TREA

Pyridine derivatives

Follow

Information

  • Patent Grant
  • 6656957
  • Patent Number
    6,656,957
  • Date Filed
    Monday, November 27, 2000
    24 years ago
  • Date Issued
    Tuesday, December 2, 2003
    21 years ago
Information
Abstract
A compound of formula I whereinX represents an optionally halo-substituted (C2-4)alkynylene group bonded via vicinal unsaturated carbon atoms.
Description




The invention relates to the use of 2-arylalkenyl-, 2-heteroarylalkenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- and 2-heteroarylazo-pyridines for modulating the activity of mGluRs and for treating mGluR5 mediated diseases, to pharmaceutical compositions for use in such therapy, as well as to novel 2-arylalkenyl-, 2-heteroarylalkenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- and 2-heteroarylazo-pyridines.




It has been found that 2-arylalkenyl-, 2-heteroarylalkenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- and 2-heteroarylazo-pyridines including the pharmaceutically acceptable salts (hereinafter agents of the invention) are useful as modulators of mGluRs. Modulation of mGluRs can be demonstrated in a variety of ways, inter alia, in binding assays and functional assays such as second messenger assays or measurement of changes in intracellular calcium concentrations. For example, measurement of the inositol phosphate turnover in recombinant cell lines expressing hmGluR5a showed, for selected agents of the invention, IC


50


values of about 1 nM to about 50 μM.




In particular, the agents of the invention have valuable pharmacological properties. For example, they exhibit a marked and selective modulating, especially antagonistic, action at human metabotropic glutamate receptors (mGluRs). This can be determined in vitro for example at recombinant human metabotropic glutamate receptors, especially PLC-coupled subtypes thereof such as mGluR5, using different procedures like, for example, measurement of the inhibition of the agonist induced elevation of intracellular Ca


2+


concentration in accordance with L. P. Daggett et al. Neuropharm. Vol. 34, pages 871-886 (1995), P. J. Flor et al., J. Neurochem. Vol. 67, pages 58-63 (1996) or by determination to what extent the agonist induced elevation of the inositol phosphate turnover is inhibited as described by T. Knoepfel et al. Eur. J. Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett et al., Neuropharm. Vol. 67, pages 58-63 (1996) references cited therein. Isolation and expression of human mGluR subtypes are described in U.S. Pat. No. 5,521,297. Selected agents of the invention showed IC


50


values for the inhibition of the quisqualate-induced inositol phosphate turnover, measured in recombinant cells expressing hmGluR5a of about 1 nM to about 50 μM.




Accordingly the invention relates to agents of the invention for use in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated lull or in part by mGluR5.




Disorders associated with irregularities of the glutamatergic signal transmission are for example epilepsy, cerebral ischemias, especially acute ischemias, ischemic diseases of the eye, muscle spasms such as local or general spasticity and, in particular, convulsions or pain.




Nervous system disorders mediated full or in part by mGluR5 are for example 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 and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression and pain.




The invention also relates to the use of agents of the invention, in the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by Group I mGluRs.




Furthermore the invention relates to the use of agents of the invention for the manufacture of a pharmaceutical composition designed for the treatment of disorders associated with irregularities of the glutamatergic signal transmission, and of nervous system disorders mediated full or in part by Group I mGluRs.




In a further aspect the invention relates to a method of treating disorders mediated full or in part by group I mGluRs (preferentially mGluR5) which method comprises administering to a warm-blooded organism in need of such treatment a therapeutically effective amount of an agent of the invention.




In still a further aspect, the invention relates to novel 2-arylalkenyl-, 2-heteroarylalkenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- and 2-heteroarylazo-pyridines and their salts, and to a process for preparing them.




Moreover the invention relates to a pharmaceutical composition comprising as pharmaceutical active ingredient, together with customary pharmaceutical excipients, a novel 2-arylalkenyl-, 2-heteroarylalkenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- or 2-heteroarylazo-pyridine or a pharmaceutically acceptable salt thereof.




Agents of the invention are for example compounds of formula I











wherein




R


1


denotes hydrogen, lower alkyl, hydroxy-lower alkyl lower alkyl-amino, piperidino, carboxy, esterified carboxy, amidated carboxy, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-lower-alkyl-N-phenylcarbamoyl, lower alkoxy, halo-lower alkyl or halo-lower alkoxy,




R


2


denotes hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,




R


3


represents hydrogen, lower alkyl, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl, hydroxy- lower alkyl, di- lower alkyl- aminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy,




R


4


represents hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, unsubstituted or hydroxy-substituted lower alkyleneamino-lower alkyl, lower alkoxy, lower alkanoyloxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, phthalimido-lower alkoxy, unsubstituted or hydroxy- or 2-oxo-imidazolidin-1-yl-substituted lower alkyleneamino-lower alkoxy, carboxy, esterified or amidated carboxy, carboxy-lower-alkoxy or esterified carboxy-lower-alkoxy,




X represents an optionally halo-substituted lower alkenylene or alkynylene group bonded via vicinal unsaturated carbon atoms or an azo (—N═N—) group, and




R


5


denotes an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from lower alkyl, halo, halo-lower alkyl, halo-lower alkoxy, lower alkenyl, lower alkynyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkynyl, hydroxy, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, amino-, lower alkylamino-, lower alkanoylamino- or N-lower alkyl-N-lower alkanoylamino-lower alkoxy, unsubstituted or lower alkyl- lower alkoxy-, halo- and/or trifluoromethyl-substituted phenoxy, unsubstituted or lower alkyl- lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkoxy, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, carboxy-lower alkylamino, esterified carboxy-lower alkylamino, amidated carboxy-lower alkylamino, phosphono-lower alkylamino, esterified phosphono-lower alkylamino, nitro, amino, lower alkylamino, di-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 lower alkyl- lower alkoxy-, halo- and/or trifluoromethyl-substituted, customary photoaffinity ligands and customary radioactive markers, inclusive of their N-oxides and their pharmaceutically acceptable salts.




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




Also included are both total and partial salts, that is to say salts with 1, 2 or 3, preferably 2, equivalents of base per mole of acid of formula I, or salts with 1, 2 or 3 equivalents, preferably 1 equivalent, of acid per mole of base of formula I.




For the purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and they are therefore preferred.




Halo in the present description denotes fluorine, chlorine, bromine or iodine.




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




Preferred compounds of formula I are those wherein




X represents an optionally halo-substituted (C


2-4


)alkenylene or alkynylene group bonded via vicinal unsaturated carbon atoms,




R


1


is hydrogen, (C


1-4


) alkyl, (C


1-4


)alkoxy, hydroxy(C


1-4


)alkyl, cyano, ethynyl, carboxy, (C


1-4


)alkoxycarbonyl, di(C


1-4


)alkylamino, (C


1-6


)alkylaminocarbonyl, or trifluoromethylphenylaminocarbonyl,




R


2


is hydrogen, hydroxy, (C


1-4


) alkyl, hydroxy (C


1-4


) alkyl, (C


1-4


) alkoxy, carboxy, (C


2-5


)alkanoyloxy, (C


1-4


) alkoxycarbonyl, di(C


1-4


)alkylamino(C


1-4


)alkanoyl, di(C


1-4


)alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,




R


3


is hydrogen, (C


1-4


) alkyl, carboxy, (C


1-4


)alkoxycarbonyl, (C


1-4


)alkylcarbamoyl, hydroxy(C


1-4


)alkyl, di(C


1-4


)alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy,




R


4


is hydrogen, hydroxy, (C


1-4


)alkoxy, carboxy, (C


2-5


)alkanoyloxy, (C


1-4


)alkoxycarbonyl, amino(C


1-4


)alkoxy, di(C


1-4


)alkylamino(C


1-4


)alkoxy, di(C


1-4


)alkylamino(C


1-4


)alkyl, carboxy (C


1-4


)alkylcarbonyl, (C


1-4


)alkoxycarbonyl(C


1-4


)alkoxy, hydroxy(C


1-4


)alkyl, di(C


1-4


)alkylamino(C


1-4


)alkoxy, m-hydroxy-p-azidophenylcarbonylamino(C


1-4


)alkoxy, or and




R


5


is a group of formula











 wherein




R


a


and R


b


independently are hydrogen, hydroxy, halogen, nitro, cyano, carboxy, (C


1-4


)alkyl, (C


1-4


)alkoxy, hydroxy(C


1-4


)alkyl, (C


1-4


)alkoxycarbonyl, (C


2-7


)alkanoyl, (C


2-5


)alkanoyloxy, (C


2-5


)alkanoyloxy (C


1-4


)alkyl, trifluoromethyl, trifluoromnethoxy, trimethylsilylethynyl, (C


2-5


)alkynyl, amino, azido, amino (C


1-4


)alkoxy, (C


2-5


)alkanoylamino (C


1-4


)alkoxy, (C


1-4


)alkylamino (C


1-4


)alkoxy, di(C


1-4


)alkylamino (C


1-4


)alkoxy, (C


1-4


)alkylamino, di(C


1-4


)alkylamino, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C


2-5


)alkanoylamino, benzylcarbonylamino, (C


1-4


)alkylaminocarbonylamino, (C


1-4


)alkoxycarbonyl-aminocarbonylamino or (C


1-4


)alkylsulfonyl,




R


c


is hydrogen, fluorine, chlorine, bromine, hydroxy, (C


1-4


)alkyl, (C


2-5


)alkanoyloxy, (C


1-4


)alkoxy or cyano, and




R


d


is hydrogen, halogen or (C


1-4


)alkyl.




