CZ200068A3 - Pyridine derivatives and pharmaceutical preparation containing thereof - Google Patents

Abstract

Compounds of formula I wherein X 1 and R 1 to R 1 have specific meanings are useful for treating diseases β2 mediated wholly or partially by mGluR5.

Description

Pyridine derivatives and a pharmaceutical composition containing them

Obiest tgclmiXy

The invention relates to the use of 2-arylalkenylpyridines, 2-heteroarylalkenylpyridines, 2-arylalkinylpyridines, 2-heteroarylalkinylpyridines, 2-arylazopyridines and 2-heteroarylazopyridines for modulating mGluR efficacy and for treating mGluR5-mediated diseases of mGluR5, , azopyridines.

New 2-arylalkenylpyridines, 2-hetero2-arylalkinylpyridines, 2-heteroaryl-2-arylazopyridines and 2-heteroaryl.

ÍC.

It has been found that 2-arylalkenylpyridines, 2-heteroarylalkenylpyridines, 2-arylalkinylpyridines, 2-heteroarylalkinylpyridines, 2-arylazopyridines and 2-heteroarylazopyridines, including their pharmaceutically acceptable salts (hereinafter referred to as agents of the invention) are useful as mGluR modulators. Modulation of mGluR can be demonstrated in various ways, including, but not limited to, binding and functional assays, such as second information assays or measuring changes in intracellular calcium concentrations. For example, measurements of the conversion of inositol phosphate in recombinant cell lines expressing hmGluRSa show IC ₅₀ values of about 1 nM to about 50 µΜ for selected agents of the invention.

In particular, the agents of the invention have valuable pharmacological properties. For example, they show marked and selective modulation, in particular antagonistic action on human metabotropic na

-2 ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Glutamate receptors (mGluR). This can be determined in vitro, for example, at recombinant human metabotropic glutamate receptors, particularly at their PLC-coupled subparts, such as mGluRS, using various techniques such as measuring inhibition of agonist-induced increases in intracellular Ca ²⁺ concentrations, as described in L .

P. Daggett et al., Neuropharm, Vol. 34, pp. 871-886 (1995),

P. J. Flor et al., J. Neurochem., Vol. 67, pp. 58-63 (1996) or by determining to what extent the agonist-induced increase is

Inositol phosphate inhibition inhibited as described in the work

T. Knoepfel et al., Eur. J. Pharmacol., Vol. 288, pp. 389-392 (1994), LP Daggett et al., Neuropharm., Vol. 67, pp. 58-63 (1996). Isolation and expression of human mGluR subtypes are described in US Pat. No. 5 521 297. Selected agents of the invention exhibit IC _S0 for inhibition of quisqualate-induced inositol phosphate turnover, measured in recombinant cells expressed as hmGluR5a of about 1 nM to about 50 μΜ.

The present invention provides agents for use in the treatment of diseases associated with glutamatergic signal transduction irregularities and diseases of the nervous system mediated in whole or in part by mGluR5.

Diseases associated with irregularities in glutamatergic signal transmission are, for example, epilepsy, cerebral ischemia, particularly acute ischemia, ischemic eye diseases,

3, muscle cramps such as local or total cramping and especially convulsions or pain.

For example, diseases of the nervous system mediated wholly or partially by mGluR5 are acute, traumatic and chronic

- degenerative processes in the nervous system such as Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression and pain.

The invention also relates to the use of the agents of the invention in the treatment of diseases associated with irregularities in glutamatergic signal transmission and nervous system disorders mediated in whole or in part by group I mGluR.

Furthermore, the invention relates to the use of the agents of the invention for the preparation of a pharmaceutical composition intended for the treatment of diseases associated with irregularities in glutamatergic signal transmission and nervous system disorders mediated in whole or in part by mGluR group I.

Further, the invention relates to a method of treating diseases mediated wholly or partially by Group I mGluR (particularly mGluR5), the method comprising administering a therapeutically effective amount of an agent of the invention to a warm-blooded organism in need thereof.

Yet another feature of the invention is the novel 2-arylalkenylpyridines, 2-heteroarylalkenylpyridines, 2-arylalkinylpyridines,

2-heteroarylacinylpyridines, 2-arylazopyridines and 2-heteroarylazopyridines and their salts. and a process for their preparation.

In addition, the invention relates to a pharmaceutical composition comprising, as a pharmaceutically active ingredient, together with the conventional pharmaceutical excipients, the novel 2-arallalkenylpyridine,

2-heteroarylacenylpyridine, 2-arylakinylpyridine, 2-heteroarylalkynylpyridine, 2-arylazopyridine or 2-heteroarylazopyridine or a pharmaceutically acceptable salt thereof.

The agents of the invention are, for example, compounds of formula Ifc

X — FL: d where

R _x is hydrogen, lower alkyl, hydroxy substituted lower alkyl, lower alkylamino, piperidino, carboxy, esterified carboxy, amidated carboxy, N-lower alkyl-N-phenylcarbamoyl unsubstituted or substituted lower alkyl, lower alkoxy, lower alkoxy, / or a trifluoromethyl group, a lower alkoxy group, a halogen atom substituted with a lower alkyl group or a halogen atom substituted with a, lower alkoxy group,

R ₂ is hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-substituted lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy, 4- (4-fluorobenzoyl) piperidin-1-yl-carboxy, 4- tert-butyloxycarbonylpiperazin-1-yl-carboxy,

4- (4-Azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy. or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carboxy,

R ₃ represents a hydrogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a hydroxy-substituted lower alkyl group, a di-lower alkyl-aminomethyl group, a morpholinocarbonyl group or 4- (4-fluorobenzoyl) -piperidin-1-yl -carboxy,

R ₄ is hydrogen, lower alkyl, * hydroxy, hydroxy substituted lower alkyl, amino nižšialkylovou group, lower alkylamine-nižšíalkylovou group, a di-lower £ alkylamino-lower £ alkyl, nižšíalkylenamino-nižšíalkylovou unsubstituted or substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino-loweralkoxy, loweralkylamino-loweralkoxy, di-loweralkylamino-loweralkoxy, phthalimido-loweralkoxy, loweralkyleneamino-5-

lower alkoxy unsubstituted or substituted by hydroxy or substituted 2-oxo-imidazolidin-1-yl, carboxy, esterified or amidated carboxy, carboxy-loweralkoxy or esterified carboxy-loweralkoxy,

X represents an optionally halogen-substituted lower alkenylene group or an alkynylene group bonded via vicinal unsaturated carbon atoms or an azo group. (-N = N-), and R ₅ represents an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, lower alkenyl, lower alkynyl, phenyl unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, phenyl loweralkynyl unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, hydroxy, hydroxy substituted lower alkyl lower alkanoyloxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, amino, lower alkylamino, lower alkanoylamine or N-lower alkyl-N-lower alkanoylamino-lower alkoxy, phenoxy unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, phenyl-lower alkoxy unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, carboxy-lower alkylamino, esterified carboxy-lower, alkylamino, amidated carboxy-lower · · ··· ·

-6alkylamino, phosphono-lower alkylamino, esterified phosphono-lower alkylamino, nitro, amino, lower alkylamino, lower alkylamino, acylamino, N-acyl-N-lower alkylamino, phenylamino, phenyl-lower alkyl-amino or cycloalkyl-lower alkyl-amino, cycloalkyl-lower-alkylamino alkylamino, each of which may be unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, in the form of conventional photoaffinity ligands and usually radiolabelled, including their N-oxides and their pharmaceutically acceptable salts.

Compounds of formula I having basic groups may form acid addition salts and compounds of formula I having acidic groups may form salts with bases. Compounds of formula I having basic groups and additionally having at least one acid group may also form internal salts.

The invention also includes both full and partial salts, i.e. salts with 1, 2 or 3, preferably 2, base equivalents per mole of acid of formula (I) or salts with 1, 2 or 3 equivalents, preferably 1 equivalent, acid per mole of base of formula I.

Pharmaceutically unacceptable salts may also be used for isolation or purification purposes. Only pharmaceutically acceptable, non-toxic salts are used therapeutically and are therefore preferred.

By halogen atom is meant fluorine, chlorine, bromine or iodine.

When X is an alkenylene group, the trans configuration is preferred.

Preferred compounds of formula I are those in which:

-X represents an optionally halogen-substituted alkenylene or alkynylene group having 2 to 4 carbon atoms bonded via vicinal unsaturated carbon atoms,

R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 hydroxyalkyl group, a cyano group, an ethynyl group, a carboxy group, a C 1 -C 4 alkoxycarbonyl group, a (C 1 -C 4) dialkylamino group, a (C 1 -C 6) alkylaminocarbonyl group, a trifluoromethylphenylaminocarbonyl group,

R ₂ is hydrogen, hydroxy, alkyl of 1 to 4 carbon atoms, hydroxyalkyl groups having from 1 to 4 carbon atoms, alkoxy of 1-4 carbon atoms, carboxy, alkanoyloxy of 2-5 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, a dialkylaminoalkanoyl group having 1 to 4 carbon atoms in each alkyl moiety and having 1 to 4 carbon atoms in an alkanoyl moiety, a dialkylaminomethyl group having 1 to 4 carbon atoms in each alkyl moiety, 4- (4-fluorobenzoyl) - piperidin-1-yl-carboxy, 4-tert-butyloxycarbonyl-piperazin-1-yl-carboxy,

4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carboxy,

R ₃ represents a hydrogen atom, a C 1 -C 4 alkyl group, a carboxy group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 alkylcarbamoyl group, a C 1 -C 4 hydroxyalkyl group, (C 1 -C 4) dialkylaminomethyl, morpholinocarbonyl or 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy,

R ₄ represents a hydrogen atom, a hydroxy group, a C 1 -C 4 alkoxy group, a carboxy group, a C 2 -C 5 alkanoyloxy group, a C 1 -C 4 alkoxycarbonyl group

-8Φ in the alkoxy moiety, C 1 -C 4 aminoalkoxy, C 1 -C 4 dialkylaminoalkoxy in each alkyl C 1 -C 4 alkoxy, C 1 -C 4 dialkylaminoalkyl, C 1 -C 4 carboxyalkylcarbonyl, C 1 -C 4 alkoxycarbonylalkoxy, hydroxyalkyl (C 1 -C 4), (C 1 -C 4) dialkylaminoalkoxy (C 1 -C 4) alkoxy, m-hydroxy-p-azidophenylcarbonylamino (C 1 -C 4) alkoxy group, and

'N

those where

R _a and R t are independently hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, alkoxycarbonyl (C1 -C4) alkoxy, (C2 -C7) alkanoyl, (C2 -C5) alkanoyloxy, (C2 -C5) alkanoyloxyalkyl and (C1 -C4) alkyl. trifluoromethyl, trifluoromethoxy, trimethylsilylethinyl, C 2 -C 5 alkynyl, amino, azido, C 1 -C 4 aminoalkoxy,

-9alkanoylaminoalkoxy having 2 to 5 carbon atoms in the alkanoyl moiety having 1 to 4 carbon atoms in the alkoxy moiety, alkylaminoalkoxy having 1 to 4 carbon atoms in the alkyl moiety and having 1 to 4 carbon atoms in the dialkyl amino moiety and having 1 to 4 carbon atoms in the alkoxy moiety, C 1 to C 4 alkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolecarbonyl, tetrazolecarbonyl, tetrazolecarbonyl, tetrazolecarbonyl carbon, benzylcarbonylamino, C 1 -C 4 alkylaminocarbonylamino, C 1 -C 4 alkoxycarbonylaminocarbonylamino or C 1 -C 4 alkylsulfonyl,

R _c is hydrogen, fluorine, chlorine, bromine, hydroxyl, alkyl. group with 1 to. 4. carbon atoms, C 2 -C 5 alkanoyloxy, C 1 -C 4 alkoxy or cyano; and

R _d represents a hydrogen atom, a halogen atom or a C 1 -C 4 alkyl group.

