MC1186A1 - QUINAZOLINE DERIVATIVES - Google Patents

Description

The present invention relates to novel chemical compounds. More particularly, the present invention relates to novel pyridoxine derivatives of general formula where Exj, &2 e"k independently represent a hydrogen, a lower alkanoyl, or a lower alkoiyl, and represents a cyano, a 5-tetrazoyl, a halogen, or a radical of formula

0 II

-THAT

where A represents a hydroxy, a lower alkoxy, a di-C2-Cr(C2-Cy)alkoylamino-(C2-Cy)alkoyl, a pivaloyloxymethoxy or -ÏÏR^Rg, where R^ and Eg independently represent a hydrogen, a lower alkoxy or a di-(C2-Cr(C2-Cy)alkoyl, provided that R^ is different from a halogen when R1, R2 and R^ represent a lower alkoxy,

the acidic addition salts of this substance usable in pharmacy and, where A represents a hydroxyl group, also the salts of this substance formed with a base and usable in pharmacy

As used here, the term "lower alkyl" denotes a straight- or branched-chain saturated hydrocarbon group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, β-butyl, neopentyl, pentyl, heptyl, etc. The term "lower alkoxy" denotes an alkoxy group where the lower alkyl group is as described above, for example, methoxy, ethoxy, propoxy, pentoxy, etc. The term "halogen" denotes the 4 atoms of bromine, chlorine, fluorine, and iodine. The term "alcanoyl"

2

inferior11 denotes an alcanoyl group derived from an aliphatic carboxy-ligate acid having from i to 7 carbon atoms, for example the. formyl-e, acetyl, propionyl, etc. As examples of groups "âi—(C^-Cy)alet^laminD-{C2-C1p)alcaxy'", we must mention— 3 dimethylamine ethos, diethylamine ethos, dipropylaminoethoxy, diethylaminoethoxy, dimethylamine ethos, dipentylamine ethos, etc. As examples of groups Mdi—(C^—C1,r7)alcoylaminoethoxy-(C2-Dy)alcaxyl:M9, we find dimethylaminoethyl, diethylaminoethyl, 1 ethylmethylaminenoethyl, dipropylaminoethyl, etc.*

The particular compounds covered by the present invention include those which correspond to formula I above and where ILj, Sg e"k independently represent a hydrogen, or a lower alkyl, and where E^ has the meaning given above. Other particular compounds of formula I above include those where at least two of the radicals S^9 Ep E^ are different from a hydrogen and represent a lower alkyl, and where E^ has the meaning given above.

In another particular respect, the invention ccs-20 takes the compounds of formula I above where E^ represents a radical of formula ^

ill

-THAT

where A represents a di-(CvpCy)alci^lajnino-{C2~C^)alkoxy or a 23 pivaloyloxymethoxy and where E^5 ^ independently represent a hydrogen or a lower alkool.

Another group of particular compounds of formula I above is represented by those where at least one of the radicals E^j ^ E2 and E^ represents a lower alkanoyl. Preferred compounds of formula I above are those where EP and E^ represent a hydrogen. In a preferred respect, the invention includes compounds of formula I above where E^ represents a hydrogen or a lower alkanoyl, preferably a lower alkanoyl, E^ preferably represents a radical of formula O

-$-A.

The preferred meanings of A are hydroxy and di-CC^—C^)-

3

alcoylaminoCCg-Cr^alkoxy, with hydroxy being particularly preferred.

From what has been said above, it follows that compounds of formula I are particularly preferred when R2 e"^ 5 H,, represents a hydrogen, represents a lower alkyl and R^ represents ]j

-Q-OH.

Preferred types of compounds with formula I also include those where R2 and R^ represent hydrogen, R^ re-10 represents hydrogen, a lower alkanoyl, or a lower alkanoyl, and R^ represents a radical of formula jj

-THAT

where A represents a di-(C,j-C1-7)alcoylamino-(C2-Cr7) alkoxy.

