For the treatment of neurogenic inflammation

 

A new tool for the treatment of neurogenic inflammation. The tool is a compound of General formula (I) with the values of the radicals shown in formula, formerly known as fungicidal compound. The invention expands the Arsenal of the declared destination. 3 C.p. f-crystals, 2 PL.

The invention relates to medicine and veterinary medicine, namely to the use of certain derivatives of aryl(or heteroaryl)asolitarynote General formula (I) and their physiologically acceptable salts in the manufacture of drugs used in the treatment of human and/or veterinary medicine for the treatment of neurogenic inflammation observed in various pathological processes, such as diabetes, asthma, cystitis, gingivitis, headache, dermatitis, rhinitis, psoriasis, inflammation of the sciatic and lumbar nerves, gastrointestinal tract, eye inflammation, and so on,

Neurogenic inflammation is observed in various pathological conditions and is characterized by vasodilatation and plasma radiolabeled in zones where can be found semilinearly fiber. Activation of these fibers leads to the release of the afferent nervous about the s neurogenic inflammation [Gyorfi A., et al., J. Clin. Calls. 19 (10), 731-736 (1992)]. Substance P plays an important role as a major mediator of the induction of neurogenic inflammation by increasing vascular permeability due to release of histamine from mast cells and interaction with endothelial cells [Inoue H., et al. Inflamm. Res. 44, 125-130 (1995); Piotrowkski W. et al., Br. J. Dermatol. 114, 37-46 (1986); M. A. Lowman et al., Br. J. Pharmacol. 95, 121-130 (1988); C. M. Fewtrell et al., J. Ziche M. et al., Microvas. Res. 40, 264-278 (1990)]. It was reported that CGRP may contribute to plasma extravasation induced by substance P in the rat trachea and, therefore, plays an important role in the modulation of neurogenic inflammation of the respiratory tract [Brokaw J. J. et al., Lung 170 (2), 85-93 (1992)]. Neuropeptides (among other CGRP and substance P) detected in the primary demyelinating afferent neurons as of neurotransmitters [Holzer P. , Neuroscience 24, 739-768 (1988)]. Neurogenic inflammation with reflex vasodilatation of the axon plasma and edema radiolabeled can be caused by using cells through activation of primary afferent neurons. Indeed, acute inflammatory reactions, including the formation of edema, vasodilation and blisters, are induced in response to intradermal injection of neuropeptides [Gamse R. et al., Eur. J. Pharmacol. 114, 61-66 (198 the LM and they play a key role in skin inflammation [Farber E. M. et al., J. Am. Acad. Dermatol. 14, 305-311 (1986); Wallengren J. et al., Acta Derm. Venerol. (Stockh.) 66, 23-28 (1986)].

Patent applicants ER 289380 and ES 9800793 (later publication) described carbinol derivatives of the General formula (I)where AG denotes a benzene ring or a substituted or unsubstituted thiophene ring, R1means a hydrogen atom or a lower alkyl group from C1to C4; R2means dialkylaminoalkyl or azaheterocyclic radical, Het means azole, as well as their physiologically acceptable salts.

Applicants have described various methods for obtaining enantiomerically pure compounds of General formula (I) in PCT/ER/05596, ES 9701728 (late publication) and ES 9800793 (late edition), EP 1086682 A2.

In the present application discloses that compounds of General formula (I) and their physiologically acceptable salts are particularly useful in the manufacture of drugs used in humans and/or in veterinary medicine for the treatment or attenuation of neurogenic inflammation observed in various pathological processes, such as diabetes, asthma, cystitis, gingivitis, headache, dermatitis, rhinitis, psoriasis, inflammation of the sciatic and lumbar nerves, jednoho aryl(or heteroaryl)asolitarynote General formula (I)where AG denotes unsubstituted phenyl or thienyl radical, or possibly substituted by 1-3 identical or different substituents selected from the group consisting of fluorine atoms, chlorine, bromine, methyl, triptorelin and metaxylene groups; R1means a hydrogen atom or a lower alkyl group, a C1-C4;
R2means dialkyl(C1-C4)aminoalkyl(C2-C3or azaheterocyclic(C2-C3); and
Het means a five-membered nitrogen-containing heterocyclic aromatic ring which contains one to three nitrogen atoms, unsubstituted or possibly substituted by one or two substituents, identical or different, selected from the group consisting of fluorine atoms, chlorine, bromine and methyl group;
or one of its physiologically acceptable salts in the manufacture of a drug for treatment of neurogenic inflammation in mammals, including humans.

The term "alkyl group of C1-C4" means a radical with a linear or branched chain, derived from a saturated hydrocarbon of 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

The term "dialkyl(C1-C41-C4)amine or a cyclic amine, such as dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidinylmethyl, morpholinylmethyl, pyrrolidinyloxyl etc.

Illustrative examples of compounds covered by this invention include:
()-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole,
()-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazolate,
(+)-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole,
(-)-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazole,
(+)-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazolate,
(-)-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazolate,
()-5-{-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole,
()-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazolate,
(+)-5-{-[2-(dimethylamino)ethoxy]-2-thienylmethyl}-1-methyl-1H-pyrazole,
(-)-5-{-[2-(dimethylamine} -1-methyl-1H-pyrazolate,
(-)-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazolate.

Compounds of General formula (I) can be synthesized in accordance with the methods described in EP 289380, EP 1086682 and ES 9800793. Compounds of General formula (I) have stereogenic (chiral) centers, and the invention relates to the use of pure enantiomers and mixtures of enantiomers. Enantiomers can be obtained by some of the methods described by the applicants in PCT/ER/05596, ES 9701538, ES 9701728 or ES 9800793.

