HRP920760A2 - Process for the preparation of benzocycloalkenyl dihydroxy alkane acid derivatives and medicaments containing them - Google Patents

Description

The field of technology

The invention is from the field of organic and pharmaceutical chemistry.

Technical problem

This invention relates to new derivatives of benzocycloalkenyl dihydroxy alkanoic acids. the procedure for obtaining them and the medicines containing them.

State of the art

It is known that certain derivatives of dihydroxy-3,5-methyl-3-pentenoic acid, known as "mevalonic acid" inhibit the enzyme hydroxy-3-methyl-glutaryl coenzyme A reductase, responsible for cholesterol biosynthesis (see SINGER et Coll. Proc . Se. Exper. Biol. Med, 102,275, 1959).

Recently, a derivative of mevalonic acid under the name "Lovastatin", formerly "Mevinolin", has been proposed as the active principle of medicinal preparations applicable in the treatment of hypercholesterolemia (see, patent US 4231938 in the name of the company MERCK).

Description of the solution to the technical problem

It has now been found by chance that new derivatives of benzocycloalkenyl dihydroxy alkanoic acids have hypocholesterol-inducing, antithrombotic and antifungal properties.

More specifically, the invention relates to compounds of formula I

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in which X represents a methylene series -CH2-, an oxygen or sulfur atom, R1 and R2 may also be identical or different and represent hydrogen atoms or alkyl radicals with 1-3 carbon atoms. R1 and R2 can also form together an alkylene chain -(CH2)n-, which can be symmetrically substituted with one or two alkyl radicals containing 1-3 carbon atoms and n can have a value of 4 or 5.

R3 and R4 which can be identical or different and represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, N,N-dialkylamino with 1-3 carbon atoms, alkyl with 1-4 carbon atoms, alkoxy with 1 - 5 carbon atoms, alkylthio with 1-3 carbon atoms or phenyl optionally substituted with two or more substituents that can be identical or different and represent radicals: alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or halogen atoms (fluorine or chlorine), in the case when one of the substituents R3 or R4 represents radicals: trifluoromethyl, N,N-dialkylamino, phenyl or substituted phenyl, this is located at the ends 3', 4' or 5' (meta or para) according to formula I, and the second substituent represents a hydrogen atom.

R5 and R6, which can be identical or different, represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or a phenyl radical that can be substituted with two or more substituents that can be identical or different and can be radicals: alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or halogens (chlorine or fluorine) in the case when one of the substituents R5 or R6 represents radicals: trifluoromethyl, phenyl or substituted phenyl, this is located at the peaks 6 or 7 according to formula I, and the second substituent is a hydrogen atom.

Substituents R3 and R4, i.e. R5 and R6, can form a whole at the same time, provided that they are located on two adjacent vertices, diradicals: diethylene, alkylene and alkylenedioxy of the corresponding formulas: -CH=CH-CH=CH-, -(CH2)m-, - O(CH2)PO- in which m can take the value 3 and 4, and p the value 1 and 2, and when R3 and R4 or R5 and R6 form an alkylenedioxy diradical, it is attached to the ends 3' and 4' and 4' and 5 ' or 6 and 7, according to formula 1.

Substituents R7 and R8 each represent a hydrogen atom, forming together with the existing C-C bond a double bond of trans geometry (E).

Substituents R9 and R10 each represent a hydrogen atom and together they form a dialkylmethylene residue with 1 - 3 carbon atoms.

R11 can represent a hydroxyl radical, whereby the compounds of formula I are carboxylic acids in free form.

The compounds of formula I can also be obtained in the form of esters and amides, which also form part of the invention.

Physiologically acceptable esters and amides of formula I, in which the substituent R11 represents the radicals alkoxy with 1 - 4 carbon atoms, benzyloxy, alkylamino and N,N-dialkylamino with 1 - 3 carbon atoms, imino with 4 - 6 carbon atoms, cycloalkylamino with 3 to 6 carbon atoms, amino and benzylamino radicals.

Compounds of the formula I in the form of salts, i.e. the formula in which the substituent R11 represents a residue of the formula +OM+ in which M+ denotes a pharmaceutically acceptable cation are also part of the invention; among these, sodium, potassium, magnesium or ammonium salts are most preferred.

Compounds of formula I can exist in the form of delta-lactone, when the substituent R11 forms a simple bond with the substituent R9; compounds of formula I in delta-lactone form equally form part of the invention.

According to the preferred form, the subject of the invention are compounds of formula I in which the substituents R1 and R2 are identical or form one alkylene chain: -(CH2)n-, unsubstituted where the number N is 4 or 5.

The extraordinary meaning of the substituents R1 and R2 when they denote alkyl radicals with 1-3 carbon atoms is, for example, methyl.

An extraordinary value of n when the substituents R1 and R2 build an ethylene chain -(CH2)n- is, for example, 4.

Extraordinary meanings for one or both of the substituents R 3 and R 4 are given below.

- when it represents a halogen atom (fluorine or chlorine);

- when it represents an alkyl radical with 1-4 carbon atoms; methyl or ethyl;

- when it represents an alkoxy radical with 1 - 5 carbon atoms: methoxy or ethoxy;

- when it represents an alkylthio radical with 1 to 3 carbon atoms: methylthio;

- when it represents a substituted phenyl radical: phenyl para substituted with a fluorine atom, a methyl radical or a methoxy radical.

The extraordinary value of m when the substituents R3 and R4 form a diradical: -(CH2)m- is, for example, 4.

The extraordinary value of p when the substituents R3 and R4 form an alkylenedioxy diradical: -O(CH2)PO- is, for example, 1.

Extremely suitable arrangements of radicals R3 and R4 are, for example, realized when R3 and R44 represent alkyl radicals with 1 to 4 carbon atoms and/or halogen atoms, or one halogen atom and one alkoxy radical with 1 to 5 carbon atoms, when one of substituents R3 and R4 are a halogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1-5 carbon atoms, an alkylthio radical with 1-3 carbon atoms, and the second is a hydrogen atom.

Specifically suitable arrangements of the radicals R3 and R4 are, for example, realized when these represent methyl radicals in position 3' and 5', a fluorine atom in position 4' and a methyl radical in position 3', fluorine atoms in position 3' and 4', an atom fluorine in position 3' or 4' and a hydrogen atom, methyl and ethyl radical in position 4' and a hydrogen atom, methoxy radical in position 3' or 4' and a hydrogen atom, chlorine atom in position 3' and 4' and a hydrogen atom hydrogen atoms. An extraordinary meaning of one of the substituents R5 and R6 is, for example:

- when it represents a halogen atom: (fluorine and chlorine);

- when it represents an alkyl radical with 1-3 carbon atoms: methoxy;

- when it represents a substituted phenyl radical in the para position with a fluorine or chlorine atom or with a methoxy radical.

An extraordinary value of m when the substituents R5 and R6 build together an alkylene chain -(CH2)m- is, for example, the value 4.

The extraordinary value of p when the substituents R5 and R6 build together the alkylenedioxy chain -O(CH2)pO is the value 1.

Extremely suitable arrangements of radicals R5 and R6 are realized, for example, when they represent halogen atoms (fluorine, chlorine, bromine), alkyl radicals with 1 - 3 carbon atoms or alkoxy radicals with 1 - 3 carbon atoms or when one of the substituents R5 and R6 represents a halogen atom which can be fluorine, chlorine or bromine or represents an alkyl radical with 1-3 carbon atoms or an alkoxy radical with 1-3 carbon atoms, and the second substituent is a hydrogen atom.

Specifically suitable arrangements of radicals R5 and R6 are, for example, realized when they represent methyl radicals in positions 5 and 7, a chlorine atom in position 6 and a hydrogen atom, a methoxy radical in position 6 and a hydrogen atom, a fluorine atom in position 6 or a 7 atom hydrogen, a methyl radical in position 6 or 7 and a hydrogen atom, a fluoro-4 phenyl radical in position 6 or 7 and a hydrogen atom, or two hydrogen atoms.

An extraordinary meaning of the substituents R9 and R10 that form a dialkylmethylene residue is, for example, dimethylmethylene.

Extraordinary meanings of the substituent R11 are given in the following text:

- when it represents an alkoxy radical with 1 - 4 carbon atoms: methoxy or ethoxy;

- when it represents an alkylamino radical with 1-3 carbon atoms;

- when it represents the N,N-dialkylamino radical with 1-3 carbon atoms: diethylamino;

- when it represents an imino radical with 4 to 6 carbon atoms: pyrrolidino.

Compounds of formula 1 in which the substituents R7 and R8 together form one bond are among the preferred compounds of formula 1 whose substituents R7 and R8 each represent a hydrogen atom.

All else being equal, compounds of formula I in which the substituents R9 and R10 each represent a hydrogen atom are preferred over compounds in which the substituents R9 and R10 form a dialkylene residue.

All else being equal, the non-lactone compounds of formula I are preferred over the delta-lactone compounds.

Among the compounds of formula I, non-lactone compounds, esters, amides and salts are generally preferred over the free acids.

All else being equal, erythro stereoisomers are preferred over threo stereoisomers (the terms erythro and threo refer to the relative orientation of the OR9 and OR10 groups).

Among the delta-lactone compounds of formula I, trans stereoisomers are preferred over cis stereoisomers (the terms cis and trans refer to the relative positions of the axial or equatorial two substituents of the delta-lactone ring).

Specific groups of compounds of the invention that are extremely desirable include compounds of formula I in which:

A) X denotes oxygen or sulfur atoms or a methylene chain, R3 and R4 each denote a methyl radical or form together a tetramethylene chain -(CH2)4-, only one of the radicals R3 and R4 form a bond together and R9 and R10 each represent a hydrogen atom.

B) X, R1, R2, R7, R8, R9 and R10 have the meanings given immediately above in A), one of the substituents R3 and R4 represents a hydrogen atom and the other a fluorine or chlorine atom and only one of the substituents R3 and R4 represents an atom of hydrogen.

C) X, R1, R2, R7, R8, R9 and R1 have the meanings defined above in A), one of the substituents R3 and R4 is a hydrogen atom and the other represents a fluorine or chlorine atom and each of the substituents R3 and R4 represents hydrogen atom.

D) X, R 1 , R 2 , R 7 , R 8 , R 9 and R 10 have the meanings specifically defined in A), two substituents R 3 and R 4 are hydrogen atoms and only one of the substituents R 3 and R 4 denotes a hydrogen atom.

E) X, R3, R4, R5, R6, R7, R8, R9, R10 have the meanings defined above in C), and R3 and R4 together form a tetramethylene chain -(CH2)4-.

F) X, R1, R2, R7, R8, R9, R10 have identical meanings given above in E) and each of the substituents R3 and R4 represents a hydrogen atom.

Each compound of formula I contains at least two centers of asymmetry which are the carbon atoms bearing the residues OR9 and OR10, when the substituents R9 and R10 each represent a hydrogen atom or together form a dialkylmethylene residue or which are the hydroxyl carbon and the tertiary carbon atom placed in the alpha position of the intracyclic oxygen atom while the substituents R9 and R10 form a bond together.

