JP2001527078A - Novel farnesyltransferase inhibitors, their preparation, pharmaceutical compositions containing them and their use for the preparation of medicaments - Google Patents

Abstract

(57) Summary The present invention relates to novel products of general formula (I), their preparation, pharmaceutical compositions containing them and their use for preparing medicaments. In the salts of the products of the general formula (I) and of the general formula (I) of the racemates or of the optical isomers or mixtures of these optical isomers: Het represents a monocyclic or polycyclic system, in which case At least one of the rings contains 1 to 4 heteroatoms; Ar is an optionally substituted phenyl residue, a heterocyclic substituted phenyl residue, a polycyclic or heterocyclic aromatic. represents Zokuzanmoto; R represents _{-COOH, -COOR 4, -CON (R} 5) a (R ₆₎ residues, wherein, R ₄ = alkyl, R ₅ = H, alkyl, R ₆ = alkyl, hydrogen, hydroxy, optionally amino substituted alkoxy; R _1, R ₂ = hydrogen, halogen, alkyl, alkoxy, alkylthio, alkoxycarbonyl; R ₃ = hydrogen, alkyl, alkylthio; X = methylene, a Ken-1,1-diyl, cycloalkane-1,1-diyl. The product of general formula (I) is a funesyltransferase inhibitor. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of the formula (I)

[0002]

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Novel derivatives of the invention, their preparation, pharmaceutical compositions containing them and their use for the preparation of medicaments.

The protein farnesyltransferase is farnesyl pyrophosphate (F
PP) to express a certain number of proteins, especially the ras oncogene
An enzyme that catalyzes the transfer of a farnesyl group to the terminal cysteine residue of the tetrapeptide sequence CAAX of the as protein.

[0005] The ras oncogene (H-, N- or K- ras ) is known to play an important role in cell signaling pathways and cell division processes. Mutations in the ras oncogene or its overexpression are often associated with human cancers; mutated p21Ras proteins are found in many human cancers, especially in over 50% of colon cancers and 90% of pancreatic cancers (Kohl et al., Science, 26
0, 1834-1837, 1993).

[0006] The ability of the mutated p21Ras protein to induce cell proliferation and transform normal cells into cancer cells is hindered by the inhibition of farnesyltransferase, and thus farnesylation of the p21Ras protein.

Furthermore, although not expressing mutated or overexpressed ras, tumor cell lines with oncogenes or overexpressed oncoproteins that such farnesylation of proteins mutated using signaling pathway as normal ra s Has been shown to be effective against
Agasu et al., Cancer Research 55, 5310-5314,
1995: Sepp-Lorenzino et al., Cancer Research.
55, 5302-5309, 1995).

[0008] Farnesyltransferase inhibitors are inhibitors of cell proliferation, and are therefore anticancer and antileukemic agents.

[0009] Patent FR 95/08296 describes a benzoperhydroisoindole, a farnesyltransferase inhibitor derived from a compound in which the isoindole ring is fused to a phenyl ring.

According to the invention, the novel compounds of general formula (I) have, among other modifications, the heterocyclic system Het fused to an isoindole ring.

Now, the novel products of general formula (I) of the prototype structure have quite unexpectedly and unexpectedly a strong inhibitory activity on farnesyltransferase and are notable anticancer and antileukemic agents Has been found and this is also the subject of the present invention.

In particular, the biological activity of the compounds according to the invention is significantly improved, inter alia, by replacing the benzo ring in the benzoperhydroisoindole skeleton with a heterocyclic system fused to the isoindole skeleton, Contrary to expectations.

The present invention provides compounds of the general formula I

[0014]

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Wherein: Het represents a fused monocyclic, bicyclic or tricyclic system, wherein each ring, which may be saturated or unsaturated, is 4- to 7-membered and At least one of the rings contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur atoms, which may be the same or different; optionally substituted heteroatoms The cyclic system can be fused to the isoindole ring via any two of its adjacent atoms; preferably, Het contains a nitrogen or sulfur atom.
Represents a 9 to 9 membered aromatic monocyclic or bicyclic system, and Het represents, by way of non-limiting method, the following residues: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, preferably, Het is thienyl or indolyl residue; benzofuranyl, benzothienyl, chromenyl, also may be selected from indolyl or quinolyl and their iso isomers desirable in the present invention, Het is thienyl; - Ar -Optionally a halogen atom and an alkyl residue such as methyl, such alkyl residue optionally being perhalogenated such as trifluoromethyl, such as alkenyl, mercapto, alkylthio, cyano or methoxy Alkoxy, the alkyl part of which is A phenyl residue optionally substituted with one or more atoms or residues which may be optionally perhalogenated, such as fluoromethoxy, or A phenyl residue fused to a 4- to 7-membered heterocycle containing one or more heteroatoms selected from nitrogen and sulfur atoms, the bicyclic system so formed is especially 2,3- Dihydro-1,4-benzodioxin-6-yl, 2,3-
Dihydrobenzofuran-5-yl and 2,3-dihydrobenzopyran-6-yl residues;-1- or 2-naphthyl, 5-indanyl or 1,2,3,4-tetrahydro-6 An aromatic or non-aromatic polycyclic residue, such as naphthyl, or-one or more selected from oxygen, nitrogen and sulfur atoms linked to a fused ring via a carbon-carbon bond. 5- to 12-membered aromatic or non-aromatic heterocyclic residues containing heteroatoms, which are, where appropriate, halogen atoms and alkyl, alkenyl, hydroxyl, alkoxy, mercapto, alkylthio, cyano and trio Substituted with one or more atoms or residues which may be the same or different selected from fluoromethyl residues, preferably Ar A phenyl residue optionally substituted, preferably at the 4-position, optionally with an alkyl residue, preferably a methyl, alkoxy residue, preferably a methoxy or trifluoromethyl residue, or also 2, Represents any of the phenyl residues fused to a heterocyclic ring forming a bicyclic system such as 3-dihydro-1,4-benzodioxin-6-yl; preferably, Ar is unsubstituted or Preferably represents a phenyl residue substituted at the 4-position with an alkyl residue, preferably a methyl, alkoxy residue, preferably a methoxy, -R represents a residue of the general formula -CO-Z, wherein Z It represents the following: - hydroxyl residue or, - residue of formula -OR _4, wherein, R ₄ represents an alkyl residue such as methyl, or - the formula -N (R ₅₎ (R ₆ ) Residue Wherein - R ₅ represents a hydrogen atom or an alkyl radical, and - R ₆ is - optionally, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, mercapto, alkylthio, alkoxycarbonyl, carboxyl or cyano residue, when May or may not contain one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms optionally substituted by
An alkyl residue, such as methyl, which may be substituted by a -12-membered mono- or polycyclic aromatic residue, wherein said aromatic residue is especially a 2-, 3- or 4-pyridyl residue, preferably It may be a 3-pyridyl or 4-pyridyl residue, or a 2- or 4-imidazolyl residue or a 2- or 4-thiazolyl residue or a pyridine N-oxide residue, or optionally one or more A phenyl residue optionally substituted by a halogen atom or by one or more trifluoromethyl groups or by one or more alkyl, alkenyl, alkoxy, alkylthio or alkylamino residues, or also 1- or May be a 2-naphthyl residue, or-a hydrogen atom,-a hydroxyl residue,-optionally the following residues- Alkyl,-aryl, such as phenyl, optionally substituted with one or more residues which may be the same or different selected from alkyl and alkoxy residues,-from nitrogen, oxygen and sulfur atoms 5-7 membered heterocyclyl containing one or more heteroatoms selected, with one or more residues optionally the same or different selected from alkyl and alkoxy residues An optionally substituted arylcarbonyl, such as benzoyl, an amino residue optionally substituted with one or two residues which may be the same or different, selected from-optionally substituted with a phenyl residue Wherein R is a carboxyl residue or a -COOMe residue, or alternatively a residue -C Represents _{N (R 5) (R 6} ), wherein, if R ₅ represents a hydrogen atom, R ₆ is phenyl or pyridyl residue, preferably 3-pyridyl or 4-pyridyl, or 2- or 4-imidazolyl, Or represents an alkyl residue, preferably methyl, substituted by an aryl residue such as a 2- or 4-thiazolyl residue; very preferably, R is a carboxyl residue or a -COOMe residue or also a residue -CON (R ₅ ) (R ₆ ) wherein R ₅ represents a hydrogen atom, wherein R ₆ is an alkyl residue such as methyl substituted with an aryl residue such as phenyl or pyridyl residue. Even more preferably, R is a carboxyl residue or-
Represents a COOMe residue; R ₁ and R ₂ may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl residue or an alkoxy residue such as methoxy, each optionally being a dialkylamino residue, an alkylthio residue; Residue or an alkoxycarbonyl residue, preferably one of the symbols R ₁ or R ₂ represents a hydrogen atom and the other symbol represents an alkoxy residue such as methoxy, and more R ₃ represents a hydrogen atom, an alkyl residue or an alkylthio residue; preferably R ₃ represents a hydrogen atom or a methyl residue; R ₃ represents a hydrogen atom; - X is a 1,1-alkenediyl residues or 3 to 6 carbon atoms such as methylene residue or Binirujiiru Wherein X represents a methylene or vinyldiyl group, particularly preferably X represents a vinyldiyl group, or a racemic form thereof, or an optical isomer thereof, or an optical isomer thereof And a salt of the product of general formula (I).

In the above and following definitions: an “alkyl” residue or moiety comprises 1 to 6 carbon atoms, straight or branched.
Define a hydrocarbon residue or moiety having: methyl, ethyl, propyl, butyl,
Pentyl and hexyl residues or moieties and the correspondingiso,secas well aster t Isomers, preferably methyl, ethyl, propyl and butyl residues and the corresponding iso ,secas well astertRepresents an isomer;-an "alkenyl" residue or moiety is an unsaturated carbon containing 2 to 4 carbon atoms.
Defines hydrogen hydride residues or moieties, vinyl, allyl, 2-propenyl and 1-2,
-Or 3-butenyl residues or moieties and the correspondingiso,secas well aste rt Represents an isomer;-an "alkoxy" residue or moiety is a residue or containing 1 to 4 carbon atoms
Moieties, methoxy, ethoxy, propoxy and butoxy residues and the corresponding
Toiso,secas well astertRepresents an isomer.

Preferably, the compounds of the present invention are those wherein Het represents a thienyl or indolyl residue, and Ar is, where appropriate, preferably in the 4-position, optionally an alkyl residue such as methyl, an alkoxy residue such as methoxy. Fused to a phenyl residue optionally substituted with a residue or a trifluoromethyl residue, or a heterocyclic ring forming a bicyclic system such as 2,3-dihydro-1,4-benzodioxin-6-yl R represents a carboxyl residue, a —COOMe residue or alternatively a residue —CON (R ₅ ) (R ₆ ), wherein R ₅ represents a hydrogen atom, and R ₆ is a phenyl residue or substituted with 3- or 4-pyridyl residue, alkyl residue represents such as methyl; represents one hydrogen atom of the symbols R ₁ or R _2, and another Symbol represents an alkoxy residue such as methoxy, it is more preferably attached at the ortho position on the phenyl ring, R ₃ represents a hydrogen atom, and X represents a Binirujiiru group, racemic or optically thereof It has the general formula (I) and its salts in the form of a mixture of isomers or optical isomers thereof.

Preferably, the compounds of the invention are those wherein Het represents a thienyl or indolyl residue and Ar is substituted, as appropriate, with an alkyl residue such as methyl, an alkoxy or trifluoromethyl residue such as methoxy. Represents an optionally substituted phenyl residue; R represents a carboxyl residue or a —COOMe residue; one of the symbols R ₁ or R ₂ represents a hydrogen atom, and the other symbol represents A methoxy residue, which is more preferably bonded ortho to the phenyl ring, R ₃ represents a hydrogen atom, and X represents a vinyldiyl group, racemic or its optical isomer or its optical isomer Formula (I) of a mixture of
And its salts.

In the text above and below, the expression “optical isomers” or optically active forms refers to pure forms of said optical isomers or optionally to “enriched” mixtures of optical isomers, ie Defines a mixture containing the optical isomer or the form.

In the present invention, compounds of the general formula (I) in dextrorotatory form are preferred.

As non-limiting examples of the claimed compounds, more specifically the following compounds: (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-
Methoxyphenyl) propenoyl] -8-phenyl-2,3,3a, 4,8,8
a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-
Methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3
a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- ( 2-
Methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl)
-2,3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N-benzyl-4,8 -Etano-2
-[2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [
2,3-f] isoindole-3a-carboxamide, (3aRS, 4SR, 10SR, 10aRS) -4,9-ethano-2- [2- (
2-methoxyphenyl) -2-propene-1-oil] -10- (4-methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-indolo [
2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-4,8- ethano-2- [2- (2-methoxyphenyl) Propenoyl ] -8- (4 -methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxamide , (3aRS, 4SR, 8SR, 8aRS)-4,8-ethano-8- (4-methoxamine Shifeniru) -2- [2- (2-methoxyphenyl) propenoyl] -2,3, 3a, 4,8,8a- hexahydro -1H- thieno [ 2,3-f] Isoindo Le -3a- carboxylate, (3aRS, 4SR, 8SR, 8aRS) -4,8- ethano-8- (4-methoxamine Shifeniru) -2- [2- (2- main Kishifeniru) propenoyl] -2,3, 3a, 4,8,8a- hexahydro -1H- thieno [2,3-f] Isoindo Le -3a- carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N- ( 3-pyridyl) methyl-8- (benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [2- (2 -methoxyphenyl) propenoyl] -2,3,3a, 4,4 8,8a- Hekisahi mud -1H- thieno [2,3-f] are independently selected from isoindole -3a- carboxamide, in the form of racemates or mixtures of the optical isomers or optical isomers thereof, preferably Mention may be made of dextrorotatory forms of the compounds and salts thereof.

More preferably, according to the invention, the following products, especially in the form of a racemate or an optical isomer or a mixture of optical isomers, preferably in the dextrorotatory form: (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-
Methoxyphenyl) propenoyl] -8-phenyl-2,3,3a, 4,8,8
a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-
Methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3
a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- ( 2-
Methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl)
-2,3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 10SR, 10aRS) -4,9-ethano-2 − [2- (
2-methoxyphenyl) -2-propene-1-oil] -10- (4-methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-indolo [
2,3-f] isoindole -3a- carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8- ethano-8- (4-methoxamine Shifeniru) -2- [2- (2-methoxyphenyl) propenoyl] -2,3, 3a, 4,8,8a- hexahydro -1H- thieno [2,3-f] Isoindo Le -3a- carboxylic acids and in particular (3aRS, 4SR, 8SR, 8aRS ) -4,8- Etano-2- [2- (2-
Methoxyphenyl) propenoyl] -8- (methylphenyl) -2,3,3a,
4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3
a-carboxylic acids and salts thereof.

The most particularly useful optical isomers of the compounds of the general formula (I) according to the invention include, in particular: (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-
Methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3
A dextrorotatory enantiomer of a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid or a mixture of optical isomers containing predominantly the optical isomer Can be mentioned.

Applicants also present below various methods and reaction intermediates that can be used to prepare compounds of general formula (I) without any limitation of the invention. It goes without saying that it is within the ability of a person skilled in the art to develop analogous methods for providing these same compounds with these methods and / or intermediate products.

According to the present invention, general formula (II):

[0026]

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Wherein R ₁ and R ₂ are defined by the general formula I, and X is as defined above, an acid, its methyl ester or a derivative of this acid such as a halide or anhydride With the general formula (III):

[0028]

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Wherein Het, Ar, R and R ₃ are defined by the general formula I, and G ₁ represents a hydrogen atom by acting on the product of the general formula (I ), Wherein G ₁ is benzyl, benzyloxycarbonyl, tert-butoxycarbonyl or butoxycarbonyl or. . . . . Preferably, the general formula (III) represents a protecting group for an amine function, such as a benzyl residue which is subsequently converted to a vinyloxycarbonyl residue when the heterocycle Het represents a sulfur-containing heterocycle such as thiophene. ), By hydrogenolysis in the presence of a catalyst such as palladium on charcoal if G ₁ represents a benzyl or benzyloxycarbonyl residue, or G ₁ is tert-butoxycarbonyl, vinyloxycarbonyl or When it represents a benzyloxycarbonyl residue, it can be obtained by hydrolysis in an acidic medium.

In the text below, the definition where G ₁ represents a benzyl residue is given by way of example only, and refers to an amine function such as a benzyl, benzyloxycarbonyl, tert-butoxycarbonyl or vinyloxycarbonyl residue. It will be apparent to one skilled in the art to adapt various methods to other protecting groups.

Typically, the reaction of the product of general formula (II) in acid form with the product of general formula (III) is carried out at a temperature between 0 ° C. and the reflux temperature of the reaction mixture at 1-ethyl-3- [ Coupling agents such as 3- (dimethylamino) propyl] carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate hexafluorophosphate and optionally hydroxy In the presence of an activator such as benzotriazole,
It is carried out by treatment in an organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane.

Typically, the reaction of the product of general formula (II) with the product of general formula (III) in methyl ester form at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, such as dioxane or dichloromethane It is carried out by treating in an organic solvent such as a halogenated aliphatic hydrocarbon.

Typically, the reaction of the product of the general formula (II) in halide form with the product of the general formula (III) is carried out at a temperature between 0 ° C. and the reflux temperature of the reaction mixture with a base (tertiary fatty acid). By treatment in an organic solvent such as a halogenated aliphatic hydrocarbon such as dichloromethane in the presence of an aromatic amine).

Typically, the reaction of the product of general formula (II) in anhydrous form with the product of general formula (III) is carried out at a temperature between 0 and 50 ° C. with a base (tertiary aliphatic amine, pyridine Or 4
-Dimethyl-aminopyridine) in the presence of an organic solvent such as a halogenated aliphatic hydrocarbon, for example dichloromethane.

Furthermore, after the reaction of II and III, where R represents the residue —CO—OR ₄ and R ₄ represents an alkyl residue, the resulting product may optionally be saponified to give R The product of general formula (I) representing a carboxyl residue can be obtained.

Typically, such as sodium hydroxide, potassium hydroxide or sodium carbonate, in an organic solvent such as an alcohol, for example methanol or ethanol, or an ether, for example dioxane, at a temperature between 20 ° C. and the reflux temperature of the solvent. the inorganic bases, R is a product of general formula (I) represents an ester of the general formula -CO-oR ₄ R is saponified products of general formula (I) to or contains a carboxyl residue.

According to the invention, by esterification of the product of general formula (I) wherein Z represents a hydroxyl residue, -R represents a residue of the general formula -CO-Z and Z represents a residue -OR ₄ Wherein R ₄ represents an alkyl residue, a new product of general formula (I) can be obtained.

Typically, the esterification is treated in an acidic medium with an alcohol of the general formula R ₄ —OH, wherein R ₄ is as defined above, at a temperature between 0 and 50 ° C., or Using an alkyl halide of the general formula R ₄ —Hal, wherein Hal represents a halogen atom (iodine), in an alkaline medium (carbonate of an alkali metal or alkaline earth metal such as cesium carbonate) or dimethyl The treatment is carried out in an organic solvent such as formamide.

According to the invention, for the products of general formula (I) in which R represents a carboxyl residue, the general formula: HN (R ₅ ) (R ₆ ) wherein R ₅ and R ₆ are defined above by the action of a is, the product as, R represents a residue of the general formula -CO-Z, wherein: Z represents a residue _{-N (R 5) (R 6} ), in which case, R ₅ and R ₆ are as defined in formula (I), it is possible to obtain novel products of general formula (I).

First, the general formula (I) wherein R dissolved in dichloromethane represents a carboxyl residue
) With oxalyl chloride to form an intermediate acid chloride, followed by reaction of a compound of general formula HN (R ₅ ) (R ₆ ), optionally in the presence of a base such as triethylamine. -Or at a temperature between 0 and 50 ° C., N, N′-carbonyldiimidazole,
Coupling agents such as 1,1-dicyclohexylcarbodiimide, 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate In the presence, in an organic solvent such as a halogenated solvent such as alcohol (ethanol) or dichloromethane, R
It is particularly advantageous to react directly the compound of the general formula (I) with a compound of the general formula HN (R ₅ ) (R ₆ ), wherein

When at least one of the symbols R ₅ and R ₆ is substituted with an amine residue, tert-butoxycarbonyl is used before coupling of the appropriate acid with an amine of the general formula HN (R ₅ ) (R ₆ ). , Protecting it with a protecting group such as benzyloxycarbonyl or a benzyl residue, and then reacting with hydrogen in the presence of a catalyst such as palladium-carbon, for example, if it represents a benzyl or benzyloxycarbonyl residue. It is particularly advantageous to replace the protecting group with a hydrogen atom by hydrogenolysis with or by hydrolysis in an acidic medium if it represents a tert-butoxycarbonyl or benzyloxycarbonyl residue.

