DE2315422A1 - NEW PYRIDO (1,2-A) PYRIMIDINE AND NEW PYRIDO (1,2-A) (1,3) -DIAZEPINE DERIVATIVES AND METHOD FOR PREPARING THE SAME - Google Patents

Description

Pafenfamvdf Dr.-bg. Loiiahos

Annasirafje 19 phone 555061

Frankfurt (Main), ά. March 26, 1973

Cblnoin Gyogyszer -es Yegyeszeti Termekek G-yara RT., Budapest IV., To utca 1-5, Uagarn

NEW PYRIDO O- , 2-a / PYRIMIDINE- AND NEW PYRIDO / l, 2-a7-A, 37 · DIAZEPINE DERIVATIVES AND METHOD FOR MANUFACTURING THE SAME

The substituted 2-pyridilamino-methylenemalonates obtained by the condensation of the substituted 2-A-mino-pyridine and the ethoxymethylene malonic acid diethyl ester, cyclized in diphyl under reflux, depending on the position of the substituents present on the pyridine ring, form either pyridol / l> 2-a7pyrimidine derivatives If there is a hydrogen atom at the 6-position, 7 »or 1,8-naphthiridine derivatives / in the case of a substituted pyridine ring in the 6-position 7 & · Am. Chem. Soc. 70 33U8-5O / 19 ^ 87 7.

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The two types of reaction pathways are illustrated in Fig. 1.

Further reports report on other ring-closing reactions of the substituted -2-pyridil-aminomethylene-malonates carried out in diphyl, which lead to pyridpA, 2a7pyrimidine derivatives fj. -Am. "Chem.Sog. TfT5491-7 / 195277, Indian J. Chem * 9 2O1 ~ 6 fl. 9717, J * Chöm. Soc. 1971 2735-87 · Instead of diphyl oil, other high-emitting solvents are also used £ & § k Patent No. 3,072,485 /.

In the case of a distillation at low pressure of the substituted 2-pyridil-amino-methyl-aceto-acetate obtained by the condensation of the substituted 2-aminopyridine and ethoxy-methylene-aceto-acetate or ethoxy-methyl-cyano-acetate or cyano-acstate forms a pyrido / 1,2a7pyrimidine derivative C3 \ Am. Chem. Soc. J30 3o66-9 £ 195877 in every case / so also in the case of a 6-sub "stitutiorj?" that the description of the experimental part is rather sketchy and that the reactions described for the 6-methyl-2-amino-pyri € li? iderivat are not reproducible. This deficiency of the article has also been drawn attention by other authors / J. Het "Chem. JB, 759-762 / 197177 ·

The cyclization of 2-pyridil-aminomethylene-malonates was again carried out in polyphosphoric acid . &. Org. Chem. 3J_ 3015-20 / 196877. In this case, a pyridil-aminomethylene-malonate is also formed from the 6-alkyl-sulfated 2-pyridil-aminomethylene-malonates; Mixture of phosphorus oxychloride-polyphosphoric acid is carried out / English Patent No. 1 209 9467 ·

In connection with the application of the PyridqA, 2a7 "

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pyrimidins is used in photographic applications as a sensitizer Agent cited / USA Patent No. 3 072 4587, furthermore the blood sugar lowering effect des S-methyl-ii-oxo-S-ethoxy-carbonyl-ifH-pyrido / i ^ cJ-pyrimidine / Indian J. Chem. £ 201-6 / 197177, and also over the analgesic effect of 1,6-dimethyl-3-ethoxycarbonyl-4-oxa-6,7 , 8,9-tetrahydro-4H-pyridoA, 2a-pyrimidinium methosulphate reports / doctor. Research 2_1 729-38 / 197177.

The first pyridoA, 2a7A »37 diazepine derivative was prepared by the reaction of 2-aminopyridine and tetraalkylsuccinic acid chloride / Are. Pharm. 2 76 181-5 Λ93877.

The reaction of 2-amino-pyridine and ) T- bromo-butyril bromide also leads to the pyridoZl, 2a7- / l »37-diazepine derivative / j. Chem. Soc. 1964 2763-697.

Furthermore, the production of the IQa- -Cyclopentyl-perhydro-pyrido / 1,2a7Z1,37diazepin-7-one / USA Patent No. 3,334,099.7 reports by reacting 5-cyclopentyl-5-oxo-pentanoic acid and 1,4-diamino-butane. In connection with this connection it is about the one exerted on the central nervous system and about the anti-inflammatory one Reported effect.

The present invention relates to new compounds of general formula I and their salts and quaternary Salts

R, and R ₂ each represent a hydrogen atom or together form a group of the formula -CH = CH-CH = CH- attached to two adjacent carbon atoms of the ring A * the A ring may carry one or more substituents

R _{u is} a carboxyl group or a carboxylic acid derivative radical;

R _{3 is} an oxo group if n = 0; or hydrogen, halogen, hydroxy, alkoxy, aralkoxy, aryloxy, nitro or

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χ, 2345422

Is amino if η = 1;

m = 0 if η = 1 or m = 1 or 2 if η = 0, where if η = 1, one of the dashed lines denotes a single bond and the other denotes a double bond and if η = 0, the endocyclic full line is a Single bond and the exocyclic dashed line represents a double bond /.

