Indolin-2-one derivatives, method of obtaining them and pharmaceutic compositions containing such derivatives

This is the new indclin-2-oncwś parade, so the need to create them and the fsrmsceutycenś composition. This newer procession significantly disadvantages the lycopretin and / or octytocin formulas and may disgust them from the fsemscuric compositions.

Wsecpeśsyns jśtt about the ensne s ttydiuśtycenym today and influenced ns esgulsion of the tarsus pressure. Stimulujś ons tzśrśg birth recśproeów: Vi (Vu, V, b or V₃), V2.

You can find this skill in the liver, neek or brain, platelets, nseks, mice, glands nsdnceces, central pessimism or judgments. Oxyrccyns ms has a pptid structure similar to that of vseopretin. Rścśptoey cctrocyins ensemble the thistle ns in the capillary; they find ties of the ts of the musculo-nsothelial tutks, in the central nshevcwym and in nseksch. You have learned about different descriptions in: Jsed S. et al., ^ stoprettinś and Oxytocynś Receptcrs: sn Oveeviśw in Pecgeess ”in: Endccrinclcgy, Imurs H. snd Shizumś K., publishes expśrts Mśdics, Amstśedsm, 1988, 1183-1188 and in the following sets, 1987, Peślśd: Peślśd 10), 481-485, J. Lsb. Clin. Mśd., 1989, 114 (6), 617-632 and Phąemsccl. Rśv., 1991, 43 (1), 73-108. Vesoprinsia zsłsią today hormonslnś, nsceynicwo-systrynś, nsceynicwo-systrynś, hepatocellular, nsceynicwo, systiureryczny and sgeosgaging process of today, central and peripheral system of nephroscitis, and obturation of systolic and pulmonary nephrosis. This octocin was associated with porcdcm, lsktsia and textural learning.

Antsgonitts of vseopretin V2 (nsnsns nsws: "AVP-2 snrsgcniists" or "V2 sntsgonists") may have the essence of the antisectics, which today are typically induced by the presence of , tskiś jsk fuectcmid or hydecchloIΌtiseyd. Most of them, after a long day of today, give you hypoxia and blood.

Pieewtzy sntsgcnisrs rsceptcrów V2 of arginine-vseopestin (dslśj ewsny AVP), OPC31260, tighten in clinical trials. Pceówniś today OPC-31260 with typical diuśtyksmi, tskie jsk furotśmid, pokseujś, tski tskijs tsisktywniś tpeeyjs wdnej diureete and lower impact, or ms bsrdec ms bad influence with large dswksch, ns sound, etc. . J. Phsrmscol., 1992, 105, 787-791) and u humanx (Akihieo O. et al., J. Glin. Invśtt., 1993, 92, 2653-2659, and Akihiec O. et al., J. Phsemscol. Exp. Thse., 1995, 272, 546-551).

The process of indoline ^ -one is described in Ι ^ ήΙ ^ -ζ ^ You can remember, with the title of an example, about a quote from ZA 830952, which, by listing the derivative, is an anti-pressure agent, somebody inhibits the quetion of the drug 1.5 by causing me to sweat.

187 093

A number of patent applications or patents also describe a number of non-peptide compounds with affinity for vasopressin and / or oxytocin receptors. This is the case, for example, in EP 382,185, which describes carbostyril derivatives which are vasopressin antagonists useful as vasodilators, antihypertensive agents, diuretics and platelet antiaggregants; EP 444,945 describes spiropiperidine derivatives useful especially in dysmenorrhea; EP 514,667 describes benzoazepine derivatives useful especially in renal dysfunction, blood sodium deficiency, diabetes or alternatively in the treatment and prophylaxis of hypertension and in the inhibition of platelet aggregation: JP 03127732 describes indole derivatives as vasopressin antagonists.

Benzyl or sulfonylindoin derivatives and indole derivatives have also been described as vasopressin antagonists. In this connection, mention may be made of the documents: EP 469,984, EP 526,348, EP 636,608, EP 636,609, WO 93/15051 and WO 95/18105, although these documents do not describe compounds which are selectively active on the AVP-2 receptor.

Certain indolinones have been found to have an outstanding affinity for the vasopressin and / or oxytocin receptors. These new indolin-2-ones are essentially potent and selective AVP-2 antagonists.

Moreover, taking into account their structure, and in particular the presence of various polar functional groups, especially soy convertible functional groups, these molecules are readily dispersible and / or soluble in water, which gives them increased pharmacological activity, and also allows easy preparation of injectable pharmaceutical dosage forms. .

The compounds of the invention are the indolinone derivatives of formula 1.2 (or I)

<img file="PL187093B1_D0001.tif" />

wherein

- Rj is a hydrogen atom; hydroxy; halogen atom; (Ci-C7) alkyl; (C1-C7) polyfluoroalkyl; (C1-C7) -alkoxy; a (C1-C7) alkylthio; (C1-C7) -polifluoroalkoxy; (C3-C7) cycloalkyloxy; (C3-C7) cycloalkylthio; cycloalkylmethoxy or cycloalkylmethylthio, wherein cycloalkyl is C1-C7 cycloalkyl; phenoxy; benzyloxy; nitro; or cyano;

- R3 and R4, independently of each other, represent a hydrogen atom; halogen atom; (C1-C7) -alkyl; (C2-C7) alkenyl; (C1-C7) polyhaloalkyl; phenyl or benzyl; a cyano group; nitro; -NR5R0; hydroxyamino; hydroxy; OR7; SR7; -COOR₈, -CONR9R10; or -CSNR9R10 with the proviso that at least one of R3 and R4 is other than hydrogen;

- R5 and R6 are each independently hydrogen; (C 1 -C 7) alkyl; (C2-C7) alkenyl; phenyl; benzyl; (C1-C6 -alkylcarbonyl; (C1-C7) -alkylthiocarbonyl; (C3-C7) -cycloalkylcarbonyl; (C3-C7) -cycloalkylthiocarbonyl; benzoyl; thienylcarbonyl; furylcarbonyl; (C1-C7) -alkyloxycarbonyl; phenzyloxycarbonyl; carbamoyl or thiocarbamoyl which is unsubstituted or substituted with R9 and R10 or, alternatively, R5 and R6 form, with an atom

187 093 nitrogen to which they are attached, a heterocyclic group selected from the group consisting of: pyrrolidide, pyrroline, pyrrole, indoline, indole and piperidine;

- R7 is (C1-CO-alkyl; (C2-C7) -alkenyl; phenyl; benzyl; (C3-C7) -cycloalkyl; (C1-C7) -polifluoroalkyl; formyl; (C1-C7) -alkylcarbonyl; benzoyl; or benzylcarbonyl;

- Re is a hydrogen atom; (C 1 -C 4 -alkyl; phenyl or benzyl;

- R9 and Rio each independently represent a hydrogen atom; (C 1 -C 7) -alkyl; (C 1 -C 7) -polifluoroalkyl; (C 2 -C 7) -alkenyl; (C 1 -C 7) -cycloalkyl, optionally substituted with hydroxy (C 1 -C 4) -alkyl; pyridyl; phenyl; thienyl ; furyl; (C4-C7) -azacycloalkyl, or, alternatively, R9 and R10 form with the nitrogen atom to which they are bound a heterocyclic group selected from the group consisting of: pyrrolidine, piperidine or piperazine which are di-substituted or substituted with (Ci- C4) -alkyl;

- T is (C1-C6-alkylene which is optionally interrupted by (C3-C6) -cycloalkylene, said alkylene being optionally substituted one or more times on the same carbon atom with (C1-C3) -alkyl; or alternatively T is a direct bond;

- Z is -NR11R12; - + NRuRi2 (Ci-C4) -alkyl (A ') wherein (A') is an anion, -N (O) Ri | Ri₂; -COOR11; -NR11COR12; -CONRnRn; with the proviso that when T is methylene or a direct bond, Z cannot be: -NR11R12; -NRiiR ^ - &lt;C1-C₇) -alkyl (A '); -N (O) R_nR12, -NRnCORn;

- Rn and Riz each independently represent a hydrogen atom; (Ci-C7) alkyl; (Ci-C4) alkoxy; (Ci-C7) cycloalkyl; phenyl; (Ci-C3) -alkylenecycloalkyl wherein cycloalkyl is C3-C7 cycloalkyl, or (C1-C3) -alkiledofedyl, which groups may be mono- or multi-substituted with Ri3; or, alternatively, Ri and Ri2 optionally form, with the nitrogen atom to which they are attached, a heterocyclic system selected from the group consisting of: azetidine, pyrrolipid, piperidine, piperazine, piperazinone, morpholine, morpholinone, thiomorpholine and hexahydroazepine, which heterocyclic system is optionally one - or multi-substituted with Rii;

- Ri3 is (Ci-C4) alkyl; a hydroxyl group; hydroxyalkyloxy, (C 1 -C 4) alkoxy; a group NRi4Ri5 wherein Ri4 and Ri5 are each independently hydrogen or (Ci-C4) alkyl; amidino; guanidino; imidazolyl; pyridyl; indolyl; or tetra.hyproizochidolyl;

- the phenyl group being a substituent of Ri, R3, R4, R5, R6, R7, Rs, R9, Rio, Rii and Ri2 can be di-disubstituted, or mono- and disubstituted by (C1-C7) alkyl, (C1-C7) alkoxy, trifluoromethyl, halogen or substituted with (C1-C7) alkyl, (C1-C7) alkoxy or halogen; and their salts, solvates and hydrates.

Particularly preferred are the derivatives of formula 1.3:

<img file="PL187093B1_D0002.tif" />

wherein R1, R3 and R4 are as defined above for formula 1.2, T is (C1-C3) alkiled and Z is amino, 2-hydroxyethylamide, 2- (2-hydroxy) ethyloxyethylamine, mor10

187 093 folinyl or carboxyl; their salts, solvates or hydrates. Even more preferred is the derivative of formula 1.4:

<img file="PL187093B1_D0003.tif" />

in which R._b T and Z are as defined above, one of their salts, solvates or hydrates. The second group of compounds according to the invention are the indolinone derivatives of the formula III:

<img file="PL187093B1_D0004.tif" />

in which R.₍, and T are as defined above and X is halogen, mesyloxy; or tosyloxy, or, alternatively, X is an azide, or one of their salts, solvates, or hydrates;

Particularly preferred derivatives include: * 5-ethoxy-3-spiro- [4- (3-chloropropyloxy) cyclohexane] indolin-2-one; * 5-ethoxy-3-spiro- [4- (2-chloroethyloxy) cyclohexane] indolin-2-one; * 5-chloro-3-spiro- [4- (2-chloroethyloxy) cyclohexane] indolin-2-one; or * 5-ethoxy-3-spiro- [4- (2-toxicoxyethyloxy) cyclohexane] indolin-2-one.

The second group of particularly preferred derivatives includes:

* 5-chloro-3-spiro- [4- (2-morpholinoethyloxy) -cyclohexane] -1 - [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2-aminoethyloxy) -cyclohexane] -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2- (N-methyl-N- (2-hydroxyethyl) -amino) -ethyloxy) cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2 -methoxybenzenesulfonyl] indolin-2-one;

* 5-ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2-morpholinoethyloxy) cyclohexane] indolin-2-one;

* 5-ethoxy-3-spiro- (4-carboxymethyloxycyclohexane) -1- (4-N-tert-butylcarbamoyl-2-methoxybenzenesulfonyl) indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2-morpholmoethyloxy) -cyclohexane] -1- [4- (N-tert-amylbutylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2-carboxyethyloxy) -cyclohexane] -1 - [4- (N-tert-amylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

* 5-ethoxy-1- [4- (N ', N'-diethylureido) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2-dimethylaminoethyloxy) cyclohexane] indolin-2-one;

187 093 * 5-ethoxy-3-spyO- [4- (o- (4-ethoxypiperPyno) ethyloxy) cyclohexone] -1 - [4- (N-ter (-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

* S-st4xy-3-spiro-te- (2-glycylaminoethyloxy) cyc] ohexane] -1-te-kN-tort-butylcarba (m4-yl) -2 (meth4kPobenzenesulf4nyl-ind4lin-2-one;

* S-et4xy · -3-spiro- [e ((2 ((N, N (dimethołglycγlliammo) ethyloxy) -cyck) hexane | -l- | 4- (N^ltort-butyl-4ka (bam-4-yl) -2-meth4-pybenzene-4-sulfonyl 4] indoline (2-4n;

* S-cblυro-3-spiro-t4 - ('N- (3-dimstoloaminopropolo) -carbamoylmethyl-) kpy) -cγklohekpa (n4 | -1th ((N-terΐ-buΐ \ docarbamoyl) -2-mstokpybenzenosιllf4noio] indolin-2-one;

* S-st4xy-3-spiro-te- (2- (e-dimstyl4amin4butyrylamino) ethyl4xy) -cyclohexane] -1 (te (N-tert-butyl4carbamoyl) (2-meth4-benzenesulfonolmdolm-2-one;

* S-ethoxy-3-spiro- [4- (2- (2-hydroxyethylamin4) ethyloxy) -cycl4hexan4] -1-te- (N-tert-butylca (bamoyl4) -2-motoc [ybenzene-4-sulf4nyl4-indolin-2-4n; or * S (Stoxy-3-spiro- [4- (2- (2- (2-hydroxyethyloxy) ethylamino) ethyloxy) -cyclohexane] -1-th (kb-tert-butylcarbamoyl) -2-methoxobenzene-4sulfonyl] ind4lin-2-one ;

and their pharmaceutically acceptable salts, solvates and hydrates. The most preferred derivative is S-et4xy-1 (te- (N-tort (butylcarbamoyl4) -2 (methocpybenzine-pulfonyl- (3-ppiro-te- (2-m4rf4lin4-ethyloxo) -cyclohexane] -indolin-2-one; acceptable salts, solvates and hydrates.