When at least one of the symbols R ₅ and R ₆ is substituted with a carboxyl residue,
Prior to coupling of the amine of general formula HN (R ₅ ) (R ₆ ) with a suitable acid, a protecting group such as an alkyl residue optionally substituted by a phenyl residue, such as a benzyl residue. And then replacing the protecting group with a hydrogen atom, for example by hydrogenolysis with hydrogen in the presence of a catalyst such as palladium on charcoal, or by saponification under the conditions described above. Particularly useful.

In the product of general formula (I), R ₅ represents a hydrogen atom or an alkyl residue containing 1 to 6 carbon atoms, and R ₆ is an alkoxy residue substituted by a phenyl residue. By hydrogenolysis in the presence of a catalyst such as palladium on charcoal; or between -20 ° C and room temperature if the alkyl residue substituted with a phenyl residue is a benzyl residue. at a temperature, an organic solvent such as nitromethane, by treatment with aluminum chloride in the presence of anisole, by carrying out the replacement of the hydroxyl residues of the alkoxy radical substituted with phenyl residue, and R ₅ is It is possible to obtain the products of the general formula (I) which represent a hydrogen atom or an alkyl residue containing 1 to 4 carbon atoms and R ₆ represents a hydroxyl residue.

According to the invention, under normal esterification conditions, using an aliphatic acid or a derivative of this acid such as a halide or anhydride, one of the symbols R ₁ or R ₂ represents a hydroxyl residue Acylation of the product of formula (I) can give a product of general formula (I) in which _one of the symbols R ₁ or R ₂ represents an alkylcarbonyloxy residue.

With respect to the above intermediate products, methods and compounds useful for obtaining them are also provided below.

General formula (III):

[0047]

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Wherein Het, Ar, R and R ₃ are defined by the general formula I, and G ₁ represents a hydrogen atom or a protecting group for an amine group such as benzyl. Of the most particularly important ones.

Usually, the general formula (IV):

[0050]

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Wherein: Het, Ar and R ₃ are as defined above; G ₁ represents a protecting group such as a benzyl residue; and R ₄ represents 1 to 4 carbon atoms. Trifluoromethanesulfonic acid on the product of which represents an alkyl residue containing, followed by hydrogenolysis under the conditions described above, optionally followed optionally in an organic solvent By replacing a hydrogen atom with a tert-butoxycarbonyl residue by the action of tert-butoxycarbonyl anhydride or by a benzyloxycarbonyl residue by the action of benzyloxycarbonyl chloride in an organic solvent, When the ring Het represents a thiophene ring, vinyl chloroformate or chloroform at a temperature between 0 ° C. and room temperature in an organic solvent such as dichloromethane. Ethyl or 2-chloroethyl chloroformate or chloroformic 2,
With an alkyl chloroformate such as 2,2-trichloroethyl, optionally followed by an organic solvent such as an alcohol, for example methanol or ethanol, or an ether, for example tetrahydrofuran or dioxane, typically
The resulting intermediate carbamic acid is subjected to acid hydrolysis using a ₁ to 6 M aqueous solution of hydrochloric acid, whereby the group G ₁ is replaced with a hydrogen atom, whereby R represents a carboxyl residue or the residue of the general formula COOR ₄ . The product of general formula (III) representing the group can be obtained.

Typically, the Friedel-Crafts intramolecular cyclization of the product of general formula (IV) to the product of general formula (III) is optionally carried out in the presence of a catalytic amount of trifluoromethanesulfonic anhydride. Or optionally by continuous addition, by the action of a strong acid such as an excess of 3 to 15 molar equivalents of trifluoromethanesulfonic acid.
The treatment is carried out for several minutes to several days in an organic solvent such as dichloromethane at a temperature between to the reflux temperature. Also, Friedel-Crafts type intramolecular cyclization can be carried out in an organic solvent such as dichloromethane, nitromethane or nitrobenzene, optionally in the form of a complex with diethyl ether, such as aluminum chloride or titanium tetrachloride or boron trifluoride. It may be carried out by the action of a Lewis acid.

After this reaction, the resulting product may optionally be saponified, and optionally the benzyl residue may be replaced by a hydrogen atom.

Under ordinary conditions, the general formula (V):

[0055]

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Wherein Het, R ₃ , R ₄ and G ₁ are as defined above. For products of the general formula Ar—Mg—Hal, where Ar is as defined above And Hal represents a halogen atom, and an organomagnesium derivative of the general formula Ar-Li, wherein Ar is as defined above, is reacted under ordinary conditions by an organolithium reagent under ordinary conditions. The product of general formula (IV) can be obtained as such.

As a rule, customarily and optionally, Imamoto (Tetrahedron)
Lett. 1985, p. The reaction of the arylmagnesium reagent obtained with the ketone derivative of the general formula (V) in the presence of anhydrous cerium (III) chloride under the conditions described by H. 4763) is carried out in an organic solvent such as diethyl ether or tetrahydrofuran. At a temperature between 0 ° C. and the reflux temperature of the reaction mixture for a few minutes to 24 hours. However, treatment in toluene, optionally as a mixture with diethyl ether or tetrahydrofuran, has been found to be particularly beneficial.

Typically, the reaction of the conventionally obtained aryllithium reagent with the ketone derivative of the general formula (V) is carried out in an organic solvent, for example diethyl ether or tetrahydrofuran, at a temperature between −78 ° C. and −20 ° C. For several minutes to 4 hours. However, optionally as a mixture with diethyl ether or tetrahydrofuran,
Treating in toluene has been found to be particularly beneficial.

Advantageously, in the context of the present invention, the formation of a stable and characterizable intermediate of the general formula (VI), characterized by the presence of an arylethylene function in the 7-position, leads to the general formula (V)
A production method has been developed which enables the compound of the general formula (III) to be obtained from the compound of the formula (1).

More specifically, the general formula (VI) in which the expected product (III) is obtained by conversion of the compound by Friedel-Crafts type intramolecular cyclization

[0061]

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Wherein R ₃ , R ₄ , Het, Ar and G ₁ are as defined above, via formation of an intermediate of the general formula (V):

[0063]

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Wherein Het, R ₃ , R ₄ and G ₁ are as defined above, wherein the compound in the form of a racemate of or an optical isomer or a mixture of optical isomers thereof and salts thereof are generally Formula III

[0065]

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Wherein R ₃ , Het, Ar and R are as defined in general formula I, and G ₁ represents a benzyl residue.

The method developed has been described in succession as follows:-Coupling of hydrazine with a ketone derivative of the general formula (V) at the 7-position gives a hydrazone followed by a Barton reaction (J. Chem. Soc. 1962, p.
. 470) to give iodoethylene derivatives by the action of iodine;
With an arylboronic acid of the general formula Ar-B (OH) ₂ as defined above (Suzuki reaction (Tetrahedron Lett., 1979, p. 3437)
), Or optionally trimer anhydrides with, or Ar is aryl stannane of general formula Ar-SnMe ₃ is as defined above (still reaction (Angew.Chem.Int.Ed arylboronic acid. Engl., 1986, p.508.
)) The palladium coupling reaction gives the arylethylene intermediate of general formula (VI), which is converted by Friedel-Crafts type intramolecular cyclization to give the expected product (II
I), or enol triflate at the 7-position by reaction of trifluoromethanesulfonic anhydride with a ketone derivative of general formula (V) (Org. Synth., 1
990, p. 116); then, the general formula Ar-B, wherein Ar is as defined above.
(Stillation reaction (Tetrahedron Lett., 1979, p. 3437)) with an arylboronic acid of (OH) ₂ or with an arylstannane of the general formula Ar—SnMe ₃ where Ar is as defined above (Angew. Chem. Int. Ed. Engl., 1986, p. 508)) The arylethylene intermediate of the general formula (VI) is obtained by a palladium coupling reaction, which is subjected to a Friedel-Crafts type intramolecular cyclization. To obtain the expected product (III).

Typically, the ketone derivative of the general formula (V) is treated with a 3 to 20 molar equivalent excess of hydrazine hydrate for several minutes to several hours in a solvent such as ethanol at reflux temperature. next,
The hydrazone thus obtained is stirred with excess iodine for several hours at a temperature near 20 ° C. in the presence of an aliphatic tertiary amine such as triethylamine to obtain an iodoethylene derivative.

Typically, the ketone derivative of the general formula (V) is converted to 2,6-di-tert in an organic solvent such as dichloromethane at a temperature near room temperature according to Sang (Synthesis, 1980, p. 283). Trifluoromethanesulfonic anhydride in the presence of an organic base such as -butyl-4-methylpyridine, or in an organic solvent such as dichloromethane or 1,2-dimethoxyethane in the presence of a base such as lithium diisopropylamide. , Bis (trifluoromethylsulfonyl) amide, such as MacMurry (Tetrahedro)
n Lett. 1983, p. 997), N, N-bis (trifluoromethylsulfonyl) aniline or Comins (Tetrahedron).
Lett. 1992, p. Treatment with 2- [N, N-bis (trifluoromethylsulfonyl) amino] pyridine according to 979) gives the enol triflate.

Typically, the coupling between the iodoethylene derivative or enol triflate obtained above and the arylboronic acid conventionally obtained and optionally isolated in trimer anhydride form is carried out at a temperature near the reflux temperature, A catalytic amount of a palladium (0) derivative,
Performed by stirring for several hours in a two-phase system consisting of an organic solvent, preferably a mixture of toluene and methanol, and a basic aqueous solution, preferably a 2N sodium carbonate solution, preferably in the presence of tetrakis (triphenylphosphine) palladium. Thus, an arylethylene compound of the general formula (VI) is obtained.

Typically, the coupling between the iodoethylene derivative or enol triflate obtained above and the arylstannane conventionally obtained is carried out at a temperature between 50 ° C. and 100 ° C., in a catalytic amount of a palladium (0) derivative, The stirring is carried out for several hours in a polar aprotic organic solvent, preferably dimethylformamide or N-methylpyrrolidone, preferably in the presence of tetrakis (triphenylphosphine) palladium, to give the arylethylene of the general formula (VI) Obtain the compound.

Typically, a Friedel-Crafts intramolecular cyclization of a compound of general formula (VI) to a product of general formula (III) is preferred for intramolecular cyclization of a product of general formula (IV). Performed under the conditions described above.

Advantageously, in the context of the present invention, the compounds of the general formula (VI) which can optionally be isolated
From the compound of general formula (V) via the formation of an intermediate of general formula (V) as defined above (
A second production method has also been developed which makes it possible to obtain the compounds of III). This second method is characterized in that the aryl residue Ar is a phenyl ring, optionally substituted in the para or meta-para or meta-para-meta position with an electron donating group, or is essentially electron rich. Most particularly useful when representing a heterocyclic residue or a heterocyclic residue suitably substituted with an electron donating group, this second method involves a Friedel-Crafts intermolecular and then intramolecular cyclization. In an organic solvent in the presence of an excess of a strong acid such as trifluoromethanesulfonic acid or optionally a Lewis acid such as aluminum chloride, with an aromatic or heterocyclic hydrocarbon in an organic solvent. It is to make Ar-H react directly.

The method developed involves the use of an excess of trifluoromethanesulfonic acid (from 5 to 20 molar equivalents) in an organic solvent such as dichloromethane at a temperature near room temperature with the general formula (
V) consists in coupling the product of (I) for several hours to several days. Depending on the molar equivalent number and concentration of trifluoromethanesulfonic acid and the nature of the residue Ar and the substituents it carries, this reaction leads directly to compounds of the general formula (III) or to intermediate compounds of the general formula (VI), Next, it is cyclized to the compound of general formula (III) as described above.

Further, without limitation, a functional group substitution reaction (eg, replacement of a halogen atom with a cyano group by palladium coupling), a dealkylation reaction (eg, with BBr ₃ ), an alkylation reaction (particularly, BBr ₂₎ The compound of general formula (I) or (III) is converted to a compound of general formula (I) or (III) by applying or adapting a known method for general functionalization such as an alkylation-cyclization reaction by the action of A) the aromatic ring A of the corresponding compound
It can be obtained by functionalizing the substituent of r.

Another subject of the present invention is a compound represented by the general formula (VI):

[0077]

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Wherein R ₃ , Het and Ar are as defined in general formula I, G ₁ represents a benzyl residue, and R ₄ represents an alkyl residue containing 1-4 carbon atoms. It also relates to these compounds and their salts in the form of the racemate of or the optical isomers or mixtures of the optical isomers of

General formula:

[0080]

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Wherein Het, R ₃ and R ₄ are as defined above. For a cyclohexenone derivative of the formula, N-trialkyl bearing a protecting group for an amine function, such as a benzyl residue. Silylmethyl-N-alkoxy-methylamine, for example, Chem. Pharm. Bull. R ₃ , R ₄ , Het and Ar are reacted with N-trimethylsilylmethyl-Nn-butoxymethylbenzylamine, which can be prepared under the conditions described in And the product of general formula (V), wherein G ₁ represents a benzyl residue, can be obtained.

The reaction is typically carried out in an organic solvent such as a halogenated aliphatic hydrocarbon, for example dichloromethane, at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, in the presence of a strong acid such as trifluoroacetic acid. I do.

An aliphatic alcohol of the general formula R ₄ OH containing 1 to 4 carbon atoms in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid at a temperature between 0 ° C. and the reflux temperature of the reaction mixture. Using an alkyl halide (iodide) in the presence of an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene or an inorganic base such as cesium carbonate. And treating in a solvent selected from tetrahydrofuran, dimethylformamide, acetone and dioxane to obtain a compound of the general formula (VIII)

[0084]

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Wherein R ₃ and Het are as defined in general formula (I). The product of general formula (VII) can be obtained by esterification of the corresponding acid of

By heating to a temperature near 190 ° C. (J. Org. Chem., 197)
1, p. 3707), or by thermal dehydration by heating to the reflux temperature of toluene in the presence of p-toluenesulfonic acid, or by dehydration in an acidic medium in a solvent such as THF, especially in the presence of hydrochloric acid, or At a temperature between 0 and 50 ° C., by the action of an inorganic base such as sodium hydroxide, the general formula (IX)

[0087]

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Wherein Het and R ₃ are as defined above, 1- in the form of a racemate of or an optical isomer thereof or a mixture of optical isomers thereof
From cyclohexanol-1-carboxylic acid, 1-cyclohexene-1-carboxylic acid of general formula (VIII) wherein Het and R ₃ are as defined above can be obtained.

Methyl vinyl ketone and general formula (X)

[0090]

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Wherein Het and R ₃ are as defined above, by the action of the heteroarylpyruvic acid or optionally the corresponding ester
It is possible to obtain acids of the general formula (IX) in which Het and R ₃ are as defined above, usually in the presence of an inorganic base such as sodium hydroxide (according to J. Org. Chem., 1971, 3707). Below, it is treated in an aqueous-alcoholic medium such as a methanol-water mixture.

Org. Synth. , 1943, p. By heating in hydrochloric acid according to 519,

[0093]

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Wherein Het is as defined above, hydrolyzing the corresponding α-acetamidovinyl acid; or Synth. Coll. Vol. V, p. According to 627, 2
By heating in 0% sodium hydroxide, general formula (XII)

[0095]

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Wherein Het is as defined above. By hydrolysis of the corresponding hydantoin of formula ( _III ), a heteroarylpyruvic acid of general formula (X) wherein R ₃ represents a hydrogen atom can be obtained.

By the action of N-acetylglycine in acetic anhydride refluxed in the presence of sodium acetate, Org. Synth. 1939, p. According to the general formula (XIII)

[0098]

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Wherein Het is as defined above, from which the α-acetamidovinyl acid of general formula (XI) can be obtained from the corresponding aldehyde. Next, the intermediate azlactone thus obtained is hydrolyzed to the corresponding α-acetamidovinyl acid by refluxing in acetone water.

The Org. Synth. Coll. Vol. V, p. According to 267, 130
The hydantoin of general formula (XII) can be obtained by heating the hydantoin and the corresponding aldehyde of general formula (XIII) in the presence of an organic base such as piperidine at a temperature around ℃.

An alkyl oxalate such as ethyl oxalate and a compound of the formula (XIV) in the presence of an organic base such as n-butyllithium at a temperature near -70 ° C.

[0102]

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Wherein Het is as defined above, and R ₃ represents the corresponding carboxylic acid of an alkyl or alkylthio residue, followed by Tetrahedron Lett
. Can be obtained by decarboxylation of processing under the conditions described in 1981,2439-42 general formula R ₃ represents an alkyl or alkylthio residue heteroarylene Rupirubin acid ester (X).

Esterification and amidation under the conditions described above, followed by cyclization under the conditions described above under the action of trifluoromethanesulfonic acid, the product of general formula (IV) in which R represents a carboxyl residue From general formula (III)

[0105]

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Where Het, Ar, R ₃ and G ₁ are as defined above, and R represents the residue —CO—Z, where: Z is the residue —OR ₄ or —N ( R ₅ ) (R ₆ ) can be obtained.

Also according to the invention, Het, Ar, R ₁ , R ₂ , R ₃ and X are as defined above, and R represents the residue COOR ₄ , wherein R ₄ is Are obtained from the product of general formula (V) wherein Het, R ₃ and R ₄ are as defined above, and G ₁ represents a hydrogen atom. You can also.

According to the present invention, the compound represented by the general formula (V)

[0109]

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[0110] In the formula, G ₁ represents a hydrogen atom, a product of, starting from the product of general formula (III) where G ₁ is represents a protecting group of the amine function, general G ₁ is hydrogen Under the conditions described above for the preparation of the product of the formula (III), it is obtained from the product of the general formula (V), wherein G ₁ represents a protecting group for the amine function.

By treating as follows, the product of general formula (V) in which G ₁ represents a hydrogen atom is converted to a compound of general formula (XV):

[0112]

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Wherein Het, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, converted into the product of the general formula (III) in which G ₁ represents a hydrogen atom Under the conditions described above for the action of the product of general formula (II) on the product of formula (II), the acid of general formula (II) on the product of general formula (V) wherein G ₁ represents a hydrogen atom or The product of the general formula (XV) can be obtained by the action of the chloride or anhydride.

Treatment under the conditions described above for the action of the organomagnesium or organolithium derivative of the general formula Ar-Mg-X or Ar-Li on the product of the general formula (V), General formula Ar- in which X represents a halogen atom with respect to the product
By reacting a metal derivative of Mg-X or Ar-Li, the compound represented by the general formula (XV
) Of the general formula (XVI):

[0115]

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Wherein Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above, converted to the product

Treatment under the conditions described above for the effect of trifluoromethanesulfonic acid or Lewis acid on the product of general formula (IV), the trifluoromethanesulfonic acid or Lewis acid on product of general formula (XVI) By the action, general formula (XVI)
Is converted to a product of general formula (I) wherein Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above.

In the presence of trifluoromethanesulfonic acid or Lewis acid, aromatic carbonization to products of general formula (XV) wherein Het, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined above by the action of the aromatic heterocyclic Ar-H, as defined hydrogen or above, Ar is as defined above, and R represents a residue -COOR _4, wherein, R ₄ is 1-4 To obtain a product of the general formula (I) which represents an alkyl residue having the carbon atom of

The reaction mixtures obtained by the various methods described above may be combined with standard physical methods (eg,
Treatment by evaporation, extraction, distillation, chromatography or crystallization) or by chemical methods (eg salt formation).

Optionally, the compounds of general formula (I) can also be converted into addition salts with such acids by the action of inorganic or organic acids in organic solvents such as alcohols, ketones, ethers or chlorinated solvents. Good. These salts also form part of the invention.

The optical isomers of the products of the general formula (I) can be obtained from the corresponding racemic products by customary separation methods. It is particularly advantageous to perform the separation by high performance liquid chromatography using a modified Pirkle-type chiral stationary phase, eluting with a suitable solvent.

Preferably, the aminoalkyl arm containing 3 to 14 carbon atoms attached to the amine function of the aminopropyl silica allows a chiral selector, preferably 3,5-dinitrophenylalanine, to be spaced from the silica. A phase that is arranged and blocks the free silanol functionality with a trialkylsilyl residue can be used as the chiral stationary phase.

