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

3-SPIROINDOLIN-2-OON DERIVATIVES Kül VASOPPRESSINER / OR OXYTOCIN RECEPTOR LIGANDS,

THE METHOD OF THEIR MANUFACTURE, INCLUDING THEM

PHARMACEUTICAL COMPOSITIONS AND THEIR USE

FOR THE MANUFACTURE OF MEDICINAL PRODUCTS

The present invention relates to novel indolin-2-one derivatives and a process for their preparation. These novel derivatives have affinity for the vasopressin and / or oxytocin receptors and can therefore be active ingredients in pharmaceutical compositions.

Vasopressin is a hormone known for its antidiuretic and arterial pressure regulating effects. It stimulates several types of receptors: V, (V_1a, V_1b or V₃), V₂. These receptors are located in the liver, blood vessels (heart, kidney or cerebral blood vessels), platelets, kidney, uterus, adrenal glands, central nervous system or pituitary gland. Oxytocin has a peptide structure similar to vasopressin. Oxytocin receptors have also been found in uterine smooth muscle, and have also been found in breast myoepithelial cells, central nervous system and kidney. The location of the various receptors is described in Jard, S. Vasopressin and Oxytocin Receptors: An OverView in Progress in Endocrinology, Imura, H. and Shizurne, K., published by Experta Medica, Amsterdam, 1988, 1183-1188; Presse Medicale, 16 (10): 481-485, 1987; J. Lab. Clin. Med. 114 (6): 617632 (1989); Pharmacol. Rev., 1991, 43 (1), 73-108. Thus, vasopressin exerts its hormonal, cardiovascular, hepatic, renal, antidiuretic, and

EE 04433 B1 has effects on the central and peripheral nervous system, uterine and intestinal regions, and the ocular and pulmonary systems. Oxytocin is involved in childbirth, lactation and sexual behavior.

Arginine-Vasopressin V₂receptor antagonists (also known as AVP-2 antagonists or V₂-antagonists) may be recommended as potent aquarets that act specifically on the reabsorption of water in the kidneys without causing electrolytes (Na⁺ or K⁺) loss usually caused by clinically used diuretics such as furosemide or hydrochlorothiazide. The latter causes hypokalaemia and hyponatraemia after prolonged treatment.

The first arginine-vasopressin (hereinafter AVP) V₂receptor antagonist, OPC-31260, is currently in clinical development. Comparison of OPC-31260 with conventional diuretics such as furosemide in animals (Yoshitaka, Y. et al., Br. J. Pharmacol. 105: 787-791 (1992)) and in humans (Akihiro, O. et al., J. Clin. Invest. , 1992, 92, 2653-2659, and Akihiro, 0, et al., J. Pharmacol. Exp. Ther., 272, 546-551 (1995)), show that this compound selectively promotes aqueous dehydration and has little or no effect on ion secretion. at high doses.

Indolin-2-one derivatives are described in the literature. Examples include ZA 830 952, which describes useful derivatives which inhibit the converting enzyme as antihypertensive agents, or FR 1 509 373,

EE 04433 B1 discloses diuretic compounds that potassium excretion.

Several patent applications and patents also disclose non-5 peptide compounds which have affinity for vasopressin and / or oxytocin receptors. For example, EP 382,185, which discloses carbostyryl derivatives which are vasopressin antagonists and useful as anti-vasodilators, hypotensive agents, diuretics and antiplatelet agents; EP 444,945, which describes spiropiperidine derivatives which are particularly useful in dysmenorrhea; EP 514 667, which describes benzazepine derivatives which are particularly useful in the treatment and prophylaxis of renal dysfunction, hyponatraemia, diabetes or, alternatively, in the control and prevention of hypertension and platelet aggregation; JP 03 127 732, which describes indole derivatives as vasopressin antagonists.

Benzyl or sulfonylindoline derivatives and indoline derivatives are also described as antagonists. EP 469 984, EP 526 348, EP 636 608, EP 636 609, WO 93/15051 and WO 95/18105 can be mentioned in this regard, but these documents do not describe compounds that act selectively on the AVP-2 receptor.

It has now been found that certain indolinones have excellent affinity for vasopressin and / or oxytocin receptors. These novel indolin-2-ones are potent and selective AVP-2 antagonists. Moreover, given their structure and especially the various polar functional groups, especially the salt-forming functional groups, these molecules are easily dispersible and / or water-soluble, which gives them an improved pharmacological action and also allows easy preparation of injectable pharmaceutical dosage forms.

Thus, according to one aspect, the present invention relates to novel indolin-2-ones of formula (I)

<img file="EE04433B1_D0001.tif" />

in what

R, and R₂ each independently is hydrogen, hydroxy, halogen, (C 1 -C 6)₇) alkyl, (C 1 -C 4)₇) polyfluoroalkyl, (C., C₇) alkoxy, (C 1 -C 4)₇) alkylthio, (C 1 -C 4)₇) polyfluoroalkoxy, (C₃-C₇) cycloalkyloxy, (C₃-C₇) cycloalkylthio, cycloalkylmethoxy or cycloalkylmethylthio, wherein the cycloalkyl is (C₃-C₇) a group, phenoxy, benzyloxy, nitro or cyano;

R₃ and R₄ each independently replaces one or more times the phenyl group and is hydrogen, halogen, (C, -C)₇) alkyl, (C₂-C₇) alkenyl, (C 1 -C 4)₇) polyhaloalkyl, phenyl, benzyl, cyano, nitro, -NR₅R₆-,

EE 04433 B1 hydroxyamino, hydroxyl, OR₇-, SR_?-, -COORg-,

-CONR₉R_1q- or -CSNR₉R_1Qa group wherein at least one R₃and R₄ radicals are different from hydrogen;

R₅ and R₆ each independently is hydrogen, (C 1 -C 4)₇) alkyl, (C₂C₇) alkenyl, phenyl, benzyl, (C₁—C₇) alkylcarbonyl, (C₁—C₇) alkylthiocarbonyl, (C₃-C₇) cycloalkylcarbonyl, (C₃-C₇) cycloalkylthiocarbonyl, benzoyl, thienylcarbonyl, furylcarbonyl, (C 1 -C 4 alkyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl or thiocarbamoyl) unsubstituted or R 1 or R₁₀or, alternatively, R₅ and R₆ together with the nitrogen atom to which they are attached form a heterocyclic group selected from pyrrolidine, pyrroline, pyrrole, indoline, indole and piperidine;

R₇ is (C., - C₇) alkyl, (C₂-C₇) alkenyl, phenyl, benzyl, (C₃-C₇) cycloalkyl, (C 1 -C 4) polyfluoroalkyl, formyl, (C 1 -C 4)₇a) alkylcarbonyl, benzoyl or benzylcarbonyl;

R₈ is hydrogen, (C, -, C)₇a) alkyl, phenyl or benzyl;

R? and R₁₀ each independently is hydrogen, (C 1 -C 4)₇) alkyl, (C, C)₇) polyfluoroalkyl, (C₂-C₇) alkenyl, (C₃-C₇Cycloalkyl optionally substituted with hydroxy (C 1 - C 5)₁-C₄) alkyl, pyridyl, phenyl, thienyl, furyl or, alternatively, R? and R_1o together with the nitrogen atom to which they are attached form pyrrolidine, piperidine and piperazine, which are unsubstituted or (C, - C₄) substituted with alkyl groups, and (C₄-C₇) a heterocyclic group selected from azacycloalkyl;

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W is -CH₂- or -SO₂-;

Cy, together with the carbon atom to which it is attached, forms a saturated or unsaturated non-aromatic (C₃-C₁₂hydrocarbon ring which is optionally fused or substituted with one or more (C 1 - C 4)₇) alkyl, said groups being substituted one or more times on the same carbon atom, or substituted with (C)₃-C₆) with a spirocycloalkyl group;

T is (C, - C)₄) alkylene group optionally interrupted (C₃-C₆a) cycloalkylene, said alkylene groups optionally being mono- or polysubstituted at the same carbon atom with a (C 1 -C 3) alkyl group, or alternatively T is a direct bond;

Z is -NR 1 R 4, alkyl (A '), wherein (A') represents an anion, preferably Cl ', Br', 1 'or

CH₃SO₄-N (O) R 4 -R 4 -, -COOR 4 -, -NR 4 -COR 4 -, benzyloxycarbonylamino, -CONR 4 - R 4 -, it is understood that when T is methylene or a direct bond, Z cannot be -NR ^ R ^ -, -⁺NR₁₁R₁₂(C₁-C₄) alkyl,

-N (O) R₁₁R₁₂-, -NR 4 -COR 4 -, benzyloxycarbonylamino;

R_n and R₁₂ each independently is hydrogen, (C 1 -C 4)₇) alkyl, (C_n —

C₄) alkoxy, (C₃-C₇) cycloalkyl, phenyl, (C 1 -C 4)₃a) alkylene cycloalkyl wherein the cycloalkyl is (C₃-C_?) group, or (C., - C₃a) alkylene phenyl, said groups being optionally mono- or poly-substituted R₁₃or, alternatively, R_n and R₁₂ optionally together with the nitrogen atom to which they are attached form a heterocycle selected from the heterocycles of azetidine, pyrrolidine, piperidine, piperazine, piperaE 04433 B1, morpholine, morpholinone, thiomorpholine and hexahydroazepine, optionally mono- or poly-substituted R₁₃or thiomorpholine-1,1-dioxide or thiomorpholine-1-oxide or, alternatively, R_1Z is pyrrolidone or piperidone;

R₁₃ is hydroxyl, (C, -C₄) alkyl, (C 1 -C 6)₄) alkoxy, mercapto, (C 1 -C 4) alkylthio, (C 1 -C 4)₄) alkylsulfinyl, (C 1 -C 4)₄) alkylsulfonyl, benzyloxy, hydroxyalkyloxy,

-NR₁₄R₁₅a group wherein R₁₄ and R₁₅ each independently is hydrogen, (C 1 -C₄) alkyl, (C₃—C₄) alkyloxycarbonyl or benzyloxycarbonyl, carboxyl, (C 1-4) alkyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, amidino, guanidino, imidazolyl, thienyl, pyridyl, indolyl and tetrahydroisoquinol, salts, solvates or hydrates.

It should be noted that compounds of formula (I) wherein R₃ and R₄ are hydrogen, known compounds and compounds wherein -OTZ is

-Ο-Νζζ or -O-CH₂-N 1 are unstable and thus do not fall within the scope of the present invention.

Among these compounds, compounds of formula (Ia) are preferred

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<img file="EE04433B1_D0002.tif" />

(la) in which

R₁ to R₄, W, T and Cy are as defined for compounds of formula (I);

Za is -NR ^ R ^ -,⁺NR₁₁R₁₂(C₁-C₄) alkyl (A '), wherein (A') represents an anion, preferably Cl ', Br', 1 'or CH₃SO₄-N (O) R 4 -R 4 -, -COOR 4 -, -NR 4 COR 4 -, benzyloxycarbonylamino, -CONR₁ ^^ - a group;

R 4 and R 4₁₂ each independently is hydrogen, (C 1 -C 4)₇) alkyl, (C., C₄) alkoxy, (C₃-C₇) cycloalkyl, phenyl, (C 1 -C 4 alkylene cycloalkyl) wherein the cycloalkyl is (C₃-C₇) group, or (C., - C₃) an alkylene phenyl group, said groups being optionally mono- or poly-substituted R₁₃, or, alternatively, and R₁₂ optionally together with the nitrogen atom to which they are attached form a heterocycle selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, piperazinone, morpholine, morpholinone, thiomorpholine and hexahydroazepine, optionally mono- or poly-substituted R₁₃or thiomorpholine-1,1-dioxide or thiomorpholine-1-oxide;

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R₁₃ is hydroxyl, (C₁—C₄) alkoxy, thiol, alkylthio, (C 1 -C 4)₄) alkylsulfinyl, (C 1-4) alkylsulfonyl, -NR₁₄R₁₅a group wherein R₁₄ and R₁₅ each independently is (C 1 -C 4)₄) alkyl, carboxyl, carbamoyl, amidino, guanidino, imidazolyl, thienyl, pyridyl, indolyl or tetrahydroisoquinolyl, and salts thereof.

