US2010317635A1PendingUtilityA1
Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators
Est. expiryJun 16, 2029(~2.9 yrs left)· nominal 20-yr term from priority
Inventors:Fernand Labrie
A61P 3/06A61P 43/00A61P 5/32A61P 9/00A61P 3/10A61P 9/10A61P 5/24A61P 9/12A61P 35/00A61P 5/50A61P 25/28A61P 25/20A61P 25/00A61P 3/04A61P 3/00A61P 15/08A61P 15/02A61P 19/10A61P 21/00A61P 15/12A61K 31/5685A61K 31/568A61K 31/085A61K 31/453A61K 9/20A61K 31/192A61K 9/0034A61K 31/4025A61K 31/138A61K 31/4535A61K 31/40A61K 31/4436A61K 9/02A61K 9/48
50
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Novel methods for reduction or elimination the incidence of hot flushes, vasomotor symptoms, and night sweats while decreasing the risk of acquiring breast, uterine or endometrial cancer and furthermore having beneficial effect by inhibiting the development of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, diabetes type 2, loss of muscle mass, adiposity, Alzheimer's disease, loss of cognition, loss of memory, or vaginal dryness in susceptible warm-blooded animals including humans involving administration of an amount of a sex steroid precursor, particularly dehydroepiandrosterone (DHEA) and an antiestrogen or a selective estrogen receptor modulator, particularly compounds having the general structure: Pharmaceutical compositions for delivery of active ingredient(s) and kit(s) useful to the invention are also disclosed.
Claims
exact text as granted — not AI-modified1 . A method of reducing or eliminating the incidence of symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, said method comprising administering to a patient in need of said elimination or reduction, (i) a therapeutically effective amount of a sex steroid precursor or prodrug thereof in association with (ii) a therapeutically effective amount of a selective estrogen receptor modulator or an antiestrogen or prodrug of either.
2 . The method of claims 1 wherein said sex steroid precursor is selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androst-5-ene-3β,17β-diol, 4-androstene-3,17-dione, and a prodrug of any of the foregoing precursors.
3 . A pharmaceutical composition for reducing or eliminating symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, comprising:
a) a pharmaceutically acceptable excipient, diluent or carrier; b) at least one sex steroid precursor or prodrug thereof; and c) at least one selective estrogen receptor modulator or an antiestrogen or prodrug of either; wherein said pharmaceutical composition is provided in packaging that directs use of said composition for reduction or elimination of at least one symptom selected from the group consisting of hot flushes, vasomotor symptoms and night sweats.
4 . The pharmaceutical composition of claim 3 wherein both sex steroid precursor and selective receptor modulator or antiestrogen are formulated together in a pharmaceutical delivery form selected from the group consisting of pill, tablet, cream, gel, intravaginal suppository, and intravaginal ovule.
5 . A kit for reducing or eliminating symptoms selected from the group consisting of hot flushes, vasomotor symptoms, and night sweats, comprising (i) a first container having therein a at least one sex steroid precursor or a prodrug thereof; (ii) a second container having therein a at least one selective estrogen receptor modulator, or an antiestrogen or prodrug of either of the foregoing; and (iii) instructions for using the kit for the reduction or elimination of at least one symptom selected from the group consisting of hot flushes, vasomotor symptoms and night sweats.
6 . The method of claim 1 wherein the selective estrogen receptor modulator has a molecular formula with the following features:
a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
7 . The method of claim 6 wherein the side chain is selected from the group consisting of:
8 . The method of claim 1 wherein the selective estrogen receptor modulator is selected from the group consisting of a triphenylethylene derivative, indole derivative, benzopyran derivative, Tamoxifen, Toremifene, CC 8490, SERM 3471, HMR 3339, HMR 3656, Raloxifene, LY 335124, LY 326315, Arzoxifene (LY 353381), SH 646, Pipendoxifene (ERA 923), Bazedoxifene (TSE 424, WAY 140424), Oporia (Lasoxifene) and centchroman derivative.
