MXPA97009466A - Medicine to inhibit the melan - Google Patents
Medicine to inhibit the melanInfo
- Publication number
- MXPA97009466A MXPA97009466A MXPA/A/1997/009466A MX9709466A MXPA97009466A MX PA97009466 A MXPA97009466 A MX PA97009466A MX 9709466 A MX9709466 A MX 9709466A MX PA97009466 A MXPA97009466 A MX PA97009466A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- melanoma
- raloxifene
- formula
- inhibiting
- Prior art date
Links
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- 229940079593 drugs Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 206010025650 Malignant melanoma Diseases 0.000 claims abstract description 24
- 201000001441 melanoma Diseases 0.000 claims abstract description 24
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- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
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- 230000003211 malignant Effects 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical class [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229960004723 phenylbutyrate Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M pyridine-4-carboxylate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
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- 230000004083 survival Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
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Abstract
A method for inhibiting melanoma is described, which comprises administering to a human in need thereof an effective amount of a compound having the formula I, wherein R1 and R3 are independently hydrogen, -CH3, (a) or (b) ), wherein Ar is optionally substituted phenyl, R 2 is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino, or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with one or more melano-inhibiting agents.
Description
MEDICINE TO INHIBIT MELANOMA
BACKGROUND OF THE INVENTION
Melanoma is a malignant tumor of the melanocytes mainly located in the skin. Melanoma occurs mainly in adults and commonly arises from a benign pigmented nevus. Any increase in size, change in color, or start of stinging are all early signs that may indicate a malignant change. Malignant melanoma currently accounts for approximately 1% of all cancer deaths. The incidence rate, however, of melanoma is increasing at a faster rate than any other neoplasm, except for lung cancer in women. The greatest danger with melanoma is metastasis by local extension through the lymphatic and ematogenous routes to distant sites. While any organ may be involved by metastases, the lung and liver are common sites. Melanoma that has spread to distant sites is infrequently curable with standard therapy, although long-term survival
REF: 26327
The term is occasionally achieved by the resection of metastases. For a long time such patients are suitable candidates for clinical trials that explore new forms of chemotherapy or biological response modifiers. Currently, after approximately 20 years of experimentation, dacarbazine (DTIC) is the only agent approved by the FDA for the treatment of metastatic melanoma, and combinations of chemotherapeutic agents that are conclusively more effective than dacarbazine alone have not been shown. Dacarbazine therapy is associated with the response rate of 15 to 25%, with only 5% of patients achieving a complete response. Therefore, there is a strong interest in finding a more beneficial treatment regimen and additional agents to inhibit melanoma.
BRIEF DESCRIPTION OF THE INVENTION
This invention provides methods for inhibiting melanoma, comprising administering to a human in need thereof an effective amount of a compound of formula I
wherein R1 and R3 are independently O O
II II hydrogen, CH3, -C- (alkyl of 1 to 6 carbon atoms), or -C-Ar, wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and the pharmaceutically acceptable salts and solvates thereof, alone or in combination with one or more melanoma inhibiting agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I, are useful for inhibiting melanoma.
The methods of use provided by this invention are practiced by administering to a human in need thereof, a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, which is effective to inhibit melanoma, alone or in combination with one or more melanoma inhibiting agents. The term "inhibit" includes its generally accepted meaning, which includes prohibition, prevention, containment, and decrease, detention, or reversal. As such, the present method includes medical therapeutic and / or prophylactic administration, as appropriate. Raloxifene, a compound of this invention wherein this is the hydrochloride salt of a compound of formula I, R1 and R3 are hydrogen and R2 is 1-piperidinyl, is a nuclear regulatory molecule. Raloxifene has been found to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti-estrogen, and which blocked the ability of estrogen to activate uterine tissue and dependent breast cancers of estrogen. Of course, raloxifene does not block the action of
estrogen in some cells; however, in other cell types, raloxifene activates the same genes as estrogen, and shows the same pharmacology, for example, osteoporosis, hyperlipidemia. As a result, raloxifene has also been termed as an anti-estrogen with mixed agonist-antagonist properties. The only profile that shows raloxifene and that differs from that of estrogen is now thought to be due to the single activation and / or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to activation and / or gene deletion by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptor, the pharmacological consequence of the regulation of the gene, of the two, is not easily predicted and is unique to each of them. In general, the compound is formulated with common excipients, diluents, or carriers, and compressed in the form of tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by intramuscular or intravenous routes. The compounds can be administered transdermally, and can be
formulated as sustained release dosage forms and the like. The compounds used in the methods of the present invention can be made according to established procedures, such as those detailed in U.S. Patent Nos. 4,133,814, 4,418,068, and 4,380,635 all of which are incorporated by reference herein. In general, the process begins with a benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The initial compound is protected, acylated, and deprotected to form the compounds of formula I. Examples of the preparation of such compounds are given in the North American patents discussed above. Optionally substituted phenyl includes phenyl and phenyl substituted once or twice with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl, nitro, chloro, fluoro, or tri (chloro or fluoro) methyl. The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts, with a wide variety of organic and inorganic acids and bases, and include the physiologically acceptable salts thereof.
which are frequently used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric acids and the like. Salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts include in this manner the salts of acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate. , β-hydroxybutyrate, butyne-1,4-dioate, hexin-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, alato, maleate, hydroxyaleate, malonate mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monoacid phosphate, diacid phosphate, metaphosphate, pyrophosphate, propiolate,
propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-brornophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate, p-toluenesulfonate, xylene sulfonate, tartrate, and the like. A preferred salt is the hydrochloride salt. The pharmaceutically acceptable acid addition salts are typically formed by the reaction of a compound of the formula I with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene. The salt normally precipitates from the solution within about one hour to 10 days, and can be isolated by filtration, or the solvent can be removed by conventional means. The bases commonly used for the formation of salts include ammonium hydroxide and alkali metal and alkaline earth metal hydroxide, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. The bases especially useful in the preparation of
Addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. The pharmaceutically acceptable salts generally have improved solubility characteristics compared to the compound from which they are derived, and are thus often more suitable for formation as liquids or emulsions. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for delaying dissolution such as paraffin;
resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration, or as solutions suitable for parenteral administration, for example by intramuscular, subcutaneous, or intravenous routes. In addition, the compounds are well suited for formulation as sustained release dosage forms and the like. The formulations can thus be constituted so that they release the active ingredient only or preferably at a particular site of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices can be made, for example, from polymeric substances or waxes. The regimen and the particular dosage of a compound of formula I required to inhibit melanoma according to this invention, will depend on the severity of the condition, the route of administration, and the related factors that
They will be decided by the attending physician. In general, the accepted and effective daily doses will be from about 0.1 to about 1000 mg / day, and more typically from about 50 to about 200 mg / day. Such doses will be administered to a subject in need thereof at one time up to approximately three times a day, or more frequently as necessary, and for a sufficient time to effectively inhibit melanoma. The invention also encompasses the administration in combination of a compound of the formula I together with one or more melanoma inhibiting agents. Such agents include cisplatin, dacarbazine, and carmustine. It is usually preferred to administer a compound of the formula I in the form of a salt by the addition of acid, as is customary in the administration of pharmaceutical products having an alkaline group, such as the piperidino ring. It is also advantageous to administer such compound by the oral route. For such purposes, the following oral dosage forms are available.
Formulations
In the following formulations, "Active ingredient" means a compound of the formula I.
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following ingredients:
Ingredient Quantity (mg / capsule) Active Ingredient 0.1 - 1000
Starch, NF 0 - 650
Flowable powder starch 0 - 650
Fluid silicone of 350 centistokes 0 - 15
The ingredients are mixed, passed through a No. 45 mesh American sieve, and filled into hard gelatin capsules.
Examples of raloxifene-specific capsule formulations, which have been elaborated, include those shown below:
Formulation 2: Raloxifene capsule
Ingredient Quantity (mg / capsule)
Raloxifene 1 Starch, NF 112 Fluid starch powder 225.3 350 centistokes fluid silicone 1.7
Formulation 3: Raloxifene capsule
Ingredient Quantity (mg / capsule)
Raloxifene 5 Starch, NF 108 Fluid starch powder 225.3 Fluidized silicone 350 centistokes 1.7
Formulation 4: Raloxifene Capsule
Ingredient Quantity (mg / capsule) Raloxifene 10 Starch, NF 103 Fluid starch powder 225.3 350 centistokes fluid silicone 1.7
Formulation 5: Raloxifene Capsule
Ingredient Quantity (mg / capsule) Raloxifene 50 Starch, NF 150 Fluid starch powder 397 Fluid silicone 350 centistokes 3.0
The above specific formulations may be changed in compliance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients:
Formulation 6: Tablets
Ingredient Quantity (mg / tablet; Active Ingredient 0.1 - 1000 Cellulose, microcrystalline 0 - 650 Silicon dioxide, smoked 0 - 650 Stearic acid 0 - 15
The components are mixed and compressed to form tablets.
