The use of anti-estrogenic compounds, and pharmaceutically acceptable salts and solvate to reduce the concentration of glucose in the blood and pharmaceutical drug

 

(57) Abstract:

A new tool and a pharmaceutical composition based on it to reduce the level of glucose in the blood. This antiestrogen compounds and their pharmaceutically acceptable salt and solvate : [6-hydroxy-2-(4-hydroxyphenyl)benzo[b] Tien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]metano or [6-hydroxy-2(4-hydroxyphenyl)benzo[b] Tien-3-yl] [4-[2-(1-pyrrolidinyl)ethoxy]phenyl] metano. The invention expands the Arsenal of tools and pharmaceutical compositions specified destination. 2 c. and 1 C.p. f-crystals, 3 tables.

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

Diabetes mellitus is a systemic disease, characterized by impaired insulin action and other regulatory hormones in the metabolism of carbohydrates, fats and proteins, as well as in the structure and function of blood vessels. The primary symptom of diabetes is hyperglycemia, often accompanied by glycosuria (presence in the urine of more glucose) and polyuria (the release of a large volume of urine). Additional symptoms appear in chronic and long-term diabetes. These symptoms include degeneration of the walls of the blood sucking is the most susceptible. As such, long-term diabetes mellitus, even in the treatment of insulin, leading to blindness.

There are two types of diabetes. Diabetes type I is youthful, associated with ketosis, developed in the early period of life, have severe symptoms and in the near term vascular lesions. Regulation of this type of diabetes is difficult and requires exogenous insulin injections. Diabetes mellitus type II adult, resistant to ketosis, developed in the late period of life are softer and more slowly.

One of the most significant advances in the history of medical science came in 1922, when Banting and best demonstrated therapeutic effects of insulin in diabetic dogs. However, even today the picture of the main biochemical abnormalities caused by disease, not clear and diabetes remains a major problem for medicine. I believe that 12% of the U.S. population affected by different forms of diabetes. Oral administration of hypoglycemic agents has become an important breakthrough in the treatment of hyperglycemia. Oral hyperglycemic drugs are usually used to treat diabetes in adults. Monitoring glucose metabolism in animal models and in humans with diabetes type II, naveena prompted the study of the influence of androgens and estrogenos on the level of glucose in the blood. Introduction testosterone normal rats or rats with a remote ovary leads to a noticeable resistance to insulin, which correlates with morphological changes in the muscles, Holman and others , Am. J. Physiol., 259, E555-560 (1990); ibid, 262, E851-855 (1992). Streptozotocin diabetic rats implanted testosterone is an antagonist of the ability of residual insulin to maintain glycemic control, Le and others, Endocrinology, 116, 2450-2455 (1985). On the contrary, glucosuria disappears castrated diabetic KK mice and appears again, with the substitution of androgens in these mice, Nonaka and other Jpn. J. Vet. Sci. , 50, 1121-1123 (1988); Higuichi etc., Exp. Anim., 38, 25-29 (1989).

The results of the introduction of estrogen also confirm the hypothesis that the balance between endogene and estrogen is crucial for the development of hyperglycemia. Daily administration of estradiol diabetic KK mice normalizes glucose levels in the blood and eliminates the glycosuria, Toshiro and others, Jpn. J. Vet. Sci., 51, 823-826 (1989). Estradiol also lowers the level of blood glucose in mice C57BL-6J-ob/ob, Dubuc, Proc. Soc. Exp. Biol. Med., 180, 468-473 (1985) and C57BL/KsJ-db/db, Harris, Anatomical Record, 225, 310-317 (1989).

The present invention provides a method of reducing the concentration of glucose in blood is piticescu effective amount of an antiestrogen compound or its pharmaceutically acceptable salt or MES.

