JP2000514441A - Use of 3,4-diphenylchroman for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome - Google Patents

Abstract

(57) Summary The present invention provides a compound of general formula I for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome: Wherein R ¹ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halogen, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy or ( _tertiary amino) (C _1-6 alkoxy R ² and R ³ are independently hydrogen or C _1-6 alkyl) or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION 3 for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome Of 4,4-diphenylchroman Field of the invention   The present invention relates to a compound of general formula I for inhibiting one or more symptoms of premenstrual syndrome. Regarding the use of The present invention relates to pharmaceutical compositions containing these compounds, and compounds thereof. And methods of using their pharmaceutical compositions. Background of the Invention   Premenstrual syndrome (PMS) affects the majority of women with normally functioning ovaries This is a common state. The cause is not yet known, but the It appears to be related to strogen and progesterone fluctuations. PMS for late luteal phase Also called symptomatic group (or late luteal dysfolia disease).   The symptoms that occur can be both physiological and mental in nature. Irritant, Snappiness and irritability, depression and aggression are most commonly Although a reported mental condition, tension and anxiety are also frequent. Early menstruation and menstruation Mental and behavioral symptoms that have been suggested to occur during the period Insomnia, confusion, poor judgment, poor concentration, crying, loneliness, calm Includes absence, irritability, and mood swings. The effects of these symptoms can vary widely. Is multiplied by physiological symptoms. The most commonly reported symptoms are fatigue, abdomen The sensation of swelling and breast swelling and weight gain. Suggested to occur Other symptoms that have been If dizzy, faint, faint, sweaty, nausea, vomiting, hot flashes, muscle stiffness, headache, sickness Badness, low back pain, general pain, and water retention, such as weight gain, skin disorders, painful chest, And swelling.   Numerous treatments have been suggested to alleviate or minimize symptoms of premenstrual syndrome . These include, for example, non-pharmaceutical treatments, such as total energy intake and protein, Fats, carbohydrates, vitamin B₆And E consumption variations and, for example, Oenothera containing gnesium or calcium and gamolenic acid Including oil supply. Other treatments include non-hormonal treatments, such as serotonin reuptake inhibitors. Bitter and hormonal treatments, such as with progesterone and progestogen Treatment, oral contraceptive combination, estrogen replacement therapy, danazol and gonadoto Including robin hormone agonists (eg, Drug theraby in reproductive end ocrinology, edited by Jean Ginsburg, Chapter 7 entltled “Premenstrual S yndrome "(Abukhalil, I.E.H5: 107-115)).   Although various treatment options are available, many women have premenstrual syndrome on a monthly basis. Continue to suffer. Accordingly, the present invention relates to a method for treating one or more women in premenstrual syndrome. Provided are methods for alleviating a number of menstrual symptoms, and compositions therefor.   St. chroman is a non-steroid known to have antiestrogen activity Compound. It is used in India as an oral contraceptive. ( For example, Salmon et al., U.S. Patent 4,447,622; Singh et al.,Acta Endocrinal (Copenh) 12 6  (1992), 444-450; Grubb,Curr Opin Obstet Gynecol 3 (1991), 491-495; San karan et al.Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). St. chroman is also being studied as an anticancer drug for the treatment of advanced breast cancer ( Misra et al .;Int J Cancer 43(1989) 781-783). Present Now, racemic St. chroman is represented by a large decrease in serum concentration It has been found as a potential cholesterol lowering drug (S.D.Bain et al.J.Min Bon Res , 9 (1994) S394)   U.S. Pat.No. 5,453,442 discloses administering a compound of Formula I as set forth herein. Reduces serum cholesterol in humans, inhibits smooth muscle cell proliferation, Thus, a method of inhibiting fibrotic diseases of the uterus and endometriosis in women is described. Further, U.S. Patent 5,280,040 discloses 3,4-diarylchromans and their medicaments. Describes a method and pharmaceutical composition for reducing bone loss using pharmaceutically acceptable salts I do. No disclosure of patents using compounds to treat or alleviate premenstrual syndrome .   