The present invention further relates to a process for the preparation of compounds of the general formula I and their salts and quaternary salts, characterized in that
a_7 cyclizes a compound of the formula II / in which R ₁ , R 2 and A have the above meanings; R ₅ and R _{g denote} a carboxyl group or a carboxylic acid derivative radical and p = 1 or 2j; or

b7 a compound of the formula III or its salt / in which R ₁ »R ₂ and A have the above meanings? reacts with a compound of the formula IV / in which R ₅ "R _g and ρ have the above meaning? and the compound of formula II formed cyclizes;

and, if desired, in a compound of the formula V / in which R ₁ , R ₂ , n, m, A and the dashed lines have the above meaning ₃
Rg a carboxyl group or a carboxylic acid derivative radical

kai means;
R _{7 is} an oxo group if η = 0 or R _{7 is} hydrogen,

If η = 17, a R _g group is converted into an R ^ group and / or an R ₇ group into an R ₃ group and, if desired, a compound of the formula I obtained in this way is converted into a salt or quaternary salt converts or releases a compound of the formula I from its salt or quaternary salt.

The starting compounds of the formula II used in the ring closure are prepared by reaction a compound of the formula III with a compound

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of formula IV.

You can also proceed in the following manner: The in the implementation of the compounds of the formulas III and IV obtained compound of formula II is cyclized without isolation from the reaction mixture.

The compounds of the formulas I, II, III and V can optionally have one or more substituents on ring A, for example the following groups: alkyl groups / e.g. methyl, ethyl group, etc.J, nitro group, halogen atoms / e.g. Chlorine atom, etc. * J, hydroxyl group, alkoxy group / eg ethoxy group, etc. _v 7, carboxy1 group, alkoxycarbonyl group / eg ethoxycarbonyl group, etc. 7, carboxamide group, amino group, alkylamino -Group / e.g. methylamino group, etc. ^ 7, acylamino group / e.g. acetylamino group, etc., J.

Compounds of the formulas II or IV in which Rc and R _{R are} a carboxyl group or an AIk-

° ^D η

oxyicarbonyl group / e.g. Athoxycarbonyl group / mean.

The cyclization can be advantageous in the presence of inert solvents or acidic condensing agents carried out at temperatures between 25 ° C and fOO ° C will.

Diphyl oil proves itself as an inert solvent, Paraffin oil, trichlorobenzene or mineral oil fractions.

Phosphorous oxyhalides / eg phosphorus oxyhalotide, phosphorus oxybromide7, phosphorus trihalides / eg phosphorus trichloride prove themselves as acidic condensing agents? » Thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid and polyphosphoric acid ethyl ester or mixtures thereof.

The compounds of the general formula V obtained during ring closure can be classified into two subgroups as well as the connections of general

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nen formula Va as PyridoZl ₉ 2aJpyi * imidine derivatives ₉ fn s O ₉ m = Ij, and Vb Pyrido-A, 2a7A ₉ 3id £ azepinderivatii ₉ in = 1,

. m - 0; R ^, R ₁₇₉ Rg, R ₂ A and the meaning of the streaked bond as above7 "which are formed next to one another in the course of the ring joint - / partly from a compound of the general formula II ₉ -wherein ρ ~ £ 7 and the separation of these compounds is based on their different basicity or their different characteristics in the reaction mixture *

For example, if the Cyklisiexnmg is performed in Diphylöl is diluted the reaction mixture SIACH-Dec ¹ completion of the reaction with Petr © lather ⁵ and e ^ st ~ the compound of general formula Va with 5% hydrochloric acid, shaken, then the Geraisch 20 % Ig <sr hydrochloric acid extracted and the compound obtained from the general formula Vb »The further processing takes place ss-. ready, according to various methods »·

If the cyclization is carried out on the basis of condensate substances. ^ g. B. with

"Ride-Polyphosphorsäuregemiseh? ₉ see © id @ -t -salt of the compound of the _{general ©! * formula fa aas 9} which the reaction mixture after the end of the ring ending with absolute alcohol ss ^ setst @ This salt is filtered. The filtrate is extracted from water and the compounds of the general formula ¥ b with “benzene. Further processing is carried out using separate known methods.

Even the recognition of Nmae itself iit u & © s "- surprising that during the Falie w © m thsrnisehdEi Eimgsehluse the ^{6-substituted-2-Pyi>} idiliMin © ^<= a @ th | ^r lea '= üiii © Eate.- the cyclization does not take place on the nitrogen stone of the' Pppielin ring, but on the 3 »St £ ejk © ta £ fat © sa on the pyridine ring, and thus Eicht © in Fyr2.d@£2 . _D 2a7-pyrimidine ₉ but a Maphtirid £ nd © i »i ^ at is formed Γζ · Β. J. Am. Chem. Soce-70 33 «» 8-SO Ä

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starting from the homologous 6-substituted compounds of the general formula II, the cyclization both on thermal As in the presence of acidic condensing agents, the ring closure is always at the nitrogen atom of the pyridine ring takes place.

