Note: Descriptions are shown in the official language in which they were submitted.
1 1~¢~7
The present invention describes new processes for the preparation of carbostyrilderivatives of general formula
~ 0 - D - S0 - R , ~I)
wherein Rl R4
W represents a vinylene group optionally substituted with a methyl group or
the ethylene group
D represents a straight or branched chain alkylene group with 2 to 6 carbon
atoms, a straight or branched chain hydroxyalkylene group with 3 to 6
carbon atoms or a xylylene group,
m represents the number 0, 1 or 2,
Rl represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,
R2 represents a cycloalkyl group with 3 to 6 carbon atoms, an aryl group wlth
6 to 10 carbon atoms, an aralkyl group with 7 to 11 carbon atoms, a hetero-
aryl group with 4 to 9 carbon atoms or a heteroalkyl group with 5 to 10
carbon atoms each containing a nitrogen atom and/or an oxygen or sulfur
atom or two nitrogen atoms, provided that:
(i) the above mentioned aromatic nuclei may be mono- or disubstituted by an
alkyl group with 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetyl-
amino, nitro, carboxyl, cyclohexylJ phenyl group or a halogen atom; and : -
~ii) additionally the above mentioned monosubstituted phenyl group may be mono-
or disubstituted by alkyl groups with 1 to 4 carbon atoms and/or halogen
atoms ~whereby the substituents of the phenyl nucleus may be ~he same or
different;
or R2 represents the 1,2,4-triazolyl, triphenylmethyl, 4,5-bis-~p-chloro-
'3~`'
~.1, -1-
.. . . ..
.. ., , , , . :. , '' '. .';
:
, ' :' ~
1 15~57
phenyl)-oxazol -2-yl, N-methyl-cyclohexylamino-carbonylmethyl or amino-
iminomethyl group; or, when either
m represents the number 1 or
D represents a straight- or branched chain hydroxyalkylene group with 3 to
6 carbon atoms or a xylylene group,
R2 may also represent an alkyl group with l to 6 carbon atoms;
R3 and R4, which may be the same or different, represent hydrogen atoms or
halogen atoms, alkyl groups with 1 to 4 carbon atoms, amino, acetylamino or
nitro groups.
The compounds of general formula I possess valuable pharmacological properties.
They possess not only a positive inotropic activity but in particular anti-
thrombotic activities. These compounds are described in more detail in our
Canadian Patent No. 1,116,600 issued January 19, 1982. It has now been found
that the carbostyrils of general formula I can be prepared according to the
following processes:
a) Cyclisation of a compound, optionally formed in situ in the reaction mixture,
of general formula
" R3
Z - C - W ~ ~
H - Ni ~ 0 - D - Sm - R2 , (II)
Rl 4
wherein
D, W, Rl, R2, R3, R4, and m are as defined above and Z represents a nucleo-
philically exchangeable group. Typical groups of this type are the hydroxy
~ -2-
, .
~15~5~
group, a halogen atom, an al~oxy, aryloxy or aralkoxy group, other groups
can also ~e used.
The cyclisation is preferably carried out in the presence of a con-lensing
agentJ such as sulfuric acid, conc. hydrochloric acid, phosphoric acid or
thionyl chlorideJ appropriately in a solvent such as glacial acetic acid,
tetrahydrofurane, dioxane, chloroform, tuluene, ethanol or in an excess of
the used condensing agent at elevated temperatures, e.g. at temperatures
between 50 and 200C, preferably however, at temperatures between 80 and
150C. The reaction can, however, also be carried out without a solvent
and/or condensing agent.
It is not necessary to isolate a compound of general formula II, which is
used as starting agent. This compound can be prepared in situ from the
corresponding nitro compound, e.g. by reduction of the nitro group with
hydrogen in the presence of a hydrogenating catalyst such as palladium/
charcoal, palladium/calcium carbonate or palladium/calcium carbonate + lead
acetate (Lindlar-catalyst), by reduction with metals such as iron, tin or
zinc in the presence of an acid, by reduction with salts such as iron-~II)-
sulfate, zinc-(II)-chloride, chromo-(II)-chloride or sodium di~hionite or
by reduction with hydrazine in the presence of Raney-Nickel.
