DE2262912A1 - PYRIDO SQUARE CLAMP ON 3.4-SQUARE CLAMP FOR PYRIDAZINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents

Description

ryrido / 5 ^ -d7pyridazine derivatives and processes for their

Manufacturing

The invention "relates to new pyrido / 3, 4-c [7pyridazine derivatives with a strong diuretic effect.

Numerous types of diuretics, some of which are in the Practices have been developed. Typical examples are the chlorothiazide derivatives, acetazolamide, Triamteren, trifrocin and purosemide should be mentioned. However, the known diuretics are not very satisfactory because they have one or more of the following disadvantages exhibit: They promote the excretion of potassium and sodium, cause side effects (e.g. increase in the blood sugar level and the uric acid level in the blood serum) if taken for a long time and have a fairly low diuretic effect and fairly high toxicity.

The new pyrido / 3 *, 4-d7pyridazine derivatives have those above mentioned disadvantages do not have and proved to be effective and improved diuretics. Subject of Accordingly, the invention relates to the new pyrido / 3,4-d7pyridazine derivatives and their pharmaceutically acceptable salts as well as an industrially feasible process for the manufacture

309828/1137

creation of these new connections «

The pyrido / 3,4-d7pyridazine derivatives according to the invention have the general formula

(D

in which R _{1 is} a hydrogen atom or a lower alkyl radical with 1 "to 4 carbon atoms, R _{2 is} an alkyl radical with 1 to 4 carbon atoms, an aralkyl radical with 7 to 8 carbon atoms or an unsubstituted or with a lower alkoxy radical with 1 until

3 carbon atoms, a lower alkyl radical with 1 to 3 carbon atoms, a halogen atom or a nitro group Phenyl radical, naphthyl radical, furyl radical or pyridyl radical, R, represents a hydrogen atom or a lower alkoxy radical with 1 to

4 carbon atoms and R. a morpholite group which is unsubstituted or substituted by a methyl radical or ethyl radical, Is piperidino group or pyrrolidino group.

The alkyl radical with 1 to 4 carbon atoms, for which R ₁ and Rp can stand, is, for example, a methyl radical, ethyl test, n-propyl radical, isopropyl radical, n-butyl radical, isobutyl radical, sec-butyl radical or tert-butyl radical.

The aralkyl radical for which R _{2 can} stand is, for example, a benzyl radical or phenylethyl radical.

The lower alkoxy radical with 1 to 4 carbon atoms for which R ₅ can represent, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy are possible.

In the case of the alkoxy radical with 1 to 3 carbon atoms, the substituent of the radical R _{2 is, for example, a methoxy radical, eth-}

309828/1 137

oxy radical, n-propoxy radical or isopropoxy radical, in the case of dea Alkyl radical with 1 to 3 carbon atoms, for example a methyl radical, ethyl radical, n-propyl radical or isopropyl radical and in the case of the halogen atom, for example, a chlorine atom, bromine atom, fluorine atom or iodine atom.

The radicals R ₂ or R. can be substituted one or more times and preferably contain one or two substituents. If these radicals are polysubstituted, the substituents can be identical or different.

The pharmaceutically acceptable salts of the compounds (i) are salts with inorganic acids, e.g. hydrochloric acid, Sulfuric acid, nitric acid and phosphoric acid, and salts with organic acids, e.g. oxalic acid, fumaric acid, tartaric acid and malic acid, in. question »

The compounds of the general formula (I) and their Pharmaceutically acceptable salts can be prepared according to processes (A) and (B) described below will.

In process (A) the compounds (I) are prepared using compounds of the general formula

R, X

J- I

(II)

in which R ₁ , R ₂ and R ^ have the meanings given above and X is a halogen atom or an idio group, are reacted with an unsubstituted or substituted with a methyl or ethyl radical morpholine, piperidine or pyrrolidine.

According to process (B), the compounds (I) are oxidized by compounds of the general formula

309828/1 1 37

(in)

in which R ₂ , R * and R. have the meanings given above and Rc is an easily split off hydrocarbon radical.

