The use of 2-phenyl-3-koivistoinen for inhibition of cns disorders in postmenopausal women


(57) Abstract:

The invention relates to medicine, specifically to gynecology. Proposed a new way of inhibition of one or more CNS disorders in postmenopausal women, representing a compound of formula

< / BR>
where R1and R3are independently hydrogen,- CH3- (C1- C6alkyl) or ,

where Ar is an appropriately substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino-and piperidino, or their pharmaceutically acceptable salts. The invention expands the Arsenal of tools specified destination. 3 C.p. f-crystals.

Women in menopause sensations of anxiety, anxiety, depression, stress and irritability begin for another premenopause and can correlate with reduced levels of estrogen in the body, and therefore to treat these symptoms recommended estrogenzawisimaya therapy (Malleson J., Lancet, 2: 158, (1953); Wilson et. al., J. Am. Geriatric Soc., 11:347, (1963).

The mechanism of the protective action of estrogen in this case is unknown, although preferred, may be associated with potential influence of estrogen on biogenic amines, such as gray in postmenopausal women reduced (G. Gonzales, et. al., Maturitas 17, 23-29 (1993), and serotone (as well as some other biogenic amines) plays a likely role in the development of depression. Phillips and Sherwin (Psychoneuro-endocrinology. 17: 485-495 (1992)) reported that women with menopause caused by surgery who received estrogen, test scores will learn in the short-term and long-term memory is higher than that of similar women, untreated estrogen. There are two hypothetical hypothesis to explain this effect. There is some evidence that certain agonists of estrogen (or antiestrogens, such as tamoxifen, interact with muscarinic receptors (Ben-Baruch G. et/ al., Molec. Pharmacol., 21:287-293 (1982), and muscarinic agonists (M2) is known to have a positive impact in a number of tasks on associative memory and have indications for clinical use in Alzheimer's disease. The second interesting hypothesis can be associated with neurocinema, such as substance P, which, as you know, has neurotrophic function, and property improve memory (Thoenen H., Trends in Neuroscience, 14 : 165 - 170 (1991); Huston J. et al., Neurosei. Biobehav. Rev. 13 : 171 - 180 (1989), and thus, through the impact of either the receptor for the neurotransmitter in the Central nervous system, or neuropeptides influence on cognitive processes. This activity is most relevant can be evaluated in humans, although for preclinical testing of various suitable experimental model (i.e., training in the maze, the attenuation of the acquired reflex I. D.).

Probably the most frequent complication associated with Central nervous system, women in the climatic period are the tides. Although they undoubtedly represent a physical process carried out by the effects on the microcirculation, the current data present compelling evidence in favor of perspective about initiating the influence of the Central nervous system (Lomax P., et. al., Pharmac. Ther. 57 : 347 - 358 (1993)).

In regard to tissue selective agonist/antagonist of the estrogen it is thought that, like raloxifene, may be the ideal treatment, providing the desired effect without unwanted side effects on reproductive tissue.

The present invention is methods of inhibiting disorders of the Central nervous system in postmenopausal women, including the introduction of women in need of treatment, an effective amount of a compound described by formula I.

< / BR>
where R1and R3are independently hydrogen, -CH3or

where Ar is a neo - piperidino and their pharmaceutically acceptable salts and solvate.

The present invention relates to the discovery that the selected group of 2-phenyl-3-koivistoinen (benzothiophene) of the formula I are suitable to correct disorders of the Central nervous system in women being post-menopausal. The treatment method proposed in this invention, applicable in practice by introducing the necessary dose of the compounds of formula I or pharmacologically acceptable salts of MES, which are effective for the inhibition of one or more disorders of the Central nervous system. The term inhibition indicates its basic common meaning, which includes prophylactic treatment of a human subject exposed to the symptoms described, allowing to control and/or to treat existing symptoms. As such, the present method includes both campaign - medical therapeutic and/or prophylactic treatment depending on the indications. For disorders of the CNS are the most well-known disorders that are included in the determination by professionals in this area and that most often affect women in post-menopausal status: anxiety, depression, tension, irritability, mood swings, defects of motivation, reduced memory and processes of filling.

