substituted compound, for example with potassium permanganate for instance.

The Cj - C4 esters of the compound of formula I may be prepared by reacting a compound of formula V wherein R2 is a chlorocarbonyl group with an aliphatic alcohol containing from 1 to 4 carbon atoms.

The compound of formula I obtained by methods a) - c) forms salts with inorganic or organic bases. Suitable bases are, for example sodium W hydroxide or potassium hydroxide. Conversely, if a salt of the compound of formula I is first obtained, the free acid of the formula I may be liberated therefrom by conventional methods.

According to a further feature of the invention there are provided pharmaceutical compositions comprising, as active ingredient, a compound of formula I as hereinbefore defined or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient.

The pharmaceutical compositions according to the invention can, for example, be in a form suitable for oral, rectal, parenteral, pulmonary or topical administration, suitable forms of administration being, for example, capsules, tablets, coated tablets, solutions, suspensions, aerosols, sterile isotonic solutions, creams, ointments, lotions, emulsions, sprays or suppositories.

If desired, the compositions according to the invention can be in dosage unit form. When administered by the pulmonary route, each dosage unit preferably comprises 20 to 500 pg/kg of the active Ingredient, for oral administration 1 to 50 mg of the active ingredient and for intravenous administration 0.2 to 10 mg of the active ingredient. For nasal or ocular administration each dosage unit preferably comprises 0.5 to 25 mg of active ingredient. In general, the specific dose administered depends on the nature of the condition which is to be treated. - 5 Tablets may, for example, be obtained by mixing the active ingredient with known excipients, for example with inert diluents such as calcium carbonate, magnesium stearate or talcum and/or agents for obtaining sustained release, such as carboxypolymethylene, carboxymethyl cellu5 lose, cellulose, acetate-phthalate or polyvinyl acetate. The tablets may, if desired, consist of several layers, for example to obtain sustained release or to avoid incompatibilities.

Coated tablets may be obtained by coating tablet cores prepared analogously to the tablets described above, v/ith agents commonly applied for tablet coating, for example, polyvinylpyrrolidone, shellac, gum arabic, talcum, titanium dioxide or sugar. To obtain sustained release or for avoiding incompatibilities the core may also consist of several layers. The tablet coating may also consist of several layers whereby the excipients mentioned above for tablets may be used.

Capsules comprising the active ingredient according to the invention may bs produced, for example, by mixing the active ingredient with inert carriers such as lactose or sorbitol and filling gelatin capsules with the mixture.

For pulmonary administration, the active ingredient according to the 2Q invention may be conveniently combined with conventional aerosol formulations and filtellnto spray cans, preferably cans provided v/ith metering means. The active ingredients may also, if desired, be made into aerosol formulations in micronised form (generally with a particle size of 2 to 6 yra), optionally with the addition of micronised carriers such as lactose. These formulations may be filled into hard gelatin capsules. Conventional devices for powder inhalation are generally used, and into each capsule preferably 2 to 40 mg of active ingredient and 0 to 40 mg of lactose are filled.

The following examples illustrate the invention: - 6 45257 Example 1 11-0χο-11-Η-ρνΓΪί1οΓ2 .l-b1-ouinazoline-2-carboxylic..aei_d Molar quantities of 2,4-dimethylaniline and 2-bromopyridine are condensed at 160 to 180°C and 2,4-dimethyl-N-pyridyl5 (2)-aniline (having a melting point after purification via the fumarate of 65 to 68°¾) is obtained. Heating it with acetic anhydride gives N-pyridyl(2)-N-2,4-dimethylphenylacetamide. 60 g of this acetamide are oxidized with' 218 g of potassium permanganate and 75.5 g of magnesium sulfate in 2 1 of water between 40 and 90°C.

The manganese dioxide produced is removed by suction filtration and the mother liquor acidified with acetic acid. The compound that crystallises out slowly is removed by i suction filtration.