Examples of preferred compounds with formula I include the following:

8-Methyl-11-oxo-11α-pyridoxine(2,1-b7quinazoline-2-carbo3cylic acid;

s

8-is6propyl-11-oxo-1<1H-pyridoi/25l-b7quinazoline-2-carboxylic acid;

20 The (2-diethylaminoethyl)ester of 8-isopropyl-11-oxo-11H-pyridoJ/2î/l-h7quinazoline~2-car"boxylic acid.

Examples of compounds with formula I include the following

8-n-propyl-11-oxo-11H-pyrido/2,1-b7quinazoline-2-carbo-25 xyl acid;

8-n-butyl-11-oxo-11H-pyrido/2,1-b7quinazoline-2-carboxylic acid;

8-t-butyl-11-oxo-11H-pyridoxine/2,1-b7q"U.inazoline-2-carboxylic acid;

30 6-methyl-11-oxo-11α-pyrido/5,1-β7quinazoline-2-carboxylic acid;

6-ethyl-11-oxo-11ïL-pyridoi^/2,'1-b7<3.u:i-ri;asolir'e-2-carboxy-lic acid;

L1 6-n-propyl-11-oxo-11H-pyridoxine/2,/1-b7quinazoline~2-car-35 boxyl acid;

6-n-butyl acid ~ 11-oxo-11Iî-pyrido^2,1-b7quinazoline-2-carbo-

4

xylique;

L1 6-t-butyl-11-oxo-11E-pyrido/2,1~b/<3.uiEa2;oline-2-carbyl; etc...

According to the present invention, the compounds of formula I above and their pharmaceutically usable acidic addition salts, and, where A represents a hydroxyl group, also their pharmaceutically usable salts formed with a base, can be prepared by a process which involves a) to prepare the compounds of formula I above, where E represents a halogen and where L], R2 and R2 have the meanings given above, treating a compound of general formula

20 where E represents a hydrogen or a lower alkyl group and where 2 represents a halogen,

with a halopyridine derivative of general formula

25

III

30

35

iv where Rxj, R2, E^ and X have the meanings given above, or b) to prepare the compounds of formula I above where E^ represents a cyano and where R2 and R^ have the meanings given above, that is to say the compounds of general formula

NC

there

5

where Pl^j s ^2 e"k ^3 yes: the given signification above, of tfcrai-"fcer nn composed of general formula

where X' represents bromine, iodine, and cû î^3 3L-, and 32^ ©n"fc the

10. Meaning given above.

with cuprous cyanide, or

$0 to prepare the compounds of formula 1 below-

above, where JLj represents the radical of the formula

O

If

15 -D-A

where A represents nn-faydroxy, that is to say, the compounds of general formula

20

MQOO

THE

25

where 2Lp ^2 and IRj °^t the meaning given above, of "ferai— •ter nn compound of formula 1b above with nickel carbonjle under an atmosphere of carbon monoxide in the presence of an alkaline earth metal oxide or of hydrolyzing nn compound of formula 30 above, or d.) to prepare the compounds of formula 1 ci-<&essns where represents nn radical of formula

î

-THAT

35 where A represents lower alkoxy and where ïLp $2 ^ ^3 OI1^ ^

6

meaning given above., to de-esterify a compound of for-

urnule le ci-dessns., or

<e) to prepare the compounds of formula I above-

dessns where IL represents a radical of forrnnle ^ 0

t- M

5 -D-A

cru A represents a radical of formula -ER^Eg and where E>], Eg, E^, E^ ©i; Eg have the meaning given above, to subject a compound of the formula above to ammonolysis with an amino compound of general formula

SSE^Eg (1Y)

©ù R^ ei; Eg have the meaning given above, or

"15 f) to prepare the compounds of formula I below-

above, where Ry represents a radical of the formula ^ 0

II

-D-A

where A represents a di-(C,j-Cy)alkoxy di-(C2-Cy)alkoxy and where E^j, 20 E2 and E^ have the meanings given above, to treat a compound of the above formula with a di-(C,j-Cr7)alkylamino-(C2-Oy)alkyl halide or to subject an acid chloride of a compound of the above formula to alcoholysis with a di-(O^-Cy)alkylamino-(C2-Cy)alkyl or

25 .g) to prepare the compounds of formula I below-

above, where R^ represents a 5-tetrazoyl, and where E^, R2 and R^ have the meaning given above, to treat a compound of the formula above with an alkali metal azohydride, or

11) to prepare the compounds of formula I below •

30 above where R,. represents a radical of formula

0 11

-THAT

where A represents a pivaloylor^ymétiioxy and where E^, E2 and R^ have the meaning indicated above, to treat a compound of the formula above with a tertiary organic base and the

chloro-, bromo-, or iodimethyl pivalate, and i) if desired, to transform a compound obtained into a salt usable in pharmacy

According to variant a) of the process, an anthranilic acid or an ester of formula II, a known compound or a compound that can be prepared by known processes, is reacted with a halopyridine of formula III, also a known compound or one that can be prepared by known processes, at a temperature ranging from about 100°C to about 200°C, with or without a solvent. The reaction is carried out in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide, cesium iodide, etc. The solvents that can be used in the reaction are high-boiling solvents such as acetic acid, diglyme, triglyme, etc. It is convenient to carry out the reaction at atmospheric pressure. The product of the reaction can be collected by known processes, such as crystallization, etc.

