NO129298B - - Google Patents

Description

Analogy method for the production of

therapeutically effective pyrazolo (1,5-b)-phthalazine-

1,5 (10H)-diones.

The present invention relates to an analogue method for the production of therapeutically effective pyrazolo (1,5-b)-phthalazine-

1,5 (lOH)-diones with the formula:

wherein R 1 and R 2 are selected from hydrogen, lower alkyl, halo-lower alkyl, benzyl, phenyl and lower aliphatic acyl, and wherein R 1 and R 2

together with the attached nitrogen atom can also form a saturated 5-6-membered heterocyclic ring which can contain one or two hetero-

atoms selected from nitrogen and oxygen, R^ is selected from hydrogen,

halogen, lower alkyl, phenyl and lower-aliphatic acyl, and Ru represents hydrogen, lower alkyl and phenyl.

According to the invention, the compounds of formula I are prepared by bringing a phthalazine compound of the formula: where R^ has the above meaning, into contact with an equimolar amount of an acyl chloride of the formula: where R^ and R'2 are the same as R. ^ and R2 other than hydrogen and acyl, R'^ represents halogen, lower alkyl and phenyl, in an inert organic solvent in the presence of a tertiary amine. The reaction time may vary depending on the acyl chloride used,

but usually from 2-6 hours is sufficient to complete the reaction. Benzene, toluene, xylene and other cyclic, unsaturated hydrocarbons can be used as said solvent, although oxygenated solvents such as dioxane and tetrahydrofuran can also be used. The preferred tertiary amines are tri-lower alkylamines, such as trimethylamine, triethylamine, etc., although aliphatic amines such as tris-CB-hydroxyethyl)amine or heterocyclic amines such as piperidine or morpholine can also be used. The reaction is preferably carried out at room temperature.

Said pyrazolophthalazinones prepared as described above can, if desired, be subjected to further treatment, thereby modifying the substituent groups attached to the 5-ring.

These modifications can be carried out by commonly known methods, and can lead to the formation of compounds which are also included in the present invention.

When R'2 is halogen, the 2-halogen compound can thus be hydrogenated in the presence of palladium on charcoal as a catalyst,

at room temperature and atmospheric pressure. This wears it out accordingly

2- unsubstituted pyrazolo-phthalazinon which, if desired, can be converted into the corresponding 2-acyl derivative by treatment with a carboxylic acid chloride or acid anhydride.

Furthermore, when R'^ and R'2 are benzyl radicals, these can be cleaved off by catalytic hydrogenation in the presence of palladium on charcoal as a catalyst. This hydrogenation can be carried out in a lower alkanol solution at temperatures from 50 to 100°C and at a pressure varying from 10 to 50 atmospheres. The 3-amino derivative obtained can, if desired, be converted into the corresponding 3-acylamino or diacylamino derivative by treatment with a carboxylic acid chloride or acid anhydride in the presence of an excess of a tertiary base.

In addition to the following exemplified compounds, the following pyrazolophthalazinones are representative and can be prepared by the methods set forth herein: 2-methyl-3-dipentylamino-1H-pyrazolo[1,2-b]phthalazine-1,5 (1OH)-dione ,

2-methyl-3-di-tert-pentylamino-1H-pyrazolo[1,2-b]-phthalazine-1,5(10H)-dione,

2-phenyl-3-dibutylamino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-phenyl-3-pyrrolidino-1H-pyrazolo[1,2-b]phthalazine-1,5~

(1OH)-dione,

2-phenyl-3-piperidino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-phenyl-3-morpholino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-chloro-3-dipropylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione,

2-chloro-3-dibutylamino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-chloro-3-(N-phenyl-N-methylamino)-1H-pyrazolo[1,2-b]-phthalazine-1,5(1OH)-dione,

2-chloro-3-pyrrolidino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-chloro-3-morpholino-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione,

2-methyl-3-piperidino-10-methyl-1H-pyrazolo[1,2-b]-phthalazine-1,5(10H)-dione,

2-chloro-3-diethylamino-10-methyl-1H-pyrazolo 11,2-b]-phthalazine-1,5(1OH)-dione,

2-chloro-3-pyrrolidino-10-methyl-1H-pyrazolo[1,2-b]-phthalazine-1,5(10H)-dione,

2-methyl-3-piperidino-10-phenyl-1H-pyras;olo[1,2-b]-phthalazino-1,5(10H)-dione,

2-methyl-3-diethylamino-10-phenyl-1H-pyrazolo[1,2-b]-phthalazino-1,5(10H)-dione,

2-chloro-3-pyrrolidino-10-phenyl-1H-pyrazolo[1,2-b]-phthalazine-1,5(10H)-dione.

