FI73216B - ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV KONDENSERADE PYRIMIDINDERIVAT, DERAS OPTISKT AKTIVA ISOMERER OCH FYSIOLOGISKT GODTAGBARA SALTER. - Google Patents

Description

1 73216

A new process for the preparation of condensed pyramidine derivatives, their optically active isomers and physiologically acceptable salts 5 Separated from patent application 771 940.

The invention relates to a new process for the preparation of condensed pyrimidine derivatives, their optically active isomers and their physiologically tolerable salts.

The compounds according to the invention have valuable pharmacological properties, for example analgesic, anti-inflammatory, PG-antagonistic and antidepressant. In addition, some of the compounds have beneficial effects on the nervous system and an antilipemic effect.

It is known from the literature (Arzneimittelforschung 22 (1972) 815, HU patent 168 018, DE patent 2 320 377) that the starting materials of the formula (III) of the present invention have two reactive centers, namely 2 NH groups in the 1-position and the HN group of the acid amide group R in the 3-position, and that the alkylation or acylation can take place at both positions.

It has now surprisingly been found that the alkylation of the compounds of formula (III) can be carried out regioselectively in the 1-position with a very good yield of the final product.

The compounds of the invention have the general formula (I)

30 pr S

o 1 2 wherein R is alkyl of 1 to 4 carbon atoms and R is hydrogen or methyl.

2 73216

The invention further includes optically active isomers of the compounds of general formula (I) as well as physiologically tolerable salts.

The compounds of general formula (I) are prepared according to the invention by reacting an optionally racemated or optically active condensed pyramidine derivative of general formula (III),

B

10 2

, T | / R

CHr <^ N, J "C0NX (III)

o H

Wherein R is as defined above, reacting a halide of general formula IVa R1-X (IVa) wherein R is as defined above and X is halogen or a sulphate of general formula IVb, (r1) 2so4 (IVb) wherein R is as defined above. above or with a phosphate of the general formula IVc 25 1 (R) 3 PO 4 (IVc) 35 in which R is as defined above, preferably in the presence of an acid-binding agent, and the racemate of the general formula (I) thus obtained is, if desired, decomposed into optically active substances in a manner known per se and / or the compound of general formula (I) thus obtained is converted into its physiologically tolerable salts.

In J. Chem. Soc. The following reaction is described by Perkin Transactions I, 1974, p. 1753: 3,73216

Me T | + Me2S04__. Meso: kYN'TXc ° NH. Y'NV ^ CONH2 ->

Me 0 Me 0 5

We reduction f J j m NaBH. ^ k \

10 4 ^ CONH

Me O 2 In this reaction, tetrahydropyridopyrimidine-3-acid amide is not N-alkylated with dimethyl sulfate, but N-quaternary-15 is triturated, so that the acid amide group is not quaternized. The Hek-sahydro compound is prepared in the next step by reduction.

Instead, according to the present application, the compounds are 1-N-alkylated and not N-quaternized.

20 The process according to Arzneimittelforschung 22 (1972) p. 815 alkylates an ester derivative having only one alkylatable N atom and having the formula: 25 l

γί1γΛ COEt Me O

The compounds of formula III, on the other hand, have two N atoms, which is why the regioselectivity of alkylation causes major problems. The reactivity of both NH groups has also been demonstrated in the above-mentioned publication, in which case both NH groups are acylated.

The method of the present invention is described in J. Chem. Soc. Perkin Transactions I

Both new and inventive compared to the method described in 4,73216. The yield of the process of the present invention is 80.5%, the yield of the known process is only 56.7%. Another disadvantage of the known method relates to the laa-5 of the quaternary salt. Its melting point is according to the publication 175-176 ° C, however, when prepared in chloroform 200 ° C. Moreover, the quaternary salt is not stable enough. This decomposes very easily when the ring is opened (Magyar Kemikusok Lapja 31 (1976), pp. 281-292) or through the transformation of the ring 10 (Tetrahedron Letters (1979), pp. 1337-1338). These reactions are accelerated under basic conditions, such as by NaBH4.

