Derivatives of pyridine, the pharmaceutical composition having an antagonistic effect on mglu r5man

 

Describes derivatives of pyridine of the formula (I) in which X - (C2-C4)-akinlana group attached through neighboring unsaturated carbon atoms, R1- (C1-C4)alkyl, (C1-C4) alkoxy ethinyl, (C1-C4) alkoxycarbonyl, di(C1-C4)alkylamino, R2is hydrogen, (C1-C4)alkyl, hydroxy-(C1-C4)alkyl, di(C1-C4)acylaminoacyl, 4-(4-perbenzoic)piperidine-1-ylcarbonyl, 1-tert.butyloxycarbonyl-1-ylcarbonyl, 4-(4-azido-2-hydroxybenzoyl)-piperazine-1-ylcarbonyl, R3is hydrogen, (C1-C4)alkyl, carboxy, (C1-C4) alkoxycarbonyl, hydroxy (C1-C4) alkyl, di(C1-C4) acylaminoacyl, morpholinomethyl, 4-(4-perbenzoic)piperidine-1-ylcarbonyl, R4is hydrogen, (C1-C4)alkoxy, carboxy, (C2-C5)alkanoyloxy, (C1-C4) alkoxycarbonyl, amino (C1-C4)alkoxy, di(C1-C4)alkylamino (C1-C4)alkoxy, di(C1-C4)alkylamino (C1-C4)alkyl, (C1-C4)alkoxycarbonyl (C1-C4)alkoxy, di(C1-C4)alkylamino (C1-C45. 3 S. and 3 C.p. f-crystals, 2 PL.

The invention relates to the use of 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic to modulate the activity of metabotropic glutamate receptors (mGluR) and to the treatment of mGluR5 mediated diseases, to pharmaceutical compositions intended for use in such therapy, as well as to new 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroeroticism.

It was found that 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic, including pharmaceutically acceptable salts (hereinafter tool according to the invention) can be used as modulators, mGluR. The mGluR modulation can be demonstrated in various ways, including, in particular, testing with them is th concentration of intracellular calcium. For example, for some means according to the invention in the study of exchange intitolata lines, recombinant cells expressing human mGluR5a (hmGluR5a), the resulting value IR50ranged from about 1 nm to about 50 μm.

The means according to the invention have, in particular, valuable pharmacological properties. For example, they display a marked and selective baseband, primarily antagonistic action on hmGluR. It can be installed in vitro, for example by recombinant hmGluR5, especially on the allocated using preparative thin-layer chromatography (PTH) subtypes of these receptors, such as mGluR5, using different methods, such as determination of growth inhibition concentration of intracellular CA+2induced by the agonist, in accordance with L. P. Daggett and others, Neuropharm. volume 34, S. 871-886 (1995), P. J. Flor, etc., J. Neurochem. volume 67, S. 58-63 (1996), or by determining the extent to which inhibited agonist-induced increase in the exchange of intitolata, as described in I. Knoepfel, etc., J. Pharmacol. volume 288, C. 389-392 (1994), L. P. Daggett and others, Neuropharm. volume 67, S. 50-63 (1996) and cited in these works the links. Isolation and expression of a hmGluR subtype described in the patent US 5521297. For some is the quiet was determined by the inhibition induced by quisqualate exchange intitolata, established in recombinant cells expressing hmGluR5a.

Thus, the invention relates to means according to the invention, intended for the treatment of diseases associated with impaired transmission glutamatergic signal and a disorder of the nervous system, partially or fully mediated hmGluR5.

Examples of disorders associated with impaired transmission glutamatergic signal are epilepsy, cerebral ischemia, primarily acute ischemia, ischemic eye disease, muscle spasm, such as partial or total muscle spasticity, primarily cramps or pain.

Examples of disorders of the nervous system, partially or fully operatedwith hmGluR5, are acute, traumatic and chronic degenerative processes of the nervous system such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, psychiatric diseases such as schizophrenia, anxiety, depression and pain.

The invention relates also to the use of funds according to the invention in the treatment of diseases associated with impaired transmission glutamatergic signal and disorder nereanu means according to the invention for the preparation of pharmaceutical compositions intended for the treatment of diseases associated with impaired transmission glutamatergic signal and a disorder of the nervous system, partially or fully mediated by mGluR group I.

The invention relates also to a method of treatment of diseases, completely or partially mediated by mGluR group I (preferably mGluR5), which includes the introduction in the human or warm-blooded animal in need of such treatment, a therapeutically effective amount according to the invention.

Another object of the invention is a new 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic and their salts and the way they are received.

The invention further relates to pharmaceutical compositions together with conventional pharmaceutical excipients as a pharmaceutically active component includes a new 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - or 2-heteroarylboronic or its pharmaceutically acceptable salt.

