JPS5824559A - Novel sulfimine compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel sulfimines of the general formula, their salts with strong acids, more particularly their physiologically compatible acid addition salts, pharmaceutical compositions containing these compounds and processes for their preparation. .

The novel compounds of general formula I above have useful pharmacological properties, in particular antithrombotic properties.

In the above general formula (III), n represents 0 or 1, and A is methylene, vinylene or ethylene, which may optionally be substituted by one or two alkyl groups each having 1 to 6 carbon atoms. represents a group in which B is a linear group having 2 to 6 carbon atoms.

Alternatively, it represents a branched alkylene group.

R1 is an alkyl group having 1 to 6 carbon atoms optionally substituted by a phenyl group;
or a phenyl group (however, each of the above phenyl nuclei is an alkyl group having 1 to 4 carbon atoms, a halogen atom, 1
alkoxy groups having from 6 to 6 carbon atoms, cyclohexyl, phenylmodic or halophenyl groups), alkyl groups having 4 to 7 carbon atoms, cycloalkyl groups having 6 to 7 carbon atoms; , phenyl radicals which are di- or tri-substituted by alkyl radicals having 1 to 4 carbon atoms, or by alkoxy radicals having 1 to 3 carbon atoms, and/or by halogen atoms; or by an alkoxy group having from 1 to 6 carbon atoms, and/or by a halogen atom, a hydroxyroxy or aminophenyl group ((the substituents on the phenyl nucleus may be the same or R2 represents a hydrogen atom or an organic carboxylic acid, an organic or represents an acyl group of an inorganic sulfonic acid or carbonic acid derivative.Here, the predicate "acyl group" in the definition of R2 group is
In detail, aliphatic saturated or unsaturated alkanoic acids (which may be substituted depending on the case), aromatic carboxylic acids which may be substituted depending on the case (one of them
=CH group or one or two -CH- groups may each be substituted by an oxygen, sulfur or nitrogen atom)
or it represents an acyl group or a hydroxysulfonyl group of a carbonic ester, or of an optionally substituted carbamic acid, or of an aliphatic or aromatic sulfonic acid. The halogen atoms mentioned may in particular be fluorine, chlorine or bromine atoms.

Within the definition of the A, B, R1 and R2 groups above, A may represent, for example, a methylene, methylmethylene, dimethylmethylene, diethylmethylene, diprobylmethylene, vinylene, methylvinylene or ethylene group, and B , for example, ethylene, n-propylene, n-butylene, n-benthylene, n-hexylene, 1-methyl-
Ethylene, 2-methyl-ethylene, 1-methyl-n-propylene, 2-mesol-n-propylene, 6-methyl-
n-7'lopylene, 1-methyl-n-butylene, 2-methyl-n-butylene, 3-methyl-n-butylene, 4-
Methyl-n-phthylene, 1-methyl-n-pentelene,
2-methyl-n-bentylene, 3-methyl-n-pentylene, 4-methyl-n-pentylene, 5-methyl-n-
Bentirene, 1,1-dimethyl-ethylene-1,2-dimethyl-ethylene, 212-dimethyl-ethylene, 1.
1-dimethyl-n-propylene, 2,2-dimethyl-n
-propylene, 3゜3-dimethyl-n-propylene, 1
, 2-dimethyl-n-propylene, 1,6-dimethyl-n-propylene, 1,1-dimethyl-n-butylene, 2
゜2-dimethyl-n-butylene, 6,3-dimethyl-n
-butylene, 4,4-dimethyl-n-butylene, 1,2
-dimethyl-n-butylene, 1,6-dimethyl-n-butylene, 1,4-dimethyl-n-butylene, 2,6-dimethyl-n-butylene, 1-ethyl-ethylene, 2-ethyl-ethylene, 1 -ethyl-n-propylene, 2-ethyl-n-propylene, 6-ethyl-n-propylene,
1-ethyl-n-butylene, 2-ethyl-n-butylene, 3-ethyl-n-butylene, 4-ethyl-n-butylene, 1-methyl-2-ethyl-ethylene.

1-Methyl-2-ethyl-n-propylene, 1-methyl-3-ethyl-n-propylene, 1-methyl-2-7'
It may represent a propylethylene, 1-propyl-ethylene, 1-butyl-ethylene or a 1-7'propylene group, R1 being, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tartbutyl, pentyl. , neopentyl, tertpentyl, hephisyl,
Butyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 3-phenylpropyl, fluorobenzyl, chlorobenzyl, bromobenzyl, methylbenzyl, inglobilbenzyl, methoxybenzyl, ethoxybenzyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, dimethylphenyl, inglovirphenyl. T er t.

Butylphenyl, methoxyphenyl, ethoxyphenyl, phthylphenyl, cyclohexylphenyl, diphenyl, fluorophenyl-phenyl, chlorophenyl-phenyl, cyfluorophenyl, dichlorophenyl,
cyglomophenyl, dimethoxyphenyl, methoxychlorophenyl, methoxy-bromophenyl, methyl-t@
rt, phthylphenyl, methyl-chloro-phenyl,
Methyl-bromophenyl, tart, 7'thyl-bromophenyl, cycloaminophenyl, cyclo-aminophenyl, dimethyl-aminophenyl, cyclo-hydroxyphenyl, cyclo-hydroxyphenyl, dimethyl-hydroxy-phenyl, c, art ,
7'thyl-hydroxyphenyl, trimethoxy-phenyl, naphthyl, methoxynaphthyl or pyridyl group, and R2 is, for example, a hydrogen atom, formyl, acetyl, fropionyl, pivaloyl, pentanoyl.

Hexanoyl, heptanoyl, octanoyl, nonanoyl, methoxyacetyl, methoxypropionyl, binanoyl, benzoyl, fluorobenzoyl, chlorobenzoyl, bromobenzoyl, cyanobenzoyl, methylbenzoyl, ethylbenzoyl, inopropylbenzoyl, tert, butylbenzoyl, difluorobenzoyl
Dichlorobenzoyl, dimethylbenzoyl, trimethylbenzoyl, naphthoyl, pyridinoyl, thenoyl,
Acetoxy-benzoyl, hydroxysulfonyl, ethylsulfonyl, ethylsulfonyl, camphorsulfonyl, phenylsulfonyl, methylphenyl-sulfonyl, fluorophenylsulfonyl, chlorophenylsulfonyl, fromophenylsulfonyl, pentamethylphenylsulfonyl, naphthylsulfonyl, methoxycarbonyl, ethoxycarbonyl, It may also represent a propophi dicarbonyl, isopropoxycarbonyl, benzyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl or chlorophenylaminocarbonyl group.

In preferred compounds of the above general formula I, n represents 0 or 1, and A represents dimethylmethylene, vinyl/or ethylene group.

straight-chain alkylene in which B has 3 to 5 carbon atoms/
represents an alkyl group in which R1 has 1 to 6 carbon atoms, benzyl, phenylethyl, cyclohexyl, naphthyl,
methoxy-naphthyl or pyridyl radicals, optionally substituted by alkyl radicals having 1 to 4 carbon atoms, or methoxy, cyclohexyl, phenyl4L<, even if substituted by fluorophenyl radicals or by fluorine, chlorine or bromine atoms. good phenyl group, 1
an alkyl group having up to 4 carbon atoms, a methoxy group, a phenyl group disubstituted by chlorine and/or bromine atoms (however, the substituents on the phenyl nucleus may be the same or different), or 2 represents an aminophenyl, hydroxy-phenyl or methoxyphenyl group substituted by a chlorine or bromine atom, two methoxy groups or two alkyl groups each having 1 to 4 carbon atoms, and R3 is hydrogen, if Alkanoyl radicals having 1 to 8 carbon atoms optionally substituted by methoxy radicals, optionally substituted by halogen atoms or by cyano radicals or by alkyl radicals having 1 to 4 carbon atoms; an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, optionally substituted by a chlorophenyl group or by one or two methyl groups; The radicals are compounds representing naphthoyl, binanoyl, camphorsulfonyl, beta/methylphenylsulfonyl, pyridinoyl or hachinoyl groups, and their salts with strong acids. Particularly preferred compounds of the above general formula I are While.

n represents 1, 5 represents dimethylmethylene, vinylene or haethylene group, B represents n-butylene group, R1 is methyl, thyl or methoxynaphthyl group, optionally substituted by methoxy group or fluorine or chlorine atom; a phenyl group optionally substituted by two chlorine or bromine atoms, or a methylbromophenyl, 4-7minor 3,5-dibrof-phenyl or di-t@rt, butyl-hydroxy-phenyl group and R2 is a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms, or a benzoyl or phenylsulfonyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms, and It is a salt with a strong acid that is physiologically compatible with it.

According to the invention, novel compounds are obtained by the following method: a) For the preparation of compounds of the general formula I, in which n represents 1 and R2 represents a hydrogen atom, compounds of the general formula (wherein A, B and R1 is the same as defined above) is reacted with the hydrazoic acid optionally formed in the reaction mixture.

This reaction is carried out using a solvent or mixture of solvents such as methylene chloride,
in dimethylformamide or tetrahydrofuran at a temperature between 0 and 40'O, preferably between 10 and 6
It is suitably carried out at a temperature of between 5°C. The reaction is particularly advantageously carried out using an alkali azide, for example sodium azide, and polyphosphoric acid as solvent.

1)) To produce a compound of the general formula I in which R represents a hydrogen atom, a sulfonyl group of the general formula (wherein jL, B, n and R1 are the same as defined above) is converted into a sulfonyl group of the general formula % Formula % (1) (wherein X represents a carbonyl or sulfonyl group,
and R5 is an aryl group disubstituted at the 〇-position, for example 2
,4.6-)limethylphenyl or 2,4,6
- ) IJ (inpropylphenyl group or when the upper hydroxyl group X represents a sulfonyl group) is reacted with a compound.

This reaction is carried out using a solvent or mixture of solvents such as methylene chloride,
It is suitably carried out in chloroform, dimethylformamide, tetrahydrofuran or dioxane at a temperature between 0 and 50°C, preferably between 5 and 40°C.

However, in a particularly advantageous embodiment of the reaction, the compounds of general formula I are used without prior isolation, or are prepared in the reaction mixture.

c) To prepare compounds of general formula I in which n represents 1, mercapto compounds of general formula (wherein A, B, R1 and R2 are as defined above) are oxidized.

This oxidation is carried out in a solvent or mixture of solvents, e.g.
in water/pyridine, methanol, ethanol, acetate/, formic acid, glacial acetic acid, trifluoroacetic acid or dilute sulfuric acid.
Preferably it is carried out at a temperature between -80°C and 1°ooC (depending on the oxidizing agent used). The reaction is carried out using one equivalent of an oxidizing agent, such as hydrogen peroxide in glacial acetic acid or formic acid at 0 to 20°C, or in acetone at 0 to 60°C. from 0 to 500 G in glacial acetic acid or trifluoroacetic acid using
It is particularly advantageous to carry out the reaction using sodium metaperiodate in aqueous methanol or ethanol at 15 to 25°C.

+1) To produce a compound of the general formula (3) in which R2 does not represent a hydrogen atom, a compound of the general formula (where n, A, B and R1 are the same as defined above) is acylated.

The reaction can be carried out using a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxic acid, etc. acid activated with a corresponding acylating agent, such as an acid, or in the presence of a dehydrogenating agent, such as thionyl chloride, with its anhydride, such as acetic anhydride, with its ester, such as p-toluenesulfo/ with ethyl acid or diethyl carbonate, with its norogenides such as acetyl chloride, ethyl chloroformate) with p-) toluenesulfonic acid chloride, or with the corresponding incyanate (although these may optionally be used as solvents) ), optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine (although the latter may simultaneously be used as a solvent), -25
and 100'C, but preferably -10
and 18°C.

A hydroxy compound of the general formula (wherein A is the same as defined above) or its salt with an inorganic or tertiary organic base is added to a hydroxy compound of the general formula (wherein A is the same as defined above) Excerpt 1.Z represents a nucleophilically exchangeable group such as a halogen atom or a sulfonic acid ester group such as a chlorine, bromine or iodine atom or a p-toluenesulfonyloxy or methanesulfonyloxy group.

