DD286580A5 - METHOD FOR PRODUCING AMIDINOHYDRAZONES 2-SUBSTITUTED BENZOPHENONE - Google Patents

Abstract

The invention relates to a process for the preparation of amidinohydrazones of 2-substituted benzophenones of the general formula I. The object of the invention is to develop 2-substituted benzophenone amidinohydrazones having an antiarrhythmic and anti-ischemic action as well as a large therapeutic range and a long duration of action. The task of developing a preparation process for such compounds was achieved by reacting 2-substituted benzophenones with aminoguanidine salts. Formula I

Description

-2- 286 580 Field of application of the invention

The invention relates to a process for the preparation of amidinohydrazones of 2-substituted benzophenones of general formula I.

/ J-R

C = N, NH-C-HX

^S NH-R '

in the

A = NH ₂ , NHAalkyl, N (alkyl) ₂ , OH, OAlkyl, COOH

B = H, halogen, OH, OAlkyl, alkyl, NO ₂

C = H, halogen

R u. R '- H, phenyl, substituted phenyl

and HX mean a common for pharmaceuticals inorganic or organic acid.

Among these compounds, there are biologically active substances, especially those which have antiarrhythmic and anti-ischemic action with a relatively large therapeutic range and long duration of action. The invention is applicable in the pharmaceutical industry.

Characteristic of bekannton technical solutions

The reaction of carbonyl compounds with aminoguanidines to give amidinohydrazones is known in principle (see Houben-Weyl, "Methoden der Organischen Chemie", Georg Thieme Verlag Stuttgart, Vol.7 / 1, p.470 [1954], Vol.7 / 2 b 1958 [1976]; Vol.8 / 1, p.192-19311952)).

The previously described amidinohydrazones of benzophenone and benzophenone derivatives do not correspond to the general formula I. In no case do the known compounds have a hydrophilic substituent in the 2 · (or 2'-) position. The amidinohydrazones of benzophenone and 4-hydroxybenzophenone have been described as having analgesic, spasmolytic and antiinflammatory activity (Ugine Kuhlman, Fr.PM7.858, Fr.181927, v.30.12.1968, issued 20.4.1970, K1.A6IK, C07C) , Particularly intensively multi-substituted Benzophenonamidinohydrazone were processed, the Halogenbzw usually. Wear trifluoromethyl substituents in 3- to 4- or Ί'-position. These compounds have been described primarily for their suitability as antimalarials (Do Amaral, JR, et al., J.mod.Chem.12,21 (1969), Ruiz, R., and DMAviado, Pharmacology 4,45 (1970); French , F., et al., J. Med. Chem., 14, 862 [1971]) as well as their antineoplastic (cytotoxic) properties (Baiocchi, F., eial., J. Med. Chem., 6,431 [1963]; French, FA, et al., Cancer Chem. part. 2,2,177 [1971]). Antifungalo, antibacterial, antiviral and Antimycoplasma-Wirkungön should also 'N-substituiertoAmidinohydrazoneS ^^ - have trisubstituted benzophenones, being mentioned as substituents CI _{1 is} CH _3, OH and OCH ₁ (Nishimura, T., et al, Jap.P.. 79115330, v. 27.2.1978, dated 7.9.1979, class A61 K31 / 15, C07 C133 / 10). In two of the already mentioned compounds with antimalarial activity a weak antiarrhythmic effect was described as a side effect. It is the 4-fluoro-4'-trifluoromethylbonzophenonamidinohydrazone and the S ^ -Dichlor ^ '- trifluoromethylbenzophenonamidinohydrazone. However, these compounds are not suitable for therapeutic use (Ruiz, R., and DM Aviado, loc. Cit.) Because of the low strength of this quality of action and the very low therapeutic width due to their high toxicity.

Object of the invention

The object of the invention is to develop new compounds of the type of the 2-substituted benzophenone amide ionhydrazones with antiarrhythmic and antiischemic action as well as a broad therapeutic range and a long duration of action.

-3- 286 580 Presentation of the Essence of the Invention

The invention has for its object to provide a process for the preparation of Amidinohydrazonen 2-substituted benzophenones.