Since each compound, free acid, ester, amide, salt or delta-lactone given by formula I can exist in the form of at least four stereoisomers of two and two diastereomers, the usual configurational designations R and S with RR, SS, RS and SR are used or for the form of racemic mixtures of diastereomers, RR-SS and RS-SR.

All these isomers equally form part of the invention.

Compounds of formula I may contain two more centers of symmetry, when the substituents R1 and R2 are different, this gives additional stereoisomers which are also part of the invention.

It is within the normal competence of the specialist to isolate or synthesize the optically active form of the compounds of formula I, for example by separating the racemates or by special synthesis of the optically active compound and to determine the biological properties of the isomers thus isolated following the experiments given below.

For physiologically acceptable ester and amide, the ester or amide of the compound according to the invention is taken, which when hydrolyzed under physiological conditions, gives a physiologically acceptable alcohol or amine, that is, non-toxic in the desired doses.

The term "alkyl" refers to a saturated hydrocarbon, linear or branched, derived from the corresponding alkane by the removal of one hydrogen atom.

The term "Alkoxy" means an alkyl radical as defined above, which is attached to the basic molecule via an oxygen atom.

The term "alkylamino" refers to a nitrogen atom substituted with a hydrogen atom and an alkyl radical as defined above, and whose free valency has been used for bonding to the parent molecule.

The term "N,N-dialkylamino" means an alkylamino radical as defined above whose hydrogen atom has been replaced by an alkyl radical as defined above.

The term "imino" refers to a dialkylamino radical, as defined above, whose two alkyl radicals together form an alkylene chain.

The term "dialkyl of one to x carbon atoms" means each of two alkyl radicals forming a dialkyl radical which may independently contain from 1 to x carbon atoms.

As specific compounds of the invention, the names of individual examples can be cited, the following compounds whose formulas are given in the attachment:

Connection no. 1: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3-7-dihydroxy-3,5 - heptane-6-ethylate.

Connection no. 2: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate.

Connection no. 3: (+,-)-6E-erythro-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benothiapyran-3-yl)7-dihydroxy-3,5-hepten-6-methylate .

Connection no. 4: (+,-)-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate.

Connection no. 5: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3-7-dihydroxy-3,5-heptene -6- sodium ester.

Connection no. 6: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- heptene-6-benzilate.

Connection no. 7: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5 - N-methyl-hepten-6-amide.

Connection no. 8: (+,-)-trans-(1E-((fluoro-4-phenyl)4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethenyl)-6- hydroxy-4-tetrahydro-3,4,5,6-pyranone-2.

Connection no. 9: (+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6,-(((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1 -2, 1'- cyclopentyl)-3)-2-ethyl)-6-pyranone-2.

Connection no. 10: (+,-)-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7dihydroxy-3,5-heptane sodium ester .

Connection no. 11: (+,-)-((1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethenyl)-6-dimethyl -2,2-dioxan-1,3-yl-4) ethyl acetate.

Connection no. 12: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene-6-ethylate.

Connection no. 13: (+,-)-6E-erythro-((ethyl-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6-ethylate.

Connection no. 14: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-6-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene- 6-ethylate.

Connection no. 15: (+,-)-6E-erythro-(fluoro-7-phenyl-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-dihydroxy-3,5-heptene-6 - methylate.

Connection no. 16: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1-cyclopeutil)-3)-7-heptene- 6-ethylate.

Connection no. 17: (+,-)-6E-erythro-((fluoro-3-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene- 6-ethylate.

Connection no. 18: (+,-)-6E-erythro-dihydroxy-3,5((methoxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7 heptene - 6- ethylate.

Connection no. 19: (+,-)-6E-erythro-((chloro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6-ethylate.

Connection no. 20: (+,-)-6E-erythro-dihydroxy-3,5-((naphthyl-1-)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene -6-ethylate.

Connection no. 21: (+,-)-6E-erythro-hydroxy-3,5-((dimethyl-3,5-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)- 7-heptene-6-ethylate.

Connection no. 22: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dimethyl-5,7-spiro(2H-benzopyran-1-2,1 '-cyclopentyl)-3 )-7- dihydroxy-3,5-heptene-6-methylate.

Connection no. 23: (+,-)-6E-erythro-((ethoxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1 '-cyclopentyl)-3 )-7-dihydroxy-3,5 – heptene-6-methylate.

Connection no. 24: (+,-)-6E-erythro-dihydroxy-3,5-((isopropyloxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3) -7- heptene-6-methylate.

Connection no. 25: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-methoxy-6-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3 )-7-dihydroxy-3 ,5 - heptene-6-methylate.

Connection no. 26: (+,-)-6E-erythro-((trifluoromethyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- heptene-6-methylate.

Connection no. 27: (+,-)-6E-erythro-dihydroxy-3,5-((n-pentyl-oxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-heptene-6-methylate.

Connection no. 28: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-naphtho(b)pyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy -3,5-heptene-6-methylate.

Connection no. 29: (+,-)-6E-erythro-dihydroxy-3,5-((methylthio-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7- heptene-6-methylate.

Connection no. 30: (+,-)-6E-erythro-((tertiobutyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5-heptene -6 ethylate.

Connection no. 31: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclohexyl)-3)-7-dihydroxy-3,5- heptene-6 ethylate.

Connection no. 32: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-isoproxy-7-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy- 3,5 – heptene-6 methylate.

Connection no. 33: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy-3,5 –heptene-6-amide.

Connection no. 34: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -N-isopropyl-hepten-6 amide.

Connection no. 35: (+,-)-6E-erythro-((biphenyl-1,1-yl-4-)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy -3,5-N,N-tetramethylene-heptene-6 amide.

Connection no. 36: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3 -7-dihydroxy-3,5 - N-cyclohexyl-hepten-6 amide.

Connection no. 37: (+,-)-6E-erythro-N-benzyl-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)3 )-7-dihydroxy-3 ,5 - hepten-6 amide.

Connection no. 38: (+,-)-6E-erythro-(ethyl-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- sodium heptene-6 ester.

Connection no. 39: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-6-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene- 6 sodium ester.

Connection no. 40: (+,-)-6E-erythro-dihydroxy-3,5-((isopropyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7- sodium heptene-6-ester.

Connection no. 41: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-6 sodium ester.

Connection no. 42: (+,-)-6E-erythro-((chloro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6 ester sodium.

Connection no. 43: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-2H-benzopyran-1-yl-3)-7-heptau-6 ethylate.

Connection no. 44: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dimethyl-2,2-2H-benzopyran-1-yl-3)-7-dihydroxy-3,5-heptene- 6 methylate.

Connection no. 45: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-isopropyl-2-2H-benzopyran-1-yl-dilyhydroxy-3,5-hepten-6 ethylate.

Connection no. 46: (+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6-(1E-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)- 2-ethenyl)-6-2H-pyranone-2.

Connection no. 47: (+,-)-trans-(1E(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-2-ethenyl)-hydroxy-4-tetrahydro-3,4,5 ,6-2H-pyranone-2.

Connection no. 48: (+,-)-trans-(1E(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-2-ethenyl)-hydroxy-4-tetrahydro-3,4,5 ,6-2H-pyranone-2.

Connection no. 49: (+,-)-trans-bihydroxy-4-tetrahydro-3,4,5,6,-(1E82H-dimethyl-2,2-phenyl-4-benzothiapyranyl-3)-2-ethenyl)-6- 2H-pyranone-2.

Connection no. 50: (+,-)-erythro-dihydroxy-3,5-(phenyl-4-spiro(dihydro-1,2-naphthalene-2,r-cyclopentyl)-3 )-7-heptene-6-methylate.

Connection no. 51: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dihydro-1,2-dimethyl-2,2-naphthyl-3)-7-dihydroxy-3,5-heptene- 6 methylate.

Connection no. 52: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-keptene-6 methylate.

Connection no. 53: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopentyl-3)-7-dihydroxy-3,5- heptene-6 methylate.

Connection no. 54: (+,-)-6E-erythro-((-chloro-4-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopeutil)-3 )-7-dihydroxy-3 ,5 -heptene-6 methylate.

Connection no. 55: (+,-)-6E-erythro-((-chloro-4-methyl)-4-dihydro-1,2-dimethyl-2,2-naphthyl-3)-7-dihydroxy-3,5-heptene -6 methylate.

Connection no. 56: (+,-)-6E-erythro-((fluoro-3-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopentyl-3)-7-dihydroxy-3,5 -heptene-6 methylate.

Connection no. 57: (+,-)-6E-erythro-((-fluoro-4-phenyl)-4-dihydro-1,2-naphthyl-3)-7-dihydroxy-3,5-heptene-6 ester sodium.

Connection no. 58: (+,-)-6E-erythro-(dihydro-1,2-isopropyl-2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6 methylate.

The connection would. 59: (+,-)-6E-erythro-(dihydro-1,2-methyl-2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-3,5-heptene-6 methylate .

Connection no. 60: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-8-(methyl-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,r-cyclopentyl) - 3)-7-heptene-6 methylate.

Connection no. 61: (+,-)-6E-erythro-(chloro-6-(chloro-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,1'-cyclopentyl)-3)-7- dihydroxy -3,5- heptene-6 methylate.

Connection no. 62: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-8-(methoxy-4-phenyl)-4-spiro(dihydro-1,2-uaphthalene-2, 1'-cyclopentyl) -3)- 7 -heptene-6 methylate.

Connection no. 63: (+,-)-6E-erythro-(chloro-(fluoro-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,1'-cyclopentyl)-3)-7-dihydroxy- 3,5-heptene-6 methylate.

Connection no. 64: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-methoxy-7-naphthyl-3)-7-dihydroxy-3,5-heptene-6 methylate.

Connection no. 65: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzothiapyran-1-2,1'-cyclopeutil)-3)-7-heptene-6 sodium ester.

Connection no. 66: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-4-phenyl)-4-spiro(2H-benzothiapyran-1-2,1'-cyclopentyl)-3)-7-heptene -6 methylate.

Connection no. 67: (+r)-6E-erythro-dihydroxy-3,5-(phenyl-4-dimethyl-2,2-2H-benzothiapyrayl-3)-7-heptene-6 methylate.

Connection no. 68: (+r)-6E-erythro-dihydroxy-3,5-(phenn-4-dimethyl-2,2-2H-benzothiapyranyl-3)-7-heptene-6 sodium ester.

The invention also relates to methods for obtaining compounds according to the invention characterized by comprising at least:

a) reduction of the keto-ester of the general formula 4, in which X, R1, R2, R3, R4, R5, R6, R7, R8 and R11 have the general meanings or those already defined in the previous text,

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and if it happened,

b) transesterification of compounds of formula 1 or alcoholysis of compounds of formula 1 in the form of delta-lactoil or alkylation of compounds of formula 1 in the form of salts,

c) hydrolysis of the compound of formula 1 in the form of an ester or delta lactone,

d) when R7 and R8 or R9 and R11 form a simple connection; treating the corresponding compounds of formula 1 in salt form with tertiary chloramine,

e) when R7, R8 and R10 denote a hydrogen atom, and R9 and R11 form one bond together; catalytic reduction of delta lactone compounds of formula 1 in which R7 and R8 form one bond; lactonization of acid compounds of the corresponding formula 1 in which R7, Rx and R10 denote a hydrogen atom;

f) aminolysis of compounds of formula 1 in the form of esters or delta-lactones;

g) when R9 and R10 form together a dialkylmethylene residue; cyclization of the corresponding compounds of formula 1, wherein R 9 and R 10 each represent a hydrogen atom with an alkoxyalkene.

