Note: Descriptions are shown in the official language in which they were submitted.
~300~50
The invention relates to 6-aminomethyl-furo-(3,4-c)-
pyridine derivatives, to a process for their preparation and
to pharmaceutical compositions containing them.
The invention provides the 1,3-dihydro-6-aminomethyl-7-
hydroxy-furo-(3,4-c)-pyridine derivatives of the general
formula I
r I Al
HO
H2N - C~ N
wherein each of Al and A2 independently represents a hydrogen
atom, a straight chain saturated or unsaturated hydrocarbon
group having from 1 to 5 carbon atoms, a heterocyclic group
having up to 6 ring atoms, a cycloalkyl group, a phenyl group
or a phenylalkyl group, each of the groups represented by Al
and A2 being unsubstituted or being substituted by one or more
chlorine or fluorine atoms, trifluoromethyl groups, alkyl
groups having from 1 to 5 carbon atoms, alkoxy groups having
from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5
carbon atoms, dialkylamino groups in which each alkyl group
has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in
which each of the two alkyl groups and the alkoxy group has
from 1 to 5 carbon atoms or a ~ or ~ -alkoxy-N-pyrrolidinyl
groups in which the alkoxy group has from 1 to 5 carbon
. q~
~300150
atoms ; and further provides pharmaceutically acceptable salts
of such compounds.
The compounds according to the invention are of
interest for their therapeutical activity, principally in the
field of antiallergic action.
The invention also provides a process for the
preparation of the above mentioned compounds, the process
comprising reacting the 6-formyl-7-hydroxy-furo-(3,4-c)-
pyridine derivatives of the general formula II
I--Al
l ~II
HO ~ Y
~ ~ ~2
OHC N or M- CHO
wherein Al and A2 have the above meanings with a
stoichiometric amount of hydroxylamine and of NaOH, in water,
at room temperature, then hydrogenating the oxime thus
obtained, at room temperature, under normal pressure, in
acetic acid, by hydrogen in the presence of a Pd/C catalyst,
according to the following reaction scheme :
NH2H H2
~l- CHO - ~ M- CH = N - OH ~ I
Pd/C
~300150
The ~- formyl -7 -hydroxy- furo- (3,4-c) -pyridine
derivatives II may be obtained from corresponding 6-methyl-7-
hydroxy-furo-(3,4-c)-pyridine derivatives of the general
formula III
HIC ~ Al III
wherein Al and A2 have the above meanings by the following
sequence of reactions :
o
r~ Al
HO ~ / ~ ¦ m-chloro peroxybenzoic
~ I 2 acid
H C ~ N~
HO~ Al (CF3 CO)2 0
H3C
1300150
-- 4 --
o
HO ~ Al MnO2
l~ IJ 2
~ ~N~
HO - CH2
r 1~ Al
HO ~
, IJ 2
~ ~ Nf
OHC
The compocndsdi III are disclosed in our Patent
No. l 175 837 and/Patent Application No. 451 348.
The preparation of one only of the starting compounds,
l,3-dihydro-3-~-chlorophenyl-6-formyl-7-hydroxy-furo-(3,4-c)-
pyridine, is now described in detail, other starting materialsbeing obtained by the same way.
a) Into a one litre reactor fitted with stirring,
warming and cooling means, 22.3 9 of 1,3-dihydro-3-p-chloro-
phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine were treated
at 0C, in the presence of 300 ml of methylene dichloride,
with 18.2 9 of m-peroxybenzoic acid, slowly added. After
stirring overnight at room temperature, there were added 150
ml of 10 % sodium sulphate solution. After stirring and
decantation, the methylene dichloride phase was washed with
the same amount of sodium sulphate solution, twice with 150 ml
of sodium bicarbonate solution and three times with 100 ml of
water, and then dried over anhydrous sodium sulphate. On
evaporation to dryness, there was obtained a beige precipitate
which was washed with petroleum ether, filtered and dried.
1300~50
Yield 22.9 g (96 %) of 1,3-dihydro-3-p-chlorophenyl-6-methyl-
7-hydroxy-furo-(3,4-c)-pyridine-N-oxide.
b) In the same reactor as above, the 22.9 g of the
compound obtained in the previous step were treated at 0-5C,
in the presence of 175 ml of methylene dichloride, with 4.3 ml
of trifluoroacetic anhydride added dropwise under stirring.
