CS236488B2 - Method of new suphimines production - Google Patents

Description

The present invention provides a process for the preparation of the novel sulfimines of formula (I)

and their strong acid salts, especially their physiologically tolerable acid salts, and medicaments containing these compounds.

The novel compounds of formula (I) have valuable pharmacological properties, in particular antithrombotic activity.

In the above general formula I д is 0 or 1,

A represents a dimethylmethylene, vinylene or ethylene group,

V represents a straight-chain alkylene group having 3 to 5 carbon atoms,

R ₁ is C 1 -C 6 alkyl, benzyl, phenylethyl, cyclohexyl, naphthyl or methoxynaphthyl, phenyl, optionally substituted with C 1 -C 4 alkyl, methoxy, cyclohexyl, phenyl or fluorophenyl, fluorine, chlorine or bromine, a phenyl group disubstituted by C 1 -C 4 alkyl, methoxy, chlorine and / or bromine, the substituents on the phenyl core being the same

23648 $ or a different, or amino, foil, hydroxyphenyl or methoxyphenyl group. substituted with two chlorine or bromine atoms, two or two alkyl-containing groups. vLdy. 1-4 carbon atoms.

Better by the bargain. substances. In accordance with the present invention there are provided compounds of formula (I) wherein:

And with a dimethyldimethylphenyl, vinylooo or hthylon group,

B is a n-butyioxycycline

R 1 is a numeric methyl or methyl oxybutylpiperidine, conjugate, e.g. In the case of methalo, fluorine or chlorine, a methyl group having two centimeters of chlorine or methylbromyl, 4-amino-3,5-dibromo-4-yl or L-tertiarylhyro: qrliIyгOovoo group, their physiologically sodίΑζϋβΙ ^ sod 'with weak acids. ·

In the present invention, the above novel compounds are obtained by the sulfoxide of formula II

H (Π) in which g, A, B, with R f is m. as defined above, is reacted with a compound of formula III

(III) in which

X is selected from the group consisting of a group or a group

R3 ',. represents in the o-position a dihydroxy sapin such as 2,4,6-phenyl-2,4-triylbenzyl or 2,4,6-trifluoromethyl, or also a hydroxy group when X is an alpha-biphenyl. ^^ ·

The reaction according to the invention is expediently carried out in a solvent or in a solvent such as in a solvent. The reaction is carried out by treating a compound of the formula ## STR5 ## particularly preferably at a temperature between 0 and 50 DEG C., preferably between 5 and 40 DEG C. The reaction is carried out in the absence of a preceding tunnel or is optionally prepared directly in the reaction. . srnměi. . If desired, the compounds of the formula I according to the invention can be converted into sodium with silica. · Like acid. for example, hydrochloric acid, acids. sulfuric acid or melitylliiULfoiboá.

The compounds of formulas (II) and (III) used as starting materials are initially known from Liura et al. can be obtained by perverse processes. ,

Compounds of formula (III) used as. The starting materials are preferably obtained by reacting the corresponding Okiarbotyl or O-sulphorylacethydroxy ester with sulfuric acid and the following. extraction after addition of the base.

As mentioned above, report. the compounds of the formula I have valuable pharmacological properties, in particular an entithrombotic effect. These compounds inhibit prostaglandin Ig synthesis. (prrttacyclin), which inhibits platelet aggregation.

Compounds of general interest. Formula I further inhibits the metastasis of the tumors, which is based on their following properties:

1. The disclosed substances inhibit the frefrdiasterasl produced by platelets, known as a tumor metastasis initiator [h. Gastp & Tarornbosis Re se arch., 277-289 (1974). and KV No, Scénce '212. 1270' - 1272. (198l ^j .

2. The compounds described will cause a prolonged bleeding time, i.e., they inhibit the primary hemootsse, i.e., the first adhesion of the thrombocytes to the damaged vessel to form a pure platelet thrombus, even at a very low dose. This can be explained only by reducing platelet function, but by increasing the release of prostacyclin by vascular endothelial cells. This clarification is confirmed by the fact that the bleeding time is not prolonged in the event of bleeding. that. the synthesis of the growth cells is interrupted. previous applications substances braking cyklooxhgenasl _c Compounds of the invention therefore allows for organize this previously unknown, optimum kombinaci.dvou active principle ,. namely, increasing the level of adenoainmorphate (CAMP) by stimulating the production (prrstacyУkin) a. at the same time by inhibiting its degradation (braking. creation ^^ йкёНаходу).

The above-described enhancement of the prophylactic activity and / or the synthesis of pracycline; Yippee . by Honna [K. ^V · Honn,. Science ^{212, 1270-1272} . ⁽¹⁹ 81) J also ^p M Due to the wheezing of many tumors ·

For example, the biological properties of the following compounds were tested as described below: A and 6- (4-bettyl8L.frxim.noriltry) ,1,44dilhildoOcabirtyr nentythylene ιULfrate,

В ^»6 ^ (4- ei ^{e l i} lsul ^of oximinr utolχ) _-3> ⁴ ^ -d ^ihld □ Jcθj'bir ^with ylil,;

C and 6- [4- (4-fluorophenyl) -roxybin] -triazole-3,4-dihl (heterocyclyl),

D = 6 - [(4-chlorophenylsULFrimino)] duloryl-3,4‘-dihl (drecabirtylil,

E = 6 · [4- (4ΊRorphelltluloximiro) butoxl] ^ μΤο ^ ιΠ,. '

