CA1126732A - Thieno(3,2-c)- and thieno(2,3-c)pyridines, process for their preparation and therapeutic composition containing them - Google Patents
Thieno(3,2-c)- and thieno(2,3-c)pyridines, process for their preparation and therapeutic composition containing themInfo
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- CA1126732A CA1126732A CA321,393A CA321393A CA1126732A CA 1126732 A CA1126732 A CA 1126732A CA 321393 A CA321393 A CA 321393A CA 1126732 A CA1126732 A CA 1126732A
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to new thieno [3,2-c]
and thieno [2,3-c]pyridines having the formulae:
and
This invention relates to new thieno [3,2-c]
and thieno [2,3-c]pyridines having the formulae:
and
Description
~126,732 Thieno ~,2- ~ and thieno ~,3- ~pyridines, process for their preparation and therapeutic composition containing them This invention relates to new thieno ~,2- ~
and ~,3- ~pyridines, to a process for their preparation and to their therapeutic applications.
The new derivatives of this invention have one of the following formulae:
~Rl 1~ ~1CON~ ~ ~R2 ~I) (II) in which Rl and R2 represent independently: hydrogen;
an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group; an aryl or aralkyl group optionally substituted on a phenyl nucleus with one or more halogen atoms or lower alkyl, lower alkoxy, hydroxy or tri-~: fluoromethyl groups; a heteroaryl or heteroaralkyl group; or a group having the formula:
~ R3 : ~ 2 n \ R4 in which n is 2 or 3 and R and R are independently a Cl 4 alkyl radical or, together with the nitrogen atomto which they are attached, form a heterocycle which may carry a second heteroatom selected from oxygen, sulfur ~: and nitrogen, which nitrogen may carry:a Cl 4 alkyl radical; or Rl and R , together with the nitrogen atom to which they are attached, form a heterocycle which may ; carry a second heteroatom selected from oxygen, sulfur ~ ~ and nitrogen, which nitrogen may carry a lower alkyl `~ group, a benzyl radical or a phenyl radical which may itself be optionally substituted with one or more , :~ :
3~12~ 2 halogen atoms or lower alkyl, lower alkoxy or trifluoro-methyl groups.
The invention inclucles also within its scope the pharmaceutically acceptable acid addition salts of said derivatives with inorganic or organic acids.
When Rl and/or R2 represent an aralkyl group, the latter is typically a benzyl or phenethyl group;
when they represent a heteroaralkyl group, the latter is typically a (3-pyridyl)methyl or (4-pyridyl)methyl group.
By "lower alkyl" or "lower alkoxy" groups are meant groups having 1 6 carbon atoms and, particularly, 1-4 carbon atoms.
This invention relates also to a process for ~; the preparation of compounds having above defined formula (I) or (II), comprising reacting an amine having the formula:
~ ~ ~Rl 1~ ~ HN
in which Rl and R2 are as previously defined, with a mixed anhydride of the formula (III) or (IV) in which ~i ~; R is a Cl 3 alkyl group:
r O~C~DR ~
to give the derivative of the formula (I) or (II), respectively. ~;
The starting compounds (III) and (IV) are in~
turn prepared by~condensation, in the presence o~ tri-ethylamine, of a thienopyridine of the formula (V) or~
(VI): ;
:
:, ~: ~ :
'~ : . .
i: ~, ,. ' . ., . ! . . . ~, , , -~2~73%
~COOH \ ~COOH
(V) (.VI) with an alk~1 chloroformate of the formula ClCOOR in which.R has th.e previously defined meaning.
Both reactions are preferably effected sequen-tially in the same container: mixed anhydrides (III) : and ( IV) are first prepared at temperatures between -5 and +15 & within an inert solvent such as chloroform or :~ : ~Rl ~: methylene chloride;~amine HN ~ 3 , pure or dissolved in R
a solvent such as benzene, toluene, chloroform or methylene chloride is then added at the same tempera- :
ture, after which the mixture.is left aside at room temperature. ~ ~ ~
Thienopyridines (V) and (VI~ used as starting materials may be prepared according to a process com-prising reacting a compound of the formula:
OH
or with`nitrous~acidi and~dehydrating:and removing the :
nitroso group of the~resulting :compounds~by reaction with-;~an alkali met~al~hydroxlde and subsequent neutral zatlon.
The starting materials of the formula (VII) or (VIII) may in turn be prepared:by reacting a compound~ of ~ :~
the formula~
, - , - 1 . ............. , ~12~73%
OH
~ COOH
and ~,3- ~pyridines, to a process for their preparation and to their therapeutic applications.
The new derivatives of this invention have one of the following formulae:
~Rl 1~ ~1CON~ ~ ~R2 ~I) (II) in which Rl and R2 represent independently: hydrogen;
an alkyl group; a cycloalkyl group; an alkenyl group; an alkynyl group; an aryl or aralkyl group optionally substituted on a phenyl nucleus with one or more halogen atoms or lower alkyl, lower alkoxy, hydroxy or tri-~: fluoromethyl groups; a heteroaryl or heteroaralkyl group; or a group having the formula:
~ R3 : ~ 2 n \ R4 in which n is 2 or 3 and R and R are independently a Cl 4 alkyl radical or, together with the nitrogen atomto which they are attached, form a heterocycle which may carry a second heteroatom selected from oxygen, sulfur ~: and nitrogen, which nitrogen may carry:a Cl 4 alkyl radical; or Rl and R , together with the nitrogen atom to which they are attached, form a heterocycle which may ; carry a second heteroatom selected from oxygen, sulfur ~ ~ and nitrogen, which nitrogen may carry a lower alkyl `~ group, a benzyl radical or a phenyl radical which may itself be optionally substituted with one or more , :~ :
3~12~ 2 halogen atoms or lower alkyl, lower alkoxy or trifluoro-methyl groups.
The invention inclucles also within its scope the pharmaceutically acceptable acid addition salts of said derivatives with inorganic or organic acids.
When Rl and/or R2 represent an aralkyl group, the latter is typically a benzyl or phenethyl group;
when they represent a heteroaralkyl group, the latter is typically a (3-pyridyl)methyl or (4-pyridyl)methyl group.
By "lower alkyl" or "lower alkoxy" groups are meant groups having 1 6 carbon atoms and, particularly, 1-4 carbon atoms.
This invention relates also to a process for ~; the preparation of compounds having above defined formula (I) or (II), comprising reacting an amine having the formula:
~ ~ ~Rl 1~ ~ HN
in which Rl and R2 are as previously defined, with a mixed anhydride of the formula (III) or (IV) in which ~i ~; R is a Cl 3 alkyl group:
r O~C~DR ~
to give the derivative of the formula (I) or (II), respectively. ~;
The starting compounds (III) and (IV) are in~
turn prepared by~condensation, in the presence o~ tri-ethylamine, of a thienopyridine of the formula (V) or~
(VI): ;
:
:, ~: ~ :
'~ : . .
i: ~, ,. ' . ., . ! . . . ~, , , -~2~73%
~COOH \ ~COOH
(V) (.VI) with an alk~1 chloroformate of the formula ClCOOR in which.R has th.e previously defined meaning.
Both reactions are preferably effected sequen-tially in the same container: mixed anhydrides (III) : and ( IV) are first prepared at temperatures between -5 and +15 & within an inert solvent such as chloroform or :~ : ~Rl ~: methylene chloride;~amine HN ~ 3 , pure or dissolved in R
a solvent such as benzene, toluene, chloroform or methylene chloride is then added at the same tempera- :
ture, after which the mixture.is left aside at room temperature. ~ ~ ~
Thienopyridines (V) and (VI~ used as starting materials may be prepared according to a process com-prising reacting a compound of the formula:
OH
or with`nitrous~acidi and~dehydrating:and removing the :
nitroso group of the~resulting :compounds~by reaction with-;~an alkali met~al~hydroxlde and subsequent neutral zatlon.
The starting materials of the formula (VII) or (VIII) may in turn be prepared:by reacting a compound~ of ~ :~
the formula~
, - , - 1 . ............. , ~12~73%
OH
~ COOH
2 or ~ NH2 OH
with an aqueous formaldehyde solution, in the presence of a strong acid.
The following non-limiting Examples are giyen to illustrate this invention.
