SK126993A3 - Thiopyranopyrrole derivatives, method of their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

New thiopyranopyrrole derivatives of general formula (I) in which X is an oxygen atom or an NH radical, R1 is phenyl, which is optionally substituted, cyclohexadienyl, naphthyl or heterocyclyl, R2 is H, halogen, OH, alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyloxy, alkylthio, acyloxy, carboxy, optionally substituted alkyloxycarbonyl, benzyloxycarbonyl, amino or acylamino, and n is 0, 1 or 2, in their stereoisomeric forms and their mixtures, optionally their salts when they exist and their preparation. The new derivatives according to the invention are particularly advantageous as antagonists of substance P. <IMAGE>

Description

The invention relates to novel thiopyranopyrrole derivatives w of the general formula I

as well as their salts, if any, which antagonize the effects of substance P and are also useful in the therapeutic areas in which the effects of said substance P are applied.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,042,707 discloses products derived from isoindoles having the general formula:

These substances are said to have opium efficacy.

The above products are not active against substance P.

European patent application 0068822 has disclosed herbicidally active compounds of the general formula

^x w *

wherein X may be a sulfur atom, R 1 and R 2 are a hydrogen atom or an alkyl group and R is a substituted phenyl group.

research, and despite INS, (5) 1 39 (. 1 982)), did not specifically affect P am until now, despite an aroused interest (M. R. Hanley, found a compound that did not The structure of the derivatives of formula I is very important.

Accordingly, thiopyranopyrro are the subject of the invention

The present invention provides compounds of formula I

(I)

Ktorom · in which

X represents an oxygen atom or an NH group,

R 1 represents a phenyl group which is optionally substituted by one or more substituents from the group consisting of a halogen atom, a hydroxy group, an alkyl group which may optionally be substituted (by halogen atoms or amine atoms) and alkyl or amino alkyloxy or alkylthio, which may optionally be substituted by hydroxy, amino, and alkylamino or dialkylamino, which may be optionally substituted (phenyl;

* · *. ·. . . _% Λ · β '.

ϋ

R 1 is hydroxy or amino; or an amino group whose alkyl radicals form with the ator nitrogen to which they are attached, a 5- or b-valuable n-heterocycle which may contain yet another heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted by alkyl, hydroxy or hydroxyalkyl), or substituted by amino, alkylamino or dialkylamino, the alkyl radicals of which can form a heterocycle as defined above with the nitrogen atom to which they are attached or represents a cyclohexadienic group, a naphthyl group or a saturated and unsaturated mono- or polycyclic group containing 5 to 9 carbon atoms and one or more non-heteroatoms selected from oxygen, nitrogen or sulfur. means a hydrogen or halogen atom or a hydroxy group, an alkyl group, an amino group, an alkyl amine group, a remote amine alkyl group, an alkyloxy group, an alkyl group, an acyl group an oxy group, a carboxyl group, an alkyloxycarbonyl group, a dialkylaminoalkyloxycarbonyl group, a benzyloxycarbonyl group, an amino group, an acylamino group, or an alkyloxycarbonyl group, and

means an integer oo 0 to 2.

The above-mentioned alkyl or acyl groups contain 1 to 4 carbon atoms in the straight or branched chain carbon.

when R 1 contains a halogen atom, the halogen atom may be selected from the group consisting of a chlorine atom, a bromine atom, a fluorine atom and an iodine atom.

when R 1 is a saturated or unsaturated mono or polycyclic non-heterocyclic group, examples of such a group include, in particular, a thienyl group, a furyl group, a pyridyl group, a d 111 other hunting group. buyin, n-4-yl, z-n-iyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrrolyl, triazolyl, thiadiazolyl, clonyl, butocyanol natty ridinyl group.

in the case where R is a phenyl group substituted by a heterocyclic-bearing chain, then such a heterocycle may be selected from the group consisting of pyrrolidinyl, morphol, a pyridinyl group, a tetrahydropyridinyl group, or a piperidine group; or a thiomorpholine group.

otherwise, the compounds of formula (I) exhibit different forms of stereoisomerization and it is understood that iopyranopyrrole derivatives having the (4aR, 7aKj) or (4aS, 7aSj) configuration in the pure state or in the form of cis (4aRS, 7aRS) configurations are also within the scope of the invention.

Compounds of formula (I) in which n = 1 also exhibit axial and equatoriain stechimetry at the S-oxide level.

It is understood that the R and S derivatives in the -1 position as well as mixtures thereof are also within the scope of the invention.

In addition, when R 1 is otherwise known as a hydrogen atom, the substituted chain at the thiopyranopyrrole has a chiral center and it is understood that the corresponding stereoisomeric forms and mixtures thereof are within the scope of the invention.

The thiopyranopyrrole derivatives of the formula I can be obtained by treatment with an acid of the formula III -

COOH (II) a 1 e D or e is the active reaction of this acid, wherein in formula (ii) R ia κ _; have the aforementioned 11-opyropyrrolidine derivative of the general formula iii

(O) (III) in which n is as defined above, and optionally subsequently converting the amide obtained to an amidine for which X in the general formula (I) is NH.

It goes without saying that amino groups, alkyl amino groups or carboxy groups contained in the general substituents R 1 and / or R 2 are preferably protected by protective groups before the reaction itself. This protection is accomplished using any suitable compatible protective group whose introduction and later removal will not adversely affect the rest of the molecule. In particular, the methods described by T. w-Greeno, Protective Uroups in Urganic Synthesis, A. WileyInterscience Publication 11 98 i), or Mc.umie, Protective Groups in Organic Chemistry, Plenum Pres (1973), will be used.

By way of illustration,

an amino group or an alkylamino group may be reacted with a methoxycarbonyl group, an ethoxycarbonyl group, tert. butoxycarbonyl, and 11yloxycarbonyl, vinyloxycarbonyl, trichloroethoxycarbonyl, trinotroacetyl, trifluoroacetyl, cn 1 -acetyl, trityl, oenzhydryl, allyl, benzyl, acyl, benzyl , benzyloxycarbonyl or substituted derivatives thereof, and

the carboxyl group may be protected by a methyl group, an ethyl group, a tert-butyl group, a benzyl group,

- O, uDstituted d o i o o o o o o o o snynyaryl group.

When in addition R; is a hydroxy group, then it is preferably pre-protected with a protecting group. This protection is carried out, for example, by an acetoxy group, a triakylisilyl group, a benzyl group or, in the form of a carbonate, by a -COORa group in which Ra represents an alkyl or benzyl group.

If the condensation of the reactive acid derivative of the general formula (II) is carried out, then preferably an acid chloride, anhydride, mixed anhydride or reactive ester is used, in which the ester residue is, for example, succinimido, oenzotriazol-1-yl, -nitrophenyl, 2,4-dimtrophenyl, pentachlorophenyl or phthalimido or any of these derivatives.

The reaction is typically carried out at -40 to 40 ° C in an organic solvent such as a chlorinated solvent (e.g., chloromethane, dichloroethane and chloroform), an ether (e.g., tetrahydrofuran or dioxane), an ester (e.g., ethyl acetate, amide (e.g., di-meth). or acetonitrile or ketone (e.g. acetone), or a mixture of these solvents, in the presence of an acid acceptor, such as a nitrogenous organic base, e.g. pyriaine, dimethylaminopyridine, N-methylmorpholine or trialkylamine (in particular triethylamine) or an epoxide (e.g. propylene oxide) and it is also possible to work in the presence of a condensation agent such as a carbodiirnide (e.g. dicyclohexylcarbodium 11 or or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide), Ν, Ν 1'-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-ahydroquinoline, or also in the inorganic environment in the presence of an alkaline The alkali metal-based reagents, such as, for example, salt bicarbonate, and then optionally converting the amide obtained into an amidine as defined above.

I

Conversion of an amide of formula I to an amine in which a is NH is accomplished by first preparing a derivative of formula IV

(17) wherein R ', R' and n are as defined above, Y is chlorine, methoxy or ethoxy and Z is chloride, tetrafluoroborate, fluorosulfonate, trifluoromethylsulfonate, methylsulfonate or an ethyisuironate ion, followed by treatment of the thus obtained derivative of the general formula IV with ammonia.

The preparation of a derivative of the formula IV in which Y represents a chlorine atom, a methoxy group or an ethoxy group is carried out by treatment with a reagent such as phosgene, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxaiyl chioride, tri chloromethyl chloroformate, triethyl (or trimethyl) oxonium tetrafluoroborate, methyl (or ethyl) tritiate, methyl (or ethyl) fluorosulfonate or methyl (or ethyl) sulfate. This reaction is carried out in a chlorinated solvent (e.g. dichloromethane and dichloroethane) or in an aromatic hydrocarbon (e.g. toluene) at a temperature of from 0 ° C to the reflux temperature of the reaction mixture. The treatment of the derivative of formula XI with ammonia is carried out in an anhydrous organic solvent such as a chlorinated solvent (e.g. dichloromethane or dichloroethane), an alcohol / chlorinated solvent mixture, an ether (e.g. tetrahydrofuran), an ester (e.g. ethyl acetate), an aromatic a solvent (e.g. toluene) or a mixture of these solvents at a temperature from -20 ° C to the reflux temperature of the reaction mixture.

It is not necessary for the reaction of formula IV to be pre-isolated from the reaction mixture i.

ο

The thiopyranopyrrole derivatives of the general formula wherein R 1 is an alkyloxyphenyl group, the alkyl radical of which is substituted or unsubstituted and R 1 has a meaning other than a halogen atom, can also be prepared according to the invention from a thiopyranopyrrole derivative in which R. represents a hydroxyphenyl group by treatment with the corresponding halogen derivative of the general formula V in a basic medium in which Kal represents a halogen atom and R. represents an alkyl group optionally substituted by a hydroxy group, an amidyl amine group "which in turn is a phenyl group, a hydroxy group or a dialkylamino group, wherein the nano, alkylamino or optionally substituted or amino group, the alkyl radicals form with the nitrogen atom to which they are attached a heterocycle which has been as defined above in relation to Formula I.

This reaction is usually carried out in the presence of a base such as an alkali metal hydride, hydroxide, alkoxide or carbonate in an organic solvent such as an amide (e.g. dimethylformamide), an aromatic hydrocarbon (e.g. toluene), ketone (e.g. butanone) or a mixture of these solvents. at a temperature between 20 ° C and the reflux temperature of the reaction mixture.

When R a carries a substituent that could interfere with the ongoing reaction, it is preferred that the substituent be pre-protected with a protecting group. The introduction and removal of such a protecting group is carried out as described above.

Thiopyranopyrrole derivatives wherein X is NH, can be prepared from a thiopyranopyrrole of formula (I);

III by the action of a compound of the formula VI.