An object of the present invention is to alleviate one or more symptoms associated with premenstrual syndrome. To provide a compound that can be Brief description of the invention   The present invention provides a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome. General formula I for the construction: (Where R¹, R^FourAnd R^FiveRepresents hydrogen, hydroxy, halogen, trifluoro, Lomethyl, C_1-6-Alkyl, C_1-6-Alkoxy or (tertiary amino) (C_1-6− Alkoxy); R^TwoObihi R^ThreeIs Individually, hydrogen or C_1-6Or a pharmaceutically acceptable compound thereof. Provide the use of salt. Detailed description of the invention   The present invention relates to a group of 3,4-diarylchromans of the formula I, which is associated with premenstrual syndrome. Based on the finding that it helps to alleviate one or more symptoms. This allows the book The invention relates to pharmaceutically acceptable for the manufacture of a pharmaceutical composition for the treatment of premenstrual syndrome Formula I in combination with a carrier to be prepared: (Where R¹, R^FourAnd R^FiveRepresents hydrogen, hydroxy, halogen, trifluoro, With lomethyl, lower alkyl, lower alkoxy or (tertiary amino) (lower alkoxy) Yes; R^TwoAnd R^ThreeIs independently hydrogen or lower alkyl) or Provides its use as a pharmaceutically acceptable salt. As a result, the present invention A patient in need of treatment is administered an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. A method of inhibiting one or more symptoms of premenstrual syndrome, including administering. for The word "suppression" prevents female human patients from suffering from, for example, PMS symptoms Doing, stopping each symptom, alleviating one or more symptoms, and And / or including its generally accepted meaning, including treating an existing condition. Defined It is. This allows the method to be suitable for both medical and / or prophylactic treatment. Including   In the present invention, the compound of formula I referred to in claim 1 is premenstrual in a patient Used to control one or more symptoms of the syndrome. In formula I, R¹, R^FourAnd R^FiveIs independently hydrogen, hydroxy, halogen, trifluoromethyl, C_1-6 Alkyl, C_1-6Alkoxy or (tertiary amino) (C_1-6Alkoxy); R^Two And R^ThreeIs independently hydrogen or C_1-6Alkyl. As used herein, The term "lower alkyl" refers to straight and branched chain alkyl groups containing 1 to 6 carbon atoms, such as For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethyl Including rubutyl and the like. The term "lower alkoxy" refers to a straight chain containing 1 to 6 carbon atoms or Branched alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropo Xy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n -Hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. “ "Halogen" includes chloro, fluoro, bromo and iodo. As used herein, the term “(Tertiary amino) (lower alkoxy)” refers to a lower tertiary amino-substituted lower It is an alkoxy group. Tertiary amino groups include N, N-dialkylamines, such as N, N. N-dimethylamino, N, N-diethylamino, N, N-dipropylamino and N, N-dibutylamino or polymethyleneimine such as piperidine, pyrrolidine , N-methylpiperazine, or morpholine. Preferred compounds are , R¹Is lower alkoxy; R^TwoAnd R^ThreeIs lower alkyl, especially methyl R^FourIs hydrogen; and R^FiveIs polymethyleneimine type (tertiary amino) (lower Alkoxy)). In a particularly preferred embodiment And R¹Is in position 7 and is lower alkoxy, especially methoxy;^TwoAnd R^ThreeEach of Each is methyl, R^FourIs hydrogen and R^FiveIs in position 4 (tertiary amino) ( A lower alkoxy) group, for example 2- (pyrrolidin-1-yl) ethoxy. Good A preferred compound is R¹Is C_1-6R is alkoxy;^TwoAnd R^ThreeIs C_1-6Alkyl, Especially methyl; R^FourIs hydrogen: and R^FiveIs a polymethyleneimine type (No. Triamino) (C_1-6Alkoxy)). In a particularly preferred embodiment Where R¹Is in 7th place and C_1-6Alkoxy, especially methoxy; R^TwoAnd R^Threeof Each is methyl, R^FourIs hydrogen and R^FiveIs in position 4 (tertiary amino) (C_1-6An alkoxy) group, for example of the formula II: 2- (pyrrolidin-1-yl) ethoxy.   All pharmaceutically acceptable salts of the compounds of formula I referred to are included in the present invention .   Preference is given to using compounds of the formula I in the trans configuration. These compounds , May be used as a racemic mixture, or may be an isolated d- or l-enane Thiomers may be used. The trans-1-enantiomer is more preferred.   Particularly preferred compounds for use in the present invention are those of formula IV referred to in claim 11:Is St. Croman.   While only one enantiomer is shown, Formula IV shows the tri- and 4-phenyl groups As used herein to refer to a lance configuration and d- and l-enantiomers It will be understood that both and racemic mixtures are included.   3,4-Diaryl chromans are incorporated herein by reference or by reference. U.S. Pat.No. 3,340,276 to Carney et al., U.S. Pat.No. 3,822,287 to Bolger and Ray et al. (J. Med Chem 19 (1979), 276-279). Cis isomerism US Patent for Transformation of Body into Trans Configuration by Organometallic-Based Catalytic Rearrangement No. 3,822,287. Optically active d- and 1-enantiomers are Formation of the optically active acid salt which undergoes rehydrolysis to form the required enantiomer By doing so, US Pat. No. 4,447,622 (incorporated herein by reference). Can be prepared as disclosed by Salpan et al. R^TwoIs R^ThreeWhen Differently, R^FourIs R^FiveIf different from general formula I covers eight optical isomers.   