Cyclic oxaphosfinane compounds and their analogues for the treatment of fibrous diseases

Abstract

The present invention relates to the use of heterocyclic phosphonic compounds or compositions comprising the same for the treatment of fibrotic disorders. More particularly, the present invention relates to compounds of general formula (1) as claimed herein or compositions comprising the same for use in the treatment of fibrotic disorders.

Description

[Technical Field]

[0001] The present invention relates to the use of heterocyclic phosphone compounds or compositions containing the same for the treatment of fibrous diseases. [Background technology]

[0002] Under normal circumstances, an organism's organs or tissues respond to injury through a repair process aimed at restoring the functional integrity of the damaged tissue. The tissue repair response is self-limiting and ceases once wound healing is complete. Under pathological conditions, the tissue repair response escapes regulatory mechanisms, developing into an uncontrolled wound healing response that leads to fibrosis. This results in the prolonged and progressive accumulation of excessive fibrous material, altering and disrupting the structure and function of normal organs.

[0003] Excessive accumulation and buildup of extracellular matrix (ECM) components such as collagen and fibronectin can lead to tissue hardening and scarring, causing abnormal organ remodeling and ultimately potentially leading to organ failure in fibrous diseases.

[0004] Wounds in parenchymal organs typically involve activation that triggers an inflammatory response, including endothelial damage, platelet aggregation, and infiltration of neutrophils, macrophages, eosinophils, and lymphocytes into the wound site. Infiltrating inflammatory cells and affected epithelial cells secrete various growth factors and cytokines that further amplify the inflammatory response. Molecules such as TGF-β, PDGF, and IL-13 activate macrophages, leading to the recruitment, proliferation, and activation of fibroblasts at the wound site. Activated fibroblasts or myofibroblasts express smooth muscle actin and secrete collagen and other ECM components that stabilize the cell basal layer. This allows epithelial and endothelial cells to proliferate and migrate beyond the temporary matrix to regenerate damaged tissue. Once complete, the inflammatory process ends as the fibroblasts undergo apoptosis, leading to the dissipation of the wound response.

[0005] In fibrotic remodeling, persistent tissue damage or injury, or dysregulation of repair mechanisms, leads to an inadequate wound response. Excessive accumulation and increased cross-linking of collagen and extracellular matrix (ECM) occur, resulting in an excessive buildup of ECM beyond normal requirements, which is associated with persistent myofibroblast activation, epithelial cell damage, and loss of normal tissue structure and function.

[0006] Abnormal wound healing (fibrosis) can be associated with any organ or tissue that gives rise to various fibrotic diseases, such as the kidneys, lungs, intestines, skin, aorta, or liver. The causes of fibrotic diseases can vary depending on the organ or tissue involved and are often unknown. Hepatic fibrosis and ultimately cirrhosis result from chronic liver damage due to exposure to various factors, including environmental and dietary factors or infectious pathogens. Persistent excessive consumption of alcohol or high-fat / sugar diets can also lead to cirrhosis. Similarly, diabetes, hypertension, exposure to toxins, and various autoimmune diseases can damage the kidneys, leading to fibrotic remodeling and loss of renal function. Many types of inflammatory bowel diseases, such as Crohn's disease or celiac disease, can lead to fibrotic remodeling that causes stricture and / or malabsorption.

[0007] Treatment for progressive fibrosis should aim to treat the underlying cause. For example, this could involve avoiding hypertension through better blood pressure control, improving glucose management in diabetes, or avoiding exposure to damaging allergens or toxins. However, some fibrotic diseases do not respond well to treatment of the underlying injury, and organ failure may progress regardless of the state of the underlying injury that triggers the onset of the wound process. This is the case with chronic kidney disease, where progression to progressive kidney disease or end-stage renal failure may be observed after treatment of immunological injury, correction of hypertension, or improvement of diabetes, which are some of the underlying causes of renal fibrosis.

[0008] Much progress has been made in understanding the mechanisms leading to various fibrotic diseases. Many different cell types have been associated not only with wound healing but also with fibrosis and the self-persistence of fibrotic diseases. Knowledge of the roles played by various cell products that affect fibrosis is also increasing, with many having fibrosis-promoting effects and others having protective effects against fibrosis. In the former, CD4+ Th2 cells, the response mediated by the production of IL-4, IL-5, IL-13, and IL-21 leads to an increase in the fibrotic process, while CD4+ Th1 cells possessing the interferon-γ and IL-12 chemokines are protective against fibrosis. The transforming growth factor beta (TGF-β) pathway has been demonstrated to contribute to almost all types of fibrosis, but IL-4 has been shown to be far more powerful than TGF-β in inducing the fibrotic response. Other molecules or genes that have been reported to contribute include type I, III, and VI procollagens, arginase-1, lysyl oxidase, matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue matrix metalloproteinase-1 inhibitor (TIMP-1), as well as heme oxygenase, type III procollagen, secretory phosphorylated protein 1, type V procollagen, reticulocarbine, and fibrillin 1. The fibrosis-promoting effect of angiotensin II has been widely studied, particularly in cardiac fibrosis.

[0009] Despite tremendous progress in identifying the cells and molecular mechanisms involved in the transition from necessary wound healing processes to abnormal and harmful spontaneous fibrosis, concrete treatments for fibrotic diseases remain largely unproposed.

[0010] Pirfenidone is a small molecule drug approved in Japan in 2008 and in Europe in 2011 for the treatment of idiopathic pulmonary fibrosis (IPF), and it has antifibrotic activity by downmodulating TGF-β. Nintedanib is a triangiokinase inhibitor that reduces or blocks tyrosine kinase activity induced by VEGF, FGF, and PDGF. Both compounds reduce fibrosis in IPF, but their demonstrated clinical utility is limited (extension of survival by 2 years), and they have numerous side effects.

[0011] To date, there are no other approved treatments for fibrosis-related diseases. Nevertheless, 45% of all deaths in developed countries worldwide are attributable to several types of chronic fibroproliferative disorders. Therefore, there is an unmet medical need for specific treatments for fibrotic diseases, which has a very significant societal impact. Accordingly, the object of this invention is to provide a novel method for treating fibrotic diseases.