Me Γ 0H "e 15 Meso '| ^ 1] I I h, and I„ X - *

Y'11 Y ^ CONII, - Ύ ...... r "cOtlH

I H 2 Me O z

Me O L

20 Me i I> ί J = CHNHMe

tr

ΤΠ 2 Me O

Me O

25

In the process according to the invention, the pyramidine derivative of the general formula (III) is treated with substances suitable for attaching a group R to a molecule. Thus, for example, all halides of the general formula (IVa) can be used. Chlorides, bromides or iodides are preferably used. The group r "* can also be attached by reacting the starting material with sulfates of general formula (IVb) or phosphates of general formula (IVc). The reaction is preferably carried out at a temperature of 20 to 250 ° C and in the presence of a diluent. The reaction is preferably carried out in the presence of an acid acceptor. Suitable acid acceptors are, for example, alkali metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, or metal hydrogens carbonate, preferably sulfates or phosphates of formula (IVc) or in the presence of water, alcohols, ketones, dimethylformamide, aromatic hydrocarbons, formamide, hexa-10-methylphosphoric triamide, acetonitrile or mixtures of these solvents.

In order to isolate the condensed pyrimidine derivatives of the general formula (I) thus obtained, the reaction mixture is treated in a manner known per se.

The hexahydro compounds of the general formula (III) used as starting materials are prepared from 6,7,8,9-tetrahydropyrido-pyrimidines by reduction with NaBH 4.

The compounds of formulas (IVa), (IVb) and (IVc) are commercially available chemicals.

The condensed pyrimidine derivatives of the general formula I have valuable pharmacological properties, as a result of which they can be used in the pharmaceutical industry. Individual members of the group of compounds have analgesic, anti-inflammatory, PG-antagonistic and Antide-25 repressive properties, while some other compounds of the invention further have beneficial effects on the nervous system as well as antilipemic effects.

The pharmacological activity of the compounds of this invention is illustrated by experiments performed using a representative representative of these compounds in the 1,6-dimensional

3X

style 4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [2-a] pyrrole

aX

mididine-3-carboxamide (CH-127). The results of the toxicity study are presented in Table 1.

Table 1 35 Toxicity values for 1,6-dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide (CH-127) 6,73216

Species Route of administration LD ^ oral 370 rat intravenous 210 subcutaneous 280 5 mice oral 360

Equivalent values for 1-ethyl-6-methyl-4-oxo-1,6,7,8,

dX

9,9a-Hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid

3.X

acid dide (compound of Example 2) and 1-n-butyl-10 6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido

3X 3X

For β-1,2-α-pyrimidine-3-carboxylic acid amide (compound of Example 4) were 420 and 700 mg / kg (experimental animals were rats and the test compound was administered orally).

The toxicity values obtained for intravenous administration of CH-127 are compared in Table 2 with the toxicity values of a known analgesic compound, PROBO1 · ^, whereby due to the different molecular weights of the compounds, intravenous toxicity values are also given. The table shows that CH-127 is about 11/2 times less toxic than PROBOi / ® when administered intravenously.

Table 2

Toxicity values for PROBO1 ^ and CH-127 (intrave administration) 25 Compound LDj.q mg / kg Molecular weight Molar toxicity mM / kg PROBOlP 220 362.41 0.60 CH-127 210 223.27 0.94

Table 3 shows the analgesic activity values of compound (CH-127) and PROBON® obtained using the "hot plate" test (J. Pharm. Exp. Ther. 80, 130/19 4 4_7; Kiserleti Orvostudomany 2 , 295/19507) · The experimental animals were mice.

Table 3 35 Analgesic results obtained using the hot plate test in mice 7 73216

Compound Method of Administration ED5q m <? / Kg Molar ED 2 QraM / kg PROBON® Intravenous 52 0.14 Subcutaneous 66 0.18 CH-127 Intravenous 13 0.058 5 Subcutaneous 25 0.11

Table 4 compares the analgesic effect of the two compounds in the "writhing" experiment (Fed. Proc. 15, 494 719567; J. Pharm. Exp. Ther. 133, 400 / fl961j).

Table 4 10 Analgesic results obtained using the writhing test in mice

Compound Method of administration ED ™ Molar Therapeutic index- mg7Kg ED, .- mM / kg si LDqn / ED ^ n PROBOtP oral 380 1.05 2.9 ^ intravenous 140 0.38 subcutaneous 215 0.59 CH-127 oral 58 0 , 26 6.2 intravenous 34 0.15 subcutaneous 43 0.19 - 2q Table 5 compares the anti-inflammatory effect of CH-127 and phenylbutazone. The anti-inflammatory effect was studied by the known "rat paw edema" method, and the drugs were administered orally.

