CH635100A5 - Process for the preparation of novel pyrido[1,2-a]pyrimidine derivatives - Google Patents

Description

635 100

2nd

PATENT CLAIMS 1. Process for the preparation of new pyrido [1,2-a] pyrimidine derivatives of the general formula

CON

wherein

R represents hydrogen or Ci to Ce alkyl,

R1 is Ci to G> alkyl and R2 and R3 independently of one another are hydrogen, Ci to Cs alkyl or Ce to Cio aryl,

and of their physiologically tolerable salts, characterized in that a pyrimidine derivative of the general formula

CON

-R, (II)

• R "

binding of the general formula I undergoes a racemate separation.

The invention relates to a process for the preparation of new pyrido [1,2-a] pyrimidine derivatives of the general formula

(I)

(I)

bliss

R represents hydrogen or Ci to Cs alkyl,

25 R1 stand for Ci- to Cö-alkyl and

R2 and R3 independently of one another hydrogen, Ci to

Có-alkyl or Có- to Cio-aryl mean as well as their physiologically tolerable salts.

The compounds produced according to the invention have 30 valuable pharmacological effects, e.g. analgesic, anti-inflammatory, PG-antagonistic and antidepressant effects. Some of the compounds also have other beneficial effects on the nervous system and anti-lipemic effects. The process according to the invention is characterized in that a condensed pyrimidine derivative of the general formula in which R, R1, R2 and R3 have the above meaning, or a salt thereof, and if desired a compound of the general formula (I) obtained in a physiologically tolerated salt transferred or released from a salt obtained.

2. The method according to claim 1, characterized in that one carries out the reduction by catalytic hydrogenation.

3. The method according to claim 2, characterized in that the catalytic hydrogenation is carried out in the presence of palladium-activated carbon or Raney nickel as a catalyst.

4. The method according to claim 2 or 3, characterized in that the catalytic hydrogenation is carried out at atmospheric pressure or at an excess pressure of preferably 1 to 15 bar.

5. The method according to claim 1, characterized in that one carries out the reduction with a complex metal hydride.

6. The method according to claim 5, characterized in that sodium borohydride, sodium bis (2-methoxy-ethoxy) aluminum hydride, potassium borohydride or lithium aluminum hydride is used as the complex metal hydride.

7. The method according to any one of claims 1 to 6, characterized in that the reduction is carried out at a temperature between 0 ° C and 150 ° C.

8. The method according to any one of claims 1 to 7, characterized in that an obtained racemate of a ver

wherein R, R ', R2 and R3 have the meaning given above, or a salt thereof, for example by catalytic hydrogenation or with a complex metal hydride, and if desired converting a compound of the general formula (I) obtained into a physiologically tolerable salt or from one released salt released.

Both an optically active isomer and the racemate can be used as the pyrimidine derivative of the formula II.

In the case of catalytic hydrogenation, it can be reduced either at atmospheric pressure or under excess pressure, preferably under an excess pressure of 1 to 15 bar. Palladium, preferably applied to a 65 activated carbon support, or Raney nickel are suitable as catalysts. Sodium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, potassium borohydride, lithium aluminum hydride can be used as complex metal hydrides. At

45

50

55

3rd

635100

of the reduction carried out with complex metal hydrides, the choice of solvent depends on the reducing agent. The reducing media are water, alcohols, preferably methanol or ethanol, and also aromatic hydrocarbons, e.g. Benzene, toluene, or ether, preferably diethyl ether, tetrahydrofuran or dioxane in question.

In the case of catalytic hydrogenation, the reaction mixture is evaporated after the catalyst has been filtered off. If reduction is carried out with complex metal hydrides, the work-up depends on the solvent. After the excess reducing agent has decomposed, the solvent is evaporated if organic solvents are used. When working in an aqueous medium, the reaction mixture is preferably shaken out with chloroform or benzene and the compound of the general formula

(I) obtained by evaporating the organic phase. The condensed pyrimidine derivatives of the general formula (II) or their salts, preferably the hydrochlorides, hydrobromides or methyl sulfates, are used as the starting material. The reaction temperature is advantageously 0 to 150 ° C.

To prepare the pyrido [1,2-a] pyrimidine derivatives of the general formula (I), it is also possible to use optically active condensed pyrimidine derivatives of the general formula

(II) going out.

