Note: Descriptions are shown in the official language in which they were submitted.
~lazsc3
This invention relates to substituted sulphoximides
corresponding to the following general formula
,Rl ,R3
0 = S ~ N - CH2 - N - R4 . (R5X) (I)
R2 -- .
in which Rl and R2 independently of one another represent
optionally substituted aryl, R3 and R4, which may be the same
or different, represent optionally substituted, straight-chain
or branched alkyl or, together with the nitrogen atom, form
a pyrrolidino, piperidino or morpholino ring, R5 represents
a hydrogen atom or a straight-chain or branched alkyl group,
X is an inorganic or organic anion of a physiologically
compatible acid and n has the value O or 1,
and to the salts of these compounds.
The present invention also relates to medicaments which
are characterised in that, in addition to a standard excipient
and/or diluent, they contain an effective quantity of at
least one substituted sulphoximide of the type described
above.
In general formula (I), the substituents Rl and R2,
which may be the same or different, represent optionally
substituted aryl groups. The groups Rl and R are preferably
phenyl groups.
The groups R and R , which may be the same or different,
are alkyl groups, such as straight-chain or branched alkyl
groups containing from 1 to 12 carbo atoms, preferably from
1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms
,~
,~1
8~
-- 3
and, most preferably, from 1 to 3 carbon atoms, for example
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl
or hexyl groups. Preferably, the groups R3 and R4 each
represent an ethyl group. In addition, the radieals R3 and
R4, together with the nitrogen atom, may form a heterocyclie
ring, particularly a pyrrolidino, piperidino or morpholino
ring. -
The radieal R5 represents a hydrogen atom or a straightchain or branched alkyl group, particularly a lower alkyl
group containing from 1 to 6 and preferably from 1 to 3 carbon
atoms. The radical R5 preferably represents a methyl group.
X represents an inorganic or organie anion of a
physiologieally compatible aeid, partieularly hydroehlorie
or hydrobromie aeid, whilst n has the value O or 1.
15The compounds aeeording to the invention may be
produced by reacting an S,S-diaryl sulphoximide corresponding
to the following general formula
,Rl
O - S = NH (II)
R2
in whieh Rl and R2 are as defined above,
with formaldehyde and a seeondary amine eorresponding to
the following general formula
R3
IN \
R4 (III)
in which R3 and R are as defined above,
in a water-immiseible solvent on the lines of a Mannieh
synthesis and optionally converting the compound obtained into
8~3
its tertiary salt.
The reaction takes place in accordance with the
following scheme:
R R3 Rl R3
, 2 < R4 ~~~~~~~ 0=S N-CH -N C
The reaction is carried out in a water-immiscible solvent,
the water of reaction being azeotropically removed through
a water separator. Examples of suitable water-immiscible
solvents are benzene, toluene and xylene, benzene being
preferred.
According to the invention, the reaction is carried out
at the boiling temperature of the solvent used or of the
azeotrope formed with water. The reaction time is generally
from 2 to 8 hours. The molar ratio between the individual
starting compounds is from 1:1:1 to 1:1:4, preferably 1:1:1.
After the calculated amount of water has been separated in
the water separator, the water-immiscible solvent is evaporated
off under normal or reduced pressure. If the product is
obtained as an oil, it may be purified by fractionation in
a fine vacuum. Solid products may be purified in the usual
way bY recrystallisation under dry conditions. In this way,
the required N-dialkyl aminomethyl-S,S-diaryl sulphoximides
may be separated off from unreacted starting material and
bis-(dialkylamino)-methanes and bis-(S,S-diaryl sulphoximido)-
methanes possibly formed as secondary products.
The tertiary salts are produced for example by standard
alkylation methods in dry, inert solvents, such as ethers
or acetonitrile.
The compounds corresponding to formula I show
.~
-- 5 --
pharmacological activity, for example as spasmolytics, which
makes them appear suitable for use as medicaments.
The compounds according to the invention were tested
for their spasmolytic and broncholytic activity both in vivo
and also in vitro. They proved to be highly effective
spasmolytics with neurotropic and musculotropic activity
by comparison with atropine. Bronchospasms induced
by histamine and acetyl choline were persistently eliminated.
The favourable effect after intragastral and intraduodenal
administration is indicative of good enteral resorption. The
compounds according to the invention proved to be relatively
non-toxic in the acute toxicity test.
Particulars of the pharmacological properties of the
compounds according to the invention are given in Tables I
to III.