According to variant b) of the process, the bromo or iodo fraction of a compound of formula Ib can be transformed into a nitrile fraction by treating the compound of formula Ib with cuprous cyanide in an inert solvent such as 1-methyl-2-pyrrolidinone or a similar compound, at the reflux temperature of the reaction mixture or a temperature close to it. The reaction mixture is then treated with a solution of water, hydrochloric acid, and ferric chloride. The desired nitrile is collected by known methods, such as crystallization, etc.

According to variant c) of the process, a compound of formula Ib can be transformed into a compound of formula le by treating the compound of formula Ib with nickel carbonyl in the presence of an alkaline earth metal hydroxide, such as calcium hydroxide, under pressure and in a carbon monoxide atmosphere at a temperature ranging from 100°C to about 150°C. It is convenient to carry out the reaction in a polar solvent with a high boiling point, such as DMF or a similar compound. A compound of formula le can be obtained by conventional methods, such as crystallization, etc.

8

A nitrile of formula la can also be transformed into an acid of formula ^c by hydrolysis with a mineral acid, such as sulfuric acid, hydrochloric acid, etc.* in the presence of a solvent, such as acetic acid, propionic acid, F, etc.

According to variant d) of the process, an acid of formula le can be transformed to give the corresponding ester by known methods. For example, an alkali metal salt of an acid such as described above, such as sodium salt 10, can be reacted with a substituted or unsubstituted alkyl halide using known reaction conditions, for example in an inert solvent such as DMF, etc., at a temperature ranging from approximately room temperature to the reflux temperature of the reaction mixture.

15 According to variant e) of the process, an acid of formula le can be transformed into the corresponding amide by known processes. For example, an acid as described above is treated with thionyl chloride, and the corresponding acid chloride is obtained. This is then treated with the corresponding amine, for example ammonia, dimethylamine, the

3-Diethylaminopropylamine, etc., in the presence of a solvent such as THFc. The desired amide is then collected by known processes such as crystallization.

According to variant f) of the process, an acid of formula 25 can be transformed to give the di-(C₆H₁₂O₆)alkoylamino-(C₂-Cr₂)alkoyl ester by known processes. For example, an acid such as described above is treated with the corresponding di-(C₆H₁₂O₆)alkoylamino-(C₂-Cr₂)alkoyl halide under reflux conditions in a solvent, for example an alkanol such as isopropanol, etc., and the product is collected by known processes, such as crystallization; or alternatively, the said compound is treated with thionyl chloride and the corresponding acid chloride is obtained; This latter compound is reacted with a di-(C-Cy-alcoylamino-CCg-Cy)alkanol in an inert solvent, such as THP or a similar substance, at a temperature ranging from approximately 0°C to approximately 100°C, and then the desired final product is collected by known processes, such as o

9

crystallization, etc.,...

According to variant g) of the process, a compound of formula I, where is a 5-tetrazolyl compound, can be prepared from the corresponding compound of formula la. More specifically, the corresponding compound of formula la is treated with an alkali metal azothydide, such as potassium azothydide, sodium azothydide, etc., in the presence of ammonium chloride. It is convenient to carry out the reaction in the presence of a solvent such as a polar aprotic solvent, for example, dimethyl sulfoxide, Un, etc. The desired tetrazolyl compound is then collected by known methods, for example, crystallization, etc.

According to variant h) of the process, a compound of formula 1, where A is a pivaloyloxymethoxy, can be prepared by treating the compound of the corresponding formula with a tertiary organic base, such as a lower amine trialkyl and chloro-, bromo-, or iodomethyl pivalate in an inert solvent such as DLOF, etc., at a temperature ranging from approximately room temperature to approximately 120°C. The desired final product can be collected by known processes, such as a Dri-stallization.

Compounds of formula 1, where A is a hydroxyl group, form salts usable in pharmacy with the bases. Examples of such bases include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides, such as calcium hydroxide, barium hydroxide, etc.; alkali metal oxides, such as sodium ethoxide, potassium ethoxide; and organic bases such as piperidine, diethylamine, 1-methylglucamine, etc.

The compounds of formula 1 also form salts usable in pharmacy with acids. Examples of such acids include organic and inorganic acids usable in pharmacy, such as methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.