The reaction is carried out in a suitable solvent or mixture of solvents such as dioxane, tetrahydrofuran, chloroform or toluene, but preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide or dimethyl sulfoxide, optionally with an alkali base such as sodium carbonate. , potassium carbonate or sodium hydroxide, at a temperature between 0°C and the boiling temperature of the solvent used, for example between 0 and 100°C, but preferably between 10 and 50°C. At a temperature between
It is appropriate to do so. This reaction, however, may also be carried out without a solvent.

f) To prepare a compound of the general formula I in which n represents 0, a thioether of the general formula (wherein M, B and R1 are as defined above) is combined with a thioether of the general formula (wherein Hal! is chlorine or a bromine atom, and He has the same meaning as R2 above except for hydrogen), or an alkali salt thereof, and optionally then hydrolyzed.

The reaction is preferably carried out with an alkali salt of a compound of the general formula
for example in the presence of a sodium salt and optionally an organic base such as an alkali base, in a solvent or a mixture of solvents such as methanol, methanol/water or ethanol, suitably at a temperature between 0 and 80°C. O, but preferably at a temperature between 5 and 50°C. in the presence of a solvent or a mixture of solvents such as water,
In methanol, water/methanol or tetrahydrofura//water at a temperature up to the boiling temperature of the solvent used.
be exposed.

The compounds of general formula I obtained according to the invention may then, if desired, be converted into their salts with strong acids. Suitable acids include, for example, hydrochloric acid, sulfuric acid or mesitylenesulfonic acid.

The compounds of the general formulas 2 to 3 used as starting materials are in some cases known from the literature or can be obtained using customary methods.

Thus, for example, a compound of general formula 1 or lla used as a starting material is mP41-0.003.77
1 Oh! bi)'(ySpecflf明1a4P 3042 <
532.5 (dated November 12, 1980) or may be prepared using the method described in KP-A I-0,003,771.

The compounds of general formula I used as starting materials are preferably obtained by reacting the corresponding O-carbonyl- or 0-sulfonyl-acetohydroxamate esters with sulfuric acid and then extraction after addition of a base.

The mercapto compound of the general formula (1) used as a starting material is, for example, the corresponding thioether opo47
or by reacting with o-mesitylenesulfonyl-hydroxylamine.

Compounds of general formula V obtained as starting materials can be prepared, for example, by oxidation and subsequent hydrolysis of the corresponding mercapto compounds (obtained by reaction of the corresponding thioethers with chloroamines) or with the corresponding mercapto or sulfinyl compounds. -obtained by reaction with mesitylene-sulfonyl-hydroxylamine.

Compounds of the general formula (1) used as starting materials can be prepared, for example, by reacting the corresponding sulfinyl compound (obtained by oxidation of the corresponding thioether) with the corresponding fbo-mesitylenesulfonyl-hydroxyl-amine, optionally followed by acylation. obtained by

The compound of general formula (1) used as a starting material can be obtained, for example, by reacting the corresponding hydroxy or mercapto compound with the corresponding halide in the presence of a base.

For example, the compound of the general formula (1) used as a starting material can be prepared by converting the corresponding amide into a hypohalide (hypoha
'1ite).

As mentioned above, the new compounds of general formula I have useful pharmacological properties, more particularly antithrombotic effects.

These increase the synthesis of aggregation-inhibiting grosstagladine 2 (prostacyclin). Furthermore, the compound of the general formula (■) in which n represents 0 is a useful intermediate for the production of a new compound of the general formula (■) in which n represents 1. This is based on the following properties of the compounds produced according to the invention: t These are platelets (pl
atelet) is a phosphogesterase inhibitor, and these are also known to be inhibitors of lying ulcers (H, Ga5tpar).
, Thrombosis Research
5earch) 5, 277-289 (1974) and K, P (, Ho 7 (K, V.

Honn), 8cienae 2
12.1270-1272 (1981)).

2. The compounds markedly increase the bleeding time, i.e. they inhibit hemostasis, reduce platelets in damaged blood vessels.
yte) to produce platelet aggregates (even at very low doses). Expression■
However, this cannot be explained solely by the platelet function, and it is thought that this must be due to increased dissociation of prostacyclin from vascular endothelial cells.

This is confirmed by the fact that the prolongation of the bleeding time does not occur if the synthesis of prostacyclin in endothelial cells is previously blocked by administration of a cyclooxygenase inhibitor. The present compound thus exhibits a previously unknown optimal combination of two fundamental effects: increased OAMP levels by stimulating production (prostacyclin) and simultaneously inhibiting degradation (PDIli inhibition);
Configure. By HONN (K.V.)
Horn (K, V, Honn) Science 212.12
70-1272 (1981)), the observed increase in prostacyclin activity or prostacyclin synthesis in the vascular wall is also responsible for inhibiting tumor metastasis.

For example, the following compounds were examined for their physical properties by the methods described below.

A=6- (4-methylsulfoxyiminophthoxy)
-3,4-dihydro-carbostyryl-mesitylenesulfonate, B = 6- (4-phenylsulfoximino-butoxy) -3,4-dihydro-carbostyryl, 0 = 6-(
4-(4-fluorophenylsulfo.

ximino)-butoxy)-3,4-dihydrocarbostyryl, D=6-(4-(4-chlorophenylsulfoximino)-butoxy)-3,4-dihydrocarbostyryl, 11f=6-(4-(N -Acetyl-6,4-dichlorophenylsulfoxy ξ)-butoxy]-6t 4-
Dihydrocarbostyril.

ν=6-('4-'(N-p-)luenesulfonyl-3
．． 4-dichlorophenyl-sulfoxy-imino)-butoxy]6,4-dihydrocarbostyryl, G=6-(4-(4-fluorophenylsulfoximino)-butoxytwocarbostyryl, H=6-(4-(
410 Lophenylsulfoximino)-butoxytwocarbostyryl, Aero-(4-(3-methyl-4-bromophenylsulfoximino)-butoxytwocarbostyryl, K=6- (4-(4-tart, butyl Phenyl-sulfoxy[zeta])-butoxy)-,3,4-dihydro-carbostyryl.

L=6-(4-(4-cyclohexylphenyl-sulfoximino)-butoxy]-6.4-dihydrolocalbostyryl, '=6-(4-(4-t, ert, butylphenyl-sulfoximino)-butoxytwo Carbostyryl, N=6- (4-cyclohexyl-sulfoximino-
butoxy)-carbostyryl, (i)=6-(4-(N-butyryl-6,4-dichlorophenyl-sulfoximino)-phthoxy]-3,4-
Dihydrocarbostyryl, P=5-(4-(N-acetyl-4-chlorophenyl-
Sulfoximino)-butoxy)-3゜3-dimethyl-
Indolin-2-one, Q=6- (4-(N -4-
tert, heyl-6,4-dimethoxyphenyl-
Sulfoximino)-putoxy)-3,4-dihydrocarbostyryl and H=6-(4-(3,4-dimethoxyphenylsulfoxiinno)-butoxy),6,4-dihydrocarbostyryl: 1, FDP inhibition principle CAMP is hydrolyzed to AMP by phosphogesterase (PDIe) K from a variety of sources including platelets.

PDB-inhibitors inhibit this hydrolysis, and this PDK-inhibition is concentration dependent.

Method The phosphogesterase used is made by centrifugal extraction at 10.000% I from frozen human platelets in water and then thawed.

0.1 mol/l trihydroxy-aminomethane (p)
17.4), 6 mmol/l magnesium chloride, 1
mmol/l AMP, 1 μmol/l 5H-CAM
A mixture of 0.5' P (about 10 MB9/μmol specific, active), PDE and the test inhibitor (water for control) is incubated at 57° C. for 15 min. Incubate 't' 0.5117 zinc sulfate (0,2
66 mol/l) and 0.5 Will barium hydroxide (
0,226 mol/l).

The precipitate was centrifuged, and the unreacted 'H-CAMP in the supernatant was removed.
The activity remaining in the sample is measured. Compare the results of the inhibitor and the control and calculate the concentration of each inhibitor required for %50% inhibitory effect (C30): A 4
5 B2. O C1,2 D O,84 K O,84 y O,90 G O,'40 HO,17 I O,039 K O,24 L 0.052 M O,21 N O,68 oo,55 Pl,8 The inhibitory effect of C5,1 R1,6 tumor metastasis was also demonstrated by gas doper (Ga5-tp
ar) etc. (Thrombosis Research (Thro
mbosis Research) 5 e 227
289 (1974)'t-), and can be demonstrated as effective in blocking tumor cell embolism. The test substance is administered prior to implantation of the tumor cells and survival of the test animals is determined by comparison with controls.

2. Measurement of prolongation of bleeding time Introduction: Humans and other warm-blooded animals have sophisticated mechanisms to protect themselves from blood loss due to injury. This mechanism consists of platelets, which very quickly seal the injured vessel with their adhesive properties, thereby providing primary hemostasis. Furthermore, in addition to this purely cellular hemostasis mechanism, the body has a blood clotting mechanism. During the processing of the cellulose mechanism, plasma factors (proteins) are activated and eventually convert into plasma fiderinogen and fidelin clots. Primary hemostasis and coagulation mechanisms, regulated primarily by thrombocytes but also by prostacytic activity of the vessel wall, complement each other in their common goal of effectively rewarming the body from blood loss.

It has been noted that in some diseases coagulation and thrombocyte aggregation occur even in intact blood vessels. The effect of coumarin and heparin on the coagulation mechanism is known and can be easily determined using known coagulation tests in which the clotting time t is prolonged under the influence of these substances. (Plasma recalcification time; Quick's test, calcification time, etc.).

In the event of an injury, the first rapid stoppage of bleeding is caused by the attachment and aggregation of thrombocytes on the blood vessel wall;
The functionality of embolocytes or the zolostacycle activity of the vessel wall can be easily measured by measuring the bleeding time Y in standardized lesions. Normal bleeding times in humans are between 1 and 6 minutes (assuming there are sufficient intact, effective embolocytes).

- If the thrombocyte count is normal and the bleeding time is prolonged, it indicates an abnormality of the thrombocytes and/or increased prostacycry/activity in the vessel wall. This is seen in congenital errors in thrombocyte function.

If, on the other hand, spontaneous aggregation of thrombocytes and closure of the arterial system
If drug inhibition is desired, effective treatments that affect thrombocytosis or vessel wall activity should prolong bleeding time. Therefore, when antithrombotic substances are used, the bleeding time is expected to be prolonged, and since the plasma coagulation mechanism is not affected, the clotting time is normal.

Literature: W.D.

Keidel): Kurz R7 Astes Lehrdeckder Physiology (Kurzgefasstes
Lahrbuchder Physiology
), Georg Thieme Vsrlag Stadtgart
tgart) 1967, page 51: Methods of hemostasis.

K to measure bleeding time, 2.5 w/kl of test compound is orally administered to sentient mice. After 1 hour, cut off the tip of the tail 'i' 0.511 of each mouse and gently remove a small drop of blood every 50 seconds with filter paper. The number of blood drops thus obtained is used to measure the bleeding time (5 animals per experiment).

The results in the following table represent the prolongation (%) compared to the control group: A 75 B > 161 125 D 55 E > 194 F > 212 () 85 H7B r > 275 K > 180 L > 191 M > 191 N'> ( Observation period: 14 days): A >250 Da (0 deaths among 10 animals) B
>25019 (0 deaths in 10 animals)C>250mg
(0 deaths in 1o animals) D >250m9 (10
0 deaths in 1000 animals) E > 1000 1000 deaths in 10 animals 0) 1'> 25011 g (0 deaths in 10 animals) () > 250 mg (0 deaths in 10 animals) H > 250 ~ (10 animals Death among animals 0)
>250 Da (0 deaths in 10 animals) In view of their pharmacological properties mentioned above, the novel compounds prepared according to the present invention are effective against thromboembolic diseases such as coronary infarction, cerebral infarction, so-called transient ischemic attacks. It is suitable for the prevention of temporary black lining, as well as for the prevention of hardening of the arteries, and for the prevention of metastasis.

The dosage required to achieve these effects is approximately 0
．． 1 to 4 m9/body weight, preferably 0.2 to 5
In9/weight loss, 2 to 4 times per 71 days.

This includes the compounds of general formula I prepared according to the invention and their physiologically compatible acid addition salts, optionally in combination with other active substances, 111i or two or more inert commonly used carriers and.