_ble
Acute toxicity
LD50-values after 1 week's observation in male NMRI-mice
Compound Administration LD50(confidence limits
route
p< 0.05) mg/kg
Example 2 i.g. 330.98 (224.48 - 487.99)
Example 3 i.g. 319.55 (254.95 - 400.53)
Example 2 i.v. 7.91 (6.78 - 9.22)
Example 3 i.v. 7.33 (5.94 - 9.04)
Table II
Spasmolysis in vitro
Guinea pigs~ileum-pA2-values
Agonist ACH Histamine BaC12
~ mpound ED50 (mole)
Example 2 8.21 ~ 0.25 8.1 ~ 0.21 approx.lxlO
Example 3 8.0 ~ 0.23 8.0 ~ 0.35 approx.3.3xlO
,,j
` - 6 ~ 28~
Table III
.
Broncholysis
Compound . 50 ~ ~g ~ g) i.d. 100 ( g/ g)
1 minute after 30 minutes after
administration administration
Hi ACH Hi ACH
_ _
Example 2 0.3 1.2 25 50
Example 3 0.5 2.5 25 50
The compounds according to the invention may be made
up into medicaments in the usual way, i.e. in the form of
tablets, capsules, dra~ees, drops, suppositories, injections
or preparations for inhalation.
They may he administered orally, rectally or by inhalation
or injection. The invention is illustrated by the following
examples.
EX~PLE 1
N-pyrrolidinomethyl-S,S-diphenyl sulphoximide:
5.4 g 10.025 mole) of S,S-diphenyl sulphoximide, 1.8 g
(0.025 mole) of pyrrolidine and 2.2 g of 35 ~ formaldehyde
solution are boiled in 100 ml of benzene in a water separator
until the calculated quantity of water has been separated
(approximately 1 hour). The solvent is then evaporated.
Removal of the last traces of solvent by distillation in a
fine vacuum leaves an oily product which crystallises at
room temperature.
Colourless crystals. M.p.: 59 to 61C
Yield: 7.4 g (98% of the theoretical)
Analysis: C17H20N2OS MW: 300.43
Calculated: C = 67.97 H = 6.71 N = 9.32 S = 10.67
Abserved: C = 67.72 H = 6.16 N = 8.78 S = 10.85
11~2B~3
- 7 -
H-NMR (CDC13): 1.5 to 1.95 and 2.5 to 2.95 (m, pyrrolidine),
4.1 (s,CH2), 7.2 to 8.2 (m, arom, CH)
IR (KBr): 3060, 2950, 2860, 1580, 1475, 1440, 1390, 1350
1230 (N=S=O asym.), 1150, 1120, (N=S=0 sym.),
1070, 1025, 1000, 880, 760, 730.
EXAMPLE 2
N-(N'methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide
bromide:
6 g (0.02 mole) of N-pyrrolidinomethyl-S,S-diphenyl
sulphoximide are dissolved in 150 ml of anhydrous acetonitrile
and the resulting solution is cooled to around -40C in an
inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide
are added to the intensively stirred solution, followed by
stirring for about 12 hours with gradual heating to room
temperature. The solvent is then removed in a rotary
evaporator. The residue is purified by recrystallisation
from acetonitrile~ether.
Colourless crystals. M.p.: 138 to 140C
Yield: 6.7 g (85~ of the theoretical)
Analysis: C18 23 2 MW: 395.36
Calculated: C = 54.68 H = 5.86 N = 7.08 S = 8.11
Observed: C = 54.55 H = 5.75 N = 7.09 S = 8.05
H-NMR (DMSO-d6): 1.8 to 2.3 and 3.3 to 3.8 (m, pyrrolidine),
3.15 (s, C~3), 4.6 ~s, CH2), 7.5 to 8.3
(m, arom, CH)
IR (KBr): 3040, 3000, 2980, 1575, 1465, 1440, 1405, 1295,
1260, 1230, (N=S=0 asym.), 1150 (N=S-0 sym.),
1080, 1020, 990, 960, 930, 900, 885, 775.
EXAMPLE 3
N-(N'-methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide
chloride:
In a l-litre three-neckéd flask equipped with a stirrer,
~l~Z8~3
-- 8
thermometer, gas inlet tube and drying tube, 18 g (0.06 mole)
of N-pyrrolidinomethyl-S,S-diphenyt sulphoximide are dissolved
in 250 ml of anhydrous ace-tonitrile and the resulting solution
cooled to around -40C in an inert gas atmosphere. Methyl
chloride is introduced in excess into the intensively stirred
solution for about 2 hours, followed by stirring for about
12 hours at around -20C. The solution is then concentrated
_ vacuo to approximately half its volume. The quaternary
salt is precipitated by the addition of dry ether, filtered
off in the absence of moisture, washed with dry ether and
dried _ vacuo.
