CA2138498A1 - Methods of inhibiting hirsutism and alopecia in women - Google Patents
Methods of inhibiting hirsutism and alopecia in womenInfo
- Publication number
- CA2138498A1 CA2138498A1 CA002138498A CA2138498A CA2138498A1 CA 2138498 A1 CA2138498 A1 CA 2138498A1 CA 002138498 A CA002138498 A CA 002138498A CA 2138498 A CA2138498 A CA 2138498A CA 2138498 A1 CA2138498 A1 CA 2138498A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- alopecia
- hirsutism
- women
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
A method of inhibiting hirsutism or alopecia in women comprising administering to a female human in need of treatment an effective amount of a compound having the formula (I) wherein R1 and R3 are independently hydrogen, -CH3, , or , wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.
R2 is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.
Description
Z~3~34~8 -METHODS OE INHIBITING HIRSUTISM AND ALOPECIA IN WOMEN
Hirsutism (hypertrichosis) is characterized by excessive growth of hair. In women, hirsutism refers specifically to excessive growth of hair in a male pattern and distributlon. Clinically, hirsutism in women is seen as a growth of terminal hair on the face (particularly on the upper lip), the chin, chest, back, and lower abdomen (escutcheon). This growth of hair is often seen as unsightly and can be the cause of embarrassment and psychological distress. Hirsutism is a common occurrence at the menopause, but can occur any time after puberty.
The etiology of the condition has been linked to over production of androyens by either the ovaries or adrenal glands or both.
Hirsutsim in women can be treated in a variety of ways. Cosmetic treatment of the condition, including shaving, plucking of hairs, and bleaching, while effective in improving the appearance of the patient, are only palliative and must be constantly re-applied.
Glucocortacoid steroids are often effective; however, they have the potential of serious side-effects such as Cushing's Syndrome. Oral contraceptives can be effective;
however, care must be taken because certain progestins used in common oral contraceptive regiments may actually contribute hirsutism because of their androgenic side-effects. Cimetidine and Spironolactone have shown some effectiveness in the treatment of hirsutism; however, each of these can have unwanted side-effects. Clearly, a more effective and better tolerated agent would be useful.
Alopecia (hair loss) can occur in women for a variety of reasons, and includes female pattern alopecia.
Female pattern alopecia is characterized by chronic and progressive hair loss often beginning around thirty years of age and accelerating at menopause. The hair loss is usually confined to thecentral scalp in a diffuse pattern.
213l3~8 This loss of hair is cosmetically damaging and often psychologically disturbing to the patient. The etiology of the condition has been linked to an elevated level of androgens and the subsequent response of androgen sensitive hair follicles. Treatment of the condition is primarily cosmetic in nature, e. g., wigs, hair styles which cover the effected area, etc. The drug, Spironolactone, has been used, but does have side-effects. Clearly, an effective treatment for this condition would be useful.
This invention provides methods for inhibiting hirsutism or alopecia in women comprising administering to a female human in need of treatment an effective amount of a compound of formula I
,~ OCH2CH2,--R2 ~
RlO~OR~
(I) wherein Rl and R3 are independently hydrogen, O O
-CH3 -C-(Cl-C6 alkyl), or -C-Ar , wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.
Hirsutism (hypertrichosis) is characterized by excessive growth of hair. In women, hirsutism refers specifically to excessive growth of hair in a male pattern and distributlon. Clinically, hirsutism in women is seen as a growth of terminal hair on the face (particularly on the upper lip), the chin, chest, back, and lower abdomen (escutcheon). This growth of hair is often seen as unsightly and can be the cause of embarrassment and psychological distress. Hirsutism is a common occurrence at the menopause, but can occur any time after puberty.
The etiology of the condition has been linked to over production of androyens by either the ovaries or adrenal glands or both.
Hirsutsim in women can be treated in a variety of ways. Cosmetic treatment of the condition, including shaving, plucking of hairs, and bleaching, while effective in improving the appearance of the patient, are only palliative and must be constantly re-applied.
Glucocortacoid steroids are often effective; however, they have the potential of serious side-effects such as Cushing's Syndrome. Oral contraceptives can be effective;
however, care must be taken because certain progestins used in common oral contraceptive regiments may actually contribute hirsutism because of their androgenic side-effects. Cimetidine and Spironolactone have shown some effectiveness in the treatment of hirsutism; however, each of these can have unwanted side-effects. Clearly, a more effective and better tolerated agent would be useful.