The means according to the invention are, for example, the compounds of formula Iin which R1denotes hydrogen, lower alkyl, COO is th carboxy, amidinophenoxy carboxy, unsubstituted or (ness.) alkyl-, (NISS. )alkoxy, halogen - and/or triftorperasin N-(NISS. )alkyl-N-phenylcarbamoyl, (ness.)alkoxy, halogen(ness.)alkyl or halogen(NISS. )alkoxy, R2denotes hydrogen, (ness.) alkyl, carboxy, esterified carboxy, amidinophenoxy carboxy, hydroxy (ness.) alkyl, hydroxyl, (NISS. )alkoxy or (ness.)alkanoyloxy, 4-(4-perbenzoic)piperidine-1-icebox, 4-tert-butyloxycarbonyl-1 icebox, 4-(4-azido-2-hydroxybenzoyl)piperazine-1-icebox or 4-(4-azido-2-hydroxy-3-iodobenzoyl) piperazine-1 - icebox, R3denotes hydrogen, (ness.)alkyl, carboxy, (ness.)alkoxycarbonyl, (ness.)allylcarbamate, hydroxy(ness.)alkyl, di(ness.)acylaminoacyl, morpholinoethyl or 4-(4-perbenzoic)piperidine-1-icebox, R4denotes hydrogen, (ness.)alkyl, hydroxyl, hydroxy(ness.)alkyl, amino (ness.) alkyl, (ness.)alkylamino (ness.)alkyl, di(NISS. )alkylamino(NISS. )alkyl, unsubstituted or replacement (NISS. )alkylamino (NISS. ) alkyl, (NISS. )alkoxy, (ness.)alkanoyloxy, amino (NISS. ) alkoxy-, (NISS. )alkylamino(NISS. )alkoxy, di(ness.)alkylamino (ness.) alkoxy, phthalimido(ness.)alkoxy, unsubstituted or hydroxy-or 2-accomidate, carboxy(ness.)alkoxy or esterified carboxy (ness.)alkoxy, X denotes optional alojamiento lower alkynylamino or alkynylamino group attached through neighboring unsaturated carbon atoms, or azo(-N=N-)group, and R5denotes an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from (NISS. )alkyl, halogen, halogen (ness.)of alkyl, halogen (NISS. )alkoxy, (ness.)alkenyl, (ness.)the quinil, unsubstituted or (ness.)alkyl-, (ness.)alkoxy-, halogen - and/or triftormetilfosfinov phenyl, unsubstituted or (NISS. )alkyl-, (ness.)alkoxy-, halogen - and/or triftormetilfosfinov phenyl(ness.)the quinil, hydroxyl, hydroxy(ness.)of alkyl, (NISS. )alkanoyloxy(NISS. )alkyl, (NISS. )alkoxy, (NISS. )alkenylamine, (NISS. )alkylenedioxy, (NISS. )alkanoyloxy, amino, (ness.)alkylamino-, (NISS. )alkanolamines and N-(ness.)alkyl-N-(ness.)alkanolamine (ness.)alkoxy, unsubstituted or (NISS. )alkyl-, (ness.)alkoxy-, halogen - and/or triftormetilfosfinov phenoxy, unsubstituted or (ness.)alkyl-, (ness.)alkoxy-, halogen - and/or triftormetilfosfinov phenyl(ness.)alkoxy, acyl, carboxy, esterified is amino, amidinophenoxy carboxy (NISS. )alkylamino-, phosphono(ness.)alkylamino-etherified phosphono(NISS. )alkylamino-, nitro-, amino-, (ness.)-alkylamino-, di(NISS. )alkylamino, acylamino-, N-acyl-N-(NISS. )alkylamino, phenylamino, phenyl (NISS. )alkylamino, cycloalkyl(NISS. )alkylamino and heteroaryl(NISS. )alkylamino, each of which may be unsubstituted or (NISS. )alkyl-, (ness.)alkoxy-, halogen - and/or triftormetilfosfinov, normal photoaffinity ligands and normal radioactive markers, including their N-oxides and their pharmaceutically acceptable salts.

The compounds of formula I containing a basic group capable of forming an acid additive salts, and the compounds of formula I containing an acid group can form salts with bases. The compounds of formula I containing a basic group, and also containing at least one acid group capable of forming internal salts.

It also includes both full and partial salts, i.e., in other words, salt with 1, 2 or 3 EQ., preferably with 2 EQ., base per mole of acid of formula I or salts with 1, 2 or 3 EQ., preferably 1 equiv., acid per mole of base formula I.

For isolation and purification can also be used f Okecie salt, and therefore they are preferred.

In the present description, the term "halogen" is used to denote a fluorine atom, chlorine, bromine or iodine.

When X denotes alkynylamino group, the preferred TRANS-configuration.

Preferred compounds of formula I are those in which X denotes optional alojamiento (C2-C4) alkenylamine or alkynylamino group attached through neighboring unsaturated carbon atoms,
R1denotes hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, ethinyl, carboxy, (C1-C4)alkoxycarbonyl, di(C1With4)alkylamino, (C1-C6)alkylaminocarbonyl, triftormetilfullerenov,
R2denotes hydrogen, hydroxyl, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, carboxy, (C2-C5)alkanoyloxy, (C1-C4) alkoxycarbonyl, di(C1-C4)alkylamino(C1-C4)alkanoyl, di(C1-C4)acylaminoacyl, 4-(4-perbenzoic)piperidine-1-icebox, 4-tert-butyloxycarbonyl-1 icebox, 4-(4-azido-2-hydroxybenzoyl) piperaz the1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, (C1-C4)allylcarbamate, hydroxy(C1-C4)alkyl, di(C1-C4) acylaminoacyl,
morpholinoethyl or 4-(4-perbenzoic)piperidine-1-icebox,
R4denotes hydrogen, hydroxyl, (C1-C4) alkoxy, carboxy, (C2-C5)alkanoyloxy, (C1-C4)alkoxycarbonyl, amino(C1-C4) alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkyl, carboxy (C1-C4) alkylsulphonyl, (C1-C4) alkoxycarbonyl (C1-C4) alkoxy, hydroxy(C1-C4)alkyl or m-hydroxy-p-azithromycinonline(C1-C4) alkoxy and
R5denotes a group of the formula





