SK18899A3 - 7'alpha'-('xi'-aminoalkyl)estratrienes, process for preparing the same, pharmaceutical preparations containing said 7'alpha'-('xi'- -aminoalkyl)estratrienes and their use for preparing medicaments - Google Patents

Description

The invention relates to 7α-β-aminoalkyl) estratrienes, a process for their preparation, pharmaceutical compositions containing them and their use in the manufacture of medicaments.

BACKGROUND OF THE INVENTION

Compounds with antiestrogenic properties, i.e. estrogen inhibitory substances, have been described in many publications. Steroid derivatives resulting from EP-A 0 138 504 and in particular 7- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -n-nonyl] steroid derivatives, which are structurally closest to the compounds of the present invention, are to be considered. -estra-1,3,5 (10) -triene-3,17β-diol (EP-A 0 138 504, page 58, penultimate compound). This compound is also currently in clinical development for hormone-dependent tumors (breast cancer) and represents the best known compound, that is, the compound with the strongest antiestrogenic effect, of these steroid derivatives.

Pharmaceutical compositions containing sex steroid inhibitors having a steroid backbone having a 7-side chain in the presence of at least one additional substituent at the 14, 15 or 16 position are the subject of EP-A 0 376 576 and need to be considered as the closest prior art.

A large number of various compounds, inter alia of steroidal origin, as well as the 2-phenyl-indole backbone, which act as antiestrogens and / or suppress estrogen biosynthesis are disclosed in WO 93/10741.

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Other steroidal anti-estrogens that carry the 11β-phenyl moiety are described in EP-AS 0 384 and 0 629 635.

SUMMARY OF THE INVENTION

The present invention relates to the 7α-β-aminoalkyl) estratrienes of formula I

wherein the side chain SK represents the remainder of the sub-formula

- (CH) m -N-CH-CH- (CH ₂ ) _n -SO _x - (CH ₂ ) ₃ -E

I I I

A B D wherein m is 4, 5 or 6, n is 0, 1 or 2 and x is 0, 1 or 2,

A represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,

B and D represent a hydrogen atom, or

A and B together represent an alkylene group - (CH ₂ ) _p -, wherein p = 2, 3, 4 or 5 and D represents a hydrogen atom, or

A and D together are an alkylene group - _{(CH2) p} - wherein p is 2, 3 or 4 and B is hydrogen, and

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E represents an unsubstituted or one to five times fluorinated ethyl radical or a terminal substituent - (Chhh- in the side chain is replaced by an optionally substituted aryl or heteroaryl radical which is bonded directly or via a mono-, di- or trimethylene group to a sulfur atom,

R ³ represents a hydrogen atom, a hydrocarbon radical of up to 8 carbon atoms or a radical of the formula R ³ '-C (O) -, wherein:

R ³ 'represents a hydrogen atom or a hydrocarbon radical having up to 8 carbon atoms or a phenyl radical; R ¹¹ represents a hydrogen atom, a halogen atom or a nitrooxy group

-o-no ₂

R ¹⁴ , R ^15a , R ^15b , R ^16a and R ^16b are all hydrogen or

R ¹⁴ and R ^15a represent an additional bond or a methylene bridge, or

R ( ^15b) is methyl and R ( ^{15a) is} hydrogen or

R ^15a and R ^15b are each methyl or

R ^15b and R ^16b together represent a methylene bridge, or

R ^16a or R ^16b represent a halogen atom or R ^16a and R ^16b together represent a methylidene group, and the other substituents R ¹⁴ , R ^15a , R ^15b , R ^16a and R ^16b each represent a hydrogen atom,

R ¹⁷ 'in the α- or β-position represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms or a trifluoromethyl group and

R ¹⁷ represents a hydrogen atom or a radical of R ¹⁷ '-C (O), wherein

R ¹⁷ 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or, when R ¹⁷ ' is in the α-position, R ¹⁷ 'together with R ¹⁴ represents ethanomostic,

With the proviso that when A and B do not together represent - (CH ₂ ) _p - or A and D together represent at least one of R ¹¹ , R ¹⁴ , R ^15a , R ^15b , R ^16a and R ^16b , they do not represent a hydrogen atom as well as their physiologically acceptable addition salts with organic and inorganic acids.

The present invention furthermore relates to pharmaceutical preparations containing compounds of the formula I as well as their physiologically acceptable salts with organic and inorganic acids and their use in the manufacture of medicaments.

Preferably, in the compounds of formula I, the nitrogen atom in the side chain is separated by five methylene groups from the carbon atom 7 of the steroid structure.

When A is an alkyl group of up to 5 carbon atoms, it is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or neopentyl group. Preferred as A is methyl.

The index n may have a value of 0, 1 or 2, and when A represents a hydrogen atom or an alkyl group of up to 5 carbon atoms, a value of 1 for n is preferred so that the nitrogen atom and the sulfur atom are separated by three methylene groups.

The nitrogen atom may be part of a four- to seven-membered or five to seven-membered heterocycle which is substituted at the 2- or 3-position of the - (CH ₂ ) n -SO _x - (CH ₂ ) ₃ -E side chain residue.

Preferably A and B together represent a trimethylene group, i.e., together with the nitrogen atom and its adjacent carbon atoms in the 2-position form a substituted pyrrolidine ring.

In the latter case, a value of 0 is preferred for n and a value of 0 for x.

The sulfur atom in the side chain may exist as a single sulfur bridge (sulfide), such as sulfone or sulfoxide. Sulfides are preferred.

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The residue E is one to five times a fluorinated ethyl residue, but the perfluorinated residue is preferred.

When the terminal substituent - (CH ₂ ) ₃ -E is replaced in the terminal chain by an optionally substituted aryl or heterocyclic radical which is bonded directly or through a monomethylene, dimethylene or trimethylene group to the sulfur atom, the aryl radical is preferably a phenyl radical. In the case of a heteroaryl radical, this is preferably a 2-furyl or 2-thienyl radical. As a substituent on this aryl or heteroaryl radical, for example, there may be pentafluoroethyl or trifluoromethyl, preferably trifluoromethyl and this again preferably at the 4-position of the phenyl radical. The 2-furyl or 2-thienyl radical is preferably separated from the sulfur atom by a methylene group.

The R ³ substituent at the 3-oxygen atom it is primarily a hydrogen atom. However, the hydroxyl group may be etherified by a straight or branched, saturated or unsaturated hydrocarbon radical of up to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl or esterified with an acyl radical R ³ '-C (O) -, wherein R ³ ' represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a phenyl radical.

The substituent R ¹¹ may be a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine and iodine, or a nitrooxy group. A fluorine atom is preferred.

When R ¹¹ is a hydrogen atom or when A and B together are - _{(CH2) q} -, or A and D together do not mean a - _{(CH2) q,} and a D-ring substitution from the group consisting of 14,15-double bond, , 14a, 15 amethylene, βδ-methyl, 15,15-dimethyl, 15β, 1 ββ-methylene, 16α-halogen or 16β-halogen and in particular 16α-fluoro, 16-methylidene or 14α, 17α-ethano. Preferred are the 153-methyl group and the 16α-fluoro atom.

R ¹⁷ 'may be in the α- or β- position.

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In the case of an alkyl group having 1 to 5 carbon atoms, this is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or neopentyl. C 2 -C 5 alkenyl groups include, for example, vinyl or allyl. Exemplary representatives of an alkynyl group having 2 to 5 carbon atoms are ethynyl and 1-propynyl.

When the R ¹⁷ 'in the position alpha, there is in particular H, methyl or trifluoromethyl or together with R ¹⁴ is ethano-bridge.

For the R ¹⁷ 'in the β-position, the hydrogen atom and the methyl group may be mentioned first.

Particularly preferred are those compounds of formula I wherein the side chain SK is either a radical of the partial formula - (CH ₂ ) ₅ -N (CH 3) (CH ₂ ) 3 -SO _x - (CH 2) 3 -C ₂ H 5, wherein x = 0, 1 or 2 or - (CH ₂ ) ₅ -N (A) - (CHB) -CH 2 -S (CH ₂ ) ₃ -C ₂ F ₅ , wherein A + B = - (CH ₂ ) ₃ -. In the latter case, the compounds preferably have a 17α-hydrogen atom.

Inorganic and organic acids known to those skilled in the art for the formation of physiologically acceptable salts are suitable for the formation of acid addition salts. Acid addition salts include, in particular, hydrochlorides and methanesulfonates.

Particularly preferred are the following compounds of the present invention:

- 14,17-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -trien-3,17β-όΐοΙ

- 14,17-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

- 3,17β-diacetoxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene

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- 14,17-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

- 17α-Trifluoromethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene -3,17p-diol

- 15β, 16β-ηβί3ηο-17α-ΓηθΙγΙ-7α- {5- [Ν-η'ΊθίγΙ-Ν-3- (4,4,5,5,5-β-β-β-pentylthio) -propylamino] -pentyl} -estra 1,3,5 (10) -ίπέη-3,17β-όίοΙ

- 15β, 163-methano-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoro-)

pentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17b-thiol

- 15β, 16β-methano-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene-3,17β-όϊοΙ

- 15β, 16β-ΓΠθί 3ηο-7α- {5- [Ν-ΝηθίγΙ-Ν-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

- 15β-Methyl-7α- [5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene -3,17β-όΐοΙ

- 15β, 17α-Dimethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-ool

11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) - triene-3,17β-όίοΙ

11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,? - diol

- 11 β-ΙΙΙ0Γ-7α- {5- [Ν-ΠΊθίγΙ-Ν-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,17β-oleol

- 16cc-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

- 16α-Fluoro-4-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -triene-3,17-diol

- 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-oleol

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- 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-άίοΙ

- 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentane-sulfonyl) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene-3,17β-όΐοΙ

- 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -trien-3 , 17β-άίοΙ

- 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene -3,17β-iol

- 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) -methoxy -3,17β ^ ίοΙ

- 7α- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} estra-1,3,5 (10), 14-tetraene-3 .17 β-di oI

7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] pentyl} -estra-1,3,5 (10), 14-tetraene-3,4-diene; diol

- 7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] pentyl} -estra-1,3,5 (10), 14-tetraene-3 , 1LP-diol

-7- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-3 17 β-diol

- 7 - {5 - [(2R) -2- (4,4,5,5,5-Pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-3 , 1 β-d iol

- 17α-Methyl-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -triene-3,17 β-diol

11-p-fluoro-7x- {5- (2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 ( 10) -triene-3,1-β-diol

11-p-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra1,3,5 (10) -triene-3,17β-diol

-1'-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] -pentyl} -estra-1,3 , 5 (10) -triene-3,17β-0ΐοΙ

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11β-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) pyrrolidin-1-yl] -pentyl} -estra- 1,3,5 (10) -triene-3,1-β-diol

11β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) pyrrolidin-1-yl] -pentyl} -estra-1,3 , 5 (10) -triene-3,17β-όίοΙ

- 7 - {5 - [(2S) -2- (4,4,5,5,5-Pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] pentyl) -estra-1,3,5 (10) -trien-3 , 17β-όίοΙ

- 7 - {5 - [(2S) -2- (4,4,5,5,5-Pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -triene-3,17β -άΐοΙ

11β-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-oleol

- 11 β-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3, 5 (10) -triene-3,17β-άίοΙ

- 11 p-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3, 5 (10) -triene-3,17β-oleol

- 11 β-ΙΙΙ0Γ-7α .- {5- [Ν-ΐηβΐνΙ-Ν-2- (4,4,5,5,5-ρβηΐ3ΑυόΓρβηίόη5υΙίθΓ ^ Ι) ethylamino-pentyl} -estra-1,3,5 (10 ) -triene-3,17β-άίοΙ

- 11 β-ΙΙυόΓ-7α- {5- [Ν-θΠθίγΙ-Ν-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3-hydroxy-estra-1,3,5 (10) -trien-17-one

- 11 β-Fluoro-7α- {6- [N-methyl-N-3- (4 ₁ 4,5,5,5-pentafluoropentylthio) -propylamino] hexyl} -estra-1,3,5 (10) - triene-3,17 β-diol

- 11 β-Fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -hexyl} -estra-1,3,5 (10) - triene-3,17β-όίοΙ

- 11 β-ΓΙΙ0Γ-7α- (5 - {[Ν-3- (ίυΓέη-2 ^ ΙιτΐΘίγΙίίο)) -ρΓ (^ Ι] -Ν-ΓΤ ^ ΐ3Γηίηο} - ρθΓ ^ Ι) estra-1,3,5 (10) -triene-3,1-β-diol

-1'-Fluoro-7α- (5- {N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino} -pentyl) estra-1,3,5 (10) -triene- 3,17β-ΰϊοΙ

- 1 '4-Fluoro-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene-3,17β -όίοΙ

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- 11β-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) pyrrolidin-1-yl] pentyl} -estra-1,3, 5 (10) -triene-3,17-diol

- 1'-Fluoro-17α-methyl-7α- {5 - [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] pentyl} -estra-1, 3,5 (10) -triene-3,17β-άίοΙ

- 113-fluoro-7a- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -trien-3,17β-άΐοΙ

11-3-Fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17β-iol iol

-1'-Fluoro-7α- (5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,1 β-diol.

The compounds of formula I are substances with a very potent antiestrogenic action.

The compounds of the present invention are in part pure antiestrogens or in the other part so-called antiestrogens. partial antagonists, i.e., antiestrogens having an estrogenic partial effect such as tamoxifen or raloxifene. In any case, the agonistic, estrogenic effect in the compounds of the present invention is clearly weaker than that of tamoxifen. In contrast to tamoxifen, the partial antagonists of the formula I exhibit their agonist, estrogenic effect by tissue selective. In particular, an agonist effect occurs in bones, the cardiovascular system and the central nervous system (CNS). For example, no agonist effect occurs in the uterus.

The compounds of the present invention are antiestrogens with a stronger antiestrogenic effect than the 7- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -n-nonyl] -estra-1,3,5 (10) -triene contemplated to date. -3,? - diol.

The compounds of the formula I according to the invention are distinguished by novel side chains on the carbon atom 7 of the steroid structure, as compared to the steroid derivatives known according to EP-A 0 138 504 and EP-A 0 367 576. This structural modification results in particularly highly anti-estrogenically active compounds, as shown in the transactivation assay.

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The compounds of the formula I differ from the compounds according to EP-A 0 138 504 in addition in substitution on the carbon atom 11 and / or the D-ring (except when A and B together represent - (CH2) _P - or A and D together are - _{(CH2) q} -. in comparison to the compounds according to EP-a-0367576, the compounds of formula I to carry on the carbon atom 11 and / or the D-ring, the same or else different substituents.

The disclaimer in the definition of the compounds of the formula I are selected compounds described in the undisclosed DE DE 196 22 457.

The antiestrogenic effect of the compounds of the present invention was determined by a transactivation assay (Demirpence E., Duchesne, M.-J., Badia

E., Gagne D. and Pons M .: MVLN Cell: A Bioluminiscent MCF-7-Derived Cell Line to Study the Modulation of Estrogenic Activity; J. Steroid. Mol. Biol., Vol. 46, no. 3, 355-364 (1993), as well as Berry M., Metzger D., Chambon P .: The role of the two activating domains of the estrogen receptor in the cell-type and promotercontext dependent agonist activity of the anti-estrogen 4- hydroxy tamoxifen; The EMBO Journal, vol. 9, 2811-2818 (1990)).

Hela cells are transiently transfected with a human estrogen receptor expression vector (HEGO) and a Vit-TK-CAT reportgene and MVLN cells stably with a Vit-TK-LUC reportgene. Estrogenic potency in the presence of 0.1 nM estradiol was determined.

The IC 50 for the novel compounds is in the nanomolar range. In the Helabunk line as well as the MLVN-cell line, the compounds of Examples 12, 15, 18, 25, 29, 31 and 36 as well as 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) - n-nonyl] -estra-1,3,5 (10) -triene-3,17β-oleol of the following IC 50 values (carrying out the test according to the references cited above):

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compound IC ₅₀ (nM) Hela cells IC 50 (nM) of MVLN-cells pr. 12 0.06 2.4 pr. 15 0.06 1.4 pr. 18 0.05 0.13 pr. 25 0.06 0.15 pr. 29 0.13 0.2 pr. 31 0.1 0.2 pr. 36 0.05 0.4 cf. 7 [9- (4,4,5,5,5pentafluórpentánsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17-diol 0.5 6.0

The in vivo test also demonstrates the superiority of the compounds of the present invention over 7α- [9- (4,4,5,5,5-pentafluoropentanesulfinyl) -nonyl] -estra1,3,5 (10) -triene-3,17β- diol. The following tests were performed:

1. Uterine growth test in infantile rats, p. about. (antiestrogenic effect test)

2. Tumor test: anti-tumor effect on hormone-dependent breast cancer (DMBA * = induced mammary carcinoma in rats * = dimethylbenzantracene)

1. Uterine growth test in infantile rats (antiestrogenic effect)

Principle of the method

In rodents, the uterus responds to estrogen delivery by weight gain (both proliferation and water storage). This growth is inhibited by dose-dependent administration of anti-estrogen-acting compounds.

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Perform an experiment

The animals

Infantile male rats weighing 35 to 45 g at the start of the experiment, for a dose of 5 to 6 animals.

Formulation and application of substances

For p. about. application, the substance is dissolved in one part of ethanol (E) and made up with 9 parts of peanut oil (EO).

Conducting an experiment

Young rats weaned directly from their mothers should be fed immediately - also in an animal cage - due to habituation one day prior to treatment. The treatment is then performed daily once every three days in combination with 0.5 µg of estradiol benzoate (EB). EB is always administered subcutaneously (s.c.), whereas the test substance is administered orally (p. O.). 24 hours after the last application, the animals are weighed, sacrificed and the uterus removed. The dissected uterus was determined to have a wet weight (no content).

inspection

Negative Control: vehicle (E / EÔ), 0.2 ml / animal / day

Positive control: 0.5 µg EB / 0.1 ml / animal / day.

evaluation

Mean values with standard deviation (X + SD) as well as the significance of differences for the control group (EB) in the Dunnett's test are obtained from the organ relative weights (mg / 100 g body weight) for each group. Calculation of inhibition (in%) compared to EB-control is performed using a program. The relative effect of the test substances is performed by covariance and regression analysis.

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Antiestrogenic effect in rats

The compound of Ex. 0.1 mg / kg p.o. % inhibition IC ₅₀ 12 91 0.01 15 33 0.24 18 16 > 0.30 29 80 0.01 31 71 0.04 36 62 0.03 Cf.. ZM 182 780 8 0.39

These results demonstrate a much higher antiestrogenic effect of the compounds of Formula I compared to 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -n-nonyl] -estra-1,3,5 (10) -triene- 3,17β-diol, always after oral administration.

The compounds of the present invention exhibit improved bioavailability after oral administration.

2. Tumor test

Effect on tumor growth in DMBA * -models in rats (DMBA-tumormodel) * 9,10-dimethyl-1,2-benzantracene

Biological basis

The growth of DMBA-induced mammary tumor in rats is largely dependent on estrogens and prolactin. Effective antiestrogens, antigestagens and aromatase inhibitors lead to inhibition of tumor growth. Substances that have antigonadotropic and androgenic properties also develop a tumor-inhibiting effect.