The thio group to be removed by the above reaction is usually a residue of the general ones Formula -S (O) mR, where m is 0, 1 or 2 and R is a lower alkyl radical having 1 to 2 carbon atoms, an aralkyl radical with 7 to 8 carbon atoms, e.g. a benzyl radical or pbenylethyl radical or an aromatic radical, e.g. a phenyl radical or tolyl radical.

The easily split off hydrocarbon radical is generally an aralkyl radical with 7 to 8 carbon atoms, for example a benzyl radical or phenylethyl radical, or an alkyl radical or alkenyl radical with 1 to 4 carbon atoms, for example an isopropyl radical, tert-butyl radical, sec-butyl radical or Allyl residue. The alkyl radical or alkenyl radical is preferably branched.

Possible halogen atoms for which X is, for example, chlorine, bromine, fluorine and iodine.

The starting compounds (II) and (III) can be prepared by known processes.

The starting compounds of the general formula (II) in which X is a halogen atom are prepared, for example by converting compounds of the general formulas

COOR _fi R ₂ I.

R * 3

(IV)

309828/113 7

22S29Y2

in which R ₁ , R ₂ and R * have the meanings given above and ■ tic is a lower alkyl radical having 1 to 5 carbon atoms, with hydrazine to form compounds of the general formula

3 0 (VI)

in which IL, R ₂ ^{and <ä} % ^ ^{iö have the meanings given} above, and reaction of the compounds (VI) with Biösphöro-xychlö'-rid to give compounds of the general formula

in which R ^, R ₂ and R * have the meanings given above and Y is a halogen atom *

The starting compounds of the formula (H) * in which X is a is ihio group are prepared by reacting the compounds of the general formula (VII) with a metal hydrosulfide, e.g. sodium hydrosulfide, to compounds of general formula

SH

(VIII).

in which R ^, R ₂ and R_- have the abovementioned meanings, and initialization of the compounds obtained (VIII) with a compound of the general formula

RZ (ϊχ)

in which R has the meaning given above and Z is a halogen

309828/1137

atom or an aromatic sulfonyloxy group, e.g. p-Toluolsulfonyloxyest is, to compounds of the general formula

in which R ₁ , R ₂ and R * have the meanings given above, and optionally by reacting the compounds (X) with an oxidizing agent, for example hydrogen peroxide, m-chloroperbenzoic acid and peracetic acid, to form compounds of the general formulas

SOR

iand / pder

SOR

(XI) (XII)

wherein R ₁ , R ₂ , R-, and R have the meanings given above.

The starting compounds of the general formula (III) are for example, prepared by a process in which compounds of the general formula

h ? 4

R / T T (ΧΙΟ)

in which R ₂ , R ^, R ^ and R ^ have the abovementioned meanings, in the manner described in connection with process (A) and hydrogenating these compounds in the presence of a catalyst, for example palladium carbon.

If in the process (A) of the compound (II) in the X

3098 2 8/1137

is a halogen atom, the reaction is carried out in the presence or absence of a solvent » All solvents that do not interfere with the reaction are suitable, e.g. alcohols such as methyl alcohol and Ethyl alcohol, ether, e.g. "Tetrahydrofuran and ethyl ether, Hydrocarbons and halogenated hydrocarbons such as benzene and chloroform and esters such as ethyl acetate. To remove the hydrogen halide formed as a by-product during the reaction, the reaction system a suitable basic reagent such as pyridine and N, N-dimethylaniline can also be added as an acid acceptor.

The substituted or unsubstituted morpholine, piperidine or pyrrolidine is generally used in an amount of at least 2 moles per mole of the compound (II). If the cyclic amine is used in excess, can it serves both as a solvent for the reaction and as an acid acceptor.

The reaction temperature is generally in the range of -20 ° to 300 ⁰ O, preferably in the range of 15 ° to 150 C. The reaction is generally complete in a time of 1 to 5 hours.