Compounds produced according to the present invention have high anti-inflammatory, analgesic and antipyretic activity coupled with low toxicity. When the new derivatives were tested on rats, remarkable activity was achieved in carrageenin and granuloma pallet samples. It was found that the compounds were pharmacologically active per os even at doses that were from 10 - 12 times less than the toxic dose, which in rats varies from 500 to 1000 mg/kg per os.

The preferred route of administration is oral or rectal, although other routes can also be used. In the first case, the compounds are processed into pharmaceutical doses in the form of

tablets, capsules, elixirs, solutions or the like. The dosage unit can contain the usual diluents such as starch, gum, alcohols, sugars, fatty acids, etc. Furthermore, the rectal route has proven to be very suitable, and the compound is supplied in this case in the form of a suppository, optionally mixed with usual diluents, such as coconut butter, wax, spermaceti or polyoxyethylene glycols and their derivatives.

The dose range. is from 0.05 to 1.0 g/day, preferably administered in divided doses.

The following examples illustrate the invention.

Example 1

2-Methyl-3-diethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione.

A solution of 98.5 g of 3,4-dihydro-1(2H)-phthalazinone and 157.7 g of triethylamine in 4600 ml of anhydrous toluene cooled to 0°C,

163 g of 2-(α-chloro-α-diethylaminomethylidene)-propionyl chloride in 500 ml of anhydrous toluene was slowly added over 30 minutes. The temperature was slowly raised to room temperature and the reaction mixture stirred for 2 hours. After this, the liquid was filtered, washed three times with water and made anhydrous over sodium sulfate. The solvent was then distilled off in vacuo, and the residue crystallized from acetone. The yield was 132.4 g (69.6#) of 2-methyl-3-diethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione, mp 125-127°C. Example 2

2-butyl 3-diethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione.

14.b g of 3,4-dihydro-1(2H)-phthalazinone dissolved in a mixture of 29 ml of triethylamine and 300 ml of anhydrous dioxane was reacted at 5-10°C with 33 g (75$ w/w) of 2-[ α-chloro-α-diethylaminomethylidene]-caproyl chloride in 100 ml of anhydrous toluene, essentially by the method described in example 1. The yield was 24.5 g (75.0%) of 2-butyl-3-diethylamino- 1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione, boiling point 190°C/0.6 mm Hg.

Example 3

2-Methyl-3-dimethylamino-1H-pyrazolo-[1,2-b]phthalazine-1,5(10H)-dione.

This compound was prepared by the method as stated in example 1 from 14.8 g of 3,4-dihydro-1(2H)-phthalazinone and 18.2 g of 2-(α-chloro-α-dimethylaminomethylidene)-propionyl chloride. Yield 20.8 g (81.0$) of 2-methyl-3-dimethylamino-1H-pyrazolo[1,2-b] phthalazine-1,5(10H)-dione, m.p. 142-144°C.

Example 4

2-butyl-3-dimethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione.

This compound was prepared via the method as stated in example 1 from 12.7 g of 3,4-dihydro-1(2H)-phthalazinone and 19.3 g of 2-(tx-chloro-α-dimethylaminomethylidene)caproyl chloride. The yield was 20.1 g (78.2%) of 2-butyl-3-dimethylamino-1H-pyrazolo[1,2-b]-

phthalazine-1,5(10H)-dione, m.p. 114.5 - 117.5°C

Example 5

2-phenyl-3-dimethylamino-1H-pyrazolo[1,2-b7phthalazine-1,5(10H)-dione.

