CH653031A5 - 2,4,8-Triazaphenalenium salts and process for their preparation - Google Patents

Description

The present invention relates to new 2,4,8-triazaphenalenium salts, e.g. their geometric and optical isomers and a process for the preparation of the compounds. These compounds have an anti-asthmatic effect and can therefore be used as active ingredients in pharmaceutical preparations in human therapy.

The 2,4,8-triazaphenalenium salts have not hitherto been described in the specialist literature, so the compounds according to the invention are the first representatives of the new ring system.

The new compounds according to the invention can be represented by the general formula s

10th

15

20th

25th

30th

35

40

45

50

55

60

«5

3rd

653031

1 2 R 'R ^ N

e

CD

wherein R3-R5 are as indicated above - and if desired, the resulting compound of the general formula I - wherein R'-R8 are as stated above, R9 and R10 together form a chemical hyphen and s X is chlorine - with a compound of the general formula

MeX

(IV)

be characterized. In the formula, R1 represents alkyl with 1-4 carbon atoms or phenyl,

R2 for alkyl with 1-4 carbon atoms,

R3 for alkyl with 1-4 carbon atoms, aralkyl with 7-12 carbon atoms, or phenyl,

R4 represents hydrogen, alkyl having 1-4 carbon atoms, aralkyl having 7-12 carbon atoms, or phenyl, which may be mono- or polysubstituted by identical or different substituents, namely by Ci-4 alkyl, Ci-4 alkoxy, Ci-4 dialkylamino, halogen , Hydroxyl, or nitro may be substituted or

R3 and R4 together can form a group of the formula

(V)

form what

R11 represents hydrogen or Ci-4 alkyl,

R5 denotes hydrogen, alkyl with 1-4 carbon atoms, phenyl, which may optionally be repeated one or more times by the same or different groups, e.g. can be substituted by Ci-4 alkyl, Ci-4 alkoxy, Ci-4 dialkylamino, halogen, hydroxyl or nitro with the condition that when R4 is hydrogen, Rs is not a hydrogen atom, R6 is hydrogen, Ci-4 alkyl ,

R7 means hydrogen, Ci-4 alkyl, phenyl, C2-s-alkoxycarbonyl, nitrii,

R8 represents hydrogen or Ci-4 alkyl,

R9 and R10 together form a chemical bond or R9 represents -SO3- and R10 represents hydrogen, where, if R9 and R10 together form a chemical bond, X represents halogen, perchlorate, fluoroborate, nitrate, sulfate, rhodanide, azide or cyanate and furthermore, if R9 is -SO3- and R10 are hydrogen, X is zero.

The compounds of general formula I can be prepared so that compounds of general formula

1 2 R R N

R

R '

10 where Me is alkali and X is halogen, perchlorate, fluoroborate, nitrate, sulfate, rhodanide, azide, cyanate or hydrosulfite ion - is implemented. The reaction is preferably carried out in an inert organic solvent, e.g. in aliphatic or aromatic hydrocarbons, in ether, 15 ketone, particularly preferably in acetonitrile or dioxane at -20-100 ° C in an equimolar ratio or with a 20-100 mol% excess of azomethines of the general formula III. The product is e.g. by filtering,

or isolated after removal of the solvent by crystallization.

The anion is preferably obtained by decomposing the quaternary chloride of the general formula I with an aqueous solution of the salt of the general formula IV at 0-25 ° C. exchanged and the excreted product is isolated by filtration.

The starting materials of the general formula II can be prepared from nitrogen bridgehead compounds and phosgene-imminium chlorides by the method described in BE-PS 873 193. The azomethines of the general formula III can be prepared by a method known from the literature: [R. W. Layer: Che. Rev. 63,489 (1963); R. Tiollais: Bull. Soc. Chim. France 708 (1947)].

The optically active compounds of the general formula I can be obtained by reacting the compounds of the general formula II prepared from the optically active nitrogen nitrogen bridgehead compounds with azomethines.

The present invention also relates to the preparation of geometric isomers of the compounds of the general formula I. Geometric isomers are formed if R8 is Ci-4 alkyl or if R9 is SO3- and R10 is hydrogen.

