WO2012134446A1 - Dérivés d'épiandrostérone et/ou d'androstérone et leur procédé d'utilisation - Google Patents

Dérivés d'épiandrostérone et/ou d'androstérone et leur procédé d'utilisation Download PDF

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WO2012134446A1
WO2012134446A1 PCT/US2011/030306 US2011030306W WO2012134446A1 WO 2012134446 A1 WO2012134446 A1 WO 2012134446A1 US 2011030306 W US2011030306 W US 2011030306W WO 2012134446 A1 WO2012134446 A1 WO 2012134446A1
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heterocycle
group
alkyl
compound
cycloalkyl
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Li-Xi Yang
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Catholic Healthcare West
Sutter West Bay Hospitals
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Catholic Healthcare West
Sutter West Bay Hospitals
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group

Definitions

  • the disclosure relates to novel steroids and more particularly to androsterone and epiandrosterone derivatives useful as anti-cancer, anti-obesity, anti-diabetic and hypolipidemic agents .
  • DHEA Dehydroepiandorsterone
  • dehydroepiandrosterone-sulfate are major adrenal secretory products in many mammalian species.
  • DHEA-sulfate is the main precursor of placental estrogen and is converted into active androgens in peripheral tissue, there is no strong biological role for either DHEA or DHEA-sulfate in the normal subject.
  • steroids are associated with cell proliferative disorders as well as other androgen-associated disorders .
  • Examples of androgen-associated disorders include, but are not limited to, prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome.
  • estrogen-associated disorders include, but are not limited to, breast cancer, endometriosis, leiomyoma, and precocious puberty .
  • the disclosure provides androsterone and epiandrosterone derivatives, methods of synthesis thereof, and methods of use thereof, for the treatment of various androgen- and estrogen- associated, androgen-sensitive , and estrogen-sensitive disorders.
  • androsterone and/or epiandrosterone derivatives disclosed herein inhibit breast cancer cell growth via counteracting the effect of female hormones and/or inhibit cell proliferation by binding to female hormone receptors (e.g., as antagonists) , and/or induce apoptosis in abnormally dividing cells found with androgen and estrogen associated cell proliferative disorders .
  • the disclosure provides
  • epiandrosterone and/or androsterone ester compounds include, pharmaceutical compositions thereof, and methods of use therof (e.g., for the treatment of cancer) .
  • the disclosure provides epiandrosterone and/or androsterone-camptothecin combination compounds, pharmaceutical compositions therof, methods of use thereof (e.g., for the treatment of cancer) .
  • Figure 1 shows the effect of an androsteron derivative of the disclosure on cancer cells.
  • Figure 2 shows that OL-1 is significantly more effective in killing DU-145 human prostate cancer cells than topotecan and irinotecan .
  • Figure 3 shows that OL-2 is very effective in killing
  • PC-3 human prostate cancer cells with an IC50 of 131 nM.
  • FIG. 4 shows that OL-3 is very effective in killing
  • PC-3 human prostate cancer cells with an IC50 of 18 nM.
  • Figure 5 shows that OL-2 is highly effective in killing human malignant peripheral nerve sheath tumor (MPNST) cells, with an IC50 of 76 nM.
  • Figure 6 shows that OL-3 is extremely effective in killing human malignant peripheral nerve sheath tumor (MPNST) cells, with an IC50 of 4 nM.
  • MPNST peripheral nerve sheath tumor
  • Figure 7 shows that OL-2 is effective in killing SF295 human glioblastoma cells, with an IC50 of 290 nM.
  • Figure 8 shows that OL-3 is highly effective in killing
  • Figure 9 demonstrates that OL-1, OL-2, and OL-3 are all effective in inhibiting the growth of PC-3 prostate cancer xenografts in mice (tumor volume) as compared to the control group. OL-3 was the most effective compound in controlling the growth of PC-3 xenografts.
  • Figure 10 shows that for the PC-3 tumor volume to reach 1000 cu.mm in size only takes around 7 days for the control, around 13 days for OL-1 treated mice, around 25 days for OL-2 treated mice, and around 38 days for OL-3 treated mice .
  • Figure 11 shows that mice bearing PC-3 tumors lived for about 10 days for the control, around 18 days for OL-1 and OL-2 treated mice, and around 45 days for OL-3 treated mice .
  • Figure 12 demonstrates that OL-1, OL-2, and OL-3 are all very effective in inhibiting the growth of DU-145 human prostate cancer xenografts in mice (tumor volume) as compared to the control group.
  • Figure 13 shows that for the DU-145 tumor volume to reach 1000 cu.mm in size only takes around 16 days for the control, around 56 days for OL-1 and OL-2 treated mice, and around 62 days for OL-3 treated mice.
  • Figure 14 shows that mice bearing DU-145 tumors lived for about 27 days for the control, around 60 days for OL-1 and OL-3 treated mice, and around 57 days for OL-2 treated mice.
  • tetrahydrofuran BOC, tert-butyl carbamate; TFA, trifluoroacetic acid; NMR, nuclear magnetic resonance; MeOH, methanol; Ar, aryl, BCS, bovine calf serum; and HBSS, Hank's balanced salt solution.
  • Aryl refers to any functional group or substituent derived from an aromatic ring.
  • aryl can refer to a monocyclic ring or to an extended aryl ring system comprised of 2 to 6 aryl rings which are fused together, i.e. bi-, tri-, tetra-, penta-, or hexa- cyclic. Additionally, for purposes of this invention "aryl” will refer to both unsubstituted and substituted aromatic rings or a combination thereof for an extended aryl ring system, unless specifically stated otherwise. In one embodiment "aryl” refers to an unsubstituted aryl ring. In another embodiment "aryl” refers to a substituted aryl ring. In a preferred embodiment a substituted aryl has one or more electron withdrawing groups covalently bound to an aryl .
  • Heterocycle refers to a cyclic compound which has atoms of at least two different elements as members of its ring.
  • heterocycle can refer to a monocyclic ring or to an extended heterocyclic ring system comprised of 2 to 6 heterocyclic rings which are fused together, i.e. bi-, tri-, tetra- , penta-, or hexa- cyclic.
  • heterocycle will refer to both unsubstituted and substituted heterocyclic rings and a combination thereof for an extended heterocyclic ring system, unless specifically stated otherwise.
  • heterocycle refers to an
  • heterocycle refers to a substituted heterocyclic ring.
  • a substituted heterocyclic has one or more electron withdrawing groups covalently bound to a heterocycle.
  • Cycloalkyl refers to a cyclic compound which has only carbons as members of its ring.
  • cycloalkyl can refer to a monocyclic ring or to an extended cycloalkyl ring system comprised of 2 to 6 cycloalkyl rings which are fused together, i.e. bi-, tri-, tetra-, penta-, or hexa- cyclic.