The mixture was stirred overnight at room temperature, and
then cooled and treated dropwise with 95 ml of methanol. After
evaporation to dryness, the residue was taken up in 300 ml of
chloroform, washed twice with 75 ml of 10 % sodium bicarbonate
solution and three times with 100 ml of water and dried on
anhydrous sodium sulphate. The chloroform was evaporated off
and the residue was washed with diethyl ether and dried under
reduced pressure. Yield 21.3 g (93 %) of 1,3-dihydro-3-~-
chlorophenyl-6-hydroxymethyl-7-hydroxy-furo-(3,4-c)-pyridine.
c) In a 2 litre reactor, the 21.3 g of the compound
obtained in the previous step were treated with 27 g of
manganese dioxide in the presence of 0.9 litre of chloroform
at 28-30C, under stirring for 3 hours. After separation,
fitration, washing with chloroform and then with ethyl
acetate, the solution was evaporated to dryness and the paste
treated with isopropyl oxide then with pentane. There was thus
obtained 20.1 g (95 %) of 1,3-dihydro-3-P-chlorophenyl-6-
formyl-7-hydroxy-furo-(3,4-c)-pyridine.
The invention further provides a pharmaceutical
composition comprising a 1,3-dihydro-6-aminomethyl-7-hydroxy-
furo-(3,4-c)-pyridine derivative of the general formula I as
above defined or a pharmaceutically acceptable salt thereof in
admixture with a pharmaceutically acceptable diluent or
carrier.
The invention is illustrated by the following examples.
13~0~S0
Example 1
1~3-dihYdro-3-methYl-6-aminomethyl-7-hydroxy-furo-(3r4-c)
pyridine
Into a 2 litre reactor, at room temperature, were
poured 71.2 g (0.4 mol) of 1,3-dihydro-3-methyl-6-formyl-7-
hydroxy-furo-(3,4-c)-pyridine, 270 ml of lN sodium hydroxide
and then, dropwise under stirring, 27.8 g (0.4 mol) of
hydroxylamine hydrochloride dissolved in 200 ml of water.
Stirring was maintained for 10 hours and the reacting mixture
was filtered, to give, after washing with water and drying, 74
g (96 %) of the corresponding 6-oxime derivative.
The 74 g of the 6-oxime derivative were then poured
with 0.9 litre of acetic acid into a closed reactor fitted
with gaseous circulation means ; after circulating nitrogen
15 g of Palladium on Carbon catalyst were placed in the
reactor and the mixture was stirred at room temperature with a
measured hydrogen addition under normal pressure, for 4 hours.
After filtration of the reacting mixture, it was
evaporated to dryness. The residue was treated with toluene
and then with methanol from which were recrystallized 70 g
(76 %) of the acetate of 1,3-dihydro-3-methyl-6-aminomethyl-7-
hydroxy-furo-(3,4-c)-pyridine, a beige product melting at
167C (Tottoli), the analysis of which showed a good
correspondence with the formula C9Hl2N2O2, C2H4O2 . This
compound was insoluble in water.
As the same route was used for all the synthetized
compounds, operative details will not be repeated in the
following examples. The corresponding bases (without the
acetic moiety) and other salts of said bases are obtained as
usual.