EX~PLE 1 6-Methylaminocarbonyl-thieno ~,2- ~pyridine ,~
Formula (I): NRlR = NHCH . Derivative~ n 1 To a solution of 6-carboxy-thieno ~,2- ~pyri-10 dine (10 g; 0.050 mole) and triethylamine (5.6 g; 0.057 mole) in dry chloroform (500 cc) maintained~at 10C, i9 slowly added ethyl chloroformate (6.2 ~; 0.057 mole),~
with vigorous stirring. When addition is complete, stirring is continued at room temperature for a further 40~minutes, after which a solution of methylamlne (~ g;
0.064 mole) in~benzène (50 cc) is~added dropwise thereto. ~--~ ~ The reaction mixture is then left aside at;room tempera-~; ture for 4 hours,~evaporated to dryness,~and the residue is taken up into ether. The ether phase~is washed with~
a saturated;aqueous sodium carbonate~solution, dried~
over~sodium sulfate and evaporated to dryness.
The solid residue is recrystallized from benzene-dlisopropyl ether. ~Plnkl~sh crystals; m.p. =
99C.~ Yield: 79%. ~
6-~-Dimethylaminoethy~laminocarbonyl-thieno ~,2- ~pyri-dine Formula (I) NR R =~NH(CH2)2N(cH3)2 Derivative n2 ~ ~;
To a solution of 6-carboxy-thieno ~,2-~pyri-30 dine tl0 g; 0.056 mole) ànd triethylamine t5.6 g; 0.057 mole) in dry~chloroform t300 cc) malntained at 10C~, is slowly added ethyl chloroformate t6.2 g; 0.057 mole3 i7~
with vigorous stirring. On completion of the addition, stirring is continued at room temperature for a further 40 minutes, after which ~-dimethylaminoethylamine (5.4 g;
0.061 mole) is added dropwise. The reaction mixture is left aside at room temperature Eor 3.5 hours; it is then evaporated to dryness and the residue is taken up into N
hydrochloric acid. The acid aqueous phase is washed with ether and is then made alkaline with 6N sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts are dried over dry sodium sulfate and evaporated to dryness. The oily residue is - purified via its dihydrochloride. Beige crystals; m.p.
= 170C (isopropanol-methanol). Yield: 75%.
5-t4-p.Chlorophenyl-l-piperazinyl)carbonyl-thieno-~,3- ~pyridine Formula (II): NR R = N N ~ Cl. Derivative n3 To a solution of 5-carboxy-thieno ~,3- ~pyri-dine (12 g; 0.067 mole) and triethylamine (6.9 g; 0.068 20 mole) in dry chloroform (250 cc) maintained at 10C, is slowly added ethyl chloroformate (7.3 g; 0.068 mole), with vigorous stirring. Stirring is then continued at ~; ~ room temperature for 50 minutes and p-chlorophenyl piperazine (13.2 g; 0.067 mole) dissolved in chloroform (50 cc) is then added dropwise. The reaction mixture is left aside at room temperature for 5 hours, after which it is evaporated to dryness and the residue is taken up into methylene chloride. The methylene chloride phase is washed with a saturated aqueous sodium bicarbonate solution, dried over dry sodium sulfate and evaporated to dryness. The resulting crystals are purified by ~;~ column chromatography through silica (eluent: ethyl acetate). White crystals, m.p. = 170C (isopropanol-diisopropyl ether). Yield: 41%.
: :
:~6.~
6-Ethylaminocarbonyl-thieno~ ,2- ~pyridine Formula (I): NRlR = NHC2H5. Derivative n4 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and ethylamine. Beige crystals; m.p. = 110C
(diisopropyl ether3. Yield: 87%.
5-Isopropylaminocarbonyl-thieno ~,3- ~pyridine Formula (II): NRlR2 = NHC3H7. Derivative n5 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-~; pyridine and isopropylamine. Light brown crystals, m.p. = 102C (diisopropyl ether). Yield: 80%.
6-n.Butylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHC4Hg. Derivative n6 This compound is prepared according;to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and n-butylamine. Hydrochloride: orange-yellow ; crystals, m.p. 104C (acetonitrile). Yield: 55%.
6-Octylaminocarbonyl-thieno ~,2- ~pyrldine ~;~ Formula (I): NRlR = NHC8H17. Derivative~n7 This compound is prepared according to the procedure of Example~l, from 6-carboxy-thieno ~,2- ~-pyridine and octylamine. White crystals, m.p. = 63C
(diisopropyl ether)~. ~Yl~eld: 54~
; EXAMPLE 8 6-Dimethylaminocarbonyl-thieno ~ ,2- ~pyridine FormuIa (I): NRlR = N(CH3)2. Derivative n 8 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and dimethylamine. White crystals; m.p. = 93C
(diisopropyl ether). Yield: 55%.
; ~: : :
: :
~2f~f73Z
6-Diethylaminocarbonyl-thieno ~,2-~/'pyridine Formula (I) NR R = N(C2H5)2 Derivative n9 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and diethylamine. Beige-crystals; m.p. = 119C
(diisopropyl ether). Yield: 80%.
6-(l-Pyrrolidinyljcarbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N~ Derivative n 10 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2-~/'-pyridine and pyrrolidine. Off-white crystals; m.p. =
105 & (diisopropyl ether). Yield: 52%.
6-Piperidinocarbonyl-thieno ~ ,2- ~ pyridine !
Formula ~I): NRlR2 = ~ Derivative n 11 f This compound is prepared according to the proeedure of Example 1, from 6-earboxy-thieno ~, 2-~f'-pyridine and piperidine. Light brown powder; m.p. =
145C (diisopropyl ether). Yield: 96%.
6-Morpholinocarbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N O Derivative n 12 ~ ~
\ :
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and morpholine. White crystals; m.p. = 136C
(benzene-diisopropyl ether). Yield: 79%.
30 5-Benzylaminocarbonyl-thieno ~,3-~/'pyridine Formula (II): NR R = NHCH2C6H5. Derivative n 13 :: :
: . ~
, .
i~2~i73~
This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and benzylamine. Beige crystals; m.p. = 113C
(isopropanol). Yield: 75%.
6-o.Chlorobenzylaminocarbonyl-thieno~,2- ~p~ridine Formula (I): NR R = NHCH2 ~ Derivative n 14 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and o.chlorobenzylamine. Beige powder; m.p. =169C (methanol). Yield: 58%.
6-Phenethylaminocarbonyl-thieno~,2- ~pyridine Formula (I) NRlR2 = NHCH2CH2C6~5 Derivative n15 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and phenethylamine. Beige crystals; m.p. =
127C (isopropanol-diisopropyl ether). Yield 66%.
6-Allylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHCH2-CH=CH2. Derivative n 16 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and allylamine. Oxalate: white crystals; ;~
m.p. = 131& (ethyl acetate). Yield: 54%.
6-Propargylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHCH2C_CH. Derivative n 17 This compound is prèpared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and propargylamine. Pinkish crystals, m.p. =
134C (isopropanol-diisopropyl etber). YieLd: 60%.
~121~i73~
g 6-~-Diethylaminoethylaminocarbonyl-thieno~,2- ~pyridine Formula (I): NRlR = NH(CH2~2N(C2H5)2. Derivative n 18 This compound i5 prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and ~-diethylaminoethylamine. Dihydrochloride:
beige crystals; m.p. = 145C (:isopropanol-methanol).
Yield: 81%.
6-~-Morpholinoethylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NH(CH2)2N 3 Derivative n 19 This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and N-(2-aminoethyl)-morpholine. White crystals; m.p. = 104C (isopropanol-diisopropyl ether).
Yield: 71%.
6-y-Dimethylaminopropylaminocarbonyl-thieno ~,2- ~pyri-dine Formula (I): NRlR = NH(CH2)3N(CH3)2. Derivative n20 This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and y-dimethylaminopropylamine. Dihydro-chloride: beige crystals; m.p. = 146C (ethanol).
Yield: 77%. ~ ;
5-(4-Pyridyl-methyl)aminocarbonyl-thieno ~,3- ~pyridine Formula (II): NR R = NHCH ~ N Derivative n 21 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and 4-aminomethyl-pyridine. Light brown crystals; m.p. = 167C (isopropanol-diisopropyl ether).
Yield: 78%.
~ ~ .
.. . . . . .... .. . .... . . . . . . .. ~ .. . . .
.. .. . . . .. .. . .. . ... .. . .. . . . ..
i732 6-(4-Pyridyl-meth~yl)aminocarbonyl-thieno~,2- ~pyridine 1 2 ~
Formula (I): NR R = NHCH2 ~ N Derivative n22 This c~mpound is prepared according to the procedure of Example 3, from 6-carboxy-thieno ~,2- ~_ pyridine and 4-aminomethyl-pyridine. Orange crystals;
m.p. = 146C (ethyl acetate). Yield: 98%.
