TWI293880B - Use of pdgf receptor tryosine kinase inhibitors for the treatment of diabetic nephropathy - Google Patents

Description

Ί293880 Revision ^J^90H2100 V. INSTRUCTION DESCRIPTION (1) ^ ί lit 11 mtl f ® f ^ ^ ^ ^ pdgf^ ^ ^ ^ ^ ^ ^ Especially N-phenyl-2-pyrimidinamine derivative of formula I付/ΛΛ The definition of this article 'This compound group is hereinafter referred to as x W • 2) is used in the manufacture of pharmaceutical compositions for the treatment of diabetic nephropathy. The method for treating warm-blooded animals including human diabetic nephropathy An effective amount of a compound of the invention is administered to a warm-blooded animal having diabetic nephropathy. The present invention relates to the use of a PDGF receptor tyrosine kinase inhibitor for the manufacture of a medicament for the treatment of urinary nephropathy. In particular, the present invention relates to a novel use of the quinone-phenyl-2-pyrimidinamine derivative of the formula 1 for the manufacture of a medicament for the treatment of diabetic nephropathy:

Wherein + R is a 4-pyrene ratio ligament; a 1-methyl-1 fluorene-fluorenyl group; an amino group or an amino group-low alkyl group-substituted phenyl group, wherein the amine group in each case is a free state, an alkane Alkyl or thiol; 1 Η-fluorenyl or a fluorene group bonded to a 5-membered ring carbon atom or a ring bonded with a ring carbon atom and unsubstituted or substituted with a nitrogen atom via an oxygen atom a substituted or lower alkyl-substituted pyridyl group;

O:\69\69403-920909.ptc Page 8 1293880 _ Case No. 90112100_年月日日 Revision__ V. Description of invention (2) R and R are independent of each other as hydrogen or lower alkyl; The R 4 , R 5 , R e , R R R groups are each a nitro group, a fluorine-substituted lower alkoxy group or a group of the formula II: -N(R9)~C( = X)-(Y)n-R10 (II) wherein R is hydrogen or a low carbon alkyl group, • X is an oxo group, a sulfur, an imido group, an N-lower alkyl imine group, a hydroxyimino group or a 0-lower alkyl hydroxy imine a group, Y is an oxygen or NH group, η is 0 or 1, and R is an aliphatic group containing at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, Heterocyclic or heterocyclic-aliphatic, and the remaining R4, R5, Re, R戌R groups are independently hydrogen, unsubstituted or dream free or alkylated amine, piperidinyl, piperidinyl, pyrrolidinyl Or morpholine 1 substituted lower alkyl, or lower alkyl fluorenyl, trifluoromethyl, free, squamous or esterified hydroxy, free, alkylated or deuterated amine or free or esterified carboxyl, or A salt of at least one salt forming compound. Preferably, the methyl-1H-D ratio of the aryl group is a group of a sulfonyl group 1H or a group of a group of a fluorenyl-3-H-indole-3-yl group. Amino- or amine-lower alkyl-substituted phenyl R i (wherein the amine group in each case is free, burned or brewed) is substituted at any desired position (ortho, meta or para) The base, wherein;): the meta-amine group is preferably a mono- or di-low-carboamine group, for example, a dimethylamino group, and the lower alkyl group of the amine lower alkyl group is preferably a straight #c" c crazy base, such as sulfhydryl or ethyl.