31174 / H

Animal material

Female rats 45 to 47 days of age (Sprague-Dawley, breeder ZIH or Mollegrad), for a group of 8 to 10 animals.

Conducting an experiment

The animals receive a single dose of 10 mg DMBA orally. The animals are then examined once a week for palpation for tumor development. 6 to 10 weeks after DMBA treatment, about 1 to 10 tumors per animal develop. Tumor size is determined weekly using a caliper. When at least one tumor reaches a defined size (tumor area 150 mm ² ), the animal is ovariectomized, or treatment of the animal with the test substance begins. The treatment is usually performed for about 28 days daily (see experimental design for details). Tumor size is further determined once a week.

evaluation

The total tumor size per animal is determined before the start of treatment (preliminary value). The average percent change in tumor size relative to baseline is then calculated for each group. In addition, the percentage of animals in the group whose tumors were (1) totally suppressed (total regression), (2) partially suppressed (partial regression), (3) unchanged (no change), or further increased (magnification) was determined.

The found values are tested for significance and graphically in Dunnett's test.

Test results

At an oral dose of 3 mg / kg per day 11β-fluoro-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol (compound of Example 29) is more potent than at an oral dose of 10 mg / kg

31174 / H per day 7α- [9- (4,4,5,5,5-pentafluoropentanesulfinyl) -nonyl] -estra-1,3,5 (10) -triene-3,7β-diol, which causes at this dose only slight effect compared to intact control. Ovariectomy leads to total tumor remission (Fig. 1).

The compounds inhibit growth of hormone-dependent tumor cells, in particular they inhibit the growth of estrogen-dependent human mammary tumor cells (MCF-7).

The antiproliferative activity of the novel compounds in mammary carcinoma cell lines is higher than that of 7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) -nnonyl] -estra-1,3,5 (10) -triene-3,173-d iolu.

Pure antiestrogens within the meaning of the present invention are those compounds of formula I which exhibit no or only a slight agonist effect (up to about 10% of the effect of estradiol) in the following in vitro test for estrogenic activity.

The estrogenic partial effect is also determined by means of a transactivation experiment. Hela cells are transfected with a human estrogen receptor expression vector (HEGO) and with the rPR-TK-CAT reportgene. This reportgene contains the "Estrogen Responsive Element" of the rabbit progesterone-receptor gene (+ 698 / + 729-region) before the TK-CAT gene (Savouret

JF, Bailly, A., Misrahi, M., Rauch, C., Redeuilh, G., Chauchereau, A., Milgrom, E., Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene, EMBO J 10, 1875-1883 (1991)).

Estrogenic potency at a concentration of 1 μΜ was determined.

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Example compound Activation of the rPR-TK promoter (% estradiol) * 12 -11 15 -25 18 -24 25 -21 29 10 31 -5 36 -6 Comp. ZM 182780 -15

* Negative value means suppression of reportgene activity below control value

The compounds of the present invention, especially when they are pure antiestrogens, are useful in the treatment of estrogen-dependent diseases such as mammo-carcinoma (secondary therapy of tamoxifen-resistant mamocarcinoma; adjuvant treatment of mammo-carcinoma instead of tamoxifen), endometrial cancer, hyperplasia anovulatory infertility and melamoma. Pure antiestrogens of the formula I can furthermore be used as components in the products described in EP 346 014 B1 which contain estrogen and pure antiestrogen, although for simultaneous, sequential or separate use for selective estrogen therapy of perimenopausal and postmenopausal women. The compounds of the formula I, in particular as pure antiestrogens, can be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).

Other indications in which compounds of formula I may be considered are male hair loss, diffuse alopecia,

31174 / H chemotherapy-induced alopecia as well as hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996), 12525-12530).

In addition, the compounds of formula (I) may be used in the manufacture of a medicament for the treatment of endometriosis and endometrial cancer.

Furthermore, the compounds of the formula I can be used for the production of pharmaceutical preparations for controlling male and female fertility (male fertility control: DE-A 195 10 862.0).

The compounds of formula I having a tissue selective estrogenic partial effect may primarily find use for the prophylaxis and therapy of osteoporosis and for the manufacture of preparations for substitution therapy in premenopause, perimenopause and postmenopause (HRT) (Black LJ, Sato M., Rowley ER, Magee DE). Bekele A., Wiliams DC, Cullinan GJ, Bendele R., Kauffman RF, Bensch WR, Frolik CA, Dates JD and Bryant HU: Raloxifene (LY 139481 HC1) J Clin Invest 93: 63-69 (1994). The estrogenic partial effect occurs exclusively on the desired target organ.

The invention also relates to pharmaceutical preparations containing at least one compound of the formula I (or physiologically acceptable addition salts with organic and inorganic acids) and the use of these compounds for the manufacture of medicaments, in particular for the treatment of estrogen-dependent diseases and tumors and hormone replacement therapy drugs. (HRT).

The compounds of the present invention and their acid addition salts are suitable for the manufacture of pharmaceutical compositions and compositions. The pharmaceutical preparations or medicaments contain as active ingredient one or more of the compounds according to the invention or their acid addition salts, optionally in admixture with other pharmacologically or pharmaceutically active substances. The manufacture of medicaments is accomplished by known methods in which known and conventional pharmaceutical excipients as well as other conventional carriers and diluents can be used.

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Suitable carriers and excipients are, for example, those recommended or referred to in the following publications as excipients for pharmacy, cosmetics and related fields: Ullmans Encyklopädie der technischen Chemie, vol. 4 (1953), p. 1 to 39, Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918 et seq .; H. v. Czetsch Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind. Heft 2, 1961, p. 72 et seq .; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und Angrenzende Gebiete Cantor KG. Aulendorf in Wuttember 1971

The compounds may be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds may also be implanted into tissue. The amount of compounds administered varies over a wide range and any effective amount can be covered. Depending on the condition to be treated and the type of application, the amount of compound administered may be 0.1 to 25 mg / kg body weight, preferably 0.5 to 5 mg / kg body weight, per day. In humans, this corresponds to a daily dose of 5 to 1250 mg. The preferred daily dose in humans is 50 to 200 mg. This is particularly true for tumor therapy.

For oral administration, capsules, pills, tablets, dragees and the like are suitable. Dosage units may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier such as starch, sugar, sorbitol, gelatin, glidants, silicic acid, talc and the like. Single dosage units for oral administration may contain, for example, 5 to 500 mg of active ingredient.

In order to achieve better biocompatibility of the active ingredient, the compounds may be formulated as cyclodextrin clathrates. To this end, the compounds are reacted with α-, β- or γ-cyclodextrin or its derivatives (PCT / EP / 95/026 56).

For parenteral administration, the active compounds may be dissolved or suspended in a physiologically acceptable diluent. Very often oils are used as diluents without or with the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent. As examples used

31174 / H oils include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be used in the form of depot injections or implanted preparations, which may be formulated so as to provide a delayed release of the active ingredient.

The implants may contain, as inert materials, for example, biodegradable polymers or synthetic silicones, such as silicone rubber. In addition, the active compounds may be incorporated, for example, in patches for percutaneous administration.

The compounds of the present invention can be prepared as outlined below. The following examples serve to illustrate the invention in more detail. Analogous procedures using analogous reagents to those described in the Examples yield all compounds of Formula I. The saponification of ester groups as well as esterification and etherification of free hydroxyl groups are carried out according to conventional organic chemistry procedures. In view of the different reactivity of the esterified and free 3- and 17-hydroxyl groups, the 3,17-diesters can be selectively cleaved at the 3-position and the 3-hydroxy-17-acyloxy compound can then be further functionalized at the 3-position. Likewise, the 3,17-dihydroxy compound can be selectively esterified or etherified only in the 3-position and then a deliberate introduction into the 17-position of a residue other than that already present in the 3-position,

Acid addition salts of the compounds of formula I can also be prepared from compounds of formula I by conventional methods.

The following examples serve to illustrate the invention in more detail.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

14,17-ethano-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10) - triene-3,17β-iol

31174 / H

a) 7α- (5-tert-Butyldimethylsilyloxypentyl) -estr-4-ene-3,17-dione

In 70 ml of absolute tetrahydrofuran, 15.1 g of magnesium shavings are reacted with 175.6 g of 1-bromo-5-tert-butyl-dimethylsilyloxypentane (Tetrahedron Letters 23, 1982, 40, 4147-4150) dissolved in 600 ml of absolute tetrahydrofuran , to the Grignard reagent. To this solution, cooled to -20 ° C, 59 g of copper (I) iodide are added under a nitrogen atmosphere and then, within one hour, 50 g of estra-4-diene-3,17-dione (Steroids, vol. 1, 1963, 233). -249) dissolved in 300 mL of absolute tetrahydrofuran. For working-up, 37.5 ml of acetic acid are added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel. 35.4 g of 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-ene-3,17-dione are obtained.

[.alpha.] _D @ ²² = + 52.8 DEG (c = 0.535% in chloroform).

b) 7cc- (5-hydroxypentyl) -estr-4-ene-3,17-dione

A solution of 125.4 g of 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-ene-3,17-dione in 625 ml of methanol and 347 ml of water is stirred at 50 ° C for

2.5 hours with 694 ml glacial acetic acid. Evaporation in vacuo at 60 ° C gave 94.1 g of crude 7α- (5-hydroxypentyl) -estr-4-ene-3,17-dione as an oil.

c) 7α- (5-acetoxypentyl) -estr-4-ene-3,17-dione

A solution of 94 g of 7a- (5-hydroxypentyl) -estr-4-ene-3,17-dione in 620 ml of pyridine is slowly mixed with 310 ml of acetic anhydride and stirred for 2 hours at 25 ° C. It is then slowly treated with 116 ml of water, while cooling with ice, diluted with 3 L of diethyl ether, the organic phase is washed with sodium bicarbonate solution, dried and evaporated. The residue is chromatographed on silica gel to give

31174 / H 84.4 g of 7- (5-acetoxypentyl) -estr-4-ene-3,17-dione as an oily liquid

d) 7α- (5-acetoxypentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one

To a solution of 82.3 g of 7- (5-acetoxypentyl) -estr-4-ene-3,17-dione in 936 ml of acetonitrile is added, at a bath temperature of 80 ° C, 17.8 g of lithium bromide and 92.83 g of copper bromide . After 10 minutes at a bath temperature of 80 ° C, the reaction solution is cooled, extracted three times with ethyl acetate, washed with water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel to give 60.4 g of 7a- (5-acetoxypentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one as an oily liquid.

e) 3-Acetoxy-7α- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-17-one

A solution of 60.4 g of 7cc- (5-acetoxypentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one in 300 ml of pyridine is stirred with 150 ml of acetic anhydride for one hour at room temperature. It is then precipitated with an ice / water / hydrochloric acid mixture, taken up in ethyl acetate, washed neutral with sodium hydrogen carbonate solution and brine, dried over sodium sulphate and evaporated in vacuo. 63.9 g of 3-acetoxy-7a- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-17-one is obtained in the form of an oily liquid.

f) 3-Acetoxy-7α- (5-acetoxypentyl) -17,17-ethylenedioxy-estra-1,3,5 (10) -triene

A solution of 63.9 g of 3-acetoxy-7a- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-17-one is stirred in 460 ml of dichloromethane with 460 ml of ethylene glycol, 155 ml of trimethyl orthoformate and 1.2 g. p-toluenesulfonic acid for 3 hours at 50 ° C. The reaction mixture is then diluted with dichloromethane, washed with sodium bicarbonate solution and brine, dried

31174 / H anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using hexane / ethyl acetate. 63.2 g of 3-acetoxy-7a- (5-acetoxypentyl) -17,17-ethylenedioxy-estra-1,3,5 (10) -triene is obtained in the form of an oily liquid.

g) 3-acetoxy-7α- (5-acetoxypentyl) -16α-bromo-17,17-ethylenedioxy-estra-1,3,5 (10) triene.

A solution of 63.2 g of 3-acetoxy-7α- (5-acetoxypentyl) -17,17-ethylenedioxy-estra-1,3,5 (10) -triene in 630 ml of tetrahydrofuran was added portionwise at 0 ° C to 61.7 g of pyridine hydrobromide perbromide and the reaction mixture is stirred for 2 hours at 0 ° C. A solution of 15 g of sodium sulfide in 70 ml of water is then added, diluted with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 74.1 g of 3acetoxy-7a- (5-acetoxypentyl) -16a-bromo-17,17-ethylenedioxy-estra-1,3,5 (10) triene are obtained in the form of an oily liquid.

h) 17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-3-ol

A solution of 74.1 g of 3-acetoxy-7a- (5-acetoxypentyl) -16a-bromo-17,17-ethylenedioxy-estra-1,3,5 (10) -triene in 740 ml of dimethylsulfoxide and 74 ml of methyl alcohol is stirred with 74 g of potassium hydroxide for 7.5 hours at a bath temperature of 85 ° C. The reaction mixture was then precipitated with ice / water / sodium chloride, taken up in ethyl acetate, washed neutral, dried over anhydrous sodium sulfate, evaporated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 36.12 g of 17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-3-ol are obtained in the form of a foam.

(i) 3-hydroxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one

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A solution of 36.12 g of 17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at a temperature of room with 2.76 g of p-toluenesulfonic acid. The mixture is then concentrated in vacuo to 1/3 volume, taken up in ethyl acetate, washed neutral, dried over sodium sulphate and concentrated in vacuo. 31.7 g of 3-hydroxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one are obtained in the form of a crystalline substance, m.p. 194-196 ° C.

j) 3,17-diacetoxy-7α- (5-acetoxypentyl) -estra-1,3,5 (10), 14,16-pentaene

A solution of 15.7 g of 3-hydroxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one in 330 ml of acetic anhydride is stirred for 4 hours at room temperature with 4, 6 g of p-toluenesulfonic acid. The reaction mixture is then precipitated with pyridine / water / sodium chloride, taken up in ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane / ethyl acetate. ethyl acetate. 11.1 g of pure 3,17-diacetoxy-7α- (5-acetoxypentyl) estra-1,3,5 (10), 14,16-pentaene are obtained in the form of an oily liquid.

k) 3,17β-diacetoxy-7α- (5-acetoxypentyl) -14α, 17α-etheno-estra-1,3,5 (10) -tene

11.0 g of 3,17-diacetoxy-7a- (5-acetoxypentyl) -estra-1,3,5 (10), 14,16pentaene in 120 ml of benzene are treated at 30.0 MPa at 175 ° C. for 6.5 days with ethene. The mixture was then taken up in ethyl acetate, washed with sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 8.4 g of 3,17β-diacetoxy-7α- (5-acetoxypentyl) -14α, 17α-ethenoestra-1,3,5 (10) -triene are obtained in the form of a foam.

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(l) 3,17β-diacetoxy-7α- (5-acetoxypentyl) -14α, 17α-ethano-estra-1,3,5 (10) -triene

A solution of 8.4 g of 3,17β-diacetoxy-7α- (5-acetoxypentyl) -14α, 17α-etheno-estra-1,3,5 (10) -triene in 200 mL of ethyl acetate was shaken at room temperature under hydrogen for one hour. atmosphere with 1.5 g palladium on carbon (10%). The catalyst is filtered off with suction on celite and washed with ethyl acetate, the solution is concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 6.0 g of 3,17β-diacetoxy-7α- (5-acetoxypentyl) -14α, 17α-ethano-estra-1,3,5 (10) -triene is obtained as a foam.

m) 14α, 17α-ethano-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -triene-3,17β-oleol

A solution of 6.0 g of 3,4-diacetoxy-7α- (5-acetoxypentyl) -14a, 17α-ethano-estra-1,3,5 (10) -triene in 100 ml of 1 M potassium hydroxide solution is allowed to stand for 7.5 hours. hours at room temperature. It is then added to 1 M hydrochloric acid, extracted three times with ethyl acetate, washed with sodium bicarbonate solution and sodium chloride solution, dried over sodium sulphate, concentrated in vacuo and recrystallized from acetone-hexane. 4.57 g of 14α, 17α-ethano-7α- (5-hydroxypentyl) estra-1,3,5 (10) -triene-3,17β-όίοΙυ is obtained in the form of a colorless crystalline substance, m.p. 63-65 °. C.

n) 3-benzyloxy-14a, 17a-ethano-7α- (5-hydroxypentyl) -estra-1,3,5 (10) triene-17β-οΙ

A solution of 4.5 g of 14α, 17α-ethano-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -triene-3,17β-diol in 90 ml of acetonitrile is stirred at 80 ° C for 6.5 hours. C with 1.91 g of potassium carbonate and 1.53 ml of benzyl bromide. The reaction mixture is then concentrated to 1/3 volume in vacuo, added to water, extracted three times with ethyl acetate, washed neutral and dried

31174 / H anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / acetone. 4.8 g of 3-benzyloxy-14α, 17α-ethano-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17β-ol is obtained in the form of a foam.

o) 3-Benzyloxy-14α, 17α-ethano-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) trien-17β-ol

A solution of 4.8 g of 3-benzyloxy-14α, 17α-ethano-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17β-ol in 50 mL of pyridine is stirred at 0 ° C for 4 hours. hours with 3.63 g of toluenesulfonic anhydride. The reaction mixture was then diluted with ethyl acetate, extracted with 2M hydrochloric acid, washed neutral, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / ethyl acetate. 4.75 g of 3-benzyloxy-14α, 17α-ethano-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17β-ol is obtained in the form of a foam.

p) 3-benzyloxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -trien-17β-οΙ

A solution of 4.7 g of 3-benzyloxy-14α, 17α-ethano-7α- (5-tosyloxypentyl) -estra1,3,5 (10) -triene-17β-ο1υι in 100 mL of dimethylformamide is stirred for 4 hours at a bath temperature of 80 ° C. ° C with 2.7 g of methyl [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] amine. The reaction mixture was then added to water, extracted three times with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 3.8 g of 3-benzyloxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1 are obtained. 3,5 (10) -trien-17β-ol as an oily liquid.

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q) 14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) ) -triene-17-diol

A solution of 3.7 g of 3-benzyloxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1 3,5 (10) -trien-17β-ol in 65 ml of dichloromethane was stirred at 0 ° C for 5 minutes with 2.1 ml of N, N-dimethylaniline, mixed with 2.75 g of anhydrous aluminum chloride and the reaction mixture was Stir for 3.5 hours at 0 ° C. It is then treated with a saturated aqueous solution of potassium sodium tartrate, poured into water, extracted three times with dichloromethane, washed neutral, dried over sodium sulphate and concentrated in vacuo. 6.3 g of crude product are obtained, which is chromatographed on silica gel with dichloromethane / methanol. 2.85 g of pure 14a, 17cc-ethano-7α- {5 [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra 1,3 are obtained. 5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 63-67 ° C.

[.alpha.] _D @ ²² = + 19.4 DEG (c = 0.505% in chloroform).

