MXPA99009227A - Novel 4- halogenated steroids, preparation method and intermediates, application as medicines and pharmaceutical compositions containing same - Google Patents
Novel 4- halogenated steroids, preparation method and intermediates, application as medicines and pharmaceutical compositions containing sameInfo
- Publication number
- MXPA99009227A MXPA99009227A MXPA/A/1999/009227A MX9909227A MXPA99009227A MX PA99009227 A MXPA99009227 A MX PA99009227A MX 9909227 A MX9909227 A MX 9909227A MX PA99009227 A MXPA99009227 A MX PA99009227A
- Authority
- MX
- Mexico
- Prior art keywords
- chloro
- estra
- triene
- 17beta
- ethoxy
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 9
- 229940079593 drugs Drugs 0.000 title claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000003431 steroids Chemical class 0.000 title description 6
- 239000000543 intermediate Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 132
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 68
- -1 alkynyl radical Chemical class 0.000 claims description 65
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 35
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 31
- 239000011780 sodium chloride Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 150000007513 acids Chemical class 0.000 claims description 23
- 238000007792 addition Methods 0.000 claims description 23
- 238000005899 aromatization reaction Methods 0.000 claims description 22
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 238000010511 deprotection reaction Methods 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 16
- 150000003254 radicals Chemical class 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 230000004224 protection Effects 0.000 claims description 11
- JUKPWJGBANNWMW-VWBFHTRKSA-N Eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
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- 239000003638 reducing agent Substances 0.000 claims description 10
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 125000005842 heteroatoms Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- OSDLLIBGSJNGJE-UHFFFAOYSA-N Chloroxylenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 230000000875 corresponding Effects 0.000 claims description 7
- 150000002829 nitrogen Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
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- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
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- 239000011593 sulfur Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- LGHBWDKMGOIZKH-CBZIJGRNSA-N 3-Deoxyestrone Chemical compound C1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 LGHBWDKMGOIZKH-CBZIJGRNSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims description 3
- ITZHHMQIKLMWIN-UHFFFAOYSA-N 1,3$l^{2}-thiazolidine Chemical group C1CSC[N]1 ITZHHMQIKLMWIN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003870 2-(1-piperidinyl)ethoxy group Chemical group [*]OC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004434 sulfur atoms Chemical group 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- JNKQAHJZAUFSLB-BAWYVGMJSA-N (8S,9R,11S,13S,14S,17S)-4-chloro-11-[4-[2-(diethylamino)ethoxy]phenyl]-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound C1=CC(OCCN(CC)CC)=CC=C1[C@@H]1[C@@H]2C3=CC=C(O)C(Cl)=C3CC[C@H]2[C@@H]2CC[C@H](O)[C@@]2(C)C1 JNKQAHJZAUFSLB-BAWYVGMJSA-N 0.000 claims 1
- 101700073665 ENO3 Proteins 0.000 claims 1
- 241000806990 Hala Species 0.000 claims 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N N-Hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 claims 1
- 235000005311 Pandanus odoratissimus Nutrition 0.000 claims 1
- 125000002393 azetidinyl group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 claims 1
- 125000004585 polycyclic heterocycle group Chemical group 0.000 claims 1
- 239000000047 product Substances 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
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- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
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Abstract
La invención tiene por objeto los compuestos de fórmula (I), en la cual X es unátomo de halógeno, D representa el resto de un ciclo pentagonal o hexagonal eventualmente sustituido y eventualmente portador de insaturación, R1,R2,R3 y n son tales como están definidos en la descripción, su procedimiento y medio de preparación;su aplicación como medicamento y las composiciones farmacéuticas que los contienen.
Description
NEW 4-HALOGENATED STEROIDS, ITS PROCEDURE AND MEANS
OF PREPARATION, ITS APPLICATION AS MEDICINES AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
FIELD OF THE INVENTION The present invention relates to the allogenated steroid compositions, their preparation process, their use as medicaments and the pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Osteoporosis is a pathology characterized by a quantitative and qualitative reduction of bone tissue, sufficient to generate vertebral or peripheral fractures, spontaneously or in the case of minimal trauma. Although this condition is of multifactorial origin, it is menopause that represents the predominant factor of bone loss or osteopenia for women. Said osteopenia manifests itself in a rarefaction and a modification of the structure of the porous bones which must accentuate, as a consequence, the skeletal fragility and the risk of fractures. The loss of bone mass is strongly accentuated after "menopause"
REF .: 31439 cause of suppression of ovarian function and reaches 3 to 5% per year, to lessen after 65 years. For therapeutic purposes, postmenopausal hormone deficiency can be compensated by hormone replacement therapy where estrogen plays an important role in the preservation of bone mass. But estrogen therapy over time can sometimes be accompanied by undesirable effects on the reproductive system (endometrial hyperplasia, breast tumor, etc.), which is a major drawback and limits its application. Therefore, it is convenient to find other compounds than estradiol, which has a dissociated estrogenic activity, namely an activity at a bone level, with no or insignificant endometrial hyperplasia, nor the proliferation of the mammary tumor.
DESCRIPTION OF THE INVENTION
The subject of the invention is therefore the compounds of general formula (I):
wherein: Rx represents a hydrogen atom, a radical (CH2) m-Ar, (CO) -Ar, (CH2) m -Alk or (CO) -Alk, R2 represents a radical derived from a hydrocarbon, linear or branched, saturated or unsaturated, containing 1 to 6 carbon atoms, D represents the remainder of a pentagonal or hexagonal cycle optionally substituted and optionally unsaturated, X represents a halogen atom, and is chosen from 0, S, SO , S02 and NH, n is an integer that varies between 2 and 8, Q is R3 and R4, identical or different, represent a hydrogen atom, a grouping (CH2) m-Ar, (CH2) m-Het or (CH2) ) ffiAlk, ie R3 and R4 form together with the nitrogen atom to which they are attached, a mono or polycyclic, saturated or unsaturated, aromatic or non-aromatic heterocycle, of 3 to 15 bonds with optionally from 1 to 3 additional heteroatoms chosen from oxygen, sulfur and nitrogen, unsubstituted or substituted, Ar represents a carbocyclic aryl grouping that e contains from 6 to 18 carbon atoms, Het represents a radical derived from an aromatic or non-aromatic heterocycle, saturated or unsaturated, containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from oxygen atoms, of nitrogen or sulfur, Alk represents a radical derived from a non-aromatic hydrocarbon, linear, branched or cyclic, saturated or unsaturated, and contains from 1 to 12 carbon atoms, - the radicals Ar, Het or Alk can be substituted or not substituted, m represents 0,1,2 or 3, as well as their addition salts with bases or acids. Halogen means: iodine, bromine, chlorine or fluorine.
The following values are defined by (CH2) m: single bond when m equals 0, CH2, (CH2) 2 and (CH2) 3. By the term Ar, which represents the carbocyclic aryl group and which comprises from 6 to 18 carbon atoms, is meant a derivative of an aromatic cyclic hydrocarbon such as the phenyl, naphthyl, phenanthrenyl radical or a
-derived from a bicyclic or condensed tricyclic hydrocarbon containing a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The union takes place at the level of the benzene cycle. It is preferably phenyl. By the term Het representing a radical derived from an aromatic or non-aromatic heterocycle, saturated or unsaturated, containing from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from the oxygen, nitrogen and sulfur atoms, it is mainly noted: heterocyclic monocyclic radicals, for example, thienyl, furyl, pyranyl, pyrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl radicals , tetrazolyl, fused heterocyclic rings, for example, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho [2,3-b] thienyl, thiantrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxythiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, inoxalinyl, quinazolinyl, cinolinyl, pteridinyl, -carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or even the condensed polycyclic systems constituted of heterocyclic monocyclics such as those noted above, for example, furo [2, 3-b] pyrol or thieno [2, 3-b] furan, - or saturated heterocycles such as pyrolidine, piperidine, morpholine. By the term Alk which represents a radical derived from a non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon, it is noted in the case of acyclic hydrocarbons, the alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl , tertbutyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3, 3-dimethylpentyl, 3-ethylpentyl, n-octyl , 2, 2-dimethylexyl, 3, 3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl radicals such as vinyl, propenyl, isoprenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl and in the case of cyclic radicals, cycloalkyls radicals such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. It will preferably be methyl and ethyl radicals. By CO-Alk is meant, preferably, COCH3 and COEt, by Co-Ar is meant, preferably, the benzoyl radical, when m is different from .zero, (CH2) m-Ar will be, preferably, the benzyl group. When R3 and R4 together with the nitrogen atom, to which they are attached, form a heterocycle, they are mainly mono or bicyclic heterocycles optionally containing a further heteroatom chosen from oxygen and nitrogen, such as the following unsaturated heterocycles: pyrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazolinyl, pyrazolinyl, thiazolinyl or, more particularly, the following saturated heterocycles:
When the different groups Alk, Ar, Het, as well as the remainder of a pentagonal or hexagonal cycle mentioned above, are substituted, they can be substituted mainly by the following radicals: halogen, namely fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amine, alkylamine such as methylamine or ethylamine, dialkyl amine such as dimethylamine, diethylamine, methylethylamine, each of these dialkylamine radicals are optionally in the form of an oxide, aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamine ethyloxy, optionally acylated hydroxyl, acyl such as acetyl, propionyl, butyryl, benzoyl, free carboxy, esterified such as alkoxycarbonyl , for example, methoxy carbonyl or ethoxy carbonyl, cyano, trifluoromethyl, aryl such as phenyl or, aralkyl such as benzyl, alkyl, alkenyl or alkynyl, these radicals themselves being optionally substituted by the aforementioned halogen, alkyl, alkoxy, alkylthio, aminoalkyl or dialkylamino radicals. Of course, the term "substituted" indicates that one or more substituents, identical or different, may be present. In the case of Het, the substituents may be at the level of NH or a carbon atom. Of course, the values of Rl t R2, R3 and R4 are independent of each other. The invention naturally extends to the salts of the compounds of formula (I), such as, for example, salts formed with mineral or organic acids on the amine. It can then be hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, ropionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonic acids such as methane or ethane sulphonic acids , arylsulfonic, such as benzene or paratoluene sulphonic and arylcarboxylic acids. When the compounds of formula (I) have an acid function, the invention extends to the alkali metal, alkaline earth or optionally substituted ammonium salts. The subject of the invention is, very particularly, the compounds of general formula (I), as indicated above, in which D represents the remainder of a pentagonal cycle of the formula:
in which R2 retains the same significance as before, that is, R5 represents an OH radical, O- (CH2) m-Alk, O- (CO) -Alk, 0- (CH2) m-Ar, 0- (CO ) -Ar, O- (CH2) m-Het, O- (CO) -Het and Rb represents a hydrogen atom, an alkyl, alkenyl or alkenyl radical containing from 1 to 6 carbon atoms, substituted or unsubstituted, m, Alk, Ar and Het are as indicated above,
that is, Rs and R6 together with the carbon atom that contains one of the following cycles:
in which Z represents a grouping - (CH2)? ~ where -CH = CH- (CH2) 1,. 1 is an integer between 1 and 4 and 1 'is an integer equivalent to 1 or to 2,
