GB2093024A

GB2093024A - 2,3,8-Triazaphenalenium salts and their preparation

Info

Publication number: GB2093024A
Application number: GB8203978A
Authority: GB
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1981-02-13
Filing date: 1982-02-11
Publication date: 1982-08-25
Also published as: ATA47682A; CH653031A5; GB2093024B; FR2499993A1; FR2499993B1; BE892120A; AT381094B; HU183330B

Abstract

2,4,8-Triazaphenalenium salts are described of the general formula… …<IMAGE>… wherein… R<1> stands for C1-4 alkyl or phenyl,… R<2> stands for C1-4 alkyl or phenyl,… R<3> represents C1-4 alkyl, C7-12 aralkyl or phenyl,… R<4> represents hydrogen, C1-4 alkyl,… C7-12 aralkyl, phenyl (optionally substituted by one or more groups which are the same or different and selected from C1-4 alkyl, C1-4 alkoxy, C1-4dialkylamino, halogen, hydroxy and nitro) or… R<3> and R<4> when taken together form a group of the general formula… …<IMAGE>… wherein R<11> is hydrogen or C1-4 alkoxy,… R<5> stands for hydrogen, C1-4 alkyl, phenyl (optionally substituted by one or more groups which are the same or different and selected from C1-4alkyl, C1-4 alkoxy, C1-4 dialkylamino, halogen, hydroxy and nitro),… with the proviso that when R<4> is hydrogen, R<5> is other than hydrogen,… R<6> stands for hydrogen or C1-4 alkyl,… R<7> stands for hydrogen, C1-4 alkyl, phenyl, C2-5 alkoxy-carbonyl or nitrile,… R<8> stands for hydrogen or C1-4 alkyl, and… … … (a) R<9> and R<10> taken together form a chemical bond and X is an anion or … (b) R<10> is hydrogen then X represents -SO3<(-)> attached to the molecule in place of R<9>. … …<??>The compounds of the formula I have anti-asthmatic activity.

Description

1 GB2093024A 1

SPECIFICATION

2,4,8-Triazaphenalenium salts and their preparation The present invention relates to new 2,4,8-triazaphenalenium salts, geometrical and optical 5 isomers thereof and a process for their preparation.

These compounds show antiasthmatic activity and can be thus employed as active ingredients of pharmaceutical compositions for human therapy.

2,4,8-Triazaphenalenium salts have not been disclosed in the prior art and thus the compounds of the invention are the first representatives of this new ring system.

The new compounds can be characterized by the general formula 1 R 3 1 2 1 R R N N R4 X a 1 & R 0 R 6 R9 --V R7 - N_. i R10 a 0 wherein R' stands for C1-4 alkyl or phenyl, 25 R 2 stands for C1-4 alkyl or phenyl (I) R3 represents C,-, alkyl, C7-12 aralkyl or phenyl, R 4 represents hydrogen, C,-4 alkyl, C7-12 aralkyl, or phenyl (optionally substituted by one or more groups, which are the same or different and selected from C,- 4 alkyl, C1-4 alkoxy, C1-4 dialkylamino, halogen, hydroxy and nitro) or R 3 and R 4 when taken together form a group of the general formula R 11W R (V) wherein W' is hydrogen or Cl-4 aikoxy, R 5 stands for hydrogen, C1-4 alkyl, phenyl (optionally substituted by one or more groups which are the same or different and selected from C1-4 alky], C1-4 alkoxy, C1-4 dialkylamino, halogen, hydroxy and nitro), with the proviso that when R 4 stands for hydrogen then R5 is other than hydrogen, R6 stands for hydrogen or C1-4 alky], R 7 stands for hydrogen, C,_4 alkyl, phenyl, C2-, alkoxy-carbonyl or nitrile. R8 stands for hydrogen or C,-4 alkyl, and (a) R' and RIO taken together form a chemical bond and X is an anion (e.g. perchlorate, halide, 45 fluoroborate, nitrate, sulfate, rhodanide, azide or cyanate) or (b) RIO is hydrogen and X represents -SO3G attached to the molecule the place of R9.