[0012] In the present invention, the results disclosed herein demonstrate that certain glycomimetic compounds have antifibrotic effects both in vitro and in vivo, and therefore these compounds can be used to design effective novel methods for the treatment of fibrotic diseases. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] WO2009 / 004096 [Patent Document 2] WO2014 / 128429 [Patent Document 3] WO2018 / 054925 [Non-patent literature]

[0014] [Non-Patent Document 1] "Essentials of Glycobiology", edited by Varki et al., Chapter 2 (Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1999)

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Means for Solving the Problems

[0015] The present invention provides a family of heterocyclic phosphon compounds, more particularly the compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinan, for use in the treatment of fibrotic diseases.

Brief Description of the Drawings

[0016] [Figure 1] It is a figure of the staining of kidney sections of the control and uremic rat groups. A) Sirius red staining as a fibrosis marker. B) Immunostaining of Mgat5. Magnification x200. (*p≤0.05; **p≤0.01) [Figure 2] It is a figure of the Sirius red staining of kidney sections. C: Control + placebo. C+3.1: Control + compound 3.1. SNX: SNX + placebo. SNX+3.1: SNX + compound 3.1. Magnification x200. (*p≤0.05) [Figure 3]Figures of immunostaining of kidney sections for type 1, 3, and 4 collagen. A) Type 1 collagen. B) Type 4 collagen. C) Type 3 collagen. C: Control + placebo. C+3.1: Control + compound 3.1. SNX: SNX + placebo. SNX+3.1: SNX + compound 3.1. Magnification x200. (*p≦0.05; **p≦0.01; ***p≦0.001 and ****p≦0.0001) [Figure 4] Figure of LPHA staining as a glycan marker for MGAT5 activity in kidney sections. C: Control + placebo. C+3.1: Control + compound 3.1. SNX: SNX + placebo. SNX+3.1: SNX + compound 3.1. Magnification x200. (*p≦0.05; **p≦0.01) [Figure 5] Figure of staining of aortic ring sections cultured in control and calcified media. A) Von Kossa staining as a calcification marker. B) Sirius red staining C) Immunostaining of GnT-V. Magnification x200. [Figure 6] Figure of the cutting pattern of the left lateral lobe of the mouse liver for histological analysis. Fragments a and c are stored at -80°C, and fragment b is used for immunostaining. [Figure 7] Figure of the body weight tracking of NASH model mice for 21 days. Vehicle group: placebo, 10 ml / kg, oral, twice a day. Compound 3.1 group: 15 mg / kg, oral, twice a day. Telmisartan group: 10 mg / kg, oral, once a day. (*p≦0.05; **p≦0.01; ***p≦0.001 and ****p≦0.0001) [Figure 8] Figure of Sirius red staining of histological sections of mouse liver. Magnification x200. [Figure 9] Figure of the quantification of the fibrotic area using Sirius red staining of histological sections of mouse liver. The area is expressed as a percentage and corresponds to the ratio: surface stained with Sirius red / surface of the section. Magnification x200. (p<0.01)

Mode for Carrying Out the Invention

[0017] The present invention relates to the use of a heterocyclic phosphone compound of formula (1), as detailed below, more particularly compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane (also known as compound 3.1), for the treatment of fibrotic diseases. The compound has previously been described as an anticancer agent for reducing or preventing the appearance of metastases, as disclosed in PCT patent applications WO2009 / 004096 and WO2014 / 128429.

[0018] The compound used in accordance with the present invention has the following formula (1).

[0019] [ka]

[0020] (In the formula, Y represents an oxygen, sulfur, or selenium atom, preferably an oxygen atom.) Z represents an NR6 group where O, S, Se, NH, or R6 is an aryl or optionally substituted alkyl group, preferably an oxygen atom. R1 represents a hydrogen atom, an optionally substituted alkyl group, or an aryl group. R 2a This represents a hydrogen atom, halogen, azide (N3), carbonic acid or dithiocarbonate group, 1H-[1,2,3]triazolyl group or -X-R2 group, X represents oxygen, sulfur, selenium atom, NH or NR7 group, R7 is optionally a substituted aryl or alkyl group, and X preferably represents O or NH. R2 represents an aryl group, an optionally substituted alkyl group, a hydrogen atom, a trichloroacetimidate group (-C(=NH)CCl3), an acyl, formyl, sulfonyl, sulfinyl, tert-butyldiphenylsilyl, an allyl group, saccharyl, an ester, an amide, a thioamide, or a sulfonamide group, or X-R2 represents a P(O)R2R6 group, where R2 and R6 independently represent an aryl group, an optionally substituted alkyl group, an OH group, an alkoxy, or an aryloxy group. R3 and R4 independently represent an aryl, optionally substituted alkyl group, hydrogen atom, trichloroacetoimidate group, acyl, formyl, sulfonyl, sulfinyl, tert-butyldiphenylsilyl group, allyl, saccharyl, ester, amide, thioamide, or sulfonamide group, or R3 and R4 together form a divalent group of formula -R3-R4-, where -R3-R4- preferably represents a linear alkylene group such as isopropylidene, benzylidene, diphenylmethylidene, cyclohexylmethylidene group, or their substituted analogs, e.g., 4-methoxybenzylidene group, or ethylene group (to form a propane-1,2-diol group). R5 represents a hydrocarbon group containing a hydrogen atom, or one or more heteroatoms preferably selected from oxygen, sulfur, or nitrogen, more preferably oxygen.

[0021] In this specification, names of compounds are generally used according to their conventional definitions.

[0022] As used herein, "alkyl" means a linear or branched, saturated or unsaturated hydrocarbon group having 1 to 25 carbon atoms, particularly including an acyclic group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl, or n-hexyl groups, preferably a cycloalkyl group having 3 to 7 carbon atoms, and preferably a cycloalkylmethyl group having 4 to 8 carbon atoms.

[0023] As used herein, “substituted alkyl” means an alkyl group, such as those defined above, which is bonded via sp3 carbon atoms, substituted with one or more aryl groups, and / or contains one or more heteroatoms such as N, S, or O. Preferred examples include arylalkyl groups, e.g., (-CPh3)-trityl group, benzyl group (denoted as Bn), or 4-methoxybenzyl group; alkoxyalkyl groups, particularly dialkoxymethyl groups, e.g., diethoxymethyl or dimethoxymethyl group; and CH2CO2R11 groups, where R11 represents an optionally substituted alkyl or aryl group.