Alternatively, the tablets each containing 0.1-1000 mg of active ingredient are constituted as follows:
Formulation 7: Tablets
Ingredient Quantity (mg / tablet)
Active Ingredient 0.1 - 1000
Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1
The active ingredient, starch, and cellulose are passed through a No. 45 mesh American sieve and mixed thoroughly. The solution of the polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a No. 14 North American mesh screen. The granules thus produced are dried at 50-60 ° C and passed through a North American mesh screen No. 18. Carboxymethyl starch
Sodium, magnesium stearate, and talcum, previously passed through a No. 60 mesh American sieve, are then added to the granules which, after mixing, are compressed in a tabletting machine, to produce tablets . The suspensions each containing 0.1 to 1000 mg of medication per 5 ml of dose, are elaborated as follows:
Formulation 8: Suspensions
Ingredient Quantity (mg / 5 ml) Active Ingredient 0.1 - 1000 mg Sodium Carboxymethylcellulose 50 mg Syrup 1.25 mg
Benzoic acid solution 0.10 ml Flavor c. s. C color. s. Purified water cbp 5 ml
The medicament is passed through a No. 45 mesh US sieve and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The acid solution
Benzoic, the flavoring, and the color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
ESSAYS
A colony formation test is used to test the activity of the formulated compound. In the test for the effects of brief exposure of the compound of formula I on melanoma cells, a suspension of single cells of melanoma cells are seeded onto 60 mm tissue culture dishes (Corning, Corning, NY) 20,000 cells / box, leaving 2-4 hours for them to be coupled. The compound is added to the boxes and incubated for 1 hour, then the boxes are washed three times with saline buffered with phosphate
(Sigma Chemical Co., St. Louis, MO) and the cells are harvested by trypsinization, washed once more to remove the drug, and resuspended in 5 ml of the complete medium containing 0.3% agar solution.
(Difco, Detroit, MI). The cell suspension is mixed thoroughly and then aliquots are taken at 1 ml / box, in triplicate, on 35 mm plates prepared
previously, they contain a solidified 1% agarose base layer. The agar containing the cell suspension is allowed to solidify at room temperature and the boxes are incubated at 37 ° C in humidified 5% C02. Colonies greater than 125 μM are counted after 5 days for continuous cell lines or 7-14 days for primary cells. An assay is performed using continuous exposure of the formulated compound, by resuspending the melanoma cells in 0.3% agar solution (Difco, Detroit, MI) at 4000 cells / ml, aliquots of this suspension are taken in tubes containing the formulated compound and complete medium, for example, RPMI 1640 (Irving Scientific, Santa Ana, CA) supplemented with 10% fetal bovine serum (HyClone, Logan, __JJT), 50 μg / ml gentamicin (Gemini Bio-Products, Calabases , CA), 2 mM L-glutamine, 10 nM hydrocortisone, 5 μg / ml insulin, 5 μg / ml human transferrin, 10 nM estradiol, and 5 ng / ml selenium (Sigma Chemical Co., St. Louis, MO ). The cell suspension is mixed thoroughly and aliquots are then taken at 1 ml / box, in triplicate, on pre-prepared 35 mm boxes, containing a base layer of solidified 1% agarose. The agar containing the cell suspension is left
solidify at room temperature, and the boxes are incubated at 37 ° C in an environment of 5% humidified C02. Colonies greater than 125 μM are counted after 5 days for continuous cell lines or 7-14 days for primary cells. The activity in at least one of the above assays indicates the utility for inhibiting melanoma.
Claims (5)
1. The use of a compound for the preparation of a medicament for inhibiting melanoma, wherein a human in need thereof is administered an effective amount of a compound having the formula: wherein R1 and R3 are independently O O II II hydrogen, CH3, -C- (alkyl of 1 to 6 carbon atoms), or -C-Ar, wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salt and solvate thereof, alone or in combination with one or more melanoma inhibiting agents.
2. The use according to claim 1, wherein the compound is the hydrochloride salt thereof.
3. The use according to claim 1, wherein the compound is or its hydrochloride salt.
4. The use according to claim 1, wherein the administration is in combination with one or more cisplatin dacarbazine or carmustine.