in which Raand Rbeach independently of one another denotes hydrogen, hydroxyl, halogen, nitro, cyano, carboxy, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, (C1- 1-C4)alkyl, trifluoromethyl, triptoreline, trimethylsilylethynyl, (C2-C5)quinil, amino, azido-, amino(C1With4)alkoxy, (C2-C5)alkanolamine(C1-C4)alkoxy, (C1-C4)alkylamino(C1-C4)alkoxy, di (C1-C4) alkylamino(C1-C4) alkoxy, (C1-C4)alkylamino-, di(C1-C4)alkylamino, monohalobenzene, titelmelodie, taylorlovesyouuu, triftormetilfullerenov, tetrazolyl, (C2-C5)alkanolamine, benzylcarbamoyl-, (C1-C4)alkylaminocarbonyl-, (C1-C4)alkoxycarbonylmethyl or (C1-C4)alkylsulfonyl, Rcdenotes hydrogen, fluorine, chlorine, bromine, hydroxyl, (C1-C4)alkyl, (C2With5)alkanoyloxy, (C1-C4)alkoxy or cyano and
Rddenotes hydrogen, halogen or (C1-C4)alkyl.

More preferred compounds of formula I are those in which
X has the values listed above, and
R1denotes hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, ethinyl or di(C1-C4)alcelam/sub>-C4)acylaminoacyl, 4-(4-perbenzoic) piperidine-1-icebox, 4-tert-butyloxycarbonyl-1 icebox, 4-(4-azido-2-hydroxybenzoyl)piperazine-1-icebox or 4- (4-azido-2-hydroxy-3-iodobenzoyl)piperazine-1-icebox,
R3has the meaning specified above,
R4denotes hydrogen, hydroxyl, carboxy, (C2-C5)alkanoyloxy, (C1-C4)alkoxycarbonyl, amino(C1-C4)alkoxy, di (C1-C4) alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkyl or hydroxy(C1-C4)alkyl and
R5denotes a group of the formula

in which Raand Rbeach independently of one another denotes hydrogen, halogen, nitro, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, trifluoromethyl, triptoreline or (C2-C5)quinil and
Rcand Rdhave the values specified above.

The means according to the invention include, for example, compounds described in the following examples.

The usefulness of the tools according to the invention in the treatment of the aforementioned diseases could confirm during a series of standard tests, including a description of what electroshock, in doses of from about 10 to 100 mg/kg intraperitoneal or oral administration of 0.25 for 8 h prior to the study [see E. A. Swinyard, J. Pharm. Assoc. Scient. Ed.38, 201 (1949), J. Pharmacol. Exptl. Therap. 106. 319 (1952)].

In doses of from about 4 to 40 mg/kg oral introduction means according to the invention exhibit the ability to reverse the hyperalgesia induced by complete adjuvant's adjuvant (PAF) [see J. Donnerer and others, Neuroscience 49. 693-698 (1992), and C. J. Woolf, Neuroscience 62, 327-331 (1994)].

Obviously, if all the above indications the appropriate dose will vary depending on, for example, from specifically used compounds of the subject, route of administration and the nature and severity of the disease condition, wherein the treatment. Typically, however, satisfactory results in animals are achieved with a daily dose of from about 0.5 to about 100 mg/kg body weight of the animal. In the case of larger mammals, for example humans, the recommended daily dose is from about 5 to 1500 mg, preferably from about 10 to about 1000 mg of the compound that it is expedient to introduce into the body in the form of fractional doses up to 4 times a day, or in the form of a medicinal product with the continuous release.

The preferred connection when the above-mentioned 6-sterilely (B), 2-(3-perforating)-6-methylpyridin (b) and 2-(4-ethoxy-3-cryptomaterial)-6-methylpyridin (G). It was found, for example, that in the above model electroshock-induced seizure, the compounds a and B show the anticonvulsant effect in the case of pre intraperitoneal introduction when values of the ED50respectively, 30 and 35 mg/kg (pre-processing, respectively, 4 h and 15 min) and that the model of hyperalgesia caused by the above-mentioned PAF, compounds C and D are capable of reversal of hyperalgesia when values of the ED50respectively 4.2 and 19 mg/kg in the case of oral administration (3 h post-processing).

As indicated above, the means according to the invention include 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic and their salts, which are referred to as "compounds of the invention".