The compounds of formula 1 and their usable salts in pharmacy inhibit cutaneous anaphylaxis in rats, and are therefore useful in the prevention of allergic reactions; they

10

They are, for example, useful in the prophylactic treatment of bronchial asthma. Their anti-anaphylactic activity can be demonstrated by the passive skin anaphylaxis test (PCA test).

in rats. This experiment involves passive lo-5 sensitization of rats by intradermal injection of antisera.

After a 24-hour latency period, the control compound, in this case a pyridoxine,1-beta/quinazoline, is administered intraperitoneally and followed, after 5 minutes, by an intravenous injection of reagent and Evans blue dye. The manifestations related to the localized antigen-antibody reaction lead to the formation of dermal papules, the size of which is measured. The ability of the experimental compound to reduce the size of the papules, compared to that of the controls, is taken as a measure of its activity.

15 When an experimental compound of this invention, such as 8-isopropyl-11-oxo-11H-pyrido-2,1-b7quinazoline-2-carboxylic acid at a dose of 16 mg/kg intraperitoneally, is used, the reduction in the size of the wheals is 81%.

20. Compounds of formula I and their pharmaceutically usable salts can be administered orally or parenterally as anti-allergic agents, 5 for example in the prophylactic treatment of bronchial asthma, with dose adjustments for individual needs. They can be administered therapeutically, 25 for example orally or parenterally, by incorporating a therapeutic dose in a conventional base form.

such as tablets, capsules, elixirs, suspensions, solutions, etc. They can be administered mixed with conventional pharmaceutical carriers or excipients, such as corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose, etc. Furthermore, they can be administered in the presence of buffers or agents used to adjust isotonicity, and, if desired, the basic pharmaceutical forms can be subjected to conventional pharmaceutical handling, such as sterilization. As mentioned above, the dosage can be adjusted to individual needs. The compositions can also...

O

11

to include other therapeutically useful substances.

The amount of active drugs present in the basic forms described above is variable. "However, capsules or tablets containing approximately 10 mg to approximately 20 mg of the base of formula I or an equivalent amount of a medically acceptable salt of this substance are preferred.

The frequency with which a patient is administered a basic form of this kind varies according to the amount of active drug present and the patient's needs. However, under ordinary circumstances, up to approximately 20 mg/kg of the compound may be administered daily in several doses. It should be understood, however, that the doses mentioned here are only examples and do not in any way limit the scope or application of this invention. The following examples illustrate the invention more precisely. All temperatures are in degrees Celsius.

- EXAMPLE 1 -

Preparation of 2-bromo-11-oxo-11α-pyrido-2β,1-b7quinazoline hydrochloride

An intimate mixture of 100.0 g of 2-chloropyridine, 83.0 g of 5-bromoanthranilic acid, and 1.0 g of potassium iodide is heated overnight to a bath temperature of 14.5–1500°C under a stream of argon. Upon cooling, the crude product is triturated with 150 mL of boiling ethanol and collected to give 105.4 g (86%) of 2-bromo-11-oxo-11H-pyridoxine/2,1-12/quinazoline hydrochloride, melting at 280–282°C (dec.). The analytical sample is obtained from aqueous hydrochloric acid-DIXF-ethanol; it melts at 278–281°C.

3° - EXAMPLE 2 -

Preparation of 11-oxo-11α-pyridoxine-2,1-β7quinazoline-2-carboxylic acid

A suspension of 1500 g of 35 2-bromo-11-oxo-11I-pyridoxine and 360 g of hydroxide is placed

12

of calcium in 105 3nl of IfilTF annexed at 5% in a "bottle of

3?ischer-Porter of 170 cur and we replace 1 atmosphere with carbon monoxide. Approximately 10 ml of nickel carbo-

Nyle with a syringe needle and we increase the pressure of the

2 ^

5 carbon monoside up to 1.4 3 cg/cm³. At the same time as the bath temperature rises to 110-115°C, the pressure increases to 2.8

p ikg/cia approximately, and the yellow suspension becomes a green solution. After 25 h total, the mixture is allowed to cool, diluted with 300 ml of hydrochloric acid 1]? and filtered. The filter cake is triturated with very hot 19 ethanDl-DLiB1 and the filtrate deposits 3923 g of crude 11-oxo-112-pyridoxine-2,1-d7-qninazoline-2-carbosyl acid, 3?^ greater than 3*10°. The filter cake is dissolved in 200 ml of IMF containing 10 ml of ammonia, the solution is filtered, and the filtrate is diluted with 15 ml of water and acetic acid to precipitate 3.37 g of 11-Oxo-1H-pyrido-2,1-β-guirazolin-2-carboxylic acid, greater than 510°. The two collections are combined and tritured with ethanol, 3, 3, 4, and acetic acid to give 6.35 g (4-8%) of 11-Oxo-1H-pyrido-2,1-β-guirazolin-2-carbosyl acid, P₃₅₄.

