阅读说明：本技术 化合物在制备治疗肝纤维药物中的用途 (Application of compound in preparation of medicine for treating hepatic fibrosis ) 是由 杜亚楠 尤志峰 周律 于 2020-05-22 设计创作，主要内容包括：本发明提出了化合物在制备药物中的用途,所述药物用于治疗肝纤维化,所述化合物为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药。本发明的化合物能够高效地治疗肝纤维化疾病,具有良好的吸收性、较高的生物活性和利用度,溶解性高,低毒,尤其是在体内具有较强的稳定性,不易分解,药效时间长,从而起到治疗肝纤维化的效果,应用前景好。<Image he="458" wi="700" file="DDA0002504350390000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides application of a compound in preparing a medicament for treating hepatic fibrosis, wherein the compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I). The compound of the invention can effectively treat hepatic fibrosis diseases, has good absorbability, higher bioactivity and utilization degree, high solubility and low toxicity, particularly has stronger stability in vivo, is not easy to decompose, has long drug effect time, thus playing a role in treating hepatic fibrosis and having good application prospect.)

1. Use of a compound for the preparation of a medicament for the treatment of liver fibrosis,

the compound is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I);

2. use according to claim 1, wherein the compound is suitable for inhibiting collagen fibre precipitation in liver tissue.

3. Use according to claim 1, wherein the compound is suitable for reducing the expression of the fibrosis marker genes col1a1 and Acta 2.

4. Use according to claim 1, characterized in that said compound is suitable for inhibiting the activation of hepatic stellate cells.

5. The use according to claim 1, wherein the medicament is administered in a dose of 100 to 150mg/kg body weight of the human.

6. Use according to claim 1, wherein the medicament is for the treatment of periportal fibrosis, bridging liver fibrosis or cirrhosis.

7. A pharmaceutical composition for treating liver fibrosis, comprising:

a compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound represented by formula (I); and

pharmaceutically acceptable adjuvants, carriers, excipients, vehicles or combinations thereof;

8. a pharmaceutical combination for the treatment of liver fibrosis, comprising:

a compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound represented by formula (I);

at least one drug for treating liver fibers;

Technical Field

The present invention relates to the field of medicine. In particular, the invention relates to application of a compound in preparing a medicament for treating hepatic fibrosis.

Background

Hepatic fibrosis is the result of the callus reaction of liver to treat various persistent injury factors, and the main characteristics include: activation of hepatic stellate cells, hepatic sinus endothelial cell vascularization, collagen deposition, and the like. In recent years, liver fibrosis and liver fibrosis-related diseases such as cirrhosis and liver cancer have become increasingly harmful and have become a serious life safety threatening disease category for humans. About 8 million people worldwide are reported to suffer from liver diseases, and the number of people suffering from liver diseases in our country is as high as 3 million. In developed countries, nearly 45% of human deaths are associated with fibrotic diseases. If liver fibrosis is not treated, at least 33% of patients turn to cirrhosis within 20 years, and once cirrhosis has developed ascites symptoms, 50% of them die within 2 years.

Modern biology and medicine development, liver fibrosis pathogenesis and molecular signal change are clearer, but at present, no effective treatment measures are available for treating hepatic fibrosis except for removing fundamental pathogenic factors (such as hepatitis B and hepatitis C virus), and at present, FDA (food and drug administration) does not approve medicines and treatments for hepatic fibrosis, so that research and development of medicines for hepatic fibrosis are one of hot spots in basic research fields and pharmaceutical fields at present.

Therefore, the current drugs for treating hepatic fibrosis still remain to be studied.

Disclosure of Invention

The present invention aims to solve at least to some extent at least one of the technical problems of the prior art. Therefore, the invention provides the application of the compound in preparing the medicine, the medicine composition or the medicine combination for treating hepatic fibrosis, the medicine composition or the medicine combination can effectively treat hepatic fibrosis diseases, and has good absorbability, higher bioactivity and utilization degree, high solubility, low toxicity, stronger stability in vivo, difficult decomposition and long drug effect time, thereby having the effect of treating hepatic fibrosis and good application prospect.

