Thiazolobenzoheterocycles, their preparation and medicaments...

Details Thiazolobenzoheterocycles, their preparation and medicaments... Thiazolobenzoheterocycles, their preparation and medicaments...

2001-11-15

2002-07-23

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S346000, C544S353000, C544S354000

Reexamination Certificate

active

06423715

ABSTRACT:

Thiazolobenzoheterocycle derivatives are described by A. RICHARDSON, J. Org. Chem., 28, 2581-87 (1963) but no pharmacological activity is mentioned for these products.
The present invention relates to compounds of formula:
their salts, processes for preparing them and the medicaments containing them.
In formula (I),
R
1
represents a sulphur or selenium atom,
R
2
represents a hydrogen atom or an alkyl radical,
—R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—CH
2
—, —CH(R
7
) —CH
2
—CH
2
—, —CH
2
—CH
2
—CH(R
8
)—, —CH
2
—CH(R
9
)—CH
2
—, —CH
2
—CH—S—, —CH—CH
2
—SO—, —CH
2
—CH
2
—SO
2
—, —CH
2
—CH
2
—Se—, —CH
2
—CH
2
—O—, —CH
2
—CH
2
—CO—, —CH
2
—CH
2
—N(R
10
)—, —CH
2
—CO—N(R
10
)—, —CH
2
—CF
2
—CH
2
—, —CH
2
—CF
2
—CH(OH)—, —CH
2
—CH(R
13
)—S—, —CH
2
—CH(R
13
)—SO— or —CH
2
—CH(R
13
)—SO
2
—,
R
6
represents a polyfluoroalkyl, polyfluoroalkoxy or polyfluoroalkylthio radical,
R
7
represents an alkyl, —CH
2
OH, —CH
2
—SO
2
-alk or —CH
2
—NR
11
R
12
radical,
R
8
represents a radical alkyl, hydroxyl, —CH
2
OH, —NR
11
R
12
, —CH
2
—NR
11
R
12
, —S-alk, —SO-alk, —SO
2
-alk, thienyl, furyl, phenyl or phenyl substituted with a substituent chosen from halogen atoms and alkyl and alkoxy radicals,
R
9
represents an alkyl or —CH
2
OH radical,
R
10
represents a hydrogen atom or an alkyl radical,
R
11
represents a hydrogen atom or an alkyl, —CO-alk or —CO—CF
3
radical,
R
12
represents a hydrogen atom or an alkyl radical, or alternatively R
11
and R
12
form with the nitrogen atom to which they are attached a saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur, this heterocycle being unsubstituted or substituted with one or more substituents chosen from alkyl, phenyl, halophenyl and phenylalkyl radicals,
R
13
represents an alkyl or —CH
2
OH radical, alk represents an alkyl radical.
In the preceding definitions and in those which will be given hereinafter, unless otherwise indicated, the alkyl an d alkoxy radicals and portions contain 1 to 6 straight- or branched-chain carbon atoms and the halogen atoms are bromine chlorine, fluorine and iodine atoms.
Among the polyfluoroalkyl radicals, there may be mentioned the trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, perfluoropropyl and perfluorobutyl radicals.
Among the polyfluoroalkoxy radicals, there may be mentioned the trifluoromethoxy, perfluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoropropoxy and perfluorobutoxy radicals.
Among the polyfluoroalkylthio radicals, there may be mentioned the trifluoromethylthic, perfluoroethylthio and perfluoropropylthio radicals.
The preferred polyfluoroalkyl, polyfluoroalkoxy and polyfluoroalkylthio radicals are trifluoromethyl, trifluoromethpxy, pentafluoroethoxy and trifluoromethylthio radicals.
As saturated or unsaturated 5- or 6-membered heterocycle optionally containing another heteroatom chosen from nitrogen, oxygen and sulphur, there may be mentioned pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, these heterocycles being unsubstituted or substituted with an alkyl, phenyl, halophenyl or phenylalkyl radical.
The invention also relates to the addition salts of the compounds of formula (I) with inorganic or organic acids.
The compounds of formula (I) which contain one or more asymmetric centres have isomeric forms; these isomers and mixtures form part of the invention. The racemates and the enantiomers of these compounds also form part of the invention.
The compounds of formula (I) for which R
1
represents a sulphur or selenium atom, R
2
represents a hydrogen atom, —R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—CH
2
—, —CH(R
7
)—CH
2
—CH
2
—CH
2
—CH
2
—CH(R
8
)—, —CH
2
—CH(R
9
)—CH
2
—, —CH
2
—CH
2
—S—, —CH
2