Even more preferred are compounds of formula I wherein X is as defined above and

R _x is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, ethynyl or C 1 -C 4 dialkylamino in each alkyl moiety.

R ₂ represents a hydrogen atom, a hydroxy group, a carboxy group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 dialkylaminomethyl group in each alkyl part, a 4- (4-fluorobenzoyl) -piperidin-1-ylcarboxy group 4- (4-tert-butyloxycarbonylpiperazin-1-yl-carboxy), 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-ylcarboxy-10 · 4 ··· 94 · 49 49 · 9 4 4 · 4 9 49 4

4 43 4 9 4 9 «

94,449 494 44 9

9 9 4 4 4 9 44 3

4-444-4444 or 4- (4-azolo-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carboxy;

R ₃ has the abovementioned meaning,

R ₄ is hydrogen, hydroxy, carboxy, C 2 -C 5 alkanoyloxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 aminoalkoxy, C 1 -C 4 dialkylaminoalkoxy in each alkyl moiety and s 1 to. C 4 alkoxy, C 1 -C 4 dialkylaminoalkyl or C 1 -C 4 hydroxyalkyl; and

_R represents a group of the formulas

hydrogen, a halogen atom, an alkyl group having 1 to 4 atoms wherein

R _a and R _b are independently from nitro, cyano, carbon, C 1 -C 4 alkoxy, trifluoromethyl, trifluoromethoxy or C 2 -C 5 alkynyl and R _c and R _d are as defined above.

Agents of the invention include, for example, the compounds described below in the Examples.

The usefulness of the agents of the invention for the treatment of the above diseases can be confirmed in a number of standard tests, including the following:

At doses of about 10 to 100 mg / kg i.p. or p.o. when pretreated for 15 minutes to 8 hours, the agents of the invention exhibit anticonvulsant activity in an electroshock-induced convulsion model [see E. A. Swinyard, J. Pharm. Assoc. Scient. Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952)].

-1144 4444 44 4 44 ·· • 4 44 44 4444

4,444 4,444

44 44 4 4

444 44.4 4444

44 444 44 44

At doses of about 4 to about 40 mg / kg p.o. exhibit agents of the invention reversal in complete Freund's adjuvant (FCA) hyperalgesia [see J. Donnerer et al. Neuroscience 4: 969-698 (1992) and C.J. Woolf, Neuroscience, 2: 327-331 (1994).

For all of the above indications, appropriate dosages will of course depend, for example, on the compound employed, the host, the mode of administration, and the nature and severity of the condition being treated. However, in general, animals will achieve sufficient results at an indicated daily dose of from about 0.5 to about 100 mg / kg body weight. In larger mammals, for example in humans, the indicated daily doses range from about 5 to 1500 mg, preferably about 10 to about 1000 mg, of a compound suitably administered in divided doses up to four times daily or in the form of delayed release.

Preferred compounds for the above indications are (3- {2- [2-trans- (3,5-dichlorophenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine (A), 2- methyl-6-styryl-pyridine (B), 2- (3-fluoro-phenylethynyl) -6-methyl-pyridine (C), and

2- (4-Ethoxy-3-trifluoromethyl-phenylethynyl) -6-methyl-pyridine (D). It has for example been found that the above stated concentrations vul fps model induced by electroshock Compounds A and B possess anticonvulsant activity with ED _S0 30 and 35 mg / kg ip (pretreatment in time: 4 hours and 15 minutes), and that in the above model, hyperalgesia induced by FCA compounds C and D show a hyperalgesia turnover with ED _{50 of} 4.2 and 19 mg / kg po (after pretreatment at 3 hours).

As mentioned above, the agents of the invention include the novel 2-arylalkenylpyridines, 2-heteroarylalkenylpyridines,

2-Arylalkynyl pyridines, 2-heteroarylalkynyl pyridines, 2-arylazopyridines and 2-heteroarylazopyridines and salts thereof are hereinafter referred to as compounds of the invention.

Compounds of the invention include compounds of formula I as defined above, and salts thereof, wherein X and R 1

• 9 • • ···· 9 9 4 9 94 · • 4 · 49 • .9 4 • • 9 • 4 • • • • 9 • 9 4 • 4 9 4 • • • 9 • • 4 « 4 • 4 • 9 9 • 9 • 9

to R ₅ are as defined above, provided that when R ₃ is a hydrogen atom,

(a) in compounds of formula I wherein R _1, R ₂ and R ₄ are hydrogen, R ₅ is other than phenyl, monohalophenyl, 2,4- and

3,4-dichlorophenyl, 3- and 4-trifluoromethylphenyl, methylphenyl,

3,4- and 2,5-dimethylphenyl, 4-isopropylphenyl, 3,5-di-tert-butylphenyl, methoxyphenyl, 3,4-dimethoxyphenyl, 2,4,5- and 3,4,5-trimethoxyphenyl, hydroxyphenyl, 3, 5-dihydroxyphenyl, 4-hydroxy-3,5-dimethylphenyl, 3-hydroxy-4-methoxy- and 4-hydroxy-3-methoxyphenyl, 4-hydroxy- (3-methyl-5-tert-butyl-), 2- and

4-acetylaminophenyl, 3,5-diisopropyl- and 3,5-di-tert-butyl) phenyl, 4-carboxy- and 4-ethoxycarbonylphenyl, 4-cyanophenyl,

3-methoxycarbonylphenyl, 3-carboxy-5-methoxyphenyl, 2-pyridinyl,

5-chloro-2-pyridinyl and 6-methyl-2-pyridinyl when X is ethenylene, or R ₅ 'is other than phenyl, 4-methylphenyl,

4-methoxyphenyl, 4-bromophenyl and 2- and 4-chlorophenyl when X is 1,2-propylene attached to R ₅ at the 2-position, or R ₅ is other than phenyl, 2- and 4-chlorophenyl and 3-methoxyphenyl enyl when X is

1,2-propylene attached to R ₅ in position 1 or R ₅ other than

4-methoxyphenyl when X is 2,3-but-2-enylene;

1,2-but-1-enylene attached to R ₅ in the 2-position, or R ₅ is other than

4-methoxyphenyl and 4-isopropylphenyl when X is

2,3-pent-2-enylene attached, to R _s in the 3-position, or R _s is other than phenyl, 4-methylphenyl, methoxyphenyl and 4-hydroxyphenyl when X is 3,4-hex-3-enylene,

b) in compounds of formula I wherein R ₁ is methyl and R ₂ and R ₄ are hydrogen, R ₅ is other than phenyl, 3-methylphenyl,

2-methoxyphenyl, 2-chlorophenyl, 4-cyanophenyl, 2-pyridinyl and

6-methyl-2-pyridinyl when X is ethenylene,

c) in compounds of formula I wherein R ₁ and R ₂ are hydrogen atoms

R ₄ is carboxy, R ₅ is other than phenyl,

3-methylphenyl, 4-methoxyphenyl and 4-bromophenyl when X is ethenylene,

-1344 ···· 4 4 • · 4 · · 4 ·· 4 • 4 4

4 44

4 4

4 4

4 4

4 444

44

4 4 4

4 4 4

4 4 4

4 4 4

44

d) in compounds of formula I wherein R ₄ and R ₂ are hydrogen and R 4 is methyl, R _E is other than phenyl, 3-methoxy-,

4-methoxy- and 3,4-dimethoxyphenyl, 2-chloro- and 2,4-dichlorophenyl and 6-methylpyrid-2-yl when X is ethenylene or R ₅ is other than phenyl when X is 1,2-prop -1-enylene attached to R ₅ in position 2,

e) in compounds of formula I, wherein R _x and R ₂ are hydrogen and R ₄ is 2-or 3-dimethylaminoethoxykarbonyl dimethylaminopropyloxykarbonyl, _R is other than 4-methoxyphenyl when X denotes ethenylene,

f) in compounds of formula I wherein R ₁ and R ₂ are hydrogen and R ₄ is 2-dimethoxyethoxy, R ₅ is other than phenyl,

4-methylphenyl and 4-methoxycarbonylphenyl when X is ethenylene,

g) R ₅ is other than phenyl when R 1 and R ₂ are hydrogen and R ₄ is hydroxy or ethoxycarbonyl, or when R ₁ and R ₂ are hydrogen and R ₄ is hydroxy, or when R ₂ is methyl, R 2 R ₂ is hydrogen and R ₄ is methoxy, or R ₂ is but-1-enyl, R ₂ is hydrogen and R ₄ is hydrogen, or R _x is hydrogen and R ₄ is 2-dimethoxyethoxy, and X is in in each case ethenylene, and provided that when R ₃ is a hydrogen atom and X is ethenylene, a ') R ₅ is other than phenyl, 2- and 4-nitrophenyl, 4-aminophenyl,

4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxycarbonylphenyl, 5-formyl-2-methoxyphenyl, 5-carboxy-2-methylphenyl and pyridyl when R _1, R ₂ and R ₄ are hydrogen, b ') compounds of the general formula. I ,, wherein R ₂ and R ₄ are hydrogen and _R is different from phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 2-methoxyphenyl when R _x is methyl, R ₅ is other than a 6-bromopyridine -2-yl when R ₁ is bromo and R ₅ is other than 6-hexyloxypyridin-2-yl when R ₂ is hexyloxy, c ') in compounds of formula I wherein R ₂ and R ₄ are hydrogen and R ₆ is other than phenyl, 4-aminophenyl and 4-propylphenyl when R ₂ is methyl, R ₅ is other than phenyl, 4-cyanophenyl and

fe fefe · fefe ·

-14 • fefe * fe fe • fefe feef

4-pentylphenyl, when R ₂ is ethyl, R ₅ is other than

3-cyano-4-ethoxyphenyl and 3-bromo-4-methoxyphenyl when R ₂ is butyl,

R ₅ is other than 4-methoxyphenyl and 4-butyloxyphenyl when R ₂ is pentyl, R ₅ is other than 4-tert-butylphenyl, 3-tert-butyl-4-hydroxyphenyl, 4-tert-butyl-3- hydroxyphenyl and 4-hexyloxyphenyl when _R2 is carboxy, _R is other than phenyl when _R2 is methoxycarbonyl or methylcarbamoyl, _R4 is other than 3 - terč.butylfeny1, 3-tert-butyl-4-hydroxyphenyl, and 4- (4-methylpentyl) phenyl when R ₂ is ethoxycarbonyl and R ₅ is other than

4- pentyloxyphenyl when _R2 is 2-methylbutoxycarbonyl,

(d) in compounds of formula I wherein R ₁ and R ₂ are hydrogen and R ₅ is other than phenyl when R ₄ is hydroxy, methyl, ethyl, carboxy,. a methoxycarbonyl or carbamoyl group.