F and [[¼ (4-chloro-biphenyl-1-hydroxy-amino) -butoxy] -carbosyl, /

G = 6- 4- '33'> ethyl-4-irrIm (»nlL3lfo: dLImno) biltrX] kaiirir,

H = 6- [4- (4-tert-butyllllllllllllimlnr) iuto-3,4-dihyidioccaiortyr],

Even with 6- [4- (4-chlorophenol; lllllfrximine) iutoryl-3,4-dihydrophenyl] ethyl,

K. and o- [4 '(4-tert-butyllllllllOoxibinr) iltr2qlkEU ^ birtylil,

L and 6- (4-cyclohexylthylfrxibinrbulory) kkarreylil and ‘. X.. '‘F, ·

3 = б » ⁵ ) · (3, 4 (Urnetho) phenyl sulfoximinoObutcoyl) dihydrocarbostyril ·

1 · Braking fkBfkdiesheresd creation

Principle:

cAMP is hydrolyzed by a variety of sources, including platelets, from fksfkdiesteraak (ΡΠΕ), and is hydrolyzed by and adenosiOMooofoeffectic acid (AM).

Method:

As fotfodietherata ae it uses the suppimatant produced by the centrifugation of human platelets at 10 000 g, which is melted with water and then allowed to thaw again ·

0.3 m of a mixture containing 0.1% by weight of methyl methans (pH 7.4); 3 naVllti ^'h chloride steed ^No -oate ^{h, 1} moVlitr'. ^ ^ OlAitr -сАДО peciiftc ^ ^ around 10 MBq activity nmll-PDE and the test substance. or water in. the control sample, ee 15 rubbing .When incubated at 37 ⁰ _E N

The incubation is stopped by adding 0.5 OL. zinc sulfate (0.266 mL / ltr) and 0.5 µl of barium hydroxide (0.226 moHl-tr), precipitate. It is centrifuged and found to be unattractive in the pellet. crushing rate oezreo ^g quonum ^E-cAMP. . > From porovnitaí ^samples. e otaahen. The build-up substances and samples. The control is calculated for each test substance the concentration required for the 50% braking effect (IC ₅₀ ).

The calculated values are shown in the following table:

Test substance

AND

C B

C

D

E

F

G ^;

H \

I.

TO

L · Λ .. ·· '.

m:.,

ICj0 (fuoioiitr)

2.0 ', 2

0.84

0.40

0J7

0,039.

, 0.24 * 0.052

0.21

0.68

1.6

Braking. The effect on tumor meeastase can be found in Gastpsra poodle and spooky (see Thromboois Research). 277 -. In this case, the test substance is administered prior to the transplantation of the tumor cells and the sequence of survival of the test animals, such as rats, in the control animals.

2 · Determination of prolongation .. bleeding time

Organism. humans, as well as organisms, eplokreíní animals. is equipped with a sagging mechanism which. has it. Reading of blood before wound blood injury This system is t-selected by platelets. (t hr ^ ^ o ^ m ^ t ^ b ^^ octt which, because of their - βϋιβζΙίηίΛ ί ^^ Μΐύ quickly in Oix ^ i ^ ^ i ^ ^0: even damaged blood vessels and thus ^^^ <^ ^ ol Primary hemoosase In this purely cellular mechanism, the haemostasis has a body.

In this system, the plasma factor (protein) is brought into an effective form that ultimately causes the conversion of plasma fibrinogen to fibrin clot. The prehemostasis system, which is essentially controlled by thrombooyts, but also, for the vascular wall activity, and the clotting system complement each other · more effectively protect the body from blood loss ·

In many diseases, even with a non-intact vascular system, the clotting process can occur, as well as thrombocyte aggregation. The attenuation of the blood clotting system by cummrine or heparin is known and can be easily measured by known blood clotting tests which monitor the prolongation of bleeding time by the test substance (plasma recalcification time, Quick test, thrombin time below).

Since, in the case of injuries, it leads to the first rapid arrest due to adhesion and thrombocyte aggregation on the vessel wall, the thrombocyte function and / or proetacycline activity can be well detected by means of standardized injury · vascular walls by bleeding time · 1 to 3 minutes, assuming normal thrombocyte function and sufficient blood counts · PM normal counts · thrombocyte · indicates prolonged bleeding time impaired thrombocyte function · and / or increased prostacyclin adenity of vascular wall · This occurs for example in In contrast, thrombocyte tendency to cluster spontaneously with subsequent vascular occlusion in the arterial system by drug action should be prevented. Sequentially prolong the bleeding time due to the successful treatment of thrombocytes or vascular wall with therapy. The application of an antithrombotically active substance is thus expected to result in a longer bleeding time and, since the plasmital clotting system is not affected in any way.

References: W · D · Ko.del; Kirzgefaptes Lehrbuch der ΠhfiS · · ULugi Georg, Georg Thiene Verleig Stuttgart 1967, · page · 31: Der BlutstiLuungsvoreane ·

To determine the bleeding time, the test substances are applied with awake carcasses · orally at a dose of 2.5 mg · kg. After one hour, approximately 0.5 · λ of each animal is cut off from the tip of the tail and blood is taken at intervals. Carefully suck off the filter paper for 30 seconds. The number of blood spots thus obtained is a measure of bleeding time. · Each experiment is carried out on 5 animals. The figures summarized in the following table represent the increase in bleeding time in percent as compared to the control experiment.

Test substance Increased bleeding time in% after · · 1 hour

AND

BC

D E F

G

H I K

L

M> 161

125> 275> 180> 191> $ 1> 184> 218

Acute toxicity

The acute toxicity of the test substances should be ascertained in groups of mice receiving a single oral dose at all times. Experimental mice were observed for 14 days.