Alopecia (hair loss) can occur in women for a variety of reasons, and includes female pattern alopecia.
Female pattern alopecia is characterized by chronic and progressive hair loss often beginning around thirty years of age and accelerating at menopause. The hair loss is usually confined to thecentral scalp in a diffuse pattern.
213l3~8 This loss of hair is cosmetically damaging and often psychologically disturbing to the patient. The etiology of the condition has been linked to an elevated level of androgens and the subsequent response of androgen sensitive hair follicles. Treatment of the condition is primarily cosmetic in nature, e. g., wigs, hair styles which cover the effected area, etc. The drug, Spironolactone, has been used, but does have side-effects. Clearly, an effective treatment for this condition would be useful.
This invention provides methods for inhibiting hirsutism or alopecia in women comprising administering to a female human in need of treatment an effective amount of a compound of formula I
,~ OCH2CH2,--R2 ~
RlO~OR~
(I) wherein Rl and R3 are independently hydrogen, O O
-CH3 -C-(Cl-C6 alkyl), or -C-Ar , wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino, and piperidino; and pharmaceutically acceptable salts and solvates thereof.
- 2~31 3498 x-9450 -3-The current invention concerns the discovery that a select group of 2-phenyl-3-aroylbenzothiophenes (benzothiophenes), those of formula I, are useful for inhibiting alopecia or hirsutism in women. The methods of treatment provided by this invention are practiced by administering to a human in need a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit alopecia or hirsutism. The term inhibit is defined to include its generally accepted meaning which includes prophylactically treating a human subject to incurring a problem described, and holding in check and/or treating an existing problem.
As such, the present method includes both medical therapeutic and/or prophylactic treatment, as appropriate.
Raloxifene, a compound of this invention wherein it is the hydrochloride salt of a compound of formula 1, Rl and R3 are hydrogen and R2 is l-piperidinyl, is a nuclear regulatory molecule. Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti-estrogen in that it blocked the ability of estrogen to activate uterine tissue and estrogen dependent breast cancers. Indeed, raloxifene does block the action of estrogen in some cells; however in other cell types, raloxifene activates the same genes as estrogen does and displays the same pharmacology, e.g., osteoporosis, hyperlipidemia. As a result, raloxifene has been referred to as an anti-estrogen with mixed agonist-antagonist properties. The unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and/or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to the activation and/or suppression of genes by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen utilize and compete for the same receptor, the pharmacological outcome from gene ` ~ Z~3B~98 regulation of the two is not easily predicted and is unique to each.
Generally, the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes. The compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
The compounds used in the methods of the current 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 starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group. The starting compound is protected, acylated, and deprotected to form the formula I compounds.
Examples of the preparation of such compounds are provided in the U.S. patents discussed above. Substituted phenyl includes phenyl substituted once or twice with Cl-C6 alkyl, Cl-C4 alkoxy, hydroxy, 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 which are often 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 and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, 2138~98 -x-9450 -5-phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ~-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinn~m~te, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of 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 out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines.
Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and cyclohexylamine.
21384~8 , ~ ~
, The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more ~men~hle to formulation as llquids or emulsions.
Pharmaceutical formulations can be prepared by procedures 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 carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone;
moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding 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 polyethyl glycols.
The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
The formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
The particular dosage of a compound of formula I
required to inhibit alopecia or hirsutism, according to this invention will depend upon the severity of the X138~8 -condition, the route of administration, and related factors that will be decided by the attending physician.
Generally, 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 dosages will be administered to a subject in need of treatment from once to about three times each day, or more often as needed to effectively treat the problem.
It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceuticals bearing a basic group, such as the piperidino ring.
Formulations In the formulations which follow, ~Active ingredient" means a compound of formula I.
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following:
IngredientQuantity (mg/capsule) Active ingredient 0.1 - 1000 Starch, NF O - 650 Starch flowable powderO - 650 Silicone fluid 350 centistokes 0 - 15 The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
Examples of specific capsule formulations of raloxifene that have been made include those shown below:
-Formulation 2: Raloxifene capsule Ingredient Quantity (mg/capsule) Raloxifene Starch, NF 112 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 3: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 5 Starch, NF 108 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 4: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 10 Starch, NF 103 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 5: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 50 Starch, NF 150 Starch flowable powder 397 Silicone fluid 350 centistokes 3.0 The specific formulations above may be changed in compliance with the reasonable variations provided.