  • cycloalkyl will refer to both unsubstituted and substituted cycloalkyl rings or a combination thereof for an extended cycloalkyl ring system, unless specifically stated otherwise.
  • cycloalkyl refers to an unsubstituted cycloalkyl ring.
  • cycloalkyl refers to a substituted cycloalkyl ring.
  • a substituted cycloalkyl has one or more electron withdrawing groups covalently bound to a cycloalkyl.
  • fused ring system refers to a ring system comprised of at least 2 fused rings and up to 10 fused rings that are comprised of a combination of cylcoalkyl, heterocycle, and aryl rings.
  • fused ring system will refer to both unsubstituted and substituted rings, and a combination thereof, unless specifically stated otherwise. In one embodiment “fused ring system” refers to only unsubstituted rings. In another embodiment “fused ring system” refers to only substituted rings.
  • substituted fused ring system refers to one or more electron withdrawing groups covalently bound to one or more aryl, cycloalkyl, or heterocycle rings that are part of the "fused ring system" .
  • "Substituted" with respect to a ring structure refers to one or more functional groups covalently bound to the core ring structure .
  • Electrode withdrawing group refers to a functional group attached to a ring or ring system, whether that ring is aryl, heterocycle, cycloalkyl, or a fused ring system, which draws electron density away from the ring (makes the rings more
  • electrophilic examples include, but are not limited to, nitros, trihalides, halogens, cyanos, sulfonates, carboxylic acids, esters, and carbonyls.
  • (Ci to C 6 ) with respect to a chemical function group, such as (Ci to C 6 )alkyl, refers to a substituent that has one to six carbons .
  • Nonstereospecific covalent bonds are depicted by a line that has uniform thickness, while stereospecific bonds are represented by lines that are wider at one end than the other that have a wedge shape, which is either solid, indicating an element that is coming towards the viewer, or hashed, indicating an element that is going away from the viewer.
  • the single line connecting the 0 and steroid ring in Formula II would indicate that this bond is nonstereospecific, so that compounds of Formula II, for the purposes of this disclosure, include androsterone and/or epiandrosterone derivative compounds.
  • disorder as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disease”, “syndrome” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
  • carrier or “excipient” means a
  • pharmaceutically acceptable carrier or excipient comprises any and all solvents, dispersive agents or media, coating (s), antimicrobial agents, iso/hypo/hypertonic agents, absorption- modifying agents, and the like.
  • the term "protected" in respect to a functional group refers to chemically modifying a functional group so that it is no longer reacts in a manner that would be expected if the functional group was not protected, allowing for chemoselectivity .
  • protected functional group can be subsequently deprotected in later steps to restore the functional group to its state prior to being protected.
  • linker portion in respect to a reactant, refers to a covalently bonded organic compound containing at least 2 carbons where a carboxylic acid group is on one end, and the other end is covalently bonded to hydroxyl group of a camptothecin or camptothecin molecule, forming an ester bond.
  • Androstenone is a steroid hormone excreted in urine that reinforces masculine characteristics having the general formula as set forth in Formula I (a) :
  • Epiandrostenone is a steroid hormone excreted in that reinforces masculine characteristics having the general formula as set forth in Formula I (b) :
  • R 2 is either -(CY 2 ) W -, -aryl-, -cycloalkyl-, -heterocycle-, -fused ring system-, - (CY 2 ) w -heterocycle- , - (CY 2 ) w -cycloalkyl- , - (CY 2 ) w -aryl-, - (CY 2 ) W -L- (CY 2 ) Z -, - (CY 2 ) W -L- (CY 2 ) x -aryl-, - (CY 2 ) W -L- (CY 2 ) x -aryl- (CY 2 ) Z -,
  • R 2 With respect to R 2 , the left side of the formula is connected to R 3 (indicated by the dashed line) while the right side is connected to R 1 (indicated by a dashed line), e.g. - (CY 2 ) w -aryl- should be interpreted as R 3 -
  • R 3 is either a hydroxyl, aryl, cycloalkyl, heterocycle, fused ring system, -O-aryl, -O-cycloalkyl , -O-heterocycle , -O-fused ring system, -0- (CY 2 ) complicat-cycloalkyl, -0- (CY 2 ) w -cycloalkyl- (CY 2 ) z - (CY 3 ) , -0-
  • R 4 is independently either an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aldehyde, carbonyl, alkoxycarbonyl , carboxyl, heterocycle, fused ring system, amino, imino, imido, azido, azo, alkylamine, arylamine, alkoxy, aryloxy, cyano, cyanato, hydroxyl, nitroso, or nitro .
  • Y is either H, D, R 4 , OR 4 , N(R 4 ) 2 , SR 4 , cyano, CA 3 , CA 2 R 4 , CA(R 4 ) 2 , C(R 4 ) 3 , or halogen.
  • A is either H, D, or halogen.
  • w, x, y, and Z is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, wherein when w, x, y, or Z is 0 then the carbon containing group is absent and is replaced by a covalent bond to the next defined group.
  • w is 0, CH 2 -0- (CH 2 )
  • w -aryl should be interpreted for the purposes of this disclosure as CH 2 -0-aryl, wherein "-" indicates a single covalent bond.
  • a triple covalent bond is indicated by "#", for example (C#C) .
  • a compound has structural Formula II
  • the aryl, heterocycle, and fused ring system of R 1 , R 2 , R 3 and/or R 4 are substituted.
  • said substituted aryl, heterocycle, and fused ring system of R 1 , R 2 , R 3 and/or R 4 are substituted with one or more electron withdrawing groups.
  • said substituted aryl, heterocycle, and fused ring system of R 1 , R 2 , R 3 and/or R 4 are substituted only with electron withdrawing groups.
  • R 2 , R 3 and/or R 4 heterocycle is a nitrogen-containing heterocycle, and if the R 1 , R 2 , R 3 and/or R 4 fused ring system contains a heterocycle it is a nitrogen-containing heterocycle.
  • the nitrogen-containing heterocycle of R 1 , R 2 , R 3 and/or R 4 is aromatic.
  • Aromatic nitrogen-containing heterocycles typically contain a 5- or 6-membered monocyclic substituent, or are bicyclic or tricyclic fused ring systems comprised of 4-, 5- or 6-membered monocyclic rings.
  • Aromatic nitrogen-containing heterocycles typically contain a 5- or 6-membered monocyclic substituent, or are bicyclic or tricyclic fused ring systems comprised of 4-, 5- or 6-membered monocyclic rings.
  • a nitrogen containing heterocycle of R 1 , R 2 , R 3 and/or R 4 is aromatic and composed of 1 or more 4-, 5- or 6-membered rings .