If in a corresponding nitro compound m represents the number 1, the reduc-
tion of the nitro group is appropriately carried out with an equivalent
amount of the necessary reducing agent, e.g. with a metal salt such as iron-
(II)-sulfate, tin-(II)-chloride, chromo-(II)-chloride or sodium dithionite,
or with hydrogen in the presence of a deactivated hydrogenation catalyst,
e.g. in the presence of palladium/calcium carbonate + lead acetate. If,
-3-
. ~,
, :; :~ ~ :
1 1 5 ~ v 5 7
for example, the reduction is carried out in the presence of palladium/charcoal, the sulfoxyl group is also partly reduced.
If, furthermore, in a corresponding nitro compound W represents the viny-
lene group, this group can be hydrogenated to the corresponding ethylene
group, especially if the reduction is carried out with catalytically acti-
vated hydrogen, e.g. with hydrogen in the presence of palladium/charcoal.
b) For the preparation of compounds of general formula I, wherein m represents
the number 2:
Reaction of a carbostyril of general formula
W ~ R3
0 N ~ 0 - D - Y , ~III)
Rl 4
wherein
D, W, Rl, R3, and R4 are defined as mentioned before and Y represents a
nucleophilically exchangeable group such as a halogen atom or a sulfonic
acid ester radical, e.g. a chlorine, bromine, iodine atom, a p-toluene sul-
fonyloxy or methane sulfonyloxy groupJ with a metal salt of general formula
Me ~ ~ S02 - R2 ~IV)
wherein
R3 is defined as mentioned before and
Me represents an alkali or alkaline earth/2- metal atom such as the sodium,
potassium or calcium/2-atom.
--4--
. .
-. .:, : -; ,
, :. ;.
1 1~6~7
The reaction is carried out appropriately in a suitable solvent such as
dioxane, tetrahydrofurane, chloroform or toluene, preferably, however, in
a waterfree aprotic solvent such as acetone, dimethylformamide or dimethyl-
sulfoxide, optionally in the presence of an alkali base such as sodium car-
bonate, potassium carbonate or sodium hydroxide at temperatures between 0C
and the boiling temperature of the used solvent, e.g. at temperatures be-
tween O and 100 !C, preferably, however, at temperatures between 10 and 50~.
The reaction can also be carried out in the absence of a solvent.
c) For the preparation of compounds of general formula I, wherein W represents
the vinylene group and m represents the number O or 2.
Cyclisa~ion of a compound, optionally formed in the reaction mixture, of
general formula
OHC ~ R3
CH3CO \ ~ J ~ - D - Sm ~ R2, ,(V)
Rl
wherein
Rl, R2, R3, R4, D and m are defined as mentioned before or the acetal there-
of.
The cyclisation is carried out appropriately in glacial acetic acid or ace-
tic anhydride in the presence of an alkaliacetate such as sodium or po~as-
sium acetate at temperatures between 80 and 160C, preferably at the boiling
--5--
.: . . .
.,, ;
., . ; :1
::
. . ~
5 7
temperature of the reaction mixture, e.g. at temperatures between 118 and140C. A compound of general formula V is prepared appropriately by re-
duction of a corresponding nitro compound in the presence of ace~yl chloride
or acetic anhydride, this compound has not to be isolated.
The compounds o general formulae II to V which are used as starting mat-
erials are partly known from the literature, or they can be obtained ac-
cording to known methods.
Thus, a compound of general formula II is obtained by reduction of a cor-
l~; responding ~itro compound, which is obtained by alkylation of a correspond-
ing 2-nitro-5-hydroxy compound with a corresponding ~, ~ diahalogen alkane,
subsequent reaction with a corresponding mercapto compound and optionally
by subsequent oxidation with hydrogen peroxide.