The results are summarized in the following reports:

Test substance

Indicative acute toxicity

AND > 250 mg (none OF 10 of animals did not die) В > 250 mg (none of 10 of animals did not die) C > 250 mg (none 2 10 of animals did not die) D > 250 mg (none OF 10 of animals did not die) E > 250 mg (none 2 10 of animals did not die) F > 250 mg (none of 10 of animals did not die) G > 250 mg (none 2 10 of animals did not die)

The novel compounds of this invention on the basis of their aforementioned pharmacological properties к profýlacl thrombolysis embollckých diseases such as cardiac infarction, cerebral infarction, transient TSV · ischemickýeh seizures _э Ameurosis fugax, к prophylaxis of arteriosclerosis а к prophylaxis of metastasis ·

In order to achieve the corresponding effects, the compounds described are expediently administered two to four times a day in a dose of 0.1 to 4 mg / kg body weight, preferably 0.2 to 3 mg / kg body weight. and their physiologically tolerated strong acid addition salts, optionally and other active ingredients, together with one or more conventional inert carriers and / or diluents, for example, and corn starch, milk sugar, / polyvinylpyrrolidone, citric acid, tartaric acid, water, aqueous ethanol, aqueous glycerin, aqueous sorbitol, non-ionic surfactants such as polyoxyethylene fatty acid esters, aqueous polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose, or fat-containing substances, such as hardened fat, or β-suitable mixtures of these materials, in suitable formulations, such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, tendons or suppositories.

The invention is illustrated by the following non-limiting examples.

He did

6- [4- (3,4-Dichlorophenylsulfoximino) butoxy] -3,4-dihydrocarbostyrene

Dissolve 24.0 g (0.84 mol) of ethyl O-mesitylenesulphonylacethydroxamoyl in 35 ml of dioxane and add 17 ml of 90% sulfuric acid dropwise with vigorous stirring at 20 to 23 for 20 minutes. the mixture is poured into 300 ml of ice-water and the resulting O-mesitylenesulphonylhydroxylamine is extracted with 100 ml of methylene chloride. The extract is washed twice more with ice-cold water and dried over magnesium sulphate. 0.03 mol) of 6- [4- (3,4-dichlorophenylsulfinyl) butoxy] -3,4-dihydrocarbostyril and the mixture was stirred at room temperature for 18 hours. The thick crystals suspension, which was difficult to stir, was diluted with 120 ml of ethyl acetate and The crystalline 6- (4- (3,4-dichlorophenylsulfoximino) butoxy) -3,4-dihydrocarbonylthiophenyltylene sulfonate is filtered off with suction. To obtain the free base, this salt is suspended in 60 ml of methanol and the suspension is stirred with 17 ml of 2N sodium hydroxide solution. whereby all solid materials go into solution »from which a white 6- [4- (3,4-dichlorophenyl sulfoximino) butoxy] -3,4-dihydrocarbostyril precipitates ·

The product melting at 160-161 ° C yielded 10.4 g (81.1% of theory).

The above reaction can also be carried out using chloroform, dimethylformamide, tetrahydrofuran or dioxane as the solvent.

Example 2

6- {4- (4-tert-butylphenyleulfoximino) butoxy] -3,4-dihydrocarbostyril

The title compound was prepared in an analogous manner to that in Example 1 from 6-tert-butylphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril and C 6 mesitylenesulfonylhydroxylamine.

The product melting at 201-203 ° C resulted in a yield of 44% of theory.

Example 3

6- (3,5-di-tert-butyl-4-hydroxyphenylsulfoximino) butoxy] -3,4-dihydrocarboatyril

The title compound was prepared in an analogous manner to Example 1 from [4- (3,5-di-tert-butyl-1-ynyloxy) -phenylsulfines-butoxy] -1,4-dihydrocarbostyril and O-methylitylene sulfonylhydroxylamine.

The product melting at 110-112 ° C resulted in a yield of 52% of theory.

Example 4

6- (4-cyclohexylphenylsulfoxiaino) butoxy} -3,4-dihydrocarbostyril

The title compound was prepared analogický® postupe® as in Example 1 from 6- _[4- (4-'Cyklohexylfenyl8Ulfinyl) butoty] -3,4-O-dihydrokarboetyrilu and mesitylensulfonylhydroxyleminu ..

M.p. 174 DEG-176 DEG C., yielding 65% of theory.

Example 5

6- (4- (4-Biphenylylsulfoxiaino) butoxy) -3,4-dihydrocarbostyril

The title compound was prepared in a manner analogous to Example 1, starting from β-N- (4-biphenylsulfinyl) butoxy] -3,4-dihydrocarbostyril and O-mesitylenesulfonylhydroxylamine.

Melting point: 184-186 DEG C. yields 64% of theory.

Example 6

6- [4- (Naphthyl-2-sulfoxysino) butoxy] -3,4-dihydrocarbostyril

The title compound was prepared in a manner analogous to that of Example 1, with 6- (4- (2-naphthylsulfinyl) butoxy] -3,4-dihydrocarbostyril and O-mesitylenesulfonylhydroxy 1aain.

The product melting at 151-152 ° C yielded 71% of theory

Example 1 a d 7

6- [4- (4-Chlorophenylsulfoximino) -thioyl-5H-dihydrocarbostyril

The title compound is prepared analogously ^ to Example 1 from 6- [4- (4- chlfrfenyla · ^{u y} lfir ιl) Bufo У ^] - '· 3,4 · okaiboftyгilu dhУfd-N-ethylamine neeitylensiti.frwlhydtO .

The product, m.p. 150-151 ° ^C, resolves in a yield of 6% of theory.