~300~50
-- 7
Example 2
1,3-dihYdro-3-Propyl-6-aminomethyl-7-hvdroxy-furo-(3~4-c) -
pyridine
Starting with 1,3-dihydro-3-propyl-6-formyl-7-hydroxy-
furo-(3,4-c)-pyridine, there was obtained (yield 77 %) a pale
beige product, melting at 187C (Tottoli)* insoluble in water,
the analysis of which showed a good correspondence with the
formula C11~16N22 C2H42'
Example 3
1,3-dihYdro-3-(3'~4~,5'-trImethoxyphenyl)-ethyl-6-aminomethvl-
7-hydroxY-furo-(3,4-c)-Pvridine
Starting with 1,3-dihydro-3-(3',4',5'-trimethoxy-
phenyl)-ethyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there
was obtained (yield 61 %), a white product, melting at
140-144C (Tottoli)*, insoluble in water, the analysis of which
showed a good correspondence with the formula
ClgH24N2O5 C2H42
Example 4
1,3-dihvdro-3-cvclohexYl-6-aminomethyl-7-hYdroxy-furo-(3,4-c)-
pyridine
Starting with 1,3-dihydro-3-cyclohexyl-6-formyl-7-
hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 67 %)
a white product, melting at 173-177C (Tottoli)*, insoluble in
water, the analysis of which showed a good correspondence with
the formula C14H20N22 C2 4 2
Example 5
1,3-dihYdro-3- ~ -thienyl-6-aminomethyl-7-hydroxy-furo-(3,4-c)-
pyridine
Starting with 1,3-dihydro-3- ~ -thienyl-6-formyl-7-
hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 58 %)
~? * Trademark
Si~
1300150
-- 8
a yellowish product, melting at 148C (Tottoli), insoluble in
water, the analysis of which showed a good correspondence with
the formula C12H12N22Sl C2H4 2
Example 6
1,3-dihydro-3-phenyl-6-aminomethyl-7-hydro Y-furo-~-3r4-c)
pyridine
Starting with 1,3-dihydro-3-phenyl-6-formyl-7-hydroxy-
furo-(3,4-c)-pyridine, there was obtained (yield 82 %1 a pale
beige product, melting at 188C (Tottoli), insoluble in water,
the analysis of which showed a good correspondence with the
formula C14H14N22 C2H42-
Example 7
1,3-dihYdro-3-P-chlorophenY1-6-aminomethyl-7-hydroxy-furo-
Starting with 1,3-dihydro-3-p-chlorophenyl-6-formyl~7-
hydroxy-furo-(3,4-c)~pyridine, there was obtained (yield 86 %)
a pale beige product, melting at 204-206C (Tottoli),
insoluble in water, the analysis of which showed a good
correspondence with the formula C14H13ClN2O2. C2H4O2.
Example 8
1,3-dihydro-3-(2',3'-dichlorophenyl)-6-aminomethyl-7-hydroxy-
furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-(2',3'-dichlorophenyl)-6-
formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained
(yield 72 %) a pale yellow product, melting at 193-196C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C14Hl2cl2N2o2~ C2H4O2.
1300~50
Example_9
1,3-dihYdro-3-p-fluorophenyl-6-aminomethyl-7-hydroxy-furo-
(3,4-c)-pYridine
S~arting with 1,3-dihydro-3-p-fluorophenyl-6-formyl-7-
hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 69 %)
a pale beige product, melting at 183-187C (Tottoli),
insoluble in water, the analysis of which showed a good
correspondence with the formula C14H13FN2o2 C2H4O2.
Example 10
1,3-dihydro-3-p-toluyl-6-aminomethyl-7-hvdroxy-furo-(3,4-c)-
pyridine
Starting with 1,3-dihydro-3-p-toluyl-6-formyl-7-hydroxy
-furo-(3,4-c)-pyridine, there was obtained (yield 78 %) a pale
beige product, melting at 158-160C (Tottoli), insoluble in
water, the analysis of which showed a good correspondence with
the formula C15H16N22 C2H4 2
E ample 11
1,3-dihYdro-3-p-methoxyPhenyl-6-aminomethyl-7-hydroxy-furo-
(3,4-c)-pyridine
Starting with 1,3-dihydro-3-p-methoxyphenyl-6-formyl-
7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield
62 ~) a pale beige product, melting at 144-149C (Tottoli),
insoluble in water, the analysis of which showed a good
correspondence with the formula C15H16N2O3. C2H4O2.
Example 12
1,3-dihydro-3-~3',4',5'-trimethoxy)-ehenyl-6-amlnomethyl-7-
hydroxy-furo-(3,4-c)-pyridlne
Starting with 1,3-dihydro-3-(3',4',5'-trimethoxy)-
phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was
1300~50
-- 10 --
obtained (yield 49 %) a whitish product, melting at 137-141C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C17H20N2O5. C2H4O2.
Example 13
1~3-dihydro-3-m-trifluorometh5 ~ henyl-6-aminomethyl-7-hydr
furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-m-trifluoromethylphenyl-
6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained
(yield 84 %) of a white product, melting at 197-203C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C15H13F3N2O2 C2H4O2.