More preferred compounds of formula I are those wherein X is as defined above and




R


1


is hydrogen, (C


1-4


) alkyl, (C


1-4


)alkoxy, cyano, ethynyl or di(C


1-4


)alkylamino,




R


2


is hydrogen, hydroxy, carboxy, (C


1-4


) alkoxycarbonyl, di(C


1-4


)alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy,




R


3


is as defined above,




R


4


is hydrogen, hydroxy, carboxy, (C


2-5


)alkanoyloxy, (C


1-4


)alkoxycarbonyl, amino/(C


1-4


)alkoxy, di(C


1-4


)alkylamino(C


1-4


)alkoxy, di(C


1-4


)alkylamino(C


1-4


)alkyl or hydroxy(C


1-4


)alkyl, and




R


5


is a group of formula











 wherein




R


a


and R


b


independently are hydrogen, halogen, nitro, cyano, (C


1-4


)alkyl, (C


1.4


)alkoxy, trifluoromethyl, trifluoromethoxy or (C


2-5


)alkynyl, and




R


c


and R


d


are as defined above.




The agents of the invention include, for example, the compounds described in the examples hereinafter.




The usefulness of the agents of the invention in the treatment of the above-mentioned disorders could be confirmed in a range of standard tests including those indicated below:




At doses of about 10 to 100 mg/kg i.p. or p.o. with pretreatment times of 15 min. to 8 hours, the agents of the invention show anticonvulsive activity in the electroshock induced convulsion model [cf. E. A. Swinyard, J. Pharm. Assoc. Scient. Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952)].




At doses of about 4 to about 40 mg/kg p.o., the agents of the invention show reversal of Freund complete adjuvant (FCA) induced hyperalgesia [cf. J. Donnerer et al., Neuroscience 49, 693-698 (1992) and C. J. Woolf, Neuroscience 62, 327-331 (1994)].




For all the above mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.5 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 to 1500 mg, preferably about 10 to about 1000 mg of the compound conveniently administered in divided doses up to 4 times a day or in sustained release form.




Preferred compounds for the above mentioned indications include (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 determined that in the above-mentioned electroshock induced convulsion model, compounds A and B show anticonvulsive activity with ED


50


of 30 and 35 mg/kg i.p. respectively (pretreatment times: 4 hours and 15 min. respectively) and that in the above-mentioned FCA induced hyperalgesia model, compounds C and D show reversal of the hyperalgesia with ED


50


s of 4.2 and 19 mg/kg p.o. respectively (post-treatment time: 3 hours).




As indicated above, the agents of the invention include novel 2-arylalkenyl-, 2-heteroarylaikenyl-, 2-arylalkynyl-, 2-heteroarylalkynyl-, 2-arylazo- and 2-heteroarylazopyridines and their salts, hereinafter referred to as “compounds of the invention”.




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


1


to R


5


are as defined above, provided that when R


3


is hydrogen,




a) in compounds of the formula I in which R


1


, R


2


and R


4


are hydrogen, R


5


is different from 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-dimethyl-phenyl, 3-hydroxy-4-methoxy- and 4-hydroxy-3-methoxy-phenyl, 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-methoxy-phenyl, 2-pyridinyl, 5-chloro-2-pyridinyl and 6-methyl-2-pyridinyl when X denotes ethenylene, or R


5


is different from phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-bromophenyl and 2- and 4-chlorophenyl when X denotes 1,2-propylene attached to R


5


in 2-position, or R


5


is different from phenyl, 2- and 4-chlorophenyl and 3-methoxyphenyl when X denotes 1,2-propylene attached to R


5


in 1-position, or R


5


is different from 4-methoxyphenyl when X denotes 2,3-but-2-enylene or 1,2-but-1-enylene attached to R


5


in 2-position, or R


5


is different from 4-methoxyphenyl and 4-isopropyphenyl when X denotes 2,3-pent-2-enylene attached to R


5


in 3-position, or R


5


is different from phenyl, 4-methylphenyl, methoxyphenyl and 4-hydroxyphenyl when X denotes 3,4-hex-3-enylene;




b) in compounds of the formula I in which R


1


is methyl and R


2


and R


4


are hydrogen, R


5


is different from phenyl, 3-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 4-cyanophenyl, 2-pyridinyl and 6-methyl-2-pyridinyl when X denotes ethenylene;




c) in compounds of the formula I in which R


1


and R


2


are hydrogen and R


4


is carboxy, R


5


is different from phenyl, 3-methylphenyl, 4-methoxyphenyl and 4-bromophenyl when X denotes ethenylene;




d) in compounds of the formula I in which R


1


and R


2


are hydrogen and R


4


is methyl, R


5


is different from phenyl, 3-methoxy-, 4-methoxy- and 3,4-dimethoxyphenyl, 2-chloro- and 2,4-dichlorophenyl and 6-methyl-pyrid-2yl when X denotes ethenylene or R


5


is different from phenyl when X is 1,2-prop-1-enylene attached to R


5


in 2-position;




e) in compounds of the formula I wherein R


1


and R


2


are hydrogen and R


4


is 2-dimethylaminoethoxycarbonyl or 3-dimethylaminopropyloxycarbonyl, R


5


is different from 4-methoxy-phenyl when X denotes ethenylene;




f) in compounds of the formula I in which R


1


and R


2


are hydrogen and R


4


is 2-dimethoxyethoxy, R


5


is different from phenyl, 4-methylphenyl and 4-methoxycarbonylphenyl when X denotes ethenylene;




g) R


5


is different from phenyl when R


1


and R


2


are hydrogen and R


4


is hydroxy or ethoxycarbonyl, or when R


1


is methyl, R


2


is hydrogen and R


4


is methoxy, or R


1


is but-1-enyl, R


2


is hydrogen and R


4


is hydrogen, or R


1


is hydrogen and R


4


is 2-dimethoxyethoxy, and X is, in each case, ethenylene, and provided that, when R


3


is hydrogen and X is ethynylene,




a′) R


5


is different from phenyl, 2- and 4-nitrophenyl, 4-aminophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethoxycarbonylphenyl, 5-formyl-2-methoxy-phenyl, 5-carboxy-2-methoxy-phenyl and pyridyl when R


1


, R


2


and R


4


are hydrogen;




b′) in compounds of the formula I in which R


2


and R


4


are hydrogen, R


5


is different from phenyl, 3-methylphenyl. 6-methylpyridin-2-yl and 2-methoxyphenyl when R


5


is methyl, R


5


is different from 6-bromopyridin-2-yl when R


1


is bromo, and R


5


is different from 6-hexyloxypyridin-2-yl when R


1


denotes hexyloxy;




c′) in compounds of the formula I wherein R


1


and R


4


are hydrogen, R


5


is different from phenyl, 4-aminophenyl and 4-propylphenyl when R


2


is methyl, R


5


is different from phenyl, 4-cyanophenyl and 4-pentylphenyl when R


2


is ethyl, R


5


is different from 3-cyano-4-ethoxyphenyl and 3-bromo-4-methoxy-phenyl when R


2


is butyl, R


5


is different from 4-methoxy-phenyl and 4 butyloxyphenyl when R


2


is pentyl, R


5


is different from 4-ter.-butylphenyl, 3-tert.-butyl-4-hydroxy-phenyl, 4-tert.-butyl-3-hydroxy-phenyl,and 4-hexyloxyphenyl when R


2


is carboxy, R


5


is different from phenyl when R


2


is methoxycarbonyl or methylcarbamoyl, R


4


is different from 3-tert.-butylphenyl, 3-tert.-butyl-4-hydroxy-phenyl and 4-(4-methylpentyl)phenyl when R


2


is ethoxycarbonyl, and R


5


is different from 4-pentyloxyphenyl when R


2


is 2-methylbutyloxycarbonyl;




d′) in compounds of the formula I wherein R


1


and R


2


are hydrogen, R


5


is different from phenyl when R


4


is hydroxy, methyl, ethyl, carboxy, methoxycarbonyl or carbamoyl.




Preferred compounds of the invention are as indicated above for the agents of the invention.




The compounds of the invention can be prepared in analogy to the synthesis of known compounds of formula I.




Thus the compounds of the invention which are of formula I can be prepared for example by a process which comprises




a) reacting a compound of the formula II











 with a compound of the formula Y


2


—R


5


(III), in which either one of Y


1


and Y


2


denotes lower alkanoyl and the other one represents lower alkyl or triarylphosphoranylidenemethyl, or one of Y


1


and Y


2


denotes a reactive esterified hydroxy group and the other one represents a group Y


3


—X— in which Y


3


is hydrogen or a metallic group, and R


1


, R


2


, R


3


, R


4


and R


5


have the meanings indicated hereinbefore and functional groups R


1


, R


2


, R


3


and R


4


as well as functional substituents of R


5


may be temporarily protected, or




b) eliminating H—Y


4


from a compound of the formula IV











 in which Y


4


denotes an electrofugal group and R


1


, R


2


, R


3


, R


4


, X and R


5


have the meanings indicated hereinbefore and functional groups R


1


, R


2


, R


3


and R


4


as well as functional substituents of R


5


may temporarily be protected, removing any temporary protecting groups




and, if desired, converting a compound of formula I obtainable by the above-defined processes into a different compound of formula I, resolving a mixture of isomers that may be obtained into the individual isomers and/or converting a compound of formula I having at least one salt-forming group obtainable by the above-defined processes into a salt, or converting a salt obtainable by the above-defined processes into the corresponding free compound or into a different salt.