The object has been achieved in that benzophenones of the general formula II

C = O

A - NH], NHalkyl, N (alkyl) ₂ , OH, OAlkyl, COOH B = H, halogen, OH, OAlkyl, alkyl, NO,

C = H, halogen

mean, with Aminoguanldlnsalzon the general formula I.

NR H ₂ N-NH-C

ⁿ NH-R '

in which R and R '= H, phenyl or substituted phenyl, are reacted.

The reaction is carried out in a suitable solvent, preferably ethanol or aqueous ethanol, with addition of acid,

z. As hydrochloric acid or nitric acid, usually carried out under reflux conditions.

The compounds prepared according to the method can occur in each case in the Z and in the Ε form, wherein as a rule Mixtures of the two stereoisomers can be obtained. If necessary, a separation by fractional Crystallization be made because the conversion of pure crystalline salts because of the relatively high energy barrier

between the two stereoisomeric forms is immeasurably slow.

The compounds prepared according to the method are novel and show, in particular the Z-form, biological effect

All antiarrhythmic and antiischemic effect with relatively large therapeutic range and long duration of action. The anti-arrhythmic effect quality of the compounds mentioned has been demonstrated in relation to numerous forms of arrhythmia.

The test erfoi _ü 's after intravenous and oral administration to the animal experimental models Aconitinarrhythmie,

g-strophanthinarrhythmia and Ca-arrhythmia and 3 versus ischemic-induced arrhythmias at

Occlusion model. Particularly striking was the 2-amino-5-chlorobenzophenone-amidinohydrazone. This substance is

antiarrhythmic highly effective, which is demonstrated by the example of the rat Aconitinarrhythmie after intravenous and oral administration based on the determined from the dose-response curves ED _2O words.

The studies on dose-response dependence on the acoriitin model were carried out comparatively for the Z isomer, the E-! Somere and the Z / E mixture of 2-amino-5-chlorobenzophenone amidinohydrazone. The following ED ₂₀ values for the beidon stereoisomers and the mixture illustrate a stronger one

Antiarrhythmic activity for the Z-isomer, which could be demonstrated both after intravenous and nr.ch oral administration:

Substance iv-ED _N (mol / kg) po-ED _N (mol / kg)

Z-isomer 4.0 x ίο- · 3.5 · ΙΟ " ⁵ E-isomer 1.1 · 10 "» 7. "· io- ⁴ Z / E Gemiich 1.2 * ΙΟ " ⁶ 2.1 ΙΟ " ⁴

In contrast, quinidine and ajmaline on the rat aconitin model are much weaker in both types of administration

effective.

In addition, both the Z and the Ε-isomers of the rat Aconitinarrhythmie unfold after a single oral dose

strikingly longer duration of action than that of quinidine, ajmaline and duopyramide.

Both stereoisomers also show a consistent and very low intravenous and oral levels in the rat

Toxicity.

On the basis of the determined LD ₁₀ and ED ₂₀ values in the rat, a great therapeutic can be achieved in particular for the Z isomer Derive index after iV and po application. The therapeutic quotients (Q) for the Z-form have become Q ,. _v . - 40 and Qp o. ~ 74 calculated.

Another positive result of the Z-form, apart from the very good antiarrhythmic activity, is the anti-ischemic active component which could be detected on the models of isopronalin ischemia and coronary occlusion.

Overall, the antiarrhythmics mentioned with additional antiischemic efficacy are to be assessed as an internationally new class of substances with a novel mechanism of action.

The invention will be explained in more detail by exemplary embodiments.

AusfOhrungtbelsplele

1.) Preparation of Amldinohydrazon Mulls of 2-Substituted Benzophenones 0.1 mol of the benzophenone in question and 0.11 mol of aminoguanidine salt are dissolved in ethanol (100-150 ml) with warming and the solution, after addition of the calculated amount of the respective conc. Mineral acid (see Table 1) heated on the boiling water bath. After the specified reaction times, some reaction products crystallize from the batches. In other cases, a concentration of the solution i. Vak. to about one-third of their volume and possibly adding ether to the concentrate to separate the products. They are filtered off with suction, washed with a little ethanol and then with acetone or ether and dried. Purification can be carried out by recrystallization or UmfSllung.