20

- 3ZEEEEE 3 -

ïréparation de 1" 8-metbyl-11-oxo-11S-pyrido^/2 j1-b7-quin azolin e-2-c arb oxyli-nue

An intimate mixture of 5.10 g of 5-bromoanthranilic acid, 6.7 g of 2-chlor-5-3-ethylpyridine, and 67 g of potassium iodide is heated at a bath temperature of 14-5°C for 25-8 hours. After cooling, the mixture is diluted with 15 mL of ethanol and filtered to give 3.57 g (4-5% 3 g of 2-bromo-8-ethyl-11-oxo-1-pyridoxine-2-bitoquinoline at 277-281°C). A mixture of 3.00 g of the above pyridoquinoline and 0.73 g of calcium hydroxide in 21 mL of 5% aqueous DMP is placed in an 85 cm³ Pischer-Porter bottle under a humid atmosphere. Nitric oxide. Approximately 3 ml of nickel carbonyl is added and the bottle is pressurized to 1-1.4 kg/

p N

35 cm" with carbon monoxide. The bath temperature is raised to 115° for 24 hours and, during cooling, the

13

mix with 15 ml of 6N hydrochloric acid. After stirring overnight, filter the suspension and recrystallize the solid collected from the DKF and DMP-ether to give 54 S (67%) of 8-methyl-11-oxo-1-pyridoxine-2,1-beta-quinazoli-5-xie-2-carboxylic acid, Pj» 359° ♦

- EXAMPLE 4 -

Preparation of 2-chloro-5-(1-hydro:xy-1-methylethyl)pyridirium

10. 75 ml of phosphorus chloride and 144 g of phosphorus pentachloride are added to 100 g of 6-chloronicotinoyl acid and mixed thoroughly. The reaction mixture is slowly heated to 80°C in an oil bath for 20 min while stirring. The bath temperature is raised to 125°C, the solution is stirred, and refluxed for 1 h. After concentration under reduced pressure, anhydrous toluene is added, and the solution is concentrated again, ultimately using an oil pump, to give 6-chloronicotinoyl chloride as a colorless solid.

20. This acid chloride is dissolved in 600 ml of anhydrous ether and added dropwise for 2 hours to a methylmagnesium iodide solution prepared from 137 ml of methyl iodide and 50 g of magnesium in 700 ml of anhydrous ether. The reaction mixture is stirred and allowed to flow back.

25 for 3 h. After carefully pouring the cooled reaction mixture onto ice and 200 ml of acetic acid, the aqueous layer is made basic (pE 9) with 425 ml of sodium hydroxide 6If. The ether is separated and the aqueous layer is saturated with sodium chloride and extracted 4 times with ether.

30 After drying the collected extract on anhydrous magnesium sulfate, the extract is concentrated under vacuum to give a yellow solid (112 g). Crystallization of ethyl hexane acetate yields 44.5 g of 2-chloro-5-(1-hydroxy-1-methylethyl)-pyridine, P. 70-74°, £ the first harvest. From

35 ether-hexane-a second harvest of 2-chloro-5-(1-hydroxy-1-methylethyl)pyridine (46.7 Pj> 67-71°)

- [EXAMPLE 5 -

Preparation of 2-chloro-c-iso'-dropenyrp:yridine

A solution of 92.6 g of 2-chloro-5-(1-hydro-1-netethylethyl)pyridine, 4.6 g of p-toluenesulfonic acid monohydrate, and 0.9 g of hydroquinone in 1.5 L of anhydrous xylene is stirred and refluxed under a Dean-Stark water separator for 4.5 h. The xylene solution is washed with a saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The xylene is removed by distillation (40-48°/14 mm) through a Claisen column. Distillation of the residual oil through a Yigreux column gives 75.6 g of pure 2-chloro-5-isopropenylpyridine, 110-114°/8 mm.

~ BXSLÎPLS 6 -

Preparation of 2-bromo-8-isopropyl-11-oxo-11β-pyridoxine/2,1β7 quinazoline

A solution of 86.9 g of 2-chloro-5-isopropenylpyridine and 8.7 g of platinum oxide in 1 liter of ethanol is shaken at atmospheric pressure in a hydrogen atmosphere for 1 h 45 min. The catalyst is removed by filtration and the filtrate is concentrated under vacuum to give an oil. Distillation through a Yigreux column gives 76.0 g of pure 2-chloro-5-isopropylpyridin©, 1-05-109 °/8 mm.