  • an aromatic nitrogen-containing heterocycle of R 1 , R 2 , R 3 and/or R 4 is selected from the group comprising: imidazole, imidazoline, pyrazole, pyrazoline, pyrazine, pyridazine, pyridine, pyrimidine, pyrrole, tetrazole, 1 , 2 , 3-triazole , 1 , 2 , 4-triazole , triazine, tetrazine, xanthine, oxazole, furazan, oxazine, purine, 2-amino- pyridine, benzimidazole, 2 , 5-diaminopyridine , 2,4- dimethylimidazole, 2 , 3-dimethylpyridine , 2, 4-dimethylpyridine, 3,5- dimethylpryidine , methoxypyridine, ⁇ -picoline, and 2,4,6- trimethylpyridine, and combinations thereof
  • Non-aromatic nitrogen-containing heterocycles typically contain a 5- or 6-membered monocyclic substituent, or are bicyclic or tricyclic fused ring systems comprised of 4-, 5- or 6-membered monocyclic rings.
  • Non-aromatic nitrogen-containing heterocycles typically contain a 5- or 6-membered monocyclic substituent, or are bicyclic or tricyclic fused ring systems comprised of 4-, 5- or 6-membered monocyclic rings.
  • a nonaromatic nitrogen containing heterocycle of R 1 , R 2 , R 3 and/or R 4 is composed of 1 or more 4-, 5-, or 6-membered rings.
  • a non-aromatic nitrogen containing heterocycles of R 1 , R 2 , R 3 and/or R 4 is selected from the group comprising: azolidine, imidazolidine, pyrazolidine , morpholine, oxazolidine, lactam, maleimide,
  • a fused ring system of R 1 , R 2 , R 3 and/or R 4 is bicylic.
  • a bicyclic ring of R 1 , R 2 , R 3 and/or R 4 is selected from the list consisting of: one (C3-C7) cycloalkyl and one phenyl ring, one heterocycle and one phenyl ring, and one (C 3 - C 7 ) cycloalkyl ring and one heterocycle ring.
  • a bicylic fused ring system of R 1 , R 2 , R 3 and/or R 4 is selected from the list comprising: indole, quinoline, phthalimide, and 8-methyl- 8-aza-bicyclo [3.2.1] octane .
  • a fused ring system of R 1 , R 2 , R 3 and/or R 4 is tricylic.
  • the tricyclic fused ring system of R 1 , R 2 , R 3 and/or R 4 is selected from the group consisting of: one phenyl, one heterocyle and one (C3-C7) cycloalkyl ring, one (C3-C7) cycloalkyl and two phenyl rings, one (C3-C7) cycloalkyl and two heterocycle rings, one heterocycle and two phenyl rings, one heterocycle and two (C 3 - C 7 ) cycloalkyl rings, one phenyl and two (C3-C7) cycloalkyl rings, and one phenyl and two heterocycle rings.
  • R 3 are selected from the group consisting of atropine, atropine derivative, scopolamine, or scopolamine derivative.
  • R 1 is selected from the group consisting of: wherein * indicates the (+) chiral center in the original molecule.
  • R 1 and/or R 3 are a camptothecin analog.
  • camptothecin (CPT) -based analogs are generally available in the art and would be known to one of ordinary skill in the art. These compounds are within the scope of invention and can be used to make CPT linked androsterone and epiandrosterone derivatives by using the methods disclosed herein or obvious variants thereof.
  • CPT analogs include, but are not limited to, (20S) -9-nitro CPT, (20S) -7-chloro-n- propyldimethylsilyl CPT, (20S) -10-hydroxy-7-chloro-n- propyldimethylsilyl CPT, (20S) -10-acetoxy-7-chloro-n- propyldimethylsilyl CPT, (20s) -7- tert-butyldimethylsilyl CPT,
  • (20S) -7-ethoxycarbonylethenyl CPT (20S) -7-cyanoethenyl CPT, (20S)- 7- (2, 2-dicyanoethenyl) CPT, (20S) -7- (2-cyano-2- ethoxycarbonyl) ethenyl CPT, (20S) -7-ethoxycarbonylethyl CPT, (20S)- 7-ethyl CPT, (20S) -7-n-propyl CPT, (20S) -7-acetoxymethyl CPT, (20S) -7-n-propylcarbonyloxymethyl CPT, (20S) -7-ethoxycarbonyl CPT, (20S) -7-ethyl-10-hydroxy CPT, (20S) -7-ethyl-lO-acetyloxy CPT, (20S) -7-methyl-lO-aminocarbonyloxy CPT, (20S) -7-n-propyl-10- piperidinocarbony
  • R 2 is selected from the group consisting of - (CY 2 ) hinder-L- (CY 2 ) x - cycloalkyl-, - (CY 2 ) W -L- (CY 2 ) x -heterocycle- , - (CY 2 ) W -L- (CY 2 ) x -aryl-, - (CY 2 ) W -L- (CY 2 ) x -fused ring system-, and -(CY 2 ) W -;
  • R 4 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aldehyde, carbonyl,
  • alkoxycarbonyl carboxyl, heterocycle, fused ring system, amino, imino, imido, azido, azo, alkylamine, arylamine, alkoxy, aryloxy, cyano, cyanato, hydroxyl, nitroso, and nitro;
  • Y is independently selected from the group consisting of H, D, R 4 , OR 4 , N(R 4 ) 2 , SR 4 , cyano, CA 3 , CA 2 R 4 , CA(R 4 ) 2 , C(R 4 ) 3 , and halogen;
  • A is independently selected from the group consisting of H, D, and halogen;
  • L is independently selected from the group consisting of 0, N(Y), S, and covalent bond;
  • w and x are independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;
  • R 2 is - (CY 2 ) register-L- (CY 2 ) -aryl-, wherein aryl is a substituted or unsubstituted phenyl and L is a covalent bond, then w and x cannot be 0;
  • R 2 is -(CY 2 ) register- L- (CY 2 ) -aryl, wherein aryl is a substituted phenyl and L is a covalent bond, then w cannot be 2 and x be 0; and if L is 0, then w cannot be 1 and x be 0.