The compounds of the formula 1 may be prepared by reacting a compound of the general formula R 1 R 2 N Ir cl)R 6 7 a R Re 7 (I1) wherein W, R 2, R 6, R 7 and R13 are as defined above---with an azomethine of the general formula R3N = CR 4 R 5 (111) wherein R 3, R 4 and R5 are as defined above.

The quaternary chloride obtained-wherein W-W are as given above and R9 and RIO form a chemical bond and X is chloride-may be converted into other compounds of formula (1) by 65 2 GB2093024A 2 methods known per se or if desired by treatment with a compound of the general formuls MeX (IV) (wherein Me stands for an alkali metal, preferably sodium or potassium, alkaline earth metal or 5 ammonium ion and X is as given above) to replace the chloride ion for another X13 anion.

The reaction is preferably performed in an inert organic solvent-in aliphatic or aromatic hydrocarbons, or chlorinated hydrocarbons, ethers, ketones, particularly in acetonitrile or dioxane-at a temperature ranging from - 20-1 00C (e.g. 60-85 C) in equimolar ratio or with a 20-100 molar % excess of the azomethine of the general formula I 11. The product may 10 be isolated for example by filtration, or crystallization followed by the removal of the solvent.

The anion exchange may preferably be performed by admixing a quaternary chloride of the general formula I with an aqueous solution of the salt of the general formula IV at 0 to 25C, and the precipitated product may be isolated by filtration.

The starting compounds of the general formula 11 may be prepared by the method disclosed in 15 BE-PS 873 193 by reacting known nitrogen bridgehead compounds with phosgene-imminium chlorides.

The azomethines of the general formula III may be prepared by a known process: [R.W. Layer: Chem. Rev. 63489 (1963); R. Tiollais: Bull. Soc. Chim. France 708 (1947)].

The optically active forms of the compounds of the general formula I may be prepared by 20 reacting compounds of the general formula 11 prepared from optically active nitrogen bridgehead compounds with azomethines.

The invention extends to the geometrical isomers of the compounds of the general formula I as well. Geometrical isomers may be formed if R11 stands for Cl-, alkyl or R9 stands for SOP and RIO represents hydrogen. The ratio of the formed geometrical isomers depends on the reaction conditions. Under the above conditions generally a mixture of geometrical isomers is obtained which may be separated if desired e.g. by fractional crystallization of chromatography.

The activity of the compounds of the general formula I is shown by the PCA test serving for the determination of the antiasthmatic activity (Ovary.: J. Immun. 81, 355 (1958)]. The tests were performed in rats. The results are summarized in Table 1.

Table 1

Compound PCA test ED.JuIA/kg 35 im.

Compound A Compound B 39.7 100 CompoundA: ll-ethoxycarbonyi-l-dimethylamino-14-methyl-6,7-dimethoxy-12- oxo2,3,4,8b, 12,14,15,1 6-octahydro-isoquinoline[2, 1 -b][2,4,8] triazaphenalenium chloride. (Example 23) Compound B: 6-ethoxycarbonyi-i-dimethylamino-2,9-dimethyl-3-isopropyl-7oxo-2,3,7,9,10,1 1- 45 hexahydro-2,3,8-triaza-phenaleniun chloride (Example 13).

The compounds of the general formula I may be employed in therapy as active ingredient of pharmaceutical compositions which additionally contain one or more inert carriers. The compositions are prepared by methods known per se.

The active ingredient content of the pharmaceutical compositions may vary within a wide range e.g. 0.005 % to 90 %.

The daily dosage may vary within a wide range, and when administered intravenously it is generally from 0. 1 to 10 mg. /body weight kg. in a single or repeated dose.

Further details of our invention are demonstrated by the following Examples, which serve merely for illustration and not for limitation.