According to the present invention, it is understood that "(C 1 -C 7) -alkyl" or "(C 1 -C 6) -alkyl" means straight or branched alkyl with 1 to 7 carbon atoms or 1 to 6 carbon atoms, respectively.

According to the present invention, it is to be understood that halogen is an atom selected from the group consisting of: fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

When a compound of the invention has one or more asymmetric carbon atoms, the optical isomers of that compound form an integral part of the invention.

Where a compound according to the invention exhibits stereoisomricity, e.g. of the axialequivalent or ZE type, the invention includes all portions of that compound.

The salts of the compounds of formula (I) according to the present invention include salts with inorganic or organic acids, which allows suitable separation or crystallization of the compounds of formula (I) such as picric acid, oxalic acid or an optically active acid, e.g. tartaric acid, dibenzoyltartaric acid, mandelic acid or camph4 sulfonic acid, and those that form a physiologically acceptable soybean, such as hydrochloride, bromide4 (ek, sulfate, bisulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalene-sulfonate or pa (atatat.

The salts of the compounds of formula (I) also include salts with organic or inorganic bases, e.g. alkali metal or alkaline earth metal salts such as sodium, potassium or calcium salts, with sodium and potassium salts being preferred, or with an amine such as trometamol, or alternatively arginine, lysine or any physiologically acceptable amine salts.

The functional groups optionally present in the molecule of the compounds of formula (I) and the reaction intermediates may be protected, in a permanent or temporary form, by protecting groups which ensure an unambiguous synthesis of the expected compounds.

By temporary protecting group for amines, alcohols, phenols, thiols or carboxylic acids is meant protecting groups as described in: Protectivs groups in Organic Syntbesis, G (esno TW and Wuts PGM, published by John Wiley and Sons, 1991 and in: Protsctivo groups, Kocienski PJ, 1994, Georg Thieme Verlag.

There may be mentioned, for example, temporary protecting groups for amines: benzyls, carbamates, (such as tert-butyloxocarbonol, which can be cleaved acidically, or bsnzoloxocarb4nol, which can be cleaved by hydrogenolysis), for carboxylic acids (alkyl esters, such as methyl, ethyl or tert-butyl esters that can be hydrolysed) in alkaline or acid medium, or benzyl esters that can be treated with w4d4 (4lizis), for alcohols or phenols, such as tst (ahydropo (anyl, mstoxomethole or methylethoxomstol, tert-butyl and benzyl ethers) and reference can be made to the well-known general methods described in: Pr4toctivs groups, cited above.

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According to the present invention, priority is given to temporary protecting groups which can be cleaved in acidic or neutral conditions by hydrogenolysis.

Stable protecting groups are those which are stable under the cleavage conditions cited above and which are capable of being present in end products. Such O or N protecting groups consist of (C1-C7) alkali or phenyl groups. Stable N protecting groups also include (C1-C5) akanoic and aroyl groups such as benzoyl.

Compounds (I) may contain groups - precursors of other functional groups which are then formed in one or more steps.

Compounds of formula (I) in which various polar functional groups, in particular soybean-forming functional groups, increase the solubility and / or availability in water, preferably contain -TZ groups.

Compounds of the invention can be prepared according to Scheme 1 below.

<img file="PL187093B1_D0005.tif" />

IFA! I'B - * · ---—-—

Another object of the present invention is a process for the preparation of the above compounds, which consists in that (1) or, when Z = NR11R121 in which R111 R12 are as defined in formula 1.21:

(1a) when at least one of Rui R12 is different from hydrogen, a compound of formula IIA:

187 093

<img file="PL187093B1_D0006.tif" />

wherein R1, R3, R4 and T are as defined for formula 1.2 and where X is halogen, tosyloxy or mesioxy, is reacted with a derivative of formula ZH where Z is as defined for formula 1.2 in a solvent selected among dimethylformamide, tetrahydrofuran or acetonitrile, at temperatures between 0 ° and 120 ° C, or (Ib) when R11 and R12 = H, a compound of formula ΠΑ in which X is azido is reduced to the amine;

(2) or when Z = -COOH, a compound of formula II'A:

<img file="PL187093B1_D0007.tif" />

(»'FQ r₄ in which R1, R3 and R4 are as defined above and T 'is T-CH2 - subjected to an oxidation reaction in an acidic solvent at a temperature between 0 ° C and 100 ° C, (3) or a compound of formula IIB:

<img file="PL187093B1_D0008.tif" />

H.

187 093, wherein Ri, T and Z are as defined above, is reacted with a compound of formula 2:

Hal-SO2 //

Ri

<img file="PL187093B1_D0009.tif" />

wherein R3 and R4 are as defined above and Hal is a halogen atom, in an anhydrous solvent, in the presence of a metal hydride or an alkali metal alkoxide, at temperatures between -40 ° and 25 ° C;

(4) be when. Z = -COOH, a compound of formula II'B:

<img file="PL187093B1_D0010.tif" />

in which R] is as defined above and T 'is T-CH2, subjected to an oxidation reaction, and then the acid of formula IIB thus obtained:

<img file="PL187093B1_D0011.tif" />

where R1 and T are as defined above are protected to protect the carboxyl group to provide an intermediate of formula IIBP:

<img file="PL187093B1_D0012.tif" />

(1 'BP) wherein R1 and T are as defined above and P is a protecting group selected from the group consisting of: alkyl, tert-butyl or benzyl, and finally, the compound of formula IIBP is treated with the derivative of formula (2), to give, upon deprotection, compound 1.2; one of its quaternary ammonium compounds, oxides, sulfones or salts.

Compounds (II A) and (II B) can be prepared from compounds (III) according to the following Scheme 2:

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SCHEME 2

<img file="PL187093B1_D0013.tif" />

Η

ΙΠ

Compounds (II A) can be prepared from indolin-2-one (III) using a benzenesulfonyl halide in an anhydrous solvent such as dimethylformamide or tetrahydrofuran in the presence of a metal hydride such as sodium hydride or an alkali metal alkoxide such as e.g. potassium tert-butoxide, at temperatures between -40 ° and 25 ° C.

Compounds (II A) can also be prepared from alcohols (II 'A) according to known general methods. Mention may be made, for example, of the triphenylphosphine / carbon tetrachloride system according to Angew. Chem. Int. Ed., 1975, 14, 801 or triphenylphosphine / C (Hal) 4 in which Hal is halogen, in the presence of pyridine according to Carbohyd. Res., 1978, 61,511 or by reaction with an aryl or alkylsulfonyl halide in the presence of a base in an inert solvent. The group X can be swapped: e.g. the sulfonate can be converted to a halide such as an iodine derivative by reaction with an alkali metal iodide such as sodium iodide according to J. Chem. Soc., 1949, 326. When X is a halogen atom, the halide (II A) can be converted to the alcohol (II 'A) by displacement with a nitrate ion which is then reduced in the presence of a metal catalyst such as palladium on carbon according to the method described in J. Med. Chem., 1995, 38, 130-136.

Compounds of formula (II 'A) can also be prepared from the corresponding indoiin-2-ones (III¹) by reaction with the starting materials (2) under the conditions already described for the conversion of compounds (III) to (II A). The alcohol group (III ') will be temporarily protected (compounds III'P) e.g. by a protecting group such as methyl or tetrahydropyranes according to EP 636,608.

Compounds (II B) can be prepared from indolin-2-one (III) by displacement of the nucleofug group X with a derivative of ZH (1) such as, for example, a primary or secondary amine, in polar solvents such as dimethylformamide, tetrahydrofuran or acetonitrile at temperatures between 0 ° and 120 ° C, according to the nucleophilic and nukonugal character.

Compounds (II B) for which -TZ is -T-COOH are prepared from alcohol (III ') in which T' is T-CH2- by oxidizing the alcohol (III ') according to the conditions described for the transformation (II'A) into (AND).

Compounds (III) are new and form part of the invention. They can be prepared according to reaction scheme 3 below:

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SCHEME 3

<img file="PL187093B1_D0014.tif" />

Ul IV

Thus, indolin-2-ones (III) can be obtained by reduction of acetals (IV) under mild conditions, e.g. according to the method described in J. Org. Chem., 1987, 52, 2594-2596, by treatment with zinc borohydride in the presence of trimethylsilyl chloride in chlorinated ethers or solvents such as, for example, dichloromethane or by treatment with dimethyl sulfide BH3 complex in the presence of trimethylsilyl triflate. in ethers or dichloromethane according to the method described in J.Org. Chem., 1993, 58, 6756-6765, or from alcohols (III '):

) -T-OH No. where Ri and T are as determined for (I), according to the methods cited above for the conversion of (II 'A) to (II A).

Acetals (IV) are prepared by well known reactions, e.g. with a ketone (V) using an alcohol by acid catalysis in a dehydrating medium. The preparation can be carried out by azeotropic removal of water or in the presence of molecular sieves according to Synthesis, 1972, 419.

Ketones (V) can be prepared from the corresponding secondary alcohols (VI) according to numerous methods well known to the person skilled in the art using, for example, oxidizing agents such as chromium oxide in acetic acid or chromium oxide complexes such as pyridinium chlorochromate in inert solvents. such as ethyl acetate or dichloromethane, or alternatively by hydrolysis of acetals (IV ').

Alcohols (VI) can be obtained from the corresponding compounds in which the hydroxyl group is protected, e.g. with methoxymethyl or tetrahydropyranyl. These compounds are described in EP 636,608 or are similarly prepared. Compounds of formula protected in this way:

187 093

<img file="PL187093B1_D0015.tif" />

are subjected to acid hydrolysis in an alcohol such as methanol or ethanol or in an ether such as tetrahydrofuran at temperatures between -5 ° and 70 ° C.

Compounds (III ') can be prepared according to Scheme 4 below:

SCHEME 4

-nhnh₂

<img file="PL187093B1_D0016.tif" />

about·

<img file="PL187093B1_D0017.tif" />

As for the preparation of compounds (III) from acetals (IV), compounds (III¹) can be prepared from a cyclic acetal (IV ') such as dioxolane which is obtained from hydrazide (VII).

The halide (III) can also be converted to (III ') according to the methods already cited for the conversion of compounds (II A) to compounds (II' A).

In contrast to the conversion of compounds (II'A) to compounds (II A) according to the methods already cited, alcohols (III ') may also be converted to compounds (III) wherein X is a nucleofugic group such as alkyl or benzenesulfonate. by reaction with an alkyl halide or phenylsulfonyl halide in inert solvents in the presence of a tertiary amine or in pyridine.

Unions (III¹) can be converted to compounds (III'P) in which the alcohol group is protected as indicated above. Compounds (III'P) can also be converted to compounds (II A) wherein X is a temporarily protected alcohol according to the reaction described previously.

Compounds (IV ') in which T is at least equal to -CH2CH2- can be prepared from ketones (V) by reaction with HO-T-OH diol according to the conditions given for the conversion of (V) to (IV). Compounds (IV) can also be obtained directly from the corresponding hydrazides (VII) by the Brunner reaction described by Moorer RF et al., J. Chem. Soc.,

187 093

1951, 3475-3478, e.g. by heating in solvents such as quinoline in the presence of an alkaline earth metal or oxide such as calcium oxide. The reaction can also be carried out by heating in an inert solvent such as tetralin, naphthalene or 1,2,3,4-tetramethylbenzene according to the method described in Wolff J. et al., Tetrahedron, 1986, 42, (15), 4267-4272, starting with a lithium salt previously prepared in an inert solvent such as tetrahydrofuran at low temperature.

These phenylhydrazide derivatives (VII) can be obtained from phenylhydrazine (IX), which are known compounds or compounds prepared according to known methods, and carboxylic acid derivatives (VIII), such as esters, chlorides or mixed anhydrides obtained by the reaction of an alkyl chloroformate, preferably isobutyl chloroformate , in the presence of a base according to conventional methods well known to a person skilled in the art. The acids (VIII) are known or prepared according to known methods.