O:\69\69403-920909.ptc Page 9 1293880 Case No. 90112100 _ Year-J_____ V. Description of Invention (3) The 1H-卩 哚 group based on the carbon atom of the 5-member ring is 1H, 哚-2-yl or 1 Η-D 哚-3-yl. a pyridyl group substituted with an unsubstituted or lower alkyl group bonded to a ring carbon atom is a lower alkyl group or a preferably unsubstituted 2 -, 4 - or preferably 3 -acridinyl group, for example, a pyridyl group, 2-Methyl-3-pyridyl or 4-hydrazino-3-indolyl. The pyridyl group in which the nitrogen atom is substituted with an oxygen atom is a group derived from pyridinium-oxide, that is, a ruthenium-oxygen ion-to-mouth ratio. Fluorine substituted lower alkoxy is a lower alkyl group having at least one, but preferably a plurality of, fluorine substituents, especially trifluoromethoxy or 1,1,2,2-tetrafluoroethoxy . When X is an oxo group, a sulfur, an imido group, a fluorene-lower alkyl imino group, a transamidimino group or a fluorene-lower alkyl hydroxyimino group, the C=X groups are respectively 00 base, C = S, 〇NH, C = N_lower alkyl, C = N-OH or C = N-〇-low carbon yard. X is preferably an oxo group. η is preferably 〇, that is, the γ group is not present. If it exists, it is preferably a sulfhydryl group. The term "low carbon" in this specification means a group containing up to 7 (and containing) carbon atoms, preferably up to 4 (and containing) carbon atoms. The low carbon alkyl groups R!, I?2, R and R are preferably a methyl group or an ethyl group. The aliphatic group R^ having up to 5 carbon atoms preferably has no more than 22 carbon atoms 'usually no more than one carbon atom and is substituted or preferably unsubstituted aliphatic nicotine' Substituted or preferably unsubstituted alkynyl, alkenyl or, preferably, alkyl such as C 5 —inferry, such as n-pentyl. The aromatic group R i has up to 2 carbon atoms and is unsubstituted or substituted, for example, unsubstituted or substituted naphthalene in each case.

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Page 10 Ί293880 ^^J〇U21〇〇

Jt3 曰 Amendment 5, invention description (4) __ ί ΐΐΐ 、, 代 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Partially better = it is substituted or preferably unsubstituted, for example, there are up to 30 in the di-diyl group, and it is better that the Suifen County always goes to the 衣 衣 曰 曰 曰 R R R R R R et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et et The 0 carbon atoms are mono-poly- and poly-substituted or preferably unsubstituted, for example, a cycloalkyl group, especially a T' K group, for example, preferably a cyclohexyl group. Cycloaliphatic _ lipid recorded only;:: or 6: shellfish f / its above-mentioned ambiguous and aliphatic radicals are preferably low-carbon burned bases, especially pots Vc up to 20 carbon materials and more than 5 or 6 ring a saturated or unsaturated monocyclic group of 3 Λ atoms, such as phenyl or 2-, 3- or 4-acridinyl or double or triple _ ring group, 1 medium, ^^1, two = phenyl is fused to the monocyclic group. Heterocyclic _ aliphatic group, r '% as defined, and aliphatic part is preferably lower alkane a group, which is substituted or preferably unsubstituted. 醚 The etherified hydroxyl group is preferably a lower alkoxy group. The esterified hydroxyl group is preferably an acid such as a lower alkanoic acid or a mineral acid such as a hydrogen-acid such as a lower group. Carbaane oxime = halogen such as zephyr, desert, or especially a fluorine or oxime esterified base. The soil 3 U alkylated amine group is, for example, a lower alkylamino group such as a guanamine group or a bismuth amide group. The halogenated amine group is, for example, a low-carboylamino group or a benzoquinone esterified carboxyl group, for example, a lower alkoxycarbonyl group such as a methoxy group.

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1293880 Case No. 90112100 Rev. 5, Inventive Note (5) Substituted phenyl groups may carry up to 5 substituents, such as fluorine 'but especially in the case of relatively large substituents, usually only 1 to 3 substituents Replace. Examples of substituted phenyl which may be specifically mentioned are 4-chlorophenyl, pentafluorophenyl, 2-carboxyphenyl, 2-methoxyphenyl, 4-fluorophenyl, 4-cyanophenyl and 4 -methylphenyl. The salt forming group of the compound of formula I is a group having basic or acidic properties. A compound having at least one basic group, such as a free amine group, a piperidinyl group or a [I-blocker group, which may be, for example, a mineral acid such as hydrochloric acid, sulfuric acid or ore acid or with a suitable organic carboxylic acid or a creatinic acid such as an aliphatic mono- Or a di-acid such as trifluoroacetic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or an amino acid Such as arginine or lysine, aromatic carboxylic acids such as benzoic acid, 2-phenoxybenzoic acid, 2-ethoxyoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-fat A family of resorcinating acids such as mandelic acid or cinnamic acid, heteroaromatic ferulic acid such as acid or isoacid, aliphatic acid such as methyl------- or 2- _ light-based sulphuric acid, or aromatic The rhein acid, such as benzene-, p-toluene- or naphthalene-2-reading acid, forms an acid addition salt. When several basic groups are present, hydrazine forms a mono- or poly-acid addition salt. A compound of formula I having an acidic group such as a free sulfhydryl group in the R 1 machine can form a metal or ammonium salt, such as an alkali or alkaline earth metal salt such as sodium, unloading, lock or calcium salts or with ammonia or a suitable organic amine such as tri-single An amine such as triethylamine or tris(2-hydroxyethyl)amine or a heterocyclic ring is an ammonium salt formed by N-ethyl hexidine or N, N,-dimethyl oxime. The compound of formula 1 which has both an acidic and a basic group can form an internal salt. For the purpose of isolation or purification and the further use of the compound as an intermediate, a pharmaceutically acceptable salt can also be used. However, only medically connectable

