WO2014207310A1 - Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase - Google Patents
Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase Download PDFInfo
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- WO2014207310A1 WO2014207310A1 PCT/FI2014/050518 FI2014050518W WO2014207310A1 WO 2014207310 A1 WO2014207310 A1 WO 2014207310A1 FI 2014050518 W FI2014050518 W FI 2014050518W WO 2014207310 A1 WO2014207310 A1 WO 2014207310A1
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- methylthiazol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/32—Antioestrogens
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0052—Nitrogen only at position 16(17)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0057—Nitrogen and oxygen
- C07J71/0068—Nitrogen and oxygen at position 16(17)
Definitions
- the present invention relates to novel estrone C-17 ketimine C-15 thiazole derivatives, to their pharmaceutically acceptable salts, and their use in therapy.
- the invention further relates to pharmaceutical compositions comprising these compounds as active ingredients and to methods for their preparation.
- 17 -hydroxysteroid dehydrogenases (17 -HSDs), also known as 17-ketosteroid reductases (17-KSR) are NAD(H)- and/or NAPD(H)-dependent alcohol oxidoreductase enzymes which catalyse the last and key step in formation of all estrogens and androgens. More specifically 17 -HSDs catalyse the dehydrogenation (oxidation) of 17-hydroxysteroids into corresponding 17- ketosteroids or hydrogenation (reduction) of inactive 17-ketosteroid s into cor- responding active 17-hydroxysteroids.
- the 17 -HSD/KSRs regulate the biological activity of the sex hormones.
- 15 human members of 17 -HSDs have been described (type 1 - 15).
- Different types of 17 -HSD/KSRs differ in their substrate and cofactor specificities.
- the 17KSR activities convert low- activity precursors to more potent forms while 17 -HSD activities decrease the potency of estrogens and androgens and consequently may protect tissues from excessive hormone action.
- Each type of 17 -HSD has a selective substrate affinity and a dis- tinctive, although in some cases overlapping, tissue distribution.
- Type 1 17 -hydroxysteroid dehydrogenase (17 -HSD1 ) is most abundantly expressed in the ovarian granulosa cells of the developing follicles in ovaries and in human placenta, both being estrogen biosynthetic tissues.
- 17 -HSD1 is expressed in estrogen target tissues, including breast, endometrium and bone.
- the human 17 -HSD1 is specific to estrogenic substrates and in vivo catalyzes the reduction of estrone to estradiol.
- Type 2 17 -hydroxysteroid dehydrogenase (17 -HSD2) on the other hand converts estradiol, testosterone and 5a-dihydrotestrosterone to their less active forms estrone, androstenedione and 5a-androstanedione, respec- tively. Due to its wide and abundant expression in number of various estrogen and androgen target tissues, such as uterus, placenta, liver and the gastrointestinal and urinary tracts, it has been suggested that type 2 enzyme protects tissues from excessive steroid actions.
- Estradiol (E2) is about 10 times as potent as estrone (E1 ) and about 80 times as potent as estratriol (E3) in its estrogenic effect. In contrast to certain other estrogens, estradiol binds well to both estrogen receptors ERa and ER , and thus regulates the expression of a variety of genes.
- 17 -HSD1 and 17 -HSD2 are present in healthy premenopausal humans, increased ratio of 17 -HSD1 to 17-HSD2 in the tumors of postmenopausal patients with hormone-dependent breast cancer has been shown in several studies.
- 17HSD1 gene amplification and loss of heterozygosity of 17HSD2 allele are potential mechanisms involved to increased reductive estrogen synthesis pathway in breast tumors.
- Increased ratio of type 1 enzyme to type 2 enzyme results in an increased level of estradiol that then promotes the proliferation of the cancerous tissue via the estrogen receptors (ER). High levels of estrogen thus support certain cancers such as breast cancer and cancer of the uterine lining i.e. endometrial cancer and uterine cancer.
- small-molecule inhibitors of 17 -HSD1 enzyme have been identified and reviewed in Poirier D. (2003) Curr Med Chem 10: 453-77 and Poirier D. (2010) Expert Opin. Ther. Patents 20(9): 1 123-1 145. Further, small molecule inhibitors of 17 -HSD's have been disclosed in WO 2001/42181 , WO 2003/022835, WO 2003/033487, WO 2004/0461 1 1 , WO 2004/060488, WO 2004/1 10459, WO 2005/032527, and WO 2005/084295.
- WO2004/085457 discloses steroidal compounds capable of inhibiting 17 -hydroxysteroid dehydrogenase.
- WO2006/003012 discloses 2- substituted D-homo-estriene derivatives suitable for the treatment of estrogen- dependent diseases that can be influenced by the inhibition of the 17 ⁇ - hydroxysteroid dehydrogenase type 1 .
- WO2006/003013 presents 2- substituted estratrienones usable for preventing and treating estrogen- dependent diseases influenced by inhibiting 17 -hydroxysteroid dehydrogen- ase type l .
- 15-substituted estradiol analogues acting as locally active estrogens are presented in WO2004/085345.
- WO2006/027347 discloses 15b-substituted estradiol derivatives having selective estrogenic activity for the treatment or prevention of estrogen receptor-related diseases and physiological conditions.
- WO2005/047303 discloses 3, 15 substituted estrone derivatives capable of inhibiting the 17 -hydroxysteroid dehydrogenase type 1 .
