SE441747B - COMMON DIHALOGEN DERIVATIVES OF CONDENSED PYRIMIDIN-4-ON COMPOUNDS - Google Patents

Description

10 15 20 25 30 35 40 8003479-6 -2 _ groups, such as alkoxy groups, and generally denotes straight or branched, aliphatic, saturated hydrocarbons containing 1 to 6, preferably 1 to 4 carbon atoms, and by way of example such groups may include methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, neo-penyl tyl, n-hexyl, etc.

The term "carboxy derivative" signify conventional carboxylic acid derivatives, such as alk- oxycarbonyl, for example lower alkoxycarbonyl, aryloxy- carbonyl, aralkoxycarbonyl or other esters, carbonyl moyl groups, optionally substituted with one or two alkyl groups (for example lower alkyl groups), aryl or clay aralkyl groups; cyano-, carboxylic acid hydrazido- or hydroxamic acid groups (-CO-NHOH).

The term "aryl" optionally denotes substituted aromatic groups such as phenyl, naphthyl and substituted derivatives thereof, and neither the pressure was used alone or as a combination link in drawings for aryl-containing groups, as appropriate substituted aromatic groups having 6 to 10 carbon atoms.

The term "aralkyl" may, for example, denote alkyl having 1 to 3 carbon atoms substituted by phenyl or naphthyl, such as benzyl, β-phenylethyl, c, β-diphenylethyl, 6,6-diphenyl-ethyl, etc., and this neither the term nor used alone or as a combination in designations for aralkyl-containing groups, such as aralkyloxy.

The term "halogen" denotes chlorine, bromine or iodine atom.

Preferred compounds of the invention are those which fall under the general formula I, where R represents hydrogen, lower alkyl, preferably methyl; RI represents carboxy, lower alkoxycarbonyl, preferred preferably methoxycarbonyl or ethoxycarbonyl; cyano, carbamoyl, lower alkyl, preferably methyl; phenyl; R2 represents hydrogen, lower alkyl, preferably methyl; X represents chlorine or bromine; n an integer 0, 1 or 2.

Compounds I containing carboxy groups forms salts with pharmaceutically acceptable bases, such as alkali metal salts, for example sodium or potassium salts 10 15 20 25 30 35 40 -s- 8003479- alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts and with organic technical amines, such as triethylamine salts, ethanolamine salts, etc.

Optical isomers of the compounds I also falls within the scope of the invention.

The new compounds I, pharmaceutically acceptable salts and optically active isomers thereof can be prepared, for example, according to any one of the following two procedures, namely (a) and (b), and these procedures fall within the scope of the invention. a) A monohalogen compound with the general men formula X RZ / R (II) (CH2) n N \ / R, where R, R 1, R 2, X and n have the meanings given above, with a halogenating agent, or b) a compound of the general formula N R * R (III) (CH2) n N \\\ v /// RI O where R, R1, R2 and n have the meanings given above, is added with a halogenating agent, whereupon, if so desires, in an association thus obtained with the general meln I converts a group represented by RI into one another group represented by RI, and possibly split takes the racemate thus obtained with the general formula In their optically active antipodes.

As indicated above under (a), 10 15 20 25 30 35 40 Soos479-6 _, _ The process is reacted with a compound of the general formula II, where R, R1, R2, X and n have the meanings given above, with an at least equivalent amount of a halogenating agent.

Preferably, the halogenating agent is used in an amount of 1 - 1.5 molar equivalents.

According to the procedure indicated in (b) above, The process is reacted with a compound of the general formula III, wherein R, R 1, R 2 and n have the meanings given above, with at least two molar equivalents of a halogenating agent.

The preferred amount of halogenating agent is 2 - 2.5 molar equivalents of compounds III.