N H (Λ / VI VI)

'' 1 P ¹ 1 u m n 11 a m D Λ 5 . ·. 1 i \ a in μι ι

vuvwuc »iumvxuiuir \ iar \ 2 111 a µ uvya“ Z Π α ΓΠ cnd ä 1ky 1 OX y - 3 k U p 1 Π u OPSdnUjUCu p Γ 1 ä 1T10 Iu á 1 Θ R oZV et V en O iu Γ cvd ZC 1 di 6 0 O

P e n z y ltio · group according to Po d 1 k y 1 o x y k d r P o n y Imets 11i o * s k ρ i u c v v v M M M M M M M M itigueiivauuv * o P ec 'of the formula Vi, which is optionally ρ ri ρ rdvenyin situ, vor 9 e 1 1 C k O iu r GZ p U 5 tdd 1 e, dkymj SC h 1 G Γ GV ä ne Γ GZ p Li S d ddi O

D d r d,,,, d d d d d e e e e e e e

(.for example

11υΡάΓι), d r O ΓΠ d 11 c k y uh i O V υυ l K <π d μ t 1 K i c u uu Uc i! j according to Po n 11 r i 1 (for example d c t o n 11 r i 1) at temperature between heat *

V o r d d e s R 1 a l e P o / d R 2 compounds in s P o c t e c t e c t e s o P 5111 u e n t s that P y m h 11 1 n t e r? r v P P e e e e e e e e e e um um um um um um um um um um um um um um um um um um skú

s u P s 111 u e n t y r r d d e n e n i d i v i u u x, where n is 1 according to Po, the invention can be oxidized by the corresponding derivative of the vseoPeone formula

1 u μ y 1 citupy i »u i u v c

For example, organic peroxyacids may be used for oxidation, such as peroxyacetic acid according to Po-eroxysulfonic acid, with 5 e 1 nu-eroxypenic acid, acid 11 nu 3 * oh 1 or ρ eroxy P enzo, 4 * n 11roperoxyPenz00vuic acid, peracetic acid, acid

per 0 x y t r 1 f I u 0 r 0 c iii a 1 6 1 n 0 v u, k y 5 e in u and 1 cuO r) ť s e t 1 n x y k y 5 s 1 i n u (nap

mono ρ eroxyftd hunting, ívci u, ky 5 s 11 nu ρ sroxykyss! 1 nu psroxykafroS uif O Π O vu 1 á SbO Bil ΓιδΓδ 1 (IU p β Γ O ^- μ ciuaysiiuvui.

Solvent (methylmethylene) at a temperature of 25 ° C can be used in the presence of titanium (IV) isopropoxide.

The reaction is carried out in chlorine

If a product of formula (I) in which n ⁼ 2 is to be obtained, then 2 equivalents of oxidation are used.

The acid of formula (II) may be prepared by methods analogous to those described in the examples, or by procedures analogous to these methods.

The derivative of the general formula (III), in which the derivative of the general formula (III) is prepared, can be prepared.

of the corresponding derivative

n ?. ₆ (VII)

One of R a in which R 5 is allyl or a group of the formula CR a R b R c in which R a and R t are hydrogen or phenyl optionally substituted by halogen, alkyl, alkyloxy a group or nitro group, and R c has the same meanings as Ra and R 6, or is an alkyloxycarbonyl group, at least being an unsubstituted or substituted phenyl group or an alkyl group containing 1 to 4 carbon atoms in a straight or branched carbon atom chain, by eliminating the group R e by any known method that does not adversely affect the rest of the molecule.

Especially if Rs know me otherwise as .a.11 y hunting ·; it can catalytic .. · hyd r.og e n.ac i ú 'v f ι f f f f f f ι α ι s s s s s s s s s s s 9 s s s u9i \ uuuuuujt vhy 9 ι ιιιι μ ι u 9 11 cuiaa - - · ··. 'X il · - I - - ·. '. - i ui μ u 9 i αυ ic, and i \ y here is a k k OuO í í. iu e * dn 0 etd ÍÍO! ) _r VO v 006 d 6 0 0 direct VK yseiincuvtuvcjai č u λ y 9 c ti ne tm avucj μι ι ιεμ luue hicuí »ισμ iuiuu

K y S ι ΟιΤι μΓυ5ιΓδυ1 p Γ 1 c μ ί e iii iii iii u u. t S p d t S S h Q t Reduction eye p Γ 1 d t7i 0 V y 5 6 1 1 Π 6. r \ r-> r »- u a _ i and fc a. , P r \ .v a l e μ i u t u u u u

fc. . fc A 11 y u 1 y hunting á 1 A fc A 1 euu and - I. • e u e Π 6 J 9A up 111 y fc » tou r> u 6p t 0 IN in

and in the alcohol,

C 1 0 v 6 j, s 6 1 1 n 6 πι Γ d VC 6 j 1 6 h 0 ky S 6 'onup i iiô r \ 6 9 a iivivi uusi * a π iu pučuucti i nt vitiyiuiiiui - ch I orety their lorformiate sieoorsny their iorformiate, to J 5 kor priprsvi

N — COO s ₇ (VII) vkt O r O t R 7 Z in in č á á á OV u u alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo alebo The action of chlorinates the solvent in some of the solvents, such as the solvent and the et al.

AA · I - i A fc fc A fc .AA fc · f W · A · · AAAA 1 A fc Γ u \ \ u u u u GT GT au \ \ \ au \ au) or in a mixture of these at a temperature between 20 action mixture i.

C Γ e t y i 0 IN U WITH to u P 1 H U ΡΛ dΠ 'i SK u μ 1 Dι d n 7 in · * Fc ,, «<« 1 1. u u y y \ 1 e U a Λ U u U U fc A 1 A 0 V d 6 Γ 0 2 pu 5 wow 1 u j ’λ 0 i * 0 Γ ι7ι y r 6 u 6 ⁵ IN H ^{Ä -} fc 'í - i 1, 1 6 L 0 Γι v H αμ r 1 1 d u 1 u u m 9 a μ i a C U • fc A ^Z i μ a. OJ L 11 and 11 u lG The U r 6 ~

vu sur anenii of group n 7 · 7 and H Λ A a ahan ΐ m!. · · .. · sal -in · .. · is carried out in acidic environment, meta η5 for 1 phon, para ^- to 1 uensu 1 phon , oh 1 pipe 1 metal or br111 UVUU! Λ UVCJ, i UilJUíiauii ;, λ λ γ

ci i i u u, mcuz i b u i u i uu u and c c u i muu u and υ 11 c 11U iu u u caM, i j. mc and i.

From the above-described conditions for the removal of R 7 groups 3 u 11 11 11 11 11 11 μ y f f O μ 3 3 ONLY the following reaction step.

u - 11 - 11 c 11 u λ y 5 S ί 1 Γ y, which can be used in both

The thiopyranopyrro ds of all of the vobeobeon s can also be cycled by a cyclic conductive reaction with a silane derivative in s o c tio n s IX

-í v- · í ·. C ₂ R (IX) in which R 5 is as defined above, (R ⁿ j ₃ denote alkyl groups and in alkyl groups and R 10 denotes an alkyl group, a cyano group or a phenylthio group) a group having a denydroth of a-4-γ-rnadium of the general formula λ (X) followed by a general formula of the formula XI

(XI)

13 Gradually, the effects of magnesium bromide and then benzene act in the presence of zirconium chloride.

Said cycloaddition reaction is carried out in the presence of a catalytic amount of an acid selected from the group consisting of trifluoroacetic acid, acetic acid, methanesulfonic acid and acids cited in the references below, in an organic solvent such as a chlorinated solvent (e.g. dichloromethane or dichloroethane), aromatic carbon , in nitrile (acetonitrile) or ether, at a temperature between 0 ° C and the reflux temperature of the reaction mixture.

The introduction of phenyl groups is carried out as described in detail in Example 1.

The silylated derivative of formula (IX) may be obtained by the following procedures:

Y.Terao et al., Chem. Bu 1 1. , 33.2762 (1,985),

A.Hosomi et al., Chem. Lett., 1111 (1984),

A. Padwa et al., Chem. Ber., 119, 813 (1986);

Tetrahedron, 4i, 3529 (1985).

A thiopyranopyrrole derivative of the general formula III in which n = 1 or. 2, may be obtained by oxidation of the corresponding derivative of the general formula III in which n = 0, the amine function of which has been preliminarily protected, and subsequent deprotection.

Said reaction is carried out as described above for the preparation of a thiopyranopyrrole derivative of the general formula I in which n = i or 2, starting from the corresponding derivative in which n = 0. they do not adversely affect the rest of the molecule, especially by the above-mentioned procedures. It is also preferred to start from a product of formula III in which n = 0, in the form of a salt with a mineral acid (e.g. ice hydrochloride or sulfate).

It will be appreciated that in the practical preparation of a product of formula (III) in which n-1 or 2, it is preferable to start from the iopyranopyrrole derivative of formula (VII) or formula (VIII) obtained in the preceding step, which reaction may be carried out directly. with one of these protected derivatives of the product of formula III.

The products of general formula III in which n = 2 can also be obtained from 3,4-dihydro-4,4-diphenyl-1,1-dioxide-2H-thiapyran of formula XII

(XII) cycloaddition reaction with a product of formula (IX), under conditions identical to those described above for the cycloaddition reaction of this product with dehydrothia-4-pyranone of formula (X), followed by deprotection of R 5 under the conditions described above.

3,4-Dihydro-4,4-dienyl-1,1-dioxide-2H-thiapyran of formula XII can be obtained by sequential oxidation of 3,4-dihydro-4,4-diphenyl-2H-thiapyran and 3,4- dihydro-4,4-diphenyl-1-oxide-2H-thiapyran of formulas XIII and XIV

said oxidation reaction is carried out under the conditions described above for the preparation of the products of the general formula I. It is not necessary to isolate from the reaction mixture S-o x i d of the general formula XI v.

The 3,4-ihydro-4,4-diphenyl-2H-thiapyran of formula (xIII) can be prepared by a method described in Example 12 below, or by a method analogous thereto.

The thiopyranopyrrole derivatives of formulas III, VII and VII exhibit various forms of stereoisomerism. If the product with the stereoisomeric (4aR, 7aK) or (4aS, 7aS) is to be obtained, then the separation of the isomeric forms is preferably carried out at the level of the derivative of the general formula III. This separation can also be carried out starting with the thiopyranopyrrole I as well. In the case of the preparation of the thiopyranopyrrole derivative in which n is 1, the separation of the axial and equatorial isomers is preferably carried out at the product level of the formula III. This separation can also be carried out starting from thiopyranopyrrole of the general formula (I).

Said separation of the stereoisomers is carried out by any known method which is compatible with the molecules of the separated stereoisomers. This separation can be accomplished, for example, by preparing an optically active salt by treatment with 1 (+) - or O (-) - mandelic acid or dibenzoyltartaric acid and subsequent resolution of the isomers by crystallization. The desired isomer is released from its salt in a basic medium. Separation of axial and equatorial isomers can be accomplished using chromatography or crystallization.

The novel thiopyrazopyrrole derivatives of formula I may optionally be purified by physical methods such as crystallization or chromatography.

The novel thiopyrazopyrrole derivatives of the general formula I in which R1 and / or R = contain amino or alkylamino substituents and / or X represents an NH group may optionally be present.

-16convert to acid addition salts. Examples of pharmaceutically acceptable acid addition salts include those formed with mineral acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, p-thienesulfonates, iso-ionates) or substitution derivatives of these compounds.

an amine to a compound such as a salt with a strong organic acid to concentrate the solution,

The novel thiopyrazopyrrole derivatives of the formula I can also, if R = is a carboxyl group, also be converted into metal salts or addition salts with nitrogenous bases using known methods. These salts may be obtained by treatment with a metal base (for example an alkali metal or alkaline earth metal), ammonia or according to the invention in a suitable solvent, alcohol, ether or water, or by a salt exchange reaction which separates after separation by filtration, decantation or

1yofi 1 izaci. Such pharmaceutically acceptable salts include alkali metal salts (sodium, potassium, lithium) or alkaline earth metals (magnesium, calcium), ammonium salts, salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diethylamine isopropylamine, Ν, Ν-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-b-phenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benznydrylamine , quinine, choline, arginine, lysine, leucine, dibenzylamine).

The thiopyranopyrrole derivatives of formula I which antagonize the effects of substance P may find use in the areas of anaigesis, asthmatic inflammation, allergies, central nervous system, cardiovascular system, such as antispasmatic or immune system, or in stimulating lacrimal secretion.

In fact, these products exhibit affinity for substance P receptors at doses ranging from. 10 to 2000 nM according to the technique described by C.M.Lee et al., Mo 1. Pharmaco123,563-69 (1983).