Table 5 25 Carrageenan-Edema ED30 = 15 mg / kg CH-127 (Prov. Soc. Exp. Biol. ED3C = 17 mg / kg CH-127 (+) 1 1 1, 544 ^ 19627) ED3Q = 11.5 mg / kg CH-127 (-) ED3q = 24 mg / kg Compound of Example 2 30 E ^ 30 = m? / kg Compound of Example 4 ED30 = ^ m9 / kg phenylbutazone

Kaolin-Puff ED3Q = 33 mg / kg CH-127 (Arch. Int. Pharmacodyn, 35 132, 16/19617) EE30 = Ng / kg phenylbutyl, ...... soni

Dextran base ED3Q = 51 mg / kg CH-127 (Arch. Int. Pharmacodyn, 102, 33/19557) ED50 = 220 m <? / Kg phenylbutazone β 73216

Table 6 below illustrates that the inhibitory effect of CH-127 is unchanged in adrenal-deprived rats, i. the anti-inflammatory effect is independent of endogenous steroids.

5 Table 6 Effect of CH-127 on normal and adrenal-deprived rats (carrageenan-Pöhö, oral)

Dose mg / kg Normal Edema inhibition (%) 10 adrenal deprived rats 25 29 25 75 50 44

Table 7 shows the synergistic effect of CH-127 when mixed with another anti-inflammatory drug.

Table 7

Compound Dose mg / kg Prevention of edema (carrageenan-Edema, oral) 20 CH-127 6.25 18 CH-127 25 30.4

Indomethacin 2.5 24

Suprofen 1.25 26.4 CH-127 + 1 6.25? 41

25 IndomethacinJ 2.5 J

CH'127 * 1 25 {83

IndomethacinJ 2.5 J

CH-127 *? 25 -) 65_7

Suprofen J 1.25) The experimental results presented in the tables above show that CH-127 is more effective in mice than the analgesic PROBO1 ^ without oral administration and also has a better therapeutic index.

Other compounds of general formula I also have equally advantageous analgesic and anti-inflammatory properties.

9 73216

The fused pyrimidine derivatives of the general formula (I) are useful in combination with other analgesic, anti-inflammatory or the like. The compounds of formula I have been shown to have a synergistic effect e.g. with morphine, 14-hydroxyazidomorphine, fentanyl, indomethacin, azidomorphine, azidocodeine, etc. This property of the compounds is of great importance, for example, in anesthesia in connection with surgery.

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

The formulations may be solid (e.g. tablets, capsules, dragees, etc.) or liquid (e.g. solutions, suspensions, emulsions). Suitable carriers for this purpose are, for example, talc, calcium carbonate, magnesium stearate, water, polyethylene glycol, etc.).

The preparations may, if desired, contain conventional excipients and additives, for example emulsifiers, disintegrants, etc.

The invention is illustrated by the following non-limiting examples.

Example 1 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-

clX clX

4H-Pyrido / 1,2-α-pyrimidine-3-carboxamide is suspended in a solution of 2 g of sodium hydroxide in 65 ml of water, while 95 g of dimethyl sulphate and a solution of 4 g of sodium hydroxide in 25 ml of water are added separately dropwise. to the reaction mixture. The reaction mixture is stirred for one hour, after which the pH is adjusted to seven by adding 10% by weight of hydrochloric acid. The aqueous solution is shaken with chloroform. The combined chloroform solution is dried over sodium sulfate and concentrated under reduced pressure. This gives 10.8 g of 1,6-dimethyl-4-oxo-1,6,7, α, ,9 8,9,9a-hexahydro-4H-pyrido [2 H] -pyrimidine-3-carboxy-ax amide. . After recrystallization from ethanol (twice), m.p. is 185-186 ° C.

5 Analysis:

Calculated: C 59.18 H 7.67 N 18.32% Found: C 58.95 H 7.69 N 18.85%

Example 2 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,19a -hexahydroxy ax 10 4H-pyrido [1,2-a] pyrimidine-3-carboxamide are suspended in a solution of 2 g sodium hydroxide in 65 ml of water, while 11.5 g of diethyl sulfate and a solution of 4 g of sodium hydroxide in 25 ml of water are added separately dropwise to the reaction mixture. The reaction mixture is stirred for 15 hours, after which the pH is adjusted to 7 by adding 10% by weight of hydrochloric acid. The aqueous solution is shaken with chloroform. The chloroform extracts are concentrated under reduced pressure to give 9.9 g of 1-ethyl-6

CLX

methyl 4-oxo-1,6,7,8,9,9aav-hexahydro-4H-pyrido [1,2-e] ax 20 pyrimidine-3-carboxamide. The melting point after recrystallization from isopropanol is 162-163 ° C.