Raloxifene connection, opisa hydrogen, and R2- 1-piperidinium, is the kernel-regulatory molecule. It was shown that raloxifene is associated with the estrogen receptor and is the starting molecule whose function and pharmacology are anti-estrogenic in nature, so that it blocks the ability of estrogen to activate the tissue of the uterus and estrogenzawisimy tumour of the breast. In fact raloxifene must activate the effects of estrogen in several types of cells; however, in other cell types raloxifene activates the same genes as estrogen and exhibits similar pharmacological properties, for example inhibits the rarefaction of bone tissue and reduction of serum lipids. In the raloxifene is considered as an antiestrogen with mixed properties agonist/antagonist. Unique properties, which manifests raloxifene and their difference from those of estrogen, as is now clear, due to the unique activation and/or suppression of various functions of genes raloxifene-estrogen receptor complex in contrast to the activation and/or suppression of genes estrogen-estrogen receptor complex. Therefore, although raloxifene and estrogen use and compete for the same receptor pharmacological re, what is the mechanism of action is certainly entirely or partially through the estrogen receptor.

Typically, the compound is mixed with common excipients, diluents or carriers, and compressed into tablet form, or prepared in the form of elixirs or solutions for convenient oral administration, or for intramuscular or intravenous administration. The connection can also be applied transdermal or can be prepared in dosage forms intended for use in measured doses of drugs with a slow release, and the like.

The compounds used in the present invention, can be obtained by methods which are described in detail in U.S. patents NOS 4133814; 4418068 and 4380635 listed in the description as references. Typically, the process begins with benzo(C) thiophene with 6-hydroxyl and 2-(4-hydroxyphenyl) group. The original connection allerban or deprived of the protective groups to obtain the compounds of formula I. Examples of the preparation of such compounds shown in the above U.S. patents. Substituted phenyl is a phenyl, substituted with one or two of the following substituents: C1-C6alkyl, Ispolzuemye in the methods of the present invention, form salts of pharmaceutically acceptable acids and bases with a variety of organic and inorganic acids and bases and include, including physiologically acceptable salts which are often used in chemical and pharmaceutical production. Such salts are also part of the present invention. Typical inorganic acids used for the formation of such salts include hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, fosfornuyu and the like. Can also be used salts derived from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxycorticosterone acids, aromatic acids, aliphatic and aromatic sulfonic acids.

Thus, such pharmaceutically acceptable salts include the acetate, phenyl acetate, trifter acetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate-hydroxybutyrate-hydroxybutyrate, Butin-1,4-diet, hexyne-1,4-diet, kapronat, kaprilat, chloride, Tsinandali, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, dihydrophosphate, monosoff, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacina, succinate, suberate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, R-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate and the like. The preferred salt is the hydrochloride.

Pharmaceutically acceptable salt accession acids are usually formed by the reaction of compounds of formula I with an equimolar or excess amount of acid. The reagents are generally mixed in an appropriate solvent, such as diethyl ether or benzene. The salt normally precipitates out of solution during the period from 1 h to 10 days and can be separated by filtration or removal of solvent in a standard way.

The base is usually used for the formation of salts include ammonium hydroxide, hydroxides of alkali and alkaline earth metals, carbonates and aliphatic primary, secondary and tertiary amines, aliphatic diethylamin, the Ethylenediamine and cyclohexylamine.

Pharmaceutically acceptable salts, as a rule, are characterized by high solubility in comparison with the reference compound, and therefore, most suitable for such dosage forms as liquids and emulsions.

