The use of 2-phenyl-3-koivistoinen to suppress defective repair tissue

 

(57) Abstract:

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. As such funds are offered the use of compounds of General formula I

< / BR>
where R1and R3independently represent hydrogen, -CH3, (C1- C6-alkyl) or where Ar is phenyl, possibly substituted;

R2selected from the group consisting of pyrrolidine and piperidine,

or its pharmaceutically acceptable salt or MES. The invention expands the Arsenal of tools specified destination. 3 S. and 9 C.p. f-crystals.

It is well known that during the life of the individual tissues and organs are exposed to many influences that can disrupt their normal function. One of the most important properties of tissues and organs is their ability to restore the damage caused to them, to maintain normal homeostasis. In many cases, this restorative function svidanie sharp and somewhat soft in nature. However, in other cases, the attempt of the specific tissue to repair the damage results in either a decrease of function of the affected tissue or to the induction of harmful effects on other tissue. Acute damage to incomplete recovery, leading to a slight decline in tissue functions, can pass unnoticed or be little value because of the reserve capacity of this tissue to maintain its proper function. In case of repeated acute injury is often observed when damage is called external surrounding factors, a small gradual decrease in tissue functions can be additive. So repeated acute injury can cause chronic condition and lead to complete cessation of function of the affected tissue or organ. Such recurrent acute damage to various organs observed in alcoholic liver disease, infections, pulmonary tract, the effect of environmental toxins on the liver, kidney and pulmonary tract and toxic action of certain drugs, such as oncolytic agents, antibiotics, anti-arthritis funds and other

In addition to acute and acute re damage, there are a large number is Ah, when damage is caused to any tissue or organ, lasts for a long period of time. Often the source of chronic damage caused by the condition inside the body, acting on certain organs and tissues that may be involved or not involved in starting the pathological process. This induction of pathology one tissue to another function of the tissue causes the formation of a full syndromes of different pathologies, which are often observed in chronic diseases. Attempts defective or improper recovery from damaged tissues or organs can be similar to that observed when trying acute recovery, or to be different from them; however, the results agree that there has been a gradual loss of function that leads to a possible full or partial disorder.

Two examples of chronic diseases that can lead to mnogogranny pathologies in which defective or inadequate tissue repair contributes to a possible disorder of the body are diabetes and autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and so kind, than some of the pathologies associated with acute damage, so they are often not recognized earlier than would be the refusal of the authority, and often originate from the cause of their injuries, the nature of which is not clear or that may be caused, at least in part, genetic predilection.

As mentioned above, many of pathology, occurring either acute or chronic damage and subsequent defective, insufficient, or inappropriate recovery from tissues or organs, associated with syndromes, i.e., pathologies of many different organs with multiple consequences. So, a single causal event may trigger a cascade of events in the different systems of the body. For example, patients suffering from systemic lupus erythematosus (SLE), can detect pathology in the kidney, vasculature, lungs and liver, mainly due to a common cause (the deposition of immune complex).

The defective nature of the recovery is different in different tissues and organs and is not always well recognized. Imperfect, inefficient or inadequate repair of damaged tissues or organs is defined as such a recovery that p is large (focal) (damage which can be compensated surrounding healthy tissue so that the tissue can generally function normally. However, if damages are repeated or chronic, these progressive reduction functions will inevitably lead to a complete breakdown and catastrophic results.

Some of the most common examples of defective recovery observed in many different tissues and organs include the increasing deposition of fibrinoid and the proliferation of supporting cells at the injury site. First, the damage can cause the rupture of the continuous system transfer liquid (and gas), such as blood vessels, arteries, Neronova pipes or air ducts. The reason for this gap may be mechanical or loss of normal adjacent cells or destruction of the matrix, forming a system. Whatever the reason, the attempt of the body to restore this gap often takes the form of the walls of the cells or matrix components, quickly closing the gap physically. It is a physical overlap of the gap, temporarily eliminating leakage, does not restore the normal functions of the system in such damaged areas. Recovery from injury is not usually returns the biological is by structural poletnosti in the arteries and blood vessels lost the permeability of the Airways in the lung, and so on Microscopic examination of these places incomplete recovery often find the deposition of fibrin, collagen and other molecules that have biological and/or physical properties of the original matrix, which they replaced. Similarly, there is often a proliferation of supporting cells (sometimes referred to as connective tissue cells), which produce more dysfunctional cells or fibrous matrix. Finally, there is often a normal growth and function of cells in certain tissues; however, this growth, although numerically and beneficial, may be inefficient from the point of view of the General functions, due to violations of the critical architecture. Thus, the total loss of the chemically or biologically important matrix, the loss of functional cells by replacing them on cell recovery or loss of critical architecture functioning of cells leads to the inability of the tissue or organ to perform its homeostatic function.

In addition, there are often inappropriate reactions to injury and recovery. The most important examples are immuno-inflammatory and inflammatory reactions in the effects, for example, bacteria, viruses or external pathogens, or useful in removing dead or dysfunctional cells or matrix in normal conditions, these reactions can begin, and out of control in places of recovery. In some cases, inappropriate reaction to certain cells can cause further damage and also harm the recovery. For example, in autoimmune diseases, the deposition of immune complex in various tissues and organs can cause local inflammation and damage, triggering the reaction of recovery and at the same time making it the restoration of defective and inefficient.

Given the above, the method of suppressing defective repair tissue and the physiological or pathological conditions caused, at least partially, this would be useful.

The present invention provides methods of suppressing defective repair tissue, including the introduction of a person in need, an effective amount of the compounds of formula I

< / BR>
in which R1and R3independently represent hydrogen, -CH3, (C1-C6-alkyl) or , where Ar is phenyl optionally substituted;

R2wymah salts and solvate.