Analysis:

Calculated: C 60.74 H 8.07 N 17.71% Found: C 60.58 H 8.08 N 17.85% Example 3 10.2 g 6-methyl-4-oxo-1,6,7,8 , 9,9a_ ^ -hexahydro-

clX clX

4H-Pyrido [1,2-a] pyrimidine-3-carboxamide and 27.3 g of triethyl phosphate are stirred at 235 ° C in the presence of 6.4 g of potassium carbonate. When gas evolution has ceased, the reaction mixture is poured into 150 ml of water and the aqueous solution is shaken with chloroform. The combined chloroform extract is concentrated under reduced pressure to give 8.5 g of 1-ethyl-6ax-methyl-4-oxo-1,6,7,8,9,9aax-hexahydro-4H-pyrido [1,2-a] pyrimidine. 3-carboxamide. Isopropanol after recrystallization is m.p. 163 ° C. The product does not cause a decrease in spin when mixed with the product of Example 2.

Example 4 10.2 g of 6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-

9.X 9X

4H-Pyrido [1,2-a] pyrimidine-3-carboxamide in 125 ml of ethanol, 25 g of n-butyl bromide and 7.5 g of potassium carbonate are heated under reflux for 30 hours. The reaction mixture is filtered and concentrated under reduced pressure to give 8.5 g of 1-n-butyl-6-methyl-4-oxo-1,6,7,8,9,9a-ax σ.χ 10 hexahydro-4H-pyrido / 1,2 1,2-α7-pyrimidine-3-carboxamide, m.p. is 160-162 ° C.

Analysis:

Calculated: C 63.37 H 8.74 N 15.84% Found: C 63.08 H 8.83 N 15.78%.

Claims (2)

12 7321 6 1. A new process for the preparation of condensed pyrimidine derivatives of the general formula I and their optically active isomers and physiologically acceptable salts, R1 N n. II R2 (I) 10. II / RN c ° N ^ ch3 γΐ ^ wherein R is alkyl of 1 to 4 carbon atoms and 2 is hydrogen or methyl, characterized in that optionally in the form of a racemate or optically active condensed pyrimidine derivatives of the general formula (III), H 2 O- I (ui) .N. J-CON 2 ch 3 Nr Xh 0 2 25 wherein R is as defined above, reacting a halide of general formula IVa, R 1 -X (IVa) wherein R 1 is as defined above and X is halogen or a sulphate of general formula IVb, (R 1 ) 2SO 4 (IVb) 35 wherein R 1 is as defined above or with a phosphate of general formula IVc, i3 7321 6 \; (R1) 3PO4 (IVc) wherein om as defined above, preferably in the presence of an acid scavenger and if desired, the racemate of general formula 5 (I) thus obtained is decomposed in a manner known per se into optically active forms and / or the compounds of general formula (I) thus obtained are physiologically converted acceptable salts. Process according to Claim 1, characterized in that said acid-binding agent is an alkali metal hydroxide, preferably sodium hydroxide or potassium hydroxide, an alkali metal carbonate, preferably sodium carbonate or potassium carbonate, or an alkali metal hydrogen carbonate, preferably sodium hydrogen carbonate or potassium hydrogen carbonate. Process according to Claim 1 or 2, characterized in that the reaction is carried out at a temperature of 20 to 250 ° C. 14 7321 6 1. For example, a compound of the pyrimide formulation of the lower form of sub-formula (I) contains 5 optically active isomers and physiologically acceptable salts of the form Rri ^ r1 / NS— CON 10 ch3 0 1 7 i vilken formula r R alkyl group 1- 4 cholomers, and R or V, or methyl, are converted to a compound, Figure 15 is a condensed pyrimidine derivative of the lower form (III), optionally in the form of a racemate or an optically active former, H 20 2 ^ I I / R (III) .N. JS — ccmJ ch - o 35 color R is defined as a phosphate with a lower formula (IVc) 25 color R is defined as a halide with a basic formula (IVa) R1-X (IVa) 30 color R is defined and X is halogen or a sulfate of the lower formula (IVb) (R1) 2S04 (IVb)