- An object of the present invention is to provide compounds useful in treating disorders and diseases associated with increased level of estradiol and/or treatable by inhibition of 17 -HSD1 enzyme. It is further an object of the present invention to provide compounds that show little or no inhibitory effect on 17 -HSD2 enzyme.
- One of the problems associated with the known 17 -HSD1 inhibitors is the disposition, in particular the metabolic stability, of the compounds. It is therefore yet a further object of the present invention to provide compounds with improved metabolic stability.
- the present invention provides a novel compound of formula (I)
- R3 is selected from the group consisting of H, C-i-6-alkyl, d-3- haloalkyl , Ci-3-perhaloalkyl , NR' 2 , N 3 , and OR3', wherein R 3 ' is selected from the group consisting of R', benzyl, succinyl , optionally acylated glucuronyl, (CH 2 ) n OH, SO 2 OH, SO 2 R", tosyl, SO 2 N(R') 2 , PO(OR') 2 , COOR'", C(O)N(R') 2 , C(O)(CH 2 ) n N(R') 2 , C(O)CH 2 NHC(O)R', C(O)CH 2 NHC(O)OR" and C(O)R"';
- R' is H or C-i-6-alkyl, Ci-3-haloalkyl, or Ci-3-perhaloalkyl, or when part of any N(R') 2 both R's together with the nitrogen they are attached to may form an 5 to 6 membered aliphatic or aromatic heterocyclic ring comprising 1 or 2 heteroatoms each independently selected from N and O;
- R" is C-i-6-alkyl , C-i-3-haloalkyl, or C-i-3-perhaloalkyl;
- R'" is Ci-is-alkyl, C 2- i8-alkenyl , -(CH 2 ) n -C3-6-cycloalkyl , or optionally substituted phenyl;
- n 1 or 2;
- R2 and R3 or R3 and R4 together with the ring carbon atoms to which they are attached, form an unsaturated or aromatic 5-membered heterocyclic ring comprising 1 or 2 heteroatoms each independently selected from N and O, optionally substituted with methyl or oxo; and
- R4 or R2, respectively, is H and halogen
- R6 which is selected from 0H and
- X is O or NH
- Compounds of the present invention may be useful in therapy, especially in the treatment or prevention of steroid hormone dependent diseases or disorders requiring the lowering of the endogenous estradiol concentration or the inhibition of 17 -HSD enzymes, in animals, in particular mammals, and humans.
- compounds of formula (I) represent inhibitors of the 17 ⁇ - HSD1 enzyme, possessing pharmacological properties for the treatment and/or prophylaxis of malignant steroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, but also for the treatment and/or prophylaxis of benign steroid dependent diseases or disorders such as endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, urinary dysfunction, polycystic ovarian syndrome or lower urinary tract syndrome.
- malignant steroid dependent diseases or disorders such as breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia
- benign steroid dependent diseases or disorders such as endometriosis
- estrogen-dependent diseases which may be treated and/or prevented with an effective amount of a compound of the invention include multiple sclerosis, obesity, rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts.
- the compounds of the present invention typically have an inhibitory activity at the 17- -HSD1 enzyme in the IC50 range of 0.1 nM to 1 ⁇ . The inhibitory activity can be measured as explained in context of the experimental examples.
- the invention also relates to pharmaceutical compositions comprising an effective amount of one or more compound(s) of formula (I).
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
- the invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of estradiol dependent malign or benign diseases and disorders.
- Compounds of the invention contain steroidal core structure having a defined stereochemistry that is the natural configuration of estrogens.
- the C-17 carbonyl group of the native estrone core is masked as a C-17 ketimine to further enhance the metabolic and/or inhibito- ry properties of the compounds of the present invention.
- halogen as used herein and hereafter by itself or as part of other groups refers to the Group Vila elements and includes F, CI, Br and I groups.
- alkyl as used herein and hereafter as such or as part of haloalkyl, perhaloalkyl or alkoxy group is an aliphatic linear, branched or cyclic, especially linear or branched, hydrocarbon group having the indicated number of carbon atoms, for example Ci -6 -alkyl has 1 to 6 carbon atoms in the alkyl moiety and thus, for example, C-i- -alkyl includes methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, isobutyl, tert-butyl and C-i -6 -alkyl additionally includes branched and straight chain pentyl and hexyl.
- haloalkyl refers to any of the above alkyl groups where one or more hydrogen atoms are replaced by halogen(s): in particular I, Br, F or CI .
- haloalkyl groups include without limitation chloromethyl, fluoromethyl and -CH 2 CF 3 .
- perhaloalkyl is understood to refer to an alkyl group, in which all the hydrogen atoms are replaced by halogen atoms. Preferred examples include trifluo- romethyl (-CF 3 ) and trichloromethyl (-CCI 3 ).
- C 3- 6-cycloalkyl refers to cy- cloalkyl groups having 3 to 6 carbon atoms and thus includes cyclopropyl, cy- clobutyl, cyclopentyl, and cyclohexyl.
- alkylenyl as used herein and hereafter, is a divalent group derived from a straight or branched chain hydrocarbon of having suitably 1 to 6 carbon atoms.
- alkylenyl include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
- alkenyl as used herein and hereafter is an unsaturated linear or branched hydrocarbon group having at least one olefinic double bond between any two carbon atoms and having the indicated number of carbon atoms, for example C 2-6 -alkenyl has 2 to 6 carbon atoms in the alkenyl moiety, such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
- alkenyls groups include, but are not limited to, linear alkenyl groups having a terminal double bond such as vinyl and allyl groups.