An alternative to the synthesis of compounds (I) in which T is -CH2- and Z is -COOZ1 in which Z1 is hydrogen, (C1-C3) -alkyl or benzyl includes the use of an alcohol of formula:

<img file="PL187093B1_D0018.tif" />

wherein R1, R3 and R4 are as defined for (I) which are known products or products prepared according to EP 636,609, alkylated with strong alkylating agents such as the triflate of formula CF5SOjO-CH-COOAik (3), formed in situ by reaction of silver triphthalate with the appropriate halogenated derivative wherein Alk is (C 1-6 C 1-6 alkyl, in halogenated solvents such as dichloromethane or carbon tetrachloride in the presence of a base, such as 2,6-di-tert-butylpyridine according to the method described for alkyl trifluoromethanesulfonates in Carbohydrate Research, 1975.44, C5-C7.

The ester thus obtained can be exchanged or cleaved off under the general conditions already given.

Alcohols (II C) can be prepared according to the following Scheme 5:

SCHEME 5

<img file="PL187093B1_D0019.tif" />

R

187 093

Alcohols (IIC) can be prepared from the protected compounds (X) by deprotection under the same conditions as for the conversion of compounds (XI) to compound II).

Compounds (X) are obtained from compounds (XI) according to the method described in EP 636,608 using halides (2) according to the conditions already described for the conversion of compounds (II B) to (I) and compounds (III) to (II A).

A compound of formula (I) may also be converted to another compound of formula (I) having a polyfunctional residue as defined for Z, in particular for -NRnCORn or for -CONR11R12, the reaction being carried out according to known peptide synthesis methods described, e.g. : Bodansky M., Principles of Peptide Synthesis, 2nd ed., 1993 and Bodansky M. in: Peptide Chemistry, Springer Verlag; thus, these methods make it possible to avoid racemization of the asymmetric centers possibly present in the amino acids.

The ZH substrates of formula (1) are commercially available or prepared according to known methods.

Derivatives of formula (2):

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they are also produced according to known methods. Thus, for example, 4-dimethylamino-benzenesulfonyl chloride is prepared according to: Sukenik CN et al., J. Am. Chem. Soc., 1977, 99, 851-858. More generally, dimethylamino substituted benzenesulfonyl halides are known or prepared by known methods; 4-benzyloxybenzenesulfonyl chloride is prepared according to EP 229,566.

Alkoxybenzenesulfonyl chloride is prepared from sodium alkoxybenzenesulfonate, which in turn is produced by reacting an alkyl halide with sodium hydroxybenzenesulfonate.

Benzenesulfonyl halides are prepared according to: Col. Czechoslov. Chem. Commun., 1984, 49, 1184, from the aniline derivatives substituted with the same group, said aniline derivatives being in turn obtained from the corresponding nitro derivatives.

Benzenesulfonyl halide (2) wherein the 4-substituent is -NHCON (CH2CH3) 2 can be prepared by reacting chlorosulfonic acid with N ', N'-diethyl-N-phenylurea, subsequently obtained by reacting aniline with diethylcarbamoyl chloride.

In case R3 or R4 is N-substituted carbamoyl, it is possible to condensate the compound (2) where R3 is a carboxylic acid precursor such as N-benzylcarbamoyl by deprotecting the protecting group by hydrogenolysis and then condensing with the desired amine or alternatively directly producing ( 2) where R3 has the expected value. The reaction is generally carried out starting from correctly selected anilines which are themselves obtained by reduction of the corresponding nitro derivatives.

The anilines are diazotized under conventional conditions with nitric acid and reacted with SO2 in the presence of cupric chloride according to J. Heterocyclic Chem., 1986, 23, 1253.

Compounds (3) are prepared from an alkyl iodoacetate and a trifluoromethanesulfonic acid salt, such as a silver salt, according to Chem. Reviews, 1977, 77.

Quaternary ammonium, N-oxide and S-oxide derivatives and sulfones of compounds (I) are part of the invention and are typically prepared by reaction with an alkyl halide, respectively, or by oxidation with hydrogen peroxide or peracid, such as peracetic acid or metachloroperbenzoic acid, in inert solvents.

The compounds of formula (I) may contain amine or acid functional groups which can be converted into amide groups by reacting with acid or amide derivatives, respectively, which may contain asymmetric carbon atoms. Mention may be made of de-demise coupling reactions, well known to the person skilled in the art, especially in peptide synthesis with reference to: Wunsch E. in: Methoden der Organischen Chemie (Synthese von Peptyden), 1974, 15, T 1 + 2, Thieme Verlag, Stuttgart or Jones

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JH, in The Peptides, 1979, 1, 65-104, Gross E., Meisnbofo (J., Academic Press, or M. Bodansky, Principles of Peptide Synthssis and Peptide Chemistry, 1993, Springer Verlag.

The compounds of formula (I) above also include those in which one or more hydrogen, carbon or halogen atoms, especially chlorine or fluorine, has been replaced by a radioactive isotope thereof, e.g. tritium or carbon-M. Such labeled compounds are useful in metabolic or pharmacokinetic studies or in biochemical assays as receptor ligands.

The affinity of the compounds of the invention for the V1 vasoprep receptors was determined in vitro using the method described in Lynch CJ et al., J. Biol. Chem., 1980, 260 (0), 28442801. This method is based on the study of the displacement of tritiated vasoconstriction associated with sites VI of rat liver cell membranes.

Similarly, the affinity of compounds (I) of the invention for oxytocin receptors was determined in vitro by displacement (adioiodinated oxytocin analogue of a receptor bound membrane preparation from the mammary glands of pregnant rats, following a method similar to that described in Elands J. et al. In Eur. J. Pharmacol., 1987, 147, 197-207.

The affinity of compounds (I) of the invention for V2 receptors was measured on a bovine kidney cell membrane preparation according to a method borrowed from Crause P. et al., Molecular and Cellular End4crinologo, 1982, 28, 029-041 and from: Stassen FL et al., J Pharmacol. Exp. Ther., 1982, 233, S0-S4.

The compounds of the invention inhibit tritiated arginine-vasopressin binding to the receptors of the membrane preparation. The IC 50 values ​​of compounds of the invention are low, generally ranging from 10'S to 10 '⁹M.

The orally administered vasopressin agonist or antagonist activity of the compounds of the invention was assessed in a normally hydrated rat (Sprague-Dawley race) according to the method described in Br. J. Pharmacol., 1992, 10S, 787-791. The diuretic effect, generally observed with the compounds of formula (I) and some of these compounds, at doses less than or equal to 10 mg / kg shows that the compounds of formula (I) form a series of potent V ^ antagonists

The compounds of the invention are active after administration by various routes, in particular by the oral route.

For these compounds, no signs of toxicity were observed at pharmacologically active doses; their toxicity is therefore consistent with their medical use as medicaments.

The compounds of the present invention make it possible to mimic or inbite, selectively, the effects of vasopressin and / or oxytocin. Of these compounds, vasopressin receptor antagonists can act in the regulation of central and peripheral circulation, especially of the coronary, renal and gastric, and water regulation, and the release of adrenocorticotropic hormone (ACTH). Vasopressin agonists may advantageously replace vasopressin or its analogs for the treatment of diabetes insipidus; they can also be used in the treatment of enuresis and regulation of bomoptazo: treatment of homophilia or von Willebrand syndrome or as an antidote to platelet aggregant, Laszlo FA, Pharmacol. Rev., 1991, 43, 73-108, Drug Iiwe.stigation, 1990, 2 (Suppl. S), 1-47. The hormones themselves: vasopressin and oxytocin and some of their peptide analogs or niopoptod4wocb have been tested and shown to be effective (Vasopressin. Gross P. et al., Edited by John Libbey Eurotoxt, 1993, especially 243-257 and S49-S62. Laszlo. FA and Laszlo FA Jr., Clinical Pe ^ pe ^^ es for Vapop (ospin Antagonists, Drug News Perspect., 1993, 6 (8); North WG, J. Clin. Endocrinol., 1991, 73, 1316-1320. Legros JJ et al., Prog. NeuroPharmacok Βΐοί. P) ychiat. I 198 8, 12, 571-S86; Andersson KE et al., Drugs Today, 1188, 22- ((7, 500-28; Stump DL et al., Drugs, 1990, 39, 38-03; Caltabiano S. et al., Drugs futura, 1988, 13, 2523-; Mura Y. Et al., Clin. Nephrel. 1993, 40, 60-61; Faseb J., 1994, 8 (0), A587: 3398).

This type of V2 antagonist molecules with an aquatic profile has a wide range of therapeutic indications and represents a significant innovation in the treatment of heart failure, blood sodium deficiency, water management disorders, water retention, etc. This type of compound can favorably replace conventional diuretics in all pathological conditions. where they are recommended for humans and animals. It is also possible in the case of such parts of the blood pressure in conjunction with some other therapies, e.g.

Zstśm compounds wśdług wynslszku the pezydstnś szczśgólniś in lśczśniu dolśgliwości cśrodkcwcgc and obwodowśgo ukłsdu ncewowśgo, ukłsdu nsceyniowc-sśrcowśgc, ukłsdu hoemonąlnegc and liver obtesru nśrśk, żołądks, jślit and lung, and in oftąlmclogii esbureśnisch eschowsnis tśksuslncgo, in cełowiśks and in zwiceeąt.

Another peecdmictśm niniśjszgc wystśmycjś fsrmscśutycenś eswiceąjącc jsko tkłsdnik tactic relationship of formula 1.2 or jśdą from jśgo fsrmscurować dopuseceąlnycb toli, hydrstów or tolwstów or tolwstów.

Kceysrnic composition eswicrs unions of an exaggerated procession.

Zsećbki, you have chosen this way according to the program and the demand for pcdswsnia.

In kcmpceycjsch fsrmscśutycznych niniśjseśgc wynslseku to podswsnis dousrnegc, podjęeykcwśgo, pcdskórnśgc, domięśniowśgo, dożylnśgo, miśjtcowśgo, dotcbswiczcgc, wcwnątrznosowcgo, preśetkómcgo, doodbytniczśgo or śródocznśgo, tkłsdniki sktywnś of wzorzś (I) pcwyżśj, or możliwś Tolsa tolwsty or hydesty may be podswsnś in posrsci jśdncstkowycb form dswkowsnis, jsko tesnins with typical fsemscsutical zsróbksmi, ewiśreętom and Cełowickowi prcfiίsktycenic or in the above mentioned disorders or diseases. Odcwiśdnic jśdnottkowś dswski podswsnis ^ jmą ^ ą forms dls douttnśj, tskiś jsk tsblśtki, kspbudki żślsryncwś, pro $ eki, grsnulki and douttnś solutions or eswictiny, polygonal or photographic, photographic, photographic, photographic, or photographic, and pcdswsnis rectal forms. Dls stctcwsnis ties, relationships along the lines may be consistent in the pottsci of pimples, lipstick, lotions or eyewash liquids.

To create a desirable profiling or tsrspcutic product, the value can be between 0.01 and 50 mg ns kg.

You can take from 0.5 to 1000 mg, use from 1 to 500 mg, and use active ingredients in the month of September with a good price. Ts dswks jśdnostkows can be podswsns 1 to 5 rsey ns dogwood, tsk to calculate today's dose 0.5 to 5000 mg, 1 to 2500 mg.

When kompozycjs ttełs jśtt wytwsrzsns in pcsrsci rsblśrśk, the main skłsdnik sktywny jśtt mretzsny of esróbką fsrmscśutyceną, tską JSK żclstyną, skecbis, lsktozs, ttśsrynisn ​​msgnśzu, tslk, gums srsbtks or the like Tsbletki możns pcwlśksć tschsrozą using pochodnśj cślulozy or other cdpowiśdnicb msterisłów or sltśrnstywniś It is possible to process tsk, so that the bowls are stretched or delayed, and tsk, so that they continuously reflect a predetermined amount of tsc.

Prepsrst in pottsci kspbudśk żślsryncwych otreymuj thia emiśtesniś tkłsdniks sktywnśgc using roecreńceslniks and by sniś oteszymsnśj miśtzniny to kspbudśk żślsjny or twsrdśjny.

Prepsrst in pottsci tyropu or nslswki or dls podswsnis in pottsci drops, you can expressive tactile in combination with tubing, kcreyttniś tubttsncja lowktslcryceną, mctylcpsrsbśnmsmbspm, mctylcpsrsbśnmmyfm, mctylcpsrsbśnmbspm, mctylcpsrs.

Dytpirgowslnś in wodziś protzki or grsnulki can swivel the active tendency with a tensile or moisturizing agents, or agents forming a swish, such as polyvinylcpieolidone or tubular cortex.

For example, in the rectal, you need to create a set of suppositories, which are prepared using a binding tube that melts the body in the rectum of the rectum, e.g.

For example, you can use a water-based solution, isotonic acid solutions or injectable solutions, and use a suitable method of mixing and / or wetting, e.g. propyl glycol or glycol.

187 093

The active ingredient may also be formulated as mirocapsules, optionally with one or more excipients or additives, or alternatively with matrices such as a polymer or cyclodextrin (patch or slow release compositions).

