CA2524568A1 - Mercapto-phenyl-naphthyl-methane derivatives and preparation thereof - Google Patents
Mercapto-phenyl-naphthyl-methane derivatives and preparation thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
Abstract
The present invention relates to the field of pharmaceuticals and organic chemistry and provides novel mercapto phenyl naphthyl methane derivatives, their pharmaceutically acceptable salts and compositions and preparation thereof, that are useful for the prevention or treatment of various medical indications associated with estrogen dependent diseases or syndromes related to osteoporosis, bone loss, bone formation, cardiovascular disorders, neurodegenerative disorders, menopausal disorders, physiological disorders, diabetes disorders, prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon, threatened or habitual abortion, obesity, ovarian development or function, post-partum lactation and depression.
Claims (100)
1. Novel mercaptophenyl naphthyl methane derivatives having structural formula Wherein, R is selected from group consisting of CO, CH2, CHOR4, wherein R4 is selected from group consisting of H, COR5, wherein R5 is selected from group consisting of C1-C6-alkyl or halo substituted C1-C6-alkyl, wherein R1 is selected from group consisting of H, OH, C1-C6-alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R2 is selected from group consisting of H, OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R3 is substituted mercapto such SO2R6, wherein R6 is selected from group consisting of C1-C6 alkyl, aminoalkyls such as pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, particularly methyl and R is CO or CHOH, C3-C7 cycloalkyl, C3-C7 heterocyclic alkyl in which heterocycle ring include group selected from group of pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, optionally substituted with 1 to 3 substituents, independently selected from the group consisting of H, OH, halo, nitro, cyano and SH, SO2R7, wherein R7 is selected from group consisting of H, halo, NHR3, N(R3)2 wherein R3 is as defined above, and halo is defined as Cl, Br and I.
2. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1 wherein, R is at C-1 position of naphthyl ring.
3. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1 includes (i) (4-Methylsulfonylphenyl)-naphth-1-yl-ketone;
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy]
ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Thiophenyl)-naphth-1-yl-ketone;
(xi) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xii) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xv) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvi) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy]
ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Thiophenyl)-naphth-1-yl-ketone;
(xi) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xii) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xv) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvi) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
4. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein dosage of the said derivatives is in the range of about 0.1 mg to 1000 mg.
5. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 19 wherein dosage of the said derivatives is preferably in the range of about 0.5 mg to 500 mg.
6. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein dosage of the said derivatives is preferably in the range of 1 mg to mg.
7. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein the effective administered dosage is administered weekly, bi-weekly, daily or twice a day or three times a day or in still more divided doses.
8. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values in range of about 0.1 to 0.8
9. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 9, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values in range of about 0.3 to 0.6.
10. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives enhance bone mineral Density (BMD) in the range of about 3-30%.
11. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 11, wherein said derivatives enhance bone mineral density in the range of about 3.7-25%.
12. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives lower total concentration of blood serum cholesterol by about 30%.
13. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 13, wherein said derivatives lower total concentration of blood serum cholesterol preferably by about 21 %.
14. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives lower tumor growth by about 30%.
15. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 15, wherein said derivatives lower tumor growth preferably by about 25%.
16. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives enhance uterine weight in the range of about 12-45%.
17. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 17, wherein said derivatives enhance uterine weight in the range of about 16-41 %.
18. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) in the range of about 0.05 to 1.5 mm2.
19. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 19, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) preferably in the range of about 0.80 to 1.38 mm2.
20. Novel mercaptophenyl naphthyl methane derivatives as claimed in claim 1, wherein said derivatives lower relative binding affinity (RBA) to estrogen receptors by about < 0.001.
21. A method for preparing novel mercaptophenyl naphthyl methane derivatives having structural formula 1 said method comprising steps of:
(a) mixing a or .beta. naphthoic acid with thioanisol or thiphenol in polyphosphoric acid at 70- 120°C for 5-10 hrs. to form a compound of formula 1, Wherein, R is selected from group consisting of CO, CH2, CHOR4, wherein R4 is selected from group consisting of H, COR5, wherein R5 is selected from group consisting of C1-C6-alkyl or halo substituted C1-C6-alkyl, wherein R1 is selected from group consisting of H, OH, C1-C6-alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R2 is selected from group consisting of H, OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R3 is substituted mercapto such as SO2R6, wherein R6 is selected from group consisting of C1-C6 alkyl, aminoalkyls such as pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, particularly methyl and R is CO or CHOH, C3-C7 cycloalkyl, C3-C7 heterocyclic alkyl in which heterocycle ring include group selected from group of pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, optionally substituted with 1 to 3 substituents, independently selected from the group consisting of H, OH, halo, nitro, cyano and SH, SO2R7, wherein R7 is selected from group consisting of H, halo, NHR3, N(R3)2 wherein R3 is as defined above, and halo is defined as Cl, Br and I.
