LU82437A1 - GEMINED DIHALOGEN DERIVATIVES OF 4 CONDENSED PYRIMIDINE-ONE COMPOUNDS, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Description

L-2508

8 0 /. * 7 7 GRAND-DUCHY OF LUXEMBOURG

Cl 0 of 09.05.1980 Monsieur the Minister of the Economy and the Middle Classes

Title issued ......................................... Intellectual Property Service

^ §§7 LUXEMBOURG

Patent Application I. Application CH.I.NOIN ..... GYOG.YSZER ... ES ..... VEGYESÄE.TI.-TERMEKEK ..... GYÄRÄ ..... RT , .., .......................................... (1), 1-5, ...... To * "utca, 1045 Budapest, ..... Hungary ,,, ...... represented by ............... .......

Jean Waxweiler, 2ï-25 Allée Scheffer, Luxembourg, acting in ^ qû'ality '"' dë" "ïnandataïre .......................... .................................................. .................................................. ....... .....................

s deposit (s) this neu ^ may nineteen hundred and eighty ................................... ... (3) at ..... 15. ,, 00 ...... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining an invention patent concerning: ........................................... .................................................. .................................................. .................................................. .. (4) “Dihaloaën derivatives ..... gemini ..... of condensed compounds ..... of pyrimidine-one 4________________, preparation process and pharmaceutical compositions containing ..... these. ' .................................................. .................................................. ........... ..........

2. the delegation of power, dated ............. Budapest____________________ I _____________ May 2, 1980_______ 3. the description in ÎU.UUçai language is ........... .................... of the invention in two copies; 4 ....... L ....................... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office on ..... nine..may-mil ..... nine · ..... cen-t.-quatre-quatre. .................................................. .................................................. ...........

declares (s) assuming responsibility for this declaration, that the inventor (s) is (are): ....................... .................................................. .................................................. .................................................. .................................................. .................................................. ... (5) (see appendix) claims (s) for the above patent application the priority of one (or more) application (s) of (6) ........ patent ...... .................................................. ..... deposited in (7) ................... Hungary ................. .................................................. .............

on ......... eleven-may ..... mi.l .... ne.uf ..... hundred ..... sixty ..... nineteen .. ... under ... on ..... no ........................... (8) ...... .......... CI-1932 ............................. Λ ....... .........................., ....................... ......, ........................................... ...............................AT.................. .......................................

in the name of TERMEKEK GYARA RT (9) elect (elect) for him / her and, if appointed, for his / her representative, in Luxembourg ...................... ..............

Jean Waxweiler, 21-25 Allée Schef fer, Luxembourg _ (io) - * request) the issue of a patent for invention for the subject Written and represented in the abovementioned appendices, - with postponement of this issue to ... .................................................. ...........month. (11) t The .................. agent ^ ..................

U, Minutes of Filing

The above application for a patent for invention has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, on: 09.05.1980 ^ Pr- the Minister at 15.00 ^ g ^ gg / £ > / the Economy and of \ \ Average Causes, l§: ^ ¾ Al

r «-l r lût ·:% fi V

u rD - '. i,? /., / V

CLAIM OF PRIORITY

Filing of the patent application in Hungary from May 11, 1979 to number CI-1932

DESCRIPTIVE MEMORY FILED IN SUPPORT OF A PATENT INVENTION APPLICATION IN THE GRAND DUCHY OF LUXEMBOURG

by; chinoin gyogyszer es vegyeszeti termekek gyara r.t.

S s / / f s S

GEMINED DIHALOGEN DERIVATIVES OF COMPOUNDS

for; of pyrimidine-one 4 condenses, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.

- 1 - Μ '

The present invention relates to dihalo ooi .fOS '' 3 derivatives of condensed genes, gemines of / pyrimidine-one 4, a process for their preparation and pharmaceutical compositions containing them. These compounds are valid intermediates for the synthesis of compounds having anti-allergic and / or anti-static properties and some of their representatives have analgesic, anti-effects; inflammatory, slow down 11 a-aggregation of platelets, ant: atherogenic ^ antiasthnatic and / or anti-allergic.