The compounds according to the invention are those compounds of the above formula I and their salts in which X and R1-R5have the meanings stated above, provided that when R3denotes hydrogen,
a) compounds of the formula I, in which each of R1, R2and R4denotes hydrogen, the values of R5different from what propylphenyl, 3,5-di-tert-butylphenyl, methoxyphenyl, 3,4-acid, 2,4,5 - and 3,4,5-trimethoxyphenyl, hydroxyphenyl, 3,5-dihydroxyphenyl, 4-hydroxy-3,5-dimetilfenil, 3-hydroxy-4-methoxy - and 4-hydroxy-3-methoxyphenyl, 4-hydroxy(3-methyl-5-tert-butyl-, 2 - and 4-acetylaminophenol, 3,5-aminobutiramida and 3,5-di-tert-butyl)phenyl, 4-carboxy-and 4-ethoxycarbonylphenyl, 4-cyanophenyl, 3-ethoxycarbonylphenyl, 3-carboxy-5-methoxyphenyl, 2-pyridinyl, 5-chloro-2-pyridinyl and 6-methyl-2-pyridinyl, when X denotes attilan, or R5other than phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-bromophenyl and 2 - and 4-chlorphenyl, when X denotes a 1,2-propylene attached to R5in the 2nd position, or the values of R5other than phenyl, 2-and 4-chlorphenyl and 3-methoxyphenyl, when X denotes a 1,2-propylene attached to R5in the 1st position, or the values of R5other than 4-methoxyphenyl, when X denotes 2,3-buta-2-Anilin or 1,2-buta-1-Anilin attached to R5in the 2nd position, or the values of R5other than 4-methoxyphenyl and 4-isopropylphenyl, when X denotes 2,3-Penta-2-Anilin attached to R5in 3rd position, or the values of R5other than phenyl, 4-methylphenyl, methoxyphenyl and 4-hydroxyphenyl, when X denotes a 3,4->denotes hydrogen, the values of R5other than phenyl, 3-methylphenyl, 2-methoxyphenyl, 2-chlorphenyl, 4-cyanophenyl, 2-pyridinyl and 6-methyl-2-pyridinyl, when X denotes ethenylene;
the compounds of the formula I, in which each of R1and R2denotes hydrogen, and R4denotes a carboxy, values of R5other than phenyl, 3-methylphenyl, 4-methoxyphenyl and 4-bromophenyl, when X denotes ethenylene;
g) compounds of the formula I, in which each of R1and R2denotes hydrogen, and R4denotes methyl, R5other than phenyl, 3-methoxy, 4-methoxy and 3,4-acid, 2-chloro - and 2,4-dichlorophenyl and 6-methylpiperid-2-yl, when X denotes attilan, or R5other than phenyl when X denotes a 1,2-prop-1-Anilin attached to R5in the 2nd position;
d) compounds of the formula I, in which each of R1and R2denotes hydrogen, and R4denotes 2-dimethylaminoethanol or 3-dimethylaminopropionitrile, the values of R5other than 4-methoxyphenyl, when X denotes ethenylene;
(e) compounds of the formula I, in which each of R1and R2denotes hydrogen, and R4denotes 2-dimethoxyethoxy, the values of R5great is icny from phenyl, when each of R1and R2denotes hydrogen, and R4denotes hydroxyl or etoxycarbonyl, or when each of R1and R2denotes hydrogen, and R4denotes hydroxyl, or when R1denotes methyl, R2denotes hydrogen, and R4denotes methoxy, or R1denotes the buta-1-enyl, R2denotes hydrogen and R4denotes hydrogen, or R1denotes hydrogen, and R4denotes 2-dimethoxyethoxy, and X in each case represents attilan, and provided that when R3denotes hydrogen, X denotes attilan,
a') the values of R5other than phenyl, 2 - and 4-nitrophenyl, 4-AMINOPHENYL, 4-chlorphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxycarbonylphenyl, 5-formyl-2-methoxyphenyl, 5-carboxy-2-methylphenyl and pyridyl when each of R1, R2and R4denotes hydrogen;
b') in the compounds of the formula I, in which each of R2and R4denotes hydrogen, the values of R5other than phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 2-methoxyphenyl, when R1denotes methyl, R5non-6-bromopyridin-2-yl, when R1denotes bromine, and R5non-6-hexyloxyphenyl-2-yl, when R5other than phenyl, 4-AMINOPHENYL and 4-propylphenyl, when R2denotes methyl, R5other than phenyl, 4-cyanophenyl and 4-pentylphenol, when R2denotes ethyl, R5other than 3-cyano-4-ethoxyphenyl and 3-bromo-4-methoxyphenyl, when R2denotes butyl, values of R5other than 4-methoxyphenyl and 4-butoxyphenyl, when R2means of pencil, the values of R5other than 4-tert-butylphenyl, 3-tert-butyl-4-hydroxyphenyl, 4-tert-butyl-3-hydroxyphenyl and 4-hexyloxyphenyl, when R2denotes a carboxy, values of R5other than phenyl when R2denotes methoxycarbonyl or ethoxycarbonyl, the values of R4other than 3-tert-butylphenyl, 3-tert-butyl-4-hydroxyphenyl and 4-(4-methylpentyl)phenyl when R2means etoxycarbonyl, and the values of R5other than 4-pentyloxide, when R2denotes 2-motivationskurser;
g') in the compounds of the formula I, in which each of R1and R2denotes hydrogen, the values of R5other than phenyl when R4denotes hydroxyl, methyl, ethyl, carboxy, methoxycarbonyl or carbarnoyl.

Preferred compounds according to the invention are aboutaam synthesis of known compounds of formula I.