Example 14
1,3-dihydro-3-p-dimethylaminoethoxyphenyl-6-aminomethyl-7-
hydroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-p-dimethylaminoethoxy-
phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was
obtained (yield 46 %) a pale yellow product, melting at
160-164C (Tottoli), insoluble in water, the analysis of which
showed a good correspondence with the formula
ClgH23N32 C2H4 2
Example 15
1,3-dihydro-3-methyl-3-~ -thienyl-6-aminomethYl-7-hydroxy-
furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-methyl-3- a -thienyl-6-
formyl-7-hydroxy-furo (3,4-c)-pyridine, there was obtained
(yield 66 ~) a white product, melting at 206-208C
(Tottoli), poorly soluble in water, the analysis of which
showed a good correspondence with the formula
13 14 2 2 2H42
1300150
-- 11 --
Example 16
1,3-dihydro-3-ethyl-3-Phenyl-6-aminomethyl-7-hydroxy-furo-
(3,4-c)-pyridine
Starting with 1,3-dihydro-3-ethyl-3-phenyl-6-~ormyl-
7-hydroxy-furo-(3,4-c)-pyridine, there was obtained (yield 80
~) a white product, melting at 207C (Tottoli), insoluble in
water, the analysis of which showed a good correspondence with
the formula C16H18N22 C2 4 2
Example 17
1,3-dihydro-3-phenyl-3-p-trifluoromethylphenyl-6-aminomethyl-
7-hYdroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-phenyl-3-p-trifluoromethyl-
phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was
obtained (yield 65 %) a white product, melting at 221C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C21H17F3N2O2. C2H4O2.
Example 18
1,3-dihydro-3-phenYl-3- ~methoxypyrrolidinyl-6-aminomethyl-7-
hydroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-phenyl-3- -methoxypyrro-
lidinyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was
obtained (yield 41 %) a yellowish product, melting at
129-132C (Tottoli), insoluble in water, the analysis of which
showed a good correspondence with the formula
ClgH22N3O3- C2H42
Example 19
1,3-dihYdro-3,3-di-p-fluorophenyl-6-aminomethYl-7-hydroxY-
furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3,3-di-p-fluorophenyl-6-
formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained
1300150
- 12 -
(yield 81 %) a pale yellow product, melting at 214C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C20Hl6F2N2o2. C2H4O2.
Example 20
1,3-dihYdro-3-a -furyl-3-p-thiomethylphenyl-6-aminomethy-l-7
hydroxy-furo-(3,4-c)-Pyridine
Starting with 1,3-dihydro-3- ~ -furyl-3-p-thiomethyl-
phenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was
obtained (yield 63 %) a whitish product, melting at 153-157C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula ClgHlgN2O3S~ C2H4O2.
Example 21
1,3-dihydro-3,3-di-~_-furyl-6-aminomethyl-7-hydroxy-furo-
(3,4-c)-pyridine
Starting with 1,3-dihydro-3,3-di- ~-furyl-6-formyl-7-
hydroxy-furo-(3,4-c)~pyridine, there was obtained (yield 72 %)
a white product, melting at 178C (Tottoli), insoluble in
water, the analysis of which showed a good correspondence with
the formula C16H14N24 C2H4 2
Example 22
1,3-dihvdro-3-cyclohexyl-3-(2',3',-dichloro)-phenyl-6-amino-
methYl-7-hydroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-cyclohexyl-3-(2',3'-
dichlorophenyl)-6- formyl -7-hydroxy- furo -(3,4-c)-pyridine,
there was obtained (yield 59 ~) a yellow product, melting at
213C (Tottoli), insoluble in water, the analysis of which
showed a good correspondence with the formula
c20H22C12N2O2~ C2H4 2
1300~50
- 13 -
Example 23
1,3-dihydro-3-vinyl-3-p-thiomethylphenyl-6-aminomethyl-7-
hydroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-vinyl-3-p-thiomethylphenyl-
6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there was obtained
(yield 66 ~) a beige product, melting at 155C (Tottoli),
insoluble in water, the analysis of which showed a good
correspondence with the formula C17Hl8N2o2s. C2H4O2.