After stirring for one hour with 5 times its quantity of concentrated hydrochloric acid at 60 to 70°C, it is-diluted with 10 times its quantity of water. The ll-oxo-ll-H-pyrido[2,l-b]-quinazoline-2-carboxylic acid precipitates gradually, and after removal is washed with water and acetonitrile Analysis: W) . ’ H% I# calc: 65,00 3.33 11.67 found: 64.95 3.46 11,58 - ,7 4S.SS7 a) Sodium Salt From ths obtained pyrido-quinaEolone carboxylic acid, the sodium, salt is obtained in water with the calculated quantity of sodium bicarbonate and subsequently precipitated with ethanol. Ό) Sthanolamine Salt le2 g of the obtained pyrido-quinazolins-earboxylic acid are suspended in 3 ml of watery 0.31 ml of ethanolamine are added,and the ethanolamine salt is precipitated with acetonitrile.

Analysis: :15H15K3°4 .. H^O C % H % ’ » % ealc: 56p43 5r33 13.17 found: 57,25 4*96 13,46 c) ·Triethanolamine Salt Froa 2O4 g of pyrido-quinazolone carccoylic acid suspended in 200 gal of acetonitrile, the above salt is produced with 336 g of triethanolamine (approx. 65%). (decomposition >200°C) Analysis: C^H^NjOg C % H % W % calc: 58.61 5.91 10,80 found: ' 53,80 5,72 11,00 ^S2S? Example 2 Methyl il-0xo-ll-H-pyrido[2,l-b]-quinazoline-2-carboxylate 6,2 g of the ll-oxo~ll-H-pyrido[2,l-b3-quinazoline-2-carb/ oxylic acid produced in Example 7 are refluxed in ten times its quantity of thionyl chloride for 1 hour. The insoluble carboxylic acid chloride is sucked off and refluxed in 10 to 20 times its quantity of methanol until complete solution. After cooling, the methyl ll-oxo-ll-H-pyrido[2,l-b]quinazoline-2-carbaxylate hydrochloride crystallizes out with one mol. of methanol (decomposition point 254°C), Analysis:Cl4K10K2G3 ; HCl .'CHjOH G % H / N / 01' / calc: 55.81 4,65 8,68 11*01 found: 55.53 4,35 8,32 11^29 Example I: Tablets Composition: ... · a) ll-oxo-ll-H-pyrido[2,1-b]-quinazoli ne2-carboxylic acid 0.100 g stearic acid 0.020 g glucose 1.890 g 2.000 g The components are processed in the conventional way to produce tablets of the composition indicated above.

Example II: Ointments g/100 g Composition: ointment active ingredient acc. to invention 2.000 fuming hydrochloride acid 0.011 sodium pyrosulfite 0.050 mixture of equal parts of cetal alcohol and stearyl alcohol 20.000 white vaseline 5.000 artificial Bergamotte oil 0,075 distilled water ad 100.00 The components are processed to produce an ointment in the usual way.

Example III: Inhalation Aerosol Composition; parts sodium salt of ll-oxo-ll-H-pyrido-[2,l-b3quinazoline-2-carboxylic acid 1.00 soja lecithin 0.20 propellant gas mixture (Frigene 11, 12 and 114) ad 100.00 The preparation is filled into aerosol containers with metering means in such a way that a dose of 5 mg of active ingredient is released. For higher doses preparations with a higher content of active ingredient are used.

Claims (32)

1. ll-oxo-ll-H-pyrido[

2. ,l-b]quinazoline-2-carboxylic acid of the formula its Cj - C4 alkyi esters and the salts thereof. 5 2. ll-oxo-ll-H-pyrido[2,l-b]-quinazoline-2-carboxylic acid and the salts thereof with sodium, ethanolamine or triethanolamine.

3. Methyl ll-oxo-ll-H-pyrido[2,1-b]-qui nazoline-2-carboxyiate.

4. A process fcr the preparation of the compounds of formula I as claimed in claim 1 which comprises reacting a compound of formula (ID (wherein X represents a halogen atom) with a compound of formula wherein Rj represents an alkyl group containing from 1 to 4 carbon atoms. - 11 48287

5. A process as claimed in claim 4, wherein the reaction is effected at an elevated temperature.

6. A process as claimed in claim 5, v/herein the reaction is effected at a temperature of 120 to 160°C. 5

7. A process as claimed in any of claims 4 to 6, wherein a compound of formula II is used in which X represents a fluorine, chlorine or bromine atom.

