Agent possessing topical anesthetic effect

FIELD: medicine, organic chemistry.

SUBSTANCE: invention proposes a derivative of 2,9-substituted imidazo[1,2-a]benzimidazole possessing the more effective topical anesthetic effect. As this derivative the invention proposes 9-(2-pyrrolidinoethyl)-2-(4-fluorophenyl)-imidazo[1,2-a]benzimidazole of the formula (I):

EFFECT: valuable medicinal property of agent.

6 tbl

 

The invention relates to medicine, specifically to the means of having local anesthetic action, after which clinical trials may be offered for local anesthesia for various surgical interventions, postoperative period, for the treatment of chronic pain syndromes, etc.

In recent years, despite a fairly large number of drugs belonging to the group of drugs local anaesthetics, is becoming increasingly important finding new painkillers. This is dictated by the needs of clinics, which are not always satisfied with the efficacy of known drugs. Moreover, the data of experimental research and the practice of anesthesia in the clinic shows that a number of substances locally an anaesthetic activity in different types of anesthesia may be unequal. So, some high-level at infiltration and block anesthesia drugs low in terminal method of pain relief, so as not penetrate the skin and mucous membranes. In addition, local anesthetic drugs have relatively high toxicity, the latter generally increases with increasing equipment efficiency and manifests itself in the form of their resorptive activity (the most dangerous effect is as CNS and cardiodepressive effects) and irritant effects (up to necrobiotic actions).

A local anesthetic of the new generation is lidocaine, which finds wide application in infiltration, conduction, spinal and, sometimes, terminal methods of pain relief (Aiews.com, Allsteel, Ethnological and other Caudal epidural anesthesia during operations on the lower extremities in traumatology and orthopedics. Anestesiol. and Reanimator., 1992, No. 5-6, p.15-17; Medmaravis, 1998).

Lidocaine is usually well tolerated, but may sometimes cause the collapse, anaphylactic reaction, changes in the contents of cytoplasmic proteins, the surface and shape of erythrocytes (Hierarchy, Anguipede etc. Withdrawal from anaphylactic shock from clinical death after injection of lidocaine. Vestn. hir. them. ICA, 1987, No. 4, p.131; Nagahiro, Iourieva, Trenado. Successful resuscitation of patients after adverse toxic reactions to lidocaine. Journal of the ear, nose and throat diseases, 1989, No. 6, p.60-61; E.Nidhiguchi et al. Factors of the share change of human erythrocytes induced with lidocaine. Cell. struct & Funct, 1989, Vol.14, p.569-577; Medmaravis, 1998).

Noteworthy is also a local anesthetic marcain (bupivacaine), which has practical application as a tool for spinal, epidural, caudal, intra-articular anesthesia, when conducting paracervical and retrobulbarno the blockades (e.g., R.P.Alston. Spinal anaecthisis with 0,5% bupivacaine 3 ml: Comparison of plain and hyperbarric solutions administered to seated patients. Brit. J. Anaesrth, 1988, Vol.61, No.4, p.385 - 389; A.R.Wolf, R.D.Val-ley, D.W.Fear et al. Bupivacaine for caudal analgesia in infants and children: the optimal effective concentration. Anaesthesiology, 1988, Vol.69, No. 1, p.101-105).

It should be noted that marcain, like dikaina not only highly active but also very toxic anesthetic (Nebraska. Local anesthetic properties of some new derivatives of piperidine and indole. Abstract. dis.... Kida. the honey. Sciences. Rostov-on-don, 1991; J.Kambarn, B.Mets, R.Hickman et al. Comparative systemic toxicity of intravenously infused bupivacaine (B)cocaine (C) and lidocaine (L) inpigs: [Abstr.] Int. Anesth. Res. Soc. 66thCongr., San Francisco, Calif., March 13-17, 1992; Anesth. and the play mode display., 1992, Vol.74, No. 25, p.87)that requires special attention when used in practical medicine. In addition, marcain can cause generalized rash, angioedema, laryngeal stridor, bronchospasm (H.Gacl, V.Reichert, R.Kaufmann. Localanastheticaintoleranz auf Leitungsanasthesia mit Prilocain und Bupivacain. Allergologie, 1992, Bd. 15, No. 3, S.89-91).

Known to be derived in a series of 1,2-disubstituted, imidazo[1,2-a]-benzimidazole, namely the dihydrochloride of 1-(3-pyrrolidinyl)-2-phenylimidazo[1,2-a]benzimidazole with local anesthetic effects at infiltration, wiring and spinal anaesthesia /patent RF №2160265, C07D 487/04, AK 31/4188,2000/. The connection has a high local anaesthetic activity, including infiltration (EC50in mm=0,31), who, however, has a fairly high acute toxicity (LD 50in mm/kg=0,110) and therefore not a high therapeutic index infiltration activity (LD50/EC50=3538,5).

