RU2168987C2 - Hypotensive agent - Google Patents

Abstract

FIELD: medicine, cardiology, pharmacy. SUBSTANCE: invention relates to use of alkylidene derivatives of benzamidrazonium salts as hypotensive agents. Use of alkylidene derivatives of benzamidrazonium salts provides to broaden assortment of the known hypotensive drugs and enhance effectiveness and safety of treatment of patients with hypertension. EFFECT: enhanced effectiveness of agent, broadened arsenal. 1 cl, 1 tbl

Description

 The invention relates to organic chemistry and relates to pharmacologically active substances.

 Guanidine derivatives, the closest in structure to compounds with hypotensive activity, are related to postganglionic adrenergic blockers (sympatholytics) by the mechanism of action.

 This group includes the hypotensive agent widely used in clinical practice - octadine (guanethidine, isobarin, etc.). With the intravenous administration of guanethidine, a short-term increase in pressure is observed (after 10-20 minutes), followed by a long-term decrease in it, the hypotensive effect with oral administration develops slowly, reaches a maximum only on the 7-8th day of treatment, but remains for a long time.

 The drug causes orthostatic hypotension and increases daily fluctuations in blood pressure, prolonged use of the drug can lead to pulmonary edema and the development of resistance. Other side effects include complaints of muscle weakness, diarrhea, dry mouth, headache, nausea (vomiting), fatigue, fainting, and sexual dysfunction in men. With the use of octadine, there is a danger of heart failure, often sharp bradycardia. Great care should be taken when prescribing it to patients with cerebral atherosclerosis, with impaired renal function, it is absolutely contraindicated in pheochromocytoma [1].

 Another sympatholytic, guanodrel, acts shorter than octadine [2], in some cases it is preferred due to its better tolerance, but it also causes a number of side effects characteristic of octadine.

 Side effects of the drugs debrisoquin and guanacline are similar to those for guanethidine, and they cause rare occurrences for octadine: debrisoquin - profuse sweating and severe headache, guanacline - tachycardia, urinary retention, lightheadedness, swelling, constipation, gynecomastia. Guanaclor and guanoxane, in addition to the disadvantages characteristic of octadine, are hypatotoxic [1].

 The use of another guanidine analogue, guanabenza, causes a number of side effects, so there may be complaints of lethargy, dry mouth, taste perversion, frequent urination and sweating, toothache and headache, trembling limbs, skin rash, nervousness. This drug also has withdrawal symptoms [1].

 Based on the foregoing, the problem of a directed search for new antihypertensive drugs, combining therapeutic efficacy and maximum safety with prolonged use, remains relevant.

 Among the previously studied compounds, some derivatives of aminoguanidine are known to have a hypotensive effect [41. The closest analogues of guanidine are derivatives of amidrazones, little has been studied, however, some substances that lower blood pressure have also been found among them [5]. In this regard, it seemed appropriate to continue the search in this direction.

 The pharmacological activity of the proposed substances has not been previously described; these compounds were used only to study chemical transformations and the phenomenon of ring-chain tautomerism [6,7).

 The objective of the invention is the creation of new effective and safe antihypertensive drugs, expanding the range of available.

 The task is realized by the use of alkylidene derivatives of benzamidrazonium salts as antihypertensive agents.

 The hypotensive activity of 1-alkylidene (arylidene) benzamidrazonium iodides was investigated. For this purpose, condensation products of benzamidrazonium iodide (I) with mono (II) (anisic aldehyde, acetone) and dicarbonyl (III) (benzoyl acetic aldehyde, acetylacetone, α-methylacetylacetone, α, α-dimethylacetylacetone, benzoylacetone, acetoacetone) were obtained connections.

IIа: R¹=H, R²=(n-СН₃О)С₆H₅; IIб: R¹=R²=CH₃;
IlIa: R¹=H, R²=CH₂COC₆H₅; IIIб: R¹=CH₃, R²=CH₂COCH₃;
IIIв: R¹=CH₃, R²=CH(CH₃)COCH₃; IIIг: R¹=CH₃, R²=С(CH₃)₂COCH₃;
IIIд: R¹=CH₃, R²=CH₂COC₆H₅; IIIe: R¹=CH₃, R²=CH₂COOC₂H₅;
IIIд: X=Cl, остальные - X=I
Бензамидразоний иодид (I) получен по методу [8), перекристаллизован из этанола, т. пл. 176-178^oC.

