Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~L25423(3
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CYCLOALKANE-INDENE-CARBOXIMIDAMIDE DERIVATIVES
The present invention is dealing with cycloalkane-indene-
carboximidamide derivatives and to a pharmaceutical preparation
which contains these novel compounds as the active constituent.
More especially, the invention relates to carboximidamide
derivatives having the general foxmula:
RY2
Rx ~ ` NHR2
~herein
~x together with either Ryl or RY2 represent the moiety ~ n
R
(the other Ry being hydrogen),
n represents the number 1, 2 or 3,
R represents hydrogen or a (1-4 C)-alkyl group,
Rl represents hydrogen, (1-4 C)-alkyl, hydroxyl,
(1-4 C)-alkoxy or anamino groupwhich-isunsubstituted
or substituted by (1-4 C)-alkyl and
R2 is hydrogen, hydroxyl or (1-4 C)-alkyl,
as well as the pharmaceutically acceptable salts thereof.
The present compounds and salts thereof exhibit powerful
blood platelet aggregation-inhibiting activity, as a result of
~-hich they are useful in combating certain cardiovascular
conditions. They have relatively few side-effects.
The compounds according to the general formula I can be
prepared in a manner usual for analogous compounds.
These compounds I can, for example, be prepared by
~f
~254230
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condensing a o- or S-alkyliso(thio)amide having the general
formula II:
RY2
RX~ ~ NR2 II
RYl~/ ZRo
or an acid addition salt thereof, with ammonia or a hydroxylamine,
hydrazine or amine derivative having the formula III:
~ Rl
H - N III
or an acid addition salt thereof, wherein Rx, Ryl, Ry2~ R, n and
Rl have the meanings given above, R21 has the same meaning as R2
but can also be an amino group which is unsubstituted or sub-
stituted by (1-4 C)-alkyl, æ represents an oxygen or sulphur atom
and Ro represents a lower alkyl group, preferably methyl or ethyl.
The compounds I wherein R2 represents hydrogen or
hydroxyl can moreover be prepared by condensatlon of the nitrile
of the general formula IV:
RY2
Ry~ ~> CN IV
wherein RX, Ryl and RY2 have the above-mentioned meaning~ with a
compound of the general formula III described above, or an acid
addition salt thereof.
The starting materials of the general formulae II and IV
required for the above condensation reactions can be prepared in a
manner customary for analogous compounds.
~L25~23~
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The attached flow sheets show a number of methods for the
preparation of these starting materials.
Compounds according to the general formula III needed in
the above-mentioned condensation reactions include, inter alia,
ammonia (NH3), methylamine, ethylamine, propylamine, isobutylamine,
butylamine, hydroxylamine, hydroxylamine methyl ether, hydroxylamine
ethyl ether, hydroxylamine propyl ether, hydrazine, l-methylhydra-
zine and l,l-dimethylhydrazine, as well as the acid addition salts
thereof.
Preferably, the substituents on the nitrogen atoms
(Rl R2) should already be present in either starting material
mentioned.
However, it is also possible to modify or introduce one
or more substituents after the above-mentioned condensation
reactions.
~54230
For example, one of the nltrogen atoms of a compound I (Rl or
R2 ~ H) can be alkylated in a known manner, for example by maans of
alkyl halides, by means of an Eschweiler-Clarke reaction or by
acylation followed by reduction. The N-hydroxyl group which may be
present in the compound of formula I ~Rl or R2 is hydroxyl~ will
also be alkylated during such an alkylation. Moreover, this N-hydroxyl
group can be specifically alkylated by means of, for example, dimethyl
sulphate.
The compounds of the formula I contain an alkaline group. They
can, depending on the medium in which they are prepared, be obtained
as free base or as an acid addition salt. However, if desired the free
base I can be prepared from the salt, for example by reaction with an
alkaline compound or by means of an ion exchanger, while the free base
I can be converted in a simple manner into an acid addition salt.
Pharmaceutically acceptable acid addition salts are obtained by
allowing the free base I to react with acids, such as hydrochloric
acid, phosphoric acid, acetic acid, propionic acid, glycolic acid,
maleic acid, fumaric acid, malonic acid. succinic acid, tartaric acid,
lactic acid, citric acid, ascorbic acid or salicylic acid.
It follows from the general formula I of the end products that
the compounds according to the invention may contain an asymetric
carbon, as a result of whlch not only racemic mixtures I but also
optically active compounds I are possible. These optically active
compounds I are also to be included among the compounds according to
the invention. They can be prepared directly from an optically active
starting material (II, IV) or be obtained by resolving the racemate I
into its optical antipodes in a manner customary for such resolutions.
