3-spiro-indolin-2-one derivatives as vasopressin and/or oxytocin receptor ligands

The present invention is a novel indolin-2-one derivative and behavior in the preparation of thelar. These new deductions are attributable to affinity for vasopressin and / or oxytidine receptors and may thus be an effective source of drug molecules.

Vasdpressin is a hormone known for urinary effects and its effect on arterial arterial control. Pad diverges the number of receptors: Vj (Vjð, Vjþ og V3), Vj. These subjects are located in the lining, the edema (wreath, nymph or brain), blood patches, nasal cavity, cervical fluid, neoplasm, mucosa or pituitary gland. Oxytdine has a peptide build up that is ifk vasopressin. Oxygen disorder is also found on the smooth muscle of the leg line; Thrombocytes are usually found in the musculoskeletal cells of the cervical clot, in the prostate and the kidney. The location of different traits is described in: Jard S. et al., "Vasopressin and Oxytocin Receptors: an Overview In Progress" in Endocrinology, Imura H. and Shizume K., published by Experta Medlca, Amsterdam, 1988,1183-1188 and i the following articles:

Press Medicate, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108. Vasopressin shows the hormonal, tracheal, hepatic, neuropathic, urinary and cohabiting effects and effects on the mid and peripheral nervous system, on the play and gametes, and on the lung and lungs. Oxytidine is involved in birth, lactation and sexual dysfunction.

The protector of the V2 protagonist in the vasopressin! (also known as "AVP-2 antagonists" or "V2 mdtlyT"), can be measured as a potent urine-releasing agent that selects selectively on reconstituted water in the kidneys without losing ions (Na⁺, K⁺), like diuretics commonly used in clinical trials, such as furosemide and hydrochlorothiazide. Path side effects, after long-term behavior, lead to hyponatraemia and hypokalaemia.

The first antagonist of V2 extensive arginine-vasopressin (hereinafter known as AVP),

OPC-31260, is currently in clinical trials. The comparative effect of OPC-31260 in the treatment of conventional diuretics, such as furosemid, demonstrates such a combination of compounds specifically through increased aqueous urine formation, and has no effect, as little as possible in single doses, on jdna uptake, in animals (Yoshitaka Y. et al. ., Br. J. Pharmacol., 1992, 105, 787-791) and manni (Akihiro O. et al., J. Clin. Invest., 1993, 92, 2653-2659, and Akihiro O. et al., Pharmacol. Exp. Ther., 1995, 272, 546-551).

Inddlin-2-dn derivatives have been described in the seeds. As used herein, Patent No. ZA 830952, which can be used as antihypertensive agents and inhibit wall enzymes, may be described in U.S. Pat. No. 1,509,373, which discloses a thiazole compound that affects potassium thiolite.

The various patent applications of these patents also describe many non-peptide compounds which have suture in the vasopressin and / or oxytidine metabolism. This is, as a matter of example, EP 382,185, which comprises carbostyryl proliferates, which are vasopressin drugs, which are useful as vectors, hypertensive agents, vasodilators and inhibitors of bipolar clusters; EP 444,945, which include spiral piperidine derivatives which are generally useful for tide pads; EP 514,667, which discloses benzazepine derivatives, which are particularly useful for renal failure disorders, hyponatraemia, diabetes or other alternatives to treatment and prophylaxis of platelet clotting: JP 03127732 as described indole derived as vasopressin antagonist.

Benzyl or sulphonylindoline derivatives and inddl derivatives have also been described as vasopressin antagonists. And finally, the term EP 469,984, EP 526,348, EP 636,608, EP 636,609, WO 93/15051 and WO 95/18105, these documents do not describe compounds that are specific to the AVP-2 taker.

It has been shown that the efficacy of indolynone shows excellent affinity for vasopressin and / or oxytidine. These new indolin-2-ions are effective and specific as AVP-2 drugs. Furthermore, if used in the midst of their construction, and in particular the presence of various polar active groups, especially active hdpa which can be transformed. In salt, these molecules are soluble and / or soluble in water, which provides a boost to pharmacological activity, making pad also suitable for injection-injectable pharmaceutical dosage forms.

For a single reason, according to one of its formulas, the present invention at inddlin-2-dna corresponding to the formula:

<img file="IS1949B_D0001.tif" />

couple as:

- R 1 represents a hydrogen atom; hydroxyl; halogen; (C1-C7) alkyl; (C1-C7) pyrafluoroalkyl; (C 1 -C 7) alkoxy; (C 1 -C 7) alkylthid; (C1-C7) pyrafluoroalkoxy; (C3-C7) cycloalkyloxy; (C3-C7) cycloalkylthio; cycloalkylmethoxy or cycloalkyl1949 methylthio wherein the cycloalkyl group is (C3-C7); phenoxy; benzyloxy; nitro: or cyano;

- R3 and R4, each independently and independently of each other represent hydrogen atom; halogen; (C1-C7) alkyl; (C2-C7) alkenyl; (C 1 -C 7) polyhaloalkyl; phenyl or benzyl; cyano; nitro;

-NR5R5 group; hydroxyamino; hydroxyl; OR7 group; SR7 group; -COORg group,

-CONRgRio group; or -CSNRgRyo group, wherein at least one of the R3 and R4 radicals is other than hydrogen;

- R5 and R8 each represent and independently of each other hydrogen atom; (C1-C7) alkyl; (C2-C7) alkenyl; phenyl; benzyl; (C4-C7) alkylcarbonyl; (C1-C7) alkylthiocarbonyl; (C4-C7) cycloalkylcarbonyl; (C4-C7) cycloalkylthiocarbonyl; benzoyl; thienylcarbonyl; furylcarbonyl; (C4-C7) alkoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; carbamoyl or thiocarbamoyl unsubstituted or substituted with R9 and R18; or R5 and R5; Rg forms, together with the nitrogen atom to which they are attached, heterocyclic groups selected from pyrididine, pyrroline, pyrrole, indoline, indole and piperidine groups;

- R7 represents (C1-C7) alkyl; (C2-C7) alkenyl; phenyl; benzyl; (C 3 -C 7) s (chloroalkyl; (C 1 -C 7) poly-fluoroalkyl; formyl; (C 1 -C 7) alkylcarbonyl; benzoyl; or benzylcarbonyl;

- Rg represents hydrogen; (Ci-C7) alkyl; phenyl; or benzyl;

- R9 and R10 represent each and independently of each other hydrogen atom; (CyC7) alkyl; (C1 -C4) fluoroalkyl; (C2-C7) alkenyl; (C3-C7) cycloalkyl, which may have a substituent hydroxyl (C1 -C4) alkyl; pyridyl; phenyl; thienyl; furyl; (C4-C7) azacycloalkyl; or Rg and R &amp; lt; q &amp; gt; together with the nitrogen atom to which they are attached, form a heterocyclic group selected from pyrrolidin, piperidine or plperazine groups which are or are unsubstituted or substituted by (C1 -C4) alkyl groups;

- T represents (C 1 -C 4) alkylene which is optionally interrupted by (C 3 -C 8) cycloalkylene, and said alkylene groups may have been replaced once or more on the same carbon atom with (C 1 -C 6)₃) Alkyl; or for other reasons that T represents a direct interface;

Z represents -NR n R 3 group; -⁺NRnRi2 (C1 -C4) -alkyl (A), wherein (A ') is an anion, called Cl, B, or CH3 SO4; -N (O) R11 R12;

-NR11COR12 bp; -CONR11R12 group; and then it is clear that when Z represents methylene or a straight bond, Z can not be -NRuR2; -⁺NRnRi2 (Ci-C4) -alkyl (A); N (O) R_nR₁₂; -NRnCORn;

- Ru and R12 represent each and independently of each other hydrogen atom;

(C_rC7) alkyl; (C₁-C₄) Alkoxy; (C3-C₇) Cycloalkyl; futile; (C₁-C₃) alkylphenylalkyl, wherein the cycloalkyl is C3-C7; or (C1 -C3) alkylene phenyl; and it is possible that the said groups are mono- or polysubstituted by R13;

or alternatively, optionally, Rn and R12 may form, together with the nitrogen atom to which they are attached, a heterocycle selected from azetidine, pyrrolidine, piperidine, piperazine, piperazine, morpholine, morpholinone, thiomorpholine and hexahydazepine heterocycles, and said heterocycle may be optionally substituted by R13;

- R 3 represents (C 1 -C 4) alkyl; hydroxyl; hydroxyalkyloxy; (Ci-C4) alkoxy; NR14R15 group wherein R14 and R15 represent each independently of a dithiometric hydrogen atom or (C1 -C4) alkyl; amidino; guanidino; fumldazolyl; pyridyl; indolyl; tetrahydroisoquinolyl;

- the phenyl group, which is a part of the Rj, R3, R4, R5, Rg, R7, Rg, Rg, Rjq, Rji and R12 substituents, unsubstituted, mono- or di-substituted (C1 -C7) ​​alkyl, (C1 -C7) ​​alkoxy, trifluoromethyl , halogen or tri-substituted with (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy or halogen;

and their solvates, solvates or water solvents.

hydrates).

Neftia requires a compound where -OTZ is -ON or -O-CH₂-NC2 are not stable and therefore do not belong to the invention.

According to the present invention, "(C 1 -C 7) alkyl or" (C 1 -C 6) alkyl is meant to represent a straight or branched alkyl group having 1 to 7 carbon atoms or 1 to 6 carbon atoms respectively in the previously mentioned sequence.

According to the present invention, it is denoted that a halogen atom is selected from fluorine, chlorine, bromine or iodine, fluorine or chlorine.

When a compound of the invention has one more more handed carbon, enantiomers of this compound form an essential part of the invention.

When a compound of the invention shows a stereochemical, as a cross-linked or ZE, the invention relates to aliphatic enantiomers of this compound.

Salts of Compounds of Formula (I) according to the present invention comprise those of inorganic and organic acids which make suitable suitable separation of the compounds of Formula (I), such as pfercic acid, oxalic acid or lactic acid, to the tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid and thresh that form a physiologically competent sdlt,

1? 49 such as hydrogen chloride, hydrogen bromide, sulfate, hydrogen sulphate, dihydrogen phosphate, malate, fumarate, 2-naphthenesulfonate or para-toluenesulfonate.

The salts of the compounds of formula (I) also comprise salts with organic and inorganic salts, for example salts of alkali metal or alkaline earth metals, such as sodium, potassium and calcium salts, sodium and potassium salts, or with amine, eln and trimetamol or to alternatively salts of argenin, of lysine or of any biochemically acceptable amine.

Active groups presently present in the compounds The compounds of formula (I) and the intermediate of the reaction can be protected, either permanently or temporarily, with protective agents capable of clarifying the compounds of the expected compounds.

Emergency protecting groups for amine, alcohol, phenol, thiol or carboxylic acids represent the protecting groups described in Protective Groups in Organic Synthesis, Greene TW and Wuts PGM, published by John Wiley and Sons, 1991 and in Protective Groups , Koclenski PJ, 1994, Georg Thleme Verlag.

For example, acylated protecting groups of amines: benzyl groups carbamate groups (such as tertbutyloxycarbonyl, which can be cleaved by acidic benzyl oxycarbonyl, which can be cleaved by hydrogenation for carboxylic acids (alkyl esters such as methyl, ethyl tertiary butyl esters, which are hydrolysed in basic acidic acid, hydrogenated benzyl esters for alcoholic phenol such as tetrahydropyranyl, methoxymethyl or methylethoxymethyl, tert-butyl and benzyl ether) and cited well-known general behaviors described ί Protective Groups, as witnessed above.

Temporary protecting groups treated by cleavage in neutral medium with hydrogenation are presented to adra.