(or) diluents such as cornstarch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, nonionic surfactants. For example, polyoxyethylene fatty acid esters, water/polyethylene glycol, zolobile/glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fats or suitable mixtures thereof and 1. - Common galenic preparations such as tablets, coated tablets, capsules, powders, suspensions,
It may be formulated into drops, ampoules, syrups or suppositories.

The following example illustrates the invention: Example 1 6-(4-phenylsulfoximino'-sotoki3.4
F (0,01 mol) of 6-(4-phenylsulfyerudetoxy)-5,4-dihydrocarbostyryl''
Neutralize 4tSO- of polyphosphoric acid and stir at 45°C. Obviously, once everything is dissolved, 0.989 (0,015 mol)
Add sodium azide Y in small portions within 50 minutes.

Nitrogen gas is slightly generated. The beige creamy-foamy mass was stirred for 5 hours at 45-50°C, then 15 l of ice was added. The resulting cloudy solution was clarified with 48 KWI of concentrated ammonia and the resinous product precipitated. is extracted with chloroform. The oily evaporation residue is recrystallized from ethyl acetate. White crystals are obtained.

M,p,: 127-129℃ Yield: 1.1 # (44.6 excellent of 31 logical value).

Example 2 6-(4-(5,4-dicophenylsulfoquinimino)-cytoxy]-3,4-dihydroca24.0 F
(0.84 mol) of ethyl 0-mesitylenesulfonyl-
Neutralize acetohydroxamate 1'55MI in dioxane, dissolve 17-9051[ill] with stirring,
Add dropwise within 20 minutes at 20-25°C. The mixture was further stirred at the same temperature for 10 minutes, then poured into ice-cold water and extracted with methylene chloride of the resulting 0-mesitylenesulfonyl-sulfonylamine v100a/.
Wash twice more with ice-cold water and dry over magnesium sulfate. 12.4 # (0.03 mol) of 6-
(4-(5°4-dichlorophenylsulfinyl)-de14-di]-3,4-dihydrocarbostyryl is added to the resulting solution and stirred for 18 hours at ambient temperature.

Just dilute the stirrable crystal slurry V1201j with ethyl acetate and then filter the crystalline 6-(4-(3,4-dichlorophenyl-sulfoximino)11°4-dihydrocarbostyryl-mesitylenesulfonate) with suction.

To obtain the free base, it is suspended in 160% methanol and stirred with 17 WLt of 2N sodium hydroxide solution until everything goes into solution. After a short time,
A white precipitate is obtained consisting of 6-C4-C5°4-dichlorophenyl-sulfoquiquimino)-sotoxy]-5,4-dihydrocarbostyryl.

M, p,: 160-161℃ Yield: 10.41i (81.1i of theory).

Example 3 6-(4-(4-tert, detylphenyl-sulfoxy))-cytoxy)1,4-dihydro-carbostyryl Similarly to Example 2, 6-C4-(4-tert, butylphenyl-sulfinyl)- 1'')-3°4-dihydrocarbostyryl and 0-mesityl/sulfonylhydroxylamine.

M, p,: 201-203 °C Yield: 44 of the theoretical value 6-C4-(5,5-tert.

dithyl-4-hydroxy-phenylsulfinyl)-cytoxy)-5,4-dihydrocarbostyryl and 0-
Manufactured from mesitylenesulfonylhydroxylamine.

M,p,: 110-112℃ Yield: 52% of theory.

Example 5 6-(4-(4-Schiff-4-hexylphenylsulfoximino)-cytoxy)-3,4-dihydro 6-(4-(4-cyclohexylphenyl-sulfinyl)-1”) as in Example 2 xy) -514-Dihydrocarbostyryl and 0-mesitylenesulfonylhydroxylamine.

M,p,: 174-176℃ Yield: Theoretical value of 65 chi.

Example 6 6-(4-(4-biphenylsulfonodiimino)) 6-(4-(4-biphenylsulfinyl))
-detΦ'J-5. Prepared from 4-dihydrocarbostyryl and 0-mesitylenesulfonylhypoxyluaquin.

M,p,: 184=186℃ Yield: Theoretical value of 64 chi.

Example 7 6-(4-(naphthyl-(2)-sulfoximino)-
Cytoxy, 1-5, 4-dihydrocarboxylic acid, 6-(4-(su7tyl-2-sulfinyl)-
Detkin]-5,4-dihydrocarbostyryl and 0
- prepared from mesitylenesulfonylhydroxylamine.

M, p,: 151-152°C Yield: 711 of theoretical value Example 8 6-(4-(4-fluorophenylsulfoximino)
-Cytoxy)-3,4-dihydrocal 2 Similarly to Example 1, 6-C4-<4-fluorophenylsulfinyl)-
7'') xy]i, 4IP hydrocarbostyryl and sodium azide in polyphosphoric acid.

M, p,: 170-175°C Yield: 78% of theory Example 9 6-[4-(4-chlorophenylsulfoximino)-
Detoxy]-5.4-dihydrocarbostyryl Example 2 and l1t1411 Prepared from 6-(4-(4-chlorotetraphenylsulfinyl)-detoxy]1,4-dihydrocarbostyryl and 0-mesitylenesulfonylhydroxylamine do.

M, p,: 150-151°C Yield: 60 theoretical values Example 10 6-C4-(5-Methyl 4-deromophenylsulfoxyinno)-detoxy]-3.4-dihi Same as Example 2 6-(4-(5-Methyl-4-deImophenylsulfinyl)-cytoxy-5.4-dihydrocarbostyryl and .-mesitylenesulfonyl-hydroxylamine are thus prepared.

M, p,: 150-152°C Yield: 60 of the theoretical value Example 11 6-C4-(5,5-dibromo-4-aminophenylsulfonodiimino)-cytoxy)-3,4 Same as Example 2 from 6-C4-C5,4-dibromo-4-aminophenyl-sulfinyl)-sotoxy)-5,4-dihyrlocalbostyryl and 0-mesitylenesulfonylhydroxylamine.

M, p,: 110-115°C Yield: 55 theoretical values Excellent Example 12 6-C4-yenylsulfoximinodetox 6-(4-7enylsulfinyludetoxy)-carboxylate in the same manner as Example 2 Styril and. - prepared from mesitylenesulfonylhydroxylamine.

M, p,: 161-162°C Yield: Theoretical value 6096 Example 15 6- (4-(4-tert, butylphenyl sulfonyl) )-detoxy]-triple is prepared from styryl and sodium azide in polyphosphoric acid.

M, p,: 208-210°C Yield: 45 theoretical values Example 14 6'-C4-C5,5-ditent, decyl-4-hydroxy-phenylsulfoximino)-cytoxytucarbostyryl Same as Example 2. 6-C4-C5,4-tert,
Detyl-4-hydroxy-phenylsulfinyl)-detoxy]carbostyryl and 0-mesitylene-sulfonylhydroxylamine are prepared.

M, I),: 205-207°C Yield: 59% of theory Example 15 6-(4-cyclohexylphenylsulfoxy 6-(4-(4-cyclohexylphenylsulfinyl)-detoxy)- Manufactured from carbostyril and sodium azide in polyphosphoric acid.

M, 1),: 195-197°C Yield: 52 theoretical values Example 16 6-(4-(4-biphenylylsulfoxyinno)-cytoxytucarbostyryl 6-[4- Prepared from (4-bifurdisulfinyl)-cytoxytucarbostyryl and O-mesitylenesulfonylhydroxylamine.

M, p,: 256-258°C Yield: 76 theoretical values Example 17 6-(4-Cyclohexylsulfoximinosotoxy)-carbostyryl 6-(4-cyclohexylsulfinyl-cytoxy) - Prepared from carbostyril and sodium azide in polyphosphoric acid.

M, 1), : 145-147 °C Yield: 47% of theory Example 18 6-C4-C4-fluorophenylsulfoxy 6-(4-(4-fluorophenylsulfinyl)-cytoxy2) It is prepared from gastyryl and o-mesitylenesulfonyl-hydroxylamine.

M, p,: 177-179°C Yield: 70% of theory Example 19 6-(4,(4-chloro-7-enylsulfoxy) 6-(4-(4-chlorophenylsulfinyl)-sotoxy) - prepared from carbostyril and 0-medi, tyrenesulfonylhydroxylamine.

M, p, : 201-205°C Yield: 79 theoretical values Example 20 6-C4-<4-detetramophenylsulfoxy ]-carbostyryl and 0-mesitylenesulfonylhydroxyl heptane.

M, p, : 211 -215°C Yield: 66% of theory Example 21 6-(4-(3,4-dichloroqphenylsulfo6-C4-C5,4-dichlorophenyl-sulfinyl) as in Example 2) -Tetoxy]-triyl is prepared from styryl and 0-mesitylenesulfonylζ-droxylamine.

M, p,: 214-216°C Yield: 73% of theory Example 22 6-C4-C5-Methyl-4-zoromophenylsulfoximino)-cytoxy]-carposti 6- C4-C5-Methyl-4-bromophenyl-sulfinyl)-detoxy]-lupostyril and sodium azide in polyphosphoric acid.

M, p,: 195-194°C Yield: theoretical 541 Example 25 6-(4-(2'-Fluoro-4-biphenylylsulfoΦdiimino)-detoxy]-carbostyryl was prepared in the same manner as in Example 2. (4-(2'-fluoro-4-
It is prepared from biphenylylsulfinyl)-tethoxy]-carbostyryl and O-mesitylenesulfonyl ζ droxylamine.

M, 1), : 191-195°C Yield: fM theoretical value 74 Example 24 6-(4-(5,5-sideroso-4-aminophenylsulfonodiimino)-detoxy]-carbostyryl Example 2 Similarly, 6-(4-(3,5-dibromo-4-
phinophenylsulfinyl)-P) quintucarbostyryl and O-mesitylenesulfonyl ζ droxylamine.

M, p,: 150-155°C Yield: 51 theoretical values Example 25 5.3-dimethyl-5-[4-(4-methylphtrinylsulfoximino)-detoxy]-indo-(4-/? prepared from indolinone-2 and 0-mesityle/sulfonyl-hydroxylamine.

M-p: 146-147°C Yield: 84 theoretical values Example 26 3.6-dimethyl-5-C4-(4-tart, f
tylphenylsulfoximino)-butoxy]--(4
-tert,butylphenylsulfinyl)-cytoxy]-indolinone-2 and 0-mesitylenesulfonyl-hydroxylamine.

M, p,: 195-197°C Yield: Jl theoretical value 851 Example 27 3.3-dimethyl-5-C4-<2-methyl-4-te
rt, f tylphenylsulfoquinimino)-1(2-
methyl-4-tert, butylphenylsulfinyl)
-Detkin]-indolino/and 0-mesityle/sulfonylruhi "Produced from roxylamine.

M, p,: 149-150°C Yield = 26 theoretical values Example 28 3.3-dimethyl-5-C4-C5,5-di-tart
, dithyl-4-human tetraxyphenylsulfo 5,5-dimethyl-5-[4-(5,5-di-tert, decyl-4-hydroxyphenylsulfoximino)-detoxy]-indo as in Example 2 Manufactured from tetrakylamine. Glass-like substance.

Rf value: 0.25 (silica gel plate, eluent:
Ethyl acetate/methylene chloride 1=1) Yield: 42% of theory Example 29 5.5-dimethyl-5-(4-cyclohexylphenylsulfoximino-butoxy)-indolinone-2 Monocyclotetrahexylphenylsulfinylde Toxi)
- Prepared from sodium azide in Inodorino/-2 and Bolily/#.

M, p,: 162-163°C Yield: 69 theoretical values Example 30 6.5-dimethyl-5-[4-(2-s7tylsulfoximino)-detoxy]-yne Plinone - Same as Example 2 3.3-dimethyl-5-[4-(2-su7-tyl-sulfinyl)-detkin]-indolinone-2 and O
- prepared from mesitylenesulfonylhydroxylamine.

M, p,: 120-121°C Yield: j! Theoretical value 64 ts Example 51 5.5-dimethyl-5-(4-Schiff-4-hexylsulfoxyiminodetoxy)-indolinone - 6.5-dimethyl-5-(4-cyclohexylsulfinyl-dolinone) under the same pressure as in Example 2. Toxy)-indolinone-2 and O-mesitylenesulfonylhydroxylamine.