Table 1

Amidinohydrazones 2-substituted benzophenones

NH

C = N-NH-C

HX

No. R ¹ R ^{1 RJ} R ⁴ X Reaction time (h) added acid Yield <%) Schmb.'C (off) Sum formula (molecular weight) Elementary analysis (%) calc .: N found: N 1 NH, H H H NO, 16 0,05MHNO, 45 189-196 (ethanol / ether) CmH "N, 0, (316,3) 26.57 26.74 2 NH, Cl H H NO, 12 0.05MHNO ₁ 47 from 232 uZ (H ₂ O) CH ₁₅ CIN ₆ O ₁ (350.8) 23,95 23,64 3 NH, NO, H H NO, 16 0,07MHNO, 40 from 237 u. Z. (methanol / ether) CuH ₁₅ N ₇ O ₅ (361.3) 27:13 27.19 4 NHCHj Cl H H NOj 24 0,1MHNO, 25 152-155 (acetone / petroleum ether) C ₁₅ H _n CIN ₈ O ₁ (264.8) 23.03 23.04 5 NHCH, Cl H H Cl 24 0,1MHCI 20 157-160 (acetone / petroleum ether) C ₁₅ H ₁₇ Cl ₂ N ₅ (338.2) 20,71 21,09 6 N (CH ₁ ), Cl H H Cl 40 0,25MHCI 90 302-306 (ethanol / ether) C ₁₁₁ H ₁₈ Cl ₂ N ₅ (352.3) 19,88 20,22 7 NH, H 3-CI H Cl 40 0,25MHCI 90 170-172 (ethanol / ether) CuH ₁₅ Cl ₂ N ₅ (324.2) 21.60 21.67 8th OH Cl H H Cl 36 0,25MHCI 65 262-265 (ethanol / ether) C ₁₄ H ₁₄ CI ₂ N ₄ O (324.9) 17,24 17,13

Continuation Table 1

No. R ' R ⁸ R ¹ R ⁴ X Reaction time (h) added acid From prey (%) Schmb.'C (off) Sum formula (molecular weight) Elementary analysis (%) calc .: N found: N 9 OCH, Cl H H Cl 24 0,25MHCI 76 160-162 (ethanol / ether) C ₁₅ H ₁₈ Cl ₂ N ₄ O (339.2) 16:52 16:33 10 COOH H H H Cl 48 0,25MHCI 24 217-220 (ethanol / ether) C ₁₆ H ₁₆ CIN ₄ O ₂ (318.8) 17.58 17.75 11 NH ₂ Cl H C ₆ H ₆ NO, 16 0.01 M ENT, 75 180-183 (propane-1-ol / ether) C ₁₀ H ₁₉ CIN ₆ O, (426.9) 19.68 19.27 12 NH; NO ₂ H CeHo NO, 24 0,01MHNO, 55 209-210 (methanol / ether) C ₂₀ H ₁₉ N ₇ O ₆ (437.4) 22.42 22,45 13 NH ₁ NO, H CjH ₄ -OCH, (2-) I 16 0.01 M HCl 85 130-133 (CHCl ₃ / ether) C ₂₁ H ₂₁ CIIN ₆ O (521.8) 13:42 13:16 14 NHCH, Cl H C ₆ H, NO, 24 0.01 M ENT, 15 158-160 (acetone / petroleum ether) C ₂₁ H ₂₁ CIN ₆ O, (440.9) 19.06 18.95

2.) Z- / E-2-Amino-5-chlorobenzophenonamydlnohydrazone · 2HCl 2 moles of 2-amino-5-chlorobenzophenone is dissolved with heating in 190 ml of ethanol and stirred with a solution of 1.2 mol of aminoguanidine hydrochloride in 100 ml of water and then with 236ml conc. Hydrochloric acid added. The batch is heated to boiling for 8 h on the water bath.

Thereafter, the product crystallized from the hot reaction mixture is filtered off with suction, washed with a little methanol and ether and then dried.