- C 2-6 -alkynyl as used herein is an unsaturated linear or branched hydrocarbon group having at least one olefinic triple bond between any two carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
- alkynyl groups include, but are not limited to, linear alkynyls groups having a terminal triple bond.
- Ci -6 -alkoxy refers to a -O- (C-i-6-alkyl) group where the "Ci -6 -alkyl” has the above-defined meaning.
- preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and iso-propyloxy.
- an 5 to 6 membered aliphatic or aromatic heterocyclic ring refers to a monocyclic ring, which may be aliphatic or aromatic and comprises 1 or 2 heteroatoms each independently selected from N and O while the remaining ring atoms are carbon atoms.
- Representing groups include pyrrol i- dinyl, piperidinyl, morpholinyl, and piperazinyl, especially morpholinyl.
- an unsaturated or aromatic 5-membered heterocyclic ring refers to a monocyclic ring which may be aromatic or unsaturated and comprises 1 or 2 heteroatoms each independently selected from N and O, while the remaining ring atoms are carbon atoms.
- the ring may be optionally substituted one or more times, in particular one time, with methyl at any suitable ring atom, including N, or with oxo at any suitable ring carbon atom.
- Preferred groups include, but are not limited to, oxazolone or and 1 ,3-oxazole, optionally substituted with methyl.
- phenyl that is either unsubstituted or substi- tuted independently with one or more, in particular 1 , 2, or 3, substituent(s) attached at any available atom to produce a stable compound, e.g. phenyl may be substituted once with a denoted substituent attached to o-, p- or m-position of the phenyl ring.
- substituted refers to a substituent group as de- fined herein in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to a non-hydrogen atom unless otherwise denoted.
- the substituent groups are each independently selected from the group consisting of halogen, C-i- -alkyl, in particular methyl; OH; C-i- -alkoxy, in particular methoxy; CN; NO 2 ; and acetoxy.
- halogen C-i- -alkyl, in particular methyl
- OH C-i- -alkoxy
- methoxy CN
- NO 2 CN
- acetoxy Preferably said phenyl is optionally substitut- ed with acetoxy.
- pharmaceutically acceptable represents being useful in the preparation a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes being useful for both veterinary use as well as human pharmaceutical use.
- acid addition salt includes any non-toxic organic and inorganic acid addition salts that compounds of formula (I) can form.
- Illustrative inorganic acids, which form suitable salts include, but are not limited to, hydrogen chloride, hydrogen bromide, sulphuric and phosphoric acids.
- Illustrative organic acids, which form suitable salts include, but are not limited to, acetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, methane sulfonic acid, salicylic acid, and the like.
- salts as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates, and the like. These salts also include salts useful for the chiral resolution of racemates.
- base addition salt includes any non-toxic base addition salts that the compound of formula (I) can form.
- Suitable base salts include, but are not limited to, those derived from inorganic bases such as alu- minum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, and zinc salts, in particular sodium and ammonium salts.
- Further examples of organic base addition salt include salts of trialkylamines, such as triethyl amine and trimethyl amine, and choline salts.
- the present invention relates to estrone C-17 ketimine C-15 thiazole compound having a formula (I)
- R3 is selected from the group consisting of H, C-i-6-alkyl, C-i-3- haloalkyl, Ci-3-perhaloalkyl, NR' 2 , N 3 , and OR3', wherein R 3 ' is selected from the group consisting of R', benzyl, succinyl, optionally acylated glucuronyl, (CH 2 ) n OH, SO 2 OH, SO 2 R", tosyl, SO 2 N(R') 2 , PO(OR') 2 , COOR'", C(O)N(R') 2 , C(O)(CH 2 ) n N(R') 2 , C(O)CH 2 NHC(O)R', C(O)CH 2 NHC(O)OR" and C(O)R"';
- R' is H or C-i-6-alkyl, Ci-3-haloalkyl, or C-i-3-perhaloalkyl, or when part of any N(R') 2 both R's together with the nitrogen they are attached to may form an 5 to 6 membered aliphatic or aromatic heterocyclic ring comprising 1 or 2 heteroatoms each independently selected from N and O;
- R" is C-i-6-alkyl, C-i-3-haloalkyl, or C-i-3-perhaloalkyl;
- R'" is Ci-is-alkyl, C 2- i8-alkenyl, -(CH 2 ) n -C3-6-cycloalkyl, or optionally substituted phenyl;
- n 1 or 2;
- R2 and R3 or R3 and R4 together with the ring carbon atoms to which they are attached, form an unsaturated or aromatic 5-membered heterocyclic ring comprising 1 or 2 heteroatoms each independently selected from N and O, optionally substituted with methyl or oxo; and
- R4 or R2, respectively, is H and halogen
- X is O or NH
- R4 is selected from the group consisting of H, halogen, CN, NO 2 , and NH 2 .
- R3 is selected from a group consisting of H, C-i-6-alkyl, C-i -3 -perhaloalkyl, N(R') 2 , N 3 , and OR', especially OH or alkoxy .
- R3 is selected from H, OH and alkoxy, especially methoxy, in particular R3 is OH or methoxy, more particularly OH.
- R7 is selected from the group consisting of R'O-Ci -3 -alkylenyl, R'S-C-i -3 -alkylenyl, and R' 2 N- Ci-3-alkylenyl.
- the invention relates to a compound of formula (I) wherein R7 is OR7' and which compound has the formula (la)
- R2, R3, R4, R5 and R6 are as defined above.