- ` 2~38~98 A tablet formulation is prepared using the ingredients below:
Formulation 6: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.1 - 1000 Cellulose, microcrystalline0 - 650 Silicon dioxide, fumed 0 - 650 Stearate acid 0 - 15 The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.1 -1000 mg of active ingredient are made up as follows:
Formulation 7: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.1 - 1000 Starch 45 Cellulose, microcrystalline35 Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60 C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are ~` ~ 213~ 8 then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.1 - 1000 mg of medicament per 5 mL dose are made as follows:
Formulation 8: Suspensions Ingredient Quantity (mg/5 ml) Active ingredient0.1 - 1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL
Flavor q.v.
Color q.v.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
The following compositions are prepared for topical application:
Formulation 9 Ingredient Quantity (mq/5 ml) Hydroxypropylcellulose 1.5 g Active Ingredient 1.5-30 g Isopropanol qs 100 g ~ ~ 2~3~
, x-9450 -11-Formulation 10 IngredientQuantity (mg/5 ml~
Hydroxypropylcellulose 1.5 g Ethyl lactate 15.0 g Active Ingredient1.5-30 g Iso~ropanol qs 100 g Formulation 11 Ingredient Quantity (mg/5 ml) Hydroxypropylcellulose 1.0 g Butylated hydroxytoluene0.02 g Active Ingredient 1.5-25 g Ethanol qs 100 g Formulation 12 Inqredient Quantity (mg/5 ml) Hydroxypropylcellulose 1.5 g Butylated hydroxytoluene0.01 g C8-Cl2 fatty acid triglycerides 10.0 g Active Ingredient 1.5-30 g Isopropanol qs 100 g Formulations 9-12 take the form of gels, and are intended for the topical treatment of acne.
Formulation 13 Ingredient Quantity (mg/5 ml) Isopropanol 46.0 g Active Ingredient 1.0-15 g C8-Cl2 fatty acid triglycerides 49.0 q Formulation 14 Ingredient Quantity (mg/5 ml) Ethanol 69.0 g Ethyl lactate 10.0 g Active Ingredient 1.5-20 g C8-C12 fatty acid triglycerides 30.0 g Formulation 15 Ingredient Quantity (mg/5 ml) Isopropanol 47.0 g Acetone 10.0 g Ethyl lactate 10.0 g Active Ingredient 1-15 g C8-C12 fatty acid triglycerides 30.0 g Formlllation 16 Inqredient Quantity (mg/5 ml) Ethanol 95.08 g Butylated hydroxytoluene0.02 g Active Ingredient 1.5-25 g Formulations 13, 14, 15, and 16 take the form of lotions.
Formulation 17 Ingredient Quantity (mg/5 ml) White vaseline 50.0 g Liquid paraffin 15.0 g Refined paraffin wax 32.0 g Active Ingredient 1-20 q ~ 2~38~98 Formulation 18 Ingredient Quantity (mg/5 ml) White vaseline 50.0 g Liquid paraffin 13.0 g Refined paraffin wax 32.0 g Active Ingredient 1-20 g Formulations 17 and 18 take the form of sticks.
TEST PROCEDURES
HIRSUTISM
Three to twenty women suffering from hirsutism are selected. These patients are initially scored for the extent and severity of hirsutism. The clinical evaluation is made by the methods described in the reference ~Methods of Skin Research," John Wiley and Sons, pp 308-318 (1985), and the references cited therein. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration.
Alternatively, they apply a 10%, by weight of active ingredient, creme or lotion once or twice a day to the affected areas. The patient continues this protocol for six months. At appropriate intervals, re-evaluation by one of the methods described above would be made.
ALOPECIA
Three to twenty women suffering from female pattern alopecia are selected. These patients are initially scorèd for the extent and severity of the alopecia. This clinical evaluation is made by the methods described in "Methods of Skin Research,~ John Wiley and Sons, pp 308-318 (1985) and Habif, T., ~Clinical 2~38~98 x-9450 -14-Dermatology,~ C. V. Mosby Co., Chapter 23, pp 493-504 (1985); and references therein, herein incorporated by reference. Especially helpful in these evaluations is the'~hair pluck~ procedure and measurement of anagen to telogen ratio. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration. Alternatively, the patients apply a 5-10% (by weight of a compound of this invention) as a creme, lotion, or shampoo to the affected area, once to twice a day. This protocol continues for six months.