that is, Rg and Rβ together form an oxo or = N-OH grouping, as well as their addition salts with the acids or bases. The subject of the invention is, very particularly, the compounds of the formula (I) as indicated above corresponding to the general formula (I "):
wherein: X 'represents a chlorine or bromine atom n' is between 2 and 5, that is, R'3 and R'4, identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms; carbon, that is, R'3 and R'4 form together with a nitrogen atom to which they are attached, a saturated mono or polycyclic radical of 3 to 15 bonds that optionally contain an additional heteroatom selected from oxygen, sulfur and nitrogen, R'd and R'e have the same significance as R5 and R6, as well as their addition salts with acids and bases. The invention has as its object, very particularly, the compounds of formula (I), as indicated above, in response to the general formula (I ') in which: that is, R'5 represents an OH and R'6 radical represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, substituted or unsubstituted, that is, R'5 and R'6 together with the carbon atom containing one of The following cycles:
that is, R'5 and R'6 together form an oxo group, as well as their addition salts with the acids or bases. The subject of the invention is, very particularly, the compounds of the formula (I) according to the general formula (I '), as indicated above, in which: X' represents a chlorine atom, n 'is equal to 2, ie and R'4, identical or different, represent an alkyl radical containing 1 to 6 carbon atoms, that is, R'3 and R'4 together with the nitrogen atom form the following saturated heterocycles:
I mean, R'5 represents an OH radical and R'6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, substituted or unsubstituted, that is, R'5 and R '6 together with the carbon atom that contains one of the following cycles.-
that is, R '5 and R's together form an oxo group, as well as their addition salts with the acids and bases. The subject of the invention is, very particularly, the compounds of formula (I) as well as their addition salts with the acids whose names are the following: -4-chloro-3-hydroxy-llβ- [4- [2- (diethylamino ) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-17-one, -4-chloro-3-hydroxy-llß- [4- [2- (l-piperidinyl) ethoxy] phenyl] estra -1, 3, 5 (10) -triene-17-one, -4-chloro-3-hydroxy-11- [4- [2- (1-pyrolidinyl) ethoxy] phenyl] estra-1, 3, 5 ( 10) -triene-17-one, -4-bromo-3-hydroxy-llß- [4- [2- (l-piperidinyl) ethoxy] phenyl] estra-1, 3, 5 (10) -triene-17- ona, -4-chloro-llß- [4- [2- (dimethylamino) ethoxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [ 4- [2- (diethylamino) ethoxy] phenyl] -estra- 1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- (l-piperidinyl) ethoxy] phenyl] -estra- 1, 3, 5 (10) -triene-3, 17beta-diol, -4-bromo-lys- [4-2- (l-piperidinyl) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] -estra- 1,3, 5 (10) -triene-3, 17 beta-diol, -4-chloro-llß- [4- [2- (diethylamino) ethoxy] phenyl] -19-nor- 17alpha-pregna- l, 3.5 (10) -triene-20-ino-3, 17beta-diol, -4-chloro-l, - [4- [3- (l-piperidinyl) propoxy] phenyl] -estra-1,3, 5 (10) -triene-3, 17 beta-diol, -4-chloro-llβ- [4- [4- (l-piperidinyl) butoxy] phenyl] -estra- 1, 3, 5 (10) -trieno- 3, 17beta-diol, -4-chloro-11β- [4- [5- (1-piperidinyl) pentyloxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -gamma acid lactone (17 alpha) -4-chloro-3, 17 beta-dihydroxy-llß- [4- [2- (diethylamino) ethoxy] phenyl] -19-nor-pregna-l, 3.5 (10) - trieno-21-carboxylic acid-gamma lactone (17alpha) -4-chloro-3,17-beta-dihydroxy-llß- [4- [2- (l-pyrolidinyl) ethoxy] phenyl] -19-nor-pregna -l, 3,5 (10) -triene-21-carboxylic acid gamma-lactone (17alpha) -4-chloro-3, 17beta-dihydroxy-llß- [4- [2- (l-piperidinyl) ethoxy] phenyl] -19-nor-pregna-l, 3,5 (10) -triene-21-carboxylic acid-gamma lactone (17alpha) -4-chloro-3, 17beta- dihydroxy-llß- [4- [3- (l-piperidinyl) ropoxy] phenyl] -19-nor-pregna-l, 3,5 (10) -triene-21-carboxylic acid-gamma lactone (17alpha) - 4-chloro-3, 17beta-dihydroxy-llβ- [4- [4- (l-piperidinyl) butoxy] phenyl] -19-nor-pregna-1, 3, 5, (10) -triene-21-carboxylic acid, -gamma lactone of the acid (17alpha) -4-chloro-3, I7beta-dihydroxy-llß- [4- [5- (l-piperidinyl) -tyloxy] -phenyl] -19-nor-pregna-l, 3.5 (10 ) -triene-2l-carboxylic acid, - (17beta) -4-chloro-llß- [4- [2- (diethylamino) ethoxy] phenyl] -spiro [estra-l, 3, 5 (10) -trieno-17, 2 '(5'H) furan] -3-ol, - (17beta) -4-chloro-l, - [4- [2- (l-piperidinyl) ethoxy] phenyl] -spiro [estra-1, 3, 5 (10) -triene-17, 2 '(5'H) furan] -3-ol, - (I7beta) -4-chloro-llß- [4- [2- (l-pyrolidinyl) ethoxy] phenyl] -spiro [estra -1, 3, 5 (10) -triene-17, 2 '(5'H) furan] -3-ol, - (17beta) -4-chloro-4', 5'-dihydro-llß- [4- [2- (1-piperidinyl) ethoxy] phenyl] -spiro [estra-1, 3, 5 (10) -triene-17, 2 '(3'H) furan] -3-ol, - (17beta) -4 -cloro-llß- [4- [3- (l -piperidinyl) propoxy] phenyl] spiro [estra-1, 3, 5 (10) -trieho-17, 2 '(5'H) -3-ol, - (17beta) -4-chloro-4 ', 5'-dihydro-llβ- [4- [3- (l-piperidinyl) propoxy] phenyl] -spiro [estra-1, 3, 5 (10) -triene -17, 2 '(3?) Furan] -3-ol, - (17beta) -4-chloro-llβ- [4- [4- (l-piperidinyl) butoxy] phenyl] -spiro [estra-1, 3 , 5 (10) -triene-17, 2 '(5'H) furan] -3-ol, - (I7beta) -4-chloro-4', 5'-dihydro-llß- [4- [4- ( l-piperidinyl) -butoxy] phenyl] spiro [estra-1, 3, 5 (10) -triene-17, 2 '(3'H) furan] -3-ol, -4-chloro-llß- [4- [2- (diethylamino) ethoxy] phenyl] -17alpha-methyl-estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-17alpha-methyl-11β- [4- [2 - (l-piperidinyl) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-3, 17beta-diol, -4-chloro-17alpha-methyl-11β- [4- [2- (l- pyrolidinyl) ethoxy] phenyl] estra-1, 3, 5 (10) -triene-3, 17beta-diol, -llβ- [4- [2- [2-asa-dicyclo (2.2.1) hept-2-il ] ethoxy] phenyl] -4-chloro-17alpha-methyl-estra-l, 3, 5 (10) -triene-3, 17beta-diol, -ll- [4-2- [2-asa-bicyclo (2.2. 1.) hept-2-yl] ethoxy] phenyl] -4-chloro-estra-1, 3,5 (10) -triene-3, 17beta-diol, -4-chloro -ll- [4- [2- [methyl (l-methylethyl) amino] ethoxy] phenyl] -estra-1, 3,5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [ 4- [2- (tetrahydro- (1H) -1,4-thiazino-4-yl), ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, - 4-Chloro-11β- [4- [2- [ethyl (propyl) amino] ethoxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-11- [4- [2- [ethyl (methyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2- [(1, 1-dimethyl-2-propynyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2 - [hexahydro-lH-azepino-1-yl) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- [ cyclohexyl (methyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-l, - [4- [2- [butyl (ethyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-lys- [4- [2- (azetidinyl) ethoxy] phenyl] -estra-1,3 , 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- [ethyl (2-prope nil) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-11- [4- [2- [cyclopentyl (methyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-l, - [4- [2- (dipropylamino) ethoxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-l, - [4- [2- (3-thiazolidinyl) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17 beta-diol, -4-chloro-l, - [4- [2- [ethyl (1-methylethyl) amino] ethoxy] phenyl] estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- [methyl (propyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-11β - [4- [2- [Butyl (methyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2 - [Methyl (2-propynyl) amino] ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-lys- [4- [2- (4- methyl-l-piperidinyl) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-lys- [4- [2- (l-piperidinyl) ethylthio] phenyl] -estra-1, 3, 5 (10) -trieno-3, 17beta-diol, -4-chloro-llß- [4- [2- (l-piperidinyl) ethylsulfinyl] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -acid 4- [4-chloro-llbeta- [4- [2- (diethylamino) ethoxy] phenyl]
17beta-hydroxy-estra-l, 3, 5 (10) -triene-3-yl-oxy] -butanoic acid, 4-chloro-3-hydroxy-llbeta- [4- [2- (l-piperidinyl)] oxime ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-17-one, -4- [[2- [4- (4-chloro-3, 17-beta-dihydroxy-estra-1, 3, 5 (10) -triene-llbeta-yl) phenoxy] ethyl] ethylamino] -butanoic acid. The invention also has, very particularly, the subject of the compound of formula (I) as indicated above, whose name is the following: -4-chloro-llß- [4- [2- (diethylamino) ethoxy] phenyl] - estra-1, 3, 5, (10) -triene-3, 17beta-diol, as well as their addition salts with the acids.
The subject of the invention is also a process for the preparation of compounds of general formula (I) as indicated above, characterized in that a compound of general formula (II) is subjected to:
in which D and R2 are as indicated above, R7 represents one of the following groupings:
in which n, Y, R3 and R4 are as indicated above, P is a protective group, Hal represents a halogen, to the action of a halogenation reagent to obtain the compound of formula (III):
which is subjected to the action of an aromatization reagent of cycle A, then to the action of a base to obtain the compound of formula (IV) corresponding to certain compounds of general formula (I):
compounds of formula (II), (III) or (IV) which are subjected if desired or necessary, in established order, to one or more of the following reactions:
-protection of compounds in which R7 is a group Ph-YH, deprotection of compounds in which R7 is a group Ph-YP, - action of a compound of formula Hal 1- (CH2) n-Hal2 on the compounds in the which R7 is a grouping -Ph-YH, Halx or Hal2, identical or different, which represent a halogen to obtain compounds in which R7 is a group -Ph-Y- (CH2) n-Hal2, - action of a compound of formula R3-NH-R4 on the compounds in which R7 is a grouping Ph-Y- (CH2) n-Hal2, to obtain compounds in which R7 is a grouping Ph-Y- (CH2) n-NR3R4, action of a halide salt (M-Hal3) on the compounds in which R7 is a grouping Ph-Y- (CH2) n-Hal2_ to obtain compounds in which R7 is a grouping -Ph-Y- (CH2) n-Hal3 , - protection of the OH grouping in position 3 or 17, - deprotection of the OH grouping in position 3 or 17, - alkylation of the OH grouping in position 3 or 17, - acylation ion of the OH grouping in position 3 or 17, - action of a reducing agent when D represents the remainder of a pentagonal cycle as indicated above and R5 and R6 together form an oxo-group, - action of an organometallic on the compounds of formula (IV) with D representing the remainder of a pentagonal cycle as described above and R5 and R6 together form an oxo group, - action of a lactonisation agent on the compounds of formula (IV) with D representing the remainder of a Pentagonal cycle as indicated above and R5 and R6 together form an oxo grouping, -action of a double bond reducing agent, when D represents the remainder of a pentagonal cycle as indicated above and R5 and R6 form together with the carbon containing them, a grouping O- (CH2) n. -CH = CH-, - action of a double-bond reducing agent, when D represents the remainder of a pentagonal cycle as indicated above, and R6 is an alkenyl or alkynyl radical containing from 2 to 6 carbon atoms, halogenation in position 4, then aromatization of cycle A, of the compound of general formula (II), aromatization of cycle A of the compound of formula (III),
- salification. The action of a halogenation reagent such as N-bromosuccinimide or N-chlorosuccinimide on the compounds of formula (II) is carried out mainly in the presence of a bipolar aprotic solvent such as dimethylformamide. The aromatization reaction that follows after the saponification reaction (action of the base) is carried out according to the known methods such as those described in European patent 0097572. A mixture of acetic anhydride and acetyl bromide is preferably used. as an aromatization agent, then a base such as soda in methanol as a saponification agent. The protection and deprotection reactions are methods known to a person skilled in the art. A fairly complete information is found in the following work: Protective groups in organic synthesis. T.W. Greene, John Wiley &; Sons (1981). The protective group P preferably represents an alkyl radical containing from 1 to 4 carbon atoms, a benzyl group, a group RcRDRESi, in which Rc, RD and RE, identical or different, independently of one another, represent , each one, an alkyl radical containing from 1 to 4 carbon atoms or a phenyl group. It is, very particularly, groupings Si (Me) 2CMe3 or -Si (Ph) 2CMe3. By way of example, the deprotection reactions of compounds of formula (II), (III) or (IV) with R7 = Ph-0P or of compounds of formula (IV) where 3 -OH is protected (3-OP) , when P is a methyl radical, they can be carried out by the action of tribromoborane in dichloromethane or hydrochloric acid in pyridine; the deprotection reactions when P is a benzyl group can be carried out by the action of hydrogen in the presence of palladium on carbon in ethyl acetate or by the action of trifluoroacetic acid, the deprotection reactions when P is a tertbutyldiphenylsilyl group can be carried out by the action of fluoride of tetrabutyl ammonium in solution in tetrahydrofuran.