Preferred compounds of the invention are designated as agents of the invention.

The compounds according to the invention can be prepared analogously to the synthesis procedures of known compounds of the general formula (I).

Thus, for example, the compounds of formula (I) may be prepared by a process comprising: (a) reacting a compound of formula (II) with a compound of formula (III) wherein one of Y ₁ and Y ₂ is lower alkanoyl and the other is lower alkyl or triarylphosphoranylidenemethyl or one of Y ₂

-1599 9 · 99 99 9 99 ·· · 9 9 · ♦ 9 9 9 ·> ·· 9 9 9 ····

99 99 99 99 99 99

999 999 9999

9 99 999 99 99 and Y ₂ denotes a reactive esterified hydroxy and the other represents a group Y ₃ -X- in which Y ₃ is hydrogen or a metallic group, and R _HR R _2, R _3, R ₄ and R ₅ have the meanings given above and functional groups R _LZ R _2, R ₃ and R ₄ as well as functional substituents of _R may be temporarily protected, or

b) removing part of HY ₄ from the compound of formula IV

wherein Y ₄ represents electrofugal group and R _HR R _2, R _3, R _4, X and R ₅ are as defined above and functional groups R _HR R _2, R ₃ and R ₄ as well as functional substituents of _R5 may be temporarily protected whereupon any temporary protected groups are removed, and.

optionally converting a compound of formula I obtained by the above methods into another compound of formula I, separating any obtained isomer mixtures into individual isomers and / or converting the obtained compound of formula I having at least one salt-forming group into a salt, or converting the obtained salt to the corresponding free compound or to another salt.

Lower alkanoyl Y ₂ or even more preferably. Y _{3 is,} for example, C 1 -C 3 alkanoyl, such as formyl, acetyl or propionyl, especially forms 1. A lower alkyl group Y ₃ or even more preferably a group Y ₂ is, for example, an alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl or propyl, in particular methyl. Triarylphosphoranylidenemethyl Y ₂ or even more preferably Y ₃ is, for example, triphenylphosphoranylidenemethyl.

When one of Y ₃ and Y ₂ is a reactive esterified hydroxy group and the other is a group of the formula Y ₃ -X-, where Y ₃ is a hydrogen atom, it is carried out with

- the advantage of condensation according to the Heck coupling method, for example in the presence of copper or a copper or noble metal catalyst and a phosphine catalyst such as palladium or a palladium salt in the presence of a triarylphosphine such as palladium acetate and triphenylphosphine or bis-triphenylphosphine-chlorine palladium (II) acid, preferably in the presence of a tri- lower alkylamine, for example trimethylamine, preferably in the presence of Cu ^x -I, in a polar organic solvent such as N, N-di-alkylalkylamide of an alkanoic acid such as dimethylforomamide; from about 15 ° C to about 120 ° C, preferably boiling.

If one of Y ₃ and Y ₂ is a reactive esterified hydroxy group and the other is a group of the formula Y ₃ -X-, where Y ₃ is a metal group such as a halogen-magnesium group, the reaction is preferably carried out according to the Grignard method. intermediate product. preferably formed in situ.

When one of Y ₃ and Y ₂ is lower alkanoyl and the other is lower alkyl, the intermolecular condensation of compounds of formulas II and III is preferably carried out according to the Shaw and Wagstaff methods or one of their many modifications.

If one of Y ₃ and Y ₂ is lower alkanoyl and the other is triarylphosphoranylidenemethyl, condensation is preferably carried out according to the known Wittig olefin formation method, preferably by forming a phosphoranylidene component from the corresponding triarylphosphonium halide in situ, for example by reacting a triarylphosphonium halide with a metal base. such as an alkali metal hydride such as sodium hydride, or an organometallic base such as a lower alkyl metal compound such as butyllithium, or an alkali metal alkanolate such as potassium tert-butoxide, preferably in an inert organic solvent such as benzene about 39 ° C, ° C and then 0 · 00 · 0 · · ~ '. . .

0 • 0 0 0

-17 is an aromatic or arylaliphatic hydrocarbon, or toluene, at a temperature of about -10 ° C to preferably at a temperature of 0 ° C to 10 room temperature first.

The Y ₄ electrofuges are, for example, esterified hydroxy groups, such as hydroxy groups esterified with an organic acid, for example a lower alkanoyloxy group, or hydroxy groups esterified with an inorganic acid, for example halo, or tertiary amino groups such as lower alkylamino, e.g. lower oxyalkyleneamino or lower thiaalkyleneamino such as pyrrolidino, piperidino, morpholino or thiomorpholino, or the corresponding quaternary ammonium groups.

Protection of functional groups with these protecting groups, protecting groups as such and reactions for their removal are described, for example, in standard works.

Removal of a portion of HY ₄ from compounds of formula IV can be carried out in a conventional manner. Thus, water or lower alkanoic acids can be removed by azeotropic distillation, for example in toluene, preferably under mildly acidic conditions. Hydrogen halides can be removed under basic conditions, such as by reaction with an alkali metal alkanolate, preferably in the corresponding lower alkanol as solvent and co-solvent, or by heating in the presence of a tertiary amine, such as the thin lower alkylamine.

Starting materials for the above reactions are generally known. The novel starting materials can be obtained by methods analogous to the preparation of known starting materials.

The compounds of formula (I) obtained by the process of the invention can be converted to other compounds of formula (I) by conventional means, for example, the free carboxy group can be esterified or amidated, the esterified or amidated carboxy group can be converted to the free carboxy group.

-1899 ··· · ··················· see More info >> 9999 9 ··· 999 999 999 · (9 · 9 9 9 5 9 9 ·

An esterified carboxy group can be converted to an unsubstituted or substituted carbamoyl group, the free amino group can be acylated or alkylated, and the free hydroxy group can be acylated.

Also, the compounds of formula I can be oxidized by conventional means, such as by reaction with organic peroxyacids, to provide the corresponding pyridine N-oxide derivatives.

Salts of the compounds of formula (I) may also be converted into the free compounds in known manner, for example by treatment with a base or an acid.

The resulting salts can be converted to other salts in a known manner.

The compounds of formula (I), including their salts, may also be obtained in the form of hydrates or may contain a solvent used in crystallization.

Due to the close relationship between the novel compounds in free form and in the form of their salts, any reference herein to free compounds and their salts is to be understood as meaning both the free compounds and the corresponding salts.

In the compound of formula I, the configuration at the individual chiral centers may be selectively changed. For example, the configuration of asymmetric carbon atoms that carry nucleophilic substituents, such as amino or hydroxy, may be altered by another type of nucleophilic substitution, optionally after conversion of the bound nucleophilic substituent to a suitable nucleofugic leaving group and reaction with an introducing substituent introducing agent, or carbon atoms having hydroxy groups. can be changed by oxidation and reduction, analogously to European patent application EP-A-0 236 734.

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

The pharmaceutically acceptable compounds of the present invention can be used, for example, to prepare pharmaceutical compositions comprising an effective amount of the active ingredient together

-19 • β φ * • • φ φ φ φ φ β · · · · · · · φ φ φ φ φ φ φ φ φ φ φ nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo nebo

The pharmaceutical compositions of the invention are those for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals), which compositions contain an effective dose of the pharmacologically active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90%, of the active ingredient. For example, the pharmaceutical compositions of the invention may be in unit dosage form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical compositions of the invention may be prepared in a conventional manner, for example, by conventional dissolution, lyophilization, mixing, granulation or mixing processes.

The doses to be administered to warm-blooded animals, for example humans, for example a body weight of about 70 kg, in particular doses effective in diseases caused or associated with irregularities in glutamatergic signal transmission, are from about 3 mg to about 3 g, preferably from about 10 mg to about 1 g, for example about 20 mg to 500 mg, per person per day, preferably divided into 1 to 4 individual doses, which may be, for example, of the same size. Usually, children receive about half the adult dose. For example, the dosage required for each individual can be monitored by measuring the concentration of the active ingredient in the serum and adjusting to an optimal level.

• »· · · · • · · • · fe • · • · • · fe · • • fe fefe • fefe • fefe «· Fe * · • fe • fefefe • fefe fefe

The present invention is by way of non-limiting examples. Celsius and pressures in Pascals.

The temperatures are given in degrees below

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzonitrile

A solution of 2,6-dimethylpyridine (4.2 mL, 36.28 mmol),

3-Cyanobenzaldehyde (4.95 g, 37.74 mmol) in acetic anhydride (6.85 mL) was heated to reflux for 16 hours. The acetic anhydride was then evaporated under reduced pressure and the residue was purified by column chromatography (silica gel 400 g). The column was eluted first with toluene (400 mL) and then with a 95: 5 mixture of toluene and ethyl acetate. The fractions containing the desired compound were combined and evaporated under reduced pressure. The solid residue was recrystallized from methylene chloride / hexane and 3.18 g of white crystals were isolated (m.p. 91-92 °).

Example 2

2- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzonitrile

2,6-Dimethylpyridine solution (5.8 ml, 50 mmol),

Of 2-cyanobenzaldehyde (6.81 g, 52 mmol) in acetic anhydride (9.5 mL) was heated to reflux for 16 hours. The acetic anhydride was then evaporated under reduced pressure and the residue was purified by column chromatography (silica gel 400 g). The column was eluted first with toluene (400 mL) and then with a 95: 5 mixture of toluene and ethyl acetate. The fractions containing the desired compound were combined and evaporated under reduced pressure. Solid residue with ·· ··

9 · · · ·

-21 • · · · · · · · · · ·

9 9 9

The product was recrystallized from methylene chloride / diisopropyl ether and the white crystals were isolated (m.p. 113-114 °).

