NZ194531A - Pharmaceutical compositions containing substituted carbostyrils - Google Patents
Pharmaceutical compositions containing substituted carbostyrilsInfo
- Publication number
- NZ194531A NZ194531A NZ194531A NZ19453180A NZ194531A NZ 194531 A NZ194531 A NZ 194531A NZ 194531 A NZ194531 A NZ 194531A NZ 19453180 A NZ19453180 A NZ 19453180A NZ 194531 A NZ194531 A NZ 194531A
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- butoxy
- melting point
- dihydrocarbostyril
- carbon atoms
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Description
New Zealand Paient Spedficaiion for Paient Number 1 94531
Priority Date(s): .'fiP.'.li.
Complete Specification Filed:
Class:
Publication Date: ... 24.AU5.iSM.
P.O. Journal, Wo: ..Wf}-.-.
IT "" '
WJZL RVFENT CFFICg
Patents Form No. 5
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION
PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION OF TUMDUR METASTASIS
I/WE DR KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a Body Corporate organised under the laws of the Federal Republic of Germany, of Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 - (Followed by page 1A)
-
Pharmaceutical compositions for the prevention of tumour metastasis
The present invention relates to pharmaceutical compositions for the treatment of humans and animals 5 for the prevention of tumour metastasis or for the prophylaxis of metastases.
It has been found that those compounds designated below as compounds of general formula I have an inhibiting activity on tumour metastasis. This activity is 10 believed to be based on a reduction of the stickiness of cancer cells, as a result of which their adhesion in the body and therefore the occurrence of metastases are prevented or avoided.
According to one aspect of the present invention 15 we therefore provide pharmaceutical compositions comprising as an active ingredient at least one compound of general formula I
W
A
R.
R.
0 -
D - SO - R_
m 2
(I)
[wherein
W represents a vinylene group optionally substituted 20 by a methyl group or a methylene or ethylene group; m is 0, 1 or 2;
D represents a straight-chained or branched alkylene group with 2 to 6 carbon atoms, a straight-chained or branched hydroxyalkylene group with 3 25 to 6 carbon atoms or a xylylene group;
represents a hydrogen atom or an alkyl group
194531
with 1 to 3 carbon atoms;
1*2 represents a cycloalkyl group with 3 to 6 carbon atoms, an aryl group with 6 to 10 carbon atoms, an aralkyl group with 7 to 11 carbon atoms, 5 a heteroaryl group with 4 to 9 carbon atoms, a heteroaralkyl group with 5 to 10 carbon atoms (the said heteroaryl group or the heteroaryl moiety of the said heteroaralkyl group containing (a) a nitrogen atom and/or an oxygen or sulphur atom or (b) two nitrogen atoms) 10 wherein the above-mentioned aryl or heteroaryl group or the aryl moieties of the above-mentioned aralkyl . or heteroaralkyl groups may optionally be monosubstituted by an alkyl group with 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl, 15 cyclohexyl or phenyl group or by a halogen atom and wherein if R2 represents a monosubstituted phenyl group or a phenylalkyl group of which the phenyl moiety is monosubstituted, such phenyl group or phenyl moiety may further be mono-or di-substituted by substi-20 tuents selected from halogen atoms and alkyl groups with 1 to 4 carbon atoms; or R2 represents a 1,2,4-triazolyl, triphenylmethyl, 4,5-bis-(p-chlorophenyl)-oxazol-2-yl, N-methy1-cyclohexylaminocarbonylmethyl or amino-iminomethyl group; or, where m is 1 or D 25 represents a straight-chained or branched hydroxyalkylene group with 3 to 6 carbon atcms or a xylylene group, R2 additionally represent an alkyl group with 1 to 6 carbon atoms,
R., and R., which can be the same or different,
3 4
each represents a hydrogen or halogen atom, an alkyl 30 group with 1 to 4 carbon atoms or an amino, acetylamino or nitro group] together with one or more pharmaceutical
-C4he/\ -t*» c\. ^crnx s>*iroJ>le fey juiC
carriers and/or excipients^ pnphijL^xn 0/ tumcur n\etartnse$.
By the expression "a halogen atom" mentioned in the definition of the radicals R2, R3 and is 35 meant especially a fluorine, chlorine, bromine or iodine atom.
1 ?
The radicals D, R^, R2, R^ and R^ may, for example, have the following meanings:-(for D) an ethylene, n-propylene,
n-butylene, n-pentylene, n-hexylene, 1-methyl-ethylene, 5 2-methyl-ethylene, 1-methyl-n-propylene, 2-methyl-
n-propylene, 3-methyl-n-propylene, 1-methyl-n-butylene,
2-methyl-n-butylene, 3-methyl-n-butylene, 4-methyl-n-butylene, 1-methyl-n-pentylene, 2-methyl-n-pentylene,
3-methyl-n-pentylene, 4-methyl-n-pentylene, 5-methyl-
n-pentylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 2,2-dimethylethylene, 1,1-dimethyl-n-propylene, 2,2-dimethyl-n-propylene, 3,3-dimethyl-n-propylene, 1,2-dimethyl-n-propylene, 1,3-dimethyl-n-propylene, 1,1-dimethyl-n-butylene, 2,2-dimethyl-n-butylene, 3,3-15 dimethyl-n-butylene, 4,4-dimethyl-n-butylene, 1,2-dimethyl-n-butylene, 1,3-dimethyl-n-butylene, 1,4-dimethyl-n-butylene, 2,3-dimethyl-n-butylene, 1-ethyl-ethylene, 2-ethyl-ethylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene, 3-ethyl-n-propylene, 1-ethyl-20 n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-butylene,
4-ethyl-n-butylene, l-methyl-2-ethyl-ethylene, 1-rnethyl-2-ethyl-n-propylene, 1-me thyl-3-ethyl-n-propylene,
1-methyl-2-propyl-ethylene, 1-propyl-ethylene, 1-butyl-ethylene, 1-propyl-n-propylene, 2-hydroxy-n-
propylene, 2-hydroxy-n-butylene, 3-hydroxy-n-butylene,
2-hydroxy-n-pentylene, 3-hydroxy-n-pentylene, 4-hydroxy-n-pentylene, 2-hydroxy-n^hexylene, 3-hydroxy-n-hexylene, l-methyl-2-hydroxy-n-propylene, 2-hydroxy-2-methyl-n-propylene, p-xylylene, o-xylylene or m-xylylene
group;
(for R^) a hydrogen atom or a methyl, ethyl,
propyl or isopropyl group;
(for R2) a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, naphthyl, 35 naphthylmethyl, cyclohexylphenyl, biphenyl, triphenylmethyl, N-methyl-cyclohexylaminocarbonylmethyl, amino-iminomethyl, pyridyl, pyridylmethyl, furfuryl, benzimidazolyl, benzothiazolyl, pyrimidyl, quinolyl, quinazolin-4-
1
A
K-
on-ylf 4,5-bis-(p-chlorophenyl)-oxazol-2-yl, pyridyloxide, methylphenyl, dimethylphenyl, tert.butylphenyl, methyl-tert.butylphenyl, methyl-pyridyl, methoxyphenyl, dimethoxyphenyl, methoxypyridyl, hydroxyphenyl, dihydroxy-5 phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, 1,2,4-triazolyl, fluoropyridyl, chlorophenyl, dichloro-phenyl, trichlorophenyl, chloropyridyl, bromophenyl, dibromophenyl, aminophenyl, acetylaminophenyl, amino-pyridyl, acetylaminopyridyl, nitrophenyl, carboxy-10 phenyl, hydroxy-dichlorophenyl, hydroxy-dibromophenyl, amino-dichlorophenyl, amino-dibromophenyl, hydroxy-di-tert.butylphenyl, methoxyfluorophenyl, methoxychloro-phenyl, methoxybromophenyl, fluoromethylphenyl, chloro-methylphenyl or bromomethylphenyl group; 15 (for and R^, which can be the same or different)
a hydrogen, fluorine, chlorine, bromine or iodine atom, or a methyl, ethyl, propyl, isopropyl, butyl, tert.butyl, nitro, amino or acetylamino group.
Compositions of the present invention include 20 in particular those compositions which contain a compound of general formula I in which:
W, D and m are as defined above;
R2 represents a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl oxide, 25 furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzothiazolyl, quinazolin-4-on-yl, 4,5-bis-(p-chlorophenyl) -oxazol-2-yl, N-methyl-cyclohexylaminocarbonyl-methyl or amino-iminomethyl group, a phenyl group optionally substituted by a carboxyl, hydroxy, methoxy, 30 amino, acetylamino, nitro, cyclohexyl or phenyl group, a phenyl group mono-or disubstituted by halogen atoms and/or alkyl groups with 1 to 4 carbon atoms, or a hydroxyphenyl, halophenyl or aminophenyl group substituted by two halogen atoms or by two alkyl 35 groups each with 1 to 4 carbon atoms;
R^ represents a hydrogen, chlorine or bromine atom or a methyl, amino, acetylamino or nitro group;
and
19453
represents a hydrogen atom.