A lower alkanoyl Y


2


or, more preferably, Y


1


group is, for example, a C


1


-C


3


alkanoyl group, such as formyl, acetyl or propionyl, especially formyl. A lower alkyl group Y


1


or, more preferably, Y


2


is, for example, a C


1


-C


3


alkyl group, such as methyl, ethyl or propyl, especially methyl. Triarylphosphoranylidenemethyl Y


2


or, more preferably, Y


1


is, for example, triphenylphosphoranylidenemethyl.




When one of Y


1


and Y


2


denotes a reactive esterified hydroxy group and the other one represents a group of the formula Y


3


—X— in which Y


3


denotes hydrogen, the condensation is preferably performed according to the Heck coupling method, for example, in the presence of copper or of a copper catalyst or of a noble metal/phosphine catalyst, such as Palladium or a Pdll salt in the presence of triaryl phosphine, for example, palladium acetate, and of triphenylphosphine, or in the presence of bis-triphenylphosphine-palladium dichloride, preferably in the presence of a tri-lower alkyl amine, for example, trimethylamine, advantageously in the presence of Cu


I


—I, in a polar organic solvent such as N,N-di-lower alkyl-alkanoic acid amide, for example, dimethylformamide, a di-lower alkyl sulfoxide, for example, dimethylsulfoxide, or dioxan, at temperatures from appropriately 15° C. to appropriately 120° C., preferably at the boil.




When one of Y


1


and Y


2


denotes a reactive esterified hydroxy group and the other one represents a group of the formula Y


3


—X— in which Y


3


denotes a metallic group such as a halo-magnesium group, the reaction is preferably performed according to Grignard method, wherein the metallic intermediate is preferably formed in situ.




When one of Y


1


and Y


2


denotes lower alkanoyl and the other one represents lower alkyl, the intermolecular condensation of compounds of the formulae II and III is preferably performed according to the Shaw and Wagstaff method or one of its many modifications.




When one of Y


1


and Y


2


denotes lower alkanoyl and the other one represents triarylphosphoranylidenemethyl, the condensation is preferably performed according to the well known Wittig olefin-building method, preferably by forming the phosphoranylidene component from a corresponding triarylphosphonium halide in situ, for example, by reacting the latter with a metal base, such as an alkalimetal hydride, such as sodium hydride, or with a metal-organic base, such as a lower alkyl metal compound, such as butyllithium, or with an alkali metal alkanolate, for example, potassium tertiary butoxide, preferably in an inert organic solvent, such as an aromatic or arylaliphatic hydrocarbon, for example, benzene or toluene, at appropriately −10° C. to appropriately 39° C., preferably first at 0° to 10° C. and then at ambient temperature.




Electrofugal groups Y


4


are, for example, esterified hydroxy groups, such as hydroxy groups esterified with an organic acid, for example, lower alkanoyloxy or hydroxy groups esterified with an anorganic acid, for example, halo groups, or tertiary amino groups, such as tri-lower alkylamino groups, for example, trimethylamino, or lower-alkyleneamino, lower azaalkyleneamino, lower-oxyalkyleneamino or lower thiaalkyleneamino groups, such as pyrrolidino, piperidino, morpholino or thiomorpholino, or corresponding quaternary ammonium groups.




The protection of functional groups by such protecting groups, the protecting groups themselves and the reactions for their removal are described, for example, in standard works.




The elimination of H—Y


4


from compounds of formula IV can be performed in a customary manner. Thus, water or lower alkanoic acids may be eliminated by means of azeotropic distillation, for example, in toluene, advantageously under mild-acidic conditions. Hydrogen halides may be removed under basic conditions such as reaction with an alkalimetal alkanolate, preferably in the corresponding lower alkanol as a solvent or co-solvent, or by heating in the presence of a tertiary amine, such as a tri-lower alkylamine.




The starting materials for the above described reactions are generally known. Novel starting materials can be obtained in manner analogous to the methods for the preparation of known starting materials.




Compounds of formula I obtainable in accordance with the process can be converted into different compounds of formula I in customary manner, for example a free carboxy group may be esterified or amidated, an esterified or amidated carboxy group may be converted into a free carboxy group, an esterified carboxy group can be converted into an unsubstituted or substituted carbamoyl group, a free amino group can be acylated or alkylated, and a free hydroxy can be acylated.




Also, compounds of the formula I can be oxidized by customary methods such as reaction with an organic peroxy acid, yielding the corresponding pyridine-N-oxide derivatives.




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




Resulting salts can be converted into different salts in a manner known per se.




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




As a result of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds and their salts is to be understood as including the free compounds, as well as the corresponding salts.




In a compound of formula I the configuration at individual chirality centers can be selectively reversed. For example, the configuration of asymmetric carbon atoms that carry nucleophilic substituents, such as amino or hydroxy, can be reversed by second order nucleophilic substitution, optionally after conversion of the bonded nucleophilic substituent into a suitable nucleofugal leaving group and reaction with a reagent introducing the original substituent, or the configuration at carbon atoms having hydroxy groups can be reversed by oxidation and reduction, analogously to European Patent Application EP-A-0 236 734.




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




The pharmacologically acceptable compounds of the present invention may be used, for example, in the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient 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 nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological 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 approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragées, tablets or capsules.




The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes.




The doses to be administered to warm-blooded animals, for example human beings, of, for example, approximately 70 kg body weight, especially the doses effective in disorders caused by or associated with irregularities of the glutamatergic signal transmission, are from approximately 3 mg to approximately 3 g, preferably from approximately 10 mg to approximately 1 g, for example approximately from 20 mg to 500 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size. Usually, children receive about half of the adult dose. The dose necessary for each individual can be monitored, for example by measuring the serum concentration of the active ingredient, and adjusted to an optimum level.











The following non-limiting Examples serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar.




EXAMPLE 1




3-[2-(6-Methylpyridin-2-yl)-vinyl-benzonitrile




A solution of 2,6-dimethyl pyridine (4.2 ml, 36.28 mMol), 3-cyanobenzaldehyde (4.95 g, 37.74 mMol) in acetic anhydride (6.85 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 400 g). The column is first eluted with toluene (400 ml) and then with toluene/ethyl acetate 95:5. The fractions containing the desired compound are combined, and evaporated in vacuo. The solid residue is recrystallized from methylene chloride/hexane and 3.18 g of white crystals are isolated. (melting point: 91-92°).




EXAMPLE 2




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




A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and 2-cyanobenzaldehyde (6.81 g, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 400 g). The column is first eluted with toluene (400 ml) and then with toluene/ethyl acetate 95:5. The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and white crystals are isolated. (melting point: 113-114°).




EXAMPLE 3




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




A solution of 2,6-dimethyl pyridine (5.8 ml, and 50 mMol), and pyridine-4-carbaldehyde (4.9 ml, and 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 16 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 4:1 (5 L), then with toluene/acetone 3:1 (5 L) and finally with toluene/acetone 2:1 (15 L). The fractions containing the desired compound are combined, evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 0.956 g of white crystals are isolated. (melting point: 72-73° C.).




EXAMPLE 4




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




A solution of 2,6-dimethyl pyridine (5.8 ml, 50 mMol), pyridine-3-carbaldehyde (4.9 ml, 52 mMol) in acetic anhydride (9.5 ml) is heated under reflux for 10 hours. The acetic anhydride is then evaporated in vacuo and the residue purified on column chromatography (silica gel 900 g). The column is first eluted with toluene/acetone 9:1 (7 L), then with toluene/acetone 4:1 (5 L) and finally with toluene/acetone 2:1 (5 L). The fractions containing the desired compound are combined, and evaporated in vacuo. The solid residue is recrystallized from methylene chloride/diisopropyl ether and 4.28 g of a colorless oil which solidify upon standing at 6-8° C.




EXAMPLE 5




2-[2-(3-Bromophenyl)ethynyl]-6-methyl-pyridine




1.2 g (2.8 mMol) of 2-[1,2-dibromo-2-(3-bromophenyl)-ethyl]-6-methyl-pyridine are dissolved in 10 ml of ethanol. 0.9 g (16.1 mMol) of potassium hydroxide (powder) are added, and the resulting suspension is heated under reflux for 4 hours. The suspension is then cooled to room temperature, poured into 100 ml of brine and extracted thrice with 30 ml each of t-butyl methyl ether. The combined organic phases are washed with 30 ml of brine, dried over Sodium sulfate, filtrated and evaporated in vacua. 0.720 g of the title compound are obtained as a colorless oil crystallizing on standing; melting point 60-61°.