A starting compound of general formula III is obtained by reaction of a
corresponding hydroxy carbostyril with a corresponding in ~, w-position
substituted alkane. The necessary corresponding 6-, 7- or 8-hydroxy-3,
4-dihydrocarbostyril is obtained by acylation of a corresponding aniline
derivative with a corresponding ~-halogen carboxylic acid derivative and
subsequent cyclisation according to Friedel-Crafts ~see J. Chem. Soc. 1955,
743 - 744, Chem. Pharm. Bull 1961, 970 - 975 and Ber. dtsch. Chem. Ges. 60,
858 ~1927)). A 5-hydroxy-3, 4-dihydrocarbostyril is obtained by cyclisa-
tion of a corresponding 2-~-cyanoethyl)-cyclohexanedione-1,3-derivative
and subsequent aromatisation for example with N-bromo-succinimide (see
Chem. and Ind. 1970, 1435). The preparation of the corresponding necessary
hydroxy-carbostyril is known from the literature ~see for example J. Amer.
Chem. Soc. 72, 346 ~1950) and ibid 76, 2402 ~1954) resp. J. Org. Chem. 33,
1089 ~1968) and ibid 36, 3493 ~1971)~.
--6--
- ::
:,
. .
A compound of general formula V used as starting compound is obtained for
example by alkylation of a corresponding hydroxy-nitro-benzaldehyde, or its
acetal or ester with a corresponding halogenide and subsequent reduction
of the nitro group in the presence of acetic anhydride.
The following examples serve to illustrate the invention:
Example 1
6-[4-(2-Pyridylsulfonyl)-butoxy]-3,4-dihydrocarbostyril
a) 2-Nitro-5-hydroxy-cinnamic acid méthyIester
21.0 g of 2-nitro-5-hydroxy-cinnamic acid ~S.N. Chakravarti and P.L.N.
Rao, Chem. Soc. 1938, 172) were dissolved in 200 ml of methanol. 86 ml of
thionylchloride were dropwisely added to this solution whilst stirring with-
in 45 minutes, whereby the temperature elevated to 36C. After stirring
for further 25 minutes the reaction mixture was cooled in the ice-bath and
18.6 g of 2-nitro-5-hydroxy-cinnamic acid methylester were obtained.
M.p.: 201-203C.
b) 2-Nitro-5-bromobutoxy-cinnamic acid methylester
A mixture of 22.3 g of 2-nitro-5-hydroxy-cinnamic acid methylester, 59.7
ml of l,4-dibromobutane and 13.8 g of potassium carbonate in 200 ml of
dimethylsulfoxide was stirred at room temperature for 15 hours. After
addition of 800 ml of water the reaction mixture was extraced with chloro-
form and after evaporation of the solvent 31.7 g of 2-nitro-5-bromobutoxy-
cinnamic acid methylester were isolated.
M.p.: 60.5 - 63C.
: : ~
.
1 15~57
c) 2-Nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamic acid-methylester
To a mixture of 5 g of potassium carbonate and 4.0 g of 2-mercaptopyridine
in lO0 ml of dimethylsulfoxide, which was stirred :Eor 60 minutes~ 10.75 g
of Z-nitro-5-bromobutoxy-cinnamic acid methylester were added and the mix-
ture was stirred for 18 hours at room temperature. 400 ml of water were
added and the oily reaction product was isolated by ether extraction.
Yield: 11.0 g ~94.2% of theory) ~ -
d) 2-Nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamic acid methylester
7.0 g of 2-nitro-5-[4-~2-pyridylmercapto)-butGxy]-cinnamic acid methylester
were dissolved in 70 ml of acetic acid. 5.0 ml of 35% hydrogen peroxide
were added and the mixture was kept standing for 3 days at room temperature.
