Methods of treating idiopathic pulmonary fibrosis

Abstract

# imgabs0. The invention relates to application of a compound with the structure shown in the specification or pharmaceutically acceptable salt, ester, stereoisomer, polymorphic substance, solvate, N-oxide, isotope labeled compound, metabolite or prodrug of the compound in preparation of a medicine for preventing, relieving and / or treating idiopathic pulmonary fibrosis, or pharmaceutically acceptable salt, ester, stereoisomer, polymorphic substance, solvate, N-oxide, isotope labeled compound, metabolite or prodrug of the compound in preparation of a medicine for preventing, relieving and / or treating idiopathic pulmonary fibrosis.

Description

[0001] This application is a divisional application of Chinese patent application 202080045478.X, filed on June 24, 2020, with the invention name “Method for treating idiopathic pulmonary fibrosis”. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to a method for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, which comprises administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof. Background Art

[0003] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lower respiratory tract fibrosis abnormality with an unknown etiology, which has an increasing incidence rate. The disease is characterized by the gradual accumulation of extracellular matrix in the interstitium. Increased fibrosis leads to reduced lung function, and patients usually die of respiratory failure or other complications within 3 years of a biopsy diagnosis. Historically, it has been proposed that a combination of corticosteroids (e.g., prednisolone) and immunosuppressants (e.g., azathioprine) and / or N-acetylcysteine ​​be used as a treatment regimen for IPF. Another drug approved for the treatment of IPF in Japan, Europe, India, and Canada is pirfenidone, which has a combined anti-inflammatory, antioxidant, and anti-fibrotic effect in an experimental model of IPF. It is the only drug observed to have prolonged progression-free survival. At present, there is no evidence that current treatment strategies can reverse fibrosis in IPF; the goal of most therapies is to reduce the rate of development of the disease and / or to prevent disease progression.

[0004] Clearly, there remains a need in the art for better and more effective treatments for IPF. Summary of the invention

[0005] In one aspect, the present invention provides a method for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0006]

[0007] in:

[0008] Ring A is The above groups are attached to the pyrimidine ring through one of the two positions marked by * or **, and the other position is attached to the carbonyl group;

[0009] R is selected from H and C 1-6 alkyl;

[0010] R 1 for

[0011] R 2 Selected from H and C 1-6 alkyl;

[0012] R 3 , R 4 , R 7 and R 8 is independently selected at each occurrence from H, halogen, -NR 5 R 6 、-OH、C 1-6 Alkyl and -OR 5 ;

[0013] R 9 and R 10 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R 5 and -C 1-6 Alkylene -O(P=O)(OH)2;

[0014] The above alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl and -OR 5 Substituents are substituted;

[0015] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0016] m is independently an integer of 0, 1, 2 or 3 at each occurrence; and

[0017] n is independently an integer of 0, 1 or 2 at each occurrence.

[0018] In another aspect, the present invention provides the use of the compound of formula (I) above or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug in the preparation of a medicament for preventing, alleviating and / or treating idiopathic pulmonary fibrosis.

[0019] In another aspect, the present invention provides a compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof for use in preventing, alleviating and / or treating idiopathic pulmonary fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1A The weight changes of animals in each group during the test period of Example 2 are shown (Day 0 is the first day of bleomycin induction).

[0021] Figure 1B The weight changes of animals in each group at the end of the test in Example 2 are shown.

[0022] Figure 2 The survival rate of each group of animals in the test of Example 2 is shown.

[0023] Figure 3 The results show the white blood cell counts in the bronchoalveolar lavage fluid of each group of animals after the administration in Example 2.

[0024] Figure 4A The results show the lung tissue fibrosis scores of each group of animals after administration in Example 2.

[0025] Figure 4B Representative Masson Trichome staining pathological staining photos of each group in Example 2 are shown.

[0026] Figure 5A The expression of TIMP-1 mRNA in the lung tissue of each group of animals after administration in Example 2 is shown.

[0027] Figure 5B The expression of COL1A1 mRNA in the lung tissues of each group of animals after administration in Example 2 is shown.

[0028] Figure 6 The results show the white blood cell counts in the bronchoalveolar lavage fluid of each group of animals after the administration in Example 3.

[0029] Fig. 7A Representative H&E staining pathological staining photos of each group in Example 3 are shown.

[0030] Figure 7B The lung injury scores of animals in each group after administration in Example 3 are shown.

[0031] Fig. 8A Representative Masson Trichome staining pathological staining photos of each group in Example 3 are shown.