The chiral phase has the following structure:

[0124]

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Wherein the symbols R ′, which may be the same or different, and R ″, which may be the same or different,
Represents an alkyl residue containing 10 carbon atoms, G ₃ represents an electron withdrawing group, and n represents an integer between 3 and 13, inclusive, which can be defined by The porosity is about 100 °.

Reacting an anhydride of an aminoalkanoic acid containing 4 to 14 carbon atoms, on which the amine function is protected with a protecting group such as a tert-butoxycarbonyl residue, on aminopropyl silica, Subsequently, the residue Si (R ′) as defined above
_3. ) Block some of the silanol functionalities by ₃ and then remove the protecting groups of the amine functionalities, then use the general formula:

[0127]

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Where G_ThreeIs as defined above, amidated with the amino acid of and finally residues Si (R ″) as defined above _Three A chiral phase can be prepared by blocking the remaining silanol functional groups with.

Typically, the action of the anhydride of the protected aminoalkanoic acid on aminopropyl silica is carried out by treating in an anhydrous organic solvent such as dimethylformamide at a temperature near 20 ° C.

Halot to aminopropyl silica grafted with aminoalkanoyl residue
In the presence of a basic agent such as pyridine,
Treatment in an organic solvent such as styrene, the group -Si (R ') as defined above _Three The blocking of the silanol functional group is carried out.

When the protecting group is a tert-butoxycarbonyl residue, removal of the protecting group from the aminoalkanoyl residue is usually carried out by the action of trifluoroacetic acid in an organic solvent such as methylene chloride.

The amidation with phenylalanine, whose amine function is protected, can be carried out in the presence of a coupling agent, such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, with an anhydrous organic compound, such as dimethylformamide. The treatment is carried out in a solvent.

Typically, the blocking of the remaining silanol function at the residue -Si (R ") ₃ as defined above is treated with a trialkylsilyl imidazole in an organic solvent such as methylene chloride. carry out.

Aminopropyl silica is prepared by the action of aminopropyltriethoxysilane on silica having a porosity of about 100 ° by treatment in the presence of an imidazole in an anhydrous organic solvent such as an aromatic hydrocarbon, for example toluene. be able to.

As shown by the examples below, farnesyltransferase and / or
Or the novel products of general formula (I) which inhibit the farnesylation of Ras proteins have remarkable anti-cancer and anti-leukemic properties.

Also, the subject of the present invention, whether inert or biologically active, is a compound of the general formula (I) in combination with one or more pharmaceutically acceptable diluents or adjuvants.
Any pharmaceutical composition containing at least one product of I).

The novel products of the general formula (I) may be in the form of non-toxic and pharmaceutically acceptable salts. Depending on the nature of the compound of general formula (I), these non-toxic salts can be inorganic acids (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid) or organic acids (acetic acid, propionic acid, succinic acid, maleic acid, With hydroxymaleic acid, benzoic acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid or oxalic acid) or with an inorganic base (sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium oxide) or an organic base (tertiary amine, (Eg, triethylamine, piperidine, benzylamine).

The present invention also provides a compound of the general formula (I) for the manufacture of a pharmaceutical composition useful for inhibiting farnesyltransferase, more specifically for inhibiting farnesylation of the ras oncogene. It also relates to the use of the compounds of I).

In particular, the invention relates to treating diseases associated with cell proliferation by inhibiting farnesyltransferase, in particular overexpressing any of the oncoproteins H-Ras, N-Ras or K-Ras or The present invention relates to the use of a compound of general formula (I) according to the invention for the manufacture of a pharmaceutical composition useful for treating diseases associated with cell proliferation, exhibiting any mutation of the corresponding ras oncogene. .

The present invention particularly includes muscle, bone or connective tissue, skin, brain, lung, genital, lymphatic or renal systems, milk or blood cells, liver, digestive system, colon, pancreas and thyroid or adrenal glands And the following pathologies: psoriasis, restenosis, solid tumor, Kaposi's sarcoma, cancer, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma,
Such as teratocarcinoma, glioma, multiple myeloma, chronic lymphocytic leukemia, acute or chronic granulocytic lymphoma and cancer of the pancreas, colon, lung, ovary, breast, brain, prostate, liver, stomach, bladder or testis General formula (I) of the present invention for the manufacture of a pharmaceutical composition useful for the treatment of diseases associated with malignant or benign cell proliferation of cells of various tissues and / or organs, including various cancers The use of the compound of

The invention relates most particularly to pancreas, colon, lung, ovary, breast, brain, prostate, liver, stomach,
Use of a compound of general formula (I) of the present invention for the manufacture of a pharmaceutical composition useful for the treatment of cancer such as bladder or testicular cancer, more preferably colon and pancreas, especially colon cancer. About use.

The compounds of the present invention are also useful for the manufacture of a medicament for the treatment and / or prevention of a pathological disorder associated with a cell signaling pathway associated with farnesyltransferase or their consequences or symptoms. there is a possibility.

Conveniently, the compounds of the present invention can be used for the manufacture of a medicament for the treatment and / or prevention of a disease associated with a cellular signaling pathway associated with Ras. Thus, the compounds of the invention can be used for the manufacture of a medicament in the treatment and / or prevention of graft rejection (such as allografts) (O'Donne)
1 et al., 1995, Kidney International, Vol. 48,
suppl. 52, p. S. 29-33).

The compounds of the present invention may also be useful for the manufacture of a medicament for inhibiting angiogenesis and acting on tumor growth (J. Rak et al., Cancer research, 55, 4575). -4580, 1995), these anti-angiogenic properties are also potentially useful for the treatment of certain forms of blindness associated with retinal neovascularization.

The compounds of the invention may also include-especially those comprising the above-mentioned cancers [pro-or-anti-
)] Diseases associated with apoptotic dysfunction;-Delta hepatitis and related viruses (JS Glenn et al., Science, 25).
6, 1331-1333, 1992), and without limitation, herpes virus,
Poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus;-for example, polyarthritis, polyarticular rheumatism, intestinal inflammation, pulmonary edema, myocardial infarction, fibrosis, lupus erythema such as Kaposi's disease, immunity- Inflammatory and / or autoimmune diseases such as glomerulonephritis and autoimmune diabetes;-cardiovascular disease (arteriosclerosis or other arterial damage), restenosis after angioplasty or vascular surgery;-bone disease, Regulation of bone metabolism, such as Paget's disease, hypercalcemia, bone metastases, osteoporosis;-hypercholesterolemia, hyperlipidemia, hyperproteinemia (hyperpopr)
oteinemia), nephrotic hyperlipidemia or atherosclerosis (Ma
diseases associated with high cholesterol levels, such as ssy et al., Lancet, 347, 102-103, 1996);-neurons associated with viral diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS. Biological diseases, neurodegenerative diseases such as retinitis, cerebral spinal cord atrophy or degeneration; for the treatment and / or prevention of the following diseases: in particular AIDS, and cystic kidney (
D. L. Schaffner et al., American Journal of P.
theory, 142, 1051-1060, 1993), neurofibromatosis,
Pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, scarring crabfoot formation and endotoxin shock; and myelodysplastic syndrome
es), dysplasia anemia, ischemic injury associated with infarction, injury associated with cerebrovascular disease, and arrhythmia, atherosclerosis, liver disease due to toxins or alcohol,
Hematological diseases including chronic or dysplastic anemia, especially musculoskeletal degenerative diseases including osteoporosis and arthritis, cystic fibrosis, multiple sclerosis, liver disease, cancer-related pain and aspirin Susceptible sinusitis (rhinosinusit)
It may also be useful for the manufacture of a medicament for the treatment and / or prevention of is).

The treatment can be carried out in particular by inhibiting tumor growth, in particular by inhibiting farnesyltransferase, or alternatively by inhibiting the growth of tumors that express an activated ras oncogene.

Another subject of the invention is a compound of formula (I) comprising one or more compatible and pharmacologically active compounds and / or radiation therapy treatments, in particular for simultaneous, separate or staggered administration. And the compounds are preferably active ingredients whose inhibitory activity on cell proliferation, in particular their activity in the treatment of cancer, is known; they are preferably tyrosine kinases. Inhibitor or another farnesyltransferase inhibitor or HMG-C
It may be an antiproliferative compound that acts at any stage of the ras oncogene signaling pathway, such as an o-reductase inhibitor, or a cytotoxic compound commonly used to treat cancer.

In particular, other therapeutic treatments and / or products that can be used in combination with the products of general formula (I) include antitumor agents, monoclonal antibodies, immunotherapy or radiation therapy or biological response modulation You can choose from substances. Response modifiers include, without limitation, interleukins, interferons (α, β or δ) and lymphokines and cytokines such as TNF. Other chemotherapeutic agents useful in the treatment of diseases due to abnormal cell proliferation include, without limitation, alkylating agents such as nitrogen mustards, e.g., mechlorethamine,
Cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates,
E.g. busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocin, triazenes such as dacarbazine, metabolic inhibitors,
For example, folate analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and thioguanine, natural products such as vinca alkaloids, such as vinblastine, vincristine and bendesin, taxoid derivatives, camptothecin derivatives Such topoisomerase inhibitors, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L
-Asparaginase, various drugs such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, corticosteroid inhibitors such as mitotene and aminoglutethimide, hormones and antagonists Corticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, estrogens such as diethylstilbestrol and ethinyl estradiol, antiestrogens such as tamoxifen, and androgens For example, testosterone propionate and fluoxymesterone.

The products of the present invention can be used to prevent or delay the onset or recurrence of pathological diseases or to treat these pathological diseases.

The products of the present invention can be administered orally, parenterally, intraperitoneally or rectally, preferably orally.

Compositions for oral administration comprise tablets, pills, powders or granules. In these compositions, the active products of the present invention are mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can comprise substances other than diluents, for example, lubricating agents such as magnesium stearate.

Using a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir containing water or an inert diluent such as liquid paraffin as a liquid composition for oral administration Can be. These compositions may also comprise substances other than diluents, for example wetting agents, sweetening or flavoring products.

The compositions of the present invention for parenteral administration may be sterile aqueous or non-aqueous solutions, suspensions or emulsions. Propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, such as ethyl oleate, can be used as the solvent or vehicle. These compositions may also contain adjuvants, especially wetting agents, emulsifiers and dispersing aids. Sterilization can be performed in a number of ways, for example, using a bacterial filter, by including a sterilizing agent in the composition, or by heating. They can also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other sterile injectable medium before use.

Compositions for rectal administration are suppositories, which may contain, in addition to the active product, excipients such as cocoa butter.

The dosage used to practice the methods of the present invention is that which allows for prophylactic treatment or maximal therapeutic response. Dosage will vary depending on the mode of administration, the particular product chosen and the individual characteristics of the individual to be treated. Generally, the dosage will be therapeutically effective for the treatment of disease due to abnormal cell proliferation, especially for cytostatic treatment. The products of the present invention can be administered as many times and as long as necessary to obtain the appropriate therapeutic effect.

In general, for humans, the dosage will preferably be 0.1 mg per day, preferably by the oral route.
To 10,000 mg / kg, preferably 100 to 200 per day.
Between 0 mg / kg. To select the most appropriate dosage, the route of administration,
It turns out that the patient's weight, general health and age, as well as any factors that may influence the efficacy of the treatment, must be taken into account.

Typically, a physician will determine the appropriate dosage as a function of the patient's age and weight, as well as any other factors relevant to the individual to be treated.

Example C illustrates a composition of the present invention.

The following examples are given as non-limiting examples of the present invention. Example 1a (3aRS, 4SR, 8SR, 8aRS) -4,8- ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- phenyl -2,3,3a, 4,8,8 a- hexahydro -1H- thieno [2,3-f] isoindole -3a- carboxymethyl phosphate methyl manufacturing process a 16.8 g (0.28 mol) of dry acetic anhydride in 75 cm ³ of sodium acetate 45.77G ( 0.4 mol) of 3-thiophenecarboxaldehyde and 33.43 g of (3-thiophenecarboxaldehyde).
0.28 mol) of a solution of N-acetylglycine in Org. Synth. , II,
Heat at 100 ° C. for 1 hour under the conditions described in 1-3, then bring the mixture to 0 ° C.
Allow to cool overnight at nearby temperature. The crystals formed are separated by filtration, thus giving 42.8 g of beige-coloured crystals, which are refluxed for 4 hours in 150 cm ³ of water and 400 cm ³ of acetone. After cooling, the solvent is evaporated off under reduced pressure and the residue is purified by recrystallization from 350 cm ³ of water. Thus, 33.79 g (39%) of 1-acetylamino-3- (3-thienyl)
-2-propenoic acid is obtained in the form of fine yellow crystals, the properties of which are as follows: Melting point = 228 ° C.

Step B 33.78 g (89 mmol) of 1-acetylamino-3- (3-thienyl) -2-propenoic acid in 360 cm ³ of 1 N aqueous hydrochloric acid was added to Org. Synth. ,
Reflux for 4 hours under the conditions described in II, 519-20. After heating for 3 hours, crystals form and after cooling to 0 ° C. they are filtered off. In this way, 22.4 g (99%) of (3-thienyl) pyruvic acid are obtained in the form of fine white crystals, the properties of which are as follows: melting point = 203-4 ° C. mass spectrum (EI) ): M / Z = 170 (M ⁺ ).

Step C To a cooled solution of 22.4 g (13 mmol) of (3-thienyl) pyruvic acid in 150 cm ³ of methanol at 0 ° C., 17.1 cm ³ (21 mmol) of methyl vinyl ketone and 7.2 g (18 mmol) of The sodium hydroxide pellets are added continuously, and the mixture is then stirred at a temperature near 20 ° C. for 2 hours. After neutralization with 60 cm ³ of 3N aqueous hydrochloric acid, the precipitate formed is separated by filtration, washed with water and then
Dry at 20 ° C. In this way, 21.85 g (70%) of 6- (3-thienyl) -3-oxo-1-cyclohexanol-1-carboxylic acid are obtained in the form of a yellow powder, the properties of which are as follows: :-Melting point = 204 ° C- ¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO-d ₆ with addition of a few drops of CD ₃ COOD-d ₄ , δ in ppm): 2.20 to 2.80 (Mt, 4H: CH ₂ CH ₂ ); 2.34 and 3.00 (2d, J = 14 Hz, 1H: C each)
_{OCH 2); 3.66 (dd,} J = 12.5 and 3Hz, 1H: ArCH); 7 . 06 (d, J = 5 Hz, 1H: H of thienyl 4); 7.24 (wide d, J =
7.36 (dd, J = 5 and 3 Hz, 1H, 3 Hz, 1H: 2H of thienyl)
: 5H of thienyl).

Step D 21.84 g (9.1 mmol) of 6- (3-thienyl) -3-oxo-1-
The cyclohexanol-1-carboxylic acid is refluxed for 3 hours in 220 cm ³ of toluene in the presence of 2.2 g of para-toluenesulfonic acid. The reaction mixture is then cooled to 5 ° C., the precipitate formed is separated by filtration, washed with isopropyl ether and then dried at 50 ° C. Thus, 18.47 g (9) containing mainly (RS) -6- (3-thienyl) -3-oxo-1-cyclohexenecarboxylic acid.
1%) is obtained in the form of a brown solid, which is used without further purification in the next step, the properties of the product are as follows:-Mass spectrum (EI): M / Z = 222 (M ⁺ ).

Step E A solution of 18.45 g (8.3 mmol) of (RS) -6- (3-thienyl) -3-oxo-1-cyclohexenecarboxylic acid in 250 cm ³ of dry acetone was added.
. 5 cm ³ (12 mmol) of methyl iodide and 16.8 cm ³ (11.2 mol)
) Of 1,8-diazabicyclo [5.4.0] undec-7-ene is added dropwise continuously, after which the mixture is refluxed for 2 hours 30 minutes. After the insoluble material has been filtered off while hot and the solvent concentrated under reduced pressure, the residue is separated on silica gel (
Purify by flash chromatography (230-400 mesh) and elute with dichloromethane. Thus, 14.84 g (76%) of (RS) -6.
Methyl-(2-thienyl) -3-oxo-1-cyclohexenecarboxylate is obtained in the form of a yellow powder, the properties of which are as follows:-Melting point = 69 ° C-Mass spectrum (EI): M / Z = 236 (M ⁺ ) ¹ H NMR spectrum (250 MHz, CDCl ₃ , δ in ppm): 05 from to _{2.55 (mt, 4H: CH 2} CH 2); 3.77 (s, 3H: CO
_{OCH 3); 4.33 (mt,} 1H: ArCH); 6.85 (s, 1H: = CH); 6.91 (dd, J = 2.5 and 2Hz, 1H: 2 of H thienyl); 6.
99 (dd, J = 5 and 2 Hz, 1H: H of thienyl 4); 7.34 (dd,
J = 5 and 2.5 Hz, 1H: H of thienyl 5).

Step F 100 cm^Three9.15 g (3.9 mmol) of methyl (RS) -6- (3-thienyl) -3-oxo-1-cyclohexenecarboxylate in dichloromethane
3.56 cm^ThreeA solution of (4.6 mmol) trifluoroacetic acid is refluxed. Next, Chem. Pharm. Bull. , 1985, 276.
16.9 g (6 mmol) of Nn-butoxymethyl-N-trimethyl
Lylmethylbenzylamine is added dropwise and the mixture is refluxed for 1 hour 30 minutes.
You. The reaction medium is then stirred at room temperature for a further 3 hours. About 25g of potassium carbonate
After stirring for 1 hour, the organic phase was concentrated and the resulting yellow oil was purified on silica gel (230
-400 mesh) and purified by chromatography on dichloromethane / acetic acid.
Elute with an ethyl mixture (99/1 by volume). Thus, 10.25 g (7
1%) of (3aRS, 4SR, 7aRS) -2-benzyl-4- (3-thienyl
) -7-oxooctahydroisoindole-3a-carboxylate is about 35
Obtained in the form of a beige colored solid melting at -40 ° C,
The properties are as follows:-Mass spectrum (EI): M / Z = 369 (M⁺)-¹1 H NMR spectrum (300 MHz, CDCl_Three, Δ in ppm): 2. 10 and 2.45 to 2.705 (2 mts, 1H and 3H: CH, respectively) _Two CH_Two); 2.70 and 2.90 (2d, J = 9.5 Hz, 1H: 3 CH each)_Two ); 2.85 and 3.08 (t and dd, respectively, J = 9.5 Hz and J = 9
. 5 and 5.5 Hz, each 1H: 1 CH_Two); 3.34 (dd, J = 9.5 and 5.5 Hz, 1H: 7a CH); 3.30 to 3.40 (mt, 1H: 4
CH); 3.49 (s, 3H: COOCH_Three); 3.58 and 3.70 (2d, J = 13.5 Hz, 1H for each: NCH_TwoAr); 6.78 (dd, J = 5 and 1.5 Hz, 1H: H of thienyl 4); 6.89 (dd, J = 3 and 1.5 Hz)
1H: 2H of thienyl; 7.22 (dd, J = 5 and 3 Hz, 1H: thienyl
7.20 to 7.40 (mt, 5H: benzylic aromatic H)
).

Step G 20 cm ³ of toluene are added to 7 cm ³ of a 3M solution of phenylmagnesium bromide in diethyl ether and the diethyl ether is evaporated off under reduced pressure. After cooling to 5 ° C., 2.58 g (7 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-4- (3-thienyl) -7-oxooctahydroisoindole-3a-carboxy in 10 cm ³ of toluene. A solution of methyl acid is added dropwise and the mixture is stirred at room temperature for 20 hours. After cooling to 0 ° C., the mixture is hydrolyzed by addition of 50 cm ³ of a saturated aqueous solution of ammonium chloride. The organic phase was separated out after settling, saturated aqueous ammonium chloride solution of 10 cm ^3, then washed successively with 2 times water 10 cm ^3, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), eluting with a cyclohexane / ethyl acetate mixture (80/20 by volume). Thus, 1.28 g (52%) of (3aRS, 4SR, 7RS, 7aRS)-
Methyl 2-benzyl-7-hydroxy-7-phenyl-4- (3-thienyl) -octahydroisoindole-3a-carboxylate is obtained in the form of a yellow powder, the properties of which are as follows: = 120 ° C-mass spectrum (EI): M / Z = 447 (M ⁺ ).