Compounds of formula 1, in which X, R1, R2, R3, R4, R5, R6, R7, R8 have the general meanings specifically defined in the preceding text and in which the substituents R9 and R10 denote each hydrogen atom can be obtained, in the form of esters, according to reaction sequences illustrated by the following scheme I:

[image]

[image]

As indicated in Scheme I, aldehyde compounds of formula 2 in which the substituents in which R1, R2, R3, R4, R5, R6, R7, R8 have the general or specific meanings already defined are subjected to aldolin condensation with the corresponding acetoacetate in the form of a double sodium salt and lithium of formula 3 in which R 11 has the meanings general or specific already defined in the middle of a polar solvent, such as THF (see KRAUS et colL J. Org. Cliem. 48, 2111, 1983) to obtain hydroxy-5-oxo-3-heptene -6-substituted-7 esters of formula 4.

Esters of formula 4, solution in an inert solvent, such as THF or ether, treated with alkaline borohydride, preferably sodium borohydride (method A) give compounds 1 in the form of a mixture of threo and erythro isomers, which can be separated by usual physicochemical methods such as, for example, chromatography.

One variant (process B) more suitable than process A, which gives the compounds according to the invention in the erythro form, consists first of all in the reduction with alkaline borohydride, in the treatment of ester 4 in a solution of a suitable solvent such as THF, with a complexing agent preferably a trialkylborane such as tributyl .

Compounds of formula 2, in which the substituents R7 and R8 form a bond together, can be obtained according to the reaction sequences illustrated in the following scheme II:

[image]

As indicated in Scheme II, compounds of formula 5, in which X, R1, R2, R3, R4, R5, R6, have the general or specific meanings already defined were obtained by the Vilsmeier reaction with N,N-dimethyl- with amino-3-acrolein (see ULLRICH et BREITHAJER, Synthesis 8, 641-645, 1983) in an inert solvent such as acetonitrile at a temperature between 20°C and the reflux temperature to give compounds of 2 trans geometry as shown by NMR by spectroscopy.

Another process for obtaining aldehydes of formula 2, in which R7 and R8 form a single bond together, is illustrated by the following Scheme IQII

[image]

As indicated in Scheme III, compounds of formula 5 are obtained by bromination reaction with N-bromosuccinamide (NBS) in N,N-dimethylformamide (DMF) or a chlorinated solvent such as carbon tetrachloride or methylene chloride to give the corresponding 3- brominated compounds which are then treated with butyllithium in a suitable solvent, preferably an ether such as, for example, diethyl ether, and then with ethoxy-3-acrolein or N,N-dimethylamino-3-acrolein to form aldehyde 2 in the trans form as shown by means of NMR spectroscopy.

An alternative procedure for obtaining intermediate aldehydes of formula 2 in which R7 and R8 form a bond together is illustrated by the following Scheme IV:

[image]

As indicated in Scheme IV, compounds of formula 5 are prepared by Vilsmeir reaction with N,N-dimethylformamide (see JACKSON et Coll. J. Am. Chem. Soc. 103, 533, 1981) in an inert solvent to build the corresponding aldehydes used in the WITTIG reaction with ethoxy"methoxy carbonyl methylene triphenyl phosphorane or with methyl ethyl phosphonoacetate (see, Organic Reactions, 14, 273, 1965) to obtain propene 3-substituted esters 8 whose configuration is trans as as shown by NMR spectroscopy.

An alternative procedure for obtaining intermediate compounds of formula 8, which are particularly suitable when X denotes a sulfur atom, consists in reacting the brominated compound of formula 6 with alkyl acrylate, preferably methyl ethyl acrylate in the presence of a base agent, such as triethylamine sodium bicarbonate, palladium dispersed on carbon, a palladium derivative such as palladium dichloride, its acetate, and a ligand, preferably a triarylphosphine such as triorthotolylphosphine, in a suitable solvent, such as N,N-dimethylformamide.

Esters 8 are reacted with diisobutylaluminum hydride (DEBAL) in a solvent medium, usually diethyl ether and THF, to give the corresponding compounds of the 9-propenol 3-substituted trans form which are then subjected to oxidation with oxalyl chloride in DMSO (see SWERN et coll, J. Org. Chem. 43 2480, 1978) with manganese dioxide in a suitable solvent such as, for example, THF, in order to obtain the aldehyde of formula 2 and geometry trans.

Aldehydes of formula 2, in which the substituents R7 and R8 each represent a hydrogen atom, can be obtained according to the reaction sequences illustrated by Scheme V as follows:

[image]

According to the reaction sequences of the Scheme, aldehydes of the formula 2 where R7 and R8 form a double bond are subjected to an acetylation reaction, for example with an orthobromomate of the formula HC(OR12)3 in which, R12 represents an alkyl radical with 1-4 carbon atoms, preferably methyl or ethyl in the presence of an acid resin or another acid-catalyzed reaction with an alcohol of the formula R12OH in which R12 has the meanings given above or can represent a radical of the formula -(CH2)qOH, in which q = 2 or 3 to build compounds 10, methylene radical -R12 ...... R11- then builds with the oxygen atoms that bind the five-membered six-membered ring.

Compounds 10 are then hydrogenated, preferably at low pressure and in the presence of a metal catalyst, such as palladium dispersed on carbon, in a suitable solvent such as THF or an alcohol such as methanol, to the corresponding 3-substituted propanaldehydes which can then be deacylated to propanaldehydes 2 procedures applicable for deacetalization, which include, for example, the treatment of acetals with an acid resin in an acetone-water mixture or, more often, with an acid catalyst, in a solvent or a mixture of suitable solvents.

An alternative for obtaining aldehyde compounds of formula 2, in which the substituents R7 and R8 each represent a hydrogen atom, consists in reacting brominated compounds of formula 6 with allyl alcohol in the presence of a base agent such as triethylamine, sodium bicarbonate, palladium dispersed on carbon or a palladium derivative such as palladium dichloride or its acetate and a ligand, preferably a triarylphosphine such as triorthotolyl phosphine in a solvent such as N,N-dimethylformamide.

Compounds of formula 5 may be prepared according to the sequences illustrated in Scheme VI which follows:

[image]

according to which ketone compounds of the formula 12, in which X, R1, R2, R5 and R6, have the general or specific meanings already defined, are treated with a lithium or magnesium compound of the formula 13, in which R3 and R4 have the general or previously defined specific meanings , works by adding 1-2 alcohols, the corresponding compound 14, which upon dehydration gives compound 5 under the action of a dehydrating agent such as potassium sulfate or paratoluenesulfonic acid.

Compounds of formula 12, in which X represents oxygen and sulfur atoms, and R1, R2, R5 and R6 have the general or specific previously defined meanings are obtained according to the procedure of KABEE et Coll. Synthesis, 12, 886, 1978.

Compounds of formula 12, in which X represents a methylene chain and R1, R2, R5 and R6 have the general or specific meanings defined above are obtained according to the reaction sequences illustrated in the following Scheme VII:

[image]

As shown in Scheme VII, the cyanoesters of formula 15, in which R1, R2, R5 and R6, have the general or specific meanings already defined, are hydrolyzed and decarbolized with glycolic potassium hydroxide to the corresponding acids 16, which cyclize to compounds 12 by heating in an acidic medium . Compounds of formula 15 are prepared according to the procedure described by PROUT et Coll, Org. Synth, Coll. vol. IV, 93, 1963.

Compounds of formula 1 in the form of esters can equally be obtained by means of transesterification of compounds of formula I, various substituents R11, or by alcoholysis of compounds of formula 1 in the form of delta-lactones or also by O-alkylation of compounds of formula 1 in the form of salts, preferably sodium salts with broinide or iodide of the formula Ru-br(I), in which R11 has the general or specific meanings previously defined.

Esters corresponding to formula 1, in which the substituents R7 and R8 each represent a hydrogen atom can also be obtained by hydrogenation of the corresponding esters of formula 1, in which the substituents R7 and R8 form a single bond, preferably under reduced pressure, in the presence of a metal catalyst such as palladium or platinum oxide in a suitable solvent such as, for example, THF.

Compounds of formula 1 in the form of salts can be obtained, for example, by basic hydrolysis with sodium potassium hydroxide in a suitable solvent, preferably alcohol, of the corresponding compounds of formula 1 in the form of esters, preferably methyl ethyl esters in the form of delta-lactone.

Delta-lactone compounds of formula 1, in which the substituents R7 and R8 together form one bond, can be obtained by reacting the corresponding compounds of formula 1 in the form of salts, preferably sodium hydroxide with chloramine, preferably chloro-2-ethyl-N,N-diethylamine in the appropriate solvent, preferably a carbonyl such as acetone or butanone.

Lactone compounds of formula 1, in which R7 and R8 and R10 represent a hydrogen atom, are obtained by lactonization of the corresponding acids of formula 1, that is, formulas in which Rn represents a hydroxy radical: the lactonization reaction is preferably performed by heating acids in an inert aromatic solvent, such as benzene, toluene, xylene and their mixture, the case requires the presence of a dehydrating agent, such as for example paratoluenesulfonic acid; another very acceptable procedure for obtaining delta-lactone compounds of formula 1, in which R7 and R8 and R10 represent a hydrogen atom, consists in hydrogenation in a heterogeneous phase of unsaturated corresponding compounds of formula 1, that is to say formulas in which R7 and R8, respectively R9 and R10 form a single bond together, in the presence of a metal catalyst, preferably palladium dispersed on the carbon of platinum oxide, in the middle of a suitable solvent, preferably an ether such as THF or an alcohol such as methanol or ethanol.

Compounds, acids of the formula 1 in which R9 and R10 each represent a hydrogen atom, can be obtained by acidifying the corresponding compounds of the formula 1 in the form of salts by further hydrogenolysis, in the presence of palladium dispersed on carbon, of the corresponding benzylic esters, that is, compounds of the formula 1 in which R11 represents benzyloxy residue.

Compounds of formula 1 in the form of amides are obtained by aminolysis with an excess of amine in the middle of a polar solvent, preferably methanol or ethanol, the corresponding esters of formula 1, preferably methylene or ethylene esters, or the corresponding compounds of formula 1 in the form of delta-lactone.

The compounds of formula 1, in which the substituents R9 and R10 together form a dialkylmethylene group in Cl-3, are obtained by the reaction of the corresponding compounds of formula 1, in which R9 and R10 each represent a hydrogen atom with the corresponding alkoxyalkene (the term alkoxyalkene means an alkene with 3 to 7 carbon atoms substituted at the double bond with an alkoxy radical, such as defined above, preferably methoxy) in a suitable solvent, such as N,N-dimethylformamide for example in the presence of an acid catalyst such as paratoluenesulfonic acid.