The term "antiestrogen" used in this description and the claims, refers to endogene, non-steroidal chemical compound that displays anti-estrogenic activity (as further defined below), but at the same time has a hormonal or estrogenic activity in some selective tissues and organs. Historically, the literature says about the antiestrogens as the compounds that bind with estrogen receptors (for example, compete with estradiol for these receptors and inhibit the reaction of the uterus or breast to estrogen in vivo. Many of these compounds have been shown to be applicable as a means against fertilization, cancer funds or funds against other pathological conditions, which is useful in the inhibition of the estrogenic activity. Many of these compounds, as noted, are a mixture of agonists-antagonists, that is, at some level dose behave as agonists of estrogen, while at higher doses are antagonists of estrogen. The ways of defining a classic antiestrogens well-known seasoned professionals, for example, described in: Hayes etc., J. A. Endocrinology, 1981, 108, 164-172. It was recently obnaroujeno.opisana on some tissues and organs, responsive to estrogen, while are antagonists estrogenic responses in other tissues and organs). It is not clear whether this distinction to explain the quantitative effect of a mixture of agonist-antagonist or a qualitatively different mechanism of action. An example of a favorable differential action is Raloxifene, which are able to reduce the level of serum lipid and reduce bone resorption without unwanted uterine effects in postmenopausal women.

It should be noted that not all compounds that can be antiestrogens according to the classical definition given above, may have activity and usefulness, described in the invention.

In General, antiestrogenic compounds claimed in this invention are those compounds are antiestrogenic in the classical sense, and which have a useful estrogenic properties. The most common compounds are chemical class triarylamine or Z-triarylphosphine. Other anti-estrogenic chemical classes based on their merits.

The preferred and most preferred compounds of this invention are those to the hydrated estrogenic side effects in organs, such as the breast and uterus, Jones and others, J. Med. Chem., 1984, 27, 1057-1066. Additionally, preferred compounds of this invention, which have a very low activity of agonists of estrogen, should be the most useful in the treatment of males to avoid the side effects of feminization, such as gynecomastia.

Antiestrogens, considered in the framework of the present invention are compounds having the apparent binding affinity for estrogen receptors, usually denoted by the value of KI, the value of which is more of 0.05 nm and less than 5000 nm, calculated from the inhibitory values IC50using the equation Ki = IC50/[1+(L/Kd)], where L is the concentration of tagged ligand and Ko is the dissociation constant of the complex ligand-receptor, defined in terms of saturation or inhibition of binding of cold ligand.

Methods of analysis for shvatyvaemost to determine antiestrogenic and estrogenic activity known experienced professionals, for example, black and hood, Life Sciences, 26, 1453-1458 (1980); black and hood, Endocrinology, 109, 987-989 (1981); black and others, Life Sciences, 32, 1031-1036 (1983). Also known relationship between the apparent (relative) affinity binding and inhibiting value IC50, concentratively method for the determination of estrogenic/antiestrogenic activities described in methods, below.

In the present invention proposed the following classes of antiestrogens useful, as I believe, in the methods of the invention: 1) triarylmethane; 2) 2,3-diaryl-2H-1-benzopyrane; 3) 1-aminoalkyl-2-phenylindole; 4) 2-phenyl-3-availbility; 5) 1-substituted-2-aryldihydropyrimidine; and 6) 2-substituted-3-arylbenzofurans. Each of these classes are described below in detail.

General chemical terms used in the description of the compounds of this invention have their usual meaning, for example, the term "alkyl" by itself or as part of another substituent refers to an alkyl radical with normal or branched chain having the specified number of carbon atoms, such as methyl, ethyl, propyl, isopropyl and higher homologues and isomers, if specified.

The term "alkoxy" denotes alkyl with an agreed number of carbon atoms associated with the core molecule by an oxygen atom, for example, methoxy, ethoxy-, propoxy-, butoxy-, pentyloxy and hexyloxy and also includes a structure with a branched chain, for example, isopropoxy and isobutoxy.

The term "C1-C7-alkanoyloxy" refers to the group-O-O(O)-Rawhere Rais hydrogen or C1-C6-alkyl and include the group and also includes the isomers of branched-chain, for example, 2,2-dimethylpropanoate - and 3.3-dimethylbutanoate.