If the cyclization is carried out in an inert solvent, x * ground compounds of the general Formula Vb is obtained where the meaning of the R- is a hydroxyl group i the endocyclic dashed line denotes a double bond and the exocyclic dashed line denotes a single bond7, which is also used in the tautomeric form can occur, where the meaning of the R- is a Οκο group, see Fig. 2.7

If the cyclization is carried out in the mixture of polyphosphoric acid-phosphoric oxychloride, obtained we compounds of the general formula Vb, in which the endocyclic dashed line is a double. bond and the exocyclic dashed line means a single bond, and the meaning of R- is a chlorine atom is.

If the cyclization is carried out in the mixture of phosphoric acid -phosphorus oxybromide, we obtain compounds of the general formula Vb, where the end cyclic dashed line denotes a double bond and the exocyclic dashed line denotes a single bond, and the meaning of R _{7 is} a hydrogen atom.

If we start from a compound of the formula II or IV, where ρ = 2, then both in the case of cyclization in an inert solvent, as well as in the presence of acidic condensing agents, only one PyridoZl, 2a7-pyrimidine compound of the general formula V, where η s 0 and m = 2.

The Rg group of the compounds of the general formula V is converted to group R ₁ ^ of the compounds of the general formula I using methods known per se.

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The case of the Rg-Athoxycarbony! Group I can e.g. The procedure is such that it is reacted with aqueous dilute sodium hydroxide solution at room temperature, the ester group is hydrolyzed, then acidified with hydrochloric acid, the acid obtained is excreted or amidated with an alcoholic ammonia solution, the acid amide derivative is obtained, which is treated with a dehydrating agent / e.g. Dicyklohexylkarbodiimid or phosphorus pentoxide can be converted into a nitrile group - ₉ or heated with hydrazine hydrate, converted into an acid hydrazide derivative in an alcoholic solution. In the case of R _g - carboxyl group may for example be taken in the manner that the acid ₉ with dry alcoholic hydrogen chloride gas is treated. Compounds of the general formula I are obtained in which R. is an alkoxy-carbonyl group. Treatment with thionyl chloride forms an acid chloride group which, when treated with ammonia ₉ , can be converted into an acid amide group. ·

The R ₇ group of the compounds of general formula I can still de.r methods known per se ζην R ₃ group of the compounds of general formula I above are performed. In the foot of R _? For example, we can proceed as follows for the hydroxy 1 group: treated with halogen ^ j, ierungsiftittein Zz.B. Phosphorus oxychloride heated? the hydroxyl group is exchanged for a halogen atom and the halogen bond obtained is, if desired, dehalogenized with a palladium catalyst in the presence of sodium acetate or, in the case of K ₇ = halogen atom / eg chlorine atom / with alcoholate / sB sodium methylate or sodium phenolate ? treated in an alkoxy, or aryloxy group, or in the case of R ₇ '= hydrogen atom, if desired treated with a Mitrierungsmittel in a nitro group is introduced, which, for example, catalytically Zz.B. can be reduced to an amino group in the presence of palladium or Raney nickelJ.

309840/1191

If desired, the compounds of general formula I can by reaction with non-toxic organic or inorganic acids, or with quaternary *} «« agents are converted into their quaternary salts. The base can be released from the salts or quaternary salts and if desired, transformed into a different salt. In this way, the following salts, for example The following are advantageously produced: hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, formic acid, acetic acid, citric acid, malic acid and salicylic acid salts or quaternary alkyl halides / e.g. Methoiodide7, alkylsulphates /5.B. Metosulphate7 »p-toluene sulphonate, benzene sulphonate, etc.

Some of the newly prepared compounds can be used as pharmaceuticals, some are they can be used as intermediates in the manufacture of medicinally valuable derivatives. Some of the representative Aunts have an analgesic, an anti-inflammatory and an antipyretic or other beneficial one the active effect exerted by the central nervous system / e.g. Sedatives, sleeping pills and tranquillants? *

In the case of use in medicine, the compounds of general formula I are in the form used by preparations containing the active ingredient and inert, non-toxic solid or liquid diluents or Carrier included. The specimens can be stored in a solid fora ft.B. Tablet, capsule, drag ^ eJ? » or liquid form / e.g. Solution, suspension, emulsion / can be applied.

For this purpose, “substances / z.B. Talc, calcium carbonate, magnesium stearate, water, polyethylene glycolate, etc.? used.

If desired, the preparations can also contain the usual additives / e.g. emulsifying agents that prevent disintegration contain promoting substances etc.