The object of the present invention is raloxifene (hydrochloric salt of the compounds of formula I in which R1and R3is hydrogen, and R2- 1-piperidinyl) and selected analogues useful in the treatment of syndromes associated with defective and ineffective or inadequate restoration of tissues or organs of the body and is caused by acute or recurrent acute or chronic damage.

The present invention concerns the discovery that a select group of 2-phenyl-3-koivistoinen (benzothiophenes) of formula I are useful for inhibition of defective repair tissue. The treatments offered by the present invention, is carried out by introducing a person in need, the dose of the compounds of formula I or its pharmaceutically acceptable salt or MES, which is effective for inhibiting imperfect repair tissue.

The definition of the term "inhibit" includes its generally accepted meaning, which includes prevention, prohibition, retention and slowing, stopping or reversing the process or intensity and retention under the control or treatment of existing characteristics. As such, the present method includes the introduction lekarstvami "defective tissue repair" includes ineffective, inappropriate or inadequate tissue repair due to at least partial destruction of tissue. The lesion can be acute, re acute or chronic and includes inappropriate inflammatory response and results in loss of normal function of the tissue or organ.

Physiological condition caused by a defective tissue repair or related to, include such conditions that at least partially caused by a defective restoration, and therefore can be considered as a symptom of imperfect repair tissue.

In General, the compound is mixed with conventional excipients, diluents and carriers and pressed into tablets or prepared in the form of elixirs or solutions for conventional oral administration, or administered intramuscularly or intravenously. The compounds can be administered transdermal or be prepared in the form of dosage forms with delayed release.

The compounds used in the method according to the present invention can be obtained according to the used methods, such as described in detail in U.S. patents NN 4133814, 4418068 and 4380635 included in the present description by reference to them. In General spinnie protect, alkylate or acelerou and remove protection for formation of compounds of formula I. Examples of the preparation of such compounds are given in U.S. patents mentioned above.

Phenyl, optionally protected, includes phenyl and phenyl, one - or twofold substituted C1-C4-alkyl, C1-C4-alkoxy, hydroxy, nitro, chlorine, fluorine or three(chlorine or fluorine)stands.

The compounds used in the methods according to the present invention form pharmaceutically acceptable acid - and basically-additive salts with various organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts also form part of the present invention. Typical inorganic salts used for the formation of such salts include hydrochloric, Hydrobromic, idiscovered, nitric, sulfuric, phosphoric, hypophosphorous, etc. Salts, derivatives of organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate mono - and decollate, aromatic acids, aliphatic and aromatic sulfonic acids, can also be the IP is t, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthyl-2-benzoate, bromide, isobutyrate, phenylbutyrate, - hydroxybutyrate, Butin-1,4-diet, hexyne-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymethyl, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, secondary acid phosphate, monopotassium phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacina, succinate, suberate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, bansilalpet, p-bromophenylacetate, chlorobenzenesulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naftaniel-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartrate, etc., the Preferred salt is the hydrochloric salt.

Pharmaceutically acceptable acid additive salts are formed by the interaction of the compounds of formula I with an equimolar or excess amount of acid. The reagents are in General mixed in a mutual solvent such as diethyl ether or benzene. the letricia or the solvent can be removed by conventional means.

The base is usually used for the formation of salts include ammonium hydroxide and a hydroxide of alkaline and alkaline-earth metals, carbonates and aliphatic primary, secondary and tertiary amines, aliphatic diamines. The Foundation is particularly useful in the preparation of salts of joining include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenimine and cyclohexylamine.

Pharmaceutically acceptable salts, as a rule, have higher solubility characteristics in comparison with the compound from which they are derived, and thus more suitable for the preparation of medicines in the form of liquids or emulsions.

Pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be mixed with conventional excipients, diluents or carriers, and formed into tablets, capsules, suspensions, powders, etc., Examples of excipients, diluents, and carriers that are suitable for such compositions include the following: fillers and inert additives, such as starch, sugars, mannitol, and silicic derivatives acid; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin and sodium bicarbonate; agents to slow the 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 stearate and magnesium and solid polietilenglikoli.

Connections can also be included in formulations of elixirs or solutions for conventional oral administration or as solutions appropriate for parenteral, such as intramuscular, subcutaneous or intravenous injection. In addition, the compounds are well suited for the formulation of dosage forms with delayed release, etc., Formulations can be made so that they were isolated active ingredient only or preferably in a particular area of the intestinal tract, possibly over a period of time. Coatings, envelopes, and protective matrices may be made, for example, polymeric substances or waxes.

The specific dose of a compound of formula I required to inhibit defective repair tissue or physiological state, at least partly due to this, coz what these factors, which will determine the attending physician. In General adopted and effective daily dosage will be from about 0.1 to about 1000 mg/day and preferably from about 50 to about 600 mg/day. Such dosages will be administered to a subject in need of treatment from one to about three times each day, or more frequently if required.

It is generally preferable to introduce the compound of formula I in the form of an acid additive salt, as it is customary in practice, the introduction of pharmaceutical preparations containing a basic group, such as piperidino ring. It is also useful to introduce the oral connection. For such purposes, the available oral dosage forms.

The recipes. In the following formulations "active ingredient" means the compounds of formula I.

Formula I: Gelatin capsules

Hard gelatin capsules are prepared using the following:

The ingredient Quantity (mg/capsule)

The active ingredient is 0.1 - 1000

Starch, NF - 0 - 650

Powder starch, fluid - 0 - 650

Silicone fluid, 350 centistoke - 0 - 15

The ingredients are mixed, passed through sieve No. 45 mesh U.S. and fill them hard gelatin capsules the tours, shown below.