The pharmaceutical preparations are prepared using well known methods. For example, compounds may be formed using well-known fillers, solvents or carriers in the form of tablets, capsules, suspensions, powders and the like. Examples of fillers, solvents and carriers that are suitable for such formulations include the following substances: fillers and diluents, such as starch, sugars, mannitol, and silicon-containing compounds; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone; moisturizing agents such as glycerol; dezintegriruetsja agents, such as calcium carbonate and sodium bicarbonate; agents, retarding dissolution such as paraffin, and accelerating the absorption, such as Quaternary ammonium compounds, surface active agents, such as cetyl alcohol, glycerol monostearate, adsorbents, HCC CLASS="ptx2">

These compounds can also be prepared in the form of Alexiou or solutions usually for oral administration or as solutions for parenteral injection, for example, intramuscular, subcutaneous or intravenous route. In addition, these compounds are well suited for creating dosed drugs with a slow release, and the like. Dosage forms can be designed in such a way that the active ingredients are allocated only or mainly in certain regions of the intestinal tract in a certain period of time. Of polymeric substances or waxes can be made covering and protective shell.

In accordance with the present invention the individual dosage of the compounds of formula I required to inhibit one or more CNS disorders in postmenopausal women, will depend on the severity of the condition, the route of administration and other related factors, the solution for which is made by the attending physician. As a rule, valid and effective daily dose range from 0.1 to 1000 mg/day, and most often ranges from 50 to 200 mg/day. The selected doses are administered to the woman in need of treatment from one to three times per day, or more frequently when neobhodimosti compound of formula 1 in the form of salts, accession acid as is customary when using drugs that carry a basic group, such as piperidino ring. There are also advantages to the introduction of such compounds oral route in postmenopausal women. For the purposes of oral administration suitable the following form.


The following dosage forms of the term "Active ingredient" means a compound of formula I.

Pharmaceutical form I:

Gelatin capsules

Hard gelatin capsules are prepared using the following ingredients:

The ingredient Quantity (mg/capsule)

Active ingredient: 0.1 to 1 000

Starch, NF - 0 - 650

Granular starch powder - 0 - 650

Selikonovaja fluid 350 centistoke - 0 - 15

The ingredients were mixed, passed through a sieve size No. 45 mesh U.S. and was filled with a mixture of hard gelatin capsules.

Examples of capsules prepared on the basis of raloxifene below:

Dosage form 2:

Capsule with raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 1

Starch, NF - 112

Granular starch powder - 225,3

Silicone fluid 350 centistoke - 1,7

Dosage form 3:

Capsules what s starch powder 225,3

Silicone fluid 350 centistoke - 1,7

Pharmaceutical form 4:

Capsule with raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 10

Starch, NF - 103

Granular starch powder - 225,3

Silicone fluid 350 centistoke - 1,7

Dosage form 5:

Capsule with raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 50

Starch, NF - 150

Granular starch powder - 397

Silicone fluid 350 centistoke - 3,0

The above dosage forms can be modified within reasonable limits.

Tableted dosage form is prepared using the following ingredients:

Dosage form 6:


The ingredient Quantity (mg/tablet)

Active ingredient: 0.1 to 1 000

Microcrystalline cellulose - 0 - 650

Silicon dioxide - 0 - 650

Stearic acid - 0 - 15

The components are mixed and pressed into tablets

As alternatives tablets, containing from 0.1 to 1000 mg of active ingredient each, are prepared as follows:

Dosage form :


The ingredient Quantity (mg/tablet)

Active ingredient: 0.1 to 1 000
Sodium carboxymethyl cellulose is 4.5

Magnesium stearate and 0.5

Talc - 1,0

The active ingredient, starch and cellulose are passed through a sieve size No. 45 mesh U.S. and thoroughly mixed. The solution of polyvinylpyrrolidone were mixed with the obtained powder and then passed through sieve No. 14 mesh U.S. dollars. Thus obtained pellets were dried at 50-60oC and again passed through the filter N 18 mesh US. Sodium carboxymethyl cellulose, magnesium stearate and talc, passing first through the N filter 60 mesh, and then added to the granules which, after careful extruded in the form of tablets.

Suspensions each containing from 0.1 to 100 mg of the active ingredient in an amount of 5 ml per dose, was prepared as follows:

Pharmaceutical form 8:


The ingredient Quantity (mg/5 ml)

The active ingredient is 0.1 - 1000 mg

Sodium carboxymethyl cellulose 50 mg

The syrup 1.25 ml

A solution of benzoic acid 0.10 ml

Flavor - q.v.