At appropriate intervals, re-evaluation by one of the methods described in the above references is made. A
positive result is exhibited by an increase in the anagen to telogen ratio or an increase in the number of terminal hairs in the affected scalp region.
Utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the symptoms when used in a study as above.
As such, the present method includes both medical therapeutic and/or prophylactic treatment, as appropriate.
Raloxifene, a compound of this invention wherein it is the hydrochloride salt of a compound of formula 1, Rl and R3 are hydrogen and R2 is l-piperidinyl, is a nuclear regulatory molecule. Raloxifene has been shown to bind to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was that of an anti-estrogen in that it blocked the ability of estrogen to activate uterine tissue and estrogen dependent breast cancers. Indeed, raloxifene does block the action of estrogen in some cells; however in other cell types, raloxifene activates the same genes as estrogen does and displays the same pharmacology, e.g., osteoporosis, hyperlipidemia. As a result, raloxifene has been referred to as an anti-estrogen with mixed agonist-antagonist properties. The unique profile which raloxifene displays and differs from that of estrogen is now thought to be due to the unique activation and/or suppression of various gene functions by the raloxifene-estrogen receptor complex as opposed to the activation and/or suppression of genes by the estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen utilize and compete for the same receptor, the pharmacological outcome from gene ` ~ Z~3B~98 regulation of the two is not easily predicted and is unique to each.
Generally, the compound is formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes. The compounds can be administered transdermally, and may be formulated as sustained release dosage forms and the like.
The compounds used in the methods of the current 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 starts with a benzo[b]thiophene having a 6-hydroxyl group and a 2-(4-hydroxyphenyl) group. The starting compound is protected, acylated, and deprotected to form the formula I compounds.
Examples of the preparation of such compounds are provided in the U.S. patents discussed above. Substituted phenyl includes phenyl substituted once or twice with Cl-C6 alkyl, Cl-C4 alkoxy, hydroxy, 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 which are often 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 and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, 2138~98 -x-9450 -5-phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ~-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinn~m~te, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzene-sulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. A preferred salt is the hydrochloride salt.
The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of 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 out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
Bases commonly used for formation of salts include ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines.
Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylene diamine and cyclohexylamine.
21384~8 , ~ ~
, The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more ~men~hle to formulation as llquids or emulsions.
Pharmaceutical formulations can be prepared by procedures 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 carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone;
moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding 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 polyethyl glycols.
The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
The formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
The particular dosage of a compound of formula I
required to inhibit alopecia or hirsutism, according to this invention will depend upon the severity of the X138~8 -condition, the route of administration, and related factors that will be decided by the attending physician.
Generally, 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 dosages will be administered to a subject in need of treatment from once to about three times each day, or more often as needed to effectively treat the problem.
It is usually preferred to administer a compound of formula I in the form of an acid addition salt, as is customary in the administration of pharmaceuticals bearing a basic group, such as the piperidino ring.
Formulations In the formulations which follow, ~Active ingredient" means a compound of formula I.
Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following:
IngredientQuantity (mg/capsule) Active ingredient 0.1 - 1000 Starch, NF O - 650 Starch flowable powderO - 650 Silicone fluid 350 centistokes 0 - 15 The ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
Examples of specific capsule formulations of raloxifene that have been made include those shown below:
-Formulation 2: Raloxifene capsule Ingredient Quantity (mg/capsule) Raloxifene Starch, NF 112 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 3: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 5 Starch, NF 108 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 4: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 10 Starch, NF 103 Starch flowable powder 225.3 Silicone fluid 350 centistokes 1.7 Formulation 5: Raloxifene capsule IngredientQuantity (mg/capsule) Raloxifene 50 Starch, NF 150 Starch flowable powder 397 Silicone fluid 350 centistokes 3.0 The specific formulations above may be changed in compliance with the reasonable variations provided.