When P is a tetrahydropyranyl group, the deprotection is carried out in the presence of an aqueous acid in an alcohol solvent and, preferably, by the action of hydrochloric acid in methanol. The action of a compound of formula Hal-L- (CH 2) n-Hal 2 on a compound of formula (II), (III) or (IV) in which R 7 = Ph-YH can be carried out, mainly, when Y = 0 , in the presence of a base in a solvent such as acetone. The action of a compound of formula R3-NH-R4 on the compounds in which R7 is a grouping Ph-Y- (CH2) n-Hal2 in the classical conditions of nucleophilic substitutions, mainly in the presence of an aprotic solvent such as tetrahydrofuran. The substitution reaction of one halogen for another when R7 is mainly a group Ph-Y- (CH2) n-Cl is preferably carried out by Nal in methyl ethyl ketone. The alkylation or acylation reactions of the OH group in position 3 or 17 are carried out by the classical methods known to those skilled in the art. The reduction of the corresponding 17-keto in alcohol (R5 = 0H and R6 = H) is carried out according to the conventional methods, mainly by the action of an alkaline borohydride such as sodium borohydride in methanol or ethanol or by the action of aluminum and lithium tetrahydride. The action of an organometallic on 17-keto allows to have access to the products of formula (IV) in which
D represents the remainder of a pentagonal cycle as indicated above, R5 is a hydroxyl and R6 represents an alkyl radical, alkenyl, optionally substituted alguinyl. The organometallic derived from an alkyl, alkenyl or alkynyl is selected from the magnesia of the formula AlkMgHal and the lithium of the formula AlkLi in which Alk represents an alkyl, alkenyl or alkynyl group containing at most 8 carbon atoms, Hal represents an atom of halogen. In a preferred embodiment of the process, Hal represents a chlorine, bromine or iodine atom; preferably of bromine. Preferably, the reaction takes place in the presence of cerium chloride. In a preferred embodiment of the process, Hal represents a chlorine, bromine or iodine atom, preferably bromine. The lactonisation reaction from 17-keto is carried out according to the method of STURTZ (ref.:G. STURTZ and J. J, YAOUANC, Syntesis, (1980, p.289) mainly in the presence of alkyl bisdimethylamidophosphate in The presence of an alkyllithium such as n-butyllithium in tetrahydrofuran The total or partial reduction reaction when Rg is an alkenyl or alkynyl radical or when R5 and R6 together with the carbon containing them form an O- (CH2) m 'group -CH = CH-, can be carried out either completely by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson's reagent or partially (alkynyl becomes alkenyl) by action of a poisoned catalyst such as palladium on barium sulfate poisoned by pyridine or triethylamine.The esterification and salification reactions are carried out by common methods known to those skilled in the art. and, more particularly, by object, a process for the preparation of compounds of general formula (I ') as indicated above, is characterized in that it exposes a compound of general formula
in which R '? and R'fi are as indicated above, R'7 represents:
to the action of a halogenation reagent to obtain the compound of formula (III):
which is subjected to the action of an aromatization reagent of cycle A, then to the action of a base to obtain the compound of formula (IV) corresponding to certain compounds of general formula (I '):
s
(IV)
compounds of formula (II '), (III') or (IV) which are subjected, if desired and if necessary, in the order indicated to one or more following reactions: protection of compounds in which R'-, is a grouping -Ph-OH, deprotection of compounds in which R'7 is a grouping Ph-OP, - action of a compound of formula Hal ^ (CH2) n-Hal2 on the compounds in which R'7 is a grouping -h-OH, Halx or Hal2 _ identical or different, representing a halogen to obtain compounds in which R7 is a group -Ph-O- (CH2) n-Hal2, - action of a compound of formula R'3 -NH-R'4 on the compounds in which R'7 is a grouping Ph-0- (CH2) n-Hal2, to obtain compounds in which R'7 is a grouping Ph-O- (CH2) n- NR '3R' 4, action of a halide salt (M-Hal3) on the compounds in which R'7 is a grouping Ph-O- (CH2) n-Hal2 to obtain compounds in which R7 is a grouping - Ph-O- (CH2) n-Hal3, - protection of the OH grouping in position 3 or 17, - deprotection of the OH grouping in position 3 or 17,
- alkylation of the OH group in position 17, - acylation of the OH group in position 17, - action of a reducing agent when R'5 and R'6 together form an oxo group, action of an organometallic on the compounds of formula (IV ) with R'5 and R'6 forming together an oxo group, - action of a lactonizing agent on the compounds of formula (IV) with R'5 and R'6 together forming an oxo group, - action of an agent of reduction of double bond when R'5 and R'6 form together with the carbon containing them a grouping O- (CH2) x. -CH = CH-, - action of a double-bond reducing agent when R'6 is an alkenyl or alkenyl radical containing from 2 to 6 carbon atoms, - halogenation in position 4, then aromatization of cycle A, of the compound of formula (II '), - aromatization of the compound of formula (III'), - salification. The compounds of the general formula (I) as well as their addition salts with the pharmaceutically acceptable acids have estrogenic, antiestrogenic and antiproliferative activities. To this title, the compounds of formula (I) can be used in the treatment of disorders related to a hypofoliculin, for example, amenorrhea, dysmenorrhoea, repeated abortions, premenstrual disorders, in the treatment of certain estrogen-dependent pathologies such such as adenomas or prostatic carcinomas, mammary carcinomas and their metastases or in the treatment of benign breast tumors, as anti-uterotrophic, as well as, in the replacement treatment of menopause and perimenopause. Symptoms and the consequences related to menopause are understood more precisely as hot flashes, sweats, atrophy and vaginal safety, urinary symptoms and, in the long term, a decrease in bone mass and an increased risk of fracture, as well as the loss of cardio-vascular protection provided by estrogen. In particular, the compounds of formula (I) as well as their addition salts with the pharmaceutically acceptable acids or bases can thus be used in the prevention or treatment of osteoporosis. The compounds of formula (I) as well as their addition salts with the pharmaceutically acceptable acids or bases can also be used in the prevention or treatment of osteoporosis in man. They can also be used in the prevention or treatment of secondary osteoporosis (eg, cortisone, related to immobilization).
The compounds of formula (I) as well as their addition salts with the pharmaceutically acceptable acids or bases possess mainly a dissociated estrogenic activity. Dissociated estrogenic activity means an estrogenic activity at the bone level that manifests itself only in a minimal activity at the uterine level, thus causing the absence of endometrial proliferation (activity much lower than that of estradiol). In addition, the compounds according to the invention have the following advantages: - They have an antiestrogenic activity at the breast level. Unlike estradiol, they do not stimulate the growth of human mammary tumor cells and can also inhibit their growth. The compounds according to the invention are thus particularly advantageous for the treatment of menopause with respect to women predisposed to breast cancer (family history) who are exempt from an estradiol replacement treatment. - They can also be used in the treatment of breast cancers. They favor a decrease in serum cholesterol levels to a level equivalent to that imposed by estradiol. They reinforce cardiovascular protection. Finally, the compounds according to the invention do not exhibit any estrogenic activity at the uterine level, nor do they need to be administered in association with any progestomimetic compound. The invention then has as its object the compounds of formula (I), as well as its addition salts with the acids or pharmaceutically acceptable bases as medicines. The subject of the invention is, more particularly, the compounds of formula (I), as well as their addition salts with pharmaceutically acceptable acids or bases, as medicaments for the prevention or treatment of osteoporosis. The invention extends to pharmaceutical compositions containing as active principle at least one of the drugs indicated above. The compounds of formula (I) are used by the digestive, parenteral or local route, for example, percutaneously. They can be supplied in the form of simple tablets or dragees, capsules, granules, suppositories, ovules, injectable preparations, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, which are prepared according to the usual methods.
The active ingredient (s) may be incorporated in the excipients commonly used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa oil, aqueous or non-aqueous vehicles, Fatty bodies of animal or vegetable origin, loe derivatives - paraffinic, glycols, various wetting agents, dieters or emulsifiers and preservatives. The useful dosage varies depending on the condition to be treated and the route of administration, - it can vary, for example, from 1 to 1000 mg per day for the adult orally. The compounds of general formula (II) or (II ') are known compounds and described in the following patent: European patent 0057115. The compounds of general formula (II) or (II') with
or R 'Hal can also be formed from compounds of formula (lia): wherein (II1 a)
in which D, R2, R'5 and R'6 are as indicated above and K represents a protective group of the ketone function, which subjects them to the action of an O-alkylation reagent of the formula Hal- (SH2) ) n-Hal, then to the action of a dehydration reagent equally capable of releasing the ketone. The compounds of formula (lia) or (II 'a) are likewise known compounds and are described in the following patent: Brevet US No. 5 043 332. The invention also has the object, as intermediates, of the compounds of formula (III), (III '), (IV) and (IV). The following examples illustrate the invention without limiting it at any time. Solvents described in the examples: AcOEt (ethyl acetate), TEA (triethylamine), CH2C12 (dichloromethane), CHC13 (chloroform), MeOH (methanol), NH4OH (ammonium hydroxide), iPrOH (isopropyl alcohol).
EXAMPLE 1: 4-chloro-3-hydroxy-llbeta- [4- [2- (1-piperidinyl) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-17-one Phase A: llbeta- [4- (2-bromoethoxy) phenyl] -estra-4,9-diene-3,17-dione a) O-alkylation 8.0 g of cyclic 3- (1,2-ethanediyl acetal) are dissolved under an inert atmosphere of 5α-hydroxy-11β- (4-hydroxy-phenyl) -pht-9-ene-3, 17-dione in 80 ml of 1,2-dibromomethane of 99%, 21 ml of 50% soda, 0.800 g of tetrabutyl ammonium bromide and stir at reflux for 1 hour, b) acid hydrolysis 93 ml of acid are added at room temperature
6M hydrochloric acid, stirred for 45 minutes, extracted, washed, dried and evaporated under reduced pressure to obtain the crude product (m = 13.17 g) which was recrystallized from a mixture of 50 ml of dichloromethane / 50 ml of isopropyl ether. 5.96 g + 7.0 g of pure expected product are obtained (Rf CH2CL2 / AcOEt 79/30 = 0.45). F = 208 ° C. IR (CHCL3) 1735 cm "1: 17 keto, 1658 and 1609 cm" 1: conjugated ketone, -1583 and 1509: aromatic. Phase B .- llbeta- [4- (2-bromoethoxy) phenyl] -4-chloro-estra-4-diene-3, 17-dione (introduction of Cl in position 4) To a solution, under inert atmosphere, at 60 ° C, of 5.025 g of the product obtained in phase A, in 67 ml of dimethylformamide, 1.86 g of N-chlorosuccinimide is added and stirred for 10 minutes. The salt water is added, extracted, dried and evaporated under reduced pressure to obtain the crude product (m = 8.149 g) which is purified by chromatography on silica by fixing with a cycloexan / ethyl acetate mixture (60/40), 5.43 g of the expected pure product are obtained (Rf: essence G / ACOEt 60/40 = 0.35). IR (CHC13) 1736 cm "1: 17 keto, -1677 cm" 1: conjugated ketone; 1609, 1582.1550 and 1509 cm "1: C = C and aromatic, Phase C: llbeta- [4- (2-bromoethoxy) phenyl] -4-chloro-3-hydroxy-estra-l, 3, 5 (10 ) triena-17-ono (aromatization of cycle A) a) Aromatization To a solution, under inert atmosphere, at room temperature of 4.7 g of the product obtained in phase B, in 50 ml of dichloromethane / siliporite, everything is added cooled, 4.7 ml of acetic anhydride and 4.7 ml of acetyl bromide and stirred for 5 hours 30 minutes b) Saponification of phenolic acetate After evaporation under reduced pressure of dichloromethane at room temperature, all of which is cooled, under an inert atmosphere, 47 ml of tetrahydrofuran, 47 ml of methanol, then 47 ml of soda are added and stirred for 1 hour at room temperature. After acidification with hydrochloric acid, they are extracted, washed, dried and evaporated under reduced pressure to obtain the crude product (m = 4.84 g) which is purified by chromatography on silica by fixing with a cycloexan / acetate mixture. of ethyl (70/30). 4.37 g of the expected product are obtained (Rf = essence G / ACOEt 70/30 = "?, 18).