Solvates and hydrates of the compounds of formula (Ia) are also preferred.

In compounds of formula (Ia), when T is a methylene group or a direct bond, Za cannot be -NR_nR₁₂-, -⁺NR₁₁R₁₂(C₁-C₄) -alkyl, -N f O R 1 R 4 -, -NR 4 R 4 -, benzyloxycarbonylamino.

For the purposes of the present invention, (C 1 -C 4 alkyl or C 1 -C 4 alkyl) represents₆) alkyl is, of course, straight or branched chain alkyl having 1 to 7 or 1 to 6 carbon atoms, respectively.

Non - aromatic (C₃-C₁₂) hydrocarbon rings include terpenic, saturated or unsaturated, fused or bridged, mono- or polycyclic radicals. These radicals are optionally mono- or poly-substituted (Ο_η—C₄) alkyl. Monocyclic radicals include cycloalkyl radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl. Polycyclic radicals include norbornane, adamantane, hexahydroindane, norbornene, dihydroEE 04433 ΒΙ phenalene, bicyclo [2.2.1] heptane, bicyclo [3.3.1] nonane or tricyclo [5.2.1.02,6] decane.

Phenyl substituents R_v R₂, R₃, R₄, R₅, R₆, R_?, R₈, R ,, R₁₀, R 4 and R 4₁₂ may be unsubstituted, mono- or di-substituted (C, C,₇) alkyl, preferably methyl, trifluoromethyl, (C 1 -C 4)₇) - alkoxy, preferably methoxy or ethoxy, or halogen, or trisubstituted (C1-C6) alkyl, (C1-C6) alkoxy or halogen.

In the present invention, halogen is understood to mean an atom selected from 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 are also within the scope of the invention.

Where the compound of the present invention is characterized by stereoisomerism, such as the axial equatorial type or ZE, the invention also encompasses all stereoisomers of the compound.

According to the present invention, salts of the compounds of formula (I) according to the invention include salts of inorganic and organic acids which allow suitable isolation or crystallization of compounds of formula (I) such as picric acid, oxalic acid or optically active acid such as tartaric, dibenzoyl tartaric, mandelic and which form physiologically acceptable salts such as

EE 04433 B1, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, maleate, fumarate, 2-naphthalenesulfonate or p-toluenesulfonate.

Salts of compounds of formula (I) also include salts with organic or inorganic bases, for example salts of alkali metals or alkaline earth metals such as sodium, potassium or calcium, with sodium or potassium salts being preferred, or salts with amines such as trometamol or, alternatively, arginine or lysine. salts of a physiologically acceptable amine.

Functional groups and reaction intermediates in the molecule of the compounds of formula (I) may be protected, either permanently or temporarily, with protecting groups that will ensure the synthesis of the desired compounds.

It is understood that protecting groups for amines, alcohols, phenols, thiols or carboxylic acids refer to the protecting groups described in Protective Groups in Organic Synthesis, Greene, TW and Wuts, PG, 1991 and Protective Groups, Kocienski, PJ. , 1994, Georg Thieme Verlag.

Temporary protecting groups include, for example, benzyl groups, carbamates, such as tert-butyloxycarbonyl, which can be cleaved in an acidic medium, or benzyloxycarbonyl, which can be cleaved by hydrogenolysis; for carboxylic acids, alkyl esters such as methyl, ethyl E 04433 B1 or tert-butyl ester which can be hydrolyzed in basic or acidic media, or benzyl esters which can be hydrogenolysed; in the case of alcohols or phenols, tetrahydropyranyl, methoxymethyl or methylethoxymethyl, tert-butyl and benzyl esters, and may also refer to the usual known methods described in the above-mentioned Protective Groups.

According to the present invention, temporary protecting groups which can be cleaved by hydrogenolysis in acidic or neutral media are preferred.

Permanent protecting groups are those protecting groups which are stable under the above cleavage conditions and which are present in the final products. Such O- or N-protecting groups are formed (C, -C₇) alkyl or phenyl. Permanent N-protecting groups also include (C 1 -C 4) alkanoyl and aryl groups such as benzoyl.

The compounds of formula (I) may contain precursors of other functional groups formed after one or more steps.

Compounds of formula (I) having various polar functions, in particular salt-forming functions, which improve water solubility, preferably carry -TZ groups.

Compounds of formula (I) wherein R is substituted are preferred₁ is indolin-2-one at position 5 and R₂ is hydrogen.

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Also preferred are compounds of formula (I) wherein R₁ is in position 5 and represents a chlorine atom or an ethoxy group and R₂ is hydrogen.

Preference is given to compounds of formula (I) wherein R₃ is hydrogen or methoxy; and R₄ is methoxy, diethylureido, tertamylcarbamoyl and tert-butylcarbamoyl at position 4 of the benzene ring.₃ is in position 2.

Also preferred are compounds of formula (I) wherein Cy is cyclohexane and the -OTZ group is at the 4 position of the cyclohexane relative to the spiro hydrocarbon.

Particular preference is given to compounds of formula (1.1)

<img file="EE04433B1_D0003.tif" />

wherein R₁, R₃, R₄, W, T and Z are as defined for formula (I), and salts, solvates or hydrates thereof.

Even more preferred are the compounds of formula (1.2)

EE 04433 Bl

<img file="EE04433B1_D0004.tif" />

(1.2) wherein R₁, R₃, R₄, T and Z are as defined for formula (I), and salts, solvates or hydrates thereof.

Compounds of formula (1.3) are highly preferred

<img file="EE04433B1_D0005.tif" />

r₄ (1.3) wherein R₁, R₃ and R₄ is as defined for formula (I), T is (C 1 -C 4) alkylene and Z is amino, 2-hydroxyethylamino, 2- (2-hydroxy) ethyloxyethylamino, morpholinyl or carboxyl, and salts, solvates or hydrates thereof .

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Even more preferred are the compounds of formula (1.4)

R

<img file="EE04433B1_D0006.tif" />

OTZ (1-4),

SO.

<img file="EE04433B1_D0007.tif" />

OCH

CONHC (CH₃)₃ wherein R 1, T and Z are as defined for formula (I), and salts, solvates or hydrates thereof.

Also preferred are compounds of formulas (1.1), (1.2), (1.3) and (1.4) wherein Z is as defined in Za, and salts thereof. The same applies to the solvates and hydrates of these compounds.

Particular preference is given to compounds of formulas (1.1), (1.2), (1.3) and (1.4) wherein

R₁ is a chlorine atom or an ethoxy group,

T is (C 1 -C 4) alkylene and Z is amino, 2-hydroxyethylamino, 2- (2-hydroxy) ethyloxyethylamino, morpholinyl or carboxyl.

Also preferred are compounds of formulas (II), (1.2), (1.3) wherein

R 1 is a chlorine atom or an ethoxy group,

R₃ is hydrogen or methoxy,

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R₄ is methoxy, diethylureido, tert-amylcarbamoyl and tert-butylcarbamoyl.

Among these compounds, preference is given to compounds wherein T is (C 1 -C 1) alkylene and Z is amino, 2-hydroxyethylamino, 2- (2-hydroxy) ethyloxyethylamino, morpholinyl or carboxyl.

Very preferred are the compounds of formulas (I), (1.1), (1.2), (1.3) and (1.4) wherein Cy is cyclohexane and the OTZ group is in the 4 position of the cyclohexane relative to the spiro hydrocarbon, in particular the following compounds:

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

EE 04433 ΒΙ * 5-Ethoxy-3-spiro- (4-carboxymethyloxycyclohexane) 1- (4-N-tert-butylcarbamoyl-2-methoxybenzenesulfonyl) -indolin-2-one, * 5-ethoxy-3-spiro- [4 - (2-Morpholinoethyloxy) cyclohexane] -1- [4- (N-tert-amylcarbamoyl) -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, * 5-Ethoxy- 3-Spiro- [4- (2- (4-ethoxypiperidino) ethyloxy) cyclohexane] -1- [4- (N-tert-butylcarbamoyl] -2-methoxybenzenesulfonyl] indolin-2-one, * 5-ethoxy-3- spiro- [4- (2-glycylamino-ethyloxy) -cyclohexane] -1- [4- (N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one, * 5-Ethoxy-3-spiro [4- (2- (N, N-dimethylglycylamino) ethyloxy) cyclohexane] -1- [4- [N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indoline-2 -one, * 5-chloro-3-spiro- [4- (N- (3-dimethylaminopropyl) carbamoylmethyloxy) cyclohexane] -1- [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,

EE 04433 ΒΙ * 5-Ethoxy-3-spiro- [4- (2- (2-hydroxyethylamino) -ethyloxy) -cyclohexane] -1- [4- [N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one, * 5-Ethoxy-3-spiro- [4- (2- (LY-glutamylamino) ethyloxy) 5 c] cyclohexane] -1- [4- [N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one, * 5-Ethoxy-3-spiro [4- (2- (L-pyroglutamylamino) ethyloxy) cyclohexane] -1- [4- [N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one, * 5-Ethoxy-3-spiro [4- (2- (2- (2-hydroxyethyloxy) ethylamino) ethyloxy) cyclohexane] -1- [4- [N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indoline-2 and pharmaceutically acceptable salts, solvates or hydrates thereof, which are particularly suitable for use in pharmaceutical compositions.

The compounds of the invention can be prepared according to Scheme 1.

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Scheme 1

<img file="EE04433B1_D0008.tif" />

(I)

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Another object of the present invention is a process for the preparation of compounds of formula (I) according to the invention, characterized in that either (1) of the compound of formula (IIA)

<img file="EE04433B1_D0009.tif" />

wherein R ,, R₂, R₃, R₄, W, Cy and T are as defined for formula (I) and X is a nucleofugic group such as halogen, preferably bromine, chlorine or iodine, or a sulfonic acid derivative such as tosyloxy or mesyloxy, is allowed to go from 0 to 120 ° C in polar solvents such as dimethylformamide, tetrahydrofuran or acetonitrile, with a derivative of formula ZH (1) wherein Z is as defined for formula (I) having a nucleophilic group capable of replacing Xi, for example, a primary or secondary amine, preferably a secondary amine, or alternatively, X is a reducing group such as an azido group, which is subsequently reduced to an amino group, or (2) when Z = -COOH, for a compound of formula (ΙΙΆ)

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<img file="EE04433B1_D0010.tif" />

(ΙΙΆ),

R wherein R_v R₂, W, R₃, R₄ and Cy is as defined for formula (I) and Τ 'is T-CH₂is reacted with an oxidant such as chromium oxide or (3) in a acidic solvent such as dilute acetic acid in the presence of an alkali metal dichromate or an alkali metal or alkaline earth metal permanganate at a temperature of 0 to 100 ° C.

<img file="EE04433B1_D0011.tif" />

wherein R_v R₂, Cy, T and Z are as defined for formula (I), at a temperature of -40 to 25 ° C in an anhydrous solvent such as tetrahydrofuran in the presence of a metal hydride such as sodium hydride or an alkali metal alcohol such as potassium tert-butanolate.