Z Example 1

3.25 9. (0.01 mole) of ethyl 9(8H)-[ (N,N-dimethyi-amino)chforomethylene]-8,7-dihydro-6methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate are dissolved in 50 mi. of anhydrous acetonitrile whereafter 0.0 1 mole (1. 19 9) of benzylidene methyl amine is added. The reaction 60 mixture is boiled for three hours and in the course of working up two thirds of the acetonitril are distilled off at atmospheric pressure and the residue is seeded to give crystals, filtered and washed with acetonitrile and air dried. Thus 4.00 g. (0.009 mole) of 1- dimethyl-amino-6 ethoxycarbonyi-3-phenyi-2,3,7,9,1 0, 11 -hexahydro-2,9-dimethyl-7-oxo-2,4, 8-triaza-phenalenium chloride are obtained. M.p.: 232'C (ethanol). In the product the phenyl group in the 3-position 65 3 GB 2 093 024A 3 is in trans configuration relative to the methyl group in the 9-position.

Analysis for the formula Of C23H29C1 NA:

calculated: C 62.08 % H 6.57% N 12.59% found: C 61.89 % H 6.58% N 12.31 % Hnmr (CDC1 J: 1.29 d (3H); 1.33 t (3H); 1.8-3.1 m (41-1); 3.27 s (3H); 3. 73 s (6H); 4.25 q (2H); 5.00 m (1 H); 6.8-7.2 m (5H); 8.27 s (1 H) 9.73 s (1 H).

13 Cnmr (CDC 1 J: 7-C 16 1.4; 11 b-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; 1 la-C 85.7; 3-C 74.8; 9-C 46.6; 2Me,NMe2 42.3; 1 O-C 2 5.3; 11 -C 18.5; 9-Me 15.2 6-COOEt 161.2, 61.1, 13. 9; Example 2 3.25 9. (0.01 mole) of ethyl 9(8H)-[(N,N-dimethyi-amino)chloromethylene)-6,7-dihydro-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3carboxylate are dissolved in 50 mi. of anhydrous ace- tonitrile and then 1. 19 9 (0.0 1 mole) benzylidene-methyl amine are added. The reaction mixture 20 is kept at room temperature for 2 days and evaporated in vacuo at WC. The obtained oil is crystallized with diethyl ether, filtered and washed with ether. Thus 4.13 g. (0.0093 mole) of 1dimethyi-amino-6-ethoxycarbonyi-3-phenyi-2,3,7,9,1 0,11 -hexahydro-2,9dimethy]-7-oxo-2,4,8triazaphenalenium chloride are obtained in the form of a diastereamer mixture. In this mixtue the ratio of the geometric isomers with respect to the relative position of the phenyl group in the 25 3-position and the methyl group in the 9-position is 1A. M. p.: 2 2 7T.

Analysis for the formulaC23H2.Cl N403:

calculated: C 62.08 % H 6.57 % N 12.59 %; found: C 62.19 % H 6.51 % N 12.49 %.

H nmr (CDC13, cis-trans isomer): 1.26d (3H); 1.31t (3H); 1.8-3.1 m (4H); 3.29 s (3.22s) (6H); 3.70 s (3.64s) (3H); 5.00 m (1 H); 6.8-7.2 m (5H); 8. 26s; (8.22s); (1 H); 9.74s (9.69s) (1 H); Example

3.25 g. (0.01 mole) of optically active (-)-ethyl 9(8H)-[(N,Ndimethylamino)-chloromethylene]-6,7-dihydro-6-methyi-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate is used as starting material and method disclosed in Example 1 is followed. Thus 4.00 9. (0. 0090 mole) of (-)-1 dimethyi-amino-6-ethoxycarbonyi-3-phenyi-2,3,7,9,10,11-hexahydro-2,9dimethy i-7-oxo-2,4,8- 40 triaza-phenalenium chloride are obtained.

M.p.: 182-188C (methylethyl ketone); [a]25= (-) 212.6 D Analysis for the formula C23H2.Cl N403:

calculated: C 62.08 % H 6.57 % N 12.59 %, found: C 62.17 % H 6.37 % N 12.45 %.

General method for the preparation of the compounds in Examples 4 to 24 0.01 mole of a-chloro-enamine corresponding to the substituents R', R 2, R6, R 7 and R8 in Table 1 is dissolved in 50 mi. of anhydrous acetonitrile and then 0.01 mole of azomethine corresponding to the substituents R 3, R 4, R5 in Table 1 is added. The reaction mixture is boiled for 2 hours, and two thirds of the acetonitrile are distilled off at atmospheric pressure and if the residue does not crystallize on seeding, the product is crystallized by digesting it with diethyl ether. The product is filtered, washed with ether and air dried. The compounds prepared are shown in Table 1.