The new pyrimido [1,2-a] pyrimidine derivatives of the general formula (I) have valuable pharmacological effects and can therefore be used in the pharmaceutical industry. Individual representatives of the connecting group show analgesic, anti-inflammatory, PG-antagonistic and antidepressant activity, while other of the compounds obtainable according to the invention have further beneficial effects on the nervous system as well as an anti-lipemic effect.

The pharmacological results are based on a typical representative of the connecting group, the 1,6m-4-oxo-1,6,7,8,9,9a, ix-hexahydro-4H-pyrido [1,2-a] pyrimidine-3- carboxamide (CH-127) demonstrated. Table 1 summarizes the results of the toxicity study.

Table 1

Toxicity data of 1,6x-dimethyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide

(CH-127)

Species Type of application LDsu (mg / kg)

Table 2

Toxicity values of PROBON ® and CH-127 after intravenous administration see

Compound LDso (mg / kg) mol. molar toxicity m M / kg

PROBON® 220 362.41 0.60

io CH-127 210 223.27 0.94

Table 3 shows the analgesic effect of CH-127 with that of PROBOB® in the hot plate test (J. Pharm. Exp. Is Ther. 80, 130, 1944; Kisérletes Orvostudomâny 2295, 1950), in Table 4 the «writhing» test (Fed. Proc. / 5494, 1956; J. Pharm. Exp. Ther. 133 400, 1961) in mice.

Table 3

20 Comparison of the analgesic effects of PROBON® and CH-127 in the hot plate test on mice

connection

application

ED50 (mg / kg)

ED50 (molar) (mM / kg)

PROBON®

i.V.

52

0.14

S.C.

66

0.18

CH-127

i.V.

13

0.058

s.c.

25th

0.11

Table 4

Comparison of the analgesic effects of PROBON® and CH-127 in the writhing test on mice

35

connection

Appi.

EDso

EDso

Therapist index

(mg / kg)

(mM / kg)

(LD50 / ED50)

PROBON®

p.os

380

1.05

2.9

i.v.

140

0.38

__

s.c.

215

0.59

-

CH-127

p.os

58

0.26

6.2

i.v.

34

0.15

-

s.c.

43

0.19

-

Table 5

Comparison of the anti-inflammatory effects of 50 CH-127 and phenylbutazone in different edema tests on the ball of the rat (Appi .: per os)

Rats peros 370 carrageenin edema IV 210 ss (Proc. Soc. Exp. Biol. 111,

s.c. 280 544.1962)

Mice peros 360

Kaolin edema

(Arch. Int. Pharmacodyn 132 6 "16.1961)

The toxicities obtained in the case of intravenous administration are compared in Table 2 with those of a known analgesic, the PROBON®, the molar values of the intravenous toxicity being given because of the different molecular weights of the two compounds. The table shows that the compound CH-127 is around one and a half times less toxic than PROBON® when administered intravenously

CH-127: EDjo = 15 mg / kg phenylbutazone:

ED30 = 60 mg / kg

CH-127: ED30 = 33 mg / kg phenylbutazone:

ED30 = 95 mg / kg

Dextran edema CH-127: ED30 = 51 mg / kg

(Arch. Int. Pharmacodyn 102 phenylbutazone:

33, 1955) ED30 = 220 mg / kg

The inhibitory effect of CH-127 does not change in adrenal tomated rats (see Table 6), i.e. the anti-inflammatory effect is independent of the endogenous steroids.

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Table 6

The anti-inflammatory effects of CH-127 on normal and adrenalectomized rats (Carrageein edema, Appi, per os)

Dose mg / kg

Edema inhibitory activity in% on normal adrenalectomized patients

Rats rats

25 75

29 50

25 44

As can be seen from the experimental data, the compound CH-127 is more effective in per os application than the analgesic PROBON®, and the therapeutic index is also more favorable.

The analgesic and anti-inflammatory activity of the other compounds of the general formula (I) is similarly good.

The pyrido [1,2-a] pyrimidine derivatives of the general formula (I) can be used in combination with other compounds which have an analgesic, anti-inflammatory or other action. For example, the connections show with morphine, 14-hydroxyazidomorphine, phentanil, indomethacin, azidomorphine, azidocodeine etc. a synergistic effect. This property of the connections has e.g. important for anesthesia during operations.

The compounds of the general formula (I) can be used as active ingredients in pharmaceutical preparations, the preparations containing the customary non-toxic, inert, solid or liquid extenders and carriers.