Example 24
10 1,3-dihydro-3-dimethYlaminopropyl-3-p-chlorophenyl-6-amino-
methyl-7-hydroxy-furo-(3,4-c)-pyridine
Starting with 1,3-dihydro-3-dimethylaminopropyl-3-p-
chlorophenyl-6-formyl-7-hydroxy-furo-(3,4-c)-pyridine, there
was obtained (yield 47 %) a white product, melting at 169C
(Tottoli), insoluble in water, the analysis of which showed a
good correspondence with the formula C19~24Cl N3O2. C2H4O2.
TOXICITY
DL50 was determined per os and IP on mice. According to
the compounds, it was comprised between 0.7 to over 2.4 g/Kg
(per os) and 0.6 to 1.65 g/Kg IP.
PHARMACOLOGY
A complete pharmacological experimentation was
conducted and the following tests are reported below.
A - Passive cutaneous anaphylaxy
This experiment was conducted as described in Fiche
Technique n 48 of J.Pharm. Paris 1979 10 (1) pages 69-72.
1300~50
- 14 -
Male Sprague-Dawley rats (180-200 g) received two
intra-dermal injections of immunserum in the back ; 72 hours
later, they received a IV (penis vein) injection of 1 ml of a
mixture of ovalbumine (5 mg/ml) and Evans blue (2.5 mg/ml)
this induced the formation of wheals around the places of
injection of immunserum. Wheals were taken 30 minutes after
this formation, measured then incubated for 24 hours at 65C
in 4 ml of formamide (for extracting the Evans blue). Optical
density of the supernatant was determined at 620 nm by a
spectrophotometer.
A first batch of 8 rats was used for control ; a second
batch (8) was used for treatment by a reference compound
(theophylline, 25 mg/Kg) and ten other batches (all of 8 rats)
were used for the treatment by 10 of the compounds of the
present invention (all at 25 mg/Kg) identified by their
example number ; for these eleven batches, the appropriate
compound was administered per os, one hour before the
injection of ovalbumine/Evans blue mixture. The percentage of
wheals reduction, in surface and in colour was determined by
comparison with the control. The results are reported on the
left part of the following table.
B - Anti-histaminic action
This experiment was conducted as described by Doepfner
W. and Cerletti A., Int. Arch. Allergy 12, 89 1958 and J.
Pharmac. and exp. Ther. (1974) 191 (2) pages 300-310.
Male Sprague-Dawley rats (140-160 g) were submitted to
hydric fast for 18 hours before receiving 1 ml/Kg of water
(for control), 0.2 of an aqueous solution or suspension of
experimented compounds. The volume of the left posterior paw
was measured by plethysmography, then 0.1 ml of 5 % histamine
hydrochloride was injected. The inflammatory response was
evaluated by a subsequent volume determination one hour later.
1300~5()
- 15 -
Batches of each 8 animals were used : one for control,
ten for tested compounds (the same as in A above) and two for
reference compounds mequitazine and promethazine, all at the
dose of 25 mg/Kg. The percentage of reduction of inflammatory
response was obtained by comparison with control. The results
are reported in the right part of the following table.
From these two experiments, it clearly appears that the
compounds of the invention present a strong anti-histaminic
action.
PRESENTATION - POSOLOGY
For human use by oral route, tablets or gelatine
capsules containing 0.20 g of a compound according to the
in~ention are preferred. By IV route, phials containing the
same amount, to be injected with a perfusion are retained.
Daily doses in human therapy are from 0.20 to 2 g per os and
0.20 to 1 g, IV.
13001S0
- 16 -
. .. .. ~
of wheals reduction Histamine induced Oedema
_ . ~ of inflammatory
Compounds Surface Colour reduction
_ _ _ . ._ - _ _ _
Theophylline - 60 - 62
.. _ _ ~
Ex 1 - 77 - 86 - 48
_ . .. _ .. _ ._ .. _
Ex 2 - 58 - 60 - 77
_.......................... ... .
Ex 4 - 61 - 66 - 59
. __
Ex 5 - 49 - 60 - 68
_ __ ...
Ex 6 - 75 - 84 - 79
. _ _
Ex 9 - 68 - 72 - 83
~x 10 - 68 - 72 - 66
.
Ex 14 - 71 - 81 - 51
_ . _
Ex 16 - 53 - 59 - 54
Ex 18 - 65 - 69 - 62
~ L . ~
Mequitazine ~ - 60
Promethazine ~ ~ 41
. . ~