(b) converting compound of formula 1 of step(a) into other derivatives by reacting the compound of formula 1 with the compounds which contribute derivatives.
(a) mixing a or .beta. naphthoic acid with thioanisol or thiphenol in polyphosphoric acid at 70- 120°C for 5-10 hrs. to form a compound of formula 1, Wherein, R is selected from group consisting of CO, CH2, CHOR4, wherein R4 is selected from group consisting of H, COR5, wherein R5 is selected from group consisting of C1-C6-alkyl or halo substituted C1-C6-alkyl, wherein R1 is selected from group consisting of H, OH, C1-C6-alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R2 is selected from group consisting of H, OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R3 is substituted mercapto such as SO2R6, wherein R6 is selected from group consisting of C1-C6 alkyl, aminoalkyls such as pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, particularly methyl and R is CO or CHOH, C3-C7 cycloalkyl, C3-C7 heterocyclic alkyl in which heterocycle ring include group selected from group of pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, optionally substituted with 1 to 3 substituents, independently selected from the group consisting of H, OH, halo, nitro, cyano and SH, SO2R7, wherein R7 is selected from group consisting of H, halo, NHR3, N(R3)2 wherein R3 is as defined above, and halo is defined as Cl, Br and I.
(b) converting compound of formula 1 of step(a) into other derivatives by reacting the compound of formula 1 with the compounds which contribute derivatives.
22. A method as claimed in claim 22, wherein, R is at C-1 position of naphthyl ring.
23. A method as claimed in claim 22, wherein derivative of formula 1 in step (b) is obtained by reacting with haloalkane particularly iodoethane, 2-iodopropane in 15% NaOH under stirring for 9-18 hrs. wherein R is CO, R1 and R2 is H, R3 is S-alkyl particularly ethyl.
24. A method as claimed in claim 22, wherein derivative of formula 1 in step (b) is obtained by reacting with with .omega.-aminoalkyl chain wherein R is CO, R1 and R2 is H, R3 is .omega.-aminoalkoxy chain particularly dimethyl, diethyl, pyrrolidine, piperidine.
25. A derivative as claimed in claim 26 wherein, reacting derivative of formula 1 in which R is CO, R1 and R2 is H, R3 is S-alkyl or SO2 preferably methyl with in sodium borohydride under stirring for 5-12 hrs. obtain a derivative wherein R
is CO or CHOH, R1 = R2 is H and R3 is S-alkyl or SO2 alkyl preferably methyl.
is CO or CHOH, R1 = R2 is H and R3 is S-alkyl or SO2 alkyl preferably methyl.
26. A method as claimed in claim 27, wherein reacting derivative of formula 1 in which is R is CO or CHOH, R1 and R2 is H and R3 is S-alkyl preferably methyl with hydrogen peroxide in acetic acid under stirring for 8-10 hrs. to obtain a derivative of formula 1 wherein, R is CO or CHOH, R1 = R2 is H and R3 is SO2 alkyl preferably methyl.
27. A method as claimed in claim 27, wherein reacting derivative of formula 1 in which is R is CHOH, R1 and R2 is H and R3 is S-alkyl preferably methyl with sodium hydride in dry benzene and refluxed for 24-30 hrs. to obtain derivative of formula 1 wherein, R is = CHOCOCH2NC5H10, R1 and R2 is H, R3 is S-alkyl more particularly methyl.
28. A method as claimed in claim 27, wherein reacting derivative of formula 1 in which is R is CHOH, R1 and R2 is H and R3 is S-alkyl preferably methyl with acetic anhydride in dry pyridine to stand for overnight wherein, R is =
CHOCOCH3, R1 and R2 is H, R3 is S-alkyl more particularly methyl.
CHOCOCH3, R1 and R2 is H, R3 is S-alkyl more particularly methyl.