If compounds of the formula (II) in which X is a thio group are used as a starting point in process (A), the reaction conditions can be carried out under the same reaction conditions as in the case in which X is a halogen atom. In this package, however, in order to achieve higher yields, it is expedient to carry out the reaction under an elevated pressure of 1 to 100 atm. (Manometer pressure) and at a temperature of 20 to 300 ⁰ C, preferably from 50 to 250 ° C, to be carried out.

In process (B), the reaction is generally carried out by combining the compounds of the general formula (III) with an oxidizing agent. Usual oxidizing agents are suitable, e.g. permanganic acid or permanganate, nitric acid, halogens, e.g. chlorine and bromine, peroxides, e.g. hydrogen peroxide, sulfuric acid

3 0 9828/1137

compounds, e.g. Caro's acid, oxygen acids, e.g. Chloric acid and bromic acid, or their salts, metal complexes, e.g. potassium ferricyanide, metal salts, e.g. iron (IIl) chloride and copper (II) sulfate, oxygen and building materials Gases, e.g. air, metal oxides, nitrobenzene and iodine compounds. Of these oxidizing agents, Xaliuiiferricyanid, Oxygen, air and nitrobenzene are preferred. When using potassium ferricyanide, it is advisable to to keep the reaction mixture alkaline.

Any solvent that does not interfere with the reaction can be used. For example, are suitable Water, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride and dichloromethane, ethers such as tetrahydrofuran and diethyl ether, and mixtures of these solvents.

The reaction is usually carried out at a temperature of -10 ° to 15O ⁰ C, preferably from 20 ° to 100 ⁰ C. It is generally completed in a time of 1 to 10 hours.

The oxidizing agent is generally used in an amount of 1 to 50 moles, preferably 1.2 to 20 moles per mole of the Compound (III) is used.

After the reaction by the method (A) or (B), the reaction product is usually out of the reaction mixture in the form of a free base by customary methods, e.g. by evaporation, crystallization or chromatography, isolated. Of course, the reaction product obtained in the form of the free base can be prepared by processes known per se be converted into the above-mentioned pharmaceutically acceptable salts.

The compounds of general formula (I) and their pharmaceutically acceptable salts are effective diuretics, which in detail have the following properties:

309828/1137

1) The compounds according to the invention are effective and strong diuretics ».

2) They have extremely low toxicity.

3) They cause the elimination of a large amount of sodium ion, but only a relatively small amount of the potassium ion as :, is sin essential element of the human body with the urine "That excretion ratio of Na ⁺ / K ⁺ in urine is thus the compounds relatively high according to the invention.

4) The compounds according to the invention can be used in humans and animals in which a maximum diuresis with known Diuretics causes a marked additional diuretic response. That fact leaves conclude that the mechanism of the diuretic action of the compounds according to the invention of the known diuretics is different. By combining the compounds according to the invention with other known ones Diuretics can thus produce a greatly increased diuretic effect.

The compounds according to the invention are used as diuretics as such or in the form of pharmaceutically acceptable ones Preparations mixed with suitable conventional carriers or adjuvants administered. As pharmaceutical preparations Tablets, granules, powders, capsules and injection liquids come in embossing that are oral or parenteral can be administered. The usual daily dose of the compounds is in the range of about 10 to 200 mg for the adults for oral administration and in the range of about 5 to 100 mg for parenteral administration. .

The invention is further illustrated by the following examples. In these examples the parts are understood as parts by weight. Parts by weight relate to parts of space as grams to cubic centimeters.