IR (CHC1, 3537 cm: OH-phenolic; 1733 cm 17 -short;
1609.1580.1511 and 1481 cm "-i ': aromatic, Phase D: 4-chloro-3-hydroxy-llbeta- [4- (2-iodoethoxy) phenyl] -estra-l, 3, 5 (10) triene -17-one (iodination) To a solution of inert atmosphere, at room temperature, of 4.11 g of the brominated derivative prepared in step C in 80 ml of methylethyl ketone, 2.44 g of sodium iodide are added. and the mixture is stirred under reflux for 1 night, water is added, the mixture is extracted, dried and evaporated under reduced pressure to obtain 4.184 g of the expected crude product (Rf = methanol / water (90/10) = 0.30). Phase E: 4-chloro-3-hydroxy-llbeta- [4- [2- (piperidinyl) ethoxy] phenyl] -estra-1,3,5 (10) thieno-17-one (replacement of iodine with piperidine) Dissolve, under an inert atmosphere, at room temperature, 1,248 g of the iodinated derivative obtained in phase D, in 25 ml of tetrahydrofuran / siliporite, add 1.35 ml of piperidine and heat at reflux for 1 hour 30 minutes. of the evaporation of tetrahydrofuran under reduced pressure to At room temperature, the water and ethyl acetate are added, washed, dried and evaporated under reduced pressure to obtain 1.185 g of crude amine derivative which is purified by chromatography on silica, fixing with the mixture ethyl acetate / triethylamine. /5. 1.039 g of the expected pure product are obtained (Rf = ethyl acetate / TEA (95/5) = 0.20).
NMR CDC13 0.45 ppm (s): CH3 in 18, -2.48 ppm: cyclic CH2-N, 2.71 ppm (t): CH2-N in the chain, -3.99 ppm (t): CH2 -0Ar; 3.99 ppm: H1X; 6.63 ppm: H2; 6.81 ppm: Hx; 6.60 ppm: Ar-0;
6, 91 ppm: Ar-C. EXAMPLE 2: 4-chloro-3-hydroxy-libe a- [4- [2- (1-pyrrolidinyl) ethoxy] phenyl] -estra-1,3,5 (10) -triene-17 -one The procedure is as follows: Example 1, phase E, but from 6 g of the iodinated derivative obtained in phase D of example 1, 60 ml of tetrahydrofuran / siliporite and 4.6 ml of pyrolidine. 4.2 g of expected pure product are obtained (Rf: ACOEt / TEA (80/20) = 0.24). NMR (CDC13): 0.45 ppm (s): CH3 in 18, -1.78 ppm (m): CH2 in N beta;
2.59 ppm (m): CH2 in N alpha; 2.84 ppm (t): CH2-N of the chain, -3.98 ppm (t): CH2-OAr, -3.98 ppm (t) Hp CH, -0 of the chain; 6.62 ppm: H2; 6.81 ppm: HX, - 6.62 ppm: Ar-0; 6.91 ppm: Ar-C. EXAMPLE 3: 4-chloro-3-hydroxy-libe a- [4- [2-diethylamino) ethoxy] phenyl [-estra-1, 3, 5 (10) -triene-17 -one The procedure is as in the example 1, in phase E, but from 1.2 g of the iodinated derivative obtained in phase D of example 1, 25 ml of tetrahydrofuran / silymporite and 1 ml of diethylamine. 0.688 g of the expected pure product is obtained (Rf: ACOEt / TEA (95/5 = 0.22). NMR (CDC13): 0.45 ppm (s) CH3 in 18; 1.03 ppm (t): '2 , 60 ppm (q) N-CH, - CH, 2.81 ppm (t¡ CH.-N of the chain, 3.93 ppm (t) CH2-0Ar, - 4.00 ppm (t) H 11 6 , 63 ppm: H2, 6.82 ppm: HL, 6.63 ppm: Ar-0, 6.91 ppm: Ar-C EXAMPLE 4 4-bromo-3-t-idroxy-llbeta- [4- [2 - (1-piperidinyl) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-17 -one Phase A: llbeta- [4- (2-chloroethoxy) phenyl] estra-4, 9-diene- 3, 17-dione (O-alkylation) To a suspension of 5 g of llbeta- (4-hydroxyphenyl) -estra-4, 9-diene-3, 17-dione, in 50 m of acetone, are added
(7.9 ml x 2) of l-bromo-2-chloroethane, followed by 6 ml of 50% soda and 500 mg of tetrabutylammonium bromide. The mixture is held for 4 hours under reflux. The water is added, extracted, dried and evaporated under reduced pressure until a crude product is obtained which is purified in the ether. 5.45 g of expected product are obtained (Rf: CH2Cl2 / acetone 90/10 = 0.82). NMR (CDC13).
0.58 3H (S): CH3 in 18; 3.80 2H (t). CH2C1; 4.28 2H (t): CH20; 4.49 1H (d): Hlx; 5.80 1H (e): H4; 6.82 2H (d): 2H arom. , - 7.08 2H (d): H arom. Phase B: 4-bromo-llbeta- [4- (2-chloroethoxy) phenyl] tetra-4,9-diene-3,17-dione (introduction of Br in batch 4) At a suspension of 5.35 g of the product from phase A in 70 g of dimethylformamide, under a nitrogen atmosphere, a solution of 2.43 g of NBromo succinimide is added. After stirring for 2 hours at room temperature, 200 ml of ethyl acetate and 400 ml of saturated NaCl water are added, the mixture is extracted, washed, washed and evaporated under reduced pressure to obtain 8 g of the crude product. purify by chromatography with dichloromethane / acetone 98/2. 4.66 g of expected pure product are obtained. (Rf CH2Cl2 / acetone 95/5 = 0.92). NMR (CDC13): 0.57 3H (s): CH3 in 18; 3.25 1H (dt): H6; 3.80 2H (t): CH_2C1; 4.20 2H (t): Cf. 20; 4.38 1H (d, long): HX1; 7.07 and 6.83 4H: AA'BB 'H arom. Phase C: 4-bromo-llbeta- [4- (2-chloroethoxy) phenyl] -3-hydroxy-tetra-1,3,5 (10) -triene-17-one (aromatization of cycle A) The procedure is as follows: in phase C of example 1, from 4.5 g of product obtained in the previous phase. 3.05 g of expected product are obtained. (Rf CH2Cl2 / AC0Et 90/10 = 0.64). NMR (CDC13): 0.45 3H (s): CH3 in 18; 3.75 2H (t): CH2C1; 4.12 2H (t): CH20; 4.00 1H (t): HX1; 5.48 1H (s): OH; 6.93 and 6.64 2H: AA'BB '4H arom.; 6.85 and 6.64 2H (d): HjH2. Step D: 4-bromo-3-hydroxy-llbeta- [4- (-2-iodo-ethoxy) phenyl] -estra-1,3,5 (10) -triene-17-one (iodination). The procedure is as in phase D of example 1, starting from 1 g of the expected product. 1.14 g of expected product are obtained. Phase E: 4-bromo-3-hydroxy-llbeta- [4 [2- (1-piperidinyl) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-17-one (substitution of iodine for piperidine) The procedure is as in phase E of example 1 starting from 1.1 g of product obtained in the previous phase. 270 mg of expected pure product are obtained (Rf ACOEt / TEA 90/10 = 0.43). NMR (CDC13): 0.45 3H (S): CH3 in 18; 2.47 4H (m): cyclic CH2N; 2.70 2H (t): Cg2-N; 3.98 2H (t): CH20; 3.98 1H (long t): HX1; 6.88 and 6.62 2H (d): Hx and H2; 6.90 and 6.62 4H.-AA'BB 'H aromatic.
EXAMPLE 4-chloro-llbeta- [4- [3- (1-piperidinyl) ropoxy] phenyl] -estra-1, 3, 5 (10) -triene-3, 17-beta-diol Phase A: 4-chloro- llbeta- [4- (phenylmethoxy) phenyl] -estra-4,9-diene-3,17-dione (chlorination in 4) To a solution, under an inert atmosphere, at 60 ° C, of 13.6 g of llß- [4- (phenylmethoxy) phenyl) -estra-4,9-diene-3,17-dione in 120 ml of dimethylformamide, add 5.295 g of N-chlorosuccinimide, stir for 10 minutes, then strain into an aqueous solution saturated NaCl, extracted, washed, dried and evaporated under reduced pressure until obtaining the crude product (m = 19,128 g). A second test is carried out, the crude product is combined and purified by chromatography with 30/70 ethyl-cycloexan acetate mixture. 23.28 g of expected pure product are obtained. (Rf ACOEt / cycloexan 30/70 = 0.19). NMR (CDC13): 0.58 (s). CH3 at 18; 3.25 (dt): equatorial 1H H6; 4.39 (di): Hn; 5.02 (S): CH2Ph; 6.89: H in Ph-O ortho; 7.06: H in Ph-O target, - 7.45: aromatic H of CH2-Ph. Step B: 4-chloro-3- [[(2,2-dimethylethyl) (diphenyl) silyl] oxy] ll-beta- [4- (phenylmethoxy) phenyl] -estra-1,3,5 (10) -triene -17-ono (aromatization / saponification / blogging of phenol) a) aromatization and saponification The procedure is as in phase C of example 1 starting from the product obtained in the previous phase. 13.5 g of expected pure product (3 -OH) are obtained. b) blocking of phenol 13.5 g + 5.6 g of product obtained in the previous phase, 191 ml of dichloromethane / siliporite, 14.5 ml of terbutyl diphenyl chlorosilane and 258 mg of 4-DMAP are dissolved under inert atmosphere. , and stir for 23 hours at reflux. They are immediately poured into the water, extracted, washed, dried and evaporated under reduced pressure to obtain 41,322 g of crude product in the form of an oil which is purified by chromatography with ethyl acetate / petroleum ether 20 / 80, then 40/60. 1.275 g of expected pure product are obtained. (Rf ACOEt / petroleum ether 20/80 = 0.27). NMR (CDC13): 0.42 (S): CH3 in 18; 1,11 (s): C (CH 3) 3; from 7.25 to 7.40-from 7.60 to 7.75 Si-Ph; 3.85 (t): H12.; 4.94 (s): CH2-Ph; 6.65: H in ortho (Ph-O), -6.84: H in para (Ph-O), -6.17 (d): Hx; 6.47 (d): H2. Stage C .- 4-Chloro-3- [[(2,2-dimethylethyl) (diphenyl) silyl] oxy] [11-beta- [4- (hydroxyphenyl) -estra-1,3,5 (10) -triene -17-ono (deprotection (debenzylation)) 20.82 g of the product obtained in the previous step in 420 ml of methanol, 15.6 g of palladium hydroxide are added to a suepeneion under an inert atmosphere at room temperature. magnesia and 40 ml of 1,4-cyclohexadiene, then maintained at reflux for 8 hours. After filtering and evaporating under reduced pressure, 22 g of crude product are obtained which is purified by chromatography with a cyclohexane / ethyl acetate 7/3 mixture. They - get 19.4 g of expected pure product. (Rf cyclohexane / ACOEt 7/3 = 0.27). NMR (CDC13): 0.42 (s): CH3 in 18; 1,11 (s): C (CH 3) 3; 3.83 (ti): H12; 4.56 (s): OH; 6.17 (d) - 6.46 (d): HX, H2; from 7.25 to 7.43 (m) 6H and 7.64 (m) 4H: SiPh2. Step D .- 4-Chloro-3- [[(2,2-dimethylethyl) (diphenyl) silyl] oxy] 11-beta- [4- (3-iodopropoxy) phenyl] -estra-1, 3, 5 (10 ) -triene-17-one (O-alkylation) 3.18 g of the product obtained in the previous phase, 15 ml of 1,3-diodopropane, 800 mg of ground soda and 300 mg are mixed for 4 hours at room temperature. of tetrabutylammonium bromide, acidified by 2N hydrochloric acid, extracted, washed, dried and evaporated under reduced pressure to obtain the crude product (39.8 g) which is purified by chromatography by fixing with the petroleum ether mixture. ACOEt 75/25. 2.43 g of expected pure product are obtained. (Rf: petroleum ether / ACOEt 80/20 = 0.3).