The preparations can be solid (e.g. tablets, capsules, coated tablets, etc.) or liquid (e.g. solutions, suspensions, emulsions). Suitable carrier substances for this purpose are e.g. Talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, etc. in question.

If desired, the preparations can contain the usual auxiliaries and additives, e.g. Emulsifiers, disintegrants, etc. contain.

The invention is illustrated by the following examples.

example 1

23.5 gl, 6-dimethyl-3- (N-methylcarbamoyl) -4-oxo-l, 6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine are dissolved in 300 ml of ethanol in the presence of 15 g of 10% palladium-activated carbon are hydrogenated at atmospheric pressure and room temperature. After 1 mol of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized twice from ethanol. 1.6eq-Dimethyl-3- (N-methycarbamoyl) -4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [1, 2-a] pyrimidine obtained.

Analysis:

Calculated: Found:

60.74% 60.95%

H H

3.07% 3.03%

N N

17.71% 17.83%

Table 7

The synergistic effect of CH-127 together with other anti-inflammatory substances

connection

dose

% Edema inhibition (carrageenin edema, app .: p.o.)

CH-127

6.25

18th

CH-127

25th

30.4

Indomethacin

2.5

24th

Suprofen

1.25

26.4

Suprofen + CH-127

1.25 + 25

65.7

Indomethacin

2.5 + 6.25

41

+ CH-127

Indomethacin

2.5 +25

83

+ CH-127

Example 2

15 6.6 g of 1,6ax-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are dissolved in 300 ml of methanol in the presence of 4, 5 g of 10% active palladium-carbon are hydrogenated at atmospheric pressure and room temperature. After absorbing 1 mole of hydrogen

20 catalyst filtered off and the filtrate evaporated under reduced pressure. The residue is recrystallized three times from ethanol. There are 2.6 gl, 6eq-dimethyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-py rido [1,2-a] pyrimidine-3-carboxamide obtained at 205 melts up to 206 ° C.

25th

Analysis:

Calculated: Found:

59.18% 59.07%

H H

7.67% 7.68%

N N

18.82% 18.85%

30th

Example 3

The procedure is as described in Example 2, but the starting material used is (-) - 1,6M-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 3-carboxamide 35 ([a] o = -70 °; c = 2, methanol). In 40% yield (-) - 1,6eq-dimethyl-4-oxo-1,6,7,8,9,9a;, »- hexahydro-4H-pyrido [1,2-a] pyrimidin-3 -carboxamide ([aß0 = -227 °; c = 1 in ethanol) obtained, which melts at 221 to 222 ° C.

40 analysis:

Calculated: Found:

C 59.18% C 59.31%

H 7.67% H 7.71%

N 18.82% N 18.80%

45 Example 4

The procedure is as described in Example 2, but the starting material is (+) - 1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine 3-carboxylic acid reamide ([a] D = + 70 °; c = 2 in methanol) was used. In such a 41% yield, (+) - 1,6eq-dimethyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide ([a] p = + 228 °; c = 1 in ethanol). The product melts at 220 to 222 ° C.

55 Analysis:

Calculated: Found:

C 59.18% C 59.19%

H 7.67% H 7.80%

N 18.82% N 18.75%

60 Example 5

14.5 g of the sulfuric acid monomethyl ester salt of (+) - 1,6ax-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [l, 2-a] pyrimidine-3-carboxamide ([a] o of this salt: + 37.5 °; c = 2 in methanol) are dissolved in 150 ml of water, and solution 65 is cooled to below 20 ° C. Then 1.82 g of sodium borohydride in 13 ml of water are added dropwise to the solution, after which the reaction mixture is stirred at room temperature for 2 hours. Then the pH of the solution

5

635100

set to neutral, and the solution is extracted twice with 50 ml of chloroform. The organic phases are combined and evaporated under reduced pressure. The residue is recrystallized from ethanol. 7.8 g (+) - l, 6ax-dimethyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [l, 2-a] pyrimidine-3-carboxamide ([< x] d = + 268 °; c = 1 in ethanol) are obtained.

The product melts at 209 to 210 ° C.