It is convenient to note that the compounds of the invention in their various forms: acid, salt, ester, amide or lactone can be mutually converted from one form to another in the procedures described above; as a consequence of this, these different forms are simultaneously intermediates in the synthesis of compounds according to the invention.

Stereoisomeric mixtures (cis, trans, threo, erythro, enantiomers) can be separated by the usual procedures, at the most convenient stages of the synthesis.

Common procedures for separation are, for example, recrystallization, chromatography, or building compounds with optimally active compounds.

Intermediate synthesis compounds corresponding to formulas 2, 4, 5, 6, 7, 8, 9, 10, or 14 equally form part of the invention, with the exception of products of formula 5 where R1 and R2 represent H and X represents S or CH2, some of of these compounds were known earlier, Degani, Ann. Chem (Rome) 1971, 61(2) p. 793-813 and Penn. J. Magn. Reson. 1975. 18(1), p. 6-11.

This invention relates equally to the preparation of synthesis intermediates.

The compounds of formula 1 have the property of inhibiting hydroxy-3 methyl-3glutaric coenzyme A, and therefore exhibit a strong hypocholesterolemic effect.

Compounds of formula 1 are capable as antagonists of the thromboxane A2 receptor, which is a feature that is explained by the antiplatelet action of platelets.

These properties of the compounds of the invention make their use as drugs for the treatment of various cardiovascular diseases, such as, for example, thrombotic manifestations of diabetes, arteriosclerosis, biperlipoproteimemia, particularly interesting.

In addition, the compounds of the invention possess antifungal properties, which makes them particularly interesting as drugs for antimycotic activity.

The pharmacological properties of the compounds according to the invention were demonstrated by the following tests:

Test A: by measuring hepatic 14C-cholesterogenesis, in vivo, in rats according to the procedure described by BUCHER et Coll, J. Biol. Chem, 222, ,1-15, 1956 and ELBERTS et Coll, Proc. Natl. Acad. Sci. USA, 77(7), 3957 - 3961, 1980.

Test B: by measuring total cholesterolemia, in vivo. in rats treated intravenously with triton WR 1339 according to the procedure described by ENDO et Coll, Biochem. Biophvs. Acta, 575, 226 - 276, 1979.

Test C: by measuring platelet aggregation induced by TXA2 receptor agonists in guinea pigs in the following manner: platelet-rich plasma (PRP) was obtained by puncturing the aorta of anesthetized animals; blood (9 vol.) was placed in a solution containing 106 mM trisodium citrate (1 vol.) to prevent coagulation. PRPs were isolated by gentle centrifugation (10 min, 380 g) and were incubated for at least 3 min (37 °C, with slow mixing) in a CHRONOLOG-400 type aggregometer. Aggregation of platelets was performed by the addition of TXA2 direct receptor agonists, such as the compound known under the code name U 46619 (20 nM) according to MALMSTEIN, Life Sci, 18, 169, 178, 1976; compounds of the invention have been tested in vitro.

For example, when testing compounds no. 1,2, 19 and 65 according to test A DE 50 was used in the amount of 0.17 mg/kg, 0.6 mg/kg, 0.09 mg/kg and 0.38 mg/kg respectively, and for Lovastatin in the same conditions 0.39 mg/kg.

For the same compounds in test B, DE 25 was used in amounts of 29, 100, 110 and 74 mg/kg respectively and 130 mg/kg for Lovastatin. In test C for compounds no. 1 and 19 use CI 50 of 91 and 28 10-6 mol/L.

This invention equally relates to medicaments containing compounds of the general formula 1 taken as such, in their pure state together with other products acceptable from a pharmaceutical point of view which may be inert or physiologically active.

These medications can be taken into the body in various forms such as tablets, dragees, capsules, granules, powders, etc. In these preparations, the active principle is a mixture of several inert diluents such as lactose and starch, in other preparations they can be present and other substances, not only diluents, for example lubricants such as talc and magnesium stearate; in the case of aqueous suspensions, elixirs for oral administration, the active ingredient can be bound with various substances for coloring and flavoring, and in the case of emulsions, the axis of suspension additives can also contain such diluents as water, ethanol, propylene glycol and the like.

Pharmaceutical preparations according to the invention, intended for oral administration and presented in the form of a single dose, contain from 1 to 500 mg of the active principle.

The following example is given not to limit but to illustrate one preparation of this type.

Example:

Active principle 10 mg

lactose 104 mg

cereal starch 30 mg

talc 2.5 mg

polyvinyl excipient 3 mg

magnesium stearate 0.5 mg

The invention is illustrated by non-limiting examples given below, in which:

- all evaporations were carried out, unless otherwise indicated, in a rotary evaporator under reduced pressure;

- all temperatures are given in degrees °C;

- when "room temperature" is indicated, it means a temperature between 18 and 25 °C;

- unless otherwise stated, the degree of progress of the reaction is controlled by thin-layer chromatography (CCM);

- new compounds are characterized by their physical constants, tahšte tt. them by the boiling point, i.e. with possibly indicating the pressure in the mihbars;

yields possibly given are given in one value which is not the highest possible;

- nuclear magnetic resonance spectra, unless otherwise stated, are proton and given at 60 Mhz in the presence of tetramethylsilane as an inert standard; chemical shifts are indicated in ppm, signals are described by the following abbreviations, s singlet, d doublet, dd i doublet i doublet, t triplet, q quartet, m multiplet;

- infrared spectra of compounds registered on tableted dispersion of potassium bromide in the case of a solid substance or film in the case of a liquid.

Example 1.

(+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptene- 6-ethylate (compound No. 1 of formula 1: X = 0, R1 - R2 = (CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 = H, R7 - R8 = bond, R11 = OC2H5).

Stage 1

(fluoro-4-phenyl)-4-dihydro-3,4-hydroxy-4-spiro(2H-benzopyran-1-2,1'-cyclopentane) (Scheme VI - formula 14).

It is done in a nitrogen atmosphere in a reactor protected from moisture. To 6.07 g (0.25 gram atoms) of magnesium suspended in 130 cm3 of diethyl ether, while maintaining a slight reflux of ether, 43.75 g (0.25 mole) of bromo-1-fluoro-4-benzene dissolved in 200 cm3 of diethyl ether. After maintaining the mixture at reflux for 4 hours, the mixture was cooled to room temperature and at this temperature 20 g (0.1 mol) of spiro(2H-benzopyran-1-2,1'-cyclopentanone-4) (obtained according to Kolbe) was added et Coll, Synthesis 12, 886, 1978) dissolved in 60 cm 3 of diethyl ether, while maintaining a gentle ether reflux.

The mixture is stirred for 2 hours at room temperature and then poured onto a frozen aqueous solution of ammonium chloride in a large excess over the stoichiometric ratio; a sufficient amount of dilute hydrochloric acid is added to completely dissolve the suspension, then the organic phase is decanted; washed with water at neutral pH and dried over sodium sulfate, filtered and the solvent evaporated; 30 g of oil is obtained, which is used as is in the continuation of the synthesis.

Stage 2:

(Fluoro-4-phenyl)4-spiro(2H-benzopyran-1-2,1'-cyclopentane) (Scheme VI - formula 5).

A mixture of 30 g (0.1 mol) of the product from step 1 and 3 g of KHSO4 (1/10 of the mass of the compound under consideration) is heated under reduced pressure (16 mm Hg) at a temperature of 120 °C for 30 minutes. Dissolve the residue in a sufficient amount of dichloromethane, wash the solution with water, then dry it over sodium sulfate, filter and evaporate the solvent; the obtained solid substance is dispersed in methyl alcohol.

tt. 76-8 ° (diisopropyl ether) - Yield 75 %.

(CCM: silica gel: ethyl acetate (AcOEt)-hexane: 5-95: 1 spot

Analysis C19H17FO M = 280.33

CH F

% calculated 81.40 6.11 6.78

% found 81.53 6.20 6.76

NMR (CDCl 3 ): 1.25 - 2.70 (m, 8H); 5.73 (s, IH); 6.50 - 7.87 (m, 8H)

Stage 3

2E-((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propen-2-al (Scheme II - formula 2)

It is done under a nitrogen atmosphere, in a reactor protected from moisture. Unless otherwise stated, during the following operations the temperature of the reaction mixture is maintained at -20 °C. In a solution of 20.9 g (0.2 mol) of N,N-dimethylamino-3 acrolein in 200 cm3 of acetonitrile, 29.1 g (0.19 mol) of phosphorus oxychloride is added at intervals of 30 minutes with stirring; stirring is required for 10 min and then 11.2 g (0.04 mol) of the compound from stage 2 dissolved in 100 cm3 of acetonitrile is added over 15 min. Leave the mixture to reach room temperature and then heat it at reflux while the departure of the product is controlled by thin-layer chromatography; in this case, the required heating time is 40 hours.

The mixture is evaporated and the residue is poured into 1000 cm3 of ice water, neutralized (pH = 9) by adding a sufficient amount of concentrated sodium carbonate, the solution is stirred for 15 min and then extracted with 1000 cm3 of methylene chloride (2 x 500 cm3). The organic layer is washed with water and dried over sodium sulfate, filtered, 1000 cm3 of hexane is added and mixed in the presence of 100 g of silica gel. After filtration and evaporation, an oil is obtained which crystallizes giving a yellow solid by dispersing in hexane,

tt. 108 - 111 °C (diisopropyl ether) - yield 8.4 g = 63 %.

Analysis C22H19FO2 M = 334.37

CH F

% calculated 79.02 5.73 5.68

% found 78.82 5.75 5.65

IR:

VCHO: 1670 cm -1 NMR (CDCl 3 ): 1.25 - 2.87 (m, 8H); 5.98 (dd, IH J = 17 Hz and 7 Hz); 6.37 - 7.5 (m, 9H); 9.25 (d, IH J = 7 Hz).

Stage 4:

(+,-)-6E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-hydroxy-5-oxo-3-heptene- 6-ethylate

(Scheme I-Formula 4).