O:\69\69403-920909.ptc Page 12 1293880 修正 Amendment 5. Inventive Note (6) ^2 11 j may be used for therapeutic purposes and therefore the salts are preferred. 3 5 9δϋ&P2FG steroidal tyrosine kinase inhibitors are disclosed in W0 98/ y, t曰 compound 62, and US 5, 〇93,330, each of which is incorporated by reference. The final product of the scent and the non-exemplary, the content of which is characterized by the persistence of proteinuria (> 30 mA / 24 hours of disease / presence) The following additional criteria are clinically diagnosable for the ί 床 bed iif urinary nephropathy and non-diabetic hematocrit hardening in countries other than ^ ^ to kidney or urinary tract disease signs. Diabetic nephropathy is the biggest cause of kidney disorders in the late Western countries. Christine: ί i ί test method and especially the test mode described in this article may show that the 2 physiotherapy or its pharmaceutically acceptable salt leads to more effective prevention or A 7 Α, hot water disease kidney disease, but It is effective for spheroid nephritis and chronic pyelonephritis. Those skilled in the art can fully select the relevant test model A ^ ' [and the therapeutic indicators and benefits shown below. For example, pharmacological activity; or wood research or proof of test procedures described later. U, a point glomerulosclerosis model with near-complete (5 / 6) nephrectomy in mice, T.W. Meyer and H.G. Renake,

Am·J· Physi〇i· 254, F856 (1988)]. i Five-week-old male rats were anesthetized with intraperitoneal injection of sodium pentobarbital and 2/3 of the kidneys were removed. One week later, the entire left kidney was removed after anesthesia. After 2 weeks of breeding, the A/G-B test (Wako Pure Chemical Co., Ltd.) was collected and used to determine the total egg, white matter content and albumin content in the urine. Based on urine protein and blood pressure, the mice were divided into two groups (vector-treated mice and the compound of the present invention 丨mg/kg/day p. 〇.

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1293880 曰 修正 Revision _#Μ_90Π?100 V. Invention description (7) Treated mice). Only the left nephrectomy mouse was also used to suspend the compound of the present invention in A. The drug is 8 weeks in total. Treatment and suspension: fish liquid once a day orally administered urine total protein and urinary albumin ί 6 and 8 weeks _ '24 hours urine collection

Insulin-dependent (NIDD) Diabetes in mice against proteinuria (Wiesda fat mouse) [H. Ikeda et al, Diabetes 30 1.0 4 5 (1 9 8 1 )] ^ J protein content, 11 Weekly Wistar fat rats were divided into 2, and (loaded limb treated old milk and mice treated with the compound of the present invention 丨 mg / kg / day ρ · 〇 ·). Non-diabetic control group G lean mice were also used. The compound of the present invention was suspended in gum arabic and the suspension was orally administered once a week for 8 weeks. 24-hour urine was collected at weeks 2, 4, 6 and 8. The urine was desalted at 3,000 r pm centrifugation and a portion of the supernatant was desalted on column PD10). Determination of total urinary protein content and albumin content by cell proliferation and extracellular matrix accumulation by Lowry and ELISA were the characteristics of human development of hematocrit and the main cause of end-stage renal disorders. Test - Test Example 3: Inhibition of in vitro proliferation of cells between glomeruli Interleukin-1 0 was shown to stimulate cell proliferation between cells in vitro and in vivo (S · J· Chadban et al. Lab· Invest· 76 (5 , 1997, 619-627). 1 0 9 7 Proliferation of mouse interglomerular cell lines (γ·Kakizaki et al., Clin·Exp. Immunol. 85(1), 1991, 157-63) by 3H-chest Analysis by ingestion of the pyridine. Cells were used in the 30-40 channels. The cells were deactivated by thermal deactivation of fetal bovine serum in RPM I 1 60 40 medium (Gibco, USA).

