Compounds, their using for treatment of disorder in portal and hepatic venous circulation

FIELD: organic chemistry, steroids, medicine.

SUBSTANCE: invention describes compounds or their salts of the general formula (I): wherein values C are disclosed in the invention description. These compounds can be used in preparing medicinal agents used in treatment of acute disorders in portal and hepatic venous circulation.

EFFECT: valuable medicinal properties of compounds.

4 cl, 1 tbl, 2 ex

 

The present invention relates to the use of drugs for the treatment of acute disorders of the hepatic and portal venous circulation or hemodynamic decompensation.

More specifically, the present invention relates to the use of drugs for the treatment of acute diseases of the hepato-portal tract, but not for the treatment of chronic liver diseases such as cirrhosis of the liver.

Disorders of the hepatic and portal venous circulation are characterized by increased intrahepatic flow resistance, or increase the flow of the portal vein due to obstacles vessel or clusters, usually caused by liver disease. Acute treatment is aimed only at reducing the increase in portal pressure, whereas chronic treatment, which begins at an early stage of the disease, is the goal simply to limit the progress of the specified diseases. The present invention relates to the treatment, can reduce portal pressure in acute stage. It is known that if the portal blood flow will not return to the physiological values, this can have serious clinical consequences for the patient, such as:

- development of portosystemic collateral circulation (the gastroesophageal varices);

direct shunting of portal blood in the Vena cava (the PE nocna encephalopathy);

- congestion of the internal organs of the abdominal cavity (malabsorption) and spleen (hypersplenism with thrombocytopenia);

- ascites.

Also in the case of chronic liver diseases such as cirrhosis, hepatitis, cancer, they worsen the portal pressure. In developed countries, cirrhosis of the liver is the most common cause of portal hypertension, although schistosomiasis is prevalent in some tropical and subtropical climates.

Other factors that may be involved in the emergence of these disorders may be associated with liver damage from alcohol, congenital hepatic fibrosis, drug poisoning, autoimmune diseases.

Acute bleeding from esophageal varices (usually from the periphery of Asiago, less often from gastric bubble and rarely from other sites) is the most common clinical picture of these disorders hepatic or portal venous circulation. Usually, patients have sudden painless upper gastrointestinal hemorrhage, often abundant. Acute bleeding is a very serious phenomenon that should be treated to eliminate the consequences, also fatal for the patient.

Pharmacological therapy for acute treatment of variceal bleeding is the use of medicinal environments the TV, able to reduce portal pressure. Can be used vasopressin, somatostatin and its analogues. However, vasopressin has side effects, such as mesenteric and myocardial ischemia. In General, the effectiveness of these drugs for the treatment of acute bleeding has not been established.

For this reason, pharmacological therapy, commonly used for the specified treatment at the acute stage, includes β-blockers, such as propranolol, nadolol, timolol, etc., These drugs can be administered alone or in combination with Mononitrate isosorbide.

β-Blockers active for the reduction of portal flow resistance, but show the following disadvantages:

they have side effects on the cardiovascular and respiratory systems. For this reason, they cannot be administered in patients with cardiovascular disease, asthma, COPD (chronic obstructive pulmonary disease) and so on,

- some patients were observed intolerance to these drugs, developing pulmonary and bronchial wheezing, shortness of breath and cardiopathy, fatigue, gastrointestinal intolerance, and hepatic encephalopathy.

For acute treatment of disturbances of the hepatic and portal venous circulation has also been used as vasodilator agents, such as, for example, the R, Mononitrate isosorbide. However, their systemic vasodilator action could not well tolerated by patients suffering from portal hypertension, in which they can cause a decrease in system pressure.

Because of the side effects shown above drugs for acute treatment of varices was used surgical techniques, such as endoscopic treatment with prophylactic sclerosis of esophageal varices, transparence intrahepatic portal-systemic shunt or surgical bypass.

Thus, the aim of the present invention is the provision of medicines, is effective for the acute treatment of disturbances of the hepatic and portal venous circulation, with an improved activity and tolerability. The treatment used for chronic stage liver disease, did not anticipate the treatment of the acute phase, in which drugs used in the chronic stage, act only in the treatment of liver diseases. As a drug commonly used to treat chronic stage may be referred to ursodesoxycholic acid (UDCA) and interferon.