Some pharmacological data of the invention

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Mass connections are the following:

link

Dose po anesthetic time / mg / kg? £ seo7 renewal%

Il

3-ethoxycarbony1-5-chlorine- -pyrido / 1,2a7A, 37-diazepine

3-Athoxycarbonyl-9-metfoyl-5-οχο-Ί, 5-dihydro-pyrido (X , 2a7 £ 1 »3j7diazepine

10-2 * 1

85

3-ethoxycarbony-S-oxo- -U, 5-dihydro-pyrido- Ω. , 2a7 £ L, 3jdiazepine

810

3-Ethoxycarbonyl-8-methyl-5-oxo-4,5-dihydro-pyridoA * 2a7 £ L, 37diazepine

1 ^ 229

SOO

3-ethoxycarbony 1-7 meth yl-5-oxo- «t, 5-dihydro-pyridoA» 2a7A, 37diazepine

3029

297

3-Athoxycarbony 1-pyrido Ci. , 2a7 A »37diazepine

4500
1 + 003

S68 56U

3-carboxy-5-chloro-7-methy 1-pyridoA, 2a7 A »37-diazepine

183 «*

213

3-ethoxy carbonyl-8-chloro -5-oxo-H, 5-dihydro-pyrido

620

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Can ρ.ο. /Continues.2 link / ing / kg? Anesthetic time 500 / secj? Renewal! Il
3-ethoxy carbonyl-7-me-
thyl-pyrido- / l, 2a7 / 1.37 -
diazepine 327

3-ethoxycarbonyl-5-chloro

-7-methyl-pyrido / l, 2a7-

/ 1,3 / diazepine 500 - »» 58

As can also be seen from the above, “these diazepine derivatives of the new type also have like the other diazepine derivatives, a considerable narcotic * - sepotenting effect. This effect can advantageously be used due to the low toxicity of the compounds be, the connections can be called minor-tranquillante be used.

Further details of the procedure are given in the examples discussed without restricting the invention to the examples.

example 1

1 «*, 6 g / 0.05 mol of 2-r5-methyl-2-pyridil? -Aaino-methylene-succinic acid diethyl ester are introduced into 100 ml of diphyl oil at 220-230 ° C. The solution will be on Heated to 250 ° C and stirred at this temperature. The calibration Ethyl alcohol forming from this reaction mixture is continuously distilled off. The alcohol calculated amount distilled off within 30 minutes.

Processing: The cooled reaction mixture is diluted with 100 ml petroleum ether, then only with 3x100 ml 5% hydrochloric acid solution, then with 3x100 ml 20% hydrochloric acid solution shaken out. The neutralization from the

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5% hydrochloric acid-aqueous phase and shaking with

Following benzene is the 3-ethoxy carbonyl-aiethyl7- ^| t-oxo-7 ~ - methyl-UH-pyrido / l ₉ 2a7pyrimidinbas8 obtained. Yield: 50-55%. The basil is crystallized twice from absolute alcohol. Q .: 128 -. 130 ⁰ C.

Calculated: C 63.40 H S ' _S 73 N 11.38% Found: C 63 _S 92 H 5 _S 58 N 11.42 %. The 20% hydrochloric acid-aqueous phase is processed similarly. The 3-ethoxycarbonyl-5-oxo-8- · -methyl-i + ₉ 5-dihydro-pyridoA _s 2a7 £ L ₉ 37diazepine base is obtained, with a yield of 25-28%. The crude product is once made from abs. Alcohol crystallized, or purified by colon chromatography. F .: 96 - 98 ° C.

Calculated: C 63.40 HS ₉ 73 N 11.38% Found: C 63.12 H 5 _s 8O N 11.28. %. In the above process j as starting material 2- £ 3-methyl-2-pyridi: L7-amino-methylene-succinic acid diethyl ester using, with a yield of 56%, we get 3- / ethoxycarbonyl-methyl / -4-oxo- 9-ynethyl- ⁱ lH-pyridoZ! L _s 2aL7r pyrimidine CP. : 88-90 ° C7.

If the starting material Z-ZS-quinolyl-aminO-methylen7-succinic acid diethyl ester is ₉ with a yield of 60%, we get 3- / ethoxycarbonyl-methyl7- - «♦ -oxo-ifH-benzo ^ f7pyrido £ L, 2a7pyrimidine Z ^- P .: 121- 122 ° C7, and with a yield of 7%, 3-ethoxy carbonyl-5-oxo- -U, S-dihydro-benzo / gJpyridoA, 2aJ / I _S 3? Diazepine / Φ .: 11O- 112 ° O7.

Example 2

Mi ^ t 14.6 g A), 05 Moi7 2- / 4-methyl-2-pyridil7- -amino-methylene-succinic acid diethyl ester is used in Example 1 described ring closure reaction carried out.

Processing: The sparingly soluble 3-ethoxy carbonyl-5- is extracted from the reaction mixture with 300 ml of petroleum ether. -oxo-9-methyl-4, 5-dihydro-pyrido / l, 2a_7 A »37-diazepine pre-

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zipited. Yield: 56%. The crystals are in 20-fold abs. Recrystallized alcohol. F .: 148-15O ⁰ C. Calculated: C 63.40 H 5.73 N 11.38% Found: C 62.90 H 5.92 N 11.44%. The diphyl petroleum ether mother liquor is extracted with hydrochloric acid solution, the aqueous acid phase is neutralized and extracted with benzene. A mixture of the above-described pyridodiazepine derivative and the corresponding pyrido / l, 2a7pyrimidine derivative is obtained. The mixture is separated using, for example, column chromatography; 3- / Athoxycarbonylmethyl7-4-oxo-8-methyl-4H-pyrido / 1,2a7pyrimidine is obtained with a yield of 10%. The crystals are in 4-fold abs. Recrystallized alcohol.