NMR (CDCl 3) 0.41 (s) CH 3 in 18; 1.10 (s) C (CH3) 3.34 (t) 0-CH2-CH2-CH2-I; 3.85 (ti i H-; 3.91 (t): O-CH2-CH2-CH2-I; 6.16 (d) -6.46 (d): Hlf H2: from 7.25 to 7, 45 6H and 7.66 4H: SiPh2 Phase E: 4-chloro-3- [[(2,2-dimethylethyl) (diphenyl) silyl] oxy] 11-beta- [4- [3- (l-piperidinyl) propoxy] phenyl] -estra- 1, 3, 5 (10) -triene-17-one (substitution of iodine for piperidine) The procedure of the product obtained in the previous stage is carried out as in phase E of example 1. obtain 2.07 g of the expected pure product (Rf .- ACOEt / TEA 98/2 = 0.23).
NMR (CDC13): 0.42 (S): CHj in 18; 1.10 (s): C (CH3) 3; 2.52: cyclic CH2-N, - 2.83: CH2N of the chain; 3.84 (ti): Hxl; 3.88
(t): CH2-0; 6.16 (D) -6.47 (D): Hx, H2; 6.56 -6.80: Ph-0;
7.25-7.40 6H and 7.65 4H: SiPh2. Phase F: 4-chloro-llbeta- [4- [3- (l-piperidinyl) propoxy] phenyl] -estra-1, 3, 5 (10) -triene-3,17-beta-diol (17-keto reduction) and protection) a) Reduction of 17-keto To a solution under inert gas at room temperature of 600 mg of the product obtained in the previous step in 4 ml of methanol and 2 ml of tetrahydrofuran are added, all cooled to an ice bath, 63 sodium borohydride mg of 97% and stirred for 50 minutes. The ethyl acetate is added, washed in the salt water, dried and evaporated under reduced pressure to obtain 614 mg of the expected crude product. b) Deprotection of phenol in 3 A solution under inert gas at room temperature of 614 mg of the product obtained above in 6 ml of tetrahydrofuran is added 1.6 ml of a solution of tetrabutyl ammonium fluoride to tetrahydrofuran and stirred for 50 minutes at room temperature. It is poured into water, extracted, washed, dried and evaporated under reduced pressure to obtain 840 mg of crude product which is purified by chromatography with dichloroethane / methanol / ammonium hydroxyl 90/10/1. 215 g of expected pure product are obtained. (Rf: CH 2 Cl 2 / MeOH / NH 4 OH 90/10/1 = 0.3). NMR (CDC13): 0.38 (S): CH3 in 18; 2.45 (m): CH2 / N; 3.72 (t): H17; 3.86: HX1, CH2-0; 6.61-6.93: Ph-O; 6.61-6.75: Hl t H2. EXAMPLE 6: 4-Chloro-llbeta- [4- [4- (l-piperidinyl) butoxy] phenyl] -es-1,3, 5 (10) -triene-3, 17-beta-diol It is from the In the same manner as in Example 5, the O-alkylation can be carried out: either with 4-chloro-l-butanol, by the reaction of
"Mitsunobu" in the presence of triphenylphosphine, diethylazodi-carboxylate in the tetrahydrofuran and the chlorinated product obtained is transformed into an iodinated product according to the procedure indicated in example 1 of phase D, that is by means of direct action with the 1, 4-diiodobutane (cf ex.6). 189 mg of expected pure product are obtained (Rf CH2CL2 / MeOH / NH4OH 90/10/1 = 0.24). EXAMPLE 7 4-Chloro-llbeta- [4- [5- (l-piperidinyl) pentyloxy] phenyl] -estra-1, 3, 5, (10) -triene-3,17-beta-diol The procedure is as follows: Example 5, the O-alkylation is carried out with the 1,5-diiodopentane. 125 mg of expected pure product are obtained. (Rf CH2Cl2 / MeOH / NH4OH 90/10/1 = 0.30). EXAMPLE 8 (17beta) 4-chloro-llbeta- [4- [2 - (1-piperidinyl) ethoxy] phenyl] -spiro- [estra-1, 3, 5 (10) -trieno-17,2 '(5' H) furan] -3-ol Phase A: (I7beta) 4-chloro-llbeta- (4-hydroxyphenyl) spiro- [estra-4, 9-diene-17, 2 '(5?) -furan] -3- No (chlorination) To a 19.16 g (17beta) -llbeta- (4-hydroxy phenyl) -spiro- [estra-4, 9-diene-17, 2 '(5?) -furan] -3-suepeneion. -no (WO 87/05908) in 100 ml of dimethylformamide, under an inert atmosphere, at 60 ° C., add 4.51 g of N-chloro succinimide and allow it to react for 10 minutes under stirring. An ice-cold solution of sodium chloride was then poured off and evaporated under reduced pressure to obtain 20.85 g of crude product. Add 8.93 g of product obtained in an annexed test carried out in the same way that the original and ee purify the whole by chromatography fixing with a mixture CH2CL2 / acetone 95/5, then recrystallized in ethyl ether. 0.98 g of expected pure product is obtained. (Rf CH2Cl2 / acetone 95/5 = 0.2). F = 258 ° C. Phase B: (I7beta) -4-chloro-llbeta- [4- (2-bromoethoxy) phenyl] -. Spiro- [estra-4, 9-diene-17, 2 '(5?) Furan] -3 -non The procedure is as in Example 1 of phase A, but from 1,2-dibromoethane. 5.34 g of expected pure product are obtained. (Rf essence G / ACOEt 75/25 = 0.21). Phase C: Aromatization and saponification Phase D: Ioduration Phase E: Piperidine condensation Phases C, D and E are carried out analogously to phases C, D and E of example 1. 0.57 g of expected pure product is obtained ( Rf ACOEt / TEA 92/8 = 0.21). NMR (CDC13): 0.48 (s): CH3 in 18; 2.47 (m): cyclic CH2-N; 2.70 (t): CH2-N chain, -3.89 (ti). H117- 3.99 (t): CH2-0 chain; 4.56: CH2-0 cycle; 5.87: H'3, H'4; 6.60 - 6.80: Hx and H2; 6.60 - 6.86: Ph-O.
EXAMPLE (17beta) 4-chloro-llbeta- [4- [2- (diethylamino) ethoxy] phenyl] -spiro- [estra-1, 3, 5, (10) -triene-17,2 '(5?) Furan ] -3-ol The procedure is as in Example 8, but with final condensation of diethylamine on the iodinated derivative. 0.512 g of expected pure product is obtained (Rf CH2Cl2 / MeOH / NH4OH 33/7 / 0.2 = 0.29). NMR (CDC13): 0.48 (S): CH3 in 18; 1.03 (t): CH2-CH3; 2.60 (q): CH.¬
CH, 2.81 (t): CH2-N; 3.89 (ti) H 11 3.93 (t; CH2-0 chain; 4.56: CH2-0 cycle (H'3); 5.87: H3, H4; 6.61-6 , 79: H2 and H2; 6.61 - 6.86: Ph-O. EXAMPLE 10: (17beta) 4-chloro-llbeta- [4- [2 - (l-pyrolidinyl) ethoxy] phenyl] -spiro- [ is tra-2, 3, 5 (10) -triene- 17, 2 '(5?) furan] -3-ol The procedure is as in Example 8, but with the final condensation of pyrolidine on the iodinated derivative. obtain 0.628 g of expected product F = 226-227 ° C (Rf CH2Cl2 / MeOH / NH4OH 93/7 / 0.2 = 0.25). NMR (CDCl3): 0.48 (s): 'CH3 in 18, 2.59 (): cyclic CH2-N, 2.80 (m): CH2-N chain, 4.56 (m): cyclic CH2-0 (H'5), -5.87 (m): H'3 / H'4; 6.60 - 6.78 (d): Hj. And H2; 6.60 - 6.86 AA'BB ': Ph-O.