In the present invention, the 3,4-diaryl chromans of Formula I are pharmaceutically acceptable. Prepared in the form of a salt, especially in the form of an acid addition salt, including salts of organic and inorganic acids. be able to. Examples of such salts are organic acids such as formic acid, fumaric acid, maleic acid Acid, acetic acid, propionic acid, Glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, Includes salts such as enic acid, benzoic acid and salicylic acid. Suitable inorganic acid addition salts include hydrochloric acid, odor Including salts such as hydrofluoric acid, sulfuric acid and phosphoric acid. Acid addition salts are a direct product of compound synthesis. Can be obtained. Instead, the free base is dissolved in a suitable solvent containing the appropriate acid. The salt may evaporate the solvent or separate the salt and the solvent. Can be isolated. A preferred salt is hydrogen fumarate.   The 3,4-diarylchromans of formula I and their salts are useful in human and veterinary medicine. For example, in the treatment of patients suffering from premenstrual syndrome. Of use in the present invention Due to the 3,4-diarylchromans of formula I and their pharmaceutically acceptable Salts may be administered parenterally, orally, nasally, rectally, subcutaneously, or intradermally or transdermally according to conventional methods. It is formulated with a pharmaceutically acceptable carrier to provide the drug for dermal administration. Formulations may include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. Liquid, powder, emulsion, suppository, liposome, transdermal patch, controlled release It may be provided in the form of a powder, a skin implant, a tablet and the like. One skilled in the art Shall, in an appropriate manner and according to acceptable practices,Remington's Pharmaceutical Scl ence (Gennaro, ed., Mack Publishing Co., Easton, PA, 1990). As such, the compounds of Formula I can be formulated.   The present invention is a pharmaceutical composition for alleviating one or more symptoms of premenstrual syndrome. Thus, in combination with a pharmaceutically acceptable carrier, diluent or excipient, the compound of formula I And at least one selected from the group consisting of analgesics, diuretics, and antihistamines. Further provided is a pharmaceutical composition comprising at least one pharmaceutical agent.   Oral administration is preferred. This allows the active compounds of the formula I to be administered orally. It is prepared in a form suitable for administration, for example in tablets or capsules. Typically, the formula A pharmaceutically acceptable salt of the compound of I is combined with a carrier and formed into tablets. You. Suitable carriers in this regard are starch, sugar, dicalcium phosphate, stearate. Includes calcium phosphate, magnesium stearate and the like. Such compositions are further modified One or more auxiliary substances such as wetting agents, emulsifiers, preservatives, stabilizers, coloring additives Objects and the like.   A pharmaceutical composition comprising a compound of Formula I is administered one or more times per day or week. Can be An effective amount of such a pharmaceutical composition is clinically useful for premenstrual syndrome. Is an amount that provides a significant effect. Such an amount may depend, in part, on the particular Condition, age, weight, and general health of the patient, and other factors apparent to those skilled in the art. Will depend on. A typical daily dosage might be 1 kg of patient per day of a compound of the present invention. A non-toxic dosage range of about 0.001 to about 75 mg / kg, preferably about 0.0 / kg / day of patient. It will contain a range of 1-75 mg, more preferably about 0.01-50 mg.   A pharmaceutical composition comprising a compound of Formula I may be administered in one or more doses per day or week. It can be administered in a dose. Instead, they are suitable for skin implants. As controlled release formulations. Implants can be up to several years Formulated to provide for release of the active compound over a required period of time. control Release formulations are described, for example, in Sanders et al. (Herein incorporated by reference).J.Pharm.S ci.73 (1964) (1294-1297,1984); U.S. Pat. No. 4,489,056; and U.S. Pat. It is disclosed in specification 4,210,644.   The following examples are provided for purposes of illustration, not limitation.   