5-~3-Pyridyl-methyl)aminocarbonyl-thieno ~,3- ~pyridine ; 10 Formula (III): NR R = NHCH2 ~ Derivative n23 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and 3-aminomethyl-pyridine. Beige crystals;
m.p. = 143C (isopropanol-diisopropyl ether). Yield:
73%. ~
6-(3-Pyridyl-methyl)aminocarbonyl-thieno~,2- ~pyridine Formula (I): NR R2 =~NHCH2 ~ ~ Derivative n24 This compound is prepared according to the ;
20 procedure of Example~3,~from 6-carboxy-thieno ~,2- ~-pyridlne~`and 3-amlnomethyl-pyridine. Beige crystals;~
E m.p.~= 137C (ethyl acetate). Yield~: 55%.
6-~(3-Trifluoromethyl-phenyl)aminocarbonyl-thieno ~ ,2- ~-~
pyridine Formula (I): NRlR = NH ~ ~ Derivative~n 25 Thi~s compound is prepared according to the~
procedure of Example l,~from 6-carboxy-thieno ~,2- ~-pyridine and m-trifluoromethylaniline. White crystals;~
30 m.p. = 151C (isopropanol-diisopropyl ether). Yield:
~ :
~;~ 62%.
:
.' . ' . . . .' , . ' . , , : . . ......... ;.', ,,: ' ' " ' , ,! ', , ,',' ' ' ' : , :. , :.:. : . . .. :: : , . ' , 3 "': '' '- ' '.' ~ ' ,' .. ' '. . ' ., . ' .. '.; .'.. ''. .. "" : '. . ' ' : ' : ., ' :' . . " ,' ~, :: ' :, ' , : ' ~ ' ;., . ' ' ',. ', ,.,' .;.: :. '" . , . ' ,.,. ;, `, , '.' I , . : " . ' , ' ,,:, . . .' 11267;~
6-(4-p.Tolyl-l-piperazinyl)carbonyl-thieno ~,2- ~pyri-din`e `
Formula (I): NR R = N~-~ ~ CH3 Derivative n26 This compound is prepared according to the procedure of Example 3, from 6--carboxy-thieno ~,2- ~-pyridine and l-p-tolyl-piperazine. Beige crystals;
m.p. = 150C (isopropanol-diisopropyl ether). Yield:
82%.
6-(4-o.Chlorophenyl-l-piperazinyl)carbonyl-thieno~ ,2- ~-pyridine Formula (I): NRlR = N~_~N ~ Derivative n 27 This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno ~,2- ~-pyridine and l-o.chlorophenyl-piperazine. Bei~e crystals; m.p. = 140C (isopropanol-diisopropyl ether).
Yield: 52%.
~` ` 20 6-(4-m.Chlorophenyl-l-piperazinyl)carbonyl-thieno ~,2- ~-pyridine ,Cl Formula (I): NR1R2~= N N ~ Derivative n28 This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno~ ,2- ~-pyridine and l-m.chlorophenyl-piperazine. White crystals; m.p. =~157C (ethyl acetate). Yield: 52%~
6-(4-p.Methoxyphenyl-l-piperazinyl)-thieno ~,2- ~pyri-` dine Formula (I): NRIR2 = N~-J ~ OCH3 Derivative n29 ;;
This compound is obtained according to the ; procedure of Example 3, from 6-caFboxy-~thieno ~,2~
':
~t .. . . ., . , ,. ,, . ., , . ., . , . , , ~ . . . .. .
., . ., . .. . . -, j; ~ , , - - ; , -i7 ~2 pyridine and l-p.methoxyphenyl-piperazine. White crystals; m.p. = 152C (ethyl acetate-diisopropyl ether).
Yield: 72%.
5-(4-o.Methoxyphenyl-l-piperazinyl)carbonyl-thieno-~,3- ~pyridine Formula (II): NR R = N~_JN ~ Derivative n 30 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and l-o.methoxyphenyl-piperazine. Bei~e crystals; m.p. = 171C (isopropanol). Yield: 62%.
6-Carbamoyl-thieno~ ,2- ~pyridine Formula (I): NRlR2 = NH2. Derivative n 31 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and ammonia. White crystals; m.p. = 172 C
(acetonitrile). Yield: 68%.
5-Carbamoyl-thieno ~,3- ~pyridine ,~
Formula (II): NRlR = NH2. Derivative n32 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and ammonia. White crystals; m.p. = 200C
(acetonitrile). Yield: 76%.
5-Phenethylaminocarbonyl-thieno ~,3- ~pyridine Formula (II) NR R2 = NHCH2CH2C6H5 Derivative n33 This compound is prepared according to the procedure of Example 1, from 5-carbonyl-thieno~,3- ~-pyridine and phenethylamine. Beige crystals; m.p. =
130C (isopropanol-diisopropyl ether). Yield: 79%.
.
;: , :- ~ .
, :
.: ,, : , .. - , ~ :
: . ,,' ~ . : :,' ~z~
6-(4-Benzy-l-l-piperazin~l)carbony-l-thieno~ ,2- ~pyridine _ .
Formula (I): NRlR2 = ~ N-CH2C6H5 . Derivative n 34 This compound is prepared according to the procedure o~ Example 3, from 6-carboxy-thieno ~,2- ~-pyridine and l-benzyl-piperazine. Dihydrochloride:
white crys-tals; m.p. = 187C (isopropanol-ethanol).
Yield: 49%.
6-(3,4-Dimethoxy-phenethyl)aminocarbonyl-thieno ~,2- ~-pyridine OCH
Formula (I): NR R = NHCH2CH2 ~ OCH3 Derivative n 35 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and (3,4-dimethoxy-phenethyl)amineO White crystals; m.p. = 125C (isopropanol-diisopropyl ether).
Yield: 77%.
5-(3 r 4-Dimethoxy-phenethyl)aminocarbonyl-thieno ~,3- ~-pyridine OCH
Formula (II) NR R = NHCH2CH2 ~ OCH3 Derivative n 36 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and (3,4-dimethoxy-phenethyl)amine. White crystals; m.p. = 125C (isopropanol-diisopropyl ether).
Yield: 73%.
3Q 6-(4-Methyl-l-piperazinyl)carbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N~_J - CH3 . Derivative n 37 This compound is prepared according to the . ~
- ~ : . : . - : ~ ::
,, ,~
~lZfi7;~
procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and l-methyl-piperazine. Maleate: brown powder;
m.p. = 168C (isopropanol). Y:ield: 83%.
The pharmacological and toxicological data reported below demonstrate the properties of the deriva-tives of this invention with respect both to their toxicity and their tolerance and to their activities, typically their sedative, anti-convulsant and anti-inflammatory activities.
Thus, this invention includes also within its scope a therapeutic composition having, in particular, sedative, anti-convulsant and anti-inflammatory activi-ties, comprising, as active ingredient, a derivative of the formula (I) or (II) or a pharmaceutically acceptable acid addition salt thereof, together with a therapeuti-cally administrable carrier.
I - TOXICOLOGICAL INVESTIGATION
The compounds of the formulae (I) and (II) benefit from an excellent tolerance and a low toxicity.
With respect to acute toxicity, the LD50/24 hrs/kg body weight, determined in mice according to the method disclosed by Miller and Tainter, by the oral route, is in excess of 400 mg for all derivatives.
According to the same method, the DL50/24 hrs/kg body weight, determined by the intravenous route, is, for example, 154 mg for derivative nl, 89 mg for derivative n2, 184 mg for derivative n10, 130 mg for derivative nll, 350 mg for derivative n12, 65 mg for derivative n18, 90 mg for derivative n22, 96 mg for derivative n24 and 105 mg for derivative n31.
In addition, the tests effected on acute, chronic, sub-chronic and delayed toxicity, in different animal species failed to evidence any local or systemic reaction, any perturbation or anomaly in the biochemical, microscopical or macroscopical examinations effected in ~, . .
~. : . . . .
- : : , ,: -, :
. ~ . : :: :
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~ ' '. :
.
;73~
the course of said experimentation.
II - P~ARMACOLOG:ICAL INVESTIGATION
1/ Sedative action A) Study of the behavior This investigation was effected according to the method disclosed by Samuel IRWIN (Ph. D. Animal and Clinical Pharmacology Technics in Drug Evaluation). The derivatives of the formulae (I) and (II) are orally administered to mice at a dosage of lOQ mg/kg. The lQ treated animals are observed during the 4 hours that follow administration of the active compound. Their behavior is studied and, in addition, the different physiological parameters (temperature, cardiac and respiratory rate) are determined. A marked decrease of motor activity and muscular tone, together with a decrease of the alertness and of the reactions to noise and to environment are noted in the treated animals.