12$42310
The present compounds accordlng to the invantlon can be
administered orally, locally or parenterally, preferably in a daily
dose of between O.Ol and 50 mg per kilogram of body weight. The
compounds are, for this purpose, converted in a customary manner into
a form suitable for oral, local or parenteral admlnistration, for
example a tablet, pill, capsule, 301ution, suspension, emulsion, paste
or spray.
An administration form for oral use is preferred.
Compounds I which are preferred are compounds whersin the
carboximidamide group has the following structure3:
,i
~ NOH ~NOH 1~
--C ~ , C\
NH2 NHOH 1 j
NOC~3 //NH
-C \ and -C \
NH2 NH2
More especially that compound of formula I is preferred wherein R
represents hydrogen, n represents the number 1 or 2, R2 is hydrogen
and Rl represents a hydroxyl group, as well as acid addition salts
thereof.
The position of the double bond between the nitrogen and carbon
atom in the carboximidamide group of formula I csnnot be specified
unam~iguously since an equilibrium will set up betwsen the groups:
~ NRl NHR
-C \ and -C ~
NHR2 NR2
Both tautomeric forms are included in the invention.
~2S4L~30
Prepar _ ion of startlng materlAl
A. Ethyl 2-cyano-2~3,5,6~7,8-hexahydro-lH-ben~ indene-2-
carboxylate
NaOC2Hs was prepared in a 10 litre 3-necked flask by adding
small pieces of sodium (1.68 moles) to absolute ethanol (900 ml) over
a period of about 1 hour. The temperature was kept at 60-70C by
controlling the speed of addition.
After all sodium had reacted, the mixture was cooled to room
temperature and thereafter dry THF (1650 ml) and ethyl cyanoacetate
(1.68 moles) were added all at once. After 5 minutes, a precipitate
began to form and slowly thickened. Afte} 30 minutes' stirring, the
reaction mixture was cooled with ica water to 10-15C and thereafter
a solution of 2,3-bis-(bromoethyl~-5,6,7,8-tetrahydro-naphthalene
(0.84 mole~ in dry THF (1000 ml) was added as rapidly as possible
(2 to 3 minutes). As a result of the exothermic character of the
reaction, the temperature rose to about 35C; thereafter the mixture
was cooled to room temperature and stirred for a further hour.
The reaction mixture was then evaporated as far as possible and
the residue was partitloned between methylene chlaride (750 ml) and
water (about 400 ml). The layers were separated and the water layer
was extracted twice wlth methyle~e chloride (250 ml). The combined
methylene chloride extracts were washed once with water (200 ml) and
dried over Na2S04. After the drying agent had been filtered off,
the filtrate was evaporated. This gave about 300 g of a yellow oil.
300 ~1 of ether were added to the residue and after seeding
80.5 g of the desired compound crystallised out.
B. 2,3,5,6,7,8-Hexahydro-lH-benzlflindene-2-carbonitrile
-
The product (0.29 mole) obtained in A. was suspended in DMS0
tl60 ml). Distilled water (12 ml) and iodine-free sodium chloride
t5.6 g) were added. Theresfter the reaction mlxture was heated to
170C for about 3 hours, with stirring, until the C02 evolution
had ceased.
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After it had cooled to room temperature, the reaction mixture was
poured out slowlyl with stirring, into distilled water (1000 ml). The
precipitate was extracted with methylene chloride (4 x 200 ml) and
the combined extracts were washed with water (200 ml), dried over
Na2S04 and evaporated. The reYidue was filtered over silica gel.
Melting point 102C.
C.. In a corresponding manner as described in A. and B. was prepared:
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carbonitrile; m.p. 48C.
Example 1
2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlfJindene-2-carboximidamide.HCl
29.2 g of sodium were dissolved in 560 ml of dry methanol and a
warm solution of 88 g of hydroxylamine hydrochlorlde in 110 ml of dry
methanol was thereafter added to this solution. The solution obtained
had a pH of 8 to 10. Thereafter, the NaCl precipitate formed was
filtered off.
The filtrate obtained was added at room tenperature, under
nitrogen, to a solution of 25 g (127 millimoles) of 2,3,5,6,7,8-
hexahydro-lH-benzlflindene-2-carbonitrile in 560 ml of dry methanol.
The reaction mixture was stirred for 3 x 24 hours at 50C under
nitrogen and was then evaporated.
The residue was thereafter stirred with 400 ml of water, after
which the precipitate was filtered off, again washed with water and
dried. Yield 28 g.
The precipitate was then dissolved in 120 ml of 5N methanolic HCl
301ution. The solution was evaporated to a volume of about 100 ml
after which 250 ml of diethyl ether were added.
The precipitate formed after some time at 0C waY filtered off
and dried.