  • R 2 is either - (CH 2 ) w -L-cyclo (C 3 -C 7 ) alkyl-, - (CH 2 ) w -L-heterocycle- where heterocycle is a fused bicyclic, tricyclic or tetracylic heterocycle made of 5- or 6-membered rings, - (CH 2 ) w -L-aryl-, - (CH 2 ) w -L-anthraquinone-, or -(CH 2 ) protest-;
  • L is either an 0, N (H) , S, or covalent bond
  • w is either an 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 2 is - (CH 2 ) w -L-aryl- where aryl is substituted with 1 to 5 substituents independently selected from the group consisting of halogen, (Ci-C 6 ) alkyl, hydroxyl, (Ci-C 6 ) alkoxy, cyano, nitro amino, (Ci-C 6 ) alkylamino, halo (Ci-C 6 ) alkylamino, halo (Ci-C 6 ) alkyl, halo (Ci ⁇ C 6 ) alkoxy, carbonyl, hydroxycarbonyl , (Ci-C 6 ) alkylcarbonyloxy, benzyloxy, a 5 or 6 membered heterocyclic ring, imide ring, (Ci ⁇ C 6 ) alkoxycarbonyl, and (Ci-C 6 ) alkylcarbonylamino ;
  • L is either an 0, N (H) , S, or covalent bond
  • w is either 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • a compound of Formula III (b) wherein: R is - (CH 2 ) w -L-aryl- where aryl is substituted with 1 to 5 substituents independently selected from the group consisting of halogen, (Ci-C 6 ) alkyl, hydroxyl, (Ci-C 6 ) alkoxy, cyano, nitro amino, (Ci-C 6 ) alkylamino, halo (Ci-C 6 ) alkylamino, halo (Ci-C 6 ) alkyl, halo (Ci ⁇ C 6 ) alkoxy, carbonyl, hydroxycarbonyl , (Ci-C 6 ) alkylcarbonyloxy, benzyloxy, a 5 or 6 membered heterocyclic ring, imide ring, (Ci ⁇ C 6 ) alkoxycarbonyl, and (Ci-C 6 ) alkylcarbonylamin
  • L is either an 0 or S
  • w is either 1, 2, or 3.
  • a compound of Formula III (b) wherein: R 2 is - (CH 2 ) -O-aryl- where aryl is a phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, methyl, methoxy, nitro, trifluoromethyl, and carbonyl.
  • a compound of Formula III (b) wherein: R 2 is - (CH 2 ) -O-aryl- where aryl is a phenyl substituted with 1 to 2 halogens.
  • a compound of Formula III (b) wherein: R 2 is - (CH 2 ) -O-aryl- where aryl is a phenyl substituted with a methyl substituent.
  • R 2 is either - (CH 2 ) -L-cyclo (C 3 -C 7 ) alkyl-, - (CH 2 ) -L-heterocycle- where heterocycle is a fused bicyclic, tricyclic or tetracylic heterocycle made of 5- or 6-membered rings, or -(CH 2 )-L- anthraquinone- ; and
  • L is either an 0, N (Y) , S, or covalent bond.
  • R 2 is either - (CH 2 ) -O-cyclo (C 3 -C 7 ) alkyl-, - (CH 2 ) -O-heterocycle- where heterocycle is a fused bicyclic, tricyclic or tetracylic heterocycle made of 5- or 6-membered rings, or -(CH 2 ) w -0- anthraquinone- ; and
  • w is either an 0, 1, 2, or 3.
  • a compound of Formula III (b) wherein: R is either - (CH 2 ) w -cyclo (C3-C7) alkyl-, - (CH 2 ) w -heterocycle- where heterocycle is a fused bicyclic, tricyclic or tetracylic
  • heterocycle made of 5- or 6-membered rings, or -(CH 2 ) consult- anthraquinone- ;
  • w is either an 0, 1, 2, or 3.
  • R 2 is - (CH 2 ) w -heterocycle- where heterocycle is a fused bicyclic, tricyclic or tetracylic heterocycle;
  • w is either an 0, 1, 2, or 3.
  • R 2 is - (CH 2 ) w -quinolin-4-yl- where quinolin-4-yl is optionally substituted;
  • w is either an 0, 1, 2, or 3.
  • R 2 is - (CH 2 ) w -2-phenylquinolin-4-yl ;
  • w is either an 0, 1, 2, or 3.
  • R 2 is - (CH 2 ) w -chromon-2-yl ;
  • w is either an 0, 1, 2, or 3.
  • R 2 is either - (CH 2 ) w -cyclo (C3-C7) alkyl- or - (CH 2 ) w -anthraquinone- ;
  • w is either an 0, 1, 2, or 3.
  • R 2 is - (CH 2 ) w -anthraquinon-l-yl- ;
  • w is either an 0, 1, 2, or 3.
  • R 3 is a residue selected from the group consisting of:
  • R 3 has the residue
  • R 5 is either H, D, halogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, hydroxyl,
  • R 5 in combination with R 6 forms an amino substituted cyclo (Ci-C 6 ) alkyl .
  • R 9 is either H, D, halogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, hydroxyl,
  • R 10 is R -0- (CH 2 ) s- .
  • R 11 is either (Ci-C 6 ) alkyl, phenyl that is optionally substituted with one to five substituents that are either a halogen, (Ci-C 6 ) alkyl, (Ci ⁇ C 6 ) alkoxy, hydroxyl, cyano, nitro, amino, halo (Ci-C 6 ) alkyl, halo (Ci ⁇ C 6 ) alkoxy, formyl, (Ci-C 6 ) alkylcarbonyl, hydroxycarbonyl, (Ci ⁇ C 6 ) alkylcarbonyloxy, benzyloxy, an optionally substituted
  • C 6 ) alkylcarbonyloxy and (Ci-C 6 ) alkylcarbonylamino, 1- or 2-naphthyl that is optionally substituted with one to four substituents that are either a halogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) alkoxy, hydroxyl, cyano, nitro, amino, halo (Ci-C 6 ) alkyl, halo (Ci-C 6 ) alkoxy, hydroxycarbonyl, (Ci-C 6 ) alkoxycarbonyl, (Ci-C 6 ) alkylcarbonyloxy, and (Ci ⁇
  • C 6 alkylcarbonylamino
  • R 12 is either a H, D, (Ci to C 6 ) alkyl, optionally substituted phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or
  • dialkylamino- (Ci-C 6 ) alkyl R 12 in combination with R 13 forms an amino substituted cyclo (Ci-C 6 ) alkyl, R 12 in combination with R 13 forms an
  • R 13 is either H, D, (Ci to C 6 ) alkyl, optionally substituted phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or dialkylamino- (Ci ⁇ C 6 ) alkyl, R 13 in combination with R 12 forms an amino substituted cyclo (Ci-C 6 ) alkyl, R 13 in combination with R 12 forms an (Ci-C 6 ) alkyl substituted heterocycle containing 1 nitrogen, or R 13 in combination with R 12 forms a (Ci-C 6 ) alkyl substituted heterocycle containing 2 nitrogens .
  • R 14 is either (Ci-C 6 ) alkoxy, cyano, amino (Ci-C 6 ) alkoxy, mono- or di- (Ci-C 6 ) alkylamino- (Ci-C 6 ) alkoxy, (Ci-C 6 ) alkylthio, amino (Ci ⁇
  • R 15 is either H, D, (Ci-C 6 ) alkyl, phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci- C 6 ) alkyl, or mono- or di- (Ci-C 6 ) alkyl, or R in combination with R 16 forms a heterocycle.