Pb.

Table 1

Example RI R 2 R 3 R 4 R5 R 6 R 7 RII Product No. Empirical Yield M.p. Solvent Analysis(%) formula % oc calculated found 4 Me Me Et Ph H H COOR Me C24H31C1N403 90 219 Et 62.80 6.81 12.21 62.63 6.80 12.16 Me Me Be Ph H H COOR Me C2qH33C1 N403 96 242 Et 66.85 6.40 10.75 66.80 6.50 10.70 6 Me Me i-Pr Ph H H COOEI: Me C25H33C1 N403 80 217 A 63.48 7.03 11.85 63.26 6.91 11.81 7 Me Me Pr Ph Me H COOR Me C26H35C1 N403 90 170 A 64.12 7.25 11.50 64.30 7.30 11.20 8 Me Me Me Ph H H COOR Me C24H31C1 N404 95 220 Et 60.69 6.58 11.80 60.58 6.56 11.70 9 Me Me Me Ph Me H COOR Me C24H3IC1 N403 95 207 A 62.80 6.81 12.21 62.96 6.79 12.13 Me Me Me Ph H H COOR Me C25 H 34C 1 N 503 97 210 Et 61.53 7.02 14.35 61.42 7.18 14.42 11 Me Me Me Ph H H COOR Me C26H35C1 N406 65 190 Et 58.37 6.59 10.47 58.17 6.53 10.46 12 Me Me Et i-Pr H H COOEI: Me C2, H 33C 1 N403 84 150-158 A 59.35 7.83 13.18 59.30 7.78 13.36 13 Me Me Me i-Pr H H COOEt Me C20H31C1 N403 80 116 A 58.45 7.60 13.63 58.29 7.58 13.60 14 Me Me Me Ph H H CN Me C2, H24C 1 N 50 97 252 A 63.40 6.08 17.60 63.36 6.31 17.50 Me Me Me Ph Me H CN Me C221-126CIN50 93 217 Ac 64.14 6.36 17.00 64.00 6.39 17.03 1 -.

M Table 1 continued Example R' R 2 R3 R 4 R5 R6 R 7 R8 Product (1) No. Empirical Yield M.p. Solvent Analysis(%) formula % c calculated found 16 Me Me Me i-Pr H H CN Me C,,H2,ClN,,O 87 194 Et 59.41 7.20 19.23 59.36 7.09 19.18 17 Me Me Me Ph H H Ph Me C2eH29C1 NO 83 169 V 69.56 6.50 12.48 69.51 6.71 12.31 18 Me Me Me Ph H H H Me C20H25C1 N,O 86 240 Et 64.42 6.75 15.03 64.38 6.74 15.19 19 Me Me Me Ph H Me Et Me C231-131 NX 10 62 163 Ac 66.57 7.52 13.50 66.32 7.48 13.29 Me Me Ph Ph H H COOR Me C2,3H3IC1 N403 80 190 Ac 66.33 6.16 11.05 66.48 6.08 11,09 21 Me Ph Me Ph H H COOR Me C28H31C1 N403 72 113 Ac 66-33 6.16 11.05 66.17 6.24 11.19 22 Me Me Me Ph H H COOR H C22H27C1 N403 93 218 Ac 61.32 6.31 13.00 23 Me Me R" = OMe H H COOR Me C261-133CIN405 80 161 61.28 6.27 13.03 Ac 60.40 6.4310.84 24 Me Me 1111 = OMe ormula V 60.31 6.40 10.81 R" = OMe H H CN Me H28C1 N 126 Et ff', C24 503 88 1.34 6.81 12.21 1.19 6.96 12.10 Et = ethanol A = acetonitrile Ac = acetone V = water G) C0 m 0 (0 W 0 NJ cl 6 GB2093024A 6 General method for the preparation of the compounds of Examples 25 to 32 4.44 9 (0.01 mole) of 1 -dimethyi-amino-6-ethoxycarbonyi-3-phenyl-2,3,7,9, 1 0,11 -hexahydro2,9-dimethyl-7-oxo-2,4,8-triaza-phenalenium chloride are dissolved in 15 mi. of water, where after a 20 % solution of an alkali metal or ammonium salt containing the desired anion is added dropwise until no further product precipitates. The precipitate is filtered, washed with water and 5 air-dried. The same method may be performed using one of the products of Examples 4 to 24 as the starting material.