Example <

6- [4- ^(J-methfl- bromíbnyLsu ^ ^ ^ xxiaiinobbHxxj - ^{3, 4-d t} h ^{y <d} ifkkU'bbftyyil

The title compound is prepared analogously to Example 1 from ⁶ - ^[4 - (3-m · ^{4 th} yl- -bгomfeJ ⁿ lst ^Uf ynyl) bu ^t oχy] -3, ^{4-di h} y ^d if ^the м ^and b © ^t rllu and ft ^ -hydroxy ^ -aeeitylensiu.foi laminate.

The product melting at ¹ 5 ° and ¹ 52 ° C in a yield reziatuje ° 6% of theory.

Example 9

6- [4- (3,5-Dibromol-4-aminophenylphosphine) butoxy] -3,4-diethylbenzyl

The title compound is prepared analogously to Example 1 from 6- [4- _(3> 4-4-dbboom aainff · ιnУ>aйfl> phenyl) butoxy | -3,4-di-ydiocarbofutil and O-methylethylenesulphonylhydroxylamine;

The product melting point, ^{from 113} and ¹¹⁰ ° ^C.-sectional U is in the above ^severe in 55% yield.

Example 10

6- (4-phenylsulfoximinebutyl) carbophthyl

The title compound was prepared in an analogous manner to that described in Example 1 of 6- (4-phenylsulfonylbutoxycarbostyril) and methylmethylenefinylhydropylamine.

The product melting at 161-162 ° C resuls in a yield of 6% of theory.

Examplet

6- [4- (3,5-di-tert · · UuУll h »ldifrxyyf · ^s Уltuuf Ootiminf) butoxy] ^ kvrbo tril

The title compound is prepared analogously to Example 1 from 6- [4 ^ _(3> ^{4-di-EIRC) U} utyl4 Уydrcxy ^{4-f f} enyltUl iIyl) butfX kaг t ^{j b i} ofttг Lu ^ marttylenrnaLfoinrl'hydroxy laminu.

The product melts at 205-207 ° C in a yield of 59% of theory.

Example 12

6- [4- (4-biphenylllLfLf ^> xximinf) butf xj carbo ^ уГ!

The title compound was prepared analogidý procedure as in Example 1 _(from 6- [4- ^(4-bi phenyl yl ^N ltul ^{y: y t} iI ll) ^U ufoxy] k8r ^b O8 yyilu and ^t ^ e ^O · ^{tt l} ylentU f · ny ^{lh d d} r ^, oxylLLtLжu ·

Melting point: 236 DEG-238 DEG C. yields 76% of theory.

Example 13

6- [4- (4-fluorophenylsulfoximino) butoxy] carbostyril

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (4-fluorophenylsulfinyl) butoxy] carbostyril and O-mesitylenesulfonylhydroxylemine.

Melting point: 177-179 ° C yields 70% of theory.

ExampleU

6- [4- (4-Chloro-phenylsulfoximino) -butoxy] -carbonyl-ril

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (4-chloro-phenyl-phenyl) -butoxy] -carbonyl-styrene and O-mityitylenesulfonyl-hydroxylamine.

The product melting at 201-203 ° C resulted in a yield of 79% of theory.

Did he?

6- [4- (4-bromophenylsulfoximino) butoxy] carbostyril

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (4-bromophenylsulfinyl) butoxy] carbostyril and O-mesitylenesulfonylhydroxylamine.

The product melting at 211-213 ⁰ C. It was obtained in a yield of 63%.

Example 1 a d 16

6- [4- (3,4-Dichloro-phenylsulfoximino) -butoxy] -carbocrile

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (3,4-dichlorophenylsulfinyl) butoxy] carbostyril and O-mesitylenesulfonylhydroxylamine.

214 DEG-216 DEG C. yields 73% of theory.

Example 17

6- [4- (3'-Fluoro-4-biphenylylsulfoximino) butoxy] carbostyril

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (2'-fluoro-4-biphenylylsulfinyl) butoxy] carbostyril and Q-aeaitylenesulfonylhydroxylamine.

The product melting at 191-193 ° C yielded 74% of theory.

Example 18

6- [4- (3,5-dibromo-4-aninophenyl sulfoximino) butoxy] carbonyl styrene

The title compound was prepared in a manner analogous to Example 1, starting from 6- [4- (3,5-dibromo-4-aminophenylsulfinyl) butoxy] carbostyril and O-mesitylenesulfonylhydroxylamine.

236486

The product having a temperature of 130 to 135 ° C was obtained in a yield of 51% ttorite.

Híklid 19

3.3- & Methyl-5- [4- (4-thienylphenylsulfonoxio) butoxy] indolin-2-one

The title compound is prepared ee enULoglckýn ▼ manner as Example 1 from IJJ-alpha- ďlmeeřhl- ^ ^ ^ methilfenilsulfiiiLlbfrrtoxiQindolii- one and ^O> meeitylei> 8vu.Lfoi ahy ⁿ <droxilemLnu.

Mp 146-147 ° C rtzu.tujt in 84% yield ·

Example 20

3.3- Dimethyl-5- [4- (4-tritylphenylphenylsulfoxminol butoxy) indolin-2-one

The title compound ee was prepared in an analogous manner to Example 1 from 3-di-3-di- _h -5- [4- (4-tert-butylphenyl) ul-1-yl] butolin-2-ol and O-nitstylthiulfoxnihidroxyl amine.

M.p. 195 DEG-197 DEG C., yields 85% of theory.

Example 21 ' 3-Dimethyl-5- (4- (2-methyl-4-tert-butylphthylsulfoxinino) butoxy) imidolin-2-one

The title compound a is prepared in an analogous manner. as in Example 1 of 3,3-dinethyl-5- [4- (2-meth) -F1-4-tert-butylbutyl-18-fluorophenyl) -butyl] indoline-20-ol and O-methylsulfonyl sulfonyl.