Analysis:

Calculated: C 59.18% H 7.67% N 18.82% Found: C 59.02% H 7.65% N 18.84%

Example 6

The procedure described in Example 5 is followed, with the difference that the starting material is (-) - 1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide-sulfuric acid monomethyl ester salt (Md = -37.5 °; c = 2 in methanol) is used. In 79% yield, (-) - 1,6ax-dimethyl-4-oxo-1,6,7,8,9,9aa.x-hexahydro-4H-pyrido [1,2-a] pyrimidine-3- Obtain car-boxamide, which melts at 209 to 210 ° C [a] p = -2610 (c = 1, ethanol).

Analysis:

Calculated: C 59.18% H 7.67% N 18.82% Found: C 59.25% H 7.71% N 18.78%

Example 7

9.0 g of the salt of l, 6-dimethyl-4-oxo-3- (N-methylcarbamoyl) -l, 6,7,8-tetrahydro-4H-pyrido [l, 2-a] pyrimidine formed with sulfuric acid monomethyl ester dissolved in 100 ml of water. The solution is cooled to below 10 ° C. and 1.8 g of sodium borohydride are added in portions within 15 minutes. The reaction mixture is stirred for 2 hours, then the pH of the solution is adjusted to 3-4 with hydrochloric acid. The solution is extracted with chloroform. The organic phase is dried over sodium sulfate, filtered off and evaporated under reduced pressure. 5.5 gl, 6ax-dimethyl-4-oxo-3- (N-methyl-carbamoyl) -l, 6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine will get. The product melts after recrystallization from ethanol at 177 to 179 ° C.

Analysis:

Calculated: C 60.74% H 8.07% N 17.71% Found: C 60.53% H 8.11% N 17.72%

Example 8

10 g of 1,7-dimethyl-4-oxo-1,6,7,8, -tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are dissolved in 120 ml of water and the solution is made up to Chilled to 20 ° C. Then 2.5 g of sodium borohydride in 20 ml of water are added dropwise to the solution, after which the reaction mixture is stirred at room temperature for 2 hours. Then the pH of the solution is set to neutral and the solution is extracted three times with 50 ml of chloroform. The organic phases are combined and evaporated under reduced pressure. The residue is recrystallized from ethanol. 6 g (89%) of 1.7eq-dimethyl-4-oxo-1,6,7,8,9,9a-hexa-hydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are obtained. The product melts at 242 to 244 °.

Analysis:

Calculated: C 59.18% H 7.67% N 18.82%

Found: C 58.95% H 7.60% N 18.63%

Example 9

20 g of 1,8-dimethyl-4-oxo-l, 6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are dissolved in 240 ml of water and the solution is reduced to below 20 ° C cooled. 5 g of sodium borohydride in 40 ml of water are then added dropwise to the solution, after which the reaction mixture is stirred at room temperature for 2 hours. Then the pH of the solution is adjusted to neutral and the solution is extracted three times with 75 ml of chloroform. The organic phases are combined and evaporated under reduced pressure. The residue is recrystallized from methanol. 12 g (89%) 1,8eq-dimethyl-4-oxo-l, 6,7,8,9,9a-hexahy dro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are obtained. The product melts at 215 to 217 ° C.

Analysis:

Calculated: C 59.18% H 7.67% N 18.82% Found: C 59.26% H 7.76% N 19.03%

Example 10

5 g of 1,8-dimethyl-4-oxo-l, 6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are dissolved in 300 ml of ethanol in the presence of 4.5 g of 10 % palladium-activated carbon hydrogenated at atmospheric pressure and room temperature. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. 3.1 g (90%) l, 8eq-dimethyl-4-oxo-l, 6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide are obtained. The product melts at 215 to 216 ° C. after recrystallization from methanol and shows no melting point depression with the product obtained according to Example 9.

Example 11

5.94 g of N-phenyl-l, 6-dimethyl-4-oxo-l, 6,7,8-tetrahydro-4H-pyrido [l, 2-a] pyrimidine-3-carboxamide are present in 300 ml of ethanol 1 g of 10% palladium-activated carbon, hydrogenated at atmospheric pressure and room temperature. After the uptake of hydrogen has ended, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue consists of 5.9 g (98%) of an oil which slowly crystallizes and is recrystallized from ethyl acetate. N-phenyl-l, 6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide is obtained, which is at 122 to 125 ° C melts.

Analysis:

Calculated: C 68.20% H 7.07% N 14.04% Found: C 68.49% H 7.03% N 13.84%

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