Preferred compositions of the present invention are those which contain a compound of the above general formula I in which:
W represents a vinylene group optionally substituted by a methyl group,or an ethylene group;
m is 0, 1 or 2;
D represents an alkylene group with 2 to 5 carbon atoms or a hydroxyalkylene group with 3 to 10 5 carbon atoms;
R^ represents a hydrogen atom;
R2 represents a cyclohexyl, phenyl, benzyl,
naphthyl, biphenylyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, 15 dichlorophenyl, trichlorophenyl, bromophenyl, dibromo-phenyl, bromo-methyl-phenyl, amino-dibromophenyl or hydroxy-di-tert.butylphenyl group; and
R^ and R^ each represent a hydrogen atom.
However, especially preferred compositions 20 according to the present invention are those which contain a compound of the above general formula I in which:
W represents an ethylene, vinylene or 2-methyl vinylene group;
m is an integer having the value 0, 1 or 2;
R^, R^ and R^ each represents a hydrogen atom;
R2 represents a cyclohexyl, phenyl, benzyl, napthyl-(2), 2-methoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-amino-3,5-dibromo-30 phenyl, 4-hydroxy-3,5-di-tert.butylphenyl or pyridyl-(2) group; and
D represents an ethylene, n-propylene, n-butylene or 2-hydroxy-n-propylene group.
As already mentioned above, the compounds of ^ 35.\the above general formula I have an inhibiting activity "} on tumour metastasis. This activity is believed
'6!
^ }jto be based on a reduction of the stickiness of cancer ^ \vAcells, as a result of which their adhesion in the
body and therefore the occurrence of metastases are prevented or avoided.
The inhibiting activity on tumour metastasis was tested as a stickiness-reducing activity based 5 on phosphodiesterase (PDE) inhibition for the following compounds:
A = 6-(4-Phenylmercapto-butoxy)-3,4-dihydrocarbostyril, B = 6-(4-Phenylsulfinylbutoxy)-3,4-dihydrocarbostyril, C = 6-(4-Phenylsulfonylbutoxy)-3r4-dihydrocarbostyril, 10 D = 6-[4-(2-Pyridylmercapto)-butoxy]-3,4-dihydrocarbo-styril,
E = 6-[4-(2-Pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyr il,
F = 6-[4-(2-Pyridylsulfonyl)-butoxy]-3,4-dihydrocarbo-15 styril,
G = 6-(2-Phenylsulfinyl-ethoxy)-3,4-dihydrocarbostyril, H = 6-(4-Benzylsulfinyl-butoxy)-3,4-dihydrocarbostyril, I = 6-[4-(4-Chlorophenylsulfinyl)-butoxy]-3,4-dihydro-carbostyril,
K = 6-(4-Cyclohexylsulfinyl-butoxy)-3,4-dihydrocarbo-styril,
L = 6-[4-(2-Naphthylsulfinyl)-butoxy]-3,4-dihydrocarbo-styril, ,
M = 6-[4-(2-Methoxyphenylsulfinyl)-butoxy]-3,4-dihydro-25 carbostyril,
N = 6-(4-Phenylsulfinyl-butoxy)-carbostyril, 0 = 6-[4-(4-Hydroxy-3,5-di-tert.butyl-phenylsulfinyl)-butoxy]-carbostyril,
P = 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]-carbo-30 styril,
Q = 4-Methyl-6-(4-phenylsulfinyl-butoxy)-carbostyril, R = 6-[4-(3,4-Dichlorophenylsulfonyl)-butoxy]-3,4-dihydrocarbostyril,
S = 6-[4-(2,5-Dichlorophenylsulfinyl)-butoxy]-3,4-35 dihydrocarbostyril,
T = 6-[4-(2-Pyridyl-sulfonyl)-butoxy]-carbostyril, U = 6-[4-(2-Naphthyl-sulfinyl)-butoxy]-3,4-dihydro-
1 €> / ^ ^
• J ' I /t- ' . -v /, N tj
■ ^ i. ^ rj
carbostyril,
V = 6-[4-(4-Biphenylylsulfinyl)-butoxy]-carbostyril, W = 6-[4-(2-Quinolylsulfinyl)-butoxy]-carbostyril, X = 6-(4-Cyclohexylsulfinyl-butoxy)-carbostyril, 5 Y = 5-Bromo-6-(4-phenylsulfinyl-butoxy)-carbostyril,
Z = 6-[2-(N-Methyl-N-cyclohexyl-carbamidomethyl-sulfinyl)-ethoxy]-carbostyril,
AA = 6-[4-(3,5-Dibromo-4-aminophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril, 10 BB = 6-[4-(3,5-Dibromo-4-aminophenylsulfinyl)-butoxy]-carbostyr il,
CC = 6-[4—(4-Cyclohexylphenylsulfinyl)-butoxy]-3,4-dihydro-carbostyril,
DD = 6-[4-(4-Cyelohexylphenylsulfinyl)-butoxy]-carbo-15 styril,
EE = 6-[4-(4-tert.-Butylphenylsulfinyl)-butoxy]-carbostyril and
FF = 6-[4-(3,4-Dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyr il.
1.) PDE inhibition Pr inciple cAMP is hydrolysed to AMP by phosphodiesterase (PDE) from various sources, including blood platelets.
This hydrolysis is inhibited by PDE inhibitors according 25 to the concentration.
Method:
The phosphodiesterase used is the 10,000 x g supernatant of human blood platelets which have 30 been frozen with water and thawed out again.
0.3 ml of a mixture which contains 0.1 mol/litre of trihydroxy-aminomethane (pH 7.4), 3 mmol/litre of magnesium chloride, 1 mmol/litre of AMP, 1 jimol/litre of ^H-cAMP (specific activity about 10 MBq/jimol) ,
PDE as well as the substance to be tested and water for the control are incubated for 15 minutes at 37UC. The incubation is stopped by the addition of
0.5 ml of zinc sulphate (0.266 mol/litre) and 0.5 ml of barium hydroxide (0.266 mol/litre), the precipitate is centrifuged and the activity remaining in the
3
supernatant of the unreacted H-cAMP is determined. From a comparison of the substance preparations and the control preparations the concentration for a 50% inhibiting activity (IC,.^) of the respective substance was calculated:
I
/SP>N
'i- ■
Substance ^SO
A 0.78
B 1.9
C 1.5
D 1.6
E 3.9
F 3.8
G 3.4
H 1.6
I 0.8
K 2.5
L 0.14
M 0.15
N 0.47
0 0.079
P 0.22
Q 0.64
R 1.8
S 2.1
T 1.0
, , U 0.14
V 0.12
W 0.14
X 0.7
Y 0.1
Z 0.5
AA 0.25
BB 0.05
CC 1.6
DD 0.04
EE 0.03
FF 0.27
J Q /
* * ~;
The inhibiting activity on tumour metastasis can be proved also according to Gastpar et al. (see Thrombosis Research j>. 277-289 (1974)) as an activity preventing tumour cell embolism. Here, the substance 5 to be tested is applied before the tumour cell transplantation and the survival rate of the test animals, for example rats, is determined against controls.
2. Acute toxicity:
The acute toxicity of the substances to be 10 tested was determined on groups of 10 mice each after oral administration of a dose of 1,000 mg/kg (observation time: 14 days):
h
Substance Acute toxicity per os
A
1,
000
mg/kg
(0
out of
animals died)
B
1,
000
mg/kg
(0
out of
animals died)
C
1,
000
mg/kg
(0
out of
animals died)
D
1,
000
mg/kg
(0
out of
animals died)
E
1,
000
mg/kg
(0
out of
animals died)
F
1,
000
mg/kg
(0
out of
animals died)
G
1,
000
mg/kg
(0
out of
animals died)
H
1,
000
mg/kg
(0
out of
animals died)
I
1,
000
mg/kg
(0
out of
animals died)
K
1,
000
mg/kg
(0
out of
animals died)
L
1,
000
mg/kg
(0
out of
animals died)
M
1,
000
mg/kg
(0
out of
animals died)
0
1,
000
mg/kg
(0
out of
animals died)
P
1,
000
mg/kg
(0
out of
animals died)
Q
1,
000
mg/kg
(0
out of
animals died)
R
1,
000
mg/kg
(0
out of
animals died)
S
1,
000
mg/kg
(0
out of
animals died)
T
1,
000
mg/kg
(0
out of
animals died)
U
1,
000
mg/kg
(0
out of
animals died)
FF1 >
1,
000
mg/kg
(0
out of
animals died)
The compositions of the present invention are conveniently in a form suitable for oral, rectal or parenteral administration. To prepare the compositions 30 of the present invention in such forms, the compounds of general formula I can be processed, optionally in combination with other active substances, into conventional pharmaceutical preparation forms such as coated tablets, tablets, capsules, suppositories 35 or suspensions.
The compositions of the present invention may advantageously be administered in doses of from 4 to 9 mg of the active ingredient of formula I per
" ' ' 1 94531
... - 12 -
kg of body weight per day, preferably in doses of 2 to 3 mg/kg and most preferably 2.5 mg/kg' administered 2 or 3 times daily. Thus the single dose for a human is about 100 to 300 mg of the active substance and 5 the compositions of the invention may be presented in the form of dosage units of such a content.