In addition, it has been shown that this is an antagonizing effect of substance P through various products. In a test carried out according to the technique described by S. Rosell et al.,

P, publ. US Von Euler &amp; Pernow, Raven Press.

Buostance. New York (1977), p.83-88 investigated at doses between 20 and 2000 nM products have been shown to be active.

Substance P is known to be applied in some pathological areas:

Agonist and antagonist of substance P, A.S. Dutta Drugs of the Future, 12 (8), 782 (1987),

- Substance P and Pain: An Updating, J.L. Henry, Tins, 3 (4), 97 (1980),

- Substance P in inflammatory reactions and pain, S. Rosell, Actual. Chim. Ther., 12ser., 249 (1,985),

- Effects of Neuropeptics on Production of Inflammatory Cytokines by Human Monocytes, M.Lotz et al., Science, 241, 1218 (1988),

- Neuropeptides and other pathogenesis of allergy, 42, 1-11 (1987),

- Substance P in Human Hypertension, J.Card.ovascular.r Pharmaco 1 ogy, 10 (suppl. 1 2), 5 1 72 (1 93 7).

In particular, the investigation of some of the novel compounds of the invention has shown that they have analgesic activity, as demonstrated by the technique described by Siegmund E. et al. in Proc. Soc. Exp. Biol. Med., 95, 729 (1957).

»/ X. ..T.

i 8

Example #

DE 50 (mg / kg, p.o.)

Example? 3

Example 10 1.7

Investigation of certain thiopyrazopyrrole derivatives of formula (I) using the technique described by A. Saris et al. in Árch. Pharmacol., 324, 212-218 (1983), and modified for mice, have been shown to have an effect on enhancing the capillary permeability due to septide (a P-agonist product), indicating anti-inflammatory activity.

Example product no. DE 50 (mg / kg, s.c.)

Example 8 0.05

Example 10 less than 0.1

Injection of substance P administered to the animal induces nypotension. Products studied by C.A. Maggi-et al. described in J.Auton. Pharmac., 7, 11-32 (1987) antagonize this hypotension in rats. This antagonism of hypotension induced by intravenous injection of substance P at a dose of 250 mg / kg is particularly achieved when said products are administered at an intravenous dose of 1 mg / kg / min for 5 minutes.

Example product no. Percentage inhibition of hypotension (with) Example 8 1 00 Example 10 100

Alternatively, the thiopyrazopyrrole derivatives of the invention do not exhibit toxicity and have been shown to be nontoxic when administered to mice subcutaneously at 40 mg / kg or orally at 100 mg / kg.

The following compounds are of particular interest:

6 - [(3-dimethylamino-2-propoxy) phenyl] acetyl] -4,4-diphenyl-1-oxidpernydrothiopyrano [2,3-c] pyrrole, [eta] &lt; 3 &gt;-( 3- (pyrrolidinyl) -1-) -2- propoxy / phenyl / acetyl / -4,4-difeny1-1oxidperhydrotiopyrano / 2,3-c / pyrrole,

6- [2- (2-methoxyphenyl) - (S) -propionyl] -4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole and

6- [2- [2- (3-dimethylaminopropoxy) phenyl] acetyl] -4,4-diphenyl-perhydrothiopyrano [2,3-c] pyrrole, in the form of their stereoisomers or mixtures thereof.

In the following, the invention will be explained in more detail by means of specific examples thereof, which, however, are intended to be illustrative only and are not intended to limit the scope of the invention, which is clearly defined by the claims. In these examples, unless otherwise stated, proton nuclear magnetic resonance spectra were determined at 250 MHz in dimethylsulfoxide. Chemical shifts are expressed in ppm.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 1.16 g of 2-dimethylaminophenyl acetic acid in 20 cm @ ^{3 of} anhydrous dichloromethane is added 1.13 g of N, N ' -carbonylimimazole. The mixture is stirred for 30 minutes at 5 ° C, followed by the addition of a solution of 2.0 g · (4a Ŕ S ', 7 and RS) 1' - 4, 4-direny 1 - 20 per h yd ro propyl o r n / 2,3-c / pyrrol och hydroxy or l or the chloride and 1.83 cm ⁱ triethylamine in 20 ^cm3 di chloro iórmetánu. The reaction mixture was stirred for one hour at 20 ^J C, then twice with 50 cm ³ of water, dried over magnesium sulfate. The solution is filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm 0.06 mm, diameter 2.8 cm, height 26 cm), eluting with a 60:40 mixture of cyclohexane and ethyl acetate, eluting under nitrogen pressure. 0.06 MPa and fractions of 60 cm ³ are collected. Fractions 6 to 20 are combined and concentrated under reduced pressure (2.7 kPa), the residue is crystallized from acetonitrile / diisopropyloxy. The crystals are centrifuged and dried. 2.16 g of (4aRS, 7aRSj-6 - [(2-dimethylaminophenyl) acetyl) -4,4-diphenyl] piperohydrothiopyrano [2,3-c] pyrrole is obtained in the form of a white solid, m.p.

(4aRS, 7aRS) -4,4-Diphenylpiperhydrothiopyrano [2,3-c] pyrrole hydrochloride can be prepared as follows.

4.35 g of (4aRS, 7aRS) -4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole were contacted for 30 minutes at 20 DEG C. with 30 cm @ ^{3 of a} 5.7N acid solution. hydrochloric acid in anhydrous dioxane. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 150 cm @ ^{3 of} ethanol. The solution is heated to boiling for 30 minutes and then concentrated to dryness. The solid is washed with 50 cm ^{3 of} diethyl ether, centrifuged and dried. 3.64 g of (4aRS, 7aRS) -4,4-diphenyl-perhydrothiopyrazo [2,3-c] pyrrole-1-hydrochloride are obtained in the form of a white solid.

Infrared spectrum:

(KBr, characteristic bands, cm ¹ )

3060, 3030, 3000, 2250, 1600, 1495, 1580, 1450, 755, 710, 700.

Ή-Nuclear Magnetic Resonance Spectrum:

(DMSO-d6, free signals) 2.2 to 2.9 (mt, 4H, CH2 in 2 and CH3 in 3),

1

4 and 3.3 (2mt, 2H, CH at 5) 08 (d, J = 12.5, , 1 H, 1 H at 7 1, 7 im, i H, H v 4a) 16 (t, J = 5,1H, , H in 7a), 1 to 7.5 (mt, , 1 OH, arom

(4aRS, 7aRS) -4,4-6-vinyloxycarbonylperhydrothiopyrazole [2,3-c] pyrrole can be prepared as follows.

To 6.2 g of (4aRS, 7aRS) -4,4-phenyl-perhydrotriopyrano [2,3-c] pyrrole in 50 cm &lt; ³ &gt; of 1,2-dichloroethane was added 0.72 cm &lt; ³ &gt; of vinyl vinyl formate. The mixture is then heated at reflux for 15 minutes, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 25 cm), eluting with a cyclohexane / ethyl acetate mixture (90:10 by volume) applied under 60 kPa of nitrogen. Fractions of 60 cm ³ are collected. Fractions 6 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and the residue is triturated in 70 cm @ ^{3 of} diisopropyl oxide. The suspension obtained is filtered and the solid is centrifuged and dried. 4.35 g of (4aRS, 7aRS) -4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole are obtained in the form of a white solid, m.p. 160 [deg.] C.

(4aRS, 7aRS) -4-Benzyl-4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole can be prepared as follows.

To a solution of 12.2 g of (4RS, 4aSR, 7aRS) -4-hydroxy-4-phenyl-6-benzyl perhydrothiopyrano [2,3-c] pyrrole in 180 cm ^{3 of} benzene is added 43.7 g of zirconium chloride . The reaction mixture is then heated at reflux for one hour, then cooled to 20 [deg. ^] C. and diluted with 200 cm &lt; ³ &gt; of dichloromethane. 150 cm @ ^{3 of a} 4N aqueous sodium hydroxide solution are added to the cold solution obtained. The suspension obtained is filtered, the filtrate is decanted, the organic phase is washed with 200 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 to P a). The oil obtained is chromatographed on a silica column (0.04 mm-0.06 mm, 5.2 cm diameter, 39 cm high) using a cyclohexane mixture.

90:10. Elution is carried out with ethyl acetate under nitrogen pressure kPa and fractions of 125 cm ³ are collected. Fractions 19 to 32 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized from 200 cm @ ^{3 of} diisopropyl oxide and the crystals are centrifuged and dried. 6.2 g of (4 and RS, 7aRS) -6-benzyl-4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole are obtained in the form of orange crystals, m.p.

(4RS, 4aSR, 7aRS) -4-Hydroxy-4-phenyl-6-benzylperhydrodiopyrano [2,3-c] pyrrole can be prepared as follows.

To a solution of phenylium bromide prepared from 19.8 cm ^{3 of} bromobenzene and 4.52 g of dry magnesium in 120 cm ³ without aqueous diethyl ether is added a solution of 21.15 g of (4aRS, 7aSR) -6-benzyl-1-4 over 30 minutes. oxoperhydrothiopyrano (2,3-c) pyrrole in 150 cm ^{3 of} anhydrous diethyl ether. The reaction mixture is stirred at reflux for 3 hours and then for 20 hours at ambient temperature. The mixture to which 200 cm ^{3 of} diethyl ether has been added is stirred with 600 cm ^{3 of} saturated aqueous ammonium chloride solution. The aqueous phase is extracted with 200 cm ³ of diethyl ether, the two combined ether extracts were washed twice with 300 cm ³ of saturated brine, dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.4 kPa) at 35 C. ^In this way, to give 12.2 g of (4RS, 4aSR., 7aRS) -4-hydroxy-4-phenyl-6-benzylperhydrotiopyrano / 2,3-c / pyrrole as a white solid, m.p. ¹³⁷ C ^J

(4aRS, 7aSR) -6-Benzyl-4-oxoperhyarothiopyrano [2,3-c] pyrrole can be prepared as follows.

To a solution of 20 g of dehydro-.alpha.-thiapyranone and 54 cm @ ^{3 of} N-butoxymethyl-N-trimethylsilylbenzyl amine in 100 cm @ ^{3 of} anhydrous dichloromethane is added -5 drops of trifluoroacetic acid, and the mixture is stirred for 4 hours. temperature 20 ° C.

3

The reaction mixture is stirred with 5 g of potassium carbonate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is chromatographed on a silica gel column (ú, 04 mm, 6 6 using an elution system of mm, diameter 9, 1 cm 3), consisting of a mixture of cyclohexane and ethyl acetate at 90:10 and then a mixture of cyclohexane and ethyl acetate at 75 Elution is carried out under a nitrogen pressure of 60 kPa and fractions of 250 cm ³ are collected, fractions 35 to 56 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 24 g (4aRS, 7aSR). 6-Benzyl-4-oxoperhydropyrano [2,3-c] pyrrole as a yellow oil.

inrracervene spectrum:

(CCl-t solution, pure eye band character, cm ^-1 )

3090, 3070, 3025, 2925, 2650, 2800, 2730, 1710, 1600, 1585, 1495, 1475, 1450,700.

¹ H-Nuclear magnetic resonance spectrum:

(C D C 1 3, main signals)

2.4 (d d, J = 10 and 7.1, 1H, 1H at position 7), 2.66 (mt, 2H, CH = at position 5),

3.05 (mt, 1H, K at 4a), 1 (d d, J = 10 and 7.5, 1H for CH- at position 7),

3.61 (s, 2H, N-CHa-Ar),

3.8 (dt, J = 7.5 and 7, 1H, H at 7a),

7.15-7.35 (mt, 5H aromatic).