- R7' is selected from the group consisting of H, methyl, ethyl, allyl, and carboxymethylenyl; in particular R7' is H or methyl. In a further aspect of this embodiment R5 and R6 are both H.
- R2 and R4 are each independently selected from the group consisting of H, halogen, branched C3-6- alkyl, C-i-3-haloalkyl, especially -CH 2 CF 3 , C-i-3-perhaloalkyl, especially CF 3 , CN, NO 2 , N 3 , N(R') 2 , especially NH 2 , (CH 2 ) n N(R') 2 , in particular R2 and R4 are each independently selected from the group consisting H, halogen, branched C3-6- alkyl, CN, NO 2 , NH 2 , (CH 2 ) n N(R') 2 .
- R3 is H or OR', preferably OR'.
- R2 and R3 or R3 and R4 together with the ring carbon atoms to which they are attached, form an oxazolone or 1 ,3-oxazole ring, optionally substituted with methyl, and R4 or R2, respectively, is selected from the group consisting of H, F, CI, Br, and I.
- the invention re- lates to a compound of formula (I) which compound has the formula (lb)
- X is NH or O, and R2, R3 and R4 are as defined above.
- a subgroup of this embodiment relates to a compound of formula (lc) or (Id)
- R2, R3 and R4 are as defined above.
- R2 and R4 are each inde- pendently selected from the group consisting of H, halogen, branched C3-6- alkyl, CN, NO 2 , NH 2 , (CH 2 ) n N(R') 2 .
- R3 is OR', wherein R' and n are as defined above, in particular H or methyl, most particularly H.
- R2 and R3 or R3 and R4 together with the ring carbon atoms to which they are attached, form an oxazolone or 1 ,3-oxazole ring, optionally substituted with methyl, and R4 or R2, respectively, is selected from the group consisting of H, F, CI, Br, and I.
- the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 and R3 or R3 and R4, together with the ring carbon atoms to which they are attached, form an unsaturated 5-membered heterocyclic ring; and which compound in particular has the formula (le) or (If)
- R2 and R4 are as defined above, preferably selected from the group consisting of H, F, CI, Br, and I, and R is H or methyl.
- R5 to R7 are as defined above.
- Compound 1 1 1 [(13S,15R)-3-Hydroxy-13-methyl-2-nitro- 15-[2-(5-methylthiazol-2-ylcarbamoyl)-ethyl]-6,7,8,9,1 1 ,12,13,14,15,16- decahydro-cyclopenta[a]phenanthren-(17E)-ylideneaminooxy]-acetic acid;
- Compound 1 12 3- ⁇ (13S,15R)-3-Hydroxy-17-[(E)-/V-urea- imino]-13-methyl-7,8,9,1 1 ,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-15-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 13 3- ⁇ (13S,15R)-2,4-Dibromo-3-hydroxy-17- [(E)-/V-urea-imino]-13-methyl-7,8,9,1 1 ,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-15-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 14 3- ⁇ (7aS,10R)-8-[(E)-Hydroxyimino]-7a- methyl-6,7,7a,8,9,10,10a,10b,1 1 ,12-decahydro-5bH-3-oxa-1 -aza- dicyclopenta[a,i]phenathren-10-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 15 3- ⁇ (7aS,10R)-8-[(E)-Methoxyimino]-7a- methyl-6,7,7a,8,9,10,10a,10b,1 1 ,12-decahydro-5bH-3-oxa-1 -aza- dicyclopenta[a,i]phenathren-10-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 16 3- ⁇ (3R,12aS)-1 -[(E)-Methoxyimino]-1 a- methyl-2,3,3a,3b,4,5,10b,1 1 ,12,12a-decahydro-1 H-7-oxa-9-aza- dicyclopenta[a,h]phenanthren-3-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 17 3- ⁇ (3R,12aS)-6-Chloro-1 -[(E)- methoxyimino]-12a-methyl-2,3,3a,3b,4,5,10b,1 1 ,12,12a-decahydro-1 H-7-oxa- 9-aza-dicyclopenta[a,h]phenanthren-3-yl ⁇ -/V-(5-methylthiazol-2- yl)propanamide;
- Compound 1 18 3- ⁇ (3R,12aS)-1 -[(E)-Methoxyimino]-8,12a dimethyl-2,3,3a,3b,4,5,10b,1 1 ,12,12a-decahydro-1 H-7-oxa-9-aza- dicyclopenta[a,h]phenanthren-3-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- Compound 1 19 3-((6aS,10S)-1 ,3-Dibromo-2-hydroxy-6a- methyl-4-nitro-4b,6,6a,10,10a,10b,1 1 ,12-octahydro-5H-8-oxa-7-aza- pentaleno[2,1 -a]phenanthren-10-yl ⁇ -/V-(5-methylthiazol-2-yl)propanamide;
- the present invention re lates to a compound of formula (I) selected from the group consisting of:
- the invention further relates to a method for the preparation of a compound of the present invention, comprising the steps of:
- R7' is H, C-i-6-alkyl, C3-6-alkenyl, or carboxy-C3-6- alkylenyl,
- a base preferably pyridine
- R7 is OR7' as defined above;
- R7' is ureido
- R2 to R6 are as defined above and R7' is ureido;
- the compound of formula (Ilia) is selected from the group consisting of hydroxyl amine, C-i-6-alkoxyl amine, 0-C2-6-alkenyl hydroxyl amine, O-carboxy-C-i-3-alkyl hydroxyl amine and semicarbazide, or hydrogen halide, preferably hydrochloride, thereof, to obtain a compound of formula (I) wherein R7 is respectively C-i-6-alkoxyl, 0-C2-6-alkenyl hydroxyl, O-carboxy-C-i- 3-alkylenyl hydroxyl or semicarbazidyl.