It can be used as a halogenating agent conventional halogenated in this field remedies. Elemental halogens, such as bromine, chlorine or iodine, halogen compounds such as bromine chloride, iodine chloride rid etc. and other halogen derivatives, such as sulforyl chloride, phosphorus pentachloride, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethyl-hydantoin, N- -bromo-caprolactam, tribromo-acetophenone, trichloromethane- sulforyl bromide and chloride, t-butyl hypochloride, hypo- bromite and hypoiodite, 1,2,4,6-tetrachloroacetanilide, 1,2-dibromo-tetrachloroethane, copper (II) bromide and chloride; and halogen complexes, such as pyridinium bromide-perbromide, phenyltrimethylammoinium perbromide, tetramethylammonium- -tribromide, dioxane-dibromide, pyrrolidone-2-hydro-tribro- mid etc was often used, possibly in the presence of a catalyst, for example a Lewis acid, such as aluminum bromide and chloride, phosphorus trichloride, sulfur, calcium oxide, UV radiation, dibenzoyl peroxide etc.

The halogenation is carried out at conventional nally. Compounds II and III are generally reacted with a suitable halogenating agent in an inert solution agents, for example alkanecarboxylic acid, halogenated hydrocarbon, etc., preferably in acetic acid or chloroform.

Optionally, acid-binding agents, such as triethylamine, acetamide, sodium acetate, etc.

The reactions are carried out at 0-160. preferably 20-60 ° C. Compounds I or salts resulting from the reaction mixture and can be recovered from this, for example by filtration, or 10 15 20 25 30 35 40 -5- 80034 they are also separated from the reaction mixture by the solvent is evaporated. The compounds I can be purified conventional way, for example by recrystallization chromatography etc.

A compound I obtained in this way if desired, converted to another compound I on and per se known manner. The transformation can take place in case of horror R1. Thus, a compound I, wherein R 1 represents carboxyl, decarboxylated in an organic solvent for example lower alkane carboxylic acids, lower alkanol etc. or in an inorganic solvent, e.g. water, at a temperature between 0 and 200 ° C, event in the presence of a mineral acid, such as hydrogen halides, good acid etc. Compounds obtained in this way with general formula I, wherein R 1 represents hydrogen, R, R X and n have the meanings given above, are isolated therefrom or reacted with one molar equivalent of a halogen remedies. In this way, compounds with d general formula I, wherein R 1 represents halogen.

Optional reaction teas listed above also falls within the scope of the invention.

Compounds of general formula I where R represents other than hydrogen, has an asymmetry center. Optically active antipodes of the compounds I produced by starting from optically active units II and III respectively. Alternatively, one can obtain racemic mixture I is decomposed in a known manner. They bow s of the general formula I, wherein R 1 represents carboxyl, may be subjected to racemate cleavage by the racemate is traded with a suitable optical stock base (for example optically active threo-1- (p-nitrophenyl) -amino-propane-1,3-diol) and separates the formed re the representatives of the diastereomeric salt pair using a their different physical properties, for example geno crystallization, whereupon the optically active antipode released from the salt by reaction with a strong ba The starting materials with the general fo meln III, where R, R1, R2 and n have the meanings given above described in previous patents (HU-PS 156 119, 158 085, 162 384 and 162 373 and NL-PS 7 212 286) o 10 15 20 8003479-6 can be prepared in the manner set forth in these writings.

The starting materials II are known (Arzneimittel Forschung / l972 / 22, 815) or can be produced by means of procedures described in the literature.

Further details can be found in the following non-limiting examples.

Example 1 1.4 9 (0.005 mol) 9-bromo-6-methyl-4-oxo- -6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine- -3-Carboxylic acid was dissolved in 15 ml of chloroform, which dried over sodium sulfate. To the solution was added dropwise, with stirring and at room temperature a solution of 0.3 ml (0.005 mol) of bromine in 5 ml chloroform. The reaction mixture was then stirred at room temperature for half an hour and received then stand overnight. The precipitated crystals was filtered off and washed with a small amount chloroform. 10 15 20 25 30 35 40 8003479-6 To the precipitate was added 10 ml of water and 10 ml of chloroform and the pH of the aqueous phase were adjusted to 2 with a 5% by weight sodium bicarbonate solution while stirring ning. The organic phase was separated, the aqueous phase the phase was shaken with chloroform (2 x 10 ml). The combined the organic phases were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. rat pressure. the residue was recrystallized from methanol and 0.3 g (16.4%) of 9,9-dibromo-6-methyl-4-oxo-6,7 8,9-Tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid mp, melting point 165 - 166%.