Step H 8 cm^Three0.72 g (1.6 mmol) of (3aRS, 4 SR, 7RS, 7aRS) -2-benzyl-7-hydroxy-7-phenyl-4 in dichloromethane.
Dissolution of methyl 3- (3-thienyl) octahydroisoindole-3a-carboxylate
0.8cm in liquid^Three(10.4 mmol) of trifluoromethanesulfonic acid are added. After stirring for 4 hours at room temperature, the reaction medium is cooled to 5 ° C. and^ThreeDiluted with dichloromethane, 5 cm^ThreeOf saturated potassium carbonate. After settling, the organic phase is separated off, washed with water, dried over sodium sulfate and then stirred for 15 minutes in the presence of 10 g of silica gel (230-400 mesh).
I do. After concentrating the solvent under reduced pressure, 680 mg (94%) of (3
aRS, 4SR, 8SR, 8aRS) -2-benzyl-4,8-ethano-8-fu
Enyl-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-
f] Methyl isoindole-3a-carboxylate is obtained in the form of a pale yellow powder,
Its properties are as follows:-Melting point = 80 ° C-¹1 H NMR spectrum (400 MHz, CDCl_Three, Δ in ppm): 1. 38-1.62-2.43 and 2.57 (4 mts, each 1H: CH_TwoCH_Two2.27 and 2.72 (t and wide d respectively, J = 9 Hz, 1H: 1 CH each) _Two ); 2.27 and 3.14 (2d, J = 10 Hz, 1H: 3 CH each)_Two); 3.
20 (wide d, J = 9 Hz, 1H: 8a CH); 3.38 and 3.67 (2d
, J = 13 Hz, each 1H: NCH_TwoAr); 3.59 (s, 3H: COOCH_Three)
3.64 (mt, 1H: 4 CH); 6.88 (d, J = 5 Hz, 1H: 5
H); 6.94 (d, J = 5 Hz, 1H: H of 6); 7.20 to 7.65
(Mt, 10H, benzyl aromatic H and phenyl aromatic H).

Step I 645 mg (1.5 mmol) of (3aRS, 4SR, 8SR, 8aRS)-
2-benzyl-4,8-ethano-8-phenyl-2,3,3a, 4,8,8a-
Stir methylhexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate and 0.2 cm ³ (3 mmol) of vinyl chloroformate in 10 cm ³ of dichloromethane at room temperature for 20 hours. After evaporation of the dichloromethane, the residue is stirred for 2 hours at reflux in 5M solution 3c m ³ of hydrogen chloride gas in methanol and isopropanol 7 cm ^3. After concentrating the solvent under reduced pressure, 20 cm ³ of a saturated aqueous solution of sodium carbonate are added and the mixture is extracted three times with 20 cm ³ of dichloromethane. The combined organic phases are washed with water, dried over magnesium sulphate and concentrated under reduced pressure, thus giving 460 mg (90%) of impure (3aRS, 4SR,
8SR, 8aRS) -4,8-ethano-8-phenyl-2,3,3a, 4,8,
Methyl 8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a brown oil which is used without further purification in the next step and has the following properties: As follows: mass spectrum (EI): M / Z = 339 (M ⁺ ).

Step J 1.01 g (3 mmol) of (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-8-phenyl-2,3,3a, 4 in 30 cm ³ of dichloromethane.
8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-
To a solution of methyl carboxylate was added 710 mg (4 mmol) of 2- (2-methoxyphenyl) propenoic acid, 770 mg (4 mmol) of 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride and 50 mg (0. 4 mmol)
N-hydroxybenzotriazole hydrate is added continuously. After stirring overnight at room temperature, 15 cm ³ of dichloromethane are added, the mixture is washed twice with 15 cm ³ of water, dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. Silica gel (23) was eluted with a cyclohexane / ethyl acetate mixture (80/20 by volume).
(0-400 mesh) by flash chromatography, and after concentrating the solvent under reduced pressure, 550 mg (40%) of (3aRS, 4SR, 8SR).
, 8aRS) -4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-phenyl-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3- f] Methyl isoindole-3a-carboxylate is obtained in the form of a white powder, the properties of which are as follows: melting point = 171 ° C. mass spectrum (EI): M / Z = 499 (M ⁺ ).

Example 1b: (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2 -methoxyphenyl) propenoyl] -8-phenyl-2,3,3a, 4,8 , 8 a- hexahydro -1H- thieno [2,3-f] production of isoindole -3a- carbonitrile phosphate 380mg of (0.66mmol) (3aRS, 4SR, 8SR, 8aRS)
-4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
Phenyl-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3
-F] Methyl isoindole-3a-carboxylate is refluxed for 4 hours in 30 cm ³ of ethanol in the presence of 30 cm ³ of a 1/10 normal aqueous sodium hydroxide solution. Then the reaction mixture is concentrated under reduced pressure and the residue is dissolved in 25 cm ³ of distilled water. The aqueous phase is washed three times with 10 cm ³ of diethyl ether and then acidified with 1N aqueous hydrochloric acid to a pH of about 2 in the presence of 20 cm ³ of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by recrystallization from 10 cm ³ of 50% aqueous ethanol. Thus, 160 mg (
50%) of (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [
2- (2-methoxyphenyl) propenoyl] -8-phenyl-2,3,3a,
4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3
The a-carboxylic acid is obtained in the form of a white solid, the properties of which are as follows: Melting point = 175 ° C. ¹ H NMR spectrum (250 MHz, (CD ₃ ) ₂ SO-d ₆ , at a temperature of 393 K). , Ppm in ppm): 1.36-1.55 and from 2.00 to 2.20 (
3 mts, respectively IH-IH and 2H: CH ₂ CH _2), 3.20 from to 3.5 0 (mt, CH of 3H, 1 of CH ₂ and 8a); 3.53 and 4.03 (its Re 3.68 (wide s, 1H: 4 CH); 3.74 (s, 3H: ArOCH ₃ ); 5 each d and wide d, J = 12.5 Hz, each 1H: 3 CH ₂ ); .56 and 5.69 (2s, each 1H: = CH _2); 6.90 from to 7.55 (mt, 11 H: H aromatic H-5 aromatic H-2-methoxyphenyl phenyl and 6 H
).

Example 2 (3aRS, 4SR, 8SR, 8aRS) -4,8-Ethano-2- [2- (2 -methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3 Process A for the preparation of a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole- 3a-carboxylic acid A obtained in Step F of Example 1 in 50 cm ³ of methanol. 0.78 g (16 mmol) of methyl (3aRS, 4SR, 7aRS) -2-benzyl-4- (3-thienyl) -7-oxooctahydroisoindole-3a-carboxylate, and 3.13 g (63 mmol). Is refluxed for 2 hours.
After concentrating the methanol under reduced pressure, the residue is dissolved in 200 cm ³ of dichloromethane, washed four times with 10 cm ³ of distilled water, dried over magnesium sulfate and concentrated under reduced pressure. Thus, 5.72 g (93%) of (3aRS, 4SR, 7
aRS) -2-Benzyl-7-hydrazono-4- (3-thienyl) octahydroisoindole-3a-carboxylate is obtained in the form of an impure yellow oil which is obtained without further purification. The properties of the product are as follows: Mass spectrum (EI): M / Z = 383 (M ⁺ ).

Step B 200 cm^Three5.72 g (15 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-7-hydrazono-4- (3-thienyl) in tetrahydrofuran
) 100 cm in solution of methyl octahydroisoindole-3a-carboxylate^Three 7.58 g (30 mmol) of iodine in tetrahydrofuran and 6.27 cm ^Three A solution of (45 mmol) triethylamine is added dropwise and the reaction medium reaches a temperature of 28-30 ° C. Continue stirring for 2 hours while returning the temperature to about 20 ° C.
. 200cm^ThreeAfter addition of ethyl acetate, the organic phase is^ThreeNato bicarbonate
Twice with a saturated aqueous solution of lithium and then 100 cm^ThreeWash twice with a saturated aqueous solution of sodium thiosulfate, dry over magnesium sulfate and concentrate under reduced pressure. Cyclohexane
Elution with a gradient of 90 / ethyl acetate mixture (from 90/10 to 10/90 by volume)
By flash chromatography on silica gel (230-400 mesh)
After purification, 2.75 g (38%) of impure (3aRS, 4SR, 7aRS
) -2-Benzyl-7-iodo-4- (3-thienyl) -1,2,3,4,5
7a-Methyl hexahydroisoindole-3a-carboxylate is a dark brown oil.
The product is used in the next step without further purification and has the following properties:
Mass spectrum (EI): M / Z = 480 (M⁺).

Step C 9 cm^Three0.96 g (2 mmol) of (3aRS, 4SR, 7a RS) -2-benzyl-7-iodo-4- (3-thienyl) -1,2,3,4 in toluene.
Methyl 5,7a-hexahydroisoindole-3a-carboxylate and 0.1 g
(0.086 mmol) of tetrakis (triphenylphosphine) palladium
4cm in solution^ThreeSolution of 0.27 g (2 mmol) of 4-methylphenylboronic acid in methanol and 21 cm^ThreeOf a 2N aqueous sodium carbonate solution are added continuously, and the mixture is then refluxed for 2 hours. After cooling to room temperature, the reaction mixture is ^Three Extraction with ethyl acetate, 50 cm^ThreeWash twice with distilled water and use magnesium sulfate
Dry and then concentrate under reduced pressure. Thus 0.89 g (100%) of
Impure (3aRS, 4SR, 7aRS) -2-benzyl-7- (4-methyl
Phenyl) -4- (3-thienyl) -1,2,3,4,5,7a-hexahydro
Methyl isoindole-3a-carboxylate is obtained in the form of a yellow oil, which is
Used in the next step without further purification, its properties are as follows:-Mass spectrum (EI): M / Z = 443 (M⁺).

Step D 0.89 g (2 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-7- (4-methylphenyl) -4-in 10 cm ³ of dichloromethane kept at a temperature near 0 ° C. To a solution of methyl (3-thienyl) -1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate was added dropwise 1.08 cm ³ (14 mmol) of trifluoromethanesulfonic acid. I do. The reaction mixture was allowed to
Stir for hours and then cool to a temperature near 0 ° C. Next, 6 cm ³ of a saturated aqueous solution of potassium carbonate is added. After settling, the organic phase is separated off, washed successively three times with 10 cm ³ of distilled water and twice with 5 cm ³ of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. Silica gel (230-400 mesh) eluting with a cyclohexane / ethyl acetate mixture (85/15 by volume)
After purification by flash chromatography in this manner,
(57%) of (3aRS, 4SR, 8SR, 8aRS) -2-benzyl-4.8
Methyl-ethano-8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is about 35-40 Obtained in the form of a gray powder melting at 0 ° C., its properties are as follows: mass spectrum (EI): M / Z = 443 (M ⁺ ).

Step E Treat as in Step I of Example 1, but at room temperature for 4 hours, 1.58 g (3.5 mmol) of (3aRS, 4SR, 8SR, 20 mmol) in 20 cm ³ of dichloromethane.
8aRS) -2-benzyl-4.8-ethano-8- (4-methylphenyl) -2
, 3,3a, 4,8,8a-Methyl hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate and 0.45 cm ³ (6.9 mmol) of vinyl chloroformate. Subsequently, the solution was returned to reflux for 1 hour in 10 cm ³ of a 5N solution of hydrochloric acid gas in 20 cm ³ of methanol and isopropanol, neutralized with an aqueous saturated solution of potassium carbonate, extracted with dichloromethane, and then 1.3 g (92%). %) Of (3a
RS, 4SR, 8SR, 8aRS) -4.8-ethano-8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f
Methyl isoindole-3a-carboxylate is obtained in the form of a brown oil which is used without further purification in the next step and has the following properties:-Mass spectrum (EI): M / Z = 353 (M ⁺ ).

[0175] The procedure is as in Step F of Example 1, Step J, 20 hours at room temperature, a solution of 30 cm ³ 1.3 g of (3.7mmol) (3aRS, 4SR, 8SR,
8aRS) -4.8-Ethano-8- (4-methylphenyl) -2,3,3a, 4
, 8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a
Methyl carboxylate, 710 mg (4 mmol) of 2- (2-methoxyphenyl) propenoic acid, 770 mg (4 mmol) of 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride and 50 mg (0.4 mmol) ) N
-Purification by flash chromatography on silica gel (230-400 mesh), eluting with a cyclohexane / ethyl acetate mixture (85/15 by volume), starting from hydrated hydroxybenzotriazole, followed by recrystallization from pentane After that, 830 mg (40%) of (3aRS, 4SR, 8SR, 8aRS)-
4.8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (
Methyl 4- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a very pale yellow powder. , Its properties are as follows: melting point = 104 ° C. mass spectrum (EI): M / Z = 513 (M ⁺ ).

Step G Treat as in Example 1b but at reflux for 4 hours at reflux with 620 mg (1.2 mmol) of (3aRS, 4SR) in 50 cm ³ of ethanol and 50 cm ³ of a 1/10 normal aqueous sodium hydroxide solution. , 8SR, 8aRS) -4.8-Ethano-2-
[2- (2-methoxyphenyl) propenoyl] -8- (4-methylphenyl)
Starting from methyl 2,2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate, purified by crystallization from pentane, 310 mg (52 %) Of (3aRS, 4SR, 8SR, 8aRS)
-4.8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
(4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-
The thieno [2,3-f] isoindole-3a-carboxylic acid is obtained in the form of a very pale yellow powder, the characteristics of which are:-melting point = 176 ° C- ¹ H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO-d ₆ , δ in ppm at a temperature of 393 K: 1.34-1.53- and 1.95 to 2.10 (3 mts, 1H-1H and 2H: CH, respectively) _{2 CH 2); 2.38 (s} , 3H
: ArCH _3); 3.20 from to 3.50 (mt, 3H: CH 1 of CH ₂ and 8a); 3.53 and 4.01 (respectively d and broad d, J = 12.5 Hz, each 1H : 3 CH _2); 3.65 (broad s, IH: 4 of CH); 3.73 (s, 3 H: ArOCH 3); 5.54 and 5.68 (2 broad s, each IH: = CH ₂ ); 6
. 90 to 7.40 (mt, 10H: ortho- and meta-aromatic H-2-methoxyphenyl aromatic H-5 H and 6 H in 4-methylphenyl).

Example 3 (3aRS, 4SR, 8SR, 8aRS) -4.8-ethano-2- [2- (2 -methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3 a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole- 3a-carboxylic acid Isolation of the dextrorotatory enantiomer 12.86 g of the compound obtained in Example 2 ( 3aRS, 4SR, 8SR, 8a
RS) -4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl]
-8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-
1H-thieno [2,3-f] isoindole-3a-carboxylic acid is converted to (R) -N
-5 consecutive injections and elutions of an n-heptane / dichloromethane / ethanol mixture (50/50/1 by volume) containing 0.05% trifluoroacetic acid on a chiral silica bearing a (3,5-dinitrobenzoyl) phenylalanine graft To separate. The first fraction to be eluted (retention time of 28 minutes) is collected, and after concentrating the solvent under reduced pressure, 5.83 g of (3aRS, 4SR, 8SR, 8aRS)
-4.8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
(4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-
The dextrorotatory enantiomer of thieno [2,3-f] isoindole-3a-carboxylic acid is obtained in the form of a white powder, whose properties are as follows:-Mass spectrum (EI): M / Z = 499 (M ⁺ )-Optical rotation: [α] ₃₆₅ ²⁰ = +106.3 +/- 1.5 ° (c = 0.5 / methanol).

The chiral silica can be prepared as follows: 948 g of aminopropyl silica (100 @ -10 μm-NH ₂ ; Macherey-Nagel) is mixed with ³ dm ³ of N, N-dimethyl in a 6 dm ³ three-necked flask. Suspend in formamide. 180 g of N-tert-butoxycarbonylamino-11-undecanoic anhydride are added and the reaction mixture is stirred at a temperature near 20 ° C. for 18 hours. The silica is separated by filtration and washed successively twice with 2500 cm ³ of dichloromethane and then twice with 2500 cm ³ of N, N-dimethylformamide. The silica thus washed is resuspended in 3 liters of N, N-dimethylformamide and 180 g of anhydrous N-tert-butoxycarbonylamino-11-
Undecanoic acid is added, after which the reaction mixture is stirred at a temperature near 20 ° C. for 18 hours. The silica was isolated by filtration, washed twice with dichloromethane 2500 cm ^3, twice with tetrahydrofuran 2 500 cm ^3, twice with methanol 2500 cm ^3,
Then, it is washed twice successively with 2500 cm ³ of diethyl ether and dried under reduced pressure at a temperature of about 20 ° C. In this way - silica 971g referred to as "BOC-C ₁₁ -C ₃ silica" is obtained in the form of a white powder, the structure confirmed by infrared spectra, and the elemental analysis (found) is: C% = 9.85; H% = 2.
05; N% = 1.05.

In a 6 dm ³ three-necked flask, 971 g of BOC-C ₁₁ -C ₃ -silica
Suspend in 500 cm ³ of dichloromethane and 470 g of imidazole. 850 cm ³ of dimethyloctylchlorosilane are added dropwise and the reaction mixture is stirred at a temperature near 20 ° C. for 16 hours. The resulting solid was separated by filtration and 2500
twice with dichloromethane cm ^3, twice with methanol 2500 cm ^3, 2500C
Wash twice with m ³ tetrahydrofuran, twice with 2500 cm ³ dichloromethane and twice with 2500 cm ³ diethyl ether, then dry under reduced pressure at a temperature close to 20 ° C. In this way, the "BOC-C ₁₁ -C ₃ - Silica _{- O-Si (CH 3)} 2 (CH 2) 7 CH 3 " and referred 1179g of silica obtained in the form of a white powder, infrared its structure Confirmed by spectrum and its elemental analysis (found): C% = 13.9, H% = 2.83, N% = 1.16.

In a 6 dm ³ three-necked flask, 1178 g of BOC-C ₁₁ -C ₃ -silica-O-
Si (CH ₃ ) ₂ (CH ₂ ) ₇ CH ₃ silica is suspended in 2500 cm ³ of a 5% solution by volume of trifluoroacetic acid in dichloromethane. The mixture is stirred at 20 ° C. Silica was separated by filtration, washed twice with dichloromethane 2500 cm ^3, 2500 cm ³ of dichloromethane / diisopropylethylamine mixture twice with (70/3 0 by volume), dichloromethane 2500 cm ^3, twice with tetrahydrofuran 2500 cm ^3, 2000 cm twice with ³ methanol, and washed twice sequentially with diethyl ether 2000 cm ^3, then dried under reduced pressure at a temperature of 50 ° C. vicinity. In this way, 1080.5 g of silica, referred to as "C ₁₁ -C ₃ -Silica-O-Si (CH ₃ ) ₂ (CH ₂ ) ₇ CH ₃ ", are obtained in the form of a white powder, the structure of Confirmed by spectrum, and its elemental analysis (found): C% = 12.6;
H% = 2.44; N% = 1.05.

[0181] 6dm^Three2500 cm dried over 4Å molecular sieves in a three neck round bottom flask^Three1080 g of C in N, N-dimethylformamide₁₁-C_Three-(Siri
F) -O-Si (CH_Three)_Two(CH_Two)₇CH_ThreeSuspend the silica. 108 g of N-benzoyl-3,5-dinitro-D-phenylalanine and 75 g of N-ethoxy
Cycarbonyl-2-ethoxy-1,2-dihydroquinoline is added. Reaction mixing
Stir things overnight. The silica is separated by filtration on a sinter funnel and then 2500 cm ^Three Twice with dichloromethane of 2500cm^ThreeTwice with tetrahydrofuran at 250
0cm^ThreeN, N-dimethylformamide and 2500 cm^ThreeDichlorometa
Wash with 2500 cm of silica thus washed^ThreeIn N, N-dimethylformamide. 108 g of N-benzoyl-3,5-dinitro-
D-phenylalanine and 75 g of N-ethoxycarbonyl-2-ethoxy-1
, 2-dihydroquinoline are added successively, then the mixture is stirred at 20 ° C. overnight.
You. The silica is separated by filtration on a sinter funnel and 2500 cm^ThreeTwice with dichloromethane of 2500cm^ThreeTwice with tetrahydrofuran of 2500cm^ThreeOf methanol
Twice and 2500cm^ThreeWashing twice with diethyl ether. After drying at 60 ° C. under reduced pressure (2.7 kPa), “DNB-D-Phe-C₁₁−
C_Three-(Silica) -O-Si (CH_Three)_Two(CH_Two)₇CH_Three1093.6
g of silica are obtained in the form of a pale yellow powder whose structure can be confirmed by infrared spectrum.
And its elemental analysis (found): C% = 14.5; H% = 2.4; N% =
1.68.