EXAMPLE 11: (17beta) 4-chloro-llbeta- [4- [3- (l-piperidinyl) propoxy] phenyl] -spiro- [estra-1, 3, 5 (10) -triene-17,2 * (5 »H) furan] -3-ol The procedure is as in Example 8, O-alkylation is carried out directly with 1,3-diiodopropane (it avoids phase D of Example 8). 0.591 g of pure expected product is obtained (Rf ACOEt / TEA 92/8 = 0.19). NMR (CDCL3). 0.48 (s): CH3 in 18, - from 2.30 to 2.50: CH2-N; 3.87 (m) CH2-0 chain, Hn 4.56: CH2-0 cycle (H's); 5.88: H'3, H'4
; 6.61-6.79; H- ,. and H2; 6.61 - 6.86: Ph-O. EXAMPLE 12: (17beta) 4-chloro-llbeta- [4- [4- (l-piperidinyl) butoxy] phenyl] -spiro- [estra-1, 3,5 (10) -triene-17, 2"(5 'H) furan] -3-ol Proceed as in example 8, phases A, B, C, D,
The O-alkylation is carried out with l-bromo-4-chlorobutane. 0.494 g of pure product is obtained. Rf ACOEt / TEA 95/5 = 0.22 F = 154 ° C NMR (CDC13): 0.50 (s): CH3 in 18; 2.36 (6H) .- CH2-N cycle, chain;
3.85 (t) CH, -0 3.89 (t) H 11 4.57 (s) CH, -0 cyclic
(H'5); 6.60 (m) (3H) -6.86 (m) (2H): Ph-O and H2, -6.79 (d): H, EXAMPLE 13 4-chloro-3-hydroxy-llbeta- [4 - [2- (1-dimethyl-adamone) ethoxy] phenyl] -estra-1, 3, 5 (10) -triene-17 -one Phase A: 4-chloro-llbeta- [4- [2- (dimethylamino) ethoxy] phenyl] - estra-4,9-diene-3,17-dione (introduction of 4-chloro) To a solution under inert atmosphere, at room temperature, of 1.08 g of llß- [4- (2 - dimethylamino) ethoxy) -.phenyl] -estra-4,9-diene-3,17-dione in 11 ml of pyridine, add 6 ml of 10% sulfuryl chloride to dichloromethane and stir for 30 minutes at room temperature. or menoe of -36 ° C. They are poured onto the sodium bicarbonate, extracted, washed, dried and evaporated under reduced pressure to obtain 1.84 g of c product which is purified by chromatography, fixing ethyl acetate / triethylamine 80/20 with the mixture. 616 mg of expected pure product are obtained. (Rf ACOEt / TEA 8/2 = 0.35). Phase B: 4-chloro-llbeta- [4- [2- (dimethylamino) ethoxy] phenyl] -3-hydroxy-estra-1, 3, 5 (10) -triene-17-one (aromatization and saponification) The reaction of aromatization, then that of saponification are carried out as in Example 1, phase C, from 700 mg of the product obtained in the previous phase. 360 mg of expected pure product are obtained. F = 254 ° C (Rf CH 2 Cl 2 / iPrOH / NH 4 OH 93/7 / 0.7 = 0.18). NMR (CDC13): 0.44 (S). CH3 at 18; 2.30 (s): NMe2; 2.67"" (m): CH2-N;
3.94 (m): CH2-0; 4.00: Hu; 6.62-6.91: Ph-O; 6.62 -6.81 (d): H1 # H2. The compound of Example 3 is prepared in the same manner. EXAMPLE 14 4-chloro-3, 17beta-dihydroxy-llbeta- [4- [2- (l-pyrolidinyl) ethoxy] phenyl] -19-x? Or-17alpha-pregna-l, 3, 5 gamma lactone 10) -triene-21-carboxylic acid To 5.93 ml of 15% n-butyllithium in hexane, under inert atmosphere, at room temperature, add 6 ml of tetrahydrofuran / siliporite, then at -50 ° C, 0.921 g of allyl bis-dimethyl idafoefoefate in solution in tetrahydrofuran, finally at -30 ° C, 0.586 g of the product obtained in example 2 and stirred for 1 hour 45 minutes at room temperature. 8 ml of 2N hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate are added, extracted, washed, dried and evaporated under reduced pressure to obtain 0.590 g of crude product which is purified by chromatography by fixing with the mixture. 60/40 ethyl acetate / triethylamine, then recrystallized from isobutanol. 0.162 g of pure expected product is obtained. F = 231 ° C Rf ACOEt / TEA 60/40 = 0.20. NMR (CDC13): 0.51 (s): CH3 in 18, -1.79 (m): CH2 in beta "of N cycle, -2.58 (m): CH2 in N alpha of cycle; 2.83 (t): CH2-N of the chain; 3.99 (t): CH2OAr; 3.99 (t): H? N.; 6.62: H2; 6.82: Hx, 6.62. ArO; 6.82: ArC. EXAMPLE 15: 4-chloro-3, 17beta-dihydroxy-llbeta- [4- [2- (l-piperidinyl) ethoxy] phenyl] -19- nor-17alpha-pregna-l, 3, 5 gamma lactone (10) ) -triene-21-carboxylic acid The procedure is as in Example 14, but from 1.179 g of the product of Example 1. 0.388 g of the expected pure product is obtained. (Rf CH2Cl2 / iPrOH / NH4OH (95/5 / 0.5 = 0.20)). NMR (CDC13): 0.52 (s): CH3 in 18; 2.50 (m): CH2-N CTICCO; 2.72 (t): CH2-N of the chain, -4.00 (t) .- CH2-OAr, -4.00 (hidden t): H1X; 6.62: H2; 6.81: Hx; 6.62: ArO; 6.85: ArC. EXAMPLE 16 4-chloro-3, 17beta-dihydroxy-llbeta- [4- [2- (diethylamino) ethoxy] phenyl] -19- nor-17alpha-pregna-l, 3,5, (10) -gluma lactone triene-21-carboxylic acid The procedure is as in Example 14, but from 0.428 g of the product of Example 3. 0.195 g of the expected pure product is obtained. (Rf ACOEt / TEA / Essence G (50/30/20 = 0.25) NMR (CDC13): 0.51 (S): CH3 in 18; 1.03 (t): N-CH2-CH_3; 2, 60 (q): N-CH2-CH3, -2.81 (t): CH2-N of the chain, -3.94 (t): C ^ -O-Ar, 3.98 (t) H,; 6.59: H2; 6.79: '=?; 6.59:
ArO; 6.85: Are. EXAMPLE 17: (17-alpha) -4-chloro-3, 17beta-dihydroxy-llbeta- [4- [3- (l-piperidinyl) propoxy] phenyl] -19-nor-pregna-l, 3 gamma lactone , 5 (10) -triene-21-carboxylic acid Phase A: Lactonization The procedure is as in Example 14, but from 1.44 g of the compound of Example 5 of phase E. 2.36 g of crude product are obtained. They are introduced directly into the deprotection reaction of phenol in 3. Phase B: Deprotection of phenol in 3. To a solution of 2.36 g of the product obtained in the previous phase in 24 ml of tetrahydrofuran, 3.8 ml are added of tetrabutyl ammonium fluoride solution in tetrahydrofuran and stirred for 50 minutes at room temperature. They are poured into water, extracted, dried and evaporated under reduced pressure to obtain 695 mg of crude product which is purified by chromatography with 93/7 dichloromethane / methanol, then recrystallization. 238 mg of pure pure product are obtained. F = 242 ° C. Rf CH2Cl2 / MeOH / NH4OH 93/7 / 0.7 = 0.28 NMR (CDC13): 0.51 (S): CH3 in 18; from 2.30 to 2.60: CH2-N; 3.88: CH2-0; 3.98 (ti): H12; 6.61, 6.87: Ar -O, Ar-C; 6.61-6.76: Hx, H2.
EXAMPLE 18: 4-chloro-3, 17beta-dihydroxy-llbeta- [4- [4- (l-piperidinyl) butoxy] phenyl] -19- nor-17alpha-pregna-1, 3, 5 gamma lactone (10) ) -triene-21-carboxylic acid The procedure is as in Example 17, but from 1.2 g of the product of Example 6 of phase E. 310 mg of expected pure product are obtained (Rf CH2Cl2 / MeOH / NH4OH 95 / 5 / 0.5 = 0.17). NMR (CDC13): 0.51 (s): CH3 in 18; 3.83 (t): CH2-0 chain, - 3.99 (ti): Hx?; 6.61-6.85: Ar-O, Ar-C; 6.61 -6.79: H,., H2. EXAMPLE 19 4-chloro-3, 17beta-dihydroxy-llbeta- [4- [5- (l-piperidinyl) pentoxy] phenyl] -19-nor-17alpha-pregna-1, 3,5 (10) gamma lactone riene-21-carboxylic acid The procedure is as in Example 17, but from 1.44 g of the product of Example 7 of phase E. 330 mg of expected pure product are obtained (Rf ACOEt / TEA 90/10 = 0 , 22). NMR (CDC13): 0.52 (s) CH, 3.83 (t) CH, -0 3.99 (t) H 11 6.60
(m) 3H, 6.67 (d) Hx, 6.85 (d) 2H: Aromatics Hx and H2. HEMPLO 20: 4-chloro-llbeta- [4- [2- (diethylamino) ethoxy] phenyl] -estra-1,3, (10) -triene-3, 17beta-diol To a solution under inert atmosphere of 241 mg of the compound of Example 3, in 4 ml of methanol, 37 mg of sodium borohydride are added, the mixture is stirred for 1 hour in an ice bath, then 2 ml of hydrochloric acid are added, then they are placed in an aqueous solution of sodium bicarbonate. sodium, extracted to ethyl acetate, washed, dried and evaporated under reduced pressure to obtain 245 mg of crude product which is purified by chromatography with a dichloromethane / methanol / ammonium hydroxide 90/10/1 mixture. 195 mg of expected pure product are obtained. Rf CH 2 Cl 2 / MeOH / NH 4 OH 90/10/1 = 0.27. NMR (CDC13): 0.32 (S): CH3; 1.03 (t): CH2CH3; 2.60 (g) CH2CH3 2.81 (t): CH2-N; 3.68: H17; 3.93 (t): CH2-0 6.62: ArO; 6.89: ArC; 6.80 ( d): Hx: 6.62 (d): H2: Analogously to example 20, the following products of formula (I ') are obtained with R'5 = OH and R'6 =
H:
EXAMPLE 25 4-Chloro-llbeta- [4- [2- (diethylamino) ethoxy] phenyl] -19-nor-17-alpha-pregna-1, 3, 5 (10) -trieno-20-ine-3.17beta -dil To a solution under inert atmosphere, of 250 mg of product of example 3, in 3 ml of tetrahydrofuran / siliporite, add 4.7 ml of a solution of 0.43 M / l of potassium acetylide, stir during 1 hour at room temperature, then add 4 ml of hydrochloric acid. Slurry in a saturated aqueous solution of sodium bicarbonate, extract, wash, dry and evaporate under reduced pressure to obtain 260 mg of crude product which is purified by chromatography with CH2Cl2 / MeOH / NH4OH 90/10 / 0.5. 215 mg of expected pure product are obtained. Rf CH 2 Cl 2 / MeOH / NH 4 OH 90/10 / 0.5 = 0.31. NMR (CDC13). 0.43 (S) in 18; 1.04 (t): CH2CH3; 2.62 (q): CH2CH3; 2.64 (s): C = C-H; 2.83 (t): CH2-N; 3.95 (t): CH2-0; 4.00 (ti): Hlx; 6.62: Ph-O; 6.90: Ph-C; 6.82 (d): Hx; 6.62 (d): H2. EXAMPLE 26: (17beta) -4-chloro-4 ', 5 * -dihydro-llbeta- [4- [2- (1-piperidinyl) ethoxy-phenyl] -spiro [estra-1, 3.5, (10) -trieno-17,2'- (3'H) -furan] -3-ol To a solution of 0.411 g of the product of Example 8 in 15 ml of ethanol and 5 ml of tetrahydrofuran, 0.041 g of catalyst Pd / is added. C of 9.5% and hydrogenated for 2 hours 30 minutes (vol. 'Of absorbed H2 = 17.5 cm 3). After filtering the catalyst, they are evaporated under reduced pressure to obtain 0.42 g of crude product which is purified by chromatography with ethyl acetate / triethylamine 92/8. 0.33 g of expected pure product is obtained. F = 170 ° C. Rf ACOEt / TEA 92/8 = 0.21. Analogously to example 26, the following products of formula (I1) are obtained, in which R'3 and R's form together with the carbon containing them the saturated cycle
Product of NR 'Rf s. Exit Ex. 27 Ex 11 Cl Piperidine 0.19 AcOEt / TEA 92/8 Ex.28 Ex. 12 Cl Piperidine 0.22 AcOEt / TEA 95/5
EXAMPLE 29 4-Chloro-llß- [4- [2- (diethylamino) ethoxy] phenyl] -17alpha-methyl-estra-1, 3, 5 (10) -triene-3, 17beta-diol a) Preparation of the cerium "To 2.42 g of CeCl3-7H20, previously dried under reduced pressure at 140 ° C for 2 hours, then placed under an inert atmosphere, 24 ml of anhydrous THF are added, the euepeneion is stirred for 2 hours, cooled to - 78 ° C and 4.35 ml of CH3Cli in the ether are added and stirred for 30 minutes at -78 ° C. b) Condensation To the temperature of -78 ° C, there is added 0.644 g of the compound prepared in Example 3 in solution in 8.5 ml of anhydrous THF and it is kept for 1 hour at this temperature. Strained in 25 ml of saturated NH4C1 solution, extracted, washed, dried and evaporated under reduced pressure to obtain 0.599 g of crude product which was purified by chromatography (after 0.192 g of crude product obtained during the addition was added). an annexed trial performed in the same way as the original) with CH2Cl2 / CH3OH / NH4OH (92/8 / 0.2), followed by ACOEt / TEA (87/13). 0.402 g of expected pure product are obtained. Rf CH2Cl2 / MeOH / NH4OH (92/8 / 0.2) = 0.18 F = 161-163 ° C. NMR (CDCl 3): 0.44 (S): CH 3 in 18; 1.28 (s): CH3 in 17; 1.03 (t): CH2CH3; 2.61 (g): CH2-CH3; 2.81 (t): CH2-N; 3.94 (t): CH2-0; 3.96: Hxl; 6.61-6.80: ^ and H2; 6.61-6.83: Ph-O.