Example 25

When using potassium iodine as the compound of the general formula IV 1 dimethyl-amino-6- 10 ethoxycarbonyl-3-phenyl-2,3,7,9, 10,11 -hexahydro-2, 9-dimethyl-7-oxo-2,4,8-triaza-phenalenium iodide is obtained. M.p.: 238-242'C.

Yield: 96%.

Analysis for the formula C23H2,IN403:

calculated: C51.47% H 5.44% N 10.44% found C 51.40% H 5.60% N 10.79%.

Example 26

When using sodium perchlorate as the compound of the general formula IV, 1-dimethylamino-6-ethoxycarbonyl-3-phenyl-2,3,7,9,1 0,11 -hexahydro-2,9dimethyl-7-oxo-2,4,8-triaza- phenalenium perchlorate is obtained.

M.p.: 190-192C, Yield: 92% Analysis for the formula C2,H29C1 N407:

calculated: C 54.28% H 5.47% found C 54.20% H 6.33% N 11.01 %; N 11.33%.

Example 27

When using sodium fluoroborate as the compound of the formula IV, 1dimethyl-amino-6ethoxycarbonyl-3-phenyl-2,3,7,9,1 0,11 -hexahydro-2,9dimethyl-7-oxo-2,4,8-triaza-phenalenium fluoroborate is obtained.

M.p.: 246'C, yield: 90 %. - Analysis for the formual C23H2,BPN403:

calculated: C 55.66% H 5.89% N 11.29 %; found: C 55.32% H 6.01% N 11.40%.

Example 28

When using potassium nitrate as the compound of the formula IV, 1dimethyl-amino-6ethoxycabony]-3-phenyi-2,3,7,9,1 0,11 -hexahydro-2,9dimethy]-7-oxo-2,4,8-triaza-phenalenium nitrate is obtained. M.p.: 232 'C, yield: 65%.

Analysis for the formula C231-12.N.O.:

Calculated: C 57.59% H 6.19% N 14.85 %; found: C 58.60% H 6.23% N 14.59 %.

Example 29

When using potassium cyanate as the compound of the formula IV, 1 dimethyl-amino-6 ethoxycarbonyl-3-phenyl 2,3,7,9,10,11 -hexahydro-2,9-dimethyl-7-oxo-2,4,8- triazaphenalenium 55 cyanate is obtained, m.p.: 193-196C, yield: 78%.

Analysis for the formula C24H2,N504:

calculated: C 63.85% H 6.47% N 15.51 %; found: C 63.51% H 6.72% N 15.38 %.

T Example 30

When using ammonium thiocyanate as the compound of the formula IV, 1dimethyl-amino-6 ethoxycarbonyl-3-phenyl-2,3,7,9,10,11-tetrahydro-2,9-dimethyl-7-oxo,2,4,8tr iaza-phenalenium65 1 r GB 2 093 024A 7 7 calculated: C 61.19% H 6.47% N 21.72 %; found: C 61.30% H 6.10% N 21.07 %.

Example 32

If as a compound of the formula IV sodium hydrosulfite is used than anhydro-1-dimethylamino-3-phenyl -2,3,5,6,7,9,10,11 -octahydro-6ethoxycarbonyl-2,9-dimethyl-5-sulfo-7-oxo-2,4,8- triaza-phenalenium hydroxide is obtained.

M.p.: 210C, yield: 80%.

Analysis for the formula C231-130 N406S:

calculated: C 56.32% H 6.16% N 11.42%; found: C 56.79% H 6.01% N 11.72%.

