United States Patent [191 4,594,421
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United States Patent [191 [11] Patent Number: 4,594,421 Bellani et al. [45] Date of Patent: Jun. 10, 1986 [54] IMIDAZOPYRIDINE COMPOUNDS [57] ‘ ABSTRACT [75] Inventors: Piero Bellani; Gaetano Clavenna; New imidazopyridine derivatives are described, having Alberta Sosio, all of Milan; Rinaldo the following formula: Pellegrini, Carbonera, all of Italy [73] Assignee: RBS Pharma (Roger Bellon Schoum) S.p.A., Milan, Italy [21] Appl. No.: 696,589 (CHM N N [22] Filed: Jan. 31, 1985 , R1 [30] Foreign Application Priority Data Feb. 2, 1984 [IT] Italy ............................. .. 19413 A/84 RR [51] Int. Cl.4 .......................................... .. C07D 487/04 wherein R represents a hydrogen atom, an alkylradi [52] US. _Cl. ............ .. 546/121; 546/264 cal of 1 to 3 carbon atoms, a methoxy group or a [58] Field of Search ....................................... .. 546/121 halogen atom, [56] References Cited R1 represents a hydrogen atom, an alkyl radical of l to 3 carbon atoms, U.S. PATENT DOCUMENTS 11 represents an integer of 1 to 10, 4,096,264 6/1978 Bochis et a1. ..................... .. 424/256 X represents a non-toxic pharmaceutically acceptable 4,141,898 2/1979 Kuhla ................................ .. 546/121 ion, which possess a skeletal muscle paralyzing activity. Primary Examiner—Richard A. Schwartz Assistant Examiner-Kurt G. Briscoe 5 Claims, No Drawings 4,594,421 1 2 ing activity, whose paralysing action promptly arises is IMIDAZOPYRIDINE COMPOUNDS short lasting and, at active doses, does not detectably interfere with the cardiovascular system. SUMMARY OF THE INVENTION The compounds of the present invention have been ,_ The object of the present invention is a new class of 5 pharmacologically studied, using as a standard imidazopyridine compounds having an interesting phar fazadinium bromide, i.e. l,l-azabis 3-methyl-2 macological activity. phenylimidazo 1,2-a pyridinium bromide, a known More precisely, the compounds of the invention have compound of the commerce, provided with a competi the following structural formula: tive skeletal muscle paralysing activity. The neuromuscular blocking activity has been evalu (1) ated: in vitro, using the phrenic-diaphragm preparation ' according to the method described by Biilbring E. (Brit. J. Pharmac. Chemother. l, 38, 1946). The preparation, 15 taken .from male Sprague-Dawley rats weighing 200-250 g, was placed into a bath for isolated organs, R1 thermostatically kept at 37° C. and containing a nutri tional liquid oxygenated with 5% carboxygen. The phrenic nerve was stimulated by means of square wave 20 RR impulses (12 per min., duration 0.5 msec., overmaximal voltage). All compounds under_examination and the wherein R represents a hydrogen atoms, an alkyl reference standard were added to the bath at cumula radical of l to 3 carbon atoms, a methoxy group or tive concentrations and showed to be active. The dose effect curve, determined for each of them, allowed to a halogen atom, 25 R1 represents a hydrogen atom, an alkyl radical of 1 calculate the EC50 or effective concentration able to to 3 carbon atoms, reduce the muscular contraction of 50% (Table 1); 11 represents an integer of l to 10, in vivo, using the sciatic-gastrocnemious preparation, X represents a pharrnaceutically acceptable ion. substantially following the method described by The abovementioned compounds (I) possess skeletal Hughes R. (Br. J. Anaesth. 44, 27, 1972). Male Sprague muscle paralysing activity, which develops through the Dawley rats weighing 200-250 g, anaesthetized (ure block of nervous impulse transmission at the level of the thane 1,2 g/kg i.p.) and submitted to forced ventilation, skeletal neuromuscular junction. were treated. The sciatic nerve was stimulated at a rate BACKGROUND OF THE INVENTION of 6 impulses per min. by means of square waves and 35 overmaximal voltage with a duration of 0.5 msec. The Drugs with this property are classi?ed, either as left carotid artery was incannulated for the continuous blockers of competitive type, if they compete with ACh registration of arterial blood pressure and heart rate. on cholinergic receptors situated on the post-junctional The compounds to be tested were administered by membrane, or as blockers of depolarizing type, if the i.v. route at increasing doses, given at .intervals of at neuromuscular block is preceded by depolarization of least 30 min. from one to another and, in any case, after the membrane. Moreover, agents provided with a com the effect of previous administration had completely bined competitive and depolarizing action are known, exhausted. even if scarcerly used in therapy. All compounds under examination