  • R 16 is either H, D, (Ci-C 6 ) alkyl, phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or di- (Ci-C 6 ) alkyl, or R 16 in
  • s is either 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • R 3 has the residue
  • R 6 is either a CH 2 NR 12 R 13 , NR 15 R 16 , or a dialkylamino-alkyl ;
  • R 7 is either (Ci-C 6 ) alkoxy, hydroxyl, halo (Ci-C 6 ) alkyl , halo(Ci- C 6 ) alkoxy, hydroxycarbonyl , formyl, (Ci-C 6 ) alkoxycarbonyl ,
  • R 8 is either H, or R 8 in combination with R 7 forms a [l,4]dioxino group ;
  • R 12 is either H, (Ci-C 6 ) alkyl, optionally substituted phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or dialkylamino- (Ci-C 6 ) alkyl, or R 12 in combination with R 13 forms an amino
  • R 13 is either H, (Ci to C 6 ) alkyl, optionally substituted phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or dialkylamino- (Ci ⁇ C 6 ) alkyl, or R 12 in combination with R 13 forms an amino substituted cyclo (Ci-C 6 ) alkyl ;
  • R 15 is either H, (Ci-C 6 ) alkyl, phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or di- (Ci-C 6 ) alkyl, or R 15 in combination with R 16 forms a heterocycle; and R is either H, (Ci-C 6 ) alkyl, phenyl, hydroxy (Ci-C 6 ) alkyl, amino (Ci-C 6 ) alkyl, or mono- or di- (Ci-C 6 ) alkyl, or R 16 in combination with R 15 forms a heterocycle.
  • R 3 has the residue
  • R 7 is either a hydroxyl, alkoxy, or alkylcarbonyloxy
  • R 12 is (Ci-C 6 ) alkyl
  • R 13 is (Ci-C 6 ) alkyl .
  • R 5 is either H, (Ci-C 6 ) alkyl or halo (Ci-C 6 ) alkyl ;
  • R 6 is either H or (Ci-C 6 ) alkyl ;
  • R 7 is either (Ci-C 6 ) alkoxy, hydroxyl, halo (Ci-C 6 ) alkoxy,
  • R 8 is either H, or R 8 in combination with R 7 forms a [l,4]dioxino group .
  • R 3 has the residue of:
  • R 5 is either H, (Ci-C 6 ) alkyl or halo (Ci-C 6 ) alkyl ;
  • R 7 is a carbamoylox .
  • R 3 has the residue of:
  • R 5 is a (Ci-C 6 ) alkyl .
  • R 5 is a (Ci-C 6 ) alkyl
  • R 7 is selected either a hydroxyl, (Ci-C 6 ) alkoxy, halogenated (C : - C 6 ) alkoxy, hydroxycarbonyl , formyl, (Ci-C 6 ) alkoxycarbonyl ,
  • R" has the residue of:
  • R 5 is a tri- (Ci-Ce) alkylsilyl
  • R 7 is either a hydroxyl, (Ci-C 6 ) alkoxy, halogenated (Ci-C 6 ) alkoxy, hydroxycarbonyl , formyl, (Ci-C 6 ) alkoxycarbonyl, carbamoyloxy, or (Ci-C 6 ) alkylcarbonyloxy.
  • R 3 has the residue selected from the group consisting of:
  • the compound of Formula II is selected from the group consisting of:
  • the methods of the disclosure utilize heterocyclic compounds in the synthesis of the androsterone and/or epiandrosterone derivatives of the disclosure.
  • the methods of the disclosure utilize camptothecin compounds in the synthesis of the androsterone derivatives and/or epiandrosterone derivatives of the disclosure.
  • composition useful for treating an androgen- associated disorder in a warm-blooded animal, which composition comprises an epiandrosterone and/or androsterone derivative compound of the disclosure in combination with a pharmaceutically- acceptable excipient.
  • compositions in the form of a liposomal composition .
  • methods to use an epiandrosterone and/or androsterone are methods to use an epiandrosterone and/or androsterone
  • derivative compound described herein in the treatment of disorders including, but not limited to, androgen-associated disorders, estrogen-associated, androgen-sensitive, and/or estrogen-sensitive disorders .
  • an epiandrosterone and/or androsterone derivative compound described herein can be used as a therapy to treat a patient that has cancer.
  • an epiandrosterone and/or androsterone derivative compound disclosed herein can form a combination therapy with another therapeutic agent .
  • therapeutic agents that can be combined with epiandrosterone and/or androsterone derivative compounds of the disclosure include, but are not limited to, LHRH agonists, flutamide, nilutamide,
  • bicalutamide antiestrogenic agents, tamoxifen, ICT 182780, toremifene, LY 335563, LY 353381, lodoxifene, levormeloxifene, trilostane, inhibitors of testosterone 5-alpha-reductase, aromatase inhibitors, and androgenic compounds.
  • a process for making a compound disclosed herein by reacting androsterone or epiandrosterone with a reactant that is composed of two portions, a camptothecin or camptothecin analog portion, and a linker portion containing a nonprotected carboxyl group.
  • this reaction is carried out in the presence of a coupling agent and a solvent system.
  • said reaction mixture further comprises a catalyst.
  • the catalyst is a nucleophilic catalyst, such as DMAP.
  • the reaction mixture solvent system contains one or more aprotic solvents, preferably one or more polar aprotic solvents, such as
  • the reaction mixture used to make a compound disclosed herein contains a carboiimide containing coupling agent, including, but not limited to, DCC, DIC and EDCI .
  • the reactant can contain one or more protected functional groups, including, but not limited to, hydroxyl, carboxyl, and amino.
  • the camptothecin or camptothecin analog portion of the reactant comprises :
  • PG refers to a protecting group, such as BOC .
  • (Ci-C 6 ) alkyl refers to where the linker portion and camptothecin or camptothecin analog portion are joined.
  • compositions containing epiandrosterone and/or androsterone derivative compounds are prepared in accordance with known formulation techniques to provide a composition suitable for oral, topical, transdermal, rectal, by inhalation, parenteral
  • compositions of the disclosure are found by reference to the 18.sup.th or 19.sup.th Edition of Remington's Pharmaceutical. Sciences, Published by the Mack Publishing Co., Easton, Pa. 18040.
  • Unit doses or multiple dose forms are contemplated, each offering advantages in certain clinical settings.
  • the unit dose would contain a predetermined quantity of active epiandrosterone and/or androsterone derivative compound calculated to produce the desired effect (s) in the setting of treating disorder.
  • the multiple dose form may be particularly useful when multiples of single doses, or fractional doses, are required to achieve the desired effect. Either of these dosing forms may have specifications that are dictated by or directly dependent upon the unique
  • An epiandrosterone and/or androsterone derivative compound may be administered orally in a suitable formulation as an ingestible tablet, including, but not limited to, a buccal tablet, capsule, caplet elixir, suspension, syrup, trouche, wafer, lozenge, and the like.