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<img file="EE04433B1_D0012.tif" />

wherein W, R₃ and R₄ is as defined for formula (I) and Hal is a halogen atom, or (4) for Z = -COOH for a compound of formula (ΙΙ'ΙΙ)

<img file="EE04433B1_D0013.tif" />

(ΙΙ'Β) in which R_v R₂ and Cy is as defined for formula (I) and Τ 'is T-CH₂, is reacted with an oxidizing agent as described for the conversion of compound (ΙΙΆ) to compound (I), then the acid of formula (IIB)

<img file="EE04433B1_D0014.tif" />

OT-COOH wherein R₁, R₂, Cy and T are as defined for formula (I), optionally protected with a carboxylic acid protecting group to provide an intermediate of formula (IIBP)

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<img file="EE04433B1_D0015.tif" />

wherein R ,, R₂, Cy and T are as defined for formula (I) and P is a protecting group selected from an alkyl group such as tert-butyl or benzyl, and finally the compound (IIBP) is reacted with a derivative of formula (2) to afford, after deprotection ) which, if necessary, is converted into one of its salts by procedures known to one skilled in the art.

Compounds (IIA) and (IIB) can be prepared from compounds (III) according to Scheme 2 below.

Scheme 2

<img file="EE04433B1_D0016.tif" />

Compounds (IIA) can be prepared from indolin-2-one (III) with a benzenesulfonyl halide when W is -SO₂or with a benzyl halide when W is -CH₂at a temperature of -40 to

EE 04433 B1C in an anhydrous solvent such as dimethylformamide or tetrahydrofuran in the presence of a metal hydride such as sodium hydride or an alkali metal alcohol such as potassium tert-butanolate.

Compounds (IIA) can also be prepared from alcohols (ΙΙΆ) by conventional methods known in the art. An example is Angew. Chem. Int. Ed. , 14, 801, 1975, triphenylphosphine / carbon tetrachloride system or in Carbohyd. Res., 61, 511 (1978), triphenylphosphine / C (Hal)₄a system wherein Hal is halogen in the presence of pyridine or by reaction with an aryl or alkylsulfonyl halide in an inert solvent in the presence of a base. The X groups can be interchanged, for example the sulfonate group can be obtained in J. Chem. Soc., 1949, 326, convert to a halide, such as a derivative of iodine, by reaction with an alkali metal iodide, such as sodium iodide. When X is halogen, the halide (IIA) can be converted to the alcohol (ΙΙΆ) by substitution with nitrate ion, which is subsequently reduced in the presence of a metal catalyst such as palladium on carbon in J. Med. Chem., 1995, 38, 130-136.

Compounds of formula (ΙΙΆ) can also be prepared from the corresponding indolin-2-ones (III ') by reaction with compounds (2) under conditions of conversion of compounds (III) to compounds (IIA) already described. The alcohol group of the compounds (III ') is temporarily protected according to EP 636 608 (compounds ΙΙΙ'Ρ) with, for example, a protecting group such as methyl or tetrahydropyranyl.

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Compounds (IIB) can be prepared from indolin-2-one by replacing the nucleofugic group X with a derivative of formula ZH, such as a primary or secondary amine, at 0 to 120 ° C in polar solvents such as dimethylformamide, tetrahydrofuran or acetonitrile, respectively. .

Compounds (IIB) wherein -TZ is -T-COOH are prepared from alcohol (III ') where T' is T-CH₂a group oxidizing an alcohol (III ') under conditions of conversion of compound (ΙΙΆ) to compound (I).

The compounds of formula (III) are novel and are within the scope of the invention. They can be prepared according to Reaction Scheme 3.

Scheme 3

<img file="EE04433B1_D0017.tif" />

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Thus, indolin-2-ones (III) can be obtained by reducing the acetals (IV) under mild conditions, for example, in J. Org. Chem., 1987, 52, 2594-2596, by the action of zinc borohydride in the presence of trimethylsilyl chloride in ethers or chlorinated solvents such as dichloromethane or dimethylsulfide-BH.₃ complex in the presence of trimethylsilyl triflate in ethers or dichloromethane, according to J. Org. Chem., 1993, 58, 6756-6765, or the formula (III⁷) alcohols

<img file="EE04433B1_D0018.tif" />

wherein R_v R₂, Cy and T are as defined for formula (I), respectively, for the compounds (II⁷A) methods for conversion to compounds (IIA).

Acetals (IV) are prepared by known reactions, for example from ketone (V) with alcohol under acidic catalysis in an dehydrating medium. The compounds can be prepared by azeotropic removal of water or in the presence of molecular sieves as described in Synthesis, 1972, 419.

The ketones (V) can be prepared from the corresponding secondary alcohols (VI) according to methods known to those skilled in the art, for example using oxidants such as chromium oxide in acetic acid medium or chromium oxide complexes such as

Pyridinium chlorochromate in inert solvents such as ethyl acetate or dichloromethane, or alternatively by hydrolysis of acetals (IV ').

The alcohol (VI) can be obtained from the corresponding compounds in which the hydroxyl group is protected, for example by methoxymethyl or tetrahydropyranyl. These compounds are described in EP 636 608 or obtained as described in the patent.

Thus protected by compounds of formula (XI)

<img file="EE04433B1_D0019.tif" />

H (XD is subjected to acidic hydrolysis at -5 to 70 ° C in an alcohol such as methanol or ethanol or in an ether such as tetrahydrofuran.

compounds (III ') can be prepared according to Scheme 4.

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Scheme 4

<img file="EE04433B1_D0020.tif" />

<img file="EE04433B1_D0021.tif" />

<img file="EE04433B1_D0022.tif" />

Just as compounds (III) can be prepared from acetals (IV), compounds (III ') 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 compound (III ') according to the methods already described for converting compounds (IIA) into compounds (IIΆ).

In contrast, and just as compounds (ΙΙΆ) can be converted to compounds (IIA) according to the methods already mentioned, alcohols (III ') can be converted to compounds (III) wherein X is a nucleofugic

A group such as an alkyl group or a benzenesulfonate by reaction with an alkyl halide or phenylsulfonyl halide in inert solvents in the presence of a tertiary amine or pyridine.

Compounds (III ') can be converted to compounds (ΙΙΙ'Ρ) in which the alcohol group is protected as indicated above. Compounds (ΙΙΙ'Ρ) can also be converted to compounds (IIA) in which X is a temporary protected alcohol group according to the reactions described above.

Compounds (IV ') wherein T is at least equal to -CH₂CH₂-, can be prepared from ketones (V) by reaction of diol with HO-T-OH under conditions of conversion of compound (V) to compound (IV). Compounds (IV ') may also be obtained directly from the corresponding hydrazides (VII) Moore, RF et al., J. Chem. Soc., 1951, 3475-3478, by heating, for example in solvents such as quinoline in the presence of a metal or alkaline earth metal oxide such as calcium oxide. The reaction may also be carried out in inert solvents such as tetralin, naphthalene or 1,2,3,4-tetramethylbenzene by heating according to the method described by Wolff, J. et al., 1986, Tetrahedron 42, (15), 4267-4272. previously prepared from a lithium salt in a low temperature inert solvent such as tetrahydrofuran.

These phenylhydrazide derivatives (VII) can be obtained from phenylhydrazine (IX), which are known or prepared by known methods, and from carboxylic acid derivatives (VIII), such as esters, chlorides or mixed anhydrides

The reaction of alkyl chloroformate, preferably isobutyl chloroformate, in the presence of a base by conventional methods known to those skilled in the art. The acids (VIII) are known or are prepared by known methods.

Compounds of formula (I) wherein T is -CH₂and Z is a -COOZ- group in which Z₁ is hydrogen, (C1-C4) alkyl or benzyl, alternatively the alcohol of formula (IIC)

<img file="EE04433B1_D0023.tif" />

(IIC) wherein R_v R₂, R₃, R₄, W and Cy are as defined for formula (I) which are known or prepared according to EP 636 609, wherein the alcohols are alkylated with a strong alkylating agent such as CF₃SO₂O-CH₂-COOAlk trifluoromethanesulfonate (3), obtained by in situ reaction of a silver triflate with a corresponding halogenated derivative wherein Alk is (C₁-C₄) alkyl group in halogenated solvents such as dichloromethane or carbon tetrachloride according to alkyl trifluoromethanesulfonates in Carbohydrate Research, 44, C, 1975₅-C₇, method described.

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The ester thus obtained may be subjected to an exchange reaction or cleaved under the conditions already mentioned.

The alcohol (IIC) can be prepared according to the following scheme

5.

Scheme 5

<img file="EE04433B1_D0024.tif" />

▼

<img file="EE04433B1_D0025.tif" />

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

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Compounds (X) are obtained from compounds (XI) by the method described in EP 636 608 using halides (2) under conditions of conversion of compounds (IIB) already described to compounds (I) and compounds (III) to compounds (IIA).

The compound of formula (I) can also be converted to another compound of formula (I) bearing a polyfunctional residue as defined for Z, in particular -NR ^ COR. ^ - or -CONR._nR₁₂wherein the reaction is carried out according to known methods for peptide synthesis, such as those described by Bodansky, M., in Principles of Peptide Synthesis, 2nd ed., 1993, and Peptide Chemistry, Springer Verlag. These methods avoid the asymmetric center racemization that can be caused by amino acids.

The reagents ZH of formula (1) are commercially available or are prepared by known methods.

Derivatives of formula (2)

<img file="EE04433B1_D0026.tif" />

are also prepared by known methods. In particular, benzenesulfonyl halides wherein W is -SO₂and R₃ and R₄ is as defined for formula (I), by known methods. For example, 4-dimethylaminobenzenesulfonyl chloride is prepared according to Sukenik, CN et al., J. Am.

Chem. Soc., 1977, 99, 851-858.

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More generally, benzenesulfonyl halides substituted with dimethylamino are known or are prepared by known methods. 4-Benzyloxybenzenesulfonyl chloride is prepared according to EP 229 566.

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

Benzenesulfonyl halides are obtained according to Col. Czechoslov. Chem. Commun., 49, 1184, 1984, substituted by the same group of aniline derivatives, said aniline derivatives being obtained from the corresponding nitroderivatives.

Benzenesulfonyl halide (2), substituted at position 4 by -NHCON (CH₂CH₃) ₂can be prepared by reacting chlorosulfonic acid with N ', N'-diethyl-N-phenylurea, which itself is obtained by reacting aniline with diethylcarbamoyl chloride.

If R₃ or R₄ is an N-substituted carbamoyl group, Compound (2) wherein R₃ the carboxylic acid precursor, such as N-benzylcarbamoyl, can be condensed, deprotected by hydrogenolysis and then condensed with the desired amine, or, alternatively, immediately prepared (2) wherein R₃ has the desired meaning. The reaction is usually carried out with appropriately selected anilines, which themselves are obtained by reduction of the corresponding nitroderivatives.

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The anilines are diazotized with nitric acid under normal conditions and allowed to react with SO_zin the presence of copper chloride according to the method described in J. Heterocyclic Chem., 1986, 23, 1253.

Benzyl halides wherein W is -CH₂is known or is prepared by known methods. For example, JV Rajanbabu, J. Org. Chem., 1986, 51, 1704-1712, and the publications cited in EP 636,609.

Halogenomethylbenzene derivatives can generally be prepared by reacting N-halosuccinimides with the corresponding methylbenzene derivatives and according to EP 229 566.

The reaction is carried out in a solvent such as carbon tetrachloride in the presence of dibenzoyl peroxide. The halomethylbenzene derivative can also be prepared from the corresponding hydroxymethylbenzene derivative by reaction with phosphorus tribromide in ether or by reaction with thionyl chloride.

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

The quaternary ammonium salts, N-oxide and S-oxide derivatives and sulfones of the compounds of formula (I) are within the scope of the invention and are prepared by conventional reaction with an alkyl halide or hydrogen peroxide or peracid,

Such as peracetic acid or m-chloroperbenzoic acid, by oxidation in inert solvents.

Compounds of formula (I) may include amines or acid functions which can be converted into amide functions by reaction with acid or amide derivatives containing asymmetric carbon atoms. The non-racemic coupling reaction known to a person skilled in the art, especially peptide chemistry, and may be referred to Wunsch, Ε. , Methoden der Organischen Chemie (Synthese von Peptiden), 15, 1974, Band 1 + 2, Thieme Verlag, Stuttgart; Jones, J. Η. , The Peptides, 1979, 1, 65-104; Gross, Ε., Meienhofer, J., Academic Press; M. Bodansky, Principles of Peptide Synthesis and Peptide Chemistry, 1993, Springer Verlag.