Accordingly, the present invention relates to the use for acute treatment of disturbances of the hepatic or portal venous blood and joints, having the following formula (I)

where:

- the relationship between a hydroxyl group and a carbon atom in the 7 position is αor β-the position where the specified communication is β-position of the steroid structure figure (I) corresponds to ursodesoxycholic acid precipitate, whereas when the above relationship is α-position of the steroid structure corresponds chenodesoxycholic acid residue;

- =- TC-Y-, where Twithis-O-, - S-, - N(R1), R1Cmeans N

- C1-C5linear or branched alkyl;

- Y is selected from Y0:

- Y0selected from accelerometry-R O, in which R' represents a linear or

branched alkyl:

;

where nf' denotes an integer from 1 to 6,

where R1f=H, CH3and nf' defined above;

YArselected:

where n3 represents an integer from 0 to 3, and n3' denotes an integer from 1 to 3;

where n3 and n3' is defined above.

The predecessors of Y having the formula (IIIR), in which the free valency on the oxygen atom is H and the free valence is here on the end carbon atom has a carboxyl or auxiliarily group, are commercially available, or they can be obtained by methods known in the art.

Compounds according to the present invention, in which there is at least one functional group that can form a salt with an acid, such as amino group, can be converted into the corresponding salt. For example, the method of obtaining salts is as follows: when the molecule is present a basic nitrogen atom, the reaction with equimolar amount of the corresponding organic or inorganic acid is carried out in an organic solvent, such as acetonitrile, Petraitiene. Examples of the organic acid is oxalic, tartaric, maleic, succinic, citric and triperoxonane acid.

Examples of inorganic acids are nitric, hydrochloric, sulphuric and phosphoric acid.

Compounds that are used for therapeutic use according to the present invention can be obtained, as described, for example, in WO 00/61604.

When used in the present invention the connection predecessors have one or more chiral centers, they can be in racemate form or a mixture of diastereomers, as individual enantiomers or diastereomers, If there is asymmetric geometric center, the connection can use the change in the CIS - or TRANS-form.

Connection objects of the present invention are formulated in the corresponding pharmaceutical compositions, in the form of long-term release for parenteral or oral administration, for example, sublingual, inhalation, transdermal, suppository or enema, according to methods known in the prior art: see, for example, "Remington''s Pharmaceutical Sciences" 15th edition.

The molar amount of the active ingredient in these compositions is usually equal to or below the number corresponding predecessor medicines.

Daily injected dose equal to or lower doses of precursor drugs. A daily dose of the precursor can be detected, for example, in "Physician''s Desk Reference".

When present in the formula (I)in which b0=1, the preferred compounds for use according to the present invention are compounds, which is the predecessor of ferulic acid, the most preferred compound is 2-metoxy-4[3-[4-(nitroxy)butoxy]-3-oxo-1-propenyl]phenyl ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid having the following formula:

Code b0=0 in the formula (I), a preferred group Y has Y0type, especially alkylenes group, R O, R' represents a Csub> 3-C6alkyl. A specific preferred compound is 4-(nitroxy)butyl ether (3α,5β,7β)-3, 7-dihydroxyfuran-24-oewoi acid of the following formula:

Drugs of the present invention, used for acute treatment of hepatic and portal hemodynamic decompensation, have surprisingly and unexpectedly good results to reduce moral pressure. In fact, the precursor compounds according to the invention, such as, for example, ursodesoxycholic acid, are effective for chronic treatment of hepatic diseases, but not to reduce portal pressure after acute treatment. In the prior art was never described the use of compounds according to the invention for the treatment of acute phase hepatic diseases, when there is a high portal pressure. In fact, in the case of States with high portal pressure, for example, 500% relative to normal values, caused by treatment norepinephrine, the compounds according to the invention is able to reduce portal pressure without affecting systemic hemodynamic parameters. In contrast to the treatment in the chronic phase of acute treatment introduction compounds according to the invention is carried out within a very short cycles, usually a few days, he is e more during the week, whereas chronic treatment introduction is carried out for long periods of time, and at least eight weeks, sometimes months, at which develops cirrhosis of the liver. Therefore it is not anticipated that short-term treatment might be able to show such a high activity for reduction of portal pressure treatment at the acute stage.

The following examples illustrate, but not limit the invention.

EXAMPLES

EXAMPLE 1

Effect of ursodesoxycholic acid and 2-methoxy-4[3-[4-(nitroxy)butoxy|-3-oxo-1-propenyl]phenyl ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid in experimental models of human liver and portal venous circulation caused by legirovaniem bile ducts and subsequent treatment with norepinephrine.