Permanent protection groups are those that are stable in the deprotection advents shown above and which can last until the end of the final product. Such O-protecting groups of N-protecting groups comprise (C 1 -C 7) alkyl-eda phenyl groups. The durable N-protecting groups also contain (C 1 -C 12 alkanoyl groups and aroyl groups, such as benzoyl.

. The compounds (I) may contain the precursor groups of other active groups that are generated later at ddru stage of the ddrum levels.

Compounds (I) in which different polar parts, especially parts that are converted to convert solubility and / or dispersibility In water, the bombs of the -TZ substituents are elevated.

The compound of formula (I) wherein the R &amp; lt; 1 &amp; gt; substituent is a chlorine-containing ethoxy group.

The compound of formula (i) wherein R3 represents hydrogen or methoxy group and R4 represents a methoxy group, diethylureido group, te / t-amylcarbamoyl group and tert-butylcarbamoyl group are those compounds selected from the group consisting of.

The compound of formula:

<img file="IS1949B_D0002.tif" />

wherein R1, R3 and R4 are as defined for (1), T represents ((4-C3) alkylene group and Z represents an amino group, 2-hydroxyethylamino group, 2- (2-hydroxy) ethyloxyethylamino group, morpholinyl group or carboxyl group, and their salts , solvents or water substances are selected in particular.

The compound of formula:

<img file="IS1949B_D0003.tif" />

wherein R 2, Tog Z are as defined for (I), and their salts, solvents of water, are particularly selected.

The compounds of Formulas (1.1), (1.2), (1.3) and (1.4) wherein:

- R y represents a chlorine atom of an ethoxy group,

- T represents (C 1 -C 3) alkylene and Z represents an amino group, 2-hydroxyethylamino group, 2- (2-hydroxy) ethyloxyethylamino group, morpholinyl group or carboxyl group are particularly selected.

The compounds of formula (1.2), (1.3) wherein:

Rj represents a chlorine atom or ethoxy group;

- R3 represents hydrogen or methoxy group;

- R4 represents a methoxy group, diethyl ether group, tert-amylcarbamoyl group and tert-butylcarbamoyl group, which are also selected from the group consisting of:

Among these compounds selected herein represents (C1 -C3) alkylene and Z represents an amino group, 2-hydroxyethylamino group, 2- (2-hydroxy) ethyloxyethylamino group, a morpholinyl group or a carboxyl group.

In particular, the compounds listed below are selected:

* 5-chloro-3-spiro- [4- (2-morpholinoethyloxy) SIKLOS-hexane] -l- [4- (N-tert-butylcarbamoyl) -2-methoxybenzene-sulfonyl] indolin-2-one;

* 5-ethoxy-3-splró- [4- (2-aminoethyloxy) cyclohexane] -l- [4- (N-tert-butylcarbamoyl) -2-methoxybenzene-súlfDnýl] indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2- (N-methyl-N- (2-hydroxyethyl) amino) ethyloxy) cyclohexane] -l- [4- (N-te / t-butyl-carbamoyl) "2metoxýbensensúlfónýl] indolin-2-one;

* 5-ethoxy-l- [4- (N- £ re-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -3sp (nut [4- (2-morpholinoethyloxy) cyclohexane] indolin-2-one;

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

* 5-ethoxy-3-spiro- [4- (2-morf6línóetýloxý) SIKLOS-hexane] -l- [4- (N-tert^u amýlkarbamóýl) -2-methoxybenzene-sulfonyl] indolin-2-one;

* 5-ethoxy-3-spiro- [4- (2-carboxyethyloxy) SIKLOS-hexane] -l- [4- (N tert -amylcarbamoyl) -2-methoxybenzene-súlf6nýl] indolin-2-one;

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

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

5-Ethoxy-3-spiro- [4- (2-glycylaminoethyloxy) -cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] indolin-2-one;

* 5-Ethoxy-3-spiro- [4- (2- (N, Nd- (methylglycylamino) -ethyloxy) -cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one ;

* 5-Chloro-3-spiro- [4- (N- (3-dimethylaminopropyl) -karbamóýlmetýloxý) cyclohexane] -l- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one;

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

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

* 5-Ethoxy-3-spiro- [4- (2- (2- (2-hydroxyethyloxy) -ethylamino) ethyloxy) cyclohexane] -l- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] índólln- 2-one;

and their pharmaceutically acceptable salts, waxes or water solvents, which are particularly useful for pharmaceutical formulations.

The compounds according to the invention can be prepared according to Scheme 1 below, wherein:

- ^ 3 &lt;βψ Tog Z are as defined for (I) or (1.2);

- R2 is hydrogen atom;

- W is SO₂;

- Cy forms, with the carbon atom to which it is attached, cyclohexane group with -OTZ, -OTX, -OH, etc. at position 4, based on the spiral molecule.

<img file="IS1949B_D0004.tif" />

Another aspect of the present invention is the preparation of the compounds of formula (I) according to the invention, characterized by:

(1) either a compound of formula:

<img file="IS1949B_D0005.tif" />

wherein R 1, R 2, R 3, R 4, W, Cy and T are as defined above and wherein X is halogen, bromine, chlorine or iodine, or tosyloxy or mesyloxy, is reacted with a derivative of formula ZH ) wherein Z is NR 4 R 5 as defined for (I), at least one of the radicals R 1 and R 12 is hydrogen, dimethylformamide, tetrahydrofuran or acetonitrile at a temperature of 0 ° and

120 DEG C., or other substituents, represents an X-dideoxy group which is lowered into an amino group;

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

<img file="IS1949B_D0006.tif" />

wherein R 1, R 2, W, R 3, R 4 and Cy are as defined above and T represents T-CH 2 - is reacted with oxidizing agent, such as chromium oxide in acidic acid, such as dilute acetic acid at a temperature of between 0 and 100 ° C, alkali metal dicromates or alkali or alkali metal permanganates;

(3) or a compound of formula:

<img file="IS1949B_D0007.tif" />

wherein R 1, R 2, Cy, T and Z groups are as defined above, is reacted with a compound of formula:

Hal-W _ ^^^R3 Wherein W, R3 and R4 are as defined above and Hal represents a halogen atom, in the presence of a metal hydride, such as, for example, sodium hydride, or alkali metal alkoxide such as, for example, potassium tert-butoxide, at a temperature per mill)

-40 ° and 25 ° C, in anhydrous solvent and tetrahydrofuran;

(4) or, when Z = -COOH, a compound of formula:

<img file="IS1949B_D0008.tif" />

wherein R 1, R 2 and Cy are as defined above and T 'represents T-Chfy, is reacted with the oxidizing agent described above for a change in (I), the acid of formula :

<img file="IS1949B_D0009.tif" />

wherein R 1, R 2, C 1 and T are as defined above, thereafter optionally protected with a carboxylic acid protecting group, to give the intermediate of formula:

<img file="IS1949B_D0010.tif" />

wherein R1, R2, Cy and T are as defined above and P represents a protecting group selected from alkyl, and tert-butyl or benzyl, and finally, this compound (1B, P) is subjected to an activity derivative of formula (2) in order to obtain, after deprotection, Compound (I); which is optionally converted into one of its salts according to a skilled person's approach.

The compounds (IIA) and (IIB) can be prepared from the compounds (III) according to the following scheme 2:

SCHEME 2 15

<img file="IS1949B_D0011.tif" />

The compounds (IIA) can be prepared from indolin-2-one (III) with benzenesulfonyl halide, in an anhydrous solvent such as dimethylformamide or tetrahydrofuran, in the presence of a metal hydride such as sodium hydride or alkali metal alkoxide, such as potassium tert-butoxide, at a temperature of mill) -40 ° and 25 ° C.

The compounds (IIA) may also be recovered from the alcohols (II 'A) according to known general methods. For example, the triphenylphosphine / carbon tetrachloride system according to Angew. Chem. Int. Ed., 1975, 14, 801 or triphenylphosphine / C (Hal) 4 system, wherein Hal represents halogen, in the presence of pyridine according to Carbohydrate. Res., 1978, 61, 511, by reaction with aryl or alkylsulfonyl halide in a recognized base in an inert solvent. The X groups can be shifted: for example, the sulfonate group can be converted to halide, such as iodine derivative, by reaction with alkali metal iodide, sodium and sodium iodide, according to 3. Chem. Soc.,

1949, 326. When X represents a halogen, the halide (Π A) in alcohol (ΙΓ A) can be converted with nitrate ion nitrile, which is subsequently reduced in the presence of metal catalysts, and palladium-on-carbon, according to the behavior described in J. Med. Chem., 1995, 38, 130-136.

The compound of formula (I) may also be prepared from the corresponding indolin-2-one (ΙΙΓ) by reaction with reagent (2) under conditions previously described for the conversion of compounds (III) to (IIA). Alcohol group on (III *) is a temporary protected agent (compound ΙΙΓ P), for example with a protecting group, such as methyl or tetrahydropyranyl, according to EP 636,608.

The compounds (IIB) can be prepared from lndolin-2-one (III) with the present moiety of the leaving group (electron-linked linker) (X-ZH derivative) (1), as well as Examples of the first degree of second degree compounds in polar solvents, elevents and dimethylformamides, tetrahydrofuran and acetonitrile at temperatures between 0 ° and 120 ° C, midad at nucleus nucleus and nudeofuge

The compound (IIB) wherein -TZ represents

-T-COOH are alkylated (ΙΙΓ) where Γ represents T-CH₂- by oxalcohol (ΠΙΟ according to the conditions described for the conversion of (IT A) f (I).

The compounds (III) are innovative and form part of the invention. Pau is prepared according to the chemical reactions in Scheme 3 below:

SCHEME 3

<img file="IS1949B_D0012.tif" />

For these reasons, indolin-2-one (III) reductions in acetone (IV) under mild conditions, according to the method described in J. Org. Chem.,

1987, 52, 2594-2596, is subjected to the activity of cyanoborohydride in the presence of trimethylsilyl chloride in ether or chlorinated solvents, such as, for example, dichloromethane, or subjected to the dimethylsulfide-BH3 complex in the presence of trimethylsilyl triflate (ether triflate) in ether or dichloromethane according to the method described in J. Org. Chem., 1993, 58, 6756-6765, or from the alcohols (ΙΙΓ):

<img file="IS1949B_D0013.tif" />

wherein R1, R2, Cy and T are as defined above, according to the methods referred to above for a change of (ΙΓΑΑ) ί (II A).

The acetals (IV) are prepared with well-known reactions, for example acid-derived from ketone (V) and alcohol in a dehydrating medium. The preparation can be carried out with an acetone removal of water or in accepted molasses, according to Synthesis, 1972,419.

Ketones (V) can be prepared from the corresponding second degree alkyds (VI) according to the methods well known in the art, for example, oxidizing agents, and chromium oxide in acetic acid or chromium oxide complexes, and pyridine dichromate, inorganic solvents and ethyl acetate or dichloromethane, or alternatively hydrolysis on the acetals (IV ').

The alcohol (VI) may be obtained from the corresponding compounds of a hydroxy group protected by a methoxymethyl group or tetrahydropyranyl group. These compounds are disclosed in EP 636608 or grafted in a controlled manner. The compounds are therefore protected according to formula:

<img file="IS1949B_D0014.tif" />

are treated with anhydrous hydrolysis in alkyd such as methanol or ethanol, or in ether, such as tetrahydrofuran, at a temperature between -5 ° and 70 ° C.

The compound (1113 can be prepared according to Scheme 4 below:

SKEMA4

<img file="IS1949B_D0015.tif" />

With respect to the addition of the compounds (III) from the acetals (IV), the compound (ΙΙΓ) of the circular acetate (Ιλ / '), such as the dioxolane, obtained from hydrazide (VII), is prepared.