- EXAMPLE 7 -

Preparation of 2-bromo-8-isopropyl-11-oxo-11E-pyridoxine/2,1-b7 quinazoline

A mixture of 58.5 g of 5-bromoanthranilic acid, 42.2 g of 2-chloro-5-isopropylpyridine, and 1.7 g of powdered potassium iodide is stirred and heated at 170°C under argon for 40 min. The bath temperature is then lowered to 165°C for 4.5 h and then to 155°C for 7 h. The solid purple cake is triturated with 250 mL of chloroform, stirred in an ice bath, and filtered to give the product (34.9 g) in the form of bran.

15

Hydrochloride: The latter is suspended in 500 ml of a saturated sodium bicarbonate solution and extracted with methylene chloride. The collected extract is dried over anhydrous magnesium sulfate, briefly stirred with charcoal, filtered, and concentrated under vacuum to give a yellow solid. Crystallization from methylene ether chloride yields 21.8 g of pure 2-bromo-8-isopropyl-11-oxo-1H-pyrido-2s1-b7q uinazoline, P^ 191-194-°, in two harvests.

■10 *^1' ^ ^^P-^E 8 —

Preparation of 8-isopropyl-11-oxo-11-pyrido/2,1-b7- acid

quinazoline-2-carboxviiaue

A mixture of 21.75 g of '2-bromo-8-isopropyl-11-oxo-11H-pyridoxine/5.1-b7g uinazoline and 5.08 g of calcium hydroxide in 200 ml of LMP and 20 ml of water' is placed in a Pischer-Porter bottle under a 15% carbon monoxide atmosphere. Approximately 20 ml of nickel carbonyl solution is added, and the bottle is pressurized.

A bottle at 1.4 kg/cm³ with carbon monoxide. The reaction mixture is stirred and heated in an oil bath at

120° for 1 h; after cooling, it is diluted with 1.2 L of water and 30 mL of hydrochloric acid. After stirring overnight, the suspension is filtered and the resistant solid is absorbed into the LMP and filtered. The filtrate is concentrated under 25° vacuum with an oil pump to give a yellow solid. Water and 5 mL of acetic acid are added, and the product is removed by filtration to give 18.35 g of crude product. Crystallization from methanol gives 15 g of pure 8-isopropyl-11-oxo-1H-pyridoxine-2-carboxylic acid, 30 Ef 312-516°

- EXAMPLE 9 -

Preparation of 2-cyano-8-isopropyl-11-oxo-11H-pyrido//2,1-b7--

quinazoline

35. A solution of 0.412 g of 2-bromo-8-isopropyl-11-oxo-1H-pyridoxine/5,1-b7quino- is shaken and heated at 180°C for 10 h.

16

zoline and 0.233 g of cuprous cyanide in 5 ml of 1-methyl-2-pyrrolidinone. A solution of 0.52 g of ferric chloride hexahydrate and 0.13 g of hydrochloric acid in 0.8 ml of water is added and the mixture is heated at 90° for 30 min. 25 ml of water is added after cooling and the reaction mixture is extracted with chloroform. The extract is washed with 1 N hydrochloric acid, 1 S sodium hydroxide, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow solid that also contains a small amount of 1-methyl-2-pyrrolidinone. Ether is added, and the product is separated by filtration to give 0.24–0 g of 2-cyano-8-isopropyl-11-oxo-11α-pyridoxine, α-207–211°. Preparative thin-layer chromatography gives the pure compound, α 212–214°.

- EXAMPLE 10 -

Preparation of 8-isopropyl-11-oxo-1H-pyridoxine-2,1-β7-quinazoline-2-carboxylic acid

A solution of 0.084 g of 2-cyano-8-isopropyl-11-oxo-11H-pyrido/2,1-β7-quinazoline in 1 ml of acetic acid, 1 ml of concentrated sulfuric acid, and 1 ml of water is stirred and refluxed for 4-5 min. The solution is concentrated to a small volume using an oil pump. After cooling in an ice bath, 50 ml of saturated sodium bicarbonate is carefully added. The mixture is then acidified with acetic acid, and the resulting solid is filtered and washed with water to give 0.063 g of pure 8-isopropyl-11-oxo-1H-pyrido/2,1-β7-quinazoline-2-carboxylic acid.

- EXAMPLE 11 -

Preparation of the hydrochloride of (2-diethylaminoethyl)ester of 8-isopropyl-11-oxo-11H-pyrido/[2,1-β7quinazolin ε-2-carboxylic acid

Dissolve 0.86 g of 2-diethylaminoethyl chloride in 5 ml of water and add 5 ml of a saturated sodium bicarbonate solution. Stir in an ice bath for 5 minutes.