Example 2

14,17-ethano-7-N- {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfinyl) -propylamino] pentyl} estra-1,3,5 (10 ) -triene-3,17-diol

A solution of 1.0 g of 14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol v

37.5 ml of methanol and 1.78 ml of water were stirred for 5 hours at room temperature with 381 mg of sodium periodate. The reaction mixture is then taken up in water, extracted three times with dichloromethane, washed neutral, dried over sodium sulphate and concentrated in vacuo. 985 mg of crude product is obtained, which is chromatographed on silica gel with dichloromethane / methanol to give 514.3 mg of pure 14,17-ethano-7α- {5- [N-methyl-N-3- (4,4-d) -propanoate. (5,5,5-pentafluoropentanesulfinyl) -propylamino] -31174 / H pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 84-86 ° C.

[.alpha.] _D @ ²² = + 13.0 DEG (c = 0.5% in chloroform).

Example 3

3,17-diacetoxy-14, 17-ethano-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3, 5 (10) -triene

A solution of 600 mg of 14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol in 2 ml of pyridine and 1 ml of acetic anhydride was stirred for 5 hours at room temperature with 5 mg of dimethylaminopyridine. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 680 mg of 3,17β-diacetoxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} is obtained. -estra-1,3,5 (10) -triene as an oily liquid.

Example 4

14,17-Ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,17β-iol

A solution of 650 mg of 3,4-diacetoxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- 1,3,5 (10) -triene in 15 ml of glacial acetic acid is stirred for 3 hours at room temperature with 1.5 g of sodium perborate tetrahydrate. The reaction mixture is then taken up in water, extracted three times with dichloromethane, washed neutral, dried over sodium sulphate and concentrated in vacuo. The residue is taken up in 10 ml of a 0.2 molar potassium hydroxide solution, stirred for 24 hours at room temperature, poured into water, extracted three times with dichloromethane, washed neutral, dried over

31174 / H anhydrous sodium sulfate and concentrated in vacuo. The residue is suspended in 20 ml of ethyl acetate, mixed with 10 ml of tin (II) chloride solution, stirred for 4 hours at room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulphate, dried in vacuo. The mixture is concentrated and the residue is chromatographed on silica gel with hexane / ethyl acetate. 300 mg of pure 14,17-ethano-7a- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3 is obtained. 5 (10) -triene-3,173-diol as a crystalline substance, m.p. 55-58 ° C.

[a] D ²² = + 19.4 ⁰ (c = 0.51% in chloroform).

Example 5

17-trifluoromethyl-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10) -triene 3,17-diol

a) 17β-Acetoxy-7α- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3-one

In 200 ml of absolute tetrahydrofuran, 22.9 g of magnesium turnings are reacted with 261 g of 1-bromo-5-tert-butyl-dimethylsilyloxypentane (Tetrahedron Letters 23, 1982, 40, 4147-4150), dissolved in 250 ml of absolute tetrahydrofuran, to Grignard reagent. To this solution, cooled to -20 ° C, 92.9 g of copper iodide are added under a nitrogen atmosphere, and then 73.5 g of 17βacetoxyestra-4,6-dien-3-one (J) are added dropwise over one hour. (Am. Chem. Soc., 80, 1958, 2596-2597), dissolved in 300 ml of absolute tetrahydrofuran. For working-up, 61.2 ml of acetic acid are added dropwise, the reaction mixture is diluted with ethyl acetate, washed with saturated ammonium chloride solution, water and sodium bicarbonate solution and dried. The residue obtained after evaporation is chromatographed on silica gel to give 48 g of 4-acetoxy-7 - (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-en-3-one.

31174 / H

b) 17β-Acetoxy-7α- (5-hydroxypentyl) -estr-4-en-3-one

A solution of 48 g of 17β-acetoxy-7a- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4en-3-one in 350 ml of methanol is allowed to stand with 35 ml of 8% v / v sulfuric acid for 30 minutes at room temperature. . The solution is then diluted with diethyl ether, washed with water until neutral and dried. Evaporation gave 37.7 g of 17β-acetoxy-7α- (5-hydroxypentyl) -estr-4-en-3-one as an oily liquid.

c) 17β-Acetoxy-7α- (5-acetoxypentyl) -estr-4-en-3-one

A solution of 37.7 g of 17β-acetoxy-7α- (5-hydroxypentyl) -estr-4-en-3-one in 160 ml of pyridine is slowly mixed with 80 ml of acetic anhydride and stirred for 16 hours at 25 ° C. The reaction mixture is then diluted with ethyl acetate and the organic phase is washed with sodium bicarbonate solution and dried and evaporated. The residue is chromatographed on silica gel to give 26.6 g of 17β-acetoxy-7α- (5-acetoxypentyl) -estr-4-en-3-one as an oily liquid [α] _D ²² = + 20.0 ° (c = 0.51% in chloroform).

d) 17β-Acetoxy-7α- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-3-ol

To a solution of 26.6 g of 17β-acetoxy-7α- (5-acetoxypentyl) -estr-4-en-3-one in 260 ml of acetonitrile heated to 80 ° C is added dropwise solution 30 over 30 minutes with stirring. 18 g of lithium bromide and 26.73 g of copper bromide in 260 ml of acetonitrile. After the addition was complete, the reaction solution was cooled, diluted with diethyl ether, washed with water and sodium bicarbonate solution and dried. After evaporation, the residue is chromatographed on silica gel to give 21.3 g of 17β-acetoxy-7α- (5-acetoxypentyl) -1,3,5 (10) -estratrien-3-ol as an oil.

[.alpha.] D @ ²² = +28.9 DEG (c = 0.535% in chloroform).

31174 / H

e) 17β-Acetoxy-7α- (5-acetoxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-

1,3,5 (10) -triene

A solution of 21.3 g of 17β-acetoxy-7a- (5-acetoxypentyl) -estra-1,3,5 (10) -trien-3-ol in 213 ml of tetrahydrofuran is left to stand for 8 hours at room temperature with 21.3 ml of 3 , 4-dihydro-2H-pyran and 1.065 g of ptoluenesulfonic acid. The reaction solution is mixed with 3 ml of pyridine, then diluted with diethyl ether, washed with water and dried. After evaporation, the residue is chromatographed on silica gel to obtain 24.3 g of 17β-acetoxy-7α- (5-acetoxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene as oily liquid.

[.alpha.] _D @ ²² = +31.5 DEG (c = 0.535% in chloroform).

f) 17β-Acetoxy-7α- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene

A solution of 10.2 g of 17β-acetoxy-7α- (5-acetoxypentyl) -3- (tetrahydropyran-2yloxy) -estra-1,3,5 (10) -triene in 205 ml of methanol is stirred for 45 minutes at 15 ° C with 33.7 ml of sodium hydroxide. The reaction mixture was diluted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. 5.6 g of 17β-acetoxy-7a- (5-hydroxypentyl) -

3- (tetrahydropyran-2-yloxy) estra-1,3,5 (10) -triene.

[α] _D ²² = + 32.2 ⁰ (c = 0.505% in chloroform).

(g) 17β-Acetoxy-3- (tetrahydropyran-2-yloxy) -7α- (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -triene

A solution of 5.5 g of 17β-acetoxy-7a- (5-hydroxypentyl) -3- (tetrahydropyran-2yloxy) -estra-1,3,5 (10) -triene in 47 ml of pyridine is allowed to stand for 45 minutes at room temperature. with 5.5 g of p-toluenesulfonic anhydride. Then

The 31174 / H reaction solution was cooled in an ice bath, mixed with 4 ml of water and stirred for 45 minutes. It is then diluted with ethyl acetate, washed with water, dried and evaporated. 8.2 g of 17β-acetoxy-3- (tetrahydropyran-2yloxy) -7- (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -triene is obtained in the form of an oily liquid.

h) 17β-Acetoxy-7α- (5-methylaminopentyl) -3- (tetrahydropyran-2-yloxy) -estra1,3,5 (10) -triene

A solution of 8.2 g of 17β-acetoxy-3- (tetrahydropyran-2-yloxy) -7- (5-ptoluolsulfonyloxypentyl) -estra-1,3,5 (10) -triene in 80 ml of tetrahydrofuran was condensed in a pressure tube and ice-cooling with 6.3 g of methylamine. The sealed pressure tube is then heated at 60 ° C for 6 hours. After cooling, the reaction mixture is evaporated to dryness in vacuo and the residue is chromatographed on silica gel. 5.1 g of 17β-acetoxy-7a- (5-methylaminopentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene is obtained in the form of an oily liquid.

[a] ²² _D = +29.7 ⁰ (c = 0.535% in chloroform).

i) 17β-Acetoxy-7α- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) -estra 1,3,5 (10) -triene

A solution of 1.64 g of 17β-acetoxy-7a- (5-methyaminopentyl) -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -triene in 25 ml of absolute dimethylformamide is stirred for 2 hours at room temperature. with 159 mg of 80% sodium hydride under a nitrogen atmosphere. 1.43 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentylsulfide in 7 ml of absolute dimethylformamide is then added dropwise and the reaction mixture is stirred for 22 hours at 80 ° C. The reaction solution is then diluted with ethyl acetate, washed with water, dried and evaporated and the residue is chromatographed on silica gel. 820 mg of 17β-acetoxy-7a31174 / H {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3 (tetrahydropyran-2-) is obtained. yloxy) -estra-1,3,5 (10) -triene as an oily liquid. [a] _D ²² = + 21.5 ⁰ (c = 0.51% in chloroform).

j) 7α- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3 (tetrahydropyran-2-yloxy) -estra-1,3 , 5 (10) -trien-17-ol

A solution of 790 mg of 17β-acetoxy-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra1 3,5 (10) -triene in 8 ml of methanol and 3 ml of tetrahydrofuran was stirred for 18 hours at room temperature with 430 mg of potassium carbonate. The reaction solution was diluted with diethyl ether, washed with water, dried and evaporated. 750 mg of crude 7- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) -estra are obtained. 1,3,5 (10) -trien-17-ol.

k) 7α- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} estra-1,3,5 (10) -triene-17β- diol

A solution of 750 mg of 7- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17β-ol in 28 ml of methanol and 2.8 ml of water are stirred for 17 hours at room temperature with 350 mg of oxalic acid. The reaction mixture was then diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried and concentrated. The residue is chromatographed on silica gel to give 640 mg of 7a- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3 5 (10) -triene-17β-diol in the form of an oily liquid.

[.alpha.] D @ ²² = +24.0 DEG (c = 0.515% in chloroform).

31174 / H

l) 7 ~ {5- [N-methyl-N-3- (4,4,5 _f 5,5-pentafluoropentylthio) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) estra-1, 3,5 (10) -trien-17-one

A solution of 900 mg of 7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17β-ol in 30 ml of toluene and 9.6 ml of cyclohexanone are mixed with a solution of 900 mg of aluminum isopropylate in 16 ml of toluene and the reaction mixture is heated under slow distillation for 30 minutes. The reaction solution was then diluted with ethyl acetate, washed with 20% sodium potassium tartrate solution, dried and evaporated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 715 mg of 7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino]. -pentyl} -3 (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one as an oily liquid.

m) 17α-Trifluoromethyl-3- (tetrahydropyran-2-yloxy) -7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- 1,3,5 (10) -trien-17β-οΙ

A solution of 500 mg of 7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1, 3,5 (10) -trien-17-one (see Ausw.-Pat. Ex. 2a) in 5 ml of absolute tetrahydrofuran is mixed with 0.27 ml of (trifluoromethyl) trimethylsilane at a bath temperature of 0 ° C. Then 0.2 ml of a 1.1 molar tetrabutylammonium fluoride solution is slowly added dropwise, stirred for 45 minutes, 1 ml of a 1.1 molar tetrabutylammonium fluoride solution is again added and stirred for a further 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo, and chromatographed on silica gel using dichloromethane / methanol. 285 mg of 17α-trifluoromethyl-3- (tetrahydropyran-2-yloxy) -7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} is obtained. -estra-1,3,5 (10) trien-17β-ol as an oily liquid.

31174 / H

n) 17α-Trifluoromethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -estra-1,3,5 (10) -trien-3,17β-diol

A solution of 280 mg of 17α-trifluoromethyl-3- (tetrahydropyran-2-yloxy) -7- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra -1,3,5 (10) Trien-17β-οΙιι in 5.6 ml methanol and 0.56 ml water was stirred with 140 ml oxalic acid for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / methanol. 215 mg of 17α-trifluoromethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) is obtained. ) triene-3,17β-diol as an oily liquid.

Example 6

15?, 16-methano-17-methyl-7 (x- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3 , 5 (10) -triene-3,17-diol

a) 3-Benzyloxy-17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraene

A solution of 32.7 g of 17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra1,3,5, (10), 15-tetraen-3-ol (see Example 1h) in 327 ml of dimethylformamide was mixed at room temperature. with 5.73 g of lithium hydroxide and the mixture is stirred for 2 hours at 60 ° C with 15.1 ml of benzyl bromide. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α- (5-hydroxypentyl) estra-1,3,5 (10), 15-tetraene are obtained.

31174 / H

b) 3-Benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one

A solution of 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α- (5-hydroxypentyl) -estra-

1.3.5 (10), 15-tetraene in 328 ml of acetone and 32.8 ml of water are stirred with 1.033 g of p-toluenesulfonic acid for 2 hours at room temperature. The reaction mixture was diluted with diethyl ether, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, evaporated in vacuo and the residue chromatographed on silica gel using dichloromethane / acetone. 25.4 g of 3-benzyloxy-7α- (5-hydroxypentyl) estra-1,3,5 (10), 15-tetraen-17-one are obtained.

c) 3-Benzyloxy-7α- (5-hydroxypentyl) -15β, 16β-methano-estra-1,3,5 (10), 15tetraen-17-one

In 65 ml of dimethyl sulfoxide, 2.861 g of trimethylsulfoxonium iodide are reacted with 345 mg of 80% sodium hydride for 2 hours at room temperature. To this solution was added 4.44 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one and the reaction mixture was stirred for 45 minutes at room temperature. The precipitated precipitate is filtered off and washed with water. This precipitate was taken up in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel with hexane / acetone. 2.8 g of 3-benzyloxy-7? - (5-hydroxypentyl) -15?, 16? -Methanol-1,3,5 (10), 15-tetraen-17-one are obtained.

[a] _D ²² = + 13.1 ⁰ (c = 0.525% in chloroform).

d) 3-benzyloxy-15β, 16β-methano-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 15tetraen-17-one

A solution of 2.5 g of 3-benzyloxy-7α- (5-hydroxypentyl) -15-β, 16β-methano-estra-1,3,5 (10), 15-tetraen-17-one in 25 ml of pyridine was mixed at room temperature. with

2.5 g of p-toluenesulfonic anhydride are allowed to stand and the reaction mixture is allowed to stand

31174 / H for 30 minutes, then mixed with 1 ml of water under ice-cooling and allowed to stand for a further 45 minutes. It is then diluted with diethyl ether, washed with water, dried over sodium sulphate and concentrated in vacuo. 3.4 g of 3-benzyloxy-15β, 16β-methano-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 15tetraen-17-one are obtained.

e) 3-benzyloxy-15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10), 15-tetraene-17-one

To a solution of 3.4 g of crude 3-benzyloxy-15β, 16β-methano-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one in 34 mL of dimethylformamide is added solution 2, 1 g of methyl [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine in 1 ml of dimethylformamide and the reaction mixture is stirred for 3.5 hours at 100 ° C. It is then diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel with dichloromethane / methanol. 2.6 g of 3-benzyloxy-15β, 16β-methano-7α- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} - are obtained. estra-1,3,5 (10), 15-tetraen-17-one as an oily liquid.

f) 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -3-hydroxy-estra-1,3 , 5 (10), 15-tetraene-17-one

A solution of 2.3 g of 3-benzyloxy-15β, 16β-methano-7α- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- 1,3,5 (10), 15-tetraen-17-one in 53 ml of dichloromethane is stirred at 0 ° C for 4.5 hours with 1.12 ml of Ν, dim-dimethylaniline and 1.64 g of aluminum chloride (anhydrous) ). The reaction mixture was diluted with ethyl acetate, washed with 30% potassium sodium tartrate solution and water, dried over anhydrous sodium sulfate, concentrated in vacuo, and chromatographed on silica gel using dichloromethane / methanol. 1.52 g of 15β, 16β are obtained

31174 / H methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl) -3-hydroxy-estra-1,3,5 ( 10), 15-tetraen-17-one in the form of an oily liquid.

[ _α ] _D ²² = -2.5 ° (c = 0.505% in chloroform).

(g) 15β, 16β-methano-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1; 3,5 (10) -triene-3,17β-diol

To a solution of 515 mg of 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-1, 3,5 (10), 15-tetraen-17-one in 10 ml of tetrahydrofuran was added dropwise at 0 ° C bath temperature with 1.8 ml of 3 molar methylmagnesium bromide solution and the reaction mixture was stirred for 2 hours at room temperature. It is then diluted with ethyl acetate, washed with saturated ammonium chloride solution and water, dried over sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel with dichloromethane / methanol. 395 mg of 15β, 16β-methano-17α-methyl-7α- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- is obtained. 1,3,5 (10) -triene-3,17βdiol in the form of an oily liquid.

[α] d ²² = -5.1 ⁰ (c = 0.52% in chloroform).

Example 7

15β, 16β-methano-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl) -estra-1,3, 5 (10) -triene-3,17-diol

A solution of 115 mg of 15β, 16β-methano-17α-methyl-7α- (5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1, 3,5 (10) -triene-3,17-diol (see example 6) in 5 ml of methanol is stirred for 3 hours at room temperature with 80 mg of sodium periodate, then diluted with ethyl acetate, washed with water, dried using anhydrous

31174 / H sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 65 mg of 15β, 16β-methano-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra are obtained. -1,3,5 (10) -triene-3,17β-diol as an oil.

[.alpha.] D @ ²² = -13.3 DEG (c = 0.27% in chloroform).

Example 8

15B, 16B-methano-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10) - triene-3,17-diol

A solution of 500 mg of 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3-hydroxy-estra-1,3 5 (10), 15-tetraen-17-one (see Example 6f) in 10 ml of methanol and 1 ml of water are stirred with 100 mg of sodium borohydride for 3 hours at room temperature. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 340 mg of 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 are obtained. (10) -triene-3,17β-diol in the form of an oily liquid.

[α] _D ²² = +1 1.9 ⁰ (c = 0.52% in chloroform).

Example 9

15B, 16B-methano-7a- {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfinyl) -propylamino] pentyl} estra-1,3,5 (10) - triene-3,17-diol

A solution of 100 mg of 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra'1,3,5 (10 -triene-3,17β-oleol (see Example 8) in 5 ml of methanol is stirred for 3 hours at room temperature with

31174 / H mg sodium periodate. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 70 mg of 15β, 16β-methano-7α {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra1,3,5 ( (10) -triene-3,17β-thiol in the form of an oily liquid.

[.alpha.] D @ ²² = +12.2 DEG (c = 0.515% in chloroform).

Example 10 4-Methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene- 3,17β-iol

a) 3-Benzyloxy-7α- (5-hydroxypentyl) -15B-methyl-estra-1,3,5 (10) -trien-17-one

To an ice-cooled solution of 11.9 ml of a 3 molar solution of methylmagnesium bromide in 68 ml of tetrahydrofuran is added 5.35 g of copper iodide under a nitrogen atmosphere, and a solution of 4.26 g of 3benzyloxy-7cc- (5-hydroxypentyl) -estra- 1,3,5 (10), 15-tetraen-17-one in 50 ml tetrahydrofuran and the reaction mixture is stirred for 30 minutes at a bath temperature of 0 ° C. The excess reagents are quenched by addition of saturated ammonium chloride solution, diluted with ethyl acetate, washed with ammonium chloride solution and water, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue chromatographed on silica gel with hexane / acetone. It is obtained as follows

3.6 g of 3-benzyloxy-7α- (5-hydroxypentyl) -1β-methyl-estra-1,3,5 (10) -trien-17-one as an oily liquid.