After distilling off the glacial acetic acid~ the reaction product was re-
crystallized from chloroform/methanol.
Yield: 3.5 g ~46.2% of theory),
M.p.: 118 - 121C.
e) 6-[4-~2-Pyridylsulfonyl)-butoxy~-3,4-dihydrocarbostyril
2.1 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy~-cinnamic acid methylester,
dissolved in 2~ ml of glacial acetic acid, were hydrogenated with 0.5 g of
10% palladium charcoal at a hydrogen pressure of 3 bar and at room tempera-
ture. After distilling off the glacial acetic acid, the residue was re-
fluxed with 20 ml of conc. hydrochloric acid for 4 hours. The reaction pro-
duct was made neutral with 2n sodium hydroxide solution and extracted with
chloroform. The evaporation residue was recrystallized from xylene.
Yield: 1.06 g ~55.6% of theory),
M.p.: 121 - 123C/
. .
:
Example 2
6-[4-(2-Pyridylsulfonyl~-butoxyJ-carbostyril
A mixture of 2.0 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamic acid
methylester and 3.0 g of sodium dithionite was refluxed in 20 ml of water and
10 ml of ethanol for 4 hours, whereby a clear solution was obtained. The re-
action mixture was evaporated and refluxed to boiling with 20 ml of conc.
hydrochloric acid for 3 hours. After neutralisation with 2n sodium hydroxide
solution the reaction product was extracted with ether and recrystallized from
xylene by addition of little dimethylformamide.
Yield: 0.5 g (29% of theory),
M.p.: 176 - 179C.
This substance can be obtained in similar way, if instead of sodium dithionite
as reduction agent hydrogen in the presence of Lindlar ca~alyst (pa}ladium
partially inactivated by lead) was used. Thereby only the nitro group was
reduced, so that the 6-[4-(2-pyridylsulfonyl)-butoxy]-carbostyril was obtained
after the treatment with conc. hydrochloric acid.
~ample 3
6-[4-~3,4-Dichlorophenylmercapto)-butoxy]-carbostyril
4.5 g of 2-nitro-5-[4-(3,4-dichlorophenylmercapto)-butoxy]-cinnamic acid methy-
lester (m.p.: 91 - 92C, prepared from 2-nitro-5-hydroxy-cinnamic acid methy
lester and 4-(3,4-dichlorophenylmercapto)-butylbromide) were refluxed with
13.9 g of sodium dithionite in a mixture of 50 ml of ethanol and 50 ml of water
for 4 hours. After removing the solvent the residue was refluxed for 4 hours
with 100 ml of conc. hydrochloric acid. ~he obtained crystalline substance
_g
,
:, :
: ~ : ::,:
1 15~7
was suction filtered and recrystallized from xylene.
Yield: 1.2 g ~31% OI theory),
M.p.: 144C.
Example 4
6-L4-~3,4-DichlorophenylsuIfonyl~-butoxy]-3,4-dihydrocarbostyril
A mixture of 5.96 g of 6-(4-bromo-butoxy)-3,4-dihydrocarbostyril~ 5.53 g of
potassium carbonate and 18.75 g of sodium salt of 3,4-dichlorophenylsuffinic
acid was stirred for 24 hours at room temperature in 50 ml of absolute dime-
thylsulfoxide. After adding 500 ml of ethyl acetate, the mixture was washedNith water and dried over magnesium sulfate. The solution was evaporated and
the crystalline reaction product was obtained.
Yield: 4.65 g ~54~ of theory),
M.p.: 170 - 171C.
Example 5
~ = . ~
6-[4-(3,4-~ichlorophenyl-sulfinyl)-butoxy]-carbostyril
a) 2-Nitro-5-[4_~3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methylester
11.2 g of 2-nitro-5-hydroxy-cinnamic acid methylester were dissolved in 150
ml of dimethylsulfoxide. The solution was mixed with 9.2 g of waterfr`ee
potassium carbonate and stirred for 15 minutes. 16.5 g of 4-(3,4-dichloro-
phenylsulfinyl)-butylbromide were added and the mixture was stirred for 40
hours at room temperature. The reaction mixture was diluted with 1000 ml
of water and extracted with a mixture of 200 ml of chloroform and 100 ml of
methanol, After evaporation of the organic solven~ an oily residue was
obtained, which was obtained in crystalline form after treating with ether.