EXAMPLE 30: 4-Chloro-17alpha-methyl-llbeta [4- [2- (1-piperidinyl) ethoxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol. The procedure is as in Example 28, but from 2.79 g of the product obtained in Example 1. 2.12 g of pure eperated product are obtained. Rf CH2C12 / CH30H / NH40H (93/7 / 0.2) = 0.19 F = 163 ° C. NMR (CDC13): 0.44 (s): CH3 in 18, - 1.28 (e): CH3 in 17; 2.48 (ti) 4H: CH2N cyclo: 2.71 (t): CH2-N chain; 3.99 (t): CH2-0; = 4.00 hidden: H1X; 6.80 (d): Hx; 6.98 (d): H2; 6.60-6.88: Ph-O
they also repaired the following compound.
fifteen
twenty
a) CH2Cl2 / MeOH / NH4OH b) TEA / AcOEt Pharmacological tests Effect on mammary cell proliferation The proliferative activity of molecules is studied comparatively with that of estradiol on MCF-7 human mammary cells in culture. To demonstrate an agonist effect of estradiol and / or molecules tested, the culture medium that maintains cells (rich in growth factors and steroids) is replaced by an impoverished medium, among others, devoid of steroids (DMEM supplemented by 5% serum free of steroids and without phenol red). The cells undergo this deprivation two days before the start of the test. After 7 days of culture in the presence of products to be studied, cell proliferation is evaluated by DNA dosage. In each assay, the effect of 10"10M estradiol (cell growth in the presence of estradiol minus cell growth in the presence of the solvent) determines 100% of the agonist activity.The activity of molecules is evaluated in comparison with this internal sample. that induce cell growth identical to that observed with the solvent are only classified as "inactive", - cells that induce cell growth lower than that observed with the solvent are classified as "inhibitors".
* Mixed: slight agonist activity in very weak concentrations and inhibitory activity in stronger concentrations. Study of the bone impact of a product in the female rat to which the ovaries were removed at the age of 3 months. Compounds A, B, C, D, E are tested to determine their effect on bone mass and on the activity of formation and resorption in the model of the rat to which the ovaries were removed at the age of three months . The animals are treated previously. Animals: Rat species Origin Sprague-Dawley Female sex Peeo 250 g 280 g Number of animals / group 8 Products: 1 - Product to be tested.- Products of examples 20,22,23,30 and i- * Vehicle (s): corn oil, methylcellulose 0.5% * Dosage: one dose per product tested (0.3 mg / kg / j)
* Number of administracionee: once / day, - 5 days / week
for 4 weeks * Route of administration: orally for products * Volume: 5 ml / kg (po) * Time between last injection and sacrifice: 24 hours * Number of administrations: 20 2 - Reference product: 17ß Estradiol is administered subcutaneously in the dose of 0.1 mg / kg / j in solution in a mixture of corn germ oil-benzyl alcohol (99: 1, v / v) in a volume of 0.2 ml / kg Experimental form Animals The study is carried out on female rats at which the ovaries were removed at the age of 3 months. The animals are kept in a conditioned room (temperature 20 ° C ± 2oC) and formed in groups of 4 in the boxes. The animals receive, ad libi tum, water devoid of minerals and compressed foods (plugs .- AO4CR-10 UAR). Surgery Female rats aged 3 months and weighing about 250 g were deprived of the ovaries under anesthesia with Imalgena 1000, in the dosie of 100 mg / kg intraperitoneally (ip) and in a volume of 1 ml / kg. They also receive the Nembutal (3 mg / kg i.p. in a volume of 0.3ml / kg). After lateral incision, the cutaneous and muscular planes are sectioned. The removal of each ovary is done after ligation of the ovary duct. The "SHAM" test rats are anesthetized under the same conditions. After the incision of the skin and muscle planes, each ovary is removed and then placed back in.
Treatment The effects of the product are determined in preventive treatment. They are administered immediately after ovariectomy. The animals are divided into groups of 8. Grupol: "SHAM" test rats receive one or a few vehicles Group 2: "OVX" test rats receive one or a few vehicles Groups X: "OVX" rats receive respectively the defined doses of one or some products to be tested.
Blood samples At the end of 4 weeks (duration of the study) the animals are decapitated by guillotine. Sera collected after centrifugation are stored at -20 ° C. The lipid balance will be established after serum dosages of the total cholesterol of triglycerides and phospholipids on a serum aliquot of 500μl. The decrease in serum cholesterol level is expressed in percent with respect to the level presented by ovariectomized animals that received no more than the solvent.
Organ sample After the animals were sacrificed the following organs served as sample: - Genital tracts The uteri are sampled. These last ones are heavy. The increase in weight is expressed as a percentage of the weight of the uteri of ovariectomized animals that received no more than the solvent. - Bone level: Bone mass (BMD or Bone mineral density) ee measured by biphotonic double-energy X-ray absorptiometry (DEXA). The measurements are carried out on the skeletal and disproved bones of all soft tissues. The BMD (Bone mineral density) is measured on the whole bone as well as on the metaphysis part at the level of the proximal extremity of the left tibia. This area is defined as the region richest in bone marrow, and as a consequence is the most sensitive to the variation of bone volume and bone mineral density. The results are expressed in percentage according to the formula BMD product tested - BMD OVX x 100 BMD SHAM - BMD OVX
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.
Claims (14)
1) Compounds of general formula (I) characterized in that R 1 represents a hydrogen atom, a radical (CH 2) m-Ar, (CH 2) m-Alk or (CO) -Alk, R2 represents a radical derived from a hydrocarbon, linear or branched, saturated or unsaturated containing 1 to 6 carbon atoms D represents the remainder of a pentagonal or hexagonal cycle optionally substituted and eventually unsaturation carrier, X represents a halogen atom, And it is chosen between O, S, SO, S02 and NH, n is an integer that varies between 2 and 8, that is, R3 and R, identical or different, represent a hydrogen atom, a grouping (CH2) m-Ar, (CH2) m-Het or (CH2) m-Alk, that is, R3 and R form together with the nitrogen atom to which they are attached, a monocyclic or polycyclic heterocycle, saturated or unsaturated, aromatic or non-aromatic, of 3 to 15 bonds with optionally from 1 to 3 additional heteroatoms chosen from oxygen , sulfur and nitrogen, unsubstituted or substituted, Ar represents a carbocyclic aryl group containing 6 carbon atoms, Het represents a radical derived from an aromatic or non-aromatic, saturated or unsaturated heterocycle, which contains from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from the oxygen, nitrogen or sulfur atoms; Alk represents a radical derived from a non-aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon, and contains from 1 to 12 carbon atoms; the radicals Ar, Het or Alk can be substituted or unsubstituted, m represents 0,1,2 or 3, as well as their addition salts with the bases or the acids.
2) Compounds of general formula (I), as set forth in claim 1, characterized by section D represents the remainder of a pentagonal cycle of formula: wherein R2 retains the same significance as in claim 1, That is, R5 represents an OH radical, O- (CH2) m-Alk, O- (CO) -Alk, 0- (CH2) m-Ar, O- (CO) -Ar, 0- (CH2) m- Het and R6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 substituted or unsubstituted carbon atoms, n, Alk, Ar and Het are as indicated in claim 1, That is, R5 and R6 together with the carbon atom that contains one of the following cycles: in which Z represents a group - (CH2)? - or -CH = CH- (CH2)? ' , 1 is an integer comprised 1 and 4 and 1 'is an integer equivalent to 1 or a 2, that is, R5 and R6 together form an oxo or = N-OH grouping, as well as their addition salts with the acids or bases.
3) Compounds of the general formula (I), as set forth in claim 1, corresponding to the general formula (I '), characterized because X 'represents a chlorine or bromine atom n 'is between 2 and 5, that is, R'3 and R'4, identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, that is R'3 and R'4 form together with the nitrogen atom to which they are attached, a saturated mono or polycyclic radical of 3 to 15 bonds optionally containing an additional heteroatom chosen from oxygen, sulfur and nitrogen, R's R's have the same meaning as R5 and R6, according to claim 2, as well as their addition salts with the acids and bases.
4) Compounds of general formula (I *), as indicated in claim 3, characterized in that that is, R'5 represents an OH radical and R'6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, substituted or unsubstituted, that is, R'5 and R'6 form together with the carbon atom that contains them, one of the following cycles: that is, R'5 and R'e together form an oxo group, as well as their addition salts with the acids or bases.
5) Compounds of general formula (I '), as set forth in claim 3 or 4, characterized in that X 'represents a chlorine atom, n' is equal to 2, that is, R'3 and R ', identical or different, represent an alkyl radical containing from 1 to 6 carbon atoms, that is, R'3 and R 'together with the nitrogen atom form the following saturated heterocycles: I be R'5 represents an OH radical and R'6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, substituted or unsubstituted, that is, R'5 and R ' e form together with the carbon atom that contains one of the following cycles: that is, R'5 and R'6 together form an oxo group, as well as their addition salts with the acids and bases.