Thus, the compounds according to the invention which correspond to the formula I, can be obtained, for example, by the method, which includes
a) reaction of compounds of formula II

with the compound of the formula Y2-R5(III) in which either one of Y1and Y2indicates the lowest alkanoyl, and the other represents lower alkyl or triarylphosphine, or one of Y1and Y2represents a reactive esterified hydroxyl group and the other denotes the group of Y3-X-, in which Y3denotes hydrogen or metal-containing group, R1, R2, R3, R4and R5have the meanings indicated above, and the functional group R1, R2, R3and R4as well as functional substituents at R5can be temporarily protected, or
b) removal of H-Y4of the compounds of formula IV

in which Y4refers to a group that is an electron donor, R1, R2, R3, R4X and R5have the meanings indicated above, and the functional group R1, R2, R3and R4as well as functional substituents at R5can be temporarily C is / establishment, which can be obtained by the above options, in another compound of formula I, separating a mixture of isomers, which can be obtained at the individual isomers and/or conversion of the compounds of formula I containing at least one salt-forming group, which can be obtained by the above described methods, the salt or the transformation of salt, which can be obtained by the above-described variants, into the corresponding free compound or into another salt.

Lowest alkanoyl Y2or, more preferably, a group Y1represents, for example, With1-C3alkanoyloxy group, such as formyl, acetyl or propionyl, in particular formyl. Lower alkyl group, Y1or, more preferably, Y2represents, for example, With1-C3alkyl group such as methyl, ethyl or propyl, especially methyl. Triarylphosphines Y2or, more preferably, Y1represents, for example, triphenylphosphorane.

When one of Y1and Y2represents a reactive esterified hydroxyl group and the other denotes a group of formula Y3-X-, in which Y3denotes hydrogen, in the preferred embodiment, the reaction of condensation provodkoy system of the noble metal/phosphine, such as palladium or a salt of palladium (II), in the presence of triarylphosphine, such as palladium acetate and triphenylphosphine, or in the presence of system bescription/paradigalla, preferably in the presence of three(NISS. )alkylamine, for example trimethylamine, expediently in the presence of C1-I, in a polar organic solvent such as an amide (N,N-di(NISS. )alkylaromatics acid, in particular dimethylformamide, di(NISS. )alkylsulfonate, for example in dimethyl sulfoxide or dioxane, at a temperature of from 15 to 120 respectivelyoC, preferably at boiling.

When one of Y1and Y2represents a reactive esterified hydroxyl group and the other denotes a group of formula Y3-X-, in which Y3denotes a metal-containing radical, such as gorodminvody radical, in the preferred embodiment, the condensation reaction is carried out in accordance with the Grignard method, according to which in the preferred embodiment, metallsoderjasimi intermediate connection receive in situ.

When one of Y1and Y2means (ness.)alkanoyl, and other means (NISS. )alkyl, in a preferred embodiment, the reaction of intermolecular candicacy.

When one of y1and Y2means (ness.)alkanoyl, and the other denotes Triarylphosphines, in the preferred embodiment, the condensation reaction is carried out in accordance with the well-known method for the synthesis of olefins Wittig, preferably by obtaining in situ phosphorylating the first component from the corresponding triarylphosphine, for example by reaction of the latter with the metal-containing base such as a hydride of an alkali metal, in particular sodium hydride, or an ORGANOMETALLIC base such as connection (NISS. )alkyl and metal, in particular utility, or alcoholate of an alkali metal, for example tert-piperonyl potassium, preferably in an inert organic solvent such as an aromatic or arylaliphatic hydrocarbon, for example benzene or toluene, at a temperature of from -10 respectively to respectively 39oWith, preferably beginning at 0 to 10oC and then at room temperature.

Groups Y4that serve as a donor of electrons, are, for example, esterified hydroxyl group, such as hydroxyl groups esterified with an organic acid, for example (ness.)alkanoyloxy - or hydroxyl, groupcache as three(NISS. )alkylamino, for example trimethylamine, or (ness.)alkylamino, (ness.)analcreampie, (ness.)oxyalkylene or (NISS. )dialkylamino groups, such as pyrolidine, piperidino, Martinova and thiomorpholine, or the corresponding Quaternary ammonium group.

Protection of the functional groups mentioned protective groups themselves protective group and the reaction of their removal are described, for example, in the well-known literary sources.

The removal process H-Y4of the compounds of formula IV can be performed in the usual way. So, for example, water or a lower aliphatic acid can be removed by azeotropic distillation, in particular in toluene, it is useful in mild acidic conditions. The hydrogen halides can be removed in basic conditions, in particular by reaction with an alcoholate of an alkali metal, preferably in the corresponding lower alcohol as a solvent or co-solvent, or exposure at elevated temperature in the presence of a tertiary amine, such as three(ness.)alkylamine.

Starting materials for carrying out the above reactions are well known. New raw materials can be obtained analogously to known methods of obtaining the original mother is to rotate to other compounds of formula I in the usual way. For example, a free carboxyl group can be atrificial or lidirovat and esterified or amidinophenoxy carboxyl group can be converted into a free carboxyl group, esterified carboxyl group can be converted into unsubstituted or substituted karbamoilnuyu group, the free amino group can be allievate or alkilirovanii, and the free hydroxyl can be allievate.