The starting material can be obtained as follows:




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




A solution of 24 ml (200 mMol) of 2,6-dimethyl pyridine and 25.6 ml (207 mMol) of 3-bromobenzaidehyde in 38 ml of acetic anhydride is heated under reflux for 7.5 hours. The acetic anhydride is then evaporated in vacuo, and the residue is dissolved in 500 ml of 4N hydrochloric acid and twice extracted with 200 ml each of hexane. The water phase is then extracted four times with 300 ml each of tert.-butyl methyl ether. The combined organic phases are washed twice with 300 ml each of a saturated solution of NaHCO


3


in water, then once with 300 ml of brine (300 ml), dried over sodium sulfate, filtrated and evaporated in vacuo yielding 4.2 g of the title compound as colorless crystals of melting point 58-590.




b) 2-[1,2-dibromo-2-(3-bromophenyl)-ethyl]-6-methyl-pyridine




1 g (3.6 mMol) of 2-(3-Bromo-phenylethynyl)-6-methyl-pyridine are dissolved in 5 ml of carbon tetrachloride, and the solution is heated to 55-60°. A solution of 0.23 ml (4.4 mMol) of bromine (Br


2


) in 1 ml of carbon tetrachloride is added dropwise. The reaction mixture is maintained at 55-60° for 30 minutes and then cooled to room temperature. The resulting precipitate is collected by filtration and dried in vacuo. 1.3 g of the title compound in form of yellow crystals of melting point 164-166 are isolated.




EXAMPLE 6




3-[2-(6-Methylpyridin-2-yl)ethynyl]-benzonitrile




A mixture of 1 g (8.54 mMol) 2-ethynyl-6-methyl-pyridine (prepared in analogy to D. E. Ames et al., Synthesis, 1981, p. 364-5), 2.3 g (12.8 mMol) 3-bromo-benzonitrile, 0.47 g (0.7 mMol) bis-(triphenylphosphine)-palladium-II-chloride, 80 mg (0.41 mMol) cuprous iodide and 1.53 ml (15 mMol) triethylamine in 10 ml dimethylformamide is stirred for 3 hours at 90° C. The reaction mixture is cooled to ambient temperature, poured into water and extracted with dichloromethane. The organic layer is dried over sodium sulfate, filtered, evaporated to dryness and the residue is purified by chromatography on silica gel with hexane/ethyl acetate (4:1) as eluant. Crystallization from hexane of the obtained product affords 0.53 g (28.4%) of the title compound as brown crystals, melting point 120-3° C.




EXAMPLE 7




In analogous manner to Example 1 (when X is alkenylene) or Example 5 (when X is alkynylene), the following compounds of formula I can be prepared:

















Melting







point






Compound of formula I




(° C.)











2-Styryl-pyridin-3-ol




249-252






2-Methyl-6-[2-(3-nitro-phenyl)-vinyl]-pyridine




100-101






2-[2-(2-Chloro-phenyl)-vinyl -pyridine




colorless







oil






2-Methyl-6-styryl-pyridine




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-chloro-phenyl)-vinyl]-pyridin-3-yl ester




 99-102






2-[2-(2-Chloro-phenyl)-vinyl]-pyridin-3-ol




232-234






6-Methyl-2-styryl-pyridin-3-ol




261 dec






Acetic acid 2-[2-(2-chloro-phenyl)-vinyl]-6-methyl-pyridin-3-




92-94






yl ester






2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-ol




232-234






(Z)-6-Methyl-2-styryl-pyridin-3-ol




145-148






2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridine




51-52






2-[2-(2-Fluoro-phenyl)-vinyl]-pyridine




69-70






2-[2-(2-Nitro-phenyl)-vinyl]-pyridine




97-99






Acetic acid 2-[2-(4-chloro-phenyl)-vinyl]-6-methyl-pyridin-3-




102-103






yl ester






Acetic acid 6-[2-(4-chloro-phenyl)-vinyl]-2-methyl-pyridin-3-




130-131






yl ester






2-[2-(4-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-ol




271-278







dec






6-[2-(4-Chloro-phenyl)-vinyl]-2-methyl-pyridin-3-ol




265-270







dec






Acetic acid 6-methyl-2-[2-(2-nitro-phenyl)-vinyl]-pyridin-3-




139-140






yl ester






6-Methyl-2-[2-(2-nitro-phenyl)-vinyl]-pyridin-3-ol




190-195







dec






Acetic acid 2-methyl-6-[2-(2-nitro-phenyl)-vinyl]-pyridin-3-




 99-100






yl ester






2-Methyl-6-[2-(2-nitro-phenyl)-vinyl]-pyridin-3-ol




230-233







dec






Acetic acid 2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-pyridin-3-




97-99






yl ester






Acetic acid 6-[2-(3-chloro-phenyl)-vinyl]-2-methyl-pyridin-3-




112-114






yl ester






2-[2-(3-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-ol




232-235






2-[2-(3-Chloro-phenyl)-vinyl]-6-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-Ethenediyl) bis[6-methyl]-pyridine




108-110






Dimethyl-[3-(6-methyl-2-styryl-pyridin-3-yloxy)-propyl]-




136-139






amine; hydrochloride salt






(E)-6-[2-(2-Pyridyl)vinyl]-2-picoline




56-57






2-Methyl-6-styryl-pyridine 1-oxide




102-103






2-Styryl-pyridine 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-vinvl)-pyridin-3-ol; HCl salt




225-228






6-Styryl-pyridine-2-carbonitrile




92-93






2-[2-(2, 6-Dichloro-phenyl)-vinyl]-6-methyl-pyridine




light yell.







oil






3-Methoxy-6-methyl-2-styryl-pyridine




light yell.







oil






6-Styryl-pyridine-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-Styryl-pyridine-2-carboxylic acid; HCl Salt




209-212






6-Styryl-pyridine-2-carboxylic acid methyl ester




87-88






Acetic acid 2-[2-(6-methyl-pyridin-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-methyl-pyridin-2-yl)-vinyl]-




102-103






phenyl ester






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




59-61






2-[2-(4-Chloro-phenyl)-vinyl]-6-methyl-pyridine




83-85






2-[2-(2-Chloro-phenyl)-vinyl]-5-ethyl-pyridine




34-35






1-(6-Styryl-pyridin-2-yl)-ethanone




67-88






6-[2-(2-Chloro-phenyl)-vinyl]-2-methyl-nicotinic acid ethyl




80-82






ester






2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-nicotinic acid ethyl




70-72






ester






2-[2-(6-Methyl-pyridin-2-yl)-vinyl]-benzoic acid; 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;




237-238






HCl salt






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-Methyl-pyridin-2-yl)-vinyl]-phenyl}-methanol;




230-231






HCl salt






6-Styryl-pyridine-2-carboxylic acid .tert.-butylamide




87-88






2-(2-Bromo-2-phenyl-vinyl]-6-methyl-pyridine; HCl salt




150-154






2-Methyl-6-phenylethynyl-pyridine; HCl salt




146-148






6-Styryl-pyridine-2-carboxylic acid hexylamide; HCl salt




118-125






6-[2-(2-Chloro-phenyl)-vinyl]-2-methyl-nicotinic acid




219-221







dec






2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-nicotinic acid




168-170






2-[2-(3,5-Dichloro-phenyl)-vinyl]-6-methyl-pyridine




75-77






2-Methyl-6-[2-(3-trifluoromethyl-phenyl)-vinyl-pyridine




44-45






(E)-6-[2-(4-pyridyl)vinyl]-2-pocoline




72-73






N,N-Diethyl-3-[2-(6-methyl-pyridin-2-yl)-vinyl]-benzamide;




227-228






HCl salt






N,N-Diethyl-4-[2-(6-methyl-pryidin-2-yl)-vinyl]-benzamide;




183-184






HCl salt






(E)-8-[2-(3-pyridyl)vinyl]-2-picoline




yellowish







oil






{2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxyl}-




colorless






acetic acid ethyl ester




gum






3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-.N.-(3-trifluoromethyl-




249-251






phenyl)-benzamide; HCl salt






4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-.N.-(3-trifluoromethyl-




160-161






phenyl)-benzamide






2-[2-(3-Nitro-phenyl)-vinyl]-pyridine




127-128






6-Styryl-pyridine-2-carboxylic acid (3-trifluoromethyl-




126-129






phenyl)-amide






2-(6-Styryl-pyridin-2-yl)-propan-2-ol, HCl salt




171-174






2-Methyl-6-(2-thiophen-2-yl-vinyl)-pyridine, HCl salt




208-211






2-[2-(3-Chloro-phenyl)-vinyl]-pyridine




51-53






2-[2-(3-Cyano-phenyl)-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-fluoro-vinyl]-6-methyl-pyridine