Recipe 2: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 1

Starch, NF - 112

Powder starch, fluid - 225,3

Silicone fluid, 350 centistoke - 1,7

Recipe 3: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 5

Starch, NF - 108

Powder starch, fluid - 225,3

Silicone fluid, 350 centistoke - 1,7

Recipe 4: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 10

Starch, NF - 103

Powder starch, fluid - 225,3

Silicone fluid, 350 centistoke - 1,7

Recipe 5: Raloxifene capsule

The ingredient Quantity (mg/capsule)

Raloxifene - 50

Starch, NF - 150

Powder starch, fluid - 397

Silicone fluid, 350 centistoke - 3,0

The above specific recipe can be modified within reasonable limits in accordance with the given options.

The tablet formulation is developed using the ingredients shown below.

Recipe 6: Tablets

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1 - 1000

Cellulose, microcrystalline and pressed into tablets.

Alternative tablets, each containing 0.1 - 1000 mg of the active ingredient, was prepared as follows:

Recipe 7:

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1 - 1000

Starch - 45

Cellulose, microcrystalline - 35

Polyvinylpyrrolidone (as 10% solution in water) - 4

Carboxymethylcellulose sodium - 4,5

Magnesium stearate and 0.5

Talc - 1

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and mix. The solution of polyvinylpyrrolidone is mixed with the obtained powder, which is then passed through sieve No. 14 mesh U.S. dollars. The obtained granules were dried at 50-60oC and passed through sieve No. 18 mesh U.S. dollars. Carboximetilkrahmal sodium, magnesium stearate and talc, previously passed through sieve # 60 mesh U.S., then added to the granules which, after mixing compressed at a tablet machine, getting pills.

Suspensions, each containing 0.1-1000 mg of drug per 5 ml dose, are as follows:

Recipe 8: Suspension

The ingredient Quantity (mg/5 ml)

The active ingredient is 0.1 - 1000 mg

Carboxymethylcellulose sodium 50 mg

The syrup 1.25 mg

A solution of benzoic acid 0.10 ml

5 ml

The drug is then passed through sieve No. 45 mesh U.S. and mixed with carboxymethylcellulose sodium and syrup to form a homogeneous paste. Benzoic acid, aromatic additive and dye diluted in a little water and add with stirring. Then add water in sufficient quantity to obtain the desired volume.

For local application of the drug formulation, comprising the compound according to the present invention, are prepared according to rules known in the pharmaceutical industry for direct application to the appropriate place. Usually forms for this purpose include ointments, lotions, pastes, jellies, sprayable solutions or aerosols. The weight percentage of compounds according to the present invention in formulations for local administration of medication will depend on various factors, but in General it will be from 0.5% to 95% of the total weight of the drug and is usually from 1% to 25% by weight.

Compositions can take the form of an aqueous or anhydrous solution or dispersion, and an alternative form of emulsion or suspension.

These compositions may contain pharmaceutically acceptable excipients and auxiliary means, well known from the technician level, the which(s) accept(s) from a physiological point of view, the selected(s), in addition to water, from solvents such as acetone, ethanol, isopropyl alcohol, glycol ethers such as the products sold under the name "Dowanol", polyglycols and polyethylene glycols WITH1-C4-alkylation short-chain acids, preferably ethyl or isopropylacetate, triglycerides of fatty acids, such as the products sold under the name "Miglyol", isopropylmyristate, animal, mineral and vegetable oils and polysiloxanes.

Compositions according to the invention may also contain thickeners, such as cellulose and/or cellulose derivatives. They may also contain resins, such as xanthan gum, guar or cerebrum or gum Arabic, or alternative glycols, Antony and montmorillonite etc.

It is possible to add, if necessary, adjuvant chosen from antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic, perfume and dyes. Can also contain other active ingredients, whether in this state or any other state.

For example, among the antioxidants moerel and its derivatives. Glenavy forms prepared mainly for local use, take the form of creams, emulsions, gels, dispersions or microemulsions, lotions, thickened to a greater or lesser extent, impregnated pads, ointments or sticks, or the form of an aerosol formulation in spray or foam form, or the form of soap.

Prepare the following compositions for topical application:

Recipe 9:

The ingredient Quantity (mg/5 ml)

Hydroxypropylcellulose - 1.5 grams

The active ingredient is 1.5 - 30 grams

Isopropanol, qs - 100 g

Recipe 10:

The ingredient Quantity (mg/5 ml)

Hydroxypropylcellulose - 1.5 grams

Ethyllactate - 15.0 g

The active ingredient is 1.5 - 30 grams

Isopropanol, qs - 100 g

Recipe 11:

The ingredient Quantity (mg/5 ml)

Hydroxypropylcellulose - 1.0 g

Bottled hydroxytrol - 0.02 g

Active ingredient: - 1.5 to 25 g

Ethanol, qs - 100 g

Recipe 12:

The ingredient Quantity (mg/5 ml)

Hydroxypropylcellulose - 1.5 grams

Bottled hydroxytrol - 0.01 g

Triglycerides C8-C12fatty acid - 10.0 g

The active ingredient is 1.5 - 30 grams

Isopropanol, qs - 100 g

Recipe 9-12 are prepared in the form relevant: - 1.0 to 15 g

Triglycerides C8-C12fatty acid - 49,0 g

Recipe 14:

The ingredient Quantity (mg/5 ml)

Ethanol - 69,0 g

Ethyllactate - 10.0 g

The active ingredient is 1.5 to 20 g

Triglycerides C8-C12fatty acids - 30,0 g

Recipe 15:

The ingredient Quantity (mg/5 ml)

Isopropanol and 47.0 g

Acetone - 10.0 g

Ethyllactate - 10.0 g

The active ingredient is 1 to 15 g

Triglycerides C8-C12fatty acids - 30,0 g

Recipe 16:

The ingredient Quantity (mg/5 ml)

Ethanol - 95,08 g

Bottled hydroxytrol - 0.02 g

The active ingredient is from 1.5 to 25 g

Formulations 13, 14, 15 and 16 are prepared in the form of lotions.