- It is well known that certain condensed lapyrimidine derivatives exhibit analgesic and other CNS activities (see UK Patent No. 1,209,946). A typical representative of these compounds is the ishosulfate d1 (ethoxycarbonyl) 3 dimethyl 1,6 oxo 4 tetrahydro 6,7,8,9- 4H-pyrido [1,2-a) pyrimidinium (PROBON, Rimazolium) which has excellent analgesic properties and is widely used in therapy (Arzneimittel Forschung 22/1972/815).

According to a characteristic of the present invention, compounds having the general formula are produced:

(R1 I

0 - 2 - where R represents hydrogen, lower alkyls or lower alkoxy carbonyls.

R ^ · represents hydrogen, lower alkyls, carboxy groups, ester groups, or derivatives thereof, cyano, phenyl or 4 halogen groups.

2 R represents hydrogen, lower alkyls or phenyls.

X represents a halogen.

/ n is an integer equal to 0, 1 or 2.

/ and the optically active enantiomorphs thereof.

The expression “lower alkyl” used here for the alkyl groups or the groups containing an alkyl, such as the alkoxy groups, generally designates the C1-6 hydrocarbons, preferably saturated aliphatic with straight or branched chain, such as the methyl groups, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, etc.

The expression "derivative of a carboxyl group" designates the derivatives of carboxylic acids such as alkoxycarbonyl for example, lower alkoxycarbonyl, aryloxycarbonyl, aral- -3-koxycarbonyl or other esters, carbamoyl groups optionally substituted by one or two alkyl groups ( for example lower alkyl), aryl, or aralkyl groups. cyano, carboxylic acid, hydrazido or / hydroxamic acid (- CO-NHOH).

The expression "aryl" used as such or in groups containing the aryl group such as aryloxy can for example designate aromatic groups Cg_ ^ Q optionally substituted such as phenyl or naphthyl or substituted derivatives thereof.

The expression "aralkyl" used as such or in groups containing the aralkyl group, such as aralkyloxy, can ^ for example, denote: alkyl substituted by phenyl or naphthyl, such as benzyl, (3 -phenyl -ethyl, d , β-diphenyl -ethyl,, diphenyl-ethyl, etc.

The expression "halogen" designates chlorine, chromium or 2 'iodine.

Preferred compounds according to the invention are compounds of general formula I where R represents hydrogen, lower alkyl, preferably methyl; R *** represents a carboxy group, a lower alkoxy-carbonyl, preferably methoxy-carbonyl or ethoxy-carbonyl. cyano, carbamoyl, lower alkyl, preferably methyl, phenyl, R represents hydrogen, lower alkyl, preferably methyl, X represents chlorine or bromine? n is an integer equal to 0, 1 or 2.

The compounds of general formula I containing carboxy groups form salts with pharmaceutically acceptable bases, such as alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts , such as calcium or magnesium salts, ammonium salts and with organic amines such as triethylamine salts, ethanolamine salts etc.

The optical isomers of the compounds of general formula I are also within the limits of the invention.

The new compounds of general formula I, their pharmaceutically acceptable salts and the optically active isomers thereof can, for example, be prepared according to the following methods (a) or (b), which methods constitute another characteristic of the present invention : a) a monohalogenated compound of the general formula:

X

11 (where 1 2 R, R, R, X and n are defined above); reacts with a halogenating agent; or b) a compound of the general formula: h ^ YhYr2 0 - 5 - (where R, R1, r2 and n are defined above) reacts with a halogenating agent and, if desired, in a compound of the general formula I obtained, we transform a group r! in another grouping r! and if desired, a racemate of the general formula I is transformed into * its optically active enantiomorphs.

According to process a) a compound of the general formula% (II) - where R, R1, R2, X and n are defined above - reacts with at least an equivalent amount of a halogenating agent. Preferably the halogenating agent is used in an amount of 1 to 1.5 molar equivalents.

According to method b) a compound of the general formula (III) - where R, R1, R2 and n are defined above - reacts with at least two molar equivalents of a halogenating agent.

The preferred amount of halogenating agent is 2 to 2.5 molar equivalents calculated for the compounds of formula (III).

As the usual halogenating agents, halogenating agents known in the art can be used.