O:\69\69403-920909.ptc Page 14 1293880 Case No. 90112100 V. INSTRUCTIONS (8) 曰 Correction (FCS), 20 mM HEPES buffer, 1〇〇u/ml cyan/ml streptomycin Wet 5% c〇 In the atmosphere, the cells between the 3 sediment culture and the kidney H were plated at low density in the RpM FCS of the 96-well flat-plate microtiter plate and allowed to attach overnight. The secondary fusion cells were then harvested for 3 days in RpMi/p·5% FCS. Following a solution containing 2 micromoles per milliliter of the compound of the invention (dissolving the compound of the invention in DMSO and in normal saline, or control, positive or negative cytokines (R&D system) as: 丨〇:丨〇 Dilute this solution) and change the medium. The cells were cultured for an additional 48 hours and delivered with 6 σ-thymidine for 6 sigma before collection. Add 11^-1〇 (20-10〇1^/ml) to the selected hole. The 6 holes were repeated 2 times in all tests and the test was repeated 3-5 times. Compared with the control group, it was observed that IL-10 promoted the proliferation of 1〇97 (25-75% increase, ρ<0·0Bu 0·0 01 vs. control group). If you use Ν-{5-[4-(4-methyl mai: 曱 )) benzhydryl]-2-methylphenyl b 4-(3-acridinyl)-2-bite As a compound of the present invention, this increase in proliferation is completely inhibited by the addition of the compound of the present invention. ϋ 试 试 U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U Antibody-induced glomerular glomerulonephritis (D · W · M as ο nA A · F · W i 1 1 iams, biochemical phase, j 187 (1), 1 9 8 0, Bu 20), Anti-mouse CD68 was used to detect macrophage e (c D. Dijkstra et al., Immunol. 54 (3), 1985, 589-99) using EDI, and the myofibroblasts were identified by 1 in 4 labeling using anti-human a- Proliferating cells were identified by smooth muscle activin 7 (Sigma Immunochemistry, St. Louis, M0) and M744, anti-BrdU (D ak 〇, G 1 〇strup, D enmark). Use multiple sheep

O:\69\69403-920909.ptc Page 15 Ί 293880 _ Case Hand _ Leg __ Year Month Day _ Amendment __ V. Invention Description (9) Anti-fetal/Anti-human type IV collagen antibody (Southern Health Technique, Birmingham, AL) examines the extracellular matrix. Intravenous injection of 5 mg/kg of OX-7 igG induced anti-Thy_i nephritis in 8 male Wistar rats (丨5 〇-丨7 〇g) (dJ· Nikolic-faterson et al. J·Am) ·Soc·Nephrol·7(7), 1996, 1006- 14)

. After the OX-7 IgG was started to be administered, the animals were intraperitoneally injected with CGP 5 7 1 486 (50 mg/kg) or vehicle control group (1% by weight) in a saline solution until day 6. Three hours before the kill, all mice were labeled with cells in the cell cycle DNA synthesis (S) stage by intraperitoneal injection of 50 mg / kg of bromodeoxyuridine (BrdU). In the first 3 hours of killing, 8 normal mice were also injected with BrdU. Urine and blood samples were collected for 24 hours on day 3 (test 剞) and day 6. Urine protein concentration was measured by the phenylethoxychlor method (I w a t a, J. et al., Clinical Chemistry, 25 (7), 1979, 1317-9). The amount of serum and urinary creatine in the serum was measured using the JaffS rate response (Larsen, K., Clin. Chim. Acta 41, 1972, 209-17)° Tissue-fixed in 4% neutral buffered valproate and embedded in In the stone. The sinus (4 micron) was stained with periodic acid Schi f f 's reagent (PAS). A nuclear quantitation was performed by examining 50 hilar vascular balls per animal. Immunostaining was performed as described by Rumble et al. J. Clin. Invest. 99, 1 9 97, 1016-1027. Dual immunohistochemical staining was performed using a microwave-based technique in the Fufolin fixed tissue fragment to avoid antibody cross-reactivity (G.H. Tesch et al., Am. J. Pathol. 151(1), 1997, 141-50). A fragment colored with BrdU or EDI antibody scored ED1+ or BrdU+. use