The compositions of the invention can be used in the treatment or prevention of various vasopressin or oxytocin mediated conditions and disorders of vasopressin or oxytocin secretion, cardiovascular disorders such as hypertension, pulmonary hypertension, heart failure, circulatory failure, myocardial infarction, atherosclerosis or arteriosclerosis coronary artery, especially in smokers, unstable angina and PTCA (transcutaneous clear coronary angiopyasty), cardiac ischemia, disorders of hemostasis, especially haemophilia, or von Wiliebrand syndrome; central nervous system disorders, migraine, cerebral vasospasm, cerebral hemorrhage, cerebral edema, depression, anxiety, bulimia, psychotic states or memory impairment, e.g. renal pathology and dysfunction such as edema, renal vasoconstriction, renal cortex necrosis, nephrotic syndrome, hypokalemia, diabetes mellitus, Schwartz-Bartter syndrome, or nephrolithiasis; gastric complaints such as gastric vasospasm, cirrhosis, ulcers, vomiting pathology, e.g. nausea, including nausea induced by chemotherapy, seasickness, and or alternatively, syndrome of inappropriate antidiuretic hormone secretion (SIADH), diabetes insipidus and enuresis; hepatic complaints such as cirrhosis of the liver; ascites and all disorders causing abnormal water retention, disorders of the adrenal gland (Cushing's disease), in particular excessive secretion of adrenocortical hormones and hyperaldosteronaemia. The compositions according to the invention can also be used in the treatment of sexual behavior disorders, excess weight and obesity, preferably replacing conventional diuretics already used in this indication. In women, the compositions of the invention can be used to treat dysmenorrhea or premature labor. The compositions of the invention can also be used in the treatment of lung cancer, encephalopathies associated with low sodium blood, Raynaud's disease, Manner's syndrome, pulmonary syndrome, glaucoma and cataract prevention, and in postoperative treatment, especially after abdominal, cardiac or haemorrhagic surgery.

The compositions of the present invention may contain, in addition to the products of formula (I) above or their pharmaceutically acceptable salts, solvates or hydrates, other active ingredients which can be used in the treatment of the disorders or diseases indicated above.

Thus, another object of the present invention are pharmaceutical compositions containing a combination of a number of active ingredients, one of which is a compound of the invention.

Thus, pharmaceutical compositions of the present invention can be prepared containing a compound of the invention in combination with a compound that acts on the reninangiotensin system, such as an enzyme conversion inhibitor, angiotensin II antagonist or renin inhibitor. The compound of the invention may also be combined with, for example, a peripheral vasodilator, calcium inhibitor, β-blocker, α-blocker, or diuretic. Such compositions will be useful especially in the treatment of hypertension or heart failure.

Two compounds of the invention can also be combined: a specific Vi receptor antagonist with a specific oxytocin antagonist, or a Vj antagonist and a V2 antagonist or a V2 antagonist and a Vj agonist.

The compositions of the present invention preferably contain a product of formula (1.2), (1.3) or (1-4) as defined above or one of its pharmaceutically acceptable salts, solvates or hydrates. Each of these compounds can also be combined with a specific angiotensin II antagonist, preferably irbesartan.

These combinations make it possible to enhance the therapeutic effect of the compounds according to the invention.

The following Preparatory Examples and Examples illustrate the invention without, however, limiting it.

Nuclear magnetic resonance spectra were performed in DMSO-d6 at 200 MHz unless otherwise stated, and chemical shifts are given in ppm.

187 093

The following abbreviations are used, s = singlet m = multiplet t = triplet q = quintuplet

Preparatory Example I.

Alcohols of formula (VI)

5-Ethoxy-3-spiio- (4-hydroxycyclohexado) idolid-2-one.

Union (VI. I)

A solution of 22 g of 5-ethoxy-3-spiro- (4-methoxymethyloxycyclohexane) iddolid-2-odium prepared according to EP 636,608 in 30 ml of methanol and 9 ml of concentrated hydrochloric acid (36%) was heated at 40 ° for 3 h. the reaction mixture was cooled and the precipitate formed was then subsequently filtered off, washed with diethyl ether and dried to obtain the polar isomer of the expected product; Mp = 225 ° C. 50 ml of water are added to the filtrate and then, successively, methanol is evaporated off, extraction is performed with dichloromethane, the organic phases are washed with water, dried and evaporated to give the expected product in the form of a mixture of isomers; Mp = 170 ° C.

5-Chloro-3-seiio- (4-hydroxycyclohexado) iddolid-2-od.

Relationship (VI. 2)

The preparation is carried out according to the same procedure as above from 5-chloro-3-seii- (4-methoxymethyloxy-cyclohexadium) -iddolide-2-ode prepared from 5-chloroindolin-2-one according to the method described in EP 636,608. The expected product is isolated after extraction with dichloromethane in the form of a mixture of isomers; Mp = 260 ° C.

Preparatory Example II

Ketones of formula (V)

5-Ethoxy-3-spπΌ- (4-oxocyclohexado) idolid-2-od.

Union (Vl)

3.8 g of 5-ethoxy-3-spiro- (4-hydroxycyclohexane) indolide-2-odium (VI. I] (mixture of isomers) and 5.8 ml of pyridine were dissolved in 250 ml of ethyl acetate and 6.3 g of chlorochromate was added Then, the reaction mixture was stirred at 25 ° C for I6 h, filtration was performed and the solvent was evaporated from the filtrate. 3.4 g of the expected product was isolated after recrystallization from toluene in the presence of active carbon; and 68 ° C.

5-Chloro-3-spiro- (4-oxocyclohexado) idolid-2-Od.

Relationship (V.2)

This compound is produced according to the same procedure as for the preparation of compound (VII) from 5-chloro-3-spiro- (4-hydroxycyclohexane) indolide-2-ode (VI.2); T. m.p. = 220 ° C.

Preparatory Example III

Acetals of formula (IV)

5-Ethoxy-3-spiro- [4,4-di (2-chloroethyloxy) -cyclohex &amp; no] id-2-drolide.

Compound (IV. I) g 5-ethoxy-3-spii- (4-oxocyclohexadium) and dolid-2-odium (Vl) was dissolved in 30 ml of toluene and 4.6 ml of 2-chloroethanol, 20 g of molecular sieves 5A and 0 , 22 g of methanesulfonic acid. The reaction mixture was slowly stirred for 8 h at 20 ° C, then filtration was performed and the molecular sieves were washed with dichloromethane. The solvent is evaporated off and the expected product is crystallized from diethyl ether; T. m.p. = i70 ° C.

-Ethoxy-3-spiro- [4,4-di (3-chloriopropyloxy) -cyclohexadium] id-2-dolide.

Relationship (IV.2)

The production is carried out according to the same procedure as for the preparation of compound (IV.i) from the same ketone (Vl) and 3-chloiopyopnool; T. m.p. = i47 ° C.

5-Chloro-3-spiro- [4,4-di (2-chloroethyloxy) -cyclohexane] id-2-drolide.

187 093

Relationship (IV.3)

The production is carried out according to the same procedure as for the preparation of compound (IV. 1) from compound (V.2) and 2-chloroethanol; T.topn. = 174 ° C.

Preparatory Example IV

Derivatives of formula (III)

5-Ethoxy-3-spiro- [4- (3-chloropropyloxy) -cyclo (exano] indolin-2-one (mixture of isomers).

Relationship (III. 1)

2.2 ml of 0.29M zinc borohydride solution in dirty ether (vym^worzony according to the method described in Chem. Pharm. Bull., 1984, 32 (4), 1411-1415) was slowly added at 0 ° C to 0.55 g of acetal (IV, 2) in 3 ml of dichloromethane, and then 0.34 ml of trimethylchlorysilane was added. The reaction mixture was stirred for 16 h at 20 ° C and then, successively: 10 ml of a saturated NaHCO3 solution were added, extraction was performed with ethyl acetate and the organic phases were washed with a saturated NaCl solution. After drying over MgSO4 and evaporation, 0.4 g of an oil is isolated, which is chromatographed on silica gel, elution being carried out with an 8/2 (v / v) cyclohexane / ethyl acetate mixture. The expected product is isolated (mixture of isomers) in the form of a resin.

1 H NMR, CDCl 3, 200 MHz: 7.75 (s, 1H), 7.03 (d, 0.25H), 6.83 (d, 0.75H), 6.79-6.65 (m, 3H ), 4.06-3.9 (q, 2H), 3.72-3.58 (m, 4H), 3.54-3.50 (m, 1H), 2.18-1.53 ​​(m , 10H). 1.37 (t, 3H).

5-Ethoxy-3-spiro- [4- (2-chloroethyxy) -cyclohexane] indolm-2-one (mixture of isomers).

Relationship (III.2)

The production is carried out according to the same procedure as for the preparation of compound (III. 1) from compound (IV. 1).

'HNMR, CDCl3, 200 MHz. 8 (s, 1H), 6.85-6.63 (m, 3H), 4.03-3.93 (q, 2H), 3.81-3.74 (m, 2H), 3.70-3. 58 (m, 3H), 2.21-1.55 (m, 8H), 1.4 (t, 3H).

-Chloro-3-spiro- [4- (2-chloroethyxy) -cycluhyxane] indolin-2-one (mixture of isomers).

Zwiąrek (III.3)

The production is carried out according to the same procedure as for the preparation of compound III. 1 from the relationship (IV.3).

1 H NMR, DMSCkd6 200 MH_with. 10.49 (s, 0.25H), 10.39 (s, 0.75H), 7.40 (s, 1H), 7.21-7.16 (d, 1H), 6.81-6, 77 (d, 1H), 3.7 (m, 4H), 3.55 (m, 1H), 1.96 (-1.61 (m, 8H).

5-Ethoxw-3-spir- [4- (2-tosyloxvtyloxy) -cyclohexane] indolm-2-yn.

The union (III.^pand.

17.97 g of tosyl chloride were added at 0 ° C to 19.25 g of the compound (III'1) described in Preparation X in 130 ml of pyridine. The reaction mixture was stirred at 20 ° C for 3 h and poured into 650 ml of water and then stirred for 30 min. 28.0 g of the spy product were isolated after filtration, washing with water and drying at 40 ° C under reduced pressure in the presence of phosphoric anhydride. Product obtained from the polar isomer (ΠΓ! To s s ^ at 152 ° C.

Preparatory Example V

Derivatives of formula (II A)

S ^ h ^ ye 1 - Η- (Ν-tert-butylcarbamoyl) -2-mrtyxybenuene-sulfonyly] -3-spiro- [4- (2-chlororyeΐy] oxy) -cyclohexane] -in0ylin-2-one (mixture of isomers ).

Relationship (HA.l)

0.29 g of potassium tert-butoxide was added to a solution cooled to -60 ° C.^atbrburnosuifonyl in 90 ml of tetrahydrofuran. The mixture was allowed to increase the temperature to 20 ° C, washed for 2 h, then 30 ml of 15% NaCl solution was added and, successively, extraction was performed with ethyl acetate, the organic phases were washed with 15% NaO solution, the organic phases were added to MgSO₄, drawing⁹ about^atrrrało and other figures^at0ano cUromatogra^ANDii on cryeminic gel, at the Nwmywanig connection, was carried out with a mixture of 85/15 (v / v) of kaklyhexfn^/ethyl octane, Nyo isolating the expected product in the form of a resin.

187 093 'H NMR, DMSO-d6 200 MHz. 8 (m, 2H), 7.5 (m, 3H), 7.04 (s, 0.75H), 6.85 (m, 1.25H), 4.0 (q, 2H), 3. 6 (s, 3H), 3.66 (s, 4H), 3.58 (s, 3H), 3.5 (m, 1H), 1.9-1.6 (m, 8H), 1.34 (s, 9H). 1.28 (t, 3H).

5-Ethoxy-1- [4- (N ', N'-diethylureido) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2-tosyloxyethyloxy) -cyclohexane] -indolin-2-one.

Relationship (II A.2)

0.25 g of tosyl chloride was added at 0 ° C to a solution of 0.18 ml of thiriethylamine and 0.25 g of 5-ethoxy-1- [4- (N ', N'-diethylureido) -2-methoxybenzenesulfonyl] -3-spiro - [4- (2-hydroxyethyloxy) -cyclohexane] indolin-2-one (prepared in EP 0.636.608) in 3 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred for 48 h at 20 ° C, 10 ml of a saturated NaHCO 3 solution was added, followed by extraction with ethyl acetate successively, the organic phases were dried over MgSO 4, the solvent was evaporated and the residue was chromatographed on silica gel; eluent: 99/1 (v / v) mixture then 95/5 dichloromethane / methanol; Mp = 80 ° C.

5-ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2-tosyloxyethyloxy) -cyclohexane] -indolin-2-one.

Relationship (II A.3)

The expected product is isolated in a similar manner as in the preparation of compound (II A.2) starting from 5-ethoxy-1- [4- (2-hydroxyethyloxy) -cyclohexane] indolin-2-one or by treating 4- (N- tert-butylcarbamoyl) -2-methoxybenzenesulfonyl reaction with a compound (III.4) under the conditions described for the preparation of compound (IIA. 1); Mp = 142 ° C.

