- Preparation method of bazedoxifene acetate crystal form A
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The invention discloses a preparation method of a bazedoxifene acetate crystal form A. The method comprises the following steps: taking 1-(4-(2-(azepine-1-yl) ethoxy) benzyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-methyl-1H-indole as a raw material; preparing bazedoxifene acetate free alkali, preparing a bazedoxifene acetate crude product, preparing a bazedoxifene acetate crystal form B, preparing a bazedoxifene acetate crystal form C and preparing the bazedoxifene acetate crystal form A. A mixed solvent is adopted in the hydrogenation process of the method; the rate and the activity of thepalladium-carbon reduction reaction are improved; an antioxidant is added, so that the stability of the bazedoxifene free alkali is improved, the conversion from the crystal form B to the crystal formC is increased in the middle, key parameters for converting the crystal form C into the crystal form A are found, the purity of the crystal form A in the next step is greatly improved, and the production cost for producing the bazedoxifene acetate crystal form A is effectively reduced.
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Paragraph 0028-0031; 0044-0046
(2020/04/22)
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- Preparation method and application of bazedoxifene acetate crystal form D
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The invention belongs to the field of medicines, and in particular relates to a preparation method and application of a bazedoxifene acetate crystal form D. The method comprises the following steps: dissolving a compound A into a first good organic solvent; adding a catalyst and ammonium formate into the first good organic solvent, and performing a reaction; performing filtration to remove the catalyst, washing the filtrate by using an inorganic alkali aqueous solution, and separating an organic phase; performing concentration on the organic phase to obtain a bazedoxifene free alkali; dissolving the bazedoxifene free base into a second good organic solvent; adding glacial acetic acid into the second good organic solvent, and performing crystallization; and performing filtration to obtain the bazedoxifene acetate crystal form D, wherein the compound A has a structure represented by a formula I shown in the description. The technical solution provided by the invention does not require high-pressure hydrogenation, the solvent system is simple, the reaction equipment requirements are low, the industrialization is easy to realize, and the obtained bazedoxifene acetate crystal form D hashigh purity.
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Paragraph 0055-0060; 0075-0080; 0093-0098; 0102-0107
(2019/07/04)
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- METHODS OF PREPARINGBAZEDOXIFENE BY NEW INTERMEDIATES
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The present invention relates to a method for manufacturing novel bazedoxifene or a pharmaceutically acceptable salt thereof. A manufacturing method according to the present invention can provide high purity and high yield of bazedoxifene, and is economical in terms of time and cost and eco-friendly due to a relatively simple manufacturing process, thereby being able to be usefully applied to mass production.COPYRIGHT KIPO 2020
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- Industrial production method for bazedoxifene acetate
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The invention discloses an industrial production method for bazedoxifene acetate. The production method comprises the following steps: taking p-hydroxy benzaldehyde as a starting material, substituting with chloracetyl-hexamethyleneimine, reducing with borohydride and chlorinating with a chlorinating agent to obtain a compound 4; reacting the compound 4 with 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole to obtain a compound 5; and carrying out debenzylation to obtain a compound 6, and salifying with acetic acid to obtain a target compound which is the bazedoxifene acetate. The defective workmanship of preparation in the prior art is solved, the used reagent is low in cost and easy to obtain, environmental pollution is small, safety is high, an operation process is simple, and thus, the bazedoxifene acetate is suitable for being produced industrially.
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- METHODS OF PREPARING BAZOEDOXIFENE
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The present invention relates to novel bazedoxifene or to a method for producing a pharmaceutically acceptable salt thereof. The production method according to the present invention can provide the bazedoxifene with high purity and high yield, and is economical and environmentally friendly in terms of time and cost due to a relatively simple manufacturing process to be usefully applied to mass production.COPYRIGHT KIPO 2018
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- Acetic acid [...] and intermediate preparation method
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The invention discloses a bazedoxifene acetate intermediate and a preparation method thereof. The invention also discloses a method for preparing bazedoxifene acetate from the bazedoxifene acetate intermediate. The invention provides a method for preparing a novel intermediate of bazedoxifene acetate key as shown in the formula (II), the intermediate employs C1-6 alkyl acyl as protective group, and the method for preparing bazedoxifene acetate using the intermediate has the following advantages: (1) high pressure hydrogenation reaction with high risk for deprotection according to the traditional method (using benzyl as a protective group for protecting phenolic group) is avoided, and thereby greatly reducing danger of the experiment; 2. the reaction time is reduced and the industrial energy consumption is reduced; 3. the reaction of the present invention does not need palladium 10% on carbon; the preparation method is environmental friendly, and is suitable for industrial production, and has the advantages of mild condition and operation convenience.