Used here nitroacetophenone ursodesoxycholic acid (NO-Urso), obtained as described in Example 1 of WO 00/61,604.

Twenty-one Wistar rat were divided into three groups of 7 animals each, and then ligated bile ducts.

Within three weeks after ligation, animals were left. As a result of ligation of the bile duct animals developed hepatic dysfunction and portal venous circulation. At the end of the third week each group was subjected to the next weekly treatment:

Group 1:control group, the treated media (1% weight/about water suspension of carboxymethylcellulose):

Group 2: treated NO-Urso at a dose of 28 mg/kg (0.04 mmol/kg), twice a day:

Group 3: treated ursodesoxycholic acid (table Urso) at a dose of 15 mg/kg (0.04 mmol/kg), twice a day.

The remaining compounds were administered via intragastric cannula in 1% aqueous suspension of carboxymethylcellulose.

At the end of treatment (fourth week) animals were obezbolivatmi of urethane and then checked the system pressure (IDA) and portal pressure (PP) catheterization of the carotid artery and the portal vein. The liver of the animal is then continuously washed with Krebs solution (40 ml/minute), balanced O2/CO2(95%-5%), using a peristalsis pump (Gilson).

Therefore evaluated the pharmacological effects of both tested compounds.

The liver of the rat is then watered with a solution of norepinephrine (1 μm) to stimulate compression intrahepatic circulation. Then in groups 2 and 3 was carried out by a separate infusion of 1 mm solution of each of the test compounds was examined changes in portal pressure.

Obtained results show that the treatment of NO-Urso or ursodesoxycholic acid does not affect systemic hemodynamic parameters, i.e. the system pressure, heart, and liver is ibros, what assessed by immunocytochemical method.

Presented in Table 1 data show that NO-Urso reduces intrahepatic resistance caused by the compression of the bile ducts and norepinephrine (NE). In fact, the introduction of NO-Urso unlike the introduction of ursodesoxycholic acid can reduce intrahepatic resistance in animals that have a high intrahepatic resistance and/or marked liver changes.

After a week of treatment caused a reduction in portal pressure at a speed of reperfusion 40 ml/minute NO-Urso 3 MND. Rats treated with Urso, showed instead an increase of 2 MND relative to control. The reduction in portal pressure induced by reperfusion NO-Urso, led to the statistical values (p<0.01).

Increase intrahepatic resistance caused by norepinephrine were significantly decreased NO-Urso, but not ursodesoxycholic acid. In fact, a 500% increase intrahepatic vascular resistance determined by the NE infusion dose of 1 μm significantly decreased the processing of NO-Urso (p<0,001), but not ursodesoxycholic acid. This result together with the observation that acute treatment NO-Urso no effect on hepatic fibrosis, confirms that NO-Urso effect in this experimental model the dynamic component (pressure from the Ude) increase in intrahepatic resistance. The comparison of the obtained data proves the effectiveness of NO-Urso in acute treatment of hemodynamic decompensation hepato-portal tract.

EXAMPLE 2

Getting 4-(nitroxy)butyl ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid (IB)

ACID (IB)

a) Synthesis of 4-bromatologia ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid

Ursodesoxycholic acid (0.5 g) was subjected to reaction with ethyl sodium (0.09 g) in DMF, to obtain the corresponding sodium salt. This solution was added dropwise into a solution of 1,4-dibromobutane (0.263 g) in DMF. The thus obtained mixture was left overnight under stirring at room temperature. The mixture was then extracted with ethyl acetate/water 2:1, the collected organic phase was dried, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel with n-hexane/ethyl acetate 1:9 as eluent, receiving 0.1 g of 4-bromatologia ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid.

1H-NMR (CDCl3ppm): 4.12 (2H, t); 3.62 (2H, m): 3.45 (2H, t), 2.3 (2H, m); 1.98-0.96 (36N, m): 0.69 3H, s).

b) Synthesis of 4-(nitroxy)butyl ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid.

To a solution of 4-bromatologia ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid (0.1 g) in acetonitrile (20 ml) under stirring was added the itrat silver (0066 g) and the mixture was heated for 6 hours under stirring at 80° C. At the end of the reaction, the precipitate was filtered, and the solvent was removed. The crude product was purified by chromatography on silica gel with methylene chloride/ethyl acetate 3/7 as eluent, receiving 50 mg of the desired compound.