Similarly, the term "C4-C7-cycloalkanones" refers to the group-O-C(O)-C3-C6-cycloalkyl, where C3-C6-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "C1-C6-alkoxy-C1-C7- alkanoyloxy" refers to the group-O-C(O)-Rb-O - C1-C6-alkyl, where Rbcall, C1-C6-alkoxycarbonylmethyl or C1-C6-alcander, and includes, for example, methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methoxyacetate, methoxypropanol, methoxybutanol, methoxybenzyloxy, methoxycinnamate, ethoxyethoxy, ethoxypropanol, ethoxymethylene, ethoxyethylene, ethoxyacrylate, propoxylate, propoxyphenol and propoxybenzaldehyde and stuff like that.

The term "unsubstituted or substituted, aryloxy" refers to the group-O-C(O)-aryl, where aryl is phenyl, naphthyl, thienyl or furyl, each group unsubstituted or monosubstituted by hydroxy-group, halogen, C1-C3-alkyl or C1-C3-Alcock "unsubstituted or substituted, aryloxypropanolamine" refers to the group-O-C(O)-O-aryl, where aryl is phenyl, naphthyl, thienyl or fullgraph, and each group of substituted or unsubstituted hydroxy-group, halogen, C1-C3-alkyl or C1-C3-alkoxy.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the above classes, which are practically non-toxic to living organisms. Typical pharmaceutically acceptable salts include salts obtained by reaction of compounds of the above classes with pharmaceutically acceptable inorganic or organic acids or pharmaceutically acceptable alkali metals or organic bases, depending on the type present in the connection assistant.

Examples of pharmaceutically acceptable inorganic acids that can be used to pharmaceutically acceptable salts include hydrochloric, phosphoric, sulfuric, Hydrobromic, idiscovered and phosphorous acid and the like acids. Examples of pharmaceutically acceptable organic acids that can be used to obtain pharmaceutically acceptable salts include alifaticheskii mono - and dicarboxylic acids, oxalic acid, carbonic, citric, and succinic acid, panels is acceptable salt, derived from inorganic and organic acids include, therefore, chlorhydrate, bromhidrosis, nitrates, sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, etherate, forgerty, acetates, propionate, formate, oxalate, citrate, lactate, p-toluensulfonate, methanesulfonate, maleate and others.

Many compounds of the above classes that contain carboxylate, carbonyl, hydroxy-group and sulfoxide group, can be converted into pharmaceutically acceptable salts by reaction with a pharmaceutically acceptable alkali metal or organic base. Examples of pharmaceutically acceptable organic bases that can be used to obtain pharmaceutically acceptable salts, include ammonia, amines such as triethanolamine, triethanolamine, ethylamine, and others. Examples of pharmaceutically acceptable bases of alkali metals include compounds of formula MOZ, where M is alkali metal, e.g. sodium, potassium or lithium, and Z is hydrogen or C1-C4-alkyl.

It should be understood that a single anion or cation forming part of any salt of this invention is not the quality.

In addition, some of the compounds proposed as useful in the methods of the present invention, may form a solvate with water or common organic solvents. Such solvate are within the present invention.

The first class of antiestrogens is triarylamine. These compounds are widely known, proposed and obtained by methods described in U.S. patent 4536516 and 2914563; Ogawa and others, Chem. Pharm. Bull., 39 (4), 911 (1991), all of which are included as references. Typical illustrative compounds of this class include Tamoxifen, Clomiphene and (z)-4-{1-[4-(2-dimethylamino)ethoxy)phenyl]-2- (4-isopropylphenyl)-1-butenyl}MENILMONTANT.

Triarylamine encompass the compounds of formula I

< / BR>
in which R is the basic ether group of the formula-OCnH2nA, where n = 2, 3, or 4 and A - dialkylamino, where the alkyl contains 1-4 carbon atoms, or a cyclic group selected from N-piperidinyl, N-pyrrolidinyl, N-morpholinyl and N-hexamethyleneimino; each of R1independently is hydrogen, hydroxy-group, a halogen or methoxy group, and their pharmaceutically acceptable salt and solvate.

U.S. patent N 4536516 describes Tamoxifen - triarylamine plucene.

Also U.S. patent N 2914563 describes triarylamine formula II,

< / BR>
in which R is the basic ether group of the formula-OCnH2nA, where n = 2, 3, or 4 and A - dialkylamino, where the alkyl groups independently 1-4 carbon atoms, or a cyclic group, such as N-piperidinyl, N-pyrrolidinyl or N-morpholinyl. The group-OCnH2nA is connected with a phenyl in the p-position to the carbon associated with ethylene. Each of R1independently is hydrogen, hydroxy-group, halogen or a methoxy group; X is halogen, and pharmaceutically acceptable salt and solvate. There are proposed methods for obtaining such compounds.