Elemental halogens such as bromine, chlorine or iodine, halogenated compounds such as bromine-chlorine, iodine-chlorine, etc. and other halogenated derivatives such as sulfuryl chloride, phosphorus pentachloride, N-chloro-succinimide, N-bromo-succinimide, N-iodo-succinimide, dibromo 1,3 dimethyl 5, hydantoin, N-bromo-caprolactam, sulfuryl bromide and sulfuryl trichloromethane chloride, tert-butyl hypochlorite, hypobromite and hypoiodite, tetrachloro 1,2,4,6 acetanilide, dibromo 1,2 tetrachloroethane, copper (II) bromide and chloride, halogenated complexes such as perbromide pyridinium bromide , phenyl trimethyl ammonium perbromide, tetramethy -6- ammonium tribromide, dioxane dibromide, hydro 2 pyrrolydone tribromide, etc. are preferably used, optionally in the presence of a catalyst, for example a Lewis acid, aluminum bromide and aluminum chloride, phosphorus trichloride, sulfur, calcium dioxide, UV irradiation, peroxide / dibenzoyfe etc.

The halogenation is carried out in the usual manner. The compounds of general formula (II) and (III), respectively generally react with a halogenating agent in an inert solvent, for example an alkanecarboxylic acid, a halogenated hydrocarbon, etc. preferably in acetic acid or chloroform. Optionally acid binding agents such as triethyl-amine, acetamide, sodium acetate etc. can also be used.

The reactions are carried out at a temperature between 0 ° C and 160 ° C / preferably 20 ° C to 60 ° C. The compounds of general formula (I) or their salts either precipitate from the reaction mixture and can be removed / for example by filtration; scdts are separated from the reaction mixture by evaporating the solvent. The compounds of general formula (I) can be purified according to usual techniques, for example by recrystallization, chromatography etc.

A compound of the general formula (I) thus obtained can be converted, if desired, into another compound of the general formula (I) by methods known per se.

The transformation can be carried out on the group R · * ". Therefore a compound of the general formula (I) where R1 is a carboxy group can be decarboxylated in an organic solvent, for example / lower alkane-carboxylic acid, lower alkanol, etc. or an inorganic solvent, for example, water at 0 to 200 ° C, optionally in the presence of a mineral acid, such as hydrogen halides, sulfuric acid, etc. The compounds of the general formula (I) obtained, where R · * - denotes hydrogen, R, R2, X and n are defined above are then isolated or they are made / react with a molar equivalent of a halogenating agent.

In this way compounds of the general formula (I), where R "* - is a halogen, are obtained. The above optional reaction steps are also within the limits of the invention.

Compounds of the general formula (I) where R is other than hydrogen have a center of asymmetry. The optically active enantiomorphs of these compounds of the general formula (I) can be prepared starting from optically active compounds of the general formula (II) and (III) respectively.

According to another possibility, a racemic compound of the general formula (I) obtained can be subjected to resolution in a process known per se. Compounds containing a carboxyl group in place of R1 of the general formula (I) can be resolved by reacting the racemate with a suitable optically active base (for example threo- (p-nitrophenyl) 1 2-amino-propane diol 1, 3) and by separating the products formed from the pair of distereomer salts based on their diflerence of physical properties, for example by crystallization and by releasing the optically active enantiomorphs, by reacting the salt with a strong base.

The starting compounds of the general formula (III) - where R, R1, R2 and n are defined above - are described in Hungarian patents Nos. 156,119, 158,085, 162,384 and 162,373, and the publication of Netherlands No. 72 12 286 and these products i - 8 -

The starting materials of the general formula (II) are known in the art (Arzneimittel Forschung 1972/22, 815) or can be prepared according to known methods.

Some representing compounds of the general formula (I) have analgesic, anti-inflammatory, inhibitory aggregation of platelets, anti-atherogenic and / or antiallergic properties while * others are valid intermediates for synthesis. of compounds having antiallergic or anti-asthmatic properties.

The compounds of general formula (I) can be used in the form of pharmaceutical compositions containing the active ingredient in association with inert solid or liquid vehicles. The compositions are prepared by methods known per se.