- Compound VII may be synthesized as disclosed in Messinger et al. Mol Cell Endocrinol. 2009 (301 ) 216-224. The detailed synthesis of compound VII starting from estrone has been described in the Solvay Pharmaceuticals' PCT applications WO2005/047303 and WO2006/125800.
- Benzyl-C15-C16-dehydroestrone II was prepared in five steps from estrone according to previously described methods.
- the compound II was treated with an allylic Grignard reagent in the presence of cuprous iodide and lithium chloride in temperature -78 °C.
- Hydroboration by borane tetrahydrofu- ran complex at room temperature to compound III and following hydrogen peroxide oxidation in alkaline conditions produced diol IV in over 90% yields.
- Jones oxidation in acetone-water afforded acid V, which was debenzylated by hydrogenation to compound VI by using Pd/C as a catalyst.
- the final step was the amide formation affording the ⁇ -thiazole VII.
- Compounds of the invention may be prepared from the correspond- ing C-17 carbonyl derivatives.
- the compound VI (2.0 g, 100 mol-%) was dissolved in acetone (40 ml). Potassium carbonate (200 mol-%) and methyl iodide (Mel) (500 mol-%) were added and stirred at room temperature (rt) overnight. Additional amounts of Mel (200 mol-%) and K 2 CO 3 (100 mol-%) were added and refluxed for 10 hours. The solvent was evaporated. The precipitate was dissolved in methanol (50 ml) and 2M NaOH-solution was added until pH was >12. The reaction mix- ture was stirred at rt for 4 hours. The reaction mixture was acidified by HCI. The product was extracted with dichloromethane (DCM) (3 x 30 ml), washed several times with water and finally with brine. The amount of the product 1 was 1 .95 g; the yield was 94%.
- DCM dichloromethane
- the compound 1 (2.0 g, 100 mol-%) was dissolved in dry DCM (80 ml). 2-Amino-5-methylthiazol (200 mol-%), /V-methylmorpholine (NMM) (300 mol-%) ja 1 -hydroxy-1 H-benzotriazole (HOBT) (170 mol-%) were added. The reaction mixture was stirred for five minutes, cooled to 0-5 °C and 1 -ethyl-3- (3'dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (220 mol-%) was added. The reaction mixture was stirred at rt overnight and then diluted with DCM, washed with 1 N HCI-solution and 5% KOH-solution. The organic phase was finally washed with water and brine. The crude product was purified by chromatography affording 1 .85 of the product; the yield was 73%.
- Acetyl chloride 34 mg, 195 mol-%) was added dropwise to a cooled (0 °C) suspension of AICI 3 (59 mg, 200 mol-%) in DCM (1 ml). To this was added dropwise a solution of the compound 2 (100 mg, 100 mol-%) in DCM (1 ml). The reaction mixture was stirred 2 h at 0 °C and stirring was continued overnight at rt. The additional suspension of AICI3 (63 mg, 210 mol-%) and acetyl chloride (32 mg, 190 mol-%) in DCM (1 ml) was added to the reaction. Ice- cold water (5 ml) and DCM (10 ml) were added to the reaction mixture and it was stirred 10 min.
- the reaction vessel was charged with the compound VII (1 .32 g, 3 mmol) and ethanol (45 ml) under nitrogen atmosphere. Tetrahydrofuran (THF) (30 ml) and ferric nitrate (600 mg, 1 .5 mmol) were added. After stirring the reaction mixture for 4 h at 60 °C, the solvents were evaporated. HPLC of the crude reaction mixture showed 45 % of 2-nitro-isomer 5 and 35 % of 4- nitroisomer 6. Purification by flash chromatography gave 358 mg of 5 and 284 mg of 6. In addition, the product mixture contained ca. 5% of 2,4-dinitro derivative 7.
- the compound 2 (100 mg, 100 mo-%) was dissolved in dry DCM (4 ml). Iodine, CF 3 COOAg (73 mg, 150 mol-%) and NaHCO 3 (124 mg, 670 mol- %) were added and the reaction mixture was stirred for three hours at -30 °C. The reaction mixture was filtered and the solid material was washed with DCM. The filtrate was evaporated followed by co-evaporation with toluene and heptane. The solid product was finally washed with heptane. The yield was 100 mg (78%).
- the compound VII (44 mg, 0.1 mmol) was dissolved into DCM and the mixture was stirred in ice bath. 45 mg (0.2 mmol) of /V-iodosuccinimide (NIS) was added and reaction mixture was stirred for 10 min at 0 °C and then reaction was allowed to warm to rt. Water was added after 20 min, the precipi- tated product was filtered, washed first with water and finally with heptane. Trituration with DCM gave 40 % of pure di-iododerivative 16.
- the compound 9 (23 mg, 0.05 mmol) was dissolved into a mixture of 0.5 ml of THF and 0.5 ml of 2N HCI and the solution chilled to 0 °C. An ice- cold solution of NaNO 2 (5 mg) was added and stirring continued 15 min. Then 30 mg of Kl in 50 ul of water was added and the reaction mixture was stirred at 80 °C for 1 h. Water was added into cooled reaction mixture and product was extracted with ethyl acetate, organic phases were washed with water and dried. After evaporation the product was purified by preparative TLC giving 7 mg of pure 17.