Analvs-: L is u La calculated for C 10 H 10 N 2 O 3 Br 2 32.81 2.75 7.65 43.65 found 33.22 2.78 7.65 43.58 Example 2 1.4 g (0.005 mol) of 9-bromo-6-methyl-4-oxo- -6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carbide oxylic acid was dissolved in 30 ml of glacial acetic acid. To the solution tes dropwise, with stirring and at room temperature a solution of 0.3 ml (0.05 mol) of bromine in 2 ml of glacial acetic acid.

The reaction mixture was then stirred at 40-60 ° C for half an hour, after which the acetic acid was distilled off reduced pressure. To the residue was added 10 ml of aqueous and 10 ml of chloroform and, while stirring, adjust the the pH of the aqueous phase was 2 with a 10% weight sodium bicarbonate solution. The organic phase separated, the aqueous phase was shaken with roform (2 x 10 ml). The combined organic phases dried over anhydrous sodium sulfate and solvent the agent was distilled off under reduced pressure. Atersto- it was recrystallized from methanol to give 0.8 g (53.8%) 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro- -4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, melting point 164-166 ° C. The product did not give melting point depression when mixed with it in the manner specified in pile 1 manufactured product.

Exemgel 3 14 g of crystalline sodium acetate and 10.4 g (0.05 mol) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidine-3-carboxylic acid was dissolved in 100 ml 10 15 20 25 30 35 40 8003479-6 glacial acetic acid. Slowly and dropwise was added to the solution at room temperature and with stirring 5.4 ml (0.1 mol) bromine. The reaction mixture was stirred at room temperature. temperature for two hours, after which the solvent is distilled off. clay under reduced pressure. To the residue was added 50 ml of water and 50 ml of chloroform, and with stirring the pH of the aqueous phase was adjusted to 2 with a 5% by weight solution. sodium carbonate. The organic phase was separated, the aqueous phase was shaken with chloroform (2x) 50 ml). The combined organic phases were dried over anhydrous sodium sulfate and the solvent distilled off clay under reduced pressure. The residue is recrystallized. serades in methanol.

9.4 g (51.3%) were thus obtained. 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidine-3-carboxylic acid, m.p. 165-166 ° C.

No melting point depression was obtained in either the product of Example 1 or the product Example 2. " Example 4 The procedure described in Example 2 was repeated with the change, that instead of the racemic (1) -9-bromo-6-methyl-4-oxo-6,7,8,9-tetra- The hydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is used. the optically active (+) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tet- hydrohydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid. MAN obtained (+) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro- -4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid, melting point 157-19 ° C. Yield 49.096. (only = + 47, s ° (c = 1, meta- nol).

Analysis 'iQ.% _ Í_ Lä'. calculated for C10N10N2O3Br 32.81 2.75 7.65 43.66 found 33.11 2.60 7.56 43.44 Example 5 The procedure described in Example 3 was repeated but with the change, that one instead for racemic (1) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidine-3-carboxylic acid used optically active (-) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido- (1,2-a) Pyrimidine-3-carboxylic acid. There was obtained (+) - 9,9-di- 10 15 20 25 30 35 40 - 9 - 8003479-6 bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2- a) pyrimidine-3-carboxylic acid. Melting point 157 - 158 ° C.

No melting point depression was obtained upon mixing of the product according to Example 4. Yield 51.2%. (a) É ° = + 47.5 ° (c = 1, methanol).

Example 6 The procedure described in Example 2 was repeated with the change that the race (1) -9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidine-3-carboxylic acid against optical active (-) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidine-3-carboxylic acid. One received (-) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidine-3-carboxylic acid. Melting point 157 - 159%. Yield 49%. (onff = -47, s ° (e = 1, me- tanol).