Halide (III) is also possible by changing the (ΠΓ) method according to the methods already known for the alteration of compounds (IIA) I compound (ΙΓ A).

Unlike, as in the case of the compounds of the compounds (IIA) according to the methods previously known, the alcohols (ΙΙΓ) have also been modified. In compound (III) wherein X is a leaving group ¹ (such as nucleophiles) such as alkyl benzenesulfonate with reaction with alkyl halide or phenylsulfonyl halide in inert solvents for the third degree of amine in pyridine.

The compounds (ΙΙΓ) may be modified by the ΙΙΓΡ where alcohol groups are protected as indicated above. The compounds (ΙΙΓΡ) are also a modified compound (II A) where X is a temporarily protected alcohol according to the previously described compounds.

The compound (IV ') in which T equals at least -CftyCfty- may be prepared from the ketones (V) by reaction with diol HO-T-OH according to the mentioned reaction steps for the conversion of (V) i (IV). The compound (IV ') can also be obtained directly from the corresponding hydrazide (VII) with the Brunner reaction described by Moore RF et al., J. Chem. Soc., 1951, 3475-3478, for example, with heat solvents, such as quinoline, (vitreous metal), such as calcium oxides. Calcium oxides are also reacted by heating in inert solvents such as tetralin , naphthalene and 1,2,3,4-tetramethylbenzene, according to the behavior described by Wolff J. et al.,

Tetrahedron, 1986,42, (15), 4267-4272, with lithium salt as the starting material prepared in an inert solvent, such as tetrahydrofuran, at low temperature.

These phenylhydrazide derivatives (VII) are thus obtained from phenylhydrazine (IX), which are known compounds of the invention, are prepared according to known methods, and derived from carboxylic acid (VIII), such as esters, chlorides, etc., with anhydride obtained by reaction of alkyl chloroformate, isobutylchlorophosphate inhibitory, based on basic practice of the skilled person. Acids (VIII) are known as prepared according to known behaviors.

Another advantage of compounds of compounds (I) wherein T represents -CH 2 - and

Z represents

-COOZi group wherein Z1 represents hydrogen, (C1 -C6) alkyl or benzyl consists of the use of an alcohol of the formula:

<img file="IS1949B_D0016.tif" />

wherein R 1, R 3, R 3, R 4, W and Cy are as defined above, as known in the art, prepared according to EP 636 609, alkylated with high molecular weight alkylating agents such as trifluoromethanesulfonate of formula CF 2 CF 3 O- COCO 2 (3) formed in the solution in situ with the reaction of silver triflate with a corresponding halogenate derivative wherein Alk represents (C 1 -C 6 alkyl, in halogen atoms, such as dichloromethane and carbon tetrachloride, In the presence of a base, such as 2.6 di-tert-butylpyridine, according to the procedure described for alkyl trifluoromethanesulfonate Carbohydrate Research, 1975.44, C5-C7.

The tests that are tested are then divided into general publications that have already been mentioned.

Alkóhóll (Il C) is thus prepared according to the following scheme 5:

SCHEME 5

<img file="IS1949B_D0017.tif" />

<img file="IS1949B_D0018.tif" />

.

The alcohol (II C) is then prepared from the protected compounds (X) with the deprotection of the compound and for the conversion of the compounds (XI) to the compound (VI).

The compounds (X) are derived from the compounds (XI) according to the procedure described in EP 636608 with the halides (2) according to the reaction steps already mentioned. In compounds of formula (I) and compounds (III) ί (II A).

A compound of formula (I) is also optionally modified. A compound of formula (1) having a polyfunctlonal residue as defined for Z, especially for -NRnCOR3, ^eamide^a for -C0NRnRi2 reaction is carried out according to known methods. In the peptide compounds described, for example, by Bodansky Μ. Principles of Peptide Synthesis 2nd ed., 1993 and Bodansky Μ. Peptide Chemistry, Springer Verlag; Because of this, these behaviors can inhibit the enantiomyopathy of the nucleic acids present in the amino acids.

The reagents ZH in formula (1) are available in the market as prepared according to known methods.

Derivative of formula (2):

<img file="IS1949B_D0019.tif" />

are also prepared according to known behaviors. Particularly, benzene-sulfonyl halide pair as W = -SO2- and R3 and R4 are as defined hereinbefore (I) are prepared with known behaviors. For this reason, 4-dimethylaminobenzenesulfonyl chloride is prepared according to Sukenik CN et al., J. Am. Chem. Soc., 1977, 99, 851-858. General, benzenesulfonyl halides substituted with dimethylamino groups are known to be known according to known methods; 4 benzyloxybenzenesulfonyl chloride is prepared according to EP 229,566.

Alkoxybenzenesulfonyl chloride is made from sodium alkoxybenzene sulfonate, which itself is prepared by reacting an alkyl halide with sodium hydroxybenzene sulfonate.

Benzensulfonylhalidine is obtained according to Col. Czechoslov. Chem.

Commun., 1984,49,1184, from the aniline fluxes of the same group, named aniline derivatives are themselves derived from the corresponding nitro groups.

Benzene sulfonyl halide (2) pair as the substituent of step 4 represents -NHCON (CH2CH3) 2 moiety is then prepared by reacting chlorosulfonic acid at. N, N'-diethyl-N-phenylpvage, which itself is obtained by reacting an alkylene with diethylcarbamoyl chloride.

in the case where R3 or R4 represent N-substituted carbamoyl, a suitable condensate is a compound of formula (2) wherein R3 is carboxylic acid, such as N-benzylcarbamoyl, to deprotect the protecting group with hydrogenation and then condensate at the desired amine , as well as the option of creating (2) straight pair as R3 is the path expected. The reaction is generally carried out from the right of aniline compounds, which are themselves obtained by the reduction of the corresponding nitrous derivatives.

Aniline compounds are diazotized by conventional contrast with nitric acid and reacted with SO2 in the presence of copper chloride according to J. Heterocyclic Chem., 1986, 23, 1253.

The compound (3) is derived from alkyl iodoacetate and from trifluoromethane-sulfonic acid salt, such as silver salt, according to Chem. Reviews, 1977, 77.

The fourth phase ammonium compound, N-oxide and S-oxide derivatives and sulfones of the compounds (I) are part of the invention and are each conventionally prepared by reaction with alkylhalide edoxidation with hydrogen peroxide such as peracetic acid or methacldipropenic acid, In inert solvents.

The compounds of formula (I) may comprise amine or acidic components which may be converted into an amide moiety by reacting each with an acid-derived amide derivative capable of containing a self-contained carbon. Nefha may be the unrestricted clot population of professional elevents, especially in the peptide molecules, and can be found in Wunsch E. in Methods of Organic Chemistry (Synthesis von Peptiden), 1974.15, Tier 1 + 2, Thieme Verlag, Stuttgart and Jones JH in The Peptides, 1979, 1.65-104, Gross E., Meienhofer J., Academic Press, ou M. Bodansky, Principles of Peptide Synthesis and Peptide Chemistry, 1993, Springer Verlag.

The compounds of formula (I) above also encompass those pairs which one more hydrogen, carbon, one or more halogen atoms, especially chlorine or fluorine atoms have been widely replaced by radioactive isotopes, to form tritium carbonate-14. Such labeled compounds are useful in research, metabolism and pharmacokinetic studies, as well as biochemical tests as volatile links.

The compounds of the invention according to the invention in the vasopressin activity were determined in vitro by using the method described (Lynch CJ et al., J. Biol. Chem., 1985, 260 (5), 2844 -2851. This behavior is based on the study of tritiated vasopressin bundled with the prosthesis of the rat.

. Similarly, the compounds of the compounds (I) according to the invention were used in an oxytodin-based assay in vitro with the use of radiolabelled oxytodin which was associated with the treatment of the mucosal membrane of pregnant rats, similar to those described by Elands J. et al., In

Eur. J. Pharmacol., 1987, 147, 197-207.

The compounds of the compounds (I) according to the invention in the V2 receptors were the mean of the residual cyanogen membrane according to Adduct Adderadri from Crause P.

et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541 and from Stassen F.

L. et al., 3 Pharmacol. Exp. Ther., 1982, 233, 50-54.

The compounds of the invention inhibit the binding of trilatad arginine vasopressin to the receptors of the prepared membranes, the IC50 values ​​of the compounds of the invention are low, generally in the range of 10 "⁵to io-⁹m.

The therapeutic agent of the antagonist The compounds of the vasopressin compositions of the invention administered by mouth were treated with a sprague-Dawley strain according to the method described in Br. J. Pharmacol., 1992, 105, 787-791. The diuretic disorders generally taken with compounds of formula (I) and, for some of these compounds, less than or equal to 10 mg / kg, show that the compounds of formula (1) form a series of potent V2 antagonists.

The compounds according to the invention are active in different ways after drug administration, but especially at intake.

No indication of the chromosomal effects of these compounds at pharmacologically effective doses and toxicity was therefore compatible with medicinal products as medicinal products.

The compounds according to the present invention make it possible to similarly inhibit, in particular, the effect of vasopressin and / or oxytosin. Medal of these substances, antagonists of vasopressin can provide a wide range of treatments for pulmonary and edema, specific coronary, nymphatic and gastrointestinal disorders, and ➢ water management and salivary renal insufficiency (ACTH) salivation. The vasopressin genome can efficiently come into the city of vasopressin as its ultimate in the treatment of dyspnoea; They can also be used for treatment of asthmatic and I-controlled blood clotting: treatment of haemophilia on Von Willebrand syndrome such as anti-blister clots, Laszlo FA, Pharmacol. Rev., 1991,43,73-108, Drug Investigation, 1990, 2 (Suppl. 5), 147. The hormones themselves: vasopressin and oxytolin and some of the peptide-derived peptides. Clinical Perspectives for Vasopressin Antagonists, Drug News Perspect., 1993,6 (8); North WG, J. Clin. Endocrinol., 1991, 73, 1316-1320. Legros JJ et al., Prog. NeuroPharmacol. Biol. Psychiat., 1988, 12, 571-586; Andersson, KE et al., Drugs Today, 1988, 24 (7), 509-528; Stump DL et al., Drugs, 1990, 39, 3853; Caltabiano S. et al., Drugs Future, 1988, 13, 25-30; Mura Y. et al., Clin. Nephrol. 1993, 40, 60-61; Faseb J., 1994, 8 (5), A587: 3398). Clinical Perspectives for Vasopressin Antagonists, Drug News Perspect., 1993,6 (8); North WG, J. Clin. Endocrinol., 1991, 73, 1316-1320. Legros JJ et al., Prog. NeuroPharmacol. Biol. Psychiat., 1988, 12, 571-586; Andersson, KE et al., Drugs Today, 1988, 24 (7), 509-528; Stump DL et al., Drugs, 1990, 39, 3853; Caltabiano S. et al., Drugs Future, 1988, 13, 25-30; Mura Y. et al., Clin. Nephrol. 1993, 40, 60-61; Faseb J., 1994, 8 (5), A587: 3398). 1993, 40, 60-61; Faseb J., 1994, 8 (5), A587: 3398). 1993, 40, 60-61; Faseb J., 1994, 8 (5), A587: 3398).

This type of V2 antifouling molecules with aquaretic profile (aquatic effect: increased volume and reduced osmotic density) has a wide range of behavioral potential, and is a major innovation in heart failure, fluid retention, fluid retention, fluid retention, and the like. Compounds can conveniently be used in the city of conventional diuretics in all diseased conditions, whether in humans or in animals. It is also possible, with such molecules, to provide hypertensive treatment in combination with antihypertensive agents other treatment types, as, for example, B

Or other antagonists of the anglotensin II receptor.