70-72






2-[2-(2,3-Dimethoxy-phenyl)-vinyl]-6-methyl-pyridine




colorless







oil






2-[2-(2,3-Dichloro-phenyl)-vinyl]-6-methyl-pyridine




67-68






2-[2-(3-Chloro-phenyl)-1-methyl-vinyl]-pyridine




colorless







oil






{2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yl}




87-90






-methanol






2-Methyl-6-[2-(3-trimethylsilanylethynyl-phenyl)-vinyl]




yellowish






-pyridine




oil






2-[2-(3,4-Difluoro-phenyl)-vinyl]-6-methyl-pyridine




61-62






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




yellowish







oil






2-[2-(3,5-Difluoro-phenyl)-vinyl]-6-methyl-pyridine




yellowish







oil






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




yellowish







oil






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




yellowish







oil






2-Methyl-6-[2- (3-phenoxy-phenyl)-vinyl-pyridine




yellowish







oil






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




68-69






2-[2-(2,5-Difluoro-phenyl)-vinyl]-6-methyl-pyridine




44-45






{2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxy}-




230-233






acetic acid






(3-{2-[2-(3-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxy}-




203-205






propyl)-dimethyl-amine






{6-[2-(2-Chloro-phenyl)-vinyl]-2-methyl-pyridin-3-yl}




131-133






methanol






2-(3-Bromo-phenylethynyl)-6-methyl-pyridine




61-63






2-Methyl-6-}2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-vinyl}-




yellowish






pyridine




oil






2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-6-methyl-pyridine




43-45






2-[2-(3-Chloro-phenyl)-vinyl]-3-methoxy-6-methyl-pyridine




52-53






Acetic acid 4-bromo-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-




yellowish






phenyl ester




oil






Acetic acid 3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl ester




yellowish







oil






2-[2-(3,4-Dichloro-phenyl)-vinyl]-6-methyl-pyridine




73-75






4-Bromo-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenol




246-248






Acetic acid 2-[2-(3,5-dichloro-phenyl)-vinyl]-6-methyl-




156-158






pyridin-3-yl ester






Acetic acid 6-[2-(3,5-dichloro-phenyl)-vinyl]-2-methyl-




159-161






pyridin-3-yl ester






Acetic acid 2-[2-(3,5-dichloro-phenyl)-vinyl]-pyridin-3-yl




154-156






ester






2-Methyl-6-(2-naphthalen-1-yl-vinyl]-pyridine




yellowish







oil






2-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-6-methyl-




 99-101






pyridine






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-




yellowish






pyridine




gum






2-[2-(3-Chloro-phenyl)-propenyl]-6-methyl-pyridine




yellowish







oil






2-[2-(2,3-Dihydro-benzofuran-5-yl)-vinyl]-6-methyl-pyridine




88-90






2-[2-(4-Fluoro-phenyl)-vinyl]-6-methyl-pyridine




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-nitro-quinoxalin-5-ylmethyl)-{3-[2-(6-




pale or-






methyl-pyridin-2-yl)-vinyl]-phenyl}-amine




ange foam






N-{3-[2- (6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-acetamide




147






N-{3-[2- (6-Methyl-pyridin-2-yl)-vinyl]-phenyl}2-phenyl-




156






acetamide






2,2-Dimethyl-N-{3-[2-6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




166-168






propionamide






Thiophene-2-carboxylic acid {3-[2-(6-methyl-pyridin-2-yl)-




197 dec






vinyl]-phenyl}-amide






Cyclohexanecarboxylic acid {3-[2-(6-methyl-pyridin-2-yl)-




215






vinyl]-phenyl}-amide






1-(4-Bromo-phenyl)-3-}3-[2-(6-methyl-pyridin-2-yl)-vinyl]-




197 dec






phenyl}-urea






2-Methyl-6-[2-(4-nitro-phenyl)-vinyl]-pyridine




134-135






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




147-148






2-[2-(3,5-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-ol




218-220






6-[2-(3,5-Dichloro-phenyl)-vinyl]-2-methyl-pyridin-3-ol




286 dec






2-[2-(3,5-Dichloro-phenyl)-vinyl]-pyridin-3-ol




240-242






2-[2-(6-Chloro-benzo[1,3]dioxol-5-yl)-vinyl]-6-methyl-




131-132






pyridine






2-[2-(2,3-Difluoro-phenyl)-vinyl]-6-methyl-pyridine




55-56






2-[2-(3,4-Dichloro-phenyl)-propenyl]-6-methyl-pyridine




yellowish







oil






2-[2-(3,5-Bis-trifluoromethyl-phenyl)-vinyl]-6-methyl-




85-86






pyridine






Acetic acid 2-methoxy-6-[2-(6-methyl-pyridin-2-yl)-vinyl]-




yellowish






phenyl ester




oil






2-Methoxy-6-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenol




118-120






2-Methyl-6-[2-(2,3,6-trifluoro-phenyl)-vinyl]-pyridine




59-62






2-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-vinyl]-6-methyl-




yellowish






pyridine




oil






2-Methyl-6-(2,3,6-trifluoro-phenylethynyl)-pyridine




93-94






Acetic acid 4-chloro-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-




yellowish






phenyl ester




oil






Acetic acid 2,6-di-.tert.-butyl-4-[2-(6-methyl-pyridin-2-yl)-




127-128






vinyl]-phenyl ester






3-(6-Methyl-pyridin-2-ylethynyl)-benzamide




187-189






Acetic acid 4-bromo-2-methoxy-6-[2-(6-methyl-pyridin-2-yl)-




151-153






vinyl]-phenyl ester






2-(6-Chloro-benzo[1,3]dioxol-5-ylethynyl)-6-methyl-pyridine




105-106







light







brown







crystais






2-[2-(3,5-Dichloro-phenyl)-vinyl]-3-methoxy-6-methyl-




127-129






pyridine






2-[2-(3,5-Dichloro-phenyl)-vinyl]-3-methoxy-pyridine




111-113






5-Azido-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenol




143 dec






2-[2-(Pyridin-3-yl)ethynyl]-6-methyl-pyridine




light







yellow







crystals







60-61






N-{3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-succinamic




212-213






acid






1-tert.-Butyl-3-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




191-192






urea






5-({3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenylamino}-meth-




250 dec






yl)-7-nitro-1,4-dihydro-quinoxaline-2,3-dione






Tetrahydro-furan-2-carboxylic acid {3-[2-(6-methyl-pyridin-




160-161






2-yl)-vinyl]-phenyl}-amide






(1-{3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenylcarbamoyl}-




colorless






2-phenyl-ethyl)-carbamic acid tert.-butyl ester




foam






({3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenylcarbamoyl}-




colorless






methyl)-carbamic acid tert.-butyl ester




foam






Diethyl-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-amine




217 dec






Ethyl-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}amine




225 dec






Ethyl-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}amine




183 dec






2-(2-Ethoxy-3,6-difluoro-phenylethynyl)-6-methyl-pyridine




yellowish







oil






2-(3,5-Difluoro-phenylethynyl)-6-methyl-pyridine




yellowish







oil






2-(3-Fluoro-phenylethynyl)-6-methyl-pyridine




26-28






2-[2-(3,5-Dimethyl-phenyl)-vinyl]-6-methyl-pyridine




56-57






2-[2-(3,4-Dimethoxy-phenyl)-vinyl]-6-methyl-pyridine




55-56






2-(3,4-Dichloro-phenylethynyl)-6-methyl-pyridine




73-74






2-(4-Ethoxy-3-trifluoromethyl-phenylethynyl)-6-methyl-




61-62






pyridine






2-(4-Fluoro-phenylethynyl)-6-methyl-pyridine




 98-100






2-Methyl-6-.o.tolylethynyl-pyridine




yellowish







oil






2-(3,4-Difluoro-phenylethynyl)-6-methyl-pyridine




65-68






2-Methyl-6-[2-(2,3,5-trichloro-phenyl)-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-nitro-phenylethynyl)-pyridine