Examples of preferred compounds of formula I are as racemic mixtures and as isolated l-cent Chroman and d-cent chroman enantiomers This is St. Croman. Further, 3,4-trans-2,2-dimethyl-3- Phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl-7 -Hydroxychroman is a preferred compound. More preferred compounds are isolated L-centchroman (l-3,4-trans-2,2-dimethyl-3-fe) Nyl-4- [4- (2-pyrrolidin-1-yl) ethoxy) phenyl] -7-me Tokicycloman;   Examples of pharmaceutically acceptable acid addition salts are inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid Or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluco Acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid , Methanesulfonic acid and malonic acid are salts with non-toxic acids.   The present invention is further described by the following examples, which limit the scope of protection. Should not be interpreted as Features disclosed in the preceding description and in the following examples , Separately and in any combination thereof, in its separate form It can be a material for recognizing the invention. Example   Control studies in clinical cases will be performed on 6 to 50 women. Those women are good ones He is in general health and has a regular menstrual period, but suffers from PMS as described above. Symptoms are reported on a questionnaire. Women in two groups, active compounds of the invention It is divided into a test group that receives and a control group that receives placebo. Te Women in strike group receive 1-500 mg of test compound orally daily for 1-6 months Accept. Carefully record the symptoms regularly throughout the study. To PMS The effect on related symptoms should be assessed between groups and before starting treatment. Are also compared for each patient. test The effect of the compound on any of the symptoms of PMS is considered positive.

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Claims (1)

[Claims] 1. General Formula I for the manufacture of a pharmaceutical composition for inhibiting one or more symptoms of premenstrual syndrome: Wherein R ¹ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, halogen, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy or ( _tertiary amino) (C _1-6 alkoxy R ² and R ³ are each independently hydrogen or C _1-6 alkyl) or a pharmaceutically acceptable salt thereof. 2. In the compound used, R ¹ is C _1-6 alkoxy, R ² and R ³ are C _1-6 alkyl, R ⁴ is hydrogen, and R ⁵ is ( _tertiary amino) C _1-6 alkoxy. Use according to claim 1, characterized in that there is. 3. 3. The use according to claim 1, wherein R ¹ is methoxy. 4. Use according to any one of claims 1 to 3, characterized in that R ² is methyl. 5. Use according to any one of claims 1-4, characterized in that R ³ is methyl. 6. Use according to any one of claims 1-5, characterized in that R ⁴ is hydrogen. 7. R ⁵ has the following formula II: The use according to any one of claims 1 to 6, wherein the group is represented by: 8. The use according to any one of claims 1 to 7, wherein the compound is an isolated d- or l-enantiomer. 9. The compound has the following general formula III: Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as defined in claim 1 above. Use of. Ten. Wherein the compound is 3,4-trans-2,2-dimethyl-3-phenyl-4 [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl-7-hydroxychroman. Use according to any one of the claims. 11． Use according to any one of the preceding claims, characterized in that the compound is an isolated 1-enantiomer. 12． The compound has the following formula IV: 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman having The use according to claim 1, wherein 13. The compound is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2- (pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman. 13. Use according to claim 12, which is an enantiomer. 14. Use according to any one of the preceding claims, characterized in that the composition is in a form suitable for oral administration. 15． Use according to any one of the preceding claims, wherein the compound is administered as a dose ranging from about 0.001 to 75 mg / kg patient per day. 16． Use according to any one of the preceding claims, characterized in that the composition is administered one or more times per day or week. 17． Use according to any one of the preceding claims, characterized in that the composition is in the form of a skin implant. 18． A method of inhibiting one or more symptoms of premenstrual syndrome, wherein the compound of formula I or a pharmaceutically acceptable compound thereof as used in any of the preceding claims in an amount sufficient to treat premenstrual syndrome. A method comprising administering to a patient a clinically effective amount of a salt. 19. A method of treating or preventing premenstrual syndrome, comprising administering to a patient in need of treatment a clinically effective amount of a compound according to any of the preceding claims and a pharmaceutically acceptable composition. A method that includes 20. Any novel feature or combination of features described herein.