For a variety of reasons, the compounds according to the invention are useful especially for the treatment of central nervous and peripheral nervous system disorders of the cardiovascular system), the endocrine and laryngeal system, the kidney region, the gastroenterology, the ophthalmic and lung regions, the ophthalmic and the ophthalmic malignant sexual harassment, in humans and animals.

Another aspect of the present invention is therefore a pharmaceutical composition comprising an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, and a suitable carrier.

The named carriers are selected according to the drug-specific composition and behavior that is caused by administration.

In the pharmaceutical compositions of the invention for oral, tongue, subcutaneous, intravenous, sd, topical, oral, oral, active metabolites of formula (I) above, Its soluble aqueous composition is then administered as a unit of administration formulations, such as a mixture of conventional pharmaceutical pathways, administering animals and humans to behaviors of predisposed diseases and diseases. The dose of injected dosage dosage consists of intravenous formulations, such as flakes, gelatin capsules, powder, colloidal and oral solutions of the throat, tongue throat, mouth, throat, nasal congestion, subcutaneous and intravenous administration and analgesic conjugation. For topical use, the compounds according to the invention may be used in cream, ointment, fertilizer.

In case of impaired dysfunction and dysfunction, the dose of active substance may vary between 0.01 and 50 mg per kg body weight per day.

Each unit dose may contain 0.5 to 1000 mg, ranging from 1 to 500 mg, of active ingredient as a substitute pharmacologist. This unit dose may be administered 1 to 5 times a day for a daily dose of 0.5 μl 5000 mg and ranges from 1 to 2500 mg.

When a solid composition is prepared in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc.. The tablets are then made with sucrose, with cellulose derivative with ddrum video sources, so you can control them by controlling their cellular activity and thus losing continuous pre-determined amount of active ingredients.

Order the gelatin capsule. Mix the active ingredient with diluent and pour the mixture into a soft gelatin gelatin capsule.

Order the form of sirdps and elixirs for the administration of the form! drop can

The content of active substances in interconnection at the site, called low-density synthesis, methylparaben and propylparaben, as well as content that gives effect and video color.

Water-dispersible powders of this kind can contain active substances that are dispersed with dispersants such as wetting agents, solvents such as polyvinylpyrrolidone, as well as synthetic materials.

For rectal administration, solutions prepared with endocrine disrupters must be used as examples of cocoa butter of ethylene glycol polymer (polyethylene glycol)).

For non-digestive medicinal products, used as dispersed in aqueous solution, isotonic saline solution for oral solution containing a drug-compatible carrier and / or a fatty agent, such as propylene glycol or butylene glycol.

Active substances can also be presented in the form of microcapsules, including one or more additional materials, as well as alternatives to the matrix.

matrices), as well as the like, such as patches, the combination of controller drivers).

The compositions according to the invention are thus used in conjunction for the prevention of different vasopressin-like oxytocin-disruptive disorders and disorders of vasopressin edoxytolin secretion, cardiovascular system such as high throat, pulmonary arterial hypertension, cardiac failure, cardiovascular failure, cardiomyopathy, stroke coronary arrhythmias, especially in the smokers' nerve, dyspnoea and percutaneous transluminal coronary angioplasty (PTCA), cardiovascular dryness, hypercholesterolemia, especially haemophilia, or von Wlllebrand syndrome; disturbances of the central nervous system, migraine, cerebral sphincter, stroke, cerebral edema, depression, anxiety, macular dysfunction, dizziness of the nervous system, for example; kidney disease and disorders of renal function, fever and edema, renal insufficiency, renal disease, nephrotic syndrome, bleeding, hypokalaemia, diabetes mellitus, Schwartz-Bartter syndrome, and nymasteina; gastrointestinal disorders, such as stomach cramps, cirrhosis, stomach ulcers, malignant vomiting, such as nausea, including nausea due to drug retention, dyspnoea or other symptoms of urinary tract infections (SIADH), io epilepsy and abdominal disorder; resembles liver cells, like corpuscles; abdominal fluid retention and any conditions leading to unintentional fluid retention, disruptive function of renal disease (Cushing's disease) and especially corticosteroid and aldosterone syndrome. The compositions of the invention can also be used to treat sexual intercourse, excessive weight and obesity by replacing standard diuretics already in use. in a woman, can be used in combination with tide pads or premature birthright. The composition according to the invention can also be used in the treatment of small cell lung cancer, cataracts due to hyponatraemia,

Raynaud's disease, meniscus syndrome, lung syndrome, glaucoma and obstruction starved and post-operative behavior, especially after retinitis, cardiovascular disease and bleeding disorders.

Compositions of the present invention may contain additional additives of formula (I) above a pharmaceutically acceptable salt, solvate or aqueous formulation, as well as other active ingredients used in the treatment of such diseases.

For this reason, another part of the present invention is a pharmaceutical formulation containing more than one active ingredient in a composition, one of which is a compound of the invention.

Accordingly, according to the present invention, pharmaceutical compositions containing Compound of the present invention are formulated with a compound which acts on renin-anglotensin kerfid, such as inhibitor of the reverse-enzyme, angiotensin II antagonist, and renin hindrance. A compound according to the invention is also optionally assembled, for example, by extinction inhibitors, calcium inhibitors, B-blockers, anti-blockers. Such combinations make particular use of cardiovascular hypertension. A compound of the invention according to the invention can also be formulated: a specific antagonist of the receptor with a specific antagonist of oxytosin or V1 antagonist and V2 antagonist or Vj antagonist and Vj antagonist.

The compositions of the present invention contain advantageously the product of formula (1.3) or (1.4) above or more of pharmaceutically acceptable salts, solvents or hydrogens thereof. Each of these compounds can also be integrated with specific angiotensin II antagonists, called irbesartan.

These compositions make it possible to enhance the therapeutic activity of the compound according to the invention.

The following PREFERENCES and EXAMPLES explain the invention without limiting it.

Chemistry spectrum was measured in DMSO-d6 unless otherwise noted at 200 MHz and chemical gaps are expressed in ppm.

The following shortcuts are used:

s = singlet m = moles spot t = triplet q = quarter plate

PREPARATION 1 Alcohol with Formula (VI)

5-Ethoxy-3-spírá- (4-hydroxycyclohexane) inddlín-2-6n. Compound (VI.1) A solution of 22 g of 5-ethoxy-3-spiro- (4-methoxy-methyloxycyclohexane) indolin-2-one, prepared according to EP 636,608 in 130 ml of methanol and 9 ml of saturated hydrochloric acid (36%) is maintained at 40 ° for 3 hours. The reaction solution is cooled and the precipitate is then filtered off, washed with diethyl ether and dried to give a polar isomer of the expected product; bm = 225 ° C. Add 50 ml of water to the filtered phase and then evaporate the methanol, extract with dichloromethane and the organic phases are washed with water, dried and evaporated to give the resulting product as a mixture of isomers; bm = 170 ° C.

5-Chloro-3-spiro- (4-hydroxycyclohexane) indolin-2-one. The compound (VL2) is carried out according to the same procedure as above from 5-chloro-3-spiro- (4-methoxy-methyloxycyclohexane) -indolin-2-one prepared from 5-chloro-indolin-2-one according to method disclosed in EP 636,608. The resulting product is isolated, after extracting with dichloromethane, as a mixture of fumers; bm = 260 ° C.

CHARACTERIZED 2 Ketones of Formula (V)

5-Ethoxy-3-spiro- (4-oxocyclohexane) indolin-2-one. Compound (Vl)

3.8 g of 5-ethoxy-3-spiro- (4-hydroxycyclohexane) -indolin-2-one (VI.I) (A mixture of isomers) and 5.8 ml of pyridine are dissolved in 250 ml of ethyl acetate and

6.3 g of pyridine dichromate, collected on top of 29 g of neutral alumina, is added. The reaction solution is at 25 ° C for 16 hours, then the solvent is evaporated and the solvent is evaporated by the siada phase. 3.4 g of the expected product are isolated by recrystallization from toluene in the presence of activated carbon; bm = 168 ° C.

5-Chloro-3-spiro- (4-oxocyclohexane) indolin-2-one. Compound (V.2)

This compound is prepared according to the behavior and in the preparation

Compound (Vl) from 5-chloro-3-spiro- (4-hydroxycyclohexane) indolin-2-one (VI.2); bm = 220 ° C.

PREPARATION 3 Asetdl with Formula (IV)

5-Ethoxy-3-spiro- [4,4-di (2-chloroethyloxy) -cyclohexane] indolin-2-one.

Compound (IV.1)

3 g of 5-ethoxy-3-spiro- (4-oxosiclohexane) indolin-2-one (Vl) are dissolved in ml of toluene and 4.6 ml of 2-chloroethane, 20 g of 5 A molar and 0.22 g of methanesulfonic acid is out there. The reaction is slowly stirred for 18 hours at 20 ° C, then carried out and the materials are washed with dichloromethane.

The solvent is evaporated and the product expected is recrystallized from diethyl ether; bm = 170^eC.

5-Ethoxy-3-spiro- [4,4-di (3-chloropropyloxy) SIKLOS-hexane] indolin-2-one. Compound (IV.2)

The payment is made according to the same method as the preparation of

Compound (IV.1) from the same ketone (V1) and 3-chloropropanol; bm = 147 ° C.

5-Chloro-3-spiro- [4,4-di (2-chloroethyloxy) -cyclohexane] -indolin-2-one. Compound (IV.3)

The provision is carried out according to the same method as the payment of

Compound (IV.1) of Compound (V.2) and 2-chloroethanol; bm = 174 ° C.

PREPARATION 4 A derivative of formula (III)

5-Ethoxy-3-spiro [4- (3-chloropropyloxy) cyclohexane] indolin-2-one (A mixture of isomers). Compound (ΙΠ.1)

2.2 ml of 0.29M solution, cinoborohydride in diethyl ether (prepared according to the method described in Chem. Pharm, Bull., 1984, 32 (4), 1411-1415) is added slowly to 0.55 g of acetone (3 ml of dichloromethane, at 0 ° C, 0.34 ml of trimethylchlorosilane are thereafter. The reaction is stirred for 16 hours at

20 ° C and then, then 10 ml of saturated NaHCO3 solution is added, extract is carried out with ethyl acetate and the liver layers are washed with saturated NaCl solution. After drying over MgSO4 and evaporation, 0.4 g of oil is added, all of which is chromatographed on silica gel eluting with 8/2 (v / v) cyclohexane / ethyl acetate triphase mixture. The expected expected product (mixture of isomers) in form) 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-chloroethyloxy) cyclohexane] -indolin-2-one (A mixture of isomers). Compound (III.2)

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

¹H NMR, CDCl₃₃, 200 MHz: δ (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).

5-Chloro-3-spiro- [4- (2-chloroethyloxy) cyclohexane] -indolin-2-one (A mixture of isomers). Compound (III.3)

The catalyst is carried out according to the same procedure as preparation of Compound III.1 from the Compound (IV.3).

1 H NMR, DMSO-d 6 200 MHz: 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-Ethoxy-3-spiro- [4- (2-methyloxy) cyclohexane] -indolin-2-one, Compound (m.4)

At 0 ° C, 17.97 g of tosyl chloride is added to 19.25 g of compound (ΙΙΓ1) as described in the order of X, 130 ml of pyridine. The reaction mixture is stirred at 20 ° C for 3 hours. The reaction solution is poured 650 ml of water and then 30 minutes. 28.06 g of the expected product were isolated after filtration, washing with water and drying at 40 ° C under vacuum in the presence of phosphoric anhydride. The product obtained by the polar isomerism (ΙΙΓ1) breaks at 152 ° C.