Example 3

2-Methyl-6- [2- (pyridin-4-yl) -vinyl] -pyridine

A solution of 2,6-dimethylpyridine (5.8 mL, 50 mmol), pyridine-4-carbaldehyde (4.9 mL, 52 mmol) in acetic anhydride (9.5 mL) was heated at reflux for 16 h. The acetic anhydride was then evaporated under reduced pressure and the residue was purified by column chromatography (silica gel 900 g). The column was eluted first with toluene / acetone 4: 1 (5 L), then with toluene / acetone 3: 1 (51) and finally with toluene / acetone.

2: 1 (15 1). The fractions containing the desired compound were combined and evaporated under reduced pressure. The solid residue is recrystallized from methylene chloride / diisopropyl ether and 0.956 g of white crystals are isolated (m.p. 72-73 ° C).

Example 4

2-Methyl-6- [2-pyridin-3-yl) -vinyl] -pyridine

A solution of 2,6-dimethylpyridine (5.8 mL, 50 mmol), pyridine-3-carbaldehyde (4.9 mL, 52 mmol) in acetic anhydride (9.5 mL) was heated at reflux for 10 hours. The acetic anhydride was then evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, 900 g). The column is eluted first with toluene / acetone 9: 1 (7 L), then with toluene / acetone 4: 1 (5 L) and finally with toluene / acetone

2: 1 (5 1). The fractions containing the desired compound were combined and evaporated under reduced pressure. The solid residue was recrystallized from methylene chloride / diisopropyl ether to give 4.28 g of a colorless oil which solidified on standing at 6-8 ° C.

• · ♦ · 4 · 4 ···

4 4 4 9 9 4 4 9 4 • 4 4 9 4 4 · 9 9 9 4 4 _ O O _ 4 4 4 4 4 4 · · 4 ·

Z- a- 4 4 44 9 44 4949

Example 5

2- [2- (3-bromophenyl) ethynyl] -6-methylpyridine

1.2 g (2.8 mmol) of 2- [1,2-dibromo-2- (3-bromophenyl) ethyl] -6-methylpyridine are dissolved in 10 ml of ethanol. 0.9 g is added. (16.1 mmol) of potassium hydroxide (powder) and the resulting suspension was heated to reflux for 4 hours. The suspension is then cooled to room temperature, poured into 100 ml of sodium chloride solution and extracted three times with 30 ml of tert-butyl methyl ether each time. The combined organic phases were washed with 30 ml of brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.720 g of the title compound is obtained as a colorless oil which crystallizes on standing, m.p. 60-61 °.

The starting materials are prepared as follows:

a) 2- [2- (3-Bromo-phenyl) -vinyl] -6-methyl-pyridine

A solution of 2,6-dimethylpyridine (24 mL, 200 mmol) and 3-bromobenzaldehyde (25.6 mL, 207 mmol) in acetic anhydride (38 mL) was heated at reflux for 7.5 h. The acetic anhydride is then evaporated under reduced pressure and the residue is dissolved in 500 ml of 4N hydrochloric acid and extracted twice with 200 ml of hexane each. The aqueous phase is then extracted four times with 300 ml of tert-butyl methyl ether each time. The combined organic phases were washed twice with 300 ml of a saturated solution of NaHCO ₃ in water, then once with 300 ml of brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 4.2 g of the title compound. in the form of colorless crystals, m.p.

b) 2- [1,2-dibromo-2- (3-bromophenyl) ethyl] -6-methylpyridine g (3.6 mmol) of 2- (3-bromophenylethynyl) -6-methylpyridine is dissolved in 5 ml of tetrachlomethane; and heat the solution to

-23 · 9 «9 a a

9 9 9 «99 a

99 to 55 ° to 60 °. mmol) of bromine Br ₂ v

Add dropwise a solution of 0.23 ml (4.4 ml of carbon tetrachloride. The reaction mixture was maintained at the temperature. 55 to 60 ⁰ for 30 minutes and then cooled to room temperature. The resulting precipitate was filtered and dried under reduced pressure. 1.3 g of the title compound are isolated as yellow crystals, m.p. 164-166 °.

Example 6

3- [2- (6-Methyl-pyridin-2-yl) -ethynyl] -benzonitrile

A mixture of 1 g (8.54 mmol) of 2-ethynyl-6-methylpyridine (prepared analogously to D. E. Ames et al., Synthesis, 1981, pp. 364-365), 2.3 g (12.8 mmol)

3-bromobenzonitrile, 0.47 g (0.7 mmol) of palladium (II) bis- (triphenylphosphine) chloride complex, 80 mg (0.41 mmol) of copper (I) iodide and 1.53 ml (15 mmol) of triethylamine in 10. ml of dimethylformamide was stirred for 3 hours at 90 ° C. The reaction mixture was cooled to room temperature, poured into water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, evaporated to dryness and the residue purified by silica gel chromatography eluting with hexane: ethyl acetate (4: 1). Crystallization of the obtained product from hexane gave 0.53 g (28.4%) of the title compound as brown crystals, m.p. 120-123 ° C.

-24 · · 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 aa · · · aa aa «·· ·« · a * ··

Example 7

The following compounds were prepared analogously to Example 1 (where X is alkenylene) or Example 5 (where X is alkynylene):

a compound of formula I mp (° C) 2-styrylpyridin-3-ol 249-252 2-Methyl-6- [2- (3-nitrophenyl) -vinyl] -pyridine 100-101 2- [2- (2-chlorophenyl) -vinyl] -pyridine colorless oil 2-methyl-6-styrylpyridine 40-42 Acetic acid 6- [2- (2-chloro-phenyl) -vinyl] -pyridin-3-yl-ester 75-77 6- [2- (2-Chloro-phenyl) -vinyl] -pyridin-3-ol 168-171 Acetic acid 2- [2- (2-chlorophenyl) -vinyl] -pyridin-3-yl ester 99-102 2- [2- (2-chlorophenyl) -vinyl] -pyridin-3-ol 232-234 6-Methyl-2-styrylpyridin-3-ol 261 rozkl. Acetic acid 2- [2- (2-chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yl-ester 92-94 2- [2- (2-chlorophenyl) -vinyl] -6-methyl-pyridin-3-ol 232-234 (Z) -6-methyl-2-styrylpyridin-3-ol 145-148 2- [2- (2-chlorophenyl) -vinyl] -6-methylpyridine 51-52 2- [2- (2-Fluorophenyl) -vinyl] -pyridine 69-70 2- [2- (2-Nitrophenyl) -vinyl] -pyridine 97-99 Acetic acid 2- [2- (4-chlorophenyl) -vinyl] -6-methylpyridin-3-yl ester 102-103 6- [2- (4-Chloro-phenyl) -vinyl] -2-methyl-pyridine-3-. -yl ester of acetic acid 130-131 2- [2- (4-chlorophenyl) -vinyl] -6-methylpyridin-3-ol 275-278 rozkl. 6- [2- (4-Chloro-phenyl) -vinyl] -2-methyl-pyridin-3-ol 265-270 rozkl. Acetic acid 6-methyl-2- [2- (2-nitrophenyl) -vinyl] -pyridin-3-yl-ester 139-140 6-Methyl-2- [2- (2-nitrophenyl) -vinyl] -pyridin-3-ol 190-195 rozkl.

0 · · · 00 0

0 • ·

-25000 00 0 0 000 • 0 0 000 000 00 00

Acetic acid 2-methyl-6- [2- (2-nitrophenyl) -vinyl] -pyridin-3-yl-ester 99-100 2-Methyl-6- [2- (2-nitrophenyl) -vinyl] -pyridin-3-ol 230-233 rozkl. Acetic acid 2- [2- (3-chlorophenyl) -vinyl] -6-methylpyridin-3-yl ester 97-99 Acetic acid 6- [2- (3-chlorophenyl) -vinyl] -2-methylpyridin-3-yl ester 112-114 2- [2- (3-chlorophenyl) -vinyl] -6-methyl-pyridin-3-ol 232-235 6- [2- (3-chlorophenyl) -vinyl] -2-methyl-pyridin-3-ol 230-232 (Z) - (6-Styryl-pyridin-2-yl) -methanol 69-70 (E) - (6-Styryl-pyridin-2-yl) -methanol 58-60 2,2'- (1,2-ethylenediyl) bis [6-methyl] pyridine 108-110 dimethyl- [3- (6-methyl-2-styrylpyridin-3-yloxy) -propyl] -amine in the form of its hydrochloride salt 136-139 (E) -6- [2- (2-pyridyl) -vinyl] -2-picoline 56-57 2-methyl-6-styrylpyridine-1-oxide 102-103 2-styrylpyridine-1-oxide 156-159 (E) -6-Methyl-2- (2-pyridin-2-yl-vinyl) -pyridin-3-ol 240-242 (Z) -6-methyl-2- (2-pyridin-2-yl-vinyl) -pyridin-3-ol as the HCl salt 225-228 6-styrylpyridine-2-carbonitrile 92-93 2- [2- (2,6-dichlorophenyl) -vinyl] -6-methylpyridine light yellow oil 3-methoxy-6-methyl-2-styrylpyridine light yellow oil 6-styrylpyridine-2-carboxylic acid amide 141-142 2- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzonitrile 113-114 3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzonitrile 91-92 4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzonitrile 131-132 6-styrylpyridine-2-carboxylic acid as the HCl salt 209-212 6-Styrylpyridine-2-carboxylic acid methyl ester 87-88 Acetic acid 2- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester colorless oil 2- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenol 227-229 Acetic acid 2-methoxy-4- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester 102-103