This compound was prepared by the method indicated in Example 1 from 19>1 g of 3,4-dihydror1(2H)-phthalazinone and. 45 g (75% w/w) of 2-(α-chloro-α-dimethylaminomethylidene)-2-phenyl-acetyl chloride. The yield was 31.5 g (76.5%) of 2-f en<y>1^-dimethyl-amino-1H-pyrazolo/-!, 2-;b7phthalazine-1,5(10H)-di^^ sm .p. 152 - 153°C.

Examples 6-23

The following compounds were prepared by the method indicated in Example 1.

Example 24

3-diethylamino-1H-pyrazolo[_>1,2-b7phthalazine-1,5(10H)-dione.

1.5 g of 2-chloro-3-diethylamino-1H-pyrazolo/-1,2-b/phthalazine-1,5(10H)-dione was dissolved in 150 ml of glacial acetic acid and hydrogenated in the presence of 0.75 g of 10% palladium on charcoal as a catalyst. The mixture was then filtered and the filtrate evaporated in vacuo to dryness. The residue consisting of 3-diethylamino-1H-pyrazolo[1,2-b7phthalazine-1,5(10H)-dione was recrystallized from acetone. Yield l.l8 g (.88.7 fo), sm.p. 135 - 137°C.

The following compounds were prepared by the method indicated in Example 2A: 25) 3-dimethylamino-1H-pyrazolo[1,2]phthalazine-1,5(10H)-dione m.p. 171-3°C (from acetone). Yield: 85%. 26) 3-morpholino-1H-pyrazolo[1,2-b/f thalazine-1,5(10H)-dione.

sm.p. 235-8°C (from ethanol). Yield: 87%.

Example 27

2-acetyl-3-diethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione

4 g of 3-diethylamino-1H-pyrazolo[1,2-b]-phthalazine-1,5-(1OH)-dione was acetylated by refluxing the compound for 1.5 hours with 8 ml of acetyl chloride. The excess of acetyl chloride was then distilled off in vacuo, the residue dissolved in 200 ml of benzene, after which the benzene solution was first washed with a 10% sodium bicarbonate solution and then with water. The organic phase was separated, dried over sodium sulphate, after which the benzene was distilled off in vacuo. The residue which consisted of 2-acetyl-3-diethylamino-1H-pyrazolo/. 1,2-b/phthalazine-1,5(10H)-dione was recrystallized from methanol. Yield: 3.7 g. (80.0 %), m.p. I74 - 176°C.

Example 28

2-acetyl-3-dimethylamino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione.

By using the method indicated in example 27> and using 3-dimethylamino-1H-pyrazolo[1,2-b/phthalazine-1,5(10H)-dione, the compound 2-acetyl-3-dimethyl-amino -1H-pyrazolo/~"1,2-b7phthalazine-1,5(10H)-dione melting at 201 - 204°C (from methanol), the yield was 63%.

Example 29

a) 2-Methyl-3-methylamino-1H-pyrazolo/<->1,2-b/phthalazine-1,5(10H)-dione. b) 2-methyl-3-(N-acetyl-N-methyl)amino-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione. a) 6.6 g of 2-methyl-3-(N-benzyl-N-methylamino)-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione were dissolved in 100 ml of ethanol and

hydrogenated during 7 hours at 75°G under a pressure of 35 atmospheres in the presence of 0.8 g of 10% palladium on charcoal as a catalyst. The mixture was then filtered, and the solution concentrated to dryness in vacuo. The residue was recrystallized from methanol and 3.1 g (64.4%) of 2-methyl-3-methylamino-1H-pyrazolo/""1,2-b/f thalazine-1,5(10H)-dione was prepared , sm.p. 207 - 209°C.

b) The corresponding 3-N_acetyl derivative was prepared by a treatment with acetic acid chloride or acetic anhydride in the presence of

an excess of triethylamine according to conventional methods. Sm.p.