The compositions can be formulated in a form suitable for oral, parenteral administration, or by inspiration, more specifically in the form of tablets, dragees, capsules, lozenges, powder / aerosol mixtures, suspensions or aqueous solutions, solutions for injection or syrup.

The compositions may contain suitable diluents or carriers, sterile aqueous solvents or non-toxic organic solvents. To compositions suitable for oral administration, the usual flavoring or softening agents may be added.

Other details of the invention are illustrated by the following examples which are given for illustrative purposes only and not limitation.

- 9 -

Example 1

1.4 g (0.005 moles) of bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4 H -pyrido [1,2 -a-] pyrimidine carboxylic-3 are dissolved in 15 ml of dried chloroform on sodium sulfate. To this solution, a solution of 0.3 ml (0.005 moles) of bromine in 5 ml of chloroform is added dropwise, with stirring at room temperature. The reaction mixture is then stirred at room temperature for half an hour and allowed to stand overnight. The precipitated crystals are filtered and washed with a small amount of chloroform.

To the precipitate, 10 ml of water, 10 ml of chloroform are added and the pH of the aqueous phase is adjusted to 2 using a 5% by weight solution of sodium bicarbonate while stirring.

The organic phase is separated, the aqueous phase is stirred with two 10 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol. 0.3 g (16.4%) of dibromo 9.9 methyl 6 oxo 4 tetrahydro acid 6,7,8.9 - 4H -pyrido [1,2 -a) pyrimidine carboxylic-3 is obtained, mp 165-166 ° C.

Analysis for cioHioN2 ° 3Br2: calculated: C 32.81%, H 2.75%, N 7.62%, Br 43.65% determined: C 33.22%, H 2.78%, N 7.65% , Br 43.58%.

Example 2

1.4 g (0.005 mole) of bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H-pyrido p., 2 -aj pyrimidine -carboxylic-3 are dissolved in 30 ml of glacial acetic acid . To the solution, a solution of 0.3 ml (0.05 mole) is added dropwise.

-10- at room temperature. The reaction mixture is stirred at 40-60 ° C for half an hour, and then the acetic acid is distilled under reduced pressure. To the residue is added 10 ml of water and 10 ml of chloroform and the pH of the aqueous phase is adjusted to 2 using a 10% by weight solution of sodium carbonate while stirring. The organic phase is separated, the aqueous phase is stirred with two 10 ml portions of chloroform. The combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled under reduced pressure. The residue is recrystallized from methanol.

0.8 g (53.8%) of dibromo 9.9 methyl 6 oxo 4 tetrahydro 6,7,8.9 -4H-pyrido [1,2-a) pyrimidine carboxylic-3 is obtained, melting point 164-166 ° C. There is no lowering of the melting point if this product is mixed with that obtained in Example 1.

Example 3

14 g of crystalline sodium acetate and 10.4 g (0.05 mole) of methyl 6 oxo 4 tetrahydro acid 6,7,8,9 -4H-pyrido £ 1,2-âj pyrimidine -carboxylic- are dissolved. 3 in 5 ml of glacial acetic acid. To the solution is added dropwise 5.4 ml (0.1 mole) of bromine at low speed, at room temperature while stirring. The reaction mixture is then stirred at room temperature for two hours, and then the solvent is distilled under reduced pressure. To the residue, 50 ml of water and 50 ml of chloroform are added and the pH of the aqueous phase is adjusted to 2 using a 5% by weight solution of sodium carbonate while stirring. The organic phase is separated, the aqueous phase is stirred with two 50 ml portions of dioroform. The combined organic phases are dried over anhydrous sodium sulfate. And the solvent is distilled under pressure -Il- Οπ obtains 9.4 g (51.3%) of dibromo acid 9.9 methyl 6 oxo 4 tetrahydro 6.7 , 8.9 -4H- pyrido P "2 'fl pyrimidine carboxylic * 3, melting point 165 -166 ° C. There is no lowering of melting point if this product is mixed with one of the products of examples 1 and 2.