PREPARATION 5 derivative of formula (IIA)

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

Compound (IIA.1)

0.29 g of potassium tert-butoxide is added to a solution of 0.75 g of chlorinated derivative (III.2) and 0.75 g of 4- (N-tert-butyl-carbamoyl) -2-methoxybenzenesulfonyl chloride in 90 ml of tetrahydrofuran, which has cooled about -60 ° C. The temperature is allowed to rise to 20 ° C, the reaction is stirred for 2 hours, 30 ml of 15% NaCl solution is then added and then extracted with ethyl acetate, the whole layers are washed with a 15% NaCl solution, anhydrous phase Dry over MgSO4. The solvent is evaporated and the precipitate is chromatographed by chromatography and silica gel eluting with 85/15 (v / v) cyclohexane / ethyl acetate stirrer mixture to isolate the products expected in the form of resins.

1 H NMR, DMSO-d 6 200 MHz: δ (m, 2H), 7.5 (m, 3H), 7.04 (s, 0.75H), 6.85 (m, 1.25H), 4.0 (q, 2H), 3.6 , 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-l- [4- (N ', N'--diethylureido) -2-methoxy-bensensúlf6nýl] -3-spiro- [4- (2-tosyloxyethyloxy) cyclohexane] indolin-2-one. Compound (II A. 2) At 0 ° C, 0.25 g of tosyl chloride bstt (solution of 0.18 ml of triethylamine and 0.25 g of 5-ethoxy-1- [4- (N ', N'-diethylureido) -2- methoxybenzenesulfonyl] -3-spiro- [4- (2-hydroxyethyloxy) cyclohexane] indolin-2-one (prepared from EP 0.636.608) 3 ml of anhydrous tetrahydrofuran. The reaction is stirred for 48 hours at 20 ° C, 10 ml of a mettadic NaHCO3 solution is added and then, extracted with ethyl acetate, the resulting phases are dried over MgSO4, the solvent is evaporated and the precipitate is chromatographed on chromatography on silica gel, phase gas: 99/1 (v / v) and then 95/5 dichloromethane / methanol; bm = 80 ° C.

5-ethoxy-l- [4- (N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -3-spiro- [4- (2-tosyloxyethyloxy) cyclohexane] indolin-2-one. Compound (II A.3)

The product obtained was isolated in a similar manner to the preparation

Compound (II A.2) by 5-ethoxy-1- [4- (2-hydroxyethyloxy) cyclohexane] indolin-2-one by reacting together 4- (N-tert-butylcarbamoyl) -2-methoxy- benzenesulfonyl chloride and compound (III.4) in the conditions described in Preparation of the Compound (IIA.1); bm = 142 ° C.

PREPARATION 6 Alcohol with Formula (ΙΑ)

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

a) 5-Ethoxy-3-spiro- [4- (2-nitrooxyethyloxy) -cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one. Compound (ΙΑ1) A mixture of 0.6 g of Compound (Π Al), 0.8 g of sodium nitrate and 0.25 g of sodium iodide in 10 ml of acetonitrile is refluxed for 48 hours. Your time is separated by filtration and the solvent is evaporated. The resulting precipitate is isolated by chromatography on silica gel eluting with 80/20 (v / v) cyclohexane / ethyl acetate stirrer mixture; bm = 80 ° C (hydrate).

b) 0.5 g of nitrate above, 0.5 ml of cyclohexene and 0.5 g of 10% palladium-on-charcoal is heated at reflux for 11 hours 115 ml of ethanol, the catalyst is separated by filtration, the solvent is evaporated and the precipitate is degraded chromatographed on silica gel eluting with dichloromethane as a phase phase and page 99/1 (v / v) dichloromethane / methanol as a phase preparation. Mix with

The expected isomers of the Arctic are isolated; bm = 120 ° C (semi-hydrate), the skautada isomer is then isolated, a crystal of isopropyl ether and ethyl acetate binder (1/1 v / v); bm = 189 ° C (hydrate).

5-Ethoxy-3-spiro- [4- (3-hydroxypropyloxy) -cyclohexane] -1- [4- (N-tB / t-butylcarbamoyl) -2-methoxy-benzenesulfonyl] indolin-2-one. Compound (ΙΓ A.2)

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

5-Ethoxy-3-Spiro- [4- (3-methoxymethyloxypropyloxy) -cyclohexane] indolin-2-one (II) 2 from Preparation X is concentrated at N-tert-amylcarbamoyl-2-methoxysulfonyl chloride according to the process described ITILREIDSLU V, Telephones receive the expected products, which are loaded as it is for the next step.

b) A mixture of 0.5 g of Compound Compound I a) 11.5 ml of methanol and 0.2 ml of methaturated hydrochloric acid (36%) is heated at 50 ° C for 11 hours.

ml of water is extracted, extracted with ethyl acetate, the solvents are evaporated and the expected yield is isolated by chromatography on silica gel eluting with 1/1 (v / v) cyclohexane / ethyl acetate phase gas mixture; bm = 120 ° C.

PREPARATION 7 lindolin-2-one of formula (II.B)

5-Chloro-3-spiro- [4- (2-morpholinoethyloxy) -cyclohexane] indolin-2-one (A mixture of isomers).

Compound (Q B.1) iO A mixture of 0.57 g of Compound (III.3), 0.5 g of morpholine and 0.27 g of

6 ml of dimethylformamide is heated for 24 hours at 85 ° C. Add 10 ml of water to the reaction mixture and add 10 ml of saturated NaHCO3 and then extract the extract twice with ethyl acetate, the organic layers are purged over MgSO4, the solvent evaporated and the precipitate is chromatographed on silica gel eluting prepared with dichloromethane as a phase phase and with 98/2 (v / v) dichloromethane / methanol phase gas mixture to isolate 0.5 g of the product obtained in the form of 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-spiro- [4- (2-N-tert-butyloxycarbonyl-N (benzyloxycarbonylmethyl) amino) ethyloxy) cyclohexane] -indolin-2-one (A mixture of isomers). Compound (II B.2)

1.5 g of tosylate (ΙΠ.4) (A mixture of isomers),

0.66 g of benzylglycine hydrochloride and 0.35 of sodium carbonate. In 80 ml of acetonitrile is heated at 60 ° C for 48 hours. The solvent is evaporated at low pressure, the precipitate is taken up with 40 ml of ethyl acetate, the liver is washed with water, dried over Na2SO4 and the solvent is evaporated. The precipitate is chromatographed on silica gel eluting with 99/1 (v / v) dichloromethane / methanol crude mixture and the residue is isolated, which is then dissolved in 20 ml of dioxane. 0.13 g of MgO and 0.539 g of di-tert-butyl dicarbonate dissolved in 110 ml of dioxane is added at 5 ° C and the reaction is stirred at 20 ° C for 16 hours. The solvent is evaporated, precipitated with ethyl acetate, the whole solution is then washed with a buffer pad at pH = 2, a saturated sodium bicarbonate solution and water.

The drying is carried out with Na2S (&gt; 4 and the solvent is evaporated. After purification by chromatography on silica gel, a pair of elution is carried out with 5/5 (v / v) ethyl acetate / cyclohexane triphase mixture, the product obtained is obtained in the form of resin .

³¹ 1949

1H NMR: 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, 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-butyloxycarbonyl-amino) ethyloxy) cyclohexane] indolin-2-one. Compound (II B.3)

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

A mixture of 1.5 g of Compound (III.4) (obtained from the polarizer (ΙΙΓ1)) and 0.23 g of sodium azide 15 ml of dimethylformamide is heated at 50 ° C for 16 hours. 30 ml of water is added, extraction is performed twice with ethyl acetate. The liver layers are dried over Na2SO4, the solvent is evaporated by partial pressure under reduced pressure until the volume is about 20 ml.

Nefhd solution is hydrogen at 60 ° C under 10θ Pa pressure in 0.6 g of Llndlar catalyst (Palladium over CaCO3). The catalyst is filtered off and the solvent is evaporated at reduced pressure. The precipitate is chromatographed on silica gel column eluting with 90/10 (v / v) dichloromethane / methanol stirring agent. The resulting hydrate hydrochloride of the product was isolated after recrystallization of the base in ethyl acetate followed by hydrochloroate in ethyl acetate; bm = 168 ° C.

b) Dissolve 0.4 ml of 2N sodium hydroxide, 0.05 g of magnesium oxide and 0.19 g of di-fezt-butyl dicarbonate. In 7 ml of dioxane, leave 0.27 g of the above-mentioned compound in 20 ml of dioxane at + 5 ° C . After stirring for 2 hours at 20 ° C, the solvent is evaporated and the ethyl acetate is slowly precipitated, the organic phase is washed with a buffer solution with a pH of 2, with sodium citric acid solution and water, each successively. Drying is carried out with Na2 SO4, the solvent is evaporated and the expected product is isolated in the form of resin.

* H RMN: 10.02 (s, 1H); 6.91 (s, 1H); 6.68 (s, 2H); 3.92 (q, 2H); 3.553.35 (m, 3H); 3.05 (m, 2H); 2.05-1.45 (m, 8H); 1.36 (s, 9H); 1.27 (t, 3H).

CHARACTERISTICS 8 Hydrazide Formula (VII)

N '- (4-Ethoxyphenyl) -4,4-ethylenedioxysiclohexane) carbohydrate. Compound (Vn.l)

At -40 ° C, 1.65 ml of isobutylchlorophthalate is added to a volume of 2.63 g of sodium 4,4-ethylene-dioxysiclohexanoate in 20 ml of tetrahydrofuran, and 1.8 ml of triethylamine is added. The reaction mixture is stirred for 2 hours at 0 ° C, 2.4 g of 4-ethoxy-phenylhydrazine hydrochloride is then added at -20 ° C, the reaction is rapid for 2 hours at 0 ° C, 100 ml of water is then poured out and extraction is performed with ethyl acetate. The lifraenu phases are then washed with water, KHSO4 solution (pH 2) and mettadri potassium carbonate solution, dried over MgSO4 and evaporated. The expected yield is obtained after crystallization from diethyl ether, bm = 158 ° C.

N'-phenyl-4,4-etýlendíoxýsíklóhexancarbohýdrasíð. Compound (VH.2)

Similarly, compound (VII.2) is derived from phenylhydrazine. m.p.

= 158 ° C.

PREPARATION 9 Asetdl Formula (IV ')

5-Ethoxy-3-spiro- (4,4-etýlenedioxysíklóhexan) indolin-2-one. compound

IV'.l

At -50 ° C, 2.15 ml of 1.6M solution of butyl lithium hexane is added to a slurry which is 1 g of hydrazide (V1.1.1) 16 ml of tetrahydrofuran. The reaction mixture is stirred for 15 minutes and 16 ml of tetralin is added. Tetrahydrofuran is eluted and heating is carried out at 180 ° C for 45 minutes.

If 20 ml of ethyl acetate are then left at room temperature, then wash with water, the liver is thickened over MgSO 4, the solvents are concentrated in vacuo and the precipitate is chromatographed on silica gel eluting with 7/3 (v / v) ) cyclohexane / ethyl acetate reaction phase. The expected product is isolated by crystallization from diethyl ether; bm = 183 ° C.

The same product is also obtained with the reaction of 5-ethoxy-3-spiro- (4-oxo-cyclohexane) indolin-2-one (Compound VI) with ethylene glycol in hexane hexane with a 5A molecular weight and a catalytic amount of para-toluenesulfonic acid.

5-Ethoxy-3-spiro- (4,4-própýlendíoxýsíklóhexan) indolin-2-6n.