According tn a—further aspect of the presenj invention we provide a method for the prophylaxis of metastases which comprises admin>s-t£ring to a 10 human or animal body an eff^ctlve amount of a compound of general formula i^ffflfdef ined above) .
In the^jrartfiod of the present invention the com^9i*flt5of formula I is preferably administered uri a composition of the present invention.
According to a yet further aspect of the present invention we provided a pack comprising a pharmaceutical composition and instructions for the use thereof in the prophylaxis of metastases; said composition comprising as an active ingredient at least one compound 20 of general formula I ( as hereinbefore defined).
In the pack according to the present invention it is preferable that the composition be a composition according to the invention.
The compounds of general formula I may be obtained 25 by processes known per se, such compounds and the preparation thereof are described and claimed in Hew Zealand Patent Specification No. 189685., For example, they are obtained by Reacting a hydroxy compound of general formula II
(II)
[wherein
R^, R^, R^ and W are as defined above] or salts thereof with inorganic or tertiary organic bases,
with a compound of general formula III
Z - D - S0m - R2 (III)
[wherein
D, R2 and m are as defined above, and 10 Z represents a nucleophilically exchangeable group such as a halogen atom or a sulphonic acid ester radical, for example a chlorine, bromine or iodine atom or a p-toluenesulphonyloxy or methane-sulphonyloxy group (see Example 1)]. 15 The reaction is appropriately effected in a suitable solvent such as dioxan, tetrahydrofuran, chloroform or toluene, but preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethyl-sulphoxide, optionally in the presence 20 of an alkali metal base such as sodium carbonate,
potassium carbonate or sodium hydroxide, at temperatures between 0UC and the boiling temperature of the solvent used, for example at temperatures between 0 and 100°C, but preferably at temperatures between 10 and 50~C. 25 The reaction can, however, also be effected without a solvent.
The compounds of general formulae II and III used as starting materials are partly known from the literature or may be obtained by processes known 30 per se. For example, a 6-, 7- or 8-hydroxy-3,4-dihydro-carbostyril of general formula II is obtained by acylation of a corresponding aniline derivative with a corresponding 8-halo-carboxylic acid derivative and subsequent cyclisation according to Friedel-Crafts 35 (see J. Chem. Soc. 1955, 743-744, Chem. Pharm.
Bull 1961, 970-975 and Ber. dtsch. Chem. Ges. 60, 858 (1927)) or a 5-hydroxy-3,4-dihydro-carbostyril of general formula II is obtained by cyclisation
of a corresponding 2-(B-cyanoethyl)-cyclohexane-dione- ' 1,3 derivative and subsequent aromatisation, for example with N-bromo-succinimide (see Chem. and Ind. 1970, 1435). The preparation of the corresponding 5 hydroxy-carbostyrils of general formula II is known from the literature (see e.g. J. Amer. Chem. Soc. 72, 346 (1950) and ibid 76, 2402 (1954) or J. Org.
Chem. 33, 1089 (1968) and ibid. 36, 3493 (1971)). Furthermore, the preparation of 5-hydroxyindole is 10 described in J. Chem. Soc. 1961, 2723.
The following Examples are intended to illustrate the invention in detail without serving to limit the scope of protection sought therefor:
• 11 c
0 n/ ''t' u
Example 1
6-(4-Phenylsulf inylbutoxy)-3,4-dihydrocarbostyril
32.6 g (0.2 mol) of 6-hydroxy-3,4-dihydrocarbo-styril (see F. Mayer et al. in Ber. dtsch. chem.
Ges. _60., 858 (1927)) and 27.6 g (0.2 mol) of potassium carbonate are stirred for 5 minutes in 600 ml of dimethylsulphoxide dried via a molecular screen and are then mixed with 52.2 g of 4-phenylsulfinylbutyl bromide (0.2 mol) (prepared from thiophenol and 1,4-10 dibromobutane and subsequent oxidation with hydrogen peroxide in glacial acetic acid; oily substance solidifying upon standing in a refrigerator). The mixture is stirred for 15 hours at 25UC and then poured into . 6 litres of water. Subsequently, it is stirred for 15 a further 13 minutes, the precipitated product is filtered off with suction and washed thoroughly with water. After drying, it is recrystallised with charcoal treatment from about 600 ml of xylene. White crystals of melting point 144.5-145 . 5UC are obtained. Yield: 20 49 g (71.3% of theory).
Example 2
-(4-Phenylmercapto-butoxy)-carbostyril
A mixture of 32.3 g of 5-hydroxycarbostyril,
30 g of potassium carbonate and 650 ml of dimethylsulphoxide dried via a molecular screen is mixed with 49 g of 4-phenylmercaptobutyl bromide. The mixture is stirred for 20 hours at 25°C and diluted with 3 litres of water and the reaction product which has crystallised 30 out is filtered off with suction. Melting point:
185-187°C (from toluene), yield: 45.0 g (70% of theory).
Example 3
6-(4-Phenylsulfonyl-butoxy)-3,4-dihydrocarbostyr il
Prepared analogously to Example 1 from 6-hydroxy-3,4-dihydro-carbostyril and 4-phenyl-sulfonyl-butyl bromide (prepared from 4-(phenylmercapto)-butyl bromide
by oxidation). Melting point: 157.5-158°C, yield 65.1% of theory.
Analogously to Examples 1, 2 and 3 the following compounds are prepared^
6-/4- (2-Pyridylmercapto) -butoxy/-3, 4-dihydrocarbostyril Melting point:^23 - 124,5 C
6- (4-Phenylmercapto-butoxy)-3,4-dihydrocarbostyril Melting point:!21.5 - 123 C
6-/44-Fluorophenylmercapto) -butoxy/- 3, 4-dihydrocarbostyril Melting point:139 - 140°C
6-/4- (4-Methylphenyl-mercapto)-butoxy/-3,4-dihydrocarbostyril •Melting point:1 20 - 121°C
6-/_4- (3-Methylphenylmereapto)-butoxy/-3,4-dihydrocarbostyril Melting point:95 - 96°C
6-/4-(4-Ch]orcphenylmercapto)-butox^/-3,4-dihydrocarbostyril 'Melting' point: 144 - 146°C
6-^4-(3 ',4-DSchlorophenylmercapto) -butoxy/-3, 4-dihydrocarbostyril Melting point:1 16,5 - 118°C
■ • I V4.J.
►
i 6-/4-(2-Methoxyphenylmercapto)-butoxy/-3,4-dihydrocarbostyril belting point: 130. 5 - 133°C
6-/4-(3-Methoxyphenylmercapto)-butoxy/-3,4-dihydrocarbostyril 'pelting point: 93.5 - 97 C
16-/4-(4-Methoxyphenylmercapto)-butox^/-3,4-dihydrocarbostyril Melting point:130.5 - 133°C
I I
'6-/4-(3,4-Dimethoxyphenylmercapto)-butoxy/-3,4-dihydrocarbostyril
Melting point: 117 - 119°C
t i
J6-/4- (4-Biphenylylmercapto)-butoxy/-3,4-dihydrocarbostyril
Melting point: 179 .5 - 181°C
! •
i i
6-(6-Phenylmercapto-hexoxy)-3,4-dihydrocarbostyril Melting,pointJ 112.5 - 113°C
J J
!6-(2-Hydroxy-3-phenylmercapto-propoxy)-3,4-dihydrocarbostyril
Melting point: 1 48 - 14 9°C
|
'7-(4-Phenylmercaptobutoxy)-3, 4-dihydrocarbostyril
Melting point:121 - 123°C
;8-(4-Phenylmercaptobutoxy)-3,4-dihydrocarbostyril Melting point: 101 - 102°C
'6-/4-(2-Quinolylmercapto)-butox^/-3,4-dihydrocarbostyril
Melting point: 115°c
\
I _■
.6-/4- (2-Quinazolin-4-cryl-mercapto) -butoxy?-3 , 4-dihydrocarbostyril
> n
Melting point: 184 .5 - 188 C
i6-(4-Triphenylmethylmercapto-butoxy)-3,4-dihydrocarbostyril Melting .point-: 169 - 170°e
: • - 19 - f i •
i i
J6-/2-(2-Naphthylmercapto)-ethoxy/-3,4-dihydrocarbostyril iMelting point:"! 47.5 - 14 7,8°C
i '
1
j 6—/2—(4-Biphenylylmercapto)-ethox^Z-3,4-dihydrocarbostyril ,'Melting point:192 - 194°C
j6-/_3- (2-Pyridylmercapto)-propoxy/-3, 4-dihydrocarbostyril
Melting point.: 108 - 108,5°C |
i
- (4-phenylmercapto-butoxy)-carbostyril
Melting point:185 - 187°C
1
j _
6-/4-(2-Naphthylmercapto)-butox^7-3,4-dihydrocarbostyril Melting point: 108.5 ;- 109 .5°C
i
I
6-(4-Cyclohexylmercaptobutoxy)-3,4-dihydrocarbostyril
Melting point 14 _ 1 1 5°C
6-(4-Benzylmercapto-butoxy)-3,4-dihydrocarbostyril Melting point:?7.5 - 78.5°C
I
t
6-^4-(2-Furylmethylmercapto)-butoxy/-3,4-dihydrocarbostyril
Melting point :?9 - 80°C
(N-0xido-2-pyridylmercapto) -butoxy/- 3,4-dihydrocarbostyril
Melting point:179.5 - 181°C
1 i i
'6-/4-(2-Pyrimidyl-mereapto)-butoxy/-3,4-dihydrocarbostyril jMelting point: 154 - 156°C
j6—/_4 — (4-Pyridylmercapto) -butoxy/-3, 4-dihydrocarbostyril
■Melting point:128 - 129°C
I .