B) Action on hypnotic drugs The compounds of the formulae (I) and (II) 2Q potentiate most markedly the action o~ hypnotic drugs.
Indeed, on oral administration to different groups of mice, at a dosage of lOQ mg/kg, 30 minutes prior to intraperitoneal injection of an infra-hypnotic dosage of sodium pentobarbital, they produce, with respect to the untreated reference animals, a marked potentiation of the action of the barbiturate.
Indeed, the number of sleeping mice, the average time to sleep and the duration of sleep are markedly increased in the treated groups. The results 3Q obtained with the more active compounds are tabulated in following Table I.
: .. , : .:
.
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TABLE I
Percent Average Average Treatment sleeping time to sleeping animals sleep time o (reference group) 0 Q 0 Derivative nl 70 8 mn 30 s 1 hr 30 mn Derivative n5 80 9 mn 15 s 1 hr 45 mn Derivative n6 80 8 mn 40 s 1 hr 48 mn Derivative n 1090 8 mn 25 s 1 hr 35 mn Derivative n 1590 8 mn 10 s 1 hr 50 mn Derivative n 1670 7 mn 50 s 1 hr 42 mn Derivative n18 80 9 mn 45 s 1 hr 38 mn Derivative n22 70 9 mn 20 s 1 hr 45 mn Derivative n23 80 7 mn 55 s 1 hr 50 mn Derivative n25 90 8 mn 10 s 1 hr 38 mn Derivative n26 90 8 mn 50 s 1 hr 35 mn Derivative n28 80 7 mn 45 s 1 hr 40 mn Derivative n29 90 8 mn 15 s 1 hr 47 mn 2/ Anti-convulsant action This action was studied with respect to electroshocks. In rats, application of an electrical stimulation in excess of the electro-convulsant thresh-old, produces experimental convulsions. The presence and duration of each convulsive phase and also the intensity of the overall seizure are compared in the reference animals and in the treated animals.
Groups of 10 rats are used per test material, and each animal is orally administered 100 mg/kg of said test material.
An electrode is positioned on either side of the basis of the tail of each animal and, 30 minutes after treatment, the animal, placed in a glass enclosure, is administered for 50 milliseconds a sinusoidal current of 50 periods/seconds of 120 volts.
:, , : .
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Passage of the current induces a convulsive seizure each phase of which (tonic, clonic, muscular relaxatlon~ is timed. The intensity of the seizure is then rated according to a scale from 0 to 4, depending on the presence of each one of the phases and their duration. The derivatives of the formulae (I) and (II) are tested comparatively with phenobarbital which pos-sesses a marked anti-convulsant action (intensity of the seizure = 2~, whereas in the untreated reference animals a maximum intensity of 4 is obtained.
It is thus determined that all the compounds of the formulae (I) and (II) produce substantial pro-tection aga;nst electroshock since the mean values of the intensity of the seizures within each group are 2.5 for derivative nl, 3 for derivative n4, 2.5 for derivative n5, 2.5 for derivative n9, 3 for derivative n13, 2.5 for derivative nl9, 2.5 for derivative n25, 2.5 for derivative n30 and 2.5 for derivative n31.
with an aqueous formaldehyde solution, in the presence of a strong acid.
The following non-limiting Examples are giyen to illustrate this invention.
EX~PLE 1 6-Methylaminocarbonyl-thieno ~,2- ~pyridine ,~
Formula (I): NRlR = NHCH . Derivative~ n 1 To a solution of 6-carboxy-thieno ~,2- ~pyri-10 dine (10 g; 0.050 mole) and triethylamine (5.6 g; 0.057 mole) in dry chloroform (500 cc) maintained~at 10C, i9 slowly added ethyl chloroformate (6.2 ~; 0.057 mole),~
with vigorous stirring. When addition is complete, stirring is continued at room temperature for a further 40~minutes, after which a solution of methylamlne (~ g;
0.064 mole) in~benzène (50 cc) is~added dropwise thereto. ~--~ ~ The reaction mixture is then left aside at;room tempera-~; ture for 4 hours,~evaporated to dryness,~and the residue is taken up into ether. The ether phase~is washed with~
a saturated;aqueous sodium carbonate~solution, dried~
over~sodium sulfate and evaporated to dryness.
The solid residue is recrystallized from benzene-dlisopropyl ether. ~Plnkl~sh crystals; m.p. =
99C.~ Yield: 79%. ~
6-~-Dimethylaminoethy~laminocarbonyl-thieno ~,2- ~pyri-dine Formula (I) NR R =~NH(CH2)2N(cH3)2 Derivative n2 ~ ~;
To a solution of 6-carboxy-thieno ~,2-~pyri-30 dine tl0 g; 0.056 mole) ànd triethylamine t5.6 g; 0.057 mole) in dry~chloroform t300 cc) malntained at 10C~, is slowly added ethyl chloroformate t6.2 g; 0.057 mole3 i7~
with vigorous stirring. On completion of the addition, stirring is continued at room temperature for a further 40 minutes, after which ~-dimethylaminoethylamine (5.4 g;
0.061 mole) is added dropwise. The reaction mixture is left aside at room temperature Eor 3.5 hours; it is then evaporated to dryness and the residue is taken up into N
hydrochloric acid. The acid aqueous phase is washed with ether and is then made alkaline with 6N sodium hydroxide and extracted with methylene chloride. The methylene chloride extracts are dried over dry sodium sulfate and evaporated to dryness. The oily residue is - purified via its dihydrochloride. Beige crystals; m.p.
= 170C (isopropanol-methanol). Yield: 75%.
5-t4-p.Chlorophenyl-l-piperazinyl)carbonyl-thieno-~,3- ~pyridine Formula (II): NR R = N N ~ Cl. Derivative n3 To a solution of 5-carboxy-thieno ~,3- ~pyri-dine (12 g; 0.067 mole) and triethylamine (6.9 g; 0.068 20 mole) in dry chloroform (250 cc) maintained at 10C, is slowly added ethyl chloroformate (7.3 g; 0.068 mole), with vigorous stirring. Stirring is then continued at ~; ~ room temperature for 50 minutes and p-chlorophenyl piperazine (13.2 g; 0.067 mole) dissolved in chloroform (50 cc) is then added dropwise. The reaction mixture is left aside at room temperature for 5 hours, after which it is evaporated to dryness and the residue is taken up into methylene chloride. The methylene chloride phase is washed with a saturated aqueous sodium bicarbonate solution, dried over dry sodium sulfate and evaporated to dryness. The resulting crystals are purified by ~;~ column chromatography through silica (eluent: ethyl acetate). White crystals, m.p. = 170C (isopropanol-diisopropyl ether). Yield: 41%.
: :
:~6.~
6-Ethylaminocarbonyl-thieno~ ,2- ~pyridine Formula (I): NRlR = NHC2H5. Derivative n4 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and ethylamine. Beige crystals; m.p. = 110C
(diisopropyl ether3. Yield: 87%.
5-Isopropylaminocarbonyl-thieno ~,3- ~pyridine Formula (II): NRlR2 = NHC3H7. Derivative n5 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-~; pyridine and isopropylamine. Light brown crystals, m.p. = 102C (diisopropyl ether). Yield: 80%.
6-n.Butylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHC4Hg. Derivative n6 This compound is prepared according;to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and n-butylamine. Hydrochloride: orange-yellow ; crystals, m.p. 104C (acetonitrile). Yield: 55%.
6-Octylaminocarbonyl-thieno ~,2- ~pyrldine ~;~ Formula (I): NRlR = NHC8H17. Derivative~n7 This compound is prepared according to the procedure of Example~l, from 6-carboxy-thieno ~,2- ~-pyridine and octylamine. White crystals, m.p. = 63C
(diisopropyl ether)~. ~Yl~eld: 54~
; EXAMPLE 8 6-Dimethylaminocarbonyl-thieno ~ ,2- ~pyridine FormuIa (I): NRlR = N(CH3)2. Derivative n 8 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and dimethylamine. White crystals; m.p. = 93C
(diisopropyl ether). Yield: 55%.
; ~: : :
: :
~2f~f73Z
6-Diethylaminocarbonyl-thieno ~,2-~/'pyridine Formula (I) NR R = N(C2H5)2 Derivative n9 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and diethylamine. Beige-crystals; m.p. = 119C
(diisopropyl ether). Yield: 80%.
6-(l-Pyrrolidinyljcarbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N~ Derivative n 10 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2-~/'-pyridine and pyrrolidine. Off-white crystals; m.p. =
105 & (diisopropyl ether). Yield: 52%.
6-Piperidinocarbonyl-thieno ~ ,2- ~ pyridine !
Formula ~I): NRlR2 = ~ Derivative n 11 f This compound is prepared according to the proeedure of Example 1, from 6-earboxy-thieno ~, 2-~f'-pyridine and piperidine. Light brown powder; m.p. =
145C (diisopropyl ether). Yield: 96%.
6-Morpholinocarbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N O Derivative n 12 ~ ~
\ :
This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and morpholine. White crystals; m.p. = 136C
(benzene-diisopropyl ether). Yield: 79%.
30 5-Benzylaminocarbonyl-thieno ~,3-~/'pyridine Formula (II): NR R = NHCH2C6H5. Derivative n 13 :: :
: . ~
, .
i~2~i73~
This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and benzylamine. Beige crystals; m.p. = 113C
(isopropanol). Yield: 75%.
6-o.Chlorobenzylaminocarbonyl-thieno~,2- ~p~ridine Formula (I): NR R = NHCH2 ~ Derivative n 14 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and o.chlorobenzylamine. Beige powder; m.p. =169C (methanol). Yield: 58%.
6-Phenethylaminocarbonyl-thieno~,2- ~pyridine Formula (I) NRlR2 = NHCH2CH2C6~5 Derivative n15 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and phenethylamine. Beige crystals; m.p. =
127C (isopropanol-diisopropyl ether). Yield 66%.
6-Allylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHCH2-CH=CH2. Derivative n 16 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and allylamine. Oxalate: white crystals; ;~
m.p. = 131& (ethyl acetate). Yield: 54%.
6-Propargylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NHCH2C_CH. Derivative n 17 This compound is prèpared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and propargylamine. Pinkish crystals, m.p. =
134C (isopropanol-diisopropyl etber). YieLd: 60%.
~121~i73~
g 6-~-Diethylaminoethylaminocarbonyl-thieno~,2- ~pyridine Formula (I): NRlR = NH(CH2~2N(C2H5)2. Derivative n 18 This compound i5 prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and ~-diethylaminoethylamine. Dihydrochloride:
beige crystals; m.p. = 145C (:isopropanol-methanol).
Yield: 81%.
6-~-Morpholinoethylaminocarbonyl-thieno ~,2- ~pyridine Formula (I): NRlR2 = NH(CH2)2N 3 Derivative n 19 This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and N-(2-aminoethyl)-morpholine. White crystals; m.p. = 104C (isopropanol-diisopropyl ether).
Yield: 71%.
6-y-Dimethylaminopropylaminocarbonyl-thieno ~,2- ~pyri-dine Formula (I): NRlR = NH(CH2)3N(CH3)2. Derivative n20 This compound is prepared according to the procedure of Example 2, from 6-carboxy-thieno ~,2- ~-pyridine and y-dimethylaminopropylamine. Dihydro-chloride: beige crystals; m.p. = 146C (ethanol).
Yield: 77%. ~ ;
5-(4-Pyridyl-methyl)aminocarbonyl-thieno ~,3- ~pyridine Formula (II): NR R = NHCH ~ N Derivative n 21 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and 4-aminomethyl-pyridine. Light brown crystals; m.p. = 167C (isopropanol-diisopropyl ether).
Yield: 78%.
~ ~ .
.. . . . . .... .. . .... . . . . . . .. ~ .. . . .
.. .. . . . .. .. . .. . ... .. . .. . . . ..
i732 6-(4-Pyridyl-meth~yl)aminocarbonyl-thieno~,2- ~pyridine 1 2 ~
Formula (I): NR R = NHCH2 ~ N Derivative n22 This c~mpound is prepared according to the procedure of Example 3, from 6-carboxy-thieno ~,2- ~_ pyridine and 4-aminomethyl-pyridine. Orange crystals;
m.p. = 146C (ethyl acetate). Yield: 98%.
5-~3-Pyridyl-methyl)aminocarbonyl-thieno ~,3- ~pyridine ; 10 Formula (III): NR R = NHCH2 ~ Derivative n23 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and 3-aminomethyl-pyridine. Beige crystals;
m.p. = 143C (isopropanol-diisopropyl ether). Yield:
73%. ~
6-(3-Pyridyl-methyl)aminocarbonyl-thieno~,2- ~pyridine Formula (I): NR R2 =~NHCH2 ~ ~ Derivative n24 This compound is prepared according to the ;
20 procedure of Example~3,~from 6-carboxy-thieno ~,2- ~-pyridlne~`and 3-amlnomethyl-pyridine. Beige crystals;~
E m.p.~= 137C (ethyl acetate). Yield~: 55%.
6-~(3-Trifluoromethyl-phenyl)aminocarbonyl-thieno ~ ,2- ~-~
pyridine Formula (I): NRlR = NH ~ ~ Derivative~n 25 Thi~s compound is prepared according to the~
procedure of Example l,~from 6-carboxy-thieno ~,2- ~-pyridine and m-trifluoromethylaniline. White crystals;~
30 m.p. = 151C (isopropanol-diisopropyl ether). Yield:
~ :
~;~ 62%.
:
.' . ' . . . .' , . ' . , , : . . ......... ;.', ,,: ' ' " ' , ,! ', , ,',' ' ' ' : , :. , :.:. : . . .. :: : , . ' , 3 "': '' '- ' '.' ~ ' ,' .. ' '. . ' ., . ' .. '.; .'.. ''. .. "" : '. . ' ' : ' : ., ' :' . . " ,' ~, :: ' :, ' , : ' ~ ' ;., . ' ' ',. ', ,.,' .;.: :. '" . , . ' ,.,. ;, `, , '.' I , . : " . ' , ' ,,:, . . .' 11267;~
6-(4-p.Tolyl-l-piperazinyl)carbonyl-thieno ~,2- ~pyri-din`e `
Formula (I): NR R = N~-~ ~ CH3 Derivative n26 This compound is prepared according to the procedure of Example 3, from 6--carboxy-thieno ~,2- ~-pyridine and l-p-tolyl-piperazine. Beige crystals;
m.p. = 150C (isopropanol-diisopropyl ether). Yield:
82%.
6-(4-o.Chlorophenyl-l-piperazinyl)carbonyl-thieno~ ,2- ~-pyridine Formula (I): NRlR = N~_~N ~ Derivative n 27 This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno ~,2- ~-pyridine and l-o.chlorophenyl-piperazine. Bei~e crystals; m.p. = 140C (isopropanol-diisopropyl ether).
Yield: 52%.
~` ` 20 6-(4-m.Chlorophenyl-l-piperazinyl)carbonyl-thieno ~,2- ~-pyridine ,Cl Formula (I): NR1R2~= N N ~ Derivative n28 This compound is prepared according to the procedure of Example 3, from 6-carboxy-thieno~ ,2- ~-pyridine and l-m.chlorophenyl-piperazine. White crystals; m.p. =~157C (ethyl acetate). Yield: 52%~
6-(4-p.Methoxyphenyl-l-piperazinyl)-thieno ~,2- ~pyri-` dine Formula (I): NRIR2 = N~-J ~ OCH3 Derivative n29 ;;
This compound is obtained according to the ; procedure of Example 3, from 6-caFboxy-~thieno ~,2~
':
~t .. . . ., . , ,. ,, . ., , . ., . , . , , ~ . . . .. .
., . ., . .. . . -, j; ~ , , - - ; , -i7 ~2 pyridine and l-p.methoxyphenyl-piperazine. White crystals; m.p. = 152C (ethyl acetate-diisopropyl ether).
Yield: 72%.
5-(4-o.Methoxyphenyl-l-piperazinyl)carbonyl-thieno-~,3- ~pyridine Formula (II): NR R = N~_JN ~ Derivative n 30 This compound is prepared according to the procedure of Example 3, from 5-carboxy-thieno ~,3- ~-pyridine and l-o.methoxyphenyl-piperazine. Bei~e crystals; m.p. = 171C (isopropanol). Yield: 62%.
6-Carbamoyl-thieno~ ,2- ~pyridine Formula (I): NRlR2 = NH2. Derivative n 31 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno ~,2- ~-pyridine and ammonia. White crystals; m.p. = 172 C
(acetonitrile). Yield: 68%.