The compounds of formula (I) also include those compounds in which one or more hydrogen, carbon or halogen, especially chlorine or fluorine, atoms are replaced by their radioactive isotopes, for example tritium or carbon-14. Such labeled compounds are useful as receptor 1 ligands in science, metabolism or pharmacokinetic studies, or biochemical assays.

The in vitro affinity of the compounds of the invention for vasopressin V1 receptors was determined using Lynch, CJ et al., J. Biol. Chem., 260, 5 (1985), 2844-2851. This method involves studying the displacement of tritium-labeled vasopressin in rat liver membrane ν1 sites.

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The affinity of the compounds of formula (I) for oxytocin receptors of the present invention was also determined in vitro by displacement of the radioactive iodine-labeled oxytocin ana5 log of the membrane preparation of pregnant rats by Elands J. et al., Eur. J. Pharmacol., 1987, 147, 197-207.

The compounds (I) of the present invention have an affinity for V₂receptor bovine membrane preparation1 by Crause P. et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541, and Stassen FL et al., J. Pharmacol. Exp. Ther., 1982, 233, 50-54.

The compounds of the invention inhibit the binding of tritium-labeled arginine-vasopressin to the membrane receptor. IC of the compounds of the invention₅₀ values ​​are low, usually within the range of 10 '⁵-10'⁹ M.

The agonist or antagonistic activity of the compounds of the present invention when administered orally to vasopressin receptors was evaluated in a normally hydrated rat (SpragueDawley line) in Br. J. Pharmacol. 105: 787-791 (1992). The diuretic activity commonly observed with compounds of formula (I) and some of these compounds at doses &lt;10 mg / kg indicates that the compounds of formula (I)₂a group of antagonists.

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The compounds of the invention exhibit activity following administration by various routes, in particular orally.

No indication of toxicity of the compounds of the present invention at pharmacologically active doses was observed and their toxicity is therefore compatible with their use as medicinal drugs.

The compounds of the present invention selectively mimic or inhibit the effects of vasopressin and / or oxytocin. Among these compounds, vasopressin receptor antagonists may exert their effects on central and peripheral blood flow regulation, particularly coronary, renal gastric circulation, regulation of water metabolism, and adrenocorticotropic hormone (ACTH) release. Vasopressin agonists may favorably replace vasopressin or analogues thereof in the treatment of diabetes mellitus, and may also be used in the treatment of enuresis and in the regulation of hemostasis: in the treatment of haemophilia or von Willebrand's syndrome or as an antiplatelet agent, Laszlo FA, Pharmacol. Rev. , 1991, 43, 73-108; Drug Investigation, 1990, 2, supplement 5, 1-47. The hormones themselves, vasopressin and oxytocin, and some of their peptide or non-peptide analogs are used as drugs and have been shown to be effective (Vasopressin. Gross P. et al., Published by John Libbey Eurotext, 1993, especially pp. 243-257 and 549-562; Laszlo FA and Laszlo FA Jr., Clinical Perspectives for Vasopressin Antagonists, Drug News Perspect. 1993, 6 (8); North WG, J. Clin. Endocrinol., 1991, 73, 1316-1320; Legros J.J. et al.

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Prog. Neuropharmacol. Biol. Psychiat. 12: 571-586 (1988);

Andersson KE et al., Drugs Today, 24 (7), 509-528 (1988);

Stump DL et al., Drugs, 39, 38-53 (1990); Caltabiano S. et al.

Drugs Future, 1988, 13, 25-30; Noise Y. et al., Clin. Nephrol.,

1993, 40, 60-61; FasebJ. 1994, 8 (5), A587, 3398).

This V₂The aquaretic profile type of antagonist molecules has broad therapeutic indications and represents an important innovation in the treatment of heart failure, hyponatraemia, water metabolism disorders, water retention and the like. Compounds of this type can favorably replace conventional diuretics in humans and animals in all pathologies in which they are indicated. Treatment of hypertension with antihypertensive drugs from other therapeutic groups, such as β-blockers, angiotensin converting enzyme inhibitors or, alternatively, angiotensin II receptor antagonists, may also be considered with such molecules.

Thus, the compounds of the invention are particularly useful in the treatment of central and peripheral nervous, cardiovascular, endocrine and hepatic, renal, gastric, intestinal and pulmonary disorders, ophthalmology, and sexual dysfunction in humans and animals.

Another object of the invention is therefore pharmaceutical compositions comprising an effective dose of a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate thereof and suitable excipients.

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Said excipients are selected according to the pharmaceutical formulation and the desired route of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the aforementioned active compounds of formula (I), or suitable salts thereof, solvates or hydrates for administration to animals and humans in unit dosage forms for the treatment and prevention of the above disorders and diseases, such as in admixture with conventional pharmaceutical carriers. Suitable unit dosage forms include oral dosage forms such as tablets, gelatin capsules, powders, granules, and orally administered solutions or suspensions; sublingual, buccal, intratracheal or intranasal dosage forms; subcutaneous, intramuscular or intravenous dosage forms; and rectal dosage forms. For topical administration, the compounds of the invention may be used as creams, ointments, lotions or eye lotions.

The dosage of the active ingredient may vary from 0.01 to 50 mg / kg body weight per day to achieve the desired prophylactic or therapeutic effect.

Each unit dose may contain from 0.5 to 1000 mg, preferably

1-500 mg of active ingredients in combination with a pharmaceutical carrier. The daily dose is 0.5-5000 mg and preferably 1-2500 mg

For administration, such a unit dose may be administered 1 to 5 times daily.

When solid compositions are prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with sucrose, cellulose derivatives or other suitable substances or, alternatively, may be formulated so as to exhibit a prolonged or delayed action and a sustained release of the active ingredient.

Gelatin capsules are prepared by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatine capsules.

Formulations for syrup or elixir or drops may contain the active ingredient in admixture with sweetening, preferably non-caloric sweetening agents, methyl paraben or propyl paraben in antiseptic strainers, as well as flavoring and suitable coloring agents.

Water soluble powders or granules may contain the active ingredient in admixture with dispersing or wetting or suspending agents, such as polyvinylpyrrolidone, as well as sweetening or flavoring agents.

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Means of rectal administration are suppositories that are prepared with binding agents that melt at body temperature, such as cocoa butter or polyethylene glycol (s).

For parenteral administration, pharmacologically compatible dispersing and / or wetting agents, for example aqueous suspensions containing propylene glycol or butylene glycol, isotonic sodium chloride solutions or sterile injectable solutions, are used.

The active ingredient may also be provided in the form of microcapsules, optionally with one or more carriers or excipients, or alternatively in matrices such as polymer or cyclodextrin (patch or sustained release compositions).

The compositions of the present invention may be used to treat various vasopressin or oxytocin dependent disorders and vasopressin or oxytocin secretion dysfunctions, cardiovascular disorders such as hypertension, pulmonary hypertension, cardiac insufficiency, cardiovascular, ischemic heart disease, haemostatic disorders, particularly haemophilia or von Willebrand syndrome, central nervous system disorders such as migraine, cerebral vasospasm, cerebral hemorrhage, cerebral edema, depression, anxiety, bulimia, psychotic states or memory disorders, renopathies and renal dysfunction such as edema, renal , hyponatraemia, hypokalaemia, diabetes mellitus, Schwartz-Bartter syndrome or kidney stones, gastrointestinal disorders such as spasm of the blood vessels, cirrhosis of the liver, ulcers, vomiting pathologies such as nausea including chemotherapy, motion sickness (kinetosis), or alternatively antidiuretic hormone secretion syndrome (SIADH), diabetes mellitus and enuresis, hepatic system disorders such as cirrhosis Cushing's Disease), and particularly in the treatment or prevention of hypercorticism and hyperaldosteronism. The compositions of the present invention may also be used in the treatment of sexual dysfunction, overweight and obesity, favorably replacing conventional diuretics already used in this indication. In women, the compositions of the invention may be used in the treatment of dysmenorrhea or in preterm labor. The compositions of the invention may also be used in the treatment of small cell lung tumorous tumors of the lung, hyponatraemic encephalopathies, Raynaud's disease, Meniere's syndrome, lung syndrome and glaucoma, especially after abdominal, cardiac or vascular surgery.

The compositions of the invention may contain, in addition to the aforementioned compounds of formula (I), or pharmaceutically acceptable salts, solvates or hydrates thereof, other active compounds which may be used in the treatment of the disorders and diseases indicated above.

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Thus, another object of the invention is pharmaceutical compositions comprising a combination of several active agents, one of which is a compound of the invention.

Thus, pharmaceutical compositions comprising a compound of the invention in combination with a compound that acts on the renin-angiotensin system, such as an angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist or renin inhibitor, can be prepared according to the invention. The compound of the invention may also be combined with, for example, a peripheral vasodilator, a calcium antagonist, a β-blocker, an α-blocker, or a diuretic. Such compositions are particularly useful in the treatment of hypertension or heart failure. Two compounds of the present invention may also be combined: a specific V1 receptor antagonist with a specific oxytocin antagonist or a V1 antagonist and a V1 antagonist.₂antagonist; or V₂antagonist and V, agonist.

The compositions of the invention preferably comprise the above compound of formula (1.1), (1.2), (1.3) or (1.4), or one of its pharmaceutically acceptable salts, solvates or hydrates. Each of these compounds may be combined with a specific angiotensin II receptor antagonist, preferably irbesartan.

Such combinations make it possible to enhance the therapeutic effects of the compounds of the invention.

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The following preparations and examples illustrate the invention without limiting it.

NMR spectrum was obtained in DMSO-d6, unless otherwise noted, at 200 MHz and chemical shifts were expressed as.

The following abbreviations are used: s = singlet m = multiplet t = triplet q = quintet

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Preparation Example I. Alcohols of Formula (VI)

5-Ethoxy-3-spiro- (4-hydroxycyclohexane) -indolin-2-one, Compound (VI.1) g A solution of 5-ethoxy-3-spiro- (4-methoxymethyloxy-cyclohexane) -indolin-2-one prepared according to EP 636 608. 130 ml of methanol and 9 ml of concentrated (36%) hydrochloric acid are heated at 40 ° C for 3 hours. The reaction mixture is cooled, the precipitate is filtered off, washed with diethyl ether and dried to give the polar isomer of the desired product. Mp 225 ° C. 50 ml of water are added to the filtrate, then methanol is evaporated off, the residue is extracted with dichloromethane, the organic phase is washed with water, dried and evaporated to give the desired product as a mixture of isomers.

Mp 170 ° C.

5-Chloro-3-spiro (4-hydroxy-cyclohexane) -indolin-2-one, Compound (VI.2)

The compound is prepared according to the above procedure from 5-chloro-3-spiro- (4-methoxymethyloxy-cyclohexane) -indolin-2-one prepared from EP-636,608 from 5-chloro-indolin-2-one. The desired product is isolated after extraction with dichloromethane as a mixture of isomers. Mp 260 ° C.

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Preparation Example II. Ketones of Formula (V)

5-Ethoxy-3-spiro- (4-oxocyclohexane) indolin-2-one, Compound (V.1)

Dissolve 3.8 g of 5-ethoxy-3-spiro- (4-hydroxycyclohexane) indolin-2-one (VI.1) (mixture of isomers) and 5.8 ml of pyridine in 250 ml of ethyl acetate and add 6.3 g of 29 g of neutral alumina pyridinium chlorochromate. The reaction mixture is stirred at 25 ° C for 16 hours, filtered and the solvent is evaporated off from the filtrate. After recrystallization from toluene in the presence of activated carbon, 3.4 g of the desired product is isolated. Mp 168 ° C.