[0024] As used herein, “alkoxy” means an alkyl group, such as an ethoxy, methoxy, or n-propoxy group, that is bonded to the rest of the molecule via an oxygen atom.

[0025] As used herein, "aryloxy" means an aryl group bonded to the rest of the molecule via an oxygen atom, such as a benzoxy group.

[0026] As used herein, “acyl” means a group obtained by removing a hydroxyl group from a carboxylic acid, preferably having the formula -C(O)R8, where R8 represents an aryl or optionally substituted alkyl group, such as an acetyl, trifluoroacetyl, propionyl, oleoyl, myristoyl, or benzoyl group.

[0027] As used herein, "sulfonyl" means a group obtained from a sulfonic acid by removing a hydroxyl group, preferably having the formula -SO2R9, where R9 optionally represents a substituted alkyl or aryl group.

[0028] As used herein, "sulfinyl" means a group obtained from sulfinic acid by removing a hydroxyl group, preferably having the formula -SOR10, where R10 optionally represents a substituted alkyl or aryl group.

[0029] As used herein, “dithiocarbonate group” means the group of formula -OC(S)SR9c, where R9c represents an optionally substituted alkyl or aryl group.

[0030] As used herein, "carbonate group" refers to the group of the formula -OC(O)OR9d, where R9d represents an optionally substituted alkyl or aryl group.

[0031] As used herein, "ester group" refers to a group of the formula -C(O)OR10', where R10' represents an optionally substituted alkyl or aryl group.

[0032] As used herein, “amide group” means a group of the formula -C(O)NR9'R9'', where R9' represents an optionally substituted alkyl or aryl group, and R9'' represents an optionally substituted alkyl, aryl group, or hydrogen atom.

[0033] As used herein, "thioamide group" means a group of the formula -C(S)NR9aR9b, where R9a represents an optionally substituted alkyl or aryl group, and R9b represents an optionally substituted alkyl, aryl group, or hydrogen atom.

[0034] As used herein, "sulfonamide group" means the group of the formula -SO2NR11'R11'', where R11' represents an optionally substituted alkyl or aryl group, and R11'' represents an optionally substituted alkyl, aryl group, or hydrogen atom.

[0035] As used herein, “aryl” means an aromatic monovalent carbocyclic group comprising one ring (e.g., a phenyl group) or multiple fused rings (e.g., naphthyl and terphenyl groups) and optionally substituted with one or more groups, for example, but not limited to, alkyl (e.g., methyl), hydroxyalkyl, amino-alkyl, hydroxyl, thiol, amino, halogeno (fluoro, bromo, iodo, chloro), nitro, alkylthio, alkoxy (e.g., methoxy), aryloxy, mono-alkylamino, dialkylamino, acyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, hydroxysulfonyl, alkoxysulfonyl, aryloxysulfonyl, alkylsulfonyl, alkylsulfinyl, cyano, trifluoromethyl, tetrazolyl, carbamoyl, alkylcarbamoyl, and dialkylcarbamoyl groups. Alternatively, two adjacent positions of the aromatic ring may be substituted with methylenedioxy or ethylenedioxy groups. As used herein, “aryl” also includes “heteroaryl” groups, i.e., aromatic rings in which one or more carbon atoms of one or more aromatic rings are substituted with one heteroatom such as a nitrogen, oxygen, phosphorus, or sulfur atom. Heteroaryl groups may have structures containing one or more aromatic rings, or structures in which one or more aromatic rings are bonded to one or more non-aromatic rings. In structures with many rings, the rings may be fused, covalently bonded, or bonded to each other via common divalent groups such as methylene, ethylene, or carbonyl groups. Preferred examples of heteroaryl groups include thiophene groups (2-thienyl, 3-thienyl), pyridine groups (2-pyridyl, 3-pyridyl, 4-pyridyl), isoxazole, phthalimide, pyrazole, indole, and furan groups, as well as their benzo-fusion analogs, phenylpyridyl ketones, quinolines, phenothiazines, carbazoles, and benzopyranones. As used herein, "saccharyl group" includes all groups resulting from the removal of a hydroxyl group or hydrogen atom (preferably a hydroxyl group) from natural or synthetic, protected or unprotected carbohydrates or sugars.The saccharyl group may include a monosaccharyl or oligosaccharyl group, such as a disaccharyl group. The saccharyl group, such as glucosyl and mannosyl groups, can arise from sugars, for example, glucuronic acid, lactose, sucrose, maltose, allose, altrose, glucose, mannose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, fructose, threose, erythrose, [beta]-DN-acetylgalactosamine, [beta]-DN-acetylglucosamine, fucose, sialic acid, N-acetylneuraminic acid, N-acetylmuramic acid, glucosamine, galactosamine, rhamnose, and protected or substituted analogs thereof substituted with, for example, acyl, alkyl, aryl, halogeno, and amino groups, as well as their desoxy analogs.

[0036] As used herein, the oligosaccharide group means a saccharide group arising from at least two covalently bonded monosaccharides, each preferably containing 1 to 3 saccharide units. For a description of saccharide structures, see Chapter 2 of "Essentials of Glycobiology," edited by Varki et al. (Cold Spring Harbor Press, Cold Spring Harbor, NY, 1999). The preferred saccharide group is the monosaccharide group. In the compound of formula (1), where R2a represents an -X-R2 group and R2 represents a saccharide group, the saccharide group is bonded via an X group, preferably O or NH, preferably O.

[0037] As used herein, "saccharide" means monosaccharide or oligosaccharide.

[0038] "Bn" represents a benzyl group, and "Ac" represents an acetyl group.

[0039] Some compounds of the present invention may exist equally in solvated or non-solvated forms, for example, as hydrates. Generally, the solvated form is equivalent to the non-solvated form and is included within the scope of the present invention. Some compounds of the present invention may have multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended use of the present invention and are included within the scope of the present invention.

[0040] The compounds of the present invention have several chiral (optical) centers, and therefore enantiomers or diastereoisomers may exist. It is understood that the present invention includes all enantiomers and diastereoisomers of the compound of formula (1), as well as mixtures thereof, in particular mixtures based on racemates. Different isomers can be separated according to methods known to those skilled in the art, in particular by silica gel chromatography or fractional crystallization.