• 9 9 9 · ·

-269 • 9 9

2- [2- (3-chlorophenyl) -vinyl] -6-methylpyridine 59-61 2- [2- (4-chlorophenyl) -vinyl] -6-methylpyridine 83-85 2- [2- (2-chlorophenyl) -vinyl] -5-ethylpyridine 34-35 1- (6-Styryl-pyridin-2-yl) -ethanone 67-68 6- [2- (2-Chloro-phenyl) -vinyl] -2-methyl-nicotinic acid ethyl ester 80-82 2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-nicotinic acid ethyl ester 70-72 2- [2- (6-methylpyridin-2-yl) -vinyl] -benzoic acid as the HCl salt 218-219 3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzoic acid 150-151 4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzoic acid 206-207 3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzoic acid methyl ester as its HCl salt 237-238 4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -benzoic acid methyl ester 112-113. 2-Methoxy-4- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 118-119 {3- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl} -methanol as HCl salt 230-231 6-Styryl-pyridine-2-carboxylic acid tert-butylamide 87-88 2- (2-bromo-2-phenylvinyl) -6-methylpyridine as the HCl salt 150-154 2-methyl-6-phenylethynylpyridine as the HCl salt 146-148 6-Styrylpyridine-2-carboxylic acid hexylamide as the HCl salt 118-125 6- [2- (2-chlorophenyl) -vinyl] -2-methylnicotinic acid 219-221 rozkl. 2- [2- (2-chlorophenyl) -vinyl] -6-methylnicotinic acid 168-170 2- [2- (3,5-dichlorophenyl) -vinyl] -6-methylpyridine 75-77, 2-methyl-> 6- [2- (3-trifluoromethylphenyl) -vinyl] -pyridine 44-45 (E) -6- [2- (4-pyridyl) vinyl] -2-picoline 72-73 N, N-diethyl-3- [2- (6-methylpyridin-2-yl) -vinyl] -benzamide as HCl salt 227-228

4 43 «· • 4»

4 ·

44 44

443 4 44 4

4 4 4 4 4 5

4 44 44 4

4 f 4 4 4 4 • 4,444 44 44

-ΖΊ4 4 4

9

Ν, N-Diethyl-4- [2- (6-methylpyridin-2-yl) -vinyl] -benzamide as HCl salt 183-184 (E) -6- [2- (3-pyridyl) vinyl] -2-picoline yellowish oil {2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -acetic acid ethyl ester colorless gumovitá substance 3- [2- (6-methylpyridin-2-yl) -vinyl] -N- (3-trifluoromethylphenyl) -benzamide as the HCl salt 249-251 4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -N- (3-trifluoromethyl-phenyl) -benzamide 160-161 2- [2- (3-nitrophenyl) -vinyl] -pyridine 127-128 6-Styryl-pyridine-2-carboxylic acid (3-trifluoromethyl-phenyl) -amide 128-129 2- (6-styrylpyridin-2-yl) -propan-2-ol in form HCl salts 171-174 2-Methyl-6- (2-thiophen-2-yl-vinyl) -pyridine as HCl salt 208-211 2- [2- (3-chlorophenyl) -vinyl] -pyridine 51-53 2- [2- (3-cyanophenyl) -vinyl] -pyridine 85-86 2- [2- (3-Bromo-phenyl) -vinyl] -6-methyl-pyridine 58-59 2- [2- (3-Bromo-phenyl) -2-fluoro-vinyl] -6-methyl-pyridine 58-59 2- [2- (3,5-dimethylphenyl) -2-fluorinyl] -6-methylpyridine 70-72 2- [2- (2,3-dimethoxyphenyl) -vinyl] -6-methylpyridine colorless oil 2- (2- (2,3-dichlorophenyl) vinyl) -6-methylpyridine 67-68 2- [2- (3-chlorophenyl) -1-methylvinyl] pyridine colorless oil {2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yl} -methanol 87-90 2-Methyl-6- [2- (3-trimethylsilanylethinylphenyl) -vinyl] -pyridine yellowish oil 2- [2- (3,4-difluorophenyl) -vinyl] -6-methylpyridine 61-62 2- [2- (3-ethynylphenyl) -vinyl] -6-methylpyridine yellowish oil 2- [2- (3,5-difluorophenyl) -vinyl] -6-methylpyridine yellowish oil 2- [2- (3-fluorophenyl) -vinyl] -6-methylpyridine yellowish oil

-28 • fefe • fe • fefe • fe. · Fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe · fe ·

2- [2- (3-methoxyphenyl) -vinyl] -6-methylpyridine yellowish oil 2-methyl-6- [2- (3-phenoxyphenyl) -vinyl] -pyridine yellowish oil 2- [2- (3-Benzyloxyphenyl) -vinyl] -6-methylpyridine 68-69 2- [2- (2,5-difluorophenyl) -vinyl] -6-methylpyridine 44-45 {2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -acetic acid 230-233 (3- {2- [2- (3-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine 203-205 {6- [2- (2-Chloro-phenyl) -vinyl] -2-methyl-pyridin-3-yl} -methanol 131-133 2- (3-bromophenylethynyl) -6-methylpyridine 61-63 2-Methyl-6- {2- [3-trifluoromethyl-phenoxy) -phenyl] -vinyl} -pyridine yellowish oil 2- [2- (3,5-dimethoxyphenyl) -vinyl] -6-methylpyridine 43-45 2- [2- (3-chlorophenyl) -vinyl] -3-methoxy-6-methylpyridine 52-53 Acetic acid 4-bromo-2- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester yellowish oil Acetic acid 3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl ester yellowish oil 2- [2- (3,4-dichlorophenyl) -vinyl] -6-methylpyridine 73-75 4-Bromo-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 246-248 Acetic acid 2- [2- (3,5-dichlorophenyl) -vinyl] -6-methylpyridin-3-yl ester 156-158 Acetic acid 6- [2- (3,5-dichloro-phenyl) -vinyl] -2-methyl-pyridin-3-yl-ester 159-161 Acetic acid 2- [2- (3,5-dichlorophenyl) -vinyl] -pyridin-3-yl ester 154-156 2-Methyl-6- (2-naphthalen-1-yl-vinyl) -pyridine yellowish oil 2- [2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -vinyl] -6-methylpyridine 99-101 2-Methyl-6- (2-naphthalen-2-yl-vinyl) -pyridine 97-99 2-methyl-6- (2-m-tolyl-vinyl) -pyridine yellowish oil 2- {2- [3- (3,5-dichloro-phenoxy) -phenyl] -vinyl} -6-methyl-pyridine yellowish gumovitá substance

-29 ················ 9 9 9 9

9 9 9 9 9 9

4 4 4 4 4 4 9 9 9 4

4 4 4 4 9 4 9 4 9

4,444 444 49 99

2- [2- (3-chlorophenyl) propenyl] -6-methylpyridine yellowish oil 2- [2- (2,3-dihydrobenzofuran-5-yl) -vinyl] -6-methylpyridine 88-90 2- [2- (4-fluorophenyl) -vinyl] -6-methylpyridine 50-51 2-Methyl-6- (2-o-tolyl-vinyl) -pyridine yellowish oil 2-Methyl-6- (2-p-tolyl-vinyl) -pyridine 85-86 2-Methyl-6- (2-p-tolyl-propenyl) -pyridine yellowish oil 3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenylamine 126-129 (2,3-Dimethoxy-7-nitroquinoxalin-5-ylmethyl) - {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amine light Orange foam N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -acetamide 147 N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -2-phenylacetamide 156 2,2-Dimethyl-N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -propionamide 166-168 Thiophene-2-carboxylic acid {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amide 197 rozkl. Cyclohexanecarboxylic acid {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amide 215 1- (4-Bromo-phenyl) -3- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl-urea 197 rozkl. 2-Methyl-6- [2- (4-nitrophenyl) -vinyl] -pyridine 134-135 4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenylamine 147-148 2- [2- (3,5-dichlorophenyl) -vinyl] -6-methyl-pyridin-3-ol 218-220 6- [2- (3,5-dichlorophenyl) -vinyl] -2-methylpyridine- -3-ol 286 rozkl. 2- [2- (3,5-dichlorophenyl) -vinyl] -pyridin-3-ol 240-242 2- [2- (6-chlorobenzo [1,3] dioxol-5-yl) -vinyl] -6-methylpyridine 131-132 2- [2- (2,3-difluorophenyl) -vinyl] -6-methylpyridine 55-56 2- [2- (3,4-dichlorophenyl) propenyl] -6-methylpyridine yellowish oil 2- [2- (3,5-bis-trifluoromethylphenyl) -vinyl] -6-methylpyridine 85-86

Acetic acid 2-methoxy-6- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester yellowish oil 2-Methoxy-6- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 118-120 2-Methyl-6- [2- (2,3,6-trifluorophenyl) -vinyl] -pyridine 59-62 2- [2- (4-fluoro-3-trifluoromethylphenyl) -vinyl] -6-methylpyridine yellowish oil 2-Methyl-6- (2,3,6-trifluorophenylethynyl) -pyridine 93-94 Acetic acid 4-chloro-2- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester yellowish oil Acetic acid 2,6-di-tert-butyl-4- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl ester 127-128 3- (6-Methyl-pyridin-2-ylethynyl) -benzamide 187-189 Acetic acid 4-bromo-2-methoxy-6- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl ester 151-153 2- (6-chlorobenzo [1,3] dioxol-5-ylethynyl) -6- -methylpyridine 105-106 light Brown crystals 2- [2- (3,5-dichlorophenyl) -vinyl] -3-methoxy-6-methylpyridine 127-129 2- [2- (3,5-dichlorophenyl) -vinyl] -3-methoxypyridine 111-113 5-Azido-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 143 rozkl. 2- [2- (pyridin-3-yl) ethynyl] -6-methylpyridine light yellow crystals 60-61 N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -succinamic acid 212-213 1-tert-Butyl-3- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -urea 191-192 5 - ({3- [2- (6-methylpyridin-2-yl) -vinyl) -phenylamino) -methyl] -7-nitro-1,4-dihydroquinoxaline-2,3-dione 250 rozkl. Tetrahydrofuran-2-carboxylic acid {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl] -amide 160-161 (1- {3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenylcarbamoyl} -2-phenylethyl) -carbamic acid tert-butyl ester colorless foam

99

9 9 9

9 9 · · ·

9 9 9

9 ···· · · 9

9 9

-319 9 9

9

9

9 99

9 9

9 9

9 9

99 9

({3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenylcarbamoyl} -methyl) -carbamic acid tert-butyl ester colorless foam diethyl- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amine 217 rozkl. ethyl- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amine 225 rozkl. ethyl- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amine 183 rozkl. 2- (2-ethoxy-3,6-difluorophenylethynyl) -6-methylpyridine yellowish oil 2- (3,5-difluorophenylethynyl) 6-methylpyridine yellowish oil 2- (3-Fluorophenylethynyl) -6-methylpyridine 26-28 2- [2- (3,5-dimethylphenyl) -vinyl] -6-methylpyridine 56-57 2- [2- (3,4-dimethoxyphenyl) -vinyl] -6-methylpyridine 55-56 2- (3,4-dichlorophenylethynyl) -6-methylpyridine 73-74 2- (4-ethoxy-3-trifluoromethylphenylethynyl) -6-methylpyridine 61-62 2- (4-fluorophenylethynyl) -6-methylpyridine · 98-100 2-methyl-6-o-tolylethynylpyridine yellowish oil 2- (3,4-difluorophenylethynyl) -6-methylpyridine 65-68 2-Methyl-6- [2- (2,3,5-trichlorophenyl) -vinyl] -pyridine 80-82 1- [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -ethanone 76-78 2-Methyl-6- (3-trifluoromethyl-phenylethynyl) -pyridine 35-37 2-Methyl-6- (3-nitrophenylethynyl) -pyridine 99.5-102.5 6- [2- (3,5-dichlorophenyl) -vinyl] -3-methoxy-2-methyl-pyridine 98-100 {2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yl} -morpholin-4-yl-methanone 123-125 (3- {2- [2- (3,5-dichloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine as its hydrochloride salt 207-210 N- (4- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl} -succinamic acid 201 rozkl.