1NMR (CDCl3, ppm); 4.3 (2H, m); 4.12 (2H, t); 3.45 (2H, 1); 2.3 (2H, m): 1.98-0.96 (36N, m): 0.69 (3H, s).

Table 1
Portal pressureSystemic hemodynamic parameters
After a week of treatment (MND)% Increase after infusion of NESystem pressure (MAP)Palpitations
Control1750092±3.3358±38
NO-Urso14*18099.6±8.4400±27
Urso1940095±12372±41
P<0.01 compared to control

Method: Normal rats were treated tematicheskie compound from example 2 (28 mg/Kg) nitroglycerin (NTG) (0.15 mg/Kg) for 5 days. After pre-compression intrahepatic vascular system response to normal disturbance caused connection is receiving according to the invention (1 mM) and NTG (0.3 mM), was studied using in situ system reperfusion of rat liver.

Results: In isolated perfuse hepatic system at constant flow 20 ml/min was not observed any difference mainly perfusion pressure between groups. The introduction of norepinephrine (NE) caused an increase intrahepatic counter depending on the input doses. Portal violation caused 0.3-30 mM of norepinephrine, was reduced by 50% in animals treated with compound 2 (p less than 0.05, n=5) without noticeable effect on blood pressure and heart of rats. The same effect of weakening the portal violations was obtained after treatment of NTG, but there was a significant systemic effects.

The compound of the present invention reduces intrahepatic opposition caused NE, no effect on systematic intrahepatic parameters, i.e. on the system pressure and heart of rats, thereby tested the compound causes a decrease in portal pressure.

1. The compound or its salt having the following formula (I):

where the bond between a hydroxyl group and a carbon atom in the 7 position is αor β-the position where the specified communication is β-position of the steroid structure figure (I) corresponds to ursodeoxycholic acids is th residue, whereas when the above relationship is α-position of the steroid structure corresponds chenodesoxycholic acid residue;

C=-TWith-Y-, where Twithis-O-, -S -, -N(R1c), R1cmeans N

C1-C5 linear or branched alkyl;

Y is selected from Yo:

Yo selected from alkylene group - R O, where R' represents a linear or branched alkyl

;

where nf denotes an integer from 1 to 6;

;;

where R1f=H, CH3and nf' defined above;

or YArselected from

where n3 represents an integer from 0 to 3, and n3' denotes an integer from 1 to 3:

where n3 and n3' is defined above.

2. The compound of formula (I) according to claim 1 of the formula where Y=Uo is alkylene-R O-, R' is alkoxy and contains from 3 to 6 carbon atoms.

3. The compound of formula (I), a 4-(nitroxy)butyl ether (3α,5β,7β)was 3.7-dihydroxyfuran-24-oewoi acid formula

4. The use of the compounds of formula (I) or its salt according to claims 1 to 3 formulas to get drug among the STW for treatment of disturbances of the hepatic and portal venous circulation.



 

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2 tbl, 4 ex

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1 tbl, 1 ex

FIELD: medicine, gastroenterology, medicinal biochemistry.

SUBSTANCE: invention relates to a method for treatment and choice of a pharmaceutical preparation used in treatment of diseases caused and accompanying with disturbance in metabolism of bile acids and cholesterol. Method involves determination of the quantitative composition of short-chain fatty acids of (C2-C4)-fraction in blood serum and feces. Method involves using preparations containing fatty acids and promoting fro dissolving cholesterol bile stones in case when the content of propionic acid is decreased from 5.6% and increasing the content of butyric acid from 3.5%, and in increasing propionic acid from 19.9% to 21.8% and butyric acid from 18.9% to 20.1% in feces. Method involves administration of preparations effecting on activity of intestine anaerobic microorganisms in case when the content of propionic acid is decreased from 5.7% to 6.5% and the content of butyric acid is increased from 2.9% to 3.4% in blood serum, and when the content of propionic acid is increased from 21.8% and that of butyric acid from 20.1% in feces. Method involves the combination of preparations containing fatty acids and promoting to dissolving cholesterol bile stones and preparations effecting on activity intestine anaerobic microorganisms when the content of propionic acid is decreased from 5.6% and less and the content of butyric acid is increased from 3.5% and above. Proposed method provides possibility for differentiating treatment based on assay of leading ethiopathogenetic mechanisms in development of choledocholithiasis.

EFFECT: improved and enhanced method of treatment.

2 tbl, 3 ex

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