Ogawa and others, the proposed triarylamine formula III

< / BR>
in which R2and R3independently selected from hydrogen or methyl; R4- isopropyl, isopropane-2-yl, mono - or dihydroxyisopropyl; R5the hydroxy - group or phosphate (-OPO3H2), and their pharmaceutically acceptable salt and solvate. This article also provides a method of obtaining such compounds.

The second class of antiestrogens is a 2,3-diaryl-2H-1-benzopyran. These compounds are proposed and obtained by methods described in EP 470 310A1 and articles Sharma and others, J. Med. Chem., 33, 3210,2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-3-(4-gidroksifenil)-2H-1 - benzopyran; 2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-3-phenyl)-7-methoxy-2H-1 - benzopyran; 2-{4-[2-(1-piperidinyl)ethoxy]phenyl}-3-(4-hydroxyphenyl)-7-hydroxy - 2H-1-benzopyran.

EP 470310 A1 describes benzopyrane formula IV

< / BR>
in which R6and R7(may be the same or different) is hydrogen, the hydroxy-group, C1-C17-alkoxygroup or C2-C18-alkoxycarbonyl; R8-

< / BR>
and their pharmaceutically acceptable salt and solvate, as well as methods for their preparation.

The third class of antiestrogens is a 1-aminoalkyl-2-phenylindole. These compounds are proposed and obtained according to the methods described by von Angerona etc., J. Med. Chem., 33, 2635 (1990), which are incorporated here by reference in its entirety.

1-Aminoalkyl-2-phenylindole described the background Angerona and others, are compounds of the formula V,

< / BR>
in which R9is hydrogen or methyl; R10and R11- methoxy or hydroxy groups; n = 4 to 8; Y is a group NR12R13where R12and R13independently are hydrogen, stands or ethyl, or one of R12or R13is hydrogen and the other is benzyl, or together with the nitrogen atom form pyrrolidinyl, piperidinyl or morpholinyl, and their pharmaceutically acceptable salts and CE of antiestrogens is a 2-phenyl-3-arovent/b/tifany; (Z-triarylphosphine). These compounds are proposed and obtained by methods described in U.S. patent N 4133814 and 4418068 and in the article by Jones and others , J. Med. Chem., 27, 1057-1066 (1984), which are incorporated here by reference in its entirety. Typical compounds of this class include Raloxifene {6-hydroxy-2-(4-hydroxyphenyl)benzo/b/Tien-3-yl}{4-2-(1-piperidinyl) ethoxy/phenyl}meanon hydrochloride, previously of keoxifene) and 6-hydroxy-2-(4-hydroxyphenyl)benzo/b/Tien-3-yl/-/4-2-(1-piperidinyl) ethoxy/phenyl} meanon hydrochloride.

2-phenyl-3-arovent/b/tifany described in U.S. patent N 4133814 and have the formula VI

< / BR>
in which R16is hydrogen, hydroxy, C1-C5-alkoxy, C1-C7-alkanoyloxy-, C3-C7-cycloalkanones-, C1-C6-alkoxy-C1-C7-alkanoyloxy-, substituted or unsubstituted, urologic or substituted or unsubstituted alloctype;

R17is hydrogen, chlorine, bromine, hydroxy, C1-C5-alkoxy, adamantoise, C1-C7-alkanoyloxy-,C3-C7-cycloalkanones-,C1-C6-alkoxy-C1-C7-alkanoyloxy-, substituted or unsubstituted, urologic or substituted or unsubstituted aryloxypropanolamine;

R18group-O is or together with the nitrogen atom form pyrrolidinyl, piperidinyl, hexamethylenimine or morpholinyl, and their pharmaceutically acceptable salt and solvate.

Methods of obtaining these compounds is proposed in U.S. patent N 4133814. Raloxifene and method thereof are described in U.S. patent N 4418068.