M, p,: 108-109°C Yield: 771 s of theory Example 52 5.5-dimethyl-5-(4-be/dylsulfo) -butoxy)-intrinon-2 and 0-mesitylenesulfonylhydroxylamine.

M, p,: 9B - 99°C Yield: 82% of theory Example 66 6.5-Dimethyl-5-[4-(4-fluorophenylsulfoximino)-tetoxy”l-1-N Same as Example 2. 6,6-dimethyl-5-[4-(4-fluorophenylsulfinyl)-detoxy]-indolinone-2 and 0-mesitylenesulfonylhydroxylamine.

M, 1),: 101-102°C Yield: 901 theoretical Example 34 6.5-dimethyl-5-(4-(4-chloro7enylsulfoximino)-detoxy]-i/trinon-2 6.5-dimethyl-5-[4-(4-
/4p-phenyl (sulfinyl)--7'') xif-indolinone-2 and 0-mesitylenesulfonylhydroxylamine.

M, p,: 156-157°C Yield: 76% of theory Example 35 3.3-dimethyl-5-(4-(4-deromofenylsulfoximino)-detoxy]-indo-(4-bromo phenylsulfinyl)-te)ki! Prepared from Schiff-indolinone-2 and 0-mesitylene-sulfonylhydroxylamine.

M, p,: 160-151°C Yield: 88 theoretical values Example 56 3.6-dimethyl-5-C4-C5,4-dichlorophenylsulfoximino)-tethoxy]--(3,4-"
) Chlorophenylsulfinyl)-detoxy]-i/dolino/-2 and O-menthylenesulfonyl-hydroxylamine.

M, p,: 147-148°C Yield: 68 theoretical values Example 37 5.5-P methyl-5-[4-(2,5-dichlorophenylsulfoxyiξ])-tetoxy]--(2,5 -1
It is prepared from chlorophenylsulfinyl)-detoxy]-indolinone-2 and 0-menthylenesulfonyl-hydroxylamine.

Rf value: 0.3 (silica gel plate, eluent: ethyl acetate/methylene chloride 1:1), yield: 18% of theory Example 38 5.5-dimethyl-5-C4-C5-・methyl-4-de gastric mophenylsulfoximino)-detoky-(5-methyl-4-bromophenylsulfinyl)-detokin]-
Prepared from indolinone-2 and 0-mesitylenesulfonyl-hydroxylamine.

M, p,: 131-152°C Yield zjJ theoretical value 841s Example 59 6.3-dimethyl-5-[4-(2'-fluoro-4-
biphenylylsulfoximino)-detoky-(2'-fluoro-4-biphenylylsulfinyl)-butoxy]
-Indolinone-2 and 0-7 Mesitylenesulfonylhydroxylamine is thus prepared.

M, p,: 177-178°C Yield: 31 theoretical 901 Example 40 6.5-dimethyl-5-(4-1,5-didep mo 4-
7minophenylsulfoximino)-non-2 and o
- prepared from mesitylenesulfonylhydroxylamine.

M, p,: 202-204°C Yield: 76% of theory Example 41 3.3-Dimethyl-5-[4-(4-methoxyphenylsulfoximino)-detoxy]-yn-(4-meth) xyphenylsulfinyl)-f) xy]-indolinone-2 and 0-mesitylene-sulfonylhydroxyluaquine.

M, p,: 140-141°C Yield: 711 of theoretical value Example 42 3.5-dimethyl-5-(4-(2-methoxyphenylsulfoxyinno)-cytoxytuindolinone-2) Summed in the same manner as in Example 2. 5.6-dimethyl-5-[4-(2-
methoxyphenylsulfinyl)-gutoxy]-indolinone-2 and. - Lit preparation from mesitylenesulfonylhydroxylamine.

Colorless resin-like substance. Rf value: 0.55 (silica gel,
[[1M ethylene/ethanol = 9:1'),
Yield = jJ theoretical 52% Example 43 5.3-dimethyl-5-(4-(5,4-dimethoxyphenylsulfoximino)-detoxy]-indolinone-2 3,3-dimethyl -5- [4-C5,
4-dimethoxy-phenylsulfinyl]-detoxy]
-indolinone-2 and. -Mesitylenesulfonylhydroxylamine is thus prepared.

M, p,: 108-109 DEG C. Yield: 79'1 of theory Example 44 3.3-Dimethyl-5-C4-C6-methomedi-naphthol-2-yl-sulfoximino)-butoSimilarly to Example 26. 5-dimethyl-5-[4-(6-methoxy-naphthol-2-yl-sulfinyl)-detoxy]-indolinone-2 and.

-Mesitylenesulfonyl-hydroxylamine.

M, p,: 174-175°C Yield: 88 theoretical values Example 45 6-(4-methylsulfoximino-cytokine)-5,
4-dihydrocarbostyryl-mesitylene 6-(4-methylsulfinyl-cytoquine)-5,
Prepared from 4-dihydrocarbostyryl and 0-mesitylenesulfonylhydroxylamine.

M, $1. : 150-155°C Yield: fM theoretical value 87 Example 46 3.3-dimethyl-5-(4-:yenylsulfoxy-ζ-nodetoxy)-indolinone-2 5.5-dimethyl-5 in the same manner as Example 2 -(4-phenylsulfinyl-
Cytoquine)-intrinon-2 and 0-mesitylenesulfonylhydroxylamine.

M, 1), : 111-112°C Yield: Theoretical value of 86ts Example 47 6-(4-(N-acetyl-3,4-dichlorophelsulfoximino)-methoxy:]-3°1.40.A
6-C4-C5,4-dichlorophenylsulfoximino)-cytoxy]-5,4-dihydrocartilstyryl Y70- of glacial acetic acid and anhydride 5if) h of 70- suspended in a mixture of 24 Stir for an hour. Mix the resulting solution with 600 mL of ice-cold water while stirring vigorously.

White crystals begin to precipitate after 10 minutes. After 1 hour, the solution is filtered off with suction, the product is washed with water and crystallized from 14ON ethanol with the addition of a small amount of activated carbon. A white crystalline material is obtained and dried in a rotating air dryer at 80°C.

M, p,: 150-152℃ Yield: 12.9jl (theoretical value of 84ts).

Example 48 6-(4-(N-carbamoyl-5,4-dichlorophenylsulfoximino)-cytokine)-1,4919(
0,0055 so) 6- (: 4- (5゜4-shi)mouth-phenylsulfoximino)-cytokin)-
The 5,4-dihydrocarbostyryl is dissolved in 7Qd of glacial acetic acid, then 2.8 g (0,055 mol) of potassium cyanide tf# are added and the mixture is stirred at ambient temperature for 3 hours. Upon subsequent addition (with stirring) of 40% water, the initially precipitated oil crystallizes out. This is filtered off with suction, recrystallized from 65 atm of ethanol and the white crystalline material VSO is dried in a rotary air dryer at VSO°C.

M,p,': 148-150°C Yield: 1.2Ii (70Ii of theory) Example 49 6-(4-(N-butyryl-6,4-dichlorophenylsulfoximino)-cytoxy]-5゜4-Dihydrocarbostyryl 5.0 N (0,007 mol) of 6-C4-(5,4
-dichlorophenylsulfoximino)-cytoxy)-
! t,4-dihydrocarbostyryl Y1511Lt was suspended in pyridine and 0.9 # (1,2X 0.0
07 mol) of n-butyric acid chloro+)Pyt is added. A pale yellow solution is formed and the mixture is heated to 40°C.

After standing for a further 90 minutes, the mixture was evaporated to dryness (under water jet vacuum using a rotary evaporator), the residue was dissolved in methylene chloride and shaken twice with 0.5N hydrochloric acid and once with water. I extract it because I'm busy. After drying over magnesium sulphate, the solvent is distilled off using a rotary evaporator and the residue is recrystallized from 15 ml of ethanol. Colorless crystals Y are obtained.

M, p,: 155-155℃ yield? 2.4F (theoretical value of 69chi).

Example 50 6-C4-CM-bipoloy-5.4-dichlorophenylsulfoximino)-cytoxy] -5゜4-dihydrocarbostyryl 6-C4-(5,4-dichlorophenyl-sulfoximino)-detoxy ]-5.4-Dihyr local prepared from bostyryl and piperic acid chloride.

M, p, 15B-160℃ Yield: 81% of theory.

Example 51 6-[4-(N-(2-methoxyacetyl)-5,4-
Dichlorophenylsulfoximino) - Prepared analogously to Example 49 from 6-[4-(5,4-dichlorophenylsulfoximino)-cytoxy]-5,4-dihydrocarbostyryl and 2-methoxyacetyl chloride.

M, p,: 105-105°C Yield: 50 theoretical values Example 52 6-[:4-(N-benzoyl-5,4-dichlorophenylsulfoximino)-cytoxy] -5° Same as Example 49 Prepared from 6-C4-C5,4-dichlorophenyl-sulfoximino)-detoxy]-5,4-dihydrocarbostyryl and benzoyl chloride.

M, pa: 110-111°C Yield: theoretical 68Llj Example 55 6-[4-(N-4-methoxybenzoyl)-5,4-
Dichlorophenylsulfoximino) - Prepared analogously to Example 49 from 6-C4-C5,4-dichlorophenylsulfoximino)-cytoxy]-3,4-dihydrocarbostyryl and 4-methoxybenzoyl chloride.

M, p,: 186-188°C Yield: 70% of theory Example 54 6-C4-CN-Nicotinoyl-5,4-dichlorophenylsulfoxy-detoxy] - 6-C4- C5,4-dichlorophenyl-sulfoacyimino>--ftoxy]-+ 5 , prepared from 4-dihydrocarbostyryl and nicotinic acid chloride hydrochloride.

M, p,: 101-105℃ Yield: 94% of theoretical value.

Example 55 6-C4-(N-(4-methylphenylsulfonyl)
-5,4-dichlorophenylsulfoximino)-cytoxy)-3,4-dihydrocarzastyryl 6-C4-<5.4-dichlorophenylsulfoximino)-sotoxy]-5,4-dihydro Produced from carbostyril and p-)luene/sulfochloride.

M, p,: 154-156°C Yield: 84 excellent examples of theory 56 6-C4-CN-C2-acetoxy-phenylacetyl)-5,4-dichlorophenylsulfoximino)-cytoxy]-5,4-dihydrocal Similarly to Example 49, 6
-(4-(i4-dichlorophenylsulfoximino)
-ethoxy]-3,4-dihydrocarbostyryl and 0-acetyl-D,L-mandelic acid chloride.

After purification with ethylene chloride on a silica gel column, 5-[
4-(N-acetyl-5,4-dichlorophenylsulfoximino)-ethoxy]-ri.

5-Dimethyl-indolinone-2 Prepared analogously to Example 47 from 5-(4-(5,4-dichlorophenylsulfoximino)-ethoxy]-6,4-dimethyl-indolinone-2 and acetic anhydride.

M, p,: 145-146°C Yield: 64 theoretical values Example 58 5-[4-(N-butyryl-6,4-dichlorophenylsulfoximino) -/')xy 1-5° Same as Example 49 5-[:4-(5,4-dichlorophenylsulfoximino)-cytoxy]-6,3-dimethyl-indolinone-2 and butyric acid chloride.

M, p,: 120-122°C Yield: 811 of theory Example 59 5-(4-(N-(2-methoxy-acetyl)-5,4
cyacetyl chloride in 6,5-dimethyl-5-(4-(5,4-dichlorophenylsulfoximino)-detoxy]-ynerlinone-2 and 2-meth) analogously to Example 49. Manufactured from.

M, p,: 126-128°C Example 60 5-(4-(N-ethoxycarbonyl-3,4-dichlorophenylsulfoximino)-ethoxy)-3,3-
Dimethyl-indolinone-2 5-(
4-(4-chlorophenylsulfoximino)-ethoxy)-3,3-dimethyl-yne P-linone-2 and ethyl chlorocarbonate.

M, p,: 102-104°C Yield: 79% of theory Example 61 5-44-(N-acetyl-4-chlorophenylsulfoximino)-ethoxy)-3,3-di Similar to Example 47 5-(4-(4-chlorophenylsulfoximino)-ethoxy)-3,3-dimethyl-indolinone-2
and acetic anhydride.