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

The compound is prepared from 5-chloro-3-spiro- (4-hydroxycyclohexane) indolin-2-one (VI.2) following the same procedure as for compound (VI). Mp 220 ° C.

Preparation Example III. Acetals of formula (IV)

5-Ethoxy-3-spiro-η 4,4-di (2-chloroethyloxy) cyclohexane-indolin-2-one, Compound (IV.1) g 5-Ethoxy-3-spiro (4-oxocyclohexane) indolin-2-one (VI) is dissolved in 30 ml of toluene and 4.6 ml of 2-chloroethanol. Add 2 g of 5 Å molecular sieve and 0.22 g of methaneEE 04433 ΒΙ sulfonic acid. The reaction mixture is stirred slowly at 20 ° C for 18 hours, then filtered and the molecular sieve washed with dichloromethane. The solvent is evaporated and the desired product is crystallized from diethyl ether. Mp 170 ° C.

5-Ethoxy-3-spiro-4,4-di- (3-chloropropyloxy) -cyclohexane indolin-2-one, Compound (IV.2)

The compound is prepared according to the same procedure as compound (IV.1) from the same ketone (VI) and 3-chloropropanol. M.p.

147 ° C.

5-Chloro-3-spiro-4,4-di- (2-chloroethyloxy) cyclohexaneindolin-2-one, Compound (IV.3)

The compound is prepared from compound (V.2) and 2-chloroethanol according to the same procedure as compound (IV.1). Mp 174 ° C.

Preparation Example IV. Derivatives of formula (III)

5-Ethoxy-3-spiro-Γ 4- (3-chloropropyloxy) -cyclohexane-indolin-2-one (mixture of isomers), Compound (III.1)

To 0.55 g of acetal (IV.2) in 3 ml of dichloromethane is added slowly, at 0 ° C, 2.2 ml of a 0.29 M solution of zinc borohydride in diethyl ether (prepared in Chem. Pharm. Bull., 1984, 32 (4), 1411-1415). , as described in the method) followed by 0.34 mL of trimethylchlorosilane. The reaction mixture is stirred at 20 ° C for 16 hours then added

EE 04433 B1 mL saturated NaHCO₃ solution, extract with ethyl acetate and wash the organic phase with saturated NaCl solution. After MgSO 4₄After drying and evaporation, 0.4 g of an oil are isolated, which is chromatographed on silica gel, eluting with 8: 2 (v / v) cyclohexane / ethyl acetate.

The desired product (mixture of isomers) is isolated as a resin. ¹1 H-NMR, CDCl 1₃, 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-1-indolin2-one (mixture of isomers), Compound (III.2)

The compound is prepared from compound (IV.1) following the same procedure as compound (III.1).

¹1 H-NMR, CDCl 1₃200 MHz: δ (s, 1H); 6.85-6.63 (m, 3H); 4,033.93 (q, 2H); 3.81-3.74 (m, 2H); 3.70-3.58 (m, 3H); 2,211.55 (m, 8H); 1.4 (t, 3H).

5-Chloro-3-spiro-Γ 4- (2-chloroethyloxy) cyclohexane) indolin-2-one (mixture of isomers), Compound (III.3)

The compound is prepared from compound (IV.3) according to the same procedure as compound (III.1).

¹1 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).

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5-Ethoxy-3-spiro-4- (2-tosyloxy) -cyclohexane-1-indolin-2one, Compound (III.4)

19.97 g of tosyl chloride are added to 19.25 g of compound (ΙΙΙΊ) described in Preparative Example X in 130 ml of pyridine at 0 ° C. The reaction mixture is stirred at 20 ° C for 3 hours. The reaction mixture is poured into 650 ml of water and then stirred for 30 minutes. After filtration, washing with water and drying in vacuo at 40 ° C in the presence of phosphoric anhydride, 28.06 g of the expected product is isolated. The product obtained from the polar isomer (ΙΙΙΊ) melts at temperature

152 ° C.

Preparation Example V. Derivatives of Formula (IIA)

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

To a solution of 0.75 g of the chlorinated derivative (III.2) and 0.75 g of 4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl chloride in 90 ml of tetrahydrofuran cooled to -60 ° C is added 0.29 g of potassium tert-butanolate. The temperature is allowed to rise to 20 ° C and the reaction mixture is stirred for 2 hours. 30 ml of a 15% NaCl solution are then added, the mixture is extracted with ethyl acetate, the organic phase is washed with 15% NaCl, dried over MgSO₄, the solvent is evaporated and the residue is chromatographed on silica gel, eluting with cyclohexane /

85: 15 (v / v) ethyl acetate: to isolate the desired product as a resin.

<td>¹H-NMR,</td><td>DMSO-d 6, 200 MHz</td><td>: 8 (m,</td><td>2H); 7.5</td><td>(m, 3H); 7.04</td><td>(s,</td>

<td>0.75H);</td><td>6.85 (m, 1.25H);</td><td>4.0 (q,</td><td>2H); 3.6</td><td>(s, 3H); 3.66</td><td>(s,</td>

<td>4H); 3,</td><td>58 (s, 3H); 3.5</td><td>(m, 1H);</td><td> 1,9-1,6</td><td>(m, 8H); 1.34</td><td>(s,</td>

9H); 1.28 (t, 3H).

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

0.18 mL of triethylamine and 0.25 g of 5-ethoxy-1- [4- (Ν ', N'-diethylureido) -2-methoxybenzenesulfonyl] -3-spiro- [4- (2-hydroxyethyloxy) cyclohexane] indoline- To a solution of 2-one (prepared according to EP 636 608) in 3 ml of anhydrous tetrahydrofuran at 0 ° C is added 0.25 g of tosyl chloride. The reaction mixture is stirred at 20 ° C for 48 hours. 10 ml of saturated NaHCO3 are then added₃ solution, extracted with ethyl acetate, the organic phase is dried over MgSO 4₄the solvent is evaporated and the residue is chromatographed on silica gel, eluting with dichloromethane / methanol 99: 1 (v / v) and then 95: 5. Mp 80 ° C.

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

The desired product is prepared in the same manner as compound (IIA.2) starting from 5-ethoxy-1- [4- (2-hydroxyethyloxy) -cyclE 04433 B1-lohexane] -indolin-2-one or by introducing 4- (N-tert-butylcarbamoyl) - 2-methoxybenzenesulfonyl chloride is reacted with compound (III.4) under the conditions of preparation of compound (IIA.l). Mp 142 ° C.

Preparation Example VI. Alcohols of formula (IIΆ)

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

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

A mixture of 0.6 g of compound (IIA.l), 0.8 g of silver nitrate and 0.25 g of sodium iodide in 10 ml of acetonitrile is heated at reflux for 48 hours. The salts are filtered off and the solvents are evaporated. The desired product is isolated by chromatography on silica gel, eluting with 80:20 v / v cyclohexane / ethyl acetate. 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 in 15 ml of ethanol are refluxed for 1 hour. The catalyst is then removed by filtration, the solvent is evaporated and the residue is chromatographed on silica gel, eluting first with dichloromethane and then with 99: 1 v / v dichloromethane / methanol. The mixture of isomers of the desired product is isolated, m.p. 120 ° C (heEE 04433 B1 mihydrate), followed by the polar isomer which is crystallized from 1: 1 (v / v) isopropyl ether / ethyl acetate, m.p. 189 ° C (hydrate).

5-Ethoxy-3-spiro-4- (3-hydroxypropyloxy) -cyclohexane-1- [4- (N-tert-amylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one 'compound (ΙΙΆ.2).

a) 5-Ethoxy-3-spiro- [4- (3-methoxymethyloxypropyloxy) cyclohexane] -1- [4- (N-tert-amylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one

The 5-ethoxy-3-spiro- [4- (3-methoxymethyloxypropyloxy) cyclohexane] indolin-2-one (III'2P) prepared according to Preparation X is condensed with N-tert-amylcarbamoyl-2-methoxysulfonyl chloride according to the procedure described in Preparation V to give the desired product. to be used in the next step.

b) 0.5 g of the compound prepared in step a) in 1.5 ml of methanol and 0.2 ml of concentrated (36%) hydrochloric acid are heated at 50 ° C for 1 hour. 5 ml of water are added, the mixture is extracted with ethyl acetate, the solvents are evaporated and the desired product is isolated after chromatography on silica gel with cyclohexane / ethyl acetate 1: 1 (v / v). Mp 120 ° C.

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Preparation Example VII. Indolin-2-one of formula (II.B)

5-Chloro-3-spiro-4- (2-morpholinoethyloxy) cyclohexane indolin-2-one (mixture of isomers), Compound (IIB.1)

A mixture of 0.57 g of compound (III.3), 0.5 g of morpholine and 0.27 g of NaI in 6 ml of dimethylformamide is heated at 85 ° C for 24 hours. 10 ml of water and 10 ml of saturated NaHCO are added to the reaction mixture₃ solution, extracted twice with ethyl acetate, the organic phases are dried over MgSO4₄the solvent is evaporated and the residue is chromatographed on silica gel, eluting first with dichloromethane and then with dichloromethane / methanol 98: 2 (v / v) to remove

0.5 g of the desired product as an oil.

¹1 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 (mixture of isomers), Compound (IIB.2)

1.5 g of tosylate (III.4) (mixture of isomers), 0.66 g of benzylglycinate hydrochloride and 0.35 g of sodium carbonate! 80 ml of acetonitrile are heated at 60 ° C for 48 hours. The solvent is evaporated off under reduced pressure, the residue is taken up in 40 ml of ethyl acetate, the organic phase is washed with water, dried over Na2₂SO₄and the solvent is evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol 99: 1 (v / v), and the resin is isolated and the solution is dissolved in 20 ml of dioxane. 0.13 g of magnesium oxide dissolved in 10 ml of dioxane and 0.539 g of di-tert-butyl dicarbonate are added at 5 [deg.] C. and the reaction mixture is stirred at 20 [deg.] C. for 16 hours. The solvent is evaporated, the residue is taken up in ethyl acetate, the organic phase is washed with a buffer solution (pH = 2),₃ solution and water. Dry over Na₂SO₄and the solvent is evaporated. After purification by silica gel chromatography eluting with ethyl acetate: cyclohexane 5: 5 (v / v), the desired product is obtained as a resin.

¹1 H-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); 3.3-3.6 (m, 5H); 1.4-2.1 (m, 8H);

1.2-1.4 (m, 12H).

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

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

A mixture of 1.5 g of compound (III.4) (prepared from the polar isomer (ΙΙΙΊ)) and 0.23 g of sodium azide in 15 ml of dimethylformamide is heated at 50 ° C for 16 hours. Add 30 ml of water, extract twice with ethyl acetate. The organic phases are dried over Na 2₂SO₄, the solvent is partially evaporated to ca. 20 mL under reduced pressure. The solution is hydrogenated at 60 ° C at 10⁶ Pa 0.6 g of Lindlar catalyst (palladium CaCO₃-l) in the presence. The catalyst 0E 03333 B1 is filtered off and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column of silica gel, eluting with a 90:10 v / v mixture of dichloromethane / methanol. The hydrochloride of the desired product is isolated after recrystallization of the base in ethyl acetate and subsequent hydrochlorination in ethyl acetate. Mp 168 ° C.

(b) At 5 [deg.] C., 0.27 g of compound (a) in 0.4 ml of 2N sodium hydroxide dissolved in 20 ml of dioxane, 0.05 g of magnesium oxide and 0.19 g of di-tert-butyl dicarbonate are added. After stirring at 20 ° C for 2 hours, the solvent is evaporated off, the residue is taken up in ethyl acetate, the organic phase is washed with a buffer solution (pH = 2),₃ solution and water. Dry over Na₂SO₄the solvent is evaporated and the desired product is isolated as a resin. ¹1 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).