and the Drugs provided with skeletal muscle paralysing ac tivity are clinically used, especially in anaesthesiology. fazadinium bromide showed to be active, so that it was Skeletal muscle paralysing agents of the depolarizing 45 possible to draw for each of them the dose-effect curve type are mainly provided with fast starting and shortly that allowed to calculate the EDSQ (effective dose caus lasting action. That makes them suitable for many thera ing the 50% reduction of muscular contraction) listed in peutic uses, even if it is known they may show serious Table 2. In addition, the time of latence (the interval complications, such as arrhythrnias, cardiac arrest and, between the administration and the maximal effect) and frequently, post-surgery muscular pains, just because of that of complete recovery have been determined. The their mechanism of action, which causes muscular fas percentage variations of arterial blood pressure and ciculation before the effect of neuromuscular block a heart rate at ED 50 on muscular contraction are reported starts. in Table 2. The skeletal paralysing agenst of competitive type do In addition to the study on rat,~ the compounds under not show the unwanted side effects, which may arise examination were administered by i.v. route to seven when using depolarizing blocking agents, but they are day-old chicks in order to observe what type of paraly characterized by a slow onset and a long lasting dura sis (?accid or spastic) had been induced. All compounds tion of action. Moreover, they could induce unwanted under examination have caused ?accid paralysis, show side effects, such as release of histamine, ganglionic ing that their mechanism of action is of a non-depolariz block, muscarinic receptor block (mainly, cardiac re 60 ing type. ceptors) and inhibition of the norepinephrine reuptake; Acute toxicity or LD50 was determined in male which effects could also induce relevant interference Sprague-Dawley rats weighing 1.2 g/kg i.p. The com with the autonomic control of circulation. pounds under examination were administered by i.v. route at different level doses (5 animals for each dose). DETAILED DESCRIPTION OF THE 65 The LD50 were then calculated according to the INVENTION method of Litch?eld J. T. and Wilcoxon F. J. (J . Phar It has now been found that the new compounds of mac. Exp. Then, 95, 99, 1949). The results obtained are formula (I) possess a competitive neuromuscular block reported in Table 3. 4,594,421 3 The compounds of the invention can be dissolved in suitable solvents making them suitable to the adminis tration, which is generally performed by parenteral, intravenous or intramuscular route. The pharmaceutical compositions can be formulated in a way suitable to 5 single or multiple dosage depending on their speci?c use. TABLE 1 (IV) Neuromuscular blocking activity "in vitro”. 10 Compound EC5Q (uM/l) Example 10 31.4 Example 9 28.9 Example 11 12.9 N Example 2 11.9 Example 12 115.2 15 (,1R1 HO Example 4 28.7 Example 8 13.6 on R1 Example 3 14.3 Example 7 15.4 Example 5 14.7 (II) Example 1 15.0 20 R 11 Fazadinium bromide 13.9 p. B TABLE 2 Neuromuscular blocking activity 25 “in vivo” and cardiovascular effects Cardiovascular @1 N (CH2). N N 1X effects Neuromuscular block Arterial Re- blood Heart R1 ED50 Latence covery pressure rate 30 Compound (pg/kg i.v.) (min.) (min.) A % A % Example 10 4.0 2.8 14.0 ~30 +28 (I) R Example 9 3.3 2.1 7.0 —31 +25 Example 11 2.1 2.3 8.8 —40 +42 Example 2 1.9 2.2 9.2 —45 +22 35 wherein R, R1, 11 and X have the above mentioned Example 12 5.6 2.6 12.2 4(a) +6 meanings. Example 4 5.0 1.3 6.2 —-28 +1 Example 8 1.3 2.1 7.7 -—-40 +68 The reaction for building the imidazolic ring usually Example 3 1.6 1.2 5.0 -—28 +40 is carried out at a temperature between 60° and 120° C. Example 7 3.0 1.5 9.8 — 50 — 8 and in practice the intermediate compound 11 may not Example 5 1.9 1.5 6.4 — 39 + 26 be isolated and the reaction may proceed until the for Example 1 ' 3.0 2.2 7.9 —37 +28 Fazadinium 1.0 1.5 6.6 — 16 +30 mation of the final compound I. bromide The intermediate compounds II are new compounds (“)—24% at minimal active dose on muscular contraction. themselves and show to be pharmacologically active. EXAMPLE 1 45 TABLE 3 l, l ’-(1,6-Hexamethylene)bis[2-(4'-fluoro)phenyl Acute toxicity in rat. ]imidazo[1,2-a]pyridinium perchlorate Compound LD50 (uM/kg i.v.) Example 10 8.8 A mixture consisting of 2.0 g of l,6-bis(2 Example 9 3.2 pyridylamino)hexane and 3.24 g a-chloro Example 11 3.1 p.fluoroacetophenone and 60 ml of 96% ethyl alcohol is Example 2 2.7 refluxed for 16 hours and then 4.0 ml of 70% perchloric Example 12 9.7 Example 4 4.3 acid is added thereto and the mixture is heated at the Example 8 2.0 boiling point for 2 hours.