29. A method as claimed in claim 27, wherein reacting derivative of formula 1 in which is R is CHOH, R1 and R2 is H and R3 is S-alkyl preferably methyl with chloroacetyl chloride in tetrahydropyran and pyridine under stirring for 1/2 hr to 3 days when the pH changed from 8 to 3 wherein R = CHOCOCH2Cl, R1 = H, R2 =
H, R3 = SMe.
H, R3 = SMe.
30. A method as claimed in claim 22, wherein derivatives are useful for the prevention or treatment of disease syndromes in mammals, particularly humans related to estrogen deficiency, osteoporosis, bone loss, bone formation, cardiovascular disorders, neurodegenerative disorders, menopausal disorders, physiological disorders, diabetes disorders, prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon, threatened or habitual abortion, obesity, ovarian development or function, post-partum lactation and depression.
31. A method as claimed in claim 22 wherein, wherein said derivatives can be administered as a pharmaceutical composition optionally alone with acceptable salts through oral, systemic, local or topical delivery, intravenous, intra-arterial, intra-muscular, subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal, transdermal or any other suitable means in any conventional liquid or solid dosage form to achieve, conventional delivery, controlled delivery or targeted delivery, optionally along with pharmaceutical acceptable diluents, in-organic salts, excipients, glidants, lubricants, sweetening agents, wetting agents, absorbents or retardants.
32. A method as claimed in claim 22, wherein, the derivatives may be delivered through gelatin capsules or compressed into the tablets or pills or may be formulated in the form of lozenges, inclusion complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
33. A method as claimed in claim 33 wherein, the pharmaceutical acceptable in-organic salts, are selected from group of formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate, sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates, and compounds thereof.
34. A method as claimed in claim 33 wherein, the pharmaceutical acceptable diluents are selected from group of lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; binder selected from group of gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; a disintegrating agent selected from group of agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; selected from group of a lubricant such as magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone or in a suitable combination thereof and glidants selected from group of colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; a sweetening agent selected from group of such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; a flavoring agent selected from group of peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; wetting agents selected from group of cetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
solution retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
solution retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
35. A method as claimed in claim 22, wherein said derivatives are in the range of about 0.1 mg to 1000 mg.
36. A method as claimed in claim 22, wherein dosage of the said derivatives is preferably in the range of about 0.5 mg to 500 mg.
37. A method as claimed in claim 22, wherein dosage of the said derivatives is preferably in the range of 1 mg to 100 mg.
38. A method as claimed in claim 22, wherein the effective administered dosage is administered weekly, bi-weekly, daily or twice a day or three times a day or in still more divided doses.
39. A method as claimed in claim 22, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values in range of about 0.1 to 0.8.
40. A method as claimed in claim 41, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values preferably in range of about 0.3 to 0.6
41. A method as claimed in claim 22, wherein said derivatives enhance bone mineral Density (BMD) in the range of about 3-30%.
42. A method as claimed in claim 43, wherein said derivatives enhance bone mineral density in the range of about 3.7-25%.
43. A method as claimed in claim 22, wherein said derivatives lower total concentration of blood serum cholesterol by about 30%.
44. A method as claimed in claim 45, wherein said derivatives lower total concentration of blood serum cholesterol preferably by about 21 %.
45. A method as claimed in claim 22, wherein said derivatives lower tumor growth by about 30%.
46. A method as claimed in claim 47, wherein said derivatives lower tumor growth preferably by about 25%.
47. A method as claimed in claim 22, wherein said derivatives enhance uterine weight in the range of about 12-45%.
48. A method as claimed in claim 49, wherein said derivatives enhance uterine weight in the range of about 16-41 %.
49. A method as claimed in claim 22, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) in the range of about 0.05 to 1.5 mm2.
50. A method as claimed in claim 51, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) preferably in the range of about 0.80 to 1.38 mm2.
51. A method as claimed in claim 22, wherein said derivatives lower relative binding affinity (RBA) to estrogen receptors by about <0.001.