The fifth class of antiestrogens is a 1-substituted-2-aryldihydropyrimidine. These compounds were obtained according to the methods described in U.S. patent N 4400543, 4323707, 4230862 and 3274213, which are fully incorporated by reference. Typical compounds of this class are Nafoxidine and Crixivan.

Examples of 1-substituted-2-alldirectories described in U.S. patent N 4230862, which describes the compounds of formula VII

< / BR>
in which Z is CH2-CH2- or-CH= CH-; R16is hydrogen, hydroxy or C1-C5-alkoxygroup; R17is hydrogen, chlorine, bromine, hydroxy, C1-C5-alkoxy, C1-C5-acyloxy-, C1-C5-alkoxycarbonyl-or adamantylamine; R18- C1-C5-alkoxygroup or group-OCH2-CH2NR19R20where R19and R20independently are C1-C4-alkyl or together with the nitrogen atom to which they relate. form pyrrolidinyl, the is hydrogen, hydroxy or C1-C5-alkoxygroup and at least one of R16and R17different from hydrogen, and their pharmaceutically acceptable sour-additive salts and solvate, as well as methods for obtaining such compounds.

Examples 1-replaced-2-alldirectories also described in U.S. patent N 3274213, which describes the compounds of formula VIII,

< / BR>
in which R19and R20- C1-C8-alkyl or together with the nitrogen atom to which they are bound, form a 5-7-membered saturated heterocyclic radical selected from pyrrolidinyl, 2-methylpyrrolidinyl, 2,2-dimethylpyrimidine, piperazinil, 4-methylpiperazine, 2,4-dimethylpiperazine, morpholinyl, piperidinyl, 2-methylpiperidine, 3-methylpiperidine, hexamethylenimine, homopiperazine and homomorpholine; q = 2-6; p = 1-4; P21- C1-C8-alkoxygroup, and their pharmaceutically acceptable salt and solvate. The method of obtaining these compounds is described in the same patent.

The sixth class of antiestrogens is a 2-substituted-3-arylbenzofurans. These compounds are proposed and obtained by methods described in the article Theo and others, J. Med. Chem., 35, 1330-1339 (1992), which is incorporated here by reference. Predloge X2- halogen; Y2- bond or methylene; R22is hydrogen or methyl; R23group-NR19R20where R19and R20independently are C1-C4-alkyl or together with the nitrogen atom to which they are bound, form pyrrolidinyl, piperidinyl, hexamethylenimine or morpholinyl, and their pharmaceutically acceptable salt and solvate. There's also the methods of obtaining these compounds.

A preferred class of compounds useful in the methods of the present invention are benzothiophene. Most preferred are benzothiophene formula X

< / BR>
in which X1- bond or methylene; R16- hydroxy-, methoxy-, C1-C7-alkanoyloxy-, C3-C7-cycloalkanones, C1-C6-alkoxy-C1-C7-alkanoyloxy, substituted or unsubstituted, urologic-, or substituted or unsubstituted aryloxypropanolamine; R17is hydrogen, chlorine, bromine, hydroxy-, methoxy-, C1-C7-alkanoyloxy, C3-C7-cycloalkanones-, C1-C6-alkoxy-C1-C7-alkanoyloxy-, substituted or unsubstituted, aryloxy-, or substituted or unsubstituted aryloxypropanolamine; Y1- heterocyclic calcluate. Especially preferred Raloxifene and its pyrrolidinyloxy similar.

The present invention provides a method of lowering glucose levels in the blood of mammals, which consists in the introduction of a therapeutically effective amount antiestrogenic compound or its pharmaceutically acceptable salt or MES. The term "therapeutically effective amount", as adopted in the description indicates the number of connections required to achieve hypoglycemic effect after administration, preferably humans, suffering from or susceptible to diabetes adults. Hypoglycemic effect considered in the present method includes both medical therapeutic and (or) preventive treatment. Also in the framework of the present invention consider concomitant treatment with oral hypoglycemic agents, insulin or derivative of insulin. Such additional therapeutic agent should be determined by the attending physician taking into account the circumstances.

The hypoglycemic activity of the compounds of the present invention was determined by testing the effectiveness of in vivo on male viable yellow mice with diabetes fat. The test method described below.