216 - 218°C (from acetone). Yield 85%;

Example SO

a) 3-ethylamino-2-methyl-1H-pyrazolo[1,2-b]phthalazine-1,5(10H)-dione. b) 3-(N-acetyl-N-ethyl)amino-2-methyl-1H-pyrazolo[-1,2-b]phthalazine-1,5(10H)-dione. a) The compounds were prepared by the same method as stated under example 29. 3-ethylamino-2-methyl-1H-pyrazolo[-1,2-b]-phthalazine-1,5(10H)-dione melts at 151 - 152°C ( from ethanol). The yield was 79%. b) 3(N-acetyl-N-ethyl)amino-2-methyl-1H-pyrazolo[1,2-b/-phthalazine-1,5(10H)-dione melts at 151 - 154°G (from acetone ).

The yield was 91%.

Example 31

a) 3-amino-2-methyl-1H-pyrazolo[_>1,2-b/phthalazine-1,5(10H)-dione

b) 3-acetylamino-2-methyl-1H-pyrazolo/<->1,2-b/phthalazine-1,5(10H)-dione c) 3"diacetylamino-2-methyl-1H-pyrazolo/~1 ,2-b/phthalazine-1,5(1H)-dione a)<1> By hydrogenating 3~dibenzylamino-2-methyl-1H-pyrazolo/~1,2-b/phthalazine-1,5(10H) -dione for 7 hours at 100°C and under 50 atmospheres of pressure and by using the same procedure as in example 29, two equimolar amounts of hydrogen were absorbed. 3-amino-2-methyl-1H-pyrazolo[1, 2-b]phthalazine-1,5(10H)-dione which melts at 241 - 245°C (from ethanol) in a yield of 75%.

b) The 3-acetylamino and 3-diacetylamino derivatives of the above-mentioned compounds were obtained by respectively treating with

one or two equimolar amounts of acetyl chloride and an excess of triethylamine.

3-Acetylamino-2-methyl-1H-pyrazolo[1,2-b]phthalazine-1,5-(1OH)-dione melts at 220 - 222°C (from acetone). The yield is H0%.

3-diacetylamino-2-methyl-1H-pyrazoloIl,2-b]phthalazine-1,5(10H)-dione melts at 162-163°C (from acetone-diethyl ether 3/1).

The yield is 47%•

Example 32

3-amino-1H-pyrazolo-[1,2-b]phthalazine-1,5(10H)-dione

By using the same procedure as indicated in the example

31 a) and by consuming 3 equimolar amounts of hydrogen, got

impure 2-chloro-3-dibenzylamino-1H-pyrazolo[1,2-b]-phthalazine-1,5(10H)-dione was prepared, which was then hydrogenated using the method in example 22 to 3-amino-1H --pyrazolo[1,2-b]phthalazine-1,5(10H)-dione. Melting point 283 - 285°C (from n.butanol).

Dividend: 20%.

Claims (1)

Analogous process for the preparation of therapeutically effective pyrazolo[1,5_b]-phthalazine-1,5(10H)-diones with the formula: where and R2 are selected from hydrogen, lower alkyl, halo-lower-alkyl, benzyl, phenyl and lower-aliphatic acyl, and where R-^ and R^ together with the associated nitrogen atom can also form a saturated 5-6-membered heterocyclic ring which may contain one or two heteroatoms selected from nitrogen and oxygen, R^ is selected from hydrogen, halogen, lower alkyl, phenyl and lower-aliphatic acyl, and Rjj represents hydrogen, lower alkyl and phenyl, characterized by bringing a phthalazine compound with the formula: 4 where Rjj has the meaning given above, in contact with an equimolar amount of an acyl chloride with the formula: where R^ and R'2 are the same as R1 and R2 except for hydrogen and acyl, R'j represents halogen, lower alkyl and phenyl, in an inert organic solvent in the presence of a tertiary amine, and where optionally: a ) when R'^ is halogen, hydrogenates the 2-halogen compound in the presence of palladium on charcoal as a catalyst, and, if desired, converts the resulting 2-unsubstituted pyrazolo-phthalazinone compound into the corresponding 2-acyl derivative by treatment with a carboxylic acid chloride or anhydride , or b) when R^ and R'2 are benzyl radicals, cleave off these radicals by catalytic hydrogenation in the presence of palladium on charcoal as catalyst, and, if desired, convert the 3-amino derivative obtained into the corresponding 3-acylamino or diacylamino derivative a treatment with a carboxylic acid chloride or anhydride in the presence of an excess of a tertiary base.