In a 4 dm ³ three-necked round bottom flask, 519 g of DNB-D-Phe-C ₁₁ -C _3- (silica) in 3000 cm ³ of N, N-dimethylformamide dried over 4 molecular sieves -O-Si (CH ₃₎ suspending ₂ (CH _{2) 7} CH _3. 4
50 cm ³ of trimethylsilylimidazole are added over 15 minutes, then the mixture is stirred overnight. The silica is separated by filtration and washed successively twice with 1500 cm ³ of tetrahydrofuran, twice with 1500 cm ³ of methanol, twice with 1500 cm ³ of acetone and twice with 1500 cm ³ of dichloromethane. After drying at a temperature of 60 ° C. under reduced pressure (2.7 kPa), “DNB-D-Phe-
C ₁₁ -C ₃ - (silica) - [O-Si (CH 3) 2 (CH 2) 7 CH 3] - [O-Si
519 g of silica, designated (CH ₃ ) ₃ ] ”, were obtained in the form of a pale yellow powder, whose structure was confirmed by its infrared spectrum and whose elemental analysis (found) was: C%
= 15.3, H% = 1.8, N% = 2.6.

N-tert-butoxycarbonyl-11-aminoundecanoic anhydride can be prepared as follows: 30.1 g of N-tert-butoxycarbonyl-11-aminoundecanoic acid in 480 cm ³ of ethyl acetate Dissolve in The solution is cooled to 5 ° C. and then, while keeping it at this temperature, a solution of 10.63 g of 1,3-dicyclohexylcarbodiimide in 120 cm ³ of ethyl acetate is added over 10 minutes. The reaction mixture is stirred at 5 ° C. for 1 hour, then at a temperature near 20 ° C. for 16 hours. The precipitate formed is separated by filtration and washed with 30 cm ³ of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The obtained solid was removed under reduced pressure (2.7 kP
Dry at 20 ° C. in a). In this way, 31 g of N-tert-butoxycarbonyl-11-aminoundecanoic anhydride are obtained in a yield of about 100%.

J. Org. Chem. , 41 , 1350 (1976).
-Butoxycarbonyl-11-aminoundecanoic acid can be prepared.

Example 4 (3aRS, 4SR, 8SR, 8aRS) -4,8-Ethano-2- [2- (2 -methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl) -2,3 , 3a, 4,8,8a- hexahydro -1H- thieno [2,3-f] Lee Soindo - le -3a- carboxylic acid production process a argon atmosphere under diethyl ether 40cm ³ 4.5g (18. 0.45 g of magnesium filings in a solution of 6 mmol) of 4-trifluoromethylbromobenzene are added in portions and the mixture is kept at reflux for 1 hour 30 minutes, then the resulting red-brown solution is cooled to 5 ° C. And 3.45 g (9.3 mmol) of (3aRS, 4) obtained in Step F of Example 1 in 25 cm ³ of diethyl ether.
A solution of methyl SR, 7aRS) -2-benzyl-4- (3-thienyl) -7-oxo-octahydroisoindole-3a-carboxylate is added dropwise. Then the mixture is stirred at room temperature for 18 hours. After hydrolysis with 16 cm ³ of saturated aqueous ammonium chloride solution and extraction with ethyl acetate, the residue is purified by crystallization from pentane. Thus, 3.9 g (81%) of (3aRS, 4SR, 7RS,
7aRS) -2-benzyl-7-hydroxy-4- (3-thienyl) -7- (4
Methyl -trifluoromethylphenyl) -octahydroisoindole-3a-carboxylate is obtained in the form of a paste-like orange-yellow solid, the properties of which are as follows:-Mass spectrum (EI): M / Z. = 515 (M ^<+> ).

[0186] The procedure is as in Step H of Step B in Example 1, at room temperature for 72 hours, a solution of 10 cm ³ 6.88 g of (13mmol) (3aRS, 4SR, 7RS,
7aRS) -2-benzyl-7-hydroxy-4- (3-thienyl) -7- (4
-Trifluoromethylphenyl) methyl octahydroisoindole-3a-carboxylate, starting from 30 cm ³ of trifluoromethanesulfonic acid and 3 cm ³ of trifluoromethanesulfonic anhydride, with a cyclohexane / ethyl acetate mixture (98/2 by volume). After elution and purification by flash chromatography on silica gel (230-400 mesh), thus 860 mg (13%) of (
3aRS, 4SR, 8SR, 8aRS) -2-benzyl-4,8-ethano-8-
Methyl (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate melts at about 40-45 ° C. Obtained in the form of a white foam, its properties are as follows:-Mass spectrum (EI): M / Z = 497 (M ⁺ ).

Step C Treat as in step I of example 1, but at room temperature for 18 hours, 0.86 g (1.7 mmol) of (3aRS, 4SR, 8SR) in 10 cm ³ of dichloromethane
, 8aRS) -2-benzyl-4,8-ethano-8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,
3-f] Methyl isoindole-3a-carboxylate and 0.2 cm ³ (3.05 mmol) of vinyl chloroformate, followed by reflux in 20 cm ³ of a 5N solution of hydrochloric acid gas in isopropanol for 4 hours. After reconstitution and neutralization with a saturated aqueous solution of potassium carbonate and extraction with dichloromethane, 0.5 g (66%) of (3aRS,
4SR, 8SR, 8aRS) -4,8-ethano-8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,
3-f] Methyl isoindole-3a-carboxylate is obtained in the form of a brown oil, which is used without further purification in the next step and the properties of the product are as follows: mass spectrum (EI): M / Z = 407 (M ⁺ ).

Step D 0.2 cm ³ (1.75 mmol) of a solution of 400 mg (1.5 mmol) of 2- (2-methoxyphenyl) propenoic acid in 15 cm ³ of dichloromethane containing 3 drops of N, N-dimethylformamide Oxalyl chloride) is added and the mixture is kept at 40 ° C. for 30 minutes. After cooling, 0.61 g (1.5 mmol) of (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-8- (4-trifluoromethylphenyl) -2,3,3a in 20 cm ³ of dichloromethane. , 4,8,8a-
A solution of methyl hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate and 303 mg (3 mmol) of triethylamine is added dropwise and the mixture is stirred at room temperature for 2 hours. After hydrolysis by addition of 20 cm ³ of water, the organic phase is separated off after settling, washed with water and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), eluting with a cyclohexane / ethyl acetate mixture (80/20 by volume). Thus, 500 mg (59%) of (3aRS, 4SR, 8SR, 8aRS)
-4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
Methyl (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a pale yellow powder. , Its properties are as follows: Melting point = 113 ° C. -Mass spectrum (EI): M / Z = 567 (M ⁺ ).

Step E Treat as in example 1b, but in refluxing 40 cm ³ of methanol and 10 cm ³ of a 1 / 10N aqueous sodium hydroxide solution at reflux for 4 hours at 300 mg (0.53 g).
mmol) of (3aRS, 4SR, 8SR, 8aRS) -4.8-ethano-2-
[2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2
Starting from methyl [3-f] isoindole-3a-carboxylate and purifying by crystallization from pentane, 243 mg (83%) of (3aRS, 4SR, 8SR)
, 8aRS) -4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8
a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid is obtained in the form of a white foam, the properties of which are as follows: Melting point = 155-60 ° C. ¹ H NMR spectrum (250 MHz, (CD ₃ ) ₂ SO-d ₆ , at 383 K, δ in ppm): 1.38-1.61 and from 1.95 to 2.20 (
3Mts, respectively IH-IH and _{2H: CH 2 CH 2);} 3.20 from 3.45
Until (mt, 3H: CH 1 of CH ₂ and 8a); 3.53 and 4.04 (their respective d and the wide d, J = 12.5 Hz, each IH: 3 of CH _2); 3.65 From 3. To 80 (mt, 1H: 4 of CH); 3.71 (s, 3H : ArOCH 3); 5.58 and 5.70 (2s, each 1H: = CH _2); from 6.90 to 7.40 (Mt, 6H: H of aromatic H-5 and H of 6 of 2-methoxyphenyl); 7.7.
0 and 7.83 (2 wide d, J = 8 Hz, 2H each: aromatic H of 4-trifluoromethylphenyl).

Embodiment 5(3aRS, 4SR, 8SR, 8aRS) -N-benzyl-4,8-ethano-2 -[2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoromethyl Tylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [ Production of 2,3-f] isoindole-3a-carboxamide 10cm^Three442 mg (0.8 mmol) of (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-methoxy
Nil) propenoyl] -8- (4-trifluoromethylphenyl) -2,3,3
a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole
154 mg (0.8 mmol) of 1-ethyl-3-
[(3-Dimethylamino) propyl] carbodiimide hydrochloride, 86 mg (0.8
mmol) of benzylamine and 11 mg (0.08 mmol) of N-hydroxy
Cybenzotriazole hydrate is added continuously. After stirring at room temperature for 20 hours,
The solvent was concentrated under reduced pressure, and the residue was filtered over silica gel (230-400 mesh).
Purified by flash chromatography, mixed with cyclohexane / ethyl acetate / acetic acid
Elute with the compound (50/48/2 by volume). Thus, 178 mg (35%
)) (3aRS, 4SR, 8SR, 8aRS) -N-benzyl-4,8-ethano
-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoro
Romethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thie
No [2,3-f] isoindole-3a-carboxamide is obtained in the form of a white powder.
And its properties are as follows: Melting point = 227 ° C. -¹1 H NMR spectrum (250 MHz, few drops of CD_ThreeCOOD was added (CD_Three)_TwoSO-d₆Δ at ppm temperature, 383 K): 1.36-1.57 and 2.00 to 2.20 (3 mts, 1H-1H and 2H: CH, respectively). _Two CH_Two); 3.15 to 3.40 (mt, 2H: 1 CH)_Two); 3.38 and 4.16 (each d and wide d, J = 12.5 Hz, 1H: 3 CH each)_Two3.57 (mt, CH of 1H: 8a); 3.68 (s, 3H: ArOCH)_Three3.86 (wide s, 1H: 4 CH); 4.24 (limit AB, 2H: NCH)_Two Ar); 5.54 and 5.68 (2s, each 1H: = CH_Two); 6.80 to 7. Up to 40 (mt, 11H: aromatic H and H-2-methoxyphenyl of H-6 of 5: 5
And benzyl aromatic H); 7.68 and 7.79 (2 wide d, J = 8 Hz, 2 each)
H: aromatic H of 4-trifluoromethylphenyl); 7.95 (remaining unseparated
(Multiple line: CONH).

[0191] Example 6 (3aRS, 4SR, 10SR, 10aRS) -4,9- ethano-2- [2- (2-methoxyphenyl) -2-propen-1-Oil] -10 (4 Mechirufu Eniru ) -2,3,3a, 4,10,10a- hexahydro -1H- indolo [2,3-f] in ethanol production isoindole -3a- carboxylic acid step a 130cm ^3, Org. Synth. 9.3 g (0.118 mol) of methyl vinyl ketone and 120 cm ^{3 of} a solution cooled to 0 ° C. of 20 g (0.098 mol) of (3-indolyl) pyruvic acid obtainable according to Of 1N aqueous sodium hydroxide is continuously added, and then the mixture is stirred at a temperature near 0 ° C. for 1 hour. After neutralizing with 1N hydrochloric acid aqueous solution of 120 cm ³ and concentrating ethanol, the formed precipitate was separated by filtration,
Wash with water and then dry at 50 ° C. Thus, 24 g (88%) of 6
-(3-Indolyl) -3-oxocyclohexane-1-ol-1-carboxylic acid is obtained in the form of a beige-coloured powder, the characteristics of which are as follows:-Melting point = 210 [deg.] C. ^-1 H NMR spectra (300 MHz, (CD ₃ ) ₂ SO-d ₆ , δ in ppm): 1.96-2.20 to 2.40 and 2.76 (3 mts, 1H-2H and 1H, respectively: CH ₂ CH _2); 2.36 and 3.09 (2d, J = 14H
z, each _{1H: COCH 2); 3.86 (} dd, J = 12.5 and 3.5Hz, 1 H: ArCH); 5.25 ( broad unresolved multiplet, 1H: OH); 6. 97 and 7.05 (2t, J = 7.5 Hz, 1H: 5H for each and 6H for indole)
7.25 (d, J = 3.5 Hz, 1H: 2H of indole); 7.32 (d
, J = 7.5 Hz, 1H: H of indole 7; 7.64 (d, J = 7.5H).
z, 1H: H of indole 4); 10.84 (wide s, 1H: N of indole
H); 12.68 (broad unseparated multiplet, 1H: COOH).

Step B 115 g (0.421 mol) of 6- (3-indolyl) -3-oxocyclohexane-1-ol-1-carboxylic acid was dissolved in 500 cm ³ of tetrahydrofuran and 1 dm ³ of 1N hydrochloric acid in water. Reflux for hours. The reaction mixture is extracted three times with 200 cm ³ of ethyl acetate, dried over magnesium sulfate and concentrated under reduced pressure. The precipitate obtained is washed with isopropyl ether and then dried at 60.degree. Thus, 96.4 g (90%) of (RS) -6- (3-indolyl)
-3-Oxocyclohexene-1-carboxylic acid is obtained in the form of an orange-colored solid, the properties of which are as follows:-melting point = 170 [deg.] C. ^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO-d ₆ , δ in ppm): from 2.05 to 2.45 (mts, 4H: CH ₂ CH ₂ ); 4.48 (wide s, 6.52 (s, 1H: COCH =); 6.96 (d,
J = 3 Hz, 1H: indole 2H); 7.04 and 7.13 (2t, J =
7.5 Hz, each 1H: 5 H and indole 6 H); 7.38 (d, J = 7
. 7.63 (d, J = 7.5 Hz, 1H)
: H of indole 4); 10.95 (broad s, 1H: NH of indole); 1
3.20 (wide unseparated multiplet, 1H: COOH).

Step C A solution of 96.4 g (0.378 mol) of (RS) -6- (3-indolyl) -3-oxocyclohexene-1-carboxylic acid in 765 cm ³ of acetone was added with 75%.
g (0.529 mol) of methyl iodide and 69 g (0.453 mol) of 1,
8-Diazabicyclo [5.4.0] undec-7-ene is added dropwise continuously, then the mixture is refluxed for 1 hour. Next, the acetone was concentrated, and the residue was dried for 1 d.
Stir with m ³ of water. After cooling to 10 ° C., the precipitate formed is separated by filtration, washed with 500 cm ³ of petroleum ether and then purified by flash chromatography on silica gel (230-400 mesh), eluting with dichloromethane. . Thus, 70.7 g (70%) of (RS) -6- (3-indolyl)
Methyl -3-oxocyclohexene-1-carboxylate is obtained in the form of a yellow powder, the properties of which are as follows:-melting point = 154 DEG C.- ¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO-d ₆ , δ in ppm): 2.10 to 2.45 (mts, 4H: CH ₂ CH ₂ ); 3.66 (s
_{, 3H: COOCH 3); 4.51} ( broad s, 1H: ArCH); 6.65 (s, 1H: COCH =); 6.98 (d, J = 3Hz, 1H: 2 of H indole
7.04 and 7.13 (2t, J = 7.5 Hz, each 1H: 5 H and indole 6 H); 7.39 (d, J = 7.5 Hz, 1 H, indole 7 H). H)
7.64 (d, J = 7.5 Hz, 1H: 4H of indole); 10.97 (
Broad s, 1H: NH of indole).

Step D A solution of 20 g (0.077 mol) of methyl (RS) -6- (3-indolyl) -3-oxocyclohexene-1-carboxylate and 0.57 cm ³ of trifluoroacetic acid in 240 cm ³ of dichloromethane To reflux. Next, Chem. Pharm. Bull. , 1985, 276 (25 g).
089 mol) of Nn-butoxymethyl-N-trimethylsilylmethylbenzylamine are added dropwise and the mixture is refluxed for 1 hour. Next, the reaction medium was changed to 20
Cool to ° C. After stirring with about 40 g of potassium carbonate for 30 minutes, the organic phase was concentrated and the yellow oil obtained was purified by flash chromatography on silica gel (230-400 mesh), giving a cyclohexane / ethyl acetate mixture (7 vol.
0/30). Thus, 13.3 g (45%) of (3aRS, 4
Methyl SR, 7aRS) -2-benzyl-4- (3-indolyl) -7-oxooctahydroisoindole-3a-carboxylate is obtained in the form of a yellow foam;
Its properties are as follows: ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm): 20 and 2.50 to 2.75 (2mts, respectively 1H and _{3H: CH 2 CH 2);} 2.79 and 2.94 (2d, J = 9.5Hz, each 1H: 3 of CH ₂₎
2.81 and 3.18 (t and dd, respectively, J = 9.5 Hz and J = 9.5
And 5 Hz, the IH: 1 of _{CH 2); 3.37 (dd,} J = 9.5 and 5 Hz, IH: 7a of CH); 3.46 (s, 3H : COOCH 3); 3.59 and 3 . 68 (2d, J = 13 Hz, each 1H: NCH ₂ Ar); 3.74 (dd, J = 10.5 and 3.5 Hz, 1H: 4 CH); 6.88 (d, J = 3 Hz, 1H:
7.03 and 7.17 (2t, J = 7.5 Hz, 1H each)
: 5H and indole 6H); 7.25 to 7.40 (mt, 6H,
7.46 (d, J = 7.5 Hz); 7 H of indole and aromatic H of benzyl;
, 1H: H of indole 4); 8.02 (broad s, 1H: NH of indole)
.

Step E (SON 2807) 40 g (0.0995 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-4- (3-indolyl) -7-oxooctahydroisoindole-3a in 400 cm ³ of methanol. -Methyl carboxylate and 85 g (1.7 mol)
Is refluxed for 2 hours. After concentrating the methanol under reduced pressure, the residue is dissolved in 400 cm ³ of dichloromethane, washed three times with 150 cm ³ of distilled water, dried over magnesium sulfate and concentrated under reduced pressure. In this way 41 g (98%) of methyl (3aRS, 4SR, 7aRS) -2-benzyl-7-hydrazono-4- (3-indolyl) octahydroisoindole-3a-carboxylate are in the form of a yellow foam. And its properties are as follows: ¹ H NMR spectrum (400 MHz, CDCl ₃ , δ in ppm): a mixture of the two isomers is found in a 70/30 ratio. * 1.90 from to 2.55 (mt, total 4H: CH ₂ CH _2); 2.65 from to 3.20 (mt, total 4H: 3 of CH ₂ and 1 CH _2); 3. 39 and 3.44 (2s, 3H in total:
COOCH _3); 3.55 from to 3.90 (mt, total 2H: CH 4 in CH and 7a); 3.65 and 3.73 (2s, total _{2H: NCH 2 Ar); 4} . 96 and 5.00 (2 broad s, total 2H; NH ₂ ); 6.85 (broad s, 1 H: 2H of indole); 6.95 to 7.60 (mt, 9H: aromatic) H); 8.03 and 8.05 (2 wide s, total 1H: NH of indole).

Step F 41 g (0.0985 mol) of (3aRS, 4SR, 7aRS) -2-benzyl-7-hydrazono-4- (3-indolyl) octahydroisoindole-3a-carboxylate in 1dm ³ of tetrahydrofuran 30 g (0.
A solution of 50.4 g (0.197 mol) of iodine in 400 cm ³ of tetrahydrofuran is added dropwise. After addition of ethyl acetate 200 cm ^3, the organic phase was washed twice with saturated sodium hydrogen carbonate aqueous solution 100 cm ^3, and washed twice with saturated aqueous sodium thiosulfate in 100 cm ^3, a saturated aqueous solution of sodium chloride in 100 cm ³ Wash twice, then dry over magnesium sulfate and concentrate under reduced pressure. After purification by chromatography on silica gel (230-400 mesh) eluting with a cyclohexane / ethyl acetate mixture (80/20 by volume), 29.8 g (58%) of (3aRS, 4SR, 7a).
RS) -2-benzyl-7-iodo-4- (3-indolyl) -1,2,3,4
Methyl 5,5,7a-hexahydroisoindole-3a-carboxylate is obtained in the form of a white foam, which has the following properties: ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm) ): 2. 44 (mt, 1H: 5 CH ₂ 1H); 2.55 to 2.95 (mt, 3 H: 5 CH ₂ another H-3 CH ₂ 1H and 1 CH ₂ 1 CH ₂ 1H); From 3.45 to 3.85 (mt, 2H: another H of 3 CH ₂ and another H of 1 CH ₂ ); 3.45 to 3.85 (mt, 2H: 4 CH and 7a 3.52 (s, 3H: COOCH ₃ ); 3.60 and 3.70 (2d, J = 14 Hz, each 1H: NCH ₂ Ar); 6.52 (mt, 1H: 6 = CH) 6.95 (d, J = 2.5 Hz, 1H: 2H of indole); 7.06 and 7.16 (2t, J = 7.5 Hz, 1H: 5H of each and 6 of indole) H);
7.20 to 7.40 (mt, 6H, 7H of indole and aromatic H of benzyl); 7.53 (d, J = 7.5Hz, 1H: 4H of indole);
04 (broad s, 1H: NH of indole).