.F: 118 - 120 ⁰ C.

Calculated: C 63.40 H 5.73 N 11.38% Found: C 63.82 H 5.82 M 11.29% '

Example 3

10.8 g / 0.1 Mo] I of 2-amino-6-methyl-pyridine and 20.2 g / 0.1 mol of 2-formylsuccinic acid diethyl ester are dissolved in 150 ml of diphyl oil. The solution is gehitzt with stirring within 1 hour at 250 ⁰ C. First water, then ethyl alcohol is distilled from the mixture. After distilling the calculated amount of water and alcohol, the solution is cooled and worked up according to Example 1. The product is purified by column chromatography. With a yield of 25%, the 3- / Athoxyke ■ QnyJ. « -Methyl7-4-oxo-6-methyl-4H-pyridoA, 2a7pyrii & idin #. ι 89-90 ° Cj

/ Calculated: C 63.40 H 5.73 N U »38 I

Found: C 63.57 H 5.58 N U, 29 IJ and with a yield of 15-20% da «3r ^

-methyl - **, 5-dihydro-pyrido / l, 2 * 7 A 98 - 100 ⁰ C?

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calculated: C 63 _s 40 H 5.73 K-11.38% Found: C 63.12 H 5.82 N 11.1 * 0 $? obtain.

Example i »a.

At 27.8 g / 0.1 mole? 2- £ 2 ~ Pvridil-amino-methylenj-succinic acid diethyl ester are 46 g / 0.3 mol? least. Phsophoroxychloride added. The mixture is warmed to boiling, then 3 ml of polyphosphoric acid is added dropwise to the solution over half an hour. After this step, the development of the salt acid gas gradually ceases in the course of a further one and a half to two hours. During which the temperature of the oil bath 130-13 5 ⁰ C, the internal temperature is between 110-120 ⁰ C. At the end of reaction, the mixture at 6O-7O ° C is cooled, then, in small Protionen, 100 ml abs . Alcohol dripped in. It separates the crystalline 3-iÜthoxykarbonyl-methyU - ^ - oxo- ^ H-pyrido / l, 2a7pyrimidin-hydrochloride from the solution.

The salt is made up of 15 times the amount of abs. Recrystallized alcohol. Q .: 239-2UQ ⁰ C *.

Calculated: C 53.65 H> », 88 N 10.42 Cl 13.19% Found: C 53.21 H 5.01 M 10.35 Cl 12.98%.

The above mother liquor is diluted with water to three times its volume and the mure-aqueous alcoholic Solution extracted with benzene. The residue is purified with vacuum fractionation or column chromatography and thus the 3-ethoxycarbonyl-5-chX © 2 »~ py2 * ido / l, 2a7-A, 37-diazepine obtained with a yield of 2-3%. F .: «t3- ^ 6 ° C.

Calculated: C 57.49 HH ₉ "* 2 N 11.18 Cl It, IU%

Found: C 57.82 H 4.68 N 10.62 Cl 13.90%. The ~ aqueous phase neutralizing »shaken out with benzene and working up the benzene solution becomes more Amount of 3-ZAthoxycarbonyl-Methy ^ - «» - oxo - «» H-pyrldo-

-1 "+ -
300840/1108

£ L »2a7pyrimidine obtained as a base. The base is made from 3-fold Section. Recrystallized alcohol. F. 115-116 ° C. Overall yield: 80-84%. Calculated: C 62.06 H 5.21 N 12.06% Found: C 62.23 H 5.31 N 12.01%.

Example 4b

If the above reaction is carried out on the ice V / that the boiling time is only 1 hour and the internal temperature of 108 - is 110 ⁰ C, we obtain the reaction mixture worked up as above in addition to 3- / Athoxykarbonyl-methyl7-4-oxo -4H-pyrido / l, 2a? Pyrimidine with a yield of 65-70% ^ the 3-ethoxycarbonyl-5- -OXO-U, 5-dihydropyridoA, 2a7 / 1 * 3? -Diazepine with a yield of 2-3 %. The base is recrystallized from 15-fold alcohol. F .: 141-143 ° C.

Calculated: C 62.06 H 5.21 N 12.09% Found: C 61.78 H 5.23 N 12.44%.

Proceeding according to procedure 4a7 and as starting substance 2- £ 5-chloro-2-pyridi ^ 7-amino-methylene-amber-

Il

Using acid ^ -diethyl ester, we get 3-ethoxycarbonyl-methyl7-4-oxo-4H-pyridoA, 2a-pyrimidine with a yield of 50-55% / F .: 141-142 ⁰ C, HCl F .: 218-219 ° C7 and 3-ethoxycarbonyl-5,8-dichloropyridoA, 2a7A »3J-diazepine with a yield of 2-3%, mp .: 87-9 ° C.

2- £ 3-hydroxy-2-pyridil7-amino-methylene-amber-

Using stinic acid diethyl ester, we get 3-ZAth-oxycarbonyl-methy: iJ-4-oxo-9-hydrox3.-4H-pyridoA, 2a7pyrimidine with a yield of 80% /."H .: 174-177 ° C, HCl, F .: 247-248 ° C, decomposition ?.