Colourless crystals. M.p : 148 to 150 C. Hygroscopic
Yield: 12 g (100% of the theoretical). MW: 350.91
H-NMR (CDC13): 1.9 to 2.5 and 3.5 to 4.1 ~m,pyrrolidine),
3.4 (s, CH3), 4.75 (s, CH2), 7.3 to 8.2
(m, arom, CH).
IR (KBr): 3300 to 3600 ~H20), 3050, 3000, 1580, 1465, 1450,
1410, 1300, 1265, 1235 (N=S=0 asym.), 1155 ~N=S=0
sym.), 1085, 1025, 995, 965, 930, 905, 885, 780.
EXAMPLE 4
N-diethylaminomethyl-S,S-diphenyl sulphoximide:
6.5 g (0.03 mole) of S,S-diphenyl sulphoximide, 2.2 g
(0.03 mole) of diethylamine and 2.6 g of 35 % formaldehyde
solution are boiled in 100 ml of ben~ene in a water separator
until the calculated quantity of water has been separated
(approximately 3 hours). The solvent is then evaporated
and the residual oil is distilled in a fine vacuum ~B~p~o 01
= 70 C).
Colourless oil.
Yield: 8.8 g (96 % of the theoretical)
Analysis: C17H22N2OS MW: 302.44
Calculated: C = 67.51 % H = 7.33 ~ N = 9.26 % S = 10.60 %
~,~
.
~l~Z8~3
g
Observed: C = 67.55 % H = 7.36 % N = 9.21 % S = 10.56 %
H-NMR (C~13): 0.95 to 1.30 (t, 2CH3), 2.55 to 3.0 (q, 2CH2),
4.2 (s,CH2), 7.2 to 8.2 (m, arom. CH)
IR (film): 3070, 2970, 2930, 1470, 1410, 1380, 1240, (N=S=0
asym.), 1210. 1130 (N-S=0 sym.), 1100, 1070
1030, 1000, 760, 730,
EXAMPLE 5
N-(N'diethyl methylammonium methyl)-S,S-diphenyl sulphoximide
bromide:
6 g (0.02 mole) of N-diethylaminomethyl-S, S-diphenyl
sulphoximide are dissolved in 150 ml of anhydrous acetonitrile
and the resulting solution is cooled to around -40C in an
inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide
are added to the intensively stirred solution, followed by
stirring for about 12 hours with gradual heating to room
temperature. The solvent is then removed in a rotary evaporator.
The residue is purified by recrystallisation from acetonitrile~
ether.
Colourless crystals. M.p.: 94 to 95C
Yield: 7.7 g (97% of the theoretical)
Analysis: C18H25BrN2OS MW: 397.38
Calculated: C = 54.41 % H = 6.34 % N - 7-05 % S = 8.07 %
Br = 20.11 %
Observed: C = 54 35 % H = 6.28 % N = 7.11 % S = 8.12 %
Br = 20.20 %
H-NMR (CDC13): 1.1 to 1.6 (t, 2CH3), 3 2 Is, CH3), 3.3 to
3.8 (q, 2CH2), 4.65 (s, CH2), 7.2 to 8.2
(m, arom. CH).
IR (KBr): 3090, 3010, 2980, 1635, 1485, 1500, 1390, 1250
(N=S=0 asym.), 1220, 1165, IN=S=0 sym.), 1100,
1050, 1000, 905, 815, 770, 745.
8~3
-- 10 --
E MPLE 6
N- piperidinomethyl-S,S-diphenyl sulphoximide:
10 9 g (0.05 mole) of S,S-diphenyl sulphoximide, 4.3 g
(0.05 mole) of piperidine and 6 g of 35 % formaldehyde solution
are boiled in 100 ml of benzene in a water separator until the
calculated quantity of water has been separated (approximately
2 to 3 hours). The benzene is then evaporated and the
residual oil is distllled in a fine vacuum (B~p~ o o1=65C).
Yield: 15 g (95 ~ of the theoretical).
Analysis: C18H22N2OS MW: 314.45
Calculated C = 68.75 % H = 7.05 ~ N = 8.91 % S = 10.20 ~
Observed: C = 68.78 % H = 7.07 ~ N = 8.99 % S = 10.28 %
H-NMR (CDC13): 1.2 to 1.8 and 2.3 to 2.9 (m, piperidine),
4.02 (s,CH2), 7.2 to 8.2 (m, arom CH).