Product at temperature. mp 149-150 ° C; yield 26% of theory;

Example 22

3.3- (Methyl-5- (4- (3,5-a-tert -butyl-4-hydroxyphenol-1-one) oxo) butoxy] -idazole-1-yl-2-one

The title compound was prepared in an analogous manner to that in Example 1 of 3,4-dimethylethyl-IV-U, 5-di-tert-butyl-4-yloxy-phenyl-4-oxyl-butoxy] indol-2-one and (1-unityitylene-8-phenyl-hydroxy-hydroxy).

The product is present in. 0.25 (glass with siliag · Llee, a mixture of equal parts of tthylacttate and netthienchoride as a beating agent) · Yield 42% ttorite ·

EXAMPLE 23

3,3- (4-methylsulfonyl) -methoxy] -idazol-2-ol

The title compound was prepared in analogy to Example 1 from 3,3-dimethyl-5- [4- (2-phthalenyl) indol-2-one] and methylmethylthiol (drug).

The product, melting at 120 DEG-121 DEG C., yields 64% of ttorite.

236468

Example 24

3.3-Dimethyl-5- (4-cyclohexylsulphoxoxamobutyl) indole: L-2-one

The title compound was prepared in a manner analogous to Example 1 from 3,3-dimethyl-5- (4-cyclohexyl) -fluorobutoxy) -indolin-2-one and O-methylthiulphonilhydroxilimine.

Melting point 108 DEG-109 DEG C. yields 77% of theory.

Example 25

3,3- (Methyl-5- (4-benzylsulfoximinobutoxy) indol-2-one)

The title compound was prepared in an analogous manner to that of Example 1 from 3,3-dimethyl-5- (4-benzylsulfinylbutoxyl) indolin-2-one and O-methylsulfonylphosphonic acid amine.

M.p. 98 DEG-99 DEG C. yields 82% of theory.

Example 26

3.3- & Lmeethi-5- Q4 (4-Fluorophenylsulfoximino) butoxi] indolin-2-one

The title compound was prepared in a manner analogous to Example 1 from 3,3-dimethyl-5- (4- (4-Luoophthylsulfinyl) butyl) indolin-2-one and Omeestylensulfonylphosphine.

M.p. 101-102 ° C, yields 90% of theory.

Example 27

3.3- ‘dimeehhi-55 [44 (4-chlorophenyl sulfoxon) bbuooy] indolin-2-one

The title compound was prepared in an analogous manner to that in Example 1 from 3,3-dimethyl-5- [4- (4-chloro-phenyl) -sulfonyl] -benzoyl-10-ol-10-ol and O-non-ethyl-soyl-phenoxy-oxo: 10-ol.

M.p. 136 DEG-137 DEG C. Result in a yield of 76% of theory.

Example 28

3 ₉ 3- (OLeelhl-5- [4M4-rlonfeollsllfooLLnnol) bltlol 10oILo-2-oo

The title compound was prepared in an analogous manner to that in Example 1 of 3,3-dimethyl-1H-5- [4- (4-bromo-1- (1-sulfonyl) -benzoyl-10-yl] -2-l-10-O and 4-chloro-10-ol-10-yl).

M.p. 160 DEG-161 DEG C. yields 88% of theory.

Example 29

3,3-Dimethyl- ⁵ "E ⁴ " O-Dichloro-phospholinylbenzyl] indolin-2-one

The title compound was prepared in a manner analogous to Example 1 from 3,3-diethyl-1,5- [4- (3,4-dichloro-lyl-8-lithium) -butoxy] -indolin-4-one and O-methyl-8-olefin.

147 DEG-148 DEG C., yields 68% of theory.

Example 30

3,3-diiethhri5-E4 · (2,5- & LcЫ.orftill8Ulfooiiiio) butooy]

The title compound was prepared in analogy to Example 1 _from - - from 3,3-diethyl-5- [4- (2,5-dihiololithi-18-ol)] butol] iidolium-α-ol and α-ethylenediamine-thiamine.

The product has a Rf value of 0.3 (plates containing equal parts of ethyl acetate and ethylene chloride as eluent). The yield is 18% of theory.

Example 31 ’

33- &lt; / RTI &gt; Ethyl-5- [4- (3-methyl-4-methylsulfonyl) oxo] butanol] indol-2-one

The title compound was' prepared analogously to Example 1 from 3,3-dliet] h ^r l 5-E4 - ((- 4-iethll booileill8U.liřlfl) bu0oJl] iidolin-2-ol and O- meitylemsvlloknrlhydroxyl amine ·

M.P. 131-132 ⁰ C. rust-ltuje in a yield of 84% ·

Example * and 32

3, d-Methyl-4- [4- (2-fluoro-4-phenyl-cyclohexyl) -imino] -butyl-indol-S-one

The title compound was prepared according to the procedure described in Example 1, starting from 3,3-dimethyl-5- [4- (2'-oxo-1-yl) -fluoril] -11-yl] -ethoxycarbonyl chloride. ] indolil - 2-olШ and OetitýleiaιQloliУ> .. -, hydrou la ^ nu ·

Melting point: 177-178 ° C, yields 90% of theory.

Example 33

3 ^ 1 ^ 111-5- E ⁴ - ⁽³ »5- ^<L) Ьřol - 4 m ^and also ^{the l} tiyl8ul oxii ⁱ io) -butoxy ^o rl 1 ^ 2 011 ^«

The title compound ae was prepared in a manner analogous to Example 1. and 3,3-а ег ^ ^ Ь Э-рМ-3 ₉ 5-dibriв 4кmiioltiyliulfiIlLl) -butoxy: ιlJ ^^ Мп 2 - one - and O-яt8itllteitilloвдlhydrooylemiiu.