It is done under a nitrogen atmosphere and in the absence of moisture, maintaining the temperature of the mixture unless otherwise stated at -20 °C. 5.6 g (0.043 mol) of ethyl acetoacetate dissolved in 25 cm3 of THF is added to a suspension of 1.2 g (0.05 mol) of sodium hydride in 300 cm3 of tetrahydrofuran (THF); the mixture is stirred for 20 min, then after 15 - 20 min, 27 cm3 of a solution of 1.6 N butyllithium in hexane (0.043 mol of BuLi) is added; after stirring the mixture for 20 minutes, 8.7 g (0.026 mol) of aldehyde from stage 3 in 140 cm3THF was added drop by drop. After stirring the mixture for 3 hours, 40 ml of 3 N hydrochloric acid solution is added drop by drop at a temperature between -20 °C and 10 °C. It is extracted in ethyl acetate, the organic phase is washed with water to pH 7, dried over sodium sulfate, then evaporated to dryness, an oil is obtained which crystallizes by dispersing in hexane. mp: 87 - 90 °C (ethyl acetate) - Yield = 110 g = 90.9 % (CCM: silica gel: AcOEt-hexane: 1 - 2: 1 spot)

Analysis C28H29FO5 M = 464.51

CH F

% calculated 72.40 6.29 4.09

% found 72.33 6.31 4.05

IR:

VOH: 3420 cm-1

VCO: 1740 and 1710 cm-1

NMR (CDCl 3 ): 1.32 (3, 3H); 1.5 - 2.35 (m, 8H); 2.52 (d, 2H); 3.92 - 4.65 (m, 39H); 5.30 (dd, IH J =15, 8 Hz); 6.25 - 7.50 (m, 8H).

Stage 5:

(+,-)-6E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl))-3)-7-dihydroxy-3,5-heptene-ethylate (compound no. 1).

It is done under a nitrogen atmosphere in a reactor protected from moisture. Unless otherwise stated, during the following operations the temperature of the reaction mixture is maintained at -70°C. In a solution of 3.25 g (0.007 mol) of the cheto ester from stage 4 in a mixture with 65 cm3 of THF and 15 cm3 of methanol, 7.7 cm3 of a solution of 1 N diethylmethoxyborane in THF (0.007 mol + 10 % wrinkle).

After stirring the mixture for 40 min, 0.29 g (0.007 mol + 10% sodium borohydride) is added. After stirring the mixture for 5 hours, it is acidified by adding 6.5 cm3 of acetic acid, after which 80 cm3 of ethyl acetate is added. The mixture is left to take room temperature; then the mixture is washed with a saturated aqueous solution of sodium bicarbonate (2 x 200 cm3) and then with water; the organic phase is decanted, dried over sodium sulfate and then the solvent is evaporated. The residual oil obtained is dissolved in 60 cm3 of methanol ; this solution is stirred for 20 min at 35 °C and then evaporated to dryness. This operation is repeated until a constant mass is reached, in this case the operation was repeated four times.

Then 3.1 g of a solid substance is obtained which is dispersed in diisopropyl ether. tt. 112 - 114 °C (ethyl acetate) - Yield = 2.48 g = 76 %. (CCM: silica gel: AcOEt-hexane: 1-1:1 stain)

Analysis C28H31FO5 M - 466.55

CH F

% calculated 72.08 6.70 4.07

% found 72.82 6.83 3.90

IR:

VOH: 3390 cm-1

VCO = 1715 cm-1

NMR (CDCl 3 ) -200 MHz: 1.275 (t, 3H); 1.20 - 1.58 (m, 2H) 1.60 - 2.29 (m, 8H); 2.36 - 2.44 (m, 2H); 4.17 (q, 2H); 4.00 - 4.29 (m, 2H); 5.34 (dd, IH J = 16.1 Hz and J = 6.3 Hz); 5.94 (dd, IH J = 16, 1 Hz and 1.2 Hz); 6.54 (dd IH J = 7.7 Hz and 1.5 Hz); 6.70 - 6.85 (m, 2H); 7.00 - 7.20 (m, 5H).

HPLC:

Silicon dioxide column 5 spherical 25 cm

UV detection - 254 nm

Mobile phase: AcOEt-hexane-AcOH: 35-65-0.01

1 peak: (11.1 min)

Example 2.

(+)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate

(Compound no. 2 - formula 1: X = CH2; R1 = R2 = CH3; R3 = R4 = R5; R6 = R9 = R10 = H; R7 and Ks = bond; R11 = OCH3)

Stage 1:

Ethyl (dimethyl-2,2-phenyl-3-propyl)-2-cyanoacetate (Scheme VII-formula 15)

A solution of 100 g (0.79 mol) of benzyl chloride in 400 cm3 of ether is added to a suspension of 19.2 g (0.79 gram atoms) of magnesium in 100 cm3 of ether while maintaining a slight reflux. The mixture is heated at reflux for 15 min and then a solution of 101.1 g (0.66 mol) of ethyl isopropylidene cyanoacetate in 130 cm3 of ether is added while maintaining a slight reflux. The mixture is heated at reflux for 2 hours, then cooled and 400 cm3 of water and then 100 cm3 of 20% H2SO4 solution are slowly added.

The mixture is then stirred for 20 minutes and the organic phase is then decanted.

The aqueous phase is extracted with ether and the combined ether phases are dried over sodium sulfate, filtered and distilled.

t key 115-121 °C - yield 147 g = 90 %.

IR:

VC=O: 1740 cm-1, VCN: 2250 cm-1

NMR (CDCCl 3 ): 1-1.5 (m, 9H); 2.75 (s, 2H); 3.25 (s, 1H; 4.2 (q, 2H); 6.7-7.6 (m, 5H).

Stage 2:

Dimethyl-3,3-phenyl-4-butanoic acid (Scheme VII - formula 16)

A solution of 70 g of potassium hydroxide in 230 cm3 of ethylene glycol is added without cooling to 70 g (0.285 mol) of the compound of stage 1.

The mixture is heated at reflux (140 °C) for 3 hours and 15 minutes. The volatile solvent was evaporated under reduced pressure of 15 mm Hg and then the mixture was heated at reflux (197 °C) for 6 hours. The mixture is cooled and 500 cm3 of water is added and extracted with ether. The aqueous phase is acidified by the addition of concentrated hydrochloric acid and extracted into benzene. The benzene phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Thus, 48.7 g of oil is isolated, which is used as such in the following synthesis. Yield = 89%.

IR:

VCO: 1700 cm-1

NMR (CDCl 3 ): 1 (s, 6H); 2.2 (s, 2H); 2.65 (s, 2H); 6.8 - 7.5 (m, 5H).

Stage 3:

Tetrahydro-1,2,3,4-dimethyl-3,3-oxo-1-naphthalene (Scheme VII - formula 12)

A mixture of 292 g of polyphosphoric acid and 860 cm 3 of xylene is heated to a temperature between 70 and 80 °C and at this temperature 48.7 g (0.253 mol) of the compound from stage 2 dissolved in 550 cm 3 of xylene is added. The mixture is heated at reflux for 6 hours and 30 minutes, then cooled, the xylene phase is decanted; 2000 cm3 is added to the remaining mineral part and extracted with xylene. The organic phases are combined again, washed with 10% aqueous Na2CO3 solution, then with water and then dried over sodium sulfate. Then the solvent is filtered and evaporated and the residual oil is distilled.

t klj.0.2 = 72 - 90 °C - yield 87.5 %.

IR:

VC=O: 1680 cm-1

NMR (CDCl 3 ) 0.8 - 1.2 (m, 6H); 2.5 (s, 2H); 2.8 (s, 2H); 7 - 7.7 (m, 3H); 8 (dd, IH).

Stage 4:

Tetrahydro-1,2,3,4-hydroxy-1-dimethyl-3,3-phenyl-1-naphthalene (Scheme VI - formula 14).

A solution of 86.95 g (0.55 mol) of bromobenzene in 150 cm3 of ether is added to 8.07 g (1.16 g atoms) of lydium suspended in 200 cm3 of ether, while maintaining a gentle reflux of the ether. The mixture was heated at reflux for 45 minutes and cooled to a temperature between 5 and 10 °C and at this temperature 38.6 g (0.19 mol) of the compound from step 3 dissolved in 150 cm 3 of ether was added.

The mixture is stirred for 4 hours at room temperature and then 150 cm3 of water is added, maintaining the temperature between 5 and 10 °C. The mixture is stirred for 15 minutes and then the organic phase is decanted, washed with water and dried over sodium sulfate and the solvent is evaporated.

A solid jute substance is obtained, which is dispersed in hexane, then strained and dried. tt. = 107-110 °C - yield = 47.4 g = 85 %.

Stage 5.

Dihydro-1,2-dimethyl-2,2-phenyl-4-naphthalene (Scheme VI-formula 5) obtained from the compound of stage 4 according to the procedure of stage 2 of example 1.

tklj 0.1 103-105 °C tt 82-84°C Yield 89 %

Analysis: C18H18 M = 234.34

CH

% calculated 92.26 7.74

% found 92.42 7.64.

NMR (CDCl 3 ): 1.05 (s, 6H); 2.7 (s, 2H); 5.7 (s, IH); 6.75 - 7.4 (m, 9H).

Stage 6:

Bromo-3-dihydro-1,2-dimethyl-2,2-phenyl-4-naphthalene (Scheme III - formula 6).

To a mixture of 27.3 g (0.117 mol) of the compound of stage 5 in 120 cm3 of DMF, well mixed, is added so that the temperature of the mixture does not exceed 30 °C, 25 g (0.14 mol) of N-bromosuccinamide dissolved in 120 cm3 of DMF.

After mixing the mixture at room temperature for 24 hours and standing at the same temperature for 48 hours, the mixture is poured into 800 cm3 of ice water, extracted with 400 cm3 of ether (2 x 200 cm). The washing extracts are combined and dried over sodium sulfate. The ether is evaporated and the residual oil is chromatographed on silica gel using hexane as eluent. Obtained after evaporation of hexane, the oil is used as such in the next synthesis. Yield = 32.4 g = 89%. NMR (CDCl 3 ): 1.2 (s, 6H); 2.95 (s, 2H); 6.3 - 7.5 (m, 9H).

Stage 7:

3E-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-3-propen-2-al (Scheme III - formula 2)

Unless otherwise indicated, the following operations are performed at a temperature of -50 °C. To a solution of 6.26 g (0.02 mol) of the compound from stage 6 in 100 cm3 of ether cooled to -50 °C and well stirred is added 13.8 cm3 of a 1.6 N solution of butyllithium in hexane (0.022 mol of BuLi). Then, after raising the temperature of the mixture to room temperature, the mixture is heated at reflux for 1 hour and 20 minutes and then cooled to a temperature between -50 and -60 °C and 2 g of dissolved N,N-dimethyl-amino-3 acrolein is added in 30 cm3 of ether.

After mixing the mixtures at -50 °C for 1 hour and 30 minutes, the mixture is left to reach room temperature; and then it is mixed for 30 minutes, after which the mixture is poured into 300 cm3 of 10% hydrochloric acid solution while stirring. The organic phase is decanted and washed with water; the aqueous phase is extracted with methylene chloride, the extract is washed with water and then all organic phases are combined; dried on sodium sulfate; the solvents are evaporated and the remaining oil crystallizes in pentane.

mp 105 - 108 °C Yield 2.6 g = 45 %.

IR:

Vc=o: 1680 cm-1

NMR (CDCl 3 ): 1.2 (s, 6H); 2.8 (s, 2H); 6.05 (dd; J = 16.5 and 7.5, IH); 6.4 - 7.5 (m, 10H); 9.5 (D:J =7.5, IH)

Stage 8:

(+)-6E-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-hydroxy-5-oxo-3-heptene-6-methylate (Scheme I - formula 4) .