Example 4

By following the process described in Example 2 but by replacing the racemic acid (+) bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H-pyrido Q., 2 -a] pyrimidine carboxyli-que- 3 by optically active (+) bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9-4H-pyrido fl, 2-âj pyrimidine carboxylic-3, we obtain (+) dibromo acid 9,9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H-pyrido (1,2-a) pyrimidine carboxylic-3, melting point 157 at 159 ° C. Yield: 49.0% (cA) ^ = + 47.5 ° (c = 1, methanol).

Analysis for ΰιοΝ10Ν2 ^ 3Β: ι :: calculated: C 32.81%, H 2.75%, N 7.65%, Br 43.66% determined: C 33.11%, H 2.60%, N 7 , 56%, Br 43.44%

Example 5

Following the process described in Example 3 but replacing the racemic acid (+) methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H-pyrido jl, 2-a | 3-carboxylic pyrimidine with (-) methyl 6-oxo-4 tetrahydro acid 6,7,8,9, -4H- pyridoQ., 2-eQ optically active carboxylic-3 pyrimidine, acid (+ ) dibromo 9.9 methyl 6 oxo 4 tetrahydro 6,7,8,9-4H-pyrido ^ 1,2-âJ pyrimidine carboxylic-3, melting point 157 at 158 ° C. There is no lowering of the melting point when the product is mixed with that of Example 4.

Yield: 51.2%, () ^ ° - + 47.5 ° (c - 1, methanol).

- 12 -

Example 6

By following the process described in example 2 but by replacing the racemic acid (+) bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H ~ pyrido Cl.2-a} pyrimidine carboxylic-3 mixture by l (-) bromo 9 methyl 6 oxo 4 tetrahydro 6,7,8,9-4H-pyrido p, 2 -a} optically active carboxylic-3-pyrimidine, we obtain (-) dibromo 9,9 methyl acid 6 oxo 4 tetrahydro 6,7,8,9 -4 H-pyrido [1,2 -a] pyrimidine carboxylic-3, melting point 157 to 159 ° C. Yield 49.5¾, = ~ 47.5 ° (c = 1, methanol).

Analysis for '· calculated: C 32.81%, H 2.75%, N 7.62%, Br 43.65%.

t determined: C 33.21%, H 2.72%, NN7.60 S, Br 43.62%.

Example 7

By following the process described in Example 3 but by replacing the racemic mixture (+) methyl 6 oxo 4 tetrahydro 6,7,8,9 -4H- pyrido [1,2 -aj pyrimidine carboxylic-3 mixture with the acid (+) methyl 6 oxo 4 tetrahydro 6,7,8,9-4H- pyrido [1,2-a] pyrimidine carboxylic-3 optically active, we obtain the acid (-) dibromo 9,9 methyl 6 oxo 4 tetrahydro 6,7,8,9 - 4H- pyrido ^ 1,2-a pyrimidine carboxylic-3, melting point 157 to 159 ° C.

Yield 51.5%. (= - 47.5 ° (c = 1, methanol). There is no lowering of the melting point by mixing this product with that of Example 6.

Examples 8 to 11

1.4 g of crystalline sodium acetate and 0.005 mole of a starting compound shown in Table 1 are dissolved in 10 ml of glacial acetic acid. To the solution is added dropwise at low speed 0.54 ml (0.01 mole) of bromine while stirring at room temperature. The reaction mixture is stirred for two hours at room temperature and then distilled

Il__J J ___iT I J_____ ___________J___ "-1 _" ___. 1Λ _ 1 - 13 - chloroform and the suspension is stirred for 15 minutes at room temperature. The crystals are filtered and washed with chloroform. The filtrate is evaporated. The residue of the solvent indicated in Table I is recrystallized.

Examples 12 to 17:

1.4 g of crystalline sodium acetate and 0.005 mole of a starting compound shown in the table are dissolved

It in 10 ml of glacial acetic acid. To the solution is added 3.2 g (0.01 mole) portion per portion of pyridinium perbromide bromide while stirring at room temperature. The reaction mixture is then stirred at room temperature for two hours and the acetic acid is distilled under reduced pressure. To the residue is added 10 ml of water and it is stirred with 3 portions of 10 ml of chloroform.

The combined organic phases are dried over anhydrous sodium sulfate and the solvent is distilled in vacuo.