[a] D ²² = + 66.4 ⁰ (c = 0.515% in chloroform).

b) 3-Benzyloxy-15β-methyl-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one

31174 / H

A solution of 3.6 g of 3-benzyloxy-7α- (5-hydroxypentyl) -15β-methyl-estra-1,3,5 (10) -trien-17-one is tosylated as described in Example 6. 4 9 g of crude 3-benzyloxy-15β-methyl-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one.

c) 3-Benzyloxy-15β-methyl-7α- (5-N-methylaminopentyl) -estra-1,3,5 (10) trien-17-one

A solution of 4.9 g of 3-benzyloxy-15β-methyl-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one in 30 mL of tetrahydrofuran was condensed in a pressure reactor with cooling with 3.8 g of methylamine, whereupon the sealed reactor is heated at 80 ° C for 5.5 hours and then cooled and opened. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol. 3.15 g of 3-benzyloxy-15β-methyl-7α- (5-N-methylaminopentyl) -estra-1,3,5 (10) -trien-17-one is obtained in the form of an oily liquid.

d) 3-Benzyloxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl) -estra-1,3,5 (10) -trien-17-one

A solution of 3.15 g of 3-benzyloxy-15β-methyl-7α- (5-N-methylaminopentyl) -estra-1,3,5 (10) -trien-17-one in 31.5 ml of absolute dimethylformamide is mixed with 228 mg of 80% by weight. % sodium hydride, then stirred for 5 hours at room temperature, mixed with 2.6 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentylsulfide in 2 ml of absolute dimethylformamide and stirred at 80 for 24 hours. C. The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel with dichloromethane / methanol. 3.1 g of 3 are obtained

31174 / H benzyloxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl) -estra-1,3,5 ( 10) -Trien-17-one in the form of an oily liquid.

e) 3-hydroxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl) -estra-1,3,5 (10) -trien-17-one

A solution of 3.1 g of 3-benzyloxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl) -estra-1,3 The 5 (10) -trien-17-one is debenzylated as described in Example 6f. 830 mg of 3-hydroxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} -estra-1,3 is obtained, 5 (10) -Trien-17-one in the form of an oily liquid.

f) 153-Methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene- 3,17-diol

A solution of 460 mg of 3-hydroxy-15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -trien-17-one is reduced as described in Example 8. 200 mg of 15β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5, 5-Pentafluoropentylthio) -propylamino] -pentyl} estra-1,3,5 (10) -triene-3,17β-diol as an oil.

[α] ²² = +4.5 ⁰ (c = 0.51% in chloroform).

Example 11

15?, 17? -Dimethyl-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10) - triene-3,17-diol

1.44 g of dried cerium chloride are stirred in 15 ml of tetrahydrofuran for 2 hours at room temperature, mixed with 3.75 ml of a 3M methylmagnesium bromide solution under ice-cooling, stirred for 15 minutes with cooling and for 30 minutes at room temperature, then a solution of 750 mg 3 is added dropwise

31174 / H hydroxy-15β-methyl-7α- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -Trien-17-one (see Example 10e) in 7 ml of tetrahydrofuran, stirred for 2 hours at room temperature and the excess reagent is quenched with saturated ammonium chloride solution, then diluted with ethyl acetate, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using dichloromethane / methanol to give 145 mg of 15β, 17α-dimethyl-7α- {5- [N-methyl-N-3]. - (4,4,5,5,5-Pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as an oily liquid.

[α] D ²² = -7.3 ⁰ (c = 0.505% in chloroform)

Example 12

1IP-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10) -triene 3,1ľp-diol

a) 1β-Fluoro-estr-4-ene-3,17-dione

To 5.0 g of 11cc-hydroxy-estr-4-ene-3,17-dione in 100 ml of toluene and 7.3 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene is added dropwise at 0 ° C 4. 6 ml of perfluorobutane-1-sulfonic acid fluoride. After 30 minutes, the solution was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel using hexane / ethyl acetate gradient to give 3.8 g of 1. β-fluoro-estr-4-ene-3,17-dione, m.p. 173-174 ° C.

b) 11β-fluoro-3-methoxy-estra-3,5-dien-17-one

31174 / H

7.8 g of 1β-fluoro-estr-4-ene-3,17-dione are stirred for 5 hours at 80 ° C in 40 ml of 2,2-dimethoxypropane with 780 mg of pyridinium toluene-4-sulfonate. Triethylamine (1.5 ml) was added, diluted with ethyl acetate and washed with saturated sodium chloride solution. Crystallization from methanol gave 5.3 g of 1β-fluoro-3-methoxy-estra-3,5-dien-17-one, m.p. 173 ° C.

c) 11β-fluoro-estra-4,6-diene-3,17-dione

To 5.0 g of 1β-fluoro-3-methoxy-estra-3,5-dien-17-one in 50 ml of dimethylformamide is added 5 ml of 10% sodium acetate solution at 0 DEG C. in portions of 2, 5 g of 1,3-dibromo-5,5-dimethylhydantoin. After 30 minutes, 2.3 g of sodium sulfite was added, followed by 2.5 g of lithium bromide and 2.0 g of lithium carbonate and stirred for 2 hours at 100 ° C. The reaction mixture is stirred into ice-water, the precipitated product is filtered off with suction, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in a vacuum. After crystallization from ethyl acetate, 3.6 g of 11-p-fluoro-estra-4,6-diene-3,17-dione, m.p. 198 DEG C., is obtained.

d) 11 p-Fluoro-7α- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-ene-3,17-dione

7.9 g of magnesium in 40 ml of tetrahydrofuran are treated under a nitrogen atmosphere with a solution of 95.3 g of 1-bromo-5-tert-butyl-dimethylsilyloxypentane (Tetrahedron Letters 1982, 4147-4150) in 260 ml of tetrahydrofuran to Grignard reagent. At -30 ° C 32 g of copper (I) iodide are added first, followed by dropwise addition of 29 g of 1β-fluoro-estra-4,6-diene-3,17-dione in 290 ml of tetrahydrofuran. After completion of the reaction, the reaction mixture was stirred with 20.4 ml of glacial acetic acid and stirred in an ice-water mixture. The precipitated product is filtered off with suction, dissolved in ethyl acetate, washed neutral with water and dried. Chromatography of the crude product on silica gel using a hexane-ethyl acetate gradient afforded 23.9 g of 1β-fluoro-7a.

31174 / H (5-tert-Butyl-dimethylsilyloxypentyl) -estr-4-ene-3,17-dione as a foam.

e) 1β-Fluoro-7α- (hydroxypentyl) -estr-4-ene-3,17-dione

A solution of 23.1 g of 11β-fluoro-7α- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-ene-3,7-dione in 115 ml of tetrahydrofuran and 64 ml of water is stirred at 50 ° C for 2.5 hours. with 128 ml of glacial acetic acid. The reaction mixture is then concentrated in vacuo, taken up in ethyl acetate, washed with water and dried. 20.4 g of 11β-fluoro-7a- (5-hydroxypentyl) -estr-4-ene-3,17-dione are obtained in the form of a foam.

f) 7α-(5-acetoxypentyl) -1β-fluoro-estr-4-ene-3,17-dione 11β-fluoro-7α- (5-hydroxypentyl) -estr-4-ene-3,17- of dione in 100 ml of pyridine is reacted for 2 hours with 50 ml of acetic anhydride at 25 ° C. Then 5 ml of water are added at 0 ° C and stirred for 45 minutes, then extracted with diethyl ether, washed with 2N sulfuric acid in the absence of pyridine, and the solution is neutralized with saturated sodium bicarbonate solution and washed with water. After drying and concentration in vacuo, the crude product obtained is chromatographed on silica gel using a hexane / ethyl acetate gradient. 17 g of 7? - (5-acetoxypentyl) -1? -Fluoroestr-4-ene-3,17-dione, m.p. 78.4 ° C, are obtained.

g) 7α- (5-acetoxypentyl) -11β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one

To 16.5 g of 7α- (5-acetoxypentyl) -1β-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile at 80 ° C was added 18.6 g of copper bromide and 3.6 g. g of lithium bromide. After 15 minutes, the reaction mixture was stirred into a water / ice mixture containing sodium bicarbonate. The precipitated product is filtered off with suction, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in a vacuum. After chromatography of the crude product on silica gel using

31174 / H gradient of hexane-ethyl acetate gave 8.5 g of 7α- (5-acetoxypentyl) 11β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one as a foam .

h) 7α- (5-acetoxypentyl) -11β-fluoro-3- (tetrahydropyran-2-yloxy) -estra-

1,3,5 (10) -trien-17-one

8.2 g of 7a- (5-acetoxypentyl) -11 p-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in 86 ml of tetrahydrofuran are stirred for 2.5 hours at room temperature with

8.6 ml of 3,4-dihydro-2H-pyran and 820 mg of p-toluenesulfonic acid hydrate. 0.5 ml of triethylamine is then added, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel using a hexane-ethyl acetate gradient yielded 7.8 g of 7α- (5-acetoxypentyl) -11β-fluoro-

3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one as a foam.

i) 11β-fluoro-7α- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra-

1,3,5 (10) -trien-17-one

7.4 g of 7α- (5-acetoxypentyl) -1β-fluoro-3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one in 370 ml of methanol and 37 ml of water at It is stirred at room temperature with 1.8 g of potassium carbonate. After 3 hours, the reaction mixture is poured into ice-water, the precipitated product is filtered off with suction, dissolved in ethyl acetate, washed neutral with water, dried and concentrated by evaporation in a vacuum. 7.0 g of 11β-fluoro-7a- (5-hydroxypentyl) -3 (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one is obtained in the form of a foam.

j) 11? -fluoro-3- (tetrahydropyran-2-yloxy) -7? - (5-p-toluenesulfonyloxypentyl) estra-1,3,5 (10) -trien-17-one

6.7 g of 1β-fluoro-7a- (5-hydroxypentyl) -3- (tetrahydropyran-2-yloxy) -estra 1,3,3,5 (10) -trien-17-one in 70 ml of pyridine is stirred for 3 hours at the temperature

31174 / H room with 6.0 g of p-toluenesulfonic anhydride. The solution was then diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. The crude product is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 5.7 g of 1β-fluoro-3- (tetrahydropyran-2-yloxy) -7a- (5-p-toluenesulfonyloxypentyl) -estra-1, 3,5 (10) -trien-17-one as a foam.

k) 11β-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) - estra-1,3,5 (10) -trien-17-one

2.0 g of 1β-fluoro-3- (tetrahydropyran-2-yloxy) -7a- (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -trien-17-one in 40 ml of dimethylformamide is stirred at 80 ° C with 1.2 g of methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine. After

The reaction mixture was treated with water for 6.5 hours, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. The crude product is chromatographed on silica gel using a methylene chloride-methanol gradient to give 1.3 g of β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) - propylamino] -pentyl} -3 (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one as an oil.

l) 11β-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3- (tetrahydropyran-2-yloxy) -estra- 1,3,5 (10) -trien-17-ol

2.0 g of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -3- (tetrahydropyran-2) -yloxy) -estra-1,3,5 (10) -trien-17-one in 17 ml of tetrahydropyran, 10 ml of ethyl alcohol and 4.2 ml of water is added portionwise at 350C with sodium borohydride. After stirring for thirty minutes, the reaction mixture is stirred into ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution and concentrated in vacuo. 1.7 g of crude 11β-fluoro-7α- {5- [N-methyl-N-3] is obtained

31174 / H (4,4,5,5,5-Pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) estra-1,3,5 (10) -trien-17β-ol as foamy substance.

m) 11β-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene -17β-άίοΙ

A solution of 1.6 g of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2) -yloxy) -estra-1,3,5 (10) trien-17β-ol in 20 mL of methanol and 2 mL of water was stirred with 1.0 g of oxalic acid. After 3 hours, the reaction mixture is poured into ice-water, extracted with methylene chloride, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel using a methylene chloride-methanol gradient afforded 1.1 g of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino]. ] -pentyl} -estra-1,3,5 (10) -triene-17β-diol, m.p. 95 ° C.

Example 13 1-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-iol iol

580 mg of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-17β-diol in 24 ml of methanol and 1.1 ml of water was stirred at room temperature with 350 mg of sodium periodate. After 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. Chromatography of the crude product on silica gel using a methylene chloride-methanol gradient afforded 287 mg of 1'-fluoro-7α- {5- [N-methyl-N-3 (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3, 17β-melting point, m.p. 87 ° C.

31174 / H

Example 14 1β-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,17β-diol

a) 11β-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) - estra-1,3,5 (10) -trien-17-one

2.0 g of 1β-fluoro-3- (tetrahydropyran-2-yloxy) -7- (5-p-toluenesulfonyloxypentyl) -estra-1,3,5 (10) -trien-17-one is stirred in 40 ml of dimethylformamide. at 80 DEG C. with 2.1 g of methyl [3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl] -amine. After 7 hours, the reaction mixture is poured into ice-water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated by evaporation in a vacuum. Chromatography of the crude product on silica gel using a methylene chloride-methanol gradient afforded 1.1 g of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino]. 1-Pentyl} -3- (tetrahydropyran-2-yloxy) -estra-1,3,5 (10) -trien-17-one as an oil.

b) 11β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) - estra-1,3,5 (10) -trien-17-ol

1.5 g of 11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) 1 -estra-1,3,5 (10) -trien-17-one was mixed portionwise at 0 ° C in a mixture of 13 ml of tetrahydrofuran, 7.5 ml of ethanol and 3.2 ml of water with 270 mg of sodium borohydride. After 90 minutes, water was added, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. 1.5 g of 11-P-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -3- (tetrahydropyran) is obtained. -2-yloxy) -estra-1,3,5 (10) -trien-17β-ol as a crude product.

31174 / H

c) 11-p-fluoro-7α- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

1.4 g of 11-p-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) 1 -estra-1,3,5 (10) -trien-17β-ol is stirred in 18 ml of methanol and 1.8 ml of water at room temperature with 900 mg of oxalic acid. After 4 hours, the reaction mixture is stirred into ice / water, the precipitated product is taken up in methylene chloride, washed with water and concentrated in vacuo. Chromatography of the crude product on silica gel using a methylene chloride-methanol alcohol gradient yields 325 mg of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] - pentyl} -estra1,3,5 (10) -triene-3,17β-diol, m.p. 70 ° C.

Example 15

16-fluoro-17-methyl-7 ~ (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10 ) -triene-3,1 β-diol

a) 7α- (5-Chloropentyl) -estr-4-ene-3,17-dione

11.6 g of magnesium shavings are suspended in 150 ml of anhydrous tetrahydrofuran and Grignard reagent is prepared using 58.8 ml of 1-bromo-5-chloropentane in 40 ml of anhydrous tetrahydrofuran. The mixture was stirred for 30 minutes at room temperature, diluted with an additional 100 mL of anhydrous tetrahydrofuran and cooled to -70 ° C. A solution of 3.03 g of copper (I) -dimethylsulfide complex in 72 ml of 1,3-dimethyltetrahydro-2 (1H) -pyrimidinone (DMPU) and 150 ml of tetrahydrofuran is then added dropwise at an external temperature of -65 to -70 ° C. Finally, a solution of 50 g of estra-4,6-diene-3,17-dione (Steroids, Vol. 1, 1963, 223) and 75 ml of trimethylchlorosilane in 700 ml of anhydrous tetrahydrofuran is added over 2.5 hours. The reaction mixture is allowed to warm slowly to room temperature with stirring in the cooling bath, acidified the next day with 48 ml.

31174 / H of acetic acid is mixed with ethyl acetate with ice cooling and stirring for 15 minutes. The organic phase is extracted three times with saturated ammonium chloride solution and the aqueous phase with ethyl acetate, after which the combined organic phases are washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated in vacuo. The residue of 53 g is chromatographed on silica gel with hexane / dichloromethane and ethyl acetate to give 35 g of 7- (5-chloropentyl) -estr-4-ene-3,17-dione.

The same product was obtained from 8.05 g of 7a- (5-hydroxypentyl) -estr-4-ene-3,17-dione (Example 1b) by reaction with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile for 3.5 hours. room temperature. The reaction mixture was diluted with dichloromethane, shaken with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue is chromatographed on silica gel using dichloromethane and ethyl acetate to give 4.08 g of 7α- (5-chloropentyl) -estr-4-ene-3,17-dione.

[.alpha.] D @ ²² = +68 DEG (c = 0.5% in chloroform).

b) 7α- (5-chloropentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one

18.96 g of 7α- (5-chloropentyl) -estr-4-ene-3,17-dione are dissolved in 350 ml of anhydrous acetonitrile and mixed with a solution of 4.36 g of copper bromide at 80 ° C under an inert gas atmosphere. in 390 ml of anhydrous acetonitrile. The reaction mixture was stirred for an additional 5 minutes, cooled in an ice bath and treated with water and ethyl acetate. The organic phase is extracted with saturated sodium bicarbonate solution and the aqueous phase with ethyl acetate, then the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue 19.1 g is chromatographed on silica gel with hexane and ethyl acetate to give 10.0 g of 7a- (5-chloropentyl) 31174 / H.

3-hydroxy-estra-1,3,5 (10) -trien-17-one, which can be recrystallized from hexane / dichloromethane. Melting point 143.5 ° C.

[.alpha.] D @ ²² = +112 DEG (c = 0.5% in chloroform).

c) bis-3,17-trimethylsilyloxy-7α- (5-chloropentyl) -estra-1,3,5 (10), 16-tetraene

5.65 g of 7a- (5-chloropentyl) -estra-1,3,5 (10) trien-3-ol-17-one, 9 ml of triethylamine and 9 ml of trifluoromethanesulfonic acid trimethylsilyl ester and the reaction mixture are dissolved in 75 ml of benzene. is heated to reflux for 2 hours. After cooling, it is diluted with hexane, the upper phase is extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Bis-3,17-trimethylsilyloxy-7α- (5-chloropentyl) -estra-1,3,5 (10), 16-tetraene is obtained as an oil.

d) 7α- (5-chloropentyl) -16α-fluoro-estra-1,3,5 (10) -trien-3-ol-17-one

The product from the previous experiment was dissolved in 150 mL of anhydrous dichloromethane and treated with 14.2 g of N-fluorobenzosulfonimide. After stirring at room temperature for 2 hours, 50 ml of 8% sulfuric acid are added, stirred vigorously for a further 3 hours, and then the phases are separated. The aqueous phase is shaken twice with dichloromethane and the organic phase is successively shaken with saturated sodium bicarbonate solution and saturated sodium chloride solution. The combined organic phases are dried over anhydrous sodium sulphate and evaporated in vacuo. The crude product (15.3 g) is chromatographed on silica gel using dichloromethane / diisopropyl ether to give 2.92 g of 7α- (5-chloropentyl) -16α-fluoro-estra-1,3,5 (10) -triene-3. 17-one in the form of an oily liquid. This material can be crystallized from diisopropyl ether. Melting point: 176 ° C.