2- £ δ-methyl-2-pyridi ^ 7-amino-methylene-succinic acid diethyl ester Applying this, we get 3- / ethoxycarbonyl-methyl7-4-oxo-6-methyl-4H-pyridoA , 2a7pyrimidine with a yield of 40% / T .: 91-92 ° C, HCl, mp .: 238-239 ° C7 and S-Athoxycarbonyl-S-chloro ^ -methyl-pyridolA, 2a7 / l »37-

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diazepine with a yield of 40% / F .: 31-36 ⁰ C ₉ HC10 _U , F .: 197-98 ⁰ C ₉ boiling point; 175-180 ⁰ CZO ₉ H.

Example 5

To 29, V g / O ₉ I Mo] J 2- / fc-methyl-2-pyridiI? -Requ

no-methylene-succinic acid diethyl ester are added 86 ₉ 0 g £ 0.3 Μοΐ7 Phosphoroxycfolorid ". The mixture is stirred 9 and choosing a = half an hour, 3 ml Polyphosphateäuz * e häszugetröpfelt ₉ then the solution is warmed to 6O-7O ° C stirred for half an hour in a 130-110 ° oil bath 0igen, hydrogen bromide gas developed = After the mixture is cooled to 70 ⁰ C and hinzugetröpfelt 100 ml abs. alcohol in small portions.

The 3- / ethoxycarbonyl-methyl7 = H «-oxo-6-methyl-

- ⁱ m-pyrido £ L, 2a7-pyrimidine hydrochloride salt crystallizes out of the solution. Yield? 30%. The crystals are recrystallized from 17 times abs "alcohol" F .; 228 ° C decomposes? ·

Calculated: C ** 7 ₉ 72 H «», 63 M 8-, 56. Br ~ 24.1 (2% Found: C, 47 88 H ^ ₉ 83 N 8 ₉ 38 Br 2U ₉ 31 I. The mother liquor of the crude product-with diluted water to the 3-fold volume and extracted with Beng © l The benzene _solution?. is then dried eingedapmft _s * The residue is terworfen a Vakuurnfpaktionierung pm =, or crystallized from 2-fold P'etrdäther. "3-Athoxykarbonyl-7-methyl-pyrido £ l, -2 € i7 / l» i7diazepin is obtained with a yield of 2 «4% obtained. F .: 67 ⁰ C ₉ boiling ..

point: 162-16i + ^o C / 0.3 Hgram; HCl salt, F. ι Calculated: C 67.81 H 6.13 N 12.17% Found: C 67 ₉ 62 "H 5.32 N 11.95%

Example 6

To the 0.14 g of A ₉ oil mol. 7 sodium hydroxide solution _{prepared with 8 ml of water, 2 9} 6 g of Zt) ₉ oil mol. 3-ethoxycarbonyl-methyl7-4-oxo-6,8-dimethyl-4H-pyridq7-

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CX »2a7pyrimidine ££. : 96 ~ 98 ° C7 and the mixture was stirred at room temperature. 20-30 minutes later we get a sharp solution. The solution is acidified to pH 3 with 20% hydrochloric acid. The precipitated crystals are filtered off with suction and washed with water. In this way we obtain 3- / carboxyl-methyl7 ~ U-oxo-6,8-dimethyl-HH- -pyrido £ 1,2a7-pyrimidine with a yield of 80%. F .: 182-183 ° C.

Calculated: C 62.06 H 5.21 N 12.06%.

Found: C 61.95 H 5.25 N 12.30%.

ti

It is made from S-Athoxycarbonyl-methy ^ -f-oxo-g- -methyl-UH-pyridoA, 247-pyrimidine 3-Z-carboxyl-methyl7-t- -oxo-9-methyl-4H-pyridoA, 2a7-pyrimidine CT. : 211-213 ° C7;

from 3-ZAthoxy! carbonyl-methy 17-U-OXO-T-ChIOr- ^ H- -pyrido O. , 2a7-pyrimidine; das / 3 -carboxy-methylJ-i-oxo -? - -chlor-4H-pyridoA, 2a7-pyrimidine Ct .: 253-255 ° C; Decomp. 7,

from S- ^ Athoxycarbonyl-methylI-H-oxo-benzo / i / -pyridoA , 2a7-pyrimidine S-Z-carboxy-methyl ^ -U-oxo-HH-benzo / "f7pyrido £ L, 2a7-pyrimidine / F .: 223-225 ° C, decomposition?

Example 7

50 ml of 2.5% NaOH solution are added to 13.3 g Λ> .05 mol7 S-carboxy-S-chloro-T-methyl-pyrido / i, 2a7A, 37diazepine. The mixture is boiled gently for an hour and a half. The solution obtained is acidified to pH 6 with 20% hydrochloric acid. The precipitated crystals are filtered off with suction and recrystallized from »» 0-fold, 96% alcohol. In this way we get 3-carboxyl-5-chloro-7-methyl-pyridoss., 2a? A, 37diazepine with a yield of 75-80%, F .: 232-23H ⁰ C.