Analysis-% _s =. : ts ii ta calculated for C 10 H 10 N 2 O 3 Br 2 32.81 2.75 7.65 43.65 found 33.21 2.72 7.60 43.62 Example 7 The procedure described in Example 3 was repeated with the change, that instead of Racemic (1) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridine rido (1,2-a) pyrimidine-3-carboxylic acid used optically active (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridine do (1,2-a) pyrimidine-3-carboxylic acid. You received (-) - -9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrimidine do (1,2-a) pyrimidine-3-carboxylic acid. Melting point 157 - 1s9 ° c. Yield s1, s%. (tuff = -47, s ° (e = 1, methanol).

No melting point depression was obtained upon mixing of the product of Example 6.

Examples 8 - 11 1.4 g of crystalline sodium acetate and as starting material 0.005 mol of one of those in Table I the indicated compounds were dissolved in 10 ml of glacial acetic acid. Long- and added dropwise to the solution while stirring. at room temperature 0.54 ml (0.01 mol) of bromine.

The reaction mixture was then stirred for two hours at room temperature, after which the acetic acid is distilled off. under reduced pressure. To the residue were added 10 10 ßl 20 25 30 35 8003479f6 _ 10 _ ml of chloroform and the suspension was stirred for 15 minutes at room temperature. The crystals were filtered off and was washed with chloroform. The filtrate was evaporated and the residue was recrystallized from the the solvent.

Example 12 - 17 1.4 g of crystalline sodium acetate and as starting material 0.005 mol of one of those in Table II the indicated compounds were dissolved in 10 ml of glacial acetic acid. To solve was added dropwise with stirring and at room temperature. temperature 3.2 g (0.01 mol) of pyridinium bromide perbromide. id. The reaction mixture was then stirred at room temperature. the temperature for two hours, after which the acetic acid is distilled off. clay under reduced pressure. To the residue was added 10 ml of water and the whole was shaken with chloroform (3 x 10 ml). The combined organic phases were dried over anhydrous sodium sulfate and the solvent distilled in vacuo. The residue was recrystallized and methanol.