The residue is recrystallized from methanol.

Examples 18 to 20:

0.05 mole of a starting compound shown in Table III (in suspension) is dissolved in 80 ml of dichloromethane and to the solution obtained (suspension) is added a solution of 13.5 g (0.1 mole) of sulfuryfe chloride in 20 ml of dichloromethane at room temperature. The reaction mixture is boiled until the evolution of gas is completed (3 to 4 hours), the solvent is distilled off and the residue is recrystallized from ethanol. Yield: 70 to 80%. The compounds obtained are indicated in Table III.

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Example 21-18

2.2 g of crystalline sodium acetate and 0.8 g (0.005 mole) of methyl 6 tetrahydro 6,7,8,9 - 4H -pyrido £ l, 2-a] pyrimidine-one are dissolved in 10 ml glacial acetic acid.

To the solution is added dropwise 1.0 ml (0.018 mole) of bromine at room temperature while stirring. The reaction mixture is then stirred at 50 to 60 ° C for half an hour and then the acetic acid is distilled under reduced pressure. To the residue is added 10 ml of chloroform and the suspension is stirred at room temperature for 15 minutes.

The crystals are filtered and washed with chloroform.

The filtrate is evaporated in vacuo. Recrystallization of the residue from methanol gives a yield of 1.5 g (74.8%) of tribromo 3,9,9 methyl 6,7,8,9 - 4H-pyrido [1,2 -a J pyrimidine-one 4 at melting point 157 -159 ° C.

Analysis for CgH ^^ OBr ^: calculated: C 26.96%, H 2.26%, N 6.98%, Br 59.79% determined: C 26.80%, H 2.06%, N 7, 00%, Br 59.00%

Example 22

By following the process described in Example 8 but starting from dimethyl 3,6 tetrahydro 6,7,8,9 - 4H- pyrido ^ 1,2 -a J pyrimidine-one 4, dibromo 9 is obtained, 9 dimethyl 3,6 - tetrahydro 6,7,8,9 - 4 H-pyrido Q., 2 -a 3 pyrimidine - one 4, melting point 114 -115 ° C. Yield 30%.

Analysis for c; L0H22N2OBr2: calculated: C 35.74%, H 3.59%, N 8.34%, Br 47.56% determiniC 35.74%, H 3.72%, N 8.22%, Br 47.85%.

Example 23 - 19 - (To a solution of 2.1 g (0.01 mole) of methyl 6 oxo 4 tetrahydro acid 6,7,8,9-4H-pyrido p., 2 -a] pyrimidine carboxylic 3 in 20 ml of chloroform ^ portion by portion is added 3.6 g (0.02 mole) of N-bromo-succinimide while stirring The reaction mixture is heated to reflux for 5 hours and the chloroform is distilled under reduced pressure 20 ml of water are added to the residue and the suspension is stirred at room temperature for 15 minutes, the insoluble crystals are filtered, dried and recrystallized from methanol to give 1.5 g (41.0%) of acid. dibromo 9.9 methyl 6 oxo 4 tetrahydro 6,7,8,9 -4 H-pyrido (1,2 -aj pyrimidine carboxylic-3, melting point 163 - 164 ° C.

There is no lowering of the melting point when this product is mixed with that of Example 1.

Example 24 To a solution of 1.04 g (0.005 moles) of methyl 6 oxo 4 tetrahydro acid 6,7,8,9 -4 H-pyrido p., 2 -â ^ pyrimidine carboxylic-3 in 10 ml of chloroform ^ 1.33 g (0.01 mol) of N-chloro-succinimide are added in small portions while stirring. The reaction mixture is then heated at reflux for 5 hours, and then the chloroform is distilled under reduced pressure. To the residue is added 10 ml of water and the suspension is stirred at room temperature for 15 minutes. The crystals are filtered, dried and recrystallized from methanol. 0.7 g (50.5%) of dichloro 9.9 methyl 6 oxo 4 tetrahydro 6,7,8.9 -4H-pyridofl, 2 -aj pyrimidine carboxylic-3 is obtained, melting point at 190 - 191 ° C. There is no lowering of the melting point if this product is mixed with that of Example 18.