Calculated: C. 55 , 83 H 3 , 83 N 11 ,8th"* Cl 1* , 98 % Found : C. 55 , 62 H 3 , 90 N 11 , 75 Cl m , 50 %.

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Example 8

_ it

2.3 g / 0.01 mol 3-ethoxy carbonyl-7-methyl ~ pyx »i-

do / i _s 2a7 / l, i7diazepine are concentrated in 3 ml. ¹ dissolved sulfuric acid. With external cooling, 2 ml of 10Q% nitric acid is instilled in at a temperature of 20-25 ° C. over a period of 10 minutes. Machher wiipd the solution at 2i "@ ~ STEM temperature for half an hour long guarded ₉ g SO Eis'gegossen and the pH of the solution with a ^1% strength 2 © © a- IaOH solution on the value of pH 2" Di The brown-colored substance selected is filtered and the S-ethoxycarbonyl-5-nitro-7-methyl-pyrido / l ₉ 2a7Zl3jdias @ pin is obtained with a yield of 69%.

The crystals crystallized from 5-faeher abs.Alkohol, we get a white colored substance ₉ at 1 OH - melts 106 ⁰ C.

Calculated: C 5S ₉ 72 H H ₉ TB N 15.27% Found: C 56.33 "H-1", 8 & 1%, _S 98%.

Example 9

2.5 g / 0.01 Hol / 3-Atfo © 2sykarbonyI-5-Qhlor-pyri ^b doA, 2a? / I, 3jdiazepin w @ rd © si in 20 ml abs. Dissolved alcohol _s then 0.8 g / 0.01 HoL? @ rhitst © ever tried g Matfieaazatat and Oj25'g Pd / C catalyst are hinsugefögto The - Beteleganis i vung takes place within 15 minutes, "ttaetsher the catalyst and the precipitated macl from .of ^ solution is filtered, the alcohol distilled _s the residue in Ben -.zol added, the Besizollösimg washed with water, dried and evaporated. The residue is purified by vacuum fractionation. 3-Ethoxycarbonyl-p ^ idoA »2a7-Af37diazepine is obtained with an itobdiat © from SS -9 ©%. F .: 52-5 ° C, boiling point: 16 ° C / O ₉ 2 Hiiä ^ Calculated: C 6S ₉ SS HS ₉ SS N 12 _{9 9} % - Found: C 66,> 8 H 5.97 N 12s9O

Example 10

To I ¹ *, 6 g / 0.05 mol? 2 ° ß-pyridilamino-methylene /

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Diethyl glutarate is 22.9 g / 0.15 mol of phosphorus oxychloride admitted. The solution is heated to the boil and 1.5 ml of polyphosphoric acid are added over half an hour trickled in. It is stirred and heated until the evolution of hydrochloric acid ceases.

Afterwards, 50 ml of abs is added to the reaction mixture, which has been cooled ^{to 70 ° C.} Alcohol dripped in. The precipitated crystals are filtered off and in 2-fold abs. Recrystallized alcohol. The 3- / 2-ethoxy carbonyl-ethyl? -4-oxo-4H-pyrido / 1,2a7pyrimidine hydrochloride salt is obtained, with a yield of 65%. F .: 187-189 ° C decomposition?

Calculated: C 55.23 H 5.3 »» N 9.91 Cl 12.5 «»% Found: C 55.05 H 5.38 N 9.87 Cl 12.71%.

Example 11

15.3 g / 0.05 Mol_7 2- £ 6-methyl-2-amino- pyridil7-methylene-glutaric acid diethyl ester are added to 100 ml Diphylöl of 200-22O ⁰ C. The solution is warmed to 250 ° C and stirred for minutes at this temperature,

ti

while the ethanol berencheter amount from the reaction mixture is distilled. After cooling, the solution is diluted with 100 ml of petroleum ether and 2 x 100 ml of 5% strength Hydrochloric acid solution shaken out. The acidic-aqueous phase is shaken through with benzene, then following the neutralization with chloroform the 3-Z "2-ethoxy carbonyl-ethyl7 -» »- -oxo-e-methyl-HH-pyrido / l, 2a7 ~ pyrimidine extracted. The chloroform solution is evaporated and the residue is crystallized with a 1-fold amount of ethyl acetate. That

pyrimidine is obtained with a yield of 55-60%, F .: 91-93 ° C, obtain.

Calculated: C 6 "", 60 H 6.20 N 10.76% Found: C 6 "" ^ 7 H 6.20 N 10.87%.