Preparation Example VIII. Hydrazides of formula (VII)

N '- (4-Ethoxyphenyl) -4,4-ethylenedioxycyclohexanecarbohydrazide. Compound (VII.1)

At -40 [deg.] C., 1.65 ml of isobutyl chloroformate, followed by 1.8 ml of triethylamine, are added to a mixture of 2.63 g of sodium 4,4-ethylenedioxycyclohexanate in 20 ml of tetrahydrofuran. The reaction mixture is stirred at 0 ° C for 2 hours. 2.4 g of 4EE 04433 B1 ethoxyphenylhydrazine hydrochloride are then added at -20 ° C. The reaction mixture is stirred at 0 ° C for 2 hours, 100 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed with KHSO₄ solution (pH = 2) and saturated potassium carbonate solution, dried over MgSO4₄and evaporate. The desired product is obtained after crystallization from diethyl ether. M.p.

158 ° C.

N '- Phenyl-4,4-ethylenedioxycyclohexanecarbohydrazide, Compound (VII.2)

Compound (VII.2) is isolated from phenylhydrazine in the same manner. Mp 158 ° C.

Preparation Example IX. Acetals of Formula (IV ')

5-Ethoxy-3-spiro- (4,4-ethylenedioxy-cyclohexane) -indolin-2-one, Compound (IV'.1)

At -50 [deg.] C., 2.15 ml of a 1.6 M solution of 1.6 M butyl lithium in hexane is added to a suspension of 1 g of hydrazine (VII.1) in 16 ml of tetrahydrofuran. The reaction mixture is stirred for 15 minutes and 16 ml of tetralin are added. The tetrahydrofuran is distilled off and heating at 180 ° C is continued for 45 minutes. 20 ml of ethyl acetate are then added at room temperature and subsequently washed with water. The organic phase is dried over MgSO 4₄the solvents are distilled off in vacuo and the residue is chromatographed on silica gel, eluting with cyclohexane / ethyl acetate 7: 3 (v / v).

EE 04433 B1. The desired product is isolated by crystallization from diethyl ether. Mp 183 ° C.

The same product is also obtained by reacting 5-ethoxy-3-spiro- (4-oxocyclohexane) indolin-2-one (Compound (VI)) with ethylene glycol in cyclohexane in the presence of 5 A molecular sieves and a catalytic amount of p-toluenesulfonic acid.

5-Ethoxy-3-spiro- (4,4-propylenedioxy-cyclohexane) -indolin2-one, Compound (IV'.2)

The compound is prepared according to the same procedure as compound (IV'.1) from the corresponding hydrazide or by reaction of 5-ethoxy-3-spiro- (4-oxocyclohexane) indolin-2-one (compound (V1)) with 1,3-propanediol in 5 and a catalytic amount of p-toluenesulfonic acid. M.p.

216 ° C.

3-Spiro- (4,4-ethylenedioxycyclohexane) indolin-2-one, Compound (IV'.3)

The compound is prepared according to the same procedure as compound (IV'.1) starting from the corresponding hydrazide (VII.2). M.p.

218 ° C.

EE 04433 Βί

Preparation Example X. Alcohols of Formulas (III⁷) ia (III⁷P)

5-Ethoxy-3-spiro-4- (2-hydroxyethyloxy) -cyclohexane indolin-2-one, Compound (III)⁷.!)

3.1 g to acetal (IV⁷.1) 20 ml of a 0.25 M solution of zinc borohydride in diethyl ether (prepared by the method described in Chem. Pharm. Bull., 1984, 32 (4), 1411-1415) are slowly added in 20 ml of dichloromethane at 0 ° C, and then 2.8 ml of trimethylsilyl chloride. The reaction mixture is stirred at 20 ° C for 16 h, then 20 mL of saturated NaHCO is added₃ solution, the solvents are evaporated, the residue is extracted with ethyl acetate, dried over MgSO 4₄the solvent is evaporated and the residue is purified by chromatography on silica gel, eluting with 67: 34 (v / v) cyclohexane / ethyl acetate. A mixture of isomers of the desired product is isolated. The polar isomer is isolated by crystallization from diethyl ether. Mp 125 ° C.

5-Ethoxy-3-spiro-4- (3-hydroxypropyloxy) -cyclohexane indolin-2-one, Compound (III)⁷.2)

The compound is prepared from acetal (IV⁷.2) following the same procedure as for compound (ΙΙΙ'.Ι). The polar isomer of the desired product is obtained. 180 ° C (hemihydrate).

EE 04433 Bl

5-Ethoxy-3-spiro-4- (3-methoxymethyloxypropyloxy) -cyclohexanedindolin-2-one, Compound (III'.2P) g 5-Ethoxy-3-spiro [4- (3-hydroxypropyloxy) -cyclohexane] indolin-2 -one (III'.2), 7.7 ml of dimethoxymethane,

A solution of 0.065 g LiBr and 0.07 g p-toluenesulfonic acid in 15 ml dichloromethane is stirred at room temperature for 24 hours and then 10 ml saturated NaCl solution is added. The phases are separated and the organic phase is dried over MgSO4₄the solvent is evaporated and, after chromatography of the residue on silica gel, eluting with a 1: 1 (v / v) cyclohexane / ethyl acetate mixture, the polar isomer of the desired product is obtained.

Mp 89 ° C.

Preparation Example XI, Protected Alcohols of Formula (X)

5-Ethoxy-3-spiro- (4-methoxymethyloxycyclohexane) -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one, Compound (Xl)

To a solution of 5-ethoxy-3-spiro- (4-methoxymethyloxy-cyclohexane) -indolin2-one (compound of formula (XI), prepared according to EP 636 608) in 80 ml of tetrahydrofuran is cooled to -40 ° C with 0.283 g of potassium tert-butanolate. The temperature is allowed to rise to 0 ° C. The mixture is then cooled to -40 ° C and 0.73 g of (2-methoxy-4-tert-butylcarbamoyl) -benzenesulfonyl chloride in 7 ml of tetrahydrofuran are added. The reaction mixture is stirred at room temperature for 2 hours, then 20 ml of water are added and the mixture is extracted

EE 04433 ΒΙ ethyl acetate, dried over MgSO 4₄the solvent is evaporated and the resulting oil is purified by chromatography on silica gel, eluting with 8: 2 (v / v) cyclohexane / ethyl acetate. The least polar isomer of the desired product is isolated, m.p. 165 ° C, followed by the polar isomer, m.p.

156 ° C.

Preparation Example XII. Alcohols of formula fllc)

5-Ethoxy-3-spiro- (4-hydroxycyclohexane) -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one, Compound (IIc.1)

A mixture of 0.24 ml concentrated (36%) hydrochloric acid and polar isomer of compound (X1) in 1.2 ml methanol is heated at 50 ° C for 1 hour. 8 ml of water are added to the reaction mixture, which is then extracted with dichloromethane, and the organic phase is dried over MgSO4.₄and the solvents are evaporated. After purification, the desired product is obtained by chromatography on silica gel, eluting with dichloromethane. Mp 268 ° C (polar isomer).

In the same manner, the least polar isomer of the desired product is isolated from the least polar isomer prepared according to (X1). 130 ° C (hemihydrate), Compound (IIc.2).

EE 04433 ΒΙ

Preparation Example XIII. Reagents of formula (2)

2-Methoxy-4-N-tert-amylcarbamoylbenzenesulfonyl chloride, Reagent (2) .1

(a) N-tert-amyl-3-methoxy-4-nitrobenzamide To a solution of 3 g of 3-methoxy-4-nitrobenzoyl chloride (prepared by refluxing 25 g of the corresponding acid and thionyl chloride for 4 hours) in 250 ml of dichloromethane is added. ml of tertamylamine. The reaction mixture is stirred at 20 ° C for 1 minute, then 100 ml of 1 N hydrochloric acid solution are added, the organic phase is separated off, washed and dried over MgSO 4.₄with. The solvent is evaporated and the residue is chromatographed on silica gel, eluting with dichloromethane, to give 31 g of the desired product. Mp 65 ° C.

In the same way, N-tert-butyl-3-methoxy-4-nitrobenzamide is prepared from N-tert-butylamine. Mp 118 ° C.

b) N-tert-amyl-3-methoxy-4-aminobenzamide), prepared with N-tert-amyl-3-methoxy-4-nitrobenzamide, 20 g of 10% palladium on carbon and 76 ml of cyclohexene in 310 ml of ethanol are refluxed for 3 hours. . The mixture is filtered and the filtrate is evaporated to give 25 g of the desired product. Mp 108 ° C.

EE 04433 Bl

In a similar manner, N-tert-butyl-3-methoxy-4-nitrobenzamide is converted to N-tert-butyl-3-methoxy-4-aminobenzamide. M.p.

160 ° C.

c) 2-Methoxy-4-tert-amylcarbamoylbenzenesulfonyl chloride for a solution of g N-tert-amyl-3-methoxy-4-aminobenzamide

103 7.9 g of sodium nitrite solution in 31 ml of water are added to 0 ml of acetic acid and 187 ml of a mixture of 36% hydrochloric acid at 0 ° C. The reaction mixture is stirred at 0 ° C for 1 hour, then the resulting solution is added at the same temperature

6.8 g of a suspension of copper chloride in 25 ml of water and 140 ml of acetic acid saturated with about 68 g of sulfur dioxide at 0 ° C. The reaction mixture is stirred at 0 ° C for 3 hours and then at 20 ° C for 16 hours. The mixture is poured onto 750 g of ice and subsequently stirred at 20 ° C for 1 hour. The precipitate is filtered, washed with water and dried under vacuum for 48 hours to give 19 g of the desired product. m.p.

104 ° C.

4-N-tert-Butylcarbamoyl-2-methoxybenzenesulfonyl chloride, Reagent (2) .2

The desired reagent is isolated in the same manner from N-tert-butyl-3-methoxy-4-aminobenzamide. Mp 148 ° C.

EE 04433 Bl

3-Methoxy-4-benzyloxycarbonyl-benzenesulfonyl chloride, Reagent (2) .3

The desired reagent is isolated from 4-amino-3-methoxybenzoic acid (m.p. 72 [deg.] C., obtained by reduction of the corresponding nitroderivative with tin in hydrochloric acid, m.p. 88 [deg.] C.) using the above reaction.

N-tert-Butyl-4-bromomethyl-3-methoxybenzamide, Reagent (2), 4 g of N-tert-butyl-4-methyl-3-methoxybenzamide, 2.4 g of Nbromosuccinimide and 0.16 g of benzoyl peroxide in 40 ml in carbon tetrachloride is stirred at 30 ° C for 48 hours. The solvent is evaporated off, 25 ml of water are added, the mixture is extracted with diethyl ether and the organic phase is dried over MgSO4.₄with. The solvent is evaporated and the residue is chromatographed on silica gel, eluting with 8: 2 (v / v) cyclohexane / ethyl acetate. The desired reagent is isolated after crystallization from isopropyl ether. Mp 114 ° C.

EE 04433 Bl

Example 1

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro-4- (2-morpholinoethyloxy) -cyclohexanindolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂-_ O least polar isomer

A mixture of 0.6 g of the chlorinated derivative (IIA.l) obtained in Preparative Example V, 0.26 g of morpholine and 0.15 g of sodium iodide in 6 ml of dimethylformamide is heated at 60 ° C under an inert atmosphere for 40 hours. The solvent is evaporated in vacuo and the residue is taken up in 20 ml of 5% NaHCO₃ aqueous solution, extracted with ethyl acetate, the organic phase is washed with 10% NaCl solution and dried over MgSO₄with. The solvent is evaporated off, and the resin is isolated, which is chromatographed on silica gel, eluting with dichloromethane: methanol 98: 2 (v / v).

The least polar isomer of the desired product is isolated (Rf = 0.5, TLC, silica, dichloromethane / methanol 95: 5 by volume). The fumarate is prepared in acetone and crystallized in diethyl ether. Mp 153 ° C (Example 1).