- the reaction vessel was charged with VII (2.97 g) in DCM (140 ml) and methanol (20 ml). This solution was added dropwise to the solution of tet- rabutylammonium tribromide in DCM/MeOH (v/v 1 :1 , 10 ml) during 30 minutes by stirring at 0-5 °C. After 60 minutes the HPLC analysis showed the formation of three products with traces of unreacted starting material; 41 % the mono- bromide 19, 38% monobromide 20 and 16% dibromide 21 .
- the reaction vessel was charged with the compound VII (4 g) and dry DCM (150 ml) at 0 °C under argon atmosphere. Diethylamine (1 .4 ml, 150 mol-%) was added dropwise, followed by sulfuryl chloride (1 .1 ml, 150 mol-%). After 30 minutes at 0 °C water was added to the reaction mixture. The organic phase was separated, dried over Na 2 SO and the solvent was evaporated. The residue was purified by column chromatography using DCM/acetone 98:2 as an eluent.
- Fluorides were prepared from the corresponding amines via thermolysis of their diazonium fluoborate salts in 0.05-0.3 mmol scale.
- the starting material, the compound 25 was brominated by using
- the starting material, the compound 26 was brominated by using
- the compound 34 was prepared from the compound 33 using trime- thyl ortoformate as reagent as described for the compound 12.
- the compound 35 was prepared from the compound 31 with trime- thyl ortoformate, by using the method described for the compound 12.
- the triflate 36 (257 mg, 0.45 mmol, 100 mol-%), 1 ,1 '- bis[(diphenylphosphino)ferrocene]di chloropalladium(ll) (22 mg, 0.027 mmol, 6 mol-%), TEA (0.19 ml, 1 .35 mmol, 300 mol-%) and 4 ml of toluene were charged into reaction vessel.
- the vessel was closed with a septum and flushed using vacuum/nitrogen, formic acid (33 ⁇ , 0.9 mmol, 200 mol-%) was added and the mixture stirred at 90 °C for 3 h.
- the reaction mixture was filtered through celite washed several times with toluene. Combined toluene fractions were washed thrice with 1 N HCI and then with water, dried and evaporated giving 178 mg (92%) of raw product, after flash chromatography 133 mg (70 %) of pure 37.
- the compound VII (100 mol-%) was dissolved into THF (1 ml) under nitrogen atmosphere. Toluene (4 ml) was added to the reaction mixture followed by addition of ethyl formate (6000 mol-%). Sodium hydride (50 %) (450 mol-%) was added and the reaction mixture was stirred overnight at rt. Additional amount of ethyl formate (6000 mol-%) and sodium hydride (450 mol-%) was added to the reaction mixture and stirring was continued overnight at rt. pH was adjusted to neutral with 0.5 N HCI and the solvents were evaporated. Water was added to the residue and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with water (10 ml) and brine (3 x 10 ml), dried over Na 2 SO 4 , filtered and evaporated. The product 40 was obtained in quantitative yield.
- Ketone (0.3 mmol) was dissolved in a mixture of ethanol (3 ml) and THF (2 ml) under nitrogen atmosphere. Pyridine (1 .5 mmol) and hydroxylamine hydrochloride (0.9 mmol) were added to this solution. The reaction mixture was refluxed for 1 -2 h. Solvents were evaporated. Water was added and the product was either filtered or extracted with ethyl acetate, washed with dilute hydrochloric acid and finally with water. Oximes were purified further by flash- chromatography if required.
- Acetylation of the compound 73 A mixture of intermediate 73 (290 mg, 0.62 mmol, 100 mol-%), acetic anhydride (320 mg, 3.1 mmol, 500 mol-%) and pyridine (590 mg, 7.44 mmol) in DCM (3 ml) was stirred for overnight at rt. DCM was added to reaction mixture and organic phase was washed with water, 1 N HCI and water, dried over Na 2 SO and the solvents were removed under reduced pressure. The yield of the compound 100 was 31 1 mg (98 %).
- the compound VII 500 mg, 100 mol-%) and ⁇ /,/V-dimethylglycine (200 mol-%) were dissolved in dry DCM (20 ml). NMM (300 mol-%) and HOBT (170 mol-%) were added to the reaction mixture. After stirring for five minutes, the reaction mixture was cooled with ice-bath. EDCI (220 mol-%) was added. The reaction mixture was stirred overnight at rt. After dilution with DCM the reaction mixture was washed several times with 1 H HCI-solution. The organic phase was washed with water and brine.
- the compound 101 was prepared using the general methyloxime- method as described for the compound 73 using dimethylglycine 101a as a starting material.
- the compound VII (100 mol-%) was dissolved in DCM (15 ml). Pyridine (1000 mol-%) and sulfamoyl chloride (500 mol-%) were added. The reac- tion was refluxed for 1 -4 hours followed by TLC. DCM was added and reaction mixture washed with water, 1 N HCI, water and brine. The reaction was dried with Na 2 SO and the solvent was evaporated. The crude product was purified by flash chromatography.
- the compound 102 was prepared using the general methyloxime- method as described for the compound 73 using sulfamate 102a as a starting material.
- the compound 103 was prepared using the general methyloxime- method as described for the compound 73 using sulfamate 103a as a starting material. The yield was 94%.