In one aspect of the invention, the invention features the use of a compound in the manufacture of a medicament. According to an embodiment of the invention, the medicament is for the treatment of liver fibrosis, the compound is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound of formula (I);

the inventor finds that the effect of the same compound on different types of fibrotic diseases (such as pulmonary fibrosis, skin fibrosis or hepatic fibrosis) is different from each other through high-throughput screening and in vivo verification of thousands of compounds, and that the curative effect of some compounds on pulmonary fibrosis is good, but the curative effect on hepatic fibrosis is rather poor, for example, Pomalidomide is reported to be used for treating skin fibrosis (Ann Rheum Dis 2012; 71: 1895-1899), but cannot be used for treating hepatic fibrosis due to liver injury (Lancet.2014; 383: 2125-2126). Finally, the compound is found to be capable of effectively treating hepatic fibrosis diseases, has good absorbability, higher bioactivity and utilization degree, high solubility and low toxicity, particularly has stronger stability in vivo, is not easy to decompose, has long drug effect time, thus playing a role in treating hepatic fibrosis and having good application prospect.

According to an embodiment of the invention, the use of the above-mentioned compounds for the preparation of a medicament may also have the following additional technical features:

according to an embodiment of the invention, the compound is adapted to inhibit collagen fibre precipitation in liver tissue.

According to embodiments of the present invention, the compounds are suitable for reducing the expression level of fibrosis marker genes col1a1 and Acta 2.

According to an embodiment of the invention, the compound is suitable for inhibiting the activation of Hepatic stellate cells (hepatostellatecells).

According to the embodiment of the invention, the administration dose of the medicine is 100-150 mg/kg of human body weight. Under the administration dosage, the purpose of treating hepatic fibrosis can be effectively achieved.

According to an embodiment of the invention, the medicament is for the treatment of periportal fibrosis, bridging liver fibrosis or cirrhosis. For patients with hepatic fibrosis, the liver fibrosis is divided into different stages according to the progression of the disease, and the different stages show different characteristics. From the aspect of anatomical pathology, hepatic fibrosis can be divided into four stages, wherein hepatic fibrosis does not exist in stage F0, portal perivenous fibrosis appears in stage F2, hepatic fibrosis is bridged in stage F3, and hepatic cirrhosis is in stage F4. The inventor finds that the compound can effectively treat hepatic fibrosis of stages F2-F4.

In yet another aspect of the present invention, the present invention provides a pharmaceutical composition for treating liver fibrosis. According to an embodiment of the invention, the pharmaceutical composition comprises: a compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound represented by formula (I); and pharmaceutically acceptable adjuvants, carriers, excipients, solvents or their combination. Therefore, the pharmaceutical composition provided by the embodiment of the invention can be used for efficiently treating hepatic fibrosis diseases, has the advantages of good absorbability, high bioactivity and availability, high solubility, low toxicity, strong stability in vivo, difficulty in decomposition and long drug effect time, and has a good application prospect.

In a further aspect of the invention, the invention proposes a pharmaceutical combination for the treatment of liver fibrosis. According to an embodiment of the invention, the pharmaceutical combination comprises: a compound which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound represented by formula (I); at least one drug for the treatment of liver fibers. Therefore, the medicine combination provided by the embodiment of the invention can be used for effectively treating hepatic fibrosis diseases, has the advantages of good absorbability, high bioactivity and availability, high solubility, low toxicity, strong stability in vivo, difficulty in decomposition and long drug effect time, and has a good application prospect.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

FIG. 1 shows a schematic flow chart of an early stage mouse liver fibrosis animal model induction and treatment scheme according to an embodiment of the present invention;

FIG. 2 shows a schematic flow chart of an animal model induction and treatment scheme of late stage mouse liver fibrosis according to an embodiment of the present invention;

FIG. 3 shows a schematic representation of histological staining identification of early stage liver fibrosis mice according to one embodiment of the present invention;