Step G 26.8 g (0.052 mol) of (3aRS, 4 SR, 7aRS) -2-benzyl-7-iodo-4- (3-indolyl) -1, in 540 cm ³ of toluene.
To a solution of methyl 2,3,4,5,7a-hexahydroisoindole-3a-carboxylate and 3.5 g of tetrakis (triphenylphosphine) palladium was added 29
It was added in 5 cm ³ methanol 7.82g of (0.0575mol) of 4-Mechirufeni Ruboron acid solution and 2N aqueous sodium carbonate 550 cm ³ in succession, then the mixture is refluxed for 1 hour. After dilution with distilled water 100 cm ^3, the reaction mixture was extracted with ethyl acetate 150 cm ^3, and washed 3 times with saturated aqueous sodium chloride 150 cm ^3, dried over magnesium sulfate, then, concentrated under reduced pressure . After purification by flash chromatography on silica gel (230-400 mesh) eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), 17.7 g (71%) of (3aRS, 4SR, 7aRS) -2. -Benzyl-7- (4-methylphenyl) -4- (3-indolyl) -1,2,3,4
The methyl 5,7a-hexahydroisoindole-3a-carboxylate is obtained in the form of a pink foam, whose properties are as follows: ¹ H NMR spectrum (300 MHz, CDCl ₃ , δ in ppm). : 2. _{37 (s, 3H: ArCH 3} ); 2.52 (dd, J = 9.5 and 6.5Hz, 1H: 1H of 1 of CH _2); 2.59 and 2.80 (2mts, the IH: 5 the C H _2); 2.87 and 3.08 (2d, J = 10Hz, each IH: 3 of CH _2); 3
. 02 (t, J = 9.5Hz, 1H: 1 Another H of _{CH 2); 3.52 (s,} 3H: COOCH 3); 3.54 and 3.67 (2d, J = 14Hz, each _{1 H: NCH 2 Ar);} 3.65 from to 3.85 (mt, 2H: 4 of CH and 7 a CH); 6.19 (mt , 1H: 6 of = CH); 6.97 (d , J = 3Hz
, 1H: 2H of indole); 7.07 and 7.17 (t, J = 7.0 respectively).
5Hz and mt, IH and 3H: 5 of H and 2 arom. H Oh belt H and CH ₃ of 6 of the indole); 7.20 from to 7.40 (mt, 8H: indole 7
2 aromatic H and aromatic H of the benzyl) meta to H-CH ₃ of; 7.61 (d, J = 7.5Hz , 1H: 4 of H indole); 8.00 (broad s, IH: Indole NH).

Step H 3.5 g (0.0073 mol) of (3aRS, 4SR, 7aRS) -2-benzyl-7- (4-methylphenyl) -4- (3-indolyl) -1,2,3,3
Methyl 4,5,7a-hexahydroisoindole-3a-carboxylate and 10
g (0.066 mol) of trifluoromethanesulfonic acid are heated at 70 ° C. for 1 hour. The reaction mixture is cooled to a temperature close to 0 ° C., 100 cm ³ of 1N aqueous sodium hydroxide solution are added, followed by extraction with 100 cm ³ of ethyl acetate. After settling, the organic phase is separated off, washed with distilled water, dried over magnesium sulfate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh) eluting with a cyclohexane / ethyl acetate mixture (95/05 by volume), 0.55 g (15.7%) of (3aRS, 4SR) was thus obtained. ,
10SR, 10aRS) -2-benzyl-4,10-ethano-10- (4-methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-indolo [2,3-f] isoindole Methyl -3a-carboxylate is obtained in the form of a white powder, the properties of which are as follows: Melting point: 92 ° C. ¹ H NMR spectrum (400 MHz, CDCl ₃ , δ in ppm): 1. 44-1.62 and 2.54 (3 mts, respectively IH-IH and _{2H: CH 2 CH 2);} 2.25 from to 2.35 (mt, 2H: 1 of CH ₂ IH and 3 C
Of H ₂ 1H); 2.42 (s, 3H : ArCH 3); 2.77 ( broad d, J = 10
Hz: 1 Another of CH ₂ of H); 3.21 (broad d, J = 10Hz, 1H: Another H 3 of CH _2); 3.25 (broad d, J = 8.5Hz, 3.43 and 3.65 (2d, J = 14 Hz, each 1H: NCH ₂ Ar); 3.48 (s, 3H: COOCH ₃ ); 3.89 (wide s, 1H: 4 CH); 7.00 to 7.10 -7.15 to 7.40 and 7.51 (2 mts and d, respectively, J = 7.5 Hz, 11H in total: H aromatic H). 7.4
3 (d, J = 8Hz, 2H: 2 aromatic H of the CH ₃ meta); 7.58 (broad s, 1H: NH).

Step I 0.5 g (0.001 mol) of (3aRS, 4SR, 10SR, 10aRS) -2-benzyl-4,10-ethano-10- (10 cm ³ in dichloromethane)
4-methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H
0 in solution of methyl indolo [2,3-f] isoindole-3a-carboxylate
. 125 cm ³ (0.0015 mol) of vinyl chloroformate are added, then the reaction mixture is refluxed for 3 hours. After evaporation of dichloromethane, the residue is separated on silica gel (
Purify by flash chromatography (230-400 mesh) and elute with a mixture of cyclohexane / ethyl acetate (80/20 by volume). Thus, 0.5 g (100%) of (3aRS, 4SR, 10SR, 10aRS) -4
, 10-Ethano-10- (4-methylphenyl) -2-vinyloxycarbonyl-2,3,3a, 4,10,10a-hexahydro-1H-indolo [2,3-
f] Methyl isoindole-3a-carboxylate is obtained in the form of a white powder, the properties of which are as follows:-Melting point: 142 [deg.] C.- ¹ H NMR spectrum (250 MHz, (CD ₃ ) ₂ SO-d ₆ in temperature of 373 K, in ppm δ): 1.44-1.68 and 2.13 (3 mts, their respective IH-IH and _{2H: CH 2 CH 2);} 2.43 (s, 3H : ArCH _3); 3.30 from to 3.50 (mt, 3H: CH 1 of CH ₂ and 10a); 3. 45 (s, 3H: COOCH ₃ ); 3.55 and 4.05 (d, J = 12.5 Hz, each 1H: 3 CH ₂ ); 3.90 (wide s, 1H: 4 CH); 4.55 and 4.83 (2dd, J = 6 and 1.5 Hz and J = 14 and 1.5, respectively)
Hz, 1H: = CH ₂ ); 6.90 to 7.05 and 7.30 to 7.50 (2 mts, 8H in total: H aromatic); 7.32 (dd, J = 14) And 6 Hz, 1H: OCH =); 9.96 (mt, 1H: NH).

Step J 4.2 g (0.0092 mol) of (3aRS, 4SR, 10SR, 10aRS) -4,10-ethano-10- (4-methylphenyl) -2-vinyloxycarbonyl- in 170 cm ³ of methanol A solution of methyl 2,3,3a, 4,10,10a-hexahydro-1H-indolo [2,3-f] isoindole-3a-carboxylate at 20 ° C. in 50 cm ³ of a 6N solution of hydrogen chloride gas in dioxane. Stir at nearby temperature for 24 hours. After evaporation of the solvent, 3.6 g (92%) of (3aRS,
4SR, 10SR, 10aRS) -4,10-ethano-10- (4-methylphenyl) -2,3,3a, 10,10a-hexahydro-1H-indolo [2,3
-F] isoindole hydrochloride is obtained in the form of a gray powder, the properties of which are as follows:-Melting point:> 260 ° C.- ¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO-d ₆ , ppm δ units): from 1.47-1.72 and 2.25 to 2.45 (3 mts, their respective IH-IH and _{2H: CH 2 CH 2);} 2.44 (s, 3H: ArCH 3 ); 3. 00-3.20 and 3.30 to 3.80 (3 mts, 1H-1 each
H and 3H: CH of CH _2-10a of one of the _{CH 2 -3); 3.46 (s} , 3H: C
OOCH _3); 3.83 (broad s, 1H: 4 of CH); 6.97 and 7.15 or et 7.50 to (mt, total 8H: aromatic H); 9.38 and 9. 63 (2
Unseparated multiplet, each _{^{1H: NH 2 + Cl -)}} ; 10.40 (s, 1H: NH).

Step K A solution of 230 mg (0.0013 mol) of 2- (2-methoxyphenyl) propenoic acid in 10 cm ³ of dichloromethane containing 0.3 cm ³ of N, N-dimethylformamide was treated with 0 cm ³ of dichloromethane in 8 cm ³ of dichloromethane. .12cm ³ (0.0013mo
l) A solution of oxalyl chloride is added dropwise. The reaction mixture is stirred for a further hour at a temperature near 20 ° C., then cooled to a temperature near 0 ° C. and, while maintaining a temperature near 0 ° C., 500 mg (0.0012 mol) of (3aRS) in 10 cm ³ of dichloromethane. , 4SR, 10SR, 10aRS) -4,10-ethano-10- (4
-Methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-
Pour dropwise into a solution of indolo [2,3-f] isoindole and 0.36 cm ³ (0.0026 mol) of triethylamine. The reaction mixture is stirred for a further 4 hours at a temperature close to 20 ° C. and poured into 30 cm ³ of distilled water. After sedimentation, the organic phase was separated off, twice with 30 cm ³ of distilled water and then with 10 cm ³ of 1N aqueous hydrochloric acid.
Wash twice, dry over magnesium sulfate and concentrate under reduced pressure. Cyclohexane /
Silica gel (230-400) eluted with an ethyl acetate mixture (75/25 by volume)
After purification by flash chromatography on a mesh), 240 mg (3
7%) of (3aRS, 4SR, 10SR, 10aRS) -4,10-ethano-2
-[2- (2-methoxyphenyl) 2-propene-1-oil] -10- (4-
Methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-indolo [2,3-f] isoindole-3a-carboxylate is obtained in the form of a white solid, the properties of which are as follows: as is: - mp> 260 ℃ - ¹ H NMR spectrum (400 MHz, (in _{CD 3) 2 SO-d 6} , 393K of temperature, in ppm δ): 1.38-1.60 and 2.12 (3 mts, their respective IH-IH and _{2H: CH 2 CH 2);} 2.42 (s, 3H: ArCH 3); 3.20 from to 3.45 (mt, 3H: 1 of CH ₂ and 10a CH); 3. _{44 (s, 3H: COOCH 3} ); 3.52 and 4.06 (respectively d and broad d, J = 12.5 Hz, each IH: 3 of _{CH 2); 3.73 (s,} 3H: ArOC H 3 ); 3.84 (broad s, IH: 4 of CH); 5.54 and 5.80 (2 broad s, each 1H: = CH _2); 6.90 from to 7.10 and 7.15 to 7 9.45 (mt, total 12H: aromatic H); 9.75 (unseparated multiplet, 1H:
NH).

Step L: 610 mg (0.0011 mol) of (3aRS, 4SR, 10SR, 10a
RS) -4,10-Ethano-2- [2- (2-methoxyphenyl) -2-propene-1-oil] -10- (4-methylphenyl) -2,3,3a, 4,10,
10a-Hexahydro-1H-indolo [2,3-f] isoindole-3a-
The methyl carboxylate is refluxed for 5 hours in 20 cm ³ of dioxane in the presence of 5 cm ³ (0.005 mol) of 1 N aqueous sodium hydroxide solution. Then the reaction mixture is concentrated under reduced pressure and the residue is dissolved in 25 cm ³ of distilled water. The aqueous phase is washed once with 20 cm ³ of dichloromethane and then acidified with a 1N aqueous hydrochloric acid solution to a pH of about 1. The mixture is extracted twice with 20 cm ³ of dichloromethane. After settling, the organic phase is separated off, washed with distilled water, dried over magnesium sulfate and concentrated under reduced pressure. The solid obtained is purified by recrystallization from methanol. Thus, 90 mg (15%) of (3aRS, 4SR, 10SR, 10aRS)-
4,10-ethano-2- [2- (2-methoxyphenyl) -2-propene-2-
Oil] -10- (4-methylphenyl) -2,3,3a, 4,10,10a-
Hexahydro-1H-indolo [2,3-f] isoindole-3a-carboxylic acid is obtained in the form of a white powder, the properties of which are as follows: Melting point = 190 ° C. ¹ H NMR spectrum (400 MHz, in _{(CD 3) 2 SO-d} 6, 413K of temperature, in ppm δ): 1.37-1.59 and 2.13 (3mts, respectively IH-IH and _{2H: CH 2 CH 2);} 2 .43 (s, 3H: ArCH ₃ ); From 20 to 3.50 (mt, 3H: CH 1 of CH ₂ and 10a); 3.5 6 and 4.04 (2d, J = 12.5Hz, each IH: 3 of CH _2); 3.76 3.86 (wide s, 1H: 4 CH); 5.56 and 5.68 (2 wide s, each 1H: = CH ₂ ); 6.90 to 7.90 (s, 3H: ArOCH ₃ ); Up to 05 and 7. 25 to 7.50 (2 mts, total 12H: aromatic H); 9.46 (
Unseparated multiplet, 1H: NH).

Example 7 (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-4,8- ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4- methylphenyl)-2,3,3a, as in manufacturing example 5 4,8,8a- hexahydro -1H- thieno [2,3-f] dextrorotatory enantiomer of isoindole -3a- carboxamide Treat with 500 mg (1 mmol) of (3aRS, 4SR, 8SR, 8aRS) in 20 cm ³ of dichloromethane for 20 hours at room temperature.
-4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
(4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-
A dextrorotatory enantiomer of thieno [2,3-f] isoindole-3a-carboxylic acid,
108 mg (1 mmol) of 3-aminomethylpyridine, 210 mg (1.1 m
mol) of 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride and 15.3 mg (0.11 mmol) of N-hydroxy-benzotriazole hydrate. After crystallization, 390 mg (
66%) of (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl]-
8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1
The dextrorotatory enantiomer of H-thieno [2,3-f] isoindole-3a-carboxamide is obtained in the form of white crystals, the characteristics of which are:-melting point = 149 ° C-mass spectrum ( EI): M / Z = 589 (M ⁺ )-Optical rotation: [α] ₃₆₅ ²⁰ = +142.7 +/- 2 ° (c = 0.5 / methanol). (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-
4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (
The levorotatory enantiomer of (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxamide can be obtained as follows. Possible: Step A Treated as in Example 3, 12.86 g of (3aRS, 4SR, 8SR
, 8aRS) -4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno Starting from [2,3-f] isoindole-3a-carboxylic acid, the second fraction eluted (retention time 52 minutes) was collected and 5.52 g of (3
aRS, 4SR, 8SR, 8aRS) -4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3a,
4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3
The levorotatory enantiomer of the a-carboxylic acid is obtained in the form of a white powder, whose properties are as follows:-Mass spectrum (EI): M / Z = 499 (M ⁺ )-Optical rotation: [α] ₃₆₅ ²⁰ = -109 +/- 1.6 [deg.] (C = 0.5 / methanol).

Step B Treat as in Example 5, but at room temperature for 20 hours, 500 mg (1 mmol) of (3aRS, 4SR, 8SR, 8aRS) in 20 cm ³ of dichloromethane.
-4,8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-
(4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-
Levorotatory enantiomer of thieno [2,3-f] isoindole-3a-carboxylic acid,
108 mg (1 mmol) of 3-aminomethylpyridine, 210 mg (1.1 m
mol) of 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride and 15.3 mg (0.11 mmol) of N-hydroxy-benzotriazole hydrate. After crystallization, 530 mg (
90%) of (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl]-
8- (4-methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1
The levorotatory enantiomer of H-thieno [2,3-f] isoindole-3a-carboxamide is obtained in the form of a white crystal, which has the following characteristics:-melting point = 150 ° C.-mass spectrum (EI ): M / Z = 589 (M ⁺ )-Optical rotation: [α] ₃₆₅ ²⁰ = + 145.7 +/− 2 ° (c = 0.5 / methanol).

[0205] Example 8 (3aRS, 4SR, 8SR, 8aRS) -4,8- ethano-8- (4-methoxamine Shifeniru) -2- [2- (2-methoxyphenyl) propenoyl]-2,3, 3a , 4,8,8A- hexahydro -1H- thieno [2,3-f] Isoindo Le -3a- diethyl ether-carboxylic acid methyl step a 10 cm ³ and 2 cm ³ of tetrahydrofuran 201mg
1.02 g (9.5 mmol) in a suspension of magnesium under an argon atmosphere.
) Of 4-bromoanisole is added. After the disappearance of magnesium, 731 mg
(3 mmol) of cerium chloride are added, then the mixture is cooled to 10 ° C. Then 1.56 g (4.2 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-4- (3-thienyl) -7-oxooctahydroisoindole-3a-carboxylate in 5 cm ³ of toluene. Is added dropwise. After stirring overnight at room temperature, the mixture is hydrolyzed by addition of 25 cm ³ of a saturated aqueous solution of ammonium chloride. The organic phase was separated out after settling, ammonium arm saturated aqueous chloride of 10 cm ^3, then washed successively with water 10 cm ^3, dried ammonium sulfate, and concentrated under reduced pressure. The residue was treated with a mixture of toluene and ethyl acetate (80 vol.
/ 20) Dissolve in 100 cm ³ and add 15 g of silica gel (230-400 mesh). After stirring for 15 minutes, the silica is filtered off. Thus, 1.37 g (68%) of (3aRS, 4SR, 7SR, 7aRS) -2-benzyl-7-hydroxy-7- (4-methoxyphenyl) -4- (3-thienyl) octahydroisoindole Methyl -3a-carboxylate is obtained in the form of a very viscous orange-colored oil whose properties are as follows:-Mass spectrum (EI): M / Z = 477 (M ⁺ ).

Step B Treat as in step H of example 1, but 1.37 g (2.9 mmol) of (3aRS, 4SR, 7SR, 7aRS) -2 in 15 cm ³ of dichloromethane.
Methyl-benzyl-7-hydroxy-7- (4-methoxyphenyl) -4- (3-thienyl) octahydroisoindole-3a-carboxylate and 1.5 g (1
0 mmol) of trifluoromethanesulfonic acid, eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) on silica gel (230-40).
After purification by flash chromatography with 0 mesh, 1.07 g (
80%) of (3aRS, 4SR, 8SR, 8aRS) -2-benzyl-4,8-
Methyl ethano-8- (4-methoxyphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate in the form of a yellow oil Obtained and its properties are as follows: Mass spectrum (EI): M / Z = 459 (M ⁺ ).

Step C Treat as in step I of example 1, but 1.37 g (3 mmol) of (3aRS, 4SR, 8SR, 8aRS)-in 10 cm ³ of dichloromethane for 4 hours.
2-benzyl-4,8-ethano-8- (4-methoxyphenyl) -2,3,3a
, 4,8,8a-Hexahydro-1H-thieno [2,3-f] -isoindole-3a-carboxylate and 639 mg of vinyl chloroformate, followed by the residue was treated with 2N HCl in methanol. The solution was treated in 5 cm ³ and 10 cm ³ of methanol at reflux for 5 hours and 910 mg (82%) of (3aRS, 4SR, 8S
R, 8aRS) -4,8-Ethano-8- (4-methoxyphenyl) -2,3,3
Methyl a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a yellow oil, the properties of which are as follows:-Mass spectrum (EI): M / Z = 369 (M ⁺ ).

Step D: A solution of 530 mg (3 mmol) of 2- (2-methoxyphenyl) propenoic acid and 545 mg (5.4 mmol) of triethylamine in 5 cm ³ of dichloromethane containing 0.1 cm ³ of N, N-dimethylformamide At 0 ° C.
mg (2.7 mmol) of oxalyl chloride are added dropwise. After stirring at room temperature for 2 hours, the solution is cooled to 0 ° C. Then, dichloromethane 910 mg of 10 cm ³ of (2.5mmol) (3aRS, 4SR, 8SR, 8aRS) -4,8-
A solution of methyl ethano-8- (4-methoxyphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is added. After stirring overnight at room temperature, 10 cm ³ of water are added. After settling, the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 mesh) and a mixture of cyclohexane and ethyl acetate (70 vol.
/ 30). Thus, 760 mg (69%) of (3aRS, 4S
R, 8SR, 8aRS) -4,8-Ethano-8- (4-methoxyphenyl) -2
-[2- (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8
Methyl a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a white powder, the properties of which are as follows:-melting point = 115 [deg.] C-mass spectrum (EI ): M / Z = 529 (M ⁺ ).