[α] D ²² = + 114 ° (c = 0.5% in chloroform).

31174 / H

e) 7α- (5-chloropentyl) -16α-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol

3.0 g of 7a- (5-chloropentyl) -16a-fluoro-estra-1,3,5 (10) -trien-3-ol-17-one are dissolved in 300 ml of anhydrous toluene under an inert gas atmosphere and mixed. with three portions of 20 ml each of a 1.5 molar solution of methyl lithium and lithium bromide in diethyl ether at room temperature for 15 minutes. After an additional 30 minutes, the reaction mixture was stirred under ice-cooling into a semi-concentrated ammonium chloride solution, acidified with 8% sulfuric acid, and extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulphate and concentrated in vacuo. 3.2 g of the crude product are chromatographed on silica gel using hexane and methyl tert-butyl ether. The polar fraction of 1.21 g is 7α- (5-chloropentyl) -16α-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol, which is recrystallized from diisopropyl ether / hexane . Melting point 70 ° C.

[.alpha.] D @ ²² = +7 DEG (c = 0.5% in chloroform).

f) 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

Dissolve 40.8 g of 7α- (5-chloropentyl) -16α-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol in 0.5 mL of dimethylformamide, add a solution of 58 mg 3 (N-methylamino) -propyl-4,4,5,5,5-pentafluoropentyl sulfide and 13 mg of lithium iodide are added and the reaction mixture is heated at 100 ° C for 17 hours under an inert gas atmosphere. After cooling, it is mixed with ethyl acetate, shaken successively with saturated sodium bicarbonate and sodium chloride solution, dried over sodium sulphate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel with ethyl acetate / methanol to give 25 mg of 16afluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5) -pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as an oil.

31174 / H

Example 16

16-fluoro-17-methyl-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] pentyl} estra-1,3,5 (10 ) -triene-3,17-diol

The non-polar product from the chromatography of Example 15e) gave 7α- (5-chloropentyl) -16α-fluoro-17β-methyl-estra-1,3,5 (10) -triene-3,17α-diol in an amount of 0.48 g. Crystallization from diisopropyl ether / hexane gave a crystalline solid, m.p. 65 ° C.

[α] D ²² = + ⁵⁰ (c = 0.5% in chloroform).

It was left as described in Example 15f) to give 23 mg of 16α-fluoro-17β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5) -pentafluórpentyltio) propylamino] pentyl} estra-1,3,5 (10) -triene-3,17 ~ -diol.

Example 17

16-fluoro-17-methyl-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfinyl) -propylamino] pentyl} estra-1,3,5 (10 ) -triene-3,17-diol

As described in Example 2, oxidation with sodium periodate yields 72 mg of 16α-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol 38 mg of 16α-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4, 4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} estra-1,3,5 (10) -triene-3,17-diol.

Example 18

16-fluoro-17-methyl-7 ~ {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfonyl) -propylamino] pentyl} estra-1,3,5 (10 ) -triene-3,17-diol

As described in Example 15f), 40.8 mg of 7α (5-chloropentyl) -16α-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol in dimethylformamide is reacted is 70 mg of 3- (N-methylamino) -propyl-4,4,5,5,5-pentafluoro

31174 / H pentylsulfone. After work-up, 21 mg of 16α-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra1,3 are obtained, 5 (10) -triene-3,17β-diol as an oily substance.

Example 19

16a-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylaminoJpentyl} estra-1,3,5 (10) -triene-3, 17p-diol

(a) 7α- (5-chloropentyl) -16α-fluoro-estra-1,3,5 (10) -triene-3,17β-diol and 7α- (5-chloropentyl) -16α-fluoro-estra-1,3, 5 (10) -triene-3,17-diol

Dissolve 392 mg of 7a- (5-chloropentyl) -16a-fluoro-estra-1,3,5 (10) -trien-3ol-17-one (Example 15d)) in 2 ml of anhydrous tetrahydrofuran and add under cooling in ice bath 1.1 ml of a 1 molar solution of lithium tert-butoxyaluminium hydride in tetrahydrofuran. The reaction mixture was allowed to stir for 30 minutes at 0 ° C, then treated with water and 8% sulfuric acid until slightly acidic, and extracted three times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness in vacuo. The crude product was chromatographed on silica gel using hexane / ethyl acetate to give 118 mg of 7α- (5-chloropentyl) 16α-fluoro-estra-1,3,5 (10) -triene-3,17β-diol and 138 mg of 7α- (5-chloropentyl) -16afluoro-estra-1,3,5 (10) -triene-3,17α-diol.

b) 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) - triene-3,17β-diol

Reaction of 100 mg of 7α- (5-chloropentyl) -16α-fluoro-estra-1,3,5 (10) -triene-3,17β-diol with 3- (N-methylamino) -propyl-4,4,5,5, Of 5-pentafluoropentylsulfide as described in Example 15f) yielded 83 mg of 16α-fluoro-7α- {5- [N-methyl-N-3]

31174 / H (4,4,5,5,5-Pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17βdiol as a foamy solid.

Example 20

16a-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylaminoJpentyl} estra-1,3,5 (10) -triene-3, 17-diol

Analogously, 75 mg of 16a-fluoro-7α- {5- [N-methyl- N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) triene-3,17a-diol as a foam.

Example 21

16a-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylaminoJpentyl} estra-1,3,5 (10) -triene-3, 17β-Iol

Oxidation 85 mg of 16α-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) - potassium periodate triene-3,17B-diol, as described in Example 17, yielded 47 mg of 16α-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5) -pentafluoropentylsulfinyl) -propylamino] pentyl} -estra-1,3,5 (10) -triene-3,17β-όίοΙυ in the form of a foam.

Example 22

16a-fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfonyl) -propylamino] pentyl} estra-1,3,5 (10) -triene 3,? - diol

As described in Example 15f), 65 mg of 7α- (5-chloropentyl) -16? -Fluoro-estra-1,3,5 (10) -triene-3,17B-diol is reacted with 90 mg of 3- (N-methylamino) - propyl-4,4,5,5,5-pentafluoropentylsulfone to give 53 mg of 16a

31174 / H fluoro-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] pentyl} -estra-1,3,5 (10) -triene-3 17β-diol as an oily substance.

Example 23

7a- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra1,3,5 (10), 14-tetraene-3,17p -d iol

a) 7α- (5-tert-Butyl-dimethylsilyloxypentyl) -estr-4-ene-3,17-dione

In 34 ml of absolute tetrahydrofuran, 8.9 g of magnesium turnings are reacted with 103 g of 1-bromo-5-tert-butyldimethylsilyloxypentane, dissolved in 110 ml of tetrahydrofuran, to Grignard reagent. To this solution at -70 to -65 ° C was added 2.5 g of copper (II) bromide complex and 60 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone and 70 ml of tetrahydrofuran and the resulting suspension was stirred for 30 minutes at -70 ° C under an argon atmosphere.

Then, a solution of 50 g of estra-4,6-diene-3,7-dione (Steroids Vol. 1, 1963, 233-249) in 370 ml of absolute tetrahydrofuran and 62 ml of chlorotrimethylsilane and the reaction mixture is added dropwise at -70 to -65 ° C. is stirred overnight at -70 ° C. For working-up, the mixture was mixed with 48 ml of glacial acetic acid at -15 ° C and, after stirring for 15 minutes at this temperature, poured into a mixture of saturated ammonium chloride solution and ethyl acetate. The organic phase is separated, washed successively with saturated ammonium chloride solution, saturated sodium bicarbonate solution and finally saturated sodium chloride solution until neutral, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel using dichloromethane / acetone to give 47 g of 7α- (5-tert-butyl-dimethylsilyloxypentyl) -estr-4-ene-3,17-dione as a yellow oil.

[.alpha.] _D @ ²² = + 62.2 DEG (c = 0.545% in chloroform).

31174 / H

b) 3-hydroxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one

Following the procedure of Example 1b, 62.7 g of 7a- (5-tert-butyldimethylsilyloxypentyl) -estr-4-ene-3,17-dione were reacted to 15.8 g of 3-hydroxy-7a- (5-hydroxypentyl) estra-1,3,5 (10) 15-tetraene-17-one.

c) 3-Benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one

A solution of 2.85 g of 3-hydroxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraen-17-one in 57 ml of acetone is mixed with 3.25 g of cesium carbonate and 1.14 g. ml of benzyl bromide and the mixture was refluxed for one hour. The reaction mixture is then concentrated, the residue is mixed with water, extracted with ethyl acetate, the organic phase is separated, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 3.12 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetraene-17. -one in the form of a foamy substance.

d) 17-acetoxy-7α- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10), 14,16-pentaene

A solution of 6.12 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 15-tetra-17-one in 717 ml of acetic anhydride is stirred with 920 mg of ptoluenesulfonic acid for one hour at room temperature. The reaction mixture is then worked up as described in Example 1j) and the crude product is chromatographed on silica gel with hexane / ethyl acetate to give 4.6 g of 17-acetoxy-7α- (5-acetoxypentyl) -3-benzyloxyestra- 1,3,5 (10), 14,16-pentaene as an oil.

e) 7α- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10), 14-tetraen-17β-ol

31174 / H

To a solution of 4.58 g of 17-acetoxy-7a- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10), 14,16-pentaene in 26.8 ml of tetrahydrofuran and 161 ml of ethyl alcohol at room temperature A solution of 1.25 g of sodium borohydride in 90 ml of ethanol and 18 ml of water is added dropwise and the mixture is stirred for one hour. The reaction mixture is then treated with 4 ml of glacial acetic acid, concentrated, and the residue is taken up in ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 2.16 g of 7α- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10), 14-tetraen-17β-ol. in the form of a foamy substance.

f) 3-Benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 14-tetraen-17β-ol

2.16 g of 7a- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10), 14-tetraene-17bol are saponified at room temperature overnight with 38 ml of 1N methanolic potassium hydroxide solution. The reaction mixture is then poured into an ice saturated sodium chloride solution, the precipitate formed is filtered off with suction, taken up in dichloromethane, washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. 1.86 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 14-tetraenol-ol are obtained in the form of a foam.

g) 3-Benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 14-tetraen-4-ol

Under the conditions of Example 1o), 3.03 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10), 14-tetraen-4-ol was reacted with 2.31 g of p- toluene sulfone in 58 ml of pyridine and chromatographed on silica gel. 3 g of 3-benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 14tetraen-4-ol are obtained in the form of a foam.

31174 / H

h) 3-Benzyloxy-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) , 14-tetraene-17-ol

A solution of 2 g of 3-benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 14-tetraen-17β-ol in 28 ml of ethyl methyl ketone is stirred with 1.77 g of N-methyl-3- (4). 4,5,5,5-pentafluoropentylthio) -propylamine in the presence of 950 mg of potassium carbonate and 230 mg of potassium iodide for 5 hours at a bath temperature of 80 ° C. The reaction mixture was then poured into brine, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 1.93 g of 3-benzyloxy-7α- {5- [N-methyl-N-3- (4,4,5,5,5) -pentafluoro-pentylthio) propylamino] -pentyl} -estra-1,3,5 (10), 14-tetraen-17β-ol as a bitumen. [.alpha.] D @ ²² = + 47.3 DEG (c = 0.505% in chloroform).

i) 7α- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra1,3,5 (10), 14-tetraene-3 17β-iol

To a solution of 850 mg of 3-benzyloxy-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) 14-Tetra-17β-ol in 10.2 ml of toluene is added dropwise at room temperature with 10.2 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene and the mixture is heated for 5 hours at a bath temperature of 120 ° C. The reaction mixture is then added dropwise to a mixture of saturated sodium chloride solution and 2N sulfuric acid under stirring under argon, extracted three times with ethyl acetate, the organic phase is washed twice with 2N sulfuric acid and three times with saturated sodium chloride solution, dried over sodium sulphate and dried. thicken. The residue is chromatographed on silica gel with hexane / ethyl acetate / 0-30% methanol to give 670 mg of 7α- {5- [N-methyl-N-3- (4,4,5,5,5) -pentafluoropentylthio) -propylamino] -pentyl} -estra1,3,5 (10), 14-tetraene-3,17β-diol as a foam.

31174 / H [α] _D ²² = +43 ° (c = 0.520% in chloroform).

Example 24

7 ~ {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfinyl) -propylamino] pentyl} estra-1,3,5 (10), 14-tetraene-3, 17 β-diol

Under the conditions described in Example 2, 400 mg of 7- {5 [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra- / 1,3 are reacted. 5 (10), 14-tetraene-3,17β-diol with 177 mg of sodium periodate and the crude product obtained is chromatographed on silica gel with ethyl acetate / methanol to give 287 mg of the title compound as a foam. .

[.alpha.] _D @ ²² = +30.7 DEG (c = 0.530% in chloroform / methanol).

Example 25

7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} estra-1,3,5 (10), 14-tetraene-3, 17β-d iol

a) 3-Benzyloxy-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) , 14-tetraene-17-ol

Under the conditions described in Example 23h), 1 g of 3-benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10), 14-tetraen-17β-ol is reacted with 990 mg of N-methyl-3- (4, 10-tetraen-17β-ol). 4,5,5,5-Pentafluoropentanesulfonyl) -propylamine and the crude product obtained is chromatographed on silica gel with ethyl acetate / methanol to give 960 mg of 3-benzyloxy-7α- {5- [N-methyl-N- 3- (4,4,5,5,5-Pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10), 14tetraen-17β-ol as an oil.

[α] D ²² = +48.5 ⁰ (c = 0.535% in chloroform).

31174 / H

b) 7α- {5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] pentyl} -estra-1,3,5 (10), 14-tetraene- 3,17-diol

A solution of 100 mg of 3-benzyloxy-7α- [5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10), 14-Tetra-17-pol in 1 ml of dichloromethane was mixed with 0.2 ml of dimethylaniline and 73 mg of aluminum chloride while cooling in an ice bath and stirred at this temperature for one hour. The reaction mixture was then poured into 1 N hydrochloric acid, shaken with ethyl acetate, washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The crude product obtained is chromatographed on silica gel using dichloromethane / 0-10% methanol to give 74 mg of the title compound as a foam.

[.alpha.] D @ ²² = + 36 DEG (c = 0.525% in chloroform / methanol).

Example 26

7 ~ {5 - [(2S) -2- (4,4,5,5,5- pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17 diol

(a) 7α- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10) -trien-17-one

A solution of 6.5 g of 7a- (5-acetoxypentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one (Example 1d)) in 65 ml of dimethylformamide is mixed with 3.3 ml of benzyl chloride. , 8.7 g of cesium carbonate and 400 mg of sodium iodide and stirred overnight at room temperature. The reaction mixture is then poured into water, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl ester

31174 / H acetic acid to give 7.26 g of 7a- (5-acetoxypentyl) -3-benzyloxyestra-1,3,5 (10) -trien-17-one as an oil.

b) 3-Benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17-one

A solution of 7.26 g of 7a- (5-acetoxypentyl) -3-benzyloxy-estra-1,3,5 (10) -trien-17-one in 80 ml of methanol and 3 ml of tetrahydrofuran is saponified with 22.2 ml of 2 N hydroxide sodium chloride overnight at room temperature. The reaction solution is then poured into 2 N hydrochloric acid, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. 6.7 g are obtained

3-Benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -trien-17-one as a foam.

c) 3-Benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one

Under the conditions of Example 1o), 6.5 g of 3-benzyloxy-7α- (5-hydroxypentyl) -estra-1,3,5 (10) -triene was reacted with 7.14 g of ptoluenesulfonic anhydride and the product obtained was chromatographed on silica gel. using hexane / ethyl acetate to give 7.45 g of 3-benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one as a foam. [a] D ²² = +80.6 ⁰ (c = 0.620% in chloroform).

d) 3-Benzyloxy-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) ) -trien-17-one

Under the conditions of Example 23h), 4.58 g of 3-benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one is reacted with 3.17 g of (2S) -2 ( 4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine and the crude product obtained is chromatographed on silica gel with hexane / ethyl acetate, yielding 3.9 g of 3-benzyloxy-7 [beta] - [5 - [(2S)]. ) -2- (4,4,5,5,5-Pentafluoro31174 / H pentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one as an oily liquid.

[α] D ²² = + 32.5 ⁰ (c = 0.117% in chloroform).

e) 3'-Hydroxy-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -t-n-17-one

Under the conditions of Example 6f), 2.05 g of 3-benzyloxy-7α {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} was debenzylated. estra-1,3,5 (10) -trien-17-one. 1.25 g of 3-hydroxy-7α- {5 - [(2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1 is obtained, 3,5 (10) -trien-17-one in the form of an oily liquid.

[a] D ²² = + 22.7 ⁰ (c = 0.475% in chloroform).

f) 7α- (5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene- 3,17-diol

Under the conditions of Example 8), 500 mg of 3-hydroxy-7α- {5 - [(2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra- 1,3,5 (10) -trien-17-one reduces 100 mg of sodium borohydride to give 325 mg of the title compound as an oily liquid.

[a] ²² D = -8.7 ⁰ (c = 0.510% in methanol).

Example 27

7 ~ {5 - [(2 R) -2- (4,4,5,5,5- pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,1 β-d iol

In an analogous manner to that described in Example 26d-f), 2.3 g were obtained

3-Benzyloxy-7α- (5-tosyloxypentyl) -estra-1,3,5 (10) -trien-17-one (26c) and 1.6 g

31174 / H (2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine 612 mg of the title compound as an oil.

Example 28

17α-Methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentyl-thiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17p-diol /

a) 7α- (5-chloropentyl) -17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol

A suspension of 5.21 g of anhydrous cerium chloride in 53.2 ml of tetrahydrofuran was stirred for 2 hours at room temperature, 7 ml of methylmagnesium bromide (3M in diethyl ether) was added dropwise at 0 ° C and the reaction mixture was stirred for 30 minutes at 0 ° C. ° C and for 15 minutes at room temperature. A solution of 1 g of 7α- (5-chloropentyl) -3-hydroxy-estra-1,3,5 (10) -trien-17-one (Example 15b)) in 24 ml of tetrahydrofuran is then added and stirred for a further 30 minutes at room temperature. . The reaction mixture is then poured into an ice-saturated solution of ammonium chloride, shaken with ethyl acetate, the organic phase is separated, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 753 mg of 7? (5-chloropentyl) -17? -Methyl-estra-1,3,5 (10) -triene-3,17? -Diol in the form of a foamy substance.

[a] D ²² = + 27.3 ⁰ (c = 0.515% in chloroform).

b) 7α- (5-iodopentyl) -17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol

A solution of 735 mg of 7α- (5-chloropentyl) -17α-methyl-estra-1,3,5 (10) -trien-3,17biol in 4 ml of ethyl methyl ketone is mixed with 5.6 g of sodium iodide and heated The mixture was heated at 80 ° C for 17 hours. The reaction mixture is then poured into water, shaken with ethyl acetate, the organic phase is washed

31174 / H saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. 834 mg of 7α- (5-iodopentyl) -17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol is obtained as a foam.