¹1 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).

EE 04433 Bl

Example 2

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-roethoxybenzenesulfonyl] -3-spiro-4- (2-morpholinoethyloxy) -cyclohexanindolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂-f / \&gt;

the most polar isomer

The most polar isomer of the desired product prepared according to Example 1 is isolated under the same conditions. R f = o, 43. M.p. 212216 ° C.

¹1 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 (m, 6H); 3.40 (m, 1H); 2.45 (m, 6H); 1.9-1.6 (m, 8H); 1.34 (s, 9H); 1.3 (t, 3H). The fumarate is prepared in acetone and crystallized in diethyl ether. Mp 172 ° C (Example 2).

Monohydrated dihydrogen phosphate is prepared by reacting monohydrated phosphoric acid with a base in ethanol. Mp 170 ° C. The nitrate is prepared by reacting an aqueous solution of nitric acid with water in ethanol. Mp 155 ° C.

EE 04433 Bl

Example 3

5-ethoxy-1- [4- (N ', N'-diethylureido) -2-methoxybenzenesulfonyl-3-spiro- [4- (2-dimethylaminoethyloxy) cyclohexane] indolin-2-one (I); R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R₄ = 4-NHCON

<img file="EE04433B1_D0027.tif" />

CH₃

CH '3

A mixture of 0.23 g of the tosylated derivative (IIA.2) from Preparation Example V in 3.3 ml of acetonitrile and 0.23 ml of 40% dimethylamine is stirred at 20 ° C for 48 hours. 1 ml of saturated NaHCO 3 is added₃ solution, extract with ethyl acetate and dry the organic phase over MgSO4₄with. The solvent is evaporated and the residue is chromatographed on silica gel, eluting with 245: 5: 0.2 (v / v) dichloromethane: methanol: aqueous ammonia. (R f = 0.5, TLC, silica, 85: 15: 1 v / v dichloromethane / methanol / 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): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -ch₂ch₂nh₂

EE 04433 Bl

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.l) obtained in Preparative Example V, 0.06 g of sodium azide and 0.126 g of sodium iodide in 5 ml of dimethylformamide is heated at 100 ° C under an inert atmosphere for 2 hours. 10 ml of water are added to the reaction mixture, the mixture is extracted with ethyl acetate, the organic phase is washed with water and dried over Na2₂SO₄with. The solvent is concentrated to a volume of about 20 mL to provide an azide solution which is used as such in the next reaction.

(b) The solution obtained in (a) is hydrogenated at 40 ° C and 10 ° C⁶ Pa 0.2 g palladium / CaCO₃ (Lindlar catalyst, 5% Pd) for 60 hours. The catalyst is removed by filtration, the solvent is evaporated and the residue is chromatographed on a column of silica gel, eluting with dichloromethane: methanol = 8: 2 (v / v). The desired product is isolated in base form and salted with fumaric acid in acetone and crystallized in isopropyl ether to give the desired product. 138 ° C (monohydrate).

The polar isomer of the desired product is isolated in a similar manner from compound (IIA.3) using the same steps. Its hydrochloride hemihydrate melts at 174 ° C.

EE 04433 Bl

Example 5

5-Chloro-3-spiro-4- (2-morpholinoethyloxy) cyclohexane-1- (4- tert -butylcarbamoyl) -2-methoxybenzenesulfonyl-indolin-2-one (I): R₁ = 5-Cl; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂ f /

To a solution of 0.21 g of compound (IIB.1) obtained in Preparative Example VII cooled to -30 ° C in 24 ml of tetrahydrofuran is added 0.073 g of potassium tert-butanolate. The temperature is allowed to rise to 0 ° C, then the mixture is cooled to -40 ° C and 0.19 g of [2-methoxy-4- (N-tert-butylcarbamoyl)] benzenesulfonyl chloride in 2 ml of tetrahydrofuran are added. The reaction mixture is stirred at -10 ° C for 2 hours, added with 15 ml of water, extracted with ethyl acetate, the organic phase is dried over MgSO₄the solvent is evaporated and the residue is purified by chromatography on silica gel, eluting with dichloromethane and then 96: 4 dichloromethane / methanol. The polar isomer of the desired product is isolated which is salified with fumaric acid in acetone. The fumarate is crystallized from diisopropyl ether. Mp 107 ° C (trihem hydrate).

EE 04433 Bl

Example 6

5-Ethoxy-3-spiro-4- (2-carboxyethyloxy) -cyclohexane-1- [4- (N-tert-amylcarbamoyl) -2-methoxy-benzenesulfonyl-indolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂; ch₃ r₄ = 4-CONH —c— c₂h₅ ; TZ = -CH₂CH₂-COOH ch₃

1.5 g of the compound obtained according to Preparative Example VI (II^ZA.2) To a solution of 9 ml of acetic acid and 10 ml of water at 0 ° C add 1 g of chromium oxide. The reaction mixture is stirred at 20 ° C for 2 hours. 80 ml of water are then added, the mixture is extracted with ethyl acetate and the organic phase is dried over MgSO4₄the solvent is evaporated and the desired product is isolated after chromatography on silica gel, eluting with a 99: 1 (v / v) dichloromethane / methanol mixture. M.p.

108 ° C (hemihydrate).

Example 7

5-Ethoxy-3-spiro-4-ethoxycarbonylmethyloxycyclohexane) 1- [4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one (I): R t = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

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

To a solution of 0.75 g of 5-ethoxy-3-spiro- (4-hydroxycyclohexane) -1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] indolin-2-one (II.Cl) in 30 ml of dichloromethane is added temEE 04433 B1. 0.47 g of 2,6-di-tert-butylpyridine, 0.54 g of silver trifluoromethanesulfonate and then 0.27 ml of ethyl iodoethanoate. The reaction mixture is stirred at 20 ° C for 48 hours and then the reaction mixture is filtered, the solvent is evaporated and the desired product is isolated after chromatography on silica gel, eluting with cyclohexane / cyclohexane / dichloromethane 20:80 (v / v) and recrystallized from 2-propanol. M.p.

165 ° C.

Example 8

5-Ethoxy-3-spiro- (4-carboxymethyloxycyclohexane) -1- (4-tert-butylcarbamoyl-2-methoxybenzenesulfonyl) -indolin2-one (I): Rt = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂COOH

0.34 g of the compound obtained in Example 7 and 0.01 g of p-toluenesulfonic acid in 3 ml of benzyl alcohol are heated at 65 ° C for 16 hours. The solvent is evaporated, then 1 ml of water and 1 ml of saturated NaHCO are added₃ solution, extract with ethyl acetate, evaporate the solvent and add 5 ml of 2-propanol, 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, then the mixture is filtered, the catalyst is washed with dichloromethane, the solvents are evaporated and the desired product is isolated and purified by chromatography on silica gel, eluting with 98: 2 dichloromethane / methanol. The desired product fraction is recrystallized

EE 04433 B1 8: 2 (v / v) isopropyl ether / ethyl acetate. Mp 175 ° C (hemihydrate).

Compounds 9 to 23 of Table 1 are prepared according to Examples 1 to 8.

Table 1

<img file="EE04433B1_D0028.tif" />

r₄

<td>For example de no</td><td>Ri</td><td>w</td><td></td><td>T</td><td>z</td><td>Salt, sol- see (1)</td><td>St °, ° c</td>

<td> 9</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃) ₃</td><td>- (CH₂)₂-</td><td> 1 !</td><td>1 hr₂o</td><td> 170</td>

<td> 10</td><td>Cl</td><td>so₂</td><td>-och₃</td><td>- &lt;ch₂)₂-</td><td>\ Vo</td><td>fuma- council 1.5 h₂o</td><td> 88</td>

<td> 11</td><td>-OC₂H₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>Π</td><td>fuma- council 2 H₂O</td><td> 160</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>

EE 04433 Bl

<td>For example de no</td><td>Rx</td><td>w</td><td> *4</td><td>T</td><td>z</td><td>Salt, sol- see (1)</td><td>St °, ° c</td>

<td> 13</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₃-</td><td>b</td><td>fuma- council 2 H₂O</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>fuma- council 1H₂O</td><td> 150</td>

<td> 15</td><td>-oc₂h₅</td><td>ch₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>b</td><td>fuma- council 1H₂O</td><td> 110</td>

<td> 16</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- &lt;ch₂)₂-</td><td>- Ν O CHj</td><td>fuma- council 1H₂O</td><td> 165</td>

<td> 17</td><td>-oc₂h₅</td><td>so₂</td><td>-conhcch₂ch₃i 1 i ch₃</td><td>- (CH₂)₂-</td><td>b</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>b</td><td>fuma- council 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>b</td><td>fuma- council 4 HP</td><td> 208</td>

<td> 20</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (ch₂)₂-</td><td>-N- ^ CH</td><td>fuma- council 1H₂O (2)</td><td> 104</td>

<td> 21</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>CH, 1 N (CH₂)₂OCH₃</td><td>fuma- council 1.5 h₂o</td><td> 100</td>

<td> 22</td><td>-oc₂h₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>o</td><td>dioxin sa- box 1H₂O</td><td> 224</td>

EE 04433 Bl

<td>For example de no</td><td></td><td>w</td><td></td><td>T</td><td>z</td><td>Salt, sol- see (1)</td><td>St °, ° c</td>

<td> 23</td><td>-OC₂H₅</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- (CH₂)₂-</td><td>-N (CH 2 CH 2)₂OCHj)₂</td><td>fuma- council 1H₂O</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>so₂</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 1 COOC (CH₃)₃</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>9th oc₂h₅</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>OH</td><td>h₂o</td><td> 80</td>

<td> 29</td><td>-oc₂h₅</td><td>so₂</td><td>-cooch₂c₆h₅</td><td>- (CH₂)₂-</td><td>9th oh₂c₆h₅</td><td> (4)</td><td> 55</td>

<td> 30</td><td>-och₂c, h,</td><td>so₂</td><td>-CONHC (CH₃)₃</td><td>- &lt;CH₂)₂-</td><td></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) (CH₂)₂O (CH₂)₂OH</td><td> (5)</td><td> 69</td>

EE 04433 Βί (1): most polar isomer, unless otherwise indicated (2): mixture of isomers (3): least polar isomer (4): 4-Hydroxypiperidine ethers are prepared by alkylation of N-tert-butyloxycarbonyl-4-hydroxypiperidine and the corresponding halide in the presence of sodium hydride and subsequent acid hydrolysis of the tert-butyloxycarbonyl group, (5) 2- (2- (N-benzylamino) ethoxy) ethanol; and reductive amination of the imine from benzaldehyde at 0 ° C in methanol.

Example 32

5-Ethoxy-3-spiro-4- (2- (2-hydroxyethylamino) -ethyloxy) -cyclohexane-1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (polar isomer) (I ): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂; r₄ = 4-conhc {ch₃)₃; tz = ch₂ch₂nhch₂ch₂oh

(a) To a solution of 0.9 g of the amine hydrochloride obtained in Example 4 cooled to 5 ° C in 8 ml of tetrahydrofuran is added 0.33 g of benzyloxyacetaldehyde followed by 0.46 g of sodium triacetoxyborohydride. The reaction mixture is stirred at 20 ° C for 3 hours, 10 ml of 1 N HCl are added, the mixture is extracted with ethyl acetate, the organic phase is washed with saturated NaCl solution, dried over MgSO₄and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column of KoEE 04433 B1 silica gel eluting with dichloromethane / methanol 98: 2 (v / v).

b) To benzyl ether dissolved in 5 ml of glacial acetic acid is added 0.4 ml of 1,4-cyclohexadiene and 0.3 g (10%) of palladium on carbon and heated at 60 ° C under a stream of nitrogen according to J. Org. Chem., 43, 21 (1978). The catalyst is filtered off with saturated NaHCO₃ 10 ml of water are added to the reaction mixture which is neutralized with the solution, extracted with ethyl acetate, washed with water, the organic phase is dried over MgSO₄and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a column of silica gel, eluting with dichloromethane: methanol 98: 2 (v / v). The desired product is isolated as the hydrochloride hydrate by preparing the hydrochloride with isopropanolic hydrochloric acid and crystallizing with diethyl ether. Mp 130 ° C.