Example 2

The procedure is as in Example 1, starting with 85 g of (2- (pyrrolidinyl-1) -phenyl) acetic acid hyarobromide and 2.0 g of (4 and RS, 7aRS) -4,4-diphenylperhydrothiopyrano). 2,3-cispyrrole hydrochloride yields 0.90 g of (4aRS, 7aRS) -6- [2- (pyrrolidinyl-1) phenyl] acetyl] -4,4-diphenylperhydrothiopyrano (2,3-c) pyrrole in the form of white crystals with a melting point of 166 ^{, J} C.

- 24 Example 3 κ a solution of 2,63 g of (4α, 3,7aRS) -4,4-diphenyiperhydrothiopyrano [2,3-c] pyrrole-1-hydrochloride and 2,42 cm ^{3 of} triethylamine in 25 cm ^{3 of} dichloromethane, cooled to ú ^{, A} solution of 1.15 cm @ ^{3 of} phenylacetyl chloride in 25 cm @ ^{3 of} dichloromethane is added over a period of 5 minutes. After stirring at 0 DEG C. for 1 day and stirring again at 20 DEG C., 20 cm @ ^{3 of} dichloromethane are added. The reaction mixture is washed twice with 100 cm @ ^{3 of} distilled water and dried over magnesium sulphate, then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04-0.06 mm, diameter

3.5 cm, height 26 cm) using a 30:20 cyclohexane / ethyl acetate mixture, eluting under a nitrogen pressure of 0.04 MPa and collecting 125 cm ^{3 of} traction. Fractions 19 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). To give 0.87 g of (4aRS, 7aRS) -6-fenylacety1-4,4-diphenylperhydrothiopyrano / 2,3-c / pyrrole as a white solid, m.p. 210 C. ^The

Example 4

To a solution of 0.29 g of 2-hydroxyphenyl 1 acetic acid in 30 cm @ ^{3 of} anhydrous dichloromethane is added 0.53 cm @ ^{3 of} ethyl chloroformate. After 15 minutes of stirring at 20 "C, the mixture was cooled to -15 C. ^In the thus cooled mixture was added 0.85 cm ³ of triethylamine. After stirring at -15 ° C for 2 hours, a suspension of 2 g of (4aRS, 7aRS) -4,4-phenyl-perhydrotranopyrano [2,3-c] pyrrole-1-hydrochloride is added over 20 minutes and 1.70 cm @ ^{3 of} triethylamine in 30 cm @ ^{3 of} dichloromethane. After stirring at 20 ° C for 20 hours ^, the reaction mixture is washed with 50 cm ^{3 of} 1N hydrochloric acid, 50 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 cm @ ^{3 of} dichloromethane, the crystals are washed with diisopropyl oxide, centrifuged and dried under reduced pressure. tl battery (2.7 kPa). 1.02 g of (4aRS, 7aRS) -4,4-diphenyl 1 - 6 - [(2-hydroxyphenyl) acetyl] perhydrothiopyrano [2,3-c] pyrrole is obtained in the form of white crystals of temperature. melt 248 ° C.

Example 5

To a solution of 1.16 g of 2-methoxyphenylacetic acid in 20 cm &^lt; ⁵ &gt; of anhydrous dichloromethane cooled to &lt; RTI ID = 0.0 &gt; C, &lt; / RTI &gt; is added 1.13 g of N, N &apos; The mixture is stirred for 4 minutes at 0 ° C, then a solution of 2.15 g of (4aR $, 7aRS) -4,4-diphenylperhydrothiopyrano (2,3-c) pyrrole hydrochloride and 0.9 cm ^{3 of} triethylamine in is added. 20 cm ^{3 of} dichloromethane. The reaction mixture was stirred for 1 hour at 0 ° C, followed by washing with saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with 30 cm @ ^{3 of} diethyl ether, 30 cm @ ^{3 of} diisopropyl oxide, and then dried under reduced pressure (2.7 kPa). 2.68 g of (4aR, 7aRS) -4,4-diphenyl-6 - [(2-methoxyphenyl) acetyl] perhydrothiopyrano] -2,3-pyrrole are obtained in the form of a white solid, m.p. "C.

Example 6 A mixture of the forms (4aR, 7aR) and (4aS, 7aS) 6- [2- (2-methoxyphenyl) (S) -propionyl] -4,4-diphenylperhydrodiopyrano [2,3-c] pyrrole can be prepared with using the procedure described in Example 5, starting from 0.89 g of 2- (2-methoxyphenyl) - (S) -propionic acid and (4aRS, 7aRS) -4,4-diphenylperhydrotyropyrano / 2,3- C / pyrro1 hydrochloride. 1.46 g of a mixture of (4aR, 7aR) and (4aS, 7aS) 6- [2- (2-methoxyphenyl) - (S) -propionyl] -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole is obtained. 1 u in the form of a white solid foamed product.

First form:

Infrared spectrum:

(characteristic strip, cm ^-1 )

3095, 3055., 3025, 2950, 2930, 2875, 2335, 1,630, 1,595, 1,490,

1565, 1425

1240, 1030, 750, 00.

Ή-Nuclear Magnetic Resonance Spectrum:

(DMSO-de + CFaCOOD, at ambient temperature, mixture of both rotamers observed, characteristic signals)

1.15 and 1.20 (2d, J = 7.5, 3H, CH 3),

2.1-2.9 (mt, 5H, 2 CHa at 5 and 3 + H at 4a),

2.36 and 3.8 (2s, 3H, OCF3).

6.7 to 7.4 (mt, 14H, aromatic).

Second form:

Infrared spectrum:

(characteristic strips, cm ^-1 )

3095, 3060, 3025, 2960, 2930, 2870, 2335, 1640, 1600, 1494,

1465, 1425, 1240, 1035, 755, 700.

¹ H-Nuclear Magnetic Resonance Spectrum:

(DMSO-de + OF 3 COOD, at ambient temperature, mixture of both rotamers observed, characteristic signals)

1.1 and 1.18 (2d, J = 7.5, 3H, CHa),

2.1-2.35 (mt, 2H, CH ₃ in 3), 2.35 to 3, 10 (mt, 3H, _CH2 at 5 + H at 4a);

3.6 and 3.8 (2s, 3H, _OCH3);

3.95 and 4.02 (mt, 1H, H at 7a),

6.7 to 7.4 (mt, 14H, aromatic).

(S) -2- (2-methoxyphenyl) propionic acid can be obtained as follows.

(S) -2- (2-methoxyphenyl) propionic acid may be prepared by a method analogous to that described by D.A. Evans et al. in Tetrahedron, 4, 5525 (1988) and described below.

To a solution of phenyl) - (S) -propionyl] -2-oxazolidinone cm4 (4S, 5S) -4-methyl-5-phenyl-3- / 2- (2-methoxy) at 5 ° C, the mixture is stirred decanted for 3 hours after heating to a temperature and the aqueous phase was furan and 30 cm &lt; 3 &gt; of water, cooled with 1.52 g of lithium hydroxide, reacted at this temperature, followed by addition of ethyl acetate, acidified with aqueous hydrochloric acid solution. in), extracted with ethyl acetate, then the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa), and the resulting solid product is drained and dried.

-2- (2-methoxyphenyl) propionic at a melting point of 102 C.

is recrystallized from hexane and 0.4 g of (S) as white crystals, / alpha / - ° H ^and 84 C = 1, CHCl 3 1) (4 S, 5 S) -4-methyl-5-phenyl-3 - [2- (2-Methoxyphenyl) - (S) -propionyl] -2-oxazolidinone can be obtained as follows.

to a solution of 10 g of (4S, 5S) -4-methyl-5-phenyl-3 - [(2-methoxyphenyl) acetyl] -2-oxazolidinone in 150 cm ^{3 of} tetrahydrofuran is added

19.1 g of sodium 1,1,3,3,3-nexamethyl disulfate. The solution was cooled to -50 ° C prior to the addition. The mixture is stirred at that temperature for 45 minutes, then 7.72 cm @ ^{3 of} methyl iodide are added. The reaction mixture is then stirred at ambient temperature, then diluted with ethyl acetate, washed with 50 cm ^{3 of} water and then 50 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl oxide, centrifuged and dried. 4.2 g of (4S, 5S) -4-methyl-5-phenyl-3- [2- (2-methoxyphenyl) - (S) -propionyl] -2-oxazolidinone are obtained in the form of a white solid.

(4S, 5S) -4-methyl-5-phenyl-3- (2-methoxyphenylacetyl) -2-oxazolidinone can be obtained as follows.

9.38 g of 2-methoxyphenylacetic acid are added to a suspension of 1.89 g of sodium hydride (80% dispersion in petrolatum) in 200 cm @ ^{3 of} anhydrous tetrahydrofuran at ambient temperature. . The suspension was cooled to -30 ° C, followed by stirring

Wv »

- 28 was added 7.77 cm ³ of pivaloyl chloride and finally a solution obtained by adding a solution of 35.27 cm ³ of 1.6 M butyl lithium in hexane to a solution of ^{(to-78, J} C) 10 g of (4S, 5S) -4 methyl-5-phenyl-2-oxazolidinone in 200 cm @ 3 of anhydrous urethane tetrahydrate and cooled to -78 ° C. The reaction mixture was stirred for 45 minutes at ^{-30, J} 0, then the best of the warm to ambient temperature was added 200 cm ³ of saturated aqueous ammonium chloride solution and then with 500 cm ³ of ethyl acetate. After decantation, the organic phase is washed twice with 100 cm ^{3 of} water and then twice with 100 cm ^{3 of} saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.06 mm, 4.8 cm diameter, 36 cm high) using a cyclohexane / ethyl acetate mixture (85:15 then 80:20 by volume), eluting under nitrogen pressure and collecting 50 cm ³ fractions. Fractions 14 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 13.6 g of (4S, 5S) -4-methyl-5-phenyl-3- (2-methoxyphenylacetyl) -2-oxazolidinone are obtained in the form of a yellow oil.

Example 7

Proceed as in Example 8, starting from 1.82 g of (1 RS, 4aRS, 7aRS) -4,4-phenyl-1-oxo-operhydrothiopyrano [2,3-c] pyrrole and 1.39 g. g of ((3-dimethylamino-2-propoxy) phenyl) acetic acid (0.3 g) (1 RS, 4aRS, 7aRS) -6 - [(3-dimethylamino-2-propoxy) phenyl]] acetyl (-4,4-diphenyl-1-oxideperhydrothiopyrano) 2,3-c] pyrrole as white crystals, m.p. 150 ° C.

To 3.98 g of 4,4-diphenyl-1-oxide-6-tert-butoxycarbonylperhydrothiopyrano [2,3-c] pyrrole (mixture of isomers 1RS, 4aSR, 7aSR and iRS, 4aRS, 7aRS) is added 40 cm ^{3 of a} mixture of concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (1/2 vol.) And the mixture. Chews were maintained-for 48 hours at a temperature of ²⁰ C. A solution of ^J is concentrated at 40 do.sucna ^The C under reduced pressure (2.7 kPa) / W d SKAH of the le j. .Select 30 cm ^{3 of} dichloromethane,

The solution is washed with 60 cm @ ^{3 of a} 2N aqueous sodium hydroxide solution, and the aqueous phase is extracted with 20 cm @ ^{3 of} dichloromethane. The organic extracts are combined, dried over magnesium sulfate, concentrated to dryness at ^{40, J} C under reduced pressure (2.7 kPa). The residue is taken up in diisopropyl oxide and then concentrated to dryness at 40 ° C under reduced pressure (2.7 and then 0.13 to P a). 3.0 g of (1RS, 4aRS, 7aRS) -4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole are obtained as a white foam.

Infrared spectrum:

(KBr, characteristic strip, cm ^-1 )

3080, 3055, 3025, 2950, 2920, 2880, 2360, 1595, 1580, 1490,

1440, 1020, 760, 740, 700.