M-1), :13B-140°C Yield: 75% of theory Example 62 5-44-(N-butyryl-4-chlorotzenylsulfoximino)-cytoxy)-3,3-dimethyl-indolinone- 2 Prepared analogously to Example 49 from 5-44-(4-chlorophenylsulfoximino)-cytoxy)-3,3-dimethyl-indolinone-2 and butyric acid chloride.

M-p: 166-168°C Yield: 68% of theory Example 63 5-(4-(N-pivaloyl-4-chlorophenylsulfoximino)-cytoxy)-3,3-dimethyl-indolinone-2 Example 49 It is prepared from 5-44-(4-chlorophenylsulfoximino)-butoxy)-3,3-dimethyl-indolinone-2 and biparic acid chloride in the same manner as above.

M, p,: 95-97°C Yield: 76% of theory Example 64 5-(4-(N-capryl-4-chlorophenylsulfoximino)-cytoxy)-3,3-zo Same as Example 49 5-[4-(4-chlorophenylsulfoximino)-butoxy)1,3-dimethyl-indolinone-2 and caprylic acid chloride. resinous material.

Rf value: 0.5 (silica gel plate, ethyl acetate/methylene chloride = 1:1), yield: 95% of theory Example 65 5-[4-(N-carbamoyl-4-chlorophenylsulfoximino)-cytoxy) 5-(4-(4-chlorophenylsulfoximino)-cytoxy)-3,3-dimethyl-indolinone-2
and potassium cyanide. Colorless resinous substance.

Rf value 70.4 (silica sol plate, ethylene chloride/ethanol =, 9:1), yield: theoretical value of 7
5% Example 66 5- (,4-(N-dimethylaminocarbonyl-4-
Chlorophenylsulfoximino)-butoxy)-3,
3-Dimethyl-indolinone-2 5 in the same manner as in Example 49
-44-(4-chlorophenylsulfoximino)-cytoxy)-3,3-dimethyl-indolinone-2 and dimethylcarbamyl chloride.

M, p,: 170-172°C Yield: 64% of theory Example 67 6-44-(N-acetyl-6,4-dimethoxyphenylsulfoximino)-cytoxy]-3,4-dihydrocarpostyryl example 47 from 6-(4-(3,4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)i,4-zophenol and acetic anhydride.

M-p-: 89-92°C Yield: 60% of theory Example 68 (S-(4-(N-butyryl-6,4-dimethoxyphenylsulfoximino)-cytoxy]-6,4-dihydro Carpostyril Produced from 6-(4-(3,4-dimethoxyphenylsulfoxy-imino)-detoxy)-6,4-zohydrocarpostyril and chloride butyrate in the same manner as in Example 49. Glass-like colorless resin something like that.

Rf value = 0.35 (silica gel plate, ethylene chloride/ethanol = 9:1).

Yield: 41% of theory Example 69 6-(4-(N-benzoyl-6,4-dimethoxyphenylsulfoximino)-cytoxy]-3,4-dihydrocarpostyryl -(3,4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)-!1,4
- prepared from dihydrocarbostyryl and penfyl chloride.

M-p, near 8-80°C Yield: 50% of theory Example 70 6-(4-(N-(4-chlorobenzoyl)-6,4-
Dimethoxyphenylsulfoxy-imino) prepared analogously to Example 49 from 6-L4-<5.4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)-3,4-dihydrocarbostyryl and 4-chlorobenzoyl-chloride .

M, p, : 154-137°C Yield - 61% of theory 0 Example 71 6-C4-(N-(4-tert,butylbenzoyl)-3,4-dimethoxyphenyl-sulfoximino)-cytoxy)-3, 4-dihydrocarbostyryl Prepared analogously to Example 49 from 6-44-(3,4-dimethoxyphenyl-sulfoximino)-detoxy]-6,4-dihydrocarbostyryl and 4-tart, butyl-benzoyl chloride.

M-p: 98-101°C Yield - 87% of theory Example 72 6-44-(N-nicotinoyl-6,4-dimethoxyphenylsulfoximino)-detoxy] 6-[4 -(3,4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)-! 1. Prepared from 4-dihydrocarzastyril and nicotinic acid chloride hydrochloride.

M,p,': 90-93°C Yield: 75% of theory Example 73 6-(4-(N-pentamethylphenylsulfonyl-3
,4-dimethoxyphenyl-sulfoximino)-cytoxy)-3,4-dihydroportion 6
-(4-(3,4-dimethoxyphenyl-sulfoxy-
Produced from imino)-cytoxy)-3,4-dihydrocarbostyryl and pentamethylbenzene-sulfonic acid chloride.

M, p,: 186-188°C Yield: 75% of theory Example 74 5-(,4-(N-acetyl-3,4-dimethoxyphenylsulfoximino)-detoxy) - 5 as in Example 47 -44-(3,4-dimethoxyphenyl-sulfoximino)-detoxy]-3,3-dimethylindolin-2-one and acetic anhydride. Glass-like resinous Rf value: 0.3 (silica gel grade, Ethylene chloride/ethanol = 9:1).

Yield: Theoretical value (Q99%.

Ex.
, 4-dimethoxyphenyl-sulfoxy-imino)-butoxy)-3,3-dimethylindolin-2-one and butyric acid chloride. resinous material.

Rf value: 0.35 (silica gel grade, ethyl acetate/methylene chloride = 1:1), yield: 92% of theoretical value Example 76 5-(4-(N-pivaloyl-3,4-dimethoxyphenylsulfoximino) -buty]-Produced from 5-t=4-(3,4-dimethoxyphenylsulfo. 0
resinous material.

Rf value: 0.45 (silica gel plate, ethyl acetate/methylene chloride = 1:1) ~ Yield: 88% of theory 0 Example 77 5-[4-(N-carbamoyl-6,4-dimethoxyphenylsulfoxy- 5-44 in the same manner as in Example 48.
-(3,4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)-3,3-dimethylindolinone-2 and potassium cyanide. resinous material.

Rf value: 0.25 (silica gel plate, ethylene chloride/ethanol = 9:1), yield: 75% of theoretical value Example 78 5-(4-(N-dimethylaminocarbonyl-3,4-
dimethoxyphenylsulfoxy-imino)-cytoxy)
-3,3-dimethylindolinone - 5-(4-(3,4-dimethoxyphenyl-sulfoxy-imino)-cytoxy)-3,3-dimethylindolinone-2 and zomethylcarbamilk as in Example 49 Manufactured from LoliP. resinous material.

Rf value: 0.3 (silica gel plate, ethylene chloride/ethanol-9:1), yield: 98% of theory Example 79 5-44-(N-4-chlorobenzoyl)-3°4-dimethoxyphenylsulfoxy imino)-cytoxy)-3
, 3-dimethyl-indolinone-2 Same as Example 49 and 5-[4-(3,4-dimethoxyphenyl-sulfoximino)-detoxy]-3,3-zomethylindolinone-2 and 4-chlorobenzoyl chloride Manufactured from.

M, p,: 174-177°C Yield: 74% of theory Example 80 5-(4-(N-nicotinoyl-3,4-dimethoxyphenylsulfoximino)-butoxy]-3,3-zomethyl-indo Linone - 5-[4-
Produced from (3,4-dimethoxyphenylsulfoximino)-detoxy]-6,3-zomethylindolinone-2 and nicotinic acid chloride hydrochloride. resinous material.

Rf value: 0.25 (silica gel plate, ethylene chloride/ethanol = 9:1), yield: 76% of theoretical value.

Example 81 6-C4-<2-N-C naphthoyl)-3,4-dimethoxyphenylsulfoximino)-puttoxyphenylsulfoximino)-cytoxycu-5,4-zohydrocarbostyryl and 2-naphthoic acid chloride Manufactured from. resinous material.

Rf value: 0.45 (silica gel plate, ethyl acetate/methylene chloride = 1:1), yield: 93% of theoretical value.

Example 82 6-(4-(N-(1-naphthoyl)-3,4-dimethoxyphenylsulfoximino)-detotoxyphenylsulfoxyimino)-butoxy)-3,4-dihydrocarzastyryl and 1-' Manufactured from naphthoic acid chloride. resinous material.

Rf value = 0.3 (silica gel plate, ethyl acetate/methylene chloride = 11), yield: 83% of theory.

Example 83 6-[4-(N-(2-chenoyl)-3,4-dimethoxyphenylsulfoximino)-detotoxyphenylsulfoximino)-detoxy]-3,4-dihydrocarbostyryl and thiophene-2 - produced from carboxylic acid chlorides. resinous material.

Rf value: 0.3 (silica sol plate, ethyl acetate/methylene chloride = 1:1), yield: 88% of theoretical value.

Example 84 6-(4-1,4-dimethoxyphenylsulfokidiimino)-cytoxy)-3,4-dihydro 6-(4-(3,4-dimethoxyphenylsulfinyl)-de)+ [C]-3゜4-dihydrocarbostyryl and. -Mesitylenesulfonyl-hydroxylamine.

M, ]>-: 154-156℃, Yield: 64% of theoretical value.

Example 85 6-L4-CM-benzoyl-4-fluorophenylsulfoximino)-cytoxy)-3,4-dihydrocarbostyryl 6-(4-(4-fluorophenylsulfoximino)- Cytoxy)-3°4-dihydrocarbostyryl and benzoyl chloride.

M-p-764-68°C, ・□ Yield: 87% of theory Example 86 6-(4-(N-(4-chlorobenzoyl)-4-fluorophenylsulfoximino)-butoxy)-3,4
- Proceed as in Example 49 of dihydrocarbostyril - (4
-fluorophenylsulfoximino)-cytoxy)-
Prepared from 3,4-dihydrocarbostyryl and 4-chlorobenzoyl-chloride.

M, p,: 164-138°C Yield: 78% of theory Example 87 6-(4-(!1,4-dichlorophenylsulfoximino)-butoxy)-6,4-zohydroca 145.59
p-Toluenesulfonic acid of 70.1.9 was dissolved in 650 M dimethylformamide with stirring, and the 6-[
4-(3,4-dichlorophenylsulfinyl)-cytoxy)-3,4-'/hydrocarbostyryl is added with stirring. Then 106.7 g of ethyl 0-mesitylenesulfonylhydroxamate are added. This reaction is slightly exothermic, so the reaction mixture is cooled to 350°C after 46 hours to ensure that the temperature does not exceed 20°C.
When adding the water from step 17 (while stirring thoroughly), it first begins to become slightly cloudy. Upon addition of the seed crystal suspension, most of the product begins to crystallize and this continues for 60 minutes, with continued stirring during this time. Add another 300 d of water with stirring to completely eliminate crystallization. After the mixture has been stirred for 30 minutes, the crystals of 0-mesitylene sulfonate thus formed are filtered off with suction and washed with water. The filter cake, still wet with water, was suspended in 500 d of methanol and 100 #110
Add the 2N hydroxide solution to one container with stirring. Rough dissolution of this material in solution results in crystallization of free sulfoxy-imine.

The mixture is stirred for a further 30 minutes at ambient temperature, filtered off with suction and washed with water-cooled methanol. The product is dried in a rotating air dryer at 80°C.

M, 1),: 160-162°C Yield: 61.7 g (84.9% of theory).

Example 88 6-[4-(3,4-dichlorophenyl-N-(4-)
6-[4-(3,4-dichlorophenyl-N)
-(4-Toluenesulfonyl)-sulfimino)-cytoxy)-3,4-dihydrocarzastyryl[6-[,4
-(3,4-zochlorophenylmerkabuto)-cytoxy)-3,4-dihydrocarbostyryl and N-chloro-4-toluenesulfonamide-sodium (chloramine T)] was dissolved in methanol and 0. 3
5a/2N sodium hydroxide solution and 0.061
A hydrogen peroxide solution of 11 (397.4 μ/ml) is added and the resulting mixture is refluxed for 4 hours. A clear solution forms when it begins to boil, and crystals precipitate after 1 hour.

After further heating, the crystals are collected by suction filtration while still hot and dried in air.