- the intermediate 104a was prepared according to the method described for the compound 103a starting from the compound VII using mesyl chloride as a reagent in 65% yield.
- the compound 104 was prepared using the general methyloxime- method as described for the compound 73 using 104a as a starting material.
- the compound VII (0.2 mmol) was dissolved in a solution of ethanol/THF (v/v 3 ml/1 ml) and warmed at 70 °C for 4 hours.
- Semicarbazide hydrochloride (0.4 mmol) and sodium acetate (0.5 mmol) were added. Stirring was continued for 1 hour. The solvents were evaporated. Water was added and the reaction mixture was stirred at rt. The produced precipitate was filtered, washed with water and heptane. The yield of the semicarbazone 112 was quantitative.
- Methanesulphonic acid (6aS,10S)-6a-methyl-10-[2-(5-methylthiazol- 2-ylcarbamoyl)-ethyl]-4b,6,6a,10,10a,10b,1 1 ,12-octahydro-5H-8-oxa-7-aza- pentaleno[2,1 -a]phenanthren-2-yl ester
- the compound 120 was isolated as a main product prepared from the compound 69 by the same method as used for the compound 119.
- the synthesis of the compound 123 was done by the same method as for the compound 121 using 2-methoxyethylamine (600 mol-%) as reagent and the compound 3 as a starting material. Reaction was refluxed for 10 hours and stirred overnight at rt.
- the compound 76 (100 mg, 0.191 mmol, 100 mol-%) and p-TsOH (33 mg, 100 mol-%) were dissolved in dry ACN (2 ml) and stirred for 15 min at rt. /V-iodosuccinimide (52 mg, 0.229 mmol, 120 mol-%) was added in portions. Reaction was stirred at rt for 2.5 hours and additional amount of N- iodosuccinimide (24 mol-%) was added. Stirring was continued overnight at rt. Water was added (5 ml) and 10% Na 2 CO 3 was added until pH 8. Product was extracted in EtOAc (3 x 10 ml). Combined organic layers were washed with 10% Na 2 SO 3 , water and brine and dried with Na 2 SO . Solvent was evaporated. Crude product (123 mg) was purified with flash chromatography. The amount of the compound 124 was 80 mg.
- Recombinant baculovirus was generated by the "Bac to Bac Expression System” (Invitrogen). Recombinant bacmid was transfected to Sd9 insect cells using "Cellfectin Reagent” (Invitrogen). 60 h later cells were harvested; the microsomal fraction was isolated as described by Puranen, T.J., Poutanen, M.H., Peltoketo, H.E., Vihko, P.T. and Vihko, R.K. (1994) Site-directed mutagenesis of the putative active site of human 17 ⁇ -hydroxysteroid dehydrogenase type 1 . Biochem. J. 304: 289-293. Aliquots were stored frozen until determination of enzymatic activity.
- Recombinant protein (1 ⁇ / ⁇ ) was incubated in 20 mM KH2PO4 pH 7.4 with 30 nM estrone (including 800 000 cpm/ml of 3 H-estrone) and 1 mM NADPH for 30 min at RT, in the presence of the potential inhibitor at concentrations 1 ⁇ or 0.1 ⁇ .
- Inhibitor stock solutions were prepared in DMSO. Final concentration of DMSO was adjusted to 1 % in all samples. The enzyme reaction was stopped by addition of 10% trichloroacetic acid (final concentration). Samples were centrifuged in a microtiter plate at 4000 rpm for 10 min.
- A-buffer 40 mM TRIS, pH8.0, 20% glycerol, 20 ⁇ NAD, 0.4 mM PMSF, 150 mM NaCI, 0.5% dodecyl- ⁇ - maltoside + protease inhibitor cocktail
- the binding affinity of the compounds of the invention to the estro- gen receptor a may be determined according to the in vitro ER binding assay described by Koffmann et al REF. Alternatively, an estrogen receptor binding assay may be performed according to international patent application WO2000/07996. Estrogen Receptor Transactivation Assays
- Compound of the invention showing binding affinity towards the estrogen receptor may be further tested with regard to their individual estrogenic or anti-estrogenic potential (Agonistic or antagonistic binding to the ERa or ER ).
- the determination of the estrogen receptor antagonistic activity may be performed according to an in vitro assay system using the MMTV-ERE-LUC reporter system for example described in US patent application US2003/0170292.
- the in vitro metabolic stability of the compounds of the invention was determined for exemplified compounds using human liver microsome and homogenate incubations.
- the incubation time points used with or without appropriate cofactors were 0 min and 60 min.
- Samples were collected at both time points and substrates were detected using LC/PDA TOF-MS.
- In vitro met- abolic stability (% remaining after 60 min in human liver homogenate or microsomes) of the compounds were calculated and the results are summarized in Table 3.
- Compounds of the invention show selective inhibitory potential of the 17 -HSD1 enzyme and little or no inhibitory activity to the 17 -HSD2 enzyme and therefor, and may be useful for the treatment of a steroid hormone dependent malign or benign disease or disorder, in particular for treatment and prevention of several estrogen dependent diseases and disorders. Further, compounds of the present invention may be useful for the treatment of diseases and disorders associated with increased levels of estradiol and which may be prevented, treated, and/or ameliorated by an inhibitor of 17 -HSD1 en- zyme.