Example 25k - 20 -

By following the process described in Example 8 but by replacing methyl 6 oxo 4 tetrahydro 6 / 7,8,9 -4 H-pyrido [1,2-a] pyrimidine carboxylic-3 acid by ethyl 3 dimethyl 2.6 tetrahydro 6,7,8,9 -4H-pyrido £ l, 2-a] pyrimidine-one 4 and by recrystallizing the crude product in a 50% aqueous solution of ethanol, bromo 9 is obtained, 9 ethyl 3 dimethyl 2,6 tetrahydro 6,7,8,9 - 4H-pyrido Ç., 2 -âJ5 pyrimidine-one 4, melting point 90 to 92 ° C. Yield 57.21.

Analysis for C12Rl6N2OBr2: calculated: C 39.59%, H 4.43%, N 7.69%, Br 43.9% determined: C 39.21%, H 4.25%, N 7.59%, Br 43.76%

Example 26

Following the process described in Example 8 but replacing methyl 6 oxo 4 tetrahydro acid 6,7,8,9 - 4H -pyrido Q., 2-ä} pyrimidine carboxylic-3 with phenyl 3 methyl 6 , tetrahydro 6,7,8,9-4H-pyrido £ ï, 2 -a ^) pyrimidine-one 4 and by recrystallizing the crude product from ethanol we obtain dibromo 9,9 phenyl 3 methyl 6 tetrahydro 6 , 7,8,5 - 4H -pyrido [1,2-a ·] pyrimidine-one 4, melting point 154 - 156 ° C. Yield 70.4%.

On analysis for C ^ gH ^^ OBi ^: calculated: C 45.26%, H 3.54%, N 7.04%, Br 40.14% determined: C 45.26%, H 3.54 %, N 7.21%, Br 40.25%.

Example 27

Dissolve 2.08 g (0.01 mole) of oxo 4 tetrahydro 4,6,7,8 - pyrrolo [i, 2 -a) ethyl pyrimidine carboxylate-3 in 10 ml of a 75% aqueous solution % (by volume) of acetic acid and 2.72 g (0.02 mole) of sodium acetate are added. Then a solution of 3.2 g (0.02 mol) of bromine in 10 ml of a solution of acetic acid 75% v - 21 "" half an hour is added dropwise and diluted with 150 ml of water and stirred with 3 4 ml portions of chloroform The combined phases of chloroform are dried over sodium sulfate and evaporated.

The oily, yellow residue crystallizes when left to stand. Recrystallization of the crude product from ethanol gives 2.2 g (60%) of dibromo 8.8 oxo 4 tetra, hydro 6,7,8,9 pyrrolo [1,2 -aj pyrimidine carboxylate-3 ethyl , melting point at 97-100 ° C.

* Analysis for C ^ qH ^ q ^ O ^ Br: calculated: C 32.81 ..%, H 2.75%, N 7.65%, Br 43.66% determined: C 33.28%, H 2 , 62%, N 7.52%, Br 43.27%

Example 28

By following the process described in Example 27 but by replacing the oxo 4 tetrahydro 4, 6,7,8 -pyrrolo £ l, 2-a * ^ pyrimidine-carboxylate-3 of ethyl by the oxo 4 hexahydro 5, 6,7,8,9,10 -4H -pyrimido (JL, 2 -a] ethyl azepine-3-carboxylate and by carrying out the reaction at 90 ° for one hour, 2.1 g (53%) of dibromo 10,10 hexahydro 5,6,7,8,9,10 - 4H- pyrido £ l, 2 -a ethyl azepine carboxylate-3.

Rf = 0.8 (4: 1 mixture of benzene and methanol,

Kieselgel 60 F254 ^

Analyzes for C12H14N203Br2: calculated: C 36.57%, H 3.58%, N 7.10%, Br 40.55% determined: C 36.32%, H 3.49%, N 7.02%, Br 41.02%.