9 . The method of claim 1 wherein the selective estrogen receptor modulator is a benzothiophene derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 3 and R 4 are either (a) independently C1-C4 alkyl, or (b) a moiety which in combination with the nitrogen to which they are bound, is selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino;
c) wherein A is selected from the group consisting of —CO—, —CHOH, and —CH 2 —;
d) wherein B is selected from the group consisting of phenylene, pyridylidene, and -cycloC 4 H 2 N 2 —.
10 . The method of claim 1 wherein the selective estrogen receptor modulator is selected from the group consisting of Raloxifene, Arzoxifene (LY 353381), LY 353381 and LY 335563.
11 . The method of claim 1 wherein the selective estrogen receptor modulator is a triphenylethylene or diphenylhydronaphthalene derivative compound of the following formula:
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 , —OCH 2 CH 2 OH, or —CH═CH—COOH(R 3 and R 4 either being independently selected from the group consisting of C1-C4 alkyl, or R 3 , R 4 , and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino);
b) wherein E and K are independently hydrogen or hydroxyl, phosphate ester, or lower alkyl, wherein J is hydrogen or halogen.
12 . The method of claim 1 wherein selective estrogen receptor modulator is Tamoxifen, OH-tamoxifen, Droloxifene, Toremifene, Iodoxifene, Lasofoxifene, iproxifene, FC 1271, and GW5638.
13 . The method of claim 1 wherein the selective estrogen receptor modulator is an indole derivative compound of the following formula:
a) wherein D is selected from the group consisting of —OCH 2 CH 2 N(R 7 )R 8 , —CH═CH—CO N(R 7 )R 8 , —CC—(CH 2 ) n —N(R 7 )R 8 (R 7 and R 8 either being independently selected from the group consisting of C 1 -C 6 alkyl, or R 7 , R 8 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein X is selected from the group consisting of: hydrogen, and C1-C6 alkyl;
c) wherein R 1 , R 2 R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 6 alkyl, and a moiety converted in vivo in hydroxyl.
14 . The method of claim 1 wherein the selective estrogen receptor modulator is selected from the group consisting of Bazedoxifene (TSE 424; WAY-TSE 424; WAY 140424; 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) and Pipendoxifene (ERA 923; 2-(4-hydroxyphenyl)-3-methyl-1-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-1H-indol-5-ol).
15 . The method of claim 1 wherein the selective estrogen receptor modulator is a centchroman derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 5 and R 6 are independently hydrogen or C 1 -C 6 alkyl;
c) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino).
16 . The method of claim 1 wherein the centchroman derivative is (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman).
17 . The method of claim 1 wherein the selective estrogen receptor modulator has the following formula:
a) wherein R 1 and R 2 are independently hydrogen, hydroxyl or a moiety which is converted to hydroxyl in vivo;
b) wherein Z is either absent or selected from the group consisting of —CH 2 —, -0-, —S— and —NR 3 — (R 3 being hydrogen or lower alkyl);
c) wherein the R100 is a bivalent moiety which distances L from the B-ring by 4-10 intervening atoms;
d) wherein L is a bivalent or trivalent moiety selected from the group of —SO—, —CON—, —N<, and —SON<;
e) wherein G 1 is selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 2 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
f) wherein G 2 is either absent or selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 1 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
g) wherein G 3 is selected from the group consisting of hydrogen, methyl and ethyl.
18 . The method of claim 1 , wherein the selective estrogen receptor modulator is a benzopyran compound of the following general structure:
or a pharmaceutically acceptable salt thereof,
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl.
19 . The method of claim 18 , wherein the benzopyran compound is optically active due to a majority of its stereoisomers having an absolute configuration S on carbon 2, said compound having the molecular structure:
a) wherein R 1 and R 2 are independently selected from the group consisting of hydroxyl and a moiety convertible in vivo to hydroxyl;
b) wherein R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and NRaRb (Ra and Rb being independently hydrogen, straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight or branched C 2 -C 6 alkynyl).
20 . The method of claim 19 wherein said compound or salt substantially lacks (2R)-enantiomer.
21 . The method of claim 1 where said selective estrogen receptor modulator is:
and is optically active due to a majority of its stereoisomers being of 2S configuration.