309828/1137

_ ic -

22629t2

Manufacture of the raw materials

1) Preparation of 1 ^ -Dichlor ^ -Cp , 4-d7pyridazine

10 parts by weight of 3,4-diethoxycarbonyl-6- (p-metboxyphenyl) -2-methylpyridine are added to 40 parts by volume of hydrazine hydrate. The mixture is refluxed for 3 hours. The precipitated crystals are filtered off, washed with ethanol and suspended in 100 parts by volume of water. The mixture is acidified with acetic acid, whereby 1,2,3,4-tetrahydro-7- (p-methoxyphenyl) -5-methyl-1,4-dioxopyrido / 3 _f 4-d7pyridazine is formed in the form of colorless fine crystals. 3.0 parts by weight of the fine crystals, 45 parts by volume of phosphorus oxychloride and 4 »5 parts by volume of N, N-dimethylaniline are mixed. The mixture is kept at a temperature of 90 to 100 ^° C. for 3 hours. The reaction mixture is then left to stand at room temperature overnight. The precipitated crystals are filtered off, washed with ether and recrystallized from chloroform, whereby the desired compound, which has a melting point of 214-219 ° C. (decomp.), Is obtained in the form of pale yellow needles.

2) Production of 1 ^ -Dimethylmercapto-T-phenyl-pyrido- 13 * 4-d / pyridazine

A methanolic solution of Kaliomhydrosulfid is through Implementation of 7 parts by weight of potassium hydroxide, 150 parts by volume Methanol and hydrogen sulfide gas produced by the known method. Become this solution 4.2 parts by weight of 1 ^ -Dichlor ^ -phenyl-pyrido / J, 4-d / pyridazine given. The resulting mixture is stirred for 3 hours at room temperature. The methanol is reduced under The pressure is evaporated and the residue is added to 50 parts by volume of water, a solution being formed. The solution will be acidified with acetic acid, whereby yellow crystals are precipitated. The crystals are filtered off with water washed and dried, 1,4-Dimercapto-7-phenyl-

309828/1137

2282912

pyrido / 3,4-d7pyridazine with a melting point of 212-215 C (dec.) is received »

3.0 parts by weight of the compound thus prepared become 220 parts by volume of a TO ^ aqueous sodium hydroxide solution given, whereupon 3.7 parts by weight of methyl iodide were added will. The mixture is 3 hours at room temperature stirred, whereby crystals are precipitated * The crystals are recrystallized from ethanol, whereby the desired Compound is obtained in the form of colorless needles with a melting point of 155 ° C «

3) "Production of 1 ^ - 7-phehylpyrido / 3,4-ä_7pyridazine

7.6 parts by weight of ethyl 2-amino-2-benzyl acrylate and 8i1 parts by weight - Parts of ethyl 2-benzoylacetate are in 10 parts by volume Dissolved methanol. The mixture is stirred for 4 days at room temperature. The methanol is under reduced pressure evaporated. 50 parts by volume of hydrazine hydrate and 10 parts by volume of water are added to the residue Heated for 7.5 hours on the reflux condenser. After cooling, the precipitated crystals are filtered off and mixed with Washed methanol, 9.0 parts by weight of the hydrazinium salt of 1 ^ -diyäroxy ^ -benzyl-T-phenylpyrido / f ^ -ciZ-pyridazine can be obtained.

9.0 parts by weight of the product are dissolved in 2.5% hydrochloric acid suspended. The mixture is stirred for 5 hours at room temperature. The precipitated crystals are filtered off and washed with methanol, 7.3 parts by weight of 1,4-dihydroxy-5-benzyl-7-phenylpyrido / f, 4-d7pyridazine can be obtained.

7.3 parts of the product are added to a mixture of 70 parts by volume of phosphorus oxychloride and 14 parts by volume of dimethylaniline. The mixture is ^{heated to 110 °} C. for 1 hour, whereupon excess phosphorus oxychloride is evaporated off under reduced pressure. The residue is poured into ice water

309828/1137

given. The precipitated crystals are filtered off and recrystallized from chloroform-ether, 8.0 parts by weight of 1,4-dichloro-5-benzyl-7-ph ^/ enylpyrido / 5't4-d7pyridazine being obtained.