99.5-







102.5






6-[2-(3,5-Dichloro-phenyl)-vinyl]-3-methoxy-2-methyl-




 98-100






pyridine






{2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yl}-




123-125






morpholin-4-yl-methanone






(3-{2-[2-(3,5-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-




207-210






yloxy}-propyl)-dimethyl-amine hydrochloride salt






N-{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-succinamic




201 dec






acid






N-{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-2-phenyl-




236-237






acetamide




dec






({4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenylcarbamoyl}-




144-145






methyl)-carbamic acid .tert.-butyl ester




dec






1-tert.-Butyl-3-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




209 dec






urea






{3-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-thiophen-2-




161-162






ylmethyl-amine hydrochloride salt






Cyclohexylmethyl-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-




178-179






phenyl}-amine hydrochloride salt




dec






{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-thiophen-2-




100






ylmethyl-amine






Cyclohexylmethyl-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-




106-167






phenyl}-amine






2-Amino-N-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




102






3-phenyl-propionamide






2-Amino-N-{3-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




105






acetamide






2-Amino-N-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-




217-219






acetamide




dec






1-[1-({2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-




amor-






yloxy}-acetyl)-piperidin-4-yl]-imidazolidin-2-one




phous







foam






(1-{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenylamino}-ethyl)-




orange






phosphonic acid dimethyl ester




amor-







phous







solid






2-[2-(2-Methoxy-phenyl)-vinyl]-6-methyl-pyridine




129-130






2-(3-Ethoxy-4-fluoro-phenylethynyl)-6-methyl-pyridine




82-83






2-(3-Chloro-phenylethynyl)-6-methyl-pyridine




57-59






1-(3-Pyridin-2-ylethynyl-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]-




121-123






phenol






2-Methyl-6-.m.-tolylethynyl-pyridine




57-58






2-(2,5-Difluoro-phenylethynyl)-6-methyl-pyridine




49-50






2-(3,5-Dimethyl-phenylethynyl)-6-methyl-pyridine




yellowish







oil






2-[2-(3,5-Dibromo-phenyl)-vinyl]-6-methyl-pyridine




68-70






2-Methyl-6-[2-(pyrimidin-5-yl)-ethynyl]-pyridine




110-112






(2-{2-[2-(3-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxy}-




165-167






ethyl)-dimethyl-amine






Acetic acid 1-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenyl}-






ethyl ester






3-(6-Methyl-pyridin-2-ylethynyl)-phenylamine




129-130






N-[3-(6-Methyl-pyridin-2-ylethynyl)-phenyl]-2-phenyl-




133-135






acetamide




dec






Thiophene-2-carboxylic acid [3-(6-methyl-pyridin-2-ylethy-




156-157






nyl)-phenyl]-amide




dec






2-Methyl-6-(thiophen-2-ylethynyl)-pyridine




34-36






3-(6-Methyl-pyridin-2-ylethynyl)-benzoic acid ethyl ester




56-58






2-(3,5-Dibromo-phenylethynyl)-6-methyl-pyridine




100:101






{2-[2-(2-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-ylmethyl}-




227-229






dimethyl-amine




dec






(3-{6-[2-(3-Chloro-phenyl)-vinyl]-2-methyl-pyridin-3-yloxy}-




184-186






propyl)-dimethyl-






5-Azido-4-iodo-2-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenol




red glass






2,6-Di-tert-butyl-4-[2-(6-methyl-pyridin-2-yl)-vinyl]-amino;




126-127






HCl salts phenol






1-{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-ethanol




97-99






2-Methyl-6-[2-(pyrimidin-2-yl)-ethynyl]-pyridine




144-145






[3-(6-Methyl-pyridin-2-ylethynyl)-phenyl]-phenyl-methanone




 99-100






6-(6-Methyl-pyridin-2-ylethynyl)-3,4-dihydro-1H-quinolin-2-




189-191






one






2-(3-{2-[2-(3-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-




101-103






yloxy}-propyl)-isoindole-1,3-dione






3-Methoxy-6-methyl-2-.m.-tolylethynyl-pyridine




brown oil






Acetic acid 2-[2-(6-methyl-pyridin-2-yl)-vinyl]-4-nitro-phenyl




129-131






ester






6-(6-Methyl-pyridin-2-ylethynyl)-indan-1-one




160-165






2-Methyl-6-[2-(pyrazin-2-yl)-ethynyl]-pyridine




95-96






N-Methyl-N-(3-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-




62-70






phenoxy}-propyl)-acetamide






2-[2-(3,5-Bis-trifluoromethyl-phenyl)-1-ethoxy-vinyl]-6-




yellow






methyl-pyridine




oil






Acetic acid 2-phenylethynyl-pyridin-3-yl ester




brown oil






Acetic acid 6-methyl-2-.m.-tolylethynyl-pyridin-3-yl ester




brown oil






Acetic acid 4-[2-(6-methyl-pyridin-2-yl)-vinyl]-2-nitro-phenyl




91-93






ester






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




275 dec






Dimethyl-[3-(2-phenylethynyl-pyridin-3-yloxyl-propyl]-amine




yellowish







oil






Dimethyl-(3-{4-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenoxy}-




240-243






propyl)-amine






1-{4-[2-(6-Methyl-pyridin-2-yl)-vinyl]-phenyl}-ethanone




56-58






2-(3-Fluoro-phenylethynyl)-quinoline




81-83






Acetic acid 2-methyl-6-styryl-pyridin-3-yl ester




93-96






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




141-143






3-Ethoxy-4-[2-(6-methyl-pyridin-2-yl)-vinyl]-2-nitro-phenol




175-178







dec






4-(6-Methyl-pyridin-2-ylethynyl)-2-nitro-phenol




184-187







dec






Acetic acid 2-[2-(6-methyl-pyridin-2-yl)-vinyl]-6-nitro-phenyl




105-110






ester




dec






Dimethyl-[3-(6-methyl-2-phenylethynyl-pyridin-3-yloxy)-




yellow






propyl]-amine




gum






2-Azido-4-[2-(6-methyl-pyridin-2-yl)-vinyl]-phenol




155-157







dec






Dimethyl-[3-(6-methyl-2-.m.-tolylethynyl-pyridin-3-yloxy)-




yellowish






propyl]-amine




oil






2-(3-Methanesulfonyl-phenylethynyl)-6-methyl-pyridine




108-110







dec






3-{2-[2-(3-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxy}-




186-189






propylamine






4-Azido-.N.-(3-{2-[2-(3-chloro-phenyl)-vinyl]-6-methyl-




 99-102






pyridin-3-yloxy}-propyl)-2-hydroxy-benzamide




dec






3-[3-(3-Dimethylamino-propoxy)-6-methyl-pyridin-2-ylethy-




yellow






nyl]-benzonitrile




gum






5-(6-Methyl-pyridin-2-ylethynyl)-indan-1-one




133-134






2-Methyl-6-(2,3,5-trichloro-phenylethynyl)-pyridine




112-114






2-[2-(6-methyl-pyridin-3-yl)ethynyl]-6-methyl-pyridine




118-119






Dimethyl-{3-[6-methyl-2-(3-trifluoromethyl-phenylethynyl-




yellow






pyridin-3-yloxy]-propyl}-amine




gum






2-[2-(6-methyl-pyridin-3-yl)ethynyl]-3-methoxy 6-methyl-




198-199






pyridine hydrochloride salt






2-Methyl-6-(5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-




50-51






pyridine






3-[2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yloxy]-




151-153






propylamine






(3-{4-Bromo-2-methoxy-6-[2-(6-methyl-pyridin-2-yl)-vinyl]-




211-215






phenoxy}-propyl)-dimethyl-amine;






[6-(3-Fluoro-phenylethynyl)-pyridin-2-yl]-dimethyl-amine




brown oil






6′-(3-Fluoro-phenylethynyl)-3,4,5,6-tetrahydro-2.H.-[1,2]




brown






bipyridinyl




gum






{3-[2-(3-Chloro-phenylethynyl)-6-methyl-pyridin-3-yloxy]-




158-160






propyl}-dimethyl-amine






4-Azido-.N.-{3-[2-(3-chloro-phenylethynyl)-6-methyl-pyridin-




161-163






3-yloxy]-propyl}-2-hydroxy-benzamide




dec






1-[3-(6-Methyl-pyridin-2-ylethynyl)-phenyl]-1H-[1,2,4]




105-110






triazole-3-carboxylic acid ethyl ester




dec






1-[3-(6-Methyl-2-phenylethynyl)-pyridin-3-yloxy)-propyl]-




108-109






piperidin-3-ol






2-Ethynyl-6-(3-fluoro-phenylethynyl)-pyridine




89-90






3-Methyl-6-(6-methyl-pyridin-2-ylethynyl)-3H-benzooxazol-




172-174






2-one






1-[3-(6-Methyl-pyridin-2-ylethynyl)-phenyl]-1H-[1,2,4]tria-




154-157






zole-3-carboxylic acid dimethylamide






1-[3-(6-Methyl-2-phenylethynyl)-pyridin-3-yloxy)-propyl]-




amor-






piperidin-4-ol




phous







white







solid






5-(6-Methyl-pyridin-2-ylethynyl)-2-nitro-phenol




150-151







dec






5-[2-Bromo-2-(6-methyl-pyridin-2-yl)-vinyl]-2-nitro-phenol




158-159






5-[2-(6-Methyl-pyridin-2-yl)-E-vinyl]-2-nitro-phenol




171-173






5-[2-(6-Methyl-pyridin-2-yl)-Z-vinyl]-2-nitro-phenol




108-110






4-Azido-2-hydroxy-.N.-[3-(6 -methyl-pyridin-2-ylethynyl)-




180-182






phenyl]-benzamide




dec






5-(3-Dimethylamino-propoxy)-6-phenylethynyl-pyridine-2-




160-162






carboxylic acid ethyl ester






6-Methyl-2-styryl-pyrimidin-4-ol




221-225






2-Ethyl-6-(3-fluoro-phenylethynyl)-pyridine




brown oil






2-(3,5-Dichloro-phenylethynyl)-6-methyl-pyridine




74-76






2-Methyl-6-(3-trifluoromethoxy-phenylethynyl)-pyridine




<30;







brown







crystals






2-Methyl-6-(3-[1,2,4]triazol-1-yl-phenylethynyl)-pyridine




128-130






4-(6-Methyl-pyridin-2-ylethynyl)-phthalonitrile




138-140






2-Methyl-6-{2-[3-(1.H.-tetrazol-5-yl)-phenyl]-vinyl}-pyridine;




234-240






compound with formic acid






3-[2-(3,5-Dichloro-phenylethynyl)-6-methyl-pyridin-3-yloxy]-




 97-100






propylamine






{3-[2-(3,5-Dichloro-phenylethynyl)-6-methyl-pyridin-3-




171-173






yloxy]-propyl}-dimethyl-amine






2-(3,5-Dimethyl-phenylethynyl)-3-methoxy-6-methyl-pyridine




yellowish







oil






2-[2-(3-Fluoro-phenyl)-vinyl]-6-methyl-pyridin-3-ol




251-253







Dec.