Compound (IV'.2)

The reaction is carried out according to the procedure described above in the presence of compound (IV'.l) from the corresponding hydrazide with the reaction of 5-ethoxy-3-spiro- (4-oxosiclohexane) indolin-2-one (Compound ( Vl)) at 1,3-propanediol in cyclohexane (vidurvist 5 A molar oil and catalytic amount of para-toluenesulfonic acid; bm = 216 ° C.

3-spiro- (4,4-etýlendíoxýsiklóhexan) indolin-2-one. Compound IV * 3. Assay is performed according to the behavior described above in addition to the compound (IV'1) with the corresponding hydrazine (VII.2) as the starting material; '

Bm = 218 ° C.

EMERGENCY Alcohol of Formula (III ') and (III' P)

5-Ethoxy-3-spiro- [4- (2-hydroxyethyloxy) cyclohexane] indolin-2'ón.

Compound (ΙΠ'.Ι)

At 0 ° C, 20.2 ml of 0.25M solution of cyanoborohydride in diethyl ether (prepared according to the method described in Chem. Pharm, Bull., 1984, 32 (4), 14111415) was added slowly to 3.1 g of acetylene IV'.1 in 20 ml of dichloromethane, and then 2.8 ml of trimethylsilyl chloride is added. The reaction mixture is stirred for 16 hours at 20 ° C, 20 ml of saturated NaHC (&gt; 3 solution is then added and then the solvent is evaporated, extracted with ethyl acetate, drying is carried out over MgSO4 then the solvent is evaporated and the precipitate is evaporated purified by chromatography on silica gel eluting with 67/34 (v / v) cyclohexane / ethyl acetate reaction mixture. A mixture of the isomeric isomers expected to isolate, followed by skating the isomer, which is crystallized from diethyl ether, bm = 125 ° C.

5-Ethoxy-3-spiro- [4- (3-hýdroxýprópýloxy) cyclohexane] ind6lín-2-one. Compound (ΠΓ.2)

The action has been carried out in accordance with the behavioral approach and above

IS Compound (ΙΙΓ.1) from the acetal (IV'.2). The skautada (diluted solder product obtained is obtained; bm = 180 ° C (semi-hydrate).

5-Ethoxy-3-spiro- [4- (3-methoxymethyloxypropyloxy) -cyclohexane] indole (n-2-one) Compound (ΙΙΓ.2Ρ)

A solution of 1 g of 5-ethoxy-3-spiro- [4- (3-hydroxy-20-propyloxy) -cyclohexane] indolin-2-one (ΙΙΓ.2), 7.7 ml of dimethoxymethane, 0.065 g of LiBr and 0.07 g of para- Toluene sulfonic acid 15 ml of dichloromethane is stirred for 24 hours at room temperature and 10 ml of a saturated NaCl solution is added. Adhering is carried out and the organic phase is dried over MgSO4 and the solvent is eluted, yielding a polarized phosomal product expected after chromatography on silica gel eluting with 1/1 (v / v) cyclohexane / ethyl acetate phase phase; bm = 89 ° C.

PREPARATION 11 Varnished alcohol of formula (X)

5-Ethoxy-3-spiro- (4-methoxymethyloxycyclohexane) -l- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one. Compound (X1)

0.283 g of potassium tert-butoxide is made up of a solution of 5-ethoxy-3-spiro (4-methoxy-methyloxycyclohexane) indolin-2-one (Compound of Formula (XI)) prepared according to EP 636,608 in 80 ml of tetrahydrofuran, which is cooled to -40 ° C. The temperature is allowed to warm to 0 ° C, then the mixture is cooled to -40 ° C and 0.73 g of (2-methoxy-4-N-tert-butylcarbamoyl) benzenesulfonyl chloride in 7 ml of tetrahydrofuran is added. The reaction mixture is stirred for 2 hours at room temperature and then, 20 ml of water is added, extraction is carried out with ethyl acetate, drying is carried out over MgSO4, the solvent is evaporated and the oil obtained is purified by chromatography on silica gel eluting with 8 / 2 (v / v) cyclohexane / ethyl acetate tripase mixture. The smaller polar isomers of the expected product are isolated; bm = 165 ° C, then skating the isomer; bm = 156 ° C.

PREPARATION 12 Alcohol of Formula (IIc)

5-Ethoxy-3-spiro- (4-hydroxycyclohexane) -l- [4- (N-tert-butylcarbamoyl) -2metoxýbensensúifónýl] indolin-2-one. Compound (Hc.l)

A mixture of polar ice (zomer compound (X1) in 1.2 ml of methanol and

0.24 ml of mettadric hydrochloric acid (36%) is heated at 50 ° C for 1 hour. Add 8 ml of water and then, extraction is carried out with dichloromethane, the complete layers are dried over MgS (&gt; 4 and the solvents are evaporated. The resulting product is obtained after purification by chromatography on silica gel eluting with dichloromethane as a phase phase;

Bm = 268 ° C (sketchy isomer).

Similarly, from the least polarized fsomer prepared according to (X.1), the least estimated isomer of the product expected is isolated; bm = 130 ° C (semi-hydrate). Compound (Ilc.2)

PREPARATION 13 Reactor of Formula (2)

2-Methoxy-4- N-tert'amýlkarbamóýlbensensúlfonýlklóríd. Reagents (2) .1

a) N-tert-amyl-3-methoxy-4-nitrobenzamide

At 10 ° C, 30 ml of tert-amylamine was dissolved in a solution of 27 g of 3-methoxy-4-nitrobenzoyl chloride (obtained from 25 g of the corresponding acid and thionyl chloride at reflux for 4 hours, then evaporation at the ceiling) ml of dichloromethane. The reaction is stirred For 30 minutes at 20 ° C, 100 ml of 1N hydrochloric acid solution is then removed, the organic phase is separated by allowing it to settle, washed and dried over MgSO4, the solvent is then evaporated and the precipitate is chromatographed on silica gel, eluting with dichloromethane as a phase phase, yielding 31 g of the expected product; bm = 65 ° C.

In the same manner as from N-tert-butylamine, N-tert-butyl-3-methoxy-4-nitrobenzamide is prepared; bm = 118 ° C.

b) N-tert-amyl-3-methoxy-4-aminobenzamide

A mixture of 31 g of N-tert-amyl-3-methoxy-4-nitrobenzamide obtained from a) 10% palladium-on-carbon and 76 ml of cyclohexene in 310 ml of ethanol is heated at reflux for 3 hours. The mixture is then filtered and the mixture is evaporated to yield 25 g of the expected product; bm = 108 ° C.

Similarly, from the compound N-te / t-butyl-3-methoxy-4-nitrobenzamide, N-tert-butyl-3-methoxy-4-aminobenzamide is prepared; bm = 160 ° C.

c) 2-Methoxy-4-tert-butylcarbamoylbenzenesulfonyl chloride.

At 0 ° C a solution of 7.9 g of sodium nitrite in 31 ml of water was added to a solution of g of N-tert-amyl-3-methoxy-4-aminobenzamide and 103 ml of acetic acid and 187 ml of 36% hydrochloric acid. The reaction mixture is for 1 hour at 0 ° C and then this solution stored at 0 ° C is poured into a slurry of 6.8 g of copper chloride In 25 ml of water and 140 ml of acetic acid at 0 ° C with about 69 g of sulfur dioxide. The reaction is stirred at 0 ° C for 3 hours and then at 20 ° C for 16 hours and the flask is poured onto 750 g of ice and then stirred for 1 hour at 20 ° C. The precipitate is filtered off and then purified with water and dried under air for 148 hours to give 19 g of the product obtained. bm = 104 ° C.

4- N-tert-Butylcarbamoyl-2-methoxybenzenesulfonyl chloride. Reagents (2) .2 Similarly, from N-tert-butyl-3-methoxy-4-amino-benzamide, the reaction material is expected to be isolated; bm = 148 ° C.

3-Methoxy-4-bensýloxykarbónylbensensúlfónýlklóríð. Reagents (2) .3

Using the same reaction as above, a benzyl ester of 4-amino-3-methoxybenzoic acid (Bm = 72 ° C, resulting from reduction of the corresponding nitrous oxide with tin of a hydrochloric acid moiety;

Bm = 88 ° C), the reagent used was isolated;

Bm = 55 ° C.

N-tert-Butyl-4-bromomethyl-3-methoxybenzamide. Reagents (2) .4 A mixture of 3 g of N-tert-butyl-4-methyl-3-methoxybenzamide, 2.4 g of Nbromosuccinimide and 0.16 g of benzoyl peroxide 140 ml of carbon tetrachloride is stirred at 30 ° C and radiant simultaneous Visible for 48 hours.

The solvent is evaporated and then thereafter 25 ml of water are added, extraction is carried out with diethyl ether, drying is carried out over MgSO 4, the solvent is evaporated and the precipitate is separated by chromatography on silica gel elution performed with 8/2 v / v) cyclohexane / ethyl acetate phase gas. The resulting reaction mixture is isolated after crystallization from isopropyl ether; bm = 114 ° C.

EXAMPLE 1

5-Ethoxy-1- [4- (N-tert-butylcarbonyl) -2-methoxy-benzenesulfonyl] -3-spiro [4- (2-moriolinoethyloxy) cyclohexane] indolin-2-one.

(I): Rt = 5-OC₂H₅; R₂ = H; R₃ = 2-DCH₃; W = SO₂;

R₄ = 4-CONHC (CH3)₃ ; TZ = -CH₂CH₂-_O:

least skated isomer.

A mixture of 0.6 g of the chlorinated dinner (Π A.1) obtained according to PREPARATION 5, 0.26 g of morpholine and 0.15 g of sodium iodide In 6 ml of dimethylformamide is heated at 60 ° C under an unsuccessful gas for 40 hours. The solvent is evaporated under aerosol and then, the precipitate is taken up in 20 ml of 5% NaHCO₃ aqueous solution, extracted with ethyl acetate, the whole layers are washed with 10% Na solution and dried over the solvent evaporated and the resin is isolated, color chromatography on silica gel eluting with 98/2 (v / v) dichloromethane / methanol phase preparation .

The least dashed isomer of the expected product is isolated (Rf =

0.5; kisil TLC; 95/5 (v / v) dichloromethane / methanol). Fumarate is prepared in acetone and is crystallized from diethyl ether; bm = 153 ° C (EXAMPLE 1).

1 H NMR, DMSO-d 6 200 MHz: 8.0 (m, 2H), 7.5 (m, 2H), 7.4 (s, 1H), 6.88 (d, 1H), 6.82 (s, 1H), 6.6 (s, 2H , fumaric acid), 4.0 (q, 2H), 3.6 (s, 3H), 3.55 (m, 7H), 2.45 (m, 6H), 2-1.4 (m, 8H), 1.34 (s, 9H), 1.3 t, 3H).

EXAMPLE 2

5-Ethoxy-l- [4- (N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -3-splró- [4- (2-morpholinoethyloxy) SIKLOS-hexane] indolin-2-one.

(I): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

γλ

R₄ = 4-CONHC (CH 3)₃ I TZ = -CH₂CH₂-_O:

most skated isomer.

The most sketched isomer of the product is prepared above the same as EXAMPLE 1 is isolated by the above-mentioned epithelium; Rf = 0.43; bm = 212 ° C-216 ° C.

1 H NMR, DMSO-d 6 200 MHz: 8.0 (m, 2H), 7.5 (m, 2H), 7.4 (s, 1H), 7.03 (s, 1H); 6.84 (d, 1H), 6.6 (s, 2H, fumaric acid), 4.0 (q, 2H), 3.6 (s, 3H), 3.5

6H), 3.40 (m, 1H), 2.45 (m, 6H), 1.9-1.6 (m, 8H), 1.34 (s, 9H), 1.3 (t, 3H).