22 . The method of claim 18 wherein the selective estrogen receptor modulator is a benzopyran salt of an acid selected from the group consisting of acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrochlorothiazide acid, hydroxy-naphthoic acid, lactic acid, maleic acid, methanesulfonic acid, methylsulfuric acid, 1,5-naphthalenedisulfonic acid, nitric acid, palmitic acid, pivalic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, and valeric acid.
23 . The method of claim 1 wherein said selective estrogen receptor modulator is:
and is optically active due to a majority of its enantiomers being of 2S configuration; and wherein the sex steroid precursor is dehydroepiandrosterone.
24 . The method of claim 1 , wherein the selective estrogen receptor modulator has no estrogenic activity in breast, uterine or endometrium tissues.
25 . The method of claim 1 , wherein said treatment also reduces the risk of the patients acquiring breast, uterine or endometrial cancer.
26 . The method of claim 1 , wherein said treatment also inhibits the development of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, diabetes type 2, loss of muscle mass, adiposity, Alzheimer's disease, loss of cognition, memory loss or vaginal dryness.
27 . The method of claim 1 , wherein the antiestrogen is Faslodex (ICI 182 780, fulvestrant, 7□-[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17□-diol).
28 . The method of claim 1 wherein said selective estrogen receptor modulator is intravaginally administered.
29 . The method of claim 21 wherein the selective estrogen receptor modulator is intravaginally administered.
30 . The method of claim 1 wherein the selective estrogen receptor modulator is orally administered.
31 . The method of claim 1 wherein the selective estrogen receptor modulator is percutaneously administered.
32 . The method of claim 1 wherein the selective estrogen receptor modulator is Opemifene.
33 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator has a molecular formula with the following features:
a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
34 . The pharmaceutical composition of claim 33 wherein the side chain is selected from the group consisting of:
35 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is selected from the group consisting of a triphenylethylene derivative, indole derivative, benzopyran derivative, Tamoxifen, Toremifene, CC 8490, SERM 3471, HMR 3339, HMR 3656, Raloxifene, LY 335124, LY 326315, Arzoxifene (LY 353381), SH 646, Pipendoxifene (ERA 923), Bazedoxifene (TSE 424, WAY 140424), Oporia (Lasoxifene) and centchroman derivative.
36 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is a benzothiophene derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 3 and R 4 are either (a) independently C1-C4 alkyl, or (b) a moiety which in combination with the nitrogen to which they are bound, is selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino;
c) wherein A is selected from the group consisting of —CO—, —CHOH, and —CH 2 —;
d) wherein B is selected from the group consisting of phenylene, pyridylidene, and -cycloC 4 H 2 N 2 —.
37 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is selected from the group consisting of Raloxifene, Arzoxifene (LY 353381), LY 353381 and LY 335563.
38 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is a triphenylethylene or diphenylhydronaphthalene derivative compound of the following formula:
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 , —OCH 2 CH 2 OH, or —CH═CH—COOH (R 3 and R 4 either being independently selected from the group consisting of C1-C4 alkyl, or R 3 , R 4 , and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino);
b) wherein E and K are independently hydrogen or hydroxyl, phosphate ester, or lower alkyl, wherein J is hydrogen or halogen.
39 . The pharmaceutical composition of claim 3 wherein selective estrogen receptor modulator is Tamoxifen, OH-tamoxifen, Droloxifene, Toremifene, Iodoxifene, Lasofoxifene, iproxifene, FC 1271, and GW5638.
40 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is an indole derivative compound of the following formula:
a) wherein D is selected from the group consisting of —OCH 2 CH 2 N(R 7 )R 8 , —CH═CH—CO N(R 7 )R 8 , —CC—(CH 2 ) n —N(R 7 )R 8 (R 7 and R 8 either being independently selected from the group consisting of C 1 -C 6 alkyl, or R 7 , R 8 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein X is selected from the group consisting of: hydrogen, and C1-C6 alkyl;
c) wherein R 1 , R 2 R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 6 alkyl, and a moiety converted in vivo in hydroxyl.
41 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is selected from the group consisting of Bazedoxifene (TSE 424; WAY-TSE 424; WAY 140424; 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) and Pipendoxifene (ERA 923; 2-(4-hydroxyphenyl)-3-methyl-1-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-1H-indol-5-ol).