  • a suitable formulation including, but not limited to, a buccal tablet, capsule, caplet elixir, suspension, syrup, trouche, wafer, lozenge, and the like.
  • the most convenient formulation is a tablet or capsule (individually or collectively designated as an "oral dosage unit") .
  • suitable formulations are prepared in accordance with standard formulating techniques available that match the characteristics of the compound to the excipients available for formulating an appropriate composition.
  • the form may deliver a compound rapidly or may be a sustained-release preparation.
  • androsterone derivative compound may be enclosed in a hard or soft capsule, may be compressed into tablets, or may be incorporated with beverages, food or otherwise into the diet.
  • the suitable formulation of an oral dosage unit may also comprise: a binder, such as gum tragacanth, acacia, com starch, and gelatin; sweetening agents such as lactose or sucrose;
  • a binder such as gum tragacanth, acacia, com starch, and gelatin
  • sweetening agents such as lactose or sucrose
  • disintegrating agents such as com starch, alginic acid and the like; a lubricant such as magnesium stearate; or flavoring such a peppermint, oil of wintergreen or the like.
  • Various other materials may be present as coating or to otherwise modify the physical form of the oral dosage unit.
  • the oral dosage unit may be coated with shellac, a sugar or both.
  • the pharmaceutical composition containing an epiandrosterone and/or androsterone derivative compound disclosed herein may be formulated as a syrup or elixir, and may contain sucrose as a sweetening agent, methyl and propylparabens as a preservative, a dye and a flavoring. Any material utilized should be pharmaceutically-acceptable and substantially non-toxic. Details of the types of excipients useful may be found in the nineteenth edition of "Remington: The Science and Practice of Pharmacy," Mack Printing Company, Easton. Pa, See particularly chapters 91-93 for a fuller discussion.
  • An epiandrosterone and/or androsterone derivative compound disclosed herien may be administered parenterally, e.g., intravenously, intramuscularly, intravenously, subcutaneously, or interperitonically .
  • the carrier or excipient or excipient mixture can be a solvent or a dispersive medium containing, for example, various polar or non-polar solvents, suitable mixtures thereof, or oils. The use of such substances and the agents for
  • compositions are well known in the art, except insofar as any conventional media or agent is incompatible with the active ingredient, use in therapeutic compositions is contemplated. Moreover, other or supplementary active ingredients can also be incorporated into the final composition.
  • Solutions of the epiandrosterone and/or androsterone derivative compound may be prepared in suitable diluents such as water, ethanol, glycerol, liquid polyethylene glycol (s) , various oils, and/or mixtures thereof, and others known to those skilled in the art.
  • suitable diluents such as water, ethanol, glycerol, liquid polyethylene glycol (s) , various oils, and/or mixtures thereof, and others known to those skilled in the art.
  • the pharmaceutical forms suitable for injectable use include, but are not limited to, sterile solutions, dispersions, emulsions, and sterile powders.
  • the final form must, be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form must be protected against contamination and must, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi.
  • a single intravenous or intraperitoneal dose can be administered. Alternatively, a slow long term infusion or multiple short term daily infusions may he utilized, typically lasting from 1 to 8 days. Alternate day or dosing once every several days may also be utilized.
  • dispersions are made by incorporating the
  • epiandrosterone and/or androsterone derivative compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above.
  • the preferred methods include vacuum drying or freeze drying to which any required ingredients are added.
  • molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized.
  • Prevention or inhibition of growth of microorganisms may be achieved through the addition of one or more antimicrobial agents such as chlorobutanol, ascorbic acid, parabens, thermerosal, or the like. It may also be preferable to include agents that alter the tonicity such as sugars or salts .
  • an epiandrosterone and/or androsterone derivative compound of the disclosure is quite water insoluble, it may be useful to provide liposomal delivery.
  • the system restrains the compound of the disclosure by incorporating, encapsulating, surrounding, or entrapping the compound of the disclosure in, on, or by lipid vesicles or liposomes, or by micelles .
  • Epiandrosterone and/or androsterone derivative compounds described herein can be used for the treatment of disorders, including, but not limited to, androgen-associated disorders, estrogen-associated disorders, androgen-sensitive disorders, and estrogen-sensitive disorders.
  • Androgen-associated disorders include, but are not limited to, prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, and polycystic ovarian syndrome.
  • Estrogen- associated disorders include, but are not limited to, breast cancer, endometriosis, leiomyoma, and precocious puberty.
  • Precocious puberty is usually associated with an excess of androgen secretion, usually of adrenal origin.
  • treatments include a blockade of adrenal secretion by
  • glucocorticoids Another treatment is the use of LHRH agonists to cause medical castration.
  • Polycystic ovarian syndrome is associated with an excess of androgen secretion by the ovaries.
  • LHRH agonists are used among other, as treatment to cause medical castration.
  • Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists ( "antiandrogens” ) or estrogen receptor antagonists ( “antiestrogens” ) , respectively. See e.g. WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also he reduced by inhibiting receptor activation using receptor antagonists, suppressing androgen or estrogen biosynthesis using inhibitors of engines that catalyze one or more steps of such biosynthesis or by-suppressing ovarian or testicular secretions by known methods .
  • Both androgen-sensitive and estrogen-sensitive disorders may be treated with an epiandrosterone and/or androsterone derivative compound of the disclosure.
  • Androgen-sensitive disorders are those whose onset or progress is aided by androgen activation of androgen receptors, and should, therefore, respond favorably to treatment with an epiandrosterone and/or androsterone derivative compound of the disclosure. In would be expected that an
  • Estrogen-sensitive disorders are those disorders whose onset or progress is aided by activation of the estrogen receptor. In would be expected that an epiandrosterone and/or androsterone derivative compound of the disclosure would reduce estrogen biosynthesis by suppressing the formation of the androgen precursors required for estrogen biosynthesis. Androgen-sensitive disorders include, but are not limited to, prostatic cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia and polycystic ovarian syndrome. Estrogen-sensitive disorders include, but are not limited to, breast cancer, endometrial cancer, endometriosis, and
  • Epiandrosterone and/or androsterone derivative compounds disclosed herein can inhibit estrogen activity while maintaining or increasing androgen activity.
  • Conditions such as breast cancer, ovarian cancer, uterine cancer, endometrial cancer and other estrogen-sensitive disorders, benefit by inhibiting estrogen related activity while maintaining or increasing androgen activity.
  • Epiandrosterone and/or androsterone derivative compounds disclosed herein therefore, can be effective treatments for disorders which respond negatively to estrogen and positively to androgen.
  • Androgen-camptothecin combination compounds disclosed herein can be effective anti-neoplastic agents.