M-p,: 155-157°C Yield: 59% of theory Example 89 6-43-(3,4-dichlorophenylsulfoximino)-propoxy)-3,4-dihydrocarbostyryl Same strain as in Example 2 Prepared from 6-(3-(3,4-dichlorophenylsulfinyl)-ypropoxy)-3°4-dihydrocarbostyryl and O-mesitylenesulfonyl-hydroxylamine.

M, p,: 144-146°C Yield: 67% of theory Example 90 6-L5-(3,4-dichlorophenylsulfoximino)-pentoxy)-3,4-dihydrorophenylsulfinyl)-pentoxy) -3° Prepared from 4-dihydrocarbostyryl and O-mesitylenesulfonylhydroxylamine.

M, p,: 154-155°C Yield - 29% of theory Example 91 6-(3-ethylsulfoximino-pro-hoxy) 6-(3-ethylsulfinylzolopoxy) as in Example 2 -Produced from 3,4-dihydrocarbostyryl and 0-mesitylenesulfonylhydroxylamine.

M, 1), : 107-109°C Yield: 61% of theory Example 92 6-(4-(N-4-cyanobenzoyl-3°4-dichlorophenylsulfoxy-imino)-butoxy)-3,
6-(
4-1,4-dichlorophenylsulfoxy-imino)-
[detoxy]-6,4-zohydrolupostyryl and 4
- Manufactured from cyanobenzoyl chloride P.

M, p,: 200-202°C Yield: 79% of theory Example 96 6-(4-(N-2-chenoyl-6,4-dichlorophenylsulfoximino)-butoxy]-3,4-dihydrocarbo Styryl is prepared analogously to Example 49 from 6-L4-(3,4-dichlorophenylsulfoxy-imino)-detoxy]-6,4-dihyPlocarbostyryl and 2-thiophene-carzanoyl chloride.

M, 1),: 100-102°C Yield: 61% of theory Example 94. 5-(4-N-(+)-1nanoyl-6,4-dichlorophenylsulfoximino)-butoxy]-6.4-
Dihydrocarbostyryl 0 M-1 prepared from 6-L4-(3,4-dichlorophenylsulfoxy-imino)-cytoxy-6,4-zohydrocarpostyril and (+)-gnanyl chloride analogously to Example 49 )-: 69-74°C Yield: 94% of theory Example 95 6-(4-(N-(-)-vinanoyl-3,4-dichlorophenylsulfoximino)-detoxy]-6.4-
Dihydrocarbostyryl is prepared analogously to Example 49 from 614-(3,4-dichlorophenylsulfoximino)-butoxy]-3,4-dihydrocarbostyryl and (-)-binanoic acid chloride.

M-p,: 69-74°C Yield: 91% of theory Example 96°, 6-(N-pentamethylphenylsulfonyl-3,4-
Dichlorophenylsulfoxy-imino)-butoxy)-
6 in the same manner as 3,4-dihydrocarbostyryl Example 49
OM-p prepared from -(4-(3,4-dichlorophenylsulfoxy-imino)-detoxy]-3,4-zohydrocarzastyryl and pentamethyl-phenyl-sulfochloride: 149-151°C Yield: theoretical 83% Example 97 6-(4-(N-methanesulfonyl-6,4-dichlorophenylsulfoximino)-detoxy]-3,4-zohydrolupostyril 6-[,4-1,4 -dichlorophenylsulfoximino)-butoxy]-3,4-dihydrocarbostyryl and methanesulfonyl chloride.

M-p: 172-174°C Yield: 37% of theory Example 98 6-(4-(N-acetyl-4-cyclohexylphenyl-sulfoxy-imino)-detoxy]-3,4-zohydrocarbostyryl example 47, 6-(4-(4-cyclobexylphenyl-sulfoximino)-butoxy]-'5, 4
- prepared from dihydrocarbostyryl and acetic anhydride.

M, p,: 135-136°C Yield: 92% of theory Example 99 6-[4-(N-pivaloyl-4-cyclohexylphenylsulfoximino)-detoxy] - 6-44 as in Example 49 -(4-Cyclohexylphenyl-sulfoxy-imino)-butoxy)-3,4-dihydrocarbostyryl and pivaloyl chloride.

M, 1), : 170-172°C Yield: 95% of theory Example 100 ゛6-(4-(N-benzoyl-4-cyclohexylphenylsulfoximino)-detoxy) - Same as Example 49 6-(4,(4-Cyclohexylphenyl-sulfoximino)-detoxy]-3t4-zohydrocarpostyryl and benzoyl chloride.

M, p, = 187-189°C Yield: 92% of theory Example 101 6-(4-(N-acetyl-4-fluorophenylsulfoximino)-butoxy)-3,4-dihydrocarbostyryl Example 47 It is prepared in a similar manner from 6-[4-<4-fluorophenylsulfoxy-imino)-butoxy]-6,4-dihydrocarbostyryl (Rf value: 0.60) and acetic anhydride.

Rf value: 0.65 (silica gel, eluent: ethylene chloride/ethanol = 85:15), yield: 54% of theory Example 102 6-(4-(N-butyroyl-4-fluorophenylsulfoximino)- butoxy)-3,4-dihydrocarbostyryl 6-[4-(4-fluorophenylsulfoxy-imino)-butoxy]-3,4-dihydrocarbostyryl (Rf value: 0.60) O Rf value: 0.70 (silica gel, eluent: tyrene chloride/ethanol = 85:15) Yield: 78% of theoretical value Example 10
3 6-(4-(N-2-methoxyacetyl-4-fluorophenylsulfoximino)-detoxy]-6,4-dihydryl 6-'(4-'<4 -Fluorophenylsulfoxy'imino)-butoxy]-3,4-
Produced from dihydrocarbostyryl (Rt value: 0.60) and '2-methoxyacetylchloriP.

Rf value: 0.66 (silica gel, eluent: ethylene chloride/ethanol = 85:15).

Yield: 67% of theory Example 104 6-[4-(N-(+)-vinanoyl-4-fluorophenylsulfoximino)-detokik]-6,4-zohyrlocarbostyryl 6- (4- Prepared analogously to Example 49 from (4-'fluorophenylsulfoximino)-butoxy)-3,4-dihydrocalcylstyryl and (+)-pinanoic acid chloride.

M-p-: 116-120°C Yield: 61% of theory Example 105 6-[4-(N-(-)-vinanoyl-4-fluorophenylsulfoximino)-butoxycou-3,4-zohir Locarzastyryl is prepared analogously to Example 49 from 6-(4-<4-fluorophenylsulfoxy-imino)-cytoxy]-3,4-dihydrocarbostyryl and (-)-pinanoic acid chloride.

M-p: 122-123°C Yield: 45% of theory Example 106 6-(4-(N-4-Toluenesulfonyl-4-fluorophenylsulfoximino)-detox 6-44 as in Example 49) -(4-Fluorophenylsulfoximino)-cytoxy]-6° Prepared from 4-dihydrocarbostyryl and 4-toluenesulfochloride.

M-p-: 67-70°C Yield: 57% of theory Example 107 6-(4-(N-(+)-10-camphorsulfonyl-4-fluorophenylsulfoxy-imino)-cytoxy)-5, 4-Dihydrocarmestyryl is prepared analogously to Example 49 from 6-(4-(4-fluorophenylsulfoximino)-cytoxy]-3°4-dihydrocarbostyryl and (+)-10-camphorsulfochloride.

M, p,: 81-100°C Yield: 61% of theory Example 108 6-(4-CN-chlorobenzoyl-4-methylsulfoximino)-cytoxy)-3,4-zo Same as Example 49 It is prepared from 6-(4-methylsulfoximino J-detoxy)-3,4-dihydrocarbostyryl and 4-chlorobenzoyl chloride.

M, p,: 176-178°C Yield: 87% of theory Example 109 6-(4-n-hexylsulfoxyiminoso) 6-(4-n-hexylsulfinyl-detoxy) as in Example 2 -Produced from 3,4-dihydrocarbostyryl and 0-mesitylenesulfonylhyproxylamine.

M-p-: 111-113°C Yield: 59% of theory Example 110 6-(N-acetyl-4-n-hexylsulfoximinodetoxy)-3,4-dihydrocarzastyryl Same as Example 47 from 6-(4-n-hexylsulfoximino-cytoxy)-3,4-dihydrocarbostyryl and acetic anhydride.

M-p-: 119-121°C Yield: 90% of theory Example 111 6-(N-benzoyl-4n-hexylsulfoximino-cytoxy)-3,4-dihydro-carbistyryl Analogously to Example 49 6-<4-n-hexylsulfoximinodetoxy) i, prepared from 4-dihydrocarbostyryl and benzoyl chloride.

M-p: 112-114°C Yield: 75% of theory Example 112 6-C,4-<2-phenylethylsulfoximino)
-cytoxy)-3,4-dihydro-carbostyryl Prepared analogously to Example 2 from 6-(4-(2-phenylethylsulfinyl)-cytoxy)-3,4-dihydrocarzastyryl and 0-mesitylenehydroxylamine .

M, p,: 15B - 159°C Yield: 69% of theory Example 113 5-(4-phenylsulfoximino-cytoxy)-3
, 4-dihydrocarbostyryl Example 2 and the same IJ as 5-
Prepared from (4-phenylsulfinyl-butoxy)-3,4-dihydrocarbostyryl and 0-mesitylenesulfonylhydroxylamine.

M, p,: 159-160°C Yield: 76% of theory Example 114 5-(N-acetyl-4-phenylsulfoximino-
(butoxy)-3,4-dihydro-carbostyryl Prepared analogously to Example 47 from 5-(4-phenylsulfoximino-butoxy)-3,4-dihydrocarbostyryl and acetic anhydride.

M-p,: 134-137°C Yield: 61% of theory Example 115 7-(4-Phenylsulfoxyiminodetoxification) 7-(4-Phenylsulfinyl-cytoxy)-3,4- Dihydrocarzastyryl. Prepared from ethyl 0-5 methylenesulfonyl hydroxamate and p-toluenesulfonic acid.

M-p: 137-139°C Yield: 81% of theory Example 116 7-(N-acetyl-4-phenylsulfoximino-
butoxy)-3,4-dihydrocarbostyryl 7-(4-phenylsulfoximino-butoxy)-! Manufactured from 1,4-dihyP-locarbostyril and acetic anhydride.

Mep: 111-113°C Yield: 78% of theory Example 117 8-(4-Phenylsulfoximino-butoxy)-3
, 4-dihydrocarbostyryl Example 2 to prepare 8-(
4-Phenylsulfinyl-butoxy)-3,4-dihydrocal is prepared from styryl and mesitylenesulfonylhydroxylamine.

M, p, near 8-80°C Yield: 96% of theory Example 118 8-(N-acetyl-4-)minonylsulfoximinodetoxy)-3,4-zohydrolocalbostillyl example 47 from 8-(4-phenylsulfoximino-butoxy)-31,4-dihydrocarbostyryl and acetic anhydride.

M-p-: 116-118°C Yield: 82% of theory Example 119 Produced from 6-(3-ethylsulfoxyiminodaloboxylproboxy)-rubostyryl and O-mesitylenesulfonylhydroxylamine OM, p,: 116-167°C Yield: 80% of theory Example 120 6-44-(N-benzoyl-4-fluorophenylsulfoximino)-butoxy]-cal? OM, p, : 137-141°C Yield: 64% of theory Example 121 6.6-Simethyl-5-(4- (3,4-dimethylphenylsulfoximino)-cytoxy]-indolinone-
2 3,6-dimethyl-5-(4-(3
,4-dimethylphenyl-sulfinyl)-detoxy]
-Indolinone-2, ethyl.

-mesitylene sulfonyl hydroxamate and p-)
Manufactured from luenesulfonic acid.

M, p,: 153-154°C Yield: 77% of theory Example 122 3,6-dimethyl-5-(4-<5
．． Prepared from 4-dimethyl-phenylsulfoximino)-detoxy]-indolinone-2 and acetic anhydride.

M, p,: 150-152°C Yield: 78% of theory Example 123 3,3-dimethyl-5-(4-methylsulfo) Example 2
3,3-dimethyl-5-(4-methylsulfinyl-butoxy)-indolinone-2 and in the same manner as . - prepared from mesitylene sulfonyl hydroxyamine.