52. A Pharmaceutical composition for treatment and/or prevention of disease syndromes related to estrogen deficiency, osteoporosis, bone loss, bone formation, cardiovascular disorders, neurodegenerative disorders, menopausal disorders, physiological disorders, diabetes disorders, prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon, threatened or habitual abortion, obesity, ovarian development or function, post-partum lactation and depression in mammals including humans, said composition comprising of novel mercaptophenyl naphthyl methane derivatives having structural formula 1 Wherein, R is selected from group consisting of CO, CH2, CHOR4, wherein R4 is selected from group consisting of H, COR5, wherein R5 is selected from group consisting of C1-C6-alkyl or halo substituted C1-C6-alkyl, wherein R1 is selected from group consisting of H, OH, C1-C6-alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R2 is selected from group consisting of H, OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R3 is substituted mercapto such as SO2R6, wherein R6 is selected from group consisting of C1-C6 alkyl, aminoalkyls such as pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, particularly methyl and R is CO or CHOH, C3-C7 cycloalkyl, C3-C7 heterocyclic alkyl in which heterocycle ring include group selected from group of pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, optionally substituted with 1 to 3 substituents, independently selected from the group consisting of H, OH, halo, nitro, cyano and SH, SO2R7, wherein R7 is selected from group consisting of H, halo, NHR3, N(R3)2 wherein R3 is as defined above, and halo is defined as Cl, Br and I, along with pharmaceutical acceptable in-organic salts, diluents, glidants, lubricants, excipients, sweetening agents, wetting agents absrobsents or retardants.
53. A pharmaceutical composition as claimed in claim 54 wherein, said derivatives include:
(i) (4-Methylsulfonylphenyl)-naphth-1-yl-ketone;
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy]
ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Methylsulfonylphenyl)-naphth-2-yl-ketone;
(xi) (4-Methylsulfonylphenyl)-naphth-2-yl-carbinol;
(xii) (4-Thiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xv) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xvi) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xviii) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xix) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
(i) (4-Methylsulfonylphenyl)-naphth-1-yl-ketone;
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy]
ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Methylsulfonylphenyl)-naphth-2-yl-ketone;
(xi) (4-Methylsulfonylphenyl)-naphth-2-yl-carbinol;
(xii) (4-Thiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xv) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xvi) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xviii) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xix) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
54. A pharmaceutical composition as claimed in claim 54, wherein, R is at C-1 position of naphthyl ring.
55. A pharmaceutical composition as claimed in claim 54, wherein composition is useful in the prevention and/or treatment of estrogen dependent or estrogen independent cancers such as prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon.
56. A pharmaceutical composition as claimed in claim 54, wherein the composition may be delivered through gelatin capsules or compressed into the tablets or pills or may be formulated in the form of lozenges, inclusion complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable carrier moieties.
57. A pharmaceutical composition as claimed in claim 54, wherein pharmaceutical acceptable salts are selected from group of formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate, sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates, and compounds thereof.
58. A pharmaceutical composition as claimed in claims 54, wherein the pharmaceutical acceptable diluents are selected from group of a lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; binder selected from group of gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; excipients selected from group of agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; lubricants selected from group of a magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone;
glidants selected from group of colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; a sweetening agent selected from group of such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; a flavoring agent selected from group of peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; wetting agents selected from group of acetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
glidants selected from group of colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; a sweetening agent selected from group of such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; a flavoring agent selected from group of peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; wetting agents selected from group of acetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
59. A pharmaceutical composition as claimed in claim 54, wherein the effective administered dosage is in the range of 0.1 mg to 1000 mg.
60. A pharmaceutical composition as claimed in claim 54, wherein the effective administered dosage is preferably in the range of 0.5 mg to 500 mg.
61. A pharmaceutical composition as claimed in claim 54, wherein the effective administered dosage is preferably in the range of 1 mg to 100 mg.
62. A pharmaceutical composition as claimed in claim 54, wherein the effective administered dosage is administered weekly, bi-weekly, daily or twice a day or three times a day or in still more divided doses.
63. A pharmaceutical composition as claimed in claim 54, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values in range of about 0.1 to 0.8.
64. A pharmaceutical composition as claimed in claim 66, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values preferably in range of about 0.3 to 0.6.
65. A pharmaceutical composition as claimed in claim 54, wherein said derivatives enhance bone mineral Density (BMD) in the range of about 3-30%.
66. A pharmaceutical composition as claimed in claim 68, wherein said derivatives enhance bone mineral density in the range of about 3.7-25%.
67. A pharmaceutical composition as claimed in claim 54, wherein said derivatives lower total concentration of blood serum cholesterol by about 30%.
68. A pharmaceutical composition as claimed in claim 70, wherein said derivatives lower total concentration of blood serum cholesterol preferably by about 21 %.