Preparatory Example VI

Alcohols of formula (II'A)

-Ethoxy-3-spiro- [4- (2-hydroxyethyloxy) cyclohexane] -1 - [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

Union (II'A.1)

a) 5-Ethoxy-3-spiro- [4- (2-nitrooxyethyloxy) -cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

Union (II'A.1)

A mixture of 0.6 g of the compound (II A.1), 0.8 g of silver nitrate and 0.25 g of sodium iodide in 10 ml of acetonitrile was refluxed for 48 h. The salts were separated by filtration and the solvents were evaporated. The expected product is isolated by chromatography on silica gel, elution being carried out with a 80/20 (v / v) cyclohexane / ethyl acetate mixture; Mp = 80 ° C (hydrate).

b) 0.5 g of the above nitrate, 0.5 ml of cyclohexene and 0.5 g of 10% palladium on carbon was heated under reflux for 1 h in 15 ml of ethanol, the catalyst was then separated by filtration, the solvent was evaporated and the residue was chromatographed on silica gel , elution being carried out with dichloromethane and then with a 99/1 (v / v) mixture of dichloromethane / methanol. The mixture of isomers of the expected product was isolated (T. mp = 120 ° C (hemihydrate)), then the polar isomer which was crystallized from a mixture of isopropyl ether and ethyl acetate (1/1; v / v); Mp = '89 ° C (hydrate).

* 5-ethoxy-3-spiro- [4- (3-hydroxypropoxy) -cyclohexane] -1 - [4- (N-tert-amylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

Union (II'A.2)

a) 5-Ethoxy-3-spiro- [4- (3-methoxymethyloxypyOpyloxy) -cyclohexane-1- [4- (N-tertamylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

5-Ethoxy-3-spiro- [4- (3-methoxymethyloxypropoxy) -cyclohexane] indolin-2-one (III'A.1) from Preparation X was condensed with N-tert-amylcarbamoyl-2-methoxysulfonyl chloride according to the procedure described in in preparatory example V, giving the expected product, used immediately in the next step.

b) A mixture of 0.5 g of the compound prepared in a) in 1.5 ml of methanol and 0.2 ml of concentrated hydrochloric acid (36%) was heated at 50 ° C for 1 h. 5 ml of water was added, extraction was performed

187 093 with ethyl acetate, the solvents are evaporated off and the expected product is isolated after chromatography on silica gel, elution being carried out with a 1/1 (v / v) cyclohexane / ethyl acetate mixture; Mp = 120 ° C.

Preparatory Example VII

Indolin-2-one of the formula (II.B)

5-Chloro-3-spjro- [4- (2-morpholyethyloxy) -cyclohexane] -indolin-2-one (mixture of isomers).

Relationship (II B.1)

A mixture of 0.57 g of the compound (III.3), 0.5 g of morpholine and 0.27 g of NaJ in 6 ml of dimethylformamide was heated for 24 h at 85 ° C. 10 ml of water and 10 ml of a saturated NaHCO3 solution were added to the reaction mixture, then, successively, extraction was performed twice with ethyl acetate, the organic phases were dried over MgSO₄, the solvent is evaporated off and the residue is chromatographed on silica gel, elution with dichloromethane and then with a 98/2 (v / v) dichloromethane / methanol mixture, isolating 0.5 g of the expected product in the form of an oil.

1 H NMR. 10.4 (s, 1H), 7.4 (s, 1H), 7.2 (d, 1H), 6.8 (d, 1H), 3.6 (m, 7H), 2.4 (m , 6H), 1.9-1.6 (m, 8H).

5-Ethoxy-3-spjro- [4- (2-N-tert-butyloxycarbonyl-N (benryloxycarbonylmethyl) -amino) ethyloxy) -cyclohexane] indolm-2-one (mixture of isomers).

Relationship (II B.2)

1.5 g of tosylate (III.4) (mixture of isomers), 0.66 g of benzyl glycinate hydrochloride and 0.35 g of sodium carbonate in 80 ml of acetonitrile was heated at 60 ° C for 48 h. The solvent was evaporated under reduced pressure, the residue was dissolved in 40 ml of ethyl acetate, the organic phase is washed with water and dried over Na2SO₄ and the solvent was evaporated. The residue is chromatographed on silica gel, elution with a 99/1 (v / v) mixture of dichloromethane / methanol is carried out and the gum is isolated and dissolved in 20 ml of dioxane. 0.13 g of MgO and 0.539 g of di-tert-butyl dicarbonate dissolved in 10 ml of dioxane at 5 ° C were added and the reaction mixture was stirred at 20 ° C for 16 h. The solvent is evaporated off, the residue is dissolved in ethyl acetate, the organic phase is washed successively with a buffer solution of pH = 2, with a saturated solution of sodium hydrogen carbonate and with water.

Drying was done over Na2SO₄ and the solvent was evaporated. After purification by chromatography on silica gel, eluting with a 5/5 (v / v) ethyl acetate / cyclohexane mixture, the expected product is obtained in the form of a gum.

Ή MNR. 10.12 (s, 0.3H); 10.03 (s, 0.7H); 7.30 (m, 5H); 6.88 (d. 1H); 6.70 (d, 2H); 5.14 (s, 0.7H); 5.12 (s, Iu 0.3H); 4.05 (m, 2H); 3.95 (q, 2H); 3.3 to 3.6 (m, 5H); 1.4 to 2.1 (m, 8H); 1.2 to 1.4 (m, 12H).

5-Ethoxy-3-spiro- [4- (2-N-tert-butyloxycarbonylamino) -ethyloxy) -cyclohexane] indolin-2-one.

Union (II B.3)

a) 5-ethoxy-3-spiro- [4- (2-aminoethyloxy) cyclohexane] indolin-2-one.

A mixture of 1.5 g of the compound (III.4) (obtained from the polar isomer (III'1) and 0.23 g of sodium azide in 15 ml of dimethylformamide was heated at 50 ° C for 16 h. 30 ml of water was added, extraction was performed with acetate twice. The organic phases were dried over NaSO 4, the solvent was partially evaporated in vacuo to a volume of about 20 ml. Said solution was hydrogenated at 60 ° C and a pressure of 10 ml.⁶ Pa in the presence of 0.6 g Lindlar catalyst (palladium on CaCOs). The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue is chromatographed on a silica gel column, elution with a 90/10 (v / v) dichloromethane / methanol mixture. The hydrochloride-hydrate of the expected product is isolated after recrystallization of the base in ethyl acetate and then it is hydrochloricated in ethyl acetate, m.p. = 168 ° C.

187 093

b) 0.4 ml of 4N W2dorotleoku eoku, 0.05 g of magnesium tissue, 19 g of di-tert-butyl carbonate dissolved in 7 ml of dioxane were successively added at about + 5 ° C to 0.27 g of the previous compound in 20 ml of dioxane. After stirring for 2 h at 20 ° C, the solvent is evaporated off and then the residue is dissolved with ethyl acetate, the organic phase is washed successively with a buffer solution of pH - 2, saturated sodium hydrogen carbonate solution and water. Drying is done on Na2SO4, the solvent is evaporated off and the expected product is isolated in the form of a gum.

1 H NMR. 10.02 (s. 1H); 6.91 (s. 1H); 6.68 (s. 2H); 3.92 (q, 2H); 3.55-3.35 (m, 3H); 3.05 (m, 2H); 2.05-1.45 (m, 8H); 1.36 (s, 9H); 1.27 (t, 3H).

Preparatory Example VIII

Hydrazides of formula (VII)

N '- (4-Ethoxyfeoyl) -4,4-ethyldeioxycyclohexaoo) -carbohydrazide.

Relationship (VII. 1)

1.65 ml of isobutyl chloroformate at -40 ° C were added to a mixture of 2.63 g of sodium 4,4-ethylenedioxycyclohexanone in 20 ml of tetrahydroxyrofiber, followed by 1.8 ml of methylamine. The reaction mixture was stirred for 2 h at 0 ° C, then 0 ° C at -20 ° C with 2.4 g of 4-ethoxyphenylhydramide hydrochloride, the reaction mixture was stirred for 2 h at 0 ° C, then 0 ° C 100 ml of water and extraction was performed with ethyl acetate. The organic phases were washed successively with water, with KHSO4 solution (pH 2) and saturated potassium carbonate solution, dried over and evaporated. The expected product is obtained after crystallization from diethyl ether; Mp = 158 ° C.

N'-phenyl-4,4-ethylene0ioksycykloheksanokarbohy0razy0.

Union (VII.2)

Similarly, compound (VII.2) was isolated from phenylhydrazine. Mp = 158 ° C.

Preparatory Example IX

Acetals of formula (IV ')

5-Ethoxy-3-spiro- (4,4-ethyloxy-oxycyclohexane) -in0olin-2-one.

Relationship (IV. 1)

2.15 ml of a 1.6 M solution of butyl lithium in hexane were added at -50 ° C to a suspension of 1 g of hydrazide (VII. 1) in 16 ml of tetrahydrofuran. The reaction mixture was stirred for 15 min and then 16 ml of tetralin were poured. The tetrahyrof5rao was distilled off and heated at 180 ° C for 45 min. 20 ml of ethyl acetate were added at room temperature, followed by successive washing with water, the organic phase was dried over MgSO4, the solvents were distilled off under reduced pressure and the residue was chromatographed on silica gel, elution being carried out with a 7/3 (vol. (v / v) cyclohexane / ethyl acetate. The expected product is isolated by crystallization from diethyl ether; T. m.p. = 183 ° C.

The same product was also obtained by the reaction of 5-ethoxy-3-spiro- (4-oxocycohexane) 10oI10-2-one (Compound V.1) with ethylene glycol in cyclohexane in the presence of molecular sieves and a catalytic amount of para-toluoosiphonic acid.

5-Ethoxy-3-spiro- (4,4-propylene-oxycyclohexaoo) -indolin-2-one.

Union (IV'.2)

The preparation is carried out according to the same procedure described above for the preparation of compound (IV11) from the appropriate hydrazide or by reactions 5-ethoxy-3-spiro- (4-oxocyclohexane) iodolin-2-oo5 (Compound (V.1)) with 1, 3-propanediol in cyclohexane in the presence of 5A molecular sieves and catalytic amounts of parαtoiueoosulfoweko acid; Mp = 216 ° C.

3-Spiro- (4,4-ethylene-oxycyclohexane) mdolm-2-oo.

Union (IV'.3)

The preparation is carried out according to the same procedure as above for the preparation of compound (IV '. 1) starting from the corresponding hydrazine (VII.2), Mp = 218 ° C.

Preparation example X

Alcohols of formula (III ') and (III' P)

5-Ethoxy-3-spiro- [4- (2-hydroxyethyloxy) -cyclohexaoo] -inoolin-2-one.

187 093

Relationship (III'.1)

20.2 ml of a 0.25 M solution of zinc Z4rowudorZ4 in the heart 1ο1: ο1ο \ ο&gt; οτι (produced according to the method described in Chem. Pharm. Bull., 1984, 32 (4), 1411-1410) was added slowly at 0 ° C About 3.1 g of acetal IV. 1 in 20 ml of dichloromethane, then 2.8 ml of t (imstyl 4-pyl chloride. The reaction mixture was stirred for 16 h at 20 ° C, then 20 ml of a saturated NaHCO3 solution were added and the solvents were successively evaporated, extraction was performed with ethyl acetate, dried over MgSO 3, the solvent was evaporated and the residue was purified by silica gel chromatography, elution by 67/34 (4b / 4bj) cyclohexane / ethyl acetate mismixture. The mixture of isomers of the expected product was isolated, and then the polar isomer which was crystallized from ethyl ether; Mp = 120 ° C.

S -Etokpo-3-ppir4- [4- (3 -hoOroksopropyl4kpy) -coklobsnsαno-inO4lin-2-one.

Relationship (III'.2)

The production was carried out according to the same procedure as above for the preparation of compound (III '. 1) from acetal (IV.2). The polar isomer of the expected product was obtained; T. m.p. = 180 ° C (bibydrate).

0 (Etonsy-3 (Spir4-t4 ((3 (met4k [imsypropylonsy) -cinl4benpane-inoolin-2 (On. Compound (III'.2P)

Solution 1 g of 0 (et4npy-3-spi (O (te-k3-hydronsypropyloxy) -cyclohexane-inoolin-2-4nu (III'.2), 7.7 ml of dimot4npymstαnu, 0.06S g LiBr and 0.07 g parat4lkenesulfonic acid in 1S ml of Oicbl4r4mstαnu was stirred for 24 h at room temperature and 10 ml of saturated NaCl solution were added. The organic phase was separated and the 4pupz4n4 phase over MgSO4, and the solvent was distilled off to obtain, after chromatography on silica gel, a polar isomer of the expected product, elution being carried out with a 1/1 (v / v) cycl4hskpan / 4-ethyl acetate mixture; Mp - 89 ° C

Preparatory Example XI

Protected alcohols of formula (X)

0-Et4xy (3-spir4- (4-meth4npymstyloxycycloxano) -1-t4- (N (tert-butylca (bamoyl4) -2 (mst4npybsnzonosulfonyl-inOolin-2 (On.