[0041] The preferred compounds of formula (1) are compounds where Y=Z=O, i.e., 1,2-oxaphosfinan 2-oxide compounds.

[0042] In the compounds of the present invention, if the R1 substituent does not represent a hydrogen atom, it is always bonded to the phosphorus atom within the ring via a carbon atom.

[0043] Preferred R1 groups include H, alkyl groups such as 2-benzyloxyethyl, ethyl, n-butyl, 3-phenylpropyl, n-octyl, dialkoxymethyl groups such as diethoxymethyl or dimethoxymethyl, aryl groups such as phenyl, 4-methylphenyl, 4-nitrophenyl, 4-aminophenyl, 4-methoxyphenyl, 3,4-difluorophenyl, 2-thienyl, 4-fluorophenyl, 4-biphenyl, 3-methylphenyl, 3-methoxyphenyl, and 3,5-difluorophenyl, as well as the following groups.

[0044] [ka]

[0045] In one specific embodiment, R1 is a phenyl group.

[0046] Preferred R2 groups include H, arylsulfonyl, methylsulfonyl, trichloroacetimidate, benzyl, saccharyl, and aryl groups, such as phenyl, 4-methylphenyl, 4-nitrophenyl, 4-aminophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, and 3,4-dinitrophenyl groups.

[0047] Preferred X-R2 groups include O-aryl, OH, NH2, NH-aryl, S-aryl, and dithiocarbonate groups, or NHCH2CO2R11 where R11 is one of the previously defined groups, NHC(O)R12 where R12 is an aryl group or an optionally substituted alkyl group, O-SO2R9 where R9 is one of the previously defined groups, NH-Bn, O-saccharyl, OC(=NH)CCl3, phosphonic acid, phosphinic acid or phosphine oxide, urea, thiourea, carbamic acid, and carbonate groups.

[0048] In one specific embodiment, X-R2 is an OH group, and preferably R1 is a phenyl group.

[0049] Preferably, R3 and R4 independently represent a hydrogen atom, a benzyl, a benzoyl, or an acetyl group, or R3 and R4 together preferably represent an isopropylidene group, forming a divalent group of the formula -R3-R4-.

[0050] In one specific embodiment, R3 and R4 represent benzyl groups, and / or R1 is a phenyl group, and / or X-R2 is an OH group.

[0051] In another specific embodiment, R3 and R4 represent benzyl groups, preferably R1 is a phenyl group, and / or X-R2 is an OH group.

[0052] According to a preferred embodiment of the present invention, R5 is such that the compound of formula (1) has the following formula (2) or (3).

[0053] [ka]

[0054] (In the formula, R1, R 2a R3, R4, Y and Z are as previously defined, and R14, R15 and R16 independently represent a hydrogen atom, an aryl, an optionally substituted alkyl group, a trichloroacetimidate group, an acyl, a formyl, a sulfonyl, a sulfinyl, a tert-butyldiphenylsilyl group, an allyl, an ester, an amide, a thioamide, or a sulfonamide group, or R15 and R16 together represent formula -R 15 -R 16 - Forms a divalent group, -R 15 -R 16 (- preferably represents isopropylidene, benzylidene, diphenylmethylidene, cyclohexylmethylidene group, and their substituted analogs, such as a linear alkylene group like a 4-methoxybenzylidene group or an ethylene group.)

[0055] In one specific embodiment, R14 represents a benzyl group, and preferably, as in at least one or more specific embodiments described in detail earlier, R3 and R4 represent benzyl groups and / or R1 is a phenyl group and / or X-R2 is an OH group.

[0056] If R5 does not represent a hydrogen atom, it preferably has 1 to 25 carbon atoms, preferably 1 to 20 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 8 carbon atoms. R5 may represent an optionally substituted alkyl group, preferably containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen, more preferably oxygen. Preferred R5 groups include alkoxyalkyl groups, such as benzyloxymethyl (-CH2OBn), -CH2OH, 2,2-dimethyl-[1,3]-dioxolan-4-yl, and 1,2-dihydroxyethyl CH(OH)CH2OH groups, which are R in formulas (2) and (3). 14 =H or Bn, R 15=R 16 =H or R 15 and R 16 together mean an isopropylidene group is formed.

[0057] According to a specific embodiment, compounds useful in the treatment of fibrosis are 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosphinan, 4-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-2-oxo-2-phenyl-tetrahydro-6λ * 5 * -[1,3]dioxolo[4,5-d][1,2]oxaphosphinan-3-aminobenzyl, more specifically (3aR,6S,7S,7aS)-7-(benzylamino)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-phenyltetrahydro-[1,3]dioxolo[4,5-d][1,2]oxaphosphinine 6-oxide (also referred to herein as Compound 3.3), N-((2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-oxide-2-phenyl-1,2-oxaphosphinan-3-yl)acetamide (also referred to herein as Compound 2.2), 4,5-bis-benzyloxy-6-benzyloxymethyl-phenyl-2-oxo-2λ5-[1,2]oxaphosphinan-3-aminobenzyl, more specifically (2S,3S,4S,5S,6R)-3-(benzylamino)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-phenyl-1,2-oxaphosphinan (also referred to herein as Compound 4.6), (2S,3S,4S,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxy-2-(4-phenoxyphenyl)-1,2-oxaphosphinan 2-oxide (also referred to herein as Compound 3.0), and Selected from the group consisting of (3aR,6R,7R,7aS)-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-oxide-6-phenyltetrahydro-[1,3]dioxolo[4,5-d][1,2]oxaphosphinin-7-ylbenzoate (also known herein as compound 4.2).

[0058] In a more specific embodiment, the compound useful in the treatment of fibrosis is 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinan.

[0059] The preparation of compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane may be carried out as described, for example, in WO2009 / 004096, WO2014 / 128429, and WO2018 / 054925.

[0060] The compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane used in accordance with the present invention preferably has the following formula (I).

[0061] [ka]

[0062] Accordingly, the present invention relates to a compound of formula (1), preferably 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane, more preferably a compound of formula (I), also known as PST3.1, for use in methods for the treatment of fibrous diseases.

[0063] In a further embodiment, the present invention relates to a compound of formula (1), as previously detailed, for use in the treatment of fibrosis by inhibition of GnT-V activity.