Mice were kept 6 in a plastic cage with bedding, water and feed Purina Formulab 5008 (Purina mills, St. Louis, MO) as much as you want. The temperature in rooms for animals maintained 23 2oC. the Light in the room with the animals was 600-1800 hours.

Antiestrogens were tested in different doses as an additive to food. Each dose antiestrogen had 6 mice, contained in one cell. The compounds were mixed in the powdered food, which was then granulated. Control mice were given pelleted feed without any test compound. Blood samples were collected from the tail vein before the experience and one week after the start of the experiment. The concentration of glucose in the blood was determined by the method of glucoseoxidase on mastrobuono analyzer 300 Alpkem (Clackamas, PR).

Figures, carried away the second table describes the individual experience. Doses are average doses based on actual food consumption and body weight. Table 2 describes the results obtained with 1C1 164384 - antiestrogen that does not have estrogenic activity, and falling out of the scope of the present invention. Statistical analysis of data was performed by the method of significant difference, based on the analysis of the variations.

The following methods describe preferred methods for the determination of estrogenic/antiestrogenic activity of compounds described above.

The density of the femur

Semidesyatipyatiletiyu female rats sprag doli (interval mass 225-275 g) were obtained from Charles river Laboratorie (Portage, M1). The rats were kept in a group of 3 and gave plenty of food (calcium content of approximately 1%) and water. The temperature in the room supported 22,21,7oC with a minimum relative humidity of 40%. Light period in the bathroom was 12 hours light and 12 hours of darkness.

One week after arrival, rats were subjected to bilateral removal of the ovaries (ovariectomy) under anesthesia (44 mg/kg Ketamine and 5 mg/kg of Xylazine (Butler, Indianapolis, IN) intramuscularly). Treatment media, estrogen or test the connection to begin on the day hero is the food in 0.5 ml of 1% carboxymethylcellulose or 20% cyclodextrin. Body weight determined at the time of the surgery and the week after and the dosage will agree with the change of body weight. Ovariectomized (ovex) rats and neuorientierung (intact) rats treated with media or the estrogen-evaluate in parallel in each group for negative and positive control.

Rats treated daily for 35 days (6 rats in the treated group) and death by asphyxiation with carbon dioxide on the 36th day. A time period of 35 days is sufficient to reduce bone density in ovariectomized rats, measured as described herein. When killing, the uterus is removed, free of extraneous tissue, and the liquid contents are removed before determining the wet weight to confirm the deficiency of estrogen associated with full oophorectomy. The weight of the uterus is usually reduced by 75% in response to oophorectomy. The uterus is then placed in 10% neutral buffered formalin for subsequent histological analysis.

The right femur is scratched and scan at the distal metaphase 1 mm from the fissures of the patella single photon absorptiometry. The results of densitometric measurements represent the calculation of the density of kostomloty femur by 25% compared with the intact control group, processed by the media. Estrogen entered into orally active form of ethinyl estradiol (EE2), prevents this loss of bone depending on the dose, but also manifests a stimulating effect on the uterus, resulting in weight of the uterus is close to the weight of the uterus intact rats at the dose of 100 g/kg

The histological parameters of the uterus

Increasing the height of the epithelium is a sign of astrogenetix therapeutic agents and may be associated with an increased spread of cancer of the uterus. It is customary to compare the increase of the height of the epithelium is relatively ovariectomized control group. Treatment with estradiol increases the height of epithelia to the thickness greater than that of intact rats. Astrogenetix also determine assessing adverse reaction penetration eosinophila in the stroma layer of the uterus. Estradiol, as expected, causes a large increase in the penetration of eosinophila.

Measured the thickness of the stroma and myometrium. Estrogen causes an increase in both these parameters. Full definition of astrogenetix possible by the sum of all four parameters.

Some data can be described as the percentage of inhibition of bone loss and percentage weight gain of the uterus, kubotani ovex animals bone density of the raw ovex animals) + (density of bone treated with estrogen ovex animal bone density of the untreated ovex animals) 100. The percentage increase in uterine weight is equal to (weight of the uterus treated avec animals - the weight of the uterus ovex animals) + (weight of the uterus treated with estrogen ovex animals - the weight of the uterus ovex animals) 100.