Relationship (X.1)

0.283 g of potassium tert-butoxide was added Oo 4cb4Ozoneg4 to -40 ° C, a solution of 0-st4xy-3 (-spir4- (4-methpymotyl4npycycle4benpαno) ind4lin (2 (4num (Compound by formula (XI)), prepared according to EP 636,608, in 80 ml of tetraO (4-furan. The mixture was allowed to raise the temperature to 0 ° C, then αs4Oz4n4 to -40 ° C. in 7 ml of tetrαbyd (ofurαnu. The reaction mixture was stirred for 2 h at room temperature, then 20 ml of water were successively added, extraction was performed with acetates, dried over MgSO 4, the solvent was evaporated and the oil obtained was purified by chromatography on silica gel, elution being carried out with a mixture of 8 / 2 (v / v) cyclohoxane / ethyl acetate. The least polar isomoms of the expected product were separated; Mp = 16 S ° C, then the polar isomer; Mp = 1S6 ° C.

Preparatory Example XII

Alcohols of formula (IIc)

S (Et4xy-3-ppir4 ((4 (byrocepycycle4hexane) -1 (te (kN-tsrt-butylO (nα (bamoyl4) -2-mstO ((k [ybenzenesulfonyl] inOolm-2-one.

Relationship (IIc. 1)

A mixture of the polar isomer of compound (X.1) in 1.2 ml of methanol and 0.24 ml of concentrated hydrochloric acid (36%) was heated at S0 ° C for 1 h. successively, extraction is performed with dichloromethane, the organic phases are dried over MgSO4 and the solvents are evaporated off.

The expected product is obtained after purification by chromatography on silica gel, elution being carried out with dichloromethane; Mp - 268 ° C (polar isomso).

187 093

In this way, from the same Polish and developed by (X. 1), the most important Polish isomśr of the product was distinguished; Mp = 130 ° C (hmihydrst). Compound (IIc.2).

Preparatory Example XIII

Substest o formula (2)

2-m-tocty-4-N-tert-smyloxrbsmoyl benzoyl chloride.

Subttrst (2) .1

s) N-tet-smyl-3-metckty-4-nitecbcnzsmid ml of tsrt-smylosmin is added at 10 ° C to a solution of 27 g of 3-methoxy-4-nitrobinzooyl chloride (ctreymsny with 25 g of the present acid and thionyl chloride in preheated Wreśnis preśe 4 h, s nsecrets, reprocessing under reduced pressure) in 250 ml of dichlcrcmsn. Teddy bear for 30 minutes at 20 ° C, for another 100 ml of a 1N solution of sclnski, an orgasmic freshen for a spiney mouthful, washing and drying it with MgSO, an exuberant and deliberate delicacy. to give 31 g of the same product; Mp = 65 ° C.

In this way, from N-tet-butylsmine, N-tet-butyl-3-meroxic-4-nitrobenzmid; Mp = 180 ° C.

b) N-tert-smylo-3-mśtokty-4-sminobcnzsmid

Mtshine 31 g of N-tert-smyl-3-nitrobenzmide will be obtained in s), 20 g of 10% psllsdu ns carbon and 76 ml of cyclchsnol in 310 ml of meshesnol was heated at a temperature of 3 h. g of the product spode; Mp = 108 ° C.

In this way, from the N-tert-butyl-3-methoxy-4-nitrobenzmide compound, the N-tert-butylc-3-tert-butylc-3-tert-butyl-4-sminobacterium compound; Mp = 160 ° C.

c) 2-mtocty-4-tert-smylcksulfonyl dense sulfonyl chloride.

A solution of 7.9 g of thodium shotite in 31 ml of water was added at 0 ° C to a solution of 25 g of N-tcrtimyl-3-methanes-4-sminobutzsimide in 103 ml of acetic acid and 187 ml of 36% potassium acid. The mixture is blended for 1 h at 0 ° C, there is a preechoic solution at 0 ° C, and 6.8 g of copper chloride in 25 ml of water and 140 ml of cctcwsgc acid at about 0 ° C at about 0 ° C dwurlśnku tisrki. The meat must be eaten at 0 ° C for 3 hours, then at 20 ° C for 16 hours, and 750 g of ice have been obtained, and for 1 hour at 20 ° C. The precipitated ODS was filtered off, then premixed with water and dried in vacuo for 48 hours, yielding 19 g of the final product; T. m.p. = 104 ° C.

4-N-tert-butyloxy-sulfonyl chloride.

Substrate (2) 2

In the tsn ssm, from N-tert-buryl-3-mtstckty-4-smmcbśnzsmidu, a spine subttrst was distinguished; Mp = 148 ° C.

3-mtcty-4-bischyloctyxrbcnylcbśnzcnculfcnyl chloride.

Substrate (2). 3

Using this reaction from the bsnzyl acid of 4-smino-3-mtoxybcneccscwcgo (T. mp = 72 ° C, ueysxnśgo from the reduction cdpcwicdniśj nitrcwśj with tin in the environment of sqcsu = 88 ° Ctclnc). the spodzisny tubstrst was distinguished; Mp = 55 ° C.

N-tcrt-butylc-4-bromomethyl-3-mcroxybshmid.

Substrate (2). 4

Mtshsnine 3 g of N-tert-butyl-4-propoxy-3-mtoxybspmide, 2.4 g of N-beomotuccinimide and 0.16 g of bcnzoyl tetrachloride in 40 ml of carbon tetrachloride at 30 ° C with a 48 hiss of whistle. Rceputeczslnik wypsrowsno, s nsrowsno, s nssnc, kotej ^, add 25 ml of water, dtetyl paste, dtetyl paste, MgSOa, manual cdpsrcwsnc, cyclohśkssn / octsn

187 093 ethyl. The expected starting material is isolated after crystallization from isopropyl ether; T. m.p. = 114 ° C.

Example 1

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2morpholinoethyloxy) cyclohexane] indolin-2-one.

(Γ): Ri = 5-OC₂H.₅; R₃ = 2-OCH3; W = SO₂;

R4 = 4-CONHC (CH₃)₃;

Z = -ch, ch₂Least polar isomer.

A mixture of 0.6 g of the chlorinated derivative (IIAi) obtained according to Preparation V, 0.26 g of morpholine and 0.15 g of sodium iodide in 6 ml of dimethylformamide was heated at 60 ° C under an inert atmosphere for 40 h. The solvent was evaporated under reduced pressure, and then, successively, the residue was dissolved in 20 ml of 5% aqueous NaHCO3 solution, extraction was performed with ethyl acetate, the organic phases were washed with 10% NaCl solution and dried over MgSO4, the solvent was evaporated and the resin was separated and chromatographed. on silica gel, elution being carried out with a 98/2 (v / v) mixture of dichloromethane / methanol.

The least polar isomer of the expected product was isolated (Rf = 0.5; TLC (silica); 95/5 (v / v) dichloromethane / methanol). The fumarate was prepared in acetone and crystallized from diethyl ether; Mp = 53 ° C (example 1).

Ή NMR, DMSO-d6 200 MHz. 8.0 (m, 2H), 7.5 (m, 2H), 7.4 (s, iH), 6.88 (d, iH), 6.82 (s, iH), 6.6 (s , 2H, fumaric acid), 4.0 (q, 2H), 3.6 (s, 3H), 3.55 (m, 7h), 2.45 (m, 6H), 2-, 4 (m, 8H). i. 34 (s, 9H). i. 3 (t, 3H).

Example 2

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybedzedosulfodyl] -3-seiro- [4- (2-morpholidoethyloxy) -cyclohexado] id-dolide-2-d.

(I '): Ri = 5-OC2H5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3 z = —ch₂ch₂The most polar isomer.

The most polar isomer of the product obtained in the Example above and isolated under the conditions given above; Rf = 0.43; Mp = 21-2 ° C -2-16 ° C.

1 H NMR, DMSO-P6 200 MHz. 8.0 (m, 2H), 7.5 (m, 2H), 7.4 (s, iH), 7.03 (s, iH); 6.84 (d, iH), 6.6 (s, 2H, fumaric acid), 4.0 (q, 2H), 3.6 (s, 3H), 3.5 (m, 6H), 3.40 (m, iH) , 2.45 (m, 6H), i, 9- i, 6 (m, 8H), i, 34 (s, 9H), i.

The fumarate was prepared in acetone and crystallized from diethyl ether; T. m.p. = i72 ° C (example 2).

Monohydrated diorophosphate was prepared by reacting modohydrate phosphoric acid with a base in ethanol; Mp = i70 ° C. The nitrate was prepared by reacting an aqueous solution of nitric acid with the base in ethanol; T. m.p. = i55 ° C.

Example 3

5-Ethoxy-i- [4- (N ', N'-diethylureido) -2-methoxybedzedosulfodyl] -3-seiro- [4- (2-dimethylamidoethyloxy) -cyclohexadium] id-dolid-2-od.

(I '): Ri = 5-OC2H5; R3 = 2-OCH3; W = SO2;

187 093 _/^C.2^H.SZ^C.2^H.5

R₄ = 4-NHCONC; T - Z = -C ^ CIŁ, c₂h₅ c₂h₅

A mixture of 0.23 g of the tosylated derivative (II A.2) obtained according to Preparation V above in 3.3 ml of acetonitrile and 0.23 ml of 40% aqueous dimethylamine solution was stirred for 48 h at 20 ° C. 1 ml of a saturated NaHC solution (03) was added and, successively, extraction was performed with ethyl acetate, dried over MgSO4, the solvent was evaporated and the residue was chromatographed on silica gel, elution with a mixture of dichloromethane / methanol / aqueous ammonia (245/5 / 0.2 v / v / v); (Rf = 0.5; TLC (silica); 85/15/1 (v / v / v) dichloromethane- / methanol / aqueous ammonia); Mp = 103 ° C.

Example 4

5-Ethoxy-3-spiro- [4- (2-aminoethyloxy) -cyclohexane] -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one (mixture of isomers) .

(I): R1 = 5-OC2H5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3; TZ = -CH2CH2NH2

a) 5-Ethoxy-3-spiro- [4- (2-azidoethyloxy) -cyclohexane) - 1- [4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one (mixture of isomers) .

A mixture of 0.5 g of the chlorinated derivative (IIA. 1) obtained above in Preparation Example 5, 0.06 g of sodium azide and 0.126 g of sodium iodide in 5 ml of dimethylformamide was heated at 100 ° C under an inert atmosphere for 2 hours. 10 ml of water was added to the reaction mixture, then extraction was performed with ethyl acetate and, successively, the organic phases were washed with water, dried over Na2SO4 and the solvent was partially concentrated to a volume of 20 ml to obtain an azide solution which was used immediately in the next reaction.

b) The solution obtained in a) was hydrogenated at 40 ° C for 60 h under 10⁶ Pa in the presence of 0.2 g Pall &amp; lt; ± / CaCO3 (Lindlar's catalyst; 5% Pd). The catalyst was separated by filtration, the solvent was evaporated and the residue was chromatographed on a silica gel column, elution being carried out with an 8/2 (v / v) dichloromethane / methanol mixture. The expected product is isolated in the form of a base and a salt is formed with fumaric acid in acetone; crystallized from isopropyl ether and the expected product is obtained; Mp = 138 ° C (monohydrate).

In the same way, the polar isomer of the expected product, the hydrochloride hemihydrated, was isolated by the same steps from compound (II A.3), which melts at 174 ° C.

Example 5

5-Chloro-3-spiro- [4- (2-morpholinoethyloxy) -cyclohex; mo] -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

(T): R1 = 5-C1; R3 = 2-OCH3; W = S02

R = 4-CONHC (CH3) 3;

<img file="PL187093B1_D0021.tif" />

0.073 g of potassium tert-butoxide was added to a solution, cooled to -30 ° C, of ​​a solution of 0.21 g of the compound (HB. 1) obtained according to Preparation VII above in 24 ml of tetrahydrofuran. The mixture was allowed to warm to 0 ° C, then cooled to -40 ° C and 0.19 g of [2-methoxy-4- (N-tert-butylcarbamoyl)] benrensulfonyl chloride in 2 ml of tetrahydrofuran was added. The reaction mixture was then stirred for 2 h at 110 ° C, 15 ml of water was added, followed by successive extraction with ethyl acetate, dried over MgSO4, the solvent was evaporated and the residue was purified by silica gel chromatography, elution with dichloromethane followed by using a 96/4 mixture of dichloromethane / methanol. The polar isomer of the expected product was isolated and a salt was formed with fumaric acid in acetone. The fumarate was crystallized from isopropyl diether; T. m.p. = 107 ° C (trihemihydrate).

187 093

Example 6

5-Ethoxa-3-spiro- [4- (2-kαrboxyethyloxy) -cyclohexane] -1- [4- (N-trrh-fmalokαrbfmoyl) -2-methoxybenuenenesulfonal] indilin-2-one.