Example 18 - 20 0.05 mol of one of those listed in Table III the starting compounds were dissolved (respectively suspended des) in 80 ml of dichloromethane and to the solution thus obtained The suspension was set at room temperature solution of 13.5 g (0.1 mol) of sulforyl chloride in 20 ml of di- chloromethane. The reaction mixture was boiled until gas evolution subsided (3 - 4 hours), after which The solvent was distilled off and the residue was recrystallized. was lysed in ethanol. Yield 70 - 80%. The results obtained the units are summarized in Table III. 8003479-6 H fi Hu fi n0QHMxlml: fl UwE fl H flfl uu flfl onußxl w ~ .w «@ o. ~ fi ww_ ~ >>.« m |> m ^ m | ~. «vom« »> m | m« | o »| m | = fl ø fl a fl ~> m. ~ | ~ _ fi Vow mw fi | w »nmu» w »| m.w.>. w | oxo» | fl u> m | m «| oHø> smuuw» | m .mo.w «fi«. NH ~ wN fl w. «mv -momz @ m = fi u Honmuwa 1 vm fl o._w |« | fi æuwa | w | soun fi w «mm | .w.>. w | oxo |« | ~ > »Wa | w flfi uHe ~ H> xonHßx | ~ | = fi w fi s fl H w fl sm fi mxonußxl _ ww.m «o« .HH H ~ .m mo_mm |> m. ~ | ~. ~ Vou fl u> @ | m «| øH | m | = fl u fl e fi»> m ^ ~ | ~ _ ~ .ow »Md | u> n ~ H» wu | m.w.ß_w | oxo | | H »æm | m« | o »u> nmu» w »| m M _w> _m «~ m. Fi H mo.m om. ~ Mv -m ~ omz ~ fl z ° ~ u fi oumuwe 1 wm fi ~. ~ W |« | H> »ws | w | aounHø | mm» .w.> _w | oxo: «| H>» me | w OH _ uwumw fi> uw | mu> m um » | fl> x0numx | m | n fl u fl E fi u> & lwm fl æuwumuhm fl æäonuøxl æm.o «wo.>« m. ~ «w.wm | ^« | ~ .fi vøw fl u> m | m «| o» | m | = fl w «e fl u> m.m1 ~ __. oø | ø> n fl ~ »w» | m.w.> _ w | oxnr »fl u> m | m« | o »w> s ~ H» w »| m ^ mm.ov o fl.> mm.m> m.wmv ~ ummo ~ z, ~ m ~ fi u m fifi o o. @ m | «| fi>» wa | w | aouß fi ø | mm | _m.>. w | oxu | «| H>» ws | wm nuæm | H> x0QHwMlm | = fl U fi E fl H> m muhm fl akonumxl ~ w.m «mm.> ow. ~ ~ fi. mm | ^ ~ | ~ .fi. ow fi H> m | m« | oH | m | = fi u fl e »> m. ~ | ~. ~ .ou ww fl | u> = ~ »uwu | m_m.>. w | oxo | | Hu> m | m «| ouø>: mH» w »| m .mw_m «ww.> mß. ~ fi w_ ~ mv ~ ummo ~ z. ~ m ° Hu Ho = m» we | mw fi w.wm | «| H>» wefw | eo ~ n fi u | @ .m | .m.>. w | oxo: v | fl> uwa | @ w um æ Z æ m w U æ = 0fi vßm fi a lamum fl uxâo UO uu uwaunm. »~ = xm» wn. wH> Hwuwa ux == m w Hmm w .mæ fl mn fi Hwânom nmmc fl cmßü lu fl m fl m wuhnub uxdøoum mn fl nwumwmmnwwub | Ewxm H a fl wnmë - 12 8003479-6 : UOC% P¶ = ._ u 0. m _> «| u = ~ _u_ mnæmawxon fl mxnmlc fl ø mw_mv Nw_ß> w_m cw_Nm | fl EHHæm ^ m | N_ «vo © fi u> m | mw | mu> mH> xonumx | m |: fi U fl E fi u> & fi m _ _ _ _ ~ _ _ __ mm fl _ | o »ø> = m» »@» | m_w _> _ w | oxor | ~ __. ow fi »> m | m« | o »u> n ~ u» wu | Aww mv mm ß mn ~ fi m Nmv um O Z mø fl u 1 ßm fi «om | v1HæuwE | w | E0nQHu | m_m | ^ | v | m_m_ß_m | oxonw | aæumE | w | ^ + v vw -ms ._ u av m _> «+ w @@ fi mw m> _mv mß_> om_m mm. muæw fifi xonnmxnmnc fl ø mm | fl E fl Hmm ^ m | m fi vo flfl uæmnmvn muæm fi æwonumxnmrn fl w fl ä fl uæmAm _ mm fi | 0uu> zmHumu | m_æ _> _ w | ox0 | | N_ fi voøwu> m | mw | 0uU>: muuwu | .ww mv mw_ß m> _ ~ _m_ ~ mV ~ »m_o ~ z__m__o 1 ßm fl o_om |« | H> uws | w | soHn_ø | m_m | A +. | m_m _> _ w | oxo- «| Hw» ws|@|.lv m fi mu> mH> xonumx | m |: fl u Nß_mv æ> _> om_w fi ß_Nm | fl E fl n> m ^ m | m_HvoøHu> m | mv | muæw fi axonumxnmlc flflfl ä fl uæmAm _ _ _ _ mm fi 10uø> Smuuwu | m_æ_ß_w | o fl w | | N_ «vouHu> m | mw | ouU> & muuøu | .ww mw mm> mb N Hm Nm. ~ Hm_o ~ z__m__u 1 mw fl> _om «« | H> »wa« w | ao »n fl u | m_m | A +. | m_m _> _ w | oxo | «| H>» wa | w |. +. N fi un * zæ mæ u * u u: »W ==: u fi umzxwnmnv uxumm w Hmm æ _m> fl m: <Hwåuom lu fi mäm muænub uxßuonm mc fi cwumummcwmub iäwxm 4.1 ... J-Uâu. 8003479-6 wHæmHmK0Qumx | muæw fi æxon B mm.m «~> _> fl w. ~ ~ Ss. ~ M» m | = fl ø fl s fl ~> m ^ ~ | ~ .H.ou fi u | u ~ x | m | = HøHa fl »> m.m | ~. ~ V ßmw |> m | mw | ouu> = ~ »uwu | m.w.>. wu | ou fl u> m | m« | oHv> nøuuw »| .ww_m «mw.> m>. ~ Hm.Nm. ~ »Mmo ~ z ° Hm = Ho n mmw m.« M | oxo | «| H>» we | w | ao »n fl ø | m_m | mwß.w | o: o:« | ~> »ms | æ > _ muæm fi ækonumxl muämaæxon mw.m «> ß.ß ow.N mß.Nm | m | = flflfl E fl H> m ^ m | m.HvouHH | uøx | m | = fl UHE fi umm ^ m | N.« v mmm |> m | mv | 0Hø> Smuuuu | m.m.ß.w | | o® «h> m | mv | 0uu> SmHawu | ^ ww.mv mw.ß mß.N «m.mmv ~ umm0 ~ Z ° Hm ° fl U I www m.mm | 0x0 | v | fl> uwE | ß | E0Hn fl® | mm | mw> .w | 0xo | v | AævwE |> m fi om_m «wo.w w«. ~ mm.om «H> wH> xonHmx | m | = HwHe fi H> mAu ~ H» mH> xonHmx | m | = fl w _ wm fi 1 ~. «. oø fl ummnmwnouwwzmuuwuu | fl s @ H> m.m | ~ .H.oø« ~> m | m «| . ^ o «.m« wm_ß m ~. ~ ~> .omv ~ um @ o ~ z @ m @ u | wm fl m.m «| m.w.>. w | oxo |« | soHn fl øsm.m | oHø> nw »» w »« m.w _> _ w | oxo | «mg umæ Zæ mæ Uæ UD NG vwd fi äw A fl mnxmuw fl v vxc fl m w awm w .wæ fl mcm Hwëuom | uHwEw wuænub ux fl øoum mu fl cwummmmcmmus | EwxN ^ .wuno ~. HH flfi wnma 14 * 8003479-6 mß_mN fl m_mH ~ o_ø ßN_mw U fl Emxonnmxlm |: fl wHE fl H> m ^ m w fl ëmxonumxl _ _ _ _ lm_ fl voUHn> m | mv | oHm>: mHumu | m_m | m |: fl UwEHH> m ^ m | N_ fi vo flfl nhmlmwlou fi ßm mm fl w md Ho «mm m« v ~ Hu ~ o_z__m ° _o NNH |.>. wuøxølwl fi aumalmnuo fl x fl wlm_m | ø>: m »» wu | m.m.>. @ | oxø | «| ~> u @ a | m ON Hwumwahuwl wH_mm wo_m mw_v ~ o_> w zmuæm fl æxonuwxnmuc fl w flfifl næmAm uwumwH> uw | mn> ma> xonumx | «M | ~ _fl. Ow fi H> m1mw | o» w> nmuuw »| m.w | m | =« w fl s_u> m ^ ~ | ~. «Voø fl u> m | m« | ou ^ wm.m ~ w «.m ~ w.« m ~.> «. ~ Hu_o ~ z__m ~ Ho | Nm |.>. W | uxo | «| ~> u @ e | w |» oHx_w | m.m fwwnmuuwulm.æ.>. W | oxo | «| H>» ws | @ ma mw.m ~ mQ.oH mw. ~ o ~ .m «m»> mH> xon »mx | m | = Hu fi s fl H> mAm m»> wH> xonH ~ x « | ~ _H.owH »> m | m« | o »u>: ~ u» @ »| m.m | m | u« m fl a fl u> m. ~ | ~. «Voø fl»> m | m «| o» ^ mm.m ~ H_.o fl om.m «~ .m« v ~ Humo ~ z ° _ = ._ u wm fl |.> _ m | oxo | «| H>» «e« w | »oHx fl ø | m_m | w >; m ~ uw »| mm> _w | oxo |« | ~ w »« e | w m fl HU w Z W I W O w U0 HG uwauøw Aumøxw fl wnv uxu fl m Hmm æ _m>. ~ mâ .ÜEHOM luamšw Ux flfl ohm mø flfl wumwmmnmmub: Ewxm HHH a fl wndå 10 15 20 25 30 35 40 _ 15- 8003479-6 Example 21 2.2 g of crystalline sodium acetate and 0.8 g (0.005 mol) of 6-methyl-6,7,8,9-tetrahydro-4H-pyridine do (1,2-a) pyrimidin-4-one was dissolved in 10 ml of glacial acetic acid. At the room temperature and while stirring were added dropwise to the solution 1.0 ml (0.018 mol) of bromine and reaction the mixture was then stirred at 50-60 ° C for half hour. The acetic acid was then distilled off under reduced pressure. pressure and the residue was added with 10 ml of chloroform.

