Note: Descriptions are shown in the official language in which they were submitted.
~126,732
-- 1 --
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%
-- 3 --
~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%
-- 4 --
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%. ~
EXAMPLE 2
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~
-- 5 --
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%.
EXAMPLE 3
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.~
EXAMPLE 4
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%.
EXAMPLE 5
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%.
EXAMPLE 6
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%.
EXAMPLE 7
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
-- 7 --
EXAMPLE 9
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%.
EXAMPLE 10
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%.
EXAMPLE 11
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%.
EXAMPLE 12
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%.
EXAMPLE 13
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%.
EXAMPLE 14
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%.
EXAMPLE 15
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%.
EXAMPLE 16
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%.
EXAMPLE 17
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
EXAMPLE 18
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%.
EXAMPLE 19
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%.
EXAMPLE 20
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%. ~ ;
EXAMPLE 21
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
-- 10 --
EXAMPLE 22
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%.
EXAMPLE 23
5-~3-Pyridyl-methyl)aminocarbonyl-thieno ~,3- ~pyridine
1 2 N
; 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%. ~
EXAMPLE 24
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%.
EXAMPLE 25
6-~(3-Trifluoromethyl-phenyl)aminocarbonyl-thieno ~ ,2- ~-~
pyridine
CF3
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;~
-- 11 --
EXAMPLE 26
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%.
EXAMPLE 27
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%.
EXAMPLE 28
~` ` 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%~
EXAMPLE 29
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
- 12 -
pyridine and l-p.methoxyphenyl-piperazine. White
crystals; m.p. = 152C (ethyl acetate-diisopropyl ether).
Yield: 72%.
EXAMPLE 30
5-(4-o.Methoxyphenyl-l-piperazinyl)carbonyl-thieno-
~,3- ~pyridine
OCH3
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%.
EXAMPLE 31
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%.
EXAMPLE 32
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%.
EXAMPLE 33
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~
- 13 -
EXAMPLE 34
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%.
EXAMPLE 35
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%.
EXAMPLE 36
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%.
EXAMPLE 37
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;~
- 14 -
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
~, . .
~. : . . . .
- : : , ,: -, :
. ~ . : :: :
-
: ~ -;
~ ' '. :
.
;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.
: .. , : .:
.
'7;3~
- 16 -
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.
. ~
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~ 18 -
TABLE II
Derivative n Percent anti-inflammatory activity after
1 hour 2 hours 3 hours 5 hours
1 35 42 46 47
4 41 46 50 58
43 49 54 56
37 42 46 51
13 34 40 45 51
38 45 49 53
18 41 46 50 55
21 40 48 51 54
22 41 47 51 55
39 46 49 52
27 41 49 52 54
38 45 49 53
32 34 41 45 47
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~
-- 19 --
TABLE III
Derivative n Percent anti-inflammatory activity after
2 hours 3 hours
1 48 56
4 52 560
47 55
13 50 56
53 60
18 49 58
21 45 52
22 51 58
51 59
27 47 56
3Q 48 56
32 52 60
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~%
- 20 -
Non-limiting Examples of pharmaceutical formu-
lations of the therapeutic composition of this invention
are given below.
1 - TABLETS
Derivative n 1 . . . . . . . . . . 0.250 g
Excipient: corn starch, magnesium stearate, stearic acid
2 - COATED TABLETS
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.
3 - CAPSULES
Derivative n13 . . . . . . . . . 0.100 g
Excipient: magnesium stearate, corn starch, lactose.
4 - SUPPOSITORIES
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;~%
- 20A -
rheumatism, ab-articular conditions, acute gout, in
post-operative plastic surgery, in traumatology and in
oto-rhinolaryngology.