(Γ): Ri = 5-OC₂H.₅; R₃ = 2-OCH3; W = SO₂;

R f = 4-CONH-C-C₂H.₅; T - Z = -CH₂CH₂-COOH I ch₃ g of chromium oxide was added at 0 ° C to a mixture of 1.5 g of the compound (II'A.2) obtained according to Preparation VI in 9 ml of acetic acid and 10 ml of the Notes. The reaction mixture was stirred for 2 h at 00 ° C, 00 ml of water were added natively and, then, it was extracted with ethyl acetate, the organic phases were dried over MgSO4, the solvent was distilled off and the expected product was separated off after chrumftograpy. on silica gel, elution being carried out with a 99/1 (ob / v) dikhlyromethphn / methanol mixture; T. m.p. = 108 ° C (^ ζ ^ .Ο ^).

Example 7

5-Etokaa-3-spiru- (4-rthxacarbonalymrthaloxacyclohexa -) - 1 - [(4-N-tert-butalycarbfmuoyl-2-mrtukay) brnur-aulfunyl] indolin-2-one.

(I '): R' = 5-OC2H5; R3 - 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3; TZ = -CH2-COO-C2H5

0.47 g of 2,6-Oi-tert-butalypyridia, 0.54 g of silver trifluoromethphosphoniphin and then 0.27 ml of ethyl iodoacetate are added at 0 ° C to a solution of 0.75 g of 5-ethoxy-3-spiro ( 4-hydroxycyclohexane) -1- [4- (N-trrit-butalocarbamoyl) -2-mrtuxabrne-aulfonyl] molin-2-un (II.C1) n 30 ml of dichloromethane. The reaction mixture is stirred for 48 h at 20 ° C, and then, successively, the reaction mixture is filtered, evaporated and the expected product is chromatographed on silica gel, eluted with cyclohexane and then with a 20/80 (v / v) cyclohexane / dichloromethane mixture, and reclaiming iuopropa l; T. m.p. = 165 ° C.

Example 8

5-Ethoxa-3-apyro (4-carbocarbonyloxacyclohexif-) - 1- (4-N-tert-butylbamyoyl-2-mtokaabenze-aulyunyl) indolm-2-yn.

(I '): R' = 5-OC2H5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3; TZ = -CH2COOH

0.34 g of the treated product in Example 7 and 0.01 g of rara-tolurilosulfinob'egy acid in 3 ml of benzyl alcohol was heated to 65 ° for 16 hours. The solvent was evaporated, and then, in turn, 1 ml of water and 1 ml of saturation were added. NfHCO3 solution, extraction is performed with ethyl acetate, the solvent is evaporated off, and then 5 ml of isopropyl, 0.25 g of 10% palladium on carbon and 0.25 ml of cyclohexene are added. The reaction mixture was heated at 80 ° C for 3 h, then, successively, the reaction mixture was filtered, the catalyst was washed with methylene chloride, the solvents evaporated, and the expected product was separated and purified by chromatography on silica gel, whereby the NymwNan was carried out using a 98 / mixture. 2 (ybj./ybj.) OicUlyromrtfn / mrtanol. Part of the expected product rekrastflizuNano with a mixture 8/2 (v / v) isopropyl ether / ethyl acetate; T. top. = 175 ° C (hemiUaOrate).

Examples 9 to 23 of Table 1 below NytNF are according to Examples 1 to 8 above.

187 093

<img file="PL187093B1_D0022.tif" />

oh₃ ο-τ — from (I) v

<img file="PL187093B1_D0023.tif" />

^R«

Table 1

<td>Number example- order</td><td>^R1</td><td>in</td><td>R4</td><td>T.</td><td>with</td><td>Salt, Solvates (1)</td><td>T._vol, ° c</td>

<td> 9</td><td>-oc₂h₅</td><td>SO2</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)2-</td><td>Ol</td><td>1H₂ABOUT</td><td> 170</td>

<td> 10</td><td>Cl</td><td>so₂</td><td>-oh₃</td><td>- (ch₂)₂-</td><td>Ό</td><td>fumarate 1.5 H.₂ABOUT</td><td> 88</td>

<td> 11</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>^^^ • COOCA</td><td>fumarate 2 H.₂ABOUT</td><td> 160</td>

<td> 12</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>-CCH₂)₃-</td><td>Ό</td><td> -(3)</td><td> 80</td>

<td> 13</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₃-</td><td> '0</td><td>fumarate 2 H.₂ABOUT</td><td> 170</td>

<td> 14</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>-N (CH₃)₂</td><td>fumarate 1 H.₂ABOUT</td><td> 150</td>

<td> 15</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- {CH₂)₂-</td><td>Ό</td><td>fumarate 1 H.₂ABOUT</td><td> 110</td>

<td> 16</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- &lt;ch₂)₂-</td><td>rC -N 0 CH,</td><td>fumarate 1 H.₂ABOUT</td><td> 165</td>

<td> 17</td><td>-oc₂h₅</td><td>so₂</td><td>-CONH-C-CH, CH, 1 ^{2 3}ch₃</td><td>- &lt;ch₂)₂-</td><td>Ό</td><td> -</td><td> 65</td>

<td> 18</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td> '0</td><td>fumarate 1.5 H.₂ABOUT</td><td> 190</td>

187 093

<td>Number example- order</td><td>^R1</td><td>in</td><td>R4</td><td>T.</td><td>with</td><td>Salt, Solvates (1)</td><td>Tt, ° C</td>

<td> 19</td><td>-OC2H5</td><td>SO2</td><td>-CONHC (CH3) 3</td><td>- (CH2) 2-</td><td>Ό</td><td>fumarate 4 h₂about</td><td> 208</td>

<td> 20</td><td>-OC2H5</td><td>SO2</td><td>-CONHC (CH3) 3</td><td>- (CH2) 2-</td><td>en, -N— | CHj)₂OH</td><td>fumarate 1 H.₂O (2)</td><td> 104</td>

<td> 21</td><td>-OC₂H.₅</td><td>SO2</td><td>-CONHC (CH3) 3</td><td>- (CH₂)₂-</td><td>CH, 1 N-iCH ^ OCHs</td><td>fumarate 1.5 H.₂ABOUT</td><td> 100</td>

<td> 22</td><td>-OC2H5</td><td>SO₂</td><td>-CONHC (CH3) 3</td><td></td><td>ABOUT</td><td>two things wian 1H₂about</td><td> 224</td>

<td> 23</td><td>-OC2H5</td><td>SO2</td><td>-CONHC (CH3) 3</td><td>- (CH2)₂-</td><td>-N-ICHjCHżOCH,) t</td><td>fumarate 1 h₂about</td><td> 98</td>

<td> 24</td><td>H.</td><td>so2</td><td>-CONHC (CH3) 3</td><td>- (CH2) 3-</td><td>COOH</td><td></td><td> 183</td>

<td> 25</td><td>Cl</td><td>so »2</td><td>-CONHC (CH3) 3</td><td>- (CH2) 3-</td><td>COOH</td><td></td><td> 163</td>

<td> 26</td><td>-OC2H5</td><td>sC&gt; 2</td><td>-CONHC (CH3&gt; 3</td><td>- (CH₂)2-</td><td>1 NH 1 COOC (CH₃) ₃</td><td>h₂about</td><td> 114</td>

<td> 27</td><td>-OC₂H.₅</td><td>SO₂</td><td>-CONHC (CH3) 3</td><td>^ CH2) 2-</td><td>9 OC, H_r</td><td>HCl H₂ABOUT (4)</td><td> 150</td>

<td> 28</td><td>^-OC2^h5</td><td>SO2</td><td>-COOCH2C₆H5</td><td>- (CH₂)₂-</td><td>0 OH</td><td>h₂about</td><td> 80</td>

<td> 29</td><td>-OC2H5</td><td>SO2</td><td>-COOCH2C₆H.₅</td><td>- &lt;CH₂)₂-</td><td>9 oh_c₆h₅</td><td> (4)</td><td> 55</td>

<td> 30</td><td></td><td>SO2</td><td>-CONHC (CH3) 3</td><td> -^(CH2⁾2^-</td><td> '0.</td><td> -</td><td> 62</td>

<td> 31</td><td>-OC2H₅</td><td>SO2</td><td>-CONHC (CH3) 3</td><td>- (CH₂)₂-</td><td>N (CH2C₆H5)</td><td> (5)</td><td> 69</td>

187 093 (1): Most polar isomers, unless otherwise indicated (2): Mixture of isomers (3): Least polar isomer (4): 4-byOr4xypipe ethers (yOins are obtained by alkylation of N-tert-butyloxy (b4nyl-4) -hydroxypipsryOine and the corresponding halide in the presence of sodium hydride followed by acid hydrolysis of the tert-butyloxycarbonyl group.

(5): 2- (2- (N-bsnzylamin4) ethoxy) ethγn4l was prepared by reductive amination of Bo (4woO4 (with sodium imine derived from 2 ((2 (aminoethoxpy) stanol and benzaldehyde, in motanol and at 0 ° C).

Example 32

S (Etokpy-3-ppiro-t4-k2 ((2-byOrokpyetyl4amino) ethyloxy) -cyclohexane] -1-t4- (4-N (tert (butyl4ka (bαmoyl) -2-mst4kpybenzsn4Pulf4nyl4-ind4lin-2 (4n (polar isomer).

(I '): R 1 = S-OC 2 s; R3 = 2-OCH3; W = SO2

R4 = 4-CONHC (CH3)₃; TZ - CH2CH2NHCH2CH2OH;

a) 0.33 g of benzyl4xyacstalOshyOu, and then 0.46 g of sodium triacstoxyborohydride, 0.10 g of the amine hydrochloride solution from Example 4 (polar isomer) in 8 ml of tetrahydrofuran was added and cooled to 0 ° C. The reaction mixture is stirred at 20 ° C for 3 h, 10 ml of 1N HCl are added, extraction is performed with ethyl acetate, the organic phase is washed with a saturated solution of NaCl, 4 pupzone 4 naO, MgSO 4 and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a silica gel column, elution being carried out with a 98/2 (v / v) dichloromethane / motanol mixture.

b) 0.4 ml of 1,4 cyclohoxaOion, 0.3 g (10%) palladium / C were added to the benzyl ether previously prepared, dissolved in 0 ml of glacial acetic acid and heated at 60 ° C under nitrogen flow for 16 h according to the method described in J. Org. Chem. 43, 21 (1978).

The catalyst was filtered off, 10 ml of water was added to the reaction mixture, which was neutralized with a saturated solution of NaHCO3; extraction was performed with ethyl acetate, washed with water, 4 [upzone 4 over MgSO 4 and the solvent was evaporated under reduced pressure. The residue is chromatographed on a silica gel column, elution being carried out with a 98/2 (v / v) Oichloromotane / Motanol mixture. The expected product is isolated in the form of the hydrochloride hydrate by preparing the hydrochloride with a solution of isopropanol in hydrochloric acid and crystallization from diethyl ether, m.p. = 130 ° C.

Example 33

S-Ethoxy-3-spiro- [4- (2- (2- (2-hydroxyethyloxy) ethylamino-ethyloxy) -cyclohexane] -1 ((t4 ((4 (N (tertbutylcarbamoyl) (2-mot4-xybonzonesulfonyl-inOolin-2) -he.

The expected compound in the form of a tri-dihydrate hydrochloride was isolated from the compound of Example 31 by the procedure described in Example 32b) in ethanol and producing the hydrochloride in ethyl ether; T. m.p. = 109 ° C.

Example 34

S4; Toxγ-3rspir4-t4 ((2- (4-beI-zyjoxypίperidγno) ethyll) xy) cyclohexane] -1- [4ka] (b4k [y (2-mstoxybenzsulf4nyl-inOolin (2-one.

(I '): R, -5-OC2H5; R3 = 2-OCH3; W - SC2;

IR = 4 (OCOOH;

tz = -ch₂ch₂:

oh₂c₆h₅ (prepared by selective denosylation according to Tetrah. Lettors, 1986, 37S3). 0.62 ml of ts (t (butyl40-methyl4Pilαnu and 0.06 ml of tristylamine) was added to 0.03 g of a solution of palladium acetate in 4 ml of dichloromethane and the reaction mixture was stirred for 1S min at 20 ° C. A solution of 1 g of the compound described in Example 29 was slowly added in 2.6 ml of dichl4r4 (in state and kept under stirring for 4 h at 20 ° C. 1 ml of acetic acid was added, followed by

187 093 was not filtered, rinsed with dichloromethane and the filtrate was washed with an aqueous ammonium chloride solution then with water. The expected product is isolated after evaporation of the solvent, crystallization from pentane and drying at 50 ° C under reduced pressure for 5 h; T. m.p. = 120 ° C.

Example 35

5-Ethoxy-3-spiro- [4- (2- (4-benzyloxypiperidine) ethyloxy) -cyclohexane] -1- [4- (N- (1-hydroxymethyl) -cyclopentylcarbamoyl-2-methoxybenzenesulfonyl] indolin-2-one .