[a] _D ²² = + 20.2 ⁰ (c = 0.500% in chloroform).

c) 17α-Methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) 1-triene-3,17β-diol

A solution of 453 mg of 7α- (5-iodopentyl) -17α-methyl-estra-1,3,5 (10) -triene-3,17biol and 390 mg of (2S) -2- (4,4,5,5,5,5) -pentafluoropentylthiomethyl) -pyrrolidine in 8 ml of N-methyl-2-pyrrolidinone is heated for 4 hours at a bath temperature of 80 ° C. The cooled reaction mixture is poured into saturated sodium bicarbonate solution, shaken with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 413 mg of the title compound as a foam.

[α] _D ²² = -25.8 ⁰ (c = 0.500% in chloroform).

Example 29

1β-Fluoro-7α- {5- (2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene-3, 17β-d iol

a) 7α- (5-Chloropentyl) -1β-fluoro-estr-4-ene-3,17-dione

A solution of 78.7 g of 1β-fluoro-7α - (- hydroxypentyl) -estr-4-ene-3,17-dione (Example 2a)) in 1.4 L of carbon tetrachloride and 475 ml of acetonitrile is stirred with 71 g of thiophenylphosphine for 8 hours. After 5 hours at room temperature, it is extracted with water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over sodium sulphate and dried in vacuo.

31174 / H thickened. The residue is chromatographed on silica gel with hexane / ethyl acetate, to give 48.0 g of 7α- (5-chloropentyl) -1-fluoro-estr-4-ene-3,17-dione as a crystalline solid, m.p. Mp 51-53 ° C.

[a] D ²² = +78.5 ⁰ (c = 0.5% in chloroform).

b) 7α- (5-chloropentyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one

To a solution of 47 g of 7a- (5-chloropentyl) -113-fluoro-estr-4-ene-3,17-dione in 470 ml of acetonitrile is added dropwise a solution of 10.34 g of lithium bromide and 53.2 g at a bath temperature of 80 ° C. g of copper (I) bromide in 280 ml of acetonitrile. After the addition of 20 ml, the solution is expected to decolorize and the remainder of the solution is added over 12 minutes and then stirred for a further 5 minutes at a bath temperature of 80 ° C. The reaction mixture was cooled to 0 ° C, treated with sodium bicarbonate solution, poured into water, extracted four times with ethyl acetate, washed neutral, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 25.3 g of 7α- (5-chloropentyl) -11 p-fluoro-3-hydroxy-estra-1,3,5 (10) - triene-17-one.

[a] D ²² = +115.4 ⁰ (c = 0.5% in chloroform).

c) 1β-Fluoro-3-hydroxy-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one

A solution of 785.9 mg of 7α- (5-chloropentyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) trien-17-one in 7 mL of N-methyl-2-pyrrolidinone was mixed with 535 mg of lithium iodide and 520 mg of (2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine and the reaction mixture was stirred for 2.5 hours at a bath temperature of 100 ° C. It is then poured into water, extracted three times with diethyl ether, the extract is washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel using the system

31174 / H dichloromethane / methanol to give 525 mg of pure 11β-fluoro-3-hydroxy-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-17-one.

[.alpha.] _D @ ²² = + 29.3 DEG (c = 0.5% in chloroform).

d) 11β-Fluoro-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene- ~ 3,17 diol

Dissolve 500 mg of 1β-fluoro-3-hydroxy-7α- {5- [2- (4,4,5,5,5-pentafluoropentyl-thiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -trien-17-one in 5 ml of tetrahydrofuran, 2.75 ml of ethyl alcohol and 1.1 ml of water, 100 mg of sodium borohydride are added at a bath temperature of 0 ° C and the reaction mixture is stirred for 30 minutes at room temperature. It is poured into water, extracted three times with ethyl acetate, washed neutral with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel using dichloromethane / methanol to give 441.3 mg of 1β-fluoro-7α- {5- [2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine-1- yl] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 174-176 ° C.

[and _D ²² = -14.9 ⁰ (c = 0.5% in pyridine).

Example 30

11.beta.-nitrooxy-7 ~ (9- [4,4,5,5,5- pentafluoropentanesulfonyl] nonyl) estra-1,3,5 (10) -triene-3,17-diol

a) 3,17β-diacetyloxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra1,3,5 (10) -triene

31174 / H

6.28 g of 7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) estra-1,3,5 (10) -triene-3,17β-diol are dissolved in 30 ml of pyridine, Stir with 15 ml of acetic anhydride while cooling with water and allow to stir at room temperature for 5 hours.

For working up, the reaction solution was poured into ice water, the diacetate was extracted with ethyl acetate, the organic phase was washed with dilute sulfuric acid, water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. An oily substance is obtained as a crude product which is taken up in 100 ml of acetic acid and mixed with 15 g of sodium perborate tetrahydrate. After. Stirring at room temperature for 5 hours completes the reaction.

The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase is de-acidified with aqueous sodium bicarbonate solution and, after drying over anhydrous sodium sulfate, filtered, concentrated and chromatographed on silica gel with hexane / ethyl acetate (7: 3). 6.83 g of product are obtained in the form of a foam.

b) 3,173-diacetyloxy-113-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] nonyl) -estra-1,3,5 (10) -trien-9-ol

To a solution of 3.0 g of 3,17β-diacetyloxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) -triene in 50 mL of aqueous Acetic acid (90%) was added with 18.6 g of cerium-ammonium nitrate and the reaction mixture was stirred for 4 hours at room temperature.

For working-up, the reaction mixture is poured into ice water, extracted with ethyl acetate and the organic phase is washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous sodium sulfate.

31174 / H

The crude product is chromatographed on silica gel using hexane / ethyl acetate (7: 3). 2.0 g of product are obtained in the form of a yellow-colored foam.

c) 3,17β-diacetyloxy-11β-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl) nonyl) -estra-1,3,5 (10) -triene

Due to the reductive removal of the 9α-hydroxy group in 3,17β-diacetyloxy-11β-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) triene- 9-ol was dissolved in starting material (25 g) in dichloromethane (25 ml), cooled to -15 ° C and treated successively with triethylsilane (15 ml) and boron trifluoride etherate (2.2 ml). After stirring at -15 ° C for 1 hour, the cooling bath was removed and allowed to reach room temperature.

For working up, the reaction mixture was poured into ice water, extracted with dichloromethane, the organic phase was washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous sodium sulfate.

The crude product was chromatographed on silica gel using hexane / ethyl acetate 9: 1. 1.3 g of product are obtained in the form of a foam.

d) 11β-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra1,3,5 (10) -triene-3,17β-diol

For the saponification, 1.0 g of 3,17β-diacetyloxy-1β-nitrooxy-7α (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra-1,3,5 (10) is dissolved. -triene in 50 ml of methanol, mixed with 20 ml of 3% methanolic potassium hydroxide and allowed to stand for 4 hours at room temperature.

The reaction mixture was stirred into ice water acidified with citric acid and then extracted with ethyl acetate. After washing

The organic phase 31174 / H with water and saturated sodium chloride solution was dried over anhydrous sodium sulfate.

The crude product is chromatographed on silica gel using hexane / ethyl acetate (gradient up to 3: 2). 0.53 g of product is obtained in the form of an oily substance.

Example 31 β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -triene-3,17-diol

a) 7α- (5-chloropentyl) -11β-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol

Under the conditions of Example 28a), 750 mg of 7α- (5-chloropentyl) -11β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-3,17-one (Example 29b)) is reacted with 4.9 ml of methylmagnesium bromide solution (3M in diethyl ether) was worked up and chromatographed. 561 mg of 7α- (5-chloropentyl) -11β-fluoro-17α-methylestra-1,3,5 (10) -triene-3,17β-diol is obtained as a foam.

[a] D ²² = + 51.6 ⁰ (c = 0.515% in chloroform).

b) 1β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] -pentyl} -estra-1,3 , 5 (10) -triene-3,17-diol

Under the conditions of Example 15f), 408 mg of 7α- (5-chloropentyl) -11β-fluoro-17α-methyl-estra-1,3,5 (10) -triene-3,17β-diol are reacted in 5 mL of N-methyl- Of 2-pyrrolidinone in the presence of 130 mg of lithium iodide with 606 mg of (2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine, worked up and chromatographed. 326 mg of the title compound of melting point 120 DEG-121 DEG C. is obtained as a crystalline substance.

[α] D ²² = -5.8 ° (c = 0.535% in chloroform).

31174 / H

Example 32 1β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) pyrrolidin-1-yl] -pentyl) -estra-1,3 , 5 (10) -triene-3,17-diol

Under the conditions of Example 13, 260 mg of 11 p-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} - was reacted. estra-1,3,5 (10) -triene-3,17β-diol (Example 31b)) with 151 mg sodium periodate, worked up and chromatographed. 129 mg of the title compound are obtained as an oil.

Example 33

3,17β-diacetoxy-1β-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -penty I } -estra-1,3,5 (10) -triene

Under the conditions of Example 3, 65 mg of 1β-fluoro-1'-methyl-1S-f (S) (4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl) -estrayl is acetylated Of 3,5 (10) -triene-3,17β-diol (Example 31b) with acetic anhydride and the crude product is oxidized as described in Example 4 with sodium perborate tetrahydrate, worked up and chromatographed. 27 mg of the title compound are obtained as an oil.

Example 34

7 ~ {5 - [(2S) -2- (4,4,5,5,5- pentafluórpentánsulfinylmetyl) -pyrrolidin-1-yl] pentyl} estra-1,3,5 (10) -triene-3, 17p-diol

Oxidation with sodium periodate affords, as described in Example 2, from 152 mg of 7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] - pentyl} -estra-1,3,5 (10) -triene-3,17β-diol (Example 26 f)) 66 mg of the title compound as an oil.

31174 / H [α] _D ²² = +11.8 ° (c = 0.53% in methanol).

Example 35

7 ~ {5 - [(2S) -2- (4,4,5,5,5- pentafluórpentánsulfonylmetyl) -pyrrolidin-1-yl] pentyl} estra-1,3,5 (10) -triene-3, 17β-d iol

Under the conditions of Example 3, 76 mg of 7α- {5 - [(2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3 is acetylated, 5 (10) -triene-3,17β-diol (Example 26f)) with acetic anhydride and the crude product is oxidized as described in Example 4 with sodium perborate tetrahydrate, worked up and chromatographed. 31 mg of the title compound are obtained as an oil.

[.alpha.] D @ ²² = + 30.6 DEG (c = 0.515% in methanol).

Example 36 p-Fluoro-17α-methyl-7α- [5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol

a) 1β-Fluoro-3-hydroxy-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra 1,3,5 (10) -trien-17-one

A solution of 2.0 g of 1β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) 1 -estra1,3,5 (10) -trien-17-one in 20 ml of methanol and 2 ml of water is stirred at room temperature with 1.2 g of oxalic acid. After 2.5 hours, the mixture is poured into ice-water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with dichloromethane / methanol to give 1.2 g of 1β-fluoro-3.

31174 / H hydroxy-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -Trien-17-one in the form of a foamy substance. [.alpha.] D @ ²² = +69 DEG C. (c = 0.5% in chloroform).

b) 11β-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3 , 5 (10) -ίπέη-3,17β ^ ίοΙ

To 5 g of 1'-fluoro-3-hydroxy-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra -1,3,5 (10) -trien-17-one in 150 ml of tetrahydrofuran was added dropwise at room temperature with 33 ml of a 1.6 molar ethereal solution of lithium ethylate. After 2.5 hours, saturated ammonium chloride solution is added under ice-cooling, the mixture is extracted with ethyl acetate, the extract is washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel containing 2% triethylamine using dichloromethane / methanol to give 2.0 g of 1'-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4 (4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra1,3,5 (10) -triene-3,17β <1 ΙοΙυ as a crystalline solid, m.p. 83 ° C.

Example 37 4-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-beta-diol

A solution of 500 mg of 1'-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3, 5 (10) -triene-3,3'-diol in 20 ml of methanol and 0.9 ml of water was stirred at room temperature with 355 mg of sodium periodate for 3 hours. The reaction mixture was poured into ice water, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using the system

31174 / H dichloromethane / methanol to give 216 mg of 1β-fluoro-17α-methyl-7α- {5 [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] - pentyl} -estra1,3,5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 83.4 ° C.

Example 38

11p-fluoro-17a-methyl-7a- {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfonyl) -propylamino] pentyl} estra-1,3,5 (10 1-triene-3,17β-diol

a) 11β-Fluoro-3-hydroxy-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra 1,3,5 (10) -trien-17-one

A solution of 3 g of 7α- (5-chloropentyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in 50 ml of dimethylformamide is stirred for 22 hours at 100 ° C.

1.6 g of lithium iodide and 6.2 g of methyl [3- (4,4,5,5,5-pentafluoropentanesulfonyl) propyl] -amine. The reaction mixture was then extracted with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with dichloromethane / methanol to give 4.5 g of 1β-fluoro-3-hydroxy-17-methyl-7α- {5- [N-methyl-N-3- (4,4, 5,5,5-pentafluoropentanesulfonyl) -propylamino] pentyl} -estra-1,3,5 (10) -trien-17-one as a foam.

b) 1β-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene-3,17-diol

A suspension of 11.4 g of anhydrous cerium chloride in 120 ml of tetrahydrofuran is stirred for 2 hours at room temperature under a nitrogen atmosphere, mixed at 0 ° C dropwise with 17.5 ml of a 3M ethereal methylmagnesium bromide solution, stirred for 30 hours. minutes, a solution of 3.5 g of 11-fluoro-3-hydroxy-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] is added. -pentyl} -estra-1,3,5 (10) -trien-17-one in 24 ml

31174 / H tetrahydrofuran and stirred for an additional 30 minutes. Saturated ammonium chloride solution was added, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / methanol to give 2.2 g of 1β-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5) 5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 82.5 ° C.

Example 39

1IP-fluoro-7a- {5- [N-methyl-N-2- (4,4,5,5,5- pentafluoropentanesulfonyl) ethylamino] pentyl} estra-1,3,5 (10) -triene 3,17b-iol

a) 7α- (5-Bromopentyl) -11β-fluoro-estr-4-ene-3,17-dione

A solution of 33 g of 1β-fluoro-7a- (5-hydroxypentyl) -estr-4-ene-3,17-dione in 330 ml of dichloromethane at -5 ° C is mixed with 28.9 g of triphenylphosphine and 36.7 g. The reaction mixture was stirred for 30 minutes. It is then mixed with dichloromethane and washed with water, saturated sodium bicarbonate solution and brine. The organic phase is separated, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane / ethyl acetate gradient to give 28.5 g of 7α- (5-bromopentyl) -11β-fluoroestr-4-ene-3,17-dione, m.p. 75-76 ° C. .

b) 7α- (5-bromopentyl) -11β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one

To 27.8 g of 7cc- (5-bromopentyl) -11β-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile is added at 80 ° C 17.0 g of copper bromide. After 8 hours, the reaction mixture is stirred into water, extracted three times with ethyl acetate, the combined organic phases are washed twice with chloride.

31174 / H with ammonium, sodium bicarbonate and sodium chloride, dried and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 20.4 g of 7? - (5-bromopentyl) -1? -Fluoro-3-hydroxy-estra-1,3,5 (10) -triene- 17-one as a colorless crystalline solid, m.p. 178 ° C.

c) 7α- (5-bromopentyl) -11β-fluoro-estra-1,3,5 (10) -triene-3,17β-diol

A solution of 16.2 g of 7α- (5-bromopentyl) -11β-fluoro-3-hydroxy-estra-1,3,5 (10) trien-17-one in 162 mL of tetrahydrofuran, 90 mL of ethyl alcohol and 36 mL of water at At 0 ° C, 4.7 g of sodium borohydride are added in portions, and the reaction mixture is stirred at 0 ° C for 2 hours. It is then added to water, extracted four times with ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated in vacuo. 17.1 g of crude product are obtained. Chromatography on silica gel with hexane / ethyl acetate yields 15.6 g of pure 7α- (5-bromopentyl) -11β-fluoro-estra-1,3,5 (10) -triene-3,17β-diol. .

d) 1β-Fluoro-7α- [5- (methylamino) -pentyl] -estra-1,3,5 (10) -triene-3,17β-diol

A solution of 2 g of 7α- (5-bromopentyl) -1β-fluoro-estra-1,3,5 (10) -triene-3,17β-diol in 20 mL of dimethylformamide is stirred with 8 mL of a 40% aqueous methylamine solution of 3.5 hours at 80 ° C. The reaction mixture was then added to water, extracted three times with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 1.77 g of 1β-fluoro-7α- [5- (methylamino) -pentyl] -estra1,3,5 (10) -triene-3,17β-diol is obtained.

e) 11-p-fluoro-7α- {5- [N-methyl-N-2- (4,4,5,5,5-pentafluoropentanesulfonyl) ethylamino] pentyl} -estra-1,3,5 (10) -triene-3,17-diol

31174 / H

A solution of 440 mg of 11β-fluoro-7α- [5- (methylamino) -pentyl} -estra-1,3,5 (10) triene-3,17β-diol in 15 mL of methanol is mixed with 500 mg of 4,4,5 Of 5,5-pentafluoropentyl vinyl sulfone at 90 ° C for one hour. The reaction mixture was poured into water, extracted three times with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / methanol to give 448 mg of 11 p-fluoro-7α- {5- [N-methyl-N-2- (4,4,5,5,5-pentafluoropentanesulfonyl)]. ethylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol as a crystalline solid, m.p. 74-76 ° C.

Intermediate 12k) is strongly antiestrogenic.

Example 40 p-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3-hydroxy-estra-1,3,5 (10 ) -trien-17-one

A solution of 1.6 g of 11β-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -3- (tetrahydropyran-2-yloxy) -estra1,3,5 (10) -trien-17-one in 20 ml of methanol and 2 ml of water are mixed with 1.0 g of oxalic acid. After 3 hours, the reaction mixture is poured into ice-water, extracted with methylene chloride, washed with saturated sodium chloride solution and concentrated in vacuo. The residue is chromatographed on silica gel using a gradient of methylene chloride-methanol to give 1.1 g of 1β-fluoro-7cc- {5- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentylthio) -propylaminojpentyl} -3-hydroxy-estra-1,3,5 (10) -trien-17-one.

[.alpha.] D @ ²² = +69 DEG C. (c = 0.5% in chloroform).