Q:\69\69403-920909.ptc Page 16 Ί293880 —_____ Case No. 90112100_年月日日 Revision 5, Invention Description (1〇) The microscope starts counting to measure the vascular bulbar region and is confined to the vascular bulb The plexus thus omits the cells in the capillary chamber. Five vascular balls and labeled cells were scored for each animal as mean ± SD per mm2. In addition, the number of cells in the double-labeled paragraph is also divided into ED1+BrdU+, ED1+BrdU-, and ED1-BrdU+: because the podocytes do not proliferate and proliferate cells in the proliferating cells of this disease model<3% The vascular endothelial cells were identified as macrophage ED1+BrdU+ or proliferating glomerular cells were ED1-BrdU+. The immunochromic fold for IgG collagen was quantified using the aforementioned computer-assisted imaging analysis (组织·A· Lehr et al., Journal of Cell Chemistry, 45(11), 1997, 1559-65). Compared with the control mice, the proteinuria of animals receiving OX-7 IgG increased mildly and was not affected by CGP 5 7 1 8 8B treatment (normal control group: 2.1 ± 0.2 mg / 24 hours; vehicle treatment) Thy-pyelonephritis: 13.4 ± 7. 2 mg / 24 hours; CGP 5 71 48B - treated Thy-Ι nephritis: 16 · 4 ± 7. 0 mg / 24 hours). In the P A S -stained fragment, excessive glomerular cells and increased glomerular matrix were seen in the blood tubes of untreated mice. These pathological changes were not seen in mice receiving CGP 5 7 1 48B. Schematic description: Animals with anti-T hy - 1 nephritis showed moderate glomerular cell hyperplasia compared with control animals, which was analyzed by nuclear count and was significantly reduced in mice treated with CGP 57 1 48B ( figure 1). Compared with the control group, the proliferation of glomerular cells (BrdU + ED) was increased 5-fold and was significantly reduced in mice treated with CGP 57 1 48B (Fig. 2). Similarly, the number of activated glomerular cells (a-smooth actin-positive) was also increased in untreated mice with anti-Thy-1 nephritis and was significantly reduced by CGP 571 48B.

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Month 曰 correction

The marker glomerular matrix of the immunostained IV kicker is accumulated in the untreated mouse and is obviously administered with CGP 57148B. The compound of the present invention has a body weight of 2 to 25 grams.

The six-fruit fruit of the filial urinary nephropathy of the filial piety; J 戍 ϋ ϋ ί ί (STZ, 55 mg ^ kg) in the above-mentioned mice induced sugar machine glucose r / t type Mo test ears within 7 days All animals developing diabetes (with == i): All diabetic mice received insulin (human glucose is ^ to maintain body weight and avoid ketonuria without causing CGP 5714SB:) 5 body, including research on 16 mice Or / disease old, no drugs; (IV) STZ one two =; iln) STZ - diabetes 0, 4, 8, 12, 24 and 32 weeks of urinary tongue. Sugar, HbA丨c, water intake and food intake. Study ==,, blood pressure, and histological analysis of cells between the leaves. Funeral ~ ^ nine, vascular bundle and vascular balloon structure. Analysis of the mouse movement ^ ^ ^ electron microscopy type scores small ball volume. ', the GBM thickness of the kidney and the kidney of the area are obtained from the above results, such as soothing by the use of tobacco inflammation, * it is small in the kidney: fine = y spheroidal kidney slow, not the compound of the present invention not only, β Xi and base Shell accumulation of Shu Shigui kidney disease, can also treat globular leap X prevention or better treatment of diabetes November inflammation, chronic pyelonephritis or IgA kidney

Ί293880 Case number 9011^1

V. Description of invention (12) Disease. The compound of the formula I of the present invention is preferably a fluorene group J. Two R4, R5, r6, R and R groups each wherein the group or the formula I匕-R is hydrogen or a lower carbon group, and X is an oxo group or a sulfur group. An imine group, an N-lower amine group or a fluorene-lower alkyl hydroxyimino group, a soil imino group, a hydroxyl group Y is an oxygen group or an NH group, η is 0 or 1, and if R? is at least An aliphatic group or an aromatic group of 5 carbon atoms, an aromatic cycloaliphatic group, a cycloaliphatic-aliphatic group, a heterocyclic ring or a heterocyclic-aliphatic group, a (III)-vector, and a remainder R 4 , R 5 , RR戌R groups independently of each other are hydrogen, unsubstituted or by a free or alkylated amine group, piperidinyl, piperidinyl, pyrrolidinyl or morpholinyl substituted lower alkyl, or lower alkane fluorenyl, trifluoro Methyl, free, etherified or esterified hydroxyl groups, free, alkylated or halogenated amine groups or free or esterified carboxyl groups, and the remainder of the substituents are as defined above. More preferably, the compound of the formula I of the present invention is a pyridyl group or an N-oxylpyridyl group in which each ring carbon atom is bonded, R and R are independently hydrogen, and R is hydrogen or a low carbon alkyl group. , a low carbon alkyl or difluoroindenyl 'R is hydrogen 'R is a nitro group, a fluorine substituted lower carbon alkoxy group or a group of formula 11 wherein R is hydrogen,