M.p. 202 DEG-204 DEG C., yields 76% of theory.

Example 34

3,3 ^ ϋ ^ 1-5- [4- (4-hexyltinoloxiloxy) buto: o] indoli ^^ - on ’

The title compound was prepared in an analogous manner to Example 1 from 3,3-dimethyl-5- [4- (4-methoxy-phenylsulfinyl) -butoxy] -indolin-2-one and O-mosenylenesulfonyl-hydroxylemine.

M.p. 140 DEG-141 DEG C., 71% of theory.

Example 35

3,3-dimethyl-5- [4- (2-methoxyphenylsulfoximino) butoxy] indolin-2-one

The title compound ae was prepared in analogy to Example 1 from 3,3-dimethyl-5- [4- (2-ethoxyphenylsulfinyl) butoxy] indclin-2-one and O-mesitylenesulfonylhydroxylamine.

The product resulted as a colorless gum of Rf &gt; 0.35 (silica gel, 9: 1 ethylene chloride: ethanol) as a solvent system.

Example 1 a d 36

3.3-Dimethyl-5- [4- (3,4-diethoxyphenyl sulfoximino) butoxy] indolin-2-one

The title compound was prepared in an analogous manner to Example 1 from 3,3-dimethyl-5- [4- (3,4-dimethoxyphenylsulfinyl) butoxy] indolin-2-one and O-mesitylenesulfonylhydroxylamine _0.

Melting point 108 DEG-109 DEG C. yields 79% of theory.

Example 37

3.3-Dimethyl-5- [4- (6-methoxy-2-naphthylsulfoximino) butoxy] indolin-2-one

The title compound was prepared in analogy to Example 1 from 3,3-dimethyl-5- [4- (6-methoxy-2-naphthylsulfinyl) butoxy] indolin-2-one and G-mesitylenesulfonylhydroxylamine.

174 DEG-175 DEG C. yields 88% of theory.

Example 38%

6- (4-Methylsulfoximinobutoxy) -3,4-dihydrocarbamethylsilyl enyl sulfonate

The title compound was prepared in a manner analogous to Example 1, starting from 6- (4-methylaulfinylbutoxy) -3,4-dihydrocarbostyril and O-mesitylenesulfonylhydroxylamine.

M.p. 130 DEG-133 DEG C. yields 87% of theory.

Example 39

3,3-dimethyl-5- (4-phenyl-sulfoximino-butoxy) -indolin-2-one

The title compound ae was prepared in analogy to Example 1 from 3,3-dimethyl-5- (4-phenylsulfinylbutoxy) indolin-2-one and O-mesitylenesulfonylhydroxylamine.

236466

The product, m.p. 111 DEG-112 DEG C., yields 86% of theory.

Example 40

6 <- E 4- (3,4-dimethoxyphenyl and foxylmino) butoxy] -3,4-dihydrocarbonyl styrile

The title compound ae was prepared in analogy to Example 1 from 6-

- 4- (3,4-dimethoxyphenyl8Uphinyl) butoxy-2,3,4'-dihydrocarbonylrile and O-mesitylenesulfonylhydroxylamine.

M.p. 154-156 ° C, yielding 64% of theory.

Example 41

6 '[<- (J, 4-Chlorophenyl sulfoximino) butoxy] -3,4-dihydrocarbostyrene

145.5 g of p-toluenesulfonic acid are dissolved in 350 ml of dimethyl forms with stirring, and 70.1 g of 6- (3,4-dichlorophenylsulfinyl) butoxy] are first added to the solution while stirring. -3,4-dihydrocarbostyril and then 106.7 g of O-mesitylene sulfonylhydroxamic acid ethyl ester. Ongoing reaction is slightly exotherane. Occasional cooling, the reaction mixture temperature below 20 ° C _# After 46 hours under vigorous stirring, 350 ml of water to them first slight turbidity. After addition of the seed crystal suspension, a large portion of the reaction product starts to crystallize with further stirring over 30 minutes. To complete the crystal, more 300 ml of water are added to the mixture, stirred for 30 minutes, the crystalline O-mesltylenesulfonic acid crystallized. and water. The still wet cake was suspended in 500 ml of methanol and 100 ml of 2N sodium hydroxide solution was added in one portion.

The solid goes into solution for a short period of time and then begins to precipitate free sulfoximine in crystalline form. The mixture is stirred at room temperature for 0.5 hour, then the product is filtered off with suction, washed with ice-cold methanol and dried in an oven and circulating air at 80 ° C.

The product, m.p. 160 DEG-162 DEG C., yields 61.7 g (64.9% of theory).

Example 1 a d 42 ‘

6- {З- (3,4-dlchlorophenylsulfoximino) propoxy] -3,4-dihydrocarbostyril

The title compound was prepared in an analogous manner to that in Example 1 of 6-

- [3- (3,4-Dichloro-phenylsulfinyl) -propoxy] -3,4-dihydrocarbonylbutyl and O-mesylene-hydroxylamine.

M.p. 144 DEG -146 DEG C., yielding 67% of theory. Example 43

6- [5- (3,4-Dichloro-phenylsulfoximino) -pentoxyl] -3,4-dihydrocarbonyl styrile

The title compound was prepared in an analogous manner to that in Example 1 of 6-

- 5- (3,4-dichlorophenyl) -8-pentoxy-3,4-dihydro (carbocarbonyl and O-mesitylenesulfonylhydroxylamine).

M.p. 154-155 ° C, yields 29% of theory.