The suspension was stirred at room temperature for 15 minutes. after which the crystals were filtered off and washed with chloroform. The filtrate was evaporated in vacuo. Through recrystallization of the residue in methanol was obtained 1.5 g (74.8%) 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H- -pyrido (1,2-a) pyrimidin-4-one. Melting point 157 - 159 ° C.

Ana1YS 'å_E å_ë å_E §_§š calculated for C 9 H 9 N 2 OBr 3 26.96 2.26 6.98 59.79 found 26.80 2.06 7.00 59.00 Example 22 The procedure described in Example 8 was repeated with the change that it was based on 3.6- -dimethyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine- -4-on. 9,9-Dibromo-3,6-dimethyl-6,7,8,9-tetra- hydro-4H-pyrido (1,2-a) pyrimidin-4-one. Melting point 114 - 11s ° c. yield 3o, o%.

Analysis - 2.2 å_E š_E å_§š calculated for C1 ° H12N2OBr2 35.74 3.59 8.34 47.56 found 35.74 3.72 8.22 47.85 Example 23 To a solution of 2.1 g (0.01 mol) of 6- Tyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine -3-Carboxylic acid in 20 ml of chloroform was added portionwise and with stirring 3.6 g (0.02 mol) of N-bromo-succinimide.

The reaction mixture was refluxed for five hours. whereupon the chloroform was distilled off under reduced pressure print. To the residue was added 20 ml of water and suspension the sion was stirred at room temperature for 15 minutes. The the insoluble crystals were filtered off, dried and crystallized from methanol. 1.5 g (41.0%) were obtained 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido- 10 15 20 25 30 35 40 8003479-6 _ 16 _ (1,2-a) pyrimidine-3-carboxylic acid. Melting point 163 - 1s4 ° c.

The product did not show any melting point depression when mixed with the product according to Example 1.

Example 24 To a solution of 1.04 g (0.005 mol) 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyridine rimidine-3-carboxylic acid in 10 ml of chloroform was added stirring and in small portions 1.33 g (0.01 mol) N-chloro-succinimide. The reaction mixture was then boiled. after under reflux for five hours, after which the chloroform was distilled off under reduced pressure. To rest4 10 ml of water were added and the suspension was stirred room temperature for 15 minutes. The crystals filter was dried, dried and recrystallized from methanol. MAN obtained 0.7 g (50.5%) of 9,9-dichloro-6-methyl-4-oxo-6,7,8,9- -tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid.

Melting point 190 - 191 ° C. The product did not give a melting point depression when mixed with the product according to Example 18.

Example 25 The procedure described in Example 8 was repeated with the change, that instead of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) PY ' rimidine-3-carboxylic acid used 3-ethyl-2,6-dimethyl-2,7 8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one and the like crystallized the crude product in 50% aqueous ethanol.