Recipe 17:

The ingredient Quantity (mg/5 ml)

White petrolatum 50.0 g

Liquid paraffin - 15.0 g

Purified paraffin wax - 32,0 g

The active ingredient is 1 - 20 g

Recipe 18:

The ingredient Quantity (mg/5 ml)

White petrolatum 50.0 g

Liquid paraffin is 13.0 g

Purified paraffin wax - 32,0 g

The active ingredient is 1 - 20 g

Formulations 17 and 18 are prepared in the form of sticks.

Illustrations of the application of the present invention will focus on States and pathologies, sate restricted to these indications. In many cases, by monitoring the growth of the fibrous matrix, many States considered medicine as fibrosis or fibrotic condition and the present invention is not limited to diseases or physiological conditions, so-called.

1. Pathology of the kidney

A. Nephrotic syndrome (NS)

The most common clinical feature observed in patients with nephrotic syndrome (NS), includes proteinuria, hypoalbuminemia, hyperlipidemia and edema. These abnormal results of clinical studies are a direct or indirect consequence of an abnormal leakage of serum proteins into the urine and subsequent loss through excretion (proteinuria). Most simply, this leakage and loss of whey proteins can be described as a loss of glomerular apparatus election filtering elements serum for excretion in the urine; however, the actual mechanisms of this loss of selectivity filter are varied and complex. These pathologies in which the violation occurs filtering, are listed below and are associated with incomplete recovery of the damage caused, first of all, the epithelium of the glomerular apparatus.

Poles the options pathology in other organs and tissues in the outwardly unrelated to her defects of the kidney.

One of the main proteins that are lost during nephrotic syndrome (NS) is albumin. Loss of albumin in serum leads to decrease of oncotic pressure of plasma and has a negative impact on the Starling forces acting across the peripheral capillaries. The decrease in oncotic pressure and imbalance of Starling forces cause water to flow from the circulation system in the intermediate tissue, especially in the areas of low pressure tissue. Such an accumulation of water in these tissues leads to swollen state, causing reduced efficiency and/or termination of tissue functions. In addition, due to the smaller effective volume of plasma, the system renin-angiotensin-aldosterone is activated, leading to retention of salt and water, thus perpetuating swollen state. The usual places affected by edema, are the lungs and limbs. Edema is often associated with certain types of cardiovascular and pulmonary failure and collapse. Modern therapeutic agent for the treatment of edema of the origin inadequate and they include furosemide, etakrinova acid and other loop diuretics and the introduction of albumin containing little salt. This treatment carries the risk of inducing OST is and is inappropriate reaction of the liver, expressed in that to compensate for the liver to increase the levels of low-density lipoprotein (LDL) and cholesterol. This increase LDL and cholesterol can lead to increased atherosclerosis and other vascular diseases. Treatment normal lepidophaite funds for this aspect of nephrotic syndrome is often unsatisfactory due to the deterioration of renal function and subsequent toxicity of therapy.

Loss of other serum proteins associated with other pathologies. For example, the loss of the main quantities of transferrin may cause certain types of anemia; loss metallovedeniye proteins leads to metabolic disorders; loss of IgG leads to increased susceptibility to infectious agents; loss T4 leads to metabolic disorders; loss cholecalciferol-binding protein leads to vitamin D deficiency, secondary to hyperthyroidism, bone disease and contributes to hypocalcemia and hypocalciuria.

Other serious pathologies associated with loss of protein is thrombosis. Higher loss of anti-thrombin III relatively procoagulation proteins may lead to the state of hypercoagulability. Thrombosis and occlusion of the vascular network of the most important PR is when there are a large number of ways to treat these diseases with varying degrees of effectiveness; however, the situation may further be complicated by the fact that many of the useful drugs carried by albumin in the circulation, thus reducing the amount of albumin in nephrotic syndrome modifies pharmokinetic these medications, making it difficult to fight against diseases. It is clear that when dealing with such a cascade of events that occurs in nephrotic syndrome (NS), it would be useful to consider the NS as the source of the problem, i.e., to normalize filtration selectivity in the kidney.

The primary cause of nephrotic syndrome (NS) is a primary glomerular disease (idiopathic nephrotic syndrome). Primary glomerular disease is further divided into four main types: disease minimal change (lipoid nephrosis, zero damage, disease, basal appendages); focal and segmental glomerulosclerosis (focal sclerosis); membrane glomerulopathy and proliferative glomerulonephritis (membranoproliferative glomerulonephritis, Crescent glomerulonephritis, clean mesangial proliferative glomerulonephritis, focal and segmental proliferative glomerulonephritis).

There are many conditions and diseases that cause neprostym, re acute or chronic in nature: Infectious factors (streptococci, infective endocarditis, secondary syphilis, sepsis, leprosy, hepatitis B, mononucleosis, malaria, schistosomiasis, pneumococcus, Mycoplasma, Staphylococcus, and filariasis); the Toxicity of drugs (heroin, probenicid, Tridion, contrast agents, antidotes and toxins, anti-arthritis drugs such as gold and penicillamine); malignant disease (Hodgkin's, lymphoma, leukemia, carcinoma, melanoma, Wilms tumor), environmental toxins (natural or unnatural, such as, for example, mercury); or Multisystem disease (SLE, purpura Seleina's disease, vasculitis syndrome Goodpasture, dermatomyositis, amyloidosis, sarcoidosis, rheumatoid arthritis, syndrome Sjogren); Hereditary-familial disease (diabetes mellitus, syndrome Alport, sickle erythrocyte disease Farbe); other diseases (syndrome Berger, thyroiditis, myxedema, malignant obesity, renal vascular hypertension, chronic allograft rejection, bee stings).

The pathogenesis of each of the four main causes of nephrotic syndrome are listed below. Central or contributing to pathological event observed in Bolshiye non-functional properties such recovery or loss of critical architecture.

1) Disease minimal change (MCD)

The pathogenesis and etiology of this disease is unknown, and cause damage to the glomerular apparatus also unknown. However, there is a deep loss of architecture in the basal processes of the epithelial cells (podocyte). It is unclear whether this is due to the specific cause of nephrotic syndrome disease recovery or impaired function of podocyte. The treatment of this disease often involves the use of glucocorticoids, cyclophosphamide and hlorambuzila, protivoprolezhnevyh and anti-inflammatory drugs that are dangerous when used for an extended period of time.

2) Focal and segmental glomerulosclerosis (focal sclerosis)

It is known that one cause of this disease is the deposition of complex IgM and participation Sz (an additional factor III, a possible inflammatory substance). The response of the tissue is the same as in the case of disease minimal changes, loss of architecture podocytes and hyalinization glomerular dysfunction in the production of the matrix. Effective treatment of this disease is not.

3) Membrane glomerulopathy

It is known that the causes of this disease are: deposition of IgG, some infectious factors, m sediments, reminiscent of a protein in the subepithelial side of the capillary walls of the glomeruli, quantitative growth and thickening of the basal membrane, all the defects of the matrix. The treatment of this disease is limited to the use of glucocorticoids, and this treatment is controversial from the point of view of its effectiveness.

4) Membranoproliferative glomerulonephritis

This group of diseases is a common pathology expansion mesangial cells and increased synthesis of matrix. This response leads to the destruction of critical architecture and selectivity of the membrane and its functions. The reason is, at least partially, the deposition of Ig. The treatment of this disease with corticosteroids and steroids may delay the progression of the disease, but it is not satisfactory. Kidney transplantation is also used to treat the disease, but the forecast is unfavorable.

B. Acute glomerulonephritis (AGN)

Acute glomerulonephritis (AGN) characterized by rapid onset of proteinuria, hematuria, azotemii (insufficient speed of glomerular filtration) and the delay of salt and water. The main pathological effects of acute glomerulonephritis - edema, congestion, krovoobrasheniya and arterial diastolicheskoe hypercapnia. These pathologies can lead what I acute in nature and often quickly resolved without significant intervention; however, it may be the most serious and lead to nephrotic syndrome or chronic nephritis. Causes of AGN can be infectious diseases - poststreptococcal glomerulonephritis, endocarditis, sepsis, pneumococcal pneumonia, typhoid fever, secondary syphilis, meningococcemia, hepatitis B, mononucleosis, mumps, measles, vaccinia, echo-virus and Coxsackie virus; Multisystem diseases - SLE, vasculitis, purpura, Selana's disease, syndrome Goodpasture; primary glomerular disease; and other sources such as serum sickness.

The pathogenesis of AGN several different pathogenesis of NS and poorly understood; however, it is often lesions, including spinal ones and similar paintings, which suggest that there is an imperfect response to damage, as observed in nephrotic syndrome. Currently, the treatment of AGN glucocorticoids brings dubious benefits. Apparently, it is advisable to use therapy used in the case of nephrotic syndrome, for the treatment of certain aspects of AGN.

C. Rapidly progressive glomerulonephritis (RPGN)

Rapidly progressive glomerulonephritis (RPGN) is similar to acute glomerulonephritis (AGN) with the exception that it quickly leads to OTK with AGN. Pathogenesis clearly shows extensive vacavilleyou growth of cells and destruction of architecture "semilunar" education. In addition, there polymerization of fibrin and focal breaks in the glomerular basal membrane. Treatment is supportive and insufficient. In this state, would have been useful tools that regulate epithelial proliferation and reproduction matrix.

D. Chronic glomerulonephritis (CGN)

As the name implies, this condition is characterized by persistent anomalies and shows progressive loss of renal function. The most unfortunate consequence CGN are hypertension and cardiovascular collapse. The cause of the disease is usually prolonged presence of NS. Its pathogenesis is marked by the growth of cells, seal tissue and abnormalities of membrane and matrix. Treatment is supportive, the effectiveness of its lack. For the treatment of CGN would be a useful tool that normalizes the growth of cells and membrane-matrix function.

II. Liver pathology

Cirrhosis is a serious pathology that involves the attempt of the liver tissue to repair the damage caused to her. Cirrhosis is often the final stage of mono nephrotic syndrome, has signs of imperfect recovery processes, including defects of the matrix, cell proliferation and architecture. Also in many cases observed at the place of recovery inappropriate inflammatory reaction that can lead to further damage.

Cirrhosis, as a General term that includes all forms of chronic spilled liver disease characterized by loss of hepatocytes, disorganization and fibrosis reticuline network, the disorganization of the mesh bed and disorganization of regenerating hepatocytes in the bundle in the fibrous matrix. Accelerating (corruption) in the event of cirrhosis is usually diffuse otmiranie cells for many reasons, listed below. Morphological changes induced by the attempt to repair this damage, extensive and have serious consequences. For example, the loss of functional hepatocytes leads to the syndrome of hepatic failure, jaundice, disorders of the Central nervous system (hepatic encephalopathy, coma), edema and ascites and cachexia. The disruption and distortion of the vascular and lymphatic bed can lead to hepatic portal hypertension and splenomegaly.

It is established that there are four and cirrhosis

Alcoholic liver disease refers to a spectrum of liver damage and may be associated with acute, recurrent acute and chronic alcoholism. There are three main components of this disease: fatty infiltration of the liver, alcoholic hepatitis and alcoholic cirrhosis. All three can be found in the same patient, and they are independent of one another. Alcoholic cirrhosis is characterized by the presence of scars, loss of hepatocytes and nodular regeneration. In areas of damage can be fibroblasts (cells of connective tissue and collagen matrix. Alcoholic cirrhosis is also known as cirrhosis of Lainnya, MicroSaver, portal cirrhosis or fatty.

Treatment of alcoholic cirrhosis - supporting in regard to induced effects. The treatment of a dysfunctional liver is not enough, but includes abstinence from alcohol and glucocorticoids.

2) Postnecrotic cirrhosis

Postnecrotic cirrhosis is the most common type of cirrhosis and is marked by extensive loss of hepatocytes, the collapse of the stromal matrix and fibrosis, producing large band of connective tissue and disordered knots regenerative cells, i.e., the state of acceleration on the CC and disrupt the architecture. In addition to imperfect recovery of the hepatic damage is often observed inadequate infiltration of inflammatory mononuclear cells, which can cause further damage. Postnecrotic cirrhosis also known as toxic cirrhosis, krupnouzlovaya cirrhosis, posthepatitic cirrhosis, cryptogenic cirrhosis and lobed cirrhosis.

The etiology of postnecrotic cirrhosis insufficiently understood; however, there is serological evidence that the usual precursor may be viral hepatitis, especially hepatitis B and hepatitis non-A and not-B. Other pathologies leading to postnecrotic cirrhosis, chemical toxins, for example phosphorus, toxins, for example Amantia phalloides; infections, such as brucellosis; parasitic infections, such as clonorchis; and advanced alcoholic liver disease. Additionally, patients with chronic active hepatitis (viral-infectious origin) can progress to postnecrotic cirrhosis.

The main complications of postnecrotic cirrhosis is similar to other types of cirrhosis, especially jaundice, ascites, pain in the abdomen, hepatic encephalopathy and portal hypertension. Treatment maintaining the ary cirrhosis

Pathogenesis and morphology are similar to those of postnecrotic cirrhosis, only large lesions, including spinal ones affect the bile ducts to a greater extent. The etiology of this disease is unknown; however, since it is a disease of middle-aged women, it is quite possible that it contains endocrine component.

Due to blockage of the bile ducts and the subsequent accumulation of bile products, the main manifestations of this disease are markedly different from other forms of cirrhosis. Often occur: dark urine, itchy skin, xanthelasma joints and skin, hyperpigmentation, hyperlipidemia and malabsorption soluble in lipids vitamins. Malabsorption of vitamin A, K and D causes osteomalacia, diarrhea and purple. Death often occurs from variceal bleeding, liver failure, infection, and surgical attempts to open the bile ducts.

Treatment or support, or surgical treatment of the underlying liver pathology is absent.

4) Cardiac cirrhosis

Cardiac cirrhosis is caused by chronic, severe right-sided congestive heart failure. This lack of blood circulation accelerates necrosis of hepatocytes and starts the cirrhotic stage. The only dostupnoye cardiovascular system

A General term for the thickening and hardening of the arterial wall is arteriosclerosis. Atherosclerosis is a mottled nodular type of arteriosclerosis. Thickening of the arterial wall due to the development of atherosclerotic plaque leads first to the restriction of blood flow. A crack or fissure in the plaque causes the development of a thrombus or clot, which leads to tissue ischemia. If it does not dissolve the clot can lead to failure of the tissue or organ and possibly death. Examples of arterial thrombotic events include stroke, myocardial infarction and peripheral vascular disease. Atherosclerosis underlies cardiovascular disease, the leading cause of death and morbidity in the United States.

There are three types of pathological changes in the arteries, associated with atherosclerosis: fatty streaks, fibrous plaques and complicated lesions. Fatty streaks occur in early life and consist of clusters filled with lipid macrophages (foam cells) and the accumulated fibrous tissue on an intim (inner lining of blood vessels). In General, these fatty streaks in themselves do not appear to be particularly dangerous; however, they can sposobmi. These plaques consist of a Central core of extracellular lipid and remnants of necrotic cells and covered with a layer of smooth muscle cells and is rich in collagen and extracellular matrix. It makes fibrous plaque lesions, place constricted blood flow in the artery. Fibrous plaque characteristic of progressive atherosclerosis. Complicated plaque is a calcified fibrous plaque, place thrombosis, necrosis and ulceration. This plaque can be a exceptional vein thrombosis, which narrows the artery and stop blood flow and causes stenosis and insufficiency of the body. Place of complicated plaques can also be area of the weakened arterial wall, which may burst, causing aneurysm or bleeding.

One theory to explain the development of atherosclerosis, is characterized as the hypothesis of the "response to injury". According to this hypothesis, endothelial cells of blood vessels lining the artery, are acute, recurrent acute or chronic damage, leading to dysfunction of endothelial cells and in some cases, cell death, resulting in the exposed underlying median and connective tissue bed. This is a violation of the continuous system ut to use factors which can stimulate the growth of cells, migration of cells and production of extracellular matrix compounds, all of which can contribute to the process of abnormal recovery. Although this recovery corrects the direct gap of the system, repeated exposure over an extended period of time can lead to the development of atherosclerotic plaques in this place, giving the example of imperfect nefiktivnogo and inappropriate repair tissue in response to the initial injury.

There are many risk factors that contribute to the atherogenic response, these factors include hyperlipidemia (hypercholesterinemia and triglyceridemia), hypertension, cigarette Smoking, hyperglycemia and diabetes mellitus, obesity, sedentary lifestyle, stress and family history of cardiovascular disease. Currently, the treatment of atherosclerosis is limited to the use of drugs that lower cholesterol and triglyceride, with the aim of modulating hyperlipidemia, as well as numerous therapies designed to impact on thrombosis associated with atherosclerosis (i.e., aspirin). Also prescribed lifestyle changes to eliminate risk factors, speechnow repair tissue.

IV. Pathology of the lungs

The General term "infiltrating" (mean diffusion into and accumulation in the tissue of those substances that are either alien to her, or endogenous substances that inhibit normal function. For example, infections (bacterial pneumonia) involve the immune or inflammatory cells in millionarie space or cause the spread of invasive neoplastic cells in the lung, these cells are foreign to the normal lung structure. In other cases, endogenous substances such as hyaline membrane, fibrous matrix, growth of normal alveolar and bronchial epithelial cells accumulate in vnutriarterialno space, leading to dysfunctional tricks in the lung.

In most cases, the lung is able to recover without lasting harmful residual effects; however, if the damage is inherently recurrent acute or chronic, increasing the number of defunct damage (defective, insufficient, or inappropriate to the recovery begins to cause failure pulmonary function. The pathogenesis of this disease is very similar to the pathogenesis described for pet epithelium. The response of the epithelium is aimed at rapid elimination of the damage caused by surface section alveolitis by producing a fibrous matrix (collagen and hyaline membrane) and hyperplastic proliferation of the cells. This new structure, restoring the barrier between the air (alveolar) and circulation (capillary) spaces, unable to selectively mediate the exchange of gases with the same efficiency that and normal tissue.

The main consequence of accumulated damage and failure of the lung is hypoxia major organs and their refusal.

Initiating or previous pathology of diffuse infiltrative lung disease are numerous and are listed in abbreviated form: infection, such as viral (influenza, CMV, and so on), bacterial (Mycoplasma, Streptococcus, Staphylococcus, and so on), parasites (schistosomiasis, Pneumocstis carinii, filaretos and so on), fungal (histoplasmosis, candidiasis, and so on); reasons related to professional activities, such as mineral dust and chemical fumes; neoplasms; congenital and familial pathologies such as cystic fibrosis; diseases of metabolism, such as uremic pneumonitis and hypercalcemia; Olesno, such as allergic pneumonia; and collagen diseases such as scleroderma, rheumatoid arthritis, SLE, etc.

Treatment of diffuse infiltrative lung disease is supportive in relation induced bound in hypoxic tissues complications and stimulating treatment of diseases. The treatment process itself defective recovery mainly limited purpose of corticosteroids, which in many cases gives only a partial effect, it is necessary to exercise caution, so as not to cause unwanted effects from using steroids.

V. Pathology caused by the regenerative response to inflammatory damage

Inflammation is an important and beneficial reaction of the body, designed to destroy invading pathogens (via the immune system) and excrete dead or dysfunctional tissue or debris. However, in some circumstances, the system becomes uncontrollable and inflammation damage normal tissue. This damage can lead to reactions imperfect recovery. Often, this reaction is defective recovery triggers inflammation, and there is a vicious circle that prieteni above. Other examples of cases where the disease is triggered by the inflammation that causes the reaction imperfect recovery is muscular dystrophy, scleroderma and disease of the colon Crown.

Raloxifen and selected analogues useful in the treatment of imperfect recovery of tissues and organs damaged by the inflammatory process, and are also subject of the present invention.

Test I. clinical evaluation is taken from 3 to 12 patients suffering from diseases that cause increased symptoms of nephrotic syndrome. The selection criteria for these patients are:

1) preferably, postmenopausal women,

2) patients suffering from diseases, often including guidance nephrotic syndrome as part of the pathology of the disease, such as diabetes, hepatitis B, patients Sjogren taking gold for the treatment of rheumatoid arthritis and so on,

3) patients who show progressive increase in proteinuria, hypoalbuminemia, hyperlipidemia and edema. These patients were prescribed by 50-600 mg of the compounds of formula I is administered orally as a once daily or divided doses. These patients remained on this regimen for up to HiperMedia or edema. For a positive result in this test was taken to reduce or reverse the development of these parameters.

Test II. Select from 3 to 50 patients suffering from diseases known that they induce nephrotic syndrome, or taking medications known that they induce nephrotic syndrome. The selection criteria for these patients: 1) preferably postmenopausal women and 2) patients who at the time of this clinical trial did not demonstrate objective evidence of nephrotic syndrome. Such patients could be women 45-55 years of age who have diabetes, but who still do not show objective evidence of diabetic complications, including renal function. Half of these patients were given a placebo. The other half were appointed 50-600 mg of the compounds of formula I, administered orally per day in single or divided doses. This treatment program lasted for 1-5 years. As a positive result in this test is estimated that by the end of the test period, the group treated with medication, will have fewer cases of pathologies associated with nephrotic syndrome, such as hyperlipidemia, proteinuria, hypoalbuminemia elmodel renal damage/recovery ("Toxicology of the Kidney", ed. by J. B. Hook and R. S. Goldstein, Raven Press Ltd., New York, 1983). RA induces nephrotic syndrome with selective proteinuria, hypoalbuminemia and high plasma cholesterol. During the early stages of the disease the rate of glomerular filtration is reduced. The model shares many clinical and morphological findings with glomerulopathies mineral changes and focal segmental glomerulosclerosis person. This model damage/recovery is marked by a significant synthesis, deposition and organization of the extracellular matrix (ECM), and begin research to study the potential usefulness of this model for the identification of agents that can positively influence tissue repair.

RA (6-dimethylaminophenyl, 3-Amin-d-ribose) is a purine antagonist with antibiotic activity. The drug inhibits protein synthesis by acting on RNA synthesis at the level of the ribosome. In this model, proteinuria begins on the fifth or seventh day after a single intravenous injection of 50-100 mg PA/kg body weight. Proteinuria reaches a peak in the middle 300 and 900 mg/24 hours after 8-12 days and disappear within 3 weeks. Histological examination can detect moderate swelling of the focal loss of the covering epithelium outside the glomerular basal membrane.

Some researchers (Diamond et al., Kidney Intl., 33: 917 (1988)) surmised that the known histological signs of focal and segmental glomerulonephritis (FSGS) is also reminiscent of atherosclerotic damage and may indicate a similar pathogenesis. In atherogenesis fabric inner side of the artery thickens and is composed of vascular smooth muscle cells (VSMC), elastic and collagen fibers and glycosaminoglycans below the endothelium. These thickened areas of the inner side of the artery contain isolated mikrofalowe foamy cells and possibly leptotyphlinae VSMC and finally appear foci of necrosis. The similarity FSCG includes mesangial extension with the proliferation mesangial cells (MC), accumulation mesangial foamy cells, deposition of amorphous residues, tissue necrosis and eventual sclerosis. Glomerular MS and VSMC very close to each other in respect of origin, microscopic anatomy, histochemistry and contractility.

Model sharp 14-day damage the kidneys.

Use female rats Spraque Dawley remote ovaries, weighing 200 to 250 grams. Animals are placed in metabolic cages during the experiment with a selection of urine every 24 hours for hisetaminum /Rompun (xylazine) (0.2 ml 1:2 mixture, intramuscularly) and they did an intravenous injection of promocinandolos (RA) /75 mg/kg, Sigma, party N 90H4034), injected oral 2.9 ml of physiological solution within a 5-minute period into the tail vein, using complete Harvard infusion pump has a 5-ml syringe pump 9 (~2.9 ml/5 minutes). Animals injected from day 0 to day 13, the dose of the compounds of formula I or 17-ethinyl estradiol (Sigma, E-4876, party N 112H0765) in 20% cyclodextrin.

A urine test for protein: the volume of urine from each rat daily record and select and freeze 1-ml sample. To determine the concentration of protein in the urine choose the protein sample Piers ICA. This highly sensitive method for the spectrometric determination of protein concentration. A standard curve is prepared by dilution of a standard solution of BSA (1 mg/ml, Pearce) physiological phosphate buffer solution Dulbecco (D-PBS) (Gibco). Using a multichannel pipette, standard solution diluted in ratio 1:2 double wells around the flexible 96-well plate Falcon 3911 Microtest III, ending the procedure with final concentration 7,81 g/ml.

Urine samples thawed and Vyachorka suspended in the ratio 1:2 across the plate. Produce seven dilutions, ending the procedure with a final dilution of 1:320. 10 g of each diluted sample is withdrawn from the microtiter tablet Falcon, using a multichannel pipette, and add to the bottom tablet Immulon 2 for the purpose of growth and reciting.

Prepare working reagent to protein by combining 50 parts of reagent A(BCA)with 1 part of reagent B(BCA) (supplied in the analytical set Pierce). 200 g of working reagent was added to the contents of each cell tablet Immulon. Tablets are close and wrapped in aluminum foil and incubated at 60oC for 30 minutes

Tablets read on an automatic microplate reader Bio-Tek, paired with the personal computer, Mac SE/30 with spectral absorption capacity of 570 nm. Receive and count data using the software Delta Soft Eliza Analysis, version 2.9 B supplied by the company Bio-Tech instruments.

Histology - Counting GN: on the 14th day take in animals the blood through the eye socket, animals killed by carbon dioxide and take out the kidneys, which are processed for histological analysis. After 24 hours of fixation of the kidneys process and kladiva and eosin and 30 glomeruli per rat evaluated according to the following criteria: (1+) Damaged 25% of renal glomeruli; the damage is minimal; the extension matrix is absent or small. (2+) Damaged 25-50%; damage moderate; significant increases or decreases the saturation of the cells; possible fusion shell/clew; the collapse of some capillary cavities; thickened basal membrane; the membrane can be detected protein droplets. (3+) Damage 51-75%; substantial damage; further growth mesangial matrix; multiple sclerosis; extensive collapse of the capillary cavities with capture of amorphous material. (4+) 76-100%; serious destruction; in most cases, renal glomeruli apparently not operational or dead; extensive sclerosis or lysis.

Semilunar education (defined as four or more contiguous epithelial cells of the Bowman capsule) increases the score by +1. The total score on the kidney is determined by multiplying the extent of the damage (from +1 to +4) on the percentage of renal glomeruli with the same degree of damage and the addition of individual results in the total amount. Final score GN is obtained by adding the results of the two kidneys.

PCNA immunohistochemistry and index of proliferating cells (PCI)

Identification of PCNA (Nuclear antigen of proliferating cells) - positive the topic labeling Biotin-streptavidin-horseradish-peroxidase (KPL N 710018) diaminobenzidine as Chromogen. PCI is determined by counting positive cells/glomerulus in each of 30 glomeruli in the kidney and then computing the average PCI/rat. No distinction is made between mesangial, endothelial or epithelial cell types.

The activity of compounds of the formula I is illustrated by the reduction of damage to the kidneys or by reference to such reduction, as defined above.

1. The use of the compounds of formula

< / BR>
where R1and R3independently represent hydrogen, -CH3, (C1-C6-alkyl) or , where Ar is phenyl, optionally substituted;

R2selected from the group consisting of pyrrolidino and piperidino,

or its pharmaceutically acceptable salt or MES to suppress defective repair of the epithelium of the glomerular apparatus.

2. Application under item 1, characterized in that the specified connection is its hydrochloric salt.

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

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

< / BR>
or its hydrochloric salt.

5. The use of the compounds of formula

R2selected from the group consisting of pyrrolidino and piperidino,

or its pharmaceutically acceptable salt or MES to suppress physiological condition associated with defective repair of the epithelium of the glomerular apparatus.

6. Application under item 5, characterized in that the specified connection is its hydrochloric salt.

7. Application under item 5, characterized in that the specified use is prophylactic.

8. Application under item 5, characterized in that the connection specified is a

< / BR>
or its hydrochloric salt.

9. The use of the compounds of formula

< / BR>
where R1and R3independently represent hydrogen, -CH3(C1-C6-alkyl) or , where Ar is phenyl, optionally substituted;

R2selected from the group consisting of pyrrolidino and piperidino,

or its pharmaceutically acceptable salt or MES as a means to suppress the defective recovery of the epithelium of the glomerular apparatus for the treatment of pathological effects, complications or symptoms of illness or painful soedinenie represents its hydrochloric salt.

11. Application under item 9, characterized in that the connection usage is preventive.

12. Application under item 9, characterized in that the connection specified is a

< / BR>
or its hydrochloric salt.

 

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3 cl, 5 dwg

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