8.0 parts of the product are dissolved in 60 parts by volume of Morsholin. The solution is kept at 150 ° C. for 2 hours, whereupon excess morpholine is evaporated off under reduced pressure. Ethanol is added to the residue. The mixture is left to stand at room temperature. The precipitated crystals are separated off and washed with ethanol, 8.0 parts by weight of 1,4-Dimorpholi & o-5-benzyl-. 7-phenyl-pyrido / 3,4-d7pyridazin are obtained of melting point 165-168 ⁰ C.

3.0 parts of the product are dissolved in 30 parts by volume of acetic acid, after which palladium-carbon is added. The catalytic hydrogenation is carried out at normal pressure. After a hydrogenation time of 21 hours, the catalyst is filtered off and the filtrate is concentrated, yellow crystals being precipitated. The crystals are washed with ether, with 1 part by weight of 1,4-dimorpholino-5-benzyl-5,6-dihydro-7-phenylpyrido / 3,4-d7pyridazin v, om melting point is obtained 168-17O ⁰ C.

example 1

0.5 parts of 1 ^ -Dichlor ^ -methyl-S-methoxypyrido / T ^ - ^ - pyridazine "and 3.6 parts of morpholine are kept at 80 ° C. for 1.5 hours, after which the excess morpholine is distilled off. The residue becomes water This oil is triturated with a small amount of methanol, crystals of 7-methyl-8-methoxy-1,4-dimorpholino-pyrido / I, 4-d7-pyridazine being formed a mixture of methanol and water (1S3) yields crystals of melting point 145-146 ⁰ C. yield 0.5 part by weight file,

3 0 9 8 2 8/1 1 37

Element arenalyae:

Calculated for C ₁₇ H ₂₄ O ₅ F ₅ :

Found; .

In the manner described above, the following connections are made:

JJ ι 6th 22629 12th , 11 6th η: 59 , 10 , 71 20 , 28 59 , 81 20 , 09

30 9 8 2.8 / 1137

R. R- R- R. Melting point and elemental analysis, $> yield, *

^{1 2? 4} appearance CHN

H -CH, -OCH, -IT \ 109-110 ⁰ C calc. 66.83 7.97 20.51

⁵ 5 v_ / pale yellow needles found 66.58 7.75 20.31

H Y3 ^H "O ^{3 158 to 172} °° calc. 66.82 6.14 18.56

66

»Y3 O,,

ro pale brown fine colored 66.64 5 »74 17.53

oo granules

- * H -OH -lTb 183 ⁰ C calc. 67.50 6.44 17.89

* w pale yellow fine found 67.38 6.43 17.61

G
^ j - granules

^H "Ο H -10 149 to 150 ⁰ C above 73.96 7.29 18.75

yellow platelets found 73.85 7.31 19.00

H-CH ₂ -O-OCH, -lC ⁰ 174 to 175 ⁰ C ber.65.65 6.46 16.62 ^ pale yellow plok- found 65.32 6.22 16.68 ken

H-CH ₂ -CH -OGH, -nQo 123 ⁰ C calc. 61.99 7.54 18.08 80 Ni

CH found 61.99 7.51 18.02 KJ

3 CD

2.0 parts of 1,4-dichloro-7-phenylpyrido / 3,4-7-pyridazine are added to 20 parts by volume of 2-methylmorpholine. The mixture is maintained 4 hours at 130 to .140 ⁰ C. The excess 2-methylmorpholxn is evaporated off under reduced pressure. Water is added to the residue, forming crude crystals which are recrystallized from η-hexane, 1,4-bis (2 ^l -methylmorphollno) -7-phenylpyrido / 5,4-d7pyi'iäazine in the form of yellow prisms of melting point 75 to 81 ⁰ C is obtained.

Elemental analysis: " CHN Calculated for C ₂₃ H ₂₇ O ₂ N ₅ : 68.12 6.71 17.27 Found: 68.26 6.95 16.98

The experiment described above is repeated, but using the same amount of 2,6-dimethylmorpholine instead of 2-methylmorpholine, 1,4-bis (2 *, 6 '-dimethylmorpholinoO ^ -phenylpyrido ^, 4-d7pyridazine of melting point 248 -25O ⁰ C is obtained in the form of yellow fine needles.