5. The use of a compound according to claim 1, for the preparation of a medicament for the treatment of melanoma that can be metastatic.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/466,673 US5843974A (en) | 1995-06-06 | 1995-06-06 | Methods of inhibiting melanoma using Benzothiophenes as cytotoxic agents per se |
US08466673 | 1995-06-06 | ||
PCT/US1996/009839 WO1996039135A1 (en) | 1995-06-06 | 1996-06-06 | Methods of inhibiting melanoma |
Publications (2)
Publication Number | Publication Date |
---|---|
MXPA97009466A true MXPA97009466A (en) | 1998-02-01 |
MX9709466A MX9709466A (en) | 1998-02-28 |
Family
ID=23852667
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX9709466A MX9709466A (en) | 1995-06-06 | 1996-06-06 | Methods of inhibiting melanoma. |
Country Status (16)
Country | Link |
---|---|
US (1) | US5843974A (en) |
EP (1) | EP0747053A3 (en) |
JP (1) | JPH11507371A (en) |
KR (1) | KR19990022364A (en) |
CN (1) | CN1192141A (en) |
AU (1) | AU702716B2 (en) |
CA (1) | CA2223157A1 (en) |
CZ (1) | CZ383197A3 (en) |
EA (1) | EA000680B1 (en) |
HU (1) | HUP9901093A3 (en) |
IL (1) | IL118574A0 (en) |
MX (1) | MX9709466A (en) |
NO (1) | NO975580L (en) |
PL (1) | PL323924A1 (en) |
WO (1) | WO1996039135A1 (en) |
ZA (1) | ZA964682B (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6670345B1 (en) | 1997-09-30 | 2003-12-30 | Dabur Research Foundation | Betulinic acid derivatives for inhabiting cancer growth and process for the manufacture of betulinic acid |
US6228850B1 (en) * | 1997-09-30 | 2001-05-08 | Dabur Research Foundation | Antiangiogenic activity of betulinic acid and its derivatives |
US6048847A (en) * | 1997-09-30 | 2000-04-11 | Dabur Research Foundation | Use of betulinic acid and its derivatives for inhibiting cancer growth and a method of monitoring this |
DK1175433T3 (en) | 1999-05-04 | 2005-09-19 | Strakan Int Ltd | Androgen glycosides and their androgenic activity |
EP1722823A2 (en) * | 2004-02-27 | 2006-11-22 | Antisense Pharma GmbH | Pharmaceutical composition |
BRPI0508970A (en) * | 2004-03-19 | 2007-08-21 | Penn State Res Found | combinatorial methods and compositions for the treatment of melanoma |
ES2765573T3 (en) * | 2012-08-13 | 2020-06-09 | Univ Rockefeller | Melanoma treatment and diagnosis |
EP3091970B1 (en) | 2014-01-10 | 2020-10-28 | Rgenix, Inc. | Lxr agonists and uses thereof |
US9758786B2 (en) | 2016-02-09 | 2017-09-12 | Autotelic, Llc | Compositions and methods for treating pancreatic cancer |
CA3078981A1 (en) | 2017-11-21 | 2019-05-31 | Rgenix, Inc. | Polymorphs and uses thereof |
WO2021119397A1 (en) | 2019-12-13 | 2021-06-17 | Rgenix, Inc. | Metal salts and uses thereof |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US4656187A (en) * | 1981-08-03 | 1987-04-07 | Eli Lilly And Company | Treatment of mammary cancer |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
TW366342B (en) * | 1992-07-28 | 1999-08-11 | Lilly Co Eli | The use of 2-phenyl-3-aroylbenzothiophenes in inhibiting bone loss |
CN1108094A (en) * | 1993-10-15 | 1995-09-13 | 伊莱利利公司 | Methods for treating resistant neoplasms |
US5457113A (en) * | 1993-10-15 | 1995-10-10 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell proliferation and restinosis |
CN1058390C (en) * | 1993-10-15 | 2000-11-15 | 伊莱利利公司 | Methods for exhibiting angiogenisis and angiogenic diseases |
US5476862A (en) * | 1993-12-21 | 1995-12-19 | Eli Lilly And Company | Methods of increasing thrombomodulin expression |
US5622975A (en) * | 1995-06-01 | 1997-04-22 | Eli Lilly And Company | Methods for inhibiting vascular smooth muscle cell migration |
US5726168A (en) * | 1995-10-12 | 1998-03-10 | Eli Lilly And Company | Lipophilic benzothiophenes |
US5780497A (en) * | 1996-04-19 | 1998-07-14 | American Home Products Corporation | 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents |
-
1995
- 1995-06-06 US US08/466,673 patent/US5843974A/en not_active Expired - Fee Related
-
1996
- 1996-05-30 EP EP96303878A patent/EP0747053A3/en not_active Withdrawn
- 1996-06-05 IL IL11857496A patent/IL118574A0/en unknown
- 1996-06-05 ZA ZA9604682A patent/ZA964682B/en unknown
- 1996-06-06 AU AU61090/96A patent/AU702716B2/en not_active Ceased
- 1996-06-06 WO PCT/US1996/009839 patent/WO1996039135A1/en not_active Application Discontinuation
- 1996-06-06 CA CA002223157A patent/CA2223157A1/en not_active Abandoned
- 1996-06-06 HU HU9901093A patent/HUP9901093A3/en unknown
- 1996-06-06 EA EA199800015A patent/EA000680B1/en not_active IP Right Cessation
- 1996-06-06 MX MX9709466A patent/MX9709466A/en unknown
- 1996-06-06 KR KR1019970708844A patent/KR19990022364A/en not_active Application Discontinuation
- 1996-06-06 PL PL96323924A patent/PL323924A1/en unknown
- 1996-06-06 CZ CZ973831A patent/CZ383197A3/en unknown
- 1996-06-06 CN CN96195876A patent/CN1192141A/en active Pending
- 1996-06-06 JP JP9502042A patent/JPH11507371A/en active Pending
-
1997
- 1997-12-03 NO NO975580A patent/NO975580L/en not_active Application Discontinuation
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