[0032] Figure 8B The fibrosis scores of lung tissues of animals in each group after administration in Example 3 are shown. DETAILED DESCRIPTION

[0033] definition

[0034] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0035] The terms "comprises," "comprising," "having," "containing," or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0036] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0037] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with 1 or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0038] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6The alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenylene group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0039] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0040] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0041] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to a saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.

[0042] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-10 membered (sub)heterocyclyl" is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl. The group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

[0043] As used herein, the terms "(ylidene)aryl" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 6-10 "(E)aryl" and "C 6-10 "Aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene) phenyl (benzene ring) or (ene) naphthyl (naphthalene ring). (Ene) aryl and aromatic ring are optionally substituted by 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0044] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused. In particular, "heteroaryl" or "heteroaromatic ring" is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0045] As used herein, the term "aralkyl" preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl may have 6-14 carbon atoms, the heteroaryl may have 5-14 ring atoms, and the alkyl may have 1-6 carbon atoms. Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0046] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0047] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle is optionally benzo-fused, and is preferably connected to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0048] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0049] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0050] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0051] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0052] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0053] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0054] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g. 35S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotope-labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0055] The term "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0056] In this article, solid lines (-), solid wedges Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0057] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0058] It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

[0059] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0060] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0061] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.

[0062] For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0063] As used herein, the term "ester" means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form). The compounds of the present invention themselves may also be esters.

[0064] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0065] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0066] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0067] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0068] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0069] The term "about" means within ±10% of the stated numerical value, preferably within ±5%, more preferably within ±2%.

[0070] The term "effective amount" refers to an amount sufficient to achieve the desired therapeutic effect under the conditions of administration, which results in improvement of pathological symptoms, disease progression, physiological conditions associated therewith, or inducing resistance to the aforementioned diseases.

[0071] As used herein, unless otherwise indicated, the terms "treating" and "treating" mean reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0072] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0074] In some embodiments, the present invention provides a method for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0075]

[0076] in:

[0077] Ring A is The above groups are attached to the pyrimidine ring through one of the two positions marked by * or **, and the other position is attached to the carbonyl group;

[0078] R is selected from H and C 1-6 alkyl;

[0079] R 1 for

[0080] R 2 Selected from H and C 1-6 alkyl;

[0081] R 3 , R 4 , R 7 and R 8 is independently selected at each occurrence from H, halogen, -NR 5 R 6 、-OH、C 1-6 Alkyl and -OR 5 ;

[0082] R 9 and R 10 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R 5 and -C 1-6Alkylene -O(P=O)(OH)2;

[0083] The above alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl and -OR 5 Substituents are substituted;

[0084] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0085] m is independently an integer of 0, 1, 2 or 3 at each occurrence; and

[0086] n is independently an integer of 0, 1 or 2 at each occurrence.

[0087] In a preferred embodiment, Ring A is The above groups are connected to the pyrimidine ring through the position marked by * and to the carbonyl group through the position marked by **, where R 10 Selected from H and C 1-6 Alkyl, preferably H or methyl.

[0088] In a preferred embodiment, ring A is preferably The above groups are attached to the pyrimidine ring via the position marked by * and to the carbonyl group via the position marked by **.

[0089] In a preferred embodiment, R is H.

[0090] In a preferred embodiment, R 2 For H.

[0091] In a preferred embodiment, R 5 and R 6 Each occurrence is independently selected from H, methyl and ethyl.

[0092] In a preferred embodiment, R 3 , R 4 , R 7 and R 8 is independently selected at each occurrence from the group consisting of H, F, Cl, Br, I, -NH2, -OH, methyl, trifluoromethyl, -CH2-Ph, methoxy, ethoxy, and -CH2OCH3.

[0093] In a preferred embodiment, R3 For H.

[0094] In a preferred embodiment, R 4 is selected from H and halogen (such as F, Cl, Br or I), preferably H or F.

[0095] In a preferred embodiment, R 7 is selected from H and halogen (such as F, Cl, Br or I), preferably H or F.

[0096] In a preferred embodiment, R 8 For H.

[0097] In a preferred embodiment, R 9 and R 10 is independently selected at each occurrence from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH2CHF2, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2-O(P=O)(OH)2,

[0098] In a preferred embodiment, R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Arylalkyl, preferably H.

[0099] In a preferred embodiment, R 10 Each occurrence is independently selected from H and C 1-6 The alkyl group is preferably H, methyl, ethyl, n-propyl or isopropyl, and most preferably H or methyl.