IIa: R ¹ = H, R ² = (n-CH ₃ O) C ₆ H ₅ ; IIb: R ¹ = R ² = CH ₃ ;
IlIa: R ¹ = H, R ² = CH ₂ COC ₆ H ₅ ; IIIb: R ¹ = CH ₃ , R ² = CH ₂ COCH ₃ ;
IIIc: R ¹ = CH ₃ , R ² = CH (CH ₃ ) COCH ₃ ; IIIg: R ¹ = CH ₃ , R ² = C (CH ₃ ) ₂ COCH ₃ ;
IIIe: R ¹ = CH ₃ , R ² = CH ₂ COC ₆ H ₅ ; IIIe: R ¹ = CH ₃ , R ² = CH ₂ COOC ₂ H ₅ ;
IIIe: X = Cl, the rest - X = I
Benzamidrazonium iodide (I) was obtained according to the method [8), recrystallized from ethanol, so pl. 176-178 ^o C.

 Compounds IIb, IIIb-d, e were obtained by known methods: 1- (2'-propylidene) benzamidrazonium iodide (IIb) - according to the method [6); 1-benzimidoyl-5-hydroxy-3,5-dimethyl-2-pyrazolinium iodide (IIIb), as well as 1-benzimidoyl-5-hydroxy-3,4,5-trimethyl-2-pyrazolinium iodide (IIIc), 3, 3-dimethyl-2,4-pentanedione benzamidrazonium iodide (IIIg) and 1-ethoxy-1,3-butanedione benzamidrazonium iodide (IIIe) according to the general method [7].

1- (4'-Methoxybenzylidene) benzamidrazonium iodide (IIa) was synthesized analogously to compound IIb according to method [6) with a yield of 97%. Mp 168-171 ^o C, recrystallized from ethanol. Found,%: C 47.22; H 4.21; N, 10.92. C ₁₅ H ₁₆ N ₃ OI. Calculated,%: C 47.26; H 4.23; N, 11.02. PMR spectrum (DMFA-d ₇ ), δ ppm: 3.90 s (OCH ₃ ); 7.0-7.4, 7.6-8.2 m (H _arom. ); 8.90 s (CH), 9.84, 10.15 br. s. (NH); NH ⁺ signal is delocalized.

1-Phenyl-1,3-propanedione benzamidrazonium iodide (IIIa)
0.08 mol (21.04 g) of benzamidrazonium iodide was dissolved in 40 ml of methanol, and 0.085 mol (12.58 g) of benzoylacetic aldehyde was added dropwise to the solution with stirring. The mixture was kept at t = 18-25 ^° C for 24 hours, then the solvent was distilled off in vacuo (at 15 mmHg) without heating, the solid residue was recrystallized or re-precipitated with ether from a solution in chloroform. Yield 64%. Mp 60-63 ^o C, purified by reprecipitation with ether from a chloroform solution. Found,%: C 63.70; H 5.32; N, 13.91. C ₁₆ H ₁₆ N ₃ OI. Calculated,%: C 63.74; H 5.35; N, 13.94. 1 H-NMR spectrum (DMSO-d ₆ ), δ ppm: 4.28 d (CH ₂ , 6 Hz); 6.03 d (CH, 10 Hz); 7.2-8.2 m (H _arom. ); 9.55.9.90 br.s (NH); 12.90 br.s (NH ⁺ ).

1-Phenyl-1,3-butanedione benzamidrazonium chloride (IIIe). Saturated aqueous solutions of 0.08 mol (21.04 g) of benzamidrazonium iodide and 0.1 mol (18.50 g) of the benzoyl acetone sodium salt were poured with stirring, kept in the cold (t = 4-6 ^° C) until a yellow precipitate formed free base (usually 24 hours). It was filtered off, the solid precipitate was recrystallized, if necessary, then dissolved in diethyl ether. Benzamidrazonium 1-phenyl-1,3-butanedione chloride was obtained by passing an equimolar amount of hydrogen chloride through an ethereal solution of its base (until the solution was completely discolored). The precipitated crystals were filtered off and dried. The total yield of 47%. Mp 182-187 ^o C. Found,%: C 64.68; H 5.71; N, 13.31. C ₁₇ H ₁₈ N ₃ OCl. Calculated,%: C 64.72; H 5.75; N, 13.32. 1 H-NMR spectrum (DMFA-d ₇ ), δ ppm: 2.12, 2.26 s and 2.34 s (CH ₃ ); 4.30 s (CH ₂ ); 5.48 and 5.69 s (CH); 7.2-7.6; 7.8 - 8.1 m (H _arom. ), The signals of NH protons are partially blocked by the multiplet H _arom. partially delocalized.