Example 44

6 "(3-ethyl sulfoximinopropoxy) -3,4-dihydrofuran; y drokarbo styril Compound of the title is prepared analogously to Example 1 from 6- (3-ethylsulfinylpropoxy) _{-3-R4-O-dihydrocarbostyril} and mesitylene sulfonate onylhydroxy lamin.

Melting point 107 DEG-109 DEG C. yields 61% of theory.

Example 1 a d 45

6- (4-n-hexyl, lsulfoxlminobux.oxy) ~ _3> 4-dihydrocarbostyril

The title compound was prepared in an analogous manner to that in Example 1 from 6- (4-n-hexylaulfinylbutoxy) -3,4-dihydrocarbonylrile and O-mesitylenesulfonylhydroxylamine.

The product, m.p. 111-113 ° C, yields 59% of theory.

Example 46

6- [4- (2-Phenylethoxyxyulfoximino) butoxy] -3,4-dihydrocarbostyril

The title compound was prepared in an analogous manner to that in Example 1 from 6- [4- (2-phenylethylsulphinyl) butoxy] -3,4'-dihydrocarbonylrile and O-mesitylene hydroxylamine.

M.p. 158 DEG-159 DEG C., yielding 69% of theory.

Example 47

5 «. (4 "sul foximinobutoxy phenyl) - 3 _R 4- dihydro Dr. Okar bo styril

The title compound was prepared in an analogous manner to that in Example 1 from 5- (4-phenylsulfinylbutoxy) -3,4-dihydrocarbostyril in O-mesitylenesulfonylhydroxylamine.

The product, m.p. 159 DEG-160 DEG C., yields 76% of theory.

Example 46

7- (4-phenylsulfoximinobutoxy) -3,4-dihydrocarbostyrrile

The title compound is prepared analogously to Example 41 from 7- (4-fenylsulfinylbutoxy) _-3> 4 ^ dihydrokarbo8tyrilu, ethyl 0-mesitylene sulfonyl 1hydroxamové only those acid and p-toluenesulfonic acid *

M.p. 137 DEG-139 DEG C., yielding 81% of theory.

Example 1 a d 49

6- (4-phenylsulfoximinobutoxy) -1,4-dihydrocarbostyril

The title compound was prepared in a manner analogous to Example 1, starting from 8- (4-phenylsulfinylbutyl) -3,4-dihydrocarbostyril and mesylene sulfonylhydroxylamine.

Melting point product. 78 to 80 ° C гузИ ^ у in 96% yield ·

Example 50 '

6- (3-ethylsolOoximinbpropoxy) crbtytyl

The title compound was prepared as described in Example 1

6- (3 ~ eeL’hl ^ зUfiiylprbpbxy) kгa * bo saw and Omeeityllii ^ UL · fbiylhydrbxyl.amLio ·

Melting point: 166-167 ° C, yields 80% of theory.

Ex. ad 1 I To 51 g ^{3 3} - ^-! ® ^ 1-5- [4- DEG ^{(3, 4} - ^dL .ie ^e ^ ^{u f} У- liyls -foxii ^{about 1} oo) ^at otbxy] ^yn-1-ol .i-2-one

Sloučenina.uvedená titled compound was prepared analogously to Example 1 from ^{3, 3} - ^yl .m ^-L u ^y '5- [4- ^{3 3,} 4-dimethyl ^h eryl8Ol ^LiY yl ^{l-yl) 0 1} uto ^Yj i ^- ethyl-2-benz, ethyl ester. (O ^ иaaityllnsolbinyUУdrbOPimboé acid a. Acid p-toluei.sUl: 0ooo ·

For a ^d ° CT mp ^153-154 ° C rezdtoje in chop ⁷ · 7% of theory

Example 52

3,3-®! Ι © 1Τι-1-5- ⁽⁴ · -metUylaolOoximinoUotbxy) iddolin-2-ol

The title compound was executed andogL ^ t ^ Lym procedure as in Example 1 and 3 _g 3 ~ -imet .mu.l-5- (4-IieeLulsιUfliyLUotbχy) bLli-ii-2-Oio and O · meitylliiolOoryLhyfdro2yLαminu,

Product at temperature. 123 DEG-124 DEG C. yields 98% of theory.

PMkla d. 53

6- (4-iethУLi01fiiinbU. · Ιtoзφ) -З _with ⁴ -diidydroklprb) siyril-LydrbglnflsOfát

Sodium (0.12 g) was dissolved in 25 mL of sodium chloride (1.3 ml) and stirred with stirring. Add 1.3 g of 6- (4-Methylphenylbutoxyl) -3,4-dihydro-4-fluorobiyrrole and mix. at 17 ° C over - 40 rubbing gives ^{0.57 PRL-gu} y ^d rb ^χy la ^iL i · - · ^O sulfoibo ^é acid ^p rice rises ^from the temperature ^{- 22} to ^- ° ^C · ReiOcční mixture was stirred overnight. The precipitated sodium sulphate is then filtered off with suction and the ethereal solution is dried by the slow addition of ether to the resin which is crystallized after trituration with ether into a somewhat horoscopic substance, which is filtered off with suction and dried in a vacuum. over calcium chloride.

M.p. 75-80 ° C. Yield 0.656 g (20% of theory).