The compounds of formula I it is possible to oxidize by conventional methods such as reaction with organic nagkalat, resulting in formation of the corresponding pyridine-N-oxide derivatives.

Salts of compounds of formula I can be converted into the free compound according to known methods, for example by treatment with a base or acid.

In known methods, the resulting salt can be converted into other salts.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates or may include the solvent used for crystallization.

Because of the close relationships between the new compounds in free form and in the form of their salts in the above and following parts of the present description, any reference to the free compounds and their salts should be considered as unsealing chiral centers can be selectively reversed. For example, the configuration of the asymmetric carbon atoms, which are nucleophilic substituents such as amino and hydroxyl groups, it is possible to reverse the reaction of nucleophilic substitution of the second order, not necessarily after translation attached nucleophilic substituent acceptable leaving group, which is a donor of protons, and reaction with a reagent that introduces a new Deputy, or the configuration of the carbon atoms in which there are a hydroxyl group, you can reverse oxidation and recovery similar to the description of EP-A 0236734.

The invention relates also to pharmaceutical compositions comprising the compounds of formula I.

Pharmaceutically acceptable compounds of the present invention can be used, for example, in the preparation of pharmaceutical compositions which include an effective amount of active component together or in a mixture with a significant amount of inorganic or organic, solid or liquid pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention are compositions for enteral, such as intranasal, rectal or oral, as well as for HRP animals which contain an effective dose of a pharmacologically active component, either individually or together with a significant number of pharmaceutically acceptable carriers. The dose of this current component depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, diseases, which need treatment, and route of administration in the body.

The pharmaceutical compositions comprise from approximately 1 to approximately 95%, preferably from about 20 to about 90% active component. On the basis of the pharmaceutical compositions according to the invention can be prepared, for example, drugs in doses at one time, such as in the form of ampoules, vials, suppositories, pills, tablets and capsules.

The pharmaceutical compositions of the present invention are prepared by methods which are known, for example, by conducting a process of dissolution, freeze-drying, mixing, granulating or medication on the honey or syrup.

Dose intended for the introduction of a warm-blooded animal, such as man, in particular, to a subject with a body weight of approximately 70 kg first dose, which leave from approximately 3 mg to approximately 3 g, preferably from about 10 mg to about 1 g, for example approximately 20-500 mg each subject per day, in the preferred embodiment, is divided into equal 1-4 single-dose preparative form of the same volume. Children usually receive about half of the adult dose of the subject. The dose required for each individual, it is possible to control, for example, by determining the serum concentration of the current component and the optimal regulation level.

Below the invention is illustrated in the examples, not limiting its scope. Temperatures are in degrees Celsius, and pressure is in millibars (mbar).

EXAMPLE 1
3-[2-(6-methylpyridin-2-yl)vinyl]benzonitrile
A solution of 4.2 ml (36,28 mmol) of 2,6-dimethylpyridine and 4.95 g (37,74 mmol) 3-cyanobenzaldehyde in 6,85 ml of acetic anhydride is refluxed for 16 hours Then vacuum evaporated acetic anhydride and the residue purified by column chromatography (400 g silica gel). Elution in column carry out the first 400 ml of toluene, and then with a mixture of toluene/ethyl acetate in a ratio of 95:5. The fractions containing the target compound are pooled and evaporated under vacuum. The solid residue is recrystallized from methylene chloride is DIN-2-yl)vinyl]benzonitrile
A solution of 5.8 ml (50 mmol) of 2,6-dimethylpyridine and for 6.81 g (52 mmol) of 2-cyanobenzaldehyde 9.5 ml of acetic anhydride is refluxed for 16 hours Then vacuum evaporated acetic anhydride and the residue purified by column chromatography (400 g silica gel). Elution in column carry out the first 400 ml of toluene, and then with a mixture of toluene/ethyl acetate in a ratio of 95:5. The fractions containing the target compound are pooled and evaporated under vacuum. The solid residue is recrystallized from methylene chloride/diisopropyl ether and produce white crystals (melting point: 113-114oC).

EXAMPLE 3
2-methyl-6-[2-(pyridin-4-yl)vinyl]pyridine
A solution of 5.8 ml (50 mmol) of 2,6-dimethylpyridine and 4.9 ml (52 mmol) of pyridine-4-carbaldehyde in 9.5 ml of acetic anhydride is refluxed for 16 hours Then vacuum evaporated acetic anhydride and the residue purified by column chromatography (900 g silica gel). Elution in column carry out the first 5 l of toluene/acetone in a ratio of 4:1, then 5 l of toluene/acetone in a ratio of 3:1 and at the end of 15 l of toluene/acetone in a ratio of 2:1. The fractions containing the target compound are pooled and evaporated under vacuum. The solid residue of paracrystals is 73oC).

EXAMPLE 4
2-methyl-6-[2-(pyridin-3-yl) vinyl]pyridine
A solution of 5.8 ml (50 mmol) of 2,6-dimethylpyridine and 4.9 ml (52 mmol) of pyridine-3-carbaldehyde in 9.5 ml of acetic anhydride is refluxed for 10 hours Then vacuum evaporated acetic anhydride and the residue purified by column chromatography (900 g silica gel). Elution in column exercise first 7 l of toluene/acetone in a ratio of 9:1, then 5 l of toluene/acetone in a ratio of 4:1 and at the end of 5 l of toluene/acetone in a ratio of 2: 1. The fractions containing the target compound are pooled and evaporated under vacuum. The solid residue is recrystallized from methylene chloride/diisopropyl ether and allocate 4,28 g of the product as a colourless oil, which solidified upon standing at 6-8oC.