¹ H-Nuclear Magnetic Resonance Spectrum:

(DMSO-de + CFaCCOD, main signals)

2.26 (broad t, J = 14.1H, 1H at position 3), 2.42 (dd, J = 10 and 9.1H, CH ₌ at position 5), 2.55 (broad d, J = 14) and 4.1 H, 1H at position 3, 3.68 (t, J = 6.1 H, H at position 7a), 3.82 (d, J = 14.1H, H at position 7),

3.8-4 (mt, 1H, CH at position 4a), 15 (dd, J = 14 and δ, 1H, H at position 7),

7.1-7.5 (mt, 10H aromatic).

4,4-Diphenyl-1-oxide-6-tert-butyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole (mixture of isomers 1 RS, 4aSR, 7aSR and 1RS, 4aRS, 7aRS) can be prepared as follows.

To a solution of (4aRS, 7aRS) -4,4-difeny1-6-terc.butyloxykarbonylperhydrotiopyrano / 2, 3-c / pyrrolo 1 u in 30 cm ³ of dichloromethane bezvoaného, cooled to 0 ^U C, a solution of 2.3 g of 3-chloroperoxybenzoic acid (85%) in 20 cm ^{3 of} dichloromethane. After 1.5 hours stirring at 3 ^U C and 1.5 h of stirring at 20 ° C ^J, the reaction mixture was washed twice with 100 cm ³ of saturated aqueous sodium bicarbonate solution and then with 100 cm ³ of distilled water, dried over it, and concentrated to dryness at 35 ° C under reduced pressure

- oU pressure (2.7 kPa). The residue is crystallized from ethyl acetate, then the crystals are washed with ethyl acetate and diisopropyl oxide, centrifuged and dried under reduced pressure (2.7 kPa). 3.98 g of 4,4-diphenyl-1-oxide-6-tert-butyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole (mixture of isomers 1RS, 4aSR, 7aSR and IR, 4aRS, 7aRS) are obtained in the form of white crystals which are: are used as such in the next reaction.

(4aRS, 7aRS) -4,4-Diphenyl-6-tert-butoxycarbonylperhydrothioparano [2,3-c] pyrrole may be prepared as follows.

To a suspension of 4.0 h (aaRS, 7aRS) -4,4-diphenylperhydrotyropyrano [2,3-c] pyrrole hydrochloride and 1.70 cm &lt; ^{3 &gt;} triethylamine in 60 cm &lt; ³ &gt; 2.89 g of di-tert-butyl di carbonate are added, followed by 0.15 g of 4-dimethylaminopyridine. The mixture was stirred for 20 hours at 20 ^U C, then the reaction solution is washed with 100 cm ³ of an aqueous solution of citric acid at pH 4 and 100 cm ³ of water, dried over magnesium sulphate and concentrated to dryness at 35 ^U C under vacuum (2.7 kPa). The residue is crystallized from diethyl ether, the crystals are centrifuged and dried. 4.27 g of (4aRS, 7aRS) -4,4-diphenyl-6-tert-butyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole are obtained as pink crystals, m.p. 162 [deg.] C.

(1RS, 4aRS, 7aRS) -4,4-Diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole can be prepared as follows.

To a solution of 25 g (4aRS, 7aRS) -4,4-di feny1perhydrotiopyrano / 2,3-c / pyrrolo 1 u in 500 cm ³ of dichloromethane and 100 cm ³ of methanol, cooled to -3 C. ^For over 40 minutes, a solution of 15.4 g of 3-chloroperoxybenzoic acid (85%) in 400 cm @ ^{3 of} dichloromethane. After stirring for 1 hour at -3 C ^The reaction mixture was washed with 200 cm ³ of 10% aqueous sodium hydrogen carbonate and then 100 cm ³ of the solution, then dried over magnesium sulphate and concentrated to dryness at 40 DEG C. in vacuo (2.7 kPa). The residue is crystallized from 50 cm &lt; ^{3 &gt; of} ethyl acetate and the crystals are crystallized

- 3 l are taken up in 200 cm ^{3 of} dichloromethane and the solution obtained is washed with 75 cm ^{3 of} aqueous sodium hydroxide solution, dried over magnesium sulphate and concentrated to dryness. The residue is crystallized from 30 cm @ ^{3 of} ethyl acetate, the crystals are washed with ethyl acetate, centrifuged and dried. 13.6 g of (1R, 4aRS, 7aRS) -4,4-diphenyl-1 - OX-i and aperhydrot thiopyran / 2, 3-c / py rro 1 is obtained as white crystals, mp 174 C ^{1 J} .

Example 8 to a solution of 1.0 g of (1R *, 4aR *, 7aR *) - (-) - 4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole and 0.81 g of 2- (2) acid] (3-am dimety1 iηο-2-propoxy) phenyl 1 / acetic acid in 60 cm ³ bezvodnéno dichloromethane, cooled to ^{0, J} C, was added 3 g 0,0 of hydroxybenzotriazole hydrate and 0.77 g i- (3- dimethylaminopropyl-3-ethylcarbonyl imide. After two hours stirring at 0 ^{1 J} C and then for 20 hours at 2 to 0 "C, the reaction mixture was washed with 20 ^cm3 of water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (granulometry 0.04-0.06 mm, diameter 2.4 cm, height 35 cm), eluting with a 60:10:10 mixture of ethyl acetate, acetic acid and water. the elution is carried out under a nitrogen pressure of 0.06 MPa and fractions of 50 cm ³ are collected. Fractions 3 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up 60 cm. ^The mixture is washed with 20 cm @ ^{3 of} 1N aqueous sodium hydroxide solution, dried over magnesium sulphate and concentrated to dryness. The solid obtained is recrystallized from a mixture of ethyl acetate and diethyl ether and the crystals obtained are washed with diisopropyl oxide, centrifuged and dried. 0.99 g of (1R *, 4aR *, 7aR *) (-) - 6- [2 - [(3-dimethylamino-2-propoxy) phenyl] acetyl] -4,4-diphenyloxy-oxa-hydrothiopyrano] is obtained, 3-cis / pyrrole as a white solid, m.p. 120 ° C.

[.alpha.] D @ ³⁰ = -323 ^u (c = 0.5, acetic acid).

D

(1R *, 4aR *, 7aR *) - (-) - 4,4-diphenyl-6-oxo-perhydrothiopyrano [2,3-c] pyridine The roll is prepared as follows.

To 7.14 g of (1RS, 4aRS, 7aRS) -4,4-diphenyl-1-oxypiperidopyrido [2,3-c] pyrrole was added 3.5 g of (S) -mandelic acid and 90 cm ³ of a 99: 1 mixture of acetonitrile and water. After stirring, the remaining solution is left at ambient temperature for 48 hours. The crystals obtained are centrifuged, washed with a mixture of acetonitrile and water, and then dried. These crystals are taken up in 200 cm @ ³ of boiling acetonitrile / water, the hot solution obtained is filtered hot and the filtrate is left at ambient temperature for 5 hours. the crystals are centrifuged, washed twice with 10 cm ^{3 of} acetonitrile and dried. 1.5 g of (S) mandelate (1R *, 4aR *, 7aR *) - 4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-o] pyrrole are obtained.

/ alpha / ³⁰ = D

228 (c = 0.44, acetic acid);

The filtrate is left at ambient temperature for 20 hours, the crystals obtained are drained, washed twice with 5 cm @ ^{3 of} acetonitrile and then dried. 0.62 g of (S) -mandelate (1R *, 4aR *, 7aR *) 4,4-diphenyl-1-oxidoperhydrothiopyrano [2,3-c] pyrrole is obtained.

[.alpha.] D @ ³⁰ = -230 (c = 0.45, acetic acid).

To 2.06 g of (S) -mandelate (1R *, 4aR *, 7aR *) -4,4-phenyl-1-oxo-perhydrothiopyrano [2,3-c] pyrrole is added 40 cm ^{3 of} dichloromethane and 7.0 cm ^{3 of} 1N aqueous sodium hyaroxide solution. The mixture is stirred for several minutes after the starting products have dissolved, then the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue was stirred in a mixture of ethyl acetate and diethyl ether and the solid was washed with diisopropyl oxide and dried. 1.1 g of (1R *, 4aR *, 7aR *) - (-) - 4,4-diphenyl-1-oxideperhydrothiopyrano [2-3-c] pyrrole are obtained in the form of a white solid, m.p. ° C

/ alpha / ^{= o} = - 405 '(c = 0.46, Acetic acid).

Example 9

To a solution of (iRS, 4aRS, 7aRS) -4,4-diphenyl-1-oxideperhydrothiopyrano (2,3-c) pyrrole and 0.68 g of acid (3- (pyrrolidinyl-1) -2-propoxy) driers 1 / acetic acid in 25 cm ³ of dry dichloromethane, cooled to ^{5, J} C, was added 0.03 g of hydroxybenzotriazole hydrate, and then a solution of 0.5 g of 1- (3-dimetylaminopropy1) -3ety 1 card .mu.m iD, point-hydroch1 oridu in 20 cm ^{3 of} anhydrous dichloromethane. After stirring at 5 DEG C. for 2 hours and at 20 DEG C. for 20 hours, the reaction mixture is washed twice with 50 cm @ ^{3 of} distilled water and dried over sodium sulphate, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (granulometer and 0.04-0.06 mm, diameter 2.4 cm, height 32 cm), eluting with a mixture of ethyl acetate, acetic acid and water (80:20:20 by volume), eluting under a nitrogen pressure of 0.03 MPa and collecting 25 cm ³ fractions. Fractions 21 to 50 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 3 cm @ ^{3 of} ethyl acetate, and the crystals obtained are then washed with ethyl acetate and isopropyl ether and dried. 0.45 g of (1RS, 4aRS, aRS) -6 H-3- (pyrrolidinyl-1) -2-propoxy / phenyl / acetyl) -4,4-diphenyl-1-oxidoperhydrothiopyrano is obtained, 3-pyrrolidine in the form of beige crystals with a melting point of 126 ° C.

Example 10

To a solution of 1.43 g of (1R *, 4aR *, 7aR *) - (-) - 4,4-diphenyl-1-oxidopernyldropyropyrano [2,3-c] pyrrole and 0.83 g of (S) -2 - (2-methoxyphenyl) propionic acid in 100 cm ^{3 of} anhydrous dichloromethane is added 0.06 g of hydroxybenzotriazole hydrate and 0.01 g of 1- (3-dimethylaminopropyl) 3-ethylcarbonyl imidohydrol After cooling the above solution to 0 ° C. After stirring at 0 ° C for 2 hours and at room temperature for 2 hours. ^The reaction mixture is washed with 50 cm @ ^{3 of} water and then dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile and the precipitated crystals are washed several times with ether and dried. 1.56 g of (1R *, 4aR *, 7aR *) - (-) - 6- [2- (2-methoxyphenyl- (S) -propionyl) -4,4-diphenyl-1-oxidopernydrothiopyrano] are obtained, 3-c / pyrrole in the form of white crystals with a melting point of 170 ° C.

[.alpha.] D @ ³⁰ = - 316 DEG (c = 0.50, acetic acid).

D

Example 11

Using the procedure described in Example 1, 0.49 g of 2-dimethylaminophenyl acetic acid, 0.50 g of N, N ' -carbonyldiimidazole, 0.70 cm &lt; ^{3 &gt; of} triethylamine and 1.0 g of (4aRS, 7aRS) -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide hydrochloride yields 0.55 g of (4aRS, 7aRS) -6 - [(2-dimethylaminophenyl)] - 4 4-perhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide in the form of white crystals, m.p. 226 [deg. ^] C.