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Claims (18)

PATENT CLAIMS ■ J /. Process for the preparation of new compounds of the formula I and their salts and quaternary salts » - '/ in which R ₁ and R ₂ each represent a hydrogen atom or together form a group of the formula -CHsCH-CHsCH- attached to two adjacent carbon atoms of the ring A; the ring Ä can optionally carry one or more substituents,
R _{4 is} a carboxyl group or a carboxylic acid derivative radical; R _{3 is} an oxo group if η = 0; or is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, aryloxy, nitro- or A-mino, if η = 1; m = 0 if η = 1 or m = 1 or 2 if η = 0, where if η = 1, one of the dashed lines denotes a single bond and the other denotes a double bond and if η = 0, the endocyclic dashed line is a single bond and the exocyclic dashed line represents a double bond? characterized in that aJ a compound of the formula II is cyclized / in which R ^ ₉ R ₂ and A have the above meaning; R ₅ and R _ß denote a carboxyl group or a carboxylic acid derivative radical and p = 1 or 27; or b_7 a compound of the formula III or its salt / in which R ₁ , R ₂ and A have the above meanings? with a compound of the formula IV reacts / in which R ₅ , Rg and ρ have the above meanings? and the compound of formula II formed cyclizes; and, if desired, in a compound of the formula V / in which R ₁₅ R ₂ * n, -m, A and the dashed lines have the meaning given above, -2o- 309840/1 198 Rg represents a carboxyl group or a carboxylic acid derivative radical;
R _{7 is} an oxo group if η = 0 or R _{7 is} hydrogen, Is halogen, hydroxy or oxo if η = 17
an Rg group into an R ^ group and / or an R _? -Gruppe is converted into an Rg group and, if desired, a compound of the formula I obtained in this way is converted into a salt or quaternary salt or a compound of the formula I
from their salt or quaternary salt. 2. The method according to claim 1, characterized
marked that one as the starting material
Compounds of the formula II or IV are used in which R ₅ and Rg are carboxyl groups or alkoxycarbonyl groups. 3. The method according to any one of claims 1 to 2, characterized in that as Starting material uses compounds of the formulas II or III in which the Α ring is replaced by one or more halogen atoms, Alkyl, nitro, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl, carboxamido, alkylamino or acylamino groups is substituted. ^. Method according to claims 1 to 3, thereby characterized in that the cyclization of the compounds of general formula II is based on thermal Ways is carried out. 5. The method according to claims 1 to U, characterized in that the thermal Cyclization is carried out in the presence of an inert solvent. 6. The method according to claims 1 to 5, characterized characterized in that diphyl oil, trichlorobenzene, paraffin oil or as the inert solvent a mineral oil fraction is used. 7. The method according to claims 1 to 3, characterized characterized that the cyclical -21- 309840/1 198 ization of the compounds of general formula II in the presence is carried out by acidic condensation tools. 8. The method according to claims 1 to 3 und'7, characterized in that as acidic condensing agent phosphorus oxychloride, Phosphoi "- oxybromide, phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric ₉ Polyphosphorsä" re _s = poly phosphoric acid · ethyl ester or its Mixtures are used. 9. The method according to claims 1 to 8 _S, characterized in that the Zykli ° sierung between temperatures of 25 ° C and 400 ⁰ C is carried out. 10. The method according to method b / desAnspruchs Ij, characterized in that the compound of the formula II formed by reacting the compounds of the formulas III and IV is cyclized directly in the reaction mixture without isolation of the same. 11. The method according to any one of claims 1 to. 10, characterized in that an R ₇ group is converted into a series of Rg groups by one of the following reactions: if R ₇ = hydrogen by reaction with halogenating agent, advantageously replaced by halogen with bromine, converted into a nitro group by reaction with a nitrating agent , the nitro group optionally reduced to an amino group, a compound in which R ₇ denotes halogen converted into an alkoxy compound by reaction with an alcoholate or converted into an aryloxy compound by reaction with a phenolate or converted into hydrogen by catalytic dehalogenation. 12. The method according to any one of claims 1 to 11, characterized in that an R group is converted into an R _u group by one of the following reactions: an alkoxycarbonyl group is hydrolyzed into the carboxyl group, by conversion with hydrazine or -22- 309840/1198 its hydrate or salt is converted into the acid hydrazide group, converted into a carobxamido group by reaction with ammonia, this group if necessary by treatment with a dehydrating agent »advantageously with phosphorus pentoxide is converted into a nitrile group or a carboxyl group is converted into an alkoxycarbohyl group by esterification or converted into an acid chloride by reaction with thionyl chloride. 13. The method according to claim 1, characterized in that a compound of Formula I with non-toxic organic or inorganic acids, advantageously with formic acid, acetic acid, Salicylic acid, citric acid or malic acid, or hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid or Perchloric acid ums etζt. IU. Method according to Claim 1, characterized . characterized in that a compound of the ¹ formula I is mixed with a quaternizing agent, advantageously with an alkyl halide, advantageously methyl iodide or a dialkyl sulfate, advantageously dimethyl sulfate or diethyl sulfate; or a p-toluenesulphonic acid ester, preferably p-toluenesulphonic acid methyl ester or benzenesulphonic acid ester, advantageously quaternized benzenesulphonic acid methyl ester. 15. Pharmaceutical preparations, thereby characterized in that they are a compound of formula I or their salts or quaternary as active ingredient Contain salts. 16. Process for the production of pharmaceutical preparations, characterized in that das8 one a compound of formula I or its salt or quaternary salt mixed with "inert solid or liquid carriers. 17. Compounds of the formula I or their salts or quaternary salts / in which the substituents are the -23- 309840/1198 claim 1 have given meaning? 18. The compounds of the formula I listed in the examples 3Q984Ö / 1 198 Blank page