5-Carbamoyl-thieno ~,3- ~pyridine ,~
Formula (II): NRlR = NH2. Derivative n32 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and ammonia. White crystals; m.p. = 200C
(acetonitrile). Yield: 76%.
5-Phenethylaminocarbonyl-thieno ~,3- ~pyridine Formula (II) NR R2 = NHCH2CH2C6H5 Derivative n33 This compound is prepared according to the procedure of Example 1, from 5-carbonyl-thieno~,3- ~-pyridine and phenethylamine. Beige crystals; m.p. =
130C (isopropanol-diisopropyl ether). Yield: 79%.
.
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6-(4-Benzy-l-l-piperazin~l)carbony-l-thieno~ ,2- ~pyridine _ .
Formula (I): NRlR2 = ~ N-CH2C6H5 . Derivative n 34 This compound is prepared according to the procedure o~ Example 3, from 6-carboxy-thieno ~,2- ~-pyridine and l-benzyl-piperazine. Dihydrochloride:
white crys-tals; m.p. = 187C (isopropanol-ethanol).
Yield: 49%.
6-(3,4-Dimethoxy-phenethyl)aminocarbonyl-thieno ~,2- ~-pyridine OCH
Formula (I): NR R = NHCH2CH2 ~ OCH3 Derivative n 35 This compound is prepared according to the procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and (3,4-dimethoxy-phenethyl)amineO White crystals; m.p. = 125C (isopropanol-diisopropyl ether).
Yield: 77%.
5-(3 r 4-Dimethoxy-phenethyl)aminocarbonyl-thieno ~,3- ~-pyridine OCH
Formula (II) NR R = NHCH2CH2 ~ OCH3 Derivative n 36 This compound is prepared according to the procedure of Example 1, from 5-carboxy-thieno ~,3- ~-pyridine and (3,4-dimethoxy-phenethyl)amine. White crystals; m.p. = 125C (isopropanol-diisopropyl ether).
Yield: 73%.
3Q 6-(4-Methyl-l-piperazinyl)carbonyl-thieno ~,2- ~pyridine Formula (I): NR R = N~_J - CH3 . Derivative n 37 This compound is prepared according to the . ~
- ~ : . : . - : ~ ::
,, ,~
~lZfi7;~
procedure of Example 1, from 6-carboxy-thieno~,2- ~-pyridine and l-methyl-piperazine. Maleate: brown powder;
m.p. = 168C (isopropanol). Y:ield: 83%.
The pharmacological and toxicological data reported below demonstrate the properties of the deriva-tives of this invention with respect both to their toxicity and their tolerance and to their activities, typically their sedative, anti-convulsant and anti-inflammatory activities.
Thus, this invention includes also within its scope a therapeutic composition having, in particular, sedative, anti-convulsant and anti-inflammatory activi-ties, comprising, as active ingredient, a derivative of the formula (I) or (II) or a pharmaceutically acceptable acid addition salt thereof, together with a therapeuti-cally administrable carrier.
I - TOXICOLOGICAL INVESTIGATION
The compounds of the formulae (I) and (II) benefit from an excellent tolerance and a low toxicity.
With respect to acute toxicity, the LD50/24 hrs/kg body weight, determined in mice according to the method disclosed by Miller and Tainter, by the oral route, is in excess of 400 mg for all derivatives.
According to the same method, the DL50/24 hrs/kg body weight, determined by the intravenous route, is, for example, 154 mg for derivative nl, 89 mg for derivative n2, 184 mg for derivative n10, 130 mg for derivative nll, 350 mg for derivative n12, 65 mg for derivative n18, 90 mg for derivative n22, 96 mg for derivative n24 and 105 mg for derivative n31.
In addition, the tests effected on acute, chronic, sub-chronic and delayed toxicity, in different animal species failed to evidence any local or systemic reaction, any perturbation or anomaly in the biochemical, microscopical or macroscopical examinations effected in ~, . .
~. : . . . .
- : : , ,: -, :
. ~ . : :: :
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.
;73~
the course of said experimentation.
II - P~ARMACOLOG:ICAL INVESTIGATION
1/ Sedative action A) Study of the behavior This investigation was effected according to the method disclosed by Samuel IRWIN (Ph. D. Animal and Clinical Pharmacology Technics in Drug Evaluation). The derivatives of the formulae (I) and (II) are orally administered to mice at a dosage of lOQ mg/kg. The lQ treated animals are observed during the 4 hours that follow administration of the active compound. Their behavior is studied and, in addition, the different physiological parameters (temperature, cardiac and respiratory rate) are determined. A marked decrease of motor activity and muscular tone, together with a decrease of the alertness and of the reactions to noise and to environment are noted in the treated animals.
B) Action on hypnotic drugs The compounds of the formulae (I) and (II) 2Q potentiate most markedly the action o~ hypnotic drugs.
Indeed, on oral administration to different groups of mice, at a dosage of lOQ mg/kg, 30 minutes prior to intraperitoneal injection of an infra-hypnotic dosage of sodium pentobarbital, they produce, with respect to the untreated reference animals, a marked potentiation of the action of the barbiturate.
Indeed, the number of sleeping mice, the average time to sleep and the duration of sleep are markedly increased in the treated groups. The results 3Q obtained with the more active compounds are tabulated in following Table I.
: .. , : .:
.
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TABLE I
Percent Average Average Treatment sleeping time to sleeping animals sleep time o (reference group) 0 Q 0 Derivative nl 70 8 mn 30 s 1 hr 30 mn Derivative n5 80 9 mn 15 s 1 hr 45 mn Derivative n6 80 8 mn 40 s 1 hr 48 mn Derivative n 1090 8 mn 25 s 1 hr 35 mn Derivative n 1590 8 mn 10 s 1 hr 50 mn Derivative n 1670 7 mn 50 s 1 hr 42 mn Derivative n18 80 9 mn 45 s 1 hr 38 mn Derivative n22 70 9 mn 20 s 1 hr 45 mn Derivative n23 80 7 mn 55 s 1 hr 50 mn Derivative n25 90 8 mn 10 s 1 hr 38 mn Derivative n26 90 8 mn 50 s 1 hr 35 mn Derivative n28 80 7 mn 45 s 1 hr 40 mn Derivative n29 90 8 mn 15 s 1 hr 47 mn 2/ Anti-convulsant action This action was studied with respect to electroshocks. In rats, application of an electrical stimulation in excess of the electro-convulsant thresh-old, produces experimental convulsions. The presence and duration of each convulsive phase and also the intensity of the overall seizure are compared in the reference animals and in the treated animals.
Groups of 10 rats are used per test material, and each animal is orally administered 100 mg/kg of said test material.
An electrode is positioned on either side of the basis of the tail of each animal and, 30 minutes after treatment, the animal, placed in a glass enclosure, is administered for 50 milliseconds a sinusoidal current of 50 periods/seconds of 120 volts.
:, , : .
: , : .: , ~ :~
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Passage of the current induces a convulsive seizure each phase of which (tonic, clonic, muscular relaxatlon~ is timed. The intensity of the seizure is then rated according to a scale from 0 to 4, depending on the presence of each one of the phases and their duration. The derivatives of the formulae (I) and (II) are tested comparatively with phenobarbital which pos-sesses a marked anti-convulsant action (intensity of the seizure = 2~, whereas in the untreated reference animals a maximum intensity of 4 is obtained.
It is thus determined that all the compounds of the formulae (I) and (II) produce substantial pro-tection aga;nst electroshock since the mean values of the intensity of the seizures within each group are 2.5 for derivative nl, 3 for derivative n4, 2.5 for derivative n5, 2.5 for derivative n9, 3 for derivative n13, 2.5 for derivative nl9, 2.5 for derivative n25, 2.5 for derivative n30 and 2.5 for derivative n31.
3/ Anti-inflammatory action A) Method of the localized carrageenin-induced edema A 1% carrageenin solution (0.1 ml) is injected at time 0 in the metatarsal flexor muscles of the right rear limb of rats. The animals of the treated group are additionally orally administered 100 mg/kg oE the test material, respectively 1 hour prior to, simultaneously with, and then 1 hour and 2.5 hours after injection of the phlogogenic agent. The percent anti-inflammatory activity is determined as a function of time, with respect to the reference group, by the determinations effected with a ROCH micrometer at times 0, 1 hr, 2 hrs, 3 hrs and 5 hrs after carrageenin administration.
The results obtained with derivatives of the formula (I~ or (II) are set forth in following Table II.