The technical result of the invention is to reduce the toxicity and increase the breadth of therapeutic action infiltration activity of local anesthetic tools.

The technical result is achieved by identifying local anesthetic effect at the surface (terminal), infiltration and spinal anesthesia have dihydrochloride 9-(2-pyrrolidinyl)-2-(4-forfinal)imidazo[1,2-a]benzimidazole of the formula I:

The invention involves an inventive step, as the number of 2,9-disubstituted of imidazo[1,2-a]benzimidazole not known compounds exhibiting local anesthetic action.

Below is the method of obtaining the compounds I, which lies in the interaction of 1-pyrrolidinyl-2-aminobenzimidazole with 4-fluoro-penacerrada and further cyclization of the intermediate formed bromide 1-pyrrolidinyl-3-(4-florfenicol)-2-aminobenzimidazole II to 9-pyrrolidinyl-2-(4-forfinal)imidazo[1,2-a]benzimidazole and translation tricyclic Foundation in the dihydrochloride I:

Example. Stage 1. Bromide 2-amino-1-(2-pyrrolidinyl)-3-(4-fluoro-phenacyl)benzimidazole (II). In hot RA the solution of 2.3 g (10 mmol) 2-amino-1-(2-pyrrolidinyl)benzimidazole in 150 ml of acetone contribute 2.17 g (10 mmol) of 4-fortunaticlomid. The mixture is stirred to dissolve the last heat before the start of precipitation and leave to stand for 4-6 h at room temperature. Then the precipitation is filtered off, thoroughly washed with acetone. Output and 88.8%, TPL 179-180°C. Found, %: C 56,34; N. Of 5.45; Br 17,68; F 4,36; N 12,56. C21H24BrFN4O. Calculated, %: 56,38; N 5,41; Br 17,86; F 4,25; N To 12.52.

Stage 2. The dihydrochloride 9-(2-pyrrolidinyl)-2-(4-forfinal)imidazo[1,2-a]benzimidazole (I). Boil 0,89 g (2 mmol) of salt II in 50 ml of water until complete reaction (3-5 h, control - TLC). Then the solution is alkalinized and the liberated base is extracted with chloroform. The extract is passed through a layer of Al2About3(eluent - CHCl3). The residue after evaporation CHCl3from the eluate was dissolved in acetone and acidified with a solution of HCl in 2-D, getting dihydrochloride I. the Output of 81.63%, TPL 257-258°C (decomp., 2-D). An NMR spectrum1N, δ, ppm: 2,08 (4H, q, -(CH2)2-); and 3.31 (2H, t, NCH2); to 3.64 (2H, t, NCH2); 3,76 (2H, t, NCH2); to 5.17 (2H, t, NCH2); 7,21 (2H, t, 3',5'-H); 7,47 (2H, dt, 2',6'-H); 7,86-TO 8.20 (4H, m, arene. N); 8,48 (1H, s, 3-H); 12,40 (1H, user. s, N+H); H+in the exchange.

Found, %: C 59,79; N The Ceiling Of 5.60; Cl 16.78 In; F Of 4.44; N 13,39. C21H21FN4·2HCl.

Calculated, %: 59,86; N. Of 5.50; Cl Equal To 16.83; F 4,51; N 13,30.

Below are the results of the pharmacological studies of the compounds I.

The basis of the research is based on Methodical is the punishment for the study of the local anaesthetic activity of pharmacological substances (Ignatov UD, Chervyakova I., Vasiliev, Y., Galenko-Yaroshevsky A.P., V. Zhukov. Guidelines for the study of the local anaesthetic activity of pharmaceutical substances //In the book: Manual on experimental (preclinical) study of new pharmacological substances /Under the General editorship of Corr-Corr. Russian Academy of medical Sciences, Professor Rugarama, 2nd ed., Rev. and ext., M,JSC Publishing house "Medicine", 2005, s-392).

The experiments were carried out in accordance with article 11 of the Declaration of Helsinki of the world medical Association (1964), "International guidelines for the conduct of biomedical research using animals" (1985) and good laboratory practice in the Russian Federation (order of the Ministry of the Russian Federation No. 267 from 19.06.2003,).

Surface (terminal) anesthesia was investigated in experiments on the cornea of rabbits using the method Rainier-Jack (Pryanishnikova N.T., Balls N.A. Trimekain. Pharmacology and clinical use. HP: Medicine, 1967, 239 C.), while simultaneously studied the possible irritant effect on Setnicar (Setnicar I. Tolerance indices of some phenoxyethylamino derivatives with local anaesthitic properties //Arzneim. Forsch., 1966, Bd. 16, No. 5, S.623).