It is obtained starting from the compound of stage 7 according to the procedure of stage 4 of example 1.

The compound is presented in the form of an oil. Yield = 87%.

NMR (CDCl 3 ): 1.1 (s, 6H); 1.9 - 2.6 (m, 3H); 2.72 (s, 2H); 3.3 (s, 2H); 3.65 (s, 3H); 3.45 (m, 2H); 4.8 - 5.35 (m, IH); 6 (d : J = 15.75; IH); 6.35 - 7.5 (m, 5H).

Stage 9:

(+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate (compound no. 2 ).

It is obtained starting from the compound of stage 8 according to the procedure of stage 5 of example 1.

Yellow solid substance.

mp: 101 - 103 °C - Yield 2.2 g = 67 %.

Analysis for: C26H30O4 M = 406.52

C N

% calculated 76.82 7.44

% found 76.57 7.43

Example 3.

(±)-6E-erythro((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-7-dihydroxy-3,5-hepten-6-methylate

(compound no. 3 - formula 1: X = S, R1 R2 = CH3, R3 = 401, R4 = R5 = R6 = R9 = R10 = H, R7 and R8 = bond, R11=OCH3).

Stage 1: (Chloro-4-phenyl)-4-dihydro-3,4-hydroxy-4-dimethyl-2,2-2H-benzothiapyran (Scheme VI - formula 14) obtained starting from dihydro-2,3dimethyl-2, 2-4H benzothia-pyran-4 according to the procedure of step 4 of example 2; it is used unprocessed in the next synthesis.

Stage 2:

(chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran (Scheme VI - formula 5) is obtained starting from the compound of stage 1 according to the procedure of stage 2 of example 1).

mp: 100-102 °C (diisopropyl ether) - Yield = 50 %. Analysis for C17H15CIS M = 286.81

C H Cl S

% calculated 71.19 5.27 12.36 11.18

% found 70.94 5.42 12.60 10.90

NMR (CDCl 3 ): 2 (s, 6H); 5.75 (s, IH); 6.75 - 7.5 (m, 8H).

Stage 3:

Bromo-3-(chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran (Scheme III - formula 6) obtained starting from the compound of stage 2 according to the procedure of stage 6 of example 2; after evaporation of the ether, the resulting solid is dispersed in a sufficient amount of methanol cooled to -20 °C, then filtered and dried to give a solid.

mp: 150 - 156 °C - yield 88 %.

NMR (CDCl 3 ): 1.6(s, 6H); 6.2-7.8(m, 8H).

It is done under a nitrogen atmosphere, in a reactor protected from room humidity.

A mixture of 20.1 g (0.055 mol) of the compound from stage 3, 27.5 cm3 (0.254 mol) of ethyl acrylate, 130 cm3 of N,N-dimethylformamide, 130 cm3 of palladium diacetate is heated at reflux; the mixture is poured onto a mixture of water and ice and extracted with a sufficient amount of ether; alternatively, the ether extract is washed in hydrochloric acid and water to pH = 7 and then dried over sodium sulfate, filtered and the residue dispersed in hexane cooled to -20 °C, after which it is filtered as a dry solid.

mp: 97 - 99 °C (CH3OH) - Yield = 91 %. Analysis for C 22 H 21 ClO 2 S M = 384.91

C H Cl S % calculated 68.65 5.50 9.21 8.33 % found 68.58 5.79 9.45 8.30

NMR (CDCl 3 ): 1 - 1.75 (m, 9H); 3.75 - 4.5 (9.2H); 5.3 - 5.75 (d, 1H); 6.5 - 7.5 (m, 9H).

Stage 5:

2E-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3yl)-3-propen-2-ol (Scheme IV - formula 9).

It is done under a nitrogen atmosphere in a reactor protected from room humidity. To a solution of 18.9 g (0.049 mol) of the compound of stage 4 in 180 cm3 of tetrahydrofuran cooled to -20 °C, 196 cm3 of a 1N solution of diisobutylaluminum hydride in tetrahydrofuran (0.049 x 4 mol of DIABAL) is added; the mixture is stirred at room temperature for 1 hour, then 200 ml of water is added to the mixture; this addition is exothermic and is carried out so that the temperature of the mixture is maintained at 30 °C; the mixture is then acidified to pH = 1 by adding a sufficient amount of concentrated hydrochloric acid, after which it is extracted with ether.

The ether phase is then washed with water until neutral and then dried over sodium sulfate; after filtering and evaporating the ether, the obtained oil is dispersed in a sufficient amount of hexane cooled to 5 °C; the resulting solid substance is strained and dried.

mp: 105 - 108 °C (hexane) - yield = 87 %.

Analysis for C20H19CIOS M = 342.87

C H Cl S

% calculated 70.06 5.59 10.34 9.35

% found 69.91 5.78 10.52 9.30

Stage 6:

2E-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-3-propen-2-al (Scheme IV - formula 2).

It is done in a reactor protected from room humidity; a mixture of 14.63 g (0.0427 mol) of the compound of stage 5, 22.26 g (0.0427 x 6 mol) of manganese dioxide and 300 cm 3 of dichloromethane is stirred at room temperature for 48 hours; the mixture is then filtered, dichloromethane evaporates from the filtrate, the solid residue is dispersed in a sufficient amount of diisopropylether, the mixture is filtered and dried.

mp: 132 - 134 °C (CH3CO2C2H5) - Yield = 82 %. Analysis for C20H17CIOS M = 340.86

C H Cl S

% calculated 70.47 5.03 10.40 9.41

% found 70.27 4.98 10.51 9.85

NMR (CDCl 3 ): 1.5 (s, 6H); 5.75 - 6.25 (9, IH); 6.75 - 7.5 (m, 9H); 9.25 - 9.5 (d, IH).

Stage 7:

(+,-)-6E-((chloro-4-phenyl)~dimethyl-2,2-2H-benzothiapyran-3-yl)-7-hydroxy-5-oxo-3-heptene-6-methylate (Scheme I - formula 4).

It was obtained from the compound of stage 6 according to the procedure of stage 4 of example 1.

mp: 86 - 88 °C (CH3OH) - Yield 94 %.

IR:

Vc=o: 1740 and 1700 cm-1

NMR (CDCl 3 ): 1.5 (s, 6H); 2.25 - 2.75 8m, 3H); 3.3 (s, 2H); 3.75 (s, 3H); 4.25 - 4.5 (m, IH); 5 - 5.55 (dd, IH); 5.75 - 6.25 (d, IH); 6.5 - 7.5 (m, 8H).

Stage 8:

(±)-6E-erythro-((-chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-7-dihydroxy-3,5-heptene-6-methylate.

(Scheme I-formula 1).

It was obtained starting from the compound of stage 7 according to the procedure of stage 5 of example 1.

mp: 115 - 117 °C (diisopropylether) - Yield 58 % Analysis for C25H27CIO4S M = 458.99

C H Cl S

% calculated 65.42 5.93 7.72 6.98

% found 65.52 6.02 7.80 7.09

IR:

Vc=o: 1720 cm-1

VOH: 3400 cm-1

NMR (CDCl3):

1.5 (s, 6H); 2.5 (d, 2H); 3 - 3.75 (m, 2H); 3.75 (s, 3H); 4 - 4.5 (m, 2H); 5 - 5.5 (dd, IH); 5.75 - 6.25 (d, IH); 6.5 - 7.5 (m, 8H).

Example 4.

(+,-)-erythro-((-fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate

(compound no. 4 - formula 1: X = 0, R1-R2 = (CH2)4-, R3 = 4'F, R4 = R5 = R6 = R7 = R8 = R9 – R10 = H, R11 = OC2H5).

Stage 1:

3E-((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propen-2-al, dimethylacetal (Scheme V-Formula 10).

It is done under a nitrogen atmosphere, in a reactor protected against moisture.

A mixture of 16.75 g (0.05 mol) of 3E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-propen-2-al obtained from spiro(2H-benzopyran-1-2,1'-cyclopentanone-4) according to the procedures of stages 1,2 and 3 of example 1 and 2.25 g of Amberlyst 15 resin, in 625 cm3 of methyl orthoformate are stirred for 7 hours at room temperature. A further 2.25 g of Amberlyst resin was added and the mixture was stirred at room temperature for 12 hours. Repeat this treatment four times, after which the mixture is filtered and the excess methyl orthoformate is evaporated; a white solid is isolated which is dispersed in hexane; the mixture is strained and dried.

mp: 112 - 114 °C - Yield = 16.3 g = 88 %.

NMR (CDCl3):

2.1 - 2.2 (m, 8H); 3.07 (s, 6H); 6.05 (d, IH, J = 5 Hz); 5.3 (dd, IH J = 5 Hz and 16 Hz); 6.05 (d, IH J = 16 Hz); 6.3 - 7.2 (m, 8H).

Stage 2:

((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propanol dimethyl acetal (Scheme V - formula 11).

At normal hydrogen pressure and room temperature, 3.8 g (0.01 mol) of the compound of stage 1 dissolved in 100 m3 of THF, in the presence of 0.5 g of palladium are dispersed on carbon. When the theoretical amount of hydrogen is adsorbed, the mixture is filtered and the THF is evaporated; the obtained oil crystallizes slowly so that the obtained solid substance is dispersed, then strained in hexane and dried.

mp: 83 - 85 °C Yield: 3.2 g = 84 %.

(CCM: silica gel: AcOEt-hexane: 1-9:1 stain)

NMR (CDCl 3 ): 1.9 - 2.5 (m, 12H); 3.2 (s, 6H); 4.15 (t, IH J = 5 Hz); 6.3 - 7.25 (m, 8H).

Stage 3:

((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3 propanal. (Scheme V - formula 2).

A mixture of 2 g (0.0052 mol) of the stage 2 compound and 2 g of Amberlyst 15 resin is mixed at room temperature for 96 hours; the resin is filtered off, the filtrate is evaporated to dryness, the resin is placed in 40 cm3 of methylene chloride, washed with water and dried over sodium sulfate, the filtrate is evaporated to dryness so that 0.9 g of oil is obtained.

mp: 118 - 120 °C (diisopropylether)

IR:

Vc=o: 1720 cm-1

NMR (CDCl 3 ): 1-2.5 (m, 10H); 6.2 - 7.2 (m, 8H); 9.55 (s, IH).

Analysis for C22H21FO2 M = 336.39

CH F

% calculated 78.55 6.29 5.65

% found 78.33 6.04 5.57.

Stage 4:

(±)-fluoro-4-phenyl)-4-spiro(24-benzopyran-1,2,1'-cyclopentyl-3)-7-hydroxy-5-oxo-3-heptane ethylate

(Scheme I - formula 4 - R7 = R8 = H)

It is obtained starting from stage 3 and according to the procedure of stage 4 of example 1.

The compound is obtained in the form of an oil (yield = 51%); is used as such in the following synthesis.

Stage 5:

(+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate (compound No. 4).

It is obtained by reduction of the compound of stage 4 according to the procedure of stage 5 of example 1.

The joint is white.

mp: 103 - 105 °C (Diisopropylether) - Yield 65 %.