6-(3-Fluoro-phenylethynyl)-2-methyl-nicotinic acid ethyl ester




84-86






2-Azido-5-(6-methyl-pyridin-2-ylethynyl)-phenol




153-155







dec






6-(3,4-Dimethoxy-phenylethynyl)-5-(3-dimethylamino-




149-152






propoxyl-pyridine-2-carboxylic acid ethyl ester






2-(4-Methoxy-3-trifluoromethyl-phenylethynyl)-6-methyl-




86-87






pyridine






2-(3-Fluoro-phenylethynyl)-6-methoxy-pyridine




brown oil






2-(3-Fluoro-phenylethynyl)-5-methyl-pyridine




74-76






6-(3,5-Dichloro-phenylethynyl)-5-(3-dimethylamino-pro-




195-198






poxy)-pyridine-2-carboxylic acid ethyl ester






5-(3-Dimethylamino-propoxy)-6-(3,5-dimethyl-phenylethy-




187-190






nyl)-pyridine-2-carboxylic acid ethyl ester






6-(3-Fluoro-phenylethynyl)-2-methyl-nicotinic 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-phenyl-




138-140






ethynyl)-2-methyl-pyridin-3-yl]-methanone






2-(3-Fluoro-phenylethynyl)-6-methyl-nicotinic acid ethyl ester




brown oil






2-(3-Fluoro-phenylethynyl)-4,6-dimethyl-pyridine




brown oil






6-(3-Fluoro-phenylethynyl)-.N.-(5-methoxy-indan-2-ylmeth-




157-159






yl)-2-methyl-nicotinamide






{[6-(3-Fluoro-phenylethynyl)-2-methoxy-pyridine-3-car-




133-135






bonyl]-amino}-phenyl-acetic acid methyl ester






2-Methyl-6-(5-methyl-thiophen-2-ylethynyl)-pyridine




58-59






2-Methyl-6-(2,3,5-trimethyl-phenylethynyl)-pyridine




brown oil






3-{2-[2-(3-Fluoro-phenyl)-vinyl]-6-methyl-pyridin-3-




86-88






yloxy}-propan-1-ol






[6-(3-Fluoro-phenylethynyl)-2-methyl-pyridin-3-ylmethyl]-




220-222






dimethyl-amine






2,2-Dimethyl-propionic acid 3-[2-(3-fluoro-phenylethynyl)-6-




yellowish






methyl-pyridin-3-yloxy]-propyl ester




oil






2-Azido-4-iodo-5-(6-methyl-pyridin-2-ylethynyl)-phenol




140 dec






6-Azido-2,4-diiodo-3-(6-methyl-pyridin-2-ylethynyl)-phenol




162 dec






4-Azido-2-hydroxy-5-iodo-.N.-[3-(6-methyl-pyridin-2-




185 dec






ylethynyl)-phenyl]-benzamide






Acetic acid 3-acetoxymethyl-5-(6-methyl-pyridin-2-




brown oil






ylethynyl)-benzyl ester






(Benzyl-{[2-(3-fluoro-phenylethynyl)-6-methyl-pyridin-3-




brown oil






yloxy]-acetyl}-amino)-acetic acid ethyl ester






2-[2-(3-Fluoro-phenyl)-vinyl]-6-methyl-isonicotinic acid ethyl




76-77






ester






3-[2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-3-yloxy]-




72-74






propan-1-ol






[3-Hydroxymethyl-5-(6-methyl-pyridin-2-ylethynyl)-phenyl]-




115-117






methanol






(3-[2-[2-(3,5-Dimethyl-phenyl)-vinyl]-6-methyl-pyridin-3-




yellowish






yloxy}-propyl)-dimethyl-amine




gum






[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-{6-[2-(3-fluoro-phenyl)-




156-158






vinyl]-2-methyl-pyridin-3-yl}-methanone






2-[2-(3-Fluoro-phenyl)-vinyl]-6-methyl-isonicotinic acid




245-248






{6-[2-(2-Chloro-phenyl)-vinyl]-2-methyl-pyridin-3-yl}-




109-112






[4-(4-fluoro-benzoyl)-piperidin-1-yl]-methanone






2-(3-Ethynyl-phenylethynyl)-6-methyl-pyridine




48-49






(3-{2-[2-(2,6-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-




207-210






yloxy}-propyl)-dimethyl-amine hydrochloride salt






(3-{2-[2-(2,3-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-




161-169






yloxy}-propyl)-dimethyl-amine-hydrochloride salt






4-[6-(3-Fluoro-phenylethynyl)-2-methyl-pyridine-3-carbonyl]-




97-99






piperazine-1-carboxylic acid .tert.-butyl ester






[6-(3-Fluoro-phenylethynyl)-2-methyl-pyridin-3-yl]-piperazin-




250-252






1-yl-methanone




dec






[4-(4-Azido-2-hydroxy-benzoyl)-piperazin-1-yl]-[6-(3-fluoro-




186-188






phenylethynyl)-2-methyl-pyridin-3-yl]-methanone




dec






(3-[2-[2-(2,4-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-




170-176






yloxy}-propyl)-dimethyl-amine hydrochloride salt






2-(3-Fluoro-phenylethynyl)-6-methyl-isonicotinic acid ethyl




89-91






ester






2-(3-Fluoro-phenylethynyl)-6-methyl-isonicotinic acid .tert.-




94-96






butyl ester






2-(3-Fluoro-phenylethynyl)-6-methyl-isonicotinic acid




231 dec






[2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-4-yl)-methanol




143-146






[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-[2-(3-fluoro-phenyl-




156-158






ethynyl)-6-methyl-pyridin-4-yl]-methanone






3-Allyloxy-2-[2-(3,5-dichloro-phenyl)-vinyl]-6-methyl-




105-106






pyridine






[2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-4-yl]-mor-




114-116






pholin-4-yl-methanone






Acetic acid 3-(6-methyl-pyridin-2-ylethynyl)-benzyl ester




brown oil






[2-(3-Fluoro-phenylethynyl)-6-methyl-pyridin-4-ylmethyl]-




209-212






dimethyl-amine






(3-{2-[2-(3,5-Dichloro-phenyl)-propenyl]-6-methyl-pyridin-3-




182-184






yloxy}-propyl)-dimethyl-amine hydrochloride salt






2-(3-Fluoro-phenylethynyl)-3-methoxy-6-methyl-pyridine




yellowish







oil






(3-{2-[2-(3,5-Dichloro-phenyl)-vinyl]-pyridin-3-yloxy}-




171-174






propyl)-dimethyl-amine hydrochloride salt






(4-Azido-2-hydroxy-5-iodo-phenyl)-{4-[6-(3-fluoro-phenyl-




195-200






ethynyl)-2-methyl-pyridine-3-carbonyl]-piperazin-1-yl}-




dec






methanone






4-Azido-.N.-{3-[2-(3-chloro-phenylethynyl)-6-methyl-pyridin-




142-150






3-yloxy]-propyl}-2-hydroxy-5-iodo-benzamide




dec






4-(2-Pyridin-2-yl-vinyl)-benzoic acid ethyl ester




100-102






(3-{2-[2-(4-Chloro-phenyl)-vinyl]-6-methyl-pyridin-3-yloxy}-




159-171






propyl)-dimethyl-amine hydrochloride salt






[3-(6-Methyl-pyridin-2-ylethynyl)-phenyl]-methanol




43-45






6-(3-Fluoro-phenylethynyl)-nicotinic acid .tert.-butyl ester




98-93






(3-{2-[2-(3,4-Dichloro-phenyl)-vinyl]-6-methyl-pyridin-3-




174-177






yloxy}-propyl)-dimethyl-amine hydrochloride salt






2-(1-Bromo-2-phenyl-vinyl)-4-methyl-pyrimidine




yellow







oil






6-(3-Fluoro-phenylethynyl)-nicotinic acid




223 dec.