15 IR (Film): 3050, 2920, 2840, 1575, 1470, 1440, 1365, 1300,
1235, (N-S=0 asym.), 1200, 1130, (N-S=0 sym.),
1100, 1060, 1035, 1020, 990, 870, 860, 760, 725.
EXAMPLE 7
N-(N'-methyl-piperidinium-methyl)-S,S-diphenyl sulphoximide
bromide:
9.4 g ~0 03 mole) of N-piperidinomethyl-S,S-diphenyl
sulphoximide are dissolved in 200 m' of anhydrous acetonitrile
and the resulting solution cooled to around -40C in an
inert gas atmosphere. 14.5 g (0.15 Mole) of methyl bromide
are added to the intensively stirred solution, followed by
stirring for about 12 hours with gradual heating to room
temperature. The solvent is then removed in a rotary
evaporator. The residue is purified by recrystallisation
from acetonitrile~ether.
30 Colourless crystals. M.p.: 104 to 105 C.
Yield: 12 g (98 % of the theoretical).
Analysis: ClgH25BrN2Os MW: 409.39
i~2~ 3
Calculated: C = 55.74 % H = 6.15 % N = 6.84 % S 3 7.83 ~
sr = 19. 52%
r)hserved: C = 55.80 % H - 6.21 % N = 6.87 % S = 7.88 %
Br = 19. 60%
5~ NMR (CDC13): 1.6 to 2.2 and 3.5 to 4.1 (m, piperidine),
4 8 (s , CH2), 7.3 to 8.3 (m, arom. CH ) .
IR (KBr): 3050j 2960, 2940, 1450, 1320, 1300, 1280, 1250
(N=S=0 asym.), 1190, 1175, (N=S=0 sym . ), 1150,
1095, 1035, 1000, 950, 885, 825, 775, 735.
10 ~: YAMPLE 8
,~_
.-morpholinomethyl-S,S-diphenyl sulphoximide:
2.2 g (0.01 mole) of S,S-diphenyl sulphoximide, 1.3 g
(0.015 mole) of morpholine and 1.5 g of 35 ~ formaldehyde
solution are boiled in 50 ml of benzene in a water separator
15 until the calculated quantity of water has been separated
(approximately 4 hours). Concentration of the benzene by
evaporation leaves a thick oil consisting of a mixture of
N-morpholinomethyl~S~S~diphen~l sulphoximide ana bis-morpholino
methane as secondary product. The secondary product is
20 distilled off in a fine vacuum ~B~p~ o ol=60C). The
residue consists of N-morpholinomethyl-S,S-diphenyl sulphoximide.
Pale yellow coloured oil.
~rield: 2.4 g ~76% of the theoretical).
Analysis: C17H20N202S MW: 316.42
25 Calculatecl:C = 64.53 % H = 6.37 % N = 8.85 % S = 10.13 %
Observed: C = 64.59 % H = 6.43 % N = 8.93 % S = 10.20 %
H-NMR (CDC13): 2.50 to 2.82 and 3.60 to 3.92 (m, morpholine),
4.0 (s,CH2), 7.2 to 8.2 (m, arom CH).
IR (Film): 3040, 2940, 2900, 2815, 1575, 1465, 1440, 1390,
1355, 1225, (N=S=O asym.), 1120, (N=S=O sym. ),
1065, 995, 855, 800, 755, 720.
2B ~3
- 12 -
EXAMPLE 9
N-(N'-methyl-morpholinium-methyl)-S,S-diphenyl sulphoximide
bromide:
9.5 g (0.03 mole) of N-morpholinomethyl-S,S-diphenyl
sulphoximide are dissolved in 200 ml of anhydrous acetonitrile
and the resulting solution cooled to around -40C in an inert
gas atmosphere. 14.5 g (0.15 mole) of methyl bromide are
added to the intensively stirred solution, followed by
stirring for about 12 hours with gradual heating to room
temperature. The solvent is then removed in a rotary
evaporator. The residue is purified by recrystallisation
from anhydrous acetonitrile~ether.
Colourless crystals. Highly hygroscopic.
M.p.: approximately room temperature.
Yield: 11 g (90 % of the theoretical).
H-~MR (CDC13): 2.55 to 2.8 and 4.0 to 4.25 (m, morpholine),
3.3 (s, CH3), 4.95 (s,CH2), 7.4 to 8.4
(m, arom. CH).