17

This solution is extracted with ether, the extract is dried over anhydrous magnesium sulfate, and concentrated under vacuum to give the base in the form of a colorless oil (0.41 g). This is added to 0.423 g of 8-isopropyl-11-oxo-11H-pyrido-2,1-h7-auinazoline-2-carboyl in 10 mL of anhydrous isopropanol, and the reaction mixture is stirred and refluxed for 3 minutes. After cooling to room temperature, the product is removed by filtration and purified by crystallization from isopropanol and then from 10 methylene ether chloride to give 0.25 g of (2-diethylaminoethyl) ester hydrochloride of 8-isopropyl-11-oxo-11H-pyrido-2,1-h7-auinazoline-2-carboyl. pure quinazoline-2-carboxylic acid, 238-239°o

- EXEIfPLE 12 -15 Formulation of capsules mg/capsule

10 mp;

20 mg

Active ingredient of formula I

10.0

2090

Lactose

215*0

205.0

Mass starch

60.0

60.0

Magnesium stearate

3.0

3.0

ïalc

12.0

12.0

Total :

300 mg

300 mg

25 Rcocédé s

Mix the active ingredient of formula I, lactose, and corn starch in a suitable mixer; grind through a suitable mill; mix with magnesium stearate and talc and feed into an encapsulating machine.

30 ~ EXAMPLE 15 -

Tablet formulation

18

mg/tablet

10 mg 20 mg

Formula I active ingredient 10.0 20.0

Lactose 182.0 172.0

Microcrystalline cellulose 60.0 60.0

Modified starch 15.0 15.0

Corn starch 30.0 30»0

Magnesium stearate 5„0 3<0

Total s 300 mg 300 mg

10 iProeédé

Mix the active ingredient of formula I, lactose, microcrystalline cellulose, modified starch and corn starch in a suitable mixer for 1 to 15 minutes. Then add the magnesium stearate and mix for 5 minutes. Compress on a suitable press.

- TEMPLE 14 -

wet granulation tablet formulation

20 mg/tablet

Active ingredient of Formula I: Lactose 25, Pregelatinized starch, Corn starch, Modified starch, Magnesium stearate

Total

10 mg

20 mg

10.0

20.0

264.0

234.0

17.5

17.5

35.0

35.0

17.3

17.5

6.0

6.0

350 mg

350 mg

30. Process: Mix the active ingredient of formula I, lactose, and pregelatinized starch in a suitable mixer. Grind through a suitable mill. Mix with the modified starch and magnesium stearate and introduce into the encapsulating machine.

Claims (1)