[0064] In a further embodiment, the present invention relates to a compound of formula (1) for use in the treatment of fibrosis by inhibiting mechanisms involved in the cell matrix and / or cell / cell interactions, including inhibition of collagen fiber production, more particularly type 1, 3 and / or 4 collagen, and / or inhibition of fibroblast migration.

[0065] The present invention further provides the use of compounds of formula (1) as defined herein, particularly 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane, preferably compounds of formula (I), also known as PST3.1, for the manufacture of pharmaceuticals or pharmaceutical compositions for the treatment of fibrotic diseases. In one specific embodiment, the treatment of fibrosis is by inhibition of GnT-V activity. In a further specific embodiment, the treatment of fibrosis is by inhibition of mechanisms involved in the cell matrix and / or cell / cell interactions, including inhibition of collagen fiber production, more particularly type 1, 3 and / or type 4 collagen, and / or inhibition of fibroblast migration.

[0066] The present invention further provides a method for treating fibrotic diseases in patients requiring such treatment by administering an effective amount of a compound of formula (1) as defined herein, particularly a compound of formula (I), also known as 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinane, preferably a compound of formula (I), also called PST3.1, to a patient requiring such treatment. In one specific embodiment, the treatment of fibrosis is by inhibition of GnT-V activity. In a further specific embodiment, the treatment of fibrosis is by inhibition of mechanisms involved in the cell matrix and / or cell / cell interactions, including inhibition of collagen fiber production, more particularly type 1, 3 and / or type 4 collagen, and / or inhibition of fibroblast migration.

[0067] According to the present invention, the term "fibrosis" specifically includes fibrosis of the lungs, kidneys, liver, heart, muscles, skin, soft tissues (e.g., mediastinum or retroperitoneum), bone marrow, intestines, aorta, and joints (e.g., knee, shoulder, or other joints). Specifically, the term "fibrous disease" arising from fibrosis includes pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endocardial myocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive nodular fibrosis (complication of pneumoconiosis), nephrogenic systemic fibrosis, Crohn's disease, keloids, old myocardial infarction, scleroderma, systemic sclerosis, arthral fibrosis, and certain forms of adhesive capsulitis.

[0068] According to one specific embodiment, the compound of formula (1) is for use in the treatment of hepatic, renal, or cutaneous fibrosis, more particularly in the treatment of renal or cutaneous fibrosis, including keloids or scleroderma.

[0069] According to one specific embodiment, the present invention relates to the use of a compound of formula (1) as defined herein for the manufacture of a pharmaceutical or pharmaceutical composition for the treatment of hepatic, renal, or cutaneous fibrosis, more particularly for the treatment of renal or cutaneous fibrosis, including keloids or scleroderma.

[0070] According to one specific embodiment, the present invention relates to a method for treating hepatic, renal, or cutaneous fibrosis in a patient requiring such treatment, more particularly for treating renal or cutaneous fibrosis, including keloids or scleroderma, by administering an effective amount of a compound of formula (1) as defined herein to the patient requiring such treatment.

[0071] According to another specific embodiment, the compound of formula (1) is intended for use in the treatment of aortic fibrosis.

[0072] According to one specific embodiment, the present invention relates to the use of a compound of formula (1) as defined herein for the manufacture of a pharmaceutical or pharmaceutical composition for the treatment of aortic fibrosis.

[0073] According to one specific embodiment, the present invention further relates to a method for treating aortic fibrosis in a patient requiring such treatment by administering an effective amount of a compound of formula (1) as defined herein to the patient requiring such treatment.

[0074] The compound of formula (1) may be provided as a pharmaceutical composition. The pharmaceutical composition may further contain a pharmaceutically acceptable adjuvant and / or carrier.

[0075] As used herein, “pharmaceutically acceptable carrier” includes any and all physiologically compatible solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic and absorption retarders, etc. The carrier may be suitable for parenteral administration, such as by injection or infusion, e.g., intravenous, intramuscular, intradermal, intraocular, intraperitoneal, subcutaneous, spinal, or other parenteral administration routes. Alternatively, the carrier may be suitable for non-parenteral administration, e.g., topical, epithelial, or mucosal administration routes. The carrier may also be suitable for oral administration. Depending on the administration route, the compounds of the present invention may be coated with a substance to protect the compounds from the action of acids and other natural conditions that may inactivate them. The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable salts. “pharmaceutically acceptable salt” means a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxic effects. Examples of such salts include acid addition salts and base addition salts.

[0076] Pharmaceutically acceptable carriers include aqueous carriers or diluents. Suitable aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, buffer water, and physiological saline. Other examples of carriers include ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). In many cases, it is desirable for the composition to contain isotonic agents, such as sugars, polyalcohols (e.g., mannitol, sorbitol, or sodium chloride). The therapeutic composition should generally be sterile and stable under manufacturing and storage conditions. The composition may be formulated as a solution, microemulsion, liposome, or other indicated structure suitable for high drug concentrations.

[0077] The pharmaceutical compositions of the present invention may contain further active ingredients. In particular, a kit comprising the compound of formula (1) as defined herein and instructions for use, for the treatment of fibrotic diseases, is also within the scope of the present invention. The kit may further contain one or more additional reagents, such as further therapeutic or prophylactic agents discussed previously. The compounds of the present invention or compositions comprising those described above may be administered for the treatment of fibrotic diseases.

[0078] In one embodiment, the treatment of a fibrous disease is a therapeutic procedure. In therapeutic application, the compound is administered to a subject already suffering from the aforementioned disorder or condition in an amount sufficient to cure, alleviate, or partially suppress one or more of the condition or its symptoms. Such a therapeutic procedure may result in a reduction in the severity of disease symptoms or an increase in the frequency or duration of asymptomatic periods. An amount sufficient to achieve this is defined as the "therapeutic effective dose."

[0079] In one embodiment, the treatment of a fibrous disease is a preventive measure. In a preventive application, the formulation is administered to a subject at risk of the aforementioned disorder or condition in an amount sufficient to prevent or reduce the subsequent effects of one or more of the conditions or symptoms thereof. The amount sufficient to achieve this is defined as the “preventive effective dose.”

[0080] Treatment involves administering a compound or a pharmaceutical composition containing the aforementioned to a patient with the diagnosed disorder, or to a healthy subject, particularly one at risk of developing fibrotic disease, in order to cure, delay, or slow the progression of the disease and thus improve the patient's condition.