69. A pharmaceutical composition as claimed in claim 54, wherein said derivatives lower tumor growth by about 30%.
70. A pharmaceutical composition as claimed in claim 72, wherein said derivatives lower tumor growth preferably by about 25%.
71. A pharmaceutical composition as claimed in claim 54, wherein said derivatives enhance uterine weight in the range of about 12-45%.
72. A pharmaceutical composition as claimed in claim 74, wherein said derivatives enhance uterine weight in the range of about 16-41 %.
73. A pharmaceutical composition as claimed in claim 54, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) in the range of about 0.05 to 1.5 mm2.
74. A pharmaceutical composition as claimed in claim 76, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) preferably in the range of about 0.80 to 1.38 mm2.
75. A pharmaceutical composition as claimed in claim 54, wherein said composition lowers relative binding affinity (RBA) to estrogen receptors by about <0.001.
76. A use for treatment and/or prevention of disease syndromes related to estrogen deficiency, osteoporosis, bone loss, bone formation, cardiovascular disorders, neurodegenerative disorders, menopausal disorders, physiological disorders, diabetes disorders, prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon, threatened or habitual abortion, obesity, ovarian development or function, post-partum lactation and depression in mammals including humans said use comprising by administering pharmaceutical effective dosage of novel mercaptophenyl naphthyl methane derivatives having structural formula 1 to the mammals, wherein structural formula is Wherein, R is selected from group consisting of CO, CH2, CHOR4, wherein R4 is selected from group consisting of H, COR5, wherein R5 is selected from group consisting of C1-C6-alkyl or halo substituted C1-C6-alkyl, wherein R1 is selected from group consisting of H, OH, C1-C6-alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R2 is selected from group consisting of H, OH, C1-C6 alkyl, C1-C6 alkyloxy, C1-C6 alkyloxy carbonyl, wherein R3 is substituted mercapto such or SO2R6, wherein R6 is selected from group consisting of C1-C6 alkyl, aminoalkyls such as pyrrolidinoethyl, piperidinoethyl, dimethylaminoethyl, diethylaminoethyl, particularly methyl and R is CO or CHOH, C3-C7 cycloalkyl, C3-C7 heterocyclic alkyl in which heterocycle ring include group selected from group of pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrol, 2H-pyrrol, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isozazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and thiazolyl, optionally substituted with 1 to 3 substituents, independently selected from the group consisting of H, OH, halo, nitro, cyano and SH, SO2R7, wherein R7 is selected from group consisting of H, halo, NHR3, N(R3)2 wherein R3 is as defined above, and halo is defined as Cl, Br and I, along with pharmaceutical acceptable in-organic salts, diluents, glidants, lubricants, excipients, sweetening agents, wetting agents absrobsents or retardants optionally along with pharmaceutical acceptable in-organic salts, diluents, glidants, lubricants, excipients, sweetening agents, wetting agents absorbents or retardants
77. A use as claimed in claim 79 wherein, said derivatives include:
(i) (4-Methylsulfonylphenyl)-naphth-1-yl-ketone;
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy] ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Thiophenyl)-naphth-1-yl-ketone;
(xi) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xii) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xv) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvi) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
(i) (4-Methylsulfonylphenyl)-naphth-1-yl-ketone;
(ii) (4-Ethylsulfonylphenyl)-naphth-1-yl-ketone;
(iii) (4-Methylthiophenyl)-naphth-1-yl-carbinol;
(iv) (4-Ethylthiophenyl)-naphth-1-yl-carbinol;
(v) (4-Methylsulfonylphenyl)-naphth-1-yl-carbinol;
(vi) (4-Ethylsulfonylphenyl)-naphth-1-yl-carbinol;
(vii) 1-Piperidino-2-[(4-methylthiophenyl)-(naphth-1-yl)-methyloxy] ethane;
(viii) (4-Methylthiophenyl)-(naphth-1-yl-methanol acetate;
(ix) (4-Methylthiophenyl)-1-naphthyl methylchloroacetate;
(x) (4-Thiophenyl)-naphth-1-yl-ketone;
(xi) (4-Ethylthiophenyl)-naphth-1-yl-ketone;
(xii) (4-Propylthiophenyl)-naphth-1-yl-ketone;
(xiii) (4-Isopropylthiophenyl)-naphth-1-yl-ketone;
(xiv) (4-Dimethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xv) (4-Diethylaminoethylthio-phenyl)-naphth-1-yl-ketone;
(xvi) (4-Pyrrolidinoethylthio-phenyl)-naphth-1-yl-ketone;
(xvii) (4-Piperidinoethylthio-phenyl)-naphth-1-yl-ketone.
