FI71937C - Process for Preparation of New Analgesic and Anti-Inflammatory Effects 1,6eg / or 1,7eg or 1β-dialkyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido / 1,2a / pyrimidine-3-carboxamide derivatives. - Google Patents

Description

1 71937

Method for the development of new analgesically and anti-inflammatory 1,6 / or 1,7 or 1,8 7-dialkyl-4-eq-eq_eq'_ oxo-1,6,7,8,9,9a-hexahydro- For the preparation of 4H-pyrido (1,2a) -pyrimidine-3-carboxamide derivatives 5

By division separated from the application 77 1940.

The invention relates to a process for the preparation of new formulas of formula I.

analgesically and anti-inflammatory 1.6 / or 1.7 or 1,8 / dialkyl-4-oxo-eq eq eq 12 1,6,7,8,9,9a-hexahydro-4H- for the preparation of pyrido [1,2a] pyrimidine-3-carboxamide derivatives and their optically active isomers and pharmaceutically acceptable salts, 15 N o CH II <

3 J I

C0N

1 2 20 wherein R is C 1-6 alkyl and R is hydrogen, C 1-4 alkyl or phenyl.

The symbol "eq" indicates that the 1,6, 1,7 or 1,8 alkyl groups are in the same plane as the ring system. From J. Chem. Soc. Perkin Transactions I 25 (1974), pp. 1753-6, is known for (-) - 1,6-dimethyl-4-oxo-

CLX

1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide with 1,6-methyl groups and a ring system at different levels. Said known compound has not been reported to have therapeutic properties.

The compounds of formula I, as well as their optically active isomers and pharmaceutically acceptable salts, can be prepared by reacting 1,6 / or 1,7 or 1,8β-dialkyl-4-oxo-1,6,7,8-tetrahydro-4H -pyrido [1,2-a] pyrimidine-3-carboxamide derivative of the formula 2 71937 E1 ir ^ / 'N -.

ch3 and II

v! —CONHR2 X!

O

Wherein R and R are as defined above, or a pharmaceutically acceptable salt or optically active isomer thereof, is catalytically reduced, after which, if desired, the compound obtained is converted into an optically active isomer and / or a pharmaceutically acceptable salt.

The catalytic hydrogenation can be carried out at atmospheric pressure or low overpressure, preferably at 1-15 atm, at a temperature of 0-150 ° C and in a suitable organic solvent or acidic aqueous medium. Palladium, preferably palladium / carbon or Raney nickel, can be used as the catalyst.

The obtained compounds are separated from the reaction mixture by filtering the catalyst and evaporating the reaction mixture.

The process uses a compound of formula II or an optically active isomer or a pharmaceutically acceptable salt thereof, preferably chloride, bromide, methyl sulfate, etc., as the starting material for the reaction.

The starting materials of the formula II are described in HU-pa-25 patent publications 156 119, 158 085, 162 384, 162 373 and 166 577 and in NL patent publication 7 212 286 or they are known per se (Arz. Forsch. 22, 815/192727). > or they can be prepared by known methods.

The therapeutic properties of the compounds of formula I are shown in Tables 1 and 2.

Table 1 shows 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2a] pyrimidine-3-carboxamide ((-) -, (+) - and ( -) - forms) pharmacological activity. Toxicity experiments were performed using 35 Wistar rats (weight 120-150 g) in groups of 10 rats with both male and female representatives. LD. »- Values

BU

II

3,71937 (48 hours) was determined by the Litchfield-Wilcoxon method. The antiphlogistic activity of the compounds was determined by the method of Winter (Proc. Soc. Exp. Biol. 1962, 111, 544) using the carrageenan paw fever test in the rat, in which 5 test compounds were administered orally to experimental animals.

table 1

Acute toxicity and anti-inflammatory activity as determined by the rat carrageenan paw test 10 Compound ^^ 50 Inflammation p.o. inhibition _mg / kg_dose effect (-) 1,6E-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-580 100 mg 55% pyrido / 1,2a / pyrimidine-3- carboxamide (+) - 1,6-N-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H 480 100 mg 54% pyrido (T, 2a) pyrimidine-3-20 carboxamide -) - 1,6eq-dimethyl-4-oxo 1,6,7,8,9,9a-hexahydro-4H-590 100 mg 50% pyrido / 1,2a7pyrimidine-3-carboxamide_ 25 Phenylbutazone_470_100 mg_45%

Table 2 compares the properties of the compounds of the formula I with 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-pyro- [1,2-a] pyrimidine methylsulfate, known from DE-A-1795769. (Probon-) to the like.

4,71937

Table 2

Rat Carrageenan Paw Test j LD P-o of formula I. i ED_. jTherapeutic 5! compound (e.g.) 30 LD50, mg / kg; mmool / kg irg / kg; ____ lia / kcj__30 1 2 580; 2.59 and 70; 0.31 8.36 and 4,480; 2.15 and 85; 0.30 5.67 j j 3__590; 2,64_ | 75; 0.34 _ 7.77_ 10 j Probor ^ (reference 1240-1600, -3.42-4.44j 290, -0.80 4.28-5.55 i compound) __! _ (___:

The table shows that the therapeutic index of the compounds of the formula I is considerably better than that of the compound known from DE-A-1795769.