Elemental analysis t C H Έ

Calculated for C ₂₅ H ₃₁ O ₂ N ₅ J 69.25 7.21 16.16 Found: 69.25, 7.17 16.19

Example 3

1.0 part 1,4-DiChIOr ^ - (p-methoxyphenyl) -5-methylpyrido- 13 * 4-d7pyridazine is added to 10 parts by volume of morpholine "The Gemis.ch is kept at 130 ° C. for 3 hours" The excess morpholine is evaporated under reduced pressure. Water is added to the residue. The crude crystals formed are filtered off and recrystallized from ithen oil, with 7- (p-iaethoxyphe: nyl) -5-methyl-1,4-aimorpholinopyrido _J / 3 ^, 4-d7pyridazine in the form of gray prisms with a melting point of 206-209 ⁰ G. " Elemental analysis:
Calculated for CpJSp ₇ O-JET, -Gef undent 65 ^ 42 6.26 16.55

6th H 6th , 46 , 26 G 54 42

3B9S28 / 1137

In the manner described above, the following compounds of the general formula (I) produced:

^R 1

-CH ₃ CH ₃ -
-CH ₃

⁴⁰ -GH oo -Wi ₃

ro

OQ

-GH,

-CH, Cl

5 ^

H Ql-

z H Cl 1 -GH,

^R 4 Melting point and
Appearance ber.
found Elemental analysis,
CH N 6.71
6.75 17.27
17.49 Cl H O 222 to 224 ⁰ C
pale yellow needles ber.
found 68.12
67.83 7.48
7.22 16.77
16.54 H -O 174 to 176 ⁰ C
yellowish-orange
colored needles ber.
found 71.91
71.95 6.08
6.00 18.36
18.03 H 163 to 164 ⁰ C
yellow granules ber.
found 62.98
63.52 5.54
5.39 19.26
18.70 H -N 0 218 ⁰ C
brown crystals ber.
found 60.54
60.12 5.68
5.68 16.44
16.24 H -N 0 246 to 247 ⁰ C
yellow needles ber.
found 62.04
62.14 5.68
5.66 16.44
16.43 8.32
8.93 H- -NO 184 to 186 ⁰ C
yellow needles ber.
found 62.04
62.10 5.38
5.54 17.01
16.8.1 8.32
8.33 H. -N O 217 to 221 ⁰ C ber.
found 61.23
61.15 5.38
5.50 17.01
16.85 8.61
8.68 H -0 179 to 180 ° G
yellow needles ber.
found 61.23
61.12 6.16
6.00 21.42
21.33 8.61
8.55 H 221 to 224 ⁰ C
yellow needles 64.27
64.15

1 part 1,4-dimethylmercapto-7-phenylpyrido / 3,4-d.7pyridazine and 10 parts by volume of morpholine are placed in a glass tube, which is then sealed. The reaction system is maintained for 8 hours at 18O ⁰ G. The excess morpholine is evaporated off under reduced pressure. Water is added to the residue. The crude crystals precipitated in the process are filtered off and then adsorbed on a silica gel column. Elation is carried out with a mixture of acetone and benzene (1: 4). The eluate is evaporated under reduced pressure. The residue is recrystallized from methanol, 1,4-dimorpholino-7-phenyl-pyrido / 3,4-d7-pyridazine being obtained in the form of pale yellow needles. -

Example 5

0.47 parts of 1 ^ -Dimorpholino ^ -benzyl- ^ ö-dihydro- ^ - phenylpyrido / 5,4-d7pyridazine are dissolved in 20 parts by volume of benzene while heating. A solution of 3 parts of potassium ferricyanide in 20 parts by volume of water is added to this solution. A solution of 1.5 parts of potassium hydroxide in 3.5 parts by volume of water is added to the mixture while stirring, and stirring is continued for a further 1.5 hours. The benzene layer is separated off and washed with 10 parts by volume of a 10% aqueous sodium hydroxide solution and twice with 50 parts by volume of water each time. The benzene layer is dried over anhydrous sodium sulfate and concentrated by evaporating the benzene under reduced pressure. The residue is recrystallized from ether to give 0.25 parts of 1,4-Dimorpholino-Gewo-7-phenylpyrido obtained 3 ~ i4-d7-pyridazin of melting point 175-176 C ^b /.