Example 12

To a suspension of 0.46 g of (4aRS, 7aRS) -4,4-dienyl-perhydrothiopyrano [2,3-c] pyrrole-1,1-dioxo-dihydrochloride in 10 cm ^{3 of} dichloromethane, After cooling to 0 ° C, 0.35 cm ^{3 of} triethylamine and a solution of 0.17 cm ^{3 of} phenylacetyl chloride in 5 cm ^{3 of} dichloromethane are added. After stirring for 1 hour at 0 ^V and then for one hour at 20 ^J C, the reaction mixture was diluted with 10 cm ³ of dichloromethane, washed twice with 30 cm ³ of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The oil obtained is crystallized in 30 cm @ ^{3 of} diethyl ether, the crystals are centrifuged and dried. 0.50 g of (4aRS, 7aRS) -4,4-diphenyl-6-phenylacetyl perhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide are obtained in the form of white crystals.

Infrared spectrum:

(character 3050, 3025, 2970, 1330, 1305, 1140, strips, cm ^-1 )

2930 1880 1630 1595 1495

1120, 765, 755, 700, 510.

455,

4 2 5,

Ή-Nuclear Magnetic Resonance Spectrum:

(DMSO-de + CFaCCOD, major signals, mixture of both rotamers was observed at ambient temperature)

2.4 8 (mt, 1H, C H - at 3),

2.8 (mt, 1H, 1H at position 5),

3.39 and 3.65 (s and ab, J = 14.2H, N-CH-CHe),

6.9 to 7.6 (mt, 15H, aromatic).

(4 and R 5, 7 and R 5) -1,4-diphenylperhydrothiopyrano [2,3-c] pyrrolo-1,1'-dexido x-d-hydroxy-1-dihydro-pyrrolo [2,3-c] pyrrolo [1,1-d] pyrido [2,3-c] pyrrolo [1,1-d] may be prepared as follows.

To 0.58 g of (4aRS, 7aRS) -4,4-dienyl-6-vinyloxycarbonyl perhydropyridyl [2,3-c] pyrrole-1,1,1-dioxide is added 25 cm @ ^{3 of a} 5.7N solution of hydrochloric acid in anhydrous dioxane, then the mixture is left under gentle heating for 30 minutes. The reaction solution is concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. The residue is taken up in 15 cm @ ^{3 of} ethanol, the solution obtained is heated at reflux for 30 minutes and then concentrated to dryness. The solid obtained is washed with ethyl acetate, centrifuged and dried. 0.46 g of (4aRS, 7aRS) -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide hydrochloride is obtained in the form of a white solid.

Infrared spectrum:

character belts, cm ^-1 ) 3055, 3030 2970 2935, 2825, 2300, 1600, 1495, 1462 13 3 5 13 15, 1300 1140 112 0, 7 70, 760, 7 10, 595, 505.

H-Nuclear Magnetic Resonance Spectrum:

(DMSQ-do + CF = CCQD, main signals)

3.84 (ab, 2H, CH2 at position 7),

4.0 (mt, 1H, H at position 4a),

4.27 (mt, 1H, H at 7a),

7.1 to 7.6 (mt, 10H, aromatic).

(4aRS, 7aRS) -4,4'-Diphenyl-6-vinyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide can be prepared as follows.

To a solution of 0.7 g of (4aRS, 7aRS) -6-benzyl-4,4-diphenylperhydro-3,6-thiopyrano [2,3-c] pyrrole-1,1-dioxide in 10 cm @ ^{3 of} 1,2-dichloroethane is added 0. 16 cm ^J in inyl chloroformate. The mixture is heated at reflux for 2 hours, then concentrated to dryness under reduced pressure (2.7 kPa) at ^{50, JC} The solid crystals were washed with diethyl ether, filtered off and dried. 0.58 g of (4aRS, 7aRS) 4,4-diphenyl-6-vinyloxycarbonylperhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide is obtained in the form of white crystals.

Infrared spectrum:

(characteristic strips, 3080, 3055, 3025, 2990, cm ^-1 )

2925 2885

1495, 1415,

1300, 1 and 50, 1 1 40,

7 1 5, 1,645, 1,595, 1,580, 1125, 945, 865, 755, 700,

510th

Ή-Nuclear Magnetic Resonance Spectrum:

OMSO-de + CFaCOOD, main signals)

2.5 to 3.45 (mt,? H, CH of Z-5, 2 and 3), 3.8 to 4.2 (mt, 4H, _CH2 at 7, H at 4 and

H in 7a),

4.46 and 4.72 (2d broad, J = 6 and J = 14, 2x1H, CH = CH2),

7.0 (dd, J = 14 and 6.1 H, OCH. :),

7.1-7.6 (mt, 10H, aromatic).

(4aRS, 7aRS) -6-Benzyl-4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide can be prepared as follows.

To a solution of 1,3 g 3,4-dihydro-4,4-diphenyl-1,1-dioxide-2H-thiapyran and 1.75 cm ^{3 of} N-butoxymethyl-N-1-methylmethylsilylmethyl 1ben of y 1 amine in 12 cm ³ of dry dichloromethane was treated with 2 drops of tri f 1uóroctovej and the mixture was stirred for 30 minutes at 30 C. ^the added again 1.75 cm ³ of N-butoxymethyl-1 ylmethyl Ntrimety1 a 1 pm benzy1 tin and 2 drops of trifluoroacetic acid and the resulting mixture was stirred at 35 ° C for 2 hours. This last operation is repeated once more, and after stirring for 1 hour, 1 g of potassium carbonate is added. The suspension is filtered, the filtrate is concentrated to dryness under reduced pressure

7 (2.7 k F'a). The residue is chromatographed on a silica gel column (granulometry 0.04-0.06 mm, diameter 3.2 cm, height 35 cm) using a mixture of cyclohexane and ethyl acetate (80:20 by volume), eluting under nitrogen pressure. 0,05 MPa and collecting fractions of 30 cm ^3rd fractions 20-28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). to give 0.7 g of (4aRS, 7aRS) -S-benzyl-4 , 4-diphenylperhydrothiopyrano / 2,3-c / pyrro1 - 1,1-ioxidu as white crystals, melting ^at 186 C.

3,4-Ohydro-4,4-diphenyl-1,1-dioxide-2H-1-pyran can be prepared as follows.

To a solution of 1.47 g of 3,4-dihydro-4,4-diphenyl-1-oxo-2H-thiapyran in 15 cm ^{3 of} anhydrous dichloromethane is added a solution of

1.12 g of 3-chloroperoxybenzoic acid (85%) in 25 cm @ ^{3 of} anhydrous dichloromethane. After stirring at 20 DEG C. for 20 hours ^, the reaction mixture is washed with 50 cm @ ^{3 of a} 10% strength aqueous sulphate solution then 50 cm @ ^{3 of a} saturated aqueous solution of hydrogen sulphate and dried over sodium sulphate and sodium carbonate. The crystalline residue is washed under reduced pressure (2.7 kPa).

under reduced pressure (2.7 kPa). diethyl ether, drained and dried and give 3 g of 3,4-dihydro-4,4di dryers 1 1,1-d ioxid-2H-tiapyránu as white crystals, melting point 166 C. ^The

3,4-Dihydro-4,4-diphenyl-1-oxide-2H-thiapyran can be prepared as follows.

Using the above procedure, 1.9 g of 3,4-dihydro-4-amine was obtained from 2.05 g of 3,4-dihydro-4,4-phenyl-2H-thiapyran and 1.67 g of 3-chloroperoxybenzoic acid (85%). 4-diphenyl-1-2H-thiapyran oxide as a white solid, m.p. 130 ° C.

3,4-Dihydro-4,4-diphenyl-2H-thiapyran can be prepared as follows.

. . Λ.

: 3 liters of acetic acid. The mixture is cooled under reduced pressure (2.7 to a suspension of 2.7 g of 4,4-diphenyl-1-oxidtetrahydrotiapyran in 30 cm ^{3 of} anhydrous toluene) and 3.95 cm ^{3 of} acid anhydride are added and heated to reflux for 3 hours. is concentrated to dryness at kPa and then 0,13 kPa (a) at 60 ° C.

The oily residue was crystallized from diisopropyl oxide and the precipitated crystals were centrifuged and dried. 2.1 g were obtained.

3.4- aihydro-4,4-diphenyl-2H-tiapyránu as white crystals, mp 78 ^o C.

4.4-Di-phenyl-1-oxidtetrahydrothiapyran can be prepared as follows.

To a solution of 25.4 g of 4,4-difenyltetrahydrotiapyránu in 130 cm ³ of dichloromethane, cooled to ^{0, J} C was added over 40 minutes a solution of 20.3 g of 3-ch1órperoxyoenzoovej (85%) in 300 cm ³ of dichloromethane. After stirring at 0 ° C for 2 hours ^, 25 cm ^{3 of a} 5% aqueous potassium bicarbonate solution are added to the mixture and the mixture is stirred for 15 minutes. The organic phase is washed again with 250 cm @ ^{3 of} potassium hydrogen carbonate solution, then dried over magnesium sulphate and concentrated to dryness (after the presence of peroxides is no longer detected) under reduced pressure (2.7 kPa). 26.9 g of 4,4-diphenyl-1-oxetetrahydrothiapyran are obtained in the product with a melting point of 122 ° C.

form of white solid

The 4,4-O-phenyl tetrahydrothiapyran can be prepared as follows.

To a suspension of 140.8 g of 3,3-diphenyl-bis-1,5-methanesulfonyloxy-pentane in 1400 sodium sulfide, with a condenser over cm ^{3 of} 1-butanol, was added 100 g of nonahydrate. The mixture was heated to reflux. cooled to ^cm: hours and about ³ HR 1otu ethyl, C. To the mixture is added 1000 cm ^{3 of} water, 500

500 cm ^{3 of} dichloromethane. After stirring, the organic phase is separated, washed successively with 1000 cm ^{3 of} water, 500 cm ^{3 of} 1N hydrochloric acid, 500 cm ^{3 of} saturated aqueous sodium hydrogen carbonate solution, 1000 cm ^{3 of} water, dried over magnesium sulphate and dried over magnesium sulfate. * ηΊ * ι *>λ'-ί ·? · ^ · ~ ťrt- * >>>> * in * »» <iJ

- 3 9 concentrated to dryness under reduced pressure at ^{60, JC} residue was allowed vykry.štal regarded as the acetate, the crystals are washed with di izopropy1oxi House, drained and dried. 76 g of 4,4-aiphenyltetrahydrothiapyran are obtained in the form of white crystals with a melting point of 134 ^U C.

3,3-Diphenyl-bis-1,5-methanesulfonyl-oxypentane can be prepared as follows.

To a solution of 95 g of 3,3-diphenylpentane-1,5-diol (prepared according to the procedure described by P. E ilbracht et al., In Chem.Ber.1 18,825839 (1935)) in 9 50 cm ³ of dichloromethane and 113 cm ³ of triethylamine, cooled to ^{-20, J} C, over 10 minutes, a solution of 62 cm ³ of methanesulphonyl chloride in 100 ^cm3 of dichloromethane. After stirring for 2 h at 20 C. ^The reaction mixture was washed twice with 500 cm ³ of water, the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is crystallized from diethyl ether and the crystals are washed with diethyl ether, centrifuged and dried. 140 g of 3,3-diphenyl-bis-1,5-methanesulfonyloxypentane are obtained in the form of white crystals having a melting point of 99 DEG C.

Example 13

To a suspension of 0.12 g of sodium hydride in 10 cm ^{3 of} anhydrous toluene, a solution of 1.4 g of (4aRS, 7aRSΙό- / 2- (2-hydroxyphenyl) acetyl) perhydrothiopyrano (2,3-c) pyrrole is added over 30 minutes. in a mixture of dimethylformamide, toluene and anhydrous tetrahydrofuran (15: 10: 5.5, v / v), and a solution of 3 g of N- (3-chloropropyl) -N, N-dimethylamine in 10 cm ^{3 of} anhydrous is then added. The reaction mixture is heated to reflux for 15 minutes, then stirred at 20 ° C for 20 hours, diluted with 100 cm ^{3 of} ethyl acetate and washed twice with 150 cm ^{3 of} distilled water and 100 cm ³ with tanks. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa), the residue is crystallized from diisopropyl loxide and the crystals obtained are drained and dried under reduced pressure.