The ratio of the geometric isomers formed depends on the reaction conditions used. Under the reaction conditions given above, a mixture of geometric isomers is usually obtained, the separation of which, if desired, e.g. by fractional crystallization or by chromatography.

The effectiveness of the compounds of the general formula I can be checked by means of a PCA test which serves to determine the antiasthmatic effect. [Ovâry, J .: J. Immun. 81,355 (1958)]. The experiments were carried out on rats. The results are summarized in Table I:

55

Table I

(II)

wherein R1, R2, R6, R7 and R8 are as indicated above - with azomethines of the general formula eo

65

connection

PCATest

ED50 µM / kg

Compound A

39.7

Compound B

100

R3N = CR4R5

(III)

Compound A: 1 l-ethoxycarbonyl-l-dimethylamino-14-methyl-6,7-dimethoxy-12-oxo-2,3,4,8b, 12,14,15,16-octa-hydro-isoquinoline- (2nd , 1 -b) (2,4,8) triazaphenalenium chloride (Example 23)

653031

Compound B: 6-ethoxycarbonyl-l-dimethylamino-2,9-dimethyl-3-isopropyl-7-oxo-2,3,7,9,10,11 -hexahydro-2,4,8, -triazaphenalenium chloride ( Example 13)

The compounds of the general formula I can be used in therapy in the form of pharmaceutical preparations containing the active ingredient and inert carriers. The pharmaceutical preparations according to the invention can be produced by methods known per se.

• The active substance content of the pharmaceutical preparations can be varied within a wide range: 0.005-90%.

The daily dose of active ingredient can be varied within a wide range, in addition to intravenous administration, the dose is generally between 0.1 and 10 mg / body weight kg in a success dose or multiple dose.

The further details of the invention can be found in the examples below without restricting the invention to the examples.

example 1

3.25 g (0.01 mol) of ethyl 9 (8H) - [(N, N-dimethylamino) chloromethylene] -6,7-dihydro-6-methyl-4-oxo-4H-pyrido [1,2-a] -pyrimidine-3-carboxylate are dissolved in 50 ml of anhydrous acetonitrile and 1.19 g (0.01 mol) of benzylidene-methyl-amine is added. The reaction mixture is boiled for 3 hours and 2A of the acetonitrile is distilled off at atmospheric pressure, the residue crystallizes on inoculation, the crystals are filtered, washed with acetonitrile and dried in air. 4.00 g (0.009 mol) of l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-2,9-dimethyl-7-oxo-2 are obtained, 4,8-triaza-phenalenium chloride. Mp: 232 ° C (ethanol). In the product, the phenyl group in the 3-position is in trans-I configuration with respect to the methyl group in the 9-position.

Analysis for the formula C23H29CIN4O3

%: C 62.08; - H 6.57; N 12.59;

Found%: C 61.89; H 6.58; N 12.31.

'Hnmr (CDCh):

1.29 d (3H); 1,331 (3H); 1.8-3.1 m (4H); 3.27 s (3H); 3.73 s (6H); 4.25 q (2H); 5.00 m (IH); 6.8-7.2 m (5H); 8.27 s (IH); 9.73 s (IH);

13Cnmr (CDCh):

7-C 161.4; 1 lb-C 154.4; 5-C 148.9; 1 ~ C 148.5; Ar-C 135.0, 129.1, 128.7, 124.4; 6-C 106.5; Ila-C 87.7; 3-C 74.8; 9-C 46.6; 2-Me, NMe2 6-COOEt 161.2.61.1.13.9;

Example 2

3.25 g (0.01 mol) of ethyl 9 (8H) - [(N, N-dimethylamino) -

chloromethylene] -6,7-dihydro-6-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate are dissolved in 50 ml of anhydrous acetonitrile and 1.19 g (0.01 Mol) of benzylidene-methylamine. The reaction mixture is kept at room temperature for 2 days and evaporated in vacuo at 20 ° C. The oil obtained is crystallized with diethyl ether, filtered and washed with ether. 4.13 g (0.0093 mol) of 1-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11 -hexahydro-2,9-dimethyl-7-oxo- 2,4,8-triaza-phenalenium chloride in the form of a mixture of diastereomers. In the mixture, the ratio of the geometric isomers is 1: 1 when one considers the relative position of the phenyl group in the 3-position with respect to the methyl group in the 9-position. Mp: 227 ° C.