42 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is a centchroman derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 5 and R 6 are independently hydrogen or C 1 -C 6 alkyl;
c) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino).
43 . The pharmaceutical composition of claim 3 wherein the centchroman derivative is (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman).
44 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator has the following formula:
a) wherein R 1 and R 2 are independently hydrogen, hydroxyl or a moiety which is converted to hydroxyl in vivo;
b) wherein Z is either absent or selected from the group consisting of —CH 2 —, -0-, —S— and —NR 3 — (R 3 being hydrogen or lower alkyl);
c) wherein the R100 is a bivalent moiety which distances L from the B-ring by 4-10 intervening atoms;
d) wherein L is a bivalent or trivalent moiety selected from the group of —SO—, —CON—, —N<, and —SON<;
e) wherein G 1 is selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 2 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
f) wherein G 2 is either absent or selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 1 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
g) wherein G 3 is selected from the group consisting of hydrogen, methyl and ethyl.
45 . The pharmaceutical composition of claim 3 , wherein the selective estrogen receptor modulator is a benzopyran compound of the following general structure:
or a pharmaceutically acceptable salt thereof,
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo to hydroxyl.
46 . The pharmaceutical composition of claim 45 , wherein the benzopyran compound is optically active due to a majority of its stereoisomers having an absolute configuration S on carbon 2, said compound having the molecular structure:
a) wherein R 1 and R 2 are independently selected from the group consisting of hydroxyl and a moiety convertible in vivo to hydroxyl;
b) wherein R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and NRaRb (Ra and Rb being independently hydrogen, straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight or branched C 2 -C 6 alkynyl).
47 . The pharmaceutical composition of claim 46 wherein said compound or salt substantially lacks (2R)-enantiomer.
48 . The pharmaceutical composition of claim 3 where said selective estrogen receptor modulator is:
and is optically active due to a majority of its stereoisomers being of 2S configuration.
49 . The pharmaceutical composition of claim 45 wherein the selective estrogen receptor modulator is a benzopyran salt of an acid selected from the group consisting of acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrochlorothiazide acid, hydroxy-naphthoic acid, lactic acid, maleic acid, methanesulfonic acid, methylsulfuric acid, 1,5-naphthalenedisulfonic acid, nitric acid, palmitic acid, pivalic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, and valeric acid.
50 . The pharmaceutical composition of claim 3 wherein said selective estrogen receptor modulator is:
and is optically active due to a majority of its enantiomers being of 2S configuration; and wherein the sex steroid precursor is dehydroepiandrosterone.
51 . The pharmaceutical composition of claim 3 , wherein the selective estrogen receptor modulator has no estrogenic activity in breast, uterine or endometrium tissues.
52 . The pharmaceutical composition of claim 3 , wherein said treatment also reduces the risk of the patients acquiring breast, uterine or endometrial cancer.
53 . The pharmaceutical composition of claim 3 , wherein said treatment also inhibits the development of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, diabetes type 2, loss of muscle mass, adiposity, Alzheimer's disease, loss of cognition, memory loss or vaginal dryness.
54 . The pharmaceutical composition of claim 3 , wherein the antiestrogen is Faslodex (ICI 182 780, fulvestrant, 7□-[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17□-diol).
55 . The pharmaceutical composition of claim 3 wherein said composition includes a dosage form for intravaginal administration.
56 . The pharmaceutical composition of claim 48 wherein said composition includes a dosage form for intravaginal administration
57 . The pharmaceutical composition of claim 3 wherein said composition includes a dosage form for oral administration.
58 . The pharmaceutical composition of claim 3 wherein said composition includes a dosage form for percutaneous administration.
59 . The pharmaceutical composition of claim 3 wherein the selective estrogen receptor modulator is Opemifene.
60 . The kit of claim 5 wherein the selective estrogen receptor modulator has a molecular formula with the following features:
a) two aromatic rings spaced by 1 to 2 intervening carbon atoms, both aromatic rings being either unsubstituted or substituted by a hydroxyl group or a group converted in vivo to hydroxyl; b) a side chain possessing an aromatic ring and a tertiary amine function or salt thereof.