19 EETVEHDIC ATI OITS 10 15 20 25 30 1) A process for preparing new pyridoxine derivatives of general formula where IS2 2^ independently represent a hydrogen, a lower alkanoyl or a lower alkanoyl and represents a cyano, a 5-tetrazoyl, a halogen or a radical of formula 0?! -0-1 •where A represents a hydroxy, a lower alkoxy, a di-(Cv1-Cy)~ alkoylamino-(C2-Cy)alkoxy, a pivaloyloxymethoxy or where IR^ and independently represent a hydrogen, a lower alkanoyl or a di- (C^-Cy )al coyl amin o- ( 0^-0^ )aie oyl e , on the condition that it is different from a halogen when ILj, E2 and represent a lower alkanoyl, the acidic addition salts of this substance usable in pharmacy and, where A represents a hydroxyl, also the salts of this substance formed with a base and usable in pharmacy, a process which involves a) to prepare the compounds of formula I above where I represents a halogen and where I1], 2^ and E^, have the meaning given above, treating a compound of general formula 35 •COOR n 20 where E represents a hydrogen or a lower alkyl group and where X represents a halogen, with a halopyridine derivative of general formula R, II! where E1, B2, E1, and X have the meanings given above, or (b) to prepare the compounds of formula I above where E1 represents a cyanoacrylate and where E1, E2, and E1 have the meanings given above, i.e., the compounds of general formula H1, where E2 and E1 have the meanings given above, by treating a compound of general formula Ib where X' represents bromine or iodine and where E1, E2, and E1 have the meanings given above, with cuprous cyanide, or (c) to prepare the compounds of formula I above where E1 represents a radical of formula C21, O1, C2, where A represents a hydroxyl, i.e., the compounds of general formula H2OC, where H2 and R1 have the meanings given above, by treating a compound of formula Ib above with nickel carbonyl under a carbon monosilicate atmosphere in the presence of an alkaline earth metal hydroxide or to hydrolyze a compound of formula a above, or d) to prepare the compounds of formula I above where R^ represents a radical of formula;O II;-C-A;where A represents a lower alkoxy and where Rg e"^ S3 on^ ^a the meaning given above, to esterify a compound of formula I above, or e) to prepare the compounds of formula I above where R^ represents a radical of formula;O I!;-C-A;where A represents a radical of formula and where R^, R2, R„,;R^ and Rg have the meaning given above, to subject a compound of formula I above to ammonolysis with an amino compound of general formula hhr5r6;(IV);22;where E^ and Eg have the meaning given below, i) to prepare the compounds of formula above where E^ represents a radical formula;0 *1 -G-A where A represents nn di— (C ^ - Cy)aie oylamind-{)a-^Gtxzy ®t where E^ and E^ have the meaning given above, to treat a compound of the formula above with nn halide of di— Vr>)alcoylanxino-(C2-Cr;)3lcoyl or to subject nn acid chloride of a compound of the formula above to an alcoDlysis with a di—(Cvj—Cy)alcqylamino-(C2—Cr^lcanol, on g) to prepare the compounds of formula 1 above where E^ represents a 5-tetrazoyl, and where £2 and E^ have the meaning given above, to treat nn compound of the formula above with an alkali metal azohydride, Or (il.) to prepare the compounds of formula 1 above where E^ represents a radical of formula O <ft -D-A where A represents a pivaloyloxymethoxy and where and 2^ have the meaning indicated above, to treat a compound of the formula above with a tertiary organic base and chloro-, 'bromine-, or iodimethyl pivalate, and 1) if desired, to transform the compound obtained into a salt usable in pharmacy" 2) A method as claimed in the claim 1 or E^j, B2 and Ej independently represent a hydrogen or a lower alkyl group 3) A process as claimed in the claim 2 where at least two of the radicals E^, E2 and E^ are different from a hydrogen •4) A method as claimed in claims 2 and 3 where E^ represents a radical of formula 23 0 I! -THAT where A represents a di-(Cyj-Cr?)alkoylamino-(C2-Cr?)alkoxy or piva-loyloxymeth.oxy0 5.5) A process as claimed in claim 1 where at least one of the radicals ILj, E2 ^ ^3 represents a lower alkanoyl'. 6) A process as claimed in any one of claims 1, 2, 4 and 5 where S2 and E^ represent hydrogen. 10 7) A process as claimed in any one of claims 1, 2, 4 and 6 where E^ represents a lower hydrogen or alkyl group 8) A process as claimed in claim 7 where Ey represents a lower alkyl. 15 9) A process such as that claimed in one of claims 1 to 3 and 5 to 8, where E^ represents a radical of form 0 H -THAT 10) A process as claimed in claim 9 where A represents a hydroxy or di-(C2-)hydroxyl(C2- Cp,) alkoxy. 11) A process as claimed in claim 2 where E2 and E1 represent a hydrogen, E1 represents a lower alkyl and E1 represents a radical of formula 25 0 ^ He -THAT 12) A process as claimed in claim 1 where E2 and E^ represent hydrogen, E^ represents a 30 hydrogen, a lower alkyl or a lower alkanoyl, and E^ represents a radical of the formula 0 J-A where A represents a di-(C^~Cr?)alcoylaciino(C2-Cr;)alkoxy. 24 13) A process as claimed in claim 2, wherein the 8-methyl-11-oxo-11E-pyriao-- acid is prepared 2^2 91 -b7quin azolin e-2-c arboxyli que • 14) A process as claimed in claim 5, wherein 8-isopropyl-11-oxo-11H-pyridoxine is prepared 1-beguinazolin 2-carboxylic acid 15) A process as claimed in claim 12, wherein the (2-diethylaminoethyl)ester of 8-isoprop5rl-11-oxo-11H-pyrido/2s1-b7quinazoline-2-carboxyli- acid is prepared 10 that 16) A process for preparing compositions having anti-allergic properties, characterized in that a pyridoxine derivative of formula I, as defined in one of the claims, is mixed as the active substance. 15 1 to 15 or a salt of this substance usable in pharmacy, with non-toxic, inert solid or liquid carriers, usable in therapy and commonly used in1- such preparations and/or excipients" ORIGINAL in pages \ containing —nor-. Renvots added word «or—word raya null c sJSOQ (C^r José CU R AU Industrial Property Attorneys, 26b,s, Princess Charlotte Blvd., Monte-Carlo By procarifKM? t WofFCIPtNN- LA^oeWs ©ie. ^SceieTt. AnomJKê-