Pharmaceutical compositions that contain the compounds of General formula (I) described by the applicants in EP 289380 and ES 9800793.

In the present invention the activity of compounds of General formula (I) in respect of neurogenic inflammation demonstrated by examining the direct effects of these compounds on neurogenic inflammation. This study was conducted by determining the inhibition of ear oedema in mice caused by capsaicin. It was also determined the effect of compounds on the spinal release of substance P and CGRP in rats. Finally, we studied the effect of compounds on the spinal release of CGRP in rats with arthritis.

In the following examples illustrates some of the features of the object of the invention to ()-5-{
The examples below to illustrate, describe some drugs test and in no way should be construed as limiting the scope of the invention.

Example 1
Effect on mouse ear oedema induced by capsaicin
Mouse ear oedema induced by capsaicin described as linked in a special way with the release of substance P [H. Inoue et al., Inflam. Res. 44, 125-130 (1995)]. Reported that capsaicin applied to the skin, causes a reaction, known as neurogenic inflammation. Assume that in this reaction involved neuropeptides (substance P, CGRP) released from the endings of afferent fibers, and histamine, recently isolated from the fat cells.

Induction of mouse ear oedema based on the method of Inoue and others [H. Inoue et al., Br. J. Pharmacol. 110, 1614-1620 (1993)]. In this method capsaicin (250 μg/5 μl of ethanol) is applied on the dorsal and on the ventral surface of the right ear of each mouse (male ICR line, 35-45 g). After 30 minutes after application of capsaicin animals were killed by displacement of the cervical vertebrae. From the tissue of the right ear using a metal cutting tool removed disk with a diameter of 7 mm and was determined by the weight of these tissue discs. The product, ()-5-{

Impact ()-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazolidine on mouse ear oedema induced by capsaicin, are given in table. 1.

Example 2
The effect on spinal release of substance P and CGRP in rats
The study was performed in vivo on rats under anesthesia with halothane gas. The study consisted in vnutriobolochechnoe perfusion with artificial cerebrospinal fluid (ACSF) with the prospect of collecting peptides released from the surface layers of the spinal cord, whereas the investigational product was administered topically or systemically. Used the method described Collin E. and employees (Naunyn-Schmiedeberg''s Arch. Pharmacol. 349, 387-393, 1994).

Studied activity ()-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl-1H-pyrazolidine entered vnutriobolochechnoe in the perfusion fluid at a concentration of 1 μm. As summarized below, ()-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl - 1H-pyrazolate inhibited AMD>)-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazolidine also reduced the release of substance P and CGRP.

Impact ()-5-{-[2-(dimethylamino)ethoxy]benzyl}-1-methyl - 1H-pyrazolidine on vnutriobolochechnoe the release of substance P and CGRP in rats is shown in table.2.

It should be noted that the effect of systemic injections ()-5-{-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazolidine on vnutriobolochechnoe the release of substance P was observed within 2 hours, and during this period of time the average inhibition was 50%.

Example 3
The effect on spinal release of CGRP in rats with arthritis.

Arthritis caused by intradermal injection of 0.05 ml of complete adjuvant's adjuvant (suspension of Mycobacterium butiricum in mineral oil) at a distance of about 3 cm from the tip of the tail rats Sprague-Dawley (weighing 150-175 g). Animals used in four weeks, when the inflammation of the paws and tail became maximum. Further tests were carried out using the same procedure vnutriobolochechnoe introduction as described in example 2.

Was administered intraperitoneally ()-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-personsfrom. The dimension of the area under the curve that was used as the evaluation release of CGRP within 3 hours after treatment, showed about 50% inhibition. Thus, it is clear that in rats with arthritis ()-5-{-[2-(dimethylamino)ethoxy] benzyl}-1-methyl-1H-pyrazolate has a significant influence on the release of CGRP.


Claims

1. Means for treating neurogenic inflammation in a mammal, including man, characterized in that it is a compound of General formula (I)

where AG is phenyl or thienyl radical, unsubstituted or optionally substituted by 1-3 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, methyl, trifloromethyl and methoxy;
R1is a hydrogen atom or an alkyl group of C1-C4;
R2- dialkyl(C1-C4)aminoalkyl(C2-C3or azaheterocyclic 1 - 3 nitrogen atom, unsubstituted or possibly substituted by one or two substituents, identical or different, selected from the group consisting of fluorine, chlorine, bromine and methyl, provided that when AG - frienldy radical, Het is a five-membered nitrogen-containing heterocyclic aromatic ring containing 1 to 3 nitrogen atom which is not substituted by 1 or 2 substituents, same or different, selected from the group consisting of fluorine, chlorine or bromine,
or its physiologically acceptable salt.

2. Means on p. 1 compounds of General formula (I) in which R1selected from hydrogen or from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, as a means for treating neurogenic inflammation in a mammal, including humans.

3. Means on p. 1 compounds of General formula (I) in which R2selected from the group consisting of dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, piperidolate, morpholinopropan and pyrrolidinyl, as a means for treating neurogenic inflammation in a mammal, including humans.

4. Means on p. 1 compounds of General formula (I) selected from the group including
()-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazolate,
(+)-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazole,
(-)-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazole,
(+)-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazolate,
(-)-5-{-[2-(dimethylamino)ethoxy] benzyl} -1-methyl-1H-pyrazolate,
()-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazole,
()-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazolate,
(+)-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazole,
(-)-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazole,
(+)-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazolate
and
(-)-5-{-[2-(dimethylamino)ethoxy] -2-thienylmethyl} -1-methyl-1H-pyrazolate.

 

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