1 Hnmr (CDCb, cis-trans isomer):

1.26 d (3H); 1.311 (3H); 1.8-3.1 m (4H); 3.29 s (3.22 s); (6H); 3.70 s (3.64 s) (3H); 5.00 m (1H); 6.8-7.2 m (5H); 8.26 s (8.22 s) (1H); 9.74 s (9.69 s) (1H);

Analysis for the formula C23H29CIN4O3:

Calc.%: C 62.08; H 6.57; N 12.59;

Found%: C 62.19; H 6.51; N, 12.49.

Example 3

3.25 g (0.01 mol) of optically active (-) ethyl 9- (8H) - [(N, N-dimethylamino) chloromethylene] -6,7-dihydro-6-methyl-4-oxo-4H -pyrido [l, 2-a] pyrimidine-3-carboxylate are used as the starting material. The procedure is as described in Example 1. 4.00 g (0.0090 mol) of (-) - l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-2,9-dimethyl 7-oxo-2,4,8-triaza-phenalenium chloride. M.p .: 182-188 ° C (methyl ethyl ketone), [aß5 = (-) - 212.6 °

Analysis for the formula C23H29CIN4O3

Calc.%: C 62.08; H 6.57; N 12.59;

Found%: C 62.17; H 6.37; N 12.45.

General procedure for the preparation of the compounds of Examples 4-24

0.01 mol of the a-chloro-enamine corresponding to the substituents R1, R2, R6, R7 and Rs of Table 1 are dissolved in 5.0 ml of anhydrous acetonitrile, 0.01 mol of the substituents R3, R4, R5 are added Table 1 corresponding azo methine. The reaction mixture is boiled for 2 hours,% of the acetonitrile is distilled off at atmospheric pressure. If the residue does not crystallize on inoculation, the product is digested with diethyl ether and the crystals thus obtained are filtered and washed with ether and dried in air. The compounds thus prepared are contained in Table 1.

4th

s

10th

15

20th

25th

30th

35

40

45

50

4 Me Me Et Ph H H COOEt Me

5 Me Me Be Ph H H COOEt Me

6 Me Me i-Pr Ph H H COOEt Me

7 Me Me Pr Ph Me H COOEt Me

8 Me Me Me Ph H H COOEt Me

9 Me Me Me Ph Me H COOEt Me

10 Me Me Me Ph H H COOEt Me

11 Me Me Me Ph H H COOEt Me

12 Me Me Et i-Pr H H COOEt Me

13 Me Me Me i-Pr H H COOEt Me

14 Me Me Me Ph H H CN Me

15 Me Me Me Ph Me H CN Me

16 Me Me Me i-Pr H H CN Me

17 Me Me Me Ph H H Ph Me

18 Me Me Me Ph H H H Me

19 Me Me Me Ph H Me Et Me

C \

\ Rs

Product (I)

Empirical yield Schp. Umkrist. Analysis (%)

Formula% ° C solution calculated found medium C H N

C24H31C1N403

90

219

Et

62.80

6.81

12.21

62.63

6.80

12.16

C29H33C1N403

96

242

Et

66.85

6.40

10.75

66.80

6.50

10.70

C25H33C1N403

80

217

A

63.48

7.03

11.85

63.26

6.91

11.81

C26H35C1N403

90

170

A

64.12

7.25

11.50

64.30

7.30

11.20

C24H31C1N404

95

220

Et

60.69

6.58

11.80

60.58

6.56

11.70

C24H31C1N403

95

207

A

62.80

6.81

12.21

62.96

6.79

12.13

C25H34C1N503

97

210

Et

61.53

7.02

14.35

61.42

7.18

14.42

C26H35C1N406

65

190

Et

58.37

6.59

10.47

58.17

6.53

10.46

C21H33C1N403

84

150-158

A

59.35

7.83

13.18

59.30

7.78

13.36

C20H31C1N4O3

80

116

A

58.45

7.60

13.63

58.29

7.58

13.60

C21H24C1N50

97

252

A

63.40

6.08

17.60

63.36

6.31

17.50

C22H26C1N50

93

217

Ac

64.14

6.36

17.00

64.00

6.39

17.03

Cl8H26ClNsO.