FIG. 4 is a schematic diagram showing the therapeutic effect of detecting REPSOX on early stage liver fibrosis according to the expression of a liver fibrosis marker gene in one embodiment of the present invention;

FIG. 5 is a schematic diagram showing the effect of detecting the activation of astrocytes and collagen deposition in early stage liver fibrosis mice according to an immunofluorescence assay in an embodiment of the present invention;

FIG. 6 shows a schematic representation of histological staining identification of advanced liver fibrosis mice according to one embodiment of the present invention;

FIG. 7 is a schematic diagram showing the therapeutic effect of detecting REPSOX on advanced liver fibrosis according to the expression of a liver fibrosis marker gene in one embodiment of the present invention;

FIG. 8 is a schematic diagram showing the effect of detecting the activation of astrocytes and the deposition of collagen in mice with advanced liver fibrosis by immunofluorescence assay according to an embodiment of the present invention.

Detailed Description

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

Definitions or general terms

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of AsymmetricSynthesis (2nd Ed. Robert E. Gawley, Jeffrey Aub é, Elsevier, Oxford, UK, 2012); eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); wilen, s.h. tablet of Resolving Agents and Optical Resolutions p.268(e.l.eliel, ed., univ.of notreddame Press, Notre Dame, IN 1972); chiral Separation Techniques: A practical apparatus (Subramanian, G.Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. Another example of tautomerism is phenol-ketone tautomerism. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in e.w. martin, "Remington's pharmaceutical sciences".

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

"isomers" are different compounds having the same molecular formula. "stereoisomers" are isomers that differ only in the spatial arrangement of the atoms. The term "isomer" as used herein includes any and all geometric isomers and stereoisomers.

The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which further comprises water bonded by non-covalent intermolecular forces in a chemical amount or in a non-chemical equivalent amount, and may be said to be an association of solvent molecules with water.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The term "prodrug", as used herein, means a compound that is converted in vivo to the compound shown in the present invention. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Permons Press,1987, J.Rautio et al, Prodrugs: Design and clinical applications, Nature Review Drug Discovery,2008,7,255 and 270, and S.J.Herr et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51, 2328 and 5.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" means those salt forms that are readily apparent to the pharmaceutical chemist as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and, as a result, flowability of the drug substance. Briefly, the pharmaceutical composition can be prepared by combining the active ingredient with a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate and the like, and salts of organic acids such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, mandelate, methanesulfonate, ethanesulfonate, toluenesulfonate, sulfosalicylate and the like, or obtained by other methods described in the literature such as ion exchange.

Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionic acid, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, picrates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, glucarates, half sulfates, heptanates, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include alkali metals, alkaline earth metals, ammonium, and the like.

The invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound shown in formula (I) or pharmaceutically acceptable stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable auxiliary materials, carriers, excipients, menstruum or combinations thereof. When the compound of the present invention is administered in the form of a medicament to a mammal such as a human, it may be administered in the form of the compound itself or may be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier.

The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions or carriers suitable for administration of the compounds of the invention to a mammal. The carrier comprises a liquid or solid filler, diluent, excipient, solvent or encapsulating material which is involved in carrying the host substance or transferring it from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible materials used in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Pharmaceutical compositions of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.

"combination" means a fixed combination or a kit of parts for combined administration in the form of a single dosage unit, wherein a compound disclosed herein and a combination partner (agent for the treatment of hepatic fibers) may be administered separately at the same time or may be administered separately at certain time intervals, in particular such that the combination partners exhibit a cooperative, e.g. synergistic, effect. The term "pharmaceutical composition" as used herein means a product resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the disclosed compounds and combination partners, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds disclosed in this invention and the combination partners, are both administered to the patient as separate entities simultaneously, jointly or sequentially with no specific time limitation.

The term "treatment" is used to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for the disease and/or adverse effects resulting from the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) preventing the occurrence of a disease or disorder in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting a disease, e.g., arresting disease progression; or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce, or inhibit a disease in the individual, including, but not limited to, administering a drug containing a compound described herein to an individual in need thereof.

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.