Fumarat is prepared in acetone and is crystallized from diethyl ether; bm = 172 ° C (EXAMPLE 2).

Water hydrogen dihydrogen phosphate is prepared by reacting water. phosphoric acid at the base (ethanol; bm = 170 [deg.] C. Nitrate is prepared by reacting nitric acid aqueous solution at the base in ethanol; bm = 155 ° C.

EXAMPLE 3

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

(I): R_x = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-NHCON '; τ-ζ = -CH 2 Cl 2 -N.

^Χ0_Λ

A mixture of 0.23 g of the tosylate derivative (II A.2) obtained above above. PREPARATION 5.3 ml of acetonitrile and 0.23 ml of 40% dimethylamine aqueous solution is stirred for 48 hours at 20 ° C. 1 ml of a solution of NaHCO3 solution is followed, followed by extraction with ethyl acetate, drying over MgSO4, the solvent is evaporated and the precipitate is chromatographed by chromatography on silica gel eluting with dichloromethane / methanol / ammonia aqueous solution (245 / 5 / 0.2 v / v / v) pharmaceutical composition; (Rf = 0.5; silica gel TLC; 85/15/1 v / v / dichloromethane / methanol / ammonia aqueous solution); bm =

103 ° C.

Example 4

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

(I): Rx = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R4 = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂NH₂

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

A mixture of 0.5 g of chlorinated crustaceans (II A.1) obtained above above

PREPARATION 5, 0.06 g of sodium azide and 0.126 g of sodium iodide 5 ml of dimethylformamide is heated at 100 DEG C. under a vacuum for 2 hours. 10 ml of water is made up of the reaction solution, then extracted with ethyl acetate and, afterwards, the resulting solids are washed with water and dried over Na₂SO4 and the volume of the solution is a reduction of the amount to be added in 20 ml to a solution of asbestos solution as used in the following reaction.

b) A solution obtained at 40 ° C For 60 hours, under 10θ Pa pressure in vials 0.2 g of palladium / CaCO₃ (Lindlar catalyst; 5% Pd). The catalyst is separated by filtration, the solvent is evaporator and the precipitate is a color difference on a silica gel column. elution performed with 8/2 (v / v) dichloromethane / methanol crude phase preparation.

The expected expected product is isolated in the form of a base and is precipitated as a salt of fumaric acid in acetone and crystallized from isopropyl ether to provide the expected expected volatility; bm = 138 ° C (elhydrate).

In the same manner, from the compound (II A.3) and by several steps, the polar isomer of the product which was suspended from the isolated, semi-hydrogenated hydrochloride isomer melting at 174 ° C.

EXAMPLE 5

5-Klór6-3-spiro- [4- (2-mortólínóetýloxý) SIKLOS-hexane] -l- [4- (N-íeftbútýlkarbamóýl) -2-methoxybenzene-sulfonyl] indolin-2-one.

(I): R_X = 5-Cl; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R₄ = 4-CONHC (CH 2)₃ ; T - Z = -CH₂CH₂- _0

0.073 g of potassium tert-butoxide is added to a solution of 0.21 g of Compound (IIb1) obtained according to PREPARATION 7 in 24 ml of tetrahydrofuran, which has always been cooled to -30 ° C. The temperature is allowed to cool at 0 ° C, the mixture is then cooled to -40 ° C and 0.19 g of [2-methoxy-4- (N-tert-butylcarbamidyl)] benzenesulfonyl chloride in 2 ml of tetrahydrofuran is added. The reaction mixture is then stirred for 2 hours at -10 ° C, 15 ml of water is added and then extracted with ethyl acetate, drying is carried out with MgSO 4 then the solvent is evaporated and the residue is purified by chromatography on silica gel , eluting with dichloride methane phase and then med

96/4 dichloromethane / methane preparation phase. The skautada ice cubes of the captured product are isolated and are precipitated as a salt of fumaric acid in acetone. Fumaratid is crystallized from diisopropyl ether; bm = 107 ° C (tri-half hydrate).

EXAMPLE 6

5-Ethoxy-3-spiro- [4- (2-carboxyethyloxy) cyclohexane] -l- [4- (N-te / tamýlkarbamóýi) -2-methoxybenzenesulfonyl] indolin-2-one.

(I): Rj = 5-OC₂H5; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

CH

I

R 1 = 4-CONH -C-C₂H₆ ; T - Z = -CH₂CH₂- COOH

I

CH₃

At 0 ° C, 1 g of krdmoxide is added in a mixture of 1.5 g of Compound (ΙΓ

A.2) obtained according to Accession 6 in 9 ml of acetic acid and 10 ml of water. The reaction solution is faster for 20 hours at 20 ° C, 80 ml of water is then filtered off and, afterwards, extracted with ethylacetate, the liver is filtered over MgSO4, the solvent is evaporated and the product obtained is isolated by Separation of silica gel eluting with 99/1 (v / v) dichloromethane / methanol feidaphasic acid; bm = 108 ° C (semi-hydrate).

EXAMPLE 7

5-Ethoxy-3-spiro- (4-etoxýkarbónýlmetýloxýsíkló-hexane) -l - [(4-N-te / -butylcarbamoyl-2-methoxy) benzene-sulfanyl] indolin-2-one.

(I): R j = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R4 = 4-CONKC (CH₃)₃; TZ = -CH₂COO-C₂H₅At 0 ° C, 0.47 g of 2,6-di-tert-butylpyridine, 0.54 g of silver trifluoromethanesulfonate and then 0.27 ml of ethyl iodoacetate are added to a solution of 0.75 g of 5-ethoxy-3-spiro- (4-hydroxy-5-cyclohexane) 1- [4- (N-tert-butyl) amyl) -2-methoxybenzenesulfonyl] indolin-2-one (Q.C1) in 30 ml of dichloromethane. The reaction mixture is stirred for 48 hours at 20 ° C and then the reaction is filtered, the solvent is evaporated and the product is expected to be isolated by chromatography on silica gel eluting with cyclohexane as phase phase and then with 20/80 (v / v) cyclohexane / dichloromethane precipitate, and recrystallized from isopropanol; bm = 165 ° C.

EXAMPLE 8

5-Ethoxy-3-spiro- (4-carboxymethyloxycyclohexane) -l- (4-N-te / -butylcarbamoyl-2-methoxybenzenesulfonyl) indolin-2-one.

(I): Rj = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R4 = 4-CONHC (CH₃)₃; TZ = -CH₂COOH

0.34 g of the product obtained in EXAMPLE 7 and 0.01 g of para-toluenesulfonic acid in 3 ml of benzyl alcohol is heated at 65 DEG for 16 hours. The solvent is evaporated and then thereafter is 1 ml of water and 1 ml of mettadri

NaHCO₃ solution is added outside, extract is performed with ethyl acetate, the solvent is evaporated and then added 5 ml of isopropanol, 0.25 g of 10% palladium-on-carbon and 0.25 ml of cyclohexene. The reaction mixture is heated at 80 ° C for 3 hours and then the reaction mixture is filtered off, the catalyst is purified with methylene chloride, the solvents are evaporated and the product obtained is isolated and purified by chromatography on silica gel eluting with 98/2 (v / v) dichloromethane / methanol phase gas. The expected yield of the product is recrystallized from 8/2 (v / v) isopropyl ether / ethyl acetate soluble; bm = 175 ° C (semi-hydrate).

EXAMPLES 9 to 23 described in TABLE 1 hereafter below are prepared, namely, DIMENSIONS 1 to 8 above.

TABLE 1

<img file="IS1949B_D0020.tif" />

<td>EXAMPLE</td><td>R</td><td>w</td><td>«4</td><td>T</td><td>z</td><td>salts</td><td>m.p.</td>

<td>number</td><td></td><td></td><td></td><td></td><td></td><td>lausnarefn</td><td>9</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>1 (1)</td><td>° C</td>

<td>9</td><td>OC₂h₅</td><td>SO₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>OH</td><td>1 h₂o</td><td>170</td>

<td>10</td><td>Cl</td><td>so₂</td><td>-OCH₃</td><td>- (CH₂) 2</td><td>Q</td><td>fumarate 1.5 h₂O</td><td>88</td>

<td>12</td><td>OC₂h₅</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂) 3-</td><td>Q</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>Q</td><td>fumarate 2H₂O</td><td>170</td>

TABLE 1 (continued 1)

<td>Dami number</td><td>R</td><td>w</td><td>R4</td><td>T</td><td>z</td><td>salt, lausnarefn i (1)</td><td>mp; ®C</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 1H₂O</td><td>150</td>

<td>17</td><td>OC₂h₅</td><td>so₂</td><td>ch₃1 -CONHCCHjCHj CH</td><td>- (CH₂)₂-</td><td>Q</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 H₂O</td><td>190</td>

<td>19</td><td>OC₂h₅</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>h</td><td>fumarate 4 H₂O</td><td>208</td>

<td>20</td><td>OC₂h₅</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>CH IC -N-CH</td><td>fumarate 1 H₂O (2)</td><td>104</td>

TABLE 1 (continued 2)

<td>Examples number</td><td>R</td><td>w</td><td>R4</td><td>T</td><td>Z</td><td>Saif, lausnarefn Id)</td><td>mp; "C</td>

<td>21</td><td>OC₂h₅</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂) 2</td><td>CH NfCH ^ jOCHj</td><td>fumarate 1.5 H₂O</td><td>100</td>

<td>22</td><td>-OC2H5</td><td>s &lt;&gt; 2</td><td>CONHC (CH₃)₃</td><td>- (CH2) 2-</td><td>\ 0 V-nch,</td><td>dioxalat 1H₂O</td><td>224</td>

<td>23</td><td>OC₂h₅</td><td>SO2</td><td>CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>«(CHjCH / JCtyj</td><td>fumarate 1H₂O</td><td>98</td>

<td>24</td><td>H</td><td>S0₂</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>S0₂</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>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH2)₂-</td><td>1 NH ioOC (CHJ,</td><td>h₂o</td><td>114</td>

<td>27</td><td>-OC2H5</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂) 2</td><td></td><td>HCl h₂o (4)</td><td>150</td>

<td>28</td><td>OC₂h₅</td><td>so₂</td><td>-COOCH2C6H5</td><td>- (CH₂) 2</td><td>Q OH</td><td>h₂o</td><td>80</td>

Tafia 1 (continued 3)

<td>examples number</td><td>* 1</td><td>w</td><td>R4</td><td>T</td><td>z</td><td>salt, lausnarefn 1 (1)</td><td>mp; ° C</td>

<td>29</td><td>OC₂H₅</td><td>so₂</td><td>-COOCH₂CgH5</td><td>- (CH₂)₂</td><td>9 OCHjCgHð</td><td>(4)</td><td>55</td>

<td>30</td><td>OCH2C5H 5</td><td>so₂</td><td>CONHC (CH₃)₃</td><td>- (CH₂)₂</td><td>Q</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 (CH₂C6H_S) (CH₂)₂O (CH ^ H</td><td>(5)</td><td>69</td>

(4): The 4-hydroxypiperidine ethers are obtained by alkylation of N-tert-butyloxycarbonyl-4-hydroxypiperidine ether. The mixture of isomers (3) hydroxy-piperidine and the corresponding halide presence of sodium hydride and then acidic hydrolysis of the tert-butyloxycarbonyl group.

(5): 2- (2- (N-benzylamino) ethoxy) ethanol was prepared with afoxanamine amination with sodium borohydride on the imine obtained from 2- (2-aminethoxy) ethanol and. benzaldehyde, in methanol and at 0 ° C.