M-p-: 123-124°C Yield: 98% of theory Example 124 3.6-dimethyl-5-[,4-(N-4-chlorophenylaminocarbonyl-methylsulfoxy 3t 6-
5-<4-methylsulfoximino-butoxy)-indolinone-2 and 4-chlorophenylisocyanate from anhydrous dioxane with a trowel at ambient temperature.
Manufactured by reacting for 0 minutes.

M, 1),: 175-177°C Yield: 89% of theory Example 125 3.3-Dimethyl-5-[4-(N-4-)luenesulfonyl-4-methylsulfoxyimino) Same as Example 49 and 3,6-dimethyl-5-(4-methylsulfoximino-butoxy)-indoly7y-2 (Rr value: [
1,45) and 4-toluenesulfochloride. Rf value = 0.70 (silica gel, eluent: ethyl acetate/methylene chloride = 11) Yield: 63% of theory Example 126 3.3-dimethyl-5-[4-(N-4-chlorobenzoyl-4- Methylsulfoxyimino) Prepared analogously to Example 49 from 3,6-dimethyl-5-(4-methylsulfoxyimino-butoxy)-indolinone-2 and 4-chlorobenzoylchloride r.
Pa M-p: 176-178°C Yield: 76% of theory Example 127 6-(4-(N-acetyl-3,4-dichlorophenylsulfoximino)-butoxy]-3°4-dihydrocarpostyryl 6.4-dichlorophenylsulfinyl-4-fomoItan is reacted with o-mesitylenesulfonylhydroxyamine analogously to Example 2 to give 3,4-dichlorophenyl-sulfoximino-4-bromobutane, which is then converted into 3
, 4-dichlorophenyl-(N-acetyl-sulfoximino)-4-bromobutane using acetic anhydride Example 4
Convert in the same manner as in 7.

M, p,: 170-173°C Yield: 98% of theory 163.2 da (0,001 mol) of 6-hydroxycarpostyryl was dissolved in 2 Illl of dimethyl sulfoxide; ,0013 mol) of 3.4-
Dichlorophenyl-(N-acetyl-sulfoximino)-4-bromobutane and 276.4■(0,002
mol) of anhydrous potassium carbonate, and the mixture was mixed with 17 mol of anhydrous potassium carbonate.
Stir at ambient temperature for an hour. This is then mixed with water in small quantities, and the reaction product crystallizes out in the form of white needles.

M-p: 149-151°C Yield: 2<57. IMg (62.5% of theory) Example 1
28 6-(4-methylsulfimino-cytoxy) = 3.4-
zohydrocarpostyl hydrochloride sulfate (
hydrogen ulfate) 0.12. ? of sodium is dissolved in 251 m of methanol, 1.3
#6-(4-methylmercapdopoxy)-3,4
- Add dihydrocarbistyryl with stirring.40
), 0.57 g of hydroxyl-amine-〇-
Add sulfonic acid at 17°C. The temperature rises to 22°C.

The mixture is stirred overnight, the precipitated sodium sulfate is removed by suction filtration, and ether is gradually added to precipitate a resinous substance, which is ground with ether to form a moisture-absorbing substance that crystallizes out. will occur. This is collected by suction filtration and dried with calcium chloride in a vacuum dryer.

M, p, near 5-80°C Yield: 0.656 & (20% of theory) Example 12
9 6-(4-(3,4-dichlorophenylsulfimino)
-cytoxy)-3,4-dihydro-cal 6-(4-(3,4-zochlorophenylmerkabuto))
-butoxy)-3,4-dihydrocarbistyryl and. -Mesitylenesulfonylhydroxyl-amine.

M-p-: 82-83℃ Yield: 49% of theoretical value.

Example 130 6-Cd-<3.4-1methoxyphenylsulfinno)-cytoxy)-3,4-dihyFLocal Same as Example 2 and 6-C4-<5.4-dimethoxyphenylmercapto)- Cytoxy)-3,4-dihydrocarbistyryl and 0-mesitylenesulfonyl-hytruxamine.

M, p,: 140-145°C Yield: 83% of theory Example 161 6-C4-<2'-Fluoro-4-biphenylylsulfimino)-cytoxytolybosetyryl mesitylene sulfonate As in Example 2. te6-[4-(2'-fluoro-4-
It is prepared from bipheni9-mercapto)-cytoxy]carbostyryl and O-mesityle/sulfonyl-hydroxylamine.

M, 1), : 125-128 °C゛Yield: 66% of theory Example 132 6-C4-(4-tert, butylpheny, rusulfy It is prepared from phenylmercapto)-cytoxy]-carbostyryl and 0-mesitylenesulfonylhydroxylamine.

M, p,: 145-150°C Yield: 551 theoretical Example 136 6-[4-(N-4-)luenesulfonyl-4-fluorophenylsulfimino)-cytoxy]0.701
S-(4-(4-,fluorophenylmercapto)-cytoxy)-3e-4-dihydrocarbistyryl 20
117 in methanol, 1.16.9ON-
A clear solution of sodium chloro-4-toluenesulfonate/amide is added. - After stirring at ambient temperature at night, the ethanol is distilled off. The residue obtained is subjected to chromatography on a silica del column using methylene chloride/ethyl acetate (1:1).

M, p,: 122-124℃ Yield: 0.59, f (jl theoretical value 57'16
) Example 134 6-(4-(N-4-)rue/sulfonyl-3゜4-dichlorophenylsulfimino)-phthoxy]-6.4-
6-(4-(3,4-dicprophenylmercabuto)-cytoxy)-3°4-dihydrocarbostyryl and N-chloro-4-toluene-sulfonamide in the same manner as in Example 135 - Manufactured from sodium.

M, p,: 150-152°C Yield: 62 theoretical values Example 135 5-(4-(N-4-Toluenesulfonyl-4-bromophenylsulfimino)-detoxy) - 5 as in Example 133 -(4-(4-bromophenylmercapto)-
cytoxy)-3,3-dimethyl-indolinone-2 and N-chloro-4-toluenesulfo/-ami'-sodium.

M, p,: 163-164°C Yield: 56% of theory Example 136 6(4-(N-4-)luenesulfonyl-methoxyfe□nylsulfimino)-butoxy)-3°4-dihydrocarbostyryl OM, p, prepared analogously to Example 163 from 6-(4-(3-methoxyphenylmercapto)-butoxy)-3,4-dihydrocarzastyryl and N-chloro-4-toluene/sulfonamide-sodium; : 110-114°C Yield: 38.1 of theory Example 167 6-(4-(N-4-Toluenesulfonyl-phenylsulfidino)-cytoxy)-5,4-1'hitocarpistyryl Same as Example 133 OM, 1 prepared from 6-(4-phenylmercapdoptoxy)-3,4-dihydrocarzastyryl (Rf value = o, a5) and N-chloro-4-toluenesulfo/amide-sodium ), : 58°C (semi-melting) Rt value: 0.57 (Silica gel, ethylene chloride/ethanol-9=1) Yield: Theoretical value of 62s Example 138 6-(4-(N-4-)Luenesulfonylcyclo Hexylsulfimino)-cytoxy)-! 1.4-lumercazotodetoxy)-3,4-dihydrocal is prepared from styryl and sodium N-chloro-4-toluenesulfonamide.

M-p: 162-165°C Yield 2l 53% of theory -Toluenesulfonamide-sodium d- et al.

Rf value: 0.32 (Silica sol plate, ethylene salt/ethanol = 9:1) Yield: 59% of theoretical value Chlorophenylsulfoximino)-cytoxy]-6.
Substrate containing 4-dihydrocarbostyryl*J
, -111 composition: 1 coated tablet core contains the following ingredients: active substance
(1) 4. OS9 lactose
(2) 27.0 g rich cornstarch
(3) 14.5-whacked polyvinyl pyrrolid/(4)
4.0 m Magnesium Stearate (5) 0.5
my50.0 g Manufacturing method: Wet substances (1) - (3) uniformly with the aqueous solution of (4), pass through a 1 m mesh-sized sieve, and dry.
Then pass it through a 111m mesh-sized sieve again. (5)
After addition, the mixture is compressed to form tablet cores.

Tablet core: 5 wφ, biconvex, round, with a common sugar coating to give a finished weight of 70 mm. ximino)--t-toxy]-3,4-
One tablet containing dihydrocarbostyril has the following ingredients: Active substance 8.0 ■ Lactose
23. Osy cornstarch
14.5my polyvinylpyrrolidone 4.0my
Magnesium stearate 0.5my50.0■ Manufacturing method: Same as for tablet core.

Description of tablet size: Weight: 50. (ly Diameter: 5 mm + Both flat surfaces 0 Both sides cut and groove C Fully Open 1 Suppository has the following ingredients: Active substance 0.025 F hard fat (
For example, Uitepsor H19 Sawabi Uitepsole W4
5) i, 69511.700 II Production: At 068° C., which melts the hard fat, the powdered active substance is dispersed homogeneously in the melt. Cool this to 35℃,
Cool slightly and pour into the fully opened mass.

Fully opened weight: 1.7j1 Example D A 100-kg suspension containing 8 kg of 6-(4-(N-acetyl-6,4-dichlorophenylsulfoximino)-phthoxy)-3,4-dihyP locarpostyril The suspension has the following components: active substance 0.1
67F carboxymethyl cellulose o, i
l1p-methyl hydroxybenzoate o,
o syp-hyperoxybenzoic acid-fr:ti+
0.011 Satsuka loin 10
．． 0g glycerol 5.0I70'1
r7pveto-# solution 20.01 fragrance
0. ! l Ii Distilled water
Total amount: 100.0jlJ Manufacturing method: Heat distilled water to 70°C. Dissolve therein with stirring methyl p-hydroxybenzoate and solol as well as glycerol and carboxymethyl cellulose.
The mixture is cooled to ambient temperature, the active substance is added and homogeneously dispersed therein with stirring. Sugar, sorbitol solution and flavor are added and dissolved and the suspension is evacuated with stirring to remove air.

Example E 100 g of 6-(4-(N-acetyl-6,4-dichlorophenylsulfoximino)-cytoxy)-3,4
- Composition containing dihydrocarbostyril: 1 tablet contains the following ingredients: Active substance 100.0 mg lactose
80.0 m cornstarch
34.0 scoops of privinyl f lolidon 4.
0η stearic acid/magnesium acid 2. Omy220
, Os+y Production method: Mix the active substance, lactose and defsin together and homogeneously wet the polyvinyl with the aqueous solution of lysate. Pass the wet mass through a sieve (2,0 m mesh size) and rack 1 dryer. After drying at 50℃, pass it through a sieve again (1.5m mesh size) and add lubricant.
The completed mixture is made into a tablet. Weight of the tablet: 220'I4 Diameter: 10syi, both planes 1 Cut surface on both sides and notches on one side Example F
-dichlorophenylsulfoximino)-dedoxy)-
! One capsule containing 1,4-dihyrocarzastyril contains the following ingredients: Active substance 150.0 g dry cornstarch approx. 180.0 g powdered lactose approx.
320.0 ■ Production: The active substance is mixed with the excipients and mixed homogeneously through a 0.75 m mesh in a suitable apparatus. Place the final mixture into size 1 hard gelatin capsules.

Capsule capacity: Approximately 320 mm Capsule shell: Hard gelatin Capsule size 150 mm 6-(4-(N-acetyl-6,4-dia
n-phenylsulfoximino)-butoxy)-3,4
-containing dihydrotetracarbostyryl 1 suppository contains the following ingredients: Active substance 150.091 Polyethylene glycol 1500 550.0 Polyethylene glycol 6000 460. Omy2000,
DIIg' and pour the melt into the pre-cooled mold.
．． Suspension containing 4-dichloro-phenylsulfoximino)-detoxy]-4-dihydrocarbostyryl The suspension of 100d has the following components: active substance
1.0Ijp-HiFFa'tV9 Methyl zoate 0.05JFp-Progyl hydroxybenzoate 0.01# Satucarose 10.019 Glycerol
5.0g 70% sorbitol solution 20
,09 ・Fragrance 0.3
1 Distilled water, total volume 100 d"Production: Heat the distilled water to 70°C. Dissolve therein the methyl and propyl p-hydroxybenzoates, without stirring, together with the sodium salt of chrycerol and carboxymethyl-cellulose. Mixture Cool to ambient temperature, add the active substance, add sugar, sorbitol solution and flavoring agent and disperse uniformly therein with one stirring;
After dissolution, the suspension is evacuated while stirring to remove air.