EXAMPLE 5
2-[2-(3-bromophenyl)ethinyl]-6-methylpyridin
1.2 g (2.8 mmol) of 2-[1,2-dibromo-2-(3-bromophenyl)ethyl] -6-methylpyridine are dissolved in 10 ml of ethanol. Add 0.9 g (16,1 mmol) of potassium hydroxide (powder) and the resulting suspension is refluxed for 4 hours Then the suspension is cooled to room temperature, poured into 100 ml of brine and extracted three times using each time in 30 ml of tert-butylmethylether EF is under vacuum. determined as 0.720 g Specified in the title compound obtained as a colorless oil, which solidified upon standing (melting point 60-61oC).

Source material may be obtained as follows.

a) 2-[2-(3-bromophenyl)vinyl]-6-methylpyridin
A solution of 24 ml (200 mmol) of 2,6-dimethylpyridine and 25.6 ml (207 mmol) of 3-bromobenzaldehyde in 38 ml of acetic anhydride is refluxed for a period of 7.5 hours Then vacuum evaporated acetic anhydride and the residue is dissolved in 500 ml of 4n. hydrochloric acid and extracted twice using each time in 200 ml of hexane. Then the aqueous phase is extracted four times using each time in 300 ml tert-butyl methyl ether. The combined organic phases are washed twice using each time in 300 ml of a saturated solution of Panso3in the water, then once with 300 ml of brine, dried over sodium sulfate, filtered and evaporated under vacuum obtaining in the form of colorless crystals of 4.2 g specified in the title compound with a melting point 58-59oC.

b) 2-[1,2-dibromo-2-(3-bromophenyl)ethyl] -6-methylpyridin
1 g (3.6 mmol) of 2-(3-brompheniramine)-6-methylpyridine are dissolved in 5 ml of carbon tetrachloride and the solution is heated to 55-60oC. For quivaut at 55-60oC for 30 min, and then cooled to room temperature. The resulting precipitate is collected by filtration and dried under vacuum. In this way, in the form of yellow crystals emit 1,3 g specified in the title compound with a melting point 164-166oC.

EXAMPLE 6
3-[2-(6-methylpyridin-2-yl)ethinyl benzonitrile
A mixture of 1 g (8,54 mmol) 2-ethinyl-6-methylpyridine (obtained analogously to the method described by D. E. Ames and others, Synthesis, 1981, S. 364-365), 2.3 g (12.8 mmol) of 3-bromobenzonitrile, of 0.47 g (0.7 mmol) of bis (triphenylphosphine) palladium (II) chloride, 80 mg (0.41 mmol) of iodide monovalent copper and 1.53 ml (15 mmol) of triethylamine in 10 ml of dimethylformamide for 3 hours and stirred at 90oC. the Reaction mixture is cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer is dried over sodium sulfate, filtered, evaporated to dryness and the residue purified by chromatography on silica gel with hexane/ethyl acetate in the ratio of 4:1 as eluent. As a result of crystallization of the resulting product from hexane in the form of brown crystals emit of 0.53 g (yield: 28.4 per cent) indicated in the title compound with a melting point 120-123oC.

EXAMPLE 7
According to the method similar to that described in organisations formula I; presented in table.1.

A typical example in the pharmaceutical composition.

As an example, the pharmaceutical composition represented by the following composition tablets, mg:
The compound of formula I - 2-[2-(pyridin-3-yl)ethinyl]-6-methylpyridin (in the form of base) - 20
Corn starch - 125
Lactose - 25
Hydroxypropylcellulose - 25
Magnesium stearate - 5
The total (table). - 200
20 g of compound of formula I in free base is added to a mixture of 125 g of corn starch 25 g of lactose and 25 g of hydroxypropylcellulose.

The resulting mixture is mixed with 5 g of magnesium stearate and pressed into tablets.

Data pharmacological studies in vivo studies are presented in table. 2.


Claims

1. Derivatives of pyridine of the formula(I)

in which X denotes (C2-C4)alkynylamino group attached through neighboring unsaturated carbon atoms;
R1means (C1-C4)alkyl, (C1-C4)alkoxy, ethinyl, (C1-C4)alkoxycarbonyl, di(C1-C4)alkylamino;
R2denotes hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, di(CArbonyl, 4-(4-azido-hydroxybenzoyl)piperazine-1-ylcarbonyl;
R3denotes hydrogen, (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, hydroxy(C1-C4)alkyl, di(C1-C4)acylaminoacyl, morpholinoethyl or 4-(4-perbenzoic)piperidine-1-ylcarbonyl;
R4denotes hydrogen, (C1-C4)alkoxy, carboxy, (C2-C5)alkanoyloxy, (C1-C4)alkoxycarbonyl, amino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkyl,
(C1-C4)alkoxycarbonyl(C1-C4)alkoxy, di(C1-C4)alkylamino(C1-C4)alkoxy or m-hydroxy-p-azithromycinonline(C1-C4)alkoxy and
R5denotes a group of the formula

where Raand Rbeach independently of one another denotes hydrogen, hydroxyl, halogen, nitro, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C2-C7)alkanoyl, (C2-C5)alkanoyloxy, (C2-C5)alkanoyloxy(C1-Withalkoxy, taylorlovesyouuu, benzylcarbamoyl or(C1-C4)alkylsulfonyl;
Rcdenotes hydrogen, fluorine, bromine, chlorine, hydroxyl, (C1-C4)alkyl;
Rddenotes hydrogen, halogen or (C1-C4)alkyl,
provided that the compounds in which R2, R3and R4represent hydrogen atoms, when R1denotes methyl, R5other than phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in the form of pharmaceutically acceptable salts.