0 pressure (2.7 kPa). 1.18 g of (<1RS, 7aRS) -6- [2- [2- (3-dimethylaminopropoxy) phenyl] acetyl] -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole are obtained as beige crystals. with a melting point of 130 ° O.

Example 14

To a suspension of 1.5 g of (4aRS, 7aRS) -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole-1,1,1-dioxide hydrochloride and 0.95 g of 1-ethoxyimino-2-ol. - (2-Methoxyphenyl) ethyl hydrochloride in 15 cm ^{3 of} 1,2-dichloroethane is added dropwise 1.16 cm ^{3 of} triethylamine. After stirring for 20 hours at ^{20, J} C there were added 30 cm ³ of dichloromethane and the mixture was successively washed with 100 cm ³ of water and 100 cm ³ of 5% aqueous potassium carbonate solution. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile and isopropyl ether. The crystals were washed with acetone and then with isopropyl oxide, centrifuged and dried. 0.83 g of (4aRS, 7aRS) -1-imino-2- (2-methoxyphenyl) -6-ethyl-14,4-diphenyl-perhydrothiopyrano [2,3-c] pyrrole-1,1-dioxide is obtained in the form of: white crystals having a melting point of 20 ° C.

Example 1 5

To the mixed and cooled solution (0 ’-’C) 1.88 g (4aRS,

7aRS) -6 - [(2-dimethylaminophenyl) acetyl] -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole in 30 cm @ ^{3 of} dichloromethane is added a solution of 0.88 g of 3-chloroperoxybenzoic acid (85%) in 15 cm ^{3 of} dichloromethane. The reaction mixture is stirred for two hours at 0 ° C, then washed twice with 30 cm ^{3 of} saturated aqueous sodium bicarbonate solution and then with 30 cm ^{3 of} water. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The yellow oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 20 cm), eluting with a 98/2 mixture of ethyl acetate and methanol, eluting under nitrogen pressure. 0.06 MPa and fractions of 60 cm ³ are collected. Fractions 9 to 32 are combined

-41 thickened under reduced pressure (2.7 KPa), - then the residue is crystallized by ľ 10 cm ^{3 of} acetonitrile and the crystals are centrifuged, filtered and dried. 0.93 g of (1RS, 4aRS, 7aRS) -6 - [(2-dimethylaminophenyl) acetyl] -4,4-diphenyl-1-oxider hydrothiopyrano [2,3-c] pyrrole is obtained in the form of white crystals having a temperature. melt 204 ^u C.

Fractions 33 to 50 are combined and concentrated to dryness and the residue is purified by chromatography under the above conditions (eluent: ethyl acetate / methanol 94: 6 by volume). Fractions 76 to 86 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile, then the crystals obtained are centrifuged and dried. 0.28 g of (1RS, 4aR3,7aRS) 6 - [(2-dimethylaminophenyl) acetyl] -4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole is obtained as a white solid, m.p. 190 ° C.

(1RS, 4aRS, 7aRS) -6 - [(2-dimethylaminophenyl) acetyl] 4,4-diphenyl-1-peroxide perhydrothiopyrano [2,3-c] pyrrole may be prepared as follows.

2.46 g of (1RS, 4aRS, 7aRS) -6 - [(2-dimethylaminophenyl) acetyl] 4,4-diphenyl-1-oxidoperhydropyrreno [2,3-c] pyrrole in 25 cm ^{3 of} mixture - concentrated hydrochloric acid (37% hydrochloric acid) and dioxane (half volume). The brine was then neutralized at 10 ° C with 20 cm ^{3 of} 4 N aqueous sodium hydroxide solution. The decanted organic phase is washed with 50 cm ^{3 of} distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. the oily residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 34 cm), eluting with ethyl acetate / methanol (95: 5 by volume), eluting under nitrogen pressure. 0.08 MPa and fractions of 25 cm ³ are collected. Fractions 72-92 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ^and C. The residue is crystallized in ethyl acetate, the crystals are washed with diisopropyl oxide, drained and dried.

jiilÚúillA

42 g of (1RS, 4aRS, 7aRS) -6- (C2-methylaminophenyl) acetyl] -4,4-diphenyl-1-oxidoperhydrothiopyrano (2,3-c) are obtained pyrrole as white crystals having a melting point of 190 ° C.

Example 1 δ

To a cooled solution of (0'-C) (4aRS, 7aRS) -6- [2- (pyrrolidinyl-1) phenyl] acetyl-4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole in 30 [deg.] C. cm ^{3 of} dichloromethane is added a solution of 0.83 g of 3-chloroperoxybenzoic acid (85 µl) in 15 cm ^{3 of} dichloromethane. After stirring at 0 DEG C. for 1 hour and at ambient temperature for 2 hours, the reaction mixture is washed with 50 cm @ ^{3 of a} saturated aqueous sodium hydrogen carbonate solution and then twice with 30 cm @ ^{3 of} water. The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 19 cm @ ^{3 of a} mixture of concentrated hydrochloric acid and dioxane (1/2 volume). After stirring for 48 hours at 20 C. ^The solution obtained was added 15 cm ³ of 4N sodium hydroxide, then the mixture was extracted with 30 cm ³ of dichloromethane. The organic phase is washed with 40 cm @ ^{3 of} water, dried over magnesium sulphate and concentrated to dryness. The residue is chromatographed on a silica gel column (0.04-0.06 mm, diameter 3.6 cm, height 40 cm), eluting with a 5: 5 by volume mixture of ethyl acetate and methanol (9: 5). under a nitrogen pressure of 0.3 MPa and fractions of 25 cm ³ are collected. Fractions 100 to 19 are combined and concentrated to dryness at reduced residue. The residue is crystallized from ethyl acetate crystals, centrifuged and dried. 0.11 g of (1RS, 4aSR, 7aSR) -6- [2- (pyrrolidinyl-1) phenyl / acetyl] 4,4-diphenyl-1-oxidoperhydrothiopyrano [2,3-c] pyrrole is obtained in the form of: of a white solid having a melting point of 190 ^U C.

pressure (2.7 kPa). acetate and

Example 17

Proceed as in the example and concentrate the chromatographic fractions 123, the residue which is allowed to crystallize, and centrifuged, washed with ethyl acetate.

16, wherein they merge to ^; 148 'azf ska sa.

of ethyl acetate. ä ', (d z ŕ ŕ ŕ p 1 o i oni oni oni)

3 are then dried. 39 g of 6- [2- (pyrrolidinyl-1) phenyl] acetyl] -4,4-1-oxidperhydrothiopyrano [2,3-c] pyrrole with configuration (1RS, 4aRS, 7aRS) are obtained in the form of a white solid. m.p. 198 ^U C.

Example 18

To a solution of 0.5 g of (4aRS, 7aRS) -6- [2- (3-dimethylaminopropoxy) phenyl] acetyl] -4,4-diphenyl perhydrothiopyrano [2,3-c] pyrrole 5 cm ³ of dry dichloromethane is added 0.15 cm ³ of trifluoroacetic acid and the mixture was cooled to 0 C ^lR after stirring for 30 minutes at 0 C, ⁱⁿ a solution of 3-chloroperoxybenzoic acid (85%) in 10 cm ³ dichloromethane. The reaction mixture is stirred for two hours at 0 DEG C., then diluted with 10 cm @ ^{3 of} dichloromethane and washed with 20 cm @ ^{3 of} 1N sodium hydroxide solution and 20 cm @ ^{3 of} saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (granulometer and 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting with a mixture of ethyl acetate, acetic acid and water (80:10:10; v / v) as the eluent. under a nitrogen pressure of 0.1 bar and collecting fractions of 25 cm ³ fractions ,, 13 and 21 are combined and a thickening i to dryness under reduced pressure. The remainder of the detergent was crystallized from a mixture of ethyl acetate and isopropyl ether, then the crystals were centrifuged and then dried to give 0.13 g of (1RS, 4aSR, 7aSR) -6- / 2- / 2- (3-dimethylaminopropoxy). phenyl (acetyl) -4,4-diphenylperhydropyrano [2,3-c] pyrrole as a beige solid, m.p. 146 DEG C.

Example 19

Following the procedure of Example 15, from 0.99 g of (4aRS, 7aRS) -4,4-diphenyl-6-phenyl-acylperhydrothiopyrano [2,3-c] pyrrole and 0.49 g of 3-chloroperoxybenzoic acid are obtained after chromatrography. 0.54 g (1 RS, 4aSR, 7a R) -4,4-diphenyl 1-6-phenylacetyl 1-t-oxoperhydrotyropyrano [2,3-c] pyrrole as white crystalline with a melting point of 217 ° C.

Example 2 G

The procedure is as in Example 15, starting from 0.99 g of (4aRS, 7aRS) -4,4-diphenyl-6-phenylacetylperhydrothiopyrano [2,3-c] pyrrole and 0.49 g of 3-chloroperoxybenzoic acid. Purification using chromatography 0.17 g of (1RS, 4aRS, 7aRS) -4,4-diphenyl-6-phenylacetyl-1-oxidoperhydrothiopyrano [2,3-c] pyrrole as white crystals, m.p.

Example 2i

The procedure is as in Example 15, starting from 0.95 g of (4aRS, 7aRS) -4,4-diphenyl-6 - [(2-methoxyphenyl-acetyl) perhydrothiopyrano] 2,3-c] pyrrole and 0. 43 g of 3-chloroperoxybenzoic acid (5%) are obtained after chromatographic purification of 1.0 g of (1RS, 4a3R, 7aSR) -6 - [(2-methoxyphenyl) acetyl] -4,4-diphenyl-1-oxidperhydrothiopyrano], 3-c / pyrrole as a white solid, m.p. 40 2 ^'J C and 0.15 g of (1RS, 4a R $, 7aRS) -6 - / (2-metoxyfenyljacetyl / -4,4-diphenyl-1 oxidperhydrothiopy in the morning (2,3-c) pyrrole as a white solid with a melting point of 254 ° C.

Example 22 To a cooled (0 ° C) solution of 1.46 g of a mixture of molds (4aR,

7aR) and (4aS, 7aSj) 6- / 2- (2-methoxyphenyl) - (S) -propion 1 / -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole in 15 cm ^{3 of} dichloromethane add solution 0, 69 g of 3-en lórperoxybenzoovej (85%) in 15 ^cm3 of dichloromethane. After three hours stirring at 5 ^lR C, the reaction mixture was washed with 30 ^cm3 of saturated aqueous sodium bicarbonate solution and twice with 30 cm ³ of water, then dried over MgSO The mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is contacted with a mixture of concentrated hydrochloric acid and dioxane (half by volume) at 20 DEG C. for 48 hours, and the solution is then washed with 12 cm @ ^{3 of a} 4N aqueous solution. sodium hydroxide and 20 cm ³ of water and then concentrated to dryness at ^{40, J} C under vacuum. the residue is chromatographed on a silica gel column (particle size 0.02 to 0.045 millimeters and diameter 3.6 cm, height 40 cm) Using an elution mixture consisting of a mixture of ethyl acetate and methanol. 95: 5 by volume, eluting under a nitrogen pressure of 0.08 MPa and collecting 60 cm ³ fractions. Fractions 22 and 42 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.4 g of (1R, 4aR, 7aR) - and (1S, 4aS, 7aS) -configuration 6- (2- (2-methoxyphenyl) - (S) -propionyl) -4,4-diphenyl-1-peroxide perhydrothiopyrano) are obtained. 2,3-cis pyrrole in the form of a mixture consisting of a white solid.