Claims (18)

1. Compounds of the general formula: Λν 0 OÙ R represents hydrogen, lower alkyl or lower alkoxy carbonyl groups; represents hydrogen, lower alkyl, carboxy, esters or derivatives thereof, cyano, phenyl or halogens. / r2 represents hydrogen, lower alkyl or phenyl groups; X represents halogens. / n is an integer of 0, 1 or 2, and the optically active enantiomorphs and the salts thereof. 2. Compounds according to claim 1, characterized in that R- ^ is a carboxy group. 3. Dibromo acid 9.9 methyl 6 oxo 4 tetrahydro 6,7,8,9-4 H-pyrido [1,2-aj pyrimidine carboxylic-3. 4. Acid (+) dibromo 9.9 methyl 6 oxo 4 tetrahydro 6, 7,8,9 - 4H -pyrido £ l, 2-aj pyrimidine carboxylic-3. - 23 - pyrido [1,2-cQ pyriraidine carboxylic-3. dibromo acid 9.9 oxo 4 tetrahydro 6,7,8,9 - 4H- pyrido [1,2-â) pyrimidine carboxylic-3. dichloro acid 9.9 methyl 6 oxo 4 tetrahydro 6,7,8,9 - 4H-pyrido [l, 2 -aj) pyriraidine carboxylic-3. dibromo acid 9.9 methyl 7 oxo 4 tetrahydro 6.7, 8.9 -4 H- pyrido fl, 2 -a} pyrimidine carboxylic-3. dibromo acid 9.9 methyl 8 oxo 4 tetrahydro 6,7,8,9 -4 H- pyrido [1,2 -a ^ J pyrimidine carboxylic-3. 4. Compounds according to claim 1, other than those claimed in claim 3 specifically described in the description. 5. Process for the preparation of the compounds according to claim 1, their salts and their optically active enantiomorphs, characterized in that it consists in reacting: or compound a) a racemic mixture of monohalogen / optically active derivative of the general formula: X 0 b) a racemic mixture or an optically active compound of the general formula: RC ^ f Vr2 ni 0 - 24 έ (where R, R ^ ", R2 and n are defined in claim 1) with a halogenating agent and, if desired, transform a group of a compound of the general formula I obtained into another group R1 and, if desired, separate a racemate of the general formula I obtained into its optically active enantiomorphs. 6. Method according to claim 5, characterized in that in case a) at least one molar equivalent of halogenating agent was used. 7. Method according to claim 5, characterized in that in case b) at least two molar equivalents of halogenated agent are used. 8. Method according to claim 5, characterized in that in any one of the cases a) and b) a halogen in the form of an element, a halogenated imide acid or an inorganic acid halide are used as halogenating agent . 9. Method according to claim 8, characterized in that% uses bromine, N-bromo-succinimide or sulfury chloride as halogenating agent. 10. Method according to claim 5, characterized in that the methods a) or b) are implemented in an inert organic solvent, preferably an alkanecarboxylic acid or a halogenated hydrocarbon. - 25 - ι 11. Method according to claim 5, characterized in that the methods a) or b) are implemented in the presence of an acid binding agent, preferably an alkali metal acetate. 12. Method according to any one of claims 5 to 11, characterized in that one proceeds to a decarboxylation of a compound of the general formula I or represented 2 * a carboxyl group, R, R, x and n are defined in claim 1, to prepare a compound in the general formula I where is hydrogen. 13. Method according to any one of claims 5 to 11, characterized in that a compound of the general formula I is reacted, where R is an isocarboxyl group and R, R, X and n are defined in the claim 1, with a halogenating agent, to prepare a compound of the general formula I, where R1 is a halogen. 14. The method of claim 13, characterized in that a halogen in the elemental state is used as a halogenating agent. ** * 15. Method according to any one of claims 5 to 11 characterized in that a compound of the general formula I is reacted, where R is hydrogen, R, R, X and n are defined in claim l , with a halogenating agent to prepare a compound of general formula I, where R ^ is halogen. - 2 6 -, 1 part from compounds of general formula II or III 1. where R is a carboxy group, R, R, X and n are defined in claim 5, to prepare compounds of general formula I where R1 is carboxy. 17. Compound according to claim 1, prepared by a process according to any one of claims 5 to 16. 18. A pharmaceutical composition comprising as active ingredient at least one compound of formula I according to claim 1 or a physiologically compatible salt in association with a pharmaceutical vehicle or excipient.