61 . The kit of claim 60 wherein the side chain is selected from the group consisting of:
62 . The kit of claim 5 wherein the selective estrogen receptor modulator is selected from the group consisting of a triphenylethylene derivative, indole derivative, benzopyran derivative, Tamoxifen, Toremifene, CC 8490, SERM 3471, HMR 3339, HMR 3656, Raloxifene, LY 335124, LY 326315, Arzoxifene (LY 353381), SH 646, Pipendoxifene (ERA 923), Bazedoxifene (TSE 424, WAY 140424), Oporia (Lasoxifene) and centchroman derivative.
63 . The kit of claim 5 wherein the selective estrogen receptor modulator is a benzothiophene derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 3 and R 4 are either (a) independently C1-C4 alkyl, or (b) a moiety which in combination with the nitrogen to which they are bound, is selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino;
c) wherein A is selected from the group consisting of —CO—, —CHOH, and —CH 2 —;
d) wherein B is selected from the group consisting of phenylene, pyridylidene, and -cycloC 4 H 2 N 2 —.
64 . The kit of claim 5 wherein the selective estrogen receptor modulator is selected from the group consisting of Raloxifene, Arzoxifene (LY 353381), LY 353381 and LY 335563.
65 . The kit of claim 5 wherein the selective estrogen receptor modulator is a triphenylethylene or diphenylhydronaphthalene derivative compound of the following formula:
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 , —OCH 2 CH 2 OH, or —CH═CH—COOH(R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 , and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino and morpholino);
b) wherein E and K are independently hydrogen or hydroxyl, phosphate ester, or lower alkyl, wherein J is hydrogen or halogen.
66 . The kit of claim 5 wherein selective estrogen receptor modulator is Tamoxifen, OH-tamoxifen, Droloxifene, Toremifene, Iodoxifene, Lasofoxifene, iproxifene, FC 1271, and GW5638.
67 . The kit of claim 5 wherein the selective estrogen receptor modulator is an indole derivative compound of the following formula:
a) wherein D is selected from the group consisting of —OCH 2 CH 2 N(R 7 )R 8 , —CH═CH—CO N(R 7 )R 8 , —CC—(CH 2 ) n —N(R 7 )R 8 (R 7 and R 8 either being independently selected from the group consisting of C 1 -C 6 alkyl, or R 7 , R 8 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein X is selected from the group consisting of: hydrogen, and C1-C6 alkyl;
c) wherein R 1 , R 2 R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of: hydrogen, hydroxyl, C 1 -C 6 alkyl, and a moiety converted in vivo in hydroxyl.
68 . The kit of claim 5 wherein the selective estrogen receptor modulator is selected from the group consisting of Bazedoxifene (TSE 424; WAY-TSE 424; WAY 140424; 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) and Pipendoxifene (ERA 923; 2-(4-hydroxyphenyl)-3-methyl-1-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-1H-indol-5-ol).
69 . The kit of claim 5 wherein the selective estrogen receptor modulator is a centchroman derivative compound of the following formula:
a) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo in hydroxyl;
b) wherein R 5 and R 6 are independently hydrogen or C 1 -C 6 alkyl;
c) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino).
70 . The kit of claim 5 wherein the centchroman derivative is (3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman).
71 . The kit of claim 5 wherein the selective estrogen receptor modulator has the following formula:
a) wherein R 1 and R 2 are independently hydrogen, hydroxyl or a moiety which is converted to hydroxyl in vivo;
b) wherein Z is either absent or selected from the group consisting of —CH 2 —, -0-, —S— and —NR 3 — (R 3 being hydrogen or lower alkyl);
c) wherein the R100 is a bivalent moiety which distances L from the B-ring by 4-10 intervening atoms;
d) wherein L is a bivalent or trivalent moiety selected from the group of —SO—, —CON—, —N<, and —SON<;
e) wherein G 1 is selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 2 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
f) wherein G 2 is either absent or selected from the group consisting of hydrogen, a C 1 to C 5 hydrocarbon, a bivalent moiety which in combination with G 1 and L is a 5- to 7-membered heterocyclic ring, and halo or unsaturated derivatives of the foregoing;
g) wherein G 3 is selected from the group consisting of hydrogen, methyl and ethyl.