A suspension of 5d has 50μ of active substance.

6-[4-(N-p-toluenesulfonyl-)
Tablet composition containing 3,4-dichloro-phenyl-sulfoximino)-butoxy)-3,4-dihyF locarpistyryl: 1 tablet contains the following ingredients: Active substance 150.0 IIy Powdered lactose 89.011 g Cornstarch
40.0 2-coloidal silicic acid
10.0 ■ Polyvinyl bipridone 10.0 ■
Magnesium stearate 1.0 ■ 300, Oq Preparation: The active substance mixed with lactose, cornstarch and silicic acid is brought to a#lI with a 20% aqueous polyvinylpyrrolidone solution and passed through a 1.5 m mesh size Oq at 45°C. The dried granulate is passed through this sieve again and mixed with the stated amount of magnesium stearate. Tablets are made by compressing the mixture.

Tablet weight: 300w1 Punch: 10■, flat plate example 1-75q of 6-(4-(N-p-)luenesulfonyl-3)
．． Coated tablets containing 4'-diclophenyl-sulfoximino)-cytoxy)-3,4-dihy,rlocarbostyril 1 The coated tablet core contains the following ingredients: Active substance
75.0 ■ Calcium phosphate
93.0■Corn starch 35.3m
y Polyvinylpyrroli Pn 10.0 ■Hydroxypropyl methylcellulose 1 5.0■Magnesium stearate 1.5 N2 3 0.0 Tomi 2 Manufacturing method: Active substances: Calcium acid, cornstarch, polyvinylpyrrolidone, hydroxyzorobyl methylcellulose and Mix with half the stated amount of magnesium stearate. A tablet-making machine is used to produce compressed tablets having a diameter of approximately 15 wx, which are passed through a 1.5 m mesh size sieve and mixed with a residual amount of magnesium stearate.

The granules are compressed into tablets having the desired shape in a tablet machine.

Weight of core = 260 ■ Punch: 9 tm, convex The tablet cores thus produced are coated with a film consisting essentially of hydroxyzolobyl methylcellulose. Polish the finished film-coated tablets with Mitsup.

Weight of coated tablet: 245wg Obviously, the general formula! All other compounds mentioned above can be used as active substances in the formulation.

Agent Akira Asamura 4 people (DE) ■ P3142904.1 @ Inventor Johannes Maximilian Wiesenberger Biberatsch 1 Heytonbeg 5, Federal Republic of Germany

Claims (1)

[Claims] (1) General formula (wherein n represents 0 or 1, A is optionally substituted by 1 or 2 alkyl groups each having 1 to 3 carbon atoms; B represents a linear or branched alkylene group having 2 to 6 carbon atoms; R1 is 1 to 3 optionally substituted by a phenyl group; an alkyl group having 4 carbon atoms;
or a phenyl group (however, each of the above phenyl nuclei is an alkyl group having 1 to 4 carbon atoms, a halogen atom, 1
E, which may be substituted by an alkoxy group, cyclohexyl, -phenyl or halophenyl group) = alkyl group having 4 to 7 carbon atoms: 6 to 7 carbon atoms cycloalkyl radicals having atoms; phenyl radicals di- or tri-substituted by alkyl radicals having 1 to 4 carbon atoms or by alkoxy radicals having 1 to 6 carbon atoms and/or by halogen atoms; or by an alkyl group having 1 to 4 carbon atoms,
or two hydroxy- or aminophenyl groups disubstituted by an alkoxy group having 1 to 6 carbon atoms and/or by a halogen atom, provided that the substituents on the phenyl nucleus may be the same or different.
, or a naphthyl group optionally substituted by an alkoxy group having 1 to 3 carbon atoms, or a pyridyl group, and R2 is a hydrogen atom or an organic carboxylic acid, an organic or inorganic sulfonic acid or A novel sulfimine (representing the acyl group of carbonic acid derivatives) and its salts with strong acids. Its acid addition salts are particularly physiologically compatible. (2) n, m, B, and R are the same as defined in claim 1, and R2 is a hydrogen atom or an aliphatic saturated or unsaturated alkanoic acid (which may be substituted depending on the case) , optionally substituted aromatic carboxylic acids (in which one 0L=OH- group or one or two 10H- groups may each be substituted by an oxygen, sulfur, or nitrogen atom) ) represents the acyl group of
or it is an acyl group or a hydroxysulfonyl group of a carbonate ester, or of an optionally substituted carbaonic acid, or of an aliphatic or aromatic sulfonic acid. Sulfitrons and their salts with strong acids, especially their physiologically compatible acid addition salts. (3) n represents 0 or 1. A represents a dimethylmethylene, vinylene or ethylene group, B represents a linear alkylene group having 6 to 5 carbon atoms, Hl is an alkyl group having 1 to 6 carbon atoms, benzyl, phenylethyl, cyclohexyl, naphthyl, methoxy-naphthyl or pyridyl radicals, optionally substituted by alkyl radicals having 1 to 4 carbon atoms or by methoxy, cyclohexyl, phenylmodyl, hafluorophenyl radicals or by fluorine, chlorine or bromine atoms; a phenyl group, optionally disubstituted by an alkyl group having 1 to 4 carbon atoms, a methoxy group, a chlorine and/or bromine atom (provided that the substituents on the 7-enyl nucleus may be the same); or 2 chlorine or bromine atoms, 2 methoxy groups or 1 to 4 each
represents an aminophenyl, hydroxyphenyl or methoxyphenyl group substituted by two alkyl groups having 1 to 8 carbon atoms, and R2 is a hydrogen atom, optionally substituted by a methoxy group; Alkanoyl radicals having carbon atoms, benzoyl or phenylsulfonyl radicals optionally substituted by norogen atoms or by cyano radicals or by alkyl radicals having 1 to 4 carbon atoms, a total of 2
alkoxycarbonyl radicals having from 4 to 4 carbon atoms, aminocarbonyl radicals optionally substituted by chlorophenyl radicals or by 1 or 2 methyl radicals, or naphthoyl, binanoyl, camphorsulfonyl, pentamethylphenyl radicals; Novel sulfimines of the general formula I according to claim 1 representing sulfonyl, pyridinoyl or thenoyl groups and physiologically compatible acid addition salts thereof with strong acids. (4) n represents 1, M represents dimethylmethylene, vinylene or ethylene group, B represents n-butylene group, R1 is methyl or methoxynaphthyl group, optionally substituted with methoxy group or fluorine or chlorine atom; a phenyl group optionally substituted by two chlorine or bromine atoms, and also a hamethylpromophenyl, 4-7minor-6,5-dibromophenyl or sheeptyl tea×hydroxy-phenyl group; R3
represents a hydrogen atom, an alkanoyl group having 1 to 6 carbon atoms, or a benzoyl or phenylsulfonyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms. A novel sulfimine with the general formula ■ and its acid addition salts with physiologically compatible strong acids. (5) General formula (in the formula, the person represents ethylene or a vinylene group, and B represents an n-butylene group. Rxri) f, phenyl, 4-fluorophenyl, 4
-chlorophenyl, 6e4-di-llorophenyl, L< represents a 3-methyl-4-bromophenyl group, and H represents a hydrogen atom, acetyl or p-)luenesulfonyl group) Claim 1 Novel sulfimine. (6) 6- (4-(N-acetyl-6,4-dichlorophenylsulfoximino)-phthoxy)-3゜4-
The compound of claim 1 which is dihydrocarbostyryl. (716-(4-(,3-Methyl-4-bromophenylsulfoximino)-butoxy]-carbostyryl) The compound according to Claim 1. (8) Patent #!P Claim 1 A pharmaceutical composition containing one compound and one or more inert carriers or diluents according to any of items 7 to 7. (9) General formula (wherein n represents 0 or 1, A represents a case) B represents a methylene, vinylene or ethylene radical optionally substituted by one or two alkyl radicals each having 1 to 6 carbon atoms; B represents a straight-chain radical having 2 to 6 carbon atoms; or represents a branched alkylene group, R1 is an alkyl group having 1 to 6 carbon atoms optionally substituted with a phenyl group,
or a phenyl group (however, each of the above 7 enyl nuclei is an alkyl group having 1 to 4 carbon atoms, a halogen atom, 1
alkoxy groups with t-3 to 3 carbon atoms (optionally substituted by cyclohexyl, phenyl or halophenyl groups), alkyl groups with 4 to 7 carbon atoms, cycloalkyl groups with 3 to 7 carbon atoms, phenyl radicals di- or tri-substituted by alkyl radicals having 1 to 4 carbon atoms, or by alkoxy radicals having 1 to 3 carbon atoms, and/or by halogen atoms, or 1 to 4
by an alkyl group having 1 carbon atoms or 1
by an alkoxy group having from 3 to 3 carbon atoms,
and (or) hydroxy- or aminophenyl groups disubstituted by halogen atoms, provided that the substituents on the diphenyl nucleus may be the same or different, or optionally alkoxy groups having 1 to 3 carbon atoms. a naphthyl group or a pyridyl group which may be substituted by a group, and - represents a hydrogen atom or an acyl group of an organic carboxylic acid, an organic or inorganic sulfonic acid or a carbonic acid derivative, and its salts with strong acids. a) To prepare a compound of the general formula I in which n represents 1 and R2 represents a hydrogen atom, a sulfoxide of the general formula (wherein A, B and R1 are as defined above) is reacted with hydrazoic acid, optionally formed during the reaction mixture, or t)) To prepare a compound of the general formula (1) in which R2 represents a hydrogen atom, the general formula (in the formula, B and R1 are the same as defined above), a sulfoxide having the general formula % (1) [wherein X represents a carbonyl or sulfonyl group,
and R3 represents an aryl group disubstituted at the 0-position, such as a 2.4.6-trimethyl or triisopropyl-phenyl group or a hydroxyl group (when X represents a sulfonyl group). or c) To produce a compound of the general formula (3) in which n represents 1, oxidize a mercapto compound of the general formula (wherein A, B, R1 and R2 are the same as defined above), or d) R,
In order to produce a compound of the general formula (3) in which does not represent a hydrogen atom, the compound of the general formula (in which n%A, B9 and R1 are the same as defined above) is acylated, or the compound of the general formula ( A hydroxy compound or its salt with an inorganic or tertiary organic base is prepared by the general formula (in which n, R1, R2 and B are the same as defined above, and 2 is the same as defined above). (representing a nucleophilically leaving group) or f) to produce a compound of the general formula (i) in which n represents 0, a compound of the general formula (in which A, B and R1 are the same as defined above) is reacted with an amide of the general formula (wherein Hal represents a chlorine or bromine atom, and R1 has the same meaning as R2 above except for hydrogen) or an alkali salt thereof, The reaction product thus obtained is then hydrolyzed and, if necessary and desired, the compound of formula (9) obtained according to the invention is then converted into its salt, in particular physiologically compatible, with a strong acid. Its manufacturing method consists of converting it into salt. (11) The process according to claim 9, characterized in that the reaction is carried out in a solvent. A process according to any one of claims 9a or 10, characterized in that the reaction is carried out at a temperature between 0 and 50°C, but preferably between 5 and 40°C. The process according to any one of the claims characterized in that it is carried out at temperature.Claims a9b, 10 or 12, characterized in that the compound of the general formula I is prepared in the reaction mixture.
Any one of the following methods. 04. Process according to claim 90 or 10, characterized in that the oxidation is carried out using one equivalent of oxidizing agent. OQ according to any one of claims 90, 10 or 14, characterized in that the reaction is carried out at a temperature between -80 and 100°C, but preferably between 0 and 60°C. Method. 91 or 10, characterized in that the reaction is carried out at a temperature between -25 and 100°C, but preferably between -10 and 80'O. One way. Process according to any one of claims 9e, 9f or 10, characterized in that the aη reaction is carried out in the presence of an alkali base. (to) Claim 90.1° or 17, characterized in that the reaction is carried out at a temperature between 0°C and the boiling temperature of the solvent used, for example between 0 and 100°C. Any one of these methods. (II) Any one of claims 9f, 10 or 17, characterized in that the reaction is carried out at a temperature between 0 and 80°C, but preferably between 5 and 50°C.
Two ways.