• · 9 9 · 9 9 9 99 99 • • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9 9 9 99 9 99 99 9 99 9 9

N- {4- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -2-phenylacetamide 236-237 rozkl. ({4- [2- (6-Methyl-pyridin-2-yl) -1-vinyl] -phenylcarbamoyl} -methyl) -carbamic acid tert-butyl ester. acid 144-145 rozkl. 1-tert-Butyl-3- {4- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -urea 209 rozkl. {3- [2- (6-Methyl-pyridin-2-yl) -vinyl) -phenyl} -thiophen-2-ylmethylamine as its hydrochloride salt 161-162 cyclohexylmethyl- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -amine ve. in the form of the hydrochloride salt 178-179 rozkl. {4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenyl} -thiophen-2-ylmethylamine 100 ALIGN! Cyclohexylmethyl- {4- [2- (6-methylpyridin-2-yl) -vinyl] -phenyl} -amine 106-107 2-Amino-N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -3-phenyl-propionamide 102 2-Amino-N- {3- [2- (6-methyl-pyridin-2-yl) -vinyl] - (phenyl) acetamide 105 2-Amino-N- {4- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenyl} -acetamide 217-219 rozkl. 1- [1 - ({2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy) -acetyl] -piperidin-4-yl] -imidazolidin-2-one amorphous foam (1- {4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenylamino} -ethyl) -phosphonic acid dimethyl ester orange amorphous solid 2- [2- (2-methoxyphenyl) -vinyl] -6-methylpyridine 129-130 2- (3-ethoxy-4-fluorophenylethynyl) -6-methylpyridine 82-83 2- (3-chlorophenylethynyl) -6-methylpyridine 57-59 1- (3-Pyridin-2-yl-ethynyl-phenyl) -ethanone 48-51 4-Chloro-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 256-260 4-Bromo-2-methoxy-6- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol 121-123 2-methyl-6-m-tolylethynylpyridine 57-58 2- (2,5-difluorophenylethynyl) -6-methylpyridine 49-50 2- (3,5-dimethylphenylethynyl) -6-methylpyridine yellowish oil -AND..........................

4 4 • 44 4 4 · 4 44 94 • 4 4 4 9 4 4 4 4 9 « • 4 9 9 4 9 4 ' 4 9 1 « • 4 4 4 9 4 4 4 4 « • 4 4 44 444 44 4 4

2- (2- (3,5-dibromophenyl) vinyl) -6-methylpyridine 68-70 2-Methyl-6- [2- (pyrimidin-5-yl) -ethinyl] -pyridine 110-112 (2- {2- [2- (3-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -ethyl) -dimethylamine 165-167 1- {4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenyl} -acetic acid ethyl ester 3- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenol 250-251 3- (6-Methyl-pyridin-2-ylethynyl) -phenylamine 129-130 N- [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -2-phenylacetamide 133-135 rozkl. Thiophene-2-carboxylic acid [3- (6-methyl-pyridin-2-ylethynyl) -phenyl] -amide 156-157 rozkl. 2-Methyl-6- (thiophen-2-ylethynyl) -pyridine 34-36 3- (6-Methyl-pyridin-2-ylethynyl) -benzoic acid ethyl ester 56-58 2- (3,5-dibromophenylethynyl) -6-methylpyridine 100-101 {2- [2- (2-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-ylmethyl} -dimethylamine 227-229 rozkl. (3- {6- [2- (3-Chloro-phenyl) -vinyl] -2-methyl-pyridin-3-yloxy} -propyl) -dimethylamine 184-186 5-Azido-4-iodo-2- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenol red glassy substance 2,6-di-tert-butyl-4- [2- (6-methylpyridin-2-yl) -vinyl] -phenol 126-127 1- {4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenyl) -ethanol 97-99 2-Methyl-6- [2- (pyrimidin-2-yl) -ethinyl] -pyridine 144-145 [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -phenylmethanone 99-100 6- (6-Methyl-pyridin-2-ylethynyl) -3,4-dihydro-1H-quinolin-2-one 189-191 2- (3- {2- [2- (3-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -isoindole-1,3-dione 101-103 3-methoxy-6-methyl-2-m-tolylethynylpyridine brown oil Acetic acid 2- [2- (6-methylpyridin-2-yl) -vinyl] -4-nitrophenyl ester 129-131 6- (6-Methyl-pyridin-2-ylethynyl) -indan-1-one 160-165 2-Methyl-6- [2- (pyrazin-2-yl) -ethinyl] -pyridine 95-96

4 4 4444 44 4 44 44 • 4 4 4 4 4 4 4 4 4 4 4 • 4 4 4 4 4 • 4 4 4 4 4 4 4 4 4 • 4 4 4 4 4 4 44 444 44 4 4

N-methyl-N- (3- {4- [2- (6-methylpyridin-2-yl) -vinyl] -phenoxy} -propyl) -acetamide 62-70 2- [2- (3,5-bis-trifluoromethylphenyl) -1-ethoxyvinyl] -6-methylpyridine yellow oil Acetic acid 2-phenylethynylpyridin-3-yl ester brown oil Acetic acid 6-methyl-2-m-tolylethynyl-pyridin-3-yl ester brown oil Acetic acid 4- [2- (6-methylpyridin-2-yl) -vinyl] -2-nitrophenyl ester 91-93 2- [2- (6-methylpyridin-2-yl) -vinyl] -4-nitrophenol 275 rozkl. dimethyl- [3- (2-phenylethynylpyridin-3-yloxy) - yellowish -propyl] -amine oil dimethyl- (3- {4- [2- (6-methylpyridin-2-yl) -vinyl] -phenoxy} -propyl) -amine 240-243 1- {4- [2- (6-Methyl-pyridin-2-yl) -vinyl] -phenyl} -ethanone 56-58 2- (3-Fluorophenylethynyl) -quinoline 81-83- Acetic acid 2-methyl-6-styrylpyridin-3-yl ester 93-96 4- [2- (6-methylpyridin-2-yl) -vinyl] -2-nitrophenol 141-143 3-Ethoxy-4- [2- (6-methyl-pyridin-2-yl) -vinyl] -2- 175-178 -nitrophenol rozkl. 4- (6-methylpyridin-2-ylethynyl) -2-nitrophenol 184-187 rozkl. 2- [2- (6-Methyl-pyridin-2-yl) -vinyl] -6-nitro- 105-100 phenylacetate rozkl. dimethyl- [3- (6-methyl-2-phenylethynylpyridine-3-) yellow -yloxy) -propyl] -amine gumovitá substance 2-Azido-4- [2- (6-methyl-pyridin-2-yl) -vinyl] - 155-157 -phenol rozkl. dimethyl- [3- (6-methyl-2-m-tolylethynylpyridine- yellowish -3-yloxy) -propyl] -amine oil 2- (3-methanesulfonylphenylethinyl) -6-methyl- 108-110 pyridine rozkl. 3- {2- [2- (3-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propylamine 186-189 4-Azido-N- (3- {2- [2- (3-chlorophenyl) -vinyl] -6- 99-102 methylpyridin-3-yloxy} propyl) -2-hydroxybenzamide rozkl.

• Φ · Μ · φ φ φφ ' * φ φ φ · φ · • • φ φ φ φ φ φ • • φ φ • φ φ φ φ • φ φ φφ φ φφ φφφ φφ

3- [3- (3-dimethylaminopropoxy) -6-methylpyridin-2-ylethynyl] -benzonitrile yellow gumovitá substance 5- (6-Methyl-pyridin-2-ylethynyl) -indan-1-one 133-134 2-methyl-6- (2,3,5-trichlorophenylethynyl) -pyridine 112-114 2- [2- (6-methylpyridin-3-yl) ethynyl] -6-methylpyridine 118-119 dimethyl- {3- [6-methyl-2- (3-trifluoromethyl-phenylethinyl) -pyridin-3-yloxy] -propyl} -amine yellow gumovitá substance 2- [2- (6-methylpyridin-3-yl) ethynyl] -3-methoxy-6-methylpyridine as its hydrochloride salt 198-199 2-Methyl-6- (5,6,7,8-tetrahydro-naphthalen-2-ylethynyl) -pyridine 50-51 3- [2- (3-Chloro-phenylethynyl) -6-methyl-pyridin-3-yloxy] -propylamine 151-153 (3- {4-Bromo-2-methoxy-6- [2- (6-methyl-pyridin-2-yl) -vinyl] -phenoxy} -propyl) -dimethylamine 211-215 [6- (3-Fluorophenylethynyl) -pyridin-2-yl] -dimethylamine brown oil 6 '- (3-fluorophenylethinyl) -3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl Brown gumovitá substance {3- [2- (3-Chloro-phenylethynyl) -6-methyl-pyridin-3-yloxy] -propyl} -dimethylamine 158-160 4-Azido-N- {3- [2- (3-chloro-phenylethynyl) -6-methyl-pyridin-3-yloxy] -propyl} -2-hydroxy-benzamide 161-163 rozkl. 1- [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -1H- [1,2,4] triazole-3-carboxylic acid ethyl ester 105-110 rozkl. 1- [3- (6-Methyl-2-phenylethynyl-pyridin-3-yloxy) -propyl] -piperidin-3-ol 108-109 2-ethynyl-6- (3-fluorophenylethynyl) -pyridine 89-90 3-Methyl-6- (6-methyl-pyridin-2-ylethynyl) -3H-benzoxazol-2-one 172-174 1- [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -1H- [1,2,4] triazole-3-carboxylic acid dimethylamide 154-157 1- [3- (6-Methyl-2-phenylethynyl-pyridin-3-yloxy) -propyl] -piperidin-4-ol amorphous white solid

99 ·· »·· 99 9 * 9 99 9 · 9 9 9 99 9 9 9 9 9 · 9 • · 9 · • 9 9 9 9 9 9 9 9 9 9 9 99 9 99 999 9 · • 9