[0100] In a preferred embodiment, the present invention provides a method for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0101]

[0102] wherein each group is as defined above.

[0103] In a preferred embodiment, the present invention provides a method for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0104]

[0105] Where R 10 It is H or methyl, preferably methyl.

[0106] In a preferred embodiment, the compound has the following structure:

[0107]

[0108]

[0109] In some embodiments, the compound is prepared according to the method disclosed in WO 2019 / 001572 A1 (which is incorporated herein by reference).

[0110] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in an amount of about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day.

[0111] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg per unit dose. , about 75μg / kg, about 100μg / kg, about 125μg / kg, about 150μg / kg, about 175μg / kg, about 200μg / kg, about 225μg / kg, about 250μg / kg, about 275μg / kg, about 300μg / kg, about 325μg / kg, about 350μg / kg, about 375μg / kg, about 400μg / kg, about 425μg / kg, about 450μg / kg, about 475μg / kg, about 500μg / kg, about 525μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about The present invention relates to an agent that is administered in an amount of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

[0112] In some embodiments, the daily dose of the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered once or divided into two, three or four doses.

[0113] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year, or at least 2 years.

[0114] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of treatment, wherein each course of treatment lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days. , at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between each two courses of treatment.

[0115] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation or by inhalation.

[0116] In some embodiments, the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in a dosage form selected from tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.

[0117] The present invention covers any combination of the above embodiments.

[0118] Example

[0119] In order to make the purpose and technical scheme of the present invention clearer, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, the specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0120] Compound 128 used in the example has the following structure, which was prepared according to the method disclosed in WO 2019 / 001572 A1.

[0121]

[0122] Example 1. ROCK2 kinase activity detection

[0123] Kinase IC was performed using the commercial CISBIO Kinase Assay Kit HTRF KinEASE-STK S2 Kit (62ST2PEC). 50 The kinase ROCK2 (01-119) used in the reaction was purchased from Carna Biosciences.

[0124] Before the experiment, according to the instructions of the kinase detection kit, the following working solutions were prepared with corresponding reagents as needed: 1× kinase buffer, 5× STK-S2 substrate working solution (1.5 μM) and 5× ATP working solution (1.5 μM), 5× ROCK2 kinase working solution, 4× streptavidin-XL665 working solution, 4× STK-Ab-cryptate 2 detection solution, and then the following operations were performed.

[0125] A 10000nM compound solution was prepared using 1× kinase buffer with a DMSO concentration of 2.5%, and the compound was diluted stepwise using the above kinase buffer containing DMSO to obtain 9 test compound solutions of different concentrations. In addition to the test compound wells, positive wells (containing all reagents except the compound) and negative wells (containing all reagents except the test compound and kinase) were set. 4μL of the test compound solution was added to all reaction wells except the control wells (positive wells and negative wells), and 4μL of 2.5% DMSO solution was added to the control wells. Then, 2μM substrate (i.e., 2μL 5×STK-S2 substrate working solution) was added to all reaction wells. 2μL of 5×ROCK2 kinase working solution (containing 1.4ng ROCK2 kinase) was added to all reaction wells except the negative wells, and the negative wells were supplemented with 2μL of 1× kinase buffer. 2μL of 5×ATP working solution was added to all reaction wells and incubated at room temperature for 2 hours. After the kinase reaction is completed, 5 μL of 4×streptavidin-XL665 working solution is added to all reaction wells, and 5 μL of 4×STK-Ab-cryptate 2 detection solution is immediately added after mixing. After incubation at room temperature for 1 hour, the fluorescence signal is detected using ENVISION (Perkinelmer) instrument (excitation wavelength is 320 nm, emission wavelength is 665 nm and 615 nm). The inhibition rate in each well is calculated by the fluorescence intensity value of each well: ER (Emission Ratio, emission ratio) = (fluorescence intensity at 665 nm / fluorescence intensity at 615 nm); inhibition rate = (ER positive-ER test compound) / (ER positive-ER negative)*100%, and the curve is drawn using the software PRISM 5.0, and the half-maximal inhibition concentration (IC) of each test compound is obtained by fitting using PRISM 5.0. 50 ). Compound IC 50 The values ​​are shown in the following table.