Z-2-Amino-5-chlorobenzophenonamidinohydrazone · 2HCl Yield: 45%, colorless crystals. Schmb.: 238-296 ⁰ C u. Dec. (Ethanol) (discoloration from 160 ° C.) C ₁₄ H ₁₆ Cl ₁ N ₆ (360.7) Ber .:% N 19.41 Gef .:% N 19.21

UV [^ ₁₁ (I ₀ C)]: 251 nm (4.26), 283 nm (4.31) (methanol) The crude product can be recrystallized from ethanol. The compound then crystallizes out with 1 mole of ethanol. Colorless crystals. Schmb.: 280-282 ⁰ C u. Dec. (Ethanol) CI ₆ H ₂₂ CIjN ₆ O (406.7) Calc .:% N 17.22 V:% N 17.52

The filtrate of the hot reaction mixture is allowed to stand. After cooling to room temperature, the crystallized product is filtered off, washed with a little methanol and ether and recrystallized. E-2-amino-5-chlorobenzophenone amidinohydrazone 2HCl Yield: 47%, colorless crystals. (/ Conc ethanol. HCI) Schmb .: 194-197 ⁰ C (discoloration from 16O ⁰ C, droplets of from 180 ⁰ C) C ₁₄ H ₁₆ CIjN ₆ (360.7) Calc .: 19.41% N Found .: % N 19.10

UV [^ _1x (IgC)): 231nm (4.37), 253nm (4.38) X _lh : 280nm (4.06), 372nm (3.72)

3.) Z '/ E ^ -Amlno-S-chlorobenzophenonamldlnohydrazon 0.5 mol of Z- or E ^ -Amino-S-chlorbenzophenonamidinohydrazondihydrochlorid be suspended in 3400ml or 1500ml of water and mixed with 500 ml of 3N KOH with constant stirring. Stirring is continued for 1 h at room temperature.

It is then filtered off, washed thoroughly with water, filtered under suction and dried.

Z-2-amino-5-chlorobenzophenone amidinohydrazone Yield: 85%, amorphous colorless powder.

Schmb.: 176-184'C

C ₁₄ H ₁₄ CIN ₆ (287.8) Calc .:% N24.34 Found:% N24.34

E-2-Amino-5-chlorobenzophenone amidinohydrazone Yield: 75%, amorphous yellow powder. Schmb .: 174 -194 ⁰ C (with decomposition). C ₁₄ H ₁₄ CIN ₆ (287.8) Calc .: 24.34% N Found .: 24.53% N

4.) Z 1 -Amino-S-chlorobenzophenone amide-1-hydrazone acetate

1) 0.5 mol of Z ^ -Amino-S-chlorbenzophenonamidinohydrazon be '* dissolved in acetone (about 500ml) with gentle warming, the optionally filtered solution is treated with 0.5 mol of acetic acid and the acetate was brought to crystallization by trituration It is filtered off, washed with a little acetone and ether and dried.

Yield: 90%, colorless crystals. Mb: 164-17O ⁰ C (droplets from 13O ⁰ C) (acetone) CuH ₁₁ CIN (O, (347.8) boron:% N 20.13 Gef .:% N 20.33 UV [^ _1x (IgC )): 251 nm (4.28), 283 nm (4.32) (methanol)

2) Dissolve 0.1 mol of Z-2-amino-5-chlorobenzophenone amidinohydrazondihydrochloride and 10 moles of sodium acetate (anhydrous) with 500 ml of ethanol and heat the mixture on a water bath for 2 hours. After cooling the mixture is filtered, treated with ether until cloudy and filtered again. Thereafter, the filtrate is largely concentrated and the remaining syrupy residue is added with gentle warming in acetone. When rubbing begins the crystallization. A second fraction crystallizes from the mother liquor when washing with a little acetone after aspiration of the main amount.

Yield: 70%, colorless crystals

5.) E ^ -amino-B-chlorobenzophenone amylphthalohydrezone acetate

0.5 mol of E-2-amino-5-chlorobenzophenonamidinohydrazone are dissolved under gentle heating in 450 ml of acetone. The optionally filtered solution is treated with 0.5 mol of acetic acid, wherein the acetate crystallized out immediately. It is filtered off, washed with a little acetone and dried

Yield: 95%, yellow crystals. Schmb .: from 186 ° Cu.Zers. (Droplets from 163 ° C) (acetone) C, _s H "CIN _b O ₂ (347.8) Ben:% N 20.13 Gef .:% N 20.20

UVI Xn _11x (IgC) I: 232 nm (4.39), 253 nm (4.39), Xn ₁ : 281.5 nm (4.06), 371 nm (3.78) (methanol)

6.) Preparation of further salts of Z-Z-Amino-S-chlorobenzophenone amide-1-hydrazone0.01 mol of Z-2-amino-5-chlorobenzophenone amidinohydrazone and 0.01 mol of alkanesulfonic acid or 0.02 mol of di- or

Tricarboxylic acid are dissolved in methanol or ethanol with slight warming. The salts either crystallize. Cool the solution or after addition of ether and trituration. Tartrate and citrate are initially greasy, but would

when triturated with ether several times.