5- (6-methylpyridin-2-ylethynyl) -2-nitrophenol 150-151 rozkl. 5- [2-Bromo-2- (6-methyl-pyridin-2-yl) -vinyl] -2-nitrophenol 158-159 5- [2- (6-Methyl-pyridin-2-yl) -E-vinyl] -2-nitrophenol 171-173 5- [2- (6-Methyl-pyridin-2-yl) -Z-vinyl] -2-nitrophenol 108-110 4-Azido-2-hydroxy-N- [3- (6-methylpyridin-2-yl) -pyridine] 180-182 ethynyl) -phenyl] -benzamide rozkl. 5- (3-Dimethylaminopropoxy) -6-phenylethynyl-pyridine-2-carboxylic acid ethyl ester 160-162 6-Methyl-2-styrylpyrimidin-4-ol 221-225 2-ethyl-6- (3-fluorophenylethynyl) -pyridine brown oil, 2- (3,5-dichlorophenylethynyl) -6-methylpyridine 74-76 2-Methyl-6- (3-trifluoromethoxyphenylethinyl) - <30, brown -pyridine _t crystals 2-Methyl-6- '(3- [1,2,4] triazol-1-yl-phenyl-ethynyl) -pyridine 128-130 4- (6-Methyl-pyridin-2-ylethynyl) -phthalonitrile 138-140 2-Methyl-6- {2- [3- (1H-tetrazol-5-yl) -phenyl] -J-vinyl} -pyridine, formic acid compound 234-240 ·] 3- [2- (3,5-dichloro-phenylethynyl) -6-methyl-pyridin-3-yloxy] -propylamine 97-100 {3- [2- ‘(3,5-dichlorophenylethynyl) -6-methyl-. pyridin-3-yloxy] -propyl} -dimethylamine 171-173 2- (3,5-dimethylphenylethynyl) -3-methoxy-6- yellowish -methylpyridine oil 2- [2- (3-fluorophenyl) -vinyl] -6-methyl-pyridin-3-ol 251-253 rozkl. 6- (3-Fluoro-phenylethynyl) -2-methyl-nicotinic acid ethyl ester 84-86 2-Azido-5- (6-methyl-pyridin-2-ylethynyl) -phenol 153-155 rozkl. 6- (3,4-dimethoxyphenylethinyl) -5- (3-dimethylaminopropoxy) -pyridine-2-carboxylic acid ethyl ester 149-152 2- (4-methoxy-3-trifluoromethylphenylethinyl) -6-methylpyridine 86-87 2- (3-fluorophenylethynyl) -6-methoxypyridine brown oil

• ·

2- (3-fluorophenylethynyl) -5-methylpyridine 74-76 6- (3,5-Dichloro-phenylethynyl) -5- (3-dimethylaminopropoxy) -pyridine-2-carboxylic acid ethyl ester 195-198 5- (3-Dimethylaminopropoxy) -6- (3,5-dimethylphenylethinyl) -pyridine-2-carboxylic acid ethyl ester 187-190 6- (3-Fluorophenylethynyl) -2-methylnicorinic acid 173-175 [6- (3-Fluoro-phenylethynyl) -2-methyl-pyridin-3-yl] -methanol 116-118 [4- (4-Fluoro-benzoyl) -piperidin-1-yl] - [6- (3-fluoro-phenylethynyl) -2-methyl-pyridin-3-yl] -methanone 138-140 2- (3-Fluoro-phenylethynyl) -6-methyl-nicotinic acid ethyl ester brown oil 2- (3-Fluorophenylethynyl) -4,6-dimethylpyridine brown oil 6- (3-Fluorophenylethynyl) -N- (5-methoxyindan-2-ylmethyl) -2-methylnicotinamide 157-159 {[6- (3-Fluoro-phenylethinyl) -2-methyl-pyridine-3-carbonyl] -amino} -phenylacetic acid methyl ester 133-135 2-Methyl-6- (5-methylthiophen-2-ylethynyl) -pyridine 58-59 2-Methyl-6- (2,3,5-trimethyl-phenylethynyl) -pyridine brown oil 3- {2- [2- (3-Fluorophenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propan-1-ol 86-88 [6- (3-Fluoro-phenylethynyl) -2-methyl-pyridin-3-ylmethyl] -dimethylamine 220-222 2,2-Dimethylpropionic acid 3- [2- (3-fluorophenylethinyl) -6-methylpyridin-3-yloxy] propyl ester yellowish oil 2-Azido-4-iodo-5- (6-methyl-pyridin-2-ylethynyl) -phenol 140 rozkl. 6-Azido-2,4-diiodo-3- (6-methylpyridin-2-ylethynyl) phenol 162 rozkl. 4-Azido-2-hydroxy-5-iodo-N- [3- (6-methylpyridin-2-yl-ethynyl) -phenyl] -benzamide 185 rozkl. Acetic acid 3-acetoxymethyl-5- (6-methylpyridin-2-ylethynyl) -benzyl ester brown oil

• · · · · ·

(Benzyl - {[2- (3-fluorophenylethinyl) -6-methylpyridin-3-ylbxy] acetyl} aminoacetic acid ethyl ester brown oil 2- [2- (3-Fluorophenyl) -vinyl] -6-methyl-isonicotinic acid ethyl ester 76-77 3- [2- (3-Fluorophenylethynyl) -6-methyl-pyridin-3-yloxy] -propan-1-ol 72-74. [3-Hydroxymethyl-5- (6-methyl-pyridin-2-ylethynyl) -phenyl] -methanol 115-117 (3- {2- [2- (3,5-Dimethyl-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine yellowish gumovitá substance [4- (4-Fluoro-benzoyl) -piperidin-1-yl] - {6- [2- (3-fluoro-phenyl) -vinyl] -2-methyl-pyridin-3-yl} -methanone 156-158 2- [2- (3-Fluorophenyl) -vinyl] -6-methyl-isonicotinic acid 245-2.48 (6- [2- (2-Chloro-phenyl) -vinyl] -2-methyl-pyridin-3-yl} - [4- (4-fluoro-benzoyl) -piperidin-1-yl] -methanone 109-112 2- (3-ethynyl-phenylethynyl) -6-methyl-pyridine 48-49 j (3- {2- [2- (2,6-dichloro-phenyl) -vinyl] -6-methyl- pyridin-3-yloxy} -propyl) -dimethylamine as the hydrochloride salt 207-210 (3- {2- [2- (2,3-Dichloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine as its hydrochloride salt 161-169 4- [6- (3-Fluoro-phenylethynyl) -2-methyl-pyridine-3-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester 97-99 [6- (3-Fluoro-phenylethynyl) -2-methyl-pyridin-3-yl] -piperazin-1-yl-methanone 250-252 rozkl. [4- (4-Azido-2-hydroxy-benzoyl) -piperazin-1-yl] - [6- (3-fluoro-phenylethynyl) -2-methyl-pyridin-3-yl] -methanone 186-188 rozkl. (3- {2- [2- (2,4-Dichloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy} -propyl) -dimethylamine as its hydrochloride salt 170-176 2- (3-fluorophenylethynyl) -6-methylisonicotinic acid ethyl ester 89-91 2- (3-Fluorophenylethynyl) -6-methyl-isonicotinic acid tert-butyl ester 94-96

• • • •

2- (3-fluorophenylethynyl) -6-methylisonicotinic acid 231 rozkl. [2- (3-Fluorophenylethynyl) -6-methyl-pyridin-4-yl] -methanol 143-146 [4- (4-Fluorobenzoyl) -piperidin-1-yl] - [2- (3-fluorophenylethinyl) -6-methyl-pyridin-4-yl] -methanone 156-158 3-Allyloxy-2- [2- (3,5-dichloro-phenyl) -vinyl] -6-methyl-pyridine 105-106 [2- (3-Fluoro-phenylethynyl) -6-methyl-pyridin-4-yl] -morpholin-4-yl-methanone 114-116 Acetic acid 3- (6-methylpyridin-2-ylethynyl) -benzyl ester brown oil [2- (3-Fluoro-phenylethynyl) -6-methyl-pyridin-4-ylmethyl] -dimethylamine 209-212 (3- {2- [2- (3,5-Dichloro-phenyl) -propenyl] -6-methyl-pyridin-3-yloxy) -propyl] -dimethylamine as its hydrochloride salt 182-184 2- (3-fluorophenylethynyl) -3-methoxy-6-methylpyridine yellowish oil (3- {2- [2- (3,5-dichloro-phenyl) -vinyl] -pyridin-3-yloxy} -propyl) -dimethylamine as its hydrochloride salt 171-174 (4-Azido-2-hydroxy-5-iodophenyl) - {4- [6- (3-fluorophenylethinyl) -2-methylpyridine-3-carbonyl] -piperazin-1-yl} -methanone 195-200 rozkl. 4-Azido-N- {3- [2- (3-chloro-phenylethynyl) -6-methyl-pyridin-3-yloxy] -propyl} -2-hydroxy-5-iodobenzamide 142-150 rozkl. 4- (2-Pyridin-2-yl-vinyl) -benzoic acid ethyl ester 100-102 (3- {2- [2- (4-Chloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy) -propyl] -dimethylamine as its hydrochloride salt 159-171 [3- (6-Methyl-pyridin-2-ylethynyl) -phenyl] -methanol 43-45 6- (3-Fluorophenylethynyl) -nicotinic acid tert-butyl ester 96-98 (3- {2- [2- (3,4-Dichloro-phenyl) -vinyl] -6-methyl-pyridin-3-yloxy) -propyl] -dimethylamine as its hydrochloride salt 174-177 2- (1-bromo-2-phenylvinyl) -4-methylpyrimidine yellow oil

• ·

-40 »· · · · · · ·

6- (3-Fluorophenylethynyl) -nicotinic acid 223 rozkl. [4- (4-Fluorobenzoyl) -piperidin-1-yl] - [6- (3-fluorophenylethinyl) -pyridin-3-yl] -methanone 136.0-139.0 2- (2-tert-butoxy-3,6-difluorophenylethynyl) -6-methylpyridine 72.0-74.0 2-Methyl-6- [2- (2,4,5-trifluorophenyl) -vinyl] -pyridine 74-76 2-methyl-6- [2- (2,3,4-trifluorophenyl) -vinyl) -pyridine 79-82 3- (6-Methyl-pyridin-2-ylethynyl) -phenol 142-144 2-Methyl-6- [2- (3,4,5-trifluorophenyl) -vinyl] -pyridine 74-76 2- (3-methoxyphenylethynyl) -6-methylpyridine 55-57 2-methyl-6- (2,3,4-trifluorophenylethynyl) -pyridine 104-106

m.p. = melting point dec. = decomposition

Claims (8)