[0209] Example 9 (3aRS, 4SR, 8SR, 8aRS) -4,8- ethano-8- (4-methoxamine Shifeniru) -2- [2- (2-methoxyphenyl) propenoyl]-2,3, 3a , 4,8,8A- be treated as in hexahydro -1H- thieno [2,3-f] production example of Isoindo Le -3a- carboxylic acid 1 ', but 4 hours 4 cm ³ of dioxane at 50 ° C. 340 mg (0.64 mmol) of (3aRS, 4SR, 8SR, 8aRS)
-4,8-Ethano-8- (4-methoxyphenyl) -2- [2- (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-hexahydro-1H
-Methyl thieno [2,3-f] isoindole-3a-carboxylate and 0.38
Starting from 5N aqueous sodium hydroxide cm ^3, it was purified by chromatography on prep plates silica gel (of 0.2mm thick, with a mixture of cyclohexane and ethyl acetate from 50/50 by volume up to 5/95 Elution), 120 m
g (36%) of (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-8
-(4-methoxyphenyl) -2- [2- (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f
The isoindole-3a-carboxylic acid is obtained in the form of a white powder, the properties of which are as follows:-melting point = 178 [deg.] C-mass spectrum (EI): M / Z = 515 (M ^<+> ).

Example 10 (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-8- (benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [ 2- (2 - methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a- Hekisahi mud -1H- thieno [2,3-f] of the manufacturing process a 30 cm ³ of isoindole -3a- carboxamide 1.35 g (2.8 mmol) of (3aRS, 4SR, 7aRS) -2-benzyl-7-oxo-4- (3-thienyl) octahydroisoindole-3a-carboxylate in dichloromethane and 1.36 g (10 mmol) of methyl
3 g (20 mmol) of trifluoromethanesulfonic acid are added to a solution of benzodioxane cooled to 0 ° C.). After stirring for 2 hours at room temperature, the reaction medium is hydrolyzed by addition of 20 cm ³ of a saturated aqueous solution of sodium hydrogen carbonate. After settling, the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (230-400 mesh) and a mixture of cyclohexane and ethyl acetate (80/20 by volume)
). Thus, 1.07 g (40%) of (3aRS, 4SR, 8
SR, 8aRS) -8- (Benzo-1,4-dioxan-6-yl) -2-benzyl-4,8-ethano-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2 Methyl [, 3-f] isoindole-3a-carboxylate is obtained in the form of a yellow oil, whose properties are as follows:-Mass spectrum (EI): M / Z = 487 (M ⁺ ).

Step B Treat as in step I of example 1, but 584 mg (1.2 mmol) of (3aRS, 4SR, 8SR, 8aRS in 5 cm ³ of dichloromethane for 4 h
) -8- (Benzo-1,4-dioxan-6-yl) -2-benzyl-4,8-
Ethano-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-
f] Methyl isoindole-3a-carboxylate and 256 mg (2.4 mmol
)), Followed by the residue is treated with 2 parts of HCl in methanol.
N 2 solution at 5 cm ³ and 5 cm ³ of methanol at reflux for 2 hours, 480 mg (
99%) of (3aRS, 4SR, 8SR, 8aRS) -8- (benzo-1,4-
Methyl dioxan-6-yl) -4,8-ethano-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is a yellow oil. Obtained in form and used for the rest of the synthesis without further purification, its properties are as follows:-Mass spectrum (EI): M / Z = 397 (M ⁺ ).

Step C Treat as in step D of example 8, but 250 mg (1.4 mmol) of 2- (2 mmol) in 15 cm ³ of dichloromethane containing 0.1 cm ³ of N, N-dimethylformamide. -Methoxyphenyl) propenoic acid and 282 mg (2.8 m
mol) of triethylamine and 178 mg (1.4 mmol) of oxalyl chloride, starting with 480 mg (1.2 mmol) of (3aRS, 4SR, 8SR, 8aRS) -8- (benzo-1,4-) in 5 cm ³ of dichloromethane. Dioxan-6-yl) -4,8-ethano-2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate, followed by cyclohexane and After purification by flash chromatography on silica gel (230-400 mesh) eluting with a mixture of ethyl acetate (70/30 by volume), 435 mg (72%) of (3aRS, 4SR, 8SR, 8aRS) -8-
(Benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [2- (2
-Methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate is obtained in the form of a white powder and its properties Is as follows:-melting point = 148 [deg.] C-mass spectrum (EI): M / Z = 557 (M ^<+> ).

[0213] The procedure is as in Step D in Example 1 ', dioxane of 4 hours 5 cm ³ at reflux 430mg of (0.77mmol) (3aRS, 4SR, 8SR, 8aRS) -
8- (benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [2-
Methyl (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate and 0.46 cm ³ of 5N hydroxylation Starting from aqueous sodium solution and purifying by flash chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume), 305 mg (73%) of (3aRS
, 4SR, 8SR, 8aRS) -8- (Benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl] -2
, 3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid is obtained in the form of a white powder, the properties of which are as follows: = 168 ° C-mass spectrum (EI): M / Z = 543 (M ⁺ ).

Step E Treat as in example 5, but 300 mg (0.56 mmol) of (3aRS, 4SR, 8SR, 8aR) in 20 cm ³ of dichloromethane at room temperature for 20 hours.
S) -8- (Benzo-1,4-dioxan-6-yl) -4,8-ethano-2-
[2- (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a
-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, 60 mg (0.56 mmol) of 3-aminomethylpyridine, 110 mg (
0.6 mmol) of 1-ethyl-3-[(3-dimethylamino) propyl] carbodiimide hydrochloride and 8 mg (0.06 mmol) of N-hydroxybenzotriazole hydrate, starting from a mixture of dichloromethane and methanol (volume). At 9
0/10) and purified by flash chromatography on silica gel (230-400 mesh) followed by 190 mg (54%) of (3aRS, 4SR).
, 8SR, 8aRS) -N- (3-pyridyl) methyl-8- (benzo-1,4-
Dioxan-6-yl) -4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f The isoindole-3a-carboxamide is obtained in the form of white crystals, the properties of which are as follows: melting point = 155 ° C. mass spectrum (EI): M / Z = 634 (M ⁺ ) It is within the average ability of a person skilled in the art to carry out the above process using the starting materials or, in particular, to prepare the following compounds:

[0215]

[Table 1]

[0216]

[Table 2]

[0217]

[Table 3]

Example A Evaluation of the Farnesyltransferase Activity of the Compound of the Present Invention The farnesyltransferase activity was measured by the amount of farnesylated K-ras substrate or a substrate derived from the peptide corresponding to the C-terminal portion thereof. Provided by farnesyl acid (FPP).

[0219] Clearly, the biotinylated substrate used, corresponding to K-ras: BIOT- (β
_{A) 3 -S-K-D} -G- (K) 6 -S-K-T-K-C-V-I-M is, ^[3 H] its cysteine C by farnesyl transferase in the presence of -FPP
Is [ ³ H] -farnesylated. It is then placed in contact with PVT * -Streptavidin ™ beads (Amersham) and streptavidin /
It is quantified by proximity scintillation between tritium and PVT beads based on biotin interaction (SPA assay).

Experimentally, in this assay, farnesyltransferase purified according to the methods herein is diluted to a concentration that results in less than 30% substrate consumption. The final molarity of each substrate is determined by their respective Km: biotinylated K
-Ras peptide was adjusted to 50 nM and FPP to 120 nM to a final volume of 100 μl of the reaction mixture based on 50 mM Hepes pH 7.5, 5 mM MgCl ₂ , 40 mM KCl, 5 mM dithiothreitol, 0.01% Triton X100 buffer. Add 20 μl.

First, the inhibitors to be tested, dissolved in 1 mM in a suitable solvent (DMF or DMSO), are diluted in assay buffer and the reaction mixture is repeated three times at a concentration 10 times higher than their final concentration, Add in the form of 10 μl.

The reaction performed on the Optiplates 96 ™ microtitration plate is initiated by the enzyme and continued at 37 ° C. for 60 minutes. PH ₄ consisting of 0.2 MH ₃ PO ₄ , 1.5 mM MgCl ₂ , 0.5% (w / v) BSA, 0.05% (w / v) sodium azide containing 200 μg PVT-streptavidin beads. It is quenched by the addition of 150 μl of the quenching buffer mixture.

After gently stirring for 30 minutes (to eliminate chemiluminescence), read the plate with [ ³ H] CPM on a Top Count ™ scintillation counter (Packa rd) for microplates, in which case scintillation Convert them to [ ³ H] DPM using a range of colored agents that reduce (“quenching”).

After subtracting a blank containing only substrate and buffer from all inhibition values, the percentage of inhibition is calculated relative to the control without inhibitor.

[0225] using Enzfitter (TM) or Grafit (TM) software, or to measure IC ₅₀ values are calculated from the inhibition obtained with 9 different concentrations. The compounds tested according to the invention have IC ₅₀ values between 0.1 nM and 10 μm.

Example B The activity of a compound of the present invention can also be assessed by its ability to inhibit the growth of human tumor line-derived clones on agar. For example, cells from the HCT116 human colon carcinoma line supplied by the ATCC were supplemented with 2% L-glutamine, 200 U / ml penicillin and 2 mM supplemented by volume with 10% heat-inactivated fetal calf serum.
Grow as a monolayer in Dulbecco's modified Eagle culture medium containing 00 μg / ml streptomycin. Exponentially growing cells are digested with trypsin, PBS
And dilute to a final concentration of 5000 cells / ml in complete culture medium. next,
The inhibitor or control solvent to be tested is added in a volume of 50 μl to 2.5 ml of the previously prepared cell suspension and then 0.4 ml of Nob kept at 45 ° C.
The le Difco agar solution is added, then mixing is performed. The medium thus obtained is immediately poured into a Petri dish, kept at 4 ° C. for 5 minutes and then incubated at 37 ° C. in an atmosphere of 5% CO ₂ . After incubation for 12 days at 37 ° C. in an atmosphere of 5% CO ₂ , the number of cell clones (> 50 cells) is counted. Each inhibitor is tested in duplicate at a final agar concentration of 10, 1, 0.1, 0.01 and 0.001 μg / ml. Results are expressed as percentage inhibition of clonogenesis relative to untreated controls. IC ₅₀ inhibitory doses are determined graphically by semi-log means from the values obtained at each concentration.

The products of the present invention inhibit farnesylation of Ras protein by 50% at concentrations between 0.1 nM and 100 μM.

Example C Example A A gelatin capsule containing 50 mg of active product and having the following composition is prepared by conventional techniques:-Active product ... 50mg-Cellulose 18mg-Lactose ... ... 55mg-Colloidal silica ... 1mg-Sodium carboxymethyl starch ... 10mg-Talc ... 10 mg-magnesium stearate 1 mg Example B containing a 50 mg dose of the active product and having the following composition: The tablets are manufactured by the usual techniques:-Active product ...・ ・ ・ ・ ・ ・ ・ ・ ・ ・ 50mg-Lactose ・ ・ ・ ・ ・ ・ ・ 104mg ・ Cellulose ・ ・ ・ ・ ・ ・ ・40mg-Polyvidone 10mg-Sodium carboxymethyl starch 22mg-Talc ······· 10 mg-magnesium stearate ··· 2 mg-colloidal silica ······ 2 mg-hydroxymethylcellulose, glycerol A mixture of titanium oxide (72 / 3.5 / 24.5) in a suitable amount up to one finished film-coated tablet weighing 245 mg Example C containing 50 mg of the active product and having the following composition: Produce a possible solution:-Active production ... 50mg-Benzoic acid ... 80mg-Benzyl alcohol ... 0.06 ml-sodium benzoate 80 mg-95% ethanol 0.4 ml-water Sodium oxide 24mg-Propylene glycol 1.6ml-Water .... Appropriate amount up to 4ml

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] December 2, 1999 (1999.12.2)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded imageWherein -Het represents a fused monocyclic, bicyclic or tricyclic system, in which case
Or each ring, which may be unsaturated, is 4 to 7 members, and at least
One is nitrogen, oxygen and sulfur atomsSelectionSelected1From four to fourthe sameHete
A heterocyclic system which is optionally substituted
Ar can be fused to the isoindole ring via any two of the following atoms:Linear or branched C ₁ -C ₆ Alkyl residue
, Those alkyl residuesHabaMay optionally be perhalogenated,C ₂ -C ₄  Alkenyl, hydroxyl, mercapto,C ₁ -C ₆ Alkylthio, cyano or C ₂ -C ₄  Alkoxy, its alkyl moietyHabaEven if it is perhalogenated
One or more atoms, which may be the same or different, selected from
Is a phenyl residue optionally substituted with a residue, or-Dihydrobenzodioxin or dihydrobenzofuran and dihydrobenzo Selected from pyran residues Phenyl residue fused to 4- to 7-membered heterocyclic ring,; -Selected from naphthyl, indanyl and tetrahydronaphthyl groupsAromatic
Or non-aromatic polycyclic residues or selected from oxygen, nitrogen and sulfur atoms linked to a fused ring via a -carbon-carbon bond.
SelectedRuhe5- to 12-membered aromatic or non-aromatic heterocyclic residue containing a telo atom
Group, said residue is, where appropriate, a halogen atom andC ₁ -C ₆ Alkyl,C ₂ -C ₄ A
Lucenyl, hydroxyl,C ₁ -C ₄ Alkoxy, mercapto,C ₁ -C ₆ Alkyl
The same or different, selected from thio, cyano and trifluoromethyl residues
Substituted with one or more good atoms or residues, -R represents a residue of the general formula -CO-Z, wherein Z represents-a hydroxyl residue, Or-expression-OR_FourResidue, where R_FourIsC ₁ -C ₆ Represents an alkyl residue, or-a formula -N (R_Five) (R₆) Residue, where -R_FiveIs a hydrogen atom orIs C ₁ -C ₆ Represents an alkyl residue, and -R₆Is-optionally amino, alkylamino, dialkylamino, hydroxyl
,C ₂ -C ₄ Alkoxy, mercapto,Each alkyl residue contains 1 to 6 carbon atoms Have Alkylthio,The alkoxy residue has 1 to 4 carbon atomsAlkoxy
Carbonyl, carboxyl or cyano residue, optionally substituted
Contains one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms
A 5-12 membered mono- or polycyclic aromatic residue which may or may not be optionally substituted
One or more halogen atoms or one or more trifluoro
Oromethyl group or one or moreC ₁ -C ₆ Alkyl,C ₂ -C ₄ Al
Kenil,C ₁ -C ₄ Alkoxy,The alkyl group has 1 to 6 carbon atomsArchi
A phenyl residue optionally substituted with a ruthio or alkylamino residue;
Or may be substituted with a 1- or 2-naphthyl residueC ₁ -C ₆ Alkyl
A residue, or-a hydrogen atom,-a hydroxyl residue,-optionally a residue-C ₁ -C ₆ Alkyl,-possiblyC ₁ -C ₆ Alkyl andC ₂ -C ₄ Selected from alkoxy residues
May be substituted with one or more residues which may be the same or different
Phenyl residueGroup, -Selected from nitrogen, oxygen and sulfur atomsRuhe5-7 members containing a terrorist atom
Heterocyclyl,-in some casesC ₁ -C ₆ Alkyl andC ₁ -C ₄ Selected from alkoxy residues
May be substituted with one or more residues which may be the same or different
Benzoi, Substituted with one or two residues which may be the same or different selected from
An optionally substituted amino residue,-an alkoxy residue optionally substituted with a phenyl residue,₁And R_TwoMay be the same or different, a hydrogen atom, a halogen atom,C ₁ − C ₆  An alkyl residue orC ₁ -C ₄ Represents an alkoxy residue, each of which is optionally substituted with a dialkylamino residue, an alkylthio residue or an alkoxycarbonyl residue.
May beThe alkyl groups in these residues contain 1-6 carbon atoms , -R_ThreeIs a hydrogen atom,C ₁ -C ₆ Alkyl residue orIs C ₁ -C ₆ X represents a methylene residue or a 1,1-alkenediyl residue such as vinyldiyl
Or a cyclo-1,1-alkanediyl residue containing 3 to 6 carbon atoms.
Compound in the form of a racemate of, or its optical isomer or a mixture of its optical isomers
And salts of the products of general formula (I).

Embedded image Wherein: R ₁ , R ₂ and X are an acid of the formula (I), a methyl ester or a derivative of this acid such as a halide or anhydride, of the formula (III):

Embedded image Wherein Het, Ar, R and R ₃ are defined by the general formula I, and G ₁ represents a hydrogen atom, the method is carried out by acting on the product of Represents the residue —CO—OR ₄ and R ₄ represents an alkyl residue, the resulting product is saponified to give a product of general formula (I) in which R represents a carboxyl residue. A process for the preparation of a compound of general formula (I) according to any of the preceding claims, characterized in that:

Embedded image Wherein: Het, Ar, R and R ₃ are defined by the general formula I of claim 1; and G ₁ represents a hydrogen atom or a protecting group for an amine group such as benzyl.

18. The general formula (V)

Embedded image Wherein R ₃ , R ₄ and Het are as defined in the general formula (I) of claim 1,
And G ₁ represents a benzyl residue; a compound of the formula: Ar—Mg—Hal, wherein Ar is as defined in the formula (I), and Hal represents a halogen atom. Or a compound of the general formula (IV) , characterized by reacting an organolithium reagent of the general formula Ar-Li, wherein Ar is as defined above.

Embedded image Wherein, - Het, Ar and R ₃ are defined by the general formula I, - G ₁ represents a benzyl residue, - the manufacturing method of the R ₄ represents a C ₁ -C ₆ alkyl residue, compound.

19. The general formula (V):

Embedded image Wherein is as defined Het and R ₃ in the general formula (I), R ₄ represents a C ₁ -C ₆ alkyl residue, and G ₁ is for the compounds of a benzyl residue hydrazine With iodine and then with an arylboronic acid or arylstannane to give a compound of general formula (VI)

Embedded image Wherein, R _3, Het and Ar are as defined in the general formula (I), R ₄ represents a C ₁ -C ₆ alkyl residue, and G ₁ represents a benzyl residue, intermediates of Wherein the compound is converted by Friedel-Crafts type intramolecular cyclization to obtain the expected product (III).

Embedded image Wherein R ₃ , Het, Ar and R are as defined in general formula I of claim 1, and G ₁ represents a benzyl residue.

20. The general formula (VI)

Embedded image Wherein R ₃ , Het and Ar are as defined in general formula (I) of claim 1, R ₄ represents a C ₁ -C ₆ alkyl residue and G ₁ represents a benzyl residue, And a salt thereof in the form of a racemate or an optical isomer thereof or a mixture of the optical isomers thereof.

Claims21Claims18A compound of general formula (V) as defined by To An excess of strong acid, such as trifluoromethanesulfonic acid, or
In the presence of a Lewis acid such as luminiumInAromatic or heterocyclic carbonization in organic solvents
The aryl residue Ar is optionally charged with hydrogen Ar-H.
Substituted at the para or meta-para or meta-para-meta position with a child radical
A phenyl ring, or a heterocyclic residue or electron that is essentially electron-rich
18. A method as defined in claim 17 which represents a heterocyclic residue suitably substituted with a donor group.
A method for producing a compound of the general formula (III) as described above.

22. A general formula:

Embedded image Wherein, Het, which comprises carrying out the method by the action of R ₃ and R ₄ are as defined above, the cyclohexenone derivatives against N- trimethylsilylmethyl -N-n-butoxy-methylbenzylamine , R ₃ , Het and Ar are as defined in general formula I, R ₄ represents an alkyl residue and G ₁ represents a benzyl residue (V) as defined by claim 18. A method for producing the compound of

23. G ₁ is represents a protecting group of the amine function, obtained from the product of general formula as described defined by claim 18 (V), G ₁ is hydrogen,請Motomeko 18 Starting from a compound of general formula (V) as defined by formula (V), G ₁ represents a hydrogen atom, and for this product of general formula (V), a compound of general formula (II) as defined by claim 14 The method is carried out by reacting an acid or its chloride or anhydride to give a compound of the general formula (XV):

Embedded image Wherein Het, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in general formula (I), followed by the product of general formula (XV) And the general formula Ar-Mg-X
Or, by reacting a metal derivative of Ar-Li, wherein X represents a halogen atom, the product of the general formula (XV) is converted to a compound of the general formula (XVI):

Embedded image Wherein Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in general formula (I), converted to a product of formula (I) and the resulting compound of general formula (XVI) By allowing trifluoromethanesulfonic acid or Lewis acid to act on the product, Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are converted to a product of the general formula (I) Het, characterized in that it is converted into the product of general formula (I) as defined in
Ar, R _1, a manufacturing method of R _2, R _3, R ₄ and X are the general formula of claim 1 as defined in formula (I) compounds of formula (I).