Claims

1. Compounds of the general formula R 3 R 1 R

2 114 IN R4 xe R 5 R 6...I R9 R10 R 0 Ir 50 thiocyanate is obtained, M.p.: 242T, yield: 72 Analysis for the formula C24H29N503S:

calculated: C 61.65% H 6.25% N 14.98 %; found: C 61.10% H 6.20% N 14.59 %.

Example 31 When using sodium azide as the compound of the formula IV, 1-dimethyl- amino-6-ethoxycar- 10 bonyl-3-pheny 1 -2,3,7,9,10,11 -hexahydro-2,9- dimethyl-7-oxo-2,4,8-triaza-phenalenium azide is obtained. M.p.: 186C, yield: 92 Analysis for the formulaC23H2,N703:

(I) and geometrical and optical isomers thereof, wherein R' stands for C1-4 alkyl or phenyl, R 2 stands for Cl-, alkyl or phenyki, R 3 stands for C,-4 alkyl, C7-12 aralkyl or phenyl, R 4 represents hydrogen, C,-, alky], C7-12 aralkyl, or phenyl, optionally substituted by one or more groups which are the same or different and selected from C1-4 alkyl, Cl-, alkoxy, C1-4 dialkylamino, halogen, hydroxyl and nitro, or R3 and R 4 when taken together may form a group of the formula R 'l Rill)P (V) wherein W' stands for hydrogen or Cl-, alkoxy, R5 represents hydrogen, C1- 4 alkyl or phenyl (optionally substituted by one or more groups which are the same or different and selected from C1-4 alkoxy, C1-4 alky], C,- 4dialkylarnino, halogen, hydroxyl and nitro), with the proviso that 60 when R 4 is hydrogen then R5 is other than hydrogen, R6 stands for hydrogen or C1-4 alkyl, R 7 stands for hydrogen, C1-4 alkyl or phenyl, C2- Olkoxy-carbonyl or nitrile, W' represents hydrogen or C,-4 alky], and (a) R9 and RIO when taken together form a chemical bond and X is an anion, or (b) RIO is 65 hydrogen and X is a -SOJ3 ion attached to the molecule in place of R9.

8 GB2093024A 8 2. Compound as claimed in claim 1 wherein X is a halide, perchlorate, fluoroborate, nitrate, sulfate, rhodanide, azide or cyanate ion.

3. Compounds as claimed in claim 1, said compounds being the products of any one of the Examples herein.

4. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 5 to 3 as active ingredient together with one or more pharmaceutical carriers.

5. A process for the preparation of a compound as claimed in claim 1 in which R9 and RIO together form a chemical bond and X is a chloride ion, which comprises reacting a pyrido (1,2 a]pyrididine derivative of the general formula R 1 R 2 N Ir cl R 6 Q7 R 7 R8 (I1) (wherein R', R 2, R6, R 7 and W are as defined in claim 1) with an azomethine of the general 20 formula R3N = CR 4 R5 (wherein R5 are as defined above).

6. A process as claimed in claim 5 wherein the reaction is performed in an inert organic solvent.

7. A process as claimed in claim 5 or claim 6 in which the reaction temperature is 0 to 100 T.

8. A process as claimed in claim 7 in which the reaction temperature is 60-85T.

9. A process for the preparation of a compound as claimed in claim 1 in which R9 and RIO together form a chemical bond and X is an anion other than chloride or in which RIO is hydrogen and X is - S03-, which comprises treating a compound as claimed in claim 1 in which R9 and RIO together form a chemical bond and X is chloride with a compound of the 30 formula MeX, where Me is an alkali metal, alkaline earth metal or ammonium ion.

i

10. A process as claimed in claim 9 wherein Me is sodium or potassium.

11. A process as claimed in claim 9 or claim 10 wherein X in the compound MeX is as defined in claim 2.

12. A process as claimed in any one of claims 9 to 11 wherein the starting material (in which R9 and RIO together form a chemical bond and X is chloride) is produced by a process as 35 claimed in any one of claims 5 to 8.

13. A process for the preparation of a compound as claimed in claim 1, substantially as described herein in any one of the Examples.

Printed for Her Majesty's Stationery Office by Burgess Et Son (Abingdon) Ltd-1 982. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.

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