6-1 ^{[4- (3, 4} -dic lorfenFliU ^{at about} f irnlnojbitoxy] - J ^{4 3} - ^{-L. U} y ^- yr ^<i yr α'boo ^TLL -me8 ^and tyleis ^ULF BNAT

The title compound is prepared analogously to Example 1 from ^ [4- (3,4 - LCH-OTR nnimnerkapto ^ f ^ iitoxy ⁴ - dihydrokiaTbo osymiu and only those Ornees stufoinrlhydroxy ethylamine ·

M.p. 82-83 ° C (dec.), 49% yield;

236480

Example 55

6- · [4 (3,4-Dimethyl-fernlsulfiminc) butoxy] -3,4-dihydrocarbosyl-mesylene-ethylene sulfonate

The title compound was prepared anslogidým procedure as in Example 1 from · 6- (4- (3 .4 · ^s diyet0oзqffen lmeerrpPo) bjoxy ^b] -r-4 and O-di0ydrokrrro8tyrilu -msitylennulfonyl · Oydroxylaminu. '.

M.p. 140 DEG-145 DEG C., yielding 83% of theory.

Example · '..56. ;

6- [4- (2'-Fluoro-4-biphenylpyrrolidin-1-butoxy) -cycloalkylene] -phenyl] -phenolate

The title compound was prepared in an analogous manner to that in Example 1 from 6- (4- (2-fluoro-4-phenylphenylyleorapto-butoxy)] kaobogytyl and O-ylslitlene sulfonylOrdojerLamine.

M.p. 125-128, 63%.

Example · 57 ’,‘

6- £ 4- (4-tert-butylphenyl-18-sulfonyl) carbonyl-carbonyl

The title compound se..připraví anaiogiclým procedure as in example 1 from ⁶ "[Л- ^{(^} -teoc. Utylfef ^{b r r} Lyer apto) and butoэýrkrabboSyrilu -msitylenaulfon ^ ^ o ^ rojýrlamnu.

. 145 DEG-150 DEG C. yields 55% of theory.

The following compounds are also prepared by the chemical method:

6- (4'-phenolsulfonyloxybutyl) -3,4-di-orthocaaroctyrile, m.p. 127 DEG-129 DEG C .;

6- [4 - ^((l-sulfonyl fluorfenrl lkoxiπlino) butoxy] -3,4rdi0] drokarboktyr01 mp 170-173 ° C

6 - [4- (4-tert-butylphosphinylcarbonyl) butyl]] 1. m.p. 208 DEG-210 DEG C .;

6- ^{4 . ^{(4-c to r} rlkOexylfenrl8Ul xx ^{y f} n no) Ьuto ^r ^ r] ^ ^ гЪо уг ^0! of ^p lo ^y e ^y of TONI ¹⁹⁵ and I9 ^{F 7} ° C. '\ ·'. . . 145 DEG-147 DEG C. 6- (4-chloro-oxo-xyloxycarbonyl);

6 Ь- ^[3ryet01-4- · ^b royfθnf IU ^{jf r} oxi ^m AF) bbjyo ^χ rkra BST ^{r y} r ⁱ · Io toploto point ¹⁹³ and ^from 194 ° ^C>

3 Уretorlrчřl --- (R "OOklcrleefl: lsjylsulУofOIbLjo ur ^b) nrdillfolin-2-one; m.p. · 162-163 ° C. . '

Claims (4)

A process for the preparation of novel salts of the general formula (I) in which jq is 0 or 1, A modified dimethylmethylene, vioylene or ethylene skipine; B represents a straight-chain alkylene group having 3 to 5 carbon atoms, R 1 represents an alkyl group having from 1 to 6 carbon atoms, benzyl, phenylethyl ^, or the like. cyclohexyl, oophtyl, or ortho-orthophthyl, phentyl, optionally substituted with alkyloxy. 1 to. 4 atoms of UMlOm, ооПНозоу ·, cycloheeot-, bitches or ϊLLuofeelt1loíou. a fluorine, chlorine or chlorine atom. of bromine, phenyl. a dititonium group with an alkyl group having an alkyl group. 1-4 carbon atoms with thoooy groups, chlorine and / or bromine atoms; wherein ^ ^ Ьо -Шпо ^ Oa 'phenyl ^nucleus: may be the same or different, oeUo amino phenyl, or Uydroχtfentlovou ootho50tfentlov · u substituted' by two chlorine or bromine atom, two, οοϊΟο ^ groups. or two acylic. dandruff ob slujícími each case 1 to 4 carbon _ч and s ^ o-i. % of strong acids, characterized in that ^{1 is a} compound of formula (II) in which: A, B, R, O, O, as defined above, is reacted with a compound of formula III HgU-O-UR 1; * (III), in which about 1 X is a cadulonyl or sulfoyl group and R @ 3 is a di-trifluoromethyl group, such as 2,4,6-thiomethylphenyl or 2,4,6-tri-piperidinyl, or any hydrooyl when X is a sulfooyl group, and the resulting product of formula I. is optionally converted by treatment with a strong acid, oa. srooi forces, in particular oa consent physiologically. enéeitelitelouou forces ·. 19 Dec '.. <. 2. The process of item 1 for the preparation of the novel sulfoximines of the general formula Ia O (Ia) in which A, B, R, 'and Rg have. the meaning of a point, - distinguished. by the sulfoxide of the general formula. .. Ila. <- · - O / (Ha) z A, B and R 1 as defined in 1, is reacted with a compound of formula IIIa HN-O-X-R1 (IIIa), ve. which .. X is as in 1-a Rja. represents a disubstituted arplic moiety such as 2,4,6-trimethPenzene or 2,4,6-trio-propylphenylmethyl. The method of claims 1 and 2, characterized in that the reaction is carried out in a solvent such as meethyendhoride, chloroform. dimethylforaamide, tetrhprdr defense. or dioxane. 4.. Way. 3. The process of claim 1 wherein the reaction is carried out. at a temperature between 0 and 50 ° C, 9 výtodou temperature between ^p s. 5 and 40 ° C._