[0081] Subjects to be treated according to the present invention may be selected based on several criteria related to fibrotic diseases, such as previous drug treatments, associated pathologies, genotypes, exposure to risk factors, viral infections, and any other relevant biomarkers that can be evaluated by imaging methods and immunological, biochemical, enzymatic, chemical, or nucleic acid detection methods.

[0082] The effective dose for each purpose is determined by the severity of the disease or injury, as well as the subject's weight and overall physical condition.

[0083] The target of administration may be humans or non-human animals. The term "non-human animals" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Administration to humans is the usual practice.

[0084] The compound of formula (1) may be administered in an effective amount by using the previously defined pharmaceutical composition. In the context of this invention, the term "effective amount" refers to an amount of the compound sufficient to produce the desired therapeutic outcome.

[0085] The frequency and / or dosage of administration may be adapted by those skilled in the art, depending on the patient, patient weight, pathology, and dosage form. Administration may be performed daily or several times a day as needed.

[0086] In a further embodiment, the present invention provides a method for treating a fibrous disease, comprising administering an effective amount of a pharmaceutical composition containing at least one compound of formula (1) or the foregoing to a subject requiring such treatment.

[0087] The present invention is further described with reference to the following non-limiting embodiments. [Examples]

[0088] (Example 1) Materials and methods Male Sprague-Dawley rats underwent 5 / 6 subtotal nephrectomy (SNx), and these SNx rats developed tubulointerstitial fibrosis, which was used as a model for renal fibrosis. During this surgery, the right kidney was removed, and two of the three branches of the left renal artery were ligated to induce necrosis of two-thirds of the kidney. The control kidney was the right kidney before nephrectomy. Tubulointerstitial fibrosis invariably leads to decreased and incomplete renal function, regardless of primary kidney disease. It is noteworthy that plasma creatinine concentration increased from 25.7 ± 1.3 μM to 120.0 ± 33.0 μM in SNx rats. Sirius red staining highlights fibrosis by staining collagen in paraffin-embedded kidney tissue sections. Sections 5 micrometers thick were cut and placed on glass slides. The glass slides were deparaffinized and stained with Sirius red to assess collagen localization. A positive signal for collagen was observed as a deep red color. Sections were mounted in Entelan mounting medium and examined under a microscope. For each sample, quantification was performed using ImageJ software on photographs taken from 10 areas of the kidney section at 200x magnification. The stained area was measured for each kidney section. Immunohistochemical analysis of kidney sections was also performed using paraffin sections. The primary antibody, anti-Mgat5, was incubated overnight at 4°C. Development was performed using the Universal vectastain ABC kit and ImmPACT AE according to the instructions of the supplier, Vector Laboratories. Sections were then mounted in aqueous mounting medium, VectaMount® AQ, and examined under a microscope (Nikon Eclipse TE300). Quantification was performed for histological staining.

[0089] result In a subtotal nephrectomy (SNx) model, the development of fibrosis and Mgat5 overexpression were demonstrated in 12-week-old rats with renal failure (Figure 1). Before nephrectomy, collagen fibers were uniformly distributed, and numerous fibrotic aggregates were observed 12 weeks after surgery. The results showed a significant increase of 15.4 ± 1.4% in fibrosis. Mgat5 expression also significantly increased by 14.5 ± 2.6% after surgery. These results suggest that the increase in renal fibrosis is related to the increase in Mgat5 expression.

[0090] (Example 2) Materials and methods Compound 3.1 was orally administered to control rats and SNx rats (described above) at a dose of 20 mg / kg once every 28 days. The control group was administered using a medium (without compound 3.1) in the same manner as compound 3.1. Sprague Dawley rats were used. The rats were allowed to feed freely and were placed in 12-hour light cycles and 12-hour dark cycles. The rats were divided into groups of three per cage. Some rats underwent 5 / 6 subtotal nephrectomy (SNx) to induce chronic renal failure, which leads to the development of renal fibrosis. The 3.1a treatment was administered to the rats on the day of nephrectomy and continued throughout the protocol. The treatment was delivered as a nano-suspension diluted in drinking water. Control rats were given the solvent alone (placebo). Histological and immunohistochemical methods were monitored as described in Example 1.

[0091] result At week 4, plasma creatinine concentrations were measured in 3.1 and in control and SNx rats receiving placebo. Creatinine was significantly increased in nephrectomized rats (p<0.0001), which validated the model. SNx-treated rats had lower serum creatinine levels than SNx rats.

[0092] The onset of fibrosis was observed by staining histological sections with Sirius Red (Figure 2). At 4 weeks, significantly increased fibrosis was observed in SNx rats (4.1±0.2%) compared to control rats (7.7±1.3%). Compared to control SNx rats, a trend toward reduced fibrosis due to treatment was observed in SNx rats (5.8±1.2%). At this point in observation, there was no significant effect of treatment on fibrosis in healthy animals or SNx rats. Other markers, such as collagen, can be used to measure the onset of renal fibrosis (Figure 3). The results showed that SNx rats showed higher concentrations of type I, III, and IV collagen compared to control rats. Regarding type I collagen, an effect was observed compared to SNx rats, with the percentage of type I collagen tripling after nephrectomy, from 0.7±0.1% in the control group to 2.1±0.2% in the SNx group (p=0.0001) (Figure 3A). Compared to untreated rats, treated rats with renal impairment (1.3±0.3%) showed a significant decrease in type I collagen expression (p=0.014). 3.1 significantly reduces type I collagen expression in renal fibrosis. The results obtained for type IV collagen expression were similar to those for type I collagen (Figure 3B). Type IV collagen expression increased from 5.2±0.8% in the control group to 9.4±1.0% in the SNx group (p=0.0002). 3.1 significantly reduces type IV collagen in renal fibrosis (6.4±0.3% vs. 9.4±1.0%; p=0.015). SNx also had an effect on type III collagen, with the percentage of type III collagen being three times higher in nephrectomized rats compared to control rats (5.5±1% vs. 1.7±0.2%, p=0.0007, respectively) (Figure 3C). Treatment with 3.1 tended to reduce type III collagen levels in SNx rats (4.0±0.3%) compared to untreated rats (p=0.27). There was no effect on type III collagen in the control group.