The compounds of the invention may be used in compositions comprising a compound of formula I, an optically active isomer thereof or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. The carrier may be either solid or liquid, and the composition may be in solid form, for example, tablets, capsules, granules, etc .; in liquid form, for example, solutions, suspensions, emulsions, etc. Conventional carriers such as talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, etc. may be used in the compositions.

The compositions may, if desired, contain conventional excipients such as emulsifiers, disintegrants, etc.

The compounds of the formula I can also be combined with other active substances, such as, for example, other analgesic, antiphlogistic, etc. compounds. The compositions thus obtained are synergistically effective. The compounds of formula I have a synergistic effect with, for example, morphine, 1,4-hydroxyazidomorphine, fentanyl, indomethacin, azidomorphine, azidocodeine, etc.

Il 5 71 937

The invention is illustrated by the following examples. Example 1

A solution of 23.5 g of 1,6-dimethyl-3- (N-methylcarbamoyl) -4-oxo-1,6,7, -8-tetrahydro-4H-pyrido (1,2a) -5-pyrimidine In 300 ml of ethanol, is hydrogenated in the presence of an animal-carbon catalyst containing 15 g (10% by weight) of palladium at room temperature at atmospheric pressure.

After consumption of one mole of hydrogen, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized twice from ethanol to give 1,6-dimethyl-3- (N-methylcarbamoyl) -4-oxo-eg 1,6,7,8,9,9a-hexahydro-4H-pyrido ( 1, 2a) pyrimidine, o ax m.p. 203 ° C-204 ° C.

Analysis: 15 Calculated: C 60.74% H 8.07% N 17.71% Found: C 60.95% H 8.03% N 17.83%.

Example 2 6.6 g of 1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-

dX

4H-Pyrido (1,2a) pyramidine-3-carboxamide in 300 ml of 20 methanol in the presence of 4.5 g of palladium in 10% by weight of animal carbon catalyst is hydrogenated at atmospheric pressure and room temperature. After consumption of one mole of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethanol three times. 2.6 g of 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido (1,2a) pyrimidine-3-dX-carboxamide are obtained, m.p. is 205 ° -206 ° C.

Analysis:

Calculated: C 59.18% H 7.67% N 18.82% Found: C 59.07% H 7.68% N 18.85%.

Example 3

Following the procedure of Example 2, but using (-) - 1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-20 ° 4H-pyrido (1,2a) -pyrimidine-3-carboxamide / <c7D = -70; 35 c = 2, methanol) as starting material, (-) - 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido (1,2a) pyrimidine

CLX

ne-3-carboxamide. Sp. is 221 ° C-222 ° C, yield: 40%.

71937

Analysis:

Calculated: C 58.18% H 7.67% N 18.82% Found: C 59.31% H 7.71% N 18.80%.

Example 4 Following the procedure of Example 2, but starting from (+) - 1,6-dimethyl-4-oxo-1,6,7,8-

3.X

tetrahydro-4H-pyrido (1,2a) pyrimidine-3-carboxamide + 70 °; c = 2, methanol) to give (+) -1,6β-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido (1,2a) pyrrole-10 mididine-3-carboxyamide, m.p. is 220 -222UC. Yield: 41%; + 228 °; c = 1, ethanol.

Analysis:

Calculated: C 59.18% H 7.67% N 18.82% Found: C 59.19% H 7.80% N 18.75%.

15 Examples 5-7

By proceeding in the same manner as in the method described in Example 2, but using 1,7-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide as a starting material, 1.7-20 dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide. Sp. 244 ° C (recrystallized from methanol), yield 59%.

Elemental analysis:

Calculated: C 59.15 H 7.68 N 18.82 Found: C 59.02 H 7.74 N 18.95 Using 1,8-dimethyl-4-oxo-1,6,7,8-tetrahydro as starting material -4H-pyrido [1,2-a] pyrimidine-3-carboxamide is obtained from 1,8-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2 -a7pyrimidiini-3-karboksaraidi. Sp. 215-216 C.

Using N-phenyl-1,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide as starting material, N-phenyl-1 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide. Sp. 122-125 ° C, yield 5.9 g.

Il

Claims (3)

A process for the preparation of novel 1,6 / or 5,7 or 1e ®eq7-dialkyl-4-oxo-1,6,7,8,9,9a-hexahyde compounds of the formula I which have analgesic and anti-inflammatory activity. - for the preparation of ro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide derivatives and their optically active isomers and pharmaceutically acceptable salts, R1 io Ύ ^ Ν Ί ch ·! 2 I 3 N -CONHR 0 1 2 in which R is C 1-6 alkyl and R is hydrogen, alkyl or phenyl, characterized in that 1.6 / or 1.7 or 1.87 "dialkyl-4-oxo-1, 6,7,8-Tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide derivative of the formula 1 R 20 CH3 'M-CONHR2 ιτ N & 1 2 wherein R and R are as defined above, or a pharmaceutically acceptable salt or optically active isomer thereof is reduced from the catalytic process, after which, if desired, the obtained compound is converted into an optically active isomer and / or a pharmaceutically acceptable salt.