(Γ): Ri = 5-OC₂H.₅; R₃ = 2-OCH3; W = SO₂;

R₄ = 4-CONH; TZ = -ch₂ch₂ oh₂c₆h₅ ch₂oh and, 27 g of oxahl chloride was added to a suspension of 0.7 g of the compound prepared in Example 34 in 7 ml of toluene and 2.5 ml of dichloromethane, and the reaction mixture was stirred for 6 h at 20 ° C. The solvents were evaporated, the residue was dried for 2 h at 20 ° C under reduced pressure and dissolved in 20 ml of toluene, and then this solution was added to a solution cooled to about -40 ° C and 6 g of i-amino-i-cycloeedtadomethadol in 30 ml of toluene. . The reaction mixture was stirred for 2 h at 20 ° C, 30 ml of water and 100 ml of ethyl acetate were added. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. The expected product is isolated after chromatography on silica gel, elution with a 95/5 (v / v) dichloromethane / methanol mixture; T. m.p. mp = 103 ° C.

Example 36

5-Ethoxy-3-spiro- [4- (2- (4-hydroxyeipe^ryidine) ethyloxy) -cyclohexane] -1- [4- (N- (1-hydroxymethyl) -cycloeedtylcarbamoyl-2-methoxybedzedosulfodyl] idolide-2-od.

(I '): R f = 5-OC 2 H 5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONH; τ-z = -ch₂ch₂:

OH ch₂oh

The expected product is isolated in the form of the hydrated base according to the procedure described in example 32 b) starting from example 35, after chromatography on a silica gel column, elution being carried out with a 92/8 (v / v) dichloromethane / methanol mixture ; T. m.p. = i09 ° C.

Example 37

5-Ethoxy-3-seiio- [4- (2- (bedzyloxycarbodylmethylamido) -ethyloxy) -cyclohexane] - [4- (4-N-tert-butylcarbamoyl) -2-methoxybedjedosulfodyl] idolid-2-Od.

(T): R f = 5-OC 2 H 5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3; TZ = -CH2CH2NHCH2COOCH2C6H5

The residue was isolated according to the procedure described in Example 5, starting from compound (IIB.2) and 2-methoxy-4 (N-tert-butylcarbamoyl) disulfodyl chloride, and stirred for 2 h at 20 ° C in 3 ml of ethyl acetate solution saturated with hydrogen chloride gas. . The expected product is obtained after alkalization and subjected to chromatography on silica gel, elution being carried out with a 8/2 (v / v) cyclohexane / ethyl acetate mixture; the monohydrate hydrochloride melts at 60 ° C.

Example 38

5-Ethoxy-3-spiro- [4- (2- (kaiboxymethylamino) ethyloxy) -cyclohexane] -1- [4- (4-N-tertbutylcarbamoyl) -2-methoxybedzedosulfodyl] idolid-2-od.

(I) ': R f = 5-OC 2 H 5; R2 = H; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3; TZ. = -CH2CH2NHCH2COOH

0.06 g of the compound of Example 37, 6 g of cyclohexene, 0.05 g of 10% palladium / carbon in 10 ml of ethanol is refluxed for 1 h, the catalyst is filtered off and the solvent is evaporated off under reduced pressure. The expected product was isolated as

187 093 dihydrst after treating chromicidal slime, where it was eluted using 90/10 (v / v) dichloromethane / metsnol; T. m.p. = 199 ° C.

Example 39

-Hydroxy-1- [4- (N-teet-butyloxrbsmcilo) -2-broccynsulfonyl] -3-tpyro- [4- (2mcrfolincctyloxy) -cyclohckssnc] indolln-2-one. (bearish isomers).

(I '): R5-OH; R3 = 2-OCH3; W = SCh;

R4 = 4-CONHC (CH3) 3;

so

-ch, ch₂- n

The specific product was isolated in a pottsci hydest according to the procedure described in ex-38, starting from example 30; T. m.p. = 125 ° C.

Example 40

5-Ethoxy-1- [4- (N-rset-butyloxyrbsmcilo) -2-methoxybenzenesulfonyl] -3-tpπΌ- [4- (2-N-oxy-mcrfclinctyloxy) -cycloxsnc] indolin-2-one.

(I): R f = 5-OC 2 H 5; R2 = H; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3;

T — Z ⁼

<img file="PL187093B1_D0024.tif" />

ABOUT

0.8 ml of 30% hydrogen oxide add to 0.5 g of the opitsnśgc compound in the present day, 2 dissolves in 10 ml of metsnol and masticatory meat, heated at 45 ° C for 16 hours. which was eluded with the use of the bear 85/15 (vol ^ vol.) dichloeomśrsn / mśrsnol. The parental product was isolated as a semi-hydrate after recrystallization from mretsnine 40/60 (v / v) cyclohydrin / cctsn; T. m.p. = 189 ° C.

Example 41

Mctylosisrczsn 5-octoxy-1- [4- (N-tcrt-butyloxrbsmollo) -2-mcrtbutyloxrbsmollo] -3-spirc- [4- (2-N-mstylmorpholmiomctylckty) -cyclohctsnc] mdolm-2-one.

(I '): R f = 5-OC 2 H 5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3 ', \

_T._z = -CH₂CH₂-about

H, C ~ ch₃so₄

0.05 ml of dimethylsecesno added to 0.25 g of the opitoxic compound in, for example, 2 dissolved in 2.5 ml of scitonitrile and the urinary tract heated at 60 ° C for 24 hours. 40 ° C under reduced pressure for 5 h; T. m.p. = 190 ° C.

Example 42

5-Ethoxy-3-spiro- [4- (2- (2- (N-tert-butcksyxrbonylcglycylc) smlnc) srylcksy) -cyclohckssnc] -1- [4- (4-N-teet-butylsrbimoylc) -2-oxybutcinsulfcnylc ] indclin-2-on.

(I '): R1 = 5-OC2H5; R3 = 2-OCH3; W = SO2;

R4 = 4-CONHC (CH3) 3;

TZ = -CH2CH2NHCOCH2NHCOOC (CH3) 3

0.28 g of Hsktsfluorophosphorsn bsnzctriseol-1-yl-oxy-tris (dimethylmilinc) phosphonate and 0.24 ml of trisylcumin, 0.35 g of the hydrochloride of the compound from example 4 (Polish isomine) to a solution of 0.5 ° C 11 g of Ns-tset-buryloxy-xrbcnyglycine in 2 ml of sctonitrile and mixing urine at about 20 ° C for 4 hours.

187 093

The solvent was evaporated under reduced pressure, the residue was dissolved with ethyl acetate, washed successively with KHSCU / FCSO. Buffer solution pH = 2, water, saturated NaHCO3 solution and then with water. The organic phase is dried over MgSO 4, the solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica gel column, elution being carried out with a 99/1 (v / v) dichloromethane / methanol mixture. The expected product was isolated; T. top = 158 ° C.

Example 43

-Chloro-3-spiro- [4- (N - (3-dimethylaminopropyl) -carbamoylmethoxy) -cyclohexane] -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxybem: enosulfbrLyl] indolin-2- he.

(I '): Ri = 5-C1; R3 = 2-OCH3; W = S O2;

R4 = 4-CONHC (CH3) 3;

TZ = -CH2 CONH (CH2) 3N (CH3) 2

The expected product is isolated as the hydrochloride monohydrate according to the procedure described in Example 42, starting from the carboxylic acid from Example 25 and 3-dimethylaminopropanamine; T. m.p. = 135 ° C.

Compounds 44 to 50 in Table 2 below were prepared according to the procedures of Examples 42 and 43 by reacting appropriately selected amines or acids.

<img file="PL187093B1_D0025.tif" />

oh₃

<img file="PL187093B1_D0026.tif" />

CONHC (CH₃) ₃

Table 2

<td>Number example</td><td>Ri</td><td>T.</td><td>with</td><td colspan="2">Salt, Solbat (1)</td><td>T. ° c</td>

<td> 44</td><td>0-CC2H5</td><td>- (CH2) 2-</td><td>-NHCC (CH2) 1N (CHl) 2</td><td colspan="2">HCI</td><td> 151</td>

<td> 45</td><td>5-OC2H5</td><td>- (CH2) 2-</td><td>-NHCC (CH2) 3CCCCH1</td><td colspan="2"> -</td><td> 138</td>

<td> 46</td><td>5-OC2H5</td><td>- (CH2) 2-</td><td>-NHCOCH2N (CH3) 2</td><td>HCI</td><td>H.₂ABOUT</td><td> 144</td>

<td> 47</td><td>5-OC2H5</td><td>- (CH2) 2-</td><td>-NHCC (CH2) 2CCHl</td><td colspan="2">1H₂Q</td><td> 108</td>

<td> 48</td><td>5-OC2H5</td><td>- (CH2) 2-</td><td>-NHCOtC ^ bCH (NHCCCC (CH3) 3) CCCC (CHl) 1</td><td> (4)</td><td>h₂about</td><td> 133</td>

<td> 49</td><td>5-OC2H5</td><td>- (CH2) 2-</td><td>-N HCCCH (NHCCCCH2C₆H.₅)(^2)2^^^6¾</td><td colspan="2"> (5)</td><td> 108</td>

<td> 50</td><td>H.</td><td>CH2</td><td>-CONH (CH2) 2OH</td><td> 0,5</td><td>H.₂0</td><td> 183</td>

187 093 (4) starting from Ne-tert-butziokgzgktammieou tert-butyl in the natural configuration.

(5) from N-α-beozyloxycarbonyioclutamic acid y-benzyl ester in natural configuration.

Example 51

-Etoxy-3 --ρπό - [4i (2- glyc2lkIniyoethylokiy) -ckklohexanel -1- [4- (1 -N - te itNueyl curbamoyl) -2-methoxybenzenor5lfooyl]^ln0o^andiz-⁰-he.

(- '): R₁ - S-OCiI ^ R = 2-OCH^about; W = SO^about;

R4 = 4-CONHC (CH₃)_3; T._-Z = _-C H2CH2NHCOCH2NH2 ml of saturated solution of hydrogen clyloride into octame ethics deducted a suspension of 0.3 g of the compound from Example 42 in 3 ml of ethanic acetate and the reaction mixture is mixed for 2 hours. ³room empnratur5e R4npu [zczainik oOpayonzίino, crystallized from diethyl ether, dried under reduced pressure, thus obtaining the expected product in the form of 0^and0y0ta^lin chlorohydride; Mp = 169 ° C.

Example 52 ⁵-⁽-^vol.okι [y-3 “l [^ iret - [- 4- (2- (4-Sayboksyb5t; ^ I ^ (^ ezd &lt;.a) ιitl ^ lol ^: ^ 2y) ^ (^; yy ^ lιtlo ^ m ^: ^ æαn ^ t] -1 (f4 ((4 (N-teyl-butylSar⁴smoyl) -2-meth4x⁽benzene [uif5nyl4-oloyin-2 (4n.

(Il ': R, from SOC 2; R^s = 2 ^ ¾ W = SO^-;

R) = 4_-C ONHC (CH₃)₃; TZ (_-CH_eCH_cNHCO (HH_c)₃COOH

Expected ^H.The r40 product was isolated from the compound of the CsirOdd 45 according to the procedure of Example 8 by titanium [sichener with benzyl alcohol followed by hydrogen gas. T. m.p. = from 17 ^.

Example 53

5-btoxy - 3-spiIΌ- [4- (2-L-γ-gll5tamylamino) ethylxy) -cycliabexane &lt;aj-1-j'4- (4-d (te (T-butzlcarbam4oyl) -2-me⁴4kszbenzenogzί^yonzl4-mdoiin (2-4n.

(Ilk R.^and with a-OH^cH5; R. = 2-OHH. W = SO₂^;

R₄ = 4_-C ONHC (CH₃)_3; T._-Z = ₍CH_cHH_cNHCNCH_cHH_cHH (NH_c) COOH

S] 4o0ziewady pyodoct wz4dyrbHioi2C in after [^sari ch²Hr4W4^aboutOdku sprinkling according to proee0urz pp ^ n! in pyzzklαdzin 51 hillⁿ4 from the connection with Prov^fromorder 48; T. m.p. = 23C ° C.

Example 54 ⁵(Ethoxy-3-spir4- [4- (2-L-pyrogctamylamino) ethyloxy) -cyclohexanet-1- [4- (ZN-tert ((butylSar⁴amoyl) -2-me44kshbenzene [ei^with4nz^and4] in0o^andm-⁴-oz.

(Il ': R.^and with 5_-ΟΗ₂Η_5; R_{3 -} 2_-Oh_3; W = SO_2;

R4 = 4-CO NOH² OT ^;

τ

<img file="PL187093B1_D0027.tif" />

H.

A mixture of 0.245 g of the compound of Example 49, 0.5 ml of cyclhexa-diene and 0.25 g of 10% palladium / carbon in 2 ml of ethyl acetate was heated at 80 ° C. The catalyst was separated by filtration, and evaporation was performed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The solvent was poured under reduced pressure and the residue 440 was chromatographed on a S4 column over silica gel, elution being carried out with a 98/2 (v / v) diethylmethane / methanol mixture. The resulting residue was dissolved with diethyl ether; T. m.p. = 171 ° C.