-10-
., . ,. '~
- ~ . ,, .
-
Yield: 13 g ~57% of theory),
M.p.: 78 - 81~.
b) 2-A~ino-5-~4-~3,4-dichlorophenylsulfinylJ-butoxy~-cinnamic acid methyIester
4.2 g of 2-nitro-5-[4-~3,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid
methylester were hydrogenated in 100 ml of methanol with 0.5 g of Lindlar-
catalyst (palladium on calcium carbonate, partially inactivated by lead
acetate) at a hydrogen pressure of 3 bar and room temperature for 12 hours.
After removing the catalyst the solvent was e~aporated and the resinous
dark residue was used directly for the following reaction.
c) 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]-carbostyril
The 2-amino-5-[4-13,4-dichlorophenylsulfinyl)-butoxy]-cinnamic acid methy-
lester, described in the before mentioned example b), was heated -to boil-
ing with 80 ml of 5n hydrochloric acid for 3 hours and hot filtered. After
cooling the filtrate, colourless crystals were obtained.
Yield: 2.1 g (56% of theory),
.p.: 191 - 192C.
If in the before mentioned reaction procedure iron powder and 80% acetic
acid as ag~ts was used for the reduction of the 2-nitro-5-[4-(3,4-dich-
lorophenylsulfinyl)-butoxy]-cinnamic acid methylester, also 6-[4-(3,4-
dichlorophenylsulfinyl)-butoxy~-carbostyril was obtained as reaction product.
~ample 6
2.3 g of 2-nitro-5-(3~4-dichlorophenylsulfinyl~-butoxy-cinnamic acid methy-
lester were hydrogenated analogously to Example 5b in 20 ml of glacial acetic
acid and 0.2 g of palladium/charcoal at a hydrogen pressure of 3 bar and at
-11 - ,
;
~ 15~7
room temperature for 7 hours. After removing the catalyst~ the glacial acetic
acid was distilled off and the residue was heated to boiling with 40 ml of 5n
hydrochloric acid for 1 hour. After cooling the r0action mixture was extracted
with little chloroform and separated by chromatography on a thin-layer plate
(Merck silicagel 60 F254) with ethylene chloride/methanol = 9:1. The result-
ing compounds were identified in UV-light and by spraying with iodine spray.
Rf value: 0.30: 6-[4-~3,4-dichlorophenylsulfinyl)-butoxy]-carbostyril, with
iodine spray blue-violet.
0~l Rf value: 0.42: 6-[4-~3,4-dichlorophenylmercapto)-butoxy]-carbostyril, with
iodine spray firstly orange-yellow, then gradually grey-
violet.
Rf value: 0.45: 6-[4-~3,4-dichlorophenylsulfinyl)-butoxy]-3,4-dihydro-carbo-
styril, with iodine spray strongly orange-yellow.
Rf value: 0.57: 6-[4-~3,4-dichlorophenylmercapto)-butoxy]-3,4-dihydro-carbo-
styril, with iodine spray light-yolk.
Example 7
6-[4-(2 Pyridylsulfonyl~-butox _-carbostyril
a) 2-Nitro-5-(4-bromobutoxy~-benzaldehyde
A mixture of 14.4 g of 2-nitro-5-hydroxybenzaldehyde carbonate ~F.A. Mason,
J. Chem. Soc. 127, llg7 ~1925)) 3 40 ml of dibromobutane and 24 g of water-
free potassium carbonate Dn 140 ml of dimethylsulfoxide was stirred for 4
hours at room temperature. After diluting with 800 ml of water, the reaction
product was extracted with chloroform. The excess of dibromobutane was
-12-
1 156~57
removed from the oily evaporation residue by digesting several times withpetroleum ether. The remaining oily 2-nitro-5-~4-bromobutoxy)-benzalde-
hyde (21 g) was rawly further processed.