78. A use as claimed in claim 79, wherein, R is at C-1 position of naphthyl ring.
79. A use as claimed in claim 79, wherein said derivatives are useful for the prevention or treatment of disease syndromes in mammals, particularly humans related to estrogen deficiency, osteoporosis, bone loss, bone formation, cardiovascular disorders, neurodegenerative disorders, menopausal disorders, physiological disorders, diabetes disorders, prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon, threatened or habitual abortion, obesity, ovarian development or function, post-partum lactation and depression.
80. A use as claimed in claim 79, wherein pharmaceutical composition may be administered through oral, systemic, local or topical delivery, intravenous, intra-arterial, intra-muscular, subcutaneous, intra-peritoneal, intra-dermal, buccal, intranasal, inhalation, vaginal, rectal, transdermal or any other suitable means in any conventional liquid or solid dosage form to achieve, conventional delivery, controlled delivery or targeted delivery.
81. A use as claimed in claim 79, wherein pharmaceutical composition may be delivered through gelatin capsules or compressed into the tablets or pills or may be formulated in the form of lozenges, inclusion complexes with cyclodextrin derivatives, injectable depo formulations, aerosols, granules, powders, oral liquids, mucosal adhesive formulations, gel formulations, troches, elixirs, suspensions, syrups, wafers, liposomal delivery systems, implants, suppository, pessary, microemulsions, nanoemulsion, microparticles, nanoparticles, controlled release delivery systems, transdermal delivery systems, targeted delivery systems such as conjugates with monoclonal antibodies or with other suitable Garner moieties.
82. A use as claimed in claim 79 wherein, the pharmaceutical acceptable in-organic salts, are selected from group of formate, acetate, phenyl acetate, trifluroacetate, acrylate, ascorbate, benzoate, chlorobenzoates, bromobezoates, iodobenzoates, nitrobenzoates, hydroxybenzoates, alkylbenzoates, alkyloxybenzoates, alkoxycarbonylbenzoates, naphthalene-2 benzoate, butyrates, phenylbutyrates, hydroxybutyrates, caprate, caprylate, cinnamate, mandelate, mesylate, citrate, tartarate, fumarate, heptanoate, hippurate, lactate, malate, maleate, malonate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacte, succinate, suberate, sulphate, bisulphate, pyrosulphate, sulphite, bisulphate, sulphonate, benzene sulphonate, bromobenzene sulphonates, chlorobenzene sulphonates, ethane sulphonates, methane sulphonates, naphthalene sulphonates, toluene sulphonates, and compounds thereof.
83. A use as claimed in claim 79 wherein, the pharmaceutical acceptable diluents are selected from group of lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; binder selected from group of gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; a disintegrating agent selected from group of agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; selected from group of a lubricant such as magnesium stearate, calcium stearate or steorates, talc, solid polyethylene glycols, sodium lauryl sulphate or any other ingredient of the similar nature alone or in a suitable combination thereof and glidants selected from group of colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; a sweetening agent selected from group of such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; a flavoring agent selected from group of peppermint, methyl salicylate, orange flavor, vanilla flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; wetting agents selected from group of cetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
solution retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
absorbents selected from group of kaolin, bentonite clay or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof;
solution retarding agents selected from group of wax, paraffin or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof.
84. A use as claimed in claim 79, wherein dosage is in the range of about 0.1 mg to 1000 mg.
85. A use as claimed in claim 79, wherein dosage is in the range of about 0.5 mg to 500 mg.
86. A use as claimed in claim 79, wherein dosage is in the range of 1 mg to 100 mg.
87. A use as claimed in claim 79, wherein the effective administered dosage is administered weekly, bi-weekly, daily or twice a day or three times a day or in still more divided doses.
88. A use as claimed in claim 79, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values in range of about 0.1 to 0.8
89. A use as claimed in claim 92, wherein antiosteoporosis (antiresorptive) activity of the said derivatives is represented by T/C values preferably in range of about 0.3 to 0.6.
90. A use as claimed in claim 79, wherein said derivatives enhance bone mineral Density (BMD) in the range of about 3-30%.