6) Compounds of formula (I) or (I ') as indicated in one of the claims, from 1 to 5, characterized in that their names are the following: -4-chloro-3-hydroxy-llß- [ 4- [2- (diethylamino) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-17-one, -4-chloro-3-hydroxy-llβ- [4- [2- (l- piperidinyl) ethoxy] phenyl] -estra-1, 3,5 (10) -triene-17-one, -4-chloro-3-hiroxy-llß- [4- [2- (l-pyrolidinyl) ethoxy] phenyl] estra-1, 3, 5 (10) -triene-17-one -4-bromo-3-hydroxy-llß- [4- [2- (l-piperidinyl) ethoxy] phenyl] -es tra- 1,3, 5 (10) -triene- 17 -one, -4-chloro-lys- [4- [2- (dimethylamino) ethoxy] f-enyl] -estra-1,3,5 (10) -triene-3, 17beta- diol, 4-chloro-11β- [4- [2- (diethylamino) ethoxy] phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4 - [2- (l-piperidinyl) ethoxy] f-enyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-bromo-llß- [4- [2- (l- piperidinyl) ethoxy] f-enyl] -estra-1,3,5 (10) -triene-3 -3, 17-beta-diol, -4-chloro-l, - [4- [2- (1-pyrolodinyl) ethoxy] phenyl ] -estra- 1,3,5 (10) -tr Ine-3, 17beta-diol, -4-chloro-lys- [4- [2- (diethylamino) ethoxy] phenyl] -19-nor-17alpha-pregna-l, 3,5 (10) -trieno-20- ino-3, 17beta-diol, -4-chloro-llß- [4- [3- (l-piperidinyl) propoxy] f-enyl] -estra-1,3,5 (10) -triene-3, 17-beta-diol , -4-chloro-llß- [4- [4- (l-piperidinyl) butoxy] f-enyl] -estra-1,3, 5 (10) -triene-3, 17 -deta-diol, -4-chloro-lll - [4- [5- (l-piperidinyl) pentyloxy] fenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -gamma lactone of the acid (17alf a) -4- chloro-3, 17beta-dihydroxy-llß- [4- [2- (diethylamino) ethoxy] f-enyl] -19-nor-pregna-1, 3,5 (10) -triene-21-carboxylic acid, -gamma lactone acid (17alpha) -4-chloro-3,17-beta-dihydroxy-llß- [4- [2- (l-pyrolidinyl) ethoxy] phenyl] -19-nor-pregna-1, 3.5 (10) -triene-21-carboxylic acid gamma lactone (17alpha) -4-chloro-3, 17beta-dihydroxy-llß- [4- [2- (lpiperidinyl) ethoxy] phenyl] -19-nor-pregna-1, 3,5 (10) -triene-21-carboxylic acid-gamma lactone (17alpha) -4-chloro-3, 17beta-dihydroxy-llß- [4- [3 - (1-piperidinyl) pr opoxy] phenyl] -19-nor-pregna -1, 3, 5 (10) -triene-21-carboxylic acid-gamma lactone (17alpha) -4-chloro-3, 17beta-dihydroxy-llß- [ 4- [4- (1-piperidinyl) butoxy] phenyl-19-norpene-1, 3,5 (10) -triene-21-carboxylic acid, -gamma lactone of the acid (17alf a) -4-chloro-3, 17beta-dihydroxy-llß- [4 - [5 - (1-piperidinyl) pentyloxy] f enyl] - 19 -norpregna-1,3, 5 (10) -triene-21-carboxylic acid, - (17beta) -4-chloro-llß- [4- [2- (diethylamino) ethoxy] f enyl] - - spirofestra-1,3,5 (10) -triene-17, 2 '(5'H) furan ] -3-ol, - (17beta) -4-chloro-llß- [4- [2- (1-piperidinol) ethoxy] f-enyl] -spiro [estra-l, 3,5 (10) -trieno- 17, 2 '(5' H) furan] - 3 -ol, - (17beta) -4-chloro-llß- [4- [2- (l-pyrolidinyl) ethoxy] f-enyl] -spiro [estra-l, 3,5 (10) -triene-17, 2 '(5 ?) furan] -3-ol, - (17beta) -4-chloro-4 ', 5'-dihydro-llβ- [4- [2- (l-piperidinyl) ethoxy] phenyl] -spiro [estra-l, 3, 5 (10) -triene-17, 2 '(3'H) furan] -3-ol, - (17beta) -4-chloro-llß- [4- [3- (l-piperidinyl) propoxy] f-enyl] -spiro [estra-l, 3,5 (10) -trieno-17, 2 '(5 'H) -3-ol, - (17beta) -4-chloro-4 ', 5'-dihydro-llß- [4- [3- (l-piperidinyl) propoxy] phenyl] -spiro [estra-l, 3, 5 (10) -triene-17, 2 '(3'H) furan] - 3 - or 1, - (17beta) -4-chloro-lys- [4- [4- (l-piperidinyl) butoxy] f-enyl] - .spiro [estra-l, 3,5 (10) -triene-17, 2 '(5 ?) furanoj-3 -ol. - (17beta) -4-chloro-4 ', 5'-dihydro-llβ- [4- [4- (l-piperidinyl) -butoxy] phenyl] spiro [estra-l, 3,5 (10) -trieno- 17, 2 '(3?) Furan] -3-lol, -4-chloro-lll- [4- [2- (diethylamino) ethoxy] fyl] -17alf a-methyl-estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-17alpha-methyl-11β- [4- [2- (1-piperidinyl) ethoxy] phenyl] -estra-l, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-17alpha-methyl-lys- [4- [2- (l-pyrolidinyl) ethoxy] f-enyl] estra-l, 3.5 (10) - trieno-3, 17beta-diol, -ll- [4- [2- [2-asa-bicyclo (2.2.1) hept-2-yl] ethoxy] f-enyl] -4-chloro-17alpha-methyl-estradiol l, 3, 5 (10) -triene-3, 17beta-diol, -ll- [4-2- [2-asa-bicyclo (2.2.1) hept-2-yl] ethoxy] pentyl-4-chloro- estra-l, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- [methyl (1-methylethyl) amino] ethoxy] phenyl] -estra-l, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2- (tetrahydro- (1H) -1, 4-thiazino-4-yl), ethoxy] phenyl] -estra-l, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- [ethyl (propyl) amino] ethoxy] phenyl] -estra-1,3 , 5 (10) -triene-3, 17beta-diol, -4-chloro-11- [4- [2- [ethyl (methyl) amino] ethoxy] f-enyl] -estra-1, 3.5 (10) -triene-3, l7beta-diol, -4-chloro-llß- [4- [2- [(1, l-dimethyl-2-propinyl) amino] etixi] phenyl] -estra-l, 3, 5 (10 ) -trieno- 3, 17 beta-diol, -4-chloro-llß- [4- [2- [hexahydro-lH-azepino-l-yl] ethoxy] phenyl] -estra-1, 3,5 (10) -trieno- 3, 17beta- diol, -4-chloro-l, - [4- [2- [cyclohexyl (methyl) amino] ethoxy] f-enyl] -estra-1, 3,5 (10) -triene-3, 17-beta-diol, -4- chloro-llß- [4- [2- [butyl (ethyl) amino] ethoxy] f-enyl] -estra- 1,3,5 (10) -trieno-3,17beta-diol, -4-chloro-llß- [ 4- [2- (azetidinyl) ethoxy] f-enyl] -estra 1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2- [ethyl (2- propenyl) amino] ethoxy] f-enyl] -estra-1, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-lys- [4- [2- [cyclopentyl (methyl) amino] ethoxy] ] phenyl] -estra-l, 3, 5 (10) -triene-3, 17beta-diol, -4-chloro-l, - [4- [2- (dipropylamino) ethoxy] f enyl] -estra- 1,3 , 5 (10) -triene-3, 17beta-diol, -4-chloro-llß- [4- [2- (3-thiazolidinyl) ethoxy] phenyl] -estra- 1,3,5 (10) -trieno- 3, 17beta-diol, -4-chloro-11β- [4- [2- [ethyl (1-methylethyl) amino] ethoxy] phenyl] -estra-1, 3,5 (10) -trieno- 3, 17beta- diol, -4-chloro-lss - [4 - [2 - [methyl (propyl) aminoje toxi] feni 1] -estra-1, 3,5 (10) -tri eno- 3, 17beta-diol, -4-chloro-lys- [4- [2- [butyl (methyl) amino] ethoxy] f-enyl] -estra-1, 3, 5 (10) -trieno- 3, 17beta -diol, -4-chloro-llß- [4- [2- [methyl (2-propenyl) amino] ethoxy] f-enyl] -estra-1, 3,5 (10) -triene -3,17beta-diol, - 4-Chloro-11β- [4- [2- (4-methyl-1-piperinidyl) ethoxy] f-enyl] -estra-1, 3, 5 (10) -triene-3, 17-beta-diol, -4-chloro -ll- [4- [2- (1-piperidinyl) ethylt phenyl] -estra-1,3,5 (10) -triene-3, 17beta-diol, -4-chloro-11β- [4- [2 - (l-piperidinyl) ethylsulfinyl] phenyl] -estra-1,3,5 (10) -triene-3,17beta-diol, 4- [4-chloro-llbeta- [4- [2- (diethylamino)] ) ethoxy] f-enyl] -17-a-hydroxy-ester-1, 3, 5 (10) -triene-3-yl-oxy] -butanoic acid,
-Oxima of 4-chloro-3-hydroxy-llbeta- [4- [2- (l-piperidinyl) ethoxy] phenyl] -estra-l, 3,5 (10) -triene-17-one, -acid 4- [[2- [4- (4-chloro-3, 17beta-dihydroxy-estra-1,3,5 (10) -triene-llbeta-ii) f-enoxy] -hetylamino] -butanoic] 7) Compound of formula (I ) or (I ') as indicated above in any of the claims, from 1 to 5, characterized in that its name is as follows: -4-chloro-lys- [4- [2- (diethylamino) ethoxy] phenyl] -estra- 1, 3, 5 (10) -triene-3, 17beta-diol, as well as their addition salts with the acids.
8) Process for the preparation of compounds of general formula (I), as set forth in claim 1 or 2, characterized in that it is subjected to a compound of general formula (II): wherein D and R2 are as set forth in claim 1, R7 represents one of the following groupings: in which n, Y, R3 and R4 are as indicated in claim 1, P is a protective group, Hal represents a halogen, to the action of a halogenation reagent to obtain the compound of formula (III): which is subjected to the action of an aromatization reagent of cycle A, then to the action of a base to obtain the compound of formula (IV) corresponding to certain compounds of general formula (I): compounds of formula (II), (III) or (IV) That they submit themselves if desired or necessary, in established order, to one or more of the following reactions: protection of compounds in which R7 is a Ph-YH grouping, deprotection of compounds in which R7 is a Ph-YP grouping, - action of a compound of the formula Hala.- (CH2) n-Hal2 on the compounds in which R7 is a grouping - Ph-Y- (CH2) n-Hal2, action of a compound of formula R3-NH-R4 on the compounds in which R7 is a grouping Ph-Y- (CH3) n-Hal2, to obtain compounds in which R7 is a grouping Ph-Y- (CH2) n-NR3R4, action of a halide salt (M-Hal3) on the compounds in which R7 is a grouping Ph-Y- (CH2) n-Hal2 to obtain compounds in which R7 is a group -Ph-Y- (CH2) n -Hal3, - protection of the OH grouping in position 3 or 17, deprotection of the OH group in position 3 or 17, alkylation of the OH group in position 3 or 17, acylation of the OH grouping in position 3 or 17, action of a reducing agent when D represents the remainder of a pentagonal cycle as set forth in claim 2 and R5 and R6 together form an oxo group, action of an organometallic on the compounds of formula (IV) with D representing the remainder of a pentagonal cycle as set forth in claim 2 and R5 and R6 together form an oxo group, action of a lactonizing people on the compounds of formula (IV) with D representing the remainder of a pentagonal cycle as set forth in claim 2 and R5 and Re together form an oxo group, action of a double bond reducing agent, when D represents the remainder of a pentagonal cycle as set forth in claim 2 and R5 and Rs form together with the carbon containing an O- (CH2) n '-CH group = CH-, action of a double bond agent, when D represents the remainder of a pentagonal cycle as set forth in claim 2, and Rs is an alkenyl or alginyl radical containing from 2 to 6 carbon atoms, halogenation in position 4, then aromatization of cycle A, of the compound of general formula (II), aromatization of cycle A of the compound of formula (III), salification.
9) Preparation method according to claim 8 of compounds of general formula (I ') as set forth in claim 3, characterized in that a compound of general formula (II') is subjected to: wherein R'5 and R'6 are as indicated in claim 3, R'7: to the action of a halogenation reagent to obtain the compound of formula (III '): which is subjected to the action of an aromatization reagent of cycle A, then to the action of a base to obtain the compound of formula (IV) corresponding to certain compounds of general formula (I '): Compounds of formula (II ') ,, (III') or (IV) which are subjected if desired and if necessary, in the order indicated to one or more following reactions: protection of compounds in which R'7 is a grouping -Ph-OH, deprotection of compounds in which R'7 is a grouping -Ph-OP, - action of a compound of the formula Hal? - (CH2) n-Hal2 on the compounds in which R'7 is a grouping -Ph- OH, Hali or Hal2, identical or different, representing a halogen to obtain compounds in which R7 is a group -Ph-O- (CH) n-Hal2, - action of a compound of formula R'3-NH-R 'on the compounds in which R'7 is a grouping Ph-O- (CH2) n-Hal2, to obtain compounds in which R'7 is a grouping Ph-O- (CH2) n-NR'3R'4, action of a halide salt (M-hal3) on the compounds in which R'7 is a grouping Ph-O- (CH2) n-Hal2 to obtain compounds in which R7 is a group -Ph-O- (CH2 ) n-Hal3, protection of the OH grouping in position 3 or 17, deprotection of the OH group in position 3 or 17, - alkylation of the OH group in position 17, acylation of the OH grouping in position 17, action of a reducing agent when R'5 and R'6 together form an oxo group, action of an organometallic on the compounds of formula (IV) with R'5 and R'e together forming an oxo group, action of a lactonizing agent on the compounds of formula (IV) with R'5 and R'6 together forming an oxo group, action of a double-bond reducing agent when R'5 and R'6 together with the carbon containing an O- (CH2) j. -CH = CH-, - action of a double-bond reducing agent when R'6 is an alkenyl or alkynyl radical containing from 2 to 6 carbon atoms, halogenation in position 4, then aromatization of cycle A, of the compound of formula (II '), - aromatization of the compound of formula (III '), salification.
10) As drugs, the compounds of formula (I), characterized in that they are as indicated in claim 1, as well as their addition salts with pharmaceutically acceptable acids.
11) As drugs, the compounds of formula (I) or (I ') characterized in that they are as indicated in any claim from 2 to 5, as well as their addition salts with pharmaceutically acceptable acids.
12) As drugs, the compounds characterized in that they are as stated in claim 6 or 7 as well as their pharmaceutically acceptable addition salts.
13) Pharmaceutical compositions characterized in that they contain one or more drugs as indicated in any of claims 10, 11 or 12.
14) By way of new intermediate products, characterized in that the compounds of general formula (III), (III '), (IV) or (IV) are as indicated in claim 8 or 9.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR97/04321 | 1997-04-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99009227A true MXPA99009227A (en) | 2001-05-17 |
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