- ` 2~38~98 A tablet formulation is prepared using the ingredients below:
Formulation 6: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.1 - 1000 Cellulose, microcrystalline0 - 650 Silicon dioxide, fumed 0 - 650 Stearate acid 0 - 15 The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.1 -1000 mg of active ingredient are made up as follows:
Formulation 7: Tablets Ingredient Quantity (mg/tablet) Active ingredient 0.1 - 1000 Starch 45 Cellulose, microcrystalline35 Polyvinylpyrrolidone 4 (as 10% solution in water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60 C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 U.S. sieve, are ~` ~ 213~ 8 then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.1 - 1000 mg of medicament per 5 mL dose are made as follows:
Formulation 8: Suspensions Ingredient Quantity (mg/5 ml) Active ingredient0.1 - 1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 mL
Flavor q.v.
Color q.v.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
The following compositions are prepared for topical application:
Formulation 9 Ingredient Quantity (mq/5 ml) Hydroxypropylcellulose 1.5 g Active Ingredient 1.5-30 g Isopropanol qs 100 g ~ ~ 2~3~
, x-9450 -11-Formulation 10 IngredientQuantity (mg/5 ml~
Hydroxypropylcellulose 1.5 g Ethyl lactate 15.0 g Active Ingredient1.5-30 g Iso~ropanol qs 100 g Formulation 11 Ingredient Quantity (mg/5 ml) Hydroxypropylcellulose 1.0 g Butylated hydroxytoluene0.02 g Active Ingredient 1.5-25 g Ethanol qs 100 g Formulation 12 Inqredient Quantity (mg/5 ml) Hydroxypropylcellulose 1.5 g Butylated hydroxytoluene0.01 g C8-Cl2 fatty acid triglycerides 10.0 g Active Ingredient 1.5-30 g Isopropanol qs 100 g Formulations 9-12 take the form of gels, and are intended for the topical treatment of acne.
Formulation 13 Ingredient Quantity (mg/5 ml) Isopropanol 46.0 g Active Ingredient 1.0-15 g C8-Cl2 fatty acid triglycerides 49.0 q Formulation 14 Ingredient Quantity (mg/5 ml) Ethanol 69.0 g Ethyl lactate 10.0 g Active Ingredient 1.5-20 g C8-C12 fatty acid triglycerides 30.0 g Formulation 15 Ingredient Quantity (mg/5 ml) Isopropanol 47.0 g Acetone 10.0 g Ethyl lactate 10.0 g Active Ingredient 1-15 g C8-C12 fatty acid triglycerides 30.0 g Formlllation 16 Inqredient Quantity (mg/5 ml) Ethanol 95.08 g Butylated hydroxytoluene0.02 g Active Ingredient 1.5-25 g Formulations 13, 14, 15, and 16 take the form of lotions.
Formulation 17 Ingredient Quantity (mg/5 ml) White vaseline 50.0 g Liquid paraffin 15.0 g Refined paraffin wax 32.0 g Active Ingredient 1-20 q ~ 2~38~98 Formulation 18 Ingredient Quantity (mg/5 ml) White vaseline 50.0 g Liquid paraffin 13.0 g Refined paraffin wax 32.0 g Active Ingredient 1-20 g Formulations 17 and 18 take the form of sticks.
TEST PROCEDURES
HIRSUTISM
Three to twenty women suffering from hirsutism are selected. These patients are initially scored for the extent and severity of hirsutism. The clinical evaluation is made by the methods described in the reference ~Methods of Skin Research," John Wiley and Sons, pp 308-318 (1985), and the references cited therein. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration.
Alternatively, they apply a 10%, by weight of active ingredient, creme or lotion once or twice a day to the affected areas. The patient continues this protocol for six months. At appropriate intervals, re-evaluation by one of the methods described above would be made.
ALOPECIA
Three to twenty women suffering from female pattern alopecia are selected. These patients are initially scorèd for the extent and severity of the alopecia. This clinical evaluation is made by the methods described in "Methods of Skin Research,~ John Wiley and Sons, pp 308-318 (1985) and Habif, T., ~Clinical 2~38~98 x-9450 -14-Dermatology,~ C. V. Mosby Co., Chapter 23, pp 493-504 (1985); and references therein, herein incorporated by reference. Especially helpful in these evaluations is the'~hair pluck~ procedure and measurement of anagen to telogen ratio. The patients receive 10-400 mg of an active compound of this invention per day as a single or split dose by oral administration. Alternatively, the patients apply a 5-10% (by weight of a compound of this invention) as a creme, lotion, or shampoo to the affected area, once to twice a day. This protocol continues for six months.