Analysis for C28H33FO5 M = 468.54

CH F

% calculated 71.77 7.10 4.05

% found 71.63 7.11 3.98.

NMR (CDCl3):

0.9 - 2.5 (m, 17H); 2.35 (d, 2H, J = 6 Hz); 3 - 3.5 (m, 2H); 3.5 - 3.9 (m, IH); 3.9-4.4(m,3H); 6.2-7.2(m,8H).

Example 5.

(+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy-3,5-heptene- Sodium 6-ester (compound No. 5 - formula 1: X = 0, R1-R2 = -(CH2)4-; R3 = 4'F; R4 = R5 = R6 = R9 = R10 = H; R7 and R8 = bond; R11 = -O"Na+).

2.14 g (0.0046 mol) of compound no. is heated to 60 °C. 4 in 30 cm3 of ethanol to obtain a clear solution, then this solution is cooled to room temperature and an aqueous solution of sodium carbonate obtained by dissolving 0.18 g (0.0046 mol) of sodium carbonate in beads in 100 cm3 is added. The mixture is stirred for 30 min, filtered and evaporated to dryness; the residue is dried by heating at 60 °C under reduced pressure (0.05 mm Hg) for 1 hour.

tt: not defined - Yield 2.04 g = 96 %.

(CCM: silica gel: AcOEt - hexane : 1 - 1 + 3 % AcOH : 1 spot)

Analysis for C26H26FNaO5 M = 460.47

C H F Na

% calculated 67.82 5.69 4.13 4.99

% found 67.44 5.71 3.91 5.11.

Example 6.

(+,-)-6E-Erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-7-dihydroxy-3,5-heptene-6-benzylate

(compound no. 6 - formula 1 : X = O, R1- R2 = -(CH2)4-, R3 = 4'F, R4-R5 = R6 = R9 = R10 = H, R7 and R8 = bond, R11 = C6H5CH2O-).

In a solution of 1.55 g (0.00337 mol) of compound no. 5 in 40 cm3 of methyl ethyl ketone, 0.638 g (0.00337 mol + 10 %) of benzyl bromide is added and then the mixture is heated at reflux for 3 hours.

A new 0.638 g of benzyl bromide is then added and the mixture is heated at reflux for 8 hours.

The mixture is filtered, the filtrate is evaporated, then the residue is poured into a sufficient amount of ethyl acetate, the solution is washed with water, dried over sodium sulfate, filtered and evaporated to dryness.

The remaining oil is chromatographed on 15 g of silica gel using a mixture of ethyl acetate-hexane: 30 - 70 %.

The collected fraction II after evaporation of the solvent gives a solid substance which is dispersed in diisopropyl ether. The solid substance is strained and dried.

mp = 81 - 83 °C - Yield = 1.17 g = 66 %. Analysis for C33H33FO5 M = 528.59

CH F

% calculated 74.98 6.29 3.59

% found 74.91 6.23 3.55

NMR (CDCl 3 ): 1.1 - 2.3 (m, 10H); 2.45 (d, 2H J = 6.7 Hz); 2.7 - 3.2 (M, 1H (D2)); 3.3 - 3.6 (m, 1H D2O)); 3.8 - 4.5 (m, 2H); 5.0 - 5.6 (s + d, 3H); 5.9 (d, IH J = 15.7 Hz); 6.3 - 7.7 (m, 13H).

Example 7.

(+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-N- methyl-hepten-6-amide

(compound No. 7 of Formula 1: X = O; R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 =H, R7 and R8 = bond, R11 = CH3NH-) .

A solution of 0.67 g (0.00165 mol) of compound no. 1 in 25 cm3 of methylamine solution in 33% ethanol is stirred for 24 hours at room temperature. The solvent is evaporated and the residue is dispersed in 8 cm3 of ethyl acetate, filtered and dried.

mp: 150 - 152 °C - Yield = 0.52 g = 70 %.

Analysis for C27H30FNO4 M = 451.54

C H N F

% calculated 71.66 6.90 3.10 4.20 %

found 71.47 6.76 2.93 4.08.

Example 8.

(+,-)-trans-(1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethanyl)-6-hydroxy- 4-tetrahydro-3,4,5,6-2H-pyranone-2 (Compound No. 8 - formula 1: X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R10 = H, R7 and R8 = bond, R9 and R11 = bond).

It is insulated from moisture.

It is heated at reflux for 3 hours, a mixture of 6 g (0.0135 mol) compound no. 4 and 1.94 g (0.0135 mol) of chloro-2-ethyl diethyl amine in 120 cm of R7 and R8 acetone. Acetone is evaporated and the residue is poured into a sufficient amount of ethyl acetate. The solution is washed in water to pH 7 and then dried over sodium sulfate. Filter and evaporate the ethyl acetate.

A solid substance is obtained which is directly recrystallized from 120 cm R7 and R8 of ethyl acetate. mp: 188 - 191 °C - Yield = 4.27 g - 79 %. Analysis for

C26H25FO4 M = 420.49

CH F

% calculated 74.27 5.99 4.52 %

found 74.07 6.04 4.49

NMR (DMSOd 6 ) -200 MHz: 1.45 - 2.20 (m, 10H); 2.34 (dd, 1 J - 16 Hz and 3.45 Hz); 3.93 - 4.10 (m, IH); 4.85 - 5.0 (m, IH); 5.11 (d, IH J = 3.3 Hz); 4.42 (dd, IH J = 16.3 Hz and 6.7 Hz); 6.02 (d, IH J = 16.3 Hz); 6.42 - 6.54 (m IH); 6.72 - 6.83 (m, 2H); 7.07 - 7.34 (m, 5H).

Example 9.

(+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6-(((-fluoro-4-phenyl)-4-spiro (2H-benzopyran-1-2,1'-cyclopropyl) -3)- 2-ethyl)-6- pyranone-2 (Compound No. 9 - formula 1 : X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 =R10 = H, R9 and R11 = bond).

1.72 g (0.00409 mol) of compound no. is hydrogenated at normal pressure and room temperature. 9 in 70 cm of R4 = R5 = R6 THF in the presence of 0.1 g of palladium dispersed on carbon. When the theoretical amount of hydrogen has been adsorbed, the mixture is filtered, the filtrate is evaporated and the resulting residue is dispersed in diisopropyl ether. The solid substance thus obtained is strained and dried.

mp: 156 - 157 °C (diisopropylether) - Yield = 0.7 g = 41 %.

Analysis for C26H27FO4 M = 422.50

CH F

% calculated 73.91 6.44 4.50

% found 73.83 6.32 4.40

NMR (DMSOd 6 ) - 200 MHz: 1.38 - 2.21 (m, 14H); 2.39 (dd, IH J = 17.2 Hz and 2.8 Hz); 2.57 (dd, IH J = 17.2 and 4.6 Hz); 3.96 - 4.11 (m, IH); 4.25 - 4.46 (m, IH); 5.04 (d, IH J = 3.2 Hz); 6.31 - 6.41 (m, 1H); 6.69 - 6.85 (m, 2H); 7.02 - 7.34 (m, 5H).

Example 10.

(+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-hethane sodium ester

(compound no. 10 - formula 1; X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 = R10 = H, R9 and R11 = -ONa+).

A mixture of 0.22 g (0.00052 mol) of compound no. 9 and 0.52 cm3 (0.00052 mol - 5 %) of a 1 N aqueous solution of sodium carbonate in 25 cm3 of ethanol. Ethanol is evaporated and the residue is dispersed in ether, the resulting solid is filtered and dried. (CCM: silica gel: AcOEt - hexane: 1 -1 + 3 % AcOH : 1 spot).

tt: not defined - Yield = 0.12 g = 50 %.

Analysis for C26H28FNaO5 M = 462.48

C H F Na

% calculated 67.52 6.10 4.11 4.97

% found 67.30 5.92 3.90 5.00

Example 11.

(+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5-heptane ethylate (compound no 4)

1.4 g (0.003 mol) of compound no. is hydrogenated at normal pressure. 1 dissolved in 100 cm3 of THF and in the presence of 0.6 g of palladium dispersed on carbon. After the theoretical amount of hydrogen has been adsorbed, the mixture is filtered, the filtrate is evaporated to dryness and the residue thus obtained is dispersed in hexane, filtered and dried.

mp: 103 - 105 °C (diisopropylether) - Yield = 1 g = 71 %.

Example 12.

(+,-)-trans-((1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3-2-ethenyl)-6-dirnethyl- 2,2-diohexane-1,3-yl-4)ethyl acetate (compound No. 11 - formula 1: X + O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = H, R7 and R8 = bond, R9 - R10 = (CH3)2C-, R11 = OC2H5).

A mixture of 2 g (0.0043 mol) of compound no. 1, 0.7 g of methoxy-2-propene and 8 mg of paratoluenesulfonic acid monohydrate in 25 cm3 of DMF for 48 hours. Add 125 cm3 of ether and wash with saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate, filtered and dried to dryness. An oil is obtained which crystallizes from hexane, is filtered, dried and chromatographed on 20 g of silica gel using a mixture of hexane-ethyl acetate: 1-1 as solvent and eluent.

mp: 103 - 105 °C - Yield = 0.95 g = 44 %.

Analysis for C31H35FO5 M = 506.61

CH F

% calculated 73.50 6.96 3.75

% found 73.64 6.98 3.73

NMR (CDCl3)

0.9 - 2.5 (m, 16H); 3.9 - 4.5 (m, 2H); 4.05 (q, 2H); 5.15 (dd, IH); 5.95 (d, IH); 6.2-7.25 (m, 8H).

In the following examples of the compounds of the invention, the abbreviations used have the following meanings: Me = methyl, Et = ethyl, Pr - prpol, Bz = benzyl, Pen = pentyl, Tbu = tetriobutyl, iPr = isopropyl, Phe = phenyl, Pyr = pyrrolidino.

Example 13.

By using the procedure according to examples 1-12, compounds (table below) were obtained, formula 1 in which X = O, R1 and R2 build a chain -(CH2)n-, R7 and R8 together build a single bond, R9 and R10 each represent hydrogen atom:

[image]

Example 14.

Using the procedure of the corresponding examples 1-12, compounds (given in the table below) of formula 1 were obtained in which X - O, R4 = R5 = R9 = R10 = H and R7 and R8 form a bond:

[image]

Example 15.

By using the procedure of the corresponding examples 1-12, the compounds (given in the table below) of formula 1 were obtained, in which R4 = R6 = R10 = H, and R7 and R8, that is, R9 and R11 together form one simple bond:

[image]

Example 16.

Using the procedures of the corresponding examples 1 - 12, compounds (table below) of formula 1 were obtained in which X = CH2 or S, R4 = R6 = R9 = R10 = H, R7 and R8 form a simple bond:

[image]

Using the step procedures of the corresponding intermediate examples 1-4, the intermediate compounds collected in the following non-limiting examples were obtained.

Example 17.

Intermediate compounds of the general formula 4 in which X = O, R1 and R2 form a chain -(CH2)m R7 and R8 form one bond together, R9 denotes a hydrogen atom:

[image]

Example 18.