Dio salts are filtered off and reprecipitated or recrystallized (Table 2). Table 2: Other salts of Z 1 -Amino-S-chlorobenzophenone amidinohydrazone

C = N ^N NH

No. HX designation Molecular formula (molar mass) Schmb.'C from: Elementary analysis ber.:%N gef.:%N Yield (based on base) 1 CHjSO ₃ H methanesulfonate C ₁₅ H ₁₁ CINsO ₃ S (383.9) 251-253 methanol / ether) 18,24 17,95 65 2 CjHjSOjH ethanesulfonate C ₁₆ HjOCINsOiS 200-204 (ethanol / ether) 17.60 17.46 80 3 HOCjH ₄ SOjH 2-hydroxyethane-1-sulfonate (isothionate, oxesylate) CuH ₂ OCINsO ₄ S (431.9) 160-163 (ethanol / ether) 16,92 17,11 70 4 HOOC-CHj-CH ₂ -COOH succinate C ₁₁ H ₂₀ CINsO ₄ (405.8) 197-199 (methanol) 17.26 17.37 60

Continuation Table 2

No. HX designation Molecular formula (molar mass) Schmb. ° C cus: Elementary analysis ber.:%N gef.:%N Yield (based on base) 5 HOOC-C = C-COOH H H maleate C ₁₈ H ₁₈ CIN ₆ O ₄ (403.8) 185-189 (methanol) 17,35 17,13 55 β , HOOC-CHOH-CHOH-COOH tartrate CH ₂₀ CIN ₅ O, (437.8) ab124u. Dec. (Methanol / ether) 16.00 15.83 35 7 HOOC-CHr C (OHhCH ₂ COOH COOH citrate C ₂₀ H ₂₂ CIN ₆ O ₇ from 139 u. Dec. (Methanol / ether) 14.65 14.56 30

Claims (5)

1. A process for the preparation of 2-substituted Benzophenonamldinohydrazone the al formula I, in the A = NH ₂ , NHalkyl »N (alkyl) ₂ , OH, Oalkyl, COOH
B = H, halogen, OH, Oalkyl, alkyl / NO ₂
C = H, halogen R u. R '= H, phenyl or substituted phenyl and HX is a common for pharmaceuticals inorganic or organic acid, eg. Acetic acid, hydrochloric acid, sulfuric acid, alkanesulfonic acid, aliphatic dicarboxylic acid (succinic acid, maleic acid, D (+) - tartaric acid), citric acid, characterized = N, NH-C that 2-substituted benzophenones of the general formula II, in which A, B and C have the same meaning as in formula I, with aminoguanidine salts of the general formula III in which R and R 'have the same meaning as in Formol I, CO H₂N-NH-C-HX ^X NH - R ' be implemented. 2. The method according to claim 1, characterized in that as benzophenones of the general formula II preferably soiche be reacted with an amino or substituted amino group in the 2-position. 3. The method according to claim Ί and 2, characterized in that the reaction is preferably carried out in ethanol or aqueous ethanol under Rückflußbedjängungen. 4. The method according to claim 1, 2 and 3, characterized in that the compounds of formula I are separated by fractional crystallization or reprecipitation in the respective Z and Ε forms. 5. Process according to Claims 1, 2, 3 and 4, characterized in that the compounds of the formula I in which HX is an acid other than that used for the condensation reaction are prepared by reacting the salts obtained by condensation with either excess alkali hydroxide solution are converted into the corresponding base and these are reacted with one to two molar amount of the respective acid, or with the molar amount of an alkali metal salt of the respective acid in a suitable solvent, preferably ethanol, are reacted. ι