At appropriate intervals, re-evaluation by one of the methods described in the above references is made. A
positive result is exhibited by an increase in the anagen to telogen ratio or an increase in the number of terminal hairs in the affected scalp region.
Utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the symptoms when used in a study as above.
Claims (8)
1. A compound having the formula (I) wherein R1 and R3 are independently hydrogen, -CH3, , or , wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidino and piperidino; or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting hirsutism in a woman.
R2 is selected from the group consisting of pyrrolidino and piperidino; or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting hirsutism in a woman.
2. The compound of Claim 1 wherein said compound is the hydrochloride salt thereof.
3. The compound of Claim 1 wherein its administration is prophylactic.
4. The compound of Claim 1 wherein said compound is or its hydrochloride salt.
5. A compound having the formula (I) wherein R1 and R3 are independently hydrogen, -CH3, , or , wherein Ar is optionally substituted phenyl;
R2 is selected from the group consisting of pyrrolidino and piperidino; or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting alopecia in a woman.
R2 is selected from the group consisting of pyrrolidino and piperidino; or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting alopecia in a woman.
6. The compound of Claim 5 wherein said compound is the hydrochloride salt thereof.
7. The compound of Claim 5 wherein its administration is prophylactic.
8. The compound of Claim 5 wherein said compound is or its hydrochloride salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/171,089 | 1993-12-21 | ||
| US08/171,089 US5574048A (en) | 1993-12-21 | 1993-12-21 | Methods of inhibiting hirsutism and alopecia in women |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2138498A1 true CA2138498A1 (en) | 1995-06-22 |
Family
ID=22622479
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002138498A Abandoned CA2138498A1 (en) | 1993-12-21 | 1994-12-19 | Methods of inhibiting hirsutism and alopecia in women |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US5574048A (en) |
| EP (1) | EP0659414B1 (en) |
| JP (1) | JPH07215864A (en) |
| KR (1) | KR950016728A (en) |
| CN (1) | CN1107703A (en) |
| AT (1) | ATE203406T1 (en) |
| AU (1) | AU690162B2 (en) |
| CA (1) | CA2138498A1 (en) |
| CZ (1) | CZ321394A3 (en) |
| DE (1) | DE69427807T2 (en) |
| DK (1) | DK0659414T3 (en) |
| ES (1) | ES2157961T3 (en) |
| GR (1) | GR3036977T3 (en) |
| HU (1) | HUT71479A (en) |
| IL (1) | IL112040A0 (en) |
| NO (1) | NO944920L (en) |
| NZ (1) | NZ270171A (en) |
| PH (1) | PH31440A (en) |
| PT (1) | PT659414E (en) |
| RU (1) | RU94044457A (en) |
| SI (1) | SI0659414T1 (en) |
| ZA (1) | ZA9410092B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5965551A (en) * | 1996-02-21 | 1999-10-12 | North Carolina State University | Method of treating alopecia |
| TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
| IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
| WO2000066612A1 (en) | 1999-05-04 | 2000-11-09 | Strakan Limited | Androgen glycosides and androgenic activity thereof |
| US20060263452A1 (en) * | 2005-05-17 | 2006-11-23 | Alwyn Dowell | Topical composition containing essential oils |
| CA2769512C (en) | 2009-07-29 | 2019-07-09 | Duke University | Compositions comprising fp receptor antagonists and their use for inhibiting hair growth |
Family Cites Families (7)
| 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 |
| US4859585A (en) * | 1986-04-17 | 1989-08-22 | Trustees Of Tufts College | In-vitro methods for identifying compositions which are agonists and antagonists of estrogens |
| 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 |
| US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