- inflammatory diseases and conditions include, but are not limited to, breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metror- rhagia, prostadynia, benign prostatic hyperplasia, urinary dysfunction, polycystic ovarian syndrome, lower urinary tract syndrome, multiple sclerosis, obesity, rheumatoid arthritis, colon cancer, tissue wounds, skin wrinkles and cataracts.
- Treatment or prevention includes prophylaxis, or prevention of, as well as lowering the individual's risk of falling ill with the named disorder or condition, or alleviation, amelioration, elimination, or cure of the said disorder once it has been established.
- Compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 pg/kg to about 300 mg/kg, preferably between 1 .0 pg/kg to 10 mg/kg body weight.
- Compounds of the pre- sent invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- An effective amount refers to an amount of a compound that confers a therapeutic effect on the treated subject.
- the therapeutic effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. subject gives an indication of or feels an effect).
- Such treatment need not necessarily completely ameliorate the condition of disease. Further, such treatment or prevention can be used in conjunction with other traditional treatments for reducing the condition known to those skilled in the art.
- Compounds of the invention are most preferably used alone or in combination i.e. administered simultaneously, separately or sequentially with other active ingredients.
- Compounds of the invention may be administered by various routes, for example, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, and by intradermal injections, and via transdermal, rectal, buccal, oromucosal, nasal, ocular routes and via inhalation and via implant.
- compositions of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
- compounds of formula (I) can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutically active ingredients, which are obtainable from compounds of formula (I), for example by introduction of substituents or modification of functional groups.
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KR1020167001998A KR20160042873A (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
JP2016522679A JP6556125B2 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase |
BR112015031846A BR112015031846A8 (en) | 2013-06-25 | 2014-06-25 | stratrientiazole derivatives, their uses, and pharmaceutical composition |
MA38694A MA38694B1 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active derivatives of estratriene thiazole substituted in position 17 as 17beta.-hydroxysteroid dehydrogenase inhibitors |
EA201690077A EA201690077A1 (en) | 2013-06-25 | 2014-06-25 | THERAPEUTICALLY ACTIVE DERIVATIVES OF ESTRATRIEN-THIAZOLE |
TN2015000555A TN2015000555A1 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
CN201480046108.2A CN105518015B (en) | 2013-06-25 | 2014-06-25 | 17 nitrogen as 17 beta hydroxysteroid dehydrogenase inhibitors of therapeutic activity replace estratriene thiazole |
US14/392,291 US9663549B2 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratreinthiazole derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase |
SG11201510251TA SG11201510251TA (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
AU2014300894A AU2014300894A1 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
CA2914667A CA2914667A1 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
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EP14742254.7A EP3013846B1 (en) | 2013-06-25 | 2014-06-25 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
IL242968A IL242968A0 (en) | 2013-06-25 | 2015-12-06 | Therapeutically active 17-nitrogen substituted estratrienthiazole derivatives as inhibitors of 17.beta.-hydroxysteroid dehydrogenase |
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WO2016102776A1 (en) * | 2014-12-23 | 2016-06-30 | Forendo Pharma Ltd | Prodrugs of 17.beta.-hsd1 -inhibitors |
WO2016102775A1 (en) * | 2014-12-23 | 2016-06-30 | Forendo Pharma Ltd | PRODRUGS OF 17β-HSD1 -INHIBITORS |
WO2017211330A1 (en) | 2016-06-07 | 2017-12-14 | Ustav Organicke Chemie A Biochemie Av Cr, V.V.I. | 15β-SUBSTITUTED ESTRONE DERIVATIVES AS SELECTIVE INHIBITORS OF 17β-HYDROXYSTEOID-DEHYDROGENASES, METHOD OF PREPARATION AND USE THEREOF |
US20180354984A1 (en) * | 2017-06-08 | 2018-12-13 | Forendo Pharma Ltd | Therapeutically active steroidal derivatives |
WO2020115371A1 (en) | 2018-12-05 | 2020-06-11 | Forendo Pharma Ltd | Estra-1,3,5(10)-triene compounds condensed in position 16(17) with a pyrazole ring as inhibitors of 17-hsd1 |
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CN114644673B (en) * | 2020-12-19 | 2023-12-26 | 上海喀露蓝科技有限公司 | Estradiol derivative, preparation method thereof and application thereof in medicine |
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Also Published As
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US20170081357A1 (en) | 2017-03-23 |
US9663549B2 (en) | 2017-05-30 |
EA201690077A1 (en) | 2016-09-30 |
CN105518015A (en) | 2016-04-20 |
MX2015017879A (en) | 2017-03-01 |
SG11201510251TA (en) | 2016-01-28 |
EP3013846B1 (en) | 2017-08-09 |
BR112015031846A2 (en) | 2017-07-25 |
KR20160042873A (en) | 2016-04-20 |
AU2014300894A1 (en) | 2016-01-28 |
IL242968A0 (en) | 2016-02-01 |
TN2015000555A1 (en) | 2017-04-06 |
BR112015031846A8 (en) | 2018-03-06 |
TW201534612A (en) | 2015-09-16 |
CN105518015B (en) | 2017-09-15 |
JP6556125B2 (en) | 2019-08-07 |
MA38694A2 (en) | 2017-12-29 |
AR096729A1 (en) | 2016-01-27 |
HK1217495A1 (en) | 2017-01-13 |
CA2914667A1 (en) | 2014-12-31 |
EP3013846A1 (en) | 2016-05-04 |
JP2016523886A (en) | 2016-08-12 |
MA38694B1 (en) | 2020-01-31 |
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