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- Preparation method of selective estrogen receptor modulator bazedoxifene and key intermediate thereof
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The invention discloses a preparation method of a selective estrogen receptor modulator bazedoxifene and a key intermediate thereof. The chemical name of the selective estrogen receptor modulator bazedoxifene is 1-[4-(2-azacyclo cycloheptane-1-ethoxyl-benzyl)]-2-(4-hydroxyl-phenyl)-3-methyl-1H-indole-5-phenol. The chemical formula of the selective estrogen receptor modulator is C30H34N2O3. The preparation process is concise in process, the raw materials are easily available, the preparation method is economical and environment-friendly, the product yield and the product purity are high, industrialization is favorably achieved, and the production cost is lowered. The preparation method is suitable for batched production. The searched novel intermediate and the preparation method thereof areof great significance in economic technology of bazedoxifene.
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Paragraph 0014; 0016
(2018/06/15)
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- Efficient preparation method of bazedoxifene
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The invention discloses a preparation method of bazedoxifene. The preparation method comprises the following steps: (a) taking 1-(4-(2-(azepane-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole, adding a polar organic solvent, an aprotic lewis acid organic solution and a hydrogen ion provider, and stirring at 0-40 DEG C to obtain a reaction liquid; and (b) separating and purifying the reaction liquid obtained in the step (a) to obtain bazedoxifene. In the method disclosed by the invention, the low-cost and easily available aprotic lewis acid such as boron trifluoride is adopted as a catalyst for preparing bazedoxifene, the reaction conditions are mild, the operation is convenient, the safety is high, and the energy consumption is low; the obtained bazedoxifene has high yield and high purity, and the preparation difficulty and production cost of bazedoxifene are lowered; and the method brings a remarkable positive effect and is very suitable for industrialized use.
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- PROCESSES AND INTERMEDIATES FOR PREPARING INDOLE PHARMACEUTICALS
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The invention described herein pertains to processes and intermediates for preparing indole containing pharmaceuticals, particularly to processes and intermediates for preparing selective estrogen receptor modulators, such as bazedoxifene.
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Page/Page column 25; 28; 29
(2014/12/12)
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- NOVEL PROCESS FOR THE PREPARATION OF BAZEDOXIFENE ACETATE AND INTERMEDIATES THEREOF
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A novel process is described for the preparation of pharmaceutically useful compounds such as 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid commonly known as bazedoxifene acetate of the formula-1 using 2-(4-{[5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl-4-methylbenzenzene-1-sulfonate (formula 2a)
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- In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H- indol-5-ol in human liver microsomes
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Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5-hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3-methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole- based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLMs) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N-dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes.
- Lu?in, Tina Trdan,Toma?i?, Tihomir,Trontelj, Jurij,Mrhar, Ale?,Peterlin-Ma?i?, Lucija
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- PREPARATION OF CRYSTALLINE BAZEDOXIFENE AND ITS SALTS
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Aspects of the present disclosure include crystalline bazedoxifene free base, crystalline bazedoxifene acetate Form D, and processes for their preparation. The drug compound having the adopted name "bazedoxifene acetate" has a chemical name 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid, and has the chemical structure shown below as Formula I.
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Page/Page column 23
(2012/04/04)
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- PROCESSES FOR THE SYNTHESIS OF BAZEDOXIFENE ACETATE AND INTERMEDIATES THEREOF
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Efficient processes for the synthesis of pharmaceutically useful compounds such as (1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetic acid commonly known as bazedoxifene acetate (Formula IX) using cyanomethoxybenzyl halides of Formula III, where X=Halogens e.g., Cl, F, Br, I; G=Any electron donating or electron withdrawing substituent.
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Page/Page column 9
(2012/10/08)
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- PREPARATION OF BAZEDOXIFENE AND ITS SALTS
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Processes for preparing bazedoxifene and its pharmaceutically acceptable salts, substantially free from process related impurities and process intermediates.
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- SALTS OF BAZEDOXIFENE
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The invention deals with new crystalline salts of bazedoxifene, by means of which a high API quality can be achieved in a high yield.
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Page/Page column 5
(2010/10/03)
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- METHODS OF PREPARING POLYMORPHIC FORM A OF BAZEDOXIFENE ACETATE
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The present invention relates to methods of preparing polymorphic Form A of bazedoxifene acetate, and increasing its stability, and polymorphic Form A prepared by such methods.
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Page/Page column 13-14
(2009/10/09)
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- BAZEDOXIFENE BIS-PHOSPHORATES
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Bazedoxifene bis-phosphorates, pharmaceutical compositions containing the same, preparations thereof, and therapeutic uses thereof are disclosed.
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Page/Page column 32
(2008/12/07)
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- GLUCOPYRANOSIDES CONJUGATES OF 2-(4-HYDROXY-PHENYL)-1- 4-(2-AMIN-1-YL-ETHOXY)-BENZYL]-1H-INDOL-5-OLS
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This invention provides tissue selective estrogens of formula (I) having structure (I) wherein: R1 and R2 are independently, hydrogen, alkyl chain of 1-6 carbon atoms, benzyl, acyl of 2-7 carbon atoms, benzoyl, (1) or (2); X is hydrogen, alkyl of 1-6 carbon atoms, CN, halogen, trifuoromethyl, or thioalkyl of 1-6 carbon atoms; n = 1-3; with the proviso that at least one of R1 or R2 is (1) or (2); or a pharmaceutically acceptable salt thereof.