 The antihypertensive effect of the compounds was studied on normotensive Wistar rats, as well as hypertensive SHR animals of both sexes, anesthetized with hexenal (60 mg / kg ip). The change in pressure was controlled in a direct way. All substances were administered in the form of aqueous solutions intravenously in doses of 0.01-200 mg / kg.

Acute toxicity was determined on white mice by intraperitoneal administration, LD _{50 was} calculated by the Miller – Taint method [9).

 It was found that with a single intravenous administration to laboratory animals, the compounds caused a significant and prolonged (within 24 hours of observation) drop in blood pressure. The effective dose range ranged from 0.01 to 150 mg / kg (see table).

 It was found that when administered in small doses (less than 2-5 mg / kg), all substances caused prolonged stable hypotension. An increase in the administered dose for most of the studied compounds led to a multiphase change in blood pressure characteristic of sympatholytics. So, at first a short phase of hypotension developed, then a slight increase in blood pressure was observed, which lasted an average of 10-30 minutes and was accompanied by increased and increased heart rate. After the hypertensive phase, prolonged hypotension developed.

 As can be seen from the table. effective doses of the compounds generally do not exceed 5 mg / kg, i.e., their hypotensive effect upon intravenous administration, unlike octadine, is not accompanied by an undesirable pressor reaction.

 The antihypertensive effect of all the studied substances in small doses in normo- and hypertensive animals was equally pronounced. With an increase in dose (more than 10-15 mg / kg), differences were noted: in the same doses, the decrease in blood pressure in normal and hypertensive animals was different. So, the higher the blood pressure before the administration of the drugs, the more their hypotensive effect was manifested.

 When comparing the obtained substances with known means - clonidine and guanethidine [10] - it becomes obvious that the compounds studied in many indicators, such as the breadth of the therapeutic effect, the magnitude and duration of the antihypertensive effect, low toxicity, etc., exceed the antihypertensive drugs used in medical practice both sympatholytic and other mechanisms of action (see table). The presence of a pronounced prolongation effect in the synthesized compounds will reduce both the therapeutic dose and the frequency of their administration.

 It was found that in addition to normalizing blood pressure, compounds I, IIb, IIIc cause a decrease in emotional stress, relieve pain, normalize heart rate, eliminate hypoxia, and the above effects favor the treatment of hypertension.

 Thus, all the proposed substances to one degree or another exhibit a hypotensive effect, which makes them promising for further in-depth studies.

LIST OF REFERENCES
1. Ed. V.V. Snacks. Clinical Pharmacology. Medicine, M., 1978, p. 92, 174.

 2. L.N. Yakhontov, S.C. Liberman. UVF, N 3, s. 269-286, 1987.

 3. Ed. J.E.F. Reynolds, Martindale The Extra Pharmacopoeia, 28 Edition, The Pharmaceuti-cal Press, London, 1982, pp. 142-148.

 4. J. Augstein, S. M. Green, A. M. Monroe, ets. J. Med. Chem., Vol. 10 (3), pp. 391-400, 1967.

 5. Ch. St. Davis, Patent USA 3458500, 1969. RZhim 17H279, 1970.

 6. B. A. Khrustalen, V.P. Sergutin, K.N. Zelenin, and others. HCG, N 9, p. 1264-1267, 1982.

 7. V.A. Khrustalev, O.V. Solod, K.N. Zelenin. ZhORKh, T. 22 (3), p. 500, 1986.

 8. K.M. Doyle, F. Kurzer, Synthesis, N 8, pp. 583-584, 1974.

9. M. L. Belenky. Elements of a quantitative assessment of the pharmacological effect. Gos. published honey. literature, L., 1963, p. 72,
10. RAMaxwell, AJPlummer, F. Schneider etc., J. Pharm. Exp. Ter., Vol. 128 (1), pp. 22-29, 1960; CT Dollery, B.Sc. Birm, D.Emslie-Smith etc., Lancet, ii, pp. 381-387, 1960; Lh. Page, HP Dustan, JAMA, vol. 170 (11), p. 1265, 1959.

Claims (1)

Antihypertensive agent, which is an alkylidene derivative of benzamidrazonium salts of the general formula

where at R ¹ = H, R ² = - (n-CH ₃ O) C ₆ H ₅ , -CH ₂ COC ₆ H ₅ , X = I;
when R ¹ = CH ₃ , R ² = CH ₃ , -CH ₂ COCH ₃ , -CH (CH ₃ ) COCH ₃ , C (CH ₃ ) ₂ COCH ₃ , -CH ₂ COOC ₂ H ₅ , X = I;
when R ¹ = CH ₃ , R ² = CH ₂ COC ₆ H ₅ , X = Cl.

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