[0093] Glycosylation resulting from MGAT5 activity is specifically measured by L-PHA lectin staining. These results allow for evaluation of the effectiveness of treatment 3.1 on this pathway (Figure 4). PHA-L staining increased from 3.7±0.4% in the control group to 6.8±1.0% in the SNx group. Compared to untreated rats, a significant decrease in PHA-L staining was observed in treated rats with renal impairment (5.1±0.5% vs. 6.8±1.0%).

[0094] (Example 3) Materials and methods The model for vascular fibrosis is ex vivo aortic ring calcification. Aortic calcification is a classic complication of renal failure (chronic kidney disease) and is also a model for vascular fibrosis, which is strongly involved in cardiovascular disease. The thoracic aorta was harvested from the descending portion of the aorta that crosses the diaphragm. Adjacent connective tissue was gently removed, and the aorta was washed with PBS three times consecutively. The aorta was cut into rings approximately 2 mm thick, and the aortic rings were cultured for 14 days in a 24-well plate containing Dulbecco's modified Eagle medium with 15% FCS and 3.8 mM NaH2PO4 / Na2HPO4 added, along with 4.5 g L-1 glucose, 10 mM sodium pyruvate, and 50 mg / mL-1 ascorbic acid, to induce calcification. Histological and immunohistochemical methods were monitored as described in Example 1.

[0095] result Aortic rings cultured in calcified medium exhibited positive von Kossa staining distributed along the medial layer of the arterial explant, indicating mediacalcsis associated with fibrosis (Figures 5A and 5B). No calcium deposition was observed in aortic rings in control medium. Fibrosis was five times more prevalent in the ex vivo model of calcified aortic rings, and immunohistochemistry for GnT-V showed a significant increase in the corresponding GnT-V protein compared to non-calcified aortic rings (14.0±2.7% compared to 3.5±0.7%).

[0096] (Example 4) Materials and methods NIH3T3 fibroblasts were seeded at a rate of 40,000 cells per cm² in 24-well plates with DMEM + 10% FBS.

[0097] Prior to wound treatment, cells were washed twice in serum-free DMEM and then incubated under appropriate conditions: DMEM + 2.5% FBS, TGFβ+ / -, PST3.1+ / -.

[0098] TGFβ 5 ng / ml; PST3.1 1 μM, n=6 wells per treatment.

[0099] At time t0, the cell layer is scratched using a needle and observed under a microscope, with three images taken per well using imageJ software with a scale criterion to measure the width of the scratches.

[0100] Scratches are measured under a microscope by taking three photographs using the same criteria and scale 24 hours after incubation under the desired conditions.

[0101] The data is processed by calculating the percentage at the end of the process.

[0102] result The results are summarized in Table 1 below.

[0103] [Table 1]

[0104] Compound 3.1 appears to be the most active compound in this wound healing inhibition test.

[0105] (Example 5) The STAM model (developed and standardized by SMC Laboratories, Japan, https: / / www.smccro-lab.com / ) replicates the disease progression of human non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In 25% of affected patients (i.e., 20%-25% of the adult population), non-alcoholic fatty liver disease progresses to NASH, which increases the risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is a major determinant of mortality (https: / / doi.org / 10.1053 / j.gastro.2019.11.311). In this model, a single dose of streptozotocin is administered to 2-day-old male C57BL / 6 mice to reduce insulin secretion. At 4 weeks of age, the mice are introduced to a high-fat diet. This model has a background of late-stage type 2 diabetes progressing to fatty liver, NASH, fibrosis, and consequently liver cancer (HCC). Compared to other NASH-HCC mouse models, the disease progresses relatively quickly, with 100% of the animals developing liver cancer by 20 weeks of age.

[0106] The model can reproduce many of the pathological characteristics of human NASH. Cellular swelling and degeneration are characteristic pathological features of human NASH; burned-out NASH is characterized by a decrease in lipid droplets as fibrosis progresses. Progression of fibrosis occurring around the central vein. A gradual increase in ALT (liver injury marker). Increased levels of NASH markers such as CK-18. Increased levels of human HCC markers, such as glutamine synthase, glypican-3, and AFP, have been observed.

[0107] Materials and methods C57BL / 6JJmsSlc mice (14-day-old gestation females) were obtained from Japan SLC, Inc. (Japan). Two days after birth, a single subcutaneous injection of streptozotocin 200 μg (STZ, Sigma-Aldrich, USA) solution induced NASH in male mice. After 4 weeks of age, they were fed a high-fat diet (HFD, 57 kcal% fat, Cat#HFD32, CLEA Japan, Inc., Japan).

[0108] Sterile solid HFDs were freely supplied and replaced once every two days according to the manufacturer's instructions. The NASH model mice were then randomized into three groups of 10 six-week-old mice each, based on body weight, the day before the start of treatment. Randomization was performed using weight-stratified random sampling with Excel software. NASH model mice were stratified by body weight to minimize the standard deviation and difference in mean body weight between groups. Group 1: Vessel (10 NASH mice, 6-9 weeks old, orally administered placebo nano-suspension at a volume of 10 mL / kg twice daily). Group 2: Compound 3.1 (PST3.1) (6-9 weeks old, compound 3.1 nano-suspension administered at a dose of 15 mg / kg, volume of 10 mL / kg twice daily (2 * (10 NASH mice administered orally at 15 mg / kg / day). Group 3: Telmisartan (10 NASH mice, 6-9 weeks old, were orally administered a medium supplemented with telmisartan at a dose of 10 mg / kg once daily, in a volume of 10 mL / kg). The medium and compound 3.1 were supplied by Phost'in Therapeutics SAS. Telmisartan (Micardis®) was purchased from Boehringer Ingelheim GmbH (Germany).

[0109] Telmisartan, a low-molecular-weight antihypertensive drug, has been used due to its antifibrotic activity, but its clinical use is limited because it causes systemic hypotension (https: / / doi.org / 10.1038 / s41551-018-0279-x).

[0110] [Table 2]

[0111] Three weeks after treatment, the mice were sacrificed, and the whole livers were collected and washed with cold saline. Individual whole livers (parietal and visceral) were photographed. Liver mass was measured, and the liver-to-body weight ratio was calculated. The lateral left lobe of the liver was separated, dissected as shown in Figure 6, and preserved as described below. a: Liver samples were embedded in Optimal Cutting Temperature (OCT, Sakura Finetek Japan, Japan) compound and stored at -80°C. b: Liver specimens were fixed in Bouin's solution (Sigma-Aldrich, Japan) for 24 hours. After fixation, these specimens were embedded in paraffin for Sirius Red staining. c: Liver samples were flash-frozen in liquid nitrogen and stored at -80°C.