Example 33

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

The title compound is isolated as the hydrochloride trihydrate by the procedure described in Preparation Example 32b) by debenzylation of the compound obtained in Preparation 31 in ethanol and preparation of the hydrochloride in diethyl ether. M.p.

159 ° C.

EE 04433 Bl

Example 34

5-Ethoxy-3-spiro-T 4- (2- (4-benzyloxy-piperidino) -ethyloxy) -cyclohexane-1 -1,4-carboxy-2-methoxy-benzenesulfonyl-indolin-2-one (I): R 1 = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

OCH CH

R₄ = 4-OCOOH; TZ = -CH₂CH₂N (prepared by the process of selective debenzylation according to Tetrah. Letters, 1986, 3753).

To a solution of 0.03 g of palladium acetate in 4 ml of dichloromethane is added 0.62 ml of tert-butyldimethylsilane and 0.06 ml of triethylamine and the reaction mixture is stirred at 20 ° C for 15 minutes. Slowly add 1 g of the compound of Example 29 in 2.6 mL of dichloromethane and then stir at 20 ° C for 4 hours. Add 1 ml of acetic acid, filter, wash with dichloromethane and wash the filtrate with aqueous ammonium chloride then water. The desired product is isolated after evaporation of the solvent, crystallization from pentane and drying under vacuum at 50 ° C for 5 hours. Mp 120 ° C.

EE 04433 Bl

Example 35

5-Ethoxy-3-spiro- (4- (2- (4-benzyloxy-piperidino) -ethyloxy) -cyclohexane-1- [4- (N- (1-hydroxymethyl) -cyclopentylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I): R₃ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

<img file="EE04433B1_D0029.tif" />

To a suspension of 0.7 g of the compound obtained in Example 34 in 7 ml of toluene and 2.5 ml of dichloromethane is added 1.27 g of oxalyl chloride and the reaction mixture is stirred at 20 ° C for 6 hours. The solvents are evaporated and the residue is dried under vacuum at 20 ° C for 2 hours. The residue is then dissolved in 20 ml of toluene and the solution is added to a solution of 1.16 g of 1-amino-1-cyclopentane-methanol in 30 ml of toluene cooled to about -40 ° C. The reaction mixture is stirred at 20 ° C for 2 hours and 30 ml of water and 100 ml of ethyl acetate are added. The organic phase is dried over Na 2₂SO₄and evaporated under reduced pressure. The desired product is isolated after chromatography on silica gel, eluting with dichloromethane: methanol 95: 5 (v / v). Mp 103 ° C.

EE 04433 ΒΙ

Example 36

5-Ethoxy-3-spiro- [4- (2- (4-hydroxypiperidino) -ethyloxy) -cyclohexane 1 -1- [4- (6- (1-hydroxymethyl) -cyclopentylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I) R, = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

<img file="EE04433B1_D0030.tif" />

The desired product is isolated in the hydrated base form according to the procedure described in Example 32b) starting from the compound obtained in Example 35 after column chromatography on silica gel, eluting with dichloromethane: methanol 92: 8 (v / v). Mp 109 ° C.

Example 37

5-Ethoxy-3-spiro-4- (2- (benzyloxycarbonylmethylamino) -ethyloxy) -cyclohexane 1 -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

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

The residue is isolated according to the procedure described in Example 5 starting from compound (IIB.2) and 2-methoxy-4- (N-tert-butylcarbamoyl) -benzenesulfonyl chloride and stirring at 20 ° C for 2 hours in 3 ml of ethyl acetate acetate saturated with gaseous hydrochloric acid. The desired product is obtained after basification and chromatography on silica gel, eluting with cyclohexane / ethyl acetate 8: 2 (v / v)

EE 04433 B1. The monohydrated hydrochloride salts boil at 160 ° C.

Example 38

5-Ethoxy-3-spiro-Γ 4- (2- (carboxymethylamino) -ethyloxy) -cyclohexane-1-Γ 4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl-indolin-2-one (I): R₁ = 5-OC₂H₅; 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 on carbon in 10 ml of ethanol are heated at reflux for 1 hour 30 minutes. The catalyst is filtered off and the solvent is evaporated off under reduced pressure. The desired product is isolated as the dihydrate after chromatography on silica gel, eluting with dichloromethane: methanol 90: 10 (v / v). Mp 199 ° C.

Example 39

5-Hydroxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro-4- (2-morpholinoethyloxy) -cyclohexanindol-2-one (mixture of isomers) (I): R₁ = 5-OH; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

/ \

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂-No

EE 04433 Bl

The desired product is isolated as the hydrate according to the procedure described in Example 38 starting from the compound obtained in Example 30. Mp 125 ° C.

Example 40

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl] -3-spiro-4- (2-N-oxide-morpholinoethyloxy) -cyclohexanedindolin-2-one (I): R t = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃) ₃; TZ

-CH CH-N

To 0.5 g of the compound described in Example 2 dissolved in 10 ml of methanol is added 0.8 ml of 30% hydrogen peroxide and the reaction mixture is heated at 45 ° C for 16 hours. The solvent is evaporated off under reduced pressure and the residue is chromatographed on silica gel, eluting with dichloromethane: methanol 85: 15 (v / v). The desired product is isolated as a hemihydrate after recrystallization from cyclohexane / ethyl acetate 40:60 (v / v). Mp 189 ° C.

EE 04433 Bl

Example 41

5-Ethoxy-1- [4- (N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -3-spiro-4- (2-N-methyl-morpholinium-ethyloxy) -cyclohexane-indolin-2-one methyl-sulfate (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

Θ / \

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂ N ^ _ Q ch₃ O ³ ch₃so₄

To 0.25 g of the compound described in Example 2, dissolved in 2.5 ml of acetonitrile, is added 0.05 ml of dimethyl sulfate and the reaction mixture is heated at 60 ° C for 24 hours. The solvent is evaporated and the desired product is isolated as a hemihydrate after crystallization from diethyl ether and drying under vacuum at 5 ° C for 5 hours. Mp 190 ° C.

Example 42

5-Ethoxy-3-spiro-4- (2- (2- (N-tert-butoxycarbonylglycyl) amino) -ethyloxy) -cyclohexane -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl-indolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂-NHCOCH₂NHCOOC (CH₃) ₃

To a solution of 0.11 g of α-α-tert-butyloxycarbonylglycine in 2 ml of acetonitrile is added 0.28 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 0.24 ml of triethylamine at 5 ° C, followed by 0.35 g of the compound obtained in Example 4. (polar isomer) hydrogen chloride 04433 B1 di. The mixture is stirred at 20 ° C for 4 hours. The solvent is evaporated off under reduced pressure, the residue is taken up in ethyl acetate and washed with KHSO₄/ K₂SO₄ buffer solution, pH - 2, water, saturated NaHCO3₃ solution and then again with water. The organic phase is dried over MgSO 4₄the solvent is evaporated off under reduced pressure and the residue is chromatographed on a column of silica gel, eluting with a 99: 1 (v / v) dichloromethane / methanol mixture. The desired product is isolated. Mp 158 ° C.

Example 43

5-Chloro-3-spiro-Γ 4- (N- (3-dimethylaminopropyl) carbamoylmethoxy) cyclohexane-1-4- (4-N-tert-butylcarbamoyl) -2-methoxybenzenesulfonyl-indolin-2-one (I): R₁ = 5-C1; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

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

The desired product is isolated as the hydrochloride monohydrate according to the procedure described in Example 42 starting from the carboxylic acid and 3-dimethylaminopropanamine obtained in Example 25. M.p. 135 ° C.

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

EE 04433 Bl

Table 2

<img file="EE04433B1_D0031.tif" />

SO,

OCH₃

CONHC (CH₃)₃

<td>For example de no</td><td>^R1</td><td>T</td><td>z</td><td>Salt, sol- see (1)</td><td>st °, ° 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> 45</td><td>5-OC₂H₅</td><td>- (CH₂)₂-</td><td>-NHCO (CH₂)₃COOCH₃</td><td> -</td><td> 138</td>

<td> 46</td><td>5-OC₂H_s</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>1 hr₂o</td><td> 108</td>

<td> 48</td><td>5-OC₂H_s</td><td>- (CH₂)₂-</td><td>-NHCOfCH ^ CH (NHCOOC (CH₃)₃) COOC (CH₃)₃</td><td>(4) h₂o</td><td> 133</td>

<td> 49</td><td>5-OC₂H_s</td><td>- (CH₂)₂-</td><td>-NHCOCH (NHCOOCH₂C₆H₅) (CH₂)₂COOCH₂C₆H₅</td><td> (5)</td><td> 108</td>

<td> 50</td><td>H</td><td>ch₂</td><td>-CONH (CH₂)₂OH</td><td>0.5 h₂o</td><td> 183</td>

(4): Starting from the natural configuration of tert-butyl N-atert-butyloxyglutamate, (5): Starting from the γ-benzyl ester of the natural configuration Na-benzyloxycarbonylglutamic acid.

EE 04433 Bl

Example 51

5-Ethoxy-3-spiro-4- (2-glycylaminoethyloxy-cyclohexane-1-4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl-indolin-2-one (I): R t = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃) ₃; TZ = -CH₂CH₂NHCOCH₂NH₂

To a suspension of 0.3 g of the compound of Example 42 in 3 ml of ethyl acetate is added 3 ml of a solution of ethyl acetate saturated with hydrochloric acid gas at 5 ° C, and the reaction mixture is stirred at room temperature for 2 hours. The solvent is evaporated, crystallized from diethyl ether, dried in vacuo to give the desired product as the hydrochloride dihydrate.

Mp 169 ° C.

Example 52

5-Ethoxy-3-spiro- [4- (2- (4-carboxy-butyramido) -ethyloxy) -cyclohexane-1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I): R₁ = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = S0₂;

R₄ = 4-CONHC (CH₃) ₃; TZ = -CH₂CH₂NHCO (CH₂) ₃COOH

The desired product is obtained from the compound obtained in Example 45 following the procedure of Example 8 by transesterification with benzyl alcohol followed by hydrogenolysis. Mp 117 ° C.

EE 04433 Bl

Example 53

5-Ethoxy-3-spiro-4- (2- (N-glutamylamino) -ethyloxy) -cyclohexane -1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I): R, = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

R₄ = 4-CONHC (CH₃)₃; TZ = -CH₂CH₂NHCOCH₂CH₂CH (NH₂) COOH

The desired product is isolated as the hydrochloride according to the procedure described in Example 51 starting from the compound obtained according to Example 48. Mp 230 ° C.

Example 54

5-Ethoxy-3-spiro-4- (2- (L-pyroglutamylamino) -ethyloxy) -cyclohexane-1- [4- (4-N-tert-butylcarbamoyl) -2-methoxy-benzenesulfonyl] -indolin-2-one (I): R , = 5-OC₂H₅; R₂ = H; R₃ = 2-OCH₃; W = SO₂;

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

<img file="EE04433B1_D0032.tif" />

A mixture of 0.245 g of the compound obtained in Example 49, 0.5 ml of cyclohexadiene and 0.25 g of 10% palladium on carbon in 2 ml of ethyl acetate is heated to 80 ° C. The catalyst is removed by filtration, the solvent is evaporated off under reduced pressure, the residue is taken up in ethyl acetate and washed with saturated NaHCO3.₃ solution. The solvent is evaporated off under reduced pressure and the residue is chromatographed on a column of silica gel, eluting with

EE 04433 98 98: 2 by volume dichloromethane: methanol. The resulting residue is taken up in diethyl ether. Mp 171 ° C.