8. A process as claimed in any of claims 4 to 7, wherein the reaction is effected in the presence of a high boiling solvent.

9. 10 9. A process as claimed in claim 8, v/herein the high boiling solvent comprises dimethylformamide or sulfolane. 10. A process as claimed in any of claims 4 to 9, wherein the reaction is effected in the presence of an acid-acceptor.

10. 11. A process as claimed in claim 10, v/herein the acid-acceptor com15 prises an excess of the compound of formula III.

11. 12. A process for the preparation of a compound of formula I as Glaimed in claim 1 which comprises oxidizing a compound of formula and subsequently acidifying the compound thereby formed.

12. 13. A process as claimed in claim 12, wherein the oxidation is effected at an elevated temperature. 12 4S2S7

13. 14. A process as claimed in either of claims 12 and 13, wherein the oxidation is effected with an aqueous solution of potassium permanganate buffered with magnesium sulphate.

14. 15. A process as claimed in any of claims 12 to 14, wherein the acid5 ification is effected with a mineral or organic acid.

15. 16. A process as claimed in claim 15, wherein the acid comprises hydrochloric acid.

16. 17. A process for the preparation of Ci - C4 asters of the compound of formula I as claimed in claim I, wherein a compound of 10 formula (wherein Rg represents a chlorocarbonyl group) is reacted with an aliphatic alcohol containing frcm 1 to 4 carbon atoms. IS. A process for the preparation of a compound of formula I as claimed in claim 1, wherein a compound of formula (wherein Rg represents an ester group) is saponified.

17. 19. A process for the preparation of a compound of formula I as claimed in claim 1, wherein a compound of formula (wherein Rg represents a methyl group) is oxidised.

18. 20. A process as claimed in claim 19, wherein the oxidation is effected with potassium permanganate.

19. 21. A process, as claimed in any of claims 4 to 16 or 18 to 19, wherein the compound produced is converted to a salt thereof with an organic or inorganic base.

20. 22. A.process for tha preparation of compounds of general formula I ana the salts thereof substantially as herein described.

21. 23. A process for the preparation of compounds substantially as herein described in either of Examples 1 and 2.

22. 24. Compounds whenever prepared by a process as claimed in any of claims 4 to 19.

23. 25. Pharmaceutical compositions comprising, as active ingredient, a compound of formula I as defined in claim 1, its Ci - C4 esters or a physiologically acceptable sale thereof in association v/ith a pharmaceutical carrier or excipient.

24. 26. Pharmaceutical compositions as claimed in claim 25, v/herein the pharmaceutical carrier or excipient is in a form suitable for oral, rectal, parenteral, pulmonary or topical administration.

25. 27.. Compositions as claimed in either of claims 25 and 26 in the form of capsules, tablets, coated tablets, solutions, suspensions, aerosols, sterile isotonic solutions, creams, ointments, lotions, emulsions, sprays or suppositories. - 14 45257

26. 28. Compositions as claimed in any of claims 25 to 27 in dosage unit form.

27. 29. Compositions as claimed in claim 28 for pulmonary administration, wherein each dosage unit comprises from 20 to 500 iig/kg of the said 5 active ingredient.

28. 30. Compositions as claimed in claim 28 for oral administration, wherein each dosage unit comprises 1 to 50 mg of the said active ingredient.

29. 31. Compositions as claimed in claim 28 for intravenous administra10 tion, wherein each dosage unit comprises 0.2 to 10 mg of the said active ingredient.

30. 32. Compositions as claimed in claim 28 for nasal or ocular administration, wherein each dosage unit comprises from 0.5 to 25 mg of the said active Ingredient. 15

31. 33. Pharmaceutical compositions as claimed in any one of claims 25 to 32 substantially as herein described.

32. 34. Pharmaceutical compositions substantially as herein described in either of Examples I and i’.