PATENT REQUIREMENTS Use of a compound of formula I X-FL (I) wherein X is optionally a halogen substituted lower alkenylene group or an alkynylene group bonded via vicinal unsaturated carbon atoms or an azo group (-N = N-), Rj is hydrogen, lower alkyl, hydroxy substituted lower alkyl, lower alkylamino, piperidino, carboxy, esterified carboxy, amidated carboxy, N-loweralkyl-N-phenylcarbamoyl unsubstituted or substituted lower alkyl, lower alkoxy, atom / or trifluoromethyl, lower alkoxy, halogen substituted lower alkyl or halogen substituted lower alkoxy, R ₂ is hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-substituted lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy, 4- (4-fluorobenzoyl) -piperidin-l-yl-carboxy, 4 - a target, butyloxycarbonylpiperazin-1-yl-carboxy, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carboxy, R1 represents a hydrogen atom, a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, a lower alkyl group; 4 4 4 4 4 4 4 4 4 4 4 4 -42-carbamoyl, hydroxy-substituted lower alkyl, di-loweralkyl-aminomethyl, morpholinocarbonyl or 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy, R <represents a hydrogen atom, a lower alkyl group, a hydroxy group, a hydroxy substituted lower alkyl group, an amino-lower alkyl group, a lower alkylamino-lower alkyl group, a di-loweralkylamino-lower alkyl group, a loweralkyleneamino-lower alkyl group unsubstituted or substituted hydroxy; lower alkoxy, lower alkanoyloxy, amino-loweralkoxy, loweralkylamino-loweralkoxy, di-loweralkylamino-loweralkoxy, phthalimido-loweralkoxy, loweralkylene amino-loweralkoxy, unsubstituted or substituted carboxy, or substituted 2-carboxy, or substituted 2-carboxy; a lower alkoxy group or an esterified carboxy-lower alkoxy group, and _R is an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, lower alkenyl, lower alkynyl, phenyl unsubstituted or substituted lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, phenyl loweralkynyl unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, hydroxy, hydroxy substituted lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, amino, lower alkylamino, lower alkanoylamino not N-lower> 9 · · 9 · -43► 9 9 «» 9 9 .1 ► 9 9 I ► 9 9 I Alkyl-N-lower alkanoylamino-lower alkoxy, phenoxy unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, phenyl-lower alkoxy unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, carboxy-lower alkylamino, esterified carboxy-lower alkylamino, amidated carboxy-lower alkylamino, phosphono-lower alkylamino, esterified phosphono-lower, lower alkylamino,. lower alkylamino, acylamino, N-acyl-N-lower alkylamino, phenylamino, phenyl-lower alkylamino, cycloalkyl-lower alkylamino or. heteroaryl-lower alkylamino, each of which may be unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or methyl, in free form or in the form of photoaffinity radiolabeled, N-oxide or a pharmaceutically acceptable salt, for the preparation of a pharmaceutical a composition intended for the treatment of diseases associated with glutamatergic signal, and trifluoro-ligand, with irregularities in the transmission of nerve system diseases mediated in whole or in part by mGluR5. 2. A compound of formula I X — FL (I) ···· -44- • · · · · · • · · • · · • · · • · · · · * · ·· ·· • i · i · i • * · · · · · . ·· ······ • · · ··· · «» ·· ·· ·· where X stands for optionally atom halogen substituted alkynylene group up 2 to 4 carbon atoms tied through vicinal unsaturated atoms carbon or azo group (-N = N-) Rj means an alkyl group with 1 to 4. carbon atoms, (C 1 -C 4) alkoxy, (C 1 -C 4) hydroxyalkyl, cyano, ethynyl, carboxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkylamino (C 1 -C 4) alkylamino group; (C 1 -C 6) alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl, R ₂ represents hydrogen, hydroxy, alkyl of 1-4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, alkoxy of 1-4 carbon atoms, carboxy, alkanoyloxy of 2-5 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, dialkylaminoalkanoyl group having 1 to 4 carbon atoms in each alkyl moiety and having 1 to 4 carbon atoms in the alkanoyl moiety, dialkylaminomethyl group having 1 to 4 carbon atoms in each alkyl moiety, 4- (4-fluorobenzoyl) -piperidine 1-yl-carboxy, 4-tert-butyloxycarbonyl-piperazin-1-ylcarboxy 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -piperazin-1-yl-carboxy, R ₃ represents a hydrogen atom, a C 1 -C 4 alkyl group, a carboxy group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 alkylcarbamoyl group, a C 1 -C 4 hydroxyalkyl group a (C 1 -C 4) dialkylaminomethyl group, a morpholinocarbonyl group or a 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy group, R ₄ is hydrogen, hydroxy, C 1 -C 4 alkoxy, carboxy, C 2 -C 5 alkanoyloxy -45 • 99 · 9 * 99 99 9 9 9 9 · · · 9 9 9 · 99 99 carbon atoms, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 aminoalkoxy, C 1 -C 4 dialkylaminoalkoxy, C 1 -C 4 alkoxy, C 1 -C 4 dialkylaminoalkyl up to 4 carbon atoms in all alkyl moieties, carboxyalkylcarbonyl of 1 to 4 carbon atoms in the alkyl moiety, alkoxycarbonylalkoxy of 1 to 4 carbon atoms in each alkoxy moiety, hydroxyalkyl of 1 to 4 carbon atoms, dialkylaminoalkoxy of 1 to 4 carbon atoms in each of the alkyl moieties having from 1 to 4 carbon atoms in the alkoxy moiety, m-hydroxy-p-azidophenylcarbonylaminoalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, and R ₅ represents a group of formulas wherein: R _a and R _b are independently hydrogen, hydroxy, halogen, nitro, cyano, carboxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 hydroxyalkyl, alkoxycarbonyl (C 1 -C 4) alkoxy group, (C 2 -C 7) alkanoyl, (C 2 -C 5) alkanoyloxy, alkanoyloxyalkyl -4644 ·· 4 4 4 4 4 4 4 4 4 4 4 C 2 -C 5 alkanoyl and C 1 -C 4 alkyl, trifluoromethyl, trifluoromethoxy, trimethylsilylethinyl, C 2 -C 5 alkynyl, amino, azido, C 1 -C 2 alkanoylaminoalkoxy alkanoyl moieties of up to 4 carbon atoms in the alkoxy moiety, alkylaminoalkoxy of 1 to 4 carbon atoms in the alkyl moiety of the alkoxy moiety, up to 4 carbon atoms, 5 carbon atoms in and of the alkylaminoalkoxy of 1 to 4 carbon atoms in each alkyl moiety az 4 carbon atoms of the alkoxy moiety, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino in each alkyl moiety, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, alkylamino, benzoylamino, benzoylamino, benzylamino, benzylamino, benzylamino, benzylamino (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonylaminocarbonylamino or (C 1 -C 4) alkylsulfonyl group; R _c is hydrogen, fluoro, chloro, bromo, hydroxy, C 1 -C 4 alkyl, C 2 -C 5 alkanoyloxy, C 1 -C 4 alkoxy or cyano; and R _d is hydrogen, halogen or C 1 -C 4 alkyl, with the proviso that in compounds where R ₂ , R ₃ and R ₄ are hydrogen when R _x is methyl, R ₅ is other than phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in the form of a pharmaceutically acceptable salt. A compound of formula (I) according to claim 2, wherein the compound of formula (I) as defined in claim 1, wherein: X is an optionally substituted C 2 -C 4 alkynylene group bonded via vicinal unsaturated carbon atoms or an azo group (-N-N-), R ₁ is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano, ethynyl or C 1 -C 4 dialkylamino in each alkyl moiety, R ₂ is hydrogen, hydroxy, carboxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 dialkylaminomethyl in each alkyl moiety, 4- (4-fluorobenzoyl) -piperidin-1-ylcarboxy, 4 -tert-butyloxycarbonylpiperazin-1-yl-carboxy, 4- (4-azido-2-hydroxybenzoyl) -piperazin-1-yl-carboxy or 4- (4-azido-2-hydroxy-3-iodobenzoyl) -piperazine-1 -yl-carboxy, R ₃ is hydrogen, C 1 -C 4 alkyl, carboxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbamoyl, C 1 -C 4 hydroxyalkyl, (C 1 -C 4) dialkylaminomethyl, morpholinocarbonyl or 4- (4-fluorobenzoyl) -piperidin-1-yl-carboxy, R ₄ is hydrogen, hydroxy,. carboxy, C 2 -C 5 alkanoyloxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 aminoalkoxy, C 1 -C 4 dialkylaminoalkoxy in each C 1 -C 4 alkyl moiety alkoxy moieties, a (C 1 -C 4) dialkylaminoalkyl group. an alkyl moiety or a (C 1 -C 4) hydroxyalkyl group; and R ₅ is a radical of formula 9 9 ···· -488 9 9 9 99 9 99 9 9 9 9 99 99 where R _a and R _b are independently hydrogen, halogen, nitro, cyano, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl, trifluoromethoxy or (C 2 -C 5) alkynyl , R _c is hydrogen, fluoro, chloro, bromo, hydroxy, C 1 -C 4 alkyl, C 2 -C 5 alkanoyloxy, C 1 -C 4 alkoxy or cyano; and R _d is hydrogen, halogen or C 1 -C 4 alkyl, provided that in compounds wherein R ₂ , R ₃ and R ₄ are hydrogen, when R ₃ is methyl, R ₅ is other than phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in the form of a pharmaceutically acceptable salt. The compound in free form or in claim 2, wherein. X is ethinylene, a pharmaceutically acceptable salt form. ve The compound of claim 2, wherein R ₅ is other than optionally substituted phenyl and X is ethinylene, in free form or in the form of a pharmaceutically acceptable salt. The compound of claim 2, wherein R ₅ is optionally substituted pyridin-3-yl and X is ethinylene, in free form or in the form of a pharmaceutically acceptable salt. 2- [2- (pyridin-3-yl) ethynyl] -6-methylpyridine in free form or in pharmaceutically acceptable salt form. 44 44 4 4 4 9 9 4 4 4 -498. A pharmaceutical composition comprising, as a pharmaceutically active ingredient, together with conventional pharmaceutical excipients, a compound according to any one of claims 2 to 7, in free form or in the form of a pharmaceutically acceptable salt. A method for treating diseases mediated in whole or in part by mGluR1 or mGluR5, comprising administering to a warm-blooded organism in need of such treatment a therapeutically effective amount of a compound according to any one of claims 2 to 7, in free form or in pharmaceutically acceptable salt form. .