Yleld: 26 g of the compound shown in the title.
Rf in methylene chloride:methanol (9~ 0.44 on SiO2; melting
point: 213C (with decomposition).
~254230
Example 2
The followlng are prepared in a manner analogous to Example 1:
2,3,5,6,7,8-hexahydro-N-hydroxy-o-methyl-lH-benzlf~indene-2-
carboximidamide.HCl, melting point 205C (with decomposition~;
1,2,3,5,6,7-hexahydro-N-hydroxy-~-indacene-2-carboximidamide.
HCl, melting point: 215C (with decomposition);
1,2,3,5,6,7-hexahydro-N-hydroxy-6-methyl-s-indacene-2-
carboximidamide.HCl, melting point: 194-195C
1,2,3,5,6,7,8,9-octahydro-N-hydroxy-cycloheptlflindene-2-
ca}boximidamide;
2,3,4,5,6,7-hexahydro-N-hydroxy-lH-benzle~indene-2-
carboximidamide.HCl, melting point: 194C (dec.);
2,3,4,5,6,7-hexahydro-N-hydroxy-5-methyl-lH-benz[elindene-2-
carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-as-indacene-2-
carboximidamide.HCl;
1,2,3,4,5,6-hexahydro-N-hydroxy-6-methyl-a~-indacene-2-
carboximidamide.HCl;
1,2,3,4,5,6,7,8-octahydro-N-hydroxy-cyclohept~e]indene-2-
carboximidamide.
Example 3
2,3,5,6,7,8-Hexahydro-N-methoxy-lH-benzlfJindene-2
carboximidamide.HCl
Method A
A sodium methanolate solution prepared by di3solving 3.45 g
(150 millimoles) of sodium in 50 ml of methanol, was added to a
solution of 12.5 g (150 millimoles) of hydroxylamine methyl ether
hydrochloride in 60 ml of methanol.
After the mixture had been stirred for about 5 minutes, the
sodium chloride formed was filtered off and the filtrate was added to
10 g (50 mi:llimoles) of 2~3~5~6~7~8-hexahydro-lH-benzlfJindene-2
carbonitrile.
125423C~
After 15 hours' atirring at 50C, the methanol was removed and
the residue W83 stirred with 250 ml of water.
After the precipitnte had been filtered off, washed neutral with
water and dried to constant weight, the amidoxime was suspended in 35
ml of methanol and acidified wlth 2N methanolic HCl solution.
After addition of 165 ml of ether to the solution, the
hydrochloride crystallised out. Yield 10.6 g.
Method B
0.5 ml of water, 0.53 g (2 millimoles) of 2,3,5,6,7,8-hexahydro-
N-hydroxy-lH-ben~lfJlndene-2-carboxlmidamide hydrochloride and, after
a few mlnutes' stirrlng, 0.3 ml (about 3 millimoles) of dimethyl
sulphate, were added successively to a solution of g2 mg
4 millimoles) of sodium in 5 ml of ethanol.
After the mlxture had been stirred for 1 hour at room
temperature, 2 millimoles of sodium ethanolate solution and 0.2 ml
(0.2 millimole) of dimethyl sulphate were furthermore added.
After this mixture had been stirred for some time at room
temperature, the solvent was evaporated off. The residue was then
taken up in ethyl acetate and washed 3 times with water. The organic
layer was dried over sodium sulphate and then evaporated to dryness,
and the residue was subsequently converted to the hydrochloric acid
salt by suspending lt ln 3 ml of methanol and acldifying wlth 2N
methanolic HCl.
Addition of 3 ml of ether to the solution caused the
hydrochlorlde to crystallise out. Yleld 355 mg.
~25423(~
Example 4
2,3,5,6,7,8-Hexahydro-N,N'-dihydroxy-lH-benz¦f~indene-2-
carboximidamide.
Small portions of about 7.5 millimoles of a sodium methanolate
solution were added, with stirring, to a suspension of 10 g
(50 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benz~flindene-2-
carbonitrile and 10.5 g (150 millimoles) of hydroxylamine
hydrochloride in 80 ml of methanol, at 45C. In total, about
40 millimoles of sodium methanolate were used, spread over 48 hours.
After the mixture had cooled to room temperature, 80 ml of ether
were added and the precipitate was filtered off. This precipitate was
subsequently stirred twice with 50 ml of water to remove salts, and
was then recrystallised from methanollether. Yield 7.0 g, melting
point 151 C.