EXAMPLE 32

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

(I): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

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

a) 0.33 g of benzyloxyacetaldehyde and then 0.46 g of sodium triacetoxyborohydride is added an external solution of 0.9 g of aminochloride of EXAMPLE 4 (polar isomers) in 8 ml of tetrahydrofuran, cooled to 5 ° C. The reaction mixture is stirred at 20 ° C for 3 hours, 10 ml of 1N HCl is added, extract is carried out with ethyl acetate, the organic phase is concentrated with a saturated NaCl solution, dried over MgS (4) and the solvent is evaporated under ice-cold pressure. The precipitate is chromatographed on silica gel column eluting with 98/2 (v / v) dichloromethane / methanol stirrer mixture.

b) 0.4 ml of 1,4-cyclohexadiene, 0.3 g of (10%) palladium / C is the off-white benzyl ether obtained, dissolved in 5 ml (sediment and heated at 60 ° C under a bulging nitrogen for 16 hours according to the behavior described], Org., Chem., 43, 21 (1978).

The catalyst is filtered off, 10 ml of water is poured into a reaction mixture which is neutralized with methtadri NaHCO₃ solution; extract is carried out with ethyl acetate, powder is carried out with water, dried over MgSO4 and the solvent is evaporated under ice-cold pressure. The precipitate is chromatographed on silica gel column eluting with 98/2 (v / v) dichloromethane / methanol phase gas mixture. The resulting product is isolated in the form of hydrate hydrochloride by the preparation of hydrochloride with hydrochloric acid isopropanol solution and crystals of diethyl ether, Bm = 130 ° C.

EXAMPLE 33

5-Ethoxy-3-spiro- [4- (2- (2- (2-hydroxyethyloxy) ethyl) ethyloxy) cyclohexane] -l- [4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2- one.

A compound that Wist was aware of! the hydrochloride of the hydrochloride is isolated by debenzylation of the compound of EXAMPLE 31 according to the procedure described in DEM132b) in ethanol and by the preparation of the hydrochloride in ethyl ether; bm = 159^eC.

EXAMPLE 34

5-Ethoxy-3-spiro- [4- (2- (4-benzyloxypiperidinol) ethyloxy) cyclohexane] -1- [4-carboxy-2-methoxybenzenesulfonyl] indolin-2-one.

(I): Rj = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R₄ = 4-COOH;

TZ = -CH, CH, and₂c₆h₅ (prepared with specific tetrabenzylation according to Tetrah. Letters, 1986, 3753). 0.62 ml of tert-butyldimethylsilane and 0.06 ml of triethylamine are added

0.03 g of palladium acetate solution 14 ml of dichloromethane and the reaction solution is faster for 15 minutes at 20 ° C. A solution of 1 g of the compound described in EXAMPLE 29 2.6 ml of dichloromethane is slowly quenched and allowed to stand for 4 hours at

20 ° C. 1 ml of acetic acid is added, then filtered, purified with dichloromethane and the filtration liquid with ammonia chloride aqueous solution and then with water. The resulting product was isolated by evaporation of the solvent, crystalline pentane and purrkud at 50 ° C under air for 5 hours; bm = 120 ° C.

EXAMPLE 35

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

(1): R_t = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONH

TZ s-CH 2 CH,

0CH.CH, '2 6 5

CH, 0h

1.27 g of oxalyl chloride is added to a slurry 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 is stirred for 6 hours at 20 ° C. The solvents are evaporated, the precipitate is purrkad For 2 hours at 20 ° C under air and dissolved in 20 ml of toluene, this solution is dissolved in a solution of 1.16 g of 1-amino-1-cyclopentane-methanol in 30 ml of tduene , which has lasted about -40 ° C. The reaction mixture is stirred for 2 hours at 20 ° C, 30 ml of water and 100 ml of ethyl acetate is absent. The organic phases are purred over Na₂SO4 and evaporated under ice-cold pressure. The resulting product is isolated by chromatography on silica gel eluting with 95/5 (v / v) dichloromethane / methanol preparation phase; bm = 103 ° C.

EXAMPLE 36

5-Ethoxy-3-spiro- [4- (2- (4-hydroxypiperidin) ethyloxy) cyclohexane] -1- [4- (N- (1-hydroxymethyl) silylpentylcarbamidyl-2-methoxybenzenesulfonyl] indinyl 2- dn.

(I): R 1 = 5-OC₂H₅; R_z = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONH

TZ = -ch₂ch₂,

CH.OH

The resulting product is isolated in the form of hydrate base according to the procedure described in Example 32 b) starting in Example 35, after chromatography on silica gel eluting with 92/8 (v / v) dichloromethane / methanol phase gas; bm = 109 ° C.

EXAMPLE37 does not belong to the invention

5-Ethoxy-3-spiro- [4- (2- (bensýloxykarbónýlméthyl-amino) ethyloxy) cyclohexane] -l- [4- (4-N-fe / t-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

(I): R_x = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R4 = 4-CONHC (CH₃)₃ ; TZ = -CH₂CH₂NHCH₂Cooch₂C₆H_S

The precipitate is isolated according to the procedure described. EXAMPLE 5 wherein the compound is compound (Π B.2) and 2-methoxy-4 (N-tert-butylcarbamoyl) benzenesulfonyl chloride, and for 2 hours at 20 ° C, 3 ml of Ethyl acetate solution which is saturated with hydrochloric acid. The resulting product is obtained after the solution is basified and chromatographed on silica gel eluting with 8/2 (v / v) dialkylhexane / ethyl acetate phase gas eluting hydrochloride melt at 160 ° C.

DEMM138 does not belong to the invention

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

(I): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R4 - 4-CONHC (CH₃)₃ ; TZ = -CH₂CH₂NHCH₂COOH 0.06 g of the Compound (EXAMPLE37, 6 g of cyclohexene, 0.05 g of 10% palladium / carbon in 10 ml of ethanol is heated at reflux for 1 hour and 30 minutes, the catalyst is filtered off and the solvent is evaporated under ice-cold pressure. The precipitate was isolated by chromatography on silica gel eluting eluted with 90/10 (v / v) dichloromethane / methanol phase gasoline b.p. = 199 ° C.

EXAMPLE 39

5-Hydroxy-l- [4- (N-te / t-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -3-spiro- [4- (2-morpholinoethyloxy) SIKLOS-hexane] indolin-2-one. (Mixture of isdmerum) (I): Rj = 5-OH; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃

Z = -CH 2 CH-N 0 w

The expected yield is isolated in a hydrated form according to the procedure described in EXAMPLE 38 pair starting with Compound of Example 30; bm = 125 ° C.

EXAMPLE 40

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

(I): R 1 = 5-OC 2 H 5; R2 = H; R₃ = 2-OCH3; W = SO₂;

R₄ = 4-CONHC (CH₃)₃ / ~ \

TZ = -CH 2 CH 2 -N + 0

0.8 ml of 30% hydrogen peroxide is added to 0.5 g of the compound described in EXAMPLE 2 dissolved in ml of methanol and the reaction mixture is heated at 45 ° C for 16 hours. The solvent is evaporated at low pressure and the precipitate is filtered on silica gel eluting with 85/15 (v / v) dichloromethane / methanol phase gas. The expected product is isolated in a semi-hydrogenated form! after recrystallization from 40/60 (v / v) cyclohexane / ethyl acetate binder; bm = 189 ° C.

EXAMPLE 41

Methyl sulfate of 5-ethoxy-4- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro [4- (2-N-methylmorpholinomethyloxy) cyclohexane] indolin-2-one.

(I): Rj = 5-OC₂H₅; R2 = H; R₃ = 2-OCH₃; W = SO₂;

R₄= 4-CONHC (CH₃)₃ ; TZ = -CH₂CH-NO.

CH, Θ ³ ch₃so₄

0.05 ml of dimethyl sulfate is dissolved in 0.25 g of the compound described in EXAMPLE 2 dissolved in 2.5 ml of acetonitrile and the reaction is heated at 60 ° C for 24 hours. The solvent is evaporated and the product obtained is isolated in a semi-aqueous form after crystallization from diethyl ether and sparging at 40 ° C for 5 hours; bm = 190 ° C.

EXAMPLE 42 does not include the invention

5-Ethoxy-3-spiro- [4- (2- (2- (N-tert - bútoxýkarbónýlglýsýl) amino) ethyloxy) cyclohexane] -l- [4- (4-N-tert-butyl-carbamoyl) -2-methoxybenzenesulfonyl ] indolin-2-one.

(I): R 1 = 5-OC 2 H 5; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R4 = 4-GNOHC (CH₃)₃;

TZ = -CH₂CH₂-NHCOCH₂NHCOOC {CH₃)₃

0.28 g of benzootriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate and 0.24 ml of triethylamine and then 0.35 g of hydrochloride

The compound of EXAMPLE 4 (polar isomer) is added to a solution of 0.11 g of Na-tert-butyloxycarbonylglycine in 2 ml of acetonitrile at 5 DEG C. and stirred at about 20 DEG C. for 4 hours.

The solvent is evaporated under reduced pressure, the precipitate is taken up with ethyl acetate, then washed with KHSO4 / K2SO4 buffer solution at pH = 2, with water, saturated NaHCO₃ solution and then with water. The organic phase is dried over MgSO4 and the solvent is evaporated under reduced pressure and the precipitate is chromatographed on silica gel column eluting with 99/1 (v / v) dichloromethane / methanol crude mixture. The expected product is isolated; bm = 158 ° C.

EXAMPLE 43

5-Chloro-3-spiro- [4- (N- (3-dímetýlamín6própýl) carbamoylmethoxy) cyclohexane] -l- [4- (4-N-tert-butyl-carbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

(I): R 1 = 5-Cl; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R4 = 4-CONHC (CH₃)₃ ; TZ = -CH₂CONH (CH₂)₃N (CH₃) 2

The expected yield is isolated on eluted hydrochloride according to the procedure described in Example 42 and starting with carboxylic acid from Example 25 and 3-dimethylaminopropanamine; bm = 135 ° C.

Compounds 44 to 50 listed in Table 2 below are prepared according to the procedures of Examples 42 and 43 by reaction of amine or selected acids in a videotype manner.

TABLE 2

<img file="IS1949B_D0021.tif" />

<td>Examples number</td><td>R</td><td>T</td><td>z</td><td>salt, solvates (1)</td><td>mp; • C</td>

<td>44</td><td>5-OC₂H₅</td><td>- (CH₂)₂-</td><td>-NHCO (CH₂)₃N (CH₃)₂</td><td>HCl</td><td>151</td>

<td>46</td><td>5-OC₂H₅</td><td>(CH₂)₂-</td><td>-NHCOCH₂N (CH₃)₂</td><td>HCl H2O</td><td>144</td>

<td>47</td><td>5-OC₂H₅</td><td>- (CH2)₂</td><td>-NHCO (CH₂)₂OCH₃</td><td>1H₂O</td><td>108</td>

<td>50</td><td>H</td><td>ch₂</td><td>-CONH (CH₂)₂OH</td><td>0.5 H₂0</td><td>183</td>

EXAMPLE 51

5-Ethoxy-3rspíró- [4- (2-gl ^ ýlamínóelýloxý) cyclohexane] -L "[4- (4-N-íierf^:butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one.

(I): Rx = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R4 = 4-CONHC (CH₃)₃ ; TZ = -CH₂CH₂NHCOCH₂NH₂ ml of a mettadri solution of hydrochloric acid gase in ethyl acetate is added to a slurry of 0.3 g of the compound of Example 42 (3 ml of ethyl acetate at 5 ° C and the reaction is stirred for 2 hours at room temperature. The solvent is evaporated, crystallization is carried out in diethyl ether, drying is under vacuum to obtain the products expected in the form of dihydric hydrochloride; Bm = 169^eC.