24. Whether case biologically active inactive, one or at least one of the products of more pharmaceutically combination with diluent or excipient acceptable general formula (I) Pharmaceutical composition characterized by containing.

25. Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition useful for inhibiting farnesyltransferase.

Use according to claim 26 of the general formula for the manufacture of a pharmaceutical composition for the treatment and / or prevention of pathological diseases associated with cell signaling pathways associated with farnesyl transferase compound of formula (I).

27. The method according to claim 27, comprising muscle, bone or connective tissue, skin, brain, lung, genital organs, lymphatic or renal system, milk or blood cells, liver, digestive system, colon, pancreas and thyroid or adrenal gland and Pathology: psoriasis, restenosis, solid tumor, Kaposi's sarcoma, cancer, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma, teratocarcinoma, glioma, multiple myeloma, chronic A variety of tissues and / or organs, including lymphocytic leukemia, acute or chronic granulocytic lymphoma and cancers such as pancreatic, colon, lung, ovarian, breast, brain, prostate, liver, stomach, bladder or testicular cancers Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition for the treatment of a disease associated with malignant or benign cell proliferation of cells.

28. A compound of the general formula (I) for the manufacture of a pharmaceutical composition useful for the treatment of diseases associated with cell proliferation by inhibiting farnesyltransferase.
Use of the compound of (1).

29. general formula for the manufacture of a pharmaceutical composition for the treatment of cancer (
Use of the compounds of I).

30. Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition for the treatment of colon and / or pancreatic cancer.

31. One or a combination of the products of more compatible and pharmacologically active compounds of the general formula (I).

32. A combination with radiation therapy, by inhibiting farnesyl trans Blow over zero, use of a product of general formula for the manufacture of a medicament for the intended treatment of diseases associated with cell proliferation (I) .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 1/18 A61P 1/18 11/00 11/00 13/08 13/08 13/12 13/12 15 / 00 15/00 17/00 17/00 17/06 17/06 19/00 19/00 21/00 21/00 35/00 35/00 35/02 35/02 43/00 111 43/00 111 C07D 209/44 C07D 209/44 409/04 409/04 491/048 491/048 495/04 103 495/04 103 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, B , KG, KZ, MD, RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CU, CZ, EE, GD, GE, HR, HU, ID, IL, IN , IS, JP, KP, KR, LC, LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU (72) Inventor Snigo-Thompson, Juan Bienne France F-75012 Paris Rijkocott 25 F term (reference) 4C050 AA03 AA08 BB04 CC04 EE02 FF03 FF05 GG01 GG03 HH01 HH02 HH04 4C063A CC92 DD07 4C071 AA03 AA08 BB01 BB06 CC01 CC21 EE13 FF03 GG01 HH28 JJ01 JJ05 JJ06 KK01 LL01 4C086 AA01 AA02 AA03 AA04 CB03 CB27 MA01 MA04 ZA02 ZA16 ZA33 ZA34 ZA36 ZA75 ZAZZAB ZA69 4C204 BB01 BB04 CB04 DB25 EB02 F B10 GB07 GB26 GB28 GB32

Claims (34)

[Claims] 1. A compound of the general formula I Wherein-Het represents a fused monocyclic, bicyclic or tricyclic system, wherein each ring, which may be saturated or unsaturated, is 4 to 7 members and At least one contains from 1 to 4 heteroatoms, independently selected from nitrogen, oxygen and sulfur atoms, which may be the same or different; optionally substituted heterocyclic systems Can be fused to the isoindole ring via any two of its adjacent atoms; -Ar is -optionally a halogen atom and an alkyl residue such as methyl, wherein the alkyl residue is a trifluoromethyl An alkoxy, such as alkenyl, hydroxyl, mercapto, alkylthio, cyano or methoxy, optionally alkylated, wherein the alkyl portion is trifluoromethoxy. A phenyl residue which may be optionally substituted with one or more atoms or residues which may be optionally perhalogenated, such as oxygen, nitrogen and A phenyl residue fused to a 4- to 7-membered heterocycle containing one or more heteroatoms selected from sulfur atoms, especially the system comprising 2,3-dihydro-1,4-benzodioxin-6- Yl, 2,3-dihydrobenzofuran-
Selected from 5-yl and 2,3-dihydrobenzopyran-6-yl residues or residues such as 1- or 2-naphthyl, 5-indanyl or 1,2,3,4-tetrahydro-6-naphthyl. One or more selected from oxygen, nitrogen and sulfur atoms, connected to the condensed ring via a carbon-carbon bond, or-an aromatic or non-aromatic polycyclic residue. A 5- to 12-membered aromatic or non-aromatic heterocyclic residue containing a heteroatom of, where appropriate, a halogen atom and alkyl, alkenyl, hydroxyl, alkoxy, mercapto, alkylthio, cyano and Substituted with one or more atoms or residues, which may be the same or different, selected from trifluoromethyl residues, -R is a group of the general formula -CO-Z Residues represent, where, Z is representative of the following, the - hydroxyl residue or, - residue of formula -OR _4, wherein, R ₄ represents an alkyl residue such as methyl, or - residue of formula _{-N (R 5) (R 6} ), wherein - R ₅ represents a hydrogen atom or an alkyl radical, and - R ₆ is - optionally, amino, alkylamino, dialkylamino, hydroxyl, alkoxy , Mercapto, alkylthio, alkoxycarbonyl, carboxyl or cyano residues, which may or may not contain one or more heteroatoms selected from optionally substituted oxygen, nitrogen and sulfur atoms.5
1 to 12 membered mono- or polycyclic aromatic residues or optionally at one or more halogen atoms or at one or more trifluoromethyl groups or
A phenyl residue optionally substituted by one or more alkyl, alkenyl, alkoxy, alkylthio or alkylamino residues, or also 1-
Or an alkyl residue, such as methyl, which may be substituted with a 2-naphthyl residue, or-a hydrogen atom,-a hydroxyl residue,-optionally a residue-alkyl,-optionally An aryl such as phenyl, optionally substituted with one or more residues which may be the same or different selected from alkyl and alkoxy residues,-one selected from nitrogen, oxygen and sulfur atoms Or a 5-7 membered heterocyclyl containing or more heteroatoms, optionally substituted with one or more residues which may be the same or different selected from alkyl and alkoxy residues. An amino residue optionally substituted with one or two residues which may be the same or different and selected from arylcarbonyl such as benzoyl; R ₁ and R ₂ may be the same or different and represent a hydrogen atom, a halogen atom, an alkyl residue or a methoxy group,-an alkoxy residue optionally substituted by a phenyl residue; X represents an alkoxy residue, each of which may be optionally substituted by a dialkylamino residue, an alkylthio residue or an alkoxycarbonyl residue;-R ₃ represents a hydrogen atom, an alkyl residue or an alkylthio residue; Represents a methylene residue or a 1,1-alkenediyl residue such as vinyldiyl or a cyclo-1,1-alkanediyl residue containing 3 to 6 carbon atoms, or a racemic form thereof or an optical isomer thereof or Novel compounds in the form of mixtures of optical isomers and salts of the products of general formula (I). 2. Het is selected from the following residues: thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, chromenyl, indolyl or quinolyl and their iso isomers. The compound of the general formula (I) according to claim 1, characterized in that: 3. The compound of the general formula (I) according to claim 1, wherein Het represents a thienyl or indolyl residue. 4. R ₆ is 2-, 3- or 4-pyridyl residue, preferably 3-pyridyl or 4-pyridyl residue, or 2- or 4-imidazolyl residue or 2- or 4-thiazolyl residue. Or a general formula (I) according to any of the preceding claims, characterized in that it can be selected from pyridine N-oxide residues.
Compound. 5. Ar is a phenyl residue, where appropriate, preferably in the 4-position, optionally substituted by an alkyl, alkoxy or trifluoromethyl residue, or 2,3-dihydro-1,4 The general formula (1) according to any one of the preceding claims, characterized in that it represents any phenyl residue fused to a heterocyclic ring forming a bicyclic system such as -benzodioxin-6-yl. Compound of I). 6. R represents a carboxyl residue or a —COOMe residue, or alternatively a residue —CON (R ₅ ) (R ₆ ), wherein when R ₅ represents a hydrogen atom, R ₆ is phenyl or A compound of general formula (I) according to any of the preceding claims, characterized in that it represents an alkyl residue substituted by an aryl residue such as a pyridyl residue. 7. A compound according to claim 1, wherein _{one of the} symbols R ₁ or R ₂ represents a hydrogen atom and the other symbol represents an alkoxy residue. Compound of I). 8. The compound of the general formula (I) according to claim 1, wherein R ₃ represents a hydrogen atom or a methyl residue. 9. A compound of the general formula (I) according to claim 1, wherein X represents a methylene or vinyldiyl group. 10. Het represents a thienyl or indolyl residue, and Ar is optionally substituted by an alkyl, alkoxy or trifluoromethyl residue, an optionally substituted phenyl residue, or a heteroatom. A phenyl residue which is fused to a ring to form a bicyclic system; R is a carboxyl residue or a -COOMe residue, or alternatively a residue -CON (
R ₅ ) (R ₆ ), wherein R ₅ represents a hydrogen atom and R ₆ represents an alkyl residue substituted by phenyl or a 3- or 4-pyridyl residue; the symbols R ₁ or R ₂ represents a hydrogen atom, the other symbol represents an alkoxy residue, R ₃ represents a hydrogen atom, and X represents a vinyldiyl group, racemic or its optical isomer or Compounds of general formula (I) as defined in any of the preceding claims and salts thereof, in the form of a mixture of its optical isomers. 11. (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl] -8-phenyl-2,
3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2 − (2-
Methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3
a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- ( 2-
Methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl)
-2,3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N-benzyl-4,8 -Etano-2
-[2- (2-methoxyphenyl) propenoyl] -8- (4-trifluoromethylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [
2,3-f] isoindole-3a-carboxamide, (3aRS, 4SR, 10SR, 10aRS) -4,9-ethano-2- [2- (
2-methoxyphenyl) -2-propene-1-oil] -10- (4-methylphenyl) -2,3,3a, 4,10,10a-hexahydro-1H-indolo [
2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-4,
8-Ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-
(Methylphenyl) -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxamide, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano -8- (4-methoxyphenyl) -2- [2- (2-methoxyphenyl) propenoyl] -2,3
3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylate, (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-8- (4- Methoxyphenyl) -2- [2- (2-methoxyphenyl) propenoyl] -2,3
3a, 4,8,8a-Hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxylic acid, (3aRS, 4SR, 8SR, 8aRS) -N- (3-pyridyl) methyl-8-
(Benzo-1,4-dioxan-6-yl) -4,8-ethano-2- [2- (2
-Methoxyphenyl) propenoyl] -2,3,3a, 4,8,8a-hexahydro-1H-thieno [2,3-f] isoindole-3a-carboxamide. A compound of the general formula (I) and a salt thereof in the form of a racemate or an optical isomer thereof or a mixture of optical isomers thereof. 12. (3aRS, 4SR, 8SR, 8aRS) -4,8-ethano-2- [2- (2-methoxyphenyl) propenoyl] -8- (4-methylphenyl) -2,3,3a, 4,8,8a-Hexahydro-1H-thieno [2,3
-F] A compound in the form of a racemate or an optical isomer thereof or a mixture of optical isomers thereof, and a salt thereof, which is isoindole-3a-carboxylic acid. 13. A compound of general formula (I) according to any of the preceding claims, characterized in that it is preferably in the dextrorotatory form. 14. A compound of the general formula (II): Wherein: R ₁ , R ₂ and X are an acid of the formula (I), a methyl ester or a derivative of this acid such as a halide or anhydride, of the formula (III): Wherein Het, Ar, R and R ₃ are defined by the general formula I and G ₁ represents a hydrogen atom. The method is carried out by acting on the product of represents a residue -CO-OR _4, characterized in that R ₄ may represent an alkyl residue, which was saponified and the resulting product, R to obtain a product of general formula (I) to a carboxyl residue A method for producing a compound of the general formula (I) according to any one of the preceding claims. 15. An alcohol of the general formula R ₄ —OH, wherein R ₄ is as defined above, or Hal is a halogen atom (iodine) of the general formula R ₄ —Hal. Wherein the method is carried out by esterifying the product of general formula (I) wherein Z represents a hydroxyl residue with an alkyl halide of represents a residue, Z represents a residue -OR _4, R ₄ represents an alkyl residue, claim 1
13. A method for producing the compound of the general formula (I) according to any one of 13. 16. - First oxalyl chloride, followed by reacting the compound of the general formula HN (R ₅₎ (R _6), the - or the general formula HN (R ₅₎ directly reacting a compound of (R ₆₎ By reacting the product of general formula (I) wherein R represents a carboxyl residue with the general formula: HN (R ₅ ) (R ₆ ) wherein R ₅ and R ₆ are as defined above which comprises carrying out the method by the action of the product, R represents a residue of the general formula -CO-Z, wherein: Z is residue -N (R ₅₎ a (R ₆₎ Wherein R ₅ and R ₆ are as defined in general formula (I), wherein the compound of general formula (I) is as defined in any one of claims 1 to 13. 17. A compound of the general formula (III): Wherein Het, Ar, R and R ₃ are defined by the general formula I, and G ₁ represents a hydrogen atom or a protecting group for an amine group such as benzyl. 18. A compound of the general formula (IV): Wherein Het, Ar and R ₃ are defined by the general formula I, G ₁ represents a benzyl residue, and R ₄ represents an alkyl residue. Followed by replacing the group G ₁ with a hydrogen atom, characterized by the general formula (III): Wherein: Het, Ar and R ₃ are defined by the general formula I, G ₁ represents a protecting group of the amine functional groups such as hydrogen atoms or benzyl, and R represents a residue COOR _4, R ₄ is generally A process for the preparation of a compound of the formula 19. A compound of the general formula (V) Wherein R ₃ , R ₄ and Het are as defined in general formula (I), and G ₁ represents a benzyl residue, starting from a compound of general formula Ar-Mg-Hal, Ar is as defined in general formula (I), and Hal represents a halogen atom, or an organomagnesium derivative of the general formula Ar-Li, or an organolithium reagent of the general formula Ar-Li, wherein Ar is as defined above. A process for the preparation of a compound of general formula (IV) as defined in claim 18, characterized in that the process is carried out by the action of 20. The general formula (V): Wherein Het and R ₃ are as defined in general formula (I), R ₄ represents an alkyl residue and G ₁ represents a benzyl residue, starting from a compound of general formula (VI) Embedded image Wherein R ₃ , Het and Ar are as defined in general formula (I), R ₄ represents an alkyl residue, and G ₁ represents a benzyl residue. Wherein the expected product (III) is obtained by converting the compound by Friedel-Crafts type intramolecular cyclization to give the expected product (III). Wherein R ₃ , Het, Ar and R are as defined in general formula I, and G ₁ represents a benzyl residue. 21. The general formula (VI) Wherein R ₃ , Het and Ar are as defined in general formula (I), R ₄ represents an alkyl residue and G ₁ represents a benzyl residue, , A racemate or an optical isomer thereof or a mixture of optical isomers thereof and a salt thereof. 22. The general formula (V) Wherein Het and R ₃ are as defined in general formula (I), R ₄ represents an alkyl residue, and G ₁ represents a benzyl residue. Conversion to iodoethylene derivatives or to enol triflates and palladium coupling reactions known as Suzuki reactions with arylboronic acids or arylstannanes and still (St)
22. A reaction known as an ille) reaction is continued.
A method for producing a compound of general formula (VI) as defined in 23. Starting from a compound of general formula (V) as defined by claim 19, via the formation of an optionally isolable intermediate of general formula (VI) as defined by claim 21: A tandem reaction of Friedel-Crafts type intermolecular and then intramolecular cyclization in an organic solvent in the presence of an excess of a strong acid such as trifluoromethanesulfonic acid or optionally a Lewis acid such as aluminum chloride. Wherein the aryl residue Ar is optionally an electron-donating group, wherein the compound of general formula (V) is directly reacted with an aromatic or heterocyclic hydrocarbon Ar-H as defined by Appropriately substituted with a phenyl ring which may be substituted at the para or meta-para-meta position, or an essentially electron-rich heterocyclic residue or an electron donating group. To represent a heterocyclic residue which, process for the preparation of a compound of general formula as defined in claim 17 (III). 24. The general formula: Wherein Het, R ₃ and R ₄ are as defined above. For a cyclohexenone derivative of the formula: N-trialkylsilylmethyl-N bearing a protecting group for an amine function such as a benzyl residue - alkoxymethyl amine, which comprises carrying out the method by acting as N- trimethylsilylmethyl -N-n-butoxy-methylbenzylamine, be as R _3, Het and Ar are as defined in the general formula I , R ₄ represents an alkyl residue, and G ₁ is represents a benzyl residue, process for the preparation of a compound of general formula as defined by claim 19 (V). 25. Starting from the product of general formula (IV) as defined by claim 18, wherein R represents a carboxyl residue, esterification and amidation under the conditions described above, followed by trifluoromethanesulfone General formula (III), characterized in that the process is carried out by cyclization under the action of an acid. Wherein Het, Ar and R ₃ are as defined in general formula (I), G ₁ represents a benzyl residue, and R represents a residue —CO—Z, wherein: Z is a residue —OR ₄ or —N (R ₅ ) (R ₆ ), wherein R ₄ , R ₅ and R ₆ are represented by the general formula (
A process for the preparation of a compound as defined in I). 26. The process according to claim 19, wherein G ₁ represents a protecting group for the amine function, obtained from the product of general formula (V) as defined by claim 19, wherein G ₁ represents a hydrogen atom. Starting from a compound of general formula (V) as defined by formula (V), wherein G ₁ represents a hydrogen atom, the product of general formula (V) The method is carried out by reacting an acid or its chloride or anhydride to give a compound of general formula (XV): Wherein Het, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in general formula (I), followed by the product of general formula (XV) And the general formula Ar-Mg-X
Alternatively, by reacting a metal derivative of Ar-Li, wherein X represents a halogen atom, the product of general formula (XV) is converted to a product of general formula (XVI): Wherein Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in general formula (I), converted to a product of formula (I) and the resulting compound of general formula (XVI) By allowing trifluoromethanesulfonic acid or Lewis acid to act on the product, Het, Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are converted to a product of the general formula (I) Het, characterized in that it is converted into the product of general formula (I) as defined in
A process for producing a compound of general formula (I) wherein Ar, R ₁ , R ₂ , R ₃ , R ₄ and X are as defined in general formula (I). 27. Inert or biologically active at least one product of the general formula (I) in combination with one or more pharmaceutically acceptable diluents or excipients Pharmaceutical composition characterized by containing. 28. Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition useful for inhibiting farnesyltransferase. 29. Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition for the treatment and / or prevention of a pathological disease associated with a cell signaling pathway associated with farnesyltransferase. 30. comprising muscle, bone or connective tissue, skin, brain, lung, genital, lymphatic or renal system, milk or blood cells, liver, digestive system, colon, pancreas and thyroid or adrenal gland, and Pathology: psoriasis, restenosis, solid tumor, Kaposi's sarcoma, cancer, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanoma, teratocarcinoma, glioma, multiple myeloma, chronic A variety of tissues and / or organs, including lymphocytic leukemia, acute or chronic granulocytic lymphoma and cancers such as pancreatic, colon, lung, ovarian, breast, brain, prostate, liver, stomach, bladder or testicular cancers Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition for the treatment of a disease associated with malignant or benign cell proliferation of cells. 31. A compound of the general formula (I) for the manufacture of a pharmaceutical composition useful for the treatment of diseases associated with cell proliferation by inhibiting farnesyltransferase.
Use of the compound of (1). 32. The general formula for the manufacture of a pharmaceutical composition for the treatment of cancer:
Use of the compounds of I). 33. Use of a compound of general formula (I) for the manufacture of a pharmaceutical composition for the treatment of colon and / or pancreatic cancer. 34. A combination of one or more compatible and pharmacologically effective compounds and / or radiation therapy treatments with a product of general formula (I).