Infrared spectrum:

(characteristic strips, cm ^-1 ):

3060, 3025, 2970, 2935, 2880, 2840, 1640, 1595, 1490,

1446, 1425, 1245, 1020, 755, 705.

. ¹ Ri ^ j ^ et resonance spectrum:

{at ambient temperature, a mixture of both rotamers of each configuration is observed, characteristic signals)

1.2-1.4 (mt, 3H, CH 3),

3.60 and 3.87 (3 s, 3H, OCK ₃ ),

6.6 to 7.4 (mt, 14H aromatic).

EXAMPLE 23 The procedure of Example 22 is followed by pooling and evaporation to dryness by fractionation chromatography 13 to 20, followed by crystallization from acetonitrile.

The crystals are centrifuged, washed with acetone, tritrile and diisopropyl, then dried. 0.02 g of a mixture of configurations (1R, 4aS, 7aS) and (1S, 4aR, 7aR) 6- / 2- (2-methoxyphenyl) - (S) -propion 1 / -4,4-diphenyl 1- 1-oxopyridhydropyrido [2,3-c] pyrrole as a white solid.

Infrared spectrum:

(character of the same eye band, cm ^-1 )

3060, 3030, 3000, 2970, 2935, 2880, 2840, 1640, 1595, 1490,

1485, 1445, 1420, 1370, 1240, 1050, 1040, 1030, 755, -705. -. : - '//

Magnet-Nuclear Magnetic Resonance Spectrum :. 'v' / · / ^; · 'T

- 46 observed mixture of both (OMSO-de. + CFaCOOD, at ambient temperature, rotamers, characteristic signals), 1 - 1, 3 (mt, 3 H, CH 3),

3.35 and 3.81 (2 s, 3H, 0CH _3).

6.7 to 7.5 (mt, 14H aromatic).

Example 24 To a solution of 0.3 cm ^{3 of} titanium isopropoxide in 10 cm ^{3 of} dichloromethane and 0.018 cm ^{3 of} water, a solution of 0.4 g of (4aRS, 7aRS) -6 - / (2-methoxyphenyl) is added under a nitrogen atmosphere. ) Acetyl 1, 4,4-dihydroxybenzoate (2,3-c) pyrrole in 4 cm ^{3 of} dichloromethane. The mixture was cooled to ^{-20, JC,} followed by the addition of 0.16 cm ³ of 70% aqueous terc.buty1hydrogénperoxidu. After stirring for 6 hours at -20 DEG C., 0.01 cm @ ³ of tert-butyl hydrogen peroxide solution are added to the suspension obtained. After one hour and 30 minutes at ^{-20, J} C, the reaction was quenched with 2.0 cm ³ of water and the gel was filtered. The dichloromethane phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile, the crystals are taken up in dichloromethane and the solution obtained is chromatographed on a silica gel column (0.04-0.06 mm, 2 cm in diameter, 20 cm in height), eluting with a mixture of methanol and ethyl acetate by volume. a ratio of 10:90, eluting under nitrogen pressure of 0.06 MPa and collecting fractions of 30 cm ³ . Fractions 5 and 6 are combined and concentrated to dryness under reduced pressure. 0.06 g of (4aRS, 7aRS) -6 - [(2-methoxyphenyl) acetyl] -4,4-diphenyl 11, idioxide perhydrothiopyrano [2,3-c] pyrrole is obtained in the form of a white solid. m.p. 285 C. ^the fractions 24 and 25 are combined and concentrated to dryness. After crystallization from acetonitrile, 0.26 g of (1RS, 4aSR, 7aSR) -6 - [(2-methoxyphenyl) acetyl] -4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole is obtained. as a white solid, m.p. 240 ^U C.

The invention also relates to pharmaceutical compositions which are constituted by a compound of the general formula (I) or by salt formation, if such salts exist, wherein:

These compositions optionally comprise any other pharmaceutically acceptable substance which may be inert or physiologically active. The compositions of the invention may be used in the form of parenteral, oral, rectal or topical administration.

Sterile compositions for parenteral administration, which may in particular be used in the form of perfusions, are preferably aqueous or non-aqueous solutions, suspensions or emulsions. As the solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents can be used. These compositions may also contain additives, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be accomplished in various ways, for example, by aseptic filtration, introduction of sterilizing agents, irradiation or heating. These compositions can also be prepared in a sterile solid form, which, if used, can be dissolved in a sterile injectable medium.

Compositions for rectal administration are lace or rectal capsules which contain, in addition to the active ingredient, pharmaceutical excipients such as cocoa butter, semisynthetic glycerides or polyglycols.

Tablets, pills, powders or granules can be used as solid compositions for oral administration. In these compositions, the active compound of the invention (optionally in combination with another pharmaceutically compatible substance) is admixed with one or more diluents and / or one or more excipients such as sucrose, lactose or starch. These compositions may also contain substances other than diluents, for example lubricants such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used. These compositions may also contain substances other than diluents, for example wetting, sweetening or flavoring agents.

Compositions administered topically may be, for example, creams, ointments and creams.

In human medicine, the compounds of the invention may in particular be used to alleviate post-traumatic, post-surgical, menstrual and cephalic pain, in the treatment of anxiety, psychosis, Parkinson's disease, schizophrenia, Alzheimer's disease, in myorelaxation applications, in the treatment of convulsive contractions, pain conditions and pain. gastrointestinal inflammations (ulcerative colitis, irritable bowel syndrome, Crohn's disease), urinary tract (cystitis) and airways (asthma, rhinitis), in the treatment of gynecological disorders and in the treatment of migraine. The novel thiopyranopyrrole derivatives are also useful in the treatment of rheumatoid atritis and disorders caused by immune system dysfunction, in dermatology such as psoriasis, cold sores, inflammation of urticaria, eczema and photodermatosis, as well as in the treatment of eye and dental inflammations.

The compounds of the invention may also find use in the treatment of cardiovascular disorders, for example hypotension.

Applicable doses of these compounds are dependent upon the desired effect and duration of treatment. When administered to adults, these doses are usually 0.25 to 1500 mg valuable in divided doses or doses.

Usually, it is the attending physician who determines the dosages and their distribution that will be most appropriate to the age, weight and other characteristics of the patient.

The following example illustrates the composition of the invention and is not limiting.

A conventional technique is to take tablets having the following composition:

í1RS, 4aRS, 7aRS) -6 - /// bipyrrolidinyl-3-one) -2-propoxy / ŕenyl / acetyl / -4,4-diŕenyl-1-oxide-perhydrotiopyrano-

/ 2,3-c / pyrro1 25 mg starch 8 3 mg silica 30 mg magnesium stearate 3 mg

t »

Claims (10)

Novel thiopyranopyrrole derivatives of general formula x II N '- C - CH - (O) wherein X represents an oxygen atom or a group NH, _w R, represents a phenyl group optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, an alkyl group which may optionally be substituted by halogen atoms or amino groups, and alkyl amine; ino-groups or dialkyl amine groups; an alkyloxy or alkylthio group, which may be optionally substituted by hydroxy, amino, alkylamino or diaphthalino groups, which in turn may be optionally substituted by phenyl, hydroxy or amino; or dialkylamino groups whose alkyl radicals form with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle which may contain another heteroatom selected from the group consisting of oxygen, sulfur or nitrogen and which is optionally substituted by an alkyl group , hydroxy or hydroxyalkyl; and optionally substituted amino-, alkylamino- or diamino groups, the alkyl radicals of which may form with the nitrogen atom to which they are attached a heterocycle as defined above, or a cyclohexadienyl, naphthyl or saturated group. A 5 or 5 unsaturated, mono or polycyclic heterocyclyl group containing 5 to 9 carbon atoms and one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and R 2 represents a hydrogen atom or a halogen atom or a hydroxy group, an alkyl group, an aminoalkyl group, an alkylaminoalkyl group, a dialkylamino group, an alkyloxy group, an alkylthio group, an acyloxy group, a carboxyl group, and an alkoxycarbonyl group an dialkylaminoalkyloxycarbonyl, benzyloxycarbonyl, amino, acylamino or alkyloxycarbonylamino group; and n is an integer from 0 to 2. wherein the above alkyl and acyl groups are straight or branched groups containing 1 to 4 carbon atoms, in the form of stereoisomers or mixtures thereof, as well as salts, if any. 2. 6 - // (3-dimethylamino-2-propoxy) phenyl / acetyl / -4 _I, 4-diphenyl-1oxidpernydrotiopyrano / 2,3-c / 1 pyrrolo as stereo isomers and mixtures thereof. 3. 6 - [[3- (Pyrrolidinyl-1) -2-propoxy] phenyl] acetyl] -4,4-diphenyl-1-oxypyrhydropyrido [2 ', 3-c] pyrrole in the form of stereoisomers or mixtures thereof. 4. 6- [2- (2-Methoxyphenyl) - (S) -propionyl] 4,4-diphenyl-1-oxideperhydrothiopyrano [2,3-c] pyrrole in the form of stereoisomers or mixtures thereof. 5. 6- [2- (3-Dimethylaminopropoxy) phenyl] acetyl] -4,4-diphenylperhydrothiopyrano [2,3-c] pyrrole in the form of stereoisomers and mixtures thereof. 6. A process for the preparation of a novel thyropyridine derivative according to claim 1, characterized in that the acid liner is 1 or 1. Reactive acid derivative of the general formula f. ₁ - ck - COOH in which Rt and Rc are as defined in claim 1, reacted with a thiopyranopyrrole derivative of the general formula (O) n wherein n is as defined in claim 1, subsequently the amide obtained is optionally converted to an amidine for which X is NH, and the product obtained is optionally converted to a salt, if any. A process for the preparation of a thiopyranooyrrole derivative according to claim 1, wherein R 1 represents a 1-oxyphenyl group, the alkyl radical of which is optionally substituted, R 2 has a meaning other than the hydroxy group on an and X have the meanings defined in claim 1, a halogenated derivative of the general formula R-i-Hal, in which Ra. means an alkyl group which is optionally substituted by a hydroxy group and a 1-amino group or a dialkylamino group which is optionally substituted by a phenyl group, a hydroxy group or an amino group, or a dialkyl amine group wherein the alkyl radicals form with the nitrogen atom to which they are attached a heterocycle as defined in claim 1 and Hal represents a halogen atom, reacts with the thiopyranopyrrole derivative according to claim 1, wherein R 1 represents a hydroxyphenyl group, followed by optionally the hydroxyl function is removed and the product obtained is optionally converted to a salt, if any. A process for the preparation of a thiopyranopyrrole derivative according to claim 1, wherein X is NH and R 1, R 2, R 3, R 3, R 3, R 3, R 3 and R 3. and n have the meanings defined in claim 1, characterized in that the compound of formula (I) is a compound of formula (I) Wherein R 1 and R a are as defined in claim 1 and R 5 is a straight or branched (C 1 -C 4) alkyloxy group or a methyl group, a methyl group, an ethyl group, a benzyl group or an alkyloxycarbonyl group; The bonyimethyl group, or optionally a salt thereof, is reacted with a iopyranopyrrole derivative of the general formula (n) as defined in claim 1, followed by optionally converting the obtained product into a salt, if any. A process for the preparation of a thiopyranopyrrole derivative according to claim 1, wherein n is 1 or 2, characterized in that the corresponding derivative according to claim 1 is oxidized, wherein n * is 0, then the product obtained is optionally converted into a salt, if any. Pharmaceutical composition, characterized in that it contains at least one product according to any one of claims 1 to 5, alone or in combination with one or more additives and / or with one or more diluents which are compatible '''files' and ^r rmaceut ly and pr JATEL.