[0126] Table 1

[0127] Compound <![CDATA[ROCK2 IC 50 nM]]> Compound <![CDATA[ROCK2 IC 50 nM]]> Compound 006 34 Compound 011 9 Compound 007 33 Compound 020 44 Compound 008 24 Compound 021 45 Compound 009 12 Compound 022 75 Compound 010 61 Compound 128 27

[0128] Example 2. Effects of Testing Compounds for Treating Idiopathic Pulmonary Fibrosis (IPF) in a BLM-Induced Mouse Model

[0129] 60 C57BL / 6 mice (purchased from Shanghai Shrek) were adaptively raised for 1 week, and 50 animals were randomly selected and the IPF animal model was established by intratracheal injection (IT) of 3 mg / kg bleomycin (BLM, purchased from SIGMA, #SIGMA-P9564). The remaining 10 animals were injected with a normal saline of the same volume as the injected bleomycin, and set as the normal group (N=10). The day of injection of bleomycin was set as day 0 (D0); on the 6th day, they were randomly divided into 4 groups according to body weight: solvent group (N=14), compound 007 administration group (N=12), compound 128 administration group (N=12) and positive control pirfenidone (purchased from SIGMA, #SIGMA-P2116) administration group (N=12). The animal grouping is shown in Table 2.

[0130] Table 2. Animal groups

[0131]

[0132] On days 8-21, the animals in each group were dosed: the normal group and the vehicle group were gavaged with vehicle 1 (solvent 1 is: 20% PEG 400+5% Tween 80+75% ddH2O), the compound 007-dosed group was gavaged with compound 007 (prepared with solvent 1), the compound 128-dosed group was gavaged with compound 128 (prepared with solvent 1), and the pirfenidone-dosed group was gavaged with pirfenidone (solvent 2: 0.2% methylcellulose+0.5% Tween 80+99.3% ddH2O).

[0133] Record daily body weight and weight change (weight change on day 21 is calculated as follows: weight change on day 21 = weight on day 21 - weight on day 0). Figure 1A and 1B .

[0134] Record the animal survival rate, the results are shown in Figure 2 .Depend on Figure 2 The results show that at the end of the test, the survival rate of animals in the group administered with compound 007 was significantly higher, indicating that compound 007 is well tolerated.

[0135] The animals were euthanized 2 hours after dosing on day 21, and bronchoalveolar lavage fluid was collected for white blood cell (WBC) counts. Figure 3 .Depend on Figure 3 As can be seen, there was no significant difference in the total white blood cell count in the bronchoalveolar lavage fluid of animals in each drug group.

[0136] The left lung of the animal was fixed for histopathological examination, and the lung injury Ashcroft score was scored by Masson Trichome staining. The scoring criteria were as reported in the literature Ashcroft T et al., Journal of clinical pathology. 1988. After 100 times magnification, each continuous field of view was scored (ranging from 0 points (normal lung)) to 8 points (complete fibrous occlusion in the field of view)), and the scores of 5 parts were taken to calculate the average value. The results are shown in Figure 4A and 4B .Depend on Figure 4A and 4B The results showed that after the administration, compound 007 significantly reduced the collagen accumulation in the lungs of mice and significantly reduced the degree of lung fibrosis in mice, and its therapeutic effect was significantly better than pirfenidone and compound 128.

[0137] Real-time fluorescence quantitative PCR was used to detect the mRNA levels of lung tissue fibrosis-related protein collagen 1A1 (COL1A1) and tissue metal matrix protein inhibitor protein 1 (TIMP-1) in lung tissue after administration. Specifically, the lung tissue fragments were transferred to a centrifuge tube containing 1 mL of TRIzol reagent (Invitrogen, catalog number 15596018), the lung tissue was ground at low temperature by a tissue grinder, and total cell RNA was extracted, and cDNA was synthesized by reverse transcription using the TransScript All-in-One First-StrandcDNASynthesis SuperMix for qPCR (One-Step gDNARemoval) (All-Gold, catalog number AT341-02) kit, and the mRNA expression changes of COL1A1 and TIMP-1 in lung tissue were detected by fluorescence quantitative PCR.

[0138] In the real-time fluorescence quantitative PCR method, the β-actin gene was used as the internal reference gene to normalize the data; the primer sequences used were all from the PrimerBank website, with the website ID numbers being 34328108a1 (COL1A1 primer), 6755795a1 (TIMP-1 primer) and 6671509a1 (β-actin primer), and all three pairs of primers were synthesized by Invitrogen.

[0139] Results Figure 5A and 5B The results showed that the upregulation of TIMP-1 expression in lung tissue induced by bleomycin was significantly inhibited by compound 007 (P<0.05), and the pirfenidone group had moderate inhibition but no statistical difference; the upregulation of COL1A1 expression induced by bleomycin was significantly inhibited by compound 007 and pirfenidone.