87

194

Et

59.41

7.20

19.23

59.36

7.09

19.18

C26H29C1N40

83

169

V

69.56

6.50

12.48

69.51

6.71

12.31

C20H25C1N4O

86

240

Et

64.42

6.75

15.03

64.38

6.74

15.19

C23H31N4C10

62

163

Ac

66.57

7.52

13.50

66.32

7.48

13.29

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General procedure for the preparation of the compounds of Examples 25-32

4.44 g (0.01 mol) of l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,1 l-hexahydro-2,9-dimethyl-7- 5 oxo-2,4,8-triaza-phenalenium chloride are dissolved in 15 ml of water, whereupon the 20% solution of the alkali salt containing the corresponding anion is added dropwise to the solution of the quaternary salt until further precipitation does not occur. The precipitate is filtered, washed with 10% water and dried in air. The procedure is as described above, even if the starting quaternary chloride was a product of Examples 4-24.

15

20th

Example 25

If potassium iodide is used as the compound of the formula IV, the product obtained is l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-2,9-dimethyl-7- oxo-2,4,8-triazaphenalenium iodide. Mp: 238-242 ° C, yield: 96%.

Analysis for the formula C23H29IN4O3

Ber. %: Found%:

C 51.47; C 51.40;

H 5.44; H 5.60;

N 10.44; N 10.79.

25th

Example 26

If sodium perchlorate is used as the compound of the general formula IV, 1-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-30 2,9-dimethyl- 7-oxo-2,4,8-triazaphenalenium perchlorate. Mp: 190-192 ° C, yield: 92%.

Analysis for the formula C23H29CIN4O7:

35 Ber.%: Gef.%:

C 54.28; C 54.20;

H 5.47; N H 6.33; N

11.01 ;. 11.38.

Example 27

If 40 sodium fluoroborate is used as a compound of the general formula IV, 1-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-2,9-dimethyl-7 is obtained -oxo-2,4,8-triazaphenalenium fluoroborate. Mp: 246 ° C, yield: 90%.

45 Analysis for the formula C23H29BF4N4O3

Ber. %: Found%:

C 55.66; C 55.32;

H 5.89; H 6.01;

N 11.29; N 11.40.

50

Example 28

If potassium nitrate is used as a compound of the general formula IV, l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-hexahydro-2,9-dimethyl-7- oxo-2,4,8-triazaphenalenium nitrate. Mp: 55 232 ° C, yield: 65%.

Analysis for the formula C23H29N5O6:

Ber. %: 60%:

C 58.59; C 58.60;

H 6.19; H 6.23;

N 14.85; N 14.59.

Example 29

If 65 cyanate is used as a compound of the general formula IV, 1-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10, ll-hexahydro-2,9-dimethyl is obtained -7-oxo-2,4,8-triazaphenalenium cyanate. Mp: 193-196 ° C, yield: 78%.

7

653031

Analysis for the formula C24H29N5O4:

Calc.%: C 63.85; H 6.47; N 15.51;

Found%: C 63.51; H 6.72; N 15.38.

Example 30

If ammonium thiocyanate is used as a compound of the general formula IV, l-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,10, hexahydro-2,9-dimethyl-7- oxo-2,4,8-triazaphenalenium thiocyanate. Mp: 242 ° C, yield: 72%.

Analysis for the formula C24H29N5O3S:

Calc.%: C 61.65; H 6.25; N 14.98;

Found%: C 61.10; H 6.20; N 14.59.

Example 31

If sodium azide is used as the compound of the general formula IV, l-dimethylamino-6- is obtained.

ethoxycarbonyl-3-phenyl-2,3,7,9,10,11 -hexahydro-2,9-dimethyl-7-oxo-2,4,8-triaza-phenalenium azide. Mp: 186 ° C, yield: 92%.

s Analysis for the formula C23H29N7O3:

Calc.%: C 61.19; H 6.47; N, 21.72;

Found%: C 61.30; H 6.10; N 21.07.

10 Example 32

If sodium hydrosulfite is used as the compound of the general formula IV, 1-dimethylamino-2,3,5,6,7,9,10,11 -octahydro-6-ethoxycarbonyl-2,9-dimethyl-5 is obtained -sulfo-7-oxo-2,4,8-triaza-phenalenium hydroxide. is mp: 210 ° C, yield: 80%.