The level of lipids in serum

Semidesyatipyatiletiyu female rats sprag Lawley (int weight 200-225 g) were obtained from Charles river Laboratories (Portage, M1). Animals were subjected to either bilateral ovariectomy (OVX), or surgical procedure shame in Charles Laboratories and transported in one week. After arrival, the animals were kept in metal hanging cages in a group of 3 or 4 in the cage and got plenty of food (calcium content of approximately 0.5%) and within one week. In a room maintained temperature 22,21,7oC with a minimum relative humidity of 40%. Light conditions in the room was 12 hours light and 12 hours of darkness.

Dosage regimen/tissue Collection

After a one-week acclimatization period (two weeks after OVX) began daily dosage of the test compounds. All compounds were introduced peroral is, 17-ethinylestradiol and the test compound was given orally as a suspension in 1% carboxymethylcellulose or 20% cyclodextrin. Animals were given doses daily for 4 days. After the regime of dosing, animals were weighed and anestesiologi with a mixture of Ketamine: Xylazine (2:1 V/V) and the sample of blood was collected by puncture of the heart. Animals were then killed by Aspicia carbon dioxide, the uterus was removed through an incision and determine the wet weight.

Analysis of cholesterol

The blood samples were allowed to shrink at room temperature for 2 hours and serum was obtained by subsequent centrifugation for 10 minutes at 300 rpm, the serum Cholesterol was determined using vysokobarotermicheskogo analysis of the cholesterol of the Boehringer Mannheim Diagnostics. Briefly, cholesterol was oxidized to the cholesterol-4-EN-3-one and hydrogen peroxide. Hydrogen peroxide is then introduced into the reaction with phenol and 4-aminophenazone in the presence of peroxidase to obtain p-hinolinovogo dye, which is easily determined spectrophotometrically at 500 nm. The cholesterol concentration was then calculated from the standard curve. All analysis performed with the use of the device Viomak Automated Markstein.

Analysis easygamestation in 50 volumes of buffer 50 mm Tris (pH 8.0), containing 0.005% Triton X-100. After addition of 0.01% hydrogen peroxide and 10 mm o-phenylenediamine (final concentration) and Tris buffer for one minute see an increase in absorption at 450 nm. The presence of eosinophil in the uterus is an indication of estrogenic activity of compounds. Maximum speed 15 second interval established in the initial, linear range of the reaction curve.

The experimental group

All of the experimental group consisted of 5-6 animals. Oophorectomy in rats caused an increase in serum cholesterol as compared with intact control animals, treated by the media. Estrogen entered into orally active form of ethinyl estradiol (EE2), causes a decrease in serum cholesterol, depending on the dose, but it also has a stimulating activity on the uterus, resulting in weight of the uterus is close to the weight of the uterus intact rats at the dose of 100 mg/kg/day.

Histological parameters

Histological evaluation performed as described above.

Inhibitory activity of compounds on estrogenzawisimy tumor mammals, estimated according to the methods described in U.S. patent N 4133814 and 4418068.

Dnevne dose will be in the range of 10-1000 mg/kg of body weight. For the treatment of adults preferred interval 50-600 mg/kg in single or divided doses. However, it should be understood that the actual number of input connections will be determined by the doctor depending on the circumstances, including treatable condition, the choice of the introduced compound, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration. Thus, the above intervals doses do not limit the scope of the invention. While these compounds are preferably administered orally, they can also enter various other ways, such as transdermal, subcutaneous, intranasally, intramuscular and intravenous route.

Although it is possible to use compounds of the invention directly, but it is preferable to use them in the form of pharmaceutical preparations containing a pharmaceutically acceptable carrier, diluent or excipient and a compound of the invention. Such preparations contain from 0.01 to 99% of the compound of the invention.

In the manufacture of preparations of the present invention, the active ingredient will usually be mixed with at least one carrier, or diluted at least adniel serves as a diluent, he can be a solid, semi-solid or liquid material acting as a carrier, excipient or medium for the active ingredient. Thus, drugs can be in the form of tablets, granules, pills, powders, pellets, bags, starch capsules, Alexiou, emulsions, solutions, syrups, suspensions, aerosols (solid or liquid) and a soft and hard gelatin capsules.