  • Camptothecin inhibits topoisomerase , an enzyme that is required for unwiding and relaxing DNA during molecular events, such as replication and transcription.
  • Epiandrosterone and/or androsterone derivative compounds of the disclosure that contain a camptothecin or camptothecin component, would have an additive anti-neoplastic effect.
  • an androsterone and/or epiandrosterone derivative of the disclosure can be utilized as part of a
  • a combination therapy can include an
  • an anti-cancer agent selected from the group including, but not limited to, alkylating agents, anti-metabolite agents, mitotic inhibitors, tyrosine kinase inhibitors, topoisomerase inhibitors, cancer immunotherapy monoclonal antibodies, and anti-tumor antibiotic agents.
  • Epiandrosterone and/or androsterone derivative compounds of the disclosure can be utilized as part of a combination therapy with other strategies, which modulate androgen- or estrogen- associated disorders through other mechanisms, thus providing for synergistic combinations.
  • An androsterone and/or epiandrosterone derivatives of the disclosure can be utilized as part of a combination therapy with other strategies, which modulate androgen- or estrogen- associated disorders and disorders through other mechanisms, thus providing synergistic combinations.
  • a combination therapy can include an androsterone and/or epiandrosterone derivative of the disclosure with an agent selected from the group including, but not limited to, LHRH agonists (see, e.g., U.S. Pat. No.
  • raloxifene Pfizer Inc., USA
  • raloxifene Eli Lilly and Co., USA
  • LY 335563 and LY 353381 Eli Lilly and Co., USA
  • lodoxifene (SmithKline Beecham, USA)
  • levormeloxifene Novo
  • trilostane 2a-cyano-4a, 5a-epoxy-17 - hydroxyandrostan-3-one
  • inhibitors of testosterone 5-alpha- reductase e.g., PROSCAR
  • an aromatase inhibitor e.g., AR1MIDEX
  • androgenic compounds e.g., medroxyprogesterone acetate, and megestrol acetate
  • the attending clinician will typically target the subject's serum concentration between 0.5 ng/rnl and 100 ng/ml, more typically between 1 ng/ml and 20 ng/ml, and more commonly between 1 ng/ml and 10 ng/ml. Serum concentration may be measured by various techniques known in the art (e.g.. LC/MS) .
  • the dosage which is usually effective to provide the desired serum levels is between 1.0. mg and 1.000 mg of active ingredient per day per 50 kg of body weight, typically between 10 mg and 500 mg and more commonly between 10 mg and 100 mg .
  • dosage will vary with the bioavailability of the chosen inhibitor and with individual subject's response.
  • the attending clinician will typically monitor aa individual subject's response and metabolism and adjust the subject's dosage accordingly.
  • a lower dosage is typically used, e.g. 10 mg to 100 mg per day per 50 kg of body weight.
  • epiandrosterone and/or androsterone derivative compound of the disclosure can be used in any of the therapies discussed herein, and may be formulated in pharmaceutical compositions which may include one or more additional active ingredients as discussed above. Alternatively, they may each be administered individually separately or simultaneously. In some embodiments of the
  • one or more active ingredients are formulated in a single pharmaceutical composition.
  • Reactions a, b and c are provided as representative methods to make androsterone or epiandrosterone derivative
  • Reaction a compound 1 can coupled to a R 1 compound containing a carboxylic acid group in presence of an appropriate coupling reagent, such as N,N '-dicyclohexylcarbodiimide (DCC) , in an appropriate solvent, such as dichloromethane, to afford compound 2.
  • an appropriate coupling reagent such as N,N '-dicyclohexylcarbodiimide (DCC)
  • DCC N,N '-dicyclohexylcarbodiimide
  • dichloromethane dichloromethane
  • the rate of reaction a can be increased by adding an appropriate catalyst, such as 4-dimethylaminopyridine (DMAP) .
  • DMAP 4-dimethylaminopyridine
  • Reaction b compound 1 can be coupled to a R 1 compound containing an activated carboxylic acid derivative group, such as an acyl halide, in the presence of an appropriate base, such as triethylamine , in an appropriate solvent, such as dichloromethane, to give compound 2.
  • an activated carboxylic acid derivative group such as an acyl halide
  • an appropriate base such as triethylamine
  • an appropriate solvent such as dichloromethane
  • Reaction c compound 1 can be linked to a R 1 compound containing an appropriate leaving group (LG) through a SN 2
  • Reactions d and e are provided as representative methods to make androsterone or epiandrosterone derivative compounds of the disclosure and should not be interpreted as the definitive methods to make the androsterone or epiandrosterone derivative compounds as disclosed herein. It can be expected that there may additional steps for protecting and deprotecting functional groups that may be involved in competing reactions .
  • Reaction d compound 3 can coupled to compound 4 in presence of an appropriate coupling reagent, such as l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide) (EDCI), in an appropriate solvent, such as dichloromethane, to afford compound 5 .
  • an appropriate coupling reagent such as l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide) (EDCI)
  • EDCI l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide)
  • dichloromethane an appropriate solvent
  • the rate of reaction d can be increased by adding an appropriate catalyst, such as 4-dimethylaminopyridine (DMAP) .
  • DMAP 4-dimethylaminopyridine
  • Reaction e compound 5 can be coupled to compound 1 in presence of an appropriate coupling reagent, such as l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide) (EDCI), in an appropriate solvent, such as dichloromethane, to afford compound 6 .
  • an appropriate coupling reagent such as l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide) (EDCI)
  • EDCI l-ethyl-3- (3- dimethylaminopropyl ) carbodiimide)
  • dichloromethane an appropriate solvent
  • the rate of reaction e can be increased by adding an appropriate catalyst, such as 4-dimethylaminopyridine (DMAP) .
  • DMAP 4-dimethylaminopyridine
  • Camptothecin-20S-O-ester of 4-carboxyphenoxyacetate (intermediate 1) .
  • a mixture of camptothecin (100 mg, 0.287 mmol) , 4-carboxyphenoxyacetic acid (112 mg, 0.57 mmol), EDCI (82 mg, 0.43 mmol), DMAP (10 mg, 0.1 mmol), N, AT -dimethylformamide (4 mL) , and dichloromethane (4 mL) was stirred at ambient temperature for 48 h. The mixture was diluted by adding dichloromethane (50 mL) .
  • Scheme III is illustrative of the synthesis route to make 4- (4-Ethyl-3, 13-dioxo-3, 4,12, 13-tetrahydro-lH-2-oxa-6, 12a- diaza-dibenzo [b, h] fluoren-4-yloxycarbonylmethoxy) -benzoic acid 10 , 13-dimethyl-17-oxo-hexadecahydro-cyclopenta [ a ] phenanthren-3-yl ester (OL-1) .