There was obtained 9,9-dibromo-3-ethyl-2,6-dimethyl-6,7,8,9-tet- rahydro-4H-pyrido (1,2-apyrimidine-bon. Melting point 90 - 92 ° C. Yield s7.2%.

Analysis - §_Q §__ §__% Br calculated for C1¿H1 $ N20Br2 39.59 4.43 7.69 43.9 found 39.21 4.25 7.59 43.76 Example 26 The procedure described in Example 8 was repeated with the change, that instead of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyridine rimidine-3-carboxylic acid used 3-phenyl-6-methyl-6,7,8 9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one and recrystalline 10 15 20 25 30 35 40 _ 1, _ 8003479-6 tallied crude product in ethanol. 9,9-dibromo- -3-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyridine riminain-Lz-on. melting point 154 - 1 ° C. Yield 10,411.

Analysis - LE LE ill Lä calculated for C 15 H 11 N 2 O Brz 45.26 3.54 7.04 40.14 found 45.26 3.54 7.21 40.25 Example 27 2.08 g (0.01 mol) of ethyl 4-xo-4,6,7,8-tet- rahydro-pyrrolo (1,2-a) pyrimidine-3-carboxylate was dissolved in 10 ml of a 75% (v / v) aqueous solution of acetic acid and 2.72 g (0.02 mol) of sodium acetate were added. Where- after, a solution of 3.2 g (0.02 mol) was added dropwise. bromine in 10 ml of a 75% (v / v) acetic acid solution.

The reaction mixture was then stirred at 60 ° C for one half an hour, then dilute with 150 ml of water and shaken with chloroform (3 x 4 ml). The combined The roform phases were dried over sodium sulfate and evaporated. des. The yellow, oily residue crystallized when it was allowed to stand. By recrystallization of crude products 2.2 g (60%) of ethyl 8,8-dibromo-4-oxo- -6,7,8,9-tetrahydro-pyrrolo (1,2-a) pyrimidine-3-carboxy- lazy. melting point 97 - 100 ° C.

Analysis - yyyy §__ §__% Br calculated for C10H1 ° N2O3Br 32.81 2.75 7.65 43.66 found 33.28 2.62 7.52 43.27 Exemgel 28 The procedure described in Example 27 was repeated with the change, that instead of ethyl 4-oxo-4,6,7,8, -tetrahydro-pyrrolo (1,2-a) pyrimethyl din-3-carbon monoxide-4-oxo-5,6,7,8,9,10-hexahyd- ro-4H-pyrimido (1,2-a) azepine-3-carboxylate and carried out the reaction at 90 ° C for one hour. 2.1 g (53%) were obtained ethyl 1-10, 1-aibromo-s, e, 7, s, 9, 1o-hexahydro-ua-PYIimiäO <1f2 ' -a) azepine-3-carboxylate.

Rf = 0.8 (a mixture of benzene and methanol 4: 1, Kie- selgel 60 Fzsg).

Analysis - §_§ §_§ §__% Br calculated for C 12 H 11 N 2 O 3 Br 2 36.57 3.58 7.10 40.55 found 36.32 3.49 7.02 41.02

Claims (8)

8003479-6 18 PATEN TKRAV Compounds of the general formula R 2 (I) wherein R represents hydrogen, lower alkyl or lower alkoxycarbonyl; R 1 represents hydrogen, lower alkyl or carboxy or an ester or a derivative of carboxy, cyano, phenyl or halogen; R 2 represents hydrogen, lower alkyl or phenyl; X represents halogen; n is an integer 0, 1 or 2, and optically active antipodes and salts thereof. The compound 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1. The compound (+) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1. The compound (-) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1. The compound 9,9-dibromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine <3-carboxylic acid according to claim 1. The compound 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1. The compound 9,9-dibromo-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1. 8003479-6 19 8. The compound 9,9-dibromo-8-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid according to claim 1.