» —» ' —
i6-,/4- (2-Benzimidazolylmercapto) -butoxy/-3, 4-dihydrocarbostyril
.Melting point: 100 - 103°C
: • • . - 20 -
i I
I
. 6-/_4- (2-Benzthiazolyl-mercapto) -butox^y-3, 4-dihydrocarbostyril
Melting point:157 - 158°C
i
I
6-(2-Phenylmercapto-ethoxy)-3,4-dihydrocarbostyril
Melting point: 132 - 133.5°C I
I
j6-(3-Phenylmercapto-propoxy)-3,4-dihydrocarbostyril pelting point: 111- 112°C
1-Methy 1-6^-(4-phenylmercapto-butoxy) - 3, 4-dihydrocarbostyril Melting-point: 79.5 - 80.5°C
'6-(4-Phenylmercapto-butoxy)-carbostyril Melting'point: 162 - 164°C
-(4-Phenylmercapto-butoxy)-carbostyril Melting point:185 - 187°C (from toluene)
6-(4-Phenylmercapto-butoxy)-carbostyril
(Melting point: 161 - 163°C I
8-(4-Phenylmercapto-butoxy)-carbostyril Melting, point: 119 - 120°C
6-(4-Amino-iminomethylmercapto-butoxy)-3,4-dihydrocarbostyril Melting point:140 - 141.8°C
I !
6-(4-Benzylmercapto-butoxy)-3,4-dihydrocarbostyril
Melting point:76 - 7 8°C
i
,6- (5-Phenylmercaptopentoxy) - 3,4-dihydrocarbostyril
1 o
Melting point: 117 - 119 C
I
i • _
6-/5- (2-Pyridyl-mercapto) -pentoxy/-3,4-dihydro.carbostyril Melting point: 113 - 114.8°C
] 5- (2-Hydroxy-3-phenylmercapto-propoxy)-3,4-dihydrocarbostyril Melting point: 135 - 137°C
I f
!
j6—/_4 — (4-Hydroxyphenylmercapto) -butoxy/-3,4-dihydrocarbostyril Melting point:191»5 - 193.0°C
i
I .
j6-/4-(4-Acetaminophenylmercapto)-butoxy/-3,4-dihydrocarbosty-•ril
Melting point: 162«5 - 163.0°C
! _ 6-/4- (4 , 5-Di-p-chloropheny toxazol-2-yl-mercapto) -butoxY_/-3 , 4-
.dihydrocarbostyril
Melting point:110 - 115°C
I I
,7- (4-Phenylmercapto-butoxy) -carbostyril Melting point:157.5 - 158.5°C
i
6-£4-(2 ',5-Dichlorcphenylmercapto) -butoxy/-3, 4-dihydrocarbostyril Melting point: 133 - 134°C
i
6-£4- (4-Hydroxy-3,5-di-tert.butyl-phenylmercapto)-butoxy/-3,4-dihydrocarbostyril
Melting point:146 - 14 7°C
6-^4-(2-Carboxyphenylmercapto)-butoxy/-3/4-dihydrocarbostyril
Melting point:176 - 179°C
;
6-(3-Benzylmercapto-propoxy)-3,4-dihydrocarbostyril Melting point:*97.5 - 99.0°C
- (3-tert.Butylmercapto-2-hydroxy-propaxy) -3, 4-dihydrocarbostyril
Melting poiht:105 - 109°C
i
\
>
4-Methyl-6-(4-phenylmercapto-butoxy)-carbostyril
Melting point:148 - 150°C
22
J4-Methy1-6-/4-(2-pyridylmercapto)-butoxy/-carbostyril
' o
Melting £>oint: 149 - 151 C
|4-Methyl-6-/_4- (2-quinolylmercapto)-butoxY/-carbostyril jMelting point: 162 - 163°C
! _
j6-^_4- (4-Chlor©phenylmercaptc>>-butox£/-carbostyril
Melting point:168 - 170°C
»
•6-^_4- (3 ,4-Dichlorophenylmercapto) -butox^7~carbostyril
1 o
Melting point:149 - 152 C
l
I
6-^4- (2,5-Dichlorophenylmercaptc}>-butoxY/-carbostyril
Melting point:175 - 176°C »
I
I
6-/4- (4-Fluorophenylmercapto) -butoxy/-carbostyril pelting" po'irit :149 - 1 50°C
i
6-/4'— (4-Hydroxy-3, 5-di-tert.butyl-phenylmercapto) -butoxy/-carbostyril
^Melting point: 172 - 173°C
, 6 —! ^_4 — (4-Biphenylyl-mercapto) -butoxy_/-carbostyril jMelting point:191 - 192°C
6-/4-(4-Nitro-phenylmercapto)-butox£/-carbostyril Melting;-point: 184 - 185°C
.6-£4- (2-Quinolylmercapto) -butoxy/-carbostyril Melting-point:132°c
;5-(4-Phenylmercapto-butoxy)-oxindole 'Melting point:131 - 132°C
1
,6-^4-(Phenylmercaptomethyl)-benzyloxy/-3,4-dihydrocarbostyril Melting point:139 - 141°C
1 C / ; 1
6-(4-Cyclohexylmercapto-butoxy)-carbostyril Melting point: 153- 159°C
6-^4-(4-Bromophenylmercapto)-butox£]-carbostyril Melting point: 156 - 158°C
6-[4-(3-Methyl-4-bromo-phenylmercapto)-butoxy]-carbostyril Melting point: 16 7 - 169°C
6- 0-(1,2,4-Triazol-3-yl-mercapto)-butoxyj-carbostyril Melting point: 203 - 206°C
6- [4-(2,4,5-Trichlorophenylmercapto)-butoxyj-carbostyril Melting point: 177 — 178°C
6- [4- (3, 5-Dibromo-4-amino-phenylmercapto)-butoxyJ-3, 4-dihydro-carbostyril
Melting point: 90 - 92°C
6- |4- (3,5-Dibromo-4-amino-phenylmercapto) -butoxyj-carbostyril Melting point: 15 3 - 155°C
6- [5- (4-Bromo-3-methyl-phenylmercapto) -butoxyH-3 , 4-dihydro-carbostyril
Melting point: 10 4 - 109°C
6- £4-(2,5-Dibromo-phenylmercapto)-butoxyj-3,4-dihydrocarbostyril
Melting point: 12 7 - 129°C
6- (2,5-Dibromo-phenylmercapto)-butoxyj-carbostyril Melting point: 178 - 185°C
6- [3-(3,4-Dichloro-phenylmercapto)-propoxyj-3,4-dihydrocarbostyril
Melting point: 106 - 107°C
16-/4- (4-Cyclohexyl-phenylmercapto)-butoxy/-3, 4-dihydrocarbo-istyril j Melting'point:118 - 120°C
!6-/_4- (4-Cyclohexyl-phenylmercapto) -butoxY./-carbostyril Melting;.point: 165 - 167°C
J 6-/4—(4-tert.Butyl-phenylmercapto)-butoxy7-3,4-dihydrocarbo-Istyril iMelting-point: 1 26 - 127°C
6-/4- (4-tert.Butyl-phenylmercapto)-butox^/-carbostyril pelting point:156 - 158°C
i
I _
! 6-/2-(N-Methyl-N-cyclohexyl-carbamidomethylmercapto)-athoxy/-'carbostyril -
Revalue: 0.41 (Kieselgel plates? eluant: ethylene ,chloride/mathanol= 95:5).
I
1 —. _
!6-£5-(3f4-Dich]orophenylmercapto)-pentoxY/-3,4-dihydrocarbo-Jstyril
■Melting' point: "* ^
I
6-^_4- (2-Methy 1-4-tert .butyl-phenylmercapto) -butoxy/-3 , 4-dihydro-:carbostyril
Melting point:81 - 85°C
I
16-/4-(3,5rDichloro-^hydroxy-phenylmercapto)-butoxy/-3,4-di-jhydro-carbostyril Melting point:110 - 114°C
-Bromo-6- (4-phenylmercaptobutoxy) -carbostyril Melting'point:209 - 213°C
-Nitro-6-(4-phenylmercaptobutoxy)-carbostyril Melting-point} 228 - 2 30°C
-Acetamino-6-(4-phenylmercaptobutoxy)-carbostyril Melting point: 238 - 240°C
6-/4-(1,2,4-Triazol-3-yl-mercapto)-butox^/-3,4-dihydrocarbostyril jMelting point: 152 - 154°C
I
f.