Example 41

31174 / H

11p-fluoro-7a- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylaminoJhexyl} estra-1,3,5 (10) -triene-3, 17β-iol

a) 7α- (6-Chlorohexyl) -1'-fluoro-estr-4-ene-3,17-dione

To a suspension of 6.8 g of magnesium turnings in 100 ml of tetrahydrofuran, 30 ml of a solution of 41 ml of 1-bromo-6-chloro-hexane in 270 ml of tetrahydrofuran was first added under nitrogen. After the reaction has subsided, the remaining solution is added dropwise such that the internal temperature does not exceed 35 ° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper (I) iodide in 120 ml of tetrahydrofuran at 0 ° C, raising the internal temperature to 40 ° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one is now added and the reaction mixture is stirred for 30 minutes at 40 ° C. A clear solution is obtained which is added dropwise to the Grignard solution, cooled to -40 ° C. It is then stirred for 30 minutes at -30 ° C and treated dropwise with a solution of 25.3 g of 1'-fluoro-estra-4,6-diene-3,17-dione in 230 ml at -50 ° C. tetrahydrofuran, 24.6 mL of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one and 55 mL of trimethylchlorosilane such that the internal temperature does not exceed -40 ° C. The reaction mixture was stirred under cooling for one hour, then 32 ml of glacial acetic acid was added dropwise, the cooling bath was removed and stirred for another hour at room temperature. For working-up, the reaction mixture is taken up in 1.5 l of water, diluted with an equal amount of ethyl acetate, the precipitate is separated over celite, washed with ethyl acetate, the aqueous phase is extracted three times with ethyl acetate, the combined organic phases are washed with sodium bicarbonate solution. and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 25.2 g of 7α- (6-chlorohexyl) -1'-fluoro-estr-4-ene-3,7-dione.

b) 7α- (6-chlorohexyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one

31174 / H

To 25.2 g of 7? - (6-chlorohexyl) -1? -Fluoro-estr-4-ene-3,17-dione in 175 ml of anhydrous acetonitrile at 80 ° C is added 28.1 g of copper bromide and? 4 g of lithium bromide in 105 ml of anhydrous acetonitrile. After 15 minutes, the reaction mixture was cooled to 0 ° C and 250 mL of saturated sodium bicarbonate solution was added dropwise. The reaction solution was stirred into 1 liter of water, acidified to pH 6 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with hexane / ethyl acetate gradient to give 5.7 g of 7α- (6-chlorohexyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in the form of a foamy substance.

c) 1β-Fluoro-3-hydroxy-7α- (6-iodo-hexyl) -estra-1,3,5 (10) -trien-17-one

2.7 g of 7a- (6-chlorohexyl) -11? -Fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one are dissolved in 40 ml of ethyl methyl ketone, mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90 ° C. For working-up, the reaction mixture was cooled to room temperature, stirred in water, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. 3.4 g of 1β-fluoro-3-hydroxy-7a- (6-iodohexyl) -estra-1,3,5 (10) -trien-17-one is obtained as a crude product which is used as is in the following stage. .

d) 11β-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -hexyl} -estra-1,3, 5 (10) -trien-17-one

2.5 g of 1β-fluoro-3-hydroxy-7α- (6-iodo-hexyl) -estra-1,3,5 (10) -trien-17-one in 20 ml of anhydrous dimethylformamide are stirred at a bath temperature of 100 ° C with 2.0 g of methyl [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine. After two hours the reaction mixture is poured into a semi-saturated sodium bicarbonate solution,

31174 / H was extracted three times with methylene chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using a methylene chloride-methanol gradient to give 3.15 g of 11β-fluoro-3-hydroxy-7α- {6- | N-methyl-N-3- (4,4,5,5,5) , 5-pentafluoropentylthio) propylamino] hexyl} estra-1,3,5 (10) -trien-17-one.

e) 113-Fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] hexyl} -estra-1,3,5 (10) - triene-3,17-diol

250 mg of 1β-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1,3,5 (10) -Trien-17-one is dissolved in 4.5 ml of methanol and treated portionwise with 60 mg of sodium borohydride at 0 ° C. After stirring at room temperature for 3 hours, the solvent is stripped off in vacuo, the residue is mixed with saturated sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a methylene chloride / methanol gradient to give 165 mg of 1β-fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl } -estra-1,3,5 (10) -triene-3,17-diol as a foamy substance.

[a] D ²² = + 37 ⁰ (c = 1.01% in chloroform).

Example 42 p-Fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] hexyl} -estra-1,3,5 (10) -triene- 3,17-diol

(a) 11-p-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -hexyl} -estra-1,3, 5 (10) -trien-17-one

31174 / H

500 mg 11-p-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -hexyl} -estra-1,3 5 (10) -trien-17-one is dissolved in 17 ml of methanol and 3.3 ml of water, mixed with 262 mg of sodium periodate and stirred for 2 hours at room temperature. For working-up, the reaction mixture is mixed with half-saturated sodium chloride solution, extracted three times with methylene chloride, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a methylene chloride-methanol gradient to give 165 mg of 11-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5- pentafluoropentanesulfinyl) propylamino] -hexyl} -estra-1,3,5 (10) -trien-17-one as a foam.

[α] ²² = + 45 ^° (c = 1.015% in chloroform).

b) 11β-fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -hexyl} -estra-1,3,5 (10) ) -triene-3,17-diol

149 mg of 1β-fluoro-3-hydroxy-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -hexyl} -estra-1,3, 5 (10) -Trien-17-one was dissolved in 3 ml of methanol and treated portionwise with 35 mg of sodium borohydride. After stirring for 30 minutes at room temperature, the solvent is removed in vacuo, the residue is mixed with water, extracted three times with methylene chloride, dried over sodium sulphate and concentrated in vacuo. Preparative thin layer chromatography using methylene chloride / methanol (9: 1) gave 109 mg of 11B-fluoro-7α- {6- [N-methyl-N-

3- (4,4,5,5,5-Pentafluoropentanesulfinyl) -propylamino] -hexyl} -estra-1,3,5 (10) -triene-3,17-diol as a foam.

[.alpha.] D @ ²² = +24 DEG (c = 0.51% in chloroform).

Example 43

31174 / 1H-fluoro-7a- (5 - {[N-3- (furan-2-ylmethylthio) -propyl] -N-methyl-amino} -pentyl) -estra1,3,5 (10) -triene- 3,17-diol

a) 7α- (5-chloropentyl) -11β-fluoro-estr-4-ene-3,17-dione

To a suspension of 7.2 g of magnesium turnings in 100 ml of tetrahydrofuran, a 20% solution of 39 ml of 1-bromo-5-chloropentane in 300 ml of tetrahydrofuran was first added under a nitrogen atmosphere. After starting the reaction, which can be achieved by the addition of iodine and dibromomethane, the remaining solution is added dropwise so that the internal temperature of 35 ° C does not rise. In a second flask, 51.2 g of lithium bromide was added to a suspension of 28.1 g of copper (I) iodide in 130 ml of tetrahydrofuran at 0 ° C, increasing the temperature to 40 ° C. Without cooling, 49.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one is now added and stirred for 15 minutes at 40 ° C. A clear solution is obtained which is added dropwise to a Grignard reagent cooled to -50 ° C. The reaction mixture is stirred for 15 minutes at -30 ° C and treated dropwise with a solution of 25 g of 1'-fluoro-estra-4,6-diene-3,17-dione in 260 ml of tetrahydrofuran at -70 ° C. 26 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- (1H) -pyrimidin-2-one and 59 ml of trimethylchlorosilane such that the internal temperature does not exceed -65 ° C. Then, it is stirred in the cold for 30 minutes, 34.7 ml of glacial acetic acid is added dropwise, the cooling bath is removed and the mixture is stirred for one hour at room temperature. For working-up, the reaction mixture is taken up in 1.5 l of water, diluted with an equal amount of ethyl acetate, the precipitate is separated over celite, washed with ethyl acetate, the aqueous phase is extracted three times with ethyl acetate, the combined organic phases are washed with sodium bicarbonate solution. and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 22.1 g of 7a- (5-chloropentyl) -1'-fluoro-estr-4-ene-3,17-dione.

b) 7α- (5-chloropentyl) -11β-β-β-β-β-γ-γ-1,3,5 (10) -trien-17-one

31174 / H

To 22.1 g of 7α- (5-chloropentyl) -1β-fluoro-estr-4-ene-3,17-dione in 160 mL of anhydrous acetonitrile at 80 ° C was added 25.4 g of copper bromide in 95 mL of anhydrous acetonitrile. After 20 minutes, the reaction mixture was cooled to 0 ° C and 200 mL of saturated sodium bicarbonate solution was added dropwise. The reaction solution is stirred into 750 ml of water, acidified to pH 6 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 14.7 g of 7α- (5-chloropentyl) -11β-fluoro-3-hydroxy-estra-1,3,5 (10) -triene-17. -one.

c) 1β-Fluoro-3-hydroxy-7α- (5-iodopentyl) -estra-1,3,5 (10) -trien-17-one

Dissolve 5.0 g of 7α- (5-chloropentyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in 40 ml of ethyl methyl ketone, mix with 5,7 g of sodium iodide and stirred overnight at a bath temperature of 90 ° C. For working-up, the reaction mixture was cooled to room temperature, stirred in water, extracted three times with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. 6.8 g of 11β-fluoro-3-hydroxy-7α- (5-iodopentyl) -estra-1,3,5 (10) -trien-17-one is obtained as a crude product which is used as is in the following stage. .

d) 1β-Fluoro-3-hydroxy-7α- [5- (methylamino) -pentyl] -estra-1,3,5 (10) -trien-17-one

In a solution of 6.8 g of 1β-fluoro-3-hydroxy-7a- (5-iodopentyl) -estra-1,3,5 (10) trien-17-one in 35 ml of anhydrous tetrahydrofuran at -78 ° C is condensed 5.1 g of methylamine and the mixture was stirred overnight at room temperature in a pressure reactor. The pressure reactor was then opened at -20 ° C and allowed to warm to room temperature while excess methylamine was evaporated. The reaction mixture is then added to a saturated solution of bicarbonate

31174 / H sodium, extracted three times with ethyl acetate, dried over anhydrous magnesium sulphate and concentrated in vacuo. It is obtained as follows

6.7 g of 11-p-fluoro-3-hydroxy-7α- [5- (methylamino) -pentyl] -estra-1,3,5 (10) -trien-17-one as a crude product.

e) 11-p-fluoro-7α- (5 - ([N-3- (furan-2-ylmethylthio) -propyl] -N-methyl-amino} -pentyl) -3-hydroxy-estra-1,3,5 (10 ) -trien-17-one

526 mg of 1β-fluoro-3-hydroxy-7α- [5- (methylamino) -pentyl) -estra-1,3,5 (10) trien-17-one and 95 mg of 2- (chloro-propylthiomethyl) furan Dissolve in 5 ml of ethyl methyl ketone, mix with 112 mg of sodium iodide and 104 mg of potassium carbonate and stir for 3 hours at a bath temperature of 90 ° C. For working-up, the reaction mixture is poured into semi-saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel using a gradient of methylene chloride / methyl alcohol to give 229 mg of 1β-fluoro-7α- (5 - {[N-3- (furan-2-ylmethylthio) propyl] -N-methylamino} pentyl 13-Hydroxy-estra-1,3,5 (10) -trien-17-one as a foam.

f) 11β-Fluoro-7α- (5 - {[N-3- (furan-2-ylmethylthio) -propyl] -N-methyl-amino} -pentyl) estra-1,3,5 (10) -triene- 3,17β-όίοΙ

217 mg of 1β-fluoro-7α- (5 - {[N-3- (furan-2-ylmethylthio) -propyl] -N-methylamino} -pentyl) -3-hydroxy-estra-1,3,5 (10 1-Trien-17-one is dissolved in 6 ml of methanol and treated portionwise with 0 mg of sodium borohydride at 0 ° C. After stirring at room temperature for 1 hour, the solvent is removed in vacuo, the residue is treated with saturated sodium chloride solution, extracted three times with methylene chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel using a methylene chloride gradient

31174 / H methyl alcohol to give 146 mg of 1β-fluoro-7a- (5 - {[N-3- (furan-2-ylmethylthio) propyl] -N-methylamino} -pentyl) -estra-1, 3,5 (10) -triene-3,17β-diol as a foam.

Example 44

11p-fluoro-7 ~ (5- (N-methyl- [N-3- (thiophen-2-yl methylthio) propyl] amino} -pentyl) -estra-1,3,5 (10) -triene-3,17 diol

a) 1β-Fluoro-3-hydroxy-7α- (5- [N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino} pentyl) -estra-1,3,5 (10) ) -trien-17-one

526 mg of 1β-fluoro-3-hydroxy-7α- (5- (methylamino) -pentyl) -estra-1,3,5 (10) trien-17-one and 103 mg of 2- (3-chloropropylthiomethyl) thiophene Dissolve in 5 ml of ethyl methyl ketone, mix with 112 mg of sodium iodide and 104 mg of potassium carbonate and stir for 4.5 hours at a bath temperature of 90 ° C. For working-up, the reaction mixture is poured into semi-saturated sodium bicarbonate solution, extracted three times with methylene chloride, the extract is washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a methylene chloride-methanol gradient to give 191 mg of 1β-fluoro-3-hydroxy-7α- (5- {N-methyl- [N-3- (thiophen-2-ylmethylthio) - propyl] amino} -pentyl) -estra-1,3,5 (10) -trien-17-one as a foam.

b) 11-p-fluoro-7α- (5- {N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino} -pentyl) estra-1,3,5 (10) -triene -3,17β-ool

185 mg of 1β-fluoro-3-hydroxy-7α- (5- {N-methyl- [N-3- (thiophen-2-ylmethylthio) propyl] -amino} -pentyl) -estra-1,3,5 ( 10) -Trien-17-one is dissolved in 5 ml of methanol and mixed portionwise with 28 mg of sodium borohydride. After stirring for 45 minutes at room temperature, the solvent was largely under vacuum

31174 / H is stripped off, the residue is treated with saturated sodium chloride solution, extracted three times with methylene chloride, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using a methylene chloride-methanol gradient to give 93 mg of 1β-fluoro-7α- (5- {N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino Pentyl) -estra-1,3,5 (10) -triene-3,17β-diol as a foam.

Example 45 p-Fluoro-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene-3,17p- d iol

a) 1β-Fluoro-3-hydroxy-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene- 17-one

A solution of 0.5 g of 7α- (5-chloropentyl) -1β-fluoro-3-hydroxy-estra-1,3,5 (10) -trien-17-one in 4 ml of dimethylformamide is stirred with 0.55 g of (2S). Of 2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine and 0.32 g of lithium iodide for 2 hours at a bath temperature of 100 ° C. The reaction mixture is then added to sodium bicarbonate solution, extracted three times with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / acetone to give 0.45 g of 11-fluoro-3-hydroxy-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl]. ] pentyl} estra-1,3,5 (10) -trien-17-one.

[.alpha.] D @ ²² = +32.7 DEG (c = 0.51% in chloroform).

b) 11β-Fluoro-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene-3,17β- ό iol

31174 / H

A solution of 0.43 g of 11β-fluoro-3-hydroxy-7α- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10 1-trien-17-one in 4 ml of tetrahydrofuran, 2.3 ml of ethyl alcohol and 1 ml of water are treated portionwise at 0 ° C with 111 mg of sodium borohydride and stirred for 2 hours. It is then poured into ice water, extracted three times with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / acetone to give 0.32 g of 11-fluoro-7a- {5 - [(2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -triene-3,17-diol.

[.alpha.] D @ ²² = + 16.2 DEG (c = 0.51% in methanol).

Example 46

11β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) pyrrolidin-1-yl] pentyl} -estra-1,3, 5 (10) -triene-3,17β-άϊοΙ

A solution of 0.2 g of 11B-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra -1,3,5 (10) -triene-3,17B-diol in 5.8 ml of methanol and 2.9 ml of water was stirred for 5 hours at room temperature with 82 mg of sodium periodate. The reaction mixture is then taken up in water, extracted three times with dichloromethane, the extract is washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. The obtained 210 mg of crude product is chromatographed on silica gel using dichloromethane / methanol to give 105 mg of 14,17-ethano-7α- {5- [N-methyl-N-3 (4,4,5,5,5) -pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17B-diol (IR 1610 and 1190 (cm) ^-1 ).

Example 47

31174 / 1H-fluoro-17α-methyl-7α- {5 - [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3 , 5 (1 O) -triene-3,170-diol

Analogously to Example 29, 11β-fluoro-17α-methyl-7α- {5 - [(2R) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} - estra-1,3,5 (10) -trién3,170-diol.

[α] _D ²² = +68.7 ⁰ (c = 0.74% in chloroform).

Example 48

11β-Fluoro-7α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) pyrrolidin-1-yl] -pentyl} -estra-1,3,5 ( 10) -triene-3,170-diol

A solution of 100 mg of 3,170-diacetoxy-110-fluoro-17α-methyl-7α- {5 - [(2S) -2 (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} - estra-1,3,5 (10) triene in 1.3 ml of a 0.2 M methanolic potassium hydroxide solution was stirred for 2 hours at room temperature. The reaction mixture was poured into water, extracted three times with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / acetone to give 63 mg of 1β-fluoro-17α-methyl-7α- (5 - [(2S) -2 (4,4,5,5,5-pentafluoropentanesulfonylmethyl)). pyrrolidin-1-yl] pentyl} estra-1,3,5 (10) -triene-3,17-diol (IR 1710, 1660 and 1610 (cm) ^-1).

Example 49 1-Fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) - triene-3,17-diol

Solution 300 mg 1β-Fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol in 4.3 ml of methanol and 2.1 ml of water was stirred for 4 hours at room temperature with 131 mg of sodium periodate. The reaction mixture is then added to water three times

31174 / H was extracted with ethyl acetate, the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane / ethyl acetate to give 203 mg of 11-p-fluoro-7α {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) - pyrrolidin-1-yl] pentyl} estra-1,3,5 (10) -triene-3,17-diol.

[α] D ²² = +1 1.8 ⁰ (c = 0.53% in methanol).

Example 50 β-Fluoro-1α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol

Analogous to that described in Example 48, 1β-fluoro-7α- {5 - [(2S) -2 (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentylene} - was obtained - estra-1,3,5 (10) -triene-3,17β-όίοΙ.

[a] ²² _D = +30.6 ⁰ (c = 0.515% in methanol).

Production of starting compounds:

N-methyl- [3- (4,4,5,5,5- pentafluoropentylthio) -propyl] -amine

a) 3-iodopropyl-4,4,5,5,5-pentafluoropentyl sulfide

A solution of 22.8 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentylsulfide in 500 ml of ethyl methyl ketone is stirred for 5 hours at a bath temperature of 100 [deg.] C. under a nitrogen atmosphere with 40 g of sodium iodide and evaporated in vacuo to dryness. The residue is taken up in water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentylsulfide are obtained.

31174 / H

b) N-methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine

In a solution of 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentylsulfide in 200 ml of absolute tetrahydrofuran, 45 g of methylamine is condensed at -78 ° C and stirred in a pressure reactor for 90 minutes at room temperature. and for 4 hours at 60 ° C. To open the reactor, allow the reaction mixture to cool to room temperature overnight and then cool to -78 ° C. After opening the reactor, the contents were allowed to warm to room temperature, excess methylamine was evaporated, diluted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with dichloromethane / methanol to give 15.7 g of N-methyl- [3- (4,4,5,5,5-pentafluoropentylthio) -propyl] -amine as an oil.