  • CPT-phenoxyacetic acid A mixture of camptothecin (100 mg, 0.29 mmol) , 4-carboxyphenoxyacetic acid (112 mg, 0.57 mmol) , EDCI
  • Scheme IV is illustrative of the synthesis route to make 4- (10-diethylaminomethyl-4-ethyl-9-hydroxy-3, 13-dioxo-3, 4,12, 13- tetrahydro-lH-2-oxa-6, 12a-diaza-dibenzo [b, h] fluoren-4yl- oxycarbonylmethoxy) -benzoic acid 10, 13-dimethyl-17-oxo- hexadecahydrocyclopenta [ a] phenanthren-3yl-ester (OL-2) .
  • BOC-CPT-CPA A mixture of BOC-CPT, 4-carboxyphenoxyacetic acid (CPA), EDCI, DMAP, and dichloromethane was stirred at ambient temperature for 24 hr . The resulting solution was diluted with dichloromethane. The dichloromethane containing organic layer was washed sequentially with a saturated NH 4 C1 solution, water, and brine. After drying over MgS04, the solvent was removed in vacuo. The resulting residue was then purified by flash column
  • BOC-CP -androgen (Intermediate 2) : A mixture of BOC-CPT- CPA, epiandrosterone , EDCI, DMAP, and dichloromethane was stirred at ambient temperature for 24 hr . The resulting solution was diluted with dichloromethane. The dichloromethane containing organic layer was washed sequentially with a 5% Na 2 C0 3 solution, water, and brine. After drying over MgS0 4 , the solvent was removed in vacuo.
  • Scheme V is illustrative of the synthesis route to make 3 , 5-dinitro-benzoic acid 4- ⁇ 2- [4- (10, 13-dimethyl-17-oxo- hexadecahydro-cyclopent [a] phenanthren-3-yloxycarbonyl) -phenoxy] - acetoxy ⁇ -4 -ethyl-3, 13-dioxo-3, 4,12, 13-tetrahydro-lH-2-oxa-6, 12a- diaza-dibenzo [b, h] fluoren- 9yl ester (OL-3) .
  • camptothecin-based analog including those camptothecin-based analogs disclosed herein
  • an androsterone or epiandrosterone analog in accordance to the procedures disclosed herein or obvious variants thereof, compounds of the disclosure will be obtained. These compounds will exhibit the desired characteristics to a greater or lesser extent.
  • HCT116 cells colonal carcinoma cells
  • epiandrosterone and/or androsterone derivative compounds as disclosed herein.
  • the results are presented in Table 1.
  • Epiandrosterone and/or androsterone derivative compounds of the disclosure were less toxic to normal cells while being effective at killing cancer cells (particularly breast cancer cells) .
  • HCT116 Cell Survival Studies with Epiandrosterone and/or Androsterone Derivative Compounds of the Disclosure To test the cytotoxicity of androsterone and/or epiandrosterone derivatives of the disclosure on cancer cells, HCT116 cells
  • colonal carcinoma cells were plated in 60 mm Petri dishes containing 2.7 ml of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/ml penicillin and 100 g/mL streptomycin) .
  • the cells were incubated in a C0 2 incubator at 37 °C for 5 hours to allow for cell attachment to the bottom of the Petri dishes.
  • a stock solution containing either the compound of Example 8 or 9 was made right before the experiment in fresh medium at ten times the final concentration. Then 0.3 ml of this stock solution was added to the 2.7 mL of medium containing 5% bovine calf serum (BCS) in the Petri dish.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/ml penicillin and 100 g/mL streptomycin
  • the cells were then incubated with the compounds for 72 hours at 37 °C. At the end of incubation, the drug-containing media was decanted off, the cells were washed with 4 ml of Hank's Balance Salt Solution (HBSS) , and then 5 mL of fresh medium containing 15% BCS was added. The dishes were returned to the incubator to allow for colony formation. After 8 days, the cell colonies were stained with methylene blue (0.3% in ethanol) and then counted using a colony counter. Cell survival was calculated and the IC 50 values (the drug concentration producing 50% inhibition of colony formation) were determined for each compound tested. The IC50 values were 2.5 nM for Example 9
  • HBSS Hank's Balance Salt Solution
  • Example 8 (010216) and 3.5 nM for Example 8 (0103021) .
  • the results are presented in Table 2.
  • OL-2 and OL-3 proved to be very effective against PC-3 human prostate cancer cells.
  • the IC50 values for OL-2 and OL-3 were 131 nM and 18 nM, respectively.
  • OL-2 and OL-3 exhibited high effectiveness in killing on human malignant peripheral nerve sheath tumor (MPNST) cells (ST88-14) and SF295 human glioblastoma cells (Figs. 5-8 ) .
  • the IC50 values for OL-2 and OL-3 in killing ST88-14 cells were 76 nM and 4 nM, respectively.
  • the IC50 values for OL-2 and OL-3 in killing SF295 cells were 290 nM and 31 nM,
  • the MTD values of OL-1, OL-2 and OL-3 would be higher than 500 mg/kg.
  • the toxicity data suggests that the toxicity of epiandrosterone and/or androsterone derivatives of the disclosure in normal mice is extremely low (for OL-1, OL-2, and OL-3) or predicted to be extremely low for other nontested epiandrosterone and/or androsterone derivatives disclosed herein.
  • OL-3 was the most effective compound in controlling the growth of PC-3 xenografts.
  • OL-3 treated group one mouse exhibited tumor-free.
  • the survival time of the nude mice treated with OL-3 was remarkably longer than that of the mice treated with OL-1 or OL-2.
  • the results in Figs. 12-14 showed that all three OL compounds were also markedly effective in inhibiting the growth of DU-145 prostate cancer xenografts, compared with the control group.
  • the survival time of the mice treated with both OL- 1 and OL-3 was longer than that of the mice treated with OL-2.
  • the data in Fig. 13 showed that the mean time for tumor volume reaching 1,000 cu .
  • mm in the group treated with OL-3 was notably longer than that of the groups treated with OL-1 and OL-2. All the results demonstrate that OL-1, OL-2 and OL-3 were significantly effective and non-toxic compounds against both PC-3 and DU-145 human prostate cancer xenografts. Untested epiandrosterone and/or androsterone derivative compounds of the disclosure are likely to be effective anti-neoplastic agents.

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Abstract

Dérivés d'épiandrostérone et/ou d'androstérone de Formule II, leur procédé de préparation, compositions pharmaceutiques les contenant, et leurs procédés d'utilisation.
PCT/US2011/030306 2011-03-29 2011-03-29 Dérivés d'épiandrostérone et/ou d'androstérone et leur procédé d'utilisation Ceased WO2012134446A1 (fr)

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US11952349B2 (en) 2019-11-13 2024-04-09 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
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