16-£4-( .2 / 4, 5-Trichlorqpheny lmercapto) -butox^/-3,4-dihydrocarbostyril
' o
Melting point*: 144 - 1 45 C
J 6-/3^ 3 r 4-Dichloropheny]mercapto) -2-hydroxy-propoxy/-3, 4-
jdihydrocarbostyril jMelting point: 175 - 1 76°C
!6-/2-Phenylmercaptomethyl-benzyloxy_/-3,4-dihydrocarbostyril jR_' Value: ,0.35 (Thin layer chromatography - Kieselgel - eluant
I
■chloroform/ethyl acetate = 1/1) .
i6-/4-(3-Hydroxy-pyrid-2-yl-mercapto)-butoxy/-3,4-dihydrocarbo-jstyril jMelting point: 211 - 216°C
I
I
j6—^/2— (N-Methyl-N-cyclohexyl-carbamidomethylmercapto) -ethox^7~ |3,4-dihydrocarbostyril value: 0.46 (Kieselgel plates> eluant: ethylene jchloride/methanol = 9 5/5)
6-/4-(2-Pyridylsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point: 144 -5 - 146°C
I
6-/4-(4-Fluorcphenylsulfinyl) -butox^/-3, 4-dihydrocarbostyril Melting point: 184.5 - 186°C
16-/_4- (4-Methylphenyl-sulf inyl) -butoxy/-3 , 4-dihydrocarbostyril :Meltirig point:149.5 - 150°C
6-/4-(3-Methylphenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril
|R^ value: 0.48 (Thin layer chromatography - Kieselgel - eluant:
Ibenzene/ethanol/conc. ammonia = 7 5/2 5/1).
!
I _
,6-/4 -(4-Chlorophenylsulfinyl) -butoxY/-3, 4-dihydrocarbostyril ^Melting point: 148 - 14 9 .5°C
:6-/_4-(3 , 4-Dichlorcphenylsulf inyl) -butox^/-3, 4-dihydrocarbostyril Melting point: 106.5 - 108°C
I
1 —
'6-/4-(2-Methoxyphenylsulfinyl)-butox^/-3,4-dihydrocarbostyril
Melting point: 162 - 163°C
♦
1
6-/4-(3-Methoxyphenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point: 147 - 14 8°C
j
6-/4-(4-Methoxyphenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point:132 - 133°C
6-/4-(3,4-Dimethoxyphenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril
Melting point:145 - 14 7°C
I
>6-/4-(4-Biphenylylsulfinyl)-butox^/-3,4-dihydrocarbostyril Melting point:192 - 192.5°C
1
6-/_4- (2-Naphthylsulf inyl) -butoxy/-3 , 4-dihydrocarbostyril Melting point:147 .5 - 148 .5°C
j6-/5-(2-Pyridylsulfinyl)-pentox^/-3,4-dihydrocarbostyril Melting point:116 - 118°C
6-(2-Methylsulfinylethoxy)-3,4-dihydrocarbostyril Melting point:129 - 131.5°C
6-(4-Methylsulfinylbutoxy)-3,4-dihydrocarbostyril Melting point:128.5 - 130.5°C
»
I
I
j.6- (4-Cyclohexylsulf inyl-butoxy) -3, 4-dihydrocarbostyril Melting point:153 - 155.5°C
[6-(4-Benzylsulf inyl-butoxy)-3,4-dihydrocarbostyril Melting point:141.5 - 142°C
i
I
6-/4-(2-Furylmethylsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point:135 -136°C
j6-/4-(2-Pyrimidylsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point:154 - 156°C
I
6-/4-(2-Benzimidazolylsulfinyl)-butoxy/-3,4-dihydrocarbostyril
Melting point:180 - 182°C
i
I
I
16—/_4 — (2-Benzthiazolylsulfinyl)-butoxy/-3, 4-dihydrocarbostyril Melting point:183 - 184°C
| 4 ;
6-(2-Phenylsulfinyl-ethoxy)-3,4-dihydrocarbostyril i
Melting point:171 - 172°C
I
|6-(3-Phenylsulfinyl-propoxy)-3,4-dihydrocarbostyril Melting point:131.5 - 133.5°C
jl-Methyl-6-(4-phenylsulfinyl-butoxy)-3,4-dihydrocarbostyril Melting point:82 - 82 5°C
6- (6-Phenylsulfinyl-hexoxy)-3,4-dihydrocarbostyril Melting point:119.5 - 121.5°C
' - 28 - tO./:
! • > b A--.S
r r ^
w j6-(2-Hydroxy-3-phenylsulfinylpropoxy)-3,4-dihydrocarbostyril pelting point:185 - 187°C
i
!
j7- (4-Phenylsulfinyl-butoxy)-3,4-dihydrocarbostyril 'Melting point:134 - 136°C
I
j8- (4-Phenylsulfinyl-butoxy)-3, 4-dihydrocarbostyril value: 0.60 (Thin layer chromatography - Kieselgel - eluant: benzene/ethanol/conc. ammonia = 75/25/1).
I
I
6-/2-(2-Naphthylsulfinyl)-athox^/-3,4-dihycarbostyril Melting point:186.5 - 187.5°C
I
I
6-/2-(4-Biphenylyl-sulfinyl)-ethox^/-3,4-dihydrocarbostyril Melting point:195 - 19 6°C
I "
-(4-Phenylsulfinyl-butoxy)-3,4-dihydrocarbostyril Melting point:136 - 138°C
I
|
-(4-Phenylsulfinyl-butoxy)-carbostyril jMelting point: 155 - 157°C
6-(4-Phenylsulfinyl-butoxy)-carbostyril Melting point:181 - 182.5°C
I
! v
;7_ (4-Phenylsulf inyl-butoxy) -carbostyril Melting point:193 - 194°C
I
8-(4-Phenylsulfinyl-butoxy)-carbostyril Melting point:125.5 - 126.5°C
,6- (5-Phenylsulfinyl-pentoxy)-3,4-dihydrocarbostyril Melting point:104 - 109.5°C
'5-(2-Hydroxy-3-phenylsulfinyl-propoxy)-3,4-dihydrocarbostyril Melting point:186 - 188°C
•! - 29 -
I 1 ' "
6-/4- (4-Hydroxyphenylsulfin.yl) -butoxy/-3 , 4-dihydrocarbostyril
Melting point:206 - 207.8°C
6-/4 - (2-Pyridylsulfinyl)-butox^/-carbostyril Melting point:152 - 154°C
-/4- (2, 5-Dichlorophenylsulfinyl) -butoxy/-3 , 4-dihydrocarbostyril .Melting point:185 - 186°C
6-£4-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfinyl)-butoxy/-3,4-jdihydrocarbostyril jMelting point:193 - 194°C
i
8-(4-phenylsulfinyl-butoxy)-carbostyril Melting point:125.5 - 126.5°C
6- (5-Phenylsulfinyl-pentoxy)-3,4-dihydrocarbostyril Melting point:104 - 109.5°C
j5-(2-Hydroxy-3-phenylsulfinyl-propoxy)-3,4-dihydrocarbostyril Melting point:186 - 188°C
!
|6-/4-(4-Hydroxyphenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril belting point:206 - 207.8°C
I
I '
16-/4-(4-AcetaminophenyIsulfinyl)-butoxy/-3,4-dihydrocarbostyril Melting point:202.0 - 203.8°C
I
!6-/4-(2,5-Dichlorophenylsulfinyl) -butoxy/-3 , 4-dihydrocarbostyril Melting point: 185 - 186°C
I
I
j6-/4-(4-Hydroxy-3,5-di-tert.-butyl-phenylsulfinyl)-butoxy/-3,4-
jdihydrocarbostyril
Melting point:170 - 171°C
, _ "30 - ^ £■*■■■->
j " jU " (f j6-/4-(2-Carboxy-phenylsulfinyl)-butoxy/-3,4-dihydrocarbostyril jMelting point:194 - 196°C
6-/4-(4-Pyridylsulfinyl)-butox^/-3,4-dihydrocarbostyril Melting point:154°C
J6-/3- (3 ,4-Dichlorcphenylsulf iny 1) -2-hydroxy-propox^/- 3, 4-dihydro-'carbostyril belting point: 108 - 110°C
6- (3-Benzylsulfinyl-propoxy)-3,4-dihydrocarbostyril ■lelting point: 144»5 - 147.0°C
j5- (3-tert.Butylsulfinyl-2-hydroxy-propoxy)-3,4-dihydrocarbo-'styril
Melting point:175 - 177°C
i
4-Methyl-6-(4-phenylsulfinyl-butoxy)-carbostyril Melting point:167 - 168°C
I
4-Methyl-6-/4-(2-pyridylsulfinyl)-butox^/-carbostyril Melting point:167 - 169°C
I ■
|4-Methyl-6-/4-(2-quinolylsulfinyl)-butox£/-carbostyril
Melting point:189 - 190°C
| _ .
i 4-Me thy 1-6-/^4- (4-biphenylylsulf inyl) -butoxy/-carbos tyril jMelting point: 161 - 162°C
I
6-/_4-(4-Chlorophenylsulf inyl) -butoxy/-carbos tyril jMelting point:157 - 158°C
I
!