Elemental analysis: Sf ₅ O ₂ .0, 5H ₂ O MBB C_ • H 18th _Y_ Calculated for C ₂₁ H ₀ ,] 65 , 26 6th , 26 18th , 12 Found: 65 , 26 6th , 28 , 18

.309828 / 1 137

Example 6

1 part i ^ -Diraorpholino ^ -phenylpyrido / f ^ -d / pyridazine is dissolved in 50 parts by volume of ethanol while heating. The solution is 10 parts by volume of a 10bigen ethanol Hydrochloric acid solution added. The mixture is cooled, 1,4-dimorpholino-7-phenylpyrido / 3,4-d.7-pyridazine hydrochloride is precipitated. The product (1 part by weight) is filtered off and recrystallized from 50 parts by volume of ethanol, the desired compound being obtained in high purity in the form of orange needles with a melting point of 176-181 ° C will.

Elemental analysis: C H N

Calculated for C ₂₁ H ₂₄ O ₂ N ₅ Cl 60.93 5.84 16.92 Found: 60.74 5.70 16.72

Example 7

In the manner described in Example 1, the following pyrido / 3,4-d7pyridazine derivatives of the general Formula (I) produced:

^R 1 R ₂ H
-OC ₄ H ₉
(n) V Enamel
point and
Appearance Elemental analysis, $ H
H -OHj -O 130-131 ⁰ C.
orange
colored
Tile
108-110 ⁰ C
pale brown
ne needles CHN cal. 73.01 6.71 20.28
found 72.90 6.62 19.96
calc. 61.99 7.54 18.08
found 61.85 7.58 17.95

309828/1137

Claims (25)