91. A use as claimed in claim 94, wherein said derivatives enhance bone mineral density in the range of about 3.7-25%.
92. A use as claimed in claim 79, wherein said derivatives lower total concentration of blood serum cholesterol by about 30%.
93. A use as claimed in claim 96, wherein said derivatives lower total concentration of blood serum cholesterol preferably by about 21 %.
94. A use as claimed in claim 79, wherein said derivatives lower tumor growth by about 30%.
95. A use as claimed in claim 98, wherein said derivatives lower tumor growth preferably by about 25%.
96. A use as claimed in claim 79, wherein said derivatives enhance uterine weight in the range of about 12-45%.
97. A use as claimed in claim 100, wherein said derivatives enhance uterine weight in the range of about 16-41%.
98. A use as claimed in claim 79, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) in the range of about 0.05 to 1.5 mm2.
99. A use as claimed in claim 102, wherein said derivatives enhance the uterine morphometry (i.e Uterus and Endometrium) preferably in the range of about 0.80 to 1.38 mm2.
100. A use as claimed in claim 79, wherein said composition lowers relative binding affinity (RBA) to estrogen receptors by about <0.001.
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| US60/458,401 | 2003-03-31 | ||
| PCT/IB2003/006247 WO2004087644A1 (en) | 2003-03-31 | 2003-12-23 | Mercapto-phenyl-naphthyl-methane derivatives and preparation thereof |
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| CA2524568C CA2524568C (en) | 2012-07-17 |
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| EP (1) | EP1692101B1 (en) |
| CN (1) | CN100569747C (en) |
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| AU (1) | AU2003288644A1 (en) |
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| MX2016014281A (en) | 2014-05-22 | 2017-02-22 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies. |
| EP3288384A4 (en) * | 2015-05-01 | 2019-01-23 | Georgia State University Research Foundation | Benzhydrol derivatives for the management of conditions related to hypoxia inducible factors |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| WO2017173071A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
| WO2017173044A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd Inc. | Steroid hormone compositions in medium chain oils |
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| US5807873A (en) * | 1996-04-04 | 1998-09-15 | Laboratories Upsa | Diarylmethylidenefuran derivatives and their uses in therapeutics |
| FR2747123B1 (en) * | 1996-04-04 | 1998-06-26 | Union Pharma Scient Appl | NOVEL DIARYLMETHYLIDENE TETRAHYDROFURANE DERIVATIVES, PROCESSES FOR THEIR PREPARATION, AND THERAPEUTIC USES |
| IT1298159B1 (en) * | 1997-01-28 | 1999-12-20 | Hoffmann La Roche | DERIVATIVES OF A 5-AROYLNAPHTHALENE |
| DE60234095D1 (en) * | 2001-06-11 | 2009-12-03 | Basf Se | OXIM ESTER PHOTOINITIATORS WITH COMBINED STRUCTURE |
-
2003
- 2003-12-23 CA CA2524568A patent/CA2524568C/en not_active Expired - Fee Related
- 2003-12-23 AU AU2003288644A patent/AU2003288644A1/en not_active Abandoned
- 2003-12-23 WO PCT/IB2003/006247 patent/WO2004087644A1/en not_active Application Discontinuation
- 2003-12-23 AT AT03780487T patent/ATE515493T1/en not_active IP Right Cessation
- 2003-12-23 CN CNB2003801103274A patent/CN100569747C/en not_active Expired - Fee Related
- 2003-12-23 EP EP03780487A patent/EP1692101B1/en not_active Expired - Lifetime
-
2004
- 2004-03-26 US US10/809,845 patent/US7250446B2/en active Active
-
2007
- 2007-06-15 US US11/812,251 patent/US7582653B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US7582653B2 (en) | 2009-09-01 |
| US7250446B2 (en) | 2007-07-31 |
| CA2524568C (en) | 2012-07-17 |
| WO2004087644A1 (en) | 2004-10-14 |
| EP1692101A1 (en) | 2006-08-23 |
| US20070244161A1 (en) | 2007-10-18 |
| AU2003288644A1 (en) | 2004-10-25 |
| EP1692101B1 (en) | 2011-07-06 |
| US20040229869A1 (en) | 2004-11-18 |
| CN1802348A (en) | 2006-07-12 |
| ATE515493T1 (en) | 2011-07-15 |
| CN100569747C (en) | 2009-12-16 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
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