!6-^_4-( 3 / 4-Dichlorqphenylsulf inyl) -butoxy/-carbos tyril jMelting point: 191 - 196°C
;6-/4-{ 2 ,5-Dichloropheny lsulf inyl) -butoxy/-carbostyril Melting point:200 - 202°C
i i
i _
|6-/4-(4'-Fluorophenylsu If inyl) -butoxy/-car bos tyril Melting point:164 - 165°C
i
.6-/4-(4-Hydroxy-3,5-di-tert.butylphenylsulfinyl)-butoxy/-carbostyril
:Melting point:192 - 194°C
i
6-/4-(4-Biphenylylsulfinyl)-butoxy/-carbostyril .Melting point:196 - 197°C
i
'6-/4-(4-Nitrophenylsulfinyl)-butoxy/-carbostyril •'Melting point:l83 - 184°c
6-/4-(2-Quinolylsulfinyl)-butoxy/-carbostyril Melting point:161 - 162°C
-(4-Phenylsulfinyl-butoxy)-oxindole Melting point:114 - 116°C
6-r/2- (Phenylsulfinylmethyl) -benzyloxy/-3 , 4-dihydro-carbostyril pelting point:133 - 135°C
i
6-/?-(Phenylsulfinyl)-benzoylox^/-3, 4-dihydrocarbostyril .Melting point: 179 — 18
i
6- (4-Cyclohexylsulfinyl-butoxy)-carbostyril Melting point:169 - 170°C
6-/4-(4-Bromcphenylsulfinyl)-butox^/-carbostyril Melting point:168 - 170°C
> 6-£4- (3-Methyl-4-br.omcr-phenylsulf inyl) -butoxy/-carbostyril Melting point:169 - 172°C
- 32 - ^
, 6-/_4-(2 ,4 ,5-Trich lor cphenylsulf inyl) -butoxy/-carbostyril iMelting point: 206 - 208°C
j 6-/4-(3 , 5-Dibromo-4-amino-phenyl-sulf inyl) -butoxy/-3, 4-dihydro-icarbostyril
,Melting point:144 - 14 6°C
i6-/4-(3 ,5-Dibromo-4-amino-phenylsulf inyl) -butox;^/-carbostyril jM«
lelting point:205 - 207°C
16-/4-(4-Br omo-3-me thy 1-phenylsulf inyl) -butoxy/-3, 4-dihydrocarbo-
jstyril
.Melting point: 129 - 130°C
l6-/4-( 2 ,5-Dibromo-phenylsulf inyl) -butoxy/-3 , 4-dihydrocarbostyril
[Melting point:1 82 - 184°C
'6-/4- ( 2 ,5-Dibromo-pheny lsulf inyl) -butox^/-carbostyril ^Melting point:187 - 189°C
!
j6-/3-( 3 ,4-Dichloro-pheny lsulf inyl) -propoxy/-3, 4-dihydrocarbostyril iMelting point: 170 - 172°C
I
! _ i .. _
.6-/4- (4-Cyclohexyl-phenylsulfinyl) -butoxY_/-3, 4-dihydrocarbo-!styril
IMelting point:155 - 157°C
I I
(6-/4-(4-Cyclohexyl-phenylsulfinyl)-butox^/-carbostyril IMelting point:188 - 190°C I
I
i 6-/4-(4-tert.Butyl-phenylsulfinyl)-butoxy/-3,4-dihydrocarbosty-
!ril
Melting point:121 - 123 C
I _ -
16-/_4- (4-tert .Butyl-phenylsulfinyl) -butox^/-carbostyril jMelting point:164 - 166°C
;6-/4- (2-Quinolylsulfinyl)-butox£/-3,4-dihydrocarbostyril .Melting' point: 1 54 - 157°C
i
!6-/2-(N-Methy1-N-cyclohexyl-carbamidomethylsulfinyl)-ethoxy/-i3,4-dihydrocarbostyril Malting point:143 - 14 6°C
6-/2-(N-Methy1-N-cyclohexyl-carbamidomethylsulfinyl)-ethoxy/-carbostyril
Melting point:128 - 130°C
6-/_5- (3 ,4-Dichlorophenylsulf inyl) -pentoxy_/-3 , 4-dihydrocarbostyril
Melting point:165 - 166°C
6-/4-(2-Methyl-4-tert.butyl-phenylsulfinyl)-butoxy/-3,4-di-hydrocarbostyril
Revalue: 0.54 (Kieselgel plates; eluant: ethylene chloride/methanol = 95:5)
-Nitro-6-(4-phenylsulfinylbutoxy)-carbostyril Melting point:192 - 194°C
-Acetamido-6-(4-phenylsulfinylbutoxy)-carbostyri1 Melting point:213 - 217°C
3
-Bromo-6-( 4-pheny Is ulf inylbutoxy) - carbos tyril Melting point:190 - 191°C
4-Methyl-6-/4- (2-pyridylsulf inyl) -butox^_/-carbostyril Melting point:166 - 168°C
6-(4-tert.Butylsulfinyl-butoxy)-3,4-dihydrocarbostyril Melting point:126 - 128°C
6-/4-(1,2,4-Triazol-3-yl-sulfinyl)-butox^/-carbostyril Revalue: 0.12 (Kieselgel plates; eluant: ethylene chlorid^/methanol = 95:5)
1 6-/4-(1,2,4-Triazol-3-y1-sulfiny1)-butoxy/-3,4-dihydrocarbo-
; styril i
Re value: 0.18 (Kieselgel plates; eluant:.ethylene chlorid6/methanol = 95:5)
6-^4-(2-Pyridylsulfonyl)-butoxy/-3,4-dihydrocarbostyril Melting point:123.8 - 125°C
6-/4-(3,4-Dimethoxyphenylsulfonyl)-butoxy/-3,4-dihydrocarbo-! styril i
iMelting point:158 - 160 C
' 6-/5-(2-Pyridylsulfonyl)-pentox^/-3,4-dihydrocarbostyril
Melting point:113.5 - 11 5 .0°C
I 7- (4-phenylsulfonyl-butoxy)-carbostyril jMelting point:199 - 201°C
! 6- (2-Phenylsulfonyl-ethoxy)-3,4-dihydrocarbostyril
IMelting point:185 - 186°C
i i
i i1-Methyl-6-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril 'Melting point:108 - 109°C
!.
i ..
; 6-(2-Hydroxy-3-phenylsulfonyl-propoxy)-3,4-dihydrocarbostyril iMelting point:170 - 172°C
i
I
I
j 7-(4-Phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril Melting point:178 .5 - 179 .5°C
8- (4-Phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril .Melting point:114.5 - 115°C
6-/4- (2-Benzthiazolyl-sulfonyl)-butox_y/-3,4-dihydrocarbostyril Melting point:146 - 149°C
- 35
;5-(4-Phenylsulfonyl-butoxy)-3,4-dihydrocarbostyril 'Melting point:187 - 189°C
1945
6-/4-(2-Naphthylsulfonyl)-butoxy_/-3,4-dihydrocarbostyril Melting point:173 - 175°C
' 6—/4 —(4-Biphenylylsulfonyl)-butoxyj-carbostyril Melting point: 213 - 215°C
16- (4-Phenylsulfonyl-butoxy)-carbostyril Melting point:212 - 213°C
I l
I
- (4-Phenylsulfonyl-butoxy)-carbostyril Melting point:182 - 183°C
\
i
I I
'5-(2-Hydroxy-3-phenvlsulfonyl-propoxy)-3,4-dihydrocarbostyril Melting point:168 - 170°C
i
6-/4-(4-Hydroxyphenylsulfonyl)-butoxy7~3,4-dihydrocarbostyril Melting point:219 - 219,5°C
6-/4-(4-Acetaminophenylsulfonyl)-butoxy/-3,4-dihydrocarbostyril Melting point:143.5 - 14 7.0°C
8-(4-Phenylsulfonyl-butoxy)-carbostyril Melting point:146 - 147°C
i i
6-/4- (2 / 5-Dichlorqpheny lsulf onyl) -butoxy/-3, 4-dihydrocarbostyril Melting point:174.5 - 175.5°C
i
6-/4-(3 / 4-Dichlorcphenylsulfonyl) -butoxy/-3 , 4-dihydrocarbostyril
Melting point:172 - 173°C
j6-^4-(4-Hydroxy-3, 5-di-tert.butyl-phenylsulfonyl)-butoxy/-3,4-dihydrocarbostyril Melting point:165 - 167°C
j6-^4-(4-Pyridylsulfony1)-butox^7-3,4-dihydrocarbostyril .Melting point:179 - 183°C
-(3-tert.Butylsulfonyl-2-hydroxy-propoxy)-3,4-dihydrocarbo styril
Melting point:210 - 212°C
6-14- (2-Pyridyl-sulfonyl) -butox^_/-carbostyril
Melting point:179 - 180°C
4-Methyl-6-(4-phenylsulfonyl-butoxy)-carbostyril 'Melting point:21 7 - 219°C
!