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Page/Page column 23
(2010/11/08)
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- CRYSTALLINE POLYMORPH OF BAZEDOXIFENE ACETATE
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The present invention is directed to a crystalline polymorph of bazedoxifene acetate, compositions containing the same, preparations thereof, and uses thereof.
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Page/Page column 15-16
(2008/06/13)
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- Methods of treating breast disorders
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This invention comprises methods of treating treatment of breast disorder comprising administration of a compound of the formulae I or II: 1wherein Z is a moiety selected from the group of: 2wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: 3R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Combination therapy for inhibiting sphincter incontinence
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This invention comprises methods of inducing or maintaining sphincter continence, or inhibiting or alleviating incontinence, in a mammal comprising administration of a compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, benzyloxy, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Methods of treating neuropeptide Y-related conditions
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This invention comprises methods of treating treatment or prevention of diseases associated with an excess of neuropeptide Y comprising administration of a compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Methods of treating excessive intraocular pressure
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This invention comprises methods of treatment, prevention, inhibition or alleviation of the problems associated with excessive intraocular pressure comprising administration of a compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Methods of treating prosthesis-related bone degeneration
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This invention comprises methods of treating bone prosthesis degeneration comprising administration of a compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatentated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Methods for increasing nitric oxide synthase activity
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This invention provides methods of increasing or maintaining mammalian nitric oxide synthase activity and output of nitric oxide comprising administering a compound of the formulae: 1wherein Z is a moiety selected from the group of: 2wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: 3R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Methods of inhibiting uterotrophic effects of estrogenic agents
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This invention comprises methods and pharmaceutical compositions for minimizing in a mammal the uterotrophic effect of a therapeutic compound selected from the group of tamoxifen, droloxifene, raloxifene, idoxifene, centrochroman, levor, meloxifene, TAT-59, GW 5838, or LY-353381 (?), comprising administration of a compound of the formulae I or II: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, or halogens; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Pharmaceutical compositions of estrogenic agents
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This invention comprises novel pharmaceutical carrier or excipient systems and oral pharmaceutical formulations comprising as an active ingredient raloxifene, amoxifen, droloxifene, arzoxifene, or CP 336156, or analogs thereof, or a compound of the formulae I or wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or CF3, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof; and excipients chosen from pharmaceutical fillers, glidants, lubricants, wetting agents and antioxidants.
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- Combinations of statins and estrogenic agents
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This invention comprises methods of treating cardiovascular disorders and lowering blood LDL levels comprising administration of a statin and compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Combinations of bisphosphonates and estrogenic agents
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This invention comprises methods of treating bone disorders comprising administration of a bisphosphonate and compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1 is selected from H, OH or the C1-C12 esters or C1-C12 alkyl ethers thereof, benzyloxy, or halogen; or C1-C4 halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6 are H, OH or C1-C12 esters or C1-C12 alkyl ethers thereof, halogens, or C1-C4 halogenated ethers, cyano, C1-C6 alkyl, or trifluoromethyl, with the proviso that, when R1 is H, R2 is not OH; Y is the moiety: R7 and R8 are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Combinations of SSRI and estrogenic agents
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This invention comprises methods of depression, anxiety, generalized anxiety disorder (GAD), hot flush, post partum depression, premenstrual syndrome, obesity, obsessive compulsive disorder, post-traumatic stress disorder, social phobia, disruptive behavior disorders, impulse control disorders, borderline personality disorder, chronic fatigue disorder, premature ejaculation, pain, attention deficit disorders, with and without hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa, or Shy Drager Syndrome comprising administration of a selective serotonin reuptake inhibitor and compound of the formulae I or II: wherein Z is a moiety selected from the group of: wherein: R1is selected from H, OH or the C1-C12esters or C1-C12alkyl ethers thereof, benzyloxy, or halogen; or C1-C4halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R2, R3, R4, R5, and R6are H, OH or C1-C12esters or C1-C12alkyl ethers thereof, halogens, or C1-C4halogenated ethers, cyano, C1-C6alkyl, or trifluoromethyl, with the proviso that, when R1is H, R2is not OH; Y is the moiety: R7and R8are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.
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- Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols
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This invention provides tissue selective estrogens of formula I having the structure wherein: R1and R2are independently, hydrogen, alkyl chain of 1-6 carbon atoms, benzyl, acyl of 2-7 carbon atoms, benzoyl, X is hydrogen, alkyl of 1-6 carbon atoms, CN, halogen, trifluoromethyl, or thioalkyl of 1-6 carbon atoms; n=1-3; with the proviso that at least one of R1or R2are not hydrogen, alkyl chain of 1-6 carbon atoms, benzyl, acyl of 2-7 carbon atoms, or benzoyl; or a pharmaceutically acceptable salt thereof.
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- 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations
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The present invention relates to new formulations containing one or more estrogens and 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, which have the general structures below:
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- 2-PHENYL-1-[4-(2-AMINOETHOXY)-BENZYL]-INDOLES AS ESTROGENIC AGENTS
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The present invention relates to new 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, which have the general structures below: STR1
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