Infiltration anesthesia was investigated in experiments on Guinea pigs (Udinov et al., 2005; Bulbring E., J. Wajda Biological comparison of local anaesthetica II]. pharmacol. and exp. therap., 1945, vol.85, No.1, p.78-84).

Spinal anesthesia was studied in experiments on rats bloodless" method, developed in the Institute of pharmacology RAMS (Udinov et al., 2005). This change in pain thresholds were determined by mechanical irritation of the root of the tail.

Acute toxicity was investigated [determined the median lethal (lethal) dose - LD50] in experiments on mice at subcutaneous (Prozorovsky V.B. have been Using the method of least squares for probit analysis of the mortality curves //Pharmacol. and toxicol., 1962, T. 25, No. 1, s-119).

As the comparison drug were taken lidocaine (in the study of surface and infiltration anesthesia) and marcain (the study of spinal anesthesia).

Statistical processing of data carried in graded form, spent Mladenka (Belenky, M. elements of a quantitative evaluation of the pharmacological effect., L., 1963, 152 C.) and with tables Col (N. Samoilov. Table of values for the mean error and the confidence interval of the arithmetic mean of the values of the variational series., Tomsk, 1970, 63 S.).

Accounting research results, expressed in an alternative form, the definition of LD50, EK50, confidence intervals and therapeutic index, or the breadth of therapeutic action (LD50/EC50) was carried out by the methods described Webpersonals (1962) and Mladencem (1963).

It was established that in terms of the behavior of chestney anesthesia in experiments on the cornea of rabbits indexes Rainier, expressing the power of anesthetic action in the investigated concentrations for compounds I in 0.25, 0.5 and 1.0% of the solutions are 210,7, 1078,8 and 1204,7, whereas for lidocaine in 1.0, 2.0 and 5.0% of the solutions - 297,9, 354,8 and 676,9 respectively (table 1).

The connection I, as lidocaine, in the investigated solutions do not intrude on the conjunctiva of the eye.

Table 1.
Comparative activity of (index Rainier) salt I and lidocaine under surface anesthesia in experiments on the cornea of rabbits
Concentration %Index Rainier1
Ilidocaine
0,25210,7±60,8

(64,2÷356,2)
-
0,51078,8±63,3

(926,8÷1230,8)
-
1,01204,7±48,8

(1087,5÷1321,9)
297,9±20,7

(248,2÷347,6)
2,0354,8±17,8

(315,6÷394,0)
5,0676,9±21,3

(625,7÷728,2)
1Presents arithmetic average, calculated from 6 (I) and 8 (lidocaine) experiments, with the standard error of the mean.
Note. In brackets: round - confidence limits at p=0.05.

The timing of the onset of anesthesia and start of full anesthesia by instillation into the conjunctival SAC of the eyes of solutions of compound I (0.5 and 1.0%) and lidocaine (1,0, 2,0 and 5,0%) were within 2 and 3 min, respectively; the exception was a 0.25% solution of salt I, for which the first indicator was equal to 3-5 min, the second one for 5 - 8 minutes completion Time for full anesthesia and the total duration of anesthesia under the influence of 0.25, 0.5 and 1.0% solutions of compound I was 12.5 and 31,7, 34.2 and 66,7, 55,8 and 75.0 min, and when the use of 1.0, 2.0 and 5.0% of solutions of lidocaine to 5.8 and 18.8, 7,4 and 22.5, 25,6 and 35.4 min, respectively (table 2).

On the local anaesthetic activity when comparing EC50expressed in mm, and therapeutic index is compound I, respectively 20.1 times more significant and 9.6 times has a great breadth of therapeutic action than lidocaine (table 3).

When infiltration anesthesia in experiments on Guinea pigs minimum anesthetic concentration of salt I is 0,0156%for lidocaine - 0,0625%. Full analgesic effect (100%anesthesia for 30 min) causes the salt I in a 0.125% solution, whereas lidocaine - 0.5% solution (table 4).

Mapping EC50expressed in mm, showed (table 5)that the connection I 6,95 times more active, che is lidocaine. In terms of the breadth of therapeutic action in his 3.30 times that of lidocaine.

In terms of spinal anesthesia in rats the compound I and marcain taken in a 0.5% solution caused the analgesic effect almost immediately after their introduction into the spinal canal. The depth of anesthesia after 5 min (for both agents) and for 40-45 minutes (salt I) and 30-35 min (for marcaine) was 100%. The duration of analgesic action under the influence I was equal 76,0, and when using marcaine was 44.5 min, i.e. according to this indicator, the first substance in 1,71 times higher than the second (table 6). The connection I like Marciano, caused mild respiratory depression within 7-15 minutes

Thus, the connection I activity in the surface and infiltration anesthesia and breadth of therapeutic action significantly superior to lidocaine, but when spinal anesthesia is marcain.