|4-Me thyl-6-/4-(2-pyridylsulfonyl)-butoxy/-carbostyril jMelting point:195 - 197°C
i4-Methyl-6-/_4- (2-quinolylsulfonyl)-butox^/-carbostyril iMelting point:199 - 203°C
i 6—/4 — (4-chlorcpheny lsulf inyl)-butoxy ]- carbos tyril Melting point:1 97 - 199°C
j j6-£4 -(•3 ,4-Dichloropheny lsulf onyl) -butoxj^/-carbos tyril jMelting point:188 - 190°C
'6-^4- (2, 5-Dichlorcphenylsulfonyl) -butoxj:/-carbostyril Melting point:203 - 205°C
i
■ 6-^4- (4-Fiuorophenylsulfonyl) -butox£/-carbostyril 'Melting point:209 - 211°C
! ^_
'6-/_4- (4-Hydroxy-3, 5-di-tert .butylphenylsulfonyl) -butoxy/-Jcarbostyril
Melting point:242 - 244°C
!
'6-/4-(4-Biphenylyl-sulfonyl)-butox^/-carbostyril
'.Melting pointy 13 - 215°C
a - •
••s-
O ^ :
K)
;6-/4-(4-Nitrophenylsulfonyl)-butoxY/-carbostyril
Melting' point:230 - 232°C
6-/4-(2-Quinolylsulfonyl)-butoxy/-carbostyril Melting point:197 - 198°C
6-/4-(3-Methyl-4-brcmo-phenylsulfonyl)-butoxy/-carbostyril jMelting point:163 - 167°C
i
I _ _
16—/4 — (3 , 5-Dibromo-4-amino-phenylsulfonyl) -butoxy/-3 , 4-dihydro-•carbostyril
Melting point:157 - 159°C
I
j
6-^4 ~(3 , 5-Dibrcmo-4-amino-phenylsulfonyl)-butoxy7~carbostyril Melting point:238 - 241°C
i
I
16—/4 — (4-Cyclohexyl-phenylsulfonyl)-butox^/-3,4-dihydrocarbostyriJ Melting,point:172 - 174°C
i j6-^_4- (4-Cyclohexyl-phenylsulfinyl) -butox^/-3, 4-dihydrocarbo-jstyril
■Melting point: 155 - 157°C.
6-/4-(4-tert.Butyl-phenylsulfonyl)-butoxy/-carbostyril ;Melting point:203 - 205°C
I
(6-/4- (2- Quinolylsulfony 1) -butoxy/-3, 4-dihydrocarbostyril jRf value: 0,50 (Kieselgel plates; eluant: benzene/
jethanol/conc. ammonia = 75:25:2)
I
j 6-/2-(N-Methy1-N-cyclohexy1-carbamidomethy1sulfonyl)-ethoxy/-3,4-dihydrocarbostyril Melting point:110- 111°C
i 6-/2-(N-Methyl-N-cyclohexyl-carbamidomethylsulfonyl)-ethoxy/-Jcarbostyril jvalue: 0.39 (Kieselgel plates; eluant: ethylene j chlor id e/m e tha.no 1_. = 9 5_._5J
6-[3-(3,4-Dichlorophenylsulfonyl)-propoxy]-3,4-dihydrocarbostyril
Melting point: 187 - 188°C
6-[5-(3,4-Dichlorophenylsulfonyl)-pentoxy]-3,4-dihydrocarbostyril
Melting point: 176 - 178°C
6-[4-(1,2,4-Triazol-3-yl-sulfonyl)-butoxy]-3,4-dihydrocarbostyril
Melting point: 217 - 224°C
/
6-(5-Phenylsulfonyl-pentoxy)-3,4-dihydrocarbostyril Melting point: 13 6.5 - 13 7.8°C
Example A
Tablets containing 100 mg of 6-[4-(2-pyridylsul£onyl)-butoxy ] -34-d ihydrocarbos tyr il
Composition:
1 tablet contains:
Active substance
100
.0
mg
Lactose
80
.0
mg
Corn starch
34
.0
mg
Polyvinyl pyrrolidone
4
.0
mg
Magnesium stearate
2
.0
mg
22 0.0 mg
Preparation:
The active substance, lactose and starch are mixed and moistened homogeneously with an aqueous solution of polyvinyl pyrrolidone. After screening of the moist mass (2.0 mm mesh size) and drying in a shelf dryer 20 at 50°C screening is effected again (1.5 mm mesh size) and the lubricant is added. The mixture ready for pressing is processed into tablets.
Tablet weight: 220 mg
Diameter: 10 mm, biplanar with facet on both sides 25 and dividing notch on one side.
Example B
Hard gelatine capsules containing 150 mg of 6-[4-(3,4-d ichlorophenylsulf inyl-butoxy]-3,4-dihydrocarbostyr il
1
capsule contains:
Active substance 150.0 mg
Corn starch dried about 180.0 mg
Lactose powdered about 87.0 mg
Magnesium stearate 3.0 mg about 320.0 mg
u» W
Preparation:
The active substance is mixed with the excipients, passed through a screen of 0.75 mm mesh size and mixed homogeneously in a suitable apparatus. The final mixture 5 is filled into hard gelatine capsules of size 1.
Capsule filling: about 320 mg Capsule case: hard gelatine capsule size
1.
Example C
Suppositories containing 150 mg of 6-(4-phenylsulfonyl-butoxy)-3,4-dihydrocarbostyr il
1 suppository contains:
Active substance 150.0 mg
Polyethylene glycol -
1500 550.0 mg
Polyethylene glycol
6000 460.0 mg
Polyoxyethylene sorbitan monostearate 840.0 mg
2,000.0 mg
Preparation:
After the suppository mass has been melted the active substance is distributed homogeneously therein and the melt is poured into precooled moulds.
Example D
Suspension containing 50 mg of 6-[4-(2-pyridylsulfonyl) butoxy]-3,4-dihydrocarbostyril per 5 ml
100 ml of suspension contain:
Active substance 1.0 g
Carboxymethylcellulose sodium salt 0.1 g
Methyl p-hydroxy-
benzoate 0.05 g
Propyl p-hydroxy
benzoate
0
.01
g
Cane sugar
.0
g
Glycerol
.0
g
Sorbitol solution 70%
.0
g
Aroma
0
.3
g
Distilled water
sufficient to make
100
ml
Preparation;
Distilled water is heated to 70"C. Methyl p-hydroxybenzoate and propyl p-hydroxybenzoate as well as glycerol and carboxymethylcellulose sodium salt are dissolved therein with stirring. The mixture is 15 cooled to room temperature and the active substance is added with stirring and .dispersed homogeneously.
After the sugar, the sorbitol solution and the aroma have been added and dissolved the suspension is evacuated with stirring to remove air. 5 ml of suspension contain 20 50 mg of active substance.
Example E
Tablets containing 150 mg of 6-[2- (3 ,4-dichlorophenyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyril
Composition:
1 tablet contains:
Active substance
150
.0
mg
Lactose powdered
89
.0
mg
Corn starch
40
.0
mg
Colloidal silicic acid
.0
mg
Polyvinyl pyrrolidone
.0
mg
Magnesium stearate
1
.0
mg
3 0 0.0 mg
Preparation:
The active substance mixed with lactose, corn
I 9 4
42
starch and silicic acid is moistened with a 20% aqueous polyvinyl pyrrolidone solution and passed through a screen of 1.5 mm mesh size. The granulate dried at 45°C is again passed through the same screen and mixed 5 with the specified quantity of magnesium stearate.
Tablets are pressed from the mixture.
Tablet weight: 300 mg Dye: 10 mm, flat
Example F
Coated tablets containing 75 mg of 6-[4-(2-pyridylsulfonyl)-butoxy]-3,4-dihydrocarbostyr il
1 coated tablet core contains:
Active substance 75.0 mg
The active substance is mixed with calcium phosphate, corn starch, polyvinyl pyrrolidone, hydroxypropylmethyl-cellulose and half the specified quantity of magnesium stearate. On a tabletting machine pressed articles 30 are made with a diameter of about 13 mm which are passed on a suitable machine through a screen of 1.5 mm mesh size and mixed with the remaining quantity of magnesium stearate. This granulate is pressed on a tabletting machine into tablets of the desired form.
Core weight: 230 mg Dye: 9 mm, curved.