[0112] Sections were prepared from paraffin blocks of liver tissue using a rotary microtome (Leica Microsystems). After sectioning, each slide was numbered for blind evaluation.

[0113] To visualize collagen deposits, Bouin-fixed liver sections were stained using picrosilius red solution (FUJIFILM Wako Pure Chemical Corporation). In short, the sections were deparaffinized and hydrophilized with xylene, a series of 100-70% alcohols and RO water, and then treated with 0.03% picrosilius red solution (Cat No.: 194-16202) for 60 minutes. After washing with 0.5% acetic acid solution and RO water, the stained sections were dehydrated and cleared with a series of 70-100% alcohols and xylene, then mounted in Entellan® new (Merck, Germany) and used for observation.

[0114] For quantitative analysis of fibrosis area, bright-field images of Sirius Red stained sections around the central vein were obtained at 200x magnification using a digital camera (DFC295; Leica, Germany), and the positive area in 5 ranges / section was measured using ImageJ. Statistical analysis was performed using Prism software 6 (GraphPad Software, USA). The Bonferroni multiple comparison test was used for statistical analysis. Results were expressed as mean ± SD. The following comparisons were made between groups: 1) Group 1 (media) vs. Group 2 (PhOx430); 2) Group 1 (media) vs. Group 3 (telmisartan).

[0115] result Three weeks after treatment, no death, weight loss, or clinical signs were observed in the animals in group 2 treated with compound 3.1 (see Figure 7).

[0116] Quantitative analysis of Sirius Red-stained liver sections demonstrates a clear and significant reduction in fibrosis development after oral administration of the compound 3.1 nanometer suspension in this mouse model (see Figures 8 and 9). Group 1, vehicle: positive area 0.84±0.31% Group 2, Compound 3.1: Positive area 0.47±0.12%, p-value <0.01. Group 3, telmisartan: positive area 0.50 ± 0.24%, p value < 0.01.

Claims

1. A composition for treating fibrotic diseases comprising a compound of formula (2) or (3), wherein the compound has the following formula (2) or (3). 【Chemistry 1】 (In the formula, Y represents an oxygen atom, Z represents an oxygen atom. R 1 represents a hydrogen atom, an optionally substituted alkyl group, or an aryl group. R 2a This consists of a hydrogen atom, a halogen, and an azide (N 3 ), represents a carbonic acid or dithiocarbonate group, a 1H-[1,2,3]triazolyl group or -X-R2 group, X is oxygen, sulfur, selenium, NH or NR 7 Represents the base, R 7 is optionally substituted aryl or alkyl group, and X preferably represents O or NH. R 2 is an aryl group, an optionally substituted alkyl group, a hydrogen atom, a trichloroacetimidate group (-C(=NH)CCl 3 ), acyl, formyl, sulfonyl, sulfinyl, tert-butyldiphenylsilyl, allyl group, saccaryl, ester, amide, thioamide, sulfonamide group, or X-R 2 is P(O)R 2 R 6 group, and R 2 and R 6 each independently represent an aryl group, an optionally substituted alkyl group, OH, an alkoxy or an aryloxy group, R 3 and R 4 These independently represent aryl, optionally substituted alkyl, hydrogen atom, trichloroacetimidate group, acyl, formyl, sulfonyl, sulfinyl, tert-butyldiphenylsilyl group, allyl, ester, amide, thioamide, sulfonamide group, or R 3 and R 4 Together with the formula -R 3 -R 4 - Forms a divalent group, -R 3 -R 4 - preferably represents isopropylidene, benzylidene, diphenylmethylidene, cyclohexylmethylidene group, and their substituted analogs, such as a linear alkylene group like a 4-methoxybenzylidene group or an ethylene group. R14, R15, and R16 independently represent a hydrogen atom, an aryl group, an optionally substituted alkyl group, a trichloroacetimidate group, an acyl, a formyl, a sulfonyl, a sulfinyl, a tert-butyldiphenylsilyl group, an allyl, an ester, an amide, a thioamide, or a sulfonamide group, or R15 and R16 together form a divalent group of the formula -R15-R16-, where -R15-R16- preferably represents a linear alkylene group such as isopropylidene, benzylidene, diphenylmethylidene, a cyclohexylmethylidene group, or their substituted analogs, such as a 4-methoxybenzylidene group, or an ethylene group, and preferably R14 represents a benzyl group.

2. The composition according to claim 1, wherein the fibrotic disease is fibrosis of the lungs, heart, liver, kidneys, muscles, skin, soft tissues, bone marrow, intestines, aorta, or joints.

3. The composition according to claim 1, wherein the fibrous disease is a skin disease, kidney disease, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endocardial cardiomyopathy, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloid, old myocardial infarction, scleroderma, systemic sclerosis, arthral fibrosis, or adhesive capsulitis.

4. The composition according to claim 1, wherein the fibrotic disease is hepatic or renal fibrosis.

5. The composition according to claim 1, wherein the fibrous disease is aortic fibrosis.

6. The composition according to claim 1, wherein the fibrous disease is a cutaneous fibrosis including keloids or scleroderma.

7. The composition according to any one of claims 1 to 6, wherein R1 is a phenyl group and / or X-R2 is an OH group and / or R3 and R4 represent benzyl groups.

8. The composition according to any one of claims 1 to 7, wherein the compound of formula (2) or (3) is 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl-2-oxo-2λ5-[1,2]oxaphosfinan.

9. The composition according to any one of claims 1 to 8, wherein the compound has the following formula (I). 【Chemistry 2】

10. The composition according to any one of claims 1 to 9, wherein the treatment of fibrosis is by inhibiting mechanisms involved in the cell matrix and / or cell / cell interactions, including inhibiting the production of collagen fibers, more particularly type 1, 3 and / or 4 collagen, and / or inhibiting fibroblast migration.

11. A kit for treating fibrotic disease, comprising a compound of formula (2) or (3) as defined in any one of claims 1 and 7 to 9, and instructions for use.

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