Rf value: 0.75 (thinlayer plate ~Merck silicagel 60 F 254)~ eluant: ethy-
lene chloride/methanol = 9:1)).
b) 2-Nitro-S-[4-(2-pyridylmercapto~-butoxy]-benzaldehyde
A mixture of 21 g of the raw 2-nitro-5-(4-bromobutoxy)-benzaldehyde, 11.6 g
of 2-mercaptopyridine and 20 g of waterfree potassium carbonate was stirred
for 6 hours at room temperature in 100 ml of dimethylsulfoxide. The reaction
mixture was diluted with 500 ml of water, extracted with chlaroform and the
organic solvent was removed in vacuo.
.
c) 2-Acetamino-5-[4-(2-pyridylsulfonyl)-butoxy]-beniald~yde-diacetate
6.6 g of the raw 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-benzaldehyde were
heated to boiling with 3 ml of acetic acid anhydride and 0.01 g of water-
free zinc chloride for 30 minutes. After cooling the reaction mixture was
stirred with 60 ml of glacial acetic acid and 2!5 g of 35% hydrogen peroxide
for 15 hours at room temperature. ~le reaction mixture was hydrogenated in
a parr-apparatus by addition of 0.1 g of palladium/charcoal at a hydrogen
pressure of 3 bar for 11 hours at room temperature. For the acetylation of
the formed amino compound the reaction mixture was evaporated in vacuo to
dryness, heated again with 20 ml of acetic acid anhydride for 30 minutes and
the excess acetic acid anhydride and glacial acetic acid was distilled off.
d) 6-[4-(2-Pyridylsulfonyl~-bu~oxy]-carbostyril
~ ..... - -- -- - .
The distillation residue from the preparation mentioned before was heated
-13-
. : ~
,: . ~ . : .,
l 156~7
to boiling with 20 ml of ace,tic acid anhydride and 5 g of waterfree potas-
sium acetate for 14 hours. After cooling 20 ml of water were added and the
mixture was kept standing over night. Colourless crystals were obtained.
Yield: 2.9 g (41% of theory)
M.p,: 178 - 179~.
Example 8
6-[4-(2-PyridylsulfonylJ-butoxy]-carbostyril
a) 2-Nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-benzaldehyde
1,0 g of the 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-benzaldehyde prepre-
pared analogously to Example 7b were dissolved in 100 ml of glacial acetic
acid, 1~.~0 ml of 35% hydrogen peroxide was added and the solution was stir-
red for 60 hours at room temperature. After diluting with 200 ml of water,
t,he reaction mixture was extracted with chloroform/methanol = 2:1 and after
evaporation an oil was obtained.
Yield: 1 g (91% of theory),
Rf-value: 0,17 (silicagel fluorescent plate ~erck 60 F254 developing agent:
cyclohexane/ethyl acetate = 1:2.
b) 2-Amino-5-[4-(2-pyridylsulfonyl)-butoxy~-benzaldehyde
The oil obtained analogously to a) was reduced with ferrous sulfate-hepta-
hydrate/conc. aqueous ammonia at 90C.
c) 6-[4-~2-PyridylsulfonylJ-butoxy]-carbostyril
The 2-amino-5-[4-(2-pyridylsulfonyl)-butoxy]-benzaldehyde obtained analo-
gously to Example b) was acetylated with acetic anh~dride:pyridine. After
-14-
5 7
distilling off the volatile parts, the reaction mixture was again taken up
in acetic anhydride and refluxed for 5 hours with waterfree potassium ace-
tate. After cooling the product was diluted with water and extracted with
chloroform/methanol -:2:1. After a short time the evaporation residue
crystallized a~d the product obtained was recrystallized from xylene by
addition of little dimethylformaldehyde.