The coated tablet cores prepared in this way are covered with a coating consisting essentially of hydroxy-
Calcium phosphate
Corn starch
Polyvinyl pyrrolidone
Hydroxypropylmethyl-cellulose
Magnesium stearate
93.0 mg 35.5 mg 10.0 mg
.0 mg 1.5 mg
230.0 mg
Preparation:
Claims (16)
1. Pharmaceutical compositions comprising as an active ingredient at least one compound of general formula I w— 0 - D - SO R 2 (I) m 0' R 4 1 [wherein W represents a vinylene group^optionally substituted by a methyl group^or a methylene or ethylene group; m is 0, 1 or 2; D represents a straight-chained or branched alkylene group with 2 to 6 carbon atoms, a straight-chained or branched hydroxyalkylene group with 3 to 6 carbon atoms or a xylylene group; R^ 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 with 6 to 10 carbon atoms, an aralkyl group with 7 to 11 carbon atoms, a heteroaryl group with 4 to 9 carbon atoms, a heteroaralkyl group with 5 to 10 carbon atoms (the said heteroaryl group or the heteroaryl moiety of the said heteroaralkyl group containing (a) a nitrogen atom and/or an oxygen or sulphur atom or (b) two nitrogen atoms) wherein the above-mentioned aryl or heteroaryl group or the aryl moieties of the above-mentioned aralkyl or heteroaralkyl groups may optionally be monosubstituted by an alkyl group with 1 to 4 carbon atoms, by a hydroxy, methoxy, amino, acetylamino, nitro, carboxyl, cyclohexyl or phenyl group or by a halogen atom and wherein if R2 represents a monosubstituted phenyl 194531 - 45 - group or a phenylalkyl group of which the phenyl moiety is monosubstituted, such phenyl group or phenyl moiety may further be mono-or di-substituted by substi-tuents selected from halogen atoms and alkyl groups with 1 to 4 carbon atoms atoms; or 1*2 represents a 1,2,4-triazolyl, triphenylmethyl, 4,5-bis-(p-chloro-phenyl)-oxazol-2-yl, N-methyl-cyclohexylaminocarbonyl-methyl or amino-iminomethyl group; or, where m is 1 or D represents a straight-chained or branched hydroxyalkylene group with 3 to 6 carbon atone or a xylylene group, it ay additionally represent an alkyl group with 1 to 6 carbon atoms, and R^, which can be the same or different, each represents a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms or an amino, acetylamino or nitro group] together with one or more pharmaceutical j , . loktn -th <x -form SU\lablc -for jUSC JJi -tht carriers and/or excipients^ J pnphylaxis c/ tumour metastases.
2. Pharmaceutical compositions as claimed in claim 1 comprising as an active ingredient at least one . er€<Vi Wi b / rn and R. compound of general formula I^ {wherein W,—D and—ra are as defined in claim 1; R2 represents a cyclohexyl, benzyl, naphthyl, pyridyl, pyrimidyl, 1,2,4-triazolyl, pyridyl oxide, furfuryl, triphenylmethyl, quinolyl, benzimidazolyl, benzothiazolyl, quinazolin-4-on-yl, 4,5-bis-(p-chloro- phenyl)-oxazol-2-yl, N-methyl-cyclohexylaminocarbonyl- methyl or amino-iminomethyl group, a phenyl group optionally substituted by a carboxyl, hydroxy, methoxy, amino, acetylamino, nitro, cyclohexyl or phenyl group, a phenyl-group mono- or disubstituted by halogen atoms and/or alkyl groups with 1 to 4 carbon atoms, ^ or a hydroxyphenyl, halophenyl or aminophenyl group §•. substituted by two halogen atoms or by two alkyl groups each with 1 to 4 carbon atoms; represents a hydrogen, chlorine or bromine atom or a methyl, amino, acetylamino or nitro group; and R^ represents a hydrogen atom.
3. Pharmaceutical compositions as claimed in claim 19453 - 46 - 1 comprising as an active ingredient at least one compound o£ general formula I ^wherein W represents a vinylene group optionally substituted by a methyl group^or an ethylene group; m is 0, 1 or 2; D represents an alkylene group with 2 to 5 carbon atoms or a hydroxyalkylene group with 3 to 5 carbon atoms; represents a hydrogen atom; 1*2 represents a cyclohexyl, phenyl, benzyl, naphthyl, biphenylyl, cyclohexylphenyl, pyridyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, bromophenyl, dibromo-phenyl, bromo-methyl-phenyl, amino-dibromophenyl, or hydroxy-di-tert.butylphenyl group; and R^ and R^ each represent a hydrogen atom.
4. Pharmaceutical compositions as claimed in claim 1 comprising as active ingredient at least one compound of formula I /wherein W represents an ethylene, vinylene or 2-methyl vinylene group; m is an integer having the value 0, 1 or 2; R^, R^ and R^ each represents a hydrogen atom, R2 represents a cyclohexyl, phenyl, benzyl, napthyl-(2), 2-methoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-amino-3,5-dibromo-phenyl, 4-hydroxy-3,5-di-tert.butylphenyl or pyridyl-(2) group; and D represents an ethylene, n-propylene, n-butylene or 2-hydroxy-n-propylene group.
5. Pharmaceutical compositions as claimed in claim 1 comprising as active ingredient at least one compound of general formula 1 as herein specifically identified.
6. Pharmaceutical compositions as claimed in any one of claims 1 to 5 in a form suitable for oral, rectal or parenteral administration.
7. Pharmaceutical compositions as claimed in claim 6 in the forms of tablets, coated tablets, capsules, 194531 - 47 - suppositories or suspensions.
8. Pharmaceutical compositions as claimed in any one of the preceding claims in dosage unit form.
9. Pharmaceutical compositions as claimed in claim 8 wherein the said dosage unit comprises from 100 to 300 mg of at least one compound of general formula 1 (as defined in claim 1). , _ , , . , irhar#\accuti$a.
L compos*tons Containi/ty least one—tfiwacund— 10r ^Pharmaooutloal compositions ae claimed—in any— <femoral joctnoda t as—defined in claim—i—whe.n -used in the tteatfwonb of-''■one of claims 1—to 9 tor" uac—in the treatment: oc humans or animals——the prophylaxis of metastases.• to ► Jrf..
Pharmaceutical compositions as claimed in any one of the preceding claims substantially as herein described. 1-2.
A—roo-thod—fot—the- prophylaxis of metastases - which comprises administering to a human or animal body an effective amount of a compound of general formula I (as defined in clai/m 1).
13. A method as claimed in claim 12 comprising the administration of a composition as claimed in any one of claims 1 to 1-
14. A method as claimea in either of claims 12 and 13 wherein from 4 uo 9 mg/(kg of body weight) of a compound of formi/la I is administered daily.
15. A method as claimed in any one of claims 12 to 14 wherein the ^aid administration is effected 2 or 3 times dail}
16. A method as claimed in any one of claims 12 to 15 wherein tne said administration is of about 2^.5 mg/kg o£ body weight,—effected 2 or—3—times da-i-l-y-»— • A pack comprising a pharmaceutical composition and instructions for the use thereof in the prophylaxis of metastases; said composition comprising as an active ingredient at least one compound of general formula I (as defined in claim 1) . // A pack as claimed in claim Jt?" wherein the composition is , to 1 to tion is a composition as claimed in any one of claims BALDWIN, SON & CAREY ' ..'-4 .!'
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792931741 DE2931741A1 (en) | 1979-08-04 | 1979-08-04 | anti-metastasis medicaments - comprising derivs. of carbostyril and analogues |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ194531A true NZ194531A (en) | 1984-08-24 |
Family
ID=6077677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ194531A NZ194531A (en) | 1979-08-04 | 1980-08-01 | Pharmaceutical compositions containing substituted carbostyrils |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5636452A (en) |
| AU (1) | AU539070B2 (en) |
| BE (1) | BE884628A (en) |
| DE (1) | DE2931741A1 (en) |
| IT (1) | IT1212438B (en) |
| NZ (1) | NZ194531A (en) |
| ZA (1) | ZA804680B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2121148A1 (en) * | 1992-08-19 | 1994-03-03 | Satoru Nakai | Apoptosis regulator |
| US5635514A (en) * | 1994-10-25 | 1997-06-03 | G. D. Searle & Company | Heteroaralkyl and heteroarylthioalkyl thiophenolic compounds as 5-lipoxgenase inhibitors |
-
1979
- 1979-08-04 DE DE19792931741 patent/DE2931741A1/en not_active Withdrawn
-
1980
- 1980-06-30 IT IT8023121A patent/IT1212438B/en active
- 1980-08-01 JP JP10631980A patent/JPS5636452A/en active Pending
- 1980-08-01 NZ NZ194531A patent/NZ194531A/en unknown
- 1980-08-01 AU AU61006/80A patent/AU539070B2/en not_active Ceased
- 1980-08-01 ZA ZA00804680A patent/ZA804680B/en unknown
- 1980-08-04 BE BE0/201645A patent/BE884628A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE884628A (en) | 1981-02-04 |
| AU539070B2 (en) | 1984-09-13 |
| AU6100680A (en) | 1981-02-12 |
| DE2931741A1 (en) | 1981-02-26 |
| ZA804680B (en) | 1982-04-28 |
| JPS5636452A (en) | 1981-04-09 |
| IT8023121A0 (en) | 1980-06-30 |
| IT1212438B (en) | 1989-11-22 |
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