1293880 曰 ___ Case No. 90112100 V. DESCRIPTION OF THE INVENTION (13) X is an oxo group, η is 〇 and R 丨 is a pyridyl group bonded with a carbon atom, an unsubstituted or known lower alkoxy group, a carboxyl group, The lower alkyl group is substituted with its ^, fluorenyl group, ^ c^ ^ & . 2_^ ^ ^ R is hydrogen. The substituted base group, and the one group is a low carbon burn, and the preferred compound of the present invention is a compound wherein R and r are at least a group and the remaining substituents are as defined above. Preferably, in all of the above compounds of the formula I of the present invention, wherein R is a pyridyl group bonded to a carbon atom, R 2 , R 3 , R 5 , R and R are hydrogen, R is a lower alkyl group, and R is a group of formula II. Wherein R 9^7 :®α ' X is an oxo group, η is 0, and R 1 (A 4-methylpipedylmethyl group. All of the above compounds of the formula I of the present invention are particularly preferably CGp 571 48B {N - 丨5-[4-(4-methylindolyl)phenylhydrazinyl]_2-methylphenyl}_4 13 than dimethyl)-2 - oxazepine amine}. The compounds of the invention are excellent for use with monoterpene sulphonates. The compounds of the formula I according to the invention are generally and in particular disclosed in the patent applications Ερ 0 5 64 4 0 9 Α1 and WO 9 9/ 0 3854', in particular the compound term and the end product of the process, so that the final product body, the pharmaceutical process and the patent application 7 ^范

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1293880 ML· 90112100 V. INSTRUCTIONS (14) Circumstances are hereby incorporated by reference. The A body is crystallization-modified, such as cancer, thrombus, psoriasis, and chemistry in the present EP 564 564 409 A1. According to the present invention, accidental disease, spheroid nephritis, and slowness. In a preferred embodiment of the present invention, urinary nephropathy, spheroidality, medicine, and nephritis, chronic pyelonephritis or a compound known in the art can reduce side effects. Preferably, the compounds of the invention are administered. Λ_3 also contains the corresponding inscriptions. The gastric "structure" and correspondingly, the compound of the formula I of the present invention can be used to treat the compound of the present invention and the arterial hardness, and it is beneficial to have a kidney disease in the case of S 2 5 . Compared with the medicine for treating diabetic sputum, sputum pyelonephritis or igA nephropathy, he treats diabetic nephropathy and spheroidal I g A nephropathy, the present invention is used to manufacture a medicine for treating diabetic nephropathy, according to the present invention In particular, the present invention also provides a method for treating warm blood movements containing humans, wherein the warm-blooded animal has diabetic nephropathy, spheroidal lunar inflammatory disease, chronic pyelonephritis, IgA nephropathy or better diabetic nephropathy. Administration of a therapeutically effective amount of a compound of the invention. In a preferred embodiment of the invention, a vascular ball in a warm-blooded animal (or a human having a developmental vascular disease) is one of the test systems described herein. Compared with the number of cells, proliferation of glomerular cells or activation of glomerular cells, administration of a drug comprising the compound of the present invention can effectively reduce excessive coil cells and decrease glomerular cells. One or reduced glomerular cell activation. Another preferred embodiment of the present invention, the test of the system described herein, for example, having an anti-nephritis -Thy-1 mice (such as developmental or preferably with bulb