Dye - q.v.

Purified water to 5 ml

The drug was passed through a sieve of mesh U.S. and was mixed with the sodium carboxymethyl cellulose and syrup until a homogeneous paste. The solution Ben is nom stirring. To obtain the desired volume of the entire suspension was added the required amount of water.

Method research

For clinical radiation was chosen from 5 to 50 women. All women were postmenopausal, i.e. had no menstruation for at least 6-12 months prior to the study were generally healthy and complained of one or more of the above symptoms from the Central nervous system. Due idiosyncracies and subjective nature of these disorders, the study included a control group of pregnant women who received a placebo.

Thus, women did in two groups, one of which received the active compound of this invention, and the other a placebo. Women in the experimental group were treated orally with 50 to 200 mg of active substance per day. This therapy lasted from 3 to 12 months. The exact protocols take into account the number and severity of the above disorders in both groups with the subsequent comparison of these results at the end of the study. Comparison of the results was performed between members of groups, and for each woman separately compared the symptoms before and after treatment.

The effectiveness of the compounds of the present invention is illustrated by the positive vozdeystviyna connection formula:

< / BR>
where R1and R3are independently hydrogen, -CH3or where AG is optionally substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino-and piperidino, or its pharmaceutically acceptable salts, for the inhibition of one or more CNS disorders in women in the postmenopausal period, including anxiety, depression, tension, irritability, motivational defects, memory loss and impaired cognitive function.

2. Application under item 1, characterized in that the said compound is the hydrochloride.

3. Application under item 1, characterized in that the specified use is prophylactic.

4. Application under item 1, characterized in that the specified connection is

< / BR>
or its hydrochloride.


Same patents:

The invention relates to 4-aryloxy - or 4-aaltio-piperidinyl derivative of the formula (I):

< / BR>

R1and R2each, independently of one another, signify unsubstituted or one - or twofold substituted with A, OH, OA, aryloxy with 6-10 C atoms, aralkylated with 7-11 C atoms, -O-(CH2)n-O-, Gal, CF3, NO2, NH2, NHA, NA2, NHAc, NAAc, NHSO2A and/or NASO2A phenyl residues;

X denotes O, S, SO or SO2;

"m" denotes 1, 2 or 3;

"n" represents 1 or 2;

A stands for an alkyl residue with 1-6 C-atoms;

Gal denotes F, Cl, Br or iodine;

and Ac denotes alkanoyl with 1-8 C-atoms, arkanoid with 1-10 C-atoms or aroyl with 7-11 C atoms, and their physiologically acceptable salts

The invention relates to the field of pharmaceutical and organic chemistry and relates to new inclusion complexes and pharmaceutical compositions based on them, which are used for treatment of certain medical conditions in mammals

The invention relates to pharmacology, specifically to the means of suppressing defective repair of epithelium glomerulosa apparatus or physiological condition caused by a defective restoration of specified tissue complications, complications or conditions that cause nephrotic syndrome

The invention relates to a method of reducing glucose in the blood of people, especially patients with diabetes

The invention relates to new cycloalkenyl exhibiting the properties of inhibitors of the biosynthesis of cholesterol, in particular, inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity and can find application in the treatment and prevention of, for example, hyperlipidemia, hypercholesterinemia, atherosclerosis, and pharmaceuticals based on them

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to pharmaceutical compositions for topical application for the treatment of allergic diseases of the eye and nose

Derived indole // 2137759

Antihypoxic complex // 2137478
The invention relates to medicine, specifically to pharmacology

The invention relates to certain derivatives of tetrahydrocarbazole for use in the treatment of disorders characterized by excessive expansion of the lumen of blood vessels, in particular the treatment of migraine

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes

Antitumor agent // 2136278
The invention relates to the field of medicine and relates to antitumor therapy

The invention relates to the field of pharmaceutical and organic chemistry and relates to new inclusion complexes and pharmaceutical compositions based on them, which are used for treatment of certain medical conditions in mammals