2. Connection on p. 1, in which X denotes ethynylene, in free form or in the form of pharmaceutically acceptable salts.

3. Connection on p. 1, in which the values of R5other than optionally substituted phenyl, and X denotes ethynylene, in free form or in the form of pharmaceutically acceptable salts.

4. Connection on p. 1, which is R5is optionally substituted pyridin-3-yl, and X denotes ethynylene, in free form or in the form of pharmaceutically acceptable salts.

5. 2-[2-(pyridin-3-yl)ethinyl] -6-methylpyridin in free form or in the form of pharmaceutically acceptable salts.

6. Pharmaceutical composition, obladaet filler as a pharmaceutically active component a compound according to any one of paragraphs. 1-5 in free form or in the form of pharmaceutically acceptable salts.

 

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The invention relates to substituted 3-cyanohydrins formula (1), where R1, R2, R3, R4, Y and X are such as defined in the claims

The invention relates to a vitreous form 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic] -N-methylamino] -2,6-dichloraniline] -2-methylinosine, how you can get it by heating the crystalline modification a or a mixture of crystalline modification a and crystalline modification of hydrate 8-[3-[N-[(E)-3-(6-acetamidophenyl-3-yl)agrilogic]-N-methylamino] -2,6-dichloraniline] -2-methylinosine at a temperature below its melting point and then cooled

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The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

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where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

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is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

Arylalkylamine // 2201923
The invention relates to arylalkylamines formula I, where B - A, OA, NH2, CF3, aromatic heterocycle selected from pyridine, pyrazine and pyrimidine; Q is absent or denotes alkylene with 1-6 carbon atoms; R1and R2independently from each other represent OR5where R5- Or cycloalkyl with 3-7 carbon atoms; And the alkyl with 1-10 carbon atoms, and their physiologically acceptable salts

The invention relates to a new method of obtaining derivatives of 3-pyrrolin-2-carboxylic acid of the formula I, where1- C1-C6-allyloxycarbonyl; R2is hydroxyl, WITH1-C4-alkoxy or their ammonium salts, the removal of base sulfoxylate residue from the compounds of formula II, where R1and R2as above; R3- C1-C6-alkyl, benzyl, trifluoromethyl, naphthyl, phenyl which may be substituted by a residue comprising SN3, NO2, halogen

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to new derivatives of azetidine and pyrrolidine General formula

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where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

The invention relates to new carboxyterminal cyclic carboxamide derivative of formula 1

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where G1- CH2; G2- C(O); m = 2 or 3, n is 0 or 1; R1is 1-3 substituent, independently selected from H, G, C1-C6alkoxy; R2is 1-3 substituent, independently selected from H, C1-C6alkoxy; R3means N or

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R4- H; Ar1means

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R8means 1-3 substituent, independently selected from H, G; R9means N;

And means

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where p = 1, 2, 3, or 4; X is-O-, -CH2-; R10-H, C1-C6alkyl or

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where q = 2 or 3; R5- C1-C4alkyl, (CH2)2HE; R6- C1-C4alkyl, -(CH2)2HE, (CH2)2N(CH3)2; R5', R6' - C1-C4alkyl; R7- C1-C6alkyl, and the stereoisomers and pharmaceutically acceptable salts

The invention relates to new derivatives of pyrrolidine or piperidine F.-ly (I), their enantiomers and pharmaceutically acceptable salts

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where R10- H or C(O)N(R1)YZ, R1- N, Y - (CH2)p, (CH2)qCH(R3) or CH(R3)(CH2)q, R3- aryl, aralkyl or heteroaryl, q = 1-3, p = 2 or 3, Z - CO2H, CO2-alkyl or 5-tetrazol, X-S(O) M-(CH2)nor piperidine-1-yl, m = 2, n = 2, R5Mr. And selected from piperidine-2-yl, piperidine-3-yl, piperidine-4-yl or N-substituted piperidine

The invention relates to a piperidine derivative of General formula I

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and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

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The invention relates to new derivatives of 4-hydroxypiperidine formula I

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where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

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The invention relates to medicine, in particular to the use of compounds of formula (I), where R represents a group NR2R3or group OR4, R1represents methyl; R2and R4each independently represent hydrogen or C1-4alkyl; R3represents hydrogen, C1-4alkyl or CH2OH, and X-is physiologically appropriate protivoiona, for the treatment of skin diseases or disorders, hair loss, sunburn, burns, obvalivanie and for healing of wounds, also described pharmaceutical drugs are based on compounds of the formula (I), in particular for local use
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