[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-[6-(3-fluoro-phenyl-




136.0-






ethynyl)-pyridin-3-yl]-methanone




139.0






2-(2-.tert.-Butoxy-3,6-difluoro-phenylethynyl)-6-methyl-




72.0-74.0






pyridine






2-Methyl-6-[2-(2,4,5-trifluoro-phenyl)-vinyl]-pyridine




74-76






2-Methyl-6-[2-(2,3,4-trifluoro-phenyl)-vinyl]-pyridine




79-82






3-(6-Methyl-pyridin-2-ylethynyl)-phenol




142-144






2-Methyl-6-[2-(3,4,5-trifluoro-phenyl)-vinyl]-pyridine




74-76






2-(3-Methoxy-phenylethynyl)-6-methyl-pyridine




55-57






2-Methyl-6-(2,3,4-trifluoro-phenylethynyl)-pyridine




104-106











(dec = decomposition)












Claims
  • 1. A compound of formula I whereinX represents an optionally halo-substituted (C2-4)alkynylene group bonded via vicinal unsaturated carbon atoms, R1 is (C1-4) alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, cyano, ethynyl, carboxy, (C1-4)alkoxycarbonyl, di(C1-4)alkylamino, (C1-6)alkylaminocarbonyl, trifluoromethylphenylaminocarbonyl, R2 is hydrogen, hydroxy, (C1-4) alkyl, hydroxy (C1-4) alkyl, (C1-4) alkoxy, carboxy, (C2-5)alkanoyloxy, (C1-4) alkoxycarbonyl, di(C1-4)alkylamino(C1-4)alkanoyl, di(C1-4)alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy, R3 is hydrogen, (C2-4) alkyl, carboxy, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbamoyl, hydroxy(C1-4)alkyl, di(C1-4)alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, R4 is hydrogen, hydroxy, (C1-4)alkoxy, carboxy, (C2-5)alkanoyloxy, (C1-4)alkoxycarbonyl, amino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkyl, carboxy (C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyl(C1-4)alkoxy, hydroxy(C1-4)alkyl, di(C1-4)alkylamino(C1-4)alkoxy, m-hydroxy-p-azidophenylcarbonylamino(C1-4)alkoxy, and R5 is a group of formula  wherein Ra and Rb independently are hydrogen, hydroxy, halogen, nitro, cyano, carboxy, (C1-4)alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, (C1-4)alkoxycarbonyl, (C2-7)alkanoyl, (C2-5)alkanoyloxy, (C2-5)alkanoyloxy(C1-4)alkyl, trifluoromethyl, trifluoromethoxy, trimethylsilylethynyl, (C2-5)alkynyl, amino, azido, amino (C1-4)alkoxy, (C2-5)alkanoylamino(C1-4)alkoxy, (C1-4)alkylamino(C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, (C1-4)alkylamino, di(C1-4)alkylamino, monohalobenzylamino, thienylmethylamino, thienylcarbonylamino, trifluoromethylphenylaminocarbonyl, tetrazolyl, (C2-5)alkanoylamino, benzylcarbonylamino, (C1-4)alkylamino carbonylamino, (C1-4)alkoxycarbonyl-aminocarbonylamino or (C1-4)alkylsulfonyl, Rc is hydrogen, fluorine, chlorine, bromine, hydroxy, (C1-4)alkyl, (C2-5)alkanoyloxy, (C1-4)alkoxy or cyano, and Rd is hydrogen, halogen or (C1-4)alkyl, provided that in compounds wherein R2, R3 and R4 are hydrogen, when R1 is methyl, R5 is different from phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in form of a pharmaceutically acceptable salt.
  • 2. A compound of formula I according to claim 1, whereinX represents an optionally halo-substituted (C2-4) alkynylene group bonded via vicinal unsaturated carbon atoms, R1 is (C1-4) alkyl, (C1-4)alkoxy, cyano, ethynyl or di(C1-4)alkylamino, R2 is hydrogen, hydroxy, carboxy, (C1-4) alkoxycarbonyl, di(C1-4)alkylaminomethyl, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy, R3 is hydrogen, (C1-4) alkyl, carboxy, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbamoyl, hydroxy(C1-4)alkyl, di(C1-4)alkylaminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, R4 is hydrogen, hydroxy, carboxy, (C2-5)alkanoyloxy, (C1-4)alkoxycarbonyl, amino (C1-4)alkoxy, di(C1-4)alkylamino(C1-4)alkoxy, di(C2-4)alkylamino(C1-4)alkyl or hydroxy(C1-4)alkyl, and R5 is a group of formula whereinRa and Rb independently are hydrogen, halogen, nitro, cyano, (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl, trifluoromethoxy or (C2-5)alkynyl, Rc is hydrogen, fluorine, chlorine, bromine, hydroxy, (C1-4)alkyl, (C2-5)alkanoyloxy, (C1-4)alkoxy or cyano, and Rd is hydrogen, halogen or (C1-4)alkyl, provided that in compounds wherein R2, R3 and R4 are hydrogen, when R1 is methyl, R5 is different from phenyl, 3-methylphenyl, 6-methylpyridin-2-yl and 3-methoxyphenyl, in free form or in form of a pharmaceutically acceptable salt.
  • 3. A compound according to claim 1 wherein X is ethynylene, in free form or in form of a pharmaceutically acceptable salt.
  • 4. A compound according to claim 1 wherein R5 is different from optionally substituted phenyl and X is ethynylene, in free form or in form of a pharmaceutically acceptable salt.
  • 5. A compound according to claim 1 wherein R5 is optionally substituted pyridin-3-yl and X is ethynylene, in free form or in form of a pharmaceutically acceptable salt.
  • 6. A compound which is 2-[2-(Pyridin-3-yl)ethynyl]-6-methyl-pyridine in free form or in form of a pharmaceutically acceptable form.
  • 7. A method of treating disorders which are mediated fully or in part by mGluR1 or mGluR5, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I whereinX represents an optionally halo-substituted lower alkenylene or alkynylene group bonded via vicinal unsaturated carbon atoms or an azo (—N═N—) group, R1 denotes hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkyl-amino, piperidino, carboxy, esterified carboxy, amidated carboxy, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-lower-alkyl-N-phenylcarbamoyl, lower alkoxy, halo-lower alkyl or halo-lower alkoxy, R2 denotes hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy, 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, 4-t.-butyloxycarbonyl-piperazin-1-yl-carboxy, 4-(4-azido-2-hydroxybenzoyl)-piperazin-1-yl-carboxy or 4-(4-azido-2-hydroxy-3-iodo-benzoyl)-piperazin-1-yl-carboxy, R3 represents hydrogen, lower alkyl, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl, hydroxy-lower alkyl, di-lower alkyl-aminomethyl, morpholinocarbonyl or 4-(4-fluoro-benzoyl)-piperidin-1-yl-carboxy, R4 represents hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, unsubstituted or hydroxy-substituted lower alkyleneamino-lower alkyl, lower alkoxy, lower alkanoyloxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, phthalimido-lower alkoxy, unsubstituted or hydroxy- or 2-oxo-imidazolidin-1-yl-substituted lower alkyleneamino-lower alkoxy, carboxy, esterified or amidated carboxy, carboxy-lower-alkoxy or esterified carboxy-lower-alkoxy, and R5 denotes an aromatic or heteroaromatic group which is unsubstituted or substituted by one or more substituents selected from lower alkyl, halo, halo-lower alkyl, halo-lower alkoxy, lower alkenyl, lower alkynyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkynyl, hydroxy, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, amino-, lower alkylamino-, lower alkanoylamino- or N-lower alkyl-N-lower alkanoylamino-lower alkoxy, unsubstituted or lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted phenoxy, unsubstituted or lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted phenyl-lower alkoxy, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, carboxy-lower alkylamino, esterified carboxy-lower alkylamino, amidated carboxy-lower alkylamino, phosphono-lower alkylamino, esterified phosphono-lower alkylamino, nitro, amino, lower alkylamino, di-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 lower alkyl-lower alkoxy-, halo- and/or trifluoromethyl-substituted, in free form or in the form of a photoaffinity ligand, a radioactive marker, an N-oxide or a pharmaceutically acceptable salt.
  • 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound according to claim 1, in free form or in the form of a pharmaceutically acceptable salt.
Parent Case Info

This is a continuation of U.S. application Ser. No. 09/462,511, having a 371 date of Feb. 24, 2000, now abandoned, which application is a 371 of International Application No. PCT/EP98/04266, filed Jul. 9, 1998.

US Referenced Citations (2)
Number Name Date Kind
4006240 Ho et al. Feb 1977 A
5013744 Chandraratna May 1991 A
Foreign Referenced Citations (5)
Number Date Country
181 568 May 1986 EP
334 119 Sep 1989 EP
WO 9223357 Nov 1993 WO
WO 97 05109 Feb 1997 WO
WO 97 19049 May 1997 WO
Non-Patent Literature Citations (11)
Entry
Dowell, R.I. et al., European Journal of Medicinal Chemistry, vol. 28, No. 6, pp. 513-516 (1993).
Lazer, E.S. et al., Journal of Medicinal Chemistry, vol. 33, No. 7, pp. 1892-1898 (1990).
Bahner, C.T. et al., Arzneim, Forsch./Drug Res., vol. 31, No. 3, pp. 404-406 (1981).
Honma, Y. et al., Journal of Medicinal Chemistry, vol. 27, No. 2, pp. 125-128 (1984).
Mori, M. et al., Agricultural and Biological Chemistry, vol. 46, No. 1, pp. 309-311 (1982).
Jerchel, D. et al., Justus Liebigs Ann.Chem., vol. 613, pp. 171-177 (1958).
Chemical Abstracts, vol. 53, 5263g (1957).
Sadao, Arai et al., Journal of Heterocyclic Chemistry, vol. 29, pp. 215-220 (1992).
Shaw, B.D. et al., Journal of the Chemical Society, pp. 79-83 (1932).
Derwent Abstract 82777 D/45, J5 6123-903, Sep. 29, 1981.
Derwent Abstract 00693 E/01, J5 6154-401, Nov. 30, 1981.
Continuations (1)
Number Date Country
Parent 09/462511 US
Child 09/722803 US