In addition, compound I is less toxic (LD50in mm/kg=0,500) and superior therapeutic index infiltration activity (LD50/EC50=9152,2; table 5) of the dihydrochloride of 1-(3-pyrrolidinyl)-2-phenylimidazo[1,2-a]benzimidazole (LD50in mm/kg=0,110; LD50/EC50=3538,5; table 4 description of patent No. 2160265), respectively, 4.5 and 2.6 times.

On the basis of compound I possible the creation of locally-abessole the surrounding pharmaceuticals, designed for surface, infiltration and spinal anaesthetic.

Table 2
Comparative characteristic time parameters of the action of the salt I and lidocaine under surface anesthesia in experiments on the cornea of rabbits
Connection and preparationConcentration %The beginning of anesthesia, minStart full anesthesia, minThe end of a full anesthesia1, minThe total duration of anesthesia1, min
I0,253-55-812,5±0,9031,7±1,77
0,52334,2±1,7766,7±and 5.30
12355,8±7,07*75,0±7,95*
Lidocaine1235,8±0,6618,8±1,33
2237,4±0,6622,5±0,66
52325,6±1,3335,4±1,99
1Presents arithmetic average, calculated from 6 (I) and 8 (lidocaine) experiments, with the standard average error. *p<0.001 to about lidocaine, taken in the appropriate (1%) concentration

Table 3
Comparative activity [EC50and therapeutic index (the breadth of therapeutic action)] the compounds I and lidocaine under surface anesthesia in experiments on the cornea of rabbits
Connection and preparationLocally, an anaesthetic activityToxicity of 0.5% solution after subcutaneous administration to miceTherapeutic index
EC50relative1LD50relative1absoluterelative1
%mmmg/kgmm/kg
I0,39 [18] (0,28÷0,54)9,320,1210,5 [40] (204,9÷216,3)0,5000,47539,79,6
Lidocaine187,01,0258,1 [35] (271,9±299,0)1,0561,056,51,0
Note. In brackets: round - confidence limits at p=0.05, square the number of experiments.

Table 4
Comparative activity of (index Bullring and Wade) of compound I and lidocaine under local infiltration anesthesia in the experiments on the skin of Guinea pigs (n=6)
Connection and preparationIndexes Bullring and Wade at the concentrations %
0,01560,03120,06250,1250,250,5
I16,5 [45,8] (14,3÷18,7)18,2 [50,5] (17,2÷19,1)30,7 [to 85.2] (27,1÷34,2)36,0 [100,0]
Lidocaine9,8 [27,3] (7,2÷12,4)22,7 [63,0] (19,0÷26,4)29,8 [82,9] (26,2÷33,5)36,0 [100,0]
Note. In brackets: round - confidence limits at p=0.05, square the number of experiments.

1When calculating EC50to connect with I used indexes Bullring and Wade (in %) at concentrations 0,0156, 0,0312 and 0.0625%for lidocaine - 0,0625, 0.125 and 0.25%.
Table 5
Comparative activity [EC50and therapeutic index (the breadth of therapeutic action)] the compounds I and lidocaine under local infiltration anesthesia in the experiments on the skin of Guinea pigs
Connection and preparationLocally, an anaesthetic activityToxicity of 0.5% solution after subcutaneous administration to miceTherapeutic index
EC501relativeLD50relativeabsoluterelative
%mmmg/kgmm/kg
123456789
I0,023 [18] (0,015÷0,035)0,556,95210,5 [40] (204,9÷216,3)0,5000,479152,23,30
Lidocaine0,103 [18] (0,080÷of 0.133)3,821,0285,1 [35] (271,9÷299,0)1,0561,02765,31,0
Note. In brackets: round - confidence limits at p=0.05, square the number of experiments.

Table 6
Comparative activity of compound I and marcaine during spinal anesthesia in rats
Connection and preparationConcentration %The number of animalsAnesthesiaThe number of animals in which anesthesia is not coming, %The number of dead animals %
depth %duration, min
I0,510100,076,0±7,25*3010
Marcain0,510100,044,5±3,182010

Application dihydrochloride 9-(2-pyrrolidinyl)-2-(4-forefeel)imidazo[1,2-a]benzimidazole of the formula I

as a means of obladaushih the local anesthetic action.



 

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FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

The invention relates to novel oral pharmaceutical dosage forms, containing a proton pump inhibitor, that is an inhibitor of H+, K+-ATPase

The invention relates to a new mode of administration of proton pump inhibitors, t

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

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