Means for inhibiting neurotoxicity caused by beta-amyloid peptides

 

(57) Abstract:

The invention relates to medicine, specifically to pharmacology. The proposed tool for the inhibition of neurotoxicity caused-amyloid peptides. Such a proposed compound of General formula (I), formerly known as antiestrogen

< / BR>
where R1and R2independently of one another represent hydrogen;

where Ar - optional eamestly phenyl; R2is selected from the group consisting of pyrrolidino and piperidino,

or its pharmaceutically acceptable salt or MES. The invention expands the Arsenal of tools specified destination. 1 C.p. f-crystals.

Alzheimer's disease (AD) is a degenerative disorder of brain function, clinically characterized by progressive loss of memory, cognition, reasoning sanity, emotional balance, which gradually leads to a complete mental exhaustion and, ultimately, death. BA is a common cause of progressive cognitive disorders (dementia) older people and, as I believe, is in fourth place among the most frequent meditsinskii a serious public health problem of the present time and the future. Only in the United States estimated at present susceptible approximately two to three million people. It is proved that at the present time BA incurable.

Disease of the brain BA is manifested in neural degradation and typical damage that determine how amyloidogenic plaques, vascular amyloid disease of the blood or lymphatic vessels and linking thin nerve fibers in the cytoplasm of the neuron and its processes. A large number of these lesions, especially amyloidogenic plaques and binding of nerve fibers in the cytoplasm of a neuron, in patients with BA usually find in some areas of the brain that are important for memory and thinking. Fewer of these lesions and to a more limited anatomical distribution found in the brain in older people who do not suffer from clinical form BA. Amyloidogenic plaques and vascular disease blood and lymph vessels are also characteristic of the brain of patients with disease Trisomy 21 (down syndrome) and hereditary cerebral hemorrhage with amyloid degeneration of the Dutch - type (HCHWA-D). Now for the exact diagnosis it is necessary, as p is Bolshom sample brain tissue, taken at biopsy through neurosurgical operations.

Some lines clearly indicate that progressive cerebral deposition of individual amyloidogenic protein - amyloid protein (AP) plays the role of the embryo in the pathogenesis of ad and can precede the symptoms of the disorder cognitive abilities over the years and decades (see, Selkoe, (1991) Neuron 6:487). Recently it was shown that AP stands out from neural cells, grown in culture, and is present in the cerebrospinal fluid (CSF) as healthy patients and patients with BA (see Seubert et al., (1992) Nature 359: 325-327).

Possible correlation of plaque pathology was developed by several groups, showing the direct AP-toxicity against cultured neurons. Direct neurotoxicity AP, as previously reported, weakened by soapbody with TGF- (Chao et al., Soc. Neurosci. Abs., 19: 1251 (1993)).

Later, in addition to direct neurotoxicity, pathology BA was related inflammatory response in the brain of patients with AD, possibly due to AP. Limited clinical trial with NSAID is indomethacin demonstrated to slow the progression of dementia Alzheimer's disease (Rogerset et al., Science, 260: 1719 - 1720 (1993)).

Despite progress in isusablename. Treatments BA could successfully be based on the drugs that are able to increase the production in the brain of TGF-, thus reducing the neurotoxicity held-amyloid peptides, and reducing the intensity of the inflammatory reaction associated with BA.

This invention provides methods of inhibiting Alzheimer's disease, which includes the introduction of a person in need of such treatment an effective amount of the compounds of formula I

< / BR>
where R1and R3independently from each other, is hydrogen, -CH3,

where Ar is optionally substituted phenyl,

R2is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino,

and its pharmaceutically acceptable salts and MES.

This invention provides a method of increasing the allocation of TGF - in the brain, including the introduction of a person in need of treatment an effective amount of the compounds of formula I.

This invention also provides a method of inhibiting neurotoxicity held - amyloid peptides and inflammatory reaction associated with Alzheimer's disease (ad), comprising the administration to a human in need of treatment of effektivnaya group benzothiophene formula I is useful for inhibiting the effects of Alzheimer's disease and in particular, what compounds are believed to inhibit an inflammatory response associated with the disease, by increasing the excretion of TGF - in the brain. The invention includes methods of practical application through the introduction of a person in need of treatment doses of the compounds of formula I or pharmaceutically acceptable salt or MES, effective for the inhibition of Alzheimer's disease. The methods encompass both therapeutic and prophylactic use.

The term "inhibition" is used in its generally accepted meaning which includes prohibiting, preventing, restraining, slowing, stopping, reversal of the progression of, reduce severity or symptom of the disease or its consequences.

The term "effective amount" means an amount of compound necessary for inhibiting Alzheimer's disease or any symptom, inhibition of neurotoxicity held-amyloid peptides, or of the inflammatory reaction associated with Alzheimer's disease, or increased excretion of TGF - in the brain.

As a rule, the connection is included in the composition with conventional carriers, fillers, diluents, and compressed into tablets or isotone or intravenously. Connections can be entered transdermal and can be made in the form of controlled selection of the active substance, etc.

Compounds used in the methods of the present invention can be obtained according to known methods or methods similar to them, such as described in U.S. patents NN 4133814, 4418068 and 4380635, which are included in the list of references of this invention. Obtaining, as a rule, begins with the original benzo(C)thiophene having at position 6 hydroxyl group in position 2 - 4-hydroxyphenyl. In the original substance is injected protective group, acelerou, and then the protective group is removed to obtain compounds of formula I. Examples of the preparation of such compounds are given in U.S. patents mentioned above, and in examples of the present invention. Optionally substituted phenyl includes phenyl and phenyl containing as a substituent one or two groups C1-C2-alkyl, C1-C4-alkoxy, hydroxy, nitro, chlorine, fluorine or trichloro or vermeil.

One of the compounds of the present invention is raloxifene (raloxifene), the structure of which is presented below:

< / BR>
Compounds used in the methods of the present invention obrich and inorganic acids and bases, which include physiologically acceptable salts, commonly used in pharmachemie. Such salts are part of this invention. Conventional inorganic acid used for such salts include hydrochloric pomodorino, yodogawaku, nitric, sulfuric, phosphoric, hypophosphorous, etc., Salts derived from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. These pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, Naftali-2-benzoate, bromide, isobutyrate phenylbutyrate, -hydroxybutyrate, Butin-1,4-diat, hexyne-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, formate, fumarate, Piglet, heptanoate, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydratefast, dihydrophosphate, metaphosphate, pyrophosphate, propiolate (propiolate), propionate, venonat, benzene-sulfonate, p-bromophenylacetate, chlorastrolite, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, ecological, tartaric, etc., the Preferred salt is the hydrochloride.

Pharmaceutically acceptable acid additive salts are usually obtained by reaction of compounds of formula I with an equimolar amount or an excess of acid. The reagents were combined in the solvent, mutually acceptable to both reagents, such as diethyl ether or benzene. The salt normally precipitates out of solution within the time interval from 1 hour to 10 hours and can be isolated by filtration or solvent away common ways.

The base used is usually to obtain primary agents, additive salts include ammonium hydroxide and a hydroxide of alkali and alkaline earth metals, carbonates and aliphatic primary, secondary and tertiary amines, aliphatic diamines. The Foundation is particularly useful for obtaining additive salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, Ethylenediamine and cyclohexylamine.

Pharmaceutically acceptable salts obladaet more convenient for preparation of compositions in the form of solutions or emulsions.

The pharmaceutical compositions can be manufactured by well known methods. For example, the compounds can be introduced into the composition with common excipients, diluents or carriers, and is made in the form of tablets, capsules, suspensions, powders, etc., Examples of excipients, diluents, and carriers that are suitable for use in such compositions include the following: fillers or diluents, such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants, such as glycerol; dispersing agents such as calcium carbonate and sodium bicarbonate; agents slow the dissolution, such as paraffin; accelerators resorbtive, such as Quaternary ammonium derivatives; surface-active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; lubricating agents such as talc, calcium stearate and magnesium stearate and solid polyethylene glycols.

Connections can be made in the form of elixirs or solutions for convenient oral administration or as solutions for parenteral introduction is controlled by the selection of the active substance, etc. That is, the composition can be designed in such a way that they release the active ingredient only or preferably in separate parts, perhaps after some period of time. Cover, covers, and protective matrices may be made, for example, polymeric substances or waxes.

The compounds of formula I can be administered for prophylactic and/or therapeutic treatment of Alzheimer's disease. Therapeutic application of compounds are introduced to a patient already suffering from this disease.

The specific dose of a compound of formula I according to this invention will depend on the severity of the disease, the route of administration and other factors that will be considered by the attending physician. In General, acceptable and effective daily dosage will be from about 0.1 to about 1000 mg/day, more typically from about 50 to about 200 mg/day. Such dosages will be administered to a patient in need of treatment from one to about three times a day or more frequently to ensure effective treatment.

Often it will be necessary or required to enter the pharmaceutical composition directly or indirectly in the brain. Direct methods heskogo barrier. Indirect methods, which are preferred, include the manufacture of compositions for providing patentiranja drugs by the conversion of hydrophilic drugs into lipid-soluble drugs. Licentiate achieved through blocking of hydroxyl, carboxyl, primary amine groups present in the drug, to increase the lipid solubility of the drug and its ability to overcome hematoencephalic barrier. According to another method, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions, which can temporarily remove hematoencephalic barrier.

Usually preferred for use are the compounds of formula I in the form of an acid additive salt, which is most common for the drug having basic group, such as piperidinyl cycle. For these purposes, acceptable are the following forms.

Songs

The following compositions, the term "Active ingredient" means a compound of formula I.

Composition 1: Gelatin capsules

Hard gelatin capsules is obtained using the following components:

Ingredient - Koloski - 0 - 650

Liquid silicone 350 CST - 0 - 15

The ingredients are mixed, passed through a sieve size 45 mesh (U.S.) and fill them gelatine capsules.

Examples of specific compositions in the form of capsules, which contain the compound of formula I, where R2- piperidino, (raloxifene) is presented below.

Composition 2: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 1

Starch, NF - 112

The starch in the form of a flowable powder - 225,3

Liquid silicone 350 CST - 1,7

Composition 3: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 5

Starch, NF - 108

The starch in the form of a flowable powder - 225,3

Liquid silicone 350 CST - 1,7

Track 4: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 10

Starch, NF - 103

The starch in the form of a flowable powder - 225,3

Liquid silicone 350 CST - 1,7

Composition 5: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Raloxifene - 50

Starch, NF - 150

The starch in the form of a flowable powder - 397

Liquid silicone 350 CST - 3,0

The specific composition described above can be modified as per your requirements is provided below.

Track 6: Tablets

The ingredient Quantity (mg/capsule)

The active ingredient is 0.1 - 1000

Microcrystalline cellulose - 0 - 650

Silicon dioxide - 0 - 650

Stearate acid - 0 - 15

The components are mixed and pressed to form tablets.

Tablets, each containing 0.1 to 1000 mg of active ingredient, are made in another way, is presented below:

Track 7: Pills

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1 - 1000

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone (as 10% solution in water) - 4

Sodium carboxymethylcellulose is 4.5

Magnesium stearate and 0.5

Talc - 1

The active ingredient, starch and cellulose are passed through a sieve size 45 mesh (U.S.) and thoroughly mix. The solution of polyvinylpyrrolidone is mixed with the obtained powder, after which the formed mixture is passed through a sieve size of 14 mesh (U.S.). Thus obtained granules are dried at a temperature of 50-60oC and pass through a sieve of size 18 mesh (U.S.). Carboxymethylcellulose sodium, magnesium stearate and talc, previously sifted through a sieve with a size of 60 mesh (U.S.), added to the granules, which th funds in 5 ml made as follows:

Song 8: Suspension

The ingredient Quantity (mg/5 ml)

The active ingredient is 0.1 - 1000 mg

Sodium carboxymethyl cellulose 50 mg

The syrup 1.25 mg

A solution of benzoic acid 0.10 ml

Flavouring substance, O.

Dye, R.H.

Purified water To 5 ml

The drug passed through the sieve size 45 mesh (USA) and mixed with sodium carboxymethyl cellulose and syrup with the formation of a thick paste. A solution of benzoic acid, flavouring substances and dye is dissolved in a certain amount of water and added with stirring. After that add the required amount of water to obtain the desired volume.

Test

The test plan.

For tests 1 and 2 suggest the following plan of the experiment.

Emiline (amylins) can be purchased in Bachen, Inc. (Torrance, California), Peninsula Laboratories, Inc. 3 Belmont, California or may be synthesized as described below. Amyloid -(1-40) and opposite - amyloid peptide (40-1) can be purchased at Bachem, Inc. 2- microglobulin can be obtained from Sigma Chemical (St. Louis, Missouri).

Royal solutions of peptides (1M) again prepared in sterile purified amp rats (10 - 14 days in vitro) treated with peptides or solvent for 4 days. The viability of cortical cultures of rat visual estimate of phase-contrast microscopy and quantitatively assessed by measuring the amount of lactate dehydrogenase (LDH), highlighted in culturebound environment.

Test 1

Primary neurons hypogamy rats culturious in vitro by standard methods of cell cultivation. Amyloid-beta (A) peptide added to culturebound cells under normal toxic concentrations of 25 - 50 mm. Later, 4 days after treatment, the culture viability assessed by measuring the amount of lactatedehydrogenase allocated in culturebound environment. Lactatedehydrogenase (LDH) was measured in a 20 ml aliquot sustained in DMEM using standard 340 mon kinetic evaluation (Sigma Catalog Number 228 - 20) in 96-cell format. Experiments carried out at 37oC RS-managed the reader brand Microplate Biokinetics plate reader (Bio-Tek Instruments) using Delta Soft II software (v. 3.30, Biomet. Inc.) for data analysis. Quality control standards, containing normal and elevated levels of serum LDH (for example, Sigma Enzyme Controls 2N L 2E), looking at every test. The results are presented in the form of units (LDH) per liter, gdimagecolorallocate per minute in the test conditions. For protection studies, the compound of formula I added to the culture before and/or simultaneously with hamiliton-.

The activity of compounds of the formula I dismantled the decrease in the allocation of LDH in the medium (indicator of neurotoxicity) compared to control.

Test 2

From five to fifty rats subjected to occlusion of the four vessels for 15 minutes to induce total ischemia. The compound of this invention administered to the experimental and control animals before, during occlusion and/or within several hours after a 15-minute occlusion. After 3 days decapitate animals after ischemic stroke and neural lesions in hippocampus and neostriatum and visually examine standard histological methods.

The activity of compounds of the formula I dismantled the reduction of neural lesions.

Test 3

From 5 to fifty women opt for clinical research. Women are post-menopausal, that is, with the cessation of menstruation for 6 - 12 months prior to the study, diagnosed with mild stages of Alzheimer's disease (AD) and, as expected, with deteriorating symptoms of BA in the study period, but healthy in all other respects. The research is the first agent of this invention, and the other receives a placebo. Patients marked the initial symptoms characteristic of BA, that is, memory impairment, cognitive abilities, cognitive abilities, and so on Women from the experimental group receive from 50 to 200 mg of active agent per day orally. Duration of treatment is 6 to 36 months. Accurate registration of the original symptom persists in continuing the study in both groups, and at the end of the study these results are compared. Comparison of the results is carried out between members of each group and for each patient relative to the level of the symptom before the start of the study. The activity of the investigated drugs is illustrated by the typical slow weakening of cognitive abilities and/or irregularities in the behavior associated with BA.

The usefulness of the compounds of the formula I is demonstrated by the activity of at least one of the above tests.

1. The use of the compounds of formula I

< / BR>
where R1and R3independently of one another represent hydrogen,

Ar is optionally substituted phenyl;

R2is selected from the group consisting of pyrrolidino and piperidino,

or its pharmaceutically acceptable salt or MES d is shown the connection is

< / BR>
or its hydrochloride.

 

Same patents:

The invention relates to substituted derivative asalaam, which is an effective anti-Helicobacter tools that can be used as monotherapy for eradication of Helicobacter pylori and related species

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to piperidinylidene methane-anthracene of the formula I,

< / BR>
where X and Y represent hydrogen, R1represents pyridyl, substituted chiral (1-4C)-alkylsulfonyl group, and their pharmaceutically acceptable salts which are useful as antagonists of dopamine and is particularly useful as antipsychotics for the treatment of humans
The invention relates to the medical industry, antiallergic, Antiasthmatic drugs

The invention relates to medicine and relates to a new means for inhibiting the oxidation of low density lipids

The invention relates to neuroprotective 3R*, 4S* 3-[4-(4-forfinal)-4-hydroxypiperidine-1-yl] chroman-4,7-djolu, its enantiomers and pharmaceutically acceptable salts, and pharmaceutical compositions based on them, which are effective oral agents for the treatment of diseases or conditions susceptible to treatment with drugs that block NMDA receptors, as well as to a method of blocking sites of NMDA receptors

The invention relates to medicine, specifically to gynecology

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to medicine and relates to a new means for inhibiting the oxidation of low density lipids

The invention relates to medicine, specifically to gynecology

The invention relates to the field of macrolides

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

Up!