—CH
2
—Se—, —CH
2
—CH
2
—O—, —CH
2
—CH
2
—CO—, —CH
2
—CH
2
—N(R
10
)—, —CH
2
—CO—N(R
10
)—, —CH
2
—CF
2
—CH
2
—, —CH
2
—CF
2
—CH(OH)—, —CH
2
—CH(R
13
)—S—, with the proviso that R
8
does not represent a hydroxyl radical, may be prepared by reacting an alkali metal thiocyanate or an alkali metal selenocyanate with a derivative of formula:
in which R
6
has the same meanings as in formula (I),
—R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—CH
2
—, —CH(R
7
)—CH
2
—CH
2
—, —CH
2
—CH
2
CH(R
8
)—, —CH
2
—CH(R
9
)—CH
2
—, —CH
2
—CH
2
—S—, —CH
2
—CH
2
—Se—, —CH
2
—CH
2
—O—, —CH
2
—CH
2
—CO—, —CH
2
—CH
2
—N(R
10
)—, —CH
2
—CF
2
—CH
2
—, —CH
2
—, —CF
2
—CH(OH)—, —CH
2
—CH(R
13
)—S—, —CH
2
—CO—N(R
10
)— in which R
7
, R
8
, R
9
, R
10
and R
13
have the same meanings as in formula (I) with the proviso that R
8
does not represent a hydroxyl radical.
This reaction is generally carried out in the presence of bromine, chlorine, chloramide and copper(II) chloride, in an organic solvent such as acetic acid, at a temperature between 15° C. and the boiling point of the reaction medium. As alkali metal thiocyanate, it is preferable to use potassium thiocyanate. As alkali metal selenocyanate, it is preferable to use potassium selenocyanate.
The derivatives of formula (II), with the exception of 6-trifluoromethyl 1,2,3,4-tetrahydroquinoline, 2-methyl-6-trifluoromethoxy-1,2,3,4-tetrahydroquinoline, 6-trifluoromethyl-1,2,3,4-tetrahydroquinoxaline and 2-oxo-7-trifluoromethyl-3,4-dihydroquinoxaline, are new and, as such, form part of the invention.
The compounds of formula (I) for which R
2
represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I) for which R
2
represents a hydrogen atom.
This alkylation is carried out by any method which makes it possible to alkylate an imine functional group. Preferably, the procedure is carried out by means of a derivative Ra-X in which Ra represents an alkyl radical and X represents a reactive group such as a halogen atom (preferably chlorine, bromine or iodine) or a tosyloxy radical, in an in,ert organic solvent such as a lower aliphatic alcohol (ethanol, propanol or butanol for example), a ketone (acetone or methyl ethyl ketone for example) or dimethylformamide, in the presence of a base such as an alkali metal carbonate (potassium carbonate for example), at a temperature between 20° C. and the boiling point of the reaction medium.
The compounds of formula (I) for which —R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—CH(R
8
)— and R
8
represents a hydroxyl radical may be obtained by reducing a corresponding compound of formula (I) for which —R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—CO—.
This reaction is carried out by any method which makes it possible to pass from a ketone to an alcohol. The procedure is generally carried out by means of sodium borohydride, in an alcohol such as methanol or ethanol, at a temperature of between 0 and 25° C.
The compounds of formula (I) for which —R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—SO—, —CH
2
—CH
2
—SO
2
—, —CH
2
—CH(R
13
) —SO— or —CH
2
—CH(R
13
)—SO
2
may be prepared by oxidizing a corresponding compound of formula (I) for which —R
3
—R
4
—R
5
— represents a chain of formula —CH
2
—CH
2
—S—, —CH
2
—CH
2
—Se— or —CH
2
—CH(R
13
)—S—.
This oxidation is carried out according to known methods of oxidizing sulphur-containing derivatives as described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peracid or a salt of such an acid (percarboxylic or persulphonic acid, in particular perbenzoic acid, 3-chloroperbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid or monoperphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulphuric acid), in an inert solvent such as a chlorinated solvent (chloroform or dichloromethane for example), at a temperature of between 0 and 25° C. It is also possible to use hydrogen peroxide and a periodate (sodium periodate for example), in an inert solvent such as a lower aliphatic alcohol, water or a mixture

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