in which R _{1 is} a hydrogen atom or a lower alkyl radical having 1 "to 4 carbon atoms, R _{2 is} an alkyl radical having 1"to; 4.C atoms, an aralkyl radical with 7 to 8 carbon atoms or a uhsubstituierter or with a lower alkoxy radical with 1 to 3 carbon atoms, a lower alkyl radical with 1 to 3 carbon atoms, a halogen atom or a nitro group Pheayl radical, naphthyl radical, furyl radical or pyridyl radical, R, represents a hydrogen atom or a lower alkoxy radical with 1 to 4 carbon atoms and R. an unsubstituted or with one Methyl radical or ethyl radical substituted morpholino group, Piperidino group or pyrrolidine group is, as well as pharmaceutical: liribedenlcrich'e salts of these compounds. 2) Pyridö. / J ^ -d / pyridazine derivatives according to claim .1 with the formula mentioned there, in which R ^ is a hydrogen atom, R _{2 is} an unsubstituted or a lower alkoxy radical with 1 to 3 carbon atoms, a lower alkyl radical Phenyl radical substituted with 1 to 3 carbon atoms, a halogen atom or a nitro group, R is a hydrogen atom and R. is a morpholino group * 3) Pyrido / 3, ^ - d / py ^ idazinderivate according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R _{2 is} a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an aralkyl group with 7 to 8 carbon atoms or an unsubstituted phenyl group or tolyl group, R- is a hydrogen atom or an alkoxy group with 1 to 3 carbon atoms and R. * is a ■ 309828/1137 unsubstituted morpholino group, piperidino group or Is pyrrolidino. 4) pyrido / 3 _f 4-d7pyrida2inderivate according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R ₂ with an alkyl radical with 1 to 3 carbon atoms, a Alkoxy radical with 1 to 3 carbon atoms, a halogen atom or a nitro group substituted phenyl or tolyl radical or an unsubstituted or the same substituents as R ₂ containing thienyl radical, R _{5 is} a hydrogen and R. is an unsubstituted morpholino group, piperidino group or pyrrolidino group. 5) Pyrido / 3,4-d7py * "idazine derivatives according to claim 1 with the formula mentioned there, in which R. is a hydrogen atom or an alkyl radical with 1 to 3 carbon atoms, R _{2 is} an unsubstituted phenyl radical or tolyl radical, R is a hydrogen atom and R. is a morpholino group, piperidino group or pyrrolidino group substituted by a methyl radical or ethyl radical. 6) Pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a phenyl radical, R is a hydrogen atom and R. is a morpholino group. 7) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a methyl radical, R is a methoxy radical and R ^ is a piperidino group. 8) Pyrido / 3,4-d7pyridatinderivat according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a phenyl radical, R _{5 is} a hydrogen atom and R. is a morpholino group. 9) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a 309828/1 1 37 p-Methoxyphenylrest, R- a hydrogen atom and R ^ a Is morpholino, 10) pyrido / 3 ~, 4-d_7pyridazine derivative according to claim 1 with the formula mentioned there, in which R ^ is a methyl radical, R _{2 is} a p-tolyl radical, R is a hydrogen atom and R ^ is a morpholino group. 11) pyrido / 3 ~, 4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a p-methoxyphenyl radical, R is a hydrogen atom and R. is a piperidino group. 12) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, - R _{2 is} a 2-furyl radical, R is a hydrogen atom and R. is a morpholino group. 13) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a p-nitrophenyl radical, R is a hydrogen atom and R is a morpholino group, 14) Pyrido / 3,4-d_7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a p-chlorophenyl radical, R ^ is a hydrogen atom and R is a morpholino group. 15) pyrido / 3,4-d_7pyridazinderivat according to claim 1 having the specified therein Pormel in which R ₁ is a methyl radical, R ₂ is m-chlorophenyl, R, is a hydrogen atom, and R. is a morpholino ₀ 16) pyrido / 3 *, 4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a p-chlorophenyl radical, R is a hydrogen atom and R. is a morpholino group. 309828/1 137 17) pyrido / 3,4- <i7pyridazinderivat 'according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} an m-chlorophenyl radical, R is a hydrogen atom and R. is a morpholino group. 4th 18) pyrido / 3,4-c [7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a methyl radical, R _{2 is} a 3-pyridyl radical, R is a hydrogen atom and R ^ is a morpholino group. 19) Pyrido / 3,4-d_7pyridazinderi vat according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a phenyl radical, R, a hydrogen atom and R. is a piperidino group. 20) pyrido / 5,4-d_7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a sec-butyl radical, R is a methoxy radical and R is a morpholino group. 21) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom, R _{2 is} a phenyl radical, R ^ is a hydrogen atom and R. is a 2-methylmorpholino group. 22) pyrido / 3,4-d7pyridazine derivative according to claim 1 with the formula mentioned there, in which R _{1 is} a hydrogen atom. R _{2 is} phenyl, R is hydrogen and R. is 2,6-dimethylmorpholino. 23) hydrochlorides of the compounds according to claim 1 to 22, 24) Process for the preparation of pyrido / 3,4-d7pyridazine derivatives according to claims 1 to 23, characterized in that compounds of the general formula 309828/1137 .- 23 - 2262312 in which R ₁ , Rp and R, have the meanings given above and X is a halogen atom or a thio group, is reacted with an unsubstituted or substituted with a methyl or ethyl radical, piperidine or pyrrolidine. , 25) process for the preparation of pyriae / 2,4-ä_7pyridazine derivatives according to claims 1 to 23 _f characterized in that compounds of the general formula are used. I. V i ⁴ I. ^R 2 T
H in Rp ₁ R., and R. have the meanings given above and R, - is an easily aT> cleavable hydrocarbon residue, is oxidized. 309828/1137