N-methyl- [3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl] -amine

(a) 3-chloropropyl-4,4,5,5,5-pentafluoropentanesulfone

A solution of 23 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentylsulfide in 230 ml of chloroform was treated portionwise at 0 ° C with 41.8 g of 70% chloroperbenzoic acid and stirred for 1.5 hours at room temperature. It was then diluted with dichloromethane, washed with sodium bisulfite, sodium bicarbonate and sodium chloride solutions, dried over anhydrous sodium sulfate and concentrated in vacuo. 23.8 g of pure product are obtained

3-chloropropyl-4,4,5,5,5-pentafluoropentanesulfone as a crystalline solid, m.p. 74-76 ° C.

b) 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone

A solution of 23.5 g of 3-chloropropyl-4,4,5,5,5-pentafluoropentanesulfone in 500 ml of ethyl methyl ketone is stirred with 40 g of sodium iodide for 5 hours at a bath temperature of 100 ° C under a nitrogen atmosphere. Then, the reaction mixture was removed in vacuo

31174 / H is evaporated to dryness, the residue is taken up in water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 30.6 g of 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone are obtained in the form of a crystalline substance, m.p. 88-89 ° C.

c) N-methyl- [3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl] -amine

A solution of 3-iodopropyl-4,4,5,5,5-pentafluoropentanesulfone (23.5 g) in absolute tetrahydrofuran (200 ml) was condensed with methylamine (44 g) at -78 ° C and stirred in a pressure reactor for 90 minutes at room temperature. and for 4 hours at 60 ° C. To open the reactor, allow the reaction mixture to cool to room temperature overnight and then cool to -78 ° C. After opening the reactor, allow the contents to warm to room temperature, evaporating excess methylamine, diluting with ethyl acetate, washing to neutral, drying over anhydrous sodium sulfate and concentrating in vacuo. The residue is chromatographed on silica gel using dichloromethane / methanol to give 14.8 g of N-methyl- [3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propyl] amine as a crystalline solid, m.p. mp 55-57 ° C.

1-bromo-5-tert-butyldimethylsilyloxypentane

a) 5-bromo-1-pentanol

To a solution of 50 g of 5-bromopentyl acetate in 1.6 L of methanol was added dropwise 50 ml of concentrated sulfuric acid, and the reaction mixture was stirred for 30 hours at room temperature. The methanol is then stripped off in vacuo, the residue is taken up in diethyl ether, washed neutral with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 28 g of 5-bromo-1-pentanol are obtained as a crude product.

31174 / H

b) 1-bromo-5-tert-butyldimethylsilyloxypentane

A solution of 28 g of 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is mixed with 24 g of imidazole, followed by the dropwise addition of a solution of 30.3 g of tert-butyldimethylchlorosilane in 46 ml of tetrahydrofuran and stirred for 4 hours at room temperature. It is then poured into water, shaken with diethyl ether, the organic phase is washed four times with water, dried over sodium sulphate and concentrated. The crude product obtained is chromatographed on silica gel with hexane / diethyl ether to give 42 g of the title compound as a colorless liquid.

(2S) -2- (4,4,5,5,5- pentafluoropentylthiomethyl) -pyrrolidin

a) N-tert-butyloxycarbonyl-L-prolinol-p-tosylate

To a solution of N-tert-butyloxycarbonyl-L-prolinol in 170 mL of pyridine at 24 ° C was added portionwise. g of p-toluenesulfonic anhydride and the reaction mixture is stirred for 5 hours at 0 ° C. It is then poured into 2 N hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. 17.7 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate is obtained as an oily crude product.

[.alpha.] D @ ²² = -28.0 DEG (c = 0.545% in chloroform).

b) N-tert-butyloxycarbonyl- (2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidine

A solution of 3.93 g of 4,4,5,5,5-pentafluoropentylthioacetate in 18 ml of methanol is treated with 2.94 ml of sodium methoxide solution (30% in methanol) and the mixture is stirred for 30 minutes at room temperature. This reaction solution was added to a solution of 3.0 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate, and the mixture was stirred for 3 hours at room temperature and for 3 hours at 50 ° C. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is washed with saturated bicarbonate solution.

31174 / H sodium, dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel using hexane / ethyl acetate to give 2.59 g of N-tert-butyloxycarbonyl- (2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine as oily liquid. [α] D ²² = -41.3 ⁰ (c = 0.530% in chloroform).

c) (2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidine

To 5.4 ml of trifluoroacetic acid, cooled to 0 ° C, add 2.25 g of N-tert-butyloxycarbonyl- (2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidine and Stir for 1.5 hours at 0 ° C and for 16 hours at room temperature. The reaction mixture was then poured into 10% sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated. 1.8 g of the title compound is obtained as an oily crude product.

(2 R) -2- (4,4,5,5,5- pentafluoropentylthiomethyl) -pyrrolidin

In an analogous manner to that described for the preparation of (2S) -2 (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidine, 9.6 g of the title compound are obtained from 10 g of N-tert-butyloxycarbonyl-D-prolinol. in the form of an oily crude product.

(4,4,5,5,5pentafluorpentyl) vinyl sulfone

(a) (4,4,5,5,5-Pentafluoropentyl) vinyl sulfide

A solution of 40 g of 4,4,5,5,5-pentafluoropentylthioacetate in 200 ml of methanol is stirred with 34 ml of 30% sodium methylate for one hour at 25 ° C, then mixed dropwise with 21 ml of 1,2-dibromoethane, stirred The mixture was stirred for a further 2 hours at room temperature, treated dropwise with an additional 70 ml of 30% sodium methylate and stirred for a further 3 hours at 25 ° C. Then

31174 / H methanol is stripped off in vacuo, the residue is taken up in water, extracted three times with ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated in vacuo. 34 g of (4,4,5,5,5-pentafluoropentyl) vinyl sulfide are obtained.

b) (4,4,5,5,5-pentafluoropentyl) vinyl sulfone

A solution of 34 g of (4,4,5,5,5-pentafluoropentyl) -vinyl sulfide in 74 ml of glacial acetic acid is added dropwise with 59 ml of 30% hydrogen peroxide so that the reaction temperature does not exceed 70 ° C, after which the mixture is stirred for one hour at a bath temperature of 70 ° C. The reaction mixture is then taken up in water, extracted three times with ethyl acetate, the extract is washed with sodium thiosulphate solution, water and brine, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 12.3 g of (4,4,5,5,5-pentafluoropentyl) vinyl sulfone as an oily liquid.

2- (3-Chloro-propylthiomethyl) -furan

To 1.77 ml of furan-2-yl-methanethiol in 18 ml of anhydrous acetonitrile was added dropwise at 0 ° C 3.3 ml of a 30% solution of sodium methylate in methanol. After 5 minutes, 2.6 ml of 1-bromo-3-chloropropane was added dropwise, and the reaction solution was stirred for 5 hours at room temperature. For working-up, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 1.1 g of 2- (3-chloropropylthiomethyl) furan as an oil.

2- (3-Chloro-propylthiomethyl) -thiophene

31174 / H

To 1.0 g of thiophen-2-yl-methanethiol in 8 ml of anhydrous acetonitrile at 0 ° C was added dropwise 1.5 ml of a 30% solution of sodium methylate in methanol. After 5 minutes, 1.1 ml of 1-bromo-3-chloropropane was added dropwise, and the reaction solution was stirred for 5 hours at room temperature. For working-up, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel using a hexane-ethyl acetate gradient to give 1.3 g of 2- (3-chloropropylthiomethyl) thiophene as an oil.

(2 S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine

a) N-tert-Butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine

A solution of 1.65 g of 4-trifluoromethylthiophenol in 18 ml of dimethylformamide is treated with 3 g of N-tert-butyloxycarbonyl-L-prolinol-p-tosylate and the reaction mixture is stirred for 8 hours at room temperature. It is then poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane / ethyl acetate to give 2.59 g of N-tert-butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) -pyrrolidine as an oil.

b) (2S) -2- (4-trifluoromethylphenylthiomethyl) pyrrolidine

A solution of 2.55 g of N-tert-butyloxycarbonyl- (2S) -2- (4-trifluoromethylphenylthiomethyl) pyrrolidine in 5.64 ml of trifluoroacetic acid was stirred at 0 ° C for one hour and then at room temperature for 3.5 hours. . The reaction mixture is then poured into 10% sodium bicarbonate solution, extracted with ethyl acetate, washed twice with 2 N hydrochloric acid, the aqueous phase is extracted with ethyl ester, basified with sodium bicarbonate, extracted three times with ethyl acetate, washed with sodium chloride solution. , dried over anhydrous sulfate

31174 / H sodium and concentrated. 557 mg of (2S) -2- (4-trifluoromethylphenylthiomethyl) pyrrolidine is obtained.

Claims (42)

PATENT CLAIMS Substituted 7-α-β-aminoalkyl) estratrienes of the general formula I in which the side chain SK represents the remainder of the sub-formula - (CH) _m -N-CH-CH- (CH ₂ ) n -SO _x - (CH ₂ ) 3 -E I I I A B D wherein m is 4, 5 or 6, n is 0, 1 or 2 and x is 0, 1 or 2, A represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, B and D represent a hydrogen atom, or A and B together represent an alkylene group - (CH ₂ ) _p -, wherein p = 2, 3, 4 or 5 and D represents a hydrogen atom, or A and D together are an alkylene group - _{(CH2) p} - wherein p is 2, 3 or 4 and B is hydrogen, and E is unsubstituted or mono- to five times fluorinated ethyl radical or the terminal substituent - (CH _{2) 3} - in the side chain is replaced by a 31174 / H optionally substituted aryl or heteroaryl radical which is bonded directly or via a mono-, di- or trimethylene group to a sulfur atom, R ³ represents a hydrogen atom, a hydrocarbon radical of up to 8 carbon atoms or a radical of the formula R ³ '-C (O) -, wherein: R ³ 'represents a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or a phenyl radical, R ¹¹ is a hydrogen atom, a halogen atom or a nitrooxy group -O-NO 2, R ¹⁴ , R ^15a , R ^15b , R ^16a and R ^16b are all hydrogen or R ¹⁴ and R ^15a represent an additional bond or a methylene bridge, or R ( ^15b) is methyl and R ( ^{15a) is} hydrogen or R ^15a and R ^15b are each methyl or R ^15b and R ^16b together represent a methylene bridge, or R ^16a or R ^16b is halogen or R ^16a and R ^16b together represent a methylidene group, and the other substituents R ¹⁴ , R ^15a , R ^15b , R ^16a and R ^16b are each a hydrogen atom, R ¹⁷ 'in the α- or β-position represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms or a trifluoromethyl group and R ¹⁷ 'represents a hydrogen atom or a radical of the formula R ¹⁷ ' -C (O) -, wherein R ¹⁷ 'means a hydrogen atom or a hydrocarbon radical of up to 8 carbon atoms or, when R ¹⁷ ' is in the α-position, R ¹⁷ 'together with R ^{14 is an} ethano-bridge, 31174 / H 100 with the proviso that when A and B do not together represent - (CH ₂ ) _p - or A and D together represent - (CH ₂ ) _q -, at least one of R ¹¹ , R ¹⁴ , R ^15a , R ^15b R ^16a and R ^16b are not hydrogen, as well as their physiologically acceptable addition salts with organic and inorganic acids. Estratrienes according to claim 1, wherein m is 5. Estratrienes according to claim 1, wherein n is 0. Estratrienes according to claim 1, wherein n is 1. Estratrienes according to claim 1, wherein n is 2. Estratrienes according to claim 1, wherein A is a methyl group. Estratrienes according to claim 1, wherein x is 0. Estratrienes according to claim 1, wherein x is 1. Estratrienes according to claim 1, wherein x is 2. Estratrienes according to claim 6, wherein n is 1. Estratrienes according to claim 1, wherein A and B together are - (CH ₂ ) 3 -. Estratrienes according to claim 11, wherein n is 0. Estratrienes according to claim 12, wherein x is 0. Estratrienes according to claim 1, wherein E is a perfluoroethyl residue. Estratrienes according to claim 1, wherein R ³ is a hydrogen atom. Estratrienes according to claim 1, wherein R ³ is a methyl group. 17. Estratrienes according to claim 1, wherein R ³ is an acetyl group. Estratrienes according to claim 1, wherein R ¹¹ is a hydrogen atom. Estratrienes according to claim 1, wherein R ¹¹ is a fluorine atom. Estratrienes according to claim 1, wherein R ¹¹ is nitrooxy. 21. Estratrienes according to claim 1, wherein R ¹⁴ is a hydrogen atom. 31174 / H 101 Estratrienes according to claim 1, wherein R ¹⁴ together with R ^{15a form an} additional bond. Estratrienes according to claim 1, wherein R ^15b is a methyl group. Estratrienes according to claim 1, wherein R ^15b and R ^16b together form a methylene bridge. Estratrienes according to claim 1, wherein R ^16a is a halogen atom. Estratrienes according to claim 25, wherein R ^16a is a fluorine atom. Estratrienes according to claim 1, wherein R ^16a and R ^16b together form a methylidene group. 28. Estratrienes according to claim 1, wherein R ¹⁷ is in position a. Estratrienes according to claim 28, wherein R ¹⁷ is trifluoromethyl. Estratrienes according to claim 28, wherein R ¹⁷ is a methyl group. Estratrienes according to claim 28, wherein R ¹⁷ is a hydrogen atom. 32. Estratrienes according to claim 1, wherein R ¹⁷ is in position β. Estratrienes according to claim 32, wherein R ¹⁷ is a methyl group. 34. Estratrienes according to claim 32, wherein R ¹⁷ is a hydrogen atom. Estratrienes according to claim 28, wherein R ¹⁴ and R ¹⁷ together form etanomostic. Estratrienes according to claim 1, wherein SK is a radical of the formula - (CH) ₅ -N- (CH ₂ ) ₃ -SO _x - (CH ₂ ) 3 -C ₂ H ₅ I ch ₃ in which x = 0, 1 or 2. 37. Estratrienes according to claim 13, wherein m = 5, E is a perfluoroethyl residue and the conformation of the 2-carbon atom of the heterocycle is R. 31174 / H 102 38. Estratrienes according to claim 13, wherein m = 5, E is a perfluoroethyl radical and the conformation of the 2-carbon atom of the heterocycle is S. Estratrienes according to claim 37, wherein R ¹⁷ is in the α-position and is a hydrogen atom. Estratrienes according to claim 1, namely - 14,17-ethano-7a- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene -3,17p-diol - 14,17-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol - 3,17β-diacetoxy-14α, 17α-ethano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene - 14,17-ethano-7-α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 ( 10) -triene-3,17β-diol - 17α-Trifluoromethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene -3,17β-d iol - 15β, 16β-Methanol-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol - 15β, 16β-Methanol-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3 , 5 (10) -triene-3,17-diol - 15β, 16β-methano-17α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoro-pentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -triene-3,17-diol - 15β, 16β-methano-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol - 15β-Methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene -3,17p-diol - 15β, 17α-Dimethyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol 31174 / H 103 11-p-fluoro-7α- [5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) - triene-3,17β-oleol 11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,17-diol 11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) - triene-3,17-diol - 16α-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -triene-3,17β-diol - 16α-Fluoro-17β-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 ( 10) -trien-3,17cc-diol - 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol - 16α-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17β-diol - 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -triene -3.17p ~ d iol - 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -estra-1,3,5 (10) -trien-3,17β-diol - 16α-Fluoro-7α- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene 3,17-diol - 16α-Fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) propylamino] -pentyl} -estra-1,3,5 (10) -triene -3,17p-diol 7- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] -pentyl} estra-1,3,5 (10), 14-tetraene-3 17β-d iol - 7a- [5- [N-Methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) -propylamino] pentyl} -estra-1,3,5 (10), 14-tetraene-3 17β-d iol 7- {5 '[N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] pentyl} -estra-1,3,5 (10), 14-tetraene-3 , 17.beta.-diol 31174 / H 104 - 7α- {5 - [(2S) -2- (4,4,5,5,5-Pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-3 , 1 β-d iol - 7 - {5 - [(2R) -2- (4,4,5,5,5-Pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-3 , 1 β-d iol - 17α-Methyl-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -trien-3 , 17.beta.-diol - 1β-Fluoro-7α- {5- [2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] -pentyl} estra-1,3,5 (10) -trien-3 , 1 β-d iol 11-p-nitrooxy-7α- (9- [4,4,5,5,5-pentafluoropentanesulfonyl] -nonyl) -estra1,3,5 (10) -triene-3,17β-diol - 11β-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] pentyl) -estra-1,3, 5 (10) -triene-3,17-diol - 1β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinyl-methyl) pyrrolidin-1-yl] -pentyl} -estra-1, 3,5 (10) -triene-3,17-diol - 1β-Fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3 , 5 (10) -triene-3,17-diol -7- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -trien-3 17β-d iol 7- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -trien-3 17β-d iol 11-p-fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol 11β-Fluoro-17α-methyl-7α- (5- [N-methyl-N-3- (4,4,5,5,5-pentafluoro-pentanesulfinyl) propylamino] -pentyl} -estra-1,3 5 (10) -triene-3,17β-diol - 1β-Fluoro-17α-methyl-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfonyl) -propylamino] -pentyl} -estra-1,3,5 (10) -triene-3,17-diol 11-p-fluoro-7α- {5- [N-methyl-N-2- (4,4,5,5,5-pentafluoropentanesulfonyl) ethylamino] pentyl} -estra-1,3,5 (10) - triene-3,17-diol 31174 / H 105 11-p-fluoro-7α- {5- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] pentyl} -3-hydroxy-estra-1,3,5 (10) -trien-17-one 11-p-fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentylthio) -propylamino] hexyl} -estra-1,3,5 (10) -triene- 3,17-diol 11β-Fluoro-7α- {6- [N-methyl-N-3- (4,4,5,5,5-pentafluoropentanesulfinyl) propylamino] -hexyl} -estra-1,3,5 (10) -triene -3,17β-d iol - 1β-Fluoro-7α- (5 - {[N-3- (furan-2-ylmethylthio) -propyl] -N-methylamino} -pentyl) estra-1,3,5 (10) -triene- 3,17β-d iol - 1β-Fluoro-7α- (5- (N-methyl- [N-3- (thiophen-2-ylmethylthio) -propyl] -amino} -pentyl) estra-1,3,5 (10) -triene- 3,17β-d iol 11β-Fluoro-7α- {5 - [(2S) -2- (4-trifluoromethyl ifenylthiomethyl) -pyrrolidin-1-yl] pentyl} estra-1,3,5 (10) -triene- 3,17β-d iol 11-p-fluoro-17α-methyl-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentane-sulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1 , 3,5 (10) -triene-3,17-diol - 1β-Fluoro-17α-methyl-7α- {5 - [(2R) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) pyrrolidin-1-yl] -pentyl} -estra-1,3, 5 (10) -triene-3,17-diol 11β-fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentylthiomethyl) -pyrrolidin-1-yl] pentyl} -estra-1,3,5 (10) -triene-3,17-diol 11-p-fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfinylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 ( 10) -triene-3,17β-diol - 1β-Fluoro-7α- {5 - [(2S) -2- (4,4,5,5,5-pentafluoropentanesulfonylmethyl) -pyrrolidin-1-yl] -pentyl} -estra-1,3,5 (10) -triene -3,17β-d iol. 41. A pharmaceutical composition comprising, as an active ingredient, at least one compound of the formula I as claimed in claim 1, as well as a pharmaceutically acceptable carrier. Use of compounds of formula I according to claim 1 for the manufacture of medicaments. 31174 / H 600 DMBA - Induced Breast Gland Tumors p.o. % change in tumor growth