Example 5
2,3,5,6,7,8-Hexahydro-N-hydroxy-lH-benzlf¦indene-2-
carboximidamide.HCl
A solution of 20.3 millimoles of 2,3,5,6,7,8-hexahydro-lH-
benz[f~indene-2-carbonitrile in 16 ml of methylene chloride and 6 ml
of ethanol was saturated wlth HCl gas at 0C. After leaving the
mixture in a refrigerator for 24 hours, the solvents were removed and
the iminoethyl ether hydrochloride was dissolved in 100 ml of water.
This solution was treated with a sodium bicarbonate solution and then
extracted with methylene chloride, and the organic layer was washed
with water until neutral. Thereafter, the solvent was removed.
To this residue timincethyl ether) there was subsequently added a
hydroxylamine solution which was prepared by adding a solution of
120 millimoles of sodium in 10 ml of methanol to 120 millimoles of
hydroxylamine hydrochloride in 10 ml of methanol. After 45 minutes'
qtirring at room temperature, the solvent was removed and the residue
was stirred with water.
~L25~23~
The precipitate was filtared off, washed neutral with water and
dried to constant weight, giving 3.5 g of amidoxime.
A suspension of this amidoxime in 20 ml of methanol, when
acidified with 2N methanolic HCl, gave a solution of the hydrochloride
which after concentration to about 20 ml and addition of 150 ml of
ether started to crystallise. Yield 3.9 g, melting point 213C (with
decomposition).
Example 6
2,3,5,6,7,8-Nexahydro-lH-benzlf¦lndene-2-carboximidamide.HCl
4 g (20.3 millimoles) of 2,3,5,6,7,8-hexahydro-lH-benzlf~indene-
2-carbonitrile were converted to the corresponding lminoethyl ether in
the same manner as described in Example 5.
The residue obtained (iminoethyl ether) was dissolved in 14 ml of
dry methanol, after which 1.03 g of NH4Cl were added.
The reaction mixture was then stirred for some time at 40C and
then set aside at room temperature for 24 houra.
After the mixture had been evaporated and chromatographed with
methylene chloride:methanol (1:1) as eluant over a short silica gel
column, it was acidified with ethanolic HCl solution and again
evaporated. The residue was recrystallised f~om ethanol:ether (1:3).
Yield 3.7 g, melting point 279C (dec.).
Example 7
The following compounds are prepared in a corresponding manner to
that described in Example 6:
1,2,3,5,6,7-hexahydro-s-indacene-2-carboximidamide.HCl, melting
point 282 C (dec.);
2,3,4,5,6,7-hexahydro-lH-benzle~indene-2-carboximidamide.HCl,
melting point 222 C (dec.).
~254~30
12
In an analogous manner as described in Example 6 but replaclng
ammoniumchloride by methylamine the following compound~ are prepared:
2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f~indene-2-
carboximidamide;
2,3,4,5,6,7-hexahydro-N-methyl-lH-benz~elindene-2-
carboximidamide.
Example_8
2,3,5,6,7,8-Hexahydro-~-hydroxy-N'-methyl-lH-benz~flindene-2-
carboximidamide
720 mg of a 60~ dispersion of sodium hydride in oil (18
millimoles of sodium hydride) were freed from the oil with hexane
after which 13 ml of dimethylformamide were added, followed by 1.3 g
(18 millimoles) of hydroxylamine hydrochloride added over 20 minutes.
The mixture was stirred for 20 minutes, the precipitate was filtered
off, and the filtrate was added to 3.5 g (9 millimoles) of methyl-
2,3,5,6,7,8-hexahydro-N-methyl-lH-benz¦f]indene-2-carboximidothioate
hydriodide.
The reaction mixture was stirred for a further 45 minutes at room
temperature, poured out into 600 ml of water and brought to pH 9 with
4N sodium hydroxide, after which the precipitate formed was filtered
off and washed neutral. Drying to constant weight gave 1.8 g of the
carboximidamide in ~uestion, melting point 161 C.
The following compounds are prepared in an analogous manner but
using hydrazine hydrate in place of hydroxylamine hydrochloride:
2,3,5,6,7,8-Hexahydro-N-amino-N'-methyl-lH-benzlflindene-2-
carboximidamide;
2,3,4,5,6,7-hexahydro-N-amino-N'-methyl-lH-benz[e]indens-2-
carboximidamide.
-- 13 --
Flow sheet
C~h. 0~
¦ cooE~ ~yL~
,, l isOcyan~te
CN r
O~COOC~ CN
~ '
~ ~ ~0~t ¦ h~e~
O~CUO~ X} C ~H
(X~
(~ C--Nll~,
C~ C -- N ~;
~ ~advv
Flow sheet
C~ Ce-CH;Ci~-~O-C~p ~r~~S~
-- C.~ ( i')" ~ L - OC
o o
~'~ C~ ~
I
~N
~, c_ NP~