[0140] Example 3 Testing the Effect of Different Doses of Compounds for Treating Idiopathic Pulmonary Fibrosis (IPF) in a BLM-Induced Mouse Model

[0141] After C57BL / 6J mice were adapted to feeding, they were randomly divided into two groups according to their weight: one group of 15 mice was injected with 50 μL of normal saline into the airway of the animals; the other group of 90 mice was injected with 50 μL of bleomycin (2.5 mg / kg) into the airway of the animals to establish the IPF animal model. On the seventh day after the establishment of the animal model, the mice were randomly divided into groups according to their weight changes (the difference between the weight on the seventh day after the establishment of the model and the day of the establishment of the model). The drugs were continuously administered for 14 days starting from the eighth day after the establishment of the animal model. The grouping and administration information are shown in Table 3.

[0142] Table 3 Experimental animal groups and dosing regimen

[0143]

[0144] The animals were sacrificed by bleeding from the inferior vena cava 2 hours after the last administration, and the bronchoalveolar lavage fluid (BALF) was collected for white blood cell count. The results are shown in Figure 6 .

[0145] The left lung of the animal was fixed for preparation of pathological tissue sections, and H&E and Masson Trichome staining were performed for lung injury and fibrosis degree scoring. The pulmonary fibrosis scoring standard refers to the reference "Standardized quantification of pulmonary fibrosis in histological samples"; the lung tissue injury degree score is 0-16, mainly evaluated from four aspects: inflammatory cell infiltration (0-4), hemorrhage (0-4), interstitial and alveolar edema (0-4) and alveolar septum thickness (0-4) in the lung tissue. The higher the score, the higher the degree of lung tissue damage.

[0146] Compared with the model group, compound 007 significantly reduced the infiltration of leukocytes in the lungs ( Figure 6 ), lung injury ( Fig. 7A and 7B ) and degree of fibrosis ( Fig. 8A and 8B ) were also significantly improved, among which the therapeutic effects of the compound 007-30 and 100mpk dose groups were comparable to those of the pirfenidone and nintedanib dose groups, and the compound 007-300mpk dose group was superior to the pirfenidone and nintedanib dose groups in improving lung injury and fibrosis. This indicates that compound 007 can play a therapeutic role in IPF by reducing the infiltration of pulmonary leukocytes, improving lung injury and the degree of lung fibrosis, etc.

[0147] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Use of a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof in the preparation of a medicament for preventing, alleviating and / or treating idiopathic pulmonary fibrosis, wherein the compound has the following structure:

2. The use of claim 1, wherein the compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered in an amount of 0.005 mg / day to 5000 mg / day.

3. The method of claim 2, wherein the compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in an amount of 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg / day.

4. The use of claim 1, wherein the compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered in an amount of 1 ng / kg to 200 mg / kg, 1 μg / kg to 100 mg / kg or 1 mg / kg to 50 mg / kg body weight per day.

5. The method of claim 4, wherein the compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is used for daily administration at 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 75 μg / kg, 100 μg / kg, 125 μg / kg, 150 μg / kg, 175 μg / kg, 200 μg / kg g / kg, 225μg / kg, 250μg / kg, 275μg / kg, 300μg / kg, 325μg / kg, 350μg / kg, 375μg / kg, 400μg / kg, 425μg / kg, 450μg / kg, 475μg / kg, 500μg / kg, 525μg / kg, 550μg / kg, 575μg / kg, 600μg / kg, 625μg / kg, 650μg / kg, 675μg / kg, 700μg / kg, 725μg / kg, 750μg / kg, 775μg / kg, 800μg / kg, 825μg / kg, 8 50μg / kg, 875μg / kg, 900μg / kg, 925μg / kg, 950μg / kg, 975μg / kg, 1mg / kg, 5mg / kg, 10mg / kg, 15 The invention relates to the administration of an agent in an amount of 100 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg or 300 mg / kg body weight.

6. The method of claim 1, wherein the daily dose of the drug is administered once or divided into two, three or four doses.

7. The method of claim 1, wherein the medicament is used for continuous administration for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year or at least 2 years.

8. The method of claim 1, wherein the medicament is used for administration of one or more courses of treatment, wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between each two courses of treatment.

9. The use of claim 8, wherein the medicament is for administration for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 courses of treatment.

10. The use of claim 1, wherein the medicament is for administration by injection or percutaneous administration; or by oral, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation or by inhalation.

Images