| JP3157882B2 (en) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | New benzothiophene derivatives |
-
1993
- 1993-12-19 CZ CZ943213A patent/CZ321394A3/en unknown
- 1993-12-21 US US08/171,089 patent/US5574048A/en not_active Expired - Fee Related
-
1994
- 1994-12-16 RU RU94044457/14A patent/RU94044457A/en unknown
- 1994-12-19 SI SI9430389T patent/SI0659414T1/en unknown
- 1994-12-19 NZ NZ270171A patent/NZ270171A/en unknown
- 1994-12-19 AT AT94309471T patent/ATE203406T1/en not_active IP Right Cessation
- 1994-12-19 ES ES94309471T patent/ES2157961T3/en not_active Expired - Lifetime
- 1994-12-19 EP EP94309471A patent/EP0659414B1/en not_active Expired - Lifetime
- 1994-12-19 ZA ZA9410092A patent/ZA9410092B/en unknown
- 1994-12-19 KR KR1019940034919A patent/KR950016728A/en not_active Application Discontinuation
- 1994-12-19 DE DE69427807T patent/DE69427807T2/en not_active Expired - Fee Related
- 1994-12-19 PH PH49587A patent/PH31440A/en unknown
- 1994-12-19 JP JP6314549A patent/JPH07215864A/en active Pending
- 1994-12-19 DK DK94309471T patent/DK0659414T3/en active
- 1994-12-19 AU AU81550/94A patent/AU690162B2/en not_active Ceased
- 1994-12-19 HU HU9403665A patent/HUT71479A/en unknown
- 1994-12-19 CA CA002138498A patent/CA2138498A1/en not_active Abandoned
- 1994-12-19 IL IL11204094A patent/IL112040A0/en unknown
- 1994-12-19 CN CN94119731A patent/CN1107703A/en active Pending
- 1994-12-19 PT PT94309471T patent/PT659414E/en unknown
- 1994-12-19 NO NO944920A patent/NO944920L/en unknown
-
1995
- 1995-03-15 US US08/404,858 patent/US5686468A/en not_active Expired - Fee Related
-
2001
- 2001-10-22 GR GR20010401847T patent/GR3036977T3/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| US5686468A (en) | 1997-11-11 |
| US5574048A (en) | 1996-11-12 |
| CZ321394A3 (en) | 1995-08-16 |
| JPH07215864A (en) | 1995-08-15 |
| KR950016728A (en) | 1995-07-20 |
| AU8155094A (en) | 1995-06-29 |
| PH31440A (en) | 1998-11-03 |
| RU94044457A (en) | 1996-10-10 |
| NO944920L (en) | 1995-06-22 |
| GR3036977T3 (en) | 2002-01-31 |
| HU9403665D0 (en) | 1995-02-28 |
| EP0659414A2 (en) | 1995-06-28 |
| AU690162B2 (en) | 1998-04-23 |
| ATE203406T1 (en) | 2001-08-15 |
| ES2157961T3 (en) | 2001-09-01 |
| EP0659414A3 (en) | 1995-09-06 |
| ZA9410092B (en) | 1996-06-19 |
| DE69427807T2 (en) | 2001-12-06 |
| SI0659414T1 (en) | 2001-12-31 |
| EP0659414B1 (en) | 2001-07-25 |
| NO944920D0 (en) | 1994-12-19 |
| NZ270171A (en) | 1996-08-27 |
| DK0659414T3 (en) | 2001-09-24 |
| DE69427807D1 (en) | 2001-08-30 |
| PT659414E (en) | 2001-11-30 |
| CN1107703A (en) | 1995-09-06 |
| IL112040A0 (en) | 1995-03-15 |
| HUT71479A (en) | 1995-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0664124B1 (en) | Treatment of atrophy of the skin and vagina | |
| US5391557A (en) | Methods for the treatment of peri-menopausal syndrome | |
| EP0659416B1 (en) | Inhibition of seborrhea and acne | |
| US5534526A (en) | Methods for inhibiting vasomotor symptoms and attending psychological disturbances surrounding post-menopausal syndrome | |
| US5663184A (en) | Methods of inhibiting CNS problems in post-menopausal women | |
| AU701701B2 (en) | Methods of inhibiting breast disorders | |
| CA2138513A1 (en) | Methods of inhibiting myeloperoxidase activity | |
| US5451590A (en) | Methods of inhibiting sexual precocity | |
| US5578614A (en) | Methods for inhibiting weight gain or inducing weight loss | |
| US5843974A (en) | Methods of inhibiting melanoma using Benzothiophenes as cytotoxic agents per se | |
| EP0659414B1 (en) | Inhibition of hirsutism and alopecia in women | |
| US5512296A (en) | Methods for inhibiting neuronal damage | |
| US5670523A (en) | Methods of inhibiting musculoaponeurotic fibromatoses (desmoid tumors) | |
| AU707675B2 (en) | Methods of inhibiting musculoaponeurotic fibromatoses (desmoid tumors) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |