Pharmaceutical composition for treatment of diseases associated with loss of osseous mass

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.

EFFECT: valuable medicinal properties of pharmaceutical composition.

16 cl, 3 tbl, 5 ex

 

The technical field

The present invention relates to pharmaceutical compositions for the treatment of diseases associated with bone loss, containing as the active ingredient agonist EP4the receptor.

In more detail, the invention relates to pharmaceutical compositions for the treatment and/or prevention of diseases associated with bone loss, such as primary osteoporosis, secondary osteoporosis, metastases to bone, hypercalcemia, Paget's disease, bone loss and osteonecrosis etc.; and to a pharmaceutical composition for accelerating osteogenesis, such as osteogenesis after bone fracture, a bone formation after transplantation of bone, osteogenesis after operation in occasion of an artificial hip joint, osteogenesis after fusion and osteogenesis after other operations on bone regeneration and so on; and to pharmaceutical compositions for the rapid treatment of these diseases containing as active ingredient agonist EP4the receptor.

Prior art

Approximately 120-150 days bone undergoes the cycle of bone resorption by osteoclasts, the bone formation by osteoblasts and rest period (called remodeling). In a healthy adult, and bone resorption and osteogenesis are strictly controlled, so there is a slight change in the total KOs is Noah mass. However, in a patient suffering from a disease associated with bone loss, the balance between bone resorption and osteogenesis broken and there is a loss of bone mass and deterioration of bone tissue. The degree of bone loss reaches 20-30%. This patient has a tendency to bone fractures, which are sometimes the cause of bed rest, the deformation of the body or, in the worst case, death, when fractures occur in dangerous places like the hip joint, etc.

Typical disease-related bone loss is osteoporosis. Osteoporosis is a systemic disease whose main symptom is characterized by loss of bone mass and deterioration of bone tissue.

Causes of osteoporosis may be different, but the most common cause, according to age is, especially postmenopausal hormonal imbalance in women. So now as the primary treatment of osteoporosis accepted the introduction of estrogen, vitamin D, or calcitonin. However, in the treatment of hormone, there is a risk of stimulation of cancer (especially breast cancer, uterine cancer, and so on), so this treatment is unsafe.

In addition, spent the introduction of bisphosphonates as a medication of the second generation. However, the problem is that the cessation can cause Oslo is the link.

In addition, even if the above-mentioned treatment there is a possibility to delay the worsening of osteoporosis, it is difficult to regenerate bone mass which once fell.

On the other hand, prostaglandin E2(the abbreviated name of the PGE2also known as a metabolite in the arachidonic acid cascade. It is known to possess various activities, such as cytoprotective activity, contractile activity against cancer, the effect of inducing pain, stimulating effect on the motility of the gastrointestinal tract, the effect of awakening, an overwhelming effect on the secretion of acid in the stomach, hypotensive activity, diuretic activity, etc.

PGE2as believe, is related to bone resorption (J.Dent Res. 59(10), 1635 (1980); Nature 266,6455 (1977)).

In addition, there is a patent application, in which it is reported that macroscopically or microscopically observed the growth of bone and increasing bone mass in dogs, which orally or intravenously was administered PGE1or PGE2. However, the dose of each compound was 1000 mg/kg/day, which is a very high dose for PG, so it is doubtful that each named PG plays a significant role. Due to such high doses may be difficulties in obtaining funds for practice.

A recent study has proven there is Finance different subtypes of PGE 2receptor possessing distinguishing them from each other physical purpose. Currently there are four subtypes of receptors; they are named EP1, EP2, EP3, EP4(Ngishi M. and others, J.Lipid Mediators Cell Signaling 12, 379-391 (1995)). When studying the role of each receptor subtype and the detection of a compound that can form a specific bond with each receptor and can't form a relationship with any other receptors, it has become possible to obtain a tool that gives fewer side effects.

Recently revealed that agonist EP2receptor and antagonist EP4, is effective for the treatment of osteoporosis (WO98/279769) and accelerated bone resorption (GB2 330307), respectively.

In addition, in the application EP-855389 described that the compound of formula (IA) used as conjugator for EP4the receptor. In this patent application shows that the compound of formula (IA) are useful for treatment and prevention of disorders of osteogenesis. However, there is neither description nor assumptions that agonist EP4receptor or antagonist EP4is related to osteogenesis or its role in the treatment.

As mentioned above, there is an assumption that PGE2or PGE1refer to metabolites bones, and for some subtypes of this assumption is indeed confirmed. However, it is not clear what their subtypes, or what the military antagonist or agonist of the receptor, applicable.

The invention

The authors of the present invention and others have synthesized various compounds that can selectively communicate with each subtype of PGE receptor, and examined them to find compounds that affect osteogenesis, as a means for treatment of diseases associated with bone loss.

Until now it was thought that the antagonist EP4applicable for treatment of diseases associated with bone loss, due to its inhibitory action on bone resorption and agonist EP4receptor is not applicable for such treatment due to the stimulating action on bone resorption, which may cause loss of bone mass. However, unexpectedly, the authors of the present invention found that agonist EP4receptor in low doses causes an increase in bone mass and bone density, and thereby realized the present invention.

In addition, it was experimentally confirmed that the compounds of formulas (IA)-(IJ)below and represents agonists EP4receptor, really have agonistic action EP4the receptor.

The present invention relates to pharmaceutical compositions for the treatment and/or prevention of diseases associated with bone loss, containing as the active ingredient agonist EP the receptor.

According to the present invention for the first time it was confirmed that the agonist EP4receptor has activity to increase bone mass and bone density and stimulate osteogenesis action.

In the present invention, the term "disease associated with bone loss" means an illness due to conditions such as reduced bone density, degradation of bone tissue and so on, and includes, for example:

1) primary osteoporosis (for example, primary age-related osteoporosis, primary postmenopausal osteoporosis primary osteoporosis due to oophorectomy, etc.);

2) secondary osteoporosis (e.g. osteoporosis induced by glucocorticoids; osteoporosis induced hyperthyroidism; osteoporosis induced immobility; osteoporosis, heparin-induced; osteoporosis-induced immunosuppression, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis due to Cushing's syndrome, rheumatoid osteoporosis etc.);

3) diseases such bones as metastasis in bone, hypercalcemia, Paget's disease, bone loss (alveolar bone loss, depression of the bone, idiopathic bone loss in children and so on), osteonecrosis, etc.

In addition to the treatment of these diseases present izopet the tion also includes a pharmaceutical composition for accelerating osteogenesis after surgery on the bone (for example, osteogenesis after bone fractures, bone formation after transplantation of bone, osteogenesis after operation in occasion of an artificial hip joint, osteogenesis after fusion and osteogenesis after other operations on bone regeneration and so on), or stimulating treatment of the bone, or an alternative treatment by transplantation of bone.

According to the present invention agoniston EP4receptor is each connection, which can selectively form a connection with EP4receptor a subtype of PGE2receptor, and cannot or does not form a connection with any other EP1, EP2, EP3subtype receptor and has affinity for ER4.

Therefore, such compounds include agonists EP4that will be found in the future, as currently known. In addition, these agonists EP4include as compounds that do not possess PG-skeleton, and PG-skeleton.

These compounds can selectively establish communication with the EP4receptor, and they do not induce pain, which can cause EP1the relaxation of the uterus, which can cause EP2and uterine contractions, which can cause EP3so they are a means, not having any influence on the above-mentioned steps.

As shown in the experiments mentioned later, the agonist EP4 it has a strong stimulating effect on osteogenesis, so it is useful for the treatment of the mentioned diseases associated with bone loss such as osteoporosis.

The preferred compounds used in the present invention are as follows: for example, compounds selected from agonists EP4consisting of compounds of the formula (IA)

where R1Ameans hydroxy, C1-alkyloxy, or NR6AR7A(where each R6Aand R7Aindependently mean hydrogen or C1-alkyl),

R2Ameans hydrogen or a hydroxy-group,

R3Ameans:

(i) C1-alkyl, C2-alkenyl or C2-alkynyl;

(ii) phenyl or C3-cycloalkyl;

(iii) C1-alkyl, C2-alkenyl or C2-alkynyl substituted by phenyl or C3-cycloalkyl (provided that, when R2Ais hydrogen, alkyl, alkenyl and quinil in (i) and (ii) can be substituted by one hydroxy-group).

The symbol---means double or simple communication. Provided that included his 8-paranoise connection.

The compounds of formula (IB)

Where R1Bmeans hydroxy, C1-alkyloxy, or NR6VR7B(where each R63and R78independently mean hydrogen or C1-alkyl),

R2Bmeans hydrogen or a hydroxy-group,

R3Bmeans about the thuja bond or C1-alkylen,

R4Bmeans:

(i) C1-alkyl, C2-alkenyl or C2-alkynyl, substituted by one to three groups selected from C1-alkyloxy or halogen;

(ii) phenyloxy or C3-cycloalkane;

(iii) furyl, forelocks, thienyl, titilate, naphthyl, naphthyloxy, talani or talonlike;

(iv) phenyl, phenyloxy, C3-cycloalkyl or C3-cycloalkane, substituted by one to three groups selected from the following groups:

C1-alkyl,

C2-alkenyl,

C2-alkynyl,

C1-alkyloxy,

C1-alkyloxy-C1-alkyl,

C1-alkyloxy-C1-alkyloxy,

C2-alkenylacyl-C1-alkyl,

C1-alkyl, substituted by one to three hydroxy groups,

C1-alkyl, substituted by one to three halogen atoms,

C1-alkylthio,

C1-alkylthio-C1-alkyl,

C1-alkylthio-C1-alkyloxy,

C2-alkanity-C1-alkyl,

C1-alkylsulfonyl,

halogen,

trihalomethyl,

cyano,

nitro,

amino,

hydroxy,

C3-cycloalkyl,

C3-cycloalkane,

C3-cycloalkyl-C1-alkyl,

C3-cycloalkane-C1-alkyl,

phenyl,

phenyloxy,

phenyl-C1-alkyl,

phenyl-C2-alkenyl,

phenyl-C2-alkenyl,

phenyloxy-C1-alkyl,

phenyloxy-C2-alkenyl,

phenyloxy-C2-alkenyl,

furyl,

forelocks,

furyl-C1-alkyl,

forelocks-C1-alkyl,

thienyl,

titilate,

thienyl-C1-alkyl or

titilate-C1-alkyl,

(the above-mentioned phenyl, f is the Rila, thienyl or cycloalkyl can be substituted one to three groups selected from C1-Akilov, C1-alkyloxy, C1-alkyloxy-C1-Akilov, nitro, halogen, trihalomethyl, amino and hydroxy groups); or

(v) furyl, forelocks, thienyl, titilate, naphthyl, naphthyloxy, talani or palanisami, substituted by one to three groups selected from the following groups:

C1-alkyl,

C2-alkenyl,

C2-alkynyl,

C1-alkyloxy,

C1-alkyloxy-C1-alkyl,

C1-alkyloxy-C1-alkyloxy,

C2-alkenylacyl-C1-alkyl,

C1-alkyl, substituted by one to three hydroxy groups,

C1-alkyl, substituted by one to three halogen atoms,

C1-alkylthio,

C1-alkylthio-C1-alkyl,

C1-alkylthio-C1-alkyloxy,

C2-alkanity-C1-alkyl,

C1-alkylsulfonyl,

halogen,

trihalomethyl,

cyano,

nitro,

amino,

hydroxy,

C3-cycloalkyl,

C3-cycloalkane,

C3-cycloalkyl-C1-alkyl,

C3-cycloalkane-C1-alkyl,

phenyl,

phenyloxy,

phenyl-C1-alkyl,

phenyl-C2-alkenyl,

phenyl-C2-alkenyl,

phenyloxy-C1-alkyl,

phenyloxy-C2-alkenyl,

phenyloxy-C2-alkenyl,

furyl,

forelocks,

furyl-C1-alkyl,

forelocks-C1-alkyl,

thienyl,

titilate,

thienyl-C1-alkyl or

titilate-C1-alkyl.

(The above-mentioned phenyl, furyl, thienyl or cycloalkyl can be zamestitel three groups, selected from C1-alkyl, C1-alkyloxy, C1-alkyloxy-C1-alkyl, nitro, halogen, trihalomethyl, amino, and hydroxyl groups),

R5Bmeans hydrogen or C1-alkyl,

the symbol-----means a double or a simple link.

Provided that when R2Bis hydrogen, C1-alkylene represented by R3Bmay be substituted by one hydroxy-group, and that included his 8-paranoise connection)

The compounds of formula (IC)

where R1Cmeans a hydroxy-group, C1-alkyloxy, or NR6SR7C(where each R6Sand R7Cindependently mean hydrogen or C1-alkyl),

R2Cmeans oxoprop, halogen or O-COR8S(in which R8Sis C1-alnilam, phenyl, or phenyl(C1-alnilam)),

R3Smeans hydrogen or a hydroxy-group,

each RSaand R4bindependently is hydrogen or C1-alnilam,

R5Cmeans phenyl, substituted by the following groups:

(i) one to three groups selected from the group

C1-alkyloxy-C1-alkyl,

C2-alkenylacyl-C1-alkyl,

C2-alkyloxy-C1-alkyl,

C3-cycloalkane-C1-alkyl,

C3-cycloalkyl(C1-alkyloxy)-C1-alkyl,

phenyloxy-C1-alkyl,

phenyl-s-1-alkyloxy-C1-alkyl,

C1-alkylthio-C1-alkyl,

C2-alkanity-C1-alkyl,

C2-alkylthio-C1-alkyl,

C3-cycloalkyl the thio-C1-alkyl,

C3-cycloalkyl(C1-alkylthio)-C1-alkyl,

phenylthio-C1-alkyl,or

phenyl-C1-alkylthio-C1-alkyl;

(ii) the groups C1-alkyloxy-C1-alkyl and C1-alkyl,

C1-alkyloxy-C1-alkyl and C1-alkyloxy,

C1-alkyloxy-C1-alkyl and hydroxy,

C1-alkyloxy-C1-alkyl and halogen,

C1-alkylthio-C1-alkyl and C1-alkyl,

C1-alkylthio-C1-alkyl and C1-alkyloxy,

C1-alkylthio-C1-alkyl and hydroxy, or

C1-alkylthio-C1-alkyl and halogen;

(iii) halogenation or hydroxy-C1-alkilani; or

(iv) C1-alkilani and hydroxy groups;

the symbol-----means simple or double bond.

Provided that when R2Cmeans O-COR8Cthe relationship between atoms in 8-and 9-positions is a double.

The compounds of formula (ID)

where aDmeans C2-alkylene, C2-alkeran, C1-alkylene-phenylene or C2-alkeran-phenylene,

R1Dmeans a hydroxy-group, C1-alkyloxy, C1-alkyloxy-C1-alkyloxy, HO-C1-alkyloxy, or NR6DR7D(where each R6Dand R7Dindependently is hydrogen or C1-alnilam),

R2Dmeans oxoprop, halogen, or R8D-COO- (where R8Dmeans hydrogen, C1-alkyl, phenyl, phenyl(C1-alkyl), C1-alkyloxy, noos-C1-alkyl, C1-alkyloxy-carbonyl-C1-alkyl, noos-C2-alkenyl or C1-allyloxycarbonyl-C2-alkenyl),

R3Dmeans hydrogen or hydroxyprop is,

R4Dmeans alkylen,

R5Dmeans phenyl, substituted by the following groups:

(i) one to three groups selected from the group

C1-alkyloxy-C1-alkyl,

C2-alkenylacyl-C1-alkyl,

C2-alkyloxy-C1-alkyl,

C3-cycloalkane-C1-alkyl,

C3-cycloalkyl(C1-alkyloxy)-C1-alkyl,

phenyloxy-C1-alkyl,

phenyl-C1-alkyloxy-C1-alkyl,

C1-alkylthio-C1-alkyl,

C2-alkanity-C1-alkyl,

C2-alkylthio-C1-alkyl,

C3-cycloalkyl-C1-alkyl,

C3-cycloalkyl(C1-alkylthio)-C1-alkyl,

phenylthio-C1-alkyl or

phenyl-C1-alkylthio-C1-alkyl;

(ii) the groups C1-alkyloxy-C1-alkyl and C1-alkyl,

C1-alkyloxy-C1-alkyl and C1-alkyloxy,

C1-alkyloxy-C1-alkyl and hydroxy,

C1-alkyloxy-C1-alkyl and halogen-free,

C1-alkylthio-C1-alkyl and C1-alkyl,

C1-alkylthio-C1-alkyl and C1-alkyloxy,

C1-alkylthio-C1-alkyl and hydroxy, or

C1-alkylthio-C1-alkyl and Halogens;

(iii) halogen-C1-alkilani or hydroxy-C1-alkyl; or

(iv) C1-alkilani and hydroxy groups;

the symbol---means simple or double bond.

Provided that when R2Dcorresponds to the formula R9-COO-, R1Dmeans C1-alkyloxy, C1-alkyloxy-C1-alkyloxy or BUT-C1-alkyloxy, the connection between the atoms in the 8-and 9-positions is a double bond.

The preferred compounds used in this and the finding as agonists EP 4are as follows: (in brackets under each formula specified published patent or application number and the number of the example). For example, prostaglandin derivatives of formula (IE)

(WOOO/03980, example 3);

formula (IF)

(EP-985663, example 2);

formula (IG)

(PCT/JP99/04934, example 8-6);

formula (IH)

(PCT/JP99/04934, example 2) and formula (IJ)

(PCT/JP99/04934, example 2-11)

or complex alkalemia esters of these compounds, their non-toxic salts and their cyclodextrine clathrate compounds.

[Ester]

Compounds according to the present invention, represented by formulas (IA)-(IJ)can be converted to esters known methods. Conversion into the corresponding esters serves to improve stability and absorbability compounds and therefore is applicable for the preparation of pharmaceutical preparations. Preferred complex alkilany ether, more preferred C1-4 - complex alkilany ether and most preferred methyl ester.

[Sol]

Compounds according to the present invention, represented by formulas (IA)-(IJ)can be converted into the corresponding salt by the known methods. The preferred non-toxic and soluble is in salt water. Suitable salts are, for example, the following:

salts of alkali metals (potassium, sodium etc), salts of alkaline earth metals (calcium, magnesium etc), ammonium salts, salts of pharmaceutically acceptable organic amines (Tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, three(hydroxymethyl)amine, lysine, arginine, n-methyl-d-glucamine etc). Compounds according to the present invention, represented by formulas (IA)-(IJ)can be converted into the corresponding hydrates known methods.

[Clathrates]

Compounds according to the present invention, represented by formulas (IA)-(IJ), and their esters can be converted into the corresponding cyclodextrine clathrates by the method described in the specification of GB 1351238 or GB 1419221 using α-, βor γ-cyclodextrins or their mixture. Conversion into the corresponding cyclodextrine clathrates contributes to the stability and solubility of compounds in water and therefore is useful when used for pharmaceutical preparations.

[Method of preparing compounds according to the present invention]

Each of the compounds of formulas (IA)to(IJ) and the method thereof are described in the following patent applications.

The compound of formula (IA): ER-855389;

The compound of formula (I): EP-985663;

The compound of formula (IC): WO00/03980;

The compound of formula (ID): application number PCT/JP99/04934;

The compound of formula (IE): WO00/03980;

The compound of formula (IF): ER-985663;

The compound of formula (IG):application number PCT/JP99/04934;

The compound of formula (IH): application number PCT/JP99/04934;

The compound of formula (IJ): application number PCT/JP99/04934.

The best way of carrying out the invention

The following reference examples and examples are intended to illustrate, but not limit the scope of the present invention.

Example 1: stimulating osteogenesis action

They used dogs 6 months of age breed Beagle/CSK (n=3-6 per group). Each α-cyclodextrines the clathrate (containing the active ingredient in the form of α-cyclodextrine clathrate in the amount of 25% wt./wt.) methyl ester (11α,15β,13TH)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid (methyl ester compounds of formula (IE)), (11α, 15α, 13TH)-9-hydroxy-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-3,7-citeproc-13-ene acid (compound formula (IF)), (9β, 11α, 15α, 5Z, 13TH)-9-chloro-of 11.15-dihydroxy-16(3-ethoxymethylene)-17,18,19,20-tetranitro-5,13-diene acid (compound of formula (IG)), (11α, 15α, 13TH)-9-hydroxy-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranitro-13-ene acid (difficult methyl ester compounds of formula (IH)and (11α, 15α,5Z, 13TH)-9-hydroxy-of 11.15-dihydroxy-16-(3-ethoxymethylene)-17,18,19,20-tetranitro-5,13-diene acid (compound of formula (1J)) was dissolved in saline and was administered to each animal in effective doses of 2, 5, 10 and 25 µg/kg/day, continuously 24 hours a day for 4 weeks. Each test solution was injected into the femoral vein through the fixed catheter at a rate of 0.2 ml/kg/hour. Equal volume of physiological solution was injected into the animal from the control group. After introducing each animal was scored for conducting the autopsy.

(1) determination of the surface area of the bone

Separated femur was fixed with buffered solution of 10% formalin and then cut into round slices with a thickness of 10 mm perpendicular to the longitudinal axis at a distance of 25 mm on the Central side from the trochlea sulcus. Image the surface of the bone on the side near to the epiphysis, received with the camera connected to a computer, at a constant distance, and then analyzed the received digital image to determine the surface area of the bone. The results are shown in Table 1.

Table 1
The test solutionDose (mg/kg/day)The surface area of the bone (mm2)
Non-contact is Aulnay n=6 068,93±6,64
The compound(IE)according to the invention n=6277,96±6,94
The compound(IE)according to the invention n=610190,69±of 19.03***
The compound(IE)according to the invention n=425502,76±54,81***
The compound(IF)according to the invention n=35365,29±73,63
The compound(IG)according to the invention n=310140,10±28,08
The compound(IG)according to the invention n=325289,38±120,50
The compound(IH)according to the invention n=35362,99±89,56
The compound(IJ)according to the invention n=35193,23±11,32

***: p<0,001 (mean standard deviation in the test of Dunnett)

Discussion:

Group according to the invention, including the compounds of formula (IE), at doses of 10 mcg/kg/day or higher showed a 2.8-fold increase in surface area of the bone compared to the control group. Special, more than 7-fold increase in surface area of bone was observed in this group at the dose of 25 mg/kg/day.

Group according to the invention, including compounds of formula (IF), (IH) and (IJ) at the dose of 5 mg/kg/day which also showed a 2.8-to 5.3-fold increase in surface area of the bone compared to the control group. In addition, the group according to the invention, including the compounds of formula (IG) at the dose of 25 mg/kg/day also showed a 4.2-fold increase in surface area of the bone compared to the control group.

(2) Determination of bone density

After removal of the lateral x-rays of a sample 1 cm thick, used in the above-mentioned paragraph (1), the received input image data entered into the computer in order to measure the level of radiation per unit area at a constant thickness and to determine bone density (Microfocus system of x-rays μFX-1000 (Fuji Photo Film Co., Ltd.)). The results are shown in Table 2.

Table 2
The test solutionDose (mg/kg/day)Bone density (PSL/mm2)
Non-control n=605,93±0,72
The compound(IE)according to the invention n=625,63±0,70
The compound(IE)according to the invention n=6108,75±1,19***
The compound(IE)according to the invention n=42510,34±1,58***

***: p<0,001 (mean standard deviation in the test of Dunnett)

Discussion:

Group according to the invention, enabling the I the compounds of formula (IE) at doses of 10 and 25 mcg/kg/day, showed a 1.5 - and 1.7-fold increase in bone density compared with the control group, respectively. These results confirmed that these compounds with affinity to ER, stimulate a significant increase in the bone surface and bone density at the dose of 10 mg/kg/day or higher and have a stimulating osteogenesis action.

Example 2: Determination of the affinity for ER4

In the following experiments, it was confirmed that the compounds of formulas (IA)-(IJ) can communicate with E4receptor and that they have an agonistic effect on EP4the receptor.

Agonistic effect of compounds of formulas (IA)-(IJ) was determined using cells of Cho, who expressed EP4the receptor (see FEBS Letters 364,339(1995) partial changes). It was further confirmed that all connections cause an increase in the level of camp and that they are agonists EP4.

Example 3: stimulating osteogenesis action

Experimental method:

Used female rats SD 11 weeks of age (n=8, average body weight of 271 g). On the abdominal wall of the rat made an incision under anesthesia by pentobarbital for holding oophorectomy and then on the area of the incision was left seam. In the group simulation animals were the only cut and weld overlay without oophorectomy.

After 6-days after oophorectomy process is, prepared by dissolving α-cyclodextrine clathrate (containing the active ingredient in the form of α-cyclodextrine clathrate in the amount of 25% wt./wt.) difficult methyl ester (11α, 5α, 13E)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid (methyl ester of compounds of formula (IE)in saline, were injected subcutaneously in the back of each animal at a dose of 30 mg/5 ml/kg every 8 hours three times a day for 2 months. In the control group and group simulation, each animal was injected with saline. After completion of the experiment all animals were scored to perform the autopsy. Density selection left femur was determined using the equipment for the quantitative analysis of the distal bone density (XART-A, Norland/Stolatec Co.). The results are shown in the following Table.

Table 3
GroupBone density (mg/cm3) Is ± Art. from.
Group simulation404,1±87,0
The control group226,3±38,9###
Group of the compound(IE)according to the invention794,0±50,2***

###: p<0.001 profilgruppen simulation

***: p<0,001 versus the control group (both:T-test)

Discussion:

From Table 3 it is clear that the group of compounds according to the invention showed a significant increase in bone density compared with the control group (no injection).

[Toxicity]

The toxicity of the compounds of formula (IE) of the present invention is very low, so these compounds are safe for use as medicines. For example, the maximum tolerated dose of the compounds of formula (IE) i.v. in rats was 30 mg/kg of body weight or greater.

Industrial application

[Application for pharmacy]

Agonist EP4and used in the present invention has a stimulating osteogenesis effect, so it is applicable for the treatment and/or prevention of diseases associated with bone loss. In the present invention, the disease associated with loss of bone mass, means a disease that is observed in diseases associated with bone loss, followed by a decrease in bone density or degradation of bone tissue, etc. for Example, such diseases include:

1) primary osteoporosis (for example, age-related osteoporosis, primary postmenopausal osteoporosis, osteoporosis due to oophorectomy, etc.);

2) secondary osteoporosis (e.g. osteoporosis induced HL is cocorticoids; osteoporosis induced hyperthyroidism; osteoporosis induced immobility; osteoporosis, heparin-induced; osteoporosis-induced immunosuppression, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis due to Cushing's syndrome, rheumatoid osteoporosis etc.);

3) diseases such bones as metastatic bone, hypercalcemia, Paget's disease, bone loss (alveolar bone loss, depression of the bone, idiopathic bone loss in children and so on), osteonecrosis etc.

In addition, the present invention includes the acceleration of osteogenesis after operation in occasion of a bone (e.g., osteogenesis after bone fractures, bone formation after transplantation of bone, osteogenesis after operation in occasion of an artificial hip joint, osteogenesis after fusion and osteogenesis after other operations on bone regeneration and so on), enabling the treatment of bone and alternative treatment associated with transplantation of bone.

For the above purpose agonist EP4, its ester, its non-toxic salt or cyclodextrines the clathrate used in the present invention typically can be entered locally oral or parenteral administration. The conversion into the prodrug is used to reduce annoyed the e and to improve the absorptive capacity and stability, etc.

Dose that must be set depending on the age, weight, symptom, the desired therapeutic effect, the route of administration, duration of treatment, etc. For adult dosages person per dose are, in General, between 1 μg and 100 mg for oral administration up to several times a day, and between 0.1 μg and 10 mg, preferably between 0.2 mg and 5 mg, parenteral (preferably by introduction through the skin corresponding subcutaneous way or vein) up to several times a day.

As mentioned above, the dose that should be used depend on various conditions. Therefore, there are cases in which you can use dosage lower or greater than the ranges specified above.

Compounds according to the present invention can be introduced in the form of solid compositions, liquid compositions or other compositions for oral administration, or injections, skin ointments, patches or suppositories etc. for parenteral administration.

Solid compositions for oral administration include tablets, pills, capsules, powder for dispersion, granules, etc.

Capsules include hard capsules and soft capsules.

In such solid compositions one or more active compounds are mixed, with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metallosindikat magnesium.

The composition may also contain, in accordance with normal practice, additional substances, different from inert diluents: e.g. lubricating agents such as magnesium stearate, dezintegriruetsja tools such as calcium gluconates, and sporitelny funds for dissolution, such as glutamic acid, aspartic acid. Tablets or pills can be coated with film gastro - or Intercollege substances, such as sugar, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylcellulose etc. or to cover two or more films. Further, the coating can include a localized within capsules absorbent substances such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs, etc. In such liquid compositions contain one or more active compounds in inert diluent(s)commonly used in this field (e.g., purified water, ethyl alcohol). Besides inert diluents such compositions may also contain auxiliary substances such as wetting means, suspendresume tools, sweeteners, corrig the options fragrances and preservatives.

Other compositions for oral administration include compositions for spraying, which can be prepared with known methods and containing one or more active compounds. Composition for spraying may contain additional substances that differ from inert diluents: e.g. stabilizers, such as sodium hydrosulphate, stabilizers to maintain isotone, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For the preparation of such compositions for spraying, you can use the method described, for example, in U.S. patent No. 2868691 or 3095355.

Injections for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohol such as ethyl alcohol, POLYSORBATE (registered trademark), etc. Such compositions may also contain additional diluents: e.g. preserving agents, wetting means, emulsifiers, dispersing agents, stabilizers, auxiliary tools, such as tools for dissolution (e.g., glutamic what islote, asparginase acid). They can be sterilized, for example, by filtration through inhibiting bacteria filter, through the United sterilization AIDS in the compositions or irradiation. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile diluent for injection immediately prior to use.

Other compositions for parenteral administration include liquids for external use, ointments, liniments, plasters, suppositories, etc. that contain one or more active compounds and can be prepared with known methods.

Ointment aside from the basics, such as white petrolatum, may include means for adjustment of pH, surfactant, preservatives, emulsifiers, dispersing agents, stabilizers, auxiliary means for the dissolution etc.

The example 1 product form: lyophilized form

The generally accepted method the following components were mixed and sterilized solution accepted way; put portions of 1 ml in ampoules and liofilizirovanny accepted way to obtain 100 ampoules, where each contains 0.2 mg of the active ingredient.

- α-cyclodextrin complex methyl ester (11α, 15α, 13TH)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid 80 mg (active ingredient: 20 mg);

- mannitol 5 g;

- distilled water - 100 ml

Example 2, form: ointment

The generally accepted method the following components were mixed and placed 10 grams of the mixture in the test tube to get 100 tubes of ointment, where each contains 0.2 mg of active ingredient in 1 g of the mixture.

- α-cyclodextrin complex methyl ester (11α, 15α, 13TH)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid -800 mg (active ingredient: 200 mg);

white petrolatum 1 kg

1. The use of agonist of the receptor EP4for the treatment and/or prevention of diseases associated with bone loss.

2. The use according to claim 1, where the disease is associated with loss of bone mass is primary osteoporosis.

3. The use according to claim 2, where the primary osteoporosis is a senile osteoporosis, postmenopausal primary osteoporosis, osteoporosis due to oophorectomy.

4. The use according to claim 1, where the disease is associated with loss of bone mass, is a secondary osteoporosis.

5. The use according to claim 4, where secondary osteoporosis is a osteoporosis induced by glucocorticoids, osteoporosis induced hyperthyroidism, osteoporosis induced immobility, osteoporosis, heparin-induced osteoporosis, the Indus is qualified immunosuppression, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis due to Cushing's syndrome or rheumatoid osteoporosis.

6. The use according to claim 1, where the disease is associated with loss of bone mass, is a metastasis in bone, hypercalcemia, Paget's disease, bone loss, osteonecrosis.

7. The use according to claim 1 or 6, where diseases associated with bone loss, represent alveolar bone loss, depression of the bone, idiopathic bone loss in children.

8. The use according to claim 1, where the treatment of diseases associated with bone loss, represents the osteogenesis after bone fracture, a bone formation after transplantation of bone, osteogenesis after operation in occasion of an artificial hip joint, osteogenesis after spinal fusion, osteogenesis after bone regeneration and alternative transplantation bone treatment.

9. The use according to claim 1, where the agonist EP4is a compound having a skeleton of prostaglandin.

10. The use according to claim 9, where the compound having a skeleton of prostaglandin is a compound of formula (IA)

where R1Arepresents hydroxy, C1-4 alkyloxy, or NR6AR7Awhere each R6Aand R7Aindependently represents ogorodili C1-4 alkyl,

R2Arepresents hydrogen or hydroxy,

R3Arepresents:

(i) C1-8 alkyl, C2-8 alkenyl, or C2-8 quinil;

(ii) phenyl or C3-7 cycloalkyl;

(iii) C1-8 alkyl, C2-8 alkenyl or C2-8 quinil substituted by phenyl or C3-7 cycloalkyl (provided that, when R2Ais hydrogen, alkyl, alkenyl and quinil in (i) and (ii) can be substituted by one hydroxy, symbol-----means a double or a simple bond, provided that enabled his 8-paranoise connection), or its non-toxic salt or cyclodextrines the clathrate.

11. The use according to claim 9, where the compound having a skeleton of prostaglandin, is a compound of formula (IB)

where R1Brepresents hydroxy, C1-6 alkyloxy, or NR6VR7Bwhere each R6Vand R7Bindependently represents hydrogen or C1-6 alkyl,

R2Brepresents hydrogen or hydroxy,

R3Brepresents a simple bond or C1-6 alkylen,

R4Brepresents:

(i) C1-8 alkyl, C2-8 alkenyl or C2-8 quinil, substituted by one to three groups selected from C1-6 alkyloxy or halogen;

(ii) phenyloxy or C3-7 cycloalkane;

(iii) furyl, forelocks, thienyl, titilate, naphthyl, naphthas is lexi, talani or talonlike;

(iv) phenyl, phenyloxy, C3-7 cycloalkyl or C3-7 cycloalkane, substituted by one to three groups selected from the following groups:

C1-6 alkyl,

C2-6 alkenyl,

C2-6 quinil,

C1-6 alkyloxy,

C1-6 alkyloxy-C1-6 alkyl,

C1-6 alkyloxy-C1-6 alkyloxy,

C2-6 alkenylacyl-C1-6 alkyl,

C1-6 alkyl, substituted with one to three hydroxy,

C1-6 alkyl, substituted with one to three halogen atoms,

C1-6 alkylthio,

C1-6 alkylthio-C1-6 alkyl,

C1-6 alkylthio-C1-6 alkyloxy,

C2-6 alkanity-C1-6 alkyl,

C1-6 alkylsulfonyl,

halogen,

trihalomethyl,

cyano,

nitro,

amino,

hydroxy,

C3-7 cycloalkyl,

C3-7 cycloalkane,

C3-7 cycloalkyl-C1-6 alkyl,

C3-7 cycloalkane-C1-6 alkyl,

phenyl,

phenyloxy,

phenyl-C1-6 alkyl,

phenyl-C2-6 alkenyl,

phenyl-C2-6 quinil,

phenyloxy-C1-6 alkyl,

phenyloxy-C2-6 alkenyl,

phenyloxy-C2-6 quinil,

furyl,

forelocks,

furyl-C1-6 alkyl,

forelocks-C1-6 alkyl,

thienyl,

titilate,

thienyl-C1-6 alkyl or

titilate-C1-6 alkyl,

(the above-mentioned phenyl, uril, thienyl or cycloalkyl can be substituted one to three groups selected from C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxy-C1-6 alkyl, nitro, halogen, trihalomethyl, amino and hydroxy); or

(v) furyl, forelocks, thienyl, titilate, naphthyl, naphthyloxy, talani or palanisami, substituted by one to three groups selected from the following groups:

C1-6 alkyl,

C2-6 alkenyl,

C2-6 quinil,

C1-6 alkyloxy,

C1-6 alkyloxy-C1-6 alkyl,

C1-6 alkyloxy-C1-6 alkyloxy,

C2-6 alkenylacyl-C1-6 alkyl,

C1-6 alkyl, substituted with one to three hydroxy,

C1-6 alkyl, substituted with one to three halogen atoms,

C1-6 alkylthio,

C1-6 alkylthio-C1-6 alkyl,

C1-6 alkylthio-C1-6 alkyloxy,

C2-6 alkanity-C1-6 alkyl,

C1-6 alkylsulfonyl,

halogen,

trihalomethyl,

cyano,

nitro,

amino,

hydroxy,

C3-7 cycloalkyl,

C3-7 cycloalkane,

C3-7 cycloalkyl-C1-6 alkyl,

C3-7 cycloalkane-C1-6 alkyl,

phenyl,

phenyloxy,

phenyl-C1-6 alkyl,

phenyl-C2-6 alkenyl,

phenyl-C2-6 quinil,

phenyloxy-C1-6 alkyl,

phenyloxy-C2-6 alkenyl,

phenyloxy-C2-6 quinil,

furyl,

forelocks,

furyl-C1-6 alkyl,

forelocks-C1-6 alkyl,

thienyl,

titilate,

thienyl-C1-6 alkyl or

titilate-C1-6 alkyl

(the above-mentioned phenyl, furyl, thienyl or cycloalkyl can be substituted one to three groups selected from C1-6 alkyl, C1-6 alkyloxy, C1-6 alkyloxy-C1-6 alkyl, nitro, halogen, trihalomethyl, amino and hydroxy),

R5Vrepresents hydrogen or C1-6 alkyl,

the symbol-----represents a double or a simple link, (provided that when R2Bmeans hydrogen, C1-6 alkylene represented by R3Bmay be substituted by one hydroxy, and that included his 8-paranoise connection), or its non-toxic salt or cyclodextrines the clathrate.

12. The use according to claim 9, where the compound having a skeleton of prostaglandin, is a compound of formula (1C)

where R1Crepresents hydroxy, C1-6 alkyloxy or NR6CR7C(where R6Cand R7Cindependently represent hydrogen or C1-4 alkyl),

R2Crepresents oxo, halogen or O-COR8Cwhere R8Crepresents a C1-4 alkyl, phenyl or phenyl(C1-4 alkyl),

R3Crepresents hydrogen or hydroxy,

R4Caand R4Cbindependently represent is a hydrogen or C1-4 alkyl,

R5Crepresents phenyl, substituted by the following groups:

(i) one to three groups selected from the group

C1-4 alkyloxy-C1-4 alkyl,

C2-4 alkenylacyl-C1-4 alkyl,

C2-4 alkyloxy-C1-4 alkyl,

C3-7 cycloalkane-C1-4 alkyl,

C3-7 cycloalkyl(C1-4 alkyloxy)C1-4 alkyl,

phenyloxy-C1-4 alkyl,

phenyl-C1-4 alkyloxy-C 1-4 alkyl,

C1-4 alkylthio-C1-4 alkyl,

C2-4 alkanity-C1-4 alkyl,

C2-4 alkylthio-C1-4 alkyl,

C3-7 cycloalkyl-C1-4 alkyl,

C3-7 cycloalkyl(C1-4 alkylthio)C1-4 alkyl,

phenylthio-C1-4 alkyl or

phenyl-C1-4 alkylthio-C1-4 alkyl;

(ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,

C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,

C1-4 alkyloxy-C1-4 alkyl and hydroxy,

C1-4 alkyloxy-C1-4 alkyl and halogen,

C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,

C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,

C1-4 alkylthio-C1-4 alkyl and hydroxy, or

C1-4 alkylthio-C1-4 alkyl and halogen;

(iii) halogenation or hydroxy-C1-4 alkyl; or

(iv) C1-4 alkyl and hydroxy;

the symbol----means simple or double bond,

(provided that when R2Cmeans O-COR8Cthe relationship between atoms in positions 8 and 9 is a double), or toxicol salt or cyclodextrines the clathrate.

13. The use according to claim 9, where the compound having a skeleton of prostaglandin, means a compound of the formula (ID)

where aDrepresents a C2-8 alkylene, C2-8 albaniles, C1-4 alkaliphiles or C2-4 alkenylamine, R1Drepresents hydroxy, C1-6 alkyloxy, C1-6 alkyloxy-C1-6 alkyloxy, BUT-C1-6 alkyloxy or NR6DR7D(where R6Dand R7Dindependently represent hydrogen or C1-4 alkyl), R2Drepresents oxo, halogen, or R8D-COO- (where R8Drepresents hydrogen, C1-4 alkyl, phenyl, phenyl(C1-4 alkyl), C1-4 alkyloxy, noos-C1-4 alkyl, C1-4 alkylaminocarbonyl-C1-4 alkyl, noos-C2-4 alkenyl or C1-4 allyloxycarbonyl-C2-4 alkenyl),

R3Drepresents hydrogen or hydroxy,

R4Dis alkylen,

R5Drepresents phenyl, substituted by the following groups:

(i) one to three groups selected from the groups:

C1-4 alkyloxy-C1-4 alkyl,

C2-4 alkenylacyl-C1-4 alkyl,

C2-4 alkyloxy-C1-4 alkyl,

C3-7 cycloalkane-C1-4 alkyl,

C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,

phenyloxy-C1-4 alkyl,

phenyl-C1-4 alkyloxy-C1-4 alkyl,

C1-4 alkylthio-C1-4 alkyl,

C2-4 alkanity-C1-4 alkyl,

C2-4 alkylthio-C1-4 alkyl,

C3-7 cycloalkyl-C1-4 alkyl,

C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl,

phenylthio-C1-4 alkyl or

phenyl-C1-4 alkylthio-C1-4 alkyl;

(ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,

C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,

C1-4 alkyloxy-C1-4 alkyl and hydroxy,

C1-4 alkyloxy-C1-4 alkyl and halogen,

C1-4 alkylthio-C1-4 alkyl and C1-alnilam,

C1-4 alkylthio-C1-4 alkyl and C1-alkyloxy,

C1-4 alkylthio-C1-4 alkyl and hydroxy, or

C1-4 alkylthio-C1-4 alkyl and halogen;

(iii) halogen-C1-4 alkyl or hydroxy-C1-4 alkyl, or

(iv) With 1-4 alkyl and hydroxy;

the symbol----means simple or double bond,

(provided that when R2Dcorresponds to the formula R8D-COO-, R1Drepresents a C1-6 alkyloxy, C1-6 alkyloxy-C1-6 alkyloxy or BUT-C1-6 alkyloxy, the relationship between atoms in positions 8 and 9 is a double bond), or its non-toxic salt or cyclodextrines the clathrate.

14. The use according to claim 9, where the agonist EP4represents (11α,15α,13TH)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-envoy acid,

(11α,15α,13E)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)

-17,18,19,20-tetranor-3,7-citeproc-13-envoy acid, (9β, 11α, 15α, 5Z,13E)-9-chloro-of 11.15-dihydroxy-16-(3-ethoxymethylene)-17,18,19,20-tetranitro-5,13-diene acid,

(11α,15α,13E)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranitro-13-envoy acid or (11α, 15α, 5Z, 13E)-9-oxo-of 11.15-dihydroxy-16-(3-ethoxymethylene)-17,18,19,20-tetranitro-5,13-diene acid or non-toxic salts, methyl ester or α-cyclodextrine clathrates.

15. The use of the compounds of formula (I)

(11α, 15α, 13E)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid or its non-toxic salts, complex methyl ester or α-cyclodextrine clathrate for the preparation of a medicinal product for the prevention and/or treatment of diseases associated with bone loss.

16. Application α-cyclodextrine clathrate methyl ester (11α, 15α, 13E)-9-oxo-of 11.15-dihydroxy-16-(3-methoxymethyl)-17,18,19,20-tetranor-5-tiaprost-13-ene acid for the preparation of a medicinal product for the prevention and/or treatment of diseases associated with bone loss.

Priority items:

24.11.1999 according to claims 1-8, 10-16;

22.11.2000 according to claim 9.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: on should apply the suggested compound of formula 1 for treating and/or preventing osteoporosis and related osseous diseases.

EFFECT: higher efficiency of therapy and prophylaxis.

7 cl, 2 dwg, 21 ex, 6 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

FIELD: medicine, therapy.

SUBSTANCE: simultaneously for 20 d one should prescribe calcium D3 two times daily in the morning and in the evening per 1 tablet or Beresh Plus drops. The quantity of drops for daily intake is equal to patients body weight in kg and they should be introduced in three stages during meals by drinking them up with sufficient amount of water. Application of the suggested method optimizes calcium exchange in patients with osteoporosis, enables to achieve earlier and more stable results in normalization of calcium content in bones by preventing, thus, osteoporotic fractures.

EFFECT: higher efficiency of pharmacological correction.

1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to the stimulation of osteogenesis and may find application in experimental medicine and veterinary

The invention relates to the field of biotechnology, specifically to obtain protein/factor inhibiting osteoclastogenesis (OCIF), and can be used for treatment and immunological diagnosis of diseases involving bone resorption

FIELD: pharmaceutical chemistry.

SUBSTANCE: pharmaceutical composition comprises efficient amount of lipophilic medicament in combination with pharmaceutical carrier. The latter consists of propylene glycol esters of C6-C18-fatty acid with 90 wt % monoester and nonionic surfactant, whose hydrophilic/lipophilic balance exceeds 10 and is suitable to solubilize lipophilic medicament. Above-mentioned surfactant is present in amount high enough to form microemulsion with ester and medicament when in contact with aqueous medium. Preferably medicament is cyclosporine.

EFFECT: increased stability of composition to provide desired pharmacokinetics and biological accessibility of lipophilic drugs essentially non soluble in water.

34 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention relates to a method for treatment of pathology or disorder taken among inflammatory diseases. Method involves using the simultaneous, separating or distributed by time at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2. Also, invention relates to the composition comprising at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2 for using in the method for treatment of pathology or disorder taken among inflammatory diseases.

EFFECT: improved method for treatment.

21 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of HIV-infection in humans that comprises effective amount of β-D-D4FC or its pharmaceutically acceptable salts or a prodrug being optionally in a pharmaceutically acceptable carrier in combination with effective amount of compound being optionally in pharmaceutically acceptable carrier that is taken among the group consisting of indinavir, nelfinavir, saquinavir, amprenavir, efaverenza, delavirdin, nevirapin and abacavir as a single preparation and to a method for treatment or prophylaxis of HIV-infection in humans that involves administration of effective amount of this composition. Pharmaceutical composition elicits the preferred or improved pharmacokinetic parameters, parameters of biological distribution, metabolic parameters, parameters of resistance and other parameters as compared with administration of β-D-D4FC only.

EFFECT: improved method for treatment and prophylaxis, valuable properties of composition.

17 cl, 6 tbl, 2 dwg

FIELD: pharmacology and pharmacotherapy.

SUBSTANCE: invention resides in use of activated form of drug in low and ultralow dose, which activated form is obtained by way of multiple consecutive dilution and external action according to homeopathic technology, as agent for potentiation of therapeutical effects of the same drug used in therapeutical dose.

EFFECT: enhanced therapeutical effects of drug.

16 ex

FIELD: pharmacology and pharmacotherapy.

SUBSTANCE: invention resides in that therapeutic dose of drug is supplemented by activated form of the same substance obtained by way of multiple consecutive dilution and external action according to homeopathic technology, in low and ultralow dose, preferably at volume ratio from 1:1 to 1:1000.

EFFECT: enhanced specific effects of drug.

7 tbl, 16 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention relates to application of NO-releasing non-steroid antiinflammation agent as wall as pharmaceutically acceptable salt or enantiomer thereof for production of drug useful in treating of disorders associates or mediated with Helicobacter pylory; pharmaceutical composition for treating of bacterial infections, including NO-releasing non-steroid antiinflammation agent as main ingredient; and similar composition including additionally inhibitor of acid-sensitive proton pump.

EFFECT: effective agents and pharmaceutical compositions for treating of bacterial infections.

19 cl, 4 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with enhancing circulation and trophicoregenerative processes. The suggested curative-prophylactic balsam includes fresh-water sulfide-free average-ash sapropel mud of Kirek Lake, turpentine oil (oleoresin turpentine), peroxide, anionic SAS, starch taken at a certain quantitative ratio. The suggested balsam enables to efficiently enhance circulation and trophicoregenerative processes.

EFFECT: higher efficiency of application.

3 ex, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for oral administration in treatment or prophylaxis of obesity or hyperlipidemia. The composition comprises orlistat and at least one ester of fatty acids and polyols. Melting point of fatty acid ester exceeds the body temperature and polyol is taken among group including glycerol, sugars, derivatives of sugars and their mixtures. Also, invention relates to a method for preparing above described composition and to a method for treatment or prophylaxis of obesity. Invention enhances effectiveness and activity of orlistat by reducing variability of effectiveness and/or activity of orlistat between patients and frequency and severity of adverse effects.

EFFECT: improved and valuable pharmaceutical properties of compositions.

24 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 1-ethanolamide PGF of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.

EFFECT: new effective compound for relaxation of mammalian intraocular pressure.

4 cl, 1 ex, 16 dwg, 16 tbl

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