72 . The kit of claim 5 , wherein the selective estrogen receptor modulator is a benzopyran compound of the following general structure:
or a pharmaceutically acceptable salt thereof,
a) wherein D is —OCH 2 CH 2 N(R 3 )R 4 (R 3 and R 4 either being independently selected from the group consisting of C 1 -C 4 alkyl, or R 3 , R 4 and the nitrogen atom to which they are bound, together being a ring structure selected from the group consisting of pyrrolidino, dimethyl-1-pyrrolidino, methyl-1-pyrrolidinyl, piperidino, hexamethyleneimino, morpholino);
b) wherein R 1 and R 2 are independently selected from the group consisting of: hydrogen, hydroxyl, and a moiety converted in vivo to hydroxyl.
73 . The kit of claim 72 , wherein the benzopyran compound is optically active due to a majority of its stereoisomers having an absolute configuration S on carbon 2, said compound having the molecular structure:
a) wherein R 1 and R 2 are independently selected from the group consisting of hydroxyl and a moiety convertible in vivo to hydroxyl;
b) wherein R 3 is a species selected from the group consisting of saturated, unsaturated or substituted pyrrolidinyl, saturated, unsaturated or substituted piperidino, saturated, unsaturated or substituted piperidinyl, saturated, unsaturated or substituted morpholino, nitrogen-containing cyclic moiety, nitrogen-containing polycyclic moiety, and NRaRb (Ra and Rb being independently hydrogen, straight or branched C 1 -C 6 alkyl, straight or branched C 2 -C 6 alkenyl, and straight or branched C 2 -C 6 alkynyl).
74 . The kit of claim 73 wherein said compound or salt substantially lacks (2R)-enantiomer.
75 . The kit of claim 5 where said selective estrogen receptor modulator is:
and is optically active due to a majority of its stereoisomers being of 2S configuration.
76 . The kit of claim 72 wherein the selective estrogen receptor modulator is a benzopyran salt of an acid selected from the group consisting of acetic acid, adipic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrochlorothiazide acid, hydroxy-naphthoic acid, lactic acid, maleic acid, methanesulfonic acid, methylsulfuric acid, 1,5-naphthalenedisulfonic acid, nitric acid, palmitic acid, pivalic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, terephthalic acid, p-toluenesulfonic acid, and valeric acid.
77 . The kit of claim 5 wherein said selective estrogen receptor modulator is:
and is optically active due to a majority of its enantiomers being of 2S configuration; and wherein the sex steroid precursor is dehydroepiandrosterone.
78 . The kit of claim 5 wherein the selective estrogen receptor modulator has no estrogenic activity in breast, uterine or endometrium tissues.
79 . The kit of claim 5 , wherein said treatment also reduces the risk of the patients acquiring breast, uterine or endometrial cancer.
80 . The kit of claim 5 , wherein said treatment also inhibits the development of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, diabetes type 2, loss of muscle mass, adiposity, Alzheimer's disease, loss of cognition, memory loss or vaginal dryness.
81 . The kit of claim 5 , wherein the antiestrogen is Faslodex (ICI 182 780, fulvestrant, 7□-[9-(4,4,5,5,5-pentafluoro-pentylsulphinyl)nonyl]oestra-1,3,5(10)-triene-3,17□-diol).
82 . The kit of claim 5 wherein at least one component of said kit is a dosage form for intravaginal administration.
83 . The kit of claim 75 wherein at least one component of said kit is a dosage form for intravaginal administration.
84 . The kit of claim 5 wherein at least one component of said kit is a dosage form for oral administration.
85 . The kit of claim 5 wherein at least one component of said kit is a dosage form for percutaneous administration.
86 . The kit of claim 5 wherein the selective estrogen receptor modulator is Opemifene.
87 . The pharmaceutical composition of claim 3 wherein the sex steroid precursor is selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androst-5-ene-3β,17β-diol and 4-androstene-3,17-dione.
88 . The kit of claim 5 wherein the sex steroid precursor is selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androst-5-ene-3β,17β-diol and 4-androstene-3,17-dione.
89 . The kit of claim 75 wherein said selective estrogen receptor modulator is in a dosage form for intravaginal administration.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.