II wit \«t Λ_

m

I

Page 21 O:\69\69403-920909.ptc Ί293880 _ Case No. 90112100_Yearly revision _ V. Description of invention (15) Diseased humans) with increased accumulation of immunoglobulin IV collagen Compared with the number of vascular ball matrix groups in warm-blooded animals, administration of a medicament comprising the compound of the present invention can effectively reduce glomerular accumulation of immunostainable type IV collagen. The π treatment method π used herein is particularly directed to a method of preventing the diseases described herein, i.e., prophylactic administration of a medicament comprising a compound of the present invention to a healthy person to avoid the development of the diseases described herein, particularly diabetic nephropathy. The invention also relates to a pharmaceutical composition for treating spheroid nephritis, chronic pyelonephritis or IgA nephropathy or better urinary nephropathy. Treatment of diabetic nephropathy, spheroid nephritis, chronic pyelonephritis,

The pharmaceutical composition of IgA nephropathy comprises an effective amount of a compound of the invention and a pharmaceutically acceptable carrier which is suitable for topical, enteral, e.g. oral or rectal, or parenteral administration, and which is an inorganic or organic solid or liquid. For oral administration, it is especially useful to include compounds of the invention and diluents such as nipples, raisins, cane toads, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants such as citric acid, talc, Stearic acid or a salt thereof such as magnesium stearate or calcium stearate and/or a tablet or gelatin capsule of polyethylene glycol. The key agent may also include a binder such as a salt of Yinshi acid, a powder such as corn, wheat or rice starch, gelatin, methyl cellulose, carboxymethyl cellulose and/or polyvinylpyrrolidone and a disintegrating agent if necessary. For example, starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or a foaming mixture, or an adsorbent, a dye, a flavoring agent, and a sweetener. The compounds of the invention may also be administered parenterally or as a perfusate. Preferably, the solution is an isotonic aqueous solution or suspension which, for example, comprises at least one compound of the invention or with a carrier such as mannitol

O:\69\69403-920909.ptc Page 22 Ί29388ό Case No. 90Π2〗 00 Year V. Inventive Note (16) When the dry composition is used, it can be prepared before use. The pharmaceutical composition may include an excipient such as a preservative, a stabilizer, a sigma sterilizable elixirs, a lysing agent, a salt for regulating osmotic pressure, and/or a buffer D, and/or a pharmaceutically active substance. For example, antibiotic or anti-diabetic activity may be required to be about 2.0% active ingredient. u The compound can be prepared, for example, as described in WO 9 9 / 0 3 8 54 Examples 4 and 6, for example, by means of a ratio of about 2 to about 2, and (10) The dosage range of the compound of the present invention to be used is determined according to the known factors of the art, the type, body weight and age of the warm-blooded animal, the mode of administration, the particular substance used, and the condition to be treated. The compounds of the present invention are preferably administered from 1 to 4 times a day unless otherwise stated. Further, the compound of the present invention, especially {N-{ 5-[4-(4-fluorenylfluorenylfluorenyl)benzamide]- 2-methylphenyl}- 4-(3-indole) Mercapto)-2-pyrimidinamine} (〇0? 57 1 486) preferably has a dose of about 1 to 1 mg, more preferably 50 to 500 g, and preferably 25 to 25 mg/day. The scope is for the administration of warm-blooded animals, especially when the warm-blooded animal is a human with a body weight of about 7 kg.

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Claims (1)

1293880 Case No. 90112100 Lunar Amendment VI. Patent Application 1. A pharmaceutical composition for the treatment of diabetic nephropathy, comprising N - { 5-[4-(4-mercaptopiperazylmethyl) benzamidine A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable acid salt is an amino]-2-mercaptophenyl}-4(3-pyridyl)-2-pyrimidinamine. Spherical nephritis, chronic pyelonephritis or IgA kidney 2. If the patent-receiving salt is a single-dose range of pyroxen 3, a pharmaceutical composition for treating silk disease, including N-{5 - [4 - ( 4-methylpipedylmethyl)benzhydrylamino]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidineamine, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of item 3, wherein the pharmaceutical acid salt. The pharmaceutical composition according to item 3, wherein the warm-blooded animal of the tube disease of the medicine can reduce the glomerular cell thinning or decrease the activated glomerular cells. The pharmaceutical composition according to item 3, wherein the blood-blooded animal of the tube disease of the medicine can reduce the immunocommunication accumulation. 4. If the patent-receiving salt is monomethane sulfonate 5, if the patent application scope is applied to the development of cytoplasmic excess, lowering the glomerulus 6. If the patent application scope is applied to the developmental hemochromic IV Collagen vascular ball O:\69\69403-920909.ptc Page 25