Examples of suitable carriers, diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum Arabic, calcium phosphate, alginate, liquid paraffin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragakant, gelatin, molasses, methylcellulose, methyl - and propylhydroxybenzoate, vegetable oils, such as olive oil, suitable for injectable organic esters, such as etiloleat, talc, magnesium stearate, water, and mineral oil. The preparations may also contain wetting, lubricating, emulsifying and suspendresume tools, preservatives, sweetening tools, fragrances, stabilizers and flavoring means. Drugs can be designed to provide rapid, prolonged or delayed release active is of the compound of this invention can be perfectly mixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules.

The preparations are preferably in the form of a standard dose, and each dose contains 1-500 mg, usually 5 are 300 mg of the active component. The term "standard dosage" refers to physically discrete units suitable as single doses to humans and other mammals, each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, in a mixture with a suitable pharmaceutical carrier, diluent or excipient.

To more fully illustrate the invention the following examples of drugs. The examples are only illustrative and not limit the scope of the invention. Drugs can be used as active compounds any of antiestrogenic compounds described above.

The drug 1

Hard gelatin capsules get, using the components shown in the end of the description.

The above components are mixed and placed in a hard gelatin capsule in the amount of 460 mg.

Drug 2

Capsules, each containing 20 mg of the drug, do the following (see the end of the description).

Active components the new capsules.

Drug 3

Capsules, each containing 100 mg of the active component, receive according to the scheme given in the end of the description.

The above components are thoroughly mixed and placed in an empty gelatin capsule.

The drug 4

Tablets, each containing 10 mg of the active component, receive according to the scheme given in the end of the description.

The active ingredient, starch and cellulose sieved through sieve No. 45 mesh. USA and mix thoroughly. The formed powder mixed solution polyvinylpyrolidone and the mixture is sieved through sieve No. 14 mesh. USA. The resulting granules are dried at 50-60oC and sieved through sieve No. 18 mesh. USA. Then the beads add natrocarbonatite, magnesium stearate and talc, previously passed through sieve # 60 mesh. USA, mixed and compressed on a tablet machine, getting a tablet weighing 100 mg.

The drug 5

Tableted preparations can be obtained by using the components shown in the end of the description.

The components are mixed and pressed into tablets, each weighing 665 mg

The drug 6

Suspensions, each containing 5 mg of the drug at a dose of 40 ml, get the trail is Syrup - 1.25 ml

Benzoic acid solution 0.10 ml

Taste the tool is At the discretion of the

The dye is At the discretion of the

Water as you need up to 5 ml

Medication sieved N 45 USA and is mixed with the sodium carboxymethyl cellulose and syrup to form a homogeneous paste. A solution of benzoic acid, flavoring agent and the dye is diluted with some water and add with stirring. Then add a sufficient quantity to achieve the required volume.

Preparation 7

Prepare a spray solution containing components at the following concentrations,%:

Active component - 0.25

Ethanol - 29.75

The propellant 22 - 70.00

Chlorodifluoromethane is 100.00

The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30oC, and transferred to a filling device. The required amount of load then in a stainless steel container and diluted further remaining amount of propellant. Then the container is provided with a valve.

1. Application of [6-hydroxy-2-(4-hydroxyphenyl) benzo [b] Tien-3-yl] [4-[2-(1-piperidinyl) ethoxy] phenyl] methanone or [6-hydroxy -2(4-hydroxyphenyl) benzo [b] Tien-3-yl] [4-[2-is ation of glucose in the blood.

2. Application under item 1, where the specified connection is cleaners containing hydrochloride salt.

3. Pharmaceutical composition for lowering the concentration of glucose in the blood, characterized in that it contains 1 to 500 mg of the compound under item 1 or 2 in a mixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

 

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< / BR>
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< / BR>
or its physiologically acceptable salt, or metabolically labile ether complex, where R is chlorine in positions 4 and 6 of the indole ring, R2represents phenyl, possibly substituted by one or two groups selected from fluorine, trifloromethyl, lower alkyl, alkoxy, hydroxy and nitro group, X represents NH

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FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

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