M.p.: 179 - 181C.
The following compounds were prepared analogously to the Examples mentioned
before:
6-~4-Phenylmercapto-butoxy)~3,4-dihydrocarbostyril
M.p.: 121.5 - 123C
6-(4-Phenylsulfinylbutoxy)-3,4-dihydrocarbostyril
M.p.: 144.5 - 145.5C
6-~4-Phenylsulfonylbutoxy)-3,4-dihydrocarbostyril
M.p.: 157.5 - 158C
6-[4-~2-Pyridylmercapto)-butoxy]-3,4-dihydrocarbostyril
20 M.p.: 123 - 124.5C
6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 144.5 - 146C
6-[4-~2-Pyridylsulfonyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 123.8 - 125C
6-~2-Phenylsulfinyl-ethoxy)-3,4-dihydrocarbostyril
M.p.: 171 - 172C
-15-
. . .
5 7
6-~4-Benzylsulfinyl-butoxy)-3,4-dihydrocarbostyril
M.p.: 141.5 - 142C
6-[4-~4-Chlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 148 - 149.5C
6-~4-Cyclohexylsulfinyl-butoxy)-3,4-dihydrocarbostyril
M.p.: 153 - 155.5C
6-[4-~2-Naphthylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
10 M.p.: 147.5 - 148.5C
6-[4-~2-Methoxyphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p,: 130.5 - 133C
6-~4-Phenylsulfinyl-butoxy)-carbostyril
M.p.: 181 - 182.5C
6-[4-~4-Hydroxy-3,5-di-tert.butyl-phenylsulfinyl)-butoxy]-carbostyril
M.p.: 192 - 194C
6-L4-~3,4-Dichlorophenylsulfinyl)-butoxy]-carbostyril
20 M.p,: 191 - 196C
4-Methyl-6-~4-phenylsulfinyl-butoxy)-carbostyril
M.p.: 167 - 168C
6-[4-~3,4-Dichlorophenylsulfonyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 172 - 173C
6-[4-~2,5-Dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 185 - 186C
-16-
.' . ' .,
'
1 15~57
6-[4-~2-Pyridyl~-sulfonyl-butoxy~-carbostyril
M.p.: 179 - 180C
6-[4-12-Naphthyl-sulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 147.5 - 148.5C
6-[4-~4-Biphenylylsulfinyl)-butoxy]-carbostyril
M.p.: 196 - 197C
6-~4-(2-Quinolylsulfinyl)-butoxy]-carbostyril
10 M.p.: 197 - 198C
6-[4-Cyclohexylsulfinyl)-butoxy]-carbostyril
M.p.: 169 - 170C
5-Bromo-6-t4-phenylsulfinyl-butoxy)-carbostyril
M.p.: 190 - 191C
6-~2-~N-methyl-N-cyclohexyl-carbamidomethyl-sulfinyl)-ethoxyl-carbostyril
M.p.: 128 - 130C
6-[4-(3,5-Dibromo-4-aminophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
20 M.p.: 144 - 146C
6-[4-~3,5-Dibromo-4-aminophenylsulfinyl)-butoxy]-carbostyril
M.p.: 205 - 207C
6-[4-(3,4-Cyclohexylphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 155 - 157C
6-[4-(4-Cyclohexylphenylsulfinyl)-butoxy]-carbostyril
M.p.: 188 - 190c
-17-
:, .
, . ` , ~ : . ~ ~ ,: ;:
~, : . ,
~:1 5~7
6-[4-~4-tert.Butylphenylsulfinyl)-butoxy~-carbostyril
M.p.: 164 - 166C
$-[4-~3,4-Dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril
M.p.: 106.5 - 108C
M.p.: 148 - 149C ~1 x from toluene and 1 x from ethanol)
,
..
. ~.