Analysis for the formula C23H30N4O6S:

Calc.%: C 56.32; H 6.16; N 11.42;

20 Found%: C 56.79; H 6.01; N 11.72.

B

Claims (8)

653031 1 Cl R wherein R1, R2, R6, R7 and R8 as indicated above are with an azomethine of the general formula R3N = CR4R5 (III) wherein R3, R4 and R5 are implemented as indicated above. 1. 2,4,8-triazaphenalenium salts of the general formula 2. A process for the preparation of 2,4,8-triazaphenale-nium salts of the general formula (I) according to Claim 1, in which R4 to Rs are as defined above, R9 and R10 together form a chemical bond and X represents chlorine, thereby characterized in that a pyrido [1,2-a] pyrimidine derivative of the general formula 2nd R wherein R1 stands for alkyl with 1 -4 carbon atoms or phenyl, R2 stands for alkyl with 1 -4 carbon atoms, R3 represents alkyl with 1-4 carbon atoms, aralkyl with 7-12 carbon atoms or phenyl, R4 is hydrogen, alkyl having 1-4 carbon atoms, aralkyl having 7-12 carbon atoms or phenyl which is monosubstituted or substituted one or more times by identical or different substituents from the group alkyl, Ci-4 alkoxy, C1-4 dialkylamino, halogen, hydroxyl and nitro or R3 and R4 together form a group of the formula 11 11 can form in what R11 represents hydrogen or Ci-4 alkoxy, R5 is hydrogen, alkyl having 1-4 carbon atoms, or phenyl which is optionally mono- or polysubstituted by identical or different substituents from the group Ci-4 alkyl, Ci-4 alkoxy, Ci-4 dialkylamino, halogen, hydroxyl and nitro, with the condition that if R4 stands for hydrogen, R5 cannot stand for hydrogen, R6 stands for hydrogen or alkyl with 1-4 carbon atoms, R7 represents hydrogen, Ci-4 alkyl, phenyl, C2-5 alkoxycarbonyl or nitrii, Rs represents hydrogen or Ci-4 alkyl, R9 and R10 together form a chemical bond or R9 represents -SO3 "and R10 represents hydrogen, where, if R9 and R10 together form a chemical bond, X represents halogen, perchlorate, fluoroborate, nitrate, sulfate, rhodanide, azide or cyanate and furthermore, if R9 is -SO3 "and R) is hydrogen, X is zero. 2nd PATENT CLAIMS 3. The method according to claim 2 for the preparation of 2,4,8-triazaphenalenium salts of the general formula I, wherein R4-Rs are as indicated above and R9 and R10 together form a chemical bond and X represents chlorine - characterized in that reacting a pyridopyrimidine derivative of the general formula II, in which R1, R2, R6, R7 and R8 are as indicated above, with an azomethine of the general formula III, in which R3-R5 are specified in claim 1, in the presence of a solvent. 4. The method according to claim 3, characterized in that reacting the pyridopyrimidine derivative of the formula II with the azomethine of the formula III at 0-100 ° C, preferably at 60-85 ° C. 5. A process for the preparation of 2,4,8-triazaphenale-nium salts of the general formula (I) according to claim 1, characterized in that a 2,4,8-triazaphenale-nium salt of the general formula (I) , wherein R'-R8 are as stated above, R9 and R10 together form a chemical bond and X represents a chlorine, according to the process of claim 2 and the compound obtained with a compound of the general formula MeX (IV) where Me is alkali and X is halogen, rhodanide, azide, cyanate, perchlorate, fluoroborate, nitrate or sulfate. 6. The method according to claim 5, characterized in that the 2,4,8-triazaphenalenium of the general formula (I), in which X represents chlorine, obtained with the compound of the general formula (IV) in the presence of a solvent, is preferred of water. 7. A process for the preparation of geometric isomers of 2,4,8-triazaphenalenium salts of the general formula (I) according to claim 1, characterized in that a mixture of geometric isomers of compounds of the formula (I), in which R8 for Ci -4 alkyl, or R9 is SO3 and R10 is hydrogen, separates into the geometric isomers. 8. The method according to claim 7, characterized in that the separation of the geometric isomers is carried out by fractional crystallization or by chromatography.