Intermediate compounds of the general formula 4 in which X = O, R4 = R5 = R6 = R9, = and R7 and R8 form one bond:

[image]

Example 19.

Intermediate compounds of general formula 4 in which X=CH2 or S, R4=R6=R9=H, R7 and R8 form one bond and R11 = methoxy.

[image]

Example 20

Intermediate compounds of general formula 2 in which X=O, R1 and R2 form one chain -CH2)n-, and R7 and R8 form one bond

[image]

Example 21.

Intermediate compounds of the general formula 2 in which X=CH2, O or S, R4=R6=H and R7 and R8 together form one bond.

[image]

Example 22.

Intermediate compounds of the general formula 6 in which X=CH2 or S, R4=R6=H.

[image]

Example 23.

Intermediate compounds of the general formula 5 in which X=O and R1 and R2 form a tetramethylene chain -(CH2)4-

[image]

Example 24.

Intermediate compounds of the general formula 5 in which R4=R6=H.

[image]

Example 25

Intermediate compounds of the general formula 9 in which X=S and R4=R5=H.

[image]

Example 26.

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ANALYTICAL DATA

[image] [image]

* calculated with half a molecule of water

Rč: calculated

Tr: theoretical

** calculated with 1/3 water molecule

*** calculated with 1/4 water molecule

Claims (7)

1. Process for obtaining derivatives of benzocycloalkenyl dihydroxy acanic acids of the following formula 1 [image] where X represents a methylene chain -CH2-, an oxygen or sulfur atom; R1 and R2, identical or different, represent hydrogen atoms or alkyl radicals with 1-3 carbon atoms; R1 and R2 can also together form an alkylene series -(CH2)n-, where n can be 4 or 5 and can be symmetrically substituted with one or two alkyl radicals with 1-3 carbon atoms; R3 and R4, which can be identical or different, represent hydrogen, fluorine, chlorine or bromine atoms, radicals CF3, N,N-dialkylamino with 1-3 carbon atoms, alkyl with 1-4 carbon atoms, alkoxy with 1-5 carbon atoms , phenyl optionally substituted with more than two substituents that may be identical or different and represent an alkyl radical with alkyl with C1-3, or fluorine or chlorine atoms, it is understood that when one of the substituents R3 or R4 represents the radical CF3, N,N- dialkylamino, phenyl or substituted phenyl, this one is on the 3', 4' and 5' ends and the second substituent is a hydrogen atom. R5 and R6, which can be identical or different, represent hydrogen, fluorine, chlorine or bromine atoms, CF3 radicals, alkyl with C1-3, alkoxy with C1-3 or phenyl, optionally substituted with more than two alkyl radicals with C1-3, Alkoxy with C1-3 or a fluorine or chlorine atom, provided that one of the substituents is a CF3 radical, phenyl or phenyl substituted, this one is on the 6 or 7 peaks, and the other substituent is a hydrogen atom; the substituent R3 and R4, respectively R5 and R^ can also build together, in case they are on two adjacent vertices, diradicals of the formula: -CH=CH-CH=CH-, -(CH2)m- and -O(CH2)PO- in which m can be equal to 3 or 4, and p is 1 or 2, it is assumed that when R3 and R4, that is, R5 and R6 represent the diradical -O(CH2)PO-, this is located on the peaks 3" and 4' or 4' and 5' or 6 and 7; R7 and R8 substituents, each representing a hydrogen atom, form together with the existing C-C bond one double bond of trans geometry (E); R9 and R10 each represent a hydrogen atom, they form together a dialkyl methylene residue with 1-3 carbon atoms; R11 represents, with the CO group on which it lies, a free acid function, an ester, an amide salt of an acid, or builds with R9 a delta-lactone ring, indicated by the fact that it comprises at least a) reduction of keto ester of formula 4, [image] and in case it happens b) transesterification of the compound of formula 1 or alcoholysis of the compound of formula 1 in the form of delta-lactone or alkylation of the compound of formula 1 in the form of a salt and or, c) hydrolysis of the compound of formula 1 in the form of ester or delta-lactone or d) when R7 and R8, or R9 and R11 form a simple bond: treatment of the corresponding compounds of formula 1 in salt form with tertiary chloroamine or, e) when R7, R8 and R10 denote a hydrogen atom, and R9 and R11 form: catalytic reduction of delta-lactone compounds of formula 1 in which R7 and R8 form a bond or lactonization of the corresponding acid compounds of formula 1 in which R7, R8 and R10 denote an atom hydrogen or f) aminolysis of the compound of formula 1 in the form of an ester or delta-lactone or, g) when R9 and R10 form together a dialkylalkylene residue: cyclization of the corresponding compounds of formula 1 in which 9 and R10 denote each hydrogen atom with an alkoxyalkene. 2. The method according to claim 1, indicated by the fact that R11 represents a hydroxy radical, 1-4 carbon atom alkoxy, benzyloxy, 1-3 carbon atom alkylamino or N,N-dialkylamino, 4-6 carbon atom imino, cycloamino with 3-6 carbon atoms amino benzylamino or O-M+ where M+ denotes a pharmaceutically acceptable cation or R11 form a simple bond with R9. 3. The method according to claims 1 or 2, characterized by the fact that the substituents R1 and R2 each represent a methyl group, they form together a tetramethylene series, R3 and R4, respectively R5 and R6, can be identical or different and represent hydrogen, fluorine, chlorine atoms, radicals methyl or ethyl, methoxy, methylthio, phenu, fluoro-4-phenyl, methyl-4-phenyl, methoxy-4-phenyl or together form diradicals, diethylene: -CH=CH-CH=CH-, tetramethylene: -CH2)4 - ih methylenedioxy: -O(CH2)O-. 4. Procedure according to claim 1 or 2, characterized in that: A) X represents oxygen atoms, sulfur atoms, methylene series, R1 and R2 each represent a methyl radical, together they form a tetramethylene series -(CH2)4-, only one of the radicals R3 and R4, i.e. R5 or R6 represents a hydrogen atom, R7 and R8 form together the bond and R9 and R10 each represent a hydrogen atom or, B) X, R1, R2, R7, R8, R9 and R10 have the meanings given immediately before under A), one of the substituents R3 and R4 denotes a hydrogen atom, and the other a fluorine atom and only one of the substituents R5 or R6 denotes a hydrogen atom, or C) X, R1, R2, R7, R8, R9 and R10 have the meanings defined above in A), one of the substituents R3 and R4 is a hydrogen atom and the other represents a fluorine atom and each of the substituents R5 or R6 represents a hydrogen atom , or D) X, R1, R2, R7, R8, R9 and R10 have the meanings specifically defined in A), both substituents R3 and R4 are hydrogen atoms and only one of the radicals R5 or R6 denotes a hydrogen atom, or E) X, R3, R4, R5, R6, R7, R8, R9 and R10 have the meanings given above in C), and R1 and R2 build together a tetramethylene chain -(CH2)4, or F) X, R1, R2, R7, R8, R9 and R10 have the meanings given above in E) and each of the substituents R3 and R4, R5 or R6 represents a hydrogen atom. 5. Process according to claim 2, characterized in that the products (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-ben2;opyran-1-2,1) are obtained '-cyclopentyl)-3)-7-dihydroxy-3,5-heptene-6-ethylate, (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran- Sodium 1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptene-6-ester, (+,-)-6E-erythro-((dihydro-1,2-dimethyl-2, 2-phenyl)-naphthyl-3)-7-dilyhydroxy-3,5-heptene-6-methylate, (+,-)-6E-erythro- ((chloro-4-phenyl)-4-spiro-(2H- benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptene-6-ethylate, (+,-)- 6E-erythro - ((chloro -4-phenyl)-4- spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-hepten-6-ester sodium, (+,-)- 6E -erythro -dihydroxy- 3,5 - (phenyl-4-dimethyl-2,2-2H -benzothiapyranyl-3)-7-heptene-6 methylate, (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-dimethyl-2 ,2-2H-benzothiapyranyl-3)-7-hepten-6-ester sodium, (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro-(2H-benzothiapyran-1-2 ,1'-cyclopentyl)-3)-7-hepten-6 sodium ester or (+,-)-6E-erythro-((fluoro-4-phenyl)- 4- spiro (2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5-heptane ethylate. 6. Procedure for obtaining intermediate compounds when obtaining the compound of formula 1 as defined in claim 1 or 2, represented by the general formulas: [image] [image] in which R1 R2, R3, R4, R5, R6, R7, R8 R9 R10 and R11 are as defined in claim 1, and R12 represents an alkyl radical with 1-4 carbon atoms or R12 ........ R12 represents a methylene biradical -(CH2)q- where q represents 2 or 3 and builds with oxygen atoms to which a five- or six-membered ring is attached, with the exception of products of formula 5 where R1 and R2 represent hydrogen and X represents S or CH2, indicated by, which includes at least a) aldolitic condensation of the corresponding LiCH2COCH(Na)COR11 acetoacetate in a suitable solvent in the presence of a suitable complexing agent, with a suitable compound of formula 2, or b) to obtain intermediate compounds of formula 1 where R7 and R8 represent a double bond, the reaction of the corresponding compound of formula 5 with A) with N,N-dimethylamino-3-acrolein in an inert solvent at a temperature between 20 °C and the reflux temperature to obtain the corresponding compound of formula 2 in the trans form; them B) N-bromosuccinamide in a suitable solvent to obtain the corresponding compound of formula 6 with 3-bromo, i) which is reacted with butyllithium in a suitable solvent and then with ethoxy-3-acrolein or N,N-dimethylamino-3-acrolein to obtain the corresponding compound of formula 2 in the trans form; or ii) which reacts with an alkyl acrylate in the presence of a base agent and a palladium derivative in a suitable solvent to obtain the corresponding compound of formula 8, ih C) with N,N-dimethylformamide to obtain the corresponding aldehyde of formula 7, which reacts with ethoxy- or methoxy-carboxymethylene triphenyl phosphorane and methyl and ethyl triphenyl phosphonoacetate to obtain the propenoic 3-substituted ester of formula 8 in the trans form, the corresponding compound 8 is converted into the form of a 3-substituted propenol of the formula 9 in the trans form which undergoes rapid oxidation in a suitable solvent to obtain the corresponding compound of the formula 2 in the trans form, or iii) in order to obtain the compound of formula 2 where R7 and R8 represent hydrogen, deacetylation treatment of the corresponding compound of formula 11 in a catalytic acid in a suitable solvent; the corresponding compound of formula 11 is obtained by catalytic hydrogenation of the corresponding compound of formula 10 where R7 and R8 represent one double bond, obtained by acetylation of the corresponding aldehyde of formula 2 and treatment of the corresponding compound of formula 6 with an alkyl alcohol in the presence of a suitable base to obtain the corresponding aldehyde of formula 2. 7. Process for obtaining pharmaceutical preparations, characterized in that at least one compound 1 as defined in claim 1 is mixed with a pharmaceutically acceptable excipient.