. ~
.~,, ;7~2 ~ 18 -TABLE II
Derivative n Percent anti-inflammatory activity after 1 hour 2 hours 3 hours 5 hours
The results obtained with derivatives of the formula (I~ or (II) are set forth in following Table II.
. ~
.~,, ;7~2 ~ 18 -TABLE II
Derivative n Percent anti-inflammatory activity after 1 hour 2 hours 3 hours 5 hours
4 41 46 50 58 s) Method of the ovalbumin-induced systemic edema A simultaneous intraperitoneal injection of 1 ml ovalbumin and of 0.5 ml of a 1% Evans blue solution is effected in rats. On the other hand, the animals of the treated group are orally administered 100 mg/kg of the test derivative one hour prior to and simultaneously with the ovalbumin administration. The intensity of the phenomenon thus induced is rated according to a scale from 1 to 5, depending on the progress of the inflamma-tory syndrome. The mean edematous intensity and the percent decrease of the edematous reaction, with respect to the controls, are thus determined as a function of time.
The percent anti-inflamma-tory activity ob-tained 2 and 3 hours after ovalbumin injection is set forth in following Table III for some derivatives of the formula (I) or (II).
. . .
31.1;~i73~
TABLE III
Derivative n Percent anti-inflammatory activity after 2 hours 3 hours The results of said investigations provide evidence of the low toxicity and good tolerance, and also of the useful sedative, anti-convulsant and anti-inflammatory properties of the derivatives of the formula (I) or (II) that make them most valuable in human and veterinary medicine.
The composition of this invention may be formulated, for oral administration/ as tablets, coated tablets, capsules, drops and syrups. It may also be formulated: for rectal administration, as suppositories and, for parenteral administration, as injectable solutions.
Each unit dose will advantageously contain from 0.050 g to 0.500 g active ingredient. The daily dosage regimen may vary from 0.050 g to 1.50 g active ingredient, depending on the age of the patient and on the condition treated.
- . .
J.~Z~;7~%
Non-limiting Examples of pharmaceutical formu-lations of the therapeutic composition of this invention are given below.
Derivative n 1 . . . . . . . . . . 0.250 g Excipient: corn starch, magnesium stearate, stearic acid Derivative n 5 . . . . . . . . . . 0.150 g Excipient: magnesium stearate, corn starch, gum arabic, shellac, sugar, glucose, white wax, carnauba wax;
lactose, castor oil, alcohol, tartrazine-aluminum lacquer.
Derivative n13 . . . . . . . . . 0.100 g Excipient: magnesium stearate, corn starch, lactose.
Derivative n 24 . . . . . . . . . 0.150 g Semi-synthetic triglycerides, sufficient to make 1 suppository.
The percent anti-inflamma-tory activity ob-tained 2 and 3 hours after ovalbumin injection is set forth in following Table III for some derivatives of the formula (I) or (II).
. . .
31.1;~i73~
TABLE III
Derivative n Percent anti-inflammatory activity after 2 hours 3 hours The results of said investigations provide evidence of the low toxicity and good tolerance, and also of the useful sedative, anti-convulsant and anti-inflammatory properties of the derivatives of the formula (I) or (II) that make them most valuable in human and veterinary medicine.
The composition of this invention may be formulated, for oral administration/ as tablets, coated tablets, capsules, drops and syrups. It may also be formulated: for rectal administration, as suppositories and, for parenteral administration, as injectable solutions.
Each unit dose will advantageously contain from 0.050 g to 0.500 g active ingredient. The daily dosage regimen may vary from 0.050 g to 1.50 g active ingredient, depending on the age of the patient and on the condition treated.
- . .
J.~Z~;7~%
Non-limiting Examples of pharmaceutical formu-lations of the therapeutic composition of this invention are given below.
Derivative n 1 . . . . . . . . . . 0.250 g Excipient: corn starch, magnesium stearate, stearic acid Derivative n 5 . . . . . . . . . . 0.150 g Excipient: magnesium stearate, corn starch, gum arabic, shellac, sugar, glucose, white wax, carnauba wax;
lactose, castor oil, alcohol, tartrazine-aluminum lacquer.
Derivative n13 . . . . . . . . . 0.100 g Excipient: magnesium stearate, corn starch, lactose.
Derivative n 24 . . . . . . . . . 0.150 g Semi-synthetic triglycerides, sufficient to make 1 suppository.
5 - INJECTABLE SOLUTION
Derivative n31 . . . . . . . . . 0.100 g Isotonic solvent, sufficient to make 5 ml Due to their sedative and anti-convulsant action, the derivatives of the formula (I) or (II) reduce personality and behavioral disorders and facili-tate personal contacts because of improved mental equi-librium. They are applicable in children and adults in cases of aggressiveness, irritability, instability, excitation, and psychomotor agitation, and also in all manifestations of excitability.
Due to their anti-inflammatory action, when administered for short or extended treatments, they act efficiently on the inflammatory reaction to control edema, hypersecretion and exudation in the course of the different stages of inflammation. They are indicated in cases of chronic inflammatory rheumatism, degenerative - . . . - :: :
:. .. :: ~ :
~267;~%
rheumatism, ab-articular conditions, acute gout, in post-operative plastic surgery, in traumatology and in oto-rhinolaryngology.
Derivative n31 . . . . . . . . . 0.100 g Isotonic solvent, sufficient to make 5 ml Due to their sedative and anti-convulsant action, the derivatives of the formula (I) or (II) reduce personality and behavioral disorders and facili-tate personal contacts because of improved mental equi-librium. They are applicable in children and adults in cases of aggressiveness, irritability, instability, excitation, and psychomotor agitation, and also in all manifestations of excitability.
Due to their anti-inflammatory action, when administered for short or extended treatments, they act efficiently on the inflammatory reaction to control edema, hypersecretion and exudation in the course of the different stages of inflammation. They are indicated in cases of chronic inflammatory rheumatism, degenerative - . . . - :: :
:. .. :: ~ :
~267;~%
rheumatism, ab-articular conditions, acute gout, in post-operative plastic surgery, in traumatology and in oto-rhinolaryngology.
Claims (5)
1. Process for the preparation of compounds having the formula:
or (I) (II) in which R1 and R2 are:
hydrogen;
alkyl containing 1 to 8 carbon atoms;
cycloalkyl containing 3 to 6 carbon atoms;
alkenyl containing 2 to 6 carbon atoms;
alkynyl containing 2 to 6 carbon atoms;
phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl phenylalkyl wherein the alkyl group contains 1 to 4 carbon atoms and wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl;
pyridyl;
pyridylalkyl wherein the alkyl group containing 1 to 4 carbon atoms; and wherein n is 2 or 3; and wherein R3 and R4 are alkyl containing 1 to 4 carbon atoms or R3 and R4 together with the nitrogen atom to which they are attached for a heterocyclic group containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry an alkyl group containing 1 to 4 carbon atoms;
R1 and R2 together with the nitrogen atom to which they are attached may form a heterocyclic containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry:
lower alkyl benzyl wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl; and phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl and their pharmaceutically acceptable acid addition salts, comprising reacting an amine having the formula:
in which R1 and R2 are as defined above, with a mixed anhydride having the formula (III) or (IV) in which R is a C1-3 alkyl group:
or (III) (IV) to give a derivative of the formula (I) or (II), respectively.
or (I) (II) in which R1 and R2 are:
hydrogen;
alkyl containing 1 to 8 carbon atoms;
cycloalkyl containing 3 to 6 carbon atoms;
alkenyl containing 2 to 6 carbon atoms;
alkynyl containing 2 to 6 carbon atoms;
phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl phenylalkyl wherein the alkyl group contains 1 to 4 carbon atoms and wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl;
pyridyl;
pyridylalkyl wherein the alkyl group containing 1 to 4 carbon atoms; and wherein n is 2 or 3; and wherein R3 and R4 are alkyl containing 1 to 4 carbon atoms or R3 and R4 together with the nitrogen atom to which they are attached for a heterocyclic group containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry an alkyl group containing 1 to 4 carbon atoms;
R1 and R2 together with the nitrogen atom to which they are attached may form a heterocyclic containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry:
lower alkyl benzyl wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl; and phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl and their pharmaceutically acceptable acid addition salts, comprising reacting an amine having the formula:
in which R1 and R2 are as defined above, with a mixed anhydride having the formula (III) or (IV) in which R is a C1-3 alkyl group:
or (III) (IV) to give a derivative of the formula (I) or (II), respectively.
2. Process as claimed in Claim 1, wherein thienopyridines of the formula (V) or (VI) or (V) (VI) are condensed, in the presence of triethylamine, with an alkyl chloroformate having the formula ClCOOR in which R
has the meaning given in Claim 1, to give the compounds of the formula (III) or (IV), respectively.
has the meaning given in Claim 1, to give the compounds of the formula (III) or (IV), respectively.
3. Process as claimed in Claim 1, wherein the reaction is effected within an inert solvent at a temperature between -5°C and +15°C.
4. Process as claimed in Claim 2, wherein the reaction is effected within an inert solvent, at a temperature between -5°C and +15°C.
5. Compounds having the formula:
or (I) (II) in which R1 and R2 are:
hydrogen;
alkyl containing 1 to 8 carbon atoms;
cycloalkyl containing 3 to 6 carbon atoms;
alkenyl containing 2 to 6 carbon atoms;
alkynyl containing 2 to 6 carbon atoms;
phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl phenylalkyl wherein the alkyl group contains 1 to 4 carbon atoms and wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl;
pyridyl;
pyridylalkyl wherein the alkyl group containing 1 to 4 carbon atoms; and wherein n is 2 or 3; and wherein R3 and R4 are alkyl containing 1 to 4 carbon atoms or R3 and R4 together with the nitrogen atom to which they are attached for a heterocyclic group containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry an alkyl group containing 1 to 4 carbon atoms;
R1 and R2 together with the nitrogen atom to which they are attached may form a heterocyclic containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry:
lower alkyl benzyl wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl; and phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl and their pharmaceutically acceptable acid addition salts, whenever obtained by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
or (I) (II) in which R1 and R2 are:
hydrogen;
alkyl containing 1 to 8 carbon atoms;
cycloalkyl containing 3 to 6 carbon atoms;
alkenyl containing 2 to 6 carbon atoms;
alkynyl containing 2 to 6 carbon atoms;
phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl phenylalkyl wherein the alkyl group contains 1 to 4 carbon atoms and wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy;
hydroxy; and trifluoromethyl;
pyridyl;
pyridylalkyl wherein the alkyl group containing 1 to 4 carbon atoms; and wherein n is 2 or 3; and wherein R3 and R4 are alkyl containing 1 to 4 carbon atoms or R3 and R4 together with the nitrogen atom to which they are attached for a heterocyclic group containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry an alkyl group containing 1 to 4 carbon atoms;
R1 and R2 together with the nitrogen atom to which they are attached may form a heterocyclic containing 5 to 6 carbon atoms and which may carry, as a second heteroatom O, S or N which may carry:
lower alkyl benzyl wherein the phenyl group may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl; and phenyl which may be substituted with:
halogen;
lower alkyl;
lower alkoxy; and trifluoromethyl and their pharmaceutically acceptable acid addition salts, whenever obtained by a process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7804561A FR2417512A1 (en) | 1978-02-17 | 1978-02-17 | THIENO (3,2-C) AND THIENO (2,3-C) PYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THERAPEUTICS |
| FR7804561 | 1978-02-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1126732A true CA1126732A (en) | 1982-06-29 |
Family
ID=9204729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA321,393A Expired CA1126732A (en) | 1978-02-17 | 1979-02-13 | Thieno(3,2-c)- and thieno(2,3-c)pyridines, process for their preparation and therapeutic composition containing them |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP0003920B1 (en) |
| JP (1) | JPS54157599A (en) |
| AR (1) | AR227623A1 (en) |
| AT (1) | AT369369B (en) |
| AU (1) | AU519318B2 (en) |
| BE (1) | BE874228A (en) |
| CA (1) | CA1126732A (en) |
| CH (1) | CH635844A5 (en) |
| DD (1) | DD142053A5 (en) |
| DE (1) | DE2960109D1 (en) |
| DK (1) | DK146046C (en) |
| ES (1) | ES477401A1 (en) |
| FI (1) | FI66872C (en) |
| FR (1) | FR2417512A1 (en) |
| GB (1) | GB2014576B (en) |
| GR (1) | GR66844B (en) |
| HU (1) | HU178075B (en) |
| IE (1) | IE47789B1 (en) |
| IL (1) | IL56541A (en) |
| IT (1) | IT1115001B (en) |
| LU (1) | LU80861A1 (en) |
| MX (1) | MX5588E (en) |
| NO (1) | NO150483C (en) |
| NZ (1) | NZ189638A (en) |
| PH (1) | PH15171A (en) |
| PL (1) | PL117264B1 (en) |
| PT (1) | PT69220A (en) |
| RO (1) | RO76642A (en) |
| SU (1) | SU810081A3 (en) |
| YU (1) | YU26879A (en) |
| ZA (1) | ZA79513B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2525595A1 (en) * | 1982-04-27 | 1983-10-28 | Pharmuka Lab | NOVEL ARENE AND HETEROARENECARBOXAMIDE DERIVATIVES AND THEIR USE AS MEDICAMENTS |
| DE3621413A1 (en) * | 1986-06-26 | 1988-01-07 | Boehringer Ingelheim Kg | USE OF CARBOCYCLIC AND HETEROCYCLICALLY FURNISHED DIHYDROPYRIDINE AS A CARDIOPROTECTIVE AGENT AND NEW HETEROCYCLIC AND CARBOCYCLICALLY FURNISHED DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND ITS ADDITIONAL PRODUCTS |
| EP0285671B1 (en) * | 1986-10-13 | 2003-09-03 | Asahi Kasei Kabushiki Kaisha | Pyridine derivatives |
| CN101815718A (en) * | 2007-08-10 | 2010-08-25 | 克里斯捷诺米有限公司 | Pyridine derivate and using method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3845065A (en) * | 1972-02-18 | 1974-10-29 | Merck & Co Inc | 4-oxo-4,5-dihydrothieno(3,2-c)pyridines |
-
1978
- 1978-02-17 FR FR7804561A patent/FR2417512A1/en active Granted
-
1979
- 1979-01-26 EP EP79400053A patent/EP0003920B1/en not_active Expired
- 1979-01-26 DE DE7979400053T patent/DE2960109D1/en not_active Expired
- 1979-01-29 CH CH84479A patent/CH635844A5/en not_active IP Right Cessation
- 1979-01-30 GR GR58210A patent/GR66844B/el unknown
- 1979-01-30 IL IL56541A patent/IL56541A/en unknown
- 1979-01-30 IE IE163/79A patent/IE47789B1/en not_active IP Right Cessation
- 1979-01-31 LU LU80861A patent/LU80861A1/en unknown
- 1979-02-02 AU AU43897/79A patent/AU519318B2/en not_active Ceased
- 1979-02-02 ES ES477401A patent/ES477401A1/en not_active Expired
- 1979-02-06 ZA ZA79513A patent/ZA79513B/en unknown
- 1979-02-07 AR AR275419A patent/AR227623A1/en active
- 1979-02-07 DK DK50279A patent/DK146046C/en not_active IP Right Cessation
- 1979-02-07 YU YU00268/79A patent/YU26879A/en unknown
- 1979-02-09 RO RO7996565A patent/RO76642A/en unknown
- 1979-02-09 AT AT0098679A patent/AT369369B/en not_active IP Right Cessation
- 1979-02-12 FI FI790460A patent/FI66872C/en not_active IP Right Cessation
- 1979-02-13 NZ NZ189638A patent/NZ189638A/en unknown
- 1979-02-13 PT PT7969220A patent/PT69220A/en unknown
- 1979-02-13 CA CA321,393A patent/CA1126732A/en not_active Expired
- 1979-02-14 HU HU79PA1342A patent/HU178075B/en not_active IP Right Cessation
- 1979-02-15 IT IT48023/79A patent/IT1115001B/en active
- 1979-02-15 DD DD79211045A patent/DD142053A5/en not_active IP Right Cessation
- 1979-02-15 MX MX797720U patent/MX5588E/en unknown
- 1979-02-16 PL PL1979213472A patent/PL117264B1/en unknown
- 1979-02-16 NO NO790515A patent/NO150483C/en unknown
- 1979-02-16 PH PH22206A patent/PH15171A/en unknown
- 1979-02-16 BE BE0/193507A patent/BE874228A/en not_active IP Right Cessation
- 1979-02-16 SU SU792728455A patent/SU810081A3/en active
- 1979-02-16 GB GB7905508A patent